SARM1 inhibitors

Abstract

The invention provides compounds having the general formula (I) or (II) wherein R1, R2, R3, R4, X and Y are as defined herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with SARM1.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P39781

[0003] SARM1 INHIBITORS

[0004] Field of the Invention

[0005] The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Sterile Alpha And TIR Motif Containing 1 (SARM1) inhibitors for the treatment or prevention of amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease.

[0006]

[0007] of the Invention

[0008] Axonal degeneration is a central driver of disability and disease progression in neurodegenerative and neurological disorders including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson’s disease, Alzheimer’s disease and peripheral neuropathies. Due to their high energy demands in order to propagate action potentials and ensure protein transport over sometimes meter-long distances, axons are particularly sensitive to metabolic stress following for example mitochondrial disruption or microtubule disassembly. Instead of being a passive dying process however, the resulting axonal degeneration is now understood to involve key molecular components and steps. Programmed axonal degeneration, also known as Wallerian degeneration, is a key molecular mechanism driving axonal loss. As an early pathological feature of numerous neurological conditions associated with an increasing societal and economic burden, therapeutic approaches to target the prevention of axonal degeneration therefore hold significant treatment potential.

[0009] Summary of the Invention

[0010] In a first aspect, the present invention provides compounds of formula (I) or(II)

[0011] CNE / 05.12.2025

[0012]

[0013] wherein R1, R2, R3, R4, X and Y are as defined herein.

[0014] In further aspects, the invention provides compositions including the compounds of formula (I) or (II), processes of manufacturing the compounds of formula (I) or (II), and methods of using the compounds of formula (I) or (II).

[0015] Detailed Description of the Invention

[0016] Definitions

[0017] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0018] The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms. Some nonlimiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, yet non-limiting example of alkyl is methyl.The term “cycloalkyl” as used herein refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-Cio-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-Cio-cycloalkyl”). In still other preferred embodiments, the cycloalkyl group is a monocyclic or bicyclic hydrocarbon group of 3 to 6 ring carbon atoms (“C3-C6-cycloalkyl”). “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. In some particularly preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms. Some nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cubanyl, l-bicyclo[l.l.l]pentanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. A preferred, yet non-limiting example of cycloalkyl is cyclopropyl.

[0019] The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro or chloro, more preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1 -difluoroethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2,2-trifluoro-l-methyl-ethyl, l-(trifluoromethyl)propyl. A preferred, yet nonlimiting example of haloalkyl is 2,2,2-trifluoroethyl.Amother preferred, yet non-limiting example of haloalkyl is trifluoromethyl.

[0020] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, 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-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are notlimited 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.

[0021] The compounds of formula (I) or (II) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0022] The abbreviation “SARM1” refers to Sterile Alpha and TIR Motif Containing 1.

[0023] The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0024] The term “prophylaxis” or “preventing” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0025] SARM1

[0026] Axonal breakdown distal to the site of an injury is a key feature of programmed axonal degeneration or Wallerian degeneration and is characterized by mitochondrial disruption, loss of nicotinamide adenine dinucleotide (NATH), increased intracellular calcium levels and axonal fragmentation (Conforti, L., et al., Nat. Rev. Neurosci., 2014, 15, 394-409). The central component of the programmed axonal degeneration mechanism is Sterile Alpha And TIR Motif Containing 1 (SARM1) (Osterloh, J.M., et al., Science, 2012, 337, 481-484). SARM1 is an NAD+ hydrolase that depletes levels of NAD+ by cleaving it into the metabolites: nicotinamide(NAM) and adenosine diphosphate ribose (ADPR) or cyclic ADPR. The resulting loss of NAD+, an essential metabolite involved in energy metabolism and axonal homeostasis (Hopkins, E.L., et al., 2021, Front. Mol. Biosci.. 8:703532), and increase in cADPR, a modulator of intra-axonal calcium levels (Li, Y., et al., 2022, J. Cell BioL, 221, e202106080), contributes to the subsequent axonal degeneration process.

[0027] Other molecular components of the Wallerian axonal degeneration pathway have been identified including axonal survival factors like nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). Under normal conditions, axonal survival factors such as NMNAT2 are continuously turned over and replenished by anterograde transport along the axon from the cell body (Gilley, J. & Coleman, M.P., 2010, PLoS Biol., 8, el000300). NMNAT2 maintains axonal energetics by catalyzing the formation of NAD+ from nicotinamide mononucleotide (NMN) and adenosine tri-phosphate (ATP). However during injury or disease, disruption of microtubule assembly or mitochondrial depolarization in axons leads to loss of NMNAT2 transport followed by NMNAT2 depletion. SARM1 is activated in turn by reduced NMNAT2 levels as a result of loss of NAD+, a negative SARM1 ligand, and accumulation of NMN, a positive SARM1 ligand (Figley, M.D., et al., 2021, Neuron, 109, 1118-1136).

[0028] SARM1 is a multidomain protein consisting of an autoinhibitory ARM domain, tandem oligomerization SAM domains and a catalytic TIR domain. While originally thought to exist as a monomer in solution, recent high-resolution cryo-EM structures have revealed that SARM1 exists as an octamer with the ARM domains locking the TIR domains in an inactive conformation (Bratkowski, M., et al., 2020, Cell Rep., 32, 107999). This was followed by identification of an allosteric site in which both NMN and NAD+ can bind (Jiang, Y., et al., 2020, Nature, 588, 658-663; Figley, M.D., et al., 2021, Neuron, 109, 1118-1136). The increase in NMN / NAD+ during axonal injury and the higher affinity of NMN for SARM1 results in replacement of NAD+ in the allosteric pocket, releasing the ARM domains and allowing for TIR domain catalytic activity.

[0029] Both in vitro and in vivo studies of SARM1 loss-of-function have highlighted the central role of SARM1 in programmed axonal degeneration. SARM1 genetic knockout has been shown to protect axons in both human and rodent neuronal cultures following physical (axotomy) or chemical injury, for example due to chemotherapeutic drugs such as vincristine (Osterloh, J.M., et al., Science, 2012, 337, 481-484; Chen, Y., et al., 2021, Exp. Neurol., 339, 113636). In vivo, deletion of SARM1 prevents nerve fiber loss and restores normal pain sensitivity in models ofchemotherapy-induced peripheral neuropathy (Geisler, S., et al., 2016, Brain, 139, 3092-3108) and diabetic peripheral neuropathy (Cheng, Y., et al., 2019, Diabetes, 68, 2120-2130). SARM1 deletion also attenuates axonal degeneration in pre-clinical models of ALS (White, M.A., et al., Acta Neuropathol. Commun., 7, 166) and MS (Viar, K., et al., 2020, PLoS One, 15, e0235110). In models of eye disorders, SARM1 deficiency has been found to block loss of axons of retinal ganglion cells in glaucoma models (Finnegan, L.K., et al., 2022, Int. J. Mol. Sci., 23, 1606) and of photoreceptors in retinitis pigmentosa models (Ozaki, E., et al., 2020, Life Sci. Alliance., 3, e201900618). These combined studies underscore the therapeutic potential of blocking SARM1 activity to ameliorate various neurological disorders associated with axonal loss.

[0030] Compounds of the Invention

[0031] In a first aspect, the present invention provides a compound of formula (I) or (II)

[0032]

[0033] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0034] X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, -NH-, -N(CH3)-, *-OCH2-, *-NHCH2-, *-CH2O-, and *-CH2NH-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;

[0035] Y is selected from the group consisting of N and CH;

[0036] R1is selected from the group consisting of Cs-Cio-cycloalkyl, Ci-Ce-alkyl, halo-Ci-Ce- alkyl, halo-Ci-C6-alkyl-CH(OH)-, halo-Ci-C6-alkyl-C(O)-, Ci-C6-alkyl-CH(OH)-, and Ci-C6-alkyl-C(O)-;

[0037] R2is hydrogen; and

[0038] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl; or

[0039] R2and R3, taken together with the carbon atoms to which they are attached, form a C3-C6- cycloalkyl; and

[0040] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl.

[0041] In one embodiment, the present invention provides a compound of formula (I)

[0042]

[0043] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X, Y, R1, R2, R3, and R4are as defined herein.

[0044] In another embodiment, the present invention provides a compound of formula (II)

[0045]

[0046] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y, R1, and R4are as defined herein.

[0047] In a preferred embodiment, the present invention provides a compound of formula (la)

[0048]

[0049] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, and R4are as defined herein.

[0050] In a preferred embodiment, the present invention provides a compound of formula (Ila)

[0051]

[0052] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R'and R4are as defined herein.

[0053] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0054] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0055] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, *-0CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring.

[0056] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of -CH2- and -CH2CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring.

[0057] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of Cs-Cio-cycloalkyl, halo-Ci-Ce-alkyl, and halo-Ci-Ce-alkyl-CH(OH)-.

[0058] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of halo-Ci-Ce-alkyl, and halo-Ci-Ce-alkyl-CH(OH)-.

[0059] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is Cs-Cio-cycloalkyl.

[0060] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of:

[0061]

[0062] In one embodiment, the present invention provides a compound of formula (II) as described

[0063] herein, or a pharmaceutically acceptable salt thereof, wherein R1is

[0064]

[0065] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of:

[0066]

[0067] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0068] R2and R3are both hydrogen; or

[0069] R2and R3, taken together with the carbon atoms to which they are attached, form a C3-C6- cycloalkyl.

[0070] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0071] R2and R3are both hydrogen; or

[0072] R2and R3, taken together with the carbon atoms to which they are attached, form a cyclopropyl.

[0073] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3are both hydrogen.In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0074] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0075] X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, and *-OCH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;

[0076] Y is CH;

[0077] R1is selected from the group consisting of Cs-Cio-cycloalkyl, halo-Ci-Ce-alkyl, and halo-Ci-C6-alkyl-CH(OH)-;

[0078] R2and R3are both hydrogen; or

[0079] R2and R3, taken together with the carbon atoms to which they are attached, form a C3-C6- cycloalkyl; and

[0080] R4is hydrogen.

[0081] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0082] X is selected from the group consisting of -CH2-, -CH2CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;

[0083] Y is CH;

[0084] R1is selected from the group consisting of halo-Ci-Ce-alkyl and halo-Ci-Ce-alkyl- CH(OH)-;

[0085] R2, R3, and R4is hydrogen.

[0086] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0087] X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, and *-OCH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;

[0088] Y is CH;

[0089] R1is:

[0090]

[0091] R2and R3are both hydrogen; or

[0092] R2and R3, taken together with the carbon atoms to which they are attached, form a cyclopropyl; and

[0093] R4is hydrogen.

[0094] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0095] X is selected from the group consisting of -CH2-, -CH2CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;

[0096] Y is CH;

[0097] R1is:

[0098]

[0099] R2, R3, and R4is hydrogen.

[0100] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0101] X isN;

[0102] R1is Cs-Cio-cycloalkyl;

[0103] R4is hydrogen.

[0104] In a preferred embodiment, the present invention provides a compound of formula (II) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl.

[0105] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is selected from:

[0106] (5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline or (5R)-5-(2- cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline;

[0107] (5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline or (5R)-5-(2- cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline;5-(2-cyclopropyl-lH-imidazol-4-yl)phthalazine;

[0108] (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)- 5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline;

[0109] (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)- 5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline;

[0110] (lS)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol; (1 aS, 7b S)-7b-(2-cyclopropyl- lH-imidazol-5-yl)- 1 , 1 a, 2, 3 - tetrahydrocyclopropa[f]isoquinoline or (laR,7bR)-7b-(2-cyclopropyl-lH-imidazol-5- yl)-l,la,2,3-tetrahydrocyclopropa[f]isoquinoline;

[0111] (lS)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol; (4R)-4-(2-cyclopropyl-lH-imidazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine or (4S)-4- (2-cyclopropyl-lH-imidazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine;

[0112] (4S)-4-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-3,4-dihydro-2H-pyrano[2,3-c]pyridine or (4R)-4-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-3,4-dihydro-2H-pyrano[2,3- c]pyridine;

[0113] (5R)-5-(2-cyclopropyl-lH-imidazol-5-yl)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridine or (5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridine; (5R)-5-(2-cyclopropyl-lH-imidazol-5-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine or (5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine; and

[0114] (5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9-tetrahydro-5H- cyclohepta[c]pyridine or (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9- tetrahydro-5H-cyclohepta[c]pyridine.

[0115] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from:

[0116] (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)- 5-[2-(2, 2, 2-tri fluoroethyl)- lH-imidazol-5-yl]-5, 6, 7, 8-tetrahydroisoquinoline;

[0117] (lS)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol; and(5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9-tetrahydro-5H- cyclohepta[c]pyridine or (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9- tetrahydro-5H-cyclohepta[c]pyridine.

[0118] In some embodiments, the compounds of formula (I) or (II) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) or (II) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) or (II) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,nC,13C,14C,13N,15N,15O,170,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I) or (II), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) or (II) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0119] Substitution with heavier isotopes, such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Therefore, in one embodiment, the present invention provides compounds of formula (I) or (II) wherein one or more, for example 1 to 6, in particular 1 to 3 hydrogen atoms are replaced by deuterium.

[0120] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0121] Isotopically-labeled compounds of formula (I) or (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0122] Processes

[0123]

[0124] The preparation of compounds of formula (I) or (II) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification ofthe resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.

[0125] If one of the starting materials, intermediates or compounds of formula (I) or (II) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0126] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) or (III) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) or (II) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I) or (II).

[0127] A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) or (II) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc.

[0128] 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0129] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0130] In more detail, the compounds of formula (I) or (II) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reactionconditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0131] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.

[0132] The following abbreviations are used in the present text:

[0133] °C = degree(s) Celsius; Ar = Argon; aq. = aqueous; / / -BuLi = / / -butyllithiumCH^CN = acetonitrile; CO2 = carbon dioxide; Cui = Copper(I) iodide; DCM = dichloromethane; DEA = diethylamine; DMF = A,A-dimethylformamide; ESI = electrospray ionization; EtsN = trimethylamine; EtOAc = ethyl acetate; EtOH = ethanol; FC = flash chromatography; g = gram(s); GC-MS = gas chromatography - mass spectrometry; h = hour(s); H2 = hydrogen; H2O = water; HC1 = hydrogen chloride; HPLC = high performance liquid chromatography; IPA = isopropanol; K2CO3 = potassium carbonate; KH2PO4 = potassium phosphate; LDA = lithium A-(propan-2-yl)propan-2-aminide; M = molar(s); MeOH = methanol; mg = milligram(s); min = minute(s); mL = milliliter(s); mm = millimeter(s); MS = mass spectrum; MTBE = methyl tert-butyl ether; m / z = mass-to-charge ratio; mmol = millimole(s); Na2COs = sodium carbonate; NaH = sodium hydride; NaHCCh = sodium bicarbonate; Na2SO4 = sodium sulfate; Na2S20s = sodium thiosulfate; NBS = N-bromosuccinimide; NH3 = ammonia; NH4CI = ammonium chloride; nm = nanometer(s); Pd / C = Palladium on charcoal; Pd(dppf)2C12-CH2C12 = 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; Pd(OAc)2 = Palladium(II) acetate; Pd(PPhs)4 = Palladium-tetrakis(triphenylphosphine); RP = reverse phase; SFC = supercritical fluid chromatography; SiCh = silicon dioxide; OTf = triflate; SnBusCl = tributyltin chloride; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TifO'Prfl = Titanium(IV) isopropoxide; TMS = trimethylsilyl; tR = retention time; XPhos = dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane; XPhos Pd G2 = chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II); pL = microliter(s); pm = micrometer(s), pmol = micromole(s).

[0134] General procedures

[0135] Compounds of general formula (I), where R2,R3= H, depicted as 1 in Scheme 1, can be prepared from bromides of general formula 2 (Scheme 1). Suitably protected bromides of general formula 2 can be engaged in a Miyaura borylation reaction using bis(pinacolato)diboron, a base such as KOAc, and a catalyst such as Pd^ppfhCh CFECh in a solvent such as 1,4-di oxane, to give intermediates of general formula 3. The in situ generated intermediates 3 can then be treated with enol triflates of general formula 4, KH2PO4, XPhos, and Pd(OAc)2, to generate compounds of general formula 5 via a Suzuki-Miyaura cross-coupling. Subsequent hydrogenation of the alkene 5 using for example H2 and Pd / C in EtOAc followed by deprotection using a suitable method for the given protecting group (PG) affords compounds of general formula 1.

[0136]

[0137] Scheme 1Alternatively, compounds of general formula (I), where R ,R3= H, depicted as 1 in Scheme 2, can be prepared starting from suitably protected imidazoles of general formula 6. Imidazoles 6 can be deprotonated using w-BuLi followed by treatment with SnBusCl, to give stannanes of general formula 7. A Stille cross-coupling between stannanes 7 and enol tritiates 4 using for example Cui, Pd(PPhs)4, in a solvent such as DMF, generates intermediates of general formula 5. Subsequent hydrogenation of the alkenes 5 using for example H2 and Pd / C in EtOAc followed by deprotection using a suitable method for the given protecting group (PG) affords compounds of general formula 1

[0138]

[0139] Scheme 2

[0140] Compounds of general formula (II) can be prepared starting from bromides 8 (Scheme 3). Bromides of general formula 8 can be converted to the corresponding boron esters 9 in a Miyaura borylation using for example but not limited to bis(pinacolato)diboron, KOAc, and Pd(dppf)C12-CH2C12 in 1,4-di oxane. Boron esters 9 can be coupled with suitably protected bromides 2 in a Suzuki Miyaura cross-coupling using e.g. K2CO3 and Pd(dppf)C12-CH2C12 in 1,4-dioxane / EEO, to generate intermediates of general formula 10. A suitable deprotection step of intermediates 10 generates compounds of general formula (II).

[0141]

[0142] Scheme 3

[0143] Compounds of general formula (I), where R2and R3, taken together with the carbon atoms to which they are attached, form a Cs-cycloalkyl, depicted in Scheme 4 as compound 11, can be prepared starting from intermediates of general formula 5. Alkenes 5 can be cyclopropanated in a Corey-Chaykovsky reaction, using a base such as KO / Bu and trimethyl sulf oxonium iodide in a solvent such as THF, which affords, following a suitable deprotection step, compounds of general formula 11.

[0144]

[0145] Scheme 4

[0146] Alternatively, compounds of general formula (I) where R2,R3= H, depicted as compounds 1 in Scheme 5, can be prepared starting from ketones 12 and imidazoles 6. Deprotonation of imidazoles 6 using a base such as w-BuLi followed by addition of ketones of general formula 12, preferably activated with Lewis acid LaCh-2 LiCl, affords alcohols 13. Dehydration of alcohols 13 using e.g. but not limited to Zn in AcOH followed by a suitable de-protection step, gives compounds of general formula 1.

[0147]

[0148] Scheme 5

[0149] Intermediates of general formula 2 where R1= halo-Ci-Ce-alkyl or halo-Ci-Ce-alkyl-CH(OH)-, depicted as intermediates 14 in Scheme 6, can be prepared from suitably protected aldehydes 15.

[0150] Aldehydes 15 can be treated with CsF and CFsSiMes, to give the corresponding alcohols 16.

[0151] Alcohols 16 can be dehydrated using e.g. imidazole, b and PPI13 in THF to generate the corresponding fluoroalkylated imidazoles of general formula 14.

[0152]

[0153] Scheme 6

[0154] Building blocks of general formula 4 can be prepared from the corresponding ketones 12 (Scheme 7). Treatment of ketones 12 with a base such as LiHMDS in THF followed by triflation of the in situ generated enolate by a tritiating agent (e.g. Comins’ reagent or Tf2O) affords enol tritiates of general formula 4.

[0155]

[0156] Scheme 7

[0157] Alternatively, ketones of general formula 12 where X = *-0CH2-, depicted as 17 in Scheme 8, can be prepared from hydroxypyridines 18 and alcohol 19. A Mitsunobu reaction between hydroxypyridines 18 and alcohol 19 in the presence of PI13P and DIAD in THF affords ethers 20.

[0158] Alternatively, hydroxypyridines 18 can be alkylated with the corresponding alkyl halides of alcohol 19 in the presence of a base such as K2CO3 in a solvent such as DMF, to give the sameproduct 20 (not shown). Ethers 20 can by cyclized to a-cyano-ketones 21 using first a strong base such as KOlBu followed by treatment with an acid such as acetic acid. Treatment of a-cyano-ketones 21 under acidic conditions (HCI, acetic acid) at elevated temperatures affords ketones 17.

[0159]

[0160] Scheme 8

[0161] Alternatively, building blocks of general formula 5 can be prepared from enol tritiates 4 (Scheme 9). A Miyaura borylation of enol tritiates 4 using for example Pd(PPh3)2C12, bis(pinacolato)diboron, KOPh and PPhs in toluene affords boron esters 22. A Suzuki-Miyaura cross-coupling between building blocks 22 and 2 using but not limited to XPhos Pd G2, ISfeCCh in l,4-dioxane / H2O, affords the corresponding alkenes of general formula 5.

[0162]

[0163] Scheme 9

[0164] Starting materials such as aryl bromides can be prepared from commercially available building blocks in a simple halogenation step using standard reaction conditions (e.g. NBS) known to a person skilled in the art.

[0165] Commercially available imidazoles can be protected using methods of known to a person skilled in the art. Two regioisomers can be isolated, and either of them can be used for the synthesis described in the schemes above.

[0166] Compounds of general formula (la) and (Ila) can be prepared according to the schemes described above.SARM1 Inhibitory Activity

[0167] Compounds of the present invention are SARM1 inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) or (II) as described herein for inhibiting the function of human SARM1 in a subject in need thereof.

[0168] In a further aspect, the present invention provides compounds of formula (I) or (II) as described herein for use in a method of inhibiting the function of human SARM1 in a subject in need thereof.

[0169] In a further aspect, the present invention provides the use of compounds of formula (I) or (II) as described herein for the preparation of a medicament for inhibiting the function of human SARM1 in a subject in need thereof.

[0170] In a further aspect, the present invention provides a method for inhibiting the function of human SARM1 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) or (II) as described herein to the subject.

[0171] SARM1 inhibitory potency of the compounds of formula (I) or (II) according to the invention was measured using the following assay.

[0172] Enzymatic reactions were ran in a lOpL volume consisting of 8nM human SARM1 (aa28-724), lOOpM Nicotinamide (NMN) and 30pM Nicotinamide Adenine Dinculeotide (NAD). Assay reagents were prepared in 25mM HEPES pH 7.2, 50mM NaCl, ImM EDTA and 0.0025% Tween20. To determine compound ICso’s, reactions were incubated for 60minutes at room temperature in the presence of a 12-point concentration response curve of compound (starting concentration lOOpM; 1 in 3 dilution between each point; 2% DMSO) and then quenched with 40pL of 0.125% Formic Acid. The peak area of NAD and linear ADPR were measured by a RapidFire High Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API5000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA). The ratio of linear ADPR to NAD peak area was then plotted against compound concentration to obtain an IC50 as fitted via non-linear regression.

[0173] SARM1 inhibitory potencies of the compounds of formula (I) or (II) according to the invention as measured in the assay described above are presented in Table 1.Table 1

[0174]

[0175]

[0176] Using the Compounds of the Invention

[0177] In one aspect, the present invention provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance.

[0178] In a further aspect, the present invention provides a method of treating or preventing a condition associated with SARM1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0179] In a further aspect, the present invention provides a compound of formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with SARM1 in a subj ect in need thereof.

[0180] In a further aspect, the present invention provides the use of a compound of formula (I) or (II) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceuticalcomposition described herein, in a method of treating or preventing a condition associated with SARM1 in a subject in need thereof.

[0181] In a further aspect, the present invention provides the use of a compound of formula (I) or (II) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with SARM1 in a subject in need thereof.

[0182] In one embodiment, said condition associated with SARM1 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system.

[0183] In one embodiment, said condition affecting the nervous system is neurodegenerative disorder.

[0184] In one embodiment, said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease.

[0185] In a preferred embodiment, said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, and multiple sclerosis.

[0186] In a particularly preferred embodiment, said condition associated with SARM1 is amyotrophic lateral sclerosis.

[0187] In a particularly preferred embodiment, said condition associated with SARM1 is spinal muscular atrophy.

[0188] In a particularly preferred embodiment, said condition associated with SARM1 is chemotherapy induced peripheral neuropathy.

[0189] In a particularly preferred embodiment, said condition associated with SARM1 is diabetes induced peripheral neuropathy.

[0190] In a particularly preferred embodiment, said condition associated with SARM1 is multiple sclerosis.Pharmaceutical Compositions and Administration

[0191] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) as described herein and a therapeutically inert carrier.

[0192] In one embodiment, there is provided a pharmaceutical composition according to Example 14 or 15.

[0193] The compounds of formula (I) or (II) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0194] The compounds of formula (I) or (II) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0195] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0196] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0197] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0198] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0199] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosityincreasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

[0200] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0201] In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

[0202] The compounds of formula (I) or (II) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned. The relative configuration at the tetrahydrofuran ring can be either cis or trans and was assigned arbitrarily.

[0203] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0204] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. Where more than one name is associated with a Formula (I) or (II), compound or intermediate, the chemical structure shall define the compound.

[0205] Example 1

[0206] (5S)-5-(2-Cyclopropyl-lH-inudazol-5-yl)-5,6, 7,8-tetrahydroisoquinoline or (5R)-5-(2-cyclopropyl-lH-imidazol-5-yl)-5, 6, 7, 8-tetrahydroisoquinoline

[0207]

[0208] A mixture of 2-[[2-cyclopropyl-5-(7,8-dihydroisoquinolin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (395 mg, 1.07 mmol) and Pd / C 10% (35 mg, 0.033 mmol) in THF (8 mL) was stirred for 4 h at 40 °C under an H2 atmosphere (3 bar). The mixture was filtered off and evaporated. A solution of the crude product (415 mg, 1.07 mmol) in DCM (2 mL) was treated with TFA (2.05 mL, 26.67 mmol) and the reaction mixture was stirred for 18 h at 230C, before being evaporated. Purification by FC (SiCL; DCM / (MeOH + 25% aq. NH3) 97:3) followed by chiral SFC (Column chiral IH, 5 pm, 250 x 20 mm, 15% MeOH + 0.2% DEA) gave the title compound as the first eluting enantiomer (52 mg, 19% yield, tR = 3.139 min) and as an off-white solid. MS (ESI): m / z = 240.3 [M+H]+

[0209] Step a) 2-[(2-cyclopropyl-5-tributylstannyl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane

[0210] To a solution of 2-[(2-cyclopropylimidazol-l-yl)methoxy]ethyl-trimethyl-silane (B.l; 1.39 g, 5.81 mmol) in anhydrous THF (20 mL) cooled down to -78 °C under an inert atmosphere was slowly added a 1.6 M w-BuLi solution in hexanes (4.00 mL, 6.39 mmol) and the reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was then allowed to warm up to -35 °C after which it was stirred at -35 °C for 45 min. A solution of tri-w-butyltin chloride (1.66 mL, 6.1 mmol) in anhydrous THF (12 mL) was added to the reaction mixture at -35 °C. After complete addition, the reaction was stirred at -35 °C for 1 h and then let to warm up to 23 °C. The reaction was quenched by addition of few drops of saturated aqueous solution NH4CI and the reaction mixture was then partitioned between EtOAc and a 1 M aqueous NaHCCL solution. The organic phase was collected, dried over Na2SO4 and evaporated to give the title compound (3.30 g, 91% yield) as a yellow oil which was used without further purification. MS (ESI): m / z = 529.3 [M+H]+

[0211] Step b) 2-[[2-cyclopropyl-5-(7,8-dihydroisoquinolin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane

[0212] To a microwave vial was added Pd(PPhs)4 (93.11 mg, 80.58 pmol) and Cui (51.15 mg, 268.59 pmol) after which the vial was sealed and the atmosphere was replaced for Ar by repeating 3 times vacuum evacuation / Ar backfill. A solution of 7,8-dihydroisoquinolin-5-yl trifluoromethanesulfonate (B.l; 750 mg, 2.69 mmol) in DMF (6 mL) was added to the vialfollowed by a solution of 2-[(2-cyclopropyl-5-tributylstannyl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane (1.83 g, 2.95 mmol) in DMF (6 mL) after which the reaction mixture was sparged with Ar for a few minutes. The reaction mixture was stirred at 70 °C for 18 h. Volatiles were removed in vacuo, the crude residue was partitioned between EtOAc and saturated aqueous Na2COs. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; heptane / (EtOAc:EtOH 3:1)) gave the title compound (436 mg, 42% yield) as a light yellow viscous oil. MS (ESI): m / z = 368.4 [M+H]+

[0213] Example 2

[0214] (5S)-5-(2-Cyclopropyl-lH-inudazol-5-yl)-5,6, 7,8-tetrahydroisoquinoline or (5R)-5-(2-cyclopropyl-lH-imidazol-5-yl)-5, 6, 7, 8-tetrahydroisoquinoline

[0215]

[0216] A mixture of 2-[[2-cyclopropyl-5-(7,8-dihydroisoquinolin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (395 mg, 1.07 mmol) and Pd / C 10% (35 mg, 0.033 mmol) in THF (8 mL) was stirred for 4 h at 40 °C under an EE atmosphere (3 bar). The mixture was filtered off and evaporated. A solution of the crude product (415 mg, 1.07 mmol) in DCM (2 mL) was treated with TFA (2.05 mL, 26.67 mmol) and the reaction mixture was stirred for 18 h at 23 ° C, before being evaporated. Purification by FC (SiCh; DCM / (MeOH:25% aq. NH3) 97:3) followed by chiral SFC (Column chiral IH, 5 pm, 250 x 20 mm, 15%MeOH +0.2%DEA) gave the title compound as the second eluting enantiomer (53 mg, 19% yield, tR = 3.540 min) as an off-white solid. MS (ESI): m / z = 240.3 [M+H]+

[0217] Example 3

[0218] 5-(2-Cyclopropyl-lH-inndazol-4-yl)phthalazine

[0219]

[0220] To a solution of 2-[(2-cyclopropyl-4-phthalazin-5-yl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane (68 mg, 0.157 mmol) in EtOH (2 mL) was added 4 M HC1 in water (1.17 mL, 4.7 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 21 h, before being evaporated. The residue was diluted in DCM and water, then quenched with a saturated solution of sodium hydrogen carbonate. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. Purification by RP-HPLC gave the title compound (9 mg, 25% yield) as a yellow solid. MS (ESI): m / z = 237.2 [M+H]+

[0221] Step a) 2-[ ( 4-bromo-2-cyclopropyl-imidazol-l-yl)methoxy ethyl-trimethyl-silane

[0222] To a solution of 2-[(2-cyclopropylimidazol-l-yl)methoxy]ethyl-trimethyl-silane (B.l; 560 mg, 2.23 mmol) in acetonitrile (22.4 mL) was added NBS (397 mg, 2.23 mmol) at 23 °C. The reaction mixture was stirred at for 5 min at 23 °C, before being evaporated. Purification by FC (SiCL; Heptane / EtOAc) gave the title compound (335 mg, 45% yield) as a yellow oil. MS (ESI): m / z = 319.2 [M+H]+

[0223] Step b) 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phthalazine

[0224] To a solution of 5-bromophthalazine (CAS RN: 103119-78-4; 200 mg, 956.75 pmol) in 1,4-dioxane (3 mL) were added bis(pinacolato)diboron (292 mg, 1.15 mmol), potassium acetate (282 mg, 2.87 mmol) and l,l'-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (79 mg, 95.68 pmol) under Ar. The reaction mixture was stirred at 80 °C for 22 h. Bis(pinacolato)diboron (243 mg, 956.75 pmol), potassium acetate (282 mg, 2.87 mmol) and l,l'-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (79 mg, 95.68 pmol) were added. The mixture was stirred at 85 °C for 2 days, before being cooled down, filtered, and evaporated. Purification by FC (SiCL; DCM / MeOH) gave the title compound (172 mg, 60% yield) as a brown oil. MS (ESI): m / z = 175.1 [M-Pinacol+H]+

[0225] Step c) 2-[ (2-cyclopropyl-4-phthalazin-5-yl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane

[0226] To a solution of 2-[(4-bromo-2-cyclopropyl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane (100 mg, 315.16 pmol) and 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phthalazine (104 mg,346.68 pmol) in 1,4-dioxane (3 mL) and water (300 pL) were added K2CO3 (131 mg, 945.48 pmol) and l,r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride di chloromethane complex (26 mg, 31.52 pmol), at 23 °C under Ar. The reaction mixture was stirred at 80 °C for 15 h, before being cooled down and evaporated. Purification by FC (SiCL; DCM / MeOH) gave the title compound (68 mg, 50% yield) as a brown oil. MS (ESI): m / z = 367.3 [M+H]+

[0227] Example 4

[0228] (5S)-5-[2-(2,2,2-Trifluoroethyl)-lH-inudazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)-5-[2- (2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-5, 6, 7, 8-tetrahydroisoquinoline

[0229]

[0230] A mixture of trimethyl-[2-[[5-(5,6,7,8-tetrahydroisoquinolin-5-yl)-2-(2,2,2-trifhioroethyl)imidazol-l-yl]methoxy]ethyl] silane (100 mg, 0.24 mmol) and TFA (1 mL) in DCM (4 mL) was stirred at 25 °C for 24 h, before being evaporated. The residue was dissolved in EtOAc and washed by saturated NaHCCL aqueous solution. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by RP-HPLC followed by chiral SFC (Chiralcel OD-H, 5 pm, 250 x 4.6 mm, hexane / IPA / MeOH, 95:2.5:2.5) gave the title compound as the first eluting enantiomer (8 mg, 10% yield) and as a yellow oil. MS (ESI): m / z = 282.2 [M+H]+

[0231] Step a) 2-[[4-(7,8-dihydroisoquinolin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane

[0232] A mixture of bis(pinacol)diborane (1.82 g, 7.16 mmol), potassium acetate (1.05 g, 10.74 mmol) and 7,8-dihydroisoquinolin-5-yl trifluoromethanesulfonate (B.2; 2.0 g, 7.16 mmol) in 1,4-dioxane (68 mL), was purged with Ar for 5 min. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.88 g, 1.07 mmol) was added and the mixture was purged again with Ar. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and 1,4-dioxane (52 mL) and water (30 mL) were added to the filtrate followed by addition of phosphoric acid, potassium salt (3.8 g, 17.91 mmol) and 2-[[4-bromo-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (B.4; 2.57 g, 7.16 mmol). Thereaction mixture was purged with Ar and then XPhos (0.34 g, 0.72 mmol) and palladium (II) acetate (80 mg, 0.36 mmol) were added. The mixture was degassed again and stirred at 90 °C for 16 h. The reaction mixture was concentrated and diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCh; Hexane / EtOAc) gave the title compound (130 mg, 4% yield) as a brown oil. MS (ESI): m / z = 410.4 [M+H]+

[0233] Step b) trimethyl-[2-[[4-(5, 6, 7,8-tetrahydroisoquinolin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl methoxy ] ethyl silane

[0234] A stirred solution of 2-[[4-(7,8-dihydroisoquinolin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (87 mg, 0.21 mmol) andPd / C (10%) (10 mg) in EtOAc (12 mL) was stirred under a EE atmosphere (1 bar) for 4 h at 25 °C. The reaction mixture was filtered and evaporated to give the title compound (90 mg, 95% yield) as a light brown oil. MS (ESI): m / z = 412.0 [M+H]+

[0235] Example 5

[0236] (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)-5-[2- (2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-5, 6, 7, 8-tetrahydroisoquinoline

[0237]

[0238] A mixture of trimethyl-[2-[[5-(5,6,7,8-tetrahydroisoquinolin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl] silane (100 mg, 0.24 mmol) and TFA (1 mL) in DCM (4 mL) was stirred at 25 °C for 24 h, before being evaporated. The residue was dissolved in EtOAc and washed by saturated NaHCOs aqueous solution. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by RP-HPLC followed by chiral SFC (Chiralcel OD-H, 5 pm, 250 x 4.6 mm, hexane / IPA / MeOH, 95:2.5:2.5) gave the title compound as the second eluting enantiomer (8 mg, 10% yield, tR= 17.616 min) and as a yellow oil. MS (ESI): m / z = 282.2 [M+H]+Example 6

[0239] (lS)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-inudazol-2-yl]ethanol

[0240]

[0241] A solution of (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]ethanol or (1 S)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]ethanol (100 mg, 0.200 mmol) and TFA (2.0 mL, 0.2 mmol) in DCM (4 mL) was stirred for 24 h at 25 °C, before being evaporated. The residue was dissolved in EtOAc and washed by a saturated NaHCOs aqueous solution. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by RP-HPLC gave the title compound (5 mg, 8% yield) as a white solid. MS (ESI): m / z = 298.2 [M+H]+

[0242] Step a) (1 S)-l-[ 4-(7, 8-dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl ]-2, 2, 2-trifluoro-ethanol or ( 1R)-1~[ 4-(7, 8-dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl -2, 2, 2-trifluoro-ethanol

[0243] A mixture of bis(pinacol)diborane (1.82 g, 7.16 mmol), potassium acetate (0.67 mL, 10.74 mmol) and 7,8-dihydroisoquinolin-5-yl trifluoromethanesulfonate (B.2; 2.0 g, 7.16 mmol) in 1,4-dioxane (68 mL), was purged with Ar for 5 min. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.88 g, 1.07 mmol) was added and the mixture was purged again with Ar. The reaction mixture was stirred at 90 °C for 16 h, before being filtered. The filtrate was diluted with 1,4-Dioxane (52 mL) and water (30 mL). Phosphoric acid, potassium salt (1.48 mL, 17.91 mmol), l-[4-bromo-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifhioro-ethanol (B.3; 2.69 g, 7.16 mmol) were added to the reaction mixture which was again purged with Ar followed by addition of XPhos (0.34 g, 0.72 mmol) and palladium (II) acetate (80 mg, 0.36 mmol). The mixture was degassed again and stirred at 90 °C for 16 h. The reaction mixture was evaporated, diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCL; CHCI3 / CH3CN) followed by chiral SFC (Chiralcel OJ-H, 5 pm, 250 x 4.6 mm, Hexane / IPA+ 0.1% DEA) gave the title compound as the first eluting enantiomer (110 mg, 3% yield, tR = 9.694 min) and as a dark brown oil. MS (ESI): m / z = 426.2 [M+H]+

[0244] Step b) (lR)-2,2,2-trifluoro-l-[4-(5,6, 7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]ethanol or (lS)-2,2,2-trifluoro-l-[4-(5,6, 7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl] ethanol

[0245] A solution of (lR)-l-[4-(7,8-dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifluoro-ethanol or (lS)-l-[4-(7,8-dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifluoro-ethanol (110 mg, 0.23 mmol) and Pd / C (10%) (10 mg) in EtOAc (15 mL) was stirred under a EE atmosphere (1 bar) for 8 h at 25 °C. The reaction mixture was filtered and evaporated to give the title compound (100 mg, 85% yield) as a brown oil. MS (ESI): m / z = 428.2 [M+H]+

[0246] Example 7

[0247] (laS,7bS)-7b-(2-cyclopropyl-lH-imidazol-5-yl)-l,la,2,3-tetrahydrocyclopropa[f]isoquinoline or (laR, 7bR)-7b-(2-cyclopropyl-lH-imidazol-5-yl)-l,la,2,3- tetrahydrocyclopropa{f]isoquinoline

[0248]

[0249] 2-[[5-(l,la,2,3-Tetrahydrocycloprop[f]isoquinolin-7b-yl)-2-cyclopropyl-imidazol-l-yl]methoxy] ethyl-trimethyl-silane (385 mg, 1.01 mmol) was dissolved in TFA (4.28 mL, 55.49 mmol) and the reaction mixture was stirred at 23 °C for 18 h, before being evaporated. Purification by FC (SiCh; DCM / (MeOH + 25% aq. NH3) 97:3) followed by chiral SFC (Column chiral Whelk(r,r), 5 pm, 250 x 20 mm, 28% MeOH + 0.2% DEA) gave the second eluting enantiomer as the title compound (53 mg, 18% yield, tR = 2.662 min) and as an off-white solid. MS (ESI): m / z = 252.2 [M+H]+

[0250] Step a) 2-[[5-( 1, la, 2, 3-tetrahydrocycloprop[f]isoquinolin- 7b-yl)-2-cyclopropyl-imidazol-l-yl methoxy Jethyl-trimethyl-silaneTo a vial containing a suspension of [keto(dimethyl)sulfuraniumyl]methane iodide (367 mg, 1.67 mmol) in anhydrous THF (4.5 mL) under an inert atmosphere was added KO'Bu (1.0 M solution inTHF; 1.67 mL, 1.67 mmol) after which the reaction mixture was stirred at 23 °C for 1 hfollowed by addition of a solution of 2-[[2-cyclopropyl-5-(7,8-dihydroisoquinolin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (Intermediate Example 1, step b) (430 mg, 1.11 mmol) in anhydrous THF (2.5 mL). The reaction mixture was then stirred at 65 °C for 3 h, before being treated with a few drops of water and evaporated. The crude residue was then partitioned between EtOAc and saturated aqueous ISfeCCL. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Purification by FC (SiO?; Heptane / EtOAc) gave the title compound (387 mg, 87% yield) as a light yellow viscous oil. MS (ESI): m / z = 382.4 [M+H]+

[0251] Example 8

[0252] (lS)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-inudazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-inudazol-2-yl]ethanol

[0253]

[0254] A solution of (lS)-2,2,2-trifhioro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]ethanol (36 mg, 0.07 mmol) and trifluoroacetic acid (1.0 mL) in DCM (2 mL) was stirred for 24 h at 25 °C, before being evaporated. The obtained residue was dissolved in EtOAc and washed by saturated NaHCOs aqueous solution. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by RP-HPLC gave the title compound (8 mg, 38% yield) as a white solid. MS (ESI): m / z = 298.0 [M+H]+

[0255] Step a) (lS)-l-[4-(7,8-Dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]- 2,2,2-trifluoro-ethanol or (lR)-l-[4-(7,8-Dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl -2, 2, 2-trifluoro-ethanolA mixture of bis(pinacol)diborane (1.82 g, 7.16 mmol), potassium acetate (0.67 mL, 10.74 mmol) and 7,8-dihydroisoquinolin-5-yl trifluoromethanesulfonate (B.2; 2.0 g, 7.16 mmol) in 1,4-dioxane (68 mL), was purged with Ar for 5 min. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.88 g, 1.07 mmol) was added and the mixture was purged again with Ar. The reaction mixture was stirred at 90 °C for 16 h, before being filtered. The filtrate was diluted with 1,4-Dioxane (52 mL) and water (30 mL). Phosphoric acid, potassium salt (1.48 mL, 17.91 mmol), l-[4-bromo-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifhioro-ethanol (B.3; 2.69 g, 7.16 mmol) were added to the reaction mixture which was again purged with Ar followed by addition of XPhos (0.34 g, 0.72 mmol) and palladium (II) acetate (80 mg, 0.36 mmol). The mixture was degassed again and stirred at 90 °C for 16 h. The reaction mixture was evaporated, diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCL; CHCI3 / CH3CN) followed by chiral SFC (Chiralcel OJ-H, 5 pm, 250 x 4.6 mm, Hexane / IPA + 0.1% DEA) gave the title compound as the second eluting enantiomer (130 mg, 3% yield, tR = 25.147 min) and as a dark brown oil. MS (ESI): m / z = 426.2 [M+H]+

[0256] Step b) (lS)-2,2,2-trifluoro-l-[4-(5,6, 7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6, 7,8-tetrahydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl] ethanol

[0257] A solution of (1 S)-l-[4-(7,8-dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifluoro-ethanol or (lR)-l-[4-(7,8-dihydroisoquinolin-5-yl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifluoro-ethanol (110 mg, 0.23 mmol) and Pd / C (10%) (10 mg) in EtOAc (15 mL) was stirred under a H2 atmosphere (1 bar) for 8 h at 25 °C. The reaction mixture was filtered and evaporated to give the title compound (120 mg, 86% yield) as a brown oil. MS (ESI): m / z = 428.2 [M+H]+

[0258] Example 9

[0259] (4R)-4-(2-cyclopropyl-lH-inudazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine or (4S)-4-(2- cyclopropyl-lH-inudazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine

[0260]

[0261] Step a) 4-[2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-2, 3-dihydropyrano[2, 3-c]pyridin-4-ol

[0262] To a solution of 2-[(2-cyclopropylimidazol-l-yl)methoxy]ethyl-trimethyl-silane (B.l; 575 mg, 2.41 mmol) in anhydrous THF (7 mL) cooled down to -78 °C under an inert atmosphere was slowly added w-BuLi 1.6 M solution in hexanes (1.38 mL, 2.21 mmol). The reaction mixture was stirred at -78 °C for 30 min, before being warmed up to -40 °C and stirred for another 45 min at this temperature. In a separate vial: To a solution of 2,3-dihydropyrano[2,3-c]pyridin-4-one (CAS RN: 2091452-31-0; 0.300 g, 2.01 mmol) in anhydrous THF (3 mL) under an inert atmosphere was added a 0.6 M Lanthanum(III) chloride bis(lithium chloride) complex solution in THF (3.35 mL, 2.01 mmol) and the mixture was stirred at 23 °C for 10 min after which this solution was added to the reaction mixture at -40 °C. After complete addition, the reaction was stirred at -40 °C for 1 h. The reaction was quenched by addition of a few drops of saturated aqueous solution NH4CI and the reaction mixture was then partitioned between EtOAc and 1 M aqueous NaHCCL solution. The organic phase was collected, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCL; Heptane / (EtOAc:EtOH 3 : 1)) gave the title compound (621 mg, 76% yield) as a light yellow gum. MS (ESI): m / z = 388.3 [M+H]+

[0263] Step b) 2-[[2-cyclopropyl-5-(3, 4-dihydro-2H-pyrano[2, 3-c]pyridin-4-yl)imidazol-l-yl methoxy Jethyl-trimethyl-silane

[0264] To a solution of 4-[2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-2,3-dihydropyrano[2,3-c]pyridin-4-ol (620 mg, 1.6 mmol) in acetic acid (6 mL) was added zinc (837 mg, 12.8 mmol) and the reaction mixture was stirred at 80 °C for 2 h. Additional zinc (837 mg, 12.8 mmol) was added to the reaction mixture, which was then stirred at 80 °C for 18 h. Volatiles were removed in vacuo, the crude residue was poured into a bi-phasic mixture of EtOAc and 5 N aqueous NaOH and the bi-phasic mixture was stirred for 10 min. The insolubles were removed by filtration over a pad of Celite and the bi-phasic filtrate poured into a separating funnel. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2;Heptane / (EtOAc:EtOH 3:1)) gave the title compound (184 mg, 29% yield) as a light yellow gum. MS (ESI): m / z = 3723 [M+H]+

[0265] Step c) 2-[[2-cyclopropyl-5-[ ( 4R)-3, 4-dihydro-2H-pyrano[ 2, 3-c ]pyridin-4-yl Jimidazol-1-yl methoxy ]ethyl-trimethyl-silane or 2-[[2-cyclopropyl-5-[ ( 4S)-3, 4-dihydro-2H-pyrano[ 2,3-c ]pyridin-4-yl ]imidazol-l-yl methoxy ethyl-trimethyl-silane

[0266] 2-[[2-Cyclopropyl-5-(3,4-dihydro-2J / -pyrano[2,3-c]pyridin-4-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (184 mg, 0.47 mmol) was separated by chiral SFC (Column chiral OD-H, 5 pm, 250 x 20 mm, 11% MeOH) to give the title compound (78 mg, 42% yield, tR = 3.767 min) as light yellow gum and as the second eluting enantiomer. MS(ESI): m / z = 372.3 [M+H]+

[0267] Step d) (4R)-4-(2-cyclopropyl-lH-imidazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine or (4S)~ 4-( 2-cyclopropyl-lH-imidazol-5-yl)-3, 4-dihydro-2H-pyrano[ 2, 3-c ] pyridine

[0268] A solution of 2-[[2-cyclopropyl-5-[(4A)-3,4-dihydro-2J / -pyrano[2,3-c]pyridin-4-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane or 2-[[2-cyclopropyl-5-[(45)-3,4-dihydro-2J / -pyrano[2,3-c]pyridin-4-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane (78 mg, 209.93 pmol) in TFA (1.0 mL, 12.97 mmol) was stirred at 23 °C for 18 h, before being evaporated. Purification by RP-HPLC gave the title compound (35 mg, 66% yield) as a white solid. MS (ESI): m / z = 242.2 (M+H]+

[0269] Example 10

[0270] (4S)-4-[2-(2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-3,4-dihydro-2H-pyrano[2,3-c]pyridine or (4R)-4-[2-(2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-3,4-dihydro-2H-pyrano[2,3-c]pyridine

[0271]

[0272] A solution of 2-[[5-(3,4-dihydro-2J / -pyrano[2,3-c]pyridin-4-yl)-2-(2,2,2-trifluoroethyl)imidazol- l-yl]methoxy]ethyl-trimethyl-silane (123 mg, 0.23 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at 25 °C for 48 h, before being evaporated. The mixture was diluted with a saturated aqueous NaHCCL solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated. Purification by chiral SFC (Chromatorex PEI, 5 um, 100 x 19mm, Hexane / (IPA:MeOH 50:50)) to give the title compound (16 mg, 24% yield, tR = 16.465 min) as the second eluting enantiomer and as a beige solid. MS (ESI): m / z = 284.0 [M+H]+

[0273] Step a) 2H-pyrano[2,3-c]pyridin-4-yl trifluor ome thane sulfonate

[0274] 2,3-Dihydropyrano[2,3-c]pyridin-4-one (CAS RN: 2091452-31-0; 0.63 g, 4.22 mmol) was dissolved in THF (15 mL) and cooled down to -78 °C, before being treated dropwise with lithium bis(trimethylsilyl)amide (20% in THF; 5.49 mL, 5.49 mmol). The mixture was stirred for 1 h at -78 °C, and 2-[A,A-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (2.16 g, 5.49 mmol) in THF (15 mL) was added dropwise at 0° C. The mixture was stirred for 2 h at this temperature, before being diluted with NH4CI (10% aq. solution) and extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSCU, filtered and evaporated. Purification by FC (SiCL, CHCI3 / CH3CN) gave the title compound (0.85 g, 68% yield) as a brown oil. MS (ESI): m / z = 282.0 [M+H]+

[0275] Step b) trimethyl-[2-[[4-(2H-pyrano[2,3-c]pyridin-4-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl Jmethoxy ] ethyl J silane

[0276] A mixture of bis(pinacol)diborane (2.17 g, 8.53 mmol), potassium acetate (1.26 g, 12.8 mmol) and 2H-pyrano[2,3-c]pyridin-4-yl trifluoromethanesulfonate (2.4 g, 8.53 mmol) in 1,4-dioxane (84 mL) was purged with Ar for 5 min. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (1.04 g, 1.28 mmol) was added and the mixture was purged again with Ar. The reaction mixture was stirred at 90 °C for 16 h, before being cooled down to 23 °C, filtered, and diluted with 1,4-dioxane (60 mL) and water (36 mL). Phosphoric acid, potassium salt (4.53 g, 21.34 mmol), 2-[[4-bromo-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (B.4; 3.07 g, 8.53 mmol) were added. The reaction mixture was purged with Ar followed by addition of XPhos (407 mg, 0.85 mmol) and palladium (II) acetate (96 mg, 0.43 mmol). The mixture was degassed again and stirred at 90 °C for 16 h. The reaction mixture was concentrated and diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2, CHCI3 / CH3CN) gave the title compound (0.17 g, 3% yield) as a brown oil. MS (ESI): m / z = 412.2 [M+H]+

[0277] Step c) 2-[ [4-(3, 4-dihydro-2H-pyrano[ 2, 3-c ]pyridin-4-yl)-2-(2, 2, 2-trifluoroethyl)imidazol-l-yl methoxy Jethyl-trimethyl-silane

[0278] A solution of trimethyl-[2-[[4-(2H-pyrano[2,3-c]pyridin-4-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl]silane (170 mg, 0.27 mmol) and Pd / C (10%) (10 mg) in EtOAc (6 mL) wasstirred under a EE atmosphere (1 bar) for 18 h at 25 °C. The reaction mixture was filtered and the filtrate was evaporated. Purification by RP-HPLC gave the title compound (52 mg, 41% yield) as a brown oil. MS (ESI): m / z = 414.2 [M+H]+

[0279] Example 11

[0280] (5R)-5-(2-cyclopropyl-lH-inudazol-5-yl)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridine or (5S)-5- (2-cyclopropyl-lH-inudazol-5-yl)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridine

[0281]

[0282] A solution of 2-[[2-cyclopropyl-5-[(5A)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridin-5-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane or 2-[[2-cyclopropyl-5-[(55')-2,3,4,5-tetrahydrooxepino[2,3-c]pyridin-5-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane (80 mg, 207.48 pmol) in TFA (799 pL, 10.37 mmol) was stirred at 23 °C for 18 h, before being evaporated. Purification by RP-HPLC gave the title compound (37 mg, 66% yield) as a white solid. MS (ESI): m / z = 256.1 [M+H]+

[0283] Step a) 3-(3-cyanopropoxy)isonicotinic acid methyl ester

[0284] To a solution of 3-hydroxyisonicotinic acid methyl ester (CAS RN: 10128-72-0; 13.5 g, 88.15 mmol) in THF (300 mL) was added PI13P (26.59 g, 101.4 mmol) and 4-hydroxybutyronitrile (CAS RN: 628-22-8; 8.63 g, 101.4 mmol). The reaction mixture was cooled down to 0 °C and DIAD (19.7 mL, 101.4 mmol) was added. The reaction mixture was stirredfor 18 h at 23 °C. The volatiles were evaporated. Purification by FC (SiCL; heptane / EtOAc / EtOH) gave the title compound (17.02 g, 86% yield) as a light red solid. MS (ESI): m / z = 221.1 [M+H]+

[0285] Step b) 5-keto-3, 4-dihydro-2H-oxepino[ 2, 3-c ]pyridine-4-carbonitrile

[0286] To a solution of 3-(3-cyanopropoxy)isonicotinic acid methyl ester (8.34 g, 37.11 mmol) in THF (250 mL) at 0 °C was added 1 M potassium te / 7-butoxide solution in THF (44.5 mL, 44.54 mmol). The reaction mixture was stirred for 1 h at 0 °C, before being quenched with acetic acid (2.55 mL, 44.54 mmol) at that temperature and warmed to 23 °C. The volatiles were evaporated. Purificationby FC (SiCh; DCM / MeOH) gave the title compound (7.09 g, 96% yield) as a yellow solid. MS (ESI): m / z = 189.0 [M+H]+

[0287] Step c) 3,4-dihydro-2H-oxepino[2,3-c]pyridin-5-one

[0288] To a suspension of 5-keto-3,4-dihydro-2J / -oxepino[2,3-c]pyridine-4-carbonitrile (6.02 g, 31.99 mmol) in acetic acid (51 mL) was added 25% aq. HC1 solution (50.5 mL, 415.9 mmol). The reaction mixture was stirred for 18 h at 100 °C. The volatiles were evaporated and the residue was partitioned between DCM and saturated aq. ISfeCCh solution. The aq. phase was back-extracted with DCM. The combined organic layers were dried over ISfeSCU, filtered and evaporated to give the title compound (4.93 g, 90% yield) as a yellow solid, that was used without further purification in the next step. MS (ESI): m / z = 164.0 [M+H]+

[0289] Step d) trifluor ome thane sulfonic acid 2,3-dihydrooxepino[2,3-c]pyridin-5-yl ester

[0290] To a solution of 3,4-dihydro-2H-oxepino[2,3-c]pyridin-5-one (500 mg, 3.06 mmol) in anhydrous THF (11 mL) cooled down to -78 °C was slowly added LiHMDS 1.0 M solution in THF (3.52 mL, 3.52 mmol). The reaction mixture was stirred at -78 °C for 30 min and then let to slowly warm up to 0 °C by removing the cooling bath after which a solution of A-(5-chloro-2-pyridyl)-l,l,l-trifluoro-N-triflyl-methanesulfonamide (1.32 g, 3.37 mmol) in anhydrous THF (3 mL) was added to the reaction mixture at 0 °C. The reaction mixture was then stirred at 0 °C for 30 min and let to warm up to 23 °C after which the reaction was stirred at 23 °C for 18 h. The reaction mixture was quenched by addition of a few mL of saturated aqueous NH4CI solution and the reaction mixture was poured into a separating funnel containing EtOAc and saturated aqueous Na2COs. After extraction, the organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2, HeptaneZEtOAc) gave the title compound (288 mg, 30% yield) as a yellow viscous oil. MS (ESI): m / z = 296.1 [M+H]+

[0291] Note: The product should be stored under Ar atmosphere at -18°C.

[0292] Step e) 2-[[2-cyclopropyl-5-(2,3-dihydrooxepino[2,3-c]pyridin-5-yl)imidazol-l-yl methoxy Jethyl-trimethyl-silane

[0293] To a microwave vial was added Pd(PPh3)4 (148 mg, 128.03 pmol) and Cui (24 mg, 128.03 pmol) after which the vial was sealed and the atmosphere was replaced for Ar by repeating 3 times vacuum evacuation / Ar backfill. A solution of trifluoromethanesulfonic acid 2,3-dihydrooxepino[2,3-c]pyridin-5-yl ester (420 mg, 1.28 mmol) in DMF (3.73 mL)was added to the vial followed by a solution of 2-[(2-cyclopropyl-5-trimethylstannyl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane (B.5; 685 mg, 1.54 mmol) in DMF (3.73 mL) after which the reaction mixture was sparged with Ar for a few minutes. The reaction mixture was stirred at 80 °C for 18 h. Volatiles were removed in vacuo and the obtained crude residue was then partitioned between EtOAc and a 1 M aqueous Na2COs solution. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2, Heptane / (EtOAc:EtOH 3:1)) gave the title compound (92 mg, 18% yield) as a yellow viscous oil. MS (ESI): m / z = 384.3 [M+H]+

[0294] Step j) 2-[[2-cyclopropyl-5-(2, 3, 4, 5-tetrahydrooxepino[2, 3-c ]pyridin-5-yl)imidazol-l-yl Jmethoxy Jethyl-trimethyl-silane

[0295] A solution of 2-[[2-cyclopropyl-4-(2,3-dihydrooxepino[2,3-c]pyridin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (280 mg, 0.730 mmol) and Pd / C 10% (28 mg, 0.0263 mmol) in THF (6 mL) was stirred under an EE atmosphere (8 bar) at 60 °C for 18 h. The reaction mixture was filtered, and the filtrate was evaporated down to dryness to give the title compound (261 mg, 83% yield) as a light yellow gum which was directly used in the next step. MS (ESI): m / z = 386.3 [M+H]+

[0296] Step g) 2-[[2-cyclopropyl-5-[(5R)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridin-5-yl]imidazol-l-yl methoxy Jethyl-trimethyl-silane or 2-[[2-cyclopropyl-5-[ (5S)-2, 3, 4, 5-tetrahydrooxepino[ 2, 3-c ]pyridin-5-yl ]imidazol-l-yl Jmethoxy Jethyl-trimethyl-silane

[0297] The racemate 2-[[2-cyclopropyl-5-(2,3,4,5-tetrahydrooxepino[2,3-c]pyridin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (260 mg, 0.675 mmol) was separated by chiral SFC (chiral IC 5 pm, 250 x 20 mm, CCE / MeOH + 0.2% DEA) to give the title compound (83 mg, 30% yield, tR = 3.390 min) as the second eluting enantiomer and as a light yellow gum. MS (ESI): m / z = 386.3 [M+H]+

[0298] Example 12

[0299] (5R)-5-(2-cyclopropyl-lH-inudazol-5-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine or (5S)~ 5-(2-cyclopropyl-lH-imidazol-5-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine

[0300]

[0301] A solution of 2-[[2-cyclopropyl-5-[(5R)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane or 2-[[2-cyclopropyl-5-[(5S)-6,7,8,9-tetrahydro- 5H-cyclohepta[c]pyridin-5-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane (120 mg, 312.82 pmol) in TFA (1.08 mL, 14.08 mmol) was stirred at 23 °C for 18 h, before being evaporated. Purification by RP-HPLC gave the title compound (49 mg, 59% yield) as a light yellow gum. MS (ESI): m / z = 254.2 [M+H]+

[0302] Step a) 2-[[2-cyclopropyl-5-(8, 9-dihydro- 7H-cyclohepta[c]pyridin-5-yl)imidazol-l-yl Jmethoxy Jethyl-trimethyl-silane

[0303] To a microwave vial was added Pd(PPhs)4 (142 mg, 122.76 pmol) and Cui (23 mg, 122.76 pmol) after which the vial was sealed and the atmosphere was replaced for Ar by repeating 3 times vacuum evacuation / Ar backfill. A solution of trifluoromethanesulfonic acid 8,9-dihydro-7H-cy cl ohepta[c]pyri din-5 -yl ester (B.6; 400 mg, 1.23 mmol) in DMF (3 mL) was added to the vial followed by a solution of 2-[(2-cyclopropyl-5-trimethylstannyl-imidazol-l-yl)methoxy]ethyl-trimethyl-silane (B.5; 657 mg, 1.47 mmol) in DMF (3 mL) after which the reaction mixture was sparged with Ar for a few minutes. The reaction mixture was stirred at 80 °C for 18 h. Volatiles were removed in vacuo and the obtained crude residue was then partitioned between EtOAc and aqueous Na2COs 1 M. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2, heptane:(EtOAc:EtOH 3:1)) to give the title compound (391 mg, 71% yield) as a yellow gum. MS (ESI): m / z = 382.3 [M+H]+

[0304] Step b) 2-[[2-cyclopropyl-5-(6, 7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl)imidazol-l-yl methoxy Jethyl-trimethyl-silane

[0305] A solution of 2-[[2-cyclopropyl-5-(6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (385 mg, 1.01 mmol) and Pd / C 10% (50 mg, 0.0470 mmol) in THF (8 mL) was stirred under an EE atmosphere (8 bar) at 60 °C for 18 h. The reaction mixture was filtered to remove catalyst and the filtrate was evaporated down to dryness to give the titlecompound (342 mg, 94% yield) as a light yellow gum which was used crude without further purification. MS (ESI): m / z = 384.3 [M+H]+

[0306] Step c) 2-[ [ 2-cyclopropyl-5-[ (5R)-6,7, 8, 9-tetrahydro-5H-cyclohepta[ c ]pyridin-5-yl Jimidazol-1-yl]methoxy]ethyl-trimethyl-silane or 2-[[2-cyclopropyl-5-[(5S)-6, 7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl]imidazol-l-yl]methoxy]ethyl-trimethyl-silane

[0307] The racemate 2-[[2-cyclopropyl-5-(6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (260mg, 0.675 mmol) was separated by chiral SFC (chiral column IK, 5 pm, 250 x 20 mm, CCh / MeOH +0.2% DEA) to yield the title compound (123 mg, 34% yield, tR = 4.542 min) as the second eluting enantiomer and as light yellow viscous oil. MS (ESI): m / z = 384.3 [M+H]+

[0308] Example 13

[0309] (5R)-5-[2-(2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine or (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-inudazol-5-yl]-6,7,8,9-tetrahydro-5H- cyclohepta[c]pyridine

[0310]

[0311] The racemate 5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine (100 mg, 0.339 mmol) was separated by chiral SFC (chiral column OZ, 5 pm, 250 x 20 mm, CCh / MeOH +0.2% DEA) to give the title compound (32 mg, 30% yield, tR = 3.456 min) as the second eluting compound and as a yellow gum. MS (ESI): m / z = 296.2 [M+H]+

[0312] Step a) 5-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-8, 9 -dihydro- 7H-cyclohepta[ c ] pyridine

[0313] To a sealed vial containing bis(triphenylphosphine)palladium(II) dichloride (112 mg, 159.54 pmol), bis(pinacolato)diboron (1.01 g, 3.99 mmol), potassium phenoxide (591 mg, 4.47 mmol), PhsP (50 mg, 191.45 pmol) under an inert atmosphere was added a solution of trifluoromethanesulfonic acid 8,9-dihydro-7H-cyclohepta[c]pyridin-5-yl ester (B.6; 985 mg, 3.19 mmol) in anhydrous toluene (12 mL). The reaction mixture was then stirred at 75 °C for 3 h, beforebeing evaporated. Purification by FC (SiCL, Heptane / (EtOAc:Et3N 95:5)) gave the title compound (589 mg, 27% yield) as a light yellow viscous oil. MS (ESI): m / z = 272.2 [M+H]+

[0314] Step b) 2-[[4-(8,9-dihydro-7H-cyclohepta[c]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl methoxy Jethyl-trimethyl-silane

[0315] To a microwave vial was added 2-[[4-bromo-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane (B.4; 270 mg, 751.54 pmol), XPhos Pd G2 (59 mg, 75.15 pmol), the vial was sealed and the atmosphere was changed to Ar by repeating 3x vacuum evacuation / Ar back-filling followed by addition of a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-cyclohepta[c]pyridine (586 mg, 864.28 pmol) in toluene (3 mL) and a solution of ISfeCCL (239 mg, 2.25 mmol) in water (1 mL). The reaction was then stirred at 80 °C for 18 h. The reaction mixture was poured into a separating funnel containing EtOAc and sat. aq. NaHCCL for extraction. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO?; Heptane / EtOAc) to give the title compound (153 mg, 46% yield) as an orange viscous oil. MS (ESI): m / z = 424.3 [M+H]+

[0316] Step c) trimethyl- [2- [[5-(6, 7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl)-2-(2,2,2-trifhioroethyl)imidazol-l-yl methoxy ] ethyl silane

[0317] A solution of 2-[[4-(8,9-dihydro-7H-cyclohepta[c]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol- l-yl]methoxy]ethyl-trimethyl-silane (185 mg, 0.437 mmol) and Pd / C 10% (36 mg, 0.034 mmol) in THF (4 mL) was stirred under an EE atmosphere (8 bar) at 60 °C for 18 h. The reaction mixture was filtered to remove catalyst and the filtrate was evaporated, to give the title compound (178 mg, 77% yield) as an orange viscous oil which was used crude without further purification. MS (ESI): m / z = 426.3 [M+H]+

[0318] Step d) 5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6, 7 ,8,9-tetrahydro-5H-cyclohepta[ c ] pyridine

[0319] A solution of trimethyl-[2-[[5-(6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-5-yl)-2-(2,2,2-trifluoroethyl)imidazol-l-yl]methoxy]ethyl] silane (178 mg, 334.61 pmol) in TFA (1.42 mL, 18.4 mmol) was stirred at 23 °C for 18 h, before being evaporated. Purification by FC (SiCL, DCM / (MeOH:aq. NH395:5)) gave the title compound (102 mg, 98% yield) as an orange gum. MS (ESI): m / z = 296.2 [M+H]+Building blocks

[0320] Building block 1 (B.l )

[0321] 2-[(2-Cyclopropylinudazol-l-yl)methoxy]ethyl-trimethyl-silane

[0322] To a solution of 4-cyclopropyl-LH-imidazole (CAS RN: 89830-98-8; 3.50 g, 32.37 mmol) inDMF (120 mL) was added NaH (1.42 g, 35.6 mmol) portionwise, at 0 °C. The mixture was stirred for 30 min at this temperature, and for 30 min at 23 °C, before being treated with 2-(trimethylsilyl)ethoxymethyl chloride (6.03 mL, 33.98 mmol). The mixture was stirred at 23 °C for 18 h, before being treated with a saturated aqueous solution NH4CI and concentrated in vacuo.

[0323] The crude residue was partitioned between EtOAc and saturated aqueous NaHCCh. The organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Purification by FC (SiO?; heptane / (EtOAc:EtOH 3 : 1)) gave the title compound (B.l; 6.80 g, 76% yield) as a yellow oil. MS (ESI): m / z = 239.2 [M+H]+

[0324] Building block 2 (B.2)

[0325] 7, 8-Dihydroisoquinolin-5-yl trifluoromethanesulfonate

[0326] To a solution of 7,8-dihydro-6J / -isoquinolin-5-one (CAS RN: 21917-86-2; 4.50 g, 30.57 mmol) in anhydrous THF (75 mL) was slowly added a 2 M LDA solution in THF (18.34 mL, 36.69 mmol), at -78 °C under Ar. The reaction mixture was stirred at -78 °C for 1 h after which a solution of A-(5-chloro-2-pyridyl)-l,l,l-trifhioro-A-triflyl-methanesulfonamide (16.6 mL, 36.69 mmol) in anhydrous THF (30 mL) was added to the reaction mixture at -78 °C. The reaction mixture was then stirred at -78 °C for 30 min and the reaction mixture was slowly let to warm up to 0 °C and stirred at 0 °C for 1 h. The reaction mixture was quenched by addition of saturated aqueous solution Na2CC>3 and the reaction mixture was poured into a separating funnel containing EtOAc and saturated aqueous solution Na2COs. After extraction, the organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; Heptane / (EtOAc:EtOH 3:1)) gave the title compound (B.l; 6.80 g, 76% yield) as an orange viscous oil. MS (ESI): m / z = 280.1 [M+H]+(Note: the compound was stored at -18°C under Ar)

[0327] Building block 3 (B.3)1-[4-Bromo-l-(2-trimethylsilylethoxymethyl)inudazol-2-yl]-2,2,2-trifluoro-ethanol Cesium fluoride (5.46 g, 35.92 mmol) was added portionwise to a solution of 4-bromo-l-(2-trimethylsilylethoxymethyl)imidazole-2-carbaldehyde (8.6 g, 23.95 mmol) in THF (150 mL) at 25 °C. The reaction mixture was stirred for 15 min at this temperature, before being treated dropwise with trifluoromethyltrimethylsilane (6.81 g, 47.9 mmol). The resulting mixture was stirred for 24 h at 23 °C, before being filtered and evaporated. The residue was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCh; Hexane / MTBE) gave the title compound (B.3; 6.2 g, 66% yield) as a yellow solid. MS (ESI): m / z = 375.0 / 377.0 [M+H]+

[0328] Step a) 4-bromo-l-(2-trimethylsilylethoxymethyl)imidazole-2-carbaldehyde

[0329] Cesium carbonate (10.56 g, 32.4 mmol) was added to a solution of 4-bromo-U / -imidazole-2-carbaldehyde (CAS RN: 1260876-31-0; 5.4 g, 30.86 mmol) inDMF (100 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C, before being treated slowly by 2-(trimethylsilyl)ethoxymethyl chloride (7.1 mL, 40.12 mmol). The resulting mixture was stirred 12 h at 23 °C and then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated, to give the title compound (8.6 g, 84% yield) as a brown oil. GC-MS: m / z = 233.0 [M-TMS]+

[0330] Building block 4 (B.4)

[0331] 2-[[4-Bromo-2-(2,2,2-trifluoroethyl)inudazol-l-yl]methoxy]ethyl-trimethyl-silane Imidazole (181 mg, 2.66 mmol), iodine (676 mg, 2.66 mmol) and triphenylphosphine (699 mg, 2.66 mmol) were added to a solution of l-[4-bromo-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,2,2-trifluoro-ethanol (B.3; 500 mg, 1.33 mmol) in THF (70 mL) and the resulting mixture was stirred at 65 °C for 48 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic layer was washed by Na2S20s (10% aq. solution) and brine. The organic phase was dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; Hexane / MTBE) gave the title compound (B.4; 250 mg, 53% yield) as a yellow solid. MS (ESI): m / z = 359.0 [M+H]+

[0332] Building block 5 (B.5)

[0333] 2-[(2-Cyclopropyl-5-trimethylstannyl-inudazol-l-yl)methoxy]ethyl-trimethyl-silaneTo a solution of 2-[(2-cyclopropylimidazol-l-yl)methoxy]ethyl-trimethyl-silane (B.l; 1.5 g, 6.29 mmol) in anhydrous THF (21 mL) cooled down to -78 °C under an inert atmosphere was slowly added BuLi 1.6 M solution in hexanes (4.33 mL, 6.92 mmol) and the reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was then let to warm up to -35 °C after which it was stirred at -35 °C for 45 min. A solution of trimethyltin chloride 1.0 M solution in THF (6.61 mL, 6.61 mmol) was added to the reaction mixture at -35 °C. After complete addition, the reaction was stirred at -35 °C for 1 h and then let to warm up to 23 °C. The reaction was quenched by addition of few drops of saturated aqueous solution NH4CI and the reaction mixture was then partitioned between EtOAc and aqueous NaHCCL 1 M solution. The organic phase was collected, dried over Na2SO4 and evaporated down to dryness to give the title compound (B.5; 2.35 g, 84% yield) as a light yellow viscous oil which was used without further purification (purity estimated at 90%). MS (ESI): m / z = 403.3 [M+H]+

[0334] Building block 6 (B.6)

[0335] Trifluoromethanesulfonic acid 8,9-dihydro-7H-cyclohepta[c]pyridin-5-yl ester

[0336] To a solution of 6,7,8,9-tetrahydrocyclohepta[c]pyridin-5-one (CAS RN: 95207-84-4; 2.0 g, 12.41 mmol) in anhydrous THF (40 mL) cooled down to -78 °C was slowly added LDA 2.0 M solution in THF (7.75 mL, 15.51 mmol). The reaction mixture was stirred at -78 °C for 1 h after which a solution of N-(5-chloro-2-pyridyl)-l,l,l-trifhioro-N-triflyl-methanesulfonamide (6.09 g, 15.51 mmol) in anhydrous THF (16 mL) was added to the reaction mixture at -78 °C. The reaction mixture was then stirred at -78 °C for 60 min. The reaction was let to warm up to -45 °C and stirred at -45 °C for 3 h. The reaction mixture was quenched by addition of saturated aqueous solution NaHCCL and the reaction mixture was poured into a separating funnel containing EtOAc and sat. aq. NaHCCh. After extraction, the organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2, Heptane / (EtOAc:Et3N 95:5)) gave the title compound (B.6;

[0337] 2.5 g, 64% yield) as a light yellow viscous oil. MS (ESI): m / z = 294.1 [M+H]+

[0338] Example 14

[0339] A compound of formula (I) or (II) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[0340] Per tablet

[0341] Active ingredient 200 mg

[0342] Microcrystalline cellulose 155 mgCom starch 25 mg

[0343] Talc 25 mg

[0344] Hydroxypropylmethylcellulose 20 mg

[0345] 425 mg

[0346] Example 15

[0347] A compound of formula (I) or (II) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[0348] Per capsule

[0349] Active ingredient 100.0 mg

[0350] Com starch 20.0 mg

[0351] Lactose 95.0 mg

[0352] Talc 4.5 mg

[0353] Magnesium stearate 0.5 mg

[0354] 220.0 mg

Claims

1. Claims1. A compound of formula (I) or (II)or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, -NH-, - N(CH3)-, *-OCH2-, *-NHCH2-, *-CH2O-, and *-CH2NH-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring; Y is selected from the group consisting of N and CH;R1is selected from the group consisting of Cs-Cio-cycloalkyl, Ci-Ce-alkyl, halo- Ci-C6-alkyl, halo-Ci-C6-alkyl-CH(OH)-, halo-Ci-C6-alkyl-C(O)-, Ci-C6-alkyl- CH(OH)-, and Ci-C6-alkyl-C(O)-;R2is hydrogen; andR3is selected from the group consisting of hydrogen and Ci-Ce-alkyl; or R2and R3, taken together with the carbon atoms to which they are attached, form a Cs-Ce-cycloalkyl; andR4is selected from the group consisting of hydrogen and Ci-Ce-alkyl.

2. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (la) or (Ila)3. The compound of formula (I) according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

4. The compound of formula (II) according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is N.

5. The compound of formula (I) according to any one of claims 1 to 3, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, *-0CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring.

6. The compound of formula (I) according to any one of claims 1 to 3, or 5, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of -CH2- and -CH2CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring.

7. The compound of formula (I) or (II) according to any one of claims 1 to 6, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of Cs-Cio-cycloalkyl, halo-Ci-Ce-alkyl, and halo-Ci-C6-alkyl-CH(OH)-.

8. The compound of formula (I) or (II) according to any one of claims 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of halo-Ci-Ce-alkyl and halo-Ci-Ce-alkyl- CH(OH)-.

9. The compound of formula (I) or (II) according to any one of claims 1 to 7, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of:- so - 10. The compound of formula (I) or (II) according to any one of claims 1 to 9, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1isselected from the group consisting11. The compound of formula (I) according to any one of claims 1 to 3, or 5 to 10, or a pharmaceutically acceptable salt thereof, wherein:R2and R3are both hydrogen; orR2and R3, taken together with the carbon atoms to which they are attached, form a Cs-Ce-cycloalkyl.

12. The compound of formula (I) according to any one of claims 1 to 3, or 5 to 11, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:R2and R3are both is hydrogen; orR2and R3, taken together with the carbon atoms to which they are attached, form a cyclopropyl.

13. The compound of formula (I) to any one of claims 1 to 3, or 5 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R3are both hydrogen.

14. The compound of formula (I) or (II) according to any one of claims 1 to 13, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

15. A compound of formula (I) according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, and *-OCH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;Y is CH;R1is selected from the group consisting of Cs-Cio-cycloalkyl, halo-Ci-Ce-alkyl, and halo-Ci-Ce-alkyl-CH(OH)-;R2and R3are both hydrogen; orR2and R3, taken together with the carbon atoms to which they are attached, form a Cs-Ce-cycloalkyl; andR4is hydrogen.

16. A compound of formula (I) according to claim 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:X is selected from the group consisting of -CH2-, -CH2CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;Y is CH;R1is selected from the group consisting of halo-Ci-Ce-alkyl and halo-Ci-Ce-alkyl- CH(OH)-;R2, R3, and R4are all hydrogen.

17. A compound of formula (I) according to claim 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:X is selected from the group consisting of -CH2-, -CH2CH2-, -O-, and *-0CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;Y is CH;R1is:R2and R3are both hydrogen; orR2and R3, taken together with the carbon atoms to which they are attached, form a cyclopropyl; andR4is hydrogen.

18. A compound of formula (I) according to claim 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:X is selected from the group consisting of -CH2-, -CH2CH2-, wherein the asterisk indicates the point of attachment of X to the adjacent aromatic ring;Y is CH;R1is:R2, R3, and R4are all hydrogen.

19. A compound of formula (II) according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:Y is N;R1is Cs-Cio-cycloalkyl;R4is hydrogen.

20. A compound of formula (II) according to claim 19, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl.

21. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:(5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline or (5R)-5- (2-cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline;(5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline or (5R)-5- (2-cyclopropyl-lH-imidazol-5-yl)-5,6,7,8-tetrahydroisoquinoline;5-(2-cyclopropyl-lH-imidazol-4-yl)phthalazine;(5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline; (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline; (lS)-2,2,2-trifhioro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2- yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH- imi dazol -2-yl ] ethanol ;(1 aS, 7b S)-7b-(2-cyclopropyl- lH-imidazol-5-yl)- 1 , 1 a, 2, 3 - tetrahydrocyclopropa[f]isoquinoline or (laR,7bR)-7b-(2-cyclopropyl-lH- imidazol-5-yl)-l,la,2,3-tetrahydrocyclopropa[f]isoquinoline;(lS)-2,2,2-trifhioro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2- yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH- imi dazol -2-yl ] ethanol ;(4R)-4-(2-cyclopropyl-lH-imidazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine or (4S)-4-(2-cyclopropyl-lH-imidazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine; (4S)-4-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-3,4-dihydro-2H-pyrano[2,3- c]pyridine or (4R)-4-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-3,4-dihydro-2H- pyrano[2,3-c]pyridine;(5R)-5-(2-cyclopropyl-lH-imidazol-5-yl)-2,3,4,5-tetrahydrooxepino[2,3-c]pyridine or (5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-2,3,4,5-tetrahydrooxepino[2,3- c]pyridine;(5R)-5-(2-cyclopropyl-lH-imidazol-5-yl)-6,7,8,9-tetrahydro-5H- cyclohepta[c]pyridine or (5S)-5-(2-cyclopropyl-lH-imidazol-5-yl)-6,7,8,9- tetrahydro-5H-cyclohepta[c]pyridine; and(5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9-tetrahydro-5H- cyclohepta[c]pyridine or (5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]- 6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine.

22. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:(5S)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline or (5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-5,6,7,8-tetrahydroisoquinoline; (lS)-2,2,2-trifhioro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH-imidazol-2- yl]ethanol or (lR)-2,2,2-trifluoro-l-[4-(5,6,7,8-tetrahydroisoquinolin-5-yl)-lH- imidazol-2-yl]ethanol; and(5R)-5-[2-(2,2,2-trifluoroethyl)-lH-imidazol-5-yl]-6,7,8,9-tetrahydro-5H- cyclohepta[c]pyridine or (5S)-5-[2-(2,2,2-trifhroroethyl)-lH-imidazol-5-yl]-6,7,8,9- tetrahydro-5H-cyclohepta[c]pyridine.

23. The compound according to any one of claims 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

25. A method of treating or preventing a condition associated with SARM1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 24.

26. The method according to claim 25, wherein said condition associated with SARM1 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system.

27. The method according to claim 26, wherein said condition affecting the nervous system is neurodegenerative disorder.

28. The method according to claim 25, wherein said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease.

29. A compound according to any one of claims 1 to 22, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for use in a method according to any one of claims 25 to 28.

30. Use of a compound according to any one of claims 1 to 22, or a tautomer thereof, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 24, in a method according to any one of claims 25 to 28.

31. Use of a compound according to any one of claims 1 to 22, or a tautomer thereof, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to any one of claims 25 to 28.

32. The invention as described hereinbefore.

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