Benzofuran derivatives as inhibitors of SARM1

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; which is useful in the treatment of diseases.

Description

[0001] THERAPEUTIC AGENTS

[0002] The invention relates to benzofuran-containing compounds and their pharmaceutically acceptable salts and solvates and their use in therapy.

[0003] The compounds according to the present invention are inhibitors of SARM1 and accordingly are of benefit as pharmaceutical agents for the treatment of diseases in which SARM1 plays a role, notably for the treatment of chemotherapy-induced peripheral neuropathy (CIPN).

[0004] BACKGROUND OF THE INVENTION SARM1 is a cellular NADase that plays a key role in driving axonal degeneration in multiple neurological conditions. Enzymatic inhibition may therefore mitigate axonal damage and provide symptomatic benefit to patients.

[0005] Axonal degeneration leads to disease progression and accumulation of disability in many degenerative diseases of the peripheral nervous system (PNS) and central nervous systems (CNS), such as multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), or acute conditions such as traumatic brain injury. Pathological axonal degeneration is also a feature of chemical-induced damage such as in chemotherapy-induced peripheral neuropathy (CIPN). Therefore, axonal protection is an important neuroprotective approach to treatment in chronic and acute central nervous system (CNS) and peripheral nervous system (PNS) neurodegenerative disorders. (Hughes RO, BosanacT, MaoX, EngberTM, DiAntonio A, Milbrandt J, Devraj R, Krauss R. “Small Molecule SARM1 Inhibitors Recapitulate the SARM1 - / -Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate”. Cell Rep. 2021 Jan 5; 34 (1): 108588. doi: 10.1016 / j. celrep. 2020.108588. PMID: 33406435; PMCID: PMC8179325.), (Bosanac T, Hughes RO, Engber TM, Devraj R, Brearley A, Danker K, Young K, Kopatz J, Hermann M, Berthemy A, Boyce S, Bentley J, Krauss R, “Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy”, Brain, 2021, awab 184, https: / / doi. org / 10.1093 / brain / awab184).

[0006] It has notably been found that SARM1 plays a central role in promoting axon, retinal ganglion cells (RCG) and oligodendrocyte loss in Glaucoma (Woo Ko K, Milbrandt J, DiAntonio A, “SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration”, Journal of Cell Biology, 2020, Vol. 219, No 8).

[0007] The incidence of many of these diseases and disorders increases with age and is rapidly increasing as demographics change, which lead to substantive costs to treat these diseases.

[0008] There have been attempts to provide compounds that modulate the activity of SARM1. For example, WO2024 / 077273 and WO2024 / 216209 disclose compounds useful for the treatment of neurodegenerative diseases and / or axonal degeneration, however, there is still a need to identify compounds which have therapeutic utility in the treatment or prevention of disorders where SARM1 plays a role. SUMMARY OF THE INVENTION

[0009] It has been found that compounds of formula (I) and their pharmaceutically acceptable salts can be useful for this purpose.

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

[0011]

[0012] or a pharmaceutically acceptable salt or solvate thereof;

[0013] wherein:

[0014] Ring A is selected from C5-10heteroaryl, bridged bicyclic C5-10heterocycloalkyl or C4-10heterocycloalkyl;

[0015] R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;

[0016] wherein R1aand R1bare independently selected from H or C1-3alkyl;

[0017] R2is selected from H, Ci-salkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0018] R3is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, oxo (=O), C0-3alkylOH, C0-3alkylCN and NR3aR3b;

[0019] wherein R3aand R3bare independently selected from H or C1-3alkyl;

[0020] R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol halogen, Co-salkylOH, Co-3alkylCN, C3-6heteroaryl, NR4aR4band CONR4eR4f;

[0021] wherein

[0022] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0023] R4aand R4bare independently selected from H or C1-3alkyl; and

[0024] R4eand R4fare independently selected from H or Ci-3alkyl;

[0025] Z is selected from NH, CR5and CR5R5c;

[0026] R5is selected from H, C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR5aR5b

[0027] wherein the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0028] R5aand R5bare independently selected from H or C1-3alkyl; and

[0029] R5cis selected from H or halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl;

[0030] m is selected from 0, 1 and 2;

[0031] n is selected from 0, 1, 2 and 3;

[0032] p is selected from 0, 1 and 2; and

[0033] q is selected from 1 or 2.

[0034] In a second aspect, the present invention provides a compound of formula (I’)

[0035]

[0036] or a pharmaceutically acceptable salt or solvate thereof;

[0037] wherein:

[0038] Ring A is selected from C5-10heteroaryl or C5-10heterocycloalkyl;

[0039] R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;

[0040] wherein R1aand R1bare independently selected from H or C1-3alkyl;

[0041] R2is selected from H, Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0042] R3is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, oxo (=O), C0-3alkylOH, C0-3alkylCN and NR3aR3b;

[0043] wherein R3aand R3bare independently selected from H or C1-3alkyl;

[0044] R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol, halogen, Co-salkylOH, Co-3alkylCN, C3-6heteroaryl, NR4aR4band CONR4eR4f;

[0045] wherein

[0046] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0047] R4aand R4bare independently selected from H or C1-3alkyl; and

[0048] R4eand R4fare independently selected from H or Ci-3alkyl;

[0049] Z is selected from NH, CR5and CR5R5c; R5is selected from H, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylOH, C0-3alkylCN, C3-6cycloalkyl, C3-6heteroaryl and NR5aR5b

[0050] wherein

[0051] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C-i-salkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0052] R5aand R5bare independently selected from H or C1-3alkyl; and

[0053] R5cis selected from H or halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl;

[0054] m is selected from 0, 1 and 2;

[0055] n is selected from 0, 1, 2 and 3;

[0056] p is selected from 0, 1 and 2; and

[0057] q is selected from 1 or 2.

[0058] In a third aspect, the present invention provides a compound of formula (I”)

[0059]

[0060] or a pharmaceutically acceptable salt or solvate thereof;

[0061] wherein:

[0062] Ring A is selected from Cs-wheteroaryl or Cs-wheterocycloalkyl;

[0063] R1is selected from C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylCN and NR1aR1b;

[0064] wherein R1aand R1bare independently selected from H orC1-3alkyl;

[0065] R2is selected from H, C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl and halogen;

[0066] R3is selected from C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl, halogen, oxo (=0), Co-salkylOH, Co-salkylCN and NR3aR3b;

[0067] wherein R3aand R3bare independently selected from H or C1-3alkyl;

[0068] R4is selected from C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR4aR4b

[0069] wherein

[0070] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen; and R4aand R4bare independently selected from H or C1-3alkyl; Z is selected from NH or CR5;

[0071] R5is selected from H, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylOH, C0-3alkylCN, C3-6heteroaryl and NR5aR5b

[0072] wherein

[0073] the C3-6heteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen; and R5aand R5bare independently selected from H or C1-3alkyl;

[0074] m is selected from 0, 1 and 2;

[0075] n is selected from 0, 1, 2 and 3;

[0076] p is selected from 0, 1 and 2; and

[0077] q is selected from 1 or 2.

[0078] In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0079] In another aspect, the present invention provides for the use of a compound of formula (I), or a pharmaceutically salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of diseases and / or disorders in which SARM1 plays a role.

[0080] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically salt or solvate thereof, for use in the treatment or prevention of a disease and / or disorder in which SARM1 plays a role.

[0081] In another aspect, the present invention provides a method for the treatment and / or prevention of disorders for which the administration of inhibitors of SARM1 is indicated, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0082] In another aspect, the disease or disorder is selected from neurological disorders, such as peripheral nervous system (PNS) disease, diabetic neuropathy or motor neuron disease, traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury, diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN) or chemotherapy induced cognitive impairment; ocular indications, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as motor neuron disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD); or autoimmune and inflammatory diseases. DETAILED DESCRIPTION OF THE INVENTION

[0083] In a first aspect, the present invention provides a compound of formula (I)

[0084]

[0085] or a pharmaceutically acceptable salt or solvate thereof;

[0086] wherein:

[0087] Ring A is selected from C5-10heteroaryl, bridged bicyclic C5-10heterocycloalkyl or C4-10heterocycloalkyl;

[0088] R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;

[0089] wherein R1aand R1bare independently selected from H or C1-3alkyl;

[0090] R2is selected from H, Ci-salkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0091] R3is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, oxo (=O), C0-3alkylOH, C0-3alkylCN and NR3aR3b;

[0092] wherein R3aand R3bare independently selected from H or C1-3alkyl;

[0093] R4is selected from Ci-salkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol halogen, Co-salkylOH, Co-3alkylCN, C3-6heteroaryl, NR4aR4band CONR4eR4f;

[0094] wherein

[0095] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0096] R4aand R4bare independently selected from H or C1-3alkyl; and

[0097] R4eand R4fare independently selected from H or Ci-3alkyl;

[0098] Z is selected from NH, CR5and CR5R5c;

[0099] R5is selected from H, Ci-salkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR5aR5b

[0100] wherein

[0101] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C-i-salkyl, C1-3alkoxy, Ci-shaloalkyl and halogen;

[0102] R5aand R5bare independently selected from H or C1-3alkyl; and R5cis selected from H or halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl;

[0103] m is selected from 0, 1 and 2;

[0104] n is selected from 0, 1, 2 and 3;

[0105] p is selected from 0, 1 and 2; and

[0106] q is selected from 1 or 2.

[0107] In a second aspect, the present invention provides a compound of formula (I’)

[0108]

[0109] or a pharmaceutically acceptable salt or solvate thereof;

[0110] wherein:

[0111] Ring A is selected from C5-10heteroaryl or C5-10heterocycloalkyl;

[0112] R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;

[0113] wherein R1aand R1bare independently selected from H or C1-3alkyl;

[0114] R2is selected from H, C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0115] R3is selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, oxo (=0), Co-salkylOH, Co-salkylCN and NR3aR3b;

[0116] wherein R3aand R3bare independently selected from H or C1-3alkyl;

[0117] R4is selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol halogen, Co-salkylOH, Co-3alkylCN, C3-6heteroaryl, NR4aR4band CONR4eR4f;

[0118] wherein

[0119] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0120] R4aand R4bare independently selected from H or C1-3alkyl; and

[0121] R4eand R4fare independently selected from H or C1-3alkyl;

[0122] Z is selected from NH, CR5and CR5R5c;

[0123] R5is selected from H, C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR5aR5b wherein

[0124] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from Ci-salkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0125] R5aand R5bare independently selected from H or C1-3alkyl; and

[0126] R5cis selected from H or halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl;

[0127] m is selected from 0, 1 and 2;

[0128] n is selected from 0, 1, 2 and 3;

[0129] p is selected from 0, 1 and 2; and

[0130] q is selected from 1 or 2.

[0131] In a third aspect, the present invention provides a compound of formula (I”)

[0132]

[0133] or a pharmaceutically acceptable salt or solvate thereof;

[0134] wherein:

[0135] Ring A is selected from C5-10heteroaryl or C5-10heterocycloalkyl;

[0136] R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;

[0137] wherein R1aand R1bare independently selected from H orC1-3alkyl;

[0138] R2is selected from H, Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;

[0139] R3is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, oxo (=O), C0-3alkylOH, C0-3alkylCN and NR3aR3b;

[0140] wherein R3aand R3bare independently selected from H or C1-3alkyl;

[0141] R4is selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR4aR4b

[0142] wherein

[0143] the Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen; and R4aand R4bare independently selected from H or C1-3alkyl;

[0144] Z is selected from NH or CR5; R5is selected from H, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylOH, C0-3alkylCN, C3-6heteroaryl and NR5aR5b

[0145] wherein

[0146] the C3-6heteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen; and R5aand R5bare independently selected from H or C1-3alkyl;

[0147] m is selected from 0, 1 and 2;

[0148] n is selected from 0, 1, 2 and 3;

[0149] p is selected from 0, 1 and 2; and

[0150] q is selected from 1 or 2.

[0151] The compounds of formula (I), (I’) and (I’”) may be referred to herein as “compounds of the invention” or “compounds according to the invention”. It will be appreciated that compounds of formulae (I’), (I”) and (I’”) are all sub-formulae of the compound of formula (I). Any reference to a compound of formula (I) contained herein, will therefore include compounds of formulae (I’), (I”), and (I’”).

[0152] The invention further provides a pharmaceutically acceptable salt or solvate of a compound of formula (I). The invention further provides a pharmaceutically acceptable salt of a compound of formula (I). The invention further provides a pharmaceutically acceptable solvate of a compound of formula (I). The invention further provides a compound of formula (I) as the free base.

[0153] The compound of formula (I), and pharmaceutically acceptable salts or solvates thereof, may be referred to herein as ‘compound(s) of the invention’.

[0154] The term “Ci-3alkyl” group as used herein, whether alone or forming part of a larger group, e.g. Ci-3alkoxy, refers to straight or branched, monovalent, saturated aliphatic hydrocarbon chains of 1 to 3 carbon atoms. Examples of Ci-3alkyl are methyl, ethyl, propyl or isopropyl. Examples of Ci-3alkoxy include methoxy, ethoxy and propoxy (which includes n-propoxy and isopropoxy).

[0155] The term “Ci-3alkoxy” also extends to embodiments in which the oxygen atom is located within the alkyl chain, for example CH(CH3)(OCH3). Thus, in one embodiment the alkoxy is linked through carbon to the remainder of the molecule. In another embodiment the alkoxy is linked through oxygen to the remainder of the molecule, for example OCi-3alkyl.

[0156] The term " Co-salkylOH" as used herein refers to straight or branched, monovalent, saturated aliphatic hydrocarbon chains of 0 to 3 carbon atoms bonded to a hydroxyl group. Examples of Co-3alkylOH include OH, CH(CH3)OH and CH2OH.

[0157] The term " Co-salkylCN" as used herein refers to straight or branched, monovalent, saturated aliphatic hydrocarbon chains of 0 to 3 carbon atoms bonded to a cyano group. Examples of C0-3alkylCN include CN and CH2CN. The term " Ci-3alkyldiol" as used herein refers to straight or branched, monovalent, saturated aliphatic hydrocarbon chains of 1 to 3 carbon atoms bonded to two hydroxyl groups. Examples of Ci.3alkyldiol include CH(OH)CH2OH.

[0158] The term " Cs-ecycloalkyl" as used herein refers to monovalent groups of 3 to 6 carbon atoms derived from a saturated monocyclic hydrocarbon. Example Cs-ecycloalkyl groups include cyclopropyl.

[0159] The term “haloalkyl” as used herein, such as in Ci-3haloalkyl, is a straight ora branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro. A suitable example of haloalkyl according to the present invention is CF3.

[0160] The terms “Halo,” “halogen,” and “halide” are used indifferently and represent a chloro, fluoro, bromo, or iodo atom. Suitable examples of halogens according to the present invention include chloro and fluoro.

[0161] The term “heteroaryl” as used herein, such as in Cs- heteroaryl or Cs-eheteroaryl represents aromatic carbocyclic groups containing the specified number of carbon atoms, having at least an aromatic single ring or multiple condensed rings, wherein one or more of the said carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen. Suitable examples of heteroaryl according to the present invention are oxadiazole, pyridone, pyridine, imidazole, pyrazole, triazole and thiazole. Suitable examples of heteroaryl according to the present invention are pyridone, pyridine, imidazole, pyrazole, triazole and thiazole. A particular example is pyridine. Another example is oxadiazole.

[0162] The term “heterocycloalkyl” as used herein, such as in C^wheterocycloalkyl and Cs-ioheterocycloalkyl, is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, wherein at least one of the carbon atoms in the ring is replaced by a heteroatom such as oxygen, sulphur and nitrogen. Examples of heterocycloalkyl according to the present invention are imidazolidine.

[0163] The term “bridged heterocycloalkyl” as used herein, such as in bridged bicyclic Cs-ioheterocycloalkyl, is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, wherein at least one of the carbon atoms in a ring is replaced by a heteroatom such as oxygen, sulphur and nitrogen, and the molecule has a rigid, three-dimensional structure wherein the two rings are connected by a bridge of one or more atoms.

[0164] Some of the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may exist in tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. Examples of tautomers include keto (CH2C=0)<->enol (CH=COH) tautomers or amide (NHC=O)<->hydroxyimine (N=COH) tautomers or 2-hydroxypyridine<->pyridinone. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. It is also to be understood that each individual atom in formula (I) or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.

[0165] Thus, by way of example, each individual hydrogen atom in formula (I) or in the formulae depicted hereinafter may be present as a1H,2H (deuterium) or3H (tritium) atom, preferably1H or2H. Similarly, by way of example, each individual carbon atom in formula (I) or in the formulae depicted hereinafter, may be present as a11C,12C,13C or14C atom, preferably12C. Similarly, by way of example, each individual fluorine atom may be present as18F or19F. Thus, the present invention, also includes within its scope, isotopically-labelled compounds of formula (I).

[0166] Accordingly, the present invention also includes within its scope isotopically-labelled compounds of formula (I). In particular, the present invention includes deuterated forms of the compound of formula (I) and deuterated forms of pharmaceutically acceptable salts and solvates of the compound of formula (I).

[0167] Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.

[0168] Stereoisomers of the compound of formula (I) include cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers of the compound of formula (I), including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).

[0169] The carbon-carbon bonds of the compounds of formula (I) are depicted herein using a solid line ( - '), a solid wedge ( ""■■•;), or a dotted wedge ( "•*'•■)). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of formula (I’) and formula (I) may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.

[0170] It will be appreciated by one skilled in the art, that a racemic mixture may be depicted with wedge and hash bonds, accompanied by the notation (±) and / or the ‘rac-‘ prefix in the name. For compounds with more than one stereocentre, this notation is used to clarify preferred relative stereochemistry preceding a potential chiral separation step. Simiarly or an " OR" label may be used, to indicate that a single configuration is present, but the exact nature of the stereochemical center is unknown.

[0171] In particular, the compounds of the invention form a 3D bicyclic moiety of the following

[0172] structures (wherein indicates the point of attachment to the rest of the molecule):

[0173]

[0174] or Specific embodiments of compounds of formula (I) according to the present invention are described hereafter.

[0175] In one embodiment, Ring A is Cs-wheteroaryl. In another embodiment, Ring A is C4-ioheteroaryl. In one aspect of this embodiment, Ring A is a Csheteroaryl. Illustratively, Ring A represents, triazole and imidazole. In one aspect of this embodiment, Ring A is a Csheteroaryl. Illustratively, Ring A represents pyridine, pyrimidine and pyridazine. Illustratively, Ring A represents pyridine.

[0176] In one embodiment, Ring A is Cs-wheterocycloalkyl. In one aspect of this embodiment, Ring A is Csheterocycloalkyl. Illustratively, Ring A represents imidazolidine.

[0177] In one embodiment, Ring A is a bridged bicyclic Cs-wheterocycloalkyl.

[0178] In one embodiment, Ring A is selected from Csheteroaryl, Csheteroaryl and Csheterocycloalkyl.

[0179] In one embodiment, Ring A is selected from Csheteroaryl or Csheterocycloalkyl.

[0180] In one embodiment, R3is selected from Ciwalkyl, Ciwalkoxy, Ciwhaloalkyl, halogen, oxo (=0), CH2OH, CN and NR3aR3b. In one embodiment, R3is selected from Ciwalkyl, Ciwalkoxy, C1-shaloalkyl, halogen, oxo (=0), CH2OH and CN. In one aspect of this embodiment, R3is selected from Ciwalkyl, Ciwalkoxy, Ciwhaloalkyl, halogen (such as chloro or fluoro), oxo (=0), CH2OH, CN and NR3aR3b. In another aspect of this embodiment, R3is selected from Ciwalkyl, Ciwalkoxy, C1-shaloalkyl, halogen and oxo (=0). In another aspect of this embodiment, R3is selected from CH3, OCH3, CF3, halogen (such as chloro or fluoro) and oxo (=0). In another aspect of this embodiment, R3is selected from CH3, OCH3, CF3, and oxo (=0). In another aspect of this embodiment, R3is selected from CH3, OCH3, CF3, chloro, fluoro and oxo (=0). Illustratively, R3is selected from Cisalkyl (such as CH3), CowalkylOH (such as OH) halogen (such as chloro or fluoro) and oxo (=0). Illustratively, R3is selected from Ciwalkyl (such as CH3), halogen (such as chloro or fluoro) and oxo (=0). Illustratively, R3is selected from CH3, OH, halogen (such as chloro or fluoro) and oxo (=0). II ustratively, R3is oxo (=0).

[0181] In one embodiment, R3aand R3bare independently selected from H or CH3. In another aspect of this embodiment, R3aand R3bare both H. In another aspect of this embodiment, R3ais H and R3bis CH3. In another aspect of this embodiment, R3bis H and R3ais CH3. In one embodiment, n is 0, 1 or 2. In one aspect of this embodiment, n is 0 or 1. In another aspect of this embodiment, n is 0 such that R3is absent. In another aspect of this embodiment, n is 1. In another aspect of this embodiment, n is 2.

[0182] In one embodiment, R3is selected from Ci-3al kyl, Ci-3alkoxy, Ci-shaloalkyl, halogen and oxo (=0) and n is 0 or 1. In another embodiment, R3is selected from Ci-3al kyl (such as CH3), Ci-3alkoxy (such as OCH3), Co-salkylOH (such as OH), Ci-shaloalkyl (such as CF3), halogen (such as chloro and fluoro) and oxo (=0) and n 1 or 2. In one aspect of this embodiment, R3is selected from Cisal kyl (such as CH3), C1-3alkoxy (such as OCH3), Co-salkylOH (such as OH), Ci-shaloalkyl (such as CF3), halogen (such as chloro and fluoro) and oxo (=0) and n 1.

[0183] Illustratively, when Ring A is Ceheteroaryl, e.g. pyridine, n is 0 such that R3is absent.

[0184] Illustratively, when Ring A is Csheterocycloalkyl e.g. imidazolidine / azapyrrolidine, n is 1 and R3is oxo (=0), such that an imidazolidone moiety is formed.

[0185] In one embodiment, Ring A, n and R3form the following moieties, (wherein

[0186] indicates the point of attachment to the rest of the molecule):

[0187]

[0188] In another embodiment, Ring A, n and R3form the following moieties, (wherein

[0189] indicates the point of attachment to the rest of the molecule):

[0190]

[0191] In another embodiment, Ring A, n and R3form the following moieties, (wherein indicates the point of attachment to the rest of the molecule):

[0192]

[0193] In one embodiment, R1is selected from Ci-3al kyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, CN and-NR1aR1bIn one aspect of this embodiment, R1is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen (such as chloro or fluoro). In another aspect of this embodiment, R1is selected from CH3, OCH3, CF3 and halogen (such as chloro or fluoro). In another aspect of this embodiment, R1is selected from CH3, OCH3 and CF3. In another aspect of this embodiment, R1is Ci-3alkyl. Illustratively, R1is CH3.

[0194] In one embodiment, R1aand R1bare independently selected from H or CH3. In one aspect of this embodiment, R1aand R1bare both H. In another aspect of this embodiment, R1ais H and R1bis CH3. In another aspect of this embodiment, R1bis H and R1ais CH3.

[0195] In one embodiment, R2is selected from H, CH3, OCH3, CF3 and halogen (such as chloro or fluoro). In one aspect of this embodiment, R2is selected from H and Ci-3alkyl. In another aspect of this embodiment, R2is selected from H and CH3. Illustratively, R2is H.

[0196] In one embodiment, R1is Ci-3alkyl and R2is H. Ilustratively, R1is CH3and R2is H.

[0197] In one embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol, halogen (such as chloro or fluoro), Ci-salkylOH, CN, Cs-eheteroaryl, NR4aR4band CONR4eR4f. In one aspect of this embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen (such as chloro or fluoro), Ci-salkylOH, CN, Cs-eheteroaryl and NR4aR4b. In another aspect of this embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol, halogen (such as chloro or fluoro), Ci-salkylOH, CN, Cs-eheteroaryl, NR4aR4band CONR4eR4f. In another aspect of this embodiment, R4is selected from Ci-3al kyl, Ci-3alkoxy, halogen (such as chloro or fluoro), C1-salkylOH and Cs-eheteroaryl. In another aspect of this embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-salkylOH and halogen (such as chloro or fluoro). Illustratively, R4is selected from CH3, CH(CH3)(OCH3), CH(CH3)OH, CH(OH)CH2OH, CONH2and CONH(CH3). Illustratively, R4is selected from CH3, CH(CH3)(OCH3), CH(CH3)OH and halogen (such as chloro or fluoro). Illustratively, R4is selected from CH3, CH(CH3)(OCH3) and CH(CH3)OH.

[0198] In another aspect of this embodiment, when R4is Cs-eheteroaryl, the heteroaryl may be optionally substituted by one or two groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen (such as chloro or fluoro). In anotheraspect of this embodiment, when R4is Cs-eheteroaryl, the heteroaryl may be optionally substituted by one or two groups selected from Ci-3alkyl, C1- salkoxy, Ci-3haloalkyl and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R4is Cs-eheteroaryl, the heteroaryl may be optionally substituted by a group selected from CH3, OCH3, CF3, CHF2, OCHF2 and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R4is Cs-eheteroaryl, the heteroaryl may be optionally substituted by Ci-3alkyl (such as CH3). In another aspect of this embodiment, when R4is Csheteroaryl, the heteroaryl may be optionally substituted by a group selected from CH3, OCH3, CF3 and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R4is Csheteroaryl, the heteroaryl may be optionally substituted by a group selected from CH3, OCH3, CF3 and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R4is Csheteroaryl, the heteroaryl may be optionally substituted by Ci-3alkyl (such as CH3). In another aspect of this embodiment, when R4is Csheteroaryl, the heteroaryl may be optionally substituted by Ci-3alkyl (such as CH3).

[0199] In another aspect of this embodiment, R4is selected from

[0200]

[0201] , wherein

[0202] indicates the point of attachment to the rest of the molecule and R* represents Ci-3alkyl (such as CH3), Ci-3alkoxy (such as OCH3), Ci-shaloalkyl (such as CF3) and halogen (such as chloro or fluoro).

[0203] In one embodiment, R4aand R4bare independently selected from H or CH3. In one aspect of this embodiment, R4aand R4bare both H. In another aspect of this embodiment, R4ais H and R4bis CH3. In another aspect of this embodiment, R4bis H and R4ais CH3.

[0204] In one embodiment, R4eand R4fare independently selected from H or CH3. In one aspect of this embodiment, R4eand R4fare both H. In another aspect of this embodiment, R4eis H and R4fis CH3. In another aspect of this embodiment, R4fis H and R4eis CH3.

[0205] In one embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-salkylOH, halogen (such as chloro or fluoro) and CONR4eR4f; and p is 1.

[0206] In one embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, halogen (such as chloro or fluoro) and CONR4eR4f; and p is 1.

[0207] In one embodiment, R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-salkylOH and halogen (such as chloro or fluoro); and p is selected from 0 or 1. Illustratively, p is 0, such that R4is absent.

[0208] In one embodiment, Z is NH. In another embodiment, Z is CR5. In another embodiment, Z is CR5R5c.

[0209] In one embodiment, R5is selected from H, Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen (such as chloro or fluoro), Ci-salkylOH, CN, Cs-sheteroaryl and NR5aR5b. In one aspect of this embodiment, R5is selected from H, Ci-3alkyl, Ci-shaloalkyl, Co-salkylCN, Cs-scycloalkyl and halogen. In one aspect of this embodiment, R5is selected from H, Ci-3alkyl, Ci-3alkoxy, halogen (such as chloro or fluoro), Ci-salkylOH and Cs-sheteroaryl. In one aspect of this embodiment, R5is selected from H, Ci-3alkyl (such as CH3), Ci-shaloalkyl (such as CF3), Co-salkylCN (CN), C3-ecycloalkyl and halogen (such as chloro or fluoro). In one aspect of this embodiment, R5is selected from H, Ci-3alkyl, Ci-3alkoxy, Ci-salkylOH and halogen (such as chloro or fluoro). In one aspect of this embodiment, R5is selected from H or Ci-3alkyl. Illustratively, R5is selected from H or CH3. Illustratively, R5is selected from H, CF3 and CH3.

[0210] In another aspect of this embodiment, when R5is Cs-eheteroaryl, the heteroaryl may be optionally substituted by one or two groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen (such as chloro or fluoro). In anotheraspect of this embodiment, when R5is Cs-eheteroaryl, the heteroaryl may be optionally substituted by one or two groups selected from Ci-3alkyl, Cisalkoxy, Ci-shaloalkyl and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R5is Cs-eheteroaryl, the heteroaryl may be optionally substituted by a group selected from CH3, OCH3, CF3, CHF2, OCHF2 and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R5is Cs-eheteroaryl, the heteroaryl may be optionally substituted by Ci-3alkyl (such as CH3). In another aspect of this embodiment, when R5is Cs-eheteroaryl, the heteroaryl may be optionally substituted by a group selected from CH3, OCH3, CF3 and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R5is Csheteroaryl, the heteroaryl may be optionally substituted by a group selected from CH3, OCH3, CF3 and halogen (such as chloro or fluoro). In another aspect of this embodiment, when R5is Csheteroaryl, the heteroaryl may be optionally substituted by Ci-3alkyl (such as CH3). Illustratively, R5is oxadiazole, optionally substituted by Ci-3alkyl (such as CH3).

[0211] In one embodiment, R5aand R5bare independently selected from H or CH3. In one aspect of this embodiment, R5aand R5bare both H. In anotheraspect of this embodiment, R5ais H and R5bis CH3. In another aspect of this embodiment, R5bis H and R5ais CH3.

[0212] In one embodiment, R5cis halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl.

[0213] In one embodiment, Z is CR5and R5is selected from H, Ci-3alkyl (such as CH3) and Ci-shaloalkyl (such as CF3). In one aspect of this embodiment, Z is CR5and R5is selected from H or Ci-salkyl. In one aspect of this embodiment, Z is CR5and R5is selected from H, CH3 and CF3. In one aspect of this embodiment, Z is CR5and R5is selected from H or CH3.

[0214] In one embodiment, m is selected from 0 or 1. In one aspect of this embodiment, m is 0. In another aspect of this embodiment, m is 1. In another embodiment, m is selected from 1 or 2. In another aspect of this embodiment, m is 2.

[0215] In one embodiment, p is selected from 0 or 1. In one aspect of this embodiment, p is 0 such that R4is absent. In another aspect of this embodiment, p is 1.

[0216] In one embodiment, q is 1. In another embodiment, q is 2.

[0217] In one embodiment, q is selected from 1 or 2 and m is selected from 1 or 2.

[0218] In a further aspect, the present invention provides a compound of formula (II)

[0219]

[0220] or a pharmaceutically acceptable salt or solvate thereof;

[0221] wherein:

[0222] Ring A is a Ceheteroaryl or Csheterocycloalkyl; and

[0223] R3, R4, Z, n, m, p and q are as defined in any one of the aspects or embodiments above.

[0224] In a further aspect, the present invention provides a compound of formula (III)

[0225]

[0226] or a pharmaceutically acceptable salt or solvate thereof;

[0227] wherein:

[0228] Ring A, R3, R4, n, q and m are as defined in any one of the aspects or embodiments above.

[0229] In a further aspect, the present invention provides a compound of formula (IV)

[0230]

[0231] or a pharmaceutically acceptable salt or solvate thereof;

[0232] wherein: Ring A is a Ceheteroaryl or Csheterocycloalkyl;

[0233] Z is CR5; wherein R5is H or Ci-3alkyl (such as methyl); and

[0234] R3, R4, q, n and m are as defined in any one of the aspects or embodiments above.

[0235] In a further aspect, the present invention provides a compound of formula (V)

[0236]

[0237] or a pharmaceutically acceptable salt or solvate thereof;

[0238] wherein:

[0239] Ring A, n and R3form the following moieties, wherein indicates the point of attachment to the rest of the molecule and n and R3are as defined in any one of the aspects or embodiments above:

[0240]

[0241] Z, R4, q and m are as defined in any one of the aspects or embodiments above.

[0242] In a further aspect, the present invention provides a compound of formula (VI)

[0243]

[0244] (VI)

[0245] or a pharmaceutically acceptable salt or solvate thereof;

[0246] wherein:

[0247] Ring A is a Ceheteroaryl or Csheterocycloalkyl; and R3, n, Z and q are as defined in any one of the aspects or embodiments above.

[0248] It will be appreciated that compounds of formulae (II), (III), (IV), (V) and (VI), are all subformulae of the compound of formula (I). Any reference to a compound of formula (I) contained herein, will therefore include compounds of formulae (II), (III), (IV), (V) and (VI).

[0249] The compound of formula (I) may be referred to herein as “the compound of the invention” or “the compound according to the invention”.

[0250] The invention provides a pharmaceutically acceptable salt or solvate of a compound of formula (I). The invention further provides a pharmaceutically acceptable salt of a compound of formula (I). The invention further provides a pharmaceutically acceptable solvate of a compound of formula (I). The invention further provides a compound of formula (I) as the free base.

[0251] The compound of formula (I), and pharmaceutically acceptable salts or solvates thereof, may be referred to herein as “compound(s) of the invention”.

[0252] Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, their individual stereoisomers, and pharmaceutical acceptable salts and solvates thereof.

[0253] In a particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of:

[0254] 1 -[6-methyl-3-[(1 S,5R)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]benzofuran-5- yl]imidazolidin-2-one;

[0255] 1-[3-[(1R,3S,5S)-1-[(1S or 1R)-1-hydroxyethyl]-3-methyl-6-azabicyclo[3.1,1]heptane-6- carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0256] 1 -[3-[(1 R,3S,5S)-1 -[(1 S or 1 R)-1 -methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6- carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0257] 1 -[3-[(1 R,3S,5S)-1 -[(1 R or 1 S)-1 -methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6- carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0258] 1-[3-(7-azabicyclo[4.1.1]octane-7-carbonyl)-6-methyl-benzofuran-5-yl]imidazolidin-2-one; 7-azabicyclo[2.2.1]heptan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone; and 7-azabicyclo[4.1.1]octan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone.

[0259] In another particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of:

[0260] 1 -[6-methyl-3-[(1 S,5R)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]benzofuran-5-yl]imidazolidin-2-one;

[0261] 1-[3-[(1R,3S,5S)-1-[(1S or 1R)-1-hydroxyethyl]-3-methyl-6-azabicyclo[3.1,1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0262] 1 -[3-[(1 R,3S,5S)-1 -[(1 S or 1 R)-1 -methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one; 1-[3-[(1R,3S,5S)-1-[(1R or 1S)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0263] 1-[3-(7-azabicyclo[4.1.1]octane-7-carbonyl)-6-methyl-benzofuran-5-yl]imidazolidin-2-one; 7-azabicyclo[2.2.1]heptan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone;

[0264] 7-azabicyclo[4.1.1]octan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone;

[0265] (1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-[6-methyl-5-(1-methyl-1,2,4-triazol-3-yl)-1-benzofuran-3-yl]methanone;

[0266] 5-methyl-3-[6-methyl-3-[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridin-2-one;

[0267] [(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-[6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-yl]methanone;

[0268] 5-methyl-3-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]-1H-pyridin-2-one;

[0269] [5-(5-fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-yl]-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methanone;

[0270] 1-[3-[(1S,3S,5R)-1-[1-hydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0271] 5-[6-methyl-3-[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one;

[0272] 5-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one;

[0273] 3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0274] 4-methyl-3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0275] 4-methyl-3-(6-methyl-3-((1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0276] 5-fluoro-3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0277] 1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;

[0278] 1-[3-[(1S,3S,5R)-1-[(1S or 1R)-1,2-dihydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0279] 1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;

[0280] 1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one; (1 / ?,3S,5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1 ]heptane-1 -carboxamide; and

[0281] (1F?,3S,5S)-A / ,3-dimethyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1 ]heptane-1 -carboxamide.

[0282] In another particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of:

[0283] 1 -[6-methyl-3-[(1 S,5F?)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]benzofuran-5-yl]imidazolidin-2-one;

[0284] 1-[3-[(1F?,3S,5S)-1-[(1S or 1F?)-1-hydroxyethyl]-3-methyl-6-azabicyclo[3.1,1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0285] 1 -[3-[(1R,3S,5S)-1-[(1S or 1R)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0286] 1-[3-[(1R,3S,5S)-1-[(1R or 1S)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0287] 1-[3-(7-azabicyclo[4.1.1]octane-7-carbonyl)-6-methyl-benzofuran-5-yl]imidazolidin-2-one; 7-azabicyclo[2.2.1]heptan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone;

[0288] 7-azabicyclo[4.1.1]octan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone;

[0289] (1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-[6-methyl-5-(1-methyl-1,2,4-triazol-3-yl)-1-benzofuran-3-yl]methanone;

[0290] 5-methyl-3-[6-methyl-3-[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridin-2-one;

[0291] [(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-[6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-yl]methanone;

[0292] 5-methyl-3-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]-1H-pyridin-2-one;

[0293] [5-(5-fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-yl]-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methanone;

[0294] 1-[3-[(1S,3S,5R)-1-[1-hydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0295] 5-[6-methyl-3-[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one;

[0296] 5-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one;

[0297] 3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0298] 4-methyl-3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one; 4-methyl-3-(6-methyl-3-((1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0299] 5-fluoro-3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;

[0300] 1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;

[0301] 1-[3-[(1S,3S,5R)-1-[(1S or 1R)-1,2-dihydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;

[0302] 1-(6-methyl-3-((1 / ?,3S,5S)-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;

[0303] 1-(6-methyl-3-((1 / ?,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1 ]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;

[0304] (1 / ?,3S,5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1 ]heptane-1 -carboxamide;

[0305] (1 / ?,3S,5S)-A / ,3-dimethyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1 ]heptane-1 -carboxamide;

[0306] [(1S,5 / ?)-3-Methyl-8-azabicyclo[3.2.1]octan-8-yl]-(6-methyl-5-pyridazin-3-yl-1-benzofuran-3-yl)methanone;

[0307] 4-[6-Methyl-3-[(1S,5 / ?)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-1-benzofuran-5-yl]-1H-pyridazin-6-one;

[0308] [(1S,5F?)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-[6-methyl-5-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-benzofuran-3-yl]methanone;

[0309] [5-(3-hydroxyazetidin-1-yl)-6-methyl-1-benzofuran-3-yl]-[(1S,5 / ?)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl] methanone;

[0310] 4-(6-Methyl-3-((1 / ?,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1,1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;

[0311] 6-Fluoro-4-(6-methyl-3-((1F?,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1,1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;

[0312] 4-(6-Methyl-3-((1F?,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1,1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;

[0313] 6-Fluoro-4-(6-methyl-3-((1F?,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1,1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;

[0314] 3-Fluoro-5-[6-methyl-3-[(1S,5F?)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]- 1 H-pyridazin-6-one;

[0315] 3-Fluoro-5-[6-methyl-3-[(1 S,5F?)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]benzofuran-5-yl]-1 H-pyridazin-6-one; and

[0316] 3-Fluoro-5-[6-methyl-3-[(1F?,3S,5S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one. THERAPEUTIC INDICATIONS

[0317] The present invention also provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

[0318] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of diseases and / or disorders in which SARM1 plays a role.

[0319] In the following aspects, the compound of formula (I) as defined above is an inhibitor of SARM1. Compounds of the invention can inhibit the activity of SARM1. For example, the compounds of the invention can be used to inhibit activity or a function of SARM1 in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound according to the invention to the cell, individual, or patient.

[0320] As used herein, the term "in a cell" includes both inside the cell membrane and on the surface of the cell membrane.

[0321] Compounds of the invention, as SARM1 inhibitors, can increase levels of NAD+ in a cell. Accordingly, the present invention is further directed to a method of increasing the level of NAD+ in a sample or in a patient, comprising contacting the sample or administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the increased level of NAD+ is relative to the level of NAD+ prior to the contacting or administering.

[0322] Compounds of the invention are also useful to inhibit axonal degeneration. Accordingly, the present invention is notably directed to a method of inhibiting axonal degeneration in a sample or in a patient, comprising contacting the sample or administering to the patient an inhibiting amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0323] The compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of SARM1. The compounds of the invention are notably useful in the treatment and prevention of neurological disorders. The term "neurological disorder" generally refers to a disorder affecting the nervous system, including the central nervous system or the peripheral nervous system. The term "neurological disorder" also includes ocular indications having a nexus to the nervous system.

[0324] The neurological disorder treatable or preventable by administration of a compound of the invention includes neurodegenerative diseases. Neurodegenerative diseases are characterized by damage to the central nervous system and can be identified by progressive dysfunction, degeneration, and death of specific populations of neurons which are often synaptically interconnected. Neurodegenerative diseases notably include motor neuron diseases.

[0325] Examples of neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD).

[0326] Neurological disorders include various peripheral nervous system (PNS) disease, such as diabetic neuropathy, motor neuron disease, such as amyotrophic lateral sclerosis. It does also include diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN), chemotherapy induced cognitive impairment.

[0327] Neurological disorders include traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury. According to another embodiment, neurological disorders include ocular conditions, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration.

[0328] Neurological disorders also include autoimmune and inflammatory diseases.

[0329] In a first embodiment, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of a disease and / or disorder in which SARM1 plays a role.

[0330] In an aspect of this embodiment, the present invention therefore provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of axonal degeneration; neurological disorders, such as autoimmune and inflammatory diseases; ocular conditions such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD); or traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury.

[0331] In another aspect of this embodiment, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of various peripheral nervous system (PNS) diseases, such as diabetic neuropathy; or motor neuron disease, such as amyotrophic lateral sclerosis.

[0332] In another aspect of this embodiment, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and / or prevention of diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN), or chemotherapy induced cognitive impairment.

[0333] In a second embodiment, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of diseases and / or disorders in which SARM1 plays a role.

[0334] In an aspect of this embodiment, the present invention therefore provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and / or prevention of axonal degeneration; neurological disorders, such as autoimmune and inflammatory diseases; ocular conditions, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD); or traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury. In another aspect of this embodiment, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treatment and / or prevention of various peripheral nervous system (PNS) disease, such as diabetic neuropathy, or motor neuron disease, such as amyotrophic lateral sclerosis.

[0335] In another aspect of this embodiment, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and / or prevention of diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN), or chemotherapy induced cognitive impairment.

[0336] In a third embodiment, the present invention provides a method for the treatment and / or prevention of disorders for which the administration of inhibitors of SARM1 is indicated, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

[0337] In an aspect of this embodiment, the present invention provides a method for the treatment and / or prevention of one or more selected from axonal degeneration; neurological disorders, such as autoimmune and inflammatory diseases; ocular conditions, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD); and traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

[0338] In another aspect of this embodiment, the present invention provides a method for the treatment / and or prevention of various peripheral nervous system (PNS) disease, such as diabetic neuropathy, and motor neuron disease, such as amyotrophic lateral sclerosis, which comprises administering to a patient in need of such treatment of an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

[0339] In another aspect of this embodiment, the present invention provides a method for the treatment and / or prevention of diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN), and chemotherapy induced cognitive impairment, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

[0340] As used herein, the term “patient” refers to a mammal that is afflicted with one or more disorders associated with function or expression of SARM1. It will be understood that the most preferred patient is a human.

[0341] It is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders, or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. Thus, the terms “treatment” and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, and is intended to include prophylactic treatment of such disorders, but does not necessarily indicate a total elimination of all disorder symptoms.

[0342] Activity in any of the above-mentioned therapeutic indications or disorders can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and / or in the design of clinical trials in general.

[0343] For use in medicine, the salts of the compounds of formula (I) (which includes compounds of the formulae (II), (III) (IV), (VI) and (VII)) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0344] Typically, the phrase "pharmaceutically acceptable" is used to refer to those compounds, materials, compositions, dosage forms and the like which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, for example human beings, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0345] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents or water.

[0346] The present invention also includes within its scope co-crystals of the compounds of formula (I) above. The technical term “co-crystal” is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0347] Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

[0348] The invention also includes within its scope pro-drug forms of the compounds of formula (I) and its various sub-scopes and sub-groups. PHARMACEUTICAL COMPOSITIONS

[0349] For treating diseases, compounds of formula (I) or their pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.

[0350] Therefore, another embodiment of the present invention concerns a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0351] To prepare a pharmaceutical composition according to the invention, one or more of the compounds of formula (I) or a pharmaceutically acceptable salt thereof is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.

[0352] Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral, intranasal, or intratumoral.

[0353] Pharmaceutical compositions comprising compounds according to the invention can, for example, be administered orally, parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation, intranasally or by ophthalmic administration.

[0354] Pharmaceutical compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing-gums and the like.

[0355] To this end the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.

[0356] The invention also contemplates compositions which can release the active substance in a controlled manner. Pharmaceutical compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.

[0357] In addition to the active ingredient, these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.

[0358] These pharmaceutical forms are prepared using methods which are routinely used by pharmacists. The amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient’s sex, age, weight and medical condition, as well as on the method of administration. Thus, the quantity of compound of formula (I) in compositions for oral administration is at least 0.5 % by weight and can be up to 80 % by weight with respect to the total weight of the composition.

[0359] In accordance with the invention, it has also been found that the compounds of formula (I) or the pharmaceutically acceptable salts thereof can be administered alone or in combination with other pharmaceutically active ingredients.

[0360] In particular, compounds of formula (I) according to the present invention could be combined with other active ingredients that increase intracellular reactive oxygen species, regulate amino acid metabolism or with immunotherapeutic agents.

[0361] In compositions for parenteral administration, the quantity of compound of formula (I) present is at least 0.5 % by weight and can be up to 33 % by weight with respect to the total weight of the composition. For the preferred parenteral compositions, the dosage unit is in the range 0.5 mg to 3000 mg of compounds of formula (I).

[0362] The daily dose can fall within a wide range of dosage units of compound of formula (I) and is generally in the range 0.5 to 3000 mg. However, it should be understood that the specific doses can be adapted to particular cases depending on the individual requirements, at the physician’s discretion.

[0363] SYNTHETIC SCHEMES

[0364] It will be apparent to the person skilled in the art that there are various synthetic pathways that can lead to the compounds according to the invention. The following processes are aimed at illustrating some of these synthetic pathways but should not be construed in any way as a limitation on how the compounds according to the invention should be made.

[0365] During any of the below synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

[0366] The compounds Formula (I) according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.

[0367] All starting materials, unless otherwise stated, are commercially available or may be prepared by methods known to one skilled in the art.

[0368] The following description of synthetic schemes provides for means of preparing compounds of formula (I). Scheme 1 This scheme is suitable for compounds where the point of attachment in Ring A is via a nitrogen atom, such that a N-C bond is formed to the benzofuran core.

[0369]

[0370] Compound (1) may be prepared by the reaction of e.g. 4-bromo-3-methylphenol and paraformaldehyde in the presence of a suitable base, such as TEA, in a suitable solvent, such as acetonitrile, at elevated temperatures. Compound (1) is then reacted with ethyl 2-diazoacetate at a suitable temperature, e.g. room temperature, in a suitable solvent, such as DCM, in the presence of a suitable catalyst e.g. HBF4.OEt2. The resultant compound, compound (2), is then coupled with the appropriate “Ring A” moiety, compound (3) e.g. 2-imidazolidone, via a suitable C-N coupling reaction, such as Buchwald coupling. One skilled in the art would recognise that this C-N bond could also be made via alternative means such as Chan-Lam coupling between the appropriate coupling partners. The reaction proceeds using a suitable palladium catalyst e.g. Ephos Pd G4 at elevated temperatures, to yield compound (4). Hydrolysis of compound (4) using e.g. lithium hydroxide, in a suitable solvent such as THF and elevated temperatures, yields compound (5). Compound (5) is then coupled with the appropriate amine, compound (6) e.g. 7-azabicyclo[4.1,1]octane, using an appropriate solvent, e.g. DMF, at a suitable temperature and using a suitable base, e.g. DIPEA, and a suitable coupling agent such as HATU. It will be appreciated by one skilled in art, that compounds of formula (I) may also be made by performing the Buchwald coupling and hydrolysis / amide steps in a different order.

[0371] Compounds of formula (I) may also be prepared via the following alternative Scheme.

[0372] Scheme 2: This scheme is suitable for compounds where the point of attachment in Ring A, is via a carbon atom, such that a C-C bond is formed to the benzofuran core.

[0373]

[0374] Compound (1) may be prepared by the reaction of a suitable starting material e.g. 4-bromo-3-methylphenol and paraformaldehyde in the presence of a suitable base, such as TEA, in a suitable solvent, such as acetonitrile, at elevated temperatures. Compound (1) is then reacted with ethyl 2-diazoacetate at a suitable temperature, e.g. room temperature, in a suitable solvent, such as DCM, in the presence of a suitable catalyst e.g. HBF4. OEt2. The resultant compound, compound (2), can then be coupled with the appropriate “Ring A” moiety, compound (3’) e.g. tributyl(2-pyridyl)stannane, via a Stille coupling. Alternatively, compounds (2) and (3) may be coupled using a Suzuki coupling. The reaction proceeds using a suitable palladium catalyst e.g. PdCl2(PPh3)2 at elevated temperatures, under an inert atmosphere to yield compound (4’). Alternative C-C coupling reactions via, for example, a Suzuki-Miyaura reaction between the appropriate reagents would be alternatives, as known to one skilled in the art. Hydrolysis of compound (4’) using e.g. lithium hydroxide and a suitable solvent, such as THF / H2O, and elevated temperatures, yields compound (5’). Compound (5’) is then coupled with the appropriate amine compound (6’), e.g. 7-azabicyclo[4.1,1]octane, using an appropriate solvent, e.g. DMF, at a suitable temperature and using a suitable base, e.g. DIPEA, and a suitable coupling agent such as HATU. It will also be appreciated by one skilled in the art that the cross-coupling and amide coupling steps may be performed in the reverse order.

[0375] Scheme 3 Preparation of (cis)-3-methyl-6-azabicyclo[3.1.1] heptane hydrochloride (10), an example azabicyclic moiety (6) and (6’). Deprotection /

[0376] HCI salt Amidation Cyclization formation

[0377]

[0378]

[0379] (8)

[0380]

[0381] The azabicyclic moiety (cis)-3-methyl-6-azabicyclo[3.1.1] heptane hydrochloride may be prepared by reacting compound (7) with picolinic acid in the presence of a base such as DIPEA, a coupling agent such as HATU, in a suitable solvent such as DCM. The resultant compound, compound (8) undergoes cyclisation via a C-H functionalisation reaction with a suitable set of conditions, such as using silver acetate, 1,4-benzoquinone, trisodium phosphate and iodopentafluorobenzene in the presence of a suitable catalyst e.g. Pd(OAc)2. The reaction proceeds in a suitable solvent, such as 1,1,2,2-tetrachloroethane, at elevated temperatures. The resultant compound, compound (9), is then deprotected, for example via reaction with sodium hydroxide in a suitable solvent, such as ethanol and DCM, at elevated temperatures, to yield compound (10).

[0382] Scheme 4 Preparation of (1 F?,3S,5S)-1 -(1 -methoxyethyl)-3-methyl-6-azabicyclo[3.1.1 ]heptane (11) and 1-[(1F?,3S,5S)-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl]ethanol (12), example azabicyclic moiety’s (6) and (6’).

[0383]

[0384] (24) (23) (11) (12) 3-Methylcyclohexan-1-one, compound (13), is cyclised by reacting with a suitable set of conditions, such as potassium cyanide and ammonium carbonate in a suitable solvent such as ethanol and water, with heating, while under a nitrogen atmosphere via a Bucherer-Bergs reaction.

[0385] The resultant compound, compound (14), undergoes hydrolysis using a suitable base such as KOH, while in a suitable solvent such as ethanol and water. The reaction proceeds under a high temperature, suitably 140 °C, and under nitrogen to produce compound (15). Compound (15) is then esterified by the reaction with thionyl chloride in a suitable solvent such as methanol, under nitrogen at an elevated temperature. The resultant compound, compound (16), undergoes amidation by reaction with e.g. pyridine-2-carboxylic acid in the presence of a suitable coupling agent e.g. HATU and a base such as TEA, in a suitable solvent such as DMF to yield compound (17). Compound (17) then undergoes cyclisation via a C-H functionalisation reaction with a suitable set of conditions, such as using silver acetate, 1,4-benzoquinone, trisodium phosphate and iodopentafluorobenzene in the presence of a suitable catalyst e.g. Pd(OAc)2 at a suitable temperature, such as 150 °C, to yield compounds (18) and (19). After chiral seperation, compound (19) is then saponified using a base such as sodium hydroxide in a suitable solvent e.g. methanol. The resultant compound (20) is then amidated by reaction with e.g. A / , O-dimethylhydroxylamine in the presence of a base such as DIPEA in a suitable solvent e.g. DMF. The resultant compound, compound (21), then undergoes addition and reduction reactions to produce compound (23). The addition reaction proceeds in the presence of e.g. methyllithium at a suitable temperature, e.g. -78 °C, in a suitable solvent such as THF. The reduction reaction proceeds in the presence of a reducing reagent, e.g. NaBH4, in a suitable solvent, e.g. methanol, at reduced temperatures. Compound (23) is then methylated via reaction with iodomethane in the presence of a base such as sodium hydride, in a suitable solvent such as DMF. The resultant mixture, containingcompounds (23) and (24) undergoes deprotection, via reaction with e.g. methylmagnesium bromide, in a suitable solvent, such as THF, at reduced temperatures to yield the final compounds (11) and (12).

[0386] Scheme 5: Preparation of Compound (33) an example azabicyclic moiety (6) and (6’).

[0387] Hydrolysis Esterification Protection

[0388] (27)

[0389]

[0390] HO-N VNH2 (31) R** Hydrolysis Coupling Deprotection then cyclisation

[0391] (33)

[0392]

[0393] (30) The starting material (26), where R* is, for example, a methyl group, may be prepared via methods analogous to e.g. scheme 1 above. Compound (26) is then hydrolysed, for example with a suitable hydroxide such as NaOH in a suitable solvent such as EtOH at a suitable temperature such as 90 °C. Esterification is then performed on the resultant compound (27), for example by treating with SOCl₂ in a suitable solvent such as MeOH at a suitable temperature such as 0 °C to room temperature to yield compound (28). This is followed by protection of the amine nitrogen with a suitable protecting group such as Boc using suitable conditions such as Boc₂O with a suitable base like Et₃N and a suitable catalyst such as DMAP to yield compound (29). The protection proceeds in a suitable solvent such as DCM and MeOH at a suitable temperature such as room temperature. The ester (29) is then hydrolysed, for example with a suitable hydroxide such as NaOH in a suitable solvent such as MeOH at a suitable temperature such as room temperature to yield compound (30). A 1,2,4-oxadiazole is formed via coupling with a suitable reagent such as N-hydroxyacetimidamide, wherein R** is e.g. methyl (31) under suitable conditions, such as HATU and a base such as DIPEA in a suitable solvent like DMF at a suitable temperature such as room temperature. Cyclisation may be effected by heating to a suitable temperature such as 100 °C. Deprotection to provide the azabicyclic moiety product can be performed using techniques known to those skilled in the art. In the case where the PG is Boc, then, amongst other possible methods, deprotection may occur by treatment with TMSOTf in DCM at 0 °C to room temperature.

[0394] Scheme 6: Preparation of Compound (37) an example azabicyclic moiety.

[0395]

[0396] The starting material (30) may be prepared via methods known to one skilled in the art or via scheme 5 above. Compound (30) is then reacted with a suitable amine source such as NH4CI and a suitable chemical reagent e.g. HATU in the presence of a suitable base such as DIPEA. The reaction proceeds in a suitable polar solvent such as DMF at a suitable temperature e.g. room temperature to yield the amide (34). Compound (34) is then converted to the nitrile via reaction with a suitable base, such as triethylamine, in the presence of a suitable reagent e.g. trifluoroacetic anhydride. The reaction proceeds in a suitable solvent such as THF and at a suitable temperature e.g. 0°C raising to room temperature. The nitrile compound (35) is then converted to compound (36) via reaction with a suitable base, such as sodium methoxide in a suitable solvent e.g. methanol at a suitable temperature e.g. 0°C. Compound (36) is then converted to compound (37). In this case, a two-step reaction was used to form the triazine, initially heating with hydrazine hydrate at an elevated temperature eg 80 °C, followed by cyclisation with oxalaldehyde.

[0397] Scheme 7: Preparation of azabicyclic moiety e.g. (39)

[0398]

[0399] The starting material (compound (30)) may be made by methods outlined in scheme 5 above. This compound is then converted to the amide (compound (38)) via reaction with a suitable hydrazide e.g. acetohydrazide in the presence of a suitable base e.g. DIPEA and a suitable coupling agent such as HATU. The reaction proceeds in a suitable solvent such as DMF at a suitable temperature such as room temperature. The resultant amide (compound (38)) is cyclised to form compound (39) via reaction with a suitable inorganic base such as caesium carbonate and a suitable reagent e.g. p-toluenesulfonyl chloride. The reaction proceeds in the presence of a suitable solvent such as acetonitrile, and at a suitable temperature e.g. room temperature.

[0400] Scheme 8: Preparation of azabicyclic moiety e.g. (41))

[0401] 1. S-BuLi

[0402] 2. Electrophile

[0403]

[0404] A suitable starting material (compound (40), wherein q is 2), is reacted with a suitable base such as sec-butyllithium with a suitable amine ligand e.g. TMEDA. This is then followed by reaction with a suitable electrophile e.g. acetaldehyde to yield compound (41), wherein R*** is e.g. methyl. Both parts of the reaction proceed in a suitable solvent such as diethyl ether at a suitable temperature e.g. -78°C. It will be appreciated by one skilled in the art that a chiral ligand may be employed in applicable reactions to maintain enantiomeric control. Similarly, chiral separation may be performed at various stages of the reaction to separate the desired and / or undesired isomers.

[0405] Where a mixture of products is obtained from any of the processes described above for the preparation of a compound according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and / or alumina in conjunction with an appropriate solvent system.

[0406] Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. Alternatively, the non desired enantiomer may be racemized into the desired enantiomer, in the presence of an acid or a base, according to methods known to the person skilled in the art, or according to methods described in the accompanying Examples.

[0407] The inhibition of SARM1 cellular activity by compounds of formula (I) can be tested with human immortalized cells (HEK293T) overexpressing human SARM1 in a CZ-48 assay as disclosed herein.

[0408] The efficacy of the compounds, according to the Examples, to inhibit SARM1 is represented by measuring the EC50 which corresponds to the concentration of compound necessary to rescue 50% of cellular ATP levels after full (>80%) cellular SARM1 activation. This concentration is postulated to reflect 50% of SARM1 inhibition in a cellular context. pICso values correspond to -log of the IC50 in Molar.

[0409] When tested, Example compounds 1 to 36 of formula (I) according to the present invention, display values of pICso greater than or equal to 6.0, suitably greater than or equal to 6.5, preferably greater than 7.0. When tested compounds according to Examples, display values of pICso greater than or equal to about 6.0.

[0410] In the CZ-48 Assays described herein, the lower the value of the IC50 (the higher the value of the pICso is), the less compound is needed to perform the same amount of inhibition and therefore the higher is the inhibition potency. This assay gives an indication of activity in a cellular context and therefore is a better predictor of the activity of a compound in vivo.

[0411] The following Examples illustrate the preparation of compounds according to the invention.

[0412] EXPERIMENTAL SECTION

[0413] I. Abbreviations / recurrent reagents

[0414] Where an abbreviation is not listed, the term should take its general meaning, as understood by one skilled in the art.

[0415] ACN / MeCN Acetonitrile

[0416] BQ 1,4-benzoquinone

[0417] CDCl₃ Chloroform-d₃

[0418] CD3OD Methanol-d4

[0419] C6F5I lodopentafluorobenzene

[0420] DCC N, N'-Dicyclohexylcarbodiimide

[0421] DCM Dichloromethane

[0422] DIPEA N, N-Diisopropylethylamine

[0423] DMAP 4-Dimethylaminopyridine

[0424] DMSO Dimethyl sulfoxide

[0425] e.e. Enantiomeric excess

[0426] Ephos Pd G4 [Dicyclohexyl[3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)[1, 1

[0427] biphenyl]-2-yl]phosphine-KP](methanesulfonato-KO)[2'- (methylamino-KN)[1, 1 '-biphenyl]-2-yl-KC]palladium

[0428] ESI Electrospray ionisation

[0429] g Gram

[0430] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0431] h Hour(s)

[0432] HBF4.OEt2Tetrafluoroboric acid diethyl ether complex

[0433] HPLC High performance liquid chromatography

[0434] IR Infra-red KOAc Potassium acetate

[0435] K3PO4 Potassium phosphate (tribasic)

[0436] LCMS Liquid chromatography–mass spectrometry

[0437] M Molar

[0438] mg Milligram

[0439] MHz Megahertz

[0440] min(s) Minute(s)

[0441] mL / ml Millilitre

[0442] mM Millimolar

[0443] mmol Millimole

[0444] M Mass spectrometry

[0445] N Normality

[0446] Na3PO4 Trisodium phosphate

[0447] NEt3 / TEA Triethylamine

[0448] NMR Nuclear magnetic resonance

[0449] PE Petroleum ether

[0450] pH Potential of hydrogen; a measure of the acidity or basicity of an aqueous solution

[0451] Pd(amphos)Cl2 Bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(ll) Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0),

[0452] PdCl2(dppf) [1,1'-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride Pd(PPh3)2CI2Bis(triphenylphosphine)palladium(ll) dichloride

[0453] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0454] PyAOP ((7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate)

[0455] Rac Racemic

[0456] r.t. Room temperature

[0457] RT Retention time

[0458] RuPhos Pd G4 [Dicyclohexyl(2',6'-diisopropoxy-2-biphenylyl)phosphine- KP](methanesulfonatato-KO)[2'-(methylamino-KN)-2-biphenylyl- KC2]palladium

[0459] Sat. aq. Saturated aqueous

[0460] SFC Supercritical fluid chromatography

[0461] Soln. Solution

[0462] TATU 0-(7-Azabenzotriazole-1-yl)-N, N, N’, N’-tetramethyluronium tetrafluoroborate

[0463] TFA Trifluoroacetic acid TCE 1,1,2,2-tetrachloroethane

[0464] TMSCI Trimethylsilyl chloride

[0465] TMSOTf Trimethylsilyl trifluoromethanesulfonate

[0466] UV Ultraviolet

[0467] VCD Vibrational circular dichroism

[0468] XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'- amino-1,1'-biphenyl)]palladium(ll) methanesulfonate

[0469] Xphos 2-Dicyclohexylphosphino-2', 4', 6'-triisopropyl biphenyl

[0470] Naming convention:

[0471] IUPAC names of chemical reagents, Intermediates and Examples have been generated using any of the following naming systems: (Biovia Draw 2024) version 24.1 (24.1.0.1865); Pipeline Pilot (version 23.1); or ChemDraw Professional (version 21.0.0.28) alongside the appropriate Add-in’s e.g., Excel (Version 2408) and ChemDraw for Excel 21. Depending on the Kekule structures of chemical reagents, Intermediates and Examples, these naming systems may generate different chemical names.

[0472] The name provided by some naming systems e.g. Biovia Draw does not necessarily provide all stereochemical information for meso compounds. In order to clarify stereochemistry in these cases, the nomenclature may be used where ‘cis’ / ’trans’ is used to define the relationship between the carbon bridge CH2 and the substituent on the 6-membered ring. In particular, the example below shows the nomenclature that may be used for3-methyl-6-azabicyclo[3.1.1]heptane.

[0473]

[0474] (cis) (trans)

[0475] (1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane (1?,5S)-3-methyl-6-azabicyclo[3.1.1]heptane (cis)-3-methyl-6-azabicyclo[3.1.1]heptane (trans)-3-methyl-6-azabicyclo[3.1.1 ]heptane

[0476] II. Analytical and synthetic methods

[0477] All NMRs were obtained either at 300 MHz, 400 MHz or 500 MHz. The compounds are studied in deuterated solvents such as DMSO-d6, CDCl₃, MeOD or D2O. Chemical shifts are given in ppm relative to the residual undeuterated solvent signal in the spectrum.

[0478] Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, double doublet etc. All LCMS retention times are in minutes.

[0479] LCMS data for all Intermediates were determined using either Method 1 A, Method 2B, Method 3B, Method 3C, Method 3D, Method 4 or Method 6. LCMS data for all Examples were determined by using Method 5.

[0480] LCMS Method 1A

[0481] AColumn: Phenomenex Gemini NX-C18, 2 x20 mm, 3 pm

[0482] Temperature: 40 °C

[0483] Flow Rate: 1.0 mL / min

[0484] Solvent A: 10 mM Ammonium formate in water + 0.1% Ammonia solution

[0485] Solvent B: MeCN / H₂O / Ammonia Solution (95 / 5 / 0.1)

[0486] Gradient program:

[0487] Time %A %B

[0488] 0.00 95 5

[0489] 1.50 5 95

[0490] 2.25 5 95

[0491] 2.50 95 5

[0492]

[0493] LCMS Method 2B

[0494] Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 pm

[0495] Temperature: 45 °C

[0496] Flow Rate: 0.8 mL / min

[0497] Solvent A: H20 / MeCN / ammonium_formate (95% / 5% / 63mg / L) + 100pL / L NH4OH

[0498] Solvent B: MeCN / H20 / ammonium_formate (95% / 5% / 63mg / L) + 100pL / L NH4OH

[0499] Gradient program:

[0500] Time %A %B

[0501] 0 99 1

[0502] 0.15 99 1

[0503] 1.6 5 95

[0504] 1.65 5 95

[0505] 2 5 95

[0506] 2.05 99 1

[0507] 2.75 99 1

[0508]

[0509] LCMS Method 3B

[0510] Column: Waters Cortecs C18, 90A, 2.7pm, 30 x 2.1 mm Temperature: 40 °C

[0511] Flow Rate: 1.35 mL / min

[0512] Solvents: A: 0.1% formic acid in H2O, B: MeCN

[0513] Time %A %B

[0514] 0.00 98 2

[0515] 2.5 0 100

[0516] 3 0 100

[0517]

[0518] LCMS Method 3C

[0519] Column: Waters BEH C18, 2.1 mm x30 mm, 1.7 pm, 130A Temperature: 40 °C

[0520] Flow Rate: 1.35 mL / min

[0521] Solvents: A: 0.2% NH3in H2O, B: MeCN

[0522] Time %A %B

[0523] 0.00 98 2

[0524] 2.5 0 100

[0525] 3 0 100

[0526]

[0527] LCMS Method 3D

[0528] Column: Acquity UPLC CSH C18, 130 A, 1.7 pm, 2.1 x 30 mm Temperature: 40 °C

[0529] Flow Rate: 0.77 mL / min

[0530] Solvents: A: 10 mM NH4OAC in H2O, B: MeCN

[0531] Time %A %B

[0532] 0.00 98 2

[0533] 2.5 0 100

[0534] 3 0 100

[0535]

[0536] LCMS Method 4

[0537] Column: Waters XBridge C18, 30 x 2.1 mm, 2.5 pm

[0538] Flow Rate: 1.0 mL / min

[0539] Solvent A: 5 mM ammonium formate in water + 0.1% NH4OH Solvent B: MeCN + 5% solvent A + 0.1% NH4OH

[0540] Gradient program: Time %A %B

[0541] 0.0 95 5

[0542] 4.0 5 95

[0543] 5.0 5 95

[0544] 5.1 95 5

[0545] 6.5 95 5

[0546]

[0547] LCMS Method 5

[0548] Column: Waters UPLC X Bridge BEH (C18, 2.1 x 50 mm, 2.5 pm)

[0549] Temperature: 45 °C

[0550] Flow Rate: 1.0 mL / min

[0551] Solvent A: 10 mM ammonium formate in water + 0.1% formic acid

[0552] Solvent B: 95% acetonitrile + 5% H2O + 0.1% formic acid

[0553] Gradient program:

[0554] Time %A %B

[0555] 0.0 95 50

[0556] 0.10 95 5

[0557] 2.10 5 95

[0558] 2.35 5 95

[0559] 2.80 95 5

[0560]

[0561] -

[0562] LCMS Method 6

[0563] The LCMS measurement was performed using Agilent 1260 series LC / Mass system or Waters Acquity UPLC / MS system operating in ES (+) or (-) ionization mode; T = 30 °C; flow rate = 1.5 mL / min; detected wavelength: 214 nm and 254 nm. LC detector: diode-array detector (DAD) or photo-diode array detector (PDA) or variable wavelength detector (VWD); Mass detector: SQ Detector or SQ Detector 2 (electrospray ionization source); Column: Sunfire C18 column (5 pm, 4.6 x 50 mm) or Waters Acquity UPLC BEH C18 column (1.7 pm, 2.1 x 50 mm) etc.

[0564] GC: Instrument: Agilent 7820A; Column: Agilent DB-624 column, 30 m x 0.45 mm I. D., 2.55 mm Film; Inlet temperature: 250 °C; Split rate: 20:1; Oven temperature: Initial 40 °C, hold 3 min; Ramp at 10 °C / min to 230 °C, hold 3 min; Gas flow rate: Nitrogen, 3 mL / minute; FID detector: Temperature: 300 °C H2 Flow: 40 mL / min, Air Flow: 400 mL / min, N2 Flow: 25 mL / min; Injection volume: 1 mL; Typical run time: 25 min; Diluents: ACN; Needle wash solvent: ACN

[0565] Vibrational Circular Dichroism (VCD) Method The absolute configuration of selected compounds was determined using VCD spectroscopy: IR and VCD spectra were recorded on a BioTools ChirallR-2X MIR FT-VCD spectrometer equipped with dual photoelastic modulators (dualPEM). Samples of between 5-10 mg were dissolved in 150 pL CDCl₃ or DMSO-d6and transferred to a BaF2 liquid IR cell with a path length of 0.075 mm before IR / VCD data was collected between 1,000-2,000 cm-1 for up to 16 hours. Theoretical IR / VCD spectra were generated at the B3PW91 / cc-pVTZ level of theory using the Maestro (Schrodinger, Inc.) and Gaussian09 (Gaussian Inc.) software packages. A visual comparison of the experimental and theoretical datasets was made using Excel (Microsoft) and CompareVOA (BioTools Inc.).

[0566] When analytical methods are not specified in the below protocols, the methods used were similar to the ones described above. It will be apparent to the person skilled in the art that there are analytical and preparative chromatographic methods analogues to the ones described above can be use for the below procedures.

[0567] All starting materials are commercially available or may be made by methods known to one skilled in the art.

[0568] III. INTERMEDIATES

[0569] INTERMEDIATE 1: Af-frac-M R,3R)-3-methylcvclohexyllpyridine-2-carboxamide

[0570]

[0571] To a solution of trans-3-methylcyclohexylamine (10 g, 86.5 mmol) in DCM (200 mL) were added picolinic acid (11.8 g, 94.9 mmol), HATU (40.7 g, 104 mmol) and DIPEA (29 mL, 175 mmol). The reaction mixture was stirred at r.t. for 18 h. After completion, the reaction mixture was diluted with DCM (200 ml), washed with water (2 x 200 ml) and with brine (200 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by reverse phase HPLC under basic conditions then chiral separation by SFC (column: Chiralpak AD 50 x 279 mm, 300 g, 20 pm, Flow Rate: 360 ml / min, Co-Solvent-A: MeOH (2%)) was performed to afford the tittle compound as colourless oil (3.2 g, 17%). LCMS (Method 2B): [M+H]+m / z 219, RT 1.51 minutes.1H NMR (400 MHz, CDCl3) 68.55 (d, J = 4.9 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J = 7.8 Hz, 1 H), 7.84 (t, J = 7.8 Hz, 1 H), 7.45 - 7.38 (m, 1 H), 4.35 (dt, J = 8.5, 4.5 Hz, 1 H), 1.86 - 1.70 (m, 3H), 1.68 - 1.62 (m, 3H), 1.62 - 1.52 (m, 1 H), 1.43 - 1.32 (m, 1 H), 1.09 (t, J = 11.2 Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3H). INTERMEDIATE 2: Kc / s)-3-Methyl-6-azabicvclor3.1.1lheptan-6-yll-(2-pyridyl)methanone

[0572]

[0573] To a solution of N-[rac-(1R,3R)-3-methylcyclohexyl]pyridine-2-carboxamide (prepared according to the procedure of Intermediate 1) (2 g, 9.16 mmol) in 1,1,2,2-tetrachloroethane (80 mL) were added silver acetate (7.7 g, 46 mmol), 1,4-benzoquinone (890 mg, 8.2 mmol), trisodium phosphate (7.4 g, 46 mmol), iodopentafluorobenzene (21 mL, 156 mmol) and Pd(OAc)2 (617 mg, 2.7 mmol). The reaction mixture was stirred at 140 °C for 18 h. After completion, the reaction mixture was filtered to a pad of Celite® and washed with EtOAc. The filtrate was concentrated under reduced pressure and the crude mixture was purified by normal phase chromatography (Cartridge Interchim 120 g, Solvent A = n-Heptane, Solvent B = EtOAc, gradient 80%A:20%B to 50%A:50%B) to afford the title compound as an orange oil (0.56 g, 28%). LCMS (Method 2B): [M+H]+m / z 217, RT 1.15 minutes.1H NMR (500 MHz, CDCl3) 68.57 (dt, J = 4.9, 1.2 Hz, 1H), 8.10 (dt, J = 7.8, 1.2 Hz, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1 H), 7.35 (ddd, J = 7.6, 4.7, 1.3 Hz, 1 H), 5.11 (td, J = 6.2, 4.1 Hz, 1 H), 4.56 (ddd, J = 6.7, 5.3, 3.9 Hz, 1 H), 2.78 (dtt, J = 8.6, 6.7, 1.9 Hz, 1 H), 2.74 - 2.57 (m, 1 H), 2.48 (dddd, J = 13.6, 7.7, 5.4, 1.8 Hz, 1H), 2.07 - 1.95 (m, 1H), 1.42 (ddd, J = 13.1, 9.2, 5.8 Hz, 2H), 1.33 - 1.19 (m, 2H), 1.03 (d, J = 6.8 Hz, 3H).

[0574] INTERMEDIATE 3: (c / s)-3-Methyl-6-azabicyclor3.1.1l heptane hydrochloride

[0575]

[0576] To a solution of [(cis)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-(2-pyridyl)methanone (prepared according to the procedure of Intermediate 2) (540 mg, 2.5 mmol) in EtOH (20 mL), was added sodium hydroxide (1.0 g, 25 mmol). The reaction mixture was stirred at 115 °C for 1 h in a microwave. The mixture was then concentrated in vacuo (max 35 °C), and DCM was added to the crude mixture, which was sonicated to form a precipitate. The precipitate was filtered through a pad of Celite® and rinsed with DCM (250 mL). The filtrate was concentrated in vacuo (max 35 °C) and the residue was again filtered through a pad of Celite®, washed with DCM and concentrated. A solution of hydrochloric acid (4 M HCI in dioxane, 10 mL) was added to form the hydrochloride salt, while stirring at r.t. for 15 min. The crude mixture was concentrated in vacuo (max 35 °C) to afford the title compound as a brown solid (280 mg, 75%) and used in the next step without further purification. LCMS (Method 2B): [M+H]+m / z 112.1, RT 0.66 min.1H NMR (400 MHz, CDCl3) 6 10.02 (s, 1 H), 8.59 (s, 1 H), 4.37 -4.30 (m, 2H), 3.11 (q, = 7.4 Hz, 1H), 2.79 (h, = 7.4 Hz, 1H), 2.73 -2.62 (m, 2H), 1.64 - 1.54 (m, 1H), 1.39 (dd, J= 10.1, 5.5 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H).

[0577] INTERMEDIATE 4: Rac-(5R,7R)-7-methyl-1,3-diazaspiro[4.5]decane-2, 4-dione

[0578]

[0579]

[0580] 3-Methylcyclohexan-1-one (100 g, 0.89 mol), (NH4)2CO3 (257 g, 2.8 mol) and KCN (92.9 g, 1.4 mol) were added successively to a solution of EtOH (500 mL) and H2O (500 mL). The reaction mixture was stirred under nitrogen at 65 °C for 12 h. The resulting mixture was cooled to r.t. and the resulting solid was filtered and washed with H2O (2 x 300 mL) to give the title compound (145 g, 85%).1H NMR (400 MHz, DMSO-d6) 5 10.51 (s, 1H), 8.41 (s, 1H), 1.49 - 1.45 (m, 3H), 1.28 -1.21 (m, 4H), 1.24 (t, J = 12.8 Hz, 1 H), 0.96 - 0.85 (m, 4H).

[0581] INTERMEDIATE 5: Rac-(1R,3R)-1-amino-3-methyl-cvclohexanecarboxylic acid

[0582]

[0583]

[0584] HO

[0585] Rac-(5R,7R)-7-methyl-1,3-diazaspiro[4.5]decane-2, 4-dione (prepared according to the procedure of Intermediate 4) (100 g, 0.55 mol) and KOH (102 g, 1.81 mol) were added successively to a solution of n-BuOH (500 mL) and H2O (200 mL). The reaction mixture was heated to reflux under N2 at 140 °C for 72 h. The mixture was treated with 6 N HCI (aq., 350 mL) and concentrated to give the desired crude title compound (200 g) which was used directly without further purification. LCMS (Method 6): [M+H]+m / z 158.1, RT 0.68 min.

[0586] INTERMEDIATE 6: Methyl Rac-(1R,3R)-1-amino-3-methyl-cyclohexane carboxylate

[0587]

[0588]

[0589] SOCI2 (151 g, 1.27 mol) was added to a solution of rac-(1R,3R)-1-amino-3-methyl-cyclohexanecarboxylic acid (prepared according to the procedure of Intermediate 5) (200 g, crude) in MeOH (500 mL). The reaction mixture was refluxed under nitrogen at 70 °C for 12 h. The reaction mixture was cooled to r.t. then concentrated and the residue diluted with H2O (1.0 L) and extracted with ethyl acetate (3 x 500 mL). Sat. aq. Na2COs was added to the water phase until pH = 9 and extracted with EtOAc (6 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated in vacuo to give the title compound (215.0 g, 45%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 3.60 (s, 3H), 1.88 - 1.61 (m, 4H), 1.61 -1.38 (m, 5H), 1.28 - 1.11 (m, 1 H), 0.91 - 0.67 (m, 4H).

[0590] INTERMEDIATE 7: Methyl Rac-(1R,3R)-3-methyl-1-(pyridine-2-carbonylamino) cyclohexane

[0591]

[0592] carboxylate

[0593] o

[0594]

[0595] f J

[0596] To a solution of methyl rac-(1R,3R)-1-amino-3-methyl-cyclohexane carboxylate (prepared according to the procedure of Intermediate 6) (49 g, 0.29 mol) and pyridine-2-carboxylic acid (42 g, 0.34 mol) in DMF (200 mL) was added HATU (141 g, 0.372 mol) and TEA (57.9 g, 0.572 mol). The reaction mixture was stirred at r.t. for 2 h. The reaction was poured into H2O (800 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated. The crude was purified by silica gel column (PE: EtOAc = 4:1) to give the title compound (67 g, 76%) as a white solid.1HNMR (400 MHz, CDCl₃) 68.59 (d, J = 4.0 Hz, 1 H), 8.44 (s, 1 H), 8.20 (d, J = 7.6 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.49 (d, J = 6.4 Hz, 1 H), 3.73 (s, 3H), 2.37- 2.32 (m, 2H), 1.74 - 1.63 (m, 4H), 1.62 - 1.39 (m, 2H), 0.98 - 0.94 (m, 4H).

[0597] INTERMEDIATE 8: Methyl rac-(1S,3R,5R)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.11 heptane-1 -carboxylate

[0598]

[0599] To a solution of methyl rac-(1R,3R)-3-methyl-1-(pyridine-2-carbonylamino) cyclohexane carboxylate Intermediate 7(10 g, 36 mmol), AgOAc(18.1 g, 109 mmol) and Pd(OAc)2 (1.23 g, 5.43 mmol) in TCE (300 mL) under nitrogen was added C6F5I (138 g, 470 mmol), Na3PO4 (17.8 g, 109 mmol) and BQ (4.05 g, 30.6 mmol). The reaction mixture was stirred at 150 °C under air for 12 h. A further four batches (10 g, 10 g, 10 g and 5 g) were run using the same procedure. The five batches of reaction mixture were combined, filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE: EtOAc = 4: 1) to give the title compound (5.79 g, 13%) as a red oil. LCMS (Method 6): [M+H]+m / z 275.1, RT 1.20 min.1H NMR (400 MHz, DMSO-d6) 68.65 (d, J = 4.4 Hz, 0.5H), 8.41 (d, J = 4.4 Hz, 0.5H), 7.98 - 7.94 (m, 2H), 7.60 - 7.52 (m, 1H), 5.08 - 5.05 (m, 0.5H), 4.42 - 4.39 (m, 0.5H), 3.68 (s, 1.5H), 3.51 (s, 1.5H), 2.78 - 2.70 (m, 1 H), 2.69 - 2.57 (m, 1 H), 2.48 - 2.41 (m, 0.5H), 2.18 - 2.15 (m, 0.5H), 1.67 - 1.62 (m, 2H), 1.52 (dd, J = 16.8, 8.1 Hz, 1 H), 1.38 - 1.34 (m, 1 H), 1.00 (t, J = 6.4 Hz, 3H).

[0600] INTERMEDIATE 8A and 8B: Methyl (1S,3R.5R)-3-methyl-6-(pyridine-2-carbonyl)-6-

[0601]

[0602] azabicyclo[3.1.11heptane-1 -carboxylate and methyl (1R,3S,5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1 lheptane-1 -carboxylate

[0603]

[0604] I

[0605] Methyl rac-(1 S,3R,5R)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1 ] heptane-1 -carboxylate (prepared according to the procedure of Intermediate 8) (5.70 g) was subjected to chiral purification. Purification was performed using a Lux Cellulose-2, 250 x 21.2 mm, 5 pm, flow rate 100 mL / min, column temperature 40°C, eluting with a 20-40 % methanol & 0.1 % ammonia solution gradient (60 bar), over 7.5 minutes on a Waters FractionLynx SFC Prep 150 in tandem with a QDa mass spectrometer to afford the title compounds Intermediate 8A (2.10 g) and Intermediate 8B (2.20 g). The absolute stereochemistry of Intermediate 8A (1S,3R,5R configuration) and Intermediate 8B (1R,3S,5S configuration) was determined using VCD spectroscopy.

[0606] INTERMEDIATE 9: (1R,3S,5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicvclor3.1.1lheptane-1 -carboxylic acid

[0607]

[0608] To a solution of methyl (1R,3S,5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate (prepared according to the procedure of Intermediate 8B) (715 mg, 2.61 mmol) in MeOH (8.5 mL) and water (1.5 mL) was added sodium hydroxide (156 mg, 3.90 mmol). The reaction mixture stirred for 3 h at r.t., then concentrated in vacuo to remove MeOH. 2 mL of 2 M HCI aq. was added to the aqueous phase to neutralise the solution. The aqueous was extracted with DCM, filtered through a phase separator and then concentrated in vacuo to afford the title compound (741 mg, 99%). LCMS (Method 1 A): [M+H]+ m / z 261.2, RT 0.36 minutes.1H NMR (300 MHz, DMSO) 5 12.62 (s, 1 H), 8.66 (dt, J = 4.7, 1.4 Hz, 1 H), 8.05 - 7.90 (m, 2H), 7.65 - 7.46 (m, 1H), 5.76 (s, 1H), 5.05 (dd, J = 6.9, 5.2 Hz, 1H), 2.83 - 2.61 (m, 2H), 2.18 (dt, J = 13.0, 6.4 Hz, 1 H), 1.71 - 1.44 (m, 3H), 1.43 - 1.29 (m, 1 H), 1.00 (t, J = 6.8 Hz, 3H). INTERMEDIATE 10: (1 / ?.3S.5S)- / V-rnethoxy- / V.3-dimethyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.11heptane-1 -carboxamide

[0609] OO^N"

[0610] I

[0611]

[0612] To a solution of (1R,3S,5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 9) (735 mg, 2.57 mmol) in DMF (8 mL) were added A / , O-dimethylhydroxylamine hydrochloride (278 mg, 2.79 mmol), HATU (1.01 g, 2.66 mmol) and DIPEA (1.4 mL, 8.1 mmol). The reaction mixture stirred for 2 h at r.t., then diluted with DCM and H2O. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-50% EtOAc / iso-hexane) to afford the title compound (677 mg, 87%) as a colorless oil. LCMS (Method 1A): [M+H]+m / z 304.2, RT 1.04 minutes.

[0613] INTERMEDIATE 11: 1 -f(1,3S.5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.11heptan-1 -yllethenone

[0614]

[0615] To a solution of (1R,3S,5S)-A / -methoxy-A / ,3-dimethyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1,1]heptane-1 -carboxamide (prepared according to the procedure of Intermediate 10) (675 mg, 2.23 mmol) in THF (7 mL) was added methyllithium (1.4 mL, 2.2 mmol, 1.6 mol / L diethyl ether solution) at -78 °C. The reaction mixture stirred for 2 h at -78 °C, then quenched with sat. aqueous NH4CI. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-70% EtOAc / iso-hexane) to afford the title compound (361 mg, 63%) as a colourless oil. LCMS (Method 1A): [M+H]+m / z 259.2, RT 1.10 minutes.

[0616] INTERMEDIATE 12: f(1 R,3S,5S)-1 -(1 -hydroxyethyl)-3-methyl-6-azabicyclor3.1.1 lheptan-6-yll-(2-pyridyl)methanone

[0617]

[0618] To a solution of 1-[(1R,3S,5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1,1]heptan-1-yl]ethenone (prepared according to the procedure of Intermediate 11) (355 mg, 1.37 mmol) in MeOH (5 mL) was added NaBH4 (115 mg, 3.04 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C, then quenched with sat. aq. NH4CI. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo to afford the title compound as a mixture of stereoisomers (381 mg) and as a colourless oil, which was used in the next step without further purification. LCMS (Method 1A):

[0619] [M+H]+m / z 261.2, RT 1.10 and 1.18 minutes.1H NMR (300 MHz, DMSO) 58.69 - 8.53 (m, 1H), 8.02 - 7.90 (m, 2H), 7.64 - 7.49 (m, 1 H), 5.04 - 4.87 (m, 1 H), 4.82 (d, J = 7.0 Hz, 1 H), 4.03 - 3.87 (m, 1H), 2.77 - 2.50 (m, 1H), 2.50 - 2.28 (m, 1H), 2.22 (ddd, J = 19.2, 13.0, 6.2 Hz, 1H), 1.74 (br, 1H), 1.47 - 1.21 (m, 3H), 1.13 - 0.92 (m, 6H).

[0620] INTERMEDIATE 13: [(1 R,3S,5S)-1 -(1-methoxyethyl)-3-methyl-6-azabicvclo[3.1.11heptan-6-yl1-(2-pyridyl)methanone

[0621]

[0622] To a solution of [(1R,3S,5S)-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-(2-pyridyl)methanone (prepared according to the procedure of Intermediate 12) (375 mg, 1.44 mmol) in DMF (4 mL) was added NaH (115 mg, 2.88 mmol) at 0 °C. After 30 min, iodomethane (220 pL, 3.50 mmol) was added to the reaction mixture at 0 °C, which was stirred at r.t. for 3 h. The reaction mixture was then quenched with sat. aq. NH4CI. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-50% EtOAc / iso-hexane) to afford an inseparable mixture of the title compound and residual Intermediate 12 (337 mg, 85%), all as a mixture of stereoisomers, as a colorless oil. LCMS (Method 1A): [M+H]+m / z 275.2, RT 1.19 and 1.23 minutes.

[0623] INTERMEDIATE 14 and 15: (1,3S.5S)-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1 lheptane and 1 -[(1 / ?,3S,5S)-3-methyl-6-azabicyclo[3.1.11heptan-1 -yllethanol

[0624]

[0625] To a solution containing the unseparated mixtures of [(1R,3S,5S)-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1 ]heptan-6-yl]-(2-pyridyl)methanone and [(1 R,3S,5S)-1 -(1 -methoxyethyl)-3-methyl-6-azabicyclo[3.1,1]heptan-6-yl]-(2-pyridyl)methanone (prepared according to the procedures of Intermediate 12 and 13) (330 mg, 1.20 mmol) in THF (8 mL) was added methylmagnesium bromide (5.0 mL, 15 mmol, 3 mol / L diethyl ether solution) at 0 °C. The reaction mixture was stirred at 35 °C for 5 h, then quenched with sat. aq. NH4CI. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo to afford the title compound (323 mg) as a mixture of stereoisomers and as an yellow oil, which was used in the next step without further purification. LCMS (Method 1A):

[0626] [M+H]+m / z 170.2, RT 0.75 minutes.

[0627] INTERMEDIATE 16: 5-Bromo-2-hvdroxy-4-methyl-benzaldehyde

[0628] o

[0629]

[0630] L 1

[0631] To a solution of 4-bromo-3-methylphenol (10 g, 52.4 mmol) and paraformaldehyde (8.0 g, 89 mmol) in MeCN (150 mL), was added magnesium chloride (7.6 g, 78.6 mmol) and TEA (14.7 mL, 105 mmol). The reaction mixture was stirred at 70 °C for 8 h. The reaction mixture was then quenched with H2O (150 mL), acidified with HCI (5 M, aq.) to pH ~ 5 and extracted with EtOAc. The residue was purified by flash chromatography on silica gel (100 / 0 to 75 / 25, Heptane / EtOAc) to afford the title compound as a brown solid (5.1 g, 45%). LCMS (Method 2B): [M+H]+m / z 215.1, RT 1.27 min.

[0632] INTERMEDIATE 17: Ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate

[0633] VcT

[0634]

[0635] Y O

[0636] To a solution of 5-bromo-2-hydroxy-4-methyl-benzaldehyde (prepared according to the procedure of Intermediate 16) (4.50 g, 20.9 mmol) in DCM (50 mL) was added HBF4. OEt2 (0.61 g, 2.09 mmol) followed by dropwise addition of ethyl 2-diazoacetate (3.29 mL, 31.4 mmol) at r.t.. The mixture was stirred for 30 min then concentrated in vacuo. H2SO4 (1.45 mL, 27.2 mmol) was added then the mixture was stirred for 20 min, neutralized with saturated aqueous NaHCO3solution and then stirred for a further 10 min. The reaction mixture was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (10% EtOAc in heptane) to afford the title compound (3.00 g, 48%) as a white solid. LCMS (Method 4):

[0637] [M+H]+m / z 285.5, RT 1.78 minutes.1H NMR (400 MHz, CDCl3) 68.22 (s, 1H), 8.19 (s, 1H), 7.41 (s, 1 H), 4.36-4.44 (m, 2H), 2.51 (s, 3H), 1.40-1.44 (m, 3H).

[0638] INTERMEDIATE 18: Ethyl 6-methyl-5-(2-pyridyl)benzofuran-3-carboxylate

[0639]

[0640] To a solution of ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (3.00 g, 10.6 mmol) in 1,4-dioxane (30 mL) was added PdCh(PPh3)2 (0.74 g, 1.06 mmol). The reaction mixture was purged with argon gas for 15 min then tributyl(2-pyridyl)stannane (4.68 g, 12.7 mmol) was added. The reaction mixture was purged with argon gas for another 10 min and heated at 120 °C for 16 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (50% EtOAc in heptane) to afford the title compound (2.00 g, 62%) as an off white solid. LCMS (Method 4): [M+H]+m / z 282.3, RT 2.29 minutes.1H NMR (400 MHz, CDCl₃) 68.71 (s, 1H), 8.64-8.68 (m, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 7.34-7.56 (m, 3H), 4.28-4.33 (m, 2H), 2.37 (s, 3H), 1.29-1.32 (m, 3H).

[0641] INTERMEDIATE 19: 6-Methyl-5-(2-pyridyl)benzofuran-3-carboxylic acid

[0642] OH

[0643]

[0644] To a solution of ethyl 6-methyl-5-(2-pyridyl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 18) (2.00 g, 7.11 mmol) in THF / H2O (20 mL) was added LiOH. H2O (1.49 g, 35.5 mmol) at room temperature. The reaction temperature was heated at 70°C for 8 h then concentrated in vacuo. The residue was acidified with 2N HCI to give a precipitate which was collected by filtration then washed with n-pentane and then dried in vacuo to afford the title compound (1.40 g, 78% yield) as an off-white solid. LCMS (Method 4): [M+H]+m / z 254.08, RT 1.63 minutes.1H NMR (400 MHz, CDCl₃) 5 13.01 (brs, 1H), 8.67-8.69 (m, 1H), 8.65 (s, 1H), 7.87-7.95 (m, 2H), 7.65 (s, 1 H), 7.57 (d, =7.88 Hz, 1 H), 7.37-7.44 (m, 1 H), δ 2.41 (s, 3H).

[0645] INTERMEDIATE 20: Ethyl 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylate o > —

[0646]

[0647] To a solution of ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (280 mg, 0.99 mmol) and 2-imidazolidone (180 mg, 2 mmol) in 1,4-dioxane (10 mL), was added cesium carbonate (975 mg, 2.96 mmol) and Ephos Pd G4 (95 mg, 0.1 mmol). The reaction mixture was stirred at 90 °C for 1h. Then, the reaction mixture was diluted with EtOAc (25 mL) and washed with a saturated aqueous solution of NaHCO3(2 x 10 ml). The organic layer was dried over MgSC>4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (100 / 0 to 95 / 5, DCM / MeOH) to afford the title compound as a white solid (120 mg, 42%). LCMS (Method 2B): [M+H]+m / z 289.1, RT 1.13 min.1H NMR (400 MHz, DMSO) 58.71 (s, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 6.68 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.75 (dd, J = 8.8, 6.8 Hz, 2H), 3.50 - 3.41 (m, 2H), 2.33 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0648] INTERMEDIATE 21: 6-Methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid

[0649] O

[0650]

[0651] To a solution of ethyl 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 20) (100 mg, 0.347 mmol) in THF (1.2 mL) and H2O (0.2 mL), was added LiOH. H2O (69 mg, 1.6 mmol). The reaction mixture was stirred at 50 °C for 1 h, then quenched with 0.75 mL of 2 M HCI aqueous solution. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo to afford the title compound (80 mg, 89%) as a white solid, which was used in the next step without further purification. LCMS (Method 1A): [M+H]+m / z 261.2, RT 0.33 minutes.1H NMR (300 MHz, DMSO) 5 13.01 (s, 1H), 8.62 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 6.67 (s, 1H), 3.74 (dd, J = 8.9, 6.6 Hz, 2H), 3.46 (dd, J = 9.0, 6.6 Hz, 2H), 2.33 (s, 3H).

[0652] INTERMEDIATE 22: 5-Bromo-6-methyl-benzofuran-3-carboxylic acid

[0653]

[0654] To a solution of ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (200 mg, 0.7 mmol) in THF (4 mL) and H2O (2 mL), was added LiOH. H2O (120 mg, 2.8 mmol). The reaction mixture was stirred at 70 °C for 30 min. The mixture was allowed to cool to r.t. then diluted with EtOAc (50 mL) and washed with a saturated aqueous solution of NH4CI (2 x 10 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a yellow solid (90 mg, 50%), which was used in the next step without further purification. LCMS (Method 2B): [M+H]' m / z 253.1, RT 0.85 min.

[0655] INTERMEDIATE 23: (5-Bromo-6-methyl-benzofuran-3-yl)-r(1 S,5R)-3-methyl-6-azabicyclo[3.1.11heptan-6-yl1methanone

[0656]

[0657] To a solution of 5-bromo-6-methyl-benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 22) (90 mg, 0.35 mmol) and (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane hydrochloride (prepared according to the procedure of Intermediate 3) (52 mg, 0.35 mmol) in DMF (4 mL), was added DIPEA (0.18 mL, 1.05 mmol) followed by HATU (165 mg, 0.42 mmol). The reaction mixture was stirred at r.t. for 2 h. Then, the mixture was diluted with EtOAc (25 mL) and washed with a saturated aqueous solution of NaHCO3(2x 10 ml). The organic layer was dried over MgSC>4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (90 / 10 to 40 / 60, Hexane / EtOAc) to afford the title compound as a yellow solid (85 mg, 70%), which was used in the next step without further purification. LCMS (Method 2B): [M+H]+m / z 349.1, RT 1.60.

[0658] INTERMEDIATE 24: 7-Azabicyclor4.1.1loctan-7-yl-(5-bromo-6-methyl-benzofuran-3-vDmethanone

[0659]

[0660] Prepared from 5-bromo-6-methyl-benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 22) (80 mg, 0.31 mmol) and 7-azabicyclo[4.1,1]octane (35 mg, 0.31 mmol) in accordance with the procedure described for Intermediate 23 to afford the title compound (30 mg, 27%) as a white solid. LCMS (Method 2B): [M+H]+m / z 349.1, RT 1.57 minutes.

[0661] INTERMEDIATE 25: Ethyl 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate

[0662]

[0663] To a solution of ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (0.50 g, 1.77 mmol) in 1,4-dioxane (10 mL) was added KOAc (0.52 g, 5.30 mmol) and bis(pinacolato)diboron (0.67 g, 2.65 mmol) at room temperature. The reaction mixture was purged with argon for 30 min, then PdCl2(dppf) (0.06 g, 0.08 mmol) was added. The reaction mixture was heated at 100°C for 5 h then concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-20% EtOAc / Heptane) to afford the title compound (0.50 g, 80%) as a white solid. LCMS (Method 4): [M+H]+ m / z 331.1, RT 1.86 minutes.1H NMR (400 MHz, CDCl₃) 58.46 (s, 1H), 8.15 (s, 1H), 7.30 (s, 1 H), 4.37-4.41 (m, 2H), 2.65 (s, 3H), 1.42 (t, 3H), 1.36 (s, 12H).

[0664] INTERMEDIATE 26: Ethyl 6-methyl-5-(1-methyl-1,2,4-triazol-3-yl) benzofuran-3-carboxylate

[0665]

[0666] To a solution of ethyl 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 25) (0.50 g, 1.51 mmol) and 3-bromo-1-methyl-1,2,4-triazole (0.36 g, 2.27 mmol) in 1,4-dioxane: H20 (9:1, 10 mL) was added K3PO4 (0.64 g, 3.03 mmol) at room temperature. The reaction mixture was purged with argon for 15 min then XPhos Pd G3 (0.08 g, 0.10 mmol) and XPhos (3.06 g, 0.007 mmol) were added. The reaction mixture was further purged with argon for 10 min and heated at 100°C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-70% EtOAc / Heptane) to afford the title compound (0.19 g, 39%) as an off white solid. LCMS (Method 4): [M+H]+ m / z 286.1, RT 1.36 minutes.1H NMR (400 MHz, DMSO) 58.72 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 7.65 (s, 1H), 4.33-4.38 (m, 2H), 3.95 (s, 3H), 2.67 (s, 3H), 1.35 (t, 3H).

[0667] INTERMEDIATE 27: 6-Methyl-5-(1-methyl-1,2,4-triazol-3-yl)benzofuran-3-carboxylic acid

[0668]

[0669] To a solution of ethyl 6-methyl-5-(1-methyl-1,2,4-triazol-3-yl) benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 26) (0.19 g, 0.58 mmol) in THF: H2O (7:3, 5 mL) was added LiOH- H2O (0.07 g, 1.76 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H2O (2 mL), then acidified with 6 N HCI to get the solid precipitate which was filtered and dried in vacuo to afford the title compound (0.12 g, 71%) as a white solid. LCMS (Method 4): [M+H]+ m / z 258.0, RT 1.52 minutes.1H NMR (400 MHz, DMSO-d6) 5 13.02 (br s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 7.63 (br s, 1H), 3.95 (s, 3H), 2.67 (s, 3H). INTERMEDIATE 28: Ethyl 5-(2-methoxy-5-methyl-3-pyridyl)-6-methyl-benzofuran-3-carboxylate

[0670]

[0671] To a solution of ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (0.20 g, 0.70 mmol) and 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.21 g, 0.84 mmol) in 1,4-dioxane H2O (9:1, 5 mL) was added K3PO4 (0.44 g, 2.12 mmol). The reaction mixture was purged with nitrogen for 20 min then Pd(amphos)Cl2 (0.02 g, 0.03 mmol) was added. The reaction mixture was heated at 110°C for 16 h. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-40% EtOAc / Heptane) to afford the title compound (0.46 g, 65%) as a white solid. LCMS (Method 4):

[0672] [M+H]+ m / z 326.0, RT 2.56 minutes.1H NMR (400 MHz, DMSO) 58.72 (s, 1 H), 8.04 (s, 1 H), 7.64 (d, J=7.45 Hz, 2H), 7.43 (s, 1 H), 4.30-4.36 (m, 2H), 3.77 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H), 1.30 (t, J=7.02 Hz, 3H).

[0673] INTERMEDIATE 29: Ethyl 6-methyl-5-(5-methyl-2-oxo-1H-pyridin-3-yl)benzofuran-3-carboxylate

[0674]

[0675] To a solution of ethyl 5-(2-methoxy-5-methyl-3-pyridyl)-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 28) (0.10 g, 0.30 mmol) in MeCN (5 mL) was added sodium iodide (0.13 g, 0.92 mmol) and TMSCI (0.11 mL, 0.92 mmol). The reaction mixture was heated at 80°C for 5 h. After completion, the reaction mixture was quenched with saturated Na2S2C>3 (30 mL) and extracted with DCM (3 x 30 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to afford the title compound (0.09 g, crude) as an off white solid, which was used for the next step without further purification. LCMS (Method 4): [M+H]+ m / z 312.24, RT 1.36 minutes. 1 H NMR (400 MHz, DMSO) 5 11.57 (br s, 1 H), 8.71 (s, 1H), 7.58 (s, 1H), 7.31 (d, J=2.45 Hz, 2H), 7.23 (s, 1H), 4.31-4.36 (m, 2H), 2.26 (s, 3H), 2.07 (s, 3H), 1.32 (t, J=7.09 Hz, 3H). INTERMEDIATE 30: 6-Methyl-5-(5-methyl-2-oxo-1 H-pyridin-3-yl)benzofuran-3-carboxylic acid

[0676]

[0677] To a solution of ethyl 6-methyl-5-(5-methyl-2-oxo-1H-pyridin-3-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 29) (0.09 g, 0.28 mmol) in THF: H2O (7:3, 2 mL) was added LiOH (0.04 g, 1.16 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with H2O (5 mL), then acidified with 20% Na2HPC>4 solution (5 mL) and extracted with DCM (2 x 30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with DCM / n-Pentane (1 / 10 mL) to afford the title compound (0.05 g, 61%) as a white solid. LCMS (Method 4): [M+H]+ m / z 284.18, RT 1.16 minutes.1H NMR (400 MHz, DMSO) 58.56 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 2.25 (s, 3H), 2.06 (s, 3H), 2H exchangeable protons not observed.

[0678] INTERMEDIATE 31: Ethyl 6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-carboxylate

[0679]

[0680] To a solution of ethyl 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 25) (0.33 g, 0.99 mmol) and 5-bromo-2-methyl-1 / 7-imidazole (0.32 g, 2.00 mmol) in dioxane: H20 (9:1, 5 mL) was added K2CO3(0.27 g, 2.00 mmol) at room temperature. The reaction mixture was purged with argon for 15 min followed by Pd(amphos)Cl2 (0.07 g, 0.09 mmol). The reaction mixture was further purged with argon for 10 min and heated at 100°C for 16 h. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-5% MeOH / DCM) to afford the title compound (0.15 g, 38%) as an off white solid. LCMS (Method 4): [M+H]+ m / z 285.25, RT 1.44 minutes. 1H NMR (400 MHz, DMSO) 5 12.00 (br s, 1H), 8.62 (s, 1H), 8.25 (s, 1H), 7.54 (s, 1H), 7.12 (s, 1H), 4.30-4.35 (m, 2H), 2.32 (s, 3H), 2.21 (s, 3H), 1.31-1.35 (m, 3H).

[0681] INTERMEDIATE 32: 6-Methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-carboxylic acid

[0682]

[0683] To a solution of ethyl 6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 31) (0.15 g, 0.47 mmol) in THF: H2O (7:3, 5 mL) was added LiOH. H2O (0.06 g, 1.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with H2O (2 mL), then acidified with 6 N HCI (15 mL) and the precipitated solid was filtered to afford the title compound (0.08 g, 65%) as an off white solid. LCMS (Method 4): [M+H]+ m / z 257.17, RT 1.00 minutes.1H NMR (400 MHz, DMSO) 5 13.96 (br s, 2H), 8.61 (s, 2H), 8.00 (s, 1H), 7.57 (s, 1H), 2.60 (s, 3H), 2.48 (s, 3H).

[0684] INTERMEDIATE 33: Ethyl 5-(5-1

[0685]

[0686] imidin-2-yl)-6-i

[0687]

[0688] -benzofuran-3-<

[0689]

[0690]

[0691] To a solution of ethyl 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 25) (0.70 g, 2.04 mmol) in 1,4-dioxane: H2O (9:1, 10 mL) was added 2-bromo-5-fluoropyrimidine (0.72, 4.08 mmol) and K2CO3(0.84 g, 6.12 mmol). The reaction mixture was purged with argon for 15 min then Pd(amphos)Cl2 (0.07 g, 0.10 mmol) was added. The reaction mixture was further purged with argon for 10 min and heated at 100°C for 5 h. After completion, the reaction mixture was diluted H2O (10 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-30% EtOAc / Heptane) to afford the title compound (0.33 g, 50%) as an off white solid. LCMS (Method 4): [M+H]+ m / z 301.20, RT 1.87 minutes.1H NMR (400 MHz, DMSO) 59.03 (s, 2H), 8.75 (s, 1 H), 8.34 (s, 1 H), 7.69 (s, 1 H), 4.32-4.37 (m, 2 H), 2.57 (s, 3H), 1.31-1.34 (m, 3H).

[0692] INTERMEDIATE 34: 5-(5-Fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-carboxylic acid

[0693]

[0694] To a solution of ethyl 5-(5-fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 33) (0.24 g, 75 mmol) in THF: H2O (7:3, 10 mL) was added LiOH (0.12 g, 5.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated in vacuo to get crude which was diluted with H2O (2 mL) and acidified with 6 N HCI. Then solid precipitated which was filtered and dried in vacuo to afford the title compound (0.24 g, 75%) as a white solid. LCMS (Method 4): [M+H]+ m / z 273.14, RT 1.42 minutes.1H NMR (400 MHz, DMSO) 5 13.04 (brs, 1H), 9.01 (s, 2H), 8.65 (s, 1H), 8.36 (s, 1H), 7.65 (s, 1H), 2.57 (s, 3H). 3H), 1.31-1.34 (m, 3H).

[0695] INTERMEDIATE 35: rac-tert-Butyl (1S.3S.5R)-1-[1-hvdroxyethyll-3-methyl-8-azabicyclo[3.2.11octane-8 -carboxylate

[0696]

[0697] To a solution of tert-butyl (c / s)-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (299 mg, 1.33 mmol) in Et2O (12 mL, 110 mmol, 100 mass%) were added N, N, N', N'-tetramethyl ethylenediamine (600 pL, 3.96 mmol) and sec-BuLi (2.8 mL, 3.9 mmol) at -78 °C. After the reaction mixture was stirred for 30 min at 0 °C, acetaldehyde (800 pL, 4.00 mmol) was added at -78 °C. The reaction mixture was gradually allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4CI. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-70% EtOAc / iso-hexane) to afford the title compound (211 mg, 59%) as a yellow oil. LCMS (Method 1A): [M+H] + m / z 270.2, RT 1.22 minutes.

[0698] INTERMEDIATE 36: Ethyl 6-methyl-5-(6-oxo-1H-pyridazin-5-yl)benzofuran-3-carboxylate o /

[0699]

[0700] 5-Chloro-1H-pyridazin-6-one (194 mg, 1.49 mmol), ethyl 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 25) (899 mg, 1.80 mmol), Pd2(dba)a (170 mg, 0.180 mmol), XPhos (170 mg, 0.346 mmol) and K2CO3(677 mg, 4.85 mmol) were dissolved in 1,4-dioxane (7 mL) and water (3 mL). The reaction mixture was stirred for 4 h at 100 °C under N2 atmosphere. The reaction mixture was filtered through Celite ® and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (211 mg, 59%) as a yellow solid. LCMS (Method 1 A): [M+H] + m / z 299.0, RT 1.17 minutes.1H NMR (300 MHz, DMSO) 513.24 (s, 1H), 8.75 (s, 1H), 7.98 (d, J = 3.9 Hz, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.41 (d, J = 3.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.32 (q, J = 7.1 Hz, 3H). INTERMEDIATE 37: 6-Methyl-5-(6-oxo-1H-pyridazin-5-yl)benzofuran-3-carboxylic acid

[0701]

[0702] To a solution of ethyl 6-methyl-5-(6-oxo-1H-pyridazin-5-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 36) (305 mg, 1.02 mmol) in THF (5 mL) and water (1 mL) was added LiOH. H2O (61 mg, 1.4 mmol, 98 mass%). After the reaction mixture was stirred for 2 h at 50 °C, 0.8 mL of 2 N HCI was added to neutralise the solution. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo to afford the title compound (207 mg, 56%) as a yellow solid. LCMS (Method 1A): [M+H] + m / z 271.0, RT 0.65 minutes.1H NMR (300 MHz, DMSO) 5 13.23 (s, 1H), 13.02 (s, 1H), 8.65 (s, 1H), 7.96 (d, J = 4.0 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J = 0.9 Hz, 1H), 7.41 (d, J = 4.0 Hz, 1H), 2.29 (s, 3H).

[0703] INTERMEDIATE 38: (5-Bromo-6-methyl-benzofuran-3-yl)-r(1 S,5R)-3-methyl-8-azabicyclo[3.2.11octan-8-yl1methanone

[0704]

[0705] To a solution of (c / s)-3-methyl-8-azabicyclo[3.2.1]octane hydrochloride (355 mg, 2.20 mmol), 5-bromo-6-methyl-benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 22) (430 mg, 1.69 mmol) and HATU (785 mg, 2.06 mmol) in DMF (3.5 mL) was added DIPEA (0.90 mL, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then quenched with water. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (565 mg, 93%) as a brown oil. LCMS (Method 1A): [M+H]+ m / z 362.0 RT 1.32 minutes.1H NMR (300 MHz, DMSO) 58.43 (s, 1H), 7.96 (s, 1H), 7.73 (d, J = 1.0 Hz, 1H), 4.63 (s, 1H), 4.37 (s, 2H), 2.46 (s, 3H), 2.19 (s, 4H), 1.84 - 1.70 (m, 3H), 1.36 - 1.30 (m, 1H), 1.34 - 1.25 (m, 1H), 1.12 (d, J = 7.5 Hz, 3H).

[0706] INTERMEDIATE 39: Rc / s)-3-Methyl-8-azabicyclo[3.2.11octan-8-yl1-[6-methyl-5-(4,4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yllmethanone

[0707]

[0708] (5-Bromo-6-methyl-benzofuran-3-yl)-[(1S,5 / ?)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methanone (prepared according to the procedure of Intermediate 38) (641 mg, 1.77 mmol), bis(pinacolato)diboron (541 mg, 2.13 mmol), PdCh(dppf) (110 mg, 0.150 mmol) and KOAc (632 mg, 6.38 mmol) were dissolved in 1,4-dioxane (6 mL). After being stirred at 80 °C overnight, the reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (565 mg, 93%) as a brown oil. LCMS (Method 1A): [M+H]+ m / z 410.2 RT 1.76 minutes.1H NMR (300 MHz, DMSO) 58.34 (s, 1H), 8.11 (s, 1H), 7.47 (t, J = 0.7 Hz, 1H), 4.65 (s, 1H), 4.34 (s, 1H), 2.62 - 2.56 (m, 3H), 2.20 (s, 3H), 1.98 (d, J = 7.4 Hz, 2H), 1.78 (d, J = 7.9 Hz, 4H), 1.32 (s, 12H), 1.11 (d, J = 7.4 Hz, 3H).

[0709] INTERMEDIATE 40: Ethyl 6-methyl-5-(2-oxo-1,2-dihvdropyridin-3-yl)benzofuran-3-carboxylate

[0710]

[0711] Ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (0.15 g, 0.53 mmol), (2-oxo-1,2-dihydropyridin-3-yl)boronic acid (90 mg, 0.65 mmol), Pd(dppf)Ch (37 mg, 0.05 mmol) and Na2COs (0.15 g, 1.42 mmol) were dissolved in 1,4-dioxane (7.5 mL) and H2O (0.5 mL). The mixture was purged with nitrogen for 5 minutes and stirred at 90 °C for 16 h. The reaction mixture was cooled down to r.t., filtered, washed with EtOAc (100 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% [EtOAc: EtOH 3:1] / iso-hexane) to afford the title compound (32 mg, 20 %) as a light brown solid. LCMS (Method 3B): [M+H]+ m / z 298.1, RT 1.24 min.1H NMR (500 MHz, DMSO) 5 8.21 (s, 1 H), 7.85 (s, 1 H), 7.62 - 7.33 (m, 3H), 6.37 (s, 1 H), 4.38 (q, J = 7.0 Hz, 2H), 2.38 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H). (exchangeable proton not observed)

[0712] INTERMEDIATE 41: 6-Methyl-5-(2-oxo-1,2-dihvdropyridin-3-yl)benzofuran-3-carboxylic acid

[0713]

[0714] A mixture of 6-methyl-5-(2-oxo-1,2-dihydropyridin-3-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 40) (32 mg, 0.11 mmol) and aqueous NaOH (2 M, 0.50 mL, 1.00 mmol) in EtOH (3 mL) and MeOH (1 mL) was stirred at 60 °C for 3 h. The mixture was cooled down to r.t., quenched with HCI (1M, 1 mL) to pH ~4 and diluted with H2O (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over MgSC>4, filtered and concentrated in vacuo to afford the title compound (32 mg, 90%) as a brown solid. LCMS (Method 3B): [M+H]+m / z 270.1, RT 0.97 minutes.1H NMR (500 MHz, DMSO) 5 11.76 (s, 1H), 8.60 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.48 - 7.38 (m, 2H), 6.28 (t, J = 6.6 Hz, 1 H), 2.25 (s, 3H) (exchangeable proton not observed).

[0715] INTERMEDIATE 42: Ethyl 5-(2-methoxy-4-methylpyridin-3-yl)-6-methylbenzofuran-3-carboxylate

[0716]

[0717] Prepared from ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (0.30 g, 1.06 mmol) and 2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.48 g, 1.81 mmol) in accordance with the procedure described for Intermediate 40 to afford the title compound (0.17 g, 43%) as a pale yellow oil. LCMS (Method 3B): [M+H]+m / z 326.1, RT 1.79 min.1H NMR (500 MHz, CDCl3) 68.22 (s, 1 H), 8.08 (d, J = 5.2 Hz, 1H), 7.72 (s, 1H), 7.46 (s, 1H), 6.87 (d, J= 5.2 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 3.86 (s, 3H), 2.12 (s, 3H), 1.99 (s, 3H), 1.38 (t, J= 7.1 Hz, 3H).

[0718] INTERMEDIATE 43: Ethyl 6-methyl-5-(4-methyl-2-oxo-1,2-dihvdropyridin-3-yl)benzofuran-3-carboxylate

[0719]

[0720] To a solution of ethyl 5-(2-methoxy-4-methylpyridin-3-yl)-6-methylbenzofuran-3-carboxylate (prepared according to the procedure of Intermediate 42) (0.17 g, 0.46 mmol) in MeCN (5 mL), Nal (0.25 g, 1.67 mmol) and TMSCI (0.22 mL, 1.73 mmol) were added. The resulting mixture was stirred at 70 °C for 1 h. The mixture was cooled down to r.t., quenched with aqueous Na2S20s (5%wt, 10 mL) and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (0.13 g, 87%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 312.1, RT 1.29 min.1H NMR (500 MHz, CDCl3) 5 11.54 (s, 1H), 8.69 (s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.32 (d, J = 6.7 Hz, 1H), 6.19 (d, J = 6.7 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 2.13 (s, 3H), 1.83 (s, 3H), 1.31 (t, J= 7.1 Hz, 3H).

[0721] INTERMEDIATE 44: 6-Methyl-5-(4-methyl-2-oxo-1,2-dihvdropyridin-3-yl)benzofuran-3-carboxylic acid

[0722]

[0723] Prepared from ethyl 6-methyl-5-(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 43) (0.13 g, 0.40 mmol) in accordance with the procedure described for Intermediate 41 to afford the title compound (0.13 g, 96%) as a pale yellow oil. LCMS (Method 3B): [M+H]+m / z 284.1, RT 1.03 min.1H NMR (500 MHz, DMSO) 512.92 (s, 1H), 11.53 (s, 1H), 8.60 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.31 (d, = 6.7 Hz, 1H), 6.18 (d, J = 6.8 Hz, 1 H), 2.12 (s, 3H), 1.83 (s, 3H).

[0724] INTERMEDIATE 45: Ethyl 5-(5-fluoro-2-methoxypyridin-3-yl)-6-methylbenzofuran-3-carboxylate

[0725]

[0726] Prepared from ethyl 5-bromo-6-methyl-benzofuran-3-carboxylate (prepared according to the procedure of Intermediate 17) (0.20 g, 0.71 mmol) and 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 0.87 mmol) in accordance with the procedure described for Intermediate 40 to afford the title compound (0.24 g, 94%) as a white solid. LCMS (Method 3B):

[0727] [M+H]+m / z 330.1, RT 1.85 min.1H NMR (500 MHz, CDCl₃) 68.22 (s, 1 H), 8.06 (d, J = 3.0 Hz, 1 H), 7.82 (s, 1H), 7.44 (s, 1H), 7.30 (dd, J = 7.9, 2.8 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 2.24 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0728] INTERMEDIATE 46: Ethyl 5-(5-fluoro-2-oxo-1,2-dihvdropyridin-3-yl)-6-methylbenzofuran-3-carboxylate

[0729]

[0730] Prepared from ethyl 5-(5-fluoro-2-methoxypyridin-3-yl)-6-methylbenzofuran-3-carboxylate (prepared according to the procedure of Intermediate 45) (0.15 g, 0.42 mmol) in accordance with the procedure described for Intermediate 43 to afford the title compound (83 mg, 61%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 316.0, RT 1.32 min.1H NMR (500 MHz, DMSO) 5 11.65 (s, 1 H), 8.72 (s, 1 H), 7.70 (d, J = 6.5 Hz, 2H), 7.65 - 7.55 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 2.26 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).19F{1H} NMR (471 MHz, DMSO) 5 -139.7, -149.9. (2 x F peaks due to tautomerization)

[0731] INTERMEDIATE 47: 5-(5-Fluoro-2-oxo-1,2-dihvdropyridin-3-yl)-6-methylbenzofuran-3-carboxylic acid

[0732]

[0733] Prepared from ethyl 5-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylbenzofuran-3-carboxylate (prepared according to the procedure of Intermediate 46) (83 mg, 0.25 mmol) in accordance with the procedure described for Intermediate 41 to afford the title compound (49 mg, 64%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 288.1, RT 1.04 min.

[0734] INTERMEDIATE 48: (1R,3S,5S)-3-methyl-6-azabicvclor3.1.1lheptane-1-carboxylic acid

[0735]

[0736] (1 R,3S,5S)-3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1 ]heptane-1 -carboxylate (prepared according to the procedure of Intermediate 8B) (0.70 g, 2.55 mmol) and NaOH (1.05 g, 26.3 mmol) were dissolved in EtOH (20 mL) and stirred at 90 °C for 21 h. More NaOH (0.50 g, 12.5 mmol) was added and the reaction mixture was stirred at 90 °C for 5 h. The mixture was cooled down to r.t., acidified to pH~2 with concentrated HCI (3 mL) and concentrated in vacuo to afford the title compound (0.40 g, quant.) as a pale brown solid, which was used in the next step without further purification. LCMS (Method 3B): [M+H]+m / z 156.1, RT 0.10 min.

[0737] INTERMEDIATE 49: Methyl (1R,3S,5S)-3-methyl-6-azabicvclor3.1.1lheptane-1-carboxylate

[0738]

[0739] (1 / ?,3S,5S)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 48) (0.12 g, 0.79 mmol) was dissolved in MeOH (5 mL) and SOCl₂ (0.20 mL, 2.74 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at r.t. for 21 h and concentrated in vacuo to afford the title compound (0.13 g, quant.) as a brown solid, which was used in the next step without further purification. LCMS (Method 3B): [M+H]+m / z 170.2, RT 0.10 min.

[0740] INTERMEDIATE 50: 6-(tert-Butyl) 1-methyl (1R,3S,5S)-3-methyl-6-azabicyclor3.1.1lheptane-1,6-dicarboxylate

[0741]

[0742] Methyl (1 / ?,3S,5S)-3-methyl-6-azabicyclo[3.1,1]heptane-1 -carboxylate (prepared according to the procedure of Intermediate 49) (0.13 g, 0.79 mmol), Et3N (0.22 mL, 1.57 mmol), DMAP (10 mg, 0.08 mmol) and Boc₂O (0.35 g, 1.60 mmol) were dissolved in DCM (5 mL) and MeOH (0.50 mL). The reaction mixture was stirred at r.t. for 21 h and diluted with DCM (10 mL) and H2O (15 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-20% EtOAc / iso-hexane) to afford the title compound (0.17 g, 77%) as an orange oil. LCMS (Method 3B): [M-Boc+H]+ m / z 170.2, RT 1.48 min.1H NMR (500 MHz, CDCl3) δ 3.99 (s, 1 H), 3.65 (s, 3H), 2.39 - 2.27 (m, 1 H), 1.81 - 1.70 (m, 1 H), 1.52 (dd, J = 13.4, 9.1 Hz, 1H), 1.40 - 1.27 (m, 10H), 1.26 - 1.20 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H). (2H under DMSO peak).

[0743] INTERMEDIATE 51: (1R,3S.5S)-6-(tert-Butoxycarbonyl)-3-methyl-6-azabicyclo[3.1.11heptane-1 -carboxylic acid

[0744]

[0745] NaOH (50 mg, 1.25 mmol) in H2O (0.30 mL) was added to a solution of 6-(tert-butyl) 1-methyl (1 / ?,3S,5S)-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (prepared according to the procedure of Intermediate 50) (0.17 g, 0.61 mmol) in MeOH (2 mL). The reaction mixture was stirred at r.t. for 2 h, quenched with aqueous HCI (1 M, 1 mL) to pH ~4, diluted with H2O (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (0.13 g, 76%) as an orange oil. LCMS (Method 3B): [M-tBu+H]+m / z 200.1, RT 1.30 min.1H NMR (500 MHz, DMSO) 6 12.58 (s, 1 H), 3.97 (t, J = 5.9 Hz, 1 H), 2.48 - 2.44 (m, 2H), 2.38 - 2.31 (m, 1 H), 1.81 -1.70 (m, 1H), 1.47 (dd, J= 13.5, 9.0 Hz, 1H), 1.41 - 1.30 (m, 9H), 1.28 - 1.20 (m, 2H), 1.04 (d, J = 6.8 Hz, 3H).

[0746] INTERMEDIATE 52: tert-Butyl (1,3S.5S)-3-methyl-1-(3-methyl-1.2.4-oxadiazol-5-yl)-6-azabicyclo[3.1.11heptane-6-carboxylate

[0747]

[0748] (1 / ?,3S,5S)-6-(tert-Butoxycarbonyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 51) (0.13 g, 0.47 mmol) and (E)-N'-hydroxyacetimidamide (70 mg, 0.95 mmol) were dissolved in DMF (3 mL). DIPEA (0.25 mL, 1.46 mmol) and HATU (0.37 g, 0.97 mmol) were added and the reaction mixture was stirred at r.t. for 17 h. The mixture was heated to 100 °C, stirred for 3 h, cooled down to r.t. and diluted with H2O (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with H2O (2 x 15 mL), brine (20 mL), dried over MgSC>4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% (EtOAc: EtOH 3:1) / iso-hexane) to afford the title compound (31 mg, 18%) as a yellow oil. LCMS (Method 3B): [M-tBu+H]+m / z 238.1, RT 1.52 min.1H NMR (500 MHz, DMSO) 54.11 (s, 1 H), 2.83 - 2.65 (m, 2H), 2.43 - 2.38 (m, 1H), 2.34 (s, 3H), 1.77 (dd, J = 13.2, 9.0 Hz, 1H), 1.55 (dd, J = 8.3, 3.2 Hz, 1H), 1.41 - 1.20 (m, 11 H), 1.10 (d, J = 6.7 Hz, 3H).

[0749] INTERMEDIATE 53: 3-Methyl-5-((1R.3S.5S)-3-methyl-6-azabicyclor3 lheptan-1-yl)-1,2,4-oxadiazole

[0750]

[0751] tert-Butyl (1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 52) (31 mg, 0.09 mmol) and 2,6-lutidine (70 pL, 0.60 mmol) were dissolved in DCM (2 mL), cooled to 0 °C and TMSOTf (46 pL, 0.25 mmol) was added. The mixture was warmed up to r.t., stirred for 1 h, quenched with MeOH (1 mL) and concentrated in vacuo to afford the title compound (17 mg, quant.) as an orange oil, which was used in the next step without further purification. LCMS (Method 3C): [M+H]+m / z 194.3, RT 0.88 min. INTERMEDIATE 54: tert-Butyl rac-(1S,3S,5 )-1-r2-rtert-butyl(dimethyl)silylloxy-1-hydroxy-ethyl1-3-methyl-8-azabicvclo[3.2.11octane-8-carboxylate

[0752]

[0753] To a solution of tert-butyl (c / s)-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (653 mg, 2.90 mmol) in Et2O (29 mL) were added N, N, N', N'-tetramethyl ethylenediamine (1.3 mL, 8.6 mmol) and sec-BuLi (6.2 mL, 8.7 mmol) at -78 °C. After the reaction mixture was stirred for 30 min at 0 °C, 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (1.7 mL, 8.9 mmol) was added at -78 °C. The reaction mixture was gradually allowed to warm to 0 °C and stirred for 3 hours. The reaction was quenched with saturated aqueous NH4CI. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-40% EtOAc / iso-hexane) to afford the title compound (1.28 g, 100%) as a colourless oil. LCMS (Method 1A): [M+H]+m / z 400.2, RT 1.73 minutes.

[0754] INTERMEDIATE 55: tert-Butyl rac-(1S,3S,5R)-1-((1S or 7R)-1,2-dihvdroxyethyl)-3-methyl-8-azabicyclo[3.2.11octane-8 -carboxylate

[0755]

[0756] To a solution of tert-butyl rac-(1S,3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxy-1-hydroxy-ethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (prepared according to the procedure of Intermediate 54) (502 mg, 1.13 mmol) in THF (6 mL) at 0 °C was added tetrabutylammonium fluoride (1.9 mL, 1.9 mmol, 1 mol / L). The reaction mixture was stirred at 0 °C for 4 hours and then quenched with saturated aqueous NH4CI. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (peak 2, 100 mg, 31%) as a white solid. LCMS (Method 1A): [M-Boc+H]+m / z 186.2, RT 1.27 minutes.1H NMR (300 MHz, DMSO) 54.49 - 4.38 (m, 1H), 4.28 (d, J = 21.3 Hz, 1H), 4.15 -4.04 (m, 2H), 3.47 (ddd, J = 9.5, 6.3, 3.0 Hz, 1H), 3.32 - 3.16 (m, 2H), 2.11 (td, J = 12.3, 6.1 Hz, 3H), 1.75 (dt, J = 17.0, 6.8 Hz, 1H), 1.64 - 1.44 (m, 2H), 1.41 (s, 9H), 1.36 - 1.01 (m, 2H), 1.02 (d, J = 7.1 Hz, 3H).

[0757] INTERMEDIATE 56: tert-Butyl (1R,3S,5S)-1-carbamoyl-3-methyl-6-azabicyclor3.1.1lheptane-6-carboxylate

[0758]

[0759] HATU (0.40 g, 1.05 mmol) was added to a mixture of (1 R,3S,5S)-6-(tert-butoxycarbonyl)-3-methyl-6-azabicyclo[3.1,1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 51) (0.21 g, 0.74 mmol), NH4CI (48 mg, 0.90 mmol) and DIPEA (0.40 mL, 2.34 mmol) in DMF (3 mL). The reaction was stirred at r.t. for 3 h. The mixture was diluted with H2O (10 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with H2O (20 mL) and brine (2 x 20 mL), dried over anhydrous MgSO4, filtered, and concentrated onto silica. The crude product was purified by flash chromatography on silica gel (0-100% [EtOAc: EtOH 3:1] / iso-hexane) to afford the title compound (0.13 g, 63%) as an off-white solid. LCMS (Method 3B): [M-Boc+H]+m / z 155.1, RT 1.19 min.1H NMR (500 MHz, CDCl₃) 58.10 (s, 1H), 5.34 (s, 1H), 3.97 (t, J = 5.8 Hz, 1H), 2.57 (d, J = 11.3 Hz, 2H), 2.45 (s, 1H), 1.95 - 1.87 (m, 1H), 1.68 (dd, J = 13.6, 8.8 Hz, 1H), 1.47 (s, 9H), 1.35 (d, J = 8.7 Hz, 1H), 1.28 - 1.24 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H).

[0760] INTERMEDIATE 57: tert-Butyl (1 / ?,3S,5S)-1-cvano-3-methyl-6-azabicyclor3.1.1lheptane-6-carboxylate

[0761]

[0762] To a solution of tert-butyl (1R,3S,5S)-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 56) (0.13 g, 0.47 mmol) in THF (3.5 mL) at 0 °C was added Et3N (0.14 mL, 1.03 mmol) followed by trifluoroacetic anhydride (72 pL, 0.52 mmol). The mixture was stirred for 1 h at 0 °C then warmed to r.t. and stirred for 3 h. Saturated aqueous NaHCO3(10 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-100% MTBE / iso-hexane) to afford the title compound (95 mg, 78%) as a colourless oil. LCMS (Method 3B): [M-tBu+H]+m / z 181.1, RT 1.51 min.1H NMR (500 MHz, CDCl₃) 54.11 - 4.03 (m, 1H), 2.83 (t, J = 7.7 Hz, 1 H), 2.62 (d, J = 46.9 Hz, 1 H), 2.00 - 1.92 (m, 1 H), 1.61 (s, 1 H), 1.50 (s, 9H), 1.44 -1.41 (m, 2H), 1.26 - 1.22 (m, 1 H), 1.08 (d, J = 6.9 Hz, 3H). INTERMEDIATE 58: tert-Butyl (1r?.3S,5S)-1-(imino(methoxy)methyl)-3-methyl-6-azabicyclo[3.1.11heptane-6-carboxylate

[0763]

[0764] A solution of NaOMe in MeOH (5.4 M, 70 pL, 0.38 mmol) was added to a solution of tert-butyl (1R,3S,5S)-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 57) (95 mg, 0.36 mmol) in MeOH (1 mL) at 0 °C. The reaction was allowed to warm to r.t. and was stirred for 24 h. The solvent was removed with a stream of compressed air to afford the title compound (0.25 g, quantitative yield) as a yellow oil. LCMS (Method 3C): [M+H]+m / z 269.4, RT 1.46 min.

[0765] INTERMEDIATE 59: tert-Butyl (1 / ?,3S,5S)-1-(hvdrazineyl(imino)methyl)-3-methyl-6-azabicyclo[3.1.11heptane-6-carboxylate

[0766] A

[0767]

[0768] Hydrazine hydrate (55% in H2O) (0.17 mL, 1.93 mmol) was added to a solution of tert-butyl (1 R,3S,5S)-1 -(imino(methoxy)methyl)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carboxylate (prepared according to the procedure of Intermediate 58) (0.25 g, 0.38 mmol) in EtOH (3 mL). The reaction was stirred at 80 °C for 4 h, then cooled to r.t. and concentrated in vacuo to afford the title compound (0.17 g, quantitative yield) as a yellow solid. LCMS (Method 3C): [M+H]+m / z 269.5, RT 1.12 min.

[0769] INTERMEDIATE 60: tert-Butyl (1,3S.5S)-3-methyl-1-(1.2.4-triazin-3-yl)-6-azabicyclo[3.1.11heptane-6-carboxylate

[0770]

[0771] Oxalaldehyde (40 % in H2O, 0.26 mL, 1.79 mmol) was added to a solution of tert-butyl (1 / ?,3S,5S)-1-(hydrazineyl(imino)methyl)-3-methyl-6-azabicyclo[3.1,1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 59) (0.17 g, 0.38 mmol) in EtOH (5 mL) and stirred at 80 °C for 2 h. The reaction was allowed to cool to r.t. and H2O (10 mL) and EtOAc (20 mL) were added. The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic fractions were washed with brine (40 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (14 mg, 11%) as a yellow solid. LCMS (Method 3B): [M-Boc+H]+m / z 191.1, RT 1.26 min.1H NMR (500 MHz, DMSO) 59.37 (d, J = 2.5 Hz, 1H), 8.89 (s, 1H), 4.16 (s, 1H), 3.01 (s, 1 H), 2.47 - 2.40 (m, 1H), 2.36 (p, J = 2.0 Hz, 1H), 1.98 - 1.84 (m, 2H), 1.49 (d, J = 8.1 Hz, 1H), 1.39 (brs, 9H), 1.28 - 1.21 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H).

[0772] INTERMEDIATE 61: (1 R,3S,5S)-3-Methyl-1 -(1,2.4-triazin-3-yl)-6-azabicyclor3.1.llheptane

[0773]

[0774] TFA (50 pL, 0.67 mmol) was added to a solution of tert-butyl (1F?,3S,5S)-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 60) (14 mg, 0.05 mmol) in DCM (2 mL) and the reaction stirred at r.t. for 1 h. The reaction was concentrated in vacuo to afford the title compound as the trifluoroacetate salt (13 mg, quantitative yield) as a brown oil that was used in the next step without further purification. LCMS (Method 3B): [M+H]+m / z 191.1, RT 0.14 min.

[0775] INTERMEDIATE 62: tert-Butyl (1R,3S,5S)-1-(2-acetylhvdrazine-1-carbonyl)-3-methyl-6-azabicyclo[3.1.11heptane-6-carboxylate

[0776]

[0777] To a solution of (1 / ?,3S,5S)-6-(tert-butoxycarbonyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 51) (1.83 g, 6.67 mmol), acetohydrazide (1.75 g, 23.6 mmol) and DIPEA (3.40 mL, 20.0 mmol) in DMF (15 mL) was added HATU (3.50 g, 9.20 mmol). The mixture was stirred at r.t. for 2 h. Saturated aqueous NH4CI (70 mL) was added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with H2O (70 mL), brine (70 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0-100% [3:1 EtOAc: EtOH] / iso-hexane) to afford the title compound (2.09 g, 87%) as a yellow oil. LCMS (Method 3C): [M-Boc+H]+m / z 212.3, RT 1.00 min.1H NMR (500 MHz, DMSO-d6) 59.93 -9.39 (m, 2H), 4.00 - 3.94 (m, 1 H), 2.47 - 2.33 (m, 3H), 1.84 (s, 3H), 1.77 (d, J = 9.9 Hz, 1 H), 1.54 (dd, J = 13.5, 8.8 Hz, 1H), 1.43 - 1.35 (m, 9H), 1.29 - 1.20 (m, 1H), 1.09 - 1.01 (m, 4H).

[0778] INTERMEDIATE 63: tert-Butyl (1R,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-.1. -6-(

[0779]

[0780] To a solution of tert-butyl (1R,3S,5S)-1-(2-acetylhydrazine-1-carbonyl)-3-methyl-6-azabicyclo[3.1,1]heptane-6-carboxylate (prepared according to the procedure of Intermediate62) (2.08 g, 5.81 mmol) in MeCN (50 mL) was added Cs2CO3(8.00 g, 24.6 mmol) and TsCI (1.35 g, 7.08 mmol). The mixture was stirred at r.t. for 18 h. H2O (75 mL) and a saturated aqueous NH4CI solution (25 mL) were added and the aqueous was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (2 x 100 mL), dried over MgSC>4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (1.25 g, 77%) as a white solid. LCMS (Method 3B): [M-tBu+H]+m / z 238.2, RT 1.34 min.1H NMR (500 MHz, CDCl₃) 54.27 - 4.10 (m, 1H), 3.16 - 2.94 (m, 1H), 2.93 - 2.85 (m, 1H), 2.70 - 2.45 (m, 4H), 2.12 - 1.96 (m, 1H), 1.75 (dd, J = 13.5, 9.0 Hz, 1H), 1.53 - 1.20 (m, 11 H), 1.14 (d, J = 6.8 Hz, 3H).

[0781] INTERMEDIATE 64: 2-Methvl-5-K1R,3S,5S)-3-methvl-6-azabicvclor3.1.1lheptan-1-vll-1,3,4-oxadiazole

[0782] o \. _ / fj

[0783]

[0784] To a solution of tert-butyl (1R,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1,1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 63) (80 mg, 0.27 mmol) in DCM (4 mL) at 0 °C was added 2,6-lutidine (0.18 mL, 1.50 mmol) and TMSOTf (0.13 mL, 0.69 mmol). The mixture was warmed to r.t. and stirred for 30 minutes. The reaction was quenched by the addition of MeOH (2 mL), then the reaction was concentrated in vacuo to afford the title compound (52 mg, quantitative yield) as a pale-yellow oil. LCMS (Method 3C): [M+H]+m / z 194.4, RT 0.76 min.

[0785] INTERMEDIATE 65: Methyl (1R,3S.5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.11heptane-1 -carboxylate

[0786]

[0787] HATU (438 mg, 1.15 mmol) was added to a mixture of methyl (1R,3S,5S)-3-methyl-6-azabicyclo[3.1,1]heptane-1 -carboxylate (prepared according to the procedure of Intermediate 49) (130 mg, 0.77 mmol), 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 21) and DIPEA (395 pL, 2.30 mmol) in DMF (3.5 mL). The resulting mixture was stirred at r.t. for 20 h. The mixture was diluted with a saturated aqueous NH4CI solution (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with a saturated aqueous NaHCO3solution (30 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane then 30-100% [EtOAc / EtOH(3:1)] / iso-hexane) to give the title compound (250 mg, 48%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 412.2, RT 1.18 min.

[0788] 1H NMR (500 MHz, DMSO-d6, 363K) 58.45 (d, J = 4.2 Hz, 1 H), 7.79 (s, 1 H), 7.52 (s, 1 H), 6.32 (s, 1H), 3.80 - 3.72 (m, 3H), 3.70 (s, 3H), 3.50 - 3.45 (m, 3H), 2.82 - 2.72 (m, 2H), 2.35 - 2.33 (m, 3H), 2.27 - 2.20 (m, 1H), 1.87 - 1.73 (m, 1H), 1.63 (dd, J = 13.3, 8.9 Hz, 1H), 1.35 (dd, J = 13.7, 9.0 Hz, 1 H), 1.02 (d, J = 6.8 Hz, 3H).

[0789] INTERMEDIATE 66: (1R,3S,5S)-3-Methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.11heptane-1 -carboxylic acid

[0790]

[0791] A solution of methyl (1R,3S,5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1,1]heptane-1 -carboxylate (prepared according to the procedure of Intermediate 65) (250 mg, 0.37 mmol) and LiOH·H2O (20 mg, 0.48 mmol) in THF (12 mL) and H2O (6 mL) was stirred for 2 h then more LiOH·H2O (5 mg, 0.12 mmol) was added and the mixture was stirred for 18 h. More LiOH·H2O (20 mg, 0.48 mmol) was added and the mixture was stirred for 2 h then an aqueous HCI solution (1 M, 1.1 mL) was added followed by H2O (10 mL) and brine (10 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% [EtOAc / EtOH / AcOH (75:25:2)] / iso-hexane) to give the title compound (191 mg, 100 %) as a pale yellow solid. LCMS (Method 3B):

[0792] [M+H]+m / z 398.2, RT 1.18 min.

[0793] INTERMEDIATE 67: Ethyl 5-(6-fluoro-3-oxo-2,3-dihvdropyridazin-4-yl)-6-methylbenzofuran-3-carboxylate

[0794]

[0795] A mixture of 4-bromo-6-fluoropyridazin-3(2H)-one (180 mg, 0.933 mmol), ethyl 6-methyl-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate (prepared according to a procedure analogous to that of Intermediate 25) (0.73 g, 1.87 mmol) and K2CO3(387 mg, 2.80 mmol) in 1,4-dioxane (12 mL) and water (1 mL) was sparged with N2 then XPhos Pd(crotyl)CI (Pd-170) (63 mg, 0.09 mmol) was added. The mixture was heated at 90 °C for 18 h then cooled to r.t.. The mixture was filtered, washing with DCM / MeOH (9:1, 100 mL). The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (0-10% MeOH / DCM). The product was triturated with tBME (2 x 5 mL) and the solid dried in vacuo to give the title compound (56 mg, 17%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 317.0, RT 1.36 min.1H NMR (500 MHz, DMSO) 5 12.75 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 4.41 -4.26 (m, 2H), 2.31 (s, 3H), 1.36 - 1.29 (m, 3H).19F{1H} NMR (471 MHz, DMSO) 5 -93.90.

[0796] INTERMEDIATE 68: 5-(6-Fluoro-3-oxo-2,3-dihvdropyridazin-4-yl)-6-methylbenzofuran-3-carboxylic acid

[0797] N HN

[0798]

[0799] Prepared from ethyl 5-(6-fluoro-3-oxo-2,3-dihydropyridazin-4-yl)-6-methylbenzofuran-3-carboxylate (prepared according to the procedure of Intermediate 67), (56 mg, 0.18 mmol) in accordance with the procedure described for Intermediate 37 to afford the title compound (75 mg, quant.) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 289.0, RT 1.05 min. INTERMEDIATE 69: rac-(5S,7S)-7-(Trifluoromethyl)-1,3-diazaspiror4.5ldecane-2,4-dione CF3

[0800] HN

[0801]

[0802] To a solution of 3-(trifluoromethyl)cyclohexan-1-one (40.0 g, 0.24 mol) in EtOH (400 mL) and water (400 mL) was added (NH4)2CO3(69.4 g, 0.72 mol) and KCN (18.8 g, 0.29 mol). After stirring at 85 °C for 16 h, the mixture was cooled to r.t. The mixture was diluted with ethyl acetate (2000 mL) and water (1000 mL) and the phases were separated. The water was extracted with ethyl acetate (500 mL) then the combined organic phase was washed with water (3 x 500 mL), brine (500 mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated in vacuo then EtOH (200 mL) was added and the mixture stirred at r.t. for 4 h. The product was collected by filtration, washed with EtOH (100 ml) and dried in vacuo to give the title compound (28 g, 50%) as a white solid.1H NMR (400 MHz, DMSO-d6): 5 10.76 (s, 1H), 8.19 (s, 1H), 2.53 - 2.58 (m,1 H), 1.75 - 1.86 (m, 3H), 1.53 - 1.62 (m, 4H), 1.24 - 1.33 (m, 1H).

[0803] INTERMEDIATE 70: rac-Methyl (1S,3S)-1-amino-3-(trifluoromethyl)cyclohexane-1-carboxylate

[0804] CF3

[0805]

[0806] To a solution of rac-(5S,7S)-7-(trifluoromethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (prepared according to the procedure of Intermediate 69) (28.0 g, 0.12 mol) in n-BuOH (280 mL) and H2O (280 mL) was added KOH (26.6 g, 0.474 mmol). The mixture was stirred at 145 °C for 72 h. The mixture was cooled to r.t., acidified with 6 M hydrochloride aqueous solution to pH 1-2. The mixture was concentrated in vacuo, dissolved in MeOH (250 mL), then SOCI2 (30 mL) was added. The mixture was stirred at 80 °C for 16 h. The mixture was cooled to r.t., concentrated in vacuo and diluted with ethyl acetate (400 mL) and water (200 mL). The mixture was basified to pH 10-11 with saturated sodium bicarbonate aqueous solution. The mixture was separated and the organic phase was washed with water (100 mL) and brine (100 mL), dried over Na2SC>4(s) and filtered. The filtrate was concentrated in vacuo to give the title compound (25 g, 93%) as a white solid. LCMS (Method 6): [M+H]+m / z 226.2, RT 1.03 min. INTERMEDIATE 71: rac-Methyl (lS,3S)-1-(pyridine-2-carbonylamino)-3- (trifluoro methyl Icyclohexanecarboxylate

[0807]

[0808] To a suspension of rac-methyl (1S,3S)-1-amino-3-(trifluoromethyl)cyclohexane-1-carboxylate (prepared according to the procedure of Intermediate 70) (25 g, 111 mmol) and pyridine-2-carboxylic acid (13.7 g, 111 mmol) in DCM (500 mL) was added DCC (25.2 g, 122 mmol) and DMAP (680 mg, 5.55 mmol). The mixture was stirred at r.t. for 16 h. The mixture was filtered, then the filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (petroleum ether / ethyl acetate, 0% to 35%) to obtain the title compound (24.0 g, 62%) as a yellow oil.1H NMR (400 MHz, DMSO-d6): 58.68 - 8.71 (m, 2H), 8.00 - 8.05 (m, 2H), 7.63 - 7.68 (m, 1 H), 3.63 (s, 3H), 2.67 - 2.71 (m, 1 H), 2.34 - 2.48 (m, 1 H), 2.22 - 2.24 (m, 1 H), 1.84 - 1.88 (m, 1 H), 1.73 - 1.79 (m, 2H), 1.64 - 1.66 (m, 1 H), 1.28 - 1.36 (m, 1 H).

[0809] INTERMEDIATE 72: rac-Methyl (1R,3S,5S)-6-(pyridine-2-carbonyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.11heptane-1 -carboxylate

[0810]

[0811] A mixture of rac-methyl (1S,3S)-1-(pyridine-2-carbonylamino)-3-(trifluoromethyl)cyclohexanecarboxylate (prepared according to the procedure of Intermediate 71) (10.0 g, 30.3 mmol), silver acetate (15.2 g, 90.9 mmol), palladium (II) acetate (2.04 g, 9.09 mmol), C6F5I (89 g, 303 mmol), 1,4-benzoquinone (3.28 g, 30.4 mmol) and trisodium phosphate (14.9 g, 90.9 mmol) in 1,1,2,2-tetrachloroethane (600 mL) was stirred at 145 °C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo and purified by flash chromatography (petroleum ether / ethyl acetate, 5% to 30%) followed by preparative HPLC to give the title compound (1.1 g, 11%) as an off-white oil. LCMS (Method 6): [M+H]+m / z 329.1, RT 2.46 min.1H NMR (400 MHz, DMSO) 58.67 (dd, J = 3.6, 1.2 Hz, 0.5H), 8.43 - 8.44 (m,0.5H), 7.99 - 8.01 (m, 2H), 7.55 - 7.63 (m, 1H), 5.16 - 5.19 (m, 0.5H), 4.52 - 4.55 (m. 0.5H), 3.71 (s, 1.5H), 3.52 (s, 1.5H), 2.72 - 2.92 (m, 3H), 2.55 - 2.62 (m, 0.5H), 2.37 - 2.41 (m, 0.5H), 2.03 - 2.16 (m, 1 H), 1.81 - 1.87 (m, 1 H), 1.54 - 1.61 (m, 1H).

[0812] INTERMEDIATE 73: Methyl (1.3S.5S)-6-(pyridine-2-carbonyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.11heptane-1 -carboxylate

[0813] CF3

[0814]

[0815] rac-Methyl (1R,3S,5S)-6-(pyridine-2-carbonyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate (prepared according to a procedure analogous to that of Intermediate 72) (3.5 g) was subjected to chiral purification. Purification was performed using a Daicel CHIRALPAK® IG column, 76 x 245 mm, 20 pm, flow rate 300 mL / min, column temperature 30 °C, eluting with MeCN to give the title compound (peak 1, 790 mg).

[0816] INTERMEDIATE 74: (1,3S,5S)-6-(tert-butoxycarbonyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.11heptane-1 -carboxylic acid

[0817] CF3

[0818]

[0819] BOC O

[0820] A mixture of methyl (1R,3S,5S)-6-(pyridine-2-carbonyl)-3-(trifluoromethyl)-6-azabicyclo[3.1,1]heptane-1 -carboxylate (prepared according to the procedure of Intermediate 73) (790 mg, 2.29 mmol) and NaOH (1.00 g, 25.0 mmol) in EtOH (15 mL) was heated at 80 °C for 16 h. The mixture was cooled down to r.t. and concentrated in vacuo. The residue was dissolved in H2O (10 mL) and acidified to pH ~1 with 1 M aq. HCI (~ 30 mL). The mixture was concentrated in vacuo, dissolved in 1,4-dioxane (5 mL) and H2O (5 mL) then NaOH (274 mg, 6.85 mmol) and Boc₂O (649 mg, 2.97 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 h. Additional Boc₂O (499 mg, 2.29 mmol) and NaOH (274 mg, 6.85 mmol) were added and the mixture was heated at 80 °C for 24 h. The reaction mixture was cooled to r.t. then diluted with 2 M aq. NaOH (10 mL) and washed with Et20 (3 x 10 mL). The aqueous layer was acidified with 1 M aq HCI to pH 1 (30 mL). The resulting solution was then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (650 mg, 87%) as an orange oil. LCMS (Method 3B): [M-H]- m / z 308.0, RT 1.38 min.1H NMR (500 MHz, DMSO) 512.92 (s, 1H), 4.11-4.09 (m, 1H), 2.63-2.53 (m, 3H), 2.46-2.44 (m, 1 H), 1.90 (q, J = 7.5 Hz, 1 H), 1.73-1.68 (m, 1 H), 1.47 - 1.21 (m, 10H).19F{1H} NMR (471 MHz, DMSO) 5 -71.48.

[0821] INTERMEDIATE 75: tert-butyl (1.3S.5S)-1-(5-methyl-1.3.4-oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1 lheptane-6-carboxylate

[0822] CF3

[0823]

[0824] To a solution of (1 / ?,3S,5S)-6-(tert-butoxycarbonyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1 ]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 74) (400 mg, 1.23 mmol), acetohydrazide (0.273 g, 3.69 mmol) and DIPEA (0.627 mL, 3.69 mmol) in DMF (5 mL) was added HATU (0.701 g, 1.84 mmol) at r.t.. The mixture was stirred at r.t. for 16 h. The rection mixture was then diluted with sat. aq. NH4CI solution (20 mL) and the resulting solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was then washed with saturated aqueous LiCI (20 mL) and brine (20 mL), dried over MgSC>4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (0-100% [EtOAc / EtOH 3 / 1] / iso-hexane) to afford the intermediate tert-butyl (1 R,3S,5S)-1 -(acetamidocarbamoyl)-3-(trifluoromethyl)-6-azabicyclo[3.1,1]heptane-6-carboxylate. To a solution of this intermediate (380 mg, 1.04 mmol) in MeCN (5 mL) was added Cs2CO3(1.35 g, 4.16 mmol) and tosyl chloride (228 mg, 1.20 mmol) at r.t.. The reaction mixture was then heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% [EtOAc / EtOH 3 / 1] / iso-hexane) to afford the title compound (280 mg, 74%) as a yellow solid. LCMS (Method B): [M-Boc+H]+m / z 248.1, [M+Na]+m / z 370.2, RT 1.45 min.1H NMR (500 MHz, DMSO) 54.19 (t, J = 5.7 Hz, 1H), 2.99-2.79 (m, 2H), 2.79 -2.66 (m, 1H), 2.52 (s, 3H), 2.19 (dd, J= 13.8, 8.1 Hz, 1H), 1.85 - 1.77 (m, 1H), 1.58 (d, J= 9.1 Hz, 1H), 1.51 - 1.05 (m, 10H).

[0825] 19F{1H} NMR (471 MHz, DMSO) 5 -71.45.

[0826] IV. EXAMPLES EXAMPLE 1: 146-Methyl-34(1S,5ft)-3-methyl-6-i.1.1lheptane-6- -5-' idin-2-one

[0827]

[0828] To a solution of (5-bromo-6-methyl-benzofuran-3-yl)-[(1S,5R)-3-methyl-6-azabicyclo[3.1,1]heptan-6-yl]methanone (prepared according to the procedure of Intermediate 23) (85 mg, 0.24 mmol) and 2-imidazolidone (45 mg, 0.5 mmol) in 1,4-dioxane (3 mL), was added cesium carbonate (240 mg, 0.73 mmol) and Ephos Pd G4 (25 mg, 0.26 mmol). The reaction mixture was stirred at 90 °C for 4 h. Then, the mixture was diluted with EtOAc (25 mL) and washed with a saturated aqueous solution of NaHCO3(2 x 10 ml). The organic layer was dried over MgSC>4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (100 / 0 to 95 / 5, DCM / MeOH) to afford the title compound as a white solid (40 mg, 46%). LCMS (Method 5): [M+H]+m / z 354.3, RT 1.02 min.1H NMR (400 MHz, DMSO) 58.51 (s, 1 H), 7.80 (s, 1 H), 7.57 (s, 1 H), 6.66 (s, 1 H), 4.72 (dt, J = 9.0, 4.5 Hz, 1H), 4.31 (dq, J = 6.1, 3.8 Hz, 1H), 3.73 (dd, J = 8.9, 6.7 Hz, 2H), 3.45 (dd, J = 8.8, 6.7 Hz, 2H), 2.65 (dt, J = 8.6, 6.5 Hz, 1H), 2.32 (s, 3H), 2.23 (dt, J = 13.3, 6.8 Hz, 1H), 1.78 (h, J = 8.1 Hz, 1H), 1.33 (ddd, J = 27.9, 13.5, 7.7 Hz, 2H), 1.20 (d, J = 8.4 Hz, 1H), 0.97 (d, J = 6.8 Hz, 3H).

[0829] EXAMPLE 2: 1434(1 ft.3S,5S)-14(1 S or7ft)-1-hvdroxyethyll-3-methyl-6-

[0830]

[0831] azabicyclo[3.1.11heptane-6-carbonyl1-6-methyl-benzofuran-5-yl1imidazolidin-2-one;

[0832] EXAMPLE 3: 1434(1 ft.3S,5S)-14(1 S or 7ft)-1 -methoxyethyll-3-methyl-6-azabicyclo[3.1.11heptane-6-carbonyl1-6-methyl-benzofuran-5-yl1imidazolidin-2-one; and EXAMPLE 4: 1434(1 ft.3S,5S)-14(1 ft or1S)-1-methoxyethyll-3-methyl-6-azabicyclo[3.1.11heptane-6-carbonyl1-6-methyl-benzofuran-5-yl1imidazolidin-2-one Mixed Mixed Mixed

[0833]

[0834] To a solution of 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 21) (75 mg, 0.11 mmol) in DMF (1.4 mL) were added the unseparated mixture of (1R,3S,5S)-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane and 1-[(1R,3S,5S)-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl]ethanol (prepared according to the procedures of Intermediate 14 and Intermediate 15) (156 mg), HATU (130 mg, 0.342 mmol) and DIPEA (0.3 mL, 1.7 mmol). The reaction mixture was stirred at r.t. for 1 h, then diluted with DCM and H2O. The layers were separated and the aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford Example 2 (23 mg, 20%) as a white solid; Example 3 (19 mg, 16%) as a white solid; and Example 4 (10 mg, 8%) as a white solid.

[0835] Example 2:1H NMR (400 MHz, DMSO) 58.59 (s, 1H), 7.81 (s, 1H), 7.61 - 7.56 (m, 1H), 6.65 (s, 1 H), 5.68 (s, 1 H), 4.75 (dd, J = 6.9, 5.3 Hz, 1 H), 3.92 (q, J = 6.5 Hz, 1 H), 3.74 (dd, J = 8.9, 6.6 Hz, 2H), 3.49 - 3.40 (m, 2H), 2.41 - 2.30 (m, 4H), 2.24 (dt, J = 14.0, 7.0 Hz, 1 H), 1.69 (dt, J = 15.7, 7.9 Hz, 1 H), 1.44 - 1.32 (m, 2H), 1.28 (d, J = 8.3 Hz, 1 H), 1.03 - 0.90 (m, 6H).

[0836] LCMS (Method 5): [M+H]+m / z 398.4, RT 1.08 min.

[0837] Example 3:1H NMR (400 MHz, DMSO) 58.55 (s, 1 H), 7.81 (s, 1 H), 7.56 (s, 1 H), 6.65 (s, 1 H), 4.66 (t, J = 6.1 Hz, 1 H), 3.92 (q, J = 6.3 Hz, 1 H), 3.73 (dd, J = 8.9, 6.7 Hz, 2H), 3.45 (t, J = 7.9 Hz, 2H), 3.31 (s, 3H), 2.62 (t, J = 7.5 Hz, 1H), 2.32 (s, 4H), 2.15 (dd, J = 13.1, 6.4 Hz, 1H), 1.74 (dd, J = 13.8, 5.7 Hz, 1H), 1.38 - 1.25 (m, 2H), 1.07 (d, J = 8.0 Hz, 1H), 0.95 (dt, J = 6.4, 5.2 Hz, 8H). LCMS (Method 5): [M+H]+m / z 412.4, RT 1.12 min.

[0838] Example 4:1H NMR (400 MHz, DMSO) 58.54 (s, 1H), 7.80 (s, 1H), 7.59 - 7.52 (m, 1H), 6.65 (s, 1H), 4.67 (t, J = 6.1 Hz, 1H), 3.83 (q, J = 6.2 Hz, 1H), 3.73 (dd, J = 8.9, 6.6 Hz, 2H), 3.49 - 3.41 (m, 2H), 3.29 (s, 3H), 2.56 (d, J = 8.0 Hz, 1H), 2.37 (s, 2H), 2.32 (s, 3H), 2.21 - 2.13 (m, 1H), 1.78 - 1.62 (m, 2H), 1.35 - 1.21 (m, 1H), 1.15 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 8.7 Hz, 1H), 1.03 - 0.90 (m, 4H).

[0839] LCMS (Method 5): [M+H]+m / z 412.4, RT 1.13 min.

[0840] One of the isomers of Example 2 is 1-[3-[(1R,3S,5S)-1-[(1S)-1-hydroxyethyl]-3-methyl-6-azabicyclo[3.1,1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one and the other is 1 -[3-[(1 R,3S,5S)-1 -[(7R)-1 -hydroxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one.

[0841] One of the isomers of Example 3 is 1-[3-[(1 / ?,3S,5S)-1-[(1S)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1,1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one and the other is 1 -[3-[(1 R,3S,5S)-1 -[(7 / ?)-1 -methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one.

[0842] One of the isomers of Example 4 is 1-[3-[(1 / ?,3S,5S)-1-[(1 / ?)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1,1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one and the other one is 1 -[3-[(1 R,3S,5S)-1 -[(7S)-1 -methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one.

[0843] EXAMPLE 5: 1 -13-(7--.1. -7-carbonvl)-6-methvl-benzofuran-5- id in-2 -one

[0844]

[0845] Prepared from 7-azabicyclo[4.1.1]octan-7-yl-(5-bromo-6-methyl-benzofuran-3-yl)methanone (prepared according to the procedure of Intermediate 24) (30 mg, 0.086 mmol) and 2-imidazolidone (15 mg, 0.17 mmol) in accordance with the procedure described for Example 1 to afford the title compound (4 mg, 13%) as a white solid. LCMS (Method 5): [M+H]+m / z 354.4, RT 1.09 minutes.

[0846] 1H NMR (500 MHz, DMSO) 5 8.41 (s, 1H), 7.78 (s, 1H), 7.58 - 7.54 (m, 1H), 6.67 (s, 1H), 4.86 (ddd, J = 8.7, 3.9, 1.9 Hz, 1 H), 4.52 - 4.47 (m, 1 H), 3.72 (dd, J = 8.9, 6.7 Hz, 2H), 3.44 (ddd, J = 9.3, 6.5, 1.2 Hz, 2H), 2.71 - 2.63 (m, 1H), 2.33 - 2.29 (m, 3H), 2.19 (s, 1H), 1.85 (d, J = 8.2 Hz, 1 H), 1.79 - 1.71 (m, 1 H), 1.70 (dd, J = 10.4, 1.7 Hz, 1 H), 1.70 (s, 1 H), 1.57 (s, 1 H), 1.55 (s, 1 H).

[0847] EXAMPLE 6: 7-..2.1 lheptan-7-vl-16-i

[0848]

[0849] Prepared from 6-methyl-5-(2-pyridyl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 19) (10 mg, 0.039 mmol) and 7-azabicyclo[2.2.1]heptane (5.83mg, 0.59 mmol), in accordance with the procedure described for Examples 2, 3 and 4 to afford the title compound (6.9 mg, 52%).1H NMR (500 MHz, DMSO) 58.67 (ddd, J = 4.9, 1.9, 0.9 Hz, 1 H), 8.53 (s, 1H), 7.90 (td, J= 7.7, 1.8 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.55 (dt, J= 7.9, 1.1 Hz, 1H), 7.39 (ddd, J = 7.6, 4.9, 1.1 Hz, 1 H), 4.48 (s, 2H), 2.41 (s, 3H), 1.76 (dt, J = 7.1, 2.3 Hz, 4H), 1.49 (d, J = 7.3 Hz, 4H). LCMS (Method 5): [M+H]+m / z 333.3, RT 1.07 minutes.

[0850] EXAMPLE 7: 7-i.1.1loctan-7-vl-l6-i -3-

[0851] I

[0852] '" N:

[0853]

[0854] To a solution of 6-methyl-5-(2-pyridyl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 19) (0.25 g, 0.99 mmol) in DMF (10 mL) was added HATU (0.56 g, 1.48 mmol). After stirring for 10 min, 7-azabicyclo[4.1,1]octane hydrochloride (0.29 g, 1.97 mmol) was added followed by DI PEA (0.52 mL, 2.96 mmol) at 0 °C. The reaction mixture was then heated at 70 °C for 5 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, dried over Na2SC>4, filtered, and concentrated in vacuo. The crude material was purified by reverse phase preparative to afford the title compound (0.13 g, 39% yield) as an off-white solid. LCMS (Method 5): [M+H]+m / z 347.2, RT 1.05 minutes.1H NMR (400 MHz, DMSO-d6) 58.66-8.69 (m, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.87-7.91 (m, 1H), 7.60 (s, 1H), 7.51-7.55 (m, 1H), 7.37-7.40 (m, 1H), 4.83-4.90 (m, 1 H), 4.46-4.52 (m, 1 H), 2.61-2.71 (m, 1H), 2.40 (s, 3H), 2.14-2.25 (m, 1H), 1.82-1.93 (m, 1H), 1.46-1.79 (m, 7H).

[0855] EXAMPLE 8: (1S,5 / ?)-3-methyl-6-azabicvclor3.1.1lheptan-6-yll-r6-methyl-5-(1-methyl-1,2,4-triazol-3-yl)-1 -benzofuran-3-yllmethanone

[0856]

[0857] To a solution of 6-methyl-5-(1-methyl-1,2,4-triazol-3-yl)benzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 27) (0.10 g, 0.38 mmol) in DMF (5 mL) was added HATU (0.22 g, 0.58 mmol) and DIPEA (0.20 mL, 1.17 mmol) at room temperature. Then (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane (prepared according to a procedure analogous to that of Intermediate 3) (0.06 g, 0.58 mmol) was added and the mixture stirred at room temperature for 16 h. After completion, the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (0.03 g, 22%) as a yellow solid. LCMS (Method 5): [M+H]+m / z 351.4, RT 1.21 minutes.1H NMR (400 MHz, DMSO) 58.54 (s, 1 H), 8.52 (s, 2H), 7.58 (s, 1 H), 4.69-4.72 (m, 1 H), 4.29-4.35 (m, 1 H), 3.94 (s, 3H), 2.66 (s, 3H), 2.55-2.62 (m, 1H), 2.51-2.54 (m, 1H), 2.20-2.24 (m, 1H), 1.73-1.81 (m, 1H), 1.34-1.37 (m, 2H), 1.15-1.19 (m, 1H), 0.93-0.96 (m, 3H).

[0858] EXAMPLE 9: 5-methyl-3-r6-methyl-3-K1S,5 / ?)-3-methyl-6-azabicyclor3.1.1lheptane-6-

[0859]

[0860] carbonyllbenzofuran-5-yll-1H-pyridin-2-one

[0861]

[0862] To a solution of 6-methyl-5-(5-methyl-2-oxo-1 H-pyridin-3-yl)benzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 30) (0.05 g, 0.17 mmol) in DMF (5 mL) was added HATU (0.10 g, 0.26 mmol) and DIPEA (0.07 mL, 0.53 mmol) at room temperature. Then (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane (prepared according to a procedure analogous to that of Intermediate 3) (0.02 g, 0.26 mmol) was added and stirred at room temperature for 16 h. After completion, the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (0.01 g, 64%) as an off white solid. LCMS (Method 5): [M+H]+m / z 377.4, RT 1.22 minutes.1H NMR (400 MHz, DMSO) 5 11.50 (br s, 1H), 8.46 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.27 (d, =2.50 Hz, 1H), 7.19 (s, 1H), 4.69-4.71 (m, 1H), 4.24-4.28 (m, 1H), 2.61-2.65 (m, 1H), 2.43-2.46 (m, 1H), 2.23 (s, 3H), 2.17-2.22 (m, 1H), 2.05 (s, 3H), 1.72-1.78 (m, 1H), 1.30-1.37 (m, 2H), 1.14-1.17 (m, 1H), 0.95 (d, =6.75 Hz, 3H).

[0863] EXAMPLE 10: K1S,5ft)-3-methyl-6-azabicvclor3 lheptan-6-yll-r6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-yllmethanone

[0864]

[0865] To a solution of 6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 32) (0.05 g, 0.19 mmol) in DMF (5 mL) was added HATU (0.11 g, 0.29 mmol) and DIPEA (0.07 g, 0.58 mmol) at room temperature. Then (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane (prepared according to a procedure analogous to that of Intermediate 3) (0.04 g, 0.39 mmol) was added, and the reaction was stirred at room temperature for 16 h. After completion, the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (0.017 g, 23%) as white solid. LCMS (Method 5): [M+H]+m / z 350.3, RT 0.75 minutes.1H NMR (400 MHz, DMSO) 5 11.97 (br s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.50 (s, 1H), 7.13 (s, 1H), 4.68-4.72 (m, 1H), 4.23-4.31 (m, 1H), 2.61-2.66 (m, 1H), 2.53-2.55 (m, 1H), 2.52 (s, 3H), 2.34 (s, 3H), 2.18-2.23 (m, 1H), 1.75-1.81 (m, 1 H), 1.32-1.40 (m, 2H), 1.17-1.21 (m, 1H), 0.93-0.99 (m, 3H).

[0866] EXAMPLE 11: 5-Methyl-3-r6-methyl-3-K1 S,5 / ?)-3-methyl-8-azabicyclor3.2.1 loctane-8-carbonyllbenzofuran-5-yll-1H-pyridin-2-one

[0867]

[0868] To a solution of 6-methyl-5-(5-methyl-2-oxo-1 H-pyridin-3-yl)benzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 30) (0.07 g, 0.24 mmol) in DMF (7 mL) was added HATU (0.14 g, 0.37 mmol) and DIPEA (0.07 g, 0.74 mmol) at room temperature. Then (c / s)-3-methyl-8-azabicyclo[3.2.1]octane hydrochloride (0.08 g, 0.49 mmol) was added and the reaction was stirred at room temperature for 16 h. After completion, the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (0.015 g, 15%) as white solid. LCMS (Method 5): [M+H]+m / z 391.3, RT 1.24 minutes.1H NMR (400 MHz, DMSO) 5 11.50 (br s, 1H), 8.34 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.26-7.29 (m, 1H), 7.20 (s, 1H), 4.30-4.61 (m, 2H), 2.25 (s, 3H), 2.17-2.21 (m, 2H), 2.06 (s, 3H), 1.90-2.02 (m, 2H), 1.76-1.78 (m, 3H), 1.26-1.31 (m, 2H), 1.18-1.11 (m, 3H).

[0869] EXAMPLE 12: r5-(5-Fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-yll-n 1 S,5 / ?)-3-methyl-8-azabicyclo[3.2.11octan-8-yl1methanone

[0870]

[0871] To a solution of 5-(5-fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 34) (0.08 g, 0.25 mmol) in DMF (5 mL) was added HATU (0.14 g, 0.38 mmol) and DIPEA (0.13 mL, 0.76 mmol) at room temperature. Then (c / s)-3-methyl-8-azabicyclo[3.2.1]octane hydrochloride (0.04 g, 0.30 mmol) was added and stirred at room temperature for 16 h. After completion, the reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (50 mL). The organic layerwas separated, dried overanhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (0.05 g, 57%) as a yellow solid. LCMS (Method 5): [M+H]+m / z 380.3, RT 1.50 minutes.1H NMR (400 MHz, DMSO) 5 9.01 (s, 2H), 8.42 (s, 1H), 8.17 (s, 1H), 7.63 (s, 1H), 4.59-4.68 (m, 1H), 4.34-4.40 (m, 1H), 2.59 (s, 3H), 2.13-2.24 (m, 2H), 1.94-2.01 (m, 2H), 1.75-1.82 (m, 3H), 1.26-1.31 (m, 2H), 1.08-1.12 (m, 3H).

[0872] EXAMPLE 13: 1-r3-K1S,3S,5 / ?)-1-ri-hvdroxyethyll-3-methyl-8-azabicyclor3.2.1loctane-8-carbonyll-6-methyl-benzofuran-5-yllimidazolidin-2-one

[0873]

[0874] To a solution of tert-Butyl (1S,3S,5F?)-1-[1-hydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (prepared according to a procedure analogous to that of Intermediate 35) (250 mg, 0.761 mmol) in DCM (3 mL) was added TFA (0.60 mL, 7.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h, concentrated in vacuo, then added to a mixture of 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 21) (205 mg, 0.788 mmol) and HATU (355 mg, 0.934 mmol) in DMF (2 mL) at room temperature. DIPEA (0.70 mL, 4.0 mmol) was then added and the reaction mixture was stirred at room temperature for 1 h, then quenched with water. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% EtOAc / iso-hexane, then 0-20% MeOH / EtOAc), followed by chiral purification using a Chiralpak IB, 250 x 20.0 mm, 5 pm, flow rate 100 mL / min, column temperature 40°C, eluting with a 3-40% methanol & 0.1% ammonia solution gradient (120 bar), over 10 minutes on a Waters FractionLynx SFC Prep 150 in tandem with a QDa mass spectrometer to afford the title compound (peak 1, 33 mg, 7%) as a yellow solid. LCMS (Method 5): [M+H]+m / z 412.4, RT 1.15 minutes. 1H NMR (400 MHz, DMSO) 58.36 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 6.66 (s, 1H), 5.64 (d, J = 3.9 Hz, 1H), 4.37 (dd, J = 6.3, 4.0 Hz, 1 H), 4.28 (s, 1 H), 3.73 (dq, J = 19.3, 8.2 Hz, 2H), 3.44 (t, J = 7.9 Hz, 2H), 2.45 (d, J = 7.6 Hz, 1 H), 2.32 (s, 3H), 2.11 - 1.89 (m, 3H), 1.85 - 1.68 (m, 2H), 1.58 (d, J = 11.7 Hz, 1 H), 1.42 (dd, J = 13.5, 6.5 Hz, 1H), 1.15 (dd, J = 13.3, 6.6 Hz, 1H), 1.07 (dd, J = 6.6, 1.8 Hz, 6H).

[0875] EXAMPLE 14: 5-r6-Methyl-3-r(1S.5ft)-3-methyl-6-azabicyclor3 Jlheptane-6-carbonyllbenzofuran-5-yll-1H-pyridazin-6-one

[0876]

[0877] To a solution of 6-methyl-5-(6-oxo-1 H-pyridazin-5-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 37) (205 mg, 0.569 mmol), (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane (prepared according to the procedure of Intermediate 3) (40 mg, 0.36 mmol), HATU (210 mg, 0.552 mmol) in DMF (1.8 mL) was added DIPEA (0.60 mL, 3.5 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, then quenched with water. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% EtOAc / iso-hexane, then 0-20% MeOH / EtOAc) and further purified by reverse phase preparative HPLC to afford the title compound (0.6 mg, 1%) as a white solid. LCMS (Method 5): [M+H]+m / z 364.2, RT 1.05 minutes.

[0878] EXAMPLE 15: 5-f6-Methyl-3-r(1 S,5ft)-3-methyl-8-azabicyclor3 loctane-8-carbonyllbenzofuran-5-yll-1H-pyridazin-6-one

[0879]

[0880] 5-Chloro-1H-pyridazin-6-one (70 mg, 0.54 mmol), [(c / s)-3-Methyl-8-azabicyclo[3.2.1]octan-8-yl]-[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl]methanone (prepared according to the procedure of Intermediate 39) (208 mg, 0.361 mmol), Pd2(dba)3(42 mg, 0.044 mmol), XPhos (43 mg, 0.087 mmol) and K2CO3(180 mg, 1.29 mmol) were dissolved in 1,4-dioxane (2 mL) and H2O (1 mL). The reaction mixture was stirred overnight at 100 °C under N2 atmosphere. The reaction mixture was filtered through Celite ®. The filtrate was washed with water then concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% EtOAc / iso-hexane then 0-20% MeOH / EtOAc) to afford the title compound (40 mg, 29%) as a white solid. LCMS (Method 5): [M+H]+m / z 378.4, RT 1.12 minutes.1H NMR (300 MHz, DMSO) 5 13.20 (s, 1H), 8.40 (s, 1H), 7.96 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 10.7 Hz, 2H), 7.38 (d, J = 4.0 Hz, 1H), 4.61 (s, 1H), 4.35 (s, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 1.98 (s, 2H), 1.78 (d, J = 7.8 Hz, 3H), 1.35 -1.23 (m, 2H), 1.11 (d, J = 7.4 Hz, 3H), 0.91 - 0.78 (m, 2H).

[0881] EXAMPLE 16: 3-(6-Methyl-3-((1S,5ft)-3-methyl-6-azabicvclor3.1.1lheptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one

[0882]

[0883] HATU (55 mg, 0.15 mmol) was added to a mixture of (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane (prepared according to the procedure of Intermediate 3) (0.13 M, 0.70 mL, 0.09 mmol), 6-methyl-5-(2-oxo-1,2-dihydropyridin-3-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 41) (32 mg, 0.10 mmol) and DIPEA (50 pL, 0.29 mmol) in DMF (1.5 mL). The resulting mixture was stirred at r.t. for 1.5 h, diluted with EtOAc (10 mL) and H2O (10 mL) and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with H2O (2 x 10 mL), brine (2 x 10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% [EtOAc: EtOH 3:1] / iso-hexane). The resulting residue was taken up in EtOAc (5 mL) and the precipitate was filtered and dried in vacuo to afford the title compound (7 mg, 21%) as a white solid. LCMS (Method 5): [M+H]+m / z 363.3, RT 1.14 min.1H NMR (500 MHz, DMSO) 5 11.74 (s, 1 H), 8.49 (s, 1 H), 7.71 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.40 (dd, J = 6.6, 2.0 Hz, 1H), 6.27 (t, J = 6.6 Hz, 1H), 4.72 (s, 1H), 4.29 (s, 1H), 2.65 (s, 1H), 2.24 (s, 4H), 1.84 - 1.70 (m, 1H), 1.35 (dt, J = 15.3, 8.2 Hz, 2H), 1.18 (d, J = 8.3 Hz, 1H), 0.96 (d, J = 6.8 Hz, 3H). (1H under DMSO peak, confirmed by HSQC -{2.49, 34.92})

[0884] EXAMPLE 17: 4-Methvl-3-(6-methvl-3-((1S,5R)-3-methvl-6-i.1.1lheptane-6- -5-' idin-2(1H)-one

[0885]

[0886] Prepared from 6-methyl-5-(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 44) (60 mg, 0.18 mmol) in accordance with the procedure described for EXAMPLE 16 to afford the title compound (33 mg, 51%) as a white powder. LCMS (Method 5): [M+H]+m / z 377.3, RT 1.18 min.1H NMR (500 MHz, MeOD) 58.21 (d, J = 21.0 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 7.38 (d, J = 6.8 Hz, 1H), 6.44 (d, J = 6.7 Hz, 1 H), 4.72 - 4.64 (m, 1 H), 4.50 - 4.40 (m, 1 H), 2.86 - 2.74 (m, 1 H), 2.67 - 2.59 (m, 1 H), 2.41 -2.27 (m, 1 H), 2.20 (s, 3H), 2.03 - 1.90 (m, 4H), 1.53 - 1.40 (m, 2H), 1.30 - 1.25 (m, 1 H), 1.05 (dd, J = 19.2, 6.9 Hz, 3H). (NH proton not observed)

[0887] EXAMPLE 18: 4-Methvl-3-(6-methvl-3-((1S,5R)-3-methvl-8-i.2.1loctane-8- idin-2(1H)-one

[0888]

[0889] Prepared from 6-methyl-5-(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 44) (57 mg, 0.17 mmol) and (c / s)-3-methyl-8-azabicyclo[3.2.1]octane hydrochloride (27 mg, 0.17 mmol) in accordance with the procedure described for EXAMPLE 16 to afford the title compound (30 mg, 45%) as an off-white solid. LCMS (Method 5): [M+H]+m / z 391.3, RT 1.24 min.1H NMR (500 MHz, DMSO) 5 11.50 (s, 1H), 8.33 (s, 1H), 7.56 (s, 1H), 7.30 (d, = 8.3 Hz, 2H), 6.17 (d, J = 6.7 Hz, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 2.25 -2.15 (m, 2H), 2.12 (s, 3H), 2.00 - 1.91 (m, 2H), 1.83 (s, 3H), 1.77 (d, J= 7.9 Hz, 3H), 1.28 (ddd, J= 13.6, 5.2, 2.0 Hz, 2H), 1.10 (d, J= 7.5 Hz, 3H).

[0890] EXAMPLE 19: 5-Fluoro-3-(6-methyl-3-((1S,5 / ?)-3-methyl-6-azabicvclor3.1.1lheptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one

[0891]

[0892] Prepared from 5-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylbenzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 47) (47 mg, 0.16 mmol) in accordance with the procedure described for EXAMPLE 16 to afford the title compound (23 mg, 38%) as a white solid. LCMS (Method 5): [M+H]+m / z 381.3, RT 1.18 min.1H NMR (500 MHz, MeOD) 5 8.23 (s, 1 H), 7.80 (s, 1 H), 7.57 (dd, J = 7.8, 3.3 Hz, 1 H), 7.51 (t, J = 3.2 Hz, 1 H), 7.49 - 7.45 (m, 1 H), 4.69 (td, J = 5.9, 3.7 Hz, 1H), 4.46 (q, J = 5.5 Hz, 1H), 2.78 (dtt, J = 8.6, 6.7, 1.9 Hz, 1H), 2.64 (ddd, J = 13.6, 10.0, 4.0 Hz, 1H), 2.37 - 2.29 (m, 4H), 2.03 - 1.92 (m, 1H), 1.46 (ddd, J = 13.5, 9.2, 2.0 Hz, 2H), 1.28 (d, J = 8.5 Hz, 1H), 1.05 (d, J = 6.8 Hz, 3H). (NH / OH proton not observable in MeOD)19F{1H} NMR (471 MHz, MeOD) 5 -149.96.

[0893] EXAMPLE 20: 1-(6-Methyl-3-((1ft,3S.5S)-3-methyl-1-(3-methyl-1.2.4-oxadiazol-5-yl)-6-azabicyclo[3.1.11heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one

[0894]

[0895] 3-Methyl-5-((1R,3S,5S)-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,2,4-oxadiazole (prepared according to the procedure of Intermediate 53) (18 mg, 0.09 mmol), 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylicacid (prepared according to the procedure of Intermediate 21) (45 mg, 0.16 mmol) and DIPEA (50 pL, 0.29 mmol) were dissolved in DMF (1.5 mL), then HATU (56 mg, 0.15 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and diluted with EtOAc (10 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with H2O (2 x 10 mL), brine (2 x 10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-100% EtOAc / iso-hexane) then by reverse phase chromatography on C18 silica (20%-65% then 100% MeCN / [1%NH3 in H2O]) to afford the title compound (6 mg, 14%) as a white solid. LCMS (Method 5): [M+H]+m / z 436.4, RT 1.13 min.1H NMR (500 MHz, DMSO) 5 8.71 (s, 1H), 7.76 (s, 1 H), 7.59 (s, 1 H), 6.64 (s, 1 H), 4.94 (t, J = 6.0 Hz, 1 H), 3.73 - 3.68 (m, 2H), 3.42 (t, J = 7.8 Hz, 2H), 2.99 - 2.89 (m, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.29 - 2.24 (m, 1 H), 1.94 - 1.86 (m, 1 H), 1.85 -1.77 (m, 1 H), 1.74 (d, J = 8.3 Hz, 1 H), 1.44 (dd, J = 13.7, 9.2 Hz, 1 H), 1.04 (d, J = 6.6 Hz, 3H).

[0896] EXAMPLE 21: 1434(1 S,3S,5ft)-14(1S or ffl-1, 2-dihydroxyethyll-3-methyl-8-azabicvclor3.2.11octane-8-carbonyl1-6-methyl-benzofuran-5-yl1imidazolidin-2-one

[0897]

[0898] To a solution of tert-butyl rac-(1S,3S,5R)-1-((1S or 1R)-,2-dihydroxyethyl)-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (prepared according to the procedure of Intermediate 55) (95 mg, 0.33 mmol) in DCM (1.8 mL) was added TFA (0.70 mL, 9.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The residue was dissolved in DMF (1.1 mL) then 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 21) (100 mg, 0.384 mmol), HATU (320 mg, 0.842 mmol) and DIPEA (0.60 mL, 3.5 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water. The aqueous was extracted with DCM. The combined organics were filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane, then 0-20% MeOH / EtOAc) to afford the isomeric mixture, which was then subjected to chiral purification. Purification was performed using a Regis (R, R)-Whelk-0 1, 250 x 21.1 mm, 5 pm, flow rate 100 mL / min, column temperature 40 °C, eluting with a 3-40% Methanol & 0.1% ammonia solution gradient (120 bar), over 15 minutes on a Waters FractionLynx SFC Prep 150 to afford the title compound (peak 1, 4 mg, 3%) as a yellow solid. LCMS (Method 5): [M+H]+m / z 428.2, RT 0.94 minutes.

[0899] EXAMPLE 22: 146-Methyl-34(1R3S.5S)-3-methyl-141.2,4-triazin-3-yl)-6-azabicyclo[3.1.11heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one

[0900]

[0901] Prepared from (1R,3S,5S)-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane (prepared according to the procedure of Intermediate 61) (13 mg, 0.04 mmol) and 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 21) (15 mg, 0.06 mmol) in accordance with the procedure described for EXAMPLE 3 and purified by preparative HPLC (basic) to afford the title compound (2 mg, 10%) as a white powder. LCMS (Method 5): [M+H]+m / z 433.4, RT 1.01 minutes.1H NMR (500 MHz, MeOD) 59.27 (s, 1 H), 8.82 (s, 1 H), 8.41 (s, 1 H), 7.81 (s, 1 H), 7.51 (s, 1 H), 4.97 - 4.90 (m, 1 H), 3.85 (t, J = 7.0 Hz, 2H), 3.60 (t, J = 7.1 Hz, 2H), 3.29 - 3.21 (m, 2H), 3.13 - 3.05 (m, 1H), 2.43 - 2.32 (m, 4H), 2.18 - 2.10 (m, 1H), 1.71 (d, J = 8.3 Hz, 1H), 1.54 (dd, J = 13.6, 9.2 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H). (A / / 7 proton not observed)

[0902] EXAMPLE 23: 1-(6-l -3-((1 / ?,3S,5S)-3-i

[0903]

[0904] -1,3,4-oxadiazol-2-vD-6-

[0905]

[0906] .1. -6-(

[0907]

[0908] >lidin-2-one

[0909] \.

[0910]

[0911] Prepared from 2-methyl-5-[(1R,3S,5S)-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl]-1,3,4-oxadiazole (prepared according to the procedure of Intermediate 64) (25 mg, 0.13 mmol) and 6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 21) (34 mg, 0.13 mmol) in accordance with the procedure described for EXAMPLE 3 to afford the title compound (18 mg, 31 %) as a white powder. LCMS (Method 5): [M+H]+m / z 436.50, RT 1.02 min.1H NMR (500 MHz, DMSO-d6) 68.69 (s, 1 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 6.64 (s, 1 H), 4.91 (t, J = 6.1 Hz, 1 H), 3.70 (t, J = 7.8 Hz, 2H), 3.42 (t, J = 7.8 Hz, 2H), 3.00 (s, 1 H), 2.93 (t, J = 7.6 Hz, 1 H), 2.52 (m, 3H), 2.31 (s, 3H), 2.30 - 2.23 (m, 1 H), 1.91 - 1.77 (m, 2H), 1.70 (d, J = 8.4 Hz, 1H), 1.44 (dd, J= 13.7, 8.5 Hz, 1H), 1.04 (d, = 5.9 Hz, 3H).

[0912] EXAMPLE 24: (1 / ?,3S,5S)-3-Methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-.1.1 lheptane-1 -carboxamide

[0913]

[0914] To a solution of (1 / ?,3S,5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 66) (50 mg, 0.096 mmol), NH4CI (8 mg, 0.14 mmol) and A / , A / -diisopropylethylamine (0.049 mL, 0.29 mmol) in DMF (4.5 mL) was added TATU (46 mg, 0.14 mmol). The mixture was stirred for 4 h. A saturated aqueous NH4CI solution (30 mL) was added and the mixture was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed a saturated aqueous NaHCO3solution (40 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel (0-100% [EtOAc / EtOH (3:1)] / iso-hexane) then was purified by reverse phase preparative HPLC (acidic elution) to give the title compound (14.8 mg, 37%) as a white solid. LCMS (Method 5): [M+H]+m / z 397.40, RT 0.93 min.1H NMR (500 MHz, DMSO-d6) 68.63 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.21 (s, 1 H), 6.65 (s, 1 H), 4.70 (t, J = 5.9 Hz, 1 H), 3.73 (dd, J = 8.8, 6.7 Hz, 2H), 3.49 - 3.40 (m, 2H), 2.65 -2.55 (m, 2H), 2.32 (s, 3H), 2.17 - 2.09 (m, 1H), 1.77 - 1.65 (m, 1H), 1.58 (dd, J = 13.3, 9.0 Hz, 1H), 1.41 (d, J = 8.4 Hz, 1H), 1.30 (dd, J = 13.6, 9.2 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H).

[0915] EXAMPLE 25: (1 / ?,3S,5S)-N,3-dimethyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-.1. -1 -carboxamide

[0916] - - \

[0917] H \

[0918] o y

[0919]

[0920] To a solution of (1 / ?,3S,5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (prepared according to the procedure of Intermediate 66) (50 mg, 0.095 mmol) and DIPEA (0.049 mL, 0.29 mmol) in DMF (0.5 mL) was added a solution of methylamine in THF (2 mol / L, 0.06 mL, 0.12 mmol) and TATU (46 mg, 0.14 mmol). The mixture was stirred for 2 h. A solution of methylamine in THF (2 mol / L, 0.24 mL, 0.48 mmol) was added and the mixture was stirred for 4 h. A solution of methylamine in THF (2 mol / L, 0.30 mL, 0.60 mmol) was added and the mixture was stirred for 18 h. TATU (37 mg, 0.12 mmol), A / , A / -diisopropylethylamine (0.039 mL, 0.23 mmol) and a solution of methylamine in THF (2 mol / L, 0.20 mL, 0.40 mmol) were added. The mixture was stirred for 3 h at 45 °C then cooled to r.t. A saturated aqueous NH4CI solution (20 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with a saturated aqueous NaHCO3solution (20 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel (0-100% [EtOAc / EtOH (7:3)] / isohexane) then was purified by reverse phase preparative HPLC (basic elution) to give the title compound (6 mg, 19%) as a white solid. LCMS (Method 5): [M+H]+m / z 411.4, RT 0.96 min.1H NMR (500 MHz, MeOD) 68.37 (s, 1H), 7.89 (s, 1H), 7.52 (s, 1H), 4.67 (t, J = 6.0 Hz, 1H), 3.89 (dd, J = 9.1, 7.0 Hz, 2H), 3.63 (dd, J = 9.2, 6.9 Hz, 2H), 2.80 (s, 3H), 2.77 - 2.68 (m, 2H), 2.41 (s, 3H), 2.28 - 2.16 (m, 1H), 1.93 - 1.81 (m, 1H), 1.74 (dd, J = 13.5, 9.0 Hz, 1H), 1.50 (d, J = 8.5 Hz, 1H), 1.38 (dd, J = 13.8, 9.2 Hz, 1 H), 1.04 (d, J = 6.7 Hz, 3H). (NH protons not observed).

[0921] EXAMPLE 26: K1S,5 / ?)-3-Methyl-8-azabicvclor3.2.1loctan-8-yll-(6-methyl-5-pyridazin-3-yl-1-benzofuran-3-yl)methanone

[0922]

[0923] A solution of [(c / s)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl]methanone (prepared according to the procedure of Intermediate 39) (16 mg, 0.04 mmol) in 1,4-dioxane (0.4 mL) and water (0.1 mL) was added to a mixture of potassium carbonate (18 mg, 0.13 mmol), 3-bromopyrimidine (13 mg, 0.26 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,r-biphenyl-2-yl)palladium(ll) (3 mg, 0.004 mmol) in a sealed vial. The mixture was heated at 100 °Cfor24 h, cooled to r.t., concentrated in vacuo and purified by reverse phase HPLC to give the title compound (1 mg, 9%) as a white solid. LCMS (Method 5): [M+H]+m / z 362.4, RT 1.23 min.

[0924] EXAMPLE 27: 4-r6-Methyl-3-r(1S,5 / ?)-3-methyl-8-azabicvclor3.2.1loctane-8-carbonyll-1-

[0925]

[0926] benzofuran-5-yll-1H-pyridazin-6-one

[0927]

[0928] A solution of [(c / s)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl]methanone (prepared according to the procedure of Intermediate 39) (16 mg, 0.04 mmol) in 1,4-dioxane (0.4 mL) and water (0.1 mL) was added to a mixture of potassium carbonate (18 mg, 0.13 mmol), 5-iodo-2,3-dihydropyridazin-3-one (19 mg, 0.26 mmol) and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1, T-biphenyl-2-yl)palladium(ll) (3 mg, 0.004 mmol) in a sealed vial. The mixture was heated at 100 °C for 24 h, cooled to rt, concentrated in vacuo and purified by reverse phase HPLC to give the title compound (7 mg, 45%) as a white solid. LCMS (Method 5): [M+H]+m / z 378.4, RT 1.19 min.

[0929] EXAMPLE 28: K1S,5 / ?)-3-methyl-8-azabicvclor3.2.1loctan-8-yll-r6-methyl-5-(3-methyl-3,6-diazabicyclo[3.1.11heptan-6-yl)-1 -benzofuran-3-yllmethanone

[0930]

[0931] A solution of (5-bromo-6-methyl-benzofuran-3-yl)-[(1S,5F?)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methanone (prepared according to the procedure of Intermediate 38) (10 mg, 0.03 mmol) in dry 1,4-dioxane (0.5 mL) was added to a mixture of 3-methyl-3,6-diazabicyclo[3.1.1]heptane dihydrochloride (11 mg, 0.06 mmol), RuPhos Pd G4 (2.9 mg, 0.003 mmol) and sodium tert-butoxide (10 mg, 0.10 mmol). The mixture was sonicated, placed under argon, then heated in a sealed vial at 100 °C for 6 h. Aftercooling to r.t., the mixture was concentrated in vacuo and purified by reverse phase HPLC to give the title compound (3 mg, 29%) as a white solid. LCMS (Method 5): [M+H]+m / z 394.3, RT 0.76 min.

[0932] EXAMPLE 29: r5-(3-hvdroxyazetidin-1-yl)-6-methyl-1-benzofuran-3-yll-r(1S,5 / ?)-3-methyl-8-azabicyclor3.2.1loctan-8-yllmethanone

[0933]

[0934] A mixture of (5-bromo-6-methyl-benzofuran-3-yl)-[(1S,5F?)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methanone (prepared according to the procedure of Intermediate 38) (10 mg, 0.03 mmol), 3-hydroxyazetidine hydrochloride (8 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.003 mmol), (+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2 mg, 0.003 mmol) and caesium carbonate (30 mg, 0.09 mmol) in dry 1,4-dioxane (0.5 mL) was sonicated, placed under argon, then heated in a sealed vial at 100 °C for 2 h. After cooling to r.t., the mixture was concentrated in vacuo and purified by reverse phase HPLC to give the title compound (3 mg, 28%) as a white solid. LCMS (Method 5): [M+H]+m / z 355.3, RT 1.13 min.

[0935] EXAMPLE 30: 4-(6-Methyl-3-((1 / ?.3S.5S)-3-methyl-1-(5-methyl-1.3.4-oxadiazol-2-yl)-6-azabicyclo[3.1.11heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one

[0936]

[0937] To a solution of 6-methyl-5-(3-oxo-2,3-dihydropyridazin-4-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 37) (30 mg, 0.11 mmol), 2-methyl-5-[(1R,3S,5S)-3-methyl-6-azabicyclo[3.1.1 ]heptan-1 -yl]-1,3,4-oxadiazole (prepared according to the procedure of Intermediate 64) (27 mg, 0.14 mmol) and DIPEA (0.11 mL, 0.65 mmol) in DMF (0.70 mL) was added TATU (0.10 g, 0.32 mmol). The mixture was stirred for 18 h. A saturated aqueous solution of NH4CI (20 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with saturated aqueous NaHCO3(20 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% [EtOAc / EtOH 3 / 1] in iso-hexane). The residue was dissolved in MeCN (2 mL), concentrated in vacuo and dried in a desiccator for 16 h at 40 °C to give the title compound (20 mg, 40%) as a white solid. LCMS (Method 5): [M+H]+m / z 446.3, RT 0.97 min.1H NMR (500 MHz, MeOD) 58.42 (s, 1 H), 8.00 (d, J = 4.0 Hz, 1 H), 7.81 (s, 1 H), 7.53 (s, 1 H), 7.39 (d, J = 4.0 Hz, 1 H), 4.88 - 4.86 (m, 1 H), 3.19 - 3.08 (m, 2H), 2.55 (s, 3H), 2.39 - 2.32 (m, 4H), 2.07 -1.97 (m, 1H), 1.92 (dd, J = 13.2, 9.2 Hz, 1H), 1.71 (d, J = 8.5 Hz, 1H), 1.51 (dd, J = 13.8, 9.2 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H). NH not observed.

[0938] EXAMPLE 31: 6-Fluoro-4-(6-methvl-3-((1 / ?,3S,5S)-3-methvl-1-(5-methvl-1,3,4-oxadiazol-2-vD-6-azabicvclof3.1.11heptane-6-carbonvl)benzofuran-5-vl)Pvridazin-3(2H)-one

[0939]

[0940] Prepared from 5-(6-fluoro-3-oxo-2,3-dihydropyridazin-4-yl)-6-methylbenzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 68) (75 mg, 0.18 mmol) and 2-methyl-5-[(1 / ?,3S,5S)-3-methyl-6-azabicyclo[3.1.1 ]heptan-1 -yl]-1,3,4-oxadiazole (prepared according to the procedure of Intermediate 64) (42 mg, 0.22 mmol) in accordance with the procedure described for Example 30 to give the title compound (37 mg, 43%) as a white solid. LCMS (Method 5): [M+H]+m / z 464.4, RT 1.11 min.1H NMR (500 MHz, MeOD) 58.43 (s, 1H), 7.85 (s, 1H), 7.54 (s, 1H), 7.42 (d, J = 1.9 Hz, 1 H), 3.18 - 3.08 (m, 2H), 2.55 (s, 3H), 2.37 (s, 3H), 2.36 - 2.30 (m, 1 H), 2.08 - 1.97 (m, 1H), 1.92 (dd, J = 13.0, 9.2 Hz, 1H), 1.71 (d, J = 8.5 Hz, 1H), 1.52 (dd, J = 13.8, 9.1 Hz, 1H), 1.12 (d, J = 6.6 Hz, 3H). NH not observed. One proton underwater peak.19F{1H} NMR (376 MHz, MeOD) 5 -94.93.

[0941] EXAMPLE 32: 4-(6-Methyl-3-((1 / ?,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-.1.1lheptane-6-carbonvl)benzofuran-5-vl)Pvridazin-3(2H)-one

[0942]

[0943] Prepared from 6-methyl-5-(3-oxo-2,3-dihydropyridazin-4-yl)benzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 37) (26 mg, 0.09 mmol) and 3-methyl-5-((1R,3S,5S)-3-methyl-6-azabicyclo[3.1.1 ]heptan-1 -yl)-1,2,4-oxadiazole (prepared according to the procedure of Intermediate 53) (25 mg, 0.13 mmol) in accordance with the procedure described for Example 30 and purified by reverse phase preparative HPLC (basic) to give the title compound (4 mg, 9%) as a white solid. LCMS (Method 5): [M+H]+m / z 446.5, RT 1.14 min.1H NMR (500 MHz, DMSO) 58.44 (s, 1 H), 8.00 (d, J = 4.0 Hz, 1 H), 7.81 (s, 1 H), 7.53 (s, 1 H), 7.39 (d, J = 4.0 Hz, 1 H), 4.88 (d, J = 7.4 Hz, 1H), 4.88 (s, 1H), 3.15 - 3.02 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 2.05 - 1.91 (m, 2H), 1.72 (d, J = 8.5 Hz, 1H), 1.50 (dd, J = 13.8, 9.0 Hz, 1H), 1.11 (d, J = 6.5 Hz, 3H). NH not observed.

[0944] EXAMPLE 33: 6-Fluoro-4-(6-methyl-3-((1 / ?,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.11heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one

[0945]

[0946] Prepared from 5-(6-fluoro-3-oxo-2,3-dihydropyridazin-4-yl)-6-methylbenzofuran-3-carboxylic acid (prepared according to the procedure of Intermediate 68) (25 mg, 0.05 mmol) and 3-methyl-5-((1R,3S,5S)-3-methyl-6-azabicyclo[3.1.1 ]heptan-1 -yl)-1,2,4-oxadiazole (prepared according to the procedure of Intermediate 53) (13 mg, 0.06 mmol) in accordance with the procedure described for Example 30 and purified by reverse phase chromatography on C18 silica (MeCN / water (0.1% formic acid)) to give the title compound (6 mg, 23%) as a white solid. LCMS (Method 5): [M+H]+m / z 464.4, RT 1.23 min.1H NMR (500 MHz, DMSO) 5 12.69 (s, 1H), 8.75 (s, 1H), 7.84 (s, 1H), 7.64 (s, 1 H), 7.56 (s, 1 H), 4.96 (t, J = 6.0 Hz, 1 H), 2.99 - 2.89 (m, 2H), 2.35 (s, 3H), 2.32 - 2.23 (m, 4H), 1.89 (dd, J = 13.0, 9.2 Hz, 1 H), 1.86 - 1.76 (m, 1 H), 1.74 (d, J = 8.3 Hz, 1 H), 1.44 (dd, J = 13.7, 9.1 Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H).19F{1H} NMR (471 MHz, DMSO) 5 -94.04.

[0947] EXAMPLE 34: 3-Fluoro-5-r6-methyl-3-r(1 S,5 / ?)-3-methyl-8-azabicyclor3.2.1loctane-8-carbonyllbenzofuran-5-yll-1H-pyridazin-6-one

[0948]

[0949] To a solution of (c / s)-3-methyl-8-azabicyclo[3.2.1]octane hydrochloride (9 mg, 0.06 mmol) and 5-(6-fluoro-3-oxo-2,3-dihydropyridazin-4-yl)-6-methylbenzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 68) (8 mg, 0.03 mmol) in DMF (1 mL) was added DIPEA (20 pL, 0.11 mmol) and then PyAOP (15 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with brine. The aqueous layer was extracted with DCM, filtered through a phase separator and then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the title compound (4 mg, 37%) as a white solid. LCMS (Method 5): [M+H]+m / z 396.4, RT 1.26 min.1H NMR (300 MHz, DMSO) 5 8.41 (s, 1 H), 7.61 (s, 1 H), 7.60 (s, 1 H), 7.53 (s, 1 H), 4.61 (s, 1 H), 4.35 (s, 1 H), 2.31 (s, 3H), 2.23 -2.13 (m, 3H), 2.03 - 1.90 (m, 2H), 1.78 (d, J = 7.9 Hz, 2H), 1.29 (dd, J = 14.0, 4.9 Hz, 2H), 1.11 (d, J = 7.4 Hz, 3H). No pyridazinone NH signal observed in1H NMR.

[0950] EXAMPLE 35: 3-Fluoro-5-r6-methyl-3-r(1S,5 / ?)-3-methyl-6-azabicyclor3.1.1lheptane-6-

[0951]

[0952] carbonyllbenzofuran-5-yll-1H-pyridazin-6-one

[0953]

[0954] PyAOP (20 mg, 0.038 mmol) was added to a solution of 5-(6-fluoro-3-oxo-2,3-dihydropyridazin-4-yl)-6-methylbenzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 68) (10 mg, 0.034 mmol), (c / s)-3-methyl-6-azabicyclo[3.1.1] heptane (prepared according to a procedure analogous to that of Intermediate 3) (14 mg, 0.13 mmol) and DIPEA (0.04 mL, 0.2 mmol) in DMF (0.5 mL). The reaction was stirred at room temperature for 2 h and then quenched with brine. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layer concentrated in vacuo. The residue was purified by normal phase chromatography (0-100% EtOAc / hexanes then 0-20% MeOH / EtOAc) to afford the title compound (8 mg, 62%) as a white solid. LCMS (Method 5): [M+H]+m / z 382.4, RT 1.19 min. 1 H NMR (300 MHz, DMSO) 512.73 (s, 1 H), 8.56 (s, 1 H), 7.87 (s, 1 H), 7.65 - 7.54 (m, 2H), 4.73 (s, 1 H), 4.31 (s, 1 H), 2.70 - 2.59 (m, 1H), 2.30 (s, 3H), 2.27 -2.17 (m, 2H), 1.87 - 1.70 (m, 1 H), 1.43 - 1.30 (m, 2H), 1.27 - 1.16 (m, 1 H), 0.97 (d, J = 6.8 Hz, 3H).

[0955] EXAMPLE 36: 3-Fluoro-5-r6-methyl-3-niR,3S.5S)-1-(5-methyl-1.3.4-oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.11heptane-6-carbonyl1benzofuran-5-yl1-1 H-pyridazin-6-one

[0956] N=< F

[0957] O / ('

[0958] NFF HN

[0959]

[0960] To a solution of fert-butyl (1R,3S,5S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1,1]heptane-6-carboxylate (prepared according to the procedure of Intermediate 75) (30 mg, 0.086 mmol) and 2,6-lutidine (75 pL, 0.64 mmol) in DCM (1 mL) was added trimethylsilyl trifluoromethanesulfonate (50 pL, 0.26 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h then quenched with MeOH and concentrated in vacuo. The residue was dissolved in DMF (2 mL) then 5-(6-fluoro-3-oxo-2,3-dihydropyridazin-4-yl)-6-methylbenzofuran-3-carboxylic acid (prepared according to a procedure analogous to that of Intermediate 68) (20 mg, 0.068 mmol). DI PEA (50 pL, 0.29 mmol) and then PyAOP (36 mg, 0.0678 mmol) were added and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was diluted with brine, extracted with EtOAc (3 x 10 mL) and the combined organic layer was concentrated in vacuo and purified by reverse phase preparative HPLC to afford the title compound (12 mg, 34%) as a white solid. LCMS (Method 5): [M+H]+m / z 518.4, RT 1.17 min.1H NMR (300 MHz, DMSO) 5 12.90 -12.40 (br s, 1 H), 8.76 (s, 1 H), 7.84 (s, 1 H), 7.64 (s, 1 H), 7.46 (s, 1 H), 5.04 (s, 1 H), 3.22 - 3.01 (m, 3H), 2.88 (d, J = 10.1 Hz, 1H), 2.43 (s, 1 H), 2.31 (s, 6H), 1.90 (dd, J = 14.1, 8.3 Hz, 1H), 1.75 (d, J = 9.0 Hz, 1H).

[0961] V. BIOLOGICAL ASSAYS

[0962] A) Inhibition of SARM1 CZ-48 assay

[0963] The inhibition of SARM1 cellular activity by compounds of formula (I) can be tested with human immortalized cells (HEK293T) overexpressing human SARM1. The latter will be activated with a specific SARM1 molecule (SARM1 activator) leading to excessive NAD+ consumption by active SARM1 and subsequent cell death. SARM1 inhibitors with cellular activity will prevent said cell death. Cell health is linear & positively correlated to cellular ATP levels. Cell health is measured with a Cell Titer Gio kit, quantitating cellular ATP through luminescence measurements.

[0964] The efficacy of the compounds, according to the Examples, to inhibit SARM1 is represented by measuring the EC50 which corresponds to the concentration of compound necessary to rescue 50% of cellular ATP levels after full (>80%) cellular SARM1 activation. This concentration is postulated to reflect 50% of SARM 1 inhibition in a cellular context. plC50 values correspond to -log of the IC50 in Molar. The lower the value of the IC50 (the higher the value of the pICso is), the less compound is needed to perform the same amount of inhibition and therefore the higher is the inhibition potency.

[0965] HEK293T cells were transfected with a SARM1 expression construct & selected for by antibiotic resistance. Expression was initially verified by western blot. Cells were maintained in regular growth medium as a polyclonal mix with >80% cells responsive to SARM1 activators (indicative of SARM1 expression) vs wild type HEK293T cells. Cells were frozen away with a standard approach in ready-to-use, single time aliquots. Cells were defrosted & 40pl cell suspension was seeded (Greiner, 781080) to appropriate densities & incubated for growth. 24h later, 400 nl SARM1 activator (100x) was added to cells (concentration defined by CRC to achieve > 80% SARM1 activation) immediately followed by 400nl SARM1 inhibitor compound (100X) addition. Both additions reaching a final concentration of 1X. Cells were incubated for additional 24h after which all wells were treated with 20pl Cell Titer Gio 2.0 (Promega) according to protocol of the manufacturer. Luminescence was read on Envision 2019 (Revvity) according to recommendations of the manufacturers taking all reasonable measures & controls to prevent signal cross talk to neighbouring wells.

[0966] SARM1 activator was bought commercially, resuspended in 100% DMSO to 100mM (1000X) and freshly prepared for each experiment to a 100X stock concentration in serum free growth media, ready for dispensing. DMSO only controls were similarly prepared and diluted in serum free growth media.

[0967] Compound preparation was done in a 384 well format (Greiner, 784201 or 781280), with columns dedicated to maximal and minimal inhibition controls and 1-2 rows set aside for reference compound concentration response curves (CRC), recurring in each assay plate for standardization. Each CRC was prepared in duplicate. Compounds of interested and reference compounds were diluted with available lab robots in 0.5log increments to 100X in 100% DMSO. A tool compound for maximal inhibition and a DMSO control for minimal inhibition were prepared in the dedicated columns.

[0968] When tested, Example compounds 1-36, according to the present invention, display values of pICso greater than or equal to 6.0, suitably greater than or equal to 6.5, preferably greater than or equal to 7.0. When tested compounds according to Examples 1-36, display values of pICso greater than or equal to about 6.0.

[0969] Table 1 exhibits the ranges of pICso of the compounds of formula (I) according to the present invention when tested in the Inhibition of CZ-48 assay outlined above.

[0970] Category A: about 6.00 < pICso < about 6.50;

[0971] Category B: about 6.50 < pICso < about 7.00;

[0972] Category C: pICso S about 7.00.

[0973] Table 1:

[0974] Example No. CZ48 pICso Example No. CZ48 pICso

[0975] 1 A 19 C

[0976]

[0977] 2 C 20 C 3 C 21 B

[0978] 4 B 22 B 5 A 23 A 6 A 24 A 7 A 25 A 8 A 26 A 9 C 27 A 10 A 28 A 11 C 29 A 12 A 30 C 13 A 31 C 14 B 32 C 15 B 33 C 16 C 34 C 17 A 35 C

[0979]

[0980] 18 A 36 C

[0981] As shown in this Table 1, compounds of formula (I) according to the present invention are potent inhibitors of SARM1 activity.

Claims

CLAIMS1. A compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof;wherein:Ring A is selected from C5-10heteroaryl, bridged bicyclic C5-10heterocycloalkyl or C4-10heterocycloalkyl;R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;wherein R1aand R1bare independently selected from H or C1-3alkyl;R2is selected from H, C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;R3is selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, oxo (=0), Co-salkylOH, Co-salkylCN and NR3aR3b;wherein R3aand R3bare independently selected from H or C1-3alkyl;R4is selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol halogen, Co-salkylOH, Co-3alkylCN, C3-6heteroaryl, NR4aR4band CONR4eR4f;whereinthe Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;R4aand R4bare independently selected from H or C1-3alkyl; andR4eand R4fare independently selected from H or C1-3alkyl;Z is selected from NH, CR5and CR5R5c;R5is selected from H, C1-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR5aR5bwhereinthe Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C-i-salkyl, C1-3alkoxy, Ci-shaloalkyl and halogen;R5aand R5bare independently selected from H or C1-3alkyl; andR5cis selected from H or halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl;m is selected from 0, 1 and 2;n is selected from 0, 1, 2 and 3;p is selected from 0, 1 and 2; andq is selected from 1 or 2.

2. A compound of formula (I’) according to claim 1,or a pharmaceutically acceptable salt or solvate thereof;wherein:Ring A is selected from C5-10heteroaryl or C5-10heterocycloalkyl;R1is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylCN and NR1aR1b;wherein R1aand R1bare independently selected from H or C1-3alkyl;R2is selected from H, Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;R3is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, oxo (=O), C0-3alkylOH, C0-3alkylCN and NR3aR3b;wherein R3aand R3bare independently selected from H or C1-3alkyl;R4is selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl, Ci-3alkyldiol, halogen, Co-salkylOH, Co-3alkylCN, C3-6heteroaryl, NR4aR4band CONR4eR4f;whereinthe Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from Ci-3alkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;R4aand R4bare independently selected from H or C1-3alkyl; andR4eand R4fare independently selected from H or Ci-3alkyl;Z is selected from NH, CR5and CR5R5c;R5is selected from H, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylOH, C0-3alkylCN, C3-6cycloalkyl, C3-6heteroaryl and NR5aR5b;whereinthe Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C-i-salkyl, Ci-3alkoxy, Ci-shaloalkyl and halogen;R5aand R5bare independently selected from H or C1-3alkyl; andR5cis selected from H or halogen or wherein R5and R5ctogether with the carbon atom to which they are attached form a Cs-ecycloalkyl;m is selected from 0, 1 and 2;n is selected from 0, 1, 2 and 3;p is selected from 0, 1 and 2; andq is selected from 1 or 2.

3. A compound of formula (I”) according to claim 1 or claim 2,or a pharmaceutically acceptable salt or solvate thereof;wherein:Ring A is selected from Cs-wheteroaryl or Cs-wheterocycloalkyl;R1is selected from C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylCN and NR1aR1b;wherein R1aand R1bare independently selected from H orC1-3alkyl;R2is selected from H, C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl and halogen;R3is selected from C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl, halogen, oxo (=0), Co-salkylOH, Co-salkylCN and NR3aR3b;wherein R3aand R3bare independently selected from H or C1-3alkyl;R4is selected from C1-3alkyl, C1-3alkoxy, Ci-shaloalkyl, halogen, Co-salkylOH, Co-salkylCN, Cs-eheteroaryl and NR4aR4bwhereinthe Cs-eheteroaryl may be optionally substituted by one, two or three groups selected from C-i-salkyl, C1-3alkoxy, Ci-shaloalkyl and halogen; andR4aand R4bare independently selected from H or C1-3alkyl;Z is selected from NH or CR5;R5is selected from H, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen, C0-3alkylOH, C0-3alkylCN, C3-6heteroaryl and NR5aR5bwhereinthe C3-6heteroaryl may be optionally substituted by one, two or three groups selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl and halogen; and R5aand R5bare independently selected from H or C1-3alkyl;m is selected from 0, 1 and 2;n is selected from 0, 1, 2 and 3;p is selected from 0, 1 and 2; andq is selected from 1 or 2.

4. A compound of formula (I) according to any one of claims 1 to 3 wherein Ring A is selected from C6heteroaryl or C5heterocycloalkyl.

5. A compound of formula (I) according to any one of claims 1 to 4 wherein R3is selected from C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, halogen and oxo (=O), and n is 0 or 1.

6. A compound of formula (I) according to any one of claims 1 to 5 wherein R1is C1-3alkyl and R2is H.

7. A compound of formula (I) according to any one of claims 1 to 6 wherein R4is selected from C1-3alkyl, C1-3alkoxy, C1-3alkylOH and halogen; and p is selected from 0 or 1.

8. A compound of formula (I) according to any one of claims 1 to 7 wherein Z is CR5and R5is selected from H or C1-3alkyl.

9. A compound of formula (I) according to any one of claims 1 to 8 wherein q is selected from 1 or 2, and m is selected from 1 or 2.

10. A compound of formula (I) according to any one of claims 1 to 9 selected from the group consisting of1 -[6-methyl-3-[(1 S,5R)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]benzofuran-5- yl]imidazolidin-2-one;1 -[3-[(1 R,3S,5S)-1 -[(1 S or 1 R)-1 -hydroxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6- carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;1 -[3-[(1R,3S,5S)-1-[(1S or 1R)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1.1 ]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;1-[3-[(1R,3S,5S)-1-[(1R or 1S)-1-methoxyethyl]-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;1-[3-(7-azabicyclo[4.1.1]octane-7-carbonyl)-6-methyl-benzofuran-5-yl]imidazolidin-2-one; 7-azabicyclo[2.2.1]heptan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone;7-azabicyclo[4.1.1]octan-7-yl-[6-methyl-5-(2-pyridyl)benzofuran-3-yl]methanone;(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-[6-methyl-5-(1-methyl-1,2,4-triazol-3-yl)-1-benzofuran-3-yl]methanone;5-methyl-3-[6-methyl-3-[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1 H-pyridin-2-one;[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl]-[6-methyl-5-(2-methyl-1H-imidazol-5-yl)benzofuran-3-yl]methanone;5-methyl-3-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]-1H-pyridin-2-one;[5-(5-fluoropyrimidin-2-yl)-6-methyl-benzofuran-3-yl]-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]methanone;1-[3-[(1S,3S,5R)-1-[1-hydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;5-[6-methyl-3-[(1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one;5-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one;3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;4-methyl-3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;4-methyl-3-(6-methyl-3-((1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;5-fluoro-3-(6-methyl-3-((1S,5R)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridin-2(1H)-one;1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;1-[3-[(1S,3S,5R)-1-[(1S or 1R)-1,2-dihydroxyethyl]-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-6-methyl-benzofuran-5-yl]imidazolidin-2-one;1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;1-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1 ]heptane-6-carbonyl)benzofuran-5-yl)imidazolidin-2-one;(1R,3S,5S)-3-methyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxamide;(1R,3S,5S)-N,3-dimethyl-6-(6-methyl-5-(2-oxoimidazolidin-1-yl)benzofuran-3-carbonyl)-6- azabicyclo[3.1.1 ]heptane-1 -carboxamide;[(1S,5R)-3-Methyl-8-azabicyclo[3.2.1]octan-8-yl]-(6-methyl-5-pyridazin-3-yl-1-benzofuran-3-yl)methanone;4-[6-Methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8-carbonyl]-1-benzofuran-5- yl]-1 H-pyridazin-6-one;[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-[6-methyl-5-(3-methyl-3,6- diazabicyclo[3.1.1]heptan-6-yl)-1-benzofuran-3-yl]methanone;[5-(3-hydroxyazetidin-1-yl)-6-methyl-1-benzofuran-3-yl]-[(1S,5R)-3-methyl-8- azabicyclo[3.2.1]octan-8-yl] methanone;4-(6-Methyl-3-((1R,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;6-Fluoro-4-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;4-(6-Methyl-3-((1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;6-Fluoro-4-(6-methyl-3-((1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)benzofuran-5-yl)pyridazin-3(2H)-one;3-Fluoro-5-[6-methyl-3-[(1S,5R)-3-methyl-8-azabicyclo[3.2.1]octane-8- carbonyl]benzofuran-5-yl]-1 H-pyridazin-6-one;3-Fluoro-5-[6-methyl-3-[(1 S,5R)-3-methyl-6-azabicyclo[3.1.1 ]heptane-6- carbonyl]benzofuran-5-yl]-1 H-pyridazin-6-one; and3-Fluoro-5-[6-methyl-3-[(1R,3S,5S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carbonyl]benzofuran-5-yl]-1H-pyridazin-6-one11. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 10, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. A compound of formula (I) or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 10, for use in therapy.

13. A compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 10, for use in the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

14. A compound for use according to claim 13, wherein the disease or disorder is selected from axonal degeneration; neurological disorders, such as autoimmune and inflammatory diseases; ocular conditions such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD); and traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury.

15. A compound for use according to claim 13, wherein the disease or disorder is selected from neurological disorders, such as peripheral nervous system (PNS) disease, diabetic neuropathy or motor neuron disease; traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury; diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN) or chemotherapy induced cognitive impairment; ocular indications, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as motor neuron disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD); or autoimmune and inflammatory diseases.

16. Use of a compound of formula (I), ora pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 10, for the manufacture of a medicament useful for the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

17. Use of a compound according to claim 16, wherein the disease or disorder is selected from neurological disorders, such as peripheral nervous system (PNS) disease, diabetic neuropathy or motor neuron disease; traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury; diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN) or chemotherapy induced cognitive impairment; ocular indications, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as motor neuron disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD); or autoimmune and inflammatory diseases.

18. A method for the treatment and / or prevention of a disease or disorder in which SARM1 plays a role, which comprising administering to a patient in need of such treatment an effectiveamount of a compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 10.

19. A method according to claim 18, wherein the disease or disorder is selected from neurological disorders, such as peripheral nervous system (PNS) disease, diabetic neuropathy or motor neuron disease; traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury; diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN) or chemotherapy induced cognitive impairment; ocular indications, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as motor neuron disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD); or autoimmune and inflammatory diseases.

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