Pyrrolidinone derivatives 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] PYRROLIDINONE DERIVATIVES

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

[0003] In particular, the present invention relates to lactam-containing compounds having a skeleton comprising a four-ring structure and their pharmaceutically acceptable salts and solvates and their use in therapy.

[0004] 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).

[0005] BACKGROUND 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.

[0006] 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, Bosanac T, Mao X, Engber TM, 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.

[0007] 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).

[0008] 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 signalling to induce axon degeneration”, Journal of Cell Biology, 2020, Vol. 219, No 8). 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.

[0009] There have been attempts to provide compounds that modulate the activity of SARM1. For example, W02021 / 142006 and W02022 / 046606 disclose compounds useful for the treatment of 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.

[0010] SUMMARY OF THE INVENTION

[0011] It has been found that compounds of formula (I) and their pharmaceutically acceptable salts can be useful for this purpose.

[0012] In a first aspect, the present invention provides a compound of formula (I)

[0013]

[0014] or a pharmaceutically acceptable salt or solvate thereof;

[0015] wherein:

[0016] A is selected from N, N+-O_or CRA;

[0017] B is selected from N, N+-O_or CRB;

[0018] C is selected from N, N+-0_orCRc;

[0019] RA, RBand Rcare each independently selected from H, halogen, -OH, -NH2, Ci-2alkyl, -O-Ci-2alkyl, -CN, -Ci-2alkylene-OH, -Ci-2haloalkyl and -0-Ci-2haloalkyl

[0020] D is N or CRD, wherein RDis selected from H,2H, halogen, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0021] X1is selected from H,2H, halogen, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0022] X2and X3are each independently selected from H,2H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms; E is selected from N or CRE, wherein REis selected from H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms; and

[0023] X4is selected from halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0024] X5is selected from H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0025] wherein:

[0026] (i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or

[0027] (ii) X7is H and X6is selected from the group consisting of -NX6aX6b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX6aX6b; wherein X6aand X6bare independently H or Ci-3alkyl; or

[0028] (iii) X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which may be optionally substituted by one or more substituents selected from -OH, -NX8aX8b, -Ci-2alkyl, - Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl; and

[0029] X9and X10are both independently H.

[0030] In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] DETAILED DESCRIPTION OF THE INVENTION

[0036] In a first aspect, the present invention provides a compound of formula (I)

[0037]

[0038] (i);

[0039] or a pharmaceutically acceptable salt or solvate thereof;

[0040] wherein:

[0041] A is selected from N, N+-O_or CRA;

[0042] B is selected from N, N+-O_or CRB;

[0043] C is selected from N, N+-0_orCRc;

[0044] RA, RBand Rcare each independently selected from H, halogen, -OH, -NH2, Ci-2alkyl, -O-Ci-2alkyl, -CN, -Ci-2alkylene-OH, -Ci-2haloalkyl and -0-Ci-2haloalkyl

[0045] D is N or CRD, wherein RDis selected from H,2H, halogen, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0046] X1is selected from H,2H, halogen, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms; X2and X3are each independently selected from H,2H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0047] E is selected from N or CRE, wherein REis selected from H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms; and

[0048] X4is selected from halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0049] X5is selected from H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;

[0050] wherein:

[0051] (i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or

[0052] (ii) X7is H and X6is selected from the group consisting of -NX6aX6b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX6aX6b; wherein X6aand X6bare independently H or Ci-3alkyl; or

[0053] (iii) X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which may be optionally substituted by one or more substituents selected from -OH, NX8aX8b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl; and

[0054] X9and X10are both independently H.

[0055] The compounds of formula (I) may be referred to herein as “compounds of the invention” or “compounds according to the invention”.

[0056] 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.

[0057] The compound of formula (I), and pharmaceutically acceptable salts or solvates thereof, may be referred to herein as ‘compound(s) of the invention’. The term " C1-2 alkyl" as used herein, refers to straight, monovalent, saturated aliphatic hydrocarbon chains of 1 to 2 carbon atoms. Suitable examples of Ci-2alkyl according to the present invention are methyl. Suitable examples of -O-Ci-2alkyl according to the present invention are methoxy.

[0058] The term “alkylene” as used herein, such as in -Ci-2alkylene-OH, is a bifunctional straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Suitable examples of -Ci-2alkylene groups according to the present invention, are where the group is absent (i.e. Co), methylene (Ci) and ethylene (C2). Suitable examples of C1-2alkylene groups according to the present invention, are where the group is methylene (Ci), ethylene (C2) and propylene (C3).

[0059] The term “cycloalkyl” as used herein, such as in Cs-ecycloalkyl, refers to monovalent groups of 3 to 5 carbon atoms derived from a saturated monocyclic hydrocarbon. Illustrative C3-ecycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4).

[0060] The term “halogen” as used herein, represents a chloro, fluoro, bromo, or iodo atom. Suitable examples of halogens according to the present invention include bromo, chloro and fluoro. Other suitable examples of halogens according to the present invention are fluoro or chloro.

[0061] The term “haloalkyl” as used herein, such as in Ci-2haloalkyl, whether alone or forming part of a larger group such as an O-haloalkyl group, such as in OCi-2haloalkyl, is a straight or a 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. Further suitable examples of haloalkyl according to the present invention are CHF2 and CH2CF3. Another suitable example of haloalkyl according to the present invention is CH2CHF2. Suitable examples of O-haloalkyl according to the present invention include OCF3, OCHF2 and OCH2CF3.

[0062] The term “heterocycloalkyl” as used herein, such as in Cs-eheterocycloalkyl, 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 N, S orO.

[0063] 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.

[0064] 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, byway 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).

[0065] 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).

[0066] Where any of the groups in the compounds of formula (I) is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. In one embodiment, such groups will be unsubstituted, or substituted by one, two or three two substituents. In another embodiment, such groups will be unsubstituted, or substituted by one or two substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents. In one embodiment, such groups are unsubstituted. Suitable substituents for each of the groups present on compounds of formula (I) are defined hereinafter.

[0067] It will be appreciated by one skilled in the art that the second ring (“A, B, C” ring) may be represented in either the “Kekule” or “delocalised” model e.g. as represented by:

[0068]

[0069] and for the avoidance of doubt, all configurations are herein covered.

[0070] Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.

[0071] 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). 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) 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.

[0072] 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.

[0073] In one embodiment, the substituted 2-azabicyclo[3.1.0]hexan-3-one moiety present in compounds of formula (I) is in the 1S,4 / ?,5S configuration

[0074] O

[0075]

[0076] In another embodiment, the substituted 2-azabicyclo[3.2.0]heptan-3-one moiety present in compounds of formula (I) is in the 1S,4 / ?,5S configuration

[0077] O

[0078]

[0079] Alternatively, in one embodiment the substituted pyrrolidin-2-one moiety present in compounds of formula (I) is in the 3R configuration

[0080]

[0081] In another embodiment, the substituted pyrrolidin-2-one moiety present in compounds of formula (I) is in the 3R,4R configuration O

[0082]

[0083] In another embodiment, the substituted pyrrolidin-2-one moiety present in compounds of formula (I) is in the 3R,5R configuration

[0084] O

[0085]

[0086] Specific embodiments of compounds of formula (I) according to the present invention are described hereafter.

[0087] In an embodiment, A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC. In another embodiment, A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC, and at least one of A, B and C is N.

[0088] In one aspect, two of A, B and C are N and the other one is CRA, CRBand CRCas appropriate.

[0089] In another aspect, only one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate.

[0090] In another aspect, B is CRB; and one of A and C is N and the other is CRAor CRC, as appropriate.

[0091] In one aspect, A is N, B is CRBand C is N.

[0092] In another aspect, A is CRA, B is CRBand C is N.

[0093] In a further aspect, A is N, B is CRBand C is CRC.

[0094] In an additional aspect, A is CRA, B is N and C is N.

[0095] In another aspect, A is N, B is N and C is CRC.

[0096] In a further aspect, A is CRA, B is CRBand C is CRC.

[0097] In an additional aspect, A is N, B is N and C is N.

[0098] In an embodiment, RA, RBand Rc, are each independently selected from H, F, Cl, -OH, -NH2, -Ci-2alkyl, -O-Ci-2alkyl, -CN, -Ci-2alkylene-OH, -Ci-2haloalkyl and -0-Ci-2haloalky.

[0099] In an embodiment, RA, RBand Rc, are each independently selected from H, F, Cl, -OH, -Ci-2alkyl, -O-Ci-2alkyl, -CN, -Ci-2alkylene-OH, -Ci-2haloalkyl and -0-Ci-2haloalky

[0100] In an embodiment, RA, RBand Rc, are each independently selected from H, F, Cl, -OH, -CH3, -OCH3 -CN, -CH2OH, -CF3and -OCF3.

[0101] Suitably, RA, RBand Rcare each independently selected from H, Cl, F, -OCH3and -CH2OH.

[0102] In a particular embodiment, RA, RBand Rcare all H. It will be understood that not all of RA, RBand Rcneed to be present in the compounds of formula (I). The groups of RA, RBand Rcthat are present will depend upon the identities of A, B and C, respectively.

[0103] In a particular embodiment, only one of A, B and C is N and the other two areCRA, CRBand CRcas appropriate, wherein one of RA, RBand Rcis Cl, F, -CH3, -OCH3 and -CH2OH and the other is hydrogen, as appropriate.

[0104] In a particular embodiment, two of A, B and C are N and the other one isCRA, CRBand CRcas appropriate, wherein one of RA, RBand Rcis Cl, F, -CH3, -OCH3 and -CH2OH and the other is hydrogen, as appropriate.

[0105] In another embodiment, A is CRA, wherein RAis selected from Cl, F, -CH3, -OCH3 and -CH2OH, one of B and C is N and the other is CRB(RB= hydrogen) or CRC(Rc= hydrogen), as appropriate.

[0106] In one embodiment, B is CRB, wherein RBis selected from Cl, F, -CH3, -OCH3 and -CH2OH, one of A and C is N and the other is CRA(RA= hydrogen) or CRC(Rc= hydrogen), as appropriate.

[0107] In one embodiment, C is CRC, wherein Rcis selected from Cl, F, -CH3, -OCH3 and -CH2OH, one of A and B is N and the other is CRA(RA= hydrogen) or CRB(RB= hydrogen), as appropriate.

[0108] In one embodiment, A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC, wherein RA, RBand Rcare each independently selected from Cl, F, -CH3, -OCH3 and -CH2OH. In one embodiment, at least one of A, B and C is N.

[0109] In another embodiment, A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC, wherein RA, RBand Rcare each independently selected from Cl, F, -CH3, -OCH3 and -CH2OH. In one embodiment, at least one of A, B and C is N.

[0110] In a further embodiment, A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC, wherein RA, RBand Rcare each independently selected from Cl, F, -CH3, -OCH3 and -CH2OH. In one embodiment, at least one of A, B and C is N.

[0111] In an embodiment, X1is selected from H, F, Cl, -CHsor- O-CH3. Typically, X1is selected from H, Cl, F or -OCH3. Suitably, X1is H

[0112] In an embodiment, X2and X3are each independently selected from H or -C1-2 alkyl. In another embodiment, X2and X3are each independently selected from H,2H, F, Cl, -CHsor-OCHs. In another embodiment, X2and X3are each independently selected from H, F, Cl, -CH3 or - OCH3. Typically, X2and X3are each independently selected from H, Cl, F or -OCH3. In another embodiment, X2and X3are each independently selected from H,2H, halogen, -NH2, C1-2 alkyl optionally substituted with one or more halogen atoms, and -CN.

[0113] In one embodiment, X2is H and X3is selected from H,2H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms.

[0114] In another embodiment, X2is H and X3is selected from H,2H, halogen, -NH2, C1-2 alkyl optionally substituted with one or more halogen atoms, and -CN.

[0115] In another embodiment, X2is H and X3is selected from H or C1-2 alkyl.

[0116] In one embodiment, X3is H and X2is selected from H,2H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms.

[0117] In another embodiment, X3is H and X2is selected from H,2H, halogen, -NH2, C1-2 alkyl optionally substituted with one or more halogen atoms, and -CN.

[0118] In another embodiment, X3is H and X2is selected from H or C1-2 alkyl.

[0119] Illustratively, one of X1, X2and X3is selected from H, Cl, F or -OCH3 and the others are hydrogen. In a particular embodiment, X1is H and X2and X3are independently selected from hydrogen or Ci-2alkyl, such as -CH3.

[0120] Suitably, each of X1, X2and X3are hydrogen.

[0121] In an embodiment, D is N.

[0122] In another embodiment, D is CRD.

[0123] In one embodiment, RDis selected from H,2H, F, Cl, -CH3 or -O-CH3. Typically, RDis selected from H, F, Cl, -CH₃ or -O-CH₃. Suitably, RDis H.

[0124] In a particular embodiment, D is CH.

[0125] In another embodiment, X1is H; X2and X3are each independently selected from H or C₁-₂ alkyl; and D is N or CR^D, wherein R^D is selected from H or C₁-₂ alkyl.

[0126] In another embodiment, X1is H; X2and X3are each independently selected from H or -CH3; and D is N or CRD, wherein RDis selected from H or -CH3.

[0127] In an embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3. In an embodiment, X4is halogen. Typically, X4is selected from Cl and F.

[0128] In an embodiment, X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3. In an embodiment, X5is H or halogen. Typically, X5is selected from H, Cl and F. Suitably, X5is selected from H and F.

[0129] In another embodiment, X4is halogen and X5is H or halogen. In another embodiment, X4is Cl or F and X5is H, Cl or F. In a particular embodiment, both X4and X5are halogen. In one aspect of this embodiment, X4and X5are Cl or F.

[0130] In an embodiment, E is N.

[0131] In another embodiment, E is CRE.

[0132] Typically, REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3. More typically, REis selected from H, F, Cl or -OH. Suitably, REis H.

[0133] In one embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; E is N or CRE, wherein REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3.

[0134] In another embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; E is N or CRE, wherein REis selected from H, F, Cl or -OH.

[0135] In a further embodiment, X4is selected from Cl and F; X5is selected from H, Cl and F; E is N or CRE, wherein REis selected from H, F, Cl or -OH, suitably wherein REis H.

[0136] In an additional embodiment, X4is selected from Cl and F; X5is selected from H, Cl and F (suitably from H and F); E is N or CRE, suitably wherein REis H.

[0137] In one embodiment:

[0138] (i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or

[0139] (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl or C3-6heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents selected from -OH, NX8aX8b, -C1- 2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0140] In another embodiment

[0141] (i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or

[0142] (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl or C3-6heterocycloalkyl, either of which groups may be optionally substituted by one or two substituents selected from -OH, NX8aX8b, -Ci- 2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0143] In another embodiment, X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3-eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H orCi-3alkyl.

[0144] In another embodiment, X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH.

[0145] In another embodiment, X7is H and X6is selected from -NX6aX6b, -Ci -2al ky I, -Ci -2ha loal ky I, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OCs-eheterocycloalkyl and -OC1-3alkylNX6aX6b; wherein X6aand X6bare independently H or Ci-3alkyl.

[0146] In another embodiment, X7is H and X6is selected from the group consisting of -NH2, -CH3, -CHF2, -CF3-OCH3, -OCF3, -OCHF2 and -CH2OH.

[0147] In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which may be optionally substituted by one or more substituents selected from -OH, NX8aX8b, -Ci-2alkyl, -C1-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0148] In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl or C3-6heterocycloalkyl, either of which may be optionally substituted by one or two substituents selected from -OH, NX8aX8b, -Ci-2alkyl, -C1-2haloalkyl, -O-Ci-2alkyl, -O-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0149] In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which may be optionally substituted by one substituent selected from -OH, NX8aX8b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0150] In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl optionally substituted by one substituent selected from -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH.

[0151] In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent C3-4cycloalkyl optionally substituted by one substituent selected from -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH. In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl.

[0152] In another embodiment, X6and X7when taken together with the carbon atom to which they are attached represent C3-4cycloalkyl.

[0153] In another embodiment

[0154] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3 -CHF2, - OCH3, -OCHF2, -OCF3 and -CH2OH; or

[0155] (ii) X7is H and X6is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, - OCH3, -OCF3 -OCHF2 and -CH2OH; or

[0156] (iii) X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl optionally substituted by one or two substituents selected from the group consisting of -OH, NX8aX8b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0157] In another embodiment

[0158] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, - OCH3, -OCF3,-OCHF2and -CH2OH; or

[0159] (ii) X7is H and X6is selected from the group consisting of -NH2, -CH3, -CHF2 -CF3, - OCH3, -OCF3,-OCHF2and -CH2OH; or

[0160] (iii) X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl optionally substituted by one substituent selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3and -CH2OH.

[0161] In another embodiment

[0162] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, - OCH3, -OCHF2, -OCF3 and-CH2OH; or

[0163] (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl optionally substituted by one substituent selected from the group consisting of -OH, NX8aX8b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0164] In another embodiment

[0165] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCHF2, -OCF3and -CH2OH; or (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-6cycloalkyl optionally substituted by one substituent selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH. In another embodiment

[0166] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH; or

[0167] (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-4cycloalkyl optionally substituted by one substituent selected from the group consisting of -NH2, -CH3, -CF3-CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH. In another embodiment

[0168] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2and -CH2OH; or

[0169] (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-4cycloalkyl.

[0170] It will be apparent to one skilled in the art that when X6and X7form a “cycloalkyl” or “heterocycloalkyl” moiety, the following structures are formed (wherein > represents attachment to the remainder of the molecule):

[0171]

[0172] wherein:

[0173] G represents Cs-ecycloalkyl optionally substituted by -OH, NX8aX8b, -Ci-2alkyl, -C1-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl; and

[0174] H represents Cs-eheterocycloalkyl optionally substituted by -OH, NX8aX8b, -Ci-2alkyl, -C1-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H orCi-3alkyl.

[0175] In a one embodiment, when X6and X7form a “cycloalkyl” moiety the following structure is formed (wherein represents attachment to the remainder of the molecule):

[0176]

[0177] wherein G represents C3-6cycloalkyl optionally substituted by -OH, NH2, -CH3, -C1-2haloalkyl, -OCH3, -OCF2, -CH2CN and -CH2OH.

[0178] In a particular embodiment, when X6and X7form a “cycloalkyl” moiety the following structures are formed (wherein represents attachment to the remainder of the molecule):

[0179]

[0180] or

[0181] In a particular embodiment, when X6and X7form a “cycloalkyl” moiety the following structures are formed (wherein represents attachment to the remainder of the molecule):

[0182]

[0183] In one embodiment, X9is H. In another embodiment, X10is H. In another embodiment X9and X10are both independently H. In a further aspect, the present invention provides a compound of formula (II)

[0184]

[0185] or a pharmaceutically acceptable salt or solvate thereof;

[0186] wherein X1, X2, X3, X4, X5, X6, X7, X9, X10, D and E are as defined in any one of the aspects or embodiments above.

[0187] In a further aspect, the present invention provides a compound of formula (III)

[0188]

[0189] or a pharmaceutically acceptable salt or solvate thereof;

[0190] wherein A, B, C, X4, X5, X6, X7, X9, X10, and E are as defined in any one of the aspects or embodiments above.

[0191] In a further aspect, the present invention provides a compound of formula (IV)

[0192]

[0193] (IV)

[0194] or a pharmaceutically acceptable salt or solvate thereof; wherein A, B, C, X1, X2, X3, X6, X7, X9, X10, and D, are as defined in any one of the aspects or embodiments above;

[0195] X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro.

[0196] In a further aspect, the present invention provides a compound of formula (V)

[0197]

[0198] (V)

[0199] or a pharmaceutically acceptable salt or solvate thereof;

[0200] wherein A, B, C, X6, X7, X9and X10are as defined in any one of the aspects or embodiments above;

[0201] X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro. In a further aspect, the present invention provides a compound of formula (VI)

[0202]

[0203] (VI)

[0204] or a pharmaceutically acceptable salt or solvate thereof;

[0205] wherein A, B, C, X9and X10are as defined in any one of the aspects or embodiments above;

[0206] X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro; wherein

[0207] (i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -Ci- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3- eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or

[0208] (ii) X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which groups may be optionally substituted by one or more substituents selected from -OH, NX8aX8b, -Ci- 2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0209] In a further aspect, the present invention provides a compound of formula (VII)

[0210]

[0211] (VII)

[0212] or a pharmaceutically acceptable salt or solvate thereof;

[0213] wherein A, B, C, X9and X10are as defined in any one of the aspects or embodiments above;

[0214] X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro; wherein

[0215] (i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CHF2, -OCH3, - OCHF2, -CH2CN and -CH2OH, or

[0216] (ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-4cycloalkyl optionally substituted by one substituent selected from the group consisting of -OH, NX8aX8b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

[0217] It will be appreciated that compounds of formulae (II), (III), (IV), (V), (VI) and (VII) and 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 (II), (III), (IV), (V), (VI) and (VII).

[0218] The compound of formula (I) may be referred to herein as “the compound of the invention” or “the compound according to the invention”.

[0219] 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.

[0220] The compound of formula (I), and pharmaceutically acceptable salts or solvates thereof, may be referred to herein as “compound(s) of the invention”. 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.

[0221] In a particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of:

[0222] rac-(1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[2-(4-pyridyl)pyrimidin-5-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0223] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-fluoro-6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;

[0224] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one;

[0225] (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;

[0226] (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(6-pyridazin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one;

[0227] (3 / ?,4S)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?,4 / ?)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S,4S)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S,4 / ?)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0228] (1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0229] (1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one;

[0230] (1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0231] (1S,4 / ?,5S)-4-[(5,6-difluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0232] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one;

[0233] (1 / ?,4S,5 / ?)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one;

[0234] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one; (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one;

[0235] (1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one;

[0236] (1S,4 / ?)-4-[(6-fluoro-3-pyridyl)methyl]-2-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)-2-azabicyclo[3.1,0]hexan-3-one;

[0237] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0238] (3 / ?,4 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (1S,4 / ?,5S)-4-[dideuterio-(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;

[0239] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)-dideuterio-methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;

[0240] (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-methyl-5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0241] (3 / ?,4 / ?)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; (3 / ?,4 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-4-methyl-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; (1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(hydroxymethyl)-5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0242] (1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-pyridin-4-ylpyrazin-2-yl)-2-azabicyclo[3.1,0]hexan-3-one

[0243] (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one);

[0244] (1 / ?,4S,5 / ?)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one);

[0245] (1 / ?,4 / ?,5S,6 / ?)-4-[(6-chloro-3-pyridyl)methyl]-6-(hydroxymethyl)-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;

[0246] (3S,4S)-3-((6-chloropyridin-3-yl)methyl)-4-(hydroxymethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0247] (3 / ?,4 / ?)-3-((6-chloropyridin-3-yl)methyl)-4-(hydroxymethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0248] (1S,4 / ?,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(6-(3-methylpyridin-4-yl)pyridazin-3-yl)-2-azabicyclo[3.1,0]hexan-3-one;

[0249] (1S,4 / ?,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(5-(3-methylpyridin-4-yl)pyrazin-2-yl)-2-azabicyclo[3.1,0]hexan-3-one; (3R,4R)-4-amino-3-[(6-chloro-3-pyridyl)methyl]-1 -[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3R,4R)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0250] (1S,4R,5S)-4-((6-fluoropyridin-3-yl)methyl)-2-(6-(3-methylpyridin-4-yl)pyridazin-3-yl)-2-azabicyclo[3.1,0]hexan-3-one;

[0251] (3R,5S)-3-[(6-chloro-3-pyridyl)methyl]-5-(hydroxymethyl)-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; and

[0252] (3R,5R)-3-[(6-chloro-3-pyridyl)methyl]-5-(hydroxymethyl)-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin- 2-one;

[0253] or pharmaceutical acceptable salts and solvates thereof.

[0254] In a particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of:

[0255] (3R,4R)-3-[(6-fluoro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0256] (3R,4R)-3-[(6-chloro-2-fluoro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1-(6-pyridin-4-ylpyridazin- 3-yl)pyrrolidin-2-one;

[0257] (1S,4R,5S)-4-[(6-fluoro-3-pyridinyl)methyl]-2-(3-pyridin-4-yl-1,2,4-triazin-6-yl)-2-azabicyclo[3.1,0]hexan-3-one;

[0258] (3R,4R)-3-[(6-chloro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1-(3-pyridin-4-yl-1,2,4-triazin-6-yl)pyrrolidin-2-one;

[0259] (3R,4R)-3-[(6-chloro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0260] (3R,5S)-3-[(6-chloro-3-pyridinyl)methyl]-5-(hydroxymethyl)-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0261] (3R,4R)-3-[(6-chloro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1-[6-(3-methyl-4-pyridinyl)pyridazin-3-yl]pyrrolidin-2-one;

[0262] (35.45)-3-[(4-chlorophenyl)methyl]-4-(hydroxymethyl)-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0263] (3R,4R)-3-[(4-chlorophenyl)methyl]-4-(hydroxymethyl)-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0264] (1S,4R,5R)-4-[(6-chloro-3-pyridinyl)methyl]-5-(hydroxymethyl)-2-(6-pyridin-4-ylpyridazin-3-yl)- 2-azabicyclo[3.1,0]hexan-3-one;

[0265] (35.45)-3-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1-(6-pyridin-4-ylpyridazin- 3-yl)pyrrolidin-2-one; and (3R,4R)-3-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-4-(hydroxymethyl)-1 -(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0266] or pharmaceutical acceptable salts and solvates thereof.

[0267] 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.

[0268] 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.

[0269] 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 ora 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.

[0270] As used herein, the term "in a cell" includes both inside the cell membrane and on the surface of the cell membrane.

[0271] 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, ora pharmaceutically acceptable salt thereof, wherein the increased level of NAD+ is relative to the level of NAD+ prior to the contacting or administering.

[0272] 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, ora pharmaceutically acceptable salt thereof.

[0273] 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.

[0274] 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.

[0275] Example of neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD).

[0276] 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.

[0277] 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.

[0278] Neurological disorders also include autoimmune and inflammatory diseases.

[0279] 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.

[0280] Accordingly, 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 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.

[0281] In another aspect, 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.

[0282] In further aspect, 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.

[0283] 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. In another aspect, 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 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.

[0284] In a further aspect, 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.

[0285] In another aspect, 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.

[0286] 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.

[0287] In a first aspect, 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.

[0288] In another aspect, 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.

[0289] In a further aspect, 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] For use in medicine, the salts of the compounds of formula (I) (which includes compounds of the formulae (IA), (II), (III), (IV), (V), (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.

[0294] 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.

[0295] 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.

[0296] 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).

[0297] 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.

[0298] The invention also includes within its scope pro-drug forms of the compounds of formula (I) and its various sub-scopes and sub-groups.

[0299] PHARMACEUTICAL COMPOSITIONS

[0300] 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.

[0301] Therefore, another embodiment of the present invention concerns a pharmaceutical composition comprising an effective amount of a compound of formula (I) ora pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0302] 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.

[0303] 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.

[0304] 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. 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.

[0305] 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.

[0306] 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.

[0307] 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 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.

[0308] These pharmaceutical forms are prepared using methods which are routinely used by pharmacists.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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).

[0313] 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.

[0314] SYNTHETIC ROUTES

[0315] 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.

[0316] 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.

[0317] The compounds of 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.

[0318] 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.

[0319] All starting materials, unless otherwise stated, are commercially available or may be prepared by methods known to one skilled in the art.

[0320] The following description of synthetic schemes provides for means of preparing compounds of formula (I).

[0321] In the general synthetic schemes disclosed below, ‘Hal1, Hal2and Hal3’ denote a halogen atom, such as bromine, chlorine or iodine. Hal1is suitably bromine, chlorine or iodine. Hal2is suitably bromine or iodine. Hal3is suitably chlorine, bromine or iodine.

[0322] PG denotes a protecting group for amines; suitably, PG can be Boc. -C(=O)X denotes an acyl derivative, suitably an acyl halide (such as X = Cl) or anhydride (such as X = OC(=O)CH3).

[0323] ‘Hbo’ denotes a substituent on the boron atom, wherein the substituent is suitable for use in a conjugate addition to olefins. Suitably, ‘Hbo’ may be OH.

[0324] ‘Suz’ denotes a substituent on the boron atom, wherein the substituent is suitable for use in Suzuki reaction. Suitably, ‘Suz’ can be OH or two Suz taken together form the following group, also known as ‘(pin).

[0325] CH3

[0326]

[0327] formula (I)

[0328] Suzuki coupling of compounds (1) and (2), in the presence of a suitable catalyst, such as PdCl2(dppf) CH2Cl2, yields the biaryl precursor (3). Buchwald-Hartwig amination of compound (3) with the pyrrolidone (4) yields compound (5). The amination may be carried out in the presence of a suitable catalyst (such as Pd3(dba)3), ligand (e.g. Xantphos) and a base (for example K3PO4). Compound (5) is then reacted with the halide derivative (6) under suitable conditions (such as using LDA or LiHMDS). The Buchwald animation may be replaced by a nucleophilic aromatic substitution (SNAr) reaction.

[0329] Optional epimerisation of a stereocentre in compounds of formula (I) may be effected by treating compounds of formula (I) with a suitable base (such as LiHMDS). It is possible to avoid the need for Suzuki reaction by employing a suitable starting material. Examples of a commercially available compounds (3) are 2-bromo-5-(pyridin-4- yl)pyrazine (CAS 1159819-55-2) or 3-bromo-6-pyridin-4-yl-pyridazine (1159818-39-9).

[0330] In a variation of this embodiment, compounds of formula (I), wherein X6and X7are not cyclised, can be prepared via the following Synthetic Scheme 2:

[0331] (8)

[0332]

[0333] formula (I) Compound (7) is reacted with compound (2) via a Suzuki coupling in the presence of a suitable catalyst, such as PdCl2(dppf), followed by removal of the protecting group to yield compound (8). Suitable deprotection methods will be known to the skilled person depending on the identity of the protecting group, but one suitable method, when the PG is for instance Boc, is to deprotect with trifluoroacetic acid (TFA) in a suitable solvent such as DCM. Compound (8) is then reacted with compound (9), which proceeds via a lactone ring opening and then forming a lactam moiety via an intramolecular cyclisation. The cyclisation can be a Mitsunobu-type reaction and can be carried out in the presence of a suitable phosphine, such as triphenylphosphine, and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). The resultant compound, compound (5) is then reacted with the halide derivative (6) under suitable conditions (such as LDA or LiHMDS) to yield compounds of formula (I).

[0334] In an alternative embodiment, the biaryl precursor (3’), wherein D is N, and X1, X2and X3are H, may be prepared according to Scheme 3. N=N _ Cl— 4 Cl u i1^™sA-. N-NASandmeyer Hal — ( / N02- ► = — (' N02- ».Nz— 4 / ^—N H2- — *■ N B-C then hydrogenation N= / B=C N B=C

[0335]

[0336] (10) <1 1> (12)(3.) Compound (1O) is coupled with trimethylsilylacetylene, via a Sonogashira coupling. The reaction proceeds in the presence of copper and a suitable palladium catalyst, such as Pd(PPh3)2CI2, and the TMS is removed under suitable conditions, such as with K2CO3 in MeOH. The resultant compound, compound (11) is then reacted with 3,6-dichloro-1,2,4,5-tetrazine via a Diels-Alder then retro-Diels-Alder on the alkyne, using an elevated temperature, such as 140 °C and a suitable solvent, such as o-xylene. This is then followed by hydrogenation, using a suitable palladium catalyst, such as Pd / C, under hydrogen, in a suitable solvent such as EtOH / THF. Finally, compound (12) undergoes a Sandmeyer conversion of the NH2 group to I, by reaction with a nitrate salt, such as NaNC>2 and potassium iodide, at a suitable temperature, such as 0 °C and in a suitable solvent, such as TFA.

[0337] Compounds of formula (I), when X6and X7form a fused cyclopropane ring, may be prepared via the following route, Scheme 4:

[0338]

[0339] Formula (I) Compound (13) is coupled with compound (14), where the PG is suitably p-methoxybenzyl or Boc, under suitable conditions, such as DIPEA and HATU, in a suitable solvent such as DMF. The resultant compound, compound (15), then undergoes C-H activation / cyclisation, in the presence of a suitable catalyst such as rac-BIDIME and a Pd catalyst, such as palladium(ll) acetate at an elevated temperature. A reduction reaction is then carried out on the resultant compound, compound (16) using an alkene reductant such as NiC and NiBF, after which deprotection of the N-protecting group is performed to afford compound (17). Suitable deprotection methods will be known to the skilled person depending on the identity of the protecting group, but one suitable method, when the PG is for instance Boc, is to deprotect with trifluoroacetic acid (TFA) in a suitable solvent such as DCM. It will be clear to one skilled in the art that the deprotection step may alternatively be carried out before the reduction step. Compound (17) then may be coupled with the biaryl precursor (3 or 3’) in the presence of a base such as K3PO4in a suitable solvent such as in 1,4-dioxane. The reaction proceeds in the presence of nitrogen and a suitable catalyst, such as XantPhos Pd G3 and an elevated temperature, to yield compounds of formula (I).

[0340] Compound (13), may be prepared via a Sonogashira reaction with the appropriate alkyne ester precursor, followed by ester hydrolysis to give the acid product (13).

[0341] Compounds of formula (I), when X6and X7form a fused cyclobutane ring, may be prepared via the following route, Scheme 5:

[0342]

[0343] Ir[dF(CF3)ppy]2(dbby)PF6at suitable wavelength of light, such as 365 nM. This is then followed by reduction of the double bond, e.g. by hydrogenation with hydrogen using a suitable catalyst such as Pd / C. The NH group in compound (19) is then protected with a suitable protecting group such as Boc. The resultant compound, compound (20), is then reacted with a suitable aldehyde (21) via an aldol reaction in the presence of a base, such as LiHMDS, and BF3-OEt2 at reduced temperatures, such as -78°C, in a suitable solvent such as THF. This is then followed by elimination, for example by treatment of methanesulfonyl chloride (MsCI), and addition of a suitable base such as DBU. Compound (22) then undergoes deprotection and reduction to afford compound (23). Compound (23) then may be coupled with the biaryl precursor (3 or 3’), to yield compounds of formula (I).

[0344] Compound (18) may be prepared by treating 3,3-dibromoazepan-2-one with LiCI in a suitable solvent such as DMF with heating.

[0345] In another embodiment, the reaction may proceed via compound (24) Scheme 6:

[0346]

[0347] Compound (24) is prepared via the reaction of compound (25), an N-protected 2-pyrrolidone, with the halide derivative (6) under suitable conditions (such as LDA in THF / heptane / ethylbenzene), followed by deprotection of the N-protecting group. Suitable deprotection methods will be known to the skilled person depending on the identity of the protecting group, for instance with TFA when the PG is Boc. Optional epimerisation of a stereocentre may be effected (before the deprotection step) by treatment with a suitable base (such as LiHMDS). This is followed by reaction with the biaryl precursor (3 or 3’) via a Buchwald or SNAr reaction.

[0348] In an alternative method, compound (24) may be prepared via the following scheme, scheme 7:

[0349]

[0350] N-protected 2-pyrrolidone (compound (25)) and a suitable aldehyde, compound (21), are reacted under suitable conditions (such as with a base e.g. LiHMDS) to yield compound (26). The hydroxyl group of compound (26) is changed to a leaving group (LG) under suitable conditions, such as reaction with methanesulfonyl chloride (MsCI). The resultant compound then undergoes elimination of the leaving group (LG) using a base such as DBU to yield compound (27). A reduction reaction is then carried out on compound (27) using an alkene reductant such as NiC and NiBH4, after which deprotection of the N-protecting group is performed to afford compound (24). Suitable deprotection methods will be known to the skilled person depending on the identity of the protecting group, but one suitable method, when the PG is for instance Boc, is to deprotect with trifluoroacetic acid (TFA) in a suitable solvent such as DCM. It will be clear to one skilled in the art that the deprotection step may alternatively be carried out before the elimination or the reduction step. Compound (24) then may be coupled with the biaryl precursor (3 or 3’), to yield compounds of formula (I). Where they are not commercially available, the starting materials may be prepared by methods known to the person skilled in the art.

[0351] 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.

[0352] 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.

[0353] The inhibition by compounds of formula (I) on SARM1 can be tested in various assays. In the ENAD (etheno-NAD+assay), NAD+ hydrolase activity is measured using an NAD+ analogue to produce a fluorescent product that is measured in real time.

[0354] The efficacy of the compounds according to the Examples to inhibit SARM1 is represented by measuring the ICso which corresponds to the concentration of compound necessary to inhibit 50% of NAD+hydrolase activity. pICso values correspond to -log of the ICso in Molar. When tested, the majority of example compounds 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 or equal to 7.0. When tested, compounds according to Examples 1, 2A, 3A, 4A, 5A, 6A, 6B, 6C, 6D, 7A, 8A, 9A, 10A, 11 A, 12A, 12B, 13- 24, 25A, 26A, 26B, 27, 28A, 28B, 29, 30, 31 A, 32A, 33, 34A, 34B, 35A and display values of pICso greater than or equal to about 6.0.

[0355] The inhibition of SARM1 cellular activity by compounds of formula (I) can also be tested with human immortalized cells (HEK293T) overexpressing human SARM1 in a CZ-48 assay as disclosed herein.

[0356] The efficacy of the compounds, according to the Examples, to inhibit SARM1 is represented by measuring the ECso 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% ofSARMI inhibition in a cellular context. plC50 values correspond to -log of the ICso in Molar.

[0357] When tested, the majority of example compounds of formula (I) according to the present invention, display values of pICso greater than or equal to 5.0, suitably greater than or equal to 5.5, suitably greater than or equal to 6.0, preferably greater than or equal to 6.5. When tested compounds according to Examples 1, 2A, 3A, 4A, 5A, 6A, 6B, 6C, 6D, 7A, 8A, 9A, 10A, 11 A, 12A, 12B, 13-24, 25A, 26A, 27, 28A, 28B, 29, 30, 31 A, 32A, 33, 34A, 34B and 35A, display values of plC50 greater than or equal to about 5.1.

[0358] In both the ENAD and CZ-48 Assays described herein, the lower the value of the ICso (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.

[0359] In particular, the CZ-48 assay gives an indication of activity in a cellular context and therefore is a better predictor of the activity of a compound in vivo.

[0360] In the cytochrome P450 Inhibition (ICso Shift) Assay disclosed herein the inhibitory potential of compounds of formula (I) for cytochrome P450 isoforms, was tested using isoformspecific probe substrates. Typically, the lower the ICso value of the test compound for a CYP enzyme, the higher is the potential for inhibition.

[0361] When tested certain compounds of formula (I) according to the present invention display ICso values of 25 pM against tested isoforms.

[0362] CYP inhibition is a common cause of drug-drug interactions and therefore it is desirable to have a test compound with a high ICso value to have the lowest potential for inhibition, against multiple isoforms. The following Examples illustrate the preparation of compounds according to the invention.

[0363] EXPERIMENTAL SECTION

[0364] I. Abbreviations

[0365] (1H) NMR (Proton) Nuclear magnetic resonance

[0366] BF3-Et2O Boron trifluoride etherate

[0367] Boc tert-Butoxy-carbonyl

[0368] B0C2O Di-tert-butyl decarbonate

[0369] CBr4 Carbon tetrabromide

[0370] CDCh Chloroform-d4

[0371] CD3OD Methanol-d4

[0372] CO2 Carbon dioxide

[0373] Cui Copper(l) iodide

[0374] CuCl Copper(l)chloride

[0375] CuBr Copper(ll)bromide

[0376] D2O Deuterium oxide

[0377] DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0378] DCM Dichloromethane

[0379] DEA Diethanoloamine

[0380] DIAD Diisopropyl azodicarboxylate

[0381] DIBAL-H Diiso-butyl aluminium hydride

[0382] DIPEA N, N-Diisopropylethylamine

[0383] DMAP 4-Dimethylamino-pyridine

[0384] DMF N, N-Dimethylformamide

[0385] DMSO Dimethyl sulfoxide

[0386] e.e. Enantiomeric excess

[0387] ESI Electrospray ionisation

[0388] EtOAc Ethyl acetate

[0389] EtOH Ethanol

[0390] g Gram

[0391] H or h Hour(s)

[0392] H2 Hydrogen

[0393] H2O Water

[0394] HATU 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate

[0395] HPLC High performance liquid chromatography

[0396] i-PrOH isopropanol

[0397] IR Infra-red

[0398] lr[dF(CF3)ppy]2(dbby)PF6[4,4'-Bis(1, 1 -dimethylethyl)-2,2'-bipyridine-N1, N1']bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]lridium(l II) hexafluorophosphate

[0399] JosiPhos SL-J009-1 Pd G3 {(R)-1-[(Sp)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine}[2-(2'-amino-1,1'-biphenyl)]palladium(ll) methanesulfonate

[0400] K2CO3 Potassium carbonate

[0401] K3PO4Potassium phosphate (tribasic)

[0402] KF Potassium fluoride

[0403] KO‘-Bu Potassium tert-butoxide

[0404] LCMS Liquid chromatography-mass spectrometry

[0405] LDA Lithium diisopropylamide

[0406] LiHMDS Lithium bis(trimethylsilyl)amide

[0407] LiOH-H2O Lithium hydroxide hydrate

[0408] M Molar

[0409] MeCN Acetonitrile

[0410] MeOH Methanol

[0411] 2MeTHF 2-Methyl tetra hydrofuran

[0412] MeOD Methanol-d4

[0413] mg Milligram

[0414] MgSO4Magnesium sulfate

[0415] MHz Megahertz

[0416] min.(s) Minute(s)

[0417] mL or ml Millilitre

[0418] mM Millimolar

[0419] mmol Millimole

[0420] MS Mass spectrometry

[0421] MsCI Mesyl chloride

[0422] MTBE Methyl-tert-butyl ether

[0423] N2Nitrogen NaBH4Sodium borohydride

[0424] Na2SO4Sodium sulfate

[0425] Na2S2O5Sodium metabisulfite

[0426] NaHCO3Sodium hydrogen carbonate

[0427] NaNO2Sodium nitrite

[0428] NEt3Triethylamine

[0429] NH3Ammonia

[0430] NH4CI Ammonium chloride

[0431] NH4OH Ammonium hydroxide

[0432] NiCI2Nickel dichloride

[0433] NMR Nuclear magnetic resonance

[0434] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0435] Pd / C Palladium on carbon

[0436] Pd2(dba)3T ris-dibenzylideneacetone dipalladium

[0437] PdCI2(dppf) [1,1’Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) Pd(dppf)CI2[1,1’Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) Pd(PPh3)2CI2Bis(triphenylphosphine)palladium(ll) dichloride Pd(OAc)2Palladium (II) acetate

[0438] PPh3Triphenylphosphine

[0439] r.t. Room temperature

[0440] RT Retention time

[0441] Rac-BIDIME 3-(Tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3- dihydrobenzo[d][1,3]oxaphosphole

[0442] SFC Supercritical fluid chromatography

[0443] t-Bu or tBu tert-Butyl

[0444] TBSCI tert-Butyldimethylsilyl chloride

[0445] TFA Trifluoroacetic acid

[0446] THF Tetrahydrofuran

[0447] UV Ultraviolet

[0448] VCD Vibrational circular dichroism

[0449] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XantPhos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2- amino-1,1'-biphenyl)]palladium(ll) methanesulfonate

[0450] Naming convention: 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.

[0451] Analytical Methods

[0452] All NMRs were obtained either at 300 MHz or at 400 MHz. The compounds are studied in deuterated solvents such as DMSO-de, CDCb, MeOD or D2O. Chemical shifts are given in ppm relative to the residual undeuterated solvent signal in the spectrum.

[0453] Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, double doublet etc.

[0454] All LCMS retention times are in minutes.

[0455] LCMS data for all Intermediates were determined using either Method 1 A, Method 3A, Method 3B, Method 3C, Method 3D, Method 3E or, Method 3F.

[0456] LCMS data for the majority of Examples were determined by using Method 5.

[0457] LCMS Method 1A

[0458] Column: Phenomenex Gemini NX-C18, 2 x 20 mm, 3 pm

[0459] Temperature: 40 °C

[0460] Flow Rate: 1.0 mL / min

[0461] Solvent A: 10 mM Ammonium formate in water + 0.1% Ammonia solution

[0462] Solvent B: MeCN / FhO / Ammonia Solution (95 / 5 / 0.1)

[0463] Gradient program:

[0464] Time %A %B

[0465] 0.00 95 5

[0466] 1.50 5 95

[0467] 2.25 5 95

[0468] 2.50 95 5

[0469]

[0470] LCMS Method 3A

[0471] Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 μm

[0472] Temperature: 40 °C

[0473] Flow Rate: 1.8 mL / min

[0474] Solvent A: 0.1% formic acid in H₂O

[0475] Solvent B: MeCN

[0476] Gradient program:

[0477] Time %A %B

[0478] 0.00 95 5

[0479] 1.0 0 100

[0480] 1.49 0 100

[0481]

[0482] LCMS Method 3B

[0483] Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7μm

[0484] Temperature: 40 °C

[0485] Flow Rate: 1.35 mL / min

[0486] Solvent A: 0.1% formic acid in H₂O

[0487] Solvent B: MeCN

[0488] Gradient program:

[0489] Time %A %B

[0490] 0.0 98 2

[0491] 2.5 0 100

[0492] 3.0 0 100

[0493]

[0494] LCMS Method 3C

[0495] Column: Waters BEH C18, 2.1 mm x 30 mm, 1.7 pm, 130A Temperature: 40 °C

[0496] Injection Volume: 0.6 pL

[0497] Flow Rate: 1.35 mL / min

[0498] Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by ESI Solvents: A: 0.2% Ammonia in H₂O, B: MeCN

[0499] Time %A %B

[0500] 0.00 98 2

[0501]

[0502] 2.5 0 100

[0503] 3 0 100

[0504]

[0505] LCMS Method 3D

[0506] Column: Waters BEH C18, 2.1 mm x 30 mm, 1.7 μm, 130Å Temperature: 40 °C

[0507] Injection Volume: 0.6 μL

[0508] Flow Rate: 1.8 mL / min

[0509] Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by ESI Solvents: A: 0.2% NH3in H2O, B: MeCN

[0510] Time %A %B

[0511] 0.00 95 5

[0512] 1.0 0 100

[0513] 1.49 0 100

[0514]

[0515] Method 3E - UPLC Basic Method (3 min)

[0516] Column: Waters BEH C18, 2.1 mm x 30 mm, 1.7 μm, 130Å Temperature: 40 °C

[0517] Injection Volume: 0.6 μL

[0518] Flow Rate: 1.35 mL / min

[0519] Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by ESI Solvents: A: 0.2% NH3in H2O, B: MeCN

[0520] Time %A %B

[0521] 0.00 98 2

[0522] 2.5 0 100

[0523] 3 0 100

[0524]

[0525] Method 3F - UPLC Acidic Method (3 min)

[0526] Column: Waters CSH C18, 1.7 μm, 2.1 x 30 mm, 1.7 μm, 130Å Temperature: 40 °C

[0527] Injection Volume: 0.6 μL

[0528] Flow Rate: 1.35 mL / min

[0529] Detection: UV at 210-400 nm unless otherwise indicated, MS by ESI Solvents: A: 0.1% Formic acid in H₂O, B: MeCN Time %A %B

[0530] 0.00 98 2

[0531] 2.5 0 100

[0532] 3 0 100

[0533]

[0534] LCMS Method 5

[0535] Column: Waters UPLC X Bridge BEH (C18, 2.1 x 50 mm, 2.5 μm)

[0536] Temperature: 45 °C

[0537] Flow Rate: 1.0 mL / min

[0538] Solvent A: 10 mM ammonium formate in water + 0.1% formic acid

[0539] Solvent B: 95% acetonitrile + 5% H₂O + 0.1% formic acid

[0540] Gradient program:

[0541] Time %A %B

[0542] 0.0 95 5 10

[0543] 0.10 95 5

[0544] 2.10 5 95

[0545] 2.35 5 95

[0546] 2.80 95 5

[0547]

[0548] - 1-5—1

[0549] Vibrational Circular Dichroism (VCD) Method

[0550] 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 μL CDCl3or 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-1for 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.).

[0551] 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 used for the below procedures. All starting materials are commercially available or may be made by methods known to one skilled in the art.

[0552] II. SYNTHESIS OF INTERMEDIATES

[0553] INTERMEDIATE 1: 2-(4-Pyridyl)Pyrimidin-5-amine

[0554]

[0555] 2-Chloropyrimidin-5-amine (4 g, 30.9 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.50 g, 46.3 mmol) and K2CO3(12.80 g, 92.6 mmol) were dissolved in dioxane (100 mL) and H₂O (10 mL) and the resultant suspension was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2(2.26 g, 3.09 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled down to r.t., filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% (3:1 EtOAc: EtOH) / iso-hexane) to afford the title compound (3 g, 51%) as a beige solid.1H NMR (400 MHz, DMSO) 5 8.64 (s, 2H), 8.25 (s, 2H), 8.08 (s, 2H), 6.00 (s, 2H).

[0556] INTERMEDIATE 2: 5-Bromo-2-(4-pyridyl)pyrimidine

[0557]

[0558] 2-(4-Pyridyl)pyrimidin-5-amine (prepared according to the procedure of Intermediate 1) (500 mg, 2.70 mmol) and CuBr (1.16 g, 8.10 mmol) were dissolved in MeCN (10 mL) and tBuONO (0.97 mL, 8.10 mmol) was slowly added. The resultant suspension was stirred at r.t. for 18 h. The reaction mixture was partitioned between EtOAc (40 mL) and sat. aq. NaHCO3(40 mL) and the layers separated. The organic phase was then washed with 20% Na2S2O3solution (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / heptane) to afford the title compound (150 mg, 23%) as a grey solid. LCMS (Method 3B): [M+H]+m / z 236.0 / 238.0, RT 0.83 minutes.1H NMR (400 MHz, DMSO) 59.19 (s, 2H), 8.79 (d, J = 5.1 Hz, 2H), 8.26 - 8.20 (m, 2H).

[0559]

[0560] 5-Bromo-2-(4-pyridyl)pyrimidine (prepared according to the procedure of Intermediate 2) (130 mg, 0.55 mmol), 2-azabicyclo[3.1.0]hexan-3-one (64 mg, 0.66 mmol) and K3PO4(234 mg, 1.10 mmol) were dissolved in dioxane (5 mL) and the reaction mixture was degassed with nitrogen for 5 minutes. XantPhos Pd G3 (52 mg, 0.06 mmol) was added, and the reaction mixture was further degassed with nitrogen for 5 minutes. The reaction mixture was stirred at 100 °C for 2 h and then cooled down to r.t. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography on silica gel (0-100% (3:1, EtOAc: EtOH) / iso-hexane) to afford the title compound (113 mg, 77%) as a beige solid. LCMS (Method 3A): [M+H]+m / z 253.2, RT 0.28 minutes.1H NMR (400 MHz, DMSO) 59.31 (s, 2H), 8.76 (d, J = 4.6 Hz, 2H), 8.26 - 8.19 (m, 2H), 3.80 (dddd, J = 7.4, 5.2, 2.3, 1.0 Hz, 1H), 3.03 (dd, J = 18.5, 7.3 Hz, 1 H), 2.58 - 2.53 (m, 1H, DMSO overlap), 1.79 - 1.68 (m, 1H), 1.18 - 1.08 (m, 1H), 0.68 - 0.60 (m, 1H).

[0561] INTERMEDIATE 4: 5-1

[0562]

[0563] i-2-chloro-i

[0564]

[0565] Br

[0566]

[0567] (6-Chloro-3-pyridyl)methanol (1.50 g, 10.4 mmol) was dissolved in DCM (40 mL) and PBr3(1.19 mL, 12.5 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and then diluted with sat. aq. NaHCO3(100 mL). The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo to afford the title compound (1.52 g, 67%) as a yellow turbid oil. The product was used in the next step without further purification.1H NMR (400 MHz, CDCb) 58.40 (d, J = 2.6 Hz, 1 H), 7.70 (dd, J = 8.3, 2.6 Hz, 1H), 7.33 (dd, J = 8.3, 0.7 Hz, 1H), 4.44 (s, 2H).

[0568] INTERMEDIATE 5: 2-(4-Pyridyl)pyrimidin-5-amine

[0569]

[0570] Prepared from 2,5-dibromo-3-fluoro-pyridine (1 g, 3.92 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.21 g, 5.89 mmol) in accordance with the procedure described for Intermediate 1 (THF, 70 °C, 18 h) to afford the title compound (640 mg, 47%) as a brown solid. LCMS (Method 3A): [M+H]+m / z 253.0 / 255.0, RT 0.49 minutes.1H NMR (400 MHz, DMSO) 5 8.77 (d, J= 1.6 Hz, 2H), 8.40 (dd, J= 10.9, 1.9 Hz, 1H), 7.95 - 7.85 (m, 3H).

[0571] INTERMEDIATE 6: Ethyl 3-(6-chloro-3-pyridyl)prop-2-ynoate

[0572] o

[0573]

[0574] Cl

[0575] 2-Chloro-5-iodo-pyridine (20 g, 83.5 mmol) and K2CO3(23.1 g, 167 mmol) were purged with nitrogen for 5 minutes, then dry THF (200 mL) was added. CuI (636 mg, 3.34 mmol) and Pd(PPh3)2Cl2(1.17 g, 1.67 mmol) were added, followed by the dropwise addition of ethyl prop-2-ynoate (16.9 mL, 167 mmol). The reaction was stirred at 35 °C for 5 h. The reaction was cooled to r.t. and filtered through a pad of Celite, washing with EtOAc (200 mL). The crude product was concentrated onto silica and purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (16.8 g, 80%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 210.0 / 212.0, RT 1.42 minutes.1H NMR (500 MHz, DMSO) 58.74 (dd, J = 2.4, 0.8 Hz, 1H), 8.19 (dd, J = 8.3, 2.4 Hz, 1H), 7.68 (dd, J = 8.4, 0.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0576] INTERMEDIATE 7: 3-(6-Chloro-3-pyridyl)prop-2-vnoic acid

[0577] o

[0578]

[0579] Ethyl 3-(6-chloro-3-pyridyl)prop-2-ynoate (prepared according to the procedure of Intermediate 6) (16.8 g, 66.5 mmol) was dissolved in EtOH (70 mL) and H₂O (15 mL), and LiOH-H2O (5.58 g, 133 mmol) was added. The reaction was stirred at r.t. for 30 minutes and diluted with H₂O (100 mL). The solution was acidified to ~pH 1-2 with 6 N aq. HCl (~100 mL) and the solid was collected, washed with H₂O (2 x 20 mL) and dried to afford the title compound (10.5 g, 81%) as a white solid. LCMS (Method 3B): [M+H]+m / z 182.0 / 184.0, RT 0.83 minutes.

[0580] INTERMEDIATE 8: 3-(6-Chloro-3-pyridyl)-N-cvclopropyl-N-[(4-methoxyphenyl)methyllprop-2-vnamide o

[0581]

[0582] 3-(6-Chloro-3-pyridyl)prop-2-ynoic acid (prepared according to the procedure of Intermediate 7) (4.50 g, 25.4 mmol), N-[(4-methoxyphenyl)methyl]cyclopropanamine (4.96 g, 28.0 mmol) and DIPEA (13.1 mL, 76.3 mmol) were dissolved in DMF (100 mL) and HATU (14.5 g, 38.1 mmol) was then added. The reaction mixture was stirred at r.t. for 2 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with sat. aq. NaHCO3(2 x 100 mL), 1 M aq. HCl (2 x 100 mL) and brine (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (4.99 g, 56%) as a colourless solid. LCMS (Method 3A): [M+H]+m / z 341.2 / 343.2, RT 0.70 minutes.1H NMR (400 MHz, DMSO) 58.68 (dd, J = 2.4, 0.8 Hz, 1H), 8.12 (dd, J = 8.3, 2.4 Hz, 1H), 7.65 (dd, J = 8.3, 0.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.50 (s, 2H), 3.74 (s, 3H), 2.77 - 2.67 (m, 1 H), 0.95 - 0.84 (m, 4H).

[0583] INTERMEDIATE 9: 4-r(6-Chloro-3-pyridyl)methylenel-2-r(4-methoxyphenyl)methyll-2-azabicyclo[3.1.01hexan-3-one

[0584]

[0585] A solution of 3-(6-chloro-3-pyridyl)-N-cyclopropyl-N-[(4-methoxyphenyl)methyl]prop-2-ynamide (prepared according to the procedure of Intermediate 8) (7.60 g, 21.2 mmol) in toluene (100 mL) was sparged with nitrogen for 5 minutes. Pd(OAc)2 (238 mg, 1.06 mmol) and rac-BIDIME (700 mg, 2.12 mmol) were added, and the resulting mixture was heated to 90 °C under nitrogen for 20 h, cooled to r.t. and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-60% EtOAc / iso-hexane) to afford the title compound (5.50 g, 75%) as a yellow oil. LCMS (Method 3B): [M+H]+m / z 341.1 / 343.1, RT 1.59 minutes.1H NMR (500 MHz, DMSO) 58.68 (d, J = 2.4 Hz, 1 H), 8.53 (dd, J = 8.4, 2.4 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1H), 7.30 - 7.17 (m, 2H), 6.99 (s, 1H), 6.94 - 6.82 (m, 2H), 4.52 - 4.22 (m, 2H), 3.74 (s, 3H), 3.37 (td, J = 4.6, 2.4 Hz, 1 H), 2.37 (ddd, J = 8.5, 5.5, 3.9 Hz, 1 H), 1.04 (dt, J = 8.5, 5.0 Hz, 1 H), 0.51 (td, J = 4.6, 2.3 Hz, 1H).

[0586] INTERMEDIATE 10: 4-r(6-Chloro-3-pyridyl)methylenel-2-azabicvclor3.1. Olhexan-3-one

[0587]

[0588] To a solution of 4-[(6-chloro-3-pyridyl)methylene]-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 9) (5.50 g, 15.8 mmol) in DCM (50 mL) was added trifluoromethanesulfonic acid (6.04 mL, 68.2 mmol). The reaction mixture was then stirred at r.t. for 16 h. The reaction mixture was neutralised with sat. aq. NaHCO3solution (50 mL). The resultant solution was extracted with 10% MeOH / DCM (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (3.49 g, 100%) as a brown solid. LCMS (Method 3A): [M+H]+m / z 221.1 / 223.2, RT 0.52 minutes.1H NMR (500 MHz, DMSO) 58.73 - 8.64 (m, 2H), 8.48 (dd, J = 8.5, 2.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 2.45 -2.38 (m, 1H), 1.10 - 1.03 (m, 1H), 0.70 (td, J = 4.5, 2.3 Hz, 1H). 1 H overlapped with water peak.

[0589] INTERMEDIATE 11: Rac-(1 S.4R.5S)-4-R6-Chloro-3-pyridyl)methyl1-2-

[0590]

[0591] azabicyclo[3.1.01hexan-3-one

[0592] O

[0593]

[0594] Cl

[0595] 4-[(6-Chloro-3-pyridyl)methylene]-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 10) (2.7 g, 11.6 mmol) was dissolved in EtOH (20 mL) and THF (10 mL) and NiCl2(177 mg, 1.37 mmol) was added. The mixture was cooled to 0 °C, NaBH4 (1.32 g, 34.9 mmol) was added portion wise, and the mixture was stirred at 0 °C for 2 h. The mixture was filtered through a small pad of Celite, washed with MeOH (3 x 15 mL) and the filtrate was concentrated in vacuo. The crude material was purified by reverse phase flash chromatography on C18 silica gel (5-75% MeCN / 0.1% formic acid in H₂O). The fractions containing the desired product were combined and concentrated in vacuo. The residue was triturated in MTBE (15 mL), collected and dried in vacuo to afford the title compound (1.20 g, 46%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 223.2 / 225.2, RT 0.90 minutes.1H NMR (500 MHz, DMSO) 58.34 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1 H), 3.05 - 2.91 (m, 3H), 2.45 (d, J = 11.5 Hz, 1 H), 1.35 (dq, J = 7.2, 2.5 Hz, 1 H), 0.64 (dt, J = 8.4, 5.3 Hz, 1 H), 0.30 (td, J = 5.2, 2.1 Hz, 1 H).

[0596] INTERMEDIATE 12 and INTERMEDIATE 13: (1R,4S,5R)-4-r(6-Chloro-3-pyridyl)methyll-2-.1.01hexan-3-one and (1 S,4R,5S)-4-r(6-chloro-3-pvridvl)methvll-2-..1J -3-one

[0597]

[0598] Rac-(1S,4R,5S)-4-[(6-Chloro-3-pyridyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 11) (1 g, 4.31 mmol) was subjected to chiral purification by SFC (Column: Chiralpak IH, 20 x 250mm, 5 μm; Method: 40% MeOH (5% MeCN and 0.1% NH3), 60% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compound, Intermediate 13 ((1S,4R,5S) isomer) (300 mg, 31%), as a white solid. LCMS (Method 3B): [M+H]+m / z 223.0 / 225.0, RT 0.86 minutes.1H NMR (500 MHz, DMSO) 58.34 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 3.03 -2.89 (m, 3H), 2.43 (s, 1H), 1.41 - 1.31 (m, 1H), 0.64 (dt, J = 8.5, 5.3 Hz, 1H), 0.30 (td, J = 5.2, 2.0 Hz, 1H).

[0599] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Chiralpak IH column, 4.6 x 250mm, 5pm, with mobile phase 30% MeOH (0.1% NH3), 70% CO2. The flow rate was 4 mL / min. The run time was 4 mins. Intermediate 12: RT 1.70 min. Intermediate 13: RT 3.40 min.

[0600] The absolute configuration of Intermediate 12 (1R,4S,5R-configuration) and Intermediate 13 (1S,4R,5S-configuration) was determined using VCD spectroscopy.

[0601] INTERMEDIATE 14: 3-Chloro-6-l

[0602]

[0603]

[0604] Prepared from 3,6-dichloropyridazine (10 g, 67.1 mmol) and 4-pyridylboronic acid (8.66 g, 70.5 mmol) in accordance with the procedure described for Intermediate 1 (dioxane / H20, 80 °C, 18 h) to afford the title compound (5.5 g, 30%) as a brown solid. LCMS (Method 3E): [M+H]+m / z 192.2 / 194.2, RT 0.75 minutes.1H NMR (400 MHz, DMSO) 58.82 - 8.76 (m, 2H), 8.48 (d, J = 9.1 Hz, 1H), 8.17 - 8.09 (m, 3H).

[0605] INTERMEDIATE 15: 2-Chloro-5-l

[0606]

[0607] Prepared from 5-bromo-2-chloro-pyridine (10.1 g, 52.5 mmol) and 4-pyridylboronic acid (7.40 g, 60.2 mmol) in accordance with the procedure described for Intermediate 1 (dioxane / H20, 100 °C, 2 h) to afford the title compound (4.1 g, 41%) as an off-white solid. LCMS (Method 3B):

[0608] [M+H]+m / z 191.2 / 193.2, RT 0.56 minutes.1H NMR (500 MHz, DMSO) 5 8.89 (d, J = 2.5 Hz, 1H), 8.74 - 8.64 (m, 2H), 8.31 (dd, J = 8.4, 2.7 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H).

[0609] INTERMEDIATE 16: Ethvl 3-(6-fluoro-3-pvridvl)prop-2-'

[0610]

[0611]

[0612] Prepared from 2-fluoro-5-iodo-pyridine (11.5 g, 51.6 mmol) and ethyl prop-2-ynoate (10.5 mL, 103 mmol) in accordance with the procedure described for Intermediate 6 to afford the title compound (10 g, 98%) as a yellow oil. LCMS (Method 3B): [M+H]+m / z 194.1, RT 1.30 minutes.

[0613] 1H NMR (500 MHz, DMSO) 58.62 (dt, J = 2.5, 0.9 Hz, 1H), 8.34 (ddd, J = 8.6, 7.7, 2.4 Hz, 1H), 7.36 (ddd, J = 8.6, 2.8, 0.7 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).19F NMR (471 MHz, DMSO) 5 -62.88.

[0614] INTERMEDIATE 17: 3-(6-Fluoro-3-pyridyl)prop-2-vnoic acid

[0615]

[0616] Prepared from ethyl 3-(6-fluoro-3-pyridyl)prop-2-ynoate (prepared according to the procedure of Intermediate 16) (10.3 g, 49.2 mmol) in accordance with the procedure described for Intermediate 7 to afford the title compound (6.3 g, 76%) as a white solid. LCMS (Method 3B):

[0617] [M+H]+m / z 166.1, RT 0.57 minutes.

[0618] INTERMEDIATE 18: A / -Cvclopropyl-3-(6-fluoro-3-pyridyl)-N-f(4- -2-'

[0619] 1JI

[0620]

[0621] XN^F

[0622] Prepared from 3-(6-fluoro-3-pyridyl)prop-2-ynoic acid (prepared according to the procedure of Intermediate 17) (7.5 g, 50.6 mmol) and N-[(4-methoxyphenyl)methyl]cyclopropanamine (9.87 g, 55.7 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (9.92 g, 53%) as a colourless oil. LCMS (Method 3B): [M+H]+m / z 325.2, RT 1.55 minutes.1H NMR (500 MHz, DMSO) 58.55 (q, J = 1.0 Hz, 1H), 8.26 (ddd, J = 8.6, 7.7, 2.4 Hz, 1H), 7.34 (ddd, J = 8.5, 2.8, 0.7 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.50 (s, 2H), 3.74 (s, 3H), 2.72 (tt, J = 6.7, 4.2 Hz, 1H), 0.91 (ddt, J = 6.3, 3.3, 2.1 Hz, 4H).19F NMR (471 MHz, DMSO) 5 -64.11.

[0623] INTERMEDIATE 19: 4-r(6-Fluoro-3-pvridvl)methvlenel-2-r(4-i -2- -3-one

[0624] N=\

[0625]

[0626] F Prepared from N-cyclopropyl-3-(6-fluoro-3-pyridyl)-N-[(4-methoxyphenyl)methyl]prop-2-ynamide (prepared according to the procedure of Intermediate 18) (6 g, 16.3 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (4.33 g, 76%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 325.2, RT 1.51 minutes.1H NMR (500 MHz, DMSO) 58.69 (td, J = 8.4, 2.5 Hz, 1 H), 8.54 (d, J = 2.4 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 2H), 7.16 (dd, J = 8.7, 2.8 Hz, 1 H), 7.00 (s, 1 H), 6.94 - 6.88 (m, 2H), 4.44 (d, J = 14.5 Hz, 1 H), 4.39 (d, J = 14.5 Hz, 1H), 3.74 (s, 3H), 3.36 (ddd, J = 6.8, 4.8, 2.3 Hz, 1H), 2.36 (td, J = 7.7, 4.5 Hz, 1 H), 1.02 (dt, J = 8.7, 5.0 Hz, 1 H), 0.49 (td, J = 4.7, 2.3 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -69.33. INTERMEDIATE 20: 4-f(6-Fluoro-3-i

[0627]

[0628] |-2-<.1.0lhexan-3-one

[0629] N=\

[0630]

[0631] F

[0632] Prepared from 4-[(6-fluoro-3-pyridyl)methylene]-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 19 (4.33 g, 12.4 mmol) in accordance with the procedure described for Intermediate 10 to afford the title compound (1.7 g, 64%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 205.1, RT 0.87 minutes.1H NMR (500 MHz, DMSO) 58.65 (dt, J = 8.4, 4.2 Hz, 2H), 8.53 (dd, J = 19.5, 2.5 Hz, 1 H), 7.14 (dd, J = 8.6, 2.6 Hz, 1 H), 6.96 (s, 1 H), 3.34 (s, 1 H, water peak overlap), 2.44 - 2.37 (m, 1 H), 1.07 (dt, J = 8.6, 4.9 Hz, 1 H), 0.67 (td, J = 4.6, 2.4 Hz, 1 H).

[0633] INTERMEDIATE 21: Rac-(1 S.4 / ?.5S)-4-R6-Fluoro-3-pyridyl)methyl1-2-

[0634]

[0635] azabicyclo[3.1.01hexan-3-one

[0636]

[0637] Prepared from 4-[(6-fluoro-3-pyridyl)methylene]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 20 (1.7 g, 7.91 mmol) in accordance with the procedure described for Intermediate 11 to afford the title compound (760 mg, 46%) as a white solid. LCMS (Method 3B): [M+H]+m / z 207.1, RT 0.79 minutes.1H NMR (500 MHz, DMSO) 5 8.18 - 8.11 (m, 2H), 7.93 (td, J = 8.3, 2.6 Hz, 1H), 7.12 (dd, J = 8.4, 2.9 Hz, 1H), 3.03 - 2.90 (m, 3H), 2.48 - 2.42 (m, 1 H), 1.35 (dtd, J = 8.4, 6.9, 4.8 Hz, 1 H), 0.65 (dt, J = 8.4, 5.3 Hz, 1 H), 0.30 (td, J = 5.2, 2.1 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -72.52.

[0638] INTERMEDIATE 22 and INTERMEDIATE 23: (1R,4S,5R)-4-f(6-fluoro-3-pyridyl)methyll-2-.1.0lhexan-3-one and (1S,4R,5S)-4-f(6-fluoro-3-i 1-2- 1-3-one

[0639] N=\

[0640]

[0641] F Rac-(1 S,4 / ?,5S)-4-[(6-fluoro-3-pyndyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 21) (760 mg, 3.84 mmol) was subjected to chiral purification bySFC (Column: ChiralpakIH, 20x250mm, 5 μm; Method: 45% MeOH (0.1% NH3), 55% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compound, Intermediate 23 (415 mg, 50%), as a white solid. LCMS (Method 3B): [M+H]+m / z 207.1, RT 0.78 minutes.1H NMR (400 MHz, DMSO) 58.18 - 8.12 (m, 2H), 7.93 (td, J = 8.3, 2.5 Hz, 1H), 7.12 (ddd, J = 8.4, 2.9, 0.7 Hz, 1H), 2.99 (dt, J = 10.5, 3.5 Hz, 1H), 2.93 (dddd, J = 7.2, 4.9, 2.2, 0.8 Hz, 2H), 2.48 - 2.39 (m, 1 H), 1.35 (dtdd, J = 9.0, 6.8, 4.8, 2.1 Hz, 1 H), 0.65 (ddd, J = 8.4, 5.6, 5.0 Hz, 1 H), 0.29 (tdd, J = 4.8, 2.1, 0.6 Hz, 1 H).19F NMR (376 MHz, DMSO) 5 -72.52.

[0642] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Chiralpak IH column, 4.6 x 250mm, 5pm, with mobile phase 45% MeOH (0.1% NH3), 55% CO2. The flow rate was 4 mL / min. The run time was 3 mins.

[0643] Intermediate 22: RT 1.16 min. Intermediate 23: RT 1.76 min. The absolute configuration of Intermediate 22 (1 / ?,4S,5 / ?-configuration) and Intermediate 23 (1S,4 / ?,5S-configuration) was determined using VCD spectroscopy.

[0644] INTERMEDIATE 24: 2-Bromo-5-(4-pyridyl)pyrazine

[0645] l ^ ll

[0646]

[0647] N Br

[0648] Prepared from 2-bromo-5-iodo-pyrazine (3 g, 10.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.59 g, 12.6 mmol) in accordance with the procedure described for Intermediate 1 (CPME / H2O, 80 °C, 24 h) to afford the title compound (1.5 g, 48%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 236.0 / 238.0, RT 0.70 minutes.1H NMR (400 MHz, DMSO) 59.25 (t, J = 1.3 Hz, 1H), 9.01 (d, J = 1.3 Hz, 1H), 8.76 (dt, J = 4.5, 1.3 Hz, 2H), 8.09 (dt, J = 4.6, 1.3 Hz, 2H).

[0649] INTERMEDIATE 25: tert-Butyl (4R)-4-methyl-2-oxo-pyrrolidine-1 -carboxylate

[0650]

[0651] To a stirred solution of (4 / ?)-4-methylpyrrolidin-2-one (1 g, 10.1 mmol), NEts (2.81 mL, 20.2 mmol) and DMAP (123 mg, 1.01 mmol) in DCM (20 mL) was added B0C2O (3.30 g, 15.1 mmol) and the mixture stirred for 6 h at r.t. The reaction mixture was quenched with sat. aq. NH4CI (20 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-60% MTBE / iso-hexane) to afford the title compound (1.9 g, 93%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 144.1, RT 1.12 minutes.1H NMR (500 MHz, DMSO) 53.77 (dd, J = 10.3, 7.6 Hz, 1H), 3.20 (dd, J = 10.3, 7.1 Hz, 1H), 2.56 - 2.47 (m, 1H), 2.31 (dp, J = 14.5, 7.3 Hz, 1H), 2.10 (dd, J = 16.8, 8.2 Hz, 1 H), 1.44 (s, 9H), 1.02 (d, J = 6.7 Hz, 3H).

[0652] INTERMEDIATE 26: 5-(Bromomethyl)-2-fluoro-pyridine

[0653] Br

[0654]

[0655] F

[0656] To a stirred solution of (6-fluoro-3-pyridyl)methanol (5 g, 39.3 mmol) in DCM (100 mL) at 0°C was added PPh3 (12.4 g, 47.2 mmol) followed by CBr4 (15.7 g, 47.2 mmol) and the reaction mixture was allowed to stir at 0°C for 2 h. The reaction mixture was quenched with sat. aq. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2 x25 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-40% MTBE / iso-hexane) to afford the title compound (5 g, 64%) as a yellow oil.1H NMR (500 MHz, CDCI3) 5 8.23 (d, J = 2.7 Hz, 1H), 7.84 (td, J = 7.9, 2.6 Hz, 1H), 6.93 (dd, J = 8.5, 3.0 Hz, 1H), 4.46 (s, 2H).19F NMR (471 MHz, CDCI3) 5 -67.70.

[0657] INTERMEDIATE 27: tert-Butyl (3R.4R)-3-r(6-fluoro-3-pyridyl)methylM-methyl-2-oxo-pyrrolidine-1 -carboxylate

[0658]

[0659] F

[0660] To a stirred solution of tert-butyl (4R)-4-methyl-2-oxo-pyrrolidine-1-carboxylate (prepared according to the procedure of Intermediate 25) (900 mg, 4.43 mmol) in THF (2 mL) was added LDA (1 mol / L in THF, 5.31 mL, 5.31 mmol) at -78 °C and stirred for 30 minutes. 5-(Bromomethyl)-2-fluoro-pyridine (prepared according to the procedure of Intermediate 26) (1.05 g, 5.31 mmol) in THF (10 mL) was slowly added to the reaction mixture and allowed to stir at - 78 °C for 3 h. The reaction mixture was quenched with sat. aq. NH4CI (10 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-50% (3:1, EtOAc: EtOH) / iso-hexane) to afford the title compound (1.7 g, 87%) as a white solid. LCMS (Method 3B): [M-Boc+H]+m / z 209.0, RT 1.38 minutes.1H NMR (400 MHz, DMSO) 58.09 (d, J = 2.5 Hz, 1H), 7.85 (td, J = 8.2, 2.5 Hz, 1H), 7.12 (ddd, J = 8.4, 2.9, 0.6 Hz, 1H), 3.70 (dd, J = 10.3, 7.9 Hz, 1H), 3.08 (dd, J = 10.3, 9.5 Hz, 1H), 2.97 (dd, J = 14.3, 5.9 Hz, 1H), 2.82 (dd, J = 14.3, 6.6 Hz, 1H), 2.57 (dt, J = 10.7, 6.2 Hz, 1H), 1.93 (td, J = 9.5, 4.6 Hz, 1H), 1.43 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H).19F NMR (376 MHz, DMSO) 5 -72.25.

[0661] INTERMEDIATE 28: (3R,4R)-3-r(6-Fluoro-3-pyridyl)methyll-4-methyl-Pyrrolidin-2-one o

[0662] N\

[0663]

[0664] F

[0665] To a stirred solution of tert-butyl (3R,4R)-3-[(6-fluoro-3-pyridyl)methyl]-4-methyl-2-oxo-pyrrolidine-1 -carboxylate (Prepared according to the procedure of Intermediate 27) (1.7 g, 3.86 mmol) in DCM (10 mL) was added TFA (2.87 mL, 38.6 mmol) and stirred for 4 h at r.t. The reaction mixture was concentrated in vacuo and quenched with a sat. aq. NaHCOa (15 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (540 mg, 67%) as a brown solid. LCMS (Method 3B): [M+H]+m / z 209.0, RT 0.80 minutes.1H NMR (500 MHz, DMSO) 58.10 (d, J = 2.5 Hz, 1H), 7.86 (td, J = 8.2, 2.5 Hz, 1H), 7.60 (s, 1H), 7.10 (dd, J = 8.4, 2.8 Hz, 1H), 3.17 (ddd, J = 9.3, 7.7, 1.3 Hz, 1H), 2.93 (dd, J = 14.1, 5.3 Hz, 1 H), 2.79 - 2.66 (m, 2H), 2.20 (ddd, J = 9.6, 7.0, 5.3 Hz, 1 H), 2.00 - 1.90 (m, 1 H), 0.86 (d, J = 6.6 Hz, 3H).19F NMR (471 MHz, DMSO) 5 -72.46.

[0666] INTERMEDIATE 29: 1,3-Dihvdroazepin-2-one

[0667] O

[0668]

[0669] To a solution of 3,3-dibromoazepan-2-one (5 g, 18.5 mmol) in DMF (50 mL) was added LiCI (2.35 g, 55.4 mmol). The reaction mixture was warmed to 110 °C and stirred for 48 h. The reaction mixture was then cooled to r.t. and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% EtOAc / lso-hexane) to afford the title compound (900 mg, 40%) as a colourless oil.1H NMR (400 MHz, DMSO) 59.45 (s, 1H), 6.04 - 5.83 (m, 2H), 5.52 (ddd, J = 9.0, 5.3, 1.0 Hz, 1 H), 5.33 (dt, J = 9.4, 6.8 Hz, 1 H), 2.51 (d, J = 6.8 Hz, 2H).

[0670] INTERMEDIATE 30: 2-Azabicyclor3.2.01hept-6-en-3-one

[0671]

[0672] To a solution of 1,3-dihydroazepin-2-one (prepared according to the procedure of Intermediate 29) (950 mg, 7.83 mmol) in MeCN (400 mL) was added Ir[dF(CF3)ppy]2(dtbby)PF6 (879 mg, 0.78 mmol) at r.t. The reaction mixture was then degassed with nitrogen for 5 minutes and stirred at r.t. under 365 nM lamp (450W) irradiation in a photoreactor for 3 h. The reaction mixture was concentrated in vacuo to afford the title compound (835 mg, 83%) as a yellow oil.1H NMR (400 MHz, CDCI3) 56.43 - 6.23 (m, 2H), 6.03 (s, 1 H), 4.44 (t, J = 2.8 Hz, 1 H), 3.66 - 3.52 (m, 1 H), 2.48 (dd, J = 17.9, 10.3 Hz, 1H), 2.29 (ddd, J = 17.9, 3.0, 1.3 Hz, 1H).

[0673] INTERMEDIATE 31: 2-Azabicyclor3.2.01heptan-3-one

[0674] HN

[0675]

[0676] A solution of 2-azabicyclo[3.2.0]hept-6-en-3-one (prepared according to the procedure of Intermediate 30) (825 mg, 6.43 mmol) in MeOH (50 mL) was subjected to a hydrogen atmosphere via H-Cube with a 10% Pd / C cat. cart. (Single Run, flow rate; 1 mL / min, 2 bar) at r.t. The reaction mixture was concentrated in vacuo to afford the title compound (590 mg, 70%) as a yellow solid.1H NMR (500 MHz, CDCI3) 55.83 (s, 1H), 4.09 (s, 1H), 3.13 (p, J = 7.6 Hz, 1H), 2.51 (dd, J = 17.5, 8.9 Hz, 1H), 2.38 - 2.28 (m, 2H), 2.25 - 2.15 (m, 1H), 1.97 - 1.83 (m, 2H). INTERMEDIATE 32: tert-Butvl 3-oxo-2-i.2.

[0677]

[0678]

[0679] To a solution of 2-azabicyclo[3.2.0]heptan-3-one (prepared according to the procedure of Intermediate 31) (590 mg, 4.51 mmol) in MeCN (10 mL) was added DMAP (55.1 mg, 0.451 mmol). The reaction mixture was then cooled to 0 °C and B0C2O (1.97 g, 9.02 mmol) was added at 0 °C. The reaction mixture was warmed to r.t. and stirred for 16 h. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography on silica gel (0-100% EtOAc / lso-hexane) to afford the title compound (400 mg, 41%) as a yellow oil.1H NMR (400 MHz, CDCI3) 54.43 (tt, J = 6.7, 2.2 Hz, 1H), 2.97 (p, J = 8.3 Hz, 1H), 2.70 (dd, J = 18.3, 9.2 Hz, 1H), 2.53-2.39 (m, 2H), 2.30 (tddd, J = 10.3, 8.7, 4.4, 2.1 Hz, 1 H), 2.05 - 1.96 (m, 1H), 1.87 (dtd, J = 12.4, 9.0, 6.6 Hz, 1H), 1.51 (s, 9H).

[0680] INTERMEDIATE 33: tert-Butyl 4-K6-chloro-3-pyridyl)-hvdroxy-methyll-3-oxo-2-azabicyclo[3.2.01heptane-2-carboxylate

[0681]

[0682] A solution of tert-butyl 3-oxo-2-azabicyclo[3.2.0]heptane-2-carboxylate (prepared according to the procedure of Intermediate 32) (400 mg, 1.80 mmol) in THF (8 mL) was cooled to -78 °C and LiHMDS (1.00 mol / L in THF, 2.88 mL, 2.88 mmol) was added at -78 °C. The reaction mixture was stirred at -78 °C for 1 h and then a solution of 6-chloropyridine-3-carbaldehyde (280 mg, 1.98 mmol) and BF3-OEt2 (0.29 mL, 2.33 mmol) in THF (7 mL) was slowly added at -78 °C. The reaction mixture was stirred at -78 °C for 4 h. The reaction mixture was warmed to r.t. and quenched with sat. aq. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% EtOAc / heptane) to afford the title compound (320 mg, 50%) as a yellow oil. LCMS (Method 3B): [M-Boc+H]+m / z 253.2 / 255.2, RT 1.31 and 1.37 minutes. Mix of diastereomers.1H NMR (500 MHz, DMSO) 58.39 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.4, 2.5 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 5.88 (d, J = 4.9 Hz, 1H), 5.11 (t, J = 4.2 Hz, 1H), 4.24 (s, 1H), 2.91 (t, J = 2.8 Hz, 1 H), 2.77 (d, J = 7.9 Hz, 1 H), 2.39 - 2.27 (m, 2H), 2.01 (d, J = 7.2 Hz, 1 H), 1.86 (d, J = 6.9 Hz, 1H), 1.45 (s, 9H) (major diastereomer). INTERMEDIATE 34: tert-Butyl 4-K6-chloro-3-pyridyl)methylenel-3-oxo-2-azabicyclo[3.2.01heptane-2-carboxylate

[0683]

[0684] A mixture of tert-butyl 4-[(6-chloro-3-pyridyl)-hydroxy-methyl]-3-oxo-2-azabicyclo[3.2.0]heptane-2-carboxylate (prepared according to the procedure of Intermediate 33) (325 mg, 0.78 mmol) and NEt3 (0.220 mL, 1.62 mmol) in DCM (10 mL) was cooled to 0 °C. MsCI (0.08 mL, 0.98 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with H2O (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (3x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (10 mL), cooled to 0 °C and DBU (0.21 mL, 1.60 mmol) was added. The mixture was stirred at 0 °C for 1.5 h, quenched with H2O (20 mL) and diluted with DCM (10 mL). The aqueous layer was extracted with DCM (3x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% (3:1, EtOAc: EtOH) / iso-hexane) to afford the title compound (225 mg, 79%) as a pale-yellow solid. LCMS (Method 3B): [M+H]+m / z 335.2 / 337.2, RT 1.60 minutes.1H NMR (500 MHz, DMSO) 58.55 (d, J = 2.5 Hz, 1 H), 7.91 (dd, J = 8.5, 2.5 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 2.3 Hz, 1 H), 4.49 (td, J = 7.1, 3.4 Hz, 1 H), 3.90 (t, J = 7.5 Hz, 1 H), 2.72 - 2.63 (m, 1 H), 2.54 (td, J = 6.4, 3.5 Hz, 1 H), 1.99 - 1.92 (m, 1 H), 1.90 - 1.82 (m, 1 H), 1.47 (s, 9H).

[0685] INTERMEDIATE 35: 4-f(6-Chloro-3-i

[0686]

[0687]

[0688] Prepared from tert-butyl 4-[(6-chloro-3-pyridyl)methylene]-3-oxo-2-azabicyclo[3.2.0]heptane-2-carboxylate (prepared according to the procedure of Intermediate 34) (225 mg, 0.62 mmol) in accordance with the procedure described for Intermediate 28 to afford the title compound (153 mg, 99%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 235.0 / 237.0, RT 1.07 minutes. INTERMEDIATE 36: Rac-(1 S.4R.5S)-4-R6-Chloro-3-pyridyl)methyl1-2-azabicyclo[3.2.01heptan-3-one

[0689] o

[0690] HN^\

[0691] M. \

[0692] N=(

[0693]

[0694] Cl

[0695] Prepared from 4-[(6-Chloro-3-pyridyl)methylene]-2-azabicyclo[3.2.0]heptan-3-one (prepared according to the procedure of Intermediate 35) (153 mg, 0.62 mmol) in accordance with the procedure described for Intermediate 11 to afford the title compound (44 mg, 30%) as an off-white solid. LCMS (Method 3E): [M+H]+m / z 237.1 / 239.1, RT 0.99 minutes.1H NMR (500 MHz, DMSO) 58.23 (d, J = 2.5 Hz, 1H), 7.97 (s, 1H), 7.69 (dd, J = 8.2, 2.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 3.83 (td, J = 5.5, 2.3 Hz, 1H), 2.99 (dd, J = 14.0, 4.1 Hz, 1H), 2.91 (p, J = 7.7 Hz, 1H), 2.76 - 2.59 (m, 2H), 2.24 - 2.07 (m, 2H), 1.90 - 1.74 (m, 1H), 1.59 (tdd, J = 9.2, 4.8, 3.1 Hz, 1H).

[0696] INTERMEDIATE 37: (6-Chloro-3-pyridyl)-dideuterio-methanol

[0697] D HO— ^-D

[0698] Q

[0699]

[0700] Cl

[0701] To a solution of ethyl 6-chloropyridine-3-carboxylate (2.50 g, 13.5 mmol) in THF (30.0 mL) and CD3OD (10 mL), NaBD4 (1.41 g, 33.7 mmol) was added portion wise. The resulting mixture was stirred at r.t. for 1 h, quenched with sat. aq. NH4CI (50 mL) and diluted with DCM (100 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% (3:1, EtOAc: EtOH) / iso-hexane) to afford the title compound (1.56 g, 76%) as a yellow oil. LCMS (Method 3A): [M+H]+m / z 146.2 / 148.2, RT 0.36 minutes.1H NMR (500 MHz, DMSO) 58.34 (dd, J = 2.4, 0.8 Hz, 1 H), 7.79 (dd, J = 8.2, 2.5 Hz, 1H), 7.48 (dd, J = 8.1, 0.7 Hz, 1H), 5.36 (s, 1H).

[0702] INTERMEDIATE 38: 5-rBromo(dideuterio)methyll-2-chloro-pyridine

[0703]

[0704] Prepared from (6-chloro-3-pyridyl)-dideuterio-methanol (prepared according to the procedure of Intermediate 37) (1.56 g, 8.57 mmol) in accordance with the procedure described for Intermediate 26 (THF) to afford the title compound (1.72 g, 83%) as a yellow oil. LCMS (Method 3B): [M+H]+m / z 208.0 / 210.0, RT 0.58 minutes.1H NMR (500 MHz, DMSO) 58.50 (dd, J = 2.6, 0.8 Hz, 1 H), 7.95 (dd, J = 8.3, 2.5 Hz, 1 H), 7.54 (dd, J = 8.3, 0.8 Hz, 1 H).

[0705] INTERMEDIATE 39: tert-Butyl rac-(1S,4S,5S)-4-r(6-chloro-3-pyridyl)-dideuterio-methyl]-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[0706]

[0707] Prepared from tert-butyl 3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 52) (1.56 g, 8.57 mmol) and 5-[bromo(dideuterio)methyl]-2-chloro-pyridine (prepared according to the procedure of Intermediate 38) (1.76 g, 7.25 mmol) in accordance with the procedure described for Intermediate 27 to afford the title compound (1.69 g, 68%) as a yellow oil. LCMS (Method 3B): [M-Boc+H]+m / z 225.2 / 227.2, RT 1.40 minutes.1H NMR (500 MHz, DMSO) 5 8.32 (dd, J = 2.6, 0.7 Hz, 1H), 7.78 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (dd, J = 8.1, 0.7 Hz, 1 H), 3.37 (dddd, J = 7.6, 5.5, 2.4, 1.1 Hz, 1 H), 2.86 (s, 1 H), 1.45 (d, J = 5.2 Hz, 9H), 1.29 (dddd, J = 8.4, 7.3, 4.2, 1.7 Hz, 1H), 0.92 (ddt, J = 11.5, 8.6, 6.0 Hz, 1H), 0.51 (ddd, J = 6.0, 4.9, 2.3 Hz, 1H).

[0708] INTERMEDIATE 40: tert-Butyl rac-(1S,4R,5S)-4-r(6-chloro-3-pyridyl)-dideuterio-methyl]-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[0709]

[0710] ci

[0711] A solution of te / t-butyl rac-(1S,4S,5S)-4-[(6-chloro-3-pyridyl)-dideuterio-methyl]-3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 39) (1.69 g, 4.47 mmol) in THF (30 mL) under nitrogen was cooled to -78 °C. LiHMDS (1 mol / L in THF, 5.68 mL, 5.68 mmol) was added dropwise. The mixture was stirred for 30 min at -78 °C then quenched with H2O (20 mL). The mixture was diluted with EtOAc (50 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (1.3 g, 72%) as a white solid. LCMS (Method 3B): [M-Boc+H]+m / z 225.0 / 227.0, RT 1.45 minutes.1H NMR (500 MHz, DMSO) 58.34 (dd, J = 2.6, 0.7 Hz, 1 H), 7.81 (dd, J = 8.2, 2.5 Hz, 1 H), 7.47 (dd, J = 8.1, 0.7 Hz, 1H), 3.52 (ddd, J = 7.5, 5.4, 2.2 Hz, 1H), 1.46 (d, J = 5.2 Hz, 10H), 1.39 - 1.33 (m, 2H), 0.82 (dt, J = 8.5, 5.8 Hz, 1H).

[0712] INTERMEDIATE 41: Rac- l S.4.5S)-4-K6-Chloro-3-pyridyl)-dideuterio-methyll-2-azabicyclo[3.1.01hexan-3-one

[0713] O

[0714]

[0715] Cl

[0716] Prepared from tert-butyl rac-(1 S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)-dideuterio-methyl]-3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 40) (1.3 g, 3.2 mmol) in accordance with the procedure described for Intermediate 28 to afford the title compound (510 mg, 67%) as a white solid. LCMS (Method 3B): [M+H]+ m / z 225.1 / 227.1, RT 0.90 minutes.1H NMR (500 MHz, DMSO) 58.34 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 2.98 (d, J = 7.0 Hz, 1H), 2.93 (ddd, J = 7.3, 5.0, 2.0 Hz, 1H), 1.37 - 1.29 (m, 1H), 0.64 (dt, J = 8.4, 5.3 Hz, 1H), 0.30 (td, J = 5.2, 2.1 Hz, 1H).

[0717] INTERMEDIATE 42 and 43: (1R.4S.5RM-K6-Chloro-3-pyridyl)-dideuterio-methyll-2-azabicyclo[3.1.01hexan-3-one and (1 S,4R,5S)-4-r(6-chloro-3-pyridyl)-dideuterio-methyll-2-azabicyclo[3.1.01hexan-3-one

[0718] o o

[0719]

[0720] Cl Cl

[0721] Rac-(1 S,4 / ?,5S)-4-[(6-Chloro-3-pyridyl)-dideuterio-methyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 41) (510 mg, 2.13 mmol) was subjected to chiral purification by SFC (Column: Chiralpak IH, 10 x 250mm, 5 μm; Method: 30% MeOH (0.1% NH3), 70% CO2; Column Temperature: 40 °C; Flow rate: 15 mL / min) to afford the title compound, Intermediate 43 (205 mg, 42%), as a white solid. LCMS (Method 3B): [M+H]+m / z 207.1, RT 0.87 minutes.1H NMR (500 MHz, DMSO) 5 8.34 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 2.98 (d, J = 7.0 Hz, 1H), 2.93 (ddd, J = 7.5, 5.0, 2.0 Hz, 1 H), 1.35 (dtd, J = 8.5, 7.0, 4.8 Hz, 1 H), 0.64 (dt, J = 8.4, 5.3 Hz, 1 H), 0.30 (td, J = 5.2, 2.1 Hz, 1H).

[0722] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Chiralpak IH column, 4.6 x 250mm, 5pm, with mobile phase 30% MeOH (0.1% NH3), 70% CO2. The flow rate was 4 mL / min. The run time was 4 mins. Intermediate 42: RT 1.69 min. Intermediate 43: RT 3.35 min.

[0723] The absolute configuration of Intermediate 42 (1 / ?,4S,5 / ?-configuration) and Intermediate 43 (1S,4 / ?,5S-configuration) was determined using VCD spectroscopy.

[0724] INTERMEDIATE 44: 5-Chloro-3-i I-2-I

[0725]

[0726] Prepared from 2-bromo-5-chloro-3-methyl-pyrazine (600 mg, 2.89 mmol) and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (623 mg, 3.04 mmol) in accordance with the procedure described for Intermediate 1 (2MeTHF / H2O, 70 °C, 2 h) to afford the title compound (560 mg, 75%) as an orange solid. LCMS (Method 3A): [M+H]+m / z 206.0 / 208.0, RT 0.41 minutes.1H NMR (400 MHz, DMSO) 5 8.71 - 8.63 (m, 3H), 7.62 - 7.56 (m, 2H), 2.50 (d, J = 0.7 Hz, 3H).

[0727] INTERMEDIATE 45: tert-Butyl (3,4 )-3-K6-chloro-3-pyridyl)methyll-4-methyl-2-oxo-pyrrolidine-1 -carboxylate

[0728]

[0729] Prepared from tert-butyl (4 / ?)-4-methyl-2-oxo-pyrrolidine-1 -carboxylate (prepared according to the procedure of Intermediate 25) (1 g, 4.92 mmol) and 5-(bromomethyl)-2-chloro-pyridine (prepared according to the procedure of Intermediate 4) (1.27 g, 5.41 mmol) in accordance with the procedure described for Intermediate 27 to afford the title compound (1.1 g, 68%) as a white solid. LCMS (Method 3B): [M-Boc+H]+m / z 225.0 / 227.0, RT 1.50 minutes.1H NMR (500 MHz, DMSO) 68.28 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.2, 2.4 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 3.70 (dd, J = 10.2, 8.0 Hz, 1H), 3.08 (t, J = 9.9 Hz, 1H), 2.95 (dd, J = 14.2, 6.0 Hz, 1H), 2.82 (dd, J = 14.3, 6.4 Hz, 1H), 2.58 (dt, J = 10.8, 6.2 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.43 (s, 9H), 0.89 (d, J = 6.5 Hz, 3H).

[0730] INTERMEDIATE 46: (3R,4R)-3-f(6-Chloro-3-pyridyl)methyll-4-methyl-Pyrrolidin-2-one

[0731]

[0732] o

[0733]

[0734] Cl

[0735] Prepared from tert-butyl (3 / ?,4 / ?)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-2-oxo-pyrrolidine-1-carboxylate (prepared according to the procedure of Intermediate 45) (1.1 g, 3.35 mmol) in accordance with the procedure described for Intermediate 28 to afford the title compound (600 mg, 77%) as a white solid. LCMS (Method 3B): [M+H]+m / z 225.0 / 227.2, RT 0.89 minutes.1H NMR (500 MHz, DMSO) 58.29 (d, J = 2.4 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.61 (s, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 3.21 -3.14 (m, 1 H), 2.91 (dd, J = 14.1, 5.4 Hz, 1 H), 2.75 (dd, J = 14.1, 6.9 Hz, 1H), 2.69 (t, J = 8.9 Hz, 1H), 2.21 (ddd, J = 9.7, 6.9, 5.4 Hz, 1H), 1.97 (dtd, J = 14.0, 8.9, 7.0 Hz, 1H), 0.87 (d, J = 6.6 Hz, 3H).

[0736] INTERMEDIATE 47: (3-Amino-6-chloro-pvrazin-2-'

[0737]

[0738]

[0739] Methyl 3-amino-6-chloro-pyrazine-2-carboxylate (3 g, 16 mmol) was dissolved in THF (150 mL) and DIBAL-H (1 mol / L in hexanes, 64 mL, 64 mmol) was slowly added at -40 °C. The reaction mixture was allowed to warm up to -10 °C and stirred for 1 h. Sat. aq. Rochelle salt (250 mL) was added, and the reaction mixture was stirred at r.t. for 1 h. The aqueous solution was extracted with EtOAc (2 x 200 mL) and the combined organic extracts were dried over Na2SC>4, filtered and concentrated in vacuo to afford the title compound (1.56 g, 58%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 160.1 / 162.1, RT 0.31 minutes.1H NMR (400 MHz, DMSO) 5 7.95 (d, J = 0.5 Hz, 1H), 6.41 (s, 2H), 5.38 (s, 1H), 4.44 (s, 2H). INTERMEDIATE 48: (3-Bromo-6-chloro-pyrazin-2-yl)methanol

[0740]

[0741] (3-Amino-6-chloro-pyrazin-2-yl)methanol (prepared according to the procedure of Intermediate 47) (1.25 g, 7.83 mmol) was dissolved in HBr(48% in H2O) (10 mL) and Br2 (3.53 g, 22.1 mmol) was added. A solution of NaNC>2 (1.27 g, 18.4 mmol) in H2O (10 mL) was slowly added at 0 °C. The reaction mixture was stirred at r.t. for 2 h and then diluted with H2O (50 mL) and sat. aq. Na2S2C>3 (100 mL). The aqueous solution was extracted with EtOAc (2 x 100 mL), and the combined organic extracts were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-60% EtOAc / iso-hexane) to afford the title compound (710 mg, 41%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 223.1 / 225.1 / 227.1, RT 0.62 minutes.1H NMR (400 MHz, DMSO) 58.58 (t, J = 0.6 Hz, 1 H), 4.62 (d, J = 0.7 Hz, 2H). OH not observed.

[0742] INTERMEDIATE 49: r6-Chloro-3-(4-pyridyl)pyrazin-2-yllmethanol

[0743]

[0744] Prepared from (3-bromo-6-chloro-pyrazin-2-yl)methanol (prepared according to the procedure of Intermediate 48) (100 mg, 0.45 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (96 mg, 0.47 mmol) in accordance with the procedure described for Intermediate 1 (2MeTHF / H2O, 70 °C, 2 h) to afford the title compound (87 mg, 79%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 222.0 / 224.0, RT 0.28 minutes.1H NMR (400 MHz, DMSO) 58.88 (s, 1 H), 8.79 - 8.71 (m, 2H), 7.78 - 7.72 (m, 2H), 5.74 (t, J = 5.8 Hz, 1 H), 4.56 (d, J = 5.8 Hz, 2H).

[0745] INTERMEDIATE 50: 5-Bromo-2-(4-pyridyl)pyridine

[0746]

[0747] Prepared from 5-bromo-2-iodo-pyridine (0.50 g, 1.76 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.37 g, 1.80 mmol) in accordance with the procedure described for Intermediate 1 (dioxane / H20, 100 °C, 18 h) to afford the title compound (0.20 g, 40%) as a white solid. LCMS (Method 3F): [M+H]+m / z 235.0 / 237.0, RT 0.66 minutes.1H NMR (400 MHz, DMSO) 58.87 (dd, J = 2.4, 0.8 Hz, 1 H), 8.75 - 8.70 (m, 2H), 8.24 (dd, J = 8.5, 2.4 Hz, 1 H), 8.12 (dd, J = 8.5, 0.8 Hz, 1 H), 8.08 - 8.02 (m, 2H).

[0748] INTERMEDIATE 51: tert-Butyl 2 -azabicvclo[3.1.01hexane-2 -carboxylate

[0749]

[0750] 2-Azabicyclo[3.1.0]hexane hydrochloride (1 g, 8.36 mmol) was dissolved in DCM (20 mL) and NEt3 (3 mL, 21.5 mmol) and B0C2O (2.4 g, 11.0 mmol) were added. The reaction mixture was stirred at r.t. for 18 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (1.03 g, 67%) as a colourless oil. LCMS (Method 3B): [M-tBu+H]+m / z 128.0, RT 1.41 minutes.1H NMR (400 MHz, CDCI3) 5 3.67 - 3.59 (m, 1H), 3.40 (td, J = 6.2, 2.5 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.13 - 2.03 (m, 1H), 1.94 - 1.87 (m, 1H), 1.54 - 1.49 (m, 1H), 1.47 (s, 9H), 0.67 (dtd, J = 8.7, 5.9, 1.0 Hz, 1H), 0.52 (ddd, J = 5.9, 4.8, 2.5 Hz, 1H).

[0751] INTERMEDIATE 52: tert-Butvl 3-oxo-2-i

[0752]

[0753] .1.0lhexane-2-<

[0754]

[0755] RUO2-H2O (0.23 g, 1.52 mmol) was added to a solution of NaIC (4.83 g, 22.6 mmol) in H2O (60 mL) and the resultant mixture was stirred at r.t. for 30 minutes. A solution of tert-butyl 2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 51) (1.38 g, 7.53 mmol) in EtOAc (30 mL) was added and the reaction mixture was stirred at r.t. for 16 h. The mixture was diluted with EtOAc (20 mL), filtered on Celite and washed with EtOAc (3 x 15 mL). The filtrate was diluted with H2O, the phases were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with aq. Na2S2O5 (5% wt, 2 x 20 mL), brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-60% EtOAc / iso-hexane) to afford the title compound (0.76 g, 48%) as a pale-yellow oil. LCMS (Method 3B):

[0756] [M+H]+m / z 142.1, RT 1.04 minutes.1H NMR (400 MHz, CDCI3) 5 3.60 - 3.54 (m, 1H), 2.88 (ddd, J = 18.8, 7.4, 0.7 Hz, 1H), 2.55 - 2.48 (m, 1H), 1.54 (s, 9H), 1.51 - 1.43 (m, 1H), 1.04 -0.96 (m, 1H), 0.48 - 0.42 (m, 1H). INTERMEDIATE 53: tert-Butvl 4-f(6-chloro-5-fluoro-3-i |-3-oxo-2-..1J.-2-<

[0757] 0n

[0758] PH

[0759] i: / F

[0760] N=<

[0761]

[0762] Prepared from tert-butyl 3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 52) (0.76 g, 3.59 mmol) and 6-chloro-5-fluoro-pyridine-3-carbaldehyde (0.75 g, 4.67 mmol) in accordance with the procedure described for Intermediate 33 to afford the title compound (0.87 g, 65%) as an orange solid. LCMS (Method 3F): [M-Boc+H]+m / z 257.0 / 259.0, RT 1.37 minutes.1H NMR (400 MHz, DMSO) 58.43 - 8.19 (m, 1H), 7.98 - 7.78 (m, 1 H), 6.22 - 5.80 (m, 1 H), 5.25 - 4.99 (m, 1 H), 3.49 - 3.40 (m, 1 H), 1.53 - 1.39 (m, 9H), 1.34 - 1.21 (m, 2H), 1.00 - 0.80 (m, 1 H), 0.61 - 0.40 (m, 1 H).

[0763] INTERMEDIATE 54: tert-Butvl 4-f(6-chloro-5-fluoro-3-i |-3-oxo-2-

[0764]

[0765] Prepared from tert-butyl 4-[(6-chloro-5-fluoro-3-pyridyl)-hydroxy-methyl]-3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 53) (0.87 g, 2.32 mmol) in accordance with the procedure described for Intermediate 34 to afford the title compound (0.74 g, 85%) as an orange solid. LCMS (Method 3F): [M-tBu+H]+m / z 238.2 / 240.2, RT 1.63 minutes.1H NMR (400 MHz, DMSO) 58.66 (d, J = 1.9 Hz, 1H), 8.26 (dd, J = 9.8, 2.0 Hz, 1 H), 7.37 (s, 1 H), 3.90 - 3.84 (m, 1 H), 2.71 - 2.66 (m, 1 H), 1.68 - 1.59 (m, 1 H), 1.50 (s, 9H), 1.05 - 0.98 (m, 1H).19F{1H} NMR (376 MHz, DMSO) 5 -119.50.

[0766] INTERMEDIATE 55: Rac-(1 S,4R,5S)-4-((6-Chloro-5-fluoropyridin-3-yl)methyl)-2-..1J -3-one

[0767]

[0768] TFA (1 mL, 13.5 mmol) was added to a solution of tert-butyl 4-[(6-chloro-5-fluoro-3-pyridyl)methylene]-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 54) (0.74 g, 1.97 mmol) in DCM (10 mL). The mixture was stirred at r.t. for 30 min and concentrated in vacuo. The residual material was dissolved in MeOH (10 mL) and NiCl2 (30 mg, 0.23 mmol) was added. The mixture was cooled to 0 °C, NaBH4 (0.23 g, 6.08 mmol) was added portion wise, and the mixture was stirred at 0 °C for 1 h. Additional NiCl2 (30 mg, 0.23 mmol) and NaBH4 (0.23 g, 6.08 mmol) were added, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was filtered, washed with MeOH (3 x 5 mL) and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% (3:1 EtOAc: EtOH) / iso-hexane) to afford the title compound (0.51 g, 75%) as a yellow solid. LCMS (Method 3B): [M+H]+m / z 241.1 / 243.1, RT 1.01 minutes.1H NMR (400 MHz, DMSO) 5 8.25 - 8.23 (m, 1H), 8.19 (s, 1H), 7.94 (dd, J = 9.7, 1.9 Hz, 1H), 3.09 - 2.91 (m, 3H), 2.56 -2.51 (m, 1 H), 1.43 - 1.35 (m, 1 H), 0.70 - 0.60 (m, 1 H), 0.41 - 0.23 (m, 1 H).

[0769] INTERMEDIATE 56: Trimethyl-r2-(5-nitro-2-pyridyl)ethvnyllsilane

[0770] ^Si

[0771] Y JI

[0772]

[0773] ^^NO2

[0774] A mixture of 2-bromo-5-nitro-pyridine (10.4 g, 51.2 mmol) and NEt3 (22 mL, 0.16 mol) in MeCN (200 mL) was degassed with nitrogen for 10 minutes. Pd(PPh3)2Cl2 (1.80 g, 2.56 mmol) and Cui (0.50 g, 2.63 mmol) were added, followed by the dropwise addition of trimethylsilylacetylene (10 mL, 72.2 mmol). The mixture was stirred at r.t. for 1 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-20% EtOAc / iso-hexane) to afford the title compound (6.15 g, 52%) as a brown solid. LCMS (Method 3F): [M+H]+m / z 221.2, RT 1.75 minutes.1H NMR (400 MHz, DMSO) 59.32 (dd, J = 2.6, 0.7 Hz, 1 H), 8.58 (dd, J = 8.6, 2.7 Hz, 1H), 7.82 (dd, J = 8.6, 0.8 Hz, 1H), 0.28 (s, 9H).

[0775] INTERMEDIATE 57: 2-Ethvnyl-5-nitro-pyridine

[0776]

[0777] A mixture trimethyl-[2-(5-nitro-2-pyridyl)ethynyl]silane (prepared according to the procedure of Intermediate 56) (6.15 g, 26.8 mmol) and K2CO3 (1.90 g, 13.7 mmol) in MeOH (200 mL) was stirred at r.t. for 30 min and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-20% EtOAc / heptane) to afford the title compound (4.07 g, 83%) as an orange solid. LCMS (Method 3F): [M+H]+m / z 149.0, RT 0.87 minutes.1H NMR (400 MHz, DMSO) 59.34 (dd, J = 2.7, 0.7 Hz, 1 H), 8.61 (dd, J = 8.6, 2.7 Hz, 1 H), 7.86 (dd, J = 8.6, 0.8 Hz, 1H), 4.83 (s, 1H).

[0778] INTERMEDIATE 58: 3,6-Dichloro-4-(5-nitro-2-pyridyl)pyridazine

[0779] XN

[0780] I

[0781]

[0782] 2-Ethynyl-5-nitro-pyridine (prepared according to the procedure of Intermediate 57) (3.40 g, 18.6 mmol) and 3,6-dichloro-1,2,4,5-tetrazine (2.85 g, 18.9 mmol) were dissolved in o-xylene (80 mL) and stirred at 140 °C for 17 h. The mixture was cooled down to r.t. and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% (3:1, EtOAc: EtOH) / iso-hexane). The product thus obtained was suspended in MTBE (40 mL), stirred at r.t. for 1 h, filtered, washed with MTBE (2 x 10 mL) and dried in vacuo to afford the title compound (3.60 g, 69%) as a brown solid. LCMS (Method 3F): [M+H]+m / z 271.1 / 273.1, RT 1.24 minutes.1H NMR (400 MHz, DMSO) 59.55 (dd, J = 2.6, 0.8 Hz, 1 H), 8.85 (dd, J = 8.6, 2.7 Hz, 1H), 8.36 (s, 1H), 8.21 (dd, J = 8.6, 0.8 Hz, 1H).

[0783] INTERMEDIATE 59: 6-Pyridazin-4-ylPyridin-3-amine

[0784]

[0785] 3,6-Dichloro-4-(5-nitro-2-pyridyl)pyridazine (prepared according to the procedure of Intermediate 58) (0.20 g, 0.72 mmol) was dissolved in EtOH (3 mL) and THF (4 mL) and a suspension of Pd / C (5% wt, 0.19 g, 0.09 mmol) in EtOH (2 mL) was added and the mixture was stirred at 30 °C under H2 (4 bar) for 2 h. The mixture was filtered, washed with MeOH (2 x 20 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with H2O (2 x 10 mL), sat. aq. NaHCOa (2 x 10 mL), brine (15 mL). The aqueous layer was further extracted with EtOAc (2 x 10 mL), DCM / MeOH (9:1, 2 x 15 mL) and THF / EtOAc (1:1, 2 x 15 mL). The combined organic extracts were dried over Na2SC>4, filtered and concentrated in vacuo to afford the title compound (82 mg, 65%) as a light brown solid. LCMS (Method 3F): [M+H]+m / z 173.1, RT 0.48 minutes.1H NMR (400 MHz, DMSO) 59.75 (dd, J = 2.5, 1.2 Hz, 1H), 9.15 (dd, J = 5.5, 1.2 Hz, 1 H), 8.11 (d, J = 2.7 Hz, 1 H), 8.05 (dd, J = 5.5, 2.5 Hz, 1 H), 7.93 (d, J = 8.6 Hz, 1H), 7.03 (dd, J = 8.5, 2.8 Hz, 1H), 5.96 (s, 2H).

[0786] INTERMEDIATE 60: 4-(5-lodo-2-pyridyl)pyridazine

[0787]

[0788] A solution of 6-pyridazin-4-ylpyridin-3-amine (prepared according to the procedure of Intermediate 59) (82 mg, 0.47 mmol) in TFA (5 mL) was cooled to 0 °C and a solution of NaNC>2 (0.13 g, 1.88 mmol) in H2O (1 mL) was added dropwise, followed by slow addition of a solution of KI (0.31 g, 1.87 mmol) in H2O (1 mL). The reaction mixture was stirred at 0 °C for 2 h then quenched with aq. Na2S2O5 (5% wt, 15 mL) and diluted with DCM (20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were washed with sat. aq. NaHCOa (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% (3:1, EtOAc: EtOH) / iso-hexane) to afford the title compound (25 mg, 19%) as a light brown powder. LCMS (Method 3F): [M+H]+m / z 284.0, RT 1.00 minutes.1H NMR (400 MHz, DMSO) 59.88 (dd, J = 2.5, 1.2 Hz, 1 H), 9.37 (dd, J = 5.4, 1.2 Hz, 1 H), 9.03 (dd, J = 2.2, 0.8 Hz, 1 H), 8.43 (dd, J = 8.4, 2.2 Hz, 1 H), 8.28 (dd, J = 5.4, 2.4 Hz, 1 H), 8.11 (dd, J = 8.3, 0.8 Hz, 1 H).

[0789] INTERMEDIATE 61: 4-(6-Chloro-2-methoxy-3-pyridyl)pyridazine

[0790]

[0791] Tributyl(pyridazin-4-yl)stannane (0.91 g, 2.48 mmol) was dissolved in o-xylene (15 mL) and degassed with nitrogen for 5 minutes. 3-Bromo-6-chloro-2-methoxy-pyridine (0.50 g, 2.25 mmol) and Pd(PPh3)4 (0.26 g, 0.25 mmol) were added, the reaction mixture was sealed and stirred at 115 °C for 16 h. The reaction mixture was cooled down to r.t., diluted with sat. aq. NaHCO3 (50 mL) and filtered through Celite. The filtrate was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with aq. KF (1 M, 50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% (3:1, EtOAc / EtOH) / lso-hexane) to afford the title compound (0.40 g, 80%) as a white solid. LCMS (Method 3B): [M+H]+m / z 222.1 / 224.1, RT 1.16 minutes.1H NMR (400 MHz, DMSO) 59.49 (dd, J = 2.5, 1.2 Hz, 1H), 9.30 (dd, J = 5.4, 1.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.93 (dd, J = 5.4, 2.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 3.95 (s, 3H).

[0792] INTERMEDIATE 62: Ethyl 3-(5,6-difluoro-3-pyridyl)prop-2-vnoate

[0793]

[0794] Prepared from 2,3-Difluoro-5-iodo-pyridine (0.70 g, 2.90 mmol) and ethyl prop-2-ynoate (0.62 mL, 6.12 mmol) in accordance with the procedure described for Intermediate 6 to afford the title compound (0.41 g, 65%) as a white solid. LCMS (Method 3B): [M+H]+m / z 212.0, RT 1.45 minutes.1H NMR (500 MHz, DMSO) 58.52 (td, J = 9.6, 2.0 Hz, 1 H), 8.46 - 8.43 (m, 1 H), 4.27 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).19F NMR (471 MHz, DMSO) 5 -83.22 (d, J = 28.8 Hz), -138.77 (d, J = 28.9 Hz).

[0795] INTERMEDIATE 63: 3-(5,6-Difluoro-3-pyridyl)prop-2-ynoic acid

[0796] o

[0797] Y Y

[0798]

[0799] Prepared from ethyl 3-(5,6-difluoro-3-pyridyl)prop-2-ynoate (prepared according to the procedure of Intermediate 62) (0.39 g, 1.81 mmol) in accordance with the procedure described for Intermediate 7 to afford the title compound (0.37 g, 100%) as a white solid. LCMS (Method 3B): [M+H]+m / z 184.2, RT 0.83 minutes.1H NMR (500 MHz, DMSO) 514.16 (s, 1H), 8.46 (ddd, J = 10.0, 9.1, 1.9 Hz, 1H), 8.39 (t, J = 1.7 Hz, 1H).19F NMR (471 MHz, DMSO) 5 -83.82 (d, J = 28.8 Hz), -138.91 (d, J = 28.9 Hz).

[0800] INTERMEDIATE 64: N-Cvclopropyl-3-(5.6-difluoro-3-pyridyl)-N-K4-methoxyphenyl)methyllprop-2-vnamide

[0801]

[0802] Prepared from 3-(5,6-difluoro-3-pyridyl)prop-2-ynoic acid (prepared according to the procedure of Intermediate 63) (0.37 g, 2.22 mmol) and N-[(4-methoxyphenyl)methyl]cyclopropanamine (0.43 g, 2.43 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (0.54 g, 70%) as a colourless oil. LCMS (Method 3B): [M+H]+m / z 343.2, RT 1.67 minutes.1H NMR (400 MHz, DMSO) 5 8.48 - 8.29 (m, 2H), 7.29 - 7.16 (m, 2H), 6.98 -6.86 (m, 2H), 4.75 (s, 0.40H), 4.50 (s, 1.60H), 3.74 (s, 3H), 2.77 - 2.68 (m, 1 H), 0.97 - 0.84 (m, 3H), 0.76 - 0.66 (m, 1 H).19F NMR (376 MHz, DMSO) 5 -84.46 (d, J = 28.9 Hz), -139.06 (d, J = 28.8 Hz).

[0803] INTERMEDIATE 65: 4-[(5,6-Difluoro-3-pyridyl)methylene]-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one

[0804]

[0805] Prepared from N-cyclopropyl-3-(5,6-difluoro-3-pyridyl)-N-[(4-methoxyphenyl)methyl] prop-2-ynamide (prepared according to the procedure of Intermediate 64) (0.49 g, 1.40 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (0.45 g, 90%) as an orange oil. LCMS (Method 3B): [M+H]+m / z 343.2, RT 1.67 minutes.1H NMR (500 MHz, DMSO) 5 9.06 - 8.94 (m, 1H), 8.30 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.02 (s, 1H), 6.91 (d, J = 8.3 Hz, 2H), 4.50 - 4.37 (m, 2H), 3.74 (d, J = 1.0 Hz, 3H), 3.42 - 3.36 (m, 1 H), 2.43 -2.34 (m, 1H), 1.09 - 1.02 (m, 1H), 0.56 - 0.50 (m, 1H).19F NMR (471 MHz, DMSO) 5 -89.14 (d, J = 29.3 Hz), -141.54 (d, J = 29.1 Hz).

[0806] INTERMEDIATE 66: 4-[(5,6-Difluoro-3-pyridyl)methylene]-2-azabicyclo[3.1.0]hexan-3-one

[0807]

[0808] Prepared from 4-[(5,6-difluoro-3-pyridyl)methylene]-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 65) (0.45 g, 1.26 mmol) in accordance with the procedure described for Intermediate 10 to afford the title compound (0.33 g, 100%) as an orange solid. LCMS (Method 3B): [M+H]+m / z 223, RT 1.03 minutes.1H NMR (500 MHz, DMSO) 58.94 (ddd, J = 11.9, 9.7, 2.0 Hz, 1 H), 8.77 (s, 1 H), 8.30 -8.26 (m, 1H), 6.98 (s, 1 H), 3.37- 3.31 (m, 1 H), 2.45 - 2.40 (m, 1H), 1.13- 1.07 (m, 1 H), 0.73 - 0.70 (m, 1 H).19F NMR (471 MHz, DMSO) 5 -89.36 (d, J = 29.3 Hz), -141.56 (d, J = 29.4 Hz).

[0809] INTERMEDIATE 67: Rac-(1R,4S,5R)-4-((5,6-Difluoropyridin-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-3-one

[0810]

[0811] Prepared from 4-[(5,6-difluoro-3-pyridyl)methylene]-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 66) (0.30 g, 1.35 mmol) in accordance with the procedure described for Intermediate 11 to afford the title compound (0.24 g, 64%) as an orange solid. LCMS (Method 3B): [M+H]+m / z 225.0, RT 0.93 minutes.1H NMR (500 MHz, DMSO) 5 8.18 (s, 1H), 8.02 (ddd, J = 11.1, 9.5, 2.1 Hz, 1H), 7.98 (t, J = 1.9 Hz, 1H), 3.08 - 2.93 (m, 4H), 1.41 - 1.32 (m, 1H), 0.65 (dt, J = 8.4, 5.3 Hz, 1H), 0.30 (td, J = 5.2, 2.2 Hz, 1H).19F NMR (471 MHz, DMSO) 5 -92.77 (d, J = 29.1 Hz), -141.61 (d, J = 29.1 Hz).

[0812] INTERMEDIATE 68: tert-Butyl 4-methyl-2-oxo-pyrrolidine-1-carboxylate

[0813] Prepared from 4-methylpyrrolidin-2-one (1 g, 10.1 mmol) in accordance with the procedure described for Intermediate 25 to afford the title compound (1.86 g, 88%) as a colourless oil.1H NMR (400 MHz, CDCI3) 53.86 (dd, J = 10.7, 7.6 Hz, 1 H), 3.28 (dd, J = 10.7, 6.9 Hz, 1 H), 2.63 (dd, J = 17.0, 8.1 Hz, 1H), 2.38 (dtd, J = 14.7, 8.0, 6.8 Hz, 1H), 2.15 (dd, J = 17.0, 8.0 Hz, 1H), 1.52 (s, 9H), 1.13 (d, J = 6.7 Hz, 3H).

[0814] INTERMEDIATE 69: tert-Butyl 3-[(6-chloro-3-pyridyl)-hydroxy-methyl]-4-methyl-2-oxo-pyrrolidine-1-carboxylate

[0815] OH

[0816] N:

[0817]

[0818] Prepared from tert-butyl 4-methyl-2-oxo-pyrrolidine-1 -carboxylate (prepared according to the procedure of Intermediate 68 (1 g, 4.77 mmol) and 6-chloropyridine-3-carbaldehyde (0.88 g, 6.24 mmol) in accordance with the procedure described for Intermediate 33 to afford the title compound (1.10 g, 54%) as an orange oil. LCMS (Method 3B): [M-tBu+H]+m / z 241.0 / 243.0, RT 1.31 and 1.33 minutes. Mix of diastereomers.1H NMR (500 MHz, DMSO) 58.43 (d, J = 2.5 Hz, 1 H), 7.85 (dd, J = 8.1, 2.5 Hz, 1 H), 7.49 (d, J = 8.3 Hz, 1 H), 5.93 (d, J = 4.9 Hz, 1 H), 5.26 - 5.17 (m, 1H), 3.74 (dd, J = 10.3, 8.6 Hz, 1H), 3.06-3.03 (m, 1H), 2.62 (dd, J = 8.7, 2.9 Hz, 1H), 2.42 -2.30 (m, 1H), 1.46 (s, 9H), 0.56 (d, J = 6.7 Hz, 3H) (major diastereomer).

[0819] INTERMEDIATE 70: tert-Butyl-3-[(6-chloro-3-pyridyl)methylene]-4-methyl-2-oxo-pyrrolidine-1-carboxylate

[0820] N:

[0821]

[0822] Prepared from tert-butyl 3-[(6-chloro-3-pyridyl)-hydroxy-methyl]-4-methyl-2-oxo-pyrrolidine-1-carboxylate (prepared according to the procedure of Intermediate 69 (1.10 g, 2.58 mmol) in accordance with the procedure described for Intermediate 34 to afford the title compound (1 g, 82%) as a yellow powder. LCMS (Method 3B): [M+H]+m / z 323.2 / 325.2, RT 0.67 minutes.1H NMR (400 MHz, DMSO) 58.64 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.5, 2.5 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 3.0 Hz, 1H), 4.29 (ddt, J = 8.7, 6.2, 3.2 Hz, 1H), 3.30 - 3.21 (m, 1H), 2.68 (dt, J = 18.1, 2.4 Hz, 1H), 1.49 (s, 9H), 1.26 (d, J = 6.2 Hz, 3H).

[0823] INTERMEDIATE 71: 3-r(6-Chloro-3-pyridyl)methylenel-4-methyl-Pyrrolidin-2-one

[0824]

[0825] Prepared from tert-butyl-3-[(6-chloro-3-pyridyl)methylene]-4-methyl-2-oxo-pyrrolidine-1-carboxylate (prepared according to the procedure of Intermediate 70) (1 g, 2.79 mmol) in accordance with the procedure described for Intermediate 28 to afford the title compound (0.53 g, 74%) as a white solid. LCMS (Method 3B): [M+H]+m / z 223.0 / 225.0, RT 0.93 minutes. INTERMEDIATE 72: 3-[(6-Chloro-3-pyridyl)methyl]-4-methyl-pyrrolidin-2-one

[0826] o

[0827]

[0828] Prepared from 3-[(6-chloro-3-pyridyl)methylene]-4-methyl-pyrrolidin-2-one (prepared according to the procedure of Intermediate 71) (0.53 g, 2.07 mmol) in accordance with the procedure described for Intermediate 11 to afford the title compound (0.28 g, 57%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 225.0 / 227.0, RT 0.94 minutes.1H NMR (500 MHz, DMSO) 5 8.29 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.2, 2.5 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 3.18 (ddd, J = 9.3, 7.8, 1.3 Hz, 1H), 2.92 - 2.89 (m, 1H), 2.78 -2.74 (m, 1H), 2.69 (dd, J = 9.5, 8.3 Hz, 1H), 2.21 (ddd, J = 9.6, 6.9, 5.4 Hz, 1H), 2.01 - 1.91 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H) (major diastereomer).

[0829] INTERMEDIATE 73: Dideuterio-(6-fluoro-3-i

[0830]

[0831] D D HO

[0832]

[0833] Prepared from methyl 6-fluoropyridine-3-carboxylate (1 g, 6.45 mmol) in accordance with the procedure described for Intermediate 37 to afford the title compound (0.66 g, 75%) as a paleyellow liquid. LCMS (Method 3B): [M+H]+m / z 130.1, RT 0.28 minutes.1H NMR (500 MHz, DMSO) 58.16 (dt, J = 2.1, 0.9 Hz, 1H), 7.91 (td, J = 8.3, 2.5 Hz, 1H), 7.14 (dd, J = 8.4, 2.8 Hz, 1 H), 5.31 (s, 1 H).19F NMR (471 MHz, DMSO) 5 -71.59.

[0834] INTERMEDIATE 74: 5-fBromo(dideuterio)methyl1-2-fluoro-pyridine

[0835] D D

[0836]

[0837] Prepared from dideuterio-(6-fluoro-3-pyridyl)methanol (prepared according to the procedure of Intermediate 73) (0.66 g, 4.83 mmol) in accordance with the procedure described for Intermediate 26 (THF) to afford the title compound (0.73 g, 74%) as a pale-yellow oil. LCMS (Method 3B): [M+H]+m / z 192 / 194, RT 0.98 minutes.1H NMR (500 MHz, DMSO) 58.35 - 8.33 (m, 1 H), 8.08 (td, J = 8.2, 2.6 Hz, 1 H), 7.21 (dd, J = 8.4, 2.8 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -68.94. INTERMEDIATE 75: tert-Butyl rac-(1S,4S.

[0838]

[0839] io-(6-fluoro-3-i

[0840]

[0841] -3-oxo-2-i.1.

[0842]

[0843]

[0844] Prepared from tert-butyl 3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 52) (1 g, 6.45 mmol) and 5-[bromo(dideuterio)methyl]-2-fluoro-pyridine (prepared according to the procedure of Intermediate 74) (0.76 g, 3.72 mmol) in accordance with the procedure described for Intermediate 27 to afford the title compound (0.83 g, 61%) as a pale-yellow solid. LCMS (Method 3B): [M-Boc+H]+m / z 209.1, RT 1.33 minutes.

[0845] 1H NMR (500 MHz, DMSO) 58.13 (dt, J = 2.5, 0.9 Hz, 1H), 7.90 (td, J = 8.3, 2.5 Hz, 1H), 7.14 (ddd, J = 8.5, 2.9, 0.8 Hz, 1 H), 3.40 - 3.35 (m, 1 H), 2.85 (s, 1 H), 1.45 (s, 9H), 1.33 - 1.27 (m, 1 H), 0.95 - 0.88 (m, 1 H), 0.53 - 0.48 (m, 1 H).19F NMR (471 MHz, DMSO) δ – 71.92.

[0846] INTERMEDIATE 76: tert-Butyl rac-(1S,4,5S)-4-rdideuterio-(6-fluoro-3-pyridyl)methyll-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[0847] . I on

[0848] X0A / o

[0849] O. e

[0850]

[0851] F

[0852] Prepared from tert-butyl rac-(1S,4S,5S)-4-[dideuterio-(6-fluoro-3-pyridyl)methyl]-3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 75) (0.77 g, 2.48 mmol) in accordance with the procedure described for Intermediate 40 to afford the title compound (0.99 g, 100%) as a yellow solid. LCMS (Method 3B): [M-Boc+H]+m / z 209.1, RT 1.37 minutes.1H NMR (500 MHz, DMSO) 58.16 - 8.13 (m, 1H), 7.93 (td, J = 8.3, 2.6 Hz, 1H), 7.16 - 7.12 (m, 1H), 3.53 - 3.49 (m, 1H), 3.32 (s, 1H), 1.47 (s, 9H), 1.36 - 1.33 (m, 1H), 0.86 - 0.79 (m, 1 H), 0.61 - 0.55 (m, 1 H).19F NMR (471 MHz, DMSO) 5 -72.21.

[0853] INTERMEDIATE 77: rac-(1S,4R,5S)-4-[Dideuterio-(6-fluoro-3-pyridyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one O

[0854]

[0855] Prepared from tert-butyl rac-(1 S,4R,5S)-4-[dideuterio-(6-fluoro-3-pyridyl)methyl]-3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 76 (0.99 g, 2.58 mmol) in accordance with the procedure described for Intermediate 28 to afford the title compound (0.33 g, 55%) as a pale-yellow solid. LCMS (Method 3B): [M+H]+m / z 209.2, RT 0.80 minutes.1H NMR (500 MHz, DMSO) 58.21 - 8.10 (m, 2H), 7.93 (td, J = 8.2, 2.5 Hz, 1 H), 7.12 (dd, J = 8.4, 2.8 Hz, 1 H), 2.97 (d, J = 7.0 Hz, 1 H), 2.95 - 2.91 (m, 1 H), 1.39 - 1.31 (m, 1 H), 0.68 - 0.62 (m, 1 H), 0.33 - 0.26 (m, 1 H).19F NMR (471 MHz, DMSO) 5 -72.50.

[0856] INTERMEDIATE 78 and 79: (1R,4S,5R)-4-[dideuterio-(6-fluoro-3-pyridyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one and (1S,4R,5S)-4-[dideuterio-(6-fluoro-3-pyridyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one

[0857] o o

[0858]

[0859] Rac-(1 S,4R,5S)-4-[Dideuterio-(6-fluoro-3-pyridyl)methyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 77) (0.32 g, 1.43 mmol) was subjected to chiral purification by SFC chromatography (Column: Chiralpak I H, 10 x 250mm, 5 μm; Method: 45% MeOH (0.1% NH3), 55% CO2; Column Temperature: 40 °C; Flow rate: 15 mL / min) to afford the title compounds, Intermediate 79 ((1S,4R,5S) isomer) (0.11 g, 34%), as a white solid.

[0860] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Chiralpak IH column, 4.6 x 250mm, 5pm, with mobile phase 45% MeOH (0.1% NH3), 55% CO2. The flow rate was 4 mL / min. The run time was 4 mins. Intermediate 78 RT 1.13 min. Intermediate 79 RT 1.72 min.

[0861] The absolute configuration of Intermediate 78 (1R,4S,5R-configuration) and Intermediate 79 (1S,4R,5S-configuration) was determined using VCD spectroscopy. INTERMEDIATES 80-90

[0862] GENERAL METHOD A

[0863] A solution of the corresponding lactam (0.41 mmol), the corresponding halo-heteroarene (0.42 mmol) and K3PO4(0.85 mmol) in dioxane (5 mL) was degassed with nitrogen for 5 minutes. XantPhos Pd G3 (0.04 mmol) was added, and the reaction mixture was heated at 100 °C for 1- 18 h. The reaction mixture was cooled down to r.t. and concentrated in vacuo. The residue was purified by flash chromatography on silica gel and / or by reversed phase preparative HPLC to afford the title compound.

[0864] The following Intermediates were made according to General Method A outlined above.

[0865] Table 1: Preparation methods and characterisation data of Intermediates 80-90.

[0866] Halo- LCMS

[0867] Int. Heteroarene LCMS [M+H]+

[0868] Name and Structure1HNMR

[0869] No. Method LCMS RT

[0870] Lactam

[0871] (min)

[0872] 5H (400 MHz, DMSO- rac-(1 S,4R,5S)-4-[(6-chloro- d6) = 9.00 (t, J = 1.8 Int. 5 Hz, 1H), 8.76 - 8.70

[0873] 3-pyridyl)methyl]-2-[5- 395.0 / 397.0 (m, 2H), 8.42 - 8.37 fluoro-6-(4-pyridyl)-3- (m, 1H), 8.25 (dd, J =

[0874] 13.6, 2.1 Hz, 1H), pyridyl]-2- 7.94 - 7.84 (m, 3H), azabicyclo[3.1,0]hexan-3- 7.50 (d, J = 8.1 Hz, 80 3B 1H), 3.82 (d, J = 5.9 one Hz, 1H), 3.54 (dt, J =

[0875] 11.4, 5.9 Hz, 1H), Int. 11 i UHs JLl -N. 3.08 (dd, J = 13.9, 4.9

[0876] 1.13 Hz, 1H), 2.65 (dd, J =. \ 14.0, 10.9 Hz, 1H),

[0877] 1.63 (dt, J = 13.9, 6.9 Cl Hz, 1H), 1.07 - 0.98

[0878] (m, 1H), 0.73 (t, J = 5.6 Hz, 1H).

[0879] 5H (400 MHz, DMSO- Int. 50 d6) = 9.08 (d, J = 2.6

[0880] 377.0 / 379.0 Hz, 1H), 8.72 - 8.67 rac-(1 S,4R,5S)-4-[(6-chloro- 81 3B (m, 2H), 8.40 (d, J =

[0881] 3-pyridyl)methyl]-2-[6-(4- 2.4 Hz, 1H), 8.26 (dd, Int. 11 J = 8.7, 2.6 Hz, 1H), pyridyl)-3-pyridyl]-2- 0.87 8.20 (d, J = 8.7 Hz,

[0882]

[0883] 1H), 8.08 - 8.01 (m,

[0884]

[0885] 1C- X-11O 1 -ri- XCD X lO II Xo’ I 1 1

[0886] ^ CXI ^> -L ^. a, ^. |^ J 61 H 2H) 782 [6(4idl)idi3prpranzyyyz =----.,,. Q S eo co " O -N E E ii - (dd J 8225 Hz =,.,.,

[0887] l]lidi2prronone yy-- ■r l S 't x 1= >> S CM o co ep oo if i S ’ ” £? « " ° 8 S1- x £ £ = 1H) 747 (d J 82 =,.,. co,- -'- ct>. cxi; E ib 7Z _ cxi cxi->';1' coccjCD-^ T- T-T_ co p I, ■<- - co co o - _ _ ■

[0888] H 1H) 433 (dd Jz =,,.,, S- £ E2° g S s e 7 ^2 ge ^ s£ E E E 10879 H 1H)z.,.,, S11—;1CT> CO '“ ai T- O -sf CO O ° 356 (dd J 10890 =.,.,. T 'S-X N p II - N E~ E~ cd - P ° 1^ I 72tn. io TO cxi I ct> co co S t- I< cd cd cxi ■<-, - j d o o cxi I cn ii co -j I S S T- CXI T-,-,- O H 1H) 311 (dd Jz = 134,,.,.

[0889] 14160 H 1H)z.,.,,

[0890] O \

[0891] 297 (dd J 14268 == N\.,.,.

[0892] H 1H) 284 (d Jt Clz =,,.,

[0893] 9863 H 1H) 219z.,.,,.

[0894] (d J 16483 Htz =,.,., o

[0895] X- 1H) 104 (d J 65 =,.,.

[0896] H 3H)z,. 960

[0897] I 14tn.

[0898] 3960 / 3980.. LU

[0899] CO

[0900] (1 S4 / ?5S)4[(6hl raccoro-----,,

[0901] 5fl3idl)hl]2toroprmeuyyy----- [6(4idl)idi3l]prpranyyyzy----- 2bil

[0310] h3aaccoeanzyx---.,

[0902] 85 one

[0903] I 55tn.

[0904] ^ll i

[0905] 0

[0906] ryF• -*■()-+

[0907] = N\

[0908] Cl

[0909] I 14tn(1 S4 / ?5S)4[(6fl racorou-----.,,

[0910] 3622.

[0911] 3idl)hl]2[6(4tprmeyyy----- idl)idi3l]2 prpranyyyzy----

[0912]

[0913] bil

[0310] h3 aaccoeanzyx--.,

[0914] 3B one

[0915] ^l l

[0916] I 21tn ¥ O. D

[0917] ^ 13= N\

[0918] F 5H (400 MHz, DMSO- d6) = 9.09 (d, J = 2.6 Int. 50 Hz, 1H), 8.69 (d, J = rac-(1 S,4 / ?,5S)-4-[(6-fluoro- 361.0

[0919] 5.8 Hz, 2H), 8.27 (dd, 3-pyridyl)methyl]-2-[6-(4- J = 8.7, 2.6 Hz, 1H),

[0920] 8.20 (d, J = 8.4 Hz, pyridyl)-3-pyridyl]-2- 2H), 8.07 - 8.03 (m, azabicyclo[3.1,0]hexan-3- 2H), 7.99 (td, J = 8.3,

[0921] 2.6 Hz, 1H), 7.17 (dd, one 3B

[0922] J = 8.4, 2.9 Hz, 1H), 3.78 - 3.74 (m, 1H), Int. 21 l^ll 3.54 - 3.48 (m, 1H),

[0923] 0.93 3.08 (dd, J = 14.0, 4.8

[0924] Hz, 1H), 2.64 (dd, J = 13.9, 11.0 Hz, 1H), N — \

[0925] F 1.62 - 1.55 (m, 1H),

[0926] 1.06 - 1.00 (m, 1H), 0.73 - 0.67 (m, 1H).

[0927] 5H (400 MHz, DMSO- d6) = 9.53 (d, J = 1.5 Int. 24 Hz, 1H), 9.25 (d, J = rac-(1 S,4 / ?,5S)-4-[(6-fluoro- 362.1

[0928] 1.5 Hz, 1H), 8.76 - 3-pyridyl)methyl]-2-[5-(4- 8.70 (m, 2H), 8.21 (s,

[0929] 1H), 8.11 - 8.05 (m, pyridyl)pyrazin-2-yl]-2- 2H), 8.00 (td, J = 8.2, azabicyclo[3.1,0]hexan-3- 2.6 Hz, 1H), 7.17 (dd,

[0930] J = 8.5, 2.9 Hz, 1H), one 3B 3.97 (ddd, J = 7.4, 5.4,

[0931] 2.2 Hz, 1H), 3.59 Int. 21 (ddd, J = 11.4, 7.1, 4.8 cv..

[0932] 1.02 Hz, 1H), 3.12 (dd, J =

[0933] 14.0, 4.9 Hz, 1H), 2.76 - 2.68 (m, 1H), 1.65 - 1.53 (m, 1H), N=\

[0934] F 1.02 (dt, J = 8.5, 5.8

[0935] Hz, 1H), 0.74 - 0.66 (m, 1H).

[0936] 5H (400 MHz, DMSO- d6) = 8.79 - 8.73 (m, rac-(1S,4 / ?,5S)-4-[(5,6- Int. 14 2H), 8.55 (d, J = 9.4 difluoro-3-pyridyl)methyl]-2- 380.0 Hz, 1H), 8.42 (d, J =

[0937] 9.5 Hz, 1H), 8.16 - [6-(4-pyridyl)pyridazin-3-yl]- 8.08 (m, 3H), 8.05 (d, 2-azabicyclo[3.1,0]hexan-3- J = 1.9 Hz, 1H), 4.17

[0938] (ddd, J = 7.4, 5.4, 2.2 one 3B

[0939] Hz, 1H), 3.64 (ddd, J = 11.4, 7.0, 5.1 Hz, 1H), 3.14 (dd, J = 14.0, 5.1 Int. 67

[0940] 1.07 Hz, 1H), 2.75 (dd, J =

[0941] 14.0, 10.8 Hz, 1H), v <+) ^VF1.69 - 1.59 (m, 1H), N=\ 1.11 - 1.03 (m, 1H), F

[0942]

[0943] 0.75 - 0.71 (m, 1H). 5H (400 MHz, DMSO- d6) = 8.84 - 8.70 (m, rac-(1 S,4R,5S)-4-[(6-chloro- 3H), 8.45 (d, J = 9.5 Int. 14

[0944] 3-pyridyl)methyl]-2-[6-(4- 392.1 / 394.1 Hz, 1H), 8.32 (d, J =

[0945] 2.5 Hz, 1H), 8.15 - pyridyl)pyridazin-3-yl]-2- 8.03 (m, 2H), 7.78 azabicyclo[3.2.0]heptan-3- (dd, J = 8.1, 2.5 Hz,

[0946] 1H), 7.48 (d, J = 8.1 one 3B Hz, 1H), 4.92 (t, J =

[0947] 6.4 Hz, 1H), 3.30 - l^ll 3.25 (m, 1H), 3.24 - Int. 36 T N 0 3.08 (m, 2H), 2.85

[0948] 1.17 (dd, J = 14.3, 10.9 Hz,

[0949] 1H), 2.57 - 2.52 (m, 1H), 2.21 (q, J = 10.2 Cl Hz, 1H), 1.93 (dt, J =

[0950]

[0951] 36.9, 10.8 Hz, 2H).

[0952] INTERMEDIATE 91: tert-Butyl 2-methyl-5-oxopyrrolidine-1 -carboxylate

[0953]

[0954] Prepared from 5-methylpyrrolidin-2-one (2 g, 20.2 mmol) in accordance with the procedure described for Intermediate 25 to afford the title compound (3.25 g, 80%) as a yellow oil.1H NMR (400 MHz, DMSO) 54.19 -4.07 (m, 1H), 2.65 - 2.51 (m, 1H), 2.28 (ddd, J = 17.4, 9.4, 3.1 Hz, 1H), 2.18 - 2.03 (m, 1H), 1.55 (dddd, J = 12.5, 9.2, 3.1, 2.4 Hz, 1H), 1.44 (s, 9H), 1.24 (d, J = 6.3 Hz, 3H).

[0955] INTERMEDIATE 92: tert-Butyl 3-((6-chloropyridin-3-yl)(hvdroxy)methyl)-5-methyl-2- oxopyrrolidine-1 -carboxylate

[0956]

[0957] Prepared from tert-butyl 2-methyl-5-oxopyrrolidine-1 -carboxylate (prepared according to the procedure of Intermediate 91 (2.10 g, 10.5 mmol) and 6-chloropyridine-3-carbaldehyde (1.94 g, 13.7 mmol) in accordance with the procedure described for Intermediate 33 to afford the title compound (1.72 g, 46%) as a yellow solid.1H NMR (400 MHz, DMSO) 5 8.39 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.4, 2.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 5.87 (s, 1H), 5.18 (d, J = 2.8 Hz, 1H), 4.97 (d, J = 4.2 Hz, 1H), 4.10 (ddd, J = 7.9, 6.6, 1.3 Hz, 1H), 3.13 (ddd, J = 11.4, 8.8, 3.1 Hz, 1H), 2.20 (td, J = 12.0, 8.7 Hz, 1H), 1.46 (s, 9H), 1.18 (d, J = 6.4 Hz, 3H) (major diastereomer). LCMS (Method 3B): [M-tBu+H]+m / z 241.1 / 243.1, RT 1.31 and 1.34 min.

[0958] INTERMEDIATE 93: tert-Butvl-3-((6-chloropvridin-3-' -2- -1-<

[0959]

[0960] Prepared from tert-butyl 3-((6-chloropyridin-3-yl)(hydroxy)methyl)-5-methyl-2-oxopyrrolidine-1- carboxylate (prepared according to the procedure of Intermediate 92) (1.72 g, 2.58 mmol) in accordance with the procedure described for Intermediate 34 to afford the title compound (1.28 g, 75%) as a yellow solid.1H NMR (400 MHz, DMSO) 58.64 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.5, 2.5 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 3.0 Hz, 1 H), 4.29 (ddt, J = 8.7, 6.2, 3.2 Hz, 1H), 3.30 - 3.21 (m, 1H), 2.68 (dt, J = 18.1, 2.4 Hz, 1H), 1.49 (s, 9H), 1.26 (d, J = 6.2 Hz, 3H). LCMS (Method 3A): [M+H]+m / z 323.2 / 325.2, RT 0.67 minutes.

[0961] INTERMEDIATE 94: (3-((6-chloropvridin-3-vl)methvlene)-5-i

[0962]

[0963] idin-2-one

[0964]

[0965] Prepared from tert-butyl-3-((6-chloropyridin-3-yl)methylene)-5-methyl-2-oxopyrrolidine-1- carboxylate (prepared according to the procedure of Intermediate 93) (1.16 g, 3.59 mmol) in accordance with the procedure described for Intermediate 28 to afford the title compound (0.68 g, 85%) as an off-white solid. LCMS (Method 3B): [M+H]+m / z 223.0 / 225.0, RT 0.99 minutes.

[0966] INTERMEDIATE 95: 3-((6-Chloropvridin-3-'

[0967]

[0968] idin-2-one

[0969]

[0970] Prepared from (3-((6-chloropyridin-3-yl)methylene)-5-methylpyrrolidin-2-one prepared according to the procedure of Intermediate 94 (0.68 g, 3.05 mmol) in accordance with the procedure described for Intermediate 11 to afford the title compound (0.40 g, 53%) as an off- white solid.1H NMR (500 MHz, DMSO) 5 8.27 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.74 (dt, J = 8.2, 2.5 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 3.48 (dq, J = 8.8, 6.1 Hz, 1H), 3.00 (dd, J = 13.6, 4.3 Hz, 1H), 2.67 - 2.54 (m, 2H), 2.10 (ddd, J = 12.3, 8.2, 6.2 Hz, 1H), 1.13 (ddd, J = 12.4, 10.8, 8.8 Hz, 1H), 1.03 (t, J = 6.1 Hz, 3H). (major diastereomer). LCMS (Method 3B): [M+H]+m / z 225.0 / 227.0, RT 0.96 minutes (major diastereomer).

[0971] The following Intermediates were made according to General Method A outlined above.

[0972] Table 2: Preparation methods and characterisation data of Intermediates 96-98.

[0973] Halo- LCMS

[0974] Int. Heteroarene Name and Structure LCMS [M+H]+1HNMR No. Method

[0975] Lactam LCMS RT

[0976] (min)

[0977] δ 8.79 - 8.74 (m, 2H), 8.72 (d, J = 9.4 Hz, rac-(3R,5R)-3-((6- Int. 14 1H), 8.42 (d, J = 9.4 chloropyridin-3-yl)methyl)-5- 380.0 / 382.0 Hz, 1H), 8.36 (d, J =

[0978] 2.5 Hz, 1H), 8.13 - methyl-1 - (6-(py rid i n-4- 8.08 (m, 2H), 7.82 yl)pyridazin-3-yl)pyrrolidin- (dd, J = 8.2, 2.5 Hz,

[0979] 1H), 7.48 (d, J = 8.1 2-one

[0980] 96 Hz, 1H), 4.91 (p, J =

[0981] 3B 6.7 Hz, 1H), 3.38 (tdd,

[0982] J = 14.3, 8.3, 4.0 Hz, 1H), 3.19 (dd, J = Int. 95

[0983] n y o 13.9, 4.9 Hz, 1H),

[0984] 1.12

[0985] 2.77 (dd, J = 14.0, 9.2 Hz, 1H), 2.07 (td, J = N=< 12.0, 8.3 Hz, 1H), Cl 1.86 (dd, J = 12.5, 8.6

[0986] Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H).

[0987] 5 9.52 (d, J = 1.5 Hz, rac-(1R,4S,5R)-4-((6- 1H), 9.25 (d, J = 1.5

[0988] Hz, 1H), 8.76 - 8.70 97 Int. 24 chloro-5-fluoropyridin-3- (m, 2H), 8.33 - 8.27 3B 396.0 / 398.0

[0989] yl)methyl)-2-(5-(pyridin-4- (m, 1H), 8.11 - 8.06

[0990] (m, 2H), 8.02 (dd, J = yl)pyrazin-2-yl)-2- 9.7, 2.0 Hz, 1H), 3.97

[0991]

[0992] (ddd, J = 7.4, 5.4, 2.2 azabicyclo[3.1,0]hexan-3- Hz, 1H), 3.65 (dt, J =

[0993] 11.7, 5.5 Hz, 1H), one

[0994] 3.15 (dd, J = 14.0, 5.2 Hz, 1H), 2.76 (dd, J = Int. 55 i L^, JilL N 1.14 14.0, 10.8 Hz, 1H),

[0995] X I 1.69 - 1.58 (m, 1H),. 1.02 (dt, J = 8.5, 5.8 YVp Hz, 1H), 0.76 - 0.68 * « W

[0996] Cl (m, 1H).

[0997] rac-(1R,4S,5R)-4-((6- 5 9.00 (t, J = 1.8 Hz,

[0998] 1H), 8.76 - 8.70 (m, chloro-5-fluoropyridin-3- 2H), 8.32 - 8.21 (m, Int. 5

[0999] yl)methyl)-2-(3-fluoro-[2,4'- 413.0 / 415.0 2H), 8.01 (dd, J = 9.7,

[1000] 2.0 Hz, 1H), 7.91 (dt, J bipyridin]-5-yl)-2- = 4.6, 1.4 Hz, 2H), azabicyclo[3.1,0]hexan-3- 3.84 (ddd, J = 7.4, 5.1,

[1001] 2.2 Hz, 1H), 3.59 (dt, J one 3B

[1002] = 11.4, 5.3 Hz, 1H), 3.20 - 3.07 (m, 1H), O L, JL. N. 2.76 - 2.68 (m, 1H), Int. 55 if0

[1003] 1.20 1.67 (dt, J = 13.9, 7.6

[1004] Hz, 1H), 1.03 (dt, J = 8.6, 5.6 Hz, 1H), 0.79V— ’ N®\

[1005] Cl - 0.71 (m, 1H).

[1006]

[1007] INTERMEDIATE 99: Rac-(1 / ?,5 / ?)-2-tert-butoxycarbonyl-3-oxo-2-azabicvcloI3.1. Olhexane-

[1008]

[1009] 6 -carboxylic acid

[1010]

[1011] A solution of sodium periodate (7.09 g, 32.8 mmol) and ruthenium (III) chloride hydrate (192 mg, 0.83 mmol) in H₂O (40 mL) was slowly added to a solution of rac-(1R,5R)-2-tert- butoxycarbonyl-2-azabicyclo[3.1.0]hexane-6-carboxylic acid (1.86 g, 8.18 mmol) in EtOAc (40 mL) at 0 °C. The reaction mixture was stirred at r.t. overnight, and then quenched with / -PrOH.

[1012] The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers concentrated in vacuo to afford the title compound (unknown stereochemistry) (1.85 g, 94%) as a white solid. LCMS (Method 1A): [M-fBu+H]+m / z 186.0, RT 0.16 min. INTERMEDIATE 100: tert-Butyl rac-(1R,5R)-6-(hvdroxymethyl)-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[1013] O BOC^ 11

[1014] HA-TC

[1015] £H(±)

[1016]

[1017] OH

[1018] To a solution of rac-(1R,5R)-2-tert-butoxycarbonyl-3-oxo-2-azabicyclo[3.1,0]hexane-6-carboxylic acid (prepared according to the procedure of Intermediate 99) (1.85 g, 7.67 mmol) in THF (40 mL) were added EtsN (1.4 mL, 10 mmol) and ethyl chloroformate (900 pL, 9.13 mmol) at 0 °C. After being stirred for 1 hour at 0 °C, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH (40 mL) and NaBH4 (590 mg, 15.6 mmol) was added at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C, then quenched with saturated aqueous NH4CI. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) then MeOH / EtOAc (0-5% gradient), afforded the title compound (unknown stereochemistry) (732 mg, 42%) as a white solid. LCMS (Method 1A): [M-fBu+H]+m / z 172.0, RT 0.80 min.

[1019] INTERMEDIATE 101: tert-Butyl rac-(1R,5R)-6-rrtert-butyl(dimethyl)silylloxymethyll-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[1020]

[1021] To a solution of tert-butyl rac-(1R,5R)-6-(hydroxymethyl)-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 100 (730 mg, 3.21 mmol) in DCM (10 mL) at r.t. were added imidazole (512 mg, 7.45 mmol) and TBSCI (561 mg, 3.61 mmol). The reaction mixture was stirred at r.t. for 1 hour at 0 °C, then diluted with DCM and water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / / so-hexane (0-70% gradient), afforded the title compound (unknown stereochemistry) (980 mg, 89%) as a white solid. LCMS (Method 1A): [M-Boc+H]+m / z 242.2, RT 1.65 min.

[1022] INTERMEDIATE 102: tert-Butyl rac-(1R,4S,5S)-6-rrtert-butyl(dimethyl)silylloxymethyll-4-[(6-chloro-3-pyridyl)methyl1-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[1023]

[1024] To a solution of tert-butyl rac-(1R,5 / ?)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-oxo-2-azabicyclo[3.1,0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 101) (893 mg, 2.61 mmol) in THF (15 mL) at -78 °C was added LDA (2 M THF / heptane / ethylbenzene solution, 1.3 mL, 2.6 mmol) dropwise. The mixture was stirred at -78 °C for 30 minutes, then 5-(bromomethyl)-2-chloropyridine (549 mg, 2.66 mmol) was added. The reaction was stirred at -78 °Cfor2 hours and then quenched with saturated aqueous NH4CI. The mixture was diluted with DCM and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / / so-hexane (0-80% gradient), afforded the title compound (unknown stereochemistry) (481 mg, 39%) as a white solid. LCMS (Method 1A): [M-Boc+H]+m / z 367.2, RT 1.75 min.

[1025] INTERMEDIATE 103: tert-Butyl rac-(1R,4R,5S)-6-rrtert-butyl(dimethyl)silylloxymethyll-4-[(6-chloro-3-pyridyl)methyl1-3-oxo-2-azabicyclo[3.1. OIhexane-2-carboxylate

[1026]

[1027] To a solution of tert-butyl rac-(1R,4S,5S)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[(6-chloro-3-pyridyl)methyl]-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 102) (475 mg, 1.02 mmol) in THF (10 mL) at -78 °C was added LiHMDS (1 M THF solution, 1.5 mL, 1.5 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 hour and then quenched with saturated aqueous NH4CI. The mixture was diluted with DCM and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / zso-hexane (0-60% gradient), afforded the title compound (unknown stereochemistry) (370 mg, 78%) as a white solid. LCMS (Method 1A): [M-Boc+H]+m / z 367.2, RT 1.78 min.

[1028] INTERMEDIATES 104 and 105: (1 S,4S,5 6S -[(6-chloro-3-pyridyl)methyll-6-(hydroxymethyl)-2 azabicyclo[3.1.01hexan-3-one and (1 / ?,4 / ?,5S,6 / ?)-4-r(6-chloro-3-pyridyl)methyll-6-(hydroxymethyl)-2 azabicyclo[3.1.01hexan-3-one

[1029]

[1030] To a solution of tert-butyl rac-(1 / ?,4 / ?,5S)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[(6-chloro-3-pyridyl)methyl]-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate (prepared according to the procedure of Intermediate 103) (365 mg, 0.781 mmol) in THF (4 mL) at r.t. was added TFA (1.2 mL, 16 mmol). The reaction mixture was stirred at r.t. for 2 hours and then concentrated in vacuo. The residue was subjected to chiral purification by SFC chromatography (Column: Chiralpak IG, 250 x 20.0 mm, 5 μm; Method: MeOH (3-40% gradient) and 0.1% Ammonia solution over 10 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford Intermediate 104 (believed to be (1 S,4S,5 / ?,6S) isomer) (peak 1, 45 mg, 23%, white solid) and Intermediate 105 (believed to be (1 / ?,4 / ?,5S,6R) isomer): (peak 2, 32 mg, 16%, white solid).

[1031] Intermediate 104 (believed to be (1S,4S,5R,6S)):1H NMR (300 MHz, DMSO) 58.37 (d, J = 2.5 Hz, 1 H), 8.22 (s, 1 H), 7.85 (dd, J = 8.3, 2.5 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 4.61 (t, J = 5.3 Hz, 1H), 3.27 - 3.16 (m, 2H), 2.94 (d, J = 10.3 Hz, 1H), 2.84 (d, J = 7.3 Hz, 1H), 2.45 (d, J = 14.8 Hz, 1 H), 1.30 - 1.20 (m, 1 H), 0.90 (s, 1 H). LCMS (Method 1 A): [M+H]+m / z 253.0, RT 0.71 min.

[1032] Intermediate 105 (believed to be (1R,4R,5S,6R)):1H NMR (300 MHz, DMSO) 58.37 (d, J = 2.4 Hz, 1 H), 8.22 (s, 1 H), 7.85 (dd, J = 8.2, 2.5 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 1 H), 4.61 (s, 1 H), 3.21 (d, J = 5.7 Hz, 2H), 3.00 - 2.85 (m, 2H), 2.84 (dd, J = 7.3, 1.5 Hz, 1 H), 2.51 - 2.40 (m, 1 H), 1.27 (td, J = 7.1, 4.1 Hz, 1H), 0.90 (q, J = 5.8 Hz, 1H). LCMS (Method 1A): [M+H]+m / z 253.0, RT 0.71 min. INTERMEDIATE 106: (6 7a / ?)-6-R6-chloro-3-pyridyl)methyll-3.3-dimethyl-1,6,7,7a-tetrahvdropyrrolori,2-cloxazol-5-one

[1033]

[1034] To a solution of (7a / ?)-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one (400 mg, 2.45 mmol) in THF (35 mL) at -78 °C was added LDA (2 M THF / heptane / ethylbenzene solution, 1.5 mL, 3.0 mmol) dropwise. The mixture was stirred at -78 °C for 40 minutes, then 5-(bromomethyl)-2-chloropyridine (585 mg, 2.69 mmol) was added. The reaction was stirred at -78 °C for 40 minutes and then quenched with water. The mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient), afforded the title compound, Intermediate 106 (79 mg, 11%) as a white solid.1H NMR (400 MHz, DMSO) 58.29 (d, J = 2.4 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 1H), 4.11 - 3.97 (m, 2H), 3.36 - 3.25 (m, 1H), 3.16 (dddd, J = 12.1, 9.2, 7.4, 4.8 Hz, 1H), 3.02 (dd, J = 14.1, 4.9 Hz, 1H), 2.64 (dd, J = 14.1, 9.2 Hz, 1H), 2.14 - 2.02 (m, 1H), 1.52 (s, 3H), 1.50 - 1.37 (m, 1 H), 1.35 (s, 3H). LCMS (Method 1 A): [M+H]+m / z 281.2, RT 1.00 min.

[1035] INTERMEDIATE 107: (3R,5R)-3-K6-chloro-3-pyridyl)methyll-5-(hvdroxymethyl)pyrrolidin-2 -one

[1036]

[1037] To a solution of (6R,7a / ?)-6-[(6-chloro-3-pyridyl)methyl]-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one (prepared according to the procedure of Intermediate 106) (79 mg, 0.28 mmol) in MeOH (2 mL) at r.t was added p toluenesulfonic acid monohydrate (1.1 mg, 0.006 mmol). The mixture was heated to 60 °C. After 2 hours 45 minutes, the mixture was cooled to r.t. and concentrated in vacuo to afford the title compound (66 mg, 100%), which was used for the next step without further purification. LCMS (Method 1A): [M+H]+m / z 241.2, RT 0.68 min. INTERMEDIATE 108: (6 7aS)-6-R6-chloro-3-pyridyl)methyll-3.3-dimethyl-1,6,7,7a-tetrahvdropyrrolori,2-cloxazol-5-one

[1038]

[1039] Prepared according to the procedure used for Intermediate 106 using (7aS)-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one (400 mg, 2.45 mmol) to give the title compound (637 mg, 93%) as a white solid. LCMS (Method 1 A): [M+H]+m / z 281.2, RT 0.93 min.

[1040] INTERMEDIATE 109: (3,5S)-3-r(6-chloro-3-pyridyl)methyll-5-(hvdroxymethyl)pyrrolidin-2 -one

[1041]

[1042] Prepared according to the procedure used for Intermediate 107 using (6R,7aS)-6-[(6-chloro-3-pyridyl)methyl]-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one (prepared according to the procedure of Intermediate 108) (300 mg, 1.1 mmol) with a reaction time of 1 hour 10 minutes to give the title compound (264 mg, quantitative) as a white solid. LCMS (Method 1A):

[1043] [M+H]+m / z 241.0, RT 0.69 min.

[1044] INTERMEDIATE 110: 4-(Hydroxymethyl)-1 -(4-methoxybenzyl)pyrrolidin-2-one

[1045] O

[1046]

[1047] HO

[1048] Methyl 1-[(4-methoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carboxylate (9.54 g, 34.4 mmol) was dissolved in EtOH (200 mL) and NaBH4 (6.50 g, 172 mmol) was added portion wise at 0 °C. The reaction mixture was stirred at room temperature for 4 h and then quenched with water (150 mL). The reaction mixture was partially concentrated in vacuo and the aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colourless oil (7.73 g, 94%). The product was used in the next step without further purification.

[1049] 1H NMR (500 MHz, CDCI3) 5 7.18 - 7.11 (m, 2H), 6.88 - 6.78 (m, 2H), 4.49 - 4.21 (m, 2H), 3.78 (d, J = 1.2 Hz, 3H), 3.61 - 3.55 (m, 1H), 3.52 (dd, J = 10.5, 6.6 Hz, 1H), 3.34 (ddd, J = 10.1, 8.0, 2.0 Hz, 1H), 3.11 - 3.05 (m, 1 H), 2.61 -2.45 (m, 2H), 2.26 (dd, J = 15.8, 4.6 Hz, 2H). LCMS (Method 3B): [M+H]+m / z 236.1, RT 0.79 min.

[1050] INTERMEDIATE 111: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(4-methoxybenzyl)pyrrolidin-2-one

[1051]

[1052] To a solution of 4-(hydroxymethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 110) (3.00 g, 12.8 mmol) in DCM (50 mL) was added imidazole (2.34 g, 34.4 mmol) and TBSCI (2.88 g, 19.1 mmol) at 0 °C. The reaction mixture was then warmed to r.t. and stirred for 16 h. The reaction mixture was diluted with DCM (50 mL) and was then washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica gel (0-100% EtOAc / i so- hexane) to afford the title compound as a colourless oil (4.10 g, 92%). LCMS (Method 3D): [M+H]+m / z 350.2, RT 0.78 min.

[1053] INTERMEDIATE 112: Rac-(3R,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-

[1054]

[1055] chloropyridin-3-yl)methyl)-1 -(4-methoxybenzyl)pyrrolidin-2-one

[1056] Si_ Cl

[1057]

[1058] To a solution of A / -isopropylpropan-2-amine (2.33 mL, 16.6 mmol) in THF (20 mL) was slowly added a solution of n-butyllithium in hexanes (1.60 mol / L, 10.4 mL, 16.6 mmol) at -78 °C. The reaction mixture was then stirred at -78 °C for 30 min. This was followed by the slow addition of a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 111) (4.15 g, 11.9 mmol) in THF (10 mL) at -78 °C. The reaction mixture was then stirred at -78 °C for 45 min. This was followed by the slow addition of a solution of 5-(bromomethyl)-2-chloro-pyridine (2.99 g, 13.1 mmol) in THF (20 mL) at -78 °C. The reaction mixture was then stirred at -78 °C for 2 h. The reaction mixture was warmed to r.t. and then quenched with sat. aq. NH4CI solution (50 mL). The resultant solution was extracted with EtOAc (3 x 50 mL). The combined organic extracts were then washed with brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound as a yellow oil (3.10 g, 50%).1H NMR (400 MHz, CDCh) 5 1H NMR (400 MHz, CDCI3) 58.24 (dd, J = 2.5, 0.7 Hz, 1H), 7.59 (dd, J = 8.2, 2.5 Hz, 1H), 7.21 (dd, J = 8.2, 0.7 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.85 - 6.80 (m, 2H), 4.39 (d, J = 14.5 Hz, 1H), 4.28 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.43 (dd, J = 10.1, 5.5 Hz, 1H), 3.38 (dd, J = 10.1, 5.8 Hz, 1H), 3.08 - 2.86 (m, 4H), 2.73 - 2.67 (m, 1H), 2.18 - 2.08 (m, 1H), 0.82 (s, 9H), -0.04 (s, 3H), -0.04 (s, 3H). LCMS (Method 3D): [M+H]+m / z 475.2 / 477.2, RT 0.81 minutes.

[1059] INTERMEDIATE 113: rac-(3R,4R)-3-((6-Chloropvridin-3-vl)methvl)-4-

[1060]

[1061] idin-2-one

[1062] o

[1063] HN-

[1064] ’ h

[1065] HO N

[1066] (±) ci

[1067] To a solution of rac-(3R,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 112) (2.00 g, 4.21 mmol) in MeCN (40 mL) and water (40 mL) was added ammonium cerium(IV) nitrate (11.5 g, 21.0 mmol) at 0 °C. The reaction mixture was then warmed to 60 °C and stirred for 16 h. The reaction mixture was then cooled to r.t. and was diluted with water (20 mL). The resulting solution was washed with 10% MeOH / DCM (3 x 30 mL). The aqueous layer was concentrated in vacuo to a volume of 5 mL. This was purified by reverse phase flash chromatography (0-100% MeCN / 0.1% aq. formic acid solution) to afford the title compound as a yellow solid (588 mg, 56%).1H NMR (500 MHz, DMSO-de) 58.27 (d, J = 2.5 Hz, 1 H), 7.73 (dd, J = 8.2, 2.5 Hz, 1 H), 7.58 (s, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 4.67 (t, J = 5.2 Hz, 1 H), 3.29 - 3.16 (m, 2H), 3.09 (ddd, J = 9.4, 8.2, 1.0 Hz, 1 H), 2.96 - 2.85 (m, 2H), 2.79 (dd, J = 14.0, 7.2 Hz, 1H), 2.40 (ddd, J = 8.3, 7.2, 5.4 Hz, 1H), 2.15 - 2.00 (m, 1H). LCMS (Method 3D): [M+H]+m / z 241.0 / 243.2, RT 0.37 min. INTERMEDIATE 114: rac-(3R,4R) -(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-

[1068]

[1069] chloropyridin-3-yl)methyl)pyrrolidin-2-one

[1070] o

[1071] HN^\

[1072] T Q h N=<

[1073]

[1074] Rac-(3R,4R)-3-((6-chloropyridin-3-yl)methyl)-4-(hydroxymethyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 113) (850 mg, 3.43 mmol), imidazole (630 mg, 9.25 mmol), and TBSCI (774 mg, 5.14 mmol) were dissolved in DMF (15 mL) and stirred at r.t. for 16 h. The reaction mixture was then diluted with water (30 mL) and was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with sat. aq. LiCI solution (30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound as a white solid (995 mg, 78%).1H NMR (500 MHz, DMSO-de) 5 8.28 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.2, 2.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 3.37 (dd, J = 5.8, 1.4 Hz, 2H), 3.13 (ddd, J = 9.5, 8.2, 1.1 Hz, 1H), 2.95 (dd, J = 13.9, 5.2 Hz, 1H), 2.88 (dd, J = 9.6, 7.0 Hz, 1 H), 2.76 (dd, J = 13.9, 7.8 Hz, 1H), 2.40 (td, J = 7.9, 5.1 Hz, 1H), 2.20 - 2.10 (m, 1 H), 0.80 (s, 9H), -0.05 (s, 3H), -0.05 (s, 3H). LCMS (Method 3B): [M+H]+m / z 355.1 / 357.1, RT 1.68 min.

[1075] INTERMEDIATES 115 and 116: (3S.4S) -(atert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)pyrrolidin-2-one and (3R,4R)-4-(((tert-

[1076]

[1077] butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)pyrrolidin-2-one

[1078]

[1079] Rac-(3R,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 114) (995 mg, 2.66 mmol) was subjected to chiral purification by SFC (Column: Chiralpak IH, 10 x 250mm, 5 μm; Method: 25% MeOH (0.1% NH3), 75% CO2; Column Temperature: 40 °C; Flow rate: 20 mL / min) to afford Intermediate 115 ((3S,4S) isomer) (450 mg, 45%) and Intermediate 116 ((3 / ?,4R) isomer)(490 mg, 49%) as white solids.

[1080] Intermediate 115 ((3S,4S) isomer) (peak 1):

[1081] 1H NMR (500 MHz, DMSO) 58.28 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 3.41 - 3.35 (m, 2H), 3.13 (dd, J = 9.6, 8.3 Hz, 1H), 2.95 (dd, 13.9, 5.1 Hz, 1H), 2.88 (dd, J= 9.7, 7.0 Hz, 1H), 2.76 (dd, J = 13.9, 7.8 Hz, 1H), 2.40 (m, 1H), 2.16 (m, 1H), 0.81 (s, 9H), -0.04 (s, 3H), -0.06 (s, 3H). LCMS (Method 3B): [M+H]+m / z 355.1 / 357.1, RT 1.68 min. Chiral SFC analysis (column: Chiralpak IH column, 4.6 x 250mm, 5pm, Method: 25% MeOH (0.1% NH3), 75% CO2 over 4 min, flow rate: 4 mL / min): RT 1.33 min.

[1082] Intermediate 116 ((3R, 4R) isomer) (peak 2):

[1083] 1H NMR (500 MHz, DMSO) 58.28 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.2, 2.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 3.40 - 3.35 (m, 2H), 3.13 (dd, J = 9.6, 8.3 Hz, 1H), 2.95 (dd, J = 13.9, 5.2 Hz, 1H), 2.88 (dd, J = 9.7, 7.0 Hz, 1H), 2.76 (dd, J = 13.9, 7.8 Hz, 1H), 2.40 (m, 1H), 2.16 (m, 1H), 0.81 (s, 9H), -0.04 (s, 3H), -0.06 (s, 3H). LCMS (Method 3B): [M+H]+m / z 355.1 / 357.1, RT 1.68 min. Chiral SFC analysis (column: Chiralpak IH column, 4.6 x 250mm, 5pm, Method: 25% MeOH (0.1% NH3), 75% CO2 over 4 min, flow rate: 4 mL / min): RT 1.83 min.

[1084] INTERMEDIATE 117: (3S,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one

[1085]

[1086] A mixture of 3-chloro-6-(4-pyridyl)pyridazine (136 mg, 0.68 mmol), (3S,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 115) (242 mg, 0.648 mmol) and K3PO4(412 mg, 1.94 mmol) in 2-MeTHF (12 mL) was degassed with nitrogen for 5 mins. This was followed by the addition of Pd2(dba)3(37 mg, 0.065 mmol) and XantPhos (75 mg, 0.13 mmol) at r.t.. The reaction mixture was then degassed with nitrogen for 5 mins. The reaction mixture was heated at 70 °C for 16 h, then was cooled to r.t., filtered through celite and concentrated in vacuo. The crude product was then purified by column chromatography on silica gel (0-100% (3:1 EtOAc: EtOH) / iso-hexane) to afford the title compound as a white solid (150 mg, 45%).1H NMR (500 MHz, DMSO-de) δ 8.78 - 8.73 (m, 2H), 8.70 (d, J = 9.5 Hz, 1H), 8.42 (d, J = 9.4 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1 H), 8.12 - 8.07 (m, 2H), 7.81 (dd, J = 8.2, 2.5 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1H), 4.22 (dd, J = 11.1, 8.3 Hz, 1H), 3.83 (dd, J = 11.1, 6.9 Hz, 1H), 3.59 - 3.48 (m, 2H), 3.15 (q, J = 8.8 Hz, 1 H), 3.04 - 2.89 (m, 2H), 2.42 - 2.34 (m, 1 H), 0.80 (s, 9H), -0.02 (s, 6H). LCMS (Method 3C): [M+H]+m / z 510.4 / 512.3, RT 1.97 min. Chiral SFC analysis (column: Chiralpak IH column, 4.6x250mm, 5pm, Method: 25% MeOH (0.1% NH3), 75% CO2 over 4 min, flow rate: 4 mL / min): RT 1.49 min.

[1087] INTERMEDIATE 118: (3R.4R)4-(atert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-

[1088]

[1089] 3-yl)methyl)-1-(6-(pyridin-4-yl)Pyridazin-3-yl)Pyrrolidin-2-one

[1090]

[1091] A mixture of 3-chloro-6-(4-pyridyl)pyridazine (257 mg, 1.29 mmol), (3R,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 116) (458 mg, 1.23 mmol) and K3PO4(781 mg, 3.68 mmol) in 2-MeTHF (15 mL) was degassed with nitrogen for 5 mins. This was followed by the addition of Pd2(dba)3(71 mg, 0.12 mmol) and XantPhos (142 mg, 0.25 mmol). The reaction mixture was then degassed with nitrogen for 5 mins. The reaction mixture was heated at 70 °C for 16 h, then was cooled to r.t., filtered through celite and concentrated in vacuo. The crude product was then purified by column chromatography on silica gel (0-100% (3:1 EtOAc: EtOH) / iso-hexane) to afford the title compound as a white solid (237 mg, 38%).1H NMR (500 MHz, DMSO-de) 58.80 - 8.73 (m, 2H), 8.70 (d, J = 9.4 Hz, 1H), 8.42 (d, J = 9.4 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 8.10 (d, J = 6.2 Hz, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1 H), 4.22 (dd, J = 11.1, 8.3 Hz, 1 H), 3.83 (dd, J = 11.1, 6.9 Hz, 1 H), 3.60 - 3.46 (m, 2H), 3.15 (q, J = 8.9 Hz, 1H), 3.01 -2.92 (m, 2H), 2.38 (dd, J = 13.6, 6.9 Hz, 1H), 0.80 (s, 9H), -0.02 (s, 6H). LCMS (Method 3C): [M+H]+m / z 510.2 / 512.3, RT 1.98 min. Chiral SFC analysis (column: Chiralpak IH column, 4.6 x 250mm, 5pm, Method: 25% MeOH (0.1% NH3), 75% CO2 over 4 min, flow rate: 4 mL / min): RT 1.99 min.

[1092] INTERMEDIATE 119: 3-Chloro-6-(3-methyl-4-pyridyl)pyridazine

[1093]

[1094] Prepared from (3-methyl-4-pyridyl)boronic acid (1.52 g, 11.1 mmol) and 3,6-dichloropyridazine (1.50 g, 10.1 mmol) in accordance with the procedure described for Intermediate 1 (dioxane / H20, 90 °C, 16 h) to afford the title compound (0.58 g, 28%) as a white solid. LCMS (Method 3G): [M+H]+m / z 206.2 / 208.2, RT 0.42 minutes.1H NMR (500 MHz, DMSO) 58.62 (s, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 2.5 Hz, 2H), 7.51 (d, J = 4.9 Hz, 1H), 2.34 (s, 3H).

[1095] INTERMEDIATE 120: 2-Bromo-5-l l-4-i

[1096]

[1097] Prepared from (3-methyl-4-pyridyl)boronic acid (0.87 g, 6.32 mmol) and 2-bromo-5-iodo-pyrazine (1.50 g, 5.27 mmol) in accordance with the procedure described for Intermediate 1 (dioxane / H20, 90 °C, 4 h) to afford the title compound (0.15 g, 10%) as a brown solid. LCMS (Method 3B): [M+H]+m / z 250.0 / 252.0, RT 0.62 minutes.1H NMR (400 MHz, DMSO) 59.02 (d, J = 1.4 Hz, 1 H), 8.80 (d, J = 1.4 Hz, 1 H), 8.62 - 8.53 (m, 2H), 7.54 (d, J = 5.2 Hz, 1 H), 2.38 (s, 3H).

[1098] INTERMEDIATE 121: tert-Butyl A / -tert-butoxycarbonyl-N-r6-(4-pyridyl)pyridazin-3-yllcarbamate

[1099]

[1100] tert-Butyl A / -tert-butoxycarbonyl-A / -(6-chloropyridazin-3-yl)carbamate (4.2 g, 13 mmol), pyridine-4-boronic acid hydrate (1.8 g, 13 mmol), PdCl2(dppf) (470 mg, 0.64 mmol) and potassium carbonate (3.6 g, 25 mmol) were dissolved in 1,4-dioxane (50 mL) and water (20 mL). The mixture was sparged for 10 mins with nitrogen and then stirred at 80 °C for 1 h. After cooling the reaction mixture to r.t., water and DCM were then added to the reaction mixture and the aqueous layer was extracted with DCM, filtered through a phase separator and then concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / / so-hexane (0-100% gradient) and then EtOAc / MeOH (0-30% gradient) afforded the title compound (2 g, 34%) as a pale pink semi-solid. LCMS (Method 1 A): [M+H]+m / z 373.2, RT 1.31 min.

[1101] INTERMEDIATE 122: 6-(4-Pyridyl)pyridazin-3-amine; 2,2,2-trifluoroacetic acid

[1102]

[1103] To a solution of tert-butyl A / -tert-butoxycarbonyl-N-[6-(4-pyridyl)pyridazin-3-yl]carbamate prepared according to the procedure of Intermediate 121) (2.0 g, 5.4 mmol) in DCM (21 mL) was added TFA (8.5 mL, 110 mmol). After 18 hours, the reaction mixture was concentrated in vacuo to afford the crude title compound (0.90 g, 73%) as a light pink oil. 1H NMR (400 MHz, DMSO) 5 8.68 - 8.60 (m, 2H), 8.00 - 7.94 (m, 2H), 7.64 - 7.42 (m, 1H), 6.88 (d, J = 9.3 Hz, 1H), 6.76 (s, 2H). LCMS (Method 1A): [M+H]+m / z 173.0, RT 0.34 min.

[1104] INTERMEDIATE 123: tert-Butyl A / -r(1 )-1-(hvdroxymethyl)-3-oxo-3-rr6-(4-

[1105]

[1106] Pyridyl)pyridazin-3-yl1amino1propyl1carbamate

[1107]

[1108] To a solution of 6-(4-pyridyl)pyridazin-3-amine; 2,2,2-trifluoroacetic acid (prepared according to the procedure of Intermediate 122) (550 mg, 1.9 mmol) and (R)-3-boc-amino-gamma-butyrolactone (1.01 g, 4.79 mmol) in THF (30 mL) was added / so-propylmagnesium chloride (4.8 mL, 9.6 mmol, 2 mol / L) at r.t. and the reaction mixture stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4CI solution and then water and DCM were added. The aqueous layer was extracted with DCM, filtered through a phase separator and then concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / / so-hexane (0-100% gradient) and then EtOAc / MeOH (0-30% gradient) afforded the title compound (280 mg, 37%) as a light pink oil.1H NMR (300 MHz, DMSO) 6 11.22 (s, 1 H), 8.79 - 8.71 (m, 2H), 8.45 (d, J = 9.4 Hz, 1H), 8.37 (d, J = 9.5 Hz, 1 H), 8.13 - 8.05 (m, 2H), 6.61 (d, J = 8.3 Hz, 1H), 4.78 (t, J = 5.6 Hz, 1 H), 3.92 (s, 1 H), 3.48 - 3.33 (m, 1 H), 2.71 (dd, J = 14.7, 5.2 Hz, 1 H), 2.58 (d, J = 8.3 Hz, 1 H), 1.33 (s, 9H). LCMS (Method 1 A): [M+H]+m / z 374.2, RT 0.93 min.

[1109] INTERMEDIATE 124: tert-Butyl A / -r(3 )-5-oxo-1-r6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-3-yllcarbamate

[1110]

[1111] To a solution of tert-butyl A / -[(1R)-1-(hydroxymethyl)-3-oxo-3-[[6-(4-pyridyl)pyridazin-3-yl]amino]propyl]carbamate (prepared according to the procedure of Intermediate 123) (280 mg, 0.75 mmol) in THF (20 mL) were added triphenylphosphine (414 mg, 1.50 mmol) and diisopropyl azodicarboxylate (300 pL, 1.52 mmol) at r.t. After 1 h the reaction mixture was concentrated in vacuo to a yellow oil. Purification by flash chromatography eluting with EtOAc / / so-hexane (0-100% gradient) and then EtOAc / MeOH (0-30% gradient) afforded the title compound (200 mg, 70%) as a light clear yellow oil.1H NMR (300 MHz, DMSO) 58.81 - 8.73 (m, 2H), 8.68 (d, J = 9.5 Hz, 1H), 8.42 (d, J = 9.5 Hz, 1H), 8.15 - 8.07 (m, 2H), 7.51 (s, 1H), 4.36 (dd, J = 11.0, 6.7 Hz, 1H), 4.28 (s, 1H), 4.10 - 3.99 (m, 1H), 3.01 (dd, J = 17.3, 7.9 Hz, 1H), 2.58 (d, J = 4.2 Hz, 1 H), 1.41 (s, 9H). LCMS (Method 1 A): [M+H]+m / z 356.2, RT 1.07 min.

[1112] INTERMEDIATE 125: tert-Butyl / V-R3 / ?)^-[(6-chloro-3-pyridyl)methyll-5-oxo-1-[6-(4- Pyridyl)pyridazin-3-yllpyrrolidin-3-yllcarbamate

[1113]

[1114] To a solution of tert-butyl A / -[(3F?)-5-oxo-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-3-yl]carbamate (prepared according to the procedure of Intermediate 124) (200 mg, 0.56 mmol) in THF (5 mL) at-78°C was added LDA (2 M THF / heptane / ethylbenzene solution, 700 pL, 1.4 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h, then 5-(bromomethyl)-2-chloropyridine (147 mg, 0.68 mmol) was added. The reaction was stirred at -78 °C for 3 hours and then quenched with saturated aqueous NH4CI. The mixture was diluted with DCM and the layers were separated. The aqueous layer was extracted with DCM and concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-20% gradient), afforded the title compound (80 mg, 25%) as a light pink oil. LCMS (Method 1 A): [M+H]+m / z 481.2, RT 1.27 min.

[1115] INTERMEDIATE 126: 4-(Difluoromethyl)-1-(4-methoxybenzyl)Pyrrolidin-2-one

[1116] O

[1117] N

[1118] z ~F

[1119]

[1120] F

[1121] 4-(Hydroxymethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 110) (3.0 g, 11.5 mmol) was dissolved in DMSO (30 mL) then N, N-diethylethanamine (3.1 mL, 23.0 mmol) and sulfur trioxide pyridine complex (5.5 g, 34.4 mmol) were sequentially added. The reaction mixture was stirred at r.t. for 4 h and then diluted with water (150 mL). The aqueous phase was extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the intermediate 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carbaldehyde as a yellow oil (1.51 g, 34%). 1-(4-Methoxybenzyl)-5-oxopyrrolidine-3-carbaldehyde (1.50 g, 3.9 mmol) was then dissolved in DCM (30 mL) and bis(2-methoxyethyl)aminosulfur trifluoride (2.7 mol / L, 3.00 mL, 8.1 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then quenched carefully with saturated aqueous NaHCOa (150 mL). The reaction mixture was extracted with DCM (2 x 100 mL) and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound as a yellow oil (480 mg, 45%).1H NMR (500 MHz, DMSO-d6) 57.20 - 7.12 (m, 2H), 6.93 - 6.87 (m, 2H), 6.11 (td, J = 56.5, 4.3 Hz, 1 H), 4.34 (d, J = 14.6 Hz, 1 H), 4.26 (d, J = 14.6 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J = 10.2, 8.9 Hz, 1H), 3.15 (dd, J = 10.2, 5.2 Hz, 1H), 2.87 (m, 1 H), 2.55 - 2.51 (m, 1 H), 2.30 (dd, J = 17.1, 6.1 Hz, 1 H). LCMS (Method 3D): [M+H]+m / z 256.2, RT 0.55 min. INTERMEDIATE 127: rac-(3R,4R)-3-((6-i idin-3-vl)methvl)-4-(di i-1- idin-2-one

[1122]

[1123] A solution of 4-(difluoromethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 126) (363 mg, 1.35 mmol) in THF (5 mL) under nitrogen was cooled to -78 °C. A solution of LDA in THF / hexane (1.00 mol / L, 1.49 mL, 1.49 mmol) was slowly added over 5 min and the mixture was stirred at -78 °C for 30 min. A solution of 5-(bromomethyl)-2-chloropyridine (357 mg, 1.49 mmol) in THF (2 mL) was slowly added and the resulting mixture was stirred at -78 °C for 2 h. The mixture was quenched with saturated NH4CI (50 mL) then extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-70% EtOAc / iso-hexane) to afford the title compound as a pale-yellow oil which solidified on standing (135 mg, 26%).1H NMR (400 MHz, DMSO-d6) 58.28 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.2, 2.5 Hz, 1 H), 7.43 (dd, J = 8.2, 0.7 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.07 (td, J = 56.2, 4.3 Hz, 1H), 4.32 (d, J = 14.6 Hz, 1H), 4.23 (d, J = 14.5 Hz, 1H), 3.73 (s, 3H), 3.14 - 3.02 (m, 2H), 2.95 (d, J = 5.9 Hz, 2H), 2.87 (q, J = 6.1 Hz, 1H), 2.54 (s, 1H).19F NMR (376 MHz, DMSO-d6) 5 -122.04 (d, J = 1.8 Hz). LCMS (Method 3B):

[1124] [M+H]+m / z 381.1 / 383.1, RT 1.43 min.

[1125] INTERMEDIATE 128: rac-(3R,4R)-3-((6-i idin-3-vl)methvl)-4- idin-2-one

[1126] F\

[1127] N

[1128]

[1129] To a solution of rac-(3R,4 / ?)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 127) (135 mg, 0.355 mmol) in MeCN (5 mL) and water (5 mL) was added ammonium cerium(IV) nitrate (389 mg, 0.709 mmol) at 0 °C. The reaction mixture was warmed to 60 °C and stirred for 16 h. The reaction mixture was cooled to r.t. and was diluted with water (20 mL). The resulting solution was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% [3:1 EtOAc: EtOH] / iso-hexane) to afford the title compound as a yellow solid (43 mg, 44%).1H NMR (400 MHz, DMSO-d6) 58.27 (dd, J = 2.5, 0.7 Hz, 1 H), 7.83 (s, 1 H), 7.73 (dd, J = 8.2, 2.5 Hz, 1 H), 7.45 (dd, J = 8.2, 0.7 Hz, 1 H), 6.07 (td, J = 56.2, 4.6 Hz, 1H), 3.22 - 3.12 (m, 1H), 3.12 - 3.05 (m, 1H), 2.91 (d, J = 6.1 Hz, 2H), 2.70 (dt, J = 7.7, 6.1 Hz, 1H), 2.64 -2.52 (m, 1H).19F NMR (376 MHz, DMSO-d6) 5 -121.23 (d, J = 4.0 Hz). LCMS (Method 3B): [M+H]+m / z 261.0 / 263.2, RT 0.49 min.

[1130] INTERMEDIATE 129: rac-(3R.4R)-3-a6-Chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-

[1131]

[1132] (6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one

[1133]

[1134] A mixture of 3-chloro-6-(4-pyridyl)pyridazine (26.5 mg, 0.124 mmol), rac-(3 / ?,4 / ?)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 128) (31 mg, 0.113 mmol), K3PO4(48 mg, 0.226 mmol) andXantPhos Pd G3 (10.7 mg, 0.0113 mmol) was degassed with N2 for 5 mins. 1,4-Dioxane (5 mL) was added and the mixture was degassed with N2 for 5 mins. The reaction mixture was heated at 70 °C for 5 h, then cooled to rt. The mixture was filtered through celite and concentrated in vacuo. The crude product was then purified by column chromatography on silica gel (0-100% [3:1 EtOAc: EtOH] / iso-hexane). The product was then further purified by reverse phase chromatography (0-100% MeCN / H2O (0.1 % formic acid)) to afford the title compound as an off-white solid (19 mg, 38%).1H NMR (500 MHz, DMSO-d6) 58.79 - 8.73 (m, 2H), 8.69 (d, J = 9.4 Hz, 1H), 8.44 (d, J = 9.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1 H), 6.36 - 6.15 (m, 1H), 4.27 (dd, J = 11.5, 9.0 Hz, 1H), 4.06 (dd, J = 11.5, 6.2 Hz, 1H), 3.30 - 3.25 (m, 1H), 3.17 - 3.06 (m, 2H), 2.88 - 2.75 (m, 1H).

[1135] 19F NMR (471 MHz, DMSO-d6) 5 -121.39 (d, J = 282.5 Hz), -122.14 (d, J = 282.5 Hz). LCMS (Method 3C): [M+H]+m / z 416.3 / 418.3, RT 1.26 min.

[1136] III. SYNTHESIS OF EXAMPLES EXAMPLE 1: rac-(1S,4 / ?,5S)-4-f(6-chloro-3-i -2-r2-(4-pvridvl)Pvrimidin-5- |-2-i.1.0lhexan-3-one

[1137]

[1138] Prepared from 2-[2-(4-pyridyl)pyrimidin-5-yl]-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 3 (113 mg, 0.45 mmol) and 5-(bromomethyl)-2-chloro-pyridine (prepared according to the procedure of Intermediate 4) (92 mg, 0.45 mmol) in accordance with the procedure described for Intermediate 27 to afford the title compound (6 mg, 4%) as an off-white solid. LCMS (Method 5): [M+H]+m / z 378.1, RT 0.90 minutes.1H NMR (400 MHz, DMSO) 59.32 (s, 2H), 8.79 - 8.73 (m, 2H), 8.40 (d, J = 2.5 Hz, 1 H), 8.27 - 8.20 (m, 2H), 7.88 (dd, J = 8.2, 2.5 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 3.83 (ddd, J = 7.3, 5.0, 2.1 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.08 (dd, J = 14.0, 5.0 Hz, 1H), 2.70 -2.60 (m, 2H), 1.65 (dt, J = 14.1, 7.3 Hz, 1 H), 1.07 - 0.98 (m, 1 H), 0.81 - 0.74 (m, 1 H).

[1139] EXAMPLE 2A and 2B: (1 S.4R5SM-K6-Chloro-3-pyridyl)methyll-2-r5-fluoro-6-(4-pyridyl)- 3-pyridyl1-2-azabicyclo[3.1.01hexan-3-one and (1 / ?,4S,5 / ?)-4-K6-chloro-3-pyridyl)methyll- 2-r5-fluoro-6-(4-pyridyl)-3-pyridyll-2-azabicvclor3.1.0lhexan-3-one

[1140]

[1141] rac-(1S,4 / ?,5S)-4-[(6-Chloro-3-pyridyl)methyl]-2-[5-fluoro-6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 80) (38 mg, 0.10 mmol) was subjected to chiral purification by SFC (Column: PhenomenexC3, 21 x250mm, 5 μm; Method: 25% EtOH (0.1% NH3), 75% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compound Example 2A ((1 S,4R,5S) isomer): (14 mg, 37%) as a white solid. LCMS (Method 5): [M+H]+m / z 395.2, RT 0.97 minutes.1H NMR (400 MHz, DMSO) 59.00 (t, J = 1.8 Hz, 1H), 8.76 - 8.70 (m, 2H), 8.40 (d, J = 2.5 Hz, 1H), 8.25 (dd, J = 13.6, 2.1 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.88 - 7.82 (m, 1H), 7.50 (d, J = 8.2 Hz, 1H), 3.83 (ddd, J = 7.3, 5.1, 2.1 Hz, 1H), 3.54 (ddd, J = 12.0, 7.1, 4.9 Hz, 1H), 3.08 (dd, J = 14.0, 4.9 Hz, 1H), 2.65 (dd, J = 14.0, 10.9 Hz, 1H), 1.62 (dtd, J = 8.5, 7.2, 5.2 Hz, 1H), 1.03 (ddd, J = 8.5, 6.1, 5.0 Hz, 1H), 0.73 (td, J = 5.6, 2.1 Hz, 1 H).19F NMR (376 MHz, DMSO) 5 -120.95.

[1142] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3 column, 4.6 x 250mm, 5pm, with mobile phase 25% EtOH (0.1% NH3), 75% CO2. The flow rate was 4 mL / min. The run time was 2.5 mins.

[1143] Example 2A ((1S,4R,5S) isomer): RT 1.83 min.

[1144] Example 2B ((1R,4S,5R) isomer): RT 1.61 min.

[1145] One of the isomers A and B is (1S,4R,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-fluoro-6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one and the other is (1R,4S,5R)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-fluoro-6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one.

[1146] EXAMPLE 3Aand 3B: (1 S.4 / ?.5S)-4-R6-Chloro-3-pyridvnmethyll-2-16-(4-pyridyl)-3-pyridyl1-2-azabicvclo[3.1.01hexan-3-one and (1 / ?,4S,5 / ?)-4-K6-chloro-3-pyridyl)methyll-2-r6-(4-pyridyl)-3-pyridyll-2-azabicyclor3.1.0]hexan-3-one

[1147]

[1148] rac-(1S,4R,5S)-4-[(6-Chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 81) (25 mg, 0.06 mmol) was subjected to chiral purification by SFC (Column: Phenomenex C3, 21 x 250mm, 5 μm; Method: 25% EtOH (0.2% NH3), 75% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compound Example 3A ((1S,4R,5S) isomer) (9 mg, 37%) as a white solid. LCMS (Method 5): [M+H]+m / z 377.2, RT 0.81 minutes.1H NMR (400 MHz, DMSO) 59.08 (d, J = 2.5 Hz, 1 H), 8.73 - 8.66 (m, 2H), 8.40 (d, J = 2.4 Hz, 1 H), 8.26 (dd, J = 8.7, 2.6 Hz, 1 H), 8.20 (d, J = 8.6 Hz, 1H), 8.10 - 8.03 (m, 2H), 7.87 (dd, J = 8.2, 2.5 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 3.76 (ddd, J = 7.2, 5.0, 2.1 Hz, 1H), 3.52 (ddd, J = 11.4, 7.1, 4.8 Hz, 1H), 3.07 (dd, J = 14.0, 4.8 Hz, 1 H), 2.68 - 2.62 (m, 1 H), 1.59 (dt, J = 14.2, 7.2 Hz, 1 H), 1.02 (dt, J = 8.5, 5.5 Hz, 1H), 0.74 - 0.69 (m, 1H). Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3 column, 4.6 x 250mm, 5pm, with mobile phase 25% EtOH (0.1% NH3), 75% CO2. The flow rate was 4 mL / min. The run time was 5 mins.

[1149] Example 3A ((1S,4 / ?,5S) isomer): RT 3.26 min.

[1150] Example 3B ((1 / ?,4S,5R) isomer): RT 2.96 min.

[1151] One of isomers A and B is (1S,4 / ?,5S)-4-[(6-Chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one and the other is (1 / ?,4S,5 / ?)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one.

[1152] EXAMPLE 4A and 4B: (1S,4 / ?,5S)-4-f(6-chloro-5-fluoro-3-i

[1153]

[1154] 3-pyridyl1-2-azabicvclof3.1.01hexan-3-one and (1 / ?,4S,5 / ?)-4-f(6-Chloro-5-fluoro-3- |-2-r6-(4-pvridvD-3-i.1.0lhexan-3-one

[1155]

[1156] rac-(1S,4 / ?,5S)-4-[(6-Chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 82) (22 mg, 0.06 mmol) was subjected to chiral purification by SFC (Column: ChiralPak IH, 10 x 150mm, 5 μm; Method: 40% MeOH (0.5% DEA), 60% CO2; Column Temperature: 40 °C; Flow rate: 20 mL / min) to afford the title compound Example 4A ((1 S,4R,5S) isomer) (12 mg, 44%) as a white solid. LCMS (Method 5): [M+H]+m / z 395.2, RT 0.90 minutes.1H NMR (400 MHz, DMSO) 59.08 (dd, J = 2.6, 0.8 Hz, 1 H), 8.72 - 8.67 (m, 2H), 8.30 (d, J = 1.9 Hz, 1 H), 8.26 (dd, J = 8.7, 2.6 Hz, 1 H), 8.20 (dd, J = 8.7, 0.8 Hz, 1 H), 8.06 - 8.03 (m, 2H), 8.01 (dd, J = 9.7, 2.0 Hz, 1 H), 3.82 -3.73 (m, 1H), 3.62 - 3.52 (m, 1H), 3.11 (dd, J = 14.1, 5.1 Hz, 1H), 2.70 (dd, J = 14.0, 10.9 Hz, 1H), 1.70 - 1.58 (m, 1H), 1.10 - 0.97 (m, 1H), 0.78 -0.69 (m, 1H).19F NMR (376 MHz, DMSO) 5 -120.74.

[1157] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a ChiralPak IH column, 4.6 x 250mm, 5pm, with mobile phase 60% MeOH (0.4% NH3), 40% CO2. The flow rate was 4 mL / min. The run time was 5 mins. Example 4A ((1S,4R,5S) isomer): RT 2.87 min.

[1158] Example 4B ((1R,4S,5R) isomer): RT 2.43 min.

[1159] One of isomers A and B is (1 S,4R,5S)- 4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one and the other is (1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one.

[1160] EXAMPLE 5A (1 S.4 / ?.5S) -K6-chloro-5-fluoro-3-pyridinyl)methyll-2-(6-pyridazin -yl-3-pyridinyl)-2-azabicyclo[3.1.01hexan-3-one and 5B (1 / ?,4S,5 / ?)-4-r(6-chloro-5-fluoro-3-Pyridinyl)methyll-2-(6-pyridazin-4-yl-3-pyridinyl)-2-azabicvclor3.1. Olhexan-3-one

[1161]

[1162] ci ci rac-(1S,4R,5S)-4-[(6-Chloro-5-fluoro-3-pyridyl)methyl]-2-(6-pyridazin-4-yl-3-pyridyl)-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 83) (25 mg, 0.06 mmol) was subjected to purification by chiral HPLC chromatography (Column: Chiralpak IB; 20 x 250 mm, 5 μm; Method: 9:1 EtOH / MeCN; Column Temperature: 23 °C; Flow rate: 20 mL / min) to afford the title compound Example 5A (4 mg, 16%) as a beige solid.1H NMR (500 MHz, DMSO) 59.91 (dd, J = 2.4, 1.2 Hz, 1 H), 9.35 (dd, J = 5.5, 1.2 Hz, 1 H), 9.14 (dd, J = 2.5, 0.8 Hz, 1 H), 8.35 (dd, J = 8.7, 0.8 Hz, 1 H), 8.32 - 8.26 (m, 3H), 8.01 (dd, J = 9.6, 1.9 Hz, 1 H), 3.79 (ddd, J = 7.2, 5.0, 2.2 Hz, 1 H), 3.58 (ddd, J = 11.5, 7.0, 5.1 Hz, 1 H), 3.12 (dd, J = 14.0, 5.0 Hz, 1H), 2.71 (s, 1H), 1.65 (dtd, J = 8.4, 7.1, 5.1 Hz, 1H), 1.04 (ddd, J = 8.4, 6.0, 5.0 Hz, 1H), 0.74 (td, J = 5.6, 2.1 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 396, RT 1.1 min.

[1163] Chiral data: Method: Chiral analysis was performed by chiral HPLC (Column: Chiralpak IB; 4.6 x 150mm, 3 pm; Method: 90% EtOH + 10% MeCN + 0.1% DEA; Column Temperature: 30 °C; Flow rate: 1.5 mL / min).

[1164] Example 5A ((1S,4R,5S) isomer): RT 3.94 min.

[1165] Example 5B ((1R,4S,5R) isomer): RT 3.48 min.

[1166] One of isomers A and B is (1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(6-pyridazin-4-yl-3-pyridinyl)-2-azabicyclo[3.1.0]hexan-3-one and the other is (1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(6-pyridazin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one. EXAMPLE 6A (3R,4 / ?)-3-f(6-chloro-3-i:in-3- in-2-one; 6B l-3-F(6-chloro-3-i l-4-i 1-1-1

[1167]

[1168] in -3- idin-2-one; 6C i-3-|Y6-chloro-3-i 1-1-1 in-3-’

[1169]

[1170] idin-2-one: and 6D

[1171]

[1172] i-3-r(6-Chloro-3-

[1173]

[1174] 1-1-1

[1175]

[1176] in-3-

[1177]

[1178] idin-2-one

[1179]

[1180] 3-[(6-Chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one (prepared according to the procedure of Intermediate 84) (166 mg, 0.42 mmol) was subjected to chiral purification by SFC (Column: Phenomenex C3, 20 x 250mm, 5 μm; Method: 45% MeOH (0.2% NH3), 55% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compound Example 6A (20 mg, 13%), Example 6B (24 mg, 15%), Example 6C (7 mg, 4%), Example 6D (8 mg, 5%) as white solids.

[1181] Example 6A ((3R, 4R) isomer)

[1182] LCMS (Method 5): [M+H]+m / z 380.2, RT 0.99 minutes.1H NMR (500 MHz, DMSO) 5 8.78 -8.73 (m, 2H), 8.67 (d, J = 9.4 Hz, 1 H), 8.41 (d, J = 9.4 Hz, 1 H), 8.37 (d, J = 2.4 Hz, 1 H), 8.11 -8.07 (m, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 4.33 (dd, J = 10.8, 7.9 Hz, 1H), 3.56 (dd, J = 10.7, 9.0 Hz, 1H), 3.11 (dd, J = 14.1, 5.9 Hz, 1H), 2.97 (dd, J = 14.2, 6.8 Hz, 1H), 2.84 (dt, J = 10.1, 6.4 Hz, 1H), 2.22 - 2.14 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H).

[1183] Example 6B ((3S,4S) isomer)

[1184] LCMS (Method 5): [M+H]+m / z 380.2, RT 1.01 minutes.1H NMR (500 MHz, DMSO) 5 8.82 -8.71 (m, 2H), 8.67 (d, J = 9.4 Hz, 1 H), 8.41 (d, J = 9.4 Hz, 1 H), 8.37 (d, J = 2.5 Hz, 1 H), 8.14 -8.03 (m, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 4.33 (dd, J = 10.7, 8.0 Hz, 1 H), 3.56 (dd, J = 10.8, 9.0 Hz, 1H), 3.11 (dd, J = 14.2, 6.0 Hz, 1H), 2.97 (dd, J = 14.2, 6.8 Hz, 1H), 2.84 (dt, J = 10.1, 6.4 Hz, 1H), 2.19 (dt, J = 16.4, 8.4 Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H).

[1185] Example 6C ((3R,4S) isomer)

[1186] LCMS (Method 5): [M+H]+m / z 380.2, RT 0.99 minutes.1H NMR (500 MHz, DMSO) 5 8.82 -8.71 (m, 2H), 8.69 (d, J = 9.4 Hz, 1H), 8.41 (dd, J = 6.0, 3.5 Hz, 2H), 8.17 - 8.03 (m, 2H), 7.87 (dd, J = 8.3, 2.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1 H), 4.13 (dd, J = 10.9, 6.1 Hz, 1H), 3.97 (dd, J = 10.9, 2.1 Hz, 1H), 3.38 (dt, J = 9.1, 6.8 Hz, 1H), 3.08 (dd, J = 14.8, 6.3 Hz, 1 H), 2.86 - 2.75 (m, 1H), 2.59 (qd, J = 7.0, 2.1 Hz, 1H), 1.02 (d, J = 7.0 Hz, 3H).

[1187] Example 6D ((3S,4R) isomer)

[1188] LCMS (Method 5): [M+H]+m / z 380.2, RT 0.99 minutes.1H NMR (500 MHz, DMSO) 5 8.79 -8.75 (m, 2H), 8.69 (d, J = 9.4 Hz, 1H), 8.41 (dd, J = 6.0, 3.5 Hz, 2H), 8.12 - 8.07 (m, 2H), 7.87 (dd, J = 8.3, 2.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1 H), 4.13 (dd, J = 10.9, 6.1 Hz, 1H), 3.97 (dd, J = 10.9, 2.1 Hz, 1H), 3.39 (s, 1H), 3.08 (dd, J = 14.9, 6.3 Hz, 1H), 2.81 (dd, J = 14.9, 9.2 Hz, 1H), 2.61 (d, J = 5.9 Hz, 1H), 1.03 (d, J = 7.0 Hz, 3H).

[1189] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3 column, 4.6 x 250mm, 5pm, with mobile phase 40% MeOH (0.1% NH3), 60% CO2. The flow rate was 4 mL / min. The run time was 3.5 mins.

[1190] Example 6A ((3R,4R) isomer): RT 2.30 min.

[1191] Example 6B ((3S,4S) isomer): RT 2.55 min.

[1192] Example 6C ((3R,4S) isomer): RT 2.07 min.

[1193] Example 6D ((3S,4R) isomer): RT 3.13 min.

[1194] One of isomers A, B, C and D is (3R,4S)-3-[(6-Chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one, another one is (3R,4R)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one, another one is (3S,4S)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one and another one is (3S,4R)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one. EXAMPLE 7A (1 S,4 / ?,5S)-4-K6-chloro-5-fluoro-3-pyridyl)methyll-2-r6-(4- Pyridyl)Pyridazin-3-yll-2-azabicvclo[3.1.01hexan-3-one and 7B: (1 / ?,4S,5 / ?)-4-f(6-Chloro- 5-fluoro-3-pyridyl)methyll-2-r6-(4-pyridyl)Pyridazin-3-yll-2-azabicvclor3.1.0lhexan-3-one

[1195]

[1196] rac-(1S,4 / ?,5S)-4-[(6-Chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 85) (18 mg, 0.04 mmol) was subjected to chiral purification by SFC (Column: Phenomenex C4, 10 x 250mm, 5 μm; Method: 55% MeOH (0.1% NH3), 45% CO2; Column Temperature: 40 °C; Flow rate: 20 mL / min) to afford the title compound Example 7A ((1S,4R,5S) isomer) (9 mg, 51%) as a white solid. LCMS (Method 5): [M+H]+m / z 396.2, RT 0.97 minutes.1H NMR (400 MHz, DMSO) δ 8.78 - 8.73 (m, 2H), 8.54 (d, J = 9.5 Hz, 1H), 8.42 (d, J = 9.5 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.16 - 8.07 (m, 2H), 8.02 (dd, J = 9.6, 2.0 Hz, 1H), 4.21 - 4.13 (m, 1H), 3.70 - 3.60 (m, 1H), 3.15 (dd, J = 14.0, 5.2 Hz, 1H), 2.77 (dd, J = 14.0, 10.8 Hz, 1H), 1.71 - 1.59 (m, 1H), 1.10 - 1.01 (m, 1 H), 0.81 - 0.69 (m, 1 H).19F NMR (376 MHz, DMSO) 5 -120.73.

[1197] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C4 column, 4.6 x 250mm, 5pm, with mobile phase 55% MeOH (0.1% NH3), 45% CO2. The flow rate was 4 mL / min. The run time was 10 mins.

[1198] Example 7A ((1S,4R,5S) isomer): RT 7.66 min.

[1199] Example 7B ((1R,4S,5R) isomer): RT 5.87 min.

[1200] One of isomers A and B is (1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1.0]hexan-3-one and the other is (1R,4S,5R)-4-[(6-Chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one. EXAMPLE 8A (1 S,4 / ?,5S)-4-r(6-fluoro-3-pyridyl)methyll-2-f6-(4-pyridyl)Pyridazin-3-yll-2-.1.0lhexan-3-one and 8B (1R.4S -fluoro-3-i -2-f6-(4-:in-3-vll-2-«.1.0lhexan-3-one

[1201] N=\ N=\

[1202]

[1203] F F

[1204] rac-(1S,4 / ?,5S)-4-[(6-Fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 86) (43 mg, 0.11 mmol) was subjected to chiral purification by SFC (Column: ChiralPak I H, 21 x 250mm, 5 μm; Method: 55% MeOH, 45% CO2; Column Temperature: 40 °C; Flow rate: 20 mL / min) to afford the title compound Example 8A ((1 S,4R,5S) isomer) (26 mg, 62%) as a white solid. LCMS (Method 5): [M+H]+m / z 362.2, RT 0.80 minutes.1H NMR (400 MHz, DMSO) δ 8.80 - 8.74 (m, 2H), 8.56 (d, J = 9.4 Hz, 1 H), 8.42 (d, J = 9.4 Hz, 1 H), 8.22 (d, J = 2.5 Hz, 1 H), 8.14 - 8.08 (m, 2H), 8.01 (td, J = 8.2, 2.5 Hz, 1H), 7.18 (dd, J = 8.4, 2.8 Hz, 1H), 4.20 - 4.13 (m, 1H), 3.64 -3.55 (m, 1 H), 3.12 (dd, J = 14.0, 4.9 Hz, 1 H), 2.71 (dd, J = 14.0, 11.0 Hz, 1 H), 1.65 - 1.55 (m, 1H), 1.10 - 1.03 (m, 1H), 0.76 - 0.69 (m, 1H).19F NMR (471 MHz, DMSO) 5 -72.15.

[1205] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a ChiralPak IH column, 4.6 x 250mm, 5pm, with mobile phase 60% MeOH (0.1% NH₃), 40% CO₂. The flow rate was 4 mL / min. The run time was 4 mins.

[1206] Example 8A ((1S,4R,5S) isomer): RT 2.75 min.

[1207] Example 8B ((1 / ?,4S,5 / ? J isomer): RT 1.95 min.

[1208] One of isomers A and B is (1 S,4R,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one and the other is (1R,4S,5R)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1.0]hexan-3-one. EXAMPLE 9Aand 9B: (1 S.4 / ?.5S)-4-R6-Fluoro-3-pyridyl)methyll-2-f6-(4-pyridvn-3- -2-azabicvclo[3.1.01hexan-3-one and (1 / ?,4S,5 / ?)-4-f(6-fluoro-3-pvridvl)methvll-2- l-3-pvridvll-2-<.1.0lhexan-3-one

[1209] N=\ N=\

[1210]

[1211] F F

[1212] rac-(1S,4R,5S)-4-[(6-Fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 87) (32 mg, 0.09 mmol) was subjected to chiral purification by SFC (Column: ChiralPak AY-H, 10 x 250 mm, 5 μm; Method: 50% EtOH (0.2% NH3), 50% CO2; Column Temperature: 40 °C; Flow rate: 15 mL / min) to afford the title compound Example 9A ((1 S,4R,5S) isomer): (19 mg, 58%) as a white solid. LCMS (Method 5): [M+H]+m / z 361.2, RT 0.74 minutes.1H NMR (400 MHz, DMSO) 59.08 (d, J = 2.6 Hz, 1 H), 8.74 - 8.64 (m, 2H), 8.27 (dd, J = 8.7, 2.6 Hz, 1 H), 8.23 - 8.16 (m, 2H), 8.07 -8.01 (m, 2H), 7.99 (td, J = 8.2, 2.6 Hz, 1 H), 7.17 (dd, J = 8.4, 2.8 Hz, 1 H), 3.78 - 3.74 (m, 1H), 3.54 - 3.47 (m, 1 H), 3.08 (dd, J = 14.0, 4.8 Hz, 1 H), 2.67 - 2.61 (m, 1 H), 1.62 - 1.55 (m, 1 H), 1.06 - 1.00 (m, 1 H), 0.76 - 0.68 (m, 1 H).19F NMR (471 MHz, DMSO) 5 -72.21.

[1213] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a ChiralPak AY-H column, 4.6 x 250mm, 5pm, with mobile phase 50% EtOH (0.2% NH3), 50% CO2. The flow rate was 4 mL / min. The run time was 6 mins.

[1214] Example 9A ((1S,4R,5S) isomer): RT 1.94 min.

[1215] Example 9B ((1R,4S,5R) isomer): RT 3.67 min.

[1216] One of isomers A and B is (1 S,4R,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one and the other is (1R,4S,5 / ?)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one.

[1217] EXAMPLE 10A (1 S,4 / ?,5S)-4-r(6-fluoro-3-pvridvl)methvll-2-r5-(4-pvridvl)Pvrazin-2-vll-2-.1.0lhexan-3-one and 10B: (1 / ?,4S,5 / ?)-4-r(6-Fluoro-3-pvridvl)methvll-2-r5-(4-

[1218]

[1219] zin-2-vl1-2-azabicvclof3.1.01hexan-3-one

[1220]

[1221] rac-(1 S,4R,5S)-4-[(6-Fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one (prepared according to the procedure of Intermediate 88) (36 mg, 0.10 mmol) was subjected to chiral purification by SFC (Column: ChiralPak IB-N, 20 x 250mm, 5 μm; Method: 40% MeOH (0.1% NH3), 60% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compound Example 21 A ((1S,4R,5S) isomer): (19 mg, 53%) as a white solid. LCMS (Method 5): [M+H]+m / z 362.3, RT 0.85 minutes.1H NMR (400 MHz, DMSO) 5 9.53 (d, J = 1.5 Hz, 1H), 9.25 (d, J = 1.5 Hz, 1H), 8.75 - 8.71 (m, 2H), 8.22 (d, J = 2.5 Hz, 1H), 8.11 -8.06 (m, 2H), 8.00 (td, J = 8.3, 2.6 Hz, 1H), 7.17 (dd, J = 8.4, 2.8 Hz, 1H), 3.97 (ddd, J = 7.4, 5.5, 2.2 Hz, 1H), 3.59 (ddd, J = 11.4, 7.1, 5.0 Hz, 1H), 3.12 (dd, J = 13.9, 4.9 Hz, 1H), 2.71 (dd, J = 14.0, 10.9 Hz, 1H), 1.63 - 1.54 (m, 1H), 1.02 (dt, J = 8.5, 5.8 Hz, 1H), 0.70 (td, J = 5.7, 2.1 Hz, 1 H).19F NMR (471 MHz, DMSO) 5 -72.15.

[1222] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a ChiralPak IB-N column, 4.6 x 250mm, 5pm, with mobile phase 50% MeOH (0.1% NH3), 50% CO2. The flow rate was 4 mL / min. The run time was 6 mins.

[1223] Example 10A ((1S,4R,5S) isomer): RT 3.08 min.

[1224] Example 10B ((1R,4S,5R) isomer): RT 2.77 min.

[1225] One of isomers A and B is (1 S,4R,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one and the other is (1R,4S,5R)-4-[(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one.

[1226] EXAMPLE 11 A and 11B: (1S,4R,5S)-4-r(5,6-difluoro-3-pyridyl)methyll-2-f6-(4- in-3-.1.0lhexan-3-one and (1 / ?,4S,5 / ?)-4-f(5,6-Difluoro-3-

[1227]

[1228] -2-f6-(4-i:in-3-vll-2-«.1.0lhexan-3-one

[1229]

[1230] rac-(1 S,4R,5S)-4-[(5,6-Difluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 89) (55 mg, 0.15 mmol) was subjected to chiral purification by SFC (Column: ChiralPak IH, 10 x 150 mm, 5 μm; Method: 45% EtOH (0.1% NH₃), 55% CO₂; Column Temperature: 40 °C; Flow rate: 15 mL / min) to afford the title compound Example 11 A ((1S,4R,5S) isomer) (12 mg, 22%) as a white solid. LCMS (Method 5): [M+H]+m / z 380.3, RT 0.97 minutes.1H NMR (400 MHz, DMSO) 5 8.80 - 8.75 (m, 2H), 8.55 (d, J = 9.4 Hz, 1H), 8.42 (d, J = 9.4 Hz, 1H), 8.14 - 8.08 (m, 3H), 8.05 (t, J = 1.9 Hz, 1H), 4.21 - 4.14 (m, 1H), 3.68 - 3.60 (m, 1H), 3.14 (dd, J = 14.3, 5.2 Hz, 1H), 2.75 (dd, J = 14.0, 10.8 Hz, 1H), 1.68 - 1.59 (m, 1H), 1.11 - 1.03 (m, 1H), 0.77 - 0.70 (m, 1H).19F NMR (471 MHz, DMSO) 5 -92.38 (d, J = 29.1 Hz), -141.42 (d, J = 29.3 Hz).

[1231] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3 column, 4.6 x 250mm, 5pm, with mobile phase 60% MeOH (0.1% NH₃), 40% CO₂. The flow rate was 4 mL / min. The run time was 6 mins.

[1232] Example 11 A ((1S,4R,5S) isomer): RT 2.67 min.

[1233] Example 11 B ((1R,4S,5R) isomer): RT 1.46 min.

[1234] One of isomers A and B is (1S,4R,5S)-4-[(5,6-difluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1.0]hexan-3-one and the other is (1R,4S,5R)-4-[(5,6-difluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1.0]hexan-3-one.

[1235] EXAMPLE 12A (1 S,4 / ?,5S)-4-r(6-Chloro-3-pvridvl)methvll-2-r6-(4-pvridvl)Pvridazin-3-vll-2-.2.01heptan-3-one and 12B (1 / ?,4S,5 / ?)-4-K6-chloro-3-pvridvl)methvll-2-r6-(4-

[1236]

[1237] :in-3-vll-2-azabicvclof3.2.01heptan-3-one

[1238]

[1239] ci

[1240] Rac-(1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one (prepared according to the procedure of Intermediate 90) (20 mg, 0.05 mmol) was subjected to chiral purification by SFC (Column: Phenomenex C3, 20 x 250 mm, 5 μm; Method: 35% MeOH, 65% CO₂; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compounds Example 12A ((]S,4R,5S) isomer) (5.0 mg, 25%) and Example 12B (4.5 mg, 22%) as white solids.

[1241] Example 12A ((1S,4 / ?,5S) isomer):

[1242] LCMS (Method 5): [M+H]+m / z 392.2, RT 0.99 minutes.1H NMR (400 MHz, DMSO) 58.80 (d, J = 9.4 Hz, 1H), 8.78 - 8.73 (m, 2H), 8.45 (d, J = 9.4 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.15 -8.08 (m, 2H), 7.78 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.92 (s, 1 H), 3.31 - 3.26 (m, 1H), 3.24 - 3.08 (m, 2H), 2.85 (dd, J = 14.3, 10.9 Hz, 1H), 2.56 - 2.51 (m, 1H), 2.29 -2.15 (m, 1H), 1.99 - 1.86 (m, 2H).

[1243] Example 12B ((1 / ?,4S,5R) isomer):

[1244] LCMS (Method 5): [M+H]+m / z 392.2, RT 0.99 minutes.1H NMR (400 MHz, DMSO) 58.80 (d, J = 9.5 Hz, 1 H), 8.78 - 8.72 (m, 2H), 8.45 (d, J = 9.5 Hz, 1 H), 8.32 (d, J = 2.5 Hz, 1 H), 8.14 -8.06 (m, 2H), 7.78 (dd, J = 8.2, 2.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 4.92 (t, J = 6.2 Hz, 1H), 3.31 - 3.27 (m, 1H), 3.17 (ddd, J = 27.1, 14.7, 6.2 Hz, 2H), 2.85 (dd, J = 14.3, 10.9 Hz, 1H), 2.55 -2.51 (m, 1H), 2.21 (q, J = 10.1 Hz, 1H), 1.99 - 1.84 (m, 2H).

[1245] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3 column, 4.6 x 250mm, 5pm, with mobile phase 35% MeOH (0.1% NH₃), 65% CO₂. The flow rate was 4 mL / min. The run time was 5 mins.

[1246] Example 12A ((1S,4 / ?,5S) isomer): RT 1.97 min.

[1247] Example 12B ((1 / ?,4S,5R) isomer): RT 2.99 min. One of isomers A and B is (1S,4F?,5S)-4-[(6-Chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one and the other is (1F?,4S,5F?)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one.

[1248] EXAMPLE 13: (1 S,4 / ?,5S)-4-((6-Chloropvridin-3-vl)methvD-2-(6-(pvridin-4-vl)Pvridazin-3- -2-azabicvclo[3.1.01hexan-3-one

[1249]

[1250] A mixture of 3-chloro-6-(4-pyridyl)pyridazine (prepared according to the procedure of Intermediate 14 (98 mg, 0.49 mmol), (1S,4F?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one, Intermediate 13 (0.10 g, 0.45 mmol) and K3PO4(0.19 g, 0.89 mmol) in 1,4-dioxane (3 mL) was sparged with nitrogen for 10 min. XantPhos Pd G3 (4 mg, 4.45 μmol) was added and sparged with N2 for 5 min. The reaction mixture was stirred at 70 °C for 4 h, cooled down to r.t and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-60%(3:1 EtOAc: EtOH) / iso-hexane) and reverse phase preparative HPLC to afford the title compound (45 mg, 27%) as a white solid. LCMS (Method 5): [M+H]+m / z 378.2, RT 0.91 min.1H NMR (500 MHz, DMSO) 58.80 - 8.75 (m, 2H), 8.55 (d, J = 9.5 Hz, 1 H), 8.45 - 8.39 (m, 2H), 8.14 - 8.09 (m, 2H), 7.89 (dd, J = 8.2, 2.5 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 1H), 4.17 (ddd, J = 7.4, 5.4, 2.2 Hz, 1H), 3.65 - 3.56 (m, 1H), 3.11 (dd, J = 14.0, 4.9 Hz, 1H), 2.71 (dd, J = 13.9, 10.9 Hz, 1H), 1.61 (dt, J = 14.2, 7.2 Hz, 1H), 1.06 (dt, J = 8.5, 5.8 Hz, 1H), 0.76 - 0.70 (m, 1H).

[1251] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3column, 4.6 x 250mm, 5pm, with mobile phase 60% MeOH (0.1% NH₃), 40% CO₂. The flow rate was 4 mL / min. The run time was 3 mins. Example 13: RT 2.38 min.

[1252] Examples 14 -24:

[1253] The following Examples were made according to either General Method B or General Method C. GENERAL METHOD B

[1254] A solution of the corresponding lactam (0.45 mmol), the corresponding halo-heteroarene (0.49 mmol) and K3PO4(0.89 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen for 5 minutes. XantPhos Pd G3 (0.04 mmol) was added, and the reaction mixture was heated at 70 °C for 1-5 h. The reaction mixture was cooled down to r.t. and concentrated in vacuo. The residue was purified by flash chromatography on silica gel and / or by reversed phase preparative HPLC to afford the title compound.

[1255] GENERAL METHOD C

[1256] A solution of the corresponding lactam (0.45 mmol), the corresponding halo-heteroarene (0.49 mmol) and K3PO4(0.89 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen for 5 minutes. JosiPhos SL-J009-1 Pd G3 (0.04 mmol) was added, and the reaction mixture was heated at 70 °C for 1-2 h. The reaction mixture was cooled down to r.t. and concentrated in vacuo. The residue was purified by flash chromatography on silica gel and / or by reversed phase preparative HPLC to afford the title compound.

[1257] Table 3: Preparation methods and characterisation data of Examples 14-24:

[1258] Halo- LCMS

[1259] Ex. Gener

[1260] Heteroarene Name and Structure a

[1261] [M+H]+

[1262] I1H NMR No.

[1263] Lactam Method LCMS RT

[1264] (min)

[1265] δH (500 MHz, DMSO-d6) Int. 15 = 8.92 (t, J = 1.7 Hz, (1S,4R,5S)-4-[(6-chloro-3- 377.3 1H), 8.69- 8.64 (m,

[1266] 2H), 8.40 (d, J = 2.5 Hz, pyridyl)methyl]-2-[5-(4- 1H), 8.30 (d, J = 1.7 Hz, pyridyl)-2-pyridyl]-2- 2H), 7.88 (dd, J = 8.2, azabicyclo[3.1,0]hexan-3-one 2.5 Hz, 1H), 7.81 -7.76

[1267] (m, 2H), 7.50 (d, J = 8.2 14 B Hz, 1H), 4.05- 3.99 (m,

[1268] Cl

[1269] 1H), 3.60- 3.52 (m, Int. 13

[1270] 0.90 1H), 3.10 (dd, J = 13.9,

[1271] 4.9 Hz, 1H), 2.68 (dd, J = 13.9, 11.0 Hz, 1H), N=\ 1.52 (dt, J = 13.8, 7.1 Cl

[1272] Hz, 1H), 0.98 (dt, J = 8.6, 5.9 Hz, 1H), 0.61 (d,

[1273]

[1274] J = 5.4 Hz, 1H). Halo- LCMS

[1275] Ex. Heteroarene Name and Structure Genera [M+H]+

[1276] I1H NMR No.

[1277] Lactam Method LCMS RT

[1278] (min)

[1279] δH (500 MHz, DMSO-d6) = 8.92 (t, J = 1.7 Hz, Int. 15 1H), 8.69- 8.64 (m,

[1280] 361.3 2H), 8.30 (d, J = 1.7 Hz,

[1281] 2H), 8.21 (d, J = 2.5 Hz, (1 S,4R,5S)-4-[(6-fluoro-3- 1H), 8.00 (td, J = 8.3, pyridyl)methyl]-2-[5-(4- 2.5 Hz, 1H), 7.81 -7.76

[1282] (m, 2H), 7.17 (dd, J = pyridyl)-2-pyridyl]-2- 8.4, 2.8 Hz, 1H), 4.02 azabicyclo[3.1,0]hexan-3-one (ddd, J = 7.4, 5.4, 2.2 15 Hz, 1H), 3.55 (ddd, J =

[1283] BNC1 11.5, 7.1, 4.8 Hz, 1H),

[1284] 3.11 (dd, J = 14.0, 4.8 Int. 23 Hz, 1H), 2.68 (dd, J = 0.82 13.9, 11.1 Hz, 1H), 1.51 N=\ (qd, J = 7.3, 5.1 Hz, 1H), F 0.99 (dt, J = 8.4, 5.7 Hz,

[1285] 1H), 0.63- 0.57 (m, 1H).

[1286] δH (400 MHz, DMSO-d6) = 9.53 (dd, J = 2.5, 1.2 Int. 61 Hz, 1H), 9.25 (dd, J =

[1287] 392.3 5.5, 1.2 Hz, 1H), 8.21 (d, (1S,4R,5S)-4-[(6-fluoro-3- J = 2.5 Hz, 1H), 8.15 (d, pyridyl)methyl]-2-(6-methoxy- J = 8.3 Hz, 1H), 8.00 (td, 5-pyridazin-4-yl-2-pyridyl)-2- J = 8.3, 2.6 Hz, 1H),

[1288] 7.95 - 7.90 (m, 2H), azabicyclo[3.1,0]hexan-3-one 7.17 (dd, J = 8.4, 2.8 16 Hz, 1H), 4.13 (ddd, J =

[1289] N''1 B

[1290] 7.4, 5.4, 2.1 Hz, 1H), 4.01 (s, 3H), 3.55 (ddd, Int. 23 J = 11.4, 7.0, 4.6 Hz,

[1291] 1.18 1H), 3.11 (dd, J = 14.0,

[1292] 4.7 Hz, 1H), 2.68 (dd, J N=\

[1293] F = 14.0, 11.1 Hz, 1H),

[1294] 1.55 - 1.46 (m, 1H), 0.99 (dt, J = 8.4, 5.8 Hz, 1H), 0.60 (td, J = 5.6,

[1295]

[1296] 2.1 Hz, 1H). Halo- LCMS

[1297] Ex. Heteroarene Name and Structure Genera [M+H]+

[1298] I1H NMR No.

[1299] Lactam Method LCMS RT

[1300] (min)

[1301] δH (500 MHz, DMSO-d6) = 9.53 (d, J = 1.5 Hz, Int. 24 1H), 9.25 (d, J = 1.5 Hz,

[1302] (1S,4R,5S)-4-[(6-chloro-3- 378.2 1H), 8.75- 8.71 (m,

[1303] 2H), 8.41 (d, J = 2.5 Hz, pyridyl)methyl]-2-[5-(4- 1H), 8.11 - 8.06 (m, pyridyl)pyrazin-2-yl]-2- 2H), 7.88 (dd, J = 8.2, azabicyclo[3.1,0]hexan-3-one 2.5 Hz, 1H), 7.51 (d, J =

[1304] 8.1 Hz, 1H), 3.97 (ddd, J 17 B = 7.3, 5.4, 2.1 Hz, 1H),

[1305] A A.

[1306] Il 'n o 3.60 (ddd, J = 11.4, 7.0,

[1307] 5.0 Hz, 1H), 3.11 (dd, J Int. 13 = 14.0, 4.9 Hz, 1H), 2.71

[1308] 0.96

[1309] (dd, J = 14.0, 10.9 Hz, N=\ 1H), 1.64- 1.55 (m, Cl

[1310] 1H), 1.01 (dt, J = 8.4, 5.8 Hz, 1H), 0.71 (td, J = 5.6, 2.2 Hz, 1H).

[1311] δH (500 MHz, DMSO-d6) = 8.76 (d, J = 5.2 Hz, Int. 14 (3R,4R)-3-[(6-fluoro-3- 2H), 8.68 (d, J = 9.4 Hz,

[1312] 364.3 1H), 8.41 (d, J = 9.5 Hz, pyridyl)methyl]-4-methyl-1 -[6- 1H), 8.18 (d, J = 2.3 Hz, (4-pyridyl)pyridazin-3- 1H), 8.10 (d, J = 5.1 Hz, yl]pyrrolidin-2-one 2H), 7.94 (t, J = 8.6 Hz,

[1313] 1H), 7.17- 7.11 (m, 18 B 1H), 4.36-4.29 (m, A

[1314] 1H), 3.56 (t, J = 9.9 Hz, 1H), 3.12 (dd, J = 14.3, Int. 28 5.8 Hz, 1H), 2.97 (dd, J 0.93

[1315] = 14.2, 6.9 Hz, 1H), 2.83 A (dt, J = 12.4, 6.2 Hz, F

[1316] 1H), 2.20 (t, J = 8.2 Hz, 1H), 1.03 (d, J = 6.5 Hz, 3H).

[1317] 6H (400 MHz, DMSO-de) = 8.92 (t, J = 1.7 Hz, Int. 15 1H), 8.69- 8.63 (m, (1 S,4R,5S)-4-[dideuterio-(6- 363.3 2H), 8.30 (d, J = 1.7 Hz,

[1318] 2H), 8.21 (d, J = 2.5 Hz, 19 fluoro-3-pyridyl)methyl]-2-[5- C 1H), 8.00 (td, J = 8.2, (4-pyridyl)-2-pyridyl]-2- 2.5 Hz, 1H), 7.83 -7.76

[1319] (m, 2H), 7.21 - 7.13 (m, Int. 79 1H), 4.02 (ddd, J = 7.4,

[1320] 0.82

[1321] 5.4, 2.2 Hz, 1H), 3.53 (d,

[1322]

[1323] J = 7.0 Hz, 1H), 1.59- "" S’ KJ" ■'t 1- co H-T N ■O. CO II - — CO CO " O T A. 7XCM < II C0 CM -, cp<^||o; A '-' Hlao- -H- CM ||1- co - TO - Cp- cp P I (N 2 h- „ „11O T2 nN- °? n I I r-.

[1324] LCMS G Nd S Etteneraame anrcreuux [MH] H+t+.eeroarene N II cd - TJ O <2 CD || CD N N I I CO1H NMR I

[1325] No.

[1326] LCMS RT Mhdteo LtacamQSS<t cOT: ^ " A ° 5 A O o S. T-j- (i)mn cD co od od iA J^ nZ - ^ I ^- & I ^" ii CM ’P S- S;c2 ^ ^ ^:i: oj- -d ^ cd' ^ ^ o>'' ->ur>0Oco ^ 144 ( 1H) 105bil

[0310] h3m aaccoeanonezyx---.,,.., i05I I I ‘P11® I IO II T- CN '- CN -D tO -i l T- o I i- ii | — > CD T- 095 ( 1H) 064m-.,,.

[1327] 056 ( 1H)m.,.

[1328] O U JI JI D

[1329] = N\

[1330] F

[1331] co co

[1332] 6 (400 MH DMSOd)zHe-,

[1333] 891 ( J 17 Ht = =z.,.,

[1334] (1S4R5S)4[(6hl3coro----- 1H) 870864 (,,m I 15tn-,..,.

[1335] 2H) 840 (dd J 25idl)didihl]2tt 3793 = preeromeyyuy----,.,.,.

[1336] 07 H 1H) 830 (d Jz = [5(4idl)2idl]2.,,.,prpryyyy------ 17 H 2H) 787 (dd Jz.,,.,

[1337] bil

[0310] h3 aaccoeanonezyx 8225 H 1H) 782-- =z.,.,.,,.

[1338] 776 ( 2H) 750 (ddm 20 -.,,.,

[1339] J 8207 H 1H) =z.,.,,

[1340] 402 (ddd J 7454 U J^ = JI.,.,., D

[1341] 22 H 1H) 354 (d Jz = I 43tn.,,.,.

[1342] 70 H 1H) 157146 060z-.,,..

[1343] ( 1H) 098 (d Jtm ==,,.,\ N

[1344] 8458 H 1H) 061z Cl.,.,,.

[1345] (d J 5622 H 1H)t =z,.,.,.

[1346] I 44t (1S4R5S)4[(6hl3ncoro 3923-----.,,.

[1347]

[1348] idl)hl]2[6hl5tt prmemeyyyy----- (4idl)i2l]2prpranyyyzy----- bil

[0310] h3 aaccoeanonezyx--.,

[1349] o

[1350] J T O

[1351] I 13tn.

[1352] 105.

[1353] = N\

[1354] Cl Halo- LCMS

[1355] Ex. Heteroarene Name and Structure Genera [M+H]+

[1356] I

[1357] .1H NMR No

[1358] Lactam Method LCMS RT

[1359] (min)

[1360] δH (500 MHz, DMSO-d6) = 9.65 (d, J = 1.5 Hz, 1H), 9.20 (d, J = 1.5 Int. 24 (3R,4R)-3-[(6-chloro-3- 380.3 Hz, 1H), 8.74- 8.69 (m, pyridyl)methyl]-4-methyl-1 -[5- 2H), 8.37 (d, J = 2.5 Hz,

[1361] 1H), 8.10- 8.05 (m, (4-pyridyl)pyrazin-2- 2H), 7.82 (dd, J = 8.2, yl]pyrrolidin-2-one 2.5 Hz, 1H), 7.47 (d, J = 22 8.2 Hz, 1H), 4.15 (dd, J 'A B

[1362] A.. N. = 10.7, 8.0 Hz, 1H), 3.41 Tl k O (dd, J = 10.7, 9.0 Hz,

[1363] 1H), 3.11 (dd, J = 14.2, Int.46 1.06 5.9 Hz, 1H), 2.96 (dd, J = 14.2, 6.7 Hz, 1H), 2.84 Cl (dt, J = 10.1, 6.3 Hz,

[1364] 1H), 2.18 (dt, J = 17.0, 8.7 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H).

[1365] δH (400 MHz, DMSO-d6) = 9.66 (d, J = 1.5 Hz, 1H), 9.20 (d, J = 1.6 Int. 24 364.3 Hz, 1H), 8.75- 8.69 (m,

[1366] (3R,4R)-3-[(6-fluoro-3- 2H), 8.18 (d, J = 2.5 Hz,

[1367] 1H), 8.11 - 8.05 (m, pyridyl)methyl]-4-methyl-1 -[5- 2H), 7.94 (td, J = 8.2, (4-pyridyl)pyrazin-2- 2.5 Hz, 1H), 7.14 (dd, J yl]pyrrolidin-2-one = 8.4, 2.8 Hz, 1H), 4.14

[1368] (dd, J = 10.7, 8.0 Hz, 23 C 1H), 3.41 (dd, J = 10.7,

[1369] O

[1370] if k o 9.0 Hz, 1H), 3.12 (dd, J = 14.2, 5.8 Hz, 1H), 2.97 Int. 28 (dd, J = 14.2, 6.9 Hz,

[1371] 0.98

[1372] '4"b 1H), 2.87-2.78 (m, N=\ 1H), 2.25-2.14 (m, F

[1373] 1H), 1.00 (d, J = 6.6 Hz, 3H).

[1374]

[1375] Halo- LCMS

[1376] Ex. Heteroarene Name and Structure Genera

[1377] [M+H]+

[1378] I1H NMR No.

[1379] Lactam Method LCMS RT

[1380] (min)

[1381] δH (500 MHz, DMSO-d6) = 9.45 (s, 1H), 8.74 - 8.69 (m, 2H), 8.41 (d, J Int. 49 (1S,4R,5S)-4-[(6-chloro-3- 408.3 = 2.4 Hz, 1H), 7.89 (dd, pyridyl)methyl]-2-[6- J = 8.2, 2.5 Hz, 1H), (hydroxymethyl)-5-(4- 7.81 - 7.75 (m, 2H),

[1382] 7.51 (d, J = 8.2 Hz, 1H), pyridyl)pyrazin-2-yl]-2- 5.59 (t, J = 5.5 Hz, 1H), 24 azabicyclo[3.1,0]hexan-3-one 4.66 -4.56 (m, 2H), B 4.12 -4.04 (m, 1H), A. 3.60 (ddd, J = 11.4, 7.1, Il 'n o 4.9 Hz, 1H), 3.12 (dd, J Int. 13 = 13.9, 5.0 Hz, 1H), 2.71

[1383] 0.87 (dd, J = 13.9, 10.9 Hz,

[1384] 1H), 1.59 (dtd, J = 8.5, N=\

[1385] Cl 7.0, 5.1 Hz, 1H), 1.02 (dt, J = 8.5, 5.8 Hz, 1H), 0.69 (td, J = 5.6, 2.1 Hz,

[1386]

[1387] 1H).

[1388] EXAMPLE 25A (1 S.4.5S)-4-r(6-chloro-5-fluoro-3-pyridinyl)methyll-2-(5-pyridin-4- ylpyrazin-2-yl)-2-azabicvclo[3.1.01hexan-3-one and 25B (1 / ?,4S,5 / ?)-4-K6-chloro-5-fluoro- 3-pyridinyl)methyll-2-(5-pyridin-4-ylpyrazin-2-yl)-2-azabicvclor3.1.0lhexan-3-one

[1389]

[1390] rac-(1F?,4S,5F?)-4-((6-Chloro-5-fluoropyridin-3-yl)methyl)-2-(5-(pyridin-4-yl)pyrazin-2-yl)-2- azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 97 (110.7 mg) was subjected to purification by chiral HPLC chromatography (Column: Chiralpak IH 20x250 mm, 5 μm; Flow 20 ml / min, T = 23 °C. Method: 100% MeCN) to afford the title compounds, Example 25B ((1F?,4S,5F?) isomer) (Peak 1, 20 mg, off-white solid) and Example 25A ((1S,4F?,5S) isomer) (Peak 2, 20 mg, off-white solid).

[1391] Example 25B ((1R,4S,5R) isomer) (Peak 1):1H NMR (400 MHz, DMSO) 59.52 (s, 1 H), 9.25 (s, 1H), 8.73 (d, J = 5.1 Hz, 2H), 8.30 (s, 1H), 8.15 - 8.05 (m, 2H), 8.02 (d, J = 9.7 Hz, 1H), 3.97 (t, J = 6.3 Hz, 1 H), 3.65 (dt, J = 11.6, 6.0 Hz, 1H), 3.15 (dd, J = 14.0, 5.1 Hz, 1H), 2.76 (dd, J = 13.9, 10.8 Hz, 1H), 1.64 (p, J = 7.2 Hz, 1H), 1.02 (q, J = 6.4 Hz, 1H), 0.72 (t, J = 5.9 Hz, 1H). LCMS (Method 5): [M+H]+m / z 396.2, RT 1.02 min.

[1392] Example 25A ((1S,4R,5S) isomer) (Peak 2):1H NMR (400 MHz, DMSO) 5 9.52 (s, 1H), 9.25 (s, 1 H), 8.73 (d, J = 5.1 Hz, 2H), 8.30 (s, 1 H), 8.11 - 8.06 (m, 2H), 8.02 (d, J = 9.7 Hz, 1 H), 4.02 - 3.91 (m, 1H), 3.65 (dt, J = 11.5, 6.0 Hz, 1H), 3.15 (dd, J = 14.0, 5.1 Hz, 1H), 2.76 (dd, J = 14.0, 10.9 Hz, 1H), 1.64 (p, J = 7.3 Hz, 1H), 1.10 - 0.94 (m, 1H), 0.78 - 0.64 (m, 1H). LCMS (Method 5): [M+H]+m / z 396.2, RT 1.02 min.

[1393] Chiral data: Method: Chiral analysis was performed by chiral HPLC (Column: Chiralpak IH; 4.6 x 150 mm, 3 pm; Method: 100% MeCN + 0.1% DEA; Column Temperature: 30 °C; Flow rate: 1.5 mL / min).

[1394] Example 25A ((1S,4 / ?,5S) isomer): RT 2.59 min.

[1395] Example 25B ((1 / ?,4S,5R) isomer): RT 2.30 min.

[1396] One of isomers A and B is (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-pyridin-4-ylpyrazin-2-yl)-2-azabicyclo[3.1.0]hexan-3-one and the other is (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-pyridin-4-ylpyrazin-2-yl)-2-azabicyclo[3.1.0]hexan-3-one.

[1397] EXAMPLE 26A (1 S,4 / ?,5S)-4-n6-chloro-5-fluoro-3-pyridinyl)methyll-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicvclo[3.1.0]hexan-3-one and 26B (1 / ?,4S,5 / ?)-4-K6-chloro-5-fluoro-3-pyridinyl)methyll-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1.01hexan-3-one:

[1398]

[1399] rac-(1 / ?,4S,5 / ?)-4-((6-Chloro-5-fluoropyridin-3-yl)methyl)-2-(3-fluoro-[2,4'-bipyridin]-5-yl)-2-azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 98 (108.6 mg) was subjected to purification by chiral HPLC chromatography (Column: Chiralpak IB 5pm 250x20 mm; T = 30 °C; pressure =100 bar, CO₂ Co-Solvent: MeOH 30%, Flow Rate 80 mL / min) to afford the title compounds, Example 26B ((1 / ?,4S,5R) isomer) (Peak 1, 22 mg, off-white solid) and Example 26A ((1S,4 / ?,5S) isomer) (Peak 2, 22 mg, off-white solid). Example 26B ((1R,4S,5R) isomer) (Peak 1):

[1400] 1H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.73 (d, J = 5.1 Hz, 2H), 8.29 (s, 1H), 8.25 (d, J = 13.5 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 5.0 Hz, 2H), 3.84 (t, J = 6.1 Hz, 1H), 3.59 (dt, J = 11.5, 6.2 Hz, 1 H), 3.12 (dd, J = 14.2, 5.0 Hz, 1 H), 2.78 - 2.65 (m, 1 H), 1.66 (q, J = 7.1 Hz, 1H), 1.04 (q, J = 6.5 Hz, 1H), 0.75 (s, 1H). LCMS (Method 5): [M+H]+m / z 413.2, RT 1.07 min.

[1401] Example 26A ((1S,4R,5S) isomer) (Peak 2):

[1402] 1H NMR (400 MHz, DMSO) δ 9.00 (d, J = 1.8 Hz, 1H), 8.73 (d, J = 4.9 Hz, 2H), 8.29 (s, 1H), 8.25 (dd, J = 13.6, 2.1 Hz, 1H), 8.01 (d, J = 9.7 Hz, 1H), 7.91 (d, J = 5.1 Hz, 2H), 3.84 (d, J = 6.2 Hz, 1H), 3.59 (dt, J = 11.3, 6.0 Hz, 1H), 3.12 (dd, J = 14.1, 5.1 Hz, 1H), 2.71 (dd, J = 14.2, 11.0 Hz, 1H), 1.66 (dt, J = 12.9, 6.5 Hz, 1H), 1.04 (q, J = 6.2 Hz, 1H), 0.75 (t, J = 5.6 Hz, 1H). LCMS (Method 5): [M+H]+m / z 413.2, RT 1.08 min.

[1403] Chiral data: Method: Chiral analysis was performed by chiral HPLC (Column: Chiralpak IB; 4.6 x 150 mm, 3 pm; Method: 100% MeOH + 0.1% DEA; Column Temperature: 30 °C; Flow rate: 1.5 mL / min).

[1404] Example 26A ((1S,4R,5S) isomer): RT 5.12 min.

[1405] Example 26B ((1R,4S,5R) isomer): RT 4.46 min.

[1406] One of isomers A and B is (1 S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one and the other is (1R,4S,5R)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one.

[1407] EXAMPLE 27: (1 R,4R,5S,6R)-4-r(6-chloro-3-pyridyl)methyll-6-(hvdroxymethyl)-2-r6-(4- in-3-.1? -3 -one

[1408] ifHOH

[1409]

[1410] 3-Bromo-6-(4-pyridinyl)pyridazine (45 mg, 0.19 mmol), (1R,4 / ?,5S,6R)-4-[(6-chloro-3-pyridyl)methyl]-6-(hydroxymethyl)-2 azabicyclo[3.1.0]hexan-3-one (prepared according to the procedure of Intermediate 105 (30 mg, 0.12 mmol), Pd2(dba)3(15 mg, 0.016 mmol), XantPhos (19 mg, 0.032 mmol) and K3PO4(78 mg, 0.36 mmol) were dissolved in 1,4-dioxane (2.5 mL) and the reaction mixture was heated to 70 °C for 4 hours. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with DCM, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient), and further purification by HPLC afforded the title compound (22 mg, 45%) as a white solid.1H NMR (400 MHz, DMSO) δ 8.73 - 8.67 (m, 2H), 8.49 (d, J = 9.4 Hz, 1 H), 8.41 - 8.32 (m, 2H), 8.08 - 8.02 (m, 2H), 7.87 (dd, J = 8.3, 2.5 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 1H), 4.69 (t, J = 5.4 Hz, 1H), 4.05 (dd, J = 7.4, 1.8 Hz, 1H), 3.56 (dt, J = 11.0, 5.3 Hz, 1H), 3.46 (ddd, J = 11.4, 7.1, 4.5 Hz, 1H), 3.29 (dd, J = 11.6, 6.0 Hz, 1H), 3.03 (dd, J = 13.7, 4.5 Hz, 1H), 2.65 (dd, J = 13.7, 11.1 Hz, 1H), 1.50 (td, J = 7.3, 4.5 Hz, 1H), 1.24 (q, J = 5.5 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 408.3, RT 0.79 min.

[1411] EXAMPLE 28A: (3 / ?,4 / ?)-3-((6-chloropyridin-3-yl)methyl)-4-(hvdroxymethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one

[1412]

[1413] To a solution of (3R,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 118 (237 mg, 0.460 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride in THF (1 M, 0.920 mL, 0.920 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 1 h, then was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% [3:1 EtOAc: EtOH] / isohexane) to afford the title compound as a white solid (150 mg, 81%).

[1414] 1H NMR (500 MHz, DMSO-d6) δ 8.79 - 8.74 (m, 2H), 8.69 (d, J = 9.5 Hz, 1 H), 8.41 (d, J = 9.5 Hz, 1 H), 8.35 (d, J = 2.5 Hz, 1 H), 8.12 - 8.07 (m, 2H), 7.81 (dd, J = 8.3, 2.5 Hz, 1 H), 7.47 (d, J = 8.2 Hz, 1H), 4.89 (t, J = 5.2 Hz, 1H), 4.20 (dd, J = 11.1, 8.4 Hz, 1H), 3.84 (dd, J = 11.1, 7.3 Hz, 1 H), 3.44 (dt, J = 10.1, 4.9 Hz, 1 H), 3.38 (dt, J = 11.1, 5.9 Hz, 1 H), 3.15 - 3.08 (m, 1 H), 3.03 - 2.96 (m, 2H), 2.30 (dt, J = 13.9, 7.0 Hz, 1H). LCMS (Method 5): [M+H]+m / z 396.3, RT 0.71 min.

[1415] Chiral SFC analysis (column: Phenomenex C3 column, 4.6 x 250mm, 5pm, Method: 35% MeOH (0.1% NH₃), 65% CO₂ over 4.5 min, flow rate: 4 mL / min): RT 3.05 min. EXAMPLE 28B (3S.4S)-3-((6-chloropyridin-3-yl)methyl)-4-(hvdroxymethyl)-1 -(6-(pyridin- 4-yl)pyridazin-3-yl)pyrrolidin-2-one

[1416]

[1417] To a solution of (3S,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-((6-chloropyridin-3-yl)methyl)- 5 1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 117 (146 mg, 0.284 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride in THF (1 M, 0.569 mL, 0.569 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-100% [3:1 EtOAc: EtOH] / isohexane) to afford the title 0 compound as a white solid (86 mg, 73%).1H NMR (500 MHz, DMSO-d6) δ 8.78 - 8.73 (m, 2H), 8.70 (d, J = 9.5 Hz, 1 H), 8.46 - 8.32 (m, 2H), 8.15 - 8.03 (m, 2H), 7.81 (dd, J = 8.3, 2.5 Hz, 1 H), 7.47 (d, J = 8.2 Hz, 1 H), 4.89 (s, 1 H), 4.20 (dd, J = 11.1, 8.3 Hz, 1 H), 3.84 (dd, J = 11.1, 7.3 Hz, 1H), 3.46 - 3.35 (m, 2H), 3.15 - 3.08 (m, 1H), 3.05 - 2.94 (m, 2H), 2.31 (q, J = 6.7 Hz, 1H). LCMS (Method 5): [M+H]+m / z 396.3, RT 0.71 min. Chiral SFC analysis (column: Phenomenex 5 C3 column, 4.6 x 250mm, 5pm, Method: 35% MeOH (0.1% NH₃), 65% CO₂ over 4.5 min, flow rate: 4 mL / min): RT 2.20 min.

[1418] Examples 29 and 30:

[1419] 0 The following Examples were made according to General Method B as outlined above.

[1420] Table 4: Preparation methods and characterisation data of Examples 29 and 30

[1421] Halo- LCMS

[1422] Ex. Heteroarene General [M+H]+

[1423] Name and Structure1H NMR No. Method LCMS

[1424] Lactam

[1425] RT (min)

[1426] 29 (1S,4R,5S)-4-((6- δH (500 MHz, DMSO-d6) = Int. 119 8.61 (s, 1H), 8.57 (d, J = 5.0 chloropyridin-3-yl)methyl)- B 392.30 Hz, 1H), 8.53 (d, J = 9.3 Hz, 2-(6-(3-methylpyridin-4- 1H), 8.41 (d, J = 2.6 Hz, 1H),

[1427]

[1428] 8.03 (d, J = 9.3 Hz, 1H), 7.89 yl)pyridazin-3-yl)-2- (dd, J = 8.2, 2.5 Hz, 1H), 7.52

[1429] (s, 1H), 7.50 (d, J = 2.0 Hz, azabicyclo[3.1,0]hexan-3- 1H), 4.20 -4.11 (m, 1H), 3.65 one - 3.56 (m, 1H), 3.11 (dd, J =

[1430] 13.9, 5.0 Hz, 1H), 2.71 (dd, J = Int. 13

[1431] 0.87 13.9, 10.9 Hz, 1H), 2.38 (s, 3H), 1.60 (dd, J = 8.0, 5.1 Hz, 1H), 1.06 (dt, J = 8.5, 5.8 Hz, 1H), 0.73 (t, J = 4.9 Hz, 1H). N— \

[1432] C

[1433] lnt.120 (1 S,4R,5S)-4-((6- δH (500 MHz, DMSO-d6) =

[1434] 392.30 9.52 (d, J = 1.5 Hz, 1H), 8.81 chloropyridin-3-yl)methyl)- (d, J = 1.5 Hz, 1H), 8.58 (s, 2-(5-(3-methylpyridin-4- 1H), 8.54 (d, J = 4.9 Hz, 1H),

[1435] 8.41 (d, J = 2.4 Hz, 1H), 7.88 yl)pyrazin-2-yl)-2- (dd, J = 8.3, 2.5 Hz, 1H), 7.54 azabicyclo[3.1,0]hexan-3- (d, J = 5.0 Hz, 1H), 7.51 (d, J =

[1436] 8.2 Hz, 1H), 3.96 (ddd, J = 7.4, one B

[1437] Int. 13 5.3, 2.2 Hz, 1H), 3.60 (ddd, J =

[1438] 0.93 11.5, 7.1, 4.9 Hz, 1H), 3.11 (dd, J = 14.0, 4.9 Hz, 1H), 2.71 (dd, J = 13.9, 10.9 Hz, 1H), 2.40 (s, 3H), 1.64- 1.54 (m, 1H), 1.01 (dt, J = 8.5, 5.8 Hz, ' "b

[1439] N=\ 1H), 0.71 (td, J = 5.7, 2.2 Hz, C 1H).

[1440]

[1441] EXAMPLE 31 A (3 / ?,4 / ?)-4-Amino-3-r(6-chloro-3-pyridyl)methyll-1-r6-(4-pyridyl)pyridazin- 3-yllpyrrolidin-2-one and EXAMPLE 31 B: (3S,4 / ?)-4-amino-3-K6-chloro-3-pyridyl)methyll- 1-r6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one

[1442]

[1443] NH2NH2

[1444] To a solution of tert-butyl N-[(3F?)-4-[(6-chloro-3-pyridyl)methyl]-5-oxo-1-[6-(4-pyridyl)pyridazin- 3-yl]pyrrolidin-3-yl]carbamate (prepared according to the procedure of Intermediate 125) (80 mg, 0.14 mmol) in DCM (2 mL) was added TFA (250 pL, 3.27 mmol) and the reaction mixture was stirred at r.t. for 48 h, and then concentrated in vacuo (toluene used to remove TFA) to afford the product as a brown oil. This crude material was then subjected to chiral purification using a XSelect CSH Prep Fluoro-Phenyl 5 μm OBD, 19x100 mm, flow rate 20 mL / min, column temperature 23 °C, eluting with a 15-30% 'solvent B' gradient (Solvent A - 10 mM ammonium bicarbonate in water + 0.1% ammonia solution; Solvent B - acetonitrile + 0.1% ammonia solution), over 15 minutes on a Waters FractionLynx Autopurification system in tandem with a 3100 mass spectromer to afford Example 31 B ((3S,4 / ?) isomer) (peak 1, 1 mg, 7%, white solid) and Example 31 A ((3 / ?, 4 / ?) isomer) (peak 2, 5 mg, 33%, white solid).

[1445] EXAMPLE 31 B ((3S, 4 / ?) isomer):1H NMR (400 MHz, MeOD) δ 8.77 (d, J= 9.4 Hz, 1H), 8.65 -8.58 (m, 2H), 8.33 (d, J = 2.5 Hz, 1 H), 8.19 (d, J = 9.5 Hz, 1 H), 8.05 - 7.99 (m, 2H), 7.81 (dd, J = 8.3, 2.5 Hz, 1H), 7.33 (dd, J= 8.2, 0.7 Hz, 1H), 4.12 (d, J= 3.0 Hz, 2H), 3.74 - 3.68 (m, 1H), 3.19 - 3.03 (m, 2H), 2.97 -2.86 (m, 1H). LCMS (Method 5): [M+H]+m / z 381.0, RT 0.41 min.

[1446] EXAMPLE 31 A ((3R, 4R) isomer): 1H NMR (400 MHz, MeOD) δ 8.71 (d, J = 9.5 Hz, 1H), 8.64 - 8.57 (m, 2H), 8.30 - 8.25 (m, 1H), 8.17 (d, J = 9.5 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.75 (dd, J = 8.3, 2.5 Hz, 1H), 7.31 (dd, J = 8.2, 0.7 Hz, 1H), 4.32 (dd, J = 11.2, 7.2 Hz, 1H), 3.69 (dd, J = 11.2, 6.7 Hz, 1H), 3.35 (q, J = 7.2 Hz, 1H), 3.13 - 2.98 (m, 2H), 2.79 (dt, J = 7.7, 6.2 Hz, 1H). LCMS (Method 5): [M+H]+m / z 381.2, RT 0.41 min.

[1447] LCMS (Method 5): [M+H]+ m / z 381.2, RT 0.41 min. Chiral HPLC analysis (Column: Regis ( / ?, / ?)-Whelk-0 1, 150 x 4.6 mm, 5 pM; Method: MeOH + 0.1% NH4OH (3–40%) over 12 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min):

[1448] EXAMPLE 31A ((3R,4R) isomer): 99% e.e. (RT 9.11 min).

[1449] EXAMPLE 31 B ((3S, 4 / ?) isomer): 95% e.e. (RT 8.23 min);

[1450] One of isomers A and B is (3 / ?,4 / ?)-4-amino-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one and the other is (3S,4 / ?)-4-amino-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one.

[1451] EXAMPLE 32 A & B (3 / ,4 / ?) and (3S.4S) isomers of 3-((6-chloropyridin-3-yl)methyl)-4- (difluoromethvD-1 -(6-(Pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one

[1452]

[1453] Rac-(3 / ?,4 / ?)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 129 (18 mg) was subjected to chiral purification by SFC (Column: Chiralpak IH, 10 x 250mm, 5pm; Method: 45% MeOH, 55% CO2; Column Temperature: 40 °C; Flow rate: 15 mL / min) to afford Example 32B, enantiomer 1 ((3S,4S) isomer) (Peak 1, 6 mg, white solid) and Example 32A, enantiomer 2 ((3 / ?,4R) isomer) (Peak 2, 6 mg, white solid).

[1454] Example 32B: Enantiomer 1 (peak 1) ((3S,4S) isomer):

[1455] 1H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.74 (m, 2H), 8.69 (d, J = 9.5 Hz, 1 H), 8.44 (d, J = 9.5 Hz, 1H), 8.38 - 8.31 (m, 1 H), 8.15 - 8.05 (m, 2H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.48 (dd, J = 8.2, 0.7 Hz, 1H), 6.40-6.12 (m, 1H), 4.27 (dd, J = 11.5, 9.0 Hz, 1H), 4.06 (dd, J = 11.6, 6.2 Hz, 1H), 3.30 - 3.25 (m, 1H), 3.18 - 3.03 (m, 2H), 2.88-2.74 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ19F NMR (376 MHz, DMSO) δ -121.33 (d, J = 282 Hz), -122.20 (d, J = 282 Hz). LCMS (Method 5): [M+H]+m / z 416.3, RT 1.00 min. Chiral SFC analysis (column: Chiralpak IH column, 4.6x250 mm, 5 μm, Method: 45% MeOH (0.4% NH3), 55% CO2over 5 min, flow rate: 4 mL / min): RT 2.41 min.

[1456] Example 32A: Enantiomer 2 (peak 2) ((3 / ?,4R) isomer)

[1457] 1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.73 (m, 2H), 8.69 (d, J = 9.5 Hz, 1 H), 8.44 (d, J = 9.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1 H), 8.15 - 8.04 (m, 2H), 7.81 (dd, J = 8.2, 2.5 Hz, 1H), 7.48 (dd, J = 8.2, 0.7 Hz, 1H), 6.26 (td, J = 56.0, 4.5 Hz, 1H), 4.27 (dd, J = 11.5, 8.9 Hz, 1H), 4.06 (dd, J = 11.5, 6.2 Hz, 1H), 3.28 - 3.23 (m, 1H), 3.18 - 3.03 (m, 2H), 2.88 - 2.72 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -121.33 (d, J = 282Hz), -122.20 (d, J = 282 Hz).

[1458] LCMS (Method 5): [M+H]+m / z 416.3, RT 1.01 min. Chiral SFC analysis (column: Chiralpak IH column, 4.6 x 250 mm, 5 μm, Method: 45% MeOH (0.4% NH3), 55% CO2over 5 min, flow rate: 4 mL / min): RT 3.20 min.

[1459] One of isomers A and B is (3R,4R)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one and the other is (3S,4S)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one.

[1460] The following Example was made according to either General Method B or General Method C as outlined above.

[1461] Table 5: Preparation methods and characterisation data of Example 33 Halo- LCMS [M+H] H+1H NMR Ex. eteroarene Name and Structure General

[1462] Method

[1463] Lactam LCMS RT

[1464] (min)

[1465] (500 MHz, DMSO) δH8.61 (s, 1H), 8.57 (d, J Int. 119 (1S,4R,5S)-4-((6- = 5.0 Hz, 1H), 8.54 (d,

[1466] 376.4 J = 9.3 Hz, 1H), 8.22 fluoropyridin-3-yl)methyl)-2- (d, J = 2.5 Hz, 1H), (6-(3-methylpyridin-4- 8.04 - 7.99 (m, 2H),

[1467] 7.51 (d, J = 5.0 Hz, yl)pyridazin-3-yl)-2- 1H), 7.18 (dd, J = 8.4, azabicyclo[3.1,0]hexan-3- 2.8 Hz, 1H), 4.16 (ddd, 33 one J = 7.4, 5.5, 2.2 Hz,

[1468] B

[1469] 1H), 3.59 (ddd, J = N 11.5, 7.1, 4.9 Hz, 1H), Int. 23lLArN" N 0 3.12 (dd, J= 14.0, 4.9

[1470] 0.85 Hz, 1H), 2.71 (dd, J =

[1471] 13.9, 11.0 Hz, 1H), ■p h 2.38 (s, 3H), 1.64 - N=\

[1472] F 1.55 (m, 1H), 1.06 (dt,

[1473] J = 8.5, 5.8 Hz, 1H), 0.73 (td, J= 5.6, 2.2

[1474]

[1475] Hz, 1H).

[1476] EXAMPLE 34A: (3R,5S)-3-[(6-chloro-3-pyridyl)rnethyl1-5-(hvdroxymethyl)-1-[5-(4- Pyridyl)pyrazin-2-yl1pyrrolidin-2-one

[1477]

[1478] To a screw-cap vial containing 2-bromo-5-(4-pyridyl)pyrazine (prepared according to the procedure of Intermediate 24) (50 mg, 0.21 mmol) and (3R,5S)-3-[(6-chloro-3-pyridyl)methyl]- 5-(hydroxymethyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 109) (61 mg, 0.25 mmol) in MeCN (0.5 mL) were added K2CO3 (59 mg, 0.43 mmol), N, N- dimethylethylenediamine (3.9 mg, 0.042 mmol) and cuprous iodide (4 mg, 0.021 mmol) sequentially. The mixture was sparged with N2 for 5 min and heated to 85 °C. After 1 h, the reaction mixture was cooled to r.t. and then filtered through celite. The filtrate was concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / iso-hexane (0- 100% gradient) then MeOH / DCM (0-10% gradient), and further purification by HPLC afforded the title compound as a white solid (12 mg, 14%).1H NMR (400 MHz, DMSO) δ 9.72 (d, J = 1.5 Hz, 1H), 9.21 (d, J = 1.5 Hz, 1H), 8.76 - 8.70 (m, 2H), 8.36 (d, J = 2.4 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.82 (dd, J = 8.2, 2.6 Hz, 1H), 7.49 (dd, J = 8.2, 0.7 Hz, 1H), 4.96 (t, J = 5.7 Hz, 1H), 4.62 (dd, J = 8.7, 4.6 Hz, 1H), 3.72 (dt, J = 10.8, 5.3 Hz, 1H), 3.58 (ddd, J = 11.2, 5.9, 2.6 Hz, 1H), 3.30 (s, 1H), 3.24 - 3.15 (m, 1H), 2.73 (dd, J = 13.9, 9.6 Hz, 1H), 2.18 - 2.07 (m, 1H), 2.07 -1.95 (m, 1 H). LCMS (Method 5): [M+H]+ m / z 396.1, RT 0.80 min.

[1479] EXAMPLE 34B: (3 / ?,5 / ?)-3-f(6-chloro-3-i i-1-F5-(4- idin-2-one

[1480] 2—ci

[1481]

[1482] N

[1483] To a screw-cap vial containing 2-bromo-5-(4-pyridyl)pyrazine (prepared according to the procedure of Intermediate 24) (54 mg, 0.23 mmol) and (3R,5R)-3-[(6-chloro-3-pyridyl)methyl]-5-(hydroxymethyl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 107 ) (66 mg, 0.27 mmol) in MeCN (1 mL) were added K2CO3 (63 mg, 0.46 mmol), N, N-dimethylethylenediamine (4.2 mg, 0.045 mmol) and cuprous iodide (4.4 mg, 0.023 mmol) sequentially. The mixture was sparged with N2 for 5 min and heated to 85 °C. After 2 h, the reaction mixture was cooled to r.t. and then purified by normal phase flash chromatography, eluting with EtOAc / iso-hexane (0-100% gradient) then MeOH / DCM (0-10% gradient). Further purification by HPLC afforded afford the title compound as a white solid (8 mg, 9%).1H NMR (400 MHz, DMSO) δ 9.48 (d, J = 1.5 Hz, 1 H), 9.23 (d, J = 1.5 Hz, 1 H), 8.77 - 8.71 (m, 2H), 8.38 (d, J = 2.4 Hz, 1 H), 8.13 - 8.07 (m, 2H), 7.84 (dd, J = 8.2, 2.6 Hz, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 4.57 (s, 1H), 3.79 (dd, J = 11.5, 4.1 Hz, 1H), 3.51 (d, J = 11.0 Hz, 1H), 3.22 (dd, J = 13.8, 4.9 Hz, 1H), 3.12 (dd, J = 8.3, 5.0 Hz, 1H), 2.90 (dd, J = 13.7, 9.8 Hz, 1H), 2.26 (dt, J = 12.7, 8.8 Hz, 1 H), 1.88 - 1.77 (m, 1 H). LCMS (Method 5): [M+H]+ m / z 396.2, RT 0.73 min.

[1484] EXAMPLE 35Aand 35B (3 / ?,5 / ?)-3-((6-chloropvridin-3-vl)methvl)-5-methvl-1-(6-(pvridin-4-vl)Pvridazin-3-vl)Pvrrolidin-2-one and (3S,5S)-3-((6-chloropvridin-3-vl)methvl)-5-methvl-1-(6-(pvridin-4-vl)Pvridazin-3-vl)Pvrrolidin-2-one

[1485]

[1486] / ?ac-(3 / ?,5 / ?)-3-((6-chloropyridin-3-yl)methyl)-5-methyl-1 -(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one (prepared according to the procedure of Intermediate 96) (18 mg, 0.05 mmol) was subjected to chiral purification by SFC (Column: Phenomenex C3, 20 x 250mm, 5 μm; Method: 30% MeOH, 70% CO2; Column Temperature: 30 °C; Flow rate: 65 mL / min) to afford the title compound Example 35B (3S,5S isomer) (7.5 mg, 41%) and Example 35A (3R,5R isomer) (8.0 mg, 44%) as off-white solids.

[1487] Example 35A (3R,5R isomer):

[1488] 1 H NMR (500 MHz, DMSO) δ 8.78 - 8.75 (m, 2H), 8.72 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.82 (dd, J = 8.2, 2.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 4.94 - 4.88 (m, 1H), 3.39 (s, 1H), 3.19 (dd, J = 14.0, 5.0 Hz, 1H), 2.77 (dd, J = 14.0, 9.2 Hz, 1 H), 2.12 - 2.02 (m, 1 H), 1.86 (dd, J = 12.3, 8.3 Hz, 1 H), 1.36 (d, J = 6.4 Hz, 3H). LCMS (Method 3B): [M+H]+m / z 380.0 / 382.0 RT 1.11 minutes.

[1489] Example 35B (3S,5S isomer):

[1490] 1 H NMR (500 MHz, DMSO) δ 8.78 - 8.75 (m, 2H), 8.72 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.82 (dd, J = 8.2, 2.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 4.94 - 4.88 (m, 1H), 3.39 (s, 1H), 3.19 (dd, J = 14.0, 5.0 Hz, 1H), 2.77 (dd, J = 14.0, 9.2 Hz, 1 H), 2.12 - 2.02 (m, 1 H), 1.86 (dd, J = 12.3, 8.3 Hz, 1 H), 1.36 (d, J = 6.4 Hz, 3H). LCMS (Method 3B): [M+H]+m / z 380.0 / 382.0 RT 1.12 minutes.

[1491] Chiral data: Method: Chiral analysis was performed by SFC (Waters UPC2, with a PDA and a QDA detector) using a Phenomenex C3 column, 4.6 x 250mm, 5pm, with mobile phase 30% MeOH (0.1% NH3), 70% CO2. The flow rate was 4 mL / min. The run time was 3.5 mins.

[1492] Example 35A (3R,5R isomer): RT 2.40 min.

[1493] Example 35B (3S,5S isomer): RT 1.74 min.

[1494] The following Example compounds (Examples 36 to 47) were prepared using Method(s) and / or Intermediate(s) analogous to those described above.

[1495] Table 6 Example No. Name Structure (3 / ?,4 / ?)-3-[(6-fluoro-3- pyridinyl)methyl]-4- XZH\=N (hydroxymethyl)-l - (6- py rid i n-4- ylpyridazin-3-yl)pyrrolidin-2-one

[1496] (3 / ?,4 / ?)-3-[(6-chloro-2-fluoro-3- pyridinyl)methyl]-4- (hydroxymethyl)-l - (6- py rid i n-4- ylpyridazin-3-yl)pyrrolidin-2-one

[1497] (1S,4 / ?,5S)-4-[(6-fluoro-3- pyridinyl)methyl]-2-(3-pyridin-4-yl- M

[1498] 77 — < 1,2,4-triazin-6-yl)-2- °Z / CL azabicyclo[3.1,0]hexan-3-one

[1499] (3 / ?,4 / ?)-3-[(6-chloro-3- pyridinyl)methyl]-4- (hydroxymethyl)-1-(3-pyridin-4-yl- 1,2,4-triazin-6-yl)pyrrolidin-2-one

[1500] (3 / ?,4 / ?)-3-[(6-chloro-3- pyridinyl)methyl]-4- (hydroxymethyl)-l - (5- py rid i n-4- N ylpyrazin-2-yl)pyrrolidin-2-one

[1501] 1 (3 / ?,5S)-3-[(6-chloro-3- pyridinyl)methyl]-5- p (hydroxymethyl)-l - (6- py rid i n-4- ' — ' N— N ylpyridazin-3-yl)pyrrolidin-2-one

[1502] (3 / ?,4 / ?)-3-[(6-chloro-3- pyridinyl)methyl]-4- (hydroxymethyl)-1-[6-(3-methyl-4- pyridinyl)pyridazin-3-yl]pyrrolidin- 2-one

[1503]

[1504] 43 (3S,4S)-3-[(4- chlorophenyl)methyl]-4- y (hydroxymethyl)-l - (6- py rid i n-4- y —— y

[1505] ylpyridazin-3-yl)pyrrolidin-2-one

[1506] 44 (3R,4R)-3-[(4- chlorophenyl)methyl]-4- y (hydroxymethyl)-l - (6- py rid i n-4- y —

[1507] ylpyridazin-3-yl)pyrrolidin-2-one

[1508] 45 (1S,4R,5R)-4-[(6-chloro-3- pyridinyl)methyl]-5- oyyy. \ (hydroxymethyl)-2-(6-pyridin-4- ylpyridazin-3-yl)-2- o azabicyclo[3.1,0]hexan-3-one

[1509] 46 (3S,4S)-3-[(6-chloro-5-fluoro-3- pyridinyl)methyl]-4- (hydroxymethyl)-l - (6- py rid i n-4- ylpyridazin-3-yl)pyrrolidin-2-one

[1510] 47 (3R,4R)-3-[(6-chloro-5-fluoro-3- pyridinyl)methyl]-4- (hydroxymethyl)-l - (6- py rid i n-4- O

[1511] n —N

[1512] ylpyridazin-3-yl)pyrrolidin-2-one

[1513]

[1514] IV. Biological assays

[1515] A) Inhibition of SARM1 ENAD assay

[1516] The inhibition by compounds of formula (I) on SARM1 can be tested with the ENAD (etheno-NAD+assay) which measures NAD+ hydrolase activity using an NAD+ analogue to produce a fluorescent product that is measured in real time.

[1517] The efficacy of the compounds according to the Example to inhibit SARM1 is represented by measuring the ICso which corresponds to the concentration of compound necessary to inhibit 50% of NAD+hydrolase activity. pICso values correspond to -log of the ICso in Molar. The lower the value of the ICso (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.

[1518] His-TEV-HA-Avi-humanSARM I28-724 was expressed in HEK293T cells and purified by single Ni+ affinity chromatography. Protein was eluted (200mM imidazole max) and dialysed into storage buffer (20mM Na-Phosphate buffer pH 7.5-8.0; 100mM NaCI; 1mM TCEP; 5% glycerol. Aliquot concentrations were above 1mg / ml. Superose 6 SEC showed construct eluted at approx. 640 kDa.

[1519] Stocks for SARMI activator (NMN, Sigma N3501-25mg, 50mM) and substrate (Etheno NAD+, TRC N407735, 50mM) were prepared in filter sterilized (Corning 431118) assay buffer (20mM Na-phosphate, pH7.5; 50mM NaCI; 0.001% lgepalCA-630, all Sigma with MQ H20 Lonza) and stored at -80°C. Assay is prepared in 384-well proxy plates (PE, 6008260).

[1520] 10pl of 2X SARM1 (200nM) is dispensed via Certus device followed by 0,2pl of 100X compound (100% DMSO, concentration range for 10-point CRC determination) with Mosquito device. Plate was covered, centrifuged (1’ RT, 1000 rpm) and incubated at rt for 30min with 150rpm agitation. 5pl 4XNMN(1.2mM) was dispensed with Certus device, plate CF and incubated for 30min as before. 5pl 4XENAD (0.48mM) was dispensed with Certus device, plate CF and incubated for 90min as before. Results were read on an Envision device with EX and EM filters 320 / 14nm and 400 / 25 respectively as well as a D385 single mirror.

[1521] Compound preparation was done in a 384 well format (Greiner, 784201 or 781280), with columns dedicated to maximal and minimal inhibition controls and rows set aside for reference compound concentration response curves (CRC), recurring in each assay plate for standardization. Each CRC was prepared in duplicate. A tool compound for maximal inhibition and a DMSO control for minimal inhibition were prepared in dedicated columns.

[1522] When tested, the majority of example compounds 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 7.0. When tested, compounds according to Examples 1, 2A, 3A, 4A, 5A, 6A, 6B, 6C, 6D, 7A, 8A, 9A, 10A, 11 A, 12A, 12B, 13-24, 25A, 26A, 26B, 27, 28A, 28B, 29, 30, 31 A, 32A, 33, 34A, 34B, 35A, 36-47 display values of pICso greater than or equal to about 6.0.

[1523] Table 7 exhibits the ranges of pICso of the compounds of formula (I) according to the present invention when tested in the Inhibition of ENAD assay outlined above.

[1524] Category A: about 6.0 > plC50 < about 6.50; Category B: about 6.50 < plC50 about 7.00;

[1525] Category C: plC50 > about 7.00.

[1526] N. T: not tested.

[1527] Table 7:

[1528] SARM1 ENAD SARM1 ENAD

[1529] Example

[1530] Example No. Assay Assay

[1531] No.

[1532] 1 B 24 A

[1533] 2A C 25A C

[1534] 3A C 26A C

[1535] 4A B 26B A

[1536] 5A B 27 B

[1537] 6A C 28A B

[1538] 6B B 28B A

[1539] 6C B 29 C

[1540] 6D A 30 B

[1541] 7A C 31A B

[1542] 8A B 32A B

[1543] 9A B 33 B

[1544] 10A B 34A B

[1545] 11A C 34 B A

[1546] 12A C 35A B

[1547] 12B B 36 A

[1548] 13 C 37 B

[1549] 14 C 38 B

[1550] 15 B 39 B

[1551] 16 B 40 C

[1552] 17 C 41 A

[1553] 18 C 42 A

[1554] 19 B 43 C

[1555] 20 C 44 C

[1556] 21 A 45 A

[1557] 22 C 46 A

[1558]

[1559] 23 C 47 B

[1560] As shown in this Table 7, compounds of formula (I) according to the present invention are potent inhibitors of SARM1 activity.

[1561] B) Inhibition of SARM1 CZ-48 assay

[1562] 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.

[1563] The efficacy of the compounds, according to the Examples, to inhibit SARM1 is represented by measuring the ECso 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% ofSARMI inhibition in a cellular context. plC50 values correspond to -log of the ICso in Molar. The lower the value of the ICso (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.

[1564] 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.

[1565] 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.

[1566] 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.

[1567] 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. When tested, the majority of example compounds of formula (I) according to the present invention, display values of pICso greater than or equal to 5.0, suitably greater than or equal to 5.5, suitably greater than or equal to 6.0, preferably greater than or equal to 6.5. When tested compounds according to Examples 1, 2A, 3A, 4A, 5A, 6A, 6B, 6C, 6D, 7A, 8A, 9A, 10A, 11 A, 12A, 12B, 13-24, 25A, 26A, 27, 28A, 28B, 29, 30, 31A, 32A, 33, 34A and 35A, display values of pICso greater than or equal to about 5.1.

[1568] Table 8 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.

[1569] Category A: about 5.00 > pICso < about 5.50;

[1570] Category B: about 5.50 < pICso < about 6.00;

[1571] Category C: about 6.00 < pICso < about 6.50;

[1572] Category D: pICso > about 6.50.

[1573] N. T: not tested.

[1574] Table 8:

[1575] Example SARM1 CZ- Example SARM1 CZ- No. 48 Assay No. 48 Assay

[1576] 1 C 20 D

[1577] 2A D 21 A

[1578] 2B NT 22 D

[1579] 3A C 23 D

[1580] 3B NT 24 A

[1581] 4A C 25A C

[1582] 4B NT 26A C

[1583] 5A B 27 C

[1584] 5B NT 28A B

[1585] 6A D 28B D

[1586] 6B C 29 C

[1587] 6C B 30 C

[1588] 6D B 31A B

[1589] 7A D 32A B

[1590] 7B NT 32B NT

[1591] 8A C 33 B

[1592] 8B NT 34A A

[1593] 9A C 34B A

[1594] 9B NT 35A A

[1595] 10A C 36 B

[1596] 10B NT 37 D

[1597] 11 A D 38 C

[1598] 11 B NT 39 D

[1599]

[1600] 12A D 40 D Example SARM1 CZ- Example SARM1 CZ- No. 48 Assay No. 48 Assay

[1601] 12B A 41 A

[1602] 13 D 42 C

[1603] 14 D 43 C

[1604] 15 C 44 D

[1605] 16 B 45 C

[1606] 17 D 46 A

[1607] 18 C 47 C

[1608]

[1609] 19 C

[1610] NT - Not tested

[1611] As shown in this Table 8, compounds of formula (I) according to the present invention are potent inhibitors of SARM1 activity.

[1612] C) Cytochrome P450 Inhibition (ICso Shift) Assay

[1613] Protocol Summary

[1614] The purpose of this assay is to assess the inhibitory potential of the test compound for cytochrome P450 isoforms, using isoform-specific probe substrates. Test compound (typically 6 concentrations ranging from 0.1 - 25 M) or vehicle is pre-incubated with human liver microsomes (HLM) under three different experimental conditions; for 0 minutes (to assess reversible inhibition), and for 30 minutes in the presence and absence of NADPH (to assess time-dependant inhibition), before incubation with a probe substrate. Currently, 6 substrates (phenacetin, diclofenac, S-Mephenytoin, Dextromethorphan, Midazolam and Testosterone) are used.

[1615] Reagents & Materials

[1616] 0.1 M Phosphate Buffer pH 7.4 at 37°C.

[1617] Pooled Human Liver Microsomes (HLM) prepared in above buffer at 400x incubation protein concentration.

[1618] Cofactor: NADPH -100 mM solution prepared in buffer immediately prior to pre-incubation and stored on ice until use; incubation concentration is 1 or2mM, for - or+ NADPH pre-incubation samples, respectively.

[1619] Compound Preparation The highest concentration is achieved via a direct spike (1 pL) of a 10 mM DMSO stock into the incubation (final volume 400 pL). Incubation concentration is 25pM in 0.1 M Phosphate Buffer: DMSO (99.75:0.25%, v / v). Other concentrations (10, 2.5, 1, 0.25 and 0.1 pM) are achieved in the same way, following serial dilution of the 10 mM stock in DMSO.

[1620] Probe substrates are prepared as detailed in the table below, with a direct spike (1 pL) of a stock at 405x the final incubation concentration. Final solvent concentration during the incubation is also listed in the table below.

[1621] CYP Probe [DMSO [DMSO: Buffer Final [Final Stock] Stock] (mM (% [Incubation] Solvent] (%) 1A2 Phenacetin 60 7.29 (12.15%) 18 0.28 2B6 Bupropion 60.75 N / A 150 0.5 2C8 Amodiaquine 0.81 N / A 2 0.5 2C9 Diclofenac 20 2.835 (14.18%) 7 0.29 2C19 S-Mephenytoin 50 20.25 (40.5%) 50 0.35 2D6 Dextromethorphan 20 0.81 (4.05%) 2 0.26 3A4 Midazolam 25 1.0125 (4.05%) 2.5 0.26 3A4 Testosterone 20.25 N / A 50 0.5

[1622]

[1623] Experimental Procedure

[1624] Test compound (1 pL) and human liver microsomes (395 pL) are either pre-incubated for 30 minutes in the absence and presence of NADPH (4 pl of buffer or NADPH, respectively) or undergo a 0 min pre-incubation (4 pl of buffer). Then probe substrate (1 pL) and NADPH (4 pL) are added to all conditions (in a total incubation volume of 405 pL) and incubated for 5 or 15 (2C19 only) minutes, with formation of metabolites monitored. Time dependent inhibitors are included as a positive control.

[1625] CYP Probe / Metabolite [HLM] Positive Control concentration Inhibitor mg / ml (highest 1A2 Phenacetin (18 pM) / acetaminophen 0.1 Furafylline (25 pM) 2B6 Bupropion (150 pM) / hydroxybupropion 0.1 ThioTEPA (150 pM)

[1626]

[1627] 2C8 Amodiaquine (2 pM) / N- 0.05 Gemfibrozil 1-O-p- desethylamodiaquine glucuronide (100 pM) 2C9 Diclofenac (7 pM) / 4-hydroxydiclofenac 0.5 Tienilic acid (10 pM) 2C19 S-Mephenytoin (50 pM) / 0.5 Fluoxetine (100 pM) 2D6 Dextromethorphan (2 pM) / dextrorphan 0.1 Paroxetine (1 pM) 3A4 Midazolam (2.5 pM) / 1 -hydroxymidazolam 0.1 Verapamil (25 pM) 3A4 Testosterone (50 pM) / 0.1 Verapamil (25 pM)

[1628]

[1629] Sample Analysis

[1630] An aliquot of 50 pL for each condition is transferred to a 96-well plate, and reactions are terminated by addition of ice-cold methanol (100 pL) containing a cocktail of deuterated internal standards. The termination plates are centrifuged at 2500 rpm for 30 minutes at 4 °C and supernatant (40 pL) is transferred to fresh 96-well plates. Formic acid in deionised water (60 pL) (final concentration 0.1 %) is added prior to analysis by LC-MS / MS using generic methods.

[1631] Data Analysis

[1632] A decrease in the formation of the metabolite compared to vehicle control is used to calculate an ICso value (test compound concentration which produces 50 % inhibition) for each experimental condition, via a simple Inhibitory model in an available software package as follows:

[1633] / C \

[1634] E ^max I 1 T: i cr )

[1635]

[1636] \ C + CC50 /

[1637] Where E is effect and C is the test compound concentration. The ECso value is dependent only on the inhibition effect of the test compound and is the value to calculate (commonly referred to as ICso).

[1638] Three ICso values are determined; with 0 minute pre-incubation (for reversible inhibition), and 30 minutes in presence and absence of NADPH (to assess time-dependant inhibition).

[1639] The fold shift in ICso is calculated using the following equation:

[1640] ICnfrom 30 minute pre — incubation without NADPH

[1641] Fold Shift ~r

[1642] IC50from 30 minute pre — incubation with NADPH

[1643] Typically, the lower the ICso value of the test compound fora CYP enzyme, the higher is the potential for inhibition. Table 9:

[1644] Example No. CYP Inh. 3A4 / 3A4T / 2C9 / 2D6 /

[1645] 2C19 / 1A2

[1646] ICso pM *

[1647] 2A 2 / 6 / 14 / 3 / 15 / 1

[1648] 3A 2 / 4 / 25 / 5 / 21 / 2

[1649] 6A 6 / 6 / 25 / 4 / 25 / 25

[1650] 7A 15 / 19 / 25 / 23 / 25 / 15

[1651] 8A 24 / 25 / 25 / 25 / 18 / 25

[1652] 10A 17 / 5 / 25 / 10 / 16 / 17

[1653] 11A 25 / 25 / 25 / 25 / 25 / 25

[1654] 13 12 / 19 / 25 / 21 / 25 / 10

[1655] 17 13 / 1 / 25 / 9 / 25 / 17

[1656] 18 17 / 11 / 25 / 11 / 25 / 25

[1657] 22 4 / 1 / 25 / 4 / 25 / 25

[1658] 23 9 / 4 / 25 / 10 / 4 / 25

[1659] 27 8 / 8 / 25 / 25 / 25 / 25

[1660]

[1661] 28B 25 / 25 / 25 / 25 / 25 / 25

[1662] Slight variations were observed in this assay, the results as presented are either from one particular experiment or an average of more than one experiment.

[1663] As shown in this Table 9, certain compounds of formula (I) according to the present invention, show low potential for inhibition, against multiple CYP P450 isoforms.

Claims

CLAIMS1. A compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof;wherein:A is selected from N, N+-O_or CRA;B is selected from N, N+-O_or CRB;C is selected from N, N+-O_or CRC;RA, RBand Rcare each independently selected from H, halogen, -OH, -NH2, Ci-2alkyl, -O-Ci-2alkyl, -CN, -Ci-2alkylene-OH, -Ci-2haloalkyl and -0-Ci-2haloalkylD is N or CRD, wherein RDis selected from H,2H, halogen, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;X1is selected from H,2H, D, halogen, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;X2and X3are each independently selected from H,2H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;E is selected from N orCRE, wherein REis selected from H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;X4is selected from halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;X5is selected from H, halogen, -OH, -NH2, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more halogen atoms;wherein:(i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -C1- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3-eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or(ii) X7is H and X6is selected from -NX6aX6b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O- Ci-2haloalkyl, - Ci-2alkylCN, -Ci-2alkylOH, -OCs-eheterocycloalkyl and -OCi- 3alkylNX6aX6b; wherein X6aand X6bare independently H or Ci-3alkyl; or(iii) X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which may be optionally substituted by one or more substituents selected from -OH, NX8aX8b, -Ci-2alkyl, -Ci- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl; andX9and X10are both independently H.

2. A compound according to claim 1, wherein A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC.

3. A compound according to claim 1 or claim 2, wherein two of A, B and C are N and the other one is CRA, CRBand CRCas appropriate.

4. A compound according to any one of the preceding claims, wherein RA, RBand Rcare all H.

5. A compound according to any one of the preceding claims, wherein X1is H, and X2and X3are independently selected from hydrogen or Ci-2alkyl.

6. A compound according to any one of the preceding claims, wherein D is CH.

7. A compound according to any one of the preceding claims, wherein X4is halogen.

8. A compound according to any one of the preceding claims, wherein X5is selected from H or halogen.

9. A compound according to any one of the preceding claims, wherein E is N.

10. A compound according to any one of the preceding claims, wherein(i) X6is H and X7is selected from the group consisting of -NX7aX7b, -Ci-2alkyl, -Ci- 2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN, -Ci-2alkylOH, -OC3-eheterocycloalkyl and -OCi-3alkylNX7aX7b; wherein X7aand X7bare independently H or Ci-3alkyl; or(ii) X6and X7when taken together with the carbon atom to which they are attached represent Cs-ecycloalkyl or Cs-eheterocycloalkyl, either of which groups may be optionally substituted by one or two substituents selected from -OH, -NX8aX8b, -Ci- 2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

11. A compound according to any one of the preceding claims, which is a compound of formula (VI I)or a pharmaceutically acceptable salt or solvate thereof;wherein A, B, C, X9and X10are as defined in claim 1;X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro; wherein(i) X6is H and X7is selected from the group consisting of -NH2, -CH3, -CHF2, -OCH3, -OCHF2, -CH2CN, -CH2OH, or(ii) X6and X7when taken together with the carbon atom to which they are attached represent C3-4cycloalkyl optionally substituted by one substituent selected from - OH, NX8aX8b, -Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -0-Ci-2haloalkyl, -Ci-2alkylCN and -Ci-2alkylOH; wherein X8aand X8bare independently H or Ci-3alkyl.

12. A compound according to claim 1 which is:rac-(1S,4F?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[2-(4-pyridyl)pyrimidin-5-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-fluoro-6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-(1 S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(6-pyridazin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one;(3 / ?,4S)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?,4 / ?)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S,4S)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S,4 / ?)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (1S,4 / ?,5S)-4-[(6-chloro-5-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)-3-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(5,6-difluoro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one;(1 / ?,4S,5 / ?)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.2.0]heptan-3-one;(1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1.0]hexan- 3-one;(1S,4 / ?,5S)-4-[(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1.0]hexan-3-one;(1S,4 / ?)-4-[(6-fluoro-3-pyridyl)methyl]-2-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)-2-azabicyclo[3.1,0]hexan-3-one;(1S,4 / ?,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;(3 / ?,4 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-4-methyl-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (1S,4 / ?,5S)-4-[dideuterio-(6-fluoro-3-pyridyl)methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;(1 S,4R,5S)-4-[(6-chloro-3-pyridyl)-dideuterio-methyl]-2-[5-(4-pyridyl)-2-pyridyl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4R,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-methyl-5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;(3R,4R)-3-[(6-chloro-3-pyridyl)methyl]-4-methyl-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; (3R,4R)-3-[(6-fluoro-3-pyridyl)methyl]-4-methyl-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; (1S,4R,5S)-4-[(6-chloro-3-pyridyl)methyl]-2-[6-(hydroxymethyl)-5-(4-pyridyl)pyrazin-2-yl]-2-azabicyclo[3.1,0]hexan-3-one;(1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-pyridin-4-ylpyrazin-2-yl)-2-azabicyclo[3.1,0]hexan-3-one(1S,4R,5S)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one);(1R,4S,5R)-4-[(6-chloro-5-fluoro-3-pyridinyl)methyl]-2-(5-fluoro-6-pyridin-4-yl-3-pyridinyl)-2-azabicyclo[3.1,0]hexan-3-one);(1R,4R,5S,6R)-4-[(6-chloro-3-pyridyl)methyl]-6-(hydroxymethyl)-2-[6-(4-pyridyl)pyridazin-3-yl]-2-azabicyclo[3.1,0]hexan-3-one;(3S,4S)-3-((6-chloropyridin-3-yl)methyl)-4-(hydroxymethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;(3R,4R)-3-((6-chloropyridin-3-yl)methyl)-4-(hydroxymethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;(1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(6-(3-methylpyridin-4-yl)pyridazin-3-yl)-2-azabicyclo[3.1,0]hexan-3-one;(1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(5-(3-methylpyridin-4-yl)pyrazin-2-yl)-2-azabicyclo[3.1,0]hexan-3-one;(3R,4R)-4-amino-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3R,4R)-3-((6-chloropyridin-3-yl)methyl)-4-(difluoromethyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;(1S,4R,5S)-4-((6-fluoropyridin-3-yl)methyl)-2-(6-(3-methylpyridin-4-yl)pyridazin-3-yl)-2-azabicyclo[3.1,0]hexan-3-one;(3R,5S)-3-[(6-chloro-3-pyridyl)methyl]-5-(hydroxymethyl)-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin- 2-one; or(3R,5R)-3-[(6-chloro-3-pyridyl)methyl]-5-(hydroxymethyl)-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one.

13. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), ora pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 12, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

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

15. A compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 12, for use in the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

16. A compound for use according to claim 15, 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.

17. A compound for use according to claim 15, 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. Use of a compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 12, for the manufacture of a medicament useful for the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

19. Use of a compound 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, directtrauma 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.

20. 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 effective amount of a compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 12.

21. A method according to claim 20, 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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