Pyrrolidinone derivatives

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

[0006] 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.

[0007] 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. 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 signaling 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] (i); or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0014] A is selected from N, N+-O_or CRA;

[0015] B is selected from N, N+-O_or CRB;

[0016] C is selected from N, N+-0_or CRc;

[0017] RA, RBand Rcare each independently 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;

[0018] 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;

[0019] 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;

[0020] 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;

[0021] 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;

[0022] 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;

[0023] X6is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -CN, Ci-salkylene-OH, -O-Cs-eheterocycloalkyl and -O-Ci-3alkyleneNX6aX6b; wherein X6aand X6bare independently H or Ci-2alkyl; and

[0024] X7is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -CN, Ci-salkylene-OH, -O-Cs-eheterocycloalkyl and -O-Ci-3alkyleneNX7aX7b; wherein X7aand X7bare independently H or Ci-2alkyl.

[0025] In a second aspect, the present invention also provides a compound of formula (IA)

[0026] (IA); or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0027] A is selected from N, N+-O_or CRA;

[0028] B is selected from N, N+-O_or CRB;

[0029] C is selected from N, N+-0_or CRc;

[0030] RA, RBand Rcare each independently 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; D is N or CRD, wherein RDis selected from H, 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;

[0031] X1is selected from H, 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;

[0032] X2and X3are each independently 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;

[0033] 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

[0034] 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; and

[0035] 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.

[0036] The compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of formula (I) is provided in the form of the free base.

[0037] In a third aspect, A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC.

[0038] In a fourth aspect, 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.

[0039] In a fifth aspect, A, B and C is N and the other two are CRA, CRBand CRCas appropriate.

[0040] In a sixth aspect, RA, RBand Rc, are each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms.

[0041] In a seventh aspect, X1is selected from H, F, Cl, -CHs or - O-CH3.

[0042] In a eighth aspect, X2and X3are each independently selected from H, F, Cl, -CHs or - O-CH3.

[0043] In an ninth aspect, D is N or CRDwherein RDis selected from H, F, Cl, -CH3 or -O-CH3. In a tenth aspect, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and - O-CF3 and / or X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

[0044] In a eleventh aspect, REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3 and -O-CF3.

[0045] In a twelfth aspect, X6and X7are independently H, halogen, -Ci-salkylene-OH, -O-C3- eheterocycloalkyl or -OCi-3alkyleneNH2.

[0046] In a thirteenth aspect, the compound of formula (I) is a compound of formula (II)

[0047] (ii); wherein A, B and C are selected from CH or N; X1is selected from H, F, Cl, -CHs or - O-CH3; X2and X3are each independently selected from H, F, Cl, -CHs or - O-CH3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; and E is N or CRE, wherein REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3 and -O-CF3.

[0048] In a fourteenth aspect, the compound of formula (I) is: rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0049] (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0050] (3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-methoxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(4-pyridin-4-ylphenyl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0051] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0052] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0053] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0054] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0055] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0056] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;

[0057] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;

[0058] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridazin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0059] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0060] (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0061] (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0062] (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0063] (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0064] (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0065] (3 / ?)- 3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0066] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one;

[0067] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one;

[0068] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one; rac-3-[(6-Chloro-3-pyridyl)methyl]-1-[6-(3-hydroxy-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(2,6-dideuterio -4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?)-3-[(6-Chloro-3-pyridyl)methyl]-1-[6-(2,6-dideuterio-4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; rac-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2- one;

[0069] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin- 2-one;

[0070] (3S)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-

[0071] 2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0072] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0073] (3S)-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0074] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0075] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0076] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0077] (3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4- pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0078] (3 / ?)-3,4,4,5,5-pentadeuterio-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-

[0079] 3-yl]pyrrolidin-2-one;

[0080] (3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0081] (3 / ?)-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0082] (3 / ?)-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0083] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)-dideuterio-methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2- one;

[0084] (3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2-one;

[0085] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2- one;

[0086] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2- one;

[0087] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0088] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; rac-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1 -[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0089] (3F?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0090] (3S)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0091] (3F?)-3-[(6-chloro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0092] (3F?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0093] (3F?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0094] (3F?)-3-[(6-fluoro-3-pyridinyl)methyl]-1-(2-fluoro-6-pyridin-4-yl-3-pyridinyl)pyrrolidin-2-one;

[0095] (3F?)-3-[(6-Fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one;

[0096] (3S)-3-[(6-Fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0097] (3R)- 3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0098] (3S)-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0099] (3R)-3-[(5-chloro-6-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0100] (3S)-3-[(5-chloro-6-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0101] (3R)-3-[(5-chloro-6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0102] (3S)-3-[(5-chloro-6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0103] (3R)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-fluoro-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one;

[0104] (3 ?)-(3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one;

[0105] (3S)-3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; rac-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0106] (3R)-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0107] (3S)-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0108] (3R)-3-((2-amino-6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0109] (3S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0110] (3F?)-1-[6-(3-amino-4-pyridyl)pyridazin-3-yl]-3-[(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one;

[0111] 3-[(6-chloro-3-pyridyl)methyl]-1-[1-oxido-6-(4-pyridyl)pyridin-1-ium-3-yl]pyrrolidin-2-one;

[0112] (3F?)-1-[2-(4-pyridyl)pyrimidin-5-yl]-3-[[6-(tri fluoro methyl)-3-pyridyl]methyl]pyrrolidin-2-one;

[0113] (3F?)-3-((6-chloro-4-(hydroxymethyl)pyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3- yl)pyrrolidin-2-one; (3S)-3-((6-chloro-4-(hydroxymethyl)pyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3- yl)pyrrolidin-2-one; rac-3-[[6-chloro-2-[3-(dimethylamino)propoxy]-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0114] (3 / ?)-3-[(6-chloro-2-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0115] (3S)-3-[(6-chloro-2-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0116] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0117] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[5-(3-methyl-4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one;

[0118] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(3-methyl-4-pyridyl)pyrazin-2-yl]pyrrolidin-2- one; or

[0119] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-hydroxy-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one.

[0120] In a fifteenth aspect, the compound of formula (I) is:

[0121] (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0122] (3 / ?)- 3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0123] (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0124] (3S)- 3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0125] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0126] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0127] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0128] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0129] (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0130] (3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-methoxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(4-pyridin-4-ylphenyl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0131] (3S)-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0132] (3 / ?)-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0133] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0134] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0135] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridazin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0136] (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0137] (3S)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0138] (3S)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one; or (3 / ?)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one.

[0139] In a sixteenth 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.

[0140] In a seventeenth aspect, the present invention provides for a compound of formula (I), or a pharmaceutically salt or solvate thereof, for use in the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

[0141] In a eighteenth aspect, 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.

[0142] In a nineteenth 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.

[0143] DETAILED DESCRIPTION OF THE INVENTION

[0144] In a first aspect, the present invention provides a compound of formula (I)

[0145] (i); or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0146] A is selected from N, N+-O_or CRA;

[0147] B is selected from N, N+-O_or CRB;

[0148] C is selected from N, N+-0_or CRc;

[0149] RA, RBand Rcare each independently 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;

[0150] 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;

[0151] 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;

[0152] 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;

[0153] 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; 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;

[0154] 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;

[0155] X6is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -CN, Ci-salkylene-OH, -O-Cs-eheterocycloalkyl and -O-Ci-3alkyleneNX6aX6b; wherein X6aand X6bare independently H or Ci-2alkyl; and

[0156] X7is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -CN, Ci-salkylene-OH, -O-Cs-eheterocycloalkyl and -O-Ci-3alkyleneNX7aX7b; wherein X7aand X7bare independently H or Ci-2alkyl.

[0157] In a second aspect, the present invention also provides a compound of formula (IA)

[0158] (IA); or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0159] A is selected from N, N+-O_or CRA;

[0160] B is selected from N, N+-O_or CRB;

[0161] C is selected from N, N+-0_or CRc;

[0162] RA, RBand Rcare each independently 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;

[0163] D is N or CRD, wherein RDis selected from H, 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;

[0164] X1is selected from H, 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, 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;

[0165] 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

[0166] 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; and

[0167] 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.

[0168] The compounds of formula (I) may be referred to herein as “compounds of the invention” or “compounds according to the invention”.

[0169] 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.

[0170] The compound of formula (I), and pharmaceutically salts or solvates thereof, may be referred to herein as “compound(s) of the invention”.

[0171] 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 or ethyl. Suitable examples of COi-2alkyl according to the present invention are methoxy or ethoxy.

[0172] The term “alkylene” as used herein, such as in Ci-salkylene-OH, OCi-3alkyleneNX6aX6bor OCi-3alkyleneNX7aX7bis a bifunctional straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. The alkylene group may be bonded to e.g. an -OH, NX6aX6bor NX7aX7bgroup. Suitable examples of Ci-3alkylene groups according to the present invention, are where the group is methylene (Ci), ethylene (C2) and propylene (C3).

[0173] The term “halogen” 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.

[0174] 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.

[0175] The term “heterocycloalkyl” as used herein, such as in -O-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 or O. An example of a heterocycloalkyl according to the present invention is piperidine.

[0176] 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.

[0177] 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.

[0178] Thus, by way of example, each individual hydrogen atom in formula (I) or in the formulae depicted hereinafter may be present as a1H,2H (deuterium) or3H (tritium) atom, preferably1H or2H. Similarly, by way of example, each individual carbon atom in formula (I) or in the formulae depicted hereinafter, may be present as a11C,12C,13C or14C atom, preferably12C. Similarly, by way of example, each individual fluorine atom may be present as18F or19F. Suitably, the present invention, also includes within its scope, isotopically-labelled compounds of Formula (I).

[0179] 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).

[0180] 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. Typically, such groups will be unsubstituted, or substituted by one, two or three substituents. In one embodiment, such groups are unsubstituted. Suitable substituents for each of the groups present on compounds of formula (I) are defined hereinafter. 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: and for the avoidance of doubt, all configurations are herein covered.

[0181] Compounds of formula (I) and / or their intermediates may have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem., 45 (1976) 11-30. The invention thus also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of Formula (I) or mixtures thereof (including all possible mixtures of stereoisomers). With respect to the present invention reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms (such as cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers) and mixtures thereof, unless the particular isomeric form is specifically referred to.

[0182] In particular, the compounds of formula (I) may exist as enantiomers in the (3R) or (3S) configuration. In a preferred embodiment, the compounds of formula (I) exist in the (3R) configuration.

[0183] The carbon-carbon bonds of the compounds of formula (I) are depicted herein using a solid line ( — '), a solid wedge ( or a dotted wedge ( ••••"•"J). 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.

[0184] Specific embodiments of compounds of formula (I) according to the present invention are described hereafter. 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.

[0185] In one aspect, only one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate.

[0186] In another aspect, B is CRB; and one of A and C is N and the other is CRAor CRC, as appropriate.

[0187] In one aspect, A is N, B is CRBand C is N.

[0188] In another aspect, A is CRA, B is CRBand C is N.

[0189] In a further aspect, A is N, B is CRBand C is CRC.

[0190] In an additional aspect, A is CRA, B is N and C is N.

[0191] In another aspect, A is N, B is N and C is CRC.

[0192] In a further aspect, A is CRA, B is CRBand C is CRC.

[0193] In an additional aspect, A is N, B is N and C is N.

[0194] In an embodiment, RA, RBand Rc, are each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms.

[0195] In an embodiment, RA, RBand Rc, are each independently selected from H, F, Cl, C1-2 alkyl optionally substituted with one or more halogen atoms, and -CN.

[0196] In an embodiment, RA, RBand Rc, are each independently selected from H, F, Cl, C1-2 alkyl optionally substituted with one or more F atoms, and -CN. Typically, RA, RBand Rcare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN. Suitably, RA, RBand Rcare each independently selected from H, F, -OH, -OCF3 and -O-CH3.

[0197] In a particular embodiment, RA, RBand Rcare all H.

[0198] 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.

[0199] In a particular embodiment, only one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate, wherein one of RA, RBand Rcis F, -OH or -O-CH3 and the other is hydrogen, as appropriate.

[0200] In another particular embodiment, B is CRB, wherein RBis selected from F, -OH or -O- CH3, one of A and C is N and the other is CRA(RA= hydrogen) or CRC(Rc= hydrogen), as appropriate. In a further particular embodiment, all of A, B and C are CRA, CRBand CRC, respectively, wherein each of RA, RBand Rcis H.

[0201] 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 H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms. In one embodiment, at least one of A, B and C is N.

[0202] 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 H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN. In one embodiment, at least one of A, B and C is N.

[0203] 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 H, F, - OH, -OCF3 and -O-CH3. In one embodiment, at least one of A, B and C is N.

[0204] In an embodiment, X1is selected from H, F, Cl, -CHs or- O-CH3. Typically, X1is selected from H, Cl, F or -OCH3. In a typical embodiment, X1is H.

[0205] In an embodiment, X2and X3are each independently selected from H,2H, F, Cl, -CHs or -O-CH3. In an embodiment, X2and X3are each independently selected from H, F, Cl, -CHs or - O-CH3. Typically, X2and X3are each independently selected from H, Cl, F or -O-CHs.

[0206] In an embodiment, X2and X3are each independently selected from H,2H, halogen, -NH2, C1-2 alkyl optionally substituted with one or more halogen atoms, and -CN.

[0207] In an 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.

[0208] In another 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.

[0209] In an embodiment, X2is H and X3is selected from H,2H, halogen, -NH2, C1-2 alkyl optionally substituted with one or more halogen atoms, and -CN.

[0210] 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.

[0211] Illustratively, one of X1, X2and X3is selected from H, Cl, F or -OCH3 and the others are hydrogen.

[0212] In a particular embodiment, each of X1, X2and X3are hydrogen.

[0213] In an embodiment, D is N. In another embodiment, D is CRD.

[0214] In one embodiment, RDis selected from H,2H, F, Cl, -CH3 or -O-CH3. Typically, RDis selected from H, F, Cl, -CHs or -O-CHs. Suitably, RDis H.

[0215] In one embodiment, X1is selected from H,2H, F, Cl, -CHs or -O-CHs; X2and X3are each independently selected from H, D, F, Cl, -CH3 or -O-CH3; and D is N or CRD, wherein RDis selected from H, D, F, Cl, -CHs or -O-CHs.

[0216] In one embodiment, X1is selected from H, F, Cl, -CHs or -O-CH3; X2and X3are each independently selected from H, F, Cl, -CH3 or -O-CH3; and D is N or CRD, wherein RDis selected from H, F, Cl, -CH3or -0-CH3.

[0217] In another embodiment, X1is selected from H, Cl, F or -OCH3; X2and X3are each independently selected from H, Cl, F or -OCHs; and D is N or CRD, wherein RDis selected from H, F, Cl, -CHs or -O-CHs, suitably wherein RDis H.

[0218] In a further embodiment, one of X1, X2and X3is selected from H, Cl, F or -OCHs and the others are hydrogen; and D is N or CRD, wherein RDis selected from H, F, Cl, -CHs or -O-CHs, suitably wherein RDis H.

[0219] In an embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and - O-CF3. In an embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3, - OCHF2 and -O-CF3. In an embodiment, X4is halogen. Typically, X4is selected from Cl and F.

[0220] In an embodiment, X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O- CF3. In an embodiment, X5is selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3, - OCHF2 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.

[0221] In a particular embodiment, both X4and X5are halogen. In one aspect of this embodiment, X4and X5are Cl or F.

[0222] In another particular embodiment, X4is F or Cl and X5is H. In another particular embodiment, X4is F or Cl and X5is F or Cl.

[0223] In an embodiment, E is N.

[0224] In another embodiment, E is CRE.

[0225] Typically, REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3 and -O-CF3. More typically, REis selected from H, F, Cl or -OH. Suitably, REis H.

[0226] In one embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; E is N or CRE, wherein REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3 and -O-CF3. In another embodiment, X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; E is N or CRE, wherein REis selected from H, F, Cl or -OH.

[0227] 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.

[0228] 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.

[0229] In an embodiment, X6is selected from H, halogen, -OH, -NH2, -CH3, -CF3, -O-CH3, -O- CF3, -CN and CH2OH. In an embodiment, X6is halogen. Typically, X6is selected from Cl and F.

[0230] In an embodiment, X7is selected from H, halogen, -OH, -NH2, -CH3, -CF3, -O-CH3, -O- CF3, -CN and CH2OH. In an embodiment, X7is halogen. Typically, X7is selected from Cl and F.

[0231] In another embodiment, X6and X7are independently selected from H, halogen, -C1- salkylene-OH, -O-Cs-eheterocycloalkyl or -OCi-3alkyleneNX6aX6b, wherein X6aand X6bare independently H or Ci-2alkyl.

[0232] In another embodiment, X6and X7are independently H, halogen, -Ci-salkylene-OH, -O- C3-6heterocycloalkyl or -OCi-3alkyleneNH2.

[0233] In a suitable embodiment, both X6and X7are H.

[0234] In one aspect, 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 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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. In another aspect, 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 H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3 or -O-CH3; X1is selected from H, F, Cl, -CHs or -O-CHs; X2and X3are each independently selected from H, F, Cl, -CH3or -0-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, - O-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

[0235] In a further embodiment of this aspect, 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 H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0236] In one aspect, 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, wherein RA, RBand Rcare each independently 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0237] In an embodiment of this aspect, 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, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3or -0-CH3; X1is selected from H, F, Cl, -CH3or -0-CH3; X2and X3are each independently selected from H, F, Cl, -CH3or -O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3.

[0238] In a further embodiment of this aspect, 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, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCH3; X2and X3are each independently selected from H, Cl, F or -OCH3; E is N or CRE; REis selected from H, F, Cl or - OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0239] Accordingly, in one aspect, one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate, wherein RA, RBand Rcare each independently selected from H, halogen, -OH, -NH2, CI-2alkyl, -O-Ci-2alkyl and -CN, wherein a Ci-2alkyl group can be optionally substituted with one or more halogen atoms; D is N or CRD, wherein RDis selected from H, halogen, -NH2, Ci-2alkyl, -O-Ci-2alkyl and -CN, wherein a Ci-2alkyl group can be optionally substituted with one or more halogen atoms; X1is selected from H, halogen, -NH2, Ci-2alkyl, - O-Ci-2alkyl and -CN, wherein a Ci-2alkyl group can be optionally substituted with one or more halogen atoms; X2and X3are each independently selected from H, halogen, -OH, -NH2, Ci-2alkyl, -O-Ci-2alkyl and -CN, wherein a Ci-2alkyl 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, CI-2alkyl, -O-Ci-2alkyl and -CN, wherein a Ci-2alkyl group can be optionally substituted with one or more halogen atoms; X4is selected from halogen, -OH, -NH2, Ci-2alkyl, -O-Ci-2alkyl and -CN, wherein a Ci-2alkyl group can be optionally substituted with one or more halogen atoms; and X5is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -O-Ci-2alkyl and - CN, wherein a Ci-2alkyl group can be optionally substituted with one or more halogen atoms.

[0240] In an additional embodiment of this aspect, one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, Ci-2alkyl, -O-Ci-2alkyl and -CN, wherein a Ci-2alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3or -O- CH3; X1is selected from H, F, Cl, -CH3or -0-CH3; X2and X3are each independently selected from H, F, Cl, -CH3or -O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, - CHF2, -CF3, -O-CH3and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O- CH3and -O-CF3and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3. In a further embodiment of this aspect, one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0241] In a particular embodiment of this aspect, one of RA, RBand Rcis F, -OH or -O-CHs and the other is hydrogen, as appropriate.

[0242] In another aspect, B is CRB; and one of A and C is N and the other is CRAor CRC, as appropriate, wherein RA, RBand Rcare each independently 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0243] In an additional embodiment of this aspect, B is CRB; and one of A and C is N and the other is CRAor CRC, as appropriate, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3 or -O- CH3; X1is selected from H, F, Cl, -CHs or -O-CH3; X2and X3are each independently selected from H, F, Cl, -CH3or -O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, - CHF2, -CF3, -O-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O- CH3and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

[0244] In a further embodiment of this aspect, B is CRB; and one of A and C is N and the other is CRAor CRC, as appropriate, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0245] In a particular embodiment of this aspect, RBis selected from F, -OH or -O-CH3 and one of A and C is N and the other is CRA(RA= hydrogen) or CRC(Rc= hydrogen), as appropriate.

[0246] In a further aspect of the present invention, A is N, B is CRBand C is N, wherein RBis 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0247] In an additional embodiment of this aspect, A is N, B is CRBand C is N, wherein RBis selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, - CH3 or -0-CH3; X1is selected from H, F, Cl, -CHs or -O-CHs; X2and X3are each independently selected from H, F, Cl, -CHs or -O-CHs; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, - CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O- CF3.

[0248] In a further embodiment of this aspect, A is N, B is CRBand C is N, wherein RBis selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F. In a further aspect, A is CRA, B is CRBand C is N, wherein RAand RBare each independently 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0249] In an additional embodiment of this aspect, A is CRA, B is CRBand C is N, wherein RAand RBare each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3or -0-CH3; X1is selected from H, F, Cl, -CH3or -0-CH3; X2and X3are each independently selected from H, F, Cl, -CH3or -O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3.

[0250] In a further embodiment of this aspect, A is CRA, B is CRBand C is N, wherein RAand RBare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCH3; X2and X3are each independently selected from H, Cl, F or -OCH3; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0251] In an additional aspect, A is N, B is CRBand C is CRC, wherein RBand Rcare each independently 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0252] In an additional embodiment of this aspect, A is N, B is CRBand C is CRC, wherein RBand Rcare each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3or -0-CH3; X1is selected from H, F, Cl, -CH3or-0-CH3; X2and X3are each independently selected from H, F, Cl, -CH3or - O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3and -O-CF3.

[0253] In a further embodiment of this aspect, A is N, B is CRBand C is CRC, wherein RBand Rcare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCH3; X2and X3are each independently selected from H, Cl, F or -OCH3; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0254] In one aspect, A is CRA, B is N and C is N, wherein RAis 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0255] In an additional embodiment of this aspect, A is CRA, B is N and C is N, wherein RAis selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, - CH3 or -0-CH3; X1is selected from H, F, Cl, -CHs or -O-CHs; X2and X3are each independently selected from H, F, Cl, -CHs or -O-CHs; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, - CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O- CF3.

[0256] In a further embodiment of this aspect, A is CRA, B is N and C is N, wherein RAis selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0257] In a further aspect, A is N, B is N and C is CRC, wherein Rcis 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0258] In an additional embodiment of this aspect, A is N, B is N and C is CRc, wherein Rcis selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3 or -O- CH3; X1is selected from H, F, Cl, -CHs or -O-CHs; X2and X3are each independently selected from H, F, Cl, -CH3or -O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3,- CHF2, -CF3, -0-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O- CH3and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

[0259] In a further embodiment of this aspect, A is N, B is N and C is CRC, wherein Rcis selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0260] In an additional aspect, A is CRA, B is CRBand C is CRC, wherein RA, RBand Rcare each independently 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; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0261] In an additional embodiment of this aspect, A is CRA, B is CRBand C is CRC, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and - CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms; D is N or CRD; RDis selected from H, F, Cl, -CH3 or -O-CH3; X1is selected from H, F, Cl, -CH3 or - O- CH3; X2and X3are each independently selected from H, F, Cl, -CH3 or - O-CH3; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

[0262] In a further embodiment of this aspect, A is CRA, B is CRBand C is CRC, wherein RA, RBand Rcare each independently selected from H, F, Cl, -OH, -CH3, -O-CH3, -O-CHF2, -OCF3 or -CN; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCH3; X2and X3are each independently selected from H, Cl, F or -OCHs; E is N or CRE; REis selected from H, F, Cl or - OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0263] In a particular embodiment of this aspect, each of RA, RBand Rcis H.

[0264] In a further aspect, A is N, B is N and C is N; D is N or CRD, wherein RDis selected from H, 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, 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, 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; 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; and 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.

[0265] In an additional embodiment of this aspect, A is N, B is N and C is N; D is N or CRD; RDis selected from H, F, Cl, -CH3 or -0-CH3; X1is selected from H, F, Cl, -CH3 or -O-CH3; X2and X3are each independently selected from H, F, Cl, -CHs or -O-CHs; E is N or CRE; REis selected from H, F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3 and X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

[0266] In a further embodiment of this aspect, A is N, B is N and C is N; D is N or CRD; RDis H; X1is selected from H, Cl, F or -OCHs; X2and X3are each independently selected from H, Cl, F or -OCH3; E is N or CRE; REis selected from H, F, Cl or -OH; X4is selected from Cl and F; and X5is selected from H, Cl and F.

[0267] In a further aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof; wherein A, B and C are selected from CH or N; X1is selected from H, F, Cl, -CHs or -O- CH3; X2and X3are each independently selected from H, F, Cl, -CH3 or -O-CH3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; and E is N or CRE, wherein REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3 and -O-CF3.

[0268] In an embodiment, A, B and C are selected from CH or N, wherein at least one of A, B and C is CH; X1is selected from H, Cl, F or -OCH3; X2and X3are each independently selected from H, Cl, F or -OCH3; X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and - O-CF3; X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3; E is N or CRE, wherein REis selected from H, F, Cl or -OH.

[0269] In a further embodiment, A, B and C are selected from CH or N, wherein at least one of A, B and C is CH; one of X1, X2and X3is selected from H, Cl, F or -OCH3 and the others are hydrogen; X4is selected from Cl and F; X5is selected from H, Cl and F; E is N or CH.

[0270] In a further aspect, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof; wherein A, B, C, X1, X2, X3and D, are as defined in any one of the aspects or embodiments above;

[0271] X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro.

[0272] In a further aspect, the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof; wherein A, B, C, X4, X5, X6, X7and E are as defined in any one of the aspects or embodiments above.

[0273] In a further aspect, the present invention provides a compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof; wherein A, B, and C are as defined in any one of the aspects or embodiments above;

[0274] X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro.

[0275] In a further aspect, the present invention provides a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof; wherein X1, X2, X3, X4, X5, X6, X7, D and E are as defined in any one of the aspects or embodiments above.

[0276] In a further aspect, the present invention provides a compound of formula (VII) or a pharmaceutically acceptable salt or solvate thereof; wherein X4is halogen, such as chloro or fluoro; and X5is H or halogen, such as chloro or fluoro.

[0277] It will be appreciated that compounds of formulae (IA), (II), (III), (IV), (V), (VI) and (VII) 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 (IA), (II), (III), (IV), (V), (VI) and (VII).

[0278] The compound of formula (I) may be referred to herein as “the compound of the invention” or “the compound according to the invention”.

[0279] 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.

[0280] The compound of formula (I), and pharmaceutically acceptable salts or solvates thereof, may be referred to herein as “compound(s) of the invention”.

[0281] 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.

[0282] In a particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of: rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0283] (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0284] (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0285] (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0286] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0287] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0288] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0289] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0290] (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0291] (3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-methoxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(4-pyridin-4-ylphenyl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0292] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0293] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0294] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0295] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0296] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0297] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;

[0298] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;

[0299] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridazin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0300] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0301] (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0302] (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1 -(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0303] (3R)- 3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0304] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one;

[0305] (3R)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one;

[0306] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(3-hydroxy-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(2,6-dideuterio -4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0307] (3R)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(2,6-dideuterio-4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; rac-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2- one;

[0308] (3R)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin- 2-one;

[0309] (3S)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-

[0310] 2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0311] (3R)-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0312] (3S)-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0313] (3R)-3-[(6-chloro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0314] (3R)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0315] (3R)-3-[(6-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;

[0316] (3R)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4- pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0317] (3 / ?)-3,4,4,5,5-pentadeuterio-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-

[0318] 3-yl]pyrrolidin-2-one;

[0319] (3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?)-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one; (3 / ?)-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0320] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)-dideuterio-methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2- one;

[0321] (3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2-one;

[0322] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2- one;

[0323] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2- one;

[0324] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0325] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; rac-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0326] (3S)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0327] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0328] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0329] (3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;

[0330] (3 / ?)-3-[(6-fluoro-3-pyridinyl)methyl]-1-(2-fluoro-6-pyridin-4-yl-3-pyridinyl)pyrrolidin-2-one;

[0331] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one;

[0332] (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0333] (3S)-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;

[0334] (3 / ?)-3-[(5-chloro-6-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0335] (3S)-3-[(5-chloro-6-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(5-chloro-6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0336] (3S)-3-[(5-chloro-6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0337] (3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-fluoro-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one;

[0338] (3 / ?)-(3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; (3S)-3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; rac-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0339] (3R)-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0340] (3S)-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0341] (3 / ?)-3-((2-amino-6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0342] (3S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;

[0343] (3 / ?)-1-[6-(3-amino-4-pyridyl)pyridazin-3-yl]-3-[(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one;

[0344] 3-[(6-Chloro-3-pyridyl)methyl]-1-[1-oxido-6-(4-pyridyl)pyridin-1-ium-3-yl]pyrrolidin-2-one;

[0345] (3 / ?)-1-[2-(4-pyridyl)pyrimidin-5-yl]-3-[[6-(tri fluoro methyl)-3-pyridyl]methyl]pyrrolidin-2-one;

[0346] (3 / ?)-3-((6-chloro-4-(hydroxymethyl)pyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3- yl)pyrrolidin-2-one;

[0347] (3S)-3-((6-chloro-4-(hydroxymethyl)pyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3- yl)pyrrolidin-2-one; rac-3-[[6-chloro-2-[3-(dimethylamino)propoxy]-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;

[0348] (3 / ?)-3-[(6-chloro-2-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0349] (3S)-3-[(6-chloro-2-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0350] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0351] (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[5-(3-methyl-4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one;

[0352] (3 / ?)-3-[(6-Chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(3-methyl-4-pyridyl)pyrazin-2-yl]pyrrolidin-2- one; and (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-hydroxy-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one.

[0353] In a particular embodiment, the present invention relates to compounds of formula (I) selected from the group consisting of: (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0354] (3R)- 3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0355] (3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;

[0356] (3S)- 3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0357] (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0358] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;

[0359] (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-methoxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(4-pyridin-4-ylphenyl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0360] (3S)-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0361] (3 / ?)-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;

[0362] (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one;

[0363] (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridazin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0364] (3S)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;

[0365] (3 / ?)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one; and (3 / ?)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one.

[0366] 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.

[0367] 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. In the following aspects, the compound of formula (I) as defined above is an inhibitor of SARM1. Compounds of the invention can inhibit the activity of SARM1. For example, the compounds of the invention can be used to inhibit activity or a function of SARM1 in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound according to the invention to the cell, individual, or patient.

[0368] As used herein, the term "in a cell" includes both inside the cell membrane and on the surface of the cell membrane.

[0369] 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.

[0370] Compounds of the invention are also useful to inhibit axonal degeneration. Accordingly, the present invention is notably directed to a method of inhibiting axonal degeneration in a sample or in a patient, comprising contacting the sample or administering to the patient an inhibiting amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0371] 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.

[0372] 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.

[0373] Example of neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD).

[0374] 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) and chemotherapy induced cognitive impairment. 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.

[0375] Neurological disorders also include autoimmune and inflammatory diseases.

[0376] 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.

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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. 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).

[0394] 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.

[0395] The invention also includes within its scope pro-drug forms of the compounds of formula (I) and its various sub-scopes and sub-groups.

[0396] Additionally provided are pharmaceutically acceptable prodrug derivatives of the compounds of formula (I).

[0397] A pharmaceutically acceptable prodrug such as an ester or salt of such ester, a carbamate and / or phosphate of a compound of formula (I), is any compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof

[0398] Suitably, a pharmaceutically acceptable prodrug is formed by functionalising a nitrogen atom in the first ring, for example with a group "L" as illustrated below:

[0399] In one embodiment of the invention, a compound of formula (I) is functionalised via a nitrogen atom in the first ring with a group L, wherein L is selected from: a) -CH2OC(=O)phenyl b) -CH2OC(=O)OCH3c) -CH2OC(=O)Ci-4alkyl e.g. -CH2OC(=O)CH3or -CH2OC(=O)C(CH3)3d) -CH2OC(=O)O(C2H4O)nCH3where n=1 to 5 e) -CH2OP(=O)(OH)2f) -PO(OH)O'.M+, wherein M+is a pharmaceutically acceptable monovalent counterion e.g. Na+or K+, or g) -PO(O')2.D2+, wherein D2+is a pharmaceutically acceptable divalent counterion e.g. Ca2+.

[0400] PHARMACEUTICAL COMPOSITIONS

[0401] 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.

[0402] Therefore, another embodiment of the present invention concerns a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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. 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.

[0408] 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.

[0409] These pharmaceutical forms are prepared using methods which are routinely used by pharmacists.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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).

[0414] 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. SYNTHETIC ROUTES

[0415] 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.

[0416] 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.

[0417] The compounds Formula (I) according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.

[0418] The following description of synthetic schemes provides for means of preparing compounds of formula (I).

[0419] In the general synthetic schemes disclosed below, ‘Hal1, Hal2and Hal3’ denote a halogen atom. Hal1is suitably bromine, chlorine or iodine. Hal2is suitably bromine or iodine. Hal3is suitably chlorine or bromine.

[0420] PG denotes a protecting group for amines; suitably, PG can be Boc.

[0421] -C(=O)X denotes an acyl derivative, suitably an acyl halide (such as X = Cl) or anhydride (such as X = OC(=O)CH3).

[0422] ‘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.

[0423] ‘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)T

[0424] According to one embodiment, compounds of Formula (I) may be prepared according to the following general synthetic scheme:

[0425]

[0426] Buchwald-Hartwig amination of compound 1 with 2-pyrrolidone yields compound 2. The amination may be carried out in the presence of a suitable catalyst (such as Pd2(dba)a), ligand (e.g. Xantphos) and a base (for example K3PO4). The installation of the peripheral pyridine / pyridazine ring can be effected via Suzuki coupling of compounds 2 and 3 in the presence of a suitable catalyst, such as PdCl2(dppf).CH2Cl2. A compound of Formula (I) can then be obtained by treating compound 4 with a suitable halide derivative 5 in the presence of a base (such as LiHMDS).

[0427] It may be possible to omit the Buchwald Hartwig amination step by employing a suitable starting material, as shown below. An example of a commercially available compound 2 is CAS 1027513-44-5.

[0428] In a variation of this embodiment, the order of Suzuki and alpha-benzylation steps may be changed, as follows: In another embodiment, compounds of Formula (I) may be prepared according to the following general synthetic scheme:

[0429] N-protected 2-pyrrolidone and compound 5 are reacted under suitable conditions (such as LDA in THF / heptane / ethylbenzene), followed by deprotection of the N-protecting group to afford compound 7. Suitable deprotection methods will be known to the skilled person depending on the identity of the protecting group. Buchwald Hartwig coupling of compounds 7 and 1 yields compound 6, which compound can be reacted with compound 3 using Suzuki coupling to afford a compound of Formula (I).

[0430] In another embodiment, compound 7 may be prepared according to the following general synthetic scheme:

[0431] N-protected 2-pyrrolidone and compound 16 are reacted under suitable conditions (such as with a base e.g. LiHMDS) to yield compound 17. The hydroxyl group of compound 17 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 18. A reduction reaction is then carried out on compound 18 using an alkene reductant such as NiC and NiBH4, after which deprotection of the N-protecting group is performed to afford compound 7. 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. Compounds of Formula (I) can be prepared via the Buchwald Hartwig amination using compound 7, by synthesising a suitable corresponding substrate (8) for the amination via Suzuki reaction of compounds 1 and 3: In this variation, it is possible to avoid the need for Suzuki reaction by employing a suitable starting material. Examples of a commercially available compounds 8 are 5-Bromo-2,4’- bipyridine (CAS 106047-33-0) or 3-Bromo-6-pyridin-4-yl-pyridazine (1159818-39-9).

[0432] In another embodiment, compounds of Formula (I) may be prepared according to the following general synthetic scheme:

[0433] N-acylation of aromatic amine 9 with a suitable p-halo acyl derivative of propionic acid 10 in the presence of a suitable base (such as DIPEA), followed by intramolecular cyclisation triggered by the addition of a suitable base (e.g. KOf-Bu) to form a y-lactam yields compound 2. Reacting compound 2 with compound 5 in the presence of a base (e.g. LDA) affords compound 6, which can then be subjected to Suzuki coupling with compound 3 to yield a compound of Formula (I).

[0434] Starting with compound 11 (such as commercially available 4-(pyridin-4-yl)aniline) may avoid the need for Suzuki reaction:

[0435] In one variation of this route, Suzuki reaction may be performed in the first step:

[0436] In another variation of this route, the formation of the lactam moiety may be effected by employing a suitable alternative intermediate compound 14: Thus, intermediate compound 14 can be prepared via conjugate addition of a-p- unsaturated lactone 12 with arylboron derivative 13. The reaction can be carried out in the presence of a suitable catalyst, such as Rh (I) catalyst, e.g. chloro(1 ,5-cyclooctadiene)rhodium(l) dimer.

[0437] Suzuki coupling of compounds 9 and 3 yields compound 11 , which can be reacted with compound 14 in the presence of a suitable base (e.g. isopropyl magnesium chloride) to afford compound 15. A compound of formula (I) can then be obtained by forming a lactam moiety within compound 15 via intramolecular cyclisation. The cyclisation can be a Mitsunobu-type reaction and can be carried out in the presence of triphenylphosphine and DIAD.

[0438] Where they are not commercially available, the starting materials may be prepared by methods known to the person skilled in the art.

[0439] 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.

[0440] 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.

[0441] The inhibition by compounds of formula (I) on SARM1 can be tested in various assays.

[0442] In the ENAD (etheno-NAD+assay) as disclosed herein, NAD+ hydrolase activity is measured using an NAD+ analogue to produce a fluorescent product that is measured in real time.

[0443] The efficacy of the compounds according to the Examples to inhibit SARM1 is represented by measuring the IC50 which corresponds to the concentration of compound necessary to inhibit 50% of NAD+hydrolase activity. pICso values correspond to -log of the IC50 in Molar.

[0444] 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 , 1A, 1 B, 2, 2A, 2B, 3, 4A, 4B, 5A, 5B, 6, 6A, 6B, 7, 8, 9, 10, 10A, 10B, 11 , 12, 12A, 12B, 13, 14, 15A, 15B, 16, 17, 18A, 18B, 19A, 19B, 20, 21 , 21 A, 21 B, 22A, 22B, 23, 24, 24A, 25, 25A, 25B, 26A, 26B, 27-36, 37A, 37B, 38, 39, 40A, 40B, 41-44, 45A, 45B, 46, 46A, 46B, 47A, 47B, 48A, 48B, 49, 50, 50A, 50B, 51 , 51 A, 51 B, 52A, 52B, 53, 54, 55A, 56A, 56B, 57, 58A, 58B, 59-61 and 62A, display values of pICso greater than or equal to about 6.0.

[0445] 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.

[0446] 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% of SARM1 inhibition in a cellular context. pICso values correspond to -log of the IC50 in Molar.

[0447] When tested, the majority of Example compounds of formula (I) according to the present invention, display values of pICso greater than or equal to 5.5, suitably greater than or equal to 6.0, preferably greater than or equal to 6.5. When tested compounds according to Examples 1 , 1A, 1 B, 2, 2A, 2B, 3, 4A, 4B, 5A, 5B, 6, 6A, 6B, 7, 8, 9, 10, 10A, 10B, 11 , 12A, 12B, 13, 14, 15A, 15B, 17, 19A, 19B, 20, 21 , 21A, 21 B, 22A, 22B, 23, 24, 24A, 25, 25A, 26A, 26B, 27-36, 37A, 38, 39, 40A, 40B, 41-44, 45A, 45B, 46, 46A, 46B, 47A, 48A, 50, 50A, 51 , 51 A, 51 B, 52A, 52B, 53, 54, 55A, 57, 58A, 58B, 59, 60 and 62A, display values of pICso greater than or equal to about 5.5. In both the ENAD and CZ-48 Assays described herein, the lower the value of the IC50 (the higher the value of the pICso is), the less compound is needed to perform the same amount of inhibition and therefore the higher is the inhibition potency.

[0448] 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.

[0449] In the cytochrome P450 Inhibition (IC50 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 IC50 value of the test compound for a CYP enzyme, the higher is the potential for inhibition.

[0450] When tested certain compounds of formula (I) according to the present invention display IC50 values of 25 pM against tested isoforms.

[0451] CYP inhibition is a common cause of drug-drug interactions and therefore it is desirable to have a test compound with a high IC50 value to have the lowest potential for inhibition, against multiple isoforms.

[0452] For the treatment of the diseases in which SARM1 plays a role, it may be desirable that compounds of formula (I) penetrate the blood brain barrier. In the Blood Brain Barrier assay disclosed herein certain compounds of formula (I) according to the present invention display values of ratio of unbound concentrations brain vs unbound concentrations in plasma of 0.4 (±0.1) at 2hrs.

[0453] The following Examples illustrate the preparation of compounds according to the invention.

[0454] EXPERIMENTAL SECTION

[0455] I. ABBREVIATIONS

[0456] (1H) NMR (Proton) Nuclear magnetic resonance

[0457] AcOH Acetic acid

[0458] BBr3Boron tribromide

[0459] Boc tert-Butoxy-carbonyl

[0460] B0C2O Di-tert-butyl decarbonate

[0461] CBr4 Carbon tetrabromide

[0462] CDCh Chloroform-d4

[0463] CD3OD Methanol-d4

[0464] CO2 Carbon dioxide

[0465] CuCI Copper(l)chloride D2O Deuterium oxide

[0466] Dba Dibenzylideneacetone

[0467] DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene

[0468] DCM Dichloromethane

[0469] DEA Diethanoloamine

[0470] DIAD Diisopropyl azodicarboxylate

[0471] DIPEA N,N-Diisopropylethylamine

[0472] DMA Dimethylacetamide

[0473] DMF N,N-Dimethylformamide

[0474] DMSO Dimethyl sulfoxide e.e. Enantiomeric excess

[0475] ESI Electrospray ionisation

[0476] EtOAc Ethyl acetate

[0477] EtOH Ethanol g Gram

[0478] H or h Hour(s)

[0479] H2 Hydrogen

[0480] H2O Water

[0481] HPLC High performance liquid chromatography

[0482] 'PrMgCI Iso-propylmagnesium chloride

[0483] IR Infra-red

[0484] K2CO3 Potassium carbonate

[0485] K3PO4 Potassium phosphate (tribasic)

[0486] KF Potassium fluoride

[0487] KO‘-Bu Potassium tert-butoxide

[0488] LCMS Liquid chromatography-mass spectrometry

[0489] LDA Lithium diisopropylamide

[0490] □HMDS Lithium bis(trimethylsilyl)amide

[0491] M Molar

[0492] MeCN Acetonitrile

[0493] MeOH Methanol

[0494] 2MeTHF 2-Methyl tetra hydrofuran

[0495] MeOD Methanol-d4 mg Milligram MgSC Magnesium sulfate MHz Megahertz min.(s) Minute(s) mL or ml Millilitre mM Millimolar mmol Millimole MS Mass spectrometry MsCI Mesyl chloride MTBE Methyl-tert-butyl ether N2Nitrogen NaBH4Sodium borohydride Na2SO4Sodium sulfate NaHCO3Sodium hydrogen carbonate NEt3Triethylamine NH3Ammonia NH4CI Ammonium chloride NH4OH Ammonium hydroxide NiCI2Nickel dichloride NMR Nuclear magnetic resonance Pd(PPh3)4Tetra kis(triphenylphosphine)palladium(0) Pd / C Palladium on carbon Pd2(dba)3T ris-dibenzylideneacetone dipalladium PdCI2(dppf) [1 ,1 ’Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) Pd(dppf)CI2[1 ,1 ’Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) PPh3Triphenylphosphine Rbf Round bottom Flask r.t. Room temperature

[0496] RT Retention time

[0497] RuPhos Pd G3 Methanesulfonato(2-dicyclohexylphosphino-2',6'-di- isopropoxy-1 , 1 '-biphenyl)(2'-amino-1 , 1 '-b ip he ny 1-2- yl) palladium(ll)

[0498] SFC Supercritical fluid chromatography Soln. Solution TBAF Tetrabutylammonium fluoride hydrate t-Bu tert-Butyl t-BuOH tert-Butanol t-BuONO tert-Butyl nitrite

[0499] TFA Trifluoroacetic acid

[0500] THF Tetrahydrofuran

[0501] UV Ultraviolet

[0502] VCD Vibrational circular dichroism

[0503] XantPhos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2 - amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate

[0504] Naminq convention:

[0505] 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.

[0506] Analytical Methods

[0507] All NMRs were obtained either at 300 MHz, 400 MHz or at 500 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.

[0508] Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, double doublet etc.

[0509] All LCMS retention times are in minutes.

[0510] LCMS data for all Intermediates were determined using either Method 1 A, Method 1 B, Method 2A, Method 2B, Method 3A, Method 3B, Method 3C, Method 3D or Method 4.

[0511] LCMS data for all Examples were determined by using Method 5.

[0512] LCMS Method 1A

[0513] Column: Phenomenex Gemini NX-C18, 2 x 20 mm, 3 pm Temperature: 40 °C

[0514] Flow Rate: 1.0 mL / min

[0515] Solvent A: 10 mM Ammonium formate in water + 0.1% Ammonia solution

[0516] Solvent B: MeCN / H20 / Ammonia Solution (95 / 5 / 0.1)

[0517] Gradient program:

[0518] LCMS Method 1 B

[0519] Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 pm

[0520] Temperature: 60 °C

[0521] Flow Rate: 1.5 mL / min

[0522] Solvent A: 10 mM Ammonium formate in water + 0.1% Ammonia solution

[0523] Solvent B: MeCN / H20 / Ammonia Solution (95 / 5 / 0.1)

[0524] Gradient program:

[0525] LCMS Method 2A

[0526] Column: Waters Acquity UPLC XSelect HSS T3, 2.1 x 50 mm, 1.8 pm

[0527] Temperature: 45 °C

[0528] Flow Rate: 0.8 mL / min

[0529] Solvent A: H2O / MeCN / TFA (95 / 5 / 0.05)

[0530] Solvent B: MeCN

[0531] Gradient program:

[0532] LCMS Method 2B

[0533] Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 pm

[0534] Temperature: 45 °C Flow Rate: 0.8 mL / min

[0535] Solvent A: H20 / MeCN / ammonium_formate (95% / 5% / 63mg / L) + 100pL / L NH4OH

[0536] Solvent B: MeCN / H20 / ammonium_formate (95% / 5% / 63mg / L) + 100pL / L NH4OH Gradient program: LCMS Method 3A

[0537] Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 pm

[0538] Temperature: 40 °C

[0539] Flow Rate: 1.8 mL / min

[0540] Solvent A: 0.1% formic acid in H2O Solvent B: MeCN

[0541] Gradient program:

[0542] LCMS Method 3B

[0543] Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7pm

[0544] Temperature: 40 °C

[0545] Flow Rate: 1.35 mL / min

[0546] Solvent A: 0.1% formic acid in H2O

[0547] Solvent B: MeCN

[0548] Gradient program:

[0549] LCMS Method 3C

[0550] Column: Waters BEH C18, 2.1 mm x 30 mm, 1 .7 pm, 130A

[0551] Temperature: 40 °C

[0552] Injection Volume: 0.6 pL

[0553] Flow Rate: 1.35 mL / min

[0554] Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by ESI

[0555] Solvents: A: 0.2% Ammonia in H2O, B: MeCN

[0556] LCMS Method 3D

[0557] Column: Waters BEH C18, 2.1 mm x 30 mm, 1 .7 pm, 130A

[0558] Temperature: 40 °C

[0559] Injection Volume: 0.6 pL

[0560] Flow Rate: 1.8 mL / min

[0561] Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by ESI

[0562] Solvents: A: 0.2% NH3in H2O, B: MeCN

[0563] LCMS Method 4

[0564] Column: Waters XBridge C18, 30 x 2.1 mm, 2.5 m

[0565] Flow Rate: 1.0 mL / min Solvent A: 5 mM ammonium formate in water + 0.1 % NH4OH

[0566] Solvent B: MeCN + 5% solvent A + 0.1% NH4OH

[0567] Gradient program:

[0568] LCMS Method 5 Column: Waters UPLC X Bridge BEH (C18, 2.1 x 50 mm, 2.5 pm)

[0569] Temperature: 45 °C

[0570] Flow Rate: 1.0 mL / min

[0571] Solvent A: 10 mM ammonium formate in water + 0.1% formic acid

[0572] Solvent B: 95% acetonitrile + 5% H2O + 0.1 % formic acid Gradient program: Vibrational Circular Dichroism (VCD) Method

[0573] The absolute configuration of selected compounds was determined using VCD spectroscopy: IR and VCD spectra were recorded on a BioTools ChirallR-2X MIR FT-VCD spectrometer equipped with dual photoelastic modulators (dualPEM). Samples of between 5-10 mg were dissolved in 150 pL CDCh or DMSO-de and 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.).

[0574] 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.

[0575] All starting materials are commercially available or may be made by methods known to one skilled in the art.

[0576] II. SYNTHESIS OF INTERMEDIATES

[0577] INTERMEDIATE 1 : 1-(5-Bromopyrazin-2-yl)pyrrolidin-2-one

[0578] To a solution of 2-bromo-5-iodo-pyrazine (8.0 g, 28.1 mmol) in 1 ,4-dioxane (80 mL) was added 2-pyrrolidone (2.63 g, 30.9 mmol) followed by K3PO4 (11.9 g, 56.2 mmol) at r.t. The argon gas was purged through the reaction mixture for 30 min. To this mixture was added Xantphos (0.65 g, 1.12 mmol), followed by Pd2(dba)3 (0.323 g, 0.562 mmol) at r.t. and the reaction mixture was heated to 100 °C for2 h. After completion, the reaction mixture was cooled to r.t. The reaction mixture was concentrated in vacuo. The residue was treated with H2O (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by normal phase flash chromatography (20% EtOAc in heptane) to afford the title compound as an off-white solid (4.08 g, 60%). LCMS (Method 4): [M+H]+m / z 242.1 , RT 1.32 min.1H NMR (400 MHz, DMSO-de) 5H 9.33 (s, 1 H), 8.59 (s, 1 H), 3.89-3.95 (m, 2H), 2.56-2.63 (m, 2H), 2.02-2.13 (m, 2H).

[0579] INTERMEDIATE 2: 1-r5-(4-Pyridyl)pyrazin-2-yllpyrrolidin-2-one

[0580] To a solution of Intermediate 1 (4.0 g, 16.5 mmol) in 1 ,4-dioxane: water (1 : 1 , 40 mL) was added 4-pyridylboronic acid (2.23 g, 18.2 mmol) followed by cesium carbonate (10.8 g, 33.0 mmol). Argon gas was purged through the reaction mixture for 30 min. To this mixture was added PdCl2(dppf).CH2Cl2 (1.35 g, 1.65 mmol) at r.t. and the reaction mixture was heated to 100°C for 16 h. After completion, the reaction mixture was cooled to r.t., treated with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue obtained was purified by normal phase flash chromatography (40% EtOAc in heptane) to afford the title compound as a brown solid (3.97 g, 100%). LCMS (Method 4): [M+H]+m / z 241.2, RT 1.16 min.1H NMR (400 MHz, DMSO-de) 5H 9.64 (s, 1 H), 9.18 (s, 1 H), 8.69-8.71 (m, 2H), 8.04-8.06 (m, 2H), 3.97-4.03 (m, 2H), 2.58-2.66 (m, 2H), 2.06-2.17 (m, 2H).

[0581] INTERMEDIATE 3: 1-(5-Bromo-2-pyridyl)pyrrolidin-2-one

[0582] To a solution of 5-bromo-2-iodopyridine (3.1 g, 11 mmol) and 2-pyrrolidone (910 mg, 11 mmol) in 1 ,4-dioxane (50 mL) at r.t. was sequentially added K3PO4 (6.9 g, 32 mmol), Xantphos (1.3 g, 2.1 mmol) and Pd2(dba)3 (1.0 g, 1.1 mmol) and the reaction mixture was heated to 100 °C for 5 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with EtOAcZ / so- hexane (0-100% gradient, and then MeOH / EtOAc, 0-30% gradient) to give the title compound (960 mg, 38%) as a pale-yellow solid. LCMS (Method 1A): [M+H]+m / z 241 .0 / 243.0, RT 1.1 min.1H NMR (400 MHz, DMSO-d6) 6 8.51 (dd, J = 2.6, 0.7 Hz, 1 H), 8.30 (dd, J = 8.9, 0.7 Hz, 1 H), 8.04 (dd, J = 9.0, 2.6 Hz, 1 H), 4.05 - 3.87 (m, 2H), 2.59 (dd, J = 8.4, 7.7 Hz, 2H), 2.16 - 1 .92 (m, 2H).

[0583] INTERMEDIATE 4: 1-[5-(4-Pyridyl)-2-pyridyl]pyrrolidin-2-one

[0584] To pyridine-4-boronic acid (306 mg, 2.49 mmol), Pd(dppf)Cl2 (152 mg, 0.21 mmol), K2CO3 (869 mg, 6.22 mmol) and Intermediate 3 (500 mg, 2.07 mmol) was added 1 ,4-dioxane (6 mL) and H2O (1 mL) and the reaction mixture was sparged with nitrogen for 5 minutes. The reaction mixture was then heated to 110 °C for 2 h. The reaction mixture was cooled to r.t. and diluted with H2O (10 mL) and DCM (10 mL). The aqueous layer was separated before filtering through a phase separation frit and concentrating in vacuo to afford a dark brown / black oil. Purification by flash chromatography eluting with EtOAcZ / so-hexane (0-100% gradient and then MeOHZ EtOAc, 0-30% gradient and then 0-30% MeOH / EtOAc) afforded the title compound (480 mg, 96%) as a light-yellow gum. LCMS (Method 1A): [M+H]+m / z 240.2, RT 0.90 min.1H NMR (400 MHz, DMSO-de) 5H 8.88 (dd, J = 2.6, 0.9 Hz, 1 H), 8.72 - 8.62 (m, 2H), 8.45 (dd, J = 8.8, 0.8 Hz, 1 H), 8.29 (dd, J = 8.8, 2.6 Hz, 1 H), 7.85 - 7.65 (m, 2H), 4.05 (dd, J = 7.6, 6.7 Hz, 2H), 2.62 (dd, J = 8.5, 7.6 Hz, 2H), 2.19 - 2.00 (m, 2H).

[0585] INTERMEDIATE 5: tert-Butyl 3-r(4-chlorophenyl)methyll-2-oxo-pyrrolidine-1- carboxylate

[0586] To a solution of 1-(tert-butoxycarbonyl)-2-pyrrolidinone (1 mL, 5.24 mmol) in THF (20 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 2.75 mL, 5.50 mmol). After 1 h at -78 °C, 4-chlorobenzyl bromide (1.18 g, 5.74 mmol) was added. The reaction mixture was stirred at -78 °C for 2.5 h. The progress of the reaction was monitored by LCMS. After completion of reaction, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 50mL). The organic layer was dried over MgSC , filtered and concentrated under reduced pressure to afford the title compound as a colourless oil (0.53 g,32%).1H NMR (400 MHz, CDCI3) 5H 7.28 - 7.24 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 3.67 (ddd, J = 11 .2, 8.7, 2.8 Hz, 1 H), 3.52 (td, J = 10.0, 7.2 Hz, 1 H), 3.21 (dd, J = 13.6, 3.9 Hz, 1 H), 2.83 - 2.62 (m, 2H), 2.08 - 1 .95 (m, 1 H), 1 .66 (dq, J = 12.9, 9.3 Hz, 1 H), 1 .53 (s, 9H). LCMS (Method 2A): [M+H]+m / z 254 / 256, RT 1.56 min.

[0587] INTERMEDIATE 6: 3-[(4-Chlorophenyl)methyl1pyrrolidin-2-one

[0588] Intermediate 5 (530 mg; 1.71 mmol) was dissolved in hydrochloric acid (4M solution in 1 ,4-dioxane; 5 mL) and was stirred at room temperature (r.t.) for 18 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow solid (0.31 g, 85%). LCMS (Method 2A): [M+H]+m / z 210 / 212, RT 1.14 min.

[0589] INTERMEDIATE 7: 1-(6-Bromo-3-pyridyl)-3-K4-chlorophenyl)methyllpyrrolidin-2- one

[0590] To a solution of Intermediate 6 (255 mg, 1.04 mmol) and 2-bromo-5-iodopyridine (364 mg, 1.24 mmol) in 1 ,4-dioxane (5 mL), K3PO4 (673 mg, 3.11 mmol), Pd2(dba)3 (98 mg, 0.10 mmol) and Xantphos (122 mg, 0.21 mmol) were added. The reaction mixture was stirred at 100°C for 18 h. The progress of the reaction was monitored by LCMS. After completion of reaction, the reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL) and with brine (1 x 20 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound as an orange oil (0.246 g, 64%). LCMS (Method 2A): [M+H]+m / z 363 / 365, RT 1 .54 min.

[0591] INTERMEDIATE 8: A / -(5-Bromopyrazin-2-yl)-4-chloro-butanamide

[0592] To a solution of 5-bromopyrazin-2-amine (583 mg, 3.35 mmol) and 2-chloro-1- methylpyridinium iodide (1.71 g, 6.69 mmol) in DMA (15 mL) was added DIPEA (2.21 mL, 12.7 mmol). The mixture was stirred for 2 minutes, and a solution of 4-chlorobutanoic acid (0.66 mL, 6.70 mmol) in DMA (30 mL) was added dropwise over 5 minutes. The mixture was heated to 55 °C for 16 h, and then recharged with 2-chloro-1 -methylpyridinium iodide (1.71 g,

[0593] 6.69 mmol) and DIPEA (2.21 mL, 12.7 mmol). After an additional 45 minutes at 55 °C , the mixture was cooled to r.t. and diluted with H2O (30 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer re-extracted with EtOAc (3 x 30 mL). The combined organics were washed with sat. aqueous NaHCOa (4 x 30 mL), brine (2 x 50 mL), dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with EtOAcZ / so-hexane (0-100% gradient), and then the desired compound re-dissolved in EtOAc (20 mL). This material was then washed with sat. aqueous NaHCOa (2 x 20 mL), brine (2 x 20 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound (419 mg, 45%) as a yellow solid. LCMS (Method 1A): [M+H]+m / z 278.0 / 280.2 / 280.8 / 282.0, RT 1.06 min.1H NMR (400 MHz, DMSO-d6) 6H = 11 .02 (s, 1 H), 9.15 (d, J = 1 .5 Hz, 1 H), 8.61 (d, J = 1 .5 Hz, 1 H),

[0594] 3.70 (t, J = 6.6 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.09-2.00 (m, 2H).

[0595] INTERMEDIATE 9: 1-(5-Bromopyrazin-2-yl) pyrrolidin-2-one

[0596] To a suspension of Intermediate 8 (419 mg, 1 .50 mmol) in THF (7 mL) at 0 °C was added KOf-Bu (177 mg, 1.58 mmol) in one portion. The resulting yellow solution was warmed to r.t. and stirred for 5 minutes, after which it was quenched with H2O (10 mL) and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer re-extracted with EtOAc (2 x 20 mL). The combined organics were dried (Na2SC>4) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / zso-hexane (0-100% gradient), afforded the title compound (254 mg, 70%) as a white solid.

[0597] LCMS (Method 1A): [M+H]+m / z 242.0 / 244.0, RT 0.94 min.1H NMR (400 MHz, DMSO-d6) 5H = 9.36 (d, J = 1 .5 Hz, 1 H), 8.67 (d, J = 1 .5 Hz, 1 H), 3.93 (dd, J = 7.6, 6.7 Hz, 2H), 2.62 (dd, J = 8.4, 7.7 Hz, 2H), 2.16-2.05 (m, 2H).

[0598] INTERMEDIATE 10: 1-(5-Bromopyrazin-2-yl)-3-[(6-chloro-3- pyridyl)methyllpyrrolidin-2-one

[0599] To a solution of Intermediate 9 (254 mg, 1 .05 mmol) in THF (15 mL) at -78 °C was added LDA (2 M soln, in THF / heptane / ethylbenzene, 0.58 mL, 1.20 mmol) dropwise, resulting in a red solution. The mixture was stirred at -78 °C for 1 h, then 5-(bromomethyl)-2-chloropyridine (251 mg, 1.15 mmol) was added in one portion. After 10 minutes the reaction was quenched with MeOH (5 mL), warmed to r.t. , and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / zso-hexane (0-100% gradient), afforded the title compound (254 mg, 66%, 85% purity) as a pale-yellow solid. LCMS (Method 1A): [M+H]+m / z 367.0 / 369.0 / 371.0, RT 1.26 min.

[0600] INTERMEDIATE 11 : tert-Butyl 3-r(6-chloro-3-pyridyl)methyll-2-oxo-pyrrolidine-1-

[0601] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (1.02 g, 5.51 mmol) in THF (25 mL) at -78 °C was added LDA (2 M soln, in THF / heptane / ethylbenzene, 2.75 mL, 5.50 mmol) dropwise. The mixture was stirred at -78 °C for 1 h, then 5-(bromomethyl)-2-chloropyridine (1 .08 g, 4.97 mmol) was added. After 1 h the reaction was quenched with saturated aq. NH4CI. The mixture was extracted with DCM and the combined organic layers dried (Na2SC>4) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0- 100% gradient), afforded the title compound (1 .23 g, 65%) as a yellow oil. LCMS (Method 1A): [M+H]+m / z 311 .2 / 313.2, RT 1 .21 min.1H NMR (400 MHz, DMSO-d6) 58.29 (d, J = 2.4 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.46 (dd, J = 8.2, 0.6 Hz, 1 H), 3.61 (ddd, J = 10.7, 8.7, 2.3 Hz, 1 H), 3.55 - 3.41 (m, 1 H), 3.04 (dd, J = 13.9, 5.0 Hz, 1 H), 2.91 (dtd, J = 10.8, 8.8, 5.0 Hz, 1 H), 2.67 (dd, J = 13.8, 9.1 Hz, 1 H), 1.91 (dddd, J = 12.3, 9.0, 7.1 , 2.2 Hz, 1 H), 1.71 - 1.53 (m, 1 H), 1.45 (s, 9H).

[0602] INTERMEDIATE 12: 3-r(6-Chloro-3-pyridyl)methyl]pyrrolidin-2-one

[0603] To a solution of Intermediate 11 (323 mg, 0.94 mmol) in DCM (5 mL) was added TFA (0.8 mL, 10 mmol). The mixture was stirred overnight at r.t. , then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aq. NaHCOa. The organic phase was concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0- 100% gradient) and then MeOH / EtOAc (0-20% gradient), afforded the title compound (129 mg, 66%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H 8.29 (d, J = 2.5 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.66 (s, 1 H), 7.44 (dd, J = 8.2, 0.7 Hz, 1 H), 3.16 - 3.02 (m, 2H), 3.06 - 2.92 (m, 1 H), 2.67 - 2.52 (m, 2H), 2.00 (dddd, J = 11 .7, 8.1 , 6.7, 3.3 Hz, 1 H), 1.71 - 1 .55 (m, 1 H). LCMS (Method 1A): [M+H]+m / z 211 .4 / 213.4, RT 0.74 min.

[0604] INTERMEDIATE 13 and INTERMEDIATE 14

[0605] (3S)-3-[(6-chloro-3- (3R)-3-[(6-chloro-3- pyridyl)methyl]pyrrolidin-2-one pyridyl)methyl]pyrrolidin-2-one Intermediate 13 Intermediate 14

[0606] Intermediate 12 (231 mg, 1.10 mmol) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 250 x 20.0 mm, 5 pm;Method: MeOH + 0.1% NH4OH (3 - 40%) over 7.5 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the title compounds: Intermediate 13 (Peak 1 ; 70 mg, 30%) and Intermediate 14 (Peak 2; 71 mg, 31%).

[0607] Peak 1 (Intermediate 13, (3S) enantiomer) LCMS (Method 1 B): [M+H]+m / z 211.2 / 213.2, RT 0.78 min.

[0608] Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.76 min.

[0609] Peak 2 (Intermediate 14, (3R) enantiomer): LCMS (Method 1 B): [M+H]+m / z 211.2 / 213.2, RT 0.77 min.

[0610] Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH+0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.66 min.

[0611] The absolute configuration of Intermediate 13 (S-configuration) and Intermediate 14 (R- configuration) was determined using VCD spectroscopy.

[0612] INTERMEDIATE 15: 1-r6-(4-Pyridyl)pyridazin-3-yllpyrrolidin-2-one

[0613] 1-(6-bromopyridazin-3-yl)pyrrolidin-2-one (CAS: 1027513-44-5; 53 mg, 0.22 mmol), pyridine-4-boronic acid (93 mg, 0.66 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), K2CO3 (50 mg, 0.36 mmol), 1 ,4-dioxane (1 mL) and H2O (0.5 mL) were combined together. The mixture was degassed with N2 and then stirred at 100 °C for 30 minutes. The reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / zso-hexane (0-100% gradient) afforded the title compound (36 mg, 68%) as a white solid.1H NMR (400 MHz, DMSO-de) 5H 8.81 - 8.74 (m, 2H), 8.70 (d, J = 9.5 Hz, 1 H), 8.41 (d, J = 9.5 Hz, 1 H), 8.14 - 8.08 (m, 2H), 4.23 - 4.15 (m, 2H), 2.66 (t, J = 8.0 Hz, 2H), 2.22 - 2.09 (m, 2H). LCMS (Method 1 A): [M+H]+m / z 241 .0, RT 0.59 min.

[0614] INTERMEDIATE 16: 6-Methoxy-5-(4-pyridyl)pyridin-2 -amine

[0615] To a solution of pyridine-4-boronic acid (632 mg, 5.14 mmol) in 1 ,4-dioxane / H20 (24 mL Z 6 mL) were added K2CO3 (1295 mg, 9.37 mmol), 5-bromo-6-methoxypyridin-2-amine (1.00 g, 4.68 mmol) and Pd(dppf)Cl2'CH2Cl2 (380 mg, 0. 46 mmol). The mixture was stirred for 2 h at 90 °C then taken up with DCM (50 ml) and washed with saturated aqueous NaHCOa (2 x 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with DCM / MeOH (100 / 0 to 94 / 6) to give the title compound (480 mg, 50 %) as an orange oil. LCMS (Method 2B): [M+H]+m / z 202, RT 0.88 min.

[0616] INTERMEDIATE 17: 4-Chloro-N-r6-methoxy-5-(4-pyridyl)-2-pyridyllbutanamide

[0617] To a solution of Intermediate 16 (480 mg; 2.38 mmol) in DCM (10 mL) were added 4- chlorobutyryl chloride (336 mg, 2.38 mmol) and NEta (366 mg, 3.58 mmol). The mixture was stirred for 20 h at r.t. then taken up with DCM (25 mL) and washed with a saturated aqueous solution of NaHCOa (2 x 10 mL). The organic layer was dried over MgSC , filtered, and concentrated in vacuo to give the title compound (685 mg, 93 %) as an orange solid and was used in subsequent steps without any further purification.1H NMR (400 MHz, DMSO) 5 10.48 (s, 1 H), 8.62 - 8.56 (m, 2H), 7.92 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 1 H), 7.64 - 7.57 (m, 2H), 3.93 (s, 3H), 3.70 (t, J = 6.6 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.08 - 2.00 (m, 2H). LCMS (Method 2B): [M+H]+m / z 306 / 308, RT 1 .22 min.

[0618] INTERMEDIATE 18: 1-r6-Methoxy-5-(4-pyridyl)-2-pyridyllpyrrolidin-2-one To a solution of Intermediate 17 (685 mg, 2.24 mmol) in THF (10 mL) at 0 °C was added potassium tert-butoxide (305 mg, 2.66 mmol). The mixture was stirred 4 h at room temperature. The precipitate was filtered and discarded. The filtrate was taken up with DCM (25 ml) and washed with a saturated aqueous solution of NaHCOa (2 x 10 mL). The organic layer was dried over MgSC , filtered, and concentrated in vacuo to give the title compound (490 mg, 81%) as a yellow solid and was used in subsequent steps without any further purification.1H NMR (400 MHz, CDCI3) 5 8.65 - 8.57 (m, 2H), 8.08 (d, J = 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.54 - 7.51 (m, 2H), 4.20 - 4.12 (m, 2H), 3.97 (s, 3H), 2.68 (t, J = 8.1 Hz, 2H), 2.15 (p, J = 7.8 Hz, 2H). LCMS (Method 2B): [M+H]+m / z 270, RT 1.22 min.

[0619] INTERMEDIATE 19: 34(4-Chlorophenyl)methyll-1-r6-methoxy-5-(4-pyridyl)-2-

[0620] To a solution of Intermediate 18 (245 mg, 0.91 mmol) in THF (10 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 0.5 mL, 1 mmol). The mixture was stirred for 1 h at -78 °C then 4-chlorobenzyl bromide (205 mg, 0.99 mmol) was added. The reaction mixture was stirred whilst warming to r.t. over 30 min then quenched with water (20 mL) and extracted with EtOAc (3 x20 mL). The combined organic layers were dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography to give the title compound (55 mg, 15%) as a beige solid and was used in subsequent steps without any further purification. LCMS (Method 2B): [M+H]+m / z 394 / 396, RT 1.5 min.

[0621] INTERMEDIATE 20: 4-Chloro-N-r4-(4-pyridyl)phenyllbutanamide Prepared from 4-(4-pyridyl)aniline (CAS: 13296-04-3; 270 mg, 1.59 mmol) and 4- chlorobutyryl chloride (0.18 mL, 1.59 mmol) in accordance with the procedure described for Intermediate 17. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) afforded the title compound (330 mg, 76%) as a light brown foam.1H NMR (400 MHz, DMSO-de) 5H 10.17 (s, 1 H), 8.66 - 8.48 (m, 2H), 7.90 - 7.45 (m, 6H), 3.72 (t, J = 6.5 Hz, 2H), 2.18 - 1.90 (m, 2H). LCMS (Method 1A): [M+H]+m / z 275.2, RT 1.05 min.

[0622] INTERMEDIATE 21 : 1-r4-(4-Pyridyl)phenyllpyrrolidine-2-one

[0623] Prepared from Intermediate 20 (330 mg, 1.20 mmol) and potassium tert-butoxide (142 mg, 1 .27 mmol) in accordance with the procedure described for Intermediate 18. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient, and then DCM / MeOH, 0-10% gradient) afforded the title compound (250 mg, 87 %) as a pale-yellow foam.1H NMR (400 MHz, DMSO-de) 5H 8.65 - 8.59 (m, 2H), 7.90 - 7.77 (m, 4H), 7.75 - 7.69 (m, 2H), 3.90 (t, J = 7.0 Hz, 2H), 2.58 - 2.52 (m, 2H), 2.10 (qd, J = 8.0, 6.8 Hz, 2H). LCMS (Method 1A): [M+H]+m / z 239.2, RT 0.93 min.

[0624] INTERMEDIATE 22: 1-(6-Bromo-3-pyridyl)pyrrolidin-2-one

[0625] To a solution of 2-pyrrolidinone (500 mg, 5.88 mmol) and 2-bromo-5-iodopyridine (2.06 g, 7.04 mmol) in 1 ,4-dioxane (10 mL) was added K3PO4 (3.8 g, 18 mmol), Pd2dba3 (555 mg, 0.59 mmol) and Xantphos (694 mg, 1.18 mmol). The reaction mixture was stirred at 100 °C for 18 h. The progress of the reaction was monitored by LCMS. After completion the reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL) and brine (1 x 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (0-5% MeOH in DCM) to afford the title compound as an orange oil (0.518 g, 32%). LCMS (Method 2A): [M+H]+m / z 241 / 243, RT 0.98 min.

[0626] INTERMEDIATE 23: 1-(6-Bromo-3-pyridyl)-3-K6-chloro-3-pyridyl)methyllpyrrolidin- 2 -one

[0627] To a solution of Intermediate 22 (322 mg, 1 .34 mmol) in THF (5 mL) at -78°C was added LDA (2M soln, in THF / heptane / ethylbenzene, 0.7 mL, 1.4 mmol). After 1 h at -78 °C, 5- (bromomethyl)-2-chloropyridine (281 mg, 1.33 mmol) was added and the reaction mixture was stirred at -78 °C for a further 2 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was dried over MgSC , filtered, and concentrated under reduced pressure to afford the title compound as a yellow oil (0.515 g, 100%). The material was used in subsequent steps without further purification. LCMS (Method 2A): [M+H]+m / z 366 / 368, RT 1.29 min.

[0628] INTERMEDIATE 24: 5-Bromo-3-fluoro-2-(4-pyridyl)pyridine

[0629] 2,5-dibromo-3-fluoropyridine (474 mg, 1.79 mmol), pyridine-4-boronic acid hydrate (261 mg, 1.85 mmol), Pd(dppf)Cl2 (140 mg, 0.191 mmol) and K2CO3 (564 mg, 4.04 mmol) were dissolved in 1 ,4-dioxane (9 mL) and H2O (3 mL). The mixture was degassed with N2 and then heated to 100 °C for 3 h. The reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / zso-hexane (0-100% gradient) afforded the title compound (99 mg, 22%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H 8.82 - 8.73 (m, 3H), 8.42 (dd, J = 10.9, 1.9 Hz, 1 H), 7.89 (dt, J = 4.5, 1 .6 Hz, 2H). LCMS (Method 1 A): [M+H]+m / z 253.0 / 255.0, RT 1 .11 min. INTERMEDIATE 25: 4-(5-Bromo-3-fluoro-2-pyridyl)pyridazine

[0630] 2,5-dibromo-3-fluoropyridine (325 mg, 1.22 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxoboran-2-yl)pyridazine (289 mg, 1.33 mmol), Pd(dppf)Cl2 (92 mg, 0.13 mmol) and K2CO3 (560 mg, 6.43 mmol) were dissolved in 1 ,4-dioxane (4 mL) and H2O (1 .5 mL). The mixture was degassed with N2 and then heated to 100 °C for 2 h. The reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0-100% gradient) and then MeOH / EtOAc (0- 10% gradient) afforded the title compound (30 mg, 10%) as a white solid.1H NMR (400 MHz, DMSO-de) 5H 9.71 (dt, J = 2.4, 1.2 Hz, 1 H), 9.43 (dd, J = 5.4, 1.3 Hz, 1 H), 8.85 (t, J = 1.6 Hz, 1 H), 8.50 (dd, J = 10.8, 1.8 Hz, 1 H), 8.15 (ddd, J = 5.4, 2.4, 1.2 Hz, 1 H). LCMS (Method 1A): [M+H]+m / z 254.0 / 256.0, RT 0.90 min.

[0631] INTERMEDIATE 26: 3-Bromo-6-pyridazin-4-yl-pyridazine

[0632] 3,6-dibromopyridazine (500 mg, 2.06 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxoboran-2- yl)pyridazine (520 mg, 2.40 mmol), Pd(dppf)Cl2 (156 mg, 0.213 mmol) and K2CO3 (898 mg, 6.43 mmol) were dissolved in 1 ,4-dioxane (7 mL) and H2O (3 mL). The mixture was degassed with N2 and then heated to 100 °C for 2 h. The reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient) afforded the title compound (117 mg, 22%) as a brown solid.1H NMR (400 MHz, DMSO-de) 5H 9.96 (dd, J = 2.4, 1 .3 Hz, 1 H), 9.48 (dd, J = 5.4, 1 .2 Hz, 1 H), 8.49 (d, J = 9.0 Hz, 1 H), 8.40 (dd, J = 5.4, 2.4 Hz, 1 H), 8.33 (d, J = 9.0 Hz, 1 H). LCMS (Method 1A): [M+H]+m / z 237.0 / 239.0, RT 0.49 min.

[0633] INTERMEDIATE 27: 3-n6-Chloro-3-pyridyl)methylltetrahvdrofuran-2-one

[0634] 3-Methylenetetrahydrofuran-2-one (0.45 mL, 5.10 mmol), (6-chloro-3-pyridyl)boronic acid (842 mg, 5.35 mmol) and chloro(1 ,5-cyclooctadiene)rhodium(l) dimer (126 mg, 0.26 mmol) were dissolved in 1 ,4-dioxane / H20 (6:1) (14.0 mL) and degassed with nitrogen for 5 minutes. Triethylamine (0.73 mL, 5.35 mmol) was added and the reaction mixture was stirred at 30 °C for 24 h. The reaction mixture was then concentrated in vacuo. The residue was taken up in sat. aq. NH4CI (20 mL) and the resultant mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL). The organic layer was dried over MgSC , 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 (890 mg, 57%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 5H 8.31 (d, J = 2.5 Hz, 1 H), 7.77 (dd, J = 8.2, 2.5 Hz, 1 H), 7.47 (dd, J = 8.2, 0.7 Hz, 1 H), 4.26 (td, J = 8.6, 2.5 Hz, 1 H), 4.12 (ddd, J = 10.0, 8.8, 6.5 Hz, 1 H), 3.10 - 2.95 (m, 2H), 2.73 (d, J = 7.5 Hz, 1 H), 2.16 (dddd, J = 12.4, 8.9, 6.5, 2.5 Hz, 1 H), 1.91 (dtd, J = 12.5, 10.1 , 8.5 Hz, 1 H). LCMS (Method 3A): [M+H]+m / z 212.2 / 214.2, RT 0.81 min.

[0635] INTERMEDIATE 28: 2-(4-Pyridyl)pyrimidin-5-amine

[0636] 2-Chloropyrimidin-5-amine (3.00 g, 23.2 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine (7.12 g, 34.7 mmol) and K2CO3 (9.60 g, 69.5 mmol) were dissolved in 1 ,4-dioxane (100 mL) and H2O (10 mL) and the resultant suspension was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2 (1.69 g, 2.32 mmol) was added and the reaction mixture was stirred at 80 °C for 16 h. The reaction 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) to afford the title compound (3.00 g, 70%) as a brown solid.1H NMR (400 MHz, DMSO-de) 5H 8.62 (d, J = 6.1 Hz, 2H), 8.25 (s, 2H), 8.13 - 8.00 (m, 2H), 6.00 (s, 2H). LCMS (Method 3B): [M+H]+m / z 173.0, RT 0.09 min. INTERMEDIATE 29: 2-R6-Chloro-3-pyridyl)methyl -hvdroxy-N-[2-(4- pyridyl)pyrimidin-5-yl1butanamide

[0637] Intermediate 27 (200 mg, 0.66 mmol) and Intermediate 28 (125 mg, 0.73 mmol) were dissolved in THF (10 mL) and 'PrMgCI (2 M in THF, 2mL, 2.0 mmol) was slowly added at r.t. The reaction mixture was stirred at r.t. for 3 h. The reaction mixture was quenched with sat. aq. NaHCOa (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL) and the organic phase dried over NaaSC , 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 (240 mg, 90%) as a brown solid.1H NMR (400 MHz, DMSO-de) 5H 10.48 (s, 1 H), 9.11 (s, 2H), 8.77 - 8.67 (m, 2H), 8.27 (d, J = 2.4 Hz, 1 H), 8.22 - 8.11 (m, 2H), 7.70 (dd, J = 8.3, 2.5 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 4.58 (t, J = 5.0 Hz, 1 H), 3.44 (ddq, J = 22.9, 11.3, 5.7 Hz, 2H), 2.97 - 2.80 (m, 3H), 1.84 (dt, J = 13.1 , 6.7 Hz, 1 H), 1.67 - 1.56 (m, 1 H). LCMS (Method 3B): [M+H]+m / z 384.2 / 386.1 , RT 1.18 min.

[0638] INTERMEDIATE 30: 4-(5-Bromo-2-pyridyl)pyridazine

[0639] 5-bromo-2-iodopyridine (598 mg, 2.06 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxoboran-2- yl)pyridazine (556 mg, 2.56 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol) and K2CO3 (850 mg, 6.09 mmol) were dissolved in 1 ,4-dioxane (7 mL) and H2O (1 .5 mL). The mixture was degassed with N2 and then heated to 100 °C for 2 h. The reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient) afforded the title compound (75 mg, 15%) as a white solid.1H NMR (400 MHz, DMSO-de) 6H 9.90 (dd, J = 2.5, 1 .3 Hz, 1 H), 9.39 (dd, J = 5.5, 1 .3 Hz, 1 H), 8.94 (dd, J = 2.3, 0.8 Hz, 1 H), 8.36 - 8.21 (m, 3H). LCMS (Method 1A): [M+H]+m / z 236.0 / 238.0, RT 0.92 min. INTERMEDIATE 31 : tert-Butyl 3-n6-chloro-5-fluoro-3-pyridyl)methyll-2-oxo-

[0640] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (1.55 g, 8.37 mmol) in THF (30 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 4.20 mL, 8.40 mmol) dropwise. The mixture was stirred at -78 °C for 1 h, then 5-(bromomethyl)-2-chloro-3- fluoropyridine (1.88 g, 8.38 mmol) was added. After 2 h the reaction was quenched with saturated aq. NFUCI (50 mL). The mixture was extracted with DCM (2 x 50 mL) and the combined organic layers dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0-100% gradient), afforded the title compound (2.54 g, 79%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5H 8.20 (d, J = 1 .9 Hz, 1 H), 7.89 (dd, J = 9.7, 2.0 Hz, 1 H), 3.63 (ddd, J = 10.8, 8.7, 2.3 Hz, 1 H), 3.47 (td, J = 10.1 , 7.0 Hz, 1 H), 3.09 (dd, J = 13.9, 5.1 Hz, 1 H), 2.95 (dtd, J = 10.8, 8.8, 5.2 Hz, 1 H), 2.71 (dd, J = 13.9, 9.2 Hz, 1 H), 1.94 (dtt, J = 13.2, 8.3, 6.7 Hz, 1 H), 1.71 - 1.56 (m, 1 H), 1.45 (s, 9H). LCMS (Method 1A): [M-Boc+H]+m / z 229.2, RT 1 .29 min.

[0641] INTERMEDIATE 32: 3-n6-Chloro-5-fluoro-3-pyridyl)methyllpyrrolidin-2-one

[0642] To a solution of Intermediate 31 (2.54 g, 6.57 mmol) in DCM (15 mL) was added TFA (5 mL, 65 mmol). The mixture was stirred overnight at r.t., then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aq. NaHCOa. The organic phase was concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so- hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient), afforded the title compound (530 mg, 35%) as a white solid. LCMS (Method 1 A): [M+H]+m / z 229.0 / 231 .0, RT 0.86 min. INTERMEDIATE 33 and INTERMEDIATE 34

[0643] (3S)-r(6-chloro-5-fluoro-3- -K6-chloro-5-fluoro-3- pyridyl)methyllpyrrolidin-2-one pyridyl)methyllpyrrolidin-2-one

[0644] Intermediate 33 (Peak 1) Intermediate 34 (Peak 2)

[0645] Intermediate 32 (400 mg) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IG, 250 x 20.0 mm, 5 pm;Method: MeOH (3 - 40%) over 10 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the title compounds: Intermediate 33 (Peak 1 ; 143 mg, 36%) and Intermediate 34 (Peak 2; 149 mg, 37%).

[0646] Peak 1 (Intermediate 33, (3S) enantiomer) LCMS (Method 1 B): [M+H]+m / z 229.2 / 231.2, RT 0.94 min.

[0647] Chiral SFC analysis (Column: Chiralpak IG, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1 % NH4OH (3 - 40%) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.46 min.

[0648] Peak 2 (Intermediate 34, (3R) enantiomer): LCMS (Method 1 B): [M+H]+m / z 229.2 / 231.2, RT 0.94 min.

[0649] Chiral SFC analysis (Column: Chiralpak IG, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1 % NH4OH (3 - 40%) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 5.48 min.

[0650] The absolute configuration of Intermediate 33 (S-configuration) and Intermediate 34 (R- configuration) was determined using VCD spectroscopy.

[0651] INTERMEDIATE 35: tert-Butyl 3-r(6-fluoro-3-pyridyl)methyll-2-oxo-pyrrolidine-1- carboxylate To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (1 g, 5.4 mmol) in THF (25 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 2.7 mL, 5.4 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h, and then 5-(bromomethyl)-2-fluoropyridine (962 mg, 4.86 mmol) was added and the reaction mixture was stirred at -78 °C for 1 h and warmed to r.t. and left to stir for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), then water (10 mL) and DCM (50 mL) were added to the reaction mixture. The aqueous layer was extracted with DCM (50 mL), and the combined organic layer was passed through a phase separator frit and concentrated in vacuo to a crude yellow oil. The above procedure was repeated on the same scale, and the crude residue combined with the above crude material and purified by NP flash chromatography eluting with EtOAc / iso-hexane (0-100% gradient, and then MeOH / EtOAc, 0-30% gradient) to afford the title compound (1.36g, 39%) as a pale-yellow solid.1H NMR (400 MHz, DMSO-de) 5H 8.10 (d, J = 2.5 Hz, 1 H), 7.87 (td, J = 8.2, 2.6 Hz, 1 H), 7.13 (dd, J = 8.4, 2.9 Hz, 1 H), 3.53 - 3.41 (m, 1 H), 3.05 (dd, J = 13.9, 4.8 Hz, 1 H), 2.90 (dtd, J = 10.6, 8.7, 4.8 Hz, 1 H), 2.76 - 2.58 (m, 1 H), 2.40 (t, J = 8.1 Hz, 1 H), 1.70 - 1.48 (m, 2H), 1.45 (d, J = 1.6 Hz, 9H). LCMS (Method 1A): [M- BOC+H]+195.2, RT 1.16 min.

[0652] INTERMEDIATE 36: 3-n6-Fluoro-3-pyridyl)methyllpyrrolidin-2-one

[0653] To a solution of Intermediate 35 in DCM (10 mL) was added TFA (4 mL, 52.24 mmol) and the reaction mixture was stirred at r.t. for 18 h. The reaction mixture was then concentrated in vacuo and the crude residue was dissolved in DCM (10 mL), washed with sat.aq. NaHCOa (10 mL), filtered through a phase separator and then concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / / so-hexane (0-100% gradient, and then 0- 50% MeOH / EtOAc) to afford the title compound (450 mg, 50%) as a pale-yellow solid.1H NMR (400 MHz, DMSO-de) 5H 8.10 (dt, J = 2.7, 0.8 Hz, 1 H), 7.87 (td, J = 8.3, 2.5 Hz, 1 H), 7.65 (s, 1 H), 7.11 (ddd, J = 8.4, 2.9, 0.6 Hz, 1 H), 3.20 - 3.06 (m, 1 H), 3.06 - 2.92 (m, 1 H), 2.67 - 2.51 (m, 3H), 2.05 - 1.93 (m, 1 H), 1.72 - 1.56 (m, 1 H). LCMS (Method 1A): [M+H]+m / z 195.2, RT 0.64 min. INTERMEDIATE 37 and INTERMEDIATE 38

[0654] ( pyridyl)methyllpyrrolidin-2-one Pyridyl)methyl]pyrrolidin-2-one

[0655] Intermediate 37 (Peak 1) Intermediate 38 (Peak 2)

[0656] Intermediate 36 (22.7 g) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 238 x 76 mm, 20 pm;Method: EtOH (20% isocratic) over 15 mins; Column temperature: 30 °C; Flowrate: 700 mL / min) to afford the title compounds: Intermediate 37 (Peak 1 ; 11 .0 g, 48%) and Intermediate 38 (Peak 2; 9.8 g, 43%).

[0657] Peak 1 (Intermediate 37, (3S) enantiomer) Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeCN 100% + 0.1% DEA over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 2.86 min.

[0658] Peak 2 (Intermediate 38, (3R) enantiomer) Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeCN 100% + 0.1% DEA over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 4.81 min.

[0659] The absolute configuration of Intermediate 37 (S-configuration) and Intermediate 38 (R- configuration) was determined using VCD spectroscopy.

[0660] INTERMEDIATE 39: 3-Chloro-6-(3-methoxy-4-pyridyl)pyridazine

[0661] Prepared from 3,6-dichloropyridazine (600 mg, 4.03 mmol) and (3-methoxy-4- pyridyl)boronic acid (647 mg, 4.23 mmol) in accordance with the procedure described for Intermediate 4 to afford the title compound (400 mg, 36%) as a brown solid. LCMS (Method 3B): [M+H]+m / z 222.0 / 224.1 , RT 0.68 minutes.1H NMR (500 MHz, DMSO) 5 8.23 (dd, J = 9.1 , 1.4 Hz, 1 H), 8.03 (dd, J = 8.9, 1.3 Hz, 1 H), 7.83 (s, 1 H), 7.56 (d, J = 8.2 Hz, 1 H), 7.48 (t, J = 8.4 Hz, 1 H), 3.98 (d, J = 1.4 Hz, 3H).

[0662] INTERMEDIATE 40: 4-(6-Chloropyridazin-3-yl)pyridin-3-ol

[0663] To a solution of Intermediate 39 (368 mg, 1.58 mmol) in DCM (15 mL) was added BBra (1.00 mol / L in DCM, 4.73 mL, 4.73 mmol) at 0 °C. The reaction mixture was warmed to 50 °C and stirred for 2 h. The reaction mixture was cooled to r.t. and then poured into ice water. The resultant solution was extracted with 10% MeOH / DCM (3 x 20 mL). The combined organic extracts were washed with brine (30 mL). The organic layer was dried over MgSC , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% MeOH / iso-hexane) to afford the title compound (188 mg, 46%) as a brown solid. LCMS (Method 3B): [M+H]+m / z 208.0 / 210.0, RT 0.59 minutes.1H NMR (500 MHz, DMSO) 5 8.52 - 8.46 (m, 2H), 8.42 (d, J = 5.5 Hz, 1 H), 8.19 (d, J = 5.4 Hz, 1 H), 8.14 (d, J = 9.0 Hz, 1 H). OH not observed.

[0664] INTERMEDIATE 41 : 6-(2,6-Dichloro-4-pyridyl)pyridazin-3-amine

[0665] Prepared from (2,6-dichloro-4-pyridyl)boronic acid (750 mg, 3.91 mmol) and 6- bromopyridazin-3-amine (816 mg, 4.69 mmol) in accordance with the procedure described for Intermediate 4 to afford the title compound (216 mg, 23%) as a white solid. LCMS (Method 3B): [M+H]+m / z 241.0 / 243.0, RT 0.71 minutes.1H NMR (400 MHz, DMSO-d6) 5 8.10 (s, 2H), 8.05 (d, J = 9.4 Hz, 1 H), 6.98 (s, 2H), 6.86 (d, J = 9.4 Hz, 1 H).

[0666] INTERMEDIATE 42: 6-(2,6-Dideuterio-4-pyridyl)pyridazin-3-amine

[0667] Intermediate 41 (216 mg, 0.88 mmol) and NEta (1 .00 mL, 7.17 mmol) were dissolved in a mixture of THF (10 mL) and MeOD (5 mL). The H-Cube hydrogen cell was flushed with D2O (50 mL) and then washed with THF (50 mL). The H-Cube was set up on a loop with a small 10% Pd / C CatCart at 40 °C (1 bar), 1 mL / min for 2 h. The mixture was concentrated in vacuo and the product was purified by reverse phase flash chromatography on C18 silica (10%-60% then 100% MeCN / [1%NH3 in H2O]) to afford the title compound (138 mg, 88%) as a white solid. LCMS (Method 3C): [M+H]+m / z 175.2, RT 0.63 minutes.1H NMR (400 MHz, DMSO-d6) 57.97 - 7.90 (m, 3H), 6.88 (d, J = 9.3 Hz, 1 H), 6.74 (s, 2H).

[0668] INTERMEDIATE 43: 3-Chloro-6-(2,6-dideuterio-4-pyridyl)pyridazine t-BuONO (0.35 mL, 2.65 mmol) was added to a mixture of Intermediate 42 (157 mg, 0.86 mmol) and CuCI (260 mg, 2.63 mmol) in dry DMSO (3 mL) under nitrogen. The mixture was heated to 50 °C and stirred for24 h. The mixture was cooled to r.t. , diluted with sat. aq. NaHCOa (20 mL) and EtOAc (20 mL), stirred for a few minutes, filtered through a small pad of Celite® and washed with EtOAc (2 x 10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (44 mg, 13%) as a pale yellow solid. The product was used in the next step without further purification. LCMS (Method 3C): [M+H]+m / z 194.3 / 196.2, RT 0.85 minutes.1H NMR (400 MHz, DMSO-d6) 5 8.44 (d, J = 9.0 Hz, 1 H), 8.22 - 7.98 (m, 3H). INTERMEDIATE 44: 4-(6-Chloro-2-methoxy-3-pyridyl)pyridazine

[0669] To a reaction vial charged with 3-bromo-6-chloro-2-methoxy-pyridine (500 mg, 2.25 mmol) and Pd(PPha)4 (260 mg, 0.23 mmol) was added xylene (15 mL). The reaction mixture was degassed with nitrogen for 5 mins. This was followed by the addition of tributyl(pyridazin- 4-yl)stannane (913 mg, 2.47 mmol) and the reaction mixture was degassed with nitrogen for a further s mins. The reaction vial was sealed and heated at 140 °C for 16 h. The reaction mixture was cooled to r.t. and diluted with sat. aq. NaHCOa (20 mL) and EtOAc (30 mL). The resultant solution was filtered through Celite® and the filtrate was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with 1 M aq KF solution (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0-100% (3:1 EtOAc / EtOH) / lso-hexane) to afford the title compound (210 mg, 41%) as a white solid. LCMS (Method 3A): [M+H]+m / z 222.2 / 224.0, RT 0.57 minutes.1H NMR (400 MHz, DMSO) 5 9.49 (dd, J = 2.5, 1 .2 Hz, 1 H), 9.30 (dd, J = 5.4, 1.2 Hz, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.93 (dd, J = 5.4, 2.4 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 3.95 (s, 3H).

[0670] INTERMEDIATE 45: 3-Chloro-6-(3-methyl-4-pyridyl)pyridazine

[0671] Prepared from 3,6-dichloropyridazine (560 mg, 3.76 mmol) and 3-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (906 mg, 4.13 mmol) in accordance with the procedure described for Intermediate 4 to afford the title compound (400 mg, 47%) as an orange solid. LCMS (Method 3B): [M+H]+m / z 206.0 / 208.0, RT 0.31 minutes. INTERMEDIATE 46: tert-Butyl 4-n6-chloro-3-pyridyl)methyll-2,2.3.3.4- pentadeuterio-5-oxo-pyrrolidine-1 -carboxylate

[0672] To a solution of tert-butyl 2,2,3,3,4,4-hexadeuterio-5-oxo-pyrrolidine-1-carboxylate (530 mg, 2.77 mmol) in THF (6 mL) at -78 °C was added LDA (2M in THF / heptane / ethylbenzene, 1 .4 mL, 2.8 mmol) dropwise. The mixture was stirred at -78 °C for 1 h, then 5-(bromomethyl)-2- chloropyridine (610 mg, 2.81 mmol) was added. After 1 h the reaction was quenched with saturated aq. NH4CI. The mixture was extracted with DCM and the combined organic layers were filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0-100% gradient), afforded the title compound (713 mg, 82%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 8.32 - 8.26 (m, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.46 (dd, J = 8.2, 0.7 Hz, 1 H), 3.03 (d, J = 14.0 Hz, 1 H), 2.67 (d, J = 14.1 Hz, 1 H), 1 .45 (s, 9H). LCMS (Method 1A): [M+H]+ m / z 316.2, RT 0.97 min.

[0673] INTERMEDIATE 47: 3-r(6-Chloro-3-pyridyl)methyll-3,4,4,5,5-pentadeuterio- pyrrolidin-2-one

[0674] To a solution of Intermediate 46 (710 mg, 2.25 mmol) in DCM (10 mL) was added TFA (4 mL, 50 mmol). The mixture was stirred for 2 h at r.t. , then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aq. NaHCOa. The organic phase was concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0- 100% gradient) and then MeOH / EtOAc (0-20% gradient), afforded the title compound (236 mg, 49%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.29 (dd, J = 2.5, 0.7 Hz, 1 H), 7.75 (dd, J = 8.2, 2.6 Hz, 1 H), 7.63 (s, 1 H), 7.44 (dd, J = 8.2, 0.7 Hz, 1 H), 2.97 (d, J = 14.0 Hz, 1 H), 2.61 (d, J = 14.0 Hz, 1 H). LCMS (Method 1A): [M+H1+ m / z 216.2, RT 0.64 min. INTERMEDIATE 48: 4-(6-Bromo-3-pyridyl)pyridazine

[0675] 2-Bromo-5-iodopyridine (520 mg, 1.83 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxoboran- 2-yl)pyridazine (406 mg, 1.87 mmol), Pd(dppf)Cl2 (46 mg, 0.063 mmol) and K2CO3 (569 mg, 4.08 mmol) were dissolved in 1 ,4-dioxane (2 mL) and H2O (1 mL). The mixture was degassed with N2 and then heated to 90 °C for 4 h. 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 (0-25% gradient) afforded the title compound (203 mg, 47%) as a red solid.1H NMR (400 MHz, DMSO) 5 9.73 (s, 1 H), 9.36 (d, J = 5.4 Hz, 1 H), 8.97 (d, J = 2.7 Hz, 1 H), 8.32 (dd, J = 8.4, 2.7 Hz, 1 H), 8.13 (dd, J = 5.4, 2.5 Hz, 1 H), 7.89 (d, J = 8.3 Hz, 1 H). LCMS (Method 1 A): [M+H]+ m / z 236.0 / 238.0, RT 0.78 min.

[0676] INTERMEDIATE 49: (6-Chloro-3-pyridyl)-dideuterio-methanol

[0677] To a solution of ethyl 6-chloronicotinate (1.73 g, 9.04 mmol) in THF (20 mL) and d-MeOH (5 mL) at 0°C was added sodium borodeuteride (872 mg, 18.7 mmol). The reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with sat. aq. NH4CI and extracted with DCM. The combined organic extracts were 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 (1 .05 mg, 78%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.35 (dd, J = 2.5, 0.7 Hz, 1 H), 7.79 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (dd, J = 8.2, 0.7 Hz, 1 H), 5.37 (s, 1 H). LCMS (Method 1A): [M+H]+ m / z 146.0, RT 0.35 min. INTERMEDIATE 50: 5-rBromo(dideuterio)methyll-2-chloro-pyridine

[0678] To a solution of Intermediate 49 (1.03 g, 7.08 mmol) in THF (20 mL) were added CBr4 (2.87 g, 8.65 mmol) and PPha (2.27 g, 8.65 mmol) at r.t. and the reaction mixture was stirred for 2 h. The reaction mixture was then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-70% EtOAc / iso-hexane) to afford the title compound (1.33 mg, 90%) as a white solid.1H NMR (300 MHz, DMSO) 5 8.51 (dd, J = 2.6, 0.7 Hz, 1 H), 7.96 (dd, J = 8.3, 2.5 Hz, 1 H), 7.55 (dd, J = 8.2, 0.7 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 208.0, RT 0.86 min.

[0679] INTERMEDIATE 51 : tert-Butyl 4-n6-chloro-3-pyridyl)-dideuterio-methyll-2,2,3,3,4-

[0680] To a solution of tert-butyl 2,2,3,3,4,4-hexadeuterio-5-oxo-pyrrolidine-1-carboxylate (460 mg, 2.41 mmol) in THF (5 mL) at -78 °C was added LDA (2 M soln, in THF / heptane / ethylbenzene, 1.2 mL, 2.4 mmol) dropwise. The mixture was stirred at -78 °C for

[0681] 1 h, then Intermediate 50 (510 mg, 2.45 mmol) was added. After 2 h the reaction was quenched with sat. aq. NH4CI. The mixture was extracted with DCM and the combined organic layers were filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso- hexane (0-100% gradient), afforded the title compound (598 mg, 78%) as an orange oil.1H NMR (300 MHz, DMSO) 5 8.29 (dd, J = 2.6, 0.7 Hz, 1 H), 7.74 (dd, J = 8.2, 2.5 Hz, 1 H), 7.46 (dd, J = 8.2, 0.7 Hz, 1 H), 1 .45 (s, 9H). LCMS (Method 1 A): [M-Boc+H]+ m / z 218.0, RT 0.98 min. INTERMEDIATE 52: 3-[(6-Chloro-3-pyridyl)-dideuterio-methyl1-3.4.4.5.5-

[0682] To a solution of Intermediate 51 (595 mg, 1.87 mmol) in DCM (10 mL) was added TFA (3mL, 40 mmol). The mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aq. NaHCOa. The organic phase was concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0- 100% gradient) and then MeOH / EtOAc (0-20% gradient), afforded the title compound (252 mg, 62%) as a white solid.

[0683] INTERMEDIATE 53 and INTERMEDIATE 54: (3S) and (3R) of 3-r(6-chloro-3-

[0684] Pyridyl)-dideuterio-methyl1-3,4,4,5,5-pentadeuterio-pyrrolidin-2-one

[0685] Intermediate 52 (231 mg, 1.10 mmol) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 250 x 20.0 mm, 5 pm ; Method: MeOH + 0.1% NH4OH (3 - 40%) over 7.5 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the title compounds: Intermediate 53 (Peak 1 ; 97 mg, 38%) and Intermediate 54 (Peak 2; 99 mg, 39%).

[0686] Peak 1 (Intermediate 53, (3S) enantiomer):1H NMR (300 MHz, DMSO) 5 8.29 (dd, J = 2.6, 0.7 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.62 (s, 1 H), 7.44 (dd, J = 8.2, 0.7 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 218.2, RT 0.75 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.74 min.

[0687] Peak 2 (Intermediate 54, (3R) enantiomer):1H NMR (300 MHz, DMSO) 5 8.29 (dd, J = 2.6, 0.7 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.62 (s, 1 H), 7.44 (dd, J = 8.2, 0.7 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 218.2, RT 0.77 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH+O.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.64 min.

[0688] INTERMEDIATE 55: Dideuterio-(6-fluoro-3-pyridyl)methanol

[0689] To a solution of methyl 6-fluoropyridine-3-carboxylate (1 .83 g, 11 .2 mmol) in THF (20 mL) and d-MeOH (5 mL) at 0°C was added sodium borodeuteride (872 mg, 18.7 mmol). The reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with sat. aq. NH4CI and extracted with DCM. The combined organic extracts were 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 (708 mg, 49%) as a colourless oil.1H NMR (300 MHz, DMSO) 5 8.17 (dt, J = 2.5, 0.9 Hz, 1 H), 7.92 (td, J = 8.3, 2.5 Hz, 1 H), 7.15 (ddd, J = 8.4, 2.8, 0.7 Hz, 1 H), 5.32 (s, 1 H). LCMS (Method 1A): [M+H]+ m / z 130.2, RT 0.20 min.

[0690] INTERMEDIATE 56: 5-rBromo(dideuterio)methyll-2-fluoro-pyridine

[0691] To a solution of Intermediate 55 (700 mg, 5.42 mmol) in THF (16 mL) were added CB (2.32 g, 7.00 mmol) and PPha (1 .78 g, 6.79 mmol) at r.t. and the reaction mixture was stirred for 2 h. The reaction mixture was then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-70% EtOAc / iso-hexane) to afford the title compound (628 mg, 66%) as a colourless oil.1H NMR (300 MHz, DMSO) 5 8.35 (dt, J = 2.7, 0.8 Hz, 1 H), 8.09 (ddd, J = 8.5, 7.9, 2.6 Hz, 1 H), 7.22 (ddd, J = 8.5, 2.8, 0.7 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 193.8, RT 0.76 min. INTERMEDIATE 57: tert-Butyl 2,2,3,3,4-pentadeuterio-4-rdideuterio-(6-fluoro-3- pyridyl)methyll-5-oxo-pyrrolidine-1 -carboxylate

[0692] To a solution of tert-butyl 2,2,3,3,4,4-hexadeuterio-5-oxo-pyrrolidine-1-carboxylate (510 mg, 2.67 mmol) in THF (5.5 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 1.4 mL, 2.8 mmol) dropwise. The mixture was stirred at -78 °C for 30 min, then Intermediate 56 (530 mg, 2.76 mmol) was added. After 2 h the reaction was quenched with sat. aq. NH4CI. The mixture was extracted with DCM and the combined organic layers were filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0-100% gradient), afforded the title compound (300 mg, 37%) as a paleyellow oil.1H NMR (300 MHz, DMSO) 5 8.10 (dt, J = 2.6, 0.9 Hz, 1 H), 7.86 (td, J = 8.2, 2.6 Hz, 1 H), 7.13 (ddd, J = 8.4, 2.9, 0.7 Hz, 1 H), 1.45 (s, 9H). LCMS (Method 1A): [M-Boc+H]+ m / z 202.2, RT 1.18 min.

[0693] INTERMEDIATE 58 and INTERMEDIATE 59: (3S) and of 3,4,4.5.5- Pentade uteri o-3-rdideuterio-(6-fluoro-3-pyridyl)methyllpyrrolidin-2 -one

[0694] To a solution of Intermediate 57 (295 mg, 0.979 mmol) in DCM (5 mL) was added TFA (1.5 mL, 20 mmol). The mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The residue was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 250 x 20.0 mm, 5 pm ; Method: MeOH + 0.1 % NH4OH (3 - 40%) over 7.5 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the title compounds Intermediate 58 (Peak 1 ; 66 mg, 20%) and Intermediate 59 (Peak 2; 64 mg, 19%).

[0695] Peak 1 (Intermediate 58, (3S) enantiomer):1H NMR (300 MHz, DMSO) 5 8.29 (dd, J = 2.5, 0.7 Hz, 1 H), 7.75 (dd, J = 8.2, 2.5 Hz, 1 H), 7.66 (s, 1 H), 7.44 (dd, J = 8.2, 0.7 Hz, 1 H), 3.18 - 3.00 (m, 2H), 2.57 (t, J = 9.1 Hz, 1 H), 2.07 - 1 .91 (m, 1 H), 1 .64 (ddt, J = 12.5, 9.6, 8.5 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 202.4, RT 0.60 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.28 min.

[0696] Peak 2 (Intermediate 59, (3R) enantiomer):1H NMR (300 MHz, DMSO) 5 8.10 (dt, J = 1.8, 0.8 Hz, 1 H), 7.87 (td, J = 8.3, 2.5 Hz, 1 H), 7.62 (s, 1 H), 7.11 (ddd, J = 8.5, 2.9, 0.7 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 202.2, RT 0.59 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH+0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.11 min.

[0697] INTERMEDIATE 60: tert-Butyl 3-r(6-chloro-3-pyridyl)-dideuterio-methyll-2-oxo-

[0698] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (694 mg, 3.56 mmol) in THF (7 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 1.8 mL, 3.6 mmol) dropwise. The mixture was stirred at -78 °C for 30 min, then Intermediate 50 (750 mg, 3.60 mmol) was added. After 3 h the reaction was quenched with sat. aq. NH4CI. The mixture was extracted with DCM and the combined organic layers were filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0-100% gradient), afforded the title compound (495 mg, 45%) as a pale yellow solid. LCMS (Method 1A): [M- Boc+H]+ m / z 313.0, RT 0.98 min.

[0699] INTERMEDIATE 61 and INTERMEDIATE 62: (3S) and (3R) of 3-r(6-Chloro-3- Pyridyl)-dideuterio-methyllpyrrolidin-2-one To a solution of Intermediate 60 (490 mg, 1 .57 mmol) in DCM (8 mL) was added TFA (2.4 mL, 31 mmol). The mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The residue was subjected to chiral purification by SFC chromatography (Column: Chiralpak I H, 250 x 20.0 mm, 5 pm ; Method: MeOH + 0.1% NFUOH (3 - 40%) over 7.5 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the title compounds’. Intermediate 61 (Peak 1 ; 22 mg, 11%) and Intermediate 62 (Peak 2; 22 mg, 11%).

[0700] Peak 1 (Intermediate 61, (3S) enantiomer):1H NMR (300 MHz, DMSO) 5 8.10 (dt, J = 1.8, 0.8 Hz, 1 H), 7.87 (td, J = 8.3, 2.5 Hz, 1 H), 7.62 (s, 1 H), 7.11 (ddd, J = 8.5, 2.9, 0.7 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 213.2, RT 0.76 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.75 min.

[0701] Peak 2 (Intermediate 62, (3R) enantiomer):1H NMR (300 MHz, DMSO) 5 8.10 (dt, J = 1.8, 0.8 Hz, 1 H), 7.87 (td, J = 8.3, 2.5 Hz, 1 H), 7.62 (s, 1 H), 7.11 (ddd, J = 8.5, 2.9, 0.7 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 213.2, RT 0.76 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH+0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.68 min.

[0702] INTERMEDIATE 63: tert-Butyl 3-rdideuterio-(6-fluoro-3-pyridyl)methyll-2-oxo- pyrrolidine-1 -carboxylate

[0703] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (1.51 g, 7.74 mmol) in THF (40 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 4 mL, 8.0 mmol) dropwise. The mixture was stirred at -78 °C for 30 min, then Intermediate 56 (1.57 g, 8.18 mmol) was added. After 3 h the reaction was quenched with sat. aq. NH4CI. The mixture was extracted with DCM and the combined organic layers were filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0-70% gradient), afforded the title compound (1.29 g, 51%) as a pale-yellow solid. LCMS (Method 1A): [M-Boc+H]+ m / z 197.2, RT 1.19 min. INTERMEDIATE 64 and INTERMEDIATE 65: (3S) and (3R) of 3-rDideuterio-(6- fluoro-3-pyridyl)methyllpyrrolidin-2-one

[0704] To a solution of Intermediate 63 (1.29 g, 3.92 mmol) in DCM (13 mL) was added TFA (6 mL, 80 mmol). The mixture was stirred at r.t. for 30 min, then concentrated in vacuo. The residue was subjected to chiral purification by SFC chromatography (Column: Chiralpak I H, 250 x 20.0 mm, 5 pm ; Method: MeOH + 0.1% NFUOH (3 - 40%) over 7.5 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the title compounds: Intermediate 64 (Peak 1 ; 199 mg, 26%) and Intermediate 65 (Peak 2; 176 mg, 23%).

[0705] Peak 1 (Intermediate 64, (3S) enantiomer):1H NMR (400 MHz, DMSO) 5 8.10 (q, J = 1.1 Hz, 1 H), 7.87 (td, J = 8.3, 2.5 Hz, 1 H), 7.65 (s, 1 H), 7.11 (ddd, J = 8.4, 2.9, 0.7 Hz, 1 H), 3.15 - 3.06 (m, 1 H), 3.10 - 3.01 (m, 1 H), 2.56 (t, J = 9.0 Hz, 1 H), 1.99 (dddd, J = 12.2, 8.6, 6.8, 3.3 Hz, 1 H), 1.65 (ddt, J = 12.5, 9.6, 8.5 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 197.2, RT 0.60 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.30 min.

[0706] Peak 2 (Intermediate 65, (3R) enantiomer):1H NMR (400 MHz, DMSO) 5 8.10 (q, J = 1.1 Hz, 1 H), 7.87 (td, J = 8.3, 2.5 Hz, 1 H), 7.65 (s, 1 H), 7.11 (ddd, J = 8.4, 2.9, 0.7 Hz, 1 H), 3.15 - 3.06 (m, 1 H), 3.10 - 3.01 (m, 1 H), 2.56 (t, J = 9.0 Hz, 1 H), 1.99 (dddd, J = 12.2, 8.6, 6.8, 3.3 Hz, 1 H), 1.65 (ddt, J = 12.5, 9.6, 8.5 Hz, 1 H). LCMS (Method 1 B): [M+H]+ m / z 197.2, RT 0.60 min. Chiral SFC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH+0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.14 min.

[0707] INTERMEDIATE 66: (6-Chloro-5-fluoro-3-pyridyl)-dideuterio-methanol To a solution of methyl 6-chloro-5-fluoropyridine-3-carboxylate (5.04 g, 25.3 mmol) in THF (40 mL) and d-MeOH (12 mL) at 0°C was added sodium borodeuteride (2.30 g, 49.5 mmol). The reaction mixture was stirred at r.t. for 4 h. The reaction mixture was quenched with sat. aq. NH4CI and extracted with DCM. The combined organic extracts were 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 (3.70 g, 90%) as a white solid.1H NMR (400 MHz, DMSO) 58.25 (dd, J = 1 .9, 0.8 Hz, 1 H), 7.84 (dd, J = 9.4, 1 .9 Hz, 1 H), 5.50 (s, 1 H). LCMS (Method 1 A): [M+H]+ m / z 164.0, RT 0.64 min.

[0708] INTERMEDIATE 67: 5-rBromo(dideuterio)methyll-2-chloro-3-fluoro-pyridine

[0709] To a solution of Intermediate 66 (2.03 g, 12.4 mmol) in DCM (16 mL) were added EtsN (4.2 mL, 30 mmol) and MsCI (1.2 mL, 16 mmol) at 0°C and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with sat. aq. NH4CI and extracted with DCM. The combined organic extracts were filtered and concentrated in vacuo. The residue was dissolved in THF (35 mL) and LiBr (2.72 g, 31 .3 mmol) was added. The reaction mixture was stirred at r.t. for 30 min. The reaction mixture was quenched with sat. aq. NH4CI and extracted with DCM. The combined organic extracts were filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-70% EtOAc / iso-hexane) to afford the title compound (2.48 g, 88%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.42 (dd, J = 2.0, 0.7 Hz, 1 H), 8.09 (dd, J = 9.2, 2.0 Hz, 1 H). LCMS (Method 1 A): [M+H]+ m / z 228.2, RT 1 .21 min.

[0710] INTERMEDIATE 68: tert-Butyl 3-[(6-chloro-5-fluoro-3-pyridyl)-dideuterio-methyl1-2- oxo-pyrrolidine-1 -carboxylate

[0711] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (2.20 g, 11.3 mmol) in THF (50 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 5.6 mL, 11 mmol) dropwise. The mixture was stirred at -78 °C for 30 min, then Intermediate 67 (2.56 g, 11.3 mmol) was added. After 3 h the reaction was quenched with sat. aq. NH4CI. The mixture was extracted with DCM and the combined organic layers were filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso-hexane (0-70% gradient), afforded the title compound (2.52 g, 68%) as a pale-yellow solid. LCMS (Method 1A): [M-Boc+H]+ m / z 231.2, RT 1.33 min.

[0712] INTERMEDIATE 69 and INTERMEDIATE 70: (3S) and of 3-rDideuterio-(6- fluoro-3-pyridyl)methyllpyrrolidin-2-one

[0713] Step 1 : To a solution of Intermediate 68 (2.51 g, 7.59 mmol) in DCM (25 mL) was added TFA (11 mL, 140 mmol). The mixture was stirred at r.t. for 2 h, then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aq. NaHCO3. The organic phase was concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / iso- hexane (0-100% gradient) and then MeOH / EtOAc (0-20% gradient), afforded racemic 3- [dideuterio-(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one (1.10 g) as a white solid.

[0714] Step 2: Racemic 3-[dideuterio-(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one was subjected to chiral purification by SFC chromatography (Column: Chiralpak IG, 250 x 50.0 mm, 20 pm ; Method: MeOH (20%); Column temperature: 30 °C; Flowrate: 360 mL / min) to afford the title compounds: Intermediate 69 (Peak 1 ; 377 mg, 22% over 2 steps) and Intermediate 70 (Peak 2; 366 mg, 21 % over 2 steps).

[0715] Peak 1 (Intermediate 69, (3S) enantiomer):1H NMR (400 MHz, DMSO) 5 8.20 (dd, J = 2.0, 0.9 Hz, 1 H), 7.90 (dd, J = 9.7, 2.0 Hz, 1 H), 7.69 (s, 1 H), 3.14 - 3.05 (m, 2H), 2.66 - 2.57 (m, 1 H), 2.01 (dddd, J = 12.6, 8.5, 5.5, 4.3 Hz, 1 H), 1.66 (ddt, J = 12.5, 9.8, 8.6 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 231.2, RT 0.90 min. Chiral SFC analysis (Column: Chiralpak IG, 4.6 x 150 mm, 3 pm; Method: EtOH 50% + n-heptane 50% + 0.1% DEA; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 3.35 min. Peak 2 (Intermediate 70, (3R) enantiomer):1H NMR (400 MHz, DMSO) 6 8.20 (dd, J = 2.0, 0.9 Hz, 1 H), 7.90 (dd, J = 9.7, 2.0 Hz, 1 H), 7.69 (s, 1 H), 3.14 - 3.05 (m, 2H), 2.66 - 2.57 (m, 1 H), 2.01 (dddd, J = 12.6, 8.5, 5.5, 4.3 Hz, 1 H), 1.66 (ddt, J = 12.5, 9.8, 8.6 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 231.2, RT 0.90 min. Chiral SFC analysis (Column: Chiralpak IG, 4.6 x 150 mm, 3 pm; Method: EtOH 50% + n-heptane 50% + 0.1% DEA; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 4.24 min.

[0716] INTERMEDIATE 71 : -1-(3-Chloro-1.2.4-triazin-6-yl)-3-K6-fluoro-3- pyridyl)methyl]pyrrolidin-2-one

[0717] To 6-bromo-3-chloro-1 ,2,4-triazine (800 mg, 4.1 mmol), Intermediate 38 (879 mg, 4.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (194 mg, 0.21 mmol), Xantphos (245 mg, 0.4 mmol) and potassium phosphate tribasic (2.7 g, 12 mmol) was added 1 ,4-dioxane (20 mL) and the reaction mixture was stirred at 70°C for2 hours under a N2 atmosphere. The reaction mixture was filtered through a pad of Celite®, washed with DCM and concentrated in vacuo to a crude brown oil. The crude residue was purified by normal flash chromatography (silica gel, hexanes / EtOAc, 0%-100%, then EtOAc / MeOH, 0%-20%) to afford the title compound (370 mg, 29%) as a light yellow solid.1H NMR (300 MHz, DMSO) 5 9.63 (s, 1 H), 8.17 (d, J = 2.5 Hz, 1 H), 7.94 (td, J = 8.2, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.9 Hz, 1 H), 4.05 (ddd, J = 11.2, 8.7, 2.6 Hz, 1 H), 3.84 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.25 - 3.08 (m, 2H), 2.90 - 2.75 (m, 1 H), 2.22 (dtd, J = 12.4, 7.6, 2.6 Hz, 1 H), 2.03 - 1.78 (m, 1 H). LCMS (Method 1A): [M+H]+ m / z 308.0, RT 1.15 min.

[0718] INTERMEDIATE 72: 5-Bromo-6-fluoro-pyridin-2-amine

[0719] To a solution of 6-fluoropyridin-2-amine (10 g, 89 mmol) in MeCN (100 mL) was added N-bromosuccinimide (16.2 g, 91.0 mmol, 7.72 mL) portion wise. The reaction mixture was concentrated in vacuo to give a crude brown oil. The crude residue was stirred in water (200 mL) for 30 minutes (precipitation resulted), filtered and washed with water (2 x 100 mL). The material was then dried under vacuum overnight to afford the title compound (16.7 g, 98%) as a beige solid.1H NMR (400 MHz, CDCh) 5 7.62 (dd, J = 8.9, 8.3 Hz, 1 H), 6.28 (dd, J = 8.3, 1 .4 Hz, 1 H), 5.01 (s, 1 H), 4.56 (s, 1 H). LCMS (Method 1A): [M+H]+ m / z 191.0 / 193.0, RT 0.93 min.

[0720] INTERMEDIATE 73: 6-Fluoro-5-(4-pyridyl)pyridin-2-amine

[0721] To Intermediate 72 [5-bromo-6-fluoro-pyridin-2-amine (4 g, 20.9 mmol), pyridine-4- boronic acid hydrate (4.4 g, 31.4 mmol), [1 ,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (766 mg, 1.0 mmol) and potassium carbonate (5.9 g, 41.9 mmol) was added 1 ,4-dioxane (105 mL) and water (42 mL) and the reaction mixture was sparged with N2 for 5 minutes, and then stirred at 100 °C for 7 hours. The reaction mixture was cooled to r.t. and filtered through a pad of Celite®, eluting with MeOH. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) to afford the title compound (2.9 g, 72%) as a light grey solid.1H NMR (400 MHz, DMSO) 5 8.65 - 8.52 (m, 2H), 7.85 (dd, J = 10.8, 8.3 Hz, 1 H), 7.61 - 7.49 (m, 1 H), 7.53 - 7.42 (m, 1 H), 6.76 (s, 2H), 6.46 (dd, J = 8.3, 2.1 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 190.2, RT 0.76 min.

[0722] INTERMEDIATE 74: 2-r(6-Chloro-5-fluoro-3-pyridyl)methyll-N-r6-fluoro-5-(4- pyridyl)-2-pyridyll-4-hvdroxy-butanamide

[0723] To a solution of Intermediate 73 [6-fluoro-5-(4-pyridyl)pyridin-2-amine] (942 mg, 5.0 mmol) and 3-[(6-chloro-5-fluoro-3-pyridyl)methyl]tetrahydrofuran-2-one (1040 mg, 4.5 mmol) in THF (35 mL) at r.t. was added isopropylmagnesium chloride (6.8 mL, 14 mmol, 2 mmol / mL) dropwise over 10 minutes. During the addition the mixture gets lukewarm, turns yellow and precipitation occurs. The reaction mixture was stirred at r.t. for 1 hour. The reaction mixture was quenched by the careful dropwise addition of sat. aq. NaHCOa, and the mixture extracted with EtOAc (x 3). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. Further extraction with DCM (x 2), EtOAc (x 2) was performed, and the combined organic layer was dried (Na2SO4) and concentrated in vacuo to a brown oil. Purification by flash chromatography on silica gel (0-100% EtOAc / iso-hexane) afforded the title compound (1.2 g, 63%) as a cream-coloured foam.1H NMR (400 MHz, DMSO) 5 10.84 (s, 1 H), 8.72 - 8.63 (m, 2H), 8.25 (dd, J = 10.4, 8.3 Hz, 1 H), 8.19 - 8.08 (m, 2H), 7.86 (dd, J = 9.7, 1.9 Hz, 1 H), 7.62

[0724] (dt, J = 4.5, 1 .5 Hz, 2H), 4.52 (t, J = 5.1 Hz, 1 H), 3.50 - 3.32 (m, 2H), 3.12 - 3.01 (m, 1 H), 2.97 (dd, J = 13.5, 8.2 Hz, 1 H), 2.85 (dd, J = 13.5, 6.5 Hz, 1 H), 1.84 (ddt, J = 12.5, 9.0, 6.2 Hz, 1 H), 1.59 (dtd, J = 13.6, 7.0, 4.5 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 419.0, RT 1.09 min. INTERMEDIATE 75: 2-Bromo-5-(4-pyridyl)pyridine

[0725] To 2-bromo-5-iodopyridine (1 g, 3.52 mmol), pyridine-4-boronic acid hydrate (496 mg, 3.5 mmol), [1 ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (129 mg, 0.18 mmol) and potassium carbonate (984 mg, 7.04 mmol) was added 1 ,4-dioxane (18 mL) and water (7 mL) and the reaction mixture was sparged for 10 minutes with N2 and then heated to 80 °C and stirred for 18 hours. DCM and water were added to the reaction mixture and the aqueous layer was extracted with DCM, filtered through a phase separator and then concentrated in vacuo to a brown oil. Purification by flash chromatography on silica gel (0-30% MeOH / EtOAc) afforded the title compound (587 mg, 66%) as a pale pink solid.1H NMR (300 MHz, DMSO) 5 8.87 (dd, J = 2.7, 0.7 Hz, 1 H), 8.74 - 8.66 (m, 2H), 8.20 (dd, J = 8.3, 2.7 Hz, 1 H), 7.87 - 7.77 (m, 3H). LCMS (Method 1A): [M+H]+ m / z 235.0 / 237.0, RT 0.98 min.

[0726] INTERMEDIATE 76: 3-Bromo-2-fluoro-6-(4-pyridyl)pyridine To 3-bromo-2-fluoro-6-iodopyridine (500 mg, 2 mmol), pyridine-4-boronic acid hydrate

[0727] (200 mg, 2 mmol), [1 ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (60 mg, 0.08 mmol) and potassium carbonate (400 mg, 3 mmol) was added 1 ,4-dioxane (8 mL) and water (3 mL) and the reaction mixture was sparged for 10 minutes with N2 and then heated to 80 °C for 2 hours. DCM and water were added to the reaction mixture, and the aqueous layer was extracted with DCM, filtered through a phase separator and then concentrated in vacuo to a brown oil. Purification by flash chromatography on silica gel (0-30% MeOH / EtOAc) afforded the title compound (350 mg, 80% yield) as a pale pink solid. LCMS (Method 1 A): [M+H]+ m / z 253.0 / 255.0, RT 1.19 min.

[0728] INTERMEDIATE 77: 3-r(6-Chloro-3-pyridyl)methyll-1 -(3-chloro-1 ,2,4-triazin-6- yl)pyrrolidin-2-one

[0729] A solution of 6-bromo-3-chloro-1 ,2,4-triazine (100 mg, 0.51 mmol), 3-((6-chloropyridin-3- yl)methyl)pyrrolidin-2-one (120 mg, 0.57 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), Xantphos (31 mg, 0.051 mmol) and K3PO4 (334 mg, 1.54 mmol) dissolved in 1 ,4-dioxane (3 mL) was heated in a sealed vial at 90°C for 1 hour. The reaction mixture was then filtered through a pad of Celite®, rinsed with 1 ,4-dioxane (5 mL) and the filtrate was concentrated in vacuo to a brown oil. Purification by flash chromatography on silica gel (0-100% EtOAc / iso-hexane then 0-20% MeOH / EtOAc) afforded the title compound (60 mg, 35% yield) as a light yellow solid.1H NMR (400 MHz, DMSO) 5 9.63 (s, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 7.82 (dd, J = 8.2, 2.6 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.06 (ddd, J = 11.1 , 8.7, 2.6 Hz, 1 H), 3.84 (ddd, J = 10.9, 9.1 , 7.4 Hz, 1 H), 3.24 - 3.11 (m, 2H), 2.88 - 2.77 (m, 1 H), 2.22 (dtd, J = 12.6, 7.5, 2.5 Hz, 1 H), 1 .95 - 1 .80 (m, 1 H). LCMS (Method 1A): [M+H]+ m / z 324.0 / 326.0, RT 1.19 min.

[0730] INTERMEDIATE 78: -1-(6-bromopyridazin-3-yl)-3-r(6-fluoro-3- pyridyl)methyllpyrrolidin-2-one

[0731] A mixture of (3R)-3-[(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one (1.0 g, 5.1 mmol), 3,6- dibromopyridazine (1.4 g, 5.8 mmol) and potassium phosphate tribasic (3.4 g, 16 mmol) in 1 ,4- dioxane (100 mL) was evacuated (for ~5 mins) and backfilled with N2 (3x). (+ / -)-trans-1 ,2- diaminocyclohexane (0.25 mL, 2.1 mmol, 0.40) and cuprous iodide (390 mg, 2.0 mmol) were then added, the mixture evacuated and backfilled with N2 (3x) then heated under N2 at 90 °C for 2.5 hours. The cooled mixture was diluted with water (100 mL), extracted with EtOAc (2 x 100 mL), dried (Na2SC>4), concentrated in vacuo and purified by normal flash column chromatography (silica gel, EtOAc / iso-hexane, 0%-100%) to give the title compound as a white solid (398 mg, 22%).1H NMR (400 MHz, DMSO) 5 8.55 (d, J = 9.5 Hz, 1 H), 8.15 (d, J = 2.5 Hz, 1 H), 8.01 (d, J = 9.4 Hz, 1 H), 7.92 (td, J = 8.2, 2.5 Hz, 1 H), 7.13 (ddd, J = 8.4, 2.9, 0.7 Hz, 1 H), 4.07 (ddd, J = 11 .2, 8.7, 2.6 Hz, 1 H), 3.85 (ddd, J = 10.9, 9.0, 7.4 Hz, 1 H), 3.20 - 3.06 (m, 2H), 2.87 - 2.75 (m, 1 H), 2.20 - 2.08 (m, 1 H), 1 .82 (dq, J = 12.4, 9.0 Hz, 1 H). LCMS (Method 1 A): [M+H]+ m / z 351 .0 / 353.0, RT 0.97 min.

[0732] INTERMEDIATE 79: Methyl 2-r(1-tert-butoxycarbonyl-4-piperidyl)oxyl-6-chloro- pyridine-3 -carboxylate

[0733] To a solution of methyl 6-chloro-2-fluoronicotinate (464 mg, 2.37 mmol) and 1-boc-4- hydroxypiperidine (567 mg, 2.76 mmol) in THF (12 mL) at 0 °C was added NaH (140 mg, 3.50 mmol). The reaction mixture was stirred for 3 hours, and then quenched with saturated aqueous NH4CI. The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAcZ / so-hexane (0-70% gradient), afforded the title compound (179 mg, 20%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.20 (d, J = 7.9 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H), 5.33 (tt, J = 6.6, 3.3 Hz, 1 H), 3.82 (s, 3H), 3.46 (t, J = 5.6 Hz, 4H), 1.87 (dtd, J = 13.0, 6.3, 3.4 Hz, 2H), 1.67 (dq, J = 11.6, 5.3 Hz, 2H), 1.42 (s, 9H). LCMS (Method 1A): [M-Boc+H]+m / z 271.2, RT 1.59 minutes.

[0734] INTERMEDIATE 80: tert-Butyl 4- chloro-3-(hvdroxymethyl)-2- pyridylloxylpiperidine-1 -carboxylate To a solution of Intermediate 79 (400 mg, 1 .08 mmol) in THF (6 mL) and MeOH (1 mL) at 0 °C was added NaBH4 (83 mg, 2.2 mmol). The reaction mixture was stirred at r.t. for 3 hours, and then quenched with saturated aqueous NH4CI. The aqueous layerwas extracted with DCM and the combined organic layers were concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient), afforded the title compound (279 mg, 75%) as a colourless oil.1H NMR (400 MHz, DMSO) 5 7.76 (dt, J = 7.6, 1.1 Hz, 1 H), 7.08 (d, J = 7.7 Hz, 1 H), 5.27 (t, J = 5.5 Hz, 1 H), 5.18 (tt, J = 7.3, 3.6 Hz, 1 H), 4.44 (dd, J = 5.5, 1 .1 Hz, 2H), 3.55 (ddd, J = 12.0, 7.3, 3.8 Hz, 2H), 3.35 - 3.30 (m, 2H), 1 .94 - 1 .83 (m, 2H), 1 .60 (ddt, J = 13.1 , 7.6, 3.7 Hz, 2H), 1.41 (s, 9H).

[0735] INTERMEDIATE 81: tert-Butyl 4-rr3-(bromomethyl)-6-chloro-2- pyridylloxylpiperidine-1 -carboxylate

[0736] To a solution of Intermediate 80 (275 mg, 0.802 mmol) in DCM (2 mL) were added triethylamine (0.50 mL, 3.6 mmol) and methane sulfonyl chloride (0.12 mL, 1.55 mmol) at 0°C. After 2 hours, the mixture was quenched with water. The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo. The crude obtained was dissolved in THF (8 mL) and lithium bromide (200 mg, 2.30 mmol) was added. The reaction mixture was stirred at r.t. for 30 minutes, and then quenched with water. 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 (0-70% gradient), afforded the title compound (266 mg, 82%) as a colourless oil. LCMS (Method 1A): [M-f-Bu+H]+m / z 349.0 / 351.0, RT 1.69 minutes.

[0737] INTERMEDIATE 82: tert-Butyl 4-rr3-ni-tert-butoxycarbonyl-2-oxo-pyrrolidin-3- yl)methyll-6-chloro-2-pyridylloxylpiperidine-1 -carboxylate

[0738] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (133 mg, 0.682 mmol) in THF (3 mL) at -78 °C was added LDA (2 M THF / heptane / ethylbenzene solution, 0.34 mL, 0.68 mmol) dropwise. The mixture was stirred at -78 °C for 30 minutes, then Intermediate 81 (260 mg, 0.641 mmol) was added. The reaction was stirred at -78 °C for 1.5 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), afforded the title compound (161 mg, 46%) as a white solid.1H NMR (400 MHz, DMSO) 5 7.63 (d, J = 7.7 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 5.17 (tt, J = 7.2, 3.5 Hz, 1 H), 3.63 (ddd, J = 10.9, 8.6, 2.6 Hz, 1 H), 3.58 - 3.43 (m, 1 H), 3.36 (dt, J = 9.8, 4.4 Hz, 1 H), 3.01 (dd, J = 13.7, 4.9 Hz, 1 H), 2.93 - 2.80 (m, 1 H), 1.94 - 1 .82 (m, 3H), 1 .62 (s, 2H), 1 .69 - 1 .52 (m, 1 H), 1.45 (s, 9H) 1 .41 (s, 9H), 0.90 - 0.78 (m, 1 H). LCMS (Method 1A): [M-2xBoc+H]+m / z 310.2, RT 1.69 minutes.

[0739] INTERMEDIATE 83: tert-Butyl 4-rr6-chloro-3-r(2-oxopyrrolidin-3-yl)methyl]-2- pyridylloxylpiperidine-1 -carboxylate

[0740] To a solution of Intermediate 82 (160mg, 0.314 mmol) in DCM (3 mL) at r.t. was added TFA (0.50 mL, 6.5 mmol). After 30 minutes, the reaction mixture was concentrated in vacuo. The crude obtained was dissolved in THF (3 mL) and water (0.5 mL). NaHCOa (152 mg, 1.80 mmol) and B0C2O (62 mg, 0.28 mmol) were added to the mixture, which was stirred at r.t. for 3 hours. The mixture was diluted with DCM and water. 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), afforded the title compound (89 mg, 69%) as a white solid.1H NMR (300 MHz, DMSO) 6 8.65 - 8.57 (m, 2H), 8.16 (d, J = 2.5 Hz, 1 H), 8.02 (d, J = 0.8 Hz, 2H), 7.93 (td, J = 8.3, 2.5 Hz, 1 H), 7.70 - 7.62 (m, 2H), 7.15 (dd, J = 8.4, 2.9 Hz, 1 H), 5.34 (tt, J = 7.1 , 4.8 Hz, 1 H), 4.09 - 3.96 (m, 1 H), 3.88 - 3.73 (m, 1 H), 3.58 (ddd, J = 12.2, 7.8, 4.6 Hz, 1 H), 3.22 - 3.03 (m, 2H), 2.87 - 2.74 (m, 1 H), 2.42 - 2.06 (m, 3H), 1 .97 (s, 2H), 1 .89 - 1.69 (m, 1 H). LCMS (Method 1A): [M-Boc+H]+m / z 310.2, RT 1.41 minutes.

[0741] INTERMEDIATE 84: tert-Butyl 3-r(2,6-difluoro-3-pyridyl)methyll-2-oxo-pyrrolidine- 1 -carboxylate

[0742] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (0.95 g, 5.0 mmol) in THF (26 mL) at -78°C was added LDA (2 M THF / heptane / ethylbenzene solution, 2.6 mL, 5.2 mmol) dropwise. The mixture was stirred at -78 °C for 1 hour, then 3-(bromomethyl)-2,6- difluoropyridine (0.96 g, 4.6 mmol) was added. The reaction was stirred at -78°C for 2 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), afforded the title compound (0.18 g, 9%) as a light pink oil. LCMS (Method 1A): [M- Boc+H]+m / z 213.2, RT 1.32 min.

[0743] INTERMEDIATE 85: 3-r(2,6-Difluoro-3-pyridyl)rnethyl]pyrrolidin-2-one

[0744] To a solution of Intermediate 84 (2.11 g, 6.42 mmol) in DCM (6 mL) at r.t. was added TFA (1 mL, 13 mmol). After 2 hours, the reaction mixture was concentrated in vacuo to afford the crude title compound (0.13 g, 76%) as a light brown oil. LCMS (Method 1A): [M+H]+ m / z 213.2, RT 0.84 min. INTERMEDIATE 86: tert-Butyl (6-chloro-3-formylpyridin-2-yl)carbamate

[0745] To a solution of tert-butyl A / -(6-chloro-2-pyridyl)carbamate (2.50 g, 10.9 mmol) and N,N,N',N'-tetraethylethane-1 ,2-diamine (5.80 mL, 27.2 mmol) in THF (50 mL) was added n- butyllithium (1.89 mol / L, 14.5 mL, 27.3 mmol) at -78 °C. The mixture was allowed to warm to -10 °C and stirred for 90 mins. DMF (1.70 mL, 22.0 mmol) was added at -78 °C and the reaction was stirred at r.t. for 18 h. After completion, the reaction was quenched with saturated NH4CI solution (25 mL) and diluted with EtOAc (50 mL). Saturated sodium bicarbonate solution (50 mL) was added and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (30% EtOAc in iso-hexanes) to afford the title compound (1.19 g, 38%) as a yellow solid.1H NMR (500 MHz, DMSO-de) 5 10.37 (s, 1 H), 9.83 (s, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 1.46 (s, 9H). LCMS (Method 3B): [M-H]- m / z 255.1 / 256.8, RT 1.41 min.

[0746] INTERMEDIATE 87: tert-Butyl 3-((2-((tert-butoxycarbonyl)amino)-6-chloropyridin- 3-yl)(hvdroxy)methyl)-2-oxopyrrolidine-1 -carboxylate

[0747] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (0.750 mL, 4.41 mmol) in THF (4 mL) at -78 °C was added LiHMDS (in THF) (1 .00 mol / L, 5.50 mL, 5.50 mmol) dropwise. The resulting mixture was stirred for 1 h at -78 °C, after which a solution of Intermediate 86 (1 .19 g, 4.22 mmol) in THF (4 mL) was added dropwise. The mixture was stirred for a further 2 h, then allowed to warm to r.t. and quenched with saturated NH4CI solution (15 mL). The aqueous was extracted with EtOAc (3 x 20 mL) and the combined organic layer was washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (30% EtOAc in iso-hexanes) to afford the title compound (0.92 g, 35%) as a brown oil.1H NMR (500 MHz, DMSO-d6) 5 9.33 (s, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 5.90 (d, J = 4.7 Hz, 1 H), 5.32 (dd, J = 4.8, 2.5 Hz, 1 H), 3.61 - 3.58 (m, 1 H), 3.54 - 3.50 (m, 1 H), 2.96 - 2.90 (m, 1 H), 2.89 - 2.85 (m, 1 H), 1 .96 - 1 .90 (m, 1 H), 1.45 (s, 9H), 1.44 (s, 9H). LCMS (Method 3B): [M-Hp m / z 440.1 / 442.1 , RT 1.54 / 1.55 min.

[0748] INTERMEDIATE 88: tert-Butyl 3-((2-((tert-butoxycarbonyl)amino)-6-chloropyridin- 3-yl)methylene)-2-oxopyrrolidine-1 -carboxylate

[0749] A mixture of Intermediate 87 (0.92 g, 2.08 mmol) and NEta (0.80 mL, 5.90 mmol) in DCM (15 mL) was cooled to 0 °C. MsCI (0.30 mL, 3.88 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with H2O (15 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (15 mL), cooled to 0 °C and DBU (0.75 mL, 5.81 mmol) was added. The mixture was stirred at 0 °C for 1 h, quenched with H2O (20 mL) and diluted with DCM (10 mL). The aqueous layer was extracted with DCM (3 x 10 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 (0.77 g, 76%) as a brown oil.1H NMR (500 MHz, DMSO-d6) 5 9.74 (s, 1 H), 7.99 (d, J = 8.3 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.22 (t, J = 2.9 Hz, 1 H), 3.73 (dd, J = 7.7, 6.4 Hz, 2H), 2.94 (td, J = 7.1 , 2.9 Hz, 2H), 1 .48 (s, 9H), 1 .41 (s, 9H). LCMS (Method 3C): [M-Hp m / z 422.4, RT 1.67 min.

[0750] INTERMEDIATE 89: 3-((2-Amino-6-chloropyridin-3-yl)methyl)pyrrolidin-2-one

[0751] To a stirred solution of Intermediate 88 (0.77 g, 1.81 mmol) in DCM (10 mL) was added

[0752] TFA (0.65 mL, 8.75 mmol) and stirred for 3 h at r.t. The reaction mixture was concentrated in vacuo then redissolved in MeOH (10 mL) and THF (5 mL) and cooled to 0 °C. NiCh (24.0 mg, 0.185 mmol) was added, followed by NaBH4 (275 mg, 7.26 mmol) and the reaction was stirred at 0 °C for 1 hour, then allowed to warm to room temperature and stirred for 2 hours. Additional NaBH4 (275 mg, 7.26 mmol) was added, and the reaction stirred overnight. The reaction was recharged with NiC (24.0 mg, 0.185 mmol) and NaBH4 (275 mg, 7.26 mmol) and stirred for a further 90 mins. NiC (240 mg, 1 .85 mmol) and NaBH4 (275 mg, 7.26 mmol) were added, and the reaction stirred for a further 90 mins. NaBH4 (275 mg, 7.26 mmol) was added, and the reaction stirred for 72 hours. The mixture was diluted with EtOAc (20 mL) and H2O (20 mL) and filtered through Celite®. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (159 mg, 27%) as a yellow oil.1H NMR (500 MHz, DMSO- d6) 5 7.68 (s, 1 H), 7.28 (d, J = 7.7 Hz, 1 H), 6.50 (d, J = 7.6 Hz, 1 H), 6.20 (s, 1 H), 5.70 (s, 1 H), 3.15 - 3.08 (m, 2H), 2.75 (dd, J = 14.9, 4.7 Hz, 1 H), 2.56 (qd, J = 8.4, 4.6 Hz, 1 H), 2.43 (dd, J = 14.9, 8.6 Hz, 1 H), 2.10 - 2.01 (m, 1 H), 1.66 - 1.54 (m, 1 H). LCMS (Method 3B): [M+H]+m / z 226.0 / 228.0, RT 0.86 min.

[0753] INTERMEDIATE 90: / ?ac-3-((2-amino-6-chloropyridin-3-yl)methyl)-1 -(6-(pyridin-4- yl)pyridazin-3-yl)pyrrolidin-2-one

[0754] A solution of Intermediate 89 (175 mg, 0.54 mmol), 1-(6-bromopyridazin-3-yl)pyrrolidin-2- one (175 mg, 0.73 mmol) and K3PO4 (230 mg, 1.09 mmol) in dioxane (7 mL) was degassed with nitrogen for 5 minutes. XantPhos Pd G3 (40.3 mg, 0.055 mmol) was added, and the reaction mixture was heated at 70 °C for 18 h. Additional XantPhos Pd G3 (24 mg, 0.328 mmol) was added, and the reaction mixture was heated at 80 °C for 6 h. The reaction mixture was cooled down to r.t. , filtered through Celite®, and concentrated in vacuo. The residue was purified by flash chromatography on C18 silica (5-40% MeCN / 0.1 % formic acid in H2O) to afford the title compound (15 mg, 7%) as a white solid.1H NMR (500 MHz, DMSO-d6) 5 8.78 - 8.74 (m, 2H), 8.71 (d, J = 9.4 Hz, 1 H), 8.42 (d, J = 9.5 Hz, 1 H), 8.13 - 8.08 (m, 2H), 7.35 (d, J = 7.6 Hz, 1 H), 6.53 (d, J = 7.6 Hz, 1 H), 6.27 (s, 2H), 4.24 (ddd, J = 10.9, 8.6, 2.7 Hz, 1 H), 4.03 - 3.94 (m, 1 H), 3.20 - 3.09 (m, 1 H), 2.95 (dd, J = 14.9, 5.5 Hz, 1 H), 2.69 - 2.61 (m, 1 H), 2.27 - 2.18 (m, 1 H), 1 .88 - 1 .77 (m, 1 H). LCMS (Method 3B): [M+H]+m / z 381 / 383, RT: 1 .02 min. INTERMEDIATE 91 : tert-Butyl N-r4-(4.4,5.5-tetraethyl-1.3.2-dioxaborolan-2-yl)-3- pyridyllcarbamate

[0755] To a solution of tert-butyl N-(4-bromo-3-pyridyl)carbamate (3.0 g, 11 mmol) in THF (50 mL) was added triisopropyl borate (3.80 mL, 16.5 mmol) at -78 °C. This was followed by the slow addition of n-BuLi (1 .5 M, 22 mL, 33 mmol). The reaction mixture was stirred at -78 °C for 2 h, warmed to r.t. and acidified to a pH of 4 with AcOH (~5 mL). 3,4-Diethylhexane-3,4-diol (3.83 g, 22 mmol) was added at r.t. The mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-100% (3:1 EA:EtOH) / lso-hexane) to afford the title compound (1.10 g, 24%) as a white solid.1H NMR (500 MHz, CDCh) 59.49 (s, 1 H), 8.66 (s, 1 H), 8.28 (d, J = 4.8 Hz, 1 H), 7.63 (d, J = 4.7 Hz, 1 H), 1.79 (m, 8H), 1.52 (s, 9H), 0.98 (t, J = 7.4 Hz, 12H). LCMS (Method 3C): [M+H]+m / z 377.5, RT 1.38 min.

[0756] INTERMEDIATE 92: tert-Butyl N-r4-(6-chloropyridazin-3-yl)-3-pyridyl]carbamate

[0757] Prepared from Intermediate 91 (0.30 g, 0.72 mmol) and 3,6-dichloropyridazine (0.12 g, 0.79 mmol) in accordance with the procedure described for Intermediate 4 (2MeTHF / H2O, 70 °C, 20 h) to afford the title compound (0.10 g, 36%) as a brown solid. LCMS (Method 3B): [M+H]+m / z 307.1 / 309.1 , RT 1.20 min. INTERMEDIATE 93: 4-(6-Chloropyridazin-3-yl)pyridin-3-amine

[0758] Intermediate 92 (0.10 g, 0.26 mmol) was dissolved in TFA (3 mL), and the mixture was stirred at r.t. for 16 h and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and quenched with saturated NaHCOa (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic extracts were dried over Na2SC>4, filtered and concentrated in vacuo to afford the title compound (50 mg, 74%) as a brown solid.1H NMR (500 MHz, DMSO) 5 8.37 (d, J = 9.2 Hz, 1 H), 8.26 (s, 1 H), 8.06 (d, J = 9.2 Hz, 1 H), 7.87 (d, J = 5.2 Hz, 1 H), 7.59 (d, J = 5.2 Hz, 1 H), 6.79 (s, 2H).

[0759] INTERMEDIATE 94: A / -(6-Bromo-3-pyridyl)-4-chloro-butanamide

[0760] To a solution of 6-bromopyridin-3-amine (2.00 g, 11.6 mmol) and 2-chloro-1- methylpyridinium iodide (5.91 g, 23.1 mmol) in DMA (25 mL) was added DIPEA (7.60 mL, 44.0 mmol). The mixture was stirred for 2 minutes, and a solution of 4-chlorobutanoic acid (2.30 mL, 23.0 mmol) in DMA (50 mL) was added dropwise over 5 minutes. The mixture was stirred at r.t. for 3.5 h, after which it was diluted with H2O (20 mL) and EtOAc (20 mL). The layers were separated, and the aqueous layer re-extracted with EtOAc (3 x 30 mL). The combined organics were washed with sat. aqueous NaHCOa (4 x 30 mL), brine (2 x 50 mL), dried (Na2SO4) and concentrated in vacuo. To the crude material was added MTBE (20 mL), resulting in precipitation. The suspension was stirred for 1 h and then filtered under suction, with the precipitate washed with MTBE and dried under vacuum to afford the title compound (1.10 g, 34%) as a pale pink solid.1H NMR (300 MHz, DMSO-d6) 5H = 10.33 (s, 1 H), 8.59 (d, J = 2.8 Hz, 1 H), 7.98 (dd, J = 8.7, 2.8 Hz, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 3.71 (t, J = 6.5 Hz, 2H), 2.57-2.46 (obscured t, 2H), 2.11-1.98 (m, 2H). LCMS (Method 1A): [M+H]+m / z 277.0 / 279.0, RT 1.03 min.

[0761] INTERMEDIATE 95: 1-(6-Bromo-3-pyridyl)pyrrolidin-2-one

[0762] To a suspension of Intermediate 94 (1.10 g, 4.00 mmol) in THF (25 mL) at 0 °C was added KOf-Bu (470 mg, 4.19 mmol) in one portion. The resulting yellow solution was warmed to r.t. and stirred for 2 minutes, after which it was quenched with H2O (10 mL) and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer re-extracted with EtOAc (2 x 20 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography, eluting with MeOH / DCM (0-10% gradient), afforded the title compound (880 mg, 92%) as a pale pink solid.1H NMR (400 MHz, DMSO-de) 5H = 8.67 (d, J = 3.0 Hz, 1 H), 8.14 (dd, J = 8.8, 2.9 Hz, 1 H), 7.66 (dd, J = 8.8 Hz, 1 H), 3.85 (t, J = 7.1 Hz, 2H), 2.57-2.47 (obscured m, 2H), 2.14-2.04 (m, 2H). LCMS (Method 1A): [M+H]+m / z 241.0 / 243.0, RT 0.83 min.

[0763] INTERMEDIATE 96: 1-(6-Bromo-1-oxido-pyridin-1-ium-3-yl)pyrrolidin-2-one

[0764] To a solution of Intermediate 95 (376 mg, 1.56 mmol) in DCM (12.0 mL) and MeOH (7.5 mL) at r.t. was added m-CPBA (524 mg, 2.34 mmol, 77 mass%) in one portion. The mixture was heated to 40 °C and stirred for 2 h, after which further m-CPBA (524 mg, 2.34 mmol, 77 mass%) was added. The mixture was stirred at 40 °C for 16 h and then treated with additional m-CPBA (524 mg, 2.34 mmol, 77 mass%). After a further 2 h 30 minutes the reaction was cooled to r.t. and diluted with DCM (10 mL) and H2O (10 mL). The layers were separated, and the aqueous layer re-extracted with DCM (2 x 20 mL). The combined organics were washed with sat. aq. NaHCOa, brine, passed through a phase separator and concentrated in vacuo. To the crude material was added MTBE (20 mL), resulting in precipitation. The suspension was stirred for 10 minutes and then filtered under suction, with the precipitate washed with MTBE and dried under vacuum to afford the title compound (298 mg, 71%) as a white solid.1H NMR (400 MHz, DMSO-de) 5H = 8.96 (d, J = 2.4 Hz, 1 H), 7.89 (d, J = 9.1 Hz, 1 H), 7.57 (dd, J = 9.1 , 2.4 Hz, 1 H), 3.82 (t, J = 7.1 Hz, 2H), 2.53 (t, J = 8.0 Hz, 2H), 2.13-2.03 (m, 2H).

[0765] LCMS (Method 1A): [M+H]+m / z 257.0 / 259.0, RT 0.32 min. INTERMEDIATE 97: 1-ri-Oxido-6-(4-pyridyl)pyridin-1-ium-3-yllpyrrolidin-2-one

[0766] To a 50 mL rbf was added Intermediate 96 (298 mg, 1.16 mmol), pyridine-4-boronic acid (171 mg, 1.39 mmol), Pd(dppf)Cl2 (85 mg, 0.12 mmol), K2CO3 (486 mg, 3.48 mmol), 1 ,4- dioxane (8.8 mL) and H2O (2.2 mL). The mixture was degassed with N2 for 5 minutes and then heated to 100 °C. The mixture was stirred at 100 °C for 15 minutes, after which the reaction was cooled to r.t. and filtered through Celite®, eluting with MeOH. The filtrate was concentrated in vacuo. Purification by flash chromatography, eluting with MeOH / DCM (0-10% gradient), afforded impure material which was then suspended in MTBE. The suspension was stirred for 20 minutes and then filtered under suction, with the precipitate washed with MTBE and dried under vacuum to afford the title compound (185 mg, 58%) as a brown solid.1H NMR (400 MHz, DMSO-de) 5H = 8.91 (d, J = 2.0 Hz, 1 H), 8.74-8.66 (m, 2H), 7.92-7.86 (m, 2H), 7.80 (d, J = 8.9 Hz, 1 H), 7.74 (dd, J= 9.0, 2.1 Hz, 1 H), 3.88 (t, J = 7.1 Hz, 2H), 2.57 (t, J = 8.1 Hz, 2H), 2.16- 2.06 (m, 2H). LCMS (Method 1 A): [M+H]+m / z 256.2, RT 0.57 min.

[0767] INTERMEDIATE 98: 4-Hvdroxy-N-[2-(4-pyridyl)pyrimidin-5-yll-2-[[6-

[0768] Prepared from Intermediate 28 (179 mg, 1 .04 mmol) and Intermediate 113 (290 mg, 0.95 mmol) in accordance with the procedure described for Intermediate 29 to afford the title compound (290 mg, 55%) as a yellow oil.1H NMR (400 MHz, DMSO) 5 10.50 (s, 1 H), 9.10 (s, 2H), 8.76 - 8.69 (m, 2H), 8.64 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 6.1 Hz, 2H), 7.92 (dd, J = 7.9, 2.1 Hz, 1 H), 7.83 (dd, J = 8.1 , 0.8 Hz, 1 H), 4.59 (t, J = 5.0 Hz, 1 H), 3.46 (ddq, J = 22.9, 11.3, 5.6 Hz, 2H), 3.03 - 2.89 (m, 3H), 1.87 (dq, J = 13.3, 6.3 Hz, 1 H), 1.69 - 1.58 (m, 1 H).

[0769] INTERMEDIATE 99: 1 -[2-(4-Pyridvnpyrimidin-5-yll-3-[[6-(trifluoromethyl)-3-

[0770] Pyridyllmethyllpyrrolidin-2-one

[0771] Prepared from Intermediate 98 (290 mg, 0.52 mmol) in accordance with the procedure described for Example 15 to afford the title compound (45 mg, 21%) as a yellow oil. LCMS (Method 3B): [M+H]+m / z 400.1 , RT 1.46 minutes.1H NMR (400 MHz, DMSO) 5 9.33 (s, 2H), 8.80 - 8.69 (m, 3H), 8.26 - 8.20 (m, 2H), 8.03 (dd, J = 8.0, 2.1 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 3.96 - 3.80 (m, 2H), 3.30 - 3.23 (m, 1 H), 3.19 - 3.08 (m, 1 H), 2.92 (dd, J = 13.8, 9.1 Hz, 1 H), 2.22 (dtd, J = 11 .3, 7.1 , 2.5 Hz, 1 H), 1 .95 - 1 .81 (m, 1 H).

[0772] INTERMEDIATE 100: Ethyl 5-(bromomethyl)-2-chloroisonicotinate

[0773] Ethyl 2-chloro-5-methyl-pyridine-4-carboxylate (1.00 g, 5.01 mmol), 1-bromopyrrolidine- 2, 5-dione (1070 mg, 6.01 mmol) and 2-[(E)-(1-cyano-1-methyl-ethyl)azo]-2-methyl- propanenitrile (82.3 mg, 0.501 mmol) were dissolved in CHCb (30 mL) and the reaction mixture was heated at 65 °C for 18 hours. The reaction mixture was cooled to room temperature and diluted with DCM (50 mL). The organic solution was washed with H2O (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-40% EtOAc / iso-hexane) to afford the title compound (1.1 g, 61%) as a colourless oil.1H NMR (500 MHz, DMSO-d6) 5 8.70 (s, 1 H), 7.84 (s, 1 H), 4.96 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.39 - 1.34 (m, 3H). LCMS (Method 3B): [M+H]+m / z 277.9 / 279.9 / 282.0, RT 1.54 min.

[0774] INTERMEDIATE 101 : Ethyl 5-((1-(tert-butoxycarbonyl)-2-oxopyrrolidin-3- yl)methyl)-2-chloroisonicotinate

[0775] Tert-butyl 2-oxopyrrolidine-1 -carboxylate (0.546 mL, 3.20 mmol) was dissolved in THF (10 mL) and cooled to -78 °C. LiHMDS in THF (1.00 mol / L, 3.50 mL, 3.50 mmol) was added and the reaction was stirred at -78 °C for 30 mins. A solution of Intermediate 100 (1 .07 g, 2.91 mmol) in THF (10 mL) was added dropwise and the reaction stirred for a further 2 hours. The reaction was allowed to warm to room temperature and quenched with saturated NH4CI solution (20 mL). The aqueous was extracted with EtOAc (3 x20 mL) and the combined organic fractions were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc / iso- hexane) to afford the title compound (714 mg, 55%) as a colourless oil.1H NMR (500 MHz, DMSO-de) 58.49 (s, 1 H), 7.77 (s, 1 H), 4.34 (q, J = 7.1 Hz, 2H), 3.64 (ddd, J = 10.7, 8.6, 2.4 Hz, 1 H), 3.50 - 3.36 (m, 2H), 2.92 - 2.78 (m, 2H), 1.86 (dddd, J = 12.3, 8.2, 6.9, 2.4 Hz, 1 H), 1.66 (dq, J = 12.2, 9.6 Hz, 1 H), 1.44 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H). LCMS (Method 3B): [M+H- Boc]+m / z 283.1 / 285.1 , RT 1.63 min.

[0776] INTERMEDIATE 102: Ethyl 2-chloro-5-((2-oxopyrrolidin-3-yl)methyl)isonicotinate

[0777] Intermediate 101 (714 mg, 1.68 mmol) was dissolved in DCM (10 mL) and TFA (1 .00 mL, 13.1 mmol) was added. The reaction was stirred at r.t. for 4 h. The reaction was diluted with saturated aqueous NaHCOa (10 mL) and DCM (10 mL) and stirred vigorously for 10 minutes. The aqueous was extracted with DCM (2 x 20 mL) and the organic fractions were combined, dried over anhydrous magnesium sulphate and concentrated to afford the title compound (366 mg, 60%) as a white solid.1H NMR (500 MHz, DMSO) 58.49 (s, 1 H), 7.74 (s, 1 H), 7.65 (s, 1 H), 4.34 (q, J = 7.1 Hz, 2H), 3.39 - 3.33 (m, 1 H), 3.16 - 3.05 (m, 2H), 2.76 (dd, J = 13.7, 9.3 Hz, 1 H), 2.55 (td, J = 9.1 , 5.4 Hz, 1 H), 1.94 (qd, J = 9.2, 2.9 Hz, 1 H), 1.66 (dq, J = 12.4, 8.8 Hz, 1 H), 1.33 (t, J = 7.1 Hz, 3H). LCMS (Method 3C) [M+H]+m / z 283.3 / 285.2, RT 1.08 min. INTERMEDIATE 103: 3-((6-Chloro-4-(hvdroxymethyl)pyridin-3-

[0778] Intermediate 102 (366 mg, 1.10 mmol) was dissolved in dry THF (20 mL), purged with nitrogen for 5 minutes and cooled to 0 °C. Lithium borohydride (2.00 mol / L, 1 .30 mL, 2.60 mmol) was added and the reaction stirred at r.t. for 18 h. The reaction was quenched with saturated NH4CI (20 mL) and the aqueous was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (326 mg, 99%) as a white solid.1H NMR (500 MHz, DMSO) 5 8.19 (s, 1 H), 7.68 (s, 1 H), 7.45 (s, 1 H), 5.53 (t, J = 5.4 Hz, 1 H), 4.64 - 4.50 (m, 2H), 3.19 - 3.05 (m, 2H), 2.97 (dd, J = 13.6, 3.7 Hz, 1 H), 2.58 - 2.51 (m, 2H), 2.05 - 1.96 (m, 1 H), 1 .65 (dq, J = 12.3, 8.6 Hz, 1 H). LCMS (Method 3B): [M+H]+m / z 241 .0 / 243.0, RT 0.63 min.

[0779] INTERMEDIATE 104: 3-((4-(((Tert-butyldimethylsilyl)oxy)methyl)-6-chloropyridin- 3-yl)methyl)pyrrolidin-2-one

[0780] Intermediate 103 (326 mg, 1.35 mmol), imidazole (249 mg, 3.66 mmol), and tert-butyl- chloro-dimethyl-silane (306 mg, 2.03 mmol) were dissolved in DMF (5 mL) and stirred at r.t. for 5 h. The reaction was diluted with EtOAc (50 mL) and H2O (50 mL) and partitioned. The aqueous layer extracted with additional EtOAc (2 x 30 mL) and the combined organic fractions were washed with H2O (30 mL), 1 :1 brine:H2O (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated onto silica. The crude product was purified by flash column chromatography on silica gel (12 g, 0-100% EtOAc / iso-hexane) to afford the title compound (436 mg, 73%) as a colourless oil that solidified on standing.1H NMR (500 MHz, DMSO) 58.22 (s, 1 H), 7.69 (s, 1 H), 7.41 (s, 1 H), 4.79 (qd, J = 15.4, 1.1 Hz, 2H), 3.19 - 3.06 (m, 2H), 2.97 (dd, J = 14.2, 4.3 Hz, 1 H), 2.63 - 2.51 (m, 2H), 2.03 (dtd, J = 15.2, 7.4, 2.7 Hz, 1 H), 1.65 (dq, J = 12.4, 8.8 Hz, 1 H), 0.92 (s, 9H), 0.12 (s, 6H). LCMS (Method 3B): [M+H]+m / z 355.1 / 357.1 , RT

[0781] 1.75 min.

[0782] INTERMEDIATE 105: 3-((4-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloropyridin- 3-vl)methvl)-1-(6-(pvridin-4-vl)pvridazin-3-vl)pyrrolidin-2-one

[0783] Intermediate 104 (294 mg, 0.663 mmol), 1-(6-bromopyridazin-3-yl)pyrrolidin-2-one (249 mg, 0.910 mmol), K3PO4 (352 mg, 1.66 mmol) and XantPhos Pd G3 (50.0 mg, 0.0683 mmol) were dissolved in 2-MeTHF (10 mL), purged with nitrogen for 10 minutes, and stirred at 90 °C for 24 h. The reaction was cooled to r.t. and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (12 g, 0-100% [3:1 , EtOAc:EtOH] / iso-hexane) to afford the title compound (172 mg, 36%) as an off-white solid.1H NMR (500 MHz, DMSO) 5 8.78 - 8.75 (m, 2H), 8.71 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.4 Hz, 1 H), 8.30 (s, 1 H), 8.12 - 8.08 (m, 2H), 7.45 (s, 1 H), 4.96 - 4.87 (m, 1 H), 4.30 - 4.22 (m, 1 H), 4.00 - 3.94 (m, 1 H), 3.16 - 3.06 (m, 3H), 2.97 (dd, J = 14.2, 4.3 Hz, 1 H), 1.88 (dd, J = 13.1 , 10.1 Hz, 1 H), 1.67 - 1.62 (m, 1 H), 0.93 (s, 9H), 0.13 (d, J = 2.3 Hz, 6H). LCMS (Method 3B): [M+H]+m / z 510.2 / 512.2, RT 1.89 min. hyl)pyridin-3-yl)methyl)-1 -

[0784] Intermediate 105 (198 mg, 0.272 mmol) was dissolved in THF (5 mL) and cooled to 0 °C. TBAF (1.00 mol / L, 0.300 mL, 0.300 mmol) was added and the reaction stirred at 0 °C for 1 h. The reaction was concentrated in vacuo and purified by column chromatography on C18 gel (12 g, 5-50% then 100% MeCN / 0.1% formic acid in water). The product containing fractions were concentrated and the residue dissolved in 1 : 1 DCM / MeOH (10 mL). This was washed with H2O (10 mL), then dried over anhydrous MgSC , filtered, and concentrated to afford the title compound (47 mg, 44 %) as a white solid. 1H NMR (400 MHz, DMSO) 6 8.79 - 8.75 (m, 2H), 8.71 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.27 (s, 1 H), 8.13 - 8.07 (m, 2H), 7.49 (s, 1 H), 5.57 (t, J = 5.4 Hz, 1 H), 4.64 (t, J = 5.8 Hz, 2H), 4.32 - 4.23 (m, 1 H), 4.02 - 3.92 (m, 1 H), 3.21 - 3.11 (m, 2H), 2.80 - 2.70 (m, 1 H), 2.24 - 2.15 (m, 1 H), 1.90 (d, J = 9.3 Hz, 1 H). LCMS (Method 3B): [M+H]+m / z 396.1 / 398.1 , RT 0.82 min.

[0785] INTERMEDIATE 107: 3-(Bromomethyl)-6-chloro-2 -fluoro-pyridine

[0786] To a solution of (6-chloro-2-fluoro-3-pyridyl)methanol (3.86 g, 23.9 mmol) in DCM (50 mL) were added triethylamine (8.0 mL, 57 mmol) and methane sulfonyl chloride (2.2 mL, 28 mmol) at 0 °C. After 30 minutes, the mixture was quenched with water. The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo. The crude obtained was dissolved in THF (50 mL) and lithium bromide (3.31 g, 38.1 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours, and then quenched with water. The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAcZ / so-hexane (0-70% gradient), afforded the title compound (3.49 g, 65%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.25 - 8.14 (m, 1 H), 7.57 (td, J = 7.3, 1.1 Hz, 1 H), 4.71 (s, 2H).

[0787] INTERMEDIATE 108: tert-Butyl 3-r(6-chloro-2-fluoro-3-pyridyl)methyl]-2-oxo- pyrrolidine-1 -carboxylate

[0788] To a solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (3.02 g, 15.5 mmol) in THF (50 mL) at -78 °C was added LDA (2 M THF / heptane / ethylbenzene solution, 7.7 mL, 15 mmol) dropwise. The mixture was stirred at -78 °C for 30 minutes, then Intermediate 107 (3.49 g, 15.5 mmol) was added. The reaction was stirred at -78 °C for 2 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), afforded the title compound (2.12 g, 42%) as a yellow solid.1H NMR (400 MHz, DMSO) 5 7.96 (dd, J = 9.8, 7.8 Hz, 1 H), 7.52 - 7.43 (m, 1 H), 3.65 (ddd, J = 10.6, 8.6, 2.1 Hz, 1 H), 3.48 (td, J = 10.1 , 6.9 Hz, 1 H), 3.04 (dd, J = 14.1 , 5.3 Hz, 1 H), 2.90 (dtd, J = 10.8, 8.7, 5.3 Hz, 1 H), 2.67 (dd, J = 14.1 , 9.1 Hz, 1 H), 1 .97 (dddd, J = 12.3, 8.8, 5.5, 2.1 Hz, 1 H), 1 .72 - 1 .55 (m, 1 H), 1 .45 (s, 9H). LCMS (Method 1A): [M-Boc+H]+m / z 229.0, RT 1.09 minutes.

[0789] INTERMEDIATE 109: 3-n6-Chloro-2-fluoro-3-pyridyl)methyllpyrrolidin-2-one

[0790] To a solution of Intermediate 108 (2.11 g, 6.42 mmol) in DCM (20 mL) at r.t. was added TFA (10 mL, 130 mmol). After 1 hour, the reaction mixture was concentrated in vacuo. The crude obtained was dissolved in DCM and basified by saturated aqueous NaHCOa. The aqueous layerwas extracted with DCM and concentrated in vacuo. Purification by normal phase flash chromatography, eluting with EtOAc / iso-hexane (0-100% gradient) and then MeOH / EtOAc (0-15% gradient), afforded the title compound (1 .02 g, 70%) as a white solid.1H NMR (400 MHz, DMSO) 5 7.97 (dd, J = 9.8, 7.8 Hz, 1 H), 7.70 (s, 1 H), 7.46 (dd, J = 7.8, 1 .2 Hz, 1 H), 3.20 - 3.06 (m, 2H), 3.00 (q, J = 9.5 Hz, 1 H), 2.64 - 2.52 (m, 2H), 2.11 - 1.99 (m, 1 H), 1.65 (dq, J = 12.0, 8.6 Hz, 1 H). LCMS (Method 1A): [M+H]+ m / z 229.0, RT 0.66 minutes.

[0791] INTERMEDIATE 110: 3-[(6-Chloro-2-fluoro-3-pyridyl)methyl1-1 -f6-(4- pyridyl)pyridazin-3-yllpyrrolidin-2-one

[0792] 3-Bromo-6-(4-pyridinyl)pyridazine (1.13 g, 4.42 mmol), Intermediate 109 (1.01 g, 4.42 mmol), Pd2(dba)3 (205 mg, 0.217 mmol), Xantphos (258 mg, 0.433 mmol) and K3PO4 (1.98 g, 9.14 mmol) were dissolved in 1 ,4-dioxane (15 mL) and the reaction mixture was heated to 90 °C for 3 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) afforded the title compound (1.24 g, 73%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.80 - 8.74 (m, 2H), 8.70 (d, J = 9.4 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.14 - 8.09 (m, 2H), 8.05 (dd, J = 9.8, 7.8 Hz, 1 H), 7.51 (dd, J = 7.8, 1.1 Hz, 1 H), 4.27 (ddd, J = 11.0, 8.7, 2.5 Hz, 1 H), 3.99 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.23 - 3.10 (m, 2H), 2.89 - 2.78 (m, 1 H), 2.25 (ddt, J = 15.2, 7.4, 3.7 Hz, 1 H), 1 .96 - 1 .82 (m, 1 H). LCMS (Method 1 A): [M+H]+ m / z 384.0, RT 0.96 min.

[0793] INTERMEDIATE 111 : 3-Chloro-6-(3-methyl-4-pyridyl)pyridazine

[0794] 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 4 (dioxane / H20, 90 °C, 16 h) to afford the title compound (0.58 g, 28%) as a white solid.1H NMR (500 MHz, DMSO) 5 8.62 (s, 1 H), 8.58 (d, J = 4.9 Hz, 1 H), 8.10 (d, J = 2.5 Hz, 2H), 7.51 (d, J = 4.9 Hz, 1 H), 2.34 (s, 3H). LCMS (Method 3D): [M+H]+m / z 206.2 / 208.2, RT 0.42 min.

[0795] INTERMEDIATE 112: 2-Bromo-5-(3-methyl-4-pyridyl)pyrazine

[0796] 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 4 (dioxane / H20, 90 °C, 4 h) to afford the title compound (0.15 g, 10%) as a brown solid.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). LCMS (Method 3B): [M+H]+m / z 250.0 / 252.0, RT 0.62 min. INTERMEDIATE 113: 3-R6-(T rifluoromethyl)-3-pyridyllmethylltetrahvdrofuran-2- one

[0797] 3-Methylenetetrahydrofuran-2-one (0.45 mL, 5.10 mmol), [6-(trifluoromethyl)-3- pyridyl]boronic acid (1.02 g, 5.35 mmol) and (1Z,5Z)-cycloocta-1 ,5- diene;rhodium(1 +);dichloride (126 mg, 0.26 mmol) were dissolved in dioxane / F (6:1) (14 mL) and degassed with nitrogen for 5 minutes. Triethylamine (0.73 mL, 5.35 mmol) was added, and the reaction mixture was stirred at 30 °C for 24 h. The reaction mixture was then concentrated in vacuo. The residue was taken up in sat. aq. NH4CI (20 mL) and the resultant solution was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL). The organic layer was dried over MgSC , 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 (765 mg, 49%) as a thick yellow oil. LCMS (Method 3A): [M+H]+m / z 246.2, RT 0.92 min.1H NMR (400 MHz, DMSO-d6) 5 8.69 (d, J = 2.1 Hz, 1 H), 7.99 (dd, J = 8.0, 2.1 Hz, 1 H), 7.86 (d, J = 8.1 Hz, 1 H), 4.38 - 4.22 (m, 1 H), 4.13 (ddd, J = 10.1 , 8.8, 6.5 Hz, 1 H), 3.21 - 3.03 (m, 2H), 2.87 (dd, J = 13.7, 8.9 Hz, 1 H), 2.19 (dddd, J = 12.3, 8.7, 6.5, 2.4 Hz, 1 H), 2.01 - 1.84 (m, 1 H).

[0798] III. SYNTHESIS OF EXAMPLES

[0799] EXAMPLE 1: 3-r(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2- one rac-3-r(4-chlorophenyl)methyll-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one

[0800] To a solution of Intermediate 2 (1.1 g, 4.58 mmol) in THF (60 mL) was added LiHMDS

[0801] (1 .0 M soln, in THF, 13.7 mL, 13.7 mmol) dropwise at -78 °C for 10 min under argon atmosphere and stirred for 30 min. To this mixture, was added a solution of 1-(bromomethyl)-4-chloro- benzene (0.847 g, 4.12 mmol) in THF (10 mL) dropwise over 5 min at -78 °C and stirred for 10 min. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) at -78 °C. The mixture was warmed to r.t., treated with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The resulting residue was purified by normal phase flash chromatography (2% MeOH in DCM). The obtained crude solid compound was washed with n-pentane (10 mL) and dried in vacuo to afford the title compound as a white solid (0.23 g, 14%).1H NMR (400 MHz, DMSO-d6) 5H 9.69 (s, 1 H), 9.20 (s, 1 H), 8.71-8.73 (m, 2H), 8.07-8.09 (m, 2H), 7.26-7.42 (m, 4H), 3.94-4.03 (m, 1 H), 3.76-3.86 (m, 1 H), 3.06-3.20 (m, 2H), 2.74-2.83 (m, 1 H), 2.07-2.20 (m, 1 H), 1.76-1.90 (m, 1 H). LCMS (Method 5): [M+H]+m / z 365.2, RT 1.22 min.

[0802] Examples 1A & 1B: (3S) and (3R) enantiomers of 3-K4-chlorophenyl)methyll-1-(5- idin-4-vlPvrazin-2-vl)Pvrrolidin-2-one

[0803] Example 1 (200 mg) was subjected to purification by chiral HPLC chromatography (Column: Chiralcel OJ-H; Mobile phase A: 0.1% DEA in n-Hexane, Mobile phase B: EtOH: MeOH (50:50)) to afford corresponding Enantiomer 1 (Peak 1 , 65 mg, off-white solid) and Enantiomer 2 (Peak 2, 70 mg, off-white solid).

[0804] Peak 1 : Enantiomer 1 ((3S) enantiomer):

[0805] 1H NMR (400 MHz, DMSO-d6) 5H 10.51 (d, J=1 .25 Hz, 1 H), 10.02 (d, J=1.25 Hz, 1 H), 9.51-9.54 (m, 2 H), 8.87-8.90 (m, 2H), 8.10-8.21 (m, 4H), 4.75-4.84 (m, 1 H), 4.57-4.67 (m, 1 H), 3.88-4.02 (m, 2H), 3.54-3.65 (m, 1 H), 2.88-3.00 (m, 1 H), 2.58-2.70 (m, 1 H).

[0806] LCMS (Method 5): [M+H]+m / z 365.1 , RT 1 .22 min. Peak 2: Enantiomer 2 ((3R) enantiomer) :

[0807] 1H NMR (400 MHz, DMSO-d6) 6H 10.51 (d, J=1 .25 Hz, 1 H), 10.02 (d, J=1.25 Hz, 1 H), 9.51-9.54 (m, 2 H), 8.87-8.90 (m, 2H), 8.10-8.21 (m, 4H), 4.75-4.84 (m, 1 H), 4.57-4.67 (m, 1 H), 3.88-4.02 (m, 2H), 3.54-3.65 (m, 1 H), 2.88-3.00 (m, 1 H), 2.58-2.70 (m, 1 H).

[0808] LCMS (Method 5): [M+H]+m / z 365.2, RT 1.22 min.

[0809] One of enantiomers A and B is (3 / ?)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2- yl)pyrrolidin-2-one and the other is (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2- yl)pyrrolidin-2-one.

[0810] EXAMPLE 2: 3-K4-chlorophenyl)methyll-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2- one rac-3-r(4-chlorophenyl)methyll-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one

[0811] To a solution of Intermediate 4 (80 mg, 0.33 mmol) in THF (4 mL) at -78°C was added LDA (2M soln, in THF / heptane / ethylbenzene, 200 pL, 0.4 mmol) dropwise. The reaction mixture was stirred at -78°C for 1 h and then 4-chlorobenzyl bromide (10 pL, 0.38 mmol) was added. The reaction was stirred for 10 minutes at -78°C and then removed from the dry-ice / acetone bath and allowed to warm to r.t. over 2 h. The reaction mixture was cooled to -78 °C again and then further LDA (2M soln, in THF / heptane / ethylbenzene, 100 pL, 0.2 mmol) and 4-chlorobenzyl bromide (5 pL, 0.19 mmol) was added and stirring continued at-78°C to r.t. The reaction mixture was diluted with EtOAc (20 mL) and washed with H2O (5 mL). The separated organic layer was concentrated in vacuo to give an orange solid. Purification by flash chromatography eluting with EtOAc / zso-hexane (0-100% gradient, and then 0-20% MeOH / EtOAc) afforded the title compound (53 mg, 44%) as an off white solid.1H NMR (400 MHz, CDCh) 58.76 - 8.69 (m, 2H), 8.67 (dd, J = 2.5, 0.8 Hz, 1 H), 8.60 (dd, J = 8.8, 0.8 Hz, 1 H), 8.00 (dd, J = 8.8, 2.5 Hz, 1 H), 7.55 - 7.49 (m, 2H), 7.34 - 7.27 (m, 2H), 7.26 - 7.17 (m, 2H), 4.13 (ddd, J = 11.4, 8.8, 2.9 Hz, 1 H), 3.92 (ddd, J = 11.1 , 8.9, 7.3 Hz, 1 H), 3.31 (dd, J = 13.8, 4.4 Hz, 1 H), 3.08 - 2.95 (m, 1 H), 2.83 (dd, J = 13.8, 9.2 Hz, 1 H), 2.23 (dddd, J = 12.7, 8.6, 7.3, 2.8 Hz, 1 H), 1.86 (ddt, J = 12.7, 9.9, 8.8 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 364.2, RT 1.15 min.

[0812] Example 2A & 2B: (3S) and (3R) enantiomers of 3-r(4-chlorophenyl)methyll-1-(5- pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one

[0813] Example 2 (50 mg) was subjected to purification by normal phase chiral chromatography (Column: Lux Cellulose-3, 250 x 21.2 mm, 5 pm; Mobile phase: 50:50 Heptane / EtOH over 15 min; Column temperature: ambient; Flowrate: 20 mL / min) to afford respectively enantiomer 1 (Peak 1 ; 17 mg, off-white solid) and enantiomer 2 (Peak 2; 15 mg, off-white solid) of 3-[(4- chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one.

[0814] Peak 1 : Enantiomer 1 ((3S) enantiomer) :

[0815] 1H NMR (400 MHz, DMSO-d6) 5H 8.95 (dd, J = 2.6, 0.9 Hz, 1 H), 8.79 - 8.73 (m, 2H), 8.50 (dd, J = 8.8, 0.8 Hz, 1 H), 8.38 (dd, J = 8.8, 2.6 Hz, 1 H), 7.99 (d, J = 5.8 Hz, 2H), 7.41 - 7.28 (m, 4H), 4.04 (ddd, J = 11 .2, 8.7, 2.7 Hz, 1 H), 3.83 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.20 - 3.04 (m, 2H), 2.77 (dd, J = 13.3, 8.9 Hz, 1 H), 2.15 - 2.03 (m, 1 H), 1.78 (dq, J = 12.3, 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 364.2, RT 1.14 min. Chiral HPLC analysis (Column: Lux Cellulose-3, 4.6 x 150 mm, 3 pm; Method: n-Heptane / EtOH (50 / 50) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 6.41 min.

[0816] Peak 2: Enantiomer 2 ((3 / ?) enantiomer) :

[0817] 1H NMR (400 MHz, DMSO-d6) 5H 8.94 (d, J = 2.5 Hz, 1 H), 8.77 - 8.71 (m, 2H), 8.50 (dd, J = 8.8, 0.8 Hz, 1 H), 8.37 (dd, J = 8.8, 2.6 Hz, 1 H), 7.96 (d, J = 5.3 Hz, 2H), 7.41 - 7.28 (m, 4H), 4.04 (ddd, J = 11.2, 8.7, 2.7 Hz, 1 H), 3.83 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.20 - 3.03 (m, 2H), 2.77 (dd, J = 13.3, 8.9 Hz, 1 H), 2.45 (s, 1 H), 2.15 - 2.03 (m, 1 H), 1.78 (dq, J = 12.2, 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 364.2, RT 1.14 min. Chiral HPLC analysis (Column: Lux Cellulose-3, 4.6 x 150 mm, 3 pm; Method: n-Heptane / EtOH (50 / 50) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 7.76 min. One of enantiomers A and B is (3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2- yl)pyrrolidin-2-one and the other is (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2- yl)pyrrolidin-2-one. EXAMPLE 3: 3-K4-chlorophenyl)methyll-1 -(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2- one rac-3-r(4-chlorophenyl)methyll-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one

[0818] To a solution of Intermediate 7 (68 mg, 0.19 mmol) and pyridine-4-boronic acid (27 mg, 0.22 mmol) in 1 ,4-dioxane (1 mL), K2CO3 (51 mg, 0.37 mmol) and Pd(PPha)4 (21 mg, 0.018 mmol) were added. The reaction mixture was stirred at 90 °C for 66 h. A further amount of pyridine-4-boronic acid (27 mg, 0.22 mmol) and Pd(PPha)4 (21 mg, 0.018 mmol) were added and the reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL) and brine (1 x 20 mL). The organic layer was dried over MgSC , filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford the title compound as a yellow solid (4 mg, 6%). LCMS (Method 5): [M+H]+m / z 364.2, RT 1.04 min.

[0819] EXAMPLE 4A and 4B: (3R) and (3S) enantiomers of 3-r(6-chloropyridin-3- yl)methyll-1 -(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one

[0820] Step 1 : 2-Bromo-5-(4-pyridyl)pyrazine (CAS: 1159819-55-2, 263 mg, 1.11 mmol), Intermediate 72 (210 mg, 0.997 mmol, 100 mass%), Pchdbas (95 mg, 0.10 mmol), Xantphos (110 mg, 0.184 mmol) and K3PO4 (620 mg, 2.86 mmol) were dissolved in 1 ,4-dioxane (10 mL). The reaction mixture was stirred at 90 °C under N2 atmosphere for 18 h. The reaction mixture was filtered through Celite® using MeOH as eluent and the filtrate was concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / zso-hexane (0-100% gradient, and then 0-10% MeOH / EtOAc) afforded racemic 3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2- yl)pyrrolidin-2-one (157 mg, 38%). LCMS (Method 1A): [M+H]+m / z 366.2 / 368.2, RT 1.14 min.

[0821] Step 2:

[0822] Racemic 3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one (45 mg) was subjected to chiral purification by SFC chromatography (Column: Lux Cellulose-3, 250 x 21.2 mm 5 pm;Method: MeOH + 0.1 % NH4OH (20% isocratic) over 10 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford respectively Enantiomer 1 (Peak 1 ; 13 mg, white solid) and Enantiomer 2 (Peak 2; 15 mg, white solid) of 3-[(6-chloropyridin-3-yl)methyl]-1 - (5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one

[0823] Peak 1 : Enantiomer 1 ((3S) enantiomer) :

[0824] 1H NMR (400 MHz, DMSO-d6) 5H 9.69 (d, J = 1.5 Hz, 1 H), 9.22 (d, J = 1.5 Hz, 1 H), 8.77-8.70 (m, 2H), 8.37 (d, J = 2.4 Hz, 1 H), 8.12-8.06 (m, 2H), 7.83 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.03 (ddd, J = 11.0, 8.7, 2.5 Hz, 1 H), 3.82 (ddd, J = 10.8, 9.1 , 7.3 Hz, 1 H), 3.23- 3.13 (m, 2H), 2.88-2.79 (m, 1 H), 2.23-2.12 (m, 1 H), 1.92-1.78 (m, 1 H). LCMS (Method 5): [M+H]+m / z 366.1 , RT 0.90 min. Chiral SFC analysis (Column: Lux Cellulose-3, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.37 min.

[0825] Peak 2: Enantiomer 2 ((3R) enantiomer) :

[0826] 1H NMR (400 MHz, DMSO-d6) 5H 9.69 (d, J = 1.5 Hz, 1 H), 9.22 (d, J = 1.5 Hz, 1 H), 8.77-8.70 (m, 2H), 8.37 (d, J = 2.4 Hz, 1 H), 8.12-8.06 (m, 2H), 7.83 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.03 (ddd, J = 11.0, 8.7, 2.5 Hz, 1 H), 3.82 (ddd, J = 10.8, 9.1 , 7.3 Hz, 1 H), 3.23- 3.13 (m, 2H), 2.88-2.79 (m, 1 H), 2.23-2.12 (m, 1 H), 1.92-1.78 (m, 1 H). LCMS (Method 5): [M+H]+m / z 366.2, RT 0.88 min. Chiral SFC analysis (Column: Lux Cellulose-3, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3 - 40%) over 6.5 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 4.55 min. One of enantiomers A and B is (3F?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2- yl)pyrrolidin-2-one and the other is (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4- ylpyrazin-2-yl)pyrrolidin-2-one.

[0827] EXAMPLE 5A and 5B: (3R) and (3S) enantiomers of 3-r(6-chloropyridin-3- thyll-1-(6-pvridin-4-vlpvridazin-3-vl)pyrrolidin-2-one

[0828] Step 1 :

[0829] To a solution of Intermediate 15 (59 mg, 0.25 mmol) in THF (2 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 0.15 mL, 0.30 mmol) dropwise, resulting in an orange solution. The mixture was stirred at -78 °C for 1 h, then 5-(bromomethyl)-2-chloropyridine (62 mg, 0.29 mmol) added in one portion. After 1 h the reaction was quenched with MeOH, warmed to r.t. , and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) then MeOH / EtOAc (0-20% gradient), afforded racemic 3- [(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one (35 mg) as a white solid.

[0830] Step 2:

[0831] Racemic 3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one (35 mg) was subjected to chiral purification by normal phase HPLC (Column: Chiralpak IH, 250 x 21 .5 mm 5 pm;Method: MeCN (100% isocratic) over 20 mins; Column temperature: 23 °C; Flowrate: 20 mL / min) to afford corresponding Enantiomer 1 (Peak 1 ; 7 mg, 20%) and Enantiomer 2 (Peak 2; 8 mg, 23%) of 3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin- 3-yl)pyrrolidin-2-one.

[0832] Peak 1 : Enantiomer 1 ((3F?) enantiomer) :1H NMR (400 MHz, DMSO-d6) 6H 8.79 - 8.74 (m, 2H), 8.71 (d, J = 9.4 Hz, 1 H), 8.42 (d, J = 9.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.13 - 8.07 (m, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 4.21 (ddd, J = 11.2, 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.24 - 3.11 (m, 2H), 2.89 - 2.78 (m, 1 H), 2.20 (qd, J = 7.7, 3.8 Hz, 1 H), 1.86 (dq, J = 12.3, 8.2 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 366.2, RT 0.84 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeCN + 0.1% DEA (100%) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 3.46 min.

[0833] Peak 2: Enantiomer 2 ((3S) enantiomer):

[0834] 1H NMR (400 MHz, DMSO-d6) 5H 8.79 - 8.74 (m, 2H), 8.71 (d, J = 9.4 Hz, 1 H), 8.42 (d, J = 9.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.13 - 8.07 (m, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 4.21 (ddd, J = 11.2, 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.24 - 3.11 (m, 2H), 2.89 - 2.78 (m, 1 H), 2.20 (qd, J = 7.7, 3.8 Hz, 1 H), 1.86 (dq, J = 12.3, 8.2 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 366.1 , RT 0.85 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeCN + 0.1% DEA (100%) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 4.36 min.

[0835] One of enantiomers A and B is (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin- 3-yl)pyrrolidin-2-one and the other is (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4- ylpyridazin-3-yl)pyrrolidin-2-one.

[0836] EXAMPLE 6: 3-K4-chlorophenyl)methyll-1-(6-hvdroxy-5-pyridin-4-ylpyridin-2- yl)pyrrolidin-2-one rac-3-r(4-chlorophenyl)methyll-1-(6-hvdroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2- one

[0837] To a mixture of Intermediate 19 (50 mg, 0.12 mmol) and sodium iodide (57.1 mg, 0.38 mmol) in MeCN (2 mL) was added chlorotrimethylsilane (42.0 mg, 0.38 mmol) at r.t. The reaction mixture was heated at 80 °C for 2 h. The formed precipitate was filtered and rinsed with MeCN. The residue was purified by reverse phase chromatography to give the title compound (55 mg, 100%) as a beige solid. LCMS (Method 5): [M+H]+m / z 380.2, RT 0.80 min.

[0838] Example 6A and 6B: and (3S) enantiomers of 3-K4-chlorophenyl)methyll-1-(6- hvdroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one

[0839] Example 6 (50 mg) was subjected to chiral purification by normal phase HPLC (Column: Reprosil NR-R, 250 x 20 mm 5 pm;Method: EtOH / n-Heptane (50 / 50 isocratic) over 60 mins; Column temperature: 23 °C; Flowrate: 20 mL / min) to afford the corresponding Enantiomer 1 (Peak 1 ; 25 mg, beige solid) and Enantiomer 2 (Peak 2; 25 mg, beige solid).

[0840] Peak 1 : Enantiomer 1 ((3R) enantiomer) :

[0841] 1H NMR (400 MHz, DMSO-d6) 5H 8.61 (s, 2H), 8.03 (d, J = 8.2 Hz, 1 H), 7.82 (s, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 3.90 (d, J = 9.6 Hz, 1 H), 3.81 - 3.69 (m, 1 H), 3.09 (ddt, J = 18.3, 9.4, 4.6 Hz, 2H), 2.75 (dd, J = 13.4, 8.9 Hz, 1 H), 2.14 - 1.95 (m, 1 H), 1.81 - 1.66 (m, 1 H). LCMS (Method 5): [M+H]+m / z 380.1 , RT 0.81 min. Chiral HPLC analysis (Column: Reprosil NRR, 4.6 x 150 mm, 3 pm; Method: EtOH / n-Heptane / DEA (50 / 50 / 0.1 isocratic) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 5.55 min.

[0842] Peak 2: Enantiomer 2 ((3S) enantiomer):

[0843] 1H NMR (400 MHz, DMSO-d6) 5H 8.61 (s, 2H), 8.03 (d, J = 8.2 Hz, 1 H), 7.82 (s, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 3.90 (d, J = 9.6 Hz, 1 H), 3.81 - 3.69 (m, 1 H), 3.09 (ddt, J = 18.3, 9.4, 4.6 Hz, 2H), 2.75 (dd, J = 13.4, 8.9 Hz, 1 H), 2.14 - 1.95 (m, 1 H), 1.81 - 1.66 (m, 1 H). LCMS (Method 5): [M+H]+m / z 380.2, RT 0.81 min. Chiral HPLC analysis (Column: Reprosil NRR, 4.6 x 150 mm, 3 pm; Method: EtOH / n-Heptane / DEA (50 / 50 / 0.1 isocratic) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 6.78 min.

[0844] One of enantiomers A and B is (3R)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4- ylpyridin-2-yl)pyrrolidin-2-one and the other is (3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5- pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one.

[0845] EXAMPLE 7: 3-K6-Chloropyridin-3-yl)methyll-1-(5-pyridin-4-ylpyridin-2- yl)pyrrolidin-2-one rac-3-n6-chloropyridin-3-yl)methyll-1 -(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one

[0846] To a solution of Intermediate 4 (250 mg, 1.05 mmol) in THF (8 mL) at -78°C was added LDA (2M soln, in THF / heptane / ethylbenzene, 0.60 mL, 1.2 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h and then 5-(bromomethyl)-2-chloropyridine (237 mg, 1.09 mmol) added. The reaction was stirred for 10 minutes at -78 °C and then removed from the dry- ice / acetone bath and allowed to warm to r.t. for 2h. The reaction mixture was cooled to -78 °C again and then further LDA (2M soln, in THF / heptane / ethylbenzene, 0.30 mL, 0.6 mmol) and 5- (bromomethyl)-2-chloropyridine (119 mg, 0.51 mmol) were added dropwise and then allowed to warm to r.t. for 1 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with H2O (5 mL). The separated organic layer was concentrated in vacuo to give an orange solid. Purification by reverse-phase preparative HPLC afforded the title compound (18 mg, 5%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 5H 8.89 (dd, J = 2.6, 0.8 Hz, 1 H), 8.69 - 8.63 (m, 2H), 8.47 (dd, J = 8.9, 0.8 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.32 (dd, J = 8.8, 2.6 Hz, 1 H), 7.85 - 7.76 (m, 3H), 7.48 (dd, J = 8.2, 0.7 Hz, 1 H), 4.07 (ddd, J = 11 .1 , 8.8, 2.6 Hz, 1 H), 3.83 (ddd, J = 10.9, 9.0, 7.2 Hz, 1 H), 3.21 - 3.06 (m, 2H), 2.87 - 2.76 (m, 1 H), 2.23 - 2.04 (m, 1 H), 1.86 - 1 .72 (m, 1 H). LCMS (Method 5): [M+H]+m / z 365.2, RT 0.81 min.

[0847] EXAMPLE 8: 3-K6-chloropyridin-3-yl)methyll-1 -(6-methoxy-5-pyridin-4-ylpyridin-2- yl)pyrrolidin-2-one rac-3-r(6-chloropyridin-3-yl)methyll-1-(6-methoxy-5-pyridin-4-ylpyridin-2- yl)pyrrolidin-2-one To a solution of Intermediate 18 (180 mg, 0.67 mmol) in THF (3 mL) at -78 °C was added LDA (2M soln, in THF / heptane / ethylbenzene, 0.37 mL, 0.74 mmol). The mixture was stirred for 1 h at -78 °C then 5-(bromomethyl)-2-chloro-pyridine (151.8 mg, 0.73 mmol) was added. The reaction mixture was stirred at r.t. for 1 h then taken up with DCM (25 mL) and washed with saturated aqueous NaHCOa (2 x 10 mL). The organic layer was dried over MgSC , filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (23 mg, 9 %) as a beige solid. LCMS (Method 5): [M+H]+m / z 395.0, RT 0.93 min.

[0848] EXAMPLE 9: 3-r(6-chloropyridin-3-yl)methyll-1 -(4-pyridin-4-ylphenyl)pyrrolidin-2- one rac-3-r(6-chloropyridin-3-yl)methyll-1 -(4-pyridin-4-ylphenyl)pyrrolidin-2-one

[0849] Prepared from Intermediate 21 (250 mg, 1.05 mmol) and 5-(bromomethyl)-2-chloro- pyridine (237 mg, 1.15 mmol) in accordance with the procedure described for Example 7 (adding a further portion of LDA and 5-(bromomethyl)-2-chloropyridine after 2 h). Purification by flash chromatography eluting with EtOAc / / so-hexane (0-100% gradient, and then 0-20% MeOH / EtOAc) and subsequent further purification by reverse phase preparative HPLC afforded the title compound (31 mg, 8%) as an off white solid.1H NMR (400 MHz, DMSO-de) 5H 8.65 - 8.59 (m, 2H), 8.36 (d, J = 2.5 Hz, 1 H), 7.91 - 7.78 (m, 5H), 7.76 - 7.70 (m, 2H), 7.48 (dd, J = 8.2, 0.7 Hz, 1 H), 3.86 - 3.72 (m, 2H), 3.15 (dd, J = 13.8, 4.8 Hz, 1 H), 3.04 (dtd, J = 9.8, 8.7, 4.7 Hz, 1 H), 2.80 (dd, J = 13.7, 9.0 Hz, 1 H), 2.13 (dddd, J = 12.2, 9.4, 6.4, 3.4 Hz, 1 H), 1.87 - 1.72 (m, 1 H). LCMS (Method 5): [M+H]+m / z 364.2, RT 0.76 min. EXAMPLE 10: 3-K6-chloropyridin-3-yl)methyll-1-(6-pyridin-4-ylpyridin-3- yl)pyrrolidin-2-one rac-3-r(6-chloropyridin-3-yl)methyll-1 -(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one

[0850] To a solution of Intermediate 23 (445 mg, 1.21 mmol) and pyridine-4-boronic acid (179 mg, 1.46 mmol) in 1 ,4-dioxane (10 mL) and water (1 mL), K2CO3 (336 mg, 2.43 mmol) and PdCl2(dppf).CH2Cl2(100 mg, 0.12 mmol) were added. The reaction mixture was stirred at 90 °C for 18 h then diluted with EtOAc (50 mL), washed with water (2 x 20 mL) and brine (20 mL). The organic layer was dried over MgSC , filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford the title compound as an off- white solid (32 mg, 7%). LCMS (Method 5): [M+H]+m / z 365.2, RT 0.75 min.

[0851] Example 10A & B: (3S) and (3R) enantiomers of 3-n6-chloropyridin-3-yl)methyll-1-

[0852] (6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one

[0853] Example 10 (30 mg) was subjected to chiral purification by normal phase HPLC (Column: Chiralpak IH, 250 x 20 mm 5 pm;Method: 100% MeCN (isocratic) over 30 mins; Column temperature: 23 °C; Flowrate: 20 mL / min) to afford corresponding Enantiomer 1 (Peak 1 ; 7 mg, beige solid) and Enantiomer 2 (Peak 2; 6 mg, beige solid).

[0854] Peak 1 : Enantiomer 1 ((3S) enantiomer) : LCMS (Method 5): [M+H]+m / z 365.2, RT 0.75 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: 100% MeCN + 0.1% DEA (isocratic) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 4.35 min.

[0855] Peak 2: Enantiomer 2 ((3R) enantiomer) :

[0856] LCMS (Method 5): [M+H]+m / z 365.2, RT 0.74 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: 100% MeCN + 0.1% DEA (isocratic) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 6.81 min.

[0857] One of enantiomers A and B is (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3- yl)pyrrolidin-2-one and the other one is (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4- ylpyridin-3-yl)pyrrolidin-2-one.

[0858] EXAMPLE 11 : 3-K6-chloropyridin-3-yl)methyll-1-(6-pyridazin-4-ylpyridin-3- yl)pyrrolidin-2-one rac-3-r(6-chloropyridin-3-yl)methyl]-1 -(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one

[0859] To a solution of Intermediate 23 (308 mg, 0.84 mmol) and 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridazine (219 mg, 1.01 mmol) in 1 ,4-dioxane (10 mL) and water (1 mL), K2CO3 (232 mg, 1.68 mmol) and PdCl2(dppf).CH2Cl2 (69 mg, 0.084 mmol) were added. The reaction mixture was stirred at 90 °C for 18h. Further amounts of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridazine (182 mg, 0.84 mmol) and PdCl2(dppf).CH2Cl2 (69 mg, 0.084 mmol) were added and the reaction mixture was stirred at 90 °C for a further 18 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid (6 mg, 2%). LCMS (Method 5): [M+H]+m / z 366.2, RT 0.91 min. EXAMPLES 12, 12A & 12B: racemic 3-n6-chloropyridin-3-yl)methyll-1-(5-fluoro-6-

[0860] Pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one and and (3S) enantiomers of 3-R6- chloropyridin-3-yl)methyll-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one

[0861] Step 1 :

[0862] To a solution of Intermediate 24 (99 mg, 0.39 mmol) in 1 ,4-dioxane (4 mL) was added Intermediate 12 (76 mg, 0.36 mmol) followed by Pd2(dba)3 (34 mg, 0.036 mmol), Xantphos (43 mg, 0.072 mmol) and K3PO4 (267 mg, 1 .23 mmol) at r.t. The reaction mixture was heated to 100 °C for 2 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-20% gradient), afforded racemic 3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one (61 mg, 44%) as a white solid. LCMS (Method 5): [M+H]+m / z 383.10, RT 0.91

[0863] Step 2:

[0864] Racemic 3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin- 2-one (61 mg) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 250 x 20 mm 5 pm;Method: MeOH + 0.1% NH4OH (3-40%) over 10 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford corresponding Enantiomer 1 (Peak 1 ; 10 mg, white solid) and Enantiomer 2 (Peak 2; 8 mg, white solid).

[0865] Peak 1 : Enantiomer 1 (believed to be the (3S) enantiomer):

[0866] 1H NMR (400 MHz, DMSO-d6) 5H 8.96 (t, J = 1 .8 Hz, 1 H), 8.76 - 8.70 (m, 2H), 8.36 (d, J = 2.4 Hz, 1 H), 8.31 (dd, J = 14.0, 2.2 Hz, 1 H), 7.91 (dt, J = 4.6, 1 .4 Hz, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 3.85 (dtd, J = 18.6, 9.5, 7.0 Hz, 2H), 3.21 - 3.04 (m, 2H), 2.81 (dd, J = 13.4, 8.6 Hz, 1 H), 2.18 (dtd, J = 12.0, 7.2, 2.7 Hz, 1 H), 1.84 (dq, J = 12.1 , 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 383.0, RT 0.90 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1 % NH4OH (3-40%) over 10 mins; Column temperature: 30 °C; Flowrate: 3.0 mL / min): RT 5.76 min.

[0867] Peak 2: Enantiomer 2 (believed to be the (3R) enantiomer) :

[0868] 1H NMR (400 MHz, DMSO-d6) 5H 8.96 (t, J = 1 .8 Hz, 1 H), 8.76 - 8.70 (m, 2H), 8.36 (d, J = 2.4 Hz, 1 H), 8.31 (dd, J = 14.0, 2.2 Hz, 1 H), 7.91 (dt, J = 4.6, 1.4 Hz, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 3.85 (dtd, J = 18.6, 9.5, 7.0 Hz, 2H), 3.21 - 3.04 (m, 2H), 2.81 (dd, J = 13.4, 8.6 Hz, 1 H), 2.18 (dtd, J = 12.0, 7.2, 2.7 Hz, 1 H), 1.84 (dq, J = 12.1 , 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 383.1 , RT 0.90 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1 % NH4OH (3-40%) over 10 mins; Column temperature: 30 °C; Flowrate: 3.0 mL / min): RT 7.54 min.

[0869] One of enantiomers A and B is (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4- ylpyridin-3-yl)pyrrolidin-2-one and the other is (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro- 6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one.

[0870] EXAMPLE 13: -3-K6-chloropyridin-3-yl)methyll-1-(5-fluoro-6-pyridazin-4- ylpyridin-3-yl)pyrrolidin-2-one

[0871] To a solution of Intermediate 25 (30 mg, 0.12 mmol) in 1 ,4-dioxane (1 .5 mL) was added Intermediate 14 (25 mg, 0.12 mmol) followed by Pd2(dba)3 (22 mg, 0.023 mmol), Xantphos (28 mg, 0.047 mmol) and K3PO4 (80 mg, 0.37 mmol) at r.t. and the reaction mixture was heated to 70°C for 3 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAcZ / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient), and further reverse phase preparative HPLC purification afforded the title compound (17 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H 9.75 (dt, J = 2.3, 1.1 Hz, 1 H), 9.39 (dd, J = 5.5, 1.2 Hz, 1 H), 9.02 (t, J = 1.8 Hz, 1 H), 8.39 - 8.31 (m, 2H), 8.15 (ddd, J = 5.5, 2.4, 1.1 Hz, 1 H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 3.95 - 3.78 (m, 2H), 3.21 - 3.05 (m, 2H),

[0872] 2.82 (dd, J = 13.4, 8.6 Hz, 1 H), 2.19 (dtd, J = 12.6, 7.0, 3.5 Hz, 1 H), 1.85 (dq, J = 12.3, 9.1 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 384.1 , RT 1 .04 min.

[0873] EXAMPLE 14: (3 / ?)-3-K6-chloropyridin-3-yl)methyll-1-(6-pyridazin-4-ylpyridazin-3- yl)pyrrolidin-2-one

[0874] To a solution of Intermediate 26 (77 mg, 0.29 mmol) in 1 ,4-dioxane (1 .7 mL) was added Intermediate 14 (51 mg, 0.24 mmol) followed by Pd2(dba)3 (27 mg, 0.029 mmol), Xantphos (30 mg, 0.050 mmol) and K3PO4 (160 mg, 0.739 mmol) at r.t. and the reaction mixture was heated to 70 °C for 3 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-20% gradient), and further reverse phase preparative HPLC purification afforded the title compound (13 mg, 15%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H 9.97 (dd, J = 2.4, 1.2 Hz, 1 H), 9.44 (dd, J = 5.4, 1 .3 Hz, 1 H), 8.75 (d, J = 9.5 Hz, 1 H), 8.55 (d, J = 9.5 Hz, 1 H), 8.40 - 8.33 (m, 2H), 7.83 (dd, J = 8.2, 2.6 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 4.23 (ddd, J = 11 .1 , 8.7, 2.6 Hz, 1 H), 3.98 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.26 - 3.14 (m, 2H), 2.90 - 2.79 (m, 1 H), 2.21 (dtd, J = 12.6, 7.5, 2.6 Hz, 1 H), 1 .95 - 1 .80 (m, 1 H). LCMS (Method 5): [M+H]+m / z 367.2, RT 0.91 min.

[0875] EXAMPLE 15A & B: and (3S) enantiomers of 3-K6-chloropyridin-3-yl)methyll- 1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one

[0876]

[0877] Step 1 :

[0878] To a solution of Intermediate 29 (120 mg, 0.30 mmol) in THF (20 mL) was added PPha (2eq.; 0.60 mmol) and DIAD (2eq.; 0.60 mmol). The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with sat. aq. NaHCOa (20 mL) and the resultant solution extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 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 racemic 3-[(6- chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one (20 mg, 18%) as a white solid.

[0879] Step 2:

[0880] Racemic 3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl) pyrrolidin-2-one (20 mg) was subjected to chiral purification by SFC chromatography (Column: Lux C3, 250 x 21 mm 5 pm;Method: MeOH + 0.1 % NH4OH (35% isocratic); Column temperature: 40 °C; Flowrate: 65 mL / min) to afford corresponding Enantiomer 1 (Peak 1 ; 5 mg, white solid) and Enantiomer 2 (Peak 2; 6 mg, white solid).

[0881] Peak 1 : Enantiomer 1 (believed to be the (3S) enantiomer) :

[0882] 1H NMR (500 MHz, DMSO-d6) 5H 9.32 (s, 2H), 8.75 (d, J = 6.1 Hz, 2H), 8.36 (d, J = 2.5 Hz, 1 H), 8.23 (d, J = 6.1 Hz, 2H), 7.81 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 3.93 - 3.78 (m, 2H), 3.16 (dd, J = 13.8, 5.0 Hz, 1 H), 3.12 - 3.00 (m, 1 H), 2.80 (dd, J = 13.8, 9.1 Hz, 1 H), 2.23 - 2.14 (m, 1 H), 1.90 - 1.79 (m, 1 H). LCMS (Method 5): [M+H]+m / z 366.2 , RT 0.83 minutes.

[0883] Peak 2: Enantiomer 2 (believed to be the (3R) enantiomer) :

[0884] 1H NMR (500 MHz, DMSO-d6) 5H 9.32 (s, 2H), 8.75 (d, J = 6.1 Hz, 2H), 8.36 (d, J = 2.5 Hz, 1 H), 8.23 (d, J = 6.1 Hz, 2H), 7.81 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 3.93 - 3.79 (m, 2H), 3.19 - 3.11 (m, 1 H), 3.07 (qd, J = 9.1 , 5.0 Hz, 1 H), 2.80 (dd, = 13.8, 9.1 Hz, 1 H), 2.22 - 2.15 (m, 1 H), 1.86 (dq, J = 12.3, 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 366.2 , RT 0.83 minutes.

[0885] One of enantiomers A and B is (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin- 5-yl)pyrrolidin-2-one and the other is (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4- ylpyrimidin-5-yl)pyrrolidin-2-one.

[0886] EXAMPLE 16: 3-r(6-chloropyridin-3-yl)methyll-1-(5-pyridazin-4-ylpyrazin-2- yl)pyrrolidin-2-one

[0887] To a screw-cap vial was added Intermediate 10 (83.0 mg, 0.23 mmol), 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridazine (56.0 mg, 0.27 mmol), Pd(dppf)Cl2 (17.0 mg, 0.023 mmol), K2CO3 (95.0 mg, 0.68 mmol), 1 ,4-dioxane (1 mL) and H2O (0.15 mL). The mixture was degassed with N2 for 5 minutes and then heated to 80 °C. The mixture was stirred at 80 °C for 21 h, after the reaction was recharged with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridazine (56.0 mg, 0.27 mmol) and Pd(dppf)Cl2 (17.0 mg, 0.023 mmol). The mixture was stirred at 80 °C for a further 50 minutes and then at 90 °C for 20 h. The reaction was cooled to r.t. and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so- hexane (0-100% gradient) then MeOH / DCM (0-10% gradient), and further reverse phase preparative HPLC purification afforded the title compound (4.3 mg, 5.2%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H = 9.94 (dd, J = 2.4, 1 .3 Hz, 1 H), 9.73 (d, J = 1 .5 Hz, 1 H), 9.39 (dd, J = 5.4, 1 .2 Hz, 1 H), 9.34 (d, J = 1 .5 Hz, 1 H), 8.37 (d, J = 2.5 Hz, 1 H), 8.32 (dd, J = 5.5, 2.4 Hz, 1 H), 7.83 (dd, J = 8.2, 2.6 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 4.08-4.00 (m, 1 H), 3.88- 3.78 (m, 1 H), 3.24-3.14 (m, 2H), 2.89-2.79 (m, 1 H), 2.24-2.12 (m, 1 H), 1 .92-1 .79 (m, 1 H). LCMS (Method 5): [M+H]+m / z 367.2, RT 0.97 min. EXAMPLE 17: (3 / ?)-3-K6-chloropyridin-3-yl)methyll-1-(6-pyridazin-4-ylpyridin-3- yl)pyrrolidin-2-one

[0888] To a solution of Intermediate 30 (75 mg, 0.32 mmol), Intermediate 14 (52 mg, 0.25 mmol), Pd2(dba)3 (23 mg, 0.024 mmol), Xantphos (29 mg, 0.049 mmol) and K3PO4 (150 mg, 0.693 mmol) were dissolved in in 1 ,4-dioxane (2.5 mL) and the reaction mixture was heated to 70°C for 3 h. After completion, the reaction was cooled to r.t. , filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient) afforded the title compound (18 mg, 20%) as a white solid.1H NMR (400 MHz, DMSO-de) 5H 9.91 (dd, J = 2.4, 1.3 Hz, 1 H), 9.34 (dd, J = 5.5, 1.2 Hz, 1 H), 9.12 (dd, J = 2.1 , 1.3 Hz, 1 H), 8.39 - 8.31 (m, 3H), 8.28 (dd, J = 5.4, 2.4 Hz, 1 H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (dd, J = 8.2, 0.7 Hz, 1 H), 3.86 (ddd, J = 8.7, 7.3, 5.6 Hz, 2H), 3.21 - 3.02 (m, 2H), 2.81 (dd, J = 13.7, 8.9 Hz, 1 H), 2.18 (dddd, J = 12.2, 9.7, 6.4, 3.3 Hz, 1 H), 1.91 - 1.77 (m, 1 H). LCMS (Method 5): [M+H]+m / z 366.2, RT 0.95 min.

[0889] EXAMPLE 18A and B: (3S) and enantiomers of 3-r(6-chloro-5-fluoropyridin-3- yl)methyll-1 -(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one

[0890] (3S)-3-r(6-chloro-5-fluoropyridin-3-yl)methyll-1 -(6-pyridazin-4-ylpyridazin-3- yl)pyrrolidin-2-one

[0891] To a solution of Intermediate 26 (51 mg, 0.20 mmol), Intermediate 33 (27 mg, 0.12 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos (15 mg, 0.025 mmol) and K3PO4 (77 mg, 0.36 mmol) were dissolved in in 1 ,4-dioxane (2.4 mL) and the reaction mixture was heated to 70°C for 3 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-20% gradient), and further reverse phase preparative HPLC purification afforded the title compound (4.0 mg, 8.8%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H 9.97 (dd, J = 2.5, 1.2 Hz, 1 H), 9.44 (dd, J = 5.4, 1 .2 Hz, 1 H), 8.75 (d, J = 9.5 Hz, 1 H), 8.55 (d, J = 9.5 Hz, 1 H), 8.36 (dd, J = 5.4, 2.4 Hz, 1 H), 8.30 - 8.25 (m, 1 H), 7.98 (dd, J = 9.7, 2.0 Hz, 1 H), 4.26 (ddd, J = 11 .1 , 8.8, 2.5 Hz, 1 H), 4.04 - 3.93 (m, 1 H), 3.29 - 3.17 (m, 2H), 2.94 - 2.83 (m, 1 H), 2.29 - 2.18 (m, 1 H), 1.97 - 1.82 (m, 1 H). LCMS (Method 5): [M+H]+m / z 385.2, RT 1.00 min.

[0892] (3 / ?)-3-K6-chloro-5-fluoropyridin-3-yl)methyll-1 -(6-pyridazin-4-ylpyridazin-3- yl)pyrrolidin-2-one

[0893] Prepared in an analogous manner to (3S)-3-K6-chloro-5-fluoropyridin-3-yl)methyll-1-(6- Pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one, using Intermediate 26 (65 mg, 0.25 mmol) and Intermediate 34 (45 mg, 0.20 mmol) to afford the title compound (20 mg, 26%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5H 9.97 (dd, J = 2.4, 1 .3 Hz, 1 H), 9.44 (dd, J = 5.4, 1 .2 Hz, 1 H), 8.75 (d, J = 9.5 Hz, 1 H), 8.55 (d, J = 9.4 Hz, 1 H), 8.36 (dd, J = 5.4, 2.4 Hz, 1 H), 8.28 (d, J = 1 .9 Hz, 1 H), 7.98 (dd, J = 9.7, 2.0 Hz, 1 H), 4.26 (ddd, J = 11 .1 , 8.7, 2.5 Hz, 1 H), 3.99 (ddd, J = 10.9, 9.2, 7.3 Hz, 1 H), 3.30 - 3.17 (m, 2H), 2.94 - 2.83 (m, 1 H), 2.23 (dtd, J = 12.5, 7.4, 2.4 Hz, 1 H), 1.89 (dq, J = 12.4, 9.1 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 384.9, RT 1.00 minutes.

[0894] EXAMPLE 19A and B: and (3S) enantiomers of 3-r(6-chloro-5-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one

[0895]

[0896] Step 1 :

[0897] To a solution of 3-bromo-6-(4-pyridinyl)pyridazine (CAS No: 1159818-39-9, 182 mg, 0.771 mmol), Intermediate 32 (130 mg, 0.569 mmol), Pd2(dba)3 (25 mg, 0.026 mmol), Xantphos (34 mg, 0.057 mmol) and K3PO4 (370 mg, 1.71 mmol) were dissolved in in 1 ,4-dioxane (5 mL) and the reaction mixture was heated to 90 °C for 3 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-10% gradient) afforded racemic 3-[(6-chloro-5-fluoropyridin-3-yl)methyl]- 1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one (152 mg; 51%) as an off-white solid.

[0898] Step 2:

[0899] Racemic 3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3- yl)pyrrolidin-2-one (152 mg; 51 %) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 250 x 20 mm 5 pm;Method: MeOH (3-40% gradient) over 12 min; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the corresponding Enantiomer 1 (Peak 1 ; 22 mg, white solid) and Enantiomer 2 (Peak 2; 21 mg, white solid).

[0900] Peak 1 : Enantiomer 1 ((3R) enantiomer):

[0901] 1H NMR (400 MHz, DMSO-d6) 5H 8.80 - 8.75 (m, 2H), 8.72 (d, J = 9.4 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.28 (d, J = 1 .9 Hz, 1 H), 8.14 - 8.08 (m, 2H), 7.98 (dd, J = 9.8, 2.0 Hz, 1 H), 4.25 (ddd, J = 11.1 , 8.8, 2.5 Hz, 1 H), 3.98 (ddd, J = 10.8, 9.1 , 7.3 Hz, 1 H), 3.32 - 3.16 (m, 2H), 2.93 - 2.82 (m, 1 H), 2.24 (s, 1 H), 1.96 - 1.81 (m, 1 H). LCMS (Method 5): [M+H]+m / z 384.0, RT 0.93 minutes. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3-40%) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 6.51 min. Peak 2: Enantiomer 2 ((3S) enantiomer) :

[0902] 1H NMR (400 MHz, DMSO-d6) 6H 8.80 - 8.75 (m, 2H), 8.72 (d, J = 9.4 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.28 (d, J = 1 .9 Hz, 1 H), 8.14 - 8.08 (m, 2H), 7.98 (dd, J = 9.8, 2.0 Hz, 1 H), 4.25 (ddd, J = 11.1 , 8.8, 2.5 Hz, 1 H), 3.98 (ddd, J = 10.8, 9.1 , 7.3 Hz, 1 H), 3.32 - 3.16 (m, 2H), 2.93 - 2.82 (m, 1 H), 2.24 (s, 1 H), 1.96 - 1.81 (m, 1 H). LCMS (Method 5): [M+H]+m / z 384.0, RT 0.93 minutes. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3-40%) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 8.27 min.

[0903] One of enantiomers A and B is (3R)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4- ylpyridazin-3-yl)pyrrolidin-2-one and the other is (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]- 1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one.

[0904] EXAMPLE 20: (3R)-3-K6-chloro-5-fluoropyridin-3-yl)methyll-1-(6-pyridin-4- ylpyridin-3-yl)pyrrolidin-2-one

[0905] To a solution of 5-bromo-2-(4-pyridyl)pyridine (CAS No: 106047-33-0, 156 mg, 0.664 mmol), Intermediate 34 (105 mg, 0.459 mmol), Pd2(dba)3 (48 mg, 0.051 mmol), Xantphos (62 mg, 0.19 mmol) and K3PO4 (270 mg, 1.25 mmol) were dissolved in in 1 ,4-dioxane (2.5 mL) and the reaction mixture was heated to 70 °C for 3 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with MeOH, and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc / / so-hexane (0-100% gradient) and then MeOH / EtOAc (0-15% gradient), and further purification by reverse phase preparative HPLC afforded the title compound (32 mg, 18%) as a white solid.1H NMR (400 MHz, DMSO-de) 5H 9.06 (dd, J = 2.6, 0.7 Hz, 1 H), 8.72 - 8.66 (m, 2H), 8.34 - 8.24 (m, 2H), 8.19 (dd, J = 8.8, 0.7 Hz, 1 H), 8.08 - 8.02 (m, 2H), 7.97 (dd, J = 9.8, 2.0 Hz, 1 H), 3.87 (ddd, J = 12.6, 9.4, 6.8 Hz, 2H), 3.21 (dd, J = 13.8, 5.0 Hz, 1 H), 3.17 - 3.04 (m, 1 H), 2.84 (dd, J = 13.8, 9.2 Hz, 1 H), 2.25 - 2.13 (m, 1 H), 1 .93 - 1 .78 (m, 1 H). LCMS (Method 5): [M+H]+m / z 383.2, RT 0.83 min. EXAMPLE 21 : 3-r(6-Fluoro-3-pyridyl)methyll-1 -r6-(4-pyridyl)pyridazin-3- yllpyrrolidin-2-one

[0906] To 3-bromo-6-(4-pyridyl)pyridazine (CAS No: 1159818-39-9, 213 mg, 0.90 mmol), Intermediate 36 (125 mg, 0.64 mmol), Pd2(dba)3 (61 mg, 0.064 mmol), Xantphos (77 mg, 0.13 mmol) and K3PO4 (418 mg, 1.93 mmol) was added 1 ,4-dioxane (3.5 mL) and the reaction mixture was stirred for 3 h at 70 °C. The reaction mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with EtOAc / / so-hexane (0-100% gradient, and then MeOH / EtOAc, 0-30% gradient) to afford the title compound (225 mg, 100%) as a light-yellow solid.1H NMR (400 MHz, DMSO-de) 5H 8.80 - 8.73 (m, 2H), 8.72 (d, J = 9.4 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.18 (d, J = 2.5 Hz, 1 H), 8.14 - 8.06 (m, 2H), 7.95 (td, J = 8.3, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz, 1 H), 4.21 (ddd, J = 11.1 , 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.8, 9.0, 7.3 Hz, 1 H), 3.24 - 3.11 (m, 2H), 2.90 - 2.79 (m, 1 H), 2.25 - 2.13 (m, 1 H), 1.87 (dq, J = 12.2, 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+350.2, RT 0.77 min.

[0907] Example 21 A & B: Enantiomers (3S) and (3R) of 3-r(6-fluoro-3-pyridyl)methyll-1-r6-

[0908] (4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one

[0909] Example 21 (220 mg) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IH, 250 x 20 mm 5 pm ; Method: MeOH (40% isocratic) over 14 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford the corresponding Enantiomer 1 (Peak 1 ; 5 mg, off-white solid) and Enantiomer 2 (Peak 2; 5 mg, off-white solid). Peak 1 : Enantiomer 1 (believed to be the (3S) enantiomer):

[0910] 1H NMR (400 MHz, DMSO) 5 8.80 - 8.75 (m, 2H), 8.72 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.18 (s, 1 H), 8.14 - 8.08 (m, 2H), 7.95 (td, J = 8.2, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.7 Hz, 1 H), 4.21 (ddd, J = 11.1 , 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.8, 9.0, 7.3 Hz, 1 H), 3.24 - 3.11 (m, 2H), 2.90 - 2.79 (m, 1 H), 2.19 (ddt, J = 10.3, 7.5, 3.7 Hz, 1 H), 1.95 - 1.80 (m, 1 H). LCMS (Method 5): [M+H]+m / z 350.2, RT 0.76 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3-40% gradient) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 6.26 min.

[0911] Peak 2: Enantiomer 2 (believed to be the (3R) enantiomer):

[0912] 1H NMR (400 MHz, DMSO) 5 8.80 - 8.75 (m, 2H), 8.72 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.18 (d, J = 2.5 Hz, 1 H), 8.14 - 8.08 (m, 2H), 7.95 (td, J = 8.3, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz, 1 H), 4.21 (ddd, J = 11 .1 , 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.18 (td, J = 14.2, 4.9 Hz, 2H), 2.90 - 2.79 (m, 1 H), 2.26-2.12 (m, 1 H), 1.95 - 1.80 (m, 1 H). LCMS (Method 5): [M+H]+m / z 350.2, RT 0.77 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3-40% gradient) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 6.66 min.

[0913] One of enantiomers A and B is (3R)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one and the other is (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin- 3-yl]pyrrolidin-2-one.

[0914] EXAMPLE 22A & 22B: (3S) and (3 / ?) enantiomers of 3-r(6-fluoro-3-pyridyl)methyl]- 1-f6-(4-pyridyl)-3-pyridyllpyrrolidin-2-one

[0915] Step 1 : To 5-bromo-2-(4-pyridyl)pyridine (CAS No: 106047-33-0, 170 mg, 0.72 mmol), Intermediate 36 (100 mg, 0.51 mmol), Pd2(dba)3 (50 mg, 0.053 mmol), Xantphos (62 mg, 0.10 mmol) and K3PO4 (334 mg, 1 .54 mmol) was added 1 ,4-dioxane (3 mL) and the reaction mixture was stirred for 3 h at 70 °C. The reaction mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with EtOAc / zso-hexane (0-100% gradient, and then MeOH / EtOAc, 0-30% gradient) to afford racemic 3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one (185 mg, 38%) as an off-white solid.

[0916] Step 2:

[0917] Racemic 3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one (180 mg) was subjected to chiral purification by SFC chromatography (Column: Lux C3, 250 x 20 mm 5 pm ; Method: MeOH (3-40% gradient) over 7.5 mins; Column temperature: 40 °C; Flowrate: 100 mL / min) to afford corresponding Enantiomer 1 (Peak 1 ; 36 mg, white solid) and Enantiomer 2 (Peak 2; 37 mg, white solid).

[0918] Peak 1 : Enantiomer 1 ((3S) enantiomer):

[0919] 1H NMR (400 MHz, DMSO-d6) 5H 9.05 (dd, J = 2.7, 0.7 Hz, 1 H), 8.72 - 8.66 (m, 2H), 8.30 (dd, J = 8.7, 2.7 Hz, 1 H), 8.22 - 8.14 (m, 2H), 8.08 - 8.02 (m, 2H), 7.94 (td, J = 8.2, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz, 1 H), 3.89 - 3.80 (m, 2H), 3.17 (dd, J = 13.8, 4.8 Hz, 1 H), 3.12 - 2.99 (m, 1 H), 2.81 (dd, J= 13.8, 9.1 Hz, 1 H), 2.23 - 2.10 (m, 1 H), 1.92 - 1.77 (m, 1 H). LCMS (Method 5): [M+H]+m / z 349.2, RT 0.67 min. Chiral HPLC analysis (Column: Lux C3, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1 % NH4OH (3-40% gradient) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.51 min.

[0920] Peak 2: Enantiomer 2 ((3R) enantiomer):

[0921] 1H NMR (400 MHz, DMSO-d6) 5H 9.06 (dd, J = 2.7, 0.7 Hz, 1 H), 8.72 - 8.66 (m, 2H), 8.30 (dd, J = 8.8, 2.7 Hz, 1 H), 8.22 - 8.15 (m, 2H), 8.08 - 8.02 (m, 2H), 7.94 (td, J = 8.2, 2.5 Hz, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz, 1 H), 3.84 (dd, J = 8.8, 5.0 Hz, 2H), 3.17 (dd, J = 13.8, 4.7 Hz, 1 H), 3.12 - 2.99 (m, 1 H), 2.81 (dd, J = 13.8, 9.1 Hz, 1 H), 2.16 (ddt, J = 13.2, 9.3, 4.7 Hz, 1 H), 1.84 (dq, J = 12.3, 8.9 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 349.2, RT 0.68 min. Chiral HPLC analysis (Column: Lux C3, 4.6 x 150 mm, 3 pm; Method: MeOH + 0.1% NH4OH (3-40% gradient) over 10 mins; Column temperature: 35 °C; Flowrate: 3.0 mL / min): RT 3.77 min. One of enantiomers A and B is (3R)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3- pyridyl]pyrrolidin-2-one and the other is (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3- pyridyl]pyrrolidin-2-one.

[0922] EXAMPLE 23: 3-K6-Chloro-3-pyridyl)methyll-1 -r6-(3-hvdroxy-4-pyridyl)pyridazin-3-

[0923] Intermediate 40 (100 mg, 0.39 mmol), Intermediate 12 (89.7 mg, 0.41 mmol), K3 O4 (164 mg, 0.77 mmol) and XantPhos Pd G3 (36.5 mg, 0.04 mmol) were dissolved in t-BuOH (10 mL). The reaction mixture was degassed with nitrogen for 5 mins and then heated to 100 °C for 72 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The product was purified by reversed phase preparative HPLC to afford the title compound (6 mg, 3%) as a white solid.1H NMR (400 MHz, DMSO) 5 11.93 (s, 1 H), 8.75 (d, J = 9.6 Hz, 1 H), 8.54 (d, J = 9.6 Hz, 1 H), 8.39 (s, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.21 (d, J = 5.1 Hz, 1 H), 7.89 (d, J = 5.1 Hz, 1 H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.19 (ddd, J = 11.1 , 8.7, 2.5 Hz, 1 H), 4.00 - 3.90 (m, 1 H), 3.17 (dq, J = 10.5, 4.9 Hz, 2H), 2.87 - 2.78 (m, 1 H), 2.19 (dt, J = 13.0, 7.4 Hz, 1 H), 1 .89 - 1 .83 (m, 1 H). LCMS (Method 5): [M+H]+m / z 382.2, RT 1 .01 minutes.

[0924] EXAMPLE 24: 3-K6-Chloro-3-pyridyl)methyll-1 -r6-(2,6-dideuterio-4- Pyridyl)pyridazin-3-yllpyrrolidin-2-one A mixture of Intermediate 12 (20 mg, 0.09 mmol), Intermediate 43 (18 mg, 0.09 mmol) and K3PO4 (40 mg, 0.188 mmol) in 1 ,4-dioxane (2 mL) was sparged with nitrogen for 5 min. XantPhos Pd G3 (9 mg, 0.01 mmol) was added. The mixture was heated to 70 °C and stirred for 19 h. The mixture was cooled to r.t., concentrated in vacuo and purified by flash chromatography on silica gel (0-100% [EtOAc:EtOH 3 :1] / iso-hexane) to afford the title compound (3 mg, 9%) as a white solid.1H NMR (500 MHz, DMSO-d6) 5 8.71 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.36 (d, J = 2.4 Hz, 1 H), 8.10 (s, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.25 - 4.17 (m, 1 H), 4.01 - 3.91 (m, 1 H), 3.22 - 3.12 (m, 2H), 2.86 - 2.78 (m, 1 H), 2.24 - 2.12 (m, 1 H), 1.93 - 1.79 (m, 1 H). LCMS (Method 5): [M+H]+m / z 368.2, RT 0.83 min.

[0925] EXAMPLE 24A: (3R)-3-[(6-chloro-3-pyridyl)methyl1-1 -[6-(2,6-dideuterio^- pyridyl)pyridazin-3-yllpyrrolidin-2-one

[0926] Prepared from Intermediate 43 (44 mg, 0.11 mmol) and Intermediate 14 (25 mg, 0.11 mmol) in accordance with the procedure described for Example 24 (70 °C, 5 h) to afford the title compound (4 mg, 9%) as a white solid.1H NMR (500 MHz, DMSO-d6) 5 8.71 (d, J = 9.4 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.10 (s, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.21 (ddd, J = 11.0, 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.8, 9.1 , 7.3 Hz, 1 H), 3.23 - 3.14 (m, 2H), 2.88 - 2.80 (m, 1 H), 2.23 - 2.14 (m, 1 H), 1.90 - 1.81 (m, 1 H). LCMS (Method 5): [M+H]+m / z 368.2, RT 0.85 min.

[0927] EXAMPLE 25: 3-K6-Chloro-5-fluoro-3-pyridyl)methyll-1 -(6-methoxy-5-pyridazin-4- yl-2-pyridyl)pyrrolidin-2-one

[0928] To Intermediate 44 (97.0 %, 150 mg, 0.66 mmol), Intermediate 32 (183 mg, 0.72 mmol), RuPhos Pd G3 (54.9 mg, 0.07 mmol) and K3PO4 (279 mg, 1.31 mmol) was added t-BuOH (15 mL). The resultant solution was degassed with nitrogen for 5 mins and then heated to 80 °C for 16 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The product was purified by reverse phase flash chromatography (0-100%, MeCN / 0.1% aq Formic acid) to afford the title compound (90 mg, 32%) as an off-white solid.1H NMR (400 MHz, DMSO) 5 9.52 (dd, J = 2.4, 1 .2 Hz, 1 H), 9.24 (dd, J = 5.5, 1 .2 Hz, 1 H), 8.26 (d, J = 1 .9 Hz, 1 H), 8.16 (d, J = 8.3 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.99 - 7.91 (m, 2H), 4.20 - 4.10 (m, 1 H), 3.96 (s, 3H), 3.90 - 3.80 (m, 1 H), 3.25 - 3.14 (m, 2H), 2.89 - 2.78 (m, 1 H), 2.17 - 2.09 (m, 1 H), 1.81 (q, J = 10.7 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 414.2, RT 1 .23 min.

[0929] EXAMPLES 25A and 25B: (3 / ?)-3-K6-chloro-5-fluoro-3-pyridyl)methyll-1-(6- methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one and (3S)-3-r(6-chloro-5-fluoro-3- Pyridyl)methyll-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one

[0930] Example 25 (87 mg, 0.20 mmol) was subjected to chiral purification by SFC chromatography (Column: Chiralpak IB-N, 21 x 250 mm, 5 pm; Method: EtOH / O.2% NH3 (45%); Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compounds: Example 25B (4 mg, 5%) and Example 25A (12 mg, 14%) as off-white solids. Peak 1 : Example 25B: (3S) enantiomer

[0931] 1H NMR (500 MHz, DMSO) 5 9.52 (dd, J = 2.4, 1 .2 Hz, 1 H), 9.24 (dd, J = 5.5, 1 .2 Hz, 1 H), 8.28 - 8.23 (m, 1 H), 8.16 (d, J = 8.3 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.96 (dd, J = 9.7, 2.0 Hz, 1 H), 7.93 (dd, J = 5.5, 2.5 Hz, 1 H), 4.15 (ddd, J = 11.0, 8.7, 2.4 Hz, 1 H), 3.96 (s, 3H), 3.85 (ddd, J = 11.0, 9.3, 7.2 Hz, 1 H), 3.23 - 3.14 (m, 2H), 2.86 - 2.80 (m, 1 H), 2.19 - 2.12 (m, 1 H), 1.85 - 1.76 (m, 1 H). LCMS (Method 5): [M+H]+m / z 414.2, RT 1.23 min.

[0932] Peak 2: Example 25A: (37?) enantiomer

[0933] 1H NMR (500 MHz, DMSO) 5 9.52 (dd, J = 2.4, 1.2 Hz, 1 H), 9.24 (dd, J = 5.4, 1.3 Hz, 1 H), 8.26 (d, J = 1 .9 Hz, 1 H), 8.16 (d, J = 8.3 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.96 (dd, J = 9.7, 1.9 Hz, 1 H), 7.93 (dd, J = 5.5, 2.5 Hz, 1 H), 4.15 (ddd, J = 11.0, 8.7, 2.4 Hz, 1 H), 3.96 (s, 3H), 3.85 (ddd, J = 10.9, 9.3, 7.3 Hz, 1 H), 3.24 - 3.15 (m, 2H), 2.85 - 2.79 (m, 1 H), 2.14 (ddt, J = 15.2, 11.4, 4.9 Hz, 1 H), 1.87 - 1.75 (m, 1 H). LCMS (Method 5): [M+H]+m / z 414.2, RT 1.23 min.

[0934] One of enantiomers A and B is (37?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5- pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one and the other is (3S)-3-[(6-chloro-5-fluoro-3- pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one.

[0935] EXAMPLES 26A and 26B: (3 / ?) and (3S) enantiomers of 3-K6-Chloro-3- pyridyl)methyl1-3,4,4,5,5-pentadeuterio-1 -[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one

[0936] Step 1 :

[0937] To a solution of 3-bromo-6-(4-pyridinyl)pyridazine (125 mg, 0.530 mmol), Intermediate 47) (104 mg, 0.482 mmol), Pd2(dba)3 (45 mg, 0.048 mmol), Xantphos (62 mg, 0.10 mmol) and K3PO4 (292 mg, 1 .35 mmol) were dissolved in in 1 ,4-dioxane (2.5 mL) and the reaction mixture was heated to 90°C for 3 h. 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- 15% gradient) afforded racemic 3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4- pyridyl)pyridazin-3-yl]pyrrolidin-2-one (114 mg, 64%) as a white solid.

[0938] Step 2:

[0939] Racemic 3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin- 3-yl]pyrrolidin-2-one (114 mg) was subjected to chiral purification by normal phase HPLC (Column: Chiralpak IH, 250 x 21.5 mm 5 pm ; Method: MeCN (100% isocratic) over 20 min; Column temperature: 30 °C; Flowrate: 20 (mL / min) to afford the corresponding Enantiomer 1 (Peak 1 ; 42 mg, white solid) and Enantiomer 2 (Peak 2; 42 mg, white solid) of 3-[(6-chloro-3- pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one.

[0940] Peak 1 : Enantiomer 1: Example 26A ((3R) enantiomer ):

[0941] 1 H NMR (500 MHz, DMSO) 5 8.78 (br, 2H), 8.71 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.36 (d, J = 2.4 Hz, 1 H), 8.11 (d, J = 5.0 Hz, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 3.17 (d, J = 14.0 Hz, 1 H), 2.83 (d, J = 14.0 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 371.3, RT 0.84 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeCN + 0.1% DEA (100%) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 3.48 min.

[0942] Peak 2: Enantiomer 2: Example 26B ((3S) enantiomer ):

[0943] 1 H NMR (500 MHz, DMSO) 5 8.78 (br, 2H), 8.71 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.36 (d, J = 2.4 Hz, 1 H), 8.11 (d, J = 5.0 Hz, 2H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 3.17 (d, J = 14.0 Hz, 1 H), 2.83 (d, J = 14.0 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 371.3, RT 0.85 min. Chiral HPLC analysis (Column: Chiralpak IH, 4.6 x 150 mm, 3 pm; Method: MeCN + 0.1% DEA (100%) over 8 mins; Column temperature: 30 °C; Flowrate: 1.5 mL / min): RT 4.47 min.

[0944] One of enantiomers A and B is (3R)-3-[(6-chloro-3-pyridyl)methyl]-3, 4,4,5, 5-pentadeuterio-1- [6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one and the other is (3S)-3-[(6-chloro-3-pyridyl)methyl]- 3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one. EXAMPLE 27: (3 / ?)-3-K6-chloro-3-pyridyl)methyll-1 -(5-pyridazin-4-yl-2- pyridyl)pyrrolidin-2-one

[0945] To a solution of Intermediate 48 (107 mg, 0.453 mmol) in 1 ,4-dioxane (1.8 mL) was added Intermediate 14 (75 mg, 0.36 mmol) followed by Pd2(dba)3 (60 mg, 0.064 mmol), Xantphos (80 mg, 0.13 mmol) and K3PO4 (240 mg, 1.11 mmol) at r.t. and the reaction mixture was heated to 70°C for 3 h. 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 recrystallisation or reverse phase HPLC afforded the title compound (67 mg, 52%) as a white solid.1H NMR (400 MHz, DMSO) 5 9.73 (dd, J = 2.6, 1.2 Hz, 1 H), 9.30 (dd, J = 5.5, 1.2 Hz, 1 H), 9.01 (dd, J = 2.5, 0.9 Hz, 1 H), 8.50 (dd, J = 8.8, 0.9 Hz, 1 H), 8.44 (dd, J = 8.9, 2.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.09 (dd, J = 5.5, 2.5 Hz, 1 H), 7.82 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (dd, J = 8.1 , 0.7 Hz, 1 H), 4.07 (ddd, J = 11.1 , 8.7, 2.5 Hz, 1 H), 3.84 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.16 (ddt, J = 10.0, 8.3, 4.7 Hz, 2H), 2.87 - 2.77 (m, 1 H), 2.19 - 2.07 (m, 1 H), 1.80 (dq, J = 12.1 , 9.1 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 366.2, RT 0.96 min.

[0946] EXAMPLE 28: -3-r(6-chloro-5-fluoro-3-pyridyl)methyl]-1 -(5-pyridazin-4-yl-2- pyridyl)pyrrolidin-2-one

[0947] To a solution of Intermediate 48 (40 mg, 0.17 mmol) in 1 ,4-dioxane (2 mL) was added Intermediate 34 (33 mg, 0.14 mmol) followed by Pd2(dba)3 (16 mg, 0.017 mmol), Xantphos (20 mg, 0.034 mmol) and K3PO4 (92 mg, 0.42 mmol) at r.t. and the reaction mixture was heated to 70 °C for 3 h. 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 (0-20% gradient), and further reverse phase HPLC purification afforded the title compound (10 mg, 18%) as a white solid.1H NMR (300 MHz, DMSO) 5 9.73 (dd, J = 2.5, 1 .3 Hz, 1 H), 9.30 (dd, J = 5.5, 1 .3 Hz, 1 H), 9.01 (dd, J = 2.4, 0.9 Hz, 1 H), 8.54 - 8.39 (m, 2H), 8.26 (s, 1 H), 8.09 (dd, J = 5.5, 2.5 Hz, 1 H), 7.97 (dd, = 9.7, 1.9 Hz, 1 H), 4.15 - 4.05 (m, 1 H), 3.92 - 3.80 (m, 1 H), 3.28 - 3.16 (m, 2H), 2.93 - 2.82 (m, 1 H), 2.17 - 2.10 (m, 1 H), 1.85 - 1.75 (m, 1 H). LCMS (Method 5): [M+H]+ m / z 384.2, RT 1.06 min.

[0948] EXAMPLE 29: -3-[(6-fluoro-3-pyridyl)methyl1-1-(5-pyridazin-4-yl-2- pyridyl)pyrrolidin-2-one

[0949] To a solution of Intermediate 48 (44 mg, 0.19 mmol) in 1 ,4-dioxane (1 .5 mL) was added Intermediate 38 (30 mg, 0.15 mmol) followed by Pd2(dba)3 (16 mg, 0.017 mmol), Xantphos (20 mg, 0.034 mmol) and K3PO4 (89 mg, 0.41 mmol) at r.t. and the reaction mixture was heated to 70°C for 3 h. 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 (0-20% gradient), and further reverse phase HPLC purification afforded the title compound (25 mg, 46%) as a white solid.1H NMR (300 MHz, DMSO) 5 9.73 (dd, J = 2.6, 1 .2 Hz, 1 H), 9.30 (dd, J = 5.5, 1 .2 Hz, 1 H), 9.00 (dd, J = 2.5, 0.9 Hz, 1 H), 8.55 - 8.38 (m, 2H), 8.17 (s, 1 H), 8.09 (dd, J = 5.5, 2.6 Hz, 1 H), 7.94 (td, J = 8.3, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz, 1 H), 4.06 (ddd, J = 11.2, 8.8, 2.6 Hz, 1 H), 3.84 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.24 - 3.06 (m, 2H), 2.89 - 2.75 (m, 1 H), 2.10 (s, OH), 1 .90 - 1 .71 (m, 1 H). LCMS (Method 5): [M+H]+ m / z 350.2, RT 0.895 min.

[0950] EXAMPLE 30: (3 / ?)-3-n6-chloro-3-pyridyl)-dideuterio-methyll-3,4.4.5.5- pentadeuterio-1 -[6-(4-pyridyl)pyridazin-3-yl1pyrrolidin-2-one

[0951]

[0952] To a solution of 3-bromo-6-(4-pyridinyl)pyridazine (80 mg, 0.34 mmol), Intermediate 54 (50 mg, 0.23 mmol), d2(dba)3 (28 mg, 0.030 mmol), Xantphos (30 mg, 0.050 mmol) and K3PO4 (155 mg, 0.716 mmol) were dissolved in in 1 ,4-dioxane (2.3 mL) and the reaction mixture was heated to 70°C for 3 h. 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 (0-20% gradient), and further reverse phase HPLC purification afforded the title compound (51 mg, 60%) as a white solid.1H NMR (300 MHz, DMSO) 5 8.81 - 8.67 (m, 3H), 8.48 - 8.33 (m, 2H), 8.15 - 8.07 (m, 2H), 7.83 (dd, J = 8.2, 2.5 Hz, 1 H), 7.48 (dd, J = 8.2, 0.7 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 373.2, RT 0.84 min.

[0953] EXAMPLE 31 : (3R)-3, 4,4,5, 5-pentadeuterio-3-[dideuterio-(6-fluoro-3- pyridyl)methyll-1 -r6-(4-pyridyl)pyridazin-3-yllpyrrolidin-2-one

[0954] To a solution of 3-bromo-6-(4-pyridinyl)pyridazine (40 mg, 0.17 mmol), Intermediate 59 (20 mg, 0.099 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol) and K3PO4 (65 mg, 0.30 mmol) were dissolved in in 1 ,4-dioxane (2 mL) and the reaction mixture was heated to 70°C for 3 h. 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- 20% gradient) afforded the title compound (32 mg, 90%) as a white solid.1H NMR (300 MHz, DMSO) 6 8.81 - 8.68 (m, 3H), 8.43 (d, J = 9.5 Hz, 1 H), 8.21 - 8.07 (m, 3H), 7.95 (td, J = 8.2, 2.6 Hz, 1 H), 7.15 (dd, J = 8.4, 2.9 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 357.2, RT 0.77 min.

[0955] EXAMPLE 32: -3-R6-chloro-3-pyridyl)-dideuterio-methyl1-1 -f6-(4- pyridyl)pyridazin-3-yl]pyrrolidin-2-one

[0956] To a solution of 3-bromo-6-(4-pyridinyl)pyridazine (83 mg, 0.35 mmol), Intermediate 62 (60 mg, 0.28 mmol), Pd2(dba)3 (27 mg, 0.029 mmol), Xantphos (40 mg, 0.067 mmol) and K3PO4 (173 mg, 0.799 mmol) were dissolved in in 1 ,4-dioxane (2.5 mL) and the reaction mixture was heated to 70°C for 3 h. 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 (0-20% gradient), and further recrystallization or reverse phase HPLC purification afforded the title compound (53 mg, 51%) as a white solid.1H NMR (300 MHz, DMSO) 5 8.81 - 8.67 (m, 3H), 8.48 - 8.33 (m, 2H), 8.15 - 8.07 (m, 2H), 7.83 (dd, J = 8.2, 2.5 Hz, 1 H), 7.49 (dd, J = 8.2, 0.7 Hz, 1 H), 4.22 (ddd, J = 11.2, 8.7, 2.6 Hz, 1 H), 3.97 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.17 (dd, J = 10.1 , 8.6 Hz, 1 H), 2.28 - 2.11 (m, 1 H), 1 .87 (dq, J = 12.3, 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 368.2, RT 0.84 min.

[0957] EXAMPLE 33: (3 / ?)-3-rdideuterio-(6-fluoro-3-pyridyl)methyll-1-(5-pyridazin-4-yl-2- pyridyl)pyrrolidin-2-one To a solution of Intermediate 48 (181 mg, 0.767 mmol) in 1 ,4-dioxane (3 mL) was added Intermediate 65 (120 mg, 0.612 mmol) followed by Pd2(dba)3 (69 mg, 0.073 mmol), Xantphos (79 mg, 0.13 mmol) and K3PO4 (355 mg, 1 .64 mmol) at r.t. and the reaction mixture was heated to 70°C for 3 h. 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 (0-20% gradient), and further recrystallization or reverse phase HPLC purification afforded the title compound (119 mg, 56%) as a white solid.1H NMR (400 MHz, DMSO) 5 9.73 (dd, J = 2.5, 1 .3 Hz, 1 H), 9.30 (dd, J = 5.5, 1.2 Hz, 1 H), 9.00 (dd, J = 2.5, 0.9 Hz, 1 H), 8.50 (dd, J = 8.9, 0.9 Hz, 1 H), 8.44 (dd, J = 8.9, 2.5 Hz, 1 H), 8.17 (dd, J = 2.2, 1.3 Hz, 1 H), 8.09 (dd, J = 5.5, 2.6 Hz, 1 H), 7.94 (td, J = 8.3, 2.6 Hz, 1 H), 7.15 (ddd, J = 8.5, 2.9, 0.7 Hz, 1 H), 4.06 (ddd, J = 11.1 , 8.7, 2.6 Hz, 1 H), 3.84 (ddd, J = 10.9, 9.1 , 7.3 Hz, 1 H), 3.13 (dd, J = 10.0, 8.5 Hz, 1 H), 2.11 (dddd, J = 12.3, 8.6, 7.3, 2.6 Hz, 1 H), 1.81 (ddt, J = 12.3, 10.0, 8.8 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 352.2, RT 0.90 min.

[0958] EXAMPLE 34: (3 / ?)-3-rdideuterio-(6-fluoro-3-pyridyl)methyll-1-r5-(4-pyridyl)-2- pyridyllpyrrolidin-2-one

[0959] To a solution of 2-bromo-5-(pyridin-4-yl)pyridine (82 mg, 0.35 mmol) in 1 ,4-dioxane (3 mL) was added Intermediate 65 (53 mg, 0.27 mmol) followed by Pd2(dba)3 (32 mg, 0.034 mmol), Xantphos (40 mg, 0.067 mmol) and K3PO4 (140 mg, 0.646 mmol) at r.t. and the reaction mixture was heated to 70°C for 3 h. After completion, the reaction was cooled to r.t., filtered through a pad of Celite® eluting with DCM, and concentrated in vacuo. Purification by reverse phase HPLC purification afforded the title compound (70 mg, 74%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.88 (dd, J = 2.6, 0.9 Hz, 1 H), 8.70 - 8.63 (m, 2H), 8.47 (dd, J = 8.8, 0.8 Hz, 1 H), 8.32 (dd, J = 8.8, 2.6 Hz, 1 H), 8.17 (dd, J = 2.2, 1.3 Hz, 1 H), 7.93 (td, J = 8.3, 2.6 Hz, 1 H),

[0960] 7.82 - 7.76 (m, 2H), 7.15 (ddd, J = 8.4, 2.9, 0.7 Hz, 1 H), 4.06 (ddd, J = 11.1 , 8.7, 2.7 Hz, 1 H),

[0961] 3.83 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.11 (dd, J = 10.0, 8.6 Hz, 1 H), 2.11 (dddd, J = 12.4, 8.6, 7.3, 2.6 Hz, 1 H), 1.80 (ddt, J = 12.3, 10.1 , 8.9 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 351.2, RT 0.74 min. EXAMPLE 35: -34(6-chloro-5-fluoro-3-pyridyl)-dideuterio-methyll-14544- pyridyl)pyrazin-2-yllpyrrolidin-2-one

[0962] To a solution of 2-bromo-5-(4-pyridyl)pyrazine (190 mg, 0.805 mmol) in 1 ,4-dioxane (3 mL) was added Intermediate 70 (150 mg, 0.650 mmol) followed by Pd2(dba)3 (58 mg, 0.061 mmol), Xantphos (79 mg, 0.13 mmol) and K3PO4 (286 mg, 1.32 mmol) at r.t. and the reaction mixture was heated to 70°C for 3 h. 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- 20% gradient), and further recrystallization or reverse phase HPLC purification afforded the title compound (89 mg, 35%) as a white solid.1H NMR (400 MHz, DMSO) 5 9.69 (d, J = 1.5 Hz, 1 H), 9.23 (d, J = 1 .5 Hz, 1 H), 8.77 - 8.68 (m, 2H), 8.27 (dd, J = 1 .9, 0.8 Hz, 1 H), 8.12 - 8.06 (m, 2H), 7.98 (dd, J = 9.7, 2.0 Hz, 1 H), 4.06 (ddd, J = 11 .0, 8.7, 2.5 Hz, 1 H), 3.83 (ddd, J = 10.8, 9.2, 7.3 Hz, 1 H), 3.20 (dd, J = 10.2, 8.5 Hz, 1 H), 2.25 - 2.13 (m, 1 H), 1.87 (ddt, J = 12.3, 10.3, 8.9 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 386.30, RT 0.99 min.

[0963] EXAMPLE 36: (3 / ?)-34(6-chloro-3-pyridyl)-dideuterio-methyll-14644- pyridyl)pyridazin-3-yllpyrrolidin-2-one

[0964] To a solution of 3-bromo-6-(4-pyridinyl)pyridazine (173 mg, 0.733 mmol), Intermediate 70 (141 mg, 0.61 mmol), Pd2(dba)3 (53 mg, 0.056 mmol), Xantphos (72 mg, 0.12 mmol) and K3PO4 (273 mg, 1 .26 mmol) were dissolved in in 1 ,4-dioxane (3 mL) and the reaction mixture was heated to 70°C for 3 h. 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 (0-20% gradient), and further recrystallization or reverse phase HPLC purification afforded the title compound (122 mg, 52%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.80 - 8.74 (m, 2H), 8.71 (d, J = 9.5 Hz, 1 H), 8.43 (d, J = 9.5 Hz, 1 H), 8.28 (dd, J = 2.0, 0.8 Hz, 1 H), 8.14 - 8.08 (m, 2H), 7.98 (dd, J = 9.7, 2.0 Hz, 1 H), 4.25 (ddd, J = 11.0, 8.7, 2.5 Hz, 1 H), 3.98 (ddd, J = 10.9, 9.2, 7.3 Hz, 1 H), 3.21 (dd, J = 10.1 , 8.6 Hz, 1 H), 2.28 - 2.16 (m, 1 H), 1.89 (ddt, J = 12.3, 10.1 , 8.9 Hz, 1 H). LCMS (Method 5): [M+H]+ m / z 386.3, RT 0.99 min.

[0965] EXAMPLE 37: 3-K6-Fluoro-3-pyridyl)methyll-1-r6-(3-methyl-4-pyridyl)pyridazin-3- yllpyrrolidin-2-one

[0966] Prepared from Intermediate 45 (194 mg, 0.75 mmol) and Intermediate 36 (140 mg, 0.69 mmol) in accordance with the procedure described for Example 24 (90 °C, 16 h) to afford the racemic title compound (32 mg, 13%) as a white solid.1H NMR (500 MHz, DMSO) 58.70 (d, J = 9.4 Hz, 1 H), 8.60 (s, 1 H), 8.56 (d, J = 4.9 Hz, 1 H), 8.17 (d, J = 2.5 Hz, 1 H), 8.02 (d, J = 9.4 Hz, 1 H), 7.94 (td, J = 8.3, 2.5 Hz, 1 H), 7.50 (d, J = 4.9 Hz, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz, 1 H), 4.20 (ddd, J = 11.1 , 8.7, 2.6 Hz, 1 H), 3.96 (ddd, J = 10.8, 9.0, 7.3 Hz, 1 H), 3.17 (ddt, J = 13.4, 9.9, 4.3 Hz, 2H), 2.90 - 2.74 (m, 1 H), 2.36 (s, 3H), 2.18 (dtd, J = 12.0, 7.5, 2.6 Hz, 1 H), 1.86 (dq, J = 12.2, 9.0 Hz, 1 H). LCMS (Method 3B): [M+H]+m / z 364.1 , RT 0.91 min.

[0967] EXAMPLES 37A and 37B: (3 / ?)-3-r(6-fluoro-3-pyridyl)methyll-1-r6-(3-methyl-4- pyridyl)pyridazin-3-yllpyrrolidin-2-one and (3S)-3-K6-fluoro-3-pyridyl)methyll-1 -f6-(3- methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one

[0968] Example 37 (32 mg, 0.09 mmol) was subjected to chiral purification by SFC chromatography (Column: Chiralpak C3, 20 x 250mm, 5 pm; Method: 20% MeOH (0.4% NH3), 80% CO2; Column Temperature: 40 °C; Flow rate: 65 mL / min) to afford the title compounds’. Example 37A (12 mg, 40%) and Example 37B (11 mg, 37%) as off-white solids.

[0969] Peak 1 : Example 37A ((3 / ?) enantiomer):

[0970] 1H NMR (400 MHz, DMSO) 6 8.84 (d, J = 9.3 Hz, 1 H), 8.74 (d, J = 1 .0 Hz, 1 H), 8.70 (d, J = 5.0 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 8.08 (td, J = 8.2, 2.6 Hz, 1 H), 7.63 (d, J = 5.0 Hz, 1 H), 7.28 (dd, J = 8.4, 2.8 Hz, 1 H), 4.34 (ddd, J = 11.1 , 8.6, 2.6 Hz, 1 H), 4.10 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.36 - 3.24 (m, 2H), 3.02 - 2.93 (m, 1 H), 2.50 (s, 3H), 2.39 - 2.25 (m, 1 H), 2.00 (dq, J = 12.2, 9.0 Hz, 1 H). LCMS (Method 5): [M+H]+m / z 364.2, RT 0.76 min.

[0971] Peak 2: Example 37B ((3S) enantiomer):

[0972] 1H NMR (400 MHz, DMSO) 5 8.84 (d, J = 9.4 Hz, 1 H), 8.74 (s, 1 H), 8.70 (d, J = 5.0 Hz, 1 H), 8.31 (d, J = 2.5 Hz, 1 H), 8.16 (d, J = 9.3 Hz, 1 H), 8.08 (td, J = 8.3, 2.6 Hz, 1 H), 7.63 (d, J = 5.0 Hz, 1 H), 7.34 - 7.23 (m, 1 H), 4.34 (ddd, J = 11.1 , 8.6, 2.6 Hz, 1 H), 4.10 (ddd, J = 10.9, 9.0, 7.3 Hz, 1 H), 3.38 - 3.23 (m, 2H), 3.03 - 2.92 (m, 1 H), 2.50 (s, 3H), 2.38 - 2.27 (m, 1 H), 2.10 - 1 .93 (m, 1 H). LCMS (Method 5): [M+H]+m / z 364.2, RT 0.77 min.

[0973] One of enantiomers A and B is (3R)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4- pyridyl)pyridazin-3-yl]pyrrolidin-2-one and the other is (3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6- (3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one.

[0974] EXAMPLE 38: -3-[(6-fluoro-3-pyridyl)methyl1-1 -r3-(4-pyridyl)-1 ,2,4-triazin-6- yllpyrrolidin-2-one

[0975] To Intermediate 71 (200 mg, 0.65 mmol), pyridine-4-boronic acid hydrate (92 mg, 0.65 mmol), 1 ,T-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (16 mg, 0.020 mmol) and potassium carbonate (140 mg, 1 .00 mmol) was added 1 ,4-dioxane (2 mL) and water (1 .5 mL) then the reaction mixture was stirred at 80 °C for 1 hour under N2 atmosphere. The reaction mixture was cooled and then filtered through a phase separator and the filtrate was concentrated in vacuo to a dark brown oil. The crude residue was purified by normal flash chromatography (silica gel 25 g, hexanes / EtOAc, 0%-100%, then EtOAc / MeOH, 0%-20%) to afford the title compound as an off white solid.

[0976] The reaction was repeated as follows: Intermediate 71 (3R)-1-(3-chloro-1 ,2,4-triazin-6- yl)-3-[(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one (300 mg, 0.97 mmol), pyridine-4-boronic acid hydrate (137 mg, 0.97 mmol), 1 ,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (24 mg, 0.029 mmol) and potassium carbonate (200 mg, 1.43 mmol) were dissolved in 1 ,4-dioxane (3 mL) and water (2 mL) and the reaction mixture was stirred at 80°C for 1 hour under N2 atmosphere. The reaction mixture was cooled and then filtered through a phase separator and the filtrate was concentrated in vacuo to a dark brown oil. The crude residue was purified by normal flash chromatography (silica gel 25 g, hexanes / EtOAc, 0%- 100%, then EtOAc / MeOH, 0%-20%) to afford the title compound as an off white solid.

[0977] The two samples were combined to give 30 mg impure sample, and this was purified by Reverse Phase preparative chromatography to afford the title compound (3 mg, 1 %) as an off white solid. HNMR: (300 MHz, DMSO) 5 9.82 (s, 1 H), 8.91 - 8.72 (m, 2H), 8.33 - 8.22 (m, 2H), 8.19 (s, 1 H), 8.06 - 7.86 (m, 1 H), 7.16 (dd, J = 8.5, 2.8 Hz, 1 H), 4.20-4.00 (m, 1 H), 3.96 (d, J = 8.5 Hz, 1 H), 3.20 (d, J = 10.6 Hz, 1 H), 2.90-2.63 (m, 2H), 2.34-2.18 (m, 1 H), 2.02-1.84 (m, 1 H). LCMS (Method 5): [M+H]+ m / z 351 .2, RT 0.89 min. EXAMPLE 39: (3 / ?)-3-R6-Chloro-5-fluoro-3-pyridyl)methyll-1-[5-(4- pyridyl)pyrazin-2-yllpyrrolidin-2-one

[0978] To a 25ml flask charged with 2-bromo-5-(4-pyridyl)pyrazine (CAS: 1159819-55-2, 0.107 g, 0....

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+-0_or CRc;RA, RBand Rcare each independently 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;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;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;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;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;X6is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -CN, Ci-salkylene-OH, -O-Cs-eheterocycloalkyl and -O-Ci-3alkyleneNX6aX6b; wherein X6aand X6bare independently H or Ci-2alkyl; andX7is selected from H, halogen, -OH, -NH2, Ci-2alkyl, -Ci-2haloalkyl, -O-Ci-2alkyl, -O-C1- 2haloalkyl, -CN, Ci-salkylene-OH, -O-Cs-eheterocycloalkyl and -O-Ci-3alkyleneNX7aX7b; wherein X7aand X7bare independently H or Ci-2alkyl.

2. A compound according to claim 1 , which is a compound of (IA)(IA); or a pharmaceutically acceptable salt or solvate thereof; whereinA is selected from N, N+-O_or CRA;B is selected from N, N+-O_or CRB;C is selected from N, N+-0_or CRc;RA, RBand Rcare each independently 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;D is N or CRD, wherein RDis selected from H, 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, 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, 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; andX4is 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; andX5is 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.

3. A compound according to claim 1 or claim 2, wherein A is selected from N or CRA, B is selected from N or CRBand C is selected from N or CRC.

4. A compound according to any one of the preceding claims, wherein 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.

5. A compound according to any one of the preceding claims, wherein one of A, B and C is N and the other two are CRA, CRBand CRCas appropriate.

6. A compound according to any one of the preceding claims, wherein RA, RBand Rc, are each independently selected from H, F, Cl, -OH, C1-2 alkyl, -O-C1-2 alkyl and -CN, wherein a C1-2 alkyl group can be optionally substituted with one or more F atoms.

7. A compound according to any one of the preceding claims, wherein X1is selected from H, F, Cl, -CHs or -O-CHs.

8. A compound according to any one of the preceding claims, wherein X2and X3are each independently selected from H, F, Cl, -CHs or -O-CHs.

9. A compound according to any one of the preceding claims, wherein D is N or CRDwherein RDis selected from H, F, Cl, -CHs or -O-CHs.

10. A compound according to any one of the preceding claims, wherein X4is selected from F, Cl, -OH, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3 and / or X5is selected from H, F, Cl, -CN, -CH3, -CHF2, -CF3, -O-CH3 and -O-CF3.

11. A compound according to any one of the preceding claims, wherein E is N or CREwherein REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3and -O-CF3.

12. A compound according to any one of the preceding claims, wherein X6and X7are independently selected from H, halogen, -Ci-3alkylene-OH, -0-C3-6heterocycloalkyl or - OCi-3alkyleneNH213. A compound according to any one of the preceding claims, which is a compound of formula (II)(ii); wherein A, B and C are selected from CH or N; X1is selected from H, F, Cl, -CH3or - O-CH3; X2and X3are each independently selected from H, F, Cl, -CH3or - O-CH3; 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; and E is N or CRE, wherein REis selected from H, F, Cl, -OH, -CN, -CH3, CHF2, -CF3, -O-CH3and -O-CF3.

14. A compound according to claim 1 which is: rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;rac-3-[(6-chloropyridin-3-yl)methyl]-1 -(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;(3 / ?)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;(3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-methoxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(4-pyridin-4-ylphenyl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridazin-4-ylpyrazin-2-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)- 3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one;(3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(3-hydroxy-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(2,6-dideuterio -4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(2,6-dideuterio-4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; rac-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2- one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;(3S)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(6-methoxy-5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;(3S)-3-[(6-chloro-3-pyridyl)methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-3,4,4,5,5-pentadeuterio-1-[6-(4- pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)-3,4,4,5,5-pentadeuterio-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-(5-pyridazin-4-yl-2-pyridyl)pyrrolidin-2-one;(3 / ?)-3-[dideuterio-(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)-dideuterio-methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2- one;(3 / ?)-3-[(6-chloro-3-pyridyl)-dideuterio-methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2-one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2- one;(3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one 2- one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; rac-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3S)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[6-fluoro-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one;(3 / ?)-3-[(6-fluoro-3-pyridinyl)methyl]-1-(2-fluoro-6-pyridin-4-yl-3-pyridinyl)pyrrolidin-2-one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one;(3S)-3-[(6-fluoro-3-pyridyl)methyl]-1-[5-(4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one; rac-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;(3 / ?)- 3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;(3S)-3-[(6-chloro-3-pyridyl)methyl]-1-[3-(4-pyridyl)-1 ,2,4-triazin-6-yl]pyrrolidin-2-one;(3 / ?)-3-[(5-chloro-6-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3S)-3-[(5-chloro-6-fluoropyridin-3- yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-3-[(5-chloro-6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3S)-3-[(5-chloro-6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(3-fluoro-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; rac-3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one;(3 / ?)-(3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one;(3S)-3-[[6-chloro-2-(4-piperidyloxy)-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2- one; rac-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3R)-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3S)-3-[(2,6-difluoro-3-pyridinyl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-3-((2-amino-6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;(3S)-3-((2-amino-6-chloropyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3-yl)pyrrolidin-2-one;(3 / ?)-1-[6-(3-amino-4-pyridyl)pyridazin-3-yl]-3-[(6-fluoro-3-pyridyl)methyl]pyrrolidin-2-one;3-[(6-chloro-3-pyridyl)methyl]-1-[1-oxido-6-(4-pyridyl)pyridin-1-ium-3-yl]pyrrolidin-2-one;(3 / ?)-1-[2-(4-pyridyl)pyrimidin-5-yl]-3-[[6-(tri fluoro methyl)-3-pyridyl]methyl]pyrrolidin-2-one;(3 / ?)-3-((6-chloro-4-(hydroxymethyl)pyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3- yl)pyrrolidin-2-one;(3S)-3-((6-chloro-4-(hydroxymethyl)pyridin-3-yl)methyl)-1-(6-(pyridin-4-yl)pyridazin-3- yl)pyrrolidin-2-one; rac-3-[[6-chloro-2-[3-(dimethylamino)propoxy]-3-pyridyl]methyl]-1-[6-(4-pyridyl)pyridazin-3- yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-2-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3S)-3-[(6-chloro-2-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-(3-methyl-4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[5-(3-methyl-4-pyridyl)pyrazin-2-yl]pyrrolidin-2-one;(3 / ?)-3-[(6-chloro-5-fluoro-3-pyridyl)methyl]-1-[5-(3-methyl-4-pyridyl)pyrazin-2-yl]pyrrolidin-2- one; or (3 / ?)-3-[(6-chloro-3-pyridyl)methyl]-1-[6-hydroxy-5-(4-pyridyl)-2-pyridyl]pyrrolidin-2-one.

15. A compound according to claim 1 which is:(3S)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;(3R)- 3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;(3R)-3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;(3S)- 3-[(4-chlorophenyl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyrazin-2-yl)pyrrolidin-2-one;(3R)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; rac-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; (3R)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one;(3S)-3-[(4-chlorophenyl)methyl]-1-(6-hydroxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-methoxy-5-pyridin-4-ylpyridin-2-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(4-pyridin-4-ylphenyl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3S)-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one;(3 / ?)-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(5-fluoro-6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one;(3S)-3-[(6-chloropyridin-3-yl)methyl]-1-(2-pyridin-4-ylpyrimidin-5-yl)pyrrolidin-2-one; rac-3-[(6-chloropyridin-3-yl)methyl]-1-(5-pyridazin-4-ylpyrazin-2-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one;(3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridazin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3S)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridazin-3-yl)pyrrolidin-2-one; (3 / ?)-3-[(6-chloro-5-fluoropyridin-3-yl)methyl]-1-(6-pyridin-4-ylpyridin-3-yl)pyrrolidin-2-one; rac-3-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3 / ?)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)pyridazin-3-yl]pyrrolidin-2-one; (3S)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one; or (3 / ?)-[(6-fluoro-3-pyridyl)methyl]-1-[6-(4-pyridyl)-3-pyridyl]pyrrolidin-2-one.

16. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 15, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

17. A compound of formula (I) or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 15, for use in therapy.

18. A compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 15, for use in the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

19. A compound for use according to claim 18, 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.

20. A compound for use according to claim 18, wherein the disease or disorder is selected from neurological disorders, such as peripheral nervous system (PNS) disease, diabetic neuropathy or motor neuron disease; traumatic injuries, such as traumatic brain injury, direct trauma or spinal cord injury; diseases related to chemical exposures, such as chemotherapy induced peripheral neuropathy (CIPN) or chemotherapy induced cognitive impairment; ocular indications, such as optic neuropathy, glaucoma, retinal ganglion degeneration and macular degeneration; neurodegenerative diseases, such as motor neuron disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD); or autoimmune and inflammatory diseases.21 . Use of a compound of formula (I), or a pharmaceutically salt or solvate thereof, as defined in any one of claims 1 to 15, for the manufacture of a medicament useful for the treatment and / or prevention of a disease or disorder in which SARM1 plays a role.

22. Use of a compound according to claim 21 , 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.

23. 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 15.

24. A method according to claim 23, 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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