WO2023099648A1

WO2023099648A1 - Pyraolo- and triazolo-azinone compounds and their uses

Info

Publication number: WO2023099648A1
Application number: PCT/EP2022/084007
Authority: WO
Inventors: Rebecca Elizabeth Jarvis; Dean Gordon Brown; Perla Breccia
Original assignee: Astrazeneca Ab
Priority date: 2021-12-02
Filing date: 2022-12-01
Publication date: 2023-06-08

Abstract

The specification relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions containing them and to their use in the treatment or prevention of diseases and conditions including nervous system diseases or conditions.

Description

Pyrazolo- and Triazolo-azinone Compounds and Their Uses

FIELD

The specification generally relates to substituted pyrazolo-azine and pyrazolo-azinone compounds and pharmaceutically acceptable salts thereof. These compounds and their salts selectively inhibit receptor interacting protein kinase 1 (“RIPK1”), and the specification therefore also relates to the use of such compounds and salts thereof to treat or prevent diseases and conditions including nervous system diseases or conditions. The specification further relates to pharmaceutical composition comprising such compounds and pharmaceutically acceptable salts thereof.

BACKGROUND

Receptor interacting protein kinase 1 (“RIPK1”) is a key regulator of the cellular response to tumour necrosis factor-alpha (TNFa) signalling that mediates cell survival, cell death and inflammation in a broad range of human diseases. RIPK1 is a 76 kDa protein with an amino-terminal (N-terminal) kinase domain, a carboxy-terminal (C-terminal) death domain and an intermediate domain with a receptor-interacting protein homotypic interacting motif (RHIM). Whereas the C-terminal death domain mediates homodimerization and heterodimerization with other death domain-containing proteins (Fas associated death domain protein: FADD, tumour necrosis factor (TNF) receptor 1 : TNFR1 and Fas), the N-terminal kinase domain mediates autophosphorylation to promote its own activation.

When TNFa binds to the TNFR1 receptor, receptor oligomerisation occurs and recruits multiple protein partners including RIPK1 to a state termed Complex I. In Complex I, RIPK1 possesses linear K63-linked polyubiquitination, which mediates a protein complex that includes TRAF2/5, TRADD and clAPs. Signalling via Complex I regulates activation of NF-KB and MAPK, stimulating a pro-survival signalling cascade that is dependent upon RIPKTs scaffolding role, independent of RIP1 kinase activity.

The complex I scaffold can be disrupted by inhibition of clAPs and/or K63-linked ubiquitination of RIPK1. When scaffolding is disrupted during TNFa signalling, RIPK1 dimerises and autophosphorylates on Ser166 to form Complex II - binding to TRADD, FADD and Caspase8 - also known as the death-inducing signalling complex (DISC). When Caspase8/FADD are active, complex Ila signalling results in a RIP1 kinase-independent programmed apoptosis.

If Complex ll/DISC forms but apoptosis is inhibited via Caspase8/FADD deletion/inhibition - termed Complex lib - RIPK1 forms hetero-oligomers and phosphorylates RIP3 kinase which in turn phosphorylates mixed-lineage kinase domain-like pseudokinase (MLKL). Such an activated protein complex forms oligomeric ‘necrosomes’, which initiate pro-inflammatory cytokine/chemokine production and via the formation of trimeric MLKL oligomers, instigate a violent form of cell death termed necroptosis. Necroptosis is a programmed form of necrosis, and results in the release of cell material including danger associated molecular patterns, prompting a pro-inflammatory cascade in tissue milieu.

Based on these multiple signalling pathways with the potential for inducing inflammatory and necrotic damage, RIP1 kinase inhibitors can be used to treat multiple diseases. Both genetic and pharmacological inhibition of RIPK1 kinase activity, such as treatment with Nec-1s or other inhibitors, offer complete resistance against sepsis/systemic inflammatory response syndrome (SIRS) in mice, acting as a model system for the profound effect that RIPK1 inhibition can have on ameliorating inflammatory disease states.

The necroptosis pathway and its regulator proteins (RIPK1 , RIPK3, MLKL) have been implicated in various human diseases. There is evidence for activation in diverse human disorders from post-mortem tissue analyses, genetic susceptibility of human disease and genetic/pharmacological data from preclinical models of disease (Mifflin, L., Ofengeim, D. & Yuan, J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov 19, 553- 571 (2020) and Degterev, A., Ofengeim, D. & Yuan, J. Targeting RIPK1 for the treatment of human diseases. Proc. Natl Acad. Sci. USA 116, 9714-9722 (2019) and references there in), including nervous system disorders such as amyotrophic lateral sclerosis and multiple sclerosis. RIPK1 inhibitors are being, and have been, explored in the clinic for a range of indications, but currently there has been only one clinical trial in central nervous system (CNS) related disorders.

There remains a need for RIPK1 inhibitors which are brain penetrant and which may therefore be useful in the treatment of nervous system disorders and conditions. Other properties of interest during pharmaceutical discovery and development of such RIPK1 inhibitors may relate to selectivity profile, absorption/bioavailability, distribution, metabolism, elimination, toxicity and side-effect profile, stability, manufacturability and so on.

SUMMARY

This specification describes, in part, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R¹ is H or halo; when R¹ is H, n is 0 and when R¹ is halo, n is 0, 1 or 2;

R² is a substituent on any available ring carbon atom and when present is independently selected from -F and -Cl;

R³ is H; halo; -CN; Cvsalkyl; or -O-Ci-3alkyl; wherein alkyl is optionally substituted by -OH or one or more -F;

R⁴ is Ci-4alkyl optionally substituted with one or more -F; Q^A; Q^B or Q^c;

Q^A is a C3-6cycloalkyl group optionally substituted with one or more substituents independently selected from -F, -CN, Ci-3alkyl and -O-Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F;

Q^B is a 4 to 7-membered oxygen-containing heterocyclyl group optionally substituted with one or more substituents independently selected from Ci-3alkyl, wherein alkyl is optionally substituted with -OH, -CN or one or more -F; and

Q^c is a 6-membered nitrogen-containing heterocyclyl group optionally substituted with one or more substituents independently selected from oxo, Ci-3alkyl and -C(O)Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F.

This specification also describes, in part, a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of nervous system diseases or conditions.

This specification also describes, in part, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a nervous system disease or condition. This specification also describes, in part, a method for treating a nervous system disease or condition in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments are detailed throughout the specification and will be apparent to a reader skilled in the art. The specification is not to be interpreted as being limited to any particular embodiment(s) described herein.

In one embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R¹ is H or halo; when R¹ is H, n is 0 and when R¹ is halo, n is 0, 1 or 2;

R⁴ is Ci-4alkyl optionally substituted with one or more -F; Q^A; Q^B; or Q^c;

Q^A is a C3-6cycloalkyl group optionally substituted with one or more substituents independently selected from -F, -CN, Ci-3alkyl and -O-Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F; Q^B is a 4 to 7-membered oxygen-containing heterocyclyl group optionally substituted with one or more substituents independently selected from Ci-3alkyl, wherein alkyl is optionally substituted with -OH, -CN or one or more -F; and

Q^c is a 6-membered nitrogen-containing heterocyclyl group optionally substituted with one or more substituents independently selected from oxo, Ci-salkyl and -C(O)Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F.

The term “halo” refers to fluoro, chloro or bromo.

The term “alkyl” refers to a fully saturated straight-chain or branched aliphatic group having the number of carbon atoms specified (e.g. C^alkyl refers to an alkyl group having one to 4 carbon atoms). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, f-butyl, isobutyl and sec-butyl.

In this specification chemical abbreviations familiar to the skilled person may be used including for example “Me” = methyl, “Et” = ethyl and “Pr” = propyl.

The term “cycloalkyl” refers to a saturated aliphatic ring containing from 4 to 7 carbon ring atoms. A cycloalkyl group can contain fused and/or bridged rings where the fused or bridged ring(s) are cycloalkyl groups. Suitable examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[3.1 .0]hexyl.

The term “heterocyclyl” refers to a saturated heterocyclic ring containing from 4 to 7 ring atoms. An oxygen-containing heterocyclyl contains one ring oxygen atom and may include one further ring atom selected from N, O and S and the remaining ring atoms are carbon atoms, in stable combinations known to those of skill in the art. A nitrogen-containing heterocyclyl contains one ring nitrogen atom and may include one further ring atom selected from N, O and S and the remaining ring atoms are carbon atoms, in stable combinations known to those of skill in the art. A ring nitrogen or a ring sulfur atom, independently, can optionally be oxidized, including for example -N(O)-, -S(O)-, or - S(O)₂-. A ring nitrogen atom in a heterocyclyl group can optionally be quaternized, for example, - N⁺(CH3)2-. A heterocyclyl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl or heterocyclyl groups. Examples of heterocyclic groups include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1 .0]hexanyl, oxepanyl, 3- oxabicyclo[4.1 ,0]heptanyl, 6-oxopiperidinyl and 3-azabicyclo[3.1 .0]hexanyl.

Where the term “optionally” is used, it is intended that the subsequent feature may or may not occur. As such, use of the term “optionally” includes instances where the feature is present, and also instances where the feature is not present. For example, “methyl optionally substituted by one or more F” includes -CH3, -CH2F, -CHF2 and -CF3.

The term “substituted” means that one or more hydrogens (for example 1 , 2 or 3 hydrogens, or alternatively 1 or 2 hydrogens, or alternatively 1 hydrogen) on the designated group is replaced by the indicated substituent(s) (for example 1 , 2 or 3 substituents, or alternatively 1 or 2 substituents, or alternatively 1 substituent), provided that any atom(s) bearing a substituent maintains a permitted valency. Substituent combinations encompass only stable compounds and stable synthetic intermediates. “Stable” means that the relevant compound or intermediate is sufficiently robust to be isolated and have utility either as a synthetic intermediate or as an agent having potential therapeutic utility. If a group is not described as “substituted”, or “optionally substituted”, it is to be regarded as unsubstituted (i.e. that none of the hydrogens on the designated group have been replaced).

A further embodiment provides any of the embodiments defined herein (for example the embodiment of claim 1) with the proviso that one or more specific Examples (for instance one, two or three specific Examples) selected from the group consisting of Examples 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37,

38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64,

65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 ,

92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 , 112, 113,

114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 125 is individually disclaimed.

The following embodiments of moieties X, R¹, R², R³ and R⁴ may be applied, alone or in combination, to the descriptions of the compounds of Formula (I) provided herein. The following embodiments of moieties R¹, R², R³ and R⁴ may be applied, alone or in combination, to the descriptions of the compounds of Formula (la) and (lb) provided herein.

In one embodiment, X is CH. In one embodiment, X is N.

When R¹ is H, n is 0 and R² is therefore absent.

In one embodiment, R¹ is H.

When R¹ is halo, n is 0, 1 or 2.

In one embodiment, R¹ is halo and n is 0.

In one embodiment, R¹ is halo, n is 1 and R² is -F or -Cl. In one embodiment, R¹ is halo, n is 1 and R² is -F. In one embodiment, R¹ is halo, n is 1 and R² is -Cl.

In one embodiment, R¹ is halo, n is 2 and each R² is independently selected from -F and -Cl. In one embodiment, R¹ is halo, n is 2 and both R² represent -F.

In one embodiment, R¹ is -F and n is 0.

In one embodiment, R¹ is -F, n is 1 and R² is -F or -Cl. In one embodiment, R¹ is -F, n is 1 and R² is -F. In one embodiment, R¹ is -F, n is 1 and R² is -Cl. In one embodiment, R¹ is -F, n is 2 and each R² is independently selected from -F and Cl. In one embodiment, R¹ is halo, n is 2 and both R² represent -F.

In one embodiment, R¹ is -Cl and n is 0.

In one embodiment, R¹ is -Cl, n is 1 and R² is -F or -Cl. In one embodiment, R¹ is -Cl, n is 1 and R² is -F. In one embodiment, R¹ is -Cl, n is 1 and R² is -Cl.

In one embodiment, R¹ is -Cl, n is 2 and each R² is independently selected from -F and -Cl.

In one embodiment, R¹ is -Br and n is 0.

In one embodiment, R¹ is -Br, n is 1 and R² is -F or -Cl. In one embodiment, R¹ is -Br, n is 1 and R² is -F. In one embodiment, R¹ is -Br, n is 1 and R² is -Cl.

In one embodiment, R¹ is -Br, n is 2 and each R² is independently selected from -F and -Cl.

In one embodiment, R³ is selected from H, -F, -Cl, -Br, -Me, -Et, -CHF2, -CH2F, -OMe, - OCHF2, -MeOH, -CN and cyclopropyl. In one embodiment, R³ is H or -Cl. In one embodiment, R³ is - Cl.

In one embodiment, R⁴ is Ci^alkyl optionally substituted with one or more -F. In one embodiment, R⁴ is selected from -Et, -n-Pr and -i-Pr and is optionally substituted with one or more -F. In one embodiment, R⁴ is selected from -CH2CHF2, -CH2CF3, -CH2CH2CHF2 and -C(CH3)CHF2. In one embodiment, R⁴ is -C(CH3)CHF2.

In one embodiment, R⁴ is selected from ring group Q^A, Q^B and Q^c.

In one embodiment, R⁴ is Q^A. In one embodiment, Q^A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[3.1 .0]hexyl and is optionally substituted with one or more substituents independently selected from -F, -CN, Ci salkyl and -O-Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F.

In one embodiment, Q^A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[3.1 .0]hexyl, and is optionally substituted with one or more substituents independently selected from -F, -CN, Ci salkyl and -O-Ci-2alkyl, wherein said alkyl is optionally substituted with one or more - F;

In one embodiment, Q^A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[3.1 ,0]hexan-6-yl, and is optionally substituted with one or more substituents independently selected from -F, -CN, -Me, -Et, -CH₂F, -CHF₂, -CF₃, and -OCHF2.

In one embodiment, R⁴ is Q^B. In one embodiment, Q^B is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1 .0]hexanyl, oxepanyl and 3- oxabicyclo[4.1 ,0]heptanyl, and is optionally substituted with one or more substituents independently selected from Ci^alkyl, wherein alkyl is optionally substituted with -OH, -CN or one or more -F.

In one embodiment, Q^B is selected from oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4- yl, 3-oxabicyclo[3.1 ,0]hexan-6-yl, oxepan-4-yl and 3-oxabicyclo[4.1 ,0]heptan-7-yl, and is optionally substituted with one or more substituents selected from Ci-3alkyl, wherein alkyl is optionally substituted with -OH, -CN or one or more -F.

In one embodiment, Q^B is selected from oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4- yl, 3-oxabicyclo[3.1 ,0]hexan-6-yl, oxepan-4-yl and 3-oxabicyclo[4.1 ,0]heptan-7-yl, and is optionally substituted with one or more substituents selected from -Me, -CH2F, -CHF2, -CH2CN, -CH2OH and -Et.

In one embodiment, R⁴ is Q^c. In one embodiment, Q^c is 6-membered nitrogen-containing monocyclic or fused bicyclic heterocyclyl group optionally substituted with one or more substituents independently selected from oxo, Ci sa Ikyl and -C(O)Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F.

In one embodiment, Q^c is selected from 6-oxopiperidinyl or 3-azabicyclo[3.1.0]hexanyl optionally substituted with one or more substituents selected from Cvsalkyl and -C(O)Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F.

In one embodiment, Q^c is selected from 6-oxopiperidin-3-yl or 3-azabicyclo[3.1 ,0]hexan-6-yl optionally substituted with -CH2CF3 or -C(O)Me.

In one embodiment, R⁴ is selected from -CH2CHF2, -CH2CF3, -CH2CH2CHF2, -C(CH3)CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1 ,0]hexan-6-yl, oxetan-3-yl, tetra hydrofuran- 3-yl, tetrahydropyran-4-yl, 3-oxabicyclo[3.1 ,0]hexan-6-yl, oxepan-4-yl, 3-oxabicyclo[4.1 ,0]heptan-7-yl, 6-oxopiperidin-3-yl and 3-azabicyclo[3.1 ,0]hexan-6-yl.

In one embodiment, R⁴ is selected from group consisting of

In one embodiment, the compounds of Formula (I) are compounds of Formula (la):

or a pharmaceutically acceptable salt thereof, wherein n, R¹, R², R³ and R⁴ are as defined for Formula (I).

In one embodiment, there is provided a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein: R¹ is H or halo; when R¹ is H, n is 0 and when R¹ is halo, n is 0, 1 or 2;

R² is a substituent on any available carbon atom and when present is independently selected from -F and -Cl;

R³ is selected from H; halo; -CN; Ci-3alkyl; and -O-Ci-3alkyl; wherein alkyl is optionally substituted by -OH or one or more -F; and

R⁴ is Ci-4alkyl optionally substituted with one or more -F.

In one embodiment, there is provided a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from H and halo; when R¹ is H, n is 0 and when R¹ is halo, n is 0, 1 or 2;

R³ is selected from H, -F, -Cl, -Br, -Me, -Et, -CHF₂, -CH₂F, -OMe, -OCHF₂, -MeOH, -CN and cyclopropyl; and

R⁴ is Ci-4alkyl optionally substituted with one or more -F.

In one embodiment, there is provided a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H and halo; when R¹ is H, n is 0 and when R¹ is halo, n is 0, 1 or 2;

R⁴ is selected from -Et, -n-Pr and -i-Pr and is optionally substituted with one or more -F.

R⁴ is selected from -CH₂CHF₂, -CH₂CF₃, -CH₂CH₂CHF₂ and -C(CH₃)CHF₂.

In one embodiment, the compounds of Formula (I) are compounds of Formula (lb):

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

2-benzyl-3-chloro-6-(oxetan-3-yl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one;

3-chloro-6-(2,2-difluoroethyl)-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-(oxetan-3-yl)pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-6-(3,3-difluoropropyl)-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-[(2,6-difluorophenyl)methyl]-6-(oxetan-3-yl)pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-6-(2,2-difluoroethyl)-2-[(2,6-difluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-cyclopropyl-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-6-(3,3-difluorocyclobutyl)-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(2R,4S)-2-methyltetrahydropyran-4-yl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(2S,4S)-2-methyltetrahydropyran-4-yl]pyrazolo[3,4- d]pyridazin-7-one; (1 r,3r)-3-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6- yl)cyclobutane-1 -carbonitrile;

(R)-3-chloro-6-(1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

(S)-3-chloro-6-(1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

2-(2-bromobenzyl)-3-chloro-6-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)- one;

3-chloro-2-[(2-chlorophenyl)methyl]-6-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyridazin-7-one;

6-((1 R,5S,6R)-3-oxa-bicyclo[3.1 .0]hexan-6-yl)-3-chloro-2-(2-fluorobenzyl)-2H-pyrazolo[3,4- d]pyridazin-7(6H)-one;

3-chloro-2-[(2,6-difluorophenyl)methyl]-6-[(1 R,5S)-3-oxabicyclo[3.1 ,0]hexan-6-yl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 R,5S)-3-oxabicyclo[3.1 ,0]hexan-6-yl]-2-[(2,3,6- trifluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-[(2-chloro-6-fluoro-phenyl)methyl]-6-[(1 R,5S)-3-oxabicyclo[3.1 ,0]hexan-6- yl]pyrazolo[3,4-d]pyridazin-7-one;

2-benzyl-3-chloro-6-[(1 R,5S)-3-oxabicyclo[3.1 ,0]hexan-6-yl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-6-[(1 R,5S)-3,3-difluoro-6-bicyclo[3.1 ,0]hexanyl]-2-[(2- fluorophenyl)methyl]pyrazolo[3,4-d]yridazin-7-one;

3-chloro-2-(2-fluorobenzyl)-6-((1 S,2S)-2-fluorocyclopropyl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)- one; rac-3-chloro-6-[(1 R,2R)-2-fluorocyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; rac-3-chloro-6-[(1 R)-2,2-difluorocyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 R)-2,2-difluorocyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7- one; 3-chloro-2-[(2,6-difluorophenyl)methyl]-6-[(1 S,2S)-2-fluorocyclopropyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-2-[(2,6-difluorophenyl)methyl]-6-[(1 R,2R)-2-fluorocyclopropyl]pyrazolo[3,4- d]pyridazin-7-one; rac-3-chloro-6-[(1 R,2S)-2-(difluoromethyl)cyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 R,2S)-2-(difluoromethyl)cyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 S,2R)-2-(difluoromethyl)cyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; rac-3-chloro-2-[(2-fluorophenyl)methyl]-6-[(1 R,2R)-2-methylcyclopropyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(1S,2R)-2-methylcyclopropyl]pyrazolo[3,4-d]pyridazin- 7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(1 R,2S,5S,6R)-2-methyl-3-oxabicyclo[3.1 ,0]hexan-6- yl]pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(1 R,2R,5S,6R)-2-methyl-3-oxabicyclo[3.1 ,0]hexan-6- yl]pyrazolo[3,4-d]pyridazin-7-one;

2-[(2,6-difluorophenyl)methyl]-6-[(1 R,2S)-2-fluorocyclopropyl]pyrazolo[3,4-d]pyridazin-7-one; rac-3-chloro-2-[(2-fluorophenyl)methyl]-6-[(1 R,2S)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(1 R,2S)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 S,2R)-2-ethylcyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7- one;

3-chloro-6-[(1 R,2S)-2-fluorocyclobutyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7- one;

3-chloro-6-[(1 R,2S)-2-(difluoromethyl)cyclopropyl]-2-[(2,6-difluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; 3-chloro-6-[(1 S,2R)-2-(difluoromethyl)cyclopropyl]-2-[(2,6-difluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; rac-3-chloro-6-[(1 R)-2,2-dimethylcyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one;

3-fluoro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

3-fluoro-2-[(2-fluorophenyl)methyl]-6-[(2S,4S)-2-methyltetrahydropyran-4-yl]pyrazolo[3,4- d]pyridazin-7-one;

6-((1 R,5S,6r)-3-oxa-bicyclo[3.1 ,0]hexan-6-yl)-3-(difluoromethoxy)-2-(2-fluorobenzyl)-2H- pyrazolo[3,4-d]pyridazin-7(6H)-one;

(1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6- yl)cyclopropane-1 -carbonitrile;

3-chloro-2-(2-fluorobenzyl)-6-((2R,3S)-2-methyloxetan-3-yl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

2-(2-fluorobenzyl)-6-((1 R,2R)-2-fluorocyclopropyl)-3-methyl-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-2-(2-fluorobenzyl)-6-((1 R,2R)-2-(fluoromethyl)cyclopropyl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one; rac-3-chloro-6-((1 R,2R)-2-(difluoromethoxy)cyclopropyl)-2-(2-fluorobenzyl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-2-(2-fluorobenzyl)-6-((1 R,2S,5S,6R)-2-(fluoromethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)- 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one;

3-chloro-6-((1 R,2S,5S,6R)-2-(difluoromethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2-(2- fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one;

6-((1S,5R,6r)-3-oxa-bicyclo[3.1 .0]hexan-6-yl)-3-(difluoromethyl)-2-(2-fluorobenzyl)-2H- pyrazolo[3,4-d]pyridazin-7(6H)-one;

6-((1S,5R,6r)-3-oxa-bicyclo[3.1 .0]hexan-6-yl)-2-(2-fluorobenzyl)-3-(fluoromethyl)-2H- pyrazolo[3,4-d]pyridazin-7(6H)-one; 3-chloro-2-(2-fluorobenzyl)-6-((1 R,2S)-2-methoxycyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-2-(2-fluorobenzyl)-6-((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2,6- dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one;

6-(2,6-difluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3H-pyrazolo[4,3-d][1 ,2,3]triazin-4(6H)-one;

6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4- one;

7-chloro-6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2,6-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((1 R,2S,5S,6R)-2-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((1 S,2R,5R,6S)-2-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((1 R,2R)-2-fluorocyclopropyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((1 S,2S)-2-fluorocyclopropyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2,3-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2-bromo-6-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2,3,6-trifluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2-fluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one; 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2,6-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2,3-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2,5-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(3-chloro-2-fluorobenzyl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((1 S,2S,5R,6S)-2-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((1 S,2R,5R,6S)-2-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-3-((2R,4S)-2-ethyltetrahydro-2H-pyran-4-yl)-6-(2-fluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((1 R,2R)-2-(difluoromethyl)cyclopropyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((1 S,2S)-2-(difluoromethyl)cyclopropyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

7-bromo-3-cyclohexyl-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2,6-difluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

7-chloro-3-(3,3-difluorocyclobutyl)-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-cyclopentyl-6-(2-fluorobenzyl)-7-methyl-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-cyclohexyl-6-(2,6-difluorobenzyl)-7-methyl-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4- one;

6-(2-fluorobenzyl)-7-methyl-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one; 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-methyl-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

(R)-7-chloro-6-(2,6-difluorobenzyl)-3-(6-oxopiperidin-3-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

(R)-7-chloro-6-(2-fluorobenzyl)-3-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

(R)-7-chloro-6-(2-fluorobenzyl)-3-(oxepan-4-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4- one;

7-chloro-3-cyclohexyl-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one; rac-(R)-7-chloro-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-(2-fluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,6S,7S)-3-oxabicyclo[4.1 ,0]heptan-7-yl)-7-chloro-6-(2-fluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-3-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-6-(2-fluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

2-((2R,4S)-4-(7-chloro-6-(2-fluorobenzyl)-4-oxo-4,6-dihydro-3H-pyrazolo[4,3-d][1 ,2,3]triazin-3- yl)tetrahydro-2H-pyran-2-yl)acetonitrile; rac-6-(2,6-difluorobenzyl)-3-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2,6-difluorobenzyl)-3-((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((3R)-3-methyltetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-(oxetan-3-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2,6-difluorobenzyl)-3-(oxetan-3-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4- one; rac-(R)-7-chloro-3-(2,2-dimethyloxetan-3-yl)-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((2R,4S)-2-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((2S,3R)-2-methyloxetan-3-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-[(1S)-2,2-difluoro-1-methyl-ethyl]-6-[(2,6-difluorophenyl)methyl]pyrazolo[4,3-d]triazin-4-one;

3-[(1 R)-2,2-difluoro-1-methyl-ethyl]-6-[(2,6-difluorophenyl)methyl]pyrazolo[4,3-d]triazin-4-one;

7-chloro-3-[(1 S)-2,2-difluoro-1-methyl-ethyl]-6-[(2-fluorophenyl)methyl]pyrazolo[4,3-d]triazin-4- one;

7-chloro-3-[(1 R)-2,2-difluoro-1-methyl-ethyl]-6-[(2-fluorophenyl)methyl]pyrazolo[4,3-d]triazin-4- one;

3-[(1 R)-2,2-difluoro-1-methyl-ethyl]-6-[(2-fluorophenyl)methyl]pyrazolo[4,3-d]triazin-4-one;

3-[(1S)-2,2-difluoro-1-methyl-ethyl]-6-[(2-fluorophenyl)methyl]pyrazolo[4,3-d]triazin-4-one;

3-((1S,5R,6r)-3-oxa-bicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-(fluoromethyl)-3H- pyrazolo[4,3-d][1 ,2,3]triazin-4(6H)-one;

6-(2-fluorobenzyl)-7-(fluoromethyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2,6-difluorobenzyl)-7-(fluoromethyl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2-fluorobenzyl)-7-(hydroxymethyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2,6-difluorobenzyl)-7-(difluoromethyl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-(difluoromethyl)-6-(2-fluorobenzyl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-(difluoromethyl)-6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one; 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-methoxy-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-Cyclopropyl-6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

6-(2-fluorobenzyl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-4,6-dihydro-3H-pyrazolo[4,3- d][1 ,2,3]triazine-7-carbonitrile; rac-6-(2,6-difluorobenzyl)-3-((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2,6-Difluorobenzyl)-3-((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6s)-3-acetyl-3-azabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2-fluorobenzyl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((1 R,5S,6s)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1 ,0]hexan-6- yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one; and

3-cyclohexyl-7-ethyl-6-(2-fluorobenzyl)-3H-pyrazolo[4,3-d][1 ,2,3]triazin-4(6H)-one.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-3-chloro-6-(1 ,1-difluoropropan-2-yl)-2-(2- fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one.

The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form, diluent or carrier) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a compound of Formula (I).

In one embodiment there is provided a pharmaceutically acceptable salt of a compound of Formula (I).

Compounds and salts described in this specification may exist in solvated forms and unsolvated forms. For example, a solvated form may be a hydrated form, such as a hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or an alternative quantity thereof. The specification encompasses all such solvated and unsolvated forms of compounds of Formula (I), particularly to the extent that such forms possess RIPK1 inhibitory activity, as for example measured using the tests described herein.

Atoms of the compounds and salts described in this specification may exist as their isotopes. All compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an ¹¹C or ¹³C carbon isotope, or where one or more hydrogen atoms is a ²H or ³H isotope, or where one or more nitrogen atoms is a ¹⁵N isotope or where one of more oxygen atoms is an ¹⁷O or ¹⁸O isotope) are encompassed herein.

Compounds of the application may exist in one or more geometrical, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis- and trans- forms, E- and Z-forms, and R-, S- and meso-forms. Unless otherwise stated, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaption of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaption of known methods. In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is a single optical isomer being in an enantiomeric excess (%ee) of > 95%, > 98% or > 99%. In one embodiment, the single optical isomer is present in an enantiomeric excess (%ee) of > 99%.

Certain RIPK1 inhibitors of Formula (I) may show good solubility and/or good metabolic stability.

As a result of their RIPK1 inhibitory activity, the compounds of Formula (I), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by RIPK1 , including nervous system diseases or conditions.

The term “therapy” is intended to have its normal meaning of dealing with a disease or condition in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease or condition and secondary prophylaxis whereby the disease or condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or condition, or the development of new symptoms associated with the disease or condition.

The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by RIPK1 . In one embodiment, said disease or condition mediated by RIPK1 is a nervous system disease or condition. In one embodiment, the nervous system disease or condition is a neurodegenerative disease, brain and spinal injury, Duchenne muscular dystrophy, or multiple sclerosis.

Examples of neurodegenerative disease include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Huntington’s disease and Prion diseases.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a nervous system disease or condition. In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Huntington’s disease, Prion diseases, brain and spinal injury, Duchenne muscular dystrophy and multiple sclerosis. In one embodiment, the nervous system disease or condition is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis. In one embodiment, the nervous system disease or condition is multiple sclerosis.

In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition mediated by RIPK1 . In one embodiment, the disease or condition mediated by RIPK1 is a nervous system disease or condition. In one embodiment, the nervous system disease or condition is selected from a neurodegenerative disease, brain and spinal injury, Duchenne muscular dystrophy, or multiple sclerosis.

In one embodiment there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a nervous system disease or condition. In one embodiment, the nervous system disease or condition is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis. In one embodiment, the nervous system disease or condition is multiple sclerosis. In one embodiment there is provided a method for treating a disease or condition in which inhibition of RIPK1 is beneficial in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or condition mediated by RIPK1 is a nervous system disease or condition. In one embodiment, the nervous system disease or condition is selected from the group consisting of a neurodegenerative disease, brain and spinal injury, Duchenne muscular dystrophy, or multiple sclerosis.

In one embodiment there is provided a method for treating a nervous system disease or condition in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the nervous system disease or condition is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis or multiple sclerosis. In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis. In one embodiment, the nervous system disease or condition is multiple sclerosis.

The term "therapeutically effective amount" refers to an amount of a compound of Formula (I) as described in any of the embodiments herein which is effective to provide “therapy” in a subject, or to “treat” a disease or condition in a subject. In the case of amyotrophic lateral sclerosis, the therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of “therapy” and “treatment” above. For example, the effective amount may relieve to some extent one or more of the symptoms associated with amyotrophic lateral sclerosis; reduce morbidity and mortality; improve quality of life; or a combination of such effects. As recognised by those skilled in the art, effective amounts may vary depending on route of administration, excipient usage, and co-usage with other agents. For example, where a combination therapy is used, the amount of the compound of Formula (I) or pharmaceutically acceptable salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disorder or condition in the subject. In this context, the combined amounts are in “therapeutically effective amount” if they are, when combined, sufficient to decrease the symptoms of a disease or condition response to inhibition of RIPK1 as described above.

“Subjects” include, for example, humans.

The treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds described herein, at least one other therapeutically active agent. In the treatment of ALS, a compound of Formula (I) as described in any of the embodiments herein may be administered in combination with riluzole or edavarone.

According to a further embodiment there is provided a kit comprising: a) A compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a unit dosage form; b) Container means for containing said unit dosage forms; and optionally c) Instructions for use.

The compounds of Formula (I), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.

Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

The pharmaceutical compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

The compound of Formula (I) will normally be administered to a subject at a unit dose within the range 2.5 - 5000 mg/m² body area of the subject, or approximately 0.05 -100 mg/kg, and this normally provides a therapeutically effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 0.1-250 mg of active ingredient. The daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being coadministered, and the severity of the disease or condition being treated. The pharmaceutical compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.

As such, in one embodiment there is provided a pharmaceutical composition for use in therapy, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment, there is provided a pharmaceutical composition for use in the treatment of a disease or condition in which inhibition of RIPK1 is beneficial, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment, there is provided a pharmaceutical composition for use in the treatment of a nervous system disease or condition in which inhibition of RIPK1 is beneficial, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in the treatment of a nervous system disease or condition selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Huntington’s disease, Prion diseases, brain and spinal injury, Duchenne muscular dystrophy and multiple sclerosis.

EXAMPLES

The various embodiments are illustrated by the following Examples. The specification is not to be interpreted as being limited to the Examples.

Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

In general Examples and Intermediate compounds were named using ACD Name, “Structure to Name” part of ChemDraw Ultra (CambridgeSoft).

Abbreviations

AcOH: acetic acid; DBU: 1 ,8-Diazabicyclo(5.4.0)undec-7-ene; BAST: N,N- bis(2- methoxyethyl)aminosulfur trifluoride; DMF: dimethylformamide; DMSO: dimethylsulfoxide; DCM: dichloromethane; DEA: diethylamine; KHMDS: Potassium bis(trimethylsilyl)amide; HATU:(1- [Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphat; EtOAc: ethyl acetate; DIEA: diisopropylamine; SFC: Supercritical fluid chromatography MTBE: Methyl tert-butyl ether; Pd(DTBPF): [1 ,1-Bis(di-tert-butylphosphino) ferrocene]dichloropalladium(ll); IPA isopropylalcohol; TLC: thin layer chromathography; TFA; trifluoroacetic acid; FA: formic acid; HPLC: high performance liquid chromathography; TMEDA: Tetramethylethylenediamine; RT: retention time; ES+: electrospray positive ionization; LCMS: liquid chromatography-mass spectrometry; NMR: nuclear magnetic resonance; rt room temperature.

Analytical and Purification Methods

LCMS experiments were performed using a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. LCMS was run in one of three set ups: method 1 [Halo C18 column (2.0 pm 3.0x30 mm) in combination with a gradient (5-100% B in 1.2 min.) of water and FA (0.1 %) (A) and CH3CN and FA (0.1 %) (B) at a flow rate of 1.5 mL/min]; method 2 [Halo C18 column (2.0 pm 3.0x30 mm) in combination with a gradient (5-100% B in 1.2 min.) of water and TFA (0.05%) (A) and CH3CN and TFA (0.05%)(B) at a flow rate of 1 .5 mL/min]; method 3 [Poroshell HPH C18 column (2.7 pm 3.0x50 mm) in combination with a gradient (10-95% B in 2 min.) of aqueous 46 mM ammonium carbonate/ammonia buffer at pH 10 (A) and CH3CN (B) at a flow rate of 1 .2 mL/min], The Column Oven (CTO-20AC) temperature was 40 °C. The injection volume was 1 pl. PDA (SPD-M20A) detection was in the range A (190-400) nm. The MS detector was configured with electrospray ionization as ionizable source; acquisition mode: Scan; nebulizing gas flow:1.5 L/min; drying gas flow:15 L/min; detector voltage: 0.95-1.25 kv; DL T: 250 °C; heat block T: 250 °C; scan range: 90.00 - 900.00 m/z.

NMR Spectra were recorded on a Bruker AVANCE III HD 400 (400 MHz) or Bruker AVANCE NEO 400 (400 MHz) or Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE II 300 (300 MHz) or Bruker AVANCE III 300 (300 MHz) or Bruker AVANCE III HD 300(300 MHz).

Prep HPLC preparative reverse phase HPLC was performed on a Waters instrument (2545 or 2767 or 2489) fitted with a QDa or SQ Detector 2 ESCi mass spectrometers and a Waters X-Bridge or Waters Xselect or Waters SunFire reverse-phase column (C-18, 5um, 30 mm diameter and 150 mm length with a flow rate of 60 ml/min or C-18, 5um, 19 mm diameter and 250 mm length with a flow rate of 25 ml/min).

SFC Preparative Chiral SFC was performed on a Waters instrument SFC (80 or 100 or 150 or 350) fitted with UV2489 (or mass spectrometer) and a Daicel or YMC or Phenomenex chiral column (CHIRALPAK IC I CHIRALPAK IG/ Phenomenex Lux Cellulose-3/ Phenomenex Lux Cellulose-4, 5 microns silica, 20 mm or 50 mm diameter, 250 mm length, flow rate of 40 -250 ml/min).

Chemical Drawings and Compounds Chirality Single enantiomers of chiral compounds where the absolute configuration is unknown and has been arbitrarily assigned are represented by chemical drawings showing “or” at the stereocentres and this is also highlighted in the text.

Racemic mixtures with known relative configuration are drawn with dashed bonds at the stereocentres.

Intermediates Preparation

Intermediate 1 : 5-Chloro-1 -(2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate

AcOH (18.38 ml, 321 .06 mmol) was added to a solution of sodium 1 ,4-diethoxy-1 ,3,4- trioxobutan-2-ide (45.0 g, 214.04 mmol) and (2-fluorobenzyl)hydrazine (30 g, 214.04 mmol) in 1 ,4- dioxane (300 mL). The resulting mixture was stirred at 90 °C for 2 h. After cooling to room temperature a solid (36.5 g) was collected by filtration and POCh (77 ml, 828.74 mmol) added to a mixture of the above solid and DMF (21.39 ml, 276.25 mmol) in 1 ,2-dichloroethane (360 mL). The resulting mixture was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure, the residue poured into ice water and the mixture was basified with saturated NaHCOs to pH 7-8 and extracted with DCM (3 x 150 mL). The combined organic layers were dried over Na2SC and concentrated after filtration. The obtained crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (21.1 g) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d₆) 6 1.29 (t, J = 7.1 Hz, 3H), 4.33 (q, J = 7.1 Hz, 2H), 5.56 (s, 2H), 7.14 - 7.30 (m, 3H), 7.34 - 7.48 (m, 1 H), 10.22 (s, 1 H). LCMS (method 1) m/z (ES⁺), [M+H]⁺ = 311 ; RT= 0.78 min.

The following intermediates were made through the method described above.

Intermediate 6: 3-Chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7- one

To a solution of ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (5.9 g, 18.99 mmol) in EtOH (100 mL) was added hydrazine dihydrochloride (1.99 g, 18.99 mmol). The resulting mixture was stirred at 80 °C for 3 h, concentrated and purified by flash silica chromatography (elution gradient 0 to 10% MeOH in DCM). Pure fractions were evaporated to dryness to afford 3-chloro- 2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (5.30 g, 100 %) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) 6 5.72 (s, 2H), 7.18 - 7.35 (m, 3H), 7.38 - 7.49 (m, 1 H), 8.26 (s, 1 H), 12.49 (s, 1 H). LCMS (method 1) m/z (ES⁺), [M+H]⁺ = 279; RT = 0.77 min.

The following intermediates were made through the method described above.

Intermediate 11 : (1S,5R,6s)-3-oxa-bicyclo[3.1.0]hexan-6-ylboronic acid

Step 1 : Butyllithium (250 mL, 2.5mol/L) was added slowly to DCM (42.5 mL) in THF (1 .2 L) at -100°C over a period of 30 min under N2. Trimethyl borate (76.25 mL) was added to above mixture at -100°C and stirred at -100°C for 30 min. 5N HCI (125 mL) and water (375 mL) was added above mixture at -100°C under N2 and warmed to rt. The reaction mixture was extracted with ether (3 x 500 mL), the combined organic layers were dried over Na2SC , filtered and evaporated to afford yellow oil. 2,3-dimethylbutane-2,3-diol (79.25 g, 670.61 mmol) and MgSC>4 (125 g) were added to above yellow oil in toluene (1 .3 L). The resulting mixture was stirred at 100 °C for 16 h. The solid was filtered out. The filtrate was concentrated under vacuum to afford 2-(dichloromethyl)- 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (114 g) as a yellow oil. ¹H-NMR (400 MHz, CDCh) 6 1.33 (s, 12H), 5.35 (s, 1 H).

Step 2: Sodium iodide (186 g, 1243.31 mmol) was added to 2-(dichloromethyl)-4, 4,5,5- tetramethyl-1 ,3,2- dioxaborolane (114 g, 540.57 mmol) in acetone (1200 mL) at rt under N2. The resulting mixture was stirred at 25 °C for 16 h. The solvent was removed by distillation under vacuum and the residue was poured into water (200 mL) and extracted with Et2O (3 x 200 mL). The combined organic layers were dried over Na2SC , filtered and evaporated. Hexane (100 mL) was added to the above residue and stirred for 1 h. The precipitate formed was collected by filtration to afford 2- (diiodomethyl)-4,4,5,5-tetramethyl -1 ,3,2-dioxaborolane (102 g, 47.9 %) as a light yellow solid. ¹H-NMR (300 MHz, CDCh) 6 1.30 (s, 12H), 4.29 (s, 1 H).

Step 3:TMEDA (30.7 ml, 203.15 mmol) was added slowly to Chromium(ll) chloride (25 g, 203.42 mmol) in THF (500 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 20 min to give a thick blue suspension. 2-(Diiodomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (25 g, 63.48 mmol) was added and the resulting mixture was stirred at 25 °C for 30 min. 2,5-Dihydrofuran (4.89 g, 69.83 mmol) was added and the resulting mixture was stirred at 50°C for 20 h. The mixture was filtered through a Celite pad and the filtrate was diluted with water (500 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-((1 R,5S,6s)-3-oxabicyclo [3.1 ,0]hexan-6- yl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (8.75 g, 65.5 %) as a white solid. ¹H-NMR (400 MHz, CDCh) 6 0.03-0.11 (m, 1 H), 1.23 (d, J = 7.2 Hz, 12H), 1.64 - 1.74 (m, 2H), 3.49 - 3.92 (m, 4H).

Step 4: 2-((1 R,5S,6s)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (17.5 g, 83.3 mmol) was added to sodium periodate (53.5 g, 249.9 mmol) in water (50 mL) and THF (200 mL) at 25°C. The resulting mixture was stirred at rt for 5 min. 2N HCI (29.2 ml, 58.31 mmol) was added to above mixture at 25°C. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (1 L), extracted with EtOAc (5 x 300 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated to afford ((1 R,5S,6s)-3-oxabicyclo[3.1 .0] hexan-6- yl)boronic acid (8.7 g, 82%) as a light yellow solid.

Intermediate 12: 6-((1 R,5S,6s)-3-aza-bicyclo[3.1 .0]hexan-6-yl)-3-chloro-2-(2- fluorobenzyl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one

Step 1 : CU(OAC)2 (1.214 g, 6.10 mmol) was added to 3-chloro-2-(2-fluorobenzyl)-2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one (1.7 g, 6.10 mmol), (3-(te/Y-butoxycarbonyl)-3- azabicyclo[3.1 ,0]hexan-6-yl)boronic acid (2.77 g, 12.20 mmol) and CS2CO3 (0.994 g, 3.05 mmol) in toluene (40 mL). The resulting mixture was stirred at 110 °C for 24 h under air. The solvent was removed under reduced pressure. The reaction mixture was quenched with water (200 mL), extracted with EtOAc (3 x 100 mL), the combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 5 to 100% CH3CN in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford tert- butyl-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl) -3- azabicyclo[3.1 ,0]hexane-3-carboxylate (0.570 g, 20.32 %) as a pale yellow solid. ¹H-NMR (300 MHz, DMSO-dg) 6 1.41 (s, 9H), 2.15 (q, 2H), 3.18 (d, 1 H), 3.43 (t, 1 H), 3.61 (d, 2H), 4.10 (q, 1 H), 5.73 (s, 2H), 7.17 - 7.35 (m, 3H), 7.40-7.50 (m, 1 H), 8.30 (s, 1 H). LCMS (method 2) m/z (ES⁺), [M-tBu]⁺ = 460; RT = 0.95 min.

Step 2: 7e/Y-butyl-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin- 6-yl)-3-azabicyclo[3.1 ,0]hexane-3-carboxylate (570 mg, 1.24 mmol) was added to 10 mL of 4 M HCI of dioxane solution. The resulting solution was stirred at rt for 1 h. The solvent was removed under reduced pressure to afford 6-(3-azabicyclo[3.1 ,0]hexan-6-yl)-3-chloro-2-(2-fluorobenzyl)-2,6-dihydro- 7H-pyrazolo [3,4-d]pyridazin-7-one (0.530 g) (HCI salt) as yellow solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 1.74 (s, 1 H), 1.98 (s, 1 H), 2.33 (s, 2H), 3.21 (s, 1 H), 3.57 (s, 1 H), 3.67 (s, 1 H), 3.92 (s, 1 H), 5.71 (s, 2H), 7.14 - 7.42 (m, 2H), 8.31 (s, 1 H), 9.01 (s, 1 H), 9.58 (s, 1 H). LCMS (method 2) m/z (ES⁺), [M+H]⁺ = 360; RT = 0.69 min.

Intermediate 13: rac-(1 R,5S,6R)-2-methyl-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

Step 1 : Pyridine (7.77 ml, 96.03 mmol) was added to 2-bromoethan-1-ol (10 g, 80.0 mmol) in DCM (100 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 5 min trifluoromethanesulfonic anhydride (24.83 g, 88.02 mmol) was added and stirred at 0°C for 30 min. The reaction mixture was washed sequentially with water (30 mL x 3) and brine (300 mL). The organic layer was dried over Na2SC , filtered and evaporated to afford 2-bromoethyl trifluoromethanesulfonate (14.9 g, 72.4%) as a yellow oil. ¹H NMR (300 MHz, CDCI3) 6 3.58 - 3.68 (m, 2H), 4.71 - 4.82 (m, 2H).

Step 2: Diphenylsulfane (12.87 g, 69.10 mmol) was added to 2-bromoethyl trifluoromethanesulfonate (14.8 g, 57.58 mmol) in toluene (150 mL) at 25°C under N2. The resulting mixture was stirred at 110 °C for 16 h. The reaction mixture was precipitated by the addition of ethylether. The mixture was filtered to afford (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (6.60 g, 25.9 %) as a gray solid. ¹H NMR (300 MHz, CDCI3) 6 3.65 - 3.75 (m, 2H), 4.84 - 4.94 (m, 2H), 7.67 - 7.85 (m, 6H), 8.07 - 8.18 (m, 4H); LCMS (method 1) m/z (ES⁺) [M+H]⁺ = 293; RT = 0.66 min. Step 3: K2CO3 (11.51 g, 83.26 mmol) was added to (E)-4-oxopent-2-enoic acid (9.5 g, 83.26 mmol) and (bromomethyl)benzene (28.5 g, 166.52 mmol) in DMF (100 mL) at 20°C under N2. The resulting mixture was stirred at rt for 2 h. The reaction mixture was poured into water (300 mL), extracted with EtOAc (3 x 150 mL), and washed sequentially with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SC , filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford benzyl (E)-4-oxopent-2-enoate (13.4 g, 79 %) as a yellow oil. 1 H-NMR (300 MHz, CDCh) 6 2.35 (d, J = 2.6 Hz, 3H), 5.25 (d, J = 2.5 Hz, 2H), 6.69 (dd, J = 16.1 , 2.5 Hz, 1 H), 7.06 (dd, J = 16.1 , 2.4 Hz, 1 H), 7.30 - 7.44 (m, 5H); LCMS (method 2) m/z (ES⁺), [M+H]⁺ = 205; RT = 0.85 min.

Step 4: Sodium borohydride (0.65 g, 17.15 mmol) was added to benzyl (E)-4-oxopent-2- enoate (14 g, 68.6 mmol) in DCM (140 mL) and MeOH (14 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated NH4CI (200 mL), extracted with DCM (3 x 100 mL), and washed sequentially with water (150 mL), and brine (150 mL). The organic layer was dried over Na2SC , filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford benzyl (E)-4-hydroxypent-2-enoate (11 .60 g, 83 %) as a yellow oil. 1 H-NMR (300 MHz, CDCh) 6 1 .31 (dd, J = 6.7, 0.7 Hz, 3H), 2.83 (s, 1 H), 3.72 (s, 1 H), 4.45 (qdd, J = 6.5, 4.6, 1.7 Hz, 1 H), 5.18 (s, 2H), 6.03 - 6.11 (m, 1 H), 7.00 (dd, J = 15.7, 4.6 Hz, 1 H), 7.29 - 7.43 (m, 5H); LCMS (method 2) m/z (ES⁺), [M+H]⁺ = 207; RT = 0.80 min.

Step 5: Sodium hydride (7.74 g, 194 mmol) was added to (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (30.64 g, 69.2 mmol) and benzyl (E)-4-hydroxypent-2-enoate (11.4 g, 55.3 mmol) in DCM (120 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 16 h. The reaction mixture was quenched with saturated NH4CI (200 mL), extracted with DCM (3 x 200 mL), washed sequentially with water (200 mL), and brine (150 mL). The organic layer was dried over Na2SCU, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford a yellow oil. The obtained oil was purified by flash C18-flash chromatography, elution gradient 5 to 60% CH3CN in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford benzyl 2-methyl-3-oxabicyclo[3.1 ,0]hexane-6-carboxylate (5.2 g, 50 %) as a colourless oil. ¹H NMR (300 MHz, CDCI3) 6 7.43 - 7.24 (m, 5H), 5.20 - 5.08 (m, 2H), 4.17 (q, J = 6.3 Hz, 1 H), 3.95 - 3.72 (m, 2H), 2.22 - 2.12 (m, 1 H), 2.03 (ddd, J = 7.1 , 3.2, 0.8 Hz, 1 H), 1.96 (d, J = 0.8 Hz, 1 H), 1.66 (t, J = 3.3 Hz, 1 H), 1.16 (dd, J = 6.3, 0.8 Hz, 3H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 233; RT = 0.89 min.

Step 6: Pd-C (1 .83 g, 1 .72 mmol) was added to benzyl 2-methyl-3-oxabicyclo[3.1 ,0]hexane-6- carboxylate (4 g, 17.22 mmol) in MeOH (40 mL) at 20°C under hydrogen. The resulting mixture was stirred at rt for 3 h filtered through celite and the filtrate evaporated to dryness to afford 2-methyl-3- oxabicyclo[3.1 ,0]hexane-6-carboxylic acid (2.4 g, 98 %) as a light yellow oil. ¹H NMR (300 MHz, DMSO-dg) 6 1 .06 (d, J = 6.3 Hz, 3H), 1 .29 (t, J = 3.2 Hz, 1 H), 1 .87 (dd, J = 7.1 , 3.2 Hz, 1 H), 2.03 (dt, J = 7.1 , 2.9 Hz, 1 H), 3.58 - 3.81 (m, 2H), 4.05 (q, J = 6.4 Hz, 1 H), 8.16 (s, 1 H).

Intermediate 14: 4-amino-1-(2,6-difluorobenzyl)-1 H-pyrazole-3-carboxylic acid

Step 1 : 2-(Bromomethyl)-1 ,3-difluorobenzene (13.31 g, 64.29 mmol) was added to methyl 4- nitro-1 H-pyrazole-3-carboxylate (10 g, 58.44 mmol), K2CO3 (20.19 g, 146.10 mmol) in DMF (100 mL) at rt under N2. The resulting mixture was stirred at rt for 16 h. The reaction mixture was poured into water (300 mL), extracted with EtOAc (3 x 200 mL) and washed sequentially with water (2 x 100 mL) and brine (2 x 100 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography (elution gradient 0 to 40% petroleum ether in EtOAc). Pure fractions were evaporated to dryness to afford methyl 1-(2,6- difluorobenzyl)-4-nitro-1 H-pyrazole-3-carboxylate (11.80 g, 67.9 %) as a white solid. ¹H-NMR (300 MHz, DMSO-dg) 6 3.83 (s, 3H), 5.52 (s, 2H), 7.10 - 7.25 (m, 2H), 7.51 (tt, J = 6.7, 8.3 Hz, 1 H), 9.15 (s, 1 H). LCMS (method 1) m/z (ES⁺), [M+H]⁺ = 298; RT = 0.85 min.

Step 2: Pd/C (4.3 g, 4.04 mmol) was added to methyl 1-(2,6-difluorobenzyl)-4-nitro-1 H- pyrazole-3-carboxylate (5 g, 16.82 mmol) in MeOH (100 mL) at rt under hydrogen. The flask was evacuated and flushed three times with N2, followed by flushing with hydrogen. The mixture was stirred 2h at room temperature under hydrogen and then filtered through celite. The filtrate was concentrated by distillation under vacuum to afford methyl 4-amino-1 -(2,6-difluorobenzyl)-1 H- pyrazole-3-carboxylate (4.20 g, 93 %) as a dark solid. 1 H NMR (300 MHz, DMSO-d₆) 6 3.70 (s, 3H), 4.68 (s, 2H), 5.28 (d, J = 1 .2 Hz, 2H), 7.07 - 7.25 (m, 3H), 7.47 (tt, J = 6.7, 8.2 Hz, 1 H). LCMS (method 1) m/z (ES⁺), [M+H]⁺ = 268; RT = 0.68 min.

Step 3: Lithium hydroxide (0.538 g, 22.45 mmol) was added to methyl-4-amino-1-(2,6 - difluorobenzyl)-1 H-pyrazole-3-carboxylate (2 g, 7.48 mmol) in MeOH (20 mL) and water (10 mL) at rt under N2. The resulting mixture was stirred at rt for 16 h and concentrated by distillation under vacuum. The residual mixture was adjusted to pH 5-6 with 2M HCI and the precipitate formed was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 4-amino-1- (2,6- difluorobenzyl)-1 H-pyrazole-3-carboxylic acid (1.77 g, 93 %) as a grey solid, which was used without further purification. ¹H-NMR (300 MHz, DMSO) 6 5.27 (s, 2H), 7.07 - 7.22 (m, 3H), 7.39 - 7.55 (m, 1 H). LCMS (method 1) m/z (ES⁺), [M+H]⁺ = 254; RT = 0.86 min.

The following intermediates were made through the method described above.

Intermediate 20: 4-Amino-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxylic acid

Step 1 : N-chlorosuccinimide (2.68 g, 20.06 mmol) was added to methyl 4-amino-1 -(2- fluorobenzyl)-1 H-pyrazole-3-carboxylate (5 g, 20.06 mmol) in MeCN (50 mL) at rt under N2. The resulting mixture was stirred at 60 °C for 2 h and then poured into water (200 mL), extracted with EtOAc (3 x 100 mL) and washed sequentially with water (2 x 100 mL) and brine (100 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated to afford a crude product that was purified by flash silica chromatography (elution gradient 10 to 20% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford methyl-4-amino-5-chloro-1- (2- fluorobenzyl)-1 H-pyrazole-3-carboxylate (3.80 g, 66.8 %) as a white solid. ¹H-NMR (400 MHz, DMSO) 6 3.78 (s, 3H), 5.38 (s, 2H), 7.03 - 7.12 (m, 1 H), 7.14 - 7.28 (m, 2H), 7.34 - 7.44 (m, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 284; RT = 1 .314 min.

Step 2: LiOH (1.562 g, 65.21 mmol) was added to methyl-4-amino-5-chloro-1-(2- fluorobenzyl)-1 H-pyrazole- 3-carboxylate (3.7 g, 13.04 mmol) in THF (37 mL), water (18.50 mL) at rt. The resulting mixture was stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was poured into water (30 mL) and adjusted to pH 5-6 with 2M HCI. A precipitate was collected by filtration and dried to afford 3.5 g 4-amino-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3- carboxylic acid as a white solid.

The following intermediates were made through the method described above.

General route 1

Example 1 : 2-Benzyl-3-chloro-6-(oxetan-3-yl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one

2-Benzyl-3-chloro-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (90 mg, 0.35 mmol) was added to 3-bromooxetane (473 mg, 3.45 mmol) and CS2CO3 (337 mg, 1 .04 mmol) in 1 ,4-dioxane (2 mL). The resulting mixture was stirred at 100 °C for 16 h. The solid was filtered out and filtrate was concentrated. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1 % NH3.H2O); Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 29% B to 49% B in 7 min; A 254/220 nm; RT1 : 6.70 min). Fractions containing the desired compound were evaporated to dryness to afford 2-benzyl-3- chloro-6-(oxetan-3-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.016 g, 14.6 %) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 4.83 (d, J = 7.1 Hz, 4H), 5.68 (s, 2H), 5.92 (p, J = 7.1 Hz, 1 H), 7.25 (dd, J = 7.5, 2.1 Hz, 2H), 7.27 - 7.43 (m, 3H), 8.47 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 317; RT = 2.08 min.

The following compounds were made through the method described above.

General route 2

Example 7: 3-Chloro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one

1-(Tetrahydro-2H-pyran-4-yl)hydrazine dihydrochloride (30.4 mg, 0.16 mmol) was added to ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (50 mg, 0.16 mmol) in dry EtOH (4 mL). The resulting mixture was stirred at 80 °C for 16 h, then solvent was removed under reduced pressure and the residue was purified by preparative HPLC, using decreasingly polar mixtures of water (10 mmol/L NH4HCC>3+0.1 % NH3.H2O) and CH3CN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-chloro-2-(2-fluorobenzyl)-6-(tetrahydro -2H-pyran- 4-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (27.6 mg, 47.2 %) as a white solid. ¹H NMR (400 MHz, DMSO-dg) 6 1.66 (dd, J = 12.6, 3.4 Hz, 2H) 1.97 (qd, J = 12.3, 4.6 Hz, 2H), 3.49 (td, J = 12.0, 1 .9 Hz, 2H), 3.97 (dd, J = 11 .3, 4.5 Hz, 2H), 5.09 (tt, J = 11 .6, 4.1 Hz, 1 H), 5.73 (s, 2H), 7.39 - 7.12 (m, 3H), 7.44 (q, J = 9.0, 7.4, 5.5, 1.9 Hz, 1 H), 8.40 (s, 1 H); LCMS (method 3) m/z (ES⁺), [M+H]⁺ = 363; RT = 1 .22 min. The following compounds were made through the method described above.

Example 14: (R)-3-chloro-6-(1 ,1 -difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one

Step 1 : tert-Butyl carbazate (1.405 g, 10.63 mmol) was added to 1 ,1-difluoropropan-2-one (1 g, 10.63 mmol), in MeOH (25 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL), and washed sequentially with water (30 mLx3), saturated brine (30 mL). The organic layer was dried over Na2SC , filtered and evaporated to afford crude product and purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 2-(1 ,1- difluoropropan-2-ylidene)hydrazine-1-carboxylate (1.12 g, 50.4 %) as a white solid. ¹H-NMR (300 MHz, DMSO) 6 1 .47 (s, 9H), 1 .89 (t, J = 1 .1 Hz, 3H), 6.28 (t, J = 54.0 Hz,1 H), 10.23 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H-tBu]⁺ = 153; RT = 0.607 min.

Step 2: Sodium cyanoborohydride (0.312 g, 4.97 mmol) was added to tert-butyl (E)-2-(1 ,1- difluoropropan-2-ylidene)hydrazine-1 -carboxylate (1.04 g, 4.97 mmol) in acetic acid (10 mL). The resulting mixture was stirred at RT for 2 h. The solvent was removed under reduced pressure and was basified with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with water (3 x 50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product tert-butyl 2-(1 , 1 - difluoropropan-2-yl)hydrazine-1-carboxylate (1 .00 g, 96 %), used directly in next step without further purification. ¹H NMR (300 MHz, DMSO-d6) 6 0.83 - 1 .13 (m, 3H), 1.40 (s, 9H), 3.13 (s, 1 H), 4.65 (s, 1 H), 5.81 (td, J = 56.2, 3.5 Hz, 1 H), 8.34 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H-tBu]⁺ = 155; RT = 0.667 min

Step 3: Tert-butyl 2-(1 ,1-difluoropropan-2-yl)hydrazine-1-carboxylate (1.13 g, 4.76 mmol) in 4N HCI in ethyl acetate solution (10 mL). The resulting mixture was stirred at RT for 2 h. The reaction mixture was filtered and the solid was dried under reduced pressure to afford (1 ,1-difluoropropan-2- yl)hydrazine (830.4 mg, 95%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) 6 1 .12 (d, J = 6.7 Hz, 4H), 3.40 - 3.45 (m, 1 H), 6.15 (td, J = 55 Hz, J = 3.1 Hz, 1 H), 9.56 (s, 4H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 111.

Step 4 & 5: Ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (300 mg, 0.97 mmol) was added to (1 ,1-difluoropropan-2-yl)hydrazine dihydrochloride (177 mg, 0.97 mmol) in EtOH (3 mL). The resulting mixture was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure and was purified by flash C18-flash chromatography, elution gradient 5 to 80% MeCN in water (0.01 % FA). Pure fractions were evaporated to dryness to afford rac-(R)-3-chloro-6- (1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (245 mg) as a light yellow solid. The above racemate was purified by preparative chiral-HPLC on a column CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2 M NH₃-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; gradient: 20% B to 20% B in 17 min; Wave Length: 220/254 nm; RT1 (min): 11.82; RT2 (min): 13.89; sample solvent: EtOH; injection volume: 0.5 mL.

The fractions containing the desired compound (the first peak RT1 (min): 11 .82) were evaporated to dryness to afford (R)-3-chloro-6-(1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6- dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (55 mg, 23.90 %) as an amorphous white solid. ¹H-NMR (300 MHz, DMSO-dg) 6 1.29 (d, J = 6.9 Hz, 3H), 5.21 (tt, J = 11.5, 5.7 Hz, 1 H), 5.62 (s, 2H), 6.11 (td, J = 55.9, 5.4 Hz, 1 H), 7.02 - 7.42 (m, 4H), 8.32 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 357; RT = 0.971 min, 99.9% ee.

General route 3

Example 16: 2-(2-Bromobenzyl)-3-chloro-6-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[3,4- d]pyridazin-7(6H)-one

Step 1 : 3-Chloro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one (2 g, 5.51 mmol) in trifluoromethanesulfonic acid (0.827 g, 5.51 mmol) at 25°C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was added to saturated aq. NaHCO₃ and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SC , filtered and concentrated. The residue was purified by preparative TLC (heptane: EtOAc = 1 : 1), to afford 3-chloro-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (1.4 g, 100 %) as a yellow solid. ¹H NMR (300 MHz, DMSO-d6) 6 1.77 - 1.65 (m, 2H), 1.85 - 1.95 (m, 2H), 3.57 - 3.41 (m, 2H), 3.98 (dd, J = 11.3, 4.8 Hz, 2H), 5.12 (tt, J = 9.6, 3.1 Hz, 1 H), 8.41 (d, J = 16.2 Hz, 1 H), 14.98 (s, 1 H); LCMS (method 2) m/z (ES⁺), [M+H]⁺ = 467; RT = 0.86 min.

Step 2: To 3-chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (100 mg, 0.36 mmol) in 1 ,4-dioxane (3 mL) was added to 1-bromo-2-(bromomethyl)benzene (90 mg, 0.36 mmol), cesium carbonate (117 mg, 0.36 mmol) at 60°C over a period of 16 h. The reaction mixture was concentrated, diluted with EtOAc (50 mL) and washed sequentially with water (20 mL x 2) and brine (20 mL). The combined organic layer were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1 % NH4HCO3) and CH3CN as eluents. Pure fractions were evaporated to dryness to afford 2-(2-bromobenzyl)-3-chloro-6-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one (20 mg, 13%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) 6 1 .65 (dd, J = 3.7, 12.3 Hz, 2H), 1 .96 (qd, J = 4.6, 12.3 Hz, 2H), 3.47 (t, J = 11 .9 Hz, 2H), 3.89 - 4.00 (m, 2H), 5.07 (tt, J = 4.1 , 11 .6 Hz, 1 H), 5.70 (s, 2H), 7.06 (dd, J = 1 .9, 7.5 Hz, 1 H), 7.25 - 7.44 (m, 2H), 7.68 (dd, J = 1 .5, 7.8 Hz, 1 H), 8.40 (s, 1 H) ; LCMS (method 2) m/z (ES+), [M+H]⁺ = 425 RT = 1.12 min.

The following compound was made through the method described above.

General route 4

Example 18: 6-((1 R,5S,6R)-3-oxa-bicyclo[3.1 .0]hexan-6-yl)-3-chloro-2-(2-fluorobenzyl)- 2H-pyrazolo[3,4-d]pyridazin-7(6H)-one

Copper acetate (2.2 g, 11 .48 mmol) was added to 3-chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one (3.2 g, 11.5 mmol), ((1 R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)boronic acid (2.21 g, 17.22 mmol), CS2CO3 (1 .87 g, 5.74 mmol) and pyridine (2.72 g, 34.45 mmol) in toluene (30 mL) at 25°C under oxygen. The resulting mixture was stirred at 110 °C for 16 h in a sealed tube. The reaction mixture was quenched with saturated NH4CI (50 mL), extracted with DCM (3 x 40 mL), the combined organic layers were dried over Na2SC , filtered and evaporated to afford a yellow oil. The crude product was purified by flash C18-flash chromatography, elution gradient 40 to 50% CH3CN in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford 6-((1 R,5S,6r)- 3-oxabicyclo [3.1 ,0]hexan-6-yl)-3-chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7- one (1 .30 g, 31 .4 %) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 2.16 - 2.26 (m, 2H), 3.46 (t, J = 2.6 Hz, 1 H), 3.69 (dt, J = 8.4, 1.5 Hz, 2H), 3.94 (d, J = 8.6 Hz, 2H), 5.71 (s, 2H), 7.14 - 7.33 (m, 3H), 7.35-7.45 (m, 1 H), 8.28 (s, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 361 ; RT = 1 .62 min. The following compounds were made through the method described above.

General route 5

Example 24: 3-Chloro-2-(2-fluorobenzyl)-6-((1S,2S)-2-fluorocyclopropyl)-2H- pyrazolo[3,4-d]pyridazin-7(6H)-one

Step 1 : Diphenylphosphonic azide (5.29 g, 19.22 mmol) was added to triethylamine (2.68 ml, 19.22 mmol) and (1 R,2S)-2-fluorocyclopropane-1 -carboxylic acid (1 g, 9.61 mmol) in toluene (10.00 mL) and tert-butanol (10 mL) at 25°C under N2. The resulting mixture was stirred at 25°C for 1 h then the temperature was increased to 90°C and the reaction mixture was stirred for a further 12 h. The solvent was removed under reduced pressure and the reaction mixture was poured into water (100 mL), extracted with EtOAc (3 x 60 mL). The organic layer was dried over Na2SC , filtered and evaporated to afford the crude product that was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tertbutyl ((1S,2S)-2-fluorocyclopropyl)carbamate (1 .2 g, 71.3 %) as a colourless oil. ¹H NMR (300 MHz, CDCh) 6 0.80-1.02 (m, 1 H), 1 .24 - 1 .38 (m, 1 H), 1 .46 (s, 9H), 2.90 (ddd, J = 15.4, 9.5, 5.3 Hz, 1 H), 4.65 (s, 1 H).

Step 2: Tert-butyl ((1S,2S)-2-fluorocyclopropyl)carbamate (1.0 g, 5.71 mmol) was added to methyl sulfide (1 .42 g, 22.83 mmol) and pyridine (1 .8 g, 22.83 mmol) in MeCN (20 mL) at 25°C under N2. The resulting mixture was stirred at 0 °C for 5 min. Then nitrosonium tetrafluoroborate (2.67 g, 22.83 mmol) was added slowly. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (3 x 50 mL). The organic layer was dried over Na2SC , filtered and evaporated to afford the crude product that was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl ((1S,2S)-2-fluorocyclopropyl)(nitroso)carbamate (0.480 g, 41 .2 %) as a yellow oil. ¹H NMR (400 MHz, CDCh) 6 0.91-1 .05 (m, 1 H), 1.17 - 1.33 (m, 1 H), 1 .70 (s, 9 H), 2.75- 2.85 (m, , 1 H), 4.44 (ddd, J = 6.8, 3.8, 1 .5 Hz, 1 H). Step 3: Zinc (1 .44 g, 22.04 mmol) was added slowly to tert-butyl((1 S,2S)-2- fluorocyclopropyl)(nitroso)carbamate (450 mg, 2.20 mmol) and ethyl 5-chloro-1-(2-fluorobenzyl)-4- formyl-1 H-pyrazole-3-carboxylate (685 mg, 2.20 mmol) in AcOH (2.5 ml, 44.07 mmol) and DCM (10 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 2 h and filtered through a Celite pad. The filtrate was poured into water (100 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were dried over Na2SC , filtered and evaporated to afford the crude product that was purified by preparative C18 flash column, using decreasingly polar mixtures of water (containing 0.1 % NH4HCO3) and CH3CN as eluents. Fractions containing the desired compound were evaporated to dryness to afford ethyl 4-((2-(tert-butoxycarbonyl)- 2-((1 S,2S)-2- fluorocyclopropyl)hydrazineylidene)methyl)-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxylate (0.540 g, 50.7 %) as a white solid. ¹H NMR (300 MHz, CDCI3) 6 1.21 - 1 .31 (m, 1 H), 1 .44 (dd, J = 8.1 , 6.1 Hz, 3H), 1 .56 (s, 9 H), 1 .76 - 1 .88 (m, 1 H), 2.90 - 3.06 (m, 1 H), 4.48 (q, J = 7.3 Hz, 2H), 4.81 (s, 1 H), 5.57 (s, 2H), 7.04 (dt, J = 28.9, 9.1 Hz, 4H), 8.72 (s, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 483; RT = 1.32 min.

Step 4: Ethyl-((2-(Tert-butoxycarbonyl)-2-((1 S,2S)-2- fluorocyclopropyl)hydrazineylidene)methyl)-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxylate (520 mg, 1 .1 mmol) was added in HCI/EtOH (5 mL) at 25°C under N2. The resulting mixture was stirred at 80 °C for 3 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC Column: XBridge Shield RP18 OBD Column, 30x150mm, 5um; Mobile Phase A: Water (10 mmoL/L NH4HCO3 + 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; fractions containing the desired compound were evaporated to dryness to afford 3-chloro-2- (2-fluorobenzyl)-6-((1 S,2S)-2-fluorocyclopropyl)- 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.220 g, 60%) as a white solid. ¹H NMR (300 MHz, CDCI3) 6 1.37 - 1 .53 (m, 1 H), 1 .58 - 1 .77 (m, 1 H), 4.45- 4.55 (m, 1 H), 4.95-5.05 (m, 1 H), 5.66 (s, 2H), 7.01 - 7.15 (m, 2H), 7.19 - 7.26 (m, 1 H), 7.33 (tdd, J = 7.6, 5.3, 1 .9 Hz, 1 H), 7.96 (s, 1 H); LCMS (method 2) m/z (ES⁺), [M+H]⁺ = 337; RT = 1 .66 min.

The following compounds were made according to the method described above.

General route 6

Example 45: 3-fluoro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one

Potassium fluoride (240 mg, 4.13 mmol) was added to 3-chloro-2-(2-fluorobenzyl)-6-

(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (150 mg, 0.41 mmol) and 18-crown-6 (10.93 mg, 0.04 mmol) in DMSO (2 mL) at 25°C under N2. The resulting mixture was stirred at 180 °C for 1 h (microwave). The reaction mixture was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30x150mm, 5um; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate:60 mL/min; Gradient: 33% B to 45% B in 7 min; A 254/220 nm). Fractions containing the desired compound were evaporated to dryness to afford 3-fluoro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)- 2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one (0.029 g, 21 %) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) 6 1 .60 - 1 .68 (m, 2H), 1 .88 - 2.03 (m, 2H), 3.42 - 3.53 (m, 2H), 3.91 - 4.00 (m, 2H), 5.01 - 5.12 (m, 1 H), 5.63 (s, 2H), 7.17 - 7.53 (m, 4H), 8.40 (s, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 347; RT =

1.612 min.

Example 47: 6-((1 R,5S,6r)-3-oxa-bicyclo[3.1.0]hexan-6-yl)-3-(difluoromethoxy)-2-(2- fluorobenzyl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one

Step 1 : Ethyl 5-chloro-1-(2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (2 g, 6.44 mmol) was added to sodium methoxide in MeOH (10 mL, 0.00 mmol) at 25°C under N2. The resulting mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 6 with 2M HCI and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (30 mL), dried over Na2SC>4, filtered and evaporated to afford crude product (1 g). The obtained crude was added to hydrazine dihydrochloride (0.377 g, 3.59 mmol) at 25°C under N2. The resulting mixture was stirred at 80 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by Flash-Prep-HPLC using the following conditions (Column, X Bridge Prep OBD C18 Column, 19x250 mm, 5um; mobile phase, water (10 mmol/L NH4HCO3) and CH3CN. The desired compound 2-(2-fluorobenzyl)-3-hydroxy-2H- pyrazolo[3,4-d] pyridazin-7(6H)-one (0.1 g, 10 %) was obtained as a yellow solid. LCMS (method 2) m/z (ES+) [M+H]⁺ = 261 ; RT = 0.63 min.

Step 2: Copper (II) acetate (76 mg, 0.38 mmol) was added to ((1 R,5S,6s)-3-oxabicyclo [3.1.0] hexan-6-yl) boronic acid (98 mg, 0.77 mmol), 2-(2-fluorobenzyl)-3-hydroxy-2,6-dihydro-7H- pyrazolo[3,4-d] pyridazin-7-one (100 mg, 0.38 mmol) and pyridine (93 pl, 1.15 mmol) in toluene (1 mL) at rt. The resulting mixture was stirred at 110 °C for 12 h. The solvent was removed under reduced pressure. The reaction mixture was poured into water (30 mL), extracted with EtOAc (3 x 25 mL), the combined organic layers were dried over Na2SO4, filtered and evaporated to afford crude product and purified with silica column to afford 6-((1 R,5S,6r)-3-oxa-bicyclo[3.1.0]hexan-6-yl)-2-(2- fluorobenzyl)-3- hydroxy-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one (25 mg). LCMS (method 3) m/z (ES+), [M+H]⁺ = 343; RT = 0.43 min.

Step 3: Sodium 2-chloro-2,2-difluoroacetate (20.04 mg, 0.13 mmol) was added to 6-

((1 R,5S,6r)-3-oxabicyclo [3.1.0] hexan-6-yl)-2-(2-fluorobenzyl)-3-hydroxy-2,6-dihydro-7H-pyrazolo[3,4- d] pyridazin-7-one (30 mg, 0.09 mmol) and Cesium carbonate (86 mg, 0.26 mmol) in DMF (0.5 mL) at 25°C under N2. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was dilute with EtOAc (50 mL) and washed with H2O (3 x 20 mL), and the combined organic layers were dried with Na2SC , filtered and concentrated. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm 5um; Mobile Phase A: Water (10 mmol/L NH4HCC>3+0.1 %NH3.H2O). Fractions containing the desired compound were evaporated to dryness to afford 6-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3-(difluoromethoxy)-2-(2-fluorobenzyl)-2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one (2.66 mg, 7.74 %) as a white solid. ¹H-NMR (300 MHz, MeOD) 6 2.30-2.34 (m, 2H), 3.56 (t, J = 2.6 Hz, 1 H), 3.88 - 3.73 (m, 2H), 4.07 (d, J = 8.6 Hz, 2H), 5.61 (s, 2H), 7.51 - 7.07 (m, 5H), 8.14 (t, J = 1 .2 Hz, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 393; RT = 2.24 min.

Example 48: (1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4- d]pyridazin-6-yl)cyclopropane-1 -carbonitrile

Step 1 : Rac-Ethyl-(1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4- d]pyridazin-6-yl)cyclopropane-1-carboxylate (420 mg, 1.07 mmol) (prepared according to the above step 2, starting from commercially available (2-(ethoxycarbonyl)cyclopropyl)boronic acid) was added in NH3.H2O (5 mL) at 25 °C under N2. The resulting mixture was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure and the residue was purified by flash C18-flash chromatography [elution gradient 0 to 100% CH3CN in water (0.1 % NH4HCO3)]. Pure fractions were evaporated to dryness to afford rac-(1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H- pyrazolo[3,4-d]pyridazin- 6-yl)cyclopropane-1 -carboxamide (0.3 g, 77 %) as a yellow solid. ¹H-NMR (300 MHz, DMSO-dg) 6 1.24 - 1.36 (m, 1 H), 1.42 - 1.54 (m, 1 H), 2.02 - 2.14 (m, 1 H), 4.09 - 4.21 (m, 1 H), 5.72 (s, 2H), 7.00 (s, 1 H), 7.15 - 7.33 (m, 3H), 7.35 - 7.49 (m, 1 H), 7.67 (s, 1 H), 8.30 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 362; RT = 0.89 min.

Step 2: Rac-(1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4- d]pyridazin-6-yl)cyclopropane-1 -carboxamide (300 mg, 0.83 mmol) was added to (methoxycarbonylsulfamoyl) triethylammonium hydroxide (988 mg, 4.15 mmol) in THF (5 mL) at 25 °C under N2 and the resulting mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford a crude product that was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5um; Mobile Phase A: Water (10 mmol/L NH4HCC>3+0.1 % NH3.H2O). Fractions containing the desired compound were evaporated to dryness to afford rac-(1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo [3,4-d]pyridazin-6- yl)cyclopropane-1 -carbonitrile (0.13 g, 45.6 %) as a pale yellow solid. The obtained racemate was purified by preparative chiral - HPLC (Column: CHIRALPAK IC, 5x25 cm, 5pm; Mobile Phase A: Hex : DCM= 3:1 (0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate:18 mL/min; Isocratic conditions: 50% B in 11 min; 220/254 nm; RT1 (min): 8.218; RT2 (min): 10.834. The first fractions containing the desired compound were evaporated to dryness to afford (1 R,2R)-2-(3-chloro-2-(2-fluorobenzyl)-7- oxo-2, 7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)cyclopropane-1 -carbonitrile (0.041 g, 34.2 %) as a pale yellow solid. ¹H-NMR (300 MHz, CDCI3) 6 1.61 - 1.67 (m, 1 H), 1.76 - 1.89 (m, 1 H), 2.02 - 2.14 (m, 1 H), 4.82 - 4.94 (m, 1 H), 5.67 (s, 2H), 7.03 - 7.17 (m, 2H), 7.22 - 7.26 (m, 1 H), 7.27 - 7.38 (m, 1 H), 7.97 (s, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 344; RT = 1 .55 min; ee= 99%. Absolute configuration arbitrarily assigned.

Example 49: 3-Chloro-2-(2-fluorobenzyl)-6-((2R,3S)-2-methyloxetan-3-yl)-2,6-dihydro-

7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : Tert- Butyl carbazate (1.689 g, 12.78 mmol) was added to 2-methyloxetan-3-one (1 g, 11 .62 mmol) in MeOH (10 mL) at 50 °C for 12 h. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (E)-2-(2-methyloxetan-3-ylidene)hydrazine-1 -carboxylate as a white solid (1 g). ¹H-NMR (300 MHz, DMSO-d₆) 6 1.35 (d, 3H), 1.41 (s, 9H), 5.04 (d, 2H), 5.74 (s, 1 H), 10.22 (s, 1 H). LCMS (method 2) m/z (ES+), [M-Boc] = 145; RT = 0.66 min

Step 2: Lithium triethylhydroborate (12.59 mmol) was added to tert-butyl (E)-2-(2- methyloxetan-3-ylidene)hydrazine-1 -carboxylate (840 mg, 4.20 mmol) in DCM (85 mL) at 25°C. The resulting mixture was stirred at rt for 12 h, quenched by saturated NH4CI and extracted with EtOAc (3 x 50) mL. The combined organic layers were dried over Na2SO4, filtered and evaporated to afford a crude product that was purified by flash silica chromatography (elution gradient 0 to 50% THF in petroleum ether). Pure fractions were evaporated to dryness to afford 700 mg tert-butyl 2-(2- methyloxetan-3-yl)hydrazine-1-carboxylate as a yellow oil. ¹H-NMR (400 MHz, DMSO-d₆): <5H 1.12 (3H, d, J=6.5 Hz), 1.44 (9H, s), 4.12 (1 H, qd, J=4.4, 6.5 Hz), 5.00 (1 H, d, J=4.3 Hz), 5.76 (1 H, s), 2 exchangeable protons not seen. LCMS (method 3) m/z (ES+), [M+H]⁺= 203; RT = 0.94 min.

Step 3: 4 M HCI in dioxane (1 .2 mL, 0.10 mmol was added to te/Y-butyl 2-(2-methyloxetan -3- yl)hydrazine-1 -carboxylate (500 mg) in 10 mL dioxane. The resulting mixture was stirred at 25 °C for 12 h, concentrated to dry and used directly in the next step.

Step 4: (2-Methyloxetan-3-yl)hydrazine (240 mg, 2.35 mmol) was added to ethyl 5-chloro-1- (2-fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (365 mg, 1.17 mmol) in ethanol (1 mL) at 80°C. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was purified by flash CI S- flash chromatography, elution gradient 0 to 100% CH3CN in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford 3-chloro-6-(1-chloro-3-hydroxybutan-2-yl) -2-(2-fluorobenzyl)- 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.160 g, 35.4 %) as a yellow solid. ¹H-NMR (300 MHz, DMSO-dg) 6 0.93 (d, 3H), 3.33 - 4.13 (m, 3H), 4.17 (dd, 1 H), 5.21 (d, 1 H), 5.72 (s, 2H), 6.88 - 7.79 (m, 4H), 8.43 (s, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 385; RT = 1 .29 min.

Step 5: Sodium iodide (64.2 mg, 0.43 mmol) was added to Silver (I) oxide (66.2 mg, 0.29 mmol) and 3-chloro-6-(1 -chloro-3-hydroxybutan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one (55mg, 0.14 mmol) in CH3CN (1 ml) at 60°C. The resulting mixture was stirred at 60 °C for 2 h. The reaction was diluted with water and extracted with DCM (3 x 30 mL). The combined organic layers were dried with Na2SC>4, filtered and concentrated. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm 5um; Mobile Phase A: Water (10 mmoL/L NH4HCO3+ 0.1 % NH3.H2O), mobile phase B: MeOH; Flow rate: 60 mL/min; Gradient: 42% B to 67% B in 7 min; 220/254 nm; RT1 (min): 7.18. Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2-fluorobenzyl)-6-((2R,3S)-2- methyloxetan-3-yl)-2,6-dihydro -7H-pyrazolo[3,4-d]pyridazin-7-one (15 mg) as a white solid. The racemate (10 mg) was purified by preparative chiral HPLC: Column CHIRAL ART Cellulose - SC, 2x25 cm, 5um; Mobile Phase A: Hex (0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Isocratic conditions: 50% B in 19 min; 220/254 nm; RT1 (min):15.085; RT2 (min): 16.844; fractions containing the desired compound were evaporated to dryness to afford 3-chloro-2-(2- fluorobenzyl)-6-((2R,3S)- 2-methyloxetan-3-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (4.00 mg) as a white oil and ¹H-NMR (300 MHz, CDCI3) 6 8.17 (s, 1 H), 7.33 (m, J = 10.8, 5.5, 2.6 Hz, 1 H), 7.22 (dd, J = 7.3, 1.8 Hz, 1 H), 7.14 - 6.99 (m, 2H), 5.65 (d, J = 8.6 Hz, 3H), 5.21 (t, J = 6.2 Hz, 1 H), 4.95 - 4.75 (m, 2H), 1 .56 (d, J = 6.2 Hz, 3H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 349; RT = 1 .683 min; ee= 99.52%. Absolute configuration arbitrarily assigned.

Example 50: 2-(2-Fluorobenzyl)-6-((1 R,2R)-2-fluorocyclopropyl)-3-methyl-2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one

2,4,6-Trimethyl-1 ,3,5,2,4,6-trioxatriborinane (447 mg, 3.56 mmol) was added to rac-3-chloro- 2-(2-fluorobenzyl)-6-((1 R,2R)-2-fluorocyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (200 mg, 0.59 mmol), Bis(di-te/Y-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(ll) (42.1 mg, 0.06 mmol) and K2CO3 (205 mg, 1 .48 mmol) in water (0.500 mL) and 1 ,4-dioxane (2.5 mL) at 25°C under N2 . The resulting mixture was stirred at 80 °C for 3 h. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 5 to 100% CH3CN in water. Pure fractions were evaporated to dryness and purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm 5um; Mobile Phase A: Water (10 mmoL/L NH4HCO3+ 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 33% B to 53% B in 8 min). Fractions containing the desired compound were evaporated to dryness to afford rac-2-(2- fluorobenzyl)-6-((1 R,2R)-2-fluorocyclopropyl) -3-methyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.047 g, 25.02 %) as a white solid. The racemic product was chirally separated by preparative chiral HPLC (Column: CHIRALPAK IH-3, 4.6x50 mm, 3.0 urn; Mobile Phase A: Hex (0.1 % DEA):EtOH= 80:20). The first fractions were evaporated to dryness to afford 2-(2-fluorobenzyl)-6-((1 R,2R)-2- fluorocyclopropyl) -3-methyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.034 g, 72.3 %) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 1.31 - 1 .58 (m, 2H), 2.50 (s, 3H), 4.08 (ddd, J = 16.1 , 10.1 , 5.9 Hz, 1 H), 4.99 (s, 1 H), 5.53 (s, 2H), 7.04 - 7.33 (m, 4H), 8.23 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 316; RT = 0.99 min; e.e= 100%. Absolute configuration arbitrarily assigned.

Example 51 : 3-Chloro-2-(2-fluorobenzyl)-6-((1 R,2R)-2-(fluoromethyl)cyclopropyl)-2,6- dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : Boron trifluoride ether (4.04 g, 28.45 mmol) was added in one portion to morpholinosulfur trifluoride (4.98 g, 28.45 mmol) in DCM (45 mL) at 0°C under argon. The resulting mixture was stirred at 0 °C for 15 min. Then triethylammonium fluoride (9.17 g, 56.89 mmol) was added and the resulting mixture was stirred at 0 °C for 15 min. Lastly rac-isopropyl rac-(1 R,2S)-2- (hydroxymethyl)cyclopropane-l- carboxylate (3 g, 18.96 mmol) in DCM (30 mL) was added and the resulting mixture stirred at 0 °C for 60 min. The reaction mixture was quenched with saturated NaHCOs (100 mL) and extracted with DCM (3 x 80 mL). The combined organic layers were dried over Na2SC , filtered and evaporated and purified by flash silica chromatography (elution gradient 0 to 20% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford rac-isopropyl rac- (1 R,2S)-2-(fluoromethyl)cyclopropane-1 -carboxylate (1.33 g, 43.8 %) as a colourless oil. ¹H-NMR (300 MHz, CDCb) 6 0.98 - 1 .05 (m, 2H), 1 .14 (t, J = 6.0 Hz, 6H), 1 .53 - 1 .80 (m, 2H), 4.27 - 4.75 (m, 2H), 4.94 (m, J = 12.5, 6.3 Hz, 1 H).

Step 2: Sodium hydroxide (1.498 g, 37.46 mmol) was added to rac-isopropyl (1 R,2S)-2- (fluoromethyl) cyclopropane-1 -carboxylate (1.5 g, 9.36 mmol) in MeOH (50mL)/water (10.00 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 30 min and subsequently quenched with water (50 mL). The mixture was adjusted to pH 7 with aq. NaHSO4 and extracted with DCM (3 x 50 mL). The combined organic layer were dried over Na2SC>4, filtered and evaporated to afford a crude solid that was treated with hexane (20 mL). The precipitate was collected by filtration, washed with hexane (10 mL) and dried in the vacuum oven to afford rac-(1 R,2S)-2-(fluoromethyl)cyclopropane-1- carboxylic acid (0.350 g, 31 .6 %) as a pale yellow solid. 1 H NMR (300 MHz, CDCb) 6 1.03 — 1 .20 (m, 2H), 1.64 - 1.84 (m, 2H), 4.33 - 4.77 (m, 2H), 11.44 (s, 1 H).

Step 3: Rac-(1 S,2R)-2-(fluoromethyl)cyclopropane-1 -carboxylic acid (430 mg, 3.64 mmol) was added to mesityl-13-iodanediyl diacetate (647 mg, 1.78 mmol) in toluene (50 mL) at 25°C under N2. The solvent was removed under vacuum over a time period of ~10 min (water bath 55 °C). A second 75 mL aliquot of toluene was added to the flask and the evaporation step was repeated for two more times with 50 mL toluene each time. The solvent was removed under reduced pressure and the obtained product was used in the next step without further purification, rac-(((1 R,2S)-2- (fluoromethyl)cyclopropane-l- carbonyl)oxy)(mesityl)-3-iodaneyl (1 S,2R)-2- (fluoromethyl)cyclopropane-l-carboxylate (0.850 g, 100 %) as a yellow solid.¹H NMR (300 MHz, CDCb) 6 0.85 - 1 .02 (m, 4H), 1 .49 (m, J = 12.0, 8.4, 4.2 Hz, 2H), 1 .67 (m, J = 7.6, 5.9, 1 .8 Hz, 2H), 2.26 (s, 3H), 2.60 (t, J = 2.5 Hz, 6H), 4.21 - 4.67 (m, 4H), 7.00 (s, 2H).

Step 4: 2-7erf-butyl-1 ,1 ,3,3-tetramethylguanidine (382 mg, 2.15 mmol) was added to lr[p- F(Me)ppy]2(dtbbpy)PFe (10.53 mg, 10.77 pmol), Cuprous chloride (53.3 mg, 0.54 mmol), bathophenanthroline (250 mg, 0.75 mmol), rac-(((1 R,2S)-2-(fluoromethyl)cyclopropane-1- carbonyl)oxy)(mesityl)-l3-iodaneyl (1 S,2R)-2-(fluoromethyl)cyclopropane-1 -carboxylate (1034 mg, 2.15 mmol) and 3-chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (300 mg, 1 .08 mmol) in 1 ,4-dioxane (24 mL) at 20°C under N2. The resulting mixture was stirred at 25 °C for 2 h in blue LED. After removing the solvent, the crude product was purified by flash C18-flash chromatography, elution gradient 5 to 100% CH3CN in water (0.01 % NH4HCO3). Pure fractions were evaporated to dryness and purified by preparative HPLC (Column: YMC-Actus Triart C18, 30x150 mm, 5um; Mobile Phase A: Water (10 mmoL/L NH4HCO3+ 0.1 % NH3.H2O); mobile phase B: CH3CN; flow rate: 60 mL/min; gradient: 45% B to 65% B in 8 min). Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2-fluorobenzyl)-6-((1 R,2R)-2-(fluoromethyl) cyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.040 g, 10.59 %) as a white solid. The racemate was purified by preparative chiral HPLC on a CHIRALPAK IG-3, 4.6x50 mm 3 urn column; Mobile Phase A: Hex (0.1 % DEA): EtOH= 50:50. The fractions containing the desired compound were evaporated to dryness to afford 3-chloro-2-(2-fluorobenzyl)-6-((1 R,2R)-2-(fluoromethyl) cyclopropyl)- 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (3.10 mg, 7.75 %) as a white solid. ¹H-NMR (300 MHz, CDCh) 6 0.96 - 1 .08 (m, 1 H), 1 .25 - 1 .39 (m, 1 H), 1 .75 - 1 .94 (m, 1 H), 3.93 - 4.05 (m, 1 H), 4.37 (dddd, J = 57.8, 47.8, 9.7, 6.9 Hz, 2H), 5.56 (s, 2H), 6.93 - 7.05 (m, 2H), 7.08 - 7.15 (m, 1 H), 7.17 - 7.29 (m, 1 H), 7.88 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 351 ; RT =0.63 min; e.e= 100%. Absolute configuration arbitrarily assigned.

Example 52: rac-3-Chloro-6-((1 R,2R)-2-(difluoromethoxy)cyclopropyl)-2-(2- fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : Te/Y-butyldimethylsilyl trifluoromethanesulfonate (50.3 g, 190.31 mmol) was added dropwise to 2-(1 ,3-dioxoisoindolin-2-yl)acetaldehyde (30 g, 158.59 mmol) and DBU (35.9 ml, 237.88 mmol) in DCM (300 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 2 h. The reaction was worked up by the addition of 2 N H2SO4 (100 mL), extracted with DCM (3 x 100 mL), the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (E)-2-(2-((fe/Y-butyldimethylsilyl)oxy)vinyl)isoindoline- 1 ,3-dione (4.40 g, 9.14 %) as a yellow oil. ¹H-NMR (400 MHz, CDCh) 6 0.23 (s, 6H), 0.94 (s, 9H), 6.44 (d, J = 11.4 Hz, 1 H), 7.56 (d, J = 11.4 Hz, 1 H), 7.69 - 7.76 (m, 2H), 7.81 - 7.88 (m, 2H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 304; RT = 1 .06 min. Elution gradient 5 to 10% EtOAc in petroleum ether afforded (Z)-2-(2-((7e/Y-butyldimethylsilyl)oxy)vinyl)isoindoline-1 ,3-dione (4.20 g, 8.73 %) as a yellow oil.

Step 2: Diethylzinc 1 ,0M in hexanes (72.5 ml, 72.50 mmol) and diiodomethane (5.85 ml,

72.50 mmol) was added to (E)-2-(2-((fe/Y-butyldimethylsilyl)oxy)vinyl)isoindoline-1 ,3-dione (4.4 g,

14.50 mmol) in toluene (44 mL) at 0°C under N2. The resulting mixture was stirred at 65 °C for 3 h. The mixture was worked up by the addition of 2N H2SO4 and dilution with petroleum ether. The organic phase was washed with saturated NaHCOs, dried with Na2SCU, filtered and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford trans-2-(2-((7e/Y- butyldimethylsilyl)oxy) cyclopropyl)isoindoline-1 ,3-dione (2.400 g, 52.1 %) as a yellow oil. ¹H-NMR (400 MHz, CDCh) 6 0.21 - 0.27 (m, 6H), 0.95 (s, 9H), 1.18 - 1.36 (m, 2H), 2.73 - 2.91 (m, 1 H), 3.85 - 3.99 (m, 1 H), 7.72 - 7.74 (m, 2H), 7.83 - 7.85 (m, 2H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 318; RT = 1 .02 min

Step 3: Hydrazine hydrate (2.271 g, 45.36 mmol) was added to trans-2-(2-((te/Y- butyldimethylsilyl) oxy)cyclopropyl)isoindoline-1 ,3-dione (2.4 g, 7.56 mmol) in DCM (12 mL) and EtOH (12.00 mL) at 25°C under N2. The resulting mixture was stirred at rt for 4 h. The reaction mixture was poured into water (20 mL), extracted with DCM (3 x 50 mL), the combined organic layers were dried over Na2SC , filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford trans-2-((te/Y-butyldimethylsilyl)oxy)cyclopropan-1 -amine (0.3 g, 21 %) as a pale yellow oil. ¹H-NMR (300 MHz, CDCh) 6 0.08 - 0.12 (m, 6H), 0.52 - 0.64 (m, 1 H), 0.67 - 0.77 (m, 1 H), 0.89 (s, 9H), 2.34 - 2.41 (m, 1 H), 3.18 - 3.28 (m, 1 H) (two protons were not seen).

Step 4: Boc-anhydride (409 pl, 1.76 mmol) was added to trans-2-((te/Y-butyldimethylsilyl)oxy) cyclopropan-1 -amine (330 mg, 1 .76 mmol) in DCM (4 mL) at 25°C under N2. The resulting mixture was stirred at RT for 16 h. The solvent was removed under reduced pressure to afford trans-te/Y- butyl(2-((te/Y-butyldimethylsilyl)oxy)cyclopropyl)carbamate (0.465 g, 92 %) as a colourless oil. ¹H-NMR (400 MHz, CDCh) 6 0.13 - 0.15 (m, 6H), 0.74 - 0.80 (m, 1 H), 0.91 (s, 9H), 0.95 - 1 .01 (m, 1 H), 1 .46 (s, 9H), 2.56 - 2.62 (m, 1 H), 3.30 - 3.37 (m, 1 H), 4.54 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 288; RT = 1.09 min.

Step 5: Dimethyl sulfide (443 pl, 5.98 mmol) in CH3CN (5 mL) was added to trans-te/Y-butyl (2-((te/Y-butyldimethylsilyl)oxy)cyclopropyl)carbamate (430 mg, 1.50 mmol) and pyridine (484 pl, 5.98 mmol) at 25°C under N2. Ammoniaylidyneoxonium tetrafluoroborate (699 mg, 5.98 mmol) was added after the reaction was stirred at 0 °C for 3 h. The solution was poured on to DCM and cold H2O, extracted with DCM (3 x 25 mL) and the organic layer dried over Na2SCU, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford trans-te/Y-butyl (2-((te/Y- butyldimethylsilyl)oxy)cyclopropyl)(nitroso)carbamate (0.103 g, 21.8 %) as a pale yellow oil. ¹H-NMR (400 MHz, CDCh) 6 0.12 - 0.21 (m, 6H), 0.80 - 0.86 (m, 1 H), 0.92 (s, 9H), 1.29 - 1.32 (m, 1 H), 1.55 (s, 9H), 2.31 - 2.51 (m, 1 H), 3.21 - 3.45 (m, 1 H)

Step 6: Zinc (98 mg, 1 .50 mmol) was added to rac-tert-buty\ ((1 R,2R)-2-((te/Y- butyldimethylsilyl)oxy)cyclopropyl)(nitroso)carbamate (95 mg, 0.30 mmol), ethyl 5-chloro-1-(2- fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (93 mg, 0.30 mmol) in AcOH (344 pl, 6.00 mmol) and DCM (1 mL) at 0°C under N2. The resulting mixture was stirred at rt for 1 h. The reaction mixture was filtered through celite and washed with DCM and the filtrate was adjusted to pH 7-8 with NH3H2O and extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, elution gradient 80 to 90% CH3CN in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford rac- ethyl 4-((Z)-(2-(te/Y-butoxycarbonyl)-2-((1 R,2R)-2-((te/Y-butyldimethylsilyl) oxy)cyclopropyl)hydrazineylidene)methyl)-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxylate (0.070 g, 39.2 %) as a colourless oil. ¹H-NMR (300 MHz, CDCI3) 6 -0.03 (s, 6H), 0.80 (s, 9H), 0.87 - 0.99 (m, 1 H), 1.14 - 1.17 (m, 1 H), 1.32 (t, J = 7.1 Hz, 3H), 1.43 (s, 9H), 2.47 - 2.58 (m, 1 H), 3.38 - 3.48 (m, 1 H), 4.22 - 4.45 (m, 2H), 5.45 (s, 2H), 6.80 - 6.90 (m, 1 H), 6.90 - 7.03 (m, 2H), 7.11 - 7.25 (m, 1 H), 8.60 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 595; RT = 1 .62 min.

Step 7: rac-Ethyl-4-((Z)-(2-(7e/Y-butoxycarbonyl)-2-((1 R,2R)-2-((7e/Y- butyldimethylsilyl)oxy)cyclopropyl)hydrazineylidene)methyl)-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole- 3-carboxylate (50 mg, 0.08 mmol) was added to 4M HCI in EtOH (1 mL, 4.00 mmol) at 25°C under N2. The resulting mixture was stirred at 80 °C for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm 5 urn; Mobile Phase A: Water (10 mmoL/L NH4HCO3+ 0.1 % NH3.H2O), B: CH3CN; Flow rate:60 mL/min; Gradient: 22% B to 52% B in 8 min, RT1 (min): 6.9; fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2-fluorobenzyl)-6-((1 R,2R)-2- hydroxycyclopropyl)-2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one (0.015 g, 53.3 %) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 1.05 - 1.16 (m, 1 H), 1.16 - 1.27 (m, 1 H), 3.51 - 3.62 (m, 1 H), 3.73 - 3.85 (m, 1 H), 5.68 - 5.74 (m, 3H), 7.16 - 7.31 (m, 3H), 7.35 - 7.49 (m, 1 H), 8.25 (s, 1 H). LCM (method 3) m/z (ES+), [M+H]⁺ = 335; RT = 1 .08 min.

Step 8: (Bromodifluoromethyl)trimethylsilane (86 mg, 0.42 mmol) was added to rac-3-chloro- 2- (2-fluorobenzyl)-6-((1 R,2R)-2-hydroxycyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (47 mg, 0.14 mmol), potassium acetate (55.1 mg, 0.56 mmol) in DCM (0.5 mL) and water (0.5 mL) at rt. The resulting mixture was stirred at rt for 16 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (3 x 10 mL), and washed sequentially with brine (10 mL), the combined organic layers were dried over Na2SC , filtered and evaporated to afford colourless liquid. The crude product was purified by preparative HPLC (Column: YMC-Actus Triart C18 ExRS, 30 mm x 150 mm, 5 urn; Mobile Phase A: Water (10 mmoL/L NH4HCO3+ 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate:60 mL/min; Gradient:42% B to 75% B in 7 min; K 254/220 nm; RT1 (min): 6.62. Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro- 6-((1 R,2R)-2- (difluoromethoxy)cyclopropyl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (7.60 mg, 14.07 %) as a white solid. ¹H-NMR (400 MHz, CDCI3) 6 1.57 - 1 .71 (m, 2H), 3.97 - 4.05 (m, 1 H), 4.09 - 4.17 (m, 1 H), 5.68 (s, 2H), 6.41 - 6.90 (m, 1 H), 7.07 - 7.17 (m, 2H), 7.23 - 7.31 (m, 1 H), 7.31 - 7.41 (m, 1 H), 8.00 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 385; RT = 1 .49 min.

Example 53: 3-Chloro-2-(2-fluorobenzyl)-6-((1 R,2S,5S,6R)-2-(fluoromethyl)-3- oxabicyclo[3.1.0]hexan-6-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : Vinylmagnesium bromide (413 ml, 413.05 mmol) was added to 2-((te/Y- butyldimethylsilyl)oxy)acetaldehyde (40 g, 229.47 mmol) in THF (250 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 1 h and then quenched with saturated NH4CI (200 mL) and water (500 mL). The mixture was extracted with EtOAc (2 x 500 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 1-((7e/Y-butyldimethylsilyl)oxy)but-3-en-2-ol (40.2 g, 87 %) as a colourless liquid. ¹H-NMR (300 MHz, CDCh) 6 0.05 - 0.15 (m, 6H), 0.86 - 0.98 (m, 10H), 3.41 - 3.75 (m, 2H), 4.10-4.22 (m, 1 H), 5.16 - 5.42 (m, 2H), 5.83 (m, 1 H).

Step 2: KHMDS (219 ml, 218.51 mmol) was added to 1-((7e/Y-butyldimethylsilyl)oxy)but-3-en- 2-ol (40.2 g, 198.65 mmol) in THF (400 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 1 h and then 3-bromoprop-1-ene (28.8 g, 238.38 mmol) was added slowly and stirred at 0 °C for 3 h. The reaction mixture was quenched with saturated NH4CI (150 mL), extracted with EtOAc (2 x 200 mL), the combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ((2-(allyloxy)but-3-en-1-yl)oxy)(7e/Y- butyl)dimethylsilane (38.0 g, 79 %) as a colourless oil. ¹H-NMR (300 MHz, CDCh) 6 0.08 (d, J = 2.2 Hz, 6H), 0.88 - 0.96 (m, 9H), 3.35 - 4.37 (m, 5H), 5.11 - 5.36 (m, 4H), 5.67 - 6.01 (m, 2H).

Step 3: Grubbs catalyst 2nd generation (6.70 g, 7.88 mmol) was added to ((2-(allyloxy)but-3- en-1-yl)oxy) te/Y-butyl)dimethylsilane (38.2 g, 157.57 mmol) in DCM (40 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 3 h. DMSO (33.5 ml, 472.71 mmol) was added and stirred at 25 °C for 2 h. The reaction mixture was quenched with brine (100 mL), extracted with DCM (2 x 150 mL), the combined organic layers were dried over Na2SC , filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford te/Y-butyl((2,5-dihydrofuran-2- yl)methoxy)dimethylsilane (24.90 g, 73.7 %) as a brown liquid. ¹H-NMR (300 MHz, DMSO-d₆) 6 0.17 - 0.05 (m, 6H), 0.86 (d, J = 1.2 Hz, 9H), 4.95 - 3.34 (m, 5H), 6.15 - 5.78 (m, 1 H).

Step 4: 7e/Y-butyl((2,5-dihydrofuran-2-yl)methoxy)dimethylsilane (10 g, 46.65 mmol) was added in 4M HCI of EtOH solution (40 mL) at 22°C under N2. The resulting mixture was stirred at 25 °C for 1 h. Then the solvent was removed under reduced pressure. Acetyl chloride p.a. (10.98 g, 139.94 mmol) was added to the mixture in DCM (40 mL) at 23°C under N2. The resulting mixture was stirred at 25 °C for 1 h, quenched with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford (2,5-dihydrofuran-2-yl)methyl acetate (5.6 g, 84 %) as a yellow oil. ¹H-NMR (300 MHz, CDCh) 6 2.10 (d, J = 4.4 Hz, 3H), 4.84 - 3.75 (m, 4H), 5.16 - 4.95 (m, 1 H), 6.16 - 5.70 (m, 2H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 143; RT = 0.64 min.

Step 5: TMEDA (23.78 ml, 157.58 mmol) was added to Chromium(ll) chloride (19.1 g, 158 mmol) in THF (300 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 20 min. to afford a thick blue suspension. 2-(Diiodomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (15.51 g, 39.39 mmol) was added and the resulting mixture was stirred at 25 °C for 30 mins to give a brown solution. (2,5-Dihydrofuran-2-yl)methyl acetate (5.6 g, 39.39 mmol) was added and the resulting solution was stirred at 70°C for 48 h. The mixture was filtered through a Celite pad and the filtrate quenched with water (200 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford rac-((1 R,2R,5S)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- oxabicyclo[3.1 ,0]hexan-2-yl)methyl acetate (5.40 g, 48.6 %) as a yellow oil. ¹H-NMR (300 MHz, CDCh) 6 0.15 - 0.08 (m, 1 H), 1.24 (dd, J = 5.5, 3.0 Hz, 14H), 2.09 (dd, J = 4.0, 1 .5 Hz, 3H) 4.24 - 3.22 (m, 5H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 283; RT = 0.86 min.

Step 6: Rac-((1 R,2R,5S)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- oxabicyclo[3.1 ,0]hexan-2-yl)methyl acetate (5.4 g, 19.14 mmol) was added to sodium meta periodate (12.28 g, 57.42 mmol) in water (8.00 mL) and THF (32 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 5 min. Then HCI (6.70 ml, 13.40 mmol) was added and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (400 mL), extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford yellow liquid rac-((1 R,2R,5S)-2-(acetoxymethyl) -3-oxabicyclo[3.1 ,0]hexan-6-yl)boronic acid. ¹H-NMR (400 MHz, CDCh) 6 0.26 - 0.02 (m, 1 H), 1.53 - 0.72 (m, 2H), 2.19 - 2.07 (m, 3H), 4.24 - 3.50 (m, 5H).

Step 7: Copper II acetate monohydrate (574 mg, 2.88 mmol) was added to 3-chloro-2-(2- fluorobenzyl)-2,6- dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (801 mg, 2.88 mmol), rac-((1 R,2R,5S)-2- (acetoxymethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)boronic acid (575 mg, 2.88 mmol) and pyridine (682 mg, 8.63 mmol) in DCM (5 mL) at 25°C under oxygen. The resulting mixture was stirred at 110 °C for 16 h. The reaction mixture was quenched with saturated NH4CI (100 mL), extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC , filtered and evaporated to afford a residue that was purified by preparative HPLC column using decreasingly polar mixtures of water (0.1 % NH4HCO3) and CH3CN as eluents. Fractions containing the desired compound were evaporated to dryness to afford rac-((6S)-6-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo [3,4- d]pyridazin-6-yl)-3-oxabicyclo[3.1 ,0]hexan-2-yl)methyl acetate (0.900 g, 72.3 %) as a yellow solid. ¹H-NMR (300 MHz, CDCI3) 6 1.65 (s, 1 H), 1.86 - 2.04 (m, 1 H), 2.06 - 2.16 (m, 3H), 2.17 - 2.38 (m, 1 H), 3.38 - 4.49 (m, 3H), 5.68 (s, 2H), 7.06 - 7.17 (m, 2H), 7.20 - 7.27 (m, 1 H), 7.29 - 7.40 (m, 1 H), 7.95 - 8.11 (m, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 433; RT = 0.84 min.

Step 8: Rac-((6S)-6-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4- d]pyridazin-6-yl)-3-oxabicyclo[3.1 ,0]hexan-2-yl)methyl acetate (1.7 g, 3.93 mmol) was added in 4 M HCI of EtOH solution (20 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated NaHCOs (50 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated to afford yellow solid. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5um; Mobile Phase A: Water (10 mmol/L NH4HCC>3+0.1 % NH3.H2O), Mobile Phase B: MeOH; Flow rate:60 mL/min; Gradient: 42% B to 57% B in 8 min; 254- 220 nm; RT1 (min): 6.98. Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2- fluorobenzyl)-6-((2S,6R)-2- (hydroxymethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one (0.620 g, 36.5 %) as a yellow solid. ¹H-NMR (300 MHz, CDCI3) 6 1.27 (s, 1 H), 1 .95 (dt, J = 7.6, 2.7 Hz, 1 H), 2.58 - 2.48 (m, 1 H), 3.64 (d, J = 2.6 Hz, 1 H), 3.91 (dd, J = 12.3, 4.9 Hz, 1 H), 4.11 - 3.96 (m, 2H), 4.22 (d, J = 8.7 Hz, 2H), 5.68 (s, 2H), 7.24 - 6.99 (m, 2H), 7.36 (s, 1 H), 8.07 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 391 ; RT = 0.79 min.

Step 9: Rac-3-chloro-2-(2-fluorobenzyl)-6-((1 S,2R,5R,6S)-2-(hydroxymethyl)-3- oxabicyclo[3.1 ,0]hexan-6-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (100 mg, 0.26 mmol) was added to BAST (94 pl, 0.51 mmol) in DCM (3 mL) at 25°C under N2. The resulting mixture was stirred at -40 °C for 16 h. The reaction mixture was quenched with saturated NaHCOs (100 mL), extracted with DCM (3 x 50 mL), the combined organic layers were dried over Na2SC , filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC( Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCO3+O.I % NH3.H2O), Mobile Phase B: MeOH; Flow rate:60 mL/min; Gradient: 41 % B to 71 % B in 8 min; 254-220 nm; RT1 (min): 7.37. Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2-fluorobenzyl) -6-((1 S,2R,5R,6S)-2-(fluoromethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2,6- dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.058 g, 57.7 %) as a pale yellow solid. ¹H-NMR (300 MHz, CDCI3) 6 2.25 (dd, J = 7.6, 2.5 Hz, 1 H), 2.38 (dt, J = 7.8, 3.0 Hz, 1 H), 3.79 (t, J = 2.6 Hz, 1 H), 4.04 (ddd, J = 8.3, 3.5, 1.8 Hz, 1 H), 4.14 (d, J = 8.4 Hz, 1 H), 4.60 - 4.32 (m, 3H), 5.67 (s, 2H), 7.16 - 7.02 (m, 2H), 7.23 - 7.15 (m, 1 H), 7.37 - 7.29 (m, 1 H), 7.99 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 393; RT = 1 .66 min Step 10: The crude product was purified by preparative chiral HPLC (Column: CHIRALPAK IG-3, 4.6 x 50mm, 3 urn; Mobile Phase A: (Hexane : DCM =3:1)(0.1 % DEA): EtOH= 50:50). Fractions containing the desired compound (the first fraction) were evaporated to dryness to afford 3-chloro-2- (2-fluorobenzyl) -6-((1 R,2S,5S,6R)-2-(fluoromethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one (0.019 g, 39.0 %) as a pale yellow solid. ¹H-NMR (300 MHz, CDCI3) 6 2.25 (dd, J = 7.7, 2.5 Hz, 1 H), 2.42 - 2.29 (m, 1 H), 3.79 (t, J = 2.6 Hz, 1 H), 4.05 (d, J = 5.6 Hz, 1 H), 4.14 (d, J = 8.5 Hz, 1 H), 4.41 (d, J = 23.1 Hz, 2H), 4.53 (d, J = 4.0 Hz, 1 H), 5.67 (s, 2H), 7.14 - 7.03 (m, 2H), 7.22 (d, J = 7.3 Hz, 1 H), 7.37 - 7.29 (m, 1 H), 7.99 (s, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 393; RT = 1 .68 min; e.e=99.5%. Absolute configuration arbitrarily assigned.

Example 54: 3-Chloro-6-((1 R,2S,5S,6R)-2-(difluoromethyl)-3-oxabicyclo[3.1 .0]hexan-6- yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : Rac-3-chloro-2-(2-fluorobenzyl)-6-((1 R,2S,5S,6R)-2-(hydroxymethyl)-3- oxabicyclo[3.1 ,0]hexan-6-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (300 mg, 0.77 mmol) was added to DMP (326 mg, 0.77 mmol) in DCM (5 mL) at 25°C under N2. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with saturated NaHCOs (5 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated and the crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford rac- (1 R,2R,5S,6R)-6-(3-chloro-2-(2-fluorobenzyl)- 7-oxo-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)-3- oxabicyclo[3.1 ,0]hexane-2-carbaldehyde (0.100 g, 33.5 %) as a white solid. ¹H-NMR (300 MHz, CDCh) 6 2.68 - 2.44 (m, 2H), 3.93 - 3.76 (m, 2H), 4.35 - 4.17 (m, 2H), 5.43 (t, J = 3.6 Hz, 1 H), 5.69 (s, 2H), 7.18 - 7.04 (m, 2H), 7.24 (d, J = 7.4 Hz, 1 H), 7.42 - 7.29 (m, 1 H), 8.00 (d, J = 1 .3 Hz, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 389; RT = 0.84 min.

Step 2: Rac-(1 R,2R,5S,6R)-6-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4- d]pyridazin-6-yl)-3-oxabicyclo[3.1 ,0]hexane-2-carbaldehyde (50 mg, 0.12 mmol) was added to BAST (136 pl, 0.74 mmol) in DCM (1 mL) at 25°C under N2. The resulting mixture was stirred at -40 °C for 2 h and left to reach rt. The reaction mixture was quenched with saturated NaHCOs (50 mL), extracted with DCM (3 x 50 mL), and the combined organic layers were dried over Na2SC , filtered and evaporated to afford a crude product that was purified by preparative HPLC (Column: YMC-Actus Triart C18 ExRS, 30 mm x 150 mm, 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCC>3+0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate:60 mL/min; Gradient: 37% B to 70% B in 7 min; K 254/220 nm; RT1 :6.88 min). Fractions containing the desired compound were evaporated to dryness to afford racemate (0.025 g, 49.5 %) as a yellow solid. The racemate was purified by preparative chiral separation (Column: CHIRALPAK IG, 2 x 25 cm, 5 urn; Mobile Phase A: Hex:DCM=3:1 (0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate:18 mL/min; Isocratic conditions: 50% B in 16.5 min; 254/220 nm; RT1 (min):10.691 ; RT2 (min):12.895. First eluting peak was collected and evaporated to afford 3-chloro-6-((1 S,2R,5R,6S) -2-(difluoromethyl)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2- (2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one as a white solid. ¹H-NMR (300 MHz, CDCh) 6 2.51 - 2.38 (m, 2H), 3.87 (t, J = 2.7 Hz, 1 H), 4.24 - 4.06 (m, 2H), 4.35 (ddd, J = 17.7, 8.2, 2.8 Hz, 1 H), 5.99 - 5.55 (m, 3H), 7.18 - 7.05 (m, 2H), 7.24 (dd, J = 7.4, 1.8 Hz, 1 H), 7.35 (tdd, J = 7.5, 5.3, 1.9 Hz, 1 H), 8.02 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 411 ; RT = 1.765 min; e.e= 99%. Absolute configuration arbitrarily assigned.

Example 55: 6-((1S,5R,6r)-3-oxa-bicyclo[3.1.0]hexan-6-yl)-3-(difluoromethyl)-2-(2- fluorobenzyl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one

Step 1 : PCy3-HBF4 (11.22 mg, 0.03 mmol) was added to 6-((1 R,5S,6r)-3- oxabicyclo[3.1 ,0]hexan-6-yl)- 3-chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7- one (110 mg, 0.30 mmol), 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (94 mg, 0.61 mmol), potassium phosphate (129 mg, 0.61 mmol) and PCy3 Palladacycle Gen. 3 (19.82 mg, 0.03 mmol) in 1 ,4-dioxane (2 mL) and water (0.4 mL) at 20°C under N2. The resulting mixture was stirred at 90 °C for 4 h. The reaction mixture was concentrated and purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 6- ((1 R,5S,6r)-3- oxabicyclo[3.1 ,0]hexan-6-yl)-2-(2-fluorobenzyl)-3-vinyl-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one (0.083 g, 77 %) as a yellow solid. ¹H-NMR (300 MHz, CDCh) 6 0.85 - 1 .01 (m, 1 H), 1 .24 - 1 .32 (m, 3H), 2.06 (s, 1 H), 2.26 - 2.33 (m, 2H), 3.76 - 3.90 (m, 3H), 4.18 (d, J = 8.5 Hz, 2H), 5.66 (s, 2H), 5.72 (d, J = 11.5 Hz, 1 H), 5.93 (d, J = 17.6 Hz, 1 H), 6.82 (dd, J = 17.6, 11.5 Hz, 1 H), 7.06 - 7.19 (m, 3H), 8.17 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 353; RT = 1.26 min.

Step 2: AD-mix (199 mg, 0.26 mmol) was added to 6-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6- yl)-2- (2-fluorobenzyl)-3-vinyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (60 mg, 0.17 mmol) in Tert-butanol (4.5 mL) and water(1 .5 mL) at 25°C under N2. The resulting mixture was stirred at 50 °C for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated to afford a crude product that was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3-(1 ,2- dihydroxyethyl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.040 g, 60.8 %) as a white solid. Sodium periodate (44.3 mg, 0.21 mmol) was added to above obtained intermediate (40 mg, 0.10 mmol) in THF (1 mL) and water(1 mL) at 25°C under N2. The resulting mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford 30 mg solid that was used directly.

6-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2-(2-fluorobenzyl)-7-oxo-6,7-dihydro-2H- pyrazolo[3,4-d]pyridazine-3-carbaldehyde (30 mg, 0.08 mmol) was added to BAST (46.8 pl, 0.25 mmol) in DCM (2 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated NaHCOs (20 mL), extracted with DCM (3 x 20 mL) and the combined organic layers were dried over Na2SC>4, filtered and evaporated to afford yellow oil. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30 x150 mm, 5 urn ; Mobile Phase A: Water (10 mmol/L NH4HCC>3+0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate:60 mL/min; Gradient: 36% B to 48% B in 7 min; A 254/220 nm; RT1 (min): 6.47. Fractions containing the desired compound were evaporated to dryness to afford 6-((1 R,5S,6r)-3- oxabicyclo[3.1 .0] hexan-6-yl)-3-(difluoromethyl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one (8.00 mg, 25.1 %) as a white solid. ¹H-NMR (400 MHz, CDCI3) 6 2.24 - 2.34 (m, 2H), 3.78 (t, J = 2.6 Hz, 1 H), 3.82 - 3.92 (m, J = 8.2, Hz, 2H), 4.18 (d, J = 8.6 Hz, 2H), 5.72 (s, 2H), 7.00 (s, 1 H), 7.08 - 7.20 (m, 2H), 7.29 - 7.43 (m, 2H), 8.18 (t, J = 1 .0 Hz, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 377; RT = 1 .72 min.

Example 56: 6-((1S,5R,6r)-3-oxa-bicyclo[3.1.0]hexan-6-yl)-2-(2-fluorobenzyl)-3- (fluoromethyl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one

Step 1 : 6-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3-chloro-2-(2-fluorobenzyl)-2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one (300 mg, 0.83 mmol) was added to (tributylstannyl)methanol (534 mg, 1 .66 mmol), zinc(ll) chloride (113 mg, 0.83 mmol) and XPhos Pd G3 (70.3 mg, 0.08 mmol) and XPhos (39.6 mg, 0.08 mmol) in DMF (3 mL) at 25°C under N2. The resulting mixture was stirred at 90 °C for 3 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were washed sequentially with water and brine, dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 40% water (0.1 % NH4HCO3) in CH3CN. Pure fractions were evaporated to dryness to afford 6-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-2-(2-fluorobenzyl)-3- (hydroxy methyl)- 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.090 g, 30.4 %) as a white solid. ¹H-NMR (300 MHz, CDCI3) 6 2.28 (s, 2H), 3.75 (s, 1 H), 3.85 (d, J = 8.5 Hz, 2H), 4.17 (d, J = 8.5 Hz, 2H), 4.96 (s, 2H), 5.64 (d, J = 4.0 Hz, 1 H), 5.71 (s, 2H), 7.10 (t, J = 8.2 Hz, 2H), 7.18 (d, J = 9.7 Hz, 1 H), 7.33 - 7.45 (m, 1 H), 8.14 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 357; RT = 0.73 min

Step 2: BAST (140 pl, 0.76 mmol) was added to 6-((1 R,5S,6r)-3-oxabicyclo [3.1 ,0]hexan-6- yl)-2-(2-fluorobenzyl)-3-(hydroxymethyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (90 mg, 0.25 mmol) in DCM (1 mL) at 0°C under N2. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with saturated NaHCOs (50 mL), extracted with DCM (3 x 50 mL), and washed sequentially with water and brine. The combined organic layers were dried over Na2SC , filtered and evaporated to afford a crude product that was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCC>3+0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate:60 mL/min; Gradient: 28% B to 48% B in 7 min; 254/220 nm; RT1 (min): 6.87. Fractions containing the desired compound were evaporated to dryness to afford 6-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2-(2-fluorobenzyl)-3-(fluoromethyl) -2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one (0.011 g, 12.15 %) as a white solid. ¹H-NMR (300 MHz, CDCI3) 6 2.23 - 2.31 (m, 2H), 3.76 (t, J = 2.6 Hz, 1 H), 3.84 (d, J = 8.5 Hz, 2H), 4.16 (d, J = 8.6 Hz, 2H), 5.55 (s, 1 H), 5.70 (d, J = 4.3 Hz, 3H), 7.03 - 7.17 (m, 2H), 7.26 - 7.40 (m, 2H), 8.08 (d, J = 0.6 Hz, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 359; RT = 1 .21 min.

Example 57: 3-Chloro-2-(2-fluorobenzyl)-6-((1 R,2S)-2-methoxycyclopropyl)-2,6-dihydro- 7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : ((Vinyloxy)methyl)benzene (9 g, 67.08 mmol) and rhodium(ll) acetate dimer (0.296 g, 0.67 mmol) in DCM (90 mL) at ambient temperature was treated with ethyl 2-diazoacetate (8.42 g, 73.78 mmol) in DCM (40 mL) in 4 mL portions over 1 h. The resulting green solution was stirred at rt for 8 h. The solvent was removed under reduced pressure and the residue poured into water (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ethyl 2- (benzyloxy)cyclopropane-l -carboxylate (10.90 g, 73.8 %) as a colourless oil. ¹H-NMR (300 MHz, CDCI3) 6 0.93 - 1.26 (m, 5H), 1.48 - 1.77 (m, 1 H), 3.43 - 3.68 (m, 1 H), 4.00-4.1 (dq, J = 7.1 , 16.2 Hz, 2H), 4.44 (d, J = 22.9 Hz, 2H), 7.19 - 7.28 (m, 5H).

Step 2: LiOH (2.72 g, 113.50 mmol) was added to ethyl 2-(benzyloxy)cyclopropane-1- carboxylate (5 g, 22.70 mmol) in MeOH (40 mL) and water (16 mL) at 0°C under N2. The resulting mixture was stirred at rt for 5 h. The solvent was removed under reduced pressure and the residue was poured into water (50 mL), acidified with 2M HCI and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated to afford 2- (benzyloxy)cyclopropane-l -carboxylic acid (5.20 g) as a yellow crude oil. ¹H-NMR (300 MHz, CDCh) 6 1.13 - 1.46 (m, 2H), 1.60 - 1.88 (m, 1 H), 3.65 - 3.80 (m, 1 H), 4.58 (d, J = 11.4 Hz, 2H), 7.25 - 7.42 (m, 5H), 10.30 (s, 1 H).

Step 3: Diphenylphosphinyl azide (9.87 g, 40.58 mmol) was added to 2- (benzyloxy)cyclopropane-l -carboxylic acid (5.2 g, 27.05 mmol) and TEA (5.66 ml, 40.58 mmol) in tBuOH (52 mL) at 25°C under N2. The resulting mixture was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the residue was poured into water (75 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford Te/Y-butyl (2- (benzyloxy)cyclopropyl)carbamate (5.18 g, 72.7 %) as a pale yellow oil. ¹H-NMR (300 MHz, CDCh) 6 0.7- 0.85(m, 1 H), 1.06 - 1.19 (m, 1 H), 1 .46 (d, J = 2.0 Hz, 9H), 2.62 - 2.76 (m, 1 H), 3.25 - 3.39 (m, 1 H), 4.58 - 4.72 (m, 2H), 7.30 - 7.38 (m, 5H) (one exchangeable proton not seen).

Step 4: Pd-C (8.08 g, 7.59 mmol) was added to rac-tert-buty\ 2- (benzyloxy)cyclopropyl)carbamate (4 g, 15.19 mmol) in MeOH (150 mL) at 25°C under N2. The mixture was stirred 16 h at rt under hydrogen. The reaction mixture was filtered through celite, washed with MeOH (100 mL) and dried under vacuum to afford tert-butyl ((1 R,2S)-2- hydroxycyclopropyl)carbamate (2.4 g, 91 %) as a yellow oil, which was used without further purification. ¹H-NMR (300 MHz, CDCh) 6 0.54 - 0.86 (m, 1 H), 0.88 - 1.18 (m, 1 H), 1.30 - 1.38 (m, 9H), 2.02 - 2.69 (m, 1 H), 3.12 - 3.35 (m, 1 H), two exchangeable protons not seen.

Step 5: lodomethane (1.532 g, 10.80 mmol) and CS2CO3 (7.04 g, 21.59 mmol) was added to tert-butyl-2-hydroxycyclopropyl)carbamate (1.87 g, 10.80 mmol) in DMF (15 mL) at rt. The resulting mixture was stirred at rt for 16 h. The reaction mixture was poured into water (20 mL), extracted with DCM (3 x 5 mL), and washed sequentially with water (2 x 10 mL) and brine (2 x 10 mL). The combined organic layers were dried over Na2SC>4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl-2- methoxycyclopropyl)carbamate (0.706 g, 34.9 %) as a colourless oil. ¹H-NMR (300 MHz, CDCh) 6 0.67 - 0.80 (m, 1 H), 0.96 - 1 .09 (m, 1 H), 1 .45 (d, J = 2.4 Hz, 9H), 2.52 - 2.62 (m, 1 H), 3.13 - 3.25 (m, 1 H), 3.44 (s, 3H) one exchangeable protons not seen; LCMS (method 1) m/z (ES+), [M-tBu]⁺ = 132; RT = 0.54 min.

Step 6: Dimethyl sulfide (948 pl, 12.82 mmol) in CH3CN (12 mL) was added to tert-butyl -2- methoxycyclopropyl)carbamate (600 mg, 3.20 mmol) and pyridine (1037 pl, 12.82 mmol) at 25°C under N2. ammoniaylidyneoxonium tetrafluoroborate (1497 mg, 12.82 mmol) was added portionwised after the reaction was stirred at 0 °C for 3 h. The solution was poured onto cold water and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SCU, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford te/Y-butyl-2- methoxycyclopropyl)(nitroso) carbamate (0.457 g, 66.0 %) as a pale yellow oil as isomer 1. ¹H-NMR (300 MHz, CDCb) 6 0.82 - 0.90 (m, 1 H), 1 .36 - 1 .43 (m, 1 H), 1 .64 (s, 9H), 2.40 (ddd, J = 1 .8, 5.2, 8.8 Hz, 1 H), 3.13 (ddd, J = 1.8, 4.4, 7.3 Hz, 1 H), 3.54 (s, 3H). Elution gradient 8 to 12% EtOAc in petroleum ether was as used to purify isomer 2. Pure fractions were evaporated to dryness to afford te/Y-butyl-2-methoxycyclopropyl) (nitroso)carbamate (0.091 g, 13.13 %) (isomer 2) as a yellow oil.

Step 7: Zinc (605 mg, 9.25 mmol) was added in batches to isomer 1 above and 5-chloro-1-(2- fluorobenzyl)-4-formyl-1 H-pyrazole-3-carboxylate (575 mg, 1 .85 mmol) AcOH (2.1 ml, 37.0 mmol) and DCM (10 mL) at 0°C under N2. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was filtered with celite and was poured into ammonium hydroxide (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SC , filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 50 to 70% CH3CN in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford ethyl 4-((E)-(2-(te/Y- butoxycarbonyl)-2-(2-methoxycyclopropyl)hydrazineylidene)methyl)-5-chloro-1-(2-fluorobenzyl)-1 H- pyrazole-3-carboxylate (0.630 g, 68.8 %) as a pale yellow oil. ¹H-NMR (300 MHz, CDCI3) 6 0.89 - 1 .02 (m, 1 H), 1 .45 (t, J = 7.1 Hz, 3H), 1 .43 - 1 .52 (m, 1 H), 1 .57 (s, 9H), 2.62 - 2.73 (m, 1 H), 3.53 (s, 3H), 3.53 - 3.57 (m, 1 H), 4.48 (qd, J = 2.1 , 7.1 Hz, 2H), 5.57 (s, 2H), 6.94 - 7.03 (m, 1 H), 7.05 - 7.14 (m, 2H), 7.29 - 7.35 (m, 1 H), 8.71 (s, 1 H); LCMS (method 2) m/z (ES+), [M+H]⁺ = 495; RT = 0.75 min.

Step 8: 4N HCI in EtOH (4 mL, 16.00 mmol) was added to ethyl 4-((E)-(2-(7ert- butoxycarbonyl)-2-((1 R,2S)-2 -methoxycyclopropyl)hydrazineylidene)methyl)-5-chloro-1-(2- fluorobenzyl)-1 H-pyrazole-3-carboxylate (600 mg, 1.21 mmol) at rt. The resulting mixture was stirred at 80 °C for 2 h. The solvent was removed by distillation under vacuum. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO₃+0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; : 254; 220 nm; RT1 (min): 7.57;. Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2- fluorobenzyl)-6-(2-methoxycyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4-d] pyridazin-7-one (0.217 g, 51 .3 %) as a colourless oil.

The racemate (210 mg) was purified by preparative chiral-HPLC (Column: CHIRALPAK ID, 2 x 25 cm, 5 pm; Mobile Phase A: Hex: DCM=3: 1 (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 18 mL/min; Isocratic conditions: 50% B in 21 min; : 254/220 nm; RT1 (min): 7.87; RT2(min): 16.04. The second fraction containing the desired compound were evaporated to dryness to afford 3- chloro-2-(2-fluorobenzyl)-6-((1 R,2S)-2-methoxycyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin- 7-one (0.060 g, 28.6 %) as a white solid ¹H-NMR (300 MHz, CDCb) 6 1 .23 - 1 .47 (m, 2H), 3.44 (s, 3H), 3.40 - 3.50 (m, 1 H), 3.84 (ddd, J = 1 .7, 5.2, 9.1 Hz, 1 H), 5.55 (s, 2H), 6.92 - 7.06 (m, 2H), 7.08 - 7.20 (m, 1 H), 7.15 - 7.29 (m, 1 H), 7.86 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 349; RT = 1 .65 min, e.e= 100%. Absolute configuration arbitrarily assigned.

Example 58: 3-Chloro-2-(2-fluorobenzyl)-6-((1 R,5S,6R)-1 -methyl-3- oxabicyclo[3.1.0]hexan-6-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one

Step 1 : In a 3-neck flask were added 2-methoxy-2-methylpropane (0.886 ml, 7.44 mmol) and DCM (5.2 mL). The reaction was cooled at -40 °C and diethylzinc (7.44 ml, 7.44 mmol) was carefully added dropwise under Ar. Then freshly distilled 2,2,2-trifluoroacetic acid (0.552 ml, 7.44 mmol) was carefully added dropwise (gas evolution) under Ar. The reaction was stirred at -40 °C for 15 min. In another 3-neck flask was added 2-(diiodomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.79 g, 7.08 mmol) in DCM (3.54 mL) under Ar and cooled at -40 °C. The freshly made EtZnC>2CCF3 (1 M solution) (14 mL, 2.1 eq) was added via a syringe dropwise into the previous mixture. The reaction was stirred for 30 min at -40 °C. Then a solution of (E)-(((2-methylbut-2-ene-1 ,4- diyl)bis(oxy))bis(methylene))dibenzene (1 g, 3.54 mmol) in DCM (3.54 mL) under Ar was added dropwise and the reaction was stirred and let slowly warm to room temperature for 20 h. The reaction mixture was quenched with saturated NH4CI (20 mL) and water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SC , filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 5 to 100% water (0.01 % FA) in CH3CN. Pure fractions were evaporated to dryness to afford rac-2-((2R,3S)-2,3- bis((benzyloxy)methyl)-2-methylcyclopropyl) -4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (0.480 g, 32.1 %) as a colourless oil. ¹H NMR (300 MHz, CDCI3) 6 -0.11 (d, J = 6.8 Hz, 1 H), 1.19 - 1.31 (m, 15H), 1.40 (q, J = 7.0 Hz, 1 H), 3.35 (d, J = 10.1 Hz, 1 H), 3.47 - 3.56 (m, 3H), 4.48 - 4.56 (m, 4H), 7.33 (m, 10H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 423; RT = 1.46 min.

Step 2: Pd-C (20.2 mg, 0.02 mmol) was added to rac-2-((2R,3S)-2,3-bis((benzyloxy)methyl)-

2-methyl cyclopropyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (400mg, 0.95 mmol) in MeOH (10 mL) at 25°C under H2. The resulting mixture was stirred at 25 °C for 1 h. The mixture was filtered through a Celite pad. The solvent was removed under reduced pressure and afforded rac-((1 R,2S)-1-methyl-

3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclopropane-1 ,2-diyl)dimethanol(0.230 g, 100 %) as a colourless oil . 1 H NMR (300 MHz, CDCh) 6 -0.14 (dd, J = 6.5, 3.0 Hz, 1 H), 1 .25 (dd, J = 5.0, 3.8 Hz, 12H), 1.32 (d, J = 3.0 Hz, 3H), 1.37 - 1 .44 (m, 1 H), 3.21 - 3.40 (m, 2H), 3.50 (d, J = 2.9 Hz, 1 H), 3.84 - 3.91 (m, 1 H), 4.07 - 4.15 (m, 1 H). Step 3: DIAD (217 pl, 1 .12 mmol) was added to triphenylphosphane (292 mg, 1.12 mmol) and rac-((1 R,2S)-1-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclopropane-1 ,2- diyl)dimethanol (180 mg, 0.74 mmol) in THF (3 mL) at 0°C under N2. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2 x 25 mL), the organic layer was dried over Na2SC , filtered and evaporated to afford residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford rac-4,4,5,5-tetramethyl-2-((1 R,5S)-1- methyl-3-oxa bicyclo[3.1 ,0]hexan-6-yl)-1 ,3,2-dioxaborolane (70 mg, 42.0 %) as a colourless oil. 1 H- NMR (300 MHz, CDCh) 6 0.07 (d, J = 5.0 Hz, 1 H), 0.85 - 0.93 (m, 1 H), 1 .26 (t, J = 3.5 Hz, 12H), 1.35 (d, J = 3.1 Hz, 3H), 1 .54 (dt, J = 5.2, 2.5 Hz, 1 H), 3.50 (dd, J = 8.1 , 3.1 Hz, 1 H), 3.71 - 3.83 (m, 3H).

Step 4: HCI (109 pl, 0.22 mmol) was added to sodium meta periodate (200 mg, 0.94 mmol) and 4,4,5,5-tetramethyl-2-(1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-1 ,3,2-dioxaborolane (70mg, 0.31 mmol) in THF (2 mL)/water (0.5 mL) at 25°C under hydrogen. The resulting mixture was stirred at 25 °C for 4 h, quenched with water (10 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford rac-((1 R,5S)-1-methyl-3- oxabicyclo[3.1 ,0]hexan-6-yl) boronic acid (40 mg, 90 %) as a colourless oil. ¹H NMR (300 MHz, CDCh) 6 0.17 (d, J = 4.8 Hz, 1 H), 1.39 (q, J = 4.3, 3.6 Hz, 3H), 1.68 (dt, J = 10.0, 4.9 Hz, 1 H), 3.54 (dd, J = 8.2, 3.0 Hz, 1 H), 3.73 - 3.86 (m, 3H).

Step 5: Pyridine (334 mg, 4.23 mmol) was added to Copper(ll) acetate (256 mg, 1.41 mmol), CS2CO3 (459 mg, 1.41 mmol) , 3-chloro-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7- one (393 mg, 1.41 mmol) and rac-((1 R,5S)-1-methyl-3-oxabicyclo[3.1.0]hexan-6-yl)boronic acid (200 mg, 1 .41 mmol) in toluene (4 mL) at 25°C. The resulting mixture was stirred at 110 °C for 16 h. The reaction mixture was quenched with saturated NH4CI (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Column: YMC-Actus Triart C18 ExRS, 30 mm x 150 mm, 5um; Mobile Phase A: Water (10 mmol/L NH4HCO₃+0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient:36% B to 66% B in 7 min; 254/220 nm; RT1 (min):6.42. Fractions containing the desired compound were evaporated to dryness to afford rac-3-chloro-2-(2-fluorobenzyl)- 6- ((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (0.080 g, 15.15 %) as a white solid. The racemate was purified by preparative chiral-HPLC on a Chiralpak ID-2, 2 x 25cm, 5 urn; Mobile Phase A: MTBE (0.5% 2M NH3-MeOH), Mobile Phase B:IPA; Flow rate:15 mL/min; Isocratic conditions:50% B in 14 min; 254/220 nm; RT1 (min): 8.305; RT2 (min): 10.61 . The fractions containing the desired compound were evaporated to dryness to afford 3- chloro-2-(2-fluorobenzyl)-6-((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-2,6-dihydro-7H- pyrazolo[3,4-d]pyridazin-7-one (0.033 g, 47.6 %) as a white solid. ¹H NMR (300 MHz, CDCI3) 6 1.11 (s, 3H), 2.35 (t, J = 3.0 Hz, 1 H), 3.59 (d, J = 2.8 Hz, 1 H), 3.68 (d, J = 8.3 Hz, 1 H), 3.91 - 4.01 (m, 1 H), 4.10 (d, J = 8.5 Hz, 1 H), 4.18 (d, J = 8.3 Hz, 1 H), 5.68 (s, 2H), 7.06 - 7.19 (m, 2H), 7.29 - 7.39 (m, 2H), 8.03 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 375; RT = 1 .68 min; ee= 99.9%. Absolute configuration arbitrarily assigned. General route 7

Example 59: 6-(2,6-Difluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3H-pyrazolo[4,3- d][1 ,2,3]triazin-4(6H)-one

Step 1 : HATU (330 mg, 0.87 mmol) was added to 4-amino-1-(2,6-difluorobenzyl)-1 H- pyrazole-3-carboxylic acid (200 mg, 0.79 mmol) and DIEA (414 pl, 2.37 mmol) in DMF (2 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 15 min. Tetrahydro-2H-pyran-4-amine (96 mg, 0.95 mmol) was added to above mixture at rt and the resulting mixture was stirred at rt for 1 h. The reaction mixture was evaporated and purified by C18-flash chromatography, elution gradient 50 to 60% MeOH in water (0.1 % NH4HCO3). Pure fractions were evaporated to dryness to afford 4-amino- 1- (2,6-difluorobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazole-3-carboxamide (0.227 g, 85 %) as a white solid. ¹H-NMR (400 MHz, CDCI3) 6 1 .55 - 1 .69 (m, 2H), 1 .93 - 2.01 (m, 2H), 3.48 - 3.59 (m, 3H), 3.97 - 4.05 (m, 2H), 4.07 - 4.22 (m, 1 H), 5.28 (d, J = 1 .3 Hz, 2H), 6.63 (d, J = 8.3 Hz, 1 H), 6.92 - 7.02 (m, 2H), 7.06 (s, 1 H), 7.30 - 7.41 (m, 1 H).LCMS (method 3) m/z (ES+), [M+H]⁺ = 337; RT = 0.71 min.

Step 2: Sodium nitrite (85 mg, 1.23 mmol) was added to 4-amino-1-(2,6-difluorobenzyl) -N- (tetrahydro-2H-pyran-4-yl)-1 H-pyrazole-3-carboxamide (207 mg, 0.62 mmol) in 2N HCI (3 mL) at rt. The resulting mixture was stirred at rt for 30 min. The reaction mixture was adjusted to pH 7-8 with saturated NaHCOs. The precipitate was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 6-(2,6-difluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo [4,3-d][1 ,2,3]triazin-4-one (0.123 g, 57.5 %) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) 6 1 .79 - 1.88 (m, 2H), 2.01 - 2.16 (m, 2H), 3.46 - 3.57 (m, 2H), 4.00 (dd, J = 4.4, 11.3 Hz, 2H), 5.06 - 5.19 (m, 1 H), 5.77 (s, 2H), 7.20 (t, J = 8.1 Hz, 2H), 7.47 - 7.59 (m, 1 H), 9.23 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 348; RT = 0.97 min.

The following compounds were made through the method described above.

General route 8

Example 111 : 3-((1S,5R,6r)-3-oxa-bicyclo[3.1.0]hexan-6-yl)-6-(2-fluorobenzyl)-7- (fluoromethyl)-3H-pyrazolo[4,3-d][1 ,2,3]triazin-4(6H)-one

Step 1 : Pd(Ph3P)4 (1 .761 g, 1 .52 mmol) was added to methyl 4-amino-5-bromo-1-(2- fluorobenzyl) -1 H-pyrazole-3-carboxylate (2.5 g, 7.62 mmol), 4, 4, 5, 5- tetramethyl-2-vinyl-1 ,3,2- dioxaborolane (2.35 g, 15.24 mmol) and CS2CO3 (7.45 g, 22.86 mmol) in 1 ,4-dioxane (25 mL) and water (5 mL) at rt under N2. The resulting mixture was stirred at 90 °C for 3 h, evaporated to dryness and the crude product purified by flash silica chromatography, elution gradient 5 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 4-amino -1-(2- fluorobenzyl)-5-vinyl -1 H-pyrazole-3-carboxylate (1 .6 g, 76 %) as a light yellow oil. ¹H-NMR (300 MHz, CDCI3) 6 3.93 (s, 3H), 5.34 - 5.53 (m, 4H), 6.45-6.54 (m, 1 H), 6.81 - 6.93 (m, 1 H), 6.98 - 7.11 (m, 2H), 7.18 - 7.28 (m, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 276; RT = 1 .32 min.

Step 2: LiOH (0.639 g, 26.70 mmol) was added to methyl 4-amino-1-(2-fluorobenzyl)-5-vinyl- 1 H-pyrazole -3-carboxylate (1 .47 g, 5.34 mmol) in THF (30 mL), water (15 mL) at rt. The resulting mixture was stirred at 25 °C overnight. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and adjusted to pH 5-6 with 2M HCI. The solid was collected by filtered and dried in an oven to afford 4-amino-1-(2-fluorobenzyl)-5-vinyl-1 H-pyrazole-3-carboxylic acid (1 .27 g, 91 %) as a white solid. LCMS (method 2) m/z (ES+), [M+H]⁺ = 262; RT = 1 .11 min.

Step 3: DIEA (2.487 ml, 14.24 mmol) was added to a solution of 4-amino- 1-(2-fluorobenzyl)- 5-vinyl-1 H-pyrazole-3-carboxylic acid (1.24 g, 4.75 mmol) and HATU (1.805 g, 4.75 mmol) in DMF (15 mL) at 20 °C. The resulting mixture was stirred at 25 °C for 10 min. (1 R,5S,6r)-3- oxabicyclo[3.1 ,0]hexan-6-amine hydrochloride (0.644 g, 4.75 mmol) was added to the reaction mixture that was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (60 mL), extracted with EtOAc (3 x 50 mL) and washed sequentially with brine (50 mL). The combined organic layers were dried over Na2SC , filtered and evaporated to afford a white solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-amino-N-((1 R,5S,6r) -3-oxabicyclo[3.1 ,0]hexan-6-yl)- 1-(2-fluorobenzyl)-5-vinyl-1 H-pyrazole-3-carboxamide (1 .26 g, 78 %) as a white solid. ¹H-NMR (300 MHz, CDCb) 6 1.85 - 1 .95 (m, 2H), 2.95 (s, 1 H), 3.77 (t, J = 11 .8 Hz, 4H), 4.00 - 4.18 (m, 2H), 5.30 (s, 2H), 5.37 (dd, J = 11.8, 0.9 Hz, 1 H), 5.50 (dd, J = 17.8, 0.9 Hz, 1 H), 6.50 (dd, J = 17.7, 11.8 Hz, 1 H), 6.72 - 6.87 (m, 2H), 7.07 (ddt, J = 11.8, 7.5, 1.4 Hz, 2H), 7.20 - 7.34 (m, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 343; RT = 1.11 min.

Step 4: 4-Amino-N-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-1-(2-fluorobenzyl)-5-vinyl-1 H- pyrazole-3-carboxamide (1 .26 g, 3.68 mmol) was added to sodium nitrite (0.508 g, 7.36 mmol) in HCI (2N) (15 mL) at 25°C and the resulting mixture was stirred at r.t for 15 min. The reaction mixture was quenched with saturated NaHCO3 (80 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford a white solid. The crude product was purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 3-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6- yl)-6-(2-fluorobenzyl) -7-vinyl-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.580 g, 44.6 %) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 2.38-2.45 (m, 2H), 3.43 (t, J = 2.6 Hz, 1 H), 3.75 (d, J = 8.6 Hz, 2H), 4.02 (d, J = 8.6 Hz, 2H), 5.82 (s, 2H), 5.92 (dd, J = 11.6, 1.5 Hz, 1 H), 6.72 (dd, J = 17.4, 1 .5 Hz, 1 H), 7.04 - 7.27 (m, 4H), 7.22 - 7.33 (m, 1 H), 7.40 (dd, J = 8.3, 4.8 Hz, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 354; RT = 1.14 min.

Step 5: Potassium osmate dihydrate (10.43 mg, 0.03 mmol) was added to 3-(3-oxabicyclo [3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-vinyl-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (500 mg, 1 .41 mmol), citric acid (544 mg, 2.83 mmol) and NMO (182 mg, 1 .56 mmol) in water (5 mL) and t- BuOH (5 mL). The resulting solution was stirred at 25 °C for 1 h, heated to 50 °C and stirred for 1 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3 x 50 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford 3-(3-oxabicyclo[3.1 .0] hexan-6-yl)-7- (1 ,2-dihydroxyethyl)-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.540 g, 99 %) as a pale yellow solid. ¹H NMR (300 MHz, CDCb) 6 2.42 (s, 2H), 3.41 (d, J = 9.7 Hz, 1 H), 3.73 (s, 1 H), 3.89 (d, J = 8.7 Hz, 2H), 3.99 - 4.27 (m, 4H), 4.43 (d, J = 12.0 Hz, 1 H), 5.05 (s, 1 H), 5.80- 5.85 (m, 2H), 7.13 (d, J = 9.2 Hz, 2H), 7.28 (d, J = 1.6 Hz, 2H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 388; RT = 0.71 min.

Step 6: Sodium periodate (596 mg, 2.79 mmol) was added to 3-((1 R,5S,6r)-3-oxabicyclo [3.1 ,0]hexan-6-yl)-7-(1 ,2-dihydroxyethyl)-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one (540 mg, 1 .39 mmol) in THF (8 mL) and water (8 mL) at 25°C under N2. The resulting mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 3-((1 R,5S,6r)-3- oxabicyclo [3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-4-oxo-4,6-dihydro-3H-pyrazolo[4,3-d][1 ,2,3]triazine-7- carbaldehyde (0.49 g, 99 %) as a white solid. ¹H NMR (300 MHz, CDCh) 6 1 .27 (s, 2H), 2.45 (dd, J = 3.4, 1 .9 Hz, 2H), 3.74 - 3.94 (m, 3H), 4.24 (dd, J = 8.7, 2.8 Hz, 2H), 6.10 (d, J = 2.7 Hz, 2H), 7.04 - 7.44 (m, 5H), 10.50 (d, J = 2.7 Hz, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 365; RT = 0.84 min.

Step 7: 3-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-6-(2-fluorobenzyl)-4-oxo-4,6-dihydro-3H- pyrazolo[4,3-d][1 ,2,3]triazine-7-carbaldehyde (490 mg, 1.38 mmol) was added to NaBH4 (78 mg, 2.07 mmol) in THF (20 mL)/water (0.5 mL) at 25°C under N2. The resulting mixture was stirred at rt for 10 min. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (3 x 50 mL) and the combined layers were dried over Na2SO4, filtered and evaporated to afford 3-((1 R,5S,6r)-3- oxabicyclo [3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-(hydroxymethyl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one (0.420 g, 85 %) as a yellow solid. ¹H-NMR (300 MHz, CDCh) 6 2.34 - 2.49 (m, 2H), 3.05 (s, 1 H), 3.62 (t, J = 2.6 Hz, 1 H), 3.87 (ddd, J = 8.2, 2.2, 1 .2 Hz, 2H), 4.20 (d, J = 8.7 Hz, 2H), 5.04 - 5.21 (m, 2H), 5.78 (s, 2H), 7.03 - 7.15 (m, 2H), 7.22 - 7.39 (m, 2H); LCMS (method 1) m/z (ES+), [M+H]⁺ = 358; RT = 0.71 min.

Step 8: BAST (619 pl, 3.36 mmol) was added to 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl) -6-(2-fluorobenzyl)-7-(hydroxymethyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (400 mg, 1 .12 mmol) in DCM (15 mL) at 0°C under N2. The resulting mixture was stirred at rt for 1 h, quenched with saturated NaHCO3 (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SCU, filtered and evaporated. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCO3+ 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 34% to 54% B in 7 min; A 254/220 nm; RT= 6.87 min). Fractions containing the desired compound were evaporated to dryness to afford 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-(fluoromethyl)- 3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.245 g, 60.9 %) as a white solid. ¹H NMR (400 MHz, DMSO-ch) 6 2.37 - 2.46 (m, 2H), 3.41 (d, J = 5.1 Hz, 1 H), 3.75 (dt, J = 8.5, 1 .3 Hz, 2H), 4.02 (d, J = 8.6 Hz, 2H), 5.86 (s, 2H), 6.10 (d, j=48, 1 H), 6.09 (s, 1 H), 7.16 - 7.33 (m, 3H), 7.38 - 7.48 (m, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 360; RT = 2.47 min. The following compounds were made according to the method described above.

General route 9

Example 115: 3-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-6-(2,6-difluorobenzyl)-7- (difluoromethyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one BAST (25.2 pl, 0.14 mmol) was added to 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6- (2,6- difluorobenzyl)-4-oxo-4,6-dihydro-3H-pyrazolo[4,3-d][1 ,2,3]triazine-7-carbaldehyde (synthesised according to route 10) (17 mg, 0.05 mmol) in DCM (0.5 mL) at rt under N2. The resulting mixture was stirred at rt for 1 h quenched with NaHCO3 (30 mL), extracted with EtOAc (3 x 20 mL), and washed sequentially with water (25 mL) and brine (25 mL). The combined organic layers were dried over Na2SC , filtered and evaporated. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 urn; Mobile Phase A: water (10 mmol/L NH4HCO3+0.1 % NH3.H2O), Mobile Phase B: MeOH; Flow rate:60 mL/min; Gradient: 50% to 62% B in 7 min; A 254/220 nm; RT= 6.55 min). Fractions containing the desired compound were evaporated to dryness to afford 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2,6-difluorobenzyl)-7- (difluoromethyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (4.70 mg, 26.1 %) as a white solid. ¹H-NMR (300 MHz, DMSO-d₆) 6 2.41 (s, 2H), 3.39 (s, 1 H), 3.69 - 3.78 (m, 2H), 3.97 - 4.05 (m, 2H), 5.88 (s, 2H), 7.14 - 7.26 (m, 2H), 7.47 - 7.63 (m, 1 H), 8.00 (t, J = 52.4 Hz, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 396; RT = 1 .64 min.

The following compounds were made according to the method described above.

Example 118: 3-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-6-(2-fluorobenzyl)-7 -methoxy-

3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one

Step 1 : DIEA (972 pl, 5.56 mmol) was added to 4-amino-5-chloro-1-(2-fluorobenzyl) -1 H- pyrazole-3-carboxylic acid (500 mg, 1 .85 mmol) and HATU (705 mg, 1 .85 mmol) in DMF (5 mL) at rt. The resulting mixture was stirred at 25 °C for 10 min (1 R,5S,6r)-3-oxabicyclo [3.1 ,0]hexan-6-amine hydrochloride (251 mg, 1 .85 mmol) was added and the reaction stirred at 25 °C for 1 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 50 mL), and washed sequentially with water (50 mL), and brine (50 mL). The combined organic layers were dried over Na2SC , filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-amino-N-((1 R,5S,6r)-3- oxabicyclo[3.1 ,0]hexan-6-yl)-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxamide (0.470 g, 72.3 %) as a yellow solid. 1 H-NMR (300 MHz, DMSO-d₆) 6 1 .86 - 1 .94 (m, 2H), 2.70 (s, 1 H), 3.52 - 3.66 (m, 2H), 3.82 (d, J = 8.4 Hz, 2H), 4.80 (s, 2H), 5.36 (s, 2H), 6.89-6.99 (m, 1 H), 7.17 - 7.28 (m, 2H), 7.29-7.47 (m, 1 H), 8.17 (d, J = 4.3 Hz, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 351 ; RT =

1 .17 min. Step 2: Sodium nitrite (177 mg, 2.57 mmol) was added to 4-amino-N-((1 R,5S,6r)-3- oxabicyclo [3.1.0]hexan-6-yl)-5-chloro-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxamide (450 mg, 1.28 mmol) in AcOH (5 mL) at rt. The resulting mixture was stirred at rt for 3 h and then heated to 50 °C for 16 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 50 mL), washed sequentially with water (50 mL), and brine (50 mL). The combined organic layers were separated and dried over Na2SO4, filtered and evaporated to afford crude product that was purified by flash silica chromatography, elution gradient 10 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7- hydroxy- 3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.364 g, 83 %) as a green solid. ¹H-NMR (300 MHz, CDCI3) 6 1 .88-1 .92 (m, 2H), 2.06 (s, 1 H), 3.75 (d, J = 8.6 Hz, 2H), 4.04 (d, J = 8.6 Hz, 2H), 5.06 (s, 2H), 6.63 (s, 1 H), 7.03 - 7.18 (m, 2H), 7.32 (dd, J = 7.8, 5.7 Hz, 1 H), one exchangeable proton not seen. LCMS (method 2) m/z (ES+), [M+H]⁺ = 344; RT = 1.12 min.

Step 3: DIAD (170 pl, 0.87 mmol) was added to 3-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan- 6- yl)-6-(2-fluorobenzyl)-7-hydroxy-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (150 mg, 0.44 mmol) and methanol (70.0 mg, 2.18 mmol) and triphenylphosphane (172 mg, 0.66 mmol) in dry THF (2 mL) at rt. The resulting mixture was stirred at rt for 1 h then poured onto water (30 mL), extracted with EtOAc (3 x 25 mL), and washed sequentially with water (20 m), and brine (20 mL). The combined organic layers were separated, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Column: YMC-Actus Triart C18, 30 x 250, 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 40 to 53% B in 7 min; A 254/220 nm; RT= 6.80 min. Fractions containing the desired compound were evaporated to dryness to afford 3-((1 R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-6- (2-fluorobenzyl)-7- methoxy-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.048 g, 30.7 %) as a white solid. ¹H-NMR (300 MHz, CDCI3) 6 2.34 - 2.42 (m, 2H), 3.65 (t, J = 2.6 Hz, 1 H), 3.86 (d, J = 8.6 Hz, 2H), 4.20 (d, J = 8.6 Hz, 2H), 4.58 (s, 3H), 5.43 (s, 2H), 7.01 - 7.15 (m, 2H), 7.19 - 7.25 (m, 1 H), 7.30 (d, J = 7.2 Hz, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 358; RT = 1.71 min.

Example 119: 7-Cyclopropyl-6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one

Step 1 : Pd(DTBPF)Cl2 (51.7 mg, 0.08 mmol) was added to methyl 4-amino-5-bromo-1-(2- fluorobenzyl)-1 H- pyrazole-3-carboxylate (260 mg, 0.79 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (399 mg, 2.38 mmol) and K3PO4 (504 mg, 2.38 mmol) in 1 ,4-dioxane (2 mL) and water (0.4 mL) at 25°C under N2. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 4-amino-5-cyclopropyl-1-(2- fluorobenzyl)-1 H-pyrazole -3-carboxylate (0.086 g, 37.5 %) as a yellow oil. 1 H-NMR (300 MHz, CDCb) 6 0.58 - 0.69 (m, 2H), 0.87 - 0.96 (m, 2H), 1 .24 (s, 3H), 1 .35 - 1 .44 (m, 1 H), 3.92 (s, 2H), 5.48 (s, 2H), 6.88 (t, J = 7.6 Hz, 1 H), 6.97 - 7.09 (m, 2H), 7.22 (d, J = 5.9 Hz, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 290; RT = 1 .11 min.

Step 2: Methyl 4-amino-5-cyclopropyl-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxylate (85 mg, 0.29 mmol) was added to tetrahydro-2H-pyran-4-amine (1 mL) at 25°C and the resulting mixture was stirred at 120 °C for 16 h. The precipitate was filtered, dried under vacuum and purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-amino-5-cyclopropyl-1-(2-fluorobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazole-3- carboxamide (0.040 g, 38.0 %) as a yellow solid. ¹H-NMR (300 MHz, CDCb) 6 0.83 (d, J = 5.3 Hz, 2H), 0.96 - 1.11 (m, 2H), 1.26 (s, 1 H), 1.46 - 1.66 (m, 4H), 1.97 (d, J = 13.1 Hz, 2H), 3.46-3.61 (m, 2H), 4.00 (d, J = 11.7 Hz, 2H), 4.12 (d, J = 17.0 Hz, 1 H), 5.44 (s, 2H), 6.64 (d, J = 8.1 Hz, 1 H), 6.87 (t, J = 7.4 Hz, 1 H), 7.06 - 7.14 (m, 2H) , 7.62 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 359; RT = 1.02 min.

Step 3 : Sodium nitrite (11.55 mg, 0.17 mmol) was added to 4-amino-5-cyclopropyl- 1-(2- fluorobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazole-3-carboxamide (30 mg, 0.08 mmol) in 2N HCI (2 mL) at 25°C and the resulting mixture was stirred at rt for 16 h. The reaction mixture was adjusted to pH=9 with saturated NaHCC and extracted with EtOAc (3 x 20 mL). The combined organic layers were separated, dried over Na2SC>4, filtered and evaporated. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30 xi 50mm, 5um; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 43 to 55% B in 7 min; A 254/220 nm; RT= 6.40 min. Fractions containing the desired compound were evaporated to dryness to afford 7-cyclopropyl-6-(2-fluorobenzyl)-3-(tetrahydro- 2H- pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.016 g, 51.1 %) as a white solid. ¹H- NMR (300 MHz, DMSO-d₆) 6 1 .14 - 1 .23 (m, 2H), 1 .34 - 1 .41 (m, 2H), 1 .74 - 1 .83 (m, 2H), 1 .97-2.31 (m, 2H), 2.33-2.41 (m, 1 H), 3.42-3.55 (m, 2H), 3.98 (dd, J = 11.5, 4.2 Hz, 2H), 5.03-5.15 (m, 1 H), 5.79 (s, 2H), 7.16 - 7.30 (m, 3H), 7.33 - 7.44 (m, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 370; RT =1 .85 min.

Example 120: 6-(2-fluorobenzyl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-4,6-dihydro-3H- pyrazolo[4,3-d][1 , 2, 3]triazine-7 -carbonitrile

Step 1 : NIS (0.903 g, 4.01 mmol) was added to methyl 4-amino-1-(2-fluorobenzyl)-1 H- pyrazole-3-carboxylate (1 g, 4.01 mmol) in AcOH (10 mL) at rt under N2. The resulting mixture was stirred at 60 °C for 2 h. The solvent was removed by distillation under vacuum and the residue was poured into water (10 mL), adjusted to pH (7-8) with saturated NaHCOs and extracted with DCM (3 x 30 mL). The combined organic layers were separated, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 4-amino-1-(2- fluorobenzyl)- 5-iodo-1 H-pyrazole-3-carboxylate (0.501 g, 33.3 %) as a yellow solid. ¹H-NMR (400 MHz, DMSO-dg) 6 3.78 (s, 3H), 4.65 (s, 2H), 5.40 (s, 2H), 6.85 - 6.94 (m, 1 H), 7.12 - 7.31 (m, 2H), 7.32 - 7.43 (m, 1 H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 376; RT = 1 .34 min.

Step 2: Copper(l) cyanide (359 mg, 4.01 mmol) was added to methyl 4-amino-1-(2- fluorobenzyl)-5-iodo-1 H-pyrazole-3-carboxylate (501 mg, 1.34 mmol) in NMP (5 mL) at rt under N2. The resulting mixture was stirred at 150 °C for 5 h. The reaction mixture was poured into water (50 mL), the solid was filtered out and the water extracted with EtOAc (3 x 25 mL), the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 4-amino-5-cyano-1-(2-fluorobenzyl)-1 H- pyrazole-3- carboxylate (56.0 mg, 15.29 %) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) 6 3.79 (s, 3H), 5.46 (s, 2H), 5.99 (s, 2H), 7.18 - 7.31 (m, 3H), 7.38 - 7.48 (m, 1 H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 275; RT = 1.30 min.

Step 3: Tetrahydro-2H-pyran-4-amine (1 mL) was added to methyl 4-amino-5-cyano-1-(2- fluorobenzyl) -1 H-pyrazole-3-carboxylate (50 mg, 0.18 mmol) at rt. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was purified by flash silica chromatography, elution gradient 30 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-amino-5-cyano - 1-(2-fluorobenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazole-3-carboxamide (39.0 mg, 62.3 %) as a yellow oil. LCMS (method 1) m/z (ES+), [M+H]+ = 344; RT = 1 .26 min.

Step 4: Sodium nitrite (9.04 mg, 0.13 mmol) was added to 4-amino-5-cyano-1-(2- fluorobenzyl)-N-(tetrahydro -2H-pyran-4-yl)-1 H-pyrazole-3-carboxamide (30 mg, 0.09 mmol) in AcOH (1 mL) at rt. The resulting mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Column: SunFire C18 OBD Prep Column, 100A, 5 pm, 19 mm x 250 mm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: CH3CN; Flow rate: 25 mL/min; Gradient: 50 to 60% B in 7 min; 254/220 nm; RT= 6.02 min. Fractions containing the desired compound were evaporated to dryness to afford 6-(2-fluorobenzyl)-4-oxo-3- (tetrahydro-2H-pyran-4-yl) -4,6-dihydro-3H-pyrazolo[4,3-d][1 ,2,3]triazine-7-carbonitrile (7.60 mg, 24.55 %) as a grey solid. ¹H-NMR (400 MHz, DMSO-d₆) 6 1.83 - 1.92 (m, 2H), 1.99 - 2.14 (m, 2H), 3.47 - 3.58 (m, 2H), 3.96 - 4.05 (m, 2H), 5.09 - 5.21 (m, 1 H), 5.95 (s, 2H), 7.23 - 7.34 (m, 2H), 7.44 - 7.59 (m, 2H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 355; acid, HPLC RT = 1 .39 min.

Example 121 : rac-6-(2,6-difluorobenzyl)-3-((1 R,5S,6R)-1 -methyl-3- oxabicyclo[3.1.0]hexan-6-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one

Example 122 : 6-(2,6-Difluorobenzyl)-3-((1 R,5S,6R)-1 -methyl-3-oxabicyclo[3.1 .0]hexan- 6-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one

Into a 5 mL microwave tube, pyridine (138 pl, 1.71 mmol) was added to 6-(2,6-difluorobenzyl)- 3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (150 mg, 0.57 mmol), rac-((1 R,5S)-1-methyl-3- oxabicyclo[3.1 ,0]hexan-6-yl)boronic acid (81 mg, 0.57 mmol), CS2CO3 (93 mg, 0.28 mmol) and CU(OAC)2 (113 mg, 0.57 mmol) in toluene (4 mL) at rt. The microwave tube was evacuated and flushed with oxygen, the reaction was heated to 110 °C for 16 h and cooled to rt. The reaction mixture was quenched with saturated NH4CI (100 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were dried over Na2SC , filtered and evaporated to afford a residue that was purified by preparative HPLC (Column: YMC-Actus Triart C18 ExRS, 30 mm x 150 mm, 5 urn; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 27 to 60% B in 7 min; A 254/220 nm; RT: 6.9 min. Fractions containing the desired compound were evaporated to dryness to afford rac-6-(2,6-difluorobenzyl) -3-((1 R,5S,6R)-1-methyl-3- oxabicyclo[3.1 ,0]hexan-6-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.060 g, 29.3 %) as a white solid. ¹H-NMR (300 MHz, CDCI3) 6 1 .09 (s, 3H), 2.53 (t, J = 2.9 Hz, 1 H), 3.61 (d, J = 2.8 Hz, 1 H), 3.69 (d, J = 8.4 Hz, 1 H), 3.97 (dd, J = 8.6, 3.1 Hz, 1 H), 4.16 (dd, J = 17.0, 8.5 Hz, 2H), 5.69 (d, J = 1 .2 Hz, 2H), 6.94 - 7.08 (m, 2H), 7.41 (tt, J = 8.4, 6.5 Hz, 1 H), 8.30 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 360; RT = 1 .59 min. The racemate was purified by preparative chiral-HPLC (Column: (R,R)-WHELK-O1 , 4.6 x 50mm; 3.5um; Mobile Phase A: (Hex : DCM=3:1)(0.1 % DEA ) Mobile Phase B: EtOH, Isocratic A to B 70:30. The first fraction containing the desired compound were evaporated to dryness to afford 6-(2,6-difluorobenzyl)-3- ((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.021 g) as a white solid. ¹H-NMR (300 MHz, CDCI3) 6 1 .09 (s, 3H), 2.53 (t, J = 2.9 Hz, 1 H), 3.61 (d, J = 2.8 Hz, 1 H), 3.69 (d, J = 8.4 Hz, 1 H), 3.98 (dd, J = 8.6, 3.1 Hz, 1 H), 4.16 (dd, J = 17.0, 8.5 Hz, 2H), 5.69 (d, J = 1.3 Hz, 2H), 6.94 - 7.07 (m, 2H), 7.41 (tt, J = 8.5, 6.5 Hz, 1 H), 8.30 (s, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 360; RT = 1 .58 min; e.e= 99.9%. Absolute configuration arbitrarily assigned.

Example 123: 3-((1 R,5S,6s)-3-acetyl-3-azabicyclo[3.1 .0]hexan-6-yl)-7-chloro-6-(2- fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one

Acetyl chloride (39.5 mg, 0.50 mmol) was added to 3-((1 R,5S,6s)-3-azabicyclo[3.1 ,0]hexan-6- yl)-7- chloro-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one hydrochloride (100 mg, 0.25 mmol) and TEA (105 pl, 0.76 mmol) in DCM (1 mL) at 0°C. The resulting mixture was stirred at rt for 1 h and then was poured into DCM (25 mL) and extracted with water (3 x 10 mL). The organic layer was separated, dried over Na2SC>4, filtered and evaporated. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18, 30 x 150mm, 5 urn; Mobile Phase A: Water (l Ommol/L NH4HCO3 + 0.1 % NH3.H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 28 to 36% B in 10 min; A 254/220 nm; RT= 9.92 min. Fractions containing the desired compound were evaporated to dryness to afford 3-((1 R,5S,6s)-3-acetyl-3-azabicyclo[3.1 ,0]hexan-6-yl)-7-chloro -6-(2- fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.033 g, 32.5 %) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6) 6 1 .95 (s, 3H), 2.27 - 2.35 (m, 1 H), 2.36 - 2.45 (m, 1 H), 3.38 - 3.48 (m, 2H), 3.68 - 3.76 (m, 1 H), 3.76 - 3.86 (m, 2H), 5.77 (s, 2H), 7.17 - 7.31 (m, 2H), 7.32 - 7.40 (m, 1 H), 7.40 - 7.50 (m, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 403; RT = 2.15 min.

Example 124: 7-chloro-6-(2-fluorobenzyl)-3-((1 R,5S,6s)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one

2,2,2-Trifluoroethyl trifluoromethanesulfonate (66.9 mg, 0.29 mmol) was added to 3-(3- azabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2-fluorobenzyl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin- 4-one (80 mg, 0.22 mmol) and K2CO3 (92 mg, 0.67 mmol) in MeCN (1 mL) at 25°C. The resulting mixture was stirred at 60 °C for 3 h. The solvent was removed under reduced pressure and the residue was poured into water (15 mL), extracted with EtOAc (3 x 15 mL) and the combined organic layers were separated, dried over Na2SC , filtered and evaporated. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150mm, 5 urn; Mobile Phase A: Water (0.05% NH3 H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 55 to 63% B in 8 min; A 254/220 nm; RT=7.33 min. Fractions containing the desired compound were evaporated to dryness to afford 7-chloro-6-(2-fluorobenzyl)-3-((1 R,5S,6s)-3-(2,2,2-trifluoroethyl)-3-azabicyclo [3.1 ,0]hexan-6-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one (0.030 g, 30.8 %) as a white solid.1 H NMR (300 MHz, DMSO-d₆) 6 2.17 - 2.24 (m, 2H), 2.77 - 2.86 (m, 2H), 3.25 - 3.32 (m, 3H), 3.35 - 3.40 (m, 1 H), 3.72 - 3.80 (m, 1 H), 5.77 (s, 2H), 7.18 - 7.39 (m, 3H), 7.41 - 7.50 (m, 1 H). LCMS (method 3) m/z (ES+), [M+H]⁺ = 443; RT = 1 .92 min.

Example 125: 3-Cyclohexyl-7-ethyl-6-(2-fluorobenzyl)-3H-pyrazolo[4,3-d][1 ,2,3]triazin- 4(6H)-one

Step 1 : 2N NaOH aqueous solution (50 mL, 100.00 mmol) was added to ethyl 5-ethyl-1 H- pyrazole -3-carboxylate (10 g, 59.45 mmol) in THF (100 mL) at rt. The resulting mixture was stirred at rt for 16 h. The organic solvent was removed under reduced pressure and the residual water solution was adjusted to pH 2-3 with 2M HCI. The precipitate was collected by filtration, washed with water (100 mL) and dried under vacuum to afford 5-ethyl-1 H-pyrazole-3-carboxylic acid (6.30 g, 76 %) as a white solid, which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) 6 1 .17 (t, J = 7.6 Hz, 3H), 2.55 - 2.64 (m, 2H), 6.48 (s, 1 H), 12.89 (s, 2H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 141 ; RT = 0.94 min

Step 2: Concentrated nitric acid (2.59 mL, 56.73 mmol) was added dropwise to 5-ethyl-1 H- pyrazole-3 -carboxylic acid (5.3 g, 37.82 mmol) in H2SO4 (30 mL) at 0°C. The resulting mixture was stirred at 60°C for 4 h. After cooling to rt, the mixture was poured onto ice and the precipitate was collected by filtration, washed with water and dried under vacuum to afford 5-ethyl-4-nitro-1 H- pyrazole-3-carboxylic acid (7.00 g, 100 %) as a white solid . ¹H NMR (400 MHz, DMSO-d₆)) 6 1 .23 (t, J = 7.5 Hz, 3H), 2.91 (q, J = 7.5 Hz, 2H), 13.72 (s, 1 H), 13.97 (s, 1 H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 186; RT = 0.54 min.

Step 3: 1-(Bromomethyl)-2-fluorobenzene (7.72 g, 40.83 mmol) was added portionwise to 5- ethyl-4-nitro-1 H- pyrazole-3-carboxylic acid (3.6 g, 19.44 mmol) and CS2CO3 (15.84 g, 48.61 mmol) in MeCN (50 mL) at rt. The resulting mixture was stirred at 70°C for 2 h. The solvent was removed by distillation under vacuum and water (100 mL) was added to the residue. The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were dried over Na2SC>4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-fluorobenzyl-3-ethyl- 1-(2-fluorobenzyl) -4-nitro-1 H-pyrazole-5-carboxylate (2.400 g, 30.8 %) as a yellow oil and 2- fluorobenzyl 5-ethyl-1-(2-fluorobenzyl)-4-nitro-1 H-pyrazole-3-carboxylate (4.50 g, 57.7 %) as a yellow oil. ¹H NMR (400 MHz, CDCb) 6 1 .28 (t, J = 7.5 Hz, 3H), 2.92 (q, J = 7.5 Hz, 2H), 5.43 (s, 2H), 5.47 (s, 2H), 7.01 - 7.20 (m, 5H), 7.26 - 7.36 (m, 1 H), 7.32 - 7.44 (m, 2H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 402; RT = 1.64 min.

Step 4: 1 N LiOH aqueous solution (40 mL) was added to 2-fluorobenzyl 5-ethyl-1-(2- fluorobenzyl)-4-nitro-1 H- pyrazole-3-carboxylate (4.5 g, 11.21 mmol) in THF (40 mL) at rt. The resulting mixture was stirred at rt for 16 h. The organic solvent was removed under reduced pressure and the residual mixture washed with EtOAc (2 x 25 mL). The aqueous layer was adjusted to pH 2-3 with 2M HCI and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), separated, dried over Na2SO4, filtered and evaporated to afford 5-ethyl-1-(2- fluorobenzyl)-4-nitro-1 H-pyrazole-3-carboxylic acid (3.20 g, 97 %) as a white solid. ¹H NMR (400 MHz, DMSO-cb) 6 1.10 (t, J = 7.5 Hz, 3H), 3.04 (q, J = 7.5 Hz, 2H), 5.52 (s, 2H), 7.18 - 7.31 (m, 3H), 7.38 - 7.48 (m, 1 H), 13.91 (s, 1 H). LCMS (method 1) m/z (ES+), [M+H]⁺ = 294; RT = 1.31 min.

Step 5: HATU (363 mg, 0.95 mmol) was added to 5-ethyl-1-(2-fluorobenzyl)-4-nitro-1 H- pyrazole-3-carboxylic acid (280 mg, 0.95 mmol) and DIEA (0.500 mL, 2.86 mmol) in DMF (2 mL) at rt. The resulting mixture was stirred at rt for 15 min and cyclohexanamine (95 mg, 0.95 mmol) was added to above mixture at rt. The resulting mixture was stirred at rt for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined and washed with water (2 x 300 mL) and brine (30 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-cyclohexyl-5-ethyl-1-(2-fluorobenzyl)-4- nitro-1 H-pyrazole-3-carboxamide (260 mg, 72.7 %) as a yellow solid. LCMS (method 2) m/z (ES+), [M+H]⁺ = 375; RT = 1.39 min.

Step 6: Pd-C (73.9 mg, 0.07 mmol) was added to N-cyclohexyl-5-ethyl-1 -(2-fluorobenzyl) -4- nitro-1 H-pyrazole-3-carboxamide (260 mg, 0.69 mmol) in MeOH (10 mL) at rt under hydrogen. The resulting mixture was stirred at rt for 1 h then was filtered through celite and concentrated to dry to afford 4-amino-N-cyclohexyl-5-ethyl-1-(2-fluorobenzyl)-1 H-pyrazole-3-carboxamide (196 mg, 82%) as a white solid. ¹H NMR (DMSO-d₆), 300 MHz) 6 0.89 (3H, t, J=7.5 Hz), 1.28 (5H, q, J=10.2 Hz), 1.56 (1 H, d, J=12.1 Hz), 1.72 (4H, d, J=14.2 Hz), 2.53 (1 H, d, J=7.5 Hz), 3.14 (1 H, t, J=5.3 Hz), 3.69 (1 H, s), 4.48 (2H, d, J=8.6 Hz), 5.29 (2H, s), 6.78 (1 H, td, J=7.7, 1 .7 Hz), 7.08 - 7.25 (2H, m), 7.28 - 7.43 (2H, m); LCMS (method 3) m/z (ES+), [M+H]⁺ = 345; RT = 1 .26 min.

Step 7: Sodium nitrite (68.1 mg, 0.99 mmol) was added to 4-amino-N-cyclohexyl-5-ethyl-1-(2- fluorobenzyl) -1 H-pyrazole-3-carboxamide (170 mg, 0.49 mmol) in AcOH (3 mL) at rt. The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the aqueous residue was adjusted to pH=8 with NaHCC . The aqueous mixture was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and evaporated to afford a yellow liquid. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30x150mm, 5um; Mobile Phase A: Water (0.05% NH3H2O), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 50 B to 75 B in 7 min; A 254/220 nm; RT= 6.68 min). Fractions containing the desired compound were evaporated to dryness to afford 3-cyclohexyl-7-ethyl-6-(2-fluorobenzyl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3] triazin-4-one (64.0 mg, 36.5 %) as a white solid. ¹H NMR (300 MHz, CDCh) 6 1.20 - 1.58 (m, 6H), 1.68 - 1.78 (m, 1 H), 1.86 - 2.01 (m, 6H), 3.10 (q, J = 7.6 Hz, 2H), 4.99 - 5.17 (m, 1 H), 5.61 (s, 2H), 7.00 - 7.20 (m, 3H), 7.25 - 7.38 (m, 1 H). LCMS (method 2) m/z (ES+), [M+H]⁺ = 356; RT = 2.11 min.

BIOLOGICAL ASSAYS

The following assays were used to measure the effects of the compounds of Formula (I): a) RIPK1 cellular potency assay, b) Cell death assay, c) MDCK - MDR1 Permeability and Pgp Efflux assay, d) Human Liver Microsome assay, and e) Human Hepatocyte assay.

Assay a) RIPK1 cellular potency assay

Recombinant human RIPK1 protein(1-327) was supplied by SignalChem - expressed by baculovirus in Sf9 insect cells using an N-terminal GST tag. The potency of RIPK1 inhibitors was tested in an ADP-Glo kinase assay (Promega). Compounds were plated in DMSO at serial dilution in 384 well format (Echo Qualified 384-Well Polypropylene Microplate (384PP, Labcyte)). 1X Assay Buffer was prepared with HEPES pH 7.5 (50 mM), CHAPS (0.02%), NaCI (50 mM), MgCI2 (30 mM), DTT (1 mM), BSA (0.05%) in ddH20. 2X RIPK1 mixture was prepared by adding 10 nM GST-RIPK1 (1-327) to 1X Assay Buffer. 2X Substrate Mixture was prepared by adding 50 uM ATP in 1X Assay Buffer. 5 uL per well 2X RIPK1 mixture was pre-incubated at 25°C, followed by addition of 5 uL per well 2X Substrate Mixture. Plates were incubated at 25°C for 4 hours. 10 uL per well ADP-Glo reagent was added and incubated in the dark for 40 min at room temperature, followed by addition of 20 uL per well ADP-Glo detection reagent and further incubation in the dark for 30 min at room temperature. Luminescence readings were taken on an Envision plate reader, normalised to high-low controls and presented as %inhibition= 100-100*(sample-Low)/(High-Low). IC50s were calculated using XLfit (equation 205) 4 Parameter Logistic Model.

Assay b) Cell death assay

The potency of RIP1 inhibitors to rescue necroptotic cell death was tested in HT29 (human) CellTiter Gio 2.0 assay (Promega, G9243). Compounds were plated at serial dilution in 384well format (Echo Qualified 384-Well Polypropylene Microplate (384PP, Labcyte)).

For HT29 (ATCC, HTB-38), 2000 cells/well were plated and treated with 30 ng/mL hTNF-a (R&D Systems, 210-TA-020/CF), 30 uM zVAD.fmk (MedChem Express, HY-16658) and 300 nM Birinapant (MCE, HY-16591 ) for 48 hours at 37°C, 5% CO2. 24 uL/well Cel ITiter Gio reagent was added and incubated at room temperature for 30 minutes. Luminescence signal was read on an Enspire reader, average of cells treated with DMSO, without TNFa/zVAD/Smac induction was used as positive control and average of cells treated with DMSO, with TNFa/zVAD/Smac induction as negative control. Data were normalized to % rescue with positive and negative controls and dose response curves were graphed using the non-linear regression analyses in XLfit software, and EC50 values were calculated fitting to 4 parameters model.

The examples were tested in the above assays and the data in Table 1 was observed (data shown are the arithmetic mean of IC50 and EC50 values observed from 2 or more experiments). Table 1 : Potency data for compounds in RIPK1 assay and necroptosis assay

Assay c) MDCK - MDR1 Permeability and Pgp Efflux assay The MDCK-MDR1 assay evaluates the bidirectional permeability and human Pgp efflux transporter substrate liability of a chosen compound. MDCKI-MDR1 , obtained from the National Institutes of Health (NIH, Maryland USA), are used at passages between 5 and 10 in a cell culture medium consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) with high glucose and L- glutamine supplemented with: 10% FBS, 0.1 mg/mL of streptomycin, and 100 units of penicillin. The MDCK-MDR1 cells are seeded (5.45x10⁵ cells/cm²) and incubated in HTS Transwell-96 Well Permeable Supports (Corning, Cat. No. 3391) for 4-8 days. Once the cultured MDCK-MDR1 cells have reached confluence and are differentiated, the electrical resistance across the monolayer is measured using a Millicell Epithelial Volt-Ohm measuring system. TEER values are calculated for each well in the 96 well transwell plate using the following equation:

TEER measurement (ohms) x Area of membrane (cm²) = TEER value (ohm cm²)

Any monolayer with a TEER value < 800 ohms cm², indicates poor monolayer formation, and is discarded.

Drug transport in the apical to basolateral direction and basolateral to apical direction are determined for each test compound at the same time. Compounds (at 0.1 uM) are incubated in either the apical or basolateral compartments at 37 °C for 2 hours without shaking. Pre-incubation (donor compartment) and post-incubation (donor and acceptor compartments) samples are taken for drug concentration analysis. Samples are analysed using an LC/MS/MS system to determine drug concentration in the donor and acceptor compartment samples. Generic reverse phase chromatography (Waters XSelect HSS T3 C18, 2.5um, 2.1 x 50mm column) and an appropriate MS/MS instrument were used to carry out the sample analysis in MRM mode. Subsequent to sample analysis, estimations of the apparent permeability coefficients (Papp) of compounds across MDCK- MDR1 cell monolayers and of the efflux ratio (ER) were derived by the equations below.

The apparent permeability Papp , in units of centimeter per second, can be calculated for MDCK-MDR1 drug transport assays using the following equation:

Where VA is the volume (in mL) in the acceptor well (0.3 mL forAp^BI flux and 0.1 mL for BI^Ap flux), Area is the surface area of the membrane (0.143 cm² for HTS Transwell-96 Well Permeable Supports), and time is the total transport time in seconds.

The efflux ratio can be determined using the following equation:

Where P_apP (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and P_apP (A-B) indicates the apparent permeability coefficient in apical to basolateral direction.

All compounds assessed showed good permeability and low Efflux Ratio (<1) indicating high probability of brain penetration. Data for certain compounds is provided in Table 2.

Table 2: Efflux ratio and P_app A to B values for certain compounds

Furthermore, certain RIPK1 inhibitors of Formula (I) show good metabolic stability and consequently may provide improved in vivo exposure. Pharmacokinetic data for certain compounds are shown in Table 3.

Assay d) Human Liver Microsome assay

Within human liver microsome (HLM) experiments the metabolic stability of test compounds is assessed via calculation of the intrinsic clearance. HLMs are obtained from Corning UltraPool 150 donors (catalog no. 452117) at a concentration of 20mg/ml protein and stored at -80°C prior to use. For HLM incubations, the HLM are diluted to 1 mg/mL in the incubation mixture consisting of phosphate buffer (pH7.4), NADPH (1 mmol/L final concentration) and test compound/control compound (1 uM final concentration). The initiation of the HM reaction is via the addition of test compound to the incubation mixture, The incubation mix is subsequently mixed via vortexing and incubated at 37°C in a water bath. At 0.5, 5, 10, 15, 20 and 30 minutes, 20uL of the incubation mixture is sampled and the reaction quenched in stop solution (acetonitrile). Following centrifugation of quenched samples, sample supernatant is mixed with pure water before analysis via a generic LC- MS/MS method (Waters XSelect HSST3 C18 column is utilised with water with 0.1 % formic acid and acetonitrile with 0.1 % formic acid mobile phases ).

Peak areas are determined from extracted chromatograms and the percent of parent remaining is calculated from peak area. The slope value, k, is determined by linear regression of the natural logarithm of percent parent remaining versus incubation time curve. The in vitro half-life is determined from the slope value, k, as follows:

In vitro half-life = (0.693/k)

Conversion of in vitro half-life to in vitro intrinsic clearance is performed using the following equation:

Assay e) Human Hepatocyte assay

LiverPoolTM 10-donor human hepatocytes are obtained from BioreclamationIVT (Product No. S01205) and stored at <-150°C prior to use. Human hepatocytes are removed from storage but remain at cryogenic temperatures until thawing process ensures. During thawing process, the cells are thawed quickly in a 37°C water bath. Once fully thawed, the hepatocytes are added to 50mL thawing medium at -4°C (Williams Medium E, 30% isotonic percoll, GlutaMaxTM, 15mM HEPES, 5% fetal bovine serum, 4pg/mL human recombinant insulin solution and 1 pM dexamethasone) before centrifugation at 100g for 10 minutes. Media is removed and the hepatocytes are re-suspended in incubation medium (L-15 Medium)at a density of approximately 1 .5 x 106 cells/mL. Using Cellometer Vision, the cells are counted to ensure >80% cell viability and to allow dilution of cells to a cell density of 1 x 106 cells/mL. Test compound is added (at a final concentration of 1 pM) to the 1 x 106 cells/mL hepatocytes to initiate the reaction. The hepatocytes are incubated at 37°C and shaken at 900rpm on a Eppendorf Thermomixer Comfort plate shaker. At 0.5, 5, 15, 30, 45, 60, 80, 100 and 120 minutes a sample from the hepatocyte incubation is taken and the reaction stopped in quenching solution. Following centrifugation of quenched samples, sample supernatant is mixed with pure water before analysis via a generic LC-MS/MS method.

Peak areas are determined from extracted chromatograms and the percent of parent remaining is calculated from peak area. The slope value, k, is determined by linear regression of the natural logarithm of percent parent remaining versus incubation time curve. The in vitro intrinsic clearance in human hepatocytes is calculated using the following equation:

Intrinsic clearance (pl/min/106 cells) = kV/N where V= incubation volume (0.25mL) and N-= number of hepatocytes per well (0.25 x 106 cells).

Table 3: Intrinsic clearance and LogD values for certain compounds

Claims

CLAIMS A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R¹ is H or halo; when R¹ is H, n is 0 and when R¹ is halo, n is 0, 1 or 2;

R³ is H; halo; -CN; Ci-3alkyl or -O-Ci-3alkyl; wherein alkyl is optionally substituted by -OH or one or more -F;

R⁴ is Ci-4alkyl optionally substituted with one or more -F; Q^A; Q^B or Q^c;

Q^A is a C3-6cycloalkyl group optionally substituted with one or more substituents independently selected from F, -CN, Ci-3alkyl and -O-Ci-3alkyl, wherein alkyl is optionally substituted with one or more -F;

2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein X is N.

3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein X is CH.

4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R¹ is halo.

5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R¹ is -F.

6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein R¹ is H.

7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein n is 0.

8. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein n is 1 or 2 and each R² is independently selected from -F and -Cl.

9. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R³ is H, -F, -Cl, -Br, -Me, -Et, -CN, -OMe, -OCHF2, - CH2F, -CHF2, cyclopropyl or -CH2CH.

10. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R³ is Cl.

11 . The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R⁴ is C^alkyl optionally substituted with one or more -F.

12. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R⁴ is selected from -CH2CHF2, -CH2CF3, - CH2CH2CHF2 and -C(CH₃)CHF₂.

13. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R⁴ is -C(CH3)CHF2.

14. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 10, wherein R⁴ is Q^A and is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[3.1 .0]hexyl. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 10, wherein R⁴ is Q^B and is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1 .0]hexanyl, oxepanyl and 3-oxabicyclo[4.1 ,0]heptanyl. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 10, wherein R⁴ is Q^c and is selected from 6-oxopiperidinyl and 3- azabicyclo[3.1 .0]hexanyl. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is selected from the group consisting of:

2-benzyl-3-chloro-6-(oxetan-3-yl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one;

3-chloro-2-[(2-fluorophenyl)methyl]-6-[(2S,4S)-2-methyltetrahydropyran-4-yl]pyrazolo[3,4- d]pyridazin-7-one;

(1 r,3r)-3-(3-chloro-2-(2-fluorobenzyl)-7-oxo-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6- yl)cyclobutane-1 -carbonitrile;

(R)-3-chloro-6-(1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one; (S)-3-chloro-6-(1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

6-((1 R,5S,6R)-3-oxa-bicyclo[3.1 ,0]hexan-6-yl)-3-chloro-2-(2-fluorobenzyl)-2H-pyrazolo[3,4- d]pyridazin-7(6H)-one;

3-chloro-2-(2-fluorobenzyl)-6-((1S,2S)-2-fluorocyclopropyl)-2H-pyrazolo[3,4-d]pyridazin-7(6H)- one; rac-3-chloro-6-[(1 R,2R)-2-fluorocyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; rac-3-chloro-6-[(1 R)-2,2-difluorocyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 R)-2,2-difluorocyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4-d]pyridazin-7- one;

3-chloro-2-[(2,6-difluorophenyl)methyl]-6-[(1 S,2S)-2-fluorocyclopropyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 R,2S)-2-(difluoromethyl)cyclopropyl]-2-[(2,6-difluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one;

3-chloro-6-[(1 S,2R)-2-(difluoromethyl)cyclopropyl]-2-[(2,6-difluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; rac-3-chloro-6-[(1 R)-2,2-dimethylcyclopropyl]-2-[(2-fluorophenyl)methyl]pyrazolo[3,4- d]pyridazin-7-one; 3-fluoro-2-(2-fluorobenzyl)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

6-((1S,5R,6r)-3-oxa-bicyclo[3.1 .0]hexan-6-yl)-2-(2-fluorobenzyl)-3-(fluoromethyl)-2H- pyrazolo[3,4-d]pyridazin-7(6H)-one;

3-chloro-2-(2-fluorobenzyl)-6-((1 R,2S)-2-methoxycyclopropyl)-2,6-dihydro-7H-pyrazolo[3,4- d]pyridazin-7-one;

6-(2,6-difluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3H-pyrazolo[4,3-d][1 ,2,3]triazin-4(6H)-one; 6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4- one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2-fluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2,6-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2,3-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one; 3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-chloro-6-(2,5-difluorobenzyl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

6-(2-fluorobenzyl)-7-methyl-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-methyl-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

(R)-7-chloro-6-(2,6-difluorobenzyl)-3-(6-oxopiperidin-3-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one; (R)-7-chloro-6-(2-fluorobenzyl)-3-(tetrahydrofuran-3-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

7-chloro-6-(2-fluorobenzyl)-3-((2R,4S)-2-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-3,6- dihydro-4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one; 7-chloro-6-(2-fluorobenzyl)-3-((2S,3R)-2-methyloxetan-3-yl)-3,6-dihydro-4H-pyrazolo[4,3- d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-7-(difluoromethyl)-6-(2-fluorobenzyl)-3,6-dihydro-

4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

7-(difluoromethyl)-6-(2-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

3-((1 R,5S,6r)-3-oxabicyclo[3.1 ,0]hexan-6-yl)-6-(2-fluorobenzyl)-7-methoxy-3,6-dihydro-4H- pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

120 6-(2-fluorobenzyl)-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-4,6-dihydro-3H-pyrazolo[4,3- d][1 ,2,3]triazine-7-carbonitrile; rac-6-(2,6-difluorobenzyl)-3-((1 R,5S,6R)-1-methyl-3-oxabicyclo[3.1 ,0]hexan-6-yl)-3,6-dihydro- 4H-pyrazolo[4,3-d][1 ,2,3]triazin-4-one;

18. The compound of Formula (I), as claimed in claim 1 , wherein the compound is (R)-3-chloro-6- (1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one, or a pharmaceutically acceptable salt.

19. The compound of Formula (I), as claimed in claim 1 , wherein the compound is (R)-3-chloro-6- (1 ,1-difluoropropan-2-yl)-2-(2-fluorobenzyl)-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one.

20. A pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 19, and at least one pharmaceutically acceptable excipient.

21 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 19, for use in therapy.

22. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 19, for use in the treatment of a nervous system disease or condition.

23. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as claimed in claim 22, where the nervous system disease or condition is selected from amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Huntington’s disease, Prion diseases, brain and spinal injury, Duchenne muscular dystrophy and multiple sclerosis.

24. Use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 19, for the manufacture of a medicament for the treatment of a nervous system disease or condition.

121 A method for treating a nervous system disease or condition in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 19.