Pyridazine compounds, their preparation, and their therapeutic uses

Abstract

The present invention relates to a compound of formula (I) wherein R1 is a hydrogen atom, halogen or -(C1-C2)alkyl, R2 is -halo(C1-C2)alkoxy, and R3 and R4 form together with N to which they are attached an optionally substituted 5-7 membered monocyclic heterocycloalkyl ring or an optionally substituted 8-11 membered bicyclic heterocycloalkyl ring. The present invention also relates to a medicament and a pharmaceutical composition comprising said compound of formula (I), as well as their therapeutic uses, in particular as inhibitor of NOD-like receptor protein 3 inflammasome for preventing and / or treating Parkinson's disease, frontotemporal Dementia, Multiple System Atrophy, Alzheimer's disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis or brain injury.

Description

[0001] PYRID AZINE COMPOUNDS, THEIR PREPARATION, AND THEIR THERAPEUTIC USES

[0002] FIELD OF THE DISCLOSURE

[0003] Disclosed herein are pyridazine compounds, their preparation, a medicament and a pharmaceutical composition comprising said pyridazine compounds, their use as a medicament and more particularly their use as inhibitor of NOD-like receptor protein 3 (NLRP3) inflammasome pathway, and more particularly their use in the prevention and / or in the treatment of Parkinson’ s disease, frontotemporal Dementia, Multiple System Atrophy, Alzheimer’s disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis or brain injury .

[0004] BACKGROUND OF THE DISCLOSURE

[0005] The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) or NACHT, LRR and PYD domains -containing protein 3 (NALP3), is a cytosolic sensor of diverse pathogen- and host-derived molecules. Upon activation, NLRP3 oligomerizes and recruits an adaptor protein called apoptosis-associated speck like protein (ASC). ASC then polymerizes to form a large aggregate known as ASC speck. In turn, polymerized ASC interacts with the cysteine protease caspase -1 to form a complex termed the inflammasome. This multicomplex protein forms a platform for the binding, dimerization, and activation of the caspase- 1 protease. Caspase- 1 then cleaves the precursor forms of the pro -inflammatory cytokines ILip and IL18 (termed pro- ILip and pro-IL18) and thereby activates adapted inflammatory responses. However, this pathway was shown to be associated with various inflammation associated processes and diseases, including:

[0006] - Neurodegenerative diseases such as Parkinson’s Disease (PD), Multiple System Atrophy (MSA), Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS) and Brain injury (Guan Y & Han F. Front Integr., Neurosci. 14 :37, 2020);

[0007] - Inflammatory diseases including Muckle -Wells Autoinflammatory Disorder (Agostini et al., 2004), cryopyrin-associated periodic syndrome (CAPS) (Mortimer et al., Nature Immunol. 2016, 17(10), 1176-1188); sickle cell disease; systemic lupus erythematosus (SLE); liver related diseases, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petrasek et al., J. Clin. Invest. 2012, 122, 3476- 89), and inflammatory arthritis related disorders, such as gout, pseudogout (chondrocalcinosis), osteoarthritis (Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31), and rheumatoid arthritis (Mathews et al., Ann. Rheum. Dis. 2014, 73, 1202-10), acute or chronic arthropathy, and kidney related diseases such as hyperoxaluria (Knaufetet al., Kidney Int 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al., Br. J. Pharmacol. 2016, 173, 752-10 65), hemodialysis related inflammation and diabetic nephropathy (Shahzad et al., Kidney Int. 2015, 87, 74-84);

[0008] - Obesity & insulin resistance (Rheinheimer J. et al., Metabolism Clin & Experimental 74: 1-9, 2017); Pancreatitis (Fu Q. et al., BioMed Research International Volume 2018, Article ID 12949512018); Myocarditis (Toldo S et al, Int J Cardiol 2014);

[0009] - Eye diseases, where the NLRP3 inflammasomehas been shown to contribute to diabetic retinopathy (Perrone L. et al., J. Cell. Physiol. 221: 262-272, 2009), acute glaucoma (Chi W. et al. National Academy Science 111 : 11181 -11186, 2014), age-related macular degeneration (Tseng W. A. et al., Investigative Ophthal & Visual Science 54: 11 -120, 2013), Behcet’s syndrome and dry eye disease (Zheng Q. et al., Experimental Eye Research 134: 133-140, 2015);

[0010] - Metabolic, cardiac, skin disorder & cancer, e.g., diabetic cardiomyopathy (Luo B. et al., PLoS ONE 9(8): el04771, 2014); Kawasaki disease (Jia et al. Cell Death and Disease 10:778; 2019; Anzai F. et al., J. Molecular & Cell Cardiology 138: 185 -196, 2020); cardiovascular metabolic disorders, atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure and hypertension (Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31; woundhealingand scar formation; inflammatory skin diseases (Sweeney et al., Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age- related macular degeneration; cancer related diseases, e.g., myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, colon cancer (Ridker et al., Lancet 2017, 390, 1833-42); and

[0011] - SARS-Cov-2: NLRP3 inflammasome is key player in antiviral responses (Zhao C. and Zhao W. 11, 211 : 2020; Freeman & Swartz, Frontiers in Immunol. 11, 1518, 2020).

[0012] Inhibitors of NLRP3 are potential treatments for these conditions with unmet clinical needs. Therefore, there is a need for inhibitors of the NLRP3 inflammasome pathway to provide new or alternative treatments.

[0013] SUMMARY OF THE DISCLOSURE

[0014] Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein

[0015] R1 represents a hydrogen atom, a halogen atom or a -(Ci-C2)alkyl group;

[0016] R2 represents -halo(Ci-C2)alkoxy group; and

[0017] R3 and R4 form together with the nitrogen atom to which they are attached:

[0018] - a 5 to 7 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom and comprising 4 to 6 carbon atoms; or

[0019] - a 8 to 11 membered bicyclic heterocycloalkyl ring comprising one n itrogcn atom and optionally one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 6 to 10 carbon atoms;

[0020] Said monocyclic heterocycloalkyl ring and bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-C3)alkyl- group, a hydroxy-(Ci-C3)alkyl- group, and a fluoro-(Ci-C2)alkyl- group.

[0021] Herein provided are also:

[0022] - a medicamentandapharmaceuticalcompositioncomprisingsaid compound of formula (I) as defined in the present disclosure,

[0023] - said compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, for use as a medicine, - said compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, for use as inhibitor of NOD-like receptor protein 3 (NLRP3) inflammasome,

[0024] - said compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, for use in the prevention and / or in the treatment of Parkinson’s disease, frontotemporal Dementia, Multiple System Atrophy, Alzheimer’s disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis or brain injury .

[0025] Definitions

[0026] In the context of the present disclosure, the terms below have the following definitions unless otherwise mentioned throughout the instant specification:

[0027] - a halogen atom: a fluorine (F), a chlorine (Cl), a bromine (Br) or an iodine (I) atom, and for example a fluorine or a chlorine or an iodine atom;

[0028] - a hydroxy group (also named hydroxyl group): a “-OH” group;

[0029] - a -(Cx-Cy)alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group comprising from x to y carbon atoms, for example from 1 to 3 carbon atoms, By way of examples, mention may be made of, but not limited to: methyl, ethyl, propyl groups, and the like;

[0030] - a halo(Cx-Cy)alkoxy- group: a radical -O-alkyl group in which the alkyl group is as previously defined, said alkyl group being substituted by one or more identical or different halogen atoms as previously defined. By way of examples, mention may be made of, but not limited to: trifluoro methoxy, fluoro methoxy, difluoromethoxy, chloro fluoro methoxy, chloromethoxy, dichloromethoxy, iodomethoxy, diiodomethoxy, triiodo methoxy, bromomethoxy, tribromomethoxy, trichloromethoxy, dichlorobromomethoxy groups, and the like;

[0031] - a hydroxy(Cx-Cy)alkyl- group: a alkyl group as previously defined in which one or more hydrogen atom have been replaced by one or more hydroxy group as previously defined. By way of examples, mention may be made of, but not limited to: OH-CH2-, OH-C(CH3)2-, OH-CH(CH3)- groups, and the like;

[0032] - a 5 to 7 membered monocyclic heterocycloalkyl ring (also named (C5- Cyjheterocycloalkyl group): a monocyclic alkyl group comprising, unless otherwise mentioned, from 4 to 6 carbon atoms and comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom. Such heterocycloalkyl group (or ring) may be saturated or partially saturated and unsubstituted or substituted. By way of examples of monocyclic heterocycloalkyl groups (or rings), mention may be made of, but not limited to: piperazine, morpholino, pyrrolidine, tetrahydropyrane, piperidine, thiolane, dihydrofurane, tetrah ydrofurane,2H-pyrrole, 1H-, 2H- or 3H-pyrroline, and the like;

[0033] - a 8 to 11 membered bicyclic heterocycloalkyl ring (also named (Cs-Cn)heterocycloalkyl group): a bicyclic alkyl group comprising, unless otherwise mentioned, from 6 to 10 carbon atoms and comprising one nitrogen atom and optionally one to two additional heteroatoms selected from a nitrogen atom and an oxygen atom. Such heterocycloalkyl group (or ring) may be saturated or partially saturated, and unsubstituted or substituted, and bridged or not bridged. By way of examples of bicyclic heterocycloalkyl groups (or rings), mention may be made of, but not limited to: a hexahydro-2H-pyridooxazinyl group such as a hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl group for instance a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl group, a hexahydro-2H-pyrrolopyridinyl group such as a hexahydro-2H-pyrrolo[2,3-c]pyridinyl group for instance a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl group , and the like;

[0034] - “optionally substituted” means “unsubstituted or “substituted with” ;

[0035] - R and S indicate the stereochemistry of the pseudo -asymmetric carbon atoms, according to the IUPAC rules

[0036] - in each radical or group as defined in the present disclosure, each hydrogen atom can be replaced by a deuterium atom, which forms part of the present disclosure.

[0037] DETAILED DESCRIPTION OF THE DISCLOSURE

[0038] As mentioned above, herein is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof : wherein

[0039] R1 represents a hydrogen atom, a halogen atom or a -(Ci-C2)alkyl group;

[0040] R2 represents -halo(Ci-C2)alkoxy group; and

[0041] R3 and R4 form together with the nitrogen atom to which they are attached:

[0042] - a 5 to 7 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom and comprising 4 to 6 carbon atoms; or

[0043] - a 8 to 11 membered bicyclic heterocycloalkyl ring comprising one n itrogcn atom and optionally one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 6 to 10 carbon atoms; said monocyclic heterocycloalkyl ring and bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-C3)alkyl- group, a hydroxy-(Ci-C3)alkyl- group, and a fluoro-(Ci-C2)alkyl- group.

[0044] The compounds of formula (I) may comprise one or more asymmetric carbons. They may exist in the form of enantiomers or diastereoisomers. The compounds of formula (I) may also exist in the form of cis or trans stereoisomers. These stereoisomers, enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the disclosure.

[0045] The compounds of formula (I) may be present as well under tautomer forms.

[0046] The compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Hence, herein are provided compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0047] These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided. Among suitable salts of the compounds of formula (I), trifluoro acetate, and formate may be cited.

[0048] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R1 represents a hydrogen atom, a fluorine atom or a methyl group.

[0049] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R1 represents a hydrogen atom.

[0050] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compoundsis composedof the compounds forwhich R1 represents ahalogen atom.

[0051] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compoundsis composedof the compounds forwhich R1 represents afluorine atom.

[0052] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds forwhich R1 represents a -(Ci-C2)alkyl group.

[0053] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composedof the compounds forwhich R1 represents a methyl group.

[0054] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R2 represents a difluoromethoxy- group or a trifluoromethoxy- group.

[0055] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R2 represents -halo(Cr C2)alkoxy group.

[0056] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R2 represents a difluoromethoxy- group (-OCHF2) or trifluoro methoxy- (-OCF3) group.

[0057] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 5 to 7 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom and comprising 4 to 6 carbon atoms, said monocyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selectedfrom a (Ci-C3)alkyl- group, ahydroxy-(Ci-C3)alkyl- group, and a fluoro-(Ci-C2)alkyl- group.

[0058] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 5 to 7 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom and comprising 4 to 6 carbon atoms, said monocyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a hydroxy-(Ci-C3)alkyl- group, in particular by one hydroxy-(Ci-C3)alkyl- group.

[0059] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 6 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom and comprising 4 to 5 carbon atoms, said monocyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a hydroxy-(Ci-C3)alkyl- group, in particular by one hydroxy-(Ci-C3)alkyl- group.

[0060] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 6 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and one oxygen atom and comprising 4 carbon atoms, said monocyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a hydroxy -(Ci-Csjalkyl- group, in particular by one hydroxy-(Ci-C3)alkyl- group.

[0061] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 6 membered monocyclic heterocycloalkyl ring, said 6 membered monocyclic heterocycloalkyl ring being a morpholino ring, said morpholino being unsubstituted or substituted by one to two substituents independently selectedfroma hydroxy -(Ci-Csjalkyl- group, in particular by one hydroxy-(Ci-C3)alkyl- group. Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 6 membered monocyclic heterocycloalkyl ring, said 6 membered monocyclic heterocycloalkyl ring being a morpholino ring, said morpholino being substituted by one to two -CH2-OH group, in particular by one -CH2-OH group.

[0062] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 8 to 11 membered bicyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 6 to 10 carbon atoms, said bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-Cajalkyl- group, a hydroxy-(Ci-C3)alkyl- group, and a fluoro-(Ci-C2)alkyl- group.

[0063] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 8 to 11 membered bicyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 6 to 10 carbon atoms, said bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-Cajalkyl- group, in particular by one (Ci-Cajalkyl- group.

[0064] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 9 to 10 membered bicyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 7 carbon atoms, said bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-Cajalkyl- group, in particular by one (Ci-Cajalkyl- group.

[0065] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 9 to 10 membered bicyclic heterocycloalkyl ring comprising one nitrogen atom and one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 7 carbon atoms, said bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-C3)alkyl- group, in particular by one (Ci- Ca)alkyl- group.

[0066] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached:

[0067] - a 6 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and one oxygen atom and comprising 4 carbon atoms, said monocyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a hydroxy-(Ci-C3)alkyl- group, in particular by one hydroxy-(Ci-C3)alkyl- group, for instance one OH-CH2- group, or

[0068] - a 9 to 10 membered bicyclic heterocycloalkyl ring comprising one nitrogen atom and one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 7 carbon atoms, said bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-Csjalkyl- group, in particular by one (Ci-Csjalkyl- group, for instance one methyl group or one ethyl group.

[0069] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 9 to 10 membered bicyclic heterocycloalkyl ring, said 9 to 10 membered bicyclic heterocycloalkyl ring being a hexahydro-2H-pyridooxazinyl ring such as a hexahydro-2H-pyrido[4,3-b][l,4]oxazinylring for instance a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring, or a hexahydro-2H-pyrrolopyridinyl ring such as a hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring for instance a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, said 9 to 10 membered bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-Csjalkyl- group, in particular by one (Ci- Csjalkyl- group. Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached a 9 to 10 membered bicyclic heterocycloalkyl ring, said 9 to 10 membered bicyclic heterocycloalkyl ring being a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring or a 3,3a,4,5,7,7a-hexahydro- 2H-pyrrolo[2,3-c]pyridinyl ring, said 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3- b][l,4]oxazinyl ring and 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring being substituted by one to two substituents independently selected from a methyl group and an ethyl group, in particular by one methyl group or one ethyl group.

[0070] Among the compounds of formula (I) that are subject-matter of the disclosure, a group of compounds is composed of the compounds for which R3 and R4 form together with the nitrogen atom to which they are attached:

[0071] - a morpholino ring,

[0072] - a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring or a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, said morpholino ring, 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring and 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ringbeing unsubstituted or substituted by one to two substituents independently selected from a -CH3 group (a methyl group), a -CH2-CH3 group (an ethyl group) and a -CH2-OH group (a hydroxymethyl- group), in particular by one -CH3 group, one -CH2-CH3 group or one -CH2-OH group.

[0073] According to a particular embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 represents a hydrogen atom, a fluorine atom or a methyl group,

[0074] R2 represents a difluoromethoxy- group or a trifluoromethoxy- group, and R3 and R4 form together with the nitrogen atom to which they are attached:

[0075] - a morpholino ring,

[0076] - a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring or a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, said morpholino ring, 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3- b][l,4]oxazinyl ring and 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring being unsubstituted or substituted by one to two substituents independently selected from a -CH3 group (a methyl group), a -CH2-CH3 group (an ethyl group) and a -CH2-OH group (a hydroxymethyl- group), in particular by one -CH3 group, one -CH2-CH3 group or one -CH2-OH group.

[0077] According to a particular embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 represents a hydrogen atom, or a methyl group,

[0078] R2 represents a difluoromethoxy- group or a trifluoro methoxy- group, and

[0079] R3 and R4 form together with the nitrogen atom to which they are attached:

[0080] - a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring or a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, said 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring and 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ringbeing unsubstituted or substituted by one to two substituents independently selected from a -CH3 group (a methyl group), or a -CH2-CH3 group (an ethyl group), in particular by one -CH3 group or one -CH2-CH3 group.

[0081] All these sub-groups taken alone or in combination are part of the present disclosure.

[0082] Among the compounds of formula (I) that are subject-matter of the present disclosure, mention may be made for instance to the following compounds:

[0083] (1) 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]- 5 -methylphenol;

[0084] (2) 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3- yl]phenol;

[0085] (3) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3- (trifluoromethoxy)phenol;

[0086] (4) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-3- (trifluoromethoxy)phenol;

[0087] (5) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3 -yl] -3 -(difluoro methoxy)phenol;

[0088] (6) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol; (7) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;

[0089] (8) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;

[0090] (9) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;

[0091] (10) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3 -yl] -3 -(difluoro methoxy)phenol;

[0092] (11) 3-(difluoromethoxy)-5-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4- yl]pyridazin-3-yl]phenol;

[0093] (12) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-5-methyl-3-(trifluoromethoxy)phenol;

[0094] (13) 2-[6-[(4aS,8aR)-6-methyl-3 ,4a, 5,7,8, 8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-

[0095] 4-yl]pyridazin-3-yl] -5-methy 1-3 -(trifluoro meth oxy)phenol; and their pharmaceutically acceptable salts thereof.

[0096] Preparation of the compounds of formula (I)

[0097] The compounds of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure may be prepared according to various methods. More particularly, they can be prepared as illustrated by the scheme which follow.

[0098] Synthesis scheme In this Synthesis scheme, Rl, R2, R3 and R4 are as defined in the present disclosure, and X represent independently of each other a halogen atom, such as Cl, Br or I, P represents a protecting group like a methyl group, a paramethoxybenzyl- group, a benzyl group, a methoxymethyl- group or an ethoxyethyl- group and B(OR)2 represents either a boronic acid or a boronic ester, e.g. 4,4,5,5-tetramethyl-l,3,2-dioxaborolan.

[0099] Compounds of the invention may be prepared by the Reaction scheme where a dihalo genopyridazine (GS 1) is reacted with an appropriate amine (GS 2) in a presence of a base (like K2CO3, DIPEA), at room temperature or elevated temperature (preferentially between 120-180°C) to give halogenopyridazine (GS 3). This reaction may be carried out in sealed tubes, and also under microwave irradiation. This reaction can be also realized by metal coupling, using Pd catalyst (like Pd(dppf)C12 (that is to say 1,1 '- bis(diphenylphosphino)ferrocene]palladium(II) dichloride) and a mineral base like K3PO4, at elevated temperature (typically between 100-110°C), in a non protic solvent like 1,4- dioxane to provide halogenopyridazine (GS 3). Then, this intermediate halogenopyridazine (GS 3) is reacted with an appropriate phenyl boronate derivative (GS 4), where it could be under a form of boronic acid or a boronate (like 4,4,5,5-tetramethyl-l,3,2-dioxaborolan), in a Suzuki type reaction, in the presence of a Pd catalyst (like Pd(PPh3)4, that is to say tetrakis(triphenylphosphine)palladium(0)), or Pd(dppf)C12) and a mineral base like NaHCC (that is to say sodium bicarbonate), at elevated temperature (typically between 100-140°C), in a mixture of solvent like 1,4-dioxane / water or DME (that is to say dimethoxyethane) / water to provide a compound of general formula (I) according to the present disclosure. It is to be noted that phenyl boronate derivative could be used also with a protected hydroxy function, with a methyl, or benzyl for example (GS 5), to give the appropriate phenyl pyridazine (GS 6), which is submitted to deprotection conditions (BBr3, that is to say boron tribromide), or hydrogenation for example) to provide compound of general formula (I) according to the present disclosure.

[0100] It is also to be noted that R2 group in GS4 or GS5 can primarily represent an hydroxy group, that is transformed into a halo(Ci-C2)alkyl- group, thanks to methods described in the literature and well-known by the skilled person.

[0101] The specific compounds of formula (I) or a pharmaceutically acceptable salt thereof as defined in the present disclosure are indicated in Table 1 (number, and formula) and are further detailed hereafter. In Table 1,JH NMR, and liquid chromatography / mass spectra are also indicated.

[0102] TheXH NMR of Table 1 isJH NMR Spectra (400 MHz or 500 MHz, 5 in ppm, DMSO-d6, CD3OD or CDCI3) as defined in the Experimental part. The liquid chromatography / mass spectra (LC / MS) of Table 1 were obtained according to one of the six methods described in the Experimental part.

[0103] Table 1:

[0104] EXAMPLES

[0105] The examples which follow describe the preparation of certain compounds in accordance with the disclosure. The numbers of the compounds of formula (I) exemplified below match those given above. All reactions are performed under inert atmosphere, unless otherwise stated. These examples are not limitative, and merely illustrate the present disclosure.

[0106] The following abbreviations are used in the present disclosure:

[0107] ACN, or MeCN Acetonitrile

[0108] Ar Argon

[0109] BBr3Boron tribromide

[0110] BippyPhos 5-(Di-tert-butylphosphino)-r,3',5'-triphenyl-TH-[l,4']bipyrazole

[0111] CyJohnPhos 2-(Dicyclohexylphosphino)biphenyl)

[0112] DCM Dichloromethane DIPE Diisopropyl ether

[0113] DIPEA Diisopropylethylamine

[0114] DMAP 4-Dimethylamino Pyridine DME Dimethoxyethane

[0115] DMSO Dimethyl sulfoxide

[0116] DMF N,N-dimethylformamide

[0117] Et3N or TEA Triethylamine

[0118] EtOAc Ethylacetate

[0119] HBpin Pinacolborane

[0120] HC1 Hydrogen chloride

[0121] HCOOH Formic acid

[0122] HC1 Hydrochloric acid

[0123] IL(-)ip or IL(-)lbeta Interleukin 1 beta

[0124] K2CO3Potassium carbonate

[0125] KOH Potassium hydroxyde

[0126] K3PO4Tripotassium phosphate

[0127] LiOH.HoO Lithium hydroxide monohydrate

[0128] MeOH Methanol

[0129] MgSO4Magnesium sulfate

[0130] N2Nitrogen

[0131] NH4+HCO3- Bicarbonate salt of the ammonium ion

[0132] NaBH3CN Sodium cyanoborohydride

[0133] NaH Sodium hydride

[0134] NaHCO3 Sodium bicarbonate

[0135] NaNO2Sodium nitrite

[0136] NaOH Sodium hydroxide

[0137] Na2S2O3Sodium thiosulfate

[0138] Na2SO4Sodium sulfate

[0139] NEt3or TEA Triethylamine

[0140] NH4OH Ammonium hydroxide

[0141] NH4C1 Ammonium chloride

[0142] NIS N-iodosuccinimide

[0143] Pd2(dba)3Tris(dibenzylideneacetone)dipalladium (0)

[0144] Pd(dppf)Cl21 , 1 '-bis(diphenylphosphino)ferrocene]palladium(II)dichloride

[0145] Pd(OAc)2Palladium (II) acetate Pd(PPh ’,)4 Tetrakis(triphenylphosphine)palladium(0)

[0146] PPTS Pyridinium p-toluenesulfonate

[0147] THF Tetrahydrofurane

[0148] TNF(-)alpha or TNF(-)a Tumor necrosis factor-alpha or Tumor necrosis factor-a

[0149] XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl

[0150] XPhosPdG2 Chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-l,l- biphenyl)[2-(2-amino- 1 , 1 -biphenyl)]palladium(II) rt Room temperature

[0151] Rt Retention time

[0152] SFC Supercritical fluid chromatography

[0153] °C Degree Celsius ml Milliliter(s) mmol Millimole(s) min Minute(s) pmol Micromole(s) pl Microliter(s) h Hour(s)

[0154] Analytical methods used

[0155] NMR:

[0156] The proton magnetic resonance spectra (*H NMR), as described below, are recorded at 400 MHz or 500 MHz, mainly in DMSO-de, using the DMSO peak as reference. The chemical shifts (5) are expressed in parts per million (ppm). The signals observed are expressed as follows: s = singlet; d = doublet; t = triplet; m = multiplet or br s = broad singlet; br m = broad multiplet

[0157] LCMS:

[0158] The LCMS characteristics, as described below, indicates the different high-performance liquid chromatography analytical methods used. Method E:

[0159] System Waters UPLC-DAD and QDa; ionization: electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY BEH C18 1.7pm 2.1x100mm; Column temperature: 40°C; Flow: 0.343 ml / min; Solvents: A = H2O 95%, ACN 5% (0.5g / l AcNH4); B = ACN Gradient:

[0160] (min) %A %B

[0161] 0 84.2 15.8

[0162] 0.49 84.2 15.8

[0163] 2.67 10.5 89.5

[0164] 4.61 10.5 89.5

[0165] 5.34 84.2 15.8

[0166] 6.07 84.2 15.8

[0167] Method I:

[0168] System Waters UPLC / SQD; ionization: electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS Cl 8 1.6pm 2.1x50mm; Column temperature: 55°C; Flow: 0.8 ml / min; Solvents: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid)

[0169] Gradient:

[0170] (min) %A %B

[0171] 0 98 2

[0172] 2.50 0 100

[0173] 2.90 0 100

[0174] 2.95 98 2

[0175] 3.00 98 2

[0176] Method R:

[0177] System Waters UPLC-DAD and QDa; ionization: electrospray in positive and / or negative mode (ES+ / -); Column: BEH-C18 50mm*2,l mm-l,7pm; Column temperature: 40°C; Flow: 0.5 ml / min; Solvents: A = H2O 95%, ACN 5% (0.5g / l AcNH4); B = ACN Gradient:

[0178] (min) %A %B 0 95 5

[0179] 0.2 95 5

[0180] 1.2 5 95

[0181] 2.8 5 95

[0182] 3.0 95 5

[0183] 3.4 95 5

[0184] Method S:

[0185] System Waters UPLC-DAD and QDa; ionization: electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY BEH Cl 8 1.7 pm 2.1x50mm; Column temperature: 40°C Flow: 0.50 ml / min; Solvents: A = H2O 95%, ACN 5% (0.5g / l AcNH4); B = ACN Gradient:

[0186] (min) %A %B

[0187] 0 95 5

[0188] 1 5 95

[0189] 2.6 5 95

[0190] 2.8 95 5

[0191] 3.3 95 5

[0192] 3.5 5 95

[0193] Method T:

[0194] System Waters UPLC-DAD and ZQ; ionization: electrospray in positive and / or negative mode (ES+ / -); Column: Xbridge Cl 8 100mm*4,6 mm 5pm; Column temperature: 30°C;

[0195] Flow: 0.8 ml / min; Solvents: A = H2O (0.2% NH4HCO3); B = ACN

[0196] Gradient:

[0197] (min) %A %B

[0198] 0 80 20

[0199] 0.5 80 20

[0200] 5.0 10 90

[0201] 9.0 10 90

[0202] 10.5 80 20

[0203] 12 80 20 Method U:

[0204] System Waters UPLC-SQD2; ionization: electro spray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH Cl 8+ 1.7pm 2.1x50mm; Column temperature: 60°C; Flow: 1.0 ml / min; Solvents: A = H2O (0.1% formic acid) ; B = ACN (0.1% formic acid) Gradient:

[0205] (min) %A %B

[0206] 0 97 3

[0207] 0,1 97 3

[0208] 2.10 3 97

[0209] 2.45 3 97

[0210] 3,0 97 3

[0211] Method V:

[0212] System Waters UPLC-SQD2; ionization: electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6pm 2.1x50mm; Column temperature: 50°C; Flow: 1 ml / min; Solvents: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid) Gradient:

[0213] (min) %A %B

[0214] 0 95 5

[0215] 1.50 1 99

[0216] 1.90 1 99

[0217] 1.95 95 5

[0218] 2.00 95 5

[0219] Mass spectrometry results are reported as the ratio of mass over charge.

[0220] Reactions under microwaves were realized using a Biotage Initiator apparatus.

[0221] Synthesis of examples according to Synthesis scheme 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-

[0222] 3 -yl] -5-methyl-phenol;hydrochloride Int 1.1: 2-iodo-5-methyl-benzene-l,3-diol

[0223] Y T

[0224] OH

[0225] At 0 °C, to a solution of 5 -methylbenzene- 1,3 -diol 1 (2.00 g, 16.1 mmol) in 20 ml of acetonitrile was added NIS (3.62 g, 16.1 mmol). The reaction was stirred at 0 °C for 10 minutes. The mixture was poured into a saturated solution of Na2S20a, then was extracted with EtOAc three times. The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure. The residue was triturated in DIPE. The solid was filtered and the filtrate was taken up in DCM and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH (from 100 / 0 to 95 / 5 to give the title compound as a white solid (3.30 g, 82%).

[0226] LCMS (Method S): Rt = 0.88; MS m / z [M-H]- = 249;

[0227] Int 1.2: 5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzene-l,3-diol

[0228] In a Schlenk tube, a mixture of 2-iodo-5-methyl-benzene-l,3-diol (3.30 g, 0.0132 mol) and TEA (12.9 mL, 0.0924 mol) in 55 ml of 1,4-dioxane was purged with N2. Pinacolborane (9.58 mL, 0.0660 mol) was added dropwise. After ending of bubbling, Pd(OAc)2 (148 mg, 0.000660 mol) and CyJohnPhos (463 mg, 0.00132 mol) were added and the mixture was heated at 80 °C for 18 h. After cooling down to rt, the reaction mixture was filtered, and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH (from 100 / 0 to 97 / 3 to give the title compound as an orange solid (2.53 g, 77%).

[0229] 1H NMR (400 MHz, DMSO-d6) 5 (ppm): 8.68 (s, 2H), 6.06 (d, J = 0.8 Hz, 2H), 2.11 (s, 3H), 1.28 (s, 12H).

[0230] Int 1.3: [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol

[0231] In a microwave vial, to a solution of [(2S)-morpholin-2-yl]methanol (300 mg, 1.95 mmol) in 4 ml of l-methylpyrrolidin-2-one were added DIPEA (379 mg, 0.510 mL, 2.93 mmol) and 3,6-dichloropyridazine (291 mg, 1 .95 mmol). The reaction mixture was heated at 150 °C under microwave irradiation with a power output ranging from 0 to 400 W for 1 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of heptane / EtOAc (from 100 / 0 to 50 / 50, then 30 / 70 to 0 / 100) to give the title compound as a colorless oil (262 mg, 58 %).

[0232] LCMS (Method S): Rt = 0.76; MS m / z [M-H]- = 230.1 ;

[0233] Int 1.4: (2S)-4-(6-chloropyridazin-3-yl)-2-(tetrahydropyran-2-yloxymethyl) morpholine

[0234] To a stirred solution of [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol (1.65 g, 7.18 mmol) in 33 ml of DCM were added PPTS (181 mg, 0.718 mmol) and 3,4-dihydro-2H- pyran (1.31 mL, 14.4 mmol). The reaction mixture was stirred atrtfor 18 h. A 10% aqueous solution of K2CO3 was added. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSCL, were filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of heptane / EtOAc (from 100 / 0 to 50 / 50, then 30 / 70) to give the title compound as a white solid (2.05 g, 91 %). m NMR (400 MHz, DMSO) 5 (ppm): 7.58 (dd, J = 9.6, 0.9 Hz, 1H), 7.41 (dd, J = 9.7, 2.4 Hz, 1H), 4.61 (t, J = 3.5 Hz, 1H), 4.28 - 4.18 (m, 1H), 4.11 - 4.03 (m, 1H), 3.99 - 3.91 (m, 1H), 3.81 - 3.64 (m, 3H), 3.63 - 3.54 (m, 1H), 3.52 - 3.40 (m, 2H), 3.06 - 2.92 (m, 1H), 2.86 - 2.69 (m, 1H), 1.80 - 1.57 (m, 2H), 1.53 - 1.42 (m, 4H). Int 1.5: 5-methyl-2-[6-[(2S)-2-(tetrahydropyran-2-yloxymethyl)morpholin-4-yl] pyridazin-3 -yl]benzene- 1 ,3 -diol

[0235] In a Schlenk tube, under N2, to a solution of 5-methyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzene-l,3-diol (Int 1.2 - 1.62 g, 6.48 mmol) and (2S)-4-(6- chloropyridazin-3-yl)-2-(tetrahydropyran-2-yloxymethyl)morpholine (Int 1.4 - 1.03 g, 6.48 mmol) in 19 ml of 1 ,4-dioxaneand4.5 ml of water were addedXPhos (140mg, 0.324 mmol), K2CO3 (2.69 g, 19.4 mmol) and XPhos Pd G2 (255 mg, 0.324 mmol). The reacting mixture was purged again with N2, then was heated at 90 °C for 4h. After cooling down to rt, the reaction mixture was quenched with water and was extracted with a 80 / 20 DCM / MeOH mixture. The combined organic layers were dried over MgSCC, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH (from 100 / 0 to 95 / 5) to give a first fraction of the title compound as an orange oil (559 mg, 22%), and a second fraction (1.1 g) which was repurified by flash chromatography on silica gel using a gradient of DCM / MeOH (from 100 / 0 to 97 / 3) to give a second fraction of the title compound as an orange oil (394 mg, 15%).

[0236] LCMS (Method R): Rt = 1.27; MS m / z [M-H]- = 400.2;

[0237] Int 1.6: [3-hydroxy-5-methyl-2-[6-[(2S)-2-(tetrahydropyran-2-yloxymethyl)morpholin

[0238] -4-yl]pyridazin-3-yl]phenyl] trifluoro methanesulfonate

[0239] To a solution of 5-methyl-2-[6-[(2S)-2-(tetrahydropyran-2-yloxymethyl)morpholin-4- yl]pyridazin-3-yl]benzene-l,3-diol (952 mg, 2.37 mmol) in 16 ml of dichloromethane were added TEA (0.396 mL, 2.85 mmol), 1,1,1 -triflu oro-N-phenyl-N-

[0240] (trifluoromethylsulfonyl)methanesulfonamide (932 mg, 2.61 mmol) and DMAP (29.0 mg, 0.237 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried over MgSCU, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH (from 100 / 0 to 97 / 3), then repurified by reversephase preparative LC (Glass Column YMC -Actus Triart Prep C18-S 250*50mm 15 pm Flow rate 100 ml / min-Focused isocratic mode MeCN / aq. NH4HCO30.2% pH=7.960 / 40) to give the title compoundas a colorless oil (191 mg, 15 %).

[0241] LCMS (Method T): Rt = 7.15 ; MS m / z [M-H]- = 534.3;

[0242] Int 1.7: 3-(difluoromethoxy)-5-methyl-2-[6-[(2S)-2-(tetrahydropyran-2-yloxymethyl) morpholin-4-yl]pyridazin-3-yl]phenol

[0243] Under inert atmosphere, [3-hydroxy-5-methyl-2-[6-[(2S)-2-(tetrahydropyran-2- yloxymethyl)morpholin-4-yl]pyridazin-3-yl]phenyl] trifluoromethanesulfonate (100 mg, 0.187 mmol) and KOH (210 mg, 3.75 mmol) were dissolved in 2.6 ml of ACN (2.6 mL) and 2.6 ml of water. The reaction mixture was cooled to -10 °C and l-[[bromo(difhioro)methyl]- ethoxy-phosphoryl]oxyethane (0.067 mL, 0.375 mmol) was added. The reaction mixture was stirred at -10 °C for 30 min then allowed to warm to rt. l -[[bromo(difluoro)methyl]- ethoxy-phosphoryl]oxy ethane (0.067 mL, 0.375 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was extracted twice with DCM. The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH (from 100 / 0 to 95 / 5) to give the title compound as a reddish oil (18 mg, 21 % yield), which was used without any further purification in the next step.

[0244] LCMS (Method R): Rt = 1.44; MS m / z [M-H]- = 450.1 ; 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5- methyl-phenol;hydrochloride (Example 1)

[0245] HC1 4N in dioxane (0.0498 mL, 0.199 mmol) was added dropwise to a solution of 3 - (difluoromethoxy)-5-methyl-2-[6-[(2S)-2-(tetrahydropyran-2-yloxymethyl)morpholin-4-yl] pyridazin-3-yl]phenol (18.0 mg, 3.99e-5 mol) in 3 ml of 1,4-dioxane. The mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to give, after lyophilization, the title compound as a white solid (8.0 mg, 43% yield, 87 % of purity).

[0246] Example 2: 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin- 3-yl]phenol

[0247] Int 2.1: 2-bromo-3-(ethoxymethoxy)phenol

[0248] To a solution of 2-bromobenzene-l,3-diol (26.45 mmol, 5 g) in 150 ml of dichloromethane were added DIPEA (31.74 mmol, 5.53 ml) and chloromethoxy ethane (26.45 mmol, 2.45 ml). The mixture was stirred at rt for 2h then diluted with 150 ml of diethylether and 150 ml of pentane. The organic layer was washed twice with 100 ml of water, was dried over NaoSCE filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% of diethylether in pentane to give the title compound (2.84g, 43% yield) as a colorless oil.

[0249] LCMS (Method V): Rt = 0.88; MS m / z [M+H]+= 247; Int 2.2: 2-bromo-l-(difluoromethoxy)-3-(ethoxymethoxy)benzene

[0250] To a solution of 2-bromo-3-(ethoxymethoxy)phenol (11.1 mmol, 2.74 g) in 180 ml of acetonitrile was added 4N aqueous sodium hydroxide sodium (410 mmol, 103 ml). To the biphasic mixture stirred at -25°C was added dropwise 1- [[bro mo(difluoro)methyl] -ethoxy- pho sphoryl]oxy ethane (16.6 mmol, 3 ml) and the mixture was stirred at rt for 1.5h, then diluted with 250 ml of diethylether. The organic layer was washed twice with 100 ml of water, dried over MgSC , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 50% of diethylether in pentane to give the title compound (2.73g, 83% yield) as a colorless oil. LCMS (Method V): Rt = 1.11 ; MS m / z [M-CH3-CH2-O]+= 251 ;

[0251] Int 2.3: 2-[2-(difluoromethoxy)-6-(ethoxymethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane

[0252] Under argon, at 10°C, to a solution of 2-bromo-l-(difluoromethoxy)-3- (ethoxymethoxy)benzene (0.34 mmol, 100 mg) in 10 ml of anhydrous 1,4 -dioxane were added triethylamine (0.77 mmol, 106 pl) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.94 mmol, 134 pl). Then, were added Pd(OAc)2(0.017 mmol, 3.8 mg) and dicyclohexyl-(2- phenylphenyl)phosphane (0.34 mmol, 11.8 mg) and the mixture was stirred at 90°C for 2h. After cooling down to rt, the mixture was diluted with 10 ml of diethylether and 10 ml of pentane. The organic layer was washed with 2x10 ml of water, then was dried over NaoSCU filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with an isocratic mixture of 10% of diethylether in pentane to give the title compound as a yellow oil (68 mg, 59% yield).

[0253] LCMS (Method V): Rt = 1.21 ; MS m / z [M-CH3-CH2-O]+= 299;

[0254] Int 2.4: [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol

[0255] A mixture of 3,6-dichloropyridazine (13.42 mmol, 2 g), [(2S)-morpholin-2- yl]methanol;hydrochloride (14.77 mmol, 2.27 g) and triethylamine (29.53 mmol, 4.12 ml) in 20 ml of 1 -butanol were stirred at 130°C for 5h then cooled down to rt and concentrated under reduced pressure. The residue was diluted with a mixture of 25 ml of dichloromethane and 25 ml of EtOAc, filtered and the cake was rinsed with 2x20 ml of EtOAc. The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% of EtOAc in cyclohexane to give the title compound (2.48g, 80% yield) as a white solid.

[0256] LCMS (Method I): Rt = 1.02; MS m / z [M+H]+= 230;

[0257] Int 2.5: [(2S)-4-[6-[2-(difluoromethoxy)-6-(ethoxymethoxy)phenyl]pyridazin-3-yl] morpholin-2-yl]methanol

[0258] Under Ar, to a solution of 2-[2-(difluoromethoxy)-6-(ethoxymethoxy)phenyl]-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (Int 2.3, 0.19 mmol, 66 mg) and [(2S)-4-(6- chloropyridazin-3-yl)morpholin-2-yl]methanol (Int 2.4, 0.17 mmol, 40 mg) in 5 ml of 1,4- dioxane was added a 2N sodium carbonate aqueous solution (0.52 mmol, 261 pl), then tetrakis(triphenylphosphine)palladium(0) (0.017 mmol, 20 mg). The mixture was stirred at 100°C for 3h. After cooling down to rt, the mixture was diluted with 20 ml of diethylether and the organic layer was washed with 5 ml of water. The aqueous layer was extracted with 10 ml of dichloro methane and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purifiedby flash chromatography on silica gel using a gradient of Cyclohexane / EtOAc / MeOH (from 100 / 0 / 0 to 0 / 90 / 10) to give the title compound (43 mg, 60% yield) as a yellow oil.

[0259] LCMS (Method V): Rt = 0.66; MS m / z [M+H]+= 412;

[0260] 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl] phenol (Example 2)

[0261] A solution of [(2S)-4-[6-[2-(difluoromethoxy)-6-(ethoxymethoxy)phenyl]pyridazin-3- yl]morpholin-2-yl]methanol (0.10 mmol, 43 mg) in 5 ml of acetonitrile and 1 ml of a 4N aqueous HC1 solution was stirred at rt for 18 h. The mixture was then diluted with 30 ml of dichloromethane and 30 ml of a saturated aqueous sodiumbicarbonate solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated in 3 ml of diethylether and filtered to give the title compound (32 mg, 86% yield) as a white solid.

[0262] Compounds Example 5 and 10 were synthesized analogously to Example 2 respectively starting from Int 6.3 and Int 9.1. 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-3-

[0263] ( trifluoromethoxy )phenol

[0264] Int 4.1: 3-methyl-5-(trifluoromethoxy)phenol At 0 C, to a solution of 12 ml of water and 8 ml of sulfuric acid was added 3 -methyl-5- (trifluoromethoxy)aniline (4.00 g, 0.0209 mol). NaNC>2 (2.89 g, 0.0419 mol, 2 eq.) was then added portionwise. The mixture was stirred at 0 °C for 30 min. The ice bath was removed, and mixture was warmed at 80 °C for 2h. After cooling down to rt, ethyl acetate (50 mL) was added. The organic layer was washed with water (2x50 mL) and brine (50 mL), then was dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with heptane / EtOAc 100 / 0 to 50 / 50 to give 1.9 g of a dark red-orange oil which was repurified by flash chromatography on silica gel eluting with heptane / DCM 100 / 0 to 0 / 100 to give the title compound as a dark red -o range oil (0.80 g, 20% yield). iH NMR (500 MHz, CDC13) 6 (ppm): 6.62 (s, 1H), 6.58 (d, J = 2.2 Hz, 1H), 6.52 (s, 1H), 4.88 (s, 1H), 2.31 (s, 3H).

[0265] Int 4.2: l-(ethoxymethoxy)-3-methyl-5-(trifluoromethoxy)benzene

[0266] To a solution of 3-methyl-5-(trifluoromethoxy)phenol (1,2 g, 6.22 mmol) in 17 ml of DMF was added potassium carbonate (2.58 g, 0.0187 mol). Then was dropwise added chloromethoxy ethane (1.18 g, 0.0124 mol) and the mixture was stirred at rt for 18 h. Ethyl acetate (200 mL) was added, and the resulting solution was washed with a IM sodium hydroxide solution (3x200mL), water (200 mL) and brine (200 mL), then dried over MgSC filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with heptane / DCM 100 / 0 to 70 / 30 to give the title compound as a translucide oil (0.434 g, 28% yield). iH NMR (500 MHz, CDC13) 6 (ppm): 7.30 (t, J = 8.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.89 - 6.85 (m, 1H), 5.22 - 5.18 (m, 2H), 3.75 - 3.69 (m, 2H), 1.38 (s, 12H), 1.21 (t, J = 7.1 Hz, 3H). Int 4.3: 2-[2-(ethoxymethoxy)-4-methyl-6-(trifluoromethoxy)phenyl]-4,4,5,5- tetramethyl-l,3,2-dioxaborolane

[0267] Under N2, at -78°C, to a solution of l-(ethoxymethoxy)-3-methyl-5- (trifluoromethoxy)benzene (320 mg, 0.00128 mol) in 5 ml of THF was slowly added n- butyllithium (2.5 M in hexanes, 0.614 mL, 0.00153 mol) and the mixture was stirred at -78 °C for 2h. 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.357 g, 0.00192 mol) was added and the mixture was stirred at -78 °C for 2h, then at room temperature for 18 h. An aqueous solution of 5% NH4CI (50 ml) was added, and the resulting solution was extracted with DCM (3 times). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (460 mg, -77% purity, 74% yield).

[0268] ' H NMR (500 MHz, CDCI3) 6 (ppm): 6.78 (s, 1H), 6.69 (s, 1H), 5.18 (s, 2H), 3.72 (q, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.36 (s, 12H), 1.25 - 1.20 (m, 8H; overintegration due to overlap with pinacol, expected 3H).

[0269] Int 4.4: 5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy) phenol

[0270] To a solution of 2-[2-(ethoxymethoxy)-4-methyl-6-(trifluoromethoxy)phenyl]-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (460 mg, 0.000942 mol) in 2.6 ml of 1,4 -dioxane was slowly added hydrogen chloride 4M in dioxane (1.88 mL, 0.00753 mol). The resulting mixture was stirred at 60 °C for 30 min. 40 ml of water was added and the resulting solution was extracted with DCM (3 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a brown oil (314 mg, quant). iH NMR (500 MHz, CDC13) 6 (ppm): 8.37 (s, 1H), 6.66 (s, 1H), 6.59 (s, 1H), 2.31 (s, 3H), 1.36 (s, 12H).

[0271] 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-3-(trifluoro- methoxy)phenol (Example 4)

[0272] Under N2, to a solution of 5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- (trifluoromethoxy)phenol (Int 4.4, 0.364 g, 0.00114 mol), [(2S)-4-(6-chloropyridazin-3- yl)morpholin-2-yl]methanol (Int 2.4, 175 mg, 0.000762 mol) and potassium carbonate (0.316 g, 0.00229 mol) in 4 ml of 1,4-dioxane and 1 ml of water were added XPhos Pd G2 (0.0300 g, 3.81e-5 mol), XPhos (0.0182 g, 3.81e-5 mol). The resulting mixture was stirred at 90 °C for 2h. After cooling down to rt, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with heptane / EtOAc 100 / 0 to 0 / 100 to give 272 mg of a bright yellow solid. This solid was dissolved in 5 ml of hot MeOH, then 50 ml of cold water was added. After filtration, the precipitate was washed with hot water (2x25 mL), dissolved in 20 ml of DCM and 10 ml of MeOH and concentrated under reduced pressure to give the title compound (241 mg, 82% yield) as a bright yellow solid.

[0273] Compound Example 3 was synthesized analogously to Example 4 starting from Int 3.3. Compounds Example 12 and 13 were synthesized analogously to Example 4 respectively starting from Int 6.3 and Int 7.11. 2-[6 [(3aS, 7aR)-6-methyl-3, 3a, 4,5,7, 7a-hexahydro-2H-pyrrolo[2,3-c]pyridin- l-yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol

[0274] Int 6.1: tert-butyl (3aR,7aR)-l-(6-chloropyridazin-3-yl)-3, 3a, 4,5,7, 7a-hexahydro-2H- pyrrolo[2,3-c]pyridine-6-carboxylate

[0275] In a microwave vial, a mixture of tert-butyl (3aR,7aR)-l,2,3,3a,4,5,7,7a- octahydropyrrolo[2,3-c]pyridine-6-carboxylate (1 g, 4.42 mmol), 3, 6 -dichloro pyridazine (658 mg, 4.42 mmol) and K3PO4 (8.84 mmol) in 14.5 ml of DMSO was heated at 80 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 2h. This reaction was done 3 times. Each reaction mixture was filtered, then combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with DCM / MeOH 100 / 0 to 95 / 5 to give the title compound (2.93 g, 65% yield).

[0276] 1H NMR (400 MHz, DMSO-d6) 5 (ppm): 7.53 (d, J = 9.4 Hz, 1H), 6.98 (d, J = 9.4 Hz, 1H), 4.07 - 4.03 (m, 1H), 3.67 - 3.62 (m, 1H), 3.60 - 3.49 (m, 1H), 3.41 - 3.30 (m, 3H), 3.11 - 3.04 (m, 1H), 2.46 - 2.44 (m, 1H), 2.16 - 1.90 (m, 2H), 1.80 (s, 1H), 1.62 (s, 1H), 1.53 - 0.98 (m, 9H)

[0277] Int 6.2: (3aS,7aR)-l-(6-chloropyridazin-3-yl)-2, 3,3a, 4,5, 6,7, 7a-octahydropyrrolo[2,3- c]pyridine;2,2,2-trifluoroacetaldehyde

[0278] At 0 °C, to a stirred solution of tert-butyl (3aR,7aR)-l-(6-chloropyridazin-3-yl)- 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (2.93 g, 0.00865 mol) in 45 ml of DCM was added 2,2,2-trifluoroacetic acid (6.42 mL, 0.0865 mol). The reaction mixture was stirred at rt for 18 h.

[0279] The reaction mixture was concentrated under reduced pressure, then taken up in toluene before and concentrated again under reduced pressure, to give the title compoundas a brown oil (6.36 g, quant, yield). The compound was used without further purification for the next step.

[0280] 1H NMR (400 MHz, DMSO-d6) 5 (ppm): 8.42 (s, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.04 (d, J = 9.5 Hz, 1H), 4.42 - 4.32 (m, 1H), 3.62 - 3.48 (m, 2H), 3.42 - 3.31 (m, 1H), 3.20 - 2.87 (m, 3H), 2.58 - 2.52 (m, 1H), 2.24 - 1.93 (m, 3H), 1.91 - 1.81 (m, 1H).

[0281] Int 6.3: (3aS,7aR)-l-(6-chloropyridazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H- pyrrolo[2,3-c]pyridine

[0282] Formaldehyde (37% in water) (1.01 mL, 0.0129 mol) and DIPEA (1.47 mL, 0.00857 mol) were added to a solution of (3aS,7aR)-l-(6-chloropyridazin-3-yl)-2,3,3a,4,5,6,7,7a- octahydropyrrolo[2,3-c]pyridine;2,2,2-trifluoroacetaldehyde (Int 6.2, 1.00 g, 0.00214 mol) in 30 ml of 1,2-dichloroethane. The reaction mixture was stirred at rt for 30 min then NaBH(OAc)a (681 mg, 0.00321 mol) was added portionwise. The reaction mixture was stirred at rt for 2h.

[0283] The reaction mixture was poured into ice and the organic layer was extracted with DCM. The aqueous layer was then basified with a solution of NaOH 3M, then extracted with a solution of DCM / MeOH 80 / 20, dried over MgSCU, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (431 mg, 80%).

[0284] 1H NMR (500 MHz, DMSO-d6) 5 (ppm): 7.44 (d, J = 9.5 Hz, 1H), 6.98 (d, J = 9.5 Hz, 1H), 4.17 (s, 1H), 3.55 - 3.47 (m, 1H), 3.41 - 3.32 (m, lH), 3.02 (s, 1H), 2.56 (s, 1H), 2.40 - 2.31 (m, 1H), 2.19 (s, 3H), 2.14 - 2.02 (m, 2H), 1.99 - 1.84 (m, 2H), 1.82 - 1.74 (m, 1H), 1.69 (dd, J = 13.9, 2.7 Hz, 1H). 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l-yl] pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol (Example 6)

[0285] In a microwave tube, under N2, to a solution of (3aS,7aR)-l-(6-chloropyridazin-3-yl)-6- methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine (188 mg, 0.744 mmol) and 3- (difluoromethoxy)-5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Int 7.5; 379 mg, 1.26 mmol) in 4 ml of 1,4-dioxane and 1 ml of water was added K^CCE QOS mg, 2.23 mmol). The mixture was purged with N2. XPhos (16 mg, 0.0372 mmol) and and XPhos Pd G2 (29 mg, 0.0372 mmol) were then added, and the solution was purged again with N2. The mixture was heated at 90 °C for 2h. After cooling down to rt, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / (MeOH / NH4OH 90 / 10) 100 / 0 to 90 / 10 to give a green oil (232 mg). This oil was taken up in diethyl ether and filtered. The filtrate was taken up in DCM and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / (MeOH / NH4OH 90 / 10) 100 / 0 to 90 / 10 to give the title compound as a pale-green solid (167 mg, 58%).

[0286] Compound Example 9 was synthesized analogously to Example 6 using Int 9.1. 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4] oxazin-4-yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol

[0287] Int 7.1: 2-iodo-5-methyl-benzene-l,3-diol At 0°C, to a solution of 5-methylbenzene-l,3-diol (4.00 g, 32.2 mmol) in 40 ml of acetonitrile was added NIS (7.25 g, 32.2 mmol). The reaction was stirred at 0 °C for 10 minutes. The mixture was poured into a saturated solution of Na2S20a and extracted with EtOAc three times. The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure. The residue was triturated in DIPE. The solid which precipitated was filtered off and the filtrate was taken up in DCM and concentrated under reduced pressure. This residue was purified by flash chromatography on silica gel eluting with DCM / MeOH 100 / 0 to 95 / 05 to give the title compound as a white solid (6.36 g, 79% yield).

[0288] !H NMR (500 MHz, DMSO) 5 (ppm): 9.87 (s, 2H), 6.18 (d, J= 0.8 Hz, 2H), 2.11 (s, 3H).

[0289] Int 7.2: [2-iodo-5-methyl-3-(trifluoromethylsulfonyloxy)phenyl] trifluoro- methanesulfonate

[0290] To a solution of 2-iodo-5-methyl-benzene-l,3-diol (6.22 g, 0.0249 mol) in 124 ml of dichloromethane was added DIPEA (10.2 mL, 0.0597 mol). The solution was cooled to - 78°C and triflic anhydride or also named trifluoromethanesulfonic anhydride (9.91 ml, 0.0597 mol) was dropwise added and the solution was stirred at - 78 °C for 3h. The reaction mixture was quenched with water, warmed to rt and extracted twice with DCM. The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 100 / 0 to 80 / 20 to give the title compound as an orange oil (12.46 g, 97% yield).

[0291] !H NMR (500 MHz, DMSO) 5 (ppm): 7.48 (s, 2H), 2.44 (s, 3H).

[0292] Int 7.3: (3-hydroxy-2-iodo-5-methyl-phenyl) trifluoromethanesulfonate

[0293] To a solution of [2-iodo-5-methyl-3-(trifluoromethylsulfonyloxy)phenyl] trifluoromethanesulfonate (12.5 g, 0.0242 mol) in 190 mL of 1,2 -dimethoxyethane was added cesium carbonate (13.4 g, 0.0412 mol). The reaction mixture was stirred at 80 °C for 4h. Cesium carbonate (1.58 g, 0.00485 mol) was added, and the reaction mixture was stined for another 2h. After cooling down to rt, water was added, and the reaction mixture was extracted with DCM. The organic layer was dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 100 / 0 to 80 / 20 to give the title compound as a pale-brown oil (7.75 g, 83% yield).

[0294] H NMR (400 MHz, DMSO) 5 (ppm): 10.98 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 2.27 (s, 3H).

[0295] Int 7.4: 3-(difluoromethoxy)-2-iodo-5-methyl-phenol

[0296] Under N2, to a solution of (3 -hydroxy-2-iodo-5 -meth yl-phenyl) trifluoro methanesulf onate (3.94 g, 10.3 mmol) in 80 ml of ACN and 80 ml of water was added KOH (11.6 g, 206 mmol). The reaction mixture was cooled to -20 °C and l-[[bromo(difhioro)methyl]-ethoxy- phosphoryl]oxy ethane (3.67 mL, 20.6 mmol) was dropwise added. The reaction mixture was stirred at -10 °C for 30 min, then allowed to warm to room temperature and stirred for 3h. The mixture was quenched with water and neutralized with an aqueous solution of HC1 IM. The aqueous layer was extracted with DCM. The combined organic layers were then dried over MgSCL, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 90 / 10 to 60 / 40 to give the title compound as a white solid (2.58 g, 83% yield). TI NMR (400 MHz, DMSO) 8 (ppm): 10.54 (s, 1H), 7.18 (t, 7 = 73.8 Hz, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 2.23 (s, 3H).

[0297] Int 7.5: 3-(difluoromethoxy)-5-methyl-2-(4,4,5,5-tetramethyl-1 ,2-dioxaborolan-2-yl) phenol

[0298] In a sealed tube, under N2, to a solution of 3-(difluoromethoxy)-2-iodo-5-methyl-phenol (2.47 g, 8.23 mmol) and NEt3(8.03 mL, 57.6 mmol) in 120 ml of 1,4-dioxane was slowly added HBpin (5.97 mL, 41.2 mmol). Once bubbling had ceased, Pd(OAc)2(222 mg, 0.988 mmol) and CyJohnPhos (635 mg, 1.81 mmol) were added, the mixture was purged again with N2then heated at 80 °C for 18h. Aftercoolingdown tort, water was added. The mixture was filtered on a pad of celite. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 100 / 0 to 90 / 10 to give the title compound as a red oil (497 mg, 20% yield). iH NMR (400 MHz, DMSO) 5 (ppm): 9.45 (s, 1H), 7.01 (t, J= 74.9 Hz, 1H), 6.47 (s, 1H), 6.39 (s, 1H), 2.23 (s, 3H), 1.27 (s, 12H).

[0299] Int 7.6: tert-butyl (3S,4R)-4-hydroxy-3-[(4-nitrophenyl)sulfonylamino]piperidine-l- carboxylate.

[0300] To a cooled solution (0-5°C) of tert-butyl (3S,4R)-3-amino-4-hydroxy-piperidine-l- carboxylate (46.2 mmol, 10 g) in 300 ml of dichloromethane was added triethylamine (125 mmol, 17.4 ml) and 4-nitrobenzenesulfonyl chloride (50.9 mmol, 11.3 g) and the mixture was stirred for 30 min at rt. The mixture was then diluted with 600 ml of diethylether and 500 ml of water. The organic layer was washed with 250 ml of water, 250 ml of a 5% aqueous citric acid solution and 100 ml of brine (twice), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (19.6 g, 100% yield) as a pale yellow solid.

[0301] LCMS (Method V): Rt = 0.96; MS m / z[M+H]+= 400

[0302] Int 7.7: tert-butyl (4aS,8aR)-4-(4-nitrophenyl)sulfonyl-3, 4a, 5,7,8, 8a-hexahydro-2H- pyrido[4,3-b][l,4]oxazine-6-carboxylate.

[0303] Under Ar, a suspension of tert-butyl (3S,4R)-4-hydroxy-3-[(4- nitrophenyl)sulfonylamino]piperidine-l-carboxylate (24.9 mmol, 10 g), potassium carbonate (100 mmol, 13.8 g) and 1,2 -dibromoethane (249 mmol, 21.8 ml) in 500 ml of acetonitrile was stirred at reflux for 30h. After cooling down to rt, the mixture was filtered, the cake rinsed with 50 ml of acetonitrile and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% of EtOAc in cyclohexane to give the title compound (7.35 g, 73% yield on the 2 steps) as a yellow foam.

[0304] LCMS (Method V): Rt = 1.18; MS m / z [M+H]+= 428

[0305] Int 7.8: tert-butyl (4aS,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][l,4]oxazine-6- carboxylate.

[0306] To a solution of tert-butyl (4aS,8aR)-4-(4-nitrophenyl)sulfonyl-3,4a,5,7,8,8a-hexahydro- 2H-pyrido[4,3-b][l,4]oxazine-6-carboxylate (34.4mmol, 14.7 g) and 2 -sulfanylacetic acid (82.5 mmol, 5.76 ml) in 200 ml of N,N-dimethylformamide were added lithium hydroxide hydrate (193 mmol, 8.08 g) and the mixture was stirred at rt for 18h. The mixture was then diluted with 1 L of EtOAc and washed successively with 500 ml of water, 500 ml then 250 ml of a 0.1 N sodium hydroxide aqueous solution. The aqueous layers were pooled and successively extracted with 2x500 ml of EtOAc and 2x250 ml of a mixture of chloroform / isopropanol: 90 / 10. All the organic layers were pooled and washed with 100 ml of a 0.1 N sodium hydroxide aqueous solution, then dried over Na2SO4, filtered andconcentrated under reduced pressure at 70°C to give the title compound (7.22 g, 87% yield) as a yellow oil.

[0307] LCMS (Method W): Rt = 0.42; MS m / z [M+H]+= 243)

[0308] Int 7.9: tert-butyl (4aS,8aR)-4-(6-chloropyridazin-3-yl)-3, 4a, 5,7,8, 8a-hexahydro-2H- pyrido[4,3-b][l,4]oxazine-6-carboxylate

[0309] A solution of tert-butyl (4aS,8aR)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][l,4]oxazine-6- carboxylate (24.76 mmol, 6g), 3,6 -dichlorop yridazine (37.14 mmol, 5.53g) and triethylamine (74.28 mmol, 10.4 ml) in 20 ml of 1 -butanol was stirred at 150°C for Ih while removing 1 -butanol and triethylamine under a stream of argon. The mixture was stirred at 150°C for another 1 h 30 then cooled down to rt. The mixture was triturated with 200 ml of EtOAc and filtered. The cake was rinsed with 2x50 ml of EtOAc and the filtrates were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% of EtOAc in cyclohexane to give the title compound (3.57g, 41% yield) as a yellow oil.

[0310] LCMS (Method V): Rt = 1.07; MS m / z [M+H]+= 355

[0311] Int 7.10: (4aS,8aR)-4-(6-chloropyridazin-3-yl)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3- b][l,4]oxazine

[0312] A solution of tert-butyl (4aS,8aR)-4-(6-chloropyridazin-3-yl)-3,4a,5,7,8,8a-hexahydro-2H- pyrido[4,3-b][l ,4]oxazine-6-carboxylate (7.05 mmol, 2.5g) in 45 ml of dichloromethane and 5 ml of trifluoroacetic acid was stirred at rt for 18h, then concentrated under reduced pressure. The residue was diluted with 50 ml of dichloromethane and washed with 50 ml of a saturated aqueous sodium bicarbonate solution and 10 ml of a 2N aqueous sodium carbonate solution. The pooled aqueous layers were extracted with 4x30 ml of DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.79 g, 100% yield) as a colorless oil.

[0313] LCMS (Method W): Rt = 0.58; MS m / z [M+H]+= 255

[0314] Int 7.11: (4aS,8aR)-4-(6-chloropyridazin-3-yl)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H- pyrido[4,3-b][l,4]oxazine

[0315] Under Ar, to a solution of (4aS,8aR)-4-(6-chloropyridazin-3-yl)-2,3,4a,5,6,7,8,8a- octahydropyrido[4,3-b][l,4]oxazine (7.05 mmol, 1.79 g) cooled to 0-5°C were successively added 7 ml of acetic acid, a 37% aqueous solution of formaldehyde (35 mmol, 2.7 ml) and sodium triacetoxyborohydride (13 mmol, 2.7g) portion wise. The mixture was stirred at rt for lh30). 100 ml of dichloromethane, 100 ml of a saturated aqueous sodium bicarbonate solution and 20 ml of a 2N aqueous sodium carbonate solution were added. The aqueous layer was extracted with 100 ml of dichloromethane and the pooled organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.86 g, 98% yield) as a yellow oil.

[0316] LCMS (Method W): Rt = 0.60; MS m / z [M+H]+= 269

[0317] 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4-yl] pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol (Example 7)

[0318] In a microwave tube, under N2, to a solution of (4aS,8aR)-4-(6-chloropyridazin-3-yl)-6- methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazine (Int 7.11 - 250 mg, 0.930 mmol) and 3-(difluoromethoxy)-5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenol(419 mg, 1.40 mmol) in 6 ml of 1,4 -dioxane and 1.5 ml of water was added K2CO3 (3 eq., 386 mg, 2.79 mmol). The mixture was purged with N2. XPhos (20.2 mg, 0.0465 mmol) and and XPhos Pd G2 (36.6 mg, 0.0465 mmol) were then added, and the solution was purged again with N2. The mixture was heated at 90 °C for 2h. After cooling down to rt, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / (MeOH / NH4OH 90 / 10) 100 / 0 to 90 / 10 to give a green oil (392 mg). This oil was taken up in diethyl ether and filtered. The filtrate was taken up in DCM and concentrated under reduced pressure. The residue was taken up in heptane and co-evaporated under reduced pressure three times to afford the title compound as a pale-green solid (177 mg, 47% yield).

[0319] Compound Example 8 was synthesized analogously to Example 7, using Int 8.1. 3 -(difluoro meth oxy)-5-fluoro-2- [6- [(2S)-2-(hydroxymethyl)morpholin-4- yl]pyridazin-3-yl]phenol Int 11.1: l-bromo-3-(ethoxymethoxy)-5-fluoro-benzene

[0320] Under N2, to a solution of 3-bromo-5-fluoro-phenol (5.00 g, 0.0262 mol) in 300 ml of acetone was added K2CO3 (7.24 g, 0.0524 mol). The mixture was cooled to 0 °C and chloromethoxyethane (3.64 mL, 0.0393 mol) was slowly added. The mixture was allowed to warm to rt and stirred for 18 h. EtOAc and water were added. The organic layer was separated, dried over MgSCE, filtered and concentrated under reduced pressure to give the title compound as a pale-pink oil (6.01 g, 92% yield).

[0321] ' H NMR (500 MHz, DMSO-76) 5 (ppm): 7.15 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.94 (dt, J = 10.9, 2.2 Hz, 1H), 5.28 (s, 2H), 3.66 (q, 7 = 7.1 Hz, 2H), 1.13 (t, 7 = 7.1 Hz, 3H).

[0322] Int 11.2: 3-(ethoxymethoxy)-5-fluoro-phenol

[0323] In a Schlenk tube, a mixture of l -bromo-3-(ethoxymethoxy)-5-fluoro-benzene (2.00 g, 0.00803 mol) and LiOH.HoO (56.0 %, 1.81 g, 0.0241 mol) in 20 ml of 1,4-dioxane and 2 ml of water was purged with N2. Pd2(dba)a (0.0923 g, 0.000161 mol) and BippyPhos (0.163 g, 0.000321 mol) were added. The mixture was purged again with N 2 then stirred at 100 °C for 18 h. After cooling down to rt, a IN aqueous solution of NaOH and EtOAc were added. The aqueous layer was separated and extracted with EtOAc. The aqueous layer was acidified with a IN aqueous solution of HC1 to reach pH about 7-6. The aqueous layer was then extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then taken up in toluene and concentrated under reduced pressure (3x) to give the title compound (0.902 g, 60% yield). iH NMR (400 MHz, DMSO-< / 6) 5 (ppm): 9.91 (s, 1H), 6.33 - 6.25 (m, 2H), 6.20 (dt, J =

[0324] 10.8, 2.2 Hz, 1H), 5.18 (s, 2H), 3.63 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H).

[0325] Int 11.3: 3-(ethoxymethoxy)-5-fluoro-2-iodo-phenol

[0326] At 0 °C, under N2, toasolution of 3-(ethoxymethoxy)-5-fluoro-phenol (2.10 g, 11.3 mmol) in 63 ml of toluene was added NaH 60% in mineral oil (474 mg, 11.8 mmol). The mixture was stirred atO °C for 30 min, then Iodine (3.01 g, 11.8 mmol) was added. The mixture was stirred for 30 min at 0 °C, then allowed to warm to rt and stirred for 1.5h. EtOAc and a 10% aqueous solution of NH4CI were added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 100 / 0 to 90 / 10 to give the title compound as a colorless oil (994 mg, 28% yield).

[0327] ' H NMR (400 MHz, DMSO-t / 6) 5 (ppm): 10.78 (s, 1H), 6.51 (dd, J= 11.1, 2.6 Hz, 1H), 6.40 (dd, J= 10.4, 2.6 Hz, 1H), 5.29 (s, 2H), 3.68 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0328] Int 11.4: l-(difluoromethoxy)-3-(ethoxymethoxy)-5-fluoro-2-iodo-benzene

[0329] Under N2, to a solution of 3-(ethoxymethoxy)-5-fluoro-2-iodo-phenol (1.33 g, 4.26 mmol) in 27 ml of ACN and 27 ml of H2O was added KOH (4.78 g, 85.2 mmol). The reaction mixture was cooled to -20 °C and l-[[bromo(difluoro)methyl] -ethoxy- pho sphoryl]oxy ethane (1.52mL, 8.52 mmol) was added dropwise. The reaction mixture was stirred at - 10 °C for 30 min, then allowed to warm to room temperature and stirred for 2h. The mixture was quenched with water and neutralized with an aqueous solution of HC1 IM. The aqueous layer was extracted with DCM. The combined organic layers were then dried over MgSC , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 100 / 0 to 80 / 20 to give the title compound as a colorless oil (1.39 g, 91 % yield). iH NMR (400 MHz, DMSO-t / d) 5 (ppm): 7.32 (t, J = 73.1 Hz, 1H), 6.98 (dd, J= 11.0, 2.5 Hz, 1H), 6.89 (dd, J = 9.8, 2.5 Hz, 1H), 5.38 (s, 2H), 3.70 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0330] Int 11.5: 2-[2-(difluoromethoxy)-6-(ethoxymethoxy)-4-fluoro-phenyl]-4,4,5,5- tetramethyl-l,3,2-dioxaborolane

[0331] In a sealed tube, under N2, to a solution of 1 -(difluorometho xy) -3-(ethoxymetho xy)-5- fluoro-2-iodo-benzene (1.35 g, 3.73 mmol) and NEb, (1.56 mL, 11.2 mmol) in 33 ml of 1,4- dioxane was slowly added HBpin (1.08 mL, 7.46 mmol). Once bubbling had ceased, the solution was purged with N2. Pd(OAc)2 (41.9 mg, 0.186 mmol) and CyJohnPhos (131 mg, 0.373 mmol) were added, the mixture was purged again with N2 then heated at 80 °C for 18 h. After cooling down to rt, water was added. Then a solution of aqueous NH4CI 10% was added and the solution was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with Heptane / EtOAC 100 / 0 to 40 / 60 to give the title compound as an off- white solid (1.01 g, 75% yield). iH NMR (400 MHz, DMSO-d6) 5 (ppm): 7.20 (t, J = 73.8 Hz, 1H), 6.85 (dd, J= 11.2, 2.0 Hz, IH), 6.71 (dd, J= 10.0, 1.9 Hz, IH), 5.25 (s, 2H), 3.65 (q, J= 7.0Hz, 2H), 1.28 (s, 12H), 1.12 (t, 7 = 7.1 Hz, 3H).

[0332] Int 11.6: 3-(difluoromethoxy)-5-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenol

[0333] A solution of 2-[2-(difluoromethoxy)-6-(ethoxymethoxy)-4-fluoro-phenyl]-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (1.00g, 2.76 mmol) in 26 ml of 1, 4 -dioxane and hydrogen chloride (4 M in dioxane) (5.52 mL, 22.1 mmol) was stirred at 60 °C for 1.5h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over MgSCU, filtered and concentrated under reduced pressure to give the title compound as an off-white solid (843 mg, 100% yield).

[0334] 3-(difluoromethoxy)-5-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin- 3-yl]phenol (Example 11)

[0335] In a microwave tube, under N2, to a solution of [(2S)-4-(6-chloropyridazin-3-yl)morpholin- 2-yl]methanol (Int 1.3 61.0 mg, 0.266 mmol) and 3-(difluoromethoxy)-5-fluoro-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (Int 11.6, 137 mg, 0.452 mmol) in 1.5 ml of 1,4-dioxane and0.4 ml of water was added K2CO3 (110 mg, 0.797 mmol). The mixture was purged with N2. XPhos (5.76 mg, 0.0133 mmol), and XPhos Pd G2 (10.4 mg, 0.0133 mmol) were then added, and the solution was purged again with N2. The mixture was then heated at 80 °C for2h. After cooling down tort, the mixture was concentrated underreducedpressuie. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH 100 / 0 to 95 / 05 to give a yellow solid (120 mg). This solid was purified by reverse phase preparative LC (Column spherical Cl 8 YMC 40 g, liquid loading (DMSO), mobile phase gradientO.2% aq. NPC+HCOa-ZMeCN from 60:20 to 20:60) to afford a yellow solid (83 mg). This solid was repurified by flash chromatography on silica gel using a gradient of DCM / MeOH 100 / 0 to 95 / 05 to give, af ter trituration in DIPE, the title compound as a bright yellow solid (60 mg, 61% yield).

[0336] Synthesis of other intermediates

[0337] Int 3.3: 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifhioromethoxy)phenol

[0338] Int 3.1: l-(ethoxymethoxy)-3-(trifluoromethoxy)benzene

[0339] To a solution of 3 -(trifluoro metho xy)ph enol (1.00 g, 0.00561 mol) and K2CO3 (2.33 g, 0.0168 mol) in 15 ml of DMF was added chloromethoxyethane (1.06 g, 0.0112 mol) and the mixture was stirred at room temperature for 18 h. The resulting solution was diluted in EtOAc and washed twice with water, 3 times with NaOH 1 M aqueous solution, and brine. The organic layer was dried over MgSCU, filtered and concentrated under reduced pressure to give the title compound as a clear oil (809 mg, 61%). iH NMR (500 MHz, CDC13) 6 (ppm): 7.28 (t, J = 8.3 Hz, 1H), 7.00 - 6.95 (m, 1H), 6.94 - 6.90 (m, 1H), 6.88 - 6.83 (m, 1H), 5.22 (s, 2H), 3.73 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).

[0340] Int 3.2: 2-[2-(ethoxymethoxy)-6-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1 ^- dioxaborolane

[0341] At -78°C, under N2, to a solution of l-(ethoxymethoxy)-3-(trifluoroniethoxy)benzene (700 mg, 0.00296 mol) in 10.5 ml of THF was added drop wise n -butyllithium (2.38 M in hexanes, 1.49 mL, 0.00356 mol). The mixture was stirred at -78 °C for 2h, then 2-isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (0.827 g, 0.00445 mol) was added dropwise. The mixture was stirred at -78 °C for Ih, then at room temperature for Ih. The reaction was quenched with a solution of aqueous NH4CI 5% (75 mL). The resulting solution was extracted with DCM (3 times). The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure to give the title compound as a thick orange oil (962 mg, -73% purity, 65% yield). iH NMR (500 MHz, CDC13) 6 (ppm): 7.30 (t, J = 8.3 Hz, IH), 6.98 (d, J = 8.3 Hz, IH), 6.89 - 6.85 (m, IH), 5.21 (s, 2H), 3.75 - 3.69 (m, 2H), 1.39 - 1.26 (m, 12H), 1.21 (t, J = 7.1 Hz, 3H). Appears as a mixture of ro tamers.

[0342] Int 3.3: 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)phenol

[0343] To a solution of 2-[2-(ethoxymethoxy)-6-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (73.0 %, 962 mg, 0.00194 mol) in 2 ml of 1,4-dioxane was added HQ solution 4M in dioxane (3.88 mL, 0.0155 mol) and the mixture was stirred at 60 °C f or 30 min. The mixture was poured on a saturated sodium bicarbonate aqueous solution, and the resulting mixture was extracted with DCM (3 times). The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure to give the title compound as a brown oil (596 mg, -70% purity, 71% yield).

[0344] ' H NMR (500 MHz, CDCI3) 6 (ppm): 8.44 (s, IH), 7.34 (t, J = 8.2 Hz, IH), 6.84 (dd, J = 8.4, 0.9 Hz, IH), 6.79 - 6.73 (m, IH), 1.37 (s, 12H). Int 8.1 : (4aS,8aR)-4-(6-chloropyridazin-3-yl)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H- pyrido[4,3-b][l,4]oxazine ci.

[0345] To a solution of (4aS,8aR)-4-(6-chloropyridazin-3-yl)-2,3,4a,5,6,7,8,8a- octahydropyrido[4,3-b][l,4]oxazine (Int 7.10 - 2.81 mmol, 720 mg) in 10 ml of dichloromethane were added successively 2.4 mlof acetic acid, acetaldehyde (14 mmol, 787 pl) and sodium triacetoxyborohydride (5.07 mmol, 1.07g) portionwise. The mixture was stirred at rt for 18h. The mixture was diluted with 100 ml of dichloromethane and 100 ml of a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 100 ml of DCM then with 2x100 ml of a mixture DCM / isopropanol : 90 / 10. The combined organic layers were dried overNa2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH / ACN (from 100 / 0 / 0 / 0 to 80 / 10 / 10) to give the title compound as a white solid (795 mg, 99% yield).

[0346] LCMS (Method V): Rt = 0.64; m / z; [M+H]+= 283;

[0347] Int 9.1 : (3aS,7aR)-l-(6-chloropyridazin-3-yl)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H- pyrrolo[2,3-c]pyridine

[0348] In sealed tube, to a solution of (3aS,7aR)-l-(6-chloropyridazin-3-yl)-2,3,3a,4,5,6,7,7a- octahydropyrrolo[2,3-c]pyridine;2,2,2-trifluoroacetaldehyde (2.00 g, 0.00428 mol) in 33 ml of ethanol were added acetaldehyde 5M in THF (2.58 mL, 0.0129 mol), acetic acid (258 mg, 0.00428 mol) and NaBHaCN (538 mg, 0.00856 mol). The reaction mixture was stirred atrt for Ih. The reaction mixture was concentrated under reduced pressure. The residue was purified by by flash chromatography on silica gel eluting with DCM / MeOH 100 / 0 to 85 / 15 to give the title compound as an off-white solid foam (880 mg, 77% yield).XH NMR (500 MHz, CDC13) 6 (ppm): 7.26 (s, 1H), 6.88 (s, 1H), 4.55 (s, 1H), 3.92 - 3.57 (m, 2H), 3.57 - 3.19 (m, 2H), 3.19 - 2.92 (m, 3H), 2.73 - 2.51 (m, 2H), 2.28 - 1.98 (m, 4H), 1.33 (t, 7 = 7.3 Hz, 3H). data

[0349] BIOLOGICAL ASSAYS AND DATA

[0350] The activity of a compound according to the present invention can be assessed by the following in vitro methods.

[0351] IL-ip secretion assay

[0352] Monocytic THP-1 cells were maintained in RPMI 1640 media (Gibco 21875) + 10% FBS, (Gibco 10500) + 1% penicillin / streptomycin (Gibco 15140-122). Cells were then plated at 40,000 cells per well in 384-well cell culture plates (Coming 3542) and maintained with RPMI1640 (Gibco 11835) + 5% FBS (Gibco 10500). Activation of the NLRP3 inflammasome requires both an NF-kB-dependentpriming step and the addition of a NLRP3 activator. The priming step was inducedby LPS (lOng / mL, InvivoGenref tlrl-3pelps) for 3h at 37 °C, then compound, in a 1 :3 serial dilution series in DMSO (final concentration DMSO 0.1%), and the activator nigericin (Sigma Aldrich, ref: SML1779) lOpM (final concentration) were added to the cells and co-incubatedfor 2 hours. 16 pL supernatant was removed, and IL-ip levels were monitored using an HTRF assay (Human IL lb Kits HTRF Cisbio ref: 62HILBPEH) according to manufacturers’ instructions.

[0353] Data interpretation

[0354] Data were expressed as percentage of inhibition (1%) as compared to a maximum signal control containing no small molecule (1% = 0%) according to the formula: I%=(l-((Sample- Min)) / ((Max-Min)))xl00, where:

[0355] Sample: Signal obtained in the presence of each compound tested,

[0356] Max: Maximum signal in the absence of compound added,

[0357] Min: Minimum or background signal obtained in the absence of activation signal.

[0358] Relative IC50 (IC50 rel) were obtained from a dose response curve with 10 concentrations.

[0359] Final IC50 rels are expressed as the geometric mean. Relative IC50 values were estimated with Biost@t-SPEED v2.4 internal software based on SAS system using the 4-parameter logistic model according to Ratkovsky and Reedy (DA Ratkovsky, T.J. Reedy, Choosing near-linear parameters in the four parameters logistic model radioligands andrelated assays. Biometrics, 42 (1986), 575 582 ): Y=A+C / (( I +cxp(- B*(log(X)-M)))), where:

[0360] A: Lower asymptote (BOTTOM),

[0361] A+C: Upper asymptote (TOP),

[0362] M: the logarithm of the concentration estimated at the inflexion point (the logarithm of the relative IC50), B: Slope at the inflexion point of the curve.

[0363] The results of NLRP3 IC50 are summarized in the table below: The compounds of the present invention have significant inhibitory activity on secretion of IL-1 beta by THP-1 cells. It is therefore apparent that the compounds of formula (I) have an inhibitory activity on NOD-like receptor protein 3 (NLRP3) inflammasome.

[0364] The compounds of formula (I) may thus be used as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0365] The compounds of formula (I) may thus be used as medicaments, especially medicaments which are inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0366] Thus, according to another of its aspects, a subject of the present disclosure is medicaments that comprise a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid.

[0367] These medicaments are employed therapeutically in the treatment of neurodegenerative diseases, in particular Parkinson’s disease, frontotemporal Dementia, Multiple System Atrophy, Alzheimer’s Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis or Brain injury.

[0368] According to another embodiment, the present disclosure relates to pharmaceutical compositions comprising as active principle, a compound of formula (I). These pharmaceutical compositions contain an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt of the said compound.

[0369] These pharmaceutical compositions may also contain at least one pharmaceutically acceptable excipient.

[0370] The said excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.

[0371] The compounds of formula (I) may be used in the prevention and / or in the treatment of pathologies involving NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0372] The present disclosure, according to another of its aspects, also provides a method of treating and / or preventing the pathologies indicated above.

[0373] Thus, is also described a method of treating and / or preventing Parkinson’s disease, frontotemporal Dementia, Multiple System Atrophy, Alzheimer’s Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis or Brain injury, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0374] According to one embodiment, is also described a method of treating and / or preventing Parkinson’s disease, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0375] According to another embodiment, is also described a method of treating and / or preventing frontotemporal Dementia, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0376] According to another embodiment, is also described a method of treating and / or preventing Multiple System Atrophy, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0377] According to another embodiment, is also described a method of treating and / or preventing Alzheimer’s Disease, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0378] According to another embodiment, is also described a method of treating and / or preventing Multiple Sclerosis, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0379] According to another embodiment, is also described a method of treating and / or preventing Amyotrophic Lateral Sclerosis, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0380] According to another embodiment, is also described a method of treating and / or preventing Brain injury, including administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

Claims

CLAIMS1. A compound of formula (I) or a pharmaceutically acceptable salt thereofwhereinR1 represents a hydrogen atom, a halogen atom or a -(Ci-C2)alkyl group;R2 represents -halo(Ci-C2)alkoxy group; andR3 and R4 form together with the nitrogen atom to which they are attached:- a 5 to 7 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and optionally one additional heteroatom selected from a nitrogen atom and an oxygen atom and comprising 4 to 6 carbon atoms; or- a 8 to 11 membered bicyclic heterocycloalkyl ring comprising one n itrogcn atom and optionally one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 6 to 10 carbon atoms; said monocyclic heterocycloalkyl ring and bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-C3)alkyl- group, a hydroxy-(Ci-C3)alkyl- group, and a fluoro-(Ci-C2)alkyl- group.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 represents a hydrogen atom, a fluorine atom or a methyl group.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein R2 represents a difluoromethoxy- group or a trifluoromethoxygroup.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R3 and R4 form together with the nitrogen atom to which they are attached:- a 6 membered monocyclic heterocycloalkyl ring comprising one nitrogen atom and one oxygen atom and comprising 4 carbon atoms, said monocyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a hydroxy-(Ci-C3)alkyl- group, in particular by one hydroxy-(Ci-C3)alkyl- group, for instance one OH-CH2- group, or- a 9 to 10 membered bicyclic heterocycloalkyl ring comprising one nitrogen atom and one to two additional heteroatoms independently selected from a nitrogen atom and an oxygen atom and comprising 7 carbon atoms, said bicyclic heterocycloalkyl ring being unsubstituted or substituted by one to two substituents independently selected from a (Ci-C3)alkyl- group, in particular by one (Ci-C3)alkyl- group, for instance one methyl group or one ethyl group.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R3 and R4 form together with the nitrogen atom to which they are attached :- a morpholino ring,- a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring or a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, said morpholino ring, 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazinyl ring and 3, 3a, 4, 5, 7, 7a-hexahydro-2H-pyrrolo[2, 3 -c]pyridinyl ring being unsubstituted or substituted by one to two substituents independently selected from a -CH3 group, a -CH2-CH3 group and a -CH2-OH group, in particular by one -CH3 group, one -CH2-CH3 group or one -CH2-OH group.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according any one of claims 1 to 5, wherein said compound is chosen among:(1) 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5- methylphenol;(2) 3-(difluoromethoxy)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3- yl]phenol;(3) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-(trifluoromethoxy) phenol;(4) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-3- ( trifluoromethoxy )phenol;(5) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-3-(difluoromethoxy)phenol;(6) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;(7) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;(8) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;(9) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-3-(difluoromethoxy)-5-methyl-phenol;(10) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-3-(difluoromethoxy)phenol;(11) 3-(difhioromethoxy)-5-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin- 3-yl]phenol;(12) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-l- yl]pyridazin-3-yl]-5-methyl-3-(trifluoromethoxy)phenol; and(13) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][l,4]oxazin-4- yl]pyridazin-3-yl]-5-methyl-3-(trifluorornethoxy)phenol.

7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 6, or pharmaceutically acceptable salt thereof.

8. Pharmaceutical composition, characterized in that it comprises a compound of formula (1) accordingto any one of claims 1 to 6, or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

9. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof for use as a medicine.

10. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof for use as inhibitor of NOD-like receptor protein 3 (NLRP3) inflammasome.

11. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof for use in the prevention and / or in the treatment of Parkinson’s disease, frontotemporal Dementia, Multiple System Atrophy, Alzheimer’s disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis or brain injury.

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