Pyridazine compounds, their preparation, and their therapeutic uses

Abstract

The present invention relates to a compound in which n is 1 or 2, and R1 is halogen, (C1-C4) alkyl, halo(C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C 4) The present invention relates to compounds of formula (I) wherein R1 is alkoxy, ethynyl, propargyl, or (C3-C6)cycloalkyl; or two R1 form a cyclopentane ring fused to a phenol; R2 and R3 represent H, cyano, ethynyl, propargyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, or halo(C1-C4)alkyl; or R2 and R3 together with the atoms connecting them form a (C5-C6)carbocycle fused to a pyridazine ring; and R4 and R5 together with the N to which they are attached form an optionally substituted 3- to 7-membered monocyclic heterocycloalkyl ring, 8- to 11-membered bicyclic heterocycloalkyl ring, or 7- to 12-membered bicyclic heterocyclic spiro ring. The present invention also relates to medicaments and pharmaceutical compositions comprising said compounds of formula (I), and their therapeutic uses, particularly as inhibitors of NOD-like receptor protein 3 inflammasome, for treating, for example, Parkinson's disease or frontotemporal dementia.

Description

[Technical Field]

[0001] Disclosed herein are pyridazine compounds, their preparations, medicaments and pharmaceutical compositions comprising said pyridazine compounds, their use as medicaments, more particularly their use as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway, more particularly their use in the prevention and / or treatment of Parkinson's disease, frontotemporal dementia, multiple system atrophy, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or brain injury. [Background technology]

[0002] The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) or NACHT, LRR and PYD domain-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 large aggregates known as ASC specks. In turn, polymerized ASC interacts with the cysteine ​​protease caspase-1 to form a complex called 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 proinflammatory cytokines IL1β and IL18 (termed pro-IL1β and pro-IL18), thereby activating an appropriate inflammatory response. However, this pathway has been shown to be involved in a variety of inflammation-related processes and diseases, including: - 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); - inflammatory diseases, including Muckle-Wells autoinflammatory disease (Agostini et al., 2004) cryopyrin-associated periodic syndromes (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., J. Clin. Invest. 2012, 122, 3476-89). al., Ann. Rheum. Dis. 2014, 73, 1202-10), acute or chronic arthropathy, and kidney-related diseases, such as hyperoxaluria (Knaufet et al., Kidney Int. 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al., Br. J. Pharmacol. 2016, 173, 752-10 65), hemodialysis-associated inflammation and diabetic nephropathy (Shahzad et al., Kidney Int. 2015, 87, 74-84); - 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); - NLRP3 inflammasome has 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 WA et al., Investigative Ophthalmology & Visual Science 54:11-120, 2013), Behçet's syndrome, and dry eye disease (Zheng Q. et al., Experimental Eye Research 134:133-140, 2015); - metabolic, cardiac, skin disorders and cancer, e.g., diabetic cardiomyopathy (Luo B. et al., PLoS ONE 9(8):e104771, 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); cardiometabolic disorders, atherosclerosis, type I and type II diabetes, and associated complications, peripheral arterial disease (PAD), acute heart failure and hypertension (Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31); wound healing and scar formation; inflammatory skin diseases (Sweeney et al. al., Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related diseases, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, and colorectal cancer (Ridker et al., Lancet 2017, 390, 1833-42); and - SARS-Cov-2: The NLRP3 inflammasome is central to the antiviral response (Zhao C. and Zhao W. 11,211:2020; Freeman & Swartz, Frontiers in Immunol. 11,1518,2020).

[0003] Inhibitors of NLRP3 are potential treatments for these conditions with unmet clinical need.

[0004] Therefore, inhibitors of the NLRP3 inflammasome pathway are needed to provide new or alternative treatments. Summary of the Invention [Means for solving the problem]

[0005] Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 2 to 6 carbon atoms, - an 8- to 11-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, and containing 4 to 10 carbon atoms, or - a 7-12 membered bicyclic heterocyclic spiro ring containing one nitrogen atom and optionally 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 3-11 carbon atoms; Forming The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring and bicyclic heterocycloalkyl ring are unsubstituted or can be substituted with a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino- group, (C2-C5) acyl group, hydroxy-(C1-C4) alkyl- group, SH-(C1-C4) alkyl- group, CN-(C1-C4) alkyl- group, (C1-C4) alkoxy-(C1-C4) alkyl- group, hydroxyl group, oxo group, (C3-C6) cycloalkyl group, halogen atom, halo(C1-C4) alkyl- group, cyano group, NH2-C(=O)- group, mono(C1-C4) alkoxy group, and -COH group.

[0006] Also herein; a pharmaceutical product comprising a compound of formula (I) as defined in the present disclosure or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising a compound of formula (I) as defined in the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; - a compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof for use as a medicament; - a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure for use as an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome; - a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure for use in the prevention and / or treatment of Parkinson's disease, frontotemporal dementia, multiple system atrophy, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or brain injury. is provided.

[0007] definition In the context of this disclosure, the following terms have the following definitions unless otherwise stated throughout the specification. - halogen atom: a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, for example a fluorine or chlorine or iodine atom; - Hydroxyl group: "-OH" group; - oxo group: "=O" group; - cyano group: "-C≡N" group or CN group; - -(C x ~C y ) alkyl group: a linear or branched saturated hydrocarbon aliphatic group containing x to y carbon atoms, for example, 1 to 4 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups, etc.; - -(C x ~C y ) Alkoxy group: -O-alkyl group (wherein alkyl group is as defined above). For example, -(C1-C4)alkoxy group. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy groups, etc.; - Haro (C x ~C y) Alkyl group: an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more different or identical halogen atoms as defined above. Examples may include, but are not limited to, trifluoromethyl, fluoromethyl, difluoromethyl, chloromethyl, dichloromethyl, iodomethyl, diiodomethyl, triiodomethyl, diiodofluoromethyl, bromomethyl, tribromomethyl, trichloromethyl, chlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, chloroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, iodopropyl, diiodopropyl, bromopropyl, dibromopropyl, tetraiodopropyl, pentaiodopropyl, fluoropropyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, chloro chloropropyl, dichloropropyl, trichloropropyl, tetrachloropropyl, pentachloropropyl, bromobutyl, dibromobutyl, tetraiodobutyl, pentaiodobutyl, fluorobutyl, difluorobutyl, trifluorobutyl, tetrafluorobutyl, chlorobutyl, dichlorobutyl, trichlorobutyl, tetrachlorobutyl, pentachlorobutyl, hexachlorobutyl, perfluoroethyl, perfluoropropyl, perfluorobutyl, perbromoethyl, perbromoethyl, perbromopropyl, perbromobutyl, periodoethyl, periodoethyl, periodopropyl, periodobutyl, perchloroethyl, perchloroethyl, perchloropropyl, perchlorobutyl group, and the like; - Haro (C x ~C y) Alkoxy-group: the radical -O-alkyl group, wherein the alkyl group is as defined above and said alkyl group is substituted by one or more identical or different halogen atoms as defined above, and examples may include, but are not limited to, trifluoromethoxy, fluoromethoxy, difluoromethoxy, chlorofluoromethoxy, chloromethoxy, dichloromethoxy, iodomethoxy, diiodomethoxy, triiodomethoxy, bromomethoxy, tribromomethoxy, trichloromethoxy, dichlorobromomethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, chloroethoxy, dichloroethoxy, trichloroethoxy, tetrachloroethoxy, iodopropoxy, diiodopropoxy, bromopropoxy, dibromopropoxy, tetraiodopropoxy, pentaiodopropoxy, fluoropropoxy, perfluoropropoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, chloropropoxy, dichloropropoxy, trichloropropoxy, tetrachloropropoxy, pentachloropropoxy, bromobutoxy, dibromobutoxy, tetraiodobutoxy, pentaiodobutoxy, fluorobutoxy, difluorobutoxy, trifluorobutoxy, tetrafluorobutoxy, chlorobutoxy, dichlorobutoxy, trichlorobutoxy, tetrachlorobutoxy, pentachlorobutoxy, hexachlorobutoxy, perfluoroethoxy, perfluoropropoxy, perfluorobutoxy, perbromoethoxy, perbromopropoxy, perbromobutoxy, periodethoxy, periodiodoethoxy, periodiodopropoxy, periododobutoxy, perchloroethoxy, perchloroethoxy, perchloropropoxy, and perchlorobutoxy groups; - Hydroxy (C x ~C y) Alkyl group: Examples of alkyl groups as defined above in which one or more hydrogen atoms are replaced by one or more hydroxy groups as defined above include, but are not limited to, OH-CH-, OH-C(CH)-, CH-CH(OH)-, CH(OH)-CH(OH)-, CH-CH(OH)-CH-, CH-CH(OH)-CH(OH)-, (CH)-C(OH)-CH-, (CH)-C(OH)-CH(OH)-, (CH)-C-CHOH- groups, etc.; - SH-(C1-C4)alkyl-group: an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more SH groups. Examples include, but are not limited to, SH-CH2-, SH-C(CH3)2-, CH3-CH(SH)-, CH2(SH)-CH(SH)-, CH3-CH(SH)-CH2-, (CH3)2-C(SH)-CH2-, (CH3)2-C(SH)-CH(SH)-, (CH3)3-C-CH(SH)- groups, etc.; - CN-(C1-C4) alkyl-group: an alkyl group as defined above, in which one or more hydrogen atoms are replaced by one or more CN groups. Examples include, but are not limited to, CN-CH2-, CN-C(CH3)2-, CH3-CH(CN)-, CH2(CN)-CH(CN)-, CH3-CH(CN)-CH2-, (CH3)2-C(CN)-CH2-, (CH3)2-C(CN)-CH(CN)-, (CH3)3-C-CH(CN)- groups, etc.; NH2-(C1-C4)alkyl-group: an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more NH2 groups. Examples include, but are not limited to, NH2-CH2-, NH2-C(CH3)2-, CH3-CH(NH2)-, CH2(NH2)-CH(NH2)-, CH3-CH(NH2)-CH2-, (CH3)2-C(NH2)-CH2-, (CH3)2-C(NH2)-CH(NH2)-, (CH3)3-C-CH(NH2)- groups, etc.; - mono(C1-C4) alkylamino-group: an amino group substituted with one alkyl group as defined above. Examples include, but are not limited to, CH3-NH-, CH3-CH2-NH-, CH3-CH2-CH2-NH-, CH3-CH2-CH2-CH2-NH-, (CH3)2-CH-CH2-NH-, (CH3)3-C-NH-, CH3-CH2-CH(CH3)-NH- groups, etc.; - di(C1-C4)alkylamino-group: an amino group substituted by two alkyl groups as defined above. Examples include, but are not limited to, (CH3)2N-, (CH3-CH2)2N-, (CH3)(CH3-CH2)N-, (CH3-CH2-CH2)2N-, (CH3-CH2-CH2-CH2)2N-, ((CH3)2-CH-CH2)(CH3)N-, ((CH3)3-C)(CH3CH2)N-, (CH3-CH2-CH(CH3))(CH3-CH2-CH2)N- groups, etc.; - (C2-C5) acyl-group: a (C1-C4) alkyl group as defined above linked to a -C(=O)- group. Examples include, but are not limited to, CH3-C(=O)-, CH3-CH2-C(=O)-, CH3-CH2-CH2-C(=O)-, CH3-CH2-CH2-CH2-C(=O)-, (CH3)2-CH-CH2-C(=O)-, (CH3)3-CC(=O)-, CH3-CH2-CH(CH3)-C(=O)- groups, etc.; - (C2-C5) acylamino- group: an amino group -NH- substituted with one acyl group containing 2 to 5 carbon atoms, where the acyl group is a (C1-C4) alkyl group as defined above linked to a -C(=O)- group which is itself linked to the amino group. Examples include, but are not limited to, CH3-C(=O)-NH-, CH3-CH2-C(=O)-NH-, CH3-CH2-CH2-C(=O)-NH-, CH3-CH2-CH2-CH2-C(=O)-NH-, (CH3)2-CH-CH2-C(=O)-NH-, (CH3)3-CC(=O)-NH-, CH3-CH2-CH(CH3)-C(=O)-NH- groups, etc.; - (C3-C6)cycloalkyl-group: unless otherwise specified, a saturated or partially unsaturated, unsubstituted or substituted cyclic alkyl group containing 3 to 6 carbon atoms, examples of which include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexyl, etc.; - OH-(C3-C6)cycloalkyl- group: Examples of the cyclic alkyl group as defined above, in which one or more hydrogen atoms are replaced by one or more hydroxyl groups, include, but are not limited to, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclobutenyl, hydroxycyclopentenyl, hydroxycyclohexenyl, hydroxycyclohexyl, dihydroxycyclopropyl, dihydroxycyclobutyl, trihydroxycyclopentyl, dihydroxycyclobutenyl, trihydroxycyclopentenyl, dihydroxycyclohexenyl, tetrahydroxycyclohexyl, etc.; - NH2-(C3-C6)cycloalkyl- group: a cyclic alkyl group as defined above, in which one or more hydrogen atoms are replaced by one or more NH2 groups. Examples include, but are not limited to, aminocyclopropyl, aminocyclobutyl, aminocyclopentyl, aminocyclobutenyl, aminocyclopentenyl, aminocyclohexenyl, aminocyclohexyl, diaminocyclopropyl, diaminocyclobutyl, triaminocyclopentyl, diaminocyclobutenyl, triaminocyclopentenyl, diaminocyclohexenyl, tetraaminocyclohexyl, etc.; - (C5-C6) carbocyclic ring fused to a pyridazine ring: a saturated or partially saturated ring containing 5 or 6 carbon atoms fused to a pyridazine ring, and such a carbocyclic ring may be saturated or partially saturated, unsubstituted or substituted. In other words, the (C5-C6) carbocyclic ring is not an aromatic ring, and the bicyclic structure formed by the carbocyclic ring and the pyridazine ring contains three or four double bonds. Examples include, but are not limited to, cyclopentyl fused to a pyridazine ring and cyclohexyl fused to a pyridazine ring. [ka] Tamaki et al; - a cyclopentane ring fused to a phenol group: for example, the following group: [ka] and the symbol [ka] represents the bonding site between the carbon atom of the phenol ring and the carbon atom of the pyridazine ring. In other words, the cyclopentane ring fused to the phenol group as defined in the present disclosure means an indane ring substituted with one hydroxy group, and the indane is bonded to the pyridazine ring via a single bond at the ortho position of the hydroxy group. - 3-7 membered monocyclic heterocycloalkyl ring (also called (C2-C6)heterocycloalkyl group): unless otherwise stated, a monocyclic alkyl group containing 2 to 6 carbon atoms and optionally containing one nitrogen atom and one additional heteroatom selected from nitrogen, oxygen and sulfur atoms. Such heterocycloalkyl groups can be saturated or partially saturated, unsubstituted or substituted. Examples of monocyclic heterocycloalkyl groups include, but are not limited to, azepane, piperazine, morpholino, pyrrolidine, tetrahydropyran, thietane dioxide, piperidine, thiolane, thiolane oxide, thiolane dioxide, dihydrofuran, tetrahydrofuran, azetidine, oxetane, thietane, 2H-pyrrole, 1H-, 2H- or 3H-pyrroline, tetrahydrothiophene, oxadiazole and, for example, 1,3,4-oxadiazole or 1,3,5-oxadiazole, thiadiazole and, for example, 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrazoline, pyrroline, pyrazolidine, imidazoline, imidazolidine, thiazolidine, isoxazoline, isoxazolidine, dioxalane, oxathiadiazole, oxathiadiazole, dioxazole, thiomorpholino, hexahydropyrimidine groups, and the like. - 8-11 membered bicyclic heterocycloalkyl ring ((C4-C 10) (also referred to as heterocycloalkyl groups): Unless otherwise specified, a bicyclic alkyl group containing 4 to 10 carbon atoms and one nitrogen atom and, optionally, one to three additional heteroatoms selected from nitrogen, oxygen, and sulfur atoms. Such heterocycloalkyl groups can be saturated or partially saturated, unsubstituted or substituted, and bridged or unbridged. Examples of bicyclic heterocycloalkyl groups include, but are not limited to, dihydropyrazolooxazinyl groups, such as dihydro-2H-pyrazolo[4,3-b][1,4]oxazinyl groups, such as 5,6-dihydro-2H-pyrazolo[4,3-b][1,4]oxazinyl groups; hexahydropyridoxazinyl groups or octahydropyridoxazinyl groups, such as hexahydro-2H-pyrido[3,4-b][1,4]oxazinyl groups. a hexahydro-2H-pyrido[4,3-b][1,4]oxazinyl group, a hexahydro-2H-pyrido[4,3-b][1,4]oxazinyl group, or an octahydropyrido[4,3-b][1,4]oxazinyl group, for example, a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazinyl group, a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazinyl group, or a 2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazinyl group; ]oxazinyl group; dihydropyridoxazinyl group, for example, dihydropyrido[3,4-b][1,4]oxazinyl group or dihydropyrido[4,3-b][1,4]oxazinyl ring, for example, 2,3-dihydropyrido[3,4-b][1,4]oxazinyl group or 2,3-dihydropyrido[4,3-b][1,4]oxazinyl group; hexahydropyranoxazinyl group or octahydropyranoxazinyl group, for example, hexahydro-2H-pyrano[3, 4-b][1,4]oxazinyl groups, for example, a 3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazinyl group, or a hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl group, for example, a 3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl group; an isoindoline group; an indoline group; a decahydroisoquinoline group; a decahydroquinoline group; a tetrahydroquinoline group;Dihydroquinoline or tetrahydroquinoline groups, for example, dihydro-2H-quinolinyl groups, for example, 3,4-dihydro-2H-quinolinyl groups; dihydroisoquinoline groups; azabicyclooctanyl groups, for example, azabicyclo[3.2.1]octanyl groups, for example, 6-azabicyclo[3.2.1]octanyl groups; oxazabicyclooctanyl groups, for example, oxazabicyclo[3.2.1]octanyl groups, for example, 3- an oxa-8-azabicyclo[3.2.1]octanyl group; a diazabicyclononanyl group, for example, a diazabicyclo[3.2.2]nonanyl group, for example, a 3,6-diazabicyclo[3.2.2]nonanyl group; a hexahydropyrrolooxazinyl group or an octahydropyrrolooxazinyl group, for example, a hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl group, for example, a 2,3,4a,5,7,7a-hexahydro-2 H-pyrrolo[3,4-b][1,4]oxazinyl group, 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl group, 3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl group or 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl group; dihydrobenzoxazine group, for example 2,3-dihydro-1 ,4-benzoxazine group; octahydropyridoxazinyl group, for example, octahydropyrido[4,3-b][1,4]oxazinyl group, for example, 2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazinyl group; hexahydrofuropyrrolyl ring, for example, hexahydrofuro[3,4-c]pyrrolyl ring, for example, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl ring;Hexahydropyrrolopyrrolyl rings, for example, hexahydropyrrolo[3,4-b]pyrrolyl rings or hexahydro-2H-pyrrolo[3,4-b]pyrrolyl rings, for example, 2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrolyl rings or 3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrolyl rings, hexahydropyrrolo[3,2-b]pyrrolyl rings or hexahydro-1H-pyrrolo[3,2-b]pyrrolyl rings, for example, 2,3,3a,5,6,6a-hexahydro- 1H-pyrrolo[3,2-b]pyrrolyl ring; a hexahydropyrrolopyridyl ring or an octahydropyrrolopyridyl ring, for example, a hexahydropyrrolo[3,4-c]pyridyl ring, for example, a 2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridyl ring, a hexahydropyrrolo[2,3-c]pyridyl ring, for example, a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridyl ring, or a 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridyl ring. a naphthyridinyl ring; a hexahydrocyclopentaoxazinyl group, for example, a hexahydrocyclopenta[b][1,4]oxazinyl group, for example, a 3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazinyl group; a dihydronaphthyridinyl ring, a tetrahydronaphthyridinyl ring, a hexahydronaphthyridinyl ring or an octahydronaphthyridinyl ring, for example, a dihydro-2H-naphthyridinyl ring, for example, a 3,4-dihydro-2H-1,6-naphthyridinyl ring, a hexahydro -2H-1,7-naphthyridinyl ring, for example, a 3,4,4a,5,6,8a-hexahydro-2H-1,7-naphthyridinyl ring, an octahydro-1,5-naphthyridinyl ring, for example, a 2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridinyl ring, or an octahydro-1,7-naphthyridinyl ring, for example, a 2,3,4,4a,5,6,7,8a-octahydro-1,7-naphthyridinyl ring or a 2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridinyl ring; - 7-12 membered bicyclic heterocyclic spiro rings: bicyclic heterocyclic ring systems in which the two rings have only one common atom, in particular one common carbon atom, said bicyclic heterocyclic ring systems containing one nitrogen atom and optionally 1 to 3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 3 to 11 carbon atoms. Such bicyclic heterocyclic spiro ring systems may be saturated or partially saturated, unsubstituted or substituted.Examples of bicyclic heterocyclic spiro ring systems include, but are not limited to, an azaspirononanyl ring, for example, an azaspiro[3.5]nonanyl ring, for example, a 7-azaspiro[3.5]nonanyl ring; an azaspirooctanyl ring, for example, an azaspiro[3.4]octanyl ring, for example, a 6-azaspiro[3.4]octanyl ring or a 2-azaspiro[3.4]octanyl ring; an azaspiroheptanyl ring, for example, an azaspiro[3.3]heptanyl ring, for example, a 2-azaspiro[3.3]heptanyl ring; a diazaspirononanyl ring, for example, For example, a diazaspiro[3.5]nonanyl ring, such as a 2,7-diazaspiro[3.5]nonanyl ring; a diazaspiroheptanyl ring, such as a diazaspiro[3.3]heptanyl ring, such as a 1,6-diazaspiro[3.3]heptanyl ring; an oxazaspirononanyl ring, such as an oxazaspiro[3.5]nonanyl ring, such as a 2-oxa-7-azaspiro[3.5]nonanyl ring; an oxazaspiroheptanyl ring, such as an oxazaspiro[3.3]heptanyl ring, such as a 2-oxa-6-azaspiro[3.3]heptanyl ring. dithiazaspirononanyl ring, for example, dithiazaspiro[4.4]nonanyl ring, for example, 1,4-dithia-7-azaspiro[4.4]nonanyl ring; oxadiazaspirononanyl ring, for example, oxadiazaspiro[3.5]nonanyl ring, for example, 8-oxa-2,5-diazaspiro[3.5]nonanyl ring; oxadiazaspirodecaneyl ring, for example, oxadiazaspiro[4.5]decaneyl ring, for example, 2-oxa-6,9-diazaspiro[4.5]decaneyl ring, 6-oxa-2,9-diazaspiro[4.5]decaneyl ring or 9-oxa- oxa-2,6-diazaspiro[4.5]decaneyl ring; oxadiazaspirondecaneyl ring, for example, oxadiazaspiro[5.5]undecaneyl ring, for example, 4-oxa-1,8-diazaspiro[5.5]undecaneyl ring; diazaspirodecaneyl ring, for example, diazaspiro[4.5]decaneyl ring, for example, 1,9-diazaspiro[4.5]decaneyl ring; dioxadiazaspirododecanyl ring, for example, dioxadiazaspiro[5.6]dodecanyl ring, for example, 1,11-dioxa-4,8-diazaspiro[5.6]dodecanyl ring, etc.; - "Optionally substituted" means "unsubstituted or substituted with." - R and S indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules. - in each group or group defined in this disclosure, each hydrogen atom can be replaced with a deuterium atom that forms part of this disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0008] As noted above, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 2 to 6 carbon atoms, - an 8- to 11-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, and containing 4 to 10 carbon atoms, or - a 7-12 membered bicyclic heterocyclic spiro ring containing one nitrogen atom and optionally 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 3-11 carbon atoms; Forming The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring and bicyclic heterocycloalkyl ring are unsubstituted or can be substituted with a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino- group, (C2-C5) acyl group, hydroxy-(C1-C4) alkyl- group, SH-(C1-C4) alkyl- group, CN-(C1-C4) alkyl- group, (C1-C4) alkoxy-(C1-C4) alkyl- group, hydroxyl group, oxo group, (C3-C6) cycloalkyl group, halogen atom, halo(C1-C4) alkyl- group, cyano group, NH2-C(=O)- group, mono(C1-C4) alkoxy group, and -COH group.

[0009] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 2 to 6 carbon atoms, - an 8- to 11-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, and containing 4 to 10 carbon atoms, or - a 7-12 membered bicyclic heterocyclic spiro ring containing one nitrogen atom and optionally 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 3-11 carbon atoms; Forming The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring and bicyclic heterocyclospiro ring may be unsubstituted or may be substituted with a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino- (C2-C5) acyl group, hydroxy-(C1-C4) alkyl- group, SH-(C1-C4) alkyl- group, CN-(C1-C4) alkyl- group, (C1-C4) alkoxy-(C1-C4) alkyl- group, hydroxyl group, oxo group, (C3-C6) cycloalkyl group, halogen atom, halo(C1-C4) alkyl- group, cyano group, NH2-C(=O)- group, mono(C1-C4) alkoxy group, and -COH group.

[0010] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 2 to 6 carbon atoms, - an 8- to 11-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, and containing 4 to 10 carbon atoms, or - a 7-12 membered bicyclic heterocyclic spiro ring containing one nitrogen atom and optionally 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 3-11 carbon atoms; represents The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring and bicyclic heterocyclospiro ring may be unsubstituted or may be substituted with a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino- (C2-C5) acyl group, hydroxy-(C1-C4) alkyl- group, SH-(C1-C4) alkyl- group, CN-(C1-C4) alkyl- group, (C1-C4) alkoxy-(C1-C4) alkyl- group, hydroxyl group, oxo group, (C3-C6) cycloalkyl group, halogen atom, halo(C1-C4) alkyl- group, cyano group, NH2-C(=O)- group, mono(C1-C4) alkoxy group, and -COH group.

[0011] The compounds of formula (I) may contain one or more asymmetric carbon atoms. 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, as well as mixtures thereof, including racemic mixtures, also form part of the present disclosure.

[0012] The compounds of formula (I) may also exist in tautomeric forms.

[0013] The compounds of formula (I) can exist in the form of bases, acids, zwitterions, or addition salts with acids or bases. Accordingly, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] These salts may be prepared using pharmaceutically acceptable acids or bases, although other acid or base salts useful, for example, for purifying or isolating compounds of formula (I) are also provided.

[0015] Among the suitable salts of the compounds of formula (I), mention may be made of the trifluoroacetate and formate salts.

[0016] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of compounds in which n is 1.

[0017] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of compounds in which n is 2.

[0018] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds is represented by the formula (I) in which R1 is independently of each other a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a (C3-C6) cycloalkyl group, a group of formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a halo(C1-C4)alkyl group.

[0019] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R1 independently of one another represents a fluorine atom (F), a chlorine atom (Cl), a methyl group, an ethyl group, an isopropyl group, a methoxy group, a trifluoromethoxy group, a cyclopropyl group, a -CHF2 group, an ethynyl group or a trifluoromethyl group.

[0020] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which, when n is 1, R1 is in the ortho, meta or para position on the phenyl relative to the pyridazine ring.

[0021] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which, when n is 1, R1 is in the ortho or para position on the phenyl relative to the pyridazine ring.

[0022] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which, when n is 2, the two R1's are in the ortho and para positions on the phenyl relative to the pyridazine ring.

[0023] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which, when n is 2, the two R1's are in the ortho and meta positions on the phenyl relative to the pyridazine ring.

[0024] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which, when n is 2, two R1 on adjacent carbon atoms together with the atom connecting them form a cyclopentane ring fused to a phenol group, and in particular, these two R1 are of the formula [ka] represents a group represented by the formula [ka] represents the bonding site between the carbon atom of the phenol ring and the carbon atom of the pyridazine ring.

[0025] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R2 and R3, independently of one another, represent a hydrogen atom, a cyano group, a halo(C1-C4)alkyl group, a hydroxy(C1-C4)alkyl group or a (C1-C4)alkyl group.

[0026] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R2 and R3, independently of one another, represent a hydrogen atom, a cyano group, a -CHF2 group, a trifluoromethyl group, a -CH2OH group, an ethyl group, an isopropyl group or a methyl group.

[0027] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R2 represents a hydrogen atom, a halo(C1-C4)alkyl group, a hydroxy(C1-C4)alkyl group or a (C1-C4)alkyl group.

[0028] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R2 represents a hydrogen atom, a —CHF2 group, a trifluoromethyl group, a —CH2OH group, an ethyl group, an isopropyl group or a methyl group.

[0029] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R3 represents a hydrogen atom, a cyano group, a halo(C1-C4)alkyl group, a hydroxy(C1-C4)alkyl group or a (C1-C4)alkyl group.

[0030] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of those in which R3 represents a hydrogen atom, a cyano group, a —CHF2 group, a —CH2OH group, or a methyl group.

[0031] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of compounds in which R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to a pyridazine ring.

[0032] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of compounds in which R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentyl ring fused to a pyridazine ring having the formula: [ka]

[0033] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds is provided in which R4 and R5 together with the nitrogen atom to which they are attached form the following compounds: - a 4-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 3 to 6 carbon atoms, an 8-10 membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally one or two additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, and containing 6, 7, 8 or 9 carbon atoms, or - a 7-10 or 12-membered bicyclic heterocyclic spiro ring containing one nitrogen atom and optionally 1-3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 5-8 carbon atoms; It consists of The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring and bicyclic heterocyclic spiro ring may be unsubstituted or may be substituted with a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino-group, a (C2-C5)acyl- group, a hydroxy-(C1-C4)alkyl- group, or an SH-(C1-C4) alkyl-group; substituted by 1 to 2 substituents independently selected from a CN—(C1-C4)alkyl-group, a (C1-C4)alkoxy-(C1-C4)alkyl-group, a hydroxyl group, an oxo group, a (C3-C6)cycloalkyl group, a halogen atom, a halo(C1-C4)alkyl-group, a cyano group, an NH—C(═O)-group, a mono(C1-C4)alkylamino-C(═O)-group, a di(C1-C4)alkylamino-C(═O)-group, an NH—C(═O)-(C1-C4)alkyl-group, a mono(C1-C4)alkylamino-C(═O)-(C1-C4)alkyl-group, or a di(C1-C4)alkylamino-C(═O)-(C1-C4)alkyl-group.

[0034] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds is provided in which R4 and R5 together with the nitrogen atom to which they are attached form the following compounds: - a 4-7-membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 3 to 6 carbon atoms selected from the group consisting of an azepanyl ring, a morpholino ring, a thiomorpholino ring, a piperidinyl ring, a pyrrolidinyl ring, an isoxazolidinyl ring, a piperazinyl ring, a hexahydropyrimidinyl ring and an azetidinyl ring; - an 8-10-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally one or two additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms and containing 6, 7, 8 or 9 carbon atoms selected from the group consisting of indolinyl rings; a hexahydropyridoxazinyl ring, a hexahydropyranoxazinyl ring, an octahydropyranoxazinyl ring, a dihydropyridoxazinyl ring, a dihydroquinolinyl group, a tetrahydroquinolinyl group, an azabicyclooctanyl group, an oxazabicyclooctanyl group; a di an azabicyclononanyl group, a hexahydropyrrolooxazinyl group, an octahydropyrrolooxazinyl group, a dihydrobenzoxazinyl group, an octahydropyridoxazinyl group, a hexahydrofuropyrrolyl ring, a hexahydropyrrolopyrrolyl ring, a hexahydropyrrolopyridinyl ring, an octahydropyrrolopyridinyl ring, a dihydropyrazolooxazolinyl ring, a hexahydrocyclopentaoxazinyl group, a hexahydronaphthyridinyl ring, an octahydronaphthyridinyl ring, a tetrahydronaphthyridinyl ring, and a dihydronaphthyridinyl ring; or - a 7- to 10- or 12-membered bicyclic heterocyclic spiro ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms and containing 5 to 8 carbon atoms selected from the group consisting of an azaspironanyl ring, an azaspirooctanyl ring, an azaspiroheptanyl ring, a diazaspirodecanyl ring, a diazaspirononanyl ring, a diazaspiroheptanyl ring, an oxadiazaspirodecanyl ring, an oxadiazaspironoundecanyl ring, an oxadiazaspirononanyl ring, a dioxadiazaspirododecanyl ring, an oxazaspirononanyl ring and an oxazaspiroheptanyl ring, It consists of The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring and bicyclic heterocyclic spiro ring may be unsubstituted or may be substituted with a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino- group, a (C2-C5)acyl- group, a hydroxy-(C1-C4)alkyl- group, an SH-(C1-C4) and is substituted by 1 to 2 substituents independently selected from an alkyl- group, a CN—(C1-C4)alkyl- group, a (C1-C4)alkoxy-(C1-C4)alkyl- group, a hydroxyl group, an oxo group, a (C3-C6)cycloalkyl group, a halogen atom, a halo(C1-C4)alkyl- group, a cyano group, an NH—C(═O)- group, a mono(C1-C4)alkylamino-C(═O)- group, a di(C1-C4)alkylamino-C(═O)- group, an NH—C(═O)-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-C(═O)-(C1-C4)alkyl- group, or a di(C1-C4)alkylamino-C(═O)-(C1-C4)alkyl- group.

[0035] Among the compounds of formula (I) that are the subject of the present disclosure, a group of compounds consists of the following compounds in which R4 and R5 together with the nitrogen atom to which they are attached form: an azepanyl ring that is unsubstituted or substituted by one OH-CH2- group; - Unsubstituted or methyl group, CH2F- group, NH2-CH2- group, N(CH3)2-CH2- group, CH3-NH-(CH2)2- group, SH-CH2- group, CN-CH2- group, OH-CH2- group, OH-CD2 - group, OH-(CH2)2- group, OH-C(CH3)2- group, CH3-CH(OH)- group, CH3-C(=O)-NH-CH2- group, CH3-C(=O)-NH-CH2-CH2- group CH(CH3)2-C(=O) a morpholino ring substituted by one or two substituents independently selected from an -NH-CH2- group, an NH2-C(=O)- group, an NH(CH3)-C(=O)- group, an N(CH3)2-C(=O)- group, an NH2-cyclopropyl- group, an NH2-C(=O)-CH2- group, an NH(CH3)-C(=O)-CH2- group, an NH(CH3)-C(=O)-CH2- group, an N(CH3)2-C(=O)-CH2- group, a CH3-CH2-C(=O)- group, an oxo group, and a CH3-O-CH2- group; a thiomorpholino ring that is unsubstituted or substituted by one to two oxo groups; a piperidinyl ring which is unsubstituted or substituted with 1 to 2 substituents independently selected from an NH group, an NH—CH— group, an NH(CHCH)— group, an N(CH)— group, an NH-cyclopropyl- group, an N(CH)—CH— group, an OH—CH— group, a CH—C(═O)—NH—CH— group, a cyano group, a hydroxyl group, an oxo group and a fluorine atom; a pyrrolidinyl ring that is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of NH-, NH-CH-, N(CH)-CH-, OH-CH-, CH-O-CH-, hydroxyl, and oxo; an isoxazolidinyl ring which is unsubstituted or substituted by one hydroxyl group, a piperazinyl ring that is unsubstituted or substituted with 1 to 2 substituents independently selected from methyl, oxo and OH—CH—; - a hexahydropyrimidinyl ring substituted by one oxo group; an azetidinyl ring which is unsubstituted or substituted by one OH-CH2- group, a dihydroquinolinyl ring, such as a tetrahydroquinolinyl ring or a 3,4-dihydro-2H-quinolinyl ring, which is unsubstituted or substituted by one hydroxyl group, a hexahydropyridoxazinyl ring, such as a hexahydro-2H-pyrido[3,4-b][1,4]oxazinyl ring, such as a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazinyl group, or a hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl ring, such as a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl ring, which is unsubstituted or substituted by one cyclobutyl group, one methyl group, one ethyl group, one 2,2,2-trifluoroethyl group, one 2-fluoroethyl group, one 3-fluoropropyl group, one isopropyl group or one acetyl group; unsubstituted hexahydropyranooxazinyl rings, such as hexahydro-2H-pyrano[3,4-b][1,4]oxazinyl rings, for example 3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazinyl groups, or for example hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl rings, for example 3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl rings; unsubstituted dihydropyridoxazinyl rings, such as dihydropyrido[3,4-b][1,4]oxazinyl or dihydropyrido[4,3-b][1,4]oxazinyl rings, for example 2,3-dihydropyrido[3,4-b][1,4]oxazinyl or 2,3-dihydropyrido[4,3-b][1,4]oxazinyl rings; unsubstituted dihydropyrazolooxazinyl rings, such as dihydro-2H-pyrazolo[4,3-b][1,4]oxazinyl rings, such as 5,6-dihydro-2H-pyrazolo[4,3-b][1,4]oxazinyl rings; - a dihydrobenzoxazinyl ring substituted by one hydroxyl group, for example a dihydro-1,4-benzoxazinyl ring, for example a 2,3-dihydro-1,4-benzoxazinyl ring; - a dihydronaphthyridinyl ring, such as a tetrahydronaphthyridinyl ring or a 3,4-dihydro-2H-1,6-naphthyridinyl ring, substituted by one hydroxyl group; hexahydronaphthyridinyl rings, such as hexahydro-2H-1,7-naphthyridinyl rings, for example 3,4,4a,5,6,8a-hexahydro-2H-1,7-naphthyridinyl rings substituted by one methyl group and one oxo group; an octahydronaphthyridinyl ring, such as an octahydro-1,7-naphthyridinyl ring or an octahydro-1,5-naphthyridinyl ring, substituted by one oxo group, one methyl group or one acetyl group, such as a 2,3,4,4a,5,6,7,8a-octahydro-1,7-naphthyridinyl ring, a 2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridinyl ring or a 2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridinyl ring; an octahydropyrrolopyridinyl or hexahydropyrrolopyridinyl ring, such as a hexahydro-1H-pyrrolo[3,4-c]pyridinyl ring, an octahydropyrrolo[2,3-c]pyridinyl ring or a hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, such as a 2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridinyl ring, a 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridinyl ring or a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, which is unsubstituted or substituted by one methyl group, one ethyl group, one acetyl group, one isopropyl group or one oxo group; an octahydropyrrolooxazinyl ring or a hexahydropyrrolooxazinyl ring, which is unsubstituted or substituted by one methyl group, one ethyl group or one acetyl group, such as a hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring, such as a 2,3,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring, a 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring or a 3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring, - a hexahydrocyclopentaoxazinyl ring substituted with one hydroxyl group, such as a 3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazinyl ring; - unsubstituted octahydropyrido[4,3-b][1,4]oxazinyl rings, for example octahydropyridoxazinyl rings such as 2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazinyl rings; an indolinyl ring substituted with one hydroxyl group or one -CH2OH group; a hexahydropyrrolopyrrolyl ring, such as a hexahydropyrrolo[3,4-b]pyrrolyl ring, a hexahydro-1H-pyrrolo[3,2-b]pyrrolyl ring or a hexahydro-2H-pyrrolo[3,4-b]pyrrolyl ring, such as a 2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrolyl ring, a 2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrolyl ring or a 3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrolyl ring, which is unsubstituted or substituted by one methyl group, one ethyl group or one acetyl group; - unsubstituted hexahydrofuro[3,4-c]pyrrolyl rings, for example hexahydrofuropyrrolyl rings such as 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl rings; - an azabicyclooctanyl ring, such as a 6-azabicyclo[3.2.1]octanyl ring, substituted with one hydroxyl group; - a diazabicyclononanyl ring, such as a 3,6-diazabicyclo[3.2.2]nonanyl ring substituted with one methyl group - unsubstituted oxazabicyclooctanyl rings, for example 3-oxa-8-azabicyclo[3.2.1]octanyl rings; - an azaspironanyl ring, such as an azaspiro[3.5]nonanyl ring, which is unsubstituted or substituted with one substituent selected from an NH group, a CH—C(═O)—NH— group, and a hydroxyl group; - an azaspirooctanyl ring, such as an azaspiro[3.4]octanyl ring, which is unsubstituted or substituted with one hydroxyl group; - an azaspiroheptanyl ring, such as an azaspiro[3.3]heptanyl ring, which is unsubstituted or substituted with one hydroxyl group; - a diazaspirodecanyl ring, such as a 1,9-diazaspiro[4.5]decanyl ring substituted with one methyl group; - a diazaspirononanyl ring, such as a diazaspiro[3.5]nonanyl ring, which is unsubstituted or substituted by one methyl group; a diazaspiroheptanyl ring, such as a diazaspiro[3.3]heptanyl ring, which is unsubstituted or substituted by one methyl group; - an oxadiazaspirononanyl ring, such as an 8-oxa-2,5-diazaspiro[3.5]nonanyl ring substituted with one methyl group; an oxadiazaspirodecanyl ring, such as a 2-oxa-6,9-diazaspiro[4.5]decanyl ring, a 9-oxa-2,6-diazaspiro[4.5]decanyl ring, or a 6-oxa-2,9-diazaspiro[4.5]decanyl ring, which is unsubstituted or substituted by one ethyl group or one methyl group; - an oxadiazaspironudecanyl ring substituted by one methyl group, for example a 4-oxa-1,8-diazaspiro[5.5]undecanyl ring; - dioxadiazaspirododecanyl rings, such as 1,11-dioxa-4,8-diazaspiro[5.6]dodecanyl rings substituted with one ethyl group; - an oxazaspirononanyl ring, such as an oxazaspiro[3.5]nonanyl ring; and - an oxazaspiroheptanyl ring, such as an oxazaspiro[3.3]heptanyl ring.

[0036] All these subgroups, used alone or in combination, are part of the present disclosure.

[0037] According to certain embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; and R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms, and containing 2 to 6 carbon atoms; Forming The monocyclic heterocycloalkyl ring may be unsubstituted or may be selected from the group consisting of a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino-(C2-C5)acyl group, a hydro and -COH group.

[0038] According to certain other embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms, and containing 2 to 6 carbon atoms; Forming The monocyclic heterocycloalkyl ring may be unsubstituted or may be selected from the group consisting of a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino-(C2-C5)acyl group, a hydro and -COH group.

[0039] According to certain other embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R4 and R5, together with the nitrogen atom to which they are attached, - a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms, and containing 2 to 6 carbon atoms; Forming The monocyclic heterocycloalkyl ring may be unsubstituted or may be selected from the group consisting of a (C1-C4)alkyl- group, an NH2 group, a mono(C1-C4)alkylamino- group, a di(C1-C4)alkylamino- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, an NH2-(C3-C6)cycloalkyl- group, an OH-(C3-C6)cycloalkyl- group, a mono(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a di(C1-C4)alkylamino-(C3-C6)cycloalkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino-(C2-C5)acyl group, a hydro and -COH group.

[0040] According to certain other embodiments, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R7a and R7b each independently represent a hydrogen atom, a (C1-C4) alkyl-group, an NH2 group, a mono(C1-C4) alkylamino-group, a di(C1-C4) alkylamino-group, an NH2-(C1-C4) alkyl-group, a mono(C1-C4) alkylamino-(C1-C4) alkyl-group, a di(C1-C4) alkylamino-(C1-C4) alkyl-group, an NH2-(C3-C6) cycloalkyl-group, an OH-(C3-C6) cycloalkyl-group, a mono(C1-C4) alkylamino-(C3-C6) cycloalkyl-group, a di(C1-C4) alkylamino-(C3-C6) cycloalkyl-group, a (C2-C5) acylamino-(C1-C4) alkyl-group, a (C2-C5) acylamino-group, or a (C2-C 5) Represents an acyl group, a hydroxy-(C1-C4)alkyl- group, an SH-(C1-C4)alkyl- group, a CN-(C1-C4)alkyl- group, a (C1-C4)alkoxy-(C1-C4)alkyl- group, a hydroxyl group, an oxo group, a (C3-C6)cycloalkyl group, a halogen atom, a halo(C1-C4)alkyl- group, a cyano group, an NH-C(=O)- group, a mono(C1-C4)alkylamino-C(=O)- group, a di(C1-C4)alkylamino-C(=O)- group, an NH-C(=O)-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, or a -COH group.

[0041] According to certain other embodiments, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a halo(C1-C4) alkyl group, [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, or a halo(C1-C4) alkyl group; or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; and R7a and R7b each independently represent a hydrogen atom, a (C1-C4)alkyl- group, a halo-(C1-C4)alkyl- group, an NH2-C(=O)- group, an NH2-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, a (C2-C5)acylamino-(C1-C4)alkyl- group, a hydroxy-(C1-C4)alkyl- group, an SH-(C1-C4)alkyl- group, a CN-(C1-C4)alkyl alkyl- group, (C2-C5)acyl group, mono(C1-C4)alkylamino-C(=O)- group, di(C1-C4)alkylamino-C(=O)- group, NH2-(C3-C6)cycloalkyl- group, NH2-C(=O)-(C1-C4)alkyl- group, mono(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, di(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, oxo group, or (C1-C4)alkoxy-(C1-C4)alkyl- group.

[0042] According to certain other embodiments, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a halo(C1-C4) alkyl group, [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, or a halo(C1-C4) alkyl group; or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R7a is a hydrogen atom, a (C1-C4) alkyl- group, a halo-(C1-C4) alkyl- group, an NH2-C(=O)- group, an NH2-(C1-C4) alkyl- group, a mono(C1-C4) alkylamino-(C1-C4) alkyl- group, a di(C1-C4) alkylamino-(C1-C4) alkyl- group, a (C2-C5) acylamino-(C1-C4) alkyl- group, a hydroxy-(C1-C4) alkyl- group, an SH-(C1-C4) alkyl- group, a CN-(C1-C4) alkyl- group, or ( a (C2-C5) acyl group, a mono(C1-C4)alkylamino-C(=O)- group, a di(C1-C4)alkylamino-C(=O)- group, an NH2-(C3-C6)cycloalkyl- group, an NH2-C(=O)-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, an oxo group or a (C1-C4)alkoxy-(C1-C4)alkyl- group; R7b represents a hydrogen atom or a hydroxy-(C1-C4) alkyl group.

[0043] According to certain other embodiments, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 1 or 2, R1 each independently represent a methyl group, an ethyl group, an isopropyl group, an ethynyl group, F, Cl, a methoxy group, a cyclopropyl group, a trifluoromethoxy group, or a trifluoromethyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group to form the following formula: [ka] In the formula, the symbol [ka] represents the bonding site between the carbon atom of the phenol ring and the carbon atom of the pyridazine ring, R2 and R3 each independently represent a hydrogen atom, a cyano group, a -CHF2 group, a trifluoromethyl group, an OH-CH2 group, a methyl group, an ethyl group, or an isopropyl group; or R2 and R3 on adjacent carbon atoms together with the atom connecting them form a cyclopentyl ring fused to the pyridazine ring; R7a and R7b each independently represent a hydrogen atom, methyl group, CH2F- group, NH2-CH2- group, N(CH3)2-CH2- group, SH-CH2- group, CN-CH2- group, CH3-NH-(CH2)2- group , OH-CH2- group, OH-CD2- group, OH-(CH2)2- group, OH-C(CH3)2- group, CH3-CH(OH)- group, CH3-C(=O)-NH-CH2- group, CH3-C(=O)-NH-CH 2-CH2- group CH(CH3)2-C(=O)-NH-CH2- group, NH2-C(=O)- group, NH(CH3)-C(=O)- group, N(CH3)2-C(=O)- group, NH2-cyclopropyl- group, NH Represents a 2-C(=O)-CH2- group, NH(CH3)-C(=O)-CH2- group, N(CH3)2-C(=O)-CH2- group, CH3-CH2-C(=O)- group, oxo group, or CH3-O-CH2- group.

[0044] According to certain other embodiments, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 1 or 2, R1 each independently represent a methyl group, an ethyl group, an isopropyl group, an ethynyl group, F, Cl, a methoxy group, a cyclopropyl group, a trifluoromethoxy group, or a trifluoromethyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group to form the following formula: [ka] In the formula, the symbol [ka] represents the bonding site between the carbon atom of the phenol ring and the carbon atom of the pyridazine ring, R2 and R3 each independently represent a hydrogen atom, a cyano group, a -CHF2 group, a trifluoromethyl group, an OH-CH2 group, a methyl group, an ethyl group, or an isopropyl group; or R2 and R3 on adjacent carbon atoms together with the atom connecting them form a cyclopentyl ring fused to the pyridazine ring; R7a is a hydrogen atom, methyl group, CH2F- group, NH2-CH2- group, N(CH3)2-CH2- group, SH-CH2- group, CN-CH2- group, CH3-NH-(CH2)2- group, OH-CH2- group , OH-CD2- group, OH-(CH2)2- group, OH-C(CH3)2- group, CH3-CH(OH)- group, CH3-C(=O)-NH-CH2- group, CH3-C(=O)-NH-CH2-CH2- Group CH(CH3)2-C(=O)-NH-CH2- group, NH2-C(=O)- group, NH(CH3)-C(=O)- group, N(CH3)2-C(=O)- group, NH2-cyclopropyl- group, NH2-C (=O)-CH2- group, NH(CH3)-C(=O)-CH2- group, N(CH3)2-C(=O)-CH2- group, CH3-CH2-C(=O)- group, oxo group, or CH3-O-CH2- group, R7b represents a hydrogen atom or an OH-CH2- group.

[0045] According to certain other embodiments, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; and R8a and R8b each independently represent a hydrogen atom, a (C1-C4) alkyl-group, an NH2 group, a mono(C1-C4) alkylamino-group, a di(C1-C4) alkylamino-group, an NH2-(C1-C4) alkyl-group, a mono(C1-C4) alkylamino-(C1-C4) alkyl-group, a di(C1-C4) alkylamino-(C1-C4) alkyl-group, an NH2-(C3-C6) cycloalkyl-group, an OH-(C3-C6) cycloalkyl-group, a mono(C1-C4) alkylamino-(C3-C6) cycloalkyl-group, a di(C1-C4) alkylamino-(C3-C6) cycloalkyl-group, a (C2-C5) acylamino-(C1-C4) alkyl-group, a (C2-C5) acylamino-group, or (C2-C 5) Represents an acyl group, a hydroxy-(C1-C4)alkyl- group, an SH-(C1-C4)alkyl- group, a CN-(C1-C4)alkyl- group, a (C1-C4)alkoxy-(C1-C4)alkyl- group, a hydroxyl group, an oxo group, a (C3-C6)cycloalkyl group, a halogen atom, a halo(C1-C4)alkyl- group, a cyano group, an NH-C(=O)- group, a mono(C1-C4)alkylamino-C(=O)- group, a di(C1-C4)alkylamino-C(=O)- group, an NH-C(=O)-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, or a -COH group.

[0046] According to certain other embodiments, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 2, R1 each independently represent a halogen atom, a (C1-C4) alkyl group, or a halo(C1-C4) alkyl group; R2 and R3 represent a hydrogen atom or a halo(C1-C4)alkyl group; and R8a and R8b each independently represent a hydrogen atom, an NH2- group, an NH2-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, a hydroxy-(C1-C4)alkyl- group, a (C1-C4)alkoxy-(C1-C4)alkyl- group, a hydroxyl group, or an oxo group.

[0047] According to certain other embodiments, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 2, R1 each independently represent a halogen atom, a (C1-C4) alkyl group, or a halo(C1-C4) alkyl group; R2 represents a halo(C1-C4)alkyl group or a hydrogen atom; R3 represents a hydrogen atom, R8a represents a hydrogen atom, an NH2- group, an NH2-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-(C1-C4)alkyl- group, a hydroxy-(C1-C4)alkyl- group, a (C1-C4)alkoxy-(C1-C4)alkyl- group, a hydroxyl group, or an oxo group; R8b represents a hydrogen atom or an oxo group.

[0048] According to certain other embodiments, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 2, R1 each independently represent a chlorine atom, a methyl group, or a trifluoromethyl group; R2 represents a hydrogen atom or a -CHF2 group; R3 represents a hydrogen atom, R8a and R8b each independently represent a hydrogen atom, an NH2- group, an NH2-(CH2)- group, an N(CH3)2-(CH2)- group, an OH-CH2- group, a CH3-O-CH2- group, a hydroxyl group, or an oxo group.

[0049] According to certain other embodiments, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof: During the ceremony, n is 2, R1 each independently represent a chlorine atom, a methyl group, or a trifluoromethyl group; R2 represents a hydrogen atom or a -CHF2 group; R3 represents a hydrogen atom, R8a represents a hydrogen atom, an NH2- group, an NH2-(CH2)- group, an N(CH3)2-(CH2)- group, an OH-CH2- group, a CH3-O-CH2- group, a hydroxyl group, or an oxo group; R8b represents a hydrogen atom or an oxo group.

[0050] According to certain other embodiments, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, n is 1 or 2, R1's each independently represent a halogen atom, a (C1-C4) alkyl group, a halo(C1-C4) alkyl group, a (C1-C4) alkoxy group, a halo(C1-C4) alkoxy group, a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the phenyl ring), or a (C3-C6) cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to a phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, a (C1-C4) alkyl group, a hydroxy(C1-C4) alkyl group, a halo(C1-C4) alkyl group, or a group represented by the formula [ka] wherein R6 is a hydrogen atom or a methyl group, and [ka] represents the bonding site between the carbon atom and the pyridazine ring), or or R2 and R3 on adjacent carbon atoms, together with the atom connecting them, form a (C5-C6) carbocyclic ring fused to the pyridazine ring; R9a and R9b each independently represent a hydrogen atom, a (C1-C4) alkyl-group, an NH2 group, a mono(C1-C4) alkylamino-group, a di(C1-C4) alkylamino-group, an NH2-(C1-C4) alkyl-group, a mono(C1-C4) alkylamino-(C1-C4) alkyl-group, a di(C1-C4) alkylamino-(C1-C4) alkyl-group, an NH2-(C3-C6) cycloalkyl-group, an OH-(C3-C6) cycloalkyl-group, a mono(C1-C4) alkylamino-(C3-C6) cycloalkyl-group, a di(C1-C4) alkylamino-(C3-C6) cycloalkyl-group, a (C2-C5) acylamino-(C1-C4) alkyl-group, a (C2-C5) acylamino-group, or a (C2-C 5) Represents an acyl group, a hydroxy-(C1-C4)alkyl- group, an SH-(C1-C4)alkyl- group, a CN-(C1-C4)alkyl- group, a (C1-C4)alkoxy-(C1-C4)alkyl- group, a hydroxyl group, an oxo group, a (C3-C6)cycloalkyl group, a halogen atom, a halo(C1-C4)alkyl- group, a cyano group, an NH-C(=O)- group, a mono(C1-C4)alkylamino-C(=O)- group, a di(C1-C4)alkylamino-C(=O)- group, an NH-C(=O)-(C1-C4)alkyl- group, a mono(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, a di(C1-C4)alkylamino-C(=O)-(C1-C4)alkyl- group, or a -COH group.

[0051] According to certain other embodiments, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein: During the ceremony, n is 2, R1 each independently represent a halogen atom, a (C1-C4) alkyl group, or a halo(C1-C4) alkyl group; R2 and R3 represent hydrogen atoms; R9a and R9b each independently represent a hydrogen atom, an NH2 group, a mono(C1-C4)alkylamino-group, a di(C1-C4)alkylamino-group, an NH2-(C1-C4)alkyl-group, a di(C1-C4)alkylamino-(C1-C4)alkyl-group, an NH2-(C3-C6)cycloalkyl-group, a (C2-C5)acylamino-(C1-C4)alkyl-group, a hydroxy-(C1-C4)alkyl-group, a hydroxyl group, a cyano group, an oxo group, or a halogen atom.

[0052] According to certain other embodiments, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein: During the ceremony, n is 2, R1 each independently represent a halogen atom, a (C1-C4) alkyl group, or a halo(C1-C4) alkyl group; R2 and R3 represent hydrogen atoms; R9a represents a hydrogen atom, an NH2 group, a mono(C1-C4)alkylamino-group, a di(C1-C4)alkylamino-group, an NH2-(C1-C4)alkyl-group, a di(C1-C4)alkylamino-(C1-C4)alkyl-group, an NH2-(C3-C6)cycloalkyl-group, a (C2-C5)acylamino-(C1-C4)alkyl-group, a hydroxy-(C1-C4)alkyl-group, a hydroxyl group, a cyano group, or a halogen atom; R9b represents a hydrogen atom, an oxo group or a halogen atom.

[0053] According to certain other embodiments, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein: During the ceremony, n is 2, R1 each independently represent a chlorine atom, a methyl group, or a trifluoromethyl group; R2 and R3 represent hydrogen atoms; R9a and R9b each independently represent a hydrogen atom, an NH2 group, an N(CH3)2- group, a CH3-CH2-NH- group, an NH2-CH2- group, an N(CH3)2-CH2- group, an NH2-cyclopropyl- group, a CH3-(C=O)-NH-CH2- group, an OH-CH2- group, a hydroxyl group, a cyano group, an oxo group, or a fluorine atom (F).

[0054] According to certain other embodiments, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein: During the ceremony, n is 2, R1 each independently represent a chlorine atom, a methyl group, or a trifluoromethyl group; R2 and R3 represent hydrogen atoms; R9a represents a hydrogen atom, an NH2 group, an N(CH3)2- group, a CH3-CH2-NH- group, an NH2-CH2- group, an N(CH3)2-CH2- group, an NH2-cyclopropyl- group, a CH3-(C=O)-NH-CH2- group, an OH-CH2- group, a hydroxyl group, a cyano group, or a fluorine atom (F); R9b represents a hydrogen atom, an oxo group or a fluorine atom (F).

[0055] Among the compounds of formula (I) that are the subject of the present disclosure, or pharmaceutically acceptable salts thereof, mention may be made, for example, of the following compounds: (1) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidin-4-ol; (2) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidine-4-carbonitrile; (3) 7-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-ol; (4) 3,5-dimethyl-2-[6-[rac-(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol; (5) 2-[6-[(3R)-3-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (6) 2-[6-[(3S)-3-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (7) 2-[6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid; (8) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (9) 2-[6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (10) 2-[6-[(4aR,8aS)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol enantiomer 1; (11) 2-[6-[(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; formic acid enantiomer 2; (12) 2-[6-[(4aR,8aS)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 1; (13) 2-[6-[(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 2; (14) 2-[6-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (15) 2-[6-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (16) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (17) 2-[6-[3-(1-aminocyclopropyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (18) 2-[6-[(3S)-3-(aminomethyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (19) 2-[6-[4-(aminomethyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (20) 2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (21) 3,5-dichloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (22) 2-[6-[(3R)-3-(aminomethyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (23) 2-[6-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dichloro-phenol; (24) 2-[6-[2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (25) 2-[6-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dichloro-phenol; (26) 2-[6-[2-(1-hydroxy-1-methyl-ethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (27) 2-[6-[(2R)-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (28) 2-[6-[(3S)-3-(hydroxymethyl)-1-piperidyl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (29) 3-methyl-2-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (30) 2-[6-[3-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (31) 2-[6-[(3R)-3-amino-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; formic acid; (32) 2-[6-(2-amino-7-azaspiro[3.5]nonan-7-yl)pyridazin-3-yl]-3,5-dichloro-phenol; (33) 3,5-dichloro-2-[6-[(2R)-2-(methoxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (34) 3,5-dichloro-2-[6-[(3S)-3-(hydroxymethyl)-1-piperidyl]pyridazin-3-yl]phenol; (35) 3,5-dichloro-2-[6-[(2S)-2-(methoxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (36) 3,5-dichloro-2-[6-[(3R)-3-(hydroxymethyl)-1-piperidyl]pyridazin-3-yl]phenol; (37) 7-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-ol; (38) 3,5-dichloro-2-(6-morpholinopyridazin-3-yl)phenol; (39) 3,5-dichloro-2-[6-[(2S)-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]phenol; (40) 3,5-dichloro-2-[6-[(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl]pyridazin-3-yl]phenol; (41) 3,5-dichloro-2-[6-[(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl]pyridazin-3-yl]phenol; (42) 6-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-6-azaspiro[3.4]octan-2-ol; (43) 3,5-dichloro-2-[6-[(2R)-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]phenol; (44) 3-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (45) 3-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (46) 2-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-2-azaspiro[3.3]heptan-6-ol; (47) N-[7-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-yl]acetamide; (48) 3-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (49) 3,5-dichloro-2-[6-(4,4-difluoro-1-piperidyl)pyridazin-3-yl]phenol; (50) 3,5-dichloro-2-[6-[(3R)-3-[(dimethylamino)methyl]-1-piperidyl]pyridazin-3-yl]phenol; (51) 3,5-Dichloro-2-[6-[(3S)-3-[(dimethylamino)methyl]-1-piperidyl]pyridazin-3-yl]phenol; (52) 2-[6-[2-(1-hydroxy-1-methyl-ethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 1; (53) 2-[6-[-2-(1-hydroxy-1-methyl-ethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 2; (54) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (55) 3,5-dichloro-2-[6-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridazin-3-yl]phenol; (56) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (57) N-[[(3R)-1-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (58) N-[[(3S)-1-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (59) 2-[6-[-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 1; (60) 2-[6-[-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 2; (61) 1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (62) (4S)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (63) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (64) 3,5-dichloro-2-[6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazin-3-yl]phenol; (65) 2-[6-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (66) 3,5-dichloro-2-[6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3-yl]phenol; (67) (3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidin-3-ol; (68) 2-[6-[(3S)-3-(ethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (69) 2-[6-[(3S)-3-amino-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (70) (3R)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-3-ol; (71)(3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-3-ol; (72) 2-[4-ethyl-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (73) 5-chloro-2-[4-ethyl-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (74) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-isopropyl-pyridazin-3-yl]-5-methyl-phenol; (75) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-isopropyl-pyridazin-3-yl]phenol; (76) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (77) 2-[4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl]-5-methyl-phenol; (78) 5-chloro-2-[4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl]phenol; (79) 2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (80) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4,5-dimethyl-pyridazin-3-yl]-5-methyl-phenol; (81) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4,5-dimethyl-pyridazin-3-yl]phenol; (82) 2-[6-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (83) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.5]nonan-7-ol; (84) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.4]octan-6-ol; (85) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]phenol; (86) (4S)-4-Hydroxy-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-2-one; (87) 2-[6-[(2R)-2-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid; (88) 2-[6-[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (89) 2-[6-[(2R)-2-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid; (90) 6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3-(2-hydroxy-4-methyl-phenyl)pyridazine-4-carbonitrile; (91) 3,5-dimethyl-2-[6-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridazin-3-yl]phenol; (92) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (93) 5-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]phenol; (94) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.4]octan-6-ol enantiomer 1; (95) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.4]octan-6-ol enantiomer 2; (96) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methoxy-3-methyl-phenol; (97) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (98) 2-[6-[2-[(1S)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol diastereoisomer 2; (99) 2-[6-[2-[(1S)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol diastereoisomer 1; (102) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-4-methyl-phenol; (103) 3-(4-chloro-2-hydroxy-phenyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile; (105) N-[[(2S)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (106) N-[[(2R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (107) 2-[6-[3-(hydroxymethyl)azepan-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (108) 2-[6-[2-[(1R)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol diastereoisomer 1; (109) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-3,5-dimethyl-phenol; (110)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-5-methyl-phenol; (111)2-[6-[rac-(4aS,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (112)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-3,5-dimethyl-phenol; (113)(4R)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]isoxazolidin-4-ol; (114)2-[6-[1-(hydroxymethyl)-6-azabicyclo[3.2.1]octan-6-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (115)2-[6-[(2S)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (116)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methoxy-phenol; (117) 3,5-Dichloro-2-[6-[(2S)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]phenol; (118)2-[6-[(2R)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (119)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methoxy-3-methyl-phenol; (120) 3,5-dimethyl-2-[6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-yl]phenol; (121) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethoxy)phenol; (122) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3-(hydroxymethyl)pyrrolidin-2-one; (123) 2-[6-[(3R)-3-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol, 2,2,2-trifluoroacetic acid; (124) 2-[6-[(3S)-3-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (125)2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol; (126) 1-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one; (127) 5-chloro-2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (128)2-[6-[(3S)-3-(dimethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (129) N-[[(3R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-3-yl]methyl]acetamide; (130)(4S)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-4-hydroxy-pyrrolidin-2-one; (131)(4S)-4-amino-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-2-one; (132)(4R)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (133) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-3-methyl-phenol; (134) 5-(difluoromethyl)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (135)2-[6-[(2S)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (136)2-[6-[(2R)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (137)(4R)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-4-(hydroxymethyl)pyrrolidin-2-one; (138)(4S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-4-(hydroxymethyl)pyrrolidin-2-one; (139)(3R)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3-(hydroxymethyl)pyrrolidin-2-one; (140)(3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3-(hydroxymethyl)pyrrolidin-2-one; (141) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,6-dimethylphenol; (142) 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide; (143) 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide; (144) 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (145) 5-chloro-2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (146) 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetamide; (147) 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetamide; (148) 2-[6-[(3R)-3-(dimethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (149) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-3-methyl-phenol; (150) 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N,N-dimethylacetamide; (151)2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N,N-dimethylacetamide; (152) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-4,6-dimethylphenol; (153) 3-(Difluoromethyl)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (154) 3,5-dimethyl-2-[6-[rac-(4aR,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol; (155)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (156) 1-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one; (157) 1-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one; (158) 6-(2-hydroxy-4,6-dimethyl-phenyl)-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile; (159) 3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazine-4-carbonitrile; (160) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)pyridazin-3-yl]phenol; (161) 3,5-Dichloro-2-[6-[2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (162) 4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2,3-dihydro-1,4-benzoxazin-6-ol; (163) 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile; (164) N-[[(3S)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (165)2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol; (166)(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N-methylmorpholine-2-carboxamide; (167) N-[[(3R)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (168) 2-[6-[(4aR,7aR)-4-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol; (169) 5-chloro-2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methylphenol; (170) 2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (171) 5-chloro-2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (172) 3-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (173)2-[6-[(2R,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (174) 2-[6-[2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (175) 6-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomer 1; (176) 6-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomer 2; (177) 3-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (178)2-[6-[(2R,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (179)(4S)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]isoxazolidin-4-ol; (180) 2-[6-[2-[(1R)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol diastereoisomer 2; (181)(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholine-2-carboxamide; (182)(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N-methylmorpholine-2-carboxamide; (183)(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholine-2-carboxamide; (184)(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N,N-dimethylmorpholine-2-carboxamide; (185)2-[6-[(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol; (186) 2-[4-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (187)2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (188) 5-chloro-2-[4-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (189) 5-chloro-2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (190)2-[6-[rac-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol; (191)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,4-dimethylphenol; (192) 2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (193) 4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-2,3-dihydro-1,4-benzoxazin-7-ol; (194) 2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (195)2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (196) 3,5-dimethyl-2-[6-(2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]phenol; (197)2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (198)2-[6-[(2S,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (199)2-[6-[(2S,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (200) 2-[6-[(2R,6R)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (201)2-[6-[(2R,6R)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (203) 3,5-Dichloro-2-(6-thiomorpholinopyridazin-3-yl)phenol; (204) 5-cyclopropyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (206)2-[6-[(3aS,6aR)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (207)2-[6-[(3aR,6aR)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (208)2-[6-(8-ethyl-1,11-dioxa-4,8-diazaspiro[5.6]dodecan-4-yl)pyridazin-3-yl]-3,5-dimethylphenol; (209)2-[6-[rac-(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (210)2-[6-[rac-(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (211)N-[[(3S)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (212) N-[[(3R)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (213) 1-[rac-(4aR,8aS)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (214) 1-[rac-(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (215)2-[6-(2,3-dihydropyrido[3,4-b][1,4]oxazin-1-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; (216)N-[[(2R)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (217) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-7-ol; (219)2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (220)2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (221)2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (222) 1-[rac-(4aR,8aS)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (223)2-[6-[rac-(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (224)2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (225)2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (226)2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (227) 2-[6-(6-ethyl-2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]-3,5-dimethylphenol; (228) 1-[rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-5-yl]ethanone; (229)2-[6-[rac-(3aS,6aS)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (230) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-6-ol; (231) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-8-ol; (232) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-5-ol; (233)2-[6-[(2R)-2-(2-hydroxyethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (234)2-[6-[(2S)-2-(2-hydroxyethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (235) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-5-(hydroxymethyl)piperidin-2-one; (236) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-5-ol; (237) 3,5-Dichloro-2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (238) 3,5-Dichloro-2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (239) 1-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]hexahydropyrimidin-2-one; (240) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-4-ol; (241)2-[6-[4-(hydroxymethyl)indolin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (242) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-1,6-naphthyridin-5-ol; (243) 2-[6-[rac-(3aS,6aS)-5-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (245) 5-ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methylphenol; (246) 3-Ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methylphenol; (247) 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (248) 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (249) 5-chloro-2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (250)(4S)-4-amino-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (251)2-[6-[(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (252) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (253) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-7-ol; (254) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-6-ol; (255)2-[6-[(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (256)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (257) 1-[rac-(4aS,7aS)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (258) 3-methyl-2-[6-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (259) 3-methyl-2-[6-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (260)2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (261)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (262) 1-[(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (263) 1-[(4aS,8aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (264)rac-(3aS,7aR)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one, hydrochloride; (265)2-[6-[rac-(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (266) 2-[6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (267)N-[[(2R)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (268)2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (269)rac-(3aS,7aS)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one, hydrochloride; (270)2-[6-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (271)2-[6-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (272)2-[6-(3,4-dihydro-2H-quinolin-1-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; (273) 3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (274)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-isopropyl-3-methyl-phenol; (275)N-[[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (276) N-[[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]methyl]-2-methylpropanamide; (277)N-[2-[(2R)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]ethyl]acetamide; (278)N-[2-[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]ethyl]acetamide; (279)N-[[(2R)-4-[6-(4-chloro-2-hydroxy-6-methylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]-2-methylpropanamide; (280)N-[[(2S)-4-[6-(4-chloro-2-hydroxy-6-methylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (283) 2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (284) 2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (285)N-[[(2S)-4-[6-(4-chloro-2-hydroxy-6-methylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]-2-methylpropanamide; (286)(4S)-4-Hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (287)(3R)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (288)(3S)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (289) 3-Methyl-2-[6-[rac-(4aR,7aR)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (290)(4aR,8aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-7-methyl-3,4,4a,5,6,8a-hexahydro-2H-1,7-naphthyridin-8-one; (291)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-(difluoromethyl)pyridazin-3-yl]-3,5-dimethyl-phenol; (292)(4R)-4-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (293)(4S)-4-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (295)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (296)2-[6-[(2S,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (297)2-[6-[(2S,6S)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (298)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (299)2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (300) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2,3,4,4a,5,6,7,8a-octahydro-1,7-naphthyridin-8-one; (301)2-[6-[(4aR,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (302) 2-[6-[(2R,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (303) 3,5-dimethyl-2-[6-[(2S)-2-(sulfanylmethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (304) 1-[rac-(4aR,8aS)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (305) 3,5-dimethyl-2-[6-[(2R)-2-(sulfanylmethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (306)2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (307) 5-chloro-3-methyl-2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol; (308)2-[6-[(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (309)2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (310)2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (311)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (312)2-[6-[(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (313)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (314)2-[6-[(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (315)2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (316)(4R)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (317)2-[6-(4-ethyl-1,11-dioxa-4,8-diazaspiro[5.6]dodecan-8-yl)pyridazin-3-yl]-3,5-dimethylphenol; (318) 3-Methyl-2-[6-[rac-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; hydrochloride; (320) 3-Methyl-2-[6-[rac-(4aR,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; hydrochloride; (321)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (322)2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (323)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (324) 5-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]indan-4-ol; (325)(3R)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (326)(3S)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (327)2-[(2R)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]acetonitrile; (328)2-[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]acetonitrile; (329)(6R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-(hydroxymethyl)piperazin-2-one; (330)(6S)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-(hydroxymethyl)piperazin-2-one; (331) 3-methyl-2-[6-[(2R)-2-[2-(methylamino)ethyl]morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (332) 3-methyl-2-[6-[(2S)-2-[2-(methylamino)ethyl]morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (333)2-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (334)2-[6-[(4aS,7aR)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (335) 1-[rac-(4aR,7aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (336) 1-[(4aR,8aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (337) 1-[rac-(4aR,7aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (338) 5-chloro-2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (339) 5-chloro-2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (340)2-[6-[(rac-3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (341)2-[6-[(rac-3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (342) 3,5-dimethyl-2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]phenol; (343)2-[6-[(4aS,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (344) 2-[6-[(4aR,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (345) 5-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]indan-4-ol; (346) 3-Methyl-2-[6-[rac-(3aS,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; hydrochloride; (348) 1-[(4aR,7aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (349) 1-[(4aS,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (350)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (351)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-6-fluoro-phenol; (352) 1-[(4aS,7aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (353)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-6-fluoro-3-methyl-phenol; (354)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (355)2-[6-[(4aS,8aR)-6-(2,2,2-trifluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (356)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-6-fluoro-phenol; (357)1-[(4aS,8aR)-4-[6-(4-chloro-2-hydroxy-phenyl)-5-methyl-pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (358)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-phenol; (359)2-[6-[(2S,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (360)2-[6-(5,6-dihydro-2H-pyrazolo[4,3-b][1,4]oxazin-7-yl)pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (361) 3-Methyl-2-[6-[rac-(4aR,7aS)-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (362)2-[6-(2,3-dihydropyrido[4,3-b][1,4]oxazin-4-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; (363)1-[(4aS,8aR)-4-[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (364)2-[6-[rac-(3aS,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (365)2-[6-[(2R,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (366)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (367)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (368)2-(hydroxymethyl)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-3-one; (369) 1-[(3aR,7aR)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (370) 1-[(3aS,7aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (371)2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (372)(4S)-1-[5-(difluoromethyl)-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-4-hydroxy-pyrrolidin-2-one; (373)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (374)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (375)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (376) 3-Methyl-2-[6-[rac-(4aR,7aR)-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (377) 1-[rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl]ethanone; (378)2-[6-[rac-(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (379)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (380) 1-[(4aS,8aR)-4-[6-[2-ethyl-6-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (381)1-[(4aS,8aR)-4-[6-(4-chloro-2-ethyl-6-hydroxy-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (382)2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (383)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (384)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (385)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (386) 1-[(4aS,8aR)-4-[5-(difluoromethyl)-6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (387) 1-[(4aS,8aR)-4-[5-(difluoromethyl)-6-(2-hydroxy-4-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (388)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-phenol; (389)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (390)2-[6-[(2S,6S)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (391)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (392)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (393)2-[6-[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (394) 1-[(3aR,7aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (395) 1-[(3aR,7aR)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (397)1-[(4aS,8aR)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (398)1-[(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (399)3,5-Dichloro-2-[6-(1,1-dioxo-1,4-thiazinan-4-yl)pyridazin-3-yl]phenol; (400) 3,5-dichloro-2-[6-(1-oxo-1,4-thiazinane-4-yl)pyridazin-3-yl]phenol; (402)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (403) 3,5-dimethyl-2-[6-[rac-(4aS,8aR)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol; (404)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (405) 1-[(4aS,8aR)-4-[4-(difluoromethyl)-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (406)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (407)2-[6-[(3aS,7aR)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (408)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-phenol; (409)1-[(4aS,8aR)-4-[6-(2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (410) 3,5-dimethyl-2-[6-(3-methyl-3,6-diazabicyclo[3.2.2]nonan-6-yl)pyridazin-3-yl]phenol; (411)2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (412)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (413) 1-[(3aR,7aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (414) 1-[(3aS,7aS)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (415)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (416)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (417) 3-methyl-2-[6-(3-methyl-3,6-diazabicyclo[3.2.2]nonan-6-yl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (418) 3-Ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (419)(2S)-2-(hydroxymethyl)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-3-one; (420)(2R)-2-(hydroxymethyl)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-3-one; (421)3,5-dimethyl-2-[6-[rac-(4aS,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol; (422)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-phenol; (423)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-phenol; (424) 1-[(4aS,8aR)-4-[6-(2-ethyl-6-hydroxy-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (425)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-(difluoromethyl)pyridazin-3-yl]-3-ethyl-phenol; (426)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (427)2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (428) 3,5-dimethyl-2-[6-(9-methyl-1,9-diazaspiro[4.5]decan-1-yl)pyridazin-3-yl]phenol; (429)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (430)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (431)1-[(4aS,8aR)-4-[6-(2-hydroxy-4-methyl-phenyl)-5-methyl-pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (432)2-[6-[(4aS,8aR)-6-isopropyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-phenol; (433)2-[6-[(4aS,8aR)-6-isopropyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (434)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-methyl-pyridazin-3-yl]-3,5-dimethyl-phenol; (435)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (436)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (437)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (438) 3-Methyl-2-[6-[rac-(4aS,8aR)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (439)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-methyl-pyridazin-3-yl]-3-ethyl-phenol; (440) 3,5-dimethyl-2-[6-(9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl]phenol; (441) 3,5-dimethyl-2-[6-(1-methyl-4-oxa-1,8-diazaspiro[5.5]undecan-8-yl)pyridazin-3-yl]phenol; (442) 1-[(4aS,8aR)-4-[6-(4-chloro-2-hydroxy-phenyl)-5-(difluoromethyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (443)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-ethyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (444) 3,5-dimethyl-2-[6-(6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl]phenol; (445)3,5-dimethyl-2-[6-[(5S)-9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (446) 3,5-dimethyl-2-[6-[(5R)-9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (448) 3-Methyl-2-[6-[rac-(4aS,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (449) 3,5-dimethyl-2-[6-(8-methyl-4-oxa-1,8-diazaspiro[5.5]undecan-1-yl)pyridazin-3-yl]phenol; (450) 3,5-dimethyl-2-[6-[(5R)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (451)3,5-dimethyl-2-[6-[(5S)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (452) 2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (455) 3,5-dimethyl-2-[6-(2-methyl-8-oxa-2,5-diazaspiro[3.5]nonan-5-yl)pyridazin-3-yl]phenol; (456)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (457) 1-[(3aR,7aR)-1-[6-(2-hydroxy-4-methyl-phenyl)-5-methyl-pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (458)2-[6-[rac-(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (459)2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-methyl-phenol; (460)2-[6-[rac-(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (461)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol; (462) 1-[(4aR,8aR)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]ethanone; (463) 1-[(4aS,8aS)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]ethanone; (466)(4aS,6S,7aR)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazin-6-ol; (467)(4aR,6R,7aS)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazin-6-ol; (468)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (469)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (470)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-ethyl-pyridazin-3-yl]-5-methyl-phenol; (471)5-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]indan-4-ol; (472)2-[6-[(4aS,8aR)-6-isopropyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (473)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (474)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (475)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (476)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-methyl-phenol; (477)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-methyl-phenol; (479)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-fluoro-phenol; (480)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-fluoro-phenol; (481)2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (482)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (483)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (484) 3-Methyl-2-[6-[rac-(3aS,6aS)-1-methyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (485)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (486)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (487)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-(difluoromethyl)pyridazin-3-yl]-3,5-dimethyl-phenol; (488)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-(difluoromethyl)pyridazin-3-yl]-3,5-dimethyl-phenol; (489)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (490)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (491)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (492)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (493) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol (494)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol; (496)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (497)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (498)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (499)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (500)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (501)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (502)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (503)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (504)2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (505)2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (506)2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (507)2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (508)5-ethynyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (509)2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; (510) 1-[(3aS,7aS)-1-[5-(difluoromethyl)-6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (511) 1-[(3aR,7aR)-1-[5-(difluoromethyl)-6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (512) 1-[(3aS,7aS)-1-[4-(difluoromethyl)-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (513) 1-[(3aR,7aR)-1-[4-(difluoromethyl)-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (514) 1-[(3aR,7aR)-1-[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (515)2-[6-[(4aS,8aS)-5-methyl-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (516)2-[6-[(4aR,8aR)-5-methyl-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (517)2-[6-[(4aR,8aS)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (518)2-[6-[(4aS,8aS)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (519)2-[6-[(4aR,8aR)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (520)2-[6-[(4aS,8aR)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (521)2-[6-[(4aS,8aR)-6-(2-fluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (522)2-[6-[(4aS,8aR)-6-(2-fluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (523)2-[6-[(4aR,8aR)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (524)2-[6-[(4aS,8aS)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (525)2-[6-[(4aS,8aR)-6-(2-fluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-phenol; (526)2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol; (527) 2-[6-[(4aS,8aR)-6-(3-fluoropropyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; and (528) 5-Methyl-2-[4-methyl-6- [rac-(3aS,7aR)-6-isopropyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]phenol.

[0056] Among the compounds of formula (I) or pharmaceutically acceptable salts thereof listed above, the following compounds may be mentioned, for example, as being of interest: 1, 2, 5, 6, 8, 9, 14-31, 33-36, 38-41, 43-45, 48-54, 56-63, 65, 67-82, 85-90, 92, 93, 96-99, 102, 103, 105-110, 112, 113, 115-119, 121-124, 126-153, 155-161, 163-167, 169-174, 177- 184, 186-189, 191, 192, 194, 198-201, 203, 204, 209-212, 216, 219, 220, 233-235, 237, 238, 245-250, 258, 259, 266, 267, 273-280, 283-288, 292, 293, 296, 297, 302, 303, 305, 324-332, 338, 339, 345, 359, 365, 368, 372, 390, 399, 400, 418-420, 508, and 509.

[0057] Preparation of Compounds of Formula (I) The compounds of formula (I) according to the present disclosure or pharmaceutically acceptable salts thereof can be prepared according to various methods. More specifically, they can be prepared as shown by the following schemes. [ka]

[0058] In the above Scheme 1, R1, n, R2, R3, R4, and R5 are as defined in the present disclosure; X, independently of each other, represents a halogen atom such as Cl, Br, or I; P represents a protecting group such as a methyl group, a para-methoxybenzyl group, a benzyl group, a methoxymethyl group, or an ethoxyethyl group; and B(OR)2 represents either a boronic acid or a boronic acid ester, for example, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0059] The compounds of the present invention can be prepared according to Reaction Scheme 1, in which an appropriately substituted dihalogenopyridazine (GS 1) is reacted with a suitable amine (GS 2) in the presence of a base (such as KCO, DIPEA) at room temperature or elevated temperature (preferentially 120-180 °C) to give the halogenopyridazine (GS 3). This reaction can be carried out in a sealed tube and under microwave irradiation. This reaction can also be achieved by metal coupling using a Pd catalyst (such as Pd(dppf)Cl) and a mineral base such as KPO in an aprotic solvent such as 1,4-dioxane at elevated temperature (typically 100-110 °C) to provide compounds of general formula (I) according to the present disclosure. This intermediate is then reacted with an appropriate phenylboronate derivative (GS 4), which can be in the form of a boronic acid or boronate (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane), in a Suzuki-type reaction in the presence of a Pd catalyst (e.g., Pd(PPh) or Pd(dppf)Cl) and a mineral base such as NaHCO at elevated temperatures (typically 100-140 °C) in a mixture of solvents such as 1,4-dioxane / water or DME / water, to provide compounds of general formula (I). Note that the phenylboronate derivative can be used with a protected hydroxy function, e.g., methyl or benzyl (GS 5), to provide the appropriate phenylpyridazine (GS 6), which can be subjected to deprotection conditions (BBr or, e.g., hydrogenation) to provide compounds of general formula (I) according to the present disclosure. [ka]

[0060] In the above Scheme 2, R, n, R, R, R, and R are as defined in the present disclosure; X, independently of each other, represents a halogen atom such as Cl, Br, or I; P represents a protecting group such as a methyl group, a para-methoxybenzyl group, a benzyl group, a methoxymethyl group, or an ethoxyethyl group; and B(OR) represents either a boronic acid or a boronic acid ester, for example, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0061] Compounds of the present invention can also be prepared according to Reaction Scheme 2, in which an appropriately substituted dihalogenopyridazine (GS 1) is reacted with an appropriate phenyl boronate derivative (GS 4), which may be in the form of a boronic acid or a boronate such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, in a Suzuki reaction in the presence of a Pd catalyst (such as Pd(PPh) or Pd(dppf)Cl) and an inorganic base such as NaCO, in a mixture of solvents such as 1,4-dioxane / water or DME / water at temperatures between 100 and 140 °C, to give the halogenpyrrolidine (GS 7). This intermediate is then reacted with an appropriate amine (GS 2) in the presence of a base (such as NaHCO, DIPEA) at elevated temperatures (preferentially between 130 and 180 °C), optionally also performed in a sealed tube and under microwave irradiation, to provide compounds of general formula (I) according to the present disclosure. Using similar conditions, Suzuki reactions can also be carried out using phenylboronate derivatives (GS 5) bearing a protected alcohol functionality (e.g., methyl), using appropriate amines (GS 2) under similar conditions as above to give appropriate halogenopyridazines (GS 8) obtained after N-arylation, which are then subjected to deprotection conditions (e.g., BBr3) to give compounds of general formula (I) according to the present disclosure.

[0062] The intermediate halogenopyridazine (GS 7) may also be prepared by Reaction Scheme 3 shown below. [ka]

[0063] When n is 1, R1 represents a (C1-C4) alkyl group, and R2 and R3 each independently represent a hydrogen atom or a (C1-C4) alkyl group, (GS 7) may also be prepared by Reaction Scheme 3 in which an appropriately substituted phenol (GS 9) is reacted in a Friedel-Crafts acylation with an appropriate alkanoyl chloride (GS 10) in the presence of a Lewis acid such as TiCl4 (titanium(IV) chloride) at elevated temperature (e.g., 120°C) to give the acylated phenol GS 11. This intermediate is reacted with an α-oxoacid (GS 12) in a basic medium (e.g., KOH (potassium hydroxide)) and then, after workup, reacted in the presence of hydrazine hydrate (NH2-NH2, HO) at elevated temperatures (e.g., 100 °C) to give pyridazine (GS 13). A chlorinating agent such as POCl3 (phosphoryl chloride) is then added to intermediate (GS 13) in a polar solvent, e.g., DMF, at 80-90 °C to give the chloropyridazine derivative (GS 7).

[0064] Certain compounds of formula (I) as defined in this disclosure, or pharmaceutically acceptable salts thereof, are set forth in Table 1 (number and formula) and are further detailed below. 1 The 1 H NMR and liquid chromatography / mass spectra are also shown.

[0065] Table 1 1 H NMR was as defined in the experimental section. 1 H NMR spectrum (400 MHz or 500 MHz, δ (ppm), DMSO-d6, CD3OD or CDCl3).

[0066] The liquid chromatography / mass spectra (LC / MS) in Table 1 were obtained according to one of six methods described in the Experimental Section.

[0067] [Table 1]

[0068] [Table 2]

[0069] Table 3

[0070] Table 4

[0071] Table 5

[0072] Table 6

[0073] Table 7

[0074] Table 8

[0075] Table 9

[0076] Table 10

[0077] Table 11

[0078] Table 12

[0079] Table 13

[0080] Table 14

[0081] Table 15

[0082] Table 16

[0083] Table 17

[0084] Table 18

[0085] Table 19

[0086] Table 20

[0087] Table 21

[0088] Table 22

[0089] Table 23

[0090] Table 24

[0091] Table 25

[0092] Table 26

[0093] Table 27

[0094] Table 28

[0095] Table 29

[0096] Table 30

[0097] Table 31

[0098] Table 32

[0099] Table 33

[0100] Table 34

[0101] Table 35

[0102] Table 36

[0103] Table 37

[0104] Table 38

[0105] Table 39

[0106] Table 40

[0107] Table 41

[0108] Table 42

[0109] Table 43

[0110] Table 44

[0111] Table 45

[0112] Table 46

[0113] Table 47

[0114] Table 48

[0115] Table 49

[0116] Table 50

[0117] Table 51

[0118] Table 52

[0119] Table 53

[0120] Table 54

[0121] Table 55

[0122] Table 56

[0123] Table 57

[0124] Table 58

[0125] Table 59

[0126] Table 60

[0127] Table 61

[0128] Table 62

[0129] Table 63

[0130] Table 64

[0131] Table 65

[0132] Table 66

[0133] Table 67

[0134] Table 68

[0135] Table 69

[0136] Table 70

[0137] Table 71

[0138] Table 72

[0139] Table 73

[0140] Table 74

[0141] Table 75

[0142] Table 76

[0143] Table 77

[0144] Table 78

[0145] Table 79

[0146] Table 80

[0147] Table 81

[0148] Table 82

[0149] Table 83

[0150] Table 84

[0151] Table 85

[0152] Table 86

[0153] Table 87

[0154] Table 88

[0155] Table 89

[0156] Table 90

[0157] Table 91

[0158] Table 92

[0159] Table 93

[0160] Table 94

[0161] Table 95

[0162] Table 96

[0163] Table 97

[0164] Table 98

[0165] Table 99

[0166] Table 100

[0167] Table 101

[0168] Table 102

[0169] Table 103

[0170] Table 104

[0171] Table 105

[0172] Table 106

[0173] [Table 107]

[0174] [Table 108]

[0175] [Table 109]

[0176] [Table 110]

[0177] [Table 111]

[0178] [Table 112]

[0179] [Table 113]

[0180] [Table 114]

[0181] [Table 115] [Example]

[0182] The following examples describe the preparation of specific compounds according to the present disclosure.The number of compounds of formula (I) exemplified below corresponds to that described above.Unless otherwise specified, all reactions are carried out in an inert atmosphere.These examples are not limiting and are merely illustrative of the present disclosure. Analytical data (LC-MS and 1 H RMN) was not repeated in the final compound examples, as already disclosed in Table 1.

[0183] The following abbreviations are used: ACN or MeCN acetonitrile AcOK Potassium Acetate Aq. Water-based Ar Argon BBr3 Boron Tribromide BH3-THF Borane tetrahydrofuran complex BippyPhos 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole Boc tert-butyloxycarbonyl Boc2O di-tert-butyl dicarbonate BrettPhos Pd G3 [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate BuOH butanol CO2 Carbon dioxide CV column volume DCM or CH2Cl2 dichloromethane CbzCl Benzyl chloroformate CDCl3 Deuterated Chloroform CyJohnPhos Chloro(2-dicyclohexylphosphino-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) DIAD Diisopropyl azodicarboxylate DIPE Diisopropyl Ether DIPEA Diisopropylethylamine DMAP 4-dimethylaminopyridine DME Dimethyl Ether DMF N,N-dimethylformamide DMSO-d6 hexadeuterodimethyl sulfoxide EA Ethyl acetate Et3N Triethylamine EtOH ethanol EtOAc or AcOEt ethyl acetate GPhos Pd G3 Methanesulfonato[dicyclohexyl[3-(1,1-dimethylethoxy)-6-methoxy-2',6'-bis(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](2'-amino-1,1'-biphenyl-2-yl)palladium(II) H2 Hydrogen H2O Water HATU Hexafluorophosphate Azabenzotriazole Tetramethyluronium HBpin Pinacolborane HCl Hydrogen chloride HCOOH formic acid HCl Hydrochloric acid Hept. Heptane HMDS Bis(trimethylsilyl)amine I2 Iodine IL 1b Interleukin 1 beta iPrNH2 isopropylamine iPrOH isopropanol K2CO3 Potassium Carbonate K3PO4 Tripotassium Phosphate LC liquid chromatography LiOH Lithium hydroxide LiOH·H2O Lithium hydroxide monohydrate LiHMDS Lithium bis(trimethylsilyl)amide m-CPBA m-chloroperbenzoic acid Me-THF 2-methyltetrahydrofuran MeOD Tetradeuteromethanol MeOH Methanol MgSO4 Magnesium Sulfate N2 nitrogen NaBD4 Sodium borodeuteride NaBH4 Sodium borohydride NaBH3CN Sodium cyanoborohydride NaCl Sodium chloride NaH sodium hydride NaHCO3 Sodium bicarbonate Na2CO3 Sodium Carbonate Na2SO4 Sodium Sulfate Na2S2O3 Sodium thiosulfate NaO t Bu Sodium tert-butoxide NaOH Sodium hydroxide NaOTMS Sodium trimethylsiloxide NBS N-Bromosuccinimide NEt3 or TEA triethylamine NH3.H2 aqueous ammonia NH4HCO3 Ammonium bicarbonate NMP N-methyl-2-pyrrolidone NH4Cl Ammonium chloride NH4OH Ammonium hydroxide Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium Pd(dppf)Cl2 or PdCl2(dppf)[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd-118 or Pd(dtbpf)Cl2 or PdCl2(dtbpf)[1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 Palladium(II) Acetate Pd(OH)2 palladium hydroxide Pd / C Palladium Carbon PPh3 Triphenylphosphine TBAF Tetra-n-butylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran TNF-alpha or TNF-α Tumor necrosis factor-alpha or tumor necrosis factor-α rt room temperature Rt retention time RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuphosPdG3 Methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl-palladium(II) SFC Supercritical Fluid Chromatography SiOH Silicon hydroxide SiO2 silicon dioxide Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhosPdG2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) ℃ Celsius temperature ml milliliter mmol millimole min μmol micromol μl microliter h hour

[0184] Analytical methods used NMR: Proton magnetic resonance spectrum ( 1 H NMR was recorded at 400 MHz or 500 MHz primarily in DMSO-d6, using the DMSO peak as a reference, as described below. Chemical shifts (δ) are expressed in parts per million (ppm). The observed signals are designated as follows: s = singlet; d = doublet; t = triplet; m = multiplet or br s = broad singlet; br m = broad multiplet.

[0185] LCMS: The LCMS profiles as described below indicate the different high performance liquid chromatography analytical methods used.

[0186] LCMS final compound: Method A: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18+ 1.7 μm 2.1 x 50 mm; Column temperature: 40 °C; Flow rate: 1.0 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0187] [Table 116]

[0188] Method B: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 +1.7 μm 2.1 x 50 mm; Column temperature: 60 °C Flow rate: 1.0 ml / min; Solvent: A = HO (0.1% formic acid); B = ACN (0.1% formic acid)

[0189] [Table 117]

[0190] Method C: System: SHIMADZU LCMS-2020Q array; Ionization: electrospray in positive and / or negative mode (ES+ / -); Column: Halo C18 2.7 μm 3.0 x 30 mm; Column temperature: 50 °C Flow rate: 1.5 ml / min; Solvent: A = HO (0.0375% TFA); B = ACN (0.01875% TFA)

[0191] [Table 118]

[0192] Method D: System: SHIMADZU LCMS-2020Q array; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: Halo C18 5 μm 3.0 x 30 mm; Column temperature: 50 °C Flow rate: 2 ml / min; Solvent: A = HO (0.0375% TFA); B = ACN (0.01875% TFA)

[0193] [Table 119]

[0194] Method E: System: Waters UPLC-DAD and QDa; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY BEH C18 1.7 μm 2.1 x 100 mm; Column temperature: 40 °C; Flow rate: 0.343 ml / min; Solvent: A = H2O 95%, ACN 5% (0.5 g / l AcNH4); B = ACN

[0195] [Table 120]

[0196] Method F: System: Waters UPLC-DAD and ZQ; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: Alliance YMC C18 5 μm 4.6 × 75 mm; Column temperature: 30 °C Flow rate: 1 ml / min; Solvent: A = H2O (0.2% NH4HCO3); B = ACN

[0197] [Table 121]

[0198] Method Z1: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 50 mm; Column temperature: 60 °C; Flow rate: 1.0 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0199] [Table 122]

[0200] Method Z2: System: Waters UPLC-XEVO G2S-QTOF; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY BEH C4-1.7 μm-2.1 × 150 mm; Column temperature: 35 °C; Flow rate: 0.5 ml / min; Solvent: A = H2O (0.1% formic acid + 0.2% TEA); B = CH3CN (0.1% formic acid + 0.2% TEA).

[0201] [Table 123]

[0202] Method Z3: System: Agilent Technologies 1200 Series; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: XBridge C18 3.5 μm 4.6 × 50 mm; Column temperature: 45 °C; Flow rate: 1.8 ml / min; Solvent: A = H2O (10 mM NH4HCO3); B = ACN

[0203] [Table 124]

[0204] LCMS, intermediates Method G: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 50 mm; Column temperature: 50 °C Flow rate: 0.8 ml / min; Solvent: A = HO (0.1% formic acid); B = ACN (0.1% formic acid)

[0205] [Table 125]

[0206] Method H: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 30 mm; Column temperature: 35 °C Flow rate: 0.7 ml / min; Solvent: A = HO (0.1% formic acid); B = ACN (0.1% formic acid)

[0207] [Table 126]

[0208] Method I: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6 μm 2.1 x 50 mm; Column temperature: 55 °C; Flow rate: 0.8 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0209] [Table 127]

[0210] Method K: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6 μm 2.1x50 mm; Column temperature: 50°C; Flow: 1.0 ml / min; Solvent: A = HO (0.1% trifluoroacetic acid); B = ACN (0.1% trifluoroacetic acid).

[0211] [Table 128]

[0212] Method L: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6 μm 2.1 x 50 mm; Column Temperature: 50 °C; Flow Rate: 1.0 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0213] [Table 129]

[0214] Method M: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 30 mm; Column temperature: 35 °C Flow rate: 0.7 ml / min; Solvent: A = HO (0.1% formic acid); B = ACN (0.1% formic acid)

[0215] [Table 130]

[0216] Method N: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6 μm 2.1 x 50 mm; Column temperature: 55 °C; Flow rate: 0.8 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0217] [Table 131]

[0218] Method O: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 30 mm; Column temperature: 35 °C Flow rate: 0.7 ml / min; Solvent: A = HO (0.1% formic acid); B = ACN (0.1% formic acid)

[0219] [Table 132]

[0220] Method Q: System: Waters UPLC-DAD and QDa; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: HSS-T3 50 mm*2, 1 mm-1, 8 μm; Column temperature: 40 °C; Flow rate: 0.45 ml / min; Solvent: A = H2O 95%, ACN 5% (0.5 g / l AcNH4); B = CAN; C = Acid Formaldehyde 0, 2%

[0221] [Table 133]

[0222] Method R: System: Waters UPLC-DAD and QDa; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: BEH-C18 50 mm*2, 1 mm-1, 7 μm; Column temperature: 40 °C; Flow rate: 0.5 ml / min; Solvent: A = H2O 95%, ACN 5% (0.5 g / l AcNH4); B = ACN

[0223] [Table 134]

[0224] Method S: System: Waters UPLC-DAD and QDa; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY BEH C18 1.7 μm 2.1 x 50 mm; Column temperature: 40 °C Flow rate: 0.50 ml / min; Solvent: A = H2O 95%, ACN 5% (0.5 g / l AcNH4); B = ACN

[0225] [Table 135]

[0226] Method T: System: Waters UPLC-DAD and ZQ; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: Xbridge C18 100mm*4,6mm 5μm; Column temperature: 30℃; Flow rate: 0.8ml / min; Solvent: A = H2O (0.2% NH4HCO3); B = ACN

[0227] [Table 136]

[0228] Method U: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 + 1.7 μm 2.1 x 50 mm; Column temperature: 60 °C; Flow rate: 1.0 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0229] [Table 137]

[0230] Method V: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6 μm 2.1 x 50 mm; Column temperature: 50 °C; Flow rate: 1 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0231] [Table 138]

[0232] Method W: System: Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CORTECS C18 1.6 μm 2.1 x 50 mm; Column temperature: 50 °C; Flow rate: 1 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0233] [Table 139]

[0234] Method X: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 50 mm; Column temperature: 50 °C; Flow rate: 1.0 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0235] [Table 140]

[0236] Method Y: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: ACQUITY CSH C18 1.7 μm 2.1 x 50 mm; Column temperature: 50 °C; Flow rate: 1.0 ml / min; Solvent: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0237] [Table 141]

[0238] Method Z4: System: Agilent Technologies 1200 Series; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: XBridge C18 3.5 μm 4.6 × 50 mm; Column temperature: 45 °C; Flow rate: 1.8 ml / min. Solvent: A = H2O (10 mM NH4HCO3); B = ACN.

[0239] [Table 142]

[0240] Method Z5: System: Agilent Technologies 1200 Series; ionization: electrospray in positive and / or negative mode (ES+ / -); column: Poroshell 120 EC C18 4 μm 4.6 × 50 mm; column temperature: 45 °C; flow rate: 2.0 ml / min; solvent: A = H2O (0.01% TFA); B = CAN (0.01% TFA).

[0241] [Table 143]

[0242] Method Z6: System: Agilent Technologies 1200 Series; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: Sunfire 3.5 μm 4.6 x 50 mm; Column temperature: 45 °C; Flow rate: 2.0 ml / min; Solvent: A = H2O (0.01% TFA); B = CAN (0.01% TFA).

[0243] [Table 144]

[0244] Synthesis of Examples According to Reaction Scheme 1 Example 8: 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int8.1: [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol [ka] In a microwave vial under Ar, to a solution of 3,6-dichloropyridazine (2.6 mmol, 400 mg) in 2.5 ml of NMP, [(2S)-morpholin-2-yl]methanol; hydrochloride (2.6 mmol, 400 mg) and DIPEA (5.2 mmol, 0.9 ml) were added. The vial was sealed, and the mixture was heated under microwave irradiation at 180 °C for 2.5 h. After the solution was cooled, EtOAc was added, and the solution was washed with water (3 times) and brine. The aqueous layer was extracted twice with Me-THF. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give the title compound as a yellow solid (214 mg, 36% yield). LCMS (Method G): Rt=1.19min;MS m / z[M+H] + 230

[0245] 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 8) To a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.72 mmol, 120 mg) and [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol (0.79 mmol, 183 mg) in 4.5 ml of 1,4-dioxane and 1.2 ml of water in a microwave vial under Ar, sodium carbonate (1.59 mmol, 132 mg) was added. The solution was purged with Ar for 10 minutes, and then Pd(PPh3)4 (0.036 mmol, 42 mg) was added. The vial was sealed, and the mixture was heated at 110 °C under microwave irradiation for 2.5 hours. After concentration under reduced pressure, EtOAc was added, and the resulting mixture was washed with water (three times) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (98 / 1 / 1 to 94 / 2 / 2) to give the title compound as a white solid (92 mg, 40% yield).

[0246] Compounds Examples 9, 65 and 179 were synthesized in the same manner as in Example 8.

[0247] Compounds Examples 14, 15, 16 and 20 were synthesized similarly to Example 8 using pinacolborane instead of boronic acid for the Suzuki coupling.

[0248] Compounds Examples 24 and 30 were synthesized similarly to Example 8, using pinacolborane instead of boronic acid for Suzuki coupling and KCO / DMF instead of DIPEA / NMP at 110 °C for n-arylation.

[0249] Compound Example 79 was synthesized analogously to Suzuki coupling Example 8 and n-arylation Example 85.

[0250] Compound Example 83 was synthesized similarly to Example 8 using BuOH instead of NMP at 130° C. for n-arylation.

[0251] Compounds Examples 84 and 91 were synthesized similarly to Example 8, using DME instead of 1,4-dioxane for Suzuki coupling and BuOH instead of NMP at 130° C. for n-arylation.

[0252] Compound Example 113 was synthesized similarly to Example 8 using DMSO instead of NMP at 150° C. for n-arylation.

[0253] Compound Example 418 was synthesized in a similar manner to Example 8.

[0254] Examples 10 and 11: 2-[6-[(4aR,8aS)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol and 2-[6-[(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int10.7: Benzyl rac-(4aR,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine-6-carboxylate [ka] To a solution of benzyl rac-(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (9.47 mmol, 2.75 g) in 25 mL of THF at 0 °C under N was added a 1.0 M solution of BH3-THF (8.25 mmol, 8.24 mL). The solution was stirred at 60 °C for 8 h. Then, at 0 °C, 4 mL of MeOH was added, and the mixture was stirred at 60 °C for an additional 1 h. 25 mL of 1 M aqueous HCl was added, and the mixture was stirred at 40 °C for an additional 0.5 h. The reaction mixture was concentrated under reduced pressure to give crude benzyl (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (3 g) as a yellow oil. To this oil was added 30 ml of DCM, followed by EtN (2.3 ml), BocO (16 mmol, 3.55 g), and DMAP (133 mg). The resulting solution was stirred at 25 °C for 6 h. The reaction was then poured into 30 ml of water and extracted with DCM (3 times). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using petroleum ether / ethyl acetate (10 / 1 to 1 / 1) to give 4.1 g of 6-benzyl 4-(tert-butyl)(4aR,8aS)-hexahydro-4H-pyrido[4,3-b][1,4]oxazine-4,6(5H)-dicarboxylate as a colorless oil. To 1.25 g of this oil was added 5 ml of 4 M HCl / EtOAc. The solution was stirred at 25 °C for 1 h and then concentrated under reduced pressure to give 800 mg of crude benzyl (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate as a yellow oil, which was used in the next step without further purification.

[0255] Int10.8: Benzyl rac-(4aR,8aS)-4-(6-chloropyridazin-3-yl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carboxylate [ka] To a solution of crude benzyl rac-(4aR,8aS)-2,3,4,4a,5,7,8,8a-octahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (2.06 mmol, 800 mg, salt hydrate) in 5 mL of NMP was added 1.5 mL of DIPEA and 3,6-dichloropyridazine (10 mmol, 2.16 g), and the resulting mixture was stirred at 180 °C for 1 h under microwave irradiation. After cooling the solution, the reaction was quenched with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [water (HCOOH)-ACN]; B%: 42%~72%, 10 min) to give the title compound as a yellow solid (450mg, yield 40%). 1 H NMR(400MHz,CDCl3)δ=7.38(br s,5H),7.14-6.85(m,1H),6.78-6.57(m,1H),5.35-4.93(m,2H),4.26-3.63(m,7H),3.34-2.96(m,3H),2.04-1.79(m,2H).

[0256] Int 10.9: (2-hydroxy-4,6-dimethylphenyl)boronic acid [ka] To a solution of (2-methoxy-4,6-dimethylphenyl)boronic acid (555 μmol, 100 mg) in 2 ml of DCM was added BBr (1.1 mmol, 107 μl) at −78° C., and the mixture was stirred at −78° C. for 1 hour. The reaction was then quenched by adding 10 ml of ice water at 0° C. and extracted with DCM (three times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization from petroleum ether to give the title compound as a yellow solid (40 mg, 40% yield). 1H NMR(400MHz,DMSO-d6)δ=9.12-8.86(m,1H),6.70(s,1H),6.61(s,1H),2.46(s,3H),2.25(s,3H).

[0257] Int10.10: Benzyl rac-(4aR,8aS)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carboxylate [ka] A mixture of benzyl rac-(4aR,8aS)-4-(6-chloropyridazin-3-yl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carboxylate (0.85 mmol, 330 mg), (2-methoxy-4,6-dimethylphenyl)boronic acid (1.70 mmol, 282 mg), Pd(PPh3)4 (98 mg), 2 M aqueous Na2CO3 (1.27 mL), and 1,4-dioxane (4 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 140 °C under microwave irradiation for 2 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using petroleum ether / ethyl acetate (20 / 1 to 5 / 1) to give the title compound as a yellow oil (320 mg, 82% yield). 1 H NMR(400MHz,CDCl3)δ=7.65-7.46(m,1H),7.38(br s,5H),6.86-6.71(m,2H),6.66(s,1H),5.38-4.91(m,2H),4.25-3.89(m,6H),3.79 (dt,J=3.2,11.6Hz,1H),3.48-2.99(m,3H),2.45-2.25(m,6H),2.02-1.85(m,2H).

[0258] Int10.11 or Example 195: 3,5-dimethyl-2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol [ka] To a solution of benzyl rac-(4aS,8aR)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (2.3 mmol, 1.1 g) in 25 mL of EtOH was added ammonium formate (7 mmol, 440 mg) and 10% Pd / C (440 mg), and the resulting mixture was stirred at 80 °C for 1 hour and 30 minutes under microwave irradiation. After cooling to room temperature, the mixture was filtered through a pad of Decalite® and the cake was rinsed with 50 mL of EtOH. The organic layer was concentrated under reduced pressure, and the residue was diluted with 200 mL of dichloromethane, washed twice with 200 mL of saturated aqueous sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH / ACN (100 / 0 / 0 to 80 / 10 / 10) to give the title compound as a white solid (351 mg, 44% yield).

[0259] 2-[6-[(4aR,8aS)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 10) and 2-[6-[(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 11) To a solution of 3,5-dimethyl-2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol (0.53 mmol, 180 mg) in 3 mL of DCM, cyclobutanone (1 mmol, 37 mg), AcOK (1 mmol, 52 mg), and NaBHCN (2.6 mmol, 166 mg) were added, and the mixture was stirred at 25° C. for 8 h. The reaction was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water(HCOOH)-ACN]; B%: 29%-59%, 10 min) and lyophilized. This racemate is then separated by SFC (column: Daicel Chiralpak® AD, internal diameter 250 × 30 mm, particle size 10 μm; mobile phase: eluent B: EtOH (0.1% NH OH), isocratic elution: 40% phase B in supercritical CO ; flow rate: 70 g / min; cycle time: 3.5 ° C; back pressure: 100 bar) to give two enantiomers, the first eluting as a white solid at Rt = 1.99 min (60.48 mg, Example 10, Enantiomer 1), and the second eluting as a white solid at Rt = 2.26 min (64.8 mg, Example 11, Enantiomer 2). (Absolute configuration cannot be assigned.)

[0260] The compounds of Examples 12 and 13 were synthesized similarly to Examples 10 and 11, using pinacolborolane / Na2CO3 instead of boronic acid / NaHCO3 for the Suzuki coupling.

[0261] Example 4: 3,5-Dimethyl-2-[6-[rac-(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol [ka] Int4.10: benzyl rac-(4aS,8aR)-1-(6-chloropyridazin-3-yl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazine-6-carboxylate [ka] To a solution of 3,6-dichloropyridazine (8.2 mmol, 1.2 g) in 4 mL of NMP was added DIPEA (851 μL, 65 mmol) and benzyl rac-(4aS,8aR)-1,2,3,4a,5,7,8,8a-octahydropyrido[3,4-b][1,4]oxazine-6-carboxylate (1.63 mmol, 450 mg), and the mixture was stirred at 180 °C under microwave irradiation for 1 h. After cooling the solution, water was added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [water (HCOOH)-ACN]; B%: 36%~66%, 9 min) to give the title compound as a yellow solid (270mg, yield 42%). 1 H NMR(400MHz,CDCl3)δ=7.41-7.28(m,5H),7.24(d,J=9.6Hz,1H),6.83(d,J=9.6Hz,1H),5.16(br d,J=17.2Hz,2H),4.62-4.20(m,3H),4.16-4.07(m,1H),3.73(dt,J=3.2,12.0Hz,2H),3.65 -3.53(m,1H),3.27(dt,J=3.6,12.2Hz,1H),3.15-2.75(m,2H),2.19-1.97(m,1H),1.63(br s,1H).

[0262] Int4.11: Benzyl rac-(4aS,8aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazine-6-carboxylate [ka] A mixture of benzyl rac-(4aS,8aR)-1-(6-chloropyridazin-3-yl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (103 μmol, 40 mg), (2-hydroxy-4,6-dimethylphenyl)boronic acid (103 μmol, 17 mg), 2M aqueous NaCO (155 μl), and Pd(PPh) (12 mg) in 1.5 mL of 1,4-dioxane was degassed and purged with N (3 times), and the mixture was stirred at 140 °C under microwave irradiation for 2 h. The reaction was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (HCOOH)-ACN]; B%: 29%-59%, 10 min) to give the title compound as a yellow solid (26mg, yield 53%). 1 H NMR(400MHz,CDCl3)δ=7.54(d,J=9.6Hz,1H),7.43-7.30(m,5H),6.98(d,J=9.6Hz,1H),6.77(s,1H),6.66(s,1H),5.26-5.10(m,2H),4.70-4.56(m ,1H),4.21-4.09(m,1H),3.83-3.63(m,3H),3.45-3.28(m,1H),3.16-2.8 2(m,2H),2.39(s,3H),2.31(s,3H),2.24-2.11(m,2H),1.75-1.64(m,2H).

[0263] Int4.12: 3,5-dimethyl-2-[6-[rac-(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol [ka] To a solution of benzyl rac-(4aS,8aR)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (0.055 mmol, 26 mg) in 4 mL of EtOAc under N was added Pd / C (7 mg, 10% purity). The suspension was degassed and purged with H (3 times), and the mixture was stirred under H (15 Psi) at 25 °C for 2 h. The reaction was then filtered, and the filtrate was concentrated under reduced pressure to give 18 mg of the crude title compound as a colorless oil, which was used in the next step without further purification.

[0264] 3,5-Dimethyl-2-[6-[rac-(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol (Example 4) To a solution of 3,5-dimethyl-2-[6-[rac-(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol (0.053 mmol, 18 mg) in 1 mL of DCM was added cyclobutanone (0.058 mmol, 4.35 μL), AcOK (0.058 mmol), and NaBHCN (0.105 mmol, 6.6 mg). The mixture was stirred at room temperature for 4 h. The reaction was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (HCOOH)-ACN]; B%: 1%~30%, 10 min) to give the title compound as a white solid (8 mg, 37% yield).

[0265] Example 6: 2-[6-[(3S)-3-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int6.1: [(3S)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methanol [ka] In a microwave vial, under Ar, [(3S)-morpholin-3-yl]methanol; hydrochloride (5.2 mmol, 800 mg) and DIPEA (10.4 mmol, 1, 83 ml) were added to a solution of 3,6-dichloropyridazine (5.2 mmol, 800 mg) in 3.5 ml of NMP. The vial was sealed, and the mixture was heated under microwave irradiation at 180 °C for 2.5 h. After the solution was cooled, EtOAc was added, and the solution was washed with water (3 times) and brine. The aqueous layer was extracted twice with Me-THF. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give the title compound as an orange oil (460 mg, 38% yield). LCMS (Method G): Rt=1.17min;MS m / z[M+H] + 230

[0266] 2-[6-[(3S)-3-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 6) In a microwave vial under Ar, a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.58 mmol, 97 mg) and [(3S)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methanol (0.96 mmol, 221 mg) in 1,4-dioxane (3.64 ml) was added with a solution of sodium carbonate (1.28 mmol, 106.7 mg) in water (0.91 ml). The solution was purged with Ar for 10 minutes, and then Pd(PPh3)4 (0.029 mmol, 34 mg) was added. The vial was sealed, and the mixture was heated under microwave irradiation at 75 °C for 1 hour and at 110 °C for 2 hours. Then, (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.15 mmol, 25 mg) was added, and the mixture was heated under microwave irradiation at 100 °C for 4 hours. After concentration under reduced pressure, EtOAc was added, and the resulting mixture was washed with water (3 times) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (98 / 1 / 1 to 94 / 3 / 3) to give the title compound as a yellow solid (52 mg, 28% yield). Compound Example 5 was synthesized in the same manner as Example 6.

[0267] Example 62: (4S)-4-Hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one [ka] Int 62.1: (4S)-1-(6-chloropyridazin-3-yl)-4-hydroxy-pyrrolidin-2-one [ka] To a solution of 3,6-dichloropyridazine (2.25 mmol, 335 mg) and (S)-4-hydroxy-2-pyrrolidinone (2.25 mmol, 227 mg) in 5 mL of 1,4-dioxane in a microwave vial under Ar, tripotassium phosphate (4.5 mmol, 955 mg), 1-1'-bis(diphenylphosphino)ferrocene (0.27 mmol, 150 mg), and palladium acetate (0.090 mmol, 20 mg) were added. The vial was sealed, and the mixture was heated at 100 °C under microwave irradiation for 1 h. After cooling to room temperature, the reaction mixture was filtered, the solid portion was washed with EtOAc, and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / EtOAc (100 / 0 to 20 / 80) to give the title compound as a brown solid (74 mg, 15% yield). LCMS (Method M): Rt=0.76min;MS m / z[M+H] + 214

[0268] (4S)-4-Hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one (Example 62) In a microwave vial under Ar, sodium carbonate (0.86 mmol, 91 mg) and 0.5 mL of water were added to a solution of 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (0.34 mmol, 104 mg) and (4S)-1-(6-chloropyridazin-3-yl)-4-hydroxy-pyrrolidin-2-one (0.34 mmol, 74 mg) in 1.8 mL of 1,2-dimethoxyethane. The solution was purged with Ar for 3 minutes, and then Pd(PPh3)4 (0.02 mmol, 20 mg) was added. The vial was sealed, and the mixture was heated at 100 °C under microwave irradiation for 1 hour. The reaction mixture was diluted with EtOAc and water and then filtered. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 94 / 3 / 3) to give the title compound as a white solid (80 mg, 66% yield).

[0269] Compounds Examples 61 and 86 were synthesized in a similar manner to Example 62.

[0270] Example 63: 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol [ka] Int 63.4: [(2S)-4-[6-(4-chloro-2-methoxy-6-methyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methanol [ka] Under Ar, to a solution of 2-(4-chloro-2-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.708 mmol, 200 mg) and [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol (0.708 mmol, 163 mg) in 4 mL of dimethoxyethane and 1 mL of water, 2N aqueous sodium carbonate (1.77 mmol, 0.88 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.035 mmol, 41 mg). The mixture was stirred at 90 °C for 3 h. After cooling to room temperature, DCM was added, and the mixture was washed with water. The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to afford the title compound as a yellow solid (150 mg, 61% yield). LCMS (Method I): Rt=1.31min;MS m / z[M+H] + 350.

[0271] 5-Chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol (Example 63) To a solution of [(2S)-4-[6-(4-chloro-2-methoxy-6-methyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methanol (0.391 mmol, 137 mg) in 20 mL of anhydrous DCM at 0 °C under Ar, a 1 N solution of boron tribromide in DCM (1.18 mmol, 1.18 mL) was slowly added, and the mixture was stirred at 0 °C for 3 h. Then, 3 mL of 4 N aqueous NaOH was added with vigorous stirring. After 5 min, ACN and 4 N aqueous HCl were added, and the mixture was extracted with DCM (twice). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% 95 / 5 EtOAc / MeOH in cyclohexane, and pure fractions were pooled, concentrated under reduced pressure, and then triturated in diethyl ether to give the title compound as a pale yellow solid (55 mg, 42% yield).

[0272] Compound Example 56 was synthesized in a similar manner to Example 63.

[0273] Compounds Examples 44, 45, 48 and 54 were synthesized similarly to Example 63 using OH-phenyl instead of OMe-phenyl and 1,4-dioxane instead of DME for the Suzuki coupling.

[0274] Compounds Examples 70 and 71 were synthesized similarly to Example 63 using OH-phenyl instead of OMe-phenyl, 1,4-dioxane instead of DME for Suzuki coupling, and 1,4-dioxane instead of NMP for n-arylation over 18 hours.

[0275] Example 85: 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]phenol [ka] Int 85.1: [(2S)-4-(6-chloro-5-methyl-pyridazin-3-yl)morpholin-2-yl]methanol [ka] A solution of 3,6-dichloro-4-methyl-pyridazine (24.5 mmol, 4 g), [(2S)-morpholin-2-yl]methanol; hydrochloride (24.5 mmol, 3.77 g) and EtN (54 mmol, 7.52 ml) in 50 ml of n-butanol was stirred at 130 °C for 11 hours. The mixture was cooled, diluted with 100 ml of EtOAc and 50 ml of diethyl ether, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% of a 99 / 1 mixture of EtOAc / MeOH in cyclohexane to give compound Int85.1 (2.75 g, 46% yield) as a white solid. LCMS (Method L): Rt=0.40min;MS m / z[M+H] + 244;

[0276] 5-Chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]phenol (Example 85) To a solution of 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.923 mmol, 235 mg) and [(2S)-4-(6-chloro-5-methyl-pyridazin-3-yl)morpholin-2-yl]methanol (0.615 mmol, 150 mg) in 4 mL of 1,4-dioxane under Ar, 2N aqueous sodium carbonate (1.66 mmol, 0.83 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.03 mmol, 35 mg). The mixture was stirred at 100 °C for 3 h. After cooling, EtOAc and diethyl ether were added, and the resulting mixture was washed successively with saturated aqueous NaHCO and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% MeOH in DCM to give a yellow solid residue, which was purified by preparative HPLC (column: Sunfire prep C18 OBD; 250*50 mm*10 μm; mobile phase: [water (TFA 10 -2 N)-ACN]; B%: 10%-100% in 25 min at 50 ml / min to afford the title compound as a white solid (154 mg, 74% yield).

[0277] Compounds Examples 72 to 78, 80, 81, 90, 93, 96, 97, 102 and 103 were synthesized in the same manner as in Example 85.

[0278] Examples 109, 110 and 112 were synthesized similarly to Example 85, using OH-phenylboronic acid instead of OH-phenylborolane for the Suzuki coupling.

[0279] Compound example 92 was synthesized similarly to example 85, using OH-phenylboronic acid instead of OH-phenylborolane for Suzuki coupling and NMP instead of BuOH for n-arylation.

[0280] Example 68: 2-[6-[(3S)-3-(ethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int68.1: tert-butyl N-[(3S)-1-(6-chloropyridazin-3-yl)-3-piperidyl]carbamate [ka] A solution of 3,6-dichloropyridazine (6.71 mmol, 1 g), tert-butyl N-[(3S)-3-piperidyl]carbamate (7.38 mmol, 1.48 g), and EtN (13.42 mmol, 1.87 ml) in 15 ml of NMP was stirred at 130 °C for 4.5 h. The mixture was cooled, diluted with 50 ml of EtOAc and 50 ml of diethyl ether, and washed with water (3 times). The organic layer was dried over NaSO, 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 a 95 / 5 mixture of EtOAc / MeOH in cyclohexane to give the title compound (1.92 g, 91% yield) as a white solid. LCMS (Method I): Rt=1.67min;MS m / z[M+H] + 313

[0281] Int68.2: tert-butyl N-[(3S)-1-(6-chloropyridazin-3-yl)-3-piperidyl]-N-ethyl-carbamate [ka] To a solution of tert-butyl N-[(3S)-1-(6-chloropyridazin-3-yl)-3-piperidyl]carbamate (1.6 mmol, 500 mg) in 10 ml of anhydrous DMF under Ar at −5° C., NaH (1.92 mmol, 299 mg of 60% purity) was added, and the mixture was stirred for 30 min at 0° C. Iodoethane (1.92 mmol, 153 μl) was then added, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with diethyl ether and washed successively with 2% aqueous citric acid and water (twice). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated in a solution of diethyl ether and pentane (1 / 1) to give the title compound (373 mg, 68% yield) as a white solid. LCMS (Method I): Rt=1.99min;MS m / z[M+H] + 341

[0282] Int68.3: tert-Butyl N-ethyl-N-[(3S)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-3-piperidyl]carbamate [ka] To a solution of tert-butyl N-[(3S)-1-(6-chloropyridazin-3-yl)-3-piperidyl]-N-ethylcarbamate (1.09 mmol, 373 mg) and (2-hydroxy-4,6-dimethylphenyl)boronic acid (1.42 mmol, 236 mg) in 8 mL of 1,4-dioxane and 3 mL of water under Ar, 2N aqueous sodium carbonate (3.28 mmol, 1.64 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.08 mmol, 89 mg). The mixture was stirred at 100°C for 13 hours. After cooling to room temperature, the mixture was diluted with EtOAc and diethyl ether and then washed successively with 2% aqueous citric acid and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to afford the title compound (350 mg, 75% yield) as a white solid. LCMS (Method I): Rt=1.73min;MS m / z[M+H] + 427

[0283] 2-[6-[(3S)-3-(ethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 68) A solution of tert-butyl N-ethyl-N-[(3S)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-3-piperidyl]carbamate (0.82 mmol, 350 mg) in 18 mL of DCM and 2 mL of TFA was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in DCM and washed successively with saturated aqueous NaHCO (twice) and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting solid was dried under high vacuum in the presence of phosphorus pentoxide to give the title compound as a white solid (245 mg, 91% yield).

[0284] Compound Example 69 was synthesized similarly to Example 68, using OH-phenylboronic acid instead of OMe-phenylpinacolborane for the Suzuki coupling, but without the alkylation step.

[0285] Compound 148 was synthesized in a similar manner to Example 68.

[0286] Examples 98 and 99: Two diastereoisomers of 2-[6-[2-[(1S)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int98.1 and Int99.1: Two diastereoisomers of (1S)-1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]ethanol [ka] To a solution of 3,6-dichloropyridazine (0.6 mmol, 90 mg) in 3 ml of NMP in a microwave vial, (1S)-1-morpholin-2-ylethanol hydrochloride (0.6 mmol, 100 mg) and DIPEA (0.8 mmol, 0.14 ml) were added. The vial was sealed, and the mixture was heated at 150° C. under microwave irradiation for 1 hour. After cooling, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EOAct (100 / 0 to 70 / 30) to give the title compound (64 mg, 44%) as a mixture of two diastereoisomers: LCMS (Method S): Rt=0,81min;MS m / z[M+H] + 244,2

[0287] Two diastereoisomers of 2-[6-[2-[(1S)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Examples 98 and 99) [ka] To a mixture of (1S)-1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]ethanol (0.21 mmol, 51 mg) and 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.21 mmol, 52 mg) in 0.8 mL of 1,4-dioxane and 0.2 mL of water in a microwave vial under Ar, KPO (0.63 mol, 135 mg) was added. The solution was purged with Ar for 10 minutes, and then Pd-118 (also known as Pd-118 or PdCl (dtbpf)) (0.02 mmol, 15 mg) was added. The mixture was heated at 120 °C for 18 hours. After cooling, the mixture was filtered through a Celite® pad. Water and EtOAc were added to the filtrate. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative LC (column YMC-Actus Triart Prep C18-S 150*30mm 5μm, flow rate 50ml / min-isocratic mode MeCN / aq.NH4HCO3 0.2% pH=7.9 28 / 72) to obtain two diastereoisomers, the first eluted Example 99 (diastereoisomer 1, 12mg, 17%) and the second eluted Example 98 (diastereoisomer 2, 10mg, 15%) separately.

[0288] Examples 108 and 180 Two diastereoisomers of 2-[6-[2-[(1R)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int108. ​​Two diastereoisomers of 1(1R)-1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]ethanol [ka] To a solution of 3,6-dichloropyridazine (0.6 mmol, 90 mg) in 3 ml of NMP in a microwave vial, (1R)-1-morpholin-2-ylethanol hydrochloride (0.6 mmol, 100 mg) and DIPEA (0.8 mmol, 0.14 ml) were added. The vial was sealed and the mixture was heated at 150° C. under microwave irradiation for 1 hour. After cooling, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 70 / 30) to give two diastereoisomers: Diastereoisomer 1: (16 mg, 11% yield). 1H NMR(500MHz,CDCl3)δ(ppm)7.23(d,J=9.5Hz,1H),6.92(d,J=9.5Hz,1H),4.20- 4.13(m,1H),4.12-4.09(m,1H),4.08-4.04(m,1H),3.93(dt,J=11.2,5.6Hz,1H) ,3.73(td,J=11.6,2.8Hz,1H),3.46(ddd,J=10.5,4.8,2.8Hz,1H),3.17-3.07( m,1H),3.01(dd,J=12.9,10.5Hz,1H),2.18-2.06(m,1H),1.27(d,J=6.5Hz,3H). Diastereoisomer 2: (24 mg, 17% yield). 1H NMR(500MHz,CDCl3)δ(ppm)7.24(d,J=9.5Hz,1H),6.90(d,J=9.5Hz,1H),4.18(d t,J=13.0,2.0Hz,1H),4.16-4.08(m,1H),4.03-3.96(m,1H),3.82-3.75(m,1H), 3.75-3.69(m,1H),3.38(ddd,J=10.7,6.3,2.8Hz,1H),3.10(td,J=12.3,3.6Hz, 1H),2.87(dd,J=12.8,10.8Hz,1H),2.47(d,J=3.8Hz,1H),1.26(d,J=6.5Hz,3H).

[0289] Two diastereoisomers of 2-[6-[2-[(1R)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Examples 108 and 180) Diastereoisomer 1 (Example 108) To a solution of (1R)-1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]ethanol (diastereoisomer 2, previous Example 108.1, 0.1 mmol, 24 mg) and 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.11 mmol, 27 mg) in 0.8 mL of 1,4-dioxane and 0.2 mL of water in a microwave vial under Ar, KPO (0.3 mol, 63 mg) was added. The solution was purged with Ar for 10 minutes, and then Pd-118 (0.01 mmol, 7 mg) was added. The mixture was heated at 120 °C for 18 hours. After cooling, the mixture was filtered through a Celite pad. Water and EtOAc were added to the filtrate. The organic layer was separated, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative LC (column YMC-Actus Triart Prep C18-S 150*30mm 5μm, flow rate 50ml / min, gradient MeCN / aq.NH4HCO3 0.2% pH=7.9 20 / 80 to 55 / 45 15CV gradient) to give the title compound as a white solid (6mg, 18% yield) after lyophilization.

[0290] Diastereoisomer 2 (Example 180) To a solution of (1R)-1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]ethanol (diastereoisomer 1, previous Example 108.1, 0.115 mmol, 24 mg) and 2-hydroxy-4,6-dimethyl-phenyl)boronic acid (0.172 mmol, 29 mg) in 1 mL of 1,4-dioxane and 0.25 mL of water in a microwave vial under Ar was added K2CO3 (0.23 mol, 46 mg). The solution was purged with Ar for 10 minutes, and then XPhos (0.00575 mmol, 2.74 mg) and Xphos Pd G2 (0.00575 mmol, 4.52 mg) were added. The mixture was again purged with N2 and heated at 120 °C for 18 hours. After cooling, the mixture was filtered through a Celite® pad and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH (100 / 0 to 97 / 3) to give the title compound (7.3 mg, 19%) after lyophilization.

[0291] Example 82: 2-[6-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int 82. 13-Chloro-6-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazine [ka] To a solution of 3,6-dichloropyridazine (2.68 mmol, 400 mg) in 10 mL of NMP in a microwave vial, DIPEA (2.68 mmol, 0.47 mL) and (3S)-3-(methoxymethyl)pyrrolidine (2.60 mol, 300 mg) were added. The vial was sealed, and the mixture was heated under microwave irradiation at 150° C. for 1 hour and 30 minutes. After cooling, the solution was concentrated under reduced pressure.

[0292] The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 30 / 70) to give the title compound as a white solid (450 mg, 75% yield). 1H NMR(400MHz,DMSO-d6)δ(ppm)7.46(d,J=9.5Hz,1H),6.98(d,J=9.5Hz,1H),3.59-3.49(m,2H),3.46-3.35(m,2H) ),3.27(s,3H),3.22-3.13(m,1H),2.59-2.54(m,1H),2.12-2.00(m,1H),1.95-1.85(m,1H),1.81-1.67(m,1H).

[0293] 2-[6-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 82) In a microwave vial under Ar, a solution of 3-chloro-6-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazine (0.44 mmol, 100 mg) in 1 mL of 1,4-dioxane and 0.25 mL of water was added. KPO (1.32 mmol, 280 mg) and 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.44 mmol, 110 mg) were added. The solution was purged with Ar for 10 minutes, and then Pd-118 (0.048 mmol, 31 mg) was added. The mixture was heated at 120 °C for 18 hours. After cooling, the mixture was filtered through a Celite® pad. Water and EtOAc were added to the filtrate. The organic layer was separated, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 70 / 30). The compound-containing fractions were combined, evaporated in vacuo, taken up in MeCN (1 ml), expanded with water (3 ml), and then lyophilized for 18 hours to give the title compound as a white powder (20 mg, 15%).

[0294] Compound Example 111 was synthesized in a similar manner to Example 82.

[0295] Compound Example 88 was synthesized similarly to Example 82 using BuOH instead of NMP at 120° C. for n-arylation.

[0296] Example 31: 2-[6-[(3R)-3-amino-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; formic acid [ka] Int 31.1 tert-Butyl N-[(3R)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-3-piperidyl]carbamate [ka] To a solution of (R)-3-BOC-aminopiperidine (2.2 mmol, 218 mg) and EtN (5.03 mmol, 0.7 mL) in 10 mL of ethanol, 3,6-dichloropyridazine (2.01 mmol, 300 mg) was added, and the mixture was heated to reflux for 16 h. After cooling to room temperature, 10 mL of 1,4-dioxane, 2 mL of water, cesium carbonate (3.0206 mmol, 985 mg), and (2-methoxy-4,6-dimethylphenyl)boronic acid (2.21 mmol, 400 mg) were added. The solution was purged with Ar for 10 min, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.2 mmol, 150 mg) was added, and the mixture was heated to 120 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. EtOAc was added and the resulting mixture was washed with water and brine, the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure.

[0297] The residue was purified by flash chromatography on silica gel using cyclohexane / EtOAc (100 / 0 to 0 / 100) to give the title compound as a white foam (218 mg, 26% yield). LCMS (Method I): Rt=1,54min;MS m / z[M+H] + 413

[0298] 2-[6-[(3R)-3-amino-1-piperidyl]pyridazin-3-yl]-3,5-dimethylphenol; Formic acid (Example 31) At 0°C, a 1N solution of boron tribromide in DCM (1.1 mmol, 1.1 ml) was slowly added to a solution of tert-butyl N-[(3R)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-3-piperidyl]carbamate (0.51 mmol, 210 mg) in 20 ml of DCM, and the mixture was stirred at room temperature for 3 hours. Then, MeOH was slowly added, and the solution was stirred for 20 minutes. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Sunfire prep C18 OBD; 100*30 mm*10 μm; mobile phase: [water (TFA 10 -2 N)-ACN]; B%: 10%-80% in 18 min at 50 ml / min (two purifications) to give the title compound as a pale yellow solid (12 mg, 7% yield).

[0299] Compound Example 7 was synthesized in a similar manner to Example 31.

[0300] Example 105: N-[[(2S)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide [ka] Int105.1: tert-butyl N-[[(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methyl]carbamate [ka] To a solution of 3,6-dichloropyridazine (1.76 mmol, 276 mg) in 5 mL of 1-butanol in a microwave vial, (R)-tert-butyl(morpholin-2-ylmethyl)carbamate (1.76 mmol, 400 mg) and EtN (3.9 mmol, 0.55 mL) were added. The vial was sealed, and the mixture was heated at 180 °C under microwave irradiation for 3 h. After cooling, it was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water (3 times) and brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give the title compound as a pale yellow solid (268 mg, 46% yield). LCMS (Method G): Rt=1,75min;MS m / z[M+H] + 329

[0301] Int105.2: [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanamine; hydrochloride [ka] To a solution of tert-butyl N-[[(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methyl]carbamate (0.39 mmol, 130 mg) in 3 mL of dichloromethane was added 1 mL of a 4 M solution of hydrochloric acid in 1,4-dioxane. The solution was stirred at room temperature for 3 hours and 30 minutes. The mixture was concentrated under reduced pressure, then 1 mL of MeOH was added, and the solution was concentrated under reduced pressure (three times) to give the title compound as an oil (145 mg), which was used in the next step without further purification. LCMS (Method G): Rt=0,21min;MS m / z[M+H] + 229

[0302] Int105.3: N-[[(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methyl]acetamide [ka] To a solution of [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanamine hydrochloride (0.39 mmol, 104 mg) in 2 mL of DCM was added EtN (1.0 mmol, 0.14 mL) and acetic anhydride (0.60 mmol, 0.06 mL). The mixture was stirred at room temperature for 2 hours and 30 minutes. Dichloromethane was then added, and the mixture was washed with saturated aqueous NaHCO (3 times). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound as a solid (89 mg, 83% yield). LCMS (Method L): Rt=1.36min;MS m / z[M+H]+271

[0303] N-[[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide (Example 105) In a microwave vial under Ar, a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.43 mmol, 72 mg) and N-[[(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methyl]acetamide (0.34 mmol, 90 mg) in 2 mL of 1,4-dioxane was added to a solution of sodium carbonate (1 mmol, 85 mg) in 0.5 mL of water. The mixture was purged with Ar for 10 minutes, and then Pd(PPh3)4 (0.017 mmol, 20 mg) was added. The vial was sealed, and the mixture was heated at 110 °C under microwave irradiation for 1 hour. After the solution cooled, the reaction mixture was filtered through a pad of Decalite® and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure, EtOAc was added, and the resulting mixture was washed with water (three times) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give the title compound as a white solid (47 mg, 39% yield).

[0304] Compounds Examples 106, 211, 212, 216, 267, 275, 276, 279, 280 and 285 were synthesized in a similar manner to Example 105.

[0305] Example 67: (3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidin-3-ol [ka] Int 67.1: (3S)-1-(6-chloropyridazin-3-yl)piperidin-3-ol [ka] 3,6-Dichloropyridazine (4.7 mmol, 700 mg), solution of (3S)-piperidin-3-ol; hydrochloride A mixture of Et3N (5.17 mmol, 711 mg) and Et3N (9.4 mmol, 1.31 ml) in 11 ml of NMP was stirred at 130 °C for 5 h. The mixture was cooled, diluted with EtOAc, and washed with water. The aqueous layer was extracted with EtOAc (4 times), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using cyclohexane / EtOAc (10 / 0 to 0 / 10) to give the title compound as a yellow oil (500 mg, 50% yield). LCMS (Method I): Rt=0.96min;MS m / z[M+H] + 214

[0306] Int67.2: (3S)-1-[6-(2-methoxy-4,6-dimethylphenyl)pyridazin-3-yl]piperidin-3-ol [ka] To a solution of (2-methoxy-4,6-dimethylphenyl)boronic acid (2.47 mmol, 445 mg) and (3S)-1-(6-chloropyridazin-3-yl)piperidin-3-ol (2.25 mmol, 480 mg) in 8 mL of 1,4-dioxane and 2 mL of water under Ar, cesium carbonate (4.5 mmol, 1.46 g) was added, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 mmol, 164 mg). The mixture was stirred at 100°C for 2.5 hours, and then an additional 85 mg (0.47 mmol) of (2-methoxy-4,6-dimethylphenyl)boronic acid and 150 mg (0.46 mmol) of cesium carbonate were added, and the mixture was stirred at 100°C for an additional 3 hours. The mixture was cooled, diluted with EtOAc, and washed with 5% aqueous citric acid. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated in diethyl ether and filtered off to give the title compound as a yellow solid (335 mg, 48% yield). LCMS (Method I): Rt=1.13min;MS m / z[M+H] + 314;

[0307] (3S)-1-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]piperidin-3-ol (Example 67) A solution of (3S)-1-[6-(2-methoxy-4,6-dimethylphenyl)pyridazin-3-yl]piperidin-3-ol (1.07 mmol, 335 mg) in 15 ml of DCM was cooled to 0° C. under Ar. A 1N solution of boron tribromide in DCM (2.14 mmol, 2.14 ml) was slowly added. The mixture was stirred at room temperature for 1 hour and then quenched by slowly adding 3 ml of MeOH. The resulting solution was stirred for 20 minutes and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH (100 / 0 to 95 / 5) eluting with a gradient of 0 to 5% MeOH in DCM to give the title compound as a white solid (192 mg, 60% yield).

[0308] Example 121: 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethoxy)phenol [ka] 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethoxy)phenol (Example 121) In a microwave vial under Ar, to a mixture of [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol (Int8.1) (0.287 mmol, 91.4 mg) in 1 mL of 1,4-dioxane was added 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethoxy)phenol (0.287 mmol, 66.0 mg) and KPO (0.862 mmol, 183 mg) in 0.25 mL of water. The mixture was purged with N. Then, Pd 118 (0.0316 mmol, 20.6 mg) was added and purged again with N2. The mixture was heated at 120 °C for 24 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and evaporated to give a residue that was purified by flash chromatography on silica gel using DCM / MeOH (100 / 0 to 90 / 10). Fractions containing the compound were combined and evaporated under reduced pressure to give a colorless oil (25 mg). This oil was purified by preparative HPLC (YMC-Actus Triart Prep C18-S 150*30 mm 5 μm, mobile phase: MeCN / aqueous NH4HCO3 0.2% pH=7.9; gradient from 25 / 75 to 65 / 35) to give a white solid (11 mg), which was taken up with MeCN (1 mL), diluted with water (3 mL), and then lyophilized to give the title compound as a white solid (10 mg, 9% yield).

[0309] Example 125: 2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol [ka] Int125.1: tert-Butyl (4aR,7aR)-6-(6-chloropyridazin-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate [ka] In a microwave vial, tert-butyl (4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate (1.01 mmol, 0.230 g), 3,6-dichloropyridazine (1.01 mmol, 0.150 g), and DIPEA (1.01 mmol, 0.175 ml) in 5 ml of butan-1-ol were heated at 120 °C for 2 h using a single-mode microwave (Biotage Initiator EXP 60) with a power ranging from 0 to 400 W. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel using Hept / AcOEt 100 / 0-30 / 70 to give the title compound as a white solid (224 mg, 65% yield). LCMS (Method R): Rt=1.29min;MS m / z[M+H] + =341.4

[0310] Int125.2: tert-Butyl (4aR,7aR)-6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate [ka] A mixture of tert-butyl (4aR,7aR)-6-(6-chloropyridazin-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate (0.000205 mol, 0.0700 g), KCO (0.000411 mol, 0.0568 g), (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.000308 mol, 0.0511 g) in 1 mL of water and 4 mL of 1,4-dioxane was degassed under a stream of N in a microwave vial under Ar. XPhos Pd G (1.03 e-5 mol, 0.00808 g) and XPhos (1.03 e-5 mol, 0.00490 g) were added, and the mixture was heated at 100 °C for 18 h. After cooling at room temperature, the reaction mixture was filtered through a Celite® pad and water was added. The organic layer was extracted with AcOEt, separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound as a yellow oil (65 mg, 72% yield). LCMS (Method S) Rt=1.34min;MS m / z[M+H] + =427.4

[0311] 2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol (Example 125) To a mixture of tert-butyl (4aR,7aR)-6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate (0.000152 mol, 0.0650 g) in 3 mL of dichloromethane was added TFA (0.00152 mol, 0.174 g). The mixture was then stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water and basified with 10% aqueous K2CO3, then extracted with DCM, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound as a white solid (20 mg, 40% yield).

[0312] Example 126: 1-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one [ka] Int126.1: 1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]cyclopropanol [ka] In a microwave vial, 1-morpholin-2-ylcyclopropanol hydrochloride (1.39 mmol, 250 mg), DIPEA (3.15 mmol, 0.539 mL), and 3,6-dichloropyridazine (1.57 mmol, 234 mg) were dissolved in 3.5 mL of NMP. The mixture was then heated at 150 °C for 2 h using a single-mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel using Hept / AcOEt 100 / 0 to 50 / 50, then 30 / 70, to give the title compound as a pale yellow solid (231 mg, 65% yield). LCMS (Method R): Rt=0.97;MS m / z[M+H]+=256.2;

[0313] 1-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one (Example 126) In a microwave vial under Ar, to a mixture of 1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]cyclopropanol (0.903 mmol, 231 mg) in 8 ml of 1,4-dioxane was added 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.903 mmol, 224 mg) and KPO (2.71 mmol, 575 mg) in 2 ml of water. The mixture was purged with N. Then, Pd 118 (0.0994 mmol, 64.8 mg) was added and purged with N2 again. The mixture was then heated at 120 °C for 24 hours. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 90 / 10 to give a colorless oil (57.6 mg). This oil was purified by preparative HPLC (YMC-Actus Triart Prep C18-S 150*30 mm 5 μm, mobile phase: MeCN / aqueous NH4HCO3 0.2% pH=7.9; gradient from 25 / 75 to 65 / 35) to give a white solid (47 mg), which was triturated in DIPE. The precipitate was filtered and dried under reduced pressure to give the title compound as a white solid (20 mg).

[0314] Examples 156 and 157: 1-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one and 1-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one [ka] The filtrate and the excess product of 1-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one (Example 126) were subjected to preparative chiral SFC (column: LuxCell-4 20x250 mm, mobile phase: CO2 / (MeOH+0.3% iPrNH2) 65 / 35). The compound-containing fractions were combined and evaporated in vacuo to give 20 mg of the first fraction and 19 mg of the second fraction. Both fractions were lyophilized to give 17 mg of the first enantiomer Example 156 and 16 mg of the second enantiomer Example 157, respectively (absolute configurations cannot be assigned).

[0315] Example 141: 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,6-dimethylphenol [ka] A vial was charged with [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol (0.327 mmol, 75.0 mg), potassium carbonate (0.653 mmol, 90.3 mg), XPhos Pd G2 (0.0163 mmol, 12.8 mg), and XPhos (0.0163 mmol, 7.78 mg) and then purged with nitrogen. A solution of the compound 3,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.490 mmol, 122 mg) in 2 mL of dioxane and 0.4 mL of water was added. The resulting mixture was then stirred at 100 °C for 18 h. 0.05 M aqueous HCl was added to the mixture, and the product was extracted with DCM (5 times). The aqueous layer was then neutralized to pH=7 with 1% sodium bicarbonate solution and washed with DCM (5 times). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using Hept / AcOEt 100 / 0 to 0 / 100, then 30 / 70 to give the title compound as a white solid (51 mg, 50% yield).

[0316] Compounds Examples 152, 153 and 191 were synthesized in a similar manner to Example 141.

[0317] Examples 142 and 143: 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide and 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide [ka] Int142.1: Methyl 2-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]acetate [ka] A mixture of 3,6-dichloropyridazine (0.00767 mol, 1.14 g), methyl 2-morpholin-2-ylacetate hydrochloride (0.00767 mol, 1.50 g), and DIPEA (0.0115 mol, 1.49 g) in 10 ml of butan-1-ol in a microwave vial was heated at 120° C. for 2 h using a single-mode microwave (Biotage Initiator EXP 60) with a power ranging from 0 to 400 W. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using Hept / AcOEt 100 / 0-30 / 70 to give the title compound as a yellow oil (1, 25 g, 60% yield). LCMS (Method R): Rt=1,08;MS m / z[M+H]+=272.2

[0318] Int142.2: Methyl 2-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetate [ka] In a microwave vial under Ar, methyl 2-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]acetate (2.18 mmol, 592 mg), (2-hydroxy-4,6-dimethylphenyl)boronic acid (3.27 mmol, 542 mg), XPhos (0.109 mmol, 52.0 mg), and K2CO3 (4.36 mmol, 604 mg) were added to 8 mL of 1,4-dioxane and 2 mL of water. The mixture was purged with N2, and then XPhosPdG2 (0.109 mmol, 85.9 mg) was added, and the mixture was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 05 to give the title compound as a yellow oil (697 mg, 90% yield). LCMS (Method R): Rt=1.24min;MS m / z[M+H]+=358.3

[0319] Int142.3: 2-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetic acid [ka] To a solution of methyl 2-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetate (1.95 mmol, 696 mg) in 7 mL of tetrahydrofuran and 2.3 mL of water was added LiOH monohydrate (5.84 mmol, 245 mg). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was dissolved in water, and then HCl (3 M) was added. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as an orange solid (751 mg). The product was used crude in the next step. 1H NMR(400MHz,DMSO-d6)δ(ppm)12.39(s,1H),10.10(s,1H),7.94(s,2H),6.72(s,1H), 6.66(s,1H),4.35(d,J=13.0Hz,1H),4.17(d,J=13.1Hz,1H),4.08-3.95(m,1H),3.91( dt,J=7.1,3.5Hz,1H),3.70-3.59(m,1H),3.17(t,J=12.3Hz,1H),3.00-2.89(m,1H), 2.58(dd,J=15.8,4.8Hz,1H),2.45(dd,J=15.8,7.9Hz,1H),2.26(s,3H),2.10(s,3H). LCMS (Method R): Rt=0.92min; purity 94%, MS m / z(M+H) + =344.3

[0320] 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide and 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide (Example 142 and Example 143). To a solution of 2-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetic acid (0.582 mmol, 200 mg) in 2.5 mL of N,N-dimethylformamide was added methylamine (2 M) in THF (0.641 mmol, 0.320 mL), HATU (0.641 mmol, 244 mg), and DIPEA (0.874 mmol, 0.150 mL). The reaction mixture was stirred at room temperature for 18 hours. Methylamine (2 M) in THF (0.641 mmol, 0.320 mL) was added to the mixture and stirred for an additional 5 hours. Methylamine (2 M) in THF (0.641 mmol, 0.320 mL) was added to the mixture and stirred for an additional 3 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 05 to give 32 mg of a colorless oil. This oil was purified by preparative chiral SFC (stationary phase: Chiralpak® AD-3 4.6 × 100 mm, mobile phase: CO2 / (iPrOH + 0.3% iPrNH2) 55 / 45). The compound-containing fractions were combined and evaporated in vacuo to give 10 mg of the first fraction and 8 mg of the second fraction. Both fractions were lyophilized to give 8.5 mg of the first enantiomer Example 142 and 7.5 mg of the second enantiomer Example 143, respectively (absolute configuration not assignable). Example 142 (Enantiomer 1) LCMS (Method E) Rt = 2,25 min; MS m / z [M+H] + = 357.4; ee (by analytical SFC) = 100% Example 143 (Enantiomer 2) LCMS (Method E): Rt = 2,25 min; MS m / z [M+H] + = 357.4; ee (by analytical SFC) = 100%

[0321] Examples 146 and 147: 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetamide and 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetamide To a solution of 2-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetic acid (Int142.3) (0.582 mmol, 200 mg) in 2 mL of N,N-dimethylformamide was added HATU (1.16 mmol, 443 mg), TEA (2.33 mmol, 0.325 mL), and HMDS (1.46 mmol, 0.304 mL). The reaction mixture was stirred at room temperature for 18 h, then quenched with 10% NH4Cl and stirred at room temperature for 15 min. The organic layer was extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 05 to give 136 mg of a yellowish solid. This solid was purified by preparative chiral SFC (stationary phase: Chiralpak® AS-3 4.6 × 100 mm, mobile phase: CO / (MeOH + 0.3% iPrNH) 75 / 25). The compound-containing fractions were combined and evaporated in vacuo to give 48 mg of the first enantiomer Example 146 and 45 mg of the second enantiomer Example 147 (absolute configuration not assignable). Example 146 (Enantiomer 1): LCMS (Method E): Rt = 2,32 min; MS m / z [M+H] + = 343.2; ee (by analytical SFC) = 99.2% Example 147 (Enantiomer 2) LCMS (Method E) Rt = 2,32 min; MS m / z [M+H] + = 343.2; ee (by analytical SFC) = 98.8%

[0322] Examples 150 and 151: 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N,N-dimethylacetamide and 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N,N-dimethylacetamide [ka] To a solution of 2-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetic acid (Int142.3) (0.495 mmol, 170 mg) in 2 mL of N,N-dimethylformamide was added dimethylamine (2 M) in THF (0.545 mmol, 0.272 mL), HATU (0.545 mmol, 207 mg), and DIPEA (0.743 mmol, 0.127 mL). The reaction mixture was stirred at room temperature for 18 h, then quenched with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 05 to give 62 mg of a colorless oil. This oil was purified by preparative chiral SFC (stationary phase: Chiralpak® AD-3 4.6 × 100 mm, mobile phase: CO / (iPrOH + 0.3% iPrNH) 55 / 45). The compound-containing fractions were combined and evaporated in vacuo to give, after lyophilization, 30 mg of the first enantiomer Example 150 and 27 mg of the second enantiomer Example 151 (absolute configuration not assignable). Example 150 (Enantiomer 1) LCMS (Method E): Rt = 2.59 min; MS m / z [M+H] + = 371.3; ee (by analytical SFC) = 100% Example 151 (Enantiomer 2) LCMS (Method E): Rt = 2.59 min; MS m / z [M+H] + = 371.3; ee (by analytical SFC) = 100%

[0323] Example 165: 2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol [ka] Int165.1: Methyl (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylate [ka] A mixture of methyl (2S)-morpholine-2-carboxylate hydrochloride (5.51 mmol, 1.00 g), DIPEA (8.26 mmol, 1.44 ml), and 3,6-dichloropyridazine (5.51 mmol, 0.820 g) in 12 ml of NMP in a microwave vial was heated at 150 °C for 1 h using a single-mode microwave (Biotage Initiator EXP 60) with a power ranging from 0 to 400 W. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative LC (cartridge YMC-DispoPackATODS_25 μm_300 g, flow rate 65 ml / min, eluent MeCN / water, NH4HCO3 0.2% pH = 7.9, gradient 10 / 90 to 30 / 70). The fractions containing the compound were concentrated under reduced pressure to give the title compound as a yellow oil (455 mg, 33% yield). LCMS (Method T): Rt=4.16min;MS m / z[M+H]+=257.8

[0324] Int165.2: [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]-dideuterio-methanol [ka] To a stirred solution of methyl (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylate (0.776 mmol, 200 mg) in 7 mL of MeOD at 0°C under Ar, NaBD4 (1.55 mmol, 65.0 mg) was added. The reaction mixture was stirred at room temperature for 8 h. After cooling at 0°C, NaBD4 (1.55 mmol, 65.0 mg) was added. H2O was then added slowly, and the solution was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 05 to give the title compound (110 mg, 62% yield) as a colorless oil. LCMS (Method R): Rt=0.88min;MS m / z[M+H]+=232.2;

[0325] 2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol (Example 165) To a solution of ([(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]-dideuterio-methanol (0.129 mmol, 30.0 mg) in 1.6 ml of 1,4-dioxane and 0.4 ml of water in a microwave vial under Ar, K2CO3 (0.259 mol, 35.8 mg) and (2-hydroxy-4,6-dimethylphenyl)boronic acid (1.94 mmol, 32.2 mg) were added. The reaction mixture was degassed with a stream of N2, and then XPhos (0.00647 mmol, 3.09 mg) and XPhos Pd G2 (0.00647 mol, 5.09 mg) was added, and the mixture was heated at 90° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and then purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 90 / 10. The resulting residue was lyophilized to give the title compound as a white solid (13.5 mg, 32% yield).

[0326] Compounds Examples 169 and 192 were synthesized in a similar manner to Example 165.

[0327] Example 168: 2-[6-[(4aR,7aR)-4-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol [ka] To a stirred solution of 2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol (Example 125) (0.0551 mmol, 18.0 mg) in 2 mL of ethanol in a sealed tube, acetaldehyde (0.08.27 mmol, 5.89 μl), acetic acid (0.0551 mmol, 4.03 μl), and NaBHCN (0.110 mmol, 6.93 mg) were added at room temperature. The reaction mixture was stirred at 90° C. for 15 minutes. After cooling to 0° C., ice-cold water and saturated aqueous NaHCO were slowly added. The mixture was extracted with AcOEt. The organic layer was washed with water and then brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound as a white solid (11.9 mg, 47% yield) after lyophilization.

[0328] Compound Example 185 was synthesized in a similar manner to Example 168.

[0329] Example 181: (2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholine-2-carboxamide [ka] Int181.1: (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylic acid To a mixture of 3,6-dichloropyridazine (5.51 mmol, 820 mg) in 12 ml of NMP in a microwave vial, methyl (2S)-morpholine-2-carboxylate hydrochloride (5.51 mmol, 1.00 g) and DIPEA (1.44 ml, 8.26 mmol) were added. The resulting mixture was heated at 150 °C for 1 h using a single-mode microwave (Biotage Initiator EXP 60) with a power ranging from 0 to 400 W. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative LC (YMC-DispoPackATODS 25 μm 300 g cartridge, flow rate 65 ml / min, gradient MeCN / aq. NH₄HCO₃ 0.2% pH = 7.9, gradient from 10 / 90 to 30 / 70) to give the title compound (486 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.55-7.51 (m, 1H), 7.37 (d, J = 9.7 Hz, 1H), 4.15-4.06 (m, 1H), 3.97 (dt, J = 11.4, 3.6 Hz, 1H), 3.92-3.86 (m, 1H), 3.85-3.79 (m, 1H), 3.61-3.50 (m, 1H), 3.25-3.14 (m, 2H). (COOH not visible.) LCMS (Method T) Rt=1,71min;MS m / z[M+H]+=244.1;

[0330] Int181.2: (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxamide [ka] To a stirred solution of (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylic acid (Int181.1) (0.821 mmol, 200 mg) in 3 mL of DMF was added HATU (1.23 mmol, 468 mg), TEA (2.46 mmol, 0.343 mL), and HMDS (1.54 mmol, 0.321 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed three times with aqueous KCO (10%), then dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to afford the title compound as a white solid (65 mg, 43% yield). LCMS (Method T): Rt=2.73min;MS m / z[M+H]+=242.8;

[0331] (2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholine-2-carboxamide (Example 181) In a microwave vial under Ar, a mixture of (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxamide (0.251 mmol, 61.0 mg), (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.377 mol, 62.6 mg), KCO (0.503 mmol, 69.5 mg) in 1.6 mL of 1,4-dioxane and 0.4 mL of water was degassed under N. XPhos (0.0126 mmol, 6.0 mg) and XPhos Pd G (0.0126 mmol, 9.9 mg) were added, and the mixture was heated at 90 °C for 3 h. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound as a white solid (48 mg, 58% yield).

[0332] Compound Example 183 was synthesized in a similar manner to Example 181.

[0333] Example 166: (2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N-methylmorpholine-2-carboxamide [ka] Int166.1: (2S)-4-(6-chloropyridazin-3-yl)-N-methyl-morpholine-2-carboxamide [ka] To a stirred solution of (2S)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylic acid (Int181.1) (0.821 mmol, 200 mg) in 5 mL of DMF in a sealed tube, DIPEA (1.23 mmol, 0.214 mL), HATU (0.985 mmol, 375 mg), and methylanamine hydrochloride (1.64 mmol, 111 mg) were added. The reaction mixture was stirred at room temperature for 18 hours. DIPEA (0.821 mmol, 0.143 mL) and methanamine hydrochloride (0.821 mmol, 55.4 mg) were added, and the mixture was stirred at room temperature for an additional 18 hours. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed three times with aqueous KCO solution (10%), then dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 97 / 3 to give the title compound as a white solid (55 mg, 26% yield). LCMS (Method T): Rt=3.15min;MS m / z[M+H]+=256.9

[0334] (2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N-methylmorpholine-2-carboxamide (Example 166) A mixture of (2S)-4-(6-chloropyridazin-3-yl)-N-methyl-morpholine-2-carboxamide (0.156 mmol, 40.0 mg), KCO (0.296 mmol, 40.9 mg), and (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.000222 mol, 36.9 mg) in 0.8 mL of 1,4-dioxane and 0.2 mL of water was degassed under Ar in a microwave vial. XPhos (0.00740 mmol, 0.929 mg) and XPhos Pd G (0.00740 mmol, 1.53 mg) were added, and the mixture was heated at 90 °C for 18 h. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 97 / 3 to give the title compound as a white solid (15 mg, 21% yield) after lyophilization.

[0335] Compound Example 182 was synthesized in a similar manner to Example 166.

[0336] Example 184: (2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N,N-dimethylmorpholine-2-carboxamide [ka] Int184.1: (2R)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylic acid [ka] In a microwave vial, 3,6-dichloropyridazine (5.51 mmol, 820 mg) and methyl (2R)-morpholine-2-carboxylate hydrochloride (5.51 mmol, 1.00 g) were dissolved in 10 ml of 1-methylpyrrolidin-2-one, and DIPEA (11.0 mmol, 1.42 g) was added. The mixture was heated at 150° C. for 1 hour and 30 minutes using a single-mode microwave (Biotage Initiator EXP 60) at a power ranging from 0 to 400 W. After cooling to room temperature, the mixture was concentrated under reduced pressure.

[0337] The residue was purified by reversed-phase preparative LC (spherical C18 25 μm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient 0.2% in water. NH4 + HCO3 − / MeCN 90:10 to 70:30). Fractions containing the compound were combined and concentrated under reduced pressure. A second purification by reversed-phase preparative LC (spherical C18 25 μm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient 0.2% in water. NH4 + HCO3 − / MeCN 95:5) gave the title compound as a white solid (361 mg, 27% yield). LCMS (Method Q) Rt=1,71min;MS m / z[M+H]+=244.1;

[0338] Int184.2: (2R)-4-(6-chloropyridazin-3-yl)-N,N-dimethyl-morpholine-2-carboxamide [ka] (2R)-4-(6-chloropyridazin-3-yl)morpholine-2-carboxylic acid (0.616 mmol, 150 mg) was dissolved in 2 mL of N,N-dimethylformamide. DIPEA (0.923 mmol, 158 μL) and HATU (0.739 mmol, 281 mg) were added, and the mixture was stirred for 10 minutes. N-Dimethylamine 2M in THF (1.23 mmol, 616 μL) was added, and the mixture was stirred at room temperature for 36 hours. The mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure.

[0339] The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 90 / 10 to give a white solid. After concentration, the residue was dissolved in water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white solid (25 mg, 15%). LCMS (Method T): Rt=3.45min;MS m / z[M+H]+=270.8

[0340] (2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N,N-dimethylmorpholine-2-carboxamide (Example 184) (2R)-4-(6-chloropyridazin-3-yl)-N,N-dimethyl-morpholine-2-carboxamide (0.0923 mmol, 25.0 mg) and (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.139 mmol, 23.0 mg) were dissolved in 0.8 mL of 1,4-dioxane and 0.2 mL of water. K2CO3 (0.185 mmol, 25.5 mg) was added, and the mixture was purged with N2. XPhos (0.00462 mmol, 2.20 mg) and XPhos Pd G2 (0.00462 mmol, 3.63 mg) were added, and the mixture was again purged with N2. The mixture was stirred at 90 °C for 18 h. Additional (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.139 mmol, 23.0 mg), K2CO3 (0.185 mmol, 25.5 mg), XPhos (0.00462 mmol, 2.20 mg), and XPhos Pd G2 (0.00462 mmol, 3.63 mg) were added. The mixture was purged with N2 and stirred at 90 °C for 3 h. After cooling to room temperature, water and EtOAc were added. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 90 / 10 to give the title compound as a white solid (7.6 mg, 23% yield).

[0341] Example 196 3,5-Dimethyl-2-[6-(2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]phenol [ka] Int196.1: tert-butyl 9-(6-chloropyridazin-3-yl)-2-oxa-6,9-diazaspiro[4.5]decane-6-carboxylate [ka] To a stirred solution of 3-bromo-6-chloro-pyridazine (0.825 mmol, 160 mg) in 2 mL of 1,4-dioxane at room temperature, tert-butyl 2-oxa-6,9-diazaspiro[4.5]decane-6-carboxylate (0.825 mmol, 200 mg) and sodium tert-butoxide (2.48 mmol, 238 mg) were added. The mixture was purged with N2. Then, RuPhos Pd G3 (0.0825 mmol, 69.0 mg) and RuPhos (0.0825 mmol, 0.38.5 mg) were added, and the mixture was purged with N2. The reaction mixture was stirred at 90 °C for 4 h. After cooling to room temperature, the mixture was filtered, and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound as a colorless oil (175.4 mg, 56% yield). LCMS (Method R) Rt=1.27min;MS m / z[M+H]+=355.4;

[0342] Int196.2: tert-Butyl 9-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2-oxa-6,9-diazaspiro[4.5]decane-6-carboxylate [ka] In a microwave vial under an inert atmosphere, tert-butyl 9-(6-chloropyridazin-3-yl)-2-oxa-6,9-diazaspiro[4.5]decane-6-carboxylate (0.409 mmol, 156 mg), (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.409 mmol, 67.8 mg), XPhos (0.0204 mmol, 8.86 mg), and KCO (0.817 mmol, 113 mg) were added to 2 mL of 1,4-dioxane and 0.4 mL of water. The mixture was purged with N. XPhos Pd G (0.0204 mmol, 16.1 mg) was then added, and the mixture was purged with N. The mixture was then heated at 90 °C for 4 h. The mixture was quenched with water and extracted with DCM (twice). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 97 / 03 to give the title compound as an off-white solid (137 mg, 69% yield). LCMS (Method S): Rt=1.32min;MS m / z[M+H]+=441.4

[0343] 3,5-Dimethyl-2-[6-(2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]phenol (Example 196) To a solution of tert-butyl 9-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2-oxa-6,9-diazaspiro[4.5]decane-6-carboxylate (0.296 mmol, 131 mg) in 2 mL of DCM at 0° C., TFA (2.96 mmol, 0.220 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours. After concentration under reduced pressure, the residue was dissolved in water, basified with 10% aqueous KCO, extracted with a 90 / 10 DCM / MeOH mixture, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 90 / 10 to give a colorless oil, which was triturated in DIPE, filtered, and dried under reduced pressure to give the title compound as a white solid (51 mg, 39% yield).

[0344] Example 227 2-[6-(6-ethyl-2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]-3,5-dimethylphenol [ka] To a stirred solution of 3,5-dimethyl-2-[6-(2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]phenol (Example 196, 0.0837 mmol, 28.5 mg) in 1 mL of ethanol in a sealed tube, acetaldehyde (0.126 mmol, 0.007 mL), acetic acid (0.0837 mmol, 0.00479 mL), and NaBHCN (0.167 mmol, 10.5 mg) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After cooling to room temperature, ice-cold water and a saturated solution of NaHCO were slowly added, and the mixture was extracted with AcOEt. The combined organic layers were dried over MgSO, filtered and concentrated under reduced pressure to give a residue which was purified by reverse phase (column YMC-Actus Triart Prep C18-S 150*30 mm 5 μm flow rate 50 ml / min converging gradient MeCN / aq.NH4HCO3 0.2% pH=7.9 35 / 65 to 75 / 25 converging gradient) to give the title compound as an off-white solid (6 mg, 19% yield).

[0345] Compound Example 208 was synthesized in a similar manner to Example 227.

[0346] Example 229 2-[6-[rac-(3aS,6aS)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] Int229.1: tert-Butyl rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate [ka] A mixture of tert-butyl rac-(3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrole-5-carboxylate (5.03 mmol, 1.07 g), 3,6-dichloropyridazine (5.03 mmol, 0.750 g), and DIPEA (5.03 mmol, 0.862 ml) in 26 ml of NMP was heated at 150 °C for 2 h using a single-mode microwave (Biotage Initiator EXP 60) with a power ranging from 0 to 400 W. The NMP was removed using a Genevac. Water was then added and the mixture was extracted with DCM (twice). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was triturated with a mixture of DIPE / MeCN (90 / 10). The precipitate was filtered off and dried to give the title compound a as a light brown solid (740 mg, 45%). LCMS (Method T): Rt=5.83min;MS m / z[M+H]+=324.9;

[0347] Int229.2: tert-Butyl rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate [ka] In a microwave vial, a mixture of tert-butyl rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxylate (0.308 mmol, 0.100 g), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenol (0.462 mmol, 0.140 g), and KCO (0.616 mmol, 0.0851 g) in 3.3 ml of 1,4-dioxane and 0.8 ml of water was degassed under Ar. XPhos Pd G2 (0.0154 mmol, 12.1 mg) and XPhos (0.0154 mmol, 6.68 mg) were added, and the mixture was heated at 90 °C for 3 h. After cooling to room temperature, the mixture was filtered and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound (150 mg). LCMS (Method S): Rt=1.33min;[M+H]+=465.4;

[0348] 2-[6-[rac-(3aS,6aS)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 229) TFA (3.23 mmol, 0.240 ml) was added dropwise to a solution of tert-butyl rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]μ-iridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxylate (0.323 mmol, 0.150 g) in 8 ml of DCM at room temperature. The mixture was heated at 30 °C overnight. TFA (3.23 mmol, 0.240 ml) was added dropwise, and the mixture was heated at 30 °C for 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with 10% aqueous KCO. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase (stationary phase: YMC-Actus Triart Prep C18-S 150*30 mm 5 μm, flow rate 50 ml / min, converging gradient MeCN / aq.NH4HCO3 0.2% pH=7.9 25 / 75 to 55 / 45) to give, after trituration in diPE, the title compound as a white solid (23 mg, 20% yield).

[0349] Example 243: 2-[6-[rac-(3aS,6aS)-5-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] Int243.1: rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrole [ka] TFA (0.00308 mol, 0.229 ml) was added dropwise to a solution of tert-butyl rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxylate (Int229.1, 0.00160 mmol, 0.520 g) in 15 ml of DCM at room temperature. The mixture was heated at 30 °C for 8 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with 10% aqueous KCO solution. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give 380 mg of the title compound, which was used in the next step without further purification. LCMS (Method S) Rt=0,65min;MS m / z[M+H]+=225.1;

[0350] Int243.2: rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-5-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole [ka] To a stirred solution of rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrole (1.09 mmol, 245 mg) in 10 mL of MeCN was added KCO (2.18 mmol, 301 mg) and iodoethane (1.09 mmol, 170 mg). The reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction, and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over MgSO, filtered, and concentrated under reduced pressure to give 172 mg of the title compound as a white solid, which was used in the next step without further purification. LCMS (Method S) Rt=0,75min;MS m / z[M+H]+=253.1

[0351] 2-[6-[rac-(3aS,6aS)-5-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 243) A mixture of rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-5-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole (0.673 mmol, 170 mg), KCO (1.35 mmol, 186 mg), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (0.673 mmol, 203 mg) in 5 mL of 1,4-dioxane and 1.25 mL of water was degassed under a stream of N in a microwave vial under Ar. XPhos (0.0336 mmol, 16.0 mg) and XPhos Pd G (0.0336 mmol, 26.5 mg) were added, and the mixture was heated at 90 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / (MeOH / NH4OH 10%) 100 / 0 to 90 / 10. The compound-containing fractions were combined and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography on a YMC-Actus Triart Prep C18-S 150*30mm 5μm column at a flow rate of 50ml / min with a gradient of MeCN / aq. NH4HCO3 0.2% pH=7.9 with a gradient of 40 / 60 to 60 / 40. The compound-containing fractions were combined, concentrated under reduced pressure, and lyophilized to give the title compound as a white solid (54mg, 20% yield).

[0352] Example 228: 1-[rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-5-yl]ethanone [ka] Int228.1: 1-[rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-5-yl]ethanone [ka] Acetyl chloride (0.490 mmol, 0.034 mL) was added dropwise to a solution of (3aS,6aS)-1-(6-chloropyridazin-3-yl)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrole 3 (0.445 mmol, 0.100 g) and DIPEA (0.668 mmol, 0.114 mL) in 6 mL of DCM at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was then quenched with water and extracted with DCM. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 95 / 5 to give the title compound (90 mg). LCMS (Method S): Rt=0.79min;MS m / z[M+H]+=267.1;

[0353] 1-[rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-5-yl]ethanone (Example 228) In a microwave vial under Ar, a mixture of 1-[(3aS-[(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-5-yl]ethanone (0.292 mmol, 78.0 mg), KCO (0.585 mmol, 80.8 mg), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (0.292 mmol, 88.3 mg) in 3 ml of 1,4-dioxane and 0.8 ml of water was degassed under a stream of N. XPhos (1.46 e-5 mol, 6.97 mg) and XPhos Pd G2 (1.46 e-5 mol, 11.5 mg) were added, and the mixture was heated at 90 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH 100 / 0 to 90 / 10 to give the title compound (57 mg) after trituration in di-PE.

[0354] Example 257: 1-[rac-(4aS,7aS)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone [ka] Int257.1: tert-Butyl rac-(4aS,7aS)-6-acetyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate [ka] To a solution of tert-butyl rac-(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate (1.18 mmol, 270 mg) in 10 mL of dichloromethane at 0 °C, triethylamine (1.77 mmol, 247 μL) was added, followed by acetic anhydride (1.77 mmol, 168 μL). The solution was allowed to warm to room temperature and stirred for 1 h. DCM was added to the mixture, followed by a 10% aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 307 mg of the title compound as a pale yellow oil, which was used in the next step without further purification. 1H NMR(500MHz,CDCl3)δ 4.44-4.14(m,1H),4.08-3.97(m,1H),3.90(dd,J=11.2,7.4Hz,1H),3.86-3.65(m,2H),3.63-3.55(m,1H),3.52(td,J=10 .0,7.5Hz,1H),3.41-3.23(m,1H),3.14(dd,J=11.9,9.3Hz,1H),3.07-2.93(m,1H),2.04(d,J=13.7Hz,3H),1.48(s,11H).

[0355] Int257.2: 1-[rac-(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; 2,2,2-trifluoroacetate [ka] To a solution of tert-butyl (4aS,7aS)-6-acetyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate (1.11 mmol, 300 mg) in 10 mL of dichloromethane at 0 °C, TFA (11.1 mmol, 824 μL) was slowly added. The solution was warmed to room temperature and stirred for 1 h. The solution was concentrated under reduced pressure and then coevaporated with toluene to give 530 mg of the title compound as a colorless residue, which was used in the next step without further purification. 1H NMR(400MHz,CDCl3)δ(ppm)4.34-3.85(m,5H),3.73-3.14(m,5H),2.13(s,3H).

[0356] Int257.3: 1-[rac-(4aS,7aS)-4-(6-chloropyridazin-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone [ka] In a sealed tube, a mixture of 3-bromo-6-chloropyridazine (1.17 mmol, 227 mg), sodium tert-butoxide (3.17 mmol, 304 mg), RuPhos Pd G3 (0.0528 mmol, 44.1 mg), and RuPhos (0.106 mol, 49.3 mg) was purged with N. A solution of 1-[(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-ium-6-yl]ethanone; 2,2,2-trifluoroacetate (1.06 mmol, 300 mg) in 6 mL of 1,4-dioxane was added, the mixture was again purged with N, and then heated at 100 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc and water was added. The aqueous layer was extracted 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 using DCM / MeOH 100 / 0 to 95 / 5, then isocratic 95 / 5 to give 149 mg of the title compound. LCMS (Method S): Rt=0.81min;MS m / z[M+H]+=283.1;

[0357] 1-[rac-(4aS,7aS)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone (Example 257) In a sealed tube, a mixture of (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.621 mmol, 103 mg), XPhos Pd G2 (0.0414 mmol, 32.6 mg), XPhos (0.0828 mmol, 39.5 mg), and K2CO3 (0.828 mmol, 114 mg) was purged with N2. 1-[(4aS,7aS)-4-(6-chloropyridazin-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone (0.414 mmol, 117 mg) in 5.8 mL of 1,4-dioxane and 1.2 mL of water was added, and the mixture was again purged with N2 and then heated at 90 °C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and water was added. The aqueous layer was extracted 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 using DCM / MeOH 100 / 0 to 95 / 5, then isocratic 95 / 5.

[0358] The compound-containing fractions were combined and concentrated under reduced pressure.The residue was purified by reversed-phase preparative LC (column YMC-Actus Triart Prep C18-S 150*30mm 5μm, flow rate 50ml / min, gradient MeCN / aq.NH4HCO3 0.2% pH=7.9 25 / 75 to 55 / 45 gradient), and after lyophilization, 49.0mg of the title compound was obtained as a white fluffy solid.

[0359] Example 265: 2-[6-[rac-(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] Int265.1: tert-Butyl rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate [ka] A mixture of tert-butyl rac-(3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrole-5-carboxylate (5.03 mmol, 1.07 g), 3,6-dichloropyridazine (5.03 mmol, 0.750 g), and DIPEA (5.03 mmol, 0.862 ml) in 26 ml of NMP was heated at 150 °C for 2 h using a single-mode microwave (Biotage Initiator EXP 60) with a power ranging from 0 to 400 W. The NMP was removed using a Genevac. Water was added to the residue, and the mixture was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was triturated with a mixture of DIPE / MeCN (90 / 10). The precipitate was filtered and dried to give 740 mg of the title compound as a light brown solid. LCMS (Method T) Rt=5,83min;MS m / z[M+H]+=324.9;

[0360] Int265.2: rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrole [ka] TFA (0.00308 mol, 0.229 ml) was added dropwise to a solution of tert-butyl rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxylate (0.00160 mmol, 0.520 g) in 15 ml of DCM at room temperature. The mixture was heated at 30° C. for 8 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with 10% aqueous KCO solution. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give 380 mg of the title compound, which was used without further purification. LCMS (Method S): Rt=0,65min;MS m / z[M+H]+=225.1;

[0361] Int265.3: rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole [ka] Formaldehyde (37% in water) (9.79 mmol, 0.771 ml) was added to a solution of rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrole (1.96 mmol, 440 mg) in 10 ml of methanol and 10 ml of THF and stirred at room temperature. NaBHCN (1.96 mmol, 123 mg) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / (MeOH / NHOH 10%) 100 / 0 to 90 / 10. 270 mg of the title compound was obtained (yield 57%). LCMS (Method R): Rt=0.99min;MS m / z[M+H]+=239.2;

[0362] 2-[6-[rac-(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 265) A mixture of rac-(3aS,6aS)-1-(6-chloropyridazin-3-yl)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole (1.01 mmol, 240 mg), KCO (2.01 mmol, 278 mg), and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (1.51 mmol, 456 mg) in 0.8 mL of 1,4-dioxane and 0.2 mL of water was degassed under a stream of N in a microwave vial under Ar. XPhos (0.0503 mmol, 24.0 mg) and XPhos Pd G (0.0503 mmol, 39.6 mg) were added, and the mixture was heated at 80 °C for 3 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / (MeOH / NH4OH 10%) 100 / 0 to 80 / 20. The compound-containing fractions were combined and concentrated under reduced pressure. The residue was purified by reverse-phase preparative LC (column YMC-Actus Triart Prep C18-S 150*30mm 5μm, flow rate 50ml / min, gradient MeCN / aq.NH4HCO3 0.2% pH=7.9, gradient from 45 / 55 to 65 / 35) to give 181mg of the title compound.

[0363] Examples 270 and 271: 2-[6-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol and 2-[6-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol The two enantiomers of the compound 2-[6-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 265, 360 mg) were separated by preparative chiral SFC chromatography (stationary phase: Chiralpak® AS-H 20x250 mm, mobile phase: CO2 / (iPrOH+0, 3% iPrNH2) 85 / 15). Both enantiomers were obtained, first eluting at Rt 2.64 min, Example 270 (66 mg), and second eluting at Rt 4.11 min, Example 271 (74 mg). At this stage, the absolute configuration cannot be assigned.

[0364] Example 245: 5-ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methylphenol [ka] Int245.1: 5-Ethyl-2-iodo-3-methyl-phenol [ka] To a stirred solution of 3-ethyl-5-methyl-phenol (1.00 g, 7.34 mmol) in 60 mL of toluene under Ar at 0° C., NaH (60% in mineral oil) (0.587 g, 14.7 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 30 min, and then I (1.86 g, 7.34 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 20 min, then poured into cold water and extracted with EtOAc. The organic layer was washed with aqueous NaSO. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 80 / 20). The compound-containing fractions were combined and concentrated under reduced pressure. The residue was purified by SFC Chiralpak® AD-H 20×250 mm, Chiralpak® IG 30×250 mm, mobile phase: CO 2 / (iPrOH+0, 3% iPrNH 2 ) 85 / 15 to give 445 mg of the title compound. 1H NMR(500MHz,DMSO-d6)δ(ppm)10.05(s,1H),6.63(s,1H),6.53(s,1H),2.45(q,J=7.6Hz,2H),2.31(s,3H),1.12(t,J=7.5Hz,3H). LCMS (Method S) Rt=1.33min;MS m / z[M+H]+=261.0;

[0365] Int245.2: 5-ethyl-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol [ka] In a sealed tube, NEt (0.819 mL, 5.88 mmol) was slowly added to a solution of 5-ethyl-2-iodo-3-methyl-phenol (220 mg, 0.839 mmol) and HBpin (537 mg, 4.20 mmol) in 12 mL of 1,4-dioxane. The solution was purged with N. Pd(OAc) (22.6 mg, 0.101 mmol) and CyJohnPhos (0.7 mg, 0.185 mmol) were added, and the mixture was again purged with N and then heated at 80 °C for 18 h. After cooling to room temperature, water was added. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 90 / 10) to give 164 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) δ (ppm) δ 8.72 (s, 1H), 6.46 (s, 1H), 6.41 (s, 1H), 2.46 (q, J = 7.8 Hz, 2H), 2.26 (s, 3H), 1.30 (s, 12H), 1.12 (t, J = 7.6 Hz, 3H) + unidentified impurity

[0366] 5-Ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methylphenol (Example 245) A mixture of (6-chloropyridazin-3-yl)morpholin-2-yl]methanol (88.0 mg, 0.383 mmol), K2CO3 (106 mg, 0.766 mmol), and 5-ethyl-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (140 mg, 0.534 mmol) was degassed under N2 in a microwave-safe vial. XPhos (9.34 mg, 0.0196 mmol) and XPhos Pd G2 (15.1 mg, 0.0192 mmol) were added, and the mixture was heated at 80 °C for 6 h. After cooling to room temperature, the mixture was filtered through Celite® and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH (100 / 0 to 95 / 5). The compound-containing fractions were combined and concentrated under reduced pressure. The residue was purified by reversed-phase preparative LC column YMC-Actus Triart Prep C18-S 150*30mm 5μm, flow rate 50ml / min, gradient MeCN / NH4HCO3 aqueous solution 0.2% pH=7.9 (gradient from 25 / 75 to 65 / 35), to give 22mg of the title compound after lyophilization.

[0367] Example 246: 3-ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methylphenol [ka] Int246.1: 3-Ethyl-2-iodo-5-methyl-phenol [ka] To a stirred solution of 3-ethyl-5-methyl-phenol (1.00 g, 7.34 mmol) in 60 mL of toluene under Ar at 0° C., NaH (60% in mineral oil) (0.587 g, 14.7 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 30 min, and then I (1.86 g, 7.34 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 20 min, then poured into cold water and extracted with EtOAc. The organic layer was washed with an aqueous solution of NaSO. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 80 / 20). The compound-containing fractions were combined and concentrated under reduced pressure. The residue was purified by SFC Chiralpak® AD-H 20×250 mm, Chiralpak® IG 30×250 mm, mobile phase: CO 2 / (iPrOH+0, 3% iPrNH 2 ) 85 / 15 to give 181 mg of the title compound. 1H NMR(500MHz,DMSO-d6)δ(ppm)10.03(s,1H),6.57(s,1H),6.52(s,1H),2.62(q,J=7.5Hz,2H),2.17(s,3H),1.10(t,J=7.5Hz,3H). LCMS (Method S): Rt=1.32min;MS m / z[M+H]+=261.0;

[0368] Int246.2: 3-Ethyl-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol [ka] To a solution of 3-ethyl-2-iodo-5-methyl-phenol (180 mg, 0.687 mol) and HBpin (0.498 mL, 3.43 mmol) in 8 mL of 1,4-dioxane in a sealed tube, NEt (0.670 mL, 4.81 mmol) was slowly added. The solution was purged with N. Pd(OAc) (18.5 mg, 0.0824 mmol) and CyJohnPhos (53.0 mg, 0.151 mmol) were added, and the mixture was again purged with N and then heated at 80 °C for 18 h. After cooling to room temperature, water was added. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / EtOAc (100 / 0 to 90 / 10) to give 93 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 8.81 (s, 1H), 6.44 (s, 1H), 6.40-6.35 (m, 1H), 2.59-2.50 (m, 2H), 2.17 (s, 3H), 1.29 (s, 12H), 1.08 (t, J = 7.5 Hz, 3H) + unidentified impurity.

[0369] 3-Ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methylphenol (Example 246) A mixture of [(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol (55.0 mg, 2.39 mmol), KCO (66.2 mg, 0.479 mmol), and 3-ethyl-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (94.2 mg, 0.359 mmol) in 2 mL of 1,4-dioxane and 0.5 mL of water was degassed under a stream of N in a microwave vial under Ar. XPhos (5.71 mg, 0.012 mmol) and XPhos Pd G (9.42 mg, 0.012 mmol) were added, and the mixture was heated at 80 °C for 6 h. After cooling to room temperature, the mixture was filtered through Celite® and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH (100 / 0 to 95 / 5). The compound-containing fractions were combined and concentrated under reduced pressure. The residue was purified by reverse-phase preparative LC column YMC-Actus Triart Prep C18-S 150*30mm 5μm flow rate 50ml / min gradient MeCN / NH4HCO3 aqueous solution 0.2% pH=7.9 (25 / 75 to 65 / 35 gradient) to give 14mg of the title compound after lyophilization.

[0370] Examples 260 and 261: 3-methyl-2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol and 3-methyl-2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol The two enantiomers of the compound 2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol (Example 226, 101 mg) were purified by supercritical fluid chromatography (SFC-column: Daicel Purification was carried out by Chiralpak® AD-H, 250 × 30 mm i.d., 5 μm particle size; mobile phase: CO2 / ethanol (+0.1% triethylamine) 20%; flow rate: 200 mL / min; outlet pressure: 100 bar; two injections; UV detection: 265 nm) with the first enantiomer eluting at Rt = 4.3 min (22 mg, Example 260, Enantiomer 1), 3-methyl-2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H The second enantiomer eluted at Rt = 6 min (20 mg, Example 261, Enantiomer 2) to give 3-methyl-2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol as a white solid. The absolute configuration cannot be assigned at this stage.

[0371] Compounds Examples 310 and 311 were obtained by preparative chiral SFC separation similar to Examples 260 and 261. The absolute configuration was assigned a posteriori (see chiral synthesis of Example 311).

[0372] Example 260: 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] To a solution of 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (2.23 mmol, 674 mg) and (4aS,8aR)-4-(6-chloropyridazin-3-yl)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine (Int321.3-1.49 mmol, 400 mg) in 60 mL of 1,4-dioxane and 10 mL of water was added 2N aqueous sodium carbonate (4.47 mmol, 2.23 mL). Argon was bubbled through the solution for 10 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.149 mmol, 172 mg) was added, and the solution was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was diluted with 100 mL of DCM and 100 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 2 x 50 mL of DCM, and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH / ACN / NH in MeOH (100 / 0 / 0 / 0 to 90 / 4.9 / 4.9 / 0.2) to give the title compound as a white solid (390 mg, 64% yield) after trituration with diethyl ether.

[0373] Example 127: 5-chloro-2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-phenol Int127.1: [(3S)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]methanol [ka] To a solution of 3,6-dichloropyridazine (250 mg, 1.6781 mmol) and triethylamine (515 μl, 3.6918 mmol) in 20 mL of n-butanol under Ar, [(3S)-pyrrolidin-3-yl]methanol (187 mg, 1459 mmol) was added, and the mixture was heated at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was crystallized in diethyl ether and filtered to give the title compound as a beige solid (m=190 mg, 52% yield). LCMS (Method L): Rt=0,34min;MS m / z[M+H]+=213;

[0374] Int127.2: [(3S)-1-[6-(4-chloro-2-methoxy-6-methyl-phenyl)pyridazin-3-yl]pyrrolidin-3-yl]methanol [ka] In a microwave vial under Ar, to a solution of [(3S)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]methanol (100 mg, 0.468 mmol), 2-(4-chloro-2-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg, 0.6084 mmol), sodium carbonate (117 mg, 1.4041 mmol) in 6.23 mL of 1,4-dioxane and 1.56 mL of water was added tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.0328 mmol). The mixture was heated at 120 °C under microwave irradiation for 3 hours. After cooling to room temperature, the reaction mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography SiO2DCM / MeOH (100 / 0 to 95 / 5) to give the title compound as an amorphous solid (76 mg, 48% yield). LCMS (Method L) Rt=0,54min MS m / z[M+H]+=334;

[0375] 5-Chloro-2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-phenol (Example 127) To a solution of [(3S)-1-[6-(4-chloro-2-methoxy-6-methyl-phenyl)pyridazin-3-yl]pyrrolidin-3-yl]methanol (76 mg, 0.2277 mmol) in 10 mL of dichloromethane, tribromoboron (455 μL in hexane, 0.4553 mmol, 1 mol / L) was slowly added at −5°C, and the reaction mixture was stirred at −5°C for 1 hour and 15 minutes. Additional tribromoboron (200 μL) was added, and the mixture was stirred at −5°C for another 1 hour and 15 minutes. A few drops of methanol were then slowly added at −5°C, and the mixture was basified with aqueous NaOH (5N), stirred for 5 minutes, and then acidified with aqueous SO (6%). The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was crystallized in diethyl ether, filtered off and purified by reverse phase chromatography (H20 / CH3CN) (C18, water / MeCN, gradient 95 / 5 to 5 / 95) to give the title compound as a beige solid (7 mg, 10% yield).

[0376] Example 130: (4S)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-4-hydroxypyrrolidin-2-one Int130.1: (4S)-1-(6-chloropyridazin-3-yl)-4-hydroxy-pyrrolidin-2-one [ka] To a solution of 3,6-dichloropyridazine (2.25 mmol, 335 mg) and (S)-4-hydroxy-2-pyrrolidinone (2.56 mmol, 259 mg) in 5 mL of 1,4-dioxane in a microwave vial under Ar, tripotassium phosphate (4.27 mmol, 907 mg), 1-1'-bis(diphenylphosphino)ferrocene (0.26 mmol, 142 mg), and palladium acetate (0.09 mmol, 19 mg) were added. The vial was sealed, and the mixture was heated under microwave irradiation at 110 °C for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and CHCl, filtered, the solid portion washed with EtOAc and CHCl, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / EtOAc (100 / 0 to 50 / 50) to give the title compound as a brown solid (145 mg, 32% yield). LCMS (Method M): Rt=0.76min;MS m / z[M+H]+214;

[0377] (4S)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-4-hydroxypyrrolidin-2-one (Example 130) To a solution of (4S)-1-(6-chloropyridazin-3-yl)-4-hydroxy-pyrrolidin-2-one (0.35 mmol, 75 mg) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (0.37 mmol, 69 mg) in 1.8 mL of 1,2-dimethoxyethane in a microwave vial under Ar, sodium carbonate (0.88 mmol, 93 mg) and 0.45 mL of water were added. The solution was purged with Ar, and then Pd(PPh3)4 (0.02 mmol, 20 mg) was added. The vial was sealed, and the mixture was heated at 100 °C under microwave irradiation for 1 h. The reaction mixture was diluted with EtOAc and water and filtered. The organic layer was separated, washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 93 / 3.5 / 3.5) to give the title compound as a white solid (27 mg, 24% yield).

[0378] Example 162: 4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3-dihydro-1,4-benzoxazin-6-ol [ka] Int162.1: 4-(6-chloropyridazin-3-yl)-2,3-dihydro-1,4-benzoxazin-6-ol [ka] A suspension of 3,6-dichloropyridazine (5.97 mmol, 889 mg), 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ol hydrochloride (0.75 mmol, 140 mg), and diisopropylethylamine (1.64 mmol, 0.28 ml) in 1 ml of n-butanol in a microwave vial under Ar was heated at 150 °C for 7.5 h under microwave irradiation. After addition of DCM, the organic layer was washed with water, filtered through a hydrophobic column, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 94 / 3 / 3) to give the title compound as a brown solid (63 mg, 32% yield). LCMS (Method U): Rt=1,17min;MS m / z[M+H]+=264;

[0379] 4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3-dihydro-1,4-benzoxazin-6-ol (Example 162) To a solution of 4-(6-chloropyridazin-3-yl)-2,3-dihydro-1,4-benzoxazin-6-ol (0.24 mmol, 62 mg) and (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.26 mmol, 43 mg) in 1.65 mL of 1,2-dimethoxyethane in a microwave vial under Ar, sodium carbonate (0.59 mmol, 62 mg) and 0.4 mL of water were added. The solution was purged with Ar, and then Pd(PPh3)4 (0.02 mmol, 19 mg) was added. The vial was sealed, and the mixture was heated at 100 °C under microwave irradiation for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give a brown solid (45 mg), which was further purified by reverse-phase chromatography (column X Select CSH C18 5 μm OBD, Waters, 250 × 50 mm, flow rate 80 ml / min, eluent: acetonitrile / water with 0.1% formic acid (34 / 66 to 100 / 0) to give the title compound as an off-white solid (30 mg, 37% yield).

[0380] Compounds Examples 193, 215 and 362 were synthesized in a similar manner to Example 162.

[0381] Example 123: 2-[6-[(3R)-3-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid [ka] Int123.1: tert-butyl N-[[(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methyl]carbamate [ka] In a microwave vial under Ar, to a solution of 3,6-dichloropyridazine (2.57 mmol, 404 mg) in 3 mL of NMP was added (R)-tert-butyl(morpholin-3-ylmethyl)carbamate (2.57 mmol, 586 mg) and DIPEA (5.15 mmol, 0.907 mL). The vial was sealed, and the mixture was heated under microwave irradiation at 180° C. for 2.5 h. After cooling to room temperature, DCM and brine were added. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give an orange oil (356 mg). The oil was purified by flash chromatography on silica gel using DCM / AcOEt (10 / 0 to 6 / 4) to give the title compound as a white solid (120 mg, 14% yield). LCMS (Method L): Rt=0,79min;[M+H]+=329;

[0382] Int123.2: tert-butyl N-[[(3R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3yl]morpholin-3-yl]methyl]carbamate [ka] To a solution of boronic acid (0.197 mmol, 32.8 mg) and tert-butyl N-[[(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methyl]carbamate (0.152 mmol, 50 mg) in a microwave vial, sodium carbonate (0.456 mmol, 37 mg) and 0.23 mL of water were added. The solution was purged with Ar, and then Pd(PPh3)4 (7.6 μmol, 8.8 mg) was added. The vial was sealed, and the mixture was heated at 100 °C under microwave irradiation for 1 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was diluted with EtOAc and washed with water (3 times) and brine. The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2) to give the title compound as a white solid (59 mg, 93% yield). LCMS (Method L) Rt=0,69min;MS m / z[M+H]+=415

[0383] 2-[6-[(3R)-3-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid (Example 123) To a solution of tert-butyl N-[[(3R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3yl]morpholin-3-yl]methyl]carbamate (0.14 mmol, 59 mg) in 1 mL of dichloromethane was added TFA (1.42 mmol, 0.111 mL) dropwise. The resulting solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with methanol, and concentrated under reduced pressure. The residue was suspended in diethyl ether and stirred at room temperature for 10 minutes. The suspension was filtered and dried to give the title compound as a pale yellow solid (41.9 mg, 69% yield).

[0384] Compound Example 124 was synthesized in a similar manner to Example 123.

[0385] Example 129: N-[[(3R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-3-yl]methyl]acetamide [ka] Int129.2: [(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methanamine; hydrochloride [ka] To a solution of tert-butyl N-[[(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methyl]carbamate (Int123-1) (0.26 mmol, 88 mg) in 2 mL of DCM was added dropwise HCl 4M / dioxane (2.67 mmol, 0.67 mL). The resulting solution was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give [(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methanamine. The hydrochloride salt was obtained as a pale yellow solid (80 mg, 100% yield). LCMS (Method L): Rt=0,19min;MS m / z[M+H]+=228

[0386] Int129.3: N-[[(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methyl]acetamide [ka] To a solution of [(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methanamine; hydrochloride (0.301 mmol, 80 mg) in 2 mL of DCM was added dropwise triethylamine (0.745 mmol, 0.105 mL), followed by the addition of acetic anhydride (0.452 mmol, 42.5 μL). The resulting solution was stirred at room temperature for 2 hours and 30 minutes. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 (3 times). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a white solid (52 mg, 63% yield). LCMS (Method L) Rt=0,47min;MS m / z[M+H]+=271

[0387] N-[[(3R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-3-yl]methyl]acetamide (Example 129) To a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.255 mmol, 42.3 mg) and N-[[(3R)-4-(6-chloropyridazin-3-yl)morpholin-3-yl]methyl]acetamide (0.196 mmol, 52 mg) in 1.2 mL of dioxane in a microwave vial under Ar, sodium carbonate (0.588 mmol, 48 mg) and 0.30 mL of water were added. The solution was purged with Ar, and then Pd(PPh3)4 (9.8 μmol, 11.4 mg) was added. The vial was sealed, and the mixture was heated at 110 °C under microwave irradiation for 1 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was diluted with EtOAc and washed with water (3x) and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (100 / 0 / 0 to 96 / 2 / 2), then suspended in pentane and stirred at room temperature for 10 minutes. The suspension was filtered off and dried to give the title compound as a white solid (21 mg, 30% yield).

[0388] Compound Example 154 was synthesized in a similar manner to Example 129.

[0389] Example 173: 2-[6-[(2R,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka]

[0390] Int173.1: [(2S,6R)-4-(6-chloropyridazin-3-yl)-6-(hydroxymethyl)morpholin-2-yl]methanol [ka] To a solution of 3,6-dichloropyridazine (1.30 mmol, 200 mg) in 3 mL of 1-butanol in a microwave vial under Ar, [(2S,6R)-6-(hydroxymethyl)morpholin-2-yl]methanol hydrochloride (1.30 mmol, 251 mg) and DIPEA (2.60 mmol, 0.458 mL) were added. The vial was sealed, and the mixture was heated at 130 °C under microwave irradiation for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and DCM was added. The heterogeneous mixture was stirred for 10 min, filtered, and dried under vacuum at 40 °C to give the title compound as an orange-yellow solid (125 mg, 71% yield). LCMS (Method L): Rt=0,43min;MS m / z[M+H]+=260

[0391] 2-[6-[(2R,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 173) To a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (0.175 mmol, 29 mg) and [(2S,6R)-4-(6-chloropyridazin-3-yl)-6-(hydroxymethyl)morpholin-2-yl]methanol (0.134 mmol, 35 mg) in 0.84 mL of dioxane in a microwave vial under Ar, sodium carbonate (0.404 mmol, 33 mg) and 0.21 mL of water were added. The solution was purged with Ar, and then Pd(PPh3)4 (6.7 μmol, 7.8 mg) was added. The vial was sealed, and the mixture was heated at 110 °C under microwave irradiation for 1 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. MeOH was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a Waters XSelect CSH column (C185μ 50 × 250 mm), eluent: acetonitrile / water (+0, 1% HCOOH) 2 / 98-100 / 0, flow rate 120 ml / min, to give the title compound as an orange solid (13 mg, 28% yield).

[0392] Compounds Examples 178, 198, 199, 200, 201, 258 and 259 were synthesized in a similar manner to Example 173.

[0393] Example 118: 2-[6-[(2R)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int118.1: [(2R)-1-(6-chloropyridazin-3-yl)azetidin-2-yl]methanol [ka] To a solution of 3,6-dichloropyridazine (1.68 mmol, 250 mg) and (R)-2-azetidinemethanol (1.8459 mmol, 166 mg) in 2 ml of n-butanol in a microwave vial under Ar, N,N-diisopropylamine (3.69 mmol, 477 mg) was added. The vial was sealed, and the mixture was heated at 130° C. under microwave irradiation for 2 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. DCM was added, and the organic layer was washed with water and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using AcOEt / MeOH 9 / 1 to give the title compound as a colorless oil (200 mg, 60% yield). LCMS (Method U): Rt=0,66min;MS m / z[M+H]+=200;

[0394] 2-[6-[(2R)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 118) To a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (1.04 mmol, 174 mg) and [(2R)-1-(6-chloropyridazin-3-yl)azetidin-2-yl]methanol (0.95 mmol, 190 mg) in 6 mL of 1,4-dioxane in a microwave vial under Ar was added sodium carbonate (2.85 mmol, 302 mg) and 1.5 mL of water. The solution was purged with Ar and then Pd(PPh 3)4 (0.06 mmol, 66 mg) was added. The vial was sealed, and the mixture was heated at 110 °C under microwave irradiation for 2 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. EtOAc was added, and the organic layer was washed with water (3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using DCM / MeOH / ACN (97 / 1.5 / 1.5) to give the title compound as a white solid (85 mg, 31% yield).

[0395] Compound Example 134 was synthesized in the same manner as Example 118 using Int8.1 ([(2S)-4-(6-chloropyridazin-3-yl)morpholin-2-yl]methanol).

[0396] Example 273: 3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one [ka] Int273.1: 3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-2-one [ka] Under Ar, 4-dimethylaminopyridine (1.35 mmol, 165 mg) and triethylamine (5.4 mmol, 550 mg) were added to a solution of 3-(hydroxymethyl)piperidin-2-one (4.5 mmol, 600 mg) in 3.6 mL of DMF. tert-Butyldimethylchlorosilane (4.96 mmol, 762 mg) was added slowly. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with AcOEt and poured into 5% aqueous NaHCO3 solution. The organic layer was washed with 5% aqueous NaHCO3 solution (twice) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using AcOEt / MeOH (100 / 0 to 90 / 10) to give the title compound as a colorless oil (840 mg, 77% yield). LCMS (Method L): Rt=1.09min;MS m / z[M+H] + =244.1;

[0397] 3-(Hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one (Example 273) Under Ar, a solution of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one (obtained from 900 mg of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-2-one, 1.39 mmol) in 3 ml of THF was cooled to +5°C, and then a solution of 6 ml of acetic acid and 1 ml of water was added dropwise. The reaction mixture was stirred at room temperature overnight and then heated at 50°C for 48 hours. After cooling to room temperature, the reaction mixture was poured into DCM and water. The organic layer was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using heptane / (AcOEt3 / 1EtOH)8 / 2 to give the title compound as a white solid (420 mg, 79% yield).

[0398] Compound Examples 286, 316, and 368 were synthesized in a similar manner to Example 273. Compound Examples 419 and 420 were enantiomerically separated from compound Example 368, as were compound Examples 287 and 288, using a ChiralPak® IC column.

[0399] Example 116: 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methoxy-phenol [ka] To a solution of 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.2 mmol, 300 mg) and [(2S)-4-(6-chloro-5-methyl-pyridazin-3-yl)morpholin-2-yl]methanol (Int 85.1 -0.8 mmol, 195 mg) in 5 mL of 1,4-dioxane under Ar, 2N aqueous sodium carbonate (2.16 mmol, 1.08 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.04 mmol, 46 mg). The mixture was stirred at 100 °C for 3 h. After cooling, the resulting mixture was diluted with EtOAc, and the aqueous layer was extracted again with a 70 / 30 mixture of dichloromethane / isopropanol. The combined organic layers were washed successively with water and brine. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was triturated in methanol, filtered off and the solid washed with diethyl ether to give the title compound (170 mg, 64% yield) as a yellow solid.

[0400] Compounds Examples 149 and 177 were synthesized in a similar manner to Example 116.

[0401] Example 128 2-[6-[(3S)-3-(dimethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethylphenol [ka] Int128.1: (3S)-1-(6-chloropyridazin-3-yl)-N,N-dimethyl-piperidin-3-amine [ka] A solution of 3,6-dichloropyridazine (1.42 mmol, 211 mg), (3S)-N,N-dimethylpiperidin-3-amine dihydrochloride (1.7 mmol, 342 mg), and triethylamine (4.53 mmol, 632 μL) in 14 mL of n-butanol was stirred at 120° C. for 18 h. The mixture was cooled and concentrated under reduced pressure, and the residue was diluted with 50 mL of EtOAc and then washed successively with 20 mL of saturated aqueous sodium bicarbonate and 10 mL of brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% methanol in dichloromethane to afford the title compound (165 mg, 48% yield) as a beige solid. LCMS (Method L): Rt=0.46min;MS m / z[M+H] + 241;

[0402] 2-[6-[(3S)-3-(dimethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 128) Under Ar, to a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (1.02 mmol, 169 mg) and (3S)-1-(6-chloropyridazin-3-yl)-N,N-dimethyl-piperidin-3-amine (0.68 mmol, 163 mg) in 4 mL of 1,4-dioxane, 2 N aqueous sodium carbonate (1.83 mmol, 914 μL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.034 mmol, 39 mg). The mixture was stirred at 100° C. for 3 h. After cooling, the resulting mixture was diluted with 20 mL of EtOAc, and the organic layer was washed successively with water and brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 15% MeOH in DCM to give a yellow solid residue which was triturated in a mixture of dichloromethane and pentane to give the title compound (120 mg, 54% yield) as a beige solid.

[0403] Example 119: 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methoxy-3-methyl-phenol [ka] According to the procedure of Example 85, [(2S)-4-(6-chloro-5-methyl-pyridazin-3-yl)morpholin-2-yl]methanol (Int85.1 - 1.026 mmol, 250 mg) and 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Int96.2 - 1.54 mmol, 406 mg) gave the title compound as an orange oil (30 mg, 8% yield).

[0404] Example 133: 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-3-methyl-phenol [ka] Int133.1: [(2S)-4-(6-chloro-4-methyl-pyridazin-3-yl)morpholin-2-yl]methanol [ka] A solution of 3,6-dichloro-4-methyl-pyridazine (24.5 mmol, 4 g), [(2S)-morpholin-2-yl]methanol; hydrochloride (24.5 mmol, 3.77 g) and triethylamine (54 mmol, 7.52 ml) in 50 ml of n-butanol was stirred at 130 °C for 11 h. The mixture was cooled, diluted with EtOAc and diethyl ether, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% 99 / 1 EtOAc / MeOH in cyclohexane to give the title compound (376 mg, 6% yield) as a white solid. LCMS (Method L): Rt=0.51min;MS m / z[M+H] + 244;

[0405] 5-Chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-3-methyl-phenol (Example 133) Under Ar, to a solution of (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (0.74 mmol, 138 mg) and [(2S)-4-(6-chloro-4-methyl-pyridazin-3-yl)morpholin-2-yl]methanol (Int133.1 - 0.49 mmol, 120 mg) in 4 mL of 1,4-dioxane, 2N aqueous sodium carbonate (1.33 mmol, 665 μL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.025 mmol, 28 mg). The mixture was stirred at 100 °C for 3 h. After cooling, the resulting mixture was diluted with EtOAc and diethyl ether. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH / ACN (98 / 1 / 1 to 94 / 3 / 3) to give the title compound as a yellow solid (29 mg, 17% yield).

[0406] Examples 135 and 136 2-[6-[(2S)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol and 2-[6-[(2R)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] Int135.1: 1-morpholin-2-ylcyclopropanamine; 2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl 2-(1-aminocyclopropyl)morpholine-4-carboxylate (2.48 mmol, 600 mg) in 9 ml of dichloromethane was added 1 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure to give the title compound (300 mg, 85% yield) as a yellow oil. LCMS (Method H): Rt=0.24min;MS m / z[M+H] + 143.

[0407] Int135.2: 1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]cyclopropanamine [ka] Following the procedure of Int128.1, 1-morpholin-2-ylcyclopropanamine; 2,2,2-trifluoroacetic acid (3.69 mmol, 525 mg) and 3,6-dichloropyridazine (3.36 mmol, 500 mg) gave the title compound as a yellow oil (850 mg, 99% yield). LCMS (Method H): Rt=0.80min;MS m / z[M+H] + 255

[0408] Int135.3: 2-[6-[2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (racemic) [ka] Following the procedure of Example 85, 1-[4-(6-chloropyridazin-3-yl)morpholin-2-yl]cyclopropanamine (1.77 mmol, 450 mg) affords the title compound as an orange oil (70 mg, 11% yield). LCMS (Method L): Rt=0.57min;MS m / z[M+H] + 341

[0409] 2-[6-[(2S)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol and 2-[6-[(2R)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 135: Enantiomer 1 and Example 136: Enantiomer 2) The two enantiomers of the compound 2-[6-[2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol were separated by chiral normal-phase chromatography (column: Daicel Chiralpcel® OD, internal diameter 350 × 30 mm, particle size 5 μm; mobile phase: eluent B: EtOH (0.1% TEA), isocratic elution: 80% phase B; flow rate: 45 ml / min) to give both enantiomers, the first eluting at Rt = 7.9 min (13.5 mg, Example 135, Enantiomer 1) as a white solid, and the second eluting at Rt = 15.3 min (14.2 mg, Example 136, Enantiomer 2) as a white solid (absolute configuration cannot be assigned).

[0410] Example 144: 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol [ka] Int144.1: 3,6-Dichloro-4-(difluoromethyl)pyridazine [ka] To a suspension of 3,6-dichloropyridazine (13.42 mmol, 2 g) in 20 mL of water was added 2,2-difluoroacetic acid (18.8 mmol, 1.18 mL), and the mixture was stirred at 55°C. Silver nitrate (2.68 mmol, 456 mg) solubilized in 2 mL of water and trifluoroacetic acid (2.68 mmol, 200 μL) was then added. To the mixture stirred at 55°C, a solution of ammonium persulfate (21.5 mmol, 4.9 g) in 9 mL of water was added dropwise, and the mixture was stirred at 75°C for 2 hours, then cooled to room temperature and quenched with 50 mL of saturated aqueous sodium bicarbonate and 100 mL of dichloromethane while stirring. The organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% diisopropyl ether in petroleum ether to afford the title compound (820 mg, 31% yield) as a colorless liquid. LCMS (Method L): Rt=0.96min;MS m / z[M+H] + 199.

[0411] Int144.2 and Int170.1: [(2S)-4-[6-chloro-5-(difluoromethyl)pyridazin-3-yl]morpholin-2-yl]methanol (Int144.2) and [(2S)-4-[6-chloro-4-(difluoromethyl)pyridazin-3-yl]morpholin-2-yl]methanol (Int170.1) [ka] A solution of 3,6-dichloro-4-(difluoromethyl)pyridazine (7.94 mmol, 1.58 g), [(2S)-morpholin-2-yl]methanol; hydrochloride (7.94 mmol, 1.22 g) and triethylamine (17.5 mmol, 1.43 ml) in 20 ml of n-butanol was stirred at 130 °C for 6 hours. The mixture was cooled and concentrated under reduced pressure, and the residue was taken up in 50 ml of EtOAc and filtered off. The solid was rinsed with EtOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% of a 99 / 1 mixture of EtOAc / MeOH in cyclohexane to give the title compounds Int144.2 (1.44 g, 65% yield) and Int170.1 (555 mg, 25% yield) as yellow solids. LCMS (Method L): Int144.2:Rt=0.84min;MS m / z[M+H] + 280 Int170.1:Rt=0.87min;MS m / z[M+H] + 280

[0412] 2-[4-(Difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol (Example 144) Following the procedure of Example 133, [(2S)-4-[6-chloro-5-(difluoromethyl)pyridazin-3-yl]morpholin-2-yl]methanol (Int 144.2-0.715 mmol, 200 mg) afforded the title compound as a white solid (136 mg, 54% yield).

[0413] Compound Example 145 was synthesized in a similar manner to Example 144.

[0414] Example 170: 2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol [ka] To a solution of (2-hydroxy-4,6-dimethylphenyl)boronic acid (1.43 mmol, 237 mg) and [(2S)-4-[6-chloro-4-(difluoromethyl)pyridazin-3-yl]morpholin-2-yl]methanol (Int170.1 -0.715 mmol, 200 mg) in 10 mL of 1,4-dioxane under Ar, 2N aqueous sodium carbonate (1.93 mmol, 0.965 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.036 mmol, 41 mg). The mixture was stirred at 100 °C for 3 h. After cooling, EtOAc and diethyl ether were added, and the resulting mixture was washed successively with saturated aqueous NaHCO and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of DCM / MeOH / ACN (98 / 1 / 1 to 94 / 3 / 3) to give a yellow solid residue, which was purified by prep-HPLC (column: Sunfire prep C18 OBD; 250*50 mm*10 μm; mobile phase: [water (TFA 10 -2 N)-ACN]; B%: 10%-100% at 50 ml / min for 35 min to afford the title compound as a white solid (111 mg, 42% yield).

[0415] Compounds Examples 171, 172, 194, 247, 248 and 249 were synthesized in a similar manner to Example 170.

[0416] Example 155: 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)pyridazin-3-yl]-5-methyl-phenol Int155.1: [(2S)-4-[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]morpholin-2-yl]methanol [ka] A solution of 3,6-dichloro-4-(trifluoromethyl)pyridazinel (4.61 mmol, 1 g), [(2S)-morpholin-2-yl]methanol; hydrochloride (5.07 mmol, 778 mg) and triethylamine (10.14 mmol, 1.41 ml) in 10 ml of n-butanol was stirred at 120 °C for 4 h. The mixture was cooled and concentrated under reduced pressure, and the residue was diluted with 250 ml of EtOAc and then washed with 100 ml of water. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of DCM / MeOH / ACN (98 / 1 / 1 to 94 / 3 / 3) to give the title compound (772 mg, 56% yield) as a yellow oil. LCMS (Method X): Rt=0.68min;MS m / z[M+H] + =298.

[0417] 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)pyridazin-3-yl]-5-methyl-phenol (Example 155) The procedure of Example 133 [(2S)-4-[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]morpholin-2-yl]methanol (Int155.1-0.67 mmol, 200 mg) was followed to provide the title compound as a white solid (186 mg, 74% yield).

[0418] Compound Example 160 was synthesized in a similar manner to Example 155.

[0419] Example 158: 6-(2-hydroxy-4,6-dimethyl-phenyl)-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile Int158.1: 6-chloro-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile [ka] Following the procedure for Int155. 1,3,6-Dichloropyridazine-4-carbonitrile (4.02 mmol, 700 mg) gave the title compound as a yellow oil (779 mg, 76% yield). LCMS (Method X): Rt=0.92min;MS m / z[M+H] + 255.

[0420] 6-(2-Hydroxy-4,6-dimethylphenyl)-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile (Example 158) Following the procedure of Example 133, 6-chloro-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile (Int158.1-0.785 mmol, 200 mg) afforded the title compound as a white solid (154 mg, 58% yield).

[0421] Compounds Examples 159 and 163 were synthesized in a similar manner to Example 158.

[0422] Examples 175 and 176: 6-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomer 1 and 6-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomer 2 [ka] Int175.1: 6-(6-chloropyridazin-3-yl)-6-azaspiro[3.5]nonan-2-ol [ka] A solution of 3,6-dichloropyridazine (3.02 mmol, 450 mg), 6-azaspiro[3.5]nonan-2-ol; hydrochloride (3.32 mmol, 590 mg) and triethylamine (6.64 mmol, 0.93 ml) in 5 ml of n-butanol was stirred at 130 °C for 3 h. The mixture was cooled and concentrated under reduced pressure, and the residue was diluted with 150 ml of EtOAc and then washed with 150 ml of water. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give the title compound (452 ​​mg, 59% yield) as a beige solid. LCMS (Method L): Rt=1.23min;MS m / z[M+H] + 254.

[0423] 6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol Isomer 1 and 6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol Isomer 2 (Example 175: Isomer 1 and Example 176: Isomer 2) To a solution of 6-(6-chloropyridazin-3-yl)-6-azaspiro[3.5]nonan-2-ol (1.78 mmol, 452 mg) and (2-hydroxy-4,6-dimethylphenyl)boronic acid (2.67 mmol, 444 mg) in 8 mL of 1,4-dioxane under Ar, 2N aqueous sodium carbonate (4.81 mmol, 2.4 mL) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.09 mmol, 103 mg). The mixture was stirred at 100 °C for 3 h. After cooling, EtOAc and diethyl ether were added, and the resulting mixture was washed successively with saturated aqueous NaHCO and water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of 6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomers. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of 6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol 2 and 6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomers 1. Isomer 2 and 6-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol Isomer 1. LCMS (Method L): Rt=0.70min and 0.74min; MS m / z[M+H] + =340.

[0424] The isomer mixture Isomer 1 / Isomer 2 is separated by semi-preparative chiral normal phase chromatography (Column: Daicel Chiralpak® IC, 350 × 76, 5 mm, particle size 20 μm; Mobile phase: Eluent B: EtOH (0.1% TEA), Isocratic elution: 80% Phase B; Flow rate: 400 ml / min) to give two enantiomers, the first eluting as a white solid at Rt = 16.6 min (175 mg, Example 175, Isomer 1) and the second eluting as a white solid at Rt = 17.8 min (219 mg, Example 176, Isomer 2).

[0425] Examples 186 and 187: 2-[4-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol and 2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol. [ka] Int186.1 and Int187.1: [3-chloro-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-4-yl]methanol (Int186.1) and [6-chloro-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-4-yl]methanol (Int187.1) [ka] A solution of (3,6-dichloropyridazin-4-yl)methanol (13 mmol, 2.3 g), (3S)-N,N-dimethylpiperidin-3-amine dihydrochloride (14 mmol, 2.2 g), and triethylamine (28 mmol, 3.9 ml) in 40 ml of n-butanol was stirred at 130° C. for 3 hours. The mixture was cooled and concentrated under reduced pressure, and the residue was diluted with 200 ml of EtOAc and then washed with 150 ml of water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound (165 mg, 36% yield) as a mixture and a yellow oil. LCMS (Method L): Int186.1 and Int187.1: Rt=0.83 min; MS m / z[M+H] + 260.

[0426] 2-[4-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol and 2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 186 and Example 187) Following the procedure of Example 133, a mixture (2.5 mmol, 1.3 g) of [3-chloro-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-4-yl]methanol (Int 186.1) and [6-chloro-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-4-yl]methanol (Int 187.1) gave 2-[4-(hydroxymethyl)- 6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 186 - 385 mg, 45% yield) and 2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol (Example 187 - 96 mg, 11% yield) are obtained as white solids.

[0427] Compounds Examples 188 and 189 were synthesized in a similar manner to Examples 186 and 187.

[0428] Example 197: 2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol [ka] Int197.1: Benzyl rac-(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carboxylate [ka] Following the procedure of Example 133, benzyl rac-(4aR,8aS)-4-(6-chloropyridazin-3-yl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carboxylate (Int 10.8-2.57 mmol, 1 g) gives the title compound (1.38 g, 82% yield) as a yellow oil. LCMS (Method V): Rt=1.14min;MS m / z[M+H] + 529.

[0429] 3-Methyl-2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol (Example 197) To a suspension of benzyl rac-(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carboxylate (2.61 mmol, 1.38 g) in 40 mL of EtOH was added ammonium formate (7.83 mmol, 494 mg) and 10% Pd / C (494 mg), and the resulting mixture was stirred at 80 °C for 1 h under microwave irradiation. After cooling to room temperature, the mixture was filtered through a pad of Decalite® and the cake was rinsed with 50 mL of EtOH. The organic layer was concentrated under reduced pressure, and the residue was diluted with 200 mL of dichloromethane, washed twice with 200 mL of saturated aqueous sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of DCM / MeOH / ACN (100 / 0 / 0 to 80 / 10 / 10) to give the title compound as a white solid (660 mg, 64% yield). ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, n is 1 or 2; R1 independently represents a halogen atom, (C １ ~C ４ ) alkyl group, halo (C １ ~C ４ ) alkyl group, (C １ ~C ４ ) alkoxy group, halo (C １ ~C ４ ) an alkoxy group, 【Chemistry 2】 wherein R6 is a hydrogen atom or a methyl group, and 【Transformation 3】 represents the bonding site between the carbon atom and the phenyl ring), or (C ３ ~C ６ ) represents a cycloalkyl group; or two R1 on adjacent carbon atoms, together with the atom connecting them, form a cyclopentane ring fused to the phenol group; R2 and R3 each independently represent a hydrogen atom, a cyano group, (C １ ~C ４ ) alkyl group, hydroxy (C １ ~C ４ ) alkyl group, halo (C １ ~C ４ ) an alkyl group, or a group of formula 【Chemistry 4】 wherein R6 is a hydrogen atom or a methyl group, and 【Transformation 5】 represents the bonding site between the carbon atom and the pyridazine ring), or Or, R2 and R3 on adjacent carbon atoms are fused to a pyridazine ring together with the atom connecting them (C ５ ~C ６ ) forms a carbocyclic ring, R4 and R5 together with the nitrogen atom to which they are attached represent a 3-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 2 to 6 carbon atoms, an 8- to 11-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, and containing 4 to 10 carbon atoms, or - 7-12 membered bicyclic heterocyclic spiro rings containing one nitrogen atom and optionally 1 to 3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 3 to 11 carbon atoms. Forming The monocyclic heterocycloalkyl ring, the bicyclic heterocycloalkyl ring, and the bicyclic heterocycloalkyl ring are unsubstituted or (C １ ~C ４ ) alkyl-group, NH ２ Group, Mono (C １ ~C ４ ) alkylamino-group, di(C １ ~C ４ ) alkylamino-group, NH ２ -(C １ ~C ４ ) alkyl-group, mono(C １ ~C ４ ) alkylamino-(C １ ~C ４ ) alkyl-group, di(C １ ~C ４ ) alkylamino-(C １ ~C ４ ) alkyl-group, NH ２ -(C ３ ~C ６ ) cycloalkyl-group, OH—(C ３ ~C ６ ) cycloalkyl-group, mono(C １ ~C ４ ) alkylamino-(C ３ ~C ６ ) cycloalkyl-group, di(C １ ~C ４ ) alkylamino-(C ３ ~C ６ ) cycloalkyl-group, (C ２ ~C ５ ) acylamino-(C １ ~C ４ ) alkyl-groups, (C ２ ~C ５ ) acylamino-group, (C ２ ~C ５ ) acyl group, hydroxy-(C １ ~C ４ ) alkyl-group, SH—(C １ ~C ４ ) alkyl-group, CN—(C １ ~C ４ ) alkyl-groups, (C １ ~C ４ ) alkoxy-(C １ ~C ４ ) alkyl group, hydroxyl group, oxo group, (C ３ ~C ６ ) cycloalkyl group, halogen atom, halo(C １ ~C ４ ) alkyl group, cyano group, NH ２ -C(=O)- group, mono(C １ ~C ４ ) alkylamino-C(=O)- group, di(C １ ~C ４ ) alkylamino-C(=O)- group, NH ２ -C(=O)-(C １ ~C ４ ) alkyl-group, mono(C １ ~C ４ ) alkylamino-C(═O)—(C １ ~C ４ ) alkyl-group, di(C １ ~C ４ ) alkylamino-C(═O)—(C １ ~C ４ ) an alkyl group or —CO ２ substituted by 1 to 2 substituents independently selected from H groups; A compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. 2. A compound of formula (I) according to claim 1, wherein n is 1, or a pharmaceutically acceptable salt thereof.

3. 2. The compound of formula (I) according to claim 1, wherein n is 2, or a pharmaceutically acceptable salt thereof.

4. R1 are each independently a halogen atom, (C １ ~C ４ ) alkyl group, (C １ ~C ４ ) alkoxy group, halo (C １ ~C ４ ) an alkoxy group, (C ３ ~C ６ ) a cycloalkyl group, 【Transformation 6】 wherein R6 is a hydrogen atom or a methyl group, and 【Transformation 7】 represents the point of attachment between the carbon atom and the phenyl ring) or halo (C １ ~C ４ ) alkyl group, and in particular, R1 independently represents a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, a trifluoromethoxy group, a cyclopropyl group, or —CHF ２ represents a group, an ethynyl group, or a trifluoromethyl group, or two R1 on adjacent carbon atoms together with the atom connecting them form a cyclopentane ring fused to the phenol group, in particular, these two R1 are of the formula 【Transformation 8】 A group of the formula (wherein the symbol 【Chemistry 9】 represents the bonding site between the carbon atom of the phenol ring and the carbon atom of the pyridazine ring), A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. when n is 1, R1 is in the ortho, meta or para position on the phenyl relative to the pyridazine ring, or when n is 2, the two R1's are in the ortho and para positions on the phenyl relative to the pyridazine ring, or when n is 2, the two R1's are in the ortho and meta positions on the phenyl relative to the pyridazine ring; A compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R2 and R3 are independently a hydrogen atom, a cyano group, a halo(C １ ~C ４ ) alkyl group, hydroxy (C １ ~C ４ ) alkyl group or (C １ ~C ４ ) represents an alkyl group, In particular, R2 and R3 are each independently a hydrogen atom, a cyano group, -CHF ２ group, trifluoromethyl group, —CH ２ represents an OH group, a methyl group, an ethyl group or an isopropyl group, A compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R2 and R3 on adjacent carbon atoms are fused to the pyridazine ring together with the atom connecting them (C ５ ~C ６ ) form a carbocyclic ring, in particular R2 and R3 on adjacent carbon atoms together with the atom connecting them form a cyclopentyl ring fused to the pyridazine ring; A compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. R4 and R5 together with the nitrogen atom to which they are attached represent a 4-7 membered monocyclic heterocycloalkyl ring containing one nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur atoms and containing 3 to 6 carbon atoms, an 8- to 10-membered bicyclic heterocycloalkyl ring containing one nitrogen atom and optionally one or two additional heteroatoms independently selected from nitrogen, oxygen and sulfur atoms and containing 6, 7, 8 or 9 carbon atoms, or - 7-10 or 12-membered bicyclic heterocyclic spiro rings containing one nitrogen atom and optionally 1 to 3 additional heteroatoms selected from nitrogen, oxygen and sulfur atoms, and containing 5 to 8 carbon atoms. Forming The monocyclic heterocycloalkyl ring, bicyclic heterocycloalkyl ring, and bicyclic heterocyclic spiro ring are unsubstituted or １ ~C ４ ) alkyl-group, NH ２ Group, Mono (C １ ~C ４ ) alkylamino-group, di(C １ ~C ４ ) alkylamino-group, NH ２ -(C １ ~C ４ ) alkyl-group, mono(C １ ~C ４ ) alkylamino-(C １ ~C ４ ) alkyl-group, di(C １ ~C ４ ) alkylamino-(C １ ~C ４ ) alkyl-group, NH ２ -(C ３ ~C ６ ) cycloalkyl-group, (C ２ ~C ５ ) acylamino-(C １ ~C ４ ) alkyl-groups, (C ２ ~C ５ ) acylamino-group, (C ２ ~C ５ ) acyl group, hydroxy-(C １ ~C ４ ) alkyl-group, SH—(C １ ~C ４ ) alkyl-group; CN—(C １ ~C ４ ) alkyl-groups, (C １ ~C ４ ) alkoxy-(C １ ~C ４ ) alkyl group, hydroxyl group, oxo group, (C ３ ~C ６ ) cycloalkyl group, halogen atom, halo(C １ ~C ４ ) alkyl group, cyano group, NH ２ -C(=O)- group, mono(C １ ~C ４ ) alkylamino-C(=O)- group, di(C １ ~C ４ ) alkylamino-C(=O)- group, NH ２ -C(=O)-(C １ ~C ４ ) alkyl-group, mono(C １ ~C ４ ) alkylamino-C(═O)—(C １ ~C ４ ) alkyl-group, or di(C １ ~C ４ ) alkylamino-C(═O)—(C １ ~C ４ ) substituted by 1 to 2 substituents independently selected from alkyl- groups; In particular, R4 and R5 together with the nitrogen atom to which they are attached represent: unsubstituted or containing one OH—CH ２ an azepanyl ring substituted with an - group; unsubstituted or methyl group, CH ２ F-group, NH ２ -CH ２ - group, N(CH ３ ) ２ -CH ２ - group, CH ３ -NH-(CH ２ ) ２ - group, SH-CH ２ - group, CN-CH ２ - group, OH-CH ２ - group, OH-CD ２ - group, OH-(CH ２ ) ２ - group, OH-C(CH ３ ) ２ - group, CH ３ -CH(OH)- group, CH ３ -C(=O)-NH-CH ２ - group, CH ３ -C(=O)-NH-CH ２ -CH ２ - group CH(CH ３ ) ２ -C(=O)-NH-CH ２ - group, NH ２ -C(=O)- group, NH(CH ３ )-C(=O)- group, N(CH ３ ) ２ -C(=O)- group, NH ２ -cyclopropyl- group, NH ２ —C(═O)—CH ２ - group, NH(CH ３ )-C(=O)-CH ２ - group, N(CH ３ ) ２ —C(═O)—CH ２ - group, CH ３ -CH ２ -C(=O)- group, oxo group, and CH ３ -O-CH ２ a morpholino ring substituted with one or two substituents independently selected from the - group; a thiomorpholino ring that is unsubstituted or substituted by one to two oxo groups; - unsubstituted or NH ２ Group, NH ２ -CH ２ - group, NH(CH ２ CH ３ )-group, N(CH ３ ) ２ - group, NH ２ -cyclopropyl- group, N(CH ３ ) ２ -CH ２ - group, OH-CH ２ - group, CH ３ -C(=O)-NH-CH ２ a piperidinyl ring substituted with 1 to 2 substituents independently selected from a - group, a cyano group, a hydroxyl group, an oxo group, and a fluorine atom; - unsubstituted or NH ２ - group, NH ２ -CH ２ - group, N(CH ３ ) ２ -CH ２ - group, OH-CH ２ - group, CH ３ -O-CH ２ a pyrrolidinyl ring substituted with 1 to 2 substituents independently selected from -, hydroxyl, and oxo groups; an isoxazolidinyl ring which is unsubstituted or substituted by one hydroxyl group, unsubstituted or substituted with methyl, oxo and OH—CH ２ a piperazinyl ring substituted with 1 to 2 substituents independently selected from the - group; a hexahydropyrimidinyl ring substituted by one oxo group; unsubstituted or containing one OH—CH ２ an azetidinyl ring substituted with an - group; a dihydroquinolinyl ring which is unsubstituted or substituted by one hydroxyl group, for example a tetrahydroquinolinyl ring or a 3,4-dihydro-2H-quinolinyl ring, a hexahydropyridoxazinyl ring, such as a hexahydro-2H-pyrido[3,4-b][1,4]oxazinyl ring, for example a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazinyl group, or a hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl ring, for example a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl ring, for example a 3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazinyl ring, which is unsubstituted or substituted by one cyclobutyl group, one methyl group, one ethyl group, one 2,2,2-trifluoroethyl group, one 2-fluoroethyl group, one 3-fluoropropyl group, one isopropyl group or one acetyl group; unsubstituted hexahydropyranooxazinyl rings, such as hexahydro-2H-pyrano[3,4-b][1,4]oxazinyl rings, for example 3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazinyl groups, or for example hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl rings, for example 3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazinyl rings; unsubstituted dihydropyridoxazinyl rings, such as dihydropyrido[3,4-b][1,4]oxazinyl or dihydropyrido[4,3-b][1,4]oxazinyl rings, for example 2,3-dihydropyrido[3,4-b][1,4]oxazinyl or 2,3-dihydropyrido[4,3-b][1,4]oxazinyl rings; unsubstituted dihydropyrazolooxazinyl rings, such as dihydro-2H-pyrazolo[4,3-b][1,4]oxazinyl rings, such as 5,6-dihydro-2H-pyrazolo[4,3-b][1,4]oxazinyl rings; a dihydrobenzoxazinyl ring substituted by one hydroxyl group, such as a dihydro-1,4-benzoxazinyl ring, such as a 2,3-dihydro-1,4-benzoxazinyl ring; a dihydronaphthyridinyl ring substituted by one hydroxyl group, such as a tetrahydronaphthyridinyl ring or a 3,4-dihydro-2H-1,6-naphthyridinyl ring; hexahydronaphthyridinyl rings, such as hexahydro-2H-1,7-naphthyridinyl rings, for example 3,4,4a,5,6,8a-hexahydro-2H-1,7-naphthyridinyl rings substituted by one methyl group and one oxo group; an octahydronaphthyridinyl ring, such as an octahydro-1,7-naphthyridinyl ring or an octahydro-1,5-naphthyridinyl ring, substituted by one oxo group, one methyl group or one acetyl group, such as a 2,3,4,4a,5,6,7,8a-octahydro-1,7-naphthyridinyl ring, a 2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridinyl ring or a 2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridinyl ring; an octahydropyrrolopyridinyl or hexahydropyrrolopyridinyl ring, which is unsubstituted or substituted by one methyl group, one ethyl group, one acetyl group, one isopropyl group or one oxo group, such as a hexahydro-1H-pyrrolo[3,4-c]pyridinyl ring, an octahydropyrrolo[2,3-c]pyridinyl ring or a hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring, such as a 2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridinyl ring, a 2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridinyl ring or a 3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridinyl ring; an octahydropyrrolooxazinyl or hexahydropyrrolooxazinyl ring, which is unsubstituted or substituted by one methyl group, one ethyl group or one acetyl group, such as a hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring, for example a 2,3,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring, a 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring or a 3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl ring; a hexahydrocyclopentaoxazinyl ring substituted by one hydroxyl group, such as a 3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazinyl ring; unsubstituted octahydropyrido[4,3-b][1,4]oxazinyl ring, for example an octahydropyridoxazinyl ring such as a 2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazinyl ring; - one hydroxyl group or one -CH ２ an indolinyl ring substituted with an OH group; a hexahydropyrrolopyrrolyl ring, such as a hexahydropyrrolo[3,4-b]pyrrolyl ring, a hexahydro-1H-pyrrolo[3,2-b]pyrrolyl ring or a hexahydro-2H-pyrrolo[3,4-b]pyrrolyl ring, which is unsubstituted or substituted by one methyl group, one ethyl group or one acetyl group, such as a 2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrolyl ring, a 2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrolyl ring or a 3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrolyl ring; unsubstituted hexahydrofuro[3,4-c]pyrrolyl rings, for example hexahydrofuropyrrolyl rings such as 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrolyl rings; an azabicyclooctanyl ring, such as a 6-azabicyclo[3.2.1]octanyl ring, substituted with one hydroxyl group; a diazabicyclononanyl ring, such as a 3,6-diazabicyclo[3.2.2]nonanyl ring, substituted with one methyl group; an unsubstituted oxazabicyclooctanyl ring, for example a 3-oxa-8-azabicyclo[3.2.1]octanyl ring; - unsubstituted or NH ２ Group, CH ３ an azaspironanyl ring, such as an azaspiro[3.5]nonanyl ring, substituted with one substituent selected from a —C(═O)—NH— group and a hydroxyl group; an azaspirooctanyl ring, such as an azaspiro[3.4]octanyl ring, which is unsubstituted or substituted by one hydroxyl group; an azaspiroheptanyl ring, such as an azaspiro[3.3]heptanyl ring, which is unsubstituted or substituted by one hydroxyl group; a diazaspirodecanyl ring, such as a 1,9-diazaspiro[4.5]decanyl ring, substituted with one methyl group; a diazaspirononanyl ring, such as a diazaspiro[3.5]nonanyl ring, which is unsubstituted or substituted by one methyl group; a diazaspiroheptanyl ring, such as a diazaspiro[3.3]heptanyl ring, which is unsubstituted or substituted by one methyl group, an oxadiazaspirononanyl ring, such as an 8-oxa-2,5-diazaspiro[3.5]nonanyl ring substituted by one methyl group; an oxadiazaspirodecanyl ring, such as a 2-oxa-6,9-diazaspiro[4.5]decanyl ring, a 9-oxa-2,6-diazaspiro[4.5]decanyl ring or a 6-oxa-2,9-diazaspiro[4.5]decanyl ring, which is unsubstituted or substituted by one ethyl group or one methyl group; an oxadiazaspirondecanyl ring substituted by one methyl group, for example a 4-oxa-1,8-diazaspiro[5.5]undecanyl ring; a dioxadiazaspirododecanyl ring substituted with one ethyl group, for example a 1,11-dioxa-4,8-diazaspiro[5.6]dodecanyl ring; an oxazaspirononanyl ring, such as an oxazaspiro[3.5]nonanyl ring; and - an oxazaspiroheptanyl ring, such as an oxazaspiro[3.3]heptanyl ring Forming A compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

9. The compound is selected from the group consisting of: (1) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidin-4-ol; (2) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidine-4-carbonitrile; (3) 7-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-ol; (4) 3,5-dimethyl-2-[6-[rac-(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol; (5) 2-[6-[(3R)-3-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (6) 2-[6-[(3S)-3-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (7) 2-[6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid; (8) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (9) 2-[6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (10) 2-[6-[(4aR,8aS)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol enantiomer 1; (11) 2-[6-[(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; formic acid enantiomer 2; (12) 2-[6-[(4aR,8aS)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 1; (13) 2-[6-[(4aS,8aR)-6-cyclobutyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 2; (14) 2-[6-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (15) 2-[6-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (16) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (17) 2-[6-[3-(1-aminocyclopropyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (18) 2-[6-[(3S)-3-(aminomethyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (19) 2-[6-[4-(aminomethyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (20) 2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (21) 3,5-dichloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (22) 2-[6-[(3R)-3-(aminomethyl)-1-piperidyl]pyridazin-3-yl]-3,5-dichloro-phenol; (23) 2-[6-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dichloro-phenol; (24) 2-[6-[2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (25) 2-[6-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dichloro-phenol; (26) 2-[6-[2-(1-hydroxy-1-methyl-ethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (27) 2-[6-[(2R)-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (28) 2-[6-[(3S)-3-(hydroxymethyl)-1-piperidyl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (29) 3-methyl-2-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (30) 2-[6-[3-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (31) 2-[6-[(3R)-3-amino-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; Formic acid; (32) 2-[6-(2-amino-7-azaspiro[3.5]nonan-7-yl)pyridazin-3-yl]-3,5-dichlorophenol; (33) 3,5-dichloro-2-[6-[(2R)-2-(methoxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (34) 3,5-dichloro-2-[6-[(3S)-3-(hydroxymethyl)-1-piperidyl]pyridazin-3-yl]phenol; (35) 3,5-dichloro-2-[6-[(2S)-2-(methoxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (36) 3,5-dichloro-2-[6-[(3R)-3-(hydroxymethyl)-1-piperidyl]pyridazin-3-yl]phenol; (37) 7-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-ol; (38) 3,5-dichloro-2-(6-morpholinopyridazin-3-yl)phenol; (39) 3,5-dichloro-2-[6-[(2S)-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]phenol; (40) 3,5-dichloro-2-[6-[(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl]pyridazin-3-yl]phenol; (41) 3,5-dichloro-2-[6-[(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl]pyridazin-3-yl]phenol; (42) 6-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-6-azaspiro[3.4]octan-2-ol; (43) 3,5-dichloro-2-[6-[(2R)-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]phenol; (44) 3-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (45) 3-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (46) 2-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-2-azaspiro[3.3]heptan-6-ol; (47) N-[7-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-7-azaspiro[3.5]nonan-2-yl]acetamide; (48) 3-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (49) 3,5-dichloro-2-[6-(4,4-difluoro-1-piperidyl)pyridazin-3-yl]phenol; (50) 3,5-dichloro-2-[6-[(3R)-3-[(dimethylamino)methyl]-1-piperidyl]pyridazin-3-yl]phenol; (51) 3,5-dichloro-2-[6-[(3S)-3-[(dimethylamino)methyl]-1-piperidyl]pyridazin-3-yl]phenol; (52) 2-[6-[2-(1-hydroxy-1-methyl-ethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 1; (53) 2-[6-[-2-(1-hydroxy-1-methyl-ethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 2; (54) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (55) 3,5-dichloro-2-[6-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridazin-3-yl]phenol; (56) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (57) N-[[(3R)-1-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (58) N-[[(3S)-1-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (59) 2-[6-[-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 1; (60) 2-[6-[-2-[(dimethylamino)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol enantiomer 2; (61) 1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (62) (4S)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (63) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (64) 3,5-dichloro-2-[6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazin-3-yl]phenol; (65) 2-[6-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (66) 3,5-dichloro-2-[6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridazin-3-yl]phenol; (67) (3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]piperidin-3-ol; (68) 2-[6-[(3S)-3-(ethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (69) 2-[6-[(3S)-3-amino-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (70) (3R)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-3-ol; (71) (3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-3-ol; (72) 2-[4-ethyl-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (73) 5-chloro-2-[4-ethyl-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (74) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-isopropyl-pyridazin-3-yl]-5-methyl-phenol; (75) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-isopropyl-pyridazin-3-yl]phenol; (76) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (77) 2-[4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl]-5-methyl-phenol; (78) 5-chloro-2-[4-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl]phenol; (79) 2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (80) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4,5-dimethyl-pyridazin-3-yl]-5-methyl-phenol; (81) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4,5-dimethyl-pyridazin-3-yl]phenol; (82) 2-[6-[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (83) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.5]nonan-7-ol; (84) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.4]octan-6-ol; (85) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]phenol; (86) (4S)-4-hydroxy-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-2-one; (87) 2-[6-[(2R)-2-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid; (88) 2-[6-[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (89) 2-[6-[(2R)-2-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; 2,2,2-trifluoroacetic acid; (90) 6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3-(2-hydroxy-4-methyl-phenyl)pyridazine-4-carbonitrile; (91) 3,5-dimethyl-2-[6-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridazin-3-yl]phenol; (92) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (93) 5-fluoro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]phenol; (94) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.4]octan-6-ol enantiomer 1; (95) 2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2-azaspiro[3.4]octan-6-ol enantiomer 2; (96) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methoxy-3-methyl-phenol; (97) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (98) 2-[6-[2-[(1S)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol diastereoisomer 2; (99) 2-[6-[2-[(1S)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol diastereoisomer 1; (102) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-4-methyl-phenol; (103) 3-(4-chloro-2-hydroxy-phenyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile; (105) N-[[(2S)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (106) N-[[(2R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (107) 2-[6-[3-(hydroxymethyl)azepan-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (108) 2-[6-[2-[(1R)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol diastereoisomer 1; (109) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-3,5-dimethyl-phenol; (110) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-5-methyl-phenol; (111) 2-[6-[rac-(4aS,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (112) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-3,5-dimethyl-phenol; (113) (4R)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]isoxazolidin-4-ol (114) 2-[6-[1-(hydroxymethyl)-6-azabicyclo[3.2.1]octan-6-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (115) 2-[6-[(2S)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (116) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methoxy-phenol; (117) 3,5-dichloro-2-[6-[(2S)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]phenol; (118) 2-[6-[(2R)-2-(hydroxymethyl)azetidin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (119) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methoxy-3-methyl-phenol; (120) 3,5-dimethyl-2-[6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-yl]phenol; (121) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethoxy)phenol; (122) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3-(hydroxymethyl)pyrrolidin-2-one; (123) 2-[6-[(3R)-3-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol, 2,2,2-trifluoroacetic acid; (124) 2-[6-[(3S)-3-(aminomethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (125) 2-[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol; (126) 1-[4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one; (127) 5-chloro-2-[6-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (128) 2-[6-[(3S)-3-(dimethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (129) N-[[(3R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]morpholin-3-yl]methyl]acetamide; (130) (4S)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-4-hydroxy-pyrrolidin-2-one; (131) (4S)-4-amino-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]pyrrolidin-2-one; (132) (4R)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (133) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-5-methyl-pyridazin-3-yl]-3-methyl-phenol; (134) 5-(difluoromethyl)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (135) 2-[6-[(2S)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (136) 2-[6-[(2R)-2-(1-aminocyclopropyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (137) (4R)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-4-(hydroxymethyl)pyrrolidin-2-one; (138) (4S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-4-(hydroxymethyl)pyrrolidin-2-one; (139) (3R)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3-(hydroxymethyl)pyrrolidin-2-one; (140) (3S)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3-(hydroxymethyl)pyrrolidin-2-one; (141) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,6-dimethylphenol; (142) 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide; (143) 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N-methylacetamide; (144) 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (145) 5-chloro-2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (146) 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetamide; (147) 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]acetamide; (148) 2-[6-[(3R)-3-(dimethylamino)-1-piperidyl]pyridazin-3-yl]-3,5-dimethyl-phenol; (149) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-3-methyl-phenol; (150) 2-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N,N-dimethylacetamide; (151) 2-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]-N,N-dimethylacetamide; (152) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-4,6-dimethylphenol; (153) 3-(difluoromethyl)-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (154) 3,5-dimethyl-2-[6-[rac-(4aR,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[3,4-b][1,4]oxazin-1-yl]pyridazin-3-yl]phenol; (155) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (156) 1-[(2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one; (157) 1-[(2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholin-2-yl]propan-1-one; (158) 6-(2-hydroxy-4,6-dimethyl-phenyl)-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile; (159) 3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazine-4-carbonitrile; (160) 5-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)pyridazin-3-yl]phenol; (161) 3,5-dichloro-2-[6-[2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (162) 4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2,3-dihydro-1,4-benzoxazin-6-ol; (163) 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazine-4-carbonitrile; (164) N-[[(3S)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (165) 2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol; (166) (2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N-methylmorpholine-2-carboxamide; (167) N-[[(3R)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (168) 2-[6-[(4aR,7aR)-4-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol; (169) 5-chloro-2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methylphenol; (170) 2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (171) 5-chloro-2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (172) 3-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-phenol; (173) 2-[6-[(2R,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (174) 2-[6-[2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (175) 6-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomer 1; (176) 6-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-azaspiro[3.5]nonan-2-ol isomer 2; (177) 3-chloro-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (178) 2-[6-[(2R,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (179) (4S)-2-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]isoxazolidin-4-ol; (180) 2-[6-[2-[(1R)-1-hydroxyethyl]morpholin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol diastereoisomer 2; (181) (2S)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholine-2-carboxamide; (182) (2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N-methylmorpholine-2-carboxamide; (183) (2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]morpholine-2-carboxamide; (184) (2R)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-N,N-dimethylmorpholine-2-carboxamide; (185) 2-[6-[(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyridazin-3-yl]-3,5-dimethylphenol; (186) 2-[4-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (187) 2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (188) 5-chloro-2-[4-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (189) 5-chloro-2-[5-(hydroxymethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (190) 2-[6-[rac-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethylphenol; (191) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,4-dimethylphenol; (192) 2-[6-[(2S)-2-[dideuterio(hydroxy)methyl]morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (193) 4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-2,3-dihydro-1,4-benzoxazin-7-ol; (194) 2-[5-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (195) 2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (196) 3,5-dimethyl-2-[6-(2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]phenol; (197) 2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (198) 2-[6-[(2S,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (199) 2-[6-[(2S,6S)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (200) 2-[6-[(2R,6R)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (201) 2-[6-[(2R,6R)-2,6-bis(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (203) 3,5-dichloro-2-(6-thiomorpholinopyridazin-3-yl)phenol; (204) 5-cyclopropyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (206) 2-[6-[(3aS,6aR)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (207) 2-[6-[(3aR,6aR)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (208) 2-[6-(8-ethyl-1,11-dioxa-4,8-diazaspiro[5.6]dodecan-4-yl)pyridazin-3-yl]-3,5-dimethylphenol; (209) 2-[6-[rac-(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (210) 2-[6-[rac-(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (211) N-[[(3S)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (212) N-[[(3R)-1-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3-piperidyl]methyl]acetamide; (213) 1-[rac-(4aR,8aS)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (214) 1-[rac-(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (215) 2-[6-(2,3-dihydropyrido[3,4-b][1,4]oxazin-1-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; (216) N-[[(2R)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (217) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-7-ol; (219) 2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (220) 2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (221) 2-[6-[rac-(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (222) 1-[rac-(4aR,8aS)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (223) 2-[6-[rac-(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (224) 2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (225) 2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (226) 2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (227) 2-[6-(6-ethyl-2-oxa-6,9-diazaspiro[4.5]decan-9-yl)pyridazin-3-yl]-3,5-dimethylphenol; (228) 1-[rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-5-yl]ethanone; (229) 2-[6-[rac-(3aS,6aS)-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (230) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-6-ol; (231) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-8-ol; (232) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-quinolin-5-ol; (233) 2-[6-[(2R)-2-(2-hydroxyethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (234) 2-[6-[(2S)-2-(2-hydroxyethyl)morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (235) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-5-(hydroxymethyl)piperidin-2-one; (236) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-5-ol; (237) 3,5-dichloro-2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (238) 3,5-dichloro-2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (239) 1-[6-(2,4-dichloro-6-hydroxy-phenyl)pyridazin-3-yl]hexahydropyrimidin-2-one; (240) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-4-ol; (241) 2-[6-[4-(hydroxymethyl)indolin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (242) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4-dihydro-2H-1,6-naphthyridin-5-ol; (243) 2-[6-[rac-(3aS,6aS)-5-ethyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (245) 5-ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methylphenol; (246) 3-ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methylphenol; (247) 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (248) 2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (249) 5-chloro-2-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (250) (4S)-4-amino-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (251) 2-[6-[(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (252) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (253) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-7-ol; (254) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]indolin-6-ol; (255) 2-[6-[(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (256) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (257) 1-[rac-(4aS,7aS)-4-[6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (258) 3-methyl-2-[6-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (259) 3-methyl-2-[6-[(2S)-2-methylmorpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (260) 2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (261) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (262) 1-[(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (263) 1-[(4aS,8aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (264) rac-(3aS,7aR)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one, hydrochloride; (265) 2-[6-[rac-(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (266) 2-[6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (267) N-[[(2R)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (268) 2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (269) rac-(3aS,7aS)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,6,7,7a-hexahydro-1H-pyrrolo[3,4-c]pyridin-4-one, hydrochloride; (270) 2-[6-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (271) 2-[6-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (272) 2-[6-(3,4-dihydro-2H-quinolin-1-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; (273) 3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (274) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-isopropyl-3-methyl-phenol; (275) N-[[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]methyl]acetamide; (276) N-[[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]methyl]-2-methylpropanamide; (277) N-[2-[(2R)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]ethyl]acetamide; (278) N-[2-[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]ethyl]acetamide; (279) N-[[(2R)-4-[6-(4-chloro-2-hydroxy-6-methylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]-2-methylpropanamide; and (280) N-[[(2S)-4-[6-(4-chloro-2-hydroxy-6-methylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]acetamide. (283) 2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (284) 2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (285) N-[[(2S)-4-[6-(4-chloro-2-hydroxy-6-methylphenyl)pyridazin-3-yl]morpholin-2-yl]methyl]-2-methylpropanamide; (286) (4S)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (287) (3R)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (288) (3S)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (289) 3-methyl-2-[6-[rac-(4aR,7aR)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (290) (4aR,8aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-7-methyl-3,4,4a,5,6,8a-hexahydro-2H-1,7-naphthyridin-8-one; (291) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-(difluoromethyl)pyridazin-3-yl]-3,5-dimethyl-phenol; (292) (4R)-4-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (293) (4S)-4-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (295) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (296) 2-[6-[(2S,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (297) 2-[6-[(2S,6S)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (298) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (299) 2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (300) 1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-2,3,4,4a,5,6,7,8a-octahydro-1,7-naphthyridin-8-one; (301) 2-[6-[(4aR,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (302) 2-[6-[(2R,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (303) 3,5-dimethyl-2-[6-[(2S)-2-(sulfanylmethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (304) 1-[rac-(4aR,8aS)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (305) 3,5-dimethyl-2-[6-[(2R)-2-(sulfanylmethyl)morpholin-4-yl]pyridazin-3-yl]phenol; (306) 2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (307) 5-chloro-3-methyl-2-[6-[rac-(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol; (308) 2-[6-[(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (309) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (310) 2-[6-[(4aR,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (311) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (312) 2-[6-[(4aR,8aS)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (313) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (314) 2-[6-[(4aR,8aS)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (315) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (316) (4R)-4-hydroxy-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]piperidin-2-one; (317) 2-[6-(4-ethyl-1,11-dioxa-4,8-diazaspiro[5.6]dodecan-8-yl)pyridazin-3-yl]-3,5-dimethylphenol; (318) 3-methyl-2-[6-[rac-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; hydrochloride; (320) 3-methyl-2-[6-[rac-(4aR,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; hydrochloride; (321) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (322) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (323) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (324) 5-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-methyl-pyridazin-3-yl]indan-4-ol; (325) (3R)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (326) (3S)-3-(hydroxymethyl)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]pyrrolidin-2-one; (327) 2-[(2R)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]acetonitrile; (328) 2-[(2S)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-2-yl]acetonitrile; (329) (6R)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-(hydroxymethyl)piperazin-2-one; (330) (6S)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-6-(hydroxymethyl)piperazin-2-one; (331) 3-methyl-2-[6-[(2R)-2-[2-(methylamino)ethyl]morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (332) 3-methyl-2-[6-[(2S)-2-[2-(methylamino)ethyl]morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (333) 2-[6-[(4aR,7aS)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (334) 2-[6-[(4aS,7aR)-6-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (335) 1-[rac-(4aR,7aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (336) 1-[(4aR,8aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (337) 1-[rac-(4aR,7aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (338) 5-chloro-2-[6-[(2R)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (339) 5-chloro-2-[6-[(2S)-2-(fluoromethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (340) 2-[6-[(rac-3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (341) 2-[6-[(rac-3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (342) 3,5-dimethyl-2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]phenol; (343) 2-[6-[(4aS,8aS)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (344) 2-[6-[(4aR,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (345) 5-[4-(difluoromethyl)-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]indan-4-ol; (346) 3-Methyl-2-[6-[rac-(3aS,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; hydrochloride; (348) 1-[(4aR,7aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (349) 1-[(4aS,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (350) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (351) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-6-fluoro-phenol; (352) 1-[(4aS,7aR)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]ethanone; (353) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-6-fluoro-3-methyl-phenol; (354) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (355) 2-[6-[(4aS,8aR)-6-(2,2,2-trifluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (356) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-6-fluoro-phenol; (357) 1-[(4aS,8aR)-4-[6-(4-chloro-2-hydroxy-phenyl)-5-methyl-pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (358) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-phenol; (359) 2-[6-[(2S,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (360) 2-[6-(5,6-dihydro-2H-pyrazolo[4,3-b][1,4]oxazin-7-yl)pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (361) 3-methyl-2-[6-[rac-(4aR,7aS)-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (362) 2-[6-(2,3-dihydropyrido[4,3-b][1,4]oxazin-4-yl)pyridazin-3-yl]-3,5-dimethyl-phenol; (363) 1-[(4aS,8aR)-4-[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (364) 2-[6-[rac-(3aS,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (365) 2-[6-[(2R,6R)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (366) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (367) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (368) 2-(hydroxymethyl)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-3-one; (369) 1-[(3aR,7aR)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (370) 1-[(3aS,7aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (371) 2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (372) (4S)-1-[5-(difluoromethyl)-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-4-hydroxy-pyrrolidin-2-one; (373) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (374) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (375) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (376) 3-methyl-2-[6-[rac-(4aR,7aR)-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (377) 1-[rac-(3aS,6aS)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl]ethanone; (378) 2-[6-[rac-(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (379) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (380) 1-[(4aS,8aR)-4-[6-[2-ethyl-6-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (381) 1-[(4aS,8aR)-4-[6-(4-chloro-2-ethyl-6-hydroxy-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (382) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (383) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (384) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (385) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (386) 1-[(4aS,8aR)-4-[5-(difluoromethyl)-6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (387) 1-[(4aS,8aR)-4-[5-(difluoromethyl)-6-(2-hydroxy-4-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (388) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-phenol; (389) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (390) 2-[6-[(2S,6S)-2-(hydroxymethyl)-6-methyl-morpholin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (391) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (392) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (393) 2-[6-[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (394) 1-[(3aR,7aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (395) 1-[(3aR,7aR)-1-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (397) 1-[(4aS,8aR)-4-[6-(4-chloro-2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (398) 1-[(4aR,8aS)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (399) 3,5-dichloro-2-[6-(1,1-dioxo-1,4-thiazin-4-yl)pyridazin-3-yl]phenol; (400) 3,5-dichloro-2-[6-(1-oxo-1,4-thiazinan-4-yl)pyridazin-3-yl]phenol; (402) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (403) 3,5-dimethyl-2-[6-[rac-(4aS,8aR)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol; (404) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (405) 1-[(4aS,8aR)-4-[4-(difluoromethyl)-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (406) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (407) 2-[6-[(3aS,7aR)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (408) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-phenol; (409) 1-[(4aS,8aR)-4-[6-(2-hydroxy-6-methyl-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (410) 3,5-dimethyl-2-[6-(3-methyl-3,6-diazabicyclo[3.2.2]nonan-6-yl)pyridazin-3-yl]phenol; (411) 2-[6-[(4aS,8aR)-2,3,4a,5,6,7,8,8a-octahydropyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (412) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (413) 1-[(3aR,7aR)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (414) 1-[(3aS,7aS)-1-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (415) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (416) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (417) 3-methyl-2-[6-(3-methyl-3,6-diazabicyclo[3.2.2]nonan-6-yl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (418) 3-ethyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (419) (2S)-2-(hydroxymethyl)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-3-one; (420) (2R)-2-(hydroxymethyl)-4-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]morpholin-3-one; (421) 3,5-dimethyl-2-[6-[rac-(4aS,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]phenol; (422) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-phenol; (423) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-phenol; (424) 1-[(4aS,8aR)-4-[6-(2-ethyl-6-hydroxy-phenyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (425) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-(difluoromethyl)pyridazin-3-yl]-3-ethyl-phenol; (426) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (427) 2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (428) 3,5-dimethyl-2-[6-(9-methyl-1,9-diazaspiro[4.5]decan-1-yl)pyridazin-3-yl]phenol; (429) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (430) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (431) 1-[(4aS,8aR)-4-[6-(2-hydroxy-4-methyl-phenyl)-5-methyl-pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (432) 2-[6-[(4aS,8aR)-6-isopropyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-phenol; (433) 2-[6-[(4aS,8aR)-6-isopropyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (434) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-methyl-pyridazin-3-yl]-3,5-dimethyl-phenol; (435) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (436) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (437) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (438) 3-methyl-2-[6-[rac-(4aS,8aR)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (439) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-5-methyl-pyridazin-3-yl]-3-ethyl-phenol; (440) 3,5-dimethyl-2-[6-(9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl]phenol; (441) 3,5-dimethyl-2-[6-(1-methyl-4-oxa-1,8-diazaspiro[5.5]undecan-8-yl)pyridazin-3-yl]phenol; (442) 1-[(4aS,8aR)-4-[6-(4-chloro-2-hydroxy-phenyl)-5-(difluoromethyl)pyridazin-3-yl]-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6-yl]ethanone; (443) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-ethyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol; (444) 3,5-dimethyl-2-[6-(6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl]phenol; (445) 3,5-dimethyl-2-[6-[(5S)-9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (446) 3,5-dimethyl-2-[6-[(5R)-9-methyl-6-oxa-2,9-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (448) 3-methyl-2-[6-[rac-(4aS,8aS)-3,4a,5,7,8,8a-hexahydro-2H-pyrano[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (449) 3,5-dimethyl-2-[6-(8-methyl-4-oxa-1,8-diazaspiro[5.5]undecan-1-yl)pyridazin-3-yl]phenol; (450) 3,5-dimethyl-2-[6-[(5R)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (451) 3,5-dimethyl-2-[6-[(5S)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]pyridazin-3-yl]phenol; (452) 2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (455) 3,5-dimethyl-2-[6-(2-methyl-8-oxa-2,5-diazaspiro[3.5]nonan-5-yl)pyridazin-3-yl]phenol; (456) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (457) 1-[(3aR,7aR)-1-[6-(2-hydroxy-4-methyl-phenyl)-5-methyl-pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (458) 2-[6-[rac-(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (459) 2-[6-[rac-(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-methyl-phenol; (460) 2-[6-[rac-(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (461) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol; (462) 1-[(4aR,8aR)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]ethanone; (463) 1-[(4aS,8aS)-5-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]ethanone; (466) (4aS,6S,7aR)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazin-6-ol; (467) (4aR,6R,7aS)-4-[6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,4a,5,6,7,7a-hexahydro-2H-cyclopenta[b][1,4]oxazin-6-ol; (468) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (469) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-chloro-phenol; (470) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-ethyl-pyridazin-3-yl]-5-methyl-phenol; (471) 5-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]indan-4-ol; (472) 2-[6-[(4aS,8aR)-6-isopropyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (473) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-(trifluoromethyl)phenol; (474) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (475) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-5-methyl-phenol; (476) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-methyl-phenol; (477) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-methyl-phenol; (479) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-fluoro-phenol; (480) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]-4-methyl-pyridazin-3-yl]-5-fluoro-phenol; (481) 2-[6-[(4aS,8aR)-6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (482) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (483) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (484) 3-methyl-2-[6-[rac-(3aS,6aS)-1-methyl-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (485) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (486) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-(trifluoromethyl)phenol; (487) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-(difluoromethyl)pyridazin-3-yl]-3,5-dimethyl-phenol; (488) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-(difluoromethyl)pyridazin-3-yl]-3,5-dimethyl-phenol; (489) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (490) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (491) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (492) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-ethyl-5-(trifluoromethyl)phenol; (493) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol (494) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol; (496) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (497) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (498) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (499) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-methyl-phenol; (500) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (501) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-chloro-phenol; (502) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (503) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (504) 2-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (505) 2-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (506) 2-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (507) 2-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-(difluoromethyl)pyridazin-3-yl]-5-methyl-phenol; (508) 5-ethynyl-2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-3-methyl-phenol; (509) 2-[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; (510) 1-[(3aS,7aS)-1-[5-(difluoromethyl)-6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (511) 1-[(3aR,7aR)-1-[5-(difluoromethyl)-6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (512) 1-[(3aS,7aS)-1-[4-(difluoromethyl)-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (513) 1-[(3aR,7aR)-1-[4-(difluoromethyl)-6-(2-hydroxy-4,6-dimethyl-phenyl)pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (514) 1-[(3aR,7aR)-1-[6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-pyridazin-3-yl]-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-6-yl]ethanone; (515) 2-[6-[(4aS,8aS)-5-methyl-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (516) 2-[6-[(4aR,8aR)-5-methyl-2,3,4,4a,6,7,8,8a-octahydro-1,5-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (517) 2-[6-[(4aR,8aS)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (518) 2-[6-[(4aS,8aS)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (519) 2-[6-[(4aR,8aR)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (520) 2-[6-[(4aS,8aR)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (521) 2-[6-[(4aS,8aR)-6-(2-fluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; (522) 2-[6-[(4aS,8aR)-6-(2-fluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-methyl-phenol; (523) 2-[6-[(4aR,8aR)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (524) 2-[6-[(4aS,8aS)-7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-naphthyridin-1-yl]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (525) 2-[6-[(4aS,8aR)-6-(2-fluoroethyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-phenol; (526) 2-[6-[(4aS,8aR)-6-ethyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-5-chloro-3-ethyl-phenol; (527) 2-[6-[(4aS,8aR)-6-(3-fluoropropyl)-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl]pyridazin-3-yl]-3,5-dimethyl-phenol; and (528) 5-methyl-2-[4-methyl-6-[rac-(3aS,7aR)-6-isopropyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]phenol The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from:

10. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

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

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for use as an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome.

14. 10. The compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the prophylaxis and / or 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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