Cyclopyridazine derivatives

Abstract

The present invention addresses the problem of providing a pharmaceutical composition, in particular, a compound suitable for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases. The present inventors have completed the present invention by deeply studying the exploration of a compound having an NLRP3 inflammasome activation inhibitory effect and finding that a contracted ring pyridazine derivative has an NLRP3 inflammasome activation inhibitory effect. The contracted pyridazine derivative of the present invention is expected to be used as a prophylactic and / or therapeutic agent for inflammatory diseases and / or neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to a condensed pyridazine derivative or a salt thereof which has an inhibitory effect on NLRP3 inflammasome activation and can be expected to be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases. Background Art

[0002] An inflammasome is an intracellular aggregate of proteins caused by endogenous / exogenous alarm molecules, and it is a mechanism that amplifies the inflammatory response caused by the activation of caspase1 and the induction of activation or cell death caused by the cleavage of inflammatory cytokines IL-1β and IL-18. As recognition molecules for alarm molecules, various types are known, such as NLRP1, NLRP3, NLRC4, AIM2, etc. NLRP3 recognizes cellular stress caused by extracellular ATP molecules, toxins of pathogens, crystals of uric acid or cholesterol, abnormal aggregates of proteins, etc., and is activated.

[0003] As a disease caused by a gain-of-function mutation of NLRP3, Cryopyrin-associated periodic syndrome (CAPS) (Nature Genetics, Vol. 29, No. 3, pp. 301-305, 2001) is known. In addition, it has been reported that NLRP3 inflammasome activation or expression increases in various diseases such as gout (Arthritis Research and Therapy, Vol. 12, No. 2, Article No. 206, 2010), non-alcoholic steatohepatitis (Journal of Molecular Medicine, Vol. 92, No. 10, pp. 1069-1082, 2014), inflammatory bowel disease (Gut, Vol. 59, No. 9, pp. 1192-1100, 2010), Alzheimer's disease (Nature, Vol. 493, No. 7434, pp. 674-678, 2013), Parkinson's disease (PLoS ONE, Vol. 8, No. 1, Article No. e55375, 2013), amyotrophic lateral sclerosis (Inflammation, Vol. 41, No. 1, pp. 93-103, 2018), and multiple system atrophy (Journal of Neuropathology and Exprimental Neurology, Vol. 77, No. 11, pp. 1055-1065, 2018).

[0004] In addition, it is known that NLRP3 is activated by α-synuclein fibrils to promote the production of IL-1β from microglia; and in a mouse model of α-synucleinopathy induced by α-synuclein fibrils, functional improvement was observed by administering an NLRP3 inhibitor (Science Translational Medicine, Vol. 10, Article No. eaah4066, 2018).

[0005] Patent Document 1 discloses that the compound represented by the following formula has an NLRP3 inflammasome pathway inhibitory effect (notations in the formula refer to that publication).

[0006] [Chemical Formula 1]

[0007]

[0008] Patent Document 2 discloses that the compound represented by the following formula has an NLRP3 inflammasome activation inhibitory effect (notations in the formula refer to that publication).

[0009] [Chemical Formula 2]

[0010]

[0011] Patent Document 3 discloses that the compound represented by the following formula has an NLRP3 inhibitory effect (notations in the formula refer to that publication).

[0012] [Chemical Formula 3]

[0013]

[0014] Patent Document 4 discloses that the compound represented by the following formula has an NLRP3 inflammasome inhibitory effect (notations in the formula refer to that publication).

[0015] [Chemical Formula 4]

[0016]

[0017] Patent Document 5 discloses that the compound represented by the following formula has an NLRP3 inhibitory effect (notations in the formula refer to that publication).

[0018] [Chemical Formula 5]

[0019]

[0020] Patent Document 6 discloses that the compound represented by the following formula has an NLRP1 / 3 regulatory effect (notations in the formula refer to that publication).

[0021] [Chemical Formula 6]

[0022]

[0023] It is described in Patent Document 7 that the compound represented by the following formula has an NLRP3 inflammasome inhibitory effect (the notations in the formula refer to that publication).

[0024] [Chemical Formula 7]

[0025]

[0026] It is described in Patent Document 8 that the compound represented by the following formula has a splicing regulatory effect (the notations in the formula refer to that publication).

[0027] [Chemical Formula 8]

[0028]

[0029] It is described in Patent Document 9 that the compound represented by the following formula has a splicing regulatory effect (the notations in the formula refer to that publication).

[0030] [Chemical Formula 9]

[0031]

[0032] It is described in Patent Document 10 that the compound represented by the following formula has a splicing regulatory effect (the notations in the formula refer to that publication).

[0033] [Chemical Formula 10]

[0034]

[0035] It is described in Patent Document 11 that the compound represented by the following formula has a therapeutic effect on Huntington's disease (the notations in the formula refer to that publication).

[0036] [Chemical Formula 11]

[0037]

[0038] Prior Art Documents

[0039] Patent Documents

[0040] Patent Document 1: International Publication No. 2020 / 234715

[0041] Patent Document 2: International Publication No. 2021 / 193897

[0042] Patent Document 3: US Patent No. 11319319 Specification

[0043] Patent Document 4: International Publication No. 2022 / 135567

[0044] Patent Document 5: International Publication No. WO2019 / 008025

[0045] Patent Document 6: International Publication No. WO2017 / 184604

[0046] Patent Document 7: International Publication No. WO2018 / 015445

[0047] Patent Document 8: International Publication No. WO2022 / 060951

[0048] Patent Document 9: International Publication No. WO2022 / 060943

[0049] Patent Document 10: International Publication No. WO2020 / 190793

[0050] Patent Document 11: International Publication No. WO2020 / 005873 Summary of the Invention

[0051] Problems to be Solved by the Invention

[0052] Provided is a pharmaceutical composition, particularly a compound that has an inhibitory effect on NLRP3 inflammasome activation and can be expected to be used as an active ingredient of a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases, etc.

[0053] Means for Solving the Problems

[0054] The inventors of the present invention conducted in-depth research on compounds having an inhibitory effect on NLRP3 inflammasome activation, and as a result, found that condensed pyridazine derivatives have an inhibitory effect on NLRP3 inflammasome activation and can be expected to be used as an active ingredient of a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases, etc., thereby completing the present invention.

[0055] That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more excipients.

[0056] [Chemical Formula 12]

[0057]

[0058] (In the formula, ring A is a 5- to 7-membered nitrogen-containing partially unsaturated heterocycle,

[0059] R 1a and R 1b are each independently H, C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, C 3-6Cycloalkyl, -OC 3-6 Cycloalkyl or halogen,

[0060] R 2 H or C 1-6 alkyl,

[0061] R 3a and R 3b Each independently is H, C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-substituted aryl, oxo, -C(=O)-C 1-6 Alkyl or -S(=O) 2 -C 1-6 alkyl,

[0062] R 4 For 1 to 3 R 5 Substituted C 1-6 Alkyl, can be 1 to 4 R 6 Substituted C 3-8 Cycloalkyl, can be 1 to 4 R 7 substituted 4-7 membered saturated heterocyclic group, or 1-4 R 8 Substituted heteroaryl,

[0063] R 5 , R 6 , R 7 and R 8 Each independently is C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 alkyl, 4-7 membered saturated heterocyclic group, oxo, cyano, -C(=O)-C 1-6 Alkyl, -S(=O) 2 -C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-NR 9 R 10 、-NR 9 R 10 , -C 1-6 Alkylene-OR 11 , or -OR 11 ,

[0064] R 9 , R 10 Each independently is H, C 1-6 Alkyl or -C(=O)-C 1-6 alkyl,

[0065] R 11 H, C 1-6alkyl or -C(=O)-C 1-6 alkyl.)

[0066] It should be noted that the substituent R in the formula 3a and R 3b is bonded to atoms among the atoms constituting ring A other than the two carbon atoms shared with the pyridazine ring and the nitrogen atom to which R 4 is bonded. In addition, on the premise that there is no special record, when a symbol in a certain chemical formula in this specification is also used in other chemical formulas, the same symbol represents the same meaning.

[0067] In addition, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, particularly a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases. It should be noted that this pharmaceutical composition contains a preventive and / or therapeutic agent for inflammatory diseases and / or neurodegenerative diseases containing a compound of formula (I) or a salt thereof.

[0068] In addition, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof as an NLRP3 inflammasome activation inhibitor; a compound of formula (I) or a salt thereof used as an NLRP3 inflammasome activation inhibitor; an NLRP3 inflammasome activation inhibitor containing a compound of formula (I) or a salt thereof; a pharmaceutical composition containing a compound of formula (I) or a salt thereof as an NLRP3 inflammasome activation inhibitor and one or more pharmaceutically acceptable excipients; the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament or pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases; the use of a compound of formula (I) or a salt thereof for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases; a compound of formula (I) or a salt thereof used in the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases; and a method for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases, including administering an effective amount of a compound of formula (I) or a salt thereof to a subject. It should be noted that the "subject" is a human or other animal in need of such prevention and / or treatment, and in one mode, it is a human in need of such prevention and / or treatment.

[0069] Effects of the Invention

[0070] The compound of formula (I) or a salt thereof has an inhibitory effect on NLRP3 inflammasome activation and can be used as a preventive and / or therapeutic drug for inflammatory diseases and / or neurodegenerative diseases, etc. Detailed Description of the Invention

[0071] Hereinafter, the present invention will be described in detail.

[0072] In this specification, unless otherwise specified, the following terms have the following meanings. The following definitions are for clarifying the defined terms and are not restrictive. Here, when a term used is not specifically defined, the term is used in the meaning generally accepted by those skilled in the art.

[0073] In this specification, "C" 1-6 "alkyl" is a straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 as the expression of the number of carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl, etc. As one embodiment, it is a straight-chain or branched-chain C 1-4 alkyl; as one embodiment, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; as one embodiment, it is methyl, ethyl, n-propyl, or n-butyl; as one embodiment, it is n-propyl or n-butyl; as one embodiment, it is n-propyl; as one embodiment, it is n-butyl; as one embodiment, it is methyl or ethyl; as one embodiment, it is ethyl; as one embodiment, it is methyl.

[0074] "C" 1-6 "alkylene" is a divalent saturated hydrocarbon group of straight-chain or branched-chain C 1-6 , such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, 2-methyltrimethylene, ethylmethylene, 1,2-dimethylethylene or 1,1,2,2-tetramethylethylene. As one embodiment, it is C 1-4 alkylene; as one embodiment, it is methylene, ethylene, trimethylene, 1,1-dimethylethylene, or 2,2-dimethylethylene; as one embodiment, it is ethylene, trimethylene, 1,1-dimethylethylene, or 2,2-dimethylethylene; as one embodiment, it is methylene or ethylene; as one embodiment, it is ethylene; as one embodiment, it is trimethylene; as one embodiment, it is 1,1-dimethylethylene; as one embodiment, it is 2,2-dimethylethylene; as one embodiment, it is methylene.

[0075] "C" 3-8 "cycloalkyl" is C 3-8The saturated hydrocarbon ring group may have a bridge or form a spiro ring. For example, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.3.0]octyl, bicyclo[2.2.2]octyl, spiro[2.2]pentyl, spiro[3.3]heptyl, or spiro[2.5]octyl. In one aspect, it is C 3-6 Saturated hydrocarbon ring group; in one aspect, it is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; in one aspect, it is cyclopropyl; in one aspect, it is cyclobutyl, cyclopentyl, or cyclohexyl; in one aspect, it is cyclobutyl; in one aspect, it is cyclopentyl; in one aspect, it is cyclohexyl.

[0076] The "5- to 7-membered nitrogen-containing partially unsaturated heterocycle" is a ring in which, in a 5- to 7-membered saturated hydrocarbon ring, the ring has a carbon-carbon double bond, contains one nitrogen atom as a ring-constituting atom, and may further contain 1 or more heteroatoms, particularly an oxygen atom, a nitrogen atom, or a sulfur atom as a ring-constituting atom. For example, it is pyrroline, piperidine, azepane, oxazole, imidazole, thiazole, oxazine, pyrazine, thiazine, pyrimidine, oxazepane, diazepane, or thiazepane. In one aspect, it is pyrroline, piperidine, azepane, pyrimidine, oxazepane, diazepane, or thiazepane; in one aspect, it is pyrroline, piperidine, oxazepane, or diazepane.

[0077] In the following partial structure of formula (I)

[0078] [Chemical formula 13]

[0079]

[0080] (The wavy lines respectively represent the bonding parts to the phenyl group, R 2 and R 4 in formula (I). The same applies hereinafter.) In this structure, ring A, which is a 5- to 7-membered nitrogen-containing partially unsaturated heterocycle, condenses with the pyridazine ring by sharing its double bond part, for example, to form the following partial structure, but is not limited thereto.

[0081] [Chemical formula 14]

[0082]

[0083] "A 4- to 7-membered saturated heterocyclic group" is a 4- to 7-membered saturated hydrocarbon ring group containing one or more heteroatoms, particularly oxygen, nitrogen or sulfur atoms, as ring-constituting atoms. For example, it is an oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, thiane-1-yl, oxepanyl, azepanyl, thiepanyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dithiolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxanyl, piperazinyl, dithianyl, morpholinyl, thiomorpholinyl, oxathiolanyl, dioxepanyl, diazepanyl, dithiepanyl, oxazepanyl, thiazepanyl, oxathiepanyl, but is not limited thereto. As one embodiment, it is an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, oxetanyl, azepanyl; as another embodiment, it is a tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl; further as one embodiment, it is an oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl; further as one embodiment, it is a pyrrolidinyl, tetrahydropyranyl or piperidinyl; further as one embodiment, it is a pyrrolidinyl; further as one embodiment, it is a tetrahydropyranyl; further as one embodiment, it is a piperidinyl; as another embodiment, it is an oxetanyl or tetrahydropyranyl; further as one embodiment, it is an oxetanyl.

[0084] "Aryl" is a monocyclic to tricyclic aromatic hydrocarbon ring group of C 6-14 and includes a bicyclic to tricyclic aromatic hydrocarbon ring group obtained by condensing with a C 5-8 cycloalkene at its double bond position. For example, it is a phenyl, naphthyl, tetrahydronaphthyl, indenyl, fluorenyl, etc., and as one embodiment, it is a phenyl.

[0085] "Heteroaryl" is a 5- to 6-membered aromatic hydrocarbon ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. For example, it can be exemplified by a pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl. As one embodiment, it is a pyrazolyl.

[0086] "Halogen" means F, Cl, Br or I. As one embodiment, it is F or Cl; further as one embodiment, it is F; as another embodiment, it is Cl.

[0087] "Halogenated C 1-6 alkyl" is a straight-chain or branched-chain C 1-6Alkyl. For example, the following can be cited: trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-fluoro-2-methylpropyl, difluoromethyl, difluoroethyl, fluoromethyl or chloromethyl. As one mode, it is difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl; as a further mode, it is difluoromethyl, difluoroethyl or trifluoromethyl; as a further mode, it is trifluoromethyl or difluoromethyl; as another mode, it is trifluoromethyl; as another mode, it is difluoromethyl; as another mode, it is difluoroethyl or trifluoroethyl; as one mode, it is difluoroethyl; as a further mode, it is trifluoroethyl.

[0088] In this specification, "substitutable" means unsubstituted or "substituted by one or more substituents (for example, the substituents defined below)". Substitution can be at any position as long as it is a position where hydrogen is usually present in the group. As one mode, "substitutable" is "substitutable by 1 to 4 substituents", and as another mode, it is "substitutable by 1 to 3 substituents". It should be noted that in the case of multiple substitutions, the substituents can be the same or different. As specific substituents, the following can be cited: C 1-6 alkyl, -O-C 1-6 alkyl, halo C 1-6 alkyl, -O-halo C 1-6 alkyl, C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, cyano, oxo, halogen, etc. As one mode, -O-C 1-6 alkyl can be cited.

[0089] "Substitutable aryl" is an aryl that is unsubstituted or substituted by one or more substituents. As one mode, it is an unsubstituted phenyl or a phenyl substituted by one or more substituents. As one mode, it is an unsubstituted phenyl or a phenyl substituted by -O-C 1-6 alkyl.

[0090] Even if the combination is not specifically described, one or two or more modes can be combined with another mode.

[0091] In this specification, as one mode of "inflammatory disease and / or neurodegenerative disease", it is an inflammatory disease and a neurodegenerative disease; as a further mode, it is an inflammatory disease; as another mode, it is a neurodegenerative disease.

[0092] In this specification, "inflammatory disease" refers to autoinflammatory diseases including cryopyrin-associated periodic syndrome (CAPS), gout, and pseudogout; and diseases including non-alcoholic steatohepatitis (NASH), but not limited to these. In one aspect, it is an autoinflammatory disease; in another aspect, it is CAPS; and further in one aspect, it is gout. It should be noted that "cryopyrin-associated periodic syndrome (CAPS)" is a disease composed of a group of diseases including familial cold urticaria (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease / neonatal chronic neurocutaneous arthropathy syndrome (NOMID / CINCA syndrome).

[0093] In this specification, "neurodegenerative disease" refers to a group of diseases including: α-synucleinopathies including Parkinson's disease, multiple system atrophy, and Lewy body dementia; Alzheimer's disease; amyotrophic lateral sclerosis; and multiple sclerosis, but not limited to these. In one aspect, it is Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis; and further in one aspect, it is multiple sclerosis. In another aspect, it is α-synucleinopathy; further in another aspect, it is Parkinson's disease; additionally in another aspect, it is multiple system atrophy; and additionally in another aspect, it is Lewy body dementia.

[0094] In this specification, "treatment" includes both "treatment for therapeutic purposes" and "treatment for prophylactic purposes". "Treatment for therapeutic purposes" refers to alleviating symptoms, changing the course of the disease, prolonging life, etc., and "treatment for prophylactic purposes" refers to reducing the likelihood of onset in a subject at risk of developing the disease. A "subject at risk of developing the disease" refers to an individual with known risk factors who is more likely to develop the disease than the general population.

[0095] One aspect of the compound of formula (I) or its salt in the present invention is as follows.

[0096] (1-1) The compound of formula (I) or its salt (ring A is a 5- to 7-membered nitrogen-containing partially unsaturated heterocycle).

[0097] [Chemical formula 15]

[0098]

[0099] (1-2) The compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) or its salt.

[0100] [Chemical formula 16]

[0101]

[0102] A compound of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If) according to (1-3), or a salt thereof.

[0103] A compound of formula (Ia), (Ib), (Ie), or (If) according to (1-4), or a salt thereof.

[0104] A compound of formula (Ia) according to (1-5), or a salt thereof.

[0105] A compound of formula (Ib) according to (1-6), or a salt thereof.

[0106] A compound of formula (Ic) according to (1-7), or a salt thereof.

[0107] A compound of formula (Id) according to (1-8), or a salt thereof.

[0108] A compound of formula (Ie) according to (1-9), or a salt thereof.

[0109] A compound of formula (If) according to (1-10), or a salt thereof.

[0110] A compound of formula (Ig) according to (1-11), or a salt thereof.

[0111] A compound of formula (Ia’), (Ib’), (Ic’), (Id’), (Ie’), (If’), or (Ig’) according to (1-12), or a salt thereof.

[0112] [Chemical formula 17]

[0113]

[0114] A compound of formula (Ia’), (Ib’), (Ic’), (Id’), (Ie’), or (If’) according to (1-13), or a salt thereof.

[0115] A compound of formula (Ia’), (Ib’), (Ie’), or (If’) according to (1-14), or a salt thereof.

[0116] A compound of formula (Ia’) according to (1-15), or a salt thereof.

[0117] A compound of formula (Ib’) according to (1-16), or a salt thereof.

[0118] A compound of formula (Ic’) according to (1-17), or a salt thereof.

[0119] A compound of formula (Id’) according to (1-18), or a salt thereof.

[0120] A compound of formula (Ie’) according to (1-19), or a salt thereof.

[0121] A compound of formula (If’) according to (1-20), or a salt thereof.

[0122] Compound of formula (1-21) (Ig’) or a salt thereof.

[0123] (2-1) R 1a and R 1b are each independently H, C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl or a halogen, or a salt thereof.

[0124] (2-2) R 1a and R 1b are each independently H, C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, or a halogen, or a salt thereof.

[0125] (2-3) R 1a is C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, or a halogen, R 1b is H or C 1-6 alkyl, or a salt thereof.

[0126] (2-4) R 1a is C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, or a halogen, R 1b is H, or a salt thereof.

[0127] (2-5) R 1a is -O-C 1-6 alkyl, halo-C 1-6 alkyl, or -O-halo-C 1-6 alkyl, R 1b is H, or a salt thereof.

[0128] (2-6) R 1a is -O-C 1-6 alkyl, R 1b is H, or a salt thereof.

[0129] (2-7) R 1a is halo-C 1-6Alkyl, R 1b A compound in which R is H or a salt thereof.

[0130] (2 - 8)R 1a is -O-halo-C 1-6 Alkyl, R 1b is a compound in which R is H or a salt thereof.

[0131] (2 - 9)R 1a is halo-C 1-6 alkyl, or -O-halo-C 1-6 Alkyl, R 1b is a compound in which R is H or a salt thereof.

[0132] (3 - 1)R 2 is H or C 1-6 alkyl or a salt thereof.

[0133] (3 - 2)R 2 is a compound in which R is H or a salt thereof.

[0134] (3 - 3)R 2 is C 1-6 alkyl or a salt thereof.

[0135] (4 - 1)R 3a and R 3b are each independently H, C 1-6 alkyl, -O-C 1-6 alkyl, -C 1-6 alkylene - optionally substituted aryl, oxo, -C(=O)-C 1-6 alkyl or -S(=O) 2 -C 1-6 alkyl or a salt thereof.

[0136] (4 - 2)R 3a and R 3b are each independently H, C 1-6 alkyl, -O-C 1-6 alkyl, -C 1-6 alkylene - optionally substituted aryl, oxo, or -C(=O)-C 1-6 alkyl or a salt thereof.

[0137] (4 - 3)R 3a is H, R 3b is H, C 1-6 alkyl, -O-C 1-6 alkyl, -C 1-6 alkylene - optionally substituted aryl, oxo, or -C(=O)-C 1-6 alkyl or a salt thereof.

[0138] (4 - 4)R3a is H, R 3b is H or C 1-6 a compound of an alkyl or a salt thereof.

[0139] (4 - 5)R 3a is H, R 3b is C 1-6 a compound of an alkyl or a salt thereof.

[0140] (4 - 6)R 3a and R 3b both are H or a salt thereof.

[0141] (5 - 1)R 4 is C alkyl substituted by 1 - 3 R 5 is C 1-6 alkyl, C cycloalkyl that can be substituted by 1 - 4 R 6 is C 3-8 cycloalkyl, a 4 - 7 membered saturated heterocyclic group that can be substituted by 1 - 4 R 7 or a heteroaryl that can be substituted by 1 - 4 R, or a salt thereof. 8 a compound of an alkyl or a salt thereof.

[0142] (5 - 2)R 4 is C alkyl substituted by 1 R 5 is C 1-6 alkyl, C cycloalkyl that can be substituted by 1 - 2 R 6 is C 3-8 cycloalkyl, a 4 - 7 membered saturated heterocyclic group that can be substituted by 1 - 2 R 7 or an unsubstituted heteroaryl, or a salt thereof.

[0143] (5 - 3)R 4 is C cycloalkyl that can be substituted by 1 - 4 R 6 is C 3-8 cycloalkyl, or a 4 - 7 membered saturated heterocyclic group that can be substituted by 1 - 4 R 7 or a salt thereof.

[0144] (5 - 4)R 4 is C cycloalkyl substituted by 1 R 6 is C 3-8 cycloalkyl, or a 4 - 7 membered saturated heterocyclic group substituted by 1 R 7 or a salt thereof.

[0145] (5 - 5)R 4 is C cycloalkyl that can be substituted by 1 - 4 R 6 is C 3-8 cycloalkyl, or a salt thereof.

[0146] (5 - 6)R 4 is C that can be substituted by 1 - 3 R 6 is C3-8 A compound of a cycloalkyl group or a salt thereof.

[0147] (5-7)R 4 is C which may be substituted by 1 to 2 Rs 6 a compound of a cycloalkyl group or a salt thereof. 3-8 A compound of a cycloalkyl group or a salt thereof.

[0148] (5-8)R 4 is C which may be substituted by 1 R 6 a compound of a cycloalkyl group or a salt thereof. 3-8 A compound of a cycloalkyl group or a salt thereof.

[0149] (5-9)R 4 is C substituted by 1 R 6 a compound of a cycloalkyl group or a salt thereof. 3-8 A compound of a cycloalkyl group or a salt thereof.

[0150] (5-10)R 4 is unsubstituted C 3-8 a compound of a cycloalkyl group or a salt thereof.

[0151] (5-11)R 4 is a compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 to 4 Rs 7 A compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 to 4 Rs.

[0152] (5-12)R 4 is a compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 to 3 Rs 7 A compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 to 3 Rs.

[0153] (5-13)R 4 is a compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 to 2 Rs 7 A compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 to 2 Rs.

[0154] (5-14)R 4 is a compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 R 7 A compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof which may be substituted by 1 R.

[0155] (5-15)R 4 is a compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof substituted by 1 R 7 A compound of a 4- to 7-membered saturated heterocyclic group or a salt thereof substituted by 1 R.

[0156] (5-16)R 4 is a compound of an unsubstituted 4- to 7-membered saturated heterocyclic group or a salt thereof.

[0157] (5-17)R 4 is a compound of C substituted by 1 R 5 alkyl, C which may be substituted by 1 to 2 Rs 1-6 a compound of a cycloalkyl group or a salt thereof. 6 alkyl, C which may be substituted by 1 to 2 Rs 3-8A compound having a cycloalkyl group or a 4- to 7-membered saturated heterocyclic group which may be substituted by one R 7 or a salt thereof.

[0158] (6-1) R 5 is C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, 4- to 7-membered saturated heterocyclic group, oxo, cyano, -C(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-O-C 1-6 alkyl, -C(=O)-NR 9 R 10 , -NR 9 R 10 , -C 1-6 alkylene-OR 11 , or -OR 11 or a salt thereof.

[0159] (6-2) R 5 is -NR 9 R 10 , or -OR 11 or a salt thereof.

[0160] (6-3) R 5 is -NR 9 R 10 or a salt thereof.

[0161] (6-4) R 5 is -OR 11 or a salt thereof.

[0162] (7-1) R 6 is C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, 4- to 7-membered saturated heterocyclic group, oxo, cyano, -C(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-O-C 1-6 alkyl, -C(=O)-NR 9 R 10 , -NR 9 R 10 , -C 1-6 alkylene-OR 11 , or -OR 11 or a salt thereof.

[0163] (7-2) R6 is C 1-6 alkyl, cyano, -NR 9 R 10 , or -OR 11 compound or its salt.

[0164] (7-3)R 6 is C 1-6 alkyl or -OR 11 compound or its salt.

[0165] (7-4)R 6 is -OR 11 compound or its salt.

[0166] (8-1)R 7 is C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, 4-7 membered saturated heterocyclic group, oxo, cyano, -C(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-O-C 1-6 alkyl, -C(=O)-NR 9 R 10 , -NR 9 R 10 , -C 1-6 alkylene-OR 11 , or -OR 11 compound or its salt.

[0167] (8-2)R 7 is C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, 4-7 membered saturated heterocyclic group, oxo, -C(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-O-C 1-6 alkyl, -C(=O)-NR 9 R 10 , -C 1-6 alkylene-OR 11 , or -OR 11 compound or its salt.

[0168] (8-3)R 7 is C 1-6 alkyl, oxo, or -OR 11 compound or its salt.

[0169] (8-4)R7 a compound of C 1-6 alkyl or a salt thereof.

[0170] (8-5)R 7 a compound of oxo or a salt thereof.

[0171] (8-6)R 7 is -OR 11 or a salt thereof.

[0172] (9-1)R 8 is C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, a 4- to 7-membered saturated heterocyclic group, oxo, cyano, -C(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-O-C 1-6 alkyl, -C(=O)-NR 9 R 10 、-NR 9 R 10 、-C 1-6 alkylene-OR 11 、or -OR 11 or a salt thereof.

[0173] (9-2)R 8 is C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, a 4- to 7-membered saturated heterocyclic group, -C 1-6 alkylene-OR 11 、or -OR 11 or a salt thereof.

[0174] (9-3)R 8 is a 4- to 7-membered saturated heterocyclic group or a salt thereof.

[0175] (10-1)R 9 、R 10 each independently is H, C 1-6 alkyl or -C(=O)-C 1-6 alkyl or a salt thereof.

[0176] (10-2)R 9 is H, R 10 is H, C 1-6 alkyl, or -C(=O)-C 1-6 alkyl or a salt thereof.

[0177] (10-3)R9 and R 10 are each independently H or C 1-6 alkyl compound or a salt thereof.

[0178] (10 - 4)R 9 is H, and R 10 is C 1-6 alkyl compound or a salt thereof.

[0179] (10 - 5)R 9 and R 10 are both H compound or a salt thereof.

[0180] (11 - 1)R 11 is H, C 1-6 alkyl or -C(=O)-C 1-6 alkyl compound or a salt thereof.

[0181] (11 - 2)R 11 is H or C 1-6 alkyl compound or a salt thereof.

[0182] (11 - 3)R 11 is H compound or a salt thereof.

[0183] (12) A compound or a salt thereof which is a combination of two or more of the groups described in the above (1 - 1) to (11 - 3) and does not conflict with each other. For example, the following combinations can be listed, but are not limited thereto.

[0184] (12 - 1) A compound or a salt thereof which is a combination of (1 - 1), (2 - 1), (3 - 1), (4 - 1), (5 - 1), (6 - 1), (7 - 1), (8 - 1), (9 - 1), (10 - 1) and (11 - 1).

[0185] (12 - 2) A compound or a salt thereof which is a combination of (1 - 2), (2 - 2), (3 - 1), (4 - 2), (5 - 2), (6 - 2), (7 - 2), (8 - 2), (10 - 2) and (11 - 1).

[0186] (12 - 3) A compound or a salt thereof which is a combination of (1 - 3), (2 - 2), (3 - 1), (4 - 2), (5 - 3), (7 - 2), (8 - 2), (10 - 2) and (11 - 1).

[0187] (12 - 4) A compound or a salt thereof which is a combination of (1 - 4), (2 - 5), (3 - 3), (4 - 4), (5 - 4), (7 - 4), (8 - 3) and (11 - 3).

[0188] A compound of the combination of (12-5)(1-5), (2-7), (3-3), (4-6), (5-15), and (8-5) or a salt thereof.

[0189] A compound of the combination of (12-6)(1-5), (2-8), (3-3), (4-6), (5-15), and (8-5) or a salt thereof.

[0190] A compound of the combination of (12-7)(1-2), (2-3), (3-1), (4-2), (5-2), (6-2), (7-2), (8-2), (10-2), and (11-1) or a salt thereof.

[0191] A compound of the combination of (12-8)(1-5), (2-5), (3-3), (4-6), (5-15), and (8-5) or a salt thereof.

[0192] A compound of the combination of (12-9)(1-5), (2-9), (3-3), (4-6), (5-17), (6-4), (7-3), (8-5), and (11-3) or a salt thereof.

[0193] As examples of the specific compounds included in the present invention, compounds or salts thereof selected from the following groups can be cited.

[0194] 2-{8-[(1R,2R)-2-Hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0195] 2-{4-Methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0196] 2-{8-[(3R)-1-Ethylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0197] 5-(Difluoromethoxy)-2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}phenol,

[0198] (3S,4R)-4-{3-[4-(Difluoromethoxy)-2-hydroxyphenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}oxan-3-ol,

[0199] 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}-5-(trifluoromethyl)phenol,

[0200] 5-(difluoromethoxy)-2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol,

[0201] (3S)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one,

[0202] 5-methoxy-2-{4-methyl-9-[(3R)-1-methylpiperidin-3-yl]-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol,

[0203] 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4,6-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol, and

[0204] 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol.

[0205] In addition, as examples of the specific compounds included in the present invention, compounds or their salts selected from the following groups can be cited.

[0206] 2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0207] 2-{4-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0208] 2-{8-[(3R)-1-ethylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0209] 5-(Difluoromethoxy)-2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}phenol,

[0210] (3S,4R)-4-{3-[4-(Difluoromethoxy)-2-hydroxyphenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}oxan-3-ol,

[0211] 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}-5-(trifluoromethyl)phenol,

[0212] 5-(Difluoromethoxy)-2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol,

[0213] (3S)-3-{3-[2-Hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one,

[0214] 5-Methoxy-2-{4-methyl-9-[(3R)-1-methylpiperidin-3-yl]-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol,

[0215] 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4,6-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol,

[0216] 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol, and

[0217] (3S)-3-{3-[4-(Difluoromethoxy)-2-hydroxyphenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one.

[0218] Depending on the type of substituents, tautomers or geometric isomers may exist in the compounds of formula (I). In this specification, sometimes the compounds of formula (I) or their salts are only described as one form of the isomers, but the present invention also includes other isomers, and also includes substances obtained by separating the isomers, or mixtures thereof.

[0219] In addition, when the compounds of formula (I) or their salts have an asymmetric center or axial asymmetry, enantiomers (optical isomers) based thereon may exist. The compounds of formula (I) or their salts also include any of the separated (R)-isomers, (S)-isomers, etc. enantiomers, and mixtures thereof (including racemic mixtures or non-racemic mixtures). In one embodiment, the enantiomers are "stereochemically pure". "Stereochemically pure" means a purity to such an extent that those skilled in the art can recognize it as substantially stereochemically pure. As another embodiment, the enantiomers are compounds having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or more, 95% ee or more, 98% ee or more, 99% ee or more.

[0220] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compounds represented by formula (I). Pharmaceutically acceptable prodrugs are compounds having groups that can be converted into amino groups, hydroxyl groups, carboxyl groups, etc. by solvolysis or under physiological conditions. Examples of the groups forming the prodrug can be found in Prog. Med., 5, 2157-2161 (1985), or "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Volume 7, Molecular Design, pages 163-198.

[0221] In addition, the salts of the compounds of formula (I) are pharmaceutically acceptable salts of the compounds of formula (I), and depending on the type of substituents, acid addition salts or salts with bases may sometimes be formed. Specifically, examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, xylolyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc.; salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc., organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, etc.; salts with various amino acids such as acetyl leucine and amino acid derivatives, or ammonium salts, etc.

[0222] Furthermore, the present invention also includes various hydrates or solvates and polymorphs of the compounds of formula (I) or their salts.

[0223] In addition, the present invention includes all pharmaceutically acceptable compounds of formula (I) or salts thereof labeled with one or more radioactive or non-radioactive isotopes. Examples of suitable isotopes used in the isotope labeling of the compounds of the present invention include: hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C, 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O, 17 O and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), phosphorus ( 32 P, etc.), sulfur ( 35 S, etc.) isotopes. The compounds of the present invention labeled with isotopes can be used for research such as tissue distribution studies of drugs and / or matrices. For example, radioactive isotopes such as tritium ( 3 H), carbon-14 ( 14 C), etc. can be used for this purpose because of easy labeling and simple detection. Substituting with heavier isotopes, for example, hydrogen substituted with deuterium ( 2 H), may be therapeutically advantageous due to improved metabolic stability (for example, increased half-life in vivo, reduced required dosage, reduced drug interactions). Substituting with positron-emitting isotopes ( 11 C, 18 F, 15 O and 13 N, etc.) can be used in positron emission tomography (PET) tests to test the occupancy of matrix receptors. The compounds of the present invention labeled with isotopes can generally be prepared by conventional methods known to those skilled in the art, or by using appropriately isotope-labeled reagents instead of unlabeled reagents and using the same preparation methods as in the examples or manufacturing examples.

[0224] (Manufacturing Method)

[0225] The compound of formula (I) or its salt can be produced by various known synthetic methods based on the characteristics of its basic structure or the types of substituents. At this time, depending on the type of functional group, it is sometimes technically effective to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. As such protecting groups, for example, those described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)" by Wuts (P.G.M. Wuts) and Greene (T.W. Greene) can be cited, and they can be appropriately selected according to their reaction conditions. In such a method, by introducing the protecting group and carrying out the reaction, and then removing the protecting group as needed, the desired compound can be obtained.

[0226] In addition, the prodrug of the compound of formula (I) can be produced in the same manner as the above protecting group by introducing a specific group at the stage from the raw material to the intermediate, or by further reacting the obtained compound of formula (I). The reaction can be carried out by using common methods known to those skilled in the art, such as esterification, amidation, dehydration, etc.

[0227] Hereinafter, representative production methods of the compound of formula (I) will be described. Each production method can also be carried out with reference to the references attached to this description. It should be noted that the production method of the present invention is not limited to the examples shown below.

[0228] In this specification, the following abbreviations are sometimes used.

[0229] DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, HPLC: high performance liquid chromatography, DIPEA: N,N-diisopropylethylamine, NMP: 1-methylpyrrolidin-2-one, Me: methyl, Pd-118: dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II), PdCl 2 (PPh 3 ) 2 : bis(triphenylphosphine)palladium(II) dichloride, PdCl 2 (dppf): dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), PdCl 2 (dppf)·CH 2 Cl 2 : dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane adduct, Pd 2 (dba) 3:(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium(3:2), Pd(PPh 3 ) 4 : Tetrakis(triphenylphosphine)palladium, RuPhos Pd G3: [2-(2'-Amino-1,1'-biphenyl)][2-(dicyclohexylphosphino)-2',6'-diisopropoxybiphenyl]palladium(II) methanesulfonate, SPhos Pd G3: [2-(2'-Amino-1,1'-biphenyl)][2-(dicyclohexylphosphino)-2',6'-dimethoxybiphenyl]palladium(II) methanesulfonate, THF: Tetrahydrofuran, ODS: Octadecylsilyl.

[0230] (First Preparation Method)

[0231] [Chemical Formula 18]

[0232]

[0233] (In the formula, L is -L 1 -L 2 -L 3 -L 4 -, L 1 and L 4 is CH 2 , L 2 and L 3 is a bond, CH 2 , NH, S or O, and this L is substituted by R 3a and R 3b , X 1 is halogen, mesyloxy or tosyl, R a and R b are both H, or R a and R b and the boronic acid residue bonded to this R a , R b form 4,4,5,5-tetramethyl-1,3,2-dioxaborolane together. The same applies hereinafter.)

[0234] (First Step)

[0235] This step is a step of obtaining the compound of formula (IV) through the reaction of the compound of formula (II) with the compound of formula (III). In this reaction, the compound of formula (II) and the compound of formula (III) are used in equivalent amounts or either one is used in excess, and their mixture is in the presence of silver nitrate, an acid and a peroxide, in a solvent inert to the reaction, from cooling to heating, preferably at 0 to 100 °C, and usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and halogenated hydrocarbons such as dichloromethane and chloroform can be cited; nitriles such as acetonitrile, NMP, DMF, DMSO, water and their mixtures. Examples of the acid are not particularly limited, and sulfuric acid, trifluoroacetic acid, etc. can be cited. Examples of the peroxide are not particularly limited, and ammonium persulfate, potassium persulfate, etc. can be cited.

[0236] [Literature]

[0237] Angewandte Chemie International Edition, 58, pp13666 - 13699(2019)

[0238] (Second step)

[0239] This step is a step of obtaining the compound of formula (VI) through the reaction of the compound of formula (IV) with the compound of formula (V). In this reaction, the compound of formula (IV) and the compound of formula (V) are used in equivalent amounts or either one is used in excess, and their mixture is in the presence of a base, in a solvent inert to the reaction, from cooling to heating, preferably at 0 to 190 °C, and usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and ethers such as diethyl ether, THF, 1,4 - dioxane, 1,2 - dimethoxyethane can be cited; halogenated hydrocarbons such as dichloromethane and chloroform; pyridine, acetonitrile, NMP, DMF, DMSO and their mixtures. Examples of the base are not particularly limited, and triethylamine, DIPEA, etc. can be cited. In addition, this reaction can also be carried out under microwave irradiation.

[0240] (Third step)

[0241] This step is a step of obtaining the compound of formula (I) through the reaction of the compound of formula (VI) with the compound of formula (VII). In this reaction, the compound of formula (VI) and the compound of formula (VII) are used in equivalent amounts or either one is used in excess, and their mixture is in the presence of a catalyst and a base, in a solvent inert to the reaction, from cooling to heating under reflux, preferably at room temperature to 150 °C, and usually stirred for 0.1 hour to 5 days. Examples of the catalyst used here are not particularly limited, and Pd(PPh 3 )4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf), PdCl 2 (dppf)·CH 2 Cl 2 , Pd 2 (dba) 3 , RuPhos Pd G3, SPhos Pd G3, Pd-118, etc. Examples of the base are not particularly limited and may include tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium hydroxide, sodium tert-butoxide, etc. Examples of the solvent are not particularly limited and may include ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene; water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. In addition, this reaction can also be carried out under microwave irradiation.

[0242] [Literature]

[0243] Journal of the American Chemical Society, 127, pp4685-4696(2005)

[0244] (Raw material synthesis - 1)

[0245] [Chemical formula 19]

[0246]

[0247] (In the formula, Pg represents a silicon-containing protecting group such as trimethylsilyl, tert-butyl(dimethyl)silyl, tert-butyl(diphenyl)silyl. R c represents methyl or p-methylphenyl. The same applies hereinafter.)

[0248] This preparation method is another method for synthesizing the compound (Xc) in which X 1 is a sulfonyloxy group among the synthetic intermediate (IV).

[0249] (First step)

[0250] This step is the step of obtaining the compound of formula (Xa) through the reaction of the compound of formula (VIII) with the compound of formula (IX). In the reaction of this step, the compound of formula (VIII) and the compound of formula (IX) are used in equivalent amounts or either of them is used in excess, and their mixture is stirred in a solvent inert to the reaction at a temperature from cooling to heating under reflux, preferably at room temperature to 170 °C, usually for 0.1 hour to 5 days. As the solvent used in this reaction, there is no particular limitation, and examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, 1,3,5-trimethylbenzene; halogenated hydrocarbons such as dichloromethane, chloroform, etc. and their mixtures.

[0251] (Second step)

[0252] This step is the step of obtaining the compound of formula (Xb) by deprotecting the compound of formula (Xa). This step can be carried out using the method described in "Greene’s Protective Groups in Organic Synthesis (4th Edition, 2006)".

[0253] (Third step)

[0254] This step is the step of subjecting the compound of formula (Xb) to a sulfonylation reaction to obtain the compound of formula (Xc). In the reaction of this step, the compound of formula (Xb) and the sulfonylation agent are used in equivalent amounts or either of them is used in excess, and their mixture is stirred in a solvent inert to the reaction in the presence of a base at a temperature from cooling to heating under reflux, preferably at 0 to 150 °C, usually for 0.1 hour to 5 days. As examples of the sulfonylation agent, there is no particular limitation, and examples thereof include methanesulfonyl chloride, p-toluenesulfonyl chloride. As examples of the solvent used herein, there is no particular limitation, and examples thereof include ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform; pyridine, acetonitrile, NMP, DMF, DMSO and their mixtures. As examples of the base, there is no particular limitation, and examples thereof include triethylamine, DIPEA, etc. Sometimes, the addition of 4-(dimethylamino)pyridine can make the reaction proceed smoothly.

[0255] (Raw material synthesis - 2)

[0256] [Chemical formula 20]

[0257]

[0258] (In the formula, X 2 is halogen, methanesulfonyloxy or p-toluenesulfonyloxy, R d is methyl or p-methylphenyl, Z is NR Z or S, R e 、Rf , R g , R h and R Z Two of them are R 3a and R 3b , and the remaining three are H. The same applies hereinafter.)

[0259] This preparation method is for the synthesis of compound (XIIIb) where L in the synthetic intermediate (IV) contains L 1 is CH 2 , L 2 is NH or S, L 3 and L 4 is CH 2 , X 1 is a sulfonyloxy group.

[0260] (First step)

[0261] This step is to obtain the compound of formula (XIIIa) by reacting the compound of formula (XI) with the compound of formula (XII). In the reaction of this step, the compound of formula (XI) and the compound of formula (XII) are used in equivalent amounts or either one is used in excess, and their mixture is in a solvent inert to the reaction, in the presence of a base, from cooling to heating under reflux, preferably at room temperature to 150 °C, and usually stirred for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited and may include ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform; pyridine, acetonitrile, NMP, DMF, DMSO and their mixtures. Examples of the base are not particularly limited and may include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide; organic bases such as triethylamine, DIPEA.

[0262] (Second step)

[0263] This step is to obtain the compound of formula (XIIIb) from the compound of formula (XIIIa). This reaction can use a sulfonating agent and be carried out in the same manner as the third step of raw material synthesis - 1.

[0264] (Other preparation methods)

[0265] By using the compound of formula (I) obtained by the above preparation method as a raw material and further carrying out chemical modification reactions commonly used by those skilled in the art such as alkylation, benzylation, esterification, amidation, acylation, sulfonylation, carbamate esterification, carbamoylation, oxidation reaction, reduction reaction, protection reaction, deprotection reaction, etc., other compounds of formula (I) can be obtained.

[0266] The compound of formula (I) is isolated and purified in the form of a free compound, its salt, hydrate, solvate or polymorph. The salt of the compound of formula (I) can also be prepared by a salt-forming reaction using conventional methods. Isolation and purification can be carried out by means of common chemical operations such as extraction, fractional crystallization, various fractional distillation chromatography methods, etc. Various isomers can be prepared by selecting appropriate starting compounds, or various isomers can be separated by taking advantage of the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods for racemates (e.g., fractional crystallization of diastereomeric salts formed with optically active bases or acids, chromatography using chiral columns, etc.). Additionally, optical isomers can be prepared from appropriate optically active starting compounds.

[0267] The pharmacological activity of the compound of formula (I) can be confirmed by the following several tests. It should be noted that this pharmacological activity can also be confirmed by well-known modified tests.

[0268] Test Example 1 THP-1 IL-1β Production Inhibition Test

[0269] 50 ng / mL of PMA (phorbol myristate acetate, SIGMA, P1585) was added to THP-1 cells and cultured at 37 °C for 2 days. The culture medium was replaced with serum-free RPMI-1640 medium, and the compound with a known concentration was added and cultured at 37 °C for 15 minutes. LPS (Lipopolysaccharide, SIMGA, L2880) and ATP (Adenosine triphosphate, SIGMA, A2383) were added at final concentrations of 50 ng / mL and 5 mM, respectively, and cultured at 37 °C for 2 hours. The supernatant was collected, and the concentration of IL-1β was measured by ELISA (DuoSet ELISA human IL-1β, R&D Systems, DY201). The concentration of IL-1β was plotted against the logarithm of the concentration of the test compound, and the IC 50 value was calculated by non-linear regression analysis using the Sigmoid Emax model.

[0270] The results are shown in the following table. It was confirmed that the compound of the example inhibited the activation of NLRP3 inflammasome and the production of IL-1β.

[0271] [Table 1]

[0272]

[0273] Test Example 2 Rat Central Nervous System IL-1β Production Test

[0274] Under isoflurane anesthesia, 12.5 μg / 5 μL of LPS (SIGMA, L2880) was administered into the cisterna magna of male Wistar rats aged 10 - 14 weeks. After 2 hours, the test compound suspended in a 0.5% methylcellulose solution was orally administered. Further, after 1 hour, 50 μg / 5 μL of BzATP (2’(3’)-O-(4-Benzoylbenzoyl)adenosine 5’-triphosphate triethylammonium salt, SIGMA, B6396) was administered into the cisterna magna. After 30 minutes, cerebrospinal fluid was collected. The IL-1β p17 in the cerebrospinal fluid was quantified by Western blotting using an anti-IL-1β antibody (Millipore, AB1832P), and the inhibition rate relative to the group administered with the 0.5% methylcellulose solution was calculated. In this experiment, it was confirmed that multiple compounds of formula (I) or their salts exhibited an inhibitory effect on IL-1β production in the brain.

[0275] Evaluation of Motor Function in a Mouse α-Synuclein Fibril-Induced Neuroinflammation Model in Test Example 3

[0276] For male C57BL / 6J mice, 8 μg of mouse α-synuclein fibrillar protein (StressMarq Biosciences Inc., SPR-324) was administered into the left striatum. After 13 - 14 weeks, the test compound suspended in a 0.5% methylcellulose solution was orally administered once a day. For the negative control group, a 0.5% methylcellulose solution was administered. Four weeks after the start of administration, motor function was evaluated using the wire suspension test. The mouse was made to grasp a horizontally taut wire, and after it fell, it was made to grasp again. This operation was continuously performed for 3 minutes, and the number of falls was recorded.

[0277] Based on the above results, it can be expected that the compounds of formula (I) or their salts can be used for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases, etc.

[0278] A pharmaceutical composition containing one or two or more compounds of formula (I) or their salts as an active ingredient can be prepared using excipients commonly used in the art (i.e., pharmaceutical excipients or pharmaceutical carriers, etc.) by common methods.

[0279] Administration can be achieved by oral administration using tablets, pills, capsules, granules, powders, liquid preparations, etc., or by parenteral administration using injections, suppositories, eye drops, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalants, etc. via intra-articular, intravenous, intramuscular routes, etc., in any of these ways.

[0280] As solid compositions for oral administration, tablets, powders, granules, etc. can be used. In such solid compositions, one or more active ingredients can be mixed with at least one inert excipient. The composition can contain inert additives, such as lubricants or disintegrants, stabilizers, solubilizing aids, according to conventional methods. Tablets, powders, granules or pills can be coated with wax, sugar coating or a film of gastric-soluble or enteric-soluble substances as needed.

[0281] Liquid compositions for oral administration contain pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, etc., and contain common inert diluents, such as purified water or ethanol. In addition to the inert diluent, such liquid compositions can also contain adjuvants, such as solubilizing agents, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, preservatives.

[0282] Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. As aqueous solvents, (for example) distilled water for injection or physiological saline is included. As non-aqueous solvents, there are (for example) alcohols such as ethanol. Such compositions can further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers, or solubilizing aids. They are (for example) filtered through a bacteria-retaining filter, sterilized by incorporating bactericides or irradiation. Additionally, they can also be used by preparing sterile solid compositions and dissolving or suspending them in sterile water or sterile injection solvents before use.

[0283] As topical agents, it includes ointments, plasters, creams, gels, pastes, sprays, lotions, eye drops, eye ointments, etc. It contains common ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, etc.

[0284] Mucosal agents such as inhalants or nasal agents can use solid, liquid, or semi-solid preparations and are manufactured according to previously known methods. Known excipients can also be appropriately added (for example), or pH regulators, preservatives, surfactants, lubricants, stabilizers, or thickeners can be further appropriately added. Administration can use devices for appropriate inhalation or insufflation. For example, known devices such as metered-dose inhalers or nebulizers can be used to administer the compound alone or as a formulated mixture powder, or in combination with a pharmaceutically acceptable carrier in the form of a solution or suspension. Dry powder inhalers, etc. can be used for single or multiple administrations, and dry powder or capsules containing powder can be utilized. Alternatively, it can be in the form of a pressurized aerosol spray, etc., which uses an appropriate propellant, such as a suitable gas like chlorofluorohydrocarbons or carbon dioxide.

[0285] When usually administered orally, the daily dosage is preferably about 0.001 - 100 mg / kg by weight, more preferably 0.1 - 30 mg / kg, and even more preferably 0.1 - 10 mg / kg, and this dosage can be administered once or divided into 2 - 4 times. When administered intravenously, the daily dosage is preferably about 0.0001 - 10 mg / kg by weight, and this dosage can be administered once a day or divided into multiple times. Additionally, as a mucosal agent, it is about 0.001 - 100 mg / kg by weight and can be administered once a day or divided into multiple times. The dosage should be appropriately determined according to each case, considering symptoms, age, gender, etc.

[0286] Although it varies depending on the administration route, dosage form, administration site, type of excipient or additive, the pharmaceutical composition of the present invention contains 0.01 - 100% by weight, and in one form contains 0.01 - 50% by weight of one or more compounds of formula (I) or their salts as the active ingredient.

[0287] The compound of formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases against which the compound of formula (I) is considered to be effective. When used in combination, it can be administered simultaneously, or administered continuously separately, or administered at desired time intervals. The simultaneous administration preparation can be a formulated preparation or can be made into separate preparations.

[0288] Examples

[0289] Hereinafter, based on the examples, the manufacturing method of the compound of formula (I) will be further described in detail. It should be noted that the present invention is not limited to the compounds described in the following examples. Additionally, the preparation methods of the starting compounds are shown in the preparation examples. Moreover, the manufacturing method of the compound of formula (I) is not limited to the manufacturing methods of the specific examples shown below, and the compound of formula (I) can also be manufactured by a combination of these manufacturing methods or methods that are obvious to those skilled in the art.

[0290] In addition, in the examples, production examples, and the tables described later, the following abbreviations are sometimes used.

[0291] They respectively represent: PEx: production example number, Ex: example number, PSyn: production example number produced by the same method, Syn: example number produced by the same method, Str: chemical structural formula, DAT: physicochemical data, CI+: m / z value in mass analysis (ionization method CI, [M+H]+ in the absence of special instructions), ESI+: m / z value in mass analysis (ionization method ESI, [M+H]+ in the absence of special instructions). 1 H-NMR (400 MHz, CDCl 3 ): δ value (ppm) of the signal in H-NMR in CDCl 3 1 1 H-NMR (500 MHz, CDCl 3 ): δ value (ppm) of the signal in H-NMR in CDCl 3 1 1 H-NMR (400 MHz, DMSO-d 6 ): δ value (ppm) of the signal in H-NMR in DMSO-d 6 1 1 H-NMR (500 MHz, DMSO-d 6 ): δ value (ppm) of the signal in H-NMR in DMSO-d 6 1 1 H-NMR (500 MHz, CD 3 OD): δ value (ppm) of the signal in H-NMR in CD 3 1 1 H-NMR (400 MHz, CD 3 OD): δ value (ppm) of the signal in H-NMR in CD 3 1

[0292] In the PSyn and Syn columns in the tables described later, when a hyphen (-) is described, it means that the production method is described in words in the items of the production examples or examples. ​​​​​​​​​​​​

[0293] In addition, for convenience, the concentration in mol / L is expressed as M. For example, a 1 M aqueous sodium hydroxide solution means an aqueous sodium hydroxide solution with a concentration of 1 mol / L.

[0294] Production Example 1

[0295] A mixture of 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (400 mg), (3R)-1-ethylpiperidin-3-amine dihydrochloride (321 mg), triethylamine (0.930 mL), and DMSO (4 mL) was heated at 150 °C for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 3-chloro-8-[(3R)-1-ethylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (130 mg) as an oily substance.

[0296] Production Example 2

[0297] Under an argon atmosphere, (3R)-1-methylpiperidin-3-amine dihydrochloride (1.61 g) and triethylamine (4.8 mL) were added to a mixture of 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (1.37 g) and DMSO (6 mL), and the mixture was stirred at 150 °C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 3-chloro-4-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (507 mg) as a solid.

[0298] Production Example 3

[0299] A mixture of 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (100 mg), (1R,2R)-2-aminocyclohexan-1-ol (73 mg), triethylamine (0.18 mL), and DMSO (1 mL) was stirred under microwave irradiation at 150 °C for 1 hour. After cooling the resulting mixture to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexan-1-ol (80 mg) as a solid.

[0300] Production Example 4

[0301] Under an argon atmosphere at room temperature, triethylamine (1.31 mL) was added to a mixture of (3S,4R)-4-aminooxacyclohexan-3-ol monohydrochloride (488 mg) and DMSO (5 mL), and the mixture was stirred at this temperature for 5 minutes. At room temperature, 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (500 mg) was added to the resulting mixture, and the mixture was stirred under microwave irradiation at 150 °C for 1 hour. After cooling the resulting mixture to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3S,4R)-4-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)oxacyclohexan-3-ol (325 mg) as a solid.

[0302] Production Example 5

[0303] Under an argon atmosphere, a mixture of 3,6-dichloro-4-[(2-chloroethoxy)methyl]-5-methylpyridazine (200 mg), (1R,2R)-2-aminocyclohexan-1-ol (135 mg), triethylamine (0.220 mL), and DMSO (2 mL) was stirred under microwave irradiation at 150 °C for 2 hours. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (1R,2R)-2-(3-chloro-4-methyl-7,8-dihydropyridazino[3,4-e][1,4]oxazepin-9(5H)-yl)cyclohexan-1-ol (92.4 mg) as an oil.

[0304] Production Example 6

[0305] At room temperature, (3S)-3-aminopyrrolidin-2-one (126 mg) and triethylamine (0.360 mL) were added to a mixture of ethyl 2-(3,6-dichloro-5-methylpyridazin-4-yl)-4-methylbenzenesulfonate (300 mg) and NMP (1.5 mL), and the mixture was stirred at 100 °C for 6 hours. After the resulting mixture was cooled to room temperature, ethyl acetate and saturated sodium chloride aqueous solution / water (1 / 1) were added, and the aqueous layer was extracted successively with ethyl acetate and chloroform / methanol (9 / 1). The organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (3S)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)pyrrolidin-2-one (197 mg) as a solid.

[0306] Production Example 7

[0307] At room temperature, (3R)-1-methylpiperidin-3-amine dihydrochloride (692 mg) and triethylamine (2.06 mL) were added to a mixture of 3,6-dichloro-4-[(2-chloroethoxy)methyl]-5-methylpyridazine (630 mg) and DMSO (12.6 mL), and the mixture was stirred at 150 °C for 3 hours under microwave irradiation. Ethyl acetate and saturated sodium chloride aqueous solution / water (1 / 1) were added to the resulting mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution / water (1 / 1) and then dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 3-chloro-4-methyl-9-[(3R)-1-methylpiperidin-3-yl]-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepine (35 mg) as a solid.

[0308] Production Example 8

[0309] A mixture of 2-chloro-N-[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]-N-methyl-ethan-1-amine (0.209 g), (1R,2R)-2-aminocyclohexan-1-ol (0.136 g), triethylamine (0.43 mL), and DMSO (0.8 mL) was stirred at 150 °C for 1 hour under microwave irradiation. After the reaction mixture was cooled to room temperature, it was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain (1R,2R)-2-(3-chloro-4,6-dimethyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl)cyclohexan-1-ol (0.155 g) as an oil.

[0310] Production Example 9

[0311] A mixture of 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl][(4-methoxyphenyl)methyl]amino}ethyl methanesulfonate (1.746 g), (1R,2R)-2-aminocyclohexan-1-ol (0.641 g), triethylamine (2.1 mL), and DMSO (5 mL) was stirred at 150 °C for 1.5 hours under microwave irradiation. After the reaction mixture was cooled to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1R,2R)-2-{3-chloro-6-[(4-methoxyphenyl)methyl]-4-methyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl}cyclohexan-1-ol (0.777 g) as a solid.

[0312] Production Example 26

[0313] To a mixture of 3-chloro-4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine dihydrochloride (500 mg) and acetonitrile (10 mL) at 25 °C was added potassium carbonate (1.04 g) and 2-bromoethanol (0.200 mL), and the mixture was stirred at 80 °C for 6 hours. After the resulting mixture was concentrated under reduced pressure, water and ethyl acetate were added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 2-[(3R)-3-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)piperidin-1-yl]ethan-1-ol (150 mg) as a solid.

[0314] Production Example 27

[0315] A mixture of tert-butyl (3R)-3-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)piperidine-1-carboxylate (1.5 g) and hydrogen chloride methanol solution (4 M, 10 mL) was stirred at 25 °C for 12 hours. The resulting mixture was concentrated under reduced pressure to obtain 3-chloro-4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine dihydrochloride (1.5 g) as an oil.

[0316] Production Example 30

[0317] Acetic acid (338 mg) was added to a mixture of 3-chloro-4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine dihydrochloride (1.5 g) and 1,2-dichloroethane (10 mL), and the mixture was stirred at 20 °C for 5 minutes. Oxetan-3-one (446 mg), sodium triacetoxyborohydride (1.79 g), and triethylamine (0.861 mL) were added to the resulting mixture, and the mixture was stirred at 40 °C for 12 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 3-chloro-4-methyl-8-[(3R)-1-(oxetan-3-yl)piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (230 mg) as an oil.

[0318] Production Example 32

[0319] Under ice-cooling, sulfuric acid (4.9 mL) was added to a mixture of 3,6-dichloro-4-methylpyridazine (2.99 g) and water (60 mL) over about 10 minutes. Under ice-cooling, 4-chlorobutyric acid (2.02 mL) and silver nitrate (3.12 g) were added to the resulting mixture, and then the mixture was stirred for 15 minutes in a water bath. At room temperature, a mixture of ammonium persulfate (10.5 g) and water (30 mL) was added to the resulting mixture, and then the mixture was stirred at 60 °C for 1.5 hours. At 70 °C, a mixture of 4-chlorobutyric acid (0.368 mL), ammonium persulfate (2.1 g), and water (3 mL) was added to the reaction mixture, and the mixture was stirred at this temperature for 40 minutes. At 70 °C, a mixture of 4-chlorobutyric acid (0.368 mL), ammonium persulfate (2.1 g), and water (3 mL) was added to the resulting mixture, and the mixture was stirred at this temperature for 1.5 hours. After cooling to room temperature, 28% aqueous ammonia solution was added to the reaction mixture under ice-cooling to adjust the pH to about 10. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3,6-dichloro-4-(3-chloropropyl)-5-methylpyridazine (1.51 g) as an oil.

[0320] Production Example 33

[0321] Under ice-cooling, sulfuric acid (1.6 mL) was added to a mixture of 3,6-dichloro-4-methylpyridazine (1 g) and water (30 mL). Under ice-cooling, (2-chloroethoxy)acetic acid (980 mg) and silver nitrate (210 mg) were added to the resulting mixture, and the mixture was stirred for 5 minutes. At room temperature, a mixture of ammonium persulfate (2.8 g) and water (10 mL) was added to the resulting mixture, and then the mixture was stirred at 70 °C for 3 hours. A mixture of (2-chloroethoxy)acetic acid (470 mg), ammonium persulfate (700 mg), and water (2 mL) was added to the resulting reaction mixture, and the mixture was stirred at 70 °C for 2 hours. A mixture of (2-chloroethoxy)acetic acid (470 mg), ammonium persulfate (700 mg), and water (2 mL) was added to the resulting mixture, and the mixture was stirred at 70 °C for 11 hours. 28% aqueous ammonia solution (4 mL) was added to the resulting mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3,6-dichloro-4-[(2-chloroethoxy)methyl]-5-methylpyridazine (465 mg) as a solid.

[0322] Production Example 35

[0323] At 95 °C, a mixture of 4-bromo-3-(methoxymethoxy)phenol (1.86 g), sodium chlorodifluoroacetate (2.43 g), and DMF (11 mL) was added dropwise to a mixture of potassium carbonate (1.65 g) and DMF (7.4 mL) over 1 hour, and the mixture was stirred at this temperature for 15 minutes. After cooling the reaction mixture to room temperature, potassium carbonate (1.65 g) and sodium chlorodifluoroacetate (2.43 g) were added, and the mixture was stirred at 95 °C for 1 hour. After cooling the reaction mixture to room temperature, ethyl acetate and water were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg) as an oil.

[0324] Production Example 36

[0325] To a mixture of 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg) and 1,4-dioxane (9.2 mL) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis-1,3,2-dioxaborolane (1.24 g), PdCl 2 (dppf) (238 mg), and potassium acetate (957 mg), and the mixture was stirred at 100 °C for 3 hours. After cooling the reaction mixture to room temperature, PdCl 2 (dppf) (238 mg) was added, and the mixture was stirred at 100 °C for 2 hours. After cooling the reaction mixture to room temperature, 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis-1,3,2-dioxaborolane (620 mg) was added, and the mixture was stirred at 100 °C for 3 hours. After cooling the reaction mixture to room temperature, hexane was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.98 g) as an oil.

[0326] Production Example 38

[0327] Under an argon atmosphere, a mixture of (1R,2R)-2-(3-chloro-4-methyl-7,8-dihydropyridazino[3,4-e][1,4]oxazepin-9(5H)-yl)cyclohexan-1-ol (79 mg), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg), RuPhos Pd G3 (35 mg), potassium carbonate (88 mg), 1,4-dioxane (1.6 mL), and water (0.4 mL) was stirred under microwave irradiation at 100 °C for 1.5 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (1R,2R)-2-{3-[4-(difluoromethoxy-2-(methoxymethoxy)phenyl]-4-methyl-7,8-dihydropyridazino[3,4-e][1,4]oxazepin-9(5H)-yl}cyclohexan-1-ol (113 mg) as a solid.

[0328] Production Example 39

[0329] Under an argon atmosphere, (1R,2R)-2-{3-chloro-6-[(4-methoxyphenyl)methyl]-4-methyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl}cyclohexan-1-ol (0.762 g), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (0.754 g), PdCl 2 (dppf)·CH 2 Cl 2 (0.149 g), potassium carbonate (0.506 g), 1,4-dioxane (18 mL), and water (5 mL) were stirred at 90 - 100 °C for 24 hours. After the reaction mixture was cooled to room temperature, it was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-6-[(4-methoxyphenyl)methyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.700 g) as a solid.

[0330] Production Example 45

[0331] At 25 °C, trifluoroacetic acid (103 mL) was added to a mixture of tert-butyl (3R)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate (7.4 g) and dichloromethane (100 mL), and the mixture was stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the resulting residue, and the mixture was washed with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added to the aqueous layer to adjust the pH to 8, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain 2-{4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (4.1 g) as a solid.

[0332] Production Example 46

[0333] Under a nitrogen atmosphere, at 0 °C, sodium hydride (94.5 mg, 60% dispersion in mineral oil) was added to a mixture of tert-butyl [(1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexyl]carbamate (600 mg) and DMF (10 mL), and the mixture was stirred at 25 °C for 0.5 hour. At 25 °C, iodomethane (0.147 mL) was added to the resulting mixture, and the mixture was stirred at this temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain tert-butyl [(1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexyl](methyl)carbamate (200 mg) as an oil.

[0334] Production Example 47

[0335] At 25 °C, triethylamine (0.512 mL) was added to a mixture of (1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexan-1-amine (860 mg), di-tert-butyl dicarbonate (802 mg), and dichloromethane (10 mL), and the mixture was stirred at this temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain tert-butyl [(1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexyl]carbamate (700 mg) as an oil.

[0336] Production Example 48

[0337] Under ice-cooling, triethylamine (0.840 mL), p-toluenesulfonyl chloride (920 mg), and 4-(dimethylamino)pyridine (15 mg) were added to a mixture of 2-(3,6-dichloro-5-methylpyridazin-4-yl)ethan-1-ol (500 mg) and dichloromethane (5 mL), and the mixture was stirred at this temperature for 2 hours. Dichloromethane and ice were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium chloride solution / water (1 / 1) was added to the resulting mixture, and the organic layer was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain ethyl 2-(3,6-dichloro-5-methylpyridazin-4-yl)-4-methylbenzenesulfonate (812 mg) as a solid.

[0338] Production Example 50

[0339] Under ice-cooling, a 1 M solution of tetrabutylammonium fluoride in THF (49 mL) was added to a mixture of 4-(2-{[tert-butylbis(phenyl)silyl]oxy}ethyl)-3,6-dichloro-5-methylpyridazine (14.6 g) and THF (290 mL), and the mixture was stirred at this temperature for 0.5 hour. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-(3,6-dichloro-5-methylpyridazin-4-yl)ethan-1-ol (5.55 g) as an oil.

[0340] Production Example 52

[0341] A mixture of 3,6-dichloro-1,2,4,5-tetrazine (450 mg), tert-butyl[(pent-3-yn-1-yl)oxy]bis(phenyl)silane (1.15 g), and 1,3,5-trimethylbenzene (3 mL) was stirred at 160 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-(2-{[tert-butyldi(phenyl)silyl]oxy}ethyl)-3,6-dichloro-5-methylpyridazine (1.2 g) as an oil.

[0342] Production Example 54

[0343] While stirring under ice-cooling, methanesulfonyl chloride (0.35 mL) and triethylamine (1.1 mL) were added to a mixture of 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl][(4-methoxyphenyl)methyl]amino}ethan-1-ol (1.322 g) and dichloromethane (37 mL), and the mixture was stirred for 3.5 hours while allowing it to warm to room temperature naturally. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl][(4-methoxyphenyl)methyl]amino}ethyl methanesulfonate (1.776 g) as an oil.

[0344] Production Example 55

[0345] While under ice-cooling, triethylamine (0.65 mL) and methanesulfonyl chloride (0.36 mL) were added to a mixture of 2-(3,6-dichloro-5-methylpyridazin-4-yl)ethan-1-ol (0.96 g) and ethyl acetate (10 mL), and the mixture was stirred at this temperature for 10 minutes. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to obtain 2-(3,6-dichloro-5-methylpyridazin-4-yl)ethyl methanesulfonate (1.4 g) as an oil.

[0346] Production Example 56

[0347] While at 0 °C, methanesulfonic anhydride (25 mg) was added to a mixture of 3-(3,6-dichloro-5-methylpyridazin-4-yl)-3-methoxypropan-1-ol (30 mg), triethylamine (0.018 mL), and dichloromethane (1 mL), and the mixture was stirred at this temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain 3-(3,6-dichloro-5-methylpyridazin-4-yl)-3-methoxypropyl methanesulfonate (39 mg) as an oil. It was used in the next reaction without purification.

[0348] Production Example 57

[0349] Under an argon atmosphere, triethylamine (0.81 mL) and methanesulfonyl chloride (0.25 mL) were added to a mixture of 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]sulfanyl}ethan-1-ol (0.671 g) and dichloromethane (27 mL) with ice-cooling and stirring, and the mixture was stirred for 2.5 hours while allowing it to warm naturally to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, the aqueous layer was extracted with dichloromethane, and the organic layer was washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]sulfanyl}ethyl methanesulfonate (0.770 g) as an oil.

[0350] Production Example 58

[0351] Under ice-cooling and stirring, methanesulfonyl chloride (0.43 mL) and triethylamine (1.4 mL) were added to a mixture of (2R)-2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl][(4-methoxyphenyl)methyl]amino}propan-1-ol (1.705 g) and dichloromethane (46 mL), and the mixture was stirred for 3 hours while allowing it to warm naturally to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (2R)-2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl][(4-methoxyphenyl)methyl]amino}propyl methanesulfonate (2.233 g) as an oil.

[0352] Production Example 59

[0353] Under a nitrogen atmosphere, at -78 °C, n-butyllithium (2.5 M, 0.227 mL) was added to a mixture of tert-butyl [(3-methoxypent-4-yn-1-yl)oxy]bis(phenyl)silane (100 mg) and THF (2 mL), and the mixture was stirred at this temperature for 30 minutes. Methyl iodide (0.018 mL) was added to the resulting mixture, and then the mixture was stirred at 15 °C for 90 minutes. After adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain tert-butyl [(3-methoxyhex-4-yn-1-yl)oxy]bis(phenyl)silane (80 mg) as an oil.

[0354] Production Example 60

[0355] To a mixture of 3-methoxypent-4-yn-1-ol (700 mg) and dichloromethane (10 mL) were added imidazole (626 mg) and tert-butyl(chloro)bis(phenyl)silane (1.73 mL), and the mixture was stirred at 15 °C for 12 hours. After adding water to the reaction mixture, it was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain tert-butyl [(3-methoxypent-4-yn-1-yl)oxy]bis(phenyl)silane (630 mg) as an oil.

[0356] Production Example 61

[0357] A mixture of tert-butyl [(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methylpyridazin-4-yl)methyl]carbamate (0.403 g), trifluoroacetic acid (4 mL), and dichloromethane (8 mL) was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 2-[5-(aminomethyl)-6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4-methylpyridazin-3-yl]-5-(trifluoromethyl)phenol (0.242 g) as a solid.

[0358] Production Example 62

[0359] A mixture of tert-butyl [(3,6-dichloro-5-methylpyridazin-4-yl)methyl]carbamate (1.608 g), (1R,2R)-2-aminocyclohexan-1-ol (1.261 g), DIPEA (2.3 mL), and cyclopentanol (5.5 mL) was stirred at 150 - 155 °C for 19 hours. Water and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl [(6-chloro-3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methylpyridazin-4-yl)methyl]carbamate (0.824 g) as a solid.

[0360] Production Example 63

[0361] A mixture of 1-(3,6-dichloro-5-methylpyridazin-4-yl)methanamine monohydrochloride (0.615 g), di-tert-butyl dicarbonate (0.93 mL), triethylamine (1.13 mL), and dichloromethane (9 mL) was stirred at 0 °C for 1 hour and then at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the resulting residue, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain tert-butyl [(3,6-dichloro-5-methylpyridazin-4-yl)methyl]carbamate (0.949 g) as an oil.

[0362] Production Example 64

[0363] A mixture of N-[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]-1,1,1-triphenylmethanamine (1.400 g), 1,4-dioxane solution of hydrogen chloride (4 M, 4 mL), and dichloromethane (8 mL) was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration and washed with diethyl ether to obtain 1-(3,6-dichloro-5-methylpyridazin-4-yl)methanamine monohydrochloride (0.615 g) as a solid.

[0364] Production Example 65

[0365] A mixture of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (1.003 g), 2-(methylamino)ethanol (0.47 mL), potassium carbonate (1.631 g), and acetonitrile (20 mL) was stirred at 51 °C for 5 hours. The reaction mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl](methyl)amino}ethanol (0.626 g) as an oil.

[0366] Production Example 66

[0367] A mixture of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (2.035 g), 2-{[(4-methoxyphenyl)methyl]amino}ethan-1-ol (1.441 g), potassium carbonate (2.198 g), and acetonitrile (40 mL) was stirred at 50 °C for 5 hours. After the reaction mixture was cooled to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl][(4-methoxyphenyl)methyl]amino}ethan-1-ol (1.326 g) as a solid.

[0368] Production Example 72

[0369] A mixture of (1R,2R)-2-[(2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]sulfanyl}ethyl)amino]cyclohexan-1-ol (0.217 g), DMF (6 mL), potassium carbonate (0.171 g), and copper(I) iodide (0.236 g) was stirred at 150 °C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, water was added to the filtrate, and then it was filtered through Celite again. The aqueous layer was extracted from the filtrate with ethyl acetate, and the organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1R,2R)-2-(3-chloro-4-methyl-7,8-dihydropyridazino[3,4-e][1,4]thiazepin-9(5H)-yl)cyclohexan-1-ol (0.040 g) as a solid.

[0370] Production Example 73

[0371] A mixture of 4-(bromomethyl)-3,6-dichloro-5-methylpyridazine (2.026 g), DMF (28 mL), cesium carbonate (2.711 g), and 2-mercaptoethanol (0.59 mL) was stirred at 60 - 70 °C for 3 hours. The reaction mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]sulfanyl}ethan-1-ol (0.671 g) as an oil.

[0372] Production Example 74

[0373] Under ice-cooling stirring, triethylamine (0.42 mL) and p-toluenesulfonyl chloride (0.475 g) were added to a mixture of 2-{[(3,6-dichloro-5-methylpyridazin-4-yl)methyl](methyl)amino}ethan-1-ol (0.623 g) and dichloromethane (2.5 mL), and the mixture was stirred for 42 hours while allowing it to warm up to room temperature naturally. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-N-[(3,6-dichloro-5-methylpyridazin-4-yl)methyl]-N-(methyl)ethan-1-amine (0.212 g) as an oil.

[0374] Production Example 75

[0375] A mixture of N-[3-(3,6-dichloro-5-methylpyridazin-4-yl)propyl]-1-(oxan-2-yl)-1H-pyrazol-3-amine (0.513 g), triethylamine (0.77 mL), and DMSO (3 mL) was stirred at 150 °C for 6 hours under microwave irradiation. The reaction mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). A mixture of the obtained purified product (0.219 g), potassium carbonate (0.163 g), copper(I) iodide (0.225 g), and DMF (6 mL) was stirred at 150 °C for 1 hour under microwave irradiation. The reaction mixture was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-chloro-4-methyl-8-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (0.025 g) as a solid.

[0376] Production Example 76

[0377] A mixture of tert-butyl [(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]carbamate (0.512 g), 1,4-dioxane solution of hydrogen chloride (4 M, 5 mL), and methanol (10 mL) was stirred at room temperature for 4 hours, then 1,4-dioxane solution of hydrogen chloride (4 M, 5 mL) was added, and the mixture was stirred at room temperature for 42 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to obtain (3R)-1-(2,2-difluoroethyl)piperidin-3-amine dihydrochloride (0.461 g) as a solid.

[0378] Production Example 77

[0379] A mixture of tert-butyl (3R)-piperidin-3-ylcarbamate (2.163 g), 2,2-difluoroethyl trifluoromethanesulfonate (1.7 mL), DIPEA (3.7 mL), and 1,4-dioxane (36 mL) was stirred at 80 °C for 20 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl [(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]carbamate (2.779 g) as an oil.

[0380] Production Example 78

[0381] A mixture of 4-bromo-3-(methoxymethoxy)benzaldehyde (1.086 g), N,N-diethylaminosulfur trifluoride (1.77 mL), and dichloromethane (15 mL) was stirred at 0 °C for 30 minutes and then at room temperature for 4 hours. After the reaction mixture was cooled to 0 °C, saturated aqueous sodium bicarbonate was added, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1-bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene (0.973 g) as an oil.

[0382] Production Example 79

[0383] A mixture of 2-{(7R)-9-[(1R,2R)-2-hydroxycyclohexyl]-6-[(4-methoxyphenyl)methyl]-4,7-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.590 g), trifluoroacetic acid (4 mL), and anisole (1 mL) was stirred under heating reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate, ethyl acetate, and methanol were added to the resulting residue. The aqueous layer was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 2-{(7R)-9-[(1R,2R)-2-hydroxycyclohexyl]-4,7-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.256 g) as a solid.

[0384] Production Example 80

[0385] Under a nitrogen atmosphere, at 25 °C, to a mixture of (3S)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)pyrrolidin-2-one (320 mg), 1,2-dimethoxyethane (3 mL), and water (1 mL) were added 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (627 mg), sodium carbonate (403 mg), and SPhos Pd G3 (98.8 mg). The mixture was stirred at 120 °C for 2 hours under microwave irradiation. After adding the reaction mixture to water (4 mL), it was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain (3S)-3-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one (103 mg) as a solid.

[0386] Example 1

[0387] To a mixture of (1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexan-1-ol (113 mg), 1,4-dioxane (3.5 mL), and water (0.7 mL) were added potassium carbonate (171 mg), RuPhos Pd G3 (50 mg), and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (251 mg). The mixture was stirred at 100 °C for 1.5 hours under microwave irradiation. After adding water to the reaction mixture, it was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (using neutral silica gel, hexane / ethyl acetate, and then using basic silica gel, chloroform / methanol). Diethyl ether (2 mL) and hexane (5 mL) were added to the purified product, and the solid was filtered to obtain 2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (46 mg) as a solid.

[0388] Example 2

[0389] At room temperature, RuPhos Pd G3 (7 mg) was added to a mixture of [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (35 mg), 3-chloro-4-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (24 mg), potassium carbonate (36 mg), 1,4-dioxane (2 mL), and water (0.5 mL), and the mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, silica gel was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (using neutral silica gel, chloroform / methanol, and then basic silica gel, chloroform / methanol) to obtain 2-{4-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (7.1 mg) as a solid.

[0390] Example 3

[0391] Under a nitrogen atmosphere, at 25 °C, sodium carbonate (216 mg) and SPhos Pd G3 (52.9 mg) were added to a mixture of 3-chloro-8-[(3R)-1-ethylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine (200 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (210 mg), 1,2-dimethoxyethane (8 mL), and water (1 mL), and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase preparative HPLC (ODS column, aqueous ammonia + ammonium bicarbonate solution / acetonitrile) to obtain 2-{8-[(3R)-1-ethylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (65.7 mg) as a solid.

[0392] Example 4

[0393] Under an argon atmosphere, a mixture of (1R,2R)-2-(3-chloro-4-methyl-7,8-dihydropyridazino[3,4-e][1,4]oxazepin-9(5H)-yl)cyclohexan-1-ol (90 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (120 mg), RuPhosPd G3 (38 mg), potassium carbonate (105 mg), 1,4-dioxane (2 mL), and water (0.4 mL) was stirred under microwave irradiation at 100 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using basic silica gel, chloroform / methanol, and then using neutral silica gel, chloroform / methanol). Hexane / ethyl acetate (15 / 1) was added to the purified product for suspension, and the solid was filtered to obtain 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}-5-(trifluoromethyl)phenol (76 mg) as a solid.

[0394] Example 5

[0395] Under an argon atmosphere, a mixture of (3S)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)pyrrolidin-2-one (100 mg), 1,4-dioxane (3 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (163 mg), RuPhos Pd G3 (33 mg), potassium carbonate (164 mg), and water (0.6 mL) was stirred under microwave irradiation at 100 °C for 1 hour. After cooling to room temperature, chloroform / methanol (9 / 1) and saturated aqueous sodium chloride solution / water (1 / 1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The organic layer was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (using neutral silica gel, chloroform / methanol, and then using basic silica gel, chloroform / methanol) to obtain (3S)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one (88 mg) as a solid.

[0396] Example 6

[0397] A mixture of 3-chloro-4-methyl-9-[(3R)-1-methylpiperidin-3-yl]-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepine (59 mg), 1,4-dioxane (0.8 mL), 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg), RuPhos Pd G3 (26 mg), potassium carbonate (83 mg), and water (0.2 mL) was stirred under microwave irradiation at 100 °C for 1 hour. After adding chloroform and saturated aqueous sodium chloride solution / water (1 / 1) to the reaction mixture, the organic layer was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (using basic silica gel, chloroform / methanol, and then using neutral silica gel, chloroform / methanol) to obtain 5-methoxy-2-{4-methyl-9-[(3R)-1-methylpiperidin-3-yl]-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol (50 mg) as a solid.

[0398] Example 7

[0399] Under an argon atmosphere, a mixture of (1R,2R)-2-(3-chloro-4,6-dimethyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl)cyclohexan-1-ol (0.152 g), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (0.201 g), PdCl 2 (dppf)·CH 2 Cl 2 (0.040 g), potassium carbonate (0.135 g), 1,4-dioxane (5 mL), and water (1.2 mL) was stirred at 45 °C for 1.5 hours and then at 120 °C for 13.5 hours. After cooling the reaction mixture to room temperature, it was poured into water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4,6-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.047 g) as a solid.

[0400] Example 27

[0401] Under a nitrogen atmosphere, at 25 °C, [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (149 mg), sodium carbonate (153 mg), and SPhos Pd G3 (37.7 mg) were added to a mixture of 2-[(3R)-3-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)piperidin-1-yl]ethan-1-ol (150 mg), 1,2-dimethoxyethane (1.5 mL), and water (1.5 mL). The mixture was stirred at 120 °C for 2 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by reversed-phase preparative HPLC (ODS column, hydrochloric acid / acetonitrile) to obtain 2-{8-[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol dihydrochloride (77.6 mg) as a solid.

[0402] Example 28

[0403] Under a nitrogen atmosphere, a mixture of (1R,2R)-2-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)cyclohexan-1-ol (153 mg), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (359 mg), RuPhos Pd G3 (46 mg), 1,4-dioxane (4 mL), water (1 mL), and potassium carbonate (226 mg) was stirred at 105 °C for 3 hours. After cooling to room temperature, chloroform and water were added to the mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. Methanol (3 mL) and 12 M hydrochloric acid (0.5 mL) were added to the resulting residue at room temperature, and the mixture was stirred at 60 °C for 2 hours. An aqueous sodium hydroxide solution (1 M, 6 mL) and water (4 mL) were added to the reaction mixture at room temperature, and then the mixture was extracted with chloroform / 2-propanol (5 / 1). The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol). Diisopropyl ether (2 mL) and hexane (10 mL) were added to the resulting purified product at room temperature, and the mixture was triturated. The solid was filtered off and dried under reduced pressure to obtain 5-(difluoromethoxy)-2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}phenol (140 mg) as a solid.

[0404] Example 29

[0405] Under a nitrogen atmosphere, a mixture of (3S,4R)-4-(3-chloro-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)oxan-3-ol (123 mg), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (286 mg), RuPhos Pd G3 (37.2 mg), 1,4-dioxane (4 mL), water (1 mL), and potassium carbonate (180 mg) was stirred at 105 °C for 3 hours. After cooling to room temperature, chloroform and water were added to the mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. Methanol (3 mL) and hydrochloric acid (12 M, 0.5 mL) were added to the obtained residue at room temperature, and the mixture was stirred at 60 °C for 2 hours. After adding an aqueous sodium hydroxide solution (1 M, 6 mL) and water (4 mL) to the reaction mixture at room temperature, the mixture was extracted with chloroform / 2-propanol (5 / 1). The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol). Diisopropyl ether (2 mL) and hexane (10 mL) were added to the obtained purified product at room temperature, and the mixture was triturated. The solid was filtered off and dried under reduced pressure to obtain (3S,4R)-4-{3-[4-(difluoromethoxy)-2-hydroxyphenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}oxan-3-ol (127 mg) as a solid.

[0406] Example 30

[0407] At room temperature, hydrochloric acid (12 M, 0.3 mL) was added to a mixture of (1R,2R)-2-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4-methyl-7,8-dihydropyridazino[3,4-e][1,4]oxazepin-9(5H)-yl}cyclohexan-1-ol (110 mg) and methanol (3 mL), and the mixture was stirred at 60 °C for 1.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Chloroform / methanol (10 / 1) and basic silica gel were added to the obtained residue, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, chloroform / methanol). Hexane / ethyl acetate (20 / 1) was added to the obtained purified product and the mixture was suspended. The solid was filtered off and dried under reduced pressure to obtain 5-(difluoromethoxy)-2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol (72 mg) as a solid.

[0408] Example 31

[0409] At 25 °C, trifluoroacetic acid (103 mL) was added to a mixture of tert-butyl (3R)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate (7.4 g) and dichloromethane (100 mL), and the mixture was stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Triethylamine (0.106 mL) was added to a part (386 mg) of the resulting residue and methanol (3 mL), and the pH was adjusted to about 8, then glacial acetic acid (45.9 mg) was added to adjust the pH to about 5. [(1-Ethoxycyclopropyl)oxy]tris(methyl)silane (267 mg) and titanium(IV) isopropoxide (1.09 g) were added to the resulting mixture, and the mixture was stirred at 25 °C for 30 minutes. Sodium cyanoborohydride (240 mg) was added to the resulting mixture, and the mixture was stirred at 60 °C for 16 hours. Saturated aqueous sodium bicarbonate solution (3 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the resulting residue was purified by reversed-phase preparative HPLC (ODS column, ammonia water / acetonitrile) to obtain 2-{8-[(3R)-1-cyclopropylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (97.9 mg) as a solid.

[0410] Example 32

[0411] At 25 °C, triethylamine (0.220 mL) and dichloromethane (4 mL) were added to a part (400 mg) of the residue obtained above, and then methyl chloroformate (0.082 mL) was added at 25 °C, and the mixture was stirred at this temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the resulting residue was purified by reversed-phase preparative HPLC (ODS column, ammonia water / acetonitrile) to obtain methyl (3R)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate (138 mg) as a solid.

[0412] Example 33

[0413] Under a nitrogen atmosphere, at 20 °C, triethylamine (0.133 mL) and isocyanatotris(methyl)silane (0.093 mL) were added to a mixture of 2-{4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (250 mg) and dichloromethane (10 mL), and the mixture was stirred at this temperature for 16 hours. After adding water to the reaction mixture, extraction was performed with dichloromethane. The organic layer was concentrated under reduced pressure. The obtained residue was combined with the residue obtained by performing the same operation as above using 2-{4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (50 mg) and purified by silica gel column chromatography (dichloromethane / methanol), whereby (3R)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxamide (144 mg) was obtained in solid form.

[0414] Example 34

[0415] At 0 °C, DIPEA (0.067 mL) and methanesulfonic anhydride (33.3 mg) were added to a mixture of 2-{4-methyl-8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (50 mg) and dichloromethane (2 mL), and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was combined separately with the residue obtained by performing the above operation two more times and purified by reversed-phase preparative HPLC (ODS column, aqueous ammonia + ammonium bicarbonate solution / acetonitrile), whereby 2-{8-[(3R)-1-(methanesulfonyl)piperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (107 mg) was obtained in solid form.

[0416] Example 35

[0417] At room temperature, triethylamine (0.46 mL) was added to a mixture of (1s,3s)-3-amino-1-methylcyclobutan-1-ol monohydrochloride (118 mg) and NMP (1.5 mL), and the mixture was stirred at this temperature for 5 minutes. At room temperature, 2-(3,6-dichloro-5-methylpyridazin-4-yl)ethyl 4-methylbenzenesulfonate (200 mg) was added to the resulting mixture, and the mixture was stirred at 150 °C for 1 hour under microwave irradiation. After cooling to room temperature, ethyl acetate and water were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. To the resulting residue were added 1,4-dioxane (8 mL), water (2 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (230 mg), RuPhos Pd G3 (47.1 mg), and potassium carbonate (241 mg), and the mixture was stirred at 105 °C for 2 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (5 / 1). The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol). To the resulting purified product were added 1,4-dioxane (8 mL), water (2 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (229 mg), RuPhos Pd G3 (47 mg), and potassium carbonate (240 mg), and the mixture was stirred at 105 °C for 2 hours under microwave irradiation. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with chloroform / 2-propanol (5 / 1). The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol). At room temperature, diisopropyl ether (2 mL) and hexane (10 mL) were added to the resulting purified product, and the mixture was triturated. The solid was filtered off and dried under reduced pressure to obtain 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (84.8 mg) as a solid.

[0418] Example 36

[0419] A mixture of 2-[5-(aminomethyl)-6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4-methylpyridazin-3-yl]-5-(trifluoromethyl)phenol (0.054 g), formaldehyde (37% aqueous solution, 61 μL), and methanol (1.4 mL) was stirred at room temperature for 40 minutes, then sodium triacetoxyborohydride (0.086 g) was added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4,6-dimethyl-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (0.028 g) as a solid.

[0420] Example 37

[0421] A mixture of 2-[5-(aminomethyl)-6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4-methylpyridazin-3-yl]-5-(trifluoromethyl)phenol (0.037 g), carbonyldiimidazole (0.019 g), and THF (2 mL) was stirred at room temperature for 1 hour. Ethyl acetate (6 mL) and hydrochloric acid (2 M, 6 mL) were added to the reaction mixture, and then the aqueous layer was removed. The organic layer was washed with hydrochloric acid (2 M). All the aqueous layers were combined, made basic by adding a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 8-[(1R,2R)-2-hydroxycyclohexyl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,8-dihydropyrimido[4,5-c]pyridazin-7(6H)-one (0.010 g) as a solid.

[0422] Example 38

[0423] A mixture of 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-6-[(4-methoxyphenyl)methyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.053 g), trifluoroacetic acid (0.39 mL), and anisole (98 μL) was stirred at 80 - 100 °C for 21 h. After the reaction mixture was cooled to 0 °C, saturated aqueous sodium bicarbonate was added to make it alkaline, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.010 g) as a solid.

[0424] Example 39

[0425] Under ice-cooling and stirring, acetic anhydride (33 μL) was added to a mixture of 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.123 g), DIPEA (61 μL), and dichloromethane (3 mL), and the mixture was stirred at room temperature for 3.5 h. Water was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain (1R,2R)-2-{6-acetyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl}cyclohexyl acetate (0.082 g) as a solid.

[0426] Example 40

[0427] A mixture of (1R,2R)-2-{6-acetyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl}cyclohexyl acetate (0.065 g), potassium carbonate (0.035 g), methanol (0.4 mL), and water (46 μL) was stirred at room temperature for 3.5 hours and then at 40 - 50 °C for 2.5 hours. The reaction mixture was concentrated under reduced pressure. Dichloromethane and 10% hydrochloric acid were added to the residue to dissolve it, and then the organic layer was separated using a phase separator. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, hexane was added, and the precipitated solid was filtered to obtain 1-{9-[(1R,2R)-2-hydroxycyclohexyl]-3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,7,8,9-tetrahydro-6H-pyridazino[3,4-e][1,4]diazepin-6-yl}ethan-1-one (0.056 g) as a solid.

[0428] Example 41

[0429] A mixture of 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.091 g), acetaldehyde (18 μL), sodium triacetoxyborohydride (0.092 g), and methanol (2 mL) was stirred at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the precipitated solid was filtered. The obtained solid was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain 2-{6-ethyl-9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol (0.012 g) as a solid.

[0430] Example 43

[0431] Under ice-cooling stirring, trifluoroacetic acid (85 μL) was added to a mixture of 2-{4-methyl-8-[1-(oxan-2-yl)-1H-pyrazol-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine-3-yl}-5-(trifluoromethyl)phenol (0.039 g) and dichloromethane (1 mL), and the mixture was stirred for 41 hours while allowing it to warm to room temperature naturally. The reaction mixture was cooled with ice, dichloromethane (1 mL) and trifluoroacetic acid (85 μL) were added, and the mixture was stirred for 6 hours while allowing it to warm to room temperature naturally. Then the reaction mixture was cooled with ice, dichloromethane (1 mL) and trifluoroacetic acid (85 μL) were added, and the mixture was stirred for 66 hours while allowing it to warm to room temperature naturally. The reaction mixture was cooled to 0 °C, saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 2-[4-methyl-8-(1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine-3-yl]-5-(trifluoromethyl)phenol (0.016 g) as a solid.

[0432] Example 44

[0433] A mixture of (1R,2R)-2-{3-[4-(difluoromethyl)-2-(methoxymethoxy)phenyl]-4,6-dimethyl-5,6,7,8-tetrahydro-9H-pyridazino[3,4-e][1,4]diazepin-9-yl}cyclohexan-1-ol (0.199 g), trifluoroacetic acid (0.72 mL), and dichloromethane (4.3 mL) was stirred at room temperature for 16.5 hours. The reaction mixture was cooled to 0 °C, saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted with dichloromethane / methanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol). Dichloromethane and hexane were added to the obtained purified product, and the precipitated solid was filtered to obtain 5-(difluoromethyl)-2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4,6-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}phenol (0.067 g) as a solid.

[0434] Example 45

[0435] To a mixture of (3S)-3-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one (80 mg) and 1,4-dioxane (2 mL) at 13 °C was added 4M hydrogen chloride 1,4-dioxane solution (2 mL), and the mixture was stirred at 13 °C to 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase preparative HPLC (ODS column, hydrochloric acid / acetonitrile) to obtain (3S)-3-{3-[4-(difluoromethoxy)-2-hydroxyphenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one (18 mg) as a solid.

[0436] In the same manner as the method of the above Preparation Example or Example, the compounds of Preparation Examples and Examples shown in the following table were prepared.

[0437] [Table 2-1]

[0438]

[0439] [Table 2-2]

[0440]

[0441] [Table 2-3]

[0442]

[0443] [Table 2-4]

[0444]

[0445] [Table 3-1]

[0446]

[0447] [Table 3-2]

[0448]

[0449] [Table 3-3]

[0450]

[0451] [Table 4-1]

[0452] PEx PSyn DAT 1 - ESI+; 295.1 2 - ESI+; 281.2, 283.2 3 - ESI+; 282.4, 284.4 4 - ESI+; 284.3, 286.4 5 - ESI+; 298.4, 300.4 6 - ESI+; 253.1, 255.1 7 - ESI+; 297.4, 299.3 8 - ESI+; 311.3, 313.2 9 - ESI+; 417.4, 419.3 10 1 ESI+; 308.9 11 1 ESI+; 367.1 12 1 ESI+; 296.0 13 1 ESI+; 281.2, 283.2 14 1 ESI+; 295.2, 297.2 15 1 ESI+; 267.1, 269.1 16 1 ESI+; 3383.2, 385.1 17 1 ESI+; 281.1 18 1 ESI+; 268.1 19 1 ESI+; 228.1 20 1 ESI+; 312.2, 314.0 21 1 ESI+; 277.1, 279.1 22 1 ESI+; 387.3, 389.3 23 1 ESI+; 335.3, 337.2 [M+Na]+ 24 1 ESI+; 347.2, 349.2 25 1 ESI+; 431.5, 433.5 26 - ESI+; 311.1 27 - ESI+; 267.1 28 27 ESI+, 283.1, 285.1 29 27 ESI+; 295.1 30 - ESI+; 323.1 31 30 ESI+; 297.1 32 - ESI+; 239.0 33 - ESI+; 255.1 34 32 ESI+; 254.9

[0453] [Table 4-2]

[0454]

[0455] [Table 4-3]

[0456]

[0457] [Table 4-4]

[0458]

[0459] [Table 5-1]

[0460]

[0461] [Table 5-2]

[0462]

[0463] [Table 5-3]

[0464]

[0465] [Table 5-4]

[0466]

[0467] Industrial applicability

[0468] The compound of formula (I) or a salt thereof has an inhibitory effect on NLRP3 inflammasome activation and can be expected to be used as a prophylactic and / or therapeutic agent for inflammatory diseases and / or neurodegenerative diseases.

Claims

1. A compound of formula (I) or a salt thereof, [Chemical formula 1] wherein ring A is a 5- to 7-membered nitrogen-containing partially unsaturated heterocycle, R 1a and R 1b each independently is H, C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl or halogen, R 2 is H or C 1-6 alkyl group R 3a and R 3b each independently is H, C 1-6 alkyl, -O-C 1-6 alkyl, -C 1-6 alkylene - optionally substituted aryl, oxo, -C(=O)-C 1-6 alkyl or -S(=O) 2 -C 1-6 alkyl, R 4 is C alkyl substituted by 1 to 3 R 5 alkyl, C cycloalkyl that may be substituted by 1 to 4 R 1-6 alkyl, 4- to 7-membered saturated heterocyclic group that may be substituted by 1 to 4 R 6 or heteroaryl that may be substituted by 1 to 4 R 3-8 alkyl, C cycloalkyl that may be substituted by 1 to 4 R 7 substituted 4- to 7-membered saturated heterocyclic group, or heteroaryl that may be substituted by 1 to 4 R 8 substituted heteroaryl R 5 , R 6 , R 7 and R 8 Each independently is C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 alkyl, 4-7 membered saturated heterocyclic group, oxo, cyano, -C(=O)-C 1-6 Alkyl, -S(=O) 2 -C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-NR 9 R 10 、-NR 9 R 10 , -C 1-6 Alkylene-OR 11 , or -OR 11 , R 9 、R 10 each independently is H, C 1-6 alkyl or -C(=O)-C 1-6 alkyl, R 11 is H, C 1-6 alkyl or -C(=O)-C 1-6 alkyl.

2. The compound or a salt thereof according to claim 1, wherein, formula (I) is formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), [Chemical formula 2] wherein, R 1a and R 1b each independently is H, C 1-6 alkyl, -O-C 1-6 alkyl, halo-C 1-6 alkyl, -O-halo-C 1-6 alkyl, or halogen, R 2 is H or C 1-6 alkyl group R 3a and R 3b each independently is H, C 1-6 alkyl, -O-C 1-6 alkyl, -C 1-6 alkylene - optionally substituted aryl, oxo, or -C(=O)-C 1-6 alkyl, R 4 is a C 5 alkyl group substituted by one R 1-6 a C 6 cycloalkyl group that may be substituted by 1 to 2 Rs 3-8 a 4- to 7-membered saturated heterocyclic group that may be substituted by 1 to 2 Rs 7 or an unsubstituted heteroaryl group R 5 is -NR 9 R 10 or -OR 11 , R 6 is C 1-6 alkyl, cyano, -NR 9 R 10 or -OR 11 , R 7 is C 1-6 alkyl, C 3-8 cycloalkyl, halo-C 1-6 alkyl, 4- to 7-membered saturated heterocyclic group, oxo, -C(=O)-C 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -C(=O)-O-C 1-6 alkyl, -C(=O)-NR 9 R 10 、-C 1-6 alkylene-OR 11 、or -OR 11 , R 9 is H, R 10 is H, C 1-6 alkyl, or -C(=O)-C 1-6 alkyl, R 11 is H, C 1-6 alkyl or -C(=O)-C 1-6 alkyl.

3. The compound or a salt thereof according to claim 2, wherein, formula (I) is formula (Ia), (Ib), (Ie), or (If), R 1a is -O-C 1-6 alkyl, halo-C 1-6 alkyl, or -O-halo-C 1-6 alkyl, and R 1b is H, R 2 is C 1-6 alkyl R 3a is H, R 3b is H or C 1-6 alkyl group R 4 is C substituted by one R 6 cycloalkyl, or 4- to 7-membered saturated heterocyclic group substituted by one R 3-8 or 4- to 7-membered saturated heterocyclic group substituted by one R 7 ​ R 6 is - OR 11 , R 7 is C 1-6 alkyl, oxo, or -OR 11 , R 11 is H.

4. The compound or a salt thereof according to claim 1, wherein, the compound is a compound selected from the group consisting of: 2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol, 2-{4-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol, 2-{8-[(3R)-1-ethylpiperidin-3-yl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-{8-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}phenol, (3S,4R)-4-{3-[4-(difluoromethoxy)-2-hydroxyphenyl]-4-methyl-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}oxan-3-ol, 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol, (3S)-3-{3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one, 5-methoxy-2-{4-methyl-9-[(3R)-1-methylpiperidin-3-yl]-5,7,8,9-tetrahydropyridazino[3,4-e][1,4]oxazepin-3-yl}phenol, 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4,6-dimethyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol, 2-{9-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-6,7,8,9-tetrahydro-5H-pyridazino[3,4-e][1,4]diazepin-3-yl}-5-(trifluoromethyl)phenol, and (3S)-3-{3-[4-(Difluoromethoxy)-2-hydroxyphenyl]-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}pyrrolidin-2-one.

5. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1, and one or more pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to claim 5, which is an NLRP3 inflammasome activation inhibitor.

7. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

8. Use of the compound or a salt thereof according to claim 1 in the manufacture of a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

9. Use of the compound or a salt thereof according to claim 1 for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

10. The compound or a salt thereof according to claim 1, which is used for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

11. A method for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

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