Substituted pyridazine compound

Abstract

The object of the present invention is to provide a pharmaceutical composition, particularly a compound suitable for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases. The inventors have conducted in-depth research on the exploration of compounds having an inhibitory effect on NLRP3 inflammasome activation, and found that substituted pyridazine compounds have an inhibitory effect on NLRP3 inflammasome activation, thus completing the present invention. The substituted pyridazine compounds of the present invention can be expected to be used as preventive and / or therapeutic drugs for inflammatory diseases and / or neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to a substituted pyridazine compound 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 or neurodegenerative diseases. Background Art

[0002] An inflammasome is an intracellular aggregate of proteins caused by endogenous / exogenous alarm molecules, and is a mechanism that is involved in the activation caused by the cleavage of inflammatory cytokines IL-1β and IL-18 via the activation of caspase1 or the exacerbation of the inflammatory response caused by the induction of cell death. 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) is known (Nature Genetics, Vol. 29, No. 3, pp. 301-305, 2001). 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] It is described in Patent Document 1 that the compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (for the notations in the formula, refer to this publication).

[0005] [Chemical Formula 1]

[0006]

[0007] It is described in Patent Document 2 that the compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (for the notations in the formula, refer to this publication).

[0008] [Chemical Formula 2]

[0009]

[0010] It is described in Patent Document 3 that the compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (for the notations in the formula, refer to this publication).

[0011] [Chemical Formula 3]

[0012]

[0013] In addition, it is described in Patent Document 4 published after the priority date of this application that the compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (for the notations in the formula, refer to this publication).

[0014] [Chemical Formula 4]

[0015]

[0016] Prior Art Documents

[0017] Patent Documents

[0018] Patent Document 1: International Publication No. 2019 / 008025

[0019] Patent Document 2: International Publication No. 2017 / 184604

[0020] Patent Document 3: International Publication No. 2018 / 015445

[0021] Patent Document 4: International Publication No. 2020 / 234715 Summary of the Invention

[0022] Problems to be Solved by the Invention

[0023] The present invention provides a pharmaceutical composition, particularly a compound having an inhibitory effect on NLRP3 inflammasome activation and expected to be used as an active ingredient of a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases or neurodegenerative diseases, etc.

[0024] Means for solving the problem

[0025] The present inventors have conducted in-depth studies on compounds having an inhibitory effect on NLRP3 inflammasome activation, and as a result, have found that substituted pyridazine compounds have an inhibitory effect on NLRP3 inflammasome activation and are expected to be used as active ingredients of pharmaceutical compositions for the prevention and / or treatment of inflammatory diseases and neurodegenerative diseases, etc., particularly α-synucleinopathy and multiple sclerosis, thereby completing the present invention.

[0026] 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 pharmaceutically acceptable excipients.

[0027] [Chemical formula 5]

[0028]

[0029] (In the formula, Ar is a group represented by the following formula (i) or formula (ii),

[0030] [Chemical formula 6]

[0031]

[0032] (* represents the bonding part of the pyridazine ring of formula (I).)

[0033] L is C 1-6 alkylene or C 3-8 cycloalkylene,

[0034] R 1 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl optionally substituted by 1 to 4 C 1-6 alkyl, cyano, -OR 7 or -N(C 1-6 alkyl)2,

[0035] R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl optionally substituted by 1 to 4 C 1-6 alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, -C(=O)O-C1-6 alkyl or -C(=O)NR 8 R 9 ,

[0036] R 3 is OH, -NHC(=O)R 10 or -OC(=O)-C 1-6 alkyl,

[0037] R 4 is halogen, -O-C 1-6 alkyl or halo C 1-6 alkyl,

[0038] R 5 is H, C 3-8 cycloalkyl or halo C 1-6 alkyl,

[0039] R 6 is H, halogen, -O-C 1-6 alkyl or halo C 1-6 alkyl,

[0040] R 7 is -C 1-6 alkylene-O-C 1-6 alkylene-aryl or halo C 1-6 alkyl,

[0041] R 8 and R 9 are the same or different and are H or C 1-6 alkyl, or R 8 and R 9 can also combine with the nitrogen atom to which they are attached to form morpholine, piperazine or thiomorpholine. In addition, the morpholine, piperazine or thiomorpholine can also be substituted by C 1-6 alkyl,

[0042] R 10 is C 1-6 alkyl, halo C 1-6 alkyl or C 3-8 cycloalkyl,

[0043] However,

[0044] when Ar is the group represented by formula (i) and R 5 is H, R 4 is halo C 1-6 alkyl, and either R 1 or R 2 is a group other than H.)

[0045] It should be noted that, without 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.

[0046] In addition, the present invention relates to a pharmaceutical composition for preventing and / or treating inflammatory diseases or neurodegenerative diseases, which contains a compound of formula (I) or a salt thereof and a pharmaceutically acceptable excipient. It should be noted that this pharmaceutical composition includes a preventive and / or therapeutic agent for inflammatory diseases or neurodegenerative diseases containing a compound of formula (I) or a salt thereof.

[0047] In addition, the present invention relates to a compound of formula (I) or a salt thereof as an inhibitor of NLRP3 inflammasome activation; a compound of formula (I) or a salt thereof used as an inhibitor of NLRP3 inflammasome activation; an NLRP3 inflammasome activation inhibitor containing a compound of formula (I) or a salt thereof; the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases; the use of a compound of formula (I) or a salt thereof for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases; a compound of formula (I) or a salt thereof for use in the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases; and a method for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases, which includes administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0048] It should be noted that a "subject" is a human or other animal in need of such prevention or treatment.

[0049] As one mode, it is a human in need of such prevention or treatment.

[0050] Effects of the Invention

[0051] 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. Description of the Drawings

[0052] Figure 1 Figure 1 It is a graph showing the results of evaluating the improvement effect of the compound of Example 63 on the motor disorder in the Cuprizone-induced neuroinflammation model by the hanging wire test.

[0053] Figure 2 Figure 2 It is a graph showing the results of evaluating the improvement effect of the compound of Example 63 on the motor disorder in the α-synuclein fiber-induced neuroinflammation model by the hanging wire test.

[0054] ​​​​Figure 3 Figure 3 A graph showing the results of quantifying the production amount of IL-1β in an ex vivo test of mice induced by the compound of Example 63. DETAILED DESCRIPTION

[0055] Hereinafter, the present invention will be described in detail.

[0056] 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 the terms used are not specifically defined, the terms are used in the meanings generally accepted by those skilled in the art.

[0057] In the present invention, "C 1-6 alkyl" is a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. As one embodiment, it is a linear or branched C 1-4 alkyl; as one embodiment, it is methyl, ethyl, n-propyl, isopropyl, n-butyl; as one embodiment, it is methyl; as another embodiment, it is n-propyl.

[0058] "C 3-8 cycloalkyl" is a C 3-8 saturated hydrocarbon ring group, which may have a bridge or form a spiro ring. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl or spiro[2.5]octyl. As one embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; as one embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; as yet another embodiment, it is cyclopropyl; as another embodiment, it is cyclohexyl.

[0059] "C 3-8 subcycloalkyl" is a divalent group in which two carbon atoms constituting the ring in the foregoing "C 3-8 cycloalkyl" have a bonding bond. Specifically, for example, cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl or cyclooctanediyl, and as one embodiment, it is cyclohexanediyl.

[0060] "Aryl" is a monocyclic to tricyclic aromatic hydrocarbon ring group of C 6-14 , including a ring group obtained by condensing a C 5-8 cycloalkene at its double bond site. For example, phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, etc., and as one embodiment, it is phenyl.​​

[0061] "Heteroaryl" refers to a 5- or 6-membered aromatic ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. Examples thereof include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. In one embodiment, it is furyl, imidazolyl, or pyrazolyl; in another embodiment, it is pyrazolyl.

[0062] "Halogen" refers to F, Cl, Br, or I. In one embodiment, it is F or Cl; in another embodiment, it is F; in yet another embodiment, it is Cl.

[0063] "Halogenated C 1-6 alkyl" is a straight-chain or branched C 1-6 alkyl substituted with one or more halogens. In one embodiment, it is trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-fluoro-2-methylpropyl, difluoromethyl, fluoromethyl, or chloromethyl; in another embodiment, it is trifluoromethyl; in yet another embodiment, it is difluoromethyl.

[0064] "C 1-6 alkylene" is a straight-chain or branched C 1-6 alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, 2-methyltrimethylene, ethylethylene, 1,2-dimethylethylene, or 1,1,2,2-tetramethylethylene. In one embodiment, it is C 1-4 alkylene; in another embodiment, it is methylene, ethylene, or propylene; in yet another embodiment, it is propylene.

[0065] As a specific embodiment of "when Ar is a group represented by formula (i) and R 5 is H, R 4 is halogenated C 1-6 alkyl, and any one of R 1 or R 2 is a group other than H", a specific embodiment of "a group other than H" is C 1-6 alkyl, aryl, or heteroaryl; in another embodiment, examples thereof include methyl, phenyl, or furyl.

[0066] In the present invention, "substitutable" means unsubstituted or "substituted with one or more substituents". The substitution can be at any position as long as it is a position where hydrogen is normally present in the group.

[0067] Even if the combination is not specifically described, one or two or more embodiments can be combined with another embodiment.

[0068] In the present invention, "inflammatory disease" is an autoinflammatory disease including cryopyrin-associated periodic syndromes (CAPS) composed of a disease group including familial cold urticaria (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease / chronic infantile neurocutaneous arthropathy syndrome (NOMID / CINCA syndrome), 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.

[0069] In the present invention, "neurodegenerative disease" is a disease group including the following diseases: 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. In another aspect, it is α-synucleinopathy; in yet another aspect, it is multiple system atrophy. In yet another aspect, it is α-synucleinopathy or multiple sclerosis.

[0070] One aspect of the compound of formula (I) or a salt thereof in the present invention is as follows.

[0071] (1-1) Ar is a group represented by the following formula (i) or formula (ii),

[0072] [Chemical formula 7]

[0073]

[0074] wherein, R 4 is halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, R 5 is H, C 3-8 cycloalkyl or halo-C 1-6 alkyl, R 6 is H, halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, or a salt thereof. However, when Ar is a group represented by formula (i) and R 5 is H, R 4 is halo-C 1-6 alkyl, and either R 1 or R 2 is a group other than H.

[0075] (1-2) Ar is a group represented by formula (i) or formula (ii), wherein, R 4is halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, and R 5 is C 3-8 cycloalkyl or halo-C 1-6 alkyl, and R 6 is H, halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, or a salt thereof.

[0076] (1-3) Ar is a group represented by formula (i), wherein R 4 is halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, and R 5 is C 3-8 cycloalkyl or halo-C 1-6 alkyl, or a salt thereof.

[0077] (1-4) Ar is a group represented by formula (i), wherein R 4 and R 5 are halo-C 1-6 alkyl, or a salt thereof.

[0078] (1-5) Ar is a group represented by formula (ii), wherein R 6 is H, halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, or a salt thereof.

[0079] (1-6) Ar is a group represented by formula (ii), and R 6 is halo-C 1-6 alkyl, or a salt thereof.

[0080] (2-1) L is C 1-6 alkylene or C 3-8 cycloalkylene, or a salt thereof.

[0081] (2-2) L is C 1-6 alkylene, or a salt thereof.

[0082] (2-3) L is C 3-8 cycloalkylene, or a salt thereof.

[0083] (3-1) R 1 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl optionally substituted by 1 to 4 C 1-6 alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, wherein R 7 is -C1-6 Alkylene-O-C 1-6 Alkylene-aryl or halo C 1-6 alkyl compound or its salt.

[0084] (3-2)R 1 is H, C 1-6 alkyl or C 3-8 cycloalkyl compound or its salt.

[0085] (3-3)R 1 is H or C 1-6 alkyl compound or its salt.

[0086] (3-4)R 1 is a compound of H or its salt.

[0087] (3-5)R 1 is C 1-6 alkyl compound or its salt.

[0088] (3-6)R 1 is C 1-6 alkyl, C 3-8 cycloalkyl, aryl, optionally substituted by 1 to 4 C 1-6 alkyl-substituted heteroaryl, cyano, -OR 7 or -N(C 1-6 alkyl)2, where R 7 is -C 1-6 alkylene-O-C 1-6 alkylene-aryl or halo C 1-6 alkyl compound or its salt.

[0089] (3-7)R 1 is C 1-6 alkyl or C 3-8 cycloalkyl compound or its salt.

[0090] (4-1)R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, optionally substituted by 1 to 4 C 1-6 alkyl-substituted heteroaryl, cyano, -OR 7 , -N(C 1-6 alkyl)2, -C(=O)O-C 1-6 alkyl or -C(=O)NR 8 R 9 where R 7 is -C 1-6 alkylene-O-C 1-6 alkylene-aryl or halo C 1-6 alkyl, R 8 and R9 Same or different, being H or C 1-6 An alkyl group, or R 8 And R 9 May also combine with the nitrogen atom to which they are bonded to form morpholine, piperazine or thiomorpholine. In addition, the morpholine, piperazine or thiomorpholine may also be substituted with C 1-6 An alkyl-substituted compound or a salt thereof.

[0091] (4-2)R 2 Is H, C 1-6 An alkyl group, C 3-8 A cycloalkyl group or a cyano group, or a salt thereof.

[0092] (4-3)R 2 Is H or C 1-6 An alkyl group, or a salt thereof.

[0093] (4-4)R 2 Is H, or a salt thereof.

[0094] (4-5)R 2 Is C 1-6 An alkyl group, or a salt thereof.

[0095] (5-1)R 3 Is OH, -NHC(=O)R 10 Or -OC(=O)-C 1-6 An alkyl group, wherein R 10 Is C 1-6 An alkyl group, a halogenated C 1-6 An alkyl group or C 3-8 A cycloalkyl group, or a salt thereof.

[0096] (5-2)R 3 Is OH, or a salt thereof.

[0097] (6) Among the groups described in the above (1-1) to (5-2), a compound or a salt thereof having two or more combinations that do not conflict with each other. For example, the following combinations can be cited, but are not limited thereto.

[0098] (6-1) A compound or a salt thereof having a combination of the modes of the foregoing (1-1), (2-1), (3-1), (4-1) and (5-1).

[0099] (6-2) A compound or a salt thereof having a combination of the modes of the foregoing (1-2), (2-1), (3-1), (4-1) and (5-1).

[0100] (6-3) A compound or a salt thereof having a combination of the modes of the foregoing (1-2), (2-1), (3-1), (4-1) and (5-2).

[0101] A compound or a salt thereof which is a combination of the methods described in (1-2), (2-1), (3-2), (4-2) and (5-2) above.

[0102] A compound or a salt thereof which is a combination of the methods described in (1-2), (2-1), (3-3), (4-3) and (5-2) above.

[0103] A compound or a salt thereof which is a combination of the methods described in (1-3), (2-1), (3-2), (4-2) and (5-2) above.

[0104] A compound or a salt thereof which is a combination of the methods described in (1-3), (2-1), (3-3), (4-3) and (5-2) above.

[0105] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-1), (3-3), (4-3) and (5-2) above.

[0106] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-2), (3-5), (4-4) and (5-2) above.

[0107] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-2), (3-4), (4-5) and (5-2) above.

[0108] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-2), (3-5), (4-5) and (5-2) above.

[0109] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-3), (3-5), (4-4) and (5-2) above.

[0110] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-3), (3-4), (4-5) and (5-2) above.

[0111] A compound or a salt thereof which is a combination of the methods described in (1-4), (2-3), (3-5), (4-5) and (5-2) above.

[0112] A compound or a salt thereof which is a combination of the methods described in (1-5), (2-1), (3-2), (4-2) and (5-2) above.

[0113] A compound or a salt thereof which is a combination of the methods described in (1-5), (2-1), (3-3), (4-3) and (5-2) above.

[0114] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-1), (3-3), (4-3) and (5-2) above.

[0115] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-2), (3-5), (4-4) and (5-2) above.

[0116] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-2), (3-4), (4-5) and (5-2) above.

[0117] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-2), (3-5), (4-5) and (5-2) above.

[0118] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-3), (3-5), (4-4) and (5-2) above.

[0119] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-3), (3-4), (4-5) and (5-2) above.

[0120] A compound or a salt thereof which is a combination of the methods described in (1-6), (2-3), (3-5), (4-5) and (5-2) above.

[0121] Examples of specific compounds included in the present invention may include the following compounds.

[0122] (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-4,5-dimethylpyridazin-3-yl}amino)propan-2-ol,

[0123] (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)propan-2-ol,

[0124] (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)propan-2-ol,

[0125] 2-(6-{[(2R)-2-Hydroxypropyl]amino}-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol,

[0126] 2-(6-{[(2R)-2-Hydroxypropyl]amino}-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol,

[0127] 2-(6-{[(2R)-2-Hydroxypropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol,

[0128] rac-(1R,2R)-2-({6-[2,4-Bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)cyclohexan-1-ol,

[0129] rac-(1R,2R)-2-({6-[2,4-Bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)cyclohexan-1-ol,

[0130] 2-(6-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol,

[0131] 2-(6-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride.

[0132] In addition, as examples of the specific compounds included in the present invention, the following compounds or their salts can be cited.

[0133] (A) Crystals of 2-(6-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride.

[0134] (B) Crystals of 2-(6-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride, characterized in that peaks are shown near 2θ (°) = 14.5, 16.3, 17.2, 18.4, 18.9, 22.1, 23.6, 24.9, 25.7 and 26.8 in powder X-ray diffraction using Cu as the tube target.

[0135] (C) Crystals of 2-(6-{[(lR,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride, characterized in that the starting temperature of the endothermic peak is near 227.32 °C in differential scanning calorimetry (DSC analysis).

[0136] Crystals of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride, characterized in that the onset temperature of the endothermic peak in differential scanning calorimetry (DSC analysis) is around 227.32 °C, and in powder X-ray diffraction using Cu as the tube target, peaks are shown at around 2θ (°) = 14.5, 16.3, 17.2, 18.4, 18.9, 22.1, 23.6, 24.9, 25.7 and 26.8.

[0137] The present invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases, in particular α-synucleinopathies or multiple sclerosis; the use of a compound of formula (I) or a salt thereof for the prevention and / or treatment of neurodegenerative diseases, in particular α-synucleinopathies or multiple sclerosis; a compound of formula (I) or a salt thereof for use in the prevention and / or treatment of neurodegenerative diseases, in particular α-synucleinopathies or multiple sclerosis; and a method for the prevention and / or treatment of neurodegenerative diseases, in particular α-synucleinopathies or multiple sclerosis, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0138] Furthermore, the present invention relates to a compound of formula (I) or a salt thereof, characterized in that it shows an inhibitory effect on IL-1β production in the central nervous system of a subject.

[0139] As one embodiment of the compound of formula (I) or a salt thereof in the present invention, for example, it is a compound of formula (I) or a salt thereof that shows an inhibitory effect on IL-1β production of 50% or more when the dosage is 3 mg / kg or less in the measurement method of Test Example 2; as another embodiment, it is a compound of formula (I) or a salt thereof that shows an inhibitory effect on IL-1β production of 50% or more when the dosage is 1 mg / kg or less; as yet another embodiment, it is a compound of formula (I) or a salt thereof that shows an inhibitory effect on IL-1β production of 50% or more when the dosage is 0.3 mg / kg or less.

[0140] Furthermore, as one embodiment of the compound of formula (I) or a salt thereof in the present invention, it is a compound of formula (I) or a salt thereof characterized by not showing phototoxicity. "Not showing phototoxicity" means that in the evaluation carried out according to the method described in OECD guideline for testing of chemicals 432: In vitro 3T3 NRU phototoxicity test, 2004, the phototoxicity is determined to be negative.

[0141] In addition, as a certain form of the compound of formula (I) or its salt in the present invention, it is characterized in that the IC 50 value of the hERG inhibitory activity is 10 μM or more for the compound of formula (I) or its salt.

[0142] Depending on the type of substituents, tautomers or geometric isomers may exist in the compound of formula (I). In this specification, sometimes the compound of formula (I) or its salt is only described as one form of the isomer, but the present invention also includes other isomers in addition to this, and also includes substances obtained after separation of the isomers, or mixtures thereof.

[0143] In addition, when the compound of formula (I) or its salt has an asymmetric center or axial asymmetry, enantiomers (optical isomers) may exist based on this. The compound of formula (I) or its salt also includes any of the separated (R)-form, (S)-form and other enantiomers, and mixtures thereof (including racemic mixtures or non-racemic mixtures). In a certain form, the enantiomer is "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 form, the enantiomer is a compound 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.

[0144] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compound represented by formula (I). A pharmaceutically acceptable prodrug refers to a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. by solvolysis or under physiological conditions. As the group forming the prodrug, for example, those described in Prog. Med., 5, 2157-2161 (1985), or "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Volume 7, Molecular Design, 163-198 can be cited.

[0145] In addition, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and depending on the type of substituents, an acid addition salt or a salt with a base 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; salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine; salts with various amino acids such as acetyl leucine and amino acid derivatives, or ammonium salts.

[0146] In addition, the present invention also encompasses various hydrates or solvates and polymorphs of the compound of formula (I) or its salts.

[0147] Furthermore, the present invention includes all compounds of formula (I) or their salts labeled with one or more pharmaceutically acceptable 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 in studies 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 due to the ease of labeling and simplicity of detection. Substitution with heavier isotopes, such as substitution of hydrogen with deuterium ( 2 H), may be therapeutically advantageous due to increased metabolic stability (e.g., increased half-life in vivo, reduced required dosage, reduced drug interactions). Substitution with positron-emitting isotopes ( 11 C, 18 F, 15 O, and 13 N, etc.) can be used in positron emission tomography (PET) experiments to test the occupancy of matrix receptors. The isotopically labeled compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, or by using appropriately isotopically labeled reagents in place of unlabeled reagents and utilizing the same preparation methods as in the examples or manufacturing examples.

[0148] In this specification, the "vicinity" included in the description of the diffraction angle (2θ (°)) in the powder X-ray diffraction pattern and the starting temperature (°C) of the endothermic peak in the DSC analysis refers to the error range that is generally allowable in this data measurement method, and refers to approximately the starting values of the diffraction angle and the endothermic peak. For the error range of the diffraction angle (2θ (°)) in powder X-ray diffraction, in one method, it is ±0.2°, and in another method, it is ±0.1°. For the error range of the starting temperature (°C) of the endothermic peak in DSC analysis, in one method, it is ±2°C, and in another method, it is ±1°C.

[0149] It should be noted that, due to the nature of the data, in the identification of crystal identity, the lattice spacing or the overall pattern of the powder X-ray diffraction pattern is important, and the diffraction angle and diffraction intensity may vary slightly depending on the crystal growth direction, particle size, and measurement conditions.

[0150] (Manufacturing method)

[0151] The compound of formula (I) or its salt can be manufactured by using various known synthetic methods based on the characteristics of its basic structure or substituent types. 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) in 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.

[0152] In addition, the prodrug of the compound of formula (I) can be manufactured in the same way as the above-mentioned protecting group, by introducing a specific group in 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 methods well-known to those skilled in the art such as ordinary esterification, amidation, dehydration, etc.

[0153] Hereinafter, the representative manufacturing methods of the compound of formula (I) will be described. Each manufacturing method can also be carried out with reference to the references attached to this description. It should be noted that the manufacturing method of the present invention is not limited to the examples shown below.

[0154] In this specification, the following abbreviations are sometimes used.

[0155] DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DIPEA: N,N-diisopropylethylamine, NMP: 1-methylpyrrolidin-2-one, Me: methyl, PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloride, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd2(dba)3: (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, RuPhos PdG3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TMS: trimethylsilyl.

[0156] (First preparation method)

[0157] [Chemical formula 8]

[0158]

[0159] (X 1 and X 2 are the same or different and are Cl, Br or I. Both R' and R" are H, or R' and R" combine to form 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The same applies hereinafter.)

[0160] (First step)

[0161] This step is a step of obtaining a compound of formula (Ib) by reacting a compound of formula (Ia) with a compound of formula (IIa). In this reaction, the compound of formula (Ia) and the compound of formula (IIa) are used in equal amounts or either one is used in excess, and their mixture is stirred in a solvent inert to the reaction or without a solvent, from cooling to heating under reflux, preferably at room temperature to 190 °C, usually 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, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate is sometimes advantageous for the smooth progress of the reaction. In addition, this reaction can also be carried out under microwave irradiation.)

[0162] (Second step)

[0163] This step is a step of obtaining the compound of formula (I) by the reaction of the compound of formula (Ib) with the compound of formula (IIb). In this reaction, the compound of formula (Ib) and the compound of formula (IIb) are used in equal amounts or either one is used in excess. Their mixture is stirred for 0.1 hour to 5 days under cooling to heating under reflux, preferably at room temperature to 150 °C, in the presence of a catalyst and a base, in a solvent inert to the reaction. Examples of the catalyst used here are not particularly limited, and Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhosPd G3, etc. can be cited. Examples of the base are not particularly limited, and tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, etc. can be cited. Examples of the solvent are not particularly limited, and 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 their mixtures can be cited. In addition, this reaction can also be carried out under microwave irradiation.

[0164] (Second preparation method)

[0165] [Chemical formula 9]

[0166]

[0167] (First step)

[0168] This step is a step of obtaining the compound of formula (Ic) by the reaction of the compound of formula (Ia) with the compound of formula (IIb). In this reaction, the compound of formula (Ia) and the compound of formula (IIb) are used in equal amounts or either one is used in excess. Their mixture is stirred for 0.1 hour to 5 days under cooling to heating under reflux, preferably at room temperature to 150 °C, in the presence of a catalyst and a base, in a solvent inert to the reaction. Examples of the catalyst used here are not particularly limited, and Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhosPd G3, etc. can be cited. Examples of the base are not particularly limited, and tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, etc. can be cited. Examples of the solvent are not particularly limited, and 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 their mixtures can be cited. In addition, this reaction can also be carried out under microwave irradiation.

[0169] (Second Step)

[0170] This step is the step of obtaining the compound of formula (I) by the reaction of the compound of formula (Ic) with the compound of formula (IIa). In this reaction, the compound of formula (Ic) and the compound of formula (IIa) are used in equal amounts or either one is used in excess, and their mixture is stirred in a solvent inert to the reaction or without solvent, from cooling to heating under reflux, preferably at room temperature to 190 °C, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and can include ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water, pyridine, acetonitrile, NMP, DMF, DMSO, and their mixtures. Carrying out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate is sometimes advantageous for the smooth progress of the reaction. In addition, this reaction can also be carried out under microwave irradiation.

[0171] (Other Preparation Methods)

[0172] By using the compound of formula (I) obtained by the previous preparation method as a raw material and further carrying out chemical modification reactions commonly used by those skilled in the art such as esterification, amidation, etc., other compounds of formula (I) can be obtained.

[0173] The compound of formula (I) is separated 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 formation reaction by a conventional method. Separation and purification can be carried out by applying 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 utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods of racemates (e.g., fractional crystallization of forming diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), and optical isomers can also be prepared from appropriate optically active starting compounds.

[0174] The pharmacological activity of the compound of formula (I) can be confirmed by the following tests or well-known modified tests.

[0175] Test Example 1 THP-1 IL-1β Production Test

[0176] Add 50 ng / mL of PMA (phorbol myristate acetate, SIGMA, P1585) to THP-1 cells and culture them at 37 °C for 2 days. Replace the culture medium with serum-free RPMI-1640 medium, add the compound with a known concentration, and culture at 37 °C for 15 minutes. Add LPS (Lipopolysaccharide, SIMGA, L2880) and ATP (Adenosine triphosphate, SIGMA, A2383) at final concentrations of 50 ng / mL and 5 mM respectively, and culture at 37 °C for 2 hours. Recover the supernatant, and measure the concentration of IL-1β using the ELISA method (DuoSet ELISA human IL-1β, R&D Systems, DY201). Set the IL-1β production amount under the condition of not adding the compound to be tested and the stimulating substances (LPS and ATP) as 100% inhibition, and set the IL-1β production amount under the condition of not adding the compound to be tested but adding the stimulating substances as 0% inhibition, calculate the inhibition rate at each concentration, and calculate the IC 50 value.

[0177] The results are shown in Table 1. It can be confirmed that the compound of the example inhibits the production of IL-1β.

[0178] [Table 1]

[0179] Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 54 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> 1 980 17 110 33 170 49 680 65 49 2 1800 18 260 34 21 50 1100 66 47 3 120 19 610 35 590 51 990 67 170 4 210 20 1500 36 620 52 470 68 310 5 200 21 160 37 33 53 2700 69 250 6 90 22 530 38 9.5 54 3500 70 36 7 17 23 120 39 750 55 5100 71 38 8 160 24 560 40 240 56 2500 72 17 9 14 25 500 41 200 57 1600 73 43 10 200 26 54 42 1500 58 950 74 35 11 150 27 190 43 860 59 750 75 18 12 150 28 200 44 570 60 1700 76 26 13 120 29 460 45 530 61 1500 77 89 H 330 30 510 46 120 62 2100 78 43 15 97 31 270 47 400 63 8.4 79 340 16 200 32 11 48 510 64 33 80 7.0

[0180] Test Example 2 Rat Central IL-1β Production Test

[0181] Administer 12.5 μg / 5 μL of LPS (SIGMA, L2880) into the cerebral cistern of male Wistar rats aged 10 - 14 weeks under isoflurane anesthesia. After 2 hours, orally administer the compound to be tested. In addition, after 1 hour, administer 50 μg / 5 μL of BzATP (2′(3′)-O-(4-Benzoylbenzoyl)adenosine 5′-triphosphate triethyl ammonium salt, SIGMA, B6396) into the cerebral cistern. After 30 minutes, collect cerebrospinal fluid. Quantify IL-1β p17 in the cerebrospinal fluid by Western blotting using an anti-IL-1β antibody (Millipore, AB1832P), and calculate the inhibition rate of the solvent-administered group.

[0182] For Examples 4, 9, and 63 of the compound of formula (I), the inhibition rates of IL-1β p17 in the solvent administration group are shown in Table 2. It should be noted that in the table, Dose represents the dosage of each test compound, Ex4, Ex9, and Ex63 represent Example 4, Example 9, and Example 63, respectively, and the unmeasured cases are represented as NT. It can be confirmed that these compounds show an inhibitory effect on IL-1β production in vivo.

[0183] [Table 2]

[0184] Dose Ex4 Ex9 Ex63 0.3 mg / kg NT 37％ 60％ 1 mg / kg NT 70％ 69％ 3 mg / kg 68％ 89％ 66％ 10 mg / kg 93％ NT NT 30 mg / kg 100％ NT MT

[0185] Test Example 3 Mouse Cuprizone-Induced Neuroinflammation Model

[0186] Male C57BL / 6J mice were fed a diet containing 0.2% Cuprizone (ENVIGO, TD.140801) for 40 days. The test compound was suspended in a 0.5% methylcellulose solution and orally administered once a day at doses of 1 mg / kg and 3 mg / kg starting from the day of Cuprizone intake. In the negative control group, a 0.5% methylcellulose solution was administered. Motor function was evaluated using the hanging wire test (van Putten M. ‘The use of hanging wire tests to monitor muscle strength and condition over time.’, [online], May 2019, TREAT-NMD, Experimental protocols for DMD animal models, DMD_M.2.1.004, retrieved from the internet: <URL: http: / / www.treat-nmd.eu / research / preclinical / dmd-sops / >). The mice were made to grasp a horizontally stretched wire, and the time until they fell was measured. The average value was calculated by repeating the measurement 3 times. The results of evaluating the compound of Example 63 in this test are shown in Figure 1 . In the 1 mg / kg and 3 mg / kg administration groups of the compound of Example 63, the time until falling was significantly prolonged compared to the negative control group. Thus, it can be confirmed that the compound of Example 63 shows an improvement effect on motor disorders.

[0187] Test Example 4 Mouse α-Synuclein Fiber-Induced Neuroinflammation Model

[0188] For male C57BL / 6J mice, 8 μg of mouse α-synuclein fibrillar protein (StressMarq Biosciences Inc., SPR-324) was administered to the left striatum. After 13 to 14 weeks, the test compound suspended in 0.5% methylcellulose solution was orally administered once a day at a dose of 1 mg / kg or 10 mg / kg. For the negative control group, 0.5% methylcellulose solution was administered. Four weeks after the start of dosing, motor function was evaluated by the wire hanging test. In this test, the mouse was made to grasp a horizontally taut wire, and after falling, it was made to grasp again and this operation was continued for 3 minutes, and the number of falls was recorded. The results obtained by evaluating the compound of Example 63 in this test are shown in Figure 2 . In the 1 mg / kg and 10 mg / kg dosing groups of the compound of Example 63, the number of falls was significantly reduced compared to the negative control group. Thus, it was confirmed that the compound of Example 63 showed an effect of improving dyskinesia.

[0189] Test Example 5 Mouse ex vivo IL-1β production test

[0190] The compound suspended in 0.5% methylcellulose was orally administered to male C57BL / 6J mice at a dose of 3 mg / kg, and blood was collected 1 hour and 6 hours later. LPS was added to the blood at a final concentration of 50 ng / mL and cultured at 37°C for 3 hours. Then, ATP was added at a final concentration of 5 mM and cultured at 37°C for 30 minutes. After removing blood cells by centrifugation, the concentration of IL-1β was measured by ELISA (DuoSet ELISA mouse IL-1β, R&D Systems, DY401). The results obtained by evaluating the compound of Example 63 in this test are shown in Figure 3 . The compound of Example 63 inhibited the production amount of IL-1β in the blood collected 1 hour and 6 hours after the compound administration.

[0191] Test Example 6 In vitro phototoxicity test

[0192] The evaluation of the in vitro phototoxicity test was carried out in accordance with ICH S10: Guidelines for the Phototoxicity Evaluation of Medicinal Products (Notification No. 0521-1), and in accordance with the test method described in the OECD report, OECD guideline for testing of chemicals 432: In vitro 3T3 NRU phototoxicity test, 2004. In this test, it was confirmed that the compound of Example 63 had no phototoxic effect.

[0193] Test Example 7 Safety Pharmacology Test

[0194] As a safety pharmacology test, the evaluation of the inhibitory effect on the human Ether-a-go-go Related Gene (hereinafter referred to as hERG) channel was carried out. The evaluation of the inhibitory effect on the hERG channel used a method modified from the method described in Combinatorial Chemistry & High Throughput Screening, 12, 1, 78 - 95 (2009). In this test, the compound of Example 63 showed an IC of 34.5 μM 50 .

[0195] Based on the above results, it is expected that the compound of formula (I) or its salt can be used for the prevention and / or treatment of inflammatory diseases, neurodegenerative diseases, etc.

[0196] It should be noted that it is known that in a model of multiple sclerosis induced by Cuprizone administration, the expression of NLRP3 and IL-1β is enhanced in the central nervous system (The Journal of Neuroscience, Vol. 30, No. 47, pp. 15811 - 15820). 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 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).

[0197] The compound of formula (I) or its salt shown in Table 1 showed an inhibitory effect on the production of IL-1β in Test Example 1. In addition, the compounds of Examples 4, 9 and 63 showed an inhibitory effect on the production of IL-1β in the central nervous system in Test Example 2. Furthermore, it was confirmed that the compound of Example 63 showed an improvement effect on motor disorders in the mouse cuprizone-induced neuroinflammation model of Test Example 3 and the mouse α-synuclein fibril-induced neuroinflammation model of Test Example 4. Based on the above results, it can be strongly expected that the compound of formula (I) or its salt can be used for the prevention and / or treatment of neurodegenerative diseases, especially multiple sclerosis, and α-synucleinopathies including Parkinson's disease, multiple system atrophy and Lewy body dementia.

[0198] In addition, according to the results of Test Example 5, the compound of Example 63 inhibited IL-1β production even in the blood 6 hours after oral administration. Furthermore, according to the results of Test Examples 6 and 7, the compound of Example 63 did not show phototoxicity and had a weak hERG channel inhibitory effect. Based on the above results, it can be strongly expected that the compound of Example 63 will become a pharmaceutical product with excellent persistence and high safety as an oral preparation.

[0199] A pharmaceutical composition containing one or more compounds of formula (I) or a salt thereof as an active ingredient can be prepared using excipients commonly used in the art (i.e., pharmaceutical excipients or pharmaceutical carriers, etc.) by conventional methods.

[0200] Administration can be oral administration using tablets, pills, capsules, granules, powders, liquid preparations, etc., or any one of parenteral administrations such as injections, suppositories, eye drops, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalants, etc. via intra-articular, intravenous, intramuscular, etc.

[0201] As a solid composition for oral administration, tablets, powders, granules, etc. can be used. In such a solid composition, 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.

[0202] The liquid composition for oral administration contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, etc., and contains common inert diluents such as purified water or ethanol. In addition to the inert diluent, this liquid composition can also contain adjuvants such as solubilizing agents, wetting agents, suspending agents, sweetening agents, flavoring agents, fragrances, preservatives.

[0203] The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. As an aqueous solvent, it includes (for example) distilled water for injection or physiological saline. As a non-aqueous solvent, there are (for example) alcohols such as ethanol. Such a composition 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. In addition, they can also be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injection solvent before use.

[0204] As topical agents, they include ointments, plasters, creams, gels, pastes, sprays, lotions, eye drops, eye ointments, etc. They contain common ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, etc.

[0205] For transmucosal agents such as inhalants or nasal agents, solid, liquid, or semi-solid preparations can be used and manufactured according to previously known methods. Appropriate additives can also be added, such as (for example) known excipients, or further appropriately added pH regulators, preservatives, surfactants, lubricants, stabilizers, or thickeners, etc. Administration can be carried out using devices suitable 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 used. Alternatively, it can be in the form of a pressurized aerosol spray, etc., which uses an appropriate propellant, such as a suitable gas like chlorofluorocarbon or carbon dioxide.

[0206] When usually administered orally, the daily dosage is preferably about 0.001 - 100 mg / kg of body 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 of body weight, and this dosage can be administered once a day or divided into multiple times. Additionally, as a transmucosal agent, it is about 0.001 - 100 mg / kg of body weight, administered once a day or divided into multiple times. Symptoms, age, gender, etc. should be considered, and the dosage should be appropriately determined according to each situation.

[0207] 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 mode contains 0.01 - 50% by weight of one or more compounds of formula (I) or their salts as the active ingredient.

[0208] 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 at a desired time interval. The simultaneous administration preparation can be a combined preparation or can be prepared separately.

[0209] Examples

[0210] 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. In addition, the preparation method of the starting compounds is shown in the production examples. In addition, 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 a method obvious to those skilled in the art.

[0211] It should be noted that the starting temperature of the DSC curve measured under the following conditions is recorded as the melting point in the table below. DSC measurement was performed using DSC Q2000 (manufactured by TA Instruments). Under the measurement temperature range: room temperature to 300 °C, heating rate: 10 °C / min, nitrogen flow rate: 50 mL / min, an aluminum sample pan was used, and the measurement was performed without covering the sample pan.

[0212] Powder X-ray diffraction was performed using Empyrean (manufactured by PANalytical). The tube target was Cu, the tube current was 40 mA, the tube voltage was 45 kV, the step width was 0.013°, and the wavelength was The diffraction angle range (2θ) was measured under the condition of 2.5 to 40°. It should be noted that, due to the nature of the data, in the identification of crystal identity, the lattice spacing or the overall pattern of the powder X-ray diffraction pattern is important. The error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is usually ±0.2°. However, the diffraction angle and diffraction intensity vary slightly depending on the crystal growth direction, particle size, and measurement conditions. Therefore, it should not be strictly interpreted.

[0213] In addition, in the examples, production examples, and the tables described later, the following abbreviations are sometimes used.

[0214] They respectively represent: PEx: Manufacturing example number, Ex: Example number, PSyn: Manufacturing example number manufactured in the same way, Syn: Example number manufactured in the same way, Str: Chemical structural formula, DAT: Physicochemical data, ESI+: m / z value in mass analysis (ionization method ESI, [M+H]+ when not specified), APCI / ESI+: APCI / ESI-MS (atmospheric pressure chemical ionization method APCI, APCI / ESI means simultaneous determination of APCI and ESI. [M+H]+ when not specified), API-ES+: API-ES MS (atmospheric pressure ionization - electrospray method, [M+H]+ when not specified), J: Coupling constant, s: Singlet, d: Doublet, t: Triplet, q: Quartet, dd: Double doublet, ddd: Double double doublet, tt: Triple triplet, br: Broad peak (e.g., br s), m: Multiplet, m.p.: Melting point, 2θ: Diffraction angle of the peak in powder X-ray diffraction.

[0215] In the chemical structural formulas containing stereoconfigurations in the tables described below, for the compounds marked with "#", the marked stereoconfiguration represents a relative stereoconfiguration, and otherwise the marked stereoconfiguration represents an absolute stereoconfiguration.

[0216] Recording "rac" at the beginning of the compound name indicates that the compound is a racemate.

[0217] In addition, for convenience, the concentration mol / l is expressed as M. For example, 1M sodium hydroxide aqueous solution means 1mol / l sodium hydroxide aqueous solution.

[0218] Manufacturing Example 1

[0219] A mixture of 2-(trimethylsilyl)ethanol (4.3 mL) and THF (100 mL) was cooled in ice, and under an argon atmosphere, sodium hydride (60%, paraffin oil dispersion, 1.2 g) was added, and the mixture was stirred at the same temperature for 10 minutes. To the obtained mixture, a mixture of 3,4,6-trichloropyridazine (5.0 g) and THF (25 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water and saturated sodium chloride aqueous solution were added to the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous 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 (hexane / ethyl acetate) to obtain 3,6-dichloro-4-[2-(trimethylsilyl)ethoxy]pyridazine (2.9 g) in solid form.

[0220] Manufacturing Example 2

[0221] A mixture of 3,4,6-trichloropyridazine (2.5 g), potassium carbonate (2.3 g), 18-crown-6 (0.32 g), benzene (15 mL), and 2-(benzyloxy)ethanol (2.3 g) was stirred overnight at 70 °C under an argon atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate was added and the mixture was filtered. After the filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-[2-(benzyloxy)ethoxy]-3,6-dichloropyridazine (3.4 g) as an oil.

[0222] Production Example 3

[0223] A mixture of 3,6-dichloro-4,5-dimethylpyridazine (340 mg), NMP (5 mL), (2R)-1-aminopropan-2-ol (0.23 mL), and potassium carbonate (400 mg) was stirred overnight at 100 °C. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (2R)-1-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]propan-2-ol (39 mg) as a solid.

[0224] Production Example 4

[0225] A mixture of 3,6-dichloro-4-methylpyridazine (4.0 g), isopropanol (30 mL), (2R)-1-aminopropan-2-ol (6 mL), and DIPEA (12 mL) was divided into three equal portions, and each portion was stirred at 140 °C for 3 hours under microwave irradiation. The reaction mixtures were combined and concentrated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solution was concentrated under reduced pressure, the obtained residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain (2R)-1-[(6-chloro-5-methylpyridazin-3-yl)amino]propan-2-ol (2.4 g) and (2R)-1-[(6-chloro-4-methylpyridazin-3-yl)amino]propan-2-ol (1.0 g) as solids, respectively.

[0226] Production Example 24

[0227] In a mixture of 3,6-dichloro-4-phenylpyridazine (1.0 g), [4-(trifluoromethyl)phenyl]boronic acid (0.84 g), sodium carbonate (1.4 g), 1,2-dimethoxyethane (21 mL), and water (4 mL), PdCl2(PPh3)2 (0.31 g) was added under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 6-chloro-4-phenyl-3-[4-(trifluoromethyl)phenyl]pyridazine (0.15 g) and 3-chloro-4-phenyl-6-[4-(trifluoromethyl)phenyl]pyridazine (0.70 g) as solids, respectively.

[0228] Production Example 25

[0229] In a mixture of (2R)-1-[(6-chloro-5-methylpyridazin-3-yl)amino]propan-2-ol (1.0 g), dichloromethane (10 mL), and triethylamine (2.1 mL), acetic anhydride (0.57 mL) and N,N-dimethyl-4-aminopyridine (120 mg) were added at room temperature, and the mixture was stirred overnight at the same temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate). Hexane and ethyl acetate were added to the obtained purified product, and the mixture was triturated. The precipitated solid was filtered to obtain (2R)-1-[(6-chloro-5-methylpyridazin-3-yl)amino]propan-2-yl acetate (1.1 g) as a solid.

[0230] Production Example 26

[0231] A mixture of (2R)-1-({6-chloro-4-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)propan-2-ol (800 mg), [2,4-bis(trifluoromethyl)phenyl]boronic acid (1.2 g), potassium carbonate (730 mg), water (1.6 mL), 1,4-dioxane (16 mL), and RuPhos Pd G3 (220 mg) was stirred at 100 °C for 3 hours under an argon atmosphere. After cooling the reaction mixture to room temperature, water was added, 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 magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)propan-2-ol (1.0 g) as a solid.

[0232] Production Example 30

[0233] To a mixture of tert-butyl [4-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}amino)butyl]carbamate (700 mg) and dichloromethane (10 mL), trifluoroacetic acid (TFA) (5 mL) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then concentrated under reduced pressure to obtain N 1 -{6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}butane-1,4-diamine (780 mg).

[0234] Production Example 32

[0235] To a mixture of (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)propan-2-ol (1.0 g), dichloromethane (10 mL), and triethylamine (0.88 mL), acetic anhydride (0.24 mL) and N,N-dimethyl-4-aminopyridine (51 mg) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and saturated aqueous sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)propan-2-yl acetate (1.0 g) as an oil.

[0236] Production Example 33

[0237] To a mixture of (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)propan-2-yl acetate (1.0 g) and THF (10 mL), tetrabutylammonium fluoride (1 M THF solution, 5.9 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 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 and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-hydroxypyridazin-3-yl}amino)propan-2-yl acetate (820 mg) as a solid.

[0238] Production Example 34

[0239] In a mixture of (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-hydroxypyridazin-3-yl}amino)propan-2-yl acetate (200 mg) and DMF (4 mL), sodium chlorodifluoroacetate (220 mg) and cesium carbonate (460 mg) were added at room temperature, and the mixture was stirred at 90 °C for 1 hour. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol). The obtained purified product was further purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-(difluoromethoxy)pyridazin-3-yl}amino)propan-2-yl acetate (110 mg) as an oil.

[0240] Production Example 35

[0241] As a by-product of the reaction of Example 3, 6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylic acid (150 mg) was obtained as a solid.

[0242] Production Example 39

[0243] A mixture of 3,6-dichloro-4,5-dimethylpyridazine (300 mg), 1,4-dioxane (3 mL), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (510 mg), and DIPEA (0.87 mL) was stirred at 190 °C for 6 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (1R,2R)-2-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]cyclohexan-1-ol (150 mg) as a solid.

[0244] Example 1

[0245] A mixture of 6-chloro-4-phenyl-3-[4-(trifluoromethyl)phenyl]pyridazine (100 mg) and 3-aminopropan-1-ol (6 mL) was stirred at 120 °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 dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain 3-({5-phenyl-6-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}amino)propan-1-ol (60 mg) as a solid.

[0246] Example 3

[0247] Under an argon atmosphere, ethyl 6-chloro-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylate (390 mg), [2,4-bis(trifluoromethyl)phenyl]boronic acid (580 mg), potassium carbonate (420 mg), water (1 mL), 1,4-dioxane (9 mL), and RuPhos Pd G3 (63 mg) were mixed and stirred at 100 °C for 1 hour under microwave irradiation. After concentrating the reaction mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol). Hexane and ethyl acetate were added to the obtained purified product and triturated. The precipitated solid was collected by filtration to obtain ethyl 6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylate (220 mg) as a solid.

[0248] Example 4

[0249] A mixture of (2R)-1-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]propan-2-ol (35 mg), [2,4-bis(trifluoromethyl)phenyl]boronic acid (75 mg), potassium carbonate (45 mg), water (0.20 mL), 1,4-dioxane (2 mL), and RuPhos Pd G3 (10 mg) was stirred at 100 °C for 2 hours under an argon atmosphere. After cooling the reaction mixture to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4,5-dimethylpyridazin-3-yl}amino)propan-2-ol (60 mg) as a solid.

[0250] Example 5

[0251] A mixture of (2R)-1-[(6-chloro-5-methylpyridazin-3-yl)amino]propan-2-ol (300 mg), [2,4-bis(trifluoromethyl)phenyl]boronic acid (570 mg), potassium carbonate (400 mg), water (0.6 mL), 1,4-dioxane (6 mL), and RuPhos Pd G3 (61 mg) was stirred at 100 °C for 2 hours under an argon atmosphere. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate). Ethyl acetate was added to the obtained purified product and triturated. The precipitated solid was collected by filtration to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)propan-2-ol (290 mg) as a solid.

[0252] Example 6

[0253] A mixture of (2R)-1-[(6-chloro-4-methylpyridazin-3-yl)amino]propan-2-ol (140 mg), [2,4-bis(trifluoromethyl)phenyl]boronic acid (270 mg), potassium carbonate (190 mg), water (0.3 mL), 1,4-dioxane (3 mL), and RuPhos Pd G3 (29 mg) was stirred at 100 °C for 2 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane / ethyl acetate). Hexane and ethyl acetate were added to the obtained purified product and ground. The precipitated solid was filtered to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)propan-2-ol (94 mg) as a solid.

[0254] Example 7

[0255] A mixture of (2R)-1-[(6-chloro-5-methylpyridazin-3-yl)amino]propan-2-ol (100 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (160 mg), potassium carbonate (140 mg), water (0.20 mL), 1,4-dioxane (2 mL), and RuPhos Pd G3 (21 mg) was stirred at 100 °C for 5 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol). Hexane and ethyl acetate were added to the obtained purified product and ground. The precipitated solid was filtered to obtain 2-(6-{[(2R)-2-hydroxypropyl]amino}-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (90 mg) as a solid.

[0256] Example 8

[0257] A mixture of (2R)-1-[(6-chloro-4-methylpyridazin-3-yl)amino]propan-2-ol (100 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (150 mg), potassium carbonate (140 mg), water (0.20 mL), 1,4-dioxane (2 mL), and RuPhos Pd G3 (21 mg) was stirred at 100 °C for 5 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol). Hexane and ethyl acetate were added to the obtained purified product and ground. The precipitated solid was filtered to obtain 2-(6-{[(2R)-2-hydroxypropyl]amino}-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (80 mg) as a solid.

[0258] Example 9

[0259] A mixture of (2R)-1-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]propan-2-ol (100 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (140 mg), potassium carbonate (130 mg), water (0.20 mL), 1,4-dioxane (2 mL), and RuPhos Pd G3 (20 mg) was stirred at 100 °C for 5 h under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol). Hexane and ethyl acetate were added to the obtained purified product and triturated. The precipitated solid was collected by filtration to obtain 2-(6-{[(2R)-2-hydroxypropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (110 mg) as a solid.

[0260] Example 40

[0261] A mixture of 6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylic acid (50 mg), DMF (1 mL), morpholine (0.022 mL), {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinylmethylene}dimethylammonium hexafluorophosphate (70 mg), and DIPEA (0.063 mL) was stirred at room temperature for 3 days. Water and saturated aqueous sodium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazin-4-yl)(morpholin-4-yl)methanone (20 mg) as a solid.

[0262] Example 42

[0263] To a mixture of methyl 6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylate (150 mg), 1-methylpiperazine (53 mg), and toluene (15 mL) under a nitrogen atmosphere, DIPEA (0.18 mL) and trimethylaluminum (0.26 mL) were added at room temperature, and the mixture was stirred at 80 °C for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After concentrating the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain (6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazin-4-yl)(4-methylpiperazin-1-yl)methanone (40 mg) as a solid.

[0264] Example 45

[0265] In a mixture of (2R)-N 1 -{6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}propane-1,2-diamine (100 mg) and dichloromethane (5 mL) under a nitrogen atmosphere, acetyl chloride (24 mg) and triethylamine (0.22 mL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After concentrating the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain N-[(2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}amino)propan-2-yl]acetamide (42 mg) as a solid.

[0266] Example 46

[0267] In a mixture of N 1 -{6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}butane-1,4-diamine (400 mg) and DMF (5 mL) under a nitrogen atmosphere, difluoroacetic acid (120 mg), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (600 mg), and DIPEA (0.55 mL) were added at room temperature, and the mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After concentrating the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol). The obtained purified product was further purified by reverse-phase silica gel column chromatography (0.02% aqueous TFA / acetonitrile) to obtain N-[4-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}amino)butyl]-2,2-difluoroacetamide (41 mg) as a solid.

[0268] Example 49

[0269] In a mixture of (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-(difluoromethoxy)pyridazin-3-yl}amino)propan-2-yl acetate (100 mg) and methanol (2 mL), 1 M aqueous sodium hydroxide solution (0.49 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. 1 M hydrochloric acid (0.49 mL), water, and saturated aqueous sodium chloride solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol). Ethyl acetate and 4 M hydrogen chloride in ethyl acetate solution (0.2 mL) were added to the obtained purified product, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the precipitated solid was filtered to obtain (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-(difluoromethoxy)pyridazin-3-yl}amino)propan-2-ol monohydrochloride (54 mg) as a solid.

[0270] Example 63

[0271] Under an argon atmosphere, (1R,2R)-2-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]cyclohexan-1-ol (150 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (240 mg), potassium carbonate (160 mg), water (0.3 mL), 1,4-dioxane (3 mL), and RuPhos Pd G3 (48 mg) were mixed and stirred at 100 °C for 2 hours under microwave irradiation. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / methanol). Diisopropyl ether was added to the obtained purified product and triturated. The precipitated solid was filtered to obtain 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (70 mg) as a solid.

[0272] Example 68

[0273] A mixture of 1-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]-2-methylpropan-2-ol (170 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (230 mg), potassium carbonate (200 mg), water (0.34 mL), 1,4-dioxane (3.4 mL), and RuPhosPd G3 (60 mg) was stirred at 100 °C for 5 h under an argon atmosphere. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol). Ethyl acetate was added to the obtained purified product, and the mixture was triturated. The precipitated solid was collected by filtration to obtain 2-{6-[(2-hydroxy-2-methylpropyl)amino]-4,5-dimethylpyridazin-3-yl}-5-(trifluoromethyl)phenol (72 mg) as a solid.

[0274] Example 70

[0275] A mixture of 2-(6-chloro-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (110 mg), 3-amino-1-propanol (0.17 mL), and DIPEA (0.14 mL) was stirred overnight at 120 °C under an argon atmosphere. Ethanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was washed successively with chloroform and ethyl acetate. The aqueous layer was concentrated under reduced pressure, ethanol and toluene were added to the obtained residue, and the mixture was concentrated under reduced pressure. Ethanol, toluene, and diatomaceous earth were added to the obtained residue, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2-{6-[(3-hydroxypropyl)amino]-4,5-dimethylpyridazin-3-yl}-5-(trifluoromethyl)phenol (120 mg) as an oil.

[0276] Example 76

[0277] 2-{6-[(3-Hydroxy-2-methylpropyl)amino]-4,5-dimethylpyridazin-3-yl}-5-(trifluoromethyl)phenol (430 mg) was resolved by chiral column chromatography (CHIRALPAK IA, hexane / ethanol). Then, the eluted fractions were concentrated under reduced pressure, ethyl acetate was added, and the mixture was triturated. The precipitated solid was collected by filtration to obtain 2-(6-{[(2R)-3-hydroxy-2-methylpropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (160 mg) as a solid.

[0278] Example 80

[0279] To a mixture of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (3.5 g) and methanol (70 mL), 2M hydrogen chloride methanol solution (9.2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. To the obtained residue, acetonitrile (70 mL) was added at room temperature, and the mixture was stirred at 50 °C for 3 days. The precipitated solid was filtered to obtain 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride (3.8 g) in solid form.

[0280] In the same manner as the methods of the above Preparation Examples or Examples, the compounds of the Preparation Examples and Examples shown in the following tables were prepared.

[0281] [Table 3-1]

[0282]

[0283] [Table 3-2]

[0284]

[0285] [Table 3-3]

[0286]

[0287] [Table 4-1]

[0288]

[0289] [Table 4-2]

[0290]

[0291] [Table 4-3]

[0292]

[0293] [Table 4-4]

[0294]

[0295] [Table 5-1]

[0296] PEx PSyn DAT 1 - ESI+:287, 289, 291 [M+a]+ 2 - ESI+:299, 301 3 - ESI+:216, 218 4(1) - ESI+:202, 204 4(2) - ESI+:202, 204 5 4 AP1-ES+:246 6 4 ESI+:287 7 4 ESI+:259 8 4 ESI+:301 9 4 ESI+:243, 245 10 4 APCI / ESI+:188 11 3 ESI+:260, 262 12 4 ESI+:254, 256 13 4 ESI+:282, 284 14(1) 4 ESI+;242, 244 14(2) 4 ESI+;242, 244 15 4 ESI+;338, 340 16 4 ESI+:216, 218 17 4 ESI+304, 306 18(1) 4 ESI+;230, 232 18(2) 4 ESI+;230, 232 19(1) 4 ES1+;228, 230 19(2) 4 ESI+;228, 230 20 3 ESI+:231, 233 21 4 ESI+:213, 215 22 4 ESI+:268, 270 23 4 ESI+:227, 229 24(1) - APCI / ESI+:335 24(2) - APCI / ESI+:335 25 - ESI+:244, 246 26 - ESI+:482 27 26 ESI+:424 28 26 ESI+:465 29 26 ESI+:479 30 - ESI+:379

[0297] [Table 5-2]

[0298] PEx PSyn DAT 31 30 ESI+:365 32 - ESI+:524 33 - ESI+:424 34 - ESI+:474 35 - ESI+:410 36(1) 3 ESI+:254, 256 36(2) 3 ESI+:254, 256 37 4 ESI+:264, 266 38 4 ESI+:254, 256 39 - ES1+:256, 258 40(1) 24 APCI / ESI+:273 40(2) 24 APCI / ESI+:273 41 24 ESI+:303, 305 42 3 ESI+:216, 218 43 4 ESI+:244, 246 44 4 ESI+:230, 232 45 4 ESI+:230, 232 46 4 ESI+:256, 258 47 4 ESI+:271, 273 48 4 ESI+:230, 232 49 4 ESI+:256, 258

[0299] [Table 6-1]

[0300]

[0301] [Table 6-2]

[0302]

[0303] [Table 6-3]

[0304]

[0305] [Table 6-4]

[0306]

[0307] [Table 6-5]

[0308]

[0309] [Table 6-6]

[0310]

[0311] [Table 6-7]

[0312]

[0313] Industrial applicability

[0314] 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 Ar is a group represented by the following formula (i) or formula (ii), [Chemical formula 2] * represents the bonding part of the pyridazine ring of formula (I), L is C 1-6 an alkylene or C 3-8 a cycloalkylene, R 1 is H, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, furyl or imidazolyl, R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, furyl, pyrazolyl which may be substituted by 1 to 4 C 1-6 alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, -C(=O)O-C 1-6 alkyl or -C(=O)NR 8 R 9 , R 3 is OH, -NHC(=O)R 10 or -OC(=O)-C 1-6 alkyl R 4 is halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, R 5 is H, C 3-8 cycloalkyl or halo C 1-6 alkyl, R 6 is H, halogen, -O-C 1-6 alkyl or halo-C 1-6 alkyl, R 7 is -C 1-6 alkylene -O -C 1-6 alkylene -phenyl or halo -C 1-6 alkyl, R 8 and R 9 are the same or different and are H or C 1-6 alkyl, or R 8 and R 9 may also combine with the nitrogen atom to which they are bonded to form morpholine, piperazine or thiomorpholine. In addition, the morpholine, piperazine or thiomorpholine may also be substituted by C 1-6 alkyl R 10 is C 1-6 alkyl, halo-C 1-6 alkyl or C 3-8 cycloalkyl, however, When Ar is a group represented by formula (i) and R 5 is H, R 4 is halo C 1-6 alkyl, R 1 or R 2 is a group other than H.

2. The compound or its salt according to claim 1, wherein R 5 is C 3-8 cycloalkyl or halo C 1-6 alkyl.

3. The compound or its salt according to claim 2, wherein, R 3 is OH.

4. The compound or its salt according to claim 3, wherein, R 1 is H, C 1-6 alkyl or C 3-8 cycloalkyl, R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl or cyano.

5. The compound or its salt according to claim 4, wherein, R 1 and R 2 which may be the same or different, is H or C 1-6 alkyl group.

6. The compound or its salt according to claim 5, wherein, Ar is a group represented by formula (i).

7. The compound or salt thereof according to claim 6, wherein, R 4 and R 5 is a halogenated C 1-6 alkyl group.

8. The compound or its salt according to claim 5, wherein, Ar is a group represented by formula (ii).

9. The compound or its salt according to claim 8, wherein, R 6 is a halogenated C 1-6 alkyl group.

10. The compound or its salt according to claim 1, wherein, The compound is a compound selected from the following group: (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-4,5-dimethylpyridazin-3-yl}amino)propan-2-ol, (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)propan-2-ol, (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)propan-2-ol, 2-(6-{[(2R)-2-Hydroxypropyl]amino}-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol, 2-(6-{[(2R)-2-Hydroxypropyl]amino}-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol, 2-(6-{[(2R)-2-Hydroxypropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol, rac-(1R,2R)-2-({6-[2,4-Bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)cyclohexan-1-ol, rac-(1R,2R)-2-({6-[2,4-Bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)cyclohexan-1-ol, and 2-(6-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol.

11. A pharmaceutical composition comprising the compound or a salt thereof according to claim 10, and one or more pharmaceutically acceptable excipients.

12. An NLRP3 inflammasome activation inhibitor comprising the compound or a salt thereof according to claim 10.

13. The pharmaceutical composition according to claim 11, which is a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

14. Use of the compound or a salt thereof according to claim 10 in the manufacture of a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

15. The compound or its salt according to claim 10, wherein, The compound is (2R)-1-({6-[2,4-Bis(trifluoromethyl)phenyl]-4,5-dimethylpyridazin-3-yl}amino)propan-2-ol.

16. The compound or its salt according to claim 10, wherein, The compound is 2-(6-{[(2R)-2-Hydroxypropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol.

17. The compound or its salt according to claim 10, wherein, The compound is 2-(6-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol.

18. The compound or its salt according to claim 17, which is 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride.

19. The compound or its salt according to claim 18, which is a crystal of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride, and the crystal has peaks at 2θ (°) = 14.5, 16.3, 17.2, 18.4, 18.9, 22.1, 23.6, 24.9, 25.7 and 26.8 in powder X-ray diffraction using Cu as the tube target.

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