Substituted pyridazine compounds

Abstract

The present invention addresses the problem of providing a pharmaceutical composition, in particular a compound suitable for prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.　The inventors of the present invention conducted extensive studies to find a compound that has suppressive action on NLRP3 inflammasome activation, and found that a substituted pyridazine compound has suppressive action on NLRP3 inflammasome activation, leading to completion of the present invention. The substituted pyridazine compound according to the present invention is expected to serve as a drug for prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

Description

[Technical Field]

[0001] The present invention relates to a substituted pyridazine compound or a salt thereof that has an inhibitory effect on NLRP3 inflammasome activation and is expected to be useful as an active ingredient in pharmaceutical compositions, for example, pharmaceutical compositions for the prevention and / or treatment of inflammatory diseases or neurodegenerative diseases. [Background technology]

[0002] Inflammasomes are intracellular protein assemblies triggered by endogenous and exogenous alarm molecules, amplifying the inflammatory response by cleaving and activating the inflammatory cytokines IL-1β and IL-18 through caspase-1 activation, and inducing cell death. Several types of alarm molecule recognition molecules are known, including NLRP1, NLRP3, NLRC4, and AIM2. NLRP3 is activated upon recognition of cellular stress induced by extracellular ATP molecules, pathogen toxins, uric acid and cholesterol crystals, and abnormal protein aggregates.

[0003] Cryopyrin-associated periodic syndrome (CAPS) is known as a disease caused by gain-of-function mutations in NLRP3 (Nature Genetics, Vol. 29, No. 3, pp. 301-305, 2001). It has also been reported in 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 It has been reported that the NLRP3 inflammasome is activated or its expression is increased in a wide range of diseases, including rheumatoid arthritis (e.g., rheumatoid arthritis ...

[0004] Patent Document 1 describes that the compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (see the publication for symbols in the formula). [ka]

[0005] Patent Document 2 describes that the compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (see the publication for symbols in the formula). [ka]

[0006] Patent Document 3 describes that the compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation and is useful as a therapeutic agent for various inflammatory diseases including CAPS (see the publication for symbols in the formula). [ka]

[0007] In addition, Patent Document 4, which was published after the priority date of the present application, describes 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 (see Patent Document 4 for the symbols in the formula). [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2019 / 008025 [Patent Document 2] International Publication No. 2017 / 184604 [Patent Document 3] International Publication No. 2018 / 015445 [Patent Document 4] International Publication No. 2020 / 234715 Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention provides a pharmaceutical composition, in particular a compound that has an inhibitory effect on NLRP3 inflammasome activation and is expected to be useful as an active ingredient in a pharmaceutical composition for the prevention and / or treatment of inflammatory diseases, neurodegenerative diseases, and the like. [Means for solving the problem]

[0010] As a result of extensive research into compounds that have the effect of inhibiting NLRP3 inflammasome activation, the present inventors discovered that substituted pyridazine compounds have the effect of inhibiting NLRP3 inflammasome activation and are expected to be useful as active ingredients in pharmaceutical compositions for the prevention and / or treatment of inflammatory diseases and neurodegenerative diseases, particularly α-synucleinopathy and multiple sclerosis, and thus completed the present invention.

[0011] That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (wherein Ar is a group represented by the following formula (i) or formula (ii), [ka] (* represents the bonding site of the pyridazine ring in formula (I).) L is C 1-6 Alkylene or C 3-8 is cycloalkylene, R 1 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 or -N(C 1-6 alkyl)2, R 2 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, -C(=O)O- C 1-6 Alkyl or -C(=O)NR 8 R 9 and R 3 -OH, -NHC(=O)R10 or -OC(=O)- C 1-6 is alkyl, R 4 is halogen, -OC 1-6 Alkyl or halogeno C 1-6 is alkyl, R 5 is H, C 3-8 Cycloalkyl or halogeno C 1-6 is alkyl, R 6 is H, halogen, -OC 1-6 Alkyl or halogeno C 1-6 is alkyl, R 7 Ha-C 1-6 Alkylene-OC 1-6 Alkylene-aryl or halogeno C 1-6 is alkyl, R 8 and R 9 are the same or different and may be H or C 1-6 alkyl or R 8 and R 9 may be combined with the nitrogen atom to which they are bonded to form morpholine, piperazine or thiomorpholine, and the morpholine, piperazine or thiomorpholine may be C 1-6 may be substituted with alkyl, R 10 is C 1-6 Alkyl, halogeno C 1-6 Alkyl or C 3-8 is cycloalkyl, however, Ar is a group represented by formula (i), and R 5 If H, then R 4 Halogeno C 1-6 alkyl, and R 1 or R 2 Either of the groups is a group other than H.) Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0012] The present invention also relates to a pharmaceutical composition for preventing and / or treating an inflammatory disease or a neurodegenerative disease, which comprises a compound of formula (I) or a salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition includes an agent for preventing and / or treating an inflammatory disease or a neurodegenerative disease, which comprises a compound of formula (I) or a salt thereof.

[0013] The present invention also relates to a compound of formula (I) or a salt thereof, which is an NLRP3 inflammasome activation inhibitor; a compound of formula (I) or a salt thereof for use as an NLRP3 inflammasome activation inhibitor; an NLRP3 inflammasome activation inhibitor containing a compound of formula (I) or a salt thereof; use of a compound of formula (I) or a salt thereof for producing a pharmaceutical composition for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease; use of a compound of formula (I) or a salt thereof for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease; a compound of formula (I) or a salt thereof for use in the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease; and a method for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0014] The "subject" refers to a human or other animal in need of the prevention or treatment, and in one embodiment, the subject is a human in need of the prevention or treatment. [Effects of the Invention]

[0015] The compound of formula (I) or a salt thereof has an inhibitory effect on NLRP3 inflammasome activation and can be used as a prophylactic and / or therapeutic drug for inflammatory diseases and / or neurodegenerative diseases, etc. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the results of evaluation of the effect of the compound of Example 63 on improving motor impairment in a Cuprizone-induced neuroinflammation model using a hanging wire test. [Figure 2]FIG. 2 shows the results of evaluation of the compound of Example 63 for its effect of improving motor impairment in an α-synuclein fibril-induced neuroinflammation model using a hanging wire test. [Figure 3] FIG. 3 shows the results of quantifying the amount of IL-1β produced by the compound of Example 63 in an ex vivo test in mice. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention will be described in detail below. As used herein, the following terms have the meanings indicated below unless otherwise specified. The definitions below are intended to clarify, but not limit, the defined terms. If a term is not specifically defined herein, it is used in the sense generally accepted by those skilled in the art.

[0018] In the present invention, "C 1-6 "Alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms (hereinafter referred to as C 1-6 and the like. In one embodiment, the alkyl group is a straight-chain or branched C 1-4 It is alkyl, and in one embodiment it is methyl, ethyl, n-propyl, isopropyl, or n-butyl, and in one embodiment it is methyl, and in another embodiment it is n-propyl.

[0019] "C 3-8 "Cycloalkyl" means C 3-8and may have a bridge or form a spiro ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, and spiro[2.5]octyl. In one embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, in another embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and in another embodiment, it is cyclopropyl, and in another embodiment, it is cyclohexyl.

[0020] "C 3-8 "Cycloalkylene" refers to the "C 3-8 Among "cycloalkyl," it is a divalent group in which two carbon atoms constituting the ring have bonds. Specific examples include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, and cyclooctanediyl, and one embodiment is cyclohexanediyl.

[0021] "Aryl" means C 6-14 is a monocyclic to tricyclic aromatic hydrocarbon ring group of C 5-8 It includes cycloalkene and a ring group fused at the double bond thereof, such as phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, etc., and in one embodiment, phenyl.

[0022] "Heteroaryl" refers to a 5- or 6-membered aromatic ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 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, and in another embodiment, it is pyrazolyl.

[0023] "Halogen" means F, Cl, Br, or I. In one embodiment, it is F or Cl, in another embodiment, it is F, and in another embodiment, it is Cl.

[0024] "Halogeno C 1-6 "Alkyl" means a straight or branched C alkyl group substituted with one or more halogen atoms. 1-6 In one embodiment, it is trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-fluoro-2-methylpropyl, difluoromethyl, fluoromethyl, or chloromethyl, in a further embodiment it is trifluoromethyl, and in another embodiment it is difluoromethyl.

[0025] "C 1-6 "Alkylene" means a straight or branched C 1-6 In one embodiment, C is an alkylene group, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, 2-methyltrimethylene, ethylethylene, 1,2-dimethylethylene, or 1,1,2,2-tetramethylethylene. 1-4 It is alkylene, and in a further embodiment, it is methylene, ethylene, or propylene, and in another embodiment, it is propylene.

[0026] "Ar is a group represented by formula (i), and R 5 If H, then R 4 Halogeno C 1-6 alkyl, and R 1 or R 2 One embodiment of the "group other than H" in "one of the groups other than H" is C 1-6 It is alkyl, aryl, or heteroaryl, and in a further embodiment, it is methyl, phenyl, or furyl.

[0027] In the present invention, the term "optionally substituted" means unsubstituted or "substituted with one or more substituents." The substitution may occur at any position in the group where a hydrogen atom would normally be present.

[0028] One or more embodiments may be combined with other embodiments, even if such combinations are not specifically recited.

[0029] In the present invention, "inflammatory diseases" include, but are not limited to, autoinflammatory diseases including cryopyrin-associated periodic fever syndromes (CAPS), which consist of the group of diseases including familial cold urticaria (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease / chronic infantile neurological, cutaneous, and articular syndrome (NOMID / CINCA syndrome), gout, and pseudogout, and nonalcoholic steatohepatitis (NASH). In one embodiment, the disease is an autoinflammatory disease, and in another embodiment, the disease is CAPS.

[0030] In the present invention, "neurodegenerative disease" refers to a group of diseases including, but not limited to, Parkinson's disease, α-synucleinopathies including multiple system atrophy and dementia with Lewy bodies; Alzheimer's disease; amyotrophic lateral sclerosis; and multiple sclerosis. In one embodiment, the disease is Alzheimer's disease, multiple sclerosis, or amyotrophic lateral sclerosis. In another embodiment, the disease is α-synucleinopathy, and in yet another embodiment, multiple system atrophy. In yet another embodiment, the disease is α-synucleinopathy or multiple sclerosis.

[0031] Certain embodiments of the compound of formula (I) or a salt thereof according to the present invention are shown below. (1-1) Ar is a group represented by the following formula (i) or (ii): [ka] Here, R 4 is halogen, -OC 1-6 Alkyl or halogeno C 1-6 alkyl, and R 5 is H, C 3-8Cycloalkyl or halogeno C 1-6 alkyl, and R 6 is H, halogen, -OC 1-6 Alkyl or halogeno C 1-6 A compound or a salt thereof, wherein Ar is a group represented by formula (i) and R 5 If H, then R 4 Halogeno C 1-6 alkyl, and R 1 or R 2 One of the groups is a group other than H. (1-2) Ar is a group represented by formula (i) or formula (ii), wherein R 4 is halogen, -OC 1-6 Alkyl or halogeno C 1-6 alkyl, and R 5 is C 3-8 Cycloalkyl or halogeno C 1-6 alkyl, and R 6 is H, halogen, -OC 1-6 Alkyl or halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (1-3) Ar is a group represented by formula (i), wherein R 4 is halogen, -OC 1-6 Alkyl or halogeno C 1-6 alkyl, and R 5 is C 3-8 Cycloalkyl or halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (1-4) Ar is a group represented by formula (i), wherein R 4 and R 5 Halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (1-5) Ar is a group represented by formula (ii), wherein R 6 is H, halogen, -OC 1-6 Alkyl or halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (1-6) Ar is a group represented by formula (ii), and R 6 Halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (2-1)L is C 1-6 Alkylene or C 3-8 A compound which is a cycloalkylene or a salt thereof. (2-2)L is C 1-6 A compound or a salt thereof which is alkylene. (2-3)L is C 3-8 A compound which is a cycloalkylene or a salt thereof. (3-1)R 1 But H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, where R 7 Ha-C 1-6 Alkylene-OC 1-6 Alkylene-aryl or halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (3-2)R 1 H, C 1-6 Alkyl or C 3-8 A compound or a salt thereof which is cycloalkyl. (3-3)R 1 is H or C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (3-4)R 1 is H or a salt thereof. (3-5)R 1 C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (3-6)R 1 But C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 , or -N(C 1-6 alkyl)2, where R 7 Ha-C 1-6 Alkylene-OC 1-6 Alkylene-aryl or halogeno C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (3-7)R1 C 1-6 Alkyl or C 3-8 A compound or a salt thereof which is cycloalkyl. (4-1)R 2 But H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, -C(=O)OC 1-6 Alkyl or -C(=O)NR 8 R 9 where R 7 Ha-C 1-6 Alkylene-OC 1-6 Alkylene-aryl or halogeno C 1-6 alkyl, and R 8 and R 9 are the same or different and may be H or C 1-6 alkyl or R 8 and R 9 may be combined with the nitrogen atom to which they are bonded to form morpholine, piperazine or thiomorpholine, and the morpholine, piperazine or thiomorpholine may be C 1-6 A compound or a salt thereof which may be substituted with alkyl. (4-2)R 2 H, C 1-6 Alkyl, C 3-8 A compound or a salt thereof which is cycloalkyl or cyano. (4-3)R 2 is H or C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (4-4)R 2 is H or a salt thereof. (4-5)R 2 C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (5-1)R 3 is OH, -NHC(=O)R 10 or -OC(=O)-C 1-6 alkyl, where R 10 is C 1-6Alkyl, halogeno C 1-6 Alkyl or C 3-8 A compound or a salt thereof which is cycloalkyl. (5-2)R 3 is OH or a salt thereof. (6) A compound or a salt thereof that is a combination of two or more of the embodiments of the groups described in (1-1) to (5-2) above that are not contradictory to each other. Examples include, but are not limited to, the following combinations: (6-1) A compound or a salt thereof which is a combination of the above aspects (1-1), (2-1), (3-1), (4-1) and (5-1). (6-2) A compound or a salt thereof which is a combination of the above aspects (1-2), (2-1), (3-1), (4-1) and (5-1). (6-3) A compound or a salt thereof which is a combination of the above aspects (1-2), (2-1), (3-1), (4-1) and (5-2). (6-4) A compound or a salt thereof which is a combination of the above aspects (1-2), (2-1), (3-2), (4-2) and (5-2). (6-5) A compound or a salt thereof which is a combination of the above aspects (1-2), (2-1), (3-3), (4-3) and (5-2). (6-6) A compound or a salt thereof which is a combination of the above aspects (1-3), (2-1), (3-2), (4-2) and (5-2). (6-7) A compound or a salt thereof which is a combination of the above aspects (1-3), (2-1), (3-3), (4-3) and (5-2). (6-8) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-1), (3-3), (4-3) and (5-2). (6-9) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-2), (3-5), (4-4) and (5-2). (6-10) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-2), (3-4), (4-5) and (5-2). (6-11) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-2), (3-5), (4-5) and (5-2). (6-12) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-3), (3-5), (4-4) and (5-2). (6-13) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-3), (3-4), (4-5) and (5-2). (6-14) A compound or a salt thereof which is a combination of the above embodiments (1-4), (2-3), (3-5), (4-5) and (5-2). (6-15) A compound or a salt thereof which is a combination of the above (1-5), (2-1), (3-2), (4-2) and (5-2). (6-16) A compound or a salt thereof which is a combination of the above embodiments (1-5), (2-1), (3-3), (4-3) and (5-2). (6-17) A compound or a salt thereof which is a combination of the above (1-6), (2-1), (3-3), (4-3) and (5-2). (6-18) A compound or a salt thereof which is a combination of the above (1-6), (2-2), (3-5), (4-4) and (5-2). (6-19) A compound or a salt thereof which is a combination of the above (1-6), (2-2), (3-4), (4-5) and (5-2). (6-20) A compound or a salt thereof which is a combination of the above (1-6), (2-2), (3-5), (4-5) and (5-2). (6-21) A compound or a salt thereof which is a combination of the above embodiments (1-6), (2-3), (3-5), (4-4) and (5-2). (6-22) A compound or a salt thereof which is a combination of the above (1-6), (2-3), (3-4), (4-5) and (5-2). (6-23) A compound or a salt thereof which is a combination of the above (1-6), (2-3), (3-5), (4-5) and (5-2).

[0032] Examples of specific compounds encompassed by the present invention include the following compounds: (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, 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol, 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride.

[0033] Further, examples of specific compounds encompassed by the present invention include the following compounds or salts thereof: (A) Crystal of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride. (B) A crystal of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride, characterized by 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 a Cu tube. (C) A crystal of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride, characterized by an endothermic peak onset temperature of approximately 227.32°C in differential scanning calorimetry (DSC) analysis. (D) A crystal 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 a Cu tube, the crystal exhibits peaks at around 2θ (°) = 14.5, 16.3, 17.2, 18.4, 18.9, 22.1, 23.6, 24.9, 25.7, and 26.8.

[0034] The present invention relates to use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases, particularly α-synucleinopathy or multiple sclerosis; use of a compound of formula (I) or a salt thereof for the prevention and / or treatment of neurodegenerative diseases, particularly α-synucleinopathy or multiple sclerosis; a compound of formula (I) or a salt thereof for use in the prevention and / or treatment of neurodegenerative diseases, particularly α-synucleinopathy or multiple sclerosis; and a method for the prevention and / or treatment of neurodegenerative diseases, particularly α-synucleinopathy or multiple sclerosis, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0035] The present invention also relates to a compound of formula (I) or a salt thereof, which exhibits an inhibitory effect on IL-1β production in the central nervous system of a subject.

[0036] In one embodiment of the compound of formula (I) or a salt thereof of the present invention, for example, in the measurement method of Test Example 2, the compound of formula (I) or a salt thereof exhibits an IL-1β production inhibitory effect of 50% or more at a dose of 3 mg / kg or less; in another embodiment, the compound of formula (I) or a salt thereof exhibits an IL-1β production inhibitory effect of 50% or more at a dose of 1 mg / kg or less; and in yet another embodiment, the compound of formula (I) or a salt thereof exhibits an IL-1β production inhibitory effect of 50% or more at a dose of 0.3 mg / kg or less.

[0037] Furthermore, one embodiment of the compound of formula (I) or a salt thereof in the present invention is a compound of formula (I) or a salt thereof that exhibits no phototoxic effect. "Exhibiting no phototoxic effect" means that the compound is determined to be negative for phototoxicity in an evaluation based on the method described in OECD guideline for testing of chemicals 432: In vitro 3T3 NRU phototoxicity test, 2004.

[0038] In addition, in one embodiment of the compound of formula (I) or a salt thereof of the present invention, the IC 50 The compound of formula (I) or a salt thereof is characterized in that the value of .gtoreq..times ...

[0039] The compound of formula (I) may exist in the form of tautomers or geometric isomers depending on the type of substituents. In this specification, the compound of formula (I) or a salt thereof may be described in only one isomeric form, but the present invention also includes other isomers, and also includes isolated isomers and mixtures thereof.

[0040] Furthermore, the compound of formula (I) or a salt thereof may have an asymmetric center or axial asymmetry, and therefore may exist as an enantiomer (optical isomer). The compound of formula (I) or a salt thereof encompasses both isolated individual enantiomers, such as the (R) form or the (S) form, and mixtures thereof (including racemic and non-racemic mixtures). In one embodiment, the enantiomer is "stereochemically pure." "Stereochemically pure" refers to a purity that can be recognized by those skilled in the art as being substantially stereochemically pure. In another embodiment, 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, or 99% ee or more.

[0041] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0042] The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and 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, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts.

[0043] Furthermore, the present invention also encompasses various hydrates and solvates, and crystalline polymorphic substances of the compound of formula (I) or a salt thereof.

[0044] The present invention also encompasses all compounds of formula (I) or salts thereof that are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Suitable examples of isotopes used to isotopic label 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 Isotopes of 1,2,3,4,5,6,7,8,8,9,9,9,10,11,12,13,14,15,16,17,18,19,19,19,19,19,20,21,22,23,24,25,26,27,28,29 ... 3 H), carbon-14 ( 14 Radioactive isotopes such as C may be used for this purpose due to their ease of labeling and detection. 2 Substitution with positron-emitting isotopes (H) may be therapeutically advantageous due to increased metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements, and fewer drug interactions). 11 C, 18 F, 15 O and 13 Substitution with an isotopically labeled N or the like can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described in the Examples or Preparations, using appropriate isotopically labeled reagents in place of unlabeled reagents.

[0045] In this specification, the terms "approximately" used in the descriptions of the diffraction angle (2θ (°)) in a powder X-ray diffraction pattern and the onset temperature (°C) of the endothermic peak in DSC analysis refer to the range of error normally permitted in the data measurement method, and refer to the approximate diffraction angle and onset value of the endothermic peak. The error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is ±0.2° in one embodiment, and ±0.1° in yet another embodiment. The error range of the onset temperature (°C) of the endothermic peak in DSC analysis is ±2°C in one embodiment, and ±1°C in yet another embodiment. Due to the nature of powder X-ray diffraction pattern data, the crystal lattice spacing and overall pattern are important in determining the identity of a crystal, and the diffraction angle and diffraction intensity may vary somewhat depending on the direction of crystal growth, particle size, and measurement conditions.

[0046] (Manufacturing method) The compound of formula (I) or a salt thereof can be produced by various known synthetic methods, taking advantage of characteristics based on its basic structure or the type of substituent. In this case, depending on the type of functional group, it may be effective from a manufacturing technology perspective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th ed., 2006) by PGM Wuts and TW Greene, and may be appropriately selected and used depending on the reaction conditions. In such methods, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary. Furthermore, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, as in the case of the above-mentioned protecting group, or by further reacting the obtained compound of formula (I). The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc.

[0047] Representative methods for producing the compound of formula (I) are described below. Each method can be performed by referring to the references attached to the description. However, the production methods of the present invention are not limited to the examples shown below.

[0048] In this specification, the following abbreviations may be used. 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 Pd G3: (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TMS: trimethylsilyl.

[0049] (First manufacturing method) [ka] (X 1 and X 2 are the same or different and are Cl, Br, or I. R' and R'' are both H, or R' and R'' are taken together to form 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The same applies hereinafter.)

[0050] (first step) This step involves the reaction of a compound of formula (Ia) with a compound of formula (IIa) to obtain a compound of formula (Ib). In this reaction, a mixture of compounds of formula (Ia) and formula (IIa) is used in equal amounts, or in excess of either. The mixture is stirred in a reaction-inert solvent or without solvent, under cooling to reflux, preferably at room temperature to 190°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 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 or N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, may be advantageous for smooth reaction progression. This reaction may also be carried out under microwave irradiation.

[0051] (Second process) This step involves the reaction of a compound of formula (Ib) with a compound of formula (IIb) to obtain a compound of formula (I). In this reaction, a mixture of compounds of formula (Ib) and (IIb) is used in equal amounts, or in excess of either. The resulting mixture is stirred in the presence of a catalyst and a base in a reaction-inert solvent under cooling or reflux, preferably at room temperature to 150°C, typically for 0.1 hours to 5 days. Examples of catalysts used here include, but are not limited to, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhos Pd G3, etc. Examples of bases include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium t-butoxide, etc. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0052] (Second manufacturing method) [ka]

[0053] (first step) This step involves the reaction of a compound of formula (Ia) with a compound of formula (IIb) to obtain a compound of formula (Ic). In this reaction, a mixture of compounds of formula (Ia) and (IIb) is used in equal amounts, or in excess of either. The resulting mixture is stirred in the presence of a catalyst and a base in a reaction-inert solvent under cooling to reflux, preferably at room temperature to 150°C, typically for 0.1 hours to 5 days. Examples of catalysts used here include, but are not limited to, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, and RuPhos Pd G3. Examples of bases include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium t-butoxide. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0054] (Second process) This step involves the reaction of a compound of formula (Ic) with a compound of formula (IIa) to obtain a compound of formula (I). In this reaction, a mixture of compounds of formula (Ic) and formula (IIa) is used in equal amounts, or in excess of either. The mixture is stirred in a reaction-inert solvent or without a solvent, under cooling to reflux, preferably at room temperature to 190°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 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 or N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, may be advantageous for smooth reaction progression. This reaction may also be carried out under microwave irradiation.

[0055] (Other manufacturing methods) The compound of formula (I) obtained by the above-mentioned production method can be used as a starting material to further carry out chemical modification reactions commonly used by those skilled in the art, such as esterification and amidation, to obtain another compound of formula (I).

[0056] The compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorph. A salt of the compound of formula (I) can also be produced by a conventional salt formation reaction. Isolation and purification are carried out using conventional chemical procedures such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by taking advantage of differences in physicochemical properties between isomers. For example, optical isomers can be obtained by a common optical resolution method for a racemate (e.g., fractional crystallization leading to diastereomeric salts with an optically active base or acid, or chromatography using a chiral column, etc.), or can also be produced from appropriate optically active starting compounds.

[0057] The pharmacological activity of the compounds of formula (I) can be confirmed by the following tests or by modifications of known tests.

[0058] Test Example 1 THP-1 IL-1β production test THP-1 cells were cultured for 2 days at 37°C with 50 ng / mL PMA (phorbol myristate acetate, SIGMA, P1585). The culture medium was replaced with serum-free RPMI-1640 medium, and known concentrations of compounds were added. The cells were then cultured at 37°C for 15 minutes. LPS (lipopolysaccharide, SIMGA, L2880) and ATP (adenosine triphosphate, SIGMA, A2383) were added to final concentrations of 50 ng / mL and 5 mM, respectively, and the cells were cultured at 37°C for 2 hours. The supernatant was collected, and IL-1β levels were measured by ELISA (DuoSet ELISA human IL-1β, R&D Systems, DY201). The inhibition rate for each concentration was calculated by setting the IL-1β production level as 100% when no test compound or stimulating substances (LPS and ATP) were added, and 0% when stimulating substances were added without adding the test compound. The IC was calculated by sigmoid Emax model nonlinear regression analysis. 50 The value was calculated. The results are shown in Table 1. It was confirmed that the example compounds inhibited IL-1β production.

[0059] [Table 1]

[0060] Test Example 2: Central IL-1β production test in rats Male Wistar rats (10-14 weeks old) were anesthetized with isoflurane and administered 12.5 μg / 5 μL of LPS (Sigma, L2880) intracisternally. Two hours later, the test compound was administered orally. One hour later, 50 μg / 5 μL of BzATP (2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt, Sigma, B6396) was administered intracisternally. CSF was collected 30 minutes later. IL-1β p17 was quantified by Western blotting using an anti-IL-1β antibody (Millipore, AB1832P). The percentage of inhibition relative to the vehicle-treated group was calculated. Table 2 shows the IL-1β p17 inhibition rates relative to the vehicle-administered group for Examples 4, 9, and 63, which are compounds of formula (I). In the table, "Dose" indicates the dose of each test compound, "Ex4," "Ex9," and "Ex63" indicate Examples 4, 9, and 63, respectively, and "NT" indicates cases where no measurement was performed. These compounds were confirmed to exhibit IL-1β production inhibitory activity in vivo.

[0061] [Table 2]

[0062] Test Example 3: Cuprizone-induced neuroinflammation model in mice Male C57BL / 6J mice were fed a diet containing 0.2% Cuprizone (ENVIGO, TD.140801) for 40 days. The test compound was suspended in 0.5% methylcellulose solution and orally administered at doses of 1 and 3 mg / kg once daily from the start of Cuprizone administration. The negative control group received 0.5% methylcellulose solution. Motor function was assessed using a 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 / > ) was used to evaluate the activity of mice. Mice were asked to grab onto a horizontally stretched wire, and the time it took for them to fall was measured. This was repeated three times and the average value was calculated. The results of evaluating the compound of Example 63 in this test are shown in Figure 1. The compound of Example 63 significantly extended the time it took for the mice to fall in the 1 and 3 mg / kg administration groups compared to the negative control group. This confirmed that the compound of Example 63 has an effect of improving movement disorders.

[0063] Test Example 4: Mouse α-synuclein fibril-induced neuroinflammation model Male C57BL / 6J mice were administered 8 μg of mouse α-synuclein fibrillary protein (StressMarq Biosciences Inc., SPR-324) into the left striatum. After 13–14 weeks, the test compound suspended in 0.5% methylcellulose solution was orally administered once daily at a dose of 1 or 10 mg / kg. A 0.5% methylcellulose solution was administered to the negative control group. Four weeks after the start of administration, motor function was evaluated using a hanging wire test. In this test, mice were required to grab a horizontally stretched wire, fall, and then re-grab for 3 minutes, and the number of falls was recorded. The results of evaluating the compound of Example 63 in this test are shown in Figure 2. The compound of Example 63 significantly reduced the number of falls in the 1 and 10 mg / kg groups compared to the negative control group. This confirmed that the compound of Example 63 has an effect of improving motor disorders.

[0064] Test Example 5 Ex vivo IL-1β production test in mice Male C57BL / 6J mice were orally administered a 3 mg / kg dose of the compound suspended in 0.5% methylcellulose, and blood samples were collected 1 and 6 hours later. LPS was added to the blood to a final concentration of 50 ng / mL, and the mice were incubated at 37°C for 3 hours. ATP was then added to a final concentration of 5 mM, and the mice were incubated at 37°C for 30 minutes. After centrifugation to remove blood cells, IL-1β levels were measured by ELISA (DuoSet ELISA mouse IL-1β, R&D Systems, DY401). The results of evaluating the compound of Example 63 in this test are shown in Figure 3. The compound of Example 63 suppressed IL-1β production in blood collected 1 and 6 hours after compound administration.

[0065] Test Example 6 In vitro phototoxicity test The in vitro phototoxicity test was performed in accordance with ICH S10: Guideline for the Photosafety Evaluation of Pharmaceuticals (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.

[0066] Test Example 7 Safety pharmacology test As a safety pharmacology test, the inhibitory activity of human Ether-a-go-go Related Gene (hereinafter referred to as hERG) channel was evaluated. The inhibitory activity of hERG channel was evaluated using a modified method described in Combinatorial Chemistry & High Throughput Screening, 12, 1, 78-95 (2009). In this test, the compound of Example 63 had an IC of 34.5 μM. 50 showed.

[0067] From the above results, it is expected that the compound of formula (I) or a salt thereof can be used for the prevention and / or treatment of inflammatory diseases or neurodegenerative diseases.

[0068] In addition, it is known that the expression of NLRP3 and IL-1β is increased in the central nervous system in a model of multiple sclerosis induced by cuprizone administration (The Journal of Neuroscience, Vol. 30, No. 47, pp. 15811-15820). It is also known that α-synuclein fibrils activate NLRP3, promoting IL-1β production from microglia, and that administration of an NLRP3 inhibitor improves function in a model of α-synucleinopathy induced by α-synuclein fibrils (Science Translational Medicine, Vol. 10, Article No. eaah4066, 2018). The compounds of formula (I) or salts thereof shown in Table 1 were shown to inhibit IL-1β production in Test Example 1, and the compounds of Examples 4, 9, and 63 were shown to have an inhibitory effect on IL-1β production in the central nervous system in Test Example 2. Furthermore, the compound of Example 63 was confirmed to exhibit an ameliorative effect on movement disorders in a mouse cuprizone-induced neuroinflammation model in Test Example 3 and a mouse α-synuclein fibril-induced neuroinflammation model in Test Example 4. From these results, it is highly expected that the compounds of formula (I) or salts thereof can be used for the prevention and / or treatment of neurodegenerative diseases, particularly α-synucleinopathies including multiple sclerosis, Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies.

[0069] Furthermore, the results of Test Example 5 showed that the compound of Example 63 suppressed IL-1β production in the blood even 6 hours after oral administration, and the results of Test Examples 6 and 7 showed that the compound of Example 63 did not exhibit phototoxicity and had weak hERG channel inhibitory activity. From these results, it is highly expected that the compound of Example 63 will be a pharmaceutical agent with excellent long-lasting efficacy and high safety as an oral agent.

[0070] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular, etc. injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.

[0071] Solid compositions for oral administration include tablets, powders, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a film of a gastric or enteric substance, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluents, the liquid compositions may contain adjuvants such as solubilizing agents, wetting agents, and suspending agents, as well as sweeteners, flavors, aromatics, and preservatives.

[0072] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain an isotonic agent, an antiseptic, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizing agent, or irradiation. Alternatively, sterile solid compositions can be prepared and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0073] External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, etc. They contain commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc.

[0074] Transmucosal agents such as inhalants and nasal agents may be in solid, liquid, or semisolid form and may be prepared according to conventional methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., may be added as appropriate. Administration can be performed using a suitable inhalation or insufflation device. For example, known devices such as metered-dose inhalers or nebulizers can be used to administer the compound alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers and the like may be for single or multiple doses, and can utilize dry powders or powder-containing capsules. Alternatively, the compound may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0075] In general, for oral administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered once or in two to four divided doses. For intravenous administration, the daily dosage is approximately 0.0001 to 10 mg / kg of body weight, administered once or in multiple divided doses. For transmucosal administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, administered once or in multiple divided doses. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, etc.

[0076] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0077] The compound of formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of formula (I) is considered to be effective. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately. [Example]

[0078] The production method of the compound of formula (I) will be explained in more detail below based on examples. Note that the present invention is not limited to the compounds described in the following examples. In addition, production methods of the starting compounds are shown in the production examples. In addition, the production method of the compound of formula (I) is not limited to the production methods of the specific examples shown below, and the compound of formula (I) can also be produced by a combination of these production methods or by methods that are obvious to those skilled in the art.

[0079] The onset temperatures of the DSC curves obtained under the following conditions are shown as melting points in the table below. DSC measurements were performed using a DSC Q2000 (manufactured by TA Instruments) under the following conditions: measurement temperature range: room temperature to 300°C, heating rate: 10°C / min, nitrogen flow rate: 50 mL / min, using an aluminum sample pan without a lid.

[0080] Powder X-ray diffraction was measured using an Empyrean (PANalytical) under the following conditions: tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step width: 0.013°, wavelength: 1.5418 Å, and diffraction angle range (2θ): 2.5 to 40°. Note that due to the nature of powder X-ray diffraction data, the crystal lattice spacing and overall pattern are important in determining the identity of the crystal, and the error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is usually ±0.2°, but the diffraction angle and diffraction intensity can vary slightly depending on the crystal growth direction, particle size, and measurement conditions, so this should not be interpreted strictly.

[0081] Furthermore, the following abbreviations may be used in the Examples, Production Examples and Tables below. PEx: Production Example number, Ex: Example number, PSyn: Production Example number produced by a similar method, Syn: Example number produced by a similar method, Str: Chemical structure, DAT: Physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [M+H]+), APCI / ESI+: APCI / ESI-MS (atmospheric pressure chemical ionization method APCI, APCI / ESI means simultaneous measurement of APCI and ESI. Unless otherwise specified [M+H]+), API-ES+: API-ES MS (atmospheric pressure ionization-electrospray method, unless otherwise specified [M+H]+), J: Coupling constant, s: Singlet, d: Doublet, t: Triplet, q: Quartet, dd: Double doublet, ddd: Double double doublet, tt: Triplet triplet, br: Broad line (e.g., br s), m: multiplet, mp: melting point, 2θ: diffraction angle of peak in powder X-ray diffraction.

[0082] Among the compounds in the table below whose chemical structures include configurations, compounds marked with "#" indicate that the configuration shown is relative, and all other compounds indicate that the configuration shown is absolute.

[0083] The prefix "rac" at the beginning of a compound name indicates that the compound is racemic.

[0084] For convenience, the concentration in mol / l is expressed as M. For example, a 1M aqueous solution of sodium hydroxide means a 1 mol / l aqueous solution of sodium hydroxide.

[0085] Manufacturing Example 1 A mixture of 2-(trimethylsilyl)ethanol (4.3 mL) and THF (100 mL) was ice-cooled, and then sodium hydride (60%, liquid paraffin dispersion, 1.2 g) was added under an argon atmosphere and stirred at the same temperature for 10 minutes. A mixture of 3,4,6-trichloropyridazine (5.0 g) and THF (25 mL) was added dropwise to the resulting mixture under ice-cooling and stirred at room 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 washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 3,6-dichloro-4-[2-(trimethylsilyl)ethoxy]pyridazine (2.9 g) as a solid.

[0086] Manufacturing Example 2 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. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-[2-(benzyloxy)ethoxy]-3,6-dichloropyridazine (3.4 g) as an oil.

[0087] Manufacturing Example 3 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 at 100°C overnight. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (2R)-1-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]propan-2-ol (39 mg) as a solid.

[0088] Manufacturing Example 4 A mixture of 3,6-dichloro-4-methylpyridazine (4.0 g), isopropyl alcohol (30 mL), (2R)-1-aminopropan-2-ol (6 mL), and DIPEA (12 mL) was divided into three equal portions, and each mixture was stirred at 140 °C for 3 hours under microwave irradiation. The reaction mixture was mixed and concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the resulting residue, 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, and the resulting residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to give (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.

[0089] Manufacturing Example 24 To 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) was added PdCl2(PPh3)2 (0.31 g) under a nitrogen atmosphere and stirred at 80 °C for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was 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 give 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.

[0090] Manufacturing Example 25 To 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) was added acetic anhydride (0.57 mL) and N,N-dimethyl-4-aminopyridine (120 mg) at room temperature, followed by stirring overnight at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). Hexane and ethyl acetate were added to the resulting purified product, which was then triturated. The precipitated solid was collected by filtration to give (2R)-1-[(6-chloro-5-methylpyridazin-3-yl)amino]propan-2-yl acetate (1.1 g) as a solid.

[0091] Manufacturing Example 26 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. The reaction mixture was allowed to cool to room temperature, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (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.

[0092] Manufacturing Example 30 To a mixture of t-butyl [4-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}amino)butyl]carbamate (700 mg) and dichloromethane (10 mL) was added TFA (5 mL) 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. A saturated aqueous solution of sodium bicarbonate was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, then concentrated under reduced pressure, and N 1 -{6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}butane-1,4-diamine (780 mg) was obtained.

[0093] Manufacturing Example 32 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) was added acetic anhydride (0.24 mL) and N,N-dimethyl-4-aminopyridine (51 mg) at room temperature, followed by stirring at the same temperature for 30 minutes. Water and saturated aqueous sodium chloride were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (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.

[0094] Manufacturing Example 33 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) was added tetrabutylammonium fluoride (1 M THF solution, 5.9 mL) at room temperature, followed by stirring 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 solution and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-hydroxypyridazin-3-yl}amino)propan-2-yl acetate (820 mg) as a solid.

[0095] Manufacturing Example 34 To 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) was added sodium chlorodifluoroacetate (220 mg) and cesium carbonate (460 mg) at room temperature, followed by stirring at 90°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then water was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol). The resulting product was purified by silica gel column chromatography (hexane / ethyl acetate) to give (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-(difluoromethoxy)pyridazin-3-yl}amino)propan-2-yl acetate (110 mg) as an oil.

[0096] Manufacturing Example 35 As a by-product of the reaction in Example 3, 6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylic acid (150 mg) was obtained as a solid.

[0097] Manufacturing Example 39 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, which was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1R,2R)-2-[(6-chloro-4,5-dimethylpyridazin-3-yl)amino]cyclohexan-1-ol (150 mg) as a solid.

[0098] Example 1 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. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 3-({5-phenyl-6-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}amino)propan-1-ol (60 mg) as a solid.

[0099] Example 3 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 under an argon atmosphere and stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol). Hexane and ethyl acetate were added to the resulting product, and the mixture was triturated. The precipitated solid was collected by filtration to give ethyl 6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazine-4-carboxylate (220 mg) as a solid.

[0100] Example 4 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. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4,5-dimethylpyridazin-3-yl}amino)propan-2-ol (60 mg) as a solid.

[0101] Example 5 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. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate). The resulting purified product was added with ethyl acetate and triturated. The precipitated solid was collected by filtration to give (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)propan-2-ol (290 mg) as a solid.

[0102] Example 6 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. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (hexane / ethyl acetate). The resulting purified product was triturated with hexane and ethyl acetate. The precipitated solid was collected by filtration to give (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)propan-2-ol (94 mg) as a solid.

[0103] Example 7 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. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol). The resulting purified product was added with hexane and ethyl acetate and triturated. The precipitated solid was collected by filtration to give 2-(6-{[(2R)-2-hydroxypropyl]amino}-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (90 mg) as a solid.

[0104] Example 8 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. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol). Hexane and ethyl acetate were added to the resulting purified product, and the mixture was triturated. The precipitated solid was collected by filtration to give 2-(6-{[(2R)-2-hydroxypropyl]amino}-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (80 mg) as a solid.

[0105] Example 9 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 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol). The resulting purified product was triturated with hexane and ethyl acetate. The precipitated solid was collected by filtration to give 2-(6-{[(2R)-2-hydroxypropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (110 mg) as a solid.

[0106] Example 40 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-morpholinomethylene}dimethylammonium hexafluorophosphate (70 mg), and DIPEA (0.063 mL) was stirred at room temperature for 3 days. Water and saturated aqueous sodium chloride were added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazin-4-yl)(morpholin-4-yl)methanone (20 mg) as a solid.

[0107] Example 42 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) was added DIPEA (0.18 mL) and trimethylaluminum (0.26 mL) at room temperature under a nitrogen atmosphere and stirred at 80°C for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give (6-[2,4-bis(trifluoromethyl)phenyl]-3-{[(2R)-2-hydroxypropyl]amino}pyridazin-4-yl)(4-methylpiperazin-1-yl)methanone (40 mg) as a solid.

[0108] Example 45 (2R)-N 1 To a mixture of N-{6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}propane-1,2-diamine (100 mg) and dichloromethane (5 mL), acetyl chloride (24 mg) and triethylamine (0.22 mL) were added at room temperature under a nitrogen atmosphere and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give N-[(2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}amino)propan-2-yl]acetamide (42 mg) as a solid.

[0109] Example 46 N 1To a mixture of 1,4-{6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}butane-1,4-diamine (400 mg) and DMF (5 mL), 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 under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol). The obtained purified product was purified by reverse-phase silica gel column chromatography (0.02% TFA aqueous solution / acetonitrile) to give N-[4-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}amino)butyl]-2,2-difluoroacetamide (41 mg) as a solid.

[0110] Example 49 To 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) was added 1M aqueous sodium hydroxide solution (0.49 mL) at room temperature, followed by stirring at the same temperature for 1.5 hours. 1M hydrochloric acid (0.49 mL), water, and saturated aqueous sodium chloride solution were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol). Ethyl acetate and a 4M solution of hydrogen chloride in ethyl acetate (0.2 mL) were added to the resulting purified product, followed by concentration under reduced pressure. Ethyl acetate was added to the resulting residue, and the precipitated solid was collected by filtration to give (2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-(difluoromethoxy)pyridazin-3-yl}amino)propan-2-ol monohydrochloride (54 mg) as a solid.

[0111] Example 63 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. The reaction mixture was allowed to cool to room temperature, then water was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol). The resulting purified product was added with diisopropyl ether and triturated. The precipitated solid was collected by filtration to obtain 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (70 mg) as a solid.

[0112] Example 68 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 RuPhos Pd G3 (60 mg) was stirred at 100°C for 5 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was then extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol). Ethyl acetate was added to the resulting product, and the mixture was triturated. The precipitated solid was collected by filtration to give 2-{6-[(2-hydroxy-2-methylpropyl)amino]-4,5-dimethylpyridazin-3-yl}-5-(trifluoromethyl)phenol (72 mg) as a solid.

[0113] Example 70 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 resulting residue, and the mixture was washed sequentially with chloroform and ethyl acetate. The aqueous layer was concentrated under reduced pressure, and ethanol and toluene were added to the resulting residue, followed by concentration under reduced pressure. Ethanol, toluene, and Celite were added to the resulting residue, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 2-{6-[(3-hydroxypropyl)amino]-4,5-dimethylpyridazin-3-yl}-5-(trifluoromethyl)phenol (120 mg) as an oil.

[0114] Example 76 2-{6-[(3-hydroxy-2-methylpropyl)amino]-4,5-dimethylpyridazin-3-yl}-5-(trifluoromethyl)phenol (430 mg) was separated by chiral column chromatography (CHIRALPAK IA, hexane / ethanol). The latter fraction was concentrated under reduced pressure, ethyl acetate was added, and the mixture was triturated. The precipitated solid was collected by filtration to give 2-(6-{[(2R)-3-hydroxy-2-methylpropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (160 mg) as a solid.

[0115] Example 80 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) was added 2M hydrogen chloride methanol solution (9.2 mL) at room temperature, followed by stirring at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Acetonitrile (70 mL) was added to the resulting residue at room temperature, followed by stirring at 50°C for 3 days. The precipitated solid was collected by filtration to give 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol monohydrochloride (3.8 g) as a solid.

[0116] The compounds of the Preparations and Examples shown in the following tables were prepared in the same manner as in the above Preparations and Examples.

[0117] [Table 3-1]

[0118] [Table 3-2]

[0119] [Table 3-3]

[0120] [Table 4-1]

[0121] [Table 4-2]

[0122] [Table 4-3]

[0123] [Table 4-4]

[0124] [Table 5-1]

[0125] [Table 5-2]

[0126] [Table 6-1]

[0127] [Table 6-2]

[0128] [Table 6-3]

[0129] [Table 6-4]

[0130] [Table 6-5]

[0131] [Table 6-6]

[0132] [Table 6-7] [Industrial Applicability]

[0133] The compound of formula (I) or a salt thereof has an inhibitory effect on NLRP3 inflammasome activation, and is expected to be usable as a preventive and / or therapeutic agent for inflammatory diseases and / or neurodegenerative diseases. [1] A compound of formula (I) or a salt thereof: [ka] (wherein Ar is a group represented by the following formula (i) or formula (ii), [ka] (* represents the bonding site of the pyridazine ring in formula (I).) L is C 1-6 Alkylene or C 3-8 is cycloalkylene, R 1 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 or -N(C 1-6 alkyl)2, R 2 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1-4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 , -N(C 1-6 alkyl)2, -C(=O)OC 1-6 Alkyl or -C(=O)NR 8 R 9 and R 3 -OH, -NHC(=O)R 10 or -OC(=O)-C 1-6 is alkyl, R 4 is halogen, -OC 1-6 Alkyl or halogeno C 1-6 is alkyl, R 5 is H, C3-8 Cycloalkyl or halogeno C 1-6 is alkyl, R 6 is H, halogen, -OC 1-6 Alkyl or halogeno C 1-6 is alkyl, R 7 Ha-C 1-6 Alkylene-OC 1-6 Alkylene-aryl or halogeno C 1-6 is alkyl, R 8 and R 9 are the same or different and may be H or C 1-6 alkyl or R 8 and R 9 may be combined with the nitrogen atom to which they are bonded to form morpholine, piperazine or thiomorpholine, and the morpholine, piperazine or thiomorpholine may be C 1-6 may be substituted with alkyl, R 10 is C 1-6 Alkyl, halogeno C 1-6 Alkyl or C 3-8 is cycloalkyl, provided that Ar is a group represented by formula (i), and R 5 If H, then R 4 Halogeno C 1-6 alkyl, and R 1 or R 2 Either of the groups is a group other than H.) [2] R 5 C 3-8 Cycloalkyl or halogeno C 1-6 The compound or salt thereof according to [1], wherein R is alkyl. [3] R 3 [2] The compound or salt thereof according to [2], wherein [4] R 1 H, C 1-6 Alkyl or C 3-8 is cycloalkyl, and R 2 H, C 1-6 Alkyl, C 3-8 The compound or salt thereof according to [3], wherein the cycloalkyl or cyano group is cycloalkyl or cyano. [5] R 1 and R 2 are the same or different and are H or C 1-6 The compound or salt thereof according to [4], wherein R is alkyl. [6] The compound or salt thereof according to [5], wherein Ar is a group represented by formula (i). [7] R 4 and R 5 Halogeno C 1-6 The compound or salt thereof according to [6], wherein R is alkyl. [8] The compound or salt thereof according to [5], wherein Ar is a group represented by formula (ii). [9] R 6 Halogeno C 1-6 The compound or salt thereof according to [8], wherein R is alkyl.

[10] The compound or salt thereof according to [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 according to [1] or a salt thereof and one or more pharmaceutically acceptable excipients.

[12] An NLRP3 inflammasome activation inhibitor containing the compound according to [1] or a salt thereof.

[13] The pharmaceutical composition according to

[11] , which is a pharmaceutical composition for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

[14] Use of the compound according to [1] or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

[15] Use of the compound according to [1] or a salt thereof for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

[16] The compound or salt thereof according to [1] for use in the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

[17] A method for preventing and / or treating an inflammatory disease and / or a neurodegenerative disease, comprising administering an effective amount of the compound according to [1] or a salt thereof to a subject.

Claims

1. A compound of formula (I) or a salt thereof. 【Chemical 1】 (wherein Ar is a group represented by the following formula (i) or formula (ii), 【Chemistry 2】 (* represents the bonding site of the pyridazine ring in formula (I).) L is C 1-6 Alkylene or C 3-8 is cycloalkylene, R 1 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1 to 4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 or -N(C 1-6 alkyl) 2 and R 2 is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, aryl, 1 to 4 C 1-6 Heteroaryl optionally substituted with alkyl, cyano, -OR 7 , -N(C 1-6 alkyl) 2 , -C(=O)OC 1-6 Alkyl or -C(=O)NR 8 R 9 and R 3 -OH, -NHC(=O)R 10 or -OC(=O)-C 1-6 is alkyl, R 4 is halogen, -OC 1-6 Alkyl or halogeno C 1-6 is alkyl, R 5 is H, C 3-8 Cycloalkyl or halogeno C 1-6 is alkyl, R 6 is H, halogen, -OC 1-6 Alkyl or halogeno C 1-6 is alkyl, R 7 Ha-C 1-6 Alkylene-OC 1-6 Alkylene-aryl or halogeno C 1-6 is alkyl, R 8 and R 9 are the same or different and may be H or C 1-6 alkyl or R 8 and R 9 may be combined with the nitrogen atom to which they are bonded to form morpholine, piperazine or thiomorpholine, and the morpholine, piperazine or thiomorpholine may be C 1-6 may be substituted with alkyl, R 10 is C 1-6 Alkyl, halogeno C 1-6 Alkyl or C 3-8 is cycloalkyl, provided that Ar is a group represented by formula (i), and R 5 If H, then R 4 Halogeno C 1-6 alkyl, and R 1 or R 2 Either of the groups is a group other than H.)

2. R 5 C 3-8 Cycloalkyl or halogeno C 1-6 The compound or salt thereof according to claim 1, wherein the aryl group is alkyl.

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

4. R 1 H, C 1-6 Alkyl or C 3-8 is cycloalkyl, and R 2 H, C 1-6 Alkyl, C 3-8 4. The compound or salt thereof according to claim 3, wherein the aryl group is cycloalkyl or cyano.

5. R 1 and R 2 are the same or different and are H or C 1-6 The compound or salt thereof according to claim 4, wherein the aryl group is alkyl.

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

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

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

9. R 6 Halogeno C 1-6 The compound or salt thereof according to claim 8, wherein the aryl group is alkyl.

10. 2. The compound or salt thereof 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 of claim 1 or a salt thereof and one or more pharmaceutically acceptable excipients.

12. An NLRP3 inflammasome activation inhibitor comprising the compound according to claim 1 or a salt thereof.

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

14. Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

15. 10. The compound or salt thereof according to claim 1 for use in the prevention and / or treatment of an inflammatory disease and / or a neurodegenerative disease.

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