Substituted triazine compound

Abstract

The present invention addresses the problem of providing a pharmaceutical composition, in particular, a compound suitable for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases.　The present inventors have conducted an intensive examination to search for a compound having an NLRP3 inflammasome activation inhibiting action, and have found that a substituted triazine compound has an NLRP3 inflammasome activation inhibiting action, thereby completing the present invention. A substituted triazine compound according to the present invention is expected to serve as a drug for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases.

Description

Substituted Triazine Compounds

[0001] The present invention relates to a substituted triazine 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.

[0002] Inflammasomes are intracellular protein assemblies triggered by endogenous and exogenous alarm molecules, and are responsible for amplifying inflammatory responses by cleaving and activating the inflammatory cytokines IL-1β and IL-18 through the activation of caspase 1, 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 caused 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 Experimental It has been reported that the NLRP3 inflammasome is activated or its expression is increased in a wide range of diseases, including rheumatoid arthritis (rheumatoid arthritis), rheumatoid arthritis (rheumatoid arthritis), and rheumatoid arthritis (rheumatoid arthritis).

[0004] 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 mouse model of α-synucleinopathy induced by α-synuclein fibrils (Science Translational Medicine, Vol. 10, Article No. eaah4066, 2018).

[0005] Patent Document 1 describes that a compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation (see the publication for symbols in the formula).

[0006] Patent Document 2 describes that a compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation (see the publication for symbols in the formula).

[0007] Patent Document 3 describes that a compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation (see the publication for symbols in the formula).

[0008] Patent Document 4 describes that a compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation (see the publication for symbols in the formula).

[0009] Patent Document 5, which was published after the priority date of the present application, describes that a compound represented by the following formula has the effect of inhibiting NLRP3 inflammasome activation (see Patent Document 5 for the symbols in the formula):

[0010] Furthermore, Patent Document 6 describes that a compound represented by the following formula is useful for treating Huntington's disease (B represents a heterocycle; see the publication for other symbols in the formula):

[0011] Patent Document 7 describes that a compound represented by the following formula has a function of regulating the splicing of messenger RNA (see the publication for symbols in the formula).

[0012] Patent Document 8 describes that a compound represented by the following formula has the function of regulating muscle contraction (see the publication for symbols in the formula).

[0013] International Publication No. 2020 / 234715, International Publication No. 2019 / 008025, International Publication No. 2017 / 184604, International Publication No. 2018 / 015445, International Publication No. 2021 / 193897, International Publication No. 2019 / 191229, International Publication No. 2020 / 163248, International Publication No. 2011 / 133920

[0014] 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.

[0015] As a result of extensive research into compounds that have the effect of inhibiting NLRP3 inflammasome activation, the inventors discovered that substituted triazine 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, neurodegenerative diseases, and the like, and thus completed the present invention.

[0016] 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 excipients. [In the formula, R 1 are the same or different, C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 alkyl or cyano, R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, halogeno C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 alkyl)2 or aryl, and R 3 is H or C 1-6 alkyl, and R 4 is 1 to 4 identical or different R 5 C is replaced by 1-6 Alkyl, -C 1-6 alkylene-(1 to 4 identical or different R 6 aryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 7 C optionally substituted with 3-8 cycloalkyl), -C 1-6 alkylene-(1 to 4 identical or different R 8Heteroaryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with R 10 C optionally substituted with 3-8 cycloalkyl, 1 to 4 identical or different R 11 or 1 to 4 identical or different R 12 R is a 4- to 8-membered saturated heterocyclyl optionally substituted by 5 HA-OR 13 , -NR 14 R 15 , halogen, or cyano; R 6 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 7 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 8 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6Alkylene-NR 14 R 15 , halogen, or cyano; R 9 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 is alkyl, and R 10 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, —C(O)—OH, or cyano; R 11 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 12 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-C 3-8 Cycloalkyl, -C1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , -C 1-6 Alkylene-cyano, -C 1-6 Alkylene -C(O)-OH, halogen, cyano, oxo, -C(O)-NH2, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 alkyl, and R 13 is H or C 1-6 alkyl, and R 14 and R 15 are the same or different and are H, C 1-6 Alkyl, or -C(O)-C 1-6 alkyl, n is an integer from 1 to 4, and the substituent R 1 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.

[0017] The present invention also relates to a pharmaceutical composition, particularly a pharmaceutical composition for preventing and / or treating an inflammatory disease or a neurodegenerative disease, containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. The pharmaceutical composition also includes an agent for preventing and / or treating an inflammatory disease or a neurodegenerative disease, containing a compound of formula (I) or a salt thereof.

[0018] 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 the compound of formula (I) or a salt thereof; a pharmaceutical composition containing the compound of formula (I) or a salt thereof, which is an NLRP3 inflammasome activation inhibitor, and one or more pharmaceutically acceptable excipients; use of the compound of formula (I) or a salt thereof for the manufacture of a medicament or pharmaceutical composition for the prevention and / or treatment of an inflammatory disease and / or neurodegenerative disease; use of the compound of formula (I) or a salt thereof for the prevention and / or treatment of an inflammatory disease and / or 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 neurodegenerative disease; and a method for the prevention and / or treatment of an inflammatory disease and / or neurodegenerative disease, which comprises administering an effective amount of the compound of formula (I) or a salt thereof to a subject. The "subject" refers to a human or other animal in need of prevention and / or treatment, and in one embodiment, the subject is a human in need of prevention and / or treatment.

[0019] 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.

[0020] The present invention will be described in detail below. In this specification, the following terms have the meanings indicated below unless otherwise specified. The following definitions 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.

[0021] As used herein, "C 1-6 "Alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms (hereinafter referred to as C 1-6and the like. In one embodiment, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl, etc. In one embodiment, the alkyl group is methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, or 2,2-dimethylpropyl. In another embodiment, the alkyl group is a linear or branched C 1-4 In one embodiment, it is methyl, ethyl, n-propyl, n-butyl, isobutyl, or tert-butyl, and in another embodiment, it is n-propyl or isobutyl. In another embodiment, it is methyl, ethyl, n-propyl, or isopropyl, in another embodiment, it is methyl or isopropyl, in another embodiment, it is isopropyl, and in yet another embodiment, it is methyl.

[0022] "C 1-6 "Alkylene" means a straight or branched C 1-6 and a divalent saturated hydrocarbon group such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 2-methylethylene, 2,2-dimethylethylene, 2-methyltrimethylene, ethylethylene, 1,2-dimethylethylene, or 1,1,2,2-tetramethylethylene. 1-4 It is alkylene, and in one embodiment, it is methylene or ethylene, and in a further embodiment, it is ethylene, and in another embodiment, it is methylene.

[0023] "C 3-8 "Cycloalkyl" means C 3-8It is a saturated hydrocarbon ring group of the formula (I), which may have a bridge or form a spiro ring. For example, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.3.0]octyl, spiro[2.2]pentyl, spiro[3.3]heptyl, or spiro[2.5]octyl. In one embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, or spiro[3.3]heptyl. In another embodiment, it is C 3-6 In one embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, in another embodiment it is cyclopropyl, in another embodiment it is cyclobutyl or cyclohexyl, in another embodiment it is cyclobutyl, in yet another embodiment it is cyclopentyl, and in still another embodiment it is cyclohexyl.

[0024] The term "4- to 8-membered saturated heterocyclyl" refers to a 4- to 8-membered saturated hydrocarbon ring group containing one or more heteroatoms, particularly oxygen, nitrogen, or sulfur atoms, as ring-constituting atoms, and may have a bridge or form a spiro ring. Examples include oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, oxepanyl, azepanyl, thiepanyl, oxocanyl, azocanyl, thiocanyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dithiolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, and the like. xanyl, piperazinyl, dithianyl, morpholinyl, thiomorpholinyl, oxathiaranyl, dioxepanyl, diazepanyl, dithiepanyl, oxazepanyl, thieazepanyl, oxathiepanyl, 3-oxabicyclo[3.1.0]hexyl, 2-oxaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 7-oxabicyclo[2.2.1]heptyl, or 6-azaspiro[2.5]octyl. In one embodiment, it is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, azepanyl, morpholinyl, 3-oxabicyclo[3.1.0]hexyl, or 6-azaspiro[2.5]octyl; in another embodiment, it is a 4- to 7-membered saturated heterocyclyl; in another embodiment, it is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, azepanyl, morpholinyl, or 3-oxabicyclo[3.1.0]hexyl; in another embodiment, it is tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, or morpholinyl; and in yet another embodiment, it is tetrahydrofuranyl or tetrahydropyranyl. In another embodiment, it is pyrrolidinyl or piperidinyl, in another embodiment, tetrahydropyranyl or piperidinyl, in yet another embodiment, morpholinyl, and in still another embodiment, oxetanyl or azetidinyl.

[0025] "Aryl" means C 6-14 is a monocyclic to tricyclic aromatic hydrocarbon ring group of C 5-8 It includes a cycloalkene and a ring group fused at the double bond thereof, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, fluorenyl, etc., and in one embodiment, phenyl.

[0026] "Heteroaryl" refers to a 5- to 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 pyrazolyl, pyridazinyl, or pyridyl, in another embodiment, it is pyrazolyl or pyridyl, and in yet another embodiment, it is pyrazolyl.

[0027] "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.

[0028] "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, difluoroethyl, fluoromethyl, or chloromethyl, in another embodiment, it is trifluoromethyl or difluoromethyl, in another embodiment, it is trifluoromethyl, and in another embodiment, it is difluoromethyl.

[0029] In this specification, 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.

[0030] One or more embodiments may be combined with other embodiments, even if such combinations are not specifically recited.

[0031] As used herein, "inflammatory diseases" refers to diseases including, but not limited to, cryopyrin-associated periodic fever syndromes (CAPS), autoinflammatory diseases including gout and pseudogout, and nonalcoholic steatohepatitis (NASH). In one embodiment, the disease is an autoinflammatory disease, and in another embodiment, the disease is CAPS. Note that "cryopyrin-associated periodic fever syndromes (CAPS)" refers to a 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).

[0032] As used herein, the term "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, and amyotrophic lateral sclerosis, and in another embodiment, multiple sclerosis. In another embodiment, the disease is α-synucleinopathies, in yet another embodiment, Parkinson's disease, in yet another embodiment, multiple system atrophy, and in yet another embodiment, dementia with Lewy bodies.

[0033] Some embodiments of the compound of formula (I) or a salt thereof in the present invention are shown below: (1-1) Compound of formula (I) or a salt thereof (n is a substituent R 1 represents the number of (1-2) A compound or a salt thereof, wherein the formula (I) is the following formula (Ia) (wherein k is a substituent R 1b represents the number of (2-1) A compound or a salt thereof in which n is an integer from 1 to 4. (2-2) A compound or a salt thereof in which n is an integer from 1 to 3. (2-3) A compound or a salt thereof in which n is 1 or 2. (2-4) A compound or a salt thereof in which n is 1. (3-1) A compound or a salt thereof in which k is 0 or 1. (3-2) A compound or a salt thereof in which k is 0. (4-1) R 1 are the same or different, and C1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 (4-2) A compound or a salt thereof, wherein R is alkyl, or cyano. 1 is R described in formula (Ia) 1a and R 1b A compound or a salt thereof, wherein (5-1) R 1a C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 (5-2) R is a compound or a salt thereof, wherein R is alkyl or cyano. 1a C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl or -O-halogenoC 1-6 A compound or a salt thereof in which R is alkyl. 1a Halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl or -O-halogenoC 1-6 A compound or a salt thereof in which R is alkyl. 1a Halogeno C 1-6 Alkyl, halogen, -OC 1-6 Alkyl or -O-halogenoC 1-6 A compound or a salt thereof, wherein R is alkyl. 1a Halogeno C 1-6 A compound or a salt thereof, wherein R is alkyl. 1a is a halogen atom or a salt thereof. (5-7) R 1a Ga-OC 1-6 A compound or a salt thereof, wherein R is alkyl. 1a -O-halogenoC 1-6 A compound or a salt thereof, wherein R is alkyl. 1a Halogeno C1-6 Alkyl, -OC 1-6 Alkyl or -O-halogenoC 1-6 (6-1) R is a compound or a salt thereof 1b are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl or halogen compound or its salt. (6-2) R 1b is a halogen atom or a salt thereof. 2 C 1-6 Alkyl, C 3-8 Cycloalkyl, halogeno C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 (7-2) R is a compound or a salt thereof, wherein R is alkyl, or aryl. 2 C 1-6 Alkyl, C 3-8 Cycloalkyl, halogeno C 1-6 Alkyl, -N(C 1-6 (7-3) R is a compound or a salt thereof, wherein R is alkyl, or aryl. 2 C 1-6 Alkyl or C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 2 C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 3 is H or C 1-6 A compound or a salt thereof in which R is alkyl. 3 is H or a salt thereof. (9-1) R 4 1 to 4 identical or different R 5 C is replaced by 1-6 Alkyl, -C 1-6 alkylene-(1 to 4 identical or different R 6 aryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 7 C optionally substituted with 3-8 cycloalkyl), -C 1-6alkylene-(1 to 4 identical or different R 8 Heteroaryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with R 10 C optionally substituted with 3-8 cycloalkyl, 1 to 4 identical or different R 11 or 1 to 4 identical or different R 12 (9-2) R is a 4- to 8-membered saturated heterocyclyl optionally substituted by 4 1 to 4 identical or different R 5 C is replaced by 1-6 Alkyl, -C 1-6 alkylene-(1 to 4 identical or different R 6 aryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 7 C optionally substituted with 3-8 cycloalkyl), -C 1-6 alkylene-(1 to 4 identical or different R 8 Heteroaryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with R 10 C optionally substituted with 3-8 cycloalkyl, 1 to 4 identical or different R 11 or 1 to 4 identical or different R 12 (9-3) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 1 to 4 identical or different R 5 C is replaced by 1-6 Alkyl, -C 1-6 alkylene-(1 to 4 identical or different R6 aryl optionally substituted with -C 1-6 alkylene-(1 to 4 identical or different R 7 C optionally substituted with 3-8 cycloalkyl), -C 1-6 Alkylene-heteroaryl, -C 1-6 alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with R 10 C optionally substituted with 3-8 cycloalkyl, heteroaryl, or 1 to 4 identical or different R 12 (9-4) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 Ga-C 1-6 alkylene-(1 to 4 identical or different R 7 C optionally substituted with 3-8 cycloalkyl), -C 1-6 alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with R 10 C optionally substituted with 3-8 Cycloalkyl, or 1 to 4 identical or different R 12 (9-5) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 1 to 4 identical or different R 10 C optionally substituted with 3-8 Cycloalkyl, or 1 to 4 identical or different R 12 (9-6) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 1 to 4 identical or different R 5 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 4 One to three identical or different R 5 C is replaced by 1-6A compound or a salt thereof, wherein R is alkyl. 4 One or two identical or different R 5 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 4 There is one R 5 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 4 Ga-C 1-6 alkylene-(1 to 4 identical or different R 6 (9-11) A compound or a salt thereof, wherein R is an aryl group optionally substituted with 4 Ga-C 1-6 alkylene-(1 to 3 identical or different R 6 (9-12) R is a compound or a salt thereof, 4 Ga-C 1-6 alkylene-(1 to 2 identical or different R 6 (9-13) A compound or a salt thereof, wherein R is an aryl group optionally substituted with 4 Ga-C 1-6 Alkylene-(one R 6 (9-14) A compound or a salt thereof, wherein R is an aryl group optionally substituted with 4 Ga-C 1-6 A compound or a salt thereof, wherein R is alkylene-aryl. 4 Ga-C 1-6 alkylene-(1 to 4 identical or different R 7 C optionally substituted with 3-8 (9-16) R 4 Ga-C 1-6 alkylene-(1 to 3 identical or different R 7 C optionally substituted with 3-8 (9-17) R 4 Ga-C 1-6 alkylene-(1 to 2 identical or different R 7 C optionally substituted with 3-8 (9-18) R4 Ga-C 1-6 Alkylene-(one R 7 C optionally substituted with 3-8 (cycloalkyl) or a salt thereof. (9-19) R 4 Ga-C 1-6 Alkylene-C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 4 Ga-C 1-6 alkylene-(1 to 4 identical or different R 8 (9-21) R is a compound or a salt thereof, wherein R is a heteroaryl optionally substituted with 4 Ga-C 1-6 alkylene-(1 to 3 identical or different R 8 (9-22) R is a compound or a salt thereof, wherein R is a heteroaryl optionally substituted with 4 Ga-C 1-6 alkylene-(1 to 2 identical or different R 8 (9-23) R is a compound or a salt thereof, wherein R is a heteroaryl optionally substituted with 4 Ga-C 1-6 Alkylene-(one R 8 (9-24) R is a compound or a salt thereof, wherein R is a heteroaryl optionally substituted with 4 Ga-C 1-6 A compound or a salt thereof, wherein R is alkylene-heteroaryl. 4 Ga-C 1-6 alkylene-(1 to 4 identical or different R 9 (9-26) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 Ga-C 1-6 alkylene-(1 to 3 identical or different R 9 (9-27) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 Ga-C 1-6 alkylene-(1 to 2 identical or different R 9 (9-28) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 Ga-C1-6 Alkylene-(one R 9 (9-29) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 Ga-C 1-6 A compound or a salt thereof which is alkylene-4 to 7-membered saturated heterocyclyl. (9-30) R 4 1 to 4 identical or different R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 4 One to three identical or different R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 4 One or two identical or different R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 4 There is one R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 4 C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 4 1 to 4 identical or different R 11 (9-36) R is a heteroaryl optionally substituted by 4 One to three identical or different R 11 (9-37) R is a heteroaryl optionally substituted by 4 One or two identical or different R 11 (9-38) R is a heteroaryl optionally substituted by 4 There is one R 11 (9-39) R is a heteroaryl optionally substituted with 4 is heteroaryl or a salt thereof. 4 1 to 4 identical or different R 12(9-41) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 One to three identical or different R 12 (9-42) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 One or two identical or different R 12 (9-43) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 There is one R 12 (9-44) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 is a 4- to 7-membered saturated heterocyclyl or a salt thereof. 4 Ga-C 1-6 alkylene-4 to 7-membered saturated heterocyclyl, 1 to 2 identical or different R 10 C optionally substituted with 3-8 cycloalkyl or one R 12 (9-46) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 There is one R 10 C optionally substituted with 3-8 cycloalkyl or one R 12 (9-47) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 4 Ga-C 1-6 alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with R 10 C optionally substituted with 3-8 Cycloalkyl or 1 to 4 identical or different R 12 (10-1) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 5 -OR 13 , -NR 14 R 15 , halogen, or cyano, or a salt thereof. 5 -OR13 , or -NR 14 R 15 A compound or a salt thereof represented by the formula (10-3) R 5 -OR 13 A compound or a salt thereof represented by the formula (10-4)R 5 Ga-NR 14 R 15 (11-1) R 6 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano, or a salt thereof. 6 C 1-6 Alkyl, halogeno C 1-6 Alkyl, -OR 13 , -NR 14 R 15 or a halogen compound or a salt thereof. 6 -OR 13 A compound or a salt thereof represented by the formula (12-1) R 7 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano, or a salt thereof. 7 -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , or -C 1-6 Alkylene-NR 14 R 15A compound or a salt thereof represented by the formula (12-3) R 7 -OR 13 , or -NR 14 R 15 A compound or a salt thereof, (12-4)R 7 -OR 13 A compound or a salt thereof represented by the formula (12-5) R 7 Ga-NR 14 R 15 A compound or a salt thereof represented by the formula (12-6)R 7 Ga-C 1-6 Alkylene-OR 13 , or -C 1-6 Alkylene-NR 14 R 15 A compound or a salt thereof, (12-7)R 7 Ga-C 1-6 Alkylene-OR 13 A compound or a salt thereof represented by the formula (12-8)R 7 Ga-C 1-6 Alkylene-NR 14 R 15 A compound or a salt thereof represented by the formula (13-1)R 8 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano, or a salt thereof. 8 C 1-6 Alkyl, halogeno C 1-6 Alkyl, -OR 13 , -NR 14 R 15 or a halogen compound or a salt thereof. 8 -OR 13 , -NR 14 R 15 or a halogen compound or a salt thereof. 9 C 1-6 Alkyl, halogeno C1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 9 C 1-6 Alkyl, halogeno C 1-6 Alkyl, -OR 13 , -NR 14 R 15 , halogen, oxo, or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 9 -OR 13 , -NR 14 R 15 , halogen, or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 9 -OR 13 , or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 9 -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 10 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, —C(O)—OH, or cyano, or a salt thereof. 10 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano, or a salt thereof. 10 C 1-6 Alkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano, or a salt thereof. 10 C 1-6 Alkyl, -OR 13 , -NR 14 R 15 , halogen, or cyano, or a salt thereof. 10 C 1-6 Alkyl, -OR 13 , or -NR 14 R 15 A compound or a salt thereof represented by the formula (15-6)R 10 C 1-6 Alkyl or -OR 13 A compound or a salt thereof represented by the formula (15-7)R 10 -OR 13 , or -NR 14 R 15 A compound or a salt thereof represented by the formula (15-8)R 10 -OR 13 A compound or a salt thereof represented by the formula (15-9)R 10 Ga-NR 14 R 15 A compound or a salt thereof, (16-1)R 11 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13, -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano, or a salt thereof. 11 C 1-6 Alkyl, halogeno C 1-6 Alkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 or a halogen compound or a salt thereof. 11 C 1-6 Alkyl or -C 1-6 Alkylene-OR 13 A compound or a salt thereof, (16-4)R 11 C 1-6 A compound or a salt thereof, wherein R is alkyl. 11 Ga-C 1-6 Alkylene-OR 13 A compound or a salt thereof represented by the formula (17-1)R 12 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-C 3-8 Cycloalkyl, -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , -C 1-6 Alkylene-cyano, -C 1-6 Alkylene -C(O)-OH, halogen, cyano, oxo, -C(O)-NH2, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 12 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 12 C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 12 C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -C 1-6 Alkylene-OR 13 , oxo, or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 12 C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 or oxo, or a salt thereof. 12 C 1-6 Alkyl, -OR 13 or oxo, or a salt thereof. 12 C 1-6 Alkyl or -OR 13 A compound or a salt thereof represented by the formula (17-8)R 12 -OR 13 A compound or a salt thereof, (17-9)R 12 is oxo or a salt thereof.12 C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 12 -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 12 C 1-6 Alkyl, C 3-8 cycloalkyl or -OR 13 A compound or a salt thereof, (17-13)R 12 C 1-6 A compound or a salt thereof, wherein R is alkyl. 13 is H or C 1-6 A compound or a salt thereof, wherein R is alkyl. 13 is H or a salt thereof. (18-3) R 13 C 1-6 A compound or a salt thereof, wherein R is alkyl. 14 and R 15 are the same or different, H, C 1-6 Alkyl, or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 14 and R 15 are the same or different and are H or C 1-6 A compound or a salt thereof, wherein R is alkyl. 14 and R 15 is H or a salt thereof. (19-4) R 14 -C(O)-C 1-6 alkyl, and R 15is H, or a salt thereof. (20) A compound or a salt thereof which is a combination of two or more of the embodiments of groups described in the above (1-1) to (19-4) that are not contradictory to each other. Examples include, but are not limited to, the following combinations. (20-1) A compound or a salt thereof which is a combination of the embodiments (1-1), (2-1), (4-1), (7-1), (8-1), (9-2), (10-1), (11-1), (12-1), (13-1), (14-1), (15-2), (16-1), (17-2), (18-1), and (19-1). (20-2) A compound or a salt thereof which is a combination of the above-mentioned (1-2), (3-1), (5-1), (6-1), (7-2), (8-2), (9-3), (10-1), (11-3), (12-2), (14-5), (15-3), (17-2), (18-1), and (19-1). (20-3) A compound or a salt thereof which is a combination of the above-mentioned (1-2), (3-2), (5-2), (6-1), (7-3), (8-2), (9-4), (12-2), (14-5), (15-3), (17-2), (18-1), and (19-1). (20-4) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-8), (7-4), (8-2), (9-33), (15-8), and (18-2). (20-5) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-6), (7-4), (8-2), (9-43), (17-8), and (18-2). (20-6) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-5), (7-5), (8-2), (9-32), (15-6), and (18-2). (20-7) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-7), (7-4), (8-2), (9-33), (15-8), and (18-2). (20-8) A compound or a salt thereof which is a combination of the above-mentioned embodiments (1-2), (3-2), (5-5), (7-4), (8-2), (9-43), and (17-10). (20-9) A compound or a salt thereof which is a combination of the above-mentioned embodiments (1-2), (3-2), (5-5), (7-4), (8-2), (9-33), (15-8), and (18-2).(20-10) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-5), (7-4), (8-2), (9-33), (15-9), and (19-3). (20-11) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-5), (7-4), (8-2), and (9-29). (20-12) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-5), (7-4), (8-2), (9-43), and (17-8). (20-13) A compound or a salt thereof which is a combination of the above (1-2), (3-2), (5-8), (7-4), (8-2), (9-43), and (17-8). (20-14) A compound or a salt thereof which is a combination of the above embodiments (1-2), (3-2), (5-4), (7-3), (8-2), (9-45), (15-5), (17-12), (18-2) and (19-3). (20-15) A compound or a salt thereof which is a combination of the above embodiments (1-2), (3-2), (5-9), (7-4), (8-2), (9-46), (15-7), (17-13), (18-2) and (19-3). (20-16) The compound of formula (I) is formula (Ia), and R 1a is trifluoromethyl, Cl, —O-methyl, —O-difluoromethyl, or —O-trifluoromethyl, and R 2 is methyl or cyclopropyl, R 3 is H and R 4 is -methylene-morpholinyl, one to two identical or different R 10 cyclobutyl optionally substituted with one or two identical or different R 10 cyclohexyl optionally substituted with one R 12 tetrahydropyranyl optionally substituted with one R 12 piperidinyl optionally substituted by R 10 is methyl, -OH, or -NH2, and R 12 is methyl, cyclopropyl, or —OH; and k is 0; or a salt thereof.

[0034] Examples of specific compounds encompassed by the present invention include compounds selected from the following group or salts thereof: 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol, (3S,4R)-4-{[6-(4-chloro-2-hydroxyphenyl)-5-methyl-1,2,4-triazin-3-yl]amino}oxan-3-ol, 2-(5-cyclopropyl-3-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol, 2-(3-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol, 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-[5-methyl-3-({[(2R)-morpholin-2-yl]methyl}amino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol, 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, and 5-(difluoromethoxy)-2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)phenol.

[0035] Furthermore, certain embodiments of specific compounds encompassed by the present invention include compounds or salts thereof selected from the following group: 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol, (3S,4R)-4-{[6-(4-chloro-2-hydroxyphenyl)-5-methyl-1,2,4-triazin-3-yl]amino}oxan-3-ol, 2-(5-cyclopropyl-3-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol, 2-(3-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol, 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, and 2-[5-methyl-3-({[(2R)-morpholin-2-yl]methyl}amino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol.

[0036] Examples of specific compounds encompassed by the present invention include the following compounds: 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol monohydrochloride, 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol monohydrochloride, 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol monohydrochloride, 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol dihydrochloride, and 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol dihydrochloride.

[0037] 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.

[0038] 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 and 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 would be recognized by a person 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.

[0039] 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.

[0040] 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.

[0041] Furthermore, the present invention also encompasses various hydrates and solvates, and crystalline polymorphic substances of the compound of formula (I) or a salt thereof.

[0042] 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 18O etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I etc.), phosphorus ( 32 P, etc.), sulfur ( 35 Isotopes of tritium (e.g., S) are included. Isotopically labeled compounds, drugs, and / or substrates of the present invention may be used in tissue distribution studies and other studies. For example, tritium ( 3 H), carbon 14 ( 14 Radioactive isotopes such as C may be used for this purpose due to their ease of labeling and detection. Substitution of heavier isotopes, e.g., deuterium for hydrogen ( 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.

[0043] (Production 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 raw materials to intermediates. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th ed., 2006) by P.G.M. Wuts and T.W. Greene, and can be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, conducting 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 from raw materials to intermediates, or by further reacting the resulting compound of formula (I), similar to the above-mentioned protecting groups. The reaction can be carried out by applying conventional methods known to those skilled in the art, such as esterification, amidation, and dehydration.

[0044] 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.

[0045] The following abbreviations may be used herein: CN: cyano, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DIPEA: N,N-diisopropylethylamine, mCPBA: m-chloroperbenzoic acid, NBS: N-bromosuccinimide, NCS: N-chlorosuccinimide, NIS: N-iodosuccinimide, NMP: 1-methylpyrrolidin-2-one, Me: methyl, Oxone®: potassium peroxymonosulfate, PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II). dichloride, PdCl2(dppf):[1,1'-bis(diphenylphosphino)ferrocene]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, SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 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.

[0046] (First manufacturing method) (In the formula, X 1 and X 2 are the same or different and are Cl, Br or I. a and R b are both H or R a and R b is the R a and R b is bonded to the boronic acid residue to form 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The same applies below.)

[0047] (Step 1) This step involves the reaction of a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV). In this reaction, a mixture of compounds of formula (II) and (III) 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, typically for 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 DIPEA, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydride, may be advantageous for smooth reaction progression. This reaction may also be carried out under microwave irradiation.

[0048] (Step 2) This step involves the reaction of a compound of formula (IV) with a compound of formula (V) to obtain a compound of formula (I). In this reaction, a mixture of compounds of formula (IV) and (V) is used in equal amounts, or in excess of either, and the 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), PdCl2(dppf)·CHCl2, 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 solvents 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. [References] Journal of the American Chemical Society, 127, pp. 4685-4696 (2005)

[0049] (Second manufacturing method) (In the formula, R c is C 1-6 alkyl, and m is 1 or 2. The same applies below.)

[0050] (Step 1) This step involves reacting a compound of formula (VI) with an oxidizing agent to obtain a compound of formula (VII). In this reaction, the compound of formula (VI) and the oxidizing agent are used in equal amounts, or in excess of either, and the mixture is stirred in a reaction-inert solvent under cooled to room temperature conditions, preferably at −78°C to room temperature, typically for 0.1 hours to 5 days. Examples of the oxidizing agent used here include, but are not limited to, mCPBA, hydrogen peroxide, Oxone®, etc. Examples of the solvent include, but are not limited to, halogenated solvents such as dichloromethane, chloroform, and carbon tetrachloride; ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, and xylene; and mixtures thereof.

[0051] (Step 2) This step involves the reaction of a compound of formula (VII) with a compound of formula (III) to obtain a compound of formula (VIII). In this reaction, a mixture of compounds of formula (VII) and formula (III) 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 0 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; dichloromethane; and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine or DIPEA, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydride, may be advantageous for smooth reaction progression. This reaction may also be carried out under microwave irradiation. In some cases, the compound of formula (VIII) can also be obtained by directly adding the compound of formula (III) to the reaction mixture of the first step.

[0052] (Step 3) This step involves reacting a compound of formula (VIII) with a halogenating agent to obtain a compound of formula (IV). In this reaction, the compound of formula (VIII) and the halogenating agent are used in equal amounts, or in excess of either, and the mixture is stirred in a reaction-inert solvent or without a solvent, under cooling to reflux, preferably at temperatures between −78 and 50°C, for typically 0.1 hours to 5 days. Examples of halogenating agents used here include, but are not limited to, NCS, NBS, NIS, bromine, iodine, dibromoisocyanuric acid, tetra-n-butylammonium tribromide, pyridinium tribromide, etc. Examples of solvents 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.

[0053] (Fourth Step) This step is the same as the second step of the first production process, in which a compound of formula (IV) is reacted with a compound of formula (V) to obtain a compound of formula (I).

[0054] (Other Production Methods) Using the compound of formula (I) obtained by the above production method as a starting material, other compounds of formula (I) can be obtained by further carrying out chemical modification reactions commonly used by those skilled in the art, such as alkylation, esterification, amidation, sulfonylation, deprotection reaction, etc.

[0055] 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 prepared 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 prepared by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods of racemates (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, or chromatography using chiral columns, etc.), or can also be prepared from appropriate optically active starting compounds.

[0056] The pharmacological activity of the compound of formula (I) has been confirmed by the following tests. However, the pharmacological activity can also be confirmed by well-known modified tests.

[0057] Test Example 1: THP-1 IL-1β Production Inhibition Test THP-1 cells were cultured at 37°C for 2 days after adding 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 the IL-1β concentration was measured by ELISA (DuoSet ELISA human IL-1β, R&D Systems, DY201). The IL-1β concentration was plotted against the logarithm of the test compound concentration, and the IC was calculated using sigmoid Emax model nonlinear regression analysis. 50 The values ​​were calculated. The results are shown in Tables 1-1 and 1-2. It was confirmed that the Example compounds inhibited IL-1β production.

[0058]

[0059]

[0060] Test Example 2: TNF-α Production Inhibition Test THP-1 cells were added with 50 ng / mL PMA (phorbol myristate acetate, SIGMA, P1585) and cultured at 37°C for 2 days. The culture medium was replaced with serum-free RPMI-1640 medium, and compounds of known concentrations were added and cultured at 37°C for 15 minutes. LPS (Lipopolysaccharide, SIMGA, L2880) was added to a final concentration of 50 ng / mL, and the cells were cultured at 37°C for 2 hours. The supernatant was collected, and the TNF-α concentration was measured by ELISA (DuoSet ELISA human TNF-α, R&D Systems, DY210). The TNF-α concentration was plotted against the logarithm of the test compound concentration, and the IC was determined by sigmoid Emax model nonlinear regression analysis. 50 The compounds of formula (I), Examples 27, 31, 59, 73, 75, 108, 131, 132, 141, 164, and 174, had IC values ​​of 10 μM or more in this test. 50 It was confirmed that the values ​​were

[0061] Test Example 3: Rat Central Nervous System IL-1β Production Test. Male Wistar rats aged 10 to 14 weeks were anesthetized under isoflurane and administered 12.5 μg / 5 μL of LPS (SIGMA, L2880) into the cisterna magna. Two hours later, the test compound was orally administered. One hour later, 50 μg / 5 μL of BzATP (2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt, SIGMA, B6396) was administered into the cisterna magna. Cerebrospinal fluid was collected 30 minutes later. IL-1β p17 was quantified in the cerebrospinal fluid by Western blotting using an anti-IL-1β antibody (Millipore, AB1832P). The inhibition rate 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 59, 75, 131, 132, and 164, which are compounds of formula (I). In the table, "Dose" refers to the dose of each test compound, and "Ex59," "Ex75," "Ex131," "Ex132," and "Ex164" refer to Examples 59, 75, 131, 132, and 164. These compounds were confirmed to exhibit IL-1β production inhibitory activity.

[0062]

[0063] Test Example 4: Evaluation of Motor Function in a Mouse α-Synuclein Fibril-Induced Neuroinflammation Model Male C57BL / 6J mice were administered 8 μg of mouse α-synuclein fibrillation protein (SPR-324, StressMarq Biosciences Inc.) into the left striatum. After 13 to 14 weeks, the test compound suspended in 0.5% methylcellulose solution was orally administered once daily. A negative control group received 0.5% methylcellulose solution. Four weeks after the start of administration, motor function was evaluated using a hanging wire 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. This test confirmed that a specific compound of formula (I) or a salt thereof exhibits an ameliorative effect on motor disorders.

[0064] Test Example 5: Ex vivo IL-1β Production Test in Mice Male C57BL / 6J mice were orally administered a single or multiple dose of compound suspended in 0.5% methylcellulose, and blood was collected at the desired time points. 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 removing blood cells by centrifugation, the IL-1β concentration was measured by ELISA (DuoSet ELISA mouse IL-1β, R&D Systems, DY401).

[0065] Test Example 6: In vitro phototoxicity test Evaluation of in vitro phototoxicity 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 compounds of Examples 59, 75, 131, 132, and 164 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 compounds of Examples 59, 75, 131, 132, and 164 had IC values ​​of 10 μM or more. 50 The values ​​were shown.

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

[0068] 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 59, 75, 131, 132, and 164 were shown to have an inhibitory effect on IL-1β production in the central nervous system as well in Test Example 3. Furthermore, specific compounds of formula (I) or salts thereof were shown to improve motor function in a mouse model of α-synucleinopathy induced by α-synuclein fibrils, as described 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 Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies.

[0069] Furthermore, the results of Test Examples 6 and 7 showed that the compounds of Examples 59, 75, 131, 132, and 164 did not exhibit phototoxicity and had weak hERG channel inhibitory activity. Based on these results, the compounds of Examples 59, 75, 131, 132, and 164 are highly expected to become highly safe pharmaceuticals.

[0070] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as an active ingredient can be prepared by a commonly used method using excipients commonly used in the art, i.e., pharmaceutical excipients, pharmaceutical carriers, etc. 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 injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, 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, as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid compositions may contain adjuvants such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavors, fragrances, 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] For oral administration, the daily dosage is typically 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 in a single dose or in two to four divided doses. For intravenous administration, the daily dosage is typically approximately 0.0001 to 10 mg / kg of body weight, administered once or multiple times daily. For transmucosal administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, administered once or multiple times daily. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, and other factors.

[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.

[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 in the table below as melting points. DSC measurements were performed using a DSC Q2000 (TA Instruments) under the following conditions: temperature range: 25 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, diffraction angle range (2θ): 2.5 to 40°. 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. 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] 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, EI+: m / z value in mass spectrometry (electron ionization method EI, [M]+ unless otherwise specified), ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H]+ unless otherwise specified), ESI-: m / z value in mass spectrometry (ionization method ESI, [M-H]- unless otherwise specified), FAB: m / z value in mass spectrometry (ionization method FAB, [M+H]+ unless otherwise specified), CI: m / z value in mass spectrometry (ionization method CI, [M+H]+ unless otherwise specified). 1 H-NMR (400 MHz, CDCl3): 1 δ value (ppm) of the signal in H-NMR, 1 H-NMR (400 MHz, DMSO-d6) and 1 H-NMR (500 MHz, DMSO-d6): 1 δ value (ppm) of the signal in H-NMR, 1 H-NMR (400 MHz, CD3OD) and 1 H-NMR (500 MHz, CD3OD): 1 The δ value (ppm) of the signal in H-NMR, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, tt: triple triplet, br: broad line (e.g., br s), m: multiplet, mp: melting point, 2θ: diffraction angle of the peak in powder X-ray diffraction.

[0082] In the tables below, a hyphen (-) in the columns for PSyn and Syn indicates that the production method is described in writing in the Production Examples or Examples section.

[0083] Among the compounds in the table below whose chemical structural formulas include steric configurations, compounds marked with "#" indicate that the indicated steric configuration is a relative steric configuration, and the other compounds indicate that the indicated steric configuration is an absolute steric configuration.

[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] Preparation Example 1: A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (800 mg), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (1.1 g), 1,4-dioxane (20 mL), and DIPEA (2.5 mL) was stirred at 100°C for 1 hour under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (710 mg) as a solid.

[0086] Preparation Example 11: A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (120 mg), 1,4-dioxane (5.0 mL), DIPEA (0.38 mL), and (3S,4R)-4-aminooxan-3-ol monohydrochloride (170 mg) was stirred at 100°C for 2.5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (3S,4R)-4-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]oxan-3-ol (90 mg) as an oil.

[0087] Preparation Example 53: A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (190 mg), (3R)-1-cyclopropylpiperidin-3-amine mono(trifluoroacetic acid) salt (290 mg), 1,4-dioxane (5 mL), and DIPEA (1 mL) was stirred at 100° C. for 2 hours (this mixture is referred to as Mixture A). A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (600 mg), (3R)-1-cyclopropylpiperidin-3-amine mono(trifluoroacetic acid) salt (930 mg), 1,4-dioxane (5 mL), and DIPEA (1.6 mL) was stirred at 100° C. for 2 hours (this mixture is referred to as Mixture B). Mixture A and Mixture B were combined, and basic silica gel was added, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 6-chloro-N-[(3R)-1-cyclopropylpiperidin-3-yl]-5-methyl-1,2,4-triazin-3-amine (1.2 g) as a solid.

[0088] Preparation Example 55: A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (400 mg), (1S,3R)-3-aminocyclohexan-1-ol monohydrochloride (370 mg), DIPEA (0.84 mL), and 1,4-dioxane (5 mL) was stirred at 100°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1S,3R)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (320 mg) as a solid.

[0089] Preparation Example 73: Under an argon atmosphere, a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (150 mg), 1,4-dioxane (5 mL), tert-butyl [(1R,2R)-2-aminocyclohexyl]carbamate (290 mg), and DIPEA (0.48 mL) was stirred at 90°C for 2.5 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl {(1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexyl}carbamate (280 mg) as an oil.

[0090] Preparation Example 87: To a mixture of tert-butyl (2S)-2-(aminomethyl)morpholine-4-carboxylate (400 mg) and 1,4-dioxane (6 mL) was added 3,6-dichloro-5-methyl-1,2,4-triazine (200 mg) and DIPEA (0.32 mL) at room temperature, followed by stirring at 95-99°C for 3 hours. The reaction mixture was allowed to cool to room temperature, then water was poured into it, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (2S)-2-{[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]methyl}morpholine-4-carboxylate (410 mg) as an oil.

[0091] Preparation Example 94: A mixture of 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg), 1,4-dioxane (9.2 mL), bis(pinacolato)diboron (1.2 g), PdCl(dppf) (240 mg), and potassium acetate (960 mg) was stirred at 100°C for 3 hours. After the reaction mixture was allowed to cool to room temperature, PdCl(dppf) (240 mg) was added and the mixture was stirred at 100°C for 2 hours. After the resulting mixture was allowed to cool to room temperature, bis(pinacolato)diboron (620 mg) was added and the mixture was stirred at 100°C for 3 hours. After the reaction mixture was allowed to cool to room temperature, hexane was added and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g) as an oil, which was used in the next step without purification.

[0092] Preparation Example 97: To a mixture of tert-butyl [(3R)-1-cyclopropylpiperidin-3-yl]carbamate (3 g) and dichloromethane (20 mL), TFA (5.7 mL) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Dichloromethane (10 mL) was added to the reaction mixture, and TFA (5.7 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Toluene was added to the resulting residue, and the mixture was concentrated under reduced pressure three times to give (3R)-1-cyclopropylpiperidin-3-amine mono(trifluoroacetate) salt (3.2 g) as an oil.

[0093] Preparation Example 99: To a mixture of 5-cyclopropyl-3-(methylsulfanyl)-1,2,4-triazine (150 mg) and dichloromethane (3 mL), mCPBA (70%, 550 mg) was added under ice cooling and stirred at room temperature for 2 hours. (1s,3s)-3-Amino-1-methylcyclobutan-1-ol monohydrochloride (250 mg) and DIPEA (0.62 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. (1s,3s)-3-Amino-1-methylcyclobutan-1-ol monohydrochloride (550 mg) and DIPEA (0.62 mL) were added to the resulting mixture, and the mixture was stirred at 50°C for 1 hour. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1s,3s)-3-[(5-cyclopropyl-1,2,4-triazin-3-yl)amino]-1-methylcyclobutan-1-ol (170 mg) as a solid.

[0094] Preparation Example 105: To a mixture of (1s,3s)-3-[(5-cyclopropyl-1,2,4-triazin-3-yl)amino]-1-methylcyclobutan-1-ol (170 mg), acetonitrile (4 mL), and water (6 mL), NBS (270 mg) was added under ice cooling and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1s,3s)-3-[(6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino]-1-methylcyclobutan-1-ol (180 mg) as a solid.

[0095] Preparation Example 117: Under an argon atmosphere, a mixture of tert-butyl {(1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexyl}carbamate (270 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (330 mg), 1,4-dioxane (8 mL), water (2 mL), potassium carbonate (220 mg), and PdCl(dppf)·CHCl (65 mg) was stirred at 100-110°C for 4 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl [(1R,2R)-2-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)cyclohexyl]carbamate (320 mg) as a solid.

[0096] Preparation Example 132: Under an argon atmosphere, to a mixture of tert-butyl (2S)-2-{[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]methyl}morpholine-4-carboxylate (410 mg), 1,4-dioxane (12 mL), and water (3 mL) was added [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (490 mg), potassium carbonate (330 mg), and PdCl(dppf).CHCl (96 mg) at room temperature, followed by stirring at 97-103°C for 15 hours. 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, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (2S)-2-[({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)methyl]morpholine-4-carboxylate (390 mg) as a solid.

[0097] Preparation Example 139: To a mixture of tert-butyl (3R,4R)-3-hydroxy-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-1-carboxylate (400 mg) and dichloromethane (6 mL), TFA (1.5 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform / methanol). Ethyl acetate was added to the purified product and sonicated. The precipitated solid was collected by filtration to give (3R,4R)-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidin-3-ol (170 mg) as a solid.

[0098] Preparation Example 141: To a mixture of 2-amino-5-cyclopropylphenol (3.5 g) and ethanol (50 mL), 12 M hydrochloric acid (16 mL) was added at −15°C and stirred at the same temperature for 10 minutes. Amyl nitrite (9.6 mL) was added to the resulting mixture at −15°C and stirred at the same temperature for 30 minutes. A mixture of potassium iodide (51 g) and water (50 mL) was added dropwise to the resulting mixture at −15°C, and the mixture was stirred for 20 hours under an argon atmosphere while warming from −15°C to room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 5-cyclopropyl-2-iodophenol (5 g) as an oil.

[0099] Preparation Example 142: A mixture of selenium dioxide (5.1 g), 1,1-difluoroacetone (3.2 mL), 1,4-dioxane (60 mL), and water (2 mL) was stirred at 100°C for 16 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature and then filtered through Celite®. Water (14 mL) and sodium bicarbonate (6.6 g) were added to the resulting filtrate under ice-cooling. A mixture of methyl hydrazinecarboximidothioate monohydroiodide (9.4 g) and water (81 mL) was added to the resulting mixture under ice-cooling and stirred at room temperature for 2 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium thiosulfate was added to the resulting residue, followed by extraction with chloroform. 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 obtain 5-(difluoromethyl)-3-(methylsulfanyl)-1,2,4-triazine (840 mg) as an oil.

[0100] Preparation Example 143: To a mixture of tert-butyl [(3R)-piperidin-3-yl]carbamate (5.1 g), THF (38 mL), and methanol (38 mL), [(1-ethoxycyclopropyl)oxy]tri(methyl)silane (10 mL) and acetic acid (7.3 mL) were added and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (2.4 g) was added to the resulting mixture, and the mixture was stirred at 60°C for 12 hours. The reaction mixture was allowed to cool to room temperature, and ice was added. Water and saturated aqueous sodium chloride were added to the resulting mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl [(3R)-1-cyclopropylpiperidin-3-yl]carbamate (3 g) as a solid.

[0101] Preparation Example 144: To a mixture of 5-cyclopropyl-3-(methylsulfanyl)-1,2,4-triazine (450 mg) and dichloromethane (20 mL), mCPBA (70%, 1700 mg) was added under ice cooling and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 5-cyclopropyl-3-(methanesulfonyl)-1,2,4-triazine (590 mg) as a solid.

[0102] Preparation Example 145: A mixture of 5-cyclopropyl-3-(methanesulfonyl)-1,2,4-triazine (490 mg), DIPEA (1.6 mL), (3S)-3-aminopyrrolidin-2-one monohydrochloride (340 mg), and 1,4-dioxane (5 mL) was stirred at 90°C for 4 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 and neutral silica gel, chloroform / methanol) to give (3S)-3-[(5-cyclopropyl-1,2,4-triazin-3-yl)amino]pyrrolidin-2-one (210 mg) as a solid.

[0103] Preparation Example 150: A mixture of tert-butyl (3R,4R)-3-hydroxy-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidine-1-carboxylate (500 mg), 1,4-dioxane (5.0 mL), and 4 M hydrogen chloride in 1,4-dioxane (5.0 mL) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to give (3R,4R)-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidin-3-ol monohydrochloride (500 mg) as a solid.

[0104] Preparation Example 151: To a mixture of (3R,4R)-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidin-3-ol monohydrochloride (250 mg) and dichloromethane (10 mL) was added DIPEA (0.37 mL) and acetyl chloride (0.075 mL) at 0°C under a nitrogen atmosphere, followed by stirring at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, which was then washed sequentially with water, saturated aqueous sodium chloride, and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure to give (3R,4R)-1-acetyl-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidin-3-yl acetate (280 mg) as a solid.

[0105] Preparation Example 152: Under an argon atmosphere, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (8.8 g) was added to a mixture of tert-butyl [(3S,4R)-3-hydroxyoxan-4-yl]carbamate (3.7 g) and dichloromethane (46 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature and then stirred for 2.5 hours. 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.1 g) was added to the resulting mixture, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium sulfite, followed by a saturated aqueous solution of sodium bicarbonate, was added to the reaction mixture under ice cooling. The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl [(4R)-3-oxooxan-4-yl]carbamate (3.4 g) as a solid.

[0106] Preparation Example 153: To a mixture of tert-butyl [(4R)-3-oxoxooxan-4-yl]carbamate (2.8 g) and THF (42 mL) was added 1M methylmagnesium bromide THF solution (32 mL) at −73°C to −65°C under an argon atmosphere, and the mixture was stirred for 4 hours while warming from −70°C to 8°C. The reaction mixture was warmed to room temperature and stirred at the same temperature overnight. Aqueous ammonium chloride solution was added to the resulting mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate). The resulting product was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium bicarbonate / methanol) to give tert-butyl [(3S,4R)-3-hydroxy-3-methyloxan-4-yl]carbamate (830 mg) as a solid.

[0107] Preparation Example 154: To a mixture of tert-butyl [(3S,4R)-3-hydroxy-3-methyloxan-4-yl]carbamate (890 mg) and dichloromethane (3 mL), TFA (1 mL) was added and stirred at room temperature for 2 hours. To the resulting mixture, TFA (0.50 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then 1,4-dioxane (5 mL), 3,6-dichloro-5-methyl-1,2,4-triazine (630 mg), and DIPEA (2 mL) were added to the resulting residue, followed by stirring at 100°C for 1.5 hours. Basic silica gel was added to the resulting mixture, and then the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (3S,4R)-4-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]-3-methyloxan-3-ol (380 mg) as an oil.

[0108] Preparation Example 155: To a mixture of potassium carbonate (1.7 g) and DMF (7.4 mL) at 95°C, a mixture of 4-bromo-3-(methoxymethoxy)phenol (1.9 g), sodium chlorodifluoroacetate (2.4 g), and DMF (11 mL) was added dropwise over 1 hour and stirred at the same temperature for 15 minutes. After the reaction mixture was cooled to room temperature, potassium carbonate (1.7 g) and sodium chlorodifluoroacetate (2.4 g) were added and the mixture was stirred at 95°C for 1 hour. The resulting mixture was allowed to cool to room temperature, and then ethyl acetate and water were added, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg) as an oil.

[0109] Preparation Example 156: To a mixture of 6-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methyl-N-{[(2S)-pyrrolidin-2-yl]methyl}-1,2,4-triazin-3-amine (220 mg) and dichloromethane (6 mL), DIPEA (0.16 mL) and acetic anhydride (0.085 mL) were added under ice-cooling and stirring, and the mixture was allowed to warm to room temperature and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 1-{(2S)-2-[({6-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)methyl]pyrrolidin-1-yl}ethan-1-one (160 mg) as a solid.

[0110] Preparation Example 157: A mixture of 3-(methylsulfanyl)-5-(trifluoromethyl)-1,2,4-triazine (160 mg), 1,4-dioxane (6 mL), and (R)-(-)-1-amino-2-propanol (120 mg) was stirred at room temperature for 2 days. To the reaction mixture, (R)-(-)-1-amino-2-propanol (120 mg) and 1,4-dioxane (1 mL) were added, and the mixture was stirred at room temperature for an additional 1 day. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (2R)-1-{[5-(trifluoromethyl)-1,2,4-triazin-3-yl]amino}propan-2-ol (91 mg) as an oil.

[0111] Preparation Example 158: To a mixture of (2R)-4-amino-2-methylbutan-1-ol (2.0 g) and THF (7 mL) was added dropwise di-tert-butyl dicarbonate (4.5 mL) under ice-cooling and stirring, and the mixture was stirred for 2 hours while allowing to warm to room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give tert-butyl [(3R)-4-hydroxy-3-methylbutyl]carbamate (3.6 g) as an oil.

[0112] Preparation Example 159: To a mixture of tert-butyl [(3R)-4-hydroxy-3-methylbutyl]carbamate (1.8 g), dichloromethane (30 mL), and triethylamine (1.9 mL) was added dropwise methanesulfonyl chloride (1.1 mL) under ice-cooling and stirring, followed by ice-cooling and stirring for 1.5 hours. The reaction mixture was warmed to room temperature, and saturated aqueous sodium bicarbonate (30 mL) was slowly added, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2R)-4-[(tert-butoxycarbonyl)amino]-2-methylbutyl methanesulfonate (2.7 g) as an oil.

[0113] Preparation Example 160: To a mixture of (2R)-4-[(tert-butoxycarbonyl)amino]-2-methylbutyl methanesulfonate (2.7 g) and DMF (16 mL) was added sodium azide (1.9 g) under ice-cooling and stirring. The reaction mixture was warmed to room temperature and stirred for 4 hours, then stirred at 47-56°C for 17 hours. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl [(3R)-4-azido-3-methylbutyl]carbamate (1.8 g) as an oil.

[0114] A mixture of tert-butyl [(3R)-4-azido-3-methylbutyl]carbamate (1.8 g), THF (19 mL), water (1.5 mL), and triphenylphosphine (2.2 g) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give tert-butyl [(3R)-4-amino-3-methylbutyl]carbamate (0.65 g) as an oil.

[0115] Preparation Example 162: To a mixture of tert-butyl {[1-(2-aminoethyl)cyclobutyl]methyl}carbamate (290 mg), dichloromethane (13 mL), and DIPEA (0.26 mL) was added acetic anhydride (0.14 mL) under ice-cooling and stirring, followed by stirring at room temperature for 6 hours. Water and 10% hydrochloric acid were added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl {[1-(2-acetamidoethyl)cyclobutyl]methyl}carbamate (360 mg) as an oil.

[0116] A mixture of tert-butyl [(1R,3R)-3-cyanocyclopentyl]carbamate (180 mg) and approximately 4 M hydrogen chloride in 1,4-dioxane (1 mL) was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure to give (1R,3R)-3-aminocyclopentane-1-carbonitrile monohydrochloride (150 mg) as a solid.

[0117] Preparation Example 169: To a mixture of (3R)-1-methylpiperidin-3-amine dihydrochloride (14 g) and 2-propanol (48 mL) was added DIPEA (37 mL) at room temperature and stirred at 80°C for 10 minutes. A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (8.8 g) and 2-propanol (64 mL) was added dropwise at 80°C, followed by rinsing with 2-propanol (16 mL). The mixture was stirred at 80°C for 2 hours. After cooling to room temperature, water and saturated brine were added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 6-chloro-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1,2,4-triazin-3-amine (8.8 g) as a solid.

[0118] Preparation Example 180: A mixture of 6-chloro-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1,2,4-triazin-3-amine (4.5 g), 1,4-dioxane (90 mL), water (18 mL), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12 g), RuPhos Pd G3 (1.6 g), and potassium carbonate (7.7 g) was stirred at 100°C for 14 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, chloroform / methanol (9 / 1) and water were added, and the mixture was stirred at room temperature for 10 minutes. Saturated brine was added to the mixture, and the organic layer was separated and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (basic and neutral silica gel, hexane / ethyl acetate and chloroform / methanol) to give 6-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1,2,4-triazin-3-amine (6.4 g) as a solid.

[0119] Preparation Example 190: DIPEA (2.9 mL) and chloromethyl methyl ether (1.2 mL) were added to a mixture of 4-bromo-3-hydroxybenzaldehyde (2.9 g) and dichloromethane (30 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the organic layer was separated and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-bromo-3-(methoxymethoxy)benzaldehyde (1.4 g) as an oil.

[0120] Preparation Example 192: To a mixture of 4-bromo-3-(methoxymethoxy)benzaldehyde (1.4 g) and dichloromethane (20 mL), diethylaminosulfur trifluoride (2.2 mL) was added under ice cooling and stirred at the same temperature for 1 hour. The mixture was then warmed to room temperature and stirred for 3 hours. The reaction mixture was added to a mixture of ice water, sodium bicarbonate, and chloroform and stirred. The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 1-bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene (1.3 g) as an oil.

[0121] Preparation Example 193: To a mixture of 2-(5-methyl-3-{[(3R)-piperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (160 mg), dichloromethane (4.4 mL), and methanol (0.4 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (150 mg), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (190 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 21 hours. tert-Butyl 3-oxoazetidine-1-carboxylate (150 mg) and sodium triacetoxyborohydride (190 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for an additional 25 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give tert-butyl 3-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidin-1-yl]azetidine-1-carboxylate (220 mg) as a solid.

[0122] Preparation Example 194: To a mixture of 1-(tert-butoxycarbonyl)-5-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-2-carboxylic acid (200 mg) and THF (2 mL), triethylamine (56 μL), methyl chloroformate (31 μL), and 25% aqueous ammonia (0.1 mL) were added under ice-cooling and stirring, and the mixture was allowed to warm to room temperature and stirred for 6 hours. Triethylamine (110 μL), methyl chloroformate (62 μL), and 25% aqueous ammonia (0.2 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for an additional 15 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give tert-butyl 2-carbamoyl-5-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-1-carboxylate (80 mg) as a solid.

[0123] Preparation Example 195: To a mixture of 1-tert-butyl 2-methyl 5-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-1,2-dicarboxylate (430 mg), THF (3.5 mL), methanol (0.7 mL), and water (2.5 mL), lithium hydroxide monohydrate (1.0 g) was added and stirred at 55-65°C for 3.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was adjusted to pH 3 by slowly adding 10% hydrochloric acid with stirring at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-(tert-butoxycarbonyl)-5-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-2-carboxylic acid (440 mg) as a solid.

[0124] Preparation Example 196: A mixture of tert-butyl (3R)-3-({6-[2-(acetyloxy)-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-1-carboxylate (470 mg), dichloromethane (9 mL), and TFA (1 mL) was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane (12 mL) and ethyl bromoacetate (0.3 mL) were added to the resulting residue. DIPEA (1.5 mL) was then added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give ethyl [(3R)-3-({6-[2-(acetyloxy)-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidin-1-yl]acetate (300 mg) as a solid.

[0125] Preparation Example 197: To a mixture of tert-butyl (3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-1-carboxylate (710 mg) and dichloromethane (10 mL) was added DIPEA (0.53 mL) and acetic anhydride (0.3 mL) at 0° C., followed by stirring for 5.5 hours while allowing to warm to room temperature. The reaction mixture was added to water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3R)-3-({6-[2-(acetyloxy)-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidine-1-carboxylate (470 mg) as an oil.

[0126] Example 1: Under an argon atmosphere, a mixture of (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (710 mg), 1,4-dioxane (8.6 mL), water (2.1 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (1.8 g), potassium carbonate (1.2 g), and RuPhos Pd G3 (250 mg) was stirred at 100°C for 1 hour under microwave irradiation. Under an argon atmosphere, RuPhos Pd G3 (120 mg) was added to the reaction mixture, and the mixture was stirred at 100°C for 1 hour under microwave irradiation. Water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol) to give 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (560 mg) as a solid.

[0127] Example 27: Under an argon atmosphere, a mixture of (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (170 mg), 1,4-dioxane (2.8 mL), water (0.70 mL), [2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (200 mg), potassium carbonate (290 mg), and PdCl(dppf)·CHCl (58 mg) was stirred at 100°C for 2 hours under microwave irradiation. After the reaction mixture was allowed to cool to room temperature, basic silica gel was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). The resulting purified product was added with ethyl acetate and diisopropyl ether and sonicated. The precipitated solid was collected by filtration to obtain 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol (190 mg) as a solid.

[0128] Example 31: Under an argon atmosphere, a mixture of (3S,4R)-4-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]oxan-3-ol (100 mg), 1,4-dioxane (2 mL), water (0.40 mL), (4-chloro-2-hydroxyphenyl)boronic acid (77 mg), potassium carbonate (180 mg), and PdCl(dppf)·CHCl (35 mg) was stirred at 120°C for 1 hour under microwave irradiation. Water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). Diisopropyl ether was added to the resulting purified product, followed by sonication. The precipitated solid was collected by filtration to obtain (3S,4R)-4-{[6-(4-chloro-2-hydroxyphenyl)-5-methyl-1,2,4-triazin-3-yl]amino}oxan-3-ol (44 mg) as a solid.

[0129] Example 59: A mixture of (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (70 mg), 1,4-dioxane (2.8 mL), 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (87 mg), RuPhos Pd G3 (24 mg), potassium carbonate (120 mg), and water (0.56 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, and then chloroform and water were added. The mixture was stirred at room temperature for 5 minutes. The resulting mixture was extracted with chloroform, and 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 (basic and neutral silica gel, chloroform / methanol). Diethyl ether (3 mL) and hexane (9 mL) were added to the resulting product and stirred for 5 minutes. The precipitated solid was collected by filtration to obtain 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol (80 mg) as a solid.

[0130] Example 73: A mixture of 6-chloro-N-[(3R)-1-cyclopropylpiperidin-3-yl]-5-methyl-1,2,4-triazin-3-amine (100 mg), 1,4-dioxane (3 mL), water (0.60 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (94 mg), potassium carbonate (160 mg), and PdCl(dppf)·CHCl (31 mg) was stirred at 100°C for 2 hours under an argon atmosphere. Basic silica gel was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). Diisopropyl ether and hexane were added to the resulting purified product, followed by sonication. The precipitated solid was collected by filtration (Solid A). The filtrate was concentrated under reduced pressure, followed by addition of hexane and sonication. The precipitated solid was collected by filtration (Solid B). Solid A and Solid B were combined to give 2-(3-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (45 mg) as a solid.

[0131] Example 75: A mixture of (1S,3R)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (120 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (150 mg), RuPhos Pd G3 (42 mg), potassium carbonate (140 mg), 1,4-dioxane (2.4 mL), and water (0.60 mL) was stirred at 100°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to cool to room temperature, basic silica gel was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). The resulting purified product was added with diisopropyl ether and hexane and sonicated. The precipitated solid was collected by filtration to obtain 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (160 mg) as a solid.

[0132] Example 108: A mixture of (1s,3s)-3-[(6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino]-1-methylcyclobutan-1-ol (180 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (380 mg), RuPhos Pd G3 (53 mg), potassium carbonate (340 mg), 1,4-dioxane (4 mL), and water (1 mL) was stirred at 70°C for 5 hours under an argon atmosphere. Water was added to the reaction mixture, which was then extracted with chloroform. 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 (basic and neutral silica gel, chloroform / methanol). The resulting purified product was triturated with diisopropyl ether and hexane. The precipitated solid was collected by filtration and washed with hexane to give 2-(5-cyclopropyl-3-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (48 mg) as a solid.

[0133] Example 131: A mixture of (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (99 mg), 1,4-dioxane (3 mL), water (0.60 mL), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (390 mg), RuPhos Pd G3 (35 mg), and potassium carbonate (170 mg) was stirred at 100°C for 1.7 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and methanol (3 mL) and 12M hydrochloric acid (2 mL) were added at room temperature. The mixture was then stirred at 60°C for 2 hours. Basic silica gel was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). The purified product was sonicated with diisopropyl ether, and the precipitated solid was collected by filtration to give 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol (59 mg) as a solid.

[0134] Example 132 A mixture of tert-butyl [(1R,2R)-2-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)cyclohexyl]carbamate (310 mg), dichloromethane (7 mL), and trifluoroacetic acid (0.7 mL) was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added dropwise to the reaction mixture under ice-cooling and stirring, followed by extraction with a 10:1 mixed solvent of dichloromethane and methanol. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (220 mg) as a solid.

[0135] Example 141 A mixture of tert-butyl (2S)-2-[({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)methyl]morpholine-4-carboxylate (350 mg), dichloromethane (7 mL), and trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. Trifluoroacetic acid (1 mL) was added to the reaction mixture with stirring at room temperature, and the mixture was further stirred at room temperature for 15 hours. A saturated aqueous solution of sodium bicarbonate was added dropwise to the reaction mixture with stirring on ice. Methanol was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 2-[5-methyl-3-({[(2R)-morpholin-2-yl]methyl}amino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol (210 mg) as a solid.

[0136] Example 148: To a mixture of tert-butyl [(2R)-1-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)propan-2-yl]carbamate (140 mg) and dichloromethane (5.0 mL), 4 M hydrogen chloride in 1,4-dioxane (1.0 mL) was added at 0° C. and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether to give 2-(3-{[(2R)-2-aminopropyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol monohydrochloride (70 mg) as a solid.

[0137] Example 149: A mixture of 2-(5-methyl-3-{[1-(oxan-2-yl)-1H-pyrazol-4-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (210 mg), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 4 hours. Trifluoroacetic acid (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for an additional 2 hours. Saturated aqueous sodium bicarbonate solution was added dropwise to the reaction mixture under ice-cooling and stirring, and the precipitated solid was collected by filtration and washed with water. The resulting solid was triturated with dichloromethane and hexane. The precipitated solid was collected by filtration to give 2-{5-methyl-3-[(1H-pyrazol-4-yl)amino]-1,2,4-triazin-6-yl}-5-(trifluoromethyl)phenol (140 mg) as a solid.

[0138] Example 151 To a mixture of 1-{(2S)-2-[({6-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)methyl]pyrrolidin-1-yl}ethan-1-one (150 mg) and dichloromethane (1.8 mL) was added dropwise boron tribromide (17% dichloromethane solution, 1.8 mL) under ice-cooling and stirring. The reaction mixture was stirred for 2 hours while being allowed to warm to room temperature. Under ice-cooling and stirring, saturated aqueous sodium bicarbonate solution was added dropwise to the reaction mixture, which was then warmed to room temperature and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 1-{(2S)-2-[({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)methyl]pyrrolidin-1-yl}ethan-1-one (120 mg) as a solid.

[0139] Example 152: To a mixture of 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (210 mg) and dichloromethane (6 mL) were added DIPEA (0.2 mL) and acetic anhydride (0.1 mL) under ice-cooling and stirring, and the reaction mixture was stirred for 14 hours while naturally warming to room temperature. The reaction mixture was concentrated under reduced pressure, and then methanol (2 mL), water (0.2 mL), and potassium carbonate (160 mg) were added, followed by stirring at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane, 10% hydrochloric acid, and saturated aqueous sodium bicarbonate were added, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give N-[(1R,2R)-2-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)cyclohexyl]acetamide (170 mg) as a solid.

[0140] Example 159: To a mixture of (3R,4R)-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidin-3-ol (52 mg) and dichloromethane (5 mL) was added acetyl chloride (0.050 mL) at 0°C and stirred at 0 to 10°C for 3 hours. The reaction mixture was warmed to room temperature and stirred at the same temperature for 1.5 hours. Pyridine (0.011 mL) was added to the resulting mixture and stirred at room temperature for 3 days. 1M aqueous sodium hydroxide solution (1.3 mL) was added to the reaction mixture and stirred at room temperature for 2 days. 1M hydrochloric acid (1.3 mL) was added to the resulting mixture at 0°C, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 1-[(3R,4R)-3-hydroxy-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidin-1-yl]ethan-1-one (16 mg) as a solid.

[0141] Example 160: A mixture of (3R,4R)-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidin-3-ol monohydrochloride (250 mg), dichloromethane (5.0 mL), DIPEA (0.18 mL), and methanesulfonyl chloride (0.054 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous TFA / acetonitrile) to give (3R,4R)-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)-1-(methanesulfonyl)pyrrolidin-3-ol (9 mg) as a solid.

[0142] Example 161: To a mixture of 2-(5-methyl-3-{[(3R)-pyrrolidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (120 mg), 1,4-dioxane-2,5-diol (85 mg), dichloromethane (3 mL), and acetic acid (0.40 mL), sodium triacetoxyborohydride (150 mg) was added under an argon atmosphere and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 2-(3-{[(3R)-1-(2-hydroxyethyl)pyrrolidin-3-yl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (10 mg) as a solid.

[0143] Example 163: To a mixture of (3R,4R)-1-acetyl-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidin-3-yl acetate (250 mg) and methanol (10 mL) was added potassium carbonate (240 mg) at 0°C under a nitrogen atmosphere and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 1-[(3R,4R)-3-hydroxy-4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)pyrrolidin-1-yl]ethan-1-one (45 mg) as a solid.

[0144] Example 164: To a mixture of [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (4.5 g) and 1,4-dioxane (30 mL), 6-chloro-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1,2,4-triazin-3-amine (3.5 g), RuPhos Pd G3 (1.3 g), potassium carbonate (6.0 g), and water (6 mL) were added at room temperature, and the mixture was stirred overnight at 100°C under an argon atmosphere. After cooling to room temperature, water and saturated brine were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). The obtained purified product was suspended in ethyl acetate / hexane, and the solid was collected by filtration to give 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (3.0 g) as a solid.

[0145] Example 174: To a mixture of 6-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1,2,4-triazin-3-amine (5.4 g) and methanol (50 mL) was added 12 M hydrochloric acid (10 mL) at room temperature, followed by stirring at 60°C for 1.5 hours. The reaction mixture was ice-cooled, then added to saturated aqueous sodium bicarbonate (300 mL) and stirred at room temperature for 30 minutes. The resulting mixture was extracted with chloroform and chloroform / methanol (9 / 1). The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was dissolved in chloroform / methanol (9 / 1), and basic silica gel was added. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform / methanol). Ethyl acetate (36 mL) was added to the resulting purified product, and the mixture was stirred at 80°C. Heptane (180 mL) was added at the same temperature, and the mixture was cooled to room temperature. The solid was collected by filtration to give 5-(difluoromethoxy)-2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)phenol (3.0 g) as a solid.

[0146] Example 181: To a mixture of 2-(5-methyl-3-{[(3R)-piperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (100 mg), dichloromethane (1.5 mL), and methanol (0.15 mL), acrylonitrile (28 μL) was added and stirred at room temperature for 6 hours. After that, acrylonitrile (160 μL) was added and stirred at room temperature for 26 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to give 3-[(3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)piperidin-1-yl]propanenitrile (31 mg) as a solid.

[0147] Example 182: To a mixture of methyl (1S,3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)cyclopentane-1-carboxylate (250 mg), THF (3 mL), and water (1.5 mL), lithium hydroxide monohydrate (65 mg) was added and stirred at room temperature for 17 hours. The reaction mixture was adjusted to pH 2-3 with 10% hydrochloric acid, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate (this organic layer is referred to as organic layer A). To a mixture of methyl (1S,3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)cyclopentane-1-carboxylate (55 mg), THF (0.7 mL), and water (0.35 mL), lithium hydroxide monohydrate (15 mg) was added and stirred at room temperature for 17 hours. The reaction mixture was adjusted to pH 2-3 with 10% hydrochloric acid, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate (this organic layer is referred to as organic layer B). The organic layer A and the organic layer B were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,3R)-3-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl}amino)cyclopentane-1-carboxylic acid (190 mg) as a solid.

[0148] Example 184: To a mixture of 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol (200 mg) and ethanol (1 mL), 4 M hydrogen chloride in ethyl acetate (0.23 mL) was added and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (2 mL) was added to the resulting residue, followed by stirring at 50°C for 48 hours. After cooling to room temperature, the solid was collected by filtration and washed with cold ethyl acetate (1 mL) to give 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol monohydrochloride (170 mg) as crystals.

[0149] Example 185: To a mixture of 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (100 mg), dichloromethane (2 mL), and 1,4-dioxane (1 mL), 4 M hydrogen chloride in 1,4-dioxane (0.082 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 2-butanone (2 mL) was added to the resulting residue, followed by stirring at 50°C for 72 hours. After cooling to room temperature, the solid was collected by filtration and washed with cold 2-butanone (1 mL) to give 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol monohydrochloride (31 mg) as crystals.

[0150] Example 186: To a mixture of 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol (200 mg) and ethanol (1 mL), 4M hydrogen chloride in ethyl acetate (0.2 mL) was added and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (2 mL) was added to the resulting residue, followed by stirring at 50°C for 48 hours. After cooling to room temperature, the solid was collected by filtration and washed with cold ethyl acetate (1 mL) to give 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol monohydrochloride (160 mg) as crystals.

[0151] Example 187: To a mixture of 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (200 mg) and ethanol (1 mL), 4M hydrogen chloride in ethyl acetate (0.34 mL) was added and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (2 mL) was added to the residue, followed by stirring at 50°C for 48 hours. After cooling to room temperature, the solid was collected by filtration and washed with cold ethyl acetate (1 mL) to give 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol dihydrochloride (160 mg) as crystals.

[0152] Example 188: To a mixture of 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (960 mg) and ethyl acetate (3 mL), 4 M hydrogen chloride in 1,4-dioxane (1.4 mL) and ethyl acetate (3 mL) were added, followed by stirring at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to obtain the crude product (880 mg) as a solid. A mixture of the crude product (180 mg) and ethyl acetate (2 mL) was stirred at 50°C for 62 hours. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol dihydrochloride (45 mg) as crystals.

[0153] 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.

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] 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.

Claims

1. A compound of formula (I) or a salt thereof 【Chemistry 1】 [In the formula, R 1 are the same or different, C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 alkyl or cyano; R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, halogeno C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 or aryl, R 3 is H or C 1-6 is alkyl, R 4 is 1 to 4 identical or different R 5 C replaced with 1-6 Alkyl, -C 1-6 Alkylene-(1 to 4 identical or different R 6 aryl, optionally substituted with -C 1-6 Alkylene-(1 to 4 identical or different R 7 C which may be substituted with 3-8 Cycloalkyl), -C 1-6 Alkylene-(1 to 4 identical or different R 8 Heteroaryl, optionally substituted with -C 1-6 Alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with 10 C which may be substituted with 3-8 Cycloalkyl, 1 to 4 identical or different R 11 or 1 to 4 identical or different R 12 is a 4-8 membered saturated heterocyclyl optionally substituted by R 5 -OR 13 , -NR 14 R 15 , halogen, or cyano; R 6 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 7 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 8 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 9 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O) 2 -C 1-6 is alkyl, R 10 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, -C(O)-OH, or cyano; R 11 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 12 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered saturated heterocyclyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-C 3-8 Cycloalkyl, -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , -C 1-6 Alkylene-cyano, -C 1-6 Alkylene-C(O)-OH, halogen, cyano, oxo, -C(O)-NH 2 , -C(O)-C 1-6 Alkyl, or -S(O) 2 -C 1-6 is alkyl, R 13 is H or C 1-6 is alkyl, R 14 and R 15 are the same or different, H, C 1-6 Alkyl, or -C(O)-C 1-6 is alkyl, n is an integer from 1 to 4, and the substituent R 1 represents the number of

2. R 4 1 to 4 identical or different R 5 C replaced with 1-6 Alkyl, -C 1-6 Alkylene-(1 to 4 identical or different R 6 aryl, optionally substituted with -C 1-6 Alkylene-(1 to 4 identical or different R 7 C which may be substituted with 3-8 Cycloalkyl), -C 1-6 Alkylene-(1 to 4 identical or different R 8 Heteroaryl, optionally substituted with -C 1-6 Alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with 10 C which may be substituted with 3-8 Cycloalkyl, 1 to 4 identical or different R 11 or 1 to 4 identical or different R 12 is a 4- to 7-membered saturated heterocyclyl optionally substituted by R 10 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 12 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O) 2 -C 1-6 The compound or salt thereof according to claim 1, wherein the aryl group is alkyl.

3. The compound or salt thereof according to claim 2, wherein the formula (I) is formula (Ia): 【Chemistry 2】 [In the formula, R 1a is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 alkyl or cyano; R 1b are the same or different, C 1-6 Alkyl, halogeno C 1-6 alkyl or halogen; R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, halogeno C 1-6 Alkyl, -N(C 1-6 Alkyl) 2 or aryl, R 3 is H, R 4 is 1 to 4 identical or different R 5 C replaced with 1-6 Alkyl, -C 1-6 Alkylene-(1 to 4 identical or different R 6 aryl, optionally substituted with -C 1-6 Alkylene-(1 to 4 identical or different R 7 C which may be substituted with 3-8 Cycloalkyl), -C 1-6 Alkylene-heteroaryl, -C 1-6 Alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with 10 C which may be substituted with 3-8 Cycloalkyl, heteroaryl, or 1 to 4 identical or different R 12 is a 4- to 7-membered saturated heterocyclyl optionally substituted by R 5 -OR 13 , -NR 14 R 15 , halogen, or cyano; R 6 -OR 13 and R 7 -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , or -C 1-6 Alkylene-NR 14 R 15 and R 9 -C(O)-C 1-6 is alkyl, R 10 is C 1-6 Alkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, or cyano; R 12 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 Alkylene-OR 13 , -C 1-6 Alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O) 2 -C 1-6 is alkyl, R 13 is H or C 1-6 is alkyl, R 14 and R 15 are the same or different, H, C 1-6 Alkyl, or -C(O)-C 1-6 is alkyl, k is 0 or 1, and R 1b represents the number of

4. R 1a C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl or -O-halogenoC 1-6 is alkyl, R 2 C 1-6 Alkyl or C 3-8 is cycloalkyl, R 4 Ga-C 1-6 Alkylene-(1 to 4 identical or different R 7 C which may be substituted with 3-8 Cycloalkyl), -C 1-6 Alkylene-(1 to 4 identical or different R 9 4- to 7-membered saturated heterocyclyl optionally substituted with 10 C which may be substituted with 3-8 Cycloalkyl or 1 to 4 identical or different R 12 The compound according to claim 3, wherein k is 0, or a salt thereof.

5. The compound is 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol, (3S,4R)-4-{[6-(4-chloro-2-hydroxyphenyl)-5-methyl-1,2,4-triazin-3-yl]amino}oxan-3-ol, 2-(5-cyclopropyl-3-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol, 2-(3-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol, 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, 2-[5-methyl-3-({[(2R)-morpholin-2-yl]methyl}amino)-1,2,4-triazin-6-yl]-5-(trifluoromethyl)phenol, 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol, and 5-(difluoromethoxy)-2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)phenol, 2. The compound according to claim 1, or a salt thereof, which is a compound selected from the group consisting of:

6. 2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol monohydrochloride, 2-(3-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol monohydrochloride, 5-(difluoromethoxy)-2-(3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)phenol monohydrochloride, 2-(5-methyl-3-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol dihydrochloride, and 2-(3-{[(1R,2R)-2-aminocyclohexyl]amino}-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol dihydrochloride, 2. The compound according to claim 1, or a salt thereof, which is a compound selected from the group consisting of:

7. 10. A pharmaceutical composition comprising a compound according to claim 1 or a salt thereof, and one or more pharma- ceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, which is an inhibitor of NLRP3 inflammasome activation.

9. The pharmaceutical composition according to claim 7, which is a pharmaceutical composition for preventing and / or treating an inflammatory disease and / or a neurodegenerative disease.

10. 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.

11. 2. A 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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