Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
  • C07D253/06—1,2,4-Triazines
  • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
  • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/027—Organoboranes and organoborohydrides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/025—Boronic and borinic acid compounds

Definitions

• the present invention provides a substitution that has an inhibitory effect on NLRP3 inflammasome activation and is expected to be useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the prevention and/or treatment of inflammatory diseases or neurodegenerative diseases. It relates to a triazine compound or a salt thereof.
• Inflammasomes are intracellular protein aggregates triggered by endogenous and exogenous alarm molecules. It is the mechanism responsible for the amplification of the inflammatory response by inducing death.
• alarm molecule recognition molecules such as NLRP1, NLRP3, NLRC4, and AIM2, are known. Recognize and activate stress.
• Cryopyrin-associated periodic syndrome is known as a disease caused by gain-of-function mutations in NLRP3 (Nature Genetics, Vol. 29, No. 3, pp. 301-305, 2001). ). Also, 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.
• ⁇ -synuclein fibrils activate NLRP3 and promote IL-1 ⁇ production from microglia, and that administration of NLRP3 inhibitors in a mouse model of ⁇ -synucleinopathy induced by ⁇ -synuclein fibrils It is known to show functional improvement (Science Translational Medicine, Vol. 10, Article No. eaah4066, 2018).
• Patent Document 1 describes that a compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation (see the publication for the symbols in the formula).
• Patent Document 2 describes that a compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation (see the publication for the symbols in the formula).
• Patent Document 3 describes that a compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation (see the publication for the symbols in the formula).
• Patent Document 4 describes that a compound represented by the following formula has an inhibitory effect on NLRP3 inflammasome activation (see the publication for the symbols in the formula).
• Patent Document 5 which was published after the priority date of the present application, describes that the compound represented by the following formula has an NLRP3 inflammasome activation inhibitory effect (see the publication for symbols in the formula).
• Patent Document 6 describes that a compound represented by the following formula is useful for treating Huntington's disease (B represents a heterocycle. For other symbols in the formula, see the publication).
• Patent Document 7 describes that the compound represented by the following formula has a function of regulating messenger RNA splicing (see the publication for the symbols in the formula).
• Patent Document 8 describes that the compound represented by the following formula has a function of regulating muscle contraction (see the publication for the symbols in the formula).
• a compound expected to be useful as an active ingredient of a pharmaceutical composition particularly a pharmaceutical composition for preventing and/or treating inflammatory diseases, neurodegenerative diseases, etc., which has an inhibitory effect on NLRP3 inflammasome activation. .
• the present inventors have extensively studied compounds having NLRP3 inflammasome activation inhibitory activity, and found that substituted triazine compounds have NLRP3 inflammasome activation inhibitory activity, prevent inflammatory diseases, neurodegenerative diseases, and the like.
• the inventors have completed the present invention based on the finding that they are expected to be useful as active ingredients of therapeutic pharmaceutical compositions.
• R 1 is the same or different and is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, halogen, -OC 1-6 alkyl, -O-halogenoC 1-6 alkyl, or cyano and R 2 is C 1-6 alkyl, C 3-8 cycloalkyl, halogenoC 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , or aryl; R 3 is H, or C 1-6 alkyl; R 4 is C 1-6 alkyl substituted with 1 to 4 identical or different R 5 , -C 1-6 alkylene-(substituted by 1 to 4 identical or different R 6 aryl), -C 1-6 alkylene-(C 3-8 cycl
• the present invention also provides pharmaceutical compositions containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, in particular for the prevention and/or It relates to therapeutic pharmaceutical compositions.
• the pharmaceutical composition includes a prophylactic and/or therapeutic agent for inflammatory diseases or neurodegenerative diseases containing the compound of formula (I) or a salt thereof.
• the present invention also provides the compound of formula (I) or a salt thereof which is an NLRP3 inflammasome activation inhibitor, the compound of formula (I) or a salt thereof for use as an NLRP3 inflammasome activation inhibitor, the formula NLRP3 inflammasome activation inhibitor containing the compound of (I) or a salt thereof, a compound of formula (I) or a salt thereof which is an NLRP3 inflammasome activation inhibitor, and one or more pharmaceutically acceptable Pharmaceutical compositions containing excipients, use of compounds of formula (I) or salts thereof for the manufacture of medicaments or pharmaceutical compositions for the prevention and/or treatment of inflammatory and/or neurodegenerative diseases, inflammation Use of compounds of formula (I) or salts thereof for the prevention and/or treatment of sexual and/or neurodegenerative diseases Formulas for use in the prevention and/or treatment of inflammatory and/or neurodegenerative diseases
• the present invention relates to a method for preventing and/or treating inflammatory diseases and/or neurodegenerative diseases, which comprises administer
• 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.
• C 1-6 alkyl is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), for example, 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, and the like.
• it is methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl or 2,2-dimethylpropyl; in certain embodiments, it is linear or branched C 1-4 alkyl; One embodiment is methyl, ethyl, n-propyl, n-butyl, isobutyl or tert-butyl, and another embodiment is n-propyl or isobutyl. Another embodiment is methyl, ethyl, n-propyl or isopropyl, one embodiment is methyl or isopropyl, one embodiment is isopropyl, and another embodiment is methyl.
• C 1-6 alkylene means a linear or branched C 1-6 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.
• it is C 1-4 alkylene, in another embodiment it is methylene or ethylene, in another embodiment it is ethylene, and in another embodiment it is methylene.
• the “C 3-8 cycloalkyl” is a C 3-8 saturated hydrocarbon ring group, which may have a bridge or may form a spiro ring.
• Some embodiments are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl or spiro[3.3]heptyl, and some embodiments are C 3-6 is a saturated hydrocarbon ring group of, in one aspect, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in another aspect, cyclopropyl, in another aspect, cyclobutyl or cyclohexyl, in another aspect, is cyclobutyl, in another embodiment cyclopentyl, and in another embodiment cyclohexyl.
• 4- to 8-membered saturated heterocyclyl means a 4- to 8-membered saturated hydrocarbon ring group containing one or more heteroatoms, particularly an oxygen atom, a nitrogen atom or a sulfur atom as ring-constituting atoms, and having a bridge. may form a spiro ring.
• Some embodiments are oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, azepanyl, morpholinyl, 3-oxabicyclo[3.1.0]hexyl, or 6-azaspiro[2.5]octyl.
• 4- to 7-membered saturated heterocyclyl and in one embodiment, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, azepanyl, morpholinyl, or 3-oxabicyclo [3.1.0]hexyl, and in some embodiments, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, or morpholinyl, and in another embodiment, tetrahydrofuranyl, or tetrahydropyranyl.
• Another embodiment is pyrrolidinyl or piperidinyl, another embodiment is tetrahydropyranyl or piperidinyl, another embodiment is morpholinyl, and another embodiment is oxetanyl or azetidinyl.
• Aryl is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, including a ring group condensed with a C 5-8 cycloalkene at its double bond site. Examples include phenyl, naphthyl, tetrahydronaphthyl, indenyl, fluorenyl, and the like, and phenyl as an embodiment.
• Heteroaryl is a 5-6 membered aromatic ring group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, such as pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl;
• One embodiment is pyrazolyl, pyridazinyl or pyridyl, another embodiment is pyrazolyl or pyridyl, and another embodiment is pyrazolyl.
• Halogen means F, Cl, Br or I.
• One embodiment is F or Cl, another embodiment is F, and another embodiment is Cl.
• a “halogeno C 1-6 alkyl” is a linear or branched C 1-6 alkyl group substituted with one or more halogens.
• substitution means unsubstituted or "substituted with one or more substituents". Substitution may be at any position where hydrogen normally occurs in the group.
• One or more aspects can be combined with another aspect even if the combination is not specifically described.
• an "inflammatory disease” is an autoinflammatory disease, including cryopyrin-associated periodic fever syndrome (CAPS), gout and pseudogout; and nonalcoholic steatohepatitis (NASH). is not limited to One embodiment is an autoinflammatory disease, and another embodiment is CAPS.
• cryopyrin-associated periodic fever syndrome includes familial cold urticaria (FCAS), Muckle-Wells syndrome (MWS) and neonatal onset multi-organ system inflammatory disease / chronic infantile neurocutaneous joint syndrome (NOMID /CINCA syndrome).
• neurodegenerative disease refers to alpha-synucleinopathies, including Parkinson's disease, multiple system atrophy and dementia with Lewy bodies; Alzheimer's disease; amyotrophic lateral sclerosis; and multiple sclerosis. It is a group of diseases including, but not limited to.
• One aspect is Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis, and another aspect is multiple sclerosis.
• Another embodiment is ⁇ -synucleinopathy, another embodiment is Parkinson's disease, another embodiment is multiple system atrophy, and another embodiment is dementia with Lewy bodies. is.
• a certain embodiment of the compound of formula (I) or a salt thereof in the present invention is shown below.
• (1-1) A compound of formula (I) or a salt thereof (n represents the number of R 1 substituents).
• (1-2) A compound whose formula (I) is the following formula (Ia) or a salt thereof (k represents the number of R 1b substituents).
• (2-1) a compound or a salt thereof wherein n is an integer of 1 to 4;
• (2-2) A compound or a salt thereof wherein n is an integer of 1-3.
• (2-3) A compound wherein n is 1 or 2 or a salt thereof.
• (2-4) A compound wherein n is 1 or a salt thereof.
• (3-1) A compound wherein k is 0 or 1 or a salt thereof.
• R 1 are the same or different, C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, halogen, -OC 1-6 alkyl, -O-halogenoC 1- A compound which is 6 alkyl or cyano or a salt thereof.
• (4-2) A compound or a salt thereof, wherein R 1 described in formula (I) is R 1a and R 1b described in formula (Ia).
• R 1a is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, halogen, -OC 1-6 alkyl, -O-halogenoC 1-6 alkyl, or cyano A compound or its salt.
• a compound or a salt thereof wherein R 1a is halogenoC 1-6 alkyl, C 3-8 cycloalkyl, halogen, -OC 1-6 alkyl, or -O-halogenoC 1-6 alkyl.
• a compound or a salt thereof wherein R 1a is halogenoC 1-6 alkyl, halogen, -OC 1-6 alkyl, or -O-halogeno C 1-6 alkyl.
• a compound or a salt thereof wherein R 1a is halogenoC 1-6 alkyl.
• (5-7) A compound or a salt thereof wherein R 1a is -OC 1-6 alkyl.
• a compound or a salt thereof wherein R 1a is —O-halogenoC 1-6 alkyl.
• 5-9) A compound or a salt thereof wherein R 1a is halogenoC 1-6 alkyl, -OC 1-6 alkyl, or -O-halogeno C 1-6 alkyl.
• (6-1) A compound or a salt thereof wherein R 1b is the same or different and is C 1-6 alkyl, halogenoC 1-6 alkyl, or halogen.
• (6-2) A compound or a salt thereof wherein R 1b is halogen.
• R 2 is C 1-6 alkyl, C 3-8 cycloalkyl, halogenoC 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 or aryl compound or its salt.
• R 2 Compounds or salts thereof wherein R 2 is C 1-6 alkyl, C 3-8 cycloalkyl, halogenoC 1-6 alkyl, -N(C 1-6 alkyl) 2 or aryl.
• (7-3) A compound or a salt thereof wherein R 2 is C 1-6 alkyl or C 3-8 cycloalkyl.
• a compound or a salt thereof wherein R 2 is C 1-6 alkyl.
• (7-5) A compound or a salt thereof wherein R 2 is C 3-8 cycloalkyl.
• (8-1) A compound or a salt thereof wherein R 3 is H or C 1-6 alkyl.
• (8-2) A compound in which R 3 is H or a salt thereof.
• R 4 is -C 1-6 alkylene-(C 3-8 cycloalkyl optionally substituted with 1 to 4 identical or different R 7 ), -C 1-6 alkylene- (4- to 7-membered saturated heterocyclyl optionally substituted with 1-4 identical or different R 9 ), C 3 optionally substituted with 1-4 identical or different R 10
• R 4 is C 3-8 cycloalkyl optionally substituted with 1 to 4 identical or different R 10 or substituted by 1 to 4 identical or different R 12 4- to 7-membered saturated heterocyclyl compound or a salt thereof.
• (9-6) A compound or a salt thereof wherein R 4 is C 1-6 alkyl substituted with 1 to 4 identical or different R 5 .
• (9-7) A compound or a salt thereof wherein R 4 is C 1-6 alkyl substituted with 1 to 3 identical or different R 5 .
• (9-8) A compound or a salt thereof wherein R 4 is C 1-6 alkyl substituted with 1 to 2 identical or different R 5 .
• (9-9) A compound or a salt thereof wherein R 4 is C 1-6 alkyl substituted with one R 5 .
• R 4 is a 4- to 7-membered saturated heterocyclyl optionally substituted with 1 to 4 identical or different R 12 .
• (9-41) A compound or a salt thereof wherein R 4 is a 4- to 7-membered saturated heterocyclyl optionally substituted with 1 to 3 identical or different R 12 .
• (9-42) A compound or a salt thereof wherein R 4 is a 4- to 7-membered saturated heterocyclyl optionally substituted with 1 to 2 identical or different R 12 .
• (9-43) A compound or a salt thereof wherein R 4 is a 4- to 7-membered saturated heterocyclyl optionally substituted with 1 R 12 .
• R 4 is a 4- to 7-membered saturated heterocyclyl.
• R 4 is -C 1-6 alkylene-4- to 7-membered saturated heterocyclyl, C 3-8 cycloalkyl optionally substituted with 1 to 2 identical or different R 10 , or , a compound or a salt thereof which is a 4- to 7-membered saturated heterocyclyl optionally substituted with 1 R 12 .
• R 4 is C 3-8 cycloalkyl optionally substituted with 1 R 10 or 4-7 membered saturated heterocyclyl optionally substituted with 1 R 12 compound or its salt.
• R 4 is -C 1-6 alkylene-(4- to 7-membered saturated heterocyclyl optionally substituted with 1 to 4 identical or different R 9 ), 1 to 4 identical C 3-8 cycloalkyl optionally substituted with 1 or different R 10 , or 4-7 membered saturated heterocyclyl optionally substituted with 1 to 4 identical or different R 12 compound or its salt.
• (10-1) A compound or a salt thereof wherein R 5 is -OR 13 , -NR 14 R 15 , halogen, or cyano.
• (10-2) A compound or a salt thereof wherein R 5 is -OR 13 or -NR 14 R 15 .
• (10-3) A compound in which R5 is -OR13 or a salt thereof.
• R 5 is -NR 14 R 15 or a salt thereof.
• R 6 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, or cyano.
• 11-3) A compound wherein R6 is -OR13 or a salt thereof.
• R 7 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, or cyano.
• (12-2) Compounds or salts thereof wherein R 7 is -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , or -C 1-6 alkylene-NR 14 R 15 .
• (12-3) A compound or a salt thereof wherein R 7 is -OR 13 or -NR 14 R 15 .
• (12-4) A compound in which R7 is -OR13 or a salt thereof.
• (12-5) A compound wherein R 7 is -NR 14 R 15 or a salt thereof.
• (12-6) A compound wherein R 7 is -C 1-6 alkylene-OR 13 or -C 1-6 alkylene-NR 14 R 15 or a salt thereof.
• (12-7) A compound wherein R 7 is -C 1-6 alkylene-OR 13 or a salt thereof.
• (12-8) A compound wherein R 7 is -C 1-6 alkylene-NR 14 R 15 or a salt thereof.
• R 8 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, or cyano.
• 13-3 A compound or a salt thereof wherein R 8 is -OR 13 , -NR 14 R 15 , or halogen.
• R 9 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 alkyl.
• R 9 is C 1-6 alkyl, halogenoC 1-6 alkyl, -OR 13 , -NR 14 R 15 , halogen, oxo, or -C(O)-C 1-6 alkyl Or its salt.
• (14-5) A compound or a salt thereof wherein R 9 is -C(O)-C 1-6 alkyl.
• R 10 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, -C(O)-OH, or cyano.
• R 10 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, or cyano.
• 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 A compound or a salt thereof.
• a compound or a salt thereof wherein R 10 is C 1-6 alkyl, -OR 13 , -NR 14 R 15 , halogen, or cyano.
• a compound or a salt thereof wherein R 10 is -OR 13 or -NR 14 R 15 .
• a compound wherein R 10 is -OR 13 or a salt thereof.
• R 11 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, or cyano.
• R 11 is C 1-6 alkyl, halogenoC 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 compound or a salt thereof which is halogen.
• (16-3) A compound or a salt thereof wherein R 11 is C 1-6 alkyl, or -C 1-6 alkylene-OR 13 .
• (16-4) A compound or a salt thereof wherein R 11 is C 1-6 alkyl.
• (16-5) A compound wherein R 11 is -C 1-6 alkylene-OR 13 or a salt thereof.
• R 12 is C 1-6 alkyl, halogenoC 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) -C1-6alkyl , or -S(O) 2 - C1-6alkyl , or a compound thereof salt.
• R 12 is C 1-6 alkyl, halogenoC 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -NR 14 R 15 , -C 1-6 alkylene-OR 13 , -C A compound or a salt thereof which is 1-6 alkylene-NR 14 R 15 , halogen, cyano, oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 alkyl.
• R 12 is 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 A compound or a salt thereof which is R 15 , oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 alkyl.
• R 12 is C 1-6 alkyl, C 3-8 cycloalkyl, -OR 13 , -C 1-6 alkylene-OR 13 , oxo, or -C(O)-C 1-6 alkyl; A compound or its salt.
• (19-1) A compound or a salt thereof wherein R 14 and R 15 are the same or different and are H, C 1-6 alkyl, or -C(O)-C 1-6 alkyl.
• (19-2) A compound or a salt thereof wherein R 14 and R 15 are the same or different and are H or C 1-6 alkyl.
• (19-3) A compound in which R 14 and R 15 are H or a salt thereof.
• (19-4) A compound wherein R 14 is —C(O)—C 1-6 alkyl and R 15 is H, or a salt thereof.
• (20) A compound or a salt thereof, which is a combination of two or more of the aspects of the groups described in (1-1) to (19-4) above, which are not mutually contradictory.
• Examples include, but are not limited to, the following combinations. (20-1) the above (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- A compound or a salt thereof that is a combination of aspects of 1). (20-2) the above (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 combination of aspects of (19-1) A compound or a salt thereof.
• (20-5) (1-2), (3-2), (5-6), (7-4), (8-2), (9-43), (17-8), and ( 18-2) A compound or a salt thereof that is a combination of aspects.
• (20-6) the above (1-2), (3-2), (5-5), (7-5), (8-2), (9-32), (15-6), and ( 18-2) A compound or a salt thereof that is a combination of aspects.
• (20-8) Aspects of the above (1-2), (3-2), (5-5), (7-4), (8-2), (9-43), and (17-10) A compound or a salt thereof that is a combination of (20-9) the above (1-2), (3-2), (5-5), (7-4), (8-2), (9-33), (15-8), and ( 18-2) A compound or a salt thereof that is a combination of aspects.
• (20-11) a compound that is a combination of aspects (1-2), (3-2), (5-5), (7-4), (8-2), and (9-29); or the salt.
• (20-12) Embodiments of (1-2), (3-2), (5-5), (7-4), (8-2), (9-43), and (17-8) A compound or a salt thereof that is a combination of (20-13) Embodiments of (1-2), (3-2), (5-8), (7-4), (8-2), (9-43), and (17-8) A compound or a salt thereof that is a combination of (20-14) the above (1-2), (3-2), (5-4), (7-3), (8-2), (9-45), (15-5), (17) -12), (18-2) and (19-3), or a compound or a salt thereof.
• formula (I) is formula (Ia), R 1a is trifluoromethyl, Cl, -O-methyl, -O-difluoromethyl, or -O-trifluoromethyl, R 2 is methyl or cyclopropyl, R3 is H , R 4 is -methylene-morpholinyl, cyclobutyl optionally substituted with 1 to 2 identical or different R 10 , cyclohexyl optionally substituted with 1 to 2 identical or different R 10 , tetrahydropyranyl optionally substituted with 1 R 12 or piperidinyl optionally substituted with 1 R 12 , R 10 is methyl, -OH, or -NH2 , R 12 is methyl, cyclopropyl, or -OH; A compound in which k is 0 or
• Examples of specific compounds included in 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-cycl
• a compound or a salt thereof selected from the following group can be mentioned.
• Examples of specific compounds included in 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 salt, and 2-(3- ⁇ [
• the compound of formula (I) may have tautomers and geometric isomers depending on the type of substituent.
• the compound of formula (I) or a salt thereof may be described as only one form of isomer, but the present invention also includes other isomers, and the separated isomers , or mixtures thereof.
• the compound of formula (I) or a salt thereof may have an asymmetric center or axial asymmetry, and enantiomers (optical isomers) based on this may exist.
• the compounds of formula (I) or salts thereof include any of the isolated individual enantiomers such as the (R) form, the (S) form, and mixtures thereof (including racemic and non-racemic mixtures).
• enantiomers are "stereochemically pure.”
• the term “stereochemically pure” refers to the degree of purity that a person skilled in the art can recognize as being substantially stereochemically pure.
• 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.
• the present invention also includes pharmaceutically acceptable prodrugs of the compounds represented by formula (I).
• Pharmaceutically acceptable prodrugs are compounds having groups that are convertible by solvolysis or under physiological conditions into amino groups, hydroxyl groups, carboxyl groups, and the like. Groups that form prodrugs include, for example, Prog. Med., 5, 2157-2161 (1985) and groups described in "Drug Development” (Hirokawa Shoten, 1990) Vol. 7, Molecular Design 163-198. is mentioned.
• the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and depending on the type of substituent, may form an acid addition salt or a salt with a base.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, 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, glutamic acid, etc.
• Salts salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts etc.
• inorganic bases such as sodium, potassium, magnesium, calcium and aluminum
• organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine
• salts with various amino acids and amino acid derivatives such as acetylleucine, and ammonium salts etc.
• the present invention also includes various hydrates, solvates, and crystalline polymorphs of the compound of formula (I) or salts thereof.
• the present invention also includes all pharmaceutically acceptable compounds of formula (I) or salts thereof labeled with one or more radioactive or non-radioactive isotopes.
• suitable isotopes for use in isotopically labeling the compounds of the present invention include hydrogen (such as 2 H and 3 H), carbon (such as 11 C, 13 C and 14 C), nitrogen ( 13 N and 15 N etc.), oxygen ( 15 O, 17 O and 18 O etc.), fluorine ( 18 F etc.), chlorine ( 36 Cl etc.), iodine ( 123 I and 125 I etc.), phosphorus ( 32 P etc.), sulfur ( 35 S, etc.) isotopes.
• Radioisotopes such as tritium ( 3 H), carbon-14 ( 14 C), and the like, for their ease of labeling and ease of detection, may be used for this purpose.
• Substitution with positron emitting isotopes (such as 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
• PET positron emission tomography
• Isotopically-labeled compounds of the present invention are generally prepared by conventional techniques known to those skilled in the art, or by substituting suitable isotopically-labeled reagents for unlabeled reagents. It can be produced by the same production method or the like as in Examples or Production Examples.
• the compound of formula (I) or a salt thereof can be produced by utilizing the basic structure or characteristics based on the types of substituents and applying various known synthesis methods. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted to the functional group) at the stage from raw materials to intermediates. Sometimes.
• Such protecting groups include, for example, protecting groups described in P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis (4th edition, 2006)". , may be appropriately selected and used according to these reaction conditions.
• the desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
• the prodrug of the compound of formula (I) introduces a specific group in the steps from the raw material to the intermediate, or undergoes further reaction using the obtained compound of formula (I), as with the protecting group described above.
• the reaction can be carried out by applying methods known to those skilled in the art such as ordinary esterification, amidation, dehydration and the like.
• a representative method for producing the compound of formula (I) is described below. Each manufacturing method can also be carried out with reference to the reference attached to the description. In addition, the production method of the present invention is not limited to the examples shown below.
• CN cyano
• DMF N,N-dimethylformamide
• DMSO dimethylsulfoxide
• DIPEA N,N-diisopropylethylamine
• mCPBA m-chloroperbenzoic acid
• NBS N-bromosuccinimide
• NCS N-chlorosuccinimide
• NIS N-iodosuccinimide
• NMP 1-methylpyrrolidin-2-one
• Me Me: methyl
• Oxone® potassium peroxymonosulfate
• PdCl 2 (PPh 3 ) 2 bis(triphenylphosphine)palladium(II) ) dichloride
• PdCl2 (dppf) [1,1'-bis(diphenylphosphino)ferrocene]palladium( II ) dichloride
• PdCl2(dppf) .CH2Cl2
• X 1 and X 2 are the same or different and are Cl, Br, or I.
• Ra and R b are both H, or Ra and R b are Together with the bonding boronic acid residue, it forms 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Same below.
• This step is a step of obtaining the compound of formula (IV) by reacting the compound of formula (II) with the compound of formula (III).
• the compound of formula (II) and the compound of formula (III) are used in equal amounts or in excess, and the mixture is heated to reflux under cooling in a solvent inert to the reaction or in the absence of a solvent.
• the mixture is generally stirred at room temperature to 190° C. for 0.1 hour to 5 days.
• solvent used here are not particularly limited, but ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, Alcohols such as 1-butanol, water, pyridine, acetonitrile, NMP, DMF, DMSO and mixtures thereof. It may be advantageous for the reaction to proceed smoothly 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. Moreover, you may perform this reaction under microwave irradiation.
• organic base such as triethylamine or DIPEA
• an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate or sodium hydride.
• This step is a step of obtaining the compound of formula (I) by reacting the compound of formula (IV) with the compound of formula (V).
• the compound of the formula (IV) and the compound of the formula (V) are used in equal amounts or in excess, and the mixture is treated in the presence of a catalyst and a base in a solvent inert to the reaction under cooling.
• the mixture is heated under reflux, preferably at room temperature to 150° C., and stirred for usually 0.1 hour to 5 days.
• Examples of the catalyst used here are not particularly limited, but Pd ( PPh3 ) 4 , PdCl2 ( PPh3)2 , PdCl2 ( dppf), PdCl2 (dppf) .CH2Cl2 , Pd2 (dba) 3 , RuPhos Pd G3 and the like.
• bases include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium-t-butoxide and the like.
• 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, and pyridine. , acetonitrile, NMP, DMF, DMSO and mixtures thereof. Moreover, you may perform this reaction under microwave irradiation. [Reference] Journal of the American Chemical Society, 127, pp 4685-4696 (2005)
• This step is a step of obtaining the compound of formula (VII) by reacting the compound of formula (VI) with an oxidizing agent.
• an oxidizing agent used in this reaction, the compound of the formula (VI) and an oxidizing agent are used in equal amounts or in excess, and the mixture is heated in a solvent inert to the reaction under cooling to room temperature conditions, preferably from -78°C. Stir at room temperature, usually for 0.1 hour to 5 days.
• the oxidizing agent used here include, but are not particularly limited to, mCPBA, hydrogen peroxide, Oxone (registered trademark), and the like.
• solvents include, but are not limited to, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, benzene, and toluene. , xylene, and mixtures thereof.
• halogen solvents such as dichloromethane, chloroform and carbon tetrachloride
• ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, benzene, and toluene.
• ethers such as diethyl ether, THF, 1,4-dioxane and 1,2-dimethoxyethane, benzene, and toluene.
• xylene and mixtures thereof.
• This step is a step of obtaining a compound of formula (VIII) by reacting a compound of formula (VII) with a compound of formula (III).
• the compound of formula (VII) and the compound of formula (III) are used in equal amounts or in excess, and the mixture is heated to reflux under cooling in a solvent inert to the reaction or in the absence of a solvent.
• the mixture is stirred at a temperature of 0 to 190° C., preferably 0 to 190° C., usually for 0.1 hour to 5 days.
• ethers such as diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, Alcohols such as 1-butanol, water, pyridine, acetonitrile, NMP, DMF, DMSO, dichloromethane and mixtures thereof. It may be advantageous for the reaction to proceed smoothly 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. Moreover, you may perform this reaction 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 in the first step.
• This step is a step of obtaining the compound of formula (IV) by reacting the compound of formula (VIII) with a halogenating agent.
• the compound of formula (VIII) and the halogenating agent are used in equal amounts or in excess, and the mixture thereof is heated in a solvent inert to the reaction or in the absence of a solvent, preferably under cooling to reflux. is stirred at -78 to 50°C for usually 0.1 hour to 5 days.
• halogenating agent examples include, but are not limited to, NCS, NBS, NIS, bromine, iodine, dibromoisocyanuric acid, tetra-n-butylammonium tribromide, pyridinium tribromide, and the like.
• solvents include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and the like. alcohols, water, pyridine, acetonitrile, NMP, DMF, DMSO and mixtures thereof.
• This step is the step of obtaining the compound of formula (I) by reacting the compound of formula (IV) with the compound of formula (V), like the second step of the first production method.
• the compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorphic substance.
• a salt of the compound of formula (I) can also be produced by a conventional salt-forming reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization and various fractional chromatography.
• Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers.
• optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). , or can be produced from suitable optically active starting compounds.
• the pharmacological activity of the compound of formula (I) was confirmed by the following tests. In addition, the said pharmacological activity can also be confirmed by a well-known improvement test.
• THP-1 IL-1 ⁇ Production Suppression Test THP-1 cells were added with 50 ng/mL of 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, a compound of known concentration was added, and the cells were 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 cultured at 37°C for 2 hours.
• PMA phorbol myristate acetate, SIGMA, P1585
• the culture medium was replaced with serum-free RPMI-1640 medium, a compound of known concentration was added, and the cells were cultured at 37°C for 15 minutes.
• LPS Lipopolysaccharide, SIMGA, L2880
• IL-1 ⁇ concentrations were plotted against the logarithm of test compound concentration and IC 50 values were calculated by sigmoidal Emax model nonlinear regression analysis. The results are shown in Tables 1-1 and 1-2. Example compounds were confirmed to suppress IL-1 ⁇ production.
• TNF- ⁇ Production Suppression Test THP-1 cells were added with 50 ng/mL of 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, a compound of known concentration was added, and the cells were cultured at 37°C for 15 minutes. LPS (Lipopolysaccharide, SIMGA, L2880) was added to a final concentration of 50 ng/mL, and cultured at 37°C for 2 hours. Supernatants were collected and the concentration of TNF- ⁇ was measured by ELISA (DuoSet ELISA human TNF- ⁇ , R&D Systems, DY210).
• TNF- ⁇ concentrations were plotted against the logarithm of test compound concentration and IC 50 values were calculated by sigmoidal Emax model nonlinear regression analysis.
• Compounds of formula (I) Examples 27, 31, 59, 73, 75, 108, 131, 132, 141, 164, and 174 were confirmed to exhibit IC 50 values of 10 ⁇ M or greater in this test. .
• BzATP 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt, SIGMA, B6396
• IL-1 ⁇ p17 was quantified by Western blotting using an anti-IL-1 ⁇ antibody (Millipore, AB1832P), and the inhibition rate relative to the solvent-administered group was calculated.
• Table 2 shows the inhibition rate of IL-1 ⁇ p17 for Examples 59, 75, 131, 132, and 164, which are the compounds of formula (I), relative to the solvent-administered group.
• Dose indicates the dose of each test compound
• Ex59, Ex75, Ex131, Ex132, and Ex164 indicate Examples 59, 75, 131, 132, and 164. These compounds were confirmed to exhibit IL-1 ⁇ production inhibitory action.
• Test Example 5 Mouse ex vivo IL-1 ⁇ production test A compound suspended in 0.5% methylcellulose is orally administered to male C57BL/6J mice at an arbitrary dose once or multiple times, and blood is collected after an arbitrary time. . Add LPS to the blood to a final concentration of 50 ng/mL and incubate at 37°C for 3 hours. Then add ATP to a final concentration of 5 mM and incubate at 37°C for 30 minutes. After blood cells are removed by centrifugation, IL-1 ⁇ concentration is measured by ELISA (DuoSet ELISA mouse IL-1 ⁇ , R&D Systems, DY401).
• Test Example 6 In vitro phototoxicity test The in vitro phototoxicity test was evaluated in accordance with ICH S10: Photosafety Evaluation Guideline for Pharmaceuticals (Notification No.0521-1), and the OECD guideline test method described in the OECD report. for testing of chemicals 432: In vitro 3T3 NRU phototoxicity test, 2004. In this test, the compounds of Examples 59, 75, 131, 132, and 164 were found to have no phototoxic effects.
• hERG human Ether-a-go-go Related Gene
• the compound of formula (I) or a salt thereof can be used as a highly safe drug for the prevention and/or treatment of inflammatory diseases or neurodegenerative diseases.
• the compound of formula (I) shown in Table 1 or a salt thereof was shown to suppress IL-1 ⁇ production by Test Example 1, and the compounds of Examples 59, 75, 131, 132, and 164 were: Test Example 3 showed that it also has an IL-1 ⁇ production inhibitory effect in the central nervous system. Furthermore, certain compounds of formula (I) or salts thereof were shown to improve motor function in the ⁇ -synuclein fiber-induced ⁇ -synucleinopathy mouse model described in Test Example 4. . From the above results, the compound of formula (I) or a salt thereof is useful for the prevention and/or treatment of neurodegenerative diseases, particularly ⁇ -synucleinopathies including Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. It is highly expected that it can be used.
• Test Examples 6 and 7 indicated that the compounds of Examples 59, 75, 131, 132, and 164 did not exhibit phototoxicity and had weak hERG channel inhibitory activity. Based on the above results, the compounds of Examples 59, 75, 131, 132, and 164 are strongly expected to be highly safe pharmaceuticals.
• a pharmaceutical composition containing one or more of the compounds of formula (I) or salts thereof as active ingredients can be prepared using excipients commonly used in the art, i.e., excipients for pharmaceuticals and carriers for pharmaceuticals. etc., and can be prepared by a commonly used method.
• Administration is oral administration in tablets, pills, capsules, granules, powders, liquids, etc.; Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, or an inhalant may be used.
• Solid compositions for oral administration include tablets, powders, granules and the like.
• one or more active ingredients are admixed with at least one inert excipient.
• the compositions may contain inert additives such as lubricants, disintegrants, stabilizers and solubilizers in the usual manner. Tablets, powders, granules or pills may, if desired, be coated with wax, sugar coating, or film of gastric or enteric substance.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. or containing ethanol.
• the liquid compositions may contain adjuvants such as solubilizers, wetting agents, suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
• Injections 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 comprise a tonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. They are sterilized by, for example, filtration through a bacteria-retaining filter, formulation with sterilizing agents or irradiation. They can also be used by preparing a sterile solid composition and dissolving or suspending them in sterile water or a sterile solvent for injection before use.
• External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, ophthalmic ointments, and the like. It contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like.
• Transmucosal agents such as inhalants and nasal agents are solid, liquid or semi-solid, and can be produced according to conventionally known methods.
• known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate.
• Administration can use a suitable inhalation or insufflation device.
• known devices such as metered dose inhalation devices and nebulizers are used to administer the compounds either alone or as a powder in 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 may utilize dry powder or powder-containing capsules. Alternatively, it may be in the form of a pressurized aerosol spray or the like using a suitable propellant such as a chlorofluoroalkane or carbon dioxide.
• the daily dose is about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg per body weight. or divided into 2 to 4 doses.
• the appropriate daily dose is about 0.0001 to 10 mg/kg of body weight, administered once or several times a day.
• a transmucosal agent about 0.001 to 100 mg/kg of body weight is administered once to several times a day. The dosage is appropriately determined on a case-by-case basis, taking into consideration symptoms, age, sex, and the like.
• the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, in one embodiment, 0.01 to 50% by weight of the active ingredient. or more compounds of formula (I) or salts thereof.
• 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 combinations may be administered simultaneously or administered separately sequentially or at desired time intervals.
• Co-administered formulations may be combined or formulated separately.
• the method for producing the compound of formula (I) will be described in more detail based on examples.
• the present invention is not limited to the compounds described in the following examples.
• production methods of raw material compounds are shown in production examples.
• the method for producing the compound of formula (I) is not limited only to the production methods of the specific examples shown below, and the compound of formula (I) can be produced by combining these production methods or by those skilled in the art. It can also be produced by methods that are self-evident.
• the onset temperature of the DSC curve obtained by measuring under the following conditions is shown in the table below as the melting point.
• DSC measurement was performed using DSC Q2000 (manufactured by TA Instruments) under the conditions of measurement temperature range: 25 to 300°C, heating rate: 10°C/min, nitrogen flow rate: 50 mL/min, using an aluminum sample pan. The measurement was performed without covering the sample pan.
• Powder X-ray diffraction was performed using Empyrean (manufactured by PANalytical), tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step width: 0.013°, wavelength: 1.5418 ⁇ , measurement diffraction angle range (2 ⁇ ): Measured under conditions of 2.5 to 40 degrees. Due to the nature of powder X-ray diffraction pattern data, crystal lattice spacing and the overall pattern are important in determining the identity of crystals. is usually ⁇ 0.2°, but should not be interpreted strictly because the diffraction angle and diffraction intensity can vary somewhat depending on the direction of crystal growth, particle size and measurement conditions.
• a - (hyphen) in the PSyn and Syn columns in the table below indicates that the manufacturing method is described as a sentence in the item of manufacturing examples or examples.
• the compound marked with "#" indicates that the indicated steric configuration is a relative steric configuration, and other than that, the indicated steric configuration is an absolute steric configuration. Indicates placement.
• concentration mol/L is expressed as M.
• a 1M sodium hydroxide aqueous solution means a 1 mol/L sodium hydroxide aqueous solution.
• mixture B this mixture is referred to as mixture B.
• mixture A and mixture B basic silica gel was added, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give 6-chloro-N-[(3R)-1-cyclopropylpiperidin-3-yl]-5-methyl-1,2,4 -Triazin-3-amine (1.2 g) was obtained as a solid.
• Production example 150 (3R,4R)-3-hydroxy-4-( ⁇ 6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)pyrrolidine
• a mixture of tert-butyl-1-carboxylate (500 mg), 1,4-dioxane (5.0 mL), and 4M hydrogen chloride in 1,4-dioxane (5.0 mL) was stirred at room temperature for 16 hours under a nitrogen atmosphere. did.
• the organic layer was washed with water and saturated aqueous sodium chloride solution in that order, and then dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg ) was obtained as an oil.
• Production example 180 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 A mixture of Pd G3 (1.6 g) and potassium carbonate (7.7 g) was stirred at 100°C for 14 hours under an argon atmosphere.
• Triethylamine 110 ⁇ L
• methyl chloroformate 62 ⁇ L
• 25% aqueous ammonia 0.2 mL
• the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
• Example 1 (1R,2R)-2-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (710 mg), 1,4- A mixture of 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 argon atmosphere, RuPhos Pd G3 (120 mg) was added to the reaction mixture and stirred at 100° C. for 1 hour under microwave irradiation. Water was added and extracted with chloroform.
• Example 27 (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), PdCl2 (dppf) .CH2Cl2 (58 mg) was stirred at 100° C. for 2 hours under microwave irradiation. After allowing the reaction mixture 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). Ethyl acetate and diisopropyl ether were added to the resulting purified product, followed by sonication. The precipitated solid was collected by filtration and treated with 2-(3- ⁇ [(1R,2R)-2-hydroxycyclohexyl]amino ⁇ -5-methyl-1,2,4-triazin-6-yl)-5-(tri Fluoromethoxy)phenol (190 mg) was obtained as a solid.
• Example 31 (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), PdCl2 (dppf) .CH2Cl2 ( 35 mg) The mixture of was stirred at 120° C. for 1 hour under microwave irradiation. Water was added and extracted with chloroform. After concentrating the organic layer under reduced pressure, the resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform/methanol).
• Example 59 (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. After cooling the reaction mixture to room temperature, chloroform and water were added, and the mixture was stirred at room temperature for 5 minutes.
• Example 73 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), PdCl 2 (dppf) CH 2 Cl 2 (31 mg) The mixture was stirred at 100° C. for 2 hours under an argon atmosphere.
• Example 75 (1S,3R)-3-[(6-chloro-5-methyl-1,2,4-triazin-3-yl)amino]cyclohexan-1-ol (120 mg), [2-hydroxy-4-( A mixture of 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 added under an argon atmosphere. Stirred at 100° C. for 2 hours. After allowing the reaction mixture 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). Diisopropyl ether and hexane were added to the purified product and sonicated. The precipitated solid was collected by filtration and treated with 2-(3- ⁇ [(1R,3S)-3-hydroxycyclohexyl]amino ⁇ -5-methyl-1,2,4-triazin-6-yl)-5-(tri Fluoromethyl)phenol (160 mg) was obtained as a solid.
• Example 108 (1s,3s)-3-[(6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino]-1-methylcyclobutan-1-ol (180 mg), [2- A mixture of hydroxy-4-(trifluoromethyl)phenyl]boronic acid (380 mg), RuPhos Pd G3 (53 mg), potassium carbonate (340 mg), 1,4-dioxane (4 mL), water (1 mL) was stirred at 70° C. for 5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate.
• Example 131 (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), A mixture of 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, methanol (3 mL) and 12M hydrochloric acid (2 mL) were added at room temperature, and the mixture was stirred at 60°C for 2 hours. After adding basic silica gel to the reaction mixture, 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 was added to the purified product and sonicated.
• Example 132 [(1R,2R)-2-( ⁇ 6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)cyclohexyl]carbamic acid
• tert-butyl 3 mL
• dichloromethane 7 mL
• trifluoroacetic acid 0.7 mL
• the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
• Example 141 (2S)-2-[( ⁇ 6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)methyl]morpholine-4-
• a mixture of tert-butyl 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 while stirring at room temperature, and the mixture was further stirred at room temperature for 15 hours.
• a saturated aqueous solution of sodium hydrogencarbonate was added dropwise to the reaction mixture under ice-cooling and stirring. After adding methanol, the mixture was extracted with dichloromethane.
• Example 148 [(2R)-1-( ⁇ 6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)propan-2-yl]
• tert-butyl carbamate 140 mg
• dichloromethane 5.0 mL
• 4M hydrogen chloride in 1,4-dioxane (1.0 mL) at 0°C
• Example 149 2-(5-methyl-3- ⁇ [1-(oxan-2-yl)-1H-pyrazol-4-yl]amino ⁇ -1,2,4-triazin-6-yl)-5-(trifluoro
• a mixture of methyl)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 further stirred at room temperature for 2 hours.
• a saturated aqueous solution of sodium hydrogencarbonate was added dropwise to the reaction mixture under ice-cooling and stirring, and the precipitated solid was collected by filtration and washed with water.
• Example 151 1- ⁇ (2S)-2-[( ⁇ 6-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)methyl]pyrrolidine Boron tribromide (17% dichloromethane solution, 1.8 mL) was added dropwise to a mixture of -1-yl ⁇ ethan-1-one (150 mg) and dichloromethane (1.8 mL) while stirring and cooling with ice. The reaction mixture was stirred for 2 hours while allowing the temperature to rise naturally to room temperature. A saturated aqueous sodium hydrogencarbonate solution was added dropwise to the reaction mixture under ice-cooling and stirring, and the mixture was warmed to room temperature and extracted with dichloromethane.
• Example 152 2-(3- ⁇ [(1R,2R)-2-aminocyclohexyl]amino ⁇ -5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (210 mg) and dichloromethane (6 mL) under ice-cooling and stirring, DIPEA (0.2 mL) and acetic anhydride (0.1 mL) were added, and the reaction mixture was stirred for 14 hours while allowing the temperature to rise naturally to room temperature. After concentrating the reaction mixture under reduced pressure, methanol (2 mL), water (0.2 mL) and potassium carbonate (160 mg) were added, and the mixture was stirred at room temperature for 21 hours.
• Example 159 (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), acetyl chloride (0.050 mL) was added at 0°C, and the mixture was stirred at 0°C 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 the mixture was stirred at room temperature for 3 days.
• Example 160 (3R,4R)-4-( ⁇ 6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)pyrrolidin-3-ol
• a mixture of monohydrochloride (250 mg), dichloromethane (5.0 mL), DIPEA (0.18 mL) and methanesulfonyl chloride (0.054 mL) was stirred at room temperature for 3 hours under nitrogen atmosphere.
• Example 161 2-(5-methyl-3- ⁇ [(3R)-pyrrolidin-3-yl]amino ⁇ -1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (120 mg), Sodium triacetoxyborohydride (150 mg) was added to a mixture of 1,4-dioxane-2,5-diol (85 mg), dichloromethane (3 mL), and acetic acid (0.40 mL) under an argon atmosphere, and the mixture was cooled to room temperature. and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform.
• Example 164 To a mixture of [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (4.5 g) and 1,4-dioxane (30 mL) was added 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. was stirred overnight at 100° C. under an argon atmosphere. After cooling to room temperature, water and saturated brine were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate.
• Example 174 6-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-5-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1,2,4-triazine-3- After adding 12M hydrochloric acid (10 mL) to a mixture of amine (5.4 g) and methanol (50 mL) at room temperature, the mixture was stirred at 60°C for 1.5 hours. After ice-cooling the reaction mixture, the mixture was added to saturated aqueous sodium hydrogencarbonate solution (300 mL) and stirred at room temperature for 30 minutes. The resulting mixture was extracted with chloroform and chloroform/methanol (9/1).
• Example 181 2-(5-methyl-3- ⁇ [(3R)-piperidin-3-yl]amino ⁇ -1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (100 mg), Acrylonitrile (28 ⁇ L) was added to a mixture of dichloromethane (1.5 mL) and methanol (0.15 mL) and stirred at room temperature for 6 hours, then acrylonitrile (160 ⁇ L) was added and stirred at room temperature for 26 hours.
• Example 182 (1S,3R)-3-( ⁇ 6-[2-hydroxy-4-(trifluoromethyl)phenyl]-5-methyl-1,2,4-triazin-3-yl ⁇ amino)cyclopentane-1-
• Lithium hydroxide monohydrate (65 mg) was added to a mixture of methyl carboxylate (250 mg), THF (3 mL) and water (1.5 mL), and the mixture was stirred at room temperature for 17 hours.
• 10% Hydrochloric acid was added to the reaction mixture to adjust the pH to 2 to 3, water was added, and the mixture was extracted with ethyl acetate.
• organic layer A was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate (this organic layer is referred to as organic layer A).
• Lithium hydroxide monohydrate (15 mg) was added to a mixture of methyl carboxylate (55 mg), THF (0.7 mL) and water (0.35 mL), and the mixture was stirred at room temperature for 17 hours.
• organic layer B 10% Hydrochloric acid was added to the reaction mixture to adjust the pH to 2 to 3, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate (this organic layer is referred to as organic layer B).
• Example 184 2-(3- ⁇ [(1R,2R)-2-hydroxycyclohexyl]amino ⁇ -5-methyl-1,2,4-triazin-6-yl)-5-methoxyphenol (200 mg) and ethanol (1 mL), 4M hydrogen chloride ethyl acetate solution (0.23 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate (2 mL) was added to the resulting residue, and the mixture was stirred at 50°C for 48 hours.
• Example 185 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), 4M hydrogen chloride in 1,4-dioxane (0.082 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 2-butanone (2 mL) was added to the resulting residue, and the mixture was stirred at 50°C for 72 hours.
• Example 186 5-(difluoromethoxy)-2-(3- ⁇ [(1R,2R)-2-hydroxycyclohexyl]amino ⁇ -5-methyl-1,2,4-triazin-6-yl)phenol (200 mg) and A 4M hydrogen chloride ethyl acetate solution (0.2 mL) was added to a mixture of ethanol (1 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate (2 mL) was added to the resulting residue, and the mixture was stirred at 50°C for 48 hours.
• Example 187 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 ethyl acetate solution (0.34 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate (2 mL) was added to the residue, and the mixture was stirred at 50°C for 48 hours.
• Example 188 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), 4M hydrogen chloride 1,4-dioxane solution (1.4 mL) and ethyl acetate (3 mL) were added, and the mixture was stirred at room temperature for 2 hours. After adding ethyl acetate to the reaction mixture, the precipitated solid was collected by filtration and dried to obtain a crude product (880 mg) as a solid.
• the compound of formula (I) or a salt thereof has an inhibitory effect on NLRP3 inflammasome activation, and is expected to be used as a prophylactic and/or therapeutic drug for inflammatory diseases and/or neurodegenerative diseases.

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