Annulated pyridazine 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 inventors of the present invention conducted extensive studies to find a compound that has an inhibiting action on NLRP3 inflammasome activation, and found that an annulated pyridazine compound has an inhibiting action on NLRP3 inflammasome activation, leading to the achievement of the present invention. The annulated pyridazine compound according to the present invention is expected to serve as a drug for preventing and / or treating inflammatory diseases and / or a neurodegenerative diseases.

Description

Fused Pyridazine Compounds

[0001] The present invention relates to a fused-ring pyridazine compound or a salt thereof that has an inhibitory effect on NLRP3 inflammasome activation and is expected to be useful as an active ingredient in pharmaceutical compositions, for example, pharmaceutical compositions for the prevention and / or treatment of inflammatory diseases and / 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 an inhibitory effect on the NLRP3 inflammasome pathway (R 3 , R 4 H, cyano, C 1-4 Alkyl or halogeno C 1-4 (For other symbols in the formula, see the publication.)

[0006]

[0007] Patent Document 2, 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 2 for the symbols in the formula):

[0008]

[0009] Patent Document 3, which was published after the priority date of the present application, describes that a compound represented by the following formula has an NLRP3 inhibitory activity (see Patent Document 3 for symbols in the formula):

[0010]

[0011] Patent Document 4 describes that a compound represented by the following formula has an NLRP3 inhibitory effect (see the publication for symbols in the formula).

[0012]

[0013] Patent Document 5 describes that a compound represented by the following formula has an NLRP1 / 3 regulating activity (see the publication for symbols in the formula).

[0014]

[0015] Patent Document 6 describes that a compound represented by the following formula has an NLRP3 inflammasome inhibitory effect (see the publication for symbols in the formula).

[0016]

[0017] Patent Document 7 describes that a compound represented by the following formula has a C5a receptor inhibitory effect (see the publication for symbols in the formula).

[0018]

[0019] Patent Document 8 describes that a compound represented by the following formula has an inhibitory effect on the Hedgehog signal pathway (see the publication for symbols in the formula).

[0020]

[0021] Patent Document 9 describes that a compound represented by the following formula has an inhibitory effect on the Hedgehog signal pathway (see the publication for symbols in the formula).

[0022]

[0023] Patent Document 10 describes that the compound represented by the following formula has muscarinic M4 receptor antagonist activity (see the publication for symbols in the formula).

[0024]

[0025] International Publication No. WO 2020 / 234715 International Publication No. WO 2021 / 193897 U.S. Patent No. 1,1319319 International Publication No. WO 2019 / 008025 International Publication No. WO 2017 / 184604 International Publication No. WO 2018 / 015445 International Publication No. WO 2006 / 004589 International Publication No. WO 2014 / 191737 International Publication No. WO 2015 / 001348 International Publication No. WO 2021 / 067696

[0026] 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 and / or neurodegenerative diseases, etc.

[0027] As a result of extensive research into compounds that have the effect of inhibiting NLRP3 inflammasome activation, the inventors discovered that fused-ring pyridazine compounds have the effect of inhibiting NLRP3 inflammasome activation and are expected to be useful as active ingredients in pharmaceutical compositions for the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases, etc., and thus completed the present invention.

[0028] 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.

[0029] (Wherein, ring A is C 5-8 cycloalkenyl, 5- to 11-membered partially unsaturated heterocyclyl, aryl, or heteroaryl, and R 1 are the same or different and are OH, C 1-6 Alkyl, halogeno C1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 is cycloalkyl, and R 2 are the same or different, C 1-6 Alkyl, -C 1-6 Alkylene-aryl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 alkyl, and L is -NR 3 -, -O- or -CR 4 R 5 - and R 3 is H or C 1-6 alkyl, and R 4 and R 5 are the same or different and are H or C 1-6 is alkyl, and R 6 is 1 to 4 identical or different R 7 C is replaced by 1-6 Alkyl, -C 1-6 alkylene-(1 to 4 identical or different R 8 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 11 R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 7 HA-OR 12 , -NR 13 R 14 , halogen, or cyano; R 8 and R 10 is C 1-6 Alkyl, halogeno C1-6 Alkyl, C 3-8 Cycloalkyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C 1-6 Alkylene-NR 13 R 14 , halogen, or cyano; R 9 and R 11 is C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C 1-6 Alkylene-NR 13 R 14 , halogen, cyano, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 is alkyl, and R 12 is H or C 1-6 is alkyl, and R 13 and R 14 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 m is an integer of 0 to 3, and R 2 where, when ring A is aryl or heteroaryl, formula (I) is formula (Ia),

[0030] R 1a are the same or different, C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 cycloalkyl, k is an integer from 0 to 3, and the substituent R1a Represents the number of

[0031] 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.

[0032] The present invention also relates to a pharmaceutical composition, particularly a pharmaceutical composition for preventing and / or treating inflammatory diseases and / or neurodegenerative diseases, 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 inflammatory diseases and / or neurodegenerative diseases, containing a compound of formula (I) or a salt thereof.

[0033] 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.

[0034] 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.

[0035] The present invention will be described in detail below.

[0036] As used herein, the following terms have the meanings indicated below unless otherwise specified. The definitions below are intended to clarify, but not limit, the defined terms. If a term is not specifically defined herein, it is used in the sense generally accepted by those skilled in the art.

[0037] 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 1-6 and the like. In one embodiment, the saturated hydrocarbon group is a straight-chain or branched C 1-4 It is an alkyl group, and in one embodiment it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, in another embodiment it is methyl, ethyl, n-propyl, n-butyl, or isobutyl, and in a further embodiment it is n-propyl, n-butyl, or isobutyl, in another embodiment it is methyl, ethyl, n-propyl, or isopropyl, in another embodiment it is methyl or ethyl, in another embodiment it is ethyl, and in a further embodiment it is methyl.

[0038] "C 1-6 "Alkylene" means a straight or branched C 1-6 and is a divalent saturated hydrocarbon group represented by the formula: methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, 2-methyltrimethylene, ethylethylene, 1,2-dimethylethylene, or 1,1,2,2-tetramethylethylene. 1-4It 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.

[0039] "C 3-8 "Cycloalkyl" means C 3-8 It is a saturated hydrocarbon ring group of the formula (I), which may have a bridge or may form a spiro ring. For example, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[3.3.0]octyl, bicyclo[2.2.2]octyl, spiro[2.2]pentyl, spiro[3.3]heptyl, or spiro[2.5]octyl. In one embodiment, it is C 3-6 and in one embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[1.1.1]pentyl, in another embodiment, it is cyclopropyl, in another embodiment, it is cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[1.1.1]pentyl, in another embodiment, it is cyclobutyl, cyclopentyl, or cyclohexyl, in another embodiment, it is cyclobutyl or cyclohexyl, in another embodiment, it is cyclobutyl, in another embodiment, it is cyclopentyl, and in still another embodiment, it is cyclohexyl.

[0040] "C 5-8 "Cycloalkenyl" means a C 5-8and optionally has a bridge. Examples include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octenyl. In one embodiment, it is cyclopentenyl, cyclohexenyl, cycloheptenyl, or bicyclo[2.2.2]octenyl, and in another embodiment, it is cyclopentenyl, cyclohexenyl, or cycloheptenyl, and in yet another embodiment, it is cyclopentenyl, and in another embodiment, it is cyclohexenyl, and in yet another embodiment, it is cycloheptenyl.

[0041] Ring A is C 5-8 When it is cycloalkenyl, it is a partial structure of formula (I) and formula (Ia)

[0042] (The wavy lines represent the phenyl group and the bond to L in formula (I), respectively. The same applies hereinafter.) 5-8 The cycloalkenyl is fused to the pyridazine ring at the double bond to form, for example, but not limited to, the following partial structure:

[0043]

[0044] The term "4- to 7-membered saturated heterocyclyl" refers to a 4- to 7-membered saturated hydrocarbon ring group containing one or more heteroatoms, particularly oxygen, nitrogen, or sulfur atoms, as ring-constituting atoms, such as, but not limited to, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, oxepanyl, azepanyl, thiepanyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dithiolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxanyl, piperazinyl, dithianyl, morpholinyl, thiomorpholinyl, oxathiaranyl, dioxepanyl, diazepanyl, dithiepanyl, oxazepanyl, thieazepanyl, and oxathiepanyl. In one embodiment, it is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, or tetrahydrothiopyranyl, in another embodiment, it is tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, in a further embodiment, it is pyrrolidinyl, tetrahydropyranyl, or piperidinyl, in a further embodiment, it is tetrahydropyranyl or piperidinyl, in a further embodiment, it is tetrahydrofuranyl or tetrahydropyranyl, in a further embodiment, it is tetrahydrofuranyl, and in a further embodiment, it is tetrahydropyranyl. In another embodiment, it is pyrrolidinyl or piperidinyl, in a further embodiment, it is pyrrolidinyl, and in a further embodiment, it is piperidinyl. In yet another embodiment, it is oxetanyl.

[0045] The term "5- to 11-membered partially unsaturated heterocyclyl" refers to a 5- to 11-membered hydrocarbon ring group containing one or more heteroatoms, particularly oxygen, nitrogen, or sulfur atoms, as ring-constituting atoms and having one double bond in the molecule, which may have a bridge or form a spiro ring. Examples include dihydrofuranyl, dihydropyrrolyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridyl, dihydrothiopyranyl, tetrahydrooxepinyl, tetrahydroazepinyl, tetrahydrothiepinyl, tetrahydrooxocinyl, hexahydroazocinyl, tetrahydrothiocinyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dithiolyl, dihydrooxazolyl, dihydroisoxazolyl, dihydrothiazolyl, and dihydroisothiazolyl. Examples include, but are not limited to, zolyl, dihydrodioxinyl, tetrahydropyrazinyl, dihydrodithiinyl, dihydrooxazinyl, dihydrothiazinyl, dihydrooxathiinyl, dihydrodioxepinyl, tetrahydrodiazepinyl, dihydrodithiepinyl, tetrahydrooxazepinyl, tetrahydrothiazepinyl, dihydrooxathiepinyl, 2-oxaspiro[3.5]nonenyl, 2-oxaspiro[4.5]decenyl, and 3-oxaspiro[5.5]undecenyl. In some embodiments, the aryl group is dihydrofuranyl, dihydropyrrolyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridyl, dihydrothiopyranyl, tetrahydrooxepinyl, or 2-oxaspiro[3.5]nonenyl.In one embodiment, it is a 5- to 8-membered partially unsaturated heterocyclyl, and in one embodiment, it is dihydrofuranyl, dihydropyrrolyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridyl, dihydrothiopyranyl, tetrahydrooxepinyl, tetrahydroazepinyl, tetrahydrothiepinyl, tetrahydrooxocinyl, hexahydroazocinyl, tetrahydrothiocinyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dithiolyl, dihydrooxazolyl, dihydroisoxazolyl, dihydrothiazolyl, dihydroisothiazolyl dihydropyrrolyl, dihydropyranyl, tetrahydropyridyl, tetrahydrooxepinyl, dihydrothiazinyl, dihydrooxathiinyl, dihydrodioxepinyl, tetrahydrodiazepinyl, dihydrodithiepinyl, tetrahydrooxazepinyl, tetrahydrothiazepinyl, dihydrooxathiepinyl, in one embodiment, dihydropyrrolyl, dihydropyranyl, tetrahydropyridyl, tetrahydrooxepinyl, in a further embodiment, dihydropyranyl, tetrahydropyridyl, tetrahydrooxepinyl, in another embodiment, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridyl, tetrahydrooxepinyl, in another embodiment, dihydrofuranyl, dihydropyranyl, tetrahydrooxepinyl, or 2-oxaspiro[3.5]nonenyl, in another embodiment, dihydropyranyl, in yet another embodiment, tetrahydropyridyl, and in still another embodiment, tetrahydrooxepinyl.

[0046] When ring A is a 5- to 11-membered partially unsaturated heterocyclyl, it is a partial structure of formula (I) and formula (Ia)

[0047] In the formula, the 5- to 11-membered partially unsaturated heterocyclyl is fused to a pyridazine ring at the double bond to form, for example, but not limited to, the following partial structure:

[0048]

[0049] "Aryl" means C 6-14 is a monocyclic to tricyclic aromatic hydrocarbon ring group of C 5-8It includes bicyclic to tricyclic aromatic hydrocarbon ring groups fused with cycloalkene at the double bond thereof, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, fluorenyl, etc., and in one embodiment, phenyl.

[0050] When ring A is aryl, it is a partial structure of formula (I) and formula (Ia)

[0051] In the formula, the aryl has a benzene ring fused with a pyridazine ring to form, for example, but not limited to, the following partial structure:

[0052]

[0053] "Heteroaryl" refers to a 5- to 6-membered aromatic hydrocarbon 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and tetrazinyl. In one embodiment, it is thienyl or pyridyl, in another embodiment, it is pyridyl, and in another embodiment, it is thienyl.

[0054] When ring A is heteroaryl, it is a partial structure of formula (I) and formula (Ia)

[0055] In the formula (I), the heteroaryl is fused with a pyridazine ring to form, for example, but not limited to, the following partial structure:

[0056]

[0057] "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.

[0058] "Halogeno C 1-6 "Alkyl" means a straight or branched C alkyl group substituted with one or more halogen atoms. 1-6It is an alkyl group. Examples include trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-fluoro-2-methylpropyl, difluoromethyl, difluoroethyl, fluoromethyl, and chloromethyl. In one embodiment, it is difluoroethyl, trifluoromethyl, or difluoromethyl, in another embodiment, it is trifluoromethyl or difluoromethyl, in yet another embodiment, it is trifluoromethyl, and in another embodiment, it is difluoromethyl.

[0059] 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.

[0060] One or more embodiments may be combined with other embodiments, even if such combinations are not specifically recited.

[0061] As used herein, one embodiment of "inflammatory disease and / or neurodegenerative disease" is an inflammatory disease and a neurodegenerative disease, and another embodiment is an inflammatory disease and another embodiment is a neurodegenerative disease.

[0062] 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, in another embodiment, CAPS, and in yet another embodiment, gout. 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).

[0063] 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.

[0064] As used herein, "treatment" includes both "therapeutic treatment" and "prophylactic treatment." "Therapeutic treatment" means alleviating symptoms, altering the course of a disease, extending lifespan, etc., while "prophylactic treatment" means reducing the likelihood of developing a disease in a subject at risk of developing the disease. A "subject at risk of developing a disease" refers to an individual with known risk factors who is more likely to develop a disease than the general population.

[0065] Some embodiments of the compound of formula (I) or a salt thereof in the present invention are shown below: (1-1) A compound of formula (I) or a salt thereof (n and m are each a substituent R 1 , R 2 Represents the number of. Same below.).

[0066]

[0067] However, when ring A is aryl or heteroaryl, formula (I) is formula (Ia) (k is a substituent R 1a Represents the number of. Same below.).

[0068] (1-2) A compound of formula (Ia) or a salt thereof. (1-3) A compound of formula (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix) or (Iy) or a salt thereof.

[0069] (1-4) A compound of formula (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Is), (It), (Iu), (Iv), (Iw), (Ix) or (Iy) or a salt thereof. (1-5) A compound of formula (Ib), (Ic), (Id), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Is), (It), (Iv), (Iw), (Ix) or (Iy) or a salt thereof. (1-6) A compound of formula (Ic), (Ih), (Ij), (Im), (Ix) or (Iy) or a salt thereof. (1-7) A compound of formula (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq) or (Ir) or a salt thereof. (1-8) A compound of formula (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im) or (In) or a salt thereof. (1-9) A compound of formula (Ib), (Ic), (Id) or (Ie) or a salt thereof. (1-10) A compound of formula (Ib) or a salt thereof. (1-11) A compound of formula (Ic) or a salt thereof. (1-12) A compound of formula (Id) or a salt thereof. (1-13) A compound of formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im) or (In) or a salt thereof. (1-14) A compound of formula (If), (Ig), (Ih), (Ii) or (Ij) or a salt thereof. (1-15) A compound of formula (Ig), (Ih) or (Ij) or a salt thereof. (1-16) A compound of formula (Ig) or a salt thereof. (1-17) A compound of formula (Ih) or a salt thereof. (1-18) A compound of formula (Ij) or a salt thereof. (1-19) A compound of formula (Ik), (Im) or (In) or a salt thereof. (1-20) A compound of formula (Ik) or a salt thereof. (1-21) A compound of formula (Im) or a salt thereof. (1-22) A compound of formula (In) or a salt thereof. (1-23) A compound of formula (Io), (Ip), (Iq) or (Ir) or a salt thereof. (1-24) A compound of formula (Io) or a salt thereof. (1-25) A compound of formula (Ip) or a salt thereof. (1-26) A compound of formula (Iq) or a salt thereof. (1-27) A compound of formula (Ir) or a salt thereof.(1-28) A compound of formula (Ic), (Ig), (Ih), (Ij) or (Im) or a salt thereof. (1-29) A compound of formula (Ic), (Ih), (Ij) or (Im) or a salt thereof. (1-30) A compound of formula (Ic) or formula (Ih) or a salt thereof. (1-31) A compound of formula (Ix) or a salt thereof. (1-32) A compound of formula (Iy) or a salt thereof. (1-33) A compound of formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Is), (It), (Iu), (Iv), (Iw), (Ix) or (Iy) or a salt thereof. (1-34) A compound of the formula (If), (Ig), (Ih), (Ii), (Ij), (Iu), (Iv), (Iw), or (Iy) or a salt thereof. (1-35) A compound of the formula (Ih), (Ij), (Im), (Ix), or (Iy) or a salt thereof. (1-36) A compound of the formula (If), (Ig), (Ih), (Ii), (Ij), (Iv), (Iw), or (Iy) or a salt thereof.

[0070] (2-1) Ring A is C 5-8 A compound or a salt thereof which is a cycloalkenyl, a 5- to 11-membered partially unsaturated heterocyclyl, an aryl, or a heteroaryl, provided that when ring A is an aryl or heteroaryl, formula (I) is formula (Ia) and R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 (2-2) Ring A is C 5-8 A compound or a salt thereof which is a cycloalkenyl, a 5- to 8-membered partially unsaturated heterocyclyl, an aryl, or a heteroaryl, provided that when ring A is an aryl or heteroaryl, formula (I) is formula (Ia) and R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6Alkyl or -OC 3-8 (2-3) Ring A is C 5-8 (2-4) A compound or a salt thereof in which ring A is C 5-8 (2-5) A compound or a salt thereof wherein ring A is a 5- to 8-membered partially unsaturated heterocyclyl. (2-6) A compound or a salt thereof wherein ring A is C 5-8 A compound or a salt thereof which is a cycloalkenyl, a 5- to 11-membered partially unsaturated heterocyclyl, an aryl, or a heteroaryl, provided that when ring A is an aryl or heteroaryl, formula (I) is formula (Ia) and R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl or -O-halogenoC 1-6 alkyl, and k is an integer of 0 to 2. (2-7) Ring A is C 5-8 (2-8) A compound or a salt thereof, wherein ring A is aryl or heteroaryl, provided that formula (I) is formula (Ia) and R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 (2-9) A compound or a salt thereof, wherein ring A is aryl, provided that formula (I) is formula (Ia) and R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8(2-10) A compound or a salt thereof, wherein ring A is heteroaryl, provided that formula (I) is formula (Ia) and R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 cycloalkyl, and k is an integer of 0 to 3. (2-11) A compound or a salt thereof, wherein ring A is a 5- to 11-membered partially unsaturated heterocyclyl.

[0071] (3-1) R 1 are the same or different, and OH, C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 1 are the same or different, and OH, 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, wherein the compound is alkyl.

[0072] (4-1) R 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, cyano, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl or -OC 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 1a are the same or different, and C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8Cycloalkyl, halogen, -OC 1-6 Alkyl or -O-halogenoC 1-6 A compound or a salt thereof in which R is alkyl. 1a are the same or different and are halogen C 1-6 Alkyl, halogen, or -O-halogenoC 1-6 A compound or a salt thereof in which 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. 1a -O-halogenoC 1-6 A compound or a salt thereof, wherein R is alkyl. 1a C 1-6 A compound or a salt thereof, wherein R is alkyl. 1a C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 1a Ga-OC 1-6 A compound or a salt thereof, wherein the compound is alkyl.

[0073] (5-1) R 2 are the same or different, and C 1-6 Alkyl, -C 1-6 Alkylene-aryl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 (5-2) R is a compound or a salt thereof 2 are the same or different, and C 1-6 Alkyl, -C 1-6 Alkylene-aryl, C 3-8 Cycloalkyl, halogen, -OC 1-6 Alkyl, -O-halogenoC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof in which R is alkyl. 2 are the same or different, and C 1-6 Alkyl, -C1-6 Alkylene-aryl, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof in which R is alkyl. 2 are the same or different, and C 1-6 Alkyl, -C 1-6 Alkylene-aryl, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 are the same or different, and C 1-6 Alkyl, oxo, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 are the same or different, and C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, or -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 -S(O)2-C 1-6 A compound or a salt thereof, wherein R is alkyl. 2 is oxo or a salt thereof.

[0074] (6-1) L is -NR 3 -, -O- or -CR 4 R 5 (6-2) A compound or a salt thereof wherein L is -NR 3 (6-3) A compound or a salt thereof in which L is -NR 3 - or a salt thereof. (6-4) A compound or a salt thereof wherein L is -O-. (6-5) A compound or a salt thereof wherein L is -CR 4 R 5 - or a salt thereof.

[0075] (7-1) R 3 is H or C 1-6A compound or a salt thereof in which R is alkyl. 3 is H or a salt thereof. (7-3) R 3 C 1-6 A compound or a salt thereof, wherein the compound is alkyl.

[0076] (8-1) R 4 and R 5 are the same or different and are H or C 1-6 A compound or a salt thereof in which R is alkyl. 4 and R 5 A compound or a salt thereof in which both R 4 and R 5 Both are C 1-6 A compound or a salt thereof, wherein the compound is alkyl.

[0077] (9-1) R 6 1 to 4 identical or different R 7 C is replaced by 1-6 Alkyl, -C 1-6 alkylene-(1 to 4 identical or different R 8 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 11 (9-2) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 Ga-C 1-6 alkylene-(1 to 4 identical or different R 8 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 R11 (9-3) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 There is one R 7 C is replaced by 1-6 Alkyl, -C 1-6 Alkylene-(one R 8 C optionally substituted with 3-8 cycloalkyl), -C 1-6 alkylene-(4- to 7-membered saturated heterocyclyl), one to two identical or different R 10 C optionally substituted with 3-8 Cycloalkyl, or one to two identical or different R 11 (9-4) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 1 to 4 identical or different R 10 C optionally substituted with 3-8 Cycloalkyl, or 1 to 4 identical or different R 11 (9-5) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 1 to 4 identical or different R 7 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 6 One to three identical or different R 7 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 6 One or two identical or different R 7 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 6 There is one R 7 C is replaced by 1-6 A compound or a salt thereof, wherein R is alkyl. 6 Ga-C 1-6 alkylene-(1 to 4 identical or different R 8 C optionally substituted with 3-8 (9-10) R 6 Ga-C1-6 alkylene-(1 to 3 identical or different R 8 C optionally substituted with 3-8 (9-11) R 6 Ga-C 1-6 alkylene-(1 to 2 identical or different R 8 C optionally substituted with 3-8 (9-12) R 6 Ga-C 1-6 Alkylene-(one R 8 C optionally substituted with 3-8 (9-13) R 6 Ga-C 1-6 Alkylene-C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 6 Ga-C 1-6 alkylene-(1 to 4 identical or different R 9 (9-15) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 Ga-C 1-6 alkylene-(1 to 3 identical or different R 9 (9-16) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 Ga-C 1-6 alkylene-(1 to 2 identical or different R 9 (9-17) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 Ga-C 1-6 Alkylene-(one R 9 (9-18) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 Ga-C 1-6 A compound or a salt thereof, which is alkylene-(4- to 7-membered saturated heterocyclyl). (9-19) R 6 1 to 4 identical or different R 10 C optionally substituted with 3-8A compound or a salt thereof, wherein R is cycloalkyl. 6 One to three identical or different R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 6 One or two identical or different R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 6 There is one R 10 C optionally substituted with 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 6 C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 6 1 to 4 identical or different R 11 (9-25) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 One to three identical or different R 11 (9-26) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 One or two identical or different R 11 (9-27) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 There is one R 11 (9-28) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 is a 4- to 7-membered saturated heterocyclyl or a salt thereof. 6 There is one R 7 C is replaced by 1-6 Alkyl, 1 to 2 identical or different R 10 C optionally substituted with 3-8 Cycloalkyl, or one to two identical or different R 11 (9-30) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 One or two identical or different R 10C optionally substituted with 3-8 Cycloalkyl, or one to two identical or different R 11 (9-31) R is a 4- to 7-membered saturated heterocyclyl optionally substituted by 6 There is one R 10 C optionally substituted with 3-8 cycloalkyl or one R 11 or a salt thereof.

[0078] (10-1) R 7 -OR 12 , -NR 13 R 14 , halogen, or cyano, or a salt thereof. 7 -OR 12 , or -NR 13 R 14 A compound or a salt thereof represented by the formula (10-3) R 7 -OR 12 A compound or a salt thereof represented by the formula (10-4)R 7 Ga-NR 13 R 14 A compound or a salt thereof represented by the formula (10-5) R 7 is a halogen atom or a salt thereof. 7 is cyano or a salt thereof.

[0079] (11-1) R 8 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C 1-6 Alkylene-NR 13 R 14 , halogen, or cyano, or a salt thereof. 8 -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C1-6 Alkylene-NR 13 R 14 A compound or a salt thereof, wherein (11-3)R 8 C 1-6 Alkyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , halogen, or cyano, or a salt thereof. 8 -OR 12 , -C 1-6 Alkylene-OR 12 A compound or a salt thereof represented by the formula (11-5) R 8 -OR 12 A compound or a salt thereof, wherein (11-6)R 8 Ga-C 1-6 Alkylene-OR 12 or a salt thereof.

[0080] (12-1) R 9 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C 1-6 Alkylene-NR 13 R 14 , 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, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , oxo, or -C(O)-C 1-6 A compound or a salt thereof, wherein the compound is alkyl.

[0081] (13-1) R 10 C 1-6 Alkyl, halogeno C 1-6Alkyl, C 3-8 Cycloalkyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C 1-6 Alkylene-NR 13 R 14 , halogen, or cyano, or a salt thereof. 10 C 1-6 Alkyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , halogen, or cyano, or a salt thereof. 10 C 1-6 Alkyl or -OR 12 A compound or a salt thereof represented by the formula (13-4) R 10 C 1-6 A compound or a salt thereof, wherein R is alkyl. 10 -OR 12 A compound or a salt thereof represented by the formula (13-6)R 10 Ga-NR 13 R 14 A compound or a salt thereof, (13-7)R 10 Ga-C 1-6 Alkylene-OR 12 A compound or a salt thereof represented by the formula (13-8)R 10 is a halogen or a salt thereof. 10 is cyano or a salt thereof. 10 C 1-6 Alkyl, -OR 12 , -NR 13 R 14 or cyano, or a salt thereof. 10 C 1-6 Alkyl, -OR 12 or cyano, or a salt thereof. 10 C 1-6 Alkyl, -OR 12 , -NR 13 R 14 , -C 1-6Alkylene-OR 12 or cyano, or a salt thereof.

[0082] (14-1) R 11 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , -NR 13 R 14 , -C 1-6 Alkylene-OR 12 , -C 1-6 Alkylene-NR 13 R 14 , 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. 11 C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , oxo, or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 11 C 1-6 A compound or a salt thereof, wherein R is alkyl. 11 C 3-8 A compound or a salt thereof, wherein R is cycloalkyl. 11 (14-6) R is a 4- to 7-membered saturated heterocyclyl or a salt thereof. 11 -OR 12 A compound or a salt thereof represented by the formula (14-7)R 11 is oxo or a salt thereof. 11 -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 11 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , oxo, or -C(O)-C 1-6 A compound or a salt thereof, wherein R is alkyl. 11 C1-6 Alkyl or -OR 12 A compound or a salt thereof, (14-11)R 11 C 1-6 Alkyl, halogeno C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 12 , or -C(O)-C 1-6 A compound or a salt thereof, wherein the compound is alkyl.

[0083] (15-1) R 12 is H or C 1-6 A compound or a salt thereof, wherein R is alkyl. 12 is H or a salt thereof. (15-3) R 12 C 1-6 A compound or a salt thereof, wherein the compound is alkyl.

[0084] (16-1) R 13 and R 14 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. 13 and R 14 are the same or different and are H or C 1-6 A compound or a salt thereof, wherein R is alkyl. 13 and R 14 A compound or a salt thereof in which both R 13 and R 14 are both H, or R 13 -C(O)-C 1-6 alkyl, and R 14 is H or a salt thereof. (16-5) R 13 -C(O)-C 1-6 alkyl, and R 14 is H or a salt thereof.

[0085] (17-1) A compound or a salt thereof wherein n is an integer from 1 to 4. (17-2) A compound or a salt thereof wherein n is an integer from 1 to 3. (17-3) A compound or a salt thereof wherein n is 1 or 2. (17-4) A compound or a salt thereof wherein n is 2. (17-5) A compound or a salt thereof wherein n is 1.

[0086] (18-1) A compound or a salt thereof wherein m is an integer of 0 to 3. (18-2) A compound or a salt thereof wherein m is an integer of 0 to 2. (18-3) A compound or a salt thereof wherein m is 0 or 1. (18-4) A compound or a salt thereof wherein m is 1. (18-5) A compound or a salt thereof wherein m is 0.

[0087] (19-1) A compound or a salt thereof, wherein k is an integer from 0 to 3. (19-2) A compound or a salt thereof, wherein k is an integer from 0 to 2. (19-3) A compound or a salt thereof, wherein k is 0 or 1. (19-4) A compound or a salt thereof, wherein k is 1. (19-5) A compound or a salt thereof, wherein k is 0. (19-6) A compound or a salt thereof, wherein k is 1 or 2.

[0088] (20) A compound or a salt thereof which is a combination of two or more of the embodiments of the groups described in the above (1-1) to (19-6) 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 above (1-1), (2-2), (3-1), (4-1), (5-2), (6-1), (7-1), (8-1), (9-1), (10-1), (11-1), (12-1), (13-1), (14-1), (15-1), (16-1), (17-1), (18-1), and (19-1). (20-2) A compound or a salt thereof which is a combination of the above (1-2), (2-2), (4-1), (5-2), (6-1), (7-1), (8-1), (9-1), (10-1), (11-1), (12-1), (13-1), (14-1), (15-1), (16-1), (18-1), and (19-1). (20-3) A compound or a salt thereof which is a combination of the above (1-2), (2-3), (4-1), (5-2), (6-1), (7-1), (8-1), (9-1), (10-1), (11-1), (12-1), (13-1), (14-1), (15-1), (16-1), (18-1), and (19-1). (20-4) A compound or a salt thereof which is a combination of the above (1-2), (2-6), (4-2), (5-5), (6-1), (7-2), (8-2), (9-3), (10-2), (11-3), (12-2), (13-2), (14-9), (15-2), (16-4), (18-2), and (19-2). (20-5) A compound or a salt thereof which is a combination of the above (1-2), (2-7), (4-2), (5-5), (6-3), (7-2), (9-29), (10-2), (13-2), (14-9), (15-2), (16-4), (18-2), and (19-2). (20-6) A compound or a salt thereof which is a combination of the above (1-2), (2-3), (4-3), (5-7), (6-3), (7-2), (9-30), (13-3), (14-10), (15-2), (18-3), and (19-6).(20-7) A compound or a salt thereof which is a combination of the above (1-2), (2-11), (4-2), (5-5), (6-3), (7-2), (9-29), (10-2), (13-2), (14-9), (15-2), (16-4), (18-2), and (19-2). (20-8) A compound or a salt thereof which is a combination of the above (1-34), (4-2), (5-5), (6-3), (7-2), (9-29), (10-2), (13-2), (14-10), (15-2), (16-4), (18-5), and (19-2). (20-9) A compound or a salt thereof which is a combination of the above (1-17), (4-2), (6-3), (7-2), (9-29), (10-2), (13-11), (14-10), (15-2), (16-5), (18-5), and (19-2). (20-10) A compound or a salt thereof which is a combination of the above (1-6), (4-3), (5-7), (6-3), (7-2), (9-31), (13-5), (14-3), (15-2), (18-3), and (19-4). (20-11) A compound or a salt thereof which is a combination of the above (1-35), (4-3), (5-7), (6-3), (7-2), (9-31), (13-5), (14-3), (15-2), (18-3), and (19-4). (20-12) A compound or a salt thereof which is a combination of the above (1-7), (4-2), (5-4), (6-1), (7-2), (8-2), (9-3), (10-2), (11-4), (13-2), (14-2), (15-2), (16-4), (18-3), and (19-2). (20-13) A compound or a salt thereof which is a combination of the above (1-28), (4-3), (5-7), (6-3), (7-2), (9-22), (13-5), (15-2), (18-3), and (19-4). (20-14) A compound or a salt thereof which is a combination of the above (1-11), (4-4), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-15) A compound or a salt thereof which is a combination of the above (1-17), (4-4), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4).(20-16) A compound or a salt thereof which is a combination of the above (1-17), (4-6), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-17) A compound or a salt thereof which is a combination of the above (1-11), (4-6), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-18) A compound or a salt thereof which is a combination of the above (1-21), (4-4), (5-7), (6-3), (7-2), (9-22), (13-5), (15-2), (18-4), and (19-4). (20-19) A compound or a salt thereof which is a combination of the above (1-18), (4-4), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-20) A compound or a salt thereof which is a combination of the above (1-17), (4-5), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-21) A compound or a salt thereof which is a combination of the above (1-16), (4-4), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-22) A compound or a salt thereof which is a combination of the above (1-16), (4-6), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-23) A compound or a salt thereof which is a combination of the above (1-16), (4-5), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-24) A compound or a salt thereof which is a combination of the above (1-31), (4-4), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-25) A compound or a salt thereof which is a combination of the above (1-32), (4-4), (6-3), (7-2), (9-22), (13-5), (15-2), (18-5), and (19-4). (20-26) A compound or a salt thereof which is a combination of the above (1-17), (4-6), (6-3), (7-2), (9-27), (14-3), (18-5), and (19-4).

[0089] Examples of specific compounds encompassed by the present invention include compounds selected from the following group or salts thereof: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)phenol, 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(Difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, and 5-(difluoromethyl)-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)phenol.

[0090] Furthermore, certain embodiments of specific compounds encompassed by the present invention include compounds selected from the following group or salts thereof: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)phenol, and 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol.

[0091] Furthermore, certain embodiments of specific compounds encompassed by the present invention include compounds selected from the following group or salts thereof: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-(Difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(Difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, and 5-(Difluoromethyl)-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)phenol.

[0092] Furthermore, certain embodiments of specific compounds encompassed by the present invention include compounds selected from the following group or salts thereof: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(Difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, and 5-(Difluoromethyl)-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)phenol.

[0093] Furthermore, certain embodiments of specific compounds encompassed by the present invention include compounds selected from the following group or salts thereof: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, and 5-(difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol.

[0094] Examples of specific compounds encompassed by the present invention include the following compounds: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol monohydrochloride, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol monohydrochloride, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol monohydrochloride, and 5-(Difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol dihydrochloride.

[0095] In addition, certain embodiments of specific compounds encompassed by the present invention include the following compounds: 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol monohydrochloride, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol monohydrochloride, and 5-(difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol dihydrochloride.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] Furthermore, the present invention also encompasses various hydrates and solvates, and crystalline polymorphic substances of the compound of formula (I) or a salt thereof.

[0101] The present invention also encompasses all compounds of formula (I) or salts thereof that are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Suitable examples of isotopes used to isotopic label the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O. 17 O and 18 O etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I etc.), phosphorus ( 32 P, etc.), sulfur ( 35 Isotopes of 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 13Substitution with 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 a similar method to that described in the Examples or Preparations, using an appropriate isotopically labeled reagent instead of an unlabeled reagent. For example, 2-[4-(4-aminobutoxy)phthalazin-1-yl]-5-(trifluoromethyl)phenol (the compound of Preparation Example 64) can be treated with the known [ 11 C] acetylation reaction (International Journal of Radiation Applications and Instrumentation. Part A. Applied Radiation and Isotopes, Vol. 39, No. 4, pp. 287-290, 1988) was carried out to acetylate the carbon atom of the carbonyl group of the compound of Example 81. 11 C-substituted compounds can be obtained.

[0102] (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 production technology perspective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th ed., 2006) by PGM Wuts and TW Greene, and may be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary.

[0103] Furthermore, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, as in the case of the above-mentioned protecting groups, or by further reacting the obtained compound of formula (I). The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc.

[0104] 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.

[0105] In this specification, the following abbreviations may be used.

[0106] CN: cyano, COMU: ({[(1-cyano-2-oxoethylidene)amino]oxy}-4-morpholinomethylene)dimethylammonium hexafluorophosphate, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DIPEA: N,N-diisopropylethylamine, EDC·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HOBt: 1-hydroxybenzotriazole, NMP: 1-methylpyrrolidin-2-one, Me: methyl, Oxone®: potassium peroxymonosulfate, Pd-118: [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), 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, RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate, SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate, TBS: tert-butyl(dimethyl)silyl, THF: tetrahydrofuran, Tf: trifluoromethanesulfonyl, TFA: trifluoroacetic acid, XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, ODS: octadecylsilyl.

[0107] (First manufacturing method) (X1 is a halogen and R 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.)

[0108] (Step 1) This step is a step of obtaining a compound of formula (IV) by reacting a compound of formula (IIa) with a compound of formula (IIIa) to (IIIc). Depending on the type of the linker L, the step can be selected from the following steps 1 to 5.

[0109] (First Step-1) This step involves the reaction of a compound of formula (IIa) with a compound of formula (IIIa) to obtain a compound of formula (IV) in which L is -O-. In this reaction, the compound of formula (IIa) and the compound of formula (IIIa) are used in equal amounts, or in excess of either, and the mixture is stirred in the presence of a base in a reaction-inert solvent under cooling to heating, preferably at 0 to 190°C, for typically 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated carbons such as dichloromethane and chloroform; pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. Examples of bases include, but are not limited to, sodium hydride, potassium tert-butoxide, sodium hydroxide, and potassium hydroxide. In some cases, it may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride, tetrabutylammonium bromide, 18-crown-6-ether, etc. This reaction may also be carried out under microwave irradiation.

[0110] (First Step-2) In this step, a compound of formula (IIa) is reacted with a compound of formula (IIIb) to form a compound of formula (IV) in which L is -NR 3This is a process for obtaining a compound represented by the formula (IIa)-IIIb formula. In this reaction, a compound represented by the formula (IIa) and a compound represented by the formula (IIIb) are used in equal amounts or in excess of either. This mixture is stirred in a reaction-inert solvent or without solvent, under cooling to reflux, preferably at 0°C to 220°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, 1-butanol, and cyclopentanol; water; pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine or N,N-diisopropylethylamine, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, may be advantageous for smooth reaction progression. This reaction may also be carried out under microwave irradiation.

[0111] (First Step-3) In this step, a compound of formula (IIa) is reacted with a compound of formula (IIIb) to form a compound of formula (IV) in which L is -NR 3This is a process for obtaining a compound represented by the formula (IIa)-IIIb formula. In this reaction, a compound represented by the formula (IIa) and a compound represented by the formula (IIIb) are used in equal amounts or in excess of either, and a mixture thereof is stirred in the presence of a catalyst, a ligand, 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 the catalyst used here include, but are not limited to, palladium acetate and Pd2(dba)3. Examples of the ligand include, but are not limited to, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tri-tert-butylphosphine, XPhos, and the like. Examples of the base include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, and the like. 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)

[0112] (First Step-4) In this step, a compound of formula (IIa) is reacted with a compound of formula (IIIb) to form a compound of formula (IV) in which L is -NR 3 This process comprises a first step of converting a compound of formula (IIa) to a compound of formula (IIb), and a second step of converting a compound of formula (IIb) to a compound of formula (IV).

[0113] (First Step) In this reaction, the compound of formula (IIa) is stirred in hydroiodic acid in the presence of a metal iodide under cooling to reflux, preferably at room temperature to 100° C., usually for 0.1 hours to 5 days. Examples of the metal iodide used here include, but are not limited to, sodium iodide, potassium iodide, etc.

[0114] (Second Step) In this reaction, a compound of formula (IIb) and a compound of formula (IIIb) are used in equal amounts or in excess of either. A mixture of these 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 190°C, typically for 0.1 hours to 5 days. Examples of catalysts used here include, but are not limited to, copper(I) iodide, copper(I) oxide, copper(I) bromide, copper(I) chloride, and copper(I) 2-thiophenecarboxylate. Carrying out the reaction in the presence of a ligand such as proline or ethylenediamine may be advantageous for smooth reaction progression. Examples of bases include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, and N,N-diisopropylethylamine. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, alcohols such as ethanol, 2-propanol, 1-butanol, and ethylene glycol, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0115] (First Step-5) In this step, a compound of formula (IIa) is reacted with a compound of formula (IIIc) to form a compound of formula (IV) in which L is -CR 4 R 5 This is a process for obtaining a compound represented by the formula (IIa)-IIIc. In this reaction, a compound represented by the formula (IIa) and a compound represented by the formula (IIIc) are used in equal amounts or in excess of either, and a mixture thereof is stirred in the presence of a catalyst 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 the catalyst used here include, but are not limited to, copper(I) iodide and iron(III) acetylacetonate. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be performed under microwave irradiation.

[0116] (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. 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, SPhos Pd G3, and Pd-118. Examples of bases include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium hydroxide, and sodium tert-butoxide. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0117] (Second manufacturing method) (R 6a is 1 to 4 identical or different R 7 C is replaced by 1-5 Alkyl, -C 1-5 alkylene-(1 to 4 identical or different R 8 C optionally substituted with 3-8 cycloalkyl), or -C 1-5 alkylene-(1 to 4 identical or different R 9 (4- to 7-membered saturated heterocyclyl optionally substituted with). The same applies below.)

[0118] This method is for preparing a compound of formula (I) in which L is -CR 4 R 5 - and R 4 and R 5 are both H and R6 is -CH2- (1 to 4 identical or different R 7 C is replaced by 1-5 alkyl), -CH2-C 1-5 alkylene-(1 to 4 identical or different R 8 C optionally substituted with 3-8 cycloalkyl), or -CH2-C 1-5 alkylene-(1 to 4 identical or different R 9 This is a process for obtaining compound (Iz), which is a 4- to 7-membered saturated heterocyclyl optionally substituted by

[0119] (Step 1) This step is a step of obtaining a compound of formula (VI) by reacting a compound of formula (IIa) with a compound of formula (IIId). In this reaction, a mixture of the compounds of formula (IIa) and (IIId) is used in equal amounts, or in excess of either, and is stirred in the presence of a catalyst and a base, preferably a copper salt, in a reaction-inert solvent under cooling to reflux, preferably at room temperature to 150°C, for typically 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)·CH2Cl2, and Pd2(dba)3. Examples of bases include, but are not limited to, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium tert-butoxide, triethylamine, N,N-diisopropylethylamine, diisopropylamine, and pyrrolidine. Examples of copper salts include copper(I) iodide. Examples of solvents include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation. This reaction may also be carried out after converting the compound of formula (IIa) to the compound of formula (IIb) by the first step in step 4 of the first production method. [Reference] Chemical Reviews, 107, pp. 874-922 (2007)

[0120] (Step 2) This step is a reduction reaction of a compound of formula (VI) to obtain a compound of formula (IVa). In this reaction, a compound of formula (VI) is stirred in the presence of a catalyst under a hydrogen atmosphere in a solvent inert to the reaction, typically for 0.1 hours to 5 days, under cooling to reflux, preferably at room temperature to 50°C. Examples of the catalyst used here include, but are not limited to, palladium-on-carbon, palladium hydroxide, platinum oxide, etc. Examples of the solvent include, but are not limited to, alcohols such as methanol, ethanol, and 2-propanol, water, ethyl acetate, acetic acid, and mixtures thereof.

[0121] (Step 3) This step is a step of obtaining a compound of formula (Iz) by reacting a compound of formula (IVa) with a compound of formula (V) in the same manner as in Step 2 of the first production process.

[0122] (Third manufacturing method) (R c is C 1-6 is alkyl, and X 2 is a halogen or -OTf. The same applies below.)

[0123] This production method is for a compound of formula (I) in which L is -NR 3 This is a process for obtaining compound (Iaa) in which

[0124] (Step 1) This step involves the cyanation of a compound of formula (VII) to obtain a compound of formula (VIII). In this reaction, a mixture of the compound of formula (VII) and a metal cyanide is used in equal amounts, or in excess of either. The mixture is stirred in the presence of a catalyst 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 the metal cyanide used here include, but are not limited to, zinc cyanide, copper cyanide, sodium cyanide, potassium cyanide, etc. Examples of catalysts include, but are not limited to, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf), PdCl2(dppf)·CH2Cl2, and Pd2(dba)3. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0125] (Step 2) This step is a step of obtaining a compound of formula (IX) by reacting a compound of formula (VIII) with ammonia. In this reaction, the compound of formula (VIII) and ammonia are stirred in a reaction-inert solvent under cooling to reflux, preferably at 0°C to 100°C, for typically 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, alcohols such as methanol, ethanol, and 2-propanol. This reaction may also be carried out under microwave irradiation.

[0126] (Step 3) This step involves the reaction of a compound of formula (IX) with a compound of formula (IIIb) to obtain a compound of formula (X). In this reaction, a mixture of the compounds of formula (IX) and (IIIb) is used in equal amounts, or in excess of either. The mixture is stirred 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 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, 1-butanol, and cyclopentanol; water; pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. Carrying out the reaction in the presence of an organic base such as triethylamine or N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, may be advantageous for smooth reaction progression. This reaction may also be carried out under microwave irradiation.

[0127] (Step 4) This step is a reaction of a compound of formula (X) with hydrazine monohydrate to obtain a compound of formula (XIa) and / or a compound of formula (XIb). In this reaction, the compound of formula (X) and hydrazine monohydrate are used in equal amounts, or in excess of either, and a mixture thereof is stirred in a reaction-inert solvent under cooling to reflux, preferably at 0°C to 100°C, typically for 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, alcohols such as methanol, ethanol, and 2-propanol, and acetonitrile. This reaction may also be carried out under microwave irradiation.

[0128] (Fifth Step) This step is a step for obtaining a compound of formula (IVb) from a compound of formula (XIa) or formula (XIb). 2 Depending on the type of product, you can select from the following steps 1 to 3.

[0129] (Fifth Step-1) In this step, X of the compound of formula (IVb) is obtained from the compound of formula (XIa). 2is -OTf. In this reaction, a compound of formula (XIa) and a trifluoromethanesulfonylating agent are stirred in the presence of a base in a reaction-inert solvent under cooling to reflux, preferably at 0°C to room temperature, for typically 0.1 hours to 5 days. Examples of the trifluoromethanesulfonylating agent used here include, but are not limited to, trifluoromethanesulfonic anhydride and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide. Examples of the base include, but are not limited to, sodium hydride, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, etc. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane; halocarbons such as dichloromethane and chloroform; water; pyridine; acetonitrile; NMP; DMF; DMSO; and mixtures thereof.

[0130] (Fifth Step-2) In this step, X of the compound of formula (IVb) is obtained from the compound of formula (XIa). 2 is a halogen. In this reaction, the compound of formula (XIa) and a halogenating agent are stirred in a reaction-inert solvent under cooling to reflux, preferably at 0°C to 150°C, for typically 0.1 hours to 5 days. Examples of the halogenating agent used here include, but are not limited to, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, etc. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, halogenated carbons such as dichloromethane and chloroform, NMP, DMF, and mixtures thereof.

[0131] (Fifth Step-3) In this step, X of the compound of formula (IVb) is obtained from the compound of formula (XIb). 2is a halogen atom. In this reaction, a compound of formula (XIb) and a diazotization agent are stirred in the presence of a copper halide in a reaction-inert solvent under cooling to reflux, preferably at 0°C to room temperature, for typically 0.1 hours to 5 days. Examples of the diazotization agent used here include, but are not limited to, sodium nitrite and tert-butyl nitrite. Examples of copper halides include, but are not limited to, copper(I) chloride, copper(I) bromide, copper(I) iodide, etc. Examples of solvents include, but are not limited to, halogenated carbons such as dichloromethane and chloroform, acetonitrile, NMP, DMF, and mixtures thereof. Conducting the reaction in the presence of a hydrogen halide such as hydrochloric acid, hydrobromic acid, or hydroiodic acid may be advantageous for smooth reaction progression.

[0132] (Step 6) This step involves the reaction of a compound of formula (IVb) with a compound of formula (V) to obtain a compound of formula (Iaa). In this reaction, a mixture of compounds of formula (IVb) 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, for typically 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 tert-butoxide, etc. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, pyridine, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0133] (Raw material synthesis-1) (R d is a bird (C 1-6(alkyl)silyloxy group, or pyrrolidin-1-yl group. The same applies below.)

[0134] In this production method, a compound of formula (IIa) in which ring A is C is obtained by reacting a compound of formula (XIII) with a compound of formula (XIV). 5-8 This is a process for obtaining a compound that is a cycloalkenyl or a 5- to 11-membered partially unsaturated heterocyclyl. In this process, a compound of formula (XIII) and a compound of formula (XIV) are used in equal amounts, or in excess of either, and a mixture of these is stirred in a reaction-inert solvent under cooling to reflux, preferably at room temperature to 150°C, for typically 0.1 hours to 5 days. The solvent used in this reaction is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated carbons such as dichloromethane and chloroform, and mixtures thereof.

[0135] (Raw material synthesis-2)

[0136] This production method is a method for obtaining a compound of formula (IIa) from a compound of formula (XV).

[0137] (Step 1) This step is a step of obtaining a compound of formula (XVI) by reacting a compound of formula (XV) with hydrazine monohydrate. In this reaction, an excess amount of hydrazine monohydrate is used, and a mixture of the compound of formula (XV) and the hydrazine monohydrate is stirred in a solvent inert to the reaction, either without solvent or in a solvent inert to the reaction, under cooling to reflux, preferably at room temperature to 200°C, for typically 0.1 hours to 5 days. The solvent used in this reaction is not particularly limited, but examples include alcohols such as ethanol, 2-propanol, 1-butanol, and ethylene glycol, acetonitrile, DMF, NMP, DMSO, and mixtures thereof.

[0138] (Step 2) This step is a step of obtaining a compound of formula (XVII) from a compound of formula (XVI). In this reaction, a compound of formula (XVI) is stirred in the presence of an acid in a reaction-inert solvent under cooling to reflux, preferably at room temperature to 150°C, for typically 0.1 hours to 5 days. Examples of the acid used here include, but are not limited to, hydrochloric acid, sulfuric acid, acetic acid, etc. Solvents used in this reaction include, but are not limited to, alcohols such as ethanol, 2-propanol, 1-butanol, and ethylene glycol, water, acetonitrile, DMF, NMP, DMSO, etc., and mixtures thereof.

[0139] (Step 3) This step involves reacting a compound of formula (XVII) with a chlorinating agent to obtain a compound of formula (XIIa). In this reaction, an excess amount of the chlorinating agent is used, and the mixture with the compound of formula (XVII) is stirred under cooling or reflux, preferably at room temperature to 200°C, for typically 0.1 hours to 5 days. Examples of the chlorinating agent used here include, but are not limited to, phosphorus oxychloride and thionyl chloride. Adding a small amount of DMF may be advantageous for smooth reaction.

[0140] (Raw material synthesis-3)

[0141] This production method is a method for obtaining a compound of formula (IIa) from a compound of formula (XVIII).

[0142] (Step 1) This step involves the reaction of a compound of formula (XVIII) with tert-butyl carbazate to obtain a compound of formula (XIX). In this reaction, a mixture of the compound of formula (XVIII) and tert-butyl carbazate is used in equal amounts, or in excess of either. The resulting mixture is stirred in the presence of a condensing agent 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 condensing agents used here include, but are not limited to, HATU, EDC·HCl, COMU, etc. Examples of bases include, but are not limited to, triethylamine, DIPEA, etc. Examples of solvents used in this reaction include, but are not limited to, ethers such as THF, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated carbons such as dichloromethane and chloroform; acetonitrile, NMP, DMF, DMSO, etc.; and mixtures thereof. In some cases, it is advantageous to carry out the reaction in the presence of HOBt in order to ensure smooth progress of the reaction.

[0143] (Step 2) This step is a step of obtaining a compound of formula (XVII) from a compound of formula (XIX). In this reaction, a compound of formula (XIX) is stirred in the presence of an acid in a reaction-inert solvent under cooling to reflux, preferably at room temperature to 150°C, for typically 0.1 hours to 5 days. Examples of the acid used here include, but are not limited to, hydrochloric acid and sulfuric acid. Examples of the solvent used in this reaction include, but are not limited to, water, ethyl acetate, 1,4-dioxane, etc.

[0144] (Third Step) This step is similar to the third step in Raw Material Synthesis-2, in which a compound of formula (XVII) is reacted with a chlorinating agent to obtain a compound of formula (XIIa).

[0145] (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, benzylation, esterification, amidation, acylation, sulfonylation, oxidation reaction, protection reaction, and deprotection reaction.

[0146] 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.

[0147] 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.

[0148] 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 value was calculated.

[0149] The results are shown in Table 1. It was confirmed that the example compounds inhibited the activation of NLRP3 inflammasome and suppressed IL-1β production.

[0150]

[0151]

[0152] 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 value was calculated.

[0153] Compounds of formula (I), Examples 1, 2(1), 3(1), 4(1), 5, 70, 73, 83, 88, 99, 111, 124 and 125, had IC values ​​of 10 μM or more in this test. 50 It was confirmed that the values ​​were

[0154] 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.

[0155] The following table shows the IL-1β p17 inhibition rates relative to the vehicle-administered group for Examples 1, 2(1), 3(1), and 124, which are compounds of formula (I). In the table, "Dose" refers to the dose of each test compound, "Ex1," "Ex2(1), "Ex3(1)," and "Ex124" refer to Examples 1, 2(1), 3(1), and 124, respectively, and "NT" indicates cases where no measurement was performed. These compounds were confirmed to exhibit IL-1β production inhibitory activity.

[0156]

[0157] 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 14 to 15 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.

[0158] 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).

[0159] 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 (PFSB / ELD Notification No. 0521-1) and the method described in the OECD Guidelines for the Testing of Chemicals 432: In vitro 3T3 NRU Phototoxicity Test, 2019. In this test, it was confirmed that the compounds of Example 1, Example 2(1), Example 3(1), and Example 124 had no phototoxic activity.

[0160] 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 Example 1, Example 2(1), Example 3(1), and Example 124 had an IC of 10 μM or more. 50 The values ​​were shown.

[0161] 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 and / or neurodegenerative diseases.

[0162] 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 1, 2(1), 3(1), and 124 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 inflammatory diseases and / or neurodegenerative diseases, particularly α-synucleinopathies including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies.

[0163] Furthermore, the results of Test Examples 6 and 7 showed that the compounds of Example 1, Example 2(1), Example 3(1), and Example 124 did not exhibit phototoxicity and also had weak hERG channel inhibitory activity. From these results, it is highly expected that the compounds of Example 1, Example 2(1), Example 3(1), and Example 124 will become highly safe pharmaceuticals.

[0164] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers.

[0165] Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular, etc. injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.

[0166] Solid compositions for oral administration include tablets, powders, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a film of a gastric or enteric substance, if necessary.

[0167] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluents, the liquid compositions may contain adjuvants such as solubilizing agents, wetting agents, and suspending agents, as well as sweeteners, flavors, aromatics, and preservatives.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] The onset temperatures of the DSC curves measured under the following conditions are listed in the table below. DSC measurements were performed using a DSC Q2000 (TA Instruments) with a temperature range of 25 to 300°C, a heating rate of 10°C / min, and a nitrogen flow rate of 50 mL / min. The measurements were performed using an aluminum sample pan without a lid. The onset temperatures of the DSC curves may vary slightly depending on the measurement conditions, so they should not be interpreted strictly.

[0176] Powder X-ray diffraction was measured using an Empyrean (PANalytical) under the following conditions: a Cu tube, 40 mA current, 45 kV voltage, 0.013° step width, 1.5418 Å wavelength, and a diffraction angle range (2θ) of 2.5–40°. Alternatively, a SmartLab (Rigaku) ​​was used under the following conditions: a Cu tube, 200 mA current, 45 kV voltage, 0.005° step width, 1.5418 Å wavelength, and a diffraction angle range (2θ) of 2.5–40°. Due to the nature of powder X-ray diffraction data, the crystal lattice spacing and overall pattern are important for determining the identity of crystals. The error range for the diffraction angle (2θ (°)) in powder X-ray diffraction is typically ±0.2°. However, the diffraction angle and diffraction intensity may vary slightly depending on the crystal growth direction, particle size, and measurement conditions, so this should not be interpreted strictly.

[0177] 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), 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 (500 MHz, CDCl3): 1 δ value (ppm) of the signal in H-NMR, 1 H-NMR (400 MHz, DMSO-d6): 1 δ value (ppm) of the signal in H-NMR, 1 H-NMR (500 MHz, DMSO-d6): 1 δ value (ppm) of signal in H-NMR, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, br: broad line (e.g., br s), m: multiplet, DSC 1 : Temperature at which an endothermic peak (decomposition point) is observed in DSC measurement (onset temperature), DSC 2 : The temperature (onset temperature) at which an endothermic peak (amorphous decomposition point) is observed in DSC measurement, and 2θ: The diffraction angle of the peak in powder X-ray diffraction.

[0178] 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.

[0179] 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.

[0180] Preparation Example 1: A mixture of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (10.92 g), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (16.3 g), DIPEA (28 mL), and cyclopentanol (55 mL) was stirred at 160 °C for 2 days. After the reaction mixture was allowed to cool to room temperature, water / saturated aqueous sodium chloride (1 / 1) and chloroform / methanol (9 / 1) were added, and the organic layer was separated. The aqueous layer was extracted with chloroform / methanol (9 / 1). The combined organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to give (1R,2R)-2-[(4-chloro-5,6,7,8-tetrahydrophthalazin-1-yl)amino]cyclohexan-1-ol (8.24 g) as a solid.

[0181] Preparation Example 2: To a mixture of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (1 g) and cyclopentanol (5 mL), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (1.48 g) and DIPEA (1.7 mL) were added at room temperature, followed by stirring at 160°C for 44 hours. After the reaction mixture was cooled to room temperature, chloroform and water were added, followed by stirring at room temperature for 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate, and the solution was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a mixture of (1R,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol and (1R,2R)-2-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (386 mg) as a solid.

[0182] Preparation Example 3: A mixture of 6-benzyl-1,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyridazine (1.145 g), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (890 mg), DIPEA (2.7 mL), and NMP (15 mL) was stirred at 160°C for 24 hours. To the reaction mixture, (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (420 mg) and DIPEA (1.3 mL) were added, and the mixture was stirred at 160°C for 20 hours. After the reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water / saturated aqueous sodium chloride (1 / 1) and saturated aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). From the less polar fraction, (1R,2R)-2-[(6-benzyl-1-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (36.1 mg) was obtained as a solid, and from the more polar fraction, (1R,2R)-2-[(6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (504.8 mg) was obtained as an oil.

[0183] Preparation Example 4: (1S,2R)-2-aminocyclohexan-1-ol monohydrochloride (1.48 g) and DIPEA (1.68 mL) were added to a mixture of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (1 g) and cyclopentanol (5 mL) at room temperature, followed by stirring at 160°C for 12 hours. After the reaction mixture was cooled to room temperature, DIPEA (1 mL) was added and the mixture was stirred at 160°C for 12 hours. After the reaction mixture was cooled to room temperature, chloroform / methanol (9 / 1) and water / saturated sodium chloride aqueous solution (1 / 1) were added and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After concentrating the solution, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a mixture of (1S,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol and (1S,2R)-2-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (774 mg) as a solid.

[0184] Preparation Example 5: To a mixture of 1,4-dichloro-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazine (502.7 mg) and cyclopentanol (3 mL), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (394 mg) and DIPEA (0.393 mL) were added at room temperature, and the mixture was stirred at 160 °C for 2 days under an argon atmosphere. After the reaction mixture was cooled to room temperature, chloroform / methanol (9 / 1) and saturated aqueous sodium chloride / water (1 / 1) were added, and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to give (1R,2R)-2-[(4-chloro-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)amino]cyclohexan-1-ol (57.4 mg) as an oil.

[0185] Preparation Example 42: To a mixture of 2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione (1 g) and methanol (20 mL), hydrochloric acid (12 M, 0.6 mL) and platinum oxide (100 mg) were added and stirred overnight at room temperature under a hydrogen atmosphere. Methanol (20 mL) and DMF (20 mL) were added to the reaction mixture, and the mixture was stirred under an argon atmosphere for 1 hour. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. Toluene was added to the resulting residue, and the mixture was concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate. The solid was collected by filtration and washed with ethyl acetate to give 2,3,5,6,7,8-hexahydropyrido[3,4-d]pyridazine-1,4-dione monohydrochloride (1.19 g) as a solid.

[0186] Preparation Example 43: To a mixture of 2,3,5,6,7,8-hexahydropyrido[3,4-d]pyridazine-1,4-dione monohydrochloride (800 mg) and dichloromethane (16 mL), DIPEA (0.250 mL), benzaldehyde (0.500 mL), and sodium triacetoxyborohydride (1.1 g) were added and stirred at room temperature overnight. Water was added to the reaction mixture, which was then extracted with chloroform / methanol (5 / 1). The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 6-benzyl-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyridazine-1,4-dione (515 mg) as a solid.

[0187] Preparation Example 44: A mixture of 6-benzyl-2,3,5,6,7,8-hexahydropyrido[3,4-d]pyridazine-1,4-dione (100 mg) and phosphoryl chloride (2 mL) was stirred at 120°C for 2 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of toluene and further concentration under reduced pressure. Chloroform (3 mL) was added to the resulting residue, and DIPEA (1 mL) was added under ice cooling. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 6-benzyl-1,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyridazine (87 mg) as an oil.

[0188] Preparation Example 45: Under a nitrogen atmosphere, 1,4-dichlorophthalazine (720 mg), 4-hydroxy-1λ 6 To a mixture of 1,1-thiane-1,1-dione (540 mg) and THF (14 mL), sodium hydride (55%, liquid paraffin dispersion, 190 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes, then warmed to room temperature and stirred for 3 days. Water and ethyl acetate were added to the reaction mixture, and the solid was collected by filtration, washed with water and ethyl acetate, and 4-[(4-chlorophthalazin-1-yl)oxy]-1λ 6 -thiane-1,1-dione (681 mg) was obtained as a solid.

[0189] Preparation Example 47: To a mixture of (1R,2R)-2-[(4-chloro-5,6,7,8-tetrahydrophthalazin-1-yl)amino]cyclohexan-1-ol (100 mg) and 1,4-dioxane (3.2 mL), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg), RuPhos Pd G3 (45 mg), potassium carbonate (147 mg), and water (0.64 mL) were added, followed by stirring under microwave irradiation at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then chloroform and water were added, and the organic layer was separated. The solution was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1R,2R)-2-({4-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-5,6,7,8-tetrahydrophthalazin-1-yl}amino)cyclohexan-1-ol (106 mg) as a solid.

[0190] Preparation Example 48: Under an argon atmosphere, a mixture of (1R,2R)-2-[(6-benzyl-1-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (34 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (38 mg), RuPhos Pd G3 (3 mg), potassium carbonate (38 mg), 1,4-dioxane (1 mL), and water (0.100 mL) was stirred at 130°C for 60 minutes under microwave irradiation. Water and chloroform were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-(6-benzyl-4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (15.6 mg) as a solid.

[0191] Preparation Example 63: To a mixture of tert-butyl [4-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}oxy)butyl]carbamate (1.38 g), dichloromethane (14 mL), and triethylamine (1.21 mL), acetic anhydride (0.330 mL) and 4-dimethylaminopyridine (71 mg) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate), and the resulting solid was washed with hexane / ethyl acetate (4 / 1) to give 2-(4-{4-[(tert-butoxycarbonyl)amino]butoxy}phthalazin-1-yl)-5-(trifluoromethyl)phenyl acetate (1.24 g) as a solid.

[0192] Production Example 64: To a mixture of 2-(4-{4-[(tert-butoxycarbonyl)amino]butoxy}phthalazin-1-yl)-5-(trifluoromethyl)phenyl acetate (1.24 g) and dichloromethane (13 mL), trifluoroacetic acid (1.83 mL) was added and stirred at room temperature overnight. 1 M aqueous sodium hydroxide and saturated aqueous sodium bicarbonate were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol / aqueous ammonia). The resulting residue, chloroform, and methanol were mixed and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting solid was washed with hexane / ethyl acetate (4 / 1) to give 2-[4-(4-aminobutoxy)phthalazin-1-yl]-5-(trifluoromethyl)phenol (607 mg) as a solid.

[0193] Preparation Example 65: A mixture of 2-[4-(4-aminobutoxy)phthalazin-1-yl]-5-(trifluoromethyl)phenol (403 mg), acetyl chloride (0.075 mL), DIPEA (0.495 mL), and dichloromethane (4 mL) was stirred at room temperature for 1 hour. Acetyl chloride (0.075 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. DIPEA (0.495 mL) and acetyl chloride (0.075 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Acetyl chloride (0.075 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2-[4-(4-acetamidobutoxy)phthalazin-1-yl]-5-(trifluoromethyl)phenyl acetate (401 mg) as a solid.

[0194] Preparation Example 67: Under an argon atmosphere, PdCl2(PPh3)2 (126 mg), copper(I) iodide (17 mg), and diisopropylamine (0.755 mL) were added to a mixture of 1-chloro-4-iodo-6,7-dihydro-5H-cyclopenta[d]pyridazine (500 mg), (2R)-but-3-yn-2-ol (0.150 mL), and THF (8 mL) under ice cooling. The mixture was then warmed to room temperature and stirred for 5 hours. Water and saturated aqueous ammonium chloride were added to the reaction mixture, which was then extracted with chloroform. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. The solution was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (2R)-4-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)but-3-yn-2-ol (267 mg) as an oil.

[0195] Preparation Example 69: To a mixture of (2R)-4-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)but-3-yn-2-ol (267 mg) and ethanol (6 mL), platinum oxide (67 mg) was added and stirred under a hydrogen atmosphere at room temperature for 1.5 hours. Celite® was added to the reaction mixture, and the mixture was stirred. The mixture was then filtered through Celite®, and the filtrate was concentrated under reduced pressure to give (2R)-4-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)butan-2-ol (260 mg) as an oil.

[0196] Preparation Example 70: Under an argon atmosphere, a mixture of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (1.50 g), sodium iodide (3.1 g), and 57% hydroiodic acid (9 mL) was stirred at 100°C for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium thiosulfate, and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 1-chloro-4-iodo-6,7-dihydro-5H-cyclopenta[d]pyridazine (1.9 g) as a solid.

[0197] Preparation Example 72: Under an argon atmosphere, a mixture of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (100 mg), (3-aminobicyclo[1.1.1]pentan-1-yl)methanol monohydrochloride (95 mg), palladium acetate (22 mg), (+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (90 mg), cesium carbonate (385 mg), and 1,4-dioxane (2 mL) was stirred at 100°C for 24 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give {3-[(4-chloro-5,6,7,8-tetrahydrophthalazin-1-yl)amino]bicyclo[1.1.1]pentan-1-yl}methanol (46.2 mg) as a solid.

[0198] Preparation Example 73: 3,6-Dichloro-1,2,4,5-tetrazine (1 g) was added to a mixture of tert-butyl[(3,6-dihydro-2H-pyran-4-yl)oxy]di(methyl)silane (1.42 g) and toluene (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hours and then at 120° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (1.08 g) as a solid.

[0199] Preparation Example 74: Toluene (121 mL) and 3,6-dichloro-1,2,4,5-tetrazine (6.61 g) were added to a mixture of tert-butyldi(methyl)[(2,3,6,7-tetrahydrooxepin-4-yl)oxy]silane and tert-butyldi(methyl)[(2,5,6,7-tetrahydrooxepin-4-yl)oxy]silane (11.67 g) under an argon atmosphere, and the mixture was stirred at 120°C for 24 hours. The reaction mixture was cooled to room temperature and then filtered using methanol and chloroform. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to give 1,4-dichloro-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazine (502.7 mg) as a solid.

[0200] Preparation Example 76: To a mixture of 2-amino-5-cyclopropylphenol (3.50 g) and ethanol (50 mL) was added hydrochloric acid (12 M, 15.8 mL) at −15°C and stirred at the same temperature for 10 minutes. Amyl nitrite (9.6 mL) was added to the reaction mixture at −15°C and stirred at the same temperature for 30 minutes. A mixture of potassium iodide (50.6 g) and water (50 mL) was added dropwise at −15°C, and the mixture was warmed to room temperature and stirred for 20 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride and 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.

[0201] Preparation Example 77: To a mixture of 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg) and 1,4-dioxane (9.2 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (1.24 g), PdCl(dppf) (238 mg), and potassium acetate (957 mg) were added and stirred at 100°C for 3 hours. After the reaction mixture was cooled to room temperature, PdCl(dppf) (238 mg) was added and stirred at 100°C for 2 hours. After the reaction mixture was cooled to room temperature, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (620 mg) was added and stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, hexane was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to give 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.98 g) as an oil.

[0202] Preparation Example 81: DIPEA (2.93 mL) and chloromethyl methyl ether (1.19 mL) were added to a mixture of 4-bromo-3-hydroxybenzaldehyde (2.86 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 (1.35 g) as an oil.

[0203] Preparation Example 83: To a mixture of 4-bromo-3-(methoxymethoxy)benzaldehyde (1.35 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.

[0204] Preparation Example 84: To a mixture of potassium carbonate (1.65 g) and DMF (7.4 mL), a mixture of 4-bromo-3-(methoxymethoxy)phenol (1.86 g), sodium chlorodi(fluoro)acetate (2.43 g), and DMF (11 mL) was added dropwise over 1 hour at 95°C and stirred at the same temperature for 15 minutes. After the reaction mixture was cooled to room temperature, potassium carbonate (1.65 g) and sodium chlorodi(fluoro)acetate (2.43 g) were added and stirred at 95°C for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (920 mg) as an oil.

[0205] Preparation Example 85: Under an argon atmosphere, a mixture of 1-chloro-4-iodo-5,6,7,8-tetrahydrophthalazine (500 mg), (1R,2R)-2-amino-1-methylcyclohexan-1-ol (270 mg), copper(I) iodide (30 mg), potassium phosphate (725 mg), ethylene glycol (0.100 mL), and 1-propanol (5 mL) was stirred at 90°C for 24 hours. After the reaction mixture was allowed to cool to room temperature, chloroform and saturated aqueous ammonium chloride were added, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. The solution was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1R,2R)-2-[(4-chloro-5,6,7,8-tetrahydrophthalazin-1-yl)amino]-1-methylcyclohexan-1-ol (292 mg) as a solid.

[0206] Preparation Example 86: Under an argon atmosphere, a mixture of ethyl 1-benzyl-5-[(trifluoromethanesulfonyl)oxy]-1,2,3,6-tetrahydropyridine-4-carboxylate (3.37 g), zinc cyanide (1.5 g), Pd(PPh3)4 (1.2 g), and DMF (42 mL) was stirred at 100°C for 1.5 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water / saturated aqueous sodium chloride (1 / 1) and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give ethyl 1-benzyl-5-cyano-1,2,3,6-tetrahydropyridine-4-carboxylate (2.04 g) as an oil.

[0207] Preparation Example 87: Under an argon atmosphere, a mixture of ethyl 5-[(trifluoromethanesulfonyl)oxy]-3,6-dihydro-2H-pyran-4-carboxylate (7.4 g), zinc cyanide (4.3 g), Pd(PPh3)4 (2.8 g), and DMF (74 mL) was stirred at 100°C for 2 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, which was then filtered through Celite®. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water / saturated aqueous sodium chloride (1 / 1) and 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 ethyl 5-cyano-3,6-dihydro-2H-pyran-4-carboxylate (4 g) as an oil.

[0208] Preparation Example 88: A mixture of ethyl 1-benzyl-5-cyano-1,2,3,6-tetrahydropyridine-4-carboxylate (930 mg) and ammonia (7 M methanol solution, 8 mL) was stirred under ice-cooling for 6 hours. The reaction mixture was allowed to stand in a refrigerator for 18 hours, then warmed to room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to give 3-amino-5-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-c]pyridin-1-one (828 mg) as a solid.

[0209] Preparation Example 89: Under ice cooling, ammonia (7 M methanol solution, 44 mL) was added to ethyl 5-cyano-3,6-dihydro-2H-pyran-4-carboxylate (4 g), and the mixture was stirred for 3 days at 0° C. The reaction mixture was concentrated under reduced pressure to give 3-amino-6,7-dihydropyrano[3,4-c]pyrrol-1(4H)-one (3.261 g) as a solid.

[0210] Preparation Example 90: A mixture of 3-amino-5-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-c]pyridin-1-one (825 mg), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (530 mg), DIPEA (0.7 mL), and acetonitrile (20 mL) was stirred at 70°C for 19 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 5-benzyl-3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-c]pyridin-1-one (1.12 g) as a solid.

[0211] Preparation Example 91: A mixture of 3-amino-6,7-dihydropyrano[3,4-c]pyrrol-1(4H)-one (3.26 g), (1R,2R)-2-aminocyclohexan-1-ol monohydrochloride (3.4 g), DIPEA (5.5 mL), and acetonitrile (70 mL) was stirred at 70°C for 18 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6,7-dihydropyrano[3,4-c]pyrrol-1(4H)-one (5.63 g) as a solid.

[0212] Preparation Example 92: To a mixture of 5-benzyl-3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-c]pyridin-1-one (560 mg) and ethanol (10 mL), hydrazine monohydrate (0.16 mL) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 6-benzyl-4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-ol (201 mg) as a solid.

[0213] Preparation Example 93: Under an argon atmosphere, sodium hydride (55%, liquid paraffin dispersion, 12 mg) was added to a mixture of 6-benzyl-4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-ol (90 mg) and THF (3 mL) under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (108 mg) was added to the reaction mixture, and the mixture was stirred under ice cooling for 1 hour. Water and chloroform were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate, then chloroform / ethyl acetate) to give 6-benzyl-4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl trifluoromethanesulfonate (40 mg) as a solid.

[0214] Preparation Example 94: To a mixture of tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (2 g) and dichloromethane (5 mL), sodium hydroxide (0.596 g) and benzyltriethylammonium chloride (0.922 g) were added and stirred at room temperature for 30 minutes. 1,4-Dichlorophthalazine (2.37 g) was added to the reaction mixture and stirred at room temperature for 24 hours. Water and dichloromethane were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3R)-3-[(4-chlorophthalazin-1-yl)oxy]piperidine-1-carboxylate (0.960 g) as a solid.

[0215] Preparation Example 96: To a mixture of tert-butyl (3R)-3-[(4-chlorophthalazin-1-yl)oxy]piperidine-1-carboxylate (960 mg) and dichloromethane (10 mL), a solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was triturated with diethyl ether. The solid was collected by filtration to give 1-chloro-4-{[(3R)-piperidin-3-yl]oxy}phthalazine monohydrochloride (850 mg) as a solid.

[0216] Preparation Example 97: To a mixture of 1-chloro-4-{[(3R)-piperidin-3-yl]oxy}phthalazine monohydrochloride (100 mg) and dichloromethane (2 mL), triethylamine (0.26 mL) was added and stirred at room temperature for 30 minutes. Acetyl chloride (0.04 mL) was added and stirred at the same temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure (referred to as Mixture A). To a mixture of 1-chloro-4-{[(3R)-piperidin-3-yl]oxy}phthalazine monohydrochloride (300 mg) and dichloromethane (10 mL), triethylamine (0.70 mL) was added and stirred at room temperature for 30 minutes. Acetyl chloride (0.10 mL) was added and stirred at the same temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solution was concentrated under reduced pressure (referred to as mixture B). Mixture A and mixture B were combined and purified by silica gel column chromatography (hexane / ethyl acetate) to give 1-{(3R)-3-[(4-chlorophthalazin-1-yl)oxy]piperidin-1-yl}ethan-1-one (280 mg).

[0217] Preparation Example 98: To a mixture of oxepan-4-one (5 g) and diethyl ether (50 mL) was added triethylamine (6.3 mL) under ice-cooling, followed by tert-butyldi(methyl)silyl trifluoromethanesulfonate (12.3 mL) and stirring at the same temperature for 10 minutes. Triethylamine (1.4 mL) was added to the reaction mixture, and the mixture was stirred under ice-cooling for 1.5 hours. Hexane and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solution was concentrated to give a mixture of tert-butyldi(methyl)[(2,3,6,7-tetrahydrooxepin-4-yl)oxy]silane and tert-butyldi(methyl)[(2,5,6,7-tetrahydrooxepin-4-yl)oxy]silane (11.7 g) as an oil.

[0218] Preparation Example 99: To a mixture of 3-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6,7-dihydropyrano[3,4-c]pyrrol-1(4H)-one (500 mg) and 2-propanol (20 mL), hydrazine monohydrate (0.300 mL) was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1R,2R)-2-[(1-amino-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (200 mg) as a solid.

[0219] Preparation Example 100: Under an argon atmosphere, sodium nitrite (80 mg) was added to a mixture of (1R,2R)-2-[(1-amino-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (198 mg), copper(I) chloride (75 mg), and hydrochloric acid (12 M, 2.5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Dichloromethane (10 mL), water, and triethylamine (4.2 mL) were added to the reaction mixture under ice-cooling, and the mixture was stirred. The reaction mixture was filtered through Celite® and washed with dichloromethane / methanol (10 / 1). The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium 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-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (170 mg) as a solid.

[0220] Preparation Example 101: A mixture of 2-(6-benzyl-4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (131.6 mg), 10% palladium on carbon (51% water content, 84.5 mg), and methanol (3 mL) was stirred under a hydrogen atmosphere at room temperature for 4 hours. Chloroform was added to the reaction mixture, and the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (89.3 mg) as a solid.

[0221] Preparation Example 102: To a mixture of cyclobutanone (0.640 g) and dichloromethane (25 mL) was added tert-butyl [(3R)-piperidin-3-yl]carbamate (1.524 g) and sodium triacetoxyborohydride (2.416 g) at room temperature, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into 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 (dichloromethane / methanol) to give tert-butyl [(3R)-1-cyclobutylpiperidin-3-yl]carbamate (1.940 g) as a solid.

[0222] Preparation Example 103: To a mixture of tert-butyl [(3R)-1-cyclobutylpiperidin-3-yl]carbamate (225 mg) and dichloromethane (1.8 mL) was added a 1,4-dioxane solution of hydrogen chloride (4 M, 1.8 mL) under stirring at room temperature, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give (3R)-1-cyclobutylpiperidin-3-amine dihydrochloride (250 mg) as a solid.

[0223] Production example 104 (1R,2R)-N 1 -(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)cyclohexane-1,2-diamine and (1R,2R)-N 1To a mixture of 4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)cyclohexane-1,2-diamine (393 mg), dichloromethane (14 mL), triethylamine (0.23 mL), and di-tert-butyl dicarbonate (0.34 mL) were added and stirred at room temperature for 1.5 hours. Water 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 (hexane / ethyl acetate) to give a mixture of tert-butyl {(1R,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexyl}carbamate and tert-butyl {(1R,2R)-2-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]cyclohexyl}carbamate (352 mg) as a solid.

[0224] Preparation Example 105: To a mixture of 1,4-dichloro-6-(triphenylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazine (1.569 g) and dichloromethane (18 mL) was added a 1,4-dioxane solution of hydrogen chloride (4 M, 6 mL) with stirring at room temperature, followed by stirring at room temperature for 18.5 hours. The reaction mixture was filtered, and the collected solid was washed with diethyl ether and dried under reduced pressure to give 1,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazine monohydrochloride (770 mg).

[0225] Preparation Example 106: To a mixture of 1,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazine monohydrochloride (765 mg) and dichloromethane (23 mL), triethylamine (1.4 mL) and di-tert-butyl dicarbonate (1.2 mL) were added under ice-cooling and stirring, and the mixture was allowed to warm to room temperature and stirred for 17 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether. The precipitated solid was collected by filtration and dried under reduced pressure to give tert-butyl 1,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyridazine-6-carboxylate (788 mg) as a solid. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 1,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyridazine-6-carboxylate (142 mg) as a solid.

[0226] A mixture of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (700 mg) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.4 g) was stirred at 120° C. for 24 hours. After cooling to room temperature, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give a mixture of tert-butyl (3R)-3-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]piperidine-1-carboxylate and tert-butyl (3R)-3-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]piperidine-1-carboxylate (481 mg) as a solid.

[0227] Preparation Example 116: A mixture of 1,4-dichloro-5,7-dihydrothieno[3,4-d]pyridazine (384 mg), (1R,2R)-2-aminocyclohexan-1-ol (426 mg), DIPEA (0.77 mL), and cyclopentanol (7.4 mL) was stirred at 145-155°C for 18.5 hours under an argon atmosphere. After cooling the reaction mixture to room temperature, water and saturated aqueous sodium chloride were added, followed by extraction with ethyl acetate. 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 (1R,2R)-2-[(4-chloro-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (236 mg) as a solid.

[0228] Preparation Example 120: A mixture of 1,4-dichloro-5,7-dihydrofuro[3,4-d]pyridazine (500 mg), (1S,3R)-3-aminocyclohexan-1-ol monohydrochloride (795 mg), DIPEA (1.8 mL), and cyclopentanol (5 mL) was stirred at 120-130°C for 22 hours. The reaction mixture was cooled 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, followed by ethyl acetate / methanol) to give (1S,3R)-3-[(4-chloro-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (556 mg) as a solid.

[0229] Preparation Example 122: A mixture of 2,3,5,7-tetrahydrothieno[3,4-d]pyridazine-1,4-dione (78 mg) and phosphorus oxychloride (1 mL) was stirred at 98-100°C for 2.5 hours. After cooling to room temperature, the reaction mixture was poured into ice water and washed with ice water and dichloromethane. With stirring at room temperature, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1,4-dichloro-5,7-dihydrothieno[3,4-d]pyridazine (92 mg) as a solid.

[0230] Preparation Example 128: A mixture of tert-butyl (3R)-3-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]piperidine-1-carboxylate and tert-butyl (3R)-3-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]piperidine-1-carboxylate (478 mg), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (680 mg), RuPhos Pd G3 (163 mg), potassium carbonate (450 mg), 1,4-dioxane (10 mL), and water (2 mL) was stirred at 100° C. for 4 hours. After cooling to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3R)-3-({1-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl}amino)piperidine-1-carboxylate (150 mg) and tert-butyl (3R)-3-({4-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl}amino)piperidine-1-carboxylate (200 mg), respectively, as solids.

[0231] Preparation Example 134: Under an argon atmosphere, a mixture of (1S,3R)-3-[(4-chloro-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (155 mg), 2-[4-(difluoromethyl)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (361 mg), PdCl(dppf)·CHCl (94 mg), potassium carbonate (159 mg), 1,4-dioxane (6 mL), and water (1.4 mL) was stirred at 90–110°C for 20 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was then filtered through Celite®, and the filtrate 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, then ethyl acetate / methanol) to give (1S,3R)-3-({4-[4-(difluoromethyl)-2-(methoxymethoxy)phenyl]-5,7-dihydrofuro[3,4-d]pyridazin-1-yl}amino)cyclohexan-1-ol (128 mg) as a solid.

[0232] Preparation Example 144 A reaction similar to that in Preparation Example 74 was carried out to obtain 1,4-dichloro-5,7,8,9-tetrahydrooxepino[3,4-d]pyridazine as a solid by-product.

[0233] Preparation Example 152: To a mixture of 4-{[(1R,2S)-2-{[tert-butyldi(methyl)silyl]oxy}cyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-ol (261 mg), 2,6-lutidine (0.16 mL), and dichloromethane (6 mL), trifluoromethanesulfonic anhydride (0.17 mL) was added under ice-cooling and stirred at the same temperature for 1.5 hours. Dichloromethane and water were added to the reaction mixture, and the mixture was stirred. The two layers were then separated. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-{[(1R,2S)-2-{[tert-butyldi(methyl)silyl]oxy}cyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl trifluoromethanesulfonate (311 mg) as a solid.

[0234] Preparation Example 154: Under an argon atmosphere, trifluoromethanesulfonic anhydride (14.1 mL) was added dropwise to a mixture of ethyl 5,5-dimethyl-4-oxothiolane-3-carboxylate (16.169 g), DIPEA (15.3 mL), and dichloromethane (80 mL) at −30°C with stirring. The reaction mixture was then stirred at −45 to −15°C for 1 hour. Water was added to the reaction mixture, and the mixture was 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 (hexane / ethyl acetate) to give ethyl 5,5-dimethyl-4-[(trifluoromethanesulfonyl)oxy]-2,5-dihydrothiophene-3-carboxylate (17.559 g) as an oil.

[0235] Preparation Example 159: To a mixture of (1S,2R)-2-aminocyclohexan-1-ol monohydrochloride (608 mg), dichloromethane (8 mL), and 2,6-lutidine (1.1 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.2 mL) under ice cooling, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours. To the resulting mixture, 2,6-lutidine (0.16 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.3 mL) were added at room temperature, and the mixture was stirred at the same temperature for 20 hours. Dichloromethane and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was stirred. The two layers were then separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (1R,2S)-2-{[tert-butyldi(methyl)silyl]oxy}cyclohexane-1-amine (445 mg) as an oil.

[0236] Preparation Example 160: To a mixture of tert-butyl (3R)-3-({1-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl}amino)piperidine-1-carboxylate (150 mg) and methanol (3 mL), hydrochloric acid (12 M, 0.5 mL) was added at room temperature and stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the resulting residue, chloroform / methanol (9 / 1) and basic silica gel were added and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica, chloroform / methanol) to give 5-(difluoromethoxy)-2-(4-{[(3R)-piperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (102 mg) as a solid.

[0237] Preparation Example 162 A mixture of (1R,2R)-2-[(1-chloro-5,7,8,9-tetrahydrooxepino[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol and (1R,2R)-2-[(4-chloro-5,7,8,9-tetrahydrooxepino[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (113 mg) was purified by reverse-phase preparative HPLC (ODS column, 0.1% formic acid / methanol) to give (1R,2R)-2-[(1-chloro-5,7,8,9-tetrahydrooxepino[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (62.4 mg) as an oil.

[0238] Preparation Example 163: To a mixture of 1-chloro-N-[(3R)-piperidin-3-yl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine dihydrochloride (110 mg) and DMF (6 mL) was added potassium carbonate (197.99 mg) and methyl iodide (58.10 mg) at 25°C and stirred at the same temperature for 16 hours. The reaction mixture was 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 to give 1-chloro-N-[(3R)-1-methylpiperidin-3-yl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine (110 mg) as an oil.

[0239] Preparation Example 164: To a mixture of 3-cyclopropylphenol (20 g) and chloroform (200 mL) was added N-bromosuccinimide (23.88 g) at 0° C., followed by stirring for 16 hours at 15° C. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether) to obtain 2-bromo-5-cyclopropylphenol (7.7 g) as an oil.

[0240] Preparation Example 165: A mixture of 2,5-dihydrothiophene-3,4-dicarbohydrazide (127 mg) and 10% sulfuric acid (8 mL) was stirred at 115-120°C for 1 hour. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with water and dried to give 2,3,5,7-tetrahydrothieno[3,4-d]pyridazine-1,4-dione (94 mg) as a solid.

[0241] Preparation Example 166: A mixture of 4,6-dihydro-1H,3H-thieno[3,4-c]furan-1,3-dione (308 mg), hydrazine monohydrate (0.96 mL), and 2-propanol (20 mL) was stirred at 100°C under reflux for 14.5 hours. The reaction mixture was cooled to room temperature and filtered. The collected solid was washed with 2-propanol and dried to give 2,5-dihydrothiophene-3,4-dicarbohydrazide (246 mg) as a solid.

[0242] Preparation Example 167: A mixture of tert-butyl 2-[4-(ethoxycarbonyl)-2,2-dimethyl-2,5-dihydrothiophene-3-carbonyl]hydrazine-1-carboxylate (6.259 g), hydrogen chloride in 1,4-dioxane (4 M, 9.1 mL), and ethyl acetate (90 mL) was stirred at 60-67°C for 19 hours. The reaction mixture was cooled to room temperature and filtered. The collected solid was washed with ethyl acetate and dried to give 5,5-dimethyl-2,3,5,7-tetrahydrothieno[3,4-d]pyridazine-1,4-dione (2.717 g) as a solid.

[0243] Preparation Example 168: A mixture of 4-(ethoxycarbonyl)-2,2-dimethyl-2,5-dihydrothiophene-3-carboxylic acid (5.095 g), tert-butyl carbazate (3.509 g), HATU (10.095 g), DIPEA (7.73 mL), and DMF (110 mL) was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water 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 (hexane / ethyl acetate) to give tert-butyl 2-[4-(ethoxycarbonyl)-2,2-dimethyl-2,5-dihydrothiophene-3-carbonyl]hydrazine-1-carboxylate (6.259 g) as an oil.

[0244] Preparation Example 169: Under an argon atmosphere, a mixture of ethyl 5,5-dimethyl-4-[(trifluoromethanesulfonyl)oxy]-2,5-dihydrothiophene-3-carboxylate (15.556 g), sodium formate (9.493 g), acetic anhydride (8.8 mL), DIPEA (16.3 mL), lithium chloride (5.917 g), palladium acetate (1.045 g), and DMF (230 mL) was stirred at room temperature for 17 hours. The reaction mixture was filtered, and the filtrate was adjusted to pH 1 with 10% hydrochloric acid and then 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 (dichloromethane / methanol). The resulting purified product was added with saturated aqueous sodium bicarbonate and stirred at room temperature to adjust the pH to 8, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid while stirring at room temperature, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 4-(ethoxycarbonyl)-2,2-dimethyl-2,5-dihydrothiophene-3-carboxylic acid (9.659 g) as an oil.

[0245] Example 1: Under an argon atmosphere, a mixture of (1R,2R)-2-[(4-chloro-5,6,7,8-tetrahydrophthalazin-1-yl)amino]cyclohexan-1-ol (4.4 g), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (4.5 g), RuPhos Pd G3 (1.3 g), potassium carbonate (5.4 g), 1,4-dioxane (40 mL), and water (8 mL) was stirred at 100°C for 2 hours. [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (965 mg) and RuPhos Pd G3 (260 mg) were added to the reaction mixture, and the mixture was stirred at 100°C for 3 hours. [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (965 mg) and RuPhos Pd G3 (260 mg) were added to the reaction mixture, and the mixture was stirred at 100°C for 19 hours. The reaction mixture was allowed to cool to room temperature, and water and chloroform were added to separate the organic layer. The aqueous layer was extracted with chloroform, and the combined organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic and neutral silica gel, chloroform / methanol). Ethyl acetate (10 mL) and hexane (50 mL) were added to the resulting purified product, and the mixture was stirred at room temperature for 18 hours. The solid was collected by filtration to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (3.97 g) as a solid.

[0246] Example 2: To a mixture of (1R,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol and (1R,2R)-2-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (386 mg), 1,4-dioxane (12 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (562 mg), RuPhos Pd G3 (171 mg), potassium carbonate (563 mg), and water (2.5 mL) were added and stirred at 100°C for 1.5 hours under microwave irradiation. The reaction mixture was cooled to room temperature, and then chloroform / methanol (9 / 1) and water were added to separate the organic layer. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate on neutral silica gel, followed by chloroform / methanol on basic silica gel). Diethyl ether (3 mL) and hexane (12 mL) were added to the two purified products, respectively, and the mixture was stirred for 15 minutes. The solid was collected by filtration, and 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (108 mg) was obtained as a solid from the less polar fraction, and 2-(1-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (172 mg) was obtained as a solid from the more polar fraction.

[0247] Example 3: To a mixture of (1R,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol and (1R,2R)-2-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (440 mg), 1,4-dioxane (14 mL), [2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (690 mg), RuPhos Pd G3 (195 mg), potassium carbonate (643 mg), and water (2.9 mL) were added and stirred at 100°C for 1.5 hours under microwave irradiation. The reaction mixture was cooled to room temperature, and then chloroform / methanol (9 / 1) and water were added to separate the organic layer. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate on neutral silica gel, followed by chloroform / methanol on basic silica gel). Diethyl ether (2 mL) and hexane (8 mL) were added to the two purified products, respectively, and the mixture was stirred for 30 minutes. The solid was collected by filtration, and 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol (124 mg) was obtained as a solid from the less polar fraction, and 2-(1-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol (242 mg) was obtained as a solid from the more polar fraction.

[0248] Example 4: To a mixture of (1S,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol and (1S,2R)-2-[(4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (380 mg), 1,4-dioxane (12.2 mL), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (553 mg), RuPhos Pd G3 (168 mg), potassium carbonate (555 mg), and water (2.4 mL) were added and stirred at 100°C for 1.5 hours under microwave irradiation. The reaction mixture was cooled to room temperature, and then chloroform / methanol (9 / 1) and water were added to separate the organic layer. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate on neutral silica gel, followed by chloroform / methanol on basic silica gel). Diethyl ether (2 mL) and hexane (6 mL) were added to the two purified products, respectively, and the mixture was stirred for 1 hour. The solid was collected by filtration, and 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (93 mg) was obtained as a solid from the less polar fraction, and 2-(1-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (103 mg) was obtained as a solid from the more polar fraction.

[0249] Example 5: Under an argon atmosphere, RuPhos Pd G3 (17 mg) was added to a mixture of (1R,2R)-2-[(4-chloro-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)amino]cyclohexan-1-ol (57.4 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (59.8 mg), potassium carbonate (80 mg), 1,4-dioxane (2.4 mL), and water (0.600 mL), and the mixture was stirred at 100° C. for 3 hours. RuPhos Pd G3 (16 mg) was added to the reaction mixture, and the mixture was stirred at 100° C. for 1 hour. After that, RuPhos Pd G3 (17.7 mg), 1,4-dioxane (0.800 mL), and water (0.200 mL) were added, and the mixture was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, chloroform / methanol (9 / 1), saturated aqueous sodium chloride, and water were added and stirred at room temperature for 10 minutes. The organic layer was separated and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate on neutral silica gel, then chloroform / methanol on basic silica gel) to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (9.1 mg) as a solid.

[0250] Example 70: Under an argon atmosphere, a mixture of (1R,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (150 mg), (4-chloro-2-hydroxyphenyl)boronic acid (120 mg), RuPhos Pd G3 (46 mg), potassium carbonate (150 mg), 1,4-dioxane (4 mL), and water (0.5 mL) was stirred at 100°C for 5 hours. (4-Chloro-2-hydroxyphenyl)boronic acid (120 mg) and RuPhos Pd G3 (22 mg) were added to the reaction mixture, and the mixture was stirred at 100°C for 8 hours. After cooling 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 (chloroform / methanol on basic silica gel, followed by chloroform / methanol on neutral silica gel) to obtain a solid. Hexane / ethyl acetate (10 / 1) was added to the obtained solid, and the solid was collected by filtration to give 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (25.2 mg) as a solid.

[0251] Example 73: A mixture of 2-(6-benzyl-4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (14 mg), formaldehyde (37% aqueous solution, 0.020 mL), 10% palladium on carbon (50% aqueous, 10 mg), and methanol (1 mL) was stirred under a hydrogen atmosphere at room temperature for 24 hours. Chloroform was added to the reaction mixture, which was then filtered through Celite®. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (5.6 mg) as a solid.

[0252] Example 79: To a mixture of (2R)-1-({6-benzyl-1-[2,4-bis(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4-yl}amino)propan-2-ol (30 mg) and methanol (1 mL) was added 10% palladium on carbon (50% water, 6 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. To a mixture of the resulting residue and dichloromethane (1 mL), triethylamine (0.020 mL) and acetyl chloride (6 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 1-{1-[2,4-bis(trifluoromethyl)phenyl]-4-{[(2R)-2-hydroxypropyl]amino}-7,8-dihydropyrido[3,4-d]pyridazin-6(5H)-yl}ethan-1-one (18 mg) as a solid.

[0253] Example 80: To a mixture of (2R)-1-({6-benzyl-1-[2,4-bis(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4-yl}amino)propan-2-ol (30 mg) and methanol (1 mL) was added 10% palladium on carbon (50% water, 6 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. To a mixture of the resulting residue and dichloromethane (1 mL), triethylamine (0.020 mL) and methanesulfonyl chloride (8 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (2R)-1-({1-[2,4-bis(trifluoromethyl)phenyl]-6-(methanesulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4-yl}amino)propan-2-ol (15 mg) as a solid.

[0254] Example 81: To a mixture of 2-[4-(4-acetamidobutoxy)phthalazin-1-yl]-5-(trifluoromethyl)phenyl acetate (398 mg) and methanol (8 mL), aqueous sodium hydroxide (1 M, 1.73 mL) was added and stirred at room temperature for 3 hours. Hydrochloric acid (1 M, 1.73 mL) and water were added to the reaction mixture, followed by extraction with chloroform / 2-propanol (4 / 1). The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to give N-[4-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}oxy)butyl]acetamide (309 mg) as a solid.

[0255] Example 82: To a mixture of tert-butyl [(1R,2R)-2-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)cyclohexyl]carbamate (0.440 g) and 1,4-dioxane (10 mL) was added hydrogen chloride in 1,4-dioxane (4 M, 4 mL) at 0°C, warmed to room temperature, and stirred for 4 hours. To the reaction mixture was added hydrogen chloride in 1,4-dioxane (4 M, 4 mL) at 5°C, and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to give 2-(4-{[(1R,2R)-2-aminocyclohexyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol dihydrochloride (0.375 g) as a solid.

[0256] Example 83: To a mixture of (1R,2R)-2-({4-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-5,6,7,8-tetrahydrophthalazin-1-yl}amino)cyclohexan-1-ol (106 mg) and methanol (1.1 mL), hydrochloric acid (12 M, 0.060 mL) was added and stirred at 60°C for 10 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solution was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate on neutral silica gel, followed by chloroform / methanol on basic silica gel). Diethyl ether (1 mL) and hexane (3 mL) were added to the obtained solid, and the mixture was stirred for 15 minutes. The solid was then collected by filtration to give 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)phenol (62 mg) as a solid.

[0257] Example 88: Under an argon atmosphere, potassium carbonate (159 mg), 2-[4-(difluoromethoxy)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (564 mg), and RuPhos Pd G3 (49.3 mg) were added to a mixture of (1R,2R)-2-[(1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino]cyclohexan-1-ol (162 mg), 1,4-dioxane (2 mL), and water (0.500 mL), and the mixture was stirred at 100°C for 1.5 hours. The reaction mixture was cooled to room temperature, and methanol (2 mL) and hydrochloric acid (12 M, 0.590 mL) were added. The mixture was stirred at 60°C for 2 hours. After cooling to room temperature, basic silica gel was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform / methanol on basic silica gel, then chloroform / methanol on neutral silica gel). Ethyl acetate and diisopropyl ether were added to the resulting residue, and the mixture was sonicated. The solid was collected by filtration to give 5-(difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (46.3 mg) as a solid.

[0258] Example 90: To a mixture of tert-butyl 4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-1-[2-hydroxy-4-(trifluoromethyl)phenyl]-7,8-dihydropyrido[3,4-d]pyridazine-6(5H)-carboxylate (171 mg) and dichloromethane (2.6 mL), hydrogen chloride in 1,4-dioxane (4 M, 0.84 mL) was added under ice cooling and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol dihydrochloride (162 mg) as a solid.

[0259] Example 92 Under an argon atmosphere, acetyl chloride (0.041 mL) and pyridine (0.010 mL) were added to a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (46.7 mg), dichloromethane (2 mL), and THF (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was warmed to room temperature, and aqueous sodium hydroxide solution (1 M, 1 mL) was added, followed by stirring at the same temperature for 7 hours. The reaction mixture was ice-cooled, and hydrochloric acid (1 M, 1 mL) was added. The mixture was then warmed to room temperature, and chloroform was added, followed by stirring at the same temperature for 10 minutes. The organic layer was separated and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give 1-[4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-1-[2-hydroxy-4-(trifluoromethyl)phenyl]-7,8-dihydropyrido[3,4-d]pyridazin-6(5H)-yl]ethan-1-one (17.2 mg) as a solid.

[0260] Example 93: Under an argon atmosphere, methanesulfonyl chloride (0.004 mL) and DIPEA (0.039 mL) were added to a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (18.5 mg) and dichloromethane (2 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and chloroform were added to the reaction mixture, which was then warmed to room temperature and stirred for 5 minutes. The organic layer was separated and concentrated (referred to as mixture A). Under an argon atmosphere, methanesulfonyl chloride (0.005 mL) and DIPEA (0.048 mL) were added to a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (22.9 mg) and dichloromethane (3 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate and chloroform were added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 5 minutes. The organic layer was separated and concentrated (referred to as mixture B). Mixture A and mixture B were combined and purified by silica gel column chromatography (chloroform / methanol) to give 2-[4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-(methanesulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol (13.8 mg) as a solid.

[0261] Example 94 Under an argon atmosphere, to a mixture of (1R,2R)-2-({4-[2-methoxy-4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7-yl}amino)cyclohexan-1-ol (210 mg) and dichloromethane (2.5 mL) was added dropwise boron tribromide (17% dichloromethane solution, 2.5 mL) under ice-cooling and stirring, and the mixture was stirred at 0°C for 2 hours. Saturated aqueous sodium bicarbonate and methanol were added to the reaction mixture, and the mixture was extracted with dichloromethane / methanol. 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), and the resulting purified product was triturated with dichloromethane. The precipitated solid was collected by filtration, washed with dichloromethane, and then dried under reduced pressure to give 2-(7-{[(1R,2R)-2-hydroxycyclohexyl]amino}thieno[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (75 mg) as a solid.

[0262] Example 95: To a mixture of tert-butyl [(1R,2R)-2-({4-[2-methoxy-4-(trifluoromethyl)phenyl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl}amino)cyclohexyl]carbamate (73 mg) and dichloromethane (1 mL) was added boron tribromide (17% dichloromethane solution, 0.7 mL) under ice-cooling and stirring, and the mixture was allowed to warm to room temperature while stirring for 5 hours. A saturated aqueous solution of sodium bicarbonate 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 (methanol) to give 2-(1-{[(1R,2R)-2-aminocyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (44 mg) as a solid.

[0263] Example 96 A mixture of tert-butyl (3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydrophthalazin-1-yl}amino)piperidine-1-carboxylate (194 mg), dichloromethane (4 mL), and trifluoroacetic acid (0.66 mL) was stirred at room temperature for 5.5 hours. Water was added to the reaction mixture, and the aqueous layer was washed with dichloromethane. The organic layer was extracted with 10% hydrochloric acid, and the combined aqueous layers were made basic by adding potassium carbonate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane / methanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and hexane. The precipitated solid was collected by filtration and dried under reduced pressure to give 2-(4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (80 mg) as a solid. The filtrate was concentrated under reduced pressure to give 2-(4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (42 mg) as a solid.

[0264] Example 97 A mixture of 2-(4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (42 mg), dichloromethane (1 mL), methanol (0.1 mL), 3-oxetanone (19.9 μL), and sodium triacetoxyborohydride (68 mg) was stirred at room temperature for 5 hours. 3-Oxetanone (39.9 μL) and sodium triacetoxyborohydride (136 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane / methanol. 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-(4-{[(3R)-1-(oxetan-3-yl)piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (45 mg) as a solid.

[0265] Example 98: A mixture of tert-butyl 1-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5,7-dihydro-6H-pyrrolo[3,4-d]pyridazine-6-carboxylate (264 mg), dichloromethane (5 mL), and trifluoroacetic acid (0.9 mL) was stirred at room temperature for 5 hours. To the reaction mixture, saturated aqueous sodium bicarbonate, dichloromethane, and methanol were added under ice-cooling and stirring. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate. The precipitated solid was collected by filtration and dried under reduced pressure to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (72 mg) as a solid. The filtrate was concentrated under reduced pressure to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (21 mg) as a solid.

[0266] Example 99: To a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (70 mg), methanol (1.8 mL), and 37% aqueous formaldehyde solution (20 μL) was added sodium triacetoxyborohydride (75 mg) with stirring at room temperature, followed by stirring at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water. The collected solid was dried and then triturated with hexane / ethyl acetate. The precipitated solid was collected by filtration, washed with hexane, and then dried to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (35 mg) as a solid.

[0267] Example 111: Under an argon atmosphere, a mixture of (1R,2R)-2-[(4-chloro-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)amino]cyclohexan-1-ol (236 mg), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (342 mg), PdCl(dppf)·CHCl (68 mg), potassium carbonate (229 mg), 1,4-dioxane (8 mL), and water (2 mL) was stirred at 107-112°C for 14 hours. After cooling the reaction mixture to room temperature, [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (171 mg) and PdCl(dppf)·CHCl (68 mg) were added, and the mixture was stirred at 110-120°C for an additional 2 hours. The reaction mixture was poured into a mixture of water and saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The purified product was dissolved in a small amount of dichloromethane, and hexane was added. The precipitated solid was collected by filtration and dried to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (39 mg) as a solid.

[0268] Example 112: To a mixture of 1-[4-cyclopropyl-2-(methoxymethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine (250 mg) and ethyl acetate (5 mL) was added a solution of hydrogen chloride in ethyl acetate (4 M, 4 mL) at 25°C and stirred at the same temperature for 1 hour. Water and saturated aqueous sodium bicarbonate were added to the reaction 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 the resulting residue was purified by reverse-phase preparative HPLC (ODS column, ammonia water+ammonium bicarbonate aqueous solution / acetonitrile) to give 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (29.3 mg) as a solid.

[0269] Example 114: A mixture of (1S,3R)-3-({4-[4-(difluoromethyl)-2-(methoxymethoxy)phenyl]-5,7-dihydrofuro[3,4-d]pyridazin-1-yl}amino)cyclohexan-1-ol (122 mg), trifluoroacetic acid (0.48 mL), and dichloromethane (2 mL) was stirred at room temperature for 5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture while stirring under ice cooling until the bubbling subsided, 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 (hexane / ethyl acetate) to give 5-(difluoromethyl)-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)phenol (58 mg) as a solid.

[0270] Example 117: To a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (62 mg), DIPEA (33 μL), and dichloromethane (1.6 mL), acetic anhydride (18 μL) was added with stirring under ice cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was filtered, and the collected solid was washed with dichloromethane and dried to give 1-(1-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4-[2-hydroxy-4-(trifluoromethyl)phenyl]-5,7-dihydro-6H-pyrrolo[3,4-d]pyridazin-6-yl)ethan-1-one (58 mg) as a solid.

[0271] Example 124: To a mixture of 5-(difluoromethoxy)-2-(4-{[(3R)-piperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (100 mg) and THF (4 mL) were added (1H-benzotriazol-1-yl)methanol (86 mg) and sodium acetate (55 mg) at room temperature, followed by stirring at the same temperature for 10 minutes. Sodium triacetoxyborohydride (125 mg) was added to the resulting mixture, followed by stirring at room temperature for 1 hour. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, followed by extraction with chloroform / methanol (9 / 1). The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform / methanol). The resulting purified product was triturated with hexane / ethyl acetate. The solid was collected by filtration and dried under reduced pressure to give 5-(difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (72 mg) as a solid.

[0272] Example 126 A mixture of 2-(4-{[(3R)-piperidin-3-yl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (71 mg), [(1-ethoxycyclopropyl)oxy]tri(methyl)silane (72 μL), sodium cyanoborohydride (17 mg), acetic acid (16 μL), THF (1 mL), and methanol (1 mL) was stirred at 49-54°C for 15.5 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to approximately 7-8 with the addition of 10% aqueous sodium hydroxide, followed by extraction with dichloromethane. The organic layer was washed with 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 (dichloromethane / methanol) to give 2-(4-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (15 mg) as a solid.

[0273] Example 127: To a mixture of 2-(4-{[(1R,2S)-2-{[tert-butyldi(methyl)silyl]oxy}cyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol (60 mg) and methanol (2 mL) was added hydrochloric acid (12 M, 0.5 mL) at room temperature, followed by stirring at the same temperature for 2 hours. The reaction mixture was ice-cooled, and aqueous sodium hydroxide solution (1 M, 6 mL) was added. The mixture was then extracted with chloroform and chloroform / methanol (9 / 1). The combined organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform / methanol). The resulting purified product was triturated with hexane / ethyl acetate. The solid was collected by filtration and dried under reduced pressure to give 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol (25.7 mg) as a solid.

[0274] Example 128: To a mixture of tert-butyl (3R)-3-({1-[2-hydroxy-4-(trifluoromethoxy)phenyl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl}amino)piperidine-1-carboxylate (29 mg) and dichloromethane (2 mL), TFA (0.5 mL) was added at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then THF (4 mL), sodium acetate (15 mg), and (1H-benzotriazol-1-yl)methanol (25 mg) were added to the residue and stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (36 mg) was added to the resulting mixture and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride were added to the reaction mixture, and the mixture was extracted with chloroform / methanol (9 / 1). The aqueous layer was neutralized with 1 M hydrochloric acid and then extracted with chloroform / methanol (9 / 1). The combined organic layers were dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform / methanol). The resulting purified product was triturated with hexane / ethyl acetate. The solid was collected by filtration and dried under reduced pressure to give 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol (14.3 mg) as a solid.

[0275] Example 129: To a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-thiopyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (300 mg), acetonitrile (5 mL), and water (5 mL) was added Oxone (registered trademark) (1.3 g) at 25°C, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. Acetonitrile and water were added to the resulting residue, followed by lyophilization to give 4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-1-[2-hydroxy-4-(trifluoromethyl)phenyl]-7,8-dihydro-6λ. 6 185 mg of 4-thiopyrano[3,4-d]pyridazine-6,6(5H)-dione was obtained as a solid.

[0276] Example 132 A mixture of 2-(7,7-dimethyl-4-{[(3R)-piperidin-3-yl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (50 mg), 2,2-difluoroethyl trifluoromethanesulfonate (19 μL), triethylamine (49 μL), and ethanol (1.2 mL) was stirred at 54-62°C for 17 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water 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 (hexane / ethyl acetate, followed by dichloromethane / methanol). The resulting purified product was dissolved in toluene and extracted with 5% aqueous sodium hydroxide, water, and saturated aqueous sodium chloride. The aqueous layer was washed with toluene, and 10% hydrochloric acid was added, 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. The resulting residue was purified by silica gel column chromatography (dichloromethane / hexane / methanol, then hexane / ethyl acetate) to give 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}-7,7-dimethyl-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (6 mg) as a solid.

[0277] Example 133: To a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (150 mg) and dichloromethane (1.5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.11 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (3 mL) was added and the mixture was stirred 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). Drying under reduced pressure gave 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol monohydrochloride (149 mg) as crystals.

[0278] Example 134: To a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (100 mg) and dichloromethane (2 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.074 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (2 mL) was added and the mixture was stirred at room temperature for 120 hours. The mixture was ice-cooled, and the solid was collected by filtration and washed with cold ethyl acetate (1 mL). The mixture was dried under reduced pressure to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol monohydrochloride (103 mg) as a solid.

[0279] Example 135: To a mixture of 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol (100 mg) and dichloromethane (2 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.071 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (2 mL) was added and stirred at room temperature for 120 hours. The mixture was cooled on ice, and the solid was collected by filtration and washed with cold ethyl acetate (1 mL). The mixture was dried under reduced pressure to give 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol monohydrochloride (95 mg) as crystals.

[0280] Example 136: To a mixture of 5-(difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol (100 mg) and dichloromethane (2 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.147 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (2 mL) was added and stirred at room temperature for 120 hours. The mixture was ice-cooled, and the solid was collected by filtration and washed with cold ethyl acetate (1 mL). The mixture was dried under reduced pressure to give 5-(difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol dihydrochloride (122 mg) as a solid.

[0281] 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.

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315] 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. 【Chemical 1】 (wherein, Ring A is C 5-8 cycloalkenyl, 5- to 11-membered partially unsaturated heterocyclyl, aryl or heteroaryl, R 1 is the same or different from each other and is OH, C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, halogen, cyano, -O-C 1-6 alkyl, -O-halogeno C 1-6 alkyl, or -O-C 3-8 cycloalkyl, and R 2 is the same as or different from each other, C 1-6 alkyl, -C 1-6 alkylene-aryl, C 3-8 cycloalkyl, halogen, -O-C 1-6 alkyl, -O-halogeno C 1-6 alkyl, oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 alkyl, and L is -NR 3 -, -O- or -CR 4 R 5 -, and R 3 is H or C 1-6 is alkyl, R 4 and R 5 are the same or different from each other and are H or C 1-6 alkyl, R 6 is C substituted by 1 to 4 identical or different R 7 alkyl, -C 1-6 alkylene-(1 to 4 identical or different R 1-6 optionally substituted C 8 cycloalkyl), -C 3-8 alkylene-(1 to 4 identical or different R 1-6 optionally substituted 4- to 7-membered saturated heterocyclyl), 1 to 4 identical or different R 9 optionally substituted C 10 cycloalkyl, or 1 to 4 identical or different R 3-8 optionally substituted 4- to 7-membered saturated heterocyclyl, and 11 is R 7 is -OR 12 、-NR 13 R 14 、 halogen, or cyano, and R 8 and R 10 is C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, -OR 12 , -NR 13 R 14 , -C 1-6 alkylene-OR 12 , -C 1-6 alkylene-NR 13 R 14 is halogen, or cyano, R 9 and R 11 is C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , -NR 13 R 14 , -C 1-6 alkylene-OR 12 , -C 1-6 alkylene-NR 13 R 14 , halogen, cyano, oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 , -C 1-6 alkyl, and R 12 is H, or C 1-6 is alkyl, R 13 and R 14 are the same or different from each other and are H, C 1-6 alkyl, or -C(O)-C 1-6 alkyl, and n is an integer from 1 to 4, and represents the number of substituents R 1 and m is an integer from 0 to 3 and represents the number of substituents R 2 and provided that when ring A is aryl or heteroaryl, formula (I) is formula (Ia), [Chemical 2] R 1a is the same or different from each other, and is C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, halogen, cyano, -O-C 1-6 alkyl, -O-halogeno C 1-6 alkyl, or -O-C 3-8 cycloalkyl, and k is an integer from 0 to 3 and represents the number of substituents R 1a .)

2. Ring A is C 5-8 cycloalkenyl, 5- to 8-membered partially unsaturated heterocyclyl, aryl or heteroaryl, R 2 is the same as or different from each other, and is C 1-6 alkyl, -C 1-6 alkylene-aryl, C 3-8 cycloalkyl, halogen, -O-C 1-6 alkyl, -O-halogeno C 1-6 alkyl, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 alkyl, and the compound or a salt thereof according to claim 1.

3. The compound or a salt thereof according to claim 2, wherein formula (I) is formula (Ia).

4. Ring A is C 5-8 The compound or a salt thereof according to claim 3, wherein Ring A is cycloalkenyl or a 5- to 8-membered partially unsaturated heterocyclyl.

5. Formula (I) is formula (Ia), R 1a is the same as or different from each other, C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, halogen, -O-C 1-6 alkyl, or -O-halogeno C 1-6 alkyl, and R 2 is the same as or different from each other, C 1-6 alkyl, oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 is alkyl, L is -NR 3 -, -O- or -CR 4 R 5 - and R 3 is H, R 4 and R 5 is H, R 6 wherein one R 7 substitutes C 1-6 alkyl, -C 1-6 alkylene-(one R 8 optionally substitutes C 3-8 cycloalkyl), -C 1-6 alkylene-(4- to 7-membered saturated heterocyclyl), one or two identical or different R 10 optionally substitutes C 3-8 cycloalkyl, or one or two identical or different R 11 optionally substitutes 4- to 7-membered saturated heterocyclyl; R 7 is -OR 12 or -NR 13 R 14 and R 8 and R 10 is C 1-6 alkyl, -OR 12 , -NR 13 R 14 , -C 1-6 alkylene-OR 12 , halogen, or cyano, and R 9 and R 11 is C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , oxo, or -C(O)-C 1-6 alkyl, and R 12 is H and R 13 and R 14 are both H, or R 13 is -C(O)-C 1-6 alkyl, and R 14 is H k is an integer from 0 to 2 and represents the number of substituents R 1a and wherein m is an integer of 0 to 2, and R which is a substituent 2 represents the number of, the compound according to claim 1 or a salt thereof.

6. Ring A is C 5-8 a cycloalkenyl or a 5- to 11-membered partially unsaturated heterocyclyl, L is -NR 3 - and R 6 wherein one R 7 is substituted for C 1-6 is alkyl, one or two identical or different Rs 10 which may be substituted for C 3-8 is cycloalkyl, or one or two identical or different Rs 11 which may be substituted for a 4- to 7-membered saturated heterocyclyl, and R 10 is C 1-6 alkyl, -OR 12 -NR 13 R 14 -C 1-6 alkylene-OR 12 a halogen, or cyano, and R 11 is C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , oxo, or -C(O)-C 1-6 alkyl, the compound or a salt thereof according to claim 5.

7. Ring A is C 5-8 a cycloalkenyl or a 5- to 8-membered partially unsaturated heterocyclyl, R 1a is the same as or different from each other, and is halogeno C 1-6 alkyl, halogen, or -O-halogeno C 1-6 alkyl, and R 2 is C 1-6 alkyl, and R 6 wherein R is one or two identical or different R 10 which may be substituted with C 3-8 cycloalkyl, or a 4- to 7-membered saturated heterocyclyl which may be substituted with one or two identical or different R 11 and is R 10 is C 1-6 alkyl or -OR 12 and R 11 is C 1-6 alkyl or -OR 12 and k is 1 or 2, and R which is a substituent 1a represents the number of wherein m is 0 or 1, and R is a substituent, and the number of 2 2 is as defined in claim 6, or a salt thereof.

8. Formula (I) is formula (Ia), ring A is a 5- to 11-membered partially unsaturated heterocyclyl, R 1a is the same as or different from each other, C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, halogen, -O-C 1-6 alkyl, or -O-halogeno C 1-6 alkyl, and R 2 is the same as or different from each other, and is C 1-6 alkyl, oxo, -C(O)-C 1-6 alkyl, or -S(O) 2 -C 1-6 alkyl, and L is -NR 3 - and R 3 is H, R 6 wherein one R 7 replaces C 1-6 to form alkyl, or C optionally substituted with one or two identical or different R 10 to form cycloalkyl, or a 4- to 7-membered saturated heterocyclyl optionally substituted with one or two identical or different R 3-8 wherein one or two identical or different R 11 may replace C R 7 is -OR 12 or -NR 13 R 14 and R 10 is C 1-6 alkyl, -OR 12 , -NR 13 R 14 , -C 1-6 alkylene-OR 12 is halogen, or cyano, R 11 is C 1-6 alkyl, halogeno C 1-6 alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclyl, -OR 12 , oxo, or -C(O)-C 1-6 is alkyl, R 12 is H, R 13 and R 14 are both H, or R 13 is -C(O)-C 1-6 alkyl, and R 14 is H k is an integer from 0 to 2 and represents the number of substituents R 1a and wherein m is an integer of 0 to 2, and R which is a substituent 2 represents the number of, the compound according to claim 1 or a salt thereof.

9. Formula (I) is formula (If), (Ig), (Ih), (Ii), (Ij), (Iu), (Iv), (Iw), or (Iy), [Chemical Formula 3] R 11 is C 1-6 alkyl or -OR 12 and is The compound or a salt thereof according to claim 8, wherein m is 0.

10. Formula (I) is formula (Ih), R 10 is C 1-6 alkyl, -OR 12 or cyano, and R 13 is -C(O)-C 1-6 is alkyl, and R 14 is H, the compound or a salt thereof according to claim 9.

11. The compound is, 2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-Hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-Chloro-2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-(Difluoromethoxy)-2-(4-{[(1R,2R)-2-Hydroxycyclohexyl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)phenol, 5-(Difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(Difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, and 5-(Difluoromethyl)-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)phenol The compound or a salt thereof according to claim 1, which is a compound selected from the group consisting of.

12. The compound is 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, 2-(4-{[(1R,2S)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,6,8,9-tetrahydrooxepino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, 5-chloro-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol 5-(Difluoromethoxy)-2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 5-(Difluoromethoxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol, 2-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-5,7-dihydrothieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, and 5-(Difluoromethyl)-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)phenol The compound or a salt thereof according to claim 1, which is a compound selected from the group consisting of.

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

14. The pharmaceutical composition according to claim 13, which is an NLRP3 inflammasome activation inhibitor.

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

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

17. The compound or a salt thereof according to claim 1 for use in the prevention and / or treatment of inflammatory diseases and / or neurodegenerative diseases.

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