Substituted benzene compounds

Abstract

The present invention addresses the problem of providing a compound having an NLRP3 inflammasome activation inhibitory activity and being useful for the prevention and / or treatment of autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases, or a pharmaceutically acceptable salt thereof. The solution of the present invention is a compound represented by general formula (1) or a pharmaceutically acceptable salt thereof, # imgabs0 # [wherein the symbols are as defined below. In the formula, A represents a carbon atom or the like, R1 represents a halogen atom or the like, R1'represents a hydrogen atom or the like, R1 ''represents a hydrogen atom or the like, R1' 'represents a hydrogen atom or the like, R2 represents a hydrogen atom or the like, R2'represents a hydrogen atom or the like, and R3 represents a C1-C3 alkyl group or the like.

Description

Technical Field

[0001] The present invention relates to novel substituted benzene compounds or pharmaceutically acceptable salts thereof having an NLRP3 inflammasome activation inhibitory effect, pharmaceutical compositions containing the compounds as active ingredients, and methods for producing the compounds. Background Art

[0002] NLRP3 (NLR family pyrin domain containing 3) belongs to the NLR family (nucleotide-binding domain and leucine rich repeat-containing family). It is a protein containing a pyrin domain (PYD), a nucleotide-binding site (NACHT) domain, and a leucine-rich repeat (LRR) domain. NLRP3 functions as an intracellular sensor that responds to various inflammatory danger signals, interacting with apoptosis-associated speck-like protein containing aCARD (ASC) and procaspase-1 to form the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome induces the production of the inflammatory cytokines IL-1β and IL-18, and programmed cell death (pyroptosis).

[0003] Activation of the NLRP3 inflammasome and increased production of IL-1β and IL-18 by the NLRP3 inflammasome have been reported in various autoinflammatory diseases, autoimmune diseases, and inflammatory diseases.

[0004] For example, a link has been suggested in the following diseases:

[0005] Cryopyrin-associated periodic syndrome (CAPS), an autoinflammatory disease,

[0006] Autoimmune diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitis syndrome, systemic amyloidosis, etc.

[0007] The following diseases as inflammatory diseases:

[0008] Liver-related diseases, such as alcoholic liver disease (ALD) or alcoholic steatohepatitis (ASH) / non-alcoholic steatohepatitis (NASH) / viral hepatitis, non-alcoholic fatty liver disease (NAFLD), etc.

[0009] Lung related diseases, i.e. chronic obstructive pulmonary disease (COPD) or asthma, acute lung loss (ALI), interstitial lung disease (ILD), sarcoidosis, etc.

[0010] Kidney and urinary diseases, such as diabetic nephropathy or lupus nephritis, primary hyperoxaluria, interstitial cystitis, etc.

[0011] Intestinal diseases, such as inflammatory bowel disease (IBD),

[0012] Joint-related diseases, such as gout / pseudogout or osteoarthritis,

[0013] Cardiovascular / metabolic diseases, i.e. atherosclerosis or type 1 / type 2 diabetes, heart failure, etc.

[0014] Infection-related diseases, such as SARS-CoV-2 infection or EBV infection, viral encephalitis, etc.

[0015] Eye-related diseases, such as glaucoma or optic neuritis, retinitis pigmentosa, age-related macular degeneration, etc.

[0016] Cancer-related diseases, i.e. myeloproliferative neoplasms or leukemia / myelodysplastic syndrome / myelofibrosis / lung cancer / colorectal cancer / tumor collapse syndrome / cytokine release syndrome, etc.

[0017] Neurological diseases, i.e. multiple sclerosis (as a subtype of multiple sclerosis, including relapsing-remitting multiple sclerosis / secondary progressive multiple sclerosis / primary progressive multiple sclerosis) or neurodegenerative diseases (Alzheimer's disease / Huntington's disease / Parkinson's disease / amyotrophic lateral sclerosis / multiple system atrophy / frontotemporal dementia), etc.

[0018] Mental illness, i.e. epilepsy, major depressive disorder / schizophrenia / insomnia / autism spectrum disorder / bipolar disorder / panic disorder / anxiety disorder / phobia / obsessive-compulsive disorder / post-traumatic stress disorder (PTSD) / postoperative delirium / substance-related disorders / eating disorders, etc.

[0019] Cerebrovascular disease, i.e. ischemic stroke / hemorrhagic stroke / traumatic brain injury, etc.

[0020] Therefore, inhibitors of the NLRP3 inflammasome pathway are needed as new therapeutic drugs for these inflammasome-related diseases, and several NLRP3 inflammasome inhibitors have been discovered to date.

[0021] For example, the low-molecular-weight compound MCC-950 has potent NLRP3 inflammasome inhibitory activity and excellent pharmacokinetics, and has demonstrated efficacy in various disease model animals, such as inhibition of IL-1β production and improvement of disease states (Non-Patent Documents 1, 2, and 3).

[0022] Thus, the NLRP3 inflammasome is activated in a variety of autoinflammatory, autoimmune, and / or inflammatory diseases, and NLRP3 inhibitory compounds have demonstrated efficacy in various disease model animals, suggesting the potential of NLRP3 inhibitory compounds as therapeutic agents for NLRP3 inflammasome-associated diseases. In fact, several NLRP3 inhibitory compounds, including MCC-950 analogs, are currently undergoing clinical trials.

[0023] The compound shown below is described in Patent Document 1. It is described that the compound has an NLRP3 inflammasome activation inhibitory effect and is effective for the treatment of inflammatory diseases, neurodegenerative diseases, and the like.

[0024] [Chemical Formula 1]

[0025]

[0026] Patent Document 2 describes the following compound. It is described that the compound has an NLRP3 inflammasome activation inhibitory effect and is effective for the treatment of diseases associated with NLRP3.

[0027] [Chemical Formula 2]

[0028]

[0029] The compound shown below is described in Patent Document 3. It is described that the compound has an NLRP3 inflammasome activation inhibitory effect and is effective for the treatment of diseases associated with NLRP3.

[0030] [Chemical Formula 3]

[0031]

[0032] Patent Document 4 describes the compound shown below. It is described that the compound has an NLRP3 inflammasome activation inhibitory effect and is effective for the treatment of diseases associated with NLRP3.

[0033] [Chemical Formula 4]

[0034]

[0035] The compound shown below is described in Patent Document 5. It is described that the compound has an NLRP3 inflammasome activation inhibitory effect and is effective for the treatment of diseases associated with NLRP3.

[0036] [Chemical Formula 5]

[0037]

[0038] Prior art literature

[0039] Patent Literature

[0040] Patent Document 1: WO2021 / 193897

[0041] Patent Document 2: WO2020 / 234715

[0042] Patent Document 3: WO2020 / 021447

[0043] Patent Document 4: US Pat. No. 11,319,319

[0044] Patent Document 5: WO2022 / 230912

[0045] Non-patent literature

[0046] Non-patent document 1: Coll et al., Nat. Med. 2015, 21, 248-255

[0047] Non-patent literature 2: Perera et al., Sci. Rep. 2018, 8, 8618

[0048] Non-patent literature 3: Zeng et al., Sci. Rep. 2021, 11, 19305 Summary of the Invention

[0049] Problems to be solved by the invention

[0050] The present invention aims to provide a novel compound or a pharmaceutically acceptable salt thereof that has excellent NLRP3 inflammasome activation inhibitory activity and excellent pharmacokinetics, particularly excellent central translocation, and a medicament using the same.

[0051] Means for solving problems

[0052] Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have completed the invention described below.

[0053] [1] is described below as a suitable compound or a pharmaceutically acceptable salt thereof.

[0054] More suitable is [2] or less, and particularly suitable is [8], [9],

[10] ,

[11] , etc. [1]

[0056] A compound of general formula (1) or a pharmaceutically acceptable salt thereof.

[0057] [Chemical Formula 6]

[0058]

[0059] [Where,

[0060] A is a single bond, a nitrogen atom or a carbon atom,

[0061] R 1 is a halogen atom, a cyano group, a C1-C3 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms,

[0062] R 1 ' is a hydrogen atom, a halogen atom or a C1-C3 alkyl group, or

[0063] R 1 With R 1 'Combined with each other to form

[0064] C1-C4 alkylene optionally substituted by 1 to 3 substituents selected from substituent group a, or -NH-(CH2)n- (n represents an integer of 1, 2 or 3) optionally substituted by 1 to 3 substituents selected from substituent group a

[0065] And form a ring structure,

[0066] R 1 " is a hydrogen atom or a halogen atom,

[0067] R 1 "' is a hydrogen atom, a halogen atom, a cyano group or -NH-(CH2)n- (n represents an integer of 1, 2 or 3),

[0068] When A is a nitrogen atom,

[0069] R 2 and A are combined with each other to form any partial structure selected from the group shown below:

[0070] [Chemical Formula 7]

[0071]

[0072] , where the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group a.

[0073] In addition, when A is a single bond or a carbon atom,

[0074] R 2 is a hydrogen atom, or a C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from substituent group a, or

[0075] R 2 and A are combined with each other to form any partial structure selected from the group shown below:

[0076] [Chemical Formula 8]

[0077]

[0078] , where the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group a.

[0079] R 2 ' is a hydrogen atom or a C1-C3 alkyl group, or

[0080] R 2 'with R 2 Combined with each other to form -NH-(CH2)n- (n represents an integer of 1, 2 or 3) and constitute a ring structure,

[0081] R 3 for

[0082] C1-C3 alkyl optionally substituted by 1 to 3 substituents selected from substituent group b, C2-C3 alkenyl optionally substituted by 1 to 3 substituents selected from substituent group b, C3-C6 cycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b,

[0083] C5-C8 bicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b,

[0084] C5-C8 azabicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b,

[0085] C5-C8 oxabicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b, 3-6 membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b, or

[0086] A 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group b.

[0087] The substituent group a is composed of a halogen atom, a cyano group, a C2-C3 alkenyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, a C2-C4 alkanediyl group (including 1,3-butadiene-1,4-diyl), a C1-C3 oxyalkylene group, and a cyclopropylethynyl group.

[0088] The substituent group b is composed of a hydroxyl group, a halogen atom, a hydroxy C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkylmethyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, and a 5-membered oxygen-containing saturated heterocyclic group.

[0089] [2] A compound of formula (1a) or a pharmaceutically acceptable salt thereof,

[0090] [Chemical Formula 9]

[0091]

[0092] [Where,

[0093] A is a nitrogen atom,

[0094] R 1 is a halogen atom, a cyano group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms,

[0095] R 1 ' is a hydrogen atom, a halogen atom or a C1-C3 alkyl group, or

[0096] R 1 With R 1 ' are combined with each other to form a C1-C4 alkylene group which is optionally substituted with 1 to 3 substituents selected from substituent group a' and constitute a ring structure,

[0097] R 1 " is a hydrogen atom or a halogen atom,

[0098] R 1 "' is a hydrogen atom, a halogen atom, a cyano group or a methyl group,

[0099] R 2 and A are combined with each other to form any partial structure selected from the group shown below:

[0100] [Chemical Formula 10]

[0101]

[0102] , where the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the substituted state, the partial structure is optionally substituted by 1 to 3 substituents selected from the substituent group a',

[0103] R 2 ' is a hydrogen atom or a C1-C3 alkyl group,

[0104] Or, R 2 'with R 2 Combined with each other to form -NH-(CH2)n- (n represents an integer of 1, 2 or 3) and constitute a ring structure,

[0105] R 3 for

[0106] C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from substituent group b',

[0107] C3-C6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b',

[0108] a C5-C8 bicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b',

[0109] C5-C8 azabicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b',

[0110] C5-C8 oxabicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b', 3-6 membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b', or

[0111] A 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group b'.

[0112] The substituent group a' is composed of a halogen atom, a cyano group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, a C2-C4 alkanediyl group (including 1,3-butadiene-1,4-diyl), a C1-C3 oxyalkylene group, and a cyclopropylethynyl group.

[0113] The substituent group b' is composed of a hydroxyl group, a halogen atom, a C1-C3 alkyl group, a hydroxy C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group and a 5-membered oxygen-containing saturated heterocyclic group.].

[0114] [3] A compound of formula (1b) or a pharmaceutically acceptable salt thereof,

[0115] [Chemical Formula 11]

[0116]

[0117] [Where,

[0118] R 1 is a halogen atom, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms,

[0119] R 2 and nitrogen atoms to form any partial structure selected from the group shown below:

[0120] [Chemical Formula 12]

[0121]

[0122] , where the left end of this part of the structure is R 2 The right end of this partial structure is the connecting bond of the nitrogen atom, which is represented by R for convenience. 3 In the state of substitution, the partial structure may be substituted by 1 to 3 substituents selected from the substituent group a",

[0123] R 3 for

[0124] C3-C6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b",

[0125] C6-C7 bicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b",

[0126] a 3-6 membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b", or

[0127] A 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group b".

[0128] Substituent group a" consists of a halogen atom, a cyano group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group and a C1-C3 oxyalkylene group,

[0129] Substituent group b" consists of a hydroxyl group, a halogen atom and a C1-C3 alkyl group.].

[0130] [4] The compound according to [3] or a pharmaceutically acceptable salt thereof, wherein R 1 is a trifluoromethyl group, a chlorine atom, a difluoromethoxy group, or a trifluoromethoxy group.

[0131] [5] The compound according to [3] or [4], or a pharmaceutically acceptable salt thereof, wherein:

[0132] R 2 and nitrogen atoms to form any partial structure selected from the group shown below:

[0133] [Chemical Formula 13]

[0134]

[0135] , where the left end of this part of the structure is R 2 The right end of this partial structure is the connecting bond of the nitrogen atom, which is represented by R for convenience. 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group a".

[0136] [6] The compound or pharmaceutically acceptable salt thereof according to any one of [3] to [5], wherein the partial structure is optionally substituted by 1 to 3 substituents selected from a cyano group, a fluorine atom, a methyl group, a methoxy group, a difluoromethoxy group, a propylene group, a 1-oxyethylene group, and a 2-oxyethylene group.

[0137] [7] The compound according to any one of [3] to [6] or a pharmaceutically acceptable salt thereof, wherein

[0138] R 3 is any substituent selected from the group consisting of:

[0139] [Chemical Formula 14]

[0140]

[0141] [8] Any compound selected from the following group or a pharmaceutically acceptable salt thereof,

[0142] 3-methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0143] 3-methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0144] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0145] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0146] 2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0147] 5-chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,

[0148] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0149] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0150] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0151] 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0152] 5-(difluoromethoxy)-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,

[0153] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethoxy)phenol,

[0154] 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol,

[0155] 5-chloro-2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,

[0156] 5-chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,

[0157] 5-chloro-2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol,

[0158] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0159] 7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile,

[0160] 2-[7-(5-fluoropyrimidin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,

[0161] 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,

[0162] 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,

[0163] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol. [9]

[0165] 2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0166] 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0167] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol,

[0168] 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol,

[0169] 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, or

[0170] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[10]

[0172] 2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[11]

[0174] 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[12]

[0176] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[13]

[0178] 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[14]

[0180] 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[15]

[0182] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[16]

[0184] A compound of general formula (1c) or a pharmaceutically acceptable salt thereof,

[0185] [Chemical Formula 15]

[0186]

[0187] [Where,

[0188] A is a single bond or a carbon atom,

[0189] R 1 is a halogen atom, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms,

[0190] R 2 is a hydrogen atom, or a C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from Substituent Group C, or

[0191] R 2 and A are combined with each other to form any partial structure selected from the group shown below:

[0192] [Chemical Formula 16]

[0193]

[0194] , where the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the substituted state, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group c,

[0195] R 3 for

[0196] C3-C6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group d,

[0197] C6-C7 bicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group d, or

[0198] A 3- to 6-membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group d.

[0199] The substituent group c is composed of a halogen atom, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, and a C1-C3 oxyalkylene group,

[0200] The substituent group d is composed of a hydroxyl group and a C1-C3 alkyl group. ].

[0201]

[17] The compound according to

[16] or a pharmaceutically acceptable salt thereof, wherein R 1 is a trifluoromethyl group, a chlorine atom, a difluoromethoxy group or a trifluoromethoxy group.

[0202]

[18] The compound according to

[16] or a pharmaceutically acceptable salt thereof, wherein R 1 It is trifluoromethyl.

[0203]

[19] The compound according to any one of

[16] to

[18] or a pharmaceutically acceptable salt thereof, wherein R 2 A hydrogen atom.

[0204]

[20] The compound according to any one of

[16] to

[18] or a pharmaceutically acceptable salt thereof, wherein

[0205] R 2 and A are combined with each other to form any partial structure selected from the group shown below:

[0206] [Chemical Formula 17]

[0207]

[0208] , where the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from Substituent Group C. [twenty one]

[0210] The compound or pharmaceutically acceptable salt thereof according to any one of

[16] to

[20] , wherein R 3 is any substituent selected from the following substituents,

[0211] [Chemical Formula 18]

[0212] [twenty two]

[0214] Any compound selected from the following group or a pharmaceutically acceptable salt thereof,

[0215] 3-methyl-2-{6-[(1-methylpiperidin-3-yl)methyl]pyridazin-3-yl}-5-(trifluoromethyl)phenol,

[0216] 3-methyl-2-[5-methyl-7-(1-methylpiperidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol,

[0217] 3-methyl-2-[7-(1-methylpiperidin-3-yl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol,

[0218] 3-methyl-2-{8-[(3R)-1-methylpiperidin-3-yl]cinnolin-3-yl}-5-(trifluoromethyl)phenol, 2-{8-[(3R)-1-ethylpiperidin-3-yl]cinnolin-3-yl}-3-methyl-5-(trifluoromethyl)phenol. [twenty three]

[0220] A pharmaceutical composition comprising the compound according to any one of [1] to

[22] or a pharmaceutically acceptable salt thereof as an active ingredient. [twenty four]

[0222] The pharmaceutical composition according to

[23] is used for inhibiting NLRP3 inflammasome activation.

[25]

[0224] The pharmaceutical composition according to

[23] is used for inhibiting the production of inflammatory cytokines mediated by NLRP3 inflammasome activation.

[26]

[0226] The pharmaceutical composition according to

[23] is used for inhibiting inflammatory response mediated by NLRP3 inflammasome activation.

[27]

[0228] The pharmaceutical composition according to

[23] is used for treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases.

[28]

[0230] The pharmaceutical composition according to

[27] , wherein the autoinflammatory disease, autoimmune disease and / or inflammatory disease is a disease selected from the following diseases:

[0231] Cryopyrin-associated periodic syndrome (CAPS), systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitic syndromes, systemic amyloidosis, alcoholic liver disease (ALD), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), viral hepatitis, nonalcoholic fatty liver disease (NAFLD), chronic obstructive pulmonary disease (COPD), asthma, acute lung loss (ALI), interstitial lung disease (ILD), sarcoidosis, diabetic nephropathy, lupus nephritis, primary hyperoxaluria, interstitial cystitis, inflammatory bowel disease (IBD), gout, pseudogout, osteoarthritis, atherosclerosis, type 1 / type 2 diabetes, heart failure, SARS-CoV-2 infection, EBV infection, viruses encephalitis, glaucoma, optic neuritis, retinitis pigmentosa, age-related maculopathy, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colorectal cancer, tumor disintegration syndrome / cytokine release syndrome, multiple sclerosis (as a subtype of multiple sclerosis, including relapsing-remitting multiple sclerosis / secondary progressive multiple sclerosis / primary progressive multiple sclerosis), Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, frontotemporal dementia, epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorders, phobias, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorders, eating disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury.

[29]

[0233] The pharmaceutical composition according to

[23] is used to treat multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, frontotemporal dementia, epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorder, eating disorder, ischemic stroke, hemorrhagic stroke, or traumatic brain injury.

[30]

[0235] The pharmaceutical composition according to

[23] is used to treat multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, major depressive disorder, schizophrenia, or autism spectrum disorder.

[31]

[0237] The pharmaceutical composition according to

[23] is used for treating multiple sclerosis.

[32]

[0239] The pharmaceutical composition according to

[23] is used for treating Alzheimer's disease.

[33]

[0241] The pharmaceutical composition according to

[23] is used for treating Parkinson's disease.

[34]

[0243] The pharmaceutical composition according to

[23] is used for treating multiple system atrophy.

[35]

[0245] The pharmaceutical composition according to

[23] is used for treating major depressive disorder.

[36]

[0247] The pharmaceutical composition according to

[23] is used for treating schizophrenia.

[37]

[0249] The pharmaceutical composition according to

[23] is used for treating autism spectrum disorder.

[38]

[0251] Use of the compound according to any one of [1] to

[22] or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition.

[39]

[0253] The use according to

[23] , wherein the pharmaceutical composition is used to treat autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases.

[40]

[0255] A preparation for administration to a mammal for treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases, comprising an effective amount of the compound described in any one of [1] to

[22] or a pharmaceutically acceptable salt thereof.

[41]

[0257] A method for treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases using the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[22] .

[0258] Effects of the Invention

[0259] The present invention provides novel compounds or pharmaceutically acceptable salts thereof that have excellent NLRP3 inflammasome activation inhibitory activity and unexpectedly excellent pharmacokinetics, particularly excellent central translocation properties. DETAILED DESCRIPTION

[0260] The following are definitions of the terms and symbols used in this specification. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art in the art to which the present invention belongs.

[0261] The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0262] "Carbon atom" refers to a carbon atom having four bonds, and is usually bonded to a substituent. In this specification, unless it is explicitly stated that a substituent is bonded to a bond, it is assumed that a hydrogen atom is bonded to the bond.

[0263] "Nitrogen atom" refers to a nitrogen atom having three bonds, and is usually bonded to a substituent. In this specification, unless it is explicitly stated that a substituent is bonded to a bond, it is assumed that a hydrogen atom is bonded to the bond.

[0264] The "C1-C3 alkyl group" refers to a linear or branched alkyl group having 1 to 3 carbon atoms. Examples of the C1-C3 alkyl group include methyl, ethyl, n-propyl, and isopropyl.

[0265] A "hydroxy C1-C4 alkoxy group" refers to a group formed by bonding a hydroxy group to a "C1-C4 alkyl group." Examples of the hydroxy C1-C4 alkoxy group include hydroxy-methyl, 2-hydroxy-ethyl, 1-hydroxy-ethyl, 3-hydroxy-n-propyl, 2-hydroxy-isopropyl, and 2-hydroxy-2,2-dimethyl-ethyl.

[0266] The "C1-C3 alkoxy group" refers to a group in which the above-mentioned "C1-C3 alkyl group" is bonded to an oxygen atom. Examples of the C1-C3 alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group.

[0267] "C1-C4 alkylene" refers to a linear or branched alkylene group having 1 to 4 carbon atoms. Examples of C1-C4 alkylene include methylene, 1,2-ethylene, 1,3-propylene, 1,2-isopropylene, 1,4-butylene, and 1,3-isobutylene.

[0268] "-NH-(CH2)n- (n represents an integer of 1, 2, or 3)" refers to a group formed by bonding a "C1-C3 alkylene group" to an amino group. Examples of -NH-(CH2)n- (n represents an integer of 1, 2, or 3) include aminomethylene, 1-amino-1,2-ethylene, 1-amino-1,3-propylene, 1-amino-1,2-isopropylene, 1-amino-1,4-butylene, and 1-amino-1,3-isobutylene.

[0269] "C1-C3 oxyalkylene" refers to a group formed by bonding a C1-C3 alkylene group to an oxygen atom. Examples of C1-C3 oxyalkylene include oxy-methylene, 1-oxy-1,2-ethylene, 2-oxy-1,3-ethylene, 1-oxy-1,3-propylene, 1-oxy-1,2-isopropylene, 1-oxy-1,4-butylene, and 1-oxy-1,3-isobutylene.

[0270] "C2-C4 alkanediyl (including 1,3-butadiene-1,4-diyl)" refers to an alkanediyl group having 2 to 4 carbon atoms. Examples of the C2-C4 alkanediyl group include 1,2-vinylene and 1,3-butadiene-1,4-diyl.

[0271] The "C3-C6 cycloalkyl group" refers to a 3- to 6-membered monocyclic saturated hydrocarbon ring group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0272] The "C3-C6 cycloalkylmethyl group" refers to a group in which the above-mentioned "C3-C6 cycloalkyl group" is bonded to a methyl group, and examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0273] The "C5-C8 bicycloalkyl group" refers to a bicycloalkyl group having 5 to 8 carbon atoms, and examples thereof include the following groups.

[0274] [Chemical Formula 19]

[0275]

[0276] The "C5-C8 azabicycloalkyl group" refers to a group in which one carbon atom of the above-mentioned "C5-C8 bicycloalkyl group" is replaced by a nitrogen atom, and examples thereof include the following groups.

[0277] [Chemical Formula 20]

[0278]

[0279] The "C5-C8 oxabicycloalkyl group" means a group in which one carbon atom of the above-mentioned "C5-C8 bicycloalkyl group" is replaced by an oxygen atom, and examples thereof include the following groups.

[0280] [Chemical Formula 21]

[0281]

[0282] The "3- to 6-membered nitrogen-containing saturated heterocyclic group" refers to a 3- to 6-membered nitrogen-containing saturated heterocyclic group, and examples thereof include aziridinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, and piperazinyl.

[0283] The "5- to 6-membered nitrogen-containing aromatic heterocyclic group" refers to a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group, and examples thereof include pyrrolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0284] The "5-membered oxygen-containing saturated heterocyclic group" refers to a 5-membered monocyclic oxygen-containing saturated heterocyclic group, and examples thereof include tetrahydrofuran.

[0285] "Optionally substituted" means that any position is unsubstituted or substituted with a specific number of specific substituents (any hydrogen atom is replaced with a substituent).

[0286] "Pharmaceutically acceptable salt" refers to salts that can be used as pharmaceuticals, including both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0287] "Treatment" and its derivatives refer to the alleviation, alleviation or delay of the worsening of clinical symptoms of a disease, condition, disorder, etc. (hereinafter referred to as "disease, etc.") in a patient suffering from the disease, condition, disorder, etc.

[0288] "Prevention" and its derivatives refer to hindering, inhibiting, controlling, slowing down or stopping the onset of clinical symptoms of a disease etc. in a person who may develop the disease etc. but has not yet developed the disease, or in a person who is concerned about the recurrence of the disease etc. after treatment of the disease etc.

[0289] When the compound of the present invention has a basic group such as a nitrogen-containing heterocyclic group in the molecule, it can generally form a pharmaceutically acceptable acid addition salt. Examples of such acid addition salts include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; aryl sulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleic acid, mucic acid, and adipate; and amino acid salts such as ornithine, glutamate, and aspartate. Among these, hydrohalide salts, aryl sulfonates, and organic acid salts are preferred.

[0290] Acid addition salts of the compounds of the present invention include acid addition salts formed by combining an acid added to the compound of the present invention with the compound of the present invention in any ratio. For example, hydrochloride includes salts that can be formed such as monohydrochloride, dihydrochloride, and trihydrochloride; fumarate includes salts that can be formed such as monofumarate and 1 / 2fumarate; and succinate includes salts that can be formed such as monosuccinate, 2 / 3 succinate, and 1 / 3 succinate.

[0291] When the compound of the present invention has a carboxyl group in the molecule, it can generally form a pharmaceutically acceptable base addition salt. Examples of such base addition salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as dibenzylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts.

[0292] When the compounds of the present invention have an asymmetric carbon atom in the molecule, they may exist as multiple stereoisomers (i.e., diastereomers, optical isomers) based on the asymmetric carbon atom, and the present invention includes any one of these stereoisomers, as well as mixtures containing a plurality of these stereoisomers in any ratio. In addition, isomers based on conformation or tautomerism may sometimes be generated, and such isomers or mixtures thereof are also included in the compounds of the present invention.

[0293] In the names of the compounds of the present invention, when the compound has a carbon atom serving as an asymmetric center in its structure, its absolute configuration is represented by R and S (described together with a position number).

[0294] Furthermore, when optical isomers are isolated, if the stereoconfiguration of the carbon atom serving as an asymmetric center in the structure of the compound is undefined, it is also represented by R* or S*.

[0295] In addition, by using R* and S* simultaneously, the relative configuration may be expressed even when the absolute configuration is not determined.

[0296] Furthermore, in this specification, specific examples of cases where the absolute configuration is undetermined are described below. For example, in Example 19, although a single enantiomer was isolated, its absolute configuration is undetermined. In this specification, such a compound is named "3-methyl-2-{7-[(1R,2R,5S or 1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol."

[0297] [Chemical Formula 22]

[0298]

[0299] Specifically, for portions whose absolute configuration is undetermined, they are expressed as (1R,2R,5S or 1S,2S,5R)- to indicate that their absolute configuration is a single enantiomer of either 1R,2R,5S or 1S,2S,5R. It should be noted that, in the above structural formulas, the stereostructure of a single enantiomer is expressed for convenience, but in reality, its absolute configuration is undetermined.

[0300] Furthermore, the nomenclature of the steric configuration in this specification is explained below.

[0301] Among the compounds of the present invention, there are many compounds having a 3-hydroxy-3-methylcyclobutyl structure as a partial structure thereof, as shown below.

[0302] In this specification, the following partial structures are described as

[0303] (1s,3s)-3-hydroxy-3-methylcyclobutyl, or

[0304] cis-3-hydroxy-3-methylcyclobutyl.

[0305] [Chemical Formula 23]

[0306]

[0307] For example, in Example 3, the compound having the following structure is described as

[0308] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or

[0309] 2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol

[0310] , but they all represent the same compound.

[0311] [Chemical Formula 24]

[0312]

[0313] It goes without saying that the "yields" described in the examples of the compounds of the present invention may contain impurities within a range considered in the field of organic synthesis according to common sense.

[0314] Among the diastereomers described in the examples of the compounds of the present invention, the diastereomers may be contained in equal proportions, or a specific diastereomer may be contained in a larger proportion, or a single diastereomer may be present.

[0315] The term "single diastereomer" means that the content of a specific diastereomer in a mixture of diastereomers may be 75% or more, 80% or more, or 90% or more.

[0316] In the examples of the compounds of the present invention, the enantiomeric excess (ee) of the enantiomers is not particularly described.

[0317] In this case, the ee is not particularly limited, and may be, for example, 0% ee or higher (including racemic forms), 20% ee or higher, 40% ee or higher, 60% ee or higher, 80% ee or higher, or 90% ee or higher.

[0318] The term "single enantiomer" means that in a mixture of enantiomers, the ee is, for example, 95% ee or higher, 96% ee or higher, 98% ee or higher, or 99% ee or higher.

[0319] The compounds of the present invention may be compounds labeled or substituted with isotopes (e.g., 2H, 3H, 13C, 14C, 15N, 18F, 32P, 35S, 125I, etc.). Compounds labeled or substituted with isotopes can be used as therapeutic or preventive agents, research reagents (e.g., analytical reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds of the present invention containing radioactive or non-radioactive isotopes in all proportions are within the scope of the present invention.

[0320] The compound of the present invention or a pharmaceutically acceptable salt thereof may be a crystal, and the crystal form may be a single crystal form or a mixture of multiple crystal forms.

[0321] The compounds of the present invention may exist as an unsolvated form or a solvated form. The solvated form is not particularly limited as long as it is pharmaceutically acceptable, but specifically, hydrates, ethanolates, and the like are preferred.

[0322] The compounds of the present invention may be prodrugs.

[0323] The prodrug of the compound of the present invention refers to a compound that is converted into a compound in vivo by a reaction based on an enzyme or gastric acid, etc. As a prodrug of a compound, substances having a structure that is easily hydrolyzed or metabolized after administration to humans are conceivable.

[0324] Examples of prodrugs of the compound include: when the compound has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, a compound in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidinylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); and when the compound has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxyl group is acetylated, Examples include compounds in which the carboxyl group of the compound is esterified or amidated (for example, compounds in which the carboxyl group of the compound is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalyl esterified, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidated).

[0325] Prodrugs of the compounds of the present invention can be prepared from the compounds by known methods. Furthermore, prodrugs of the compounds also include substances that transform into compounds under physiological conditions, as described in "Drug Development (Yiyaopin no Kaifa)" (Molecular Design, Volume 7, pp. 163-198), published by Hirokawa Shoten in 1990. Furthermore, the prodrugs of the compounds may be either hydrates or non-hydrates.

[0326] The compound of the present invention can also be used as a partial structure of a degradation-inducing substance for target proteins collectively referred to as TPD (Targeted Protein Degradation) by binding to a ligand of E3 ubiquitin ligase via a linker structure at any position of its chemical structure. TPD using the compound of the present invention can be prepared using any known method, for example, the method described in the following patent documents WO2015 / 160845, WO2016 / 197032, WO2019 / 199816, WO2017 / 011371, WO2016 / 105518, US10849980 B, US10464925 B, WO2013106643, US10730862 B, WO2022 / 081927, WO2022 / 081928, WO2017 / 197051, WO2019 / 060742, WO2019 / 060693, WO2019 / 099868, WO2018 / 237026, etc.

[0327] (Method for producing the compound of the present invention)

[0328] Hereinafter, a representative method for producing the compound of the present invention or a pharmaceutically acceptable salt thereof will be described.

[0329] The compound of the present invention can be produced by various production methods. The production methods shown below, and the reference examples and examples described later are merely examples, and the present invention should not be construed as being limited to these examples.

[0330] Each starting compound may also form a salt as long as it does not inhibit the reaction. Examples of the salt include the same salts as the pharmaceutically acceptable salts of the above-mentioned compounds.

[0331] Raw material compound, when not describing specific preparation method, can easily obtain commercially available product and use, or can be manufactured according to the method known to itself or according to the method of this method.In addition, the manufacturing intermediate generated in the following manufacture method can utilize the method for column chromatography (comprising normal phase and reverse phase) that has used silica gel or aluminum oxide etc., recrystallization, reprecipitation, distillation etc. to carry out separation and purification, or also can be directly used for following reaction without separation and purification.

[0332] The contents of all patent documents, non-patent documents or reference documents explicitly cited in this specification may be incorporated herein as part of this specification.

[0333] Compounds, pharmaceutically acceptable salts thereof, and their manufacturing intermediates can be manufactured by applying various known manufacturing methods based on the characteristics of the types of their basic skeletons or substituents. As known methods, for example, there are "Organic Functional Group Preparations", 2nd edition, Academic Press, Inc., 1989, "Comprehensive Organic Transformations", 2nd edition, VCH Publishers Inc., 1999, etc., the method described in.

[0334] In this case, depending on the type of functional group present in the compound, it may be effective from a production technical perspective to protect the functional group with an appropriate protecting group at the stage of a raw material or intermediate, or to replace the functional group with a group that can be easily converted into the functional group.

[0335] Examples of such functional groups include amino, hydroxyl, formyl, carbonyl, and carboxyl groups, and examples of their protecting groups include those described in PGWuts, “Protective Groups in Organic Synthesis”, 5th edition, Wiley, 2014.

[0336] The protecting group or the group that can be easily converted into the functional group may be appropriately selected and used according to the reaction conditions of each production method used for producing the compound.

[0337] According to such a method, the desired compound can be obtained by introducing the group and carrying out the reaction, and then removing the protecting group as needed or converting the group into the desired group.

[0338] In addition, the prodrug of the compound can be prepared by introducing a specific group into the raw material or intermediate stage, similarly to the above-mentioned protecting group, or by reacting the obtained compound. The reaction for preparing the prodrug can be carried out by applying conventional methods known to those skilled in the art, such as esterification, amidation, dehydration, hydrogenation, etc.

[0339] Furthermore, conversion of the functional group on the heterocyclic ring in the production intermediate used in each step of the following method can be carried out by a known method or a method in accordance therewith, or by a method described in the Examples below or a method in accordance therewith.

[0340] The compound of the present invention can be produced, for example, by the following method.

[0341] In the reaction of each step in the following method, the reaction temperature varies depending on the solvent, starting materials, reagents, etc., and the reaction time varies depending on the solvent, starting materials, reagents, reaction temperature, etc. In addition, the amount of the solvent, starting materials, reagents, etc. used can be appropriately determined according to the progress of the reaction.

[0342] Furthermore, conversion of functional groups on rings or use of protecting groups in production intermediates used in each step of the following method can be performed by known methods or methods in accordance therewith, or methods described in the Examples below or methods in accordance therewith.

[0343] In the following description, the abbreviations shown here are sometimes used.

[0344] DCE:1,2-dichloroethane

[0345] DCM: dichloromethane

[0346] DDQ:2,3-dichloro-5,6-dicyano-p-benzoquinone

[0347] DEE: Diethyl ether

[0348] DIPEA:N,N-diisopropylethylamine

[0349] DMF:N,N-dimethylformamide

[0350] DMSO: dimethyl sulfoxide

[0351] NMP: N-methyl-2-pyrrolidone

[0352] Pd2(dba)3:Tris(dibenzylideneacetone)dipalladium(0)

[0353] Pd(dppf)Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct

[0354] Pd(PPh3)4:Tetrakis(triphenylphosphine)palladium(0)

[0355] RuPhos:2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0356] TBAF:Tetrabutylammonium fluoride

[0357] tBuXPhos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0358] tBuXPhos Pd G1:[2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride

[0359] TEA:Triethylamine

[0360] TFA: trifluoroacetic acid

[0361] Tf2O:Trifluoromethanesulfonic anhydride

[0362] THF:Tetrahydrofuran

[0363] XPhos:2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0364] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0365] XPhos Pd G3:(2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0366] (Method A)

[0367] Method A represents a method for producing compound (A-VII), (A-IX) or (A-XI) of the present invention.

[0368] [Chemical Formula 25]

[0369]

[0370] (Where R 4 represents a hydrogen atom, or a substituent selected from the above-mentioned substituent group a, R A represents a hydrogen atom or a substituent selected from the above-mentioned substituent group a, and other symbols used have the same meanings as above. )

[0371] (A1 process)

[0372] This step A1 is a step of producing compound (A-III) by reacting compound (AI) and compound (A-II) in a solvent in the presence of a base.

[0373] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 1-decanol, water, acetonitrile, NMP, DMF, DMSO, and mixtures thereof, with NMP and 1,4-dioxane being suitable.

[0374] Examples of the base used include organic bases such as TEA and DIPEA, and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate, with DIPEA being suitable.

[0375] The reaction temperature is usually 0°C to 200°C, and suitably 100°C to 150°C.

[0376] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0377] Alternatively, this reaction can also be carried out under microwave irradiation.

[0378] (A2 process)

[0379] The A2 process is in R 4 =H, a step of preparing compound (A-IV) by reacting compound (A-III) with an oxidizing agent in a solvent.

[0380] Examples of the solvent include halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, and ethers such as DEE, THF, and 1,4-dioxane, with DCE being suitable.

[0381] As the oxidizing agent used, for example, manganese dioxide, DDQ, and oxygen are included, and manganese dioxide and DDQ are suitable.

[0382] The reaction temperature is usually 0°C to 200°C, and suitably 80°C.

[0383] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0384] (A3 process)

[0385] In step A3, a substituent R is introduced by reacting compound (A-IV) using any of the methods from step A3-1 to step A3-3. A A process for producing compound (AV).

[0386] (A3-1 process)

[0387] The A3-1 step is to treat compound (A-IV) by

[0388] (1) Step of introducing acetoxy group,

[0389] (2) a step of converting an acetoxy group into a hydroxyl group,

[0390] (3) Alkylation of hydroxyl groups

[0391] A process for producing compound (AV).

[0392] Hereinafter, each step will be further described.

[0393] (1) Step of introducing acetoxy group

[0394] This step is a step of reacting compound (A-IV) with an oxidizing agent in a solvent to produce a compound into which an acetoxy group has been introduced.

[0395] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO. 1,4-dioxane and acetic acid are suitable.

[0396] Examples of the catalyst used include palladium (II) acetate, copper (II) acetate, and manganese (III) acetate, with palladium (II) acetate being suitable.

[0397] Examples of the oxidizing agent include diacetoxyiodobenzene and [bis(trifluoroacetoxy)iodo]benzene, with diacetoxyiodobenzene being suitable.

[0398] The reaction temperature is usually 0°C to 200°C, and suitably 100°C.

[0399] The reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 3 hours.

[0400] (2) Step of converting acetoxy groups into hydroxyl groups

[0401] Examples of the solvent used include alcohols such as methanol and ethanol, with methanol being suitable.

[0402] Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as potassium hydrogen carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and potassium carbonate is suitable.

[0403] The reaction temperature is usually 0°C to 100°C, preferably room temperature.

[0404] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 3 hours.

[0405] (3) Alkylation of hydroxyl groups

[0406] Examples of the solvent include ethers such as THF and 1,4-dioxane, amides such as DMF and N,N-dimethylacetamide, nitriles such as acetonitrile, sulfoxides such as DMSO, water, and mixtures thereof, with DMF, acetonitrile, and water being suitable.

[0407] Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as potassium hydrogen carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, with potassium carbonate and potassium hydroxide being suitable.

[0408] Examples of the alkylating agent include methyl iodide, ethyl iodide, diethyl (bromodifluoromethyl)phosphonate, and sodium bromodifluoroacetate.

[0409] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0410] The reaction time is generally 5 minutes to 48 hours, suitably 30 minutes to 24 hours.

[0411] (A3-2 process)

[0412] This step is for compound (A-IV),

[0413] (1) The process of introducing iodine groups,

[0414] (2) Process of converting iodine group into cyano group

[0415] A process for producing compound (AV).

[0416] Hereinafter, each step will be further described.

[0417] (1) Process of introducing iodine groups

[0418] This step is a step of producing a compound into which an iodine group has been introduced by reacting compound (A-IV) in a solvent.

[0419] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DCE being suitable.

[0420] Examples of the iodination agent include N-iodosuccinimide and iodine, with N-iodosuccinimide being suitable.

[0421] The reaction temperature is usually 0°C to 200°C, suitably 60°C to 80°C.

[0422] The reaction time is generally 5 minutes to 48 hours, suitably 1 hour to 5 hours.

[0423] (2) Process of converting iodine group into cyano group

[0424] The solvent used includes, for example, ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, sulfoxides such as DMSO, and mixed solvents thereof, with DMF, 1,4-dioxane, and water being suitable.

[0425] Examples of the catalyst used include Pd(PPh3)4, Pd2(dba)3, and tBuXPhos PdG1, with Pd2(dba)3, Pd(PPh3)4, and tBuXPhos PdG1 being suitable.

[0426] Suitable cyaniding agents to be used include zinc cyanide and potassium hexacyanoferrate (II) trihydrate.

[0427] Suitable additives to be used include tBuXPhos and XPhos.

[0428] The reaction temperature is usually 0°C to 200°C, and suitably 100°C.

[0429] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0430] (A3-3 process)

[0431] This step A3-3 is a step of producing compound (AV) by reacting compound (A-IV) in a solvent to introduce fluorine.

[0432] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, sulfoxides such as DMSO, and water, with acetonitrile being suitable.

[0433] Examples of the fluorinating agent include Selectfluor (registered trademark), N-fluorobenzenesulfonimide, and 1-fluoropyridine trifluoromethanesulfonate, with Selectfluor (registered trademark) being suitable.

[0434] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0435] The reaction time is generally 5 minutes to 48 hours, suitably 1 hour to 5 hours.

[0436] (A4 process)

[0437] This step A4 is a step of producing compound (A-VII) by reacting compound (A-III) with compound (A-VI) in a solvent in the presence of a catalyst and a base.

[0438] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, acetonitrile, NMP, DMF, DMSO, and mixed solvents thereof. A mixed solvent of 1,4-dioxane and water is suitable.

[0439] Examples of the catalyst used include Pd(PPh3)4, Pd(dppf)Cl2, XPhosPdG2, and XPhosPdG3, with XPhosPdG2 being suitable.

[0440] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide, and sodium tert-butoxide, with potassium carbonate being suitable.

[0441] The reaction temperature is usually room temperature to 200°C, preferably 90°C to 120°C.

[0442] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0443] Alternatively, this reaction can also be carried out under microwave irradiation.

[0444] (A5 process)

[0445] This step A5 is a step of producing compound (A-IX) by reacting compound (AV) with compound (A-VIII) in a solvent in the presence of a catalyst and a base, and is carried out according to (step A4).

[0446] (A6 process)

[0447] In step A6, a substituent R is introduced by reacting compound (AX) using either the method (step A6-1) or (step A6-2). A A step of producing compound (A-XI).

[0448] (A6-1 process)

[0449] The A6-1 step is to treat compound (AX) by

[0450] (2a) Step of introducing a bromine group,

[0451] (2b) a step of converting a bromo group into a cyano group, or

[0452] (2c) Step of converting a bromo group into an alkyl group or an alkenyl group

[0453] A step of producing compound (A-XI).

[0454] Hereinafter, each step will be further described.

[0455] (1a) Step of introducing bromine groups

[0456] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DCE being suitable.

[0457] Examples of the brominating agent used include N-bromosuccinimide and bromine, with N-bromosuccinimide being suitable.

[0458] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0459] The reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 5 hours.

[0460] (2a) Step of converting a bromo group into a cyano group

[0461] This step is a step of producing compound (A-XI) by reacting the compound obtained in (1) in a solvent to introduce a cyano group, and is carried out according to (2) of (Step A3-2).

[0462] (2c) Step of converting a bromo group into an alkyl group or an alkenyl group

[0463] This step is a step of producing compound (A-XI) by reacting the compound obtained in (1) with various boronic acids or boronic esters in a solvent to introduce an alkyl group or an alkenyl group, and is carried out according to (Step A4).

[0464] (A6-2 process)

[0465] This process is for compound (AX), after

[0466] (1) The process of introducing iodine groups,

[0467] (2a) a step of converting an iodine group into a cyano group, or

[0468] (2b) Step of converting the iodine group into a trifluoromethyl group

[0469] A step of producing compound (A-XI).

[0470] Hereinafter, each step will be further described.

[0471] (1) Process of introducing iodine groups

[0472] This step is a step of producing a compound into which an iodine group has been introduced by reacting compound (AX) in a solvent, and is carried out according to (1) of (Step A3-2).

[0473] (2a) Step of converting iodine group into cyano group

[0474] This step is a step of producing compound (A-XI) by reacting the compound obtained in (1) in a solvent to introduce a cyano group, and is carried out according to (2) of (Step A3-2).

[0475] (2b) Step of converting the iodine group into a trifluoromethyl group

[0476] This step is a step of producing compound (A-XI) by reacting the compound obtained in (1) in a solvent to introduce a trifluoromethyl group.

[0477] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DMF being suitable.

[0478] Examples of the catalyst used include Pd(PPh3)4 and Pd2(dba)3, with Pd2(dba)3 being suitable.

[0479] Examples of the additive used include copper (I) iodide and copper (II) acetate, with copper (I) iodide being suitable.

[0480] Examples of the trifluoromethylating agent include methyl difluoro(fluorosulfonyl)acetate, trimethyl(trifluoromethyl)silane, and 1-trifluoromethyl-1,2-benzidoyl-3(1H)-one, with methyl difluoro(fluorosulfonyl)acetate being suitable.

[0481] The reaction temperature is usually 0°C to 200°C, and suitably 100°C.

[0482] The reaction time is generally 5 minutes to 48 hours, suitably 1 hour to 5 hours.

[0483] (Method B)

[0484] Method B represents a method for producing the compound (B-IX) of the present invention.

[0485] [Chemical Formula 26]

[0486]

[0487] (In the formula, X represents -CH2- or an oxygen atom, Y represents a bromine atom or an iodine atom, Z represents -CH2- or an oxygen atom, n represents an integer of 1 or 2, and other symbols used have the same meanings as above.)

[0488] (B1 process)

[0489] This step B1 is a step of producing compound (B-III) by reacting compound (BI) and compound (B-II) in a solvent in the presence of a catalyst and a base.

[0490] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, acetonitrile, NMP, DMF, DMSO, and mixed solvents thereof. A mixed solvent of 1,4-dioxane and water is suitable.

[0491] Examples of the catalyst used include Pd(PPh3)4, Pd(dppf)Cl2, XPhos Pd G2, and XPhos Pd G3, with Pd(dppf)Cl2 being preferred.

[0492] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide, and sodium tert-butoxide, with potassium carbonate being suitable.

[0493] The reaction temperature is usually room temperature to 200°C, preferably 90°C to 120°C.

[0494] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0495] (B2 process)

[0496] This step B2 is a step of producing compound (BV) by reacting compound (BI) with compound (B-IV) in a solvent in the presence of a catalyst and a base.

[0497] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as DCM, DCE, and chloroform, water, acetonitrile, NMP, DMF, and DMSO, with DMF being suitable.

[0498] Examples of the catalyst used include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , and bis(triphenylphosphine)palladium(II) dichloride, with bis(triphenylphosphine)palladium(II) dichloride being preferred.

[0499] Examples of the base used include organic bases such as TEA and DIPEA, and inorganic bases such as sodium carbonate, potassium carbonate, and cesium carbonate, with TEA being suitable.

[0500] Copper (I) iodide is suitable as the additive to be used.

[0501] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0502] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 3 hours.

[0503] (B3 process)

[0504] The B3 step is to treat compound (BV) by

[0505] (1) Step of constructing dihydrofuran by cyclization,

[0506] (2) The process of introducing iodine and acetoxy groups,

[0507] (3) Process for synthesizing vinyl iodide compounds

[0508] A step for producing compound (B-III).

[0509] Hereinafter, each step will be further described.

[0510] (1) Step of constructing dihydrofuran by cyclization

[0511] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DCE being suitable.

[0512] Suitable catalysts to be used are silver trifluoromethanesulfonate and (triphenylphosphine)gold(I) chloride.

[0513] The reaction temperature is usually -20°C to 100°C, preferably 80°C.

[0514] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0515] (2) Process of introducing iodine and acetoxy groups

[0516] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with acetic acid being preferred.

[0517] Examples of the iodination agent include N-iodosuccinimide and iodine, with N-iodosuccinimide being suitable.

[0518] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0519] The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 3 hours.

[0520] (3) Process for synthesizing vinyl iodide compounds

[0521] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DCM being suitable.

[0522] As the acid to be used, trimethylsilyl trifluoromethanesulfonate is suitable.

[0523] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0524] The reaction time is usually 1 minute to 1 hour, preferably 3 minutes to 30 minutes.

[0525] (B4 process)

[0526] This step B4 is a step of producing compound (B-VII) by reacting compound (B-III) and compound (B-VI) in a solvent in the presence of a catalyst, an additive, and a base.

[0527] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, NMP, DMF, DMSO, and mixed solvents thereof, with 1,4-dioxane, toluene, and NMP being suitable.

[0528] Examples of the catalyst used include Pd(PPh3)4, Pd2(dba)3, and copper(I) iodide, with Pd2(dba)3 and copper(I) iodide being suitable.

[0529] Examples of the additives used include RuPhos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and L-proline, with RuPhos and L-proline being suitable.

[0530] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide, and sodium tert-butoxide, with sodium tert-butoxide being suitable.

[0531] The reaction temperature is usually room temperature to 200°C, preferably 90°C to 120°C.

[0532] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0533] (B5 process)

[0534] Step B5 is a step of producing Compound (B-IX) by reacting Compound (B-VII) and Compound (B-VIII) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with Step A4.

[0535] (C Method)

[0536] Method C represents a method for producing compound (C-VI) of the present invention.

[0537] [Chemical Formula 27]

[0538]

[0539] (In the formula, the symbols used have the same meanings as above.)

[0540] (C1 process)

[0541] This step C1 is a step of producing compound (C-III) by reacting compound (CI) with compound (C-II) in a solvent in the presence of a base.

[0542] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol, acetonitrile, NMP, DMF, DMSO, and mixed solvents thereof, with methanol being preferred.

[0543] Examples of the base used include organic bases such as TEA and DIPEA, and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate, with DIPEA being suitable.

[0544] The reaction temperature is usually room temperature to 200°C, preferably room temperature to 70°C.

[0545] The reaction time is generally 5 minutes to 48 hours, suitably 1 hour to 24 hours.

[0546] (C2 process)

[0547] This step C2 is a step of producing compound (CV) by reacting compound (C-III) with compound (C-IV) in a solvent in the presence of a catalyst and a base, and is carried out according to (step A4).

[0548] (C3 process)

[0549] The C3 step is to treat compound (CV) by

[0550] (1) a step of triflation of a hydroxyl group,

[0551] (2) Step of reducing the trifluoromethanesulfonate compound

[0552] A process for producing compound (C-VI).

[0553] Hereinafter, each step will be further described.

[0554] (1) Step of triflation of hydroxyl groups

[0555] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane; halogenated hydrocarbons such as DCM, DCE, and chloroform; nitriles such as acetonitrile; organic acids such as acetic acid and TFA; amides such as DMF and N,N-dimethylacetamide; and sulfoxides such as DMSO, with DCM being suitable.

[0556] Examples of the trifluoromethanesulfonylating agent include Tf2O, N-phenylbis(trifluoromethanesulfonimide), and N,N-bis(trifluoromethanesulfonyl)-5-chloropyridin-2-amine, with N-phenylbis(trifluoromethanesulfonimide) being preferred.

[0557] The reaction temperature is usually -20°C to 100°C, preferably room temperature.

[0558] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0559] (2) Step of reducing the trifluoromethanesulfonate compound

[0560] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, NMP, DMF, DMSO, and mixed solvents thereof, with THF being suitable.

[0561] Examples of the catalyst used include Pd(PPh3)4, Pd(dppf)Cl2, XPhos Pd G2, and XPhos Pd G3, with Pd(dppf)Cl2 being preferred.

[0562] As the reducing agent used, for example, ammonium formate and dimethylphenylsilane are included, and ammonium formate is suitable.

[0563] Examples of the base used include organic bases such as TEA and DIPEA, and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate, with TEA being suitable.

[0564] The reaction temperature is usually room temperature to 200°C, preferably 90°C to 120°C.

[0565] The reaction time is generally 5 minutes to 48 hours, suitably 1 hour to 10 hours.

[0566] (D method)

[0567] Method D represents a method for producing compound (D-VI) of the present invention.

[0568] [Chemical Formula 28]

[0569]

[0570] (In the formula, the symbols used have the same meanings as above.)

[0571] (D1 process)

[0572] Step D1 is a step of producing Compound (D-III) by reacting Compound (DI) and Compound (D-II) in a solvent in the presence of a base, and is carried out in accordance with Step (A1).

[0573] (D2 process)

[0574] This step D2 is a step of producing compound (D-IV) by reacting compound (D-III) with, for example, triethyl orthoformate in the presence of an acid.

[0575] Examples of the acid used include organic acids such as formic acid, acetic acid, TFA, and p-toluenesulfonic acid, with formic acid being suitable.

[0576] The reaction temperature is usually -20°C to 100°C, preferably 100°C.

[0577] The reaction time is generally 5 minutes to 48 hours, suitably 3 hours to 24 hours.

[0578] (D3 process)

[0579] This step D3 is a step of producing compound (D-VI) by reacting compound (D-IV) and compound (DV) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with (step A4).

[0580] (E Method)

[0581] Method E represents a method for producing compound (E-VI) of the present invention.

[0582] [Chemical Formula 29]

[0583]

[0584] (In the formula, the symbols used have the same meanings as above.)

[0585] (E1 process)

[0586] Step E1 is a step of producing Compound (E-III) by reacting Compound (EI) and Compound (E-II) in the presence of a base in a solvent, and is carried out according to Step A1.

[0587] (E2 process)

[0588] Step E2 is a step of producing Compound (EV) by reacting Compound (E-III) and Compound (E-IV) in the presence of a catalyst and a base in a solvent, and is carried out in accordance with Step A4.

[0589] (E3 process)

[0590] The E3 step is for compound (EV),

[0591] (1) a step of converting a hydroxyl group into a thiocarbonate,

[0592] (2) Step of reducing the thiocarbonate compound

[0593] A process for producing compound (E-VI).

[0594] Hereinafter, each step will be further described.

[0595] (1) Step of esterifying hydroxyl groups with thiocarbonates

[0596] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, NMP, DMF, and DMSO, with DCM being suitable.

[0597] Examples of the base include organic bases such as TEA, DIPEA, and 4-dimethylaminopyridine, and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate, with 4-dimethylaminopyridine being suitable.

[0598] As the thiocarbonylating agent to be used, phenyl chlorothioformate is suitable.

[0599] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0600] The reaction time is generally 5 minutes to 96 hours, suitably 5 hours to 72 hours.

[0601] (2) Step of reducing the thiocarbonate compound

[0602] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, NMP, DMF, and DMSO, with toluene being suitable.

[0603] The free radical initiator used is, for example, azobisisobutyronitrile, benzoyl peroxide, triethylborane or diethylzinc, with azobisisobutyronitrile being suitable.

[0604] Examples of the reducing agent include tributyltin hydride and tris(trimethylsilyl)silane, with tributyltin hydride being suitable.

[0605] The reaction temperature is usually 0°C to 200°C, and suitably 110°C.

[0606] The reaction time is generally 5 minutes to 72 hours, suitably 1 hour to 5 hours.

[0607] (F method)

[0608] Method F represents a method for producing the compound (FV) of the present invention.

[0609] [Chemical formula 30]

[0610]

[0611] (In the formula, n represents an integer of 1 or 2, and other symbols used have the same meanings as above.)

[0612] (F1 process)

[0613] Step F1 is a step of producing Compound (F-III) by reacting Compound (FI) and Compound (F-II) in the presence of a base in a solvent, and is carried out according to Step A1.

[0614] (F2 process)

[0615] Step F2 is a step for producing Compound (FV) by reacting Compound (F-III) and Compound (F-IV) in the presence of a catalyst and a base in a solvent, and is carried out in accordance with Step A4.

[0616] (G method)

[0617] Method G represents a method for producing the compound (GV) of the present invention.

[0618] [Chemical Formula 31]

[0619]

[0620] (In the formula, the symbols used have the same meanings as above, except for the case where A is a nitrogen atom.)

[0621] (G1 process)

[0622] Step G1 is a step of producing Compound (G-III) by reacting Compound (GI) and Compound (G-II) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with Step A4.

[0623] (G2 process)

[0624] Step G2 is a step of producing Compound (GV) by reacting Compound (G-III) and Compound (G-IV) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with Step A4.

[0625] (H method)

[0626] Method H represents a method for producing compound (H-VI) of the present invention.

[0627] [Chemical Formula 32]

[0628]

[0629] (Where R H represents a hydrogen atom or a substituent selected from the above-mentioned substituent group a, and other symbols used have the same meanings as above. )

[0630] (H1 process)

[0631] Step H1 is a step of producing Compound (H-III) by reacting Compound (HI) and Compound (H-II) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with Step (A4).

[0632] (H2 process)

[0633] The step H2 is a step of producing compound (H-IV) by reacting compound (H-III) in the presence of an iodinating agent in a solvent.

[0634] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DMF being suitable.

[0635] Examples of the iodination agent include N-iodosuccinimide and iodine, with N-iodosuccinimide being suitable.

[0636] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0637] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0638] (H3 process)

[0639] Step H3 is a step of producing Compound (H-VI) by reacting Compound (H-IV) and Compound (HV) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with Step A4.

[0640] (I method)

[0641] Method I represents a method for producing compound (I-VI) of the present invention.

[0642] [Chemical Formula 33]

[0643]

[0644] (Where P I represents a group protecting a hydroxyl group, and other symbols used have the same meanings as above. ).

[0645] (I1 process)

[0646] This step I1 is a step of producing compound (I-III) by reacting compound (II) with compound (I-II) in a solvent in the presence of a catalyst and a base, and is carried out according to (step A4).

[0647] (I2 process)

[0648] The I2 step is to treat compound (I-III) by

[0649] (1) Removal of the protective group of the hydroxyl group, ester hydrolysis and decarbonation reaction steps,

[0650] (2) Step of triflation of the hydroxyl group

[0651] A process for producing compound (I-IV).

[0652] Hereinafter, each step will be further described.

[0653] (1) Removal of the hydroxyl protecting group, ester hydrolysis and decarbonation reaction steps

[0654] Typically, the protective group for the hydroxyl group used is a silyl group such as tert-butyldimethylsilyl, triisopropylsilyl, or tert-butyldiphenylsilyl, and triisopropyl is suitable.

[0655] Examples of the solvent include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol, water, acetonitrile, NMP, DMF, DMSO, and mixed solvents thereof, with methanol being suitable.

[0656] Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as potassium hydrogen carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, with sodium hydroxide being suitable.

[0657] The reaction temperature is usually 0°C to 200°C, and suitably 100°C.

[0658] The reaction time is generally 5 minutes to 48 hours, suitably 3 hours to 24 hours.

[0659] (2) Step of triflation of the hydroxyl group

[0660] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, halogenated hydrocarbons such as DCM, DCE, and chloroform, nitriles such as acetonitrile, organic acids such as acetic acid and TFA, amides such as DMF and N,N-dimethylacetamide, and sulfoxides such as DMSO, with DCM being suitable.

[0661] Examples of the trifluoromethanesulfonylating agent include Tf2O, N-phenylbis(trifluoromethanesulfonimide), and N,N-bis(trifluoromethylsulfonyl)-5-chloropyridin-2-amine, with Tf2O being suitable.

[0662] The reaction temperature is usually -20°C to 100°C, preferably 0°C to room temperature.

[0663] The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 5 hours.

[0664] (I3 process)

[0665] This step I3 is a step for producing compound (I-VI) by reacting compound (I-IV) with compound (IV) in a solvent in the presence of a catalyst and a base, and is carried out according to (step A4).

[0666] (J Method)

[0667] Method J represents a method for producing compound (J-VI) of the present invention.

[0668] [Chemical Formula 34]

[0669]

[0670] (Where P J represents a group protecting a hydroxyl group, and other symbols used have the same meanings as above. ).

[0671] (J1 process)

[0672] Step J1 is a step of producing Compound (J-III) by reacting Compound (JI) and Compound (J-II) in the presence of a catalyst and a base in a solvent, and is carried out in accordance with Step A4.

[0673] (J2 process)

[0674] The J2 step is to treat compound (J-III) by

[0675] (1) Step of removing the protective group of the hydroxyl group

[0676] (2) Step of triflation of the hydroxyl group

[0677] The process of producing compound (J-IV) is as follows.

[0678] Hereinafter, each step will be further described.

[0679] (1) Step of removing the protective group of the hydroxyl group

[0680] Typically, the protective group for the hydroxyl group used is a silyl group such as tert-butyldimethylsilyl, triisopropylsilyl, or tert-butyldiphenylsilyl, with triisopropylsilyl being suitable.

[0681] Examples of the solvent include ethers such as DEE, THF, and 1,4-dioxane, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol, water, acetonitrile, NMP, DMF, DMSO, and mixtures thereof, with THF being suitable.

[0682] Examples of the reagent used include TBAF, pyridine hydrogen fluoride, and triethylamine trihydrogen fluoride salt, with TBAF being suitable.

[0683] The reaction temperature is usually 0°C to 200°C, preferably room temperature.

[0684] The reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 3 hours.

[0685] (2) Step of triflation of the hydroxyl group

[0686] The step of triflation of the hydroxyl group is carried out in accordance with (2) of (I2 step).

[0687] (J3 process)

[0688] Step J3 is a step of producing compound (J-VI) by reacting compound (J-IV) and compound (JV) in a solvent in the presence of a catalyst and a base, and is carried out in accordance with step (A4).

[0689] The compound or pharmaceutically acceptable salt thereof obtained by the above-mentioned production method can be isolated and purified by conventional separation means such as recrystallization, distillation, chromatography, etc.

[0690] When the compound of the present invention or its pharmaceutically acceptable salt exists as an optical isomer based on an asymmetric carbon, it can be separated into each optical isomer by conventional optical resolution means (e.g., fractional crystallization, resolution using a chiral column). In addition, optical isomers can also be synthesized using optically pure starting materials. Furthermore, optical isomers can also be synthesized by stereoselectively carrying out each reaction using an asymmetric auxiliary group or an asymmetric catalyst.

[0691] The compound or pharmaceutically acceptable salt thereof obtained by the above-mentioned production method can be isolated and purified by conventional separation means such as recrystallization, distillation, chromatography, etc.

[0692] When the compound of the present invention or its pharmaceutically acceptable salt exists as an optical isomer based on an asymmetric carbon, it can be separated into each optical isomer by conventional optical resolution means (e.g., fractional crystallization, resolution using a chiral column). In addition, optical isomers can also be synthesized using optically pure starting materials. Furthermore, optical isomers can also be synthesized by stereoselectively carrying out each reaction using an asymmetric auxiliary group or an asymmetric catalyst.

[0693] (Pharmaceutical composition of the present invention)

[0694] The pharmaceutical composition of the present invention contains a compound or a pharmaceutically acceptable salt thereof as an active ingredient, and is a pharmaceutical composition for preventing and / or treating the following diseases, for example:

[0695] Autoinflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS); autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitis syndrome, systemic amyloidosis, etc.; inflammatory diseases such as liver-related diseases such as alcoholic liver disease (ALD), alcoholic steatohepatitis (ASH) / non-alcoholic steatohepatitis (NASH) / viral hepatitis, non-alcoholic fatty liver disease (NAFLD); lung-related diseases such as chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis, etc.; and renal and urinary tract diseases. , i.e. diabetic nephropathy, lupus nephritis, primary hyperoxaluria, interstitial cystitis, etc., intestinal related diseases, i.e. inflammatory bowel disease (IBD), etc., joint related diseases, i.e. gout / pseudogout, osteoarthritis, etc., cardiovascular / metabolic related diseases, i.e. atherosclerosis, type 1 / type 2 diabetes, heart failure, etc., infection related diseases, i.e. SARS-CoV-2 infection, EBV infection, viral encephalitis, etc., eye related diseases, i.e. glaucoma, optic neuritis, retinitis pigmentosa, age-related macular degeneration, etc., cancer related diseases, i.e. myeloproliferative neoplasms, leukemia / myelodysplastic syndrome / myelofibrosis / lung cancer / colorectal cancer / tumor disintegration syndrome / cytokine release syndrome, etc.,

[0696] Neurological diseases, namely multiple sclerosis (as a subtype of multiple sclerosis, including relapsing-remitting multiple sclerosis / secondary progressive multiple sclerosis / primary progressive multiple sclerosis), neurodegenerative diseases (Alzheimer's disease / Huntington's disease / Parkinson's disease / amyotrophic lateral sclerosis / multiple system atrophy / frontotemporal dementia), etc., mental illnesses, namely epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorders, eating disorders, etc., cerebrovascular diseases, namely ischemic stroke, hemorrhagic stroke, traumatic brain injury, etc.

[0697] The pharmaceutical composition of the present invention may be a drug consisting solely of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc. The pharmaceutical composition of the present invention may be administered to a subject (e.g., a human) in a pharmaceutically effective amount.

[0698] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, granulated sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethyl cellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), Dissolution aids (e.g. polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), suspending agents (e.g. stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc. surfactants; polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl Hydrophilic polymers such as cellulose and hydroxypropyl cellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (such as sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, etc.), buffers (such as phosphate, acetate, carbonate, citrate buffers, etc.), analgesics (such as benzyl alcohol, etc.), preservatives (such as parabens, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (such as sulfites, ascorbic acid, etc.). Salt, etc.), colorants (for example, water-soluble edible tar pigments (for example, edible red No. 2 and No. 3, edible yellow No. 4 and No. 5, edible blue No. 1 and No. 2, etc.), water-insoluble lake pigments (for example, aluminum salts of the water-soluble edible tar pigments), natural pigments (for example, β-carotene, chlorophyll, ferric oxide), etc.), sweeteners (for example, sodium saccharin, dipotassium glycyrrhizate, steviol glycosides, etc.), flavoring agents (for example, anise oil, cinnamon oil, ethyl vanillin, orange oil, etc.), aromatics, etc.

[0699] After mixing the above-mentioned components, the pharmaceutical composition of the present invention can be prepared into oral preparations such as tablets, pills, fine granules, granules, capsules, dry syrups, and elixirs according to known methods; or non-oral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drips), external preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), granules, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, and liposome preparations. Tablets or pills can be coated with a sugar coating, or a gastric or enteric coating, as needed. Preparations for non-oral administration can be sterilized, for example, by filtration through a bacteria-retaining filter, the addition of a bactericide, or irradiation. In addition, compositions obtained by dissolving or suspending a sterile solid composition in sterile water or an injection solvent before use can also be used as preparations for non-oral administration.

[0700] The content of the compound of the present invention or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is generally in the range of about 0.001 to 100% by weight, preferably in the range of about 0.01 to 50% by weight, and more preferably in the range of about 0.01 to 20% by weight, relative to the entire preparation.

[0701] The dosage and frequency of administration of the compound of the present invention or its pharmaceutically acceptable salt are determined appropriately according to individual circumstances, taking into account symptoms, the age or sex of the subject, etc. Regarding the dosage, in the case of oral administration, it is generally 0.001 mg / kg to 100 mg / kg per adult, and in the case of intravenous administration, it is generally 0.0001 mg / kg to 10 mg / kg per adult. The frequency of administration is generally once a day to 6 times or once a day to 7 days.

[0702] The compound of the present invention or a pharmaceutically acceptable salt thereof is effectively used for, for example, cryopyrin-associated periodic fever syndrome (CAPS) as an autoinflammatory disease; systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitis syndrome, systemic amyloidosis, etc. as autoimmune diseases; liver-related diseases, i.e., alcoholic liver disease (ALD), alcoholic steatohepatitis (ASH) / non-alcoholic steatohepatitis (NASH) / viral hepatitis, non-alcoholic fatty liver disease (NAFLD), etc. as inflammatory diseases; lung-related diseases, i.e., chronic obstructive pulmonary disease (COPD), asthma, acute lung loss (ALI), interstitial lung disease (ILD), meat leukoma, etc.; renal and urinary tract diseases, namely diabetic nephropathy, lupus nephritis, primary hyperoxaluria, interstitial cystitis, etc.; intestinal diseases, namely inflammatory bowel disease (IBD), etc.; joint diseases, namely gout / pseudogout, osteoarthritis, etc.; cardiovascular / metabolic diseases, namely atherosclerosis, type 1 / type 2 diabetes, heart failure, etc.; infection-related diseases, namely SARS-CoV-2 infection, EBV infection, viral encephalitis, etc.; eye-related diseases, namely glaucoma, optic neuritis, retinitis pigmentosa, age-related maculopathy, etc.; cancer-related diseases, namely myeloproliferative neoplasms, leukemia / myelodysplastic syndrome / myelofibrosis / lung cancer / colorectal cancer / tumor disintegration syndrome / cytokine release syndrome, etc.

[0703] Neurological related diseases, namely multiple sclerosis (as a subtype of multiple sclerosis, including relapsing-remitting multiple sclerosis / secondary progressive multiple sclerosis / primary progressive multiple sclerosis), neurodegenerative diseases (Alzheimer's disease / Huntington's disease / Parkinson's disease / amyotrophic lateral sclerosis / multiple system atrophy / frontotemporal dementia), mental illnesses, namely epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorders, eating disorders, etc., cerebrovascular diseases, namely ischemic stroke, hemorrhagic stroke, traumatic brain injury, etc. for prevention and / or treatment.

[0704] The compound of the present invention or its pharmaceutically acceptable salt can be used in combination with other drugs (combination drugs) as long as it does not impair its efficacy. The combination drug is not particularly limited, and can be suitable for use, for example, the above-mentioned examples of cryopyrin-associated periodic fever syndrome (CAPS) as an autoinflammatory disease; systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitis syndrome, systemic amyloidosis, etc. as autoimmune diseases; liver-related diseases as inflammatory diseases, i.e., alcoholic liver disease (ALD), alcoholic steatohepatitis (ASH) / non-alcoholic steatohepatitis (NASH) / viral hepatitis, non-alcoholic fatty liver disease (NAFLD), etc., lung-related diseases, i.e., chronic obstructive pulmonary disease (COPD), asthma, acute lung loss (ALI), interstitial lung disease (ILD), meat Tumors, etc., renal and urinary tract diseases, namely diabetic nephropathy, lupus nephritis, primary hyperoxaluria, interstitial cystitis, etc., intestinal diseases, namely inflammatory bowel disease (IBD), etc., joint diseases, namely gout / pseudogout, osteoarthritis, etc., cardiovascular / metabolic diseases, namely atherosclerosis, type 1 / type 2 diabetes, heart failure, etc., infection-related diseases, namely SARS-CoV-2 infection, EBV infection, viral encephalitis, etc., eye-related diseases, namely glaucoma, optic neuritis, retinitis pigmentosa, age-related maculopathy, etc., cancer-related diseases, namely myeloproliferative neoplasms, leukemia / myelodysplastic syndrome / myelofibrosis / lung cancer / colorectal cancer / tumor disintegration syndrome / cytokine release syndrome, etc.,

[0705] One or more known drugs conventionally used in the treatment of neurological diseases, namely multiple sclerosis (including relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, and primary progressive multiple sclerosis as subtypes of multiple sclerosis), neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, and frontotemporal dementia), psychiatric diseases, namely epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorders, and eating disorders, and cerebrovascular diseases, namely ischemic stroke, hemorrhagic stroke, and traumatic brain injury.

[0706] Examples of other drugs suitable for use in combination with the compounds of the present invention or pharmaceutically acceptable salts thereof (combination drugs) include IL-1β inhibitors (e.g., Anakinra); type I IFN receptor antagonists (e.g., Anifrolumab); TLR7 / 8 inhibitors (e.g., Enpatoran); JAK inhibitors (e.g., Tofacitinib); BTK inhibitors (e.g., Fenebrutinib); S1P receptor modulators (e.g., Fingolimod); anti-CD20 antibodies (e.g., Ocrelizumab); cholesterol-lowering drugs (e.g., Pravastatin); anti-inflammatory drugs (e.g., Prednisolone); nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., Loxonin); acetylsalicylic acid drugs (ASA) (e.g., Aspirin), and the like.

[0707] When using a combination drug, the administration period is not limited, and they can be administered to the subject simultaneously or separated by a time difference. Based on the administration of the time difference, the drug of the present invention can be administered first, followed by the combination drug, or the combination drug can be administered first, followed by the drug of the present invention. The respective administration methods can be the same or different. In addition, it is also possible to administer as a single preparation (compounding agent) containing the compound of the present invention or a pharmaceutically acceptable salt thereof and the combination drug. As a pharmaceutically acceptable carrier that can be used for the manufacture of the compounding agent, the same carrier as that used in the pharmaceutical composition of the present invention can be cited.

[0708] The dosage of the combination drug can be appropriately selected based on the dosage normally used clinically. In addition, the compound of the present invention or its pharmaceutically acceptable salt etc. and the compounding ratio of the combination drug can be appropriately selected based on the object (age, body weight, general health status, sex, degree of the disease etc. of the object), route of administration, kind of the disease, kind of the combination drug etc.

[0709] The mass ratio of the compound or its pharmaceutically acceptable salt to the combined drug is not particularly limited.

[0710] Furthermore, combination drugs that complement and / or enhance the therapeutic effects of the compound or its pharmaceutically acceptable salt also include drugs that are not discovered to date but will be discovered in the future based on the above-mentioned mechanism.

[0711] The pharmaceutical composition of the present invention can be provided in the form of a kit, along with instructions for administration, etc. The agent contained in the kit is delivered in a container made of a material that effectively maintains the activity of the components of the pharmaceutical composition over a long period of time, does not adsorb to the container, and does not deteriorate the components. For example, a sealed glass ampoule can contain a buffer solution sealed in the presence of a neutral and non-reactive gas such as nitrogen.

[0712] Instructions for use of the kit may be provided with the kit. The instructions for use of the kit may be printed on paper or the like, or may be stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.

[0713] Test Example 1: In vitro IL-1β production test

[0714] Human monocyte-derived THP-1 cells were cultured for one day in RPMI-1640 medium (Thermo #A10491-01) containing 10% bovine serum and supplemented with 200 nM phorbol 12-myristate 13-acetate (PMA, Sigma #P8139) to promote differentiation induction.

[0715] The NLRP3 inflammasome was induced by replacing the culture medium with RPMI-1640 medium without bovine serum supplemented with 0.015 mM Nigericin (Sigma #SML1779) and known concentrations of the compounds.

[0716] Two hours later, the culture supernatant was recovered and the IL-1β protein concentration was measured using AlphaLISA (registered trademark) assay (PerkinElmer #AL220C).

[0717] The IL-1β concentration under nigericin stimulation without adding the test compound was set as 0% inhibitory activity, and the IL-1β concentration under nigericin non-stimulation conditions was set as 100% inhibitory activity. The inhibition rate (inhibition %) of the test compound at each added concentration was determined.

[0718] The inhibition percentage values ​​were fitted with a sigmoid model using a logistic regression model to calculate the 50% inhibition concentration (IC 50 value).

[0719] The pharmacological activity data of the test compounds described in the Examples are shown in Table 1. The results indicate that the compounds of the present invention inhibit NLRP3 inflammasome-dependent IL-1β production.

[0720] In the table, Ex represents the example number.

[0721] [Table 1]

[0722] Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> 1 5.27 26 6.18 51 33.62 76 10.08 2 5.26 27 25.56 52 39.09 77 14.00 3 52.48 28 12.00 53 275.31 78 35.04 4 19.76 29 12.38 54 84.31 79 7.49 5 31.32 30 14.37 55 23.79 80 22.36 6 26.02 31 412.75 56 14.40 81 54.72 7 67.61 32 30.59 57 57.24 82 7.83 8 15.42 33 10.00 58 55.82 83 9.16 9 13.19 34 9.07 59 95.81 84 12.83 10 23.72 35 25.6 60 74.75 85 65.33 11 7.32 36 42.07 61 25.34 86 141.47 12 25.89 37 25.77 62 70.78 87 40.09 13 37.63 38 108.13 63 42.29 88 43.06 14 7.87 39 400.96 64 9.60 89 138.18 15 4.86 40 161.89 65 47.01 90 56.46 16 8.60 41 77.46 66 16.36 91 124.85 17 9.47 42 74.02 67 4.93 92 59.16 18 6.65 43 22.14 68 6.01 93 30.05 19 9.99 44 74.96 69 47.76 94 79.59 20 8.19 45 8.81 70 31.22 95 19.69 21 19.79 46 91.41 71 8.18 96 11.49 22 10.51 47 80.82 72 53.09 97 8.33 23 11.81 48 100.98 73 13.83 98 13.79 24 34.81 49 78.04 74 26.07 99 9.53 25 29.19 50 235.66 75 98.41

[0723] Test Example 2: Pharmacokinetics test in mice

[0724] Two hours after oral administration of the test compound (10 mg / kg) to male BALB / c mice, blood was collected from the posterior vena cava under isoflurane anesthesia, and plasma was obtained by centrifugation. Separately, brain samples were collected after euthanasia by exsanguination. Four times the wet weight of the brain was added to the obtained brain sample, and a 20% homogenate was prepared. Compound concentrations in the obtained plasma and brain homogenate were measured using LC / MS / MS. The central metastatic parameter, Kp, brain, was calculated by benchmarking the concentration in the brain homogenate with the concentration in the plasma. In the table, Ex represents the example number.

[0725] [Table 2]

[0726] Ex Kp, brain 3 1.10 4 0.65 5 1.68 10 0.70 21 0.83 27 0.92

[0727] The results of this test indicate that the compound of the present invention exhibits excellent pharmacokinetics and central delivery properties, and therefore is expected to have efficacy as an excellent drug.

[0728] Example

[0729] The present invention will be described in detail with reference to the following examples. However, these examples are for illustrative purposes only and do not limit the present invention. Various modifications may be made without departing from the scope of the present invention.

[0730] In the following examples, "%" means mol / mol% for yield, volume% for solvents used in chromatography, and weight% for other purposes.

[0731] Nuclear magnetic resonance spectroscopy (hereinafter 1 H-NMR, resonance frequency 400 MHz or 500 MHz) uses tetramethylsilane as a standard substance or the chemical shift value of the deuterated solvent used as a reference value, and the chemical shift values ​​are reported as δ values ​​(ppm).

[0732] Other abbreviations used herein have the following meanings.

[0733] s: singlet

[0734] d: doublet

[0735] dd: doublet of doublets

[0736] t:Triplet

[0737] q: quartet

[0738] m: multiplet (multiplet)

[0739] br: broad

[0740] J: coupling constant

[0741] Hz: Hertz

[0742] CDCl3: deuterated chloroform

[0743] DMSO-d6: deuterated dimethyl sulfoxide

[0744] CD3OD: deuterated methanol

[0745] 1 H-NMR: Proton Nuclear Magnetic Resonance

[0746] HPLC: High Performance Liquid Chromatography

[0747] APCI: Atmospheric Pressure Chemical Ionization

[0748] ESI: electrospray ionization

[0749] Furthermore, in the description of the Examples, the following abbreviations may be used.

[0750] ASCA-2: A metal-supported catalyst based on palladium, which is highly effective in hydrogenation reactions. It exhibits particularly high reactivity in debenzylation reactions. Manufactured by NEChemcat.

[0751] DCE:1,2-dichloroethane

[0752] DCM: dichloromethane

[0753] DEE: Diethyl ether

[0754] DDQ:2,3-dichloro-5,6-dicyano-p-benzoquinone

[0755] DIPEA:N,N-diisopropylethylamine

[0756] DMF:N,N-dimethylformamide

[0757] DMSO: dimethyl sulfoxide

[0758] iPrOBPin:2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0759] NaBH(OAc)3: Sodium triacetoxyborohydride

[0760] NMP: N-methyl-2-pyrrolidone

[0761] Pd2(dba)3:Tris(dibenzylideneacetone)dipalladium(0)

[0762] Pd(dppf)Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct

[0763] Pd(PPh3)4:Tetrakis(triphenylphosphine)palladium(0)

[0764] RuPhos:2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0765] Selectfluor (registered trademark): 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate)

[0766] TBAF:Tetrabutylammonium fluoride

[0767] tBuXPhos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0768] tBuXPhos Pd G1:[2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride

[0769] Tf2O:Trifluoromethanesulfonic anhydride

[0770] TEA:Triethylamine

[0771] THF:Tetrahydrofuran

[0772] TFA: trifluoroacetic acid

[0773] XPhos:2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0774] XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0775] XPhos Pd G3:(2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0776] Unless otherwise specified, the reagents, solvents, and apparatus used in the following examples are commercially available. Furthermore, starting compounds, unless otherwise specified, are known compounds that are commercially available or synthesized and identified using methods known per se or methods in accordance therewith.

[0777] (Example 1)

[0778] 3-Methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[0779] (1A)

[0780] 2-Iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene

[0781] 2-iodo-3-methyl-5-trifluoromethylphenol (US20200361898) (32 g, 110 mmol) and TEA (37 mL, 210 mmol) were dissolved in DCE (210 mL), and chloromethyl methyl ether (10 mL, 140 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour in a nitrogen-substituted system. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0-90 / 10 (V / V)] to obtain 21 g of the title compound as an oily substance (yield: 57%).

[0782] (1B)

[0783] 2-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0784] 2-Iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (17.1 g, 49 mmol) from Example 1A was dissolved in THF (250 mL). n-Butyllithium (1.6 M solution in n-hexane) (40 mL, 64 mmol) was added at -78°C, and the mixture was stirred at -78°C for 30 minutes in a nitrogen-purged atmosphere. iPrOBPin (15 mL, 74 mmol) was added at -78°C, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40 (v / v)) to obtain 13.5 g of the title compound as a solid (yield: 79%).

[0785] (1C)

[0786] 3,6-Dichloro-4-vinylpyridazine

[0787] 4-Bromo-3,6-dichloropyridazine (2.04 g, 9.0 mmol), potassium vinyl trifluoroborate (1.44 g, 11 mmol), and potassium carbonate (2.47 g, 18 mmol) were dissolved in a mixture of 1,4-dioxane (45 mL) and water (10 mL). Pd(dppf)Cl2 (731 mg, 0.90 mmol) was added, and the mixture was stirred at 100°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30 (v / v)) to obtain 1.34 g of the title compound as a solid (yield: 86%).

[0788] (1D)

[0789] tert-Butyl (3R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate

[0790] 3,6-Dichloro-4-vinylpyridazine (1.45 g, 8.3 mmol) and DIPEA (2.16 mL, 12 mmol) from Example 1C were dissolved in NMP (16 mL). Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.99 g, 9.9 mmol) was added and stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100 (v / v)] to obtain 971 mg of the title compound as an amorphous substance (yield: 35%).

[0791] (1E)

[0792] tert-Butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate

[0793] Tert-butyl (3R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (969 mg, 2.9 mmol) from Example 1D, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 3.4 mmol) from Example 1B, and potassium carbonate (790 mg, 5.7 mmol) were dissolved in a mixture of 1,4-dioxane (4.0 mL) and water (1.0 mL). XPhos Pd G2 (225 mg, 0.29 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 70 / 30 - 0 / 100 (V / V)] to obtain 870 mg of the title compound as an amorphous substance (yield: 58%).

[0794] (1F)

[0795] 3-Methyl-2-{7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol dihydrochloride

[0796] To tert-butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate (865 mg, 1.7 mmol) from Example 1E was added 4M hydrogen chloride-1,4-dioxane (16 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 689 mg of the crude title compound as a solid (yield: 92%).

[0797] (1G)

[0798] 3-Methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[0799] 3-Methyl-2-{7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol dihydrochloride (689 mg, 1.5 mmol) and DIPEA (0.53 mL, 3.1 mmol) from Example 1F were dissolved in DCM (15 mL). 37% formaldehyde (0.12 mL, 1.7 mmol), acetic acid (0.175 mL, 3.1 mmol), and NaBH(OAc)3 (1.30 g, 6.1 mmol) were added at 0°C and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60 (v / v)]. Ethyl acetate and n-hexane were added to the resulting solid, and the mixture was sonicated. The solid was collected by filtration to obtain 479 mg of the title compound as a solid (yield: 80%).

[0800] (Example 2)

[0801] 3-Methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[0802] (2A)

[0803] tert-Butyl (3R)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate

[0804] tert-Butyl (3R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (830 mg, 2.4 mmol) from Example 1D was dissolved in toluene (12 mL), DDQ (667 mg, 2.9 mmol) was added, and the mixture was stirred at 80°C for 1.5 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 33 / 67 (v / v)] to obtain 483 mg of the title compound as an amorphous substance (yield: 59%).

[0805] (2B)

[0806] 3-Chloro-7-[(3R)-piperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazine monohydrochloride

[0807] To tert-butyl (3R)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (284 mg, 0.84 mmol) from Example 2A was added 4M hydrogen chloride-1,4-dioxane (4.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 230 mg of the crude title compound as a solid (yield: quantitative).

[0808] (2C)

[0809] 3-Chloro-7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazine

[0810] 3-Chloro-7-[(3R)-piperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazine monohydrochloride (230 mg, 0.84 mmol) and DIPEA (0.293 mL, 1.7 mmol) from Example 2B were dissolved in DCM (4.0 mL). 37% formaldehyde (0.094 mL, 1.3 mmol), acetic acid (0.101 mL, 1.7 mmol), and NaBH(OAc)3 (713 mg, 3.4 mmol) were added at 0°C. The mixture was stirred at room temperature for 30 minutes in a nitrogen-purged atmosphere. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 - 34 / 66 (V / V)] to obtain 190 mg of the title compound as an oily substance (yield: 90%).

[0811] (2D)

[0812] 3-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazine

[0813] 3-Chloro-7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazine (315 mg, 1.3 mmol) of Example 2C, 2-(2-methoxy-6-methyl-4-(trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (US20200361898) (595 mg, 1.9 mmol), and potassium carbonate (347 mg, 2.5 mmol) were dissolved in a mixed solvent of 1,4-dioxane (6.0 mL) and water (1.5 mL), and XPhos Pd G2 (98 mg, 0.13 mmol) was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged system. The reaction solution was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 40 / 60-20 / 80 (V / V)] to obtain 497 mg of the title compound as an amorphous substance (yield: 98%).

[0814] (2E)

[0815] 3-Methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[0816] 3-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazine (497 mg, 1.2 mmol) from Example 2D was dissolved in DCM (12 mL). Boron tribromide (1.0 M solution in DCM) (6.0 mL, 6.0 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 1 hour in a nitrogen-purged atmosphere. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 98 / 2 to 95 / 5 (v / v)]. Ethyl acetate and n-hexane were added to the resulting solid, and the mixture was sonicated. The solid was filtered to obtain 345 mg of the title compound as a solid (yield: 72%).

[0817] (Example 3)

[0818] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0819] (Alternatively known as 2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[0820] (3A)

[0821] (1s,3s)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol

[0822] 3,6-Dichloro-4-vinylpyridazine (2.0 g, 11 mmol) and DIPEA (4.4 mL, 25 mmol) from Example 1C were dissolved in NMP (19 mL), and (1s,3s)-3-amino-1-methyl-cyclobutanol hydrochloride (1.7 g, 13 mmol) was added. The mixture was stirred at 150°C for 1 hour under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 98 / 2 to 90 / 10 (v / v)] to obtain 1.87 g of the title compound as an oily substance (yield: 68%).

[0823] (3B)

[0824] (1s,3s)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol

[0825] (1s,3s)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (1.87 g, 7.8 mmol) from Example 3A was dissolved in DCE (25 mL), and manganese dioxide (6.78 g, 78 mmol) was added. The mixture was stirred at 80°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100 (v / v)] to obtain 855 mg of the title compound as an amorphous substance (yield: 46%).

[0826] (3C)

[0827] (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[0828] (1s,3s)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (166 mg, 0.74 mmol) from Example 3B, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (308 mg, 0.89 mmol) from Example 1B, and potassium carbonate (204 mg, 1.5 mmol) were dissolved in a mixed solvent of 1,4-dioxane (14 mL) and water (6.0 mL). XPhos Pd G2 (58 mg, 0.074 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: DCM / methanol = 100 / 0-90 / 10 (V / V)] to obtain 301 mg of the title compound as an amorphous substance (yield: 96%).

[0829] (3D)

[0830] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0831] To (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (387 mg, 0.91 mmol) from Example 3C was added 4M hydrogen chloride-1,4-dioxane (4.6 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 100 / 0-80 / 20 (V / V)] to obtain 305 mg of the title compound as a solid (yield: 88%).

[0832] (Example 4)

[0833] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0834] (Alternatively known as 2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[0835] (4A)

[0836] 3,6-Dichloro-4-(prop-1-en-2-yl)pyridazine

[0837] 4-Bromo-3,6-dichloropyridazine (4.94 g, 22 mmol), potassium isopropenyltrifluoroborate (3.85 g, 26 mmol), and potassium carbonate (5.99 g, 43 mmol) were dissolved in a mixture of 1,4-dioxane (108 mL) and water (40 mL). Pd(dppf)Cl2 (1.77 g, 2.2 mmol) was added, and the mixture was stirred at 100°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30 (v / v)) to obtain 3.62 g of the title compound as an oily substance (yield: 88%).

[0838] (4B)

[0839] (1s,3s)-3-(3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol

[0840] 3,6-Dichloro-4-(prop-1-en-2-yl)pyridazine (244 mg, 1.3 mmol) and DIPEA (0.67 mL, 3.9 mmol) from Example 4A were dissolved in NMP (4.3 mL). (1s,3s)-3-amino-1-methyl-cyclobutanol hydrochloride (213 mg, 1.5 mmol) was added, and the mixture was stirred at 150°C for 2 hours under microwave irradiation. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40 to 0 / 100 (v / v)] to obtain 103 mg of the title compound as an amorphous substance (yield: 31%).

[0841] (4C)

[0842] (1s,3s)-3-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol

[0843] (1s,3s)-3-(3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (102 mg, 0.40 mmol) from Example 4B was dissolved in DCE (4.0 mL), and manganese dioxide (350 mg, 4.0 mmol) was added. The mixture was stirred at 80°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 65 mg of the title compound as a solid (yield: 64%).

[0844] (4D)

[0845] (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[0846] (1s,3s)-3-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (25 mg, 0.099 mmol) from Example 4C, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (41 mg, 0.12 mmol) from Example 1B, and potassium carbonate (27 mg, 0.20 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.0 mL) and water (0.5 mL). XPhos Pd G2 (7.8 mg, 0.0099 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40-0 / 100 (V / V)] to obtain 34 mg of the title compound as an amorphous substance (yield: 79%).

[0847] (4E)

[0848] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0849] To (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (34 mg, 0.078 mmol) from Example 4D was added 4M hydrogen chloride-1,4-dioxane (1.0 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 100 / 0-80 / 20 (V / V)] to obtain 27 mg of the title compound as a solid (yield: 88%).

[0850] (Example 5)

[0851] 2-{5-Fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0852] (Alternatively known as 2-[5-fluoro-7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[0853] (5A)

[0854] 3-Chloro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine

[0855] (1s,3s)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (1.5 g, 6.3 mmol) from Example 3B was dissolved in DMF (21 mL). 55% sodium hydride (550 mg, 13 mmol) and p-methoxybenzyl chloride (2.6 mL, 19 mmol) were added at 0°C. The mixture was stirred at room temperature for 6 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 75 / 25-60 / 40 (V / V)] and NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 75 / 25-65 / 35 (V / V)] to obtain 2.18 g (yield: 97%) of the title compound as an oily substance.

[0856] (5B)

[0857] 3-Chloro-5-fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine

[0858] 3-Chloro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine (2.18 g, 6.1 mmol) from Example 5A was dissolved in acetonitrile (30 mL). Selectfluor (registered trademark) (2.59 g, 7.3 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours in a nitrogen-purged atmosphere. Methanol and water were added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 65 / 35 (v / v)] to obtain 759 mg of the title compound as an oily substance (yield: 33%).

[0859] (5C)

[0860] 5-Fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[0861] 3-Chloro-5-fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine (80 mg, 0.21 mmol) from Example 5B, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 0.26 mmol) from Example 1B, and potassium carbonate (58 mg, 0.43 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.0 mL) and water (0.3 mL). XPhos Pd G2 (33 mg, 0.043 mmol) was added, and the mixture was stirred at 120° C. for 1 hour under microwave irradiation in a nitrogen-purged system. The reaction solution was returned to room temperature and purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 - 65 / 35 (V / V)] to obtain 83 mg of the title compound as an amorphous substance (yield: 70%).

[0862] (5D)

[0863] 2-[5-Fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol

[0864] 5-Fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (83 mg, 0.15 mmol) from Example 5C was dissolved in DCM (0.7 mL), TFA (0.7 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 97 / 3-90 / 10 (v / v)]. Ethyl acetate and n-hexane were added to the resulting solid, and the mixture was sonicated. The solid was filtered to obtain 42 mg of the title compound as a solid (yield: 72%).

[0865] (Example 6)

[0866] 2-{5-chloro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0867] (Alternatively known as 2-[5-chloro-7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[0868] (6A)

[0869] (1s,3s)-3-{5-chloro-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[0870] (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (54 mg, 0.13 mmol) from Example 3C was dissolved in 1,4-dioxane (1.5 mL). 1-Chloro-1,2-benzidoxyl-3(1H)-one (75 mg, 0.27 mmol) was added, and the mixture was stirred at 120°C for 40 minutes in a nitrogen-purged atmosphere. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 40 / 60 - 20 / 80 (V / V)] to obtain 35 mg of the title compound as an oily substance (yield: 60%).

[0871] (6B)

[0872] 2-{5-chloro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0873] (1s,3s)-3-{5-chloro-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (35 mg, 0.77 mmol) from Example 6A was dissolved in DCM (0.4 mL), TFA (0.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography [eluting solvent: DCM / methanol = 90 / 10 (v / v)] to obtain 15 mg of the title compound as a solid (yield: 47%).

[0874] (Example 7)

[0875] 2-{7-[(1s,3s)-3-(hydroxymethyl)-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0876] (Alternatively known as 2-[7-[cis-3-(hydroxymethyl)-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol.)

[0877] (7A)

[0878] [(1s,3s)-3-(3-Chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutyl]methanol

[0879] (3-Amino-1-methyl-cyclobutyl)methanol hydrochloride (101.4 mg, 0.67 mmol) and 3,6-dichloro-4-vinylpyridazine (117 mg, 0.67 mmol) from Example 1C were suspended in NMP (1.3 mL). DIPEA (0.343 mL, 2.0 mmol) was added, and the mixture was stirred at 130°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. Saturated aqueous sodium bicarbonate was then added to the aqueous layer, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 58 mg of the title compound as an oily substance (yield: 34%).

[0880] (7B)

[0881] 7-[(1s,3s)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylcyclobutyl]-3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[0882] [(1s,3s)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutyl]methanol (58 mg, 0.23 mmol) from Example 7A was dissolved in DMF (1.5 mL), and imidazole (47 mg, 0.69 mmol) and tert-butyldimethylsilyl chloride (69 mg, 0.46 mmol) were added, followed by stirring at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 90 mg of a crude product of the title compound as an oily substance (yield: quantitative).

[0883] (7C)

[0884] 7-[(1s,3s)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine

[0885] 7-[(1s,3s)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylcyclobutyl]-3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (90 mg, 0.24 mmol) from Example 7B was dissolved in DCE (2.0 mL), manganese dioxide (689 mg, 8.0 mmol) was added, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was returned to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 67 / 33 (v / v)] to obtain 51 mg of the title compound as an oily substance (yield: 57%).

[0886] (7D)

[0887] 7-[(1s,3s)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylcyclobutyl]-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[0888] 7-[(1s,3s)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine (51 mg, 0.14 mmol) from Example 7C, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85 mg, 0.25 mmol) from Example 1B, and potassium carbonate (39 mg, 0.28 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (0.375 mL). XPhos Pd G2 (22 mg, 0.028 mmol) was added, and the mixture was stirred at 120°C under microwave irradiation for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and separated using a phase separator (Biotage) to obtain the organic layer. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 - 80 / 20 (V / V)] to obtain 29 mg (yield: 38%) of the title compound as an oily substance.

[0889] (7E)

[0890] 2-{7-[(1s,3s)-3-(hydroxymethyl)-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0891] 4M hydrogen chloride-1,4-dioxane (1 mL) was added to 7-[(1s,3s)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylcyclobutyl]-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (29 mg, 0.053 mmol) from Example 7D, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and DCM and saturated aqueous sodium bicarbonate were added to the resulting residue. After stirring, the organic layer was separated using a phase separator (Biotage). The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: DCM / methanol = 100 / 0 to 90 / 10 (v / v)] and NH silica gel column chromatography [eluting solvent: DCM / methanol = 99 / 1 to 90 / 10 (v / v)]. Ethyl acetate / n-hexane was added to the resulting residue, and sonication was performed. The solid was collected by filtration to obtain 8.3 mg of the title compound as a solid (yield: 40%).

[0892] (Example 8)

[0893] 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[0894] (8A)

[0895] 5-(3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol

[0896] 3,6-Dichloro-4-(prop-1-en-2-yl)pyridazine (250 mg, 1.3 mmol) and DIPEA (0.460 mL, 2.6 mmol) from Example 4A were dissolved in NMP (3.5 mL). 5-Aminobicyclo[3.1.1]heptanol (185 mg, 1.5 mmol) was added, and the mixture was stirred at 150°C for 5 hours under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 98 / 2 to 95 / 5 (v / v)] to obtain 122 mg of the title compound as an amorphous substance (yield: 33%).

[0897] (8B)

[0898] 5-(3-Chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol

[0899] 5-(3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol (122 mg, 0.44 mmol) from Example 8A was dissolved in DCE (2.0 mL), and manganese dioxide (760 mg, 4.4 mmol) was added. The mixture was stirred at 80°C for 80 minutes in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 40 / 60 to 20 / 80 (v / v)] to obtain 43 mg of the title compound as a solid (yield: 35%).

[0900] (8C)

[0901] 5-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[0902] 5-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol (43 mg, 0.15 mmol) from Example 8B, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64 mg, 0.19 mmol) from Example 1B, and potassium carbonate (42 mg, 0.31 mmol) were dissolved in a mixture of 1,4-dioxane (0.8 mL) and water (0.2 mL). XPhos PdG2 (24 mg, 0.031 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 40 / 60-10 / 90 (V / V)] to obtain 64 mg of the title compound as an oily substance (yield: 90%).

[0903] (8D)

[0904] 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[0905] 5-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol (64 mg, 0.14 mmol) from Example 8C was dissolved in DCM (0.7 mL), TFA (1.4 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 97 / 3-90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the resulting solid, and the mixture was sonicated. The solid was filtered to obtain 28 mg of the title compound as a solid (yield: 48%).

[0906] (Example 9)

[0907] 5-Chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[0908] (Alternatively known as 5-chloro-2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methylphenol.)

[0909] (9A)

[0910] 5-Chloro-2-iodo-3-methylphenol

[0911] 3-Chloro-5-methylphenol (1.16 g, 8.1 mmol) was dissolved in toluene (25 mL). 55% sodium hydride (0.717 g, 16 mmol) was added at 0°C and stirred for 30 minutes. Iodine (2.08 g, 8.2 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 5 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 76 / 24 (v / v)] to obtain 1.01 g of the title compound as a solid (yield: 46%).

[0912] (9B)

[0913] 5-Chloro-2-iodo-1-(methoxymethoxy)-3-methylbenzene

[0914] 5-Chloro-2-iodo-3-methylphenol (1.01 g, 3.8 mmol) from Example 9A was dissolved in acetone (15 mL). Potassium carbonate (1.11 g, 8.0 mmol) and chloromethyl methyl ether (0.43 mL, 5.7 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 99 / 1 to 90 / 10 (v / v)] to obtain 1.09 g of the title compound as an oily substance (yield: 93%).

[0915] (9C)

[0916] 2-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0917] 5-Chloro-2-iodo-1-(methoxymethoxy)-3-methylbenzene (1.09 g, 3.5 mmol) from Example 9B was dissolved in THF (12 mL). n-Butyllithium (1.6 M in n-hexane) (3.3 mL, 5.2 mmol) was added to the reaction mixture at -78°C in a nitrogen-purged atmosphere, and the mixture was stirred for 30 minutes. iPrOBPin (1.41 mL, 7.0 mmol) was added to the reaction mixture at -78°C, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 99 / 1 to 90 / 10 (v / v)) to obtain 0.740 g of the title compound as a solid (yield: 68%).

[0918] (9D)

[0919] (1s,3s)-3-{3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[0920] (1s,3s)-3-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (0.150 g, 0.60 mmol) from Example 4C, 2-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.234 g, 0.75 mmol) from Example 9C, and potassium carbonate (0.173 g, 1.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.4 mL) and water (0.6 mL). XPhos Pd G2 (0.051 g, 0.065 mmol) was added, and the mixture was stirred at 120° C. for 3 hours in a nitrogen-purged system. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V)] to obtain 0.068 g (yield: 28%) of the title compound as an oily substance.

[0921] (9E)

[0922] 5-Chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[0923] To (1s,3s)-3-{3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (0.068 g, 0.17 mmol) from Example 9D was added 4M hydrogen chloride-1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with DCM. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10 (v / v)] to obtain 0.045 g of the title compound as a solid (yield: 74%).

[0924] (Example 10)

[0925] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0926] (Alternatively known as 2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[0927] (10A)

[0928] 7-[(1s,3s)-3-(Benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine

[0929] (1s,3s)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (4.0 g, 17 mmol) from Example 3B was dissolved in DMF (42 mL). 55% sodium hydride (1.0 g, 24 mmol) and benzyl bromide (2.6 mL, 22 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2.5 hours in a nitrogen-purged atmosphere. Water was added at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 65 / 35 (v / v)] to obtain 5.47 g of the title compound as an oily substance (yield: 99%).

[0930] (10B)

[0931] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate

[0932] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine (5.47 g, 17 mmol) from Example 10A was dissolved in acetic acid (33 mL). Palladium(II) acetate (750 mg, 3.3 mmol) and diacetoxyiodobenzene (8.0 g, 25 mmol) were added, and the mixture was stirred at 100°C for 30 minutes in a nitrogen-purged atmosphere. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the resulting residue at 0°C, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 65 / 35 (v / v)] to obtain 2.1 g (yield: 33%) of the title compound as an oily substance.

[0933] (10C)

[0934] 7-[(1s,3s)-3-(Benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol

[0935] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate (2.1 g, 5.4 mmol) from Example 10B was dissolved in methanol (27 mL). Potassium carbonate (1.9 g, 14 mmol) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The solid was filtered to obtain 1.4 g of the title compound as a solid (yield: 75%).

[0936] (10D)

[0937] 7-[(1s,3s)-3-(Benzyloxy)-3-methylcyclobutyl]-3-chloro-5-methoxy-7H-pyrrolo[2,3-c]pyridazine

[0938] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol (400 mg, 1.2 mmol) from Example 10C was dissolved in DMF (6.0 mL). Potassium carbonate (257 mg, 1.9 mmol) and iodomethane (0.094 mL, 1.5 mmol) were added at 0°C in a nitrogen-purged atmosphere, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 70 / 30 to 60 / 40 (v / v)) to obtain 317 mg of the title compound as an oily substance (yield: 76%).

[0939] (10E)

[0940] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[0941] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-5-methoxy-7H-pyrrolo[2,3-c]pyridazine (220 mg, 0.61 mmol) from Example 10D, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.74 mmol) from Example 1B, and potassium carbonate (170 mg, 1.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3.0 mL) and water (0.8 mL). XPhos Pd G2 (96 mg, 0.12 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 to 65 / 35 (v / v)] to obtain 265 mg of the title compound as a solid (yield: 80%).

[0942] (10F)

[0943] (1s,3s)-3-{5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[0944] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (265 mg, 0.49 mmol) from Example 10E was dissolved in methanol (5.0 mL), and ASCA-2 (100 mg) was added. The mixture was stirred at 65°C for 6 hours in a hydrogen-purged system. 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 [elution solvent: ethyl acetate / methanol = 100 / 0 to 97 / 3 (v / v)] to obtain 136 mg of the title compound as a solid (yield: 62%).

[0945] (10G)

[0946] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0947] (1s,3s)-3-{5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (136 mg, 0.30 mmol) from Example 10F was dissolved in DCM (1.5 mL), TFA (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 97 / 3 to 86 / 14 (v / v)]. Ethyl acetate and n-hexane were added to the resulting solid, and the mixture was sonicated. The solid was filtered to obtain 80 mg of the title compound as a solid (yield: 65%).

[0948] (Example 11)

[0949] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0950] 3-Methyl-2-{7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol dihydrochloride (108 mg, 0.23 mmol) and DIPEA (0.083 mL, 0.48 mmol) from Example 1F were dissolved in DCM (2.4 mL). Acetaldehyde (0.036 mL, 0.72 mmol), acetic acid (0.027 mL, 0.48 mmol), and NaBH(OAc)3 (203 mg, 0.95 mmol) were added at 0°C and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: DCM / methanol = 100 / 0 - 80 / 20 (V / V)] to obtain 87 mg of the title compound as a solid (yield: 89%).

[0951] (Example 12)

[0952] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0953] (Alternatively known as 2-[8-(cis-3-hydroxy-3-methylcyclobutyl)-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[0954] (12A)

[0955] 4-(2-bromocyclopent-1-en-1-yl)-3,6-dichloropyridazine

[0956] 4-Bromo-3,6-dichloropyridazine (3.20 g, 14 mmol), 2-bromo-1-cyclopentenylboronic acid (2.73 g, 14 mmol), and potassium carbonate (3.88 g, 28 mmol) were dissolved in a mixture of 1,4-dioxane (70 mL) and water (15 mL). Pd(dppf)Cl2 (0.51 g, 0.70 mmol) was added, and the mixture was stirred at 90°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature, saturated aqueous sodium bicarbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 76 / 24 (v / v)) to obtain 3.42 g of the title compound as an oily substance (yield: 83%).

[0957] (12B)

[0958] (1s,3s)-3-{[tert-Butyl(dimethyl)silyl]oxy}-3-methylcyclobutanamine

[0959] (1s,3s)-3-hydroxy-3-methylcyclobutanamine hydrochloride (2.10 g, 15 mmol) was suspended in DCM (30 mL), and imidazole (3.75 g, 55 mmol) and tert-butyldimethylsilyl chloride (3.37 g, 22 mmol) were added. The mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: DCM / methanol = 100 / 0 to 90 / 10 (v / v)] to obtain 2.50 g of the title compound as an oily substance (yield: 76%).

[0960] (12C)

[0961] 8-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazine

[0962] 4-(2-Bromocyclopent-1-en-1-yl)-3,6-dichloropyridazine (3.21 g, 11 mmol) of Example 12A and (1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutanamine (2.35 g, 11 mmol) of Example 12B were dissolved in 1,4-dioxane (55 mL), and Pd2(dba)3 (2.00 g, 2.2 mmol), RuPhos (1.00 g, 2.1 mmol) and sodium tert-butoxide (3.15 g, 33 mmol) were added, and the mixture was stirred at 110°C for 2 hours in a nitrogen-substituted system. After the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0-75 / 25 (V / V)] and NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0-75 / 25 (V / V)] to obtain 0.587 g of the title compound as a solid (yield: 14%).

[0963] (12D)

[0964] 8-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazine

[0965] 8-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazine (0.154 g, 0.39 mmol) of Example 12C, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.180 g, 0.52 mmol) of Example 1B, and potassium carbonate (0.110 g, 0.80 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.6 mL) and water (0.4 mL), and XPhos Pd G2 (0.053 g, 0.067 mmol) was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25 (v / v)] to obtain 0.112 g of the title compound as a solid (yield: 50%).

[0966] (12E)

[0967] 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[0968] To 8-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazine (0.112 g, 0.20 mmol) from Example 12D was added 4M hydrogen chloride-1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with DCM. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 100 / 0 - 90 / 10 (V / V)] to obtain 0.066 g (yield: 81%) of the title compound as a solid.

[0969] (Example 13)

[0970] 5-(Difluoromethoxy)-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[0971] (Alternatively known as 5-(difluoromethoxy)-2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methylphenol.)

[0972] (13A)

[0973] 3-(Benzyloxy)-5-methylphenol

[0974] 5-Methylresorcinol (7.0 g, 56 mmol) was dissolved in DMF (60 mL). 55% sodium hydride (4.5 g, 100 mmol) was added at 0°C and stirred for 30 minutes. A solution of benzyl bromide (6.0 mL, 51 mmol) in DMF (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 76 / 24 (v / v)) to obtain 3.7 g of the title compound as an oily substance (yield: 34%).

[0975] (13B)

[0976] 1-(Benzyloxy)-3-(difluoromethoxy)-5-methylbenzene

[0977] 3-(Benzyloxy)-5-methylphenol (3.68 g, 17 mmol) from Example 13A was dissolved in a mixed solvent of acetonitrile (40 mL) and water (40 mL). Potassium hydroxide (12.4 g, 221 mmol) and diethyl (bromodifluoromethyl)phosphonate (9.2 mL, 52 mmol) were added at 0°C, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 99 / 1 to 90 / 10 (v / v)) to obtain 3.34 g of the title compound as an oily substance (yield: 74%).

[0978] (13C)

[0979] 3-(Difluoromethoxy)-5-methylphenol

[0980] 1-(Benzyloxy)-3-(difluoromethoxy)-5-methylbenzene (3.34 g, 13 mmol) from Example 13B was dissolved in ethanol (40 mL), and ASCA-2 (0.218 g) was added. The mixture was stirred at 60°C for 2 hours in a hydrogen-purged system. 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 [eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 76 / 24 (v / v)] to obtain 2.65 g of the title compound as an oily substance (yield: quantitative).

[0981] (13D)

[0982] 5-(Difluoromethoxy)-2-iodo-3-methylphenol

[0983] 3-(Difluoromethoxy)-5-methylphenol (2.65 g, 15 mmol) from Example 13C was dissolved in toluene (45 mL). 55% sodium hydride (1.10 g, 25 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. Iodine (3.85 g, 15 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 85 / 15 (v / v)] to obtain 2.34 g of the title compound as an oily substance (yield: 51%).

[0984] (13E)

[0985] 5-(Difluoromethoxy)-2-iodo-1-(methoxymethoxy)-3-methylbenzene

[0986] 5-(Difluoromethoxy)-2-iodo-3-methylphenol (2.34 g, 7.8 mmol) from Example 13D was dissolved in DCM (25 mL). DIPEA (2.7 mL, 16 mmol) and chloromethyl methyl ether (0.88 mL, 12 mmol) were added, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 99 / 1 to 90 / 10 (v / v)] to obtain 2.24 g of the title compound as an oily substance (yield: 84%).

[0987] (13F)

[0988] 2-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0989] 5-(Difluoromethoxy)-2-iodo-1-(methoxymethoxy)-3-methylbenzene (1.92 g, 5.6 mmol) and iPrOBPin (2.3 mL, 11 mmol) from Example 13E were dissolved in THF (20 mL). n-Butyllithium (1.6 M in n-hexane) (5.3 mL, 8.4 mmol) was added at -78°C in a nitrogen-purged atmosphere, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 76 / 24 (v / v)] to obtain 1.61 g of the title compound as an oily substance (yield: 84%).

[0990] (13G)

[0991] (1s,3s)-3-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[0992] (1s,3s)-3-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (0.160 g, 0.64 mmol) from Example 4C, 2-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.283 g, 0.82 mmol) from Example 13F, and potassium carbonate (0.183 g, 1.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.6 mL). XPhos Pd G2 (0.100 g, 0.13 mmol) was added, and the mixture was stirred at 120° C. for 1 hour under microwave irradiation in a nitrogen-purged system. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V)] to obtain 0.169 g (yield: 61%) of the title compound as an oily substance.

[0993] (13H)

[0994] 5-(Difluoromethoxy)-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[0995] 4M hydrogen chloride-1,4-dioxane (4 mL) was added to (1s,3s)-3-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (0.166 g, 0.38 mmol) of Example 13G, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with DCM. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (V / V)] to obtain 0.115 g of the title compound as a solid (yield: 77%).

[0996] (Example 14)

[0997] 3-Methyl-2-{7-[(3R)-1-propylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[0998] (14A)

[0999] 7-[(3R)-1-Benzylpiperidin-3-yl]-3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1000] 3,6-Dichloro-4-vinylpyridazine (1.00 g, 5.7 mmol) and DIPEA (2.0 mL, 11 mmol) from Example 1C were dissolved in NMP (28 mL). (R)-3-amino-1-benzylpiperidine (1.30 g, 6.8 mmol) was added, and the mixture was stirred at 150°C for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50 (v / v)] to obtain 1.11 g of the title compound as an amorphous substance (yield: 59%).

[1001] (14B)

[1002] 7-[(3R)-1-Benzylpiperidin-3-yl]-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1003] 7-[(3R)-1-benzylpiperidin-3-yl]-3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.715 g, 2.2 mmol) from Example 14A, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.913 g, 2.6 mmol) from Example 1B, and potassium carbonate (0.601 g, 4.4 mmol) were dissolved in a mixture of 1,4-dioxane (8 mL) and water (2 mL). XPhos Pd G2 (0.342 g, 0.44 mmol) was added, and the mixture was stirred at 120°C for 3 hours under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to obtain 0.508 g (yield: 46%) of the title compound as an amorphous substance.

[1004] (14C)

[1005] 3-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1006] 7-[(3R)-1-benzylpiperidin-3-yl]-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.630 g, 1.2 mmol) from Example 14B was dissolved in ethanol (12 mL). ASCA-2 (0.323 g) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen-purged system, followed by heating under reflux for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 0.479 g of the crude title compound as a solid (yield: 92%).

[1007] (14D)

[1008] 3-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-propylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1009] 3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.067 g, 0.16 mmol) from Example 14C was dissolved in DCM (2 mL). Propionaldehyde (0.034 mL, 0.47 mmol) and NaBH(OAc)3 (0.13 g, 0.61 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: DCM / methanol = 100 / 0 to 70 / 30 (v / v)] to obtain 0.044 g of the title compound as an amorphous substance (yield: 60%).

[1010] (14E)

[1011] 3-Methyl-2-{7-[(3R)-1-propylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1012] 3-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-propylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.044 g, 0.095 mmol) from Example 14D was added to 4 M hydrogen chloride-1,4-dioxane (1 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to a saturated aqueous sodium bicarbonate solution, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: DCM / methanol = 100 / 0-70 / 30 (V / V)] and NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10 (V / V)] to obtain 28 mg of the title compound as a solid (yield: 70%).

[1013] (Example 15)

[1014] 3-Methyl-2-{7-[(3R)-1-(propan-2-yl)piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1015] (15A)

[1016] 3-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-(propan-2-yl)piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1017] 3-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.067 g, 0.16 mmol) from Example 14C was dissolved in DCM (2 mL). Acetone (0.56 mL, 7.7 mmol), acetic acid (0.018 mL, 0.31 mmol), and NaBH(OAc)3 (0.13 g, 0.61 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V)] to obtain 0.059 g (yield: 80%) of the title compound as an amorphous substance.

[1018] (15B)

[1019] 3-Methyl-2-{7-[(3R)-1-(propan-2-yl)piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1020] 4M hydrogen chloride-1,4-dioxane (1 mL) was added to 3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-(propan-2-yl)piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.059 g, 0.13 mmol) from Example 15A, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with DCM and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10 (v / v)] to obtain 43 mg of the title compound as a solid (yield: 81%).

[1021] (Example 16)

[1022] 7-(5-Hydroxybicyclo[3.1.1]heptan-1-yl)-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile

[1023] (16A)

[1024] 5-(3-Chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol

[1025] 3,6-Dichloro-4-vinylpyridazine (1.0 g, 5.7 mmol) and DIPEA (3.0 mL, 17 mmol) from Example 1C were dissolved in NMP (14 mL). 5-Aminobicyclo[3.1.1]heptanol (800 mg, 6.3 mmol) was added, and the mixture was stirred at 150°C for 1 hour under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 98 / 2 to 95 / 5 (v / v)] to obtain 690 mg of the title compound as a solid (yield: 45%).

[1026] (16B)

[1027] 5-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol

[1028] 5-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol (687 mg, 2.6 mmol) from Example 16A was dissolved in DCE (13 mL), and manganese dioxide (7.0 g, 78 mmol) was added. The mixture was stirred at 80°C for 30 minutes in a nitrogen-purged atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 25 / 75 to 0 / 100 (v / v)] to obtain 326 mg of the title compound as a solid (yield: 48%).

[1029] (16C)

[1030] 5-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[1031] 5-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol (260 mg, 0.99 mmol) from Example 16B, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (375 mg, 1.1 mmol) from Example 1B, and potassium carbonate (272 mg, 2.0 mmol) were dissolved in a mixture of 1,4-dioxane (3.0 mL) and water (1.0 mL). XPhos Pd G2 (155 mg, 0.20 mmol) was added, and the mixture was stirred at 120°C for 1 hour under microwave irradiation in a nitrogen-purged atmosphere. 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 brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 25 / 75 - 0 / 100 (V / V)] to obtain 340 mg of the title compound as a solid (yield: 77%).

[1032] (16D)

[1033] 7-{5-[(4-methoxybenzyl)oxy]bicyclo[3.1.1]heptan-1-yl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[1034] 5-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol (127 mg, 0.28 mmol) from Example 16C was dissolved in DMF (1.5 mL). 55% sodium hydride (24 mg, 0.57 mmol) and p-methoxybenzyl chloride (0.116 mL, 0.85 mmol) were added at 0°C. The mixture was stirred at room temperature for 70 minutes in a nitrogen-purged atmosphere. Water was added at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 - 50 / 50 (V / V)] to obtain 135 mg (yield: 84%) of the title compound as an oily substance.

[1035] (16E)

[1036] 5-iodo-7-{5-[(4-methoxybenzyl)oxy]bicyclo[3.1.1]heptan-1-yl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[1037] 7-{5-[(4-methoxybenzyl)oxy]bicyclo[3.1.1]heptan-1-yl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (135 mg, 0.24 mmol) from Example 16D was dissolved in DCE (1.0 mL), and N-iodosuccinimide (64 mg, 0.29 mmol) was added. The mixture was stirred at 60°C for 3 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 75 / 25 to 65 / 35 (v / v)] to obtain 82 mg of the title compound as an amorphous substance (yield: 50%).

[1038] (16F)

[1039] 7-{5-[(4-methoxybenzyl)oxy]bicyclo[3.1.1]heptan-1-yl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile

[1040] 5-Iodo-7-{5-[(4-methoxybenzyl)oxy]bicyclo[3.1.1]heptan-1-yl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (54 mg, 0.078 mmol) from Example 16E was dissolved in DMF (0.8 mL). 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.031 mmol), zinc cyanide (18 mg, 0.15 mmol), and Pd2(dba)3 (14 mg, 0.016 mmol) were added, and the mixture was stirred at 100°C for 1.5 hours in a nitrogen-purged atmosphere. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 - 55 / 45 (V / V)] to obtain 11 mg of the title compound as an oily substance (yield: 24%).

[1041] (16G)

[1042] 7-(5-Hydroxybicyclo[3.1.1]heptan-1-yl)-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile

[1043] 7-{5-[(4-methoxybenzyl)oxy]bicyclo[3.1.1]heptane-1-yl}-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile (14 mg, 0.024 mmol) from Example 16F was dissolved in DCM (0.3 mL), TFA (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 96 / 4 to 90 / 10 (v / v)] to obtain 5 mg of the title compound as a solid (yield: 49%).

[1044] (Example 17)

[1045] 2-{7-[(1S * ,2S * ,5R * )-8-ethyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1046] (17A)

[1047] (1S * ,2S * ,5S * )-8-Azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl 2-methyl ester

[1048] 8-Aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (J. Am. Chem. Soc. 2007, 129, 10312-10313) (2.44 g, 9.1 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (491 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen-purged atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified twice by silica gel column chromatography [eluting solvent: DCM / ethyl acetate = 98 / 2 to 92 / 8 (v / v)] to obtain 0.99 g of the first-eluting title compound as a racemic oil (yield: 40%).

[1049] (17B)

[1050] (1S * ,2S * ,5S *)-8-(tert-Butyloxycarbonyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid

[1051] The (1S of Example 17A) * ,2S * ,5S * )-8-tert-Butyl 2-methyl 8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (0.99 g, 3.7 mmol) was dissolved in methanol (20 mL), 5 M aqueous sodium hydroxide solution (7 mL) was added, and the mixture was stirred at room temperature for 80 minutes. 6 M hydrochloric acid was added to the reaction mixture at 0°C, and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.88 g (yield: 94%) of the crude title compound as a racemic solid.

[1052] (17C)

[1053] (1S * ,2S * ,5S * )-tert-butyl 2-{[(benzyloxy)carbonyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate

[1054] The (1S * ,2S * ,5S * )-8-(tert-Butyloxycarbonyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (0.84 g, 3.3 mmol) was suspended in toluene (33 mL), and TEA (0.912 mL, 6.6 mmol) and diphenylphosphoryl azide (0.851 mL, 4.0 mmol) were added. The mixture was stirred at 100°C for 1 hour in a nitrogen-purged system. Benzyl alcohol (2.72 mL, 26 mmol) was added to the reaction solution, and the mixture was stirred at 100°C for 2 hours. The reaction solution was returned to room temperature and purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30 (v / v)] to obtain 1.08 g (yield: 91%) of the title compound as a racemic solid.

[1055] (17D)

[1056] (1S * ,2S * ,5S * )-tert-Butyl 2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate

[1057] The (1S * ,2S * ,5S *tert-Butyl 2-{[(benzyloxy)carbonyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate (1.08 g, 3.0 mmol) was dissolved in ethanol (50 mL), 10% palladium on carbon (212 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen-purged atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 716 mg of a crude product of the title compound as a racemic oil (yield: quantitative).

[1058] (17E)

[1059] (1S * ,2S * ,5S * tert-Butyl 2-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1060] The (1S * ,2S * ,5S * tert-Butyl 2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (457 mg, 2.0 mmol) was dissolved in NMP (4 mL), and DIPEA (0.691 mL, 4.0 mmol) and 3,6-dichloro-4-vinylpyridazine (424 mg, 2.4 mmol) from Example 1C were added. The mixture was stirred at 150°C for 30 minutes in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 139 mg of the title compound as a racemic oil (yield: 19%).

[1061] (17F)

[1062] (1S * ,2S * ,5S * )-tert-butyl 2-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate

[1063] The (1S) of Example 17E * ,2S * ,5S *)-tert-Butyl 2-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (61 mg, 0.17 mmol), 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (82 mg, 0.23 mmol) of Example 1B, and potassium carbonate (45 mg, 0.33 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.6 mL) and water (0.4 mL), and XPhos Pd G2 (26 mg, 0.033 mmol) was added, and the mixture was stirred at 110° C. for 1 hour in a nitrogen-purged system. The reaction mixture was returned to room temperature, and DCM and water were added, followed by stirring. The organic layer was separated using a phase separator (Biotage). The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 to 0 / 100 (v / v)] to obtain 72 mg of the title compound as a racemic solid (yield: 79%).

[1064] (17G)

[1065] 2-{7-[(1S * ,2S * ,5R * )-8-Azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1066] In Example 17F (1S * ,2S * ,5S * )-2-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (72 mg, 0.13 mmol) was added with 4M hydrogen chloride-1,4-dioxane solution (1.5 mL) and methanol (0.15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with methanol and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, extracted with a mixed solvent of DCM / methanol, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 50 mg of the title compound as a racemate (solid) (yield: 94%).

[1067] (17H)

[1068] 2-{7-[(1S * ,2S *,5R * )-8-ethyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1069] The 2-{7-[(1S * ,2S * ,5R * )-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol (9 mg, 0.022 mmol) was dissolved in a mixed solvent of methanol (0.33 mL) and DCM (1 mL). Acetaldehyde (5 drops) and NaBH(OAc)3 (36 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with DCM / methanol, saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred. The organic layer was separated using a phase separator (Biotage), and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 100 / 0 to 90 / 10 (V / V)]. n-hexane / diisopropyl ether was added to the resulting residue, and sonication was performed. The solid was collected by filtration to obtain 6.3 mg of the title compound as a racemate (solid) (yield: 65%).

[1070] (Example 18)

[1071] 2-{7-[(3R)-1-cyclopropylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1072] (18A)

[1073] 7-[(3R)-1-cyclopropylpiperidin-3-yl]-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1074] 3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (0.038 g, 0.090 mmol) from Example 14C was dissolved in methanol (1 mL). (1-Ethoxycyclopropyloxy)trimethylsilane (0.11 mL, 0.55 mmol), acetic acid (0.051 mL, 0.89 mmol), and sodium cyanoborohydride (0.030 g, 0.48 mmol) were added, and the mixture was stirred at 60°C for 5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10-0 / 100 (V / V)] to obtain 0.012 g (yield: 29%) of the title compound as an oily substance.

[1075] (18B)

[1076] 2-{7-[(3R)-1-cyclopropylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1077] 7-[(3R)-1-cyclopropylpiperidin-3-yl]-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (12 mg, 0.026 mmol) from Example 18A was dissolved in DCM (0.5 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with DCM and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0 to 95 / 5 (v / v)] to obtain 5.4 mg of the title compound as a solid (yield: 50%).

[1078] (Example 19)

[1079] 3-Methyl-2-{7-[(1R,2R,5S or 1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1080] (19A)

[1081] 3-methyl-2-{7-[(1S * ,2S* ,5R * )-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1082] The 2-{7-[(1S * ,2S * ,5R * )-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol (40 mg, 0.099 mmol) was dissolved in a mixed solvent of methanol (0.67 mL) and DCM (2 mL). 37% formaldehyde (0.022 mL, 0.30 mmol) and NaBH(OAc)3 (149 mg, 0.70 mmol) were added to the nitrogen-purged system, and the mixture was stirred at room temperature for 1 hour and 20 minutes. The reaction mixture was diluted with DCM / methanol, and saturated aqueous sodium bicarbonate solution was added, followed by stirring. The organic layer was separated using a phase separator (Biotage), and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography [eluting solvent: DCM / methanol = 100 / 0 to 90 / 10 (V / V)] to obtain 39 mg (yield: 94%) of the title compound as a racemic solid.

[1083] (19B)

[1084] 3-Methyl-2-{7-[(1R,2R,5S or 1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1085] The 3-methyl-2-{7-[(1S * ,2S * ,5R * )-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol (28 mg, 0.067 mmol) was added to chiral HPLC [column: CHIRALPAK IG (20 mm ID×250 mm), mobile phase: n-hexane / 2-propanol = 60 / 40 (V / V), temperature: 40°C] to obtain 14.8 mg (yield: 53%) of the target compound eluted later as a single enantiomer (solid).

[1086] (Example 20)

[1087] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1088] (20A)

[1089] tert-Butyl (3R)-3-(3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate

[1090] 3,6-Dichloro-4-(prop-1-en-2-yl)pyridazine (8.07 g, 43 mmol) and DIPEA (15 mL, 86 mmol) from Example 4A were dissolved in NMP (45 mL), and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (10.5 g, 52 mmol) was added. The mixture was stirred at 150°C for 3 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60 (v / v)] to obtain 2.55 g of the title compound as an amorphous substance (yield: 17%).

[1091] (20B)

[1092] tert-Butyl (3R)-3-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate

[1093] tert-Butyl (3R)-3-(3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (2.55 g, 7.2 mmol) from Example 20A was dissolved in DCE (36 mL), DDQ (1.97 g, 8.7 mmol) was added, and the mixture was stirred at 80°C for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with DCM. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50 (v / v)] to obtain 1.74 g of the title compound as an amorphous substance (yield: 69%).

[1094] (20C)

[1095] tert-Butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate

[1096] Tert-butyl (3R)-3-(3-chloro-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (0.157 g, 0.45 mmol) from Example 20B, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.188 g, 0.54 mmol) from Example 1B, and potassium carbonate (0.120 g, 0.87 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). XPhos Pd G2 (0.070 g, 0.089 mmol) was added, and the mixture was stirred at 120° C. for 1 hour under microwave irradiation in a nitrogen-purged system. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 - 50 / 50 (V / V)] to obtain 0.247 g of the title compound as an amorphous substance (yield: quantitative).

[1097] (20D)

[1098] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1099] To tert-butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate (0.247 g, 0.46 mmol) from Example 20C was added 4M hydrogen chloride-1,4-dioxane (3.5 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (3 mL). Methanol (0.3 mL), acetaldehyde (0.20 mL, 8.0 mmol), and NaBH(OAc)3 (0.364 g, 1.7 mmol) were added, and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 100 / 0 - 90 / 10 (V / V)] to obtain 0.158 g (yield: 82%) of the title compound as an amorphous substance.

[1100] (Example 21)

[1101] 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1102] (Alternatively known as 2-[5-(difluoromethoxy)-7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[1103] (21A)

[1104] 3-Chloro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate

[1105] (1s,3s)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (2.0 g, 8.4 mmol) from Example 3B was dissolved in acetic acid (17 mL). Palladium(II) acetate (570 mg, 2.5 mmol) and diacetoxyiodobenzene (4.3 g, 14 mmol) were added, and the mixture was stirred at 100°C for 1 hour in a nitrogen-purged atmosphere. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the resulting residue at 0°C, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 422 mg of the title compound as an oily substance (yield: 17%).

[1106] (21B)

[1107] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate

[1108] 3-Chloro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate (1.66 g, 5.6 mmol) from Example 21A was dissolved in DMF (18 mL). Imidazole (1.15 g, 17 mmol) and tert-butyldimethylsilyl chloride (1.69 g, 11 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours in a nitrogen-purged atmosphere. Aqueous ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 75 / 25 to 10 / 90 (v / v)) to obtain 1.28 g of the title compound as an oily substance (yield: 56%).

[1109] (21C)

[1110] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol

[1111] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate (1.28 g, 3.1 mmol) of Example 21B was dissolved in methanol (15 mL), potassium carbonate (1.08 g, 7.8 mmol) was added at 0°C, and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, ethyl acetate was added, and ultrasonic treatment was performed. The solid was obtained by filtration to obtain 1.04 g of the title compound as a solid (yield: 90%).

[1112] (21D)

[1113] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5-(difluoromethoxy)-7H-pyrrolo[2,3-c]pyridazine

[1114] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol (150 mg, 0.41 mmol) from Example 21C was dissolved in a mixed solvent of acetonitrile (6.0 mL) and water (3.0 mL). Diethyl (bromodifluoromethyl)phosphonate (0.217 mL, 1.2 mmol) and potassium hydroxide (231 mg, 4.0 mmol) were added, and the mixture was stirred at room temperature for 5.5 hours in a nitrogen-purged atmosphere. Aqueous ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 - 60 / 40 (V / V)] to obtain 35 mg (yield: 21%) of the title compound as an oily substance.

[1115] (21E)

[1116] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-5-(difluoromethoxy)-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[1117] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5-(difluoromethoxy)-7H-pyrrolo[2,3-c]pyridazine (20 mg, 0.048 mmol) from Example 21D, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 mg, 0.067 mmol) from Example 1B, and potassium carbonate (13 mg, 0.096 mmol) were dissolved in a mixed solvent of 1,4-dioxane (0.6 mL) and water (0.15 mL). XPhos Pd G2 (7 mg, 0.0096 mmol) was added, and the mixture was stirred at 110° C. for 1 hour in a nitrogen-purged system. The reaction solution was returned to room temperature and purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 95 / 5 - 80 / 20 (V / V)] to obtain 22.8 mg of the title compound as a solid (yield: 79%).

[1118] (21F)

[1119] 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1120] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-5-(difluoromethoxy)-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (21.5 mg, 0.036 mmol) from Example 21E was dissolved in DCM (0.5 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution at 0°C, and the mixture was extracted with DCM. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: DCM / methanol = 98 / 2-88 / 12 (v / v)] to obtain 8.65 mg of the title compound as a solid (yield: 55%).

[1121] (Example 22)

[1122] 5-(Difluoromethoxy)-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1123] (22A)

[1124] tert-Butyl (3R)-3-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate

[1125] Tert-butyl (3R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (0.400 g, 1.2 mmol) from Example 1D, 2-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.488 g, 1.4 mmol) from Example 13F, and potassium carbonate (0.326 g, 2.4 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL). XPhos Pd G2 (0.186 g, 0.24 mmol) was added, and the mixture was stirred at 120° C. for 1 hour under microwave irradiation in a nitrogen-substituted system. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 - 25 / 75 (V / V)] to obtain 0.634 g of the title compound as an oily substance (yield: quantitative).

[1126] (22B)

[1127] 5-(Difluoromethoxy)-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1128] To tert-butyl (3R)-3-{3-[4-(difluoromethoxy)-2-(methoxymethoxy)-6-methylphenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate (0.634 g, 1.2 mmol) from Example 22A was added 4M hydrogen chloride-1,4-dioxane (12 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with DCM and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (12 mL). Methanol (1.2 mL), NaBH(OAc)3 (1.08 g, 5.1 mmol), and acetaldehyde (1.2 mL, 24 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was extracted with DCM and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 100 / 0 - 90 / 10 (V / V)] to obtain 0.310 g (yield: 63%) of the title compound as a solid.

[1129] (Example 23)

[1130] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethoxy)phenol

[1131] (23A)

[1132] 3-Methyl-5-(trifluoromethoxy)phenol

[1133] 3-Chloro-5-trifluoromethoxyphenol (3.3 g, 16 mmol), trimethylcyclotriboroxane (50% THF solution) (7.8 mL, 28 mmol), and cesium carbonate (13 g, 39 mmol) were dissolved in a mixture of 1,4-dioxane (78 mL) and water (20 mL). XPhos Pd G2 (1.2 g, 1.6 mmol) was added, and the mixture was stirred at 120°C for 5 hours in a nitrogen-purged atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40 (v / v)] to obtain 3.4 g of the title compound as an oily substance (yield: quantitative).

[1134] (23B)

[1135] 2-Iodo-3-methyl-5-(trifluoromethoxy)phenol

[1136] 3-Methyl-5-(trifluoromethoxy)phenol (3.4 g, 18 mmol) from Example 23A was dissolved in toluene (60 mL). 55% sodium hydride (1.5 g, 35 mmol) was added at 0°C and stirred for 30 minutes. Iodine (4.5 g, 18 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5.6 g of the title compound as an oily substance (yield: quantitative).

[1137] (23C)

[1138] 2-Iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethoxy)benzene

[1139] 2-Iodo-3-methyl-5-(trifluoromethoxy)phenol (5.6 g, 18 mmol) and TEA (6.1 mL, 35 mmol) from Example 23B were dissolved in DCM (88 mL). Chloromethyl methyl ether (1.7 mL, 23 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15 (v / v)] to obtain 3.1 g of the title compound as an oily substance (yield: 49%).

[1140] (23D)

[1141] 2-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1142] 2-Iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethoxy)benzene (3.06 g, 8.5 mmol) from Example 23C was dissolved in THF (42 mL). n-Butyllithium (1.6 M solution in n-hexane) (6.9 mL, 11 mmol) was added at -78°C, and the mixture was stirred at -78°C for 30 minutes in a nitrogen-purged atmosphere. iPrOBPin (3.42 mL, 17 mmol) was added at -78°C, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35 (v / v)] to obtain 1.87 g (yield: 61%) of the title compound as an oily substance.

[1143] (23E)

[1144] tert-Butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate

[1145] Tert-butyl (3R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (0.224 g, 0.66 mmol) from Example 1D, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.286 g, 0.79 mmol) from Example 23D, and potassium carbonate (0.183 g, 1.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.8 mL) and water (0.7 mL). XPhos Pd G2 (0.104 g, 0.13 mmol) was added, and the mixture was stirred at 120° C. for 1 hour under microwave irradiation in a nitrogen-substituted system. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 - 25 / 75 (V / V)] to obtain 0.126 g (yield: 35%) of the title compound as an amorphous substance.

[1146] (23F)

[1147] 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethoxy)phenol

[1148] To tert-butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethoxy)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate (0.126 g, 0.23 mmol) from Example 23E was added 4M hydrogen chloride-1,4-dioxane (3 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the residue, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (3 mL). Methanol (0.3 mL), acetaldehyde (0.50 mL, 10 mmol), and NaBH(OAc)3 (0.253 g, 1.2 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with DCM, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 100 / 0 - 90 / 10 (V / V)] to obtain 0.055 g (yield: 56%) of the title compound as a solid.

[1149] (Example 24)

[1150] 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[1151] (24A)

[1152] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine

[1153] 5-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-ol (477 mg, 1.8 mmol) from Example 16B was dissolved in DMF (6.0 mL). 55% sodium hydride (173 mg, 3.9 mmol) and benzyl bromide (0.537 mL, 4.5 mmol) were added at 0°C. The mixture was stirred at room temperature for 30 minutes in a nitrogen-purged atmosphere. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 to 70 / 30 (v / v)] to obtain 419 mg of the title compound as an oily substance (yield: 65%).

[1154] (24B)

[1155] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate

[1156] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazine (452 ​​mg, 1.3 mmol) from Example 24A was dissolved in acetic acid (3.0 mL). Palladium(II) acetate (57 mg, 0.26 mmol) and diacetoxyiodobenzene (617 mg, 1.9 mmol) were added, and the mixture was stirred at 100°C for 50 minutes in a nitrogen-purged atmosphere. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the resulting residue at 0°C, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 70 / 30 (v / v)] to obtain 171 mg of the title compound as an oily substance (yield: 33%).

[1157] (24C)

[1158] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol

[1159] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-yl acetate (171 mg, 0.42 mmol) from Example 24B was dissolved in methanol (2.0 mL). Potassium carbonate (143 mg, 1.0 mmol) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes in a nitrogen-purged atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 50 / 50 (v / v)] to obtain 90 mg of the title compound as an amorphous substance (yield: 59%).

[1160] (24D)

[1161] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-5-methoxy-7H-pyrrolo[2,3-c]pyridazine

[1162] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol (90 mg, 0.24 mmol) from Example 24C was dissolved in DMF (1.2 mL). Potassium carbonate (53 mg, 0.39 mmol) and iodomethane (0.020 mL, 0.32 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 75 / 25 to 65 / 35 (v / v)) to obtain 71 mg of the title compound as an amorphous substance (yield: 76%).

[1163] (24E)

[1164] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[1165] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-3-chloro-5-methoxy-7H-pyrrolo[2,3-c]pyridazine (71 mg, 0.18 mmol) from Example 24D, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76 mg, 0.22 mmol) from Example 1B, and potassium carbonate (51 mg, 0.37 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.0 mL) and water (0.3 mL). XPhos Pd G2 (29 mg, 0.037 mmol) was added, and the mixture was stirred at 120° C. under microwave irradiation in a nitrogen-purged system for 1 hour. The reaction mixture was returned to room temperature and purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 - 60 / 40 (V / V)] to obtain 73 mg (yield: 70%) of the title compound as an amorphous substance.

[1166] (24F)

[1167] 5-{5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[1168] 7-[5-(Benzyloxy)bicyclo[3.1.1]heptan-1-yl]-5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (73 mg, 0.13 mmol) from Example 24E was dissolved in methanol (1.5 mL), and ASCA-2 (30 mg) was added. The mixture was stirred at 65°C for 2.5 hours in a hydrogen-purged system. 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 [elution solvent: n-hexane / ethyl acetate = 25 / 75 to 0 / 100 (v / v)] to obtain 33 mg of the title compound as a solid (yield: 54%).

[1169] (24G)

[1170] 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol

[1171] 5-{5-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol (33 mg, 0.069 mmol) from Example 24F was dissolved in DCM (0.3 mL), TFA (0.3 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 97 / 3 to 90 / 10 (v / v)] to obtain 19 mg of the title compound as a solid (yield: 63%).

[1172] (Example 25)

[1173] 2-{5-ethoxy-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1174] (Alternatively known as 2-[5-ethoxy-7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol.)

[1175] (25A)

[1176] 7-[(1s,3s)-3-(Benzyloxy)-3-methylcyclobutyl]-3-chloro-5-ethoxy-7H-pyrrolo[2,3-c]pyridazine

[1177] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol (160 mg, 0.47 mmol) from Example 10C was dissolved in DMF (2.5 mL). Potassium carbonate (102 mg, 0.74 mmol) and iodoethane (0.048 mL, 0.60 mmol) were added at 0°C, and the mixture was stirred at room temperature for 4 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 75 / 25 to 60 / 40 (v / v)] to obtain 83 mg of the title compound as an oily substance (yield: 48%).

[1178] (25B)

[1179] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-5-ethoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine

[1180] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-3-chloro-5-ethoxy-7H-pyrrolo[2,3-c]pyridazine (83 mg, 0.22 mmol) from Example 25A, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92 mg, 0.27 mmol) from Example 1B, and potassium carbonate (61 mg, 0.45 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.2 mL) and water (0.3 mL). XPhos Pd G2 (35 mg, 0.045 mmol) was added, and the mixture was stirred at 120°C for 50 minutes under microwave irradiation in a nitrogen-purged atmosphere. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 65 / 35 to 55 / 45 (V / V)] and silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50 (V / V)] to obtain 88 mg of the title compound as an amorphous substance (yield: 71%).

[1181] (25C)

[1182] (1s,3s)-3-{5-ethoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[1183] 7-[(1s,3s)-3-(benzyloxy)-3-methylcyclobutyl]-5-ethoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine (88 mg, 0.16 mmol) from Example 25B was dissolved in methanol (1.5 mL). ASCA-2 (40 mg) was added, and the mixture was stirred at 60°C for 2.5 hours in a hydrogen-purged system. 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 [elution solvent: n-hexane / ethyl acetate = 25 / 75 to 0 / 100 (v / v)] to obtain 36 mg of the title compound as a solid (yield: 48%).

[1184] (25D)

[1185] 2-{5-ethoxy-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1186] (1s,3s)-3-{5-ethoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (36 mg, 0.077 mmol) from Example 25C was dissolved in DCM (0.4 mL), TFA (0.4 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 97 / 3 to 90 / 10 (v / v)] to obtain 24 mg of the title compound as a solid (yield: 74%).

[1187] (Example 26)

[1188] 5-Chloro-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1189] (26A)

[1190] tert-Butyl (3R)-3-{3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate

[1191] tert-Butyl (3R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (355 mg, 1.1 mmol) from Example 1D, 2-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (396 mg, 1.3 mmol) from Example 9C, and potassium carbonate (308 mg, 2.1 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10.4 mL) and water (2.6 mL). XPhos Pd G2 (248 mg, 0.32 mmol) was added, and the mixture was stirred at 120°C for 5 hours in a nitrogen-purged atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added, followed by celite filtration. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 65 / 35 - 5 / 95 (V / V)] to obtain 55 mg of the title compound as an amorphous substance (yield: 11%).

[1192] (26B)

[1193] 5-Chloro-3-methyl-2-{7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}phenol

[1194] tert-Butyl (3R)-3-{3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}piperidine-1-carboxylate (54.0 mg, 0.11 mmol) from Example 26A was dissolved in 1,4-dioxane (1.1 mL). 4M hydrogen chloride-1,4-dioxane (1.1 mL) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: DCM / methanol = 99 / 1 to 85 / 15 (v / v)] to obtain 25 mg of the title compound as a solid (yield: 65%).

[1195] (26C)

[1196] 5-Chloro-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1197] 5-Chloro-3-methyl-2-{7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}phenol (24.5 mg, 0.071 mmol) from Example 26B was dissolved in DCM (1.0 mL). Methanol (0.6 mL), acetaldehyde (0.021 mL, 0.42 mmol), and NaBH(OAc)3 (195.2 mg, 0.92 mmol) were added, and the mixture was stirred at room temperature for 2 days. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0 to 92 / 8 (v / v)] to obtain 17 mg of the title compound as a solid (yield: 65%).

[1198] (Example 27)

[1199] 5-Chloro-2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1200] (Alternatively known as 5-chloro-2-[5-fluoro-7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methylphenol)

[1201] (27A)

[1202] 3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine

[1203] 3-Chloro-5-fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine (200 mg, 0.53 mmol) from Example 5B, 2-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.64 mmol) from Example 9C, and potassium carbonate (150 mg, 1.1 mmol) were dissolved in a mixture of 1,4-dioxane (3.0 mL) and water (0.7 mL). XPhos Pd G2 (83 mg, 0.11 mmol) was added, and the mixture was stirred at 110°C for 70 minutes in a nitrogen-purged atmosphere. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 - 60 / 40 (V / V)] to obtain 122 mg (yield: 44%) of the title compound as an amorphous substance.

[1204] (27B)

[1205] 5-Chloro-2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1206] 3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-fluoro-7-{(1s,3s)-3-[(4-methoxybenzyl)oxy]-3-methylcyclobutyl}-7H-pyrrolo[2,3-c]pyridazine (36 mg, 0.077 mmol) from Example 27A was dissolved in DCM (0.4 mL), TFA (0.4 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 97 / 3 to 90 / 10 (v / v)] to obtain 24 mg of the title compound as a solid (yield: 74%).

[1207] (Example 28)

[1208] 5-Chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1209] (Alternatively known as 5-chloro-2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methylphenol)

[1210] (28A)

[1211] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5-methoxy-7H-pyrrolo[2,3-c]pyridazine

[1212] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazin-5-ol (350 mg, 0.95 mmol) from Example 21C was dissolved in DMF (5.0 mL). Potassium carbonate (210 mg, 1.5 mmol) and iodomethane (0.076 mL, 1.2 mmol) were added at 0°C, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 85 / 15 to 75 / 25 (v / v)] to obtain 147 mg of the title compound as an oily substance (yield: 40%).

[1213] (28B)

[1214] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazine

[1215] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5-methoxy-7H-pyrrolo[2,3-c]pyridazine (147 mg, 0.38 mmol) from Example 28A, 2-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (144 mg, 0.46 mmol) from Example 9C, and potassium carbonate (106 mg, 0.77 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.0 mL) and water (0.5 mL). XPhos Pd G2 (60 mg, 0.077 mmol) was added, and the mixture was stirred at 110°C for 80 minutes in a nitrogen-purged atmosphere. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 to 70 / 30 (v / v)] to obtain 46 mg of the title compound as an amorphous substance (yield: 22%).

[1216] (28C)

[1217] 5-Chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1218] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazine (46 mg, 0.086 mmol) from Example 28B was dissolved in DCM (0.4 mL), TFA (0.4 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 97 / 3 to 90 / 10 (V / V)] to obtain 20 mg of the title compound as a solid (yield: 62%).

[1219] (Example 29)

[1220] 5-Chloro-2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1221] (Alternatively known as 5-chloro-2-[5-(difluoromethoxy)-7-(cis-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methylphenol)

[1222] (29A)

[1223] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-(difluoromethoxy)-7H-pyrrolo[2,3-c]pyridazine

[1224] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-chloro-5-(difluoromethoxy)-7H-pyrrolo[2,3-c]pyridazine (77 mg, 0.18 mmol) from Example 21D, 2-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.22 mmol) from Example 9C, and potassium carbonate (51 mg, 0.37 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.23 mL) and water (0.31 mL). XPhos Pd G2 (14 mg, 0.018 mmol) was added, and the mixture was stirred at 110° C. for 2.5 hours in a nitrogen-purged system. The reaction mixture was returned to room temperature, diluted with DCM and water, and separated using a phase separator (Biotage). The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 95 / 5 to 75 / 25 (v / v)] to obtain 48.3 mg of the title compound as an oily substance (yield: 46%).

[1225] (29B)

[1226] 5-Chloro-2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol

[1227] 7-((1s,3s)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-methylcyclobutyl)-3-[4-chloro-2-(methoxymethoxy)-6-methylphenyl]-5-(difluoromethoxy)-7H-pyrrolo[2,3-c]pyridazine (47.3 mg, 0.083 mmol) from Example 29A was dissolved in DCM (1 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, followed by DCM / ethanol and stirring. The organic layer was separated using a phase separator (Biotage). The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: DCM / methanol = 98 / 2 to 88 / 12 (v / v)]. The residue was solidified by ethyl acetate / diisopropyl ether / n-hexane to obtain 13.9 mg of the title compound as a solid (yield: 41%).

[1228] (Example 30)

[1229] 3-Methyl-2-{6-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1230] (30A)

[1231] 3,6-Dichloro-4-[(1E)-prop-1-en-1-yl]pyridazine

[1232] Using 4-bromo-3,6-dichloropyridazine (1.01 g, 4.4 mmol), propene-1-ylboronic acid pinacol ester (894 mg, 5.3 mmol), potassium carbonate (1.47 g, 8.9 mmol), and Pd(dppf)Cl2 (434 mg, 0.44 mmol), the same method as in Example 1C was used to obtain 430 mg of the title compound as a solid (yield: 51%).

[1233] (30B)

[1234] tert-Butyl (3R)-3-(3-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate

[1235] Using 3,6-dichloro-4-[(1E)-prop-1-en-1-yl]pyridazine (250 mg, 1.3 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (320 mg, 1.6 mmol) from Example 30A, the same method as in Example 1D was used to obtain 133 mg (yield: 29%) of the title compound as a diastereomeric mixture (oily substance).

[1236] (30C)

[1237] 3-Chloro-6-methyl-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine dihydrochloride

[1238] Using tert-butyl (3R)-3-(3-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (112 mg, 0.31 mmol) and 4M hydrogen chloride-1,4-dioxane (0.70 mL) from Example 30B, the same method as in Example 2B was used to obtain 88 mg (yield: 85%) of the title compound as a diastereomeric mixture (solid).

[1239] (30D)

[1240] 3-Chloro-6-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1241] Using 3-chloro-6-methyl-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine dihydrochloride (88 mg, 0.27 mmol) from Example 30C, DIPEA (0.094 mL, 0.54 mmol), 37% formaldehyde (0.030 mL, 0.41 mmol), acetic acid (0.030 mL, 0.54 mmol), and NaBH(OAc)3 (230 mg, 1.1 mmol), the same method as in Example 1G was used to obtain 47 mg (yield: 65%) of the title compound as a mixture of diastereomers (oily substance).

[1242] (30E)

[1243] 3-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-6-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1244] Using 2-(2-methoxy-6-methyl-4-(trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US20200361898) (44 mg, 0.14 mmol), 3-chloro-6-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (45 mg, 0.17 mmol) of Example 30D, potassium carbonate (39 mg, 0.28 mmol), and XPhos Pd G2 (11 mg, 0.014 mmol), the same method as in Example 1E was used to obtain 36 mg (yield: 62%) of the title compound as a diastereomeric mixture (amorphous).

[1245] (30F)

[1246] 3-Methyl-2-{6-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1247] Using 3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-6-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (31 mg, 0.073 mmol) and boron tribromide (1.0 M DCM solution) (0.22 mL, 0.22 mmol) from Example 30E, the same method as in Example 2E was used to obtain 18 mg (yield: 60%) of the title compound as a diastereomeric mixture (solid).

[1248] (Example 31)

[1249] 3-Methyl-2-[1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(trifluoromethyl)phenol

[1250] (31A)

[1251] tert-Butyl 3-{2-[(benzyloxy)carbonyl]hydrazine}piperidine-1-carboxylate

[1252] Dissolve 1-(tert-Butoxycarbonyl)-3-piperidone (2.98 g, 15 mmol) in methanol (38 mL), add benzyl carbazate (2.73 g, 17 mmol), and stir at room temperature for 3.5 hours. Add sodium cyanoborohydride (1.87 g, 30 mmol) to the reaction mixture, and stir at room temperature for 20 hours. Add saturated aqueous sodium bicarbonate to the reaction mixture, and extract with ethyl acetate. Wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50 (v / v)] to obtain 1.95 g (yield: 37%) of the title compound as a racemic (amorphous) compound.

[1253] (31B)

[1254] tert-Butyl 3-hydrazinopiperidine-1-carboxylate acetate

[1255] tert-Butyl 3-{2-[(benzyloxy)carbonyl]hydrazine}piperidine-1-carboxylate (1.95 g, 5.6 mmol) from Example 31A was dissolved in ethanol (28 mL). Acetic acid (1.28 mL, 22 mmol) and 5% palladium on carbon (661 mg) were added, and the mixture was stirred at room temperature for 3.5 hours in a hydrogen-purged atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the crude title compound.

[1256] (31C)

[1257] tert-Butyl 3-(5-chloro-3-hydroxy-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate

[1258] Methyl 3,6-dichloropyridazine-4-carboxylate (970 mg, 4.7 mmol) was dissolved in methanol (6 mL). Tert-butyl 3-hydrazinopiperidine-1-carboxylate acetate (1.54 g, 5.6 mmol) and DIPEA (2.5 mL, 14 mmol) from Example 31B were added, and the mixture was stirred at 70°C for 12 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: DCM / ethyl acetate = 80 / 20 to 60 / 40 (v / v)] to obtain 155 mg of the title compound as a racemic solid (yield: 9% over two steps).

[1259] (31D)

[1260] tert-Butyl 3-{3-hydroxy-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-c]pyridazin-1-yl}piperidine-1-carboxylate

[1261] Using tert-butyl 3-(5-chloro-3-hydroxy-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate (206 mg, 0.58 mmol) from Example 31C, 2-(2-methoxy-6-methyl-4-(trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US20200361898) (367 mg, 1.2 mmol), potassium carbonate (160 mg, 1.2 mmol), and XPhos PdG2 (90 mg, 0.12 mmol), the same method as in Example 1E was used to obtain 193 mg (yield: 65%) of the title compound as a racemic form (amorphous).

[1262] (31E)

[1263] tert-Butyl 3-(5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-3-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate

[1264] tert-Butyl 3-{3-hydroxy-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-c]pyridazin-1-yl}piperidine-1-carboxylate (193 mg, 0.38 mmol) from Example 31D was dissolved in DCM (4 mL). TEA (0.106 mL, 0.76 mmol) and N-phenylbis(trifluoromethanesulfonimide) (203 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature for 1.5 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 [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 70 / 30 (v / v)] to obtain 150 mg of the title compound as a racemic oil (yield: 62%).

[1265] (31F)

[1266] tert-Butyl 3-{5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-c]pyridazin-1-yl}piperidine-1-carboxylate

[1267] tert-Butyl 3-(5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-3-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazolo[3,4-c]pyridazin-1-yl)piperidine-1-carboxylate (150 mg, 0.23 mmol) from Example 31E was dissolved in THF (2 mL). Pd(dppf)Cl2 (34 mg, 0.047 mmol), 1,1'-bis(diphenylphosphino)ferrocene (26 mg, 0.047 mmol), ammonium formate (73 mg, 1.2 mmol), and TEA (0.163 mL, 1.2 mmol) were added. The mixture was stirred at 75°C for 3 hours in a nitrogen-purged atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 - 60 / 40 (V / V)] to obtain 87 mg (yield: 75%) of the title compound as a racemate (oil).

[1268] (31G)

[1269] 5-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-(piperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazine monohydrochloride

[1270] Using tert-butyl 3-{5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-c]pyridazin-1-yl}piperidine-1-carboxylate (87 mg, 0.18 mmol) from Example 31F and 4M hydrogen chloride-1,4-dioxane (0.9 mL), the same method as in Example 2B was used to obtain 75 mg (yield: quantitative) of a crude product of the title compound as a racemate (solid).

[1271] (31H)

[1272] 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazine

[1273] Using 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-(piperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazine monohydrochloride (75 mg, 0.18 mmol) from Example 31G, DIPEA (0.061 mL, 0.35 mmol), 37% formaldehyde (0.019 mL, 0.26 mmol), acetic acid (0.020 mL, 0.35 mmol), and NaBH(OAc)3 (148 mg, 0.70 mmol), the same method as in Example 1G was used to obtain 62 mg (yield: 87%) of the title compound as a racemic form (oily substance).

[1274] (31I)

[1275] 3-Methyl-2-[1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-5-yl]-5-(trifluoromethyl)phenol

[1276] Using 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-(1-methylpiperidin-3-yl)-1H-pyrazolo[3,4-c]pyridazine (60 mg, 0.15 mmol) from Example 31H and boron tribromide (1.0 M DCM solution) (0.75 mL, 0.75 mmol), the same method as in Example 2E was used to obtain 35 mg (yield: 60%) of the title compound as a racemate (solid).

[1277] (Example 32)

[1278] 3-Methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-imidazo[4,5-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1279] (32A)

[1280] tert-Butyl (3R)-3-[(4-amino-6-chloropyridazin-3-yl)amino]piperidine-1-carboxylate

[1281] 3,6-Dichloropyridazin-4-amine (700 mg, 4.3 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (940 mg, 4.7 mmol) were dissolved in 1-decanol (1.4 mL), and DIPEA (1.1 mL, 6.4 mmol) was added. The mixture was stirred at 150°C for 13 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: DCM / methanol = 95 / 5 to 80 / 20 (v / v)] to obtain the crude title compound as an oily substance.

[1282] (32B)

[1283] tert-Butyl (3R)-3-(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate

[1284] To tert-butyl (3R)-3-[(4-amino-6-chloropyridazin-3-yl)amino]piperidine-1-carboxylate (590 mg, 1.8 mmol) from Example 32A, triethyl orthoformate (6.0 mL, 36 mmol) and formic acid (0.3 mL, 9.0 mmol) were added, and the mixture was stirred at 100°C for 11 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 75 / 25 to 0 / 100 (v / v)] to obtain 54 mg of the title compound as an amorphous substance (yield: 4% over two steps).

[1285] (32C)

[1286] 3-Chloro-7-[(3R)-piperidin-3-yl]-7H-imidazo[4,5-c]pyridazine monohydrochloride

[1287] Using tert-butyl (3R)-3-(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (54 mg, 0.16 mmol) from Example 32B and 4 M hydrogen chloride-1,4-dioxane (1.5 mL), the same method as in Example 2B was used to obtain 43 mg of a crude product of the title compound as a solid (yield: quantitative).

[1288] (32D)

[1289] 3-Chloro-7-[(3R)-1-methylpiperidin-3-yl]-7H-imidazo[4,5-c]pyridazine

[1290] Using 3-chloro-7-[(3R)-piperidin-3-yl]-7H-imidazo[4,5-c]pyridazine monohydrochloride (43 mg, 0.16 mmol) from Example 32C, DIPEA (0.081 mL, 0.47 mmol), 37% formaldehyde (0.020 mL, 0.27 mmol), acetic acid (0.017 mL, 0.31 mmol), and NaBH(OAc)3 (132 mg, 0.63 mmol), the same method as in Example 1G was used to obtain 19 mg of the title compound as a solid (yield: 48%).

[1291] (32E)

[1292] 3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-methylpiperidin-3-yl]-7H-imidazo[4,5-c]pyridazine

[1293] Using 3-chloro-7-[(3R)-1-methylpiperidin-3-yl]-7H-imidazo[4,5-c]pyridazine (19 mg, 0.075 mmol), 2-(2-methoxy-6-methyl-4-(trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US20200361898) (40 mg, 0.13 mmol), potassium carbonate (20 mg, 0.15 mmol), and XPhos Pd G2 (8 mg, 0.011 mmol) from Example 32D, 12 mg (yield: 39%) of the title compound were obtained as an oily substance.

[1294] (32F)

[1295] 3-Methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-imidazo[4,5-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1296] Using 3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-methylpiperidin-3-yl]-7H-imidazo[4,5-c]pyridazine (12 mg, 0.030 mmol) from Example 32E and boron tribromide (1.0 M solution in DCM) (0.15 mL, 0.15 mmol), the same method as in Example 2E was used to obtain 7.6 mg of the title compound as a solid (yield: 65%).

[1297] (Example 33)

[1298] 3-Methyl-2-{(5S or 5R)-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1299] (33A)

[1300] (3R)-tert-Butyl 3-[(5S or 5R)-3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate

[1301] Using 3,6-dichloro-4-(prop-1-en-2-yl)pyridazine (1.04 g, 5.5 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.32 g, 6.6 mmol), and DIPEA (1.44 mL, 8.3 mmol) from Example 4A, the product was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 65 / 35-45 / 55 (V / V)] using the same method as in Example 1D to obtain 92 mg (yield: 5%) of the title compound eluted first as a single diastereomer (amorphous).

[1302] (33B)

[1303] (5S or 5R)-3-Chloro-5-methyl-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine monohydrochloride

[1304] Using tert-butyl (3R)-3-[(5S or 5R)-3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate (92 mg, 0.26 mmol) from Example 33A and 4 M hydrogen chloride-1,4-dioxane (2.5 mL), the same method as in Example 2B was used to obtain 75 mg (yield: quantitative) of a crude product of the title compound as a single diastereomer (solid).

[1305] (33C)

[1306] (5S or 5R)-3-Chloro-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1307] Using (5S or 5R)-3-chloro-5-methyl-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine monohydrochloride (75 mg, 0.26 mmol), DIPEA (0.090 mL, 0.52 mmol), 37% formaldehyde (0.039 mL, 0.52 mmol), acetic acid (0.029 mL, 0.52 mmol), and NaBH(OAc)3 (219 mg, 1.04 mmol) from Example 33B, the same method as in Example 1G was used to obtain 42 mg (yield: 61%) of the title compound as a single diastereomer (oily substance).

[1308] (33D)

[1309] (5S or 5R)-3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1310] Using (5S or 5R)-3-chloro-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (35 mg, 0.13 mmol), 2-(2-methoxy-6-methyl-4-(trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US20200361898) (70 mg, 0.22 mmol), potassium carbonate (36 mg, 0.26 mmol), and XPhos Pd G2 (15 mg, 0.020 mmol) from Example 33C, 36 mg (yield: 65%) of the title compound were obtained as a single diastereomer (oily substance) using the same method as in Example 1E.

[1311] (33E)

[1312] 3-Methyl-2-{(5S or 5R)-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1313] Using (5S or 5R)-3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (36 mg, 0.086 mmol) and boron tribromide (1.0 M DCM solution) (0.4 mL, 0.40 mmol) from Example 33D, the same method as in Example 2E was used to obtain 23 mg (yield: 66%) of the title compound as a single diastereomer (solid).

[1314] (Example 34)

[1315] 3-Methyl-2-{(5R or 5S)-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1316] (34A)

[1317] tert-Butyl (3R)-3-[(5R or 5S)-3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate

[1318] Using 3,6-dichloro-4-(prop-1-en-2-yl)pyridazine (1.04 g, 5.5 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.32 g, 6.6 mmol), and DIPEA (1.44 mL, 8.3 mmol) from Example 4A, the product was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 65 / 35-45 / 55 (V / V)] using the same method as in Example 1D to obtain 95 mg (yield: 5%) of the title compound eluted later as a single diastereomer (amorphous).

[1319] (34B)

[1320] (5R or 5S)-3-Chloro-5-methyl-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine monohydrochloride

[1321] Using (3R)-3-[(5R or 5S)-3-chloro-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylic acid tert-butyl ester (95 mg, 0.27 mmol) from Example 34A and 4 M hydrogen chloride-1,4-dioxane (2.5 mL), the same method as in Example 2B was used to obtain 77 mg (yield: quantitative) of a crude product of the title compound as a single diastereomer (solid).

[1322] (34C)

[1323] (5R or 5S)-3-Chloro-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1324] Using (5R or 5S)-3-chloro-5-methyl-7-[(3R)-piperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine monohydrochloride (77 mg, 0.27 mmol) from Example 34B, DIPEA (0.092 mL, 0.53 mmol), 37% formaldehyde (0.040 mL, 0.53 mmol), acetic acid (0.030 mL, 0.53 mmol), and NaBH(OAc)3 (225 mg, 1.1 mmol), the same method as in Example 1G was used to obtain 42 mg (yield: 59%) of the title compound as a single diastereomer (oily substance).

[1325] (34D)

[1326] (5R or 5S)-3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine

[1327] Using (5R or 5S)-3-chloro-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (42 mg, 0.16 mmol) from Example 34C, 2-(2-methoxy-6-methyl-4-(trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US20200361898) (84 mg, 0.27 mmol), potassium carbonate (43 mg, 0.31 mmol), and XPhos Pd G2 (18 mg, 0.024 mmol), the same method as in Example 1E was used to obtain 60 mg (yield: 90%) of the title compound as a single diastereomer (oily substance).

[1328] (34E)

[1329] 3-Methyl-2-{(5R or 5S)-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1330] Using (5R or 5S)-3-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (60 mg, 0.14 mmol) and boron tribromide (1.0 M DCM solution) (0.7 mL, 0.70 mmol) from Example 34D, the same method as in Example 2E was used to obtain 37 mg (yield: 64%) of the title compound as a single diastereomer (solid).

[1331] (Example 35)

[1332] 3-Methyl-2-{5-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1333] (35A)

[1334] N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,6-dichloro-N-methylpyridazin-4-amine

[1335] 4-Bromo-3,6-dichloropyridazine (500 mg, 2.1 mmol) was dissolved in DMF (4.17 mL), and potassium carbonate (873 mg, 6.3 mmol) and N-[2-(tert-butyldimethylsilyloxyethyl]methanamine (448 mg, 2.3 mmol) were added. The mixture was stirred at room temperature for 1.5 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 95 / 5 to 85 / 15 (v / v)] to obtain 656 mg of the title compound as an oily substance (yield: 94%).

[1336] (35B)

[1337] 2-[(3,6-dichloropyridazin-4-yl)(methyl)amino]ethanol

[1338] N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,6-dichloro-N-methylpyridazin-4-amine (656 mg, 2.0 mmol) from Example 35A was dissolved in THF (4.88 mL), and TBAF (1.0 M THF solution) (2.34 mL, 2.3 mmol) was added. The mixture was stirred at room temperature for 30 minutes in a nitrogen-purged system. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 33 / 67 (v / v)] to obtain 279 mg of the title compound as a solid (yield: 64%).

[1339] (35C)

[1340] 2-[(3,6-dichloropyridazin-4-yl)(methyl)amino]ethyl 4-methylbenzenesulfonate

[1341] 2-[(3,6-Dichloropyridazin-4-yl)(methyl)amino]ethanol (279 mg, 1.3 mmol) from Example 35B was dissolved in DCM (2.51 mL). TEA (0.26 mL, 1.9 mmol), 4-dimethylaminopyridine (16 mg, 0.13 mmol), and p-toluenesulfonyl chloride (331 mg, 1.6 mmol) were added, and the mixture was stirred at room temperature for 3 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40 (v / v)] to obtain 357 mg of the title compound as a solid (yield: 76%).

[1342] (35D)

[1343] tert-Butyl (3R)-3-(3-chloro-5-methyl-6,7-dihydropyrazino[2,3-c]pyridazin-8(5H)-yl)piperidine-1-carboxylate

[1344] 2-[(3,6-dichloropyridazin-4-yl)(methyl)amino]ethyl 4-methylbenzenesulfonate (357 mg, 0.95 mmol) from Example 35C was dissolved in DMSO (4.74 mL). Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (213 mg, 1.0 mmol) and DIPEA (0.328 mL, 1.9 mmol) were added, and the mixture was stirred at 50°C for 15 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 67 / 33 to 33 / 67 (v / v)] to obtain 116 mg of the title compound as an amorphous substance (yield: 33%).

[1345] (35E)

[1346] 3-Chloro-5-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine

[1347] tert-Butyl (3R)-3-(3-chloro-5-methyl-6,7-dihydropyrazino[2,3-c]pyridazin-8(5H)-yl)piperidine-1-carboxylate (116 mg, 0.32 mmol) from Example 35D was dissolved in DCM (2.10 mL), TFA (1.22 mL) was added, and the mixture was stirred at room temperature for 25 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (2.10 mL). DIPEA (1.09 mL, 6.3 mmol), 37% formaldehyde (0.026 mL, 0.35 mmol), and NaBH(OAc)3 (209 mg, 0.79 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction solution, extracted with DCM, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 100 / 0 - 95 / 5 (V / V)] to obtain 65 mg of the title compound as a solid (yield: 73%).

[1348] (35F)

[1349] 3-[2-(Ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine

[1350] Using 3-chloro-5-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine (65 mg, 0.23 mmol) from Example 35E, 2-[2-(ethoxymethoxy)-6-methyl-4-trifluoromethylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US20200361898) (257 mg, 0.71 mmol), XPhos Pd G2 (36 mg, 0.046 mmol), and potassium carbonate (128 mg, 0.92 mmol), the same method as in Example 9D was used to obtain 65 mg of the title compound as a solid (yield: 59%).

[1351] (35G)

[1352] 3-Methyl-2-{5-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1353] 3-[2-(Ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazine (65 mg, 0.14 mmol) from Example 35F was dissolved in DCM (0.904 mL), TFA (0.524 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 95 / 5 to 80 / 20 (v / v)] to obtain 41.7 mg of the title compound as an amorphous substance (yield: 73%).

[1354] (Example 36)

[1355] 3-Methyl-2-{8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1356] (36A)

[1357] tert-Butyl (3R)-3-(3-chloro-5-hydroxy-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl)piperidine-1-carboxylate

[1358] Using 3-chloro-1-(3,6-dichloropyridazin-4-yl)propan-1-ol (Org. Lett. 2015, 17, 2362.) (17 mg, 0.071 mmol), DIPEA (0.36 mL, 2.1 mmol), and (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (282 mg, 1.4 mmol), the same method as in Example 1D was used to obtain 18 mg of the title compound as an oily substance (yield: 69%).

[1359] (36B)

[1360] tert-Butyl (3R)-3-{5-hydroxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate

[1361] Using tert-butyl (3R)-3-(3-chloro-5-hydroxy-6,7-dihydropyrido[2,3-c]pyridazine-8(5H)-yl)piperidine-1-carboxylate (17 mg, 0.046 mmol) from Example 36A, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19 mg, 0.055 mmol) from Example 1B, potassium carbonate (13 mg, 0.092 mmol), and XPhos Pd G2 (3.6 mg, 0.0046 mmol), the same method as in Example 1E was used to obtain 16 mg of the title compound as an oily substance (yield: 63%).

[1362] (36C)

[1363] tert-Butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-[(phenoxycarbonylthioyl)oxy]-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate

[1364] tert-Butyl (3R)-3-{5-hydroxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate (12 mg, 0.022 mmol) and 4-dimethylaminopyridine (6.4 mg, 0.052 mmol) from Example 36B were dissolved in DCM (0.21 mL). Phenyl chlorothioformate (0.0035 mL, 0.026 mmol) was added and stirred at room temperature for 3 days. Water was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 15 mg of the crude title compound as an oily substance (yield: quantitative).

[1365] (36D)

[1366] tert-Butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate

[1367] tert-Butyl (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-[(phenoxythiocarbonyl)oxy]-6,7-dihydropyrido[2,3-c]pyridazin-8(5H)-yl}piperidine-1-carboxylate (15 mg, 0.022 mmol) from Example 36C was dissolved in toluene (0.22 mL). Tributyltin hydride (0.023 mL, 0.087 mmol) and azobisisobutyronitrile (1.8 mg, 0.011 mmol) were added, and the mixture was stirred at 110°C for 3 hours in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V)] to obtain 5.6 mg (yield: 48%) of the title compound as an oily substance.

[1368] (36E)

[1369] 3-Methyl-2-{8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol dihydrochloride

[1370] Using (3R)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-6,7-dihydropyrido[2,3-c]pyridazine-8(5H)-yl}piperidine-1-carboxylic acid tert-butyl ester (5.6 mg, 0.010 mmol) of Example 36D and 4M hydrogen chloride-1,4-dioxane (0.10 mL), the same method as in Example 1F was used to obtain 4.4 mg of the title compound as an oily substance (yield: 91%).

[1371] (36F)

[1372] 3-Methyl-2-{8-[(3R)-1-methylpiperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1373] Using 3-methyl-2-{8-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol dihydrochloride (4.4 mg, 0.0096 mmol), DIPEA (0.0033 mL, 0.019 mmol), 37% formaldehyde (0.0010 mL, 0.014 mmol), acetic acid (0.0011 mL, 0.019 mmol), and NaBH(OAc)3 (8.0 mg, 0.038 mmol) from Example 36E, the same method as in Example 1G was used to obtain 3.2 mg of the title compound as an oily substance (yield: 83%).

[1374] (Example 37)

[1375] 3-Methyl-2-{5-methyl-9-[(3R)-1-methylpiperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine -3-yl}-5-(trifluoromethyl)phenol

[1376] (37A)

[1377] 3-[(3,6-Dichloropyridazin-4-yl)(methyl)amino]propan-1-ol

[1378] 4-Bromo-3,6-dichloropyridazine (400 mg, 1.7 mmol) was dissolved in DMF (6 mL), potassium carbonate (460 mg, 3.3 mmol) and 3-(methylamino)-1-propanol (0.173 mL, 1.8 mmol) were added, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 20 / 80 to 0 / 100 (v / v)] to obtain 371 mg of the title compound as a solid (yield: 94%).

[1379] (37B)

[1380] 3-[(3,6-dichloropyridazin-4-yl)(methyl)amino]propyl 4-methylbenzenesulfonate

[1381] 3-[(3,6-Dichloropyridazin-4-yl)(methyl)amino]propan-1-ol (371 mg, 1.6 mmol) from Example 37A was dissolved in DCM (8 mL). TEA (0.770 mL, 5.5 mmol), p-toluenesulfonyl chloride (508 mg, 2.7 mmol), and dimethylaminopyridine (40 mg, 0.31 mmol) were added, and the mixture was stirred at room temperature for 50 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80 (v / v)] to obtain 383 mg of the title compound as a solid (yield: 98%).

[1382] (37C)

[1383] (3R)-3-(3-chloro-5-methyl-5,6,7,8-tetrahydro-9H-pyridazin[3,4-b][1,4]diazepine -9-yl)piperidine-1-carboxylic acid tert-butyl ester

[1384] Using 3-[(3,6-dichloropyridazin-4-yl)(methyl)amino]propyl 4-methylbenzenesulfonate (383 mg, 0.98 mmol), DIPEA (0.376 mL, 2.2 mmol), and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (235 mg, 1.2 mmol) from Example 37B, the same method as in Example 1D was used to obtain 97 mg of the title compound as an amorphous substance (yield 26%).

[1385] (37D)

[1386] 3-Chloro-5-methyl-9-[(3R)-piperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine

[1387] (3R)-3-(3-chloro-5-methyl-5,6,7,8-tetrahydro-9H-pyridazin[3,4-b][1,4]diazepine of Example 37C was added. tert-Butyl (-9-yl)piperidine-1-carboxylate (97 mg, 0.25 mmol) was dissolved in DCM (1 mL), TFA (1.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: ethyl acetate / methanol = 98 / 2, DCM / methanol = 80 / 20 (v / v)] to obtain 66 mg of the title compound as an amorphous substance (yield: 92%).

[1388] (37E)

[1389] 3-Chloro-5-methyl-9-[(3R)-1-methylpiperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine

[1390] Using 3-chloro-5-methyl-9-[(3R)-piperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine (66 mg, 0.23 mmol), 37% formaldehyde (0.026 mL, 0.35 mmol), and NaBH(OAc)3 (148 mg, 0.70 mmol) were added to obtain 49 mg of the title compound as a solid (yield: 70%) by the same method as in Example 1G.

[1391] (37F)

[1392] 3-[2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-9-[(3R)-1-methylpiperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine

[1393] Using 3-chloro-5-methyl-9-[(3R)-1-methylpiperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine (49 mg, 0.17 mmol), 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Example 1B (75 mg, 0.22 mmol), potassium carbonate (45 mg, 0.33 mmol), XPhos Pd G2 (13 mg, 0.017 mmol), and the same method as in Example 1E were used to obtain 50 mg of the title compound as an amorphous substance (yield: 63%).

[1394] (37G)

[1395] 3-Methyl-2-{5-methyl-9-[(3R)-1-methylpiperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine -3-yl}-5-(trifluoromethyl)phenol

[1396] Using 3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5-methyl-9-[(3R)-1-methylpiperidin-3-yl]-6,7,8,9-tetrahydro-5H-pyridazino[3,4-b][1,4]diazepine from Example 37F (50 mg, 0.10 mmol) and TFA (0.5 mL) were added in the same manner as in Example 6B to obtain 38 mg of the title compound as a solid (yield: 84%).

[1397] (Example 38)

[1398] 2-{9-[(3R)-1-methylpiperidin-3-yl]-5,6,8,9-tetrahydro-4H,7H-1,2,6a,9-tetraazaphenalen-3-yl}-5-(trifluoromethyl)phenol

[1399] (38A)

[1400] 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)piperidin-2-one

[1401] 2-Piperidone (5.92 g, 60 mmol) was dissolved in THF (200 mL). 63% sodium hydride (2.73 g, 72 mmol) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes. (2-Bromoethoxy)tert-butyldimethylsilane (15.3 mL, 72 mmol) was added, and the mixture was stirred at 70°C for 14 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: DCM / methanol = 98 / 2 to 95 / 5 (v / v)] to obtain 6.15 g of the title compound as an oily substance (yield: 40%).

[1402] (38B)

[1403] 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)piperidine-2-thione

[1404] 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-2-one (4.34 g, 17 mmol) from Example 38A was dissolved in toluene (34 mL), Lawesson's reagent (7.16 g, 18 mmol) was added, and the mixture was stirred at 80°C for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 85 / 15 to 76 / 24 (v / v)] to obtain 980 mg of the title compound as an oily substance (yield: 21%).

[1405] (38C)

[1406] (E)-[1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)piperidin-2-ylidene](methyl)sulfonium iodide

[1407] 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)piperidine-2-thione (980 mg, 3.6 mmol) from Example 38B was dissolved in ethanol (12 mL), iodomethane (0.334 mL, 5.4 mmol) was added, and the mixture was stirred at 80°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate and n-hexane were added to the resulting residue, followed by sonication. The solid was collected by filtration to obtain 1.0 g of the title compound as a solid (yield: 67%).

[1408] (38D)

[1409] 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-5,8-dichloro-1,2,3,4-tetrahydropyrido[2,3-d]pyridazine

[1410] (E)-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-2-ylidene](methyl)sulfonium iodide (1.0 g, 2.4 mmol) from Example 38C was suspended in THF (7 mL). Potassium tert-butoxide (538 mg, 4.8 mmol) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (1.5 mL) and added to a solution of 3,6-dichloro-1,2,4,5-tetrazine (315 mg, 2.1 mmol) in toluene (5 mL) at 0°C. The mixture was stirred at room temperature for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 85 / 15 - 75 / 25 (V / V)] to obtain 160 mg of the title compound as a solid (yield: 21%).

[1411] (38E)

[1412] 2-(5,8-Dichloro-3,4-dihydropyrido[2,3-d]pyridazin-1(2H)-yl)ethanol

[1413] 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5,8-dichloro-1,2,3,4-tetrahydropyrido[2,3-d]pyridazine (193 mg, 0.53 mmol) from Example 38D was dissolved in THF (2.5 mL), and TBAF (1.0 M THF solution) (0.610 mL, 0.61 mmol) was added at 0°C, and the mixture was stirred for 40 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 25 / 75-0 / 100 (V / V)] to obtain 90 mg of the title compound as a solid (yield: 68%).

[1414] (38F)

[1415] 2-(5,8-dichloro-3,4-dihydropyrido[2,3-d]pyridazin-1(2H)-yl)ethyl 4-methylbenzenesulfonate

[1416] 2-(5,8-Dichloro-3,4-dihydropyrido[2,3-d]pyridazin-1(2H)-yl)ethanol (90 mg, 0.36 mmol) from Example 38E was dissolved in DCM (2 mL). TEA (0.152 mL, 1.1 mmol), p-toluenesulfonyl chloride (138 mg, 0.72 mmol), and dimethylaminopyridine (4 mg, 0.036 mmol) were added, and the mixture was stirred at room temperature for 105 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 65 / 35 to 40 / 60 (v / v)] to obtain 128 mg of the title compound as a solid (yield: 88%).

[1417] (38G)

[1418] 3-Chloro-9-[(3R)-1-methylpiperidin-3-yl]-5,6,8,9-tetrahydro-4H,7H-1,2,6a,9-tetraazaphenalene

[1419] 2-(5,8-dichloro-3,4-dihydropyrido[2,3-d]pyridazin-1(2H)-yl)ethyl 4-methylbenzenesulfonate (128 mg, 0.32 mmol) from Example 38F was dissolved in NMP (1.6 mL). DIPEA (0.138 mL, 0.80 mmol) and (R)-3-amino-1-methylpiperidine (47 mg, 0.41 mmol) were added, and the mixture was stirred at 100°C for 4.5 hours under microwave irradiation in a nitrogen-purged atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [elution solvent: ethyl acetate / methanol = 96 / 4 to 82 / 18 (v / v)] to obtain 21 mg of the title compound as an oily substance (yield: 21%).

[1420] (38H)

[1421] 2-{9-[(3R)-1-methylpiperidin-3-yl]-5,6,8,9-tetrahydro-4H,7H-1,2,6a,9-tetraazaphenalen-3-yl}-5-(trifluoromethyl)phenol

[1422] Using 3-chloro-9-[(3R)-1-methylpiperidin-3-yl]-5,6,8,9-tetrahydro-4H,7H-1,2,6a,9-tetraazaphenalene (21 mg, 0.068 mmol) from Example 38G, 2-hydroxy-4-trifluoromethylphenylboronic acid (18 mg, 0.089 mmol), potassium carbonate (18 mg, 0.14 mmol), and XPhos Pd G2 (10 mg, 0.013 mmol), the same method as in Example 1E was used to obtain 10 mg of the title compound as a solid (yield: 34%).

[1423] (Example 39)

[1424] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1425] (Alternatively known as 2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol.)

[1426] (39A)

[1427] 3,4,6-Trichloro-5-methylpyridazine

[1428] Phosphorus oxychloride (7.638 g, 50 mmol) was added to 4-bromo-5-methyl-1,2,3,6-tetrahydropyridazine-3,6-dione (CAS Reg. No.: 73295-61-3, 984 mg, 4.8 mmol), and the mixture was stirred at 100°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue at 0°C, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 82 / 18 (v / v)] to obtain a crude product of the title compound as a solid.

[1429] (39B)

[1430] 3,6-Dichloro-4-vinyl-5-methylpyridazine

[1431] Using 3,4,6-trichloro-5-methylpyridazine (889 mg, 4.5 mmol) from Example 39A, potassium vinyl trifluoroborate (723 mg, 5.4 mmol), potassium carbonate (1.24 g, 9.0 mmol), and Pd(dppf)Cl2 (367 mg, 0.45 mmol), the same method as in Example 1C was used to obtain 218 mg of the title compound as a solid (yield: 38% in 2 steps).

[1432] (39C)

[1433] (1s,3s)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol

[1434] Using 3,6-dichloro-4-vinyl-5-methylpyridazine (218 mg, 1.2 mmol) from Example 39B, DIPEA (0.301 mL, 1.7 mmol), and (1s,3s)-3-amino-1-methyl-cyclobutanol hydrochloride (182 mg, 1.3 mmol), the same method as in Example 1D was used to obtain 124 mg of the title compound as a solid (yield 42%).

[1435] (39D)

[1436] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol

[1437] Using (1s,3s)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (69 mg, 0.27 mmol), 2-hydroxy-4-trifluoromethylphenylboronic acid (67 mg, 0.33 mmol), potassium carbonate (75 mg, 0.54 mmol), and XPhos Pd G2 (42 mg, 0.054 mmol) from Example 39C, the same method as in Example 1E was used to obtain 50 mg of the title compound as a solid (yield: 48%).

[1438] (Example 40)

[1439] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol monohydrochloride

[1440] (Alternatively known as 2-[7-(cis-3-hydroxy-3-methylcyclobutyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol monohydrochloride.)

[1441] (40A)

[1442] (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[1443] Using (1s,3s)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (77 mg, 0.32 mmol) from Example 3A, 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (144 mg, 0.42 mmol) from Example 1B, potassium carbonate (88 mg, 0.64 mmol), and XPhos Pd G2 (25 mg, 0.032 mmol), the same method as in Example 1E was used to obtain 105 mg of the title compound as an amorphous substance (yield: 77%).

[1444] (40B)

[1445] 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol monohydrochloride

[1446] Using (1s,3s)-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (105 mg, 0.25 mmol) and TFA (1.2 mL) from Example 40A, the mixture was treated with 4 M hydrogen chloride-1,4-dioxane in the same manner as in Example 6B to obtain 40 mg of the title compound as a solid (yield: 39%).

[1447] (Example 41)

[1448] 5-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2,3-dihydro-1H-inden-4-ol

[1449] (Alternatively known as 5-[7-(cis-3-hydroxy-3-methylcyclobutyl)-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydro-1H-inden-4-ol)

[1450] (41A)

[1451] 4-(Methoxymethoxy)-2,3-dihydro-1H-indene

[1452] Using 4-indanol (3.00 g, 22 mmol), 55% sodium hydride (1.17 g, 27 mmol), and chloromethyl methyl ether (2.52 mL, 34 mmol), the same procedure as in Example 1A was used to obtain 3.97 g (yield: 99%) of the title compound as an oily substance.

[1453] (41B)

[1454] 2-[4-(Methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1455] 4-(Methoxymethoxy)-2,3-dihydro-1H-indene (3.97 g, 22 mmol) from Example 41A was dissolved in DEE (150 mL). n-Butyllithium (1.6 M solution in n-hexane) (28.4 mL, 45 mmol) was added to the nitrogen-purged system at 0°C, and the mixture was stirred at room temperature for 2 hours. iPrOBPin (13.5 mL, 67 mmol) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35 (v / v)] to obtain 2.12 g of the title compound as an oily substance (yield: 31%).

[1456] (41C)

[1457] (1s,3s)-3-(3-chloro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol

[1458] Using (1s,3s)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (79 mg, 0.31 mmol) and manganese dioxide (271 mg, 3.1 mmol) from Example 39C, the same method as in Example 4C was used to obtain 42 mg of the title compound as a solid (yield: 54%).

[1459] (41D)

[1460] (1s,3s)-3-{3-[4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol

[1461] Using (1s,3s)-3-(3-chloro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1-methylcyclobutanol (20 mg, 0.079 mmol) from Example 41C, 2-[4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (29 mg, 0.095 mmol) from Example 41B, potassium carbonate (21 mg, 0.16 mmol), and XPhos PdG2 (6.3 mg, 0.0079 mmol), the same method as in Example 1E was used to obtain 19 mg of the title compound as an amorphous substance (yield: 61%).

[1462] (41E)

[1463] 5-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-2,3-dihydro-1H-inden-4-ol

[1464] Using (1s,3s)-3-{3-[4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1-methylcyclobutanol (19 mg, 0.048 mmol) and 4M hydrogen chloride-1,4-dioxane (0.48 mL) from Example 41D, the same method as in Example 3D was used to obtain 14 mg of the title compound as a solid (yield: 83%).

[1465] (Example 42)

[1466] 2-{7-[(1S * ,2S * ,3R * )-3-hydroxy-2,3-dimethylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1467] (42A)

[1468] [(1S * ,2S * tert-Butyl 2-methyl-3-oxocyclobutyl]carbamate

[1469] Tert-butyl (1Z)-prop-1-en-1-ylcarbamate (J. Org. Chem. 2012, 77, 5894-5906) (1.61 g, 10 mmol) was dissolved in DEE (34 mL), and zinc copper couple (13.2 g) was added. Trichloroacetyl chloride (2.3 mL, 21 mmol) was added while ultrasonicating at 0°C, and the mixture was stirred at room temperature for 15 minutes. A suspension of ammonium chloride (8.2 g, 154 mmol) in methanol (41 mL) was added to the reaction mixture at 0°C, and the mixture was stirred at 60°C for 20 minutes. 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 [eluting solvent: n-hexane / ethyl acetate = 72 / 28 to 60 / 40 (v / v)] to obtain 1.4 g of the title compound as a racemic solid (yield: 69%).

[1470] (42B)

[1471] [(1S * ,2S * ,3R * tert-Butyl 3-hydroxy-2,3-dimethylcyclobutyl]carbamate

[1472] Cerium chloride (3.13 g, 13 mmol) was suspended in THF (20 mL), and 1.2 M methyl lithium (11 mL, 13 mmol) was added at -78°C, and the mixture was stirred at -78°C for 40 minutes. [(1S * ,2S * A solution of tert-butyl 2-(2-methyl-3-oxocyclobutyl)-2-methyl-3-oxocyclobutyl]carbamate (1.15 g, 5.8 mmol) in THF (11 mL) was stirred at -78°C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 45 / 55 (V / V)] to obtain 275 mg of the title compound as a racemic (amorphous) compound (yield: 22%).

[1473] (42C)

[1474] (1R * ,2S * ,3S * )-3-amino-1,2-dimethylcyclobutanol monohydrochloride

[1475] Using [(1S * ,2S * ,3R *)-tert-butyl 3-hydroxy-2,3-dimethylcyclobutyl]carbamate (275 mg, 1.3 mmol) and 4 M hydrogen chloride-1,4-dioxane (6.0 mL) were added to give 193 mg of a crude product of the title compound as a racemate (solid) (yield: quantitative).

[1476] (42D)

[1477] (1R * ,2S * ,3S * )-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,2-dimethylcyclobutanol

[1478] Using 3,6-dichloro-4-vinylpyridazine (80 mg, 0.46 mmol) of Example 1C, (1R * ,2S * ,3S * )-3-amino-1,2-dimethylcyclobutanol monohydrochloride (83 mg, 0.57 mmol) and DIPEA (0.199 mL, 1.1 mmol) were added and the same method as in Example 1D was used to obtain 53 mg (yield 45%) of the title compound as a racemate (solid).

[1479] (42E)

[1480] (1R * ,2S * ,3S * )-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,2-dimethylcyclobutanol

[1481] Using (1R * ,2S * ,3S * )-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)-1,2-dimethylcyclobutanol (52 mg, 0.20 mmol), 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Example 1B (92 mg, 0.27 mmol), potassium carbonate (57 mg, 0.41 mmol), XPhos Pd G2 (16 mg, 0.020 mmol), and the same method as in Example 1E were used to obtain 62 mg of the title compound as a racemate (solid) (yield: 69%).

[1482] (42F)

[1483] (1R * ,2S * ,3S * )-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,2-dimethylcyclobutanol

[1484] Using (1R * ,2S * ,3S * )-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,2-dimethylcyclobutanol (62 mg, 0.14 mmol), manganese dioxide (123 mg, 1.4 mmol), and the same method as in Example 4C were used to obtain 10 mg of the title compound as a racemate (solid) (yield: 16%).

[1485] (42G)

[1486] 2-{7-[(1S * ,2S * ,3R * )-3-hydroxy-2,3-dimethylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol

[1487] Using (1R * ,2S * ,3S * )-3-{3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazin-7-yl}-1,2-dimethylcyclobutanol (19 mg, 0.043 mmol), TFA (0.3 mL), and the same method as in Example 3D were used to obtain 9.6 mg (yield: 56%) of the title compound as a racemate (solid).

[1488] (Example 43)

[1489] 5-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-6-methyl-2,3-dihydro-1H-inden-4-ol

[1490] (Alternatively known as 5-[7-(cis-3-hydroxy-3-methylcyclobutyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-2,3-dihydro-1H-inden-4-ol)

[1491] (43A)

[1492] 6-Methyl-3-oxo-2,3-dihydro-1H-inden-4-yl dimethylcarbamate

[1493] 7-Hydroxy-5-methyl-1-indanone (2.00 g, 12 mmol) was dissolved in acetonitrile (100 mL), potassium carbonate (1.87 g, 14 mmol) and dimethylcarbamoyl chloride (1.25 mL, 14 mmol) were added, and the mixture was stirred at 80°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50 (v / v)] to obtain 2.66 g of the title compound as a solid (yield: 93%).

[1494] (43B)

[1495] 3-Hydroxy-6-methyl-2,3-dihydro-1H-inden-4-yl dimethylcarbamate

[1496] 6-Methyl-3-oxo-2,3-dihydro-1H-inden-4-yl dimethylcarbamate (2.66 g, 11 mmol) from Example 43A was dissolved in methanol (100 mL), sodium borohydride (570 mg, 15 mmol) was added, and the mixture was stirred at 0°C for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 40 / 60 (v / v)] to obtain 2.88 g of the title compound as an oily substance (yield: quantitative).

[1497] (43C)

[1498] 6-Methyl-1H-inden-4-yl dimethylcarbamate

[1499] 3-Hydroxy-6-methyl-2,3-dihydro-1H-inden-4-yl dimethylcarbamate (130 mg, 0.55 mmol) from Example 43B was dissolved in DCM (5.0 mL). Pyridine (0.089 mL, 1.1 mmol) and phosphorus tribromide (0.058 mL, 0.61 mmol) were added, and the mixture was stirred at 0°C for 10 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30 (v / v)] to obtain 35 mg of the title compound as an oily substance (yield: 29%).

[1500] (43D)

[1501] 6-Methyl-2,3-dihydro-1H-inden-4-yl dimethylcarbamate

[1502] 6-Methyl-1H-inden-4-yl dimethylcarbamate (716 mg, 3.3 mmol) from Example 43C was dissolved in ethanol (50 mL), and 10% palladium on carbon (701 mg) was added. The mixture was stirred at room temperature for 1 hour in a hydrogen-purged atmosphere. 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 [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35 (v / v)] to obtain 593 mg of the title compound as an oily substance (yield: 82%).

[1503] (43E)

[1504] 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-yl dimethylcarbamate

[1505] 6-Methyl-2,3-dihydro-1H-inden-4-yl dimethylcarbamate (138 mg, 0.63 mmol) from Example 43D was dissolved in DCE (6.0 mL). Palladium(II) acetate (43 mg, 0.19 mmol), trifluoromethanesulfonic acid (0.045 mL, 0.51 mmol), and N-bromosuccinimide (123 mg, 0.69 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25 (v / v)] to obtain 97 mg of the title compound as an oily substance (yield: 52%).

[1506] (43F)

[1507] 5-Bromo-6-methyl-2,3-dihydro-1H-indan-4-ol

[1508] 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-yl dimethylcarbamate (97 mg, 0.33 mmol) from Example 43E was dissolved in 1-butanol (4.0 mL), sodium hydroxide (65 mg, 1.6 mmol) was added, and the mixture was stirred at 110°C for 1 hour. 1M hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15 (v / v)] to obtain 51 mg of the title compound as an oily substance (yield: 69%).

[1509] (43G)

[1510] 5-Bromo-4-(methoxymethoxy)-6-methyl-2,3-dihydro-1H-indene

[1511] Using 5-bromo-6-methyl-2,3-dihydro-1H-indene-4-ol (51 mg, 0.23 mmol) from Example 43F, 55% sodium hydride (12 mg, 0.28 mmol), and chloromethyl methyl ether (0.025 mL, 0.33 mmol), the same method as in Example 1A was used to obtain 51 mg of the title compound as an oily substance (yield: 84%). [1512...

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof, [Chemical Formula 1] Where, A is a single bond, a nitrogen atom or a carbon atom, R 1 is a halogen atom, a cyano group, a C1-C3 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, R 1 ' is a hydrogen atom, a halogen atom or a C1-C3 alkyl group, or R 1 With R 1 'Combined with each other to form C1-C4 alkylene optionally substituted by 1 to 3 substituents selected from substituent group a, or -NH-(CH2)n- (n represents an integer of 1, 2 or 3) optionally substituted by 1 to 3 substituents selected from substituent group a And form a ring structure, R 1 " is a hydrogen atom or a halogen atom, R 1 "' is a hydrogen atom, a halogen atom, a cyano group or -NH-(CH2)n- (n represents an integer of 1, 2 or 3), in, When A is a nitrogen atom, R 2 and A are combined with each other to form any partial structure selected from the group shown below: [Chemical Formula 2] ， Among them, the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group a. In addition, when A is a single bond or a carbon atom, R 2 is a hydrogen atom, or a C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from substituent group a, or R 2 and A are combined with each other to form any partial structure selected from the group shown below: [Chemical Formula 3] ， Among them, the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group a. R 2 ' is a hydrogen atom or a C1-C3 alkyl group, or R 2 'with R 2 Combined with each other to form -NH-(CH2)n- (n represents an integer of 1, 2 or 3) and constitute a ring structure, R 3 for C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from substituent group b, C2-C3 alkenyl optionally substituted by 1 to 3 substituents selected from substituent group b, C3-C6 cycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b, C5-C8 bicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b, C5-C8 azabicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b, C5-C8 oxabicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b, 3-6 membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b, or a 5-6 membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b; The substituent group a is composed of a halogen atom, a cyano group, a C2-C3 alkenyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, a C2-C4 alkanediyl group (including 1,3-butadiene-1,4-diyl), a C1-C3 oxyalkylene group, and a cyclopropylethynyl group. The substituent group b is composed of a hydroxyl group, a halogen atom, a hydroxy C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkylmethyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted with 1 to 3 fluorine atoms, and a 5-membered oxygen-containing saturated heterocyclic group.

2. A compound of formula (1a) or a pharmaceutically acceptable salt thereof, [Chemical Formula 4] Where, A is a nitrogen atom, R 1 is a halogen atom, a cyano group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, R 1 ' is a hydrogen atom, a halogen atom or a C1-C3 alkyl group, or R 1 With R 1 ' are combined with each other to form a C1-C4 alkylene group which is optionally substituted with 1 to 3 substituents selected from substituent group a' and constitute a ring structure, R 1 " is a hydrogen atom or a halogen atom, R 1 "' is a hydrogen atom, a halogen atom, a cyano group or a methyl group, R 2 and A are combined with each other to form any partial structure selected from the group shown below: [Chemical Formula 5] ， in, The left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the substituted state, the partial structure is optionally substituted by 1 to 3 substituents selected from the substituent group a', R 2 ' is a hydrogen atom or a C1-C3 alkyl group, Or, R 2 'with R 2 Combined with each other to form -NH-(CH2)n- (n represents an integer of 1, 2 or 3) and constitute a ring structure, R 3 for C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from substituent group b', C3-C6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b', a C5-C8 bicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b', C5-C8 azabicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b', C5-C8 oxabicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group b', 3-6 membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b', or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from substituent group b'; The substituent group a' is composed of a halogen atom, a cyano group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, a C2-C4 alkanediyl group (including 1,3-butadiene-1,4-diyl), a C1-C3 oxyalkylene group, and a cyclopropylethynyl group. The substituent group b' is composed of a hydroxyl group, a halogen atom, a C1-C3 alkyl group, a hydroxy C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, and a 5-membered oxygen-containing saturated heterocyclic group.

3. A compound of formula (1b) or a pharmaceutically acceptable salt thereof, [Chemical Formula 6] Where, R 1 is a halogen atom, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, R 2 and nitrogen atoms to form any partial structure selected from the group shown below: [Chemical Formula 7] ， in, The left end of this part of the structure is R 2 The right end of this partial structure is the connecting bond of the nitrogen atom, which is represented by R for convenience. 3 In the substituted state, the partial structure is optionally substituted by 1 to 3 substituents selected from the substituent group a", R 3 for C3-C6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b", C6-C7 bicycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group b", a 3-6 membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group b", or a 5-6 membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group b"; Substituent group a" consists of a halogen atom, a cyano group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, and a C1-C3 oxyalkylene group, The substituent group b" consists of a hydroxyl group, a halogen atom, and a C1-C3 alkyl group.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is a trifluoromethyl group, a chlorine atom, a difluoromethoxy group or a trifluoromethoxy group.

5. The compound according to claim 3 or 4 or a pharmaceutically acceptable salt thereof, wherein R 2 and nitrogen atoms to form any partial structure selected from the group shown below: [Chemical Formula 8] ， Among them, the left end of this part of the structure is R 2 The right end of this partial structure is the connecting bond of the nitrogen atom, which is represented by R for convenience. 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group a".

6. The compound according to any one of claims 3 to 5 or a pharmaceutically acceptable salt thereof, wherein The partial structure is optionally substituted with 1 to 3 substituents selected from the group consisting of a cyano group, a fluorine atom, a methyl group, a methoxy group, a difluoromethoxy group, a propylene group, a 1-oxyethylene group, and a 2-oxyethylene group.

7. The compound according to any one of claims 3 to 6 or a pharmaceutically acceptable salt thereof, wherein R 3 is any substituent selected from the group consisting of: [Chemical Formula 9] 8. Any compound selected from the following group or a pharmaceutically acceptable salt thereof, 3-methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol, 3-methyl-2-{7-[(3R)-1-methylpiperidin-3-yl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-5-(trifluoromethyl)phenol, 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 5-chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol, 2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{5-(difluoromethoxy)-7-[(1s,3 s )-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 5-(difluoromethoxy)-2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol, 2-{7-[(3R)-1-ethylpiperidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethoxy)phenol, 5-{3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-7-yl}bicyclo[3.1.1]heptan-1-ol, 5-chloro-2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol, 5-chloro-2-{7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-5-methoxy-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol, 5-chloro-2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methylphenol, 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile, 2-[7-(5-fluoropyrimidin-2-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol.

9. 2-{5-fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{5-(difluoromethoxy)-7-[(1s,3 s )-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, Or 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

10. 2-{5-Fluoro-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

11. 2-{5-(difluoromethoxy)-7-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

12. 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-6H-furo[2′,3′:4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

13. 2-[(4bR,7aR)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

14. 2-[(4bS,7aS)-8-(5-fluoropyrimidin-2-yl)-6,7,7a,8-tetrahydro-4bH-furo[2',3':4,5]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

15. 2-{8-[(1s,3s)-3-hydroxy-3-methylcyclobutyl]-7,8-dihydro-5H-furo[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-3-yl}-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

16. A compound of formula (1c) or a pharmaceutically acceptable salt thereof, [Chemical Formula 10] Where, A is a single bond or a carbon atom, R 1 is a halogen atom, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, or a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, R 2 is a hydrogen atom, or a C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from Substituent Group C, or R 2 and A are combined with each other to form any partial structure selected from the group shown below: [Chemical Formula 11] ， in, The left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from substituent group c, R 3 is a C3-C6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from substituent group d, C6-C7 bicycloalkyl optionally substituted by 1 to 3 substituents selected from substituent group d, or a 3- to 6-membered nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from Substituent Group d; The substituent group c is composed of a halogen atom, a C1-C3 alkyl group optionally substituted by 1 to 3 fluorine atoms, a C1-C3 alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-C4 alkylene group, and a C1-C3 oxyalkylene group, The substituent group d is composed of a hydroxyl group and a C1-C3 alkyl group.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1 is a trifluoromethyl group, a chlorine atom, a difluoromethoxy group, or a trifluoromethoxy group.

18. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1 It is trifluoromethyl.

19. The compound according to any one of claims 16 to 18 or a pharmaceutically acceptable salt thereof, wherein R 2 A hydrogen atom.

20. The compound according to any one of claims 16 to 18 or a pharmaceutically acceptable salt thereof, wherein R 2 and A are combined with each other to form any partial structure selected from the group shown below: [Chemical Formula 12] ， Among them, the left end of this part of the structure is R 2 The right side of this part of the structure is the connecting bond of A. For convenience, it is represented as R 3 In the state of substitution, the partial structure is optionally substituted by 1 to 3 substituents selected from Substituent Group C.

21. The compound according to any one of claims 16 to 20, or a pharmaceutically acceptable salt thereof, wherein R 3 is any substituent selected from the following substituents, [Chemical Formula 13] 22. Any compound selected from the following group or a pharmaceutically acceptable salt thereof, 3-methyl-2-{6-[(1-methylpiperidin-3-yl)methyl]pyridazin-3-yl}-5-(trifluoromethyl)phenol, 3-methyl-2-[5-methyl-7-(1-methylpiperidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol, 3-methyl-2-[7-(1-methylpiperidin-3-yl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol, 3-methyl-2-{8-[(3R)-1-methylpiperidin-3-yl]cinnolin-3-yl}-5-(trifluoromethyl)phenol, 2-{8-[(3R)-1-ethylpiperidin-3-yl]cinnolin-3-yl}-3-methyl-5-(trifluoromethyl)phenol.

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 23 , which is used to inhibit NLRP3 inflammasome activation. The pharmaceutical composition according to claim 23 , which is used to inhibit the production of inflammatory cytokines mediated by NLRP3 inflammasome activation. The pharmaceutical composition according to claim 23 , which is used to inhibit inflammatory responses mediated by NLRP3 inflammasome activation.

27. The pharmaceutical composition according to claim 23, for use in treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases.

28. The pharmaceutical composition according to claim 27, wherein Autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases are diseases selected from the group consisting of: Cryopyrin-associated periodic fever syndrome (CAPS), systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, systemic scleroderma (SSc), vasculitis syndrome, systemic amyloidosis, alcoholic liver disease (ALD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), chronic obstructive pulmonary disease (COPD), asthma, acute lung loss (ALI), interstitial lung disease (ILD), sarcoidosis, diabetic nephropathy, lupus nephritis, primary hyperoxaluria, interstitial cystitis, inflammatory bowel disease (IBD), gout, pseudogout, arthritis deformans, atherosclerosis, Type 1 / type 2 diabetes, heart failure, SARS-CoV-2 infection, EBV infection, viral encephalitis, glaucoma, optic neuritis, age-related maculopathy, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colorectal cancer, tumor disintegration syndrome, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, frontotemporal dementia, epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorders, eating disorders, ischemic stroke, hemorrhagic stroke, and traumatic brain injury.

29. The pharmaceutical composition of claim 23, for treating multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, frontotemporal dementia, epilepsy, major depressive disorder, schizophrenia, insomnia, autism spectrum disorder, bipolar disorder, panic disorder, anxiety disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), postoperative delirium, substance-related disorder, eating disorder, ischemic stroke, hemorrhagic stroke, or traumatic brain injury.

30. The pharmaceutical composition of claim 23, for use in treating multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, major depressive disorder, schizophrenia, or autism spectrum disorder.

31. The pharmaceutical composition according to claim 23, for use in treating multiple sclerosis.

32. The pharmaceutical composition according to claim 23, for use in treating Alzheimer's disease.

33. The pharmaceutical composition according to claim 23, for use in treating Parkinson's disease.

34. The pharmaceutical composition according to claim 23, for use in treating multiple system atrophy.

35. The pharmaceutical composition according to claim 23, for use in treating major depressive disorder.

36. The pharmaceutical composition according to claim 23, for use in treating schizophrenia.

37. The pharmaceutical composition of claim 23, for use in treating autism spectrum disorders.

38. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition.

39. The use according to claim 23, wherein The pharmaceutical composition is a pharmaceutical composition for treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases.

40. A preparation for administration to a mammal for treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases, comprising an effective amount of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

41. A method for treating autoinflammatory diseases, autoimmune diseases and / or inflammatory diseases using the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

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