Pyrazolopyrimidine compound and pharmaceutical use thereof

Abstract

The present invention provides compounds having NF - κ B-inducing kinase inhibitory activity.SOLUTION: The present invention provides a compound of the following formula [I] or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof having NF-κB-inducing kinase inhibitory activity, a pharmaceutical composition containing the same, and medical uses thereof. [Background technology]

[0002] NF-κB (nuclear factor κB) is a protein complex that functions as a transcription factor and is composed of homo- or heterodimers of subunit proteins. Five types of NF-κB subunits have been identified: p50, p52, p65, RelB, and c-Rel.

[0003] Under normal conditions, NF-κB is inactivated by binding with proteins that suppress NF-κB, such as IκB proteins, p100 (precursor of p52), and p105 (precursor of p50). Two types of signal transduction pathways are known to activate inactive NF-κB: the canonical and non-canonical NF-κB pathways.

[0004] NF-κB-inducing kinase (NIK), also known as MAP3K14, is a serine / threonine kinase involved in signal transduction via the non-canonical NF-κB pathway. In unstimulated cells, NIK expression is maintained at low levels due to ubiquitination and degradation. When specific ligands that activate the non-canonical NF-κB pathway bind to their corresponding receptors, NIK is stabilized and accumulates. In the non-canonical NF-κB pathway, IκB kinase (IKK)α releases NFκB from its suppression. NIK phosphorylates IKKα, which then phosphorylates and degrades p100, the precursor of p52, to generate p52. p52 then heterodimerizes with RelB and translocates to the nucleus, where it regulates gene transcription. Ligands that have been reported to activate the non-classical NF-κB pathway include B cell activating factor (BAFF), CD40 ligand, OX40 ligand, lymphotoxin (LTα1β2), and receptor activator of nuclear factor-κB ligand (RANKL) (Non-patent document 1).

[0005] Clinical trials have confirmed that belimumab, an antibody against solubilized BAFF, is effective against systemic lupus erythematosus (Non-Patent Document 2). It has also been reported that a CD40 ligand antagonist was effective against Sjögren's syndrome in a phase II clinical trial (Non-Patent Document 3). Furthermore, it has been reported that several antibodies against OX40 ligand and its receptor, OX40, improved dermatitis scores in a phase II clinical trial targeting patients with atopic dermatitis (Non-Patent Document 4).

[0006] NIK expression is increased in synovial endothelial cells of patients with rheumatoid arthritis, and is thought to promote synovial inflammation (Non-Patent Document 1). Furthermore, experimental autoimmune encephalomyelitis models suggest that NIK and the non-classical NF-κB pathway are involved in the pathology, and genome-wide association studies have also reported that NIK is one of the susceptibility genes for multiple sclerosis (Non-Patent Document 1). Non-clinical studies using animal models have also suggested that the non-classical NF-κB pathway is involved in the pathology of osteoporosis, acute kidney injury, hepatitis, fatty liver, and metabolic diseases such as obesity and type 2 diabetes (Non-Patent Documents 1, 5, and 6). It has also been reported that NIK expression is elevated or activated in several cancer types, such as Hodgkin's lymphoma, acute myeloid leukemia, and melanoma, and that knockdown of NIK or treatment with a small molecule NIK inhibitor suppresses cell survival or proliferation (Non-Patent Document 5).

[0007] Based on the above, NF-κB-inducing kinase inhibitors are considered to be useful as therapeutic agents for systemic lupus erythematosus, Sjögren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Nat Rev Immunol. 2017 Sep;17(9):545-558. [Non-patent document 2] Arthritis Rheum. 2011 Dec;63(12):3918-30. [Non-patent document 3] Nat Med. 2024 Jun;30(6):1583-1592. [Non-patent document 4] Am J Clin Dermatol. 2024 May;25(3):447-461. [Non-patent document 5] Int J Mol Sci. 2020 Nov 11;21(22):8470. [Non-patent document 6] Trends Mol Med. 2019 Apr;25(4):341-360. Summary of the Invention

[0009] The present invention provides a pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof having NF-κB-inducing kinase inhibitory activity, a pharmaceutical composition containing the same, and medical uses thereof.

[0010] The present invention includes the following aspects.

[0011] [Section 1] A compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0012] [ka]

[0013] [In formula [I], R 1a teeth, (1) Hydrogen, (2) Fluorine, (3) C optionally substituted with 1 to 3 halogens 1-4 alkyl, or (4) Benzyl and; R 1b teeth, (1) Hydrogen, or (2) Fluorine and; R 2 teeth, (1) Hydrogen, (2) halogens, (3) Cyano, (4) C optionally substituted with hydroxy or halogen 1-4 alkyl, or (5) -CONHW 1 (where, the W 1is hydrogen, methyl, or ethyl), and R 3 is a halogen, or R 2 and R 3 together with the benzene ring to which they are attached, form the formula [II]:

[0014] [ka]

[0015] forming a group represented by the formula: R 4 is methyl, and R 5 teeth, (1) A 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (wherein the heteroaryl may be substituted with methyl); or (2) Vinyl or R 4 and R 5 taken together with the carbon atom to which they are attached, form the formula [III] or [IV]:

[0016] [ka]

[0017] (Where, 2 and W 3 are each independently (1) Hydrogen, or (2) Methyl is) A group represented by the formula:

[0018] [Section 2] R 2 but, (1) Hydrogen, (2) halogens, (3) Cyano, (4) C optionally substituted with hydroxy or halogen 1-4 alkyl, or (5) -CONHW 1 (where, the W 1 is hydrogen, methyl, or ethyl) and R 3 Item 2. The compound or a pharmaceutically acceptable salt thereof according to Item 1, wherein is halogen.

[0019] [Section 3] R 2 and R 3 together with the benzene ring to which they are attached, form the formula [II]:

[0020] [ka]

[0021] Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula:

[0022] [Section 4] R 4 is methyl, and R 5 but, (1) A 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (wherein the heteroaryl may be substituted with methyl); or (2) Vinyl Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

[0023] [Section 5] R 4 and R 5 together with the carbon atom to which they are attached, form the formula [III] or [IV]:

[0024] [ka]

[0025] (Where, 2 and W 3 are each independently (1) Hydrogen, or (2) Methyl is) Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula:

[0026] [Section 6] R 1a is fluorine, and R 1b Item 6. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 5, wherein is hydrogen.

[0027] [Section 7] R 1a is hydrogen, and R 1b Item 6. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 5, wherein is fluorine.

[0028] [Section 8] The following structural formula:

[0029] [ka]

[0030] Item 2. The compound according to item 1, selected from the group consisting of compounds having the formula:

[0031] [Section 9] A pharmaceutical composition comprising the compound according to any one of items 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0032] [Section 10] Item 9. An NF-κB-inducing kinase inhibitor comprising the compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof.

[0033] [Section 11] Item 9. A therapeutic or preventive agent for a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer, comprising the compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof.

[0034] [Section 12] Item 12. The therapeutic or prophylactic agent according to Item 11, wherein the cancer is Hodgkin's lymphoma, acute myeloid leukemia, or melanoma.

[0035] [Section 13] A method for inhibiting NF-κB-inducing kinase in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of items 1 to 8 or a pharmaceutically acceptable salt thereof.

[0036] [Section 14] A method for treating or preventing a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of items 1 to 8 or a pharmaceutically acceptable salt thereof.

[0037] [Section 15] Item 15. The method according to Item 14, wherein the cancer is Hodgkin's lymphoma, acute myeloid leukemia, or melanoma.

[0038] [Section 16] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 8 for the production of an NF-κB-inducing kinase inhibitor.

[0039] [Section 17] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 8 for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of systemic lupus erythematosus, Sjögren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer.

[0040] [Section 18] Item 18. The use according to Item 17, wherein the cancer is Hodgkin's lymphoma, acute myeloid leukemia, or melanoma.

[0041] [Section 19] Item 10. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 8 for use in inhibiting NF-κB-inducing kinase.

[0042] [Section 20] Item 9. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8 for use in the treatment or prevention of a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer.

[0043] [Section 21] Item 21. The compound or a pharmaceutically acceptable salt thereof according to Item 20, wherein the cancer is Hodgkin's lymphoma, acute myeloid leukemia, or melanoma. [Effects of the Invention]

[0044] The compound of formula [I] of the present invention or a pharmaceutically acceptable salt thereof has NF-κB-inducing kinase inhibitory activity and is therefore useful for the treatment or prevention of a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer (preferably Hodgkin's lymphoma, acute myeloid leukemia, and melanoma). DETAILED DESCRIPTION OF THE INVENTION

[0045] The definitions of terms used in the present invention are as follows. In chemical formula the below described:

[0046] [ka]

[0047] The wavy line indicated by indicates the bonding site of the structure or group represented by the chemical formula.

[0048] "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. 1-4 "Alkyl" is methyl, ethyl, or isopropyl. 1-4 "Alkyl" is methyl or ethyl. 1-4 The "alkyl" may be isotopically labeled, for example, methyl may be -CD3. Another preferred "C 1-4 "Alkyl" is methyl, -CD3, ethyl, or isopropyl. Another more preferred "C 1-4 "Alkyl" is methyl, -CD3, or ethyl.

[0049] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred "halogen" is fluorine, chlorine, or bromine.

[0050] The term "5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms" refers to a 5-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms. The "5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms" includes oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, and 1,2,4-triazolyl. Preferred examples of the "5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms" include oxazolyl, isoxazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,2,4-triazolyl.

[0051] The expression "α may be substituted" with β means that α is unsubstituted or any substitutable hydrogen of α is replaced with β. For example, "C optionally substituted with halogen" 1-4 "Alkyl" means C 1-4 The alkyl is unsubstituted or C 1-4 This means that any hydrogen in the alkyl is replaced with a halogen.

[0052] The term "pharmaceutically acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, etc. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a method known per se, the compound represented by formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base, or an organic base to obtain a pharmaceutically acceptable salt thereof.

[0053] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, Examples include salts with maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methyl nitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid.

[0054] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium.

[0055] Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0056] Preferred embodiments of the "pharmaceutically acceptable salt" are as follows. Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Examples of salts with organic acids include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid. Examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0057] The compound of formula [I] or a pharmaceutically acceptable salt thereof may exist as a solvate. A "solvate" is a compound of formula [I] or a pharmaceutically acceptable salt thereof in which solvent molecules are coordinated, and also includes a hydrate. The solvate is preferably a pharmaceutically acceptable solvate, and examples of the solvate include hydrates, ethanolates, dimethylsulfates, etc. of the compound of formula [I] or a pharmaceutically acceptable salt thereof. Examples thereof include nitroxide solvates.

[0058] Specifically, examples of the solvates include the hemihydrate, monohydrate, dihydrate, or monoethanolate of the compound of formula [I], or the monohydrate or 2 / 3 ethanolate of the sodium salt of the compound of formula [I] or the dihydrochloride salt thereof, etc. These solvates can be obtained according to known methods.

[0059] The compounds of formula [I] may exist as tautomers, and in that case, the compounds of formula [I] may exist as an individual tautomer or a mixture of tautomers.

[0060] The compound of formula [I] may have a carbon-carbon double bond, and in that case, the compound of formula [I] may exist as an E-isomer, a Z-isomer, or a mixture of E- and Z-isomers.

[0061] The compound of formula [I] may exist as a stereoisomer, which should be recognized as a cis / trans isomer. In this case, the compound of formula [I] may exist as a cis isomer, a trans isomer, or a mixture of cis and trans isomers.

[0062] The compound of formula [I] may have one or more asymmetric carbon atoms, in which case the compound of formula [I] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0063] The compounds of formula [I] may exist as atropisomers, in which case the compounds of formula [I] may exist as individual atropisomers or mixtures of atropisomers.

[0064] The compound of formula [I] may simultaneously contain multiple structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0065] In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned possible isomers unless otherwise noted.

[0066] Diastereomeric mixtures can be separated into individual diastereomers by conventional methods such as chromatography or crystallization, or individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or stereoselective reactions.

[0067] Separation of individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a substantially pure enantiomer, known as a chiral auxiliary, by standard methods such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by cleavage and removal of the added chiral auxiliary. Alternatively, a mixture of enantiomers can be directly separated by chromatographic methods using chiral stationary phases, which are well known in the art. Alternatively, one enantiomer can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using chiral auxiliaries and asymmetric catalysts.

[0068] Absolute configuration may be determined by X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0069] The compound of formula [I] may contain isotopes ( 2 H(D), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 18 O. 18 F, 35S, 123 Isotopically labeled compounds of formula [I] may be labeled with an isotopically labeled compound (e.g., -CD3). For example, if the compound of formula [I] has a methyl group, the methyl group may be replaced with a -CD3 group, and the compound obtained in this manner is also encompassed by the present invention. Isotopically labeled compounds of formula [I] may be useful in medicine, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostic agents (e.g., positron emission tomography (PET), single photon emission computed tomography (SPECT)). Isotopically labeled compounds of formula [I] can be prepared according to known methods or the methods described herein, using an isotopically labeled compound instead of a non-isotopically labeled compound.

[0070] The compound of formula [I] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of formula [I] or a pharmaceutically acceptable salt thereof, more preferably a compound of formula [I] or a pharmaceutically acceptable salt thereof purified to a purity of 80% or more.

[0071] The pharmaceutical composition of the present invention may be prepared by appropriately mixing the compound of formula [I] or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carriers, etc. in appropriate amounts, according to a method known in the technical field of pharmaceutical formulation. The content of the compound of formula [I] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0072] The dosage form of the pharmaceutical composition containing the compound of formula [I] or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "the pharmaceutical composition of the present invention" in this specification) includes oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0073] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed.

[0074] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and crystalline cellulose. Examples of "binders" include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like. Examples of the "fluidizing agent" include light anhydrous silicic acid, magnesium stearate, and the like. "Lubricants" include magnesium stearate, calcium stearate, talc, and the like. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, glycerin monostearate and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of "buffers" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like. "Soothing agents" include benzyl alcohol and the like. Examples of "bases" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more thereof. Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include sodium sulfite, ascorbic acid, and the like. Examples of "coloring agents" include food dyes (such as food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), β-carotene, and the like. "Sweetening agents" include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

[0075] The pharmaceutical composition of the present invention can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to humans and non-human mammals (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). The dosage of the compound of formula [I] or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the "pharmaceutically effective amount" in this specification) varies depending on the subject, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when administered orally to an adult patient is usually in the range of about 0.01 mg to 1 g per day of the compound of formula [I], which is the active ingredient. These amounts can be administered once or in divided doses.

[0076] The compound of formula [I] or a pharmaceutically acceptable salt thereof has an NF-κB-inducing kinase inhibitory activity and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating NF-κB-inducing kinase activity, such as a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer (preferably Hodgkin's lymphoma, acute myeloid leukemia, and melanoma).

[0077] "Inhibiting NF-κB-inducing kinase" means inhibiting the function of NF-κB-inducing kinase and eliminating or attenuating its activity, for example, means inhibiting the function of NF-κB-inducing kinase under the conditions of Test Example 1 described below. "Inhibiting NF-κB-inducing kinase" preferably means "inhibiting human NF-κB-inducing kinase." Inhibition of function or elimination or attenuation of activity is preferably performed for clinical applications in humans.

[0078] The term "NF-κB-inducing kinase inhibitor" refers to a drug containing a compound that exhibits the effect of inhibiting NF-κB-inducing kinase, and is preferably a "human NF-κB-inducing kinase inhibitor."

[0079] As used herein, "treatment" includes alleviation of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence.

[0080] As used herein, "prevention" means suppressing the onset of symptoms.

[0081] A preferred specific embodiment of the active ingredient in the NF-κB-inducing kinase inhibitor or pharmaceutical composition of the present invention is a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0082] Specific embodiments of the substituents of the compound of formula [I] of the present invention are exemplified below, but each substituent of the compound of formula [I] is not limited to the specific embodiments, and the compound of formula [I] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0083] R in the compound of formula [I] 1a and R 1b Specific examples of the above are given below.

[0084] The compound of formula [I] includes R 1a is fluorine and R 1b is hydrogen, or R 1a is hydrogen and R 1b is preferably fluorine.

[0085] A preferred embodiment of the compound of formula [I] is a compound of formula [Ia]:

[0086] [ka]

[0087] [During the ceremony, R 2 teeth, (1) Hydrogen, (2) halogens, (3) Cyano, (4) C optionally substituted with hydroxy or halogen 1-4 alkyl, or (5) -CONHW 1 (where, the W 1 is hydrogen, methyl, or ethyl) and R 3 is a halogen, or R 2 and R 3 together with the benzene ring to which they are attached, form the formula [II]:

[0088] [ka]

[0089] forming a group represented by R 5 teeth, (1) A 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (wherein the heteroaryl may be substituted with methyl), or (2) Vinyl or a pharmaceutically acceptable salt thereof.

[0090] Another preferred embodiment of the compound of formula [I] is a compound of formula [Ib]:

[0091] [ka]

[0092] [During the ceremony, R 2 teeth, (1) Hydrogen, (2) halogens, (3) Cyano, (4) C optionally substituted with hydroxy or halogen 1-4 alkyl, or (5) -CONHW 1 (where, the W 1 is hydrogen, methyl, or ethyl) and R 3 is a halogen, or R 2 and R 3 together with the benzene ring to which they are attached, form the formula [II]:

[0093] [ka]

[0094] forming a group represented by W 2 and W 3 are each independently (1) Hydrogen, or (2) Methyl It is. or a pharmaceutically acceptable salt thereof.

[0095] Preferred specific embodiments of the compound of formula [I] include the compounds of Examples 1 to 71 shown in the table below.

[0096] A more preferred embodiment of the compound of formula [I] is a compound represented by the following structural formula:

[0097] [ka]

[0098] or a pharmaceutically acceptable salt thereof.

[0099] [General method for preparing a compound of formula [I] or a pharmaceutically acceptable salt thereof] General methods for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof are exemplified below. However, the methods for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof are not limited to these methods. Furthermore, the salts of each compound in the general methods can be appropriately selected from the above-mentioned "pharmaceutically acceptable salts" unless otherwise specified.

[0100] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases can be used to proceed to the next step without isolation and / or purification.

[0101] In this specification, room temperature refers to a temperature in an uncontrolled state, and in one embodiment, it is 1°C to 40°C.

[0102] The abbreviations used are as follows: HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate CPME: Cyclopentyl methyl ether

[0103] [Production Method A1]: Production Method of Compound [I] or a Salt Thereof The compound of formula [I] (hereinafter also referred to as "compound [I]" in this specification) or a salt thereof can be produced, for example, by the following production method A1.

[0104] [ka]

[0105] [In the formula, R 1a , R 1b , R 2 , R 3 , R 4 , and R 5 is as defined above, L 1is a group suitable for Sonogashira coupling (e.g., trifluoromethylsulfonyloxy, bromine, etc.).

[0106] (Process A1-1) Compound [I] or a salt thereof can be produced by subjecting compound [A1-1] and compound [A1-2] to a Sonogashira coupling reaction. 1 When is trifluoromethylsulfonyloxy, the compound [A1-1] or a salt thereof can be subjected to a coupling reaction with a compound [A1-2] in a solvent in the presence of a catalyst and a base.

[0107] Examples of the solvent include amide solvents such as N,N-dimethylacetamide, sulfoxide solvents such as dimethyl sulfoxide, ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. A preferred solvent is N,N-dimethylformamide.

[0108] Examples of catalysts include tetrakis(triphenylphosphine)palladium(0), a combination of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and tris(dibenzylideneacetone)dipalladium(0), and (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonato-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium. A preferred catalyst is tetrakis(triphenylphosphine)palladium(0).

[0109] If necessary, the reaction may be carried out in the presence of a promoter, preferably copper iodide.

[0110] Examples of the base include triethylamine, diisopropylethylamine, and diisopropylamine, and the preferred base is triethylamine.

[0111] The reaction temperature is, for example, 60°C to 120°C, preferably 90°C.

[0112] The compound [A1-1] or a salt thereof can be produced, for example, by the production method S1 or S2 or Intermediate Production Example 3 described below.

[0113] The compound [A1-2] or a salt thereof is commercially available, or can be produced by, for example, the production method S3 described below or the methods described in Intermediate Production Examples 8 to 10.

[0114] [Production Method S1]: A method for producing compound [A1-1-1] or a salt thereof

[0115] In the compound represented by formula [A1-1] or a salt thereof, L 1 is trifluoromethylsulfonyloxy, the compound [A1-1-1] can be produced, for example, by the following production method S1.

[0116] [ka]

[0117] [In the formula, R 1a , R 1b , R 2 , and R 3 is as defined above, PG 1 is a suitable protecting group for a hydroxy group (e.g., p-methoxybenzyl, or benzyl), and PG 2 is a suitable protecting group for an amino group (e.g., dimethoxybenzyl).

[0118] (Process S1-1) The compound [S1-2] or a salt thereof is a compound [S1-1a] or a salt thereof, which has a protecting group PG for the hydroxy group of the compound [S1-1a] or a salt thereof. 1 and a protecting group PG for the amino group 2 The deprotection conditions are as follows: 1 and PG2 The deprotection reaction may be carried out under conditions suitable for the type of compound, for example, under acidic conditions or catalytic hydrogenation in the presence of a catalyst. These deprotection reactions may be carried out stepwise.

[0119] For example, PG 1 is p-methoxybenzyl, and PG 2 is dimethoxybenzyl, the p-methoxybenzyl group and the dimethoxybenzyl group of compound [S1-1a] or a salt thereof can be removed in a solvent in the presence of an acid to produce compound [S1-2] or a salt thereof.

[0120] Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. A preferred solvent is anisole.

[0121] Examples of the acid include trifluoroacetic acid and hydrochloric acid, and the preferred acid is trifluoroacetic acid.

[0122] The reaction temperature is, for example, 50 to 80°C, preferably 60°C.

[0123] The compound [S1-1a] or a salt thereof can be produced, for example, by Production Method B1, B2, B3, B4, B5, or B6 described below, or the method described in Intermediate Production Example 2.

[0124] (Process S1-2) The compound [A1-1-1] or a salt thereof can be produced by reacting the compound [S1-2] or a salt thereof with a trifluoromethanesulfonylating agent in a solvent in the presence of a base.

[0125] Examples of the solvent include ether solvents such as tetrahydrofuran, halogenated solvents such as dichloromethane, hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, ketone solvents such as acetone, ester solvents such as ethyl acetate, and mixed solvents thereof. A preferred solvent is tetrahydrofuran.

[0126] Examples of the trifluoromethanesulfonylating agent include trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid chloride, N,N-bis(trifluoromethylsulfonyl)aniline, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonyl)imide, etc. Preferred trifluoromethanesulfonylating agents are N,N-bis(trifluoromethylsulfonyl)aniline or N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonyl)imide.

[0127] Examples of the base include triethylamine and diisopropylethylamine, and a preferred base is triethylamine.

[0128] The reaction temperature is, for example, 0° C. to 80° C., preferably room temperature.

[0129] [Production Method S2]: A method for producing compound [A1-1-2] or a salt thereof

[0130] In the compound represented by formula [A1-1] or a salt thereof, L 1 In the case where is bromine, the compound [A1-1-2] can be produced, for example, by the following production method S2.

[0131] [ka]

[0132] [In the formula, R 1a , R 1b , R 2 , R 3 , and P.G. 2has the same meaning as above.]

[0133] (Process S2-1) The compound [A1-1-2] or a salt thereof is a compound [S1-1b] or a salt thereof, which has a protecting group PG for the amino group. 2 can be produced by deprotection in the same manner as in step S1-1.

[0134] The compound [S1-1b] or a salt thereof can be produced, for example, by the production method B1, B2, B3, B4, B5, or B6 described below.

[0135] [Production Method B1]: A method for producing compound [S1-1-1] or a salt thereof In the compound represented by formula [S1-1a] or [S1-1b] or a salt thereof, R 1a is fluorine and R 1b When is hydrogen, the compound [S1-1-1] or a salt thereof can be produced, for example, by the following production method B1.

[0136] [ka]

[0137] [In the formula, E 1 is C 1-4 is alkyl, E 2 is bromine or OPG 1 and E 3 is B(OH) or a halogen, R 2 , R 3 , P.G. 1 , and P.G. 2 has the same meaning as above.]

[0138] (Process B1-1) The compound [B1-2] or a salt thereof is a compound [B1-1] or a salt thereof, and PG 2NH2 or a salt thereof in a solvent in the presence of a base.

[0139] Examples of the solvent include ether solvents such as tetrahydrofuran, alcohol solvents such as ethanol, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as N,N-dimethylacetamide, and mixed solvents thereof. Ethanol is preferred.

[0140] Examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, and cesium carbonate. A preferred base is triethylamine.

[0141] The reaction temperature is, for example, from room temperature to 120°C, preferably from room temperature to 80°C.

[0142] The compound [B1-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0143] PG 2 NH2 or a salt thereof is commercially available or may be prepared from a commercially available product by known methods.

[0144] (Process B1-2) The compound [B1-3] or a salt thereof is a compound [B1-2] or a salt thereof, and E 1 OH can be produced by a carbonylation reaction in the presence of a catalyst and carbon monoxide in a solvent.

[0145] Examples of catalysts include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, and (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]-palladium. A preferred catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0146] Examples of the solvent include ether solvents such as tetrahydrofuran; nitrile solvents such as acetonitrile; amide solvents such as N,N-dimethylacetamide; and mixed solvents thereof. A preferred solvent is N,N-dimethylformamide. 1 OH may be used as a solvent.

[0147] If necessary, the reaction may be carried out by adding a base such as triethylamine or diisopropylethylamine. The preferred base is triethylamine.

[0148] The reaction temperature is, for example, 80°C to 150°C, preferably 120°C. E 1 OH is a commercially available product.

[0149] (Process B1-3) Compound [B1-5] or a salt thereof can be prepared by cross-coupling compound [B1-3] or a salt thereof with compound [B1-4] or a salt thereof in a solvent in the presence of a copper catalyst. Examples of cross-coupling reactions include the Chan-Lam-Evans coupling reaction and the Goldberg amination reaction (Ley, SV; Thomas, AW Angew. Chem. Int. Ed. 2003, 42, 5400).

[0150] Examples of the solvent include ether solvents such as tetrahydrofuran, halogenated solvents such as dichloromethane, hydrocarbon solvents such as toluene, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as N,N-dimethylacetamide, and mixed solvents thereof. A preferred solvent is N,N-dimethylformamide.

[0151] Copper catalysts include, for example, copper acetate, copper chloride, copper bromide, and copper iodide. A preferred copper catalyst is copper acetate.

[0152] If necessary, the above reaction may be carried out by adding a ligand such as pyridine, 1,10-phenanthroline, 1,2-diaminocyclohexane, etc. The preferred ligand is 1,10-phenanthroline.

[0153] In the case of the Chan-Lam-Evans coupling reaction, oxygen may be used as a reoxidant, and the reaction may be carried out under an oxygen atmosphere.

[0154] The reaction temperature is, for example, 40 to 120°C, preferably 60 to 80°C.

[0155] The compound [B1-4] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0156] (Process B1-4) The compound [B1-6] or a salt thereof can be produced by reducing the compound [B1-5] or a salt thereof in a solvent.

[0157] Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0158] Examples of the reducing agent include lithium aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride, and the preferred reducing agent is lithium aluminum hydride.

[0159] The reaction temperature is, for example, from −78° C. to room temperature, preferably from −10° C. to room temperature.

[0160] (Process B1-5) The compound [B1-7] or a salt thereof can be produced by oxidizing the compound [B1-6] or a salt thereof in a solvent.

[0161] Examples of the solvent include halogen-based solvents such as dichloromethane, sulfoxide-based solvents such as dimethyl sulfoxide, and mixed solvents thereof. Preferred solvents are halogen-based solvents such as dichloromethane.

[0162] Examples of the oxidizing agent include manganese dioxide, Dess-Martin periodinane, and sulfur trioxide pyridine complex. The preferred oxidizing agent is sulfur trioxide pyridine complex.

[0163] The reaction temperature is, for example, 0° C. to 60° C., preferably room temperature.

[0164] (Process B1-6) The compound [S1-1-1] or a salt thereof can be produced by deoxyfluorinating the compound [B1-7] or a salt thereof in a solvent.

[0165] Examples of the solvent include ether solvents such as tetrahydrofuran, halogenated solvents such as dichloromethane, and mixed solvents thereof. A preferred solvent is dichloromethane.

[0166] Examples of the reagent used for deoxygenative fluorination include (diethylamino)sulfur trifluoride and bis(2-methoxyethyl)aminosulfur trifluoride. A preferred reagent for deoxygenative fluorination is bis(2-methoxyethyl)aminosulfur trifluoride.

[0167] The reaction temperature is, for example, 0° C. to 40° C., preferably room temperature.

[0168] [Production Method B2]: Production Method of Compound [S1-1-2] or a Salt Thereof In the compound represented by formula [S1-1a] or [S1-1b] or a salt thereof, R 1a is hydrogen and R 1b When is hydrogen, the compound [S1-1-2] or a salt thereof can be produced, for example, by the following production method B2.

[0169] [ka]

[0170] [In the formula, E 2 is bromine or OPG 1 and R 2 , R 3 , P.G. 1 , and P.G. 2 has the same meaning as above.]

[0171] (Process B2-1) The compound [S1-1-2] or a salt thereof can be produced by deoxyfluorinating the compound [B1-6] or a salt thereof in the same manner as in step B1-6.

[0172] [Production Method B3]: Production Method of Compound [S1-1-3] or a Salt Thereof In the compound represented by formula [S1-1a] or [S1-1b] or a salt thereof, R 1a But C 1-4 alkyl or benzyl, and R 1b When is hydrogen, the compound [S1-1-3] or a salt thereof can be produced, for example, by the following production method B3.

[0173] [ka]

[0174] [In the formula, R 2 , R 3 , P.G. 2 , P.G. 1 , and E 1 is as defined above, R 1a is C 1-4 alkyl or benzyl; E 2 is bromine or OPG 1 and E 4 is methyl and E 5 is methoxy, or E 4 and E 5 together with the nitrogen atom to which they are attached form morpholine.

[0175] (Process B3-1) The compound [B3-1] or a salt thereof can be produced by hydrolyzing the ester of the compound [B1-5] or a salt thereof.

[0176] The hydrolysis conditions are E 1 It is sufficient to carry out the test under conditions suitable for the type of E. 1 When is n-butyl, it can be prepared by hydrolyzing the n-butoxycarbonyl group of the compound [B1-5] or a salt thereof in a solvent in the presence of water and a base.

[0177] Examples of the solvent include alcoholic solvents such as ethanol, ethereal solvents such as tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is methanol.

[0178] Examples of the base include sodium hydroxide and potassium hydroxide, with sodium hydroxide being preferred.

[0179] The reaction temperature is, for example, from room temperature to 120° C., preferably room temperature.

[0180] (Process B3-2) Compound [B3-2] or a salt thereof can be produced by reacting the carboxy of compound [B3-1] or a salt thereof with HNE in the presence of a condensing agent and a base in a solvent. 4 E 5 or a salt thereof.

[0181] Examples of the solvent include nitrile solvents such as acetonitrile, amide solvents such as N,N-dimethylacetamide, and mixed solvents thereof. A preferred solvent is N,N-dimethylformamide.

[0182] Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). A preferred condensing agent is HATU.

[0183] Examples of the base include triethylamine and diisopropylethylamine. A preferred base is triethylamine. If necessary, 1-hydroxybenzotriazole may be added to carry out the reaction.

[0184] The reaction temperature is, for example, 0° C. to room temperature, preferably room temperature.

[0185] HNE 4 E 5 or salts thereof are commercially available products.

[0186] (Process B3-3) The compound [B3-3] or a salt thereof is a compound [B3-2] or a salt thereof and R 1a MgBr can be produced by Grignard reaction in a solvent.

[0187] Examples of the solvent include ether solvents such as tetrahydrofuran, and the preferred solvent is tetrahydrofuran.

[0188] The reaction temperature is, for example, from −78° C. to 60° C., preferably from 0° C. to room temperature.

[0189] R 1a MgBr is commercially available or may be prepared from commercially available sources by known methods.

[0190] (Process B3-4) The compound [B3-4] or a salt thereof can be produced by reducing the compound [B3-3] or a salt thereof in a solvent in the same manner as in step B1-4.

[0191] (Process B3-5) The compound [S1-1-3] or a salt thereof can be produced by subjecting the compound [B3-4] or a salt thereof to deoxyfluorination in a solvent in the same manner as in step B1-6.

[0192] [Production Method B4]: Production Method of Compound [S1-1-4] or a Salt Thereof In the compound represented by formula [S1-1a] or [S1-1b] or a salt thereof, R 1a C optionally substituted with 1 to 3 halogens 1-4 alkyl, and R 1b When is hydrogen, the compound [S1-1-4] or a salt thereof can be produced, for example, by the following production method B4.

[0193] [ka]

[0194] [In the formula, R 1a C optionally substituted with 1 to 3 halogens 1-4 is alkyl, E 2 is bromine or OPG 1 and R 2 , R 3 , P.G. 1 , and P.G. 2 has the same meaning as above.]

[0195] (Process B4-1) The compound [B4-1] or a salt thereof can be produced by alkylating the compound [B1-7] or a salt thereof in a solvent in the presence of an alkylating agent.

[0196] Examples of the solvent include ether solvents such as tetrahydrofuran, and the preferred solvent is tetrahydrofuran.

[0197] The alkylating agent is R 1a For example, benzyl magnesium bromide may be used.

[0198] The reaction temperature is, for example, from −78° C. to room temperature, preferably from −10° C. to room temperature.

[0199] (Process B4-2) The compound [S1-1-4] or a salt thereof can be produced by subjecting the compound [B4-1] or a salt thereof to deoxyfluorination in a solvent in the same manner as in step B1-6.

[0200] [Production Method B5]: A method for producing compound [S1-1-5] or a salt thereof In the compound represented by formula [S1-1a] or [S1-1b] or a salt thereof, R 1a But C1-4 alkyl or benzyl, and R 1b In the case where is fluorine, the compound [S1-1-5] or a salt thereof can be produced, for example, by the following production method B5.

[0201] [ka]

[0202] [In the formula, R 1a is C 1-4 alkyl or benzyl; E 2 is bromine or OPG 1 and R 2 , R 3 , P.G. 1 , and P.G. 2 has the same meaning as above.]

[0203] (Process B5-1) The compound [S1-1-5] or a salt thereof can be produced by subjecting the compound [B3-3] or a salt thereof to deoxyfluorination in a solvent in the same manner as in step B1-6.

[0204] [Production Method B6]: Production Method of Compound [S1-1-6] or a Salt Thereof In the compound represented by formula [S1-1a] or [S1-1b] or a salt thereof, R 1a C optionally substituted with 1 to 3 halogens 1-4 alkyl, and R 1b In the case where is fluorine, the compound [S1-1-6] or a salt thereof can be produced, for example, by the following production method B6.

[0205] [ka]

[0206] [In the formula, R 1a C optionally substituted with 1 to 3 halogens 1-4is alkyl, E 2 is bromine or OPG 1 and R 2 , R 3 , P.G. 1 , and P.G. 2 has the same meaning as above.]

[0207] (Process B6-1) The compound [B6-1] or a salt thereof can be produced by oxidizing the compound [B4-1] or a salt thereof in a solvent in the same manner as in step B1-5.

[0208] (Process B6-2) The compound [S1-1-6] or a salt thereof can be produced by subjecting the compound [B6-1] or a salt thereof to deoxyfluorination in a solvent in the same manner as in step B1-6.

[0209] [Production Method S3]: Production Method of Compound [A1-2] or a Salt Thereof In the compound represented by formula [A1-2] or a salt thereof, R 4 is methyl and R 5 is a 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (here, the heteroaryl may be substituted with methyl), compound [A1-2] or a salt thereof can be produced, for example, by the following production method S3.

[0210] [ka]

[0211] [In the formula, R 5 is a 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (wherein the heteroaryl may be substituted with methyl).

[0212] (Process S3-1) The compound [A1-2] or a salt thereof can be produced by subjecting the compound [S3-1] or a salt thereof to a Grignard reaction with ethynylmagnesium bromide in a solvent.

[0213] Examples of the solvent include ether solvents such as tetrahydrofuran and mixed solvents thereof, with tetrahydrofuran being the preferred solvent.

[0214] The reaction temperature is, for example, from -78°C to room temperature, preferably from -78°C to 0°C.

[0215] The compound [S3-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method, for example, by the method described in Intermediate Preparation Examples 4 to 7 below.

[0216] The compound [I] of the present invention or a pharmaceutically acceptable salt thereof will be specifically described below by way of examples of preparation thereof, but the preparation method of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof is not limited thereto.

[0217] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases can be used to proceed to the next step without isolation and / or purification.

[0218] In this specification, room temperature refers to a temperature in an uncontrolled state, and in one embodiment, it is 1°C to 40°C.

[0219] [Manufacturing Example 1] Synthesis of (R)-4-(5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(isoxazol-3-yl)-3-butyn-2-ol (Example No. 1)

[0220] [ka]

[0221] (1) 3-Bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0222] [ka]

[0223] To a solution of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (20.86 g) in ethanol (400 mL), triethylamine (15 mL) and 2,4-dimethoxybenzylamine (18 g) were added and stirred for 1 day at 90° C. After the reaction solution was gradually cooled to room temperature, water (1000 mL) was added, and the resulting solid was collected by filtration, washed with 50% aqueous methanol, and dried under reduced pressure at 75° C. to give the title compound (22.68 g). 1 H-NMR (DMSO-D6) δ: 13.84 (1H, s), 8.25 (1H, s), 7.23 (1H, t, J = 5.9 Hz), 7.11 (1H, d, J = 8.3 Hz), 6.60 (1H, d, J = 2.2 Hz), 6.46 (1H, dd, J = 8.3, 2.2 Hz), 4.68 (2H, d, J = 6.2 Hz), 3.86 (3H, s), 3.73 (3H, s).

[0224] (2) 1-(3-(benzyloxy)-4-fluorophenyl)-3-bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0225] [ka]

[0226] To a solution of 3-bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (9.6 g) in N,N-dimethylformamide, (3-(benzyloxy)-4-fluorophenyl)boronic acid (16.21 g), copper(II) acetate (12 g), and pyridine (8.5 mL) were added, and the mixture was stirred at 60°C for 22 hours under an oxygen atmosphere. (3-(benzyloxy)-4-fluorophenyl)boronic acid (6.75 g) and copper(II) acetate (5.0 g) were added, and the mixture was stirred at 60°C for 26 hours. (3-(benzyloxy)-4-fluorophenyl)boronic acid (6.75 g), copper(II) acetate (5.0 g), and pyridine (4.4 mL) were added, and the mixture was stirred at 60°C for 15 hours. The reaction mixture was gradually cooled to room temperature, and a mixture of 28% aqueous ammonia (100 mL) and water (350 mL) was added, followed by stirring for 30 minutes. The resulting solid was collected by filtration and washed with water to obtain a crude product. The crude product was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (20 mL), to which was added 1N aqueous sodium hydroxide solution (100 mL) and water (350 mL). The resulting solid was collected by filtration and air-dried. The resulting crude product was dissolved in a mixture of N,N-dimethylformamide (80 mL) and tetrahydrofuran (80 mL), adsorbed onto silica gel (600 g), filtered, and washed with tetrahydrofuran (500 mL). The filtrate was concentrated under reduced pressure, and then methanol (100 mL) and tetrahydrofuran (10 mL) were added to the residue. The resulting solid was collected by filtration, washed with a mixed solution of methanol / tetrahydrofuran = 3 / 1, and then dried under reduced pressure at room temperature to obtain the title compound (7.05 g). 1 H-NMR (DMSO-D6) δ: 8.41 (1H, s), 7.97-7.95 (1H, m), 7.72-7.68 (1H, m), 7.51-7.49 (3H, m), 7.44-7.34 (4H, m), 7.13 (1H, d, J = 8.6 Hz), 6.61 (1H, d, J = 2.7 Hz), 6.47 (1H, dd, J = 8.1, 2.2 Hz), 5.25 (2H, s), 4.73 (2H, d, J = 5.9 Hz), 3.88 (3H, s), 3.74 (3H, s).

[0227] (3) Butyl 1-(3-(benzyloxy)-4-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

[0228] [ka]

[0229] To a solution of 1-(3-(benzyloxy)-4-fluorophenyl)-3-bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4 g) in N,N-dimethylformamide (40 mL), 1-butyl alcohol (20 mL), triethylamine (3.0 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (580 mg) were added and stirred under a carbon monoxide atmosphere at 120 °C for 16 hours. The reaction mixture was gradually cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50) to give the title compound (3.5 g). 1 H-NMR(DMSO-D6) δ: 8.95 (1H, t, J = 5.5 Hz), 8.44 (1H, s), 8.01 (1H, dd, J = 7.6, 2.5 Hz), 7.69-7.67 (1H, m), 7.51-7.34 (6H, m), 7.23 (1H, d, J = 8.1 Hz), 6.61 (1H, d, J = 2.3 Hz), 6.47 (1H, dd, J = 8.2, 2.4 Hz), 5.25 (2H, s), 4.70 (2H, d, J = 5.5 Hz), 4.41 (2H, t, J = 6.7 Hz), 3.84 (3H, s), 3.74 (3H, s), 1.76-1.69 (2H, m), 1.47-1.37 (2H, m), 0.93 (3H, t, J = 7.4 Hz).

[0230] (4) (1-(3-(benzyloxy)-4-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methanol

[0231] [ka]

[0232] To a suspension of aluminum lithium hydride (454 mg) in tetrahydrofuran (10 mL) was added dropwise a solution of butyl 1-(3-(benzyloxy)-4-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate (3.5 g) in tetrahydrofuran (25 mL) under an argon atmosphere and ice cooling with stirring. Water (0.454 mL), 4N aqueous sodium hydroxide solution (0.454 mL), and water (1.36 mL) were added sequentially to the reaction solution, magnesium sulfate was added, and the mixture was stirred. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.82 g). 1 H-NMR(DMSO-D6) δ: 8.46 (1H, t, J = 5.7 Hz), 8.38 (1H, s), 8.03 (1H, dd, J = 7.9, 2.5 Hz), 7.76 (1H, ddd, J = 8.8, 3.9, 2.6 Hz), 7.53-7.48 (2H, m), 7.44-7.29 (4H, m), 7.20 (1H, d, J = 8.3 Hz), 6.58 (1H, d, J = 2.3 Hz), 6.52 (1H, s), 6.45 (1H, dd, J = 8.3, 2.3 Hz), 5.23 (2H, s), 4.81 (2H, s), 4.65 (2H, d, J = 5.3 Hz), 3.82 (3H, s), 3.73 (3H, s).

[0233] (5) 1-(3-(benzyloxy)-4-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde

[0234] [ka]

[0235] To a solution of (1-(3-(benzyloxy)-4-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methanol (1.5 g) in dimethyl sulfoxide (15 mL), triethylamine (2 mL) and sulfur trioxide pyridine complex (1.39 g) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resulting solid was collected by filtration, washed successively with water and methanol, and dried under reduced pressure to give the title compound (1.49 g).

[0236] (6) 1-(3-(benzyloxy)-4-fluorophenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0237] [ka]

[0238] To a solution of 1-(3-(benzyloxy)-4-fluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde (150 mg) in dichloromethane (2 mL), bis(2-methoxyethyl)aminosulfur trifluoride (0.081 mL) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 95 / 5 to 50 / 50) to give the crude title compound (79.7 mg), which was used directly in the next step.

[0239] (7) 5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol

[0240] [ka]

[0241] Palladium-carbon (80 mg) was added to a solution of crude 1-(3-(benzyloxy)-4-fluorophenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (79.7 mg) in tetrahydrofuran (3 mL), and the mixture was stirred under a hydrogen atmosphere for 1 day. After removing the solids by filtration through Celite, palladium-carbon (120 mg) was added to the filtrate, and the mixture was stirred under a hydrogen atmosphere for 6 hours. After removing the solids by filtration through Celite, the filtrate was concentrated under reduced pressure to obtain the title compound (55.7 mg) as a crude product, which was used directly in the next step.

[0242] (8) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol 2,2,2-trifluoroacetate

[0243] [ka]

[0244] Anisole (0.02 mL) was added to a solution of 5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol (55.7 mg) in trifluoroacetic acid (2 mL), and the mixture was stirred at 70° C. for 3 hours. The reaction solution was gradually cooled to room temperature and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (27.3 mg). The filtrate was further concentrated under reduced pressure, and the residue was purified by ODS column chromatography (water / acetonitrile = 95 / 5 to 40 / 60) to give the title compound in free form (4.7 mg). 1 H-NMR(DMSO-D6) δ: 10.36 (1H, s), 8.38 (1H, s), 7.79 (1H, dd, J = 8.1, 2.8 Hz), 7.62-7.28 (3H, m).

[0245] (9) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol trifluoromethanesulfonate

[0246] [ka]

[0247] A mixture of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol 2,2,2-trifluoroacetate and its free form (32.1 mg) in tetrahydrofuran (3 mL) was added with triethylamine (0.076 mL) and 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (51.2 mg), and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (water / acetonitrile = 95 / 5 to 15 / 85) to give the title compound (20.2 mg). 1H-NMR (DMSO-D6) δ: 8.50 (1H, dd, J = 7.0, 2.7 Hz), 8.44 (1H, s), 8.40-8.34 (1H, m), 7.87 (1H, t, J = 9.4 Hz), 7.54 (1H, t, J = 53.1 Hz).

[0248] (10) Isoxazol-3-yl(morpholino)methanone

[0249] [ka]

[0250] To a solution of isoxazole-3-carboxylic acid (30 g) in tetrahydrofuran (300 mL) was added N,N-dimethylformamide (0.2 mL), and oxalyl chloride (27.9 mL) was added dropwise at room temperature under a nitrogen atmosphere while stirring. Subsequently, a mixed solution of morpholine (34.7 mL) and triethylamine (74 mL) was added dropwise to the reaction mixture under water cooling. After stirring for 30 minutes, the mixture was filtered through Celite, the solid was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the crude title compound (43.6 g), which was used directly in the next step.

[0251] (11) 1-(Isoxazol-3-yl)ethan-1-one

[0252] [ka]

[0253] A solution of isoxazol-3-yl(morpholino)methanone (43.6 g) in tetrahydrofuran (218 mL) was stirred under ice cooling and a nitrogen atmosphere, while 3 M methylmagnesium chloride solution in tetrahydrofuran (100 mL) was added dropwise. After stirring for 1 hour, 6 N hydrochloric acid (50 mL) was added dropwise, and the mixture was warmed to room temperature. Saturated aqueous ammonium chloride solution (50 mL) and water (50 mL) were added, and the mixture was separated. The aqueous layer was extracted three times with ethyl acetate (200 mL, 50 mL, 50 mL). The combined organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by vacuum distillation (55°C to 62°C / 20 mmHg) to give the title compound (17.35 g). 1 H-NMR (DMSO-D6) δ: 9.14 (1H, d, J = 1.6 Hz), 6.93 (1H, d, J = 2.2 Hz), 2.61 (3H, s).

[0254] In this reaction, deuterated methylmagnesium bromide was used instead of methylmagnesium chloride, and then the same reactions as in (12) to (15) of Production Example 1 were carried out to obtain the compound of Example No. 70.

[0255] (12) 2-(Isoxazol-3-yl)-3-butyn-2-ol

[0256] [ka]

[0257] A tetrahydrofuran solution of 1-(isoxazol-3-yl)ethan-1-one (17.35 g) was stirred under ice cooling and a nitrogen atmosphere while 0.5 M ethynylmagnesium bromide in tetrahydrofuran (344 mL) was added dropwise. After stirring for 2 hours, 6 N hydrochloric acid (57 mL) was added dropwise, and saturated aqueous ammonium chloride (100 mL), ethyl acetate (200 mL), and water (50 mL) were added at room temperature for phase separation. The aqueous layer was re-extracted twice with ethyl acetate, and the combined organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1) to give the title compound (13.92 g). 1 H-NMR (DMSO-D6) δ: 8.84 (1H, d, J = 1.6 Hz), 6.61 (1H, d, J = 1.6 Hz), 6.46 (1H, s), 3.55 (1H, s), 1.71 (3H, s).

[0258] (13) 3-((R)-2-(((3aS,6aS)-3a-allylhexahydro-6aH-cyclopenta[b]furan-6a-yl)oxy)-3-butyn-2-yl)isoxazole

[0259] [ka]

[0260] To a solution of 2-(isoxazol-3-yl)-3-butyn-2-ol (6.0 g) in tetrahydrofuran (60 mL), (S)-3a-allyl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan (9.37 g) and p-toluenesulfonic acid monohydrate (791 mg) were added and stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cooled saturated aqueous sodium bicarbonate, and ethyl acetate and water were added at room temperature for separation. The aqueous layer was re-extracted with ethyl acetate. Magnesium sulfate was added to the combined organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the crude title compound (8.08 g). 1 H-NMR (CDCl3) δ: 8.34 (1H, d, J = 1.6 Hz), 6.48 (1H, d, J = 1.6 Hz), 5.88-5.78 (1H, m), 5.10-5.02 (2H, m), 3.98-3.88 (2H, m), 2.70 (1H, s), 2.28 (1H, dd, J = 13.9, 7.3 Hz), 2.20-2.05 (2H, m), 1.99-1.91 (4H, m), 1.74-1.63 (2H, m), 1.60-1.58 (2H, m), 1.48-1.39 (1H, m).

[0261] In this reaction, the compound of Example No. 71 can be obtained by using an R-configuration chiral auxiliary and then carrying out the same reactions as in (14) and (15) of Production Example 1.

[0262] (14) (R)-2-(Isoxazol-3-yl)-3-butyn-2-ol

[0263] [ka]

[0264] To a solution of 3-((R)-2-(((3aS,6aS)-3a-allylhexahydro-6aH-cyclopenta[b]furan-6a-yl)oxy)-3-butyn-2-yl)isoxazole (8.08 g) obtained in (13) in methanol (80 mL), p-toluenesulfonic acid monohydrate (395 mg) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 50 / 50) to give the title compound (2.5 g). 1 H-NMR (DMSO-D6) δ: 8.84 (1H, d, J = 1.6 Hz), 6.61 (1H, d, J = 1.6 Hz), 6.46 (1H, s), 3.55 (1H, s), 1.71 (3H, s).

[0265] (15) (R)-4-(5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(isoxazol-3-yl)-3-butyn-2-ol

[0266] [ka]

[0267] To a solution of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol trifluoromethanesulfonate (20.2 mg) in N,N-dimethylformamide (2 mL), (R)-2-(isoxazol-3-yl)-3-butyn-2-ol (11.2 mg), triethylamine (0.033 mL), copper(I) iodide (2.7 mg), tris(dibenzylideneacetone)dipalladium(0) (8.7 mg), and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (13.5 mg) were added and stirred at 85°C for 3 hours under a nitrogen atmosphere. The reaction mixture was purified by ODS column chromatography (water / acetonitrile = 95 / 5 to 30 / 70) to give the title compound (17.2 mg). The stereochemistry of the title compound was determined by X-ray crystal structure analysis. 1 H-NMR (DMSO-D6) δ: 8.90 (1H, d, J = 2.2 Hz), 8.43 (1H, s), 8.30 (1H, dd, J = 5.9, 2.7 Hz), 8.19 (1H, ddd, J = 9.0, 4.6, 2.8 Hz), 7.56 (1H, t-like, J = 9.2 Hz), 7.53 (1H, t, J = 53.1 Hz), 6.77 (1H, s), 6.73 (1H, d, J = 1.6 Hz), 1.86 (3H, s).

[0268] Toluene (682 mL) was added to the crude product of the title compound obtained in (15) (34.1 g), and the mixture was dissolved with stirring at 125°C. The mixture was stirred at 80°C for 30 minutes and then at room temperature for 3 hours. The precipitate was collected by filtration, washed with toluene (200 mL) and hexane, and then dried under reduced pressure at 80°C to obtain type A crystals (34.7 g). Type A crystals (50 mg) of the title compound were suspended in methanol (0.5 mL), stirred at room temperature for 1 week, and the precipitated crystals were collected by filtration to obtain type B crystals of the title compound. Type B crystals of the title compound could also be obtained by dissolving the title compound (50 mg) obtained in (15) in ethanol (1 mL) at 70°C, adding water (0.5 mL), seeding with type B crystals, stirring at 50°C for 1.5 hours, then stirring at room temperature for 2 hours, and collecting the precipitated crystals by filtration.

[0269] The B-type crystals (50 mg) of the title compound were dissolved in methanol (1 mL) at 70°C, water (0.5 mL) was added, and the mixture was stirred at 50°C for 1.5 hours, followed by stirring at room temperature for 2 hours. The precipitated crystals were collected by filtration to obtain C-type crystals of the title compound. The C-type crystals of the title compound could also be obtained by dissolving the title compound (50 mg) obtained in (15) in methanol (1 mL) at 70°C, adding water (0.3 mL), seeding with C-type crystals, adding water (0.7 mL), stirring at 50°C for 1.5 hours, followed by stirring at room temperature for 2 hours, and collecting the precipitated crystals by filtration.

[0270] [Manufacturing Example 2] Synthesis of (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one (Example No. 9)

[0271] [ka]

[0272] (1) tert-Butyl 1-methyl-4,5-dioxopyrrolidine-3-carboxylate

[0273] [ka]

[0274] To a solution of tert-butyl acrylate (33.5 g) in ethanol (100 mL), 33% methylamine ethanol solution (32.5 mL) was added and stirred at room temperature for 1 day. Diethyl oxalate (35.5 mL) and 20% sodium ethoxide ethanol solution (102 mL) were added to the reaction solution, and the mixture was stirred at 85°C for 5 hours. The reaction solution was gradually cooled to room temperature and then concentrated under reduced pressure. Water (400 mL) and 6N hydrochloric acid (43.5 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (33.29 g). 1 H-NMR (DMSO-D6) δ: 11.03 (1H, s), 3.90 (2H, s), 2.94 (3H, s), 1.45 (9H, s).

[0275] (2) 1-Methylpyrrolidine-2,3-dione 2,2,2-trifluoroacetate

[0276] [ka]

[0277] Trifluoroacetic acid (166 mL) was added to tert-butyl 1-methyl-4,5-dioxopyrrolidine-3-carboxylate (33.29 g) and stirred at room temperature for 1 hour. Water (166 mL) was added to the reaction mixture, and the mixture was stirred at 75°C for 19 hours. The reaction mixture was gradually cooled to room temperature, concentrated under reduced pressure, and azeotroped sequentially with tetrahydrofuran and cyclopentyl methyl ether to give the crude product (29 g) of the title compound, which was used directly in the next step.

[0278] (3) 3-Hydroxy-1-methyl-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one

[0279] [ka]

[0280] To a solution of trimethylsilylacetylene (19.9 g) in tetrahydrofuran (180 mL) was added dropwise 2.65 M n-butyllithium hexane solution (77 mL) at -78°C under an argon atmosphere while stirring. The reaction mixture was warmed to 0°C and stirred for an additional 30 minutes. A solution of 1-methylpyrrolidine-2,3-dione 2,2,2-trifluoroacetate (29 g) in tetrahydrofuran (150 mL) was cooled to -78°C and, while stirring under an argon atmosphere, the trimethylsilylacetylene-butyllithium reaction mixture was added dropwise and stirred for 1 hour. Saturated aqueous ammonium chloride solution (300 mL) and water (100 mL) were added, and the mixture was warmed to room temperature. The mixture was then separated, and the aqueous layer was extracted sequentially with tetrahydrofuran and a 1:1 mixed solvent of tetrahydrofuran and ethyl acetate. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (7.88 g). 1 H-NMR (DMSO-D6) δ: 6.31 (1H, s), 3.32-3.20 (2H, m), 2.75 (3H, s), 2.31-2.23 (1H, m), 2.10-2.03 (1H, m), 0.13 (9H, s).

[0281] (4) 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one

[0282] [ka]

[0283] To a solution of 3-hydroxy-1-methyl-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one (7.88 g) in tetrahydrofuran (20 mL), 1 M tetrabutylammonium fluoride in tetrahydrofuran (48.5 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to give the title compound (5.0 g). 1 H-NMR (DMSO-D6) δ: 6.30 (1H, s), 3.48 (1H, s), 3.30-3.21 (2H, m), 2.75 (3H, s), 2.33-2.25 (1H, m), 2.10-2.02 (1H, m).

[0284] (5) (R)-3-(((3aS,6aS)-3a-allylhexahydro-6aH-cyclopenta[b]furan-6a-yl)oxy)-3-ethynyl-1-methylpyrrolidin-2-one

[0285] [ka]

[0286] To a solution of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (2.5 g) in tetrahydrofuran (25 mL), (S)-3a-allyl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan (4.05 g) and p-toluenesulfonic acid monohydrate (342 mg) were added and stirred at room temperature for 4 hours. The reaction mixture was added to ice-cooled saturated aqueous sodium bicarbonate, and ethyl acetate and water were added at room temperature for separation. The aqueous layer was extracted with ethyl acetate. Magnesium sulfate was added to the combined organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 50 / 50) to give the title compound (2.45 g). 1H-NMR (DMSO-D6) δ: 5.90-5.79 (1H, m), 5.09-5.00 (2H, m), 3.82-3.70 (2H, m), 3.58 (1H, s), 3.31-3.20 (2H, m), 2.80-2.72 (3H, m), 2.42-2.30 (3H, m), 2.17-1.99 (2H, m), 1.94-1.91 (1H, m), 1.86-1.79 (1H, m), 1.69-1.34 (5H, m).

[0287] (6) (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one

[0288] [ka]

[0289] To a solution of (R)-3-(((3aS,6aS)-3a-allylhexahydro-6aH-cyclopenta[b]furan-6a-yl)oxy)-3-ethynyl-1-methylpyrrolidin-2-one (2.45 g) in methanol (25 mL), p-toluenesulfonic acid hydrate (161 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (1.13 g). 1 H-NMR (DMSO-D6) δ: 6.30 (1H, s), 3.48 (1H, s), 3.30-3.21 (2H, m), 2.75 (3H, s), 2.33-2.25 (1H, m), 2.10-2.02 (1H, m).

[0290] (7) (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0291] [ka]

[0292] 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenol trifluoromethanesulfonate (50 mg) obtained by a method similar to that of Preparation Example 1 (9) N,N-dimethylformamide (2 mL) solution (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (21.2 mg), triethylamine (0.049 mL), copper (I) iodide (4.5 mg), and tetrakis (triphenylphosphine) palladium (0) (13.5 mg) were added and stirred for 2 hours under an argon atmosphere at 90 ° C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 0 / 100), and isopropanol was added. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (30.4 mg). 1 H-NMR (DMSO-D6) δ: 8.42 (1H, s), 8.29 (1H, dd, J = 6.2, 2.8 Hz), 8.18 (1H, ddd, J = 9.1, 4.5, 2.8 Hz), 7.53 (1H, t, J = 9.0 Hz), 7.51 (1H, t, J = 53.2 Hz), 6.61 (1H, s), 3.36-3.34 (2H, m), 2.79 (3H, s), 2.46-2.43 (1H, m), 2.22-2.18 (1H, m).

[0293] [Manufacturing Example 3] Synthesis of (R)-4-(5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(isoxazol-3-yl)-3-butyn-2-ol (Example No. 19)

[0294] [ka]

[0295] (1) 5-Bromo-1,2-difluoro-3-((4-methoxybenzyl)oxy)benzene

[0296] [ka]

[0297] To a solution of 5-bromo-2,3-difluorophenol (5 g) in N,N-dimethylformamide (15 mL), potassium carbonate (3.97 g), 1-(chloromethyl)-4-methoxybenzene (3.78 g), and sodium iodide (359 mg) were added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (7.39 g), which was used in the next step without measuring NMR.

[0298] (2) 2-(3,4-difluoro-5-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0299] [ka]

[0300] To a solution of 5-bromo-1,2-difluoro-3-((4-methoxybenzyl)oxy)benzene (1.2 g) in 1,4-dioxane (12 mL), bis-pinacolatodiboron (1.39 g), potassium acetate (0.72 g), and bis(tricyclohexylphosphine)palladium(0) were added, and the mixture was stirred at 110°C for 2 hours under an argon atmosphere. The reaction mixture was gradually cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 70 / 30) to give the title compound (636 mg), which was used in the next step without measuring NMR.

[0301] (3) (3,4-Difluoro-5-((4-methoxybenzyl)oxy)phenyl)boronic acid

[0302] [ka]

[0303] To a solution of 2-(3,4-difluoro-5-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (636 mg) in tetrahydrofuran (7 mL) and water (1.4 mL), 2N hydrochloric acid (0.592 mL) and sodium periodate (542 mg) were added and the mixture was stirred at room temperature for 1 hour and 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate. Magnesium sulfate was added to the combined organic layer, and the mixture was filtered. The filtrate was concentrated. Ethyl acetate and hexane were added to the residue, and the resulting solid was collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (291.6 mg). This was used in the next step without measuring NMR.

[0304] (4) 1-(3,4-difluoro-5-((4-methoxybenzyl)oxy)phenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0305] [ka]

[0306] To a solution of 3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg) obtained by a method similar to that of Intermediate Preparation Example 1 in N,N-dimethylformamide (2 mL), (3,4-difluoro-5-((4-methoxybenzyl)oxy)phenyl)boronic acid (80 mg), copper(II) acetate (37.9 mg), and 1,10-phenanthroline (75 mg) were added and stirred under an oxygen atmosphere at 60°C for 15 hours. The reaction mixture was gradually cooled to room temperature, and then water, ethyl acetate, and tetrahydrofuran were added and the mixture was separated. The aqueous layer was extracted sequentially with tetrahydrofuran and ethyl acetate. Magnesium sulfate was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 50 / 50) to give the title compound (108 mg), which was used in the next step without NMR analysis.

[0307] (5) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenol 2,2,2-trifluoroacetate

[0308] [ka]

[0309] Trifluoroacetic acid (3 mL) and anisole (0.06 mL) were added to 1-(3,4-difluoro-5-((4-methoxybenzyl)oxy)phenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (108 mg), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting title compound (79.2 mg) was used directly in the next step.

[0310] (6) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenyl trifluoromethanesulfonate

[0311] [ka]

[0312] To a solution of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenol 2,2,2-trifluoroacetate (79.2 mg) in tetrahydrofuran (3 mL), triethylamine (0.129 mL) and 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (87 mg) were added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50) to give the title compound (49.6 mg), which was used in the next step without measuring NMR.

[0313] (7) (R)-4-(5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(isoxazol-3-yl)-3-butyn-2-ol

[0314] [ka]

[0315] To a solution of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenyl trifluoromethanesulfonate (24.5 mg) in N,N-dimethylformamide (2 mL), (R)-2-(isoxazol-3-yl)-3-butyn-2-ol (10.6 mg) obtained in a manner similar to that of Preparation 1 (14), triethylamine (0.023 mL), copper(I) iodide (2.1 mg), and tetrakis(triphenylphosphine)palladium(0) (6.4 mg) were added and stirred under an argon atmosphere at 90°C for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50), followed by addition of isopropanol. The resulting solid was collected by filtration and dried under reduced pressure. The residue was purified twice by silica gel column chromatography (hexane / tetrahydrofuran=100 / 0 to 60 / 40), and then isopropanol was added. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (4.5 mg). 1 H-NMR (DMSO-D6) δ: 8.89 (1H, d, J = 1.6 Hz), 8.44 (1H, s), 8.31 (1H, ddd, J = 11.6, 6.9, 2.6 Hz), 8.17-8.15 (1H, m), 7.51 (1H, t, J = 53.1 Hz), 6.80 (1H, s), 6.71 (1H, d, J = 1.6 Hz), 1.85 (3H, s).

[0316] [Manufacturing Example 4] Synthesis of (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one (Example No. 20)

[0317] [ka]

[0318] To a solution of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-difluorophenyl trifluoromethanesulfonate (25.2 mg) obtained in a similar manner to Preparation 3 (6) in N,N-dimethylformamide (2 mL), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (7.9 mg) obtained in a similar manner to Preparation 2 (6), triethylamine (0.024 mL), copper(I) iodide (2.2 mg), and tetrakis(triphenylphosphine)palladium(0) (6.5 mg) were added and stirred under an argon atmosphere at 90 ° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50), and isopropanol was added. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (14 mg). 1 H-NMR (DMSO-D6) δ: 8.44 (1H, s), 8.29 (1H, ddd, J = 11.7, 6.8, 2.5 Hz), 8.18-8.16 (1H, m), 7.51 (1H, t, J = 53.2 Hz), 6.67 (1H, s), 3.37-3.33 (2H, m), 2.80 (3H, s), 2.45-2.43 (1H, m), 2.24-2.18 (1H, m).

[0319] [Manufacturing Example 5] Synthesis of (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-ethyl-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzamide (Example No. 37)

[0320] [ka]

[0321] (1) Methyl 3-bromo-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0322] [ka]

[0323] To a solution of methyl 3-bromo-2-fluorobenzoate (5.0 g) in tetrahydrofuran (25 mL), bispinacolatodiboron (5.45 g), 4,4'-di-tert-butyl-2,2'-bipyridine (576 mg), and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (711 mg) were added, and the mixture was stirred under an argon atmosphere at 80°C for 1 day. After the reaction mixture was gradually cooled to room temperature, 4,4'-di-tert-butyl-2,2'-bipyridine (115 mg) and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (142 mg) were added, and the mixture was stirred under an argon atmosphere at 80°C for 4 hours. After the reaction mixture was cooled to room temperature, 4,4'-di-tert-butyl-2,2'-bipyridine (403 mg) and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (498 mg) were added, and the mixture was stirred under an argon atmosphere at 80° C. for 4 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 66 / 34) to give the title compound (6.39 g). 1 H-NMR(DMSO-D6) δ: 8.07 (2H, ddd, J = 17.3, 6.7, 1.6 Hz), 3.87 (3H, s), 1.29 (12H, s).

[0324] (2) (3-Bromo-4-fluoro-5-(methoxycarbonyl)phenyl)boronic acid

[0325] [ka]

[0326] To a solution of methyl 3-bromo-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6.4 g) in tetrahydrofuran (64 mL) and water (6.4 mL), 2N hydrochloric acid (12.47 mL) and sodium periodate (5.72 g) were added and stirred at room temperature. Ethyl acetate and water were added to the reaction mixture, and the layers were separated. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Hexane was added to the residue, and the resulting solid was collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (4.72 g). This was used in the next step without measuring NMR.

[0327] (3) Methyl 3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzoate

[0328] [ka]

[0329] To a solution of 3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (350 mg) obtained by a method similar to that of Intermediate Preparation Example 1 in N,N-dimethylformamide (7 mL), (3-bromo-4-fluoro-5-(methoxycarbonyl)phenyl)boronic acid (578 mg), copper(II) acetate (190 mg), and 1,10-phenanthroline (376 mg) were added and stirred at 60°C for 15 hours under an oxygen atmosphere. The reaction mixture was gradually cooled to room temperature, and then water and ethyl acetate were added, followed by separation. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5 to 0 / 100) to give the crude title compound (202 mg), which was used directly in the next step.

[0330] (4) Methyl 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorobenzoate 2,2,2-trifluoroacetate

[0331] [ka]

[0332] Trifluoroacetic acid (3.12 mL) and anisole (0.06 mL) were added to methyl 3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzoate (208 mg), and the mixture was stirred at 60°C for 6 hours, at room temperature for 8 hours, and then at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and toluene was added thereto for azeotropy. Diisopropyl ether was added to the residue, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (77 mg). This was used in the next step without measuring NMR.

[0333] (5) Methyl (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzoate

[0334] [ka]

[0335] To a solution of methyl 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorobenzoate 2,2,2-trifluoroacetate (77 mg) in N,N-dimethylformamide, (R)-2-(isoxazol-3-yl)-3-butyn-2-ol (25.9 mg) obtained in a manner similar to that of Production Example 1 (14), triethylamine (0.061 mL), copper(I) iodide (5.5 mg), and tetrakis(triphenylphosphine)palladium(0) (16.8 mg) were added, and the mixture was stirred under an argon atmosphere at 90°C for 14 hours. The reaction mixture was gradually cooled to room temperature, and then water and ethyl acetate were added, followed by separation. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate=95 / 5 to 0 / 100) to give the title compound (64 mg). 1 H-NMR (CDCl3) δ: 8.75-8.73 (1H, m), 8.58-8.55 (2H, m), 8.42-8.42 (1H, m), 6.95 (1H, t, J = 54.1 Hz), 6.58-6.56 (1H, m), 6.16 (2H, br s), 4.20 (1H, br s), 3.98 (3H, s), 2.03 (3H, s).

[0336] (6) (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzoic acid

[0337] [ka]

[0338] To a solution of methyl (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzoate (64 mg) in methanol (0.64 mL) and tetrahydrofuran (0.64 mL), 8N aqueous potassium hydroxide solution (0.085 mL) was added and stirred at room temperature for 16 hours. 6N hydrochloric acid (0.113 mL) was added to the reaction mixture, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (52 mg). The title compound was used in the next step without measuring NMR.

[0339] (7) (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)-N-methylbenzamide

[0340] [ka]

[0341] To a solution of (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzoic acid (17.3 mg) in N,N-dimethylformamide, 2M methylamine solution (0.028 mL), diisopropylethylamine (0.020 mL), and HATU (17.2 mg) were added and stirred at room temperature for 18 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the layers were separated. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.6 mg). 1H-NMR (CD3OD) δ: 8.93 (1H, dd, J = 6.4, 2.8 Hz), 8.54-8.51 (2H, m), 8.43 (1H, d, J = 1.8 Hz), 8.43 (1H, d, J = 1.8 Hz), 6.96 (1H, t, J = 54.1 Hz), 6.57 (1H, d, J = 1.5 Hz), 5.88 (1H, s), 5.30 (1H, s), 3.07 (3H, d, J = 3.9 Hz), 1.85 (3H, s).

[0342] (8) (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-ethyl-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzamide

[0343] [ka]

[0344] (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(3-hydroxy-3-(isoxazol-3-yl)-1-butyn-1-yl)benzoic acid (17 mg) in N,N-dimethylformamide solution, 2M ethylamine-tetrahydrofuran solution (0.028 mL), diisopropylethylamine (0.019 mL), and HATU (18.3 mg) were added and stirred at room temperature for 16 hours. The reaction solution was purified by ODS column chromatography to obtain the title compound (8.6 mg). 1H-NMR (DMSO-D6) δ: 8.91 (1H, d, J = 1.5 Hz), 8.60-8.57 (1H, m), 8.45 (1H, s), 8.43 (1H, dd, J = 5.7, 3.0 Hz), 8.36 (1H, dd, J = 5.8, 2.8 Hz), 7.54 (1H, t, J = 53.2 Hz), 6.79 (1H, s), 6.73 (1H, d, J = 1.8 Hz), 1.87 (3H, s), 1.13 (3H, t, J = 7.2 Hz).

[0345] [Manufacturing Example 6] Synthesis of (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(hydroxymethyl)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one (Example No. 51)

[0346] [ka]

[0347] (1) 3-Bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzoic acid

[0348] [ka]

[0349] To a solution of methyl 3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzoate (308 mg) obtained in a similar manner to Preparation Example 5(3) in methanol (3 mL) and tetrahydrofuran (3 mL), 4N aqueous sodium hydroxide solution (0.41 mL) was added and stirred at room temperature for 3 hours. 1N hydrochloric acid (1.63 mL) was added, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (314 mg). This was used in the next step without measuring NMR.

[0350] (2) (3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)methanol

[0351] [ka]

[0352] To a solution of 3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzoic acid (100 mg) in tetrahydrofuran (3 mL) was added 1 M DIBAL-H in tetrahydrofuran (1.1 mL) under ice cooling and stirring under an argon atmosphere. The mixture was warmed to room temperature and stirred for 5 hours. Subsequently, 1 M DIBAL-H in tetrahydrofuran (1.1 mL) was added, and the mixture was stirred for an additional 3 hours. Hydrochloric acid and tetrahydrofuran were added to the reaction mixture, and the mixture was separated. The aqueous layer was re-extracted with tetrahydrofuran. The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50) to give the title compound (69 mg), which was used in the next step without measuring NMR.

[0353] (3) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorobenzyl 2,2,2-trifluoroacetate 2,2,2-trifluoroacetate

[0354] [ka]

[0355] Trifluoroacetic acid (2 mL) and anisole (0.009 mL) were added to (3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)methanol (30 mg), and the mixture was stirred at 70° C. for 5 hours. The reaction mixture was gradually cooled to room temperature and then concentrated under reduced pressure to give the title compound as a crude product (33 mg), which was used directly in the next step.

[0356] (4) (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(hydroxymethyl)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0357] [ka]

[0358] 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorobenzyl 2,2,2-trifluoroacetate 2,2,2-trifluoroacetate (33 mg) in N,N-dimethylformamide (2 mL) was diluted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (11 mg) obtained in the same manner as in (6) of Preparation 2, triethylamine (0.039 mL), copper(I) iodide (2.1 mg), and tetrakis(triphenylphosphine) After adding (vinyl)palladium(0) (6.4 mg), the mixture was stirred under an argon atmosphere at 90° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran=100 / 0 to 50 / 50). Isopropanol was added, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (4.1 mg). 1 H-NMR (DMSO-D6) δ: 8.43 (1H, s), 8.26-8.23 (2H, m), 7.52 (1H, t, J = 53.2 Hz), 6.60 (1H, s), 5.55 (1H, t, J = 5.7 Hz), 4.63 (2H, d, J = 5.5 Hz), 3.35-3.33 (2H, m), 2.79 (3H, s), 2.46-2.41 (1H, m), 2.23-2.16 (1H, m).

[0359] [Manufacturing Example 7] Synthesis of (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(fluoromethyl)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one (Example No. 41)

[0360] [ka]

[0361] (1) 1-(3-bromo-4-fluoro-5-(fluoromethyl)phenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0362] [ka]

[0363] To a solution of (3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)methanol (39 mg) obtained in a similar manner to Preparation Example 6 (2) in dichloromethane (2 mL), bis(2-methoxyethyl)aminosulfur trifluoride (0.013 mL) was added and stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50) to obtain the title compound (33.3 mg), which was used in the next step without measuring NMR.

[0364] (2) 1-(3-bromo-4-fluoro-5-(fluoromethyl)phenyl)-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2,2,2-trifluoroacetate

[0365] [ka]

[0366] To 1-(3-bromo-4-fluoro-5-(fluoromethyl)phenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (33.3 mg), trifluoroacetic acid (2 mL) and anisole (0.01 mL) were added, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a crude product (31.1 mg), which was used directly in the next step.

[0367] (3) (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(fluoromethyl)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0368] [ka]

[0369] To a solution of 1-(3-bromo-4-fluoro-5-(fluoromethyl)phenyl)-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2,2,2-trifluoroacetate (31 mg) in N,N-dimethylformamide (2 mL), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (11 mg) obtained in a similar manner to Production Example 2 (6), triethylamine (0.043 mL), copper (I) iodide (2.3 mg), and tetrakis (triphenylphosphine) palladium (0) (7.1 mg) were added, and the mixture was stirred under an argon atmosphere at 90 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran=100 / 0 to 50 / 50). Isopropanol was added, and the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (10.1 mg). 1 H-NMR (DMSO-D6) δ: 8.44 (1H, s), 8.40-8.36 (1H, m), 8.30-8.27 (1H, m), 7.52 (1H, t, J = 53.2 Hz), 6.64 (1H, s), 5.61 (2H, d, J = 46.7 Hz), 3.36-3.33 (2H, m), 2.80 (3H, s), 2.45-2.42 (1H, m), 2.24-2.17 (1H, m).

[0370] [Manufacturing Example 8] Synthesis of (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzonitrile (Example No. 64)

[0371] [ka]

[0372] (1) 3-Bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzamide

[0373] [ka]

[0374] To a solution of 3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzoic acid (50 mg) obtained in a similar manner to Preparation Example 6(1) in N,N-dimethylformamide (1 mL), ammonium chloride (9.7 mg), diisopropylethylamine (0.047 mL), and HATU (41 mg) were added and the mixture was stirred at room temperature for 1 day. Water was added to the reaction solution, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (45.1 mg), which was used in the next step without measuring NMR.

[0375] (2) 3-Bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzonitrile

[0376] [ka]

[0377] To a solution of 3-bromo-5-(3-(difluoromethyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorobenzamide (40.3 mg) in dichloromethane (2 mL), diazabicycloundecene (0.033 mL) and ethyl dichlorophosphate (0.017 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 50 / 50) to give the title compound (24.8 mg), which was used in the next step without measuring NMR.

[0378] (3) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorobenzonitrile 2,2,2-trifluoroacetate

[0379] [ka]

[0380] Trifluoroacetic acid (1 mL) and anisole (0.008 mL) were added to 1-(3-bromo-4-fluoro-5-(fluoromethyl)phenyl)-3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (24.8 mg), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a crude product (23.1 mg), which was used directly in the next step.

[0381] (4) (R)-5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)benzonitrile

[0382] [ka]

[0383] 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorobenzonitrile 2,2,2-trifluoroacetate (23.1 mg) in N,N-dimethylformamide (2 mL) solution, (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (8.4 mg) obtained in a similar manner to Preparation Example 2 (6), triethylamine (0.065 mL), copper (I) iodide (1.7 mg), and tetrakis (triphenylphosphine) palladium (0) (5.4 mg) were added and stirred for 2 hours under an argon atmosphere at 90 ° C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 0 / 100) to obtain the title compound (9.8 mg). 1 H-NMR (DMSO-D6) δ: 8.67-8.59 (2H, m), 8.46 (1H, s), 7.52 (1H, t, J = 53.2 Hz), 6.72 (1H, s), 3.38-3.33 (2H, m), 2.80 (3H, s), 2.45-2.44 (1H, m), 2.25-2.18 (1H, m).

[0384] [Manufacturing Example 9] Synthesis of (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(2-hydroxy-2-methylpropyl)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one (Example No. 43)

[0385] [ka]

[0386] (1) 1-(3-bromo-2-fluorophenyl)-2-methylpropan-2-ol

[0387] [ka]

[0388] A solution of methyl 2-(3-bromo-2-fluorophenyl)acetate (1.09 g) in tetrahydrofuran (7 mL) was stirred under ice cooling and an argon atmosphere, while 1 M methylmagnesium bromide in tetrahydrofuran (9.32 mL) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and after warming to room temperature, ethyl acetate was added and the mixture was separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20) to give the title compound (762 mg). 1 H-NMR (CDCl3) δ: 7.45-7.40 (1H, m), 7.21-7.17 (1H, m), 6.98-6.94 (1H, m), 2.83 (2H, d, J = 1.6 Hz), 1.33 (1H, br s), 1.24 (7H, d, J = 0.9 Hz).

[0389] (2) 1-(3-bromo-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropan-2-ol

[0390] [ka]

[0391] To a solution of 1-(3-bromo-2-fluorophenyl)-2-methylpropan-2-ol (762 mg) in tetrahydrofuran (4 mL), bispinacolatodiboron (783 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (41 mg), and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (51 mg) were added and stirred under an argon atmosphere at 80°C for 18 hours. After the reaction solution was gradually cooled to room temperature, 4,4'-di-tert-butyl-2,2'-bipyridine (41 mg) and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (51 mg) were added and stirred under an argon atmosphere at 80°C for 22 hours. The reaction mixture was gradually cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate=67 / 33) to give the title compound (1.13 g). 1 H-NMR (CDCl3) δ: 7.87 (1H, dd, J = 6.9, 1.6 Hz), 7.59 (1H, dd, J = 7.1, 1.5 Hz), 2.83 (2H, d, J = 1.6 Hz), 1.36 (1H, br s), 1.32 (12H, s), 1.24 (6H, d, J = 0.9 Hz).

[0392] (3) (3-Bromo-4-fluoro-5-(2-hydroxy-2-methylpropyl)phenyl)boronic acid

[0393] [ka]

[0394] To a solution of 1-(3-bromo-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropan-2-ol (1.13 g) in tetrahydrofuran (11 mL) and water (11 mL), 1N hydrochloric acid (2 mL) and sodium periodate (910 mg) were added and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, the layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were concentrated under reduced pressure to give the title compound (833 mg), which was used in the next step without measuring NMR.

[0395] (4) 1-(3-bromo-5-(3-(difluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)-2-methylpropan-2-ol

[0396] [ka]

[0397] To a solution of 3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (120 mg) obtained by a method similar to that of Intermediate Preparation Example 1 in N,N-dimethylformamide (4 mL), (3-bromo-4-fluoro-5-(2-hydroxy-2-methylpropyl)phenyl)boronic acid (129 mg), copper(II) acetate (65 mg), and 1,10-phenanthroline (129 mg) were added and stirred under an oxygen atmosphere at 60°C for 18 hours. The reaction mixture was gradually cooled to room temperature, and tetrahydrofuran was added. Insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel chromatography (hexane / ethyl acetate = 67 / 33) to give the title compound (62 mg). This was used in the next step without measuring NMR.

[0398] (5) 1-(5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorophenyl)-2-methylpropan-2-yl 2,2,2-trifluoroacetate 2,2,2-trifluoroacetate

[0399] [ka]

[0400] Trifluoroacetic acid (15 mL) and anisole (0.018 mL) were added to 1-(3-bromo-5-(3-(difluorophenyl)-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluorophenyl)-2-methylpropan-2-ol (62 mg), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was purified by thin-layer silica gel chromatography (hexane / ethyl acetate=67 / 33) to give the title compound (49 mg). 1 H-NMR (DMSO-D6) δ: 8.49 (1H, dd, J = 5.8, 2.8 Hz), 8.40 (1H, s), 8.08 (1H, dd, J = 5.9, 2.7 Hz), 7.49 (1H, t, J = 53.1 Hz), 3.33 (2H, s), 1.59 (7H, s).

[0401] (6) (R)-3-((5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3-(2-hydroxy-2-methylpropyl)phenyl)ethynyl)-3-hydroxy-1-methylpyrrolidin-2-one

[0402] [ka]

[0403] 1-(5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-bromo-2-fluorophenyl)-2-methylpropan-2-yl 2,2,2-trifluoroacetate 2,2,2-trifluoroacetate (24 mg) in N,N-dimethylformamide (1 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (12.7 mg) obtained in a similar manner to Production Example 2 (6), triethylamine (0.032 mL), copper (I) iodide (2.6 mg), and tetrakis(triphenylphosphine)palladium(0) (23.7 mg) and stirred for 2 hours at 90 ° C. under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and then methanol (1 mL) and potassium carbonate (63 mg) were added to the residue and stirred at room temperature for 2 hours. Ethyl acetate, tetrahydrofuran, and water were added to the reaction mixture, and the layers were separated. Sodium sulfate was added to the organic layer, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 50 / 50 to 15 / 85) to obtain the title compound (2.8 mg). 1 H-NMR (DMSO-D6) δ: 8.43 (1H, s), 8.22 (1H, dd, J = 5.7, 2.7 Hz), 8.05 (1H, dd, J = 6.1, 2.5 Hz), 7.52 (1H, t, J = 53.4 Hz), 6.61 (1H, s), 4.52 (1H, s), 3.38-3.34 (2H, m), 2.81 (3H, s), 2.79 (2H, s), 2.45-2.43 (1H, m), 2.25-2.17 (1H, m), 1.13 (6H, s).

[0404] [Intermediate Production Example 1] Synthesis of 3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0405] [ka]

[0406] (1) Butyl 4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

[0407] [ka]

[0408] To a solution of 3-bromo-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6 g) obtained in a similar manner to Preparation Example 1(1) in N,N-dimethylformamide (60 mL), 1-butyl alcohol (60 mL), triethylamine (6.89 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (1.35 g) were added and stirred under a carbon monoxide atmosphere at 110°C for 1 day. The reaction mixture was gradually cooled to room temperature and then concentrated under reduced pressure. Tetrahydrofuran was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and ethyl acetate (45 mL) was added to the residue. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (2.42 g). 1 H-NMR(DMSO-D6) δ: 14.23 (1H, s), 8.73 (1H, t, J = 6.0 Hz), 8.30 (1H, s), 7.20 (1H, d, J = 8.3 Hz), 6.59 (1H, d, J = 2.3 Hz), 6.46 (1H, dd. J = 12.4, 7.4 Hz), 0.91 (3H, t, J = 7.4 Hz).

[0409] (2) Butyl 4-((2,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate

[0410] [ka]

[0411] To a solution of butyl 4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate (2.12 g) in N,N-dimethylformamide (10 mL), p-toluenesulfonic acid hydrate (1.15 g) and 3,4-dihydro-2H-pyran (4.5 mL) were added and stirred at 85°C for 4 hours. The reaction mixture was gradually cooled to room temperature, and then ethyl acetate and water were added to separate the layers. The aqueous layer was re-extracted with ethyl acetate, and sodium sulfate was added to the combined organic layer. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 90 / 10 to 50 / 50) to give the crude title compound (3.6 g), which was used directly in the next step.

[0412] (3) (4-((2,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methanol

[0413] [ka]

[0414] To a solution of lithium aluminum hydride (218 mg) in tetrahydrofuran (5 mL) was added dropwise a solution of butyl 4-((2,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylate (1.8 g) in tetrahydrofuran (5 mL) under ice cooling and stirring under an argon atmosphere. Water (0.218 mL), 4N aqueous sodium hydroxide solution (0.218 mL), and water (0.218 mL) were added sequentially to the reaction mixture, which was then warmed to room temperature and stirred for 1 hour. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give the crude product (1.33 g) of the title compound, which was used directly in the next step.

[0415] (4) (4-((2,4-Dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)carbaldehyde

[0416] [ka]

[0417] Manganese dioxide (2.89 g) was added to a solution of (4-((2,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methanol (1.33 g) in CPME (10 mL), and the mixture was stirred at 120°C under an argon atmosphere for 2 hours and 30 minutes. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 90 / 10 to 50 / 50) to give the title compound (898 mg) as a crude product, which was used directly in the next step.

[0418] (5) 3-(Difluoromethyl)-N-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0419] [ka]

[0420] To a solution of (4-((2,4-dimethoxybenzyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)carbaldehyde (898 mg) in dichloromethane (10 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (1.29 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere for 7 hours. To the reaction solution, bis(2-methoxyethyl)aminosulfur trifluoride (0.33 mL) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for an additional 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 95 / 5 to 50 / 50) to give the title compound (467.4 mg). 1 H-NMR (DMSO-D6) δ: 8.38 (1H, s), 7.41 (1H, t, J = 53.4 Hz), 7.11 (1H, d, J = 8.3 Hz), 6.96 (1H, br s), 6.58 (1H, d, J = 2.3 Hz), 6.44 (1H, dd, J = 8.3, 2.5 Hz), 5.89 (1H, dd, J = 10.5, 2.4 Hz), 4.69 (2H, d, J = 5.8 Hz), 3.93 (1H, d, J = 12.9 Hz), 3.82 (3H, s), 3.72 (3H, s), 3.70-3.62 (2H, m), 2.39-2.31 (1H, m), 2.01-1.97 (1H, m), 1.88-1.85 (1H, m), 1.76-1.42 (7H, m).

[0421] (6) 3-(Difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0422] [ka]

[0423] 3-(Difluoromethyl)-N-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (457.4 mg) was added to 1N hydrogen chloride-dioxane solution (3 mL) and stirred at room temperature for 2 hours. 1N hydrogen chloride-dioxane solution (1 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. 1N hydrogen chloride-dioxane solution (1 mL) was further added to the reaction mixture and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture under ice cooling, and the aqueous layer was extracted twice with ethyl acetate at room temperature. The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 95 / 5 to 20 / 80) to give the title compound (107.5 mg). 1 H-NMR (DMSO-D6) δ: 8.33 (1H, s), 7.35 (1H, t, J = 53.6 Hz), 7.13 (1H, d, J = 8.3 Hz), 6.85 (1H, s), 6.80 (1H, br s), 6.58 (1H, d, J = 2.3 Hz), 6.44 (1H, dd, J = 8.3, 2.3 Hz), 4.68 (2H, d, J = 5.8 Hz), 3.82 (3H, s), 3.72 (3H, s).

[0424] [Intermediate Production Example 2] Synthesis of N-(2,4-dimethoxybenzyl)-1-(4-fluoro-3-((4-methoxybenzyl)oxy)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0425] [ka]

[0426] (1) 1-(4,6-dichloropyrimidin-5-yl)-2,2,2-trifluoroethan-1-one

[0427] [ka]

[0428] A 1M 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex solution in tetrahydrofuran (4.43 mL) was added dropwise to a 0.5M zinc(II) chloride solution in tetrahydrofuran (4.43 mL) at -78°C under a nitrogen atmosphere while stirring, and the mixture was stirred for 30 minutes. A solution of 4,6-dichloropyrimidine (300 mg) in tetrahydrofuran (3 mL) was added dropwise to the reaction mixture, and the mixture was warmed to 0°C and stirred for 30 minutes. A solution of copper(I) cyanide di(lithium chloride) complex in tetrahydrofuran (2.2 mL) was added dropwise to the reaction mixture at -20°C and stirred for 30 minutes. Trifluoroacetic anhydride (0.57 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic anhydride (0.57 mL) was then added dropwise, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5 to 70 / 30) to give the crude title compound (493 mg), which was used directly in the next step.

[0429] (2) 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine

[0430] [ka]

[0431] To a solution of 1-(4,6-dichloropyrimidin-5-yl)-2,2,2-trifluoroethan-1-one (490 mg) in tetrahydrofuran (3 mL), triethylamine (0.418 mL) and hydrazine hydrate (0.146 mL) were added under ice cooling. The mixture was warmed to room temperature and stirred for 30 minutes. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20 to 30 / 70) to give the crude title compound (140 mg), which was used directly in the next step.

[0432] (3) N-(2,4-dimethoxybenzyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0433] [ka]

[0434] To a solution of 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine (140 mg) in ethanol (3 mL), triethylamine (0.11 mL) and 2,4-dimethoxybenzylamine (0.11 mL) were added and the mixture was stirred at 90°C under a nitrogen atmosphere for 1 hour. The reaction mixture was gradually cooled to room temperature, and then ethyl acetate and saturated aqueous sodium bicarbonate were added and the mixture was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20 to 30 / 70) to give the title compound (83 mg). 1 H-NMR(DMSO-D6) δ: 14.40 (1H, s), 8.35 (1H, s), 7.08 (1H, d, J = 8.3 Hz), 6.80 (1H, s), 6.58 (1H, d, J = 2.3 Hz), 6.44 (1H, dd, J = 8.3, 2.3 Hz), 4.70 (2H, d, J = 5.8 Hz), 3.83 (3H, s), 3.72 (3H, s).

[0435] (4) N-(2,4-dimethoxybenzyl)-1-(4-fluoro-3-((4-methoxybenzyl)oxy)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0436] [ka]

[0437] To a solution of N-(2,4-dimethoxybenzyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (83 mg) in N,N-dimethylformamide (2 mL), (4-fluoro-3-((4-methoxybenzyl)oxy)phenyl)boronic acid (84 mg), copper(II) acetate (43 mg), and 1,10-phenanthroline (84 mg) were added and stirred at 60°C for 9 hours under an oxygen atmosphere. The reaction mixture was gradually cooled to room temperature, and then water, ethyl acetate, and tetrahydrofuran were added and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate and then with tetrahydrofuran. Sodium sulfate was added to the combined organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10 to 40 / 60) to give the title compound (101 mg). 1 H-NMR (DMSO-D6) δ: 8.49 (1H, s), 7.96 (1H, dd, J = 7.6, 2.5 Hz), 7.63 (1H, ddd, J = 8.8, 3.9, 2.5 Hz), 7.46-7.41 (3H, m), 7.12-7.09 (1H, m), 6.98-6.93 (3H, m), 6.61-6.59 (1H, m), 6.45 (1H, dd, J = 8.3, 2.3 Hz), 5.15 (2H, s), 4.75 (2H, d, J = 5.8 Hz), 3.85 (3H, s), 3.74 (4H, s), 3.72 (3H, s).

[0438] [Intermediate Production Example 3] Synthesis of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrobenzofuran-7-yl trifluoromethanesulfonate

[0439] [ka]

[0440] (1) 1-(furan-3-yl)-2-propyn-1-yl 2,2-dimethylbutanoate

[0441] [ka]

[0442] To a solution of furan-3-carbaldehyde (10 g) in tetrahydrofuran (100 mL) was added dropwise 0.5 M ethynylmagnesium chloride in tetrahydrofuran (243 mL) under ice cooling and stirring under a nitrogen atmosphere, followed by dropwise addition of 2,2-dimethylbutanoyl chloride (16.68 mL). Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, which was then warmed to room temperature and separated. The aqueous layer was re-extracted with ethyl acetate, and magnesium sulfate was added to the combined organic layer. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (18 g). 1 H-NMR (DMSO-D6) δ: 7.80 (1H, s), 7.69 (1H, s), 6.53 (1H, s), 6.34 (1H, s), 3.70 (1H, s), 1.51 (2H, q, J = 7.6 Hz), 1.10 (7H, s), 0.76 (3H, t, J = 7.3 Hz).

[0443] (2) 7-Hydroxybenzofuran-5-yl 2,2-dimethylbutanoate

[0444] [ka]

[0445] To a solution of 1-(furan-3-yl)-2-propyn-1-yl 2,2-dimethylbutanoate (18 g) in tetrahydrofuran (200 mL), tetracarbonyl-μ-chlororhodium(I) (796 mg) was added and stirred at room temperature under a carbon monoxide atmosphere for 2 days. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5 to 70 / 30) to give the title compound (12.1 g). 1 H-NMR (DMSO-D6) δ: 10.30 (1H, s), 7.96 (1H, s), 6.89 (1H, s), 6.77 (1H, s), 6.42 (1H, s), 1.67 (2H, q, J = 7.5 Hz), 1.25 (6H, s), 0.92 (3H, t, J = 7.5 Hz).

[0446] (3) 7-((4-methoxybenzyl)oxy)benzofuran-5-yl 2,2-dimethylbutanoate

[0447] [ka]

[0448] To a solution of 7-hydroxybenzofuran-5-yl 2,2-dimethylbutanoate (12.1 g) in acetone (150 mL), potassium carbonate (20.21 g), sodium iodide (7.31 g), and 4-methoxybenzyl chloride (9.16 g) were added and the mixture was stirred at 50°C for 2 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 97 / 3 to 80 / 20) to give the title compound (13.2 g). 1H-NMR (DMSO-D6) δ: 7.99 (1H, s), 7.43 (2H, d, J = 8.4 Hz), 6.97 (2H, d, J = 8.7 Hz), 6.93 (2H, s), 6.77 (1H, s), 5.18 (2H, s), 3.77 (3H, s), 1.69 (2H, q, J = 7.4 Hz), 1.27 (6H, s), 0.94 (3H, t, J = 7.3 Hz).

[0449] (4) 7-((4-methoxybenzyl)oxy)benzofuran-5-ol

[0450] [ka]

[0451] Potassium carbonate (14.85 g) was added to a solution of 7-((4-methoxybenzyl)oxy)benzofuran-5-yl 2,2-dimethylbutanoate (13.2 g) in methanol (130 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and 2N hydrochloric acid (16.5 mL) was added. Ethyl acetate was added and the layers were separated. The organic layer was washed with saturated brine, and sodium sulfate was added to the organic layer. The solid was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (9.2 g). 1 H-NMR (DMSO-D6) δ: 9.13 (1H, s), 7.81 (1H, s), 7.41 (2H, d, J = 7.8 Hz), 6.96 (2H, d, J = 7.2 Hz), 6.76 (1H, s), 6.51 (1H, s), 6.45 (1H, s), 5.12 (2H, s), 3.76 (3H, s).

[0452] (5) 7-((4-Methoxybenzyl)oxy)benzofuran-5-yl trifluoromethanesulfonate

[0453] [ka]

[0454] To a solution of 7-((4-methoxybenzyl)oxy)benzofuran-5-ol (9.2 g) in tetrahydrofuran (100 mL), triethylamine (9.49 mL) and N-phenyltrifluoromethanesulfonimide were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5 to 75 / 25) to give the crude title compound (16.3 g), which was used directly in the next step.

[0455] (6) 2-(7-((4-methoxybenzyl)oxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0456] [ka]

[0457] To a solution of 7-((4-methoxybenzyl)oxy)benzofuran-5-yl trifluoromethanesulfonate (15.3 g) in 1,4-dioxane (120 mL), bis-pinacolatodiboron (14.49 g), potassium acetate (7.46 g), and bis(tricyclohexylphosphine)palladium(0) (2.54 g) were added, and the mixture was stirred under a nitrogen atmosphere at 110° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5 to 70 / 30) to give the crude title compound (17.3 g), which was used directly in the next step.

[0458] (7) (7-((4-methoxybenzyl)oxy)benzofuran-5-yl)boronic acid

[0459] [ka]

[0460] To a solution of 2-(7-((4-methoxybenzyl)oxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (17.3 g) in tetrahydrofuran (70 mL) were added sodium periodate (29.2 g) and 1N hydrochloric acid (32 mL), and the mixture was stirred at room temperature for 1 day. Ethyl acetate and water were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine. Sodium sulfate was added to the organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20 to 40 / 60) to give the title compound (900 mg) as a crude product. This was used directly in the next step without measuring NMR.

[0461] (8) 3-(Difluoromethyl)-N-(2,4-dimethoxybenzyl)-1-(7-((4-methoxybenzyl)oxy)benzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0462] [ka]

[0463] To a solution of 3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (108 mg) obtained in a similar manner to Intermediate Production Example 1 in N,N-dimethylformamide (1 mL), (7-((4-methoxybenzyl)oxy)benzofuran-5-yl)boronic acid (125 mg), copper(II) acetate (58.2 mg), and 1,10-phenanthroline (116 mg) were added and stirred under an oxygen atmosphere at 60°C for 15 hours. After the reaction mixture was gradually cooled to room temperature, tetrahydrofuran was added, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / tetrahydrofuran = 100 / 0 to 0 / 100) to give the title compound (145 mg), which was used in the next step without measuring NMR.

[0464] (9) 5-(3-(difluoromethyl)-4-(2,4-dimethoxybenzyl)amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrobenzofuran-7-ol

[0465] [ka]

[0466] Palladium-carbon (26.3 mg) was added to a solution of 3-(difluoromethyl)-N-(2,4-dimethoxybenzyl)-1-(7-((4-methoxybenzyl)oxy)benzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (145 mg) in tetrahydrofuran (10 mL), and the mixture was pressurized with hydrogen to 4 atmospheres and stirred for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (114 mg) as a crude product, which was used directly in the next step.

[0467] (10) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrobenzofuran-7-ol 2,2,2-trifluoroacetate

[0468] [ka]

[0469] Trifluoroacetic acid (2 mL) and anisole (0.04 mL) were added to 5-(3-(difluoromethyl)-4-(2,4-dimethoxybenzyl)amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrobenzofuran-7-ol (114 mg), and the mixture was stirred at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, diisopropyl ether was added, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound as a crude product (55.4 mg), which was used directly in the next step.

[0470] (11) 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrobenzofuran-7-yl trifluoromethanesulfonate

[0471] [ka]

[0472] To a solution of 5-(4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrobenzofuran-7-ol 2,2,2-trifluoroacetate (55.5 mg) in tetrahydrofuran (2 mL), triethylamine (0.054 mL) and 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (75 mg) were added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 55 / 45 to 30 / 70) to obtain the title compound (57 mg). 1 H-NMR (DMSO-D6) δ: 8.40 (1H, s), 8.10 (1H, s), 8.01 (1H, s), 7.51 (1H, t, J = 53.2 Hz), 4.81 (2H, t, J = 8.7 Hz), 3.44 (3H, t, J = 8.5 Hz).

[0473] [Intermediate Production Example 4] Synthesis of 1-(1H-1,2,4-triazol-3-yl)ethan-1-one

[0474] [ka]

[0475] (1) 1-(diethoxymethyl)-1H-1,2,4-triazole

[0476] [ka]

[0477] Triethoxymethane (21.46 g) was added to 1H-1,2,4-triazole (1.0 g), and the mixture was stirred for 2 hours under an argon atmosphere at 100° C. The reaction mixture was concentrated under reduced pressure to obtain a crude product of the title compound, which was used directly in the next step.

[0478] (2) 1-(1H-1,2,4-triazol-3-yl)ethan-1-one

[0479] [ka]

[0480] To a solution of 1-(diethoxymethyl)-1H-1,2,4-triazole in tetrahydrofuran (50 mL) was added dropwise 2.65 M n-butyllithium in hexane (6.68 mL) under ice cooling and argon atmosphere while stirring. N,N-dimethylacetamide (1.63 mL) was then added dropwise and the mixture was stirred for 1 hour. 1N hydrochloric acid (17.37 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. Magnesium sulfate was added to the combined organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the resulting solid was collected by filtration and dried under reduced pressure to give the title compound (149.9 mg). 1 H-NMR (DMSO-D6) δ: 14.68 (1H, s), 8.58 (1H, s), 2.56 (3H, s).

[0481] [Intermediate Production Example 5] Synthesis of 1-(1,3,4-thiadiazol-2-yl)ethan-1-one

[0482] [ka]

[0483] (1) 2-(1-ethoxyvinyl)-1,3,4-thiadiazole

[0484] [ka]

[0485] To a solution of 2-bromo-1,3,4-thiadiazole (300 mg) in N,N-dimethylformamide (6 mL), tributyl(1-ethoxyvinyl)tin (985 mg), dichlorobis(triphenylphosphine)palladium(II) (128 mg), and tetrakis(triphenylphosphine)palladium(0) (210 mg) were added, and the mixture was stirred under an argon atmosphere at 120° C. for 10 hours. The reaction solution was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5 to 90 / 10) to give the title compound (140 mg). 1 H-NMR (CDCl3) δ: 9.07 (1H, s), 5.54 (1H, d, J = 2.8 Hz), 4.53 (1H, d, J = 3.0 Hz), 4.00 (2H, q, J = 7.0 Hz), 1.42 (3H, t, J = 6.9 Hz).

[0486] (2) 1-(1,3,4-thiadiazol-2-yl)ethan-1-one

[0487] [ka]

[0488] To a solution of 2-(1-ethoxyvinyl)-1,3,4-thiadiazole (140 mg) in tetrahydrofuran (4 mL), 2N hydrochloric acid (2 mL) was added and stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (5 mL) and triethylamine (0.15 mL) were added and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10 to 80 / 20) to give the title compound (27 mg). 1H-NMR (CDCl3) δ: 9.31 (1H, s), 2.85 (3H, s).

[0489] [Intermediate Production Example 6] Synthesis of 1-(1,3,4-oxadiazol-2-yl)ethan-1-one

[0490] [ka]

[0491] (1) 1-(1,3,4-oxadiazol-2-yl)ethan-1-ol

[0492] [ka]

[0493] To a solution of 1,3,4-oxadiazole (100 mg) in tetrahydrofuran (5 mL) was added 2.65 M n-butyllithium in hexane (0.539 mL) at -72 °C under a nitrogen atmosphere and stirred for 30 minutes. Acetaldehyde (314 mg) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 20 minutes. Acetic acid (0.098 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 67 / 33 to 0 / 100) to give the crude title compound (180 mg), which was used directly in the next step.

[0494] (2) 1-(1,3,4-oxadiazol-2-yl)ethan-1-one

[0495] [ka]

[0496] To a solution of 1-(1,3,4-oxadiazol-2-yl)ethan-1-ol (180 mg) obtained in (1) in chloroform (3.6 mL), Dess-Martin periodinane (535 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10 to 80 / 20) to give the title compound (80 mg). 1 H-NMR (CDCl3) δ: 8.55 (1H, s), 2.79 (3H, s).

[0497] [Intermediate Production Example 7] Synthesis of 1-(oxazol-2-yl)ethan-1-one

[0498] [ka]

[0499] To a solution of oxazole (1.6 mL) in tetrahydrofuran (15 mL) was added dropwise 2 M isopropylmagnesium chloride solution (12 mL) in tetrahydrofuran with stirring at -15°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. N-Methoxy-N-methylacetamide (2.04 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 1 day. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was separated. Sodium sulfate was added to the organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.938 g). 1 H-NMR (CDCl3) δ: 7.81 (1H, s), 7.32 (1H, s), 2.67 (3H, s).

[0500] [Intermediate Production Example 8] Synthesis of 3-ethynyl-3-hydroxy-1,5-dimethylpyrrolidin-2-one

[0501] [ka]

[0502] (1) tert-Butyl 3-(methylamino)butanoate

[0503] [ka]

[0504] To tert-butyl crotonate (2.67 g) was added 2 M methylamine-tetrahydrofuran solution (10.33 g), and the mixture was stirred for 5 days. The reaction mixture was concentrated under reduced pressure to give the title compound (1.26 g). 1 H-NMR (CDCl3) δ: 2.39 (3H, s), 2.29 (2H, ddd, J = 60.5, 15.0, 6.2 Hz), 1.83 (1H, dd, J = 6.8, 1.7 Hz), 1.44 (9H, s), 1.08 (3H, d, J = 6.5 Hz).

[0505] (2) tert-Butyl 3-(2-methoxy-N-methyl-2-oxoacetamido)butanoate

[0506] [ka]

[0507] To a solution of tert-butyl 3-(methylamino)butanoate (1.64 g) in tetrahydrofuran (13 mL), diisopropylethylamine (1.91 mL) was added, and methyl chloroglyoxylate (0.738 mL) was added dropwise under ice cooling and argon atmosphere while stirring. The mixture was warmed to room temperature and stirred for 1 day. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction mixture, and the layers were separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20) to give the title compound (1.76 g). 1H-NMR (CDCl3) δ: 3.86 (3H, d, J = 9.9 Hz), 2.85 (3H, d, J = 8.6 Hz), 2.55-2.35 (2H, m), 1.42 (9H, d, J = 2.1 Hz), 1.24 (3H, dd, J = 20.0, 6.8 Hz).

[0508] (3) tert-Butyl 1,2-dimethyl-4,5-dioxopyrrolidine-3-carboxylate

[0509] [ka]

[0510] To a solution of tert-butyl 3-(2-methoxy-N-methyl-2-oxoacetamido)butanoate (1.71 g) in toluene (34 mL), 20% sodium ethoxide in ethanol (2.84 g) was added and stirred at 85°C for 2 hours. After the reaction mixture was gradually cooled to room temperature, water (10 mL) and 2N hydrochloric acid (3.62 mL) were added, followed by extraction three times with ethyl acetate. Magnesium sulfate was added to the combined organic layer, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (1.336 g), which was used directly in the next step.

[0511] (4) 1,5-Dimethylpyrrolidine-2,3-dione 2,2,2-trifluoroacetate

[0512] [ka]

[0513] Trifluoroacetic acid (7 mL) was added to tert-butyl 1,2-dimethyl-4,5-dioxopyrrolidine-3-carboxylate (1.336 g) and stirred at room temperature for 30 minutes. Water (7 mL) was added to the reaction mixture, and the mixture was stirred at 75°C for 18 hours. The reaction mixture was concentrated under reduced pressure and azeotroped four times with CPME to give the crude product (1.13 g) of the title compound, which was used directly in the next step.

[0514] (5) 3-Hydroxy-1,5-dimethyl-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one

[0515] [ka]

[0516] To a solution of trimethylsilylacetylene (808 mg) in tetrahydrofuran (7 mL), 2.65 M n-butyllithium-hexane solution (3.11 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred for 15 minutes. The trimethylsilylacetylene-butyllithium reaction solution was added dropwise to a solution of 1,5-dimethylpyrrolidine-2,3-dione 2,2,2-trifluoroacetate (1.13 g) in tetrahydrofuran (10 mL) at -78°C under argon atmosphere, and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution (300 mL) and water (100 mL) were added to the reaction solution, and the mixture was warmed to room temperature. The layers were separated, and the aqueous layer was extracted twice with tetrahydrofuran. The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50 / 50) to give the title compound (513 mg). 1 H-NMR (CDCl3) δ: 3.63-3.55 (1H, m), 3.20 (1H, s), 2.86 (3H, s), 2.66 (1H, dd, J = 12.6, 5.9 Hz), 1.78 (1H, dd, J = 12.5, 8.3 Hz), 1.27 (3H, d, J = 6.5 Hz), 0.14 (9H, s).

[0517] (6) 3-ethynyl-3-hydroxy-1,5-dimethylpyrrolidin-2-one

[0518] [ka]

[0519] To a solution of 3-hydroxy-1,5-dimethyl-3-((trimethylsilyl)ethynyl)pyrrolidin-2-one (512 mg) in tetrahydrofuran (2 mL), 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.95 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 33 / 67) to give the title compound (333 mg). 1 H-NMR (CDCl3) δ: 3.65-3.57 (1H, m), 3.33 (1H, br s), 2.86 (3H, s), 2.69 (1H, dd, J = 12.7, 6.0 Hz), 2.52 (1H, s), 1.82 (1H, dd, J = 12.7, 8.1 Hz), 1.29 (3H, d, J = 6.5 Hz).

[0520] [Intermediate Production Example 9] Synthesis of (R)-2-(5-methylisoxazol-3-yl)-3-butyn-2-ol

[0521] [ka]

[0522] (1) 2-(5-methylisoxazol-3-yl)-3-butyn-2-ol

[0523] [ka]

[0524] To a solution of 1-(5-methylisoxazol-3-yl)ethan-1-one (2.5 g) in tetrahydrofuran (20 mL) was added dropwise 0.5 M ethynylmagnesium bromide in tetrahydrofuran (50 mL) under ice cooling and argon atmosphere while stirring. The reaction mixture was warmed to room temperature and stirred for 4 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and magnesium sulfate was added to the combined organic layer. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 70 / 30) to give the title compound (1.33 g), which was used in the next step without NMR analysis.

[0525] (2) 3-((R)-2-(((3aR,6aR)-3a-allylhexahydro-6aH-cyclopenta[b]furan-6a-yl)oxy)-3-butyn-2-yl)-5-methylisoxazole

[0526] [ka]

[0527] To a solution of 2-(5-methylisoxazol-3-yl)-3-butyn-2-ol (1,33 g) in tetrahydrofuran (25 mL), (R)-3a-allyl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan (3.96 g) and p-toluenesulfonic acid hydrate (168 mg) were added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 85 / 15) to give the title compound (1.154 g). 1H-NMR (CDCl3) δ: 6.09 (1H, q, J = 0.8 Hz), 5.88-5.77 (1H, m), 5.10-5.00 (2H, m), 3.73-3.66 (1H, m), 3.48-3.41 (1H, m), 2.66 (1H, s), 2.53-2.44 (1H, m), 2.39 (3H, s), 2.29 (1H, dd, J = 13.9, 7.2 Hz), 2.12 (1H, ddt, J = 13.9, 7.4, 1.2 Hz), 1.90-1.79 (6H, m), 1.68-1.55 (4H, m), 1.44-1.35 (1H, m).

[0528] (3) (R)-2-(5-methylisoxazol-3-yl)-3-butyn-2-ol

[0529] [ka]

[0530] To a solution of 3-((R)-2-(((3aR,6aR)-3a-allylhexahydro-6aH-cyclopenta[b]furan-6a-yl)oxy)-3-butyn-2-yl)-5-methylisoxazole (1.154 g) in methanol (10 mL), p-toluenesulfonic acid hydrate (70.2 mg) was added and stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 60 / 40) to give the title compound (579 mg). 1 H-NMR (CDCl3) δ: 6.09-6.08 (1H, m), 2.88-2.85 (1H, m), 2.69-2.56 (1H, m), 2.42 (3H, d, J = 0.9 Hz), 1.85 (3H, s).

[0531] [Intermediate Production Example 10] Synthesis of 7-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0532] [ka]

[0533] (1) 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0534] [ka]

[0535] To a solution of imidazole (2.0 g) in 1,4-dioxane (20 mL), acetic acid (0.12 mL) and acrolein (3.095 mL) were added, and the mixture was stirred under an argon atmosphere at 105° C. for 16 hours. The reaction mixture was gradually cooled to room temperature, and the resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.383 g). 1 H-NMR (DMSO-D6) δ: 7.04 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 1.2 Hz), 5.49 (1H, d, J = 5.8 Hz), 4.86-4.82 (1H, m), 4.05-3.98 (1H, m), 3.87-3.81 (1H, m), 2.81-2.72 (1H, m), 2.29-2.16 (1H, m).

[0536] (2) 5,6-Dihydro-7H-pyrrolo[1,2-a]imidazol-7-one

[0537] [ka]

[0538] Manganese dioxide (3.2 g) was added to a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol (0.64 g) obtained in (1) in dichloromethane (7 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through Celite, and insoluble matter was removed by washing with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (290 mg). 1 H-NMR (CDCl3) δ: 7.60 (1H, d, J = 0.7 Hz), 7.24 (1H, d, J = 0.7 Hz), 4.37 (2H, t, J = 5.9 Hz), 3.18 (2H, t, J = 5.9 Hz).

[0539] (3) 7-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol

[0540] [ka]

[0541] To a solution of 5,6-dihydro-7H-pyrrolo[1,2-a]imidazol-7-one (290 mg) in tetrahydrofuran (7 mL), 0.5 M ethynylmagnesium bromide in tetrahydrofuran (7.12 mL) was added dropwise under ice cooling and argon atmosphere. The reaction mixture was warmed to room temperature and stirred for 2 hours, after which acetic acid (0.204 mL) was added. The reaction mixture was filtered through Celite, and the insoluble matter was washed with a chloroform / methanol = 80 / 20 mixed solution. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol = 90 / 10) to give the title compound (185 mg). 1 H-NMR (CDCl3) δ: 7.11 (1H, d, J = 1.4 Hz), 6.83 (1H, d, J = 1.4 Hz), 4.16-3.96 (2H, m), 3.10-2.91 (2H, m), 2.55 (1H, s).

[0542] Other example compounds were obtained by the above-mentioned production methods, production examples, intermediate production examples, or methods similar thereto, or by combining known methods as necessary. The structural formulas and physical property data of the compounds of Examples 1 to 71 are shown below.

[0543] [Table 1]

[0544] [Table 2]

[0545] [Table 3]

[0546] [Table 4]

[0547] [Table 5]

[0548] [Table 6]

[0549] [Table 7]

[0550] [Table 8]

[0551] [Table 9]

[0552] [Table 10]

[0553] [Table 11]

[0554] [Table 12]

[0555] [Table 13]

[0556] [Table 14]

[0557] [Table 15]

[0558] [Table 16]

[0559] [Table 17]

[0560] Test Example 1: Evaluation of human NF-κB-inducing kinase inhibitory activity The method for evaluating the human NIK enzyme inhibitory activity by the Alpha Screen method using the phosphorylation of the substrate IKKα as an indicator is shown below.

[0561] Dimethyl sulfoxide or test compound solution diluted with Reaction Buffer (50 mM Tris-HCl pH 7.5, 2 mM DTT, 0.1% BSA, 150 mM NaCl, 0.01% Tween-20, 10 mM MgCl2) was added to a 96-well half-area plate (white flat bottom, non-binding surface, Corning) at 3 μL / well (final concentration of 0.5% dimethyl sulfoxide). Subsequently, 6 μL / well of Reaction Buffer containing NIK / MAP3K14 (Carna Biosciences, final concentration 0.04 nM) and biotinylated IKKα (Carna Biosciences, final concentration 7.5 nM) was added to all wells. Furthermore, Reaction Buffer was added to blank wells, and Reaction Buffer containing ATP (final concentration 1.9 μM) was added to vehicle-treated and test compound-treated wells at 6 μL / well. The enzyme reaction was carried out at room temperature for 1 hour. Anti-Phospho-IKK-α / β (Ser176 / 180) antibody (Cell Signaling Technology) diluted 250-fold in Stop Buffer (50 mM Tris-HCl pH 7.5, 2 mM DTT, 0.1% BSA, 150 mM NaCl, 0.01% Tween-20, 20 mM EDTA) was added at 15 μL / well and incubated at room temperature for 1 hour. Protein A Acceptor Beads (PerkinElmer) adjusted to 80 μg / mL in Stop Buffer were added at 15 μL / well and incubated at room temperature for 30 minutes. Streptavidin-coated Donor Beads (PerkinElmer) adjusted to 80 μg / mL in Stop Buffer were then added at 15 μL / well. After incubation at room temperature for 2 hours, luminescence was detected using an Enspire multimode plate reader (PerkinElmer). The inhibition rate of each test compound concentration was calculated using the following formula:

[0562]

number

[0563] IC of test compound 50 The value (50% inhibitory concentration) was calculated by fitting the inhibition rate of each test compound concentration to a logistic curve.

[0564] The evaluation results for each test compound are shown in the table below.

[0565] [Table 18]

[0566] Examples of the formulation of the present invention include the following formulations, but the present invention is not limited to these formulation examples.

[0567] Formulation Example 1 (Capsule Production) 1) 30 mg of the compound of Example 1 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0568] Formulation Example 2 (Tablet Production) 1) 10 g of the compound of Example 1 2) Lactose 50 g 3) 15g corn starch 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amount of 1), 2), and 3) and 30 g of 4) are mixed with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and compressed into tablets using a tablet press. 1,000 tablets containing 10 mg of the compound of Example 1 per tablet are thus obtained. [Industrial Applicability]

[0569] Compound [I] of the present invention or a pharmaceutically acceptable salt thereof is useful for the treatment and / or prevention of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, cancer (preferably Hodgkin's lymphoma, acute myeloid leukemia, and melanoma), etc.

[0570] This application is based on patent application No. 2024-123019 filed in Japan on July 30, 2024, the contents of which are incorporated in their entirety herein.

Claims

1. A compound of formula [I] or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In formula [I], R 1a teeth, (1) Hydrogen, (2) Fluorine, (3) C optionally substituted with 1 to 3 halogens 1-4 alkyl, or (4) Benzyl and R 1b teeth, (1) Hydrogen, or (2) Fluorine and R 2 teeth, (1) Hydrogen, (2) halogens, (3) Cyano, (4) C optionally substituted with hydroxy or halogen 1-4 alkyl, or (5) -CONHW 1 (where, the W 1 is hydrogen, methyl, or ethyl) and R 3 is a halogen, or R 2 and R 3 together with the benzene ring to which they are attached, form the formula [II]: 【Chemistry 2】 and R 4 is methyl, and R 5 teeth, (1) A 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (wherein the heteroaryl may be substituted with methyl); or (2) Vinyl or R 4 and R 5 taken together with the carbon atom to which they are attached, form the formula [III] or [IV]: 【Transformation 3】 (Where, 2 and W 3 are each independently (1) Hydrogen, or (2) Methyl is) A group represented by the formula:

2. R 2 but, (1) Hydrogen, (2) halogens, (3) Cyano, (4) C optionally substituted with hydroxy or halogen 1-4 alkyl, or (5) -CONHW 1 (where, the W 1 is hydrogen, methyl, or ethyl) and R 3 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein is halogen.

3. R 2 and R 3 together with the benzene ring to which they are attached, form the formula [II]: 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula:

4. R 4 is methyl, and R 5 but, (1) A 5-membered heteroaryl containing, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen atoms as ring-constituting atoms (wherein the heteroaryl may be substituted with methyl); or (2) Vinyl 4. The compound according to claim 1, wherein:

5. R 4 and R 5 together with the carbon atom to which they are attached, form the formula [III] or [IV]: 【Transformation 5】 (Where, 2 and W 3 are each independently (1) Hydrogen, or (2) Methyl is) The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which forms a group represented by the following formula:

6. R 1a is fluorine, and R 1b The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. R 1a is hydrogen, and R 1b The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein is fluorine.

8. The following structural formula: 【Transformation 6】 2. The compound of claim 1, selected from the group consisting of compounds having the formula:

9. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. 9. An NF-κB-inducing kinase inhibitor, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. A therapeutic or preventive agent for a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

12. A method for inhibiting NF-κB-inducing kinase in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

13. A method for treating or preventing a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

14. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of an NF-κB-inducing kinase inhibitor.

15. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer.

16. 10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in inhibiting NF-κB-inducing kinase.

17. 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of systemic lupus erythematosus, Sjogren's syndrome, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, osteoporosis, acute kidney injury, hepatitis, fatty liver, obesity, type 2 diabetes, and cancer.

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