Pyridazine compound and pharmaceutical use thereof

Abstract

The present invention provides a compound having inhibitory activity against a Mas-related G protein-coupled receptor X2. The present invention provides a compound having the following structural formula or the like, or a pharmaceutically acceptable salt thereof.

Description

Pyridazinone compounds and their medical uses

[0001] The present invention relates to a pyridazinone compound or a pharmaceutically acceptable salt thereof having inhibitory activity against Mas-related G protein-coupled receptor X2, a pharmaceutical composition containing the same, and medical uses thereof.

[0002] Mas-related G protein-coupled receptors (MRGPRs) are a group of orphan receptors. Four MRGPRX receptors are expressed in humans (MRGPRX1, MRGPRX2, MRGPRX3, and MRGPRX4). In humans, MRGPRX2 is highly expressed in mast cells, and in mouse mast cells, mrgprb2 is the functional equivalent (Non-Patent Documents 1 and 2).

[0003] Mast cells are innate immune cells that are primarily present in sites exposed to the external environment, such as the skin, oral / gastrointestinal mucosa, and respiratory tract. Mast cells express multiple receptors that respond to mechanical and chemical stimuli. Classically, upon activation by immunoglobulin E (IgE), mast cells release preformed mediators (e.g., histamine, proteases, and heparin) as well as newly synthesized mediators (e.g., thromboxane, prostaglandin D2, leukotriene C4, tumor necrosis factor α, eosinophil chemotactic factor, and platelet-activating factor). Mast cells can also be activated by IgE-independent stimuli mediated by MRGPRX2 and mrgprb2 (Non-Patent Document 1). Specifically, MRGPRX2 and mrgprb2 are sensitive to a variety of ligands, including basic secretagogues (e.g., cationic small molecules such as compound 48 / 80, ciprofloxacin, atracurium, tubocurarine, rocuronium, and succinylcholine chloride), certain drugs (e.g., cationic peptide drugs), neuropeptides (e.g., substance P), and antimicrobial peptides, and mast cells release preformed and newly synthesized mediators upon IgE-independent stimulation, similar to when activated by IgE (Non-Patent Document 1).

[0004] For example, histamine dilates postcapillary venules, activates the endothelium, and increases vascular permeability. This leads to the migration of other inflammatory cells to the release site, causing local edema, heat, and redness. Furthermore, histamine contributes to neuronal sensitization, which leads to pain or itch. Tumor necrosis factor-α also enhances inflammation in inflammatory diseases. Therefore, MRGPRX2 and mrgprb2 play an important role in the development of non-IgE-mediated pseudoallergic reactions (e.g., small molecule-induced anaphylactoid drug responses, anaphylactic shock, etc.), pain, itch, and inflammation (Non-Patent Document 1). Therefore, MRGPRX2 and mrgprb2 are thought to contribute to the pathogenesis of pseudoallergic reactions, atopic dermatitis, chronic urticaria, contact dermatitis, rosacea, rheumatoid arthritis, and inflammatory bowel disease through mast cell activation (Non-Patent Documents 1 and 3).

[0005] In addition, it has been reported that postoperative pain is alleviated in an inflammatory pain model using mrgprb2-deficient mice (Non-Patent Document 4). Furthermore, elevated concentrations of substance P have been confirmed in the serum of patients with cold-induced urticaria (Non-Patent Document 5). Furthermore, it has been shown that the chemokine CXCL14, whose expression is significantly increased in patients with idiopathic pulmonary fibrosis, potently and selectively activates MRGPRX2 (Non-Patent Document 6).

[0006] In addition, in a mouse vitiligo model, the tail skin of mrgprb2-deficient mice showed significantly lower levels of IFNγ and CD8, suggesting a relationship with vitiligo, compared with wild-type mice. ＋ It has been reported that T cell infiltration is suppressed (Non-Patent Document 7).

[0007] It is also known that the expression of antimicrobial peptides that act as ligands for MRGPRX2 increases in the gingiva of patients with periodontal disease, and it has been revealed that the number of mast cells expressing MRGPRX2 increases in the gingiva of patients with chronic periodontal disease (Non-patent Document 8).

[0008] Furthermore, increased expression of the MRGPRX2 gene has been observed in the descending colon mucosa of patients with irritable bowel syndrome (Non-Patent Document 9).

[0009] Furthermore, in an MRGPRX2 knock-in mouse model under the induction of interstitial cystitis / bladder pain syndrome, it has been shown that MRGPRX2 inhibition alleviates bladder disease (Non-Patent Document 10).

[0010] Therefore, by regulating (inhibiting) the action of MRGPRX2, it becomes possible to treat pseudoallergic reactions, atopic dermatitis, chronic urticaria (particularly chronic idiopathic urticaria), irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis, as well as other MRGPRX2-dependent diseases (Non-Patent Documents 1 and 3).

[0011] Cells. 2021 Oct 27;10(11):2906.Biochem Biophys Res Commun. 2006 Nov 3;349(4):1322-8.J Allergy Clin Immunol. 2021 Aug;148(2):293-308.Neuron. 2019 Feb 6;101(3):412-420.e3.J Invest Dermatol. 2014 Nov;134(11):2833-2836.Commun Biol. 2024 Jan 6;7(1):52.Chin Med J (Engl). 2024 Sep 30.Infect Immun. 2017 Sep 20;85(10):e00246-17Neurogastroenterol Motil. 2019 Jun;31(6):e13579.Res Sq. 2025 Mar 17:rs.3.rs-6221928.

[0012] The present invention provides a pyridazinone compound or a pharmaceutically acceptable salt thereof having inhibitory activity against Mas-related G protein-coupled receptor X2, a pharmaceutical composition containing the same, and medical uses thereof.

[0013] The present invention includes the following aspects.

[0014] [Item 1] A compound of formula [III] or a pharmaceutically acceptable salt thereof.

[0015]

[0016] {In the formula [III], X represents a halogen; R １ ' is the formula (1):

[0017]

[0018] (where R １ａ ' is (a) hydrogen, (b) C １－４ (c) alkyl, or (d) cyano, and R １ｂ ' is (a) C optionally substituted with 1 to 3 halogens １－４ alkyl, or (b) C ３－４ (2) a group represented by -SO ２ W' (where W' is: (a) C １－４ alkyl, (b) C １－４ C optionally substituted with alkyl ３－４ (c) phenyl optionally substituted with one or two halogen atoms), (3) C ３－４ cycloalkyl, or (4) bicyclo[1.1.1]pentan-1-yl; and Cy represents (1) a group of the formula:

[0019]

[0020] (where R ２ ' is (a) hydrogen, (b) C optionally substituted with 1 to 5 halogens １－４ alkyl, (c) C ３－４ cycloalkyl, or (d) -CH ２ CH ２ NHCOCH ３ indicates; R ３ is (a) hydrogen, or (b) C optionally substituted with 1 to 3 halogens １－４ alkyl; and R ４ ', R ５ ', R ６ ', and R ７ ' are each independently (a) hydrogen, (b) halogen, or (c) C １－４ represents alkyl; or R ２ ' and R６ R' together with the carbon atoms to which they are attached form a cyclopentane fused to an azetidine; or R ２ ' and R ４ ', taken together with the carbon atom to which they are attached, form a cyclopentane spiro-linked to the azetidine), or (2) a group of the formula:

[0021]

[0022] (where R ８ is (a) hydrogen, (b) phenyl, (c) C optionally substituted by hydroxy １－４ alkyl, or (d) -COOCH ３ indicates; R ９ is (a) hydrogen, (b) phenyl, or (c) -COOCH ２ CH ３ and R １０ is (a) hydrogen, (b) hydroxy, or (c) C optionally substituted by 1 to 3 Ts. １－４ alkyl (wherein each T is independently hydroxy or halogen), and R １１ is a halogen; or R １０ and R １１ are taken together with the carbon atom to which they are attached to form a C 1 which is spiro-bonded to the pyrrolidine, and which may be further substituted with 1 to 4 halogen atoms in addition to two fluorine atoms. ３－４ It represents a group represented by the formula:

[0023] [Item 2] The compound according to Item 1, which is represented by formula [I], or a pharmaceutically acceptable salt thereof.

[0024]

[0025] {In formula [I], X represents a halogen; R １ is (1) Equation:

[0026]

[0027] (where R １ａrepresents (a) hydrogen, (b) methyl, or (c) cyano; R １ｂ (a) C optionally substituted with 1 to 3 halogens １－４ (b) a group represented by the formula (2) -SO ２ W (where W is: (a) C １－４ (b) alkyl, (b) cyclopropyl which may be substituted with methyl, or (c) phenyl which may be substituted with 1 or 2 halogens), (3) cyclopropyl, or (4) bicyclo[1.1.1]pentan-1-yl; R ２ (1) hydrogen, (2) C optionally substituted with 1 to 5 halogens １－４ alkyl, (3) cyclopropyl, or (4) -CH ２ CH ２ NHCOCH ３ indicates; R ３ is (1) hydrogen, or (2) C optionally substituted with 1 to 3 halogens １－４ alkyl; and R ４ , R ５ , R ６ , and R ７ each independently represents (1) hydrogen, (2) halogen, or (3) methyl; or R ２ and R ６ taken together with the carbon atoms to which they are attached form a cyclopentane fused to an azetidine; or R ２ and R ４ taken together with the carbon atom to which they are attached form a cyclopentane spiro-linked to the azetidine.

[0028] [Section 3] R １ ', but the expression:

[0029]

[0030] (In the formula, R １ａ ' and R １ｂ Item 2. The compound according to Item 1, wherein R is a group represented by the formula: R 1 ' has the same meaning as in Item 1, or a pharmaceutically acceptable salt thereof.

[0031] [Section 4] R １ａ Item 4. The compound or a pharmaceutically acceptable salt thereof according to Item 3, wherein R is cyano.

[0032] [Section 5] R １ 'But, -SO ２ Item 2. The compound according to item 1, wherein W' is W' (wherein W' has the same meaning as in item 1), or a pharmaceutically acceptable salt thereof.

[0033] [Section 6] R ４ ', R ５ ', R ６ ', and R ７ Item 6. The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 and 3 to 5, wherein each of the ' is independently (1) hydrogen, (2) fluorine, or (3) methyl.

[0034] [Item 7] The following structural formula:

[0035]

[0036] [Item 8] A pharmaceutical composition comprising the compound according to any one of items 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] [Item 9] A Mas-related G protein-coupled receptor X2 antagonist comprising the compound according to any one of items 1 to 7 or a pharmaceutically acceptable salt thereof.

[0038] [Item 10] A therapeutic or preventive agent for a disease selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis, comprising the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof.

[0039] [Item 11] The treatment or prevention agent according to Item 10, wherein the chronic urticaria is chronic idiopathic urticaria.

[0040] [Item 12] A method for inhibiting Mas-related G protein-coupled receptor X2 in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof.

[0041] [Item 13] A method for treating or preventing a disease selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis in a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof.

[0042] [Item 14] The method according to Item 13, wherein the chronic urticaria is chronic idiopathic urticaria.

[0043] [Item 15] Use of the compound according to any one of items 1 to 7 or a pharmaceutically acceptable salt thereof for the production of a Mas-related G protein-coupled receptor X2 antagonist.

[0044] [Item 16] Use of the compound according to any one of Items 1 to 7 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 pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis.

[0045] [Item 17] The use according to Item 16, wherein the chronic urticaria is chronic idiopathic urticaria.

[0046] [Item 18] The compound according to any one of items 1 to 7 or a pharmaceutically acceptable salt thereof for use in inhibiting Mas-related G protein-coupled receptor X2.

[0047] [Item 19] The compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis.

[0048] [Item 20] The compound or a pharmaceutically acceptable salt thereof according to Item 19, wherein the chronic urticaria is chronic idiopathic urticaria.

[0049] The compound [III] of the present invention or a pharmaceutically acceptable salt thereof has an inhibitory activity against Mas-related G protein-coupled receptor X2, and is therefore useful for the treatment and / or prevention of pseudoallergy, atopic dermatitis, chronic urticaria (particularly chronic idiopathic urticaria), contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, etc.

[0050] The definitions of terms used in the present invention are as follows.

[0051] In the chemical formula:

[0052]

[0053] The wavy line represented by indicates the bonding site of the structure or group represented by the chemical formula.

[0054] "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 -CD ３ Another preferred "C １－４ "Alkyl" means methyl, -CD ３ , ethyl, or isopropyl. １－４"Alkyl" means methyl, -CD ３ , or ethyl.

[0055] "C ３－４ "Cycloalkane" means a saturated hydrocarbon having 3 or 4 carbon atoms in a single ring. ３－４ "Cycloalkyl" refers to the C ３－４ It means a monovalent group obtained by removing one hydrogen atom from a cycloalkane. ３－４ "Cycloalkyl" includes cyclopropyl and cyclobutyl. ３－４ "Cycloalkyl" is cyclopropyl.

[0056] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred "halogen" is fluorine, chlorine, or bromine.

[0057] The expression "α may be substituted" with β means that α is unsubstituted or any substitutable hydrogen of α is substituted 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.

[0058] A "pharmaceutically acceptable salt" may be any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, organic acids, inorganic bases, and organic bases. 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, pp. 1-19 (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, pp. 6665-6672 (2007). Pharmaceutically acceptable salts can be obtained by reacting a compound represented by formula [III] with an inorganic acid, organic acid, inorganic base, or organic base according to a method known per se.

[0059] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid.

[0060] Examples of 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 nitric acid, 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.

[0061] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium.

[0062] Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0063] Preferred embodiments of "pharmaceutically acceptable salts" are as follows. Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or 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, or 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.

[0064] The compound of formula [III] or a pharmaceutically acceptable salt thereof may exist as a solvate. A "solvate" is a compound of formula [III] or a pharmaceutically acceptable salt thereof in which solvent molecules are coordinated, and also includes hydrates. The solvate is preferably a pharmaceutically acceptable solvate, and examples thereof include a hydrate, ethanol solvate, and dimethyl sulfoxide solvate of the compound of formula [III] or a pharmaceutically acceptable salt thereof.

[0065] Specifically, the solvates include the hemihydrate, monohydrate, dihydrate, and monoethanolate of the compound of formula [III], or the monohydrate of the sodium salt of the compound of formula [III], the 2 / 3 ethanolate of the dihydrochloride, etc. These solvates can be obtained according to known methods.

[0066] The compounds of formula [III] may exist as tautomers, in which case the compounds of formula [III] may exist as individual tautomers or as a mixture of tautomers.

[0067] The compound of formula [III] may have a carbon-carbon double bond, and in that case, the compound of formula [III] may exist as an E-isomer, a Z-isomer, or a mixture of the E-isomer and the Z-isomer.

[0068] The compound of formula [III] may have stereoisomers that should be recognized as cis / trans isomers, and in that case, the compound of formula [III] may exist as a cis isomer, a trans isomer, or a mixture of cis and trans isomers.

[0069] The compound of formula [III] may have one or more asymmetric carbon atoms, in which case the compound of formula [III] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0070] The compounds of formula [III] may exist as atropisomers, in which case the compounds of formula [III] may exist as individual atropisomers or mixtures of atropisomers.

[0071] The compound of formula [III] may simultaneously contain multiple structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0072] In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned possible isomers unless otherwise noted.

[0073] 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.

[0074] 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, 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.

[0075] 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.

[0076] The compound of formula [III] is an isotope ( 2 H (D), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 18 O. 18 F, 35 S, 123Isotopically labeled compounds of formula [III] may be labeled with an isotopically labeled compound (e.g., -I). For example, if the compound of formula [III] 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 [III] 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 [III] can be prepared according to known methods or the methods described herein, using an isotopically labeled compound instead of a non-isotopically labeled compound.

[0077] The compound of formula [III] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of formula [III] or a pharmaceutically acceptable salt thereof, more preferably a compound of formula [III] or a pharmaceutically acceptable salt thereof purified to a purity of 80% or more.

[0078] The pharmaceutical composition of the present invention may be prepared by appropriately mixing the compound of formula [III] 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 [III] 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.

[0079] The dosage form of the pharmaceutical composition containing the compound of formula [III] 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.

[0080] 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, sweeteners, etc. may be used, if necessary.

[0081] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of "disintegrants" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose. Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of "flow agents" include light anhydrous silicic acid and magnesium stearate. Examples of "lubricants" include magnesium stearate, calcium stearate, and talc. 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, etc. Examples of "suspending agents" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, glycerin monostearate, etc. Examples of "isotonic agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, etc. Examples of "buffering agents" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, etc. Examples of "soothing agents" include benzyl alcohol, etc.Examples of the "base" 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 esters thereof, 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 (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, 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 "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc. Examples of "antioxidants" include sodium sulfite, ascorbic acid, etc. Examples of "coloring agents" include food dyes (Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, etc. Examples of "sweeteners" include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

[0082] 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 [III] 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 [III], which is the active ingredient. These amounts can be administered in one or several divided doses.

[0083] The compound of formula [III] or a pharmaceutically acceptable salt thereof has an inhibitory effect on Mas-associated G protein-coupled receptor X2, and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating the activity of Mas-associated G protein-coupled receptor X2, such as diseases selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, contact dermatitis, rosacea, rheumatoid arthritis, and inflammatory bowel disease.

[0084] "Inhibiting Mas-related G protein-coupled receptor X2" means inhibiting the signaling of Mas-related G protein-coupled receptor X2 and eliminating or attenuating its function, and for example means inhibiting the signaling of Mas-related G protein-coupled receptor X2 under the conditions of Test Example 1 described below. "Inhibiting Mas-related G protein-coupled receptor X2" preferably means "inhibiting human Mas-related G protein-coupled receptor X2." Signaling inhibition or elimination or attenuation of function is preferably performed for clinical applications in humans.

[0085] The "Mas-related G protein-coupled receptor X2 antagonist" may be any substance that inhibits Mas-related G protein-coupled receptor X2, and may be a low molecular weight compound, a nucleic acid, a polypeptide, a protein, an antibody, a vaccine, etc. The "Mas-related G protein-coupled receptor X2 antagonist" is preferably a "human Mas-related G protein-coupled receptor X2 antagonist."

[0086] As used herein, "treatment" includes alleviation of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence.

[0087] As used herein, "prevention" means suppressing the onset of symptoms.

[0088] A preferred specific embodiment of the active ingredient in the Mas-related G protein-coupled receptor X2 antagonist or pharmaceutical composition of the present invention is a compound of formula [III] or a pharmaceutically acceptable salt thereof.

[0089] An example of a preferred embodiment of each substituent of the compound of formula [III] is shown below.

[0090] X is preferably chlorine, bromine, or iodine, more preferably bromine.

[0091] R １ ' is preferably of the formula:

[0092]

[0093] (where R １ａ ' is (a) hydrogen, (b) C １－４ (c) alkyl, or (d) cyano, and R １ｂ ' is (a) C optionally substituted with 1 to 3 halogens １－４ alkyl, or (b) C ３－４ It is a group represented by the formula (representing cycloalkyl).

[0094] R １ａ is preferably cyano.

[0095] R １ｂ ' is preferably C ３－４ It is cycloalkyl, more preferably cyclopropyl.

[0096] Cy is preferably a group of the formula:

[0097]

[0098] (where R ２ ' is (a) hydrogen, (b) C optionally substituted with 1 to 5 halogens １－４ alkyl, (c) C ３－４ cycloalkyl, or (d) -CH ２ CH ２ NHCOCH ３ indicates; R ３ is (a) hydrogen, or (b) C optionally substituted with 1 to 3 halogens １－４ alkyl; and R ４ ', R ５ ', R ６ ', and R ７ ' are each independently: (a) hydrogen, (b) halogen, or (c) C １－４ alkyl; or R２ ' and R ６ R' together with the carbon atoms to which they are attached form a cyclopentane fused to an azetidine; or R ２ ' and R ４ ', taken together with the carbon atom to which they are attached, form a cyclopentane spiro-linked to the azetidine.

[0099] R ２ ' is preferably C optionally substituted with 1 to 5 halogen atoms. １－４ R is alkyl, and more preferably trifluoromethyl. ３ is preferably C optionally substituted with 1 to 3 halogens １－４ R is alkyl, and more preferably trifluoromethyl. ４ R' is preferably hydrogen. ５ R' is preferably hydrogen. ６ R' is preferably hydrogen. ７ ' is preferably hydrogen.

[0100] A preferred embodiment of the compound of formula [III] is a compound of formula [I]:

[0101]

[0102] {In formula [I], X represents a halogen; R １ is (1) Equation:

[0103]

[0104] (where R １ａ represents (a) hydrogen, (b) methyl, or (c) cyano, and R １ｂ (a) C optionally substituted with 1 to 3 halogens １－４ (b) a group represented by the formula (2) -SO ２ W (where W is: (a) C １－４(b) alkyl, (b) cyclopropyl which may be substituted with methyl, or (c) phenyl which may be substituted with 1 or 2 halogens), (3) cyclopropyl, or (4) bicyclo[1.1.1]pentan-1-yl; R ２ (1) hydrogen, (2) C optionally substituted with 1 to 5 halogens １－４ alkyl, (3) cyclopropyl, or (4) -CH ２ CH ２ NHCOCH ３ indicates; R ３ is (1) hydrogen, or (2) C optionally substituted with 1 to 3 halogens １－４ alkyl, ４ , R ５ , R ６ , and R ７ each independently represents (1) hydrogen, (2) halogen, or (3) methyl; or R ２ and R ６ taken together with the carbon atoms to which they are attached form a cyclopentane fused to an azetidine; or R ２ and R ４ taken together with the carbon atom to which they are attached form a cyclopentane spiro-linked to the azetidine.} or a pharmaceutically acceptable salt thereof.

[0105] A more preferred embodiment of the compound of formula [III] is a compound of formula [II]:

[0106]

[0107] [In formula [II], X represents a halogen; R １ is (1) Equation:

[0108]

[0109] (where R １ａ represents (a) hydrogen, (b) methyl, or (c) cyano, and R １ｂ (a) C optionally substituted with 1 to 3 halogens １－４(b) a group represented by the formula (2) -SO ２ W (where W is: (a) C １－４ (b) alkyl, (b) cyclopropyl which may be substituted with methyl, or (c) phenyl which may be substituted with 1 or 2 halogens), (3) cyclopropyl, or (4) bicyclo[1.1.1]pentan-1-yl; R ２ (1) hydrogen, (2) C optionally substituted with 1 to 5 halogens １－４ alkyl, (3) cyclopropyl, or (4) -CH ２ CH ２ NHCOCH ３ indicates; R ３ is (1) hydrogen, or (2) C optionally substituted with 1 to 3 halogens １－４ alkyl; and R ４ , R ５ , R ６ , and R ７ each independently represents (1) hydrogen, (2) halogen, or (3) methyl; or R ２ and R ６ taken together with the carbon atoms to which they are attached form a cyclopentane fused to an azetidine; or R ２ and R ４ taken together with the carbon atom to which they are attached form a cyclopentane spiro-linked to the azetidine, or a pharmaceutically acceptable salt thereof.

[0110] A further preferred embodiment of the compound of formula [III] is a compound of formula [V]:

[0111]

[0112] [In formula [V], X represents a halogen; R １ａ represents (1) hydrogen, (2) methyl, or (3) cyano; R １ｂ (1) C optionally substituted with 1 to 3 halogens １－４ (2) alkyl, or (3) cyclopropyl; ２(1) hydrogen, (2) C optionally substituted with 1 to 5 halogens １－４ alkyl, (3) cyclopropyl, or (4) -CH ２ CH ２ NHCOCH ３ and R ３ is (1) hydrogen, or (2) C optionally substituted with 1 to 3 halogens １－４ or a pharmaceutically acceptable salt thereof.

[0113] Another preferred embodiment of the compound of formula [III] is a compound of formula [IV]:

[0114]

[0115] [In formula [IV], X represents a halogen; R １ is (1) Equation:

[0116]

[0117] (where R １ａ represents (a) hydrogen, (b) methyl, or (c) cyano, and R １ｂ (a) C optionally substituted with 1 to 3 halogens １－４ (b) a group represented by the formula (2) -SO ２ W (where W is: (a) C １－４ (b) alkyl, (b) cyclopropyl which may be substituted with methyl, or (c) phenyl which may be substituted with 1 or 2 halogens), (3) cyclopropyl, or (4) bicyclo[1.1.1]pentan-1-yl; R ８ is (a) hydrogen, (b) phenyl, (c) C optionally substituted by hydroxy １－４ alkyl, or (d) -COOCH ３ indicates; R ９ is (a) hydrogen, (b) phenyl, or (c) -COOCH ２ CH ３ and R １０is (a) hydrogen, (b) hydroxy, or (c) C optionally substituted by 1 to 3 Ts. １－４ alkyl (wherein each T is independently hydroxy or halogen), and R １１ is a halogen; or R １０ and R １１ are taken together with the carbon atom to which they are attached to form a C 1 which is spiro-bonded to the pyrrolidine, and which may be further substituted with 1 to 4 halogen atoms in addition to two fluorine atoms. ３－４ or a pharmaceutically acceptable salt thereof.

[0118] Preferred specific embodiments of the compound of formula [III] include, for example, the compounds of Examples 1 to 217 shown in Tables 1 to 36 below.

[0119] A more preferred embodiment of the compound of formula [III] is a compound represented by the following structural formula:

[0120]

[0121] or a pharmaceutically acceptable salt thereof.

[0122] [General methods for producing compounds of formula [III] or pharmaceutically acceptable salts thereof] General methods for producing compounds of formula [III] or pharmaceutically acceptable salts thereof are exemplified below. However, the methods for producing compounds of formula [III] or pharmaceutically acceptable salts thereof are not limited to these methods. Furthermore, unless otherwise specified, the salts of each compound in the general methods can be appropriately selected from the above-mentioned "pharmaceutically acceptable salts".

[0123] 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, they can be used to proceed to the next step without isolation and / or purification.

[0124] In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is a temperature of 1°C to 40°C.

[0125] [Production Method A1]: Production Method of Compound [I-1] or a Salt Thereof Among the compounds of formula [III] (hereinafter also referred to as "compound [III]") or salts thereof, in the compound represented by formula [I], R １ But CHR １ａ R １ｂ In the case where the compound [I-1] or a salt thereof is:

[0126]

[0127] [In the formula, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X are as defined above, L 1 is a suitable leaving group (e.g., bromo, iodo, or trifluoromethanesulfonyloxy).

[0128] (Step A1-1) The compound [A1-3] or a salt thereof can be produced by reacting the compound [A1-1] or a salt thereof with the compound [A1-2] or a salt thereof in a solvent in the presence of a base.

[0129] Examples of the solvent include amide solvents such as N,N-dimethylformamide, sulfoxide solvents such as dimethyl sulfoxide, nitrile solvents such as acetonitrile, and mixed solvents thereof. Preferred are amide solvents such as N,N-dimethylformamide.

[0130] Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, etc. A preferred base is potassium carbonate.

[0131] The reaction temperature is, for example, 0°C to 130°C, preferably 20°C to 80°C.

[0132] The compound [A1-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0133] The compound [A1-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method, or may be prepared, for example, by the below-described Intermediate Preparation Example S1.

[0134] (Step A1-2) Compound [I-1] or a salt thereof can be produced by reacting compound [A1-3] or a salt thereof with compound [A1-4] or a salt thereof in a solvent in the presence of a base.

[0135] Examples of the solvent include amide solvents such as N,N-dimethylformamide and N-methylpyrrolidone, sulfoxide solvents such as dimethyl sulfoxide, alcohol solvents such as ethanol, and mixed solvents thereof. Preferred are amide solvents such as N,N-dimethylformamide and N-methylpyrrolidone.

[0136] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N,N-diisopropylethylamine.

[0137] The reaction temperature is, for example, 0°C to 130°C, preferably 20°C to 120°C.

[0138] Compound [A1-4] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method. Alternatively, it can be prepared, for example, by the below-described Preparation Methods M1, M2, M3, M4, M5, M6, M7, and M8, or Intermediate Preparation Example 2.

[0139] [Production Method A2]: Method for producing compound [A1-3] or a salt thereof The compound [A1-3] or a salt thereof used in Production Method A1 may be produced, for example, by Production Method A2 shown below.

[0140]

[0141] [In the formula, R 1a , R 1b and X are as defined above.]

[0142] (Step A2-1) Compound [A1-3] or a salt thereof can be produced by cyclizing compound [A2-1] or a salt thereof and compound [A2-2] or a salt thereof in a solvent in the presence of an acid.

[0143] Examples of the solvent include hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, alcohol solvents such as ethanol, water, and mixed solvents thereof. Preferred solvents are alcohol solvents such as ethanol, and water.

[0144] Examples of the acid include hydrogen chloride, hydrogen bromide, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, etc. Preferred acids are hydrogen chloride and hydrogen bromide.

[0145] The reaction temperature is, for example, 0°C to 130°C, preferably 20°C to 110°C.

[0146] The compound [A2-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0147] The compound [A2-2] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0148] [Production Method A3]: Production Method of Compound [I-2] or a Salt Thereof Among compounds [III] or salts thereof, in the compound represented by formula [I], R １ But SO ２ When W is present, the compound [I-2] or a salt thereof can be obtained, for example, by the following production method A3.

[0149]

[0150] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, and W are as defined above.]

[0151] (Step A3-1) The compound [A3-2] or a salt thereof can be produced by reacting the compound [A1-1] or a salt thereof with the compound [A3-1] or a salt thereof in a solvent in the presence of a base.

[0152] Examples of the solvent include amide solvents such as N,N-dimethylformamide, sulfoxide solvents such as dimethyl sulfoxide, nitrile solvents such as acetonitrile, and mixed solvents thereof. Preferred are amide solvents such as N,N-dimethylformamide.

[0153] Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, etc. Preferred bases are potassium carbonate and cesium carbonate.

[0154] The reaction temperature is, for example, 0°C to 80°C, preferably 20°C to 60°C.

[0155] The compound [A3-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0156] (Step A3-2) The compound [I-2] or a salt thereof can be prepared by reacting the compound [A3-2] or a salt thereof with the compound [A1-4] or a salt thereof in the same manner as in Step A1-2.

[0157] [Production Method M1]: Production Method of Compound [A1-4-1] or a Salt Thereof The compound [A1-4-1] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M1 shown below.

[0158]

[0159] [In the formula, R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0160] (Step M1-1) The compound [M1-2] or a salt thereof can be produced by converting the carboxy group of the compound [M1-1] or a salt thereof to an ester.

[0161] Examples of the solvent include hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, alcohol solvents such as methanol, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. Preferred solvents are hydrocarbon solvents such as toluene and alcohol solvents such as methanol.

[0162] Examples of the reagent used for conversion to an ester include trimethylsilyldiazomethane, a combination of concentrated sulfuric acid and methanol, a combination of potassium carbonate and methyl iodide, etc. A preferred reagent used for conversion to an ester is trimethylsilyldiazomethane.

[0163] The reaction temperature is, for example, 0° C. to 80° C., preferably 0° C. to room temperature.

[0164] The compound [M-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0165] (Step M1-2) The compound [M1-3] or a salt thereof can be produced by reacting the compound [M1-2] or a salt thereof with a Grignard reagent in a solvent.

[0166] Examples of the solvent include hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, and mixed solvents thereof. Preferred solvents are ether solvents such as tetrahydrofuran.

[0167] Examples of Grignard reagents include methylmagnesium bromide, methylmagnesium chloride, etc. A preferred Grignard reagent is methylmagnesium bromide.

[0168] The reaction temperature is, for example, from −20° C. to 70° C., preferably from 0° C. to room temperature.

[0169] (Step M1-3) Compound [A1-4-1] or a salt thereof can be produced by removing the protecting group Y of the nitrogen atom of compound [M1-3] or a salt thereof. The removal can be carried out under conditions appropriate for the type of Y. For example, when Y is tert-butyloxycarbonyl, compound [M1-3] or a salt thereof can be produced by removing the tert-butyloxycarbonyl group in a solvent in the presence of an acid.

[0170] Examples of the solvent include hydrocarbon solvents such as toluene, halogenated solvents such as dichloromethane, ether solvents such as tetrahydrofuran, alcohol solvents such as ethanol, and mixed solvents thereof. Preferred solvents are halogenated solvents such as dichloromethane.

[0171] Examples of the acid include sulfonic acids such as trifluoroacetic acid and p-toluenesulfonic acid monohydrate, and hydrogen halides such as hydrogen chloride, etc. A preferred acid is trifluoroacetic acid.

[0172] The reaction temperature is, for example, 0° C. to 100° C., preferably room temperature.

[0173] [Production Method M2]: Production Method of Compound [A1-4-2] or a Salt Thereof The compound [A1-4-2] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M2 shown below.

[0174]

[0175] [In the formula, R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0176] (Step M2-1) The compound [M2-1] or a salt thereof can be produced by reacting the compound [M1-2] or a salt thereof with a trifluoromethylating agent in a solvent.

[0177] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. A preferred solvent is 1,2-dimethoxyethane.

[0178] An example of the trifluoromethylating agent is (trifluoromethyl)trimethylsilane.

[0179] The reaction temperature is, for example, −20° C. to 60° C., preferably 0° C. to room temperature. If necessary, the reaction may be carried out in the presence of a catalyst such as cesium fluoride or tetrabutylammonium fluoride.

[0180] (Step M2-2) The compound [M2-2] or a salt thereof can be prepared by subjecting the compound [M2-1] or a salt thereof to a desilylation reaction in a solvent, followed by a reaction with a trifluoromethylating agent.

[0181] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. A preferred solvent is N,N-dimethylformamide.

[0182] Examples of the desilylation agent include tetrabutylammonium fluoride, cesium fluoride, etc. A preferred desilylation agent is tetrabutylammonium fluoride.

[0183] An example of the trifluoromethylating agent is (trifluoromethyl)trimethylsilane.

[0184] The reaction temperature is, for example, from -78°C to room temperature, preferably from -40°C to 10°C.

[0185] When the desilylation agent is tetrabutylammonium fluoride, the above reaction may be carried out by adding acetic acid as a buffer, if necessary.

[0186] (Step M2-3) The compound [A1-4-2] or a salt thereof can be produced by reacting the compound [M2-2] or a salt thereof in the same manner as in Step M1-3.

[0187] [Production Method M3]: Production Method of Compound [A1-4-3] or a Salt Thereof The compound [A1-4-3] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M3 shown below.

[0188]

[0189] [In the formula, R 2 is C 1-4 alkyl, or cyclopropyl; R 3 C optionally substituted with 1 to 5 halogens 1-4 alkyl, and R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0190] (Step M3-1) The compound [M3-1] can be produced by reacting the compound [M1-1] or a salt thereof with methoxymethylamine or a salt thereof in a solvent in the presence of a condensing agent and a base.

[0191] Examples of the solvent include halogenated solvents such as dichloromethane, ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. A preferred solvent is N,N-dimethylformamide.

[0192] Examples of condensing agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1,1'-carbonyldiimidazole, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, 1-propanephosphonic anhydride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, etc. A preferred condensing agent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0193] Examples of the base include N,N-diisopropylethylamine, triethylamine, pyridine, etc. Preferred bases are N,N-diisopropylethylamine and triethylamine.

[0194] The reaction temperature is, for example, 0° C. to 50° C., preferably 0° C. to room temperature.

[0195] [Production Method M3-2]: Production Method of Compound [M3-2] or a Salt Thereof Compound [M3-2] or a salt thereof can be produced by reacting compound [M3-1] or a salt thereof with a Grignard reagent in a solvent.

[0196] Examples of the solvent include hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0197] Grignard reagents include R 2 Examples of the magnesium bromide include methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium bromide, and cyclopropyl magnesium bromide.

[0198] The reaction temperature is, for example, from −20° C. to 70° C., preferably from 0° C. to room temperature.

[0199] (Step M3-3) The compound [M3-3] or a salt thereof can be prepared by reacting the compound [M3-2] or a salt thereof with an alkylating agent in a solvent, followed by reacting it with a desilylating agent.

[0200] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0201] The alkylating agent is R 3 Examples include (trifluoromethyl)trimethylsilane, (difluoromethyl)trimethylsilane, and trimethyl(pentafluoroethyl)silane.

[0202] Examples of the desilylation agent include tetrabutylammonium fluoride, cesium fluoride, etc. A preferred desilylation agent is tetrabutylammonium fluoride.

[0203] The reaction temperature is, for example, from −40° C. to 60° C., preferably from 0° C. to room temperature.

[0204] If necessary, 18-crown-6 may be added to carry out the above reaction.

[0205] (Step M3-4) The compound [A1-4-3] or a salt thereof can be produced by reacting the compound [M3-3] or a salt thereof in the same manner as in Step M1-3.

[0206] [Production Method M4]: Production Method of Compound [A1-4-4] or a Salt Thereof The compound [A1-4-4] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M4 shown below.

[0207]

[0208] [In the formula, R 2 C optionally substituted with 1 to 5 halogens 1-4 alkyl, and R 3 C optionally substituted with 1 to 3 halogens1-4 alkyl, and R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0209] (Step M4-1) The compound [M4-2] or a salt thereof can be produced by reacting the compound [M4-1] or a salt thereof with an oxidizing agent in a solvent.

[0210] Examples of the solvent include halogen-based solvents such as dichloromethane, nitrile-based solvents such as acetonitrile, and mixed solvents thereof. Preferred solvents are halogen-based solvents such as dichloromethane.

[0211] Examples of the oxidizing agent include Dess-Martin periodinane, a combination of dimethyl sulfoxide and pyridine-sulfur trioxide complex, a combination of dimethyl sulfoxide and oxalyl chloride and triethylamine, etc. A preferred oxidizing agent is Dess-Martin periodinane.

[0212] The reaction temperature is, for example, from −78° C. to room temperature, preferably from 0° C. to room temperature.

[0213] The compound [M4-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0214] (Step M4-2) The compound [M4-3] or a salt thereof can be prepared by reacting the compound [M4-2] or a salt thereof in the same manner as in Step M3-3.

[0215] (Step M4-3) The compound [M4-4] or a salt thereof can be prepared by reacting the compound [M4-3] or a salt thereof in the same manner as in Step M4-1.

[0216] (Step M4-4) The compound [M4-5] or a salt thereof can be prepared by reacting the compound [M4-4] or a salt thereof in the same manner as in Step M3-3.

[0217] (Step M4-5) The compound [A1-4-4] or a salt thereof can be produced by reacting the compound [M4-5] or a salt thereof in the same manner as in Step M1-3.

[0218] [Production Method M5]: Production Method of Compound [A1-4-5] or a Salt Thereof The compound [A1-4-5] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M5 shown below.

[0219]

[0220] [In the formula, R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0221] (Step M5-1) The compound [M5-1] or a salt thereof can be produced by subjecting the carbonyl group of the compound [M4-2] or a salt thereof to a nucleophilic addition reaction with acetonitrile in a solvent.

[0222] Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0223] Activating agents for acetonitrile include, for example, n-butyllithium, sec-butyllithium, and lithium bis(trimethylsilyl)amide. A preferred reagent is n-butyllithium.

[0224] The reaction temperature is, for example, from -78°C to room temperature, preferably from -78°C to 0°C.

[0225] (Step M5-2) The compound [M5-2] or a salt thereof can be produced by hydrogenating the compound [M5-1] or a salt thereof in a solvent in the presence of a catalytic amount of palladium on carbon.

[0226] Examples of the solvent include ether solvents such as tetrahydrofuran, alcohol solvents such as methanol, ester solvents such as ethyl acetate, and mixed solvents thereof. If necessary, the reaction may be carried out by adding an acid such as acetic acid. A preferred solvent is a combination of methanol and acetic acid.

[0227] The reaction temperature is, for example, 0° C. to 50° C., preferably room temperature.

[0228] (Step M5-3) The compound [M5-3] or a salt thereof can be produced by reacting the amino group of the compound [M5-2] or a salt thereof with an acetylating agent in a solvent in the presence of a base.

[0229] Examples of the solvent include hydrocarbon solvents such as toluene, halogenated solvents such as chloroform, ether solvents such as tetrahydrofuran, nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, amide solvents such as N,N-dimethylformamide, water, and mixed solvents thereof. A preferred solvent is chloroform.

[0230] Acetylation agents include, for example, acetyl chloride and acetic anhydride. A preferred acetylation agent is acetic anhydride.

[0231] Examples of the base include triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium bicarbonate, and sodium hydroxide. A preferred base is triethylamine.

[0232] The reaction temperature is, for example, 0° C. to 80° C., preferably 0° C. to room temperature.

[0233] (Step M5-4) The compound [A1-4-5] or a salt thereof can be produced by reacting the compound [M5-3] or a salt thereof in a solvent in the same manner as in Step M1-3.

[0234] [Production Method M6]: Production Method of Compound [A1-4-6] or a Salt Thereof The compound [A1-4-6] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M6 shown below.

[0235]

[0236] [In the formula, R 2 is C 1-4 alkyl, or cyclopropyl; R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0237] (Step M6-1) The compound [M6-1] can be produced by reducing the carbonyl group of the compound [M3-2] or a salt thereof in a solvent.

[0238] Examples of the solvent include ether solvents such as tetrahydrofuran, alcohol solvents such as ethanol, and mixed solvents thereof. Preferred solvents are tetrahydrofuran and methanol.

[0239] Examples of reducing agents include sodium borohydride, lithium borohydride, diisobutylaluminum hydride, and lithium aluminum hydride. A preferred reducing agent is sodium borohydride.

[0240] The reaction temperature is, for example, from −78° C. to 80° C., preferably from 0° C. to room temperature.

[0241] (Step M6-2) The compound [A1-4-6] or a salt thereof can be prepared by reacting the compound [M6-1] or a salt thereof in a solvent in the same manner as in Step M1-3.

[0242] [Production Method M7]: Production Method of Compound [A1-4-7] or a Salt Thereof The compound [A1-4-7] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M7 shown below.

[0243]

[0244] [In the formula, R 2 C optionally substituted with 1 to 5 halogens 1-4 alkyl, and R 4, R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0245] (Step M7-1) The compound [M7-1] or a salt thereof can be produced from the compound [M4-2] or a salt thereof in the same manner as in Step M3-3.

[0246] The alkylating agent is R 2 An example of such a silane is (trifluoromethyl)trimethylsilane.

[0247] (Step M7-2) The compound [A1-4-7] or a salt thereof can be prepared by reacting the compound [M7-1] or a salt thereof in a solvent in the same manner as in Step M1-3.

[0248] [Production Method M8]: Production Method of Compound [A1-4-8] or a Salt Thereof The compound [A1-4-8] or a salt thereof used in Production Methods A1 and A3 can be produced, for example, by Production Method M8 shown below.

[0249]

[0250] [In the formula, R 4 , R 5 , R 6 , and R 7 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0251] (Step M8-1) The compound [A1-4-8] or a salt thereof can be produced by reacting the compound [M4-1] or a salt thereof in a solvent in the same manner as in Step M1-3.

[0252] Among the compounds [III] or salts thereof, Cy is a compound represented by the formula:

[0253]

[0254] (each symbol in the formula has the same meaning as defined above) The compound or salt thereof which is a group represented by R in formula [III]１ ', R ２ ', R ４ ', R ５ ', R ６ ', or R ７ By using raw materials and reagents suitable for ", it can be produced in the same manner as described above.

[0255] [Production Method B1]: Production Method of Compound [IV-1] or a Salt Thereof Among compounds [III] or salts thereof, in the compound represented by formula [IV], R １ But CHR １ａ R １ｂ The compound [IV-1] represented by the formula: or a salt thereof can be prepared, for example, by the following preparation method B1.

[0256]

[0257] [In the formula, R 1a , R 1b , R 8 , R 9 , R 10 , R 11 and X are as defined above.]

[0258] (Step B1-1) Compound [IV-1] or a salt thereof can be produced by reacting compound [A1-3] or a salt thereof with compound [B1-1] or a salt thereof in a solvent in the presence of a base.

[0259] Examples of the solvent include amide solvents such as N,N-dimethylformamide and N-methylpyrrolidone, sulfoxide solvents such as dimethyl sulfoxide, alcohol solvents such as ethanol, and mixed solvents thereof. Preferred are amide solvents such as N,N-dimethylformamide and N-methylpyrrolidone.

[0260] Examples of the base include triethylamine, N,N-diisopropylethylamine, etc. A preferred base is N,N-diisopropylethylamine.

[0261] The reaction temperature is, for example, 0°C to 130°C, preferably 20°C to 120°C.

[0262] Compound [B1-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method. Alternatively, it can be prepared, for example, by the following Preparation Methods E1, E2, E3, and E4, or Intermediate Preparation Example 3.

[0263] [Production Method B2]: Production Method of Compound [IV-2] or a Salt Thereof Among compounds [III] or salts thereof, in the compound represented by formula [IV], R １ But SO ２ When W is a compound [IV-2] or a salt thereof, it can be obtained, for example, by the following production method B2.

[0264]

[0265] [In the formula, R 8 , R 9 , R 10 , R 11 , X, and W are as defined above.]

[0266] (Step B2-1) The compound [IV-2] or a salt thereof can be prepared by reacting the compound [A3-2] or a salt thereof with the compound [B1-1] or a salt thereof in the same manner as in Step B1-1.

[0267] [Production Method E1]: Production Method of Compound [B1-1-1] or a Salt Thereof The compound [B1-1-1] or a salt thereof used in Production Methods B1 and B2 can be produced, for example, by Production Method E1 shown below.

[0268]

[0269] [In the formula, R 8 , R 9 , and R 11 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0270] (Step E1-1) The compound [E1-2] or a salt thereof can be produced by reacting the compound [E1-1] or a salt thereof with an alkylating agent in a solvent in the presence of a desilylation agent.

[0271] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0272] The alkylating agent is R 11 Examples of suitable silanes include (trifluoromethyl)trimethylsilane and (difluoromethyl)trimethylsilane.

[0273] Examples of the desilylation agent include tetrabutylammonium fluoride, cesium fluoride, etc. A preferred desilylation agent is tetrabutylammonium fluoride.

[0274] The reaction temperature is, for example, from −40° C. to 60° C., preferably from 0° C. to room temperature.

[0275] If necessary, the above reaction may be carried out by adding 18-crown-6. Compound [E1-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0276] (Step E1-2) The compound [B1-1-1] or a salt thereof can be produced by reacting the compound [E1-2] or a salt thereof in the same manner as in Step M1-3.

[0277] [Production Method E2]: Production Method of Compound [B1-1-2] or a Salt Thereof The compound [B1-1-2] or a salt thereof used in Production Methods B1 and B2 can be produced, for example, by Production Method E2 shown below.

[0278]

[0279] [In the formula, R 9 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0280] (Step E2-1) The compound [E2-2] or a salt thereof can be produced by subjecting the compound [E2-1] or a salt thereof to a Wittig reaction with a phosphorus ylide prepared from a phosphonium salt in a solvent in the presence of a base.

[0281] Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, halogenated solvents such as dichloromethane, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0282] Examples of the base include potassium tert-butoxide, KHMDS, and sodium hydride, and the preferred base is potassium tert-butoxide.

[0283] Examples of the phosphonium salt include methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide, and a preferred phosphonium salt is methyltriphenylphosphonium bromide.

[0284] The reaction temperature is, for example, from −20° C. to room temperature, preferably from 0° C. to room temperature.

[0285] The compound [E2-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0286] (Step E2-2) Compound [E2-3] or a salt thereof can be produced by reacting the olefin of compound [E2-2] or a salt thereof with (trifluoromethyl)trimethylsilane in a solvent in the presence of an initiator (Angew. Chem., Int. Ed. 2011, 50, 7153.).

[0287] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. The preferred solvent is tetrahydrofuran.

[0288] Examples of initiators include sodium iodide, tetrabutylammonium fluoride, tetrabutylammonium difluorotriphenyl silicate, etc. A preferred initiator is sodium iodide.

[0289] The reaction temperature is, for example, from -50°C to 80°C, preferably from 0°C to 65°C.

[0290] (Step E2-3) The compound [E2-4] or a salt thereof can be produced by reacting the compound [E2-3] or a salt thereof with a Grignard reagent in a solvent.

[0291] Examples of the solvent include hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, and mixed solvents thereof. Preferred solvents are ether solvents such as tetrahydrofuran.

[0292] Examples of Grignard reagents include methylmagnesium bromide, methylmagnesium chloride, etc. A preferred Grignard reagent is methylmagnesium bromide.

[0293] The reaction temperature is, for example, from −20° C. to 70° C., preferably from 0° C. to room temperature.

[0294] (Step E2-4) The compound [B1-1-2] or a salt thereof can be produced by reacting the compound [E2-4] or a salt thereof in the same manner as in Step M1-3.

[0295] [Production Method E3]: Production Method of Compound [B1-1-3] or a Salt Thereof The compound [B1-1-3] or a salt thereof used in Production Methods B1 and B2 can be produced, for example, by Production Method E3 shown below.

[0296]

[0297] [In the formula, R 9 is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0298] (Step E3-1) The compound [E3-2] or a salt thereof can be produced by converting the carboxy group of the compound [E3-1] or a salt thereof to an ester.

[0299] Examples of the solvent include hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, alcohol solvents such as methanol, amide solvents such as N,N-dimethylformamide, and mixed solvents thereof. Preferred solvents are hydrocarbon solvents such as toluene and alcohol solvents such as methanol.

[0300] Examples of the reagent used for conversion to an ester include trimethylsilyldiazomethane, a combination of concentrated sulfuric acid and methanol, a combination of potassium carbonate and methyl iodide, etc. A preferred reagent used for conversion to an ester is trimethylsilyldiazomethane.

[0301] The reaction temperature is, for example, 0° C. to 80° C., preferably 0° C. to room temperature.

[0302] The compound [E3-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0303] (Step E3-2) The compound [E3-3] or a salt thereof can be produced by reacting the compound [E3-2] or a salt thereof in the same manner as in Step E2-3.

[0304] (Step E3-3) The compound [B1-1-3] or a salt thereof can be produced by reacting the compound [E3-3] or a salt thereof in the same manner as in Step M1-3.

[0305] [Production Method E4]: Production Method of Compound [B1-1-4] or a Salt Thereof The compound [B1-1-4] or a salt thereof used in Production Methods B1 and B2 can be produced, for example, by Production Method E4 shown below.

[0306]

[0307] [In the formula, R 8 and R 9is as defined above, and Y is an amine-protecting group (e.g., tert-butyloxycarbonyl).

[0308] (Step E4-1) The compound [E4-2] or a salt thereof can be prepared by reacting the compound [E4-1] or a salt thereof in the same manner as in Step E3-1.

[0309] (Step E4-2) The compound [E4-3] or a salt thereof can be produced by reacting the compound [E4-2] or a salt thereof in the same manner as in Step E2-3.

[0310] (Step E4-3) The compound [B1-1-4] or a salt thereof can be produced by reacting the compound [E4-3] or a salt thereof in the same manner as in Step M1-3.

[0311] Among the compounds [III] or salts thereof, Cy is a compound represented by the formula:

[0312]

[0313] (each symbol in the formula has the same meaning as defined above) The compound or salt thereof which is a group represented by R in formula [III] １ By using raw materials and reagents suitable for ", it can be produced in the same manner as described above.

[0314] The compound [III] of the present invention or a pharmaceutically acceptable salt thereof will be specifically described below by way of examples of its preparation, but the preparation method of the compound [III] of the present invention or a pharmaceutically acceptable salt thereof is not limited thereto.

[0315] 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, they can be used to proceed to the next step without isolation and / or purification.

[0316] In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is a temperature of 1°C to 40°C.

[0317] [Production Example 1] Synthesis of (R)-2-(5-bromo-6-oxo-4-((R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidin-1-yl)pyridazin-1(6H)-yl)-2-cyclopropylacetonitrile (Example No. 161)

[0318]

[0319] (1) (R)-3-(2-cyclopropylacetyl)-4-phenyloxazolidin-2-one

[0320]

[0321] Under an argon atmosphere, 2,2-dimethylbutyryl chloride (149 mL) and cyclopropylacetic acid (95 mL) were added to tetrahydrofuran (3000 mL) and the mixture was ice-cooled. Triethylamine (300 mL) was added dropwise, and the mixture was stirred under ice-cooling for 75 minutes. To the reaction mixture, (R)-(-)-4-phenyl-2-oxazolidinone (146.6 g) and lithium chloride (46.8 g) were added sequentially. The ice bath was removed, and the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. After stirring at room temperature for 9 hours, tetrahydrofuran (400 mL) was added and the mixture was allowed to stand over the weekend. Water (1000 mL) was added, the layers were separated, and the organic layer was concentrated under reduced pressure. The aqueous layer was further extracted twice with ethyl acetate, and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) and n-heptane (400 mL) were added to the resulting residue, and the mixture was stirred for 75 minutes under ice-cooling. The precipitated solid was collected by filtration, washed successively with chilled n-heptane / ethyl acetate = 5 / 2 (210 mL) and n-heptane, and then dried under reduced pressure to obtain the title compound (189 g). 1H-NMR (DMSO-D6) δ: 7.42-7.35 (2H, m), 7.35-7.27 (3H, m), 5.47 (1H, dd, J = 8.8, 3.5 Hz), 4.73 (1H, t, J = 8.8 Hz), 4.15 (1H, dd, J = 8.8, 3.5 Hz), 2.89 (1H, dd, J = 16.7, 7.0 Hz), 2.67 (1H, dd, J = 16.7, 7.0 Hz), 1.04-0.92 (1H, m), 0.48-0.39 (2H, m), 0.19-0.05 (2H, m).

[0322] (2) Di-tert-butyl 1-((R)-1-cyclopropyl-2-oxo-2-((R)-2-oxo-4-phenyloxazolidin-3-yl)ethyl)hydrazine-1,2-dicarbonate

[0323]

[0324] Under an argon atmosphere, a solution of (R)-3-(2-cyclopropylacetyl)-4-phenyloxazolidin-2-one (58.1 g) in tetrahydrofuran (360 mL) was cooled to -78°C. To this was added dropwise a solution of approximately 1.3 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (200 mL) over 70 minutes, followed by stirring at -78°C for 80 minutes. Separately, di-tert-butyl azodicarboxylate (62.7 g) was added to toluene (360 mL) and tetrahydrofuran (60 mL), and the mixture was cooled in a sodium chloride-ice bath. This mixture was then added dropwise to the reaction solution cooled to -78°C over 100 minutes. After washing the mixture with toluene (5 mL), a solution of acetic acid (20 mL) in tetrahydrofuran (180 mL) was added, and the mixture was stirred while warming to -5°C over 2 hours and 50 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the organic layer was concentrated under reduced pressure. The residue was combined with the aqueous layer, extracted twice with toluene, washed with saturated aqueous sodium chloride, and then the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5 / 1 to 3 / 1) to give the title compound (119 g) as a crude product, which was used in the next reaction without further purification.

[0325] (3) Di-tert-butyl (R)-1-(2-amino-1-cyclopropyl-2-oxoethyl)hydrazine-1,2-dicarbonate

[0326]

[0327] Tetrahydrofuran (300 mL) was added to di-tert-butyl 1-((R)-1-cyclopropyl-2-oxo-2-((R)-2-oxo-4-phenyloxazolidin-3-yl)ethyl)hydrazine-1,2-dicarbonate (119 g) obtained in the previous step. 28% aqueous ammonia (250 mL) was added thereto, and the mixture was stirred at room temperature for 4 hours and allowed to stand over the weekend. A saturated aqueous sodium chloride solution was added to the reaction solution, and the mixture was extracted twice with toluene. The organic layer was washed three times with a saturated aqueous sodium chloride solution and concentrated under reduced pressure. Ethyl acetate (400 mL) and hexane (800 mL) were added to the residue. (R)-3-(2-cyclopropylacetyl)-4-phenyloxazolidin-2-one was added, and the mixture was stirred at room temperature. The precipitated insoluble matter was removed by filtration, and the filtrate was concentrated. The mixture was diluted with toluene to a total volume of 230 mL, and used directly in the next reaction.

[0328] (4) (R)-2-cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetamide

[0329]

[0330] A toluene solution (63 mL) of di-tert-butyl (R)-1-(2-amino-1-cyclopropyl-2-oxoethyl)hydrazine-1,2-dicarbonate obtained in the previous step was concentrated under reduced pressure and then dried under reduced pressure. Trifluoroacetic acid (50 mL) was added thereto and stirred at room temperature for 1 hour. To the reaction solution, 3,4-dibromo-5-hydroxyfuran-2(5H)-one (16.3 g) was added under ice cooling, and cold water (50 mL) was added. The ice bath was removed, and the mixture was stirred at room temperature for 3 hours and then allowed to stand for 1 day. The reaction solution was diluted with water and extracted twice with a mixed solvent of toluene and ethyl acetate. The organic layer was washed three times with water. The solid precipitated during extraction was collected by filtration and washed with water. The collected solid and the organic layer were combined and concentrated under reduced pressure. The resulting residue was suspended in toluene and stirred at room temperature. The solid was collected by filtration, washed with toluene, and air-dried to obtain the title compound (7.24 g). 1 H-NMR (DMSO-D6) δ: 8.24 (1H, s), 7.46 (1H, br s), 7.32 (1H, br s), 4.34 (1H, d, J = 10.5 Hz), 1.56-1.39 (1H, m), 0.88-0.65 (2H, m), 0.59-0.43 (1H, m), 0.27-0.18 (1H, m).

[0331] (5) (R)-2-cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetonitrile

[0332]

[0333] (R)-2-Cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetamide (7.05 g) was suspended in pyridine (35 mL) and cooled with ice. Trifluoroacetic anhydride (5.0 mL) was added dropwise thereto, and the mixture was stirred in an ice bath for 5 minutes. Water was added to the reaction mixture, and the mixture was stirred vigorously under ice cooling. The precipitated solid was collected by filtration, washed with water and n-heptane, and then air-dried to obtain the title compound (5.4 g). 1H-NMR (DMSO-D6) δ: 8.33 (1H, s), 5.50 (1H, d, J = 9.2 Hz), 1.70-1.58 (1H, m), 0.85-0.68 (2H, m), 0.66-0.55 (1H, m), 0.54-0.41 (1H, m).

[0334] (6) tert-butyl (R)-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate

[0335]

[0336] (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (30.0 g) was dissolved in N,N-dimethylformamide (300 mL). N,O-dimethylhydroxylamine hydrochloride (16.0 g), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (68.0 g), and N,N-diisopropylethylamine (78 mL) were added thereto and stirred at room temperature for 2 hours. Water (approximately 200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4 / 1 to 1 / 2) to give the title compound (35.6 g). 1 H-NMR (DMSO-D6) δ: 5.02-4.88 (1H, m), 3.88-3.69 (2H, m), 3.65 (3H, s), 3.12 (3H, s), 2.56-2.39 (1H, m), 2.03-1.86 (1H, m), 1.34 (9H, br s).

[0337] (7) tert-butyl (R)-acetylazetidine-1-carboxylate

[0338]

[0339] tert-Butyl (R)-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (35.6 g) was mixed with tetrahydrofuran (356 mL). A 3 M solution of methylmagnesium chloride in tetrahydrofuran (58.3 mL) was added thereto at 0°C, and the mixture was stirred at room temperature for 2 hours. 1 M hydrochloric acid (approximately 100 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 1) to give the title compound (22.6 g). 1 H-NMR (DMSO-D6) δ: 4.66-4.51 (1H, m), 3.86-3.69 (2H, m), 2.48-2.34 (1H, m), 2.15 (3H, s), 2.09-1.98 (1H, m), 1.36 (9H, br s).

[0340] (8) tert-butyl (R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate

[0341]

[0342] Tert-butyl (R)-acetylazetidine-1-carboxylate (2.36 g) was mixed with tetrahydrofuran (23.6 mL). To the reaction solution, (trifluoromethyl)trimethylsilane (2.64 mL) and an approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.91 mL) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, an approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (23.7 mL) was further added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 2) to obtain the title compound (2.39 g). 1H-NMR (DMSO-D6) δ: 6.20 (1H, s), 4.29-4.22 (1H, m), 3.79-3.63 (2H, m), 2.36-2.24 (2H, m), 1.39 (9H, s), 1.29 (3H, s).

[0343] (9) (R)-2-((R)-azetidin-2-yl)-1,1,1-trifluoropropan-2-ol 2,2,2-trifluoroacetate

[0344]

[0345] Tert-butyl (R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate (2.39 g) was mixed with chloroform (23.9 mL), and trifluoroacetic acid (6.83 mL) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (3.58 g) as a crude product. This was used in the next reaction without further purification.

[0346] (10) (R)-2-(5-bromo-6-oxo-4-((R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidin-1-yl)pyridazin-1(6H)-yl)-2-cyclopropylacetonitrile

[0347]

[0348] (R)-2-Cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetonitrile (2.68 g) was mixed with N,N-dimethylformamide (25.1 mL). (R)-2-((R)-azetidin-2-yl)-1,1,1-trifluoropropan-2-ol 2,2,2-trifluoroacetate (2.51 g) obtained in the previous step and N,N-diisopropylethylamine (4.22 mL) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2 / 1 to 1 / 3). The resulting solid was crystallized using diisopropyl ether / hexane = approximately 1 / 2 (approximately 30 mL), collected by filtration, and dried under reduced pressure to give the title compound (2.56 g).1 H-NMR (DMSO-D6) δ: 7.89 (1H, s), 6.59 (1H, s), 5.43 (1H, d, J = 9.2 Hz), 4.89-4.84 (1H, m), 4.61-4.53 (1H, m), 4.07-3.99 (1H, m), 2.48-2.42 (1H, m), 2.38-2.30 (1H, m), 1.65-1.56 (1H, m), 1.34 (3H, s), 0.80-0.68 (2H, m), 0.61-0.54 (1H, m), 0.46-0.39 (1H, m).

[0349] [Production Example 2] Synthesis of 4-bromo-2-(1,1-difluoropropan-2-yl)-5-((R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidin-1-yl)pyridazin-3(2H)-one (Example Nos. 81 and 82)

[0350]

[0351] (1) tert-butyl 2-(1,1-difluoropropan-2-yl)hydrazine-1-carboxylate

[0352]

[0353] Under an argon atmosphere, tetrahydrofuran (15.0 mL) was added to tert-butyl carbazate (1.10 g), and difluoroacetone (0.9 mL) was added thereto. The mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure and then dried under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (15.0 mL), and under ice cooling, a 0.89 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (13 mL) was slowly added. The mixture was stirred at the same temperature for 20 minutes, after which the ice bath was removed and the mixture was allowed to stand under a nitrogen atmosphere for 18 hours. The reaction solution was ice-cooled, and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred until effervescence ceased and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the combined organic layer was dried over magnesium sulfate. Insoluble matter was removed by filtration and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / toluene = 1 / 1, followed by hexane / ethyl acetate = 9 / 1), azeotroped with toluene, and then dried under reduced pressure to give the title compound (0.64 g). 1 H-NMR (DMSO-D6) δ: 8.33 (1H, br s), 5.99-5.63 (1H, m), 4.64 (1H, br s), 3.23-2.98 (1H, m), 1.39 (9H, s), 0.99 (3H, d, J = 6.6 Hz).

[0354] (2) (1,1-difluoropropan-2-yl)hydrazine dihydrochloride

[0355]

[0356] To tert-butyl 2-(1,1-difluoropropan-2-yl)hydrazine-1-carboxylate (0.64 g), 4 M hydrogen chloride / ethyl acetate solution (5.0 mL) was added, and the mixture was stirred at room temperature for 6 hours and 30 minutes. The precipitated solid was collected by filtration, washed with ethyl acetate and n-heptane, and then dried under reduced pressure to obtain the title compound (0.25 g).

[0357] (3) 4,5-dibromo-2-(1,1-difluoropropan-2-yl)pyridazin-3(2H)-one

[0358]

[0359] Water (1.0 mL) and 47% hydrobromic acid (0.65 mL) were added to 3,4-dibromo-5-hydroxyfuran-2(5H)-one (351 mg) and (1,1-difluoropropan-2-yl)hydrazine dihydrochloride (250 mg), and the mixture was stirred at 80° C. for 6 hours and allowed to stand at room temperature overnight. Water was added to the reaction mixture, and the solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (415 mg). 1 H-NMR (DMSO-D6) δ: 8.27 (1H, s), 6.44-6.10 (1H, m), 5.35-5.14 (1H, m), 1.42 (3H, d, J = 7.0 Hz).

[0360] (4) 4-bromo-2-(1,1-difluoropropan-2-yl)-5-((R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidin-1-yl)pyridazin-3(2H)-one

[0361]

[0362] Trifluoroacetic acid (250 μL) was added to tert-butyl (R)-2-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate (60 mg) obtained in Production Example 1 (8), and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure and then dried under reduced pressure. 4,5-dibromo-2-(1,1-difluoropropan-2-yl)pyridazin-3(2H)-one (70 mg), N,N-dimethylformamide (300 μL), and triethylamine (150 mL) were added sequentially to the residue, and the reaction solution was stirred at 80°C for 7 hours. Water was added to the reaction solution at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure. The obtained solid was purified by silica gel thin layer chromatography (developed three times with a 3 / 2 mixture of hexane and ethyl acetate), and both diastereomers were purified by aminosilica gel column chromatography (developed with ethyl acetate), azeotroped with acetone, and then dried under reduced pressure to obtain a first diastereomer (39 mg) and a second diastereomer (38 mg). First diastereomer: 1H-NMR (DMSO-D6) δ: 7.81 (1H, s), 6.55 (1H, s), 6.37-6.03 (1H, m), 5.31-5.14 (1H, m), 4.90-4.79 (1H, m), 4.62-4.49 (1H, m), 4.05-3.93 (1H, m), 2.61-2.40 (1H, m), 2.40-2.26 (1H, m), 1.37 (3H, d, J = 7.0 Hz), 1.33 (3H, s). Second diastereomer: 1 H-NMR (DMSO-D6) δ: 7.82 (1H, s), 6.55 (1H, s), 6.37-6.07 (1H, m), 5.28-5.13 (1H, m), 4.88-4.80 (1H, m), 4.61-4.51 (1H, m), 4.03-3.92 (1H, m), 2.56-2.39 (1H, m), 2.39-2.27 (1H, m), 1.36 (3H, d, J = 7.0 Hz), 1.33 (3H, s).

[0363] [Production Example 3] Synthesis of (R)-2-(5-bromo-4-((R)-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidin-1-yl)-6-oxopyridazin-1(6H)-yl)-2-cyclopropylacetonitrile (Example No. 111)

[0364]

[0365] (1) 2-cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetonitrile

[0366]

[0367] Potassium carbonate (18.1 g) was added to a solution of 2-bromo-2-cyclopropylacetonitrile (7 g) in N,N-dimethylformamide (70 mL), and the mixture was stirred at 40°C for 1 minute. A solution of 4,5-dibromo-3(2H)-pyridazinone (12.2 g) in N,N-dimethylformamide (100 mL) was added dropwise to the reaction solution over 45 minutes, and the mixture was stirred at 40°C for 10 minutes and then at room temperature for 30 minutes. Hexane / ethyl acetate = 1 / 1 (500 mL) and ice water (500 mL) were added to the reaction solution, and the mixture was stirred. Insoluble matter was removed by filtration using Celite, and the aqueous layer was separated from the filtrate and extracted with hexane / ethyl acetate = 1 / 1 (500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate), and then suspended in hexane / ethyl acetate=10 / 1, and the solid was collected by filtration to obtain the title compound (6.1 g). 1 H-NMR (DMSO-D6) δ: 8.33 (1H, s), 5.50 (1H, d, J = 9.2 Hz), 1.69-1.58 (1H, m), 0.84-0.67 (2H, m), 0.66-0.56 (1H, m), 0.53-0.44 (1H, m).

[0368] (2) tert-butyl 2(R)-2-(2,2,2-trifluoro-1-methoxy-1-((trimethylsilyl)oxy)ethyl)azetidine-1-carboxylate

[0369]

[0370] To a solution of 1-(tert-butyl)2-methyl (R)-azetidine-1,2-dicarboxylate (31 g) in 1,2-dimethoxyethane (250 mL), (trifluoromethyl)trimethylsilane (32.1 mL) and cesium fluoride (0.438 g) were added in this order under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. Acetic acid (8.24 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1 / 0 to 10 / 1), azeotroped with hexane, and then dried under reduced pressure to give the title compound (49.7 g) as a diastereomeric mixture.1 H-NMR (DMSO-D6) δ: 4.56-4.47 (1H, m), 3.78-3.63 (2H, m), 3.46-3.40 (1.7H, m), 3.34 (1.3H, s), 2.49-2.35 (1H, m), 2.21-2.04 (1H, m), 1.38 (5.2H, s), 1.37 (3.8H, s), 0.21 (3.8H, s), 0.18 (5.2H, s).

[0371] (3) tert-butyl (R)-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate

[0372]

[0373] A solution of tert-butyl 2(R)-2-(2,2,2-trifluoro-1-methoxy-1-((trimethylsilyl)oxy)ethyl)azetidine-1-carboxylate (49.7 g) in N,N-dimethylformamide (500 mL) was cooled to an internal temperature of -44 ° C., and at the same temperature, about 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (27.8 mL) was added dropwise over 20 minutes. Subsequently, acetic acid (3.18 mL) was added dropwise over 1 minute at the same temperature, and then (trifluoromethyl)trimethylsilane (83 mL) was added dropwise over 20 minutes, and the mixture was stirred for 20 minutes while allowing the temperature to rise naturally. The internal temperature was adjusted to -15 ° C., and acetic acid (4.77 mL), and about 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (83.4 mL) were added dropwise to the reaction mixture, followed by stirring, and the internal temperature was raised to 7 ° C. over 30 minutes. To the reaction mixture, saturated aqueous ammonium chloride (150 mL) was added while maintaining the internal temperature at around 15°C, followed by water (50 mL), and the mixture was stirred at room temperature for 1 hour. Hexane / ethyl acetate (2 / 1) and water were added, followed by extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate (1 / 0 to 9 / 1)) to give the title compound (34.2 g). 1H-NMR (DMSO-D6) δ: 8.07 (1H, s), 4.80-4.71 (1H, m), 3.85-3.71 (2H, m), 2.54-2.31 (2H, m), 1.39 (9H, s).

[0374] (4) (R)-2-(azetidin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 2,2,2-trifluoroacetate

[0375]

[0376] Trifluoroacetic acid (81 mL) was added to a solution of tert-butyl (R)-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate (34 g) in chloroform (80 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, azeotroped with chloroform, and then dried under reduced pressure to obtain the title compound (35.5 g). The resulting residue was used in the next reaction without further purification.

[0377] (5) (R)-2-(5-bromo-4-((R)-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidin-1-yl)-6-oxopyridazin-1(6H)-yl)-2-cyclopropylacetonitrile

[0378]

[0379] To a solution of (R)-2-(azetidin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 2,2,2-trifluoroacetate (35.4 g) in N-methylpyrrolidone (75 mL), N,N-diisopropylethylamine (52.3 mL) was added with ice cooling in response to heat generation, and 2-cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetonitrile (25 g) was further added and stirred at 90°C overnight. N,N-Diisopropylethylamine (13.1 mL) was added to the reaction solution, and the mixture was stirred at 100°C for 3 hours. The reaction solution was concentrated under reduced pressure, and then ethyl acetate and water were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain a first crude product (39 g). Hexane / ethyl acetate = 2 / 1 (60 mL) was added to the first crude product, and the mixture was dissolved at 70 °C. Seed crystals of the title compound were inoculated and crystallized, and the mixture was allowed to stand at room temperature over the weekend. The resulting crystals were collected by filtration and washed with cold hexane / ethyl acetate = 6 / 1 to obtain the first crystal (9.5 g, 99.8% e.e., dr = 92:8). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain a second crude product (5.5 g) and its diastereomer (15 g). Triethylamine (45 mL) was added to a solution of the resulting diastereomer (15 g) in N-methylpyrrolidone (45 mL), and the mixture was stirred overnight at 100 °C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain a third crude product (5.5 g). Hexane / ethyl acetate = 2 / 1 (30 mL) was added to the third crude product (5.5 g), and the mixture was dissolved at 70 °C. Seed crystals of the title compound were seeded to crystallize the mixture, which was then allowed to stand at room temperature for 3 hours. The resulting crystals were filtered and washed with cold hexane / ethyl acetate = 6 / 1 to obtain a second crystal (1.0 g, 99.8% e.e., dr = 95:5).The crystals precipitated from the filtrate were filtered and washed with cold hexane / ethyl acetate = 6 / 1 to obtain a third crystal (2.4 g, >99% e.e., dr = 93:7). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain a fourth crude product (1.2 g). The first crystal (9.5 g) and the second crystal (1.0 g) were combined and purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 1 / 1) to obtain the title compound (9.5 g). The second crude product (5.5 g) and the fourth crude product (1.2 g) were combined and purified by chiral preparative LC (Daicel CHIRALPAK IG, acetonitrile / water = 1 / 1). The compound with the longest retention time was the title compound. The title compound (9.5 g) was dissolved in the eluate, and the solution was concentrated under reduced pressure until the water volume was approximately 1 L. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain Crystal A of the title compound (15.0 g, >99% e.e.). The stereochemistry of the title compound was determined by X-ray crystal structure analysis. Seed crystals of Crystal A of the title compound can also be obtained by carrying out this reaction, purifying the resulting diastereomeric mixture by chiral preparative LC, concentrating the eluate under reduced pressure, and then adding water to crystallize it. 1 H-NMR (DMSO-D6) δ: 8.87 (1H, s), 7.95 (1H, s), 5.43 (1H, d, J = 9.7 Hz), 5.29-5.23 (1H, m), 4.67-4.59 (1H, m), 4.09-4.00 (1H, m), 2.69-2.38 (2H, m), 1.68-1.58 (1H, m), 0.81-0.67 (2H, m), 0.61-0.53 (1H, m), 0.47-0.39 (1H, m).

[0380] 2-Propanol (0.3 mL) was added to the crude product of the title compound (100 mg) and dissolved with stirring at room temperature. Water (0.15 mL) was added at room temperature to seed the mixture and stirred for 2 hours. Water (0.15 mL) was then added at room temperature and stirred for 2 hours. Water (0.3 mL) was then added at room temperature and stirred for 24 hours. The resulting crystals were collected by filtration, washed once with a 2-propanol / water = 1 / 2 mixed solution (0.2 mL) and twice with water (0.2 mL), and then dried under reduced pressure at 40 °C to give Crystal B of the title compound (86.8 mg). Seed crystals of Crystal B of the title compound were obtained by adding 2-propanol / water = 1 / 3 (1.0 mL) to Crystal A of the title compound (50 mg), stirring at room temperature for 1 week, and collecting the resulting crystals by filtration and air-drying at room temperature.

[0381] Preparation Example 4 Synthesis of 4-bromo-2-(cyclopropylsulfonyl)-5-((R)-2-((R)-1,1,1-trifluoro-2-hydroxybutan-2-yl)azetidin-1-yl)pyridazin-3(2H)-one (Example No. 56)

[0382]

[0383] (1) 4,5-Dibromo-2-(cyclopropylsulfonyl)pyridazin-3(2H)-one

[0384]

[0385] Potassium carbonate (8.17 g) was added to a solution of 4,5-dibromo-3(2H)-pyridazinone (5 g) in N,N-dimethylformamide (50 mL), and cyclopropanesulfonyl chloride (5 mL) was added dropwise at room temperature over 10 minutes, followed by stirring at room temperature for 50 minutes. Ethyl acetate (100 mL) was added to the reaction solution, which was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to give the title compound (2.3 g). 1 H-NMR (DMSO-D6) δ: 8.28 (1H, s), 3.49-3.40 (1H, m), 1.33-1.26 (4H, m).

[0386] (2) tert-butyl (R)-2-propionylazetidine-1-carboxylate

[0387]

[0388] tert-Butyl (R)-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (500 mg) was dissolved in tetrahydrofuran (10.0 mL), and a 40% solution of ethylmagnesium bromide in 2-methyltetrahydrofuran (0.80 mL) was added at 0°C, followed by stirring overnight at room temperature. 1 M hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 1) to give the title compound (278 mg). 1 H-NMR (DMSO-D6) δ: 4.70-4.57 (1H, m), 3.86-3.69 (2H, m), 2.68-2.34 (3H, m), 2.05-1.92 (1H, m), 1.35 (9H, s), 0.96 (3H, t, J = 7.3 Hz).

[0389] (3) tert-butyl (R)-2-((R)-1,1,1-trifluoro-2-hydroxybutan-2-yl)azetidine-1-carboxylate

[0390]

[0391] tert-Butyl (R)-2-propionylazetidine-1-carboxylate (276 mg) was dissolved in tetrahydrofuran (2.76 mL), and (trifluoromethyl)trimethylsilane (288 μL) and an approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (646 μL) were added, followed by stirring at room temperature for 2 hours. An approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.59 mL) was added to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1 / 0 to 1 / 1) to give the title compound (327 mg). 1 H-NMR (DMSO-D6) δ: 6.01 (1H, s), 4.36 (1H, t, J = 7.5 Hz), 3.82-3.62 (2H, m), 2.38-2.23 (2H, m), 1.81-1.60 (2H, m), 1.39 (9H, s), 0.97-0.90 (3H, m).

[0392] (4) (R)-2-((R)-azetidin-2-yl)-1,1,1-trifluorobutan-2-ol 2,2,2-trifluoroacetate

[0393]

[0394] tert-Butyl (R)-2-((R)-1,1,1-trifluoro-2-hydroxybutan-2-yl)azetidine-1-carboxylate (765 mg) was dissolved in chloroform (4.59 mL), and trifluoroacetic acid (4.59 mL) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (1.21 g) as a crude product. The obtained crude product was used in the next reaction without further purification.

[0395] (5) 4-Bromo-2-(cyclopropylsulfonyl)-5-((R)-2-((R)-1,1,1-trifluoro-2-hydroxybutan-2-yl)azetidin-1-yl)pyridazin-3(2H)-one

[0396]

[0397] 4,5-Dibromo-2-(cyclopropylsulfonyl)pyridazin-3(2H)-one (30 mg) was mixed with N,N-dimethylformamide (300 μL), and the (R)-2-((R)-azetidin-2-yl)-1,1,1-trifluorobutan-2-ol 2,2,2-trifluoroacetate (27 mg) obtained in the previous step and N,N-diisopropylethylamine (44 μL) were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2 / 1 to 1 / 3) to obtain the title compound (32 mg). 1 H-NMR (DMSO-D6) δ: 8.03 (1H, s), 6.63 (1H, s), 4.96-4.90 (1H, m), 4.62-4.54 (1H, m), 4.20-4.14 (1H, m), 3.51-3.43 (1H, m), 2.59-2.52 (1H, m), 2.34-2.26 (1H, m), 1.82-1.71 (2H, m), 1.25-1.20 (4H, m), 0.94 (3H, t, J = 7.5 Hz).

[0398] [Production Example 5] Synthesis of 2-(cyclopropylsulfonyl)-4-iodo-5-((R)-2-((R)-1,1,1-trifluoro-2-hydroxybutan-2-yl)azetidin-1-yl)pyridazin-3(2H)-one (optically active substance of Example No. 63)

[0399]

[0400] (1) Synthesis of 5-chloro-4-iodopyridazin-3(2H)-one

[0401]

[0402] To 4,5-dichloro-3(2H)-pyridazinone (4.50 g) was added hydroiodic acid (concentration: 55 to 58%) (36.0 mL) at room temperature, and the mixture was heated to 110°C and stirred at the same temperature for 4 hours. After cooling the reaction solution to room temperature, water was added, and the solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (6.05 g) as a crude product. The obtained crude product was used in the next reaction without further purification.1 H-NMR (DMSO-D6) δ: 13.35 (1H, s), 7.87 (1H, s).

[0403] (2) 5-chloro-2-(cyclopropylsulfonyl)-4-iodopyridazin-3(2H)-one

[0404]

[0405] 5-Chloro-4-iodopyridazin-3(2H)-one (750 mg) obtained in the previous step was mixed with N,N-dimethylformamide (7.5 mL), and cyclopropanesulfonyl chloride (1.23 g) and potassium carbonate (1.21 g) were added sequentially thereto, followed by stirring at 80°C for 1 hour. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After removing insoluble matter by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 19 / 1 to 11 / 9) to give the title compound (432 mg) as a crude product. The resulting crude product was used in the next reaction without further purification. 1 H-NMR (DMSO-D6) δ: 8.07 (1H, s), 3.52-3.39 (1H, m), 1.37-1.20 (4H, m).

[0406] (3) 2-(cyclopropylsulfonyl)-4-iodo-5-((R)-2-((R)-1,1,1-trifluoro-2-hydroxybutan-2-yl)azetidin-1-yl)pyridazin-3(2H)-one

[0407]

[0408] N,N-Dimethylacetamide (0.70 mL) and triethylamine (0.16 mL) were added to 5-chloro-2-(cyclopropylsulfonyl)-4-iodopyridazin-3(2H)-one (70 mg) obtained in the previous step and (R)-2-((R)-azetidin-2-yl)-1,1,1-trifluorobutan-2-ol 2,2,2-trifluoroacetate (115 mg) obtained in Production Example 4(4), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 7 / 3 to 1 / 3) to give the title compound (68 mg). 1 H-NMR (CDCl3) δ: 7.70 (1H, s), 5.06-4.98 (1H, m), 4.83-4.77 (1H, m), 4.20-4.11 (1H, m), 3.61-3.53 (1H, m), 2.63-2.46 (3H, m), 1.89-1.76 (2H, m), 1.54-1.40 (2H, m), 1.22-1.14 (2H, m), 1.06 (3H, t, J = 7.5 Hz).

[0409] [Production Example 6] Synthesis of 2-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-6-azabicyclo[3.2.0]heptan-6-yl)-6-oxopyridazin-1(6H)-yl)-2-cyclopropylacetonitrile (Example No. 67)

[0410]

[0411] (1) tert-butyl 4-hydroxy-4-(trifluoromethyl)-6-azabicyclo[3.2.0]heptane-6-carboxylate

[0412]

[0413] tert-Butyl 4-oxo-6-azabicyclo[3.2.0]heptane-6-carboxylate (60 mg) was dissolved in tetrahydrofuran (600 μL), and (trifluoromethyl)trimethylsilane (63 μL) and an approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (142 μL) were added, followed by stirring at room temperature for 2 hours. An approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (568 μL) was added to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 2) to give the title compound (68 mg). 1 H-NMR (DMSO-D6) δ: 5.76 (1H, s), 4.48-4.34 (1H, m), 4.08-3.89 (1H, m), 3.54-3.35 (1H, m), 3.01-2.86 (1H, m), 2.28-2.02 (2H, m), 1.78-1.65 (2H, m), 1.37 (9H, s).

[0414] (2) 4-(trifluoromethyl)-6-azabicyclo[3.2.0]heptan-4-ol 2,2,2-trifluoroacetate

[0415]

[0416] tert-Butyl 4-hydroxy-4-(trifluoromethyl)-6-azabicyclo[3.2.0]heptane-6-carboxylate (68 mg) was dissolved in chloroform (683 μL), and trifluoroacetic acid (187 μL) was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (118 mg) as a crude product. The obtained crude product was used in the next reaction without further purification.

[0417] (3) 2-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-6-azabicyclo[3.2.0]heptan-6-yl)-6-oxopyridazin-1(6H)-yl)-2-cyclopropylacetonitrile

[0418]

[0419] 2-Cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetonitrile (30 mg) obtained in Production Example 3(1) was dissolved in N,N-dimethylformamide (300 μL), and 4-(trifluoromethyl)-6-azabicyclo[3.2.0]heptan-4-ol 2,2,2-trifluoroacetate (29 mg) obtained in the previous step and N,N-diisopropylethylamine (47 μL) were added thereto at room temperature, followed by stirring at 120° C. for 1 hour. The reaction solution was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2 / 1 to 1 / 3) and then further purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 2 / 3) to give the title compound (24 mg) as a diastereomeric mixture. 1 H-NMR (DMSO-D6) δ: 7.43-7.41 (1H, m), 6.79-6.76 (1H, m), 5.40-5.35 (1H, m), 5.08-5.04 (1H, m), 4.66-4.60 (1H, m), 4.39-4.34 (1H, m), 3.05-2.98 (1H, m), 2.43-2.33 (1H, m), 2.29-2.22 (1H, m), 1.90-1.70 (2H, m), 1.66-1.57 (1H, m), 0.79-0.66 (2H, m), 0.59-0.52 (1H, m), 0.43-0.36 (1H, m).

[0420] [Preparation Example 7] Synthesis of 2-(5-bromo-4-(5-hydroxy-5-(trifluoromethyl)-1-azaspiro[3.4]octan-1-yl)-6-oxopyridazin-1(6H)-yl)-2-cyclopropylacetonitrile (Example No. 128)

[0421]

[0422] (1) 1-(tert-butyl) 2-methyl 2-allylazetidine-1,2-dicarboxylate

[0423]

[0424] A solution of 1-(tert-butyl) 2-methyl azetidine-1,2-dicarboxylate (1.50 g) in tetrahydrofuran (15.0 mL) was cooled to -78°C, and a 1 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (7.67 mL) was added, followed by stirring at the same temperature for 15 minutes. Allyl bromide (0.905 mL) was added to the reaction solution at -78°C, and the mixture was gradually warmed to room temperature and stirred overnight. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 1) to give the title compound (1.40 g). 1 H-NMR (DMSO-D6) δ: 5.99-5.79 (1H, m), 5.24-5.16 (2H, m), 3.86-3.50 (5H, m), 2.76-2.48 (2H, m), 2.27-2.09 (2H, m), 1.42-1.27 (9H, m).

[0425] (2) 2-Allyl-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid

[0426]

[0427] To a solution of 1-(tert-butyl) 2-methyl 2-allylazetidine-1,2-dicarboxylate (1.40 g) in methanol (14.1 mL) was added 2 M aqueous sodium hydroxide solution (13.8 mL), and the mixture was stirred at room temperature overnight. 2 M hydrochloric acid was added to the reaction mixture, and the methanol was evaporated under reduced pressure. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.37 g). 1H-NMR (DMSO-D6) δ: 12.87 (1H, br s), 5.96-5.80 (1H, m), 5.26-5.13 (2H, m), 3.86-3.71 (1H, m), 3.65-3.46 (1H, m), 2.77-2.56 (1H, m), 2.56-2.44 (1H, m), 2.26-2.04 (2H, m), 1.46-1.27 (9H, m).

[0428] (3) tert-butyl 2-allyl-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate

[0429]

[0430] 2-Allyl-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (0.92 g) was dissolved in N,N-dimethylformamide (9.2 mL), and N,O-dimethylhydroxylamine hydrochloride (0.37 g), N,N-diisopropylethylamine (1.99 mL), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.74 g) were added thereto and stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4 / 1 to 1 / 2) to obtain the title compound (0.73 g). 1 H-NMR (DMSO-D6) δ: 5.97-5.81 (1H, m), 5.27-5.16 (2H, m), 3.67 (3H, s), 3.66-3.41 (2H, m), 3.12 (3H, s), 2.98-2.42 (2H, m), 2.32-2.12 (2H, m), 1.34 (9H, s).

[0431] (4) tert-butyl 2-acryloyl-2-allylazetidine-1-carboxylate

[0432]

[0433] A solution of tert-butyl 2-allyl-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (0.73 g) in tetrahydrofuran (7.29 mL) was cooled to 0°C, and a 2.1 M solution of vinylmagnesium chloride in tetrahydrofuran (1.47 mL) was added, followed by stirring at room temperature overnight. 1 M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 1) to give the title compound (0.34 g). 1 H-NMR (DMSO-D6) δ: 7.09-6.92 (1H, m), 6.38-6.26 (1H, m), 5.96-5.79 (2H, m), 5.27-5.17 (2H, m), 3.83-3.60 (2H, m), 2.81-2.44 (2H, m), 2.26-2.11 (2H, m), 1.38 (3.6H, s), 1.30 (5.4H, s).

[0434] (5) tert-butyl 5-oxo-1-azaspiro[3.4]oct-6-ene-1-carboxylate

[0435]

[0436] To a solution of tert-butyl 2-acryloyl-2-allylazetidine-1-carboxylate (0.34 g) in toluene (3.40 mL), (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (CAS 301224-40-8) (43 mg) was added, and the mixture was stirred for 4 hours at 90° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 1) to give the title compound (0.21 g). 1H-NMR (DMSO-D6) δ: 7.87-7.76 (1H, m), 6.29-6.18 (1H, m), 3.93-3.79 (1H, m), 3.78-3.70 (0.3H, m), 3.70-3.61 (0.7H, m), 3.06-2.87 (2H, m), 2.31-2.18 (1H, m), 2.15-2.04 (1H, m), 1.35 (2.8H, s), 1.23 (6.2H, s).

[0437] (6) tert-butyl 5-oxo-1-azaspiro[3.4]octane-1-carboxylate

[0438]

[0439] tert-Butyl 5-oxo-1-azaspiro[3.4]oct-6-ene-1-carboxylate (0.21 g) was dissolved in methanol (2.1 mL) and tetrahydrofuran (2.1 mL), and 10% palladium on carbon (0.10 g) was added thereto, followed by replacement with hydrogen. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere at 1 atmosphere pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.18 g) as a crude product. The obtained crude product was used in the next reaction without further purification.

[0440] (7) tert-butyl 5-hydroxy-5-(trifluoromethyl)-1-azaspiro[3.4]octane-1-carboxylate

[0441]

[0442] The tert-butyl 5-oxo-1-azaspiro[3.4]octane-1-carboxylate (0.18 g) obtained in the previous step was dissolved in tetrahydrofuran (1.82 mL), and (trifluoromethyl)trimethylsilane (0.18 mL) and an approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.40 mL) were added thereto, followed by stirring at room temperature for 2 hours. An approximately 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.62 mL) was added to the reaction solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 2) to give the title compound (0.17 g) as a diastereomeric mixture. 1 H-NMR (DMSO-D6) δ: 6.75 (1H, br s), 3.89-3.49 (2H, m), 2.60-2.36 (2H, m), 2.14-1.51 (6H, m), 1.40 (9H, s).

[0443] (8) 5-(trifluoromethyl)-1-azaspiro[3.4]octan-5-ol 2,2,2-trifluoroacetate

[0444]

[0445] tert-Butyl 5-hydroxy-5-(trifluoromethyl)-1-azaspiro[3.4]octane-1-carboxylate (166 mg) was dissolved in chloroform (1.64 mL), and trifluoroacetic acid (434 μL) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (258 mg) as a crude product. The obtained crude product was used in the next reaction without further purification.

[0446] (9) 2-(5-bromo-4-(5-hydroxy-5-(trifluoromethyl)-1-azaspiro[3.4]octan-1-yl)-6-oxopyridazin-1(6H)-yl)-2-cyclopropylacetonitrile

[0447]

[0448] 2-Cyclopropyl-2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetonitrile (30 mg) obtained in Production Example 3(1) was dissolved in N,N-dimethylformamide (300 μL), and 5-(trifluoromethyl)-1-azaspiro[3.4]octan-5-ol 2,2,2-trifluoroacetate (31 mg) obtained in the previous step and N,N-diisopropylethylamine (47 μL) were added thereto, followed by stirring at 120° C. for 1 hour. The reaction solution was purified by silica gel column chromatography (hexane / ethyl acetate = 19 / 1 to 1 / 3) and then further purified by ODS column chromatography (developing solvent: water / acetonitrile = 19 / 1 to 0 / 1) to give the title compound (1.2 mg) as a diastereomeric mixture. 1 H-NMR (CDCl3) δ: 7.96-7.93 (1H, m), 5.48-5.39 (1H, m), 4.85-4.76 (1H, m), 4.46-4.38 (1H, m), 2.88-2.74 (3H, m), 2.25-2.14 (2H, m), 2.12-1.72 (5H, m), 0.83-0.77 (1H, m), 0.71-0.60 (3H, m).

[0449] [Preparation Example 8] Synthesis of 4-bromo-5-(4-hydroxy-2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrrolidin-1-yl)-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one (Example No. 178)

[0450]

[0451] (1) 4,5-dibromo-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one

[0452]

[0453] N,N-Dimethylformamide (20 mL) was added to a mixture of 4,5-dibromopyridazin-3(2H)-one (2 g) and potassium carbonate (5.44 g). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.70 ml) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1 / 0 to 2 / 1) to give the title compound (2.05 g). 1 H-NMR (DMSO-D6) δ: 8.27 (1H, s), 4.99 (2H, q, J = 9.0 Hz).

[0454] (2) Methyl 4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate hydrochloride

[0455]

[0456] To a solution of 1-(tert-butyl) 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (500 mg) in tetrahydrofuran (10 mL), (trifluoromethyl)trimethylsilane (611 μL) and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.52 mL) were added in that order. Subsequently, a 4 M hydrogen chloride / ethyl acetate solution (5.14 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product (513 mg) containing the title compound. The obtained crude product was used in the next reaction without further purification.

[0457] (3) Methyl 1-(5-bromo-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-4-yl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate

[0458]

[0459] To a mixture of methyl 4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate hydrochloride (557 mg) and 4,5-dibromo-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one (250 mg), 1-methylpyrrolidin-2-one (2 mL) and triethylamine (1.04 mL) were added, and the reaction solution was stirred for 20 minutes at 80° C. The reaction solution was purified by ODS column chromatography (developing solvent: water / acetonitrile = 19 / 1 to 0 / 1) to obtain the title compound (68.2 mg). 1 H-NMR (DMSO-D6) δ: 7.87 (1H, s), 6.76 (1H, s), 5.66-5.61 (1H, m), 4.90 (2H, q, J = 9.1 Hz), 4.19-4.11 (2H, m), 3.67 (3H, s), 2.63-2.55 (1H, m), 2.39-2.32 (1H, m).

[0460] (4) 4-bromo-5-(4-hydroxy-2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrrolidin-1-yl)-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)-one

[0461]

[0462] To a solution of methyl 1-(5-bromo-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-4-yl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate (60 mg) in tetrahydrofuran (2 mL) was added dropwise a 3.4 M solution of methylmagnesium bromide in 2-methyltetrahydrofuran (0.15 mL) at 0°C, and the mixture was stirred at the same temperature for 20 minutes, followed by the addition of 2N hydrochloric acid. The reaction solution was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate) to give the title compound (10 mg). 1H-NMR (DMSO-D6) δ: 8.07 (1H, s), 6.86 (1H, s), 4.94-4.79 (2H, m), 4.74 (1H, s), 4.42 (1H, t, J = 8.0 Hz), 3.98 (1H, d, J = 12.0 Hz), 3.59 (1H, d, J = 12.8 Hz), 1.99-1.98 (2H, m), 1.10 (3H, s), 1.08 (3H, s).

[0463] [Intermediate Production Example 1] Synthesis of 2-bromo-3-methylbutanenitrile

[0464]

[0465] (1) 2-hydroxy-3-methylbutanenitrile

[0466]

[0467] Isobutyraldehyde (1.00 g) was dissolved in tetrahydrofuran (10.0 mL), and potassium carbonate (4.79 g) and trimethylsilyl cyanide (2.045 mL) were added thereto, followed by stirring at room temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 / 1 to 1 / 1) to give the title compound (81 mg). 1 H-NMR (DMSO-D6) δ: 6.33 (1H, d, J = 5.9 Hz), 4.34-4.29 (1H, m), 1.93-1.81 (1H, m), 0.98-0.92 (6H, m).

[0468] (2) 2-Bromo-3-methylbutanenitrile

[0469]

[0470] 2-Hydroxy-3-methylbutanenitrile (81 mg) obtained in the previous step was dissolved in dichloromethane (403 μL), and triphenylphosphine (319 mg) and carbon tetrabromide (269 mg) were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1 / 0 to 9 / 1) to give the title compound (37 mg). 1 H-NMR (DMSO-D6) δ: 5.14 (1H, d, J = 4.4 Hz), 2.25-2.08 (1H, m), 1.06 (6H, d, J = 6.6 Hz).

[0471] [Intermediate Production Example 2] Synthesis of 2-(azetidin-2-yl-3,3,4,4-d4)-1,1,1,3,3,3-hexafluoropropan-2-ol 4-methylbenzenesulfonate

[0472]

[0473] (1) 2-(benzylamino)ethane-1,1,2,2-d4-1-ol

[0474]

[0475] 10% Palladium carbon (315 mg), ethanol (75 mL), ethanol-1,1,2,2-d4-amine (7.13 g), and benzaldehyde (11.7 mL) were mixed in this order and purged with hydrogen. The reaction solution was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 13 hours. Celite and chloroform were added to the reaction solution, and then insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was azeotropically dehydrated with toluene and dried under reduced pressure to give a crude product (19.68 g) containing the title compound. The resulting crude product was used in the next reaction without further purification.

[0476] (2) tert-butyl N-benzyl-N-(2-hydroxyethyl-1,1,2,2-d4)glycinate

[0477]

[0478] N,N-Dimethylformamide (100 mL) was added to a mixture of 2-(benzylamino)ethan-1,1,2,2-d4-1-ol (17.08 g) and potassium carbonate (19.86 g). Under water cooling, bromoacetic acid tert-butyl ester (18.0 mL) was added dropwise over 40 minutes, and the mixture was stirred for 7 hours. Toluene and water were added to the reaction mixture, and the two layers were separated. The aqueous layer was extracted twice with toluene, and the organic layer was washed with water. The combined organic layers were extracted sequentially with 1N hydrochloric acid (150 mL), 0.1N hydrochloric acid (200 mL), and water. Under ice cooling, 4N aqueous sodium hydroxide solution (47 mL) and saturated aqueous sodium bicarbonate solution were added to the acidic aqueous layer, and the pH was adjusted to 10. Extraction was performed twice with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was azeotropically dehydrated with toluene and dried under reduced pressure to obtain the title compound (20.38 g). 1 H-NMR (DMSO-D6) δ: 7.35-7.20 (5H, m), 4.31 (1H, s), 3.75 (2H, s), 3.23 (2H, s), 1.41 (9H, s).

[0479] (3) tert-butyl N-benzyl-N-(2-chloroethyl-1,1,2,2-d4)glycinate

[0480]

[0481] Under a nitrogen atmosphere, thionyl chloride (6.48 mL) was added dropwise over 10 minutes to a solution of tert-butyl N-benzyl-N-(2-hydroxyethyl-1,1,2,2-d4)glycinate (18.4 g) in chloroform (92 mL) at 0°C. The mixture was stirred at room temperature for 10 minutes and at 60°C for 2 hours. The reaction mixture was returned to room temperature and added dropwise to a bilayer solution of 10% aqueous sodium bicarbonate (220 mL) and chloroform (40 mL) at 0°C. The bilayer solution was stirred at 0°C for 30 minutes and at room temperature for 1 hour. The two layers were separated, and the aqueous layer was extracted with chloroform (30 mL). The combined organic layers were washed with 20% aqueous sodium chloride (100 mL) and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was azeotropically dehydrated twice with toluene and dried under reduced pressure at 40°C to give the title compound (17.04 g).1 H-NMR (DMSO-D6) δ: 7.36-7.23 (5H, m), 3.79 (2H, s), 3.27 (2H, s), 1.42 (9H, s).

[0482] (4) tert-butyl 1-benzylazetidine-2-carboxylate-3,3,4,4-d4

[0483]

[0484] Under a nitrogen atmosphere, 1,3-dimethyltetrahydropyrimidin-2(1H)-one (11.33 mL) was added to a solution of tert-butyl N-benzyl-N-(2-chloroethyl-1,1,2,2-d4)glycinate (17.02 g) in tetrahydrofuran (120 mL). A 1.6 M solution of lithium hexamethyldisilazane in tetrahydrofuran (54.6 mL) was added dropwise to the reaction mixture at 0°C over 10 minutes, followed by stirring at 0°C for 45 minutes and then at room temperature for 30 minutes. Toluene (180 mL), ice (30 g), and water (150 mL) were added sequentially to the reaction mixture at room temperature, followed by stirring at room temperature for 15 minutes. The reaction mixture was separated into two layers, and the organic layer was washed sequentially with saturated aqueous ammonium chloride (100 mL) and 20% aqueous sodium chloride (100 mL). The combined aqueous layers were extracted with toluene (50 mL), the combined organic layers were dried over anhydrous sodium sulfate, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give a residue, which was purified twice by silica gel column chromatography (eluent: hexane / ethyl acetate = 6 / 1 to 1 / 1). The resulting product was azeotropically dehydrated twice with toluene (30 mL) and dried under reduced pressure at 40°C to give the title compound (11.24 g). 1 H-NMR (DMSO-D6) δ: 7.34-7.20 (5H, m), 3.75 (1H, d, J = 12.7 Hz), 3.61 (1H, s), 3.49 (1H, d, J = 12.7 Hz), 1.34 (9H, s).

[0485] (5) Di-tert-butyl azetidine-1,2-dicarboxylate-3,3,4,4-d4

[0486]

[0487] Di-tert-butyl dicarbonate (11.59 g), methanol (50 mL), and 20% palladium hydroxide on carbon (1.21 g) were added to a solution of tert-butyl 1-benzylazetidine-2-carboxylate-3,3,4,4-d4 (12.14 g) in tetrahydrofuran (50 mL), and the mixture was purged with hydrogen. The mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere at 4 atmospheres, purged with hydrogen again, and stirred at room temperature for an additional 12 hours. Insoluble matter was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 40°C to give a crude product (13.75 g) containing the title compound. The crude product was used in the next reaction without further purification. 1 H-NMR (DMSO-D6) δ: 4.37 (1H, s), 1.43 (9H, s), 1.35 (9H, s).

[0488] (6) 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid-3,3,4,4-d4

[0489]

[0490] To a mixed solution of di-tert-butyl azetidine-1,2-dicarboxylate-3,3,4,4-d4 (12.6 g) in tetrahydrofuran (80 mL) and methanol (80 mL), 4N aqueous sodium hydroxide (35.9 mL) was added at room temperature, and the mixture was stirred at room temperature for 20 hours. The organic solvent was then evaporated under reduced pressure. Water (20.5 mL) and citric acid (13.89 g) were added to the residue, and the mixture was extracted three times with chloroform (40 mL, 15 mL, 15 mL). 1M aqueous potassium hydrogen sulfate (20 mL) was added to the aqueous layer, and the mixture was extracted twice with chloroform (10 mL, 10 mL). The combined organic layers were washed with 20% aqueous sodium chloride (25 mL), and then 1M aqueous potassium hydrogen sulfate (2 mL) was added to the washed aqueous layer, and the mixture was extracted twice with chloroform (10 mL, 10 mL). The organic layers were combined and dried over anhydrous magnesium sulfate, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was azeotropically dehydrated twice with toluene (20 mL) and dried under reduced pressure at room temperature to give the title compound (9.45 g). 1H-NMR (DMSO-D6) δ: 12.78 (1H, br s), 4.41 (1H, s), 1.35 (9H, s).

[0491] (7) 1-(tert-butyl) 2-methyl azetidine-1,2-dicarboxylate-3,3,4,4-d4

[0492]

[0493] To a mixed solution of 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid-3,3,4,4-d4 (9.45 g) in toluene (95 mL) and methanol (47.3 mL), a 0.6 M hexane solution (100 mL) of trimethylsilyldiazomethane was added dropwise over 20 minutes under ice cooling. The mixture was stirred for 1 hour under ice cooling, and then acetic acid (0.79 mL) was added dropwise and stirred at room temperature for 15 minutes. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6 / 1 to 2 / 1). The resulting product was azeotropically dehydrated with toluene and dried under reduced pressure at 40 °C to give the title compound (9.87 g). 1 H-NMR (CDCl3) δ: 4.60 (1H, s), 3.78 (3H, s), 1.42 (9H, s).

[0494] (8) tert-butyl 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate-3,3,4,4-d4

[0495]

[0496] Under a nitrogen atmosphere, to a solution of 1-(tert-butyl) 2-methyl azetidine-1,2-dicarboxylate-3,3,4,4-d4 (9.87 g) in 1,2-dimethoxyethane (30 mL), (trifluoromethyl)trimethylsilane (9.96 mL) and cesium fluoride (137 mg) were added at −5° C. to 0° C., the cold bath was removed, and the internal temperature was raised to 5° C. The reaction solution was cooled to −72° C., and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (9 mL) was added dropwise over 5 minutes. After stirring at −72° C. for 45 minutes, acetic acid (1.29 mL) was added dropwise over 1 minute, N,N-dimethylformamide (49.4 mL) was added dropwise over 15 minutes, and (trifluoromethyl)trimethylsilane (23.24 mL) was added dropwise over 10 minutes. The internal temperature of the reaction solution was raised from -32°C to -30°C over 30 minutes, and after stirring at the same temperature for 2.5 hours, the internal temperature was lowered to -35°C over 10 minutes. Acetic acid (1.55 mL) was added dropwise over 2 minutes, followed by a 1M tetrabutylammonium fluoride tetrahydrofuran solution (27 mL) over 15 minutes. The cold bath was removed, and the mixture was stirred at an internal temperature of -3°C for 1 hour. Saturated aqueous ammonium chloride solution (60 mL) was added dropwise to the reaction solution over 10 minutes, followed by addition of ethyl acetate (100 mL) and stirring for 10 minutes. The two layers were separated. Hexane (50 mL) was added to the organic layer, and the mixture was washed sequentially with water (40 mL) and 20% aqueous sodium chloride solution (40 mL). The combined aqueous layers were extracted with a 1:1 mixed solvent of hexane and ethyl acetate (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate=9 / 1) to obtain the title compound (9.12 g). 1 H-NMR (CDCl3) δ: 7.31 (1H, br s), 4.71 (1H, s), 1.46 (9H, s).

[0497] (9) 2-(azetidin-2-yl-3,3,4,4-d4)-1,1,1,3,3,3-hexafluoropropan-2-ol 4-methylbenzenesulfonate

[0498]

[0499] Under a nitrogen atmosphere, tert-butyl 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate-3,3,4,4-d4 (11.85 g) in a mixed solution of ethyl acetate (23.7 mL) and tetrahydrofuran (11.85 mL), p-toluenesulfonic acid monohydrate (7.23 g) was added, and the mixture was stirred at 80 ° C. for 4 hours. After stirring, p-toluenesulfonic acid monohydrate (344 mg) was added and stirred at 80 ° C. for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was azeotropically dehydrated three times with toluene (40 mL), and then a mixed solvent of ethyl acetate and toluene (1 / 5, 60 mL) was added and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed sequentially with a mixed solvent of ethyl acetate and toluene (1 / 5), and toluene. The resulting solid was dried under reduced pressure at 50° C. for 1 hour to give the title compound (14.27 g). 1 H-NMR (DMSO-D6) δ: 9.74 (1H, br s), 9.37 (2H, br s), 7.47 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz), 5.23 (1H, s), 2.29 (3H, s).

[0500] Intermediate Production Example 3: Synthesis of 2-(3-(trifluoromethyl)pyrrolidin-3-yl)butan-2-ol

[0501]

[0502] (1) 1-benzyl-3-(trifluoromethyl)pyrrolidine-3-carboxylic acid

[0503]

[0504] Under an argon atmosphere, N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (5.55 mL) was added dropwise to a solution of 2-(trifluoromethyl)acrylic acid (3.17 g) in dichloromethane (50 mL) under ice-cooling, followed by the addition of trifluoroacetic acid (0.265 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to give a crude product (5.96 g) containing the title compound. The obtained crude product was used in the next reaction without further purification.

[0505] (2) 1-benzyl-N-methoxy-N-methyl-3-(trifluoromethyl)pyrrolidine-3-carboxamide

[0506]

[0507] Under an argon atmosphere, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.35 g), 1-hydroxy-7-azabenzotriazole (0.147 g), and N,O-dimethylhydroxylamine hydrochloride (2.32 g) were added to a solution of 1-benzyl-3-(trifluoromethyl)pyrrolidine-3-carboxylic acid (5.9 g) in acetonitrile (50 mL) at 0°C, followed by dropwise addition of triethylamine (4.51 mL) and stirring at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution, and the two layers were separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4 / 1 to 1 / 4) to give the title compound (2.26 g).

[0508] (3) 1-(1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)propan-1-one

[0509]

[0510] Under an argon atmosphere, a 3 M diethyl ether solution (1.05 mL) of ethylmagnesium bromide was added dropwise to a tetrahydrofuran (5 mL) solution of 1-benzyl-N-methoxy-N-methyl-3-(trifluoromethyl)pyrrolidine-3-carboxamide (500 mg) at 0°C, and the mixture was stirred at room temperature for 3 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction mixture, and the two layers were separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 19 / 1 to 7 / 3) to give the title compound (193 mg). 1H-NMR (DMSO-D6) δ: 7.36-7.23 (5H, m), 3.67-3.57 (2H, m), 3.15-3.10 (1H, m), 2.78-2.62 (4H, m), 2.53-2.34 (2H, m), 2.11-2.04 (1H, m), 0.97 (3H, t, J = 7.0 Hz).

[0511] (4) 2-(1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)butan-2-ol

[0512]

[0513] Under an argon atmosphere, a 3.4 M solution of methylmagnesium bromide in 2-methyltetrahydrofuran (0.59 mL) was added dropwise to a solution of 1-(1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)propan-1-one (190 mg) in tetrahydrofuran (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and 10 minutes, and then 1N hydrochloric acid and ethyl acetate were added, and the two layers were separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 97 / 3 to 7 / 3) to give the title compound (175 mg) as a diastereomeric mixture. 1 H-NMR (DMSO-D6) δ: 7.35-7.20 (5H, m), 4.59-4.56 (1H, m), 3.63-3.50 (2H, m), 2.80-2.72 (1H, m), 2.63-2.56 (2H, m), 2.18-2.07 (1H, m), 1.87-1.75 (1H, m), 1.64-1.53 ​​(0.5H, m), 1.51-1.35 (1.5H, m), 1.12 (1.5H, s), 1.07 (1.5H, s), 0.90-0.83 (3H, m).

[0514] (5) 2-(3-(trifluoromethyl)pyrrolidin-3-yl)butan-2-ol

[0515]

[0516] To a solution of 2-(1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)butan-2-ol (170 mg) in ethanol (2 mL) was added 10% palladium on carbon (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere at 4 atmospheres for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (132 mg). The obtained crude product was used in the next reaction without further purification.

[0517] 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 217 are shown in the following table.

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] Examples 3 and 4, Examples 6 and 7, Examples 14 and 15, Examples 22 and 23, Examples 25 and 26, Examples 27 and 28, Examples 29 and 30, Examples 31 and 32, Examples 33 and 34, Examples 35 and 36, Examples 37 and 38, Examples 39 and 40, Examples 41 and 42, Examples 50 and 51, Examples 52 and 53, Examples 54 and 55, Examples 61 and 62, Examples 69 and 70, Examples 71 and 72, Examples 73 and 74, Examples 75 and 76, Examples 77 and 78, Examples 79 and 80, Examples 84 and 85, Examples 90 and 91, Examples 94 and 95, Examples 96 and 97, Examples 98 and 99, Examples 104 and 105, Examples 123 and 124, Examples 137 and 138, Examples 140 and 141, Examples 144 and 145, Examples 149 and 150, and Examples 157 and 158 are diastereomeric combinations that differ in configuration at the carbon to which the cyano group is bonded.

[0576] The preparative conditions for preparative supercritical fluid chromatography (SFC preparative) were as follows: Preparative conditions for Examples 3 and 4, and Examples 6 and 7: YAMAZEN silica gel column, n-hexane / ethyl acetate; Preparative conditions for Examples 161 and 162: CHIRALPAK® IG / SFC (10 mm (ID) x 250 mm (L), 5 μm), CO ２ / MeOH (90 / 10), isocratic; Preparative conditions for Examples 208 and 209: CHIRALPAK® IA / SFC (10 mm (ID) x 250 mm (L), 5 μm), CO ２ / MeOH (65 / 35-40 / 60), gradient; Preparative conditions for Examples 215, 216, and 217: CHIRALPAK® IG / SFC (10 mm (ID) x 250 mm (L), 5 μm), CO ２ / MeOH (90 / 10), isocratic.

[0577] Test Example 1: Evaluation of MRGPRX2 signaling activity cDNAs for MRGPRX2 and the calcium-sensitive photoprotein Aequorin were each inserted into a pcDNA3.1(+) vector, and transfected into HEK293 cells (purchased from ATCC; CRL1573) using Lipofectamine 3000. The cells were incubated at 37°C and 5% CO ２ The cells were maintained in a 500-µL incubator for 48 hours, and transiently expressed cells were used for the assay. The cells were suspended in DMEM / F-12 medium containing 0.3% BSA and 10 µM luminescent substrate Coelenterazine H, plated into a 384-well assay plate at 4,000 cells per well in 20 µL, and then incubated in the dark at 25°C for 4 hours. Test compounds dissolved in dimethyl sulfoxide to a concentration of 10 mM were serially diluted 1:3 with assay buffer (DMEM / F-12 medium containing 0.3% BSA) and added to the cells to a maximum final concentration of 10 µM. The peptide agonist Substance P was suspended in assay buffer and added to the cells using the dispensing head of the FDSS7000EX to final concentrations of 0.1 µM, 1 µM, or 10 µM. Luminescence values ​​were measured over time, and IC values ​​were calculated by logistic regression analysis from plots of the area under the curve (AUC). ５０ The value was calculated.

[0578] The evaluation results for each test compound are shown in Tables 58 to 61 below.

[0579]

[0580]

[0581]

[0582]

[0583] Examples of the formulation of the present invention include the following formulations, but the present invention is not limited to these formulation examples.

[0584] Formulation Example 1 (Production of Capsules) 1) Compound of Example 3 30 mg 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.

[0585] Formulation Example 2 (Tablet Production) 1) Compound of Example 3 10 g 2) Lactose 50 g 3) Cornstarch 15 g 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amount of 1), 2), and 3) and 30 g of 4) were kneaded with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) were mixed with this sized powder and compressed into tablets using a tablet press. 1,000 tablets containing 10 mg of the compound of Example 3 per tablet were thus obtained.

[0586] The compound [III] of the present invention or a pharmaceutically acceptable salt thereof is useful for the treatment and / or prevention of pseudoallergy, atopic dermatitis, chronic urticaria (particularly chronic idiopathic urticaria), contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, etc.

[0587] This application is based on Japanese Patent Application No. 2024-106031 filed on July 1, 2024 in Japan, the contents of which are incorporated in their entirety herein.

Claims

A compound of formula [III] or a pharmaceutically acceptable salt thereof. {In formula [III], X represents a halogen; R １ 'teeth, (1) Formula: (where, R １ａ 'teeth, (a) hydrogen, (b) C １－４ alkyl, or (c) Cyano and R １ｂ 'teeth, (a) C optionally substituted with 1 to 3 halogens １－４ alkyl, or (b) C ３－４ cycloalkyl (Indicates a group represented by (2) -SO ２ W' (where W' is (a) C １－４ Alkyl, (b) C １－４ C optionally substituted with alkyl ３－４ cycloalkyl, or (c) Phenyl optionally substituted with 1 or 2 halogens (indicating (3) C ３－４ cycloalkyl, or (4) Bicyclo[1.1.1]pentan-1-yl and Cy is (1) Formula: (where, R ２ 'teeth, (a) hydrogen, (b) C optionally substituted with 1 to 5 halogens １－４ Alkyl, (c) C ３－４ cycloalkyl, or (d) -CH ２ CH ２ NHCOCH ３ indicates; R ３ teeth, (a) hydrogen, or (b) C optionally substituted with 1 to 3 halogens １－４ Alkyl and R ４ ', R ５ ', R ６ ', and R ７ ' are each independently (a) hydrogen, (b) halogen, or (c) C １－４ Alkyl or R ２ ' and R ６ ' taken together with the carbon atoms to which they are attached form a cyclopentane fused to azetidine; or R ２ ' and R ４ ' together with the carbon atom to which they are attached form a cyclopentane spiro-bonded to the azetidine) or a group represented by (2) Formula: (where, R ８ teeth, (a) hydrogen, (b) phenyl, (c) C optionally substituted by hydroxy １－４ alkyl, or (d) -COOH ３ indicates; R ９ teeth, (a) hydrogen, (b) phenyl, or (c) -COOCH ２ CH ３ and R １０ teeth, (a) hydrogen, (b) hydroxy, or (c) C optionally substituted by 1 to 3 T １－４ alkyl (wherein each T is independently hydroxy or halogen); and R １１ is a halogen; or R １０ and R １１ are taken together with the carbon atom to which they are attached to form a C 1 which may be further substituted with 1 to 4 halogen atoms in addition to two fluorine atoms spiro-bonded to the pyrrolidine. ３－４ forming a cycloalkane) A group represented by indicates.} 　 Cy is, Mode: (The symbols in the formula have the same meanings as in claim 1.) The compound according to claim 1, wherein the compound is a group represented by the formula: R １ ', but the expression: (In the formula, R １ａ ' and R １ｂ ' has the same meaning as in claim 1) 3. The compound according to claim 1 or 2, wherein the compound is a group represented by the formula: R １ａ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2; R １ 'But, -SO ２ 3. The compound according to claim 1 or 2, wherein W' is as defined in claim 1, or a pharmaceutically acceptable salt thereof. R ４ ', R ５ ', R ６ ', and R ７ ' but independently, (1) Hydrogen, (2) Fluorine, or (3) Methyl 6. The compound according to any one of claims 1 to 5, wherein: 　 The following structural formula:

2. The compound of claim 1, selected from the group consisting of compounds having the formula: 　 A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 　 A Mas-related G protein-coupled receptor X2 antagonist comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. 　 A therapeutic or preventive agent for a disease selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. 　 The therapeutic or preventive agent according to claim 10, wherein the chronic urticaria is chronic idiopathic urticaria.

10. A method for inhibiting Mas-related G protein-coupled receptor X2 in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. 　 A method for treating or preventing a disease selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the chronic urticaria is chronic idiopathic urticaria.

10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a Mas-related G protein-coupled receptor X2 antagonist. 　 Use of the compound according to any one of claims 1 to 7 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 pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis.

17. The use according to claim 16, wherein the chronic urticaria is chronic idiopathic urticaria.

10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in inhibiting the Mas-related G protein-coupled receptor X2.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of pseudoallergy, atopic dermatitis, chronic urticaria, irritant-induced urticaria, contact dermatitis, rosacea, rheumatoid arthritis, inflammatory bowel disease, idiopathic pulmonary fibrosis, vitiligo, periodontal disease, irritable bowel syndrome, and interstitial cystitis.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 19, wherein the chronic urticaria is chronic idiopathic urticaria.

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