Hydroxytriazine compounds and their medical uses

Abstract

To provide a compound that has mPGES-1 inhibitory action and is beneficial for the prophylaxis or treatment of pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, and / or malignant tumor including colorectal cancer.SOLUTION: The present invention provides a compound of formula [I-a], [I-b] or [I-c] or a pharmaceutically acceptable salt thereof, wherein each symbol is as defined in the specification.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a human prostaglandin E2 synthase-1 (mPGES-1) inhibitor. The present invention relates to a hydroxytriazine compound or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and medical uses thereof. [Background technology]

[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are They are widely used to treat illnesses accompanied by fever and pain, such as rheumatism, osteoarthritis, and headaches. NSAIDs inhibit cyclooxygenase (COX) and thus inhibit the production of prostanoids. This results in anti-inflammatory, antipyretic and analgesic effects.

[0003] There are two types of COX: COX-1, which is ubiquitously distributed and constitutively expressed, and COX-2, whose expression is induced by various pro-inflammatory stimuli, such as cytokines such as interleukin-1β (IL-1β). There are two isoforms of COX-1 and COX-2. COX-1 and COX-2 are enzymes that convert arachidonic acid derived from biological membranes into prostaglandin H2 (PGH2), a precursor of prostanoids. The conversion of PGH2 into each prostanoid (prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostaglandin I2 (PGI2), prostaglandin D2 (PGD2), thromboxane A2 (TXA2), etc.) is carried out by a specific prostanoid synthesis enzyme. These prostanoids have various physiological activities, such as inflammation induction / suppression, vasodilation / constriction, bronchial dilation / constriction, hypnosis / awakening, and fever. PGE2 is the most abundant prostaglandin in the body and is known to be strongly involved in inflammation, pain, and fever. For this reason, it is considered that the main mechanism of action of NSAIDs is to inhibit PGE2 production.

[0004] Inhibition of COX-1 or COX-2 suppresses the production of all downstream prostanoids. This is thought to be the cause of the side effects of NSAIDs. NSAIDs, which non-selectively inhibit COX, also suppress the production of PGE2 by COX-1, and since PGE2 acts protectively against gastric mucosal disorders, NSAIDs are thought to suppress gastric mucus secretion and gastric mucosal blood flow, increasing the risk of gastric perforation and bleeding. In addition, selective COX-2 inhibitors have a vasodilatory effect and a platelet aggregation inhibitory effect in vascular endothelial cells. It inhibits the production of PGI2, a blood coagulation factor produced by COX-1 in platelets. It does not suppress the production of TXA2, which is involved in the production of erythrocyte sedimentation (ECG), and is therefore thought to disrupt the balance of the blood coagulation system and increase the risk of cardiovascular disorders.

[0005] Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes the final step of PGE2 biosynthesis. It is an enzyme that mediates the synthesis of mPGES-1 and belongs to the membrane-associated proteins in eicosanoid and glutathione metabolism family (MAPEG family). The human mPGES-1 gene was cloned in 1999, and it was shown to be constitutively expressed in the placenta, prostate, testis, and mammary gland (Non-Patent Document 1). In other organs, human mPGES-1 expression is induced by various inflammatory stimuli in conjunction with COX-2. For example, the inflammatory cytokines IL-1β and Tumor Necrosis Factor-α (TNFα) promote the expression of synovial cells, osteoblasts, endothelial cells, and orbital fibers. It induces mPGES-1 expression in blastoma cells, gingival cells, chondrocytes, endothelial cells, cardiac myocytes, etc. Lipopolysaccharide (LPS), a bacterial endotoxin, induces mPGES-1 expression in macrophages, smooth muscle, and other cells.

[0006] It is believed that mPGES-1 inhibitors selectively suppress PGE2 production only in the local area of ​​inflammation or in tissues where mPGES-1 is expressed, and do not suppress the production of prostanoids other than PGE2 (PGI2, PGD2, PGF2α, TXA2, etc.) (Non-Patent Documents 2 and 3). Therefore, mPGES-1 inhibitors are equivalent to NSAIDs. However, it has the side effects of NSAIDs due to the decreased production of prostanoids other than PGE2. It is believed that this will be a drug that does not

[0007] It is also known that blocking a part of the metabolic pathway downstream of PGH2 in the arachidonic acid cascade causes PGH2 to be converted to prostanoids other than the blocked pathway, i.e., shunting occurs. The amount of PGE2 produced in macrophages was measured using macrophages derived from wild-type (WT) mice stimulated with LPS. The levels of TXB2, PGI2, PGD2, and PGF2α produced by macrophages from mPGES-1 knockout mice stimulated with LPS were lower than those of PGE2 produced by phages, but were higher than those of WT mice stimulated with LPS. It is known that the amount of each prostanoid produced in mouse macrophages is increased by mPGES-1 inhibitors, which suppress PGE2 production and also suppress the production of other prostanoids (Non-Patent Document 4). Since it increases the level of insulin resistance, it is thought to be effective in treating diseases other than those caused by NSAIDs.

[0008] The uses of mPGES-1 inhibitors are described below. (1)Pain In mPGES-1 knockout mice, the amount of PGE2 produced in the peritoneal cavity and the number of pain responses per unit time were significantly reduced in comparison with WT mice in the evaluation of pain responses induced by LPS stimulation, a model of acute inflammatory pain. Therefore, mPGES-1 inhibitors can be used as an analgesic for acute inflammatory pain. It is believed that (Non-Patent Documents 3 and 6). (2) Rheumatism The mPGES-1 gene in Swedish women increases the risk and severity of rheumatoid arthritis There are several single nucleotide polymorphisms that increase the severity of rheumatoid arthritis. In the synovium of rheumatoid arthritis patients with a single nucleotide polymorphism (Reference SNP ID number: rs23202821) that increases the severity of rheumatoid arthritis, the level was higher in patients without the mutation. Increased mPGES-1 expression has been confirmed by immunohistological analysis in response to the inflammatory response of mPGES-1 (Non-Patent Document 5). In mPGES-1 knockout mice, inflammatory cell infiltration into the joints, joint destruction, and limb swelling are significantly suppressed in a collagen-induced arthritis model, which is an animal model of rheumatoid arthritis, compared to WT mice (Non-Patent Document 6). Therefore, mPGES-1 inhibitors are considered to be a therapeutic drug for rheumatoid arthritis. can be. (3) Osteoarthritis mPGES-1 mRNA expression is increased in meniscal chondrocytes from patients with osteoarthritis (Non-Patent Reference 7). The mPGES-1 inhibitor significantly reduced osteoarthritis caused by monoiodoacetic acid compared to WT mice. The mPGES-1 inhibitor reduces the pain response in a model of osteoarthritis (Patent Document 1). It is thought to be a treatment for osteoarthritis. (4) Fever In mPGES-1 knockout mice, LPS-induced rise in body temperature is suppressed compared to WT mice (Non-Patent Document 8). Therefore, mPGES-1 inhibitors are considered to be effective antipyretics. (5) Alzheimer’s disease Long-term use of NSAIDs mitigates the onset and progression of Alzheimer's disease. In primary cultured brain neurons of QoE mice, PGE2 production is suppressed and neuronal cell death does not occur when treated with amyloid β peptide, compared to brain neurons of WT mice (Non-Patent Document 9). Therefore, mPGES-1 inhibitors are thought to be a therapeutic drug for Alzheimer's disease. (6) Multiple sclerosis Several single nucleotide polymorphisms in the EP4 gene of multiple sclerosis patients increase the risk of developing the disease. mPGES-1 protein expression has been confirmed in macrophages present in the demyelinated periventricular areas of multiple sclerosis patients. In mPGES-1 knockout mice, the multiple sclerosis syndrome was observed to be more frequent than in WT mice. In experimental autoimmune encephalomyelitis model mice, which is an animal model of chronic sclerosis, the production of PGE2 in the spinal cord is suppressed, and the progression of paralysis is inhibited (Non-Patent Document 10). It is believed to be a potential treatment for multiple sclerosis. (7) Arteriosclerosis mPGES-1 knockout mice showed atherosclerosis model in comparison with WT mice. In mice lacking the low-density lipoprotein receptor, which is a high-fat diet-fed drug, PGE2 production from vascular endothelial cells is reduced, and atheroma formation is delayed. In vascular endothelial cells, production of PGI2, which is known to have an inhibitory effect on platelet function, is increased (Non-patent Document 11). Therefore, mPGES-1 inhibitors are effective in preventing atherosclerosis. It is believed to be a preventive or therapeutic agent for sclerosis. (8) Glaucoma, ocular hypertension Glaucoma is a disease that causes characteristic changes in the optic nerve and visual field, and this optic nerve damage can usually be improved or prevented by sufficient reduction of intraocular pressure. Glaucoma can be classified as open-angle glaucoma or angle-closure glaucoma. The mPGES-1 gene is constitutively highly expressed in human conjunctiva (GEO accession No: GSE2513 (Gene Expression Omnibus: http: / / www.ncbi.nlm.nih.gov / geo / )). Glaucoma patients In the retina of mice with glaucoma, expression of mPGES-1 was increased compared to that of healthy controls. Expression of mPGES-1 is increased in the retinas of hypertensive dogs and mice compared to normal animals (GEO accession no: human GSE2378, dog GSE21879, mouse GSE3554). When PGE2 was instilled into the eyes of healthy individuals, an increase in intraocular pressure accompanied by vasodilation occurred for two hours after administration. When PGE2 is administered subconjunctivally to rabbits, intraocular pressure increases due to swelling of the ciliary body and increased aqueous humor production (Non-Patent Document 13). Prostaglandins PGF2α and PGD2 reduce intraocular pressure in rabbits (Non-Patent Document 14). PGF2α preparations promote the drainage of aqueous humor and are used as glaucoma treatments to reduce intraocular pressure. PGI2 does not show a clear effect on intraocular pressure in rabbits. It is believed that intraocular pressure decreases because the decrease in PGD2 and PGF2α suppresses aqueous humor production and / or the increase in PGD2 and PGF2α due to the shunt promotes aqueous humor outflow. When administered as eye drops to cynomolgus monkeys, it significantly reduces intraocular pressure (Patent Document 2). In addition, PGE2 enhances the expression of vascular endothelial growth factor (VEGF) from the retina (Non-Patent Document 15). VEGF produced in the retina migrates to the anterior segment of the eye, causing neovascularization in the iris, which then causes the occlusion of the angle, resulting in neovascular glaucoma in which intraocular pressure rises. The mPGES-1 inhibitor is also thought to be effective in improving and preventing neovascular glaucoma. Furthermore, because it is thought to have an anti-inflammatory effect due to the inhibition of PGE2 production, it is thought that it can be used in patients with intraocular inflammation, for whom existing prostaglandin preparations (latanoprost, etc.) should be administered with caution. Therefore, mPGES-1 inhibitors are effective treatments for glaucoma with various underlying diseases. It is thought that this will be the case. (9) Ischemic retinal disease Excessive secretion of VEGF plays a central role in ischemic retinal diseases such as diabetic retinopathy, diabetic macular edema, and retinal vein occlusion. Since PGE2 enhances the expression of VEGF (Non-Patent Document 15), it is believed that mPGES-1 inhibitors will improve these pathologies. (10) Systemic sclerosis Expression of mPGES-1 is increased in the skin of patients with systemic sclerosis compared to healthy individuals. Furthermore, mPGES-1 expression is increased in the skin of bleomycin-induced scleroderma model mice, a model of systemic scleroderma, compared to the skin of normal mice. Compared to WT mice, mPGES-1 knockout mice showed reduced accumulation of macrophages in the skin of lesions in bleomycin-induced scleroderma model mice, and reduced epidermal thickening, extracellular matrix deposition, and increased collagen fiber volume (Non-Patent Document 16). Therefore, mPGES-1 inhibitors could be a therapeutic drug for systemic scleroderma. It is thought that. (11) Malignant tumor In mPGES-1 knockout mice, the number and size of polyps in azoxymethane-induced colon cancer model mice, an animal model of colon cancer, were significantly suppressed compared to WT mice. In mPGES-1 knockout mice, the production of PGE2 in colon tumor tissue was reduced compared to WT mice, and the expression of PGI2 and peroxisome proliferator-activated receptor agonists, which inhibit the adhesion of cancer cells, was reduced. mPGES-1 knockout mice were transplanted with colon cancer or lung cancer cells into their spleens, and the tumor weight and metastasis rate to the liver were reduced after transplantation compared to WT mice. In an in vitro co-culture system with mouse bone marrow-derived macrophages, the proliferation of lung cancer cells was reduced compared to that with WT mouse bone marrow-derived macrophages, indicating that PGE2 derived from the host macrophages is involved in the proliferation of cancer cells (Non-Patent Document 17). It is believed that this will be an anticancer drug that suppresses the growth and metastasis of cancers, including colon cancer. (12) Diseases in which inhibition of PGE2 production is effective Inflammatory conditions and / or pain associated with such conditions for which NSAIDs are effective include, for example: Arthritis, gout, kidney stones, urinary stones, headache, menstrual pain, toothache, lower back pain, muscle pain, shoulder periarthritis, cervicobrachial syndrome, temporomandibular joint disorder, and inflammation and pain after surgery, trauma, and tooth extraction. Other examples include acute and chronic non-bacterial inflammation of the eye, such as uveitis, allergic conjunctivitis, and postoperative inflammation and eye pain in internal eye surgery. The main mechanism by which NSAIDs are effective is thought to be the inhibition of the production of PGE2, a pro-inflammatory substance. mPGES-1 inhibitors also have the effect of inhibiting the production of PGE2, making them suitable for the treatment of these diseases. It is believed that this could be a treatment for the condition.

[0009] mPGES-1 inhibitors are being used to treat pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, and multiple myelopathy. It is believed to be beneficial in the prevention or treatment of malignant tumors, including sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis, and colorectal cancer, and / or diseases in which inhibition of PGE2 production is effective. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2012 / 161965 [Patent Document 2] International Publication No. 2015 / 125842 [Non-patent literature]

[0011] [Non-Patent Document 1] JAKOBSSON, PJ et al. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci US A. Jun 22 1999, Vol.96, No.13, pages 7220-7225. [Non-Patent Document 2] SAMUELSSON, B et al. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev. Sep 2007, Vol.59, No.3, pages 207-224. [Non-Patent Document 3] KAMEI, D et al. Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin and synthase-1. J Biol Chem. Aug 6 2004, Vol.279, No.32, pages 33684-33695.

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[0012] The present invention relates to a hydroxytriazine compound having mPGES-1 inhibitory activity or a pharma- ceutical acceptable salt thereof. The present invention aims to provide a salt thereof, a pharmaceutical composition containing the salt, and a medical use thereof, etc. Target diseases include, for example, pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, and diseases in which inhibition of PGE2 production is effective.

[0013] The present inventors have discovered hydroxytriazine compounds having mPGES-1 inhibitory activity represented by the following formula [Ia], [Ib] or [Ic], and have completed the present invention.

[0014] That is, the present invention is as follows. [1] A compound of formula [Ia], [Ib] or [Ic], or a pharma- ceutically acceptable salt thereof:

[0015] [ka]

[0016] [In the formula, R 1 teeth, (1) Formula:

[0017] [ka]

[0018] (In the formula, R 1a is C 1-4 is alkyl, R 1b is C 1-4 alkyl or trifluoromethyl; R 1c teeth, (a) C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) C 1-4 Alkoxy, or (d) C 1-4 Alkoxy C 1-4 alkyl; or (2) Formula:

[0019] [ka]

[0020] (In the formula, n is 1, 2, 3, 4 or 5; R 1d teeth, (a) Fluoro, (b) C 1-4 Alkyl, (c) C 1-4 Fluoroalkyl, (d) C 1-4 Alkoxy, or (e) C 1-4 Alkoxy C 1-4 is alkyl. R 2 is hydrogen or C 1-4 is alkyl, R 3 teeth, (1) Hydrogen, (2) halogens, (3) C 1-4 Alkyl, or (4) C 1-4 is an alkoxy; R 4 teeth, (1) Formula:

[0021] [ka]

[0022] (In the formula, R 4a is hydrogen, C 1-4 Alkyl or C 1-4 alkoxy; or (2) Formula:

[0023] [ka]

[0024] and R 5 is C 1-6 is alkyl, R 6 teeth, (1) C 1-6 Alkyl, (2) C 3-5 cycloalkyl, or (3) C 1-4 Alkoxy C 1-4 is alkyl, X is CH2 or O (oxygen). However, in formula [Ia], R 2 C 1-4 When alkyl, R 3 is hydrogen.

[0025] [2] In formula [Ia], R 2 and R 3 are both hydrogen, and R 4 but, (1) isopropyl or tert-butyl, or (2) Formula:

[0026] [ka]

[0027] The compound according to [1], or a pharma- ceutically acceptable salt thereof,

[0028] [3] In formula [Ia], R 2 is hydrogen, R 3 is chloro, and R 4 or a pharma- ceutical acceptable salt thereof according to [1], wherein

[0029] [4] In formula [Ib], The compound or a pharma- ceutical acceptable salt thereof according to [1], wherein X is O (oxygen).

[0030] [5] In formula [Ic], R 2 is hydrogen, and R 6 or a pharma- ceutically acceptable salt thereof according to [1], wherein R is 1-methylbutyl or n-hexyl.

[0031] [6] R 1 But the formula:

[0032] [ka]

[0033] (In the formula, R 1a But, C 1-4 is alkyl, R 1b But, C 1-4 alkyl or trifluoromethyl, and R 1c but, (b) difluoromethyl or trifluoromethyl, or (c) It is methoxy. The compound according to any one of [1] to [5], wherein:

[0034] [7] R 1 But the formula:

[0035] [ka]

[0036] (In the formula, n is 3, 4 or 5, and R 1d but, (a) Fluoro, (c) C 1-4 Fluoroalkyl, (d) methoxy, or (e) Methoxymethyl. The compound according to any one of [1] to [5], wherein:

[0037] [8] n is 3 or 4, and R 1d is monofluoromethyl, difluoromethyl, or trifluoromethyl, [7] or a pharma- ceutically acceptable salt thereof.

[0038] [9] The formula:

[0039] [ka]

[0040] or a pharma- ceutically acceptable salt thereof.

[0041]

[10] A pharmaceutical composition comprising the compound according to any one of [1] to [9] or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0042]

[11] An mPGES-1 inhibitor comprising the compound according to any one of [1] to [9] or a pharma- ceutical acceptable salt thereof.

[0043]

[12] A therapeutic or preventive agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis, and / or malignant tumors, comprising the compound according to any one of [1] to [9] or a pharma- ceutical acceptable salt thereof.

[0044]

[13] An agent for treating or preventing glaucoma and / or ocular hypertension, comprising a compound according to any one of [1] to [9] or a pharma- ceutical acceptable salt thereof in combination with one or more other glaucoma therapeutic agents.

[0045]

[14] A method for inhibiting mPGES-1, comprising administering to a human a pharma- ceutically effective amount of a compound according to any one of [1] to [9] or a pharma- ceutical acceptable salt thereof.

[0046]

[15] A method for treating or preventing pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis and / or malignant tumors, comprising administering to a human a pharma- ceutical effective amount of a compound according to any one of [1] to [9] or a pharma- ceutical acceptable salt thereof.

[0047]

[16] A method for treating or preventing glaucoma and / or ocular hypertension, comprising administering to a human a pharma- ceutical effective amount of a compound according to any one of [1] to [9] or a pharma- ceutical acceptable salt thereof and one or more other glaucoma therapeutic agents.

[0048]

[17] A compound according to any one of [1] to [9] or its derivatives for producing an mPGES-1 inhibitor. Use of a pharma- ceutically acceptable salt.

[0049]

[18] Use of the compound according to any one of [1] to [9] or a pharma- ceutical ly acceptable salt thereof for the manufacture of an agent for the treatment or prevention of pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis, and / or malignant tumors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0051] "Halogen" is fluoro, chloro, bromo or iodo.

[0052] "C 1-4 "Alkyl" means a straight or branched chain alkyl having 1 to 4 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like. Preferred "C 1-4 "Alkyl" is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

[0053] "C 1-6 "Alkyl" means a straight or branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, etc. Examples of the butyl group include butyl, isohexyl, 1-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Preferred are methyl, ethyl, propyl, sec-butyl, pentyl, hexyl, 1-methylbutyl, and 2,2-dimethylbutyl.

[0054] "C 1-4 Alkoxy means a group in which the alkyl portion is as defined above as "C 1-4Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. Methoxy is preferred. be.

[0055] "C 1-4 The term "fluoroalkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms and substituted with 1 to 3 fluorines. Examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, and 2,2,2-trifluoroethyl. Preferred are monofluoromethyl, difluoromethyl and trifluoromethyl.

[0056] "C 1-4 Alkoxy C 1-4 Alkyl means "C" as defined above. 1-4 "C" as defined above substituted with "alkoxy" 1-4 Examples include methoxymethyl, 4-methoxybutyl, 3-ethoxypropyl, and 2-propoxyethyl. Preferred are 4-methoxybutyl, 3-ethoxypropyl, and 2-propoxyethyl.

[0057] "C 3-5 "Cycloalkyl" means a 3- to 5-membered monocyclic cycloalkyl. Examples include cyclopropyl, cyclobutyl, and cyclopentyl. Preferred is cyclobutyl.

[0058] Among the compounds of the formulae [Ia], [Ib] and [Ic], a preferred embodiment is the compound of the formula [Ic].

[0059] A more preferred embodiment of the compound of formula [Ic] is R 1 teeth, (1) Formula:

[0060] [ka]

[0061] (In the formula, R 1a is C 1-4 is alkyl, R 1b is C 1-4 alkyl or trifluoromethyl; R 1c teeth, (b) C 1-4 Fluoroalkyl, (c) C 1-4 Alkoxy, or (d) C 1-4 Alkoxy C 1-4 alkyl; or (2) Formula:

[0062] [ka]

[0063] (In the formula, n is 1, 2, 3, 4 or 5; R 1d teeth, (a) Fluoro, (b) C 1-4 Alkyl, (c) C 1-4 Fluoroalkyl, (d) C 1-4 Alkoxy, or (e) C 1-4 Alkoxy C 1-4 is alkyl. R 2 is hydrogen, R 6 teeth, (1) C 1-6 Alkyl, (2) C 3-5 cycloalkyl, or (3) C 1-4 Alkoxy C 1-4 It is a compound that is alkyl.

[0064] The compound of formula [Ia], [Ib] or [Ic] (hereinafter also referred to as the compound of the present invention) is pharma- ceutically approved. The acceptable salt may be any salt that forms a non-toxic salt with the compound of the present invention, and examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids, etc. Various forms of pharma- ceutically 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, p 1-19 (1977); (b) Stahl et al., “Handbook of Pharmaceutical Salt: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, p 6665-6672 (2007) Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like. 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, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Furthermore, examples of salts with organic acids include adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, edetic acid, ethane-1,2-disulfonic acid, dodecyl sulfate, ethane Sulfonic acid, glucoheptonic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcylic acid, hydrofluoric acid, hydroiodic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactobionic acid, mandelic acid, methyl sulfate, methyl nitrate, methylene bis( salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, tannic acid, teoclic acid, thiocyanic acid, or undecanoic acid. Examples of salts with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Further examples of salts with inorganic bases include salts with aluminum, barium, bismuth, lithium, or zinc. Examples of salts with organic bases include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, and the like. Furthermore, examples of salts with organic bases include salts with arecoline, betaine, clemizole, N-methylglucamine, N-benzylphenethylamine, or tris(hydroxymethyl)methylamine. Examples of salts with amino acids include salts with lysine, arginine, aspartic acid, glutamic acid, and the like. Of the above salts, salts with hydrochloric acid, sulfuric acid or p-toluenesulfonic acid are preferred. According to a known method, the compound of the present invention can be reacted with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid to obtain each salt.

[0065] The compound of the present invention or a pharma- ceutically acceptable salt thereof may exist as a solvate. The term "solvate" refers to a compound of the present invention or a pharma- ceutically acceptable salt thereof in which a solvent molecule is coordinated, and includes a hydrate. The solvate is preferably a pharma- ceutically acceptable solvate. For example, Examples of the solvate include a hydrate, an ethanol solvate, a dimethylsulfoxide solvate, etc. of the compound of the present invention or a pharma- ceutically acceptable salt thereof. Specific examples include a hemihydrate, a monohydrate, a dihydrate, or a monoethanol solvate of the compound of the present invention, or a monohydrate of the sodium salt or a 2 / 3 ethanol solvate of the dihydrochloride of the compound of the present invention. The solvates can be obtained according to known methods.

[0066] The compounds of the present invention may also contain isotopes (e.g., 2 H, 3 H, 14 C, 35 It may be labeled with S, etc.

[0067] The compounds of the present invention may exist as tautomers. In that case, the compounds of the present invention may exist as individual tautomers or mixtures of tautomers. For example, the compounds of formula [Ia] may have the tautomers shown below.

[0068] [ka]

[0069] Such tautomers are also included in the compounds represented by formula [Ia]. The compound of the present invention may have a carbon double bond. In that case, the compound of the present invention is an E-form. It may exist as either the E or Z form, or as a mixture of the E and Z forms. The compound of the present invention may have stereoisomers that should be recognized as cis / trans isomers. In that case, the compound of the present invention may exist as a cis form, a trans form, or a mixture of cis and trans forms. The compounds of the present invention may contain one or more asymmetric carbon atoms, in which case the compounds may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers. The compounds of the present invention may exist as atropisomers, whereby the compounds of the present invention may exist as individual atropisomers or mixtures of atropisomers. The compounds of the present invention may simultaneously contain structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0070] In the present specification, formulae, chemical structures, or compound names that are expressed without specifying stereochemistry include all of the above-mentioned isomers that may exist, unless otherwise noted.

[0071] Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography or crystallization, or the individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or by stereoselective reactions.

[0072] Separation of individual single enantiomers from a mixture of enantiomers can be carried out by methods well known in the art. For example, a diastereomeric mixture can be prepared by reacting a mixture of enantiomers with a compound that is a substantially pure enantiomer and is known as a chiral auxiliary. The diastereomers can be separated into their respective diastereomers by cleavage and removal of the added chiral auxiliary. The mixture of enantiomers of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, either enantiomer of a compound can be obtained by using substantially pure optically active starting materials, or by using a chiral auxiliary or an isomer of a prochiral intermediate. They can also be obtained by stereoselective synthesis using asymmetric catalysts (asymmetric induction).

[0073] The absolute configuration can be determined by X-ray crystallography of crystalline products or intermediates. In this case, crystalline products or intermediates may be used which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0074] The compound of the present invention or a pharma- ceutical acceptable salt thereof is preferably a substantially purified compound of the present invention or a pharma-ceutical acceptable salt thereof. More preferably, the compound is purified to a purity of 80% or more. The compound of the present invention or a pharma- ceutical acceptable salt thereof is

[0075] Examples of "pharmaceutical compositions" include 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.

[0076] The pharmaceutical composition of the present invention is produced by appropriately mixing an appropriate amount of the compound of the present invention or a pharma- ceutically acceptable salt thereof, or a solvate thereof with at least one or more pharma- ceutically acceptable carriers, etc., according to a method known per se in the technical field of pharmaceutical preparations. The content of the compound of the present invention or a pharma- ceutically acceptable salt thereof, or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.00001 to 100% by weight of the entire composition.

[0077] The "pharmaceutical acceptable carrier" includes various organic or inorganic carrier substances commonly used as pharmaceutical ingredients, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid preparations, or solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, surfactants, pH adjusters, thickening agents, etc. in liquid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used as necessary.

[0078] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic.

[0079] Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like.

[0080] Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.

[0081] The "fluidizing agent" includes, for example, light anhydrous silicic acid, magnesium stearate, and the like.

[0082] Examples of the "lubricant" include magnesium stearate, calcium stearate, talc, and the like.

[0083] Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

[0084] Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.

[0085] Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate, and the like.

[0086] Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.

[0087] Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, etc.

[0088] An example of the "soothing agent" is benzyl alcohol.

[0089] Examples of "surfactants" include polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60, polyethylene glycol monostearate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, alkyldiaminoethylglycine, alkylbenzenesulfonate, benzethonium chloride, and the like.

[0090] Examples of "pH adjusters" include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine, and the like.

[0091] Examples of "thickening agents" include polyvinyl alcohol, carboxyvinyl polymer, methyl cellulose, hydroxyethyl cellulose, polyethylene glycol, dextran, and the like.

[0092] Examples of the "preservative" include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.

[0093] "Antioxidants" include, for example, sodium sulfite, ascorbic acid, and the like.

[0094] Examples of "coloring agents" include food colorings (e.g., food red No. 2 or No. 3, food yellow No. 4). or No. 5, etc.), β-carotene, etc.

[0095] Examples of "sweetening agents" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

[0096] The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, topically, rectally, intravenously, etc.) to humans as well as to non-human mammals (for example, hamsters, guinea pigs, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). The dosage varies depending on the subject, disease, symptoms, dosage form, administration route, etc., but for example, for an adult patient (body weight: about 60 kg), The dosage when orally administered is usually in the range of about 0.1 μg to 10 g per day as the compound of the present invention, which is the active ingredient. This amount can be administered once or in several divided doses. Cut.

[0097] The compound of the present invention or a pharma- ceutically acceptable salt thereof, or a solvate thereof can be used in combination (hereinafter also referred to as "combination") with one or more other drugs (hereinafter also referred to as "concomitant drugs") in a manner generally used in the pharmaceutical field.

[0098] The administration time of the compound of the present invention or its pharma- ceutically acceptable salt, or its solvate, and the concomitant drug is not limited, and they may be administered to the subject as a combination drug, or both preparations may be administered simultaneously or at a certain interval. The pharmaceutical composition of the present invention may also be used as a pharmaceutical product characterized by being a kit consisting of the pharmaceutical composition of the present invention and the concomitant drug. The dosage of the concomitant drug may be selected appropriately according to the subject, disease, symptoms, dosage form, administration route, administration time, combination, etc., as long as it is in accordance with the dosage used in clinical practice. The administration form of the concomitant drug is not particularly limited, and it is sufficient that the compound of the present invention or its salt, or its solvate is combined with the concomitant drug.

[0099] Concomitant medications include prostaglandin preparations, beta-blockers, alpha-receptor agonists, sympathomimetics, alpha-blockers, carbonic anhydrase inhibitors, anticholinesterase agents, and Rho kinase inhibitors. Examples of glaucoma treatments include:

[0100] Examples of prostaglandin preparations include isopropyl unoprostone, latanoprost, travoprost, tafluprost, bimatoprost, and the like. Examples of the β-blockers include timolol maleate, befunolol hydrochloride, carteolol hydrochloride, betaxolol hydrochloride, nipradilol, levobunolol hydrochloride and the like.

[0101] Examples of α-receptor agonists include brimonidine tartrate and the like.

[0102] Sympathomimetics include, for example, dipivefrine hydrochloride, pilocarpine hydrochloride, etc.

[0103] Examples of α-blockers include bunazosin hydrochloride.

[0104] Carbonic anhydrase inhibitors include, for example, dorzolamide hydrochloride, brinzolamide, and the like.

[0105] Anticholinesterase agents include, for example, distigmine bromide and the like.

[0106] Examples of Rho kinase inhibitors include ripasudil hydrochloride hydrate.

[0107] Specific examples of the combination of drugs include a combination of one drug selected from latanoprost, travoprost, tafluprost, timolol maleate, dorzolamide hydrochloride, and brinzolamide with the compound of the present invention or a pharma- ceutical acceptable salt thereof, or a solvate thereof. Examples include combinations.

[0108] The compound of the present invention or a pharma- ceutical acceptable salt thereof has an mPGES-1 inhibitory effect, and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating mPGES-1 inhibitory activity, such as pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis, and malignant tumors including colorectal cancer. As used herein, various diseases or conditions that can be expected to be improved by regulating mPGES-1 inhibitory activity are The conditions are preferably glaucoma and ocular hypertension.

[0109] The compounds of the present invention are preferably administered in the form of a solution or suspension, more preferably in the form of a solution. The compounds of the invention are preferably administered by eye drops. In order to administer the solution by eye drop, it is preferable that the compound has high solubility. In the solvent used for the eye drop, the compound has a solubility of 0.03% or more, more preferably 0.07% or more. Further preferably, the compound has a solubility of 0.13% or more. The solvent used in the eye drops is preferably water. The solvent used in the eye drops may contain additives such as polysorbate 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. For administration by eye drop, the solution of the compound preferably has a pH of 7.0 to 8.5.

[0110] The solubility of a compound can be measured according to known methods, for example, the following method. (1) The compound is suspended in a buffer solution having a pH of 7.0 to 8.0 (e.g., Britton-Robinson buffer, etc.). If necessary, additives such as polysorbate 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil may be used. (2) After shaking at room temperature for a certain period of time, filter the suspension through a membrane filter. Dilute the filtrate appropriately to prepare the sample solution. (3) Prepare a standard solution of the compound and measure it by liquid chromatography. (4) The sample solution is measured by liquid chromatography, and the solubility of the compound is calculated using the external standard method.

[0111] As used herein, the term "inhibiting mPGES-1" means eliminating or attenuating the function of mPGES-1, and is preferably used under the conditions of Test Example 1 described below or in human clinical trials. In targeted applications, it abolishes or attenuates the function of human mPGES-1.

[0112] As used herein, "treatment" includes amelioration of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence. As used herein, "prevention" means suppressing the onset of symptoms.

[0113] Another aspect of the present invention is to provide an agent for reducing intraocular pressure, comprising the compound of the present invention or a pharma- ceutical acceptable salt thereof. Yet another aspect of the present invention is to provide an agent for reducing intraocular pressure, comprising the compound of the present invention or a pharma- ceutical acceptable salt thereof and one or more other glaucoma therapeutic agents.

[0114] Another aspect of the present invention is to provide a method for reducing intraocular pressure comprising administering to a human a compound of the present invention or a pharma- ceutically acceptable salt thereof. Yet another aspect of the present invention is to provide a method for reducing intraocular pressure comprising administering to a human a compound of the present invention or a pharma- ceutically acceptable salt thereof and one or more other glaucoma therapeutic agents. As used herein, the term "reducing intraocular pressure" refers to reducing intraocular pressure.

[0115] In this specification, the presentation of preferred aspects and options of the compounds, methods, uses and compositions of the present invention also includes the presentation of combinations of the preferred aspects and options, so long as these are combinable and not inconsistent.

[0116] The method for producing the compound of the present invention or a pharma- ceutically acceptable salt thereof is described below. However, the method for producing the compound of the present invention or a pharma- ceutically acceptable salt thereof is not limited to these methods. The compound obtained in each step can be isolated and purified by known methods such as distillation, recrystallization, column chromatography, etc., if necessary, but in some cases, it can proceed to the next step without isolation and purification.

[0117] [Manufacturing method A] Compound [Ia] can be obtained by production method A.

[0118] [ka]

[0119] (In the formula, L 1 is a leaving group such as bromo, iodo, trifluoromethanesulfonyloxy, etc.; Hal 1 is chloro or bromo; Z is -B(OH)2, -B(OR 8 )2(where R 8 is C 1-4 Alkyl or one of R 8 is the other R 8 may be bonded to form a ring), -BF3,

[0120] [ka]

[0121] Boron substituents used in Suzuki coupling reactions such as; R 7 C is methyl, ethyl, etc. 1-6 alkyl or benzyl; R 1 , R 2 , R 3 and R 4 has the same meaning as defined in the above formula [Ia].)

[0122] (Process A-1) Compound [2] can be obtained by boronizing compound [1]. For example, Compound [2] can be obtained by reacting compound [1] with a boron reagent in the presence of a base and a palladium catalyst under heating in a solvent. A ligand may be added as necessary. Examples of the boron reagent used in the reaction include 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborinane, tetrahydroxydiboron, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Examples of the palladium catalyst used in the reaction include palladium acetate, tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like. Examples of the base used in the reaction include inorganic bases such as alkali metal salts such as potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium acetate, sodium acetate, and cesium fluoride, and organic bases such as triethylamine. The ligands used in the reaction are triphenylphosphine, tricyclohexylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2-dicyclohexylphosphine, Examples include organic phosphorus ligands such as phenyl-2',6'-dimethoxybiphenyl. Examples of the solvent to be used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether; alcohol solvents such as methanol, ethanol, 1-propanol, and 2-propanol; hydrocarbon solvents such as toluene, xylene, and hexane; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and acetonitrile; mixed solvents thereof, and mixed solvents of these with water. In addition, in compound [1], L 1 When is bromo or iodo, compound [2] can also be obtained by adding an organometallic reagent to compound [1] in a solvent at -78°C to room temperature, and then reacting the product with a boron compound at -78°C to room temperature. The organometallic reagents used in the reaction are n-butyllithium, tert-butyllithium, isobutyllithium, propyl magnesium chloride, etc. The boron reagent used in the reaction includes trimethyl borate, triisopropyl borate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like. Examples of the solvent used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether; hydrocarbon solvents such as toluene, xylene, and hexane; and mixed solvents thereof. Compound [1] may be available commercially as 5-bromo-2-chloroisopropylbenzene. Alternatively, a commercially available product may be appropriately converted by a method known to those skilled in the art.

[0123] (Process A-2) Compound [4] can be obtained by Suzuki coupling reaction between compound [2] and compound [3]. For example, compound [4] can be obtained by reacting compound [2] with compound [3] in a solvent under heating in the presence of a base and a palladium catalyst. A ligand may be added as necessary. In order to prevent the Suzuki coupling reaction of the obtained compound (compound [4]) with compound [2], 1.5 equivalents or more of compound [3] are used relative to compound [2]. It is preferable. Examples of the palladium catalyst used in the reaction include palladium acetate, tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like. Examples of the base used in the reaction include inorganic bases such as alkali metal salts such as potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium acetate, sodium acetate, and cesium fluoride, and organic bases such as triethylamine. The ligands used in the reaction are triphenylphosphine, tricyclohexylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2-dicyclohexylphosphine, Examples include organic phosphorus ligands such as phenyl-2',6'-dimethoxybiphenyl. Examples of the solvent to be used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether; alcohol solvents such as methanol, ethanol, 1-propanol, and 2-propanol; hydrocarbon solvents such as toluene, xylene, and hexane; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and acetonitrile; mixed solvents thereof, and mixed solvents of these with water. Compound [2] is 3-isopropylphenylboronic acid or 3-tert-butylphenylboronic acid. Any commercially available product may be used, or may be obtained by appropriately converting a commercially available product using methods well known to those skilled in the art. Compound [3] may be a commercially available product such as 2,4-dichloro-6-methoxy-1,3,5-triazine, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art. Regarding the Suzuki coupling reaction, for example, the following review is known (SUZUKI, A et al. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem Rev. 1995, Vol. 95, pages 2457-2483.).

[0124] (Process A-3) Compound [6] can be obtained by Suzuki coupling reaction of compound [4] with boron compound [5]. For example, compound [6] can be obtained by reacting compound [4] with boron compound [5] in a solvent under heating in the presence of a base and a palladium catalyst. A ligand may be added as necessary. Examples of the palladium catalyst used in the reaction include palladium acetate, tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like. Examples of the base used in the reaction include inorganic bases such as alkali metal salts such as potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium acetate, sodium acetate, and cesium fluoride, and organic bases such as triethylamine. The ligands used in the reaction are triphenylphosphine, tricyclohexylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2-dicyclohexylphosphine, Examples include organic phosphorus ligands such as phenyl-2',6'-dimethoxybiphenyl. Examples of the solvent to be used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether; alcohol solvents such as methanol, ethanol, 1-propanol, and 2-propanol; hydrocarbon solvents such as toluene, xylene, and hexane; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and acetonitrile; mixed solvents thereof, and mixed solvents of these with water. Compound [5] is a commercially available product such as 2-chloro-5-hydroxymethylphenylboronic acid. Alternatively, a commercially available product may be appropriately converted by a method well known to those skilled in the art.

[0125] (Process A-4) Compound [7] can be obtained by converting the hydroxy group of compound [6] to an azido group and then converting it to an amino group by reduction. For example, the corresponding azide can be obtained by reacting compound [6] with an azido agent in a solvent in the presence of a base. The resulting azide can then be reacted with phosphine, and the system can be hydrolyzed by adding water and heating to obtain compound [7]. Compound [7] is preferably obtained as a salt with an inorganic acid or an organic acid by a conventional method. The azidation agent used in the reaction is diphenylphosphoryl azide, bis(p-nitrophenyl) nyl)azidophosphonates and the like. The solvent used in the reaction is tetrahydrofuran, toluene, N,N-dimethylformamide. Examples include Do. The base used for the azidation includes 1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of the phosphine include triphenylphosphine and tributylphosphine. The acid used to form the salt of compound [7] may be hydrochloric acid.

[0126] (Process A-5) Compound [9] can be obtained by the amide bond formation reaction between compound [7] and compound [8]. For example, compound [9] can be obtained by reacting compound [7] with compound [8] in a solvent in the presence of a condensing agent and an additive. A base may be added as necessary. The condensation agents used in the reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU). , (benzotriazol-1-yloxy)tripyrrolidinophosphonylidene hexafluorophosphate Examples of suitable phosphatidyl azide include PyBOP and diphenylphosphoryl azide. The additives used in the reaction include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-dimethylaminoethyl ether (DMSO), and 1-hydroxy-7-azabenzotriazole (HOA). ethylaminopyridine and the like. The base used in the reaction includes organic bases such as pyridine and triethylamine. Examples of the solvent used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether; hydrocarbon solvents such as toluene, hexane, and xylene; halogen solvents such as dichloromethane and chloroform; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, and pyridine, which may be used alone or in combination of two or more. can be used as such. Compound [8] is 3,3,3-trifluoromethyl-2,2-dimethylpropionic acid or 1-trifluoromethyl- The compound may be a commercially available product such as 3-methylcyclopentanecarboxylic acid, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0127] (Process A-6) Compound [Ia] can be obtained by converting the alkoxy group of compound [9] to a hydroxy group by hydrolysis. For example, R 7 C 1-6 In the case of alkyl, compound [9] is dissolved in a solvent. The reaction is carried out in the presence of a base at room temperature or under heating, and the resulting solution is then neutralized to give compound [Ia]. The base used in the reaction includes lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and the like. Examples of the solvent used in the reaction include mixed solvents of an alcoholic solvent such as methanol, ethanol, 1-propanol, or 2-propanol with water; or mixed solvents of these with an ether solvent such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or cyclopentyl methyl ether.

[0128] [Manufacturing method B] Compound [Ib] can be obtained by production method B.

[0129] [ka]

[0130] (In the formula, R 1 , R 2 , R 5 and X are as defined in the above formula [Ib], and L 1 , Hal 1 , Z and R 7 is the same as defined in the above Production Method A.)

[0131] (Process B-1) Compound

[11] can be obtained by boronating compound

[10] in the same manner as in step A-1 of production method A. Compound

[10] may be a commercially available product such as 3-bromophenylethyl ether, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0132] (Process B-2) In the same manner as in step A-2 of production method A, compound

[12] can be obtained by Suzuki coupling reaction between compound

[11] and compound [3].

[0133] (Process B-3) In the same manner as in step A-3 of production method A, compound

[13] can be obtained by Suzuki coupling reaction of compound

[12] with boron compound [5].

[0134] (Process B-4) In the same manner as in step A-4 of production method A, the hydroxy group of compound

[13] is azidized and then reduced to convert it to an amino group, thereby obtaining compound

[14] .

[0135] (Process B-5) In the same manner as in step A-5 of production method A, compound

[15] can be obtained by an amidation reaction between compound

[14] and compound [8].

[0136] (Process B-6) In the same manner as in step A-6 of production method A, the alkoxy group of compound

[15] can be converted to a hydroxy group by hydrolysis to obtain compound [Ib].

[0137] [Manufacturing method C] Compound [Ic] can be obtained by production method C.

[0138] [ka]

[0139] (In the formula, Hal 2 is bromo or iodo; Hal 3 is fluoro, chloro or bromo; R 1 , R 2 and R 6 is the same as defined in the above formula [Ic], and R 7 , Z., Hal 1 is the above-mentioned manufacturing method A (This definition is the same as that in

[0140] (Process C-1) Compound

[18] can be obtained by aromatic nucleophilic substitution reaction between compound

[16] and compound

[17] . For example, compound

[18] can be obtained by reacting compound

[16] with compound

[17] in a solvent in the presence of a base and an additive. Compound

[16] may be a commercially available product such as 5-bromo-2-chloropyridine, or may be obtained from a commercial source. The product may be obtained by appropriately converting a commercially available product using a method well known to those skilled in the art. Compound

[17] may be a commercially available product such as n-hexanol, or may be obtained by appropriately converting a commercially available product using a method well known to those skilled in the art. The solvents used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether; hydrocarbon solvents such as toluene and xylene; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, and pyridine. Solvents are included. Examples of the base used in the reaction include sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium and the like. Additives used in the reaction include tetra-n-butylammonium bromide, 18-crown-6, copper iodide, and the like.

[0141] (Process C-2) Compound

[19] can be obtained by boronating compound

[18] in the same manner as in step A-1 of production method A.

[0142] (Process C-3) In the same manner as in step A-2 of production method A, compound

[20] can be obtained by Suzuki coupling reaction between compound

[19] and compound [3].

[0143] (Process C-4) In the same manner as in step A-3 of production method A, compound

[21] can be obtained by Suzuki coupling reaction of compound

[20] with boron compound [5].

[0144] (Process C-5) In the same manner as in step A-4 of production method A, the hydroxy group of compound

[21] is azidized and then reduced to convert it to an amino group to obtain compound

[22] .

[0145] (Process C-6) In the same manner as in step A-5 of production method A, compound

[23] can be obtained by an amidation reaction between compound

[22] and compound [8].

[0146] (Process C-7) In the same manner as in step A-6 of production method A, the alkoxy group of compound

[23] can be converted to a hydroxy group by hydrolysis to obtain compound [Ic]. EXAMPLES

[0147] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited thereto. In the examples, the abbreviations are as follows. WSC·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt·H2O: 1-Hydroxy-1H-benzotriazole monohydrate DMSO: Dimethyl sulfoxide M:mol / L N:normality

[0148] [Production Example 1]: N-{4-chloro-3-[4-(4-chloro-3-isopropylphenyl)-6-hydroxy-1,3 Synthesis of {5,5-triazin-2-yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No. 48)

[0149] [ka]

[0150] (1) 2-(4-chloro-3-isopropylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane

[0151] [ka]

[0152] Under an argon atmosphere, a suspension of 4-bromo-1-chloro-2-isopropylbenzene (0.50 g), 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborinane (0.77 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.087 g) and potassium acetate (0.63 g) in 1,2-dimethoxyethane (5.0 ml) was stirred at 85°C for 16 hours. Ethyl acetate (10 ml) was added to this reaction solution at room temperature. This reaction solution was filtered through Celite. The mixture was filtered and eluted with ethyl acetate, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.53 g, yield 93%). 1 H-NMR (CDCl3) δ: 1.02 (6H, s), 1.27 (6H, d, J = 6.9 Hz), 3.35-3.46 (1H, m), 3.76 (4H, s), 7.31 (1H, d, J = 7.9 Hz), 7.53 (1H, dd, J = 7.9, 1.5 Hz), 7.72 (1H, d, J = 1.5 Hz).

[0153] (2) 2-Chloro-4-(4-chloro-3-isopropylphenyl)-6-methoxy-1,3,5-triazine

[0154] [ka]

[0155] Under an argon atmosphere, 2-(4-chloro-3-isopropylphenyl)-5,5- Dimethyl-1,3,2-dioxaborinane (0.53 g), 2,4-dichloro-6-methoxy-1,3,5-triazolo[1,3,5-trimethylphenyl]- ... A suspension of zinc (1.1 g), tetrakis(triphenylphosphine)palladium(0) (0.23 g), and tripotassium phosphate (2.1 g) in 1,2-dimethoxyethane (8.6 ml) and distilled water (3.2 ml). The mixture was stirred at 85° C. for 2.5 hours. Water and ethyl acetate were added to the reaction mixture at room temperature, and the mixture was separated. The organic layer was then washed with saturated saline. The organic layer was dried over sodium sulfate and then filtered. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to give a crude product (0.36 g) containing the title compound. 1 H-NMR (CDCl3) δ: 1.32 (6H, d, J = 6.7 Hz), 3.41-3.51 (1H, m), 4.17 (3H, s), 7.47 (1H, d, J = 8.3 Hz), 8.25 (1H, dd, J = 8.3, 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz).

[0156] (3) {4-chloro-3-[4-(4-chloro-3-isopropylphenyl)-6-methoxy-1,3,5-triazine {phenyl-2-yl}phenyl}methanol

[0157] [ka]

[0158] Under an argon atmosphere, the crude product of 2-chloro-4-(4-chloro-3-isopropylphenyl)-6-methoxy-1,3,5-triazine obtained in (2) above (0.36 g), 2-chloro-5-hydroxymethylphenylboronic acid (0.27 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium were A suspension of tungsten(II) dichloride dichloromethane adduct (0.050 g) and tripotassium phosphate (0.78 g) in acetonitrile (3.6 ml) and distilled water (1.8 ml) was stirred at 85°C for 1.5 hours. Water and ethyl acetate were added to this reaction solution at room temperature, and the layers were separated. The organic layer was then washed with water and then with saturated saline. This organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.29 g, yield 35% (2 steps)). 1 H-NMR (CDCl3) δ: 1.34 (6H, d, J = 6.7 Hz), 1.76 (1H, t, J = 6.0 Hz), 3.42-3.53 (1H, m), 4.22 (3H, s), 4.78 (2H, d, J = 6.0 Hz), 7.46-7.50 (2H, m), 7.55 (1H, d, J = 8.3 Hz), 8.05 (1H, d, J = 1.8 Hz), 8.35 (1H, dd, J = 8.3, 2.3 Hz), 8.58 (1H, d, J = 2.3 Hz).

[0159] (4) 4-Chloro-3-[4-(4-chloro-3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamine hydrochloride

[0160] [ka]

[0161] Under an argon atmosphere, the {4-chloro-3-[4-(4-chloro-3-isopropyl A solution of 0.29 g of 1,8-diphenylphosphoryl azide and 1,8-diphenyl-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol in toluene (1.2 ml) was added to the solution under ice cooling. Zabicyclo[5.4.0]-7-undecene (0.13 ml) was added, and the reaction solution was stirred at room temperature for 15 hours. To this reaction solution, saturated sodium bicarbonate water (0.35 ml) and distilled water (0.35 ml) were added at room temperature and stirred for 1 minute. The aqueous layer of this reaction solution was removed, and distilled water (0.70 ml) was added and stirred for 1 minute. The aqueous layer of this reaction solution was removed, and distilled water (0.70 ml) was added. This reaction solution was stirred for 1 minute. After that, the aqueous layer was removed. Triphenylphosphine (0.24 g) and distilled water (0.029 ml) were added to this reaction solution at room temperature. This reaction solution was stirred at 64° C. for 1 hour. To the liquid, acetonitrile (1.2 ml) and concentrated hydrochloric acid (0.075 ml) were added under ice cooling, and the mixture was stirred for 30 minutes. The solid was collected from the suspension by filtration and dried under reduced pressure to obtain the title compound (0.27 g, yield 87%). 1 H-NMR (DMSO-d6) δ: 1.30 (6H, d, J = 6.9 Hz), 3.36-3.44 (1H, m), 4.16 (2H, s), 4.17 (3H, s), 7.67 (1H, d, J = 8.3 Hz), 7.71 (1H, dd, J = 8.3, 2.1 Hz), 7.76 (1H, d, J = 8.3 Hz), 8.17 (1H, d, J = 2.1 Hz), 8.29 (3H, br s), 8.34 (1H, dd, J = 8.3, 2.1 Hz), 8.52 (1H, d, J = 2.1 Hz).

[0162] (5) N-{4-chloro-3-[4-(4-chloro-3-isopropylphenyl)-6-methoxy-1,3,5-trimethylphenyl]-6-methoxyphenyl 3,3,3-Trifluoro-2,2-dimethylpropionamide

[0163] [ka]

[0164] Under an argon atmosphere, 4-chloro-3-[4-(4-chloro-3-isopropyl fluoride] obtained in (4) above was To a solution of 0.080 g of 3,3,3-trifluoro-2,2-dimethylpropionic acid, 0.042 g of HOBt·H2O, and 0.052 g of WSC·HCl in N,N-dimethylformamide (1.0 ml) was added triethylamine at room temperature. Aminopropylamine (0.076 ml) was added and the mixture was stirred for 16 hours. After adding ethanol and separating the mixture, the organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.089 g, yield 90%). 1 H-NMR (CDCl3) δ: 1.33 (6H, d, J = 6.7 Hz), 1.44 (6H, s), 3.43-3.52 (1H, m), 4.21 (3H, s), 4.55 (2H, d, J = 5.8 Hz), 6.23 (1H, br s), 7.36 (1H, dd, J = 8.3, 2.3 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.94 (1H, d, J = 2.3 Hz), 8.34 (1H, dd, J = 8.3, 2.2 Hz), 8.57 (1H, d, J = 2.2 Hz).

[0165] (6) N-{4-chloro-3-[4-(4-chloro-3-isopropylphenyl)-6-hydroxy-1,3,5-trimethylphenyl] azin-2-yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide

[0166] [ka]

[0167] Under an argon atmosphere, a solution of N-{4-chloro-3-[4-(4-chloro-3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (0.089 g) obtained in (5) above in methanol (1.4 ml) was added with 4 M hydroxide at room temperature. An aqueous solution of sodium chloride (0.25 ml) was added and stirred at 65° C. for 2.5 hours. To this reaction solution, 2N hydrochloric acid (0.49 ml) and water were added at room temperature and stirred. The precipitated solid was collected by filtration and washed with water. The extract was dried under reduced pressure to obtain the title compound (0.075 g, yield 86%).

[0168] [Production Example 2]: N-(4-chloro-3-{4-hydroxy-6-[6-((R)-1-methylbutoxy)pyridine-3- 1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionyl Synthesis of amide (Example No. 25)

[0169] [ka]

[0170] (1) 5-Bromo-2-((R)-1-methylbutoxy)pyridine

[0171] [ka]

[0172] Under an argon atmosphere, 5-bromo-2-chloropyridine (1.0 g) and (R)-pentan-2-ol were Sodium hydride (0.31 g, 60% by weight oil dispersion) was added to a solution of ethanol (0.69 g) in tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for 10 minutes. After stirring at 80°C for 1 hour, a saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution at room temperature, and the mixture was separated. The organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (1.3 g, quant.). 1 H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.33-1.48 (2H, m), 1.50-1.59 (1H, m), 1.66-1.75 (1H, m), 5.10-5.18 (1H, m), 6.59 (1H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 8.8, 2.4 Hz), 8.16 (1H, d, J = 2.4 Hz).

[0173] (2) 2-Chloro-4-methoxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-trimethylpyridin-3-yl Ajin

[0174] [ka]

[0175] Under an argon atmosphere, 5-bromo-2-((R)-1-methylbutoxy)pyridine obtained in (1) above was To a mixed solution of (1.3 g) in toluene (8.5 ml) and tetrahydrofuran (2.0 ml), n-butyllithium (1.6 M n-hexane solution, 4.4 ml) was added dropwise at -78°C. After stirring for 15 minutes, triisopropyl borate (1.6 ml) was added in two portions. The mixture was warmed to room temperature and stirred for 30 minutes. A 10% aqueous solution of citric acid was added to this reaction mixture, and the mixture was stirred for 10 minutes. Ethyl acetate was added to this reaction mixture, and the layers were separated. The organic layer was then washed with water, followed by a saturated saline solution. This organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. A mixture of the resulting residue in 1,2-dimethoxyethane (28 ml) and distilled water (14 ml) was added with 2,4-dichloro-6-methoxy-1,3,5-triazine (2.8 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.21 g), and phosphoric acid. Tripotassium chloride (3.9 g) was added and the mixture was stirred at 90° C. for 1.5 hours. Water and ethyl acetate were added to the reaction solution at room temperature, and the mixture was separated. The organic layer was washed with water and saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain a crude product containing the title compound (1.1 g, yield about 60%). 1 H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.4 Hz), 1.35 (3H, d, J = 6.2 Hz), 1.38-1.50 (2H, m), 1.53-1.64 (1H, m), 1.72-1.81 (1H, m), 4.15 (3H, s), 5.31-5.40 (1H, m), 6.76 (1H, d, J = 8.8 Hz), 8.54 (1H, dd, J = 8.8, 2.1 Hz), 9.27 (1H, d, J = 2.1 Hz).

[0176] (3) (4-chloro-3-{4-methoxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5- Triazin-2-yl}phenyl)methanol

[0177] [ka]

[0178] Under an argon atmosphere, 2-chloro-4-methoxy-6-[6-((R)-1-methylbutyric acid] obtained in (2) above was The crude product of [1,3,5-triazine (3-methoxypyridin-3-yl)]-1,3,5-triazine (1.1 g), 2-chloro-5-hydroxymethylphenylboronic acid (0.76 g), [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) dichloride dichloromethane adduct (0.14 g) and tripotassium phosphate (2.2 A suspension of 1.5 g of acetonitrile (11 ml) and distilled water (6.0 ml) was stirred at 80°C for 1.5 hours. Water and ethyl acetate were added to this reaction solution at room temperature, and the mixture was separated. The organic layer was washed with saturated saline. This organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.89 g, yield 64%). 1 H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.3 Hz), 1.35 (3H, d, J = 6.2 Hz), 1.39-1.50 (2H, m), 1.57-1.64 (1H, m), 1.73-1.81 (2H, m), 4.19 (3H, s), 4.77 (2H, d, J = 6.0 Hz), 5.31-5.40 (1H, m), 6.78 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.2, 2.2 Hz), 7.54 (1H, d, J = 8.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.66 (1H, dd, J = 8.9, 2.1 Hz), 9.39 (1H, d, J = 2.1 Hz).

[0179] (4) N-(4-chloro-3-{4-methoxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide

[0180] [ka]

[0181] Under an argon atmosphere, the (4-chloro-3-{4-methoxy-6-[6-((R)-1-methyl (1,3,5-triazin-2-yl)phenyl)methanol (0.16 g To a solution of 1,8-diazabicyclo[5.4.0]-7-undecene (0.080 ml) was added at room temperature in tetrahydrofuran (1.6 ml). To this reaction solution was added 1,8-diazabicyclo[5.4.0]-7-undecene (0.080 ml) under ice cooling, and the mixture was stirred for 15 minutes. The reaction solution was stirred at 60° C. for 20 minutes. Triphenylphosphine (0.22 g) and distilled water (0.080 ml) were added to the reaction solution at room temperature, and the mixture was stirred at 60°C for 1 hour. N,N-dimethylformamide (1.6 ml), a solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid in N,N-dimethylformamide (1.9 M, 0.30 ml), HOBt·H2O (0.12 g) and WSC·HCl (0.15 g) were added to the reaction solution at room temperature, and the mixture was stirred for 15 minutes. The reaction solution was left to stand at room temperature for 15 hours. Water and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was then washed with water and then with saturated saline. The organic layer was dried over sodium sulfate, and the sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.19 g, yield 91%). 1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.3 Hz), 1.35 (3H, d, J = 6.2 Hz), 1.39-1.51 (2H, m), 1.55-1.64 (1H, m), 1.73-1.82 (1H, m), 4.19 (3H, s), 4.54 (2H, d, J = 5.8 Hz), 5.32-5.40 (1H, m), 6.22 (1H, br), 6.78 (1H, d, J = 8.8 Hz), 7.35 (1H, dd, J = 8.3, 2.3 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 2.3 Hz), 8.65 (1H, dd, J = 8.8, 2.4 Hz), 9.38 (1H, d, J = 2.4 Hz).

[0182] (5) N-(4-chloro-3-{4-hydroxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide

[0183] [ka]

[0184] Under an argon atmosphere, N-(4-chloro-3-{4-methoxy-6-[6-((R)-1-methylphenyl)- To a solution of (1,3,5-triphenylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide (0.19 g) in methanol (2.0 ml), 4M aqueous sodium hydroxide solution (0.35 ml) was added at room temperature, and the mixture was stirred at 65° C. for 1.5 hours. To this reaction solution, 2N hydrochloric acid (0.70 ml) and water were added at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, The residue was washed with water and dried under reduced pressure to obtain the title compound (0.14 g, yield 77%).

[0185] [Production Example 3]: N-(4-chloro-3-{4-hydroxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionaminium Synthesis of 49th Example

[0186] [ka]

[0187] (1) 5,5-Dimethyl-2-[3-(1-methylcyclopropyl)phenyl]-1,3,2-dioxaborinane

[0188] [ka]

[0189] Under an argon atmosphere, 1-bromo-3-(1-methylcyclopropyl)benzene (0.50 g), 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborinane (0.85 g), [1,1'-bis(diphenyl A suspension of 1,2-dimethoxyethane (5.0 ml) containing 0.096 g of (arylphosphino)ferrocene palladium(II) dichloride dichloromethane adduct and 0.70 g of potassium acetate was stirred at 85° C. for 15 hours. Ethyl acetate (10 ml) was added to the reaction mixture at room temperature. The mixture was filtered through a light filter and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.56 g, yield 95%). 1 H-NMR (CDCl3) δ: 0.68-0.71 (2H, m), 0.86-0.89 (2H, m), 1.02 (6H, s), 1.41 (3H, s), 3.77 (4H, s), 7.27 (1H, td, J = 7.5, 0.5 Hz), 7.32-7.35 (1H, m), 7.60 (1H, dt, J = 7.5, 1.3 Hz), 7.70-7.72 (1H, m).

[0190] (2) 2-Chloro-4-methoxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-triazine

[0191] [ka]

[0192] Under an argon atmosphere, 5,5-dimethyl-2-[3-(1-methylcyclopropyl)phenyl]-1,3,2-dioxaborinane (0.56 g) obtained in (1) above, 2,4-dichloro-6-methoxy-1,3,5-trimethyl A suspension of azine (1.1 g), tetrakis(triphenylphosphine)palladium(0) (0.26 g) and tripotassium phosphate (2.4 g) in 1,2-dimethoxyethane (9.8 ml) and distilled water (3.7 ml). The mixture was stirred at 85° C. for 2.5 hours. Water and ethyl acetate were added to the reaction mixture at room temperature, and the mixture was cooled to room temperature. After separation, the organic layer was washed with saturated saline. This organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain a crude product (0.47 g) containing the title compound. 1 H-NMR (CDCl3) δ: 0.77-0.81 (2H, m), 0.91-0.95 (2H, m), 1.46 (3H, s), 4.17 (3H, s), 7.41 (1H, t, J = 7.7 Hz), 7.51 (1H, dt, J = 7.7, 1.6 Hz), 8.29 (1H, dt, J = 7.7, 1.6 Hz), 8.38 (1H, t, J = 1.6 Hz).

[0193] (3) (4-chloro-3-{4-methoxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-triazin-2-yl}phenyl)methanol

[0194] [ka]

[0195] Under an argon atmosphere, 2-chloro-4-methoxy-6-[3-(1-methylcyclohexane]-2- The crude product of [1,1'-bis(diphenylphosphino)ferrocene]para (propyl)phenyl)-1,3,5-triazine (0.47 g), 2-chloro-5-hydroxymethylphenylboronic acid (0.38 g), Dium(II) dichloride dichloromethane adduct (0.069 g) and potassium phosphate tripotassium (1.1 g) A suspension of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether) in acetonitrile (4.7 ml) and distilled water (2.3 ml) was stirred at 85° C. for 1.5 hours. Water and ethyl acetate were added to this reaction solution at room temperature, and the mixture was separated. The organic layer was washed with saturated saline. This organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.42 g, yield 48% (2 steps) ) was obtained. 1 H-NMR (CDCl3) δ: 0.77-0.81 (2H, m), 0.93-0.97 (2H, m), 1.47 (3H, s), 1.80 (1H, t, J = 6.0 Hz), 4.22 (3H, s), 4.78 (2H, d, J = 6.0 Hz), 7.42 (1H, td, J = 7.7, 0.5 Hz), 7.46-7.50 (2H, m), 7.54 (1H, d, J = 8.3 Hz), 8.03 (1H, d, J = 2.3 Hz), 8.40 (1H, dt, J = 7.7, 1.6 Hz), 8.50 (1H, t, J = 1.6 Hz).

[0196] (4) 4-Chloro-3-{4-methoxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-trimethylcyclopropanediol Diphenyl-2-yl}benzylamine hydrochloride

[0197] [ka]

[0198] Under an argon atmosphere, the (4-chloro-3-{4-methoxy-6-[3-(1-methylphenyl)phenyl] A solution of 1,8-dichloropropylphenyl]-1,3,5-triazin-2-yl}phenyl)methanol (0.42 g) in toluene (1.9 ml) was added with diphenylphosphoryl azide (0.29 ml) and 1,8-dichloropropylphenyl]-1,3,5-triazin-2-yl}phenyl)methanol under ice cooling. Azabicyclo[5.4.0]-7-undecene (0.20 ml) was added. The reaction mixture was stirred at room temperature for 15 The reaction solution was stirred for 1 hour. Saturated sodium bicarbonate water (0.50 ml) and distilled water (0.50 ml) were added to the reaction solution at room temperature and stirred for 1 minute. The aqueous layer of the reaction solution was removed, and distilled water (1.0 ml) was added and stirred for 1 minute. The aqueous layer of the reaction solution was removed, and distilled water (1.0 ml) was added. The reaction solution was stirred for 1 minute. After stirring, the aqueous layer was removed. Triphenylphosphine (0.38 g) and distilled water (0.042 ml) were added to the reaction solution at room temperature. The reaction solution was stirred at 64° C. for 1 hour. To the reaction solution, acetonitrile (1.7 ml) and concentrated hydrochloric acid (0.12 ml) were added under ice cooling, and the mixture was stirred for 30 minutes. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (0.41 g, yield 88%). 1 H-NMR (DMSO-d6) δ: 0.83-0.88 (2H, m), 0.89-0.94 (2H, m), 1.45 (3H, s), 4.16 (2H, s), 4.16 (3H, s), 7.49-7.56 (2H, m), 7.71 (1H, dd, J = 8.3, 2.3 Hz), 7.75 (1H, d, J = 8.3 Hz), 8.15 (1H, d, J = 2.3 Hz), 8.27-8.34 (4H, m), 8.38-8.40 (1H, m).

[0199] (5) N-(4-chloro-3-{4-methoxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide

[0200] [ka]

[0201] Under an argon atmosphere, a solution of 4-chloro-3-{4-methoxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-triazin-2-yl}benzylamine hydrochloride (0.080 g) obtained in (4) above, 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.045 g), HOBt·HO (0.044 g) and WSC·HCl (0.055 g) in N,N-dimethylformamide (1.0 ml) was added at room temperature. Ethylamine (0.080 ml) was added and the mixture was stirred for 16 hours. Chill was added, and the layers were separated, and the organic layer was washed with saturated saline. This organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.093 g, yield 93%). 1 H-NMR (CDCl3) δ: 0.77-0.81 (2H, m), 0.93-0.96 (2H, m), 1.44 (6H, s), 1.47 (3H, s), 4.21 (3H, s), 4.55 (2H, d, J = 5.8 Hz), 6.18-6.26 (1H, m), 7.35 (1H, dd, J = 8.3, 2.3 Hz), 7.42 (1H, t, J = 7.7 Hz), 7.49 (1H, dt, J = 7.7, 1.6 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 2.3 Hz), 8.39 (1H, dt, J = 7.7, 1.6 Hz), 8.49 (1H, t, J = 1.6 Hz).

[0202] (6) N-(4-chloro-3-{4-hydroxy-6-[3-(1-methylcyclopropyl)phenyl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide

[0203] [ka]

[0204] Under an argon atmosphere, N-(4-chloro-3-{4-methoxy-6-[3-(1-methyl Cyclopropyl)phenyl]-1,3,5-triazin-2-yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide (0.093 g) in methanol (1.5 ml) was added at room temperature to give a 4M An aqueous solution of sodium hydroxide (0.27 ml) was added, and the mixture was stirred at 65° C. for 2.5 hours. To this reaction solution, 2N hydrochloric acid (0.54 ml) and water were added at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration and washed with water. The precipitate was washed and dried under reduced pressure to give the title compound (0.086 g, 94% yield).

[0205] [Production Example 4]: 1-Trifluoromethylcyclopentanecarboxylic acid 4-chloro-3-[4-hydro Synthesis of 6-(3-isopropylphenyl)-1,3,5-triazin-2-yl]benzylamide (Example No. 52)

[0206] [ka]

[0207] (1) 2-Chloro-4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazine

[0208] [ka]

[0209] Under an argon atmosphere, a suspension of 3-isopropylphenylboronic acid (6.1 g), 2,4-dichloro-6-methoxy-1,3,5-triazine (10 g), tetrakis(triphenylphosphine)palladium(0) (1.7 g) and sodium carbonate (12 g) in toluene (60 ml) and distilled water (60 ml) was The reaction mixture was filtered at room temperature and stirred at 80° C. for 3 hours. The filtrate was washed with a 1:1 mixed solvent of n-hexane and ethyl acetate and water. A 1:1 mixed solvent of n-hexane and ethyl acetate was added to the filtrate, and the layers were separated. The organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, and the sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a mixture (11 g) containing the title compound.

[0210] (2) {4-chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol

[0211] [ka]

[0212] Under an argon atmosphere, 2-chloro-4-(3-isopropylphenyl)-6-methylphenyl obtained in (1) above was A mixture of 1,3,5-triazine (14 g), 2-chloro-5-hydroxymethylphenylboronic acid (12 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (10 g), The dichloromethane adduct (1.3 g) and tripotassium phosphate (23 g) in acetonitrile (98 A suspension of 100 ml of toluene (100 ml) and distilled water (42 ml) was stirred at 80° C. for 3 hours. Saturated saline and a mixed solvent of n-hexane:ethyl acetate = 1:1 were added to the liquid, and the liquids were separated. The organic layer was washed with saturated saline. After drying the organic layer over sodium sulfate, the sodium sulfate was removed by filtration and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate and chloroform / ethyl acetate) to obtain a 1,2-dichloromethane syrup. This gave the title compound (9.2 g, yield about 47% (2 steps)). 1 H-NMR (CDCl3) δ: 1.32 (6H, d, J = 6.9 Hz), 2.04 (1H, t, J = 6.0 Hz), 2.98-3.08 (1H, m), 4.21 (3H, s), 4.75 (2H, d, J = 5.6 Hz), 7.41-7.48 (3H, m), 7.53 (1H, d, J = 8.1 Hz), 8.01 (1H, d, J = 2.4 Hz), 8.40-8.44 (1H, m), 8.46-8.47 (1H, m).

[0213] (3) 4-Chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl] Benzylamine hydrochloride

[0214] [ka]

[0215] Under an argon atmosphere, the {4-chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol (9.2 g) obtained in (2) above was dissolved in toluene (37 ml Diphenylphosphoryl azide (6.4 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (4.5 ml) were added to the solution under ice cooling. The reaction solution was stirred at room temperature for 15 hours. Saturated sodium bicarbonate water (18 ml) and distilled water (18 ml) were added to the reaction solution at room temperature, and the mixture was stirred for 1 minute. The aqueous layer of the reaction solution was removed, and distilled water (36 ml) was added and stirred for 1 minute. The aqueous layer of the reaction solution was removed, and distilled water (36 ml) was added. The reaction solution was stirred for 1 minute, and then the aqueous layer was removed. Triphenylphosphine (8.5 g) was added to the reaction solution under ice cooling, and stirred for 15 minutes. After stirring the reaction mixture at room temperature for 15 minutes, distilled water (0.92 ml) was added. The reaction mixture was stirred at 60° C. for 1 hour. Acetonitrile (37 ml) and concentrated salt were added to the reaction mixture at room temperature. Acid (2.6 ml) was added and stirred for 1 hour. The solid was filtered from this suspension and dried under reduced pressure. This gave the title compound (8.4 g, 83% yield). 1 H-NMR (DMSO-d6) δ: 1.27 (6H, d, J = 6.9 Hz), 3.00-3.09 (1H, m), 4.15 (2H, br s), 4.16 (3H, s), 7.54 (1H, t, J = 7.7 Hz), 7.58-7.60 (1H, m), 7.72-7.76 (2H, m), 8.16 (1H, br s), 8.35 (1H, dt, J = 7.7, 1.6 Hz), 8.39 (1H, br s), 8.48 (3H, br s).

[0216] (4) 1-Trifluoromethylcyclopentanecarboxylic acid 4-chloro-3-[4-(3-isopropyl phenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamide

[0217] [ka]

[0218] Under an argon atmosphere, 4-chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamine hydrochloride (0.080 g) obtained in (3) above, 1-(trifluoromethyl) To a solution of (3-methyl)cyclopentanecarboxylic acid (0.047 g), HOBt·HO (0.045 g) and WSC·HCl (0.057 g) in N,N-dimethylformamide (0.70 ml), triethylamine (0.082 ml) was added at room temperature and stirred for 18 hours. A 1:1 mixed solvent was added, the layers were separated, and the organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate) to obtain the title compound (0.094 g, yield 90%). 1 H-NMR (CDCl3) δ: 1.32 (6H, d, J = 6.9 Hz), 1.71-1.75 (4H, m), 1.96-2.06 (2H, m), 2.28-2.35 (2H, m), 2.99-3.08 (1H, m), 4.21 (3H, s), 4.56 (2H, d, J = 5.6 Hz), 6.23 (1H, br s), 7.35 (1H, dd, J = 8.1, 2.4 Hz), 7.42-7.49 (2H, m), 7.52 (1H, d, J = 8.5 Hz), 7.93 (1H, d, J = 2.4 Hz), 8.40-8.43 (1H, m), 8.46 (1H, br s).

[0219] (5) 1-Trifluoromethylcyclopentanecarboxylic acid 4-chloro-3-[4-hydroxy-6-(3-isopropylphenyl)-1,3,5-triazin-2-yl]benzylamide

[0220] [ka]

[0221] Under an argon atmosphere, 1-trifluoromethylcyclopentane carbohydrate obtained in (4) above was 4-Chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]phosphonic acid To a solution of benzylamide (0.093 g) in methanol (0.80 ml) was added 4M aqueous sodium hydroxide solution (0.13 ml) at room temperature, and the mixture was stirred at 60° C. for 3 hours. To this reaction solution, 2N hydrochloric acid (0.26 ml) and water were added at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. Drying gave the title compound (0.083 g, 92% yield).

[0222] [Production Example 5]: Synthesis of 1-fluoromethylcyclopentanecarboxylic acid

[0223] [ka]

[0224] (1) 1-Hydroxymethylcyclopentanecarboxylic acid benzyl ester

[0225] [ka]

[0226] Under an argon atmosphere, 1-hydroxymethylcyclopentanecarboxylic acid (1.1 g) was dissolved in N,N-dichloroethane. Benzyl bromide (0.94 ml) was added to a methylformamide (5.0 ml) solution at room temperature. To this reaction solution, potassium carbonate (1.3 g) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. This reaction solution was left to stand for 20 hours. To this reaction solution, water and ethyl acetate were added, and the mixture was separated, and then the organic layer was washed with saturated saline. This organic layer was dried over sodium sulfate, and then the sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a mixture containing the title compound (2.0 g). 1 H-NMR (CDCl3) δ: 1.60-1.80 (6H, m), 1.95-2.03 (2H, m), 2.45-2.50 (1H, m), 3.59 (2H, d, J = 6.9 Hz), 5.16 (2H, s), 7.30-7.39 (5H, m).

[0227] (2) 1-Trifluoromethanesulfonyloxymethylcyclopentanecarboxylate Luester

[0228] [ka]

[0229] Under an argon atmosphere, 1-hydroxymethylcyclopentane carboxylate obtained in (1) above was To a solution of a mixture (0.70 g) containing an acid benzyl ester in chloroform (3.5 ml), 2,6-lutidine (0.47 ml) and trifluoromethanesulfonic anhydride (0.50 ml) were added under ice cooling. The reaction solution was stirred at room temperature for 10 minutes. Water, a 10% aqueous citric acid solution, and chloroform were added to the reaction solution at room temperature, and the layers were separated. The organic layer was washed with a 2% aqueous citric acid solution. The mixture was dried over sodium sulfate, filtered to remove the sodium sulfate, and the filtrate was concentrated under reduced pressure to give a mixture containing the title compound (1.0 g). 1 H-NMR (CDCl3) δ: 1.64-1.88 (6H, m), 2.05-2.23 (2H, m), 4.58 (2H, s), 5.17 (2H, s), 7.29-7.40 (5H, m).

[0230] (3) 1-Fluoromethylcyclopentanecarboxylic acid benzyl ester

[0231] [ka]

[0232] Under an argon atmosphere, 1-trifluoromethanesulfonyloxymethyl A mixture (1.1 g) of tetrahydrofuran containing cyclopentanecarboxylic acid benzyl ester To the furan (5.0 ml) solution, tetrabutylammonium fluoride (approximately 1 mol / L tetrahydrofuran solution, 3.0 ml) was added under ice cooling. The reaction solution was left to stand for 63 hours, and then water and acetic acid were added. Ethyl was added and the mixture was separated. The organic layer was washed with water, then with saturated saline, dried over sodium sulfate, and filtered to remove sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.39 g, yield 62% (3 steps)). 1 H-NMR (CDCl3) δ: 1.60-1.82 (6H, m), 2.06-2.16 (2H, m), 4.47 (2H, d, J = 47.4 Hz), 5.17 (2H, s), 7.28-7.40 (5H, m).

[0233] (4) 1-Fluoromethylcyclopentanecarboxylic acid

[0234] [ka]

[0235] Under a nitrogen atmosphere, the 1-fluoromethylcyclopentanecarboxylic acid vector obtained in (3) above was A solution of benzyl ester (0.39 g) in tetrahydrofuran (4.0 ml) was added to ASCA-2 (4.5% palladium-0.5% platinum catalyst supported on activated carbon (NE Chemcat Corporation, Fine Chemical Industries, Ltd.) at room temperature. Chemical, October 1, 2002 issue, p. 5-14) (0.12 g) was added. The mixture was stirred under 1 atm hydrogen for 5 hours. Under a nitrogen atmosphere, ASCA-2 (0.20 g) was added. The mixture was stirred under 1 atm hydrogen for 15 hours. Under a nitrogen atmosphere, this reaction solution was filtered through Celite and eluted with tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain a mixture containing the title compound (0.35 g). 1 H-NMR (CDCl3) δ: 1.62-1.81 (6H, m), 2.07-2.14 (2H, m), 4.46 (2H, d, J = 47.2 Hz).

[0236] [Production Example 6]: Synthesis of 1-difluoromethylcyclopentanecarboxylic acid

[0237] [ka]

[0238] (1) 1-Formyl-cyclopentanecarboxylic acid benzyl ester

[0239] [ka]

[0240] Under an argon atmosphere, triethylamine (1.5 ml) was added to a mixture (0.70 g) containing 1-hydroxymethylcyclopentanecarboxylate benzyl ester obtained in (1) of the above Production Example 5, in a mixed solution of chloroform (3.5 ml) and dimethyl sulfoxide (7.0 ml). To this reaction solution, sulfur trioxide-pyridine complex (1.3 g) was added under ice cooling. This reaction solution was stirred at room temperature for 1 hour, and then water and ethyl acetate were added to separate the layers. This organic layer was washed with a 2% aqueous citric acid solution, then a ca. 2% aqueous sodium hypochlorite solution, and then a saturated saline solution, and the solution was separated with sodium sulfate. The mixture was dried over ice, and the sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.58 g, yield about 93%). 1 H-NMR (CDCl3) δ: 1.57-1.79 (4H, m), 2.05-2.20 (4H, m), 5.19 (2H, s), 7.30-7.41 (5H, m), 9.68 (1H, s).

[0241] (2) 1-Difluoromethylcyclopentanecarboxylic acid benzyl ester

[0242] [ka]

[0243] Under an argon atmosphere, a solution of 1-formyl-cyclopentanecarboxylic acid benzyl ester (0.10 g) obtained in (1) above in tetrahydrofuran (1.0 ml) was added with bis(2-methylcyclopentane) at room temperature. (2-methoxyethyl)aminosulfur trifluoride (0.32 ml) was added. After stirring for 14 hours, the reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then filtered to remove sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (0.094 g, yield 86%). 1 H-NMR (CDCl3) δ: 1.64-1.79 (4H, m), 1.87-2.13 (4H, m), 5.17 (2H, s), 6.14 (1H, t, J = 56.8 Hz), 7.29-7.41 (5H, m).

[0244] (3) 1-Difluoromethylcyclopentanecarboxylic acid

[0245] [ka]

[0246] Under a nitrogen atmosphere, 1-difluoromethylcyclopentanecarboxylic acid obtained in (2) above was To a solution of benzyl ester (0.094 g) in tetrahydrofuran (1.0 ml) was added ASCA-2 (0.094 g) at room temperature. The mixture was stirred for 4 hours under 1 atm hydrogen. The mixture was filtered through a light filter and eluted with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to give a mixture containing the title compound (0.046 g, yield about 75%). 1 H-NMR (CDCl3) δ: 1.65-1.79 (4H, m), 1.92-2.01 (2H, m), 2.04-2.18 (2H, m), 6.13 (1H, t, J = 56.5 Hz).

[0247] [Production Example 7]: Synthesis of 2-ethyl-2-methoxybutyric acid

[0248] [ka]

[0249] (1) 2-Ethyl-2-hydroxybutyric acid benzyl ester

[0250] [ka]

[0251] Under an argon atmosphere, triphenylphosphine (3.4 g) was added to a mixed solution of 2-ethyl-2-hydroxybutyric acid (1.0 g) in tetrahydrofuran (5.0 ml) and toluene (5.0 ml). To this reaction solution, benzyl alcohol (0.78 ml) and azodicarboxylate bis(2-methoxyethyl) ester (2.1 g) were added under ice cooling, and the reaction solution was stirred at room temperature for 1 hour. To this reaction solution, ice water and a mixed solvent of n-hexane:ethyl acetate = 1:1 were added, and after separation, the organic layer was washed with water. This organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n- The title compound (1.6 g, 93% yield) was obtained by purifying the extract with hexane / ethyl acetate. . 1 H-NMR (CDCl3) δ: 0.82 (6H, t, J = 7.5 Hz), 1.62-1.84 (4H, m), 3.16 (1H, s), 5.21 (2H, s), 7.32-7.40 (5H, m).

[0252] (2) 2-Ethyl-2-methoxybutyric acid benzyl ester

[0253] [ka]

[0254] Under an argon atmosphere, a solution of 2-ethyl-2-hydroxybutyric acid benzyl ester (1.6 g) obtained in (1) above in N,N-dimethylformamide (11 ml) was added with iodomethane (0.48 ml) under ice cooling. ml) and sodium hydride (0.31 g, 60% by weight oil dispersion). The reaction solution was stirred at room temperature for 1 hour. A 1:1 mixed solvent of hexane and ethyl acetate was added, and the layers were separated. The organic layer was washed with water. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (1.4 g, yield 81%). 1 H-NMR (CDCl3) δ: 0.81 (6H, t, J = 7.5 Hz), 1.80 (4H, q, J = 7.5 Hz), 3.22 (3H, s), 5.19 (2H, s), 7.29-7.38 (5H, m).

[0255] (3) 2-Ethyl-2-methoxybutyric acid

[0256] [ka]

[0257] Under a nitrogen atmosphere, ASCA-2 (0.14 g) was added to a solution of 2-ethyl-2-methoxybutyric acid benzyl ester (1.4 g) obtained in (2) above in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred under 1 atm hydrogen for 4 hours. Under a nitrogen atmosphere, the reaction solution was filtered through Celite, and the tetrahydrofuran The filtrate was concentrated under reduced pressure to give a mixture containing the title compound (0.83 g). 1H-NMR (CDCl3) δ: 0.85 (6H, t, J = 7.5 Hz), 1.72-1.89 (4H, m), 3.29 (3H, s).

[0258] [Production Example 8]: 2-ethyl-N-(4-chloro-3-{4-hydroxy-6-[6-((R)-1-methylbutoxy)pyridine) Synthesis of (lysine-3-yl)-1,3,5-triazin-2-yl}benzyl)-2-methoxybutanamide ( Example No. 79)

[0259] [ka]

[0260] (1)N-(4-chloro-3-{4-methoxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}benzyl)amine hydrochloride

[0261] [ka]

[0262] Under an argon atmosphere, diphenylphosphoryl azide (52.4 ml) was added dropwise to a solution of (4-chloro-3-{4-methoxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}phenyl)methanol (84.0 g) obtained in Production Example 2(3) in 1,2-dimethoxyethane (420 ml) under ice cooling. To this reaction solution, 1,8-diazabicyclo[5.4.0]-7-undecane was added under ice cooling. C. (36.3 ml) was added dropwise. After the temperature was raised to room temperature, the mixture was stirred for 15 hours. Toluene (210 ml) and 5% aqueous sodium hydrogen carbonate solution (84 ml) were added, and the mixture was stirred for 10 minutes. The aqueous layer of the reaction solution was removed, and distilled water (168 ml) was added to the organic layer, followed by stirring for 10 minutes. The aqueous layer of the reaction solution was removed, and 1,2-dimethylphenylphosphine (69.0 g) was added to the organic layer under water cooling. A solution of 220 ml of methoxyethane was added dropwise over 30 minutes. After stirring for 2 hours, the internal temperature was increased to 61°C (bath temperature 70°C). The temperature was raised to 35° C. and the mixture was stirred for 1 hour. To this reaction solution, concentrated hydrochloric acid (18.6 ml) was added dropwise under ice cooling. This reaction solution was stirred at room temperature for about 1 hour. The precipitated solid was filtered and 1,2-dimethoxy The product was washed with ethane and dried under reduced pressure to give the title compound (77.6 g, yield 85%). The mixture was used in the next step without purification.

[0263] (2) N-(4-chloro-3-{4-methoxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}benzyl)-2-ethyl-2-methoxybutanamide

[0264] [ka]

[0265] Under an argon atmosphere, N-(4-chloro-3-{4-methoxy-6-[6-((R)-1-methylphenyl)-

[0221] To a suspension of [1,3,5-triazin-2-yl]benzyl)amine hydrochloride (3.5 g) in N,N-dimethylformamide (21 ml) was added 2-ethyl-2-methoxy Butyric acid (1.32 g), diisopropylethylamine (1.62 ml), HOBt·HO (0.60 g) and WSC·HCl (1.78 g) were added and stirred for 16 hours. Distilled water (7.0 ml) was added to the reaction solution under ice cooling. The aqueous layer was extracted with a 1 / 1 mixed solvent of ethyl acetate and n-hexane (10 ml). The mixture was washed twice with distilled water, once with saturated sodium bicarbonate water, and once with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate) Purification gave the title compound (4.1 g, 97% yield). 1 H-NMR (CDCl3) δ: 0.77 (6H, t, J = 7.4 Hz), 0.94 (3H, t, J = 7.4 Hz), 1.35 (3H, d, J = 6.2 Hz), 1.39-1.50 (2H, m), 1.57-1.90 (6H, m), 3.19 (3H, s), 4.18 (3H, s), 4.52 (2H, d, J = 6.0 Hz), 5.32-5.40 (1H, m), 6.77 (1H, d, J = 8.8 Hz), 7.28 (1H, m), 7.40 (1H, dd, J = 8.2, 2.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.96 (1H, d, J = 2.2 Hz), 8.65 (1H, dd, J = 8.8, 2.5 Hz), 9.38 (1H, m).

[0266] (3) 2-Ethyl-N-(4-chloro-3-{4-hydroxy-6-[6-((R)-1-methylbutoxy)pyridin-3-yl]-1,3,5-triazin-2-yl}benzyl)-2-methoxybutanamide

[0267] [ka]

[0268] Under an argon atmosphere, N-(4-chloro-3-{4-methoxy-6-[6-((R)-1-methylphenyl)-2-(2-phenylpropanediol)-1,3-dihydro-2,4-dihydro-1,5-dihydro-2,6 ... 1,3,5-triazin-2-yl}benzyl)-2-ethyl-2-meth A solution of 4.1 g of butanamide in 16 ml of methanol and 8 ml of THF was added at room temperature. 4M aqueous sodium hydroxide solution (7.77 ml) was added and stirred for 19 hours. Under ice cooling, 2N hydrochloric acid (15.5 ml) and ethyl acetate (20 ml) were added and stirred. After separation, the aqueous layer was extracted with ethyl acetate (16 ml). The organic layers were combined and washed twice with distilled water and once with saturated saline. This organic layer was dried over sodium sulfate and then filtered to remove sodium sulfate. The thorium was removed, and the mixture was concentrated under reduced pressure to give the title compound (4.06 g, 99%). A solution of the title compound (3.4 g) in ethyl acetate (6.8 ml) was stirred at 80° C., and n-heptane (32 ml) was added. This suspension was stirred at 80° C. for 3 hours, and then at room temperature for 4 hours. The obtained solid was filtered and dried to give the title compound as crystals (3.2 g). 1 H-NMR (DMSO-d6) δ: 0.66 (6H, t, J = 7.4 Hz), 0.89 (3H, t, J = 7.3 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.33-1.45 (2H, m), 1.54-1.75 (6H, m), 3.14 (3H, s), 4.34 (2H, d, J = 6.4 Hz), 5.27-5.35 (1H, m), 6.91 (1H, d, J = 8.8 Hz), 7.45-7.53 (1H, m), 7.56-7.76 (2H, m), 8.36 (1H, t, J = 6.4 Hz), 8.48 (1H, dd, J = 8.8, 2.3 Hz), 9.08 (1H, d, J = 2.3 Hz), 13.28 (1H, br s). A suspension of the title compound (1.0 g) in distilled water (20 ml) and acetonitrile (2.0 ml) The mixture was stirred at room temperature for 18 hours. A mixed solvent of distilled water / acetonitrile (10 / 1) (10 ml) was added to the suspension, and the mixture was stirred at room temperature for 5 days. The resulting solid was filtered and dried at room temperature to obtain a monohydrate crystal of the title compound (1.0 g). The following analysis showed that the obtained crystal was a monohydrate. It was estimated that the crystals were the same as those obtained above based on the powder X-ray diffraction spectrum. The crystals were analyzed by simultaneous thermogravimetry and differential thermal analysis (TG / DTA) and were analyzed by increasing the temperature from room temperature to 50°C, and the crystals were analyzed by approximately 3.2 The weight loss was 1.0%, and the weight loss was 1.0%. The weight loss was about 3.3%. These results supported that the measured crystal was a monohydrate.

[0269] [Production Example 9]: 1-Trifluoromethylcyclohexanecarboxylic acid 4-chloro-3-[4-hydroxy Synthesis of 6-(3-isopropylphenyl)-1,3,5-triazin-2-yl]benzylamide (Example No. 71)

[0270] [ka]

[0271] (1) 1-Trifluoromethylcyclohexanecarboxylic acid 4-chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]benzylamide

[0272] [ka]

[0273] Under an argon atmosphere, 4-chloro-3-[4-(3-isopropylphenyl) A suspension of 1-(trifluoromethyl)cyclohexanediamine hydrochloride (6.00 g) in N,N-dimethylformamide (60 ml) was added to 1-(trifluoromethyl)cyclohexanediamine hydrochloride (6.00 g) at room temperature. San-1-carboxylic acid (4.35 g), triethylamine (6.19 ml), HOBt HO (3.40 g ) and WSC·HCl (4.25 g) were added and stirred for 15 hours. Water (60 ml) and ethyl acetate (100 ml) were added and the layers were separated. The resulting organic layer was diluted with saturated sodium chloride solution. The organic layer was washed three times with water, dried over sodium sulfate, and then filtered to remove sodium sulfate. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate) to obtain the title compound (7.65 g, yield 94%). Ta. 1 H-NMR (CDCl3) δ: 1.14-1.27 (1H, m), 1.32 (6H, d, J = 6.9 Hz), 1.34-1.47 (2H, m), 1.57-1.77 (5H, m), 2.19-2.27 (2H, m), 2.98-3.09 (1H, m), 4.21 (3H, s), 4.60 (2H, d, J = 5.8 Hz), 6.19-6.27 (1H, m), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.42-7.49 (2H, m), 7.53 (1H, d, J = 8.3 Hz), 7.95 (1H, d, J = 2.3 Hz), 8.40-8.43 (1H, m), 8.45-8.47 (1H, m).

[0274] (2) 1-Trifluoromethylcyclohexanecarboxylic acid 4-chloro-3-[4-hydroxy-6-(3- Isopropylphenyl)-1,3,5-triazin-2-yl]benzylamide

[0275] [ka]

[0276] Under an argon atmosphere, 1-trifluoromethylcyclohexanecarbamoyl obtained in (1) above was added to 4-Chloro-3-[4-(3-isopropylphenyl)-6-methoxy-1,3,5-triazin-2-yl]phosphonic acid A solution of benzylamide (7.55 g) in methanol (69 ml) was diluted with 4M sodium hydroxide at room temperature. Aqueous hexane solution (13.8 ml) was added and stirred at 64° C. for 2 hours. Acid (27.6 ml) and water (100 ml) were added and stirred for 3 hours. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (7.05 g, yield 95%). n-Hexane (8.0 ml) was added to a suspension of the title compound (1.0 g) in acetone (2.0 ml) at room temperature, and the mixture was stirred at 60° C. for 20 hours. The obtained solid was collected by filtration and dried to obtain the title compound as crystals (0.813 g). 1 H-NMR (DMSO-d6) δ: 1.08-1.26 (3H, m), 1.25 (6H, d, J = 8.0 Hz), 1.41-1.64 (5H, m), 2.35 (2H, d, J = 12.5 Hz), 2.96-3.03 (1H, m), 4.42 (2H, d, J = 5.9 Hz), 7.42-7.51 (2H, m), 7.56 (1H, d, J = 7.7 Hz), 7.62 (1H, d, J = 8.5 Hz), 7.67 (1H, br s), 8.15 (1H, d, J = 7.7 Hz), 8.22 (1H, br s), 8.78 (1H, t, J = 5.9 Hz).

[0277] [Production Example 10]: 1-Trifluoromethylcyclohexane carboxylate 3-[4-(3-tert-butyl) Synthesis of [phenyl]-6-hydroxy-1,3,5-triazin-2-yl-4-chlorobenzylamide (Example No. 107)

[0278] [ka]

[0279] (1) 3-[4-(3-tert-butylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4-chlorobenzylamine hydrochloride

[0280] [ka]

[0281] Under an argon atmosphere, 3-tert-butylphenylboronic acid (6.6 g), 2,4-dichloro-6-methylphenylboronic acid A suspension of 1,3,5-triazine (10.0 g), tetrakis(triphenylphosphine)palladium(0) (0.86 g) and sodium carbonate (11.8 g) in toluene (66 ml) and distilled water (66 ml) was stirred at 80° C. for 4 hours. A 1:1 mixed solvent and water were added and the layers were separated. The organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, and the sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure, and acetonitrile (70 ml) and distilled water (30 ml) were added. 2-chloro-5-hydroxymethylphenylboronic acid (8.3 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.91 g) and lithium were added to the suspension. Potassium phosphate (15.7 g) was added and the mixture was stirred at 80° C. for 3 hours. Saturated saline and a mixed solvent of n-hexane:ethyl acetate = 1:1 were added and the liquids were separated. The organic layer was washed with saturated saline. After drying the organic layer over sodium sulfate, the sodium sulfate was removed by filtration and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) and concentrated under reduced pressure. Toluene (57 ml) was added to the resulting residue under an argon atmosphere. Diphenylphosphoryl was added to this solution under ice-cooling. To the reaction mixture, azide (8.0 ml) and 1,8-diazabicyclo[5.4.0]-7-undecene (5.5 ml) were added. The reaction mixture was stirred at room temperature for 18 hours. To the reaction mixture, saturated sodium bicarbonate water (15 ml) and distilled water (15 ml) were added at room temperature and stirred for 1 minute. The aqueous layer of the reaction mixture was removed, and Distilled water (30 ml) was added and stirred for 1 minute. The aqueous layer of this reaction solution was removed, and distilled water (30 ml) was added. This reaction solution was stirred for 1 minute, and then the aqueous layer was removed. This reaction solution was cooled on ice. Triphenylphosphine (10.7 g) was added and stirred for 5 minutes. This reaction solution was stirred at room temperature for 30 minutes, and then distilled water (2.8 ml) was added. This reaction solution was stirred for 30 minutes and then heated at 60° C. for 1 hour. The reaction mixture was stirred for 1 h at room temperature. l) was added and stirred for 1 hour. The solid was filtered out from this suspension and dried under reduced pressure to give the product The title compound was obtained (11.3 g, yield 73% (3 steps)). The title compound was used in the next step without purification.

[0282] (2) 1-Trifluoromethylcyclohexanecarboxylic acid 3-[4-(3-tert-butylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4-chlorobenzylamide

[0283] [ka]

[0284] Under an argon atmosphere, 3-[4-(3-tert-butylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4-chlorobenzylamine hydrochloride (5.0 g) obtained in (1) above, 1-(trifluoromethyl)cyclohexanecarboxylic acid (3.50 g), HOBt·H2O (2.74 g) and WSC·HCl (3.43 g) were added to a solution of N,N-dimethylformamide (50 ml) at room temperature, and the mixture was stirred for 18 hours. Saturated sodium bicarbonate water (50 ml) and ethyl acetate (80 ml) were added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (6.31 g, yield 94%). 1 H-NMR (CDCl3) δ: 1.14-1.26 (1H, m), 1.34-1.47 (2H, m), 1.40 (9H, s), 1.55-1.76 (5H, m), 2.19-2.26 (2H, m), 4.21 (3H, s), 4.60 (2H, d, J = 5.8 Hz), 6.17-6.27 (1H, m), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.45 (1H, t, J = 7.7 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.62-7.65 (1H, m), 7.97 (1H, d, J = 2.3 Hz), 8.39-8.43 (1H, m), 8.66 (1H, t, J = 1.8 Hz).

[0285] (3) 1-Trifluoromethylcyclohexanecarboxylic acid 3-[4-(3-tert-butylphenyl)-6-hydroxy-1,3,5-triazin-2-yl]-4-chlorobenzylamide

[0286] [ka]

[0287] Under an argon atmosphere, 1-trifluoromethylcyclohexanecarbamoyl obtained in (2) above was added to 3-[4-(3-tert-butylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4-chlorobenzoate A solution of benzylamide (6.21 g) in methanol (55 ml) was added to 4M sodium hydroxide at room temperature. An aqueous solution (11.1 ml) was added, and the mixture was stirred at 64° C. for 2 hours. To this reaction solution, 2N hydrochloric acid (22.1 ml) and water (80 ml) were added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration. The extract was washed with water and dried under reduced pressure to give the title compound (5.84 g, yield 96%). To a solution of the product (1.0 g) in ethanol (4.0 ml) was slowly added n-hexane (40 ml) at room temperature. The resulting solid was filtered and dried to give the title compound as crystals (0.78 g). 1 H-NMR (DMSO-d6) δ: 1.11-1.63 (8H, m), 1.34 (9H, s), 2.35 (2H, d, J = 13.7 Hz), 4.42 (2H, d, J = 6.0 Hz), 7.42-7.50 (2H, m), 7.60 (1H, d, J = 8.5 Hz), 7.66-7.72 (2H, m), 8.15 (1H, d, J = 8.1 Hz), 8.38 (1H, br s), 8.78 (1H, t, J = 5.8 Hz), 13.36 (1H, br s).

[0288] [Production Example 11]: Synthesis of (R)-N-{3-[4-(3-tert-butylphenyl)-6-hydroxy-1,3,5-triazin-2-yl]-4-chlorobenzyl}-3,3,3-trifluoro-2-methoxy-2-methylpropionamide (Example No. 66)

[0289] [ka]

[0290] (1) (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid benzyl ester

[0291] [ka]

[0292] Under an argon atmosphere, benzyl bromide (1.8 ml, 15 mmol) was added to a suspension of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2.2 g, 14 mmol) and potassium carbonate (2.3 g, 16 mmol) in N,N-dimethylformamide (30 ml) at room temperature, and the mixture was stirred for 4 hours. Water and ethyl acetate were added to this reaction solution, the layers were separated, and the organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1) to give the title compound (3.0 g, yield 90%). 1 H-NMR (CDCl3) δ: 1.60 (3H, s), 3.78 (1H, s), 5.31 (2H, s), 7.33-7.42 (5H, m).

[0293] (2) (R)-3,3,3-trifluoro-2-methoxy-2-methylpropionic acid benzyl

[0294] [ka]

[0295] Under an argon atmosphere, the (R)-3,3,3-trifluoro-2-hydroxy-2-methyl- Benzyl ethylpropionate (3.4 g, 14 mmol) dissolved in N,N-dimethylformamide (40 ml) Sodium hydride (0.60 g, 60% by weight oil dispersion) was added to the liquid under ice cooling, and the mixture was stirred for 1 hour. Methyl iodide (1.3 ml, 20 mmol) was added to the reaction liquid, and the mixture was stirred at room temperature for 2 The reaction mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and the mixture was separated. The organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 15 / 1) to obtain a product. The title compound was obtained (2.8 g, yield 78%). 1 H-NMR (CDCl3) δ: 1.59 (3H, s), 3.40 (3H, s), 5.26 (2H, s), 7.31-7.37 (5H, m).

[0296] (3)(R)-3,3,3-trifluoro-2-methoxy-2-methylpropionic acid

[0297] [ka]

[0298] Under an argon atmosphere, the (R)-3,3,3-trifluoro-2-methoxy-2-methyl To a solution of benzyl dipropionate (2.8 g, 11 mmol) in ethyl acetate (50 ml) was added 10% by weight palladium on carbon (0.23 g) at room temperature, and the mixture was stirred for 5 hours under a hydrogen atmosphere at 1 atm. The reaction mixture was filtered through Celite under atmospheric pressure and eluted with ethyl acetate, and the filtrate was concentrated under reduced pressure to give the title compound (1.4 g, yield 78%). 1 H-NMR (CDCl3) δ: 1.68 (3H, s), 3.54 (3H, s).

[0299] (4)(R)-N-{3-[4-(3-tert-butylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4- Chlorobenzyl}-3,3,3-trifluoro-2-methoxy-2-methylpropionamide

[0300] [ka]

[0301] Under an argon atmosphere, 3-[4-(3-tert-butylphenyl)-6-methoxy-1,3,5-triazin-2-yl]-4-chlorobenzylamine hydrochloride (5.2 g) obtained in (1) of Production Example 10 and the above (R)-3,3,3-trifluoro-2-methoxy-2-methylpropionic acid (3.2 g) obtained in (3) To a solution of HOBt·HO (2.85 g) and WSC·HCl (3.56 g) in N,N-dimethylformamide (52 ml), triethylamine (5.18 ml) was added at room temperature and stirred for 16 hours. Saturated aqueous sodium bicarbonate (50 ml) and ethyl acetate (80 ml) were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated saline. After drying the organic layer over sodium sulfate, the sodium sulfate was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (6.55 g, yield 98%). 1 H-NMR (CDCl3) δ: 1.40 (9H, s), 1.65-1.67 (3H, m), 3.44-3.45 (3H, m), 4.21 (3H, s), 4.47-4.63 (2H, m), 7.10-7.19 (1H, m), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.45 (1H, t, J = 7.7 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.62-7.65 (1H, m), 7.96 (1H, d, J = 2.3 Hz), 8.39-8.43 (1H, m), 8.66 (1H, t, J = 1.8 Hz).

[0302] (5) (R)-N-{3-[4-(3-tert-butylphenyl)-6-hydroxy-1,3,5-triazin-2-yl]-4-chlorobenzyl}-3,3,3-trifluoro-2-methoxy-2-methylpropionamide

[0303] [ka]

[0304] Under an argon atmosphere, the (R)-N-{3-[4-(3-tert-butylphenyl)-6-methylphenyl}- A solution of [[4-chlorobenzyl]-3,3,3-trifluoro-2-methoxy-2-methylpropionamide] (6.29 g) in methanol (58 ml) was added to 4M HCl at room temperature. An aqueous solution of sodium chloride (11.7 ml) was added and stirred at 64°C for 3 hours. 2N hydrochloric acid (23.4 ml) and water (80 ml) were added dropwise to this reaction solution under ice cooling and stirred. Ethyl acetate (200 ml) and saturated saline were added to this reaction solution and the layers were separated. This organic layer was washed with saturated saline. This organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (approximately 6.4 g). A mixed solution of this title compound (6.15 g) in ethyl acetate (50 ml) and n-hexane (50 ml) was added with n-hexane (100 ml) at room temperature. ) was added dropwise over 20 minutes. The suspension was stirred at room temperature for 1.5 hours, and then n-hexane (100 The suspension was stirred at room temperature for 16 hours. The solid was collected by filtration and dried to give the title compound as crystals (5.51 g, yield 90%). 1 H-NMR (DMSO-d6) δ: 1.34 (9H, s), 1.54 (3H, s), 3.36 (3H, s), 4.33-4.45 (2H, m), 7.46 (1H, d, J = 8.3 Hz), 7.50 (1H, t, J = 7.9 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.67-7.72 (1H, m), 7.72 (1H, d, J = 7.9 Hz), 8.16 (1H, d, J = 7.9 Hz), 8.38 (1H, s), 9.02 (1H, t, J = 6.2 Hz), 13.34 (1H, br s).

[0305] [Production Example 12]: Synthesis of N-{4-chloro-3-[4-(6-hexyloxypyridin-3-yl)-6-hydroxy-1,3,5-triazin-2-yl]benzyl}-2-methoxy-2-methylpropionamide (Example Number 81)

[0306] [ka]

[0307] (1) 5-Bromo-2-hexyloxypyridine

[0308] [ka]

[0309] Under an argon atmosphere, 5-bromo-2-chloropyridine (15 g) and n-hexanol (11.7 To a solution of 1,2-dichlorophenyl ether (10 ml) in N,N-dimethylformamide (60 ml) was added potassium tert-butoxide (13.1 g) under ice-cooling and stirred for 30 minutes. This reaction solution was stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to this reaction solution, and the layers were separated. This aqueous layer was extracted with a mixed solvent of n-hexane:ethyl acetate = 1:1. The organic layers were combined and washed with water and saturated saline. This organic layer was dried over sodium sulfate, and then the sodium sulfate was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (18.8 g, 94%). 1 H-NMR (CDCl3) δ: 0.88-0.92 (3H, m), 1.29-1.37 (4H, m), 1.39-1.47 (2H, m), 1.71-1.79 (2H, m), 4.24 (2H, t, J = 6.7 Hz), 6.64 (1H, dd, J = 8.7, 0.6 Hz), 7.62 (1H, dd, J = 8.7, 2.6 Hz), 8.17 (1H, dd, J = 2.6, 0.6 Hz).

[0310] (2) [6-(hexyloxy)pyridin-3-yl]boronic acid

[0311] [ka]

[0312] Under an argon atmosphere, a mixture of 5-bromo-2-hexyloxypyridine (18.8 g) obtained in (1) above in toluene (124 ml), tetrahydrofuran (30 ml) and triisopropyl borate (21.7 ml) was added with n-butyllithium (1.55 M n-hexane solution, 61.2 ml) at -73°C. After stirring for 10 minutes, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. A 17% aqueous solution of citric acid (168 g) was added dropwise to the reaction mixture under ice cooling. The mixture was stirred for 10 minutes. To this reaction solution, n-hexane (124 ml) was added, and the layers were separated. The organic layer was extracted twice with water (30 ml). The aqueous layers were combined, and 4N aqueous sodium hydroxide solution (73 ml) was added, and the mixture was stirred for 10 minutes. The mixture was stirred (pH ≒ 7). The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the product. A mixture containing the title compound (18.1 g) was obtained. 1 H-NMR (DMSO-d6) δ: 0.87 (3H, t, J = 6.7 Hz), 1.25-1.33 (4H, m), 1.35-1.45 (2H, m), 1.65-1.73 (2H, m), 4.25 (2H, t, J = 6.7 Hz), 6.73 (1H, d, J = 8.2 Hz), 7.98 (1H, dd, J = 8.2, 1.8 Hz), 8.08 (2H, s), 8.49 (1H, br).

[0313] (3) 2-Chloro-4-(6-hexyloxypyridin-3-yl)-6-methoxy-1,3,5-triazine

[0314] [ka]

[0315] Under an argon atmosphere, a mixture of [6-(hexyloxy)pyridin-3-yl]boronic acid obtained in (2) above (9.07 g), 2,4-dichloro-6-methoxy-1,3,5-triazine (13.1 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.745 g) and potassium phosphate (23.2 g) was suspended in 1,2-dimethoxyethane (131 ml). Distilled water (65.6 ml) was added at room temperature. The mixture was stirred at 90°C for 2 hours. The reaction solution was separated at room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated saline. The organic layer was dried over sodium sulfate, and then the sodium sulfate was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (8.37 g, 71%). 1 H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.2 Hz), 1.30-1.39 (4H, m), 1.43-1.51 (2H, m), 1.76-1.83 (2H, m), 4.15 (3H, s), 4.40 (2H, t, J = 6.7 Hz), 6.81 (1H, dd, J = 8.8, 0.7 Hz), 8.56 (1H, dd, J = 8.8, 2.4 Hz), 9.28 (1H, dd, J = 2.4, 0.7 Hz).

[0316] (4) {4-chloro-3-[4-(6-hexyloxypyridin-3-yl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol

[0317] [ka]

[0318] Under an argon atmosphere, 2-chloro-4-(6-hexyloxypyridin-3-yl)-6-methoxy-1,3,5-triazine (8.37 g) obtained in (3) above and 2-chloro-5-hydroxymethylphenylboronic acid A suspension of sucrose acid (5.79 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.529 g), and tripotassium phosphate (8.25 g) in acetonitrile (59 ml) and distilled water (25 ml) was stirred at 90°C for 1.5 hours. The reaction solution was separated at room temperature. The resulting aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated saline. The organic layer was dried over sodium sulfate, and the sodium sulfate was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) and then concentrated under reduced pressure. A mixed solvent of n-hexane:ethyl acetate = 1:1 (20 ml) was added to the residue at room temperature and stirred for 1 hour. This suspension To the liquid, n-hexane (80 ml) was added at room temperature and stirred for 30 minutes. The resulting solid was collected by filtration. The mixture was then dried to give the title compound (7.26 g, yield 65%). 1 H-NMR (CDCl3) δ: 0.89-0.93 (3H, m), 1.31-1.40 (4H, m), 1.43-1.52 (2H, m), 1.77-1.84 (3H, m), 4.19 (3H, s), 4.40 (2H, t, J = 6.7 Hz), 4.77 (2H, d, J = 5.4 Hz), 6.83 (1H, dd, J = 8.7, 0.6 Hz), 7.47 (1H, dd, J = 8.2, 2.2 Hz), 7.54 (1H, d, J = 8.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.67 (1H, dd, J = 8.7, 2.3 Hz), 9.40 (1H, dd, J = 2.3, 0.6 Hz).

[0319] (5) N-{4-chloro-3-[4-(6-hexyloxypyridin-3-yl)-6-methoxy-1,3,5-triazine 2-Methoxy-2-methylpropionamide

[0320] [ka]

[0321] Under an argon atmosphere, a solution of {4-chloro-3-[4-(6-hexyloxypyridin-3-yl)-6-methoxy-1,3,5-triazin-2-yl]phenyl}methanol (7.16 g) obtained in (4) above in toluene (36 ml) and THF (7 ml) was added with diphenylphosphoryl azide (4.32 ml) under ice cooling. ) and 1,8-diazabicyclo[5.4.0]-7-undecene (3.0 ml) were added. The reaction mixture was stirred for 30 minutes, then stirred at room temperature for 14 hours. The reaction mixture was stirred at 60° C. for 1 hour. To this reaction solution, triphenylphosphine (5.69 g) and water (1.43 ml) were added at room temperature and stirred for 5 minutes. This reaction solution was stirred at 60°C for 3 hours and concentrated under reduced pressure at room temperature. Toluene was added to this residue and concentrated under reduced pressure again. 2-Methoxy-2-methylpropionic acid (2.17 g), HOBt·H2O (3.07 g) and WSC·HCl (4.80 g) were added to a solution of this residue in N,N-dimethylformamide (21 ml) at room temperature and stirred for 18 hours. Water and ethyl acetate were added to this reaction solution, and the organic layer was washed with water and saturated saline. This organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound (8.28 g, yield 94%). 1 H-NMR (CDCl3) δ: 0.91 (3H, t, J = 6.9 Hz), 1.32-1.38 (4H, m), 1.41 (6H, s), 1.43-1.51 (2H, m), 1.77-1.84 (2H, m), 3.27 (3H, s), 4.19 (3H, s), 4.40 (2H, t, J = 6.7 Hz), 4.50 (2H, d, J = 6.0 Hz), 6.82 (1H, d, J = 8.8 Hz), 7.08-7.11 (1H, m), 7.37 (1H, dd, J = 8.2, 2.0 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.95 (1H, d, J = 2.0 Hz), 8.67 (1H, dd, J = 8.8, 2.2 Hz), 9.39 (1H, d, J = 2.2 Hz).

[0322] (6) N-{4-chloro-3-[4-(6-hexyloxypyridin-3-yl)-6-hydroxy-1,3,5-trimethyl[4-(6-methylpyridin-3-yl)-2,4-dihydro ... 2-Methoxy-2-methylpropionamide

[0323] [ka]

[0324] Under an argon atmosphere, a 4M aqueous sodium hydroxide solution (0.21 ml) was added to a methanol (1.0 ml) solution of N-{4-chloro-3-[4-(6-hexyloxypyridin-3-yl)-6-methoxy-1,3,5-triazin-2-yl]benzyl}-2-methoxy-2-methylpropionamide (0.11 g) obtained in (5) above, and the mixture was stirred at 65° C. for 2 hours. 1N hydrochloric acid (0.84 ml) and water were added to the reaction solution at room temperature and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. This gave the title compound (0.091 g, yield 84%). 1 H-NMR (DMSO-d6) δ: 0.88 (3H, t, J = 6.9 Hz), 1.27 (6H, s), 1.28-1.35 (4H, m), 1.37-1.48 (2H, m), 1.68-1.75 (2H, m), 3.15 (3H, s), 4.30 (4H, t, J = 6.9 Hz), 6.81 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.1 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.54 (1H, s), 8.39-8.45 (2H, m), 8.99 (1H, s).

[0325] [Production Example 13]: Synthesis of 5-bromo-2-((R)-1-methylbutoxy)pyridine

[0326] [ka]

[0327] (1) n-Octanoic acid (R)-1-methylbutyl ester

[0328] [ka]

[0329] 2-Pentanol (927 g), n-octanoic acid (910 g), molecular sieves 4Å (464 g), and Novozym 435 (9.27 g) were mixed and stirred at an internal temperature of 41°C (bath temperature 45°C) for 7.5 hours. Celite (232 g) was added to this reaction solution at room temperature and stirred for 1 hour. This reaction solution was filtered through Celite and washed with toluene. The filtrate was concentrated under reduced pressure, and toluene (1000 mL) was added to the obtained residue and reduced The mixture was concentrated under reduced pressure. Toluene (1000 mL) was added to the residue obtained, and the mixture was concentrated under reduced pressure. Toluene (1000 mL) was added and the mixture was concentrated under reduced pressure to give a residue (1.15 kg) containing the title compound (795 g, 35% yield) and n-octanoic acid (309 g), which was used as it was in the next reaction.

[0330] (2)(R)-Pentan-2-ol

[0331] [ka]

[0332] To the residue (1.15 kg) containing octanoic acid (R)-1-methylbutyl ester (795 g) obtained in (1) above, 4 M aqueous sodium hydroxide solution (2.39 L) was added at room temperature (internal temperature rose to 39°C). This reaction solution was stirred at an internal temperature of 41°C (bath temperature of 70°C) for 1 hour, and then cooled to an internal temperature of 75°C (bath temperature of 95°C). The mixture was stirred at rt for 16.5 hours. Under ice cooling, concentrated hydrochloric acid (797 mL) was added dropwise. Toluene (200 mL) was added and the mixture was separated, and the aqueous layer was extracted once with toluene (200 mL). The organic layer was washed twice with saturated saline and dried over sodium sulfate. The resulting solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a residue (1.76 kg) containing the title compound (297 g, 91% yield) and n-octanoic acid (876 g). This was used as is in the next reaction.

[0333] (3) n-Octanoic acid (R)-1-methylbutyl ester

[0334] [ka]

[0335] To the residue (1.76 kg) containing (R)-pentan-2-ol (297 g) and n-octanoic acid (876 g) obtained in (2) above, molecular sieves 4Å (149 g) and Novozym 435 (2.97 g) were added and stirred at an internal temperature of 40°C (bath temperature of 45°C) for 7 hours. Novozym 435 (2.97 g) was added and stirred for an additional 2 hours. Celite (50 g) was added, and the mixture was allowed to cool to room temperature, filtered through Celite, and washed with toluene. The filtrate was concentrated under reduced pressure, and toluene (700 mL) was added to the resulting residue, which was then concentrated under reduced pressure. Toluene (500 mL) was added to the resulting residue, which was then concentrated under reduced pressure. Toluene (500 mL) was added to the resulting residue, which was then concentrated under reduced pressure to give a residue (1.09 kg) containing the title compound (612 g, 85% yield) and n-octanoic acid (449 g). This was used as is in the next reaction.

[0336] (4) (R)-Pentan-2-ol

[0337] [ka]

[0338] To the residue (1.09 kg) containing octanoic acid (R)-1-methylbutyl ester (612 g) obtained in (3) above, 4 M aqueous sodium hydroxide solution (2.20 L) was added at room temperature (the internal temperature rose to 41°C). The reaction solution was stirred at an internal temperature of 70°C (bath temperature of 95°C) for 16 hours. After cooling to room temperature, concentrated hydrochloric acid (530 mL) was added dropwise under ice cooling. The reaction solution was distilled at atmospheric pressure at an internal temperature of 98°C (bath temperature of 158°C) to obtain the title compound. A mixture (about 600 mL) containing the compound and water was obtained. This mixture was allowed to stand to separate. After separation, the aqueous layer was extracted once with diisopropyl ether (20 mL). The organic layers were combined and washed with 1% hydrogen carbonate. The mixture was washed with an aqueous sodium chloride solution (44 mL) and then with saturated aqueous sodium chloride solution (about 40 mL). The organic layer was dried over magnesium sulfate (20 g), filtered through Celite, and washed with diisopropyl ether. The filtrate was carefully concentrated under reduced pressure to give a toluene solution (272 g) containing the title compound (186 g, yield 74%). 1 H-NMR (CDCl3) δ: 0.90-0.96 (3H, m), 1.19 (3H, d, J = 6.2 Hz), 1.28-1.52 (4H, m), 3.77-3.86 (1H, m).

[0339] (5) 5-Bromo-2-((R)-1-methylbutoxy)pyridine

[0340] [ka]

[0341] Under an argon atmosphere, potassium tert-butoxide (16.7 g) was added to a solution of 5-bromo-2-chloropyridine (22 g) and (R)-pentan-2-ol (12.1 g) obtained in (4) above in N,N-dimethylformamide (88 ml) under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture was added potassium tert-butoxide (1.67 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous solution of ammonium chloride and acetic acid. Ethyl was added and the mixture was separated. The aqueous layer was extracted with a mixed solvent of n-hexane:ethyl acetate = 1:1. The organic layers were combined and washed with water and saturated saline. The organic layers were dried over sodium sulfate, filtered to remove the sodium sulfate, and concentrated under reduced pressure. A portion of the residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate) to obtain the title compound. 1 H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.33-1.48 (2H, m), 1.50-1.59 (1H, m), 1.66-1.75 (1H, m), 5.10-5.18 (1H, m), 6.59 (1H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 8.8, 2.4 Hz), 8.16 (1H, d, J = 2.4 Hz). When analyzed using a chiral column, the retention time of the title compound obtained was about 10 minutes, and the optical purity at this time was 99.0% ee or more. The analytical conditions using the chiral column are as follows. Measuring equipment; HPLC system Shimadzu Corporation High performance liquid chromatogram Prominence Column: Daicel CHIRALCEL AS 0.46cmφ×15cm (10μm) Column temperature: 25°C Mobile phase: n-hexane Flow rate; 1mL / 5206 Detection: UV (220nM)

[0342] Compounds of Example Nos. 1 to 145 were obtained according to the above-mentioned preparation method. Tables 1-1 to 1-19 show the structural formulas, MS data, and NMR data of the example compounds. In the tables, Notes 1 and 2 indicate the following contents. vinegar.

[0343] [ka]

[0344] Racemic mixture A was obtained in the same manner as in (1), (2), and (3) of Production Example 7, except that 2-hydroxy-2-trifluoromethylbutyric acid was used in place of 2-ethyl-2-hydroxybutyric acid. Using the racemic mixture A and (1R,2S)-(+)-1-amino-2-indanol, amidation was carried out in the same manner as in (5) of Production Example 1 to obtain a diastereomeric mixture B. Diastereomer mixture B was purified by silica gel column chromatography (Merck TLC Silica gel 60G F254 25 Glass plates, developing solvent: n-hexane / ethyl acetate = 1 / 2). By this reaction, the less polar diastereomer Compound B1 and the more polar diastereomer Compound B2 were obtained. A single diastereomer of compound B1 was hydrolyzed with KOH under heating in ethylene glycol. Thus, compound C1 was obtained. Using Compound C1 and Compound D, amidation was carried out in the same manner as in (5) of Preparation Example 1, and then the product was Hydrolysis was carried out in the same manner as in Preparation Example 1(6) to obtain Example Compound 132. Compound B2, a single diastereomer, was hydrolyzed in the same manner as in the hydrolysis of Compound B1 to obtain Compound C2. Compound C2 and Compound D were used to obtain an amide in the same manner as in Production Example 1 (5). After the reaction, hydrolysis was carried out in the same manner as in (6) of Production Example 1 to obtain Example Compound 134. . Although Example Compounds 132 and 134 are each a single diastereomer, the absolute configuration of the α-carbon of the amide has not been determined. In the table, the annotation 1 for Example Compounds 132, 133, 138, 139, 143, and 145 indicates that the compound was obtained using the less polar diastereomer B1. Note 2 in Examples 134, 135, 136, 137, 142 and 144 indicates that the compounds are highly polar diastereomeric. The results are shown to be obtained using teleomer B2.

[0345] [Table 1-1]

[0346] [Table 1-2]

[0347] [Table 1-3]

[0348] [Table 1-4]

[0349] [Table 1-5]

[0350] [Table 1-6]

[0351]

Table 1-7

[0352]

Table 1-8

[0353]

Table 1-9

[0354]

Table 1-10

[0355]

Table 1-11

[0356]

Table 1-12

[0357]

Table 1-13

[0358]

Table 1-14

[0359]

Table 1-15

[0360]

Table 1-16

[0361] [Table 1-17]

[0362] [Table 1-18]

[0363] [Table 1-19]

[0364] Test Example 1: Evaluation of human mPGES-1 enzyme inhibitory activity The inhibitory activity of the test substances against human mPGES-1 enzyme was evaluated according to the report by Xu et al. (XU, D et al. MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a selective microsomal prostaglandin E synthase-1 inhibitor, relieves pyresis and pain in preclinical models of inflammation. J Pharmacol Exp Ther. Sep 2008, Vol.326, No.3, pages 754-763.) In other words, the amount of PGE2 produced by human mPGES-1 in the presence of the test substance was measured by homogeneous time resolved fluorescence (HTRF) to determine the human mPGES-1 enzyme inhibitory activity of the test substance.

[0365] 1) Preparation of microsomal fraction from human mPGES-1 expressing cells Human mPGES-1 expression vector prepared in-house was used for PCR (Polymerase Chain Reaction) Using mide DNA (pME-18S / iPGES-1) as a template, a BamHI recognition and cleavage sequence was inserted immediately before the translation initiation codon. A DNA fragment containing human mPGES-1 with an EcoRI recognition and cleavage sequence added immediately downstream of the translation termination codon was The purified DNA fragment was digested with BamHI and EcoRI, and then digested with BamHI and EcoRI. The resulting ligation product was transformed into E. coli DH5α (TOYOBO, model number DNA-903), from which human mPGES-1 expression plasmid DNA was isolated. The base sequence of human mPGES-1 cloned into the vector was determined by the Dye Terminator method using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, model number 4337455). The sequence was identical to the protein translation region sequence of human mPGES-1 (Accession number NM_004878) registered in the NCBI Reference Database. Human mPGES-1 expression plasmid DNA was transfected into Chinese hamster ovary cells (FreeStyle CHO-S Cells, Invitrogen, product number R800-07) using a gene transfer reagent (FreeStyle MAX Reagent (Invitrogen, product number 16447-100)), and the cells were cultured for 48 hours with shaking (8% CO2, 37℃) in medium containing 8 mmol / L L-glutamine (GIBCO FreeStyle CHO Expression Medium, Invitrogen, product number 12651-022). CHO-S cells were suspended in Homogenate Buffer (100 mmol / L potassium phosphate (pH 7.4), 250 mmol / L sucrose, 100 mmol / L EDTA, Complete EDTA free (Roche, product number 1873580)). The suspended cells were disrupted for 30 seconds using an Ultrasonic Disruptor UD-201 (Tomy Seiko) at output: 3 and duty cycle: 50. The precipitate was removed by centrifugation (1,000 × g, 5 min, 4°C), and the supernatant was centrifuged (5,000 × g, 10 min, 4°C). The supernatant was further centrifuged (105,000 × g, 60 min, 4°C). The resulting precipitate was suspended in Resuspension Buffer (100 mmol / L potassium phosphate (pH 7.4), 250 mmol / L sucrose, 100 mmol / L EDTA, 10% glycerol) to prepare a microsomal fraction. The protein concentration of the microsomal fraction was measured by the Bradford method (Protein Assay Kit, Bio-Rad). The microsomal fraction was rapidly frozen using liquid nitrogen and then stored at -80°C. Rabbit anti-mPGES-1 polyclonal antibody (ThermoFisher Scientific, part number PA1-10264) was used. Human mPGES-1 in the microsomal fraction was detected by Western blotting.

[0366] 2) Evaluation of human mPGES-1 enzyme inhibitory activity In a 96-well V-bottom plate (Corning, product number 3363), test substance solution diluted with 0.1 mol / L potassium phosphate, pH 7.4 (hereafter referred to as KPB) or DMSO (Nacalai Tesque, product number 13407-45 ) was added at 5 μL / well. The final DMSO concentration during the reaction was 2% (v / v). In addition, reduced GSH (12.5 mmol / L KPB solution, SIGMA, product number G6529-25G) was added at a protein concentration of 5 μg / mL. Microsomal fractions from CHO-S cells expressing human mPGES-1, diluted to 100 μg / mL, were added to each well. The amount of microsomal fraction used was within the range in which the amount of PGE2 produced under the reaction conditions shown below and the amount of microsomal fraction used were linear. Reduced GSH (12.5 mmol / L KPB solution) was added to each well as a blank. After leaving the plate to stand at room temperature for 10 minutes, PGH2 (PGH2 dissolved in chilled acetone at 100 μg / mL was diluted to 10 μg / mL) was added to each well. Sea urchin diluted with D-PBS(-) (Nikken Biomedical Research Institute, product number CM6201), Cayman Chemical, Tin(II) chloride dihydrate (Part No. 17020) was added at 25μL / well and allowed to stand at room temperature for 45 seconds. (2 mg / mL 10 mmol / L citric acid solution, Wako Pure Chemical Industries, Ltd., product number 204-01562) was added at 50 μL / well, and the plate was gently shaken to stop the enzyme reaction. The PGE2 concentration in the enzyme reaction solution was measured using Prostaglandin E2 assay (CISbio Bioassays, product number 62P2APEC) according to the instruction manual. The standard for the calibration curve was PGE2 (Cayman Chemical, product number 14010). Time-resolved fluorescence was measured at 620 nm and 665 nm for PGE2. The PGE2 concentration was extrapolated from the PGE2 standard curve. The average PGE2 concentration in each treatment well was used as data. The mPGES-1 enzyme inhibitory activity (%) of the test substance was calculated according to the following formula 1. [Formula 1] mPGES-1 enzyme inhibitory activity (%) = (PGE2 A - PGE2 X ) / (PGE2 A - PGE2 B ) × 100 PGE2 A : PGE2 concentration in vehicle solution-treated wells PGE2 B: PGE2 concentration in blank wells PGE2 X : PGE2 concentration in test substance treated wells IC of the test substance 50 The value (50% inhibitory concentration) was calculated according to the following formula 2. [Formula 2] I C 50 Value=10 {log10(D / E) × (50 - G) / (F - G) + log10(E)} D: Test substance concentration that showed 50% or more inhibitory activity among the two points on either side of 50% inhibition E: Test substance concentration that showed 50% or less inhibitory activity among the two points on either side of 50% inhibition F: mPGES-1 enzyme inhibitory activity (%) when the test substance concentration is D G: mPGES-1 enzyme inhibitory activity (%) when the test substance concentration is E The results are shown in Tables 2-1 to 2-5.

[0367] [Table 2-1]

[0368] [Table 2-2]

[0369] [Table 2-3]

[0370] [Table 2-4]

[0371] [Table 2-5]

[0372] Test Example 2: Evaluation of PGE2 production inhibitory effect using A549 cells A549 cells (Human Science Foundation, Research Resources Bank), a human lung cancer cell line, were cultured in assay medium (containing 2% FBS (Hyclone Laboratories, product number SH30910.03), 100 units / mL penicillin, and 100 μg / mL streptomycin (Invitrogen, product number 15140-122)). The cells were suspended in Ham's F-12K (Wako Pure Chemical Industries, Ltd., product number 080-08565) and plated at 2.5 × 10 4 Seed cells at 100μL / well and incubate in a CO2 incubator at 37℃. The test substance was serially diluted with DMSO (Nacalai Tesque, product number 13407-45) and then diluted 20-fold with the assay medium to prepare a test substance application solution with a concentration 10 times the final concentration. The final DMSO concentration during the reaction was 0.5% (v / v). After removing the medium, fresh assay medium was added at 160 μL / well and the plate was left to stand in a CO2 incubator for 10 minutes. Then, test substance application solution was added at 20 μL / well and the plate was left to stand in a CO2 incubator for 30 minutes. Furthermore, recombinant human IL-1β (R&D Systems, product number 201-LB) was added at 20 μL / well (final concentration: 100 μL / well) as a stimulant that enhances PGE2 production by increasing mPGES-1 mRNA expression. The plate was then placed in a CO2 incubator for 18 hours. The supernatant was added at 180 μL per well. The tissue was then collected and the PGE2 concentration was measured using a Prostaglandin E2 assay (CISbio Bioassays, product number 62P2APEC) according to the manufacturer's instructions. The standard for the calibration curve was PGE2 (Cayman Chemical, product number 14010). Time-resolved fluorescence was measured at 620 nm and 665 nm in response to an excitation light of 337 nm using EnVision2104 (PerkinElmer). The PGE2 concentration was extrapolated from the PGE2 calibration curve. The average PGE2 concentration in the wells was used as data. The PGE2 production inhibitory activity (%) of the test substance was calculated according to the following formula 3. [Formula 3] PGE2 production inhibitory activity (%) = (PGE2 A - PGE2 X ) / (PGE2 A - PGE2 B ) × 100 PGE2 A : PGE2 concentration in vehicle solution-treated wells PGE2 B : PGE2 concentration in blank wells (no recombinant human IL-1β added) PGE2 X : PGE2 concentration in test substance treated wells IC of the test substance 50 The value (50% inhibitory concentration) was calculated according to the following formula 4. [Formula 4] I C 50 Value=10 {log10(D / E) × (50 - G) / (F - G) + log10(E)} D: Test substance concentration that showed 50% or more inhibitory activity among the two points on either side of 50% inhibition E: Test substance concentration that showed 50% or less inhibitory activity among the two points on either side of 50% inhibition F: PGE2 production inhibitory activity (%) when the test substance concentration is D G: PGE2 production inhibitory activity (%) when the test substance concentration is E The results are shown in Tables 3-1 to 3-5.

[0373] [Table 3-1]

[0374] [Table 3-2]

[0375] [Table 3-3]

[0376] [Table 3-4]

[0377] [Table 3-5]

[0378] Test Example 3: Evaluation of the effect on prostaglandin composition in aqueous humor of cynomolgus monkeys The test substance is dissolved in physiological saline containing 0.5% polysorbate 80 (Fluka) to prepare an eye drop solution (pH 7.0-8.0). Before instilling the eye drop solution, male cynomolgus monkeys were given Escaine (registered trademark) The patient was anesthetized with an inhalation anesthetic (Pfizer, generic name: isoflurane), and the corneas of both eyes were punctured with a 30G injection needle connected to a silicone catheter tube to collect aqueous humor. Instill the vehicle or test substance into the eyes once (30 μL per eye) using a micropipette. The eye drops are then applied to the eye, and the lower eyelid is gently pressed for approximately 15 seconds to lightly fix the lacrimal sac. Five minutes later, Lipopolysaccharide (LPS) is administered into the anterior chamber, and aqueous humor is then collected under anesthesia. The contralateral eye is treated in the same way. The concentration of prostaglandins in the aqueous humor is measured using an LC / MS / MS system (ultra-high performance liquid chromatography). Rough: Nexera (registered trademark) manufactured by Shimadzu Corporation, Mass spectrometer: QTRAP ( The concentration of each prostaglandin was measured using a 5500 (registered trademark) and the ratio of the concentration of each prostaglandin to the sum of all prostaglandin concentrations was calculated.

[0379] Test Example 4: Evaluation of the effect of mPGES-1 inhibitors on normal intraocular pressure in cynomolgus monkeys The study is conducted using male cynomolgus monkeys.

[0380] A one-week washout period was allowed between each test to eliminate residual effects of the test substance. Feeding on the test day will be carried out after the final measurement. The test substance is dissolved in saline containing 0.5% polysorbate 80 (Fluka) to prepare an eye drop solution. The control substance group is administered with the vehicle (saline containing 0.5% polysorbate) in the same manner as the test substance. Xalatan (registered trademark) eye drop solution 0.005% (Pfizer, generic name: latanoprost) is used as the positive control substance. The test substance is administered once per eye at 30 μL using a micropipette. The vehicle group and the positive control substance group are each administered once. Points After administration, the lower eyelid is gently pressed for about 15 seconds to lightly fix the lacrimal sac. The other eye is treated in the same way. Intraocular pressure is measured immediately before administration, and 2, 4, 8, 12, and 24 hours after administration. Before measuring intraocular pressure, the animals The dog was fixed to a monkey chair and an ophthalmic topical anesthetic (Benoxil (registered trademark) eye drops 0.4%, Santen Pharmaceutical Co., Ltd., generic name: oxybuprocaine hydrochloride) was administered as an instillation to the eye for local anesthesia. After attaching an eyelid speculum (Handaya Co., Ltd.), a pneumatic applanation tonometer (Model 30 Classic, Riker The intraocular pressure in both eyes is measured using a meter (manufactured by Toray). For each measured eye, the intraocular pressure difference from the value immediately before administration at each measurement point (ΔmmHg; rounded to one decimal place) was recorded. After calculating the intraocular pressure difference, calculate the average value for the left and right eyes and use it as the evaluation data for that individual. Calculate the average value and standard deviation (to two decimal places) of the intraocular pressure difference for each group.

[0381] Test Example 5: Solubility Measurement (1) Saturated solution of pH8.5 Britton-Robinson buffer The test substance was weighed into a glass microtube, and 1.5 mL of pH 8.5 Britton-Robinson buffer was added to disperse the substance into a suspension, which was then shaken for 18 hours at 20° C. The suspension was then filtered through a membrane filter (0.45 μm), and the filtrate was used as a sample. (2) pH8.5 Britton-Robinson buffer containing 0.5W / V% polysorbate 80 The test substance was weighed into a glass microtube, and 1.5 mL of 0.5 W / V% polysorbate 80-containing Britton-Robinson buffer at pH 8.5 was added to disperse the substance in the suspension. The suspension was then shaken at 20°C for 18 hours. Next, the suspension was filtered through a membrane filter (0.45 μm), and the filtrate was used as a sample. (3) Preparation of standard and sample solutions and solubility measurement The sample solution was prepared by diluting the sample with a water / acetonitrile mixture (1:1). The solutions were prepared by precisely weighing the test substance and diluting it with a water / acetonitrile mixture (1:1). The standard solution and the sample solution were measured by liquid chromatography, and the content of the test substance in the sample was calculated by the external standard method to determine the solubility. The results are shown in Table 4.

[0382] [Table 4]

[0383] Examples of the formulation of the present invention include the following formulations, however, the present invention is not limited to these formulation examples.

[0384] Formulation Example 1 (Capsule Production) 1) Compound of Example No. 48 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.

[0385] Formulation Example 2 (Tablet Production) 1) Compound of Example No. 48 10 g 2) Lactose 50g 3) 15 g corn starch 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amount of 1), 2), 3) and 30 g of 4) are mixed with water, vacuum dried, and granulated. 14 g of 4) and 1 g of 5) are mixed with this granulated powder and compressed into tablets using a tablet press. Each tablet contains 10 mg of the compound of Example No. 48.

[0386] Formulation Example 3 (Production of eye drops) In 100 mL of eye drops 1) Compound of Example No. 48 100 mg 2) Polysorbate 80 500 mg 3) Sodium chloride 900 mg 4) Sodium hydroxide (appropriate amount) 5) Appropriate amount of sterile purified water The above ingredients are mixed aseptically to adjust the pH to 7.9 to 8.1 to prepare the eye drops.

[0387] Preparation Example 4 (Production of eye drops) In 100 mL of eye drops 1) Compound of Example No. 48 100 mg 2) Polysorbate 80 100 mg 3) Sodium dihydrogen phosphate dihydrate 100 mg 4) Sodium chloride 900 mg 5) Benzalkonium chloride 5 mg 6) Sodium hydroxide (appropriate amount) 7) Appropriate amount of sterile purified water The above ingredients are mixed aseptically to adjust the pH to 7.9 to 8.1 to prepare the eye drops.

[0388] Formulation Example 5 (Production of eye drops) In 100 mL of eye drops 1) Compound of Example No. 48 100 mg 2) Boric acid 700 mg 3) Borax (appropriate amount) 4) Sodium chloride 500 mg 5) Sodium edetate 0.05 mg 6) Benzalkonium chloride 0.0005 mg 7) Appropriate amount of sterile purified water The above ingredients are mixed aseptically to adjust the pH to 7.9 to 8.1 to prepare the eye drops. [Industrial Applicability]

[0389] The compound of the present invention or a pharma- ceutical acceptable salt thereof has mPGES-1 inhibitory activity and is therefore useful in treating pain, The compound may be an effective drug for the prevention or treatment of malignant tumors, including rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis, and colorectal cancer, and / or diseases in which inhibition of PGE2 production is effective.

Claims

1. A compound of formula [Ic], or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, R 1 teeth, (1) Formula: 【Chemistry 2】 (In the formula, R 1a is C 1-4 is alkyl, R 1b is C 1-4 alkyl or trifluoromethyl; R 1c teeth, (a) C 1-4 Alkyl, (b) C 1-4 Fluoroalkyl, (c) C 1-4 Alkoxy, or (d) C 1-4 Alkoxy C 1-4 alkyl; or (2) Formula: 【Chemistry 3】 (In the formula, n is 1, 2, 3, 4 or 5; R 1d teeth, (a) Fluoro, (b) C 1-4 Alkyl, (c) C 1-4 Fluoroalkyl, (d) C 1-4 Alkoxy, or (e) C 1-4 Alkoxy C 1-4 is alkyl. R 2 is hydrogen, R 6 is 1-methylbutyl or n-hexyl.

2. R 1 But the formula: 【Chemistry 4】 (In the formula, R 1a But, C 1-4 is alkyl, R 1b But, C 1-4 alkyl or trifluoromethyl, and R 1c but, (b) difluoromethyl or trifluoromethyl, or (c) Methoxy.

2. The compound of claim 1, wherein:

3. R 1 But the formula: 【Chemistry 5】 (In the formula, n is 3, 4 or 5, and R 1d but, (a) Fluoro, (c) C 1-4 Fluoroalkyl, (d) methoxy, or (e) Methoxymethyl.

2. The compound of claim 1, wherein:

4. n is 3 or 4, and R 1d is monofluoromethyl, difluoromethyl or trifluoromethyl; 4. The compound according to claim 3 or a pharma- ceutically acceptable salt thereof.

5. The following formula: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

6. The following formula: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

7. The following formula: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

8. The following formula: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof.

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

10. 9. An mPGES-1 inhibitor comprising the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof.

11. A therapeutic or preventive agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis and / or malignant tumors, comprising a compound according to any one of claims 1 to 8 or a pharma- ceutical acceptable salt thereof.

12. 10. A therapeutic or prophylactic agent for glaucoma and / or ocular hypertension, comprising a compound according to any one of claims 1 to 8 or a pharma- ceutical acceptable salt thereof in combination with one or more other therapeutic agents for glaucoma.

13. A compound according to any one of claims 1 to 8 or a compound thereof for producing an mPGES-1 inhibitor. Use of a pharma- ceutically acceptable salt of

14. Use of the compound according to any one of claims 1 to 8 or a pharma- ceutical ly acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic sclerosis and / or malignant tumors.

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