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NZ721718B2 - Triazine compound and use thereof for medical purposes - Google Patents
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NZ721718B2 - Triazine compound and use thereof for medical purposes - Google Patents

Triazine compound and use thereof for medical purposes Download PDF

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NZ721718B2
NZ721718B2 NZ721718A NZ72171815A NZ721718B2 NZ 721718 B2 NZ721718 B2 NZ 721718B2 NZ 721718 A NZ721718 A NZ 721718A NZ 72171815 A NZ72171815 A NZ 72171815A NZ 721718 B2 NZ721718 B2 NZ 721718B2
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mixture
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NZ721718A
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NZ721718A (en
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Takahiro Hotta
Ikuo Mitani
Hironobu Nagamori
Yuichi Nakagawa
Masatoshi Ueda
Masaki Yamashita
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Japan Tobacco Inc
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Priority claimed from PCT/JP2015/054519 external-priority patent/WO2015125842A1/en
Publication of NZ721718A publication Critical patent/NZ721718A/en
Publication of NZ721718B2 publication Critical patent/NZ721718B2/en

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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P27/00—Drugs for disorders of the senses
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    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • Y10S514/913—

Abstract

Provided is a compound which has a mPGES-1 inhibitory activity and is useful for the prevention or treatment of pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal diseases, systemic sclerosis and malignant tumors including colorectal cancer. The present invention relates to a compound represented by formula [I] [wherein each symbol is as defined in the description] or a pharmaceutically acceptable salt thereof.

Description

(12) Granted patent specificaon (19) NZ (11) 721718 (13) B2 (47) Publicaon date: 2021.12.24 (54) TRIAZINE COMPOUND AND USE THEREOF FOR MEDICAL PURPOSES (51) Internaonal Patent Classificaon(s): C07D 251/22 A61K 31/53 A61P 9/10 A61P 17/00 A61P 19/02 A61P 25/00 A61P 25/28 A61P 27/06 A61P 29/00 A61P 35/00 A61P 43/00 C07D 401/04 C07D 401/10 C07D 401/12 C07D 403/10 C07D 405/12 C07D 471/10 (22) Filing date: (73) Owner(s): 2015.02.19 JAPAN TOBACCO INC. (23) Complete specificaon filing date: (74) Contact: 2015.02.19 PHILLIPS ORMONDE FITZPATRICK (30) Internaonal Priority Data: (72) Inventor(s): JP 2014-031035 2014.02.20 NAGAMORI, Hironobu MITANI, Ikuo (86) Internaonal Applicaon No.: YAMASHITA, Masaki HOTTA, Takahiro NAKAGAWA, Yuichi (87) Internaonal Publicaon number: UEDA, Masatoshi WO/2015/125842 (57) Abstract: Provided is a compound which has a mPGES-1 inhibitory acvity and is useful for the prevenon or treatment of pain, rheumasm, osteoarthris, fever, Alzheimer's disease, mulple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic renal diseases, systemic sclerosis and malignant tumors including colorectal cancer. The present invenon relates to a compound represented by formula [I] [wherein each symbol is as defined in the descripon] or a pharmaceucally acceptable salt thereof.
NZ 721718 B2 SPECIFICATION Title of the Invention: TRIAZINE COMPOUND AND USE THEREOF FOR MEDICAL PURPOSES TECHNICAL FIELD OF THE INVENTION 【0001】 The present invention relates to a triazine compound having a microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, pharmaceutical use thereof and the like.
BACKGROUND OF THE INVENTION 【0002】 Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for the treatment of diseases accompanying inflammation, fever and pain, for example, rheumatism, osteoarthritis, headache and the like. NSAIDs show an anti-inflammatory action, an antipyretic action and an analgesic action by preventing production of prostanoids by inhibiting cyclooxygenase (COX). 【0003】 COX includes two isoforms of COX-1 which is ubiquitously distributed and constitutively expressed, and COX-2 which expression is induced by various pro-inflammatory stimulations, for example, cytokines such as interleukin-1b (IL-1b ) and the like. COX-1 and COX-2 are enzymes that convert arachidonic acid derived from cell membrane phospholipids to prostaglandin H2 (PGH2) which is a prostanoid precursor. Specific prostanoid synthases are responsible for the conversion of PGH2 to respective prostanoids (prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostaglandin I2 (PGI2), prostaglandin D2 (PGD2), thromboxane A2 (TXA2) etc.). These prostanoids have various physiological activities, for example, induction/suppression of inflammation, vasodilation/vasoconstriction, bronchodilation/bronchoconstriction, induction of/awakening from sleep, development of fever and the like. PGE2 is the most commonly existing prostaglandin in living organisms, and is known to be deeply involved in inflammation, pain and fever.
Therefore, suppression of PGE2 production is considered the main action mechanism of NSAIDs. 【0004】 Inhibition of COX-1 or COX-2 suppresses all prostanoids production in the downstream thereof. This is considered to cause side effects of NSAIDs. Since NSAIDs that non- selectively inhibit COX also suppress production of PGE2 by COX-1 and PGE2 protectively acts on stomach mucosal injury, NSAIDs are considered to suppress secretion of gastric mucus and gastric mucosal blood flow, thereby increasing the risk of stomach perforations, bleeding and the like. While COX-2 selective inhibitors suppress production of PGI2 having a vasodilation action and a platelet aggregation inhibitory action in vascular endothelial cells, they do not suppress production of TXA2 which is a blood coagulation factor produced by platelet COX-1. Therefore, they are considered to disrupt the balance of the blood coagulation system to increase the risk of cardiovascular disorder. 【0005】 Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an enzyme that catalyzes the final step of PGE2 biosynthesis, 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 indicated to be constitutively expressed in placenta, prostate, testis and mammary gland (non- patent document 1). In other organs, human mPGES-1 gene expression is induced by various pro-inflammatory stimulations, conjugated with COX-2. For example, inflammatory cytokine IL- 1b and Tumor Necrosis Factor-α (TNF α) induce mPGES-1 expression in synovial cell, osteoblast, endothelial cell, orbital fibroblast, gingival cell, chondrocyte, endothelial cell, myocardial cell and the like. For example, Lipopolysaccharide (LPS), which is a bacterial endotoxin, induces mPGES-1 expression in macrophage, smooth muscle and the like. 【0006】 mPGES-1 inhibitor is considered to selectively suppress PGE2 production only in the topical site of inflammation or tissues where mPGES-1 is expressed, and does not suppress production of prostanoids (PGI2, PGD2, PGF2α, TXA2 etc.) other than PGE2 (non-patent documents 2, 3). Therefore, mPGES-1 inhibitor is considered to be a medicament having an efficacy equivalent to that of NSAIDs but free of side effects of NSAIDs derived from a decreased production of prostanoids other than PGE2. 【0007】 It is also known that when one of the metabolism pathways downstream from PGH2 is shut off in the arachidonic acid cascade, PGH2 is converted to prostanoids other than the shut- off pathway, or shunt occurs. That is, it is known that while the production amount of PGE2 in macrophage derived from mPGES- 1 knockout mice stimulated with LPS becomes lower than the PGE2 production amount in macrophage derived from wild-type (WT) mice stimulated with LPS, the production amounts of TXB2, PGI2, PGD2 and PGF2α in macrophage derived from mPGES-1 knockout mice stimulated with LPS increase beyond the production amounts thereof in macrophage derived from WT mice stimulated with LPS (non-patent document 4). Since mPGES-1 inhibitor increases production of other prostanoids while suppressing the PGE2 production, it is considered to be effective even for diseases different from those treated by NSAIDs. 【0008】 Use of mPGES-1 inhibitor is described below. (1) pain In mPGES-1 knockout mice, intraperitoneal PGE2 production amount and nociceptive response per unit time significantly decrease as compared to WT mice, in the evaluation of nociceptive response by LPS stimulation which is an acute inflammatory pain model. Therefore, mPGES-1 inhibitor is considered to be an analgesic for acute inflammatory pain (non- patent documents 3, 6). (2) rheumatism mPGES-1 gene of Swedish females contains some single nucleotide polymorphisms that increase the onset risk and severity of rheumatism. An increase in the mPGES-1 expression is immunohistologically confirmed in the synovium of rheumatism patients showing single nucleotide polymorphism (Reference SNP ID number: rs23202821) that increases severity, as compared to patients free of mutation (non-patent document 5). In mPGES-1 knockout mice, intraarticular infiltration of inflammatory cells, articular destruction and tumentia of the four limbs are markedly suppressed in a collagen-induced arthritis model, which is an animal model of rheumatism, as compared to WT mice (non-patent document 6). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for rheumatism. (3) osteoarthritis mRNA expression of mPGES-1 increases in meniscus cells of osteoarthritis patients (non-patent document 7). mPGES-1 inhibitor reduces nociceptive responses in osteoarthritis model using monoiodoacetic acid, as compared to WT mice (patent document 1). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for osteoarthritis. (4) fever In mPGES-1 knockout mice, body temperature elevation due to LPS stimulation is suppressed as compared to WT mice (non- patent document 8). Therefore, mPGES-1 inhibitor is considered to be an antipyretic drug. (5) Alzheimer’s disease Long-term use of NSAIDs mitigates the onset and progression of Alzheimer’s disease. Under amyloid b peptide treatment, PGE2 production in the primary culture brain neuron of mPGES-1 knockout mice is suppressed, compared to the brain neuron of WT mice, and nerve cell death does not occur (non- patent document 9). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for Alzheimer’s disease. (6) multiple sclerosis EP4 gene of multiple sclerosis patients contains some single nucleotide polymorphisms that increase the onset risk (Reference SNP ID numbers: rs9292777, rs4613763, rs1044063, rs6896969). In macrophage present in the periventricular demyelinating lesion of multiple sclerosis patients, expression of mPGES-1 protein is confirmed. In mPGES-1 knockout mice, PGE2 production in the spinal cord of experimental autoimmune encephalomyelitis model mice, which is an animal model of multiple sclerosis, is suppressed, and progression of paralysis is suppressed, as compared to WT mice, (non-patent document 10).
Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for multiple sclerosis. (7) arteriosclerosis In mPGES-1 knockout mice, PGE2 production in vascular endothelial cells of high-fat fed low density lipoprotein (LDL) receptor deficient mice, which is an atherosclerosis model, decreases, and atheroma formation is delayed as compared to WT mice. In vascular endothelial cells, production of PGI2, which is known to have a platelet function suppressive action, increases (non-patent document 11). Therefore, mPGES-1 inhibitor is considered to be a prophylactic or therapeutic drug for arteriosclerosis. (8) glaucoma, ocular hypertension Glaucoma is a disease showing a characteristic change in the optic nerve and the field of vision. Optic nerve disorder can be generally improved or suppressed by sufficiently decreasing the intraocular pressure. Glaucoma can be categorized into open angle glaucoma and closed angle glaucoma. mPGES-1 gene is constitutively highly expressed in human conjunctiva (GEO accession No: GSE2513 (Gene Expression Omnibus:http://www.ncbi.nlm.nih.gov/geo/)). In the retina of glaucoma patients, expression of mPGES-1 increases as compared to healthy individuals. In the retina of high intraocular pressure dogs and high intraocular pressure mice, which are glaucoma models, expression of mPGES-1 increases as compared to normal animals (GEO accession No: human GSE2378, dog GSE21879, mouse GSE3554).
When PGE2 is instilled into the eyes of healthy individuals, the intraocular pressure increases, along with the expansion of blood vessels, for 2 hours after instillation (non-patent document 12). When PGE2 is administered to rabbits subconjunctivally, the intraocular pressure increases due to dilatation of ciliary body and increase in the aqueous humor production (non-patent document 13). PGF2α and PGD2, which are prostaglandins that may increase when mPGES-1 is inhibited, decrease the intraocular pressure of rabbit (non-patent document 14). PGF2α formulations increase outflow of aqueous humor and are used as therapeutic drugs for glaucoma that decrease the intraocular pressure. PGI2 does not show a clear action on the intraocular pressure of rabbits. That is, the intraocular pressure is considered to decrease since decrease of PGE2 suppresses aqueous humor production by mPGES-1 inhibition, and/or since increased PGD2 and PGF2α promote outflow of aqueous humor due to shunt. Also, PGE2 promotes expression of vascular endothelial growth factor (VEGF) from retina (non-patent document 15). Since VEGF produced in retina transfers to the anterior ocular segment to cause angiogenesis glaucoma, which is increase of the intraocular pressure that is caused by obstruction of corner angle due to angiogenesis in iris, mPGES-1 inhibitor is considered to show an improvement or prophylactic effect on angiogenesis glaucoma as well.
Furthermore, considering an anti-inflammatory action by the inhibition of PGE2 production, mPGES-1 inhibitor is applicable to patients having intraocular inflammation, who require careful administration of the existing prostaglandin formulations (latanoprost etc.). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug also effective for glaucoma having various background diseases. (9) ischemic retinal disease Excessive secretion of VEGF plays a key role in ischemic retinal diseases such as diabetic retinopathy, diabetic macular edema, retinal vein occlusion and the like. Since PGE2 promotes expression of VEGF (non-patent document 15), mPGES-1 inhibitor is considered to improve these diseases. (10) systemic scleroderma Expression of mPGES-1 increases in the skin of systemic scleroderma patients, as compared to healthy individuals.
Similarly, expression of mPGES-1 increases in the skin of bleomycin induced scleroderma model mice, which is a systemic scleroderma model, as compared to the skin of normal mice. As compared to WT mice, mPGES-1 knockout mice showed a decrease in the accumulation of macrophage in the dermal lesion of bleomycin induced scleroderma model mice, and mitigation of cutaneous thickening, deposition of extracellular matrix and increase in the collagen content (non-patent document 16).
Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for systemic scleroderma. (11) cancer In mPGES-1 knockout mice, the polyp number and size were markedly suppressed in azoxymethane-induced colorectal cancer model mice, which are animal model of colorectal cancer, as compared to WT mice. In mPGES-1 knockout mice, PGE2 production in large intestinal tumor tissue decreased and production amount of PGI2 that inhibits adhesion of cancer cells and PGD2 that induces cell death via peroxisome proliferator-activated receptor γ (PPARγ) increased, as compared to WT mice. When colorectal cancer or lung cancer cells were transplanted into the spleen of mPGES-1 knockout mice, the post-transplantation weight of spleen tumor and the rate of metastasis to the liver decreased as compared to WT mice. Growth of lung cancer cells was decreased when they ware co-cultured in vitro with mPGES-1 knockout mice-derived bone marrow macrophages compared to when they ware co-cultured with WT mice-derived bone marrow macrophages, which indicates that host macrophage-derived PGE2 is involved in cancer cell growth (non-patent document 17).
Therefore, mPGES-1 inhibitor is considered to be an anticancer drug that suppresses the growth and metastasis of cancer including colorectal cancer. (12) disease for which suppression of PGE2 production is effective As inflammatory symptoms and/or pain relating to the conditions thereof, for which NSAIDs are effective, for example, arthritis, gout, nephrolithiasis, urolithiasis, headache, menstrual pain, toothache, lumbago, muscular pain, periarthritis scapulohumeralis, cervical syndrome, temporomandibular disorder, and postoperative or posttraumatic inflammation and pain, and inflammation and pain after tooth extraction can be mentioned. Besides these, acute and chronic non-bacterial inflammation of eye can be mentioned and, for example, uveitis, allergic conjunctivitis and postoperative inflammation and ophthalmalgia in intraocular operation can be mentioned.
The main mechanism for the efficacy of NSAIDs is considered to be the suppression of PGE2 production, which is an inflammation promoting substance. Since mPGES-1 inhibitor also has a suppressive action on the PGE2 production, it is considered to be a therapeutic drug for these diseases. 【0009】 The mPGES-1 inhibitor is considered to be 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, cancer including colorectal cancer and diseases for which suppression of PGE2 production is effective.
【Document List】 patent document 【0010】 patent document 1: non-patent documents 【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 U S 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 e synthase-1. J Biol Chem. Aug 6 2004, Vol.279, No.32, pages 33684-33695. non-patent document 4: TREBINO, CE et al. Redirection of eicosanoid metabolism in mPGESdeficient macrophages. J Biol Chem. Apr 29 2005, Vol.280, No.17, pages 16579-16585. non-patent document 5: KOROTKOVA, M et al. Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis. Eur J Hum Genet. Aug 2011, Vol.19, No.8, pages 908-914. non-patent document 6: TREBINO, CE et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci U S A. Jul 22 2003, Vol.100, No.15, pages 9044-9049. non-patent document 7: SUN, Y et al. Analysis of meniscal degeneration and meniscal gene expression. BMC Musculoskelet Disord. 2010, Vol.11, pages 19. non-patent document 8: ENGBLOM, D et al. Microsomal prostaglandin E synthase-1 is the central switch during immune- induced pyresis. Nat Neurosci. Nov 2003, Vol.6, No.11, pages 1137-1138. non-patent document 9: KUROKI, Y et al. Deletion of microsomal prostaglandin E synthase-1 protects neuronal cells from cytotoxic effects of beta-amyloid peptide fragment 31-35.
Biochem Biophys Res Commun. Aug 3 2012, Vol.424, No.3, pages 409-413. non-patent document 10: KIHARA, Y et al. Targeted lipidomics reveals mPGESPGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad Sci U S A. Dec 22 2009, Vol.106, No.51, pages 21807-21812. non-patent document 11: WANG, M et al. Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Proc Natl Acad Sci U S A. Sep 26 2006, Vol.103, No.39, pages 14507-14512. non-patent document 12: FLACH, AJ et al. Topical prostaglandin E2 effects on normal human intraocular pressure. J Ocul Pharmacol. Spring 1988, Vol.4, No.1, pages 13-18. non-patent document 13: NAKAJIMA, T et al. [Effects of prostaglandin E2 on intraocular pressure, anterior chamber depth and blood flow volume of the iris and the ciliary body in rabbit eyes]. Nihon Ganka Gakkai Zasshi. Apr 1992, Vol.96, No.4, pages 455-461. non-patent document 14: GOH, Y et al. Prostaglandin D2 reduces intraocular pressure. Br J Ophthalmol. Jun 1988, Vol.72, No.6, pages 461-464. non-patent document 15: YANNI, SE et al. The role of PGE2 receptor EP4 in pathologic ocular angiogenesis. Invest Ophthalmol Vis Sci. Nov 2009, Vol.50, No.11, pages 5479-5486. non-patent document 16: MCCANN, MR et al. mPGES-1 null mice are resistant to bleomycin-induced skin fibrosis. Arthritis Res Ther. 2011, Vol.13, No.1, pages R6. non-patent document 17: SASAKI, Y et al. Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis. Oncogene. Jun 14 2012, Vol.31, No.24, pages 2943-2952.
SUMMARY OF THE INVENTION 【0012】 The present invention aims to provide a triazine compound having an mPGES-1 inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and pharmaceutical use thereof and the like.
As the target disease, for example, pain, rheumatism, osteoarthritis, fever, Alzheimer’s disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer including colorectal cancer and diseases for which suppression of PGE2 production is effective can be mentioned. 【0013】 The present inventors have found a triazine compound having an mPGES-1 inhibitory activity, which is represented by the following formula [I], and completed the present invention.
Accordingly, the present invention is as follows. 【0014】 A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof: 【0015】 (R ) 【0016】 wherein X is CH or N, ring Cy is the formula: 【0017】 【0018】 the formula: 【0019】 【0020】 {wherein R is (1) halogen, (2) C alkyl, (3) cyano or (4) haloC alkyl, R is (1) halogen, (2) hydroxy, (3) carboxy, (4) C alkyl, (5) C alkoxy, (6) haloC alkoxy, (7) haloC alkyl, (8) C1-6 alkyl-carbonyl, a1 a2 a1 a2 (9) -C(O)NR R (R and R are each independently hydrogen or C1-6 alkyl) or (10) -(CnH2n)-R (n is 1, 2, 3 or 4, -(C H )- may be straight or branched n 2n chain, and R is (a) hydroxy, (b) carboxy, (c) C alkoxy, (d) C alkyl-carbonyloxy, b1 b2 b1 b2 (e) -C(O)NR R (R and R are each independently hydrogen or C alkyl), b3 b4 b3 b4 (f) -OC(O)NR R (R and R are each independently hydrogen or C alkyl), b5 b6 b7 b5 b6 b7 (g) -NR C(O)NR R (R , R and R are each independently hydrogen or C alkyl), b8 b9 b8 b9 (h) -NR R (R and R are each independently hydrogen, C alkyl or haloC alkyl), 1-6 1-4 b10 b11 b10 b11 (i) -NR S(O)2R (R and R are each independently hydrogen, C alkyl or C cycloalkyl), 1-6 3-7 b12 b13 b12 b13 (j) -NR C(O)OR (R is hydrogen or C alkyl, and R is C alkyl), b14 b15 b14 (k) -NR C(O)R (R is hydrogen or C alkyl, and R is (i) C aryl, 6-10 (ii) C alkyl (said C alkyl is optionally 1-8 1-8 substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, haloC alkyl, C alkoxy and C aryl), 1-4 1-6 6-10 (iii) adamantyl or (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2, 3 or 4 substituents selected from the group consisting of C alkyl, halogen, hydroxyl C alkyl and 1-6 1-6 halo C alkyl, and/or optionally form a fused ring with a benzene ring), or b14 b15 R and R optionally form a 4-, 5- or 6-membered lactam together with the nitrogen atom the nitrogen atom that b14 b15 R is bonded to and the carbon atom that R is bonded to (said lactam is optionally substituted by 1, 2 or 3 C1-6 alkyls, and/or optionally form a fused ring with a benzene ring), (l) the formula: 【0021】 b1 6 (R ) 【0022】 wherein m2 and m3 are each independently 1, 2 or 3, m4 is 0, 1, 2, 3 or 4, R is C alkyl or C alkoxy, and when m4 is 2, 3 1-6 1-6 or 4, each R is selected independently, or (m) the formula: 【0023】 N b 17 【0024】 wherein m5 and m6 are each independently 1, 2 or 3, and R is C alkyl or C alkoxy)), 1-6 1-6 R is (1) halogen, (2) hydroxy, (3) C alkyl or (4) -OR {R is C alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f); (a) halogen, (b) hydroxy, (c) C1-6 alkoxy, c1 c2 c1 c2 (d) -C(O)NR R (R and R are each independently hydrogen or C1-6 alkyl), (e) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC1-4 alkyl)}, and R is (1) hydrogen, (2) halogen, (3) C alkyl or (4) C alkoxy}, R is (1) halogen, (2) hydroxy, (3) C alkylsulfanyl, (4) C alkyl (said C alkyl is optionally substituted 1-6 1-6 by 1, 2 or 3 substituents selected from the group consisting of halogen, C aryl and C alkoxy), 6-10 1-6 (5) C cycloalkyl, (6) -OR {R is (a) C alkynyl, (b) C3-7 cycloalkyl optionally substituted by 1, 2 or 3 C1-6 alkyls or (c) C1-8 alkyl (said C1-8 alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v); (i) halogen, (ii) C aryl, 6-10 (iii) C alkoxy, (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl), and 1-6 1-4 (v) 4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said saturated heterocyclyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl))} or 1-6 1-4 (7) the formula: 【0025】 【0026】 wherein R is (a) C alkyl, (b) C cycloalkyl, (c) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms, or (d) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) C alkyl, (iii) haloC alkyl, (iv) C alkoxy, and (v) haloC alkoxy), and m1 is 0, 1, 2 or 3 and, when m1 is 2 or 3, each R is selected independently, excluding 4,6-bis-(2,5-dimethyl-phenyl)-1,3,5-triazinol. 【0027】 The compound of [01] or a pharmaceutically acceptable salt thereof, wherein ring Cy is the formula: 【0028】 【0029】 1 2 4 wherein R , R and R are as defined in [01]. 【0030】 The compound of [01] or a pharmaceutically acceptable salt thereof, wherein ring Cy is the formula: 【0031】 , 【0032】 1 3 4 wherein R , R and R are as defined in [01]. 【0033】 The compound of any of [01] to [03] or a pharmaceutically acceptable salt thereof, wherein X is CH. 【0034】 The compound of any of [01] to [03] or a pharmaceutically acceptable salt thereof, wherein X is N. 【0035】 The compound of any of [01] to [05] or a pharmaceutically acceptable salt thereof, wherein R is (1) chloro, (2) methyl, (3) cyano or (4) trifluoromethyl. 【0036】 The compound of any of [01] to [06] or a pharmaceutically acceptable salt thereof, wherein R is hydrogen. 【0037】 The compound of any of [01], [02] and [04] to [07] or a pharmaceutically acceptable salt thereof, wherein R is -(C H )-R (n is 1 or 2, -(C H )- may be straight or branched n 2n n 2n chain, and R is b1 b2 (a) -C(O)NR R , b5 b6 b7 (b) -NR C(O)NR R , b10 b11 (c) -NR S(O) R or b14 b15 (d) -NR C(O)R b1 b2 b5 b6 b7 b10 b11 b14 b15 (R , R , R , R , R , R , R , R , and R are as defined in 【0038】 id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"
[09] The compound of [08] or a pharmaceutically acceptable 2 b b salt thereof, wherein R is -CH -R (R is as defined in [08]). 【0039】 The compound of any of [01] and [03] to [09] or a pharmaceutically acceptable salt thereof, wherein R is (1) halogen, (2) hydroxy, (3) C alkyl or (4) -OR {R is C1-6 alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f) (a) halogen, (b) hydroxy, (c) C alkoxy, c1 c2 c1 c2 (d) -C(O)NR R (R and R are each independently hydrogen or C alkyl), (e) phenyl (said phenyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f) pyridyl (said pyridyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-6 alkyl, (iv) C alkoxy, and (v) haloC alkyl)}. 【0040】 The compound of any of [01] to [10] or a pharmaceutically acceptable salt thereof, wherein m1 is 1, and R is the formula: 【0041】 【0042】 wherein R is as defined in [01]. 【0043】 A compound selected from the following formulas: 【0044】 HO N CH O CH 【0045】 H C F H C N 【0046】 H C CH Cl N H C F 【0047】 HO N F O CH 【0048】 H C F 【0049】 N CH 【0050】 N CH 【0051】 N F F O CH 【0052】 【0053】 N CH 【0054】 HO N CH 【0055】 HO N O 【0056】 HO N O CH 【0057】 HO N CH 【0058】 HO N 【0059】 HO N 【0060】 HO N CH 【0061】 HO N CH 【0062】 【0063】 【0064】 or a pharmaceutically acceptable salt thereof. 【0065】 id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13"
[13] A pharmaceutical composition comprising the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 【0066】 id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14"
[14] An mPGES-1 inhibitor comprising the compound of any of to [12] or a pharmaceutically acceptable salt thereof. 【0067】 A therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer’s disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer or a disease for which suppression of PGE2 production is effective, comprising the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof. 【0068】 A therapeutic or prophylactic agent for glaucoma or ocular hypertension, comprising the compound of any of [01] to or a pharmaceutically acceptable salt thereof, and one or more kinds of other therapeutic agents for glaucoma in combination. 【0069】 A method of inhibiting mPGES-1, comprising administering a pharmaceutically effective amount of the compound of any of to [12] or a pharmaceutically acceptable salt thereof to a human. 【0070】 A method of treating or preventing pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer’s disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer or a disease for which suppression of PGE2 production is effective, which method comprising administering a pharmaceutically effective amount of the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof to a human. 【0071】 The method of [18] for treating or preventing glaucoma or ocular hypertension, further comprising administering a pharmaceutically effective amount of one or more kinds of other therapeutic agents for glaucoma to the human. 【0072】 Use of the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof for the production of an mPGES-1 inhibitor. 【0073】 Use of the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof for the production of a therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer’s disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer or a disease for which suppression of PGE2 production is effective.
EFFECT OF THE INVENTION 【0074】 The compound of the present invention is effective as a therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer’s disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer including colorectal cancer, a disease for which suppression of PGE2 production is effective and the like.
BRIEF DESCRIPTION OF THE DRAWINGS 【0075】 Fig. 1 shows effect of a test article (compounds of Example 2-98), a reference article (Xalatan (registered trademark)) or a vehicle (methylcellulose, MC) on the intraocular pressure immediately before and after administration in Macaca fascicularis.
DESCRIPTION OF EMBODIMENTS 【0076】 The definitions of the terms used in the present invention are as follows. 【0077】 The "halogen" is fluoro, chloro, bromo or iodo. 【0078】 The "C alkyl" means straight chain or branched chain alkyl having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 2-ethylbutyl and the like. 【0079】 The "C alkyl" means straight chain or branched chain alkyl having 1 to 8 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, 1-ethyl- propyl, 1-methylethyl-propyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. 【0080】 The "C alkoxy" means alkoxy wherein the alkyl moiety is the above-defined "C alkyl". Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 1,2,2-trimethylpropyloxy, 1,1-dimethylbutyloxy, 2,2- dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy and the like. 【0081】 The "haloC alkyl" means straight chain or branched chain alkyl having 1-4 carbon atoms, which is substituted by 1 to 9 the above-defined "halogens". When it is substituted by plural halogens, respective halogens may be the same or different. Examples thereof include 2-fluoroethyl, 2- chloroethyl, 2-bromoethyl, 3-fluoropropyl, 3-chloropropyl, 4- fluorobutyl, 4-chlorobutyl, 1,1-difluoroethyl, 1,1- difluoropropyl, 1,1-difluoromethylpropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4- trifluorobutyl, pentafluoroethyl, 2,2,2-trifluoro trifluoromethyl-ethyl and the like. 【0082】 The "haloC alkoxy" means alkoxy wherein the alkyl moiety is the above-defined "haloC alkyl". Examples thereof include fluoromethoxy, chloromethoxy, bromomethoxy, 2- fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 4-chlorobutoxy, 1,1- difluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoropropoxy, 2,2- difluoropropoxy, 3,3-difluoropropoxy, 1,1-difluoro methylpropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3- trifluoropropoxy, 4,4,4-trifluorobutoxy, pentafluoroethoxy, 2,2,2-trifluorotrifluoromethyl-ethoxy and the like. 【0083】 The "hydroxyC alkyl" means the above-defined "C 1-6 1-6 alkyl" substituted by 1 or 2 hydroxy. Examples thereof include hydroxymethyl, 2-hydroxyethyl, 1-hydroxymethylethyl, 1,2- dihydroxyethyl, 3-hydroxypropyl, 1-hydroxy-2,2-dimethylpropyl, 4-hydroxybutyl, 1-hydroxy-2,2-dimethylbutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like. 【0084】 The "C alkyl-carbonyl" means carbonyl bonded to the above-defined "C alkyl". Examples thereof include acetyl, propionyl, 2,2-dimethylpropionyl, butyryl, 3-methylbutyryl, 2,2-dimethylbutyryl, pentanoyl, 4-methylpentanoyl, hexanoyl and the like. 【0085】 The "C alkyl-carbonyloxy" means carbonyloxy bonded to the above-defined "C alkyl". Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, isopentylcarbonyloxy, 2-methylbutylcarbonyloxy, 1,1- dimethylpropylcarbonyloxy, neopentylcarbonyloxy, 3,3- dimethylbutylcarbonyloxy, 1-ethylpropylcarbonyloxy, hexylcarbonyloxy and the like. 【0086】 The "C cycloalkyl" means 3- to 7-membered monocyclic cycloalkyl. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 【0087】 The "C6-10 aryl" means 6- to 10-membered aryl. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like.
Of these, preferred is phenyl. 【0088】 The "5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms" means 5- or 6- membered monocyclic heteroaryl containing, besides carbon atoms, 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl(1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl), thiadiazolyl(1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4- thiadiazolyl), triazolyl(1,2,3-triazolyl, 1,2,4-triazolyl), pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl and the like. Of these, preferred is pyridyl. 【0089】 The "4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms" means 4-, 5- or 6-membered monocyclic saturated heterocyclyl containing, besides carbon atoms, 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The carbon atom of the heterocycle is optionally substituted by oxo. When a sulfur atom is contained as a hetero atom, the sulfur atom is optionally monooxidized or dioxidized. Examples thereof include oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidyl (including piperidino), morpholinyl (including morpholino), thiomorpholinyl (including thiomorpholino), piperazinyl, 1,1-dioxidoisothiazolidinyl, 1,1- dioxidotetrahydrothienyl, 1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiomorpholinyl (including 1,1- dioxidothiomorpholino) and the like. In addition, the saturated heterocyclyl may be partially saturated. Examples thereof include imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl and the like. Of these, preferred is oxetanyl. 【0090】 The "C alkylsulfanyl" means sulfanyl bonded to the above-defined "C alkyl". Examples thereof include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec- butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, 1,1- dimethylpropylsulfanyl, 2,2-dimethylpropylsulfanyl, hexylsulfanyl and the like. 【0091】 The "C alkynyl" means straight chain or branched chain hydrocarbon having 2 to 6 carbon atoms and at least one triple bond. Examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methylpropynyl, 3,3- dimethylbutynyl (that is, 3,3-dimethylbutynyl) and the like. 【0092】 The "-(CnH2n)-" means straight chain or branched chain alkylene having n carbon atoms and 2n hydrogen atoms. Examples thereof include -CH -, -CH CH -, -CH(CH )-, -CH CH CH -, -C(CH ) -, 2 2 2 3 2 2 2 3 2 -CH(CH )CH - and the like. 【0093】 2 b b b14 b15 When R is (10) -(C H )-R and R is (k) -NR C(O)R , n 2n "(ii) C alkyl (said C alkyl is optionally substituted by 1, 1-8 1-8 2 or 3 substituents selected from the group consisting of hydroxy, haloC alkyl, C alkoxy and C aryl)" for R 1-4 1-6 6-10 means the above-defined "C alkyl" substituted or not substituted by the same or different, 1, 2 or 3 substituents selected from the group consisting of hydroxy, the above- defined "haloC alkyl", the above-defined "C alkoxy" and the 1-4 1-6 above-defined "C aryl", at the substitutable position(s) 6-10 thereof. Examples of R include 2-ethoxy methoxypropylcarbonylamino, 1-methylmethoxy-2,2,2- trifluoroethylcarbonylamino and the like. 【0094】 2 b b b14 b15 When R is (10) -(CnH2n)-R and R is (k) -NR C(O)R , "(iv) C3-7 cycloalkyl (said C3-7 cycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of C alkyl, halogen, hydroxyC alkyl and 1-6 1-6 haloC alkyl, and/or optionally form a fused ring with a benzene ring)" for R means (1) the above-defined "C cycloalkyl" substituted by the same or different, 1, 2, 3 or 4 substituents selected from the group consisting of the above- defined "C alkyl", the above-defined "halogen", the above- defined "hydroxyC alkyl" and the above-defined "haloC 1-6 1-4 alkyl", at the substitutable position(s) thereof, (2) unsubstituted C cycloalkyl, or (3) C cycloalkyl of (1) or 3-7 3-7 (2), fused with one benzene ring at a fusible position.
Examples of R include 1,2,3,4-tetrahydro-naphthalen ylcarbonylamino, 2-methyl-indanylcarbonylamino and the like. 【0095】 2 b b b14 b15 When R is (10) -(C H )-R and R is (k) -NR C(O)R , n 2n b14 b15 "R and R optionally form a 4-, 5- or 6-membered lactam together with the nitrogen atom that R is bonded to and the b15 b carbon atom that R is bonded to" means that R is 2-oxo- azetidinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl or the like. 【0096】 In addition, in this case, "said lactam is optionally substituted by 1, 2 or 3 C alkyls, and/or optionally form a fused ring with a benzene ring" means that, in addition to the above-mentioned "lactam", (1) the same or different 1, 2 or 3 C alkyls defined above are present at the substitutable position(s) of the lactam, (2) one benzene ring is fused at the fusible position of the lactam, and (3) one benzene ring is fused at the fusible position of the lactam substituted by C alkyl(s). Examples of R include 3,4-dimethyloxo- pyrrolidinyl, 1-oxo-1,3-dihydro-isoindolyl, 3,3-dimethyl- 2-oxo-2,3-dihydro-indolyl and the like. 【0097】 In the compound represented by the formula [I], preferable embodiments of respective groups are as described below. 【0098】 R is preferably chloro, methyl, cyano or trifluoromethyl, more preferably chloro or trifluoromethyl, and further preferably chloro. 【0099】 R is preferably (1) halogen, (2) hydroxy, (3) carboxy, (5) C alkoxy, (6) haloC alkoxy, (7) haloC alkyl, (8) C alkyl-carbonyl, a1 a2 a1 a2 (9) -C(O)NR R (R and R are as defined above) or (10) -(CnH2n)-R (R is as defined above), more preferably (10) -(C H )-R (R is as defined above). n 2n R is preferably b5 b6 b7 b5 b6 b7 (g) -NR C(O)NR R (R , R and R are as defined above), b8 b9 b8 b9 (h) -NR R (R and R are as defined above), b10 b11 b10 b11 (i) -NR S(O) R (R and R are as defined above), b12 b13 b12 b13 (j) -NR C(O)OR (R and R are as defined above), b14 b15 b14 b15 (k) -NR C(O)R (R and R are as defined above, more preferably b14 b15 b14 b15 (k) -NR C(O)R (R and R are as defined above). n is preferably 1 or 2, more preferably 1.
R is preferably hydrogen or methyl, more preferably hydrogen.
R is preferably (ii) C1-4 alkyl (said C1-4 alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of hydroxy, trifluoromethyl, C1-4 alkoxy and phenyl) (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2, 3 or 4 substituents selected from the group consisting of C alkyl, halogen, hydroxyC alkyl and 1-4 1-4 trifluoromethyl), more preferably C alkyl optionally substituted by 1 or 2 trifluoromethyls and C alkoxy, or C cycloalkyl optionally 1-4 3-7 substituted by one trifluoromethyl, further preferably tert- butyl, 3,3,3-trifluoro-2,2-dimethylpropyl, 3,3,3-trifluoro methoxymethylpropyl, 3,3,3-trifluoromethyl trifluoromethylpropyl, or 1-trifluoromethylcyclopropyl. 【0100】 R is preferably (3) C alkyl or (4) -OR {R is C alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f); (a) halogen, (b) hydroxy, (c) C alkoxy, c1 c2 c1 c2 (d) -C(O)NR R (R and R are as defined above), (e) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-6 alkyl, (iv) C alkoxy, and (v) haloC alkyl)}.
R is preferably methyl optionally substituted by 1 or 2 substituents selected from the following (e) and (f); (e) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), more preferably methyl optionally substituted by 1 or 2 substituents selected from the following (e1) and (f1); (e1) phenyl (said phenyl is optionally substituted by 1 or 2 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f1) pyridyl (said pyridyl is optionally substituted by 1 or 2 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-6 alkyl, (iv) C1-6 alkoxy, and (v) haloC alkyl). 【0101】 R is preferably hydrogen, fluoro, chloro, or methyl, more preferably hydrogen. 【0102】 R is preferably (1) halogen, (4) C alkyl (said C alkyl is optionally substituted 1-6 1-6 by 1, 2 or 3 substituents selected from the group consisting of halogen, C aryl and C alkoxy), 6-10 1-6 (5) C cycloalkyl, (6) -OR {R is (a) C alkynyl, (b) C cycloalkyl optionally substituted by 1, 2 or 3 C alkyls or (c) C1-8 alkyl (said C1-8 alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v); (i) halogen, (ii) C aryl, 6-10 (iii) C alkoxy, (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl), and 1-6 1-4 (v) 4-, 5- or 6-membered saturated heterocyclyl containing one oxygen atom (said saturated heterocyclyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl))}, or 1-6 1-4 (7) the formula: 【0103】 【0104】 wherein R is (a) C alkyl, (b) C cycloalkyl, (c) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms, or (d) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) C alkyl, (iii) haloC alkyl, (iv) C alkoxy, and (v) haloC alkoxy).
R is preferably C alkyl (said C alkyl is optionally 1-8 1-8 substituted by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v); (i) halogen, (ii) C6-10 aryl, (iii) C alkoxy, (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl), and 1-6 1-4 (v) 4-, 5- or 6-membered saturated heterocyclyl containing one oxygen atom (said saturated heterocyclyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl)). 1-6 1-4 R is preferably (b) C cycloalkyl, (c) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms, or (d) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) C1-6 alkyl, (iii) haloC1-4 alkyl, (iv) C1-6 alkoxy, and (v) haloC1-4 alkoxy). 【0105】 m1 is preferably 0, 1 or 2, more preferably 1 or 2. 【0106】 In the compound represented by the formula [I], one of preferable embodiments is a compound represented by the following formula [I-A]: 【0107】 (R ) [I-A] 【0108】 wherein a carbon atom with a hydrogen atom is not substituted by R and R , 1 2 4 X, R , R and R are as defined in the aforementioned formula [I], R is (1) halogen, (4) C alkyl (said C alkyl is optionally substituted 1-6 1-6 by 1, 2 or 3 substituents selected from the group consisting of halogen, C aryl and C alkoxy), 6-10 1-6 (5) C cycloalkyl, or (6) -OR {R is (a) C alkynyl or (c) C alkyl (said C alkyl is optionally substituted 1-8 1-8 by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v); (i) halogen, (ii) C6-10 aryl, (iii) C alkoxy, (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl), and 1-6 1-4 (v) 4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said saturated heterocyclyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl))}, and 1-6 1-4 m7 is 0, 1 or 2 and, when m7 is 2, each R is selected independently. 【0109】 In a compound represented by the formula [I], one of the preferable other embodiments is a compound represented by the following formula [I-B]: 【0110】 (R ) [I-B] 【0111】 wherein a carbon atom with a hydrogen atom is not substituted by R and X, R and R are as defined in the aforementioned formula [I], R is chloro or trifluoromethyl, R is (4) C1-6 alkyl (said C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, C aryl and C alkoxy), 6-10 1-6 (6) -OR {R is C alkyl (said C alkyl is optionally substituted by 1, 2 or 1-8 1-8 3 substituents selected from the group consisting of the following (i) to (iv); (i) halogen, (ii) C aryl, 6-10 (iii) C alkoxy, and (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl))}, or 1-6 1-4 (7) the formula: 【0112】 【0113】 wherein R is (b) C cycloalkyl, or (d) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) C alkyl, (iii) haloC alkyl, (iv) C alkoxy, and (v) haloC alkoxy), and m7 is 0, 1 or 2 and, when m7 is 2, each R is selected independently. 【0114】 In a compound represented by the formula [I], one of the preferable other embodiments is a compound represented by the following formula [I-C]: 【0115】 (R ) b 15 [I-C] 【0116】 wherein X is CH or N, R is (ii) C alkyl (said C alkyl is optionally 1-4 1-4 substituted by 1 or 2 substituents selected from trifluoromethyl and methoxy) or (iv) C cycloalkyl optionally substituted by trifluoromethyl, R is (1) fluoro, (4) methyl (said methyl is optionally substituted by 3 fluoros), or (6) -OR {R is (a) C alkynyl or (c) C alkyl optionally substituted by one C 1-4 3-7 cycloalkyl (said C cycloalkyl is optionally substituted by trifluoromethyl)}, R is (1) halogen, (4) C1-4 alkyl, or (5) cyclopropyl, and m8 is 0 or 1. 【0117】 A pharmaceutically acceptable salt of a compound represented by the formula [I] (hereinafter to be also referred to as the compound of the present invention) may be any salt as long as it forms a nontoxic salt with the compound of the present invention, and examples thereof include salts with inorganic acid, salts with organic acid, salts with inorganic base, salts with organic base, salts with amino acid and the like.
Various forms of pharmaceutically acceptable salts are well known in this field and, for example, they are described in the following documents. (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 the salts with inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
Examples of the salts with organic acid 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, p-toluenesulfonic acid and the like.
Examples of the salts with organic acid include salts with adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, calcium edetate, camphoric acid, camphorsulfonic acid, carbonic acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, glucoheptonic acid, glucuronic acid, glucoheptonic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrofluoric acid, hydroiodic acid, hydroxy-naphtoic acid, 2-hydroxyethanesulfonic acid, lactobionic acid, mandelic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene sulfonic acid, 2-naphtoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, pamoic acid, pantothenic acid, pectin acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, tannic acid, teoclic acid, thiocyanic acid, undecanoic acid and the like.
Examples of the salts with inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
Furthermore, examples of the salts with inorganic base include salts with aluminum, barium, bismuth, lithium, or zinc.
Examples of the salts with organic base 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 the salts with organic base include salts with arecoline, betaine, clemizole, N- methylglucamine, N-benzylphenethylamine or tris(hydroxymethyl)methylamine.
Examples of the salts with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
Among the above-mentioned salts, preferred are salts with hydrochloric acid, sulfuric acid or p-toluenesulfonic acid.
Various salts can be obtained by reacting a compound represented by the formula [I] with inorganic base, organic base, inorganic acid, organic acid or amino acid according to a known method. 【0118】 A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof may be present as a solvate. The "solvate" is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, which is coordinated with a solvent molecule, and also encompasses hydrates. The solvate is preferably a pharmaceutically acceptable solvate, examples thereof include a hydrate, ethanolate, dimethyl sulfoxidate and the like of a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof. Specific examples include semihydrate, monohydrate, dihydrate or monoethanolate of a compound represented by the formula [I], monohydrate of sodium salt or 2/3 ethanolate of dihydrochloride of a compound represented by the formula [I], and the like.
The solvates can be obtained by a known method. 【0119】 In addition, a compound represented by the formula [I] 2 3 14 35 may be labeled with isotope (e.g., H, H, C, S etc.). 【0120】 The compound of the present invention may exist as a tautomer. In this case, the compound of the present invention can be a single tautomer or a mixture of individual tautomers.
For example, a compound represented by the formula [I] may contain a tautomer shown below 【0121】 (R ) . 【0122】 Such tautomer is also encompassed in the compound represented by the formula [I].
The compound of the present invention may have a carbon double bond. In this case, the compound of the present invention can be present as E form, Z form, or a mixture of E form and Z form.
The compound of the present invention may contain a stereoisomer that should be recognized as a cis/trans isomer.
In this case, the compound of the present invention can be present as a cis form, a trans form, or mixture of a cis form and a trans form.
The compound of the present invention may contain one or more asymmetric carbons. In this case, the compound of the present invention may be present as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.
The compound of the present invention may be present as an atropisomer. In this case, the compound of the present invention may be present as an individual atropisomer or a mixture of atropisomers.
The compound of the present invention may simultaneously contain plural structural characteristics that produce the above-mentioned isomers. Moreover, the compound of the present invention may contain the above-mentioned isomers at any ratio. 【0123】 In the absence of other reference such as annotation and the like, the formulae, chemical structures and compound names indicated in the present specification without specifying the stereochemistry thereof encompass all the above-mentioned isomers that may exist. 【0124】 A diastereomeric mixture can be separated into each diastereomer by conventional methods such as chromatography, crystallization and the like. In addition, each diastereomer can also be formed by using a stereochemically single starting material, or by a synthesis method using a stereoselective reaction. 【0125】 An enantiomeric mixture can be separated into each single enantiomer by a method well known in the pertinent field.
For example, enantiomeric mixture can be prepared by reacting the enantiomeric mixture with a substantially pure enantiomer that is known as a chiral auxiliary. The diastereomeric mixture can be separated into each diastereomer mentioned above. The diastereomer mixture can be separated into each diastereomer as mentioned above. The separated diastereomer can be converted to a desired enantiomer by removing the added chiral auxiliary by cleavage.
In addition, a mixture of enantiomers of a compound can also be directly separated by a chromatography method using a chiral solid phase well known in the pertinent field.
Alternatively, one of the enantiomers of a compound can also be obtained by using a substantially pure optically active starting material or stereoselective synthesis (asymmetric induction) of a prochiral intermediate using a chiral auxiliary and an asymmetric catalyst. 【0126】 The absolute steric configuration can be determined based on the X-ray crystal analysis of the resultant crystalline product or intermediate. In this case, a resultant crystalline product or intermediate derivatized with a reagent having an asymmetric center with a known steric configuration may be used where necessary. 【0127】 As a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, a substantially purified compound represented by the formula [I] or a pharmaceutically acceptable salt thereof is preferable. More preferred is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, which is purified to have a purity of more than 80%. 【0128】 Examples of the "pharmaceutical composition" include oral preparations such as tablet, capsule, granule, powder, troche, syrup, emulsion, suspension and the like, and parenteral agents such as external preparation, suppository, injection, eye drop, nasal preparations, pulmonary preparation and the like. 【0129】 The pharmaceutical composition of the present invention is produced according to a method known per se in the art of pharmaceutical preparations, by mixing etc. a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof with a suitable amount of at least one kind of pharmaceutically acceptable carrier and the like as appropriate. While the content of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dose and the like, it is, for example, 0.00001 to 100 wt% of the whole composition. 【0130】 Examples of the "pharmaceutically acceptable carrier" include various organic or inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, glidant, lubricant and the like for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffering agent, soothing agent, surfactant, pH adjuster, thickening agent and the like for liquid preparations. Where necessary, moreover, additives such as preservative, antioxidant, colorant, sweetening agent and the like are used. 【0131】 Examples of the "excipient" include lactose, sucrose, D- mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, gum arabic and the like. 【0132】 Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like. 【0133】 Examples of the "binder" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like. 【0134】 Examples of the "glidant" include light anhydrous silicic acid, magnesium stearate and the like. 【0135】 Examples of the "lubricant" include magnesium stearate, calcium stearate, talc and the like. 【0136】 Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. 【0137】 Examples of the "solubilizing agent" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like. 【0138】 Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate and the like. 【0139】 Examples of the "isotonicity agent" include glucose, D- sorbitol, sodium chloride, D-mannitol and the like. 【0140】 Examples of the "buffering agent" include sodium hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate and the like. 【0141】 Examples of the "soothing agent" include benzyl alcohol and the like. 【0142】 Examples of the "surfactant" include polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene sorbitan fatty acid ester, alkyldiaminoethylglycine, alkylbenzenesulfonate, benzethonium chloride and the like. 【0143】 Examples of the "pH adjuster" include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine and the like. 【0144】 Examples of the "thickening agent" include polyvinyl alcohol, carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, polyethylene glycol, dextran and the like. 【0145】 Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like. 【0146】 Examples of the "antioxidant" include sodium sulfite, ascorbic acid and the like. 【0147】 Examples of the "colorant" include food colors (e.g., Food Color Red No. 2 or 3, Food Color Yellow No. 4 or 5 etc.), b - carotene and the like. 【0148】 Examples of the "sweetening agent" include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like. 【0149】 The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., topical, rectal, intravenous administration etc.) to human as well as mammals other than human (e.g., hamster, guinea pig, cat, dog, swine, bovine, horse, sheep, monkey etc.). The dose varies depending on the subject of administration, disease, symptom, dosage form, administration route and the like. For example, the daily dose for oral administration to an adult patient (body weight: about 60 kg) is generally within the range of about 0.1 m g to 10 g, based on the compound of the present invention as the active ingredient. This amount can be administered in one to several portions. 【0150】 The above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination with one or a plurality of other medicaments (hereinafter to be also referred to as a concomitant drug) according to a method generally employed in the medical field (hereinafter to be referred to as combined use). 【0151】 The administration period of the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, and a concomitant drug is not limited, and they may be administered to an administration subject as combination preparation, or the both preparations may be administered simultaneously or at given intervals as individual preparations.
In addition, the pharmaceutical composition of the present invention and a concomitant drug may be used in the form of a kit. The dose of the concomitant drug is similar to the clinically-employed dose and can be appropriately selected according to the subject of administration, disease, symptom, dosage form, administration route, administration time, combination and the like. The administration form of the concomitant drug is not particularly limited, and it is only required that the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof is combined with a concomitant drug. 【0152】 Examples of the concomitant drug include therapeutic agents for glaucoma such as prostaglandin preparation, b blocker, α receptor agonist, sympathetic nerve stimulation agent, α blocker, carbonic anhydrase inhibitor, anticholinesterase agent, Rho kinase inhibitor and the like. 【0153】 Examples of the prostaglandin preparation include isopropyl unoprostone, latanoprost, travoprost, tafluprost, bimatoprost and the like.
Examples of the b blocker include timolol maleate, Befunolol hydrochloride, carteolol hydrochloride, betaxolol hydrochloride, nipradilol, levobunolol hydrochloride and the like. 【0154】 Examples of the α receptor agonist include brimonidine tartrate and the like. 【0155】 Examples of the sympathetic nerve stimulation agent include dipivefrin hydrochloride, pilocarpine hydrochloride and the like. 【0156】 Examples of the α blocker include bunazosin hydrochloride and the like. 【0157】 Examples of the carbonic anhydrase inhibitor include dorzolamide hydrochloride, brinzolamide and the like. 【0158】 Examples of the anticholinesterase agent include distigmine bromide and the like. 【0159】 Examples of the Rho kinase inhibitor include ripasudil hydrochloride hydrate and the like. 【0160】 An example of the specific combination of medicaments is a combination of one medicament selected from latanoprost, travoprost, tafluprost, timolol maleate, dorzolamide hydrochloride and brinzolamide, and the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof. 【0161】 Next, one example of the production methods of the compound to practice the present invention is explained below.
However, the production method of the compound of the present invention or a pharmaceutically acceptable salt thereof is not limited thereto.
Even when no directly corresponding disclosure is found in the following Production Methods, the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional group with deprotection in a subsequent step, changing the order of Production Methods and steps, appropriate use of reagents other than the exemplified reagents to promote progress of the reactions, and the like.
The treatment after reaction in each step may be conventional ones, where isolation and purification can be performed as necessary according to a method appropriately selected from conventional methods such as crystallization, recrystallization, distillation, partitioning, silica gel chromatography, preparative HPLC and the like, or a combination of those methods. In some cases, the next step may be conducted without isolation and purification.
An intermediate capable of forming a salt may also be obtained as a salt, or used as a salt for reactions. Examples of such salt include hydrochloride of an intermediate having an amino group. 【0162】 [Production Method 1-1] 【0163】 (R ) (R ) Hal N Hal X N Hal Step 11 Suzuki coupling (R ) Step 12 Suzuki coupling (R ) Step 13 hydrolysis 【0164】 wherein Hal is chloro or bromo; R is C alkyl such as methyl, ethyl and the like or benzyl; Z is a boron substituent used for the Suzuki coupling reaction 7 7 7 such as -B(OH) , -B(OR ) (wherein R is C alkyl or one R may 2 2 1-4 be bonded to the other R to form a ring), -BF , the formula 【0165】 B CH 【0166】 and the like; and X, Cy, R and m1 are as defined in the aforementioned formula [I]. 【0167】 (Step 11) Compound [3] can be obtained by the Suzuki coupling reaction of compound [1] and compound [2]. For example, compound [3] can be obtained by reacting compound [1] with compound [2] under heating in a solvent in the presence of a base and a palladium catalyst. Where necessary, a ligand may be added. Not less than 1.5 equivalents of compound [1] are preferably used relative to compound [2] to prevent the Suzuki coupling reaction from progressing twice.
Examples of the palladium catalyst to be used for the reaction include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like.
Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like, and organic bases such as triethylamine and the like.
Examples of the ligand to be used for the reaction include organic phosphine ligands (e.g., triphenylphosphine, tricyclohexylphosphine, 2,2’-bis(diphenylphosphino)-1,1’- binaphthalene, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl etc.) and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; alcohol solvents such as methanol, ethanol, 1- propanol, 2-propanol and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like; a mixed solvent thereof, and a mixed solvent thereof with water.
Compound [1] may be a commercially available product such as 2,4-dichloromethoxy-1,3,5-triazine, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
As for the Suzuki coupling reaction, for example, the following review article is known (SUZUKI, A et al. Palladium- Catalyzed Cross-Coupling Reactions of Organoboron Compounds.
Chem Rev. 1995, Vol.95, pages 2457-2483). 【0168】 (Step 12) Compound [5] can be obtained by the Suzuki coupling reaction of compound [3] and compound [4]. For example, compound [5] can be obtained by reacting compound [3] with compound [4] under heating in a solvent in the presence of a base and a palladium catalyst. Where necessary, a ligand may be added.
Examples of the palladium catalyst to be used for the reaction include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like.
Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like, and organic bases such as triethylamine and the like.
Examples of the ligand to be used for the reaction include organic phosphine ligands such as triphenylphosphine, tricyclohexylphosphine, 2,2’-bis(diphenylphosphino)-1,1’- binaphthalene, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl and the like, and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; alcohol solvents such as methanol, ethanol, 1- propanol, 2-propanol and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like; a mixed solvent thereof, and a mixed solvent thereof with water. 【0169】 (Step 13) Compound [I] can be obtained by converting the alkoxy of compound [5] to hydroxy by hydrolysis. For example, when R is C alkyl, compound [I] can be obtained by reacting compound in a solvent in the presence of a base at room temperature to under heating, and neutralizing the obtained solution.
Examples of the base to be used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and the like.
Examples of the solvent to be used for the reaction include a mixed solvent of water and alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; and a mixed solvent thereof with ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like. 【0170】 [Production Method 1-2] Compound [2] can be obtained by, for example, Production Method 1-2. 【0171】 [Production Method 1-2] 【0172】 (R ) (R ) Step 1-2 【0173】 wherein L is a leaving group such as bromo, iodo, trifluoromethanesulfonyloxy and the like, X, R and m1 are as defined in the aforementioned formula [I], and Z is as defined in the aforementioned Production Method 1-1. 【0174】 (Step 1-2) Compound [2] can be obtained by borating compound [6].
For example, compound [2] can be obtained by reacting compound with a boron reagent under heating in the presence of a base and a palladium catalyst. Where necessary, a ligand may be added Examples of the boron reagent to be used for 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, 4,4,5,5-tetramethyl-1,3,2- dioxaborolane and the like.
Examples of the palladium catalyst to be used for the reaction include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like.
Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like, and organic bases such as triethylamine and the like.
Examples of the ligand to be used for the reaction include organic phosphorus ligands (e.g., triphenylphosphine, tricyclohexylphosphine, 2,2’-bis(diphenylphosphino)-1,1’- binaphthalene, 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl etc.) and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; alcohol solvents such as methanol, ethanol, 1- propanol, 2-propanol and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like; a mixed solvent thereof, and a mixed solvent thereof with water.
Compound [2] can also be obtained by adding an organic metal reagent to compound [6] in a solvent at -78 C to room temperature, and reacting the product with a boron compound at -78 C to room temperature.
Examples of the organic metal reagent to be used for the reaction include n-butyllithium, tert-butyllithium, isopropylmagnesium chloride and the like.
Examples of the boron reagent to be used for the reaction include trimethyl borate, triisopropyl borate, 2-isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like, and a mixed solvent thereof.
In one embodiment, compound [6] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0175】 F C Cl F C Br Br Br Br 【0176】 In one embodiment, compound [2] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0177】 3 F C Z Z Z Z Cl O O O F C O Z Z Z Z Z F C Z Z O Z F C O Z O Z Z F Z Z F Cl Cl F Z Cl Z Z Z O Z F C F C F C F 3 3 3 Z Cl Z Z Z Z Z O Z O Z O Z F C Z Z Z HO S O O O Z Z Z Z Z Cl O O Z HO Z Z Z Cl Cl N N Z Z Z Z 【0178】 wherein Z is as defined in the aforementioned Production Method 1-1. 【0179】 [Production Method 1-3] Compound [4] can be obtained by, for example, Production Method 1-3. 【0180】 [Production Method 1-3] 【0181】 R 1 R Step 1-3 [8a] [7a] Step 1-3 [8b] [7b] 【0182】 1 2 3 4 wherein R , R , R and R are as defined in the aforementioned formula [I], L is as defined in the aforementioned Production Method 1-2, and Z is as defined in the aforementioned Production Method 1-1. 【0183】 (Step 1-3) Compound [4] is compound [8a] or [8b]. Compound [8a] or [8b], i.e., compound [4], can be obtained by borating compound [7a] or [7b] in the same manner as in Production Method 1-2, Step 1-2.
Compounds [7a] and [7b] may be commercially available products such as 2-bromomethylbenzonitrile and 2-bromo methylphenol, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0184】 In one embodiment, compound [4] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0185】 Cl Cl Z F Z Cl Z Z Z O Cl Cl Cl Z CF OH Z O Z Z OH Cl Cl Z Z OH Z OH F OH Z Cl Cl NH OH 【0186】 wherein Z is as defined in the aforementioned Production Method 1-1. 【0187】 [Production Method 2-1] or [Production Method 2-3] For example, compound [I-a1] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0188】 (C H ) n 2n 【0189】 1 4 b15 wherein R , R , R and n are as defined in the aforementioned formula [I], can be obtained by appropriately converting the substituent of ring Cy.
When C H is a straight chain, Production Method 2-1 is n 2n preferable, and when C H is a branched chain, Production n 2n Method 2-3 is preferable. 【0190】 [Production Method 2-1] 【0191】 1 1 R 1 R R R R R Step 22 Step 21 reduction hydrolysis Hal (C H ) Hal (C H ) Hal (C H ) t 2t t 2t t 2t O OH OH O OC Alkyl Step 24 1 R Step 25 Step 23 boration Suzuki coupling protection Hal (C H ) t 2t Z (C H ) t 2t Step 27 R 1 introduction of Step 26 R leaving group deprotection Y (C H ) t 2t (C H ) t 2t 1 R 1 Step 28 Step 29 amination deprotection (C H ) Y (C H ) t 2t t 2t R Step 210 amidation (C H ) t 2t Y (C H ) t 2t (R ) (R ) R Step 211 deprotection (C H ) n 2n (C H ) n 2n HN O HN O OH b15 OR b15 [I-a1] 【0192】 wherein Y is the formula 【0193】 (R ) 【0194】 wherein R , R and m1 are as defined in the aforementioned formula [I]; C Alkyl is C alkyl; 1-6 1-6 t is 0, 1, 2 or 3, -(C H )- may be a straight or branched t 2t chain; Hal is bromo or iodo; P is a hydroxy-protecting group such as methoxymethyl and the like; P is an amino-protecting group such as tert-butoxycarbonyl and the like; L is a leaving group such as halogen (e.g., chloro, bromo and the like), methanesulfonyloxy, p-toluenesulfonyloxy and the like; 1 4 6 b15 R , R , R , R and n are as defined in the aforementioned formula [I], and Z is as defined in the aforementioned Production Method 1-1. 【0195】 (Step 21) Compound [10] can be obtained by converting the ester of compound [9] to carboxy by hydrolysis. For example, compound can be obtained by reacting compound [9] in a solvent in the presence of a base at room temperature to under heating, and neutralizing the obtained solution.
Examples of the base to be used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and the like.
Examples of the solvent to be used for the reaction include a mixed solvent of water and alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; and a mixed solvent thereof with ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
Compound [9] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0196】 Cl Cl Cl Cl Cl OMe OMe OMe OMe Br Br Br Br O Cl O 【0197】 (Step 22) Compound [11] can be obtained by converting the carboxy of compound [10] to hydroxy by reduction. For example, compound [11] can be obtained by reacting compound [10] with a reducing agent in a solvent under ice-cooling to room temperature.
Examples of the reducing agent to be used for the reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane- tetrahydrofuran complex and the like.
Examples of the solvent to be used for the reaction include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, xylene, hexane and the like and a mixed solvent thereof. 【0198】 (Step 23) Compound [12] can be obtained by protecting the hydroxy group of compound [11]. The protection reaction can be performed by a known method according to the protecting group to be employed.
For example, when P is methoxymethyl, compound [12] can be obtained by reacting compound [11] with chloromethyl methyl ether in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether, N,N-dimethylformamide and the like in the presence of a base such as sodium hydride and the like from ice-cooling to room temperature. 【0199】 (Step 24) Compound [13] can be obtained by borating compound [12] in the same manner as in Production Method 1-2, Step 1-2. 【0200】 (Step 25) Compound [14] can be obtained by the Suzuki coupling reaction of compound [3] and compound [13] in the same manner as in Production Method 1-1, Step 12. 【0201】 (Step 26) Compound [15] can be obtained by removing P of compound by hydroxy-deprotection by a conventional method. The deprotection reaction can be performed by a known method according to the protecting group to be employed.
For example, when P is methoxymethyl, a treatment with an acid such as hydrochloric acid, trifluoroacetic acid, methanesulfonic acid and the like only needs to be performed in a single or mixed solvent of chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, ethyl acetate, ethanol, methanol, water and the like.
Compound [15] can also be obtained by the Suzuki coupling reaction of compound [3] and compound [23] represented by the formula 【0202】 (C H ) t 2t 【0203】 wherein R and R are as defined in the aforementioned formula [I], Z is as defined in the aforementioned Production Method 1- 1, and t is as defined in the aforementioned Production Method 2-1, in the same manner as in Production Method 1-1, Step 12. 【0204】 (Step 27) Compound [16] can be obtained by converting the hydroxy of compound [15] to the leaving group L . For example, when L is methanesulfonyloxy, compound [16] can be obtained by reacting compound [15] with methanesulfonyl chloride in a solvent in the presence of a base at room temperature. When L is bromo, compound [16] can be obtained by reacting compound with carbon tetrabromide in a solvent in the presence of triphenylphosphine from ice-cooling to room temperature.
Examples of the base to be used for the reaction include triethylamine, pyridine and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like.
It is possible to use dimethylsulfide instead of the above-mentioned triphenylphosphine, and N-bromosuccinimide can be used instead of the above-mentioned carbon tetrabromide. p-Toluenesulfonyl chloride and benzenesulfonyl chloride can be used instead of the above-mentioned methanesulfonyl chloride. 【0205】 (Step 28) Compound [18] can be obtained by reacting compound [16] in a solvent in the presence of a base at room temperature to under heating compound [17]. Examples of the protecting group P include tert-butoxycarbonyl.
Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., cesium carbonate, potassium phosphate, sodium carbonate, potassium carbonate etc.) and the like.
Examples of the solvent to be used for the reaction include polar solvents such as N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like. 【0206】 (Step 29) Compound [19] can be obtained by removing P of compound by amine-deprotection by a conventional method. The deprotection reaction can be performed by a known method according to the protecting group to be employed.
For example, when P is tert-butoxycarbonyl, a treatment with an acid such as hydrochloric acid, trifluoroacetic acid, methanesulfonic acid and the like only needs to be performed in a solvent.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; ester solvents such as ethyl acetate and the like; and alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like. 【0207】 (Step 210) Compound [21] can be obtained by a conventional amide bond forming reaction, for example, by reacting compound [19] with compound [20] in a solvent in the presence of a condensing agent and an additive. A base may be added as necessary.
Examples of the condensing agent to be used for the reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride (WSC･HCl), diisopropylcarbodiimide, 1,1’-carbonyldiimidazole (CDI), O-(7- azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), (benzotriazol yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide and the like.
Examples of the additive to be used for the reaction include 1-hydroxybenzotriazole (HOBt), 1-hydroxy azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4- dimethylaminopyridine and the like.
Examples of the base to be used for the reaction include organic bases such as pyridine, triethylamine and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine and the like. These may be used singly or as a mixture of two or more kinds thereof.
Compound [20] may be a commercially available product such as cyclopentanecarboxylic acid and 1- (trifluoromethyl)cyclopropanecarboxylic acid, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0208】 (Step 211) Compound [21] can be indicated as compound [22].
Compound [I-a1] can be obtained by converting the alkoxy of compound [22] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 13. 【0209】 [Production Method 2-2] Compound [10a] which is compound [10] wherein R is C alkyl or chloro can be obtained by [Production Method 2-2]. 【0210】 [Production Method 2-2] 【0211】 Step 2-2 halogenation Hal (C H ) (C H ) t 2t t 2t O OH O OH [10a] 【0212】 wherein R is C alkyl or chloro; R is as defined in the aforementioned formula [I], and Hal and t are as defined in the aforementioned Production Method 2- 1. 【0213】 (Step 2-2) Compound [10a] can be obtained by halogenating compound . For example, when Hal is iodo, compound [10a] can be obtained by reacting compound [24] with N-iodosuccinimide in an acid at room temperature.
Examples of the acid to be used for the reaction include concentrated sulfuric acid and the like.
Compound [24] may be a commercially available product such as 4-chlorophenylacetic acid, 3-(4-chlorophenyl)propionic acid, 4-(4-chlorophenyl)butanoic acid, 4-methylphenylacetic acid and 2-(4-methylphenyl)propionic acid, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0214】 [Production Method 2-3] 【0215】 Step 22 Step 21 R Suzuki coupling boration Hal (C H ) j 2j Y (C H ) j 2j Z (C H ) j 2j (C H ) O k 2k (C H ) O k 2k (C H ) O k 2k Step 24 introduction of Step 23 reduction leaving group Y (C H ) Y (C H ) j 2j j 2j (C H ) L (C H ) OH k 2k k 2k Step 26 Step 25 R deprotection amination Y (C H ) Y (C H ) j 2j j 2j (C H ) NH (C H ) N k 2k 2 k 2k 1 R (R ) Step 27 amidation Y (C H ) (C H ) j 2j n 2n HN O (C H ) NH k 2k O R 6 OR b15 H b15 id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22" id="p-22"
[22] (R ) 1 Step 28 deprotection (C H ) n 2n HN O [I-a1] 【0216】 wherein j and k are each 0, 1, 2 or 3, j+k=n-1; 1 4 5 b15 R , R , R , R and n are as defined in the aforementioned formula [I], Z is as defined in the aforementioned Production Method 1-1, 2 w 2 Hal , Y, P and L are as defined in the aforementioned Production Method 2-1. 【0217】 (Step 21) Compound [26] can be obtained by borating compound [25] in the same manner as in Production Method 1-2, Step 1-2.
Compound [25] may be a commercially available product such as 1-(3-bromochlorophenyl)propanone and 1-(3-bromo- 4-chlorophenyl)butanone, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0218】 (Step 22) Compound [27] can be obtained by the Suzuki coupling reaction of compound [3] and compound [26] in the same manner as in Production Method 1-1, Step 12. 【0219】 (Step 23) Compound [28] can be obtained by converting the carboxy of compound [27] to hydroxy by reduction. For example, compound [28] can be obtained by reacting compound [27] with a reducing agent in a solvent under ice-cooling to room temperature.
Examples of the reducing agent to be used for the reaction include sodium borohydride and the like.
Examples of the solvent to be used for the reaction include methanol, ethanol, 2-propanol, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like. 【0220】 (Step 24) Compound [29] can be obtained by converting the hydroxy of compound [28] to the leaving group L in the same manner as in Production Method 2-1, Step 27. 【0221】 (Step 25) Compound [30] can be obtained by reacting compound [29] with compound [17] in the same manner as in Production Method 2-1, Step 28. 【0222】 (Step 26) Compound [31] can be obtained by removing P of compound in the same manner as in Production Method 2-1, Step 29. 【0223】 (Step 27) Compound [32] can be obtained by reacting compound [31] with compound [20] in the same manner as in Production Method 2-1, Step 210. 【0224】 (Step 28) Compound [32] can be indicated as compound [22].
Compound [I-a1] can be obtained by converting alkoxy of compound [22] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 13. 【0225】 In Production Method 2-1, compound [I-a2] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0226】 (C H ) n 2n 【0227】 wherein R , R and n are as defined in the aforementioned formula [I], can be obtained by subjecting compound [9] to the reactions of Step 24, Step 25 and Step 211. 【0228】 In Production Method 2-1, the amide bond forming reaction b1 b2 is performed by using compound [10] and HNR R such as dimethylamine, tert-butylamine and the like and in the same manner as in Step 210. Thereafter, the resultant product is subjected to the reactions of Step 24, Step 25 and Step 211, whereby compound [I-a3] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0229】 (C H ) n 2n 【0230】 1 4 b1 b2 wherein R , R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0231】 In Production Method 2-1, compound [I-a4] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0232】 (C H ) n 2n 【0233】 wherein R , R and n are as defined in the aforementioned formula [I] can be obtained by subjecting compound [15] to the reaction of Step 211. 【0234】 In Production Method 2-1, the reaction of Step 211 is performed by using compound [15]. Thereafter, the resultant product is reacted with a C alkyl-carboxylic anhydride such as acetic anhydride, propionic anhydride and the like, whereby compound [I-a5] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0235】 (C H ) n 2n C Alkyl 【0236】 wherein R , R and n are as defined in the aforementioned formula [I] and C Alkyl is as defined in the aforementioned Production Method 2-1, can be obtained. 【0237】 In Production Method 2-1, compound [15] is reacted with b3 b4 ClC(O)NR R such as dimethylcarbamoyl chloride, diethylcarbamoyl chloride and the like in the presence of a base. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I-a6] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0238】 (C H ) n 2n b3 b4 【0239】 1 4 b3 b4 wherein R , R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0240】 In Production Method 2-1, compound [15] is subjected to an alkylation reaction by using sodium hydride and a C1-6 alkyl halide. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I-a7] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0241】 (C H ) n 2n C Alkyl 【0242】 wherein R , R and n are as defined in the aforementioned formula [I] and C Alkyl is as defined in the aforementioned Production Method 2-1, can be obtained. 【0243】 In Production Method 2-1, compound [16] is subjected to b8 b9 an amination reaction by using HNR R such as dimethylamine, diethylamine and the like. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I-a8] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0244】 (C H ) n 2n 【0245】 1 4 b8 b9 wherein R , R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0246】 In Production Method 2-1, compound [16] is reacted by b14 b15 using sodium hydride, and HNR C(O)R such as N- methylacetamide, 2-pyrrolidinone and the like. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I-a9] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0247】 (C H ) n 2n 【0248】 1 4 b14 b15 wherein R , R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0249】 In Production Method 2-1, compound [16] is reacted by using sodium hydride and compound [33] represented by the formula 【0250】 m6 R 【0251】 wherein R , m5 and m6 are as defined in the aforementioned formula [I]. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I-a10] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0252】 (C H ) n 2n 【0253】 1 4 b17 wherein R , R , R , n, m5 and m6 are as defined in the aforementioned formula [I], can be obtained. 【0254】 In Production Method 2-1, compound [19] is reacted with b6 b7 ClC(O)NR R such as dimethylcarbamoyl chloride, diethylcarbamoyl chloride and the like in the presence of a base. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I-a11] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0255】 (C H ) n 2n 【0256】 1 4 b6 b7 wherein R , R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0257】 In Production Method 2-1, compound [19] is reacted with R S(O)2Cl such as methanesulfonyl chloride and the like in the presence of a base. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I- a12] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0258】 (C H ) n 2n 【0259】 1 4 b11 wherein R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0260】 In Production Method 2-1, compound [19] is reacted with R OC(O)Cl such as ethyl chloroformate and the like in the presence of a base. Thereafter, the resultant product is subjected to the reaction of Step 211, whereby compound [I- a13] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0261】 (C H ) n 2n HN O 【0262】 1 4 b13 wherein R , R , R and n are as defined in the aforementioned formula [I], can be obtained. 【0263】 In Production Method 2-3, compound [I-a14] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0264】 (C H ) j 2j (C H ) O k 2k 【0265】 wherein R and R are as defined in the aforementioned formula [I], j and k are as defined in the aforementioned Production Method 2-2, can be obtained by subjecting compound [27] to the reaction of Step 28. 【0266】 By Production Method 2-4, compound [I-a15] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0267】 (C H ) t 2t (R ) 【0268】 1 4 b16 wherein R , R , R , m2, m3 and m4 are as defined in the aforementioned Production Method 2-1, can be obtained. 【0269】 [Production Method 2-4] 【0270】 (R ) (R ) Step 21 alkylation ( ) 2 v m3 L OP C Alkyl m2 1-6 C Alkyl 1-6 v O OP Step 24 b16 (R ) (R ) compound [19] Step 23 Step 22 amidation hydrolysis deprotection ( ) ( ) C Alkyl ( ) O OH O OH Step 25 cyclization Y (C H ) Y (C H ) t 2t t 2t NH OH O (R ) (R ) 【0271】 1 4 b16 wherein R , R , R , m2, m3 and m4 are as defined in the aforementioned formula [I] and C Alkyl, L , P , t and Y are as defined in the above-mentioned Production Method 2-1. 【0272】 (Step 21) Compound [36] can be obtained by reacting compound [34] with compound [35] in a solvent in the presence of a base.
Examples of the base to be used for the reaction include, lithium diisopropylamide, lithium bis(trimethylsilyl)amide and the like base.
Examples of the solvent to be used for the reaction include ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like, and a mixed solvent thereof.
Compound [35] may be a commercially available product such as benzyl chloromethyl ether, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0273】 (Step 22) Compound [37] can be obtained by removing P of compound in the same manner as in Production Method 2-1, Step 26. 【0274】 (Step 23) Compound [38] can be obtained by converting the ester of compound [37] to carboxy by hydrolysis in the same manner as in Production Method 2-1, Step 21. 【0275】 (Step 24) Compound [39] can be obtained by reacting compound [38] with compound [19] in a solvent in the presence of a condensing agent and an additive in the same manner as in Production Method 2-1, Step 210. 【0276】 (Step 25) Compound [40] can be obtained by cyclization of compound by intramolecular Mitsunobu reaction. For example, compound [40] can be obtained by reacting compound [39] with an azodicarboxylic acid diester (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate etc.) in a solvent in the presence of a phosphine such as triphenylphosphine, tributylphosphine and the like.
Examples of the solvent to be used for the reaction include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, N,N-dimethylformamide and the like. These may be used singly or as a mixture of two or more kinds thereof. 【0277】 [Production Method 3-1] Another method of appropriately converting the substituent of ring Cy is, for example, Production Method 3-1 for obtaining compound [I-b1] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0278】 【0279】 1 4 c wherein R , R and R are as defined in the aforementioned formula [I].
[Production Method 3-1] 【0280】 Step 31 Step 32 Step 33 R protection boration Suzuki coupling id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43" id="p-43"
[43] (R ) (R ) R Step 35 4 Mitsunobu Step 34 R X N X N reaction deprotection R OH N N OP N N OH OR OR (R ) (R ) Step 36 X N X N deprotection N N O N N O OR OH [I-b1] 【0281】 1 4 5 c wherein R , R , R , R , m1 and X are as defined in the aforementioned formula [I], Z is as defined in the above- mentioned Production Method 1-1, and Hal and P are as defined in the above-mentioned Production Method 2-1. 【0282】 (Step 31) Compound [42] can be obtained by protecting the hydroxy group of compound [41] in the same manner as in Production Method 2-1, Step 23.
Compound [41] may be a commercially available product such as 2-bromomethylphenol, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0283】 (Step 32) Compound [43] can be obtained by borating compound [42] in the same manner as in Production Method 1-3, Step 1-3. 【0284】 (Step 33) Compound [44] can be obtained by the Suzuki coupling reaction of compound [3] and compound [43] in the same manner as in Production Method 1-1, Step 12. 【0285】 (Step 34) Compound [45] can be obtained by removing P of compound in the same manner as in Production Method 2-1, Step 26. 【0286】 (Step 35) Compound [47] can be obtained by the Mitsunobu reaction of compound [45] and compound [46]. For example, compound [47] can be obtained by reacting compound [45] with compound [46] in a solvent in the presence of an azodicarboxylic acid diester (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate etc.) and a phosphine such as triphenylphosphine, tributylphosphine and the like.
Examples of the solvent to be used for the reaction include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, N,N-dimethylformamide and the like. These may be used singly or as a mixture of two or more kinds thereof.
Compound [46] may be a commercially available product such as benzyl alcohol, 2-pyridinemethanol and the like, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0287】 (Step 36) Compound [I-b1] can be obtained by converting the alkoxy of compound [47] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 13. 【0288】 In Production Method 3-1, for example, compound [I-b2] which is a compound represented by the formula [I] wherein ring Cy is the formula 【0289】 【0290】 wherein R and R are as defined in the aforementioned formula [I], can be obtained by subjecting compound [45] to the reaction of Step 36. 【0291】 [Production Method 3-2] Compound [43a] which is compound [43] wherein R is chloro or trifluoromethyl can also be obtained by [Production Method 3-2]. 【0292】 [Production Method 3-2] 【0293】 Step 32 Step 31 lithiation/ R 4 4 4 protection boration OP OP id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49" id="p-49"
[49] [43a] 【0294】 wherein R is chloro or trifluoromethyl; R is as defined in the aforementioned formula [I], Z is as defined in the aforementioned Production Method 1-1, and P is as defined in the aforementioned Production Method 2-1. 【0295】 (Step 31) Compound [49] can be obtained by protecting the hydroxy group of compound [48] in the same manner as in Production Method 2-1, Step 23.
In one embodiment, compound [48] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0296】 F C F C F C F C F C Cl Cl 3 3 3 3 3 Cl OMe OH OH OH OH OH OH 【0297】 (Step 32) Compound [43a] can be obtained by reacting compound [49] with a boron compound in a solvent in the presence of a base.
For example, compound [43a] can be obtained by adding a base to compound [49] in a solvent at -78 C to room temperature, and reacting the resultant product with a boron reagent at -78 C to room temperature.
Examples of the base to be used for the reaction include n-butyllithium, sec-butyllithium and the like.
Examples of the boron reagent to be used for the reaction include 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, trimethyl borate and the like.
Examples of the solvent to be used for the reaction include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like. 【0298】 [Production Method 4] For example, compound [I-c1] of the formula 【0299】 (R ) 【0300】 wherein R , R , X and Cy are as defined in the aforementioned formula [I], m7 is 0, 1 or 2, and when m7 is 2, each R is selected independently, can be obtained by appropriately converting the substituent of compound [2].
[Production Method 4] 【0301】 P O (R ) P O (R ) Step 4-1 Step 4-2 X N Hal Suzuki coupling Suzuki coupling x (R ) HO (R ) m 7 Step 4-4 Cy introduction of Cy Step 4-3 leaving group deprotection OR [52] L (R ) (R ) Step 4-5 m7 Step 4-6 Sonogashira X N deprotection reaction OR [54] (R ) [I-c1] 【0302】 wherein L is a leaving group such as trifluoromethanesulfonyloxy and the like; P is a hydroxy-protecting group such as benzyl and the like; 6 e R , R , R , X and Cy are as defined in the aforementioned formula [I], Hal and Z are as defined in the aforementioned Production Method 1-1, and m7 is as defined in the aforementioned formula [I-A]. 【0303】 (Step 4-1) Compound [51] can be obtained by the Suzuki coupling reaction of compound [1] and compound [50] in the same manner as in Production Method 1-1, Step 11.
Compound [50] may be a commercially available product such as 4-(benzyloxy)phenylboronic acid, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art. 【0304】 (Step 4-2) Compound [52] can be obtained by the Suzuki coupling reaction of compound [4] and compound [51] in the same manner as in Production Method 1-1, Step 12. 【0305】 (Step 4-3) Compound [53] can be obtained by removing the phenol protecting group P of compound [52]. The deprotection can be performed by a known method according to the protecting group to be employed.
For example, when P is benzyl, compound [52] only needs to be subjected to a hydrogenation reaction in a single or mixed solvent of tetrahydrofuran, ethyl acetate, ethanol, methanol, water and the like in the presence of a catalyst such as palladium carbon, platinum carbon and the like. 【0306】 (Step 4-4) Compound [54] can be obtained by converting the hydroxy to a leaving group L . For example, when the leaving group is trifluoromethanesulfonyloxy, compound [54] can be obtained by reacting compound [53] with trifluoromethanesulfonic anhydride, N-phenyl bis(trifluoromethanesulfonimide) and the like in a solvent in the presence of a base from ice-cooling to room temperature.
Examples of the base to be used for the reaction include organic bases such as pyridine, 2,6-lutidine, triethylamine and the like; inorganic bases such as alkali metal salts (e.g., cesium carbonate, sodium hydride etc.) and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine and the like, and the like.
These may be used singly or as a mixture of two or more kinds thereof. 【0307】 (Step 4-5) Compound [56] can be obtained by the Sonogashira reaction of compound [54] and compound [55]. For example, compound [56] can be obtained by reacting compound [54] with compound [55] in a solvent preferably under heating in the presence of a base, a palladium catalyst and a copper catalyst.
Examples of the palladium catalyst to be used for the reaction include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like.
Examples of the copper catalyst to be used for the reaction include copper iodide, copper bromide and the like.
Examples of the base to be used for the reaction include diethylamine, dicyclohexylamine, triethylamine, N- ethyldiisopropylamine and the like.
Examples of the solvent to be used for the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; and polar solvents such as N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine and the like. These may be used singly or as a mixture of two or more kinds thereof.
Compound [55] may be a commercially available product such as cyclohexylacetylene, 2-ethynylpyridine and the like, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
As for the Sonogashira coupling reaction, for example, the following review article is known (NAJERA, C et al. The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry. Chem Rev. 2007, Vol.107, pages 874-922.). 【0308】 (Step 4-6) Compound [I-c1] can be obtained by converting the alkoxy of compound [56] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 13. 【0309】 In Production Method 4, compound [I-c2] of the formula 【0310】 (R ) 【0311】 wherein R , X and Cy are as defined in the aforementioned formula [I], and m7 is as defined in the aforementioned formula [I-A], can be obtained by subjecting compound [53] to the reaction of Step 4-6. 【0312】 In Production Method 4, compound [I-c3] of the formula 【0313】 (R ) 【0314】 wherein R , R , X and Cy are as defined in the aforementioned formula [I], and m7 is as defined in the aforementioned formula [I-A], can be obtained by the Mitsunobu reaction of compound and R OH such as cyclohexylmethanol and the like in the same manner as in Production Method 3-1, Step 35, and subjecting the resultant product to the reaction of Step 4-6. 【0315】 In Production Method 4, the Suzuki coupling reaction of compound [54] and compound [57] of the formula 【0316】 【0317】 wherein Z is as defined in the aforementioned Production Method 1-1, is performed in the same manner as in Production Method 1- 1, Step 12. The resultant product is subjected to the reaction of Step 4-6, whereby compound [I-c4] of the formula 【0318】 (R ) 【0319】 wherein R , X and Cy are as defined in the aforementioned formula [I] and m7 is as defined in the aforementioned formula [I-A], can be obtained. 【0320】 In Production Method 4, the Suzuki coupling reaction of compound [54] and compound [58] of the formula 【0321】 【0322】 wherein m9 is 1, 2, 3, or 4, and Z is as defined in the aforementioned Production Method 1-1, is performed in the same manner as in Production Method 1-1, Step 12. After reduction of the olefin of the resultant product, the obtained product is subjected to the reaction of Step 4-6, whereby compound [I-c5] of the formula 【0323】 (R ) 【0324】 wherein m9 is as defined above, m7 is as defined in the aforementioned formula [I-A], and R , X and Cy are as defined in the aforementioned formula [I], can be obtained. For reduction reaction of the olefin, for example, a hydrogenation reaction only needs to be performed in a single or mixed solvent of tetrahydrofuran, ethyl acetate, ethanol, methanol, water and the like in the presence of a catalyst such as palladium carbon or platinum carbon and the like.
Examples 【0325】 The present invention is explained in more detail in the following by referring to Examples and Experimental Examples, which are not to be construed as limitative.
The abbreviations in the Examples are as follows.
WSC･HCl: 1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt･H O: 1-hydroxy-1H-benzotriazole monohydrate DMSO: dimethyl sulfoxide M: mol/L 【0326】 [Production Example 1] Synthesis of N-(4-chloro{4-[4-(2,2-dimethylpropoxy)phenyl]- 6-hydroxy-1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-86) 【0327】 O Cl 【0328】 (1) 2-chloro[4-(2,2-dimethylpropoxy)phenyl]methoxy-1,3,5- triazine 【0329】 Cl N Cl N Cl 【0330】 Under an argon atmosphere, a suspension of 4-(2,2- dimethylpropoxy)phenylboronic acid (2.0 g, 9.6 mmol), 2,4- dichloromethoxy-1,3,5-triazine (3.5 g, 19 mmol), [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (1.1 g, 0.96 mmol) and 2M aqueous sodium carbonate solution (14 ml, 29 mmol) in toluene (20 ml) was stirred at 100 C for 3.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=19/1 - 4/1) to give the title compound (2.3 g, yield 77%).
H-NMR (400MHz, CDCl ) δ: 1.06 (9H, s), 3.68 (2H, s), 4.14 (3H, s), 6.94-7.02 (2H, m), 8.42-8.46 (2H, m). 【0331】 (2) (4-chloro{4-[4-(2,2-dimethylpropoxy)phenyl]methoxy- 1,3,5-triazinyl}phenyl)methanol 【0332】 O O Cl N Cl N + OH N N N N 【0333】 Under an argon atmosphere, a suspension of 2-chloro[4- (2,2-dimethylpropoxy)phenyl]methoxy-1,3,5-triazine (2.3 g, 7.4 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (1.7 g, 8.9 mmol), [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.61 g, 0.74 mmol) and 2M aqueous sodium carbonate solution (15 ml, 30 mmol) in 1,4-dioxane (23 ml) was stirred at 100 C for 1.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 - 1/1) to give the title compound (1.3 g, yield 43%).
H-NMR (400MHz, CDCl ) δ: 1.06 (9H, s), 1.75 (1H, t, J = 5.9 Hz), 3.69 (2H, s), 4.19 (3H, s), 4.77 (2H, d, J = 5.9 Hz), 6.98-7.03 (2H, m), 7.46 (1H, dd, J = 8.2, 2.2 Hz), 7.53 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.52-8.58 (2H, m). 【0334】 (3) tert-butyl N-(4-chloro{4-[4-(2,2- dimethylpropoxy)phenyl]methoxy-1,3,5-triazinyl}benzyl)-N- (tert-butoxycarbonyl)carbamate 【0335】 O Cl O Cl O N N O 【0336】 Under an argon atmosphere, to a solution of (4-chloro {4-[4-(2,2-dimethylpropoxy)phenyl]methoxy-1,3,5-triazin yl}phenyl)methanol (1.3 g, 3.2 mmol) obtained in the above- mentioned (2) and triethylamine (0.58 ml, 4.2 mmol) in tetrahydrofuran (13 ml) was added methanesulfonyl chloride (0.29 ml, 3.8 mmol) under ice-cooling, and the mixture was warmed to room temperature. After stirring for 0.5 hr, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (13 ml) were added cesium carbonate (3.1 g, 9.5 mmol) and di-tert-butyl iminodicarboxylate (0.83 g, 3.8 mmol), and the mixture was stirred for 3 hr. To the reaction mixture were added water and ethyl acetate and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 -7/3) to give the title compound (1.6 g, yield 82%).
H-NMR (400MHz, CDCl ) δ: 1.06 (9H, s), 1.48 (18H, s), 3.69 (2H, s), 4.18 (3H, s), 4.83 (2H, s), 6.96-7.01 (2H, m), 7.39 (1H, dd, J = 8.2, 2.2 Hz), 7.48 (1H, d, J = 8.2 Hz), 7.98 (1H, d, J = 2.2 Hz), 8.51-8.57 (2H, m). 【0337】 (4) 4-chloro{4-[4-(2,2-dimethylpropoxy)phenyl]methoxy- 1,3,5-triazinyl}benzylamine hydrochloride 【0338】 O Cl O Cl O N NH ・HCl 【0339】 Under an argon atmosphere, to a solution of tert-butyl N- (4-chloro{4-[4-(2,2-dimethylpropoxy)phenyl]methoxy-1,3,5- triazinyl}benzyl)-N-(tert-butoxycarbonyl)carbamate (1.3 g, 2.2 mmol) obtained in the above-mentioned (3) in 1,4-dioxane (2.8 ml) was added 4M hydrogen chloride/1,4-dioxane solution (11 ml) at room temperature, and the mixture was stirred for 3 hr. The solid was collected by filtration from the suspension, and dried under reduced pressure to give the title compound (0.97 g, yield 99%).
H-NMR (400MHz, DMSO-d6) δ: 1.03 (9H, s), 3.76 (2H, s), 4.10- 4.18 (2H, m), 4.14 (3H, s), 7.11-7.17 (2H, m), 7.72 (2H, d, J = 0.9 Hz), 8.13 (1H, br s), 8.40-8.58 (5H, m). 【0340】 (5) N-(4-chloro{4-[4-(2,2-dimethylpropoxy)phenyl]methoxy- 1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide 【0341】 O Cl O Cl NH N ・HCl N N N N 【0342】 Under an argon atmosphere, to a solution of 4-chloro {4-[4-(2,2-dimethylpropoxy)phenyl]methoxy-1,3,5-triazin yl}benzylamine hydrochloride (0.97 g, 2.2 mmol) obtained in the above-mentioned (4) and 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.41 g, 2.6 mmol) in N,N-dimethylformamide (10 ml) were added HOBt･H O (0.43 g, 2.8 mmol), WSC･HCl (2.8 g, 2.8 mmol) and triethylamine (0.91 ml, 6.5 mmol) at room temperature, and the mixture was stirred for 3.5 hr. 3,3,3-Trifluoro-2,2- dimethylpropionic acid (0.067 g, 0.43 mmol), HOBt･H O (0.066 g, 0.43 mmol) and WSC･HCl (0.082 g, 0.43 mmol) were added, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate and the mixture was partitioned.
The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 - 7/3) to give the title compound (0.97 g, yield 81%).
H-NMR (400MHz, CDCl ) δ: 1.07 (9H, s), 1.44 (6H, s), 3.69 (2H, s), 4.19 (3H, s), 4.55 (2H, d, J = 5.8 Hz), 6.22 (1H, br s), 6.96-7.03 (2H, m), 7.34 (1H, dd, J = 8.3, 2.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 2.3 Hz), 8.50-8.57 (2H, m). 【0343】 (6) N-(4-chloro{4-[4-(2,2-dimethylpropoxy)phenyl]hydroxy- 1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-86) 【0344】 O Cl O Cl 【0345】 Under an argon atmosphere, to a solution of N-(4-chloro- 3-{4-[4-(2,2-dimethylpropoxy)phenyl]methoxy-1,3,5-triazin yl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide (0.97 g, 1.76 mmol) obtained in the above-mentioned (5) in methanol (10 ml) was added 4M aqueous sodium hydroxide solution (3.5 ml, 14 mmol) at room temperature, and the mixture was stirred at 65 C for 1.5 hr. To the reaction mixture were added 2M hydrochloric acid (7.0 ml, 14 mmol) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.87 g, yield 92%).
H-NMR (400MHz, DMSO-d ) δ: 1.02 (9H, s), 1.37 (6H, s), 3.73 (2H, s), 4.35 (2H, d, J = 5.8 Hz), 7.08 (2H, d, J = 9.1 Hz), 7.40 (1H, dd, J = 8.3, 2.2 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.62 (1H, d, J = 1.9 Hz), 8.29 (2H, d, J = 9.1 Hz), 8.62 (1H, t, J = 5.8 Hz), 13.13 (1H, s). 【0346】 [Production Example 2] Synthesis of 1-[4-chloro(4-hydroxyphenyl-1,3,5-triazin yl)-benzyl]-3,3-dimethyl-1,3-dihydroindolone (Example No.1- 258) 【0347】 【0348】 (1) 2-(5-bromomethylchlorophenyl)methoxyphenyl-1,3,5- triazine 【0349】 Cl Cl OH Br N N N N 【0350】 By a method similar to that in Production Example 1 (1) and (2), and using 2,4-dichloromethoxy-1,3,5-triazine, 2- chlorohydroxymethylphenylboronic acid, and phenylboronic acid instead of 4-(2,2-dimethylpropoxy)phenylboronic acid, [4- chloro(4-methoxyphenyl-1,3,5-triazinyl)phenyl]methanol was obtained.
Under an argon atmosphere, to a solution of the obtained [4-chloro(4-methoxyphenyl-1,3,5-triazin yl)phenyl]methanol (0.47 g, 1.4 mmol) and triphenylphosphine (0.56 g, 2.1 mmol) in chloroform (4.5 ml) was added carbon tetrabromide (0.71 g, 2.1 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 10 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=30/1 - 9/1) to give the title compound (0.49 g, yield 87%).
H-NMR (400MHz, CDCl ) δ: 4.22 (3H, s), 4.53 (2H, s), 7.45-7.64 (5H, m), 8.06 (1H, br s), 8.57-8.63 (2H, m). 【0351】 (2) 1-[4-chloro(4-methoxyphenyl-1,3,5-triazin yl)benzyl]-3,3-dimethyl-1,3-dihydroindolone 【0352】 N N HN 【0353】 Under an argon atmosphere, to a solution of 3,3- dimethylindolinone (0.050 g, 0.31 mmol) in N,N- dimethylformamide (1.0 ml) was added sodium hydride (0.012 g, 60 wt% oil dispersion) under ice-cooling. After stirring for min, 2-(5-bromomethylchlorophenyl)methoxyphenyl- 1,3,5-triazine (0.10 g, 0.26 mmol) obtained in the above- mentioned (1) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/2) to give the title compound (0.11 g, yield 89%).
H-NMR (400MHz, CDCl ) δ: 1.44 (6H, s), 4.18 (3H, s), 4.98 (2H, s), 6.72-6.76 (1H, m), 7.02-7.08 (1H, m), 7.13-7.19 (1H, m), 7.21-7.25 (1H, m), 7.31-7.36 (1H, m), 7.46-7.53 (3H, m), 7.55- 7.61 (1H, m), 8.00 (1H, br s), 8.51-8.58 (2H, m). 【0354】 (3) 1-[4-chloro(4-hydroxyphenyl-1,3,5-triazin yl)benzyl]-3,3-dimethyl-1,3-dihydroindolone (Example No.1- 258) 【0355】 N N O 【0356】 Under an argon atmosphere, to a solution of 1-[4-chloro- 3-(4-methoxyphenyl-1,3,5-triazinyl)benzyl]-3,3-dimethyl- 1,3-dihydroindolone (0.11 g, 0.23 mmol) obtained in the above-mentioned (2) in methanol (10 ml) was added 4M aqueous sodium hydroxide solution (0.34 ml, 1.4 mmol) at room temperature, and the mixture was stirred at 65 C for 2 hr. To the reaction mixture were added 10 wt% aqueous citric acid solution (1.4 ml) and water (7.0 ml) at room temperature, and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.10 g, yield 96%).
H-NMR (400MHz, DMSO-d ) δ: 1.34 (6H, s), 4.99 (2H, s), 6.97 (1H, d, J = 7.6 Hz), 7.05 (1H, t, J = 7.6 Hz), 7.20 (1H, t, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.48 (1H, dd, J = 8.3, 1.8 Hz), 7.55 (2H, t, J = 7.6 Hz), 7.59-7.68 (2H, m), 7.75 (1H, d, J = 1.8 Hz), 8.29 (2H, d, J = 7.6 Hz), 13.32 (1H, br s). 【0357】 [Production Example 3] Synthesis of N-[4-chloro(4-hydroxyphenyl-1,3,5-triazin yl)benzyl]-N-ethyl-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-263) 【0358】 N N O F 【0359】 (1) [4-chloro(4-methoxyphenyl-1,3,5-triazin yl)benzyl]ethylamine 【0360】 Cl Cl N Br N NH N N N N 【0361】 Under an argon atmosphere, to 2-(5-bromomethyl chlorophenyl)methoxyphenyl-1,3,5-triazine (0.20 g, 0.51 mmol) obtained in the same manner as in Production Example 2 (1) was added a solution of 2M ethylamine tetrahydrofuran (2.5 ml) at room temperature, and the mixture was stirred for 1 hr.
To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure to give the title compound (0.28 g) as a crude product.
H-NMR (400MHz, CDCl ) δ: 1.14 (3H, t, J = 7.2 Hz), 2.70 (2H, q, J = 7.2 Hz), 3.86 (2H, s), 4.22 (3H, s), 7.44 (1H, dd, J = 8.2, 2.2 Hz), 7.48-7.55 (3H, m), 7.57-7.62 (1H, m), 7.97 (1H, d, J = 2.2 Hz), 8.58-8.64 (2H, m). 【0362】 (2) N-[4-chloro(4-methoxyphenyl-1,3,5-triazin yl)benzyl]-N-ethyl-3,3,3-trifluoro-2,2-dimethylpropionamide 【0363】 Cl Cl NH N N N F N N F N N F 【0364】 Under an argon atmosphere, to a solution of [4-chloro (4-methoxyphenyl-1,3,5-triazinyl)benzyl]ethylamine (0.18 g, 0.38 mmol) obtained in the above-mentioned (1) and 3,3,3- trifluoro-2,2-dimethylpropionic acid (0.12 g, 0.76 mmol) in chloroform (2.0 ml) were added WSC･HCl (0.15 g, 0.76 mmol) and 4-dimethylaminopyridine (0.93 mg, 0.76 mmol) at room temperature, and the mixture was stirred for 16 hr. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/3) to give the title compound (0.086 g, yield 46%).
H-NMR (400MHz, CDCl ) δ: 1.20 (3H, t, J = 6.9 Hz), 1.55 (6H, s), 3.47 (2H, q, J = 6.9 Hz), 4.21 (3H, s), 4.71 (2H, s), 7.24-7.30 (1H, m), 7.45-7.63 (4H, m), 7.88 (1H,br s), 8.56-8.64 (2H, m). 【0365】 (3) N-[4-chloro(4-hydroxyphenyl-1,3,5-triazin yl)benzyl]-N-ethyl-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-263) 【0366】 N N F N N O F 【0367】 Under an argon atmosphere, to a solution of N-[4-chloro- 3-(4-methoxyphenyl-1,3,5-triazinyl)benzyl]-N-ethyl-3,3,3- trifluoro-2,2-dimethylpropionamide (0.086 g, 0.17 mmol) obtained in the above-mentioned (2) in methanol (1.5 ml) was added 4M aqueous sodium hydroxide solution (0.26 ml, 1.0 mmol) at room temperature, and the mixture was stirred at 65 C for 2 hr. At room temperature, 10 wt% aqueous citric acid solution (1.2 ml) and water (6 ml) were added, and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product. To a suspension of the crude product in ethyl acetate (1.5 ml) was added n-hexane (1.5 ml), and the mixture was stirred for 30 min. The solid was collected by filtration, dried under reduced pressure to give the title compound (0.067 g, yield 80%).
H-NMR (400MHz, DMSO-d ) δ:1.13 (3H, t, J = 6.9 Hz), 1.50 (6H, s), 3.42 (2H, br s), 4.66 (2H, s), 7.41 (1H, dd, J = 8.3, 1.8 Hz), 7.56 (2H, t, J = 7.9 Hz), 7.61-7.69 (3H, m), 8.34 (2H, d, J = 7.9 Hz), 13.33 (1H, br s). 【0368】 [Production Example 4] Synthesis of 7-tert-butyl[4-chloro(4-hydroxyphenyl- 1,3,5-triazinyl)benzyl]azaspiro[3.5]nonanone (Example No.1-266) 【0369】 【0370】 (1) methyl 1-benzyloxymethyltert-butyl- cyclohexanecarboxylate 【0371】 O O O 【0372】 Under an argon atmosphere, to a solution of methyl 4- tert-butyl-cyclohexanecarboxylate (0.46 g, 2.3 mmol) in tetrahydrofuran (2.5 ml) was added dropwise 2M heptane/tetrahydrofuran/ethylbenzene solution (1.4 ml, 2.8 mmol) of lithium diisopropylamide at -78 C over 5 min. After stirring for 1 hr, benzyl chloromethyl ether (0.38 ml, 2.8 mmol) was added dropwise over 1 min. Under ice-cooling, the mixture was stirred for 1 hr. To the reaction mixture were added 10 wt% aqueous citric acid solution (3.0 ml) and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=30/1) to give the title compound (0.49 g, yield 66%). While the title compound was obtained as a single stereoisomer, the relative configuration thereof is undetermined. Specifically, whether the methoxycarbonyl group is cis/trans relative to the tert- butyl group is undetermined.
H-NMR (400MHz, CDCl ) δ: 0.81 (9H, s), 0.88-0.99 (1H, m), 1.00-1.21 (4H, m), 1.68 (2H, d, J = 12.0 Hz), 2.29 (2H, d, J = 12.0 Hz), 3.36 (2H, s), 3.69 (3H, s), 4.48 (2H, br s), 7.22- 7.38 (5H, m). 【0373】 (2) methyl 4-tert-butylhydroxymethyl-cyclohexanecarboxylate 【0374】 O O O OH 【0375】 Under an argon atmosphere, to a solution of methyl 1- benzyloxymethyltert-butyl-cyclohexanecarboxylate (0.49 g, 1.5 mmol) obtained in the above-mentioned (1) in methanol (5.5 ml) was added ASCA-2 (4.5% palladium of activated carbon support-0.5% platinum catalyst (see N.E. CHEMCAT, Fine chemical October 1, 2002, pages 5-14), 0.20 g) at room temperature.
Under 1 atm hydrogen, the mixture was stirred for 4 hr. Under an argon atmosphere, the reaction mixture was filtered through celite, and the filtrate was eluted with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (0.27 g, yield 75%). While the title compound is a single stereoisomer, the relative configuration thereof is undetermined.
H-NMR (400MHz, CDCl ) δ: 0.83 (9H, s), 0.91-1.17 (5H, m), 1.64-1.78 (3H, m), 2.20-2.31 (2H, m), 3.53 (2H, d, J = 6.0 Hz), 3.73 (3H, s). 【0376】 (3) 4-tert-butylhydroxymethyl-cyclohexanecarboxylic acid 【0377】 O OH HO OH 【0378】 Under an argon atmosphere, to a solution of methyl 4- tert-butylhydroxymethyl-cyclohexanecarboxylate (0.27 g, 1.2 mmol) obtained in the above-mentioned (2) in methanol (1.7 ml) were added tetrahydrofuran (1.7 ml) and 4M aqueous sodium hydroxide solution (1.7 ml, 7.0 mmol) at room temperature, and the mixture was stirred at 65 C for 1.5 hr. Methanol (1.7 ml), tetrahydrofuran (1.7 ml) and 4M aqueous sodium hydroxide solution (1.7 ml, 7.0 mmol) were added, and the mixture was stirred at 65 C for 2 hr. To the reaction mixture were added 2M hydrochloric acid (7.5 ml, 15 mmol) and water at room temperature, and the mixture was stirred. Ethyl acetate was added and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=12/1) to give the title compound (0.24 g, yield 94%). While the title compound is a single stereoisomer, the relative configuration thereof is undetermined.
H-NMR (400MHz, DMSO-d6) δ: 0.80 (9H, s), 0.86-1.12 (5H, m), 1.53-1.66 (2H, m), 2.00-2.13 (2H, m), 3.31 (2H, s). 【0379】 (4) 4-tert-butylhydroxymethyl-cyclohexanecarboxylic acid 4- chloro(4-methoxyphenyl-1,3,5-triazinyl)benzylamide 【0380】 HO OH N N ・HCl 【0381】 By a method similar to that in Production Example 1 (1) - (4), and using 2,4-dichloromethoxy-1,3,5-triazine, 2-chloro- -hydroxymethylphenylboronic acid, and phenylboronic acid instead of 4-(2,2-dimethylpropoxy)phenylboronic acid, 4-chloro- 3-(4-methoxyphenyl-1,3,5-triazinyl)benzylamine hydrochloride was obtained.
Under an argon atmosphere, to a solution of the obtained 4-chloro(4-methoxyphenyl-1,3,5-triazinyl)benzylamine hydrochloride (0.90 g, 0.25 mmol) and 4-tert-butyl hydroxymethyl-cyclohexanecarboxylic acid (0.080 g, 0.37 mmol) obtained in the above-mentioned (3) in N,N-dimethylformamide (2.0 ml) were added HOBt･H O (0.057 g, 0.37 mmol), WSC･HCl (0.071 g, 0.37 mmol) and triethylamine (0.10 ml, 0.74 mmol) at room temperature, and the mixture was stirred for 13 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=1/2 - 1/3) to give the title compound (0.11 g, yield 81%). While the title compound is a single stereoisomer, the relative configuration thereof is undetermined.
H-NMR (400MHz, CDCl3) δ: 0.78 (9H, s), 0.94-1.22 (5H, m), 1.66-1.75 (2H, m), 2.22-2.30 (2H, m), 2.42 (1H, t, J = 5.0 Hz), 3.52 (2H, d, J = 5.0 Hz), 4.21 (3H, s), 4.57 (2H, d, J = 5.8 Hz), 6.46 (1H, t, J = 5.8 Hz), 7.38 (1H, dd, J = 8.3, 2.3 Hz), 7.47-7.55 (3H, m), 7.57-7.62 (1H, m), 7.97 (1H, d, J = 2.3 Hz), 8.57-8.62 (2H, m). 【0382】 (5) 7-tert-butyl[4-chloro(4-methoxyphenyl-1,3,5- triazinyl)benzyl]azaspiro[3.5]nonanone 【0383】 N OH 【0384】 Under an argon atmosphere, to a solution of 4-tert-butyl- 1-hydroxymethyl-cyclohexanecarboxylic acid 4-chloro(4- methoxyphenyl-1,3,5-triazinyl)benzylamide (0.11 g, 0.20 mmol) obtained in the above-mentioned (4) and triphenylphosphine (0.080 g, 0.30 mmol) in tetrahydrofuran (1.0 ml) was added bis(2-methoxyethyl) azodicarboxylate (0.071 g, 0.30 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.068 g, yield 66%). While the title compound is a single stereoisomer, the relative configuration of the tert-butyl group is undetermined.
H-NMR (400MHz, CDCl3) δ: 0.81-1.77 (7H, m), 0.87 (9H, s), 2.03-2.12 (2H, m), 2.87 (2H, br s), 4.21 (3H, s), 4.40 (2H, br s), 7.30-7.37 (1H, m), 7.48-7.64 (4H, m), 7.90 (1H, br s), 8.57-8.63 (2H, m). 【0385】 (6) 7-tert-butyl[4-chloro(4-hydroxyphenyl-1,3,5- triazinyl)benzyl]azaspiro[3.5]nonanone (Example No.1- 266) 【0386】 【0387】 Under an argon atmosphere, to a solution of 7-tert-butyl- 2-[4-chloro(4-methoxyphenyl-1,3,5-triazinyl)benzyl] azaspiro[3.5]nonanone (0.068 g, 0.13 mmol) obtained in the above-mentioned (5) in methanol (1.2 ml) was added 4M aqueous sodium hydroxide solution (0.20 ml, 0.81 mmol) at room temperature, and the mixture was stirred at 65 C for 1.5 hr.
At room temperature, to the reaction mixture were added 10 wt% aqueous citric acid solution (0.82 ml) and water (4.0 ml), and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.062 g, yield 94%). While the title compound is a single stereoisomer, the relative configuration of the tert-butyl group is undetermined.
H-NMR (400MHz, DMSO-d ) δ: 0.83 (9H, s), 0.90-0.99 (1H, m), 1.41-1.67 (6H, m), 1.96-2.03 (2H, m), 2.92 (2H, s), 4.38 (2H, s), 7.47 (1H, dd, J = 8.3, 1.8 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.63-7.69 (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 【0388】 [Production Example 5] Synthesis of 4-[2-(6-methylpyridinylmethoxy) trifluoromethylphenyl](4-phenylethynylphenyl)-1,3,5-triazin- 2-ol hydrochloride (Example No.2-98) 【0389】 N N O ・HCl 【0390】 (1) 2-bromomethoxymethoxytrifluoromethyl-benzene 【0391】 【0392】 Under an argon atmosphere, to a solution of 2-bromo fluorobenzotrifluoride (6.0 g, 25 mmol) and 2- (methylsulfonyl)ethanol (4.3 g, 35 mmol) in N,N- dimethylformamide (10 ml) was added sodium hydride (2.8 g, 60 wt% oil dispersion) in 3 portions under ice-cooling. After stirring at room temperature for 10 min, chloromethyl methyl ether (5.3 ml, 69 mmol) was added dropwise under ice-cooling.
After stirring for 30 min, the mixture was stirred at room temperature for 15 min. Under ice-cooling, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=12/1) to give the title compound (5.0 g, yield 70%).
H-NMR (400MHz, CDCl3) δ: 3.53 (3H, s), 5.29 (2H, s), 7.31-7.38 (3H, m). 【0393】 (2) 2-(2-methoxymethoxytrifluoromethylphenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 【0394】 【0395】 Under an argon atmosphere, to a solution of 2-bromo methoxymethoxytrifluoromethyl-benzene (4.9 g, 17 mmol) obtained in the above-mentioned (1) in tetrahydrofuran (90 ml) was added dropwise n-butyllithium (1.6M n-hexane solution, 11 ml, 17 mmol) at -78 C over 30 min. 2-Isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (3.5 ml, 17 mmol) was added dropwise over 15 min, and the mixture was warmed to room temperature and stirred for 2 hr. To the reaction mixture were added saturated ammonium chloride aqueous solution and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the title compound (2.8 g, yield 48%).
H-NMR (400MHz, CDCl ) δ: 1.39 (12H, s), 3.47 (3H, s), 5.18 (2H, s), 7.20 (1H, d, J = 8.4 Hz), 7.24-7.28 (1H, m), 7.36-7.42 (1H, 【0396】 (3) 2-(4-benzyloxyphenyl)methoxy(2-methoxymethoxy trifluoromethylphenyl)-1,3,5-triazine 【0397】 N Cl N N N N N 【0398】 By a method similar to that in Production Example 1 (1), and using 2,4-dichloromethoxy-1,3,5-triazine, and 4- (benzyloxy)phenylboronic acid instead of 4-(2,2- dimethylpropoxy)phenylboronic acid, 2-(4-benzyloxyphenyl) chloromethoxy-1,3,5-triazine was obtained.
Under an argon atmosphere, to a solution of the obtained 2-(4-benzyloxyphenyl)chloromethoxy-1,3,5-triazine (3.0 g, 9.2 mmol) and 2-(2-methoxymethoxytrifluoromethylphenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.8 g, 8.4 mmol) obtained in the above-mentioned (2) in N,N-dimethylformamide (25 ml) were added [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (1.4 g, 1.7 mmol), copper(I) iodide (0.48 g, 2.5 mmol) and 2M aqueous sodium carbonate solution (13 ml, 25 mmol), and the mixture was stirred at 115 C for 45 min.
To the reaction mixture were added water and ethyl acetate.
After stirring, the insoluble material was removed by celite filtration, and the filtrate was eluted with ethyl acetate.
The filtrate was partitioned, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/2) to give the title compound (2.0 g, yield 47%).
H-NMR (400MHz, DMSO-d ) δ: 3.39 (3H, s), 4.14 (3H, s), 5.13 (2H, s), 5.15 (2H, s), 7.02-7.08 (2H, m), 7.30-7.46 (7H, m), 7.48-7.55 (1H, m), 8.47-8.52 (2H, m). 【0399】 (4) 4-[4-methoxy(2-methoxymethoxytrifluoromethylphenyl)- 1,3,5-triazinyl]phenol 【0400】 N N O N N O 【0401】 Under an argon atmosphere, to a solution of 2-(4- benzyloxyphenyl)methoxy(2-methoxymethoxy trifluoromethylphenyl)-1,3,5-triazine (2.0 g, 4.0 mmol) obtained in the above-mentioned (3) in ethyl acetate (10 ml) were added methanol (10 ml) and 10 wt% palladium carbon (0.49 g) at room temperature. Under 1 atm hydrogen, the mixture was stirred for 2 hr. Under an argon atmosphere, the reaction mixture was filtered through celite, and the filtrate was eluted with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.6 g, yield 97%).
H-NMR(400MHz, CDCl )δ:3.39 (3H, s), 4.14 (4H, s), 5.13 (2H, s), .39 (1H, br s), 6.87-6.93 (2H, m), 7.40-7.45 (2H, m), 7.48- 7.55 (1H, m), 8.43-8.48 (2H, m). 【0402】 (5) trifluoromethanesulfonic acid 4-[4-methoxy(2- methoxymethoxytrifluoromethylphenyl)-1,3,5-triazin yl]phenyl ester 【0403】 F O F HO O N F N N N N N 【0404】 Under an argon atmosphere, to a solution of 4-[4-methoxy- 6-(2-methoxymethoxytrifluoromethylphenyl)-1,3,5-triazin yl]phenol (1.6 g, 3.9 mmol) obtained in the above-mentioned (4) in pyridine (15 ml) was added dropwise trifluoromethanesulfonic anhydride (13 ml, 7.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=3/1) to give the title compound (2.0 g, yield 95%).
H-NMR (400MHz, CDCl ) δ: 3.39 (3H, s), 4.17 (3H, s), 5.13 (2H, s), 7.37-7.48 (4H, m), 7.51-7.58 (1H, m), 8.61-8.67 (2H, m). 【0405】 (6) 2-methoxy(2-methoxymethoxytrifluoromethylphenyl) (4-phenylethynylphenyl)-1,3,5-triazine 【0406】 N N O N N O 【0407】 Under an argon atmosphere, to a solution of trifluoromethanesulfonic acid 4-[4-methoxy(2-methoxymethoxy- 6-trifluoromethylphenyl)-1,3,5-triazinyl]phenyl ester (0.50 g, 0.93 mmol) obtained in the above-mentioned (5), bis(triphenylphosphine)palladium(II)dichloride (0.098 g, 0.139 mmol) and copper(I) iodide (0.053 g, 0.28 mmol) in N,N- dimethylformamide (5.0 ml) were added triethylamine (0.39 ml, 2.8 mmol) and ethynylbenzene (0.51 ml, 4.6 mmol), and the mixture was stirred at 65 C for 2.5 hr. To the reaction mixture were added water and ethyl acetate. After stirring for 1 hr, the insoluble material was removed by celite filtration, and the filtrate was eluted with ethyl acetate. The filtrate was partitioned, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1 - 4/1) to give the title compound (0.45 g, yield 98%).
H-NMR (400MHz, DMSO-d ) δ: 3.40 (3H, s), 4.17 (3H, s), 5.14 (2H, s), 7.34-7.39 (3H, m), 7.42-7.47 (2H, m), 7.50-7.59 (3H, m), 7.62-7.67 (2H, m), 8.50-8.55 (2H, m). 【0408】 (7) 2-[4-methoxy(4-phenylethynylphenyl)-1,3,5-triazinyl]- 3-trifluoromethylphenol 【0409】 N N O N N OH O O O 【0410】 Under an argon atmosphere, to a solution of 2-methoxy (2-methoxymethoxytrifluoromethylphenyl)(4- phenylethynylphenyl)-1,3,5-triazine (0.45 g, 0.92 mmol) obtained in the above-mentioned (6) in methanol (4.5 ml) were added 1,4-dioxane (4.5 ml) and methanesulfonic acid (0.030 ml, 0.46 mmol) at room temperature. The mixture was stirred at 70 C for 5 hr, and triethylamine (0.13 ml, 0.92 mmol) was added to the reaction mixture at room temperature. To the reaction mixture was added water (45 ml), and the mixture was stirred for 30 min. The precipitated solid was collected by filtration and dried to give the title compound (0.38 g, yield 93%).
H-NMR (400MHz, CDCl ) δ: 4.23 (3H, s), 7.25-7.30 (1H, m), 7.36-7.40 (3H, m), 7.43-7.47 (1H, m), 7.50-7.60 (3H, m), 7.67- 7.72 (2H, m), 8.48-8.52 (2H, m), 12.43 (1H, br s) 【0411】 (8) 2-methoxy[2-(6-methylpyridinylmethoxy) trifluoromethylphenyl](4-phenylethynylphenyl)-1,3,5-triazine 【0412】 OH O N N N N 【0413】 Under an argon atmosphere, to a solution of 2-[4-methoxy- 6-(4-phenylethynylphenyl)-1,3,5-triazinyl] trifluoromethylphenol (0.24 g, 0.54 mmol) obtained in the above-mentioned (7), 6-methylpyridinemethanol (0.099 g, 0.80 mmol) and triphenylphosphine (0.21 g, 0.80 mmol) in tetrahydrofuran (6.0 ml) was added bis(2-methoxyethyl) azodicarboxylate (0.19 g, 0.80 mmol) in 3 portions under ice- cooling. The reaction mixture was stirred for 20 min and at room temperature for 20 hr. Thereafter, to the reaction mixture were added 6-methylpyridinemethanol (0.099 g, 0.80 mmol) and triphenylphosphine (0.21 g, 0.80 mmol), and bis(2- methoxyethyl) azodicarboxylate (0.19 g, 0.80 mmol) in 2 portions under ice-cooling. After stirring for 20 min, the reaction mixture was stirred for 10 min at room temperature.
To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/3) to give the title compound (0.28 g, yield 95%).
H-NMR (400MHz, CDCl ) δ: 2.51 (3H, s), 4.17 (3H, s), 5.21 (2H, s), 6.96-7.01 (1H, m), 7.02-7.07 (1H, m), 7.20-7.25 (1H, m), 7.33-7.42 (5H, m), 7.47-7.59 (3H, m), 7.62-7.68 (2H, m), 8.52- 8.57 (2H, m). 【0414】 (9) 4-[2-(6-methylpyridinylmethoxy) trifluoromethylphenyl](4-phenylethynylphenyl)-1,3,5-triazin- 2-ol 【0415】 N N O N N O 【0416】 Under an argon atmosphere, to a suspension of 2-methoxy- 4-[2-(6-methylpyridinylmethoxy)trifluoromethylphenyl] (4-phenylethynylphenyl)-1,3,5-triazine (0.28 g, 0.52 mmol) obtained in the above-mentioned (8) in methanol (4.6 ml) were added 4M aqueous sodium hydroxide solution (0.77 ml, 3.1 mmol) and tetrahydrofuran (0.46 ml) at room temperature. At 65 C, the reaction mixture was stirred for 3.5 hr. To the reaction mixture were added 10 wt% aqueous citric acid solution (3.2 ml) and water (16 ml) at room temperature, and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.27 g, yield 95%).
H-NMR (400MHz, DMSO-d ) δ: 2.43 (3H, s), 5.31 (2H, s), 7.07- 7.17 (2H, m), 7.43-7.49 (3H, m), 7.50-7.68 (5H, m), 7.69-7.82 (3H, m), 8.32-8.38 (2H, m), 13.63 (1H, br s). 【0417】 (10) 4-[2-(6-methylpyridinylmethoxy) trifluoromethylphenyl](4-phenylethynylphenyl)-1,3,5-triazin- 2-ol hydrochloride (Example No.2-98) 【0418】 N N O N N O OH OH ・HCl 【0419】 Under an argon atmosphere, to a solution of 4-[2-(6- methylpyridinylmethoxy)trifluoromethylphenyl](4- phenylethynylphenyl)-1,3,5-triazinol (0.27 g, 0.49 mmol) obtained in the above-mentioned (9) in 1,4-dioxane (5.3 ml) was added 4M hydrogen chloride/1,4-dioxane solution (0.37 ml, 1.5 mmol) at room temperature. To the reaction mixture was added n-hexane (21 ml), and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with n- hexane, and dried under reduced pressure to give the title compound (0.26 g, yield 91%).
H-NMR (400MHz, DMSO-d ) δ: 2.48 (3H, s), 5.37 (2H, s), 7.23 (1H, d, J = 7.3 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.48-7.45 (3H, m), 7.56 (1H, d, J = 7.9 Hz), 7.64-7.59 (2H, m), 7.67 (1H, d, J = 8.6 Hz), 7.82-7.72 (4H, m), 8.35 (2H, dd, J = 6.8, 2.0 Hz). 【0420】 [Production Example 6] Synthesis of 2-[4-chloromethyl(4,4,5,5- tetramethyl[1,3,2]dioxaborolanyl)benzyloxy]tetrahydropyran 【0421】 (1) 4-chloroiodomethylbenzoic acid 【0422】 Cl Cl O H O H 【0423】 Under an argon atmosphere, to 4-chloromethylbenzoic acid (1.9 g, 11 mmol) were added concentrated sulfuric acid (16 ml) and N-iodosuccinimide (2.7 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was carefully poured into ice water and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (3.3 g, yield 99%).
H-NMR (CDCl3) δ: 2.58 (3H, s), 7.38 (1H, br s), 8.50 (1H, s). 【0424】 (2) (4-chloroiodomethylphenyl)methanol 【0425】 I OH 【0426】 Under an argon atmosphere, to a solution of 4-chloro iodomethylbenzoic acid (2.4 g, 8.1 mmol) in tetrahydrofuran (12 ml) were added triethylamine (1.2 ml, 8.9 mmol) and isobutyl chloroformate (1.2 ml, 8.9 mmol) under ice-cooling, and the mixture was stirred for 30 min. At room temperature, the insoluble material was removed by filtration, and washed with tetrahydrofuran (36 ml). The filtrate was added dropwise to a solution of prepared sodium borohydride (0.92 g, 24 mmol) in water (4.5 ml) over 10 min under ice-cooling. After stirring at room temperature for 2 hr, to the reaction mixture was added sodium borohydride (0.30 g, 8.1 mmol), and the mixture was stirred for 1 hr. To the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform /ethyl acetate=100/0 - 95/5) to give the title compound (2.0 g, yield 88%).
H-NMR (400MHz, CDCl ) δ: 1.60 (1H, t, J = 5.7 Hz), 2.26 (3H, s), 4.63 (2H, d, J = 5.6 Hz), 7.25-7.26 (1H, m), 7.84 (1H, br s). 【0427】 (3) 2-(4-chloroiodomethylbenzyloxy)tetrahydropyran 【0428】 【0429】 Under an argon atmosphere, to a solution of (4-chloro iodomethylphenyl)methanol (2.0 g, 7.1 mmol) obtained in the above-mentioned (1) in chloroform (20 ml) were added pyridinium p-toluenesulfonate (0.27 mg, 1.1 mmol) and 3,4-dihydro-2H-pyran (0.97 ml, 11 mmol) at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the title compound (2.6 g, yield 99%).
H-NMR (400MHz, CDCl ) δ: 1.51-1.92 (6H, m), 2.26 (3H, s), 3.52-3.59 (1H, m), 3.85-3.91 (1H, m), 4.38 (1H, d, J = 12.6 Hz), 4.67-4.72 (2H, m), 7.25 (1H, br s), 7.82 (1H, br s). 【0430】 (4) 2-[4-chloromethyl(4,4,5,5- tetramethyl[1,3,2]dioxaborolanyl)benzyloxy]tetrahydropyran 【0431】 【0432】 Under an argon atmosphere, to a solution of 2-(4-chloro- -iodomethylbenzyloxy)tetrahydropyran (2.3 g, 6.2 mmol) obtained in the above-mentioned (2) in 1,4-dioxane (23 ml) were added biphenylyl-dicyclohexylphosphine (0.43 g, 1.2 mmol), palladium(II) acetate (0.070 g, 0.31 mmol), triethylamine (3.4 ml, 25 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 ml, 18 mmol) at room temperature, and the mixture was stirred at 80 C for 5 hr. Under ice-cooling, to the reaction mixture was added dropwise water, and ethyl acetate was added. After partitioning, the organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=98/2 - 80/20) to give the title compound (1.3 g, yield 60%).
H-NMR (400MHz, CDCl ) δ: 1.36 (12H, s), 1.47-1.90 (6H, m), 2.34 (3H, s), 3.52-3.59 (1H, m), 3.88-3.95 (1H, m), 4.42 (1H, d, J = 11.6 Hz), 4.67 (1H, t, J = 3.5 Hz), 4.74 (1H, d, J = 11.6 Hz), 7.18 (1H, br s), 7.63 (1H, br s). 【0433】 [Production Example 7] Synthesis of tert-butyl-(4-chloroiodo methylbenzyloxy)dimethylsilane 【0434】 (1) 3-(tert-butyl-dimethylsilanyloxymethyl)chloro methylphenylamine 【0435】 H N Si H N Si 【0436】 Under an argon atmosphere, to a solution of 3-(tert- butyldimethylsilanyloxymethyl)methyl-phenylamine (0.91 g, 3.6 mmol) in tetrahydrofuran (5.0 ml) was added N- chlorosuccinimide (0.48 g, 3.6 mmol) at room temperature.
After stirring for 22 hr, to the reaction mixture was added n- hexane (10 ml), and the insoluble material was filtered off.
The filtrate was concentrated, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.18 g, yield 17%).
H-NMR(400MHz, CDCl )δ:0.08 (6H, s), 0.92 (9H, s), 2.11 (3H, s), 4.01 (2H, br s), 4.60-4.69 (2H, m), 6.77 (1H, d, J = 8.4 Hz), 7.11 (1H, d, J = 8.4 Hz). 【0437】 (2) tert-butyl-(4-chloroiodo methylbenzyloxy)dimethylsilane 【0438】 Cl Cl H N Si I Si 【0439】 Under an argon atmosphere, to a solution of 3-(tert- butyl-dimethylsilanyloxymethyl)chloromethylphenylamine (0.18 g, 0.63 mmol) obtained in the above-mentioned (1) in acetonitrile (2.0 ml) were added iodine (0.19 g, 0.76 mmol) and tert-butyl nitrite (0.11 ml, 0.94 mmol) at room temperature, and the mixture was stirred at 65 C for 30 min. At room temperature, to the reaction mixture were added water and ethyl acetate. After partitioning, the organic layer was washed with saturated aqueous sodium hydrogen carbonate, 10 wt% aqueous sodium thiosulfate solution, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=40/1) to give the title compound (0.099 g, yield 40%).
H-NMR(400MHz, CDCl )δ:0.10 (6H, s), 0.93 (9H, s), 2.47 (3H, s), 4.68 (2H, s), 7.30 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 8.1 Hz). 【0440】 [Production Example 8] Synthesis of 2-(6-chloromethoxymethoxymethylphenyl)- 4,4,5,5-tetramethyl[1,3,2]dioxaborolane 【0441】 (1) 4-chloromethoxymethoxymethylbenzene 【0442】 Cl Cl 【0443】 Under an argon atmosphere, to a solution of 5-chloro methylphenol (1.0 g, 7.0 mmol) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.34 g, 60 wt% oil dispersion) under ice-cooling. After stirring for 15 min, the mixture was stirred at room temperature for 30 min. Under ice-cooling, chloromethyl methyl ether (0.64 ml, 8.4 mmol) was added, and the mixture was stirred for 30 min. To the reaction mixture were added water and diethyl ether, and the mixture was partitioned at room temperature. The organic layer was washed with water, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/diethyl ether=25/1) to give the title compound (1.3 g, yield 96%).
H-NMR(400MHz, CDCl )δ:2.20 (3H, s), 3.48 (3H, s), 5.18 (2H, s), 6.89 (1H, dd, J = 7.9, 2.0 Hz), 7.03-7.07 (2H, m). 【0444】 (2) 2-(6-chloromethoxymethoxymethylphenyl)-4,4,5,5- tetramethyl[1,3,2]dioxaborolane 【0445】 Cl Cl O B O 【0446】 Under an argon atmosphere, to a solution of 4-chloro methoxymethoxymethylbenzene (0.75 g, 4.0 mmol) obtained in the above-mentioned (1) in tetrahydrofuran (20 ml) was added dropwise n-butyllithium (1.6M n-hexane solution, 2.5 ml, 4.0 mmol) at -78 C over 5 min. After stirring for 30 min, 2- isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.81 ml, 4.0 mmol) was added. After stirring for 2 hr, the stirring was discontinued, and the mixture was warmed to room temperature.
After 13 hr, to the reaction mixture were added saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture was partitioned. Thereafter, the organic layer was washed with water, washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=12/1) to give the title compound (0.20 g, yield 15%).
H-NMR (400MHz, CDCl ) δ: 1.40 (12H, s), 2.27 (3H, s), 3.55 (3H, s), 5.03 (2H, s), 7.01 (1H, d, J = 8.2 Hz), 7.07-7.11 (1H, m). 【0447】 [Production Example 9] Synthesis of N-{4-chloro[4-(4-isobutylphenyl)hydroxy- 1,3,5-triazinyl]benzyl}-2,2-dimethylpropionamide (Example No.1-51) 【0448】 【0449】 (1) 2-chloro(4-isobutylphenyl)methoxy-1,3,5-triazine 【0450】 Cl N Cl N Cl 【0451】 Under an argon atmosphere, a suspension of 4-(2- methylpropyl)phenylboronic acid (35 g, 200 mmol), 2,4-dichloro- 6-methoxy-1,3,5-triazine (46 g, 260 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 g, 2.0 mmol) and sodium carbonate (63 g, 590 mmol) in toluene (280 ml) and distilled water (280 ml) was stirred at 70 C for 3.5 hr. At room temperature, to the reaction mixture were added water, ethyl acetate, and n-hexane, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure to give the title compound (60 g) as a crude product. 【0452】 (2) {4-chloro[4-(4-isobutylphenyl)methoxy-1,3,5-triazin- 2-yl]phenyl}methanol 【0453】 N Cl N OH + OH N N N N 【0454】 Under an argon atmosphere, a suspension of a crude product (60 g) of 2-chloro(4-isobutylphenyl)methoxy- 1,3,5-triazine obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (44 g, 240 mmol), [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (3.2 g, 3.9 mmol) and cesium fluoride (90 g, 590 mmol) in acetonitrile (440 ml) and distilled water (130 ml) was stirred at 67 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=7/3 - 6/4) to give the title compound (57 H-NMR (CDCl ) δ: 0.93 (6H, d, J = 6.6 Hz), 1.77 (1H, t, J = 6.1 Hz), 1.90-1.97 (1H, m), 2.57 (2H, d, J = 7.3 Hz), 4.21 (3H, s), 4.77 (2H, d, J = 6.1 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 8.3, 2.1 Hz), 7.54 (1H, d, J = 8.3 Hz), 8.01 (1H, d, J = 2.1 Hz), 8.51 (2H, d, J = 8.3 Hz). 【0455】 (3) tert-butyl N-{4-chloro[4-(4-isobutylphenyl)methoxy- 1,3,5-triazinyl]benzyl}-N-(tert-butoxycarbonyl)carbamate 【0456】 Cl O O N OH 【0457】 Under an argon atmosphere, to a solution of {4-chloro [4-(4-isobutylphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.25 g, 0.64 mmol) obtained in the above- mentioned (2) and triphenylphosphine (0.25 g, 0.96 mmol) in chloroform (2.4 ml) was added carbon tetrabromide (0.32 g, 0.96 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was subject to silica gel column chromatography (eluent: n-hexane/ethyl acetate=30/1 - 10/1), and concentrated under reduced pressure.
A solution of the residue in N,N-dimethylformamide (2.0 ml) was added to a solution of di-tert-butyl iminodicarboxylate (0.140 g, 0.64 mmol) and sodium hydride (0.026 g, 60 wt% oil dispersion) in N,N-dimethylformamide (1.0 ml) under ice-cooling, and the mixture was stirred at room temperature for 15 min.
The reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove 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 (0.27 g, yield 72%).
H-NMR (CDCl ) δ: 0.93 (6H, d, J = 6.6 Hz), 1.47 (18H, s), 1.88-1.98 (1H, m), 2.57 (2H, d, J = 7.3 Hz), 4.19 (3H, s), 4.83 (2H, s), 7.28 (2H, d, J = 8.4 Hz), 7.39 (1H, dd, J = 8.4, 2.3 Hz), 7.48 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 2.3 Hz), 8.50 (2H, dt, J = 8.4, 1.8 Hz). 【0458】 (4) 4-chloro[4-(4-isobutylphenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride 【0459】 Cl O O N NH O ・HCl N N 2 【0460】 Under an argon atmosphere, to tert-butyl N-{4-chloro [4-(4-isobutylphenyl)methoxy-1,3,5-triazinyl]benzyl}-N- (tert-butoxycarbonyl)carbamate (0.27 g, 0.46 mmol) obtained in the above-mentioned (3) was added 4M hydrogen chloride/1,4- dioxane solution (2.0 ml) at room temperature, and the mixture was stirred for 30 min. The solid was collected by filtration from the suspension, and dried under reduced pressure to give the title compound as a crude product (0.16 g). 【0461】 (5) N-{4-chloro[4-(4-isobutylphenyl)methoxy-1,3,5- triazinyl]benzyl}-2,2-dimethylpropionamide 【0462】 Cl Cl N NH N N ・HCl N N N N 【0463】 Under an argon atmosphere, to a solution of a crude product (0.035 g) of 4-chloro[4-(4-isobutylphenyl) methoxy-1,3,5-triazinyl]benzylamine hydrochloride obtained in the above-mentioned (4), HOBt･H O (0.019 g, 0.12 mmol) and WSC･HCl (0.024 g, 0.13 mmol) in N,N-dimethylformamide (1.0 ml) were added 2,2-dimethylpropionic acid (0.014 ml, 0.12 mmol) and triethylamine (0.035 ml, 0.25 mmol) at room temperature, and the mixture was stirred for 3 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to give the title compound (0.030 g).
H-NMR (CDCl3) δ: 0.93 (6H, d, J = 6.6 Hz), 1.24 (9H, s), 1.88- 1.99 (1H, m), 2.57 (2H, d, J = 7.1 Hz), 4.20 (3H, s), 4.50 (2H, d, J = 6.0 Hz), 5.98 (1H, br s), 7.29 (2H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 8.2, 2.3 Hz), 7.51 (1H, d, J = 8.2 Hz), 7.92 (1H, d, J = 2.3 Hz), 8.50 (2H, d, J = 8.3 Hz). 【0464】 (6) N-{4-chloro[4-hydroxy(4-isobutylphenyl)-1,3,5- triazinyl]benzyl}-2,2-dimethylpropionamide (Example No.1-51) 【0465】 【0466】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-isobutylphenyl)methoxy-1,3,5-triazinyl]benzyl}- 2,2-dimethylpropionamide (0.030 g, 0.064 mmol) obtained in the above-mentioned (5) in methanol (10 ml) was added 4M aqueous sodium hydroxide solution (0.096 ml) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture were added 10% aqueous citric acid solution (0.38 ml) and water (2.3 ml) at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.026 g, yield 90%). A suspension of the title compound (0.030 g) in DME (0.60 ml) was stirred at room temperature, and the solid was collected by filtration and dried to give the title compound as crystals (0.026 g). 【0467】 [Production Example 10] Synthesis of N-{4-chloro[4-(3-fluoromethylphenyl) hydroxy-1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-81) 【0468】 【0469】 (1) 2-chloro(3-fluoromethylphenyl)methoxy-1,3,5- triazine 【0470】 Cl N Cl N Cl 【0471】 Under an argon atmosphere, to a suspension of 3-fluoro methylphenylboronic acid (0.43 g, 2.8 mmol), 2,4-dichloro methoxy-1,3,5-triazine (1.0 g, 5.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) in toluene (8 ml) was added 2M aqueous tripotassium phosphate solution (4.0 ml) at room temperature, and the mixture was stirred at 100 C for 3 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, partitioned, washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/chloroform =2/3 - 1/2) to give the title compound (0.58 g, yield 81%).
H-NMR (CDCl ) δ: 2.37 (3H, d, J = 2.1 Hz), 4.17 (3H, s), 7.32 (1H, t, J = 7.9 Hz), 8.12 (1H, dd, J = 10.7, 1.7 Hz), 8.19 (1H, dd, J = 7.9, 1.7 Hz). 【0472】 (2) {4-chloro[4-(3-fluoromethylphenyl)methoxy-1,3,5- triazinyl]phenyl}methanol 【0473】 N Cl N O H F + F N N N N 【0474】 Under an argon atmosphere, to a solution of 2-chloro (3-fluoromethylphenyl)methoxy-1,3,5-triazine (0.58 g, 2.3 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.51 g, 2.7 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.18 g, 0.23 mmol) in 1,4-dioxane (9.0 ml) was added 2M aqueous sodium carbonate solution (4.5 ml), and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/3) to give the title compound (0.44 g, yield 53%).
H-NMR (CDCl ) δ: 1.76 (1H, t, J = 5.8 Hz), 2.37 (3H, d, J = 1.9 Hz), 4.21 (3H, s), 4.78 (2H, d, J = 5.8 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.47 (1H, dd, J = 8.1, 2.2 Hz), 7.54 (1H, d, J = 8.1 Hz), 8.02 (1H, d, J = 2.2 Hz), 8.23 (1H, dd, J = 10.7, 1.6 Hz), 8.29 (1H, dd, J = 7.9, 1.6 Hz). 【0475】 (3) tert-butyl N-{4-chloro[4-(3-fluoromethylphenyl) methoxy-1,3,5-triazinyl]benzyl}-N-(tert- butoxycarbonyl)carbamate 【0476】 Cl O 【0477】 Under an argon atmosphere, to a solution of {4-chloro [4-(3-fluoromethylphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.44 g, 1.2 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (13 ml) were added triethylamine (0.22 ml, 1.6 mmol) and methanesulfonyl chloride (0.10 ml, 1.3 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was added to a solution of di-tert-butyl iminodicarboxylate (0.32 g, 1.5 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in N,N-dimethylformamide (3.0 ml) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium 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 (0.64 g, yield 94%).
H-NMR (CDCl ) δ: 1.48 (18H, s), 2.37 (3H, d, J = 1.6 Hz), 4.19 (3H, s), 4.83 (2H, s), 7.31 (1H, t, J = 7.9 Hz), 7.40 (1H, dd, J = 8.4, 2.3 Hz), 7.49 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 2.3 Hz), 8.22 (1H, dd, J = 10.7, 1.6 Hz), 8.28 (1H, dd, J = 7.9, 1.6 Hz). 【0478】 (4) 4-chloro[4-(3-fluoromethylphenyl)methoxy-1,3,5- triazinyl]benzylamine hydrochloride 【0479】 Cl O O O N N H ・ H C l N N O 【0480】 Under an argon atmosphere, to a solution of tert-butyl N- {4-chloro[4-(3-fluoromethylphenyl)methoxy-1,3,5- triazinyl]benzyl}-N-(tert-butoxycarbonyl)carbamate (0.64 g, 1.1 mmol) obtained in the above-mentioned (3) in 1,4-dioxane (2.0 ml) was added 4M hydrogen chloride/1,4-dioxane solution (6.0 ml) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture was added n-hexane (32 ml), and the mixture was stirred for 45 min. The solid was collected by filtration from the suspension, and dried under reduced pressure to give the title compound (0.45 g, yield 99%).
H-NMR (DMSO-D ) δ: 2.36 (3H, d, J = 1.4 Hz), 4.13-4.19 (2H, m), 4.17 (3H, s), 7.55 (1H, t, J = 8.0 Hz), 7.71 (1H, dd, J = 8.1, 2.1 Hz), 7.75 (1H, d, J = 8.1 Hz), 8.16-8.20 (2H, m), 8.27 (1H, dd, J = 7.9, 1.6 Hz), 8.38 (3H, br s). 【0481】 (5) N-{4-chloro[4-(3-fluoromethylphenyl)methoxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0482】 N N H ・ H C l F N N O 【0483】 Under an argon atmosphere, to a solution of 4-chloro [4-(3-fluoromethylphenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride (0.070 g, 0.18 mmol) obtained in the above-mentioned (4), HOBt･H O (0.041 g, 0.27 mmol) and 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.042 g, 0.27 mmol) in N,N-dimethylformamide (1.0 ml) were added WSC･HCl (0.051 g, 0.27 mmol) and triethylamine (0.037 ml, 0.027 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.080 g, yield 90%).
H-NMR (CDCl3) δ: 1.45 (6H, s), 2.37 (3H, d, J = 1.9 Hz), 4.20 (3H, s), 4.55 (2H, d, J = 5.8 Hz), 6.23 (1H, br s), 7.30-7.37 (2H, m), 7.52 (1H, d, J = 8.4 Hz), 7.93 (1H, d, J = 2.3 Hz), 8.22 (1H, dd, J = 10.7, 1.6 Hz), 8.28 (1H, dd, J = 7.9, 1.6 Hz). 【0484】 (6) N-{4-chloro[4-(3-fluoromethyl-phenyl)hydroxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-81) 【0485】 F N N 【0486】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(3-fluoromethylphenyl)methoxy-1,3,5-triazin yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (0.077 g, 0.16 mmol) obtained in the above-mentioned (5) in methanol (1.4 ml) was added 4M aqueous sodium hydroxide solution (0.23 ml) at room temperature, and the mixture was stirred at 60 C for 2 hr.
To the reaction mixture were added 10% aqueous citric acid solution (0.070 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.070 g, yield 92%). 【0487】 [Production Example 11] Synthesis of N-{4-chloro[4-hydroxy(4-isopropylphenyl)- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-98) 【0488】 N O F 【0489】 (1) 2-chloro(4-isopropylphenyl)methoxy-1,3,5-triazine 【0490】 Cl N Cl N Cl B N N 【0491】 Under an argon atmosphere, to a suspension of 4- isopropylphenylboronic acid (0.30 g, 1.7 mmol), 2,4-dichloro methoxy-1,3,5-triazine (0.23 g, 1.4 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.11 g, 0.14 mmol) in 1,4-dioxane (4.0 ml) was added 2M aqueous sodium carbonate solution (2.0 ml) at room temperature, and the mixture was stirred at 100 C for 1.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.21 g, yield 57%).
H-NMR (CDCl ) δ: 1.29 (6H, d, J = 7.1 Hz), 2.99-3.02 (1H, m), 4.16 (3H, s), 7.34-7.38 (2H, m), 8.39-8.43 (2H, m). 【0492】 (2) {4-chloro[4-(4-isopropylphenyl)methoxy-1,3,5-triazin- 2-yl]phenyl}methanol 【0493】 N Cl N OH + OH N N N N 【0494】 Under an argon atmosphere, to a suspension of 2-chloro (4-isopropylphenyl)methoxy-1,3,5-triazine (0.21 g) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.15 g, 0.80 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.066 g, 0.080 mmol) in 1,4-dioxane (2.4 ml) was added 2M aqueous sodium carbonate solution (1.2 ml) at room temperature, and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with water, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=5/3) to give the title compound (0.15 g, yield 51%).
H-NMR (CDCl ) δ: 1.30 (6H, d, J = 7.1 Hz), 1.77 (1H, t, J = 6.1 Hz), 2.95-3.07 (1H, m), 4.20 (3H, s), 4.77 (2H, d, J = 6.1 Hz), 7.35-7.39 (2H, m), 7.46 (1H, dd, J = 8.2, 2.2 Hz), 7.54 (1H, d, J = 8.2 Hz), 8.01 (1H, dd, J = 2.2, 0.4 Hz), 8.50-8.54 (2H, m). 【0495】 (3) tert-butyl N-{4-chloro[4-(4-isopropylphenyl)methoxy- 1,3,5-triazinyl]benzyl}-N-(tert-butoxycarbonyl)carbamate 【0496】 Cl O N OH 【0497】 Under an argon atmosphere, to a solution of {4-chloro [4-(4-isopropylphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.15 g, 0.41 mmol) obtained in the above- mentioned (2) and triphenylphosphine (0.16 g, 0.62 mmol) in chloroform (1.5 ml) was added carbon tetrabromide (0.20 g, 0.62 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. The reaction mixture was applied to silica gel column chromatography (eluent: n-hexane/ethyl acetate=30/1 - 10/1) and concentrated under reduced pressure.
A solution of the residue in N,N-dimethylformamide (1.5 ml) was added to a solution of di-tert-butyl iminodicarboxylate (0.089 g, 0.41 mmol) and sodium hydride (0.016 g, 60 wt% oil dispersion) in N,N-dimethylformamide (0.70 ml) under ice- cooling, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.20 g, yield 85%).
H-NMR (CDCl ) δ: 1.30 (6H, d, J = 7.0 Hz), 1.47 (18H, s), 2.94-3.05 (1H, m), 4.19 (3H, s), 4.83 (2H, s), 7.34-7.41 (3H, m), 7.48 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 2.3 Hz), 8.49- 8.53 (2H, m). 【0498】 (4) 4-chloro[4-(4-isopropylphenyl)methoxy-1,3,5-triazin- 2-yl]benzylamine hydrochloride 【0499】 Cl O N ・HCl N N 2 【0500】 Under an argon atmosphere, to tert-butyl N-{4-chloro [4-(4-isopropylphenyl)methoxy-1,3,5-triazinyl]benzyl}-N- (tert-butoxycarbonyl)carbamate (0.20 g, 0.35 mmol) obtained in the above-mentioned (3) was added 4M hydrogen chloride/1,4- dioxane solution (2.0 ml) at room temperature, and the mixture was stirred for 1 hr. The suspension was concentrated under reduced pressure, and azeotropically distilled with ethyl acetate (twice) to give the title compound as a crude product (0.14 g). 【0501】 (5) N-{4-chloro[4-(4-isopropylphenyl)methoxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0502】 N N H N ・ H C l 【0503】 Under an argon atmosphere, to a solution of a crude product (0.10 g) of 4-chloro[4-(4-isopropylphenyl) methoxy-1,3,5-triazinyl]benzylamine hydrochloride obtained in the above-mentioned (4), HOBt･H O (0.052 g, 0.34 mmol) and WSC･HCl (0.066 g, 0.34 mmol) in N,N-dimethylformamide (1.0 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.042 g, 0.27 mmol) and triethylamine (0.069 ml, 0.49 mmol) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.054 g).
H-NMR (CDCl ) δ: 1.30 (6H, d, J = 6.8 Hz), 1.44 (6H, s), 2.95- 3.05 (1H, m), 4.18 (3H, s), 4.53 (2H, d, J = 5.7 Hz), 6.34 (1H, br s), 7.30-7.39 (3H, m), 7.50 (1H, d, J = 8.4 Hz), 7.91 (1H, d, J = 2.2 Hz), 8.49-8.53 (2H, m). 【0504】 (6) N-{4-chloro[4-hydroxy(4-isopropylphenyl)-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-98) 【0505】 N N F N N O F 【0506】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-isopropylphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.050 g, 0.099 mmol) obtained in the above-mentioned (5) in methanol (0.50 ml) was added 4M aqueous sodium hydroxide solution (0.20 ml) at room temperature, and the mixture was stirred at 60 C for 2 hr. To the reaction mixture were added 2N hydrochloric acid (0.40 ml) and water at room temperature, and the mixture was stirred.
The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.043 g, yield 89%). 【0507】 [Production Example 12] Synthesis of N-{4-chloro[4-hydroxy(4-isobutoxyphenyl)- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-109) 【0508】 O Cl 【0509】 (1) 2-chloro(4-isobutoxyphenyl)methoxy-1,3,5-triazine 【0510】 Cl N Cl 【0511】 Under an argon atmosphere, to a suspension of 4- isobutoxyphenylboronic acid (0.50 g, 2.58 mmol), 2,4-dichloro- 6-methoxy-1,3,5-triazine (0.93 g, 5.15 mmol), tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.129 mmol) and sodium carbonate (0.819 g, 7.73 mmol) in toluene (5.0 ml) was added distilled water (3.5 ml), and the mixture was stirred at 86 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=10/1) to give the title compound (0.606 g, yield 80%).
H-NMR (CDCl ) δ: 1.05 (6H, d, J = 6.7 Hz), 2.07-2.17 (1H, m), 3.81 (2H, d, J = 6.5 Hz), 4.14 (3H, s), 6.95-7.00 (2H, m), 8.42-8.46 (2H, m). 【0512】 (2) {4-chloro[4-(4-isobutoxyphenyl)methoxy-1,3,5-triazin- 2-yl]phenyl}methanol 【0513】 O O Cl N Cl N O H N N N N 【0514】 Under an argon atmosphere, a suspension of 2-chloro(4- isobutoxyphenyl)methoxy-1,3,5-triazine (0.60 g, 2.0 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.57 g, 3.1 mmol), [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.083 g, 0.10 mmol) and tripotassium phosphate (1.3 g, 6.1 mmol) in N,N-dimethylformamide (6.0 ml) was stirred at 60 C for 1.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and partitioned, washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to give the title compound (0.32 g, yield 39%).
H-NMR (CDCl ) δ: 1.05 (6H, d, J = 6.7 Hz), 1.77 (1H, t, J = .9 Hz), 2.08-2.18 (1H, m), 3.82 (2H, d, J = 6.5 Hz), 4.19 (3H, s), 4.77 (2H, d, J = 5.9 Hz), 6.98-7.01 (2H, m), 7.46 (1H, dd, J = 8.2, 2.2 Hz), 7.53 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.55 (2H, m). 【0515】 (3) tert-butyl N-{4-chloro[4-(4-isobutoxyphenyl)methoxy- 1,3,5-triazinyl]benzyl}-N-(tert-butoxycarbonyl)carbamate 【0516】 O Cl O Cl O N N O 【0517】 Under an argon atmosphere, to a solution of {4-chloro [4-(4-isobutoxyphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.24 g, 0.61 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (2.0 ml) were added triethylamine (0.11 ml, 0.79 mmol) and methanesulfonyl chloride (0.052 ml, 0.67 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (1.5 ml) were added cesium carbonate (0.59 g, 1.8 mmol) and di-tert-butyl iminodicarboxylate (0.16 g, 0.73 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium 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 (0.34 g, yield 92%).
H-NMR (CDCl ) δ: 1.05 (6H, d, J = 6.7 Hz), 1.47 (18H, s), 2.08-2.18 (1H, m), 3.82 (2H, d, J = 6.5 Hz), 4.18 (3H, s), 4.82 (2H, s), 6.96-7.00 (2H, m), 7.39 (1H, dd, J = 8.3, 2.3 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 2.3 Hz), 8.52-8.56 (2H, m). 【0518】 (4) 4-chloro[4-(4-isobutoxyphenyl)methoxy-1,3,5-triazin- 2-yl]benzylamine hydrochloride 【0519】 O Cl O N ・ H C l N N 2 N N O 【0520】 Under an argon atmosphere, to a solution of tert-butyl N- {4-chloro[4-(4-isobutoxyphenyl)methoxy-1,3,5-triazin yl]benzyl}-N-(tert-butoxycarbonyl)carbamate (0.34 g, 0.56 mmol) obtained in the above-mentioned (3) in 1,4-dioxane (1.0 ml) was added 4M hydrogen chloride/1,4-dioxane solution (3.0 ml) at room temperature, and the mixture was stirred for 2.5 hr. To the reaction mixture was added n-hexane (20 ml), and the mixture was stirred. The solid was collected by filtration from the suspension, and dried under reduced pressure to give the title compound (0.24 g, yield 95%).
H-NMR (DMSO-D ) δ: 1.01 (6H, d, J = 6.8 Hz), 2.01-2.11 (1H, m), 3.88 (2H, d, J = 6.4 Hz), 4.14 (3H, s), 4.12-4.17 (2H, m), 7.12-7.15 (2H, m), 7.72 (2H, br s), 8.13 (1H, br s), 8.40-8.51 (5H, m). 【0521】 (5) N-{4-chloro[4-(4-isobutoxyphenyl)methoxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0522】 O Cl N N H ・ H C l 【0523】 Under an argon atmosphere, to a solution of 4-chloro [4-(4-isobutoxyphenyl)methoxy-1,3,5-triazinyl]benzylamine hydrochloride (0.065 g, 0.14 mmol) obtained in the above- mentioned (4), HOBt･H O (0.033 g, 0.22 mmol) and 3,3,3- trifluoro-2,2-dimethylpropionic acid (0.034 g, 0.22 mmol) in N,N-dimethylformamide (0.70 ml) were added WSC･HCl (0.042 g, 0.22 mmol) and triethylamine (0.030 ml, 0.22 mmol) at room temperature, and the mixture was stirred for 5 hr. To the reaction mixture were added 3,3,3-trifluoro-2,2- dimethylpropionic acid (0.034 g, 0.22 mmol), WSC･HCl (0.042 g, 0.22 mmol), HOBt･H O (0.033 g, 0.22 mmol) and triethylamine (0.030 ml, 0.22 mmol), and the mixture was stirred for 1 hr.
To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (0.068 g, yield 86%).
H-NMR (CDCl ) δ: 1.06 (6H, d, J = 6.8 Hz), 1.44 (6H, br s), 2.08-2.18 (1H, m), 3.82 (2H, d, J = 6.6 Hz), 4.19 (3H, s), 4.55 (2H, d, J = 5.7 Hz), 6.21 (1H, br s), 6.97-7.01 (2H, m), 7.34 (1H, dd, J = 8.3, 2.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 2.3 Hz), 8.53-8.55 (2H, m). 【0524】 (6) N-{4-chloro[4-hydroxy(4-isobutoxyphenyl)-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-109) 【0525】 O Cl H O Cl O F F N N O 【0526】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-isobutoxyphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.066 g, 0.12 mmol) obtained in the above-mentioned (5) in methanol (1.1 ml) was added 4M aqueous sodium hydroxide solution (0.18 ml) at room temperature, and the mixture was stirred at 60 C for 2 hr. To the reaction mixture were added 10% aqueous citric acid solution (0.55 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.057 g, yield 88%). A suspension of the title compound (0.030 g) in acetonitrile (0.60 ml) was stirred at room temperature, and the solid was collected by filtration and dried to give the title compound as crystals (0.011 g). 【0527】 [Production Example 13] Synthesis of N-{4-chloro[4-hydroxy(4-propoxyphenyl)- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-122) 【0528】 O Cl N N O 【0529】 (1) 2-chloromethoxy(4-propoxyphenyl)-1,3,5-triazine 【0530】 Cl N Cl N Cl 【0531】 Under an argon atmosphere, to a suspension of 4- propoxyphenylboronic acid (1.0 g, 5.6 mmol), 2,4-dichloro methoxy-1,3,5-triazine (2.0 g, 11 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol) in toluene (25 ml) was added 2M aqueous sodium carbonate solution (8.4 ml), and the mixture was stirred at 100 C for 1 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (1.1 g, yield 70%).
H-NMR (CDCl ) δ: 1.06 (3H, t, J = 7.4 Hz), 1.83-1.87 (2H, m), 4.02 (2H, t, J = 6.6 Hz), 4.14 (3H, s), 6.96-6.99 (2H, m), 8.43-8.45 (2H, m). 【0532】 (2) {4-chloro[4-methoxy(4-propoxyphenyl)-1,3,5-triazin yl]phenyl}methanol 【0533】 O O Cl N Cl N O H N N N N 【0534】 Under an argon atmosphere, to a solution of 2-chloro methoxy(4-propoxyphenyl)-1,3,5-triazine (0.75 g, 2.7 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.60 g, 3.2 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.22 g, 0.27 mmol) in 1,4-dioxane (15 ml) was added 2M aqueous sodium carbonate solution (5.4 ml), and the mixture was stirred at 100 C for 3 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and partitioned, washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=10/1) to give the title compound (0.95 g, yield 91%).
H-NMR (CDCl ) δ: 1.07 (3H, t, J = 7.4 Hz), 1.77 (1H, t, J = 5.8 Hz), 1.84-1.87 (2H, m), 4.02 (2H, t, J = 6.6 Hz), 4.19 (3H, s), 4.77 (2H, d, J = 5.8 Hz), 7.00 (2H, d, J = 8.7 Hz), 7.45 (1H, dd, J = 8.3, 1.9 Hz), 7.53 (1H, d, J = 8.3 Hz), 8.00 (1H, d, J = 1.9 Hz), 8.55 (2H, d, J = 8.7 Hz). 【0535】 (3) tert-butyl N-{4-chloro[4-methoxy(4-propoxyphenyl)- 1,3,5-triazinyl]benzyl}-N-(tert-butoxycarbonyl)carbamate 【0536】 O Cl O Cl O N O H 【0537】 Under an argon atmosphere, to a solution of {4-chloro [4-methoxy(4-propoxyphenyl)-1,3,5-triazin yl]phenyl}methanol (0.95 g, 2.5 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (13 ml) were added triethylamine (0.45 ml, 3.2 mmol) and methanesulfonyl chloride (0.23 ml, 3.0 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (13 ml) were added cesium carbonate (2.4 g, 7.4 mmol) and di-tert-butyl iminodicarboxylate (0.64 g, 3.0 mmol) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the title compound (1.3 g, yield 90%). 【0538】 (4) 4-chloro[4-methoxy(4-propoxyphenyl)-1,3,5-triazin yl]benzylamine hydrochloride 【0539】 O O Cl O Cl O O N N H ・ H C l N N O 【0540】 Under an argon atmosphere, to tert-butyl N-{4-chloro [4-methoxy(4-propoxyphenyl)-1,3,5-triazinyl]benzyl}-N- (tert-butoxycarbonyl)carbamate(1.3 g, 2.2 mmol) obtained in the above-mentioned (3) was added 4M hydrogen chloride/1,4-dioxane solution (5.0 ml) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture were added 1,4- dioxane (2.0 ml) and n-hexane (5.0 ml), and the mixture was stirred for 45 min. The solid was collected by filtration from the suspension, and dried under reduced pressure to give the title compound (0.68 g, yield 73%).
H-NMR (DMSO-D ) δ: 1.00 (3H, t, J = 7.4 Hz), 1.73-1.83 (2H, m), 4.06 (2H, t, J = 6.5 Hz), 4.12-4.18 (2H, m), 4.14 (3H, s), 7.12-7.16 (2H, m), 7.69-7.74 (2H, m), 8.13 (1H, br s), 8.44 (3H, br s), 8.45-8.50 (2H, m). 【0541】 (5) N-{4-chloro[4-methoxy(4-propoxyphenyl)-1,3,5-triazin- 2-yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0542】 O Cl O Cl N N H ・ H C l N N O 【0543】 Under an argon atmosphere, to a solution of 4-chloro [4-methoxy(4-propoxyphenyl)-1,3,5-triazinyl]benzylamine hydrochloride (0.10 g, 0.24 mmol) obtained in the above- mentioned (4), HOBt･H O (0.054 g, 0.36 mmol) and WSC･HCl (0.068 g, 0.36 mmol) in N,N-dimethylformamide (1.5 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.056 g, 0.36 mmol) and triethylamine (0.099 ml, 0.71 mmol) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=10/3) to give the title compound (0.096 g, yield 78%).
H-NMR (DMSO-D ) δ: 1.00 (3H, t, J = 7.3 Hz), 1.39 (6H, s), 1.73-1.83 (2H, m), 4.05 (2H, t, J = 6.5 Hz), 4.11 (3H, s), 4.39 (2H, d, J = 5.9 Hz), 7.10-7.14 (2H, m), 7.44 (1H, dd, J = 8.1, 2.3 Hz), 7.61 (1H, d, J = 8.1 Hz), 7.86 (1H, d, J = 2.3 Hz), 8.42-8.47 (2H, m), 8.66 (1H, t, J = 5.9 Hz). 【0544】 (6) N-{4-chloro[4-hydroxy(4-propoxyphenyl)-1,3,5-triazin- 2-yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-122) 【0545】 O Cl O Cl N N F 【0546】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-methoxy(4-propoxyphenyl)-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.094 g, 0.18 mmol) obtained in the above-mentioned (5) in methanol (0.94 ml) was added 4M aqueous sodium hydroxide solution (0.27 ml) at room temperature, and the mixture was stirred at 65 C for 2 hr. To the reaction mixture were added 2N hydrochloric acid (0.54 ml) and water at room temperature, and the mixture was stirred.
The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.069 g, yield 75%). A suspension of the title compound (0.050 g) in acetone (1.0 ml) was dissolved by heating under reflux, and the solid was collected by filtration at room temperature and dried to give the title compound as crystals (0.012 g). 【0547】 [Production Example 14] Synthesis of N-(4-chloro{4-hydroxy[4-(1- methylcyclopropylmethoxy)phenyl]-1,3,5-triazinyl}benzyl)- 3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-128) 【0548】 【0549】 (1) 2-chloromethoxy(4-methoxymethoxyphenyl)-1,3,5- triazine 【0550】 M e O O Cl N Cl M e O O N Cl 【0551】 Under an argon atmosphere, to a suspension of 4- (methoxymethoxy)phenylboronic acid (1.0 g, 5.5 mmol), 2,4- dichloromethoxy-1,3,5-triazine (2.0 g, 11 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.64 g, 0.55 mmol) in toluene (25 ml) was added 2M aqueous sodium carbonate solution (8.3 ml), and the mixture was stirred at 100 C for 1 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1 - /1) to give the title compound (1.3 g, yield 84%). 【0552】 (2) {4-chloro[4-methoxy(4-methoxymethoxyphenyl)-1,3,5- triazinyl]phenyl}methanol 【0553】 M e O O M e O O Cl N Cl N H O O H N N N N 【0554】 Under an argon atmosphere, to a solution of 2-chloro methoxy(4-methoxymethoxyphenyl)-1,3,5-triazine (1.3 g, 4.4 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.99 g, 5.3 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.36 g, 0.44 mmol) in 1,4-dioxane (25 ml) was added 2M aqueous sodium carbonate solution (8.8 ml), and the mixture was stirred at 100 C for 3 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water, washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=10/1) to give the title compound (0.98 g, yield 56%). 【0555】 (3) tert-butyl N-{4-chloro[4-methoxy(4- methoxymethoxyphenyl)-1,3,5-triazinyl]benzyl}-N-(tert- butoxycarbonyl)carbamate 【0556】 M e O O Cl M e O O O O Cl N O H N N O N N O 【0557】 Under an argon atmosphere, to a solution of {4-chloro [4-methoxy(4-methoxymethoxyphenyl)-1,3,5-triazin yl]phenyl}methanol (0.78 g, 2.0 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (7.8 ml) were added triethylamine (0.36 ml, 2.6 mmol) and methanesulfonyl chloride (0.19 ml, 2.4 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (10 ml) were added cesium carbonate (2.0 g, 6.0 mmol) and di-tert-butyl iminodicarboxylate (0.53 g, 2.4 mmol), and the mixture was stirred for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the title compound (0.80 g, yield 68%).
H-NMR (DMSO-D ) δ: 1.42 (18H, s), 3.41 (3H, s), 4.12 (3H, s), 4.77 (2H, s), 5.32 (2H, s), 7.18-7.23 (2H, m), 7.45 (1H, dd, J = 8.2, 2.3 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.91 (1H, d, J = 2.3 Hz), 8.43-8.47 (2H, m). 【0558】 (4) 4-[4-(5-aminomethylchlorophenyl)methoxy-1,3,5- triazinyl]phenol hydrochloride 【0559】 M e O Cl O O H O N N H N O ・ H C l 【0560】 Under an argon atmosphere, to tert-butyl N-{4-chloro [4-methoxy(4-methoxymethoxyphenyl)-1,3,5-triazin yl]benzyl}-N-(tert-butoxycarbonyl)carbamate (0.40 g, 0.68 mmol) obtained in the above-mentioned (3) was added 4M hydrogen chloride/1,4-dioxane solution (2.0 ml) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added n-hexane (3.0 ml), and the mixture was stirred for 45 min.
The solid was collected by filtration, and dried under reduced pressure to give the title compound as a crude product (0.26 g). 【0561】 (5) 4-(4-{2-chloro[(3,3,3-trifluoro-2,2- dimethylpropionylamino)methyl]phenyl}methoxy-1,3,5-triazin- 2-yl)phenyl 3,3,3-trifluoro-2,2-dimethylpropionate 【0562】 F O Cl H O Cl F O N N N ・ H C l 【0563】 Under an argon atmosphere, to a solution of a crude product (0.10 g) of 4-[4-(5-aminomethylchlorophenyl) methoxy-1,3,5-triazinyl]phenol hydrochloride obtained in the above-mentioned (4), HOBt･H O (0.061 g, 0.40 mmol) and WSC･HCl (0.076 g, 0.40 mmol) in N,N-dimethylformamide (1.5 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.066 g, 0.40 mmol) and triethylamine (0.11 ml, 0.79 mmol) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform /ethyl acetate=10/1) to give the title compound (0.090 g).
H-NMR (DMSO-D ) δ: 1.39 (6H, s), 1.59 (6H, s), 4.15 (3H, s), 4.40 (2H, d, J = 6.0 Hz), 7.39-7.47 (3H, m), 7.62 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 2.1 Hz), 8.55-8.60 (2H, m), 8.66 (1H, t, J = 6.0 Hz). 【0564】 (6) N-{4-chloro[4-(4-hydroxyphenyl)methoxy-1,3,5-triazin- 2-yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0565】 H O Cl F O Cl F N N F O N N 【0566】 Under an argon atmosphere, to a solution of 4-(4-{2- chloro[(3,3,3-trifluoro-2,2- dimethylpropionylamino)methyl]phenyl}methoxy-1,3,5-triazin- 2-yl)phenyl 3,3,3-trifluoro-2,2-dimethylpropionate (0.070 g, 0.15 mmol) obtained in the above-mentioned (5) in methanol (0.70 ml) was added 5M sodium methoxide/methanol solution (0.032 ml) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was adjusted to pH=2 with 2N hydrochloric acid under ice-cooling. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform /ethyl acetate=4/1) to give the title compound (0.036 g, yield 51%).
H-NMR (DMSO-D6) δ: 1.38 (6H, s), 4.10 (3H, s), 4.39 (2H, d, J = 6.2 Hz), 6.91-6.95 (2H, m), 7.42 (1H, dd, J = 8.3, 2.3 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.84 (1H, d, J = 2.3 Hz), 8.34-8.39 (2H, m), 8.65 (1H, t, J = 6.2 Hz), 10.38 (1H, br s). 【0567】 (7) N-(4-chloro{4-methoxy[4-(1- methylcyclopropylmethoxy)phenyl]-1,3,5-triazinyl}benzyl)- 3,3,3-trifluoro-2,2-dimethylpropionamide 【0568】 O Cl H O Cl N N O 【0569】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-hydroxyphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.036 g, 0.075 mmol) obtained in the above-mentioned (6), 1-methyl- cyclopropanemethanol (0.0087 ml, 0.090 mmol) and triphenylphosphine (0.024 g, 0.090 mmol) in tetrahydrofuran (0.50 ml) was added 1.9M diethyl azodicarboxylate/toluene solution (0.051 ml, 0.098 mmol) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was stirred at room temperature for 1 hr, and 1.9M diethyl azodicarboxylate/toluene solution (0.028 ml, 0.053 mmol) was added. The reaction mixture was stirred at room temperature for 1 hr, and purified by preparative thin layer chromatography (eluent: chloroform /ethyl acetate=19/1) to give the title compound (0.029 g, yield 70%).
H-NMR (DMSO-D ) δ: 0.42 (2H, dd, J = 5.6, 4.0 Hz), 0.56 (2H, dd, J = 5.4, 4.2 Hz), 1.20 (3H, s), 1.39 (6H, s), 3.88 (2H, s), 4.11 (3H, s), 4.39 (2H, d, J = 5.9 Hz), 7.09-7.14 (2H, m), 7.43 (1H, dd, J = 8.2, 2.1 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.85 (1H, d, J = 2.1 Hz), 8.41-8.46 (2H, m), 8.66 (1H, t, J = 5.9 Hz). 【0570】 (8) N-(4-chloro{4-hydroxy[4-(1- methylcyclopropylmethoxy)phenyl]-1,3,5-triazinyl}benzyl)- 3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-128) 【0571】 O Cl N N F N N O F 【0572】 Under an argon atmosphere, to a solution of N-(4-chloro- 3-{4-methoxy[4-(1-methylcyclopropylmethoxy)phenyl]-1,3,5- triazinyl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide (0.028 g, 0.051 mmol) obtained in the above-mentioned (7) in methanol (0.28 ml) was added 4M aqueous sodium hydroxide solution (0.077 ml) at room temperature, and the mixture was stirred at 60 C for 1 hr. To the reaction mixture were added 2N hydrochloric acid (0.16 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.019 g, yield 69%). 【0573】 [Production Example 15] Synthesis of N-{4-chloro[4-(3-chloromethylphenyl) hydroxy-1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-129) 【0574】 【0575】 (1)2-chloro(3-chloromethylphenyl)methoxy-1,3,5- triazine 【0576】 Cl N + Cl Cl B 【0577】 Under an argon atmosphere, to a suspension of 3-chloro methylphenylboronic acid (0.47 g, 2.8 mmol), 2,4-dichloro methoxy-1,3,5-triazine (1.0 g, 5.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) in toluene (5.0 ml) was added 2M aqueous sodium carbonate solution (4.2 ml), and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=97/3 - 94/6) to give the title compound (0.61 g, yield 81%).
H-NMR (CDCl ) δ: 2.47 (3H, s), 4.17 (3H, s), 7.37 (1H, d, J = 8.0 Hz), 8.28 (1H, dd, J = 8.0, 1.8 Hz), 8.47 (1H, d, J = 1.8 Hz). 【0578】 (2){4-chloro[4-(3-chloromethylphenyl)methoxy-1,3,5- triazinyl]phenyl}methanol 【0579】 N Cl N H O O H Cl + Cl 【0580】 Under an argon atmosphere, to a solution of 2-chloro (3-chloromethylphenyl)methoxy-1,3,5-triazine (0.61 g, 2.3 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.51 g, 2.7 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.19 g, 0.23 mmol) in 1,4-dioxane (6.0 ml) was added 2M aqueous sodium carbonate solution (4.5 ml), and the mixture was stirred at 100 C for 1.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 - 6/4) to give the title compound (0.61 g, yield 71%).
H-NMR (CDCl ) δ: 1.81 (1H, t, J = 5.9 Hz), 2.47 (3H, s), 4.21 (3H, s), 4.78 (2H, d, J = 5.9 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.47 (1H, dd, J = 8.1, 2.2 Hz), 7.54 (1H, d, J = 8.1 Hz), 8.01 (1H, d, J = 2.2 Hz), 8.38 (1H, dd, J = 7.9, 1.8 Hz), 8.57 (1H, d, J = 1.8 Hz). 【0581】 (3)4-chloro[4-(3-chloromethylphenyl)methoxy-1,3,5- triazinyl]benzylamine hydrochloride 【0582】 Cl O N O H N N O N N H ・ H C l 【0583】 Under an argon atmosphere, to a solution of {4-chloro [4-(3-chloromethylphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.61 g, 1.6 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (6.0 ml) were added triethylamine (0.29 ml, 2.1 mmol) and methanesulfonyl chloride (0.15 ml, 1.9 mmol) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (6.0 ml) were added cesium carbonate (1.6 g, 4.8 mmol) and di-tert-butyl iminodicarboxylate (0.42 g, 1.9 mmol) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5 - 80/20). Under an argon atmosphere, to a solution of the purified product in 1,4-dioxane (2.0 ml) was added 4M hydrogen chloride /1,4-dioxane solution (8.0 ml) at room temperature, and the mixture was stirred for 2.5 hr. To the reaction mixture was added n-hexane, and the solid was collected by filtration, and dried under reduced pressure to give the title compound (0.67 g, yield 99%).
H-NMR (DMSO-D ) δ: 2.46 (3H, s), 4.12-4.21 (5H, m), 7.62 (1H, d, J = 8.0 Hz), 7.73-7.75 (2H, m), 8.17 (1H, br s), 8.38 (1H, dd, J = 8.0, 1.6 Hz), 8.47 (1H, d, J = 1.6 Hz), 8.48 (3H, br s). 【0584】 (4)N-{4-chloro[4-(3-chloromethylphenyl)methoxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0585】 N ・ H C l Cl F 【0586】 Under an argon atmosphere, to a solution of 4-chloro [4-(3-chloromethylphenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride (0.070 g, 0.17 mmol) obtained in the above-mentioned (3), HOBt･H O (0.039 g, 0.26 mmol) and WSC･ HCl (0.049 g, 0.26 mmol) in N,N-dimethylformamide (0.70 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.037 g, 0.24 mmol) and triethylamine (0.071 ml, 0.51 mmol) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 - 8/2) to give the title compound (0.072 g, yield 82%).
H-NMR (CDCl ) δ: 1.45 (6H, s), 2.47 (3H, s), 4.21 (3H, s), 4.56 (2H, d, J = 5.6 Hz), 6.24 (1H, br s), 7.34-7.39 (2H, m), 7.52 (1H, d, J = 8.2 Hz), 7.92 (1H, d, J = 2.3 Hz), 8.38 (1H, dd, J = 8.2, 1.8 Hz), 8.56 (1H, d, J = 1.8 Hz). 【0587】 (5)N-{4-chloro[4-(3-chloromethylphenyl)hydroxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-129) 【0588】 N N F N O F 【0589】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(3-chloromethylphenyl)methoxy-1,3,5-triazin yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (0.072 g, 0.14 mmol) obtained in the above-mentioned (4) in methanol (0.70 ml) was added 4M aqueous sodium hydroxide solution (0.28 ml) at room temperature, and the mixture was stirred at 60 C for 1 hr. To the reaction mixture were added 2N hydrochloric acid (0.56 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.057 g, yield 82%). 【0590】 [Production Example 16] Synthesis of N-{4-chloro[4-hydroxy(3-isopropyl trifluoromethylphenyl)-1,3,5-triazinyl]benzyl}-3,3,3- trifluoro-2,2-dimethylpropionamide (Example No.1-130) 【0591】 N N O 【0592】 (1)4-benzyloxybromotrifluoromethylbenzene 【0593】 Br O Br F 【0594】 Under an argon atmosphere, to a solution of 2-bromo fluorotrifluoromethylbenzene (1.5 g, 6.2 mmol) and sodium hydride (0.74 g, 60 wt% oil dispersion) in N,N- dimethylformamide (15 ml) was added benzyl alcohol (0.64 ml, 6.2 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was stirred at 60 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=99/1 - 98/2) to give the title compound (1.3 g, yield 69%).
H-NMR (CDCl ) δ: 5.08 (2H, s), 6.93 (1H, dd, J = 8.8, 2.4 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.33-7.41 (5H, m), 7.57 (1H, d, J = 8.8 Hz). 【0595】 (2)4-benzyloxyisopropenyltrifluoromethylbenzene 【0596】 Br O O 【0597】 Under an argon atmosphere, to a solution of 4-benzyloxy- 2-bromotrifluoromethylbenzene (1.3 g, 3.9 mmol) obtained in the above-mentioned (1) in 1,4-dioxane (13 ml) were added 2- isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.99 g, .9 mmol), [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.32 g, 0.39 mmol) and 2M aqueous sodium carbonate solution (5.9 ml) at room temperature, and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=99/1 - 97/3) to give the title compound (1.1 g, yield 99%).
H-NMR (CDCl ) δ: 2.04 (3H, s), 4.88 (1H, br s), 5.08 (2H, s), .18 (1H, br s), 6.82 (1H, d, J = 2.6 Hz), 6.89 (1H, dd, J = 8.8, 2.6 Hz), 7.31-7.42 (5H, m), 7.54 (1H, d, J = 8.8 Hz). 【0598】 (3) 3-isopropyltrifluoromethylphenol 【0599】 【0600】 Under an argon atmosphere, to a solution of 4-benzyloxy- 2-isopropenyltrifluoromethylbenzene (1.2 g, 3.9 mmol) obtained in the above-mentioned (2) in tetrahydrofuran (12 ml) was added 10 wt% palladium carbon (0.23 g) at room temperature, and the mixture was stirred under 1 atm hydrogen atmosphere for 5 hr. Under a nitrogen atmosphere, the reaction mixture was filtered through celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (0.76 g, yield 96%).
H-NMR (CDCl3) δ: 1.23 (6H, d, J = 6.7 Hz), 3.24-3.35 (1H, m), 5.04 (1H, br s), 6.66 (1H, dd, J = 8.6, 2.6 Hz), 6.87 (1H, d, J = 2.6 Hz), 7.46 (1H, d, J = 8.6 Hz). 【0601】 (4) 3-isopropyltrifluoromethylphenyl trifluoromethanesulfonate 【0602】 【0603】 Under an argon atmosphere, to a solution of 3-isopropyl- 4-trifluoromethylphenol (0.77 g, 3.8 mmol) obtained in the above-mentioned (3) in chloroform (8.0 ml) were added triethylamine (0.58 ml, 4.1 mmol) and trifluoromethanesulfonic anhydride (0.67 ml, 4.0 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To the reaction mixture were added water and chloroform, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (0.78 g, yield 62%).
H-NMR (CDCl ) δ: 1.28 (6H, d, J = 6.7 Hz), 3.34-3.46 (1H, m), 7.19 (1H, dd, J = 8.8, 2.4 Hz), 7.34 (1H, d, J = 2.4 Hz), 7.70 (1H, d, J = 8.8 Hz). 【0604】 (5) 2-(3-isopropyltrifluoromethylphenyl)-4,4,5,5- tetramethyl-[1,3,2]dioxaborolane 【0605】 F O O 【0606】 Under an argon atmosphere, to a solution of 3-isopropyl- 4-trifluoromethylphenyl trifluoromethanesulfonate (0.78 g, 2.3 mmol) obtained in the above-mentioned (4) in DMSO (8.0 ml) were added bis(pinacolato)diboron (0.71 g, 2.8 mmol), potassium acetate (0.68 g, 7.0 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.095 g, 0.12 mmol) at room temperature, and the mixture was stirred at 80 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (0.48 g, yield 66%).
H-NMR (CDCl ) δ: 1.29 (6H, d, J = 7.0 Hz), 1.36 (12H, s), 3.29-3.40 (1H, m), 7.57 (1H, d, J = 7.9 Hz), 7.68 (1H, d, J = 7.9 Hz), 7.88 (1H, br s). 【0607】 (6) 2-chloro(3-isopropyltrifluoromethylphenyl)methoxy- 1,3,5-triazine 【0608】 Cl N N Cl 【0609】 Under an argon atmosphere, to a suspension of 2-(3- isopropyltrifluoromethylphenyl)-4,4,5,5-tetramethyl- [1,3,2]dioxaborolane (0.48 g, 1.5 mmol) obtained in the above- mentioned (5), 2,4-dichloromethoxy-1,3,5-triazine (0.69 g, 3.8 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.13 g, 0.15 mmol) in 1,4-dioxane (5.0 ml) was added 2M aqueous sodium carbonate solution (3.1 mL), and the mixture was stirred at 100 C for 1 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=97/3 - 94/6) to give the title compound (0.36 g, yield 71%). 【0610】 (7) {4-chloro[4-(3-isopropyltrifluoromethylphenyl) methoxy-1,3,5-triazinyl]phenyl}methanol 【0611】 N Cl N O H N N N N 【0612】 Under an argon atmosphere, to a solution of 2-chloro (3-isopropyltrifluoromethylphenyl)methoxy-1,3,5-triazine (0.36 g, 1.1 mmol) obtained in the above-mentioned (6), 2- chlorohydroxymethylphenylboronic acid (0.25 g, 1.3 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.089 g, 0.11 mmol) in 1,4-dioxane (3.6 ml) was added 2M aqueous sodium carbonate solution (2.2 ml), and the mixture was stirred at 100 C for 1.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 - 1/1) to give the title compound (0.30 g, yield 62%).
H-NMR (CDCl ) δ: 1.36 (6H, d, J = 6.8 Hz), 1.79 (1H, t, J = 6.0 Hz), 3.37-3.48 (1H, m), 4.24 (3H, s), 4.79 (2H, d, J = 6.0 Hz), 7.49 (1H, dd, J = 8.4, 2.2 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.4 Hz), 8.07 (1H, d, J = 2.2 Hz), 8.47 (1H, d, J = 8.4 Hz), 8.73 (1H, br s). 【0613】 (8)4-chloro[4-(3-isopropyltrifluoromethylphenyl) methoxy-1,3,5-triazinyl]benzylamine hydrochloride 【0614】 Cl O O F Cl N N H ・ H C l N O H 【0615】 Under an argon atmosphere, to a solution of {4-chloro [4-(3-isopropyltrifluoromethylphenyl)methoxy-1,3,5- triazinyl]phenyl}methanol (0.30 g, 0.68 mmol) obtained in the above-mentioned (7) in tetrahydrofuran (3.0 ml) were added triethylamine (0.12 ml, 0.89 mmol) and methanesulfonyl chloride (0.063 ml, 0.82 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (3.0 ml) were added cesium carbonate (0.67 g, 2.0 mmol) and di-tert-butyl iminodicarboxylate (0.18 g, 0.82 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=95/5 - 80/20). Under an argon atmosphere, to a solution (1.0 ml) of the purified product in 1,4-dioxane was added 4M hydrogen chloride /1,4-dioxane solution (4.0 ml) at room temperature, and the mixture was stirred for 1.5 hr.
To the reaction mixture was added n-hexane, and the solid was collected by filtration and dried under reduced pressure to give the title compound (0.24 g, yield 74%).
H-NMR (DMSO-D6) δ: 1.33 (6H, d, J = 6.7 Hz), 3.28-3.40 (1H, m), 4.13-4.22 (5H, m), 7.73 (1H, dd, J = 8.2, 2.2 Hz), 7.77 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J = 8.3 Hz), 8.20 (1H, d, J = 2.2 Hz), 8.35 (3H, br s), 8.48 (1H, d, J = 8.8 Hz), 8.70 (1H, s). 【0616】 (9) N-{4-chloro[4-(3-isopropyltrifluoromethylphenyl) methoxy-1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide 【0617】 Cl Cl F F H N N H ・ H C l N N N N N N 【0618】 Under an argon atmosphere, to a solution of 4-chloro [4-(3-isopropyltrifluoromethylphenyl)methoxy-1,3,5- triazinyl]benzylamine hydrochloride (0.080 g, 0.17 mmol) obtained in the above-mentioned (8), HOBt･H2O (0.039 g, 0.26 mmol) and WSC･HCl (0.049 g, 0.26 mmol) in N,N-dimethylformamide (0.80 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.037 g, 0.24 mmol) and triethylamine (0.071 ml, 0.51 mmol) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=19/1 - 8/2) to give the title compound (0.077 g, yield 79%).
H-NMR (CDCl ) δ: 1.35 (6H, d, J = 6.0 Hz), 1.44 (6H, br s), 3.37-3.49 (1H, m), 4.23 (3H, s), 4.56 (2H, d, J = 5.8 Hz), 6.25 (1H, br s), 7.37 (1H, dd, J = 8.4, 2.3 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.96 (1H, d, J = 2.3 Hz), 8.46 (1H, d, J = 8.4 Hz), 8.72 (1H, br s). 【0619】 (10) N-{4-chloro[4-hydroxy(3-isopropyl trifluoromethylphenyl)-1,3,5-triazinyl]benzyl}-3,3,3- trifluoro-2,2-dimethylpropionamide (Example No.1-130) 【0620】 N N F N N O F 【0621】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(3-isopropyltrifluoromethylphenyl)methoxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (0.077 g, 0.13 mmol) obtained in the above-mentioned (9) in methanol (0.80 ml) was added 4M aqueous sodium hydroxide solution (0.27 ml) at room temperature, and the mixture was stirred at 60 C for 1 hr. To the reaction mixture were added 2N hydrochloric acid (0.54 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.066 g, yield 88%). 【0622】 [Production Example 17] Synthesis of N-{3-[4-(4-butoxyphenyl)hydroxy-1,3,5-triazin- 2-yl]chlorobenzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-131) 【0623】 O Cl 【0624】 (1) N-{3-[4-(4-butoxyphenyl)methoxy-1,3,5-triazinyl] chlorobenzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0625】 H O Cl O Cl N F F N N N O F O F N N N N 【0626】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-hydroxyphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.10 g, 0.21 mmol) obtained in the above-mentioned [Production Example 14] (6), n- butanol (0.023 ml, 0.25 mmol) and triphenylphosphine (0.066 g, 0.25 mmol) in tetrahydrofuran (1.0 ml) was added bis(2- methoxyethyl) azodicarboxylate (0.059 g, 0.25 mmol) under ice- cooling, and the mixture was stirred for 1 hr. To the reaction mixture were added n-butanol (0.019 ml, 0.21 mmol), triphenylphosphine (0.055 g, 0.21 mmol) and bis(2-methoxyethyl) azodicarboxylate (0.049 g, 0.21 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=1/1) to give the title compound (0.096 g, yield 85%). 【0627】 (2) N-{3-[4-(4-butoxyphenyl)hydroxy-1,3,5-triazinyl] chlorobenzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-131) 【0628】 O Cl O Cl N N O F 【0629】 Under an argon atmosphere, to a solution of N-{3-[4-(4- butoxyphenyl)methoxy-1,3,5-triazinyl]chlorobenzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.096 g, 0.18 mmol) obtained in the above-mentioned (1) in methanol (0.96 ml) was added 4M aqueous sodium hydroxide solution (0.27 ml) at room temperature, and the mixture was stirred at 65 C for 2 hr. To the reaction mixture were added 2N hydrochloric acid (0.54 ml) and water and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.086 g, yield 93%). 【0630】 [Production Example 18] Synthesis of N-{4-chloro[4-(3-cyclopropylfluorophenyl) hydroxy-1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-135) 【0631】 F Cl 【0632】 (1) 2-chloro(3-cyclopropylfluorophenyl)methoxy-1,3,5- triazine 【0633】 Cl N Cl N Cl 【0634】 Under an argon atmosphere, to a suspension of 2-(3- cyclopropylfluorophenyl)-4,4,5,5-tetramethyl- [1,3,2]dioxaborolane (0.59 g, 2.2 mmol), 2,4-dichloro methoxy-1,3,5-triazine (0.81 g, 4.5 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.18 g, 0.22 mmol) in 1,4-dioxane (3.0 ml) was added 2M aqueous sodium carbonate solution (3.4 ml), and the mixture was stirred at 100 C for 1 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=25/1 - /1) to give the title compound as a crude product (0.44 g). 【0635】 (2) {4-chloro[4-(3-cyclopropylfluorophenyl)methoxy- 1,3,5-triazinyl]phenyl}methanol 【0636】 F F Cl N Cl N H O O H N N N N 【0637】 Under an argon atmosphere, to a solution of a crude product (0.44 g) of 2-chloro(3-cyclopropylfluorophenyl)- 6-methoxy-1,3,5-triazine obtained in the above-mentioned (1), 2-chlorohydroxymethylphenylboronic acid (0.31 g, 1.6 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.11 g, 0.13 mmol) in 1,4-dioxane (5.4 ml) was added 2M aqueous sodium carbonate solution (2.7 ml), and the mixture was stirred at 100 C for 1 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/3) to give the title compound (0.32 g).
H-NMR (CDCl ) δ: 0.83-0.88 (2H, m), 1.01-1.07 (2H, m), 1.79 (1H, t, J = 6.0 Hz), 2.10-2.19 (1H, m), 4.20 (3H, s), 4.77 (2H, d, J = 6.0 Hz), 7.13 (1H, t, J = 9.2 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.54 (1H, d, J = 8.1 Hz), 8.01 (1H, br s), 8.20 (1H, d, J = 7.6 Hz), 8.38-8.41 (1H, m). 【0638】 (3) tert-butyl N-{4-chloro[4-(3-cyclopropylfluorophenyl)- 6-methoxy-1,3,5-triazinyl]benzyl}-N-(tert- butoxycarbonyl)carbamate 【0639】 F Cl F Cl 【0640】 Under an argon atmosphere, to a solution of {4-chloro [4-(3-cyclopropylfluorophenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.32 g, 0.82 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (3.3 ml) were added triethylamine (0.15 ml, 1.1 mmol) and methanesulfonyl chloride (0.076 ml, 0.98 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (3.3 ml) were added cesium carbonate (0.80 g, 2.5 mmol) and di-tert-butyl iminodicarboxylate (0.21 g, 0.98 mmol) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/1) to give the title compound (0.40 g, yield 83%).
H-NMR (CDCl ) δ: 0.84-0.88 (2H, m), 1.01-1.07 (2H, m), 1.47 (18H, s), 2.09-2.18 (1H, m), 4.18 (3H, s), 4.83 (2H, s), 7.11 (1H, dd, J = 9.7, 8.6 Hz), 7.40 (1H, dd, J = 8.3, 2.2 Hz), 7.49 (1H, d, J = 8.3 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.19 (1H, dd, J = 7.5, 2.2 Hz), 8.36-8.41 (1H, m). 【0641】 (4) 4-chloro[4-(3-cyclopropylfluorophenyl)methoxy- 1,3,5-triazinyl]benzylamine hydrochloride 【0642】 F Cl Cl O O N N H ・ H C l N N O 【0643】 Under an argon atmosphere, to tert-butyl N-{4-chloro [4-(3-cyclopropylfluorophenyl)methoxy-1,3,5-triazin yl]benzyl}-N-(tert-butoxycarbonyl)carbamate(0.40 g, 0.68 mmol) obtained in the above-mentioned (3) was added 4M hydrogen chloride/1,4-dioxane solution (3.3 ml) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added ethyl acetate (35 ml), and the mixture was stirred. The solid was collected by filtration and dried under reduced pressure to give the title compound (0.26 g, yield 89%).
H-NMR (DMSO-D ) δ: 0.78-0.83 (2H, m), 1.05-1.10 (2H, m), 2.10- 2.19 (1H, m), 4.16 (3H, s), 4.16 (2H, s), 7.39 (1H, dd, J = 9.9, 8.7 Hz), 7.71 (1H, dd, J = 8.4, 2.1 Hz), 7.75 (1H, d, J = 8.4 Hz), 8.13 (1H, dd, J = 7.7, 2.1 Hz), 8.16 (1H, d, J = 2.1 Hz), 8.35-8.37 (4H, m). 【0644】 (5) N-{4-chloro[4-(3-cyclopropylfluorophenyl)methoxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide 【0645】 F Cl N N H ・ H C l N N O 【0646】 Under an argon atmosphere, to a solution of 4-chloro [4-(3-cyclopropylfluorophenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride (0.070 g, 0.17 mmol) obtained in the above-mentioned (4), HOBt･H O (0.033 g, 0.22 mmol) and WSC･ HCl (0.041 g, 0.22 mmol) in N,N-dimethylformamide (2.0 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.034 g, 0.22 mmol) and triethylamine (0.069 ml, 0.48 mmol) at room temperature, and the mixture was stirred for 3 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/3) to give the title compound (0.082 g, yield 94%).
H-NMR (CDCl ) δ: 0.82-0.87 (2H, m), 1.01-1.05 (2H, m), 1.43 (6H, s), 2.10-2.16 (1H, m), 4.18 (3H, s), 4.54 (2H, d, J = 5.6 Hz), 6.21 (1H, br s), 7.11 (1H, t, J = 9.2 Hz), 7.34 (1H, d, J = 8.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.90 (1H, s), 8.18 (1H, d, J = 7.7 Hz), 8.36-8.40 (1H, m). 【0647】 (6) N-{4-chloro[4-(3-cyclopropylfluorophenyl)hydroxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-135) 【0648】 F Cl F Cl N N F N N O F 【0649】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(3-cyclopropylfluorophenyl)methoxy-1,3,5-triazin yl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (0.082 g, 0.16 mmol) obtained in the above-mentioned (5) in methanol (1.8 ml) was added 4M aqueous sodium hydroxide solution (0.24 ml) at room temperature, and the mixture was stirred at 60 C for 3 hr.
To the reaction mixture were added 10% aqueous citric acid solution (1.0 ml) and water, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.065 g, yield 81%). 【0650】 [Production Example 19] Synthesis of (R)-N-{4-chloro[4-(4-chloromethylphenyl) hydroxy-1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethoxy methylpropionamide (Example No.1-136) 【0651】 Cl Cl O M e 【0652】 (1) benzyl (R)-3,3,3-trifluorohydroxymethylpropionate 【0653】 O H O H H O O O O F 【0654】 Under an argon atmosphere, to a suspension of (R)-3,3,3- trifluorohydroxymethylpropionic acid (2.2 g, 14 mmol) and potassium carbonate (2.3 g, 16 mmol) in N,N-dimethylformamide (30 ml) was added benzyl bromide (1.8 ml, 15 mmol) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove 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%).
H-NMR (CDCl ) δ: 1.60 (3H, s), 3.78 (1H, s), 5.31 (2H, s), 7.33-7.42 (5H, m). 【0655】 (2) benzyl (R)-3,3,3-trifluoromethoxymethylpropionate 【0656】 O H O M e 【0657】 Under an argon atmosphere, to a solution of benzyl (R)- 3,3,3-trifluorohydroxymethylpropionate (3.4 g, 14 mmol) obtained in the above-mentioned (1) in N,N-dimethylformamide (40 ml) was added sodium hydride (0.60 g, 60 wt% oil dispersion) under ice-cooling, and the mixture was stirred for 1 hr. To the reaction mixture was added methyl iodide (1.3 ml, mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added saturated aqueous ammonium chloride and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=15/1) to give the title compound (2.8 g, yield 78%).
H-NMR (CDCl ) δ: 1.59 (3H, s), 3.40 (3H, s), 5.26 (2H, s), 7.31-7.37 (5H, m). 【0658】 (3) (R)-3,3,3-trifluoromethoxymethylpropionic acid 【0659】 O M e O M e O H O F O F 【0660】 Under an argon atmosphere, to a solution of benzyl (R)- 3,3,3-trifluoromethoxymethylpropionate (2.8 g, 11 mmol) obtained in the above-mentioned (2) in ethyl acetate (50 ml) was added 10 wt% palladium carbon (0.23 g) at room temperature, and the mixture was stirred under 1 atm hydrogen atmosphere for 5 hr. Under a nitrogen atmosphere, the reaction mixture was filtered through celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.4 g, yield 78%).
H-NMR (CDCl ) δ: 1.68 (3H, s), 3.54 (3H, s). 【0661】 (4) 2-chloro(4-chloromethylphenyl)methoxy-1,3,5- triazine 【0662】 Cl N Cl 【0663】 Under an argon atmosphere, to a suspension of 4-chloro methylphenylboronic acid (0.47 g, 2.8 mmol), 2,4-dichloro methoxy-1,3,5-triazine (1.0 g, 5.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) in toluene (5.0 ml) was added 2M aqueous sodium carbonate solution (4.2 ml), and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2 - 95/5) to give the title compound (0.50 g, yield 48%).
H-NMR (CDCl ) δ: 2.47 (3H, s), 4.17 (3H, s), 7.47 (1H, d, J = 8.4 Hz), 8.26 (1H, dd, J = 8.4, 2.1 Hz), 8.36 (1H, d, J = 2.1 Hz). 【0664】 (5) {4-chloro[4-(4-chloromethylphenyl)methoxy-1,3,5- triazinyl]phenyl}methanol 【0665】 Cl Cl Cl N Cl N O H N N N N 【0666】 Under an argon atmosphere, to a solution of 2-chloro (4-chloromethylphenyl)methoxy-1,3,5-triazine (0.50 g, 1.3 mmol) obtained in the above-mentioned (4), 2-chloro hydroxymethylphenylboronic acid (0.30 g, 1.6 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.11 g, 0.13 mmol) in 1,4-dioxane (5.0 ml) was added 2M aqueous sodium carbonate solution (2.6 ml), and the mixture was stirred at 100 C for 1.5 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 - 6/4) to give the title compound (0.40 g, yield 80%).
H-NMR (CDCl ) δ: 1.79 (1H, t, J = 5.3 Hz), 2.48 (3H, s), 4.21 (3H, s), 4.78 (2H, d, J = 5.3 Hz), 7.45-7.50 (2H, m), 7.54 (1H, d, J = 8.1 Hz), 8.01 (1H, d, J = 2.1 Hz), 8.37 (1H, dd, J = 8.4, 2.1 Hz), 8.46 (1H, d, J = 2.1 Hz). 【0667】 (6) 4-chloro[4-(4-chloromethylphenyl)methoxy-1,3,5- triazinyl]benzylamine hydrochloride 【0668】 Cl Cl Cl Cl O O Cl Cl N O H N N O N ・ H C l 【0669】 Under an argon atmosphere, to a solution of {4-chloro [4-(4-chloromethylphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.40 g, 1.1 mmol) obtained in the above- mentioned (5) in tetrahydrofuran (4.0 ml) were added triethylamine (0.19 ml, 1.4 mmol) and methanesulfonyl chloride (0.098 ml, 1.3 mmol) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (2.0 ml) were added cesium carbonate (1.0 g, 3.2 mmol) and di-tert-butyl iminodicarboxylate (0.37 g, 1.7 mmol) at room temperature, and the mixture was stirred for 3 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5 - 80/20). Under an argon atmosphere, to a solution (2.0 ml) of the purified product in 1,4-dioxane was added 4M hydrogen chloride /1,4-dioxane solution (4.0 ml) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture was added n-hexane, and the solid was collected by filtration and dried under reduced pressure to give the title compound (0.43 g, yield 99%).
H-NMR (DMSO-D ) δ: 2.47 (3H, s), 4.13-4.19 (5H, m), 7.67 (1H, d, J = 8.3 Hz), 7.71-7.76 (2H, m), 8.16 (1H, d, J = 1.6 Hz), 8.35 (1H, dd, J = 8.3, 1.6 Hz), 8.41-8.50 (4H, m). 【0670】 (7) (R)-N-{4-chloro[4-(4-chloromethylphenyl)methoxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethoxy methylpropionamide 【0671】 Cl Cl O M e Cl Cl N N H ・ H C l 【0672】 Under an argon atmosphere, to a solution of 4-chloro [4-(4-chloromethylphenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride (0.070 g, 0.17 mmol) obtained in the above-mentioned (6), HOBt･H O (0.039 g, 0.26 mmol) and WSC･ HCl (0.049 g, 0.26 mmol) in N,N-dimethylformamide (0.70 ml) were added (R)-3,3,3-trifluoromethoxymethylpropionic acid (0.038 g, 0.22 mmol) obtained in the above-mentioned (3) and triethylamine (0.071 ml, 0.51 mmol) at room temperature, and the mixture was stirred for 18 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to give the title compound (0.058 g, yield 65%).
H-NMR (CDCl ) δ: 1.66 (3H, s), 2.48 (3H, s), 3.45 (3H, s), 4.20 (3H, s), 4.48 (1H, dd, J = 15.1, 5.8 Hz), 4.63 (1H, dd, J = 15.1, 6.5 Hz), 7.16 (1H, br s), 7.37 (1H, dd, J = 8.3, 2.3 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J = 2.3 Hz), 8.36 (1H, dd, J = 8.3, 2.0 Hz), 8.46 (1H, d, J = 2.0 Hz). 【0673】 (8) (R)-N-{4-chloro[4-(4-chloromethylphenyl)hydroxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethoxy methylpropionamide (Example No.1-136) 【0674】 Cl Cl Cl Cl O M e O M e N N F N O F 【0675】 Under an argon atmosphere, to a solution of (R)-N-{4- chloro[4-(4-chloromethylphenyl)methoxy-1,3,5-triazin- 2-yl]benzyl}-3,3,3-trifluoromethoxymethylpropionamide (0.058 g, 0.11 mmol) obtained in the above-mentioned (7) in methanol (1.3 ml) was added 4M aqueous sodium hydroxide solution (0.17 ml) at room temperature, and the mixture was stirred at 60 C for 3 hr. To the reaction mixture were added % aqueous citric acid solution (0.68 ml) and water, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.051 g, yield 88%). 【0676】 [Production Example 20] Synthesis of (R)-N-{4-chloro[4-hydroxy(4-propoxyphenyl)- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethoxy methylpropionamide (Example No.1-137) 【0677】 O Cl O M e 【0678】 (1) (R)-N-{4-chloro[4-methoxy(4-propoxyphenyl)-1,3,5- triazinyl]benzyl}-3,3,3-trifluoromethoxy methylpropionamide 【0679】 O Cl O M e O Cl N N H ・ H C l 【0680】 Under an argon atmosphere, to a solution of 4-chloro [4-methoxy(4-propoxyphenyl)-1,3,5-triazinyl]benzylamine hydrochloride (0.80 g, 0.19 mmol) obtained in [Production Example 13] (4), HOBt･H O (0.044 g, 0.28 mmol) and WSC･HCl (0.055 g, 0.28 mmol) in N,N-dimethylformamide (1.0 ml) were added (R)-3,3,3-trifluoromethoxymethylpropionic acid (0.046 g, 0.27 mmol) obtained in [Production Example 19] (3) and triethylamine (0.080 ml, 0.57 mmol) at room temperature, and the mixture was stirred for 18 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n- hexane/ethyl acetate=8/2 - 3/2) to give the title compound (0.084 g, yield 82%).
H-NMR (CDCl ) δ: 1.07 (3H, t, J = 7.4 Hz), 1.66 (3H, br s), 1.81-1.90 (2H, m), 3.45 (3H, br s), 4.02 (2H, t, J = 6.5 Hz), 4.19 (3H, s), 4.50 (1H, dd, J = 15.0, 5.8 Hz), 4.59 (1H, dd, J = 15.0, 6.3 Hz), 6.97-7.02 (2H, m), 7.14 (1H, br s), 7.35 (1H, dd, J = 8.3, 2.3 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.92 (1H, d, J = 2.3 Hz), 8.52-8.56 (2H, m). 【0681】 (2) (R)-N-{4-chloro[4-hydroxy(4-propoxyphenyl)-1,3,5- triazinyl]benzyl}-3,3,3-trifluoromethoxy methylpropionamide (Example No.1-137) 【0682】 O Cl O Cl O M e O M e N N O F 【0683】 Under an argon atmosphere, to a solution of (R)-N-{4- chloro[4-methoxy(4-propoxyphenyl)-1,3,5-triazin yl]benzyl}-3,3,3-trifluoromethoxymethylpropionamide (0.084 g, 0.16 mmol) obtained in the above-mentioned (1) in methanol (0.80 ml) was added 4M aqueous sodium hydroxide solution (0.30 ml) at room temperature, and the mixture was stirred at 65 C for 1.5 hr. To the reaction mixture were added 2N hydrochloric acid (0.60 ml) and water, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.072 g, yield 89%). 【0684】 [Production Example 21] Synthesis of N-{4-chloro[4-(3,4-dimethylphenyl)hydroxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-150) 【0685】 【0686】 (1) 2-chloro(3,4-dimethylphenyl)methoxy-1,3,5-triazine 【0687】 Cl N Cl 【0688】 Under an argon atmosphere, to a suspension of 3,4- dimethylbenzeneboronic acid (0.42 g, 2.8 mmol), 2,4-dichloro methoxy-1,3,5-triazine (1.0 g, 5.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) in toluene (8.4 ml) was added 2M aqueous sodium carbonate solution (4.2 ml), and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.64 g, 92%).
H-NMR (CDCl3) δ: 2.35 (6H, s), 4.16 (3H, s), 7.26 (3H, d, J = 7.8 Hz), 8.22 (1H, dd, J = 7.8, 2.1 Hz), 8.25 (1H, d, J = 2.1 Hz). 【0689】 (2) {4-chloro[4-(3,4-dimethylphenyl)methoxy-1,3,5- triazinyl]phenyl}methanol 【0690】 N Cl N H O O H N N N N 【0691】 Under an argon atmosphere, to a solution of 2-chloro (3,4-dimethylphenyl)methoxy-1,3,5-triazine (0.64 g, 2.6 mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (0.57 g, 3.1 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.21 g, 0.26 mmol) in 1,4-dioxane (10 ml) was added 2M aqueous sodium carbonate solution (5.1 ml), and the mixture was stirred at 100 C for 1 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/3) to give the title compound (0.54 g, yield 59%).
H-NMR (CDCl ) δ: 1.87 (1H, t, J = 5.0 Hz), 2.35 (3H, s), 2.36 (3H, s), 4.20 (3H, s), 4.76 (2H, d, J = 5.0 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.45 (1H, dd, J = 8.4, 1.6 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.99 (1H, d, J = 1.6 Hz), 8.33 (1H, d, J = 8.2 Hz), 8.35 (1H, br s). 【0692】 (3) 4-chloro[4-(3,4-dimethylphenyl)methoxy-1,3,5-triazin- 2-yl]benzylamine hydrochloride 【0693】 Cl O N N H ・ H C l 【0694】 Under an argon atmosphere, to a solution of {4-chloro [4-(3,4-dimethylphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (0.54 g, 1.5 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (5.5 ml) were added triethylamine (0.28 ml, 2.0 mmol) and methanesulfonyl chloride (0.14 ml, 1.8 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (5.5 ml) were added cesium carbonate (1.5 g, 4.6 mmol) and di-tert-butyl iminodicarboxylate (0.40 g, 1.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/1). Under an argon atmosphere, to the purified product was added 4M hydrogen chloride/1,4-dioxane solution (6.5 ml) at room temperature, and the mixture was stirred for 0.5 hr. To the reaction mixture was added ethyl acetate, and the solid was collected by filtration, and dried under reduced pressure to give the title compound (0.56 g, yield 94%).
H-NMR (DMSO-D6) δ: 2.34 (3H, s), 2.35 (3H, s), 4.12-4.19 (5H, m), 7.38 (1H, d, J = 7.9 Hz), 7.69-7.75 (2H, m), 8.12 (1H, d, J = 1.9 Hz), 8.26 (1H, dd, J = 7.9, 1.6 Hz), 8.29 (1H, br s), 8.44 (3H, br s). 【0695】 (4) N-{4-chloro[4-(3,4-dimethylphenyl)methoxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide 【0696】 N ・ H C l 【0697】 Under an argon atmosphere, to a solution of 4-chloro [4-(3,4-dimethylphenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride (0.070 g, 0.18 mmol) obtained in the above-mentioned (3), HOBt･H O (0.035 g, 0.23 mmol) and WSC･ HCl (0.044 g, 0.23 mmol) in N,N-dimethylformamide (2.0 ml) were added 3,3,3-trifluoro-2,2-dimethylpropionic acid (0.036 g, 0.23 mmol) and triethylamine (0.075 ml, 0.54 mmol) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the mixture was partitioned.
The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.075 g, yield 85%).
H-NMR (CDCl ) δ: 1.44 (6H, s), 2.36 (3H, s), 2.37 (3H, s), 4.20 (3H, s), 4.55 (2H, d, J = 5.7 Hz), 6.22 (1H, br s), 7.27 (3H, d, J = 7.8 Hz), 7.35 (1H, dd, J = 8.2, 2.2 Hz), 7.52 (1H, d, J = 8.2 Hz), 7.91 (1H, d, J = 2.2 Hz), 8.32 (1H, dd, J = 7.8, 1.7 Hz), 8.35 (1H, br s). 【0698】 (5) N-{4-chloro[4-(3,4-dimethylphenyl)hydroxy-1,3,5- triazinyl]benzyl}-3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-150) 【0699】 N N F N N O 【0700】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(3,4-dimethylphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.075 g, 0.15 mmol) obtained in the above-mentioned (4) in methanol (1.8 ml) was added 4M aqueous sodium hydroxide solution (0.23 ml) at room temperature, and the mixture was stirred at 60 C for 4 hr. To the reaction mixture were added 10% aqueous citric acid solution (1.0 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.063 g, yield 86%). 【0701】 [Production Example 22] Synthesis of N-{4-chloro[4-(4-cyclopropylmethoxyphenyl) hydroxy-1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethyl trifluoromethylpropionamide (Example No.1-169) 【0702】 O Cl F 【0703】 (1) 2-chloro(4-cyclopropylmethoxyphenyl)methoxy-1,3,5- triazine 【0704】 Cl N Cl N Cl 【0705】 Under an argon atmosphere, to a suspension of 4- (cyclopropylmethoxy)benzeneboronic acid (2.5 g, 13 mmol), 2,4- dichloromethoxy-1,3,5-triazine (4.7 g, 26 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol) in toluene (25 ml) was added 2M aqueous sodium carbonate solution (20 ml), and the mixture was stirred at 100 C for 2 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=90/10 - 80/20) to give the title compound (3.0 g, 79%).
H-NMR (CDCl ) δ: 0.36-0.41 (2H, m), 0.65-0.71 (2H, m), 1.25- 1.36 (1H, m), 3.90 (2H, d, J = 7.0 Hz), 4.14 (3H, s), 6.96-7.00 (2H, m), 8.42-8.47 (2H, m). 【0706】 (2) {4-chloro[4-(4-cyclopropylmethoxyphenyl)methoxy- 1,3,5-triazinyl]phenyl}methanol 【0707】 O O Cl N Cl N O H + O H N N N N 【0708】 Under an argon atmosphere, to a solution of 2-chloro (4-cyclopropylmethoxyphenyl)methoxy-1,3,5-triazine (3.0 g, mmol) obtained in the above-mentioned (1), 2-chloro hydroxymethylphenylboronic acid (2.3 g, 12 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane adduct (0.84 g, 1.0 mmol) in 1,4-dioxane (30 ml) was added 2M aqueous sodium carbonate solution (21 ml), and the mixture was stirred at 100 C for 3 hr. At room temperature, to the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 - 1/1) to give the title compound (2.9 g, yield 71%).
H-NMR (CDCl ) δ: 0.37-0.41 (2H, m), 0.65-0.71 (2H, m), 1.27- 1.36 (1H, m), 1.76 (1H, t, J = 6.0 Hz), 3.90 (2H, d, J = 6.7 Hz), 4.19 (3H, s), 4.77 (2H, d, J = 6.0 Hz), 6.98-7.02 (2H, m), 7.46 (1H, dd, J = 8.1, 1.9 Hz), 7.53 (1H, d, J = 8.1 Hz), 8.00 (1H, d, J = 1.9 Hz), 8.53-8.57 (2H, m). 【0709】 (3) 4-chloro[4-(4-cyclopropylmethoxyphenyl)methoxy-1,3,5- triazinyl]benzylamine hydrochloride 【0710】 O Cl O Cl O O Cl N O H N N H ・ H C l 【0711】 Under an argon atmosphere, to a solution of {4-chloro [4-(4-cyclopropylmethoxyphenyl)methoxy-1,3,5-triazin yl]phenyl}methanol (2.9 g, 7.3 mmol) obtained in the above- mentioned (2) in tetrahydrofuran (29 ml) were added triethylamine (1.3 ml, 9.5 mmol) and methanesulfonyl chloride (0.68 ml, 8.7 mmol) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (29 ml) were added cesium carbonate (7.1 g, 22 mmol) and di-tert-butyl iminodicarboxylate (1.9 g, 8.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5 - 70/30). Under an argon atmosphere, to a solution (9.3 ml) of the purified product in 1,4-dioxane was added 4M hydrogen chloride/1,4-dioxane solution (37 ml) at room temperature, and the mixture was stirred for 3 hr. To the reaction mixture was added ethyl acetate, and the solid was collected by filtration, and dried under reduced pressure to give the title compound (3.1 g, yield 97%).
H-NMR (DMSO-D ) δ: 0.34-0.39 (2H, m), 0.57-0.63 (2H, m), 1.21- 1.32 (1H, m), 3.95 (2H, d, J = 7.0 Hz), 4.11-4.18 (5H, m), 7.11-7.15 (2H, m), 7.70-7.74 (2H, m), 8.13 (1H, br s), 8.42- 8.53 (5H, m). 【0712】 (4) N-{4-chloro[4-(4-cyclopropylmethoxyphenyl)methoxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethyl trifluoromethylpropionamide 【0713】 Cl F O Cl N N H ・ H C l 【0714】 Under an argon atmosphere, to a solution of 4-chloro [4-(4-cyclopropylmethoxyphenyl)methoxy-1,3,5-triazin yl]benzylamine hydrochloride (0.080 g, 0.18 mmol) obtained in the above-mentioned (3), HOBt･H O (0.037 g, 0.24 mmol) and WSC･ HCl (0.046 g, 0.24 mmol) in N,N-dimethylformamide (2.0 ml) were added 2,2-bis(trifluoromethyl)propionic acid (0.050 g, 0.24 mmol) and triethylamine (0.077 ml, 0.55 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added HOBt･H O (0.037 g, 0.24 mmol), WSC･ HCl (0.046 g, 0.24 mmol), 2,2-bis(trifluoromethyl)propionic acid (0.050 g, 0.24 mmol) and triethylamine (0.077 ml, 0.55 mmol), and the mixture was stirred for 2 hr. To the reaction mixture were added HOBt･H O (0.037 g, 0.24 mmol), WSC･HCl (0.046 g, 0.24 mmol), 2,2-bis(trifluoromethyl)propionic acid (0.050 g, 0.24 mmol) and triethylamine (0.077 ml, 0.55 mmol), and the mixture was stirred for 1.5 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (0.045 g, yield 41%).
H-NMR (CDCl ) δ: 0.36-0.41 (2H, m), 0.65-0.71 (2H, m), 1.26- 1.35 (2H, m), 1.70 (3H, s), 3.90 (2H, d, J = 6.7 Hz), 4.19 (3H, s), 4.61 (2H, d, J = 5.8 Hz), 6.49 (1H, br s), 6.98-7.02 (2H, m), 7.32 (1H, dd, J = 8.5, 2.1 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.92 (1H, d, J = 2.1 Hz), 8.52-8.56 (2H, m). 【0715】 (5) N-{4-chloro[4-(4-cyclopropylmethoxyphenyl)hydroxy- 1,3,5-triazinyl]benzyl}-3,3,3-trifluoromethyl trifluoromethylpropionamide (Example No.1-169) 【0716】 O Cl F F O Cl N N F N O F 【0717】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-cyclopropylmethoxyphenyl)methoxy-1,3,5-triazin yl]benzyl}-3,3,3-trifluoromethyl trifluoromethylpropionamide (0.045 g, 0.076 mmol) obtained in the above-mentioned (4) in methanol (0.70 ml) was added 4M aqueous sodium hydroxide solution (0.11 ml) at room temperature, and the mixture was stirred at 60 C for 4 hr. To the reaction mixture were added 10% aqueous citric acid solution (0.50 ml) and water, and the mixture was stirred at room temperature.
The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.039 g, yield 89%). 【0718】 [Production Example 23] Synthesis of 1-trifluoromethylcyclopropanecarboxylic acid 4- chloro[4-hydroxy(4-isobutoxyphenyl)-1,3,5-triazin yl]benzylamide (Example No.1-178) 【0719】 O Cl 【0720】 (1) 1-trifluoromethylcyclopropanecarboxylic acid 4-chloro[4- (4-isobutoxyphenyl)methoxy-1,3,5-triazinyl]benzylamide 【0721】 Cl Cl N N H N N ・ H C l N N N N 【0722】 Under an argon atmosphere, to a solution of 4-chloro [4-(4-isobutoxyphenyl)methoxy-1,3,5-triazinyl]benzylamine hydrochloride (0.10 g, 0.23 mmol) obtained in [Production Example 12] (4), HOBt･H O (0.049 g, 0.32 mmol) and WSC･HCl (0.061 g, 0.32 mmol) in N,N-dimethylformamide (0.75 ml) were added 1-trifluoromethylcyclopropanecarboxylic acid (0.050 g, 0.32 mmol) and triethylamine (0.064 ml, 0.46 mmol) at room temperature, and the mixture was stirred for 1.5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, then chloroform/ethyl acetate=9/1) to give the title compound (0.068 g, yield 55%).
H-NMR (DMSO-D6) δ: 1.01 (6H, d, J = 6.9 Hz), 1.23-1.27 (2H, m), 1.30-1.36 (2H, m), 2.00-2.11 (1H, m), 3.87 (2H, d, J = 6.4 Hz), 4.12 (3H, s), 4.37 (2H, d, J = 5.9 Hz), 7.11-7.15 (2H, m), 7.43 (1H, dd, J = 8.2, 2.1 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.85 (1H, d, J = 2.1 Hz), 8.43-8.47 (2H, m), 8.50 (1H, t, J = 5.9 Hz). 【0723】 (2) 1-trifluoromethyl-cyclopropanecarboxylic acid 4-chloro [4-hydroxy(4-isobutoxyphenyl)-1,3,5-triazinyl]benzylamide (Example No.1-178) 【0724】 O Cl O Cl N N F N N O F 【0725】 Under an argon atmosphere, to a solution of 1- trifluoromethylcyclopropanecarboxylic acid 4-chloro[4-(4- isobutoxyphenyl)methoxy-1,3,5-triazinyl]benzylamide (0.065 g, 0.12 mmol) obtained in the above-mentioned (1) in methanol (1.0 ml) was added 4M aqueous sodium hydroxide solution (0.12 ml) at room temperature, and the mixture was stirred at 60 C for 3 hr. To the reaction mixture were added 2N hydrochloric acid (0.24 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.060 g, yield 94%). 【0726】 [Production Example 24] Synthesis of N-(4-chloro{4-[4-((S) cyclopropylethoxy)phenyl]hydroxy-1,3,5-triazinyl}benzyl)- 3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-184) 【0727】 O Cl 【0728】 (1) N-(4-chloro{4-[4-((S)cyclopropylethoxy)phenyl] methoxy-1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide 【0729】 H O Cl O Cl N N N N N N O N N O 【0730】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-hydroxyphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.080 g, 0.17 mmol) obtained in the above-mentioned [Production Example 14] (6), (1R)cyclopropylethanol (0.029 g, 0.33 mmol) and triphenylphosphine (0.087 g, 0.33 mmol) in tetrahydrofuran (1.0 ml) was added bis(2-methoxyethyl)azodicarboxylate (0.078 g, 0.33 mmol) under ice-cooling, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.079 g, yield 86%).
H-NMR (CDCl ) δ: 0.28-0.36 (1H, m), 0.38-0.45 (1H, m), 0.53- 0.63 (2H, m), 1.12-1.21 (1H, m), 1.41 (3H, d, J = 6.0 Hz), 1.44 (6H, s), 3.95-4.05 (1H, m), 4.18 (3H, s), 4.54 (2H, d, J = 5.6 Hz), 6.20 (1H, br s), 6.95-7.00 (2H, m), 7.34 (1H, dd, J = 8.3, 1.9 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.50-8.55 (2H, m). 【0731】 (2) N-(4-chloro{4-[4-((S)cyclopropylethoxy)phenyl] hydroxy-1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-184) 【0732】 O Cl O Cl N N N N N O F 【0733】 Under an argon atmosphere, to a solution of N-(4-chloro- 3-{4-[4-((S)cyclopropylethoxy)phenyl]methoxy-1,3,5- triazinyl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide (0.079 g, 0.14 mmol) obtained in the above-mentioned (1) in methanol (1.3 ml) was added 4M aqueous sodium hydroxide solution (0.22 ml) at room temperature, and the mixture was stirred at 65 C for 4 hr. To the reaction mixture were added 10% aqueous citric acid solution (0.90 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.072 g, yield 93%). 【0734】 [Production Example 25] Synthesis of N-(4-chloro{4-[4-((R) cyclopropylethoxy)phenyl]hydroxy-1,3,5-triazinyl}benzyl)- 3,3,3-trifluoro-2,2-dimethylpropionamide (Example No.1-185) 【0735】 O Cl 【0736】 (1) N-(4-chloro{4-[4-((R)cyclopropylethoxy)phenyl] methoxy-1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide 【0737】 H O Cl O Cl N N N N N N O N N O 【0738】 Under an argon atmosphere, to a solution of N-{4-chloro- 3-[4-(4-hydroxyphenyl)methoxy-1,3,5-triazinyl]benzyl}- 3,3,3-trifluoro-2,2-dimethylpropionamide (0.080 g, 0.17 mmol) obtained in the above-mentioned [Production Example 14] (6), (1S)cyclopropylethanol (0.029 g, 0.33 mmol) and triphenylphosphine (0.087 g, 0.33 mmol) in tetrahydrofuran (1.0 ml) was added bis(2-methoxyethyl) azodicarboxylate (0.078 g, 0.33 mmol) under ice-cooling, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (0.038 g, yield 41%).
H-NMR (CDCl ) δ: 0.28-0.36 (1H, m), 0.38-0.45 (1H, m), 0.53- 0.63 (2H, m), 1.12-1.21 (1H, m), 1.41 (3H, d, J = 6.0 Hz), 1.44 (6H, s), 3.95-4.05 (1H, m), 4.18 (3H, s), 4.54 (2H, d, J = 5.6 Hz), 6.20 (1H, br s), 6.95-7.00 (2H, m), 7.34 (1H, dd, J = 8.3, 1.9 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.50-8.55 (2H, m). 【0739】 (2) N-(4-chloro{4-[4-((R)cyclopropylethoxy)phenyl] hydroxy-1,3,5-triazinyl}benzyl)-3,3,3-trifluoro-2,2- dimethylpropionamide (Example No.1-185) 【0740】 O Cl O Cl N N F N N F N N O 【0741】 Under an argon atmosphere, to a solution of N-(4-chloro- 3-{4-[4-((R)cyclopropylethoxy)phenyl]methoxy-1,3,5- triazinyl}benzyl)-3,3,3-trifluoro-2,2-dimethylpropionamide (0.038 g, 0.069 mmol) obtained in the above-mentioned (1) in methanol (0.62 ml) was added 4M aqueous sodium hydroxide solution (0.10 ml) at room temperature, and the mixture was stirred at 65 C for 4 hr. To the reaction mixture were added % aqueous citric acid solution (0.42 ml) and water at room temperature, and the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.034 g, yield 91%). 【0742】 The compounds of Example 1-1 to Example 1-267, Example 2- 1 to Example 2-130, and Example 3-1 to Example 3-23 were obtained according to the above-mentioned Production Methods.
The structural formulas and property data of the Example compounds are shown in Table 1-1 to Table 1-34, Table 2-1 to Table 2-15, and Table 3-1 to Table 3-3. In the Tables, the notes show the following. 【0743】 F Cl F Cl NaBH N N O OH racemate Cl O O N N O Production Production N N O Example 1 (3) Example 1 (4) racemate F Cl F Cl HO F N NH N N F N N N N O F Production ・HCl O O F D Example 1 (5) diastereomeric mixture racemate N N F N O F N N O F Production Example 1 (6) less polar diastereomer 1-188 silica gel F Cl F Cl chromatography N N F N N O F Production Example 1 (6) 1-189 more polar diastereomer 【0744】 Note 1 (Example No. 1-188, 1-189) Using 2,4-dichloromethoxy-1,3,5-triazine, 4-fluoro methylphenylboronic acid instead of 4-(2,2- dimethylpropoxy)phenylboronic acid, and 5-acetyl chlorophenylboronic acid instead of 2-chloro hydroxymethylphenylboronic acid, and by a method similar to that in Production Example 1 (1) and (2), compound A was obtained.
Racemic compound B was obtained by reducing the carbonyl group of compound A with sodium borohydride.
Racemic compound D was obtained by treating compound B in the same manner as in Production Example 1 (3) and (4).
Compound F as a diastereomer mixture was obtained by reacting racemic compound D with pure enantiomer compound E.
Compound F1 which is a less polar diastereomer (Merck TLC Silica gel 60G F254 25 Glassplates, eluent: n-hexane/ethyl acetate=2/1) and compound F2 which is a more polar diastereomer were obtained by purifying compound F by silica gel column chromatography. While compound F1 and compound F2 are single stereoisomers, the absolute configuration of the asymmetric carbon at the benzyl position is undetermined.
The compound of Example No. 1-188 was obtained by hydrolyzing compound F1 in the same manner as in Production Example 1 (6). Similarly, the compound of Example No. 1-189 was obtained from compound F2. While the compound of Example No. 1-188 and the compound of Example No. 1-189 are single stereoisomers, the absolute configuration of the asymmetric carbon at the benzyl position is undetermined. 【0745】 Cl Cl NaBH N O N OH Production Example 1 (3) O O K racemate HO F Cl O O N NH N N O Production Production Example 1 (5) Example 1 (4) ・HCl racemate racemate O Cl N N O F O Cl N N F silica gel less polar diastereomer N N O F chromatography N N F diastereomeric mixture N N O F more polar diastereomer N1 N N F Production less polar N N O F Example 1 (6) diastereomer 1-200 O Cl N2 N N F Production more polar F Example 1 (6) diastereomer 1-201 【0746】 Note 2 (Example No. 1-200, 1-201) Using 2,4-dichloromethoxy-1,3,5-triazine, 4-(2,2- dimethylpropoxy)phenylboronic acid, and 5-acetyl chlorophenylboronic acid instead of 2-chloro hydroxymethylphenylboronic acid, and by a method similar to that in Production Example 1 (1) and (2), compound J was obtained.
Racemic compound K was obtained by reducing the carbonyl group of compound J with sodium borohydride.
Racemic compound M was obtained by treating compound K in the same manner as in Production Example 1 (3) and (4).
Compound N as a diastereomer mixture was obtained by reacting racemic compound M with pure enantiomer compound E.
Compound N was purified by silica gel column chromatography in the same manner as in note 1, by a method similar to that in Production Example 1 (6), the compound of Example No. 1-200 was obtained from compound N1 which is a less polar diastereomer (Merck TLC Silica gel 60G F254 25 Glassplates, eluent: n-hexane/ethyl acetate=2/1), and the compound of Example No. 1-201 was obtained from compound N2 which is a more polar diastereomer. While the compounds of Example Nos. 1-200 and 1-201 are single stereoisomers, the absolute configuration of the asymmetric carbon at the benzyl position is undetermined. 【0747】 Note 3 (Example Nos. 1-256, 1-257) While they are single stereoisomers, the relative configuration thereof is undetermined. 【0748】 Note 4 (Example No. 1-266) While it is a single stereoisomer, the relative configuration of the tert-butyl group is undetermined. 【0749】 Note 5 (Example No. 1-267) While it is a single stereoisomer, the relative configuration of the methoxy group is undetermined. 【0750】 【Table 1-1】 Example Structure NMR MS(M+H) MS(M-H) Note 1H-NMR (DMSO-D6) δ: 2.50 (3H, s), 7.38 (1H, td, J = 8.3, 2.5 Hz), 7.46 (1H, dd, J = 8.4, 3 5.3 Hz), 7.56-7.65 (1H, br m), 7.95 (2H, d, J = 350 348 8.4 Hz), 8.55 (2H, d, J = 8.4 Hz), 13.33 (1H, br s).
HO F 1H-NMR (DMSO-D6) δ: 2.35 (3H, s), 2.50 (3H, s), 7.30 (1H, d, J = 7.7 Hz), 7.34 (1H, d, J = 7.7 Hz), 7.51 (1H, br s), 7.94 (2H, d, J = 346 344 8.1 Hz), 8.55 (2H, d, J = 8.1 Hz), 13.17 (1H, N br s). 1H-NMR (DMSO-D6) δ: 2.50 (3H, s), 7.45 (1H, d, J = 8.4 Hz), 7.59 (1H, dd, J = 8.4, 2.3 1-3 366 364 Hz), 7.81 (1H, br s), 7.94 (2H, d, J = 8.1 Hz), 8.54 (2H, d, J = 8.1 Hz), 13.33 (1H, s).
HO Cl 1H-NMR (DMSO-D6) δ: 2.38 (3H, s), 7.46 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 8.1 Hz), 366 364 7.64 (1H, br s), 7.94 (2H, d, J = 8.4 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.49 (1H, br s). 1H-NMR (DMSO-D6) δ: 7.69 (1H, dd, J = 8.8, 2.2 Hz), 7.83 (1H, d, J = 8.8 Hz), 7.91 1-5 436 434 (1H, d, J = 2.2 Hz), 7.95 (2H, d, J = 8.2 Hz), N 8.53 (2H, d, J = 8.2 Hz), 13.67 (1H, br s).
HO O F 1H-NMR (DMSO-D6) δ: 3.83 (3H, s), 7.21 (1H, dd, J = 8.8, 3.1 Hz), 7.41 (1H, d, J = 3.1 Hz), 7.57 (1H, d, J = 8.8 Hz), 7.94 (2H, d, J = 382 380 8.4 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.52 (1H, br s).
HO O CH 1H-NMR (DMSO-D6) δ: 7.01 (1H, dd, J = 8.6, 2.9 Hz), 7.17 (1H, s), 7.44 (1H, d, J = 8.6 368 366 N Hz), 7.94 (2H, d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 10.17 (1H, s), 13.46 (1H, br s). 1H-NMR (DMSO-D6) δ: 7.81 (1H, d, J = 8.4 Cl Hz), 7.94 (2H, d, J = 8.4 Hz), 8.12 (1H, dd, J 1-8 396 394 = 8.5, 2.0 Hz), 8.36 (1H, d, J = 1.9 Hz), 8.54 N (2H, d, J = 8.4 Hz), 13.53 (2H, br s).
HO OH 【0751】 【Table 1-2】 1H-NMR (DMSO-D6) δ: 2.63 (3H, s), 7.66 H C (1H, d, J = 8.2 Hz), 7.88 (1H, dd, J = 8.3, 1.7 1-9 400 398 Hz), 7.95 (2H, d, J = 8.4 Hz), 8.11 (1H, br s), N 8.54 (2H, d, J = 8.4 Hz), 13.41 (1H, br s).
HO F 1H-NMR (DMSO-D6) δ: 2.61 (3H, s), 7.54 H C (1H, d, J = 7.9 Hz), 7.94 (2H, d, J = 8.4 Hz), 376 374 1-10 8.04 (1H, dd, J = 7.9, 1.8 Hz), 8.30 (1H, br s), 8.55 (2H, d, J = 8.4 Hz), 13.23 (2H, br s).
HO OH 1H-NMR (DMSO-D6) δ: 2.59 (3H, s), 7.46 (1H, br s), 7.50 (1H, d, J = 8.2 Hz), 7.94 (2H, 1-11 d, J = 8.4 Hz), 8.00 (1H, dd, J = 7.9, 1.8 Hz), 375 373 8.01 (1H, br s), 8.24 (1H, br s), 8.56 (2H, d, J = 8.4 Hz), 13.28 (1H, s).
HO NH 1H-NMR (DMSO-D6) δ: 4.58 (2H, d, J = 5.5 Hz), 5.45 (1H, t, J = 5.6 Hz), 7.56 (1H, dd, J = 1-12 8.2, 2.0 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.74 382 380 (1H, br s), 7.94 (2H, d, J = 8.4 Hz), 8.54 (2H, N d, J = 8.4 Hz), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.65 (3H, s), 7.84 (1H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.4 Hz), 8.16 (1H, dd, J = 8.4, 2.2 Hz), 8.38 (1H, d, J = 394 392 1-13 2.2 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.65 (1H, HO CH 1H-NMR (DMSO-D6) δ: 1.22 (3H, t, J = 7.7 Hz), 2.50 (3H, s), 2.66 (2H, q, J = 7.6 Hz), 1-14 7.32 (1H, d, J = 7.9 Hz), 7.37 (1H, dd, J = 7.8, 360 358 1.7 Hz), 7.55 (1H, br s), 7.94 (2H, d, J = 8.4 Hz), 8.55 (2H, d, J = 8.4 Hz), 13.19 (1H, br s).
HO CH 1H-NMR (DMSO-D6) δ: 1.39 (9H, s), 4.20 (2H, d, J = 6.0 Hz), 7.47-7.53 (2H, m), 7.62 (1H, d, J = 8.4 Hz), 7.66 (1H, br s), 7.93 (2H, 481 479 1-15 N H d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.54 HO N O (1H, s).
O CH H C CH 1H-NMR (DMSO-D6) δ: 1.89 (3H, s), 4.32 (2H, d, J = 6.0 Hz), 7.49 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.67 (1H, d, J = 1-16 423 421 N 2.2 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.46 (1H, t, J = 6.0 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, HO N br s). 【0752】 【Table 1-3】 1H-NMR (DMSO-D6) δ: 4.13 (2H, br s), 7.72- 1-17 7.77 (2H, m), 7.93-7.97 (3H, m), 8.39 (3H, br 381 379 s), 8.54 (2H, d, J = 8.4 Hz), 13.67 (1H, s).
HO NH 1H-NMR (DMSO-D6) δ: 1.36 (3H, d, J = 6.4 Hz), 4.78-4.84 (1H, m), 5.42 (1H, d, J = 4.2 Hz), 7.57-7.62 (2H, m), 7.77 (1H, br s), 7.94 396 394 1-18 N (2H, d, J = 8.2 Hz), 8.54 (2H, d, J = 8.2 Hz), 13.52 (1H, br s).
HO OH 1H-NMR (DMSO-D6) δ: 3.34 (3H, s), 4.50 (2H, s), 7.57 (1H, dd, J = 8.3, 2.1 Hz), 7.65 1-19 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 2.0 Hz), 396 394 7.94 (2H, d, J = 8.4 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.54 (1H, br s).
HO O 1H-NMR (DMSO-D6) δ: 2.93 (3H, s), 4.25 (2H, d, J = 6.4 Hz), 7.60 (1H, dd, J = 8.4, 2.0 Hz), 7.66 (1H, d, J = 8.4 Hz), 7.70 (1H, t, J = 459 457 1-20 6.4 Hz), 7.78 (1H, d, J = 2.0 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.58 HO N O (1H, br s). 1H-NMR (DMSO-D6) δ: 2.07 (1.0H, s), 2.08 (2.0H, s), 2.82 (1.0H, s), 2.96 (2.0H, s), 4.56 (1.3H, s), 4.64 (0.7H, s), 7.47 (1.0H, d, J = 8.2 437 435 1-21 Hz), 7.61-7.68 (2.0H, m), 7.94 (2.0H, d, J = N CH 8.4 Hz), 8.53 (2.0H, d, J = 8.4 Hz), 13.56 HO N 3 (1.0H, s). 1H-NMR (DMSO-D6) δ: 3.56 (3H, s), 4.26 (2H, d, J = 6.2 Hz), 7.50 (1H, dd, J = 8.5, 2.1 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 1-22 439 437 2.0 Hz), 7.80 (1H, t, J = 6.2 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.54 (1H, HO N O CH 1H-NMR (DMSO-D6) δ: 3.71 (2H, s), 7.53 (1H, dd, J = 8.3, 1.9 Hz), 7.62 (1H, d, J = 8.2 Hz), 7.71 (1H, d, J = 1.8 Hz), 7.94 (2H, d, J = 410 408 1-23 8.4 Hz), 8.54 (2H, d, J = 8.4 Hz), 12.53 (1H, br s), 13.54 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 4.32 (2H, d, J = 6.0 Hz), 7.45 (1H, dd, J = 8.3, 2.1 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 1-24 465 463 2.0 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.18 (1H, t, J = 6.1 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, HO N CH br s).
O CH 【0753】 【Table 1-4】 1H-NMR (DMSO-D6) δ: 2.09 (3H, s), 5.16 (2H, s), 7.63 (1H, dd, J = 8.3, 2.1 Hz), 7.68 (1H, d, J = 8.2 Hz), 7.81 (1H, d, J = 2.0 Hz), 424 422 1-25 7.94 (2H, d, J = 8.4 Hz), 8.54 (2H, d, J = 8.4 HO O Hz), 13.57 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.59 (3H, d, J = 4.6 Hz), 3.50 (2H, s), 7.50 (1H, dd, J = 8.3, 2.1 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 1-26 N 423 421 2.0 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.01-8.06 (1H, br m), 8.54 (2H, d, J = 8.4 Hz), 13.54 N CH (1H, s). 1H-NMR (DMSO-D6) δ: 1.02 (3H, t, J = 7.6 Hz), 2.16 (2H, q, J = 7.6 Hz), 4.32 (2H, d, J = 6.0 Hz), 7.49 (1H, dd, J = 8.4, 2.2 Hz), 7.62 1-27 437 435 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 2.2 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.39 (1H, t, J = 6.0 HO N Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.04 (6H, d, J = 7.1 Hz), 2.38-2.48 (1H, m), 4.32 (2H, d, J = 6.2 Hz), 7.47 (1H, dd, J = 8.4, 2.2 Hz), 7.62 (1H, 451 449 1-28 d, J = 8.4 Hz), 7.66 (1H, d, J = 2.2 Hz), 7.94 HO N CH (2H, d, J = 8.4 Hz), 8.37 (1H, t, J = 6.2 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.11-1.40 (5H, m), 1.57-1.76 (5H, m), 2.13-2.20 (1H, m), 4.31 (2H, d, J = 6.2 Hz), 7.46 (1H, dd, J = 8.3, 2.1 1-29 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 491 489 2.0 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.34 (1H, t, J HO N = 6.1 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, O br s). 1H-NMR (DMSO-D6) δ: 1.44-1.82 (8H, m), 2.58-2.66 (1H, m), 4.32 (2H, d, J = 6.2 Hz), 7.47 (1H, dd, J = 8.3, 2.1 Hz), 7.62 (1H, d, J = 477 475 1-30 N 8.2 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.39 (1H, t, J = 6.2 Hz), 8.53 (2H, HO N d, J = 8.4 Hz), 13.55 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.20 (3H, t, J = 7.3 Hz), 3.02 (2H, q, J = 7.4 Hz), 4.23 (2H, d, J = 6.5 Hz), 7.60 (1H, dd, J = 8.4, 2.1 Hz), 7.66 1-31 473 471 (1H, d, J = 8.4 Hz), 7.72 (1H, t, J = 6.4 Hz), 7.77 (1H, d, J = 2.1 Hz), 7.94 (2H, d, J = 8.4 HO N O Hz), 8.54 (2H, d, J = 8.4 Hz), 13.57 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.31 (9H, s), 4.32 N (2H, d, J = 6.4 Hz), 7.60-7.66 (3H, m), 7.76 1-32 501 499 (1H, br s), 7.94 (2H, d, J = 8.4 Hz), 8.53 (2H, HO N d, J = 8.4 Hz), 13.58 (1H, br s).
H C CH 【0754】 【Table 1-5】 1H-NMR (DMSO-D6) δ: 1.24 (6H, d, J = 6.8 Hz), 3.14-3.20 (1H, m), 4.25 (2H, d, J = 6.4 N Hz), 7.60 (1H, dd, J = 8.5, 1.9 Hz), 7.66 (1H, 1-33 N 487 485 d, J = 8.4 Hz), 7.70 (1H, t, J = 6.5 Hz), 7.77 (1H, d, J = 1.8 Hz), 7.94 (2H, d, J = 8.2 Hz), CH 8.53 (2H, d, J = 8.2 Hz), 13.58 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.81 (6H, s), 4.28 (2H, d, J = 5.8 Hz), 6.98 (1H, t, J = 5.9 Hz), 7.50 (1H, dd, J = 8.3, 2.0 Hz), 7.59 (1H, d, J = 452 450 1-34 8.4 Hz), 7.68 (1H, d, J = 1.9 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.54 HO N CH (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 2.56 (3H, d, J = 4.6 Hz), 4.26 (2H, d, J = 6.2 Hz), 5.90 (1H, q, J = 4.6 Hz), 6.52 (1H, t, J = 6.2 Hz), 7.49 (1H, dd, 1-35 438 436 J = 8.3, 2.1 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.66 HO N (1H, d, J = 2.0 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, br s).
O CH F 1H-NMR (DMSO-D6) δ: 0.85 (3H, t, J = 7.4 Hz), 1.54 (2H, sextet, J = 7.4 Hz), 2.13 (2H, t, J = 7.4 Hz), 4.33 (2H, d, J = 6.2 Hz), 7.48 1-36 (1H, dd, J = 8.2, 2.0 Hz), 7.62 (1H, d, J = 8.2 451 449 N Hz), 7.66 (1H, d, J = 2.0 Hz), 7.94 (2H, d, J = HO N 8.2 Hz), 8.41 (1H, t, J = 6.1 Hz), 8.53 (2H, d, O CH J = 8.2 Hz), 13.55 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.87 (6H, d, J = 6.4 Hz), 1.96-2.06 (3H, m), 4.33 (2H, d, J = 6.0 N Hz), 7.48 (1H, dd, J = 8.2, 2.0 Hz), 7.61 (1H, 1-37 N 465 463 d, J = 8.2 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.93 HO N (2H, d, J = 8.4 Hz), 8.42 (1H, t, J = 6.1 Hz), O CH 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.16 (3H, t, J = 7.1 Hz), 4.01 (2H, q, J = 7.1 Hz), 4.25 (2H, d, J = 6.2 Hz), 7.50 (1H, dd, J = 8.4, 2.0 Hz), 7.63 453 451 1-38 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.76 (1H, t, J = 6.3 Hz), 7.94 (2H, d, J = 8.4 HO N Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.17 (6H, d, J = 6.2 Hz), 4.24 (2H, d, J = 6.2 Hz), 4.73-4.80 (1H, N m), 7.49 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (1H, d, 1-39 467 465 J = 8.4 Hz), 7.66-7.71 (2H, m), 7.93 (2H, d, J HO N = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.55 (1H, O CH br s). 1H-NMR (DMSO-D6) δ: 2.85 (3H, s), 3.05 (3H, s), 3.80 (2H, s), 7.47 (1H, dd, J = 8.4, 2.2 1-40 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.65 (1H, d, J = 437 435 N O 2.2 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.54 (1H, br s).
N CH 【0755】 【Table 1-6】 1H-NMR (DMSO-D6) δ: 1.25 (9H, s), 3.47 (2H, s), 7.49 (1H, dd, J = 8.5, 2.1 Hz), 7.59 1-41 (1H, d, J = 8.4 Hz), 7.66 (1H, d, J = 2.0 Hz), 465 463 N O 7.77 (1H, s), 7.94 (2H, d, J = 8.4 Hz), 8.54 HO CH (2H, d, J = 8.4 Hz), 13.54 (1H, s).
N CH 1H-NMR (DMSO-D6) δ: 1.51-1.71 (4H, m), 1.83-1.92 (4H, m), 3.47-3.54 (1H, m), 4.26 (2H, d, J = 6.4 Hz), 7.59 (1H, d, J = 8.3 Hz), 1-42 513 511 7.66 (1H, d, J = 8.3 Hz), 7.72 (1H, t, J = 6.3 HO N Hz), 7.77 (1H, s), 7.94 (2H, d, J = 8.3 Hz), 8.53 (2H, d, J = 8.3 Hz), 13.58 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 4.31 N (2H, d, J = 6.0 Hz), 7.44 (1H, dd, J = 8.2, 2.0 Hz), 7.56-7.58 (3H, m), 7.64-7.69 (2H, m), 397 395 1-43 8.18 (1H, t, J = 6.0 Hz), 8.34 (2H, d, J = 7.1 HO N CH CH Hz), 13.34 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.4 Hz), 1.13 (9H, s), 1.62-1.65 (2H, m), 2.65 Cl (2H, t, J = 7.5 Hz), 4.31 (2H, d, J = 6.0 Hz), 1-44 7.38 (2H, d, J = 8.2 Hz), 7.43 (1H, dd, J = 8.4, 439 437 N 2.0 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.64 (1H, br HO N CH s), 8.17 (1H, t, J = 6.1 Hz), 8.26 (2H, d, J = O CH 8.2 Hz), 13.25 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.51 (3H, s), 4.55 (2H, d, J = 5.5 Hz), 5.29 (1H, t, J = 5.6 Hz), 1-45 7.36 (1H, d, J = 7.9 Hz), 7.46 (1H, dd, J = 7.8, 362 360 1.7 Hz), 7.65 (1H, br s), 7.94 (2H, d, J = 8.4 N Hz), 8.55 (2H, d, J = 8.4 Hz), 13.22 (1H, br s).
HO OH 3 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 1.24 (6H, d, J = 6.8 Hz), 2.96-3.03 (1H, m), 4.31 (2H, d, J = 6.0 Hz), 7.41-7.46 (3H, m), 7.58 439 437 1-46 (1H, d, J = 8.4 Hz), 7.64 (1H, br s), 8.17 (1H, HO N CH t, J = 6.0 Hz), 8.27 (2H, d, J = 8.2 Hz), 13.26 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.88 (3H, s), 2.50 (3H, s), 4.29 (2H, d, J = 6.0 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.39 (1H, dd, J = 7.9, 1.8 Hz), 1-47 403 401 7.59 (1H, br s), 7.94 (2H, d, J = 8.2 Hz), 8.37 (1H, t, J = 6.0 Hz), 8.54 (2H, d, J = 8.2 Hz), HO N 13.26 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 2.50 (3H, s), 4.30 (2H, d, J = 6.0 Hz), 7.34-7.35 1-48 (2H, br m), 7.57 (1H, br s), 7.93 (2H, d, J = 445 443 N 8.4 Hz), 8.09 (1H, t, J = 6.1 Hz), 8.54 (2H, d, J HO N CH = 8.4 Hz), 13.24 (1H, br s).
O CH 【0756】 【Table 1-7】 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 1.25 H C Cl 3 (6H, d, J = 7.0 Hz), 2.96-3.03 (1H, m), 4.32 (2H, d, J = 5.8 Hz), 7.44 (1H, dd, J = 8.1, 1.2 439 437 1-49 N Hz), 7.48 (1H, t, J = 7.7 Hz), 7.56 (1H, d, J = HO N CH 7.7 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.65 (1H, br s), 8.16-8.20 (3H, m), 13.30 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.3 Hz), 1.13 (9H, s), 1.61-1.65 (2H, m), 2.65 (2H, t, J = 7.5 Hz), 4.31 (2H, d, J = 6.2 Hz), 1-50 439 437 H 7.43-7.50 (3H, m), 7.59 (1H, d, J = 8.2 Hz), HO N CH 7.64 (1H, br s), 8.16-8.18 (3H, m), 13.30 (1H, O CH 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.6 Hz), 1.13 (9H, s), 1.88-1.92 (1H, m), 2.55 (2H, d, J = 7.1 Hz), 4.31 (2H, d, J = 6.2 Hz), 1-51 7.35 (2H, d, J = 8.2 Hz), 7.43 (1H, dd, J = 8.4, 439 437 N 2.0 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.64 (1H, br N CH s), 8.17 (1H, t, J = 6.1 Hz), 8.26 (2H, d, J = O CH 8.4 Hz), 13.25 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.06 (3H, s), 1.14- 1.49 (8H, m), 1.91-1.98 (2H, m), 4.32 (2H, d, N J = 5.8 Hz), 7.43 (1H, d, J = 8.1 Hz), 7.52- 437 435 1-52 C H 7.59 (3H, m), 7.62-7.67 (2H, m), 8.16 (1H, t, J = 5.9 Hz), 8.32 (2H, d, J = 8.1 Hz), 13.31 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.26 (6H, s), 3.15 (3H, s), 4.32 (2H, d, J = 6.3 Hz), 7.45 (1H, d, J = 7.2 Hz), 7.53-7.59 (3H, m), 7.63-7.68 (2H, 413 411 1-53 m), 8.32 (2H, d, J = 7.9 Hz), 8.46 (1H, t, J = HO N CH 3 6.3 Hz), 13.31 (1H, br s).
O O CH F 1H-NMR (DMSO-D6) δ: 1.12 (9H, s), 4.31 F Cl (2H, d, J = 6.0 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 7.81 1-54 465 463 (1H, t, J = 7.9 Hz), 8.03 (1H, d, J = 7.4 Hz), HO N CH 8.16 (1H, t, J = 5.9 Hz), 8.57-8.63 (2H, m), O CH 13.51 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 1.22 (3H, t, J = 7.6 Hz), 2.70 (2H, q, J = 7.6 Hz), 4.31 (2H, d, J = 6.0 Hz), 7.42-7.53 (3H, m), 425 423 1-55 7.59 (1H, d, J = 8.2 Hz), 7.64 (1H, s), 8.15- HO N CH 3 8.19 (3H, m), 13.31 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.28 (6H, s), 3.17 (3H, s), 4.33 (2H, d, J = 6.2 Hz), 7.48 (1H, dd, J = 8.4, 2.1 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.67 1-56 481 479 (1H, s), 7.94 (2H, d, J = 8.3 Hz), 8.48 (1H, t, J HO N CH = 6.3 Hz), 8.52 (2H, d, J = 8.3 Hz), 13.55 (1H, br s).
O O CH 【0757】 【Table 1-8】 H C 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 1.34 H C Cl (9H, s), 4.31 (2H, d, J = 6.0 Hz), 7.43 (1H, dd, J = 8.2, 2.0 Hz), 7.49 (1H, t, J = 7.8 Hz), 7.59 1-57 453 451 (1H, d, J = 8.2 Hz), 7.66 (1H, s), 7.72 (1H, d, HO N CH J = 8.2 Hz), 8.15-8.18 (2H, m), 8.38 (1H, s), O CH 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.72 (3H, t, J = 7.4 Hz), 1.08 (6H, s), 1.49 (2H, q, J = 7.4 Hz), F Cl N 4.32 (2H, d, J = 6.0 Hz), 7.47 (1H, dd, J = 8.2, 2.0 Hz), 7.61 (1H, d, J = 8.2 Hz), 7.65 (1H, s), 479 477 1-58 7.82 (1H, t, J = 7.8 Hz), 8.04 (1H, d, J = 7.9 HO N CH 3 Hz), 8.15 (1H, t, J = 6.1 Hz), 8.59-8.63 (2H, O CH m), 13.54 (1H, s).
F Cl 1H-NMR (DMSO-D6) δ: 1.37 (6H, s), 4.36 (2H, d, J = 5.6 Hz), 7.45 (1H, d, J = 8.4 Hz), 1-59 7.62 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 7.81 519 517 HO N CH (1H, t, J = 7.7 Hz), 8.03 (1H, d, J = 7.9 Hz), 8.58-8.66 (3H, m), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 4.31 F F (2H, d, J = 6.0 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.61 (1H, d, J = 8.4 481 479 1-60 O N CH Hz), 7.64 (1H, s), 8.18 (1H, t, J = 6.0 Hz), N H C CH OH 8.46 (2H, d, J = 8.7 Hz), 13.45 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 4.31 F Cl (2H, d, J = 6.0 Hz), 7.45 (1H, dd, J = 8.4, 2.2 F O NH F N O Hz), 7.60 (1H, d, J = 8.4 Hz), 7.63-7.73 (3H, 481 479 1-61 N CH m), 8.18 (1H, t, J = 6.0 Hz), 8.21 (1H, s), 8.37 N H C CH (1H, dt, J = 7.4, 1.5 Hz), 13.50 (1H, br s). 3 1H-NMR (DMSO-D6) δ: 1.12 (9H, s), 1.34 (3H, t, J = 7.0 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.30 (2H, d, J = 6.0 Hz), 7.20 (1H, dd, J = 8.1, 1-62 2.3 Hz), 7.41-7.46 (2H, m), 7.57 (1H, d, J = 441 439 HO N CH 8.4 Hz), 7.63 (1H, s), 7.84 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 8.16 (1H, t, J = 6.0 Hz), 13.30 OH C CH (1H, br s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 2.41 (3H, s), 4.31 (2H, d, J = 6.0 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.43 (1H, d, J = 8.1 Hz), 7.59 411 409 1-63 H C N CH (1H, d, J = 8.1 Hz), 7.64 (1H, s), 8.17 (1H, t, J N H C CH = 6.0 Hz), 8.24 (2H, d, J = 8.1 Hz), 13.24 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.14 (9H, s), 2.40 H C NH (3H, s), 4.32 (2H, d, J = 6.0 Hz), 7.41-7.51 1-64 411 409 N CH (3H, m), 7.60 (1H, d, J = 8.4 Hz), 7.64 (1H, s), H C CH 3 3 8.11-8.20 (3H, m), 13.30 (1H, br s). 【0758】 【Table 1-9】 1H-NMR (DMSO-D6) δ: 1.60-1.71 (6H, m), 1.79-1.83 (6H, m), 1.94-1.98 (3H, m), 4.30 (2H, d, J = 6.0 Hz), 7.42 (1H, d, J = 8.6 Hz), 1-65 475 473 N 7.53-7.59 (3H, m), 7.63-7.68 (2H, m), 8.10 HO N (1H, t, J = 6.1 Hz), 8.34 (2H, d, J = 7.5 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.72-1.94 (2H, m), 1.99-2.08 (2H, m), 2.10-2.20 (2H, m), 3.03- 3.11 (1H, m), 4.31 (2H, d, J = 6.0 Hz), 7.45 395 393 1-66 N (1H, dd, J = 8.4, 2.0 Hz), 7.54-7.69 (5H, m), 8.28 (1H, t, J = 6.0 Hz), 8.34 (2H, d, J = 7.3 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.46-1.81 (8H, m), 2.58-2.66 (1H, m), 4.32 (2H, d, J = 6.0 Hz), 7.45 (1H, dd, J = 8.4, 2.2 Hz), 7.56 (2H, t, J = 1-67 409 407 7.6 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.64-7.69 HO N (2H, m), 8.34 (2H, d, J = 7.5 Hz), 8.40 (1H, t, J = 6.1 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.50-1.68 (4H, m), 1.82-1.91 (2H, m), 2.29-2.36 (2H, m), 4.37 (2H, d, J = 5.8 Hz), 7.41 (1H, d, J = 8.8 Hz), N 477 475 1-68 7.54 (2H, t, J = 7.7 Hz), 7.59 (1H, d, J = 8.4 HO N Hz), 7.62-7.67 (2H, m), 8.32 (2H, d, J = 7.7 Hz), 8.69 (1H, t, J = 5.9 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 4.37 (2H, d, J = 6.0 Hz), 7.44 (1H, dd, J = 8.3, 2.1 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.61 (1H, d, J = 451 449 1-69 N 8.4 Hz), 7.64-7.69 (2H, m), 8.34 (2H, d, J = HO N CH 7.5 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.35 (1H, br 1H-NMR (DMSO-D6) δ: 1.77-1.94 (2H, m), 2.30-2.39 (2H, m), 2.45-2.57 (2H, m), 4.39 (2H, d, J = 5.8 Hz), 7.44 (1H, d, J = 7.4 Hz), 1-70 N 463 461 7.54 (2H, t, J = 7.7 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.63-7.68 (2H, m), 8.33 (2H, d, J = 7.7 Hz), 8.78 (1H, t, J = 5.9 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.08-1.42 (5H, m), N 1.57-1.77 (5H, m), 2.13-2.21 (1H, m), 4.31 (2H, d, J = 6.0 Hz), 7.44 (1H, dd, J = 8.2, 2.2 423 421 1-71 Hz), 7.54-7.60 (3H, m), 7.65-7.69 (2H, m), HO N 8.33-8.35 (3H, m), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.35 (3H, s), 1.63- 1.76 (3H, m), 1.84-1.93 (1H, m), 2.30-2.37 (2H, m), 4.32 (2H, d, J = 6.2 Hz), 7.45 (1H, 1-72 dd, J = 8.4, 2.0 Hz), 7.56 (2H, t, J = 7.6 Hz), 409 407 HO 7.60 (1H, d, J = 8.4 Hz), 7.64-7.68 (2H, m), 8.18 (1H, t, J = 6.1 Hz), 8.34 (2H, d, J = 7.5 O CH Hz), 13.35 (1H, br s). 【0759】 【Table 1-10】 1H-NMR (DMSO-D6) δ: 1.19 (3H, s), 1.35- 1.43 (2H, m), 1.51-1.62 (4H, m), 1.98-2.05 (2H, m), 4.32 (2H, d, J = 6.0 Hz), 7.44 (1H, 423 421 1-73 N dd, J = 8.3, 2.1 Hz), 7.54-7.60 (3H, m), 7.64- HO N 7.69 (2H, m), 8.20 (1H, t, J = 6.1 Hz), 8.34 (2H, d, J = 7.3 Hz), 13.34 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.12 (9H, s), 4.30 (2H, d, J = 6.0 Hz), 7.37 (1H, d, J = 8.8 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.5, 1-74 N 415 413 2.0 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.62 (1H, s), HO N CH 3 8.16 (1H, t, J = 5.9 Hz), 8.38 (1H, d, J = 8.8 Hz), 8.40 (1H, d, J = 8.8 Hz), 13.33 (1H, br s).
O CH H C O 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 3.32 (3H, s), 4.31 (2H, d, J = 6.0 Hz), 4.50 (2H, s), 7.43 (1H, d, J = 8.6 Hz), 7.53 (1H, t, J = 7.7 1-75 441 439 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.63 (1H, s), HO N CH 8.18 (1H, t, J = 6.0 Hz), 8.26 (1H, d, J = 7.7 O CH H C Hz), 8.30 (1H, s), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.14 (9H, s), 4.32 (2H, d, J = 6.0 Hz), 7.45 (1H, dd, J = 8.4, 2.1 N Hz), 7.52 (1H, td, J = 8.4, 2.7 Hz), 7.59-7.63 415 413 1-76 H (2H, m), 7.65 (1H, d, J = 2.1 Hz), 8.05 (1H, dt, HO N CH J = 9.8, 2.0 Hz), 8.16-8.20 (2H, m), 13.43 OH C CH 3 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 4.37 F Cl (2H, d, J = 5.8 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.61-7.65 (2H, m), 1-77 535 533 H 7.69 (1H, t, J = 7.8 Hz), 8.21 (1H, s), 8.36 HO N F F (1H, d, J = 7.7 Hz), 8.63 (1H, t, J = 5.8 Hz), O CH 3 13.52 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.48-1.71 (4H, m), 1.81-1.94 (2H, m), 2.30-2.39 (2H, m), 4.39 (2H, d, J = 5.9 Hz), 7.45 (1H, dd, J = 8.3, 1.4 561 559 1-78 Hz), 7.59-7.75 (4H, m), 8.22 (1H, br s), 8.35- HO N 8.39 (1H, m), 8.72 (1H, t, J = 5.9 Hz), 13.51 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.50-1.69 (4H, m), F Cl 1.83-1.93 (2H, m), 2.29-2.39 (2H, m), 4.39 (2H, d, J = 6.0 Hz), 7.44 (1H, dd, J = 8.3, 1.9 1-79 545 543 Hz), 7.60-7.66 (2H, m), 7.82 (1H, t, J = 7.7 HO N Hz), 8.03 (1H, d, J = 7.7 Hz), 8.59-8.65 (2H, m), 8.71 (1H, t, J = 6.0 Hz), 13.54 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.34 (9H, s), 1.49- H C Cl 1.69 (4H, m), 1.83-1.92 (2H, m), 2.29-2.38 (2H, m), 4.38 (2H, d, J = 6.0 Hz), 7.42 (1H, d, 1-80 N J = 8.3 Hz), 7.49 (1H, t, J = 7.8 Hz), 7.61 (1H, 533 531 HO N d, J = 8.3 Hz), 7.65 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 8.15 (1H, d, J = 7.8 Hz), 8.38 (1H, s), 8.71 (1H, t, J = 6.0 Hz), 13.35 (1H, br s). 【0760】 【Table 1-11】 1H-NMR (DMSO-D6) δ: 1.37 (6H, s), 2.32 (3H, d, J = 1.2 Hz), 4.36 (2H, d, J = 5.9 Hz), F NH 7.50-7.43 (2H, m), 7.60 (1H, d, J = 8.4 Hz), 1-81 483 481 7.64 (1H, br s), 7.99 (1H, d, J = 10.9 Hz), 8.08 H C N F N H C CHF 3 3 (1H, dd, J = 7.8, 1.5 Hz), 8.63 (1H, t, J = 5.9 Hz), 13.36 (1H, s). 1H-NMR (DMSO-D6) δ: 1.13 (9H, s), 1.31 (6H, d, J = 6.0 Hz), 4.31 (2H, d, J = 6.0 Hz), 4.72-4.82 (1H, m), 7.06 (2H, d, J = 8.9 Hz), 455 453 1-82 7.42 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.63 (1H, s), 8.17 (1H, t, J = 6.0 Hz), HO N CH 8.29 (2H, d, J = 8.9 Hz), 13.12 (1H, br s).
O CH 3 1H-NMR (DMSO-D6) δ: 1.17 (6H, d, J = 6.3 H C Cl Hz), 1.34 (9H, s), 4.23 (2H, d, J = 6.0 Hz), 4.72-4.80 (1H, m), 7.43-7.52 (2H, m), 7.60 1-83 N 455 453 (1H, d, J = 8.4 Hz), 7.65-7.73 (3H, m), 8.15 HO N (1H, d, J = 7.7 Hz), 8.38 (1H, s), 13.33 (1H, br O CH 1H-NMR (DMSO-D6) δ: 1.27 (6H, s), 1.34 (9H, s), 3.16 (3H, s), 4.33 (2H, d, J = 6.3 Hz), 7.42-7.46 (1H, m), 7.49 (1H, d, J = 7.9 Hz), 1-84 469 467 H 7.57 (1H, d, J = 8.1 Hz), 7.66-7.71 (2H, m), N O CH 8.14 (1H, d, J = 7.9 Hz), 8.38 (1H, s), 8.47 O CH H C 3 (1H, t, J = 6.3 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.36 (3H, t, J = 7.0 Hz), 1.51-1.69 (4H, m), 1.84-1.91 (2H, m), N 2.30-2.38 (2H, m), 4.10 (2H, q, J = 7.0 Hz), 4.38 (2H, d, J = 6.0 Hz), 7.20 (1H, dd, J = 8.3, N F 521 519 1-85 F 2.4 Hz), 7.39-7.43 (1H, m), 7.46 (1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.63 (1H, s), 7.85 (1H, d, J = 2.4 Hz), 7.89-7.96 (1H, m), 8.71 (1H, t, J = 6.0 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.37 H C CH Cl (6H, s), 3.73 (2H, s), 4.35 (2H, d, J = 5.8 Hz), CH NH 7.08 (2H, d, J = 9.1 Hz), 7.40 (1H, dd, J = 8.3, 537 535 1-86 O N 2.2 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.62 (1H, d, H C CH F J = 1.9 Hz), 8.29 (2H, d, J = 9.1 Hz), 8.62 (1H, t, J = 5.8 Hz), 13.13 (1H, s). 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 3.36 (3H, s), 4.32-4.44 (2H, m), 7.46 (1H, d, J = 1-87 8.2 Hz), 7.53-7.71 (5H, m), 8.34 (2H, d, J = 467 465 N CH HO N O 7.5 Hz), 9.04 (1H, t, J = 6.3 Hz), 13.35 (1H, br 1H-NMR (DMSO-D6) δ: 1.00 (6H, d, J = 6.8 Hz), 1.38 (6H, s), 1.99-2.10 (1H, m), 3.83 (2H, d, J = 6.4 Hz), 4.37 (2H, d, J = 6.0 Hz), 1-88 7.23 (1H, dd, J = 8.2, 2.6 Hz), 7.41-7.49 (2H, 523 521 HO N CH m), 7.61 (1H, d, J = 8.2 Hz), 7.66 (1H, s), 7.84-7.88 (1H, m), 7.93 (1H, d, J = 7.9 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.33 (1H, br s). 【0761】 【Table 1-12】 Cl 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 3.36 (3H, s), 4.32-4.44 (2H, m), 7.46 (1H, d, J = 1-89 N 8.2 Hz), 7.53-7.71 (5H, m), 8.34 (2H, d, J = 467 465 HO N O 7.5 Hz), 9.04 (1H, t, J = 6.3 Hz), 13.35 (1H, br 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.31 (3H, s), 4.37 (2H, d, J = 5.8 Hz), 7.31 (1H, t, J = 9.1 Hz), 7.43 (1H, dd, J = 8.4, 2.0 Hz), 7.60 483 481 1-90 N (1H, d, J = 8.4 Hz), 7.63 (1H, s), 8.21 (1H, s), 8.28 (1H, d, J = 7.4 Hz), 8.64 (1H, t, J = 5.8 Hz), 13.32 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.30 (6H, d, J = 6.0 Hz), 1.38 (6H, s), 4.37 (2H, d, J = 5.8 Hz), H C Cl CH N 4.66-4.72 (1H, m), 7.20 (1H, dd, J = 8.4, 2.1 1-91 Hz), 7.42-7.47 (2H, m), 7.60 (1H, d, J = 8.4 509 507 HO Hz), 7.66 (1H, s), 7.84-7.86 (1H, m), 7.90 (1H, d, J = 7.7 Hz), 8.64 (1H, t, J = 5.8 Hz), OH C CH 13.32 (1H, br s).
H C 1H-NMR (DMSO-D6) δ: 1.34 (9H, s), 1.38 (6H, s), 4.37 (2H, d, J = 6.0 Hz), 7.42 (1H, d, H C Cl N J = 8.4 Hz), 7.48 (1H, t, J = 7.9 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.66 (1H, s), 7.70 (1H, d, J = 507 505 1-92 N F 7.7 Hz), 8.15 (1H, d, J = 7.7 Hz), 8.37-8.39 (1H, m), 8.63 (1H, t, J = 6.0 Hz), 13.33 (1H, br OH C CH 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.35 (6H, s), 4.37 (2H, d, J = 5.8 Hz), 7.30 (1H, s), N 7.44 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.4 479 477 1-93 Hz), 7.63 (1H, s), 7.96 (2H, s), 8.64 (1H, t, J = HO N F .8 Hz), 13.27 (1H, br s).
O CH H C 3 1H-NMR (DMSO-D6) δ: 1.33 (9H, s), 4.55 3 (2H, d, J = 5.8 Hz), 7.45-7.50 (3H, m), 7.52- 7.56 (2H, m), 7.61 (1H, d, J = 8.4 Hz), 7.71 1-94 473 471 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 7.89-7.91 HO N (2H, m), 8.14 (1H, d, J = 7.7 Hz), 8.37 (1H, s), 9.15 (1H, t, J = 5.8 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.6 Cl Hz), 1.38 (6H, s), 1.82-1.94 (1H, m), 2.55 (2H, d, J = 7.1 Hz), 4.37 (2H, d, J = 6.0 Hz), 507 505 1-95 7.42-7.50 (3H, m), 7.59-7.67 (2H, m), 8.12- HO N CH 8.20 (2H, m), 8.64 (1H, t, J = 6.0 Hz), 13.31 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.19 (3H, t, J = 7.1 Hz), 1.54 (3H, s), 3.46-3.54 (1H, m), 3.57- N H C 3 3.66 (1H, m), 4.40 (2H, d, J = 6.2 Hz), 7.46 1-96 N 481 479 (1H, d, J = 8.4 Hz), 7.54-7.70 (5H, m), 8.34 HO N O 3 (2H, d, J = 7.5 Hz), 8.86 (1H, t, J = 6.2 Hz), 13.35 (1H, br s). 【0762】 【Table 1-13】 1H-NMR (DMSO-D6) δ: 1.19 (3H, t, J = 7.1 Hz), 1.54 (3H, s), 3.46-3.54 (1H, m), 3.57- N H C 3.66 (1H, m), 4.40 (2H, d, J = 6.2 Hz), 7.46 1-97 N 481 479 (1H, d, J = 8.4 Hz), 7.54-7.70 (5H, m), 8.34 CH (2H, d, J = 7.5 Hz), 8.86 (1H, t, J = 6.2 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.24 (6H, d, J = 7.0 Hz), 1.38 (6H, s), 4.36 (2H, d, J = 5.8 Hz), 7.35-7.40 (3H, m), 7.54 (1H, d, J = 8.4 Hz), 493 491 1-98 7.61 (1H, d, J = 2.1 Hz), 8.25 (2H, d, J = 8.4 HO N F Hz), 8.62 (1H, t, J = 5.8 Hz), 13.26 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 4.37 (2H, d, J = 5.8 Hz), 4.86 (2H, q, J = 8.8 Hz), F 7.36 (1H, dd, J = 8.0, 2.4 Hz), 7.43 (1H, dd, J 1-99 = 8.0, 2.4 Hz), 7.53 (1H, t, J = 8.0 Hz), 7.60 549 547 HO N (1H, d, J = 8.0 Hz), 7.65 (1H, s), 7.93-7.95 (1H, m), 8.03 (1H, d, J = 7.7 Hz), 8.64 (1H, t, O CH J = 5.8 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.36 (6H, s), 1.79- 1.87 (1H, m), 1.93-2.05 (1H, m), 2.07-2.18 N (2H, m), 2.29-2.36 (2H, m), 3.55-3.64 (1H, m), 4.35 (2H, d, J = 6.0 Hz), 7.37-7.48 (3H, 505 503 1-100 m), 7.56 (1H, d, J = 8.1 Hz), 7.61 (1H, s), HO N F 8.13 (1H, d, J = 7.0 Hz), 8.18 (1H, s), 8.61 OH C CH (1H, t, J = 6.0 Hz), 13.31 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.5 Hz), 1.25 (9H, s), 1.84-1.95 (1H, m), 2.55 (2H, d, J = 7.2 Hz), 3.45 (2H, s), 7.35 (2H, d, 453 451 1-101 J = 8.1 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.57 HO (1H, d, J = 8.4 Hz), 7.65 (1H, s), 7.76 (1H, s), N CH 8.26 (2H, d, J = 8.1 Hz), 13.24 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.6 3 Hz), 1.38 (6H, s), 1.58-1.69 (2H, m), 2.64 (2H, t, J = 7.6 Hz), 4.37 (2H, d, J = 6.0 Hz), 1-102 493 491 H 7.40-7.46 (3H, m), 7.58 (1H, d, J = 8.1 Hz), F 7.63 (1H, d, J = 1.9 Hz), 8.14-8.18 (2H, m), O CH H C 3 8.63 (1H, t, J = 6.0 Hz), 13.32 (1H, br s).
O 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 3.36 (3H, s), 4.32-4.46 (2H, m), 7.48 (1H, d, J = 7.7 Hz), 7.60-7.75 (4H, m), 8.22 (1H, s), 8.37 551 549 1-103 (1H, d, J = 7.3 Hz), 9.04 (1H, t, J = 6.3 Hz), HO N O 13.52 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.4 Hz), 1.54 (3H, s), 1.58-1.69 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 3.36 (3H, s), 4.32-4.45 1-104 N 509 507 (2H, m), 7.43-7.52 (3H, m), 7.61 (1H, d, J = HO N O 3 8.4 Hz), 7.67 (1H, s), 8.13-8.19 (2H, m), 9.04 F (1H, t, J = 6.2 Hz), 13.31 (1H, br s). 【0763】 【Table 1-14】 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 2.34 Cl (3H, d, J = 1.1 Hz), 3.36 (3H, s), 4.33-4.45 (2H, m), 7.44-7.52 (2H, m), 7.61 (1H, d, J = 1-105 499 497 H 3 8.2 Hz), 7.67 (1H, s), 8.00 (1H, d, J = 11.0 HO N O CH Hz), 8.09 (1H, dd, J = 7.9, 1.5 Hz), 9.04 (1H, t, J = 6.2 Hz), 13.38 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 2.32 (3H, d, J = 1.3 Hz), 3.36 (3H, s), 4.32-4.44 (2H, m), 7.32 (1H, t, J = 9.0 Hz), 7.46 (1H, d, J = 8.3 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.65 499 497 1-106 N CH HO N (1H, s), 8.19-8.25 (1H, m), 8.28 (1H, d, J = 7.3 Hz), 9.03 (1H, t, J = 6.3 Hz), 13.33 (1H, br F s).
H C 1H-NMR (DMSO-D6) δ: 1.25 (6H, d, J = 6.9 Hz), 1.38 (6H, s), 2.94-3.06 (1H, m), 4.37 1-107 N (2H, d, J = 5.9 Hz), 7.41-7.68 (5H, m), 8.13- 493 491 HO N 8.19 (1H, m), 8.22 (1H, br s), 8.64 (1H, t, J = O 5.9 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.25 (6H, d, J = 7.3 H C Cl Hz), 1.54 (3H, s), 2.94-3.07 (1H, m), 3.36 (3H, s), 4.31-4.46 (2H, m), 7.42-7.71 (5H, m), 509 507 1-108 N CH HO N 8.16 (1H, d, J = 7.7 Hz), 8.22 (1H, br s), 9.04 (1H, t, J = 6.0 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.98 (6H, d, J = 6.5 Hz), 1.37 (6H, s), 2.07-2.00 (1H, m), 3.85 H C Cl (2H, d, J = 6.5 Hz), 4.35 (2H, d, J = 6.0 Hz), 7.07 (2H, d, J = 9.1 Hz), 7.41 (1H, dd, J = 8.1, 523 521 1-109 2.1 Hz), 7.58 (1H, d, J = 8.1 Hz), 7.62 (1H, s), N H C CHF 8.29 (2H, d, J = 9.1 Hz), 8.63 (1H, t, J = 5.9 Hz), 13.13 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.22 (3H, t, J = 7.6 Hz), 1.38 (6H, s), 2.70 (2H, q, J = 7.6 Hz), 4.37 (2H, d, J = 6.0 Hz), 7.42-7.54 (3H, m), 1-110 N 479 477 7.61 (1H, d, J = 8.4 Hz), 7.65 (1H, s), 8.16 HO N CH (1H, d, J = 7.7 Hz), 8.19 (1H, s), 8.65 (1H, t, J = 6.0 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.40 (3H, s), 4.37 (2H, d, J = 6.0 Hz), 7.41-7.50 (3H, m), 7.61 (1H, d, J = 8.4 Hz), 7.65 (1H, s), 465 463 1-111 HO N CH 3 8.11-8.18 (2H, m), 8.65 (1H, t, J = 6.0 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.42 (3H, s), 4.37 (2H, d, J = 6.0 Hz), 7.44 (1H, dd, J = 8.4, 2.1 Hz), 7.61 (2H, dd, J = 8.4, 2.1 1-112 N 499 497 Hz), 7.64 (1H, d, J = 2.1 Hz), 8.17 (1H, dd, J HO N F = 8.4, 2.1 Hz), 8.30 (1H, d, J = 2.1 Hz), 8.65 (1H, t, J = 6.0 Hz), 13.39 (1H, br s).
OH C CH 【0764】 【Table 1-15】 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 4.36 (2H, d, J = 6.0 Hz), 4.89 (2H, q, J = 8.8 Hz), 7.20 (2H, d, J = 9.1 Hz), 7.39 (1H, dd, J = 8.3, 1-113 N 549 547 2.0 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.62 (1H, d, HO N J = 2.0 Hz), 8.33 (2H, d, J = 9.1 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.24 (1H, br s).
OH C CH 1H-NMR (DMSO-D6) δ: 0.94 (6H, d, J = 6.6 O Hz), 1.37 (6H, s), 1.63 (2H, q, J = 6.6 Hz), 1.79 (1H, m), 4.04 (2H, t, J = 6.6 Hz), 4.33 1-114 (2H, d, J = 6.0 Hz), 6.95 (2H, d, J = 8.9 Hz), 537 535 7.23 (1H, d, J = 8.3 Hz), 7.42 (1H, d, J = 8.3 HO N CH Hz), 7.50 (1H, d, J = 2.0 Hz), 8.22 (2H, d, J = 8.9 Hz), 8.59 (1H, t, J = 6.0 Hz). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.55 (3H, s), 4.36 (2H, d, J = 6.0 Hz), 7.39 (2H, d, N J = 8.7 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.58 1-115 N 497 495 (1H, d, J = 8.3 Hz), 7.63 (1H, s), 8.26 (2H, d, HO N CH 3 J = 8.7 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.26 (1H, s). 1H-NMR (DMSO-D6) δ: 1.37 (6H, s), 1.94- 1.80 (4H, m), 2.11-2.04 (2H, m), 2.77-2.69 (1H, m), 4.05 (2H, d, J = 6.7 Hz), 4.35 (2H, d, N O F 1-116 J = 5.8 Hz), 7.07 (2H, d, J = 9.1 Hz), 7.40 535 533 (1H, dd, J = 8.4, 2.1 Hz), 7.57 (1H, d, J = 8.4 N H C CHF Hz), 7.62 (1H, s), 8.28 (2H, d, J = 9.1 Hz), 8.62 (1H, t, J = 5.8 Hz), 13.13 (1H, s). 3 1H-NMR (DMSO-D6) δ: 1.27 (6H, d, J = 7.1 H C Cl Hz), 1.38 (6H, s), 3.19-3.28 (1H, m), 4.37 (2H, d, J = 6.0 Hz), 7.33 (1H, t, J = 9.5 Hz), 511 509 1-117 7.44 (1H, d, J = 8.4 Hz), 7.59-7.68 (2H, m), HO N 8.21-8.26 (1H, m), 8.33 (1H, dd, J = 7.5, 2.2 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.36 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.92 (3H, t, J = 7.3 Cl Hz), 1.38 (6H, s), 1.56-1.67 (2H, m), 2.67 (2H, t, J = 7.7 Hz), 4.37 (2H, d, J = 6.0 Hz), 1-118 511 509 H 7.33 (1H, t, J = 9.3 Hz), 7.44 (1H, d, J = 8.4 HO N CH Hz), 7.59-7.66 (2H, m), 8.21-8.30 (2H, m), 8.65 (1H, t, J = 6.0 Hz), 13.34 (1H, br s). 3 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.01 (3H, t, J = 19.0 Hz), 4.37 (2H, d, J = 5.8 Hz), 7.44 (1H, dd, J = 8.4, 2.1 Hz), 7.61 (2H, d, J = 1-119 515 513 8.1 Hz), 7.65 (2H, d, J = 2.1 Hz), 7.74 (2H, d, F J = 8.4 Hz), 8.43 (2H, d, J = 8.1 Hz), 8.64 HO N (1H, t, J = 5.8 Hz), 13.46 (1H, br s).
OH C H C 1H-NMR (DMSO-D6) δ: 1.01 (6H, d, J = 6.7 Hz), 1.37 (6H, s), 2.04-2.10 (1H, m), 3.95 (2H, d, J = 6.7 Hz), 4.33 (2H, d, J = 6.0 Hz), 1-120 7.25 (1H, dd, J = 8.3, 2.2 Hz), 7.29 (1H, d, J = 591 589 8.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.51 (1H, d, J = 2.2 Hz), 8.49-8.53 (2H, m), 8.56-8.62 (1H, OH C CH m). 【0765】 【Table 1-16】 1H-NMR (DMSO-D6) δ: 1.23 (3H, t, J = 7.7 Hz), 1.54 (3H, s), 2.70 (2H, q, J = 7.7 Hz), 3.36 (3H, s), 4.32-4.45 (2H, m), 7.44-7.54 1-121 N CH 495 493 (3H, m), 7.61 (1H, d, J = 8.4 Hz), 7.67 (1H, s), HO N O 8.13-8.19 (2H, m), 9.03 (1H, t, J = 6.3 Hz), 13.31 (1H, br s).
O 1H-NMR (DMSO-D6) δ: 0.99 (3H, t, J = 7.4 Hz), 1.38 (6H, s), 1.76 (2H, m), 4.04 (2H, t, J = 6.6 Hz), 4.36 (2H, d, J = 5.8 Hz), 7.07 (2H, 1-122 N 509 507 N d, J = 8.8 Hz), 7.40 (1H, d, J = 6.0 Hz), 7.57 (1H, d, J = 6.0 Hz), 7.62 (1H, s), 8.29 (2H, d, HO N CH J = 8.8 Hz), 8.63 (1H, s), 13.14 (1H, s).
H C F 1H-NMR (DMSO-D6) δ: 1.00 (6H, d, J = 6.9 3 Hz), 1.54 (3H, s), 1.98-2.12 (1H, m), 3.36 (3H, s), 3.86 (2H, d, J = 6.2 Hz), 4.30-4.45 1-123 (2H, m), 7.09 (2H, d, J = 8.5 Hz), 7.44 (1H, d, 539 537 J = 8.5 Hz), 7.59 (1H, d, J = 8.5 Hz), 7.66 HO N O (1H, br s), 8.30 (2H, d, J = 8.9 Hz), 9.03 (1H, t, J = 6.2 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.21 (3H, t, J = 7.6 Hz), 1.38 (6H, s), 2.71 (2H, q, J = 7.6 Hz), 4.37 (2H, d, J = 6.0 Hz), 7.33 (1H, t, J = 9.3 1-124 Hz), 7.44 (1H, dd, J = 8.5, 2.1 Hz), 7.59-7.66 497 495 HO N CH (2H, m), 8.21-8.26 (1H, m), 8.30 (1H, dd, J = 7.7, 2.2 Hz), 8.65 (1H, t, J = 6.0 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.75-2.00 (2H, m), Cl 2.28-2.43 (5H, m), 2.45-2.61 (2H, m), 4.40 (2H, d, J = 5.7 Hz), 7.33 (1H, t, J = 9.1 Hz), 495 493 1-125 7.46 (1H, dd, J = 8.4, 1.8 Hz), 7.63 (1H, d, J = HO N 8.4 Hz), 7.66 (1H, br s), 8.19-8.32 (2H, m), 8.81 (1H, t, J = 5.7 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 3.36 (3H, s), 4.32-4.46 (2H, m), 7.48 (1H, dd, J = N 8.4, 1.6 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.68 1-126 535 533 (1H, br s), 7.94 (2H, d, J = 8.4 Hz), 8.53 (2H, N CH HO N O d, J = 8.4 Hz), 9.04 (1H, t, J = 6.0 Hz), 13.56 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.20-1.39 (4H, m), 2.32 (3H, s), 4.35 (2H, d, J = 5.9 Hz), 7.33 (1H, t, J = 9.1 Hz), 7.45 (1H, dd, J = 8.4, 1.8 1-127 481 479 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.64 (1H, s), HO N 8.18-8.31 (2H, m), 8.48 (1H, t, J = 5.9 Hz), 13.32 (1H, br s).
H C 1H-NMR (DMSO-D6) δ: 0.41 (2H, dd, J = .8, 4.0 Hz), 0.55 (2H, dd, J = 5.2, 4.0 Hz), N 1.19 (3H, s), 1.38 (6H, s), 3.87 (2H, s), 4.36 1-128 (2H, d, J = 5.8 Hz), 7.07 (2H, d, J = 8.9 Hz), 535 533 HO N CH 7.41 (1H, d, J = 7.3 Hz), 7.58 (1H, d, J = 7.3 Hz), 7.63 (1H, s), 8.29 (2H, d, J = 8.9 Hz), F 8.64 (1H, t, J = 5.8 Hz), 13.14 (1H, s). 【0766】 【Table 1-17】 1H-NMR (DMSO-D6) δ: 1.39 (6H, s), 2.43 (3H, s), 4.37 (2H, d, J = 6.0 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.61 1-129 N 499 497 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 8.20 (1H, dd, HO N F J = 8.4, 1.5 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.39 (1H, br s).
OH C CH 1H-NMR (DMSO-D6) δ: 1.30 (6H, d, J = 6.7 H C Hz), 1.38 (6H, s), 4.37 (2H, d, J = 5.8 Hz), 7.43 (1H, dd, J = 8.4, 2.0 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.65 (1H, d, J = 2.0 Hz), 7.83 (1H, d, 561 559 1-130 N J = 8.4 Hz), 8.29 (1H, d, J = 8.4 Hz), 8.52 HO N F F (1H, s), 8.63 (1H, t, J = 5.8 Hz), 13.55 (1H, br OH C CH 3 s). 1H-NMR (DMSO-D6) δ: 0.94 (3H, t, J = 7.3 Cl Hz), 1.38 (6H, s), 1.45 (2H, m), 1.69-1.76 (2H, m), 3.17 (2H, d, J = 5.1 Hz), 4.08 (2H, 1-131 523 521 H m), 4.37 (2H, d, J = 5.8 Hz), 7.10 (2H, d, J = HO N CH CH 9.1 Hz), 7.44 (1H, s), 7.60 (m, s), 8.31 (2H, d, J = 9.1 Hz), 8.64 (1H, s), 13.14 (1H, s). 1H-NMR (DMSO-D6) δ: 1.35 (3H, t, J = 7.1 Hz), 1.37 (6H, s), 4.13 (2H, q, J = 7.1 Hz), N 4.35 (2H, d, J = 6.0 Hz), 7.07 (2H, d, J = 8.8 1-132 N 495 493 Hz), 7.42 (aH, brs), 7.60 (2H, brs), 8.29 (2H, N CH 3 d, J = 8.8 Hz), 8.62 (1H, t, J = 6.0 Hz), 13.13 (1H, s).
O 1H-NMR (DMSO-D6) δ: 0.34 (2H, m), 0.57 (2H, m), 1.23 (1H, m), 1.37 (6H, s), 3.92 (2H, d, J = 6.7 Hz), 4.35 (2H, d, J = 6.0 Hz), 7.07 1-133 521 519 (2H, s), 7.42 (1H, s), 7.59 (2H, s), 8.28 (2H, d, HO N CH J = 9.1 Hz), 8.62 (1H, t, J = 6.0 Hz), 13.13 (1H, s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 4.36 (2H, d, J = 5.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.6 467 465 1-134 HO N CH Hz), 7.64 (1H, s), 8.23 (2H, d, J = 8.8 Hz), 8.64 (1H, t, J = 5.8 Hz), 10.46 (1H, s). 1H-NMR (DMSO-D6) δ: 0.74-0.87 (2H, m), 1.01-1.09 (2H, m), 1.38 (6H, s), 2.07-2.15 N (1H, m), 4.37 (2H, d, J = 6.0 Hz), 7.33 (1H, t, 1-135 J = 9.3 Hz), 7.44 (1H, d, J = 8.2 Hz), 7.61 509 507 HO (1H, d, J = 8.2 Hz), 7.65 (1H, s), 7.96 (1H, dd, N CH J = 7.4, 1.9 Hz), 8.15-8.21 (1H, m), 8.64 (1H, F t, J = 6.0 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 2.42 (3H, s), 3.36 (3H, s), 4.32-4.45 (2H, m), 7.46 (1H, dd, J = 8.4, 2.0 Hz), 7.58-7.68 (3H, m), 1-136 515 513 N CH 3 8.16 (1H, dd, J = 8.4, 2.0 Hz), 8.30 (1H, d, J = HO N O 2.0 Hz), 9.04 (1H, t, J = 6.2 Hz), 13.39 (1H, br 【0767】 【Table 1-18】 O 1H-NMR (DMSO-D6) δ: 0.99 (3H, t, J = 7.4 Hz), 1.54 (3H, s), 1.71-1.81 (2H, m), 3.36 (3H, s), 4.04 (2H, t, J = 6.6 Hz), 4.32- 4.43 (2H, m), 7.07 (2H, d, J = 9.0 Hz), 7.42 1-137 525 523 H (1H, dd, J = 8.3, 1.9 Hz), 7.58 (1H, d, J = 8.3 HO N O CH CH Hz), 7.65 (1H, d, J = 1.9 Hz), 8.29 (2H, d, J = 9.0 Hz), 9.03 (1H, t, J = 6.6 Hz), 13.15 (1H, br 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 2.01 (3H, t, J = 19.0 Hz), 3.36 (3H, s, J = 8.8 Hz), 4.38 (2H, dd, J = 6.3, 2.8 Hz), 7.44 (1H, dd, J 1-138 N = 8.4, 2.1 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.66 531 529 (1H, d, J = 2.1 Hz), 7.73 (2H, d, J = 8.4 Hz), O CH HO N 8.42 (2H, d, J = 8.4 Hz), 9.03 (1H, t, J = 6.3 Hz), 13.47 (1H, s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 3.86 (3H, s), 4.37 (2H, d, J = 6.0 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.59 1-139 N 481 479 (1H, d, J = 8.6 Hz), 7.64 (1H, s), 8.32 (2H, d, HO N CH 3 J = 8.8 Hz), 8.63 (1H, t, J = 6.0 Hz), 13.15 O (1H, s). 1H-NMR (DMSO-D6) δ: 1.31 (6H, d, J = 6.0 Hz), 1.38 (6H, s), 4.37 (2H, d, J = 5.8 Hz), 4.77 (1H, m), 7.06 (2H, d, J = 8.8 Hz), 7.41 509 507 1-140 (1H, d, J = 8.4 Hz), 7.59 (1H, d, J = 8.4 Hz), HO N CH 7.64 (1H, s), 8.29 (2H, d, J = 8.8 Hz), 8.63 (1H, t, J = 5.8 Hz), 13.13 (1H, s).
O 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 1.66 (2H, m), 1.85 (2H, m), 2.07 (2H, m), 4.36 (2H, d, J = 5.8 Hz), 4.81 (1H,m), 6.98 (2H, d, J = 521 519 1-141 N 8.8 Hz), 7.40 (1H, d, J = 7.9 Hz), 7.57 (1H, d, J = 7.9 Hz), 7.62 (1H, s), 8.28 (2H, d, J = 8.8 HO N CH Hz), 8.63 (1H, t, J = 5.8 Hz), 13.14 (1H, s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.83 (2H, td, J = 11.3, 5.5 Hz), 4.33 (2H, t, J = 5.8 Hz), 4.37 (2H, d, J = 6.0 Hz), 7.12 (2H, d, J = 1-142 563 561 8.8 Hz), 7.43 (1H, s), 7.58 (1H, s), 7.64 (1H, HO N CH s), 8.32 (2H, d, J = 8.8 Hz), 8.64 (1H, d, J = 6.0 Hz), 13.18 (1H, s).
O 1H-NMR (DMSO-D6) δ: 1.38 (3H, s), 1.39 (6H, s), 4.18 (2H, s), 4.32 (2H, d, J = 5.8 Hz), 4.37 (2H, d, J = 5.8 Hz), 4.51 (2H, d, J = 5.8 1-143 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.43 (1H, d, J = 551 549 HO N CH 7.7 Hz), 7.60 (1H, d, J = 7.7 Hz), 7.64 (1H, s), 8.33 (2H, d, J = 8.8 Hz), 8.64 (1H, t, J = 5.8 Hz), 13.17 (1H, s).
H C O 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 3.32 (3H, s), 3.69 (2H, t, J = 4.4 Hz), 4.21 (2H, t, J = 4.4 Hz), 4.37 (2H, d, J = 5.8 Hz), 7.11 (2H, 1-144 d, J = 8.8 Hz), 7.42 (1H, d, J = 8.1 Hz), 7.60 525 523 (1H, d, J = 8.1 Hz), 7.64 (1H, s), 8.31 (2H, d, HO N CH J = 8.8 Hz), 8.63 (1H, d, J = 5.8 Hz), 13.15 F (1H, s). 【0768】 【Table 1-19】 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.6 H C O Hz), 1.38 (6H, s), 1.80 (2H, q, J = 7.6 Hz), 4.21 (2H, s), 4.35 (2H, d, J = 6.0 Hz), 4.37 (2H, d, J = 5.8 Hz), 4.46 (2H, d, J = 6.0 Hz), 1-145 565 563 7.15 (2H, d, J = 8.8 Hz), 7.42 (1H, d, J = 8.4 HO N CH Hz), 7.59 (1H, d, J = 8.4 Hz), 7.64 (1H, s), 8.32 (2H, d, J = 8.8 Hz), 8.64 (1H, t, J =5.8 Hz), 13.17 (1H, s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 1.84 (3H, t, J = 2.2 Hz), 4.37 (2H, d, J = 5.8 Hz), 4.87 (2H, d, J = 2.2 Hz), 7.12 (2H, d, J = 8.8 1-146 519 517 N Hz), 7.43 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = HO N CH 8.4 Hz), 7.65 (1H, s), 8.32 (2H, d, J = 8.8 Hz), F 8.64 (1H, t, J = 5.8 Hz), 13.17 (1H, s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.53 (3H, s), 4.37 (2H, d, J = 6.0 Hz), 7.42 (1H, dd, J = 8.1, 2.1 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.63 1-147 N 533 531 (1H, d, J = 2.1 Hz), 7.84 (1H, d, J = 8.1 Hz), N CH 8.30 (1H, d, J = 8.1 Hz), 8.34 (1H, s), 8.64 (1H, t, J = 6.0 Hz), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.54 (3H, s), 2.54 (3H, s), 3.36 (3H, s), 4.33-4.44 (2H, m), 7.47 (1H, dd, J = 8.3, 2.0 Hz), 7.62 (1H, d, J = 8.3 1-148 N 549 547 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.86 (1H, d, J = O CH HO N 8.3 Hz), 8.31 (1H, d, J = 8.3 Hz), 8.35 (1H, s), 9.04 (1H, t, J = 6.4 Hz), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.22-1.36 (4H, m), 2.53 (3H, s), 4.34 (2H, d, J = 6.0 Hz), 7.40 N (1H, dd, J = 8.4, 2.1 Hz), 7.57 (1H, d, J = 8.4 1-149 531 529 Hz), 7.61 (1H, d, J = 2.1 Hz), 7.82 (1H, d, J = HO N 8.4 Hz), 8.30 (1H, d, J = 8.4Hz), 8.34 (1H, s), 8.47 (1H, t, J = 6.0 Hz), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.38 (6H, s), 2.31 (3H, s), 2.32 (3H, s), 4.37 (2H, d, J = 6.0 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 8.2 1-150 479 477 H Hz), 7.58-7.67 (2H, m), 8.07 (1H, d, J = 8.2 HO N CH Hz), 8.12 (1H, s), 8.65 (1H, t, J = 6.0 Hz), 13.23 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.21 (3H, t, J = 7.5 Hz), 1.54 (3H, s), 2.71 (2H, q, J = 7.5 Hz), 3.36 (3H, s), 4.32-4.45 (2H, m), 7.33 (1H, t, J 1-151 = 9.3 Hz), 7.46 (1H, dd, J = 8.4, 2.0 Hz), 7.61 513 511 N CH (1H, d, J = 8.4 Hz), 7.66 (1H, s), 8.20-8.26 HO N O 3 (1H, m), 8.29 (1H, dd, J = 7.6, 2.3 Hz), 9.04 F (1H, t, J = 6.3 Hz), 13.35 (1H, br s).
H C 1H-NMR (DMSO-D6) δ: 1.19-1.27 (5H, m), 1.32-1.37 (2H, m), 2.71 (2H, q, J = 7.5 Hz), N 4.35 (2H, d, J = 6.0 Hz), 7.33 (1H, t, J = 9.2 1-152 Hz), 7.45 (1H, dd, J = 8.4, 2.0 Hz), 7.61 (1H, 495 493 HO N d, J = 8.4 Hz), 7.65 (1H, s), 8.21-8.26 (1H, m), 8.30 (1H, dd, J = 7.5, 2.0 Hz), 8.48 (1H, t, J = 6.0 Hz), 13.34 (1H, br s). 【0769】 【Table 1-20】 Cl 1H-NMR (DMSO-D6) δ: 1.39 (6H, s), 4.37 (2H, d, J = 6.0 Hz), 7.45 (1H, dd, J = 8.3, 2.1 1-153 Hz), 7.59-7.66 (3H, m), 8.32-8.38 (1H, m), 503 501 HO N CH 8.45 (1H, dd, J = 7.4, 2.1 Hz), 8.65 (1H, t, J = 6.0 Hz), 13.48 (0H, br s). 3 1H-NMR (DMSO-D6) δ: 0.99 (3H, t, J = 7.4 Hz), 1.22-1.27 (2H, m), 1.31-1.37 (2H, m), 1.71-1.81 (2H, m), 4.04 (2H, t, J = 6.5 Hz), 4.34 (2H, d, J = 6.0 Hz), 7.09 (2H, d, J = 9.0 1-154 507 505 Hz), 7.43 (1H, dd, J = 8.4, 2.0 Hz), 7.59 (1H, HO N d, J = 8.4 Hz), 7.64 (1H, s), 8.31 (2H, d, J = O 9.0 Hz), 8.47 (1H, t, J = 6.0 Hz), 13.14 (1H, br 3 1H-NMR (DMSO-D6) δ: 0.90 (3H, t, J = 7.3 H C O 3 Hz), 1.27 (3H, d, J = 6.0 Hz), 1.37 (6H,s), 1.43 (2H, m), 1.52-1.60 (1H, m), 1.67 (1H, m), 4.37 (2H, d, J = 5.8 Hz), 4.62 (1H, m), 1-155 537 535 7.07 (2H, d, J = 9.1 Hz), 7.42 (1H, d, J = 8.1 HO N CH 3 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.64 (1H, s), 8.29 (2H, d, J = 9.1 Hz), 8.63 (1H, t, J = 5.8 Hz), 13.13 (1H, s). 3 1H-NMR (DMSO-D6) δ: 0.90 (3H, t, J = 7.3 H C O 3 Hz), 1.27 (3H, d, J = 6.0 Hz), 1.36 (6H, s), 1.43 (2H, m), 1.51-1.60 (1H, m), 1.65 (1H, m), 4.37 (2H, d, J = 5.8 Hz), 4.62 (1H, m), 1-156 537 535 7.06 (2H, d, J = 8.8 Hz), 7.41 (1H, d, J = 8.1 HO N CH Hz), 7.59 (1H, d, J = 8.1 Hz), 7.64 (1H, s), 8.29 (2H, d, J = 8.8 Hz), 8.63 (1H, t, J = 5.8 Hz), 13.13 (1H, s). 1H-NMR (DMSO-D6) δ: 0.77-0.83 (2H, m), 1.02-1.08 (2H, m), 1.22-1.27 (2H, m), 1.31-1.36 (2H, m), 2.07-2.15 (1H, m), 4.34 (2H, d, J = 5.8 Hz), 7.33 (1H, t, J = 9.3 Hz), 1-157 507 505 N 7.44 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.4 HO N Hz), 7.65 (1H, s), 7.96 (1H, d, J = 7.9 Hz), O 8.15-8.20 (1H, m), 8.47 (1H, t, J = 5.8 Hz), 13.31 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.99 (3H, t, J = 7.5 Hz), 1.21 (6H, s), 1.76 (2H,m), 3.03 (2H, s), 4.04 (2H, t, J = 6.5 Hz), 4.40 (2H, s), 7.09 453 451 1-158 (2H, d, J = 8.9 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.67 (1H, s), 8.31 HO N (2H, d, J = 8.9 Hz), 13.14 (1H, s). 1H-NMR (DMSO-D6) δ: 0.72-0.77 (2H, m), 0.97-1.04 (2H, m), 1.38 (6H, s), 1.99-2.07 (1H, m), 4.37 (2H, d, J = 6.0 Hz), 7.34-7.45 1-159 N 491 489 (3H, m), 7.59 (1H, d, J = 8.4 Hz), 7.65 (1H, s), HO N CH 3 8.03 (1H, s), 8.10 (1H, d, J = 7.7 Hz), 8.64 F (1H, t, J = 6.0 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.72-0.78 (2H, m), Cl 0.98-1.04 (2H, m), 1.21-1.27 (2H, m), 1.31- 1.36 (2H, m), 2.00-2.07 (1H, m), 4.34 (2H, d, 1-160 J = 5.8 Hz), 7.35-7.46 (3H, m), 7.60 (1H, d, J 489 487 = 8.1 Hz), 7.66 (1H, s), 8.03 (1H, s), 8.10 (1H, O d, J = 7.4 Hz), 8.47 (1H, t, J = 5.8 Hz), 13.30 (1H, br s). 【0770】 【Table 1-21】 1H-NMR (DMSO-D6) δ: 1.32-1.38 (9H, m), 2.55 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 4.35 H C N (2H, d, J = 5.8 Hz), 6.86-6.92 (2H, m), 7.39 1-161 N 509 507 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.6 Hz), HO N CH 7.62 (1H, s), 7.81 (1H, br s), 8.61 (1H, t, J = .8 Hz), 13.08 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.35 (2H, q, J = 5.1 Hz), 0.57-0.60 (2H, m), 1.22-1.30 (1H, m), 1.54 (3H, s), 3.36 (3H, s), 3.93 (2H, d, J = 7.0 Hz), 4.37 (2H, dd, J = 5.9, 2.9 Hz), 7.07 (2H, 1-162 N 537 535 d, J = 8.8 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.58 HO N CH (1H, d, J = 8.4 Hz), 7.65 (1H, s), 8.29 (2H, d, J = 8.8 Hz), 9.02 (1H, t, J = 5.9 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.33-0.37 (2H, m), 0.57-0.61 (2H, m), 1.22-1.35 (5H, m), 3.92 (2H, d, J = 7.0 Hz), 4.33 (2H, d, J = 5.8 Hz), 1-163 7.05 (2H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.3, 519 517 1.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.61 (1H, d, HO N J = 1.9 Hz), 8.28 (2H, d, J = 8.8 Hz), 8.46 (1H, t, J = 5.8 Hz), 13.15 (1H, br s).
F O 1H-NMR (DMSO-D6) δ: 1.05 (2H, m), 1.10 (2H, m), 1.38 (6H, s), 4.20 (2H, s), 4.34 (2H, d, J = 5.6 Hz), 7.02 (2H, d, J = 7.9 Hz), 7.32 1-164 589 587 (1H, d, J = 7.5 Hz), 7.49 (1H, d, J = 7.5 Hz), HO N CH 3 7.56 (1H, s), 8.26 (2H, d, J = 7.9 Hz), 8.61 (1H, t, J = 5.6 Hz), 13.18 (1H, s). 1H-NMR (DMSO-D6) δ: 0.77-0.82 (2H, m), 1.01-1.07 (2H, m), 1.54 (3H, s), 2.07-2.15 (1H, m), 3.35 (3H, s), 4.31-4.44 (2H, m), 7.32 1-165 (1H, t, J = 9.3 Hz), 7.44 (1H, d, J = 8.4 Hz), 525 523 HO N O 7.60 (1H, d, J = 8.4 Hz), 7.67 (1H, s), 7.95 3 (1H, d, J = 7.2 Hz), 8.14-8.19 (1H, m), 9.02 F (1H, t, J = 6.3 Hz), 13.31 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.33-0.38 (2H, m), 0.56-0.62 (2H, m), 1.19-1.31 (7H, m), 2.59 (2H, q, J = 12.1 Hz), 3.93 (2H, d, J = 7.1 Hz), 1-166 N 4.33 (2H, d, J = 6.0 Hz), 7.07 (2H, d, J = 9.0 535 533 F Hz), 7.42 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = HO N 8.4 Hz), 7.63 (1H, s), 8.29 (2H, d, J = 9.0 Hz), CH 8.35 (1H, t, J = 6.0 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.11-0.16 (2H, m), 0.41-0.48 (2H, m), 0.79-0.90 (1H, m), 1.38 (6H, s), 1.65 (2H, q, J = 6.5 Hz), 4.14 (2H, t, J = 6.5 Hz), 4.37 (2H, d, J = 6.0 Hz), 7.09 (2H, 1-167 535 533 d, J = 9.0 Hz), 7.41 (1H, dd, J = 8.4, 2.0 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.64 (1H, d, J = 2.0 HO N CH Hz), 8.30 (2H, d, J = 9.0 Hz), 8.64 (1H, t, J = F 6.0 Hz), 13.15 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.32-0.38 (2H, m), 0.56-0.62 (2H, m), 1.01 (3H, s), 1.12 (3H, s), 1.19-1.30 (1H, m), 1.78-1.85 (2H, m), 1.90- Cl 1.97 (2H, m), 2.95-3.05 (1H, m), 3.93 (2H, d, 493 491 1-168 J = 7.0 Hz), 4.30 (2H, d, J = 6.0 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.43 (1H, d, J = 8.4 Hz), HO N 3 7.58 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.25- O 3 8.32 (3H, m), 13.13 (1H, br s). 【0771】 【Table 1-22】 1H-NMR (DMSO-D6) δ: 0.32-0.38 (2H, m), 0.55-0.62 (2H, m), 1.20-1.29 (1H, m), 1.74 (3H, s), 3.93 (2H, d, J = 6.7 Hz), 4.43 (2H, d, 1-169 J = 6.0 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.41 575 573 F (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.4 Hz), HO F 7.65 (1H, s), 8.29 (2H, d, J = 8.4 Hz), 9.10 O F (1H, t, J = 6.0 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.33-0.38 (2H, m), O 0.56-0.62 (2H, m), 1.20-1.31 (1H, m), 1.57- 1.90 (6H, m), 1.97-2.09 (2H, m), 2.29-2.39 Cl (1H, m), 3.93 (2H, d, J = 7.1 Hz), 4.31-4.33 1-170 529 527 (2H, br m), 7.08 (2H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.64 HO N (1H, s), 8.29 (2H, d, J = 8.8 Hz), 8.50 (1H, t, J F = 6.0 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.33-0.38 (2H, m), 0.56-0.62 (2H, m), 0.79 (6H, t, J = 7.5 Hz), 1.20-1.54 (5H, m), 1.98-2.07 (1H, m), 3.94 (2H, d, J = 7.1 Hz), 4.34 (2H, d, J = 6.0 Hz), 1-171 N 481 479 7.08 (2H, d, J = 9.0 Hz), 7.46 (1H, d, J = 8.2 H Hz), 7.60 (1H, d, J = 8.2 Hz), 7.66 (1H, s), HO N CH 8.29 (2H, d, J = 9.0 Hz), 8.46 (1H, t, J = 5.7 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.99-1.33 (5H, m), 1.38 (6H, s), 1.62-1.86 (6H, m), 3.89 (2H, d, J = 6.2 Hz), 4.36 (2H, d, J = 6.0 Hz), 7.06 (2H, 1-172 N d, J = 9.0 Hz), 7.40 (1H, dd, J = 8.4, 2.0 Hz), 563 561 7.57 (1H, d, J = 8.4 Hz), 7.62 (1H, d, J = 2.0 HO N CH 3 Hz), 8.29 (2H, d, J = 9.0 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.15 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.33-0.37 (2H, m), 0.56-0.62 (2H, m), 1.11 (6H, s), 1.17 (6H, s), 1.20-1.29 (2H, m), 3.93 (2H, d, J = 7.1 Hz), 4.29 (2H, d, J = 6.0 Hz), 7.07 (2H, d, J = 8.8 1-173 507 505 Hz), 7.43 (1H, dd, J = 8.4, 2.0 Hz), 7.57 (1H, H CH d, J = 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.29 HO N (2H, d, J = 8.8 Hz), 8.37 (1H, t, J = 6.0 Hz), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.51 (3H, s), 7.49- N CH 7.46 (3H, m), 7.63-7.60 (2H, m), 7.66 (1H, d, J = 7.9 Hz), 7.77 (2H, d, J = 8.6 Hz), 7.96 389 387 1-174 (1H, d, J = 7.9 Hz), 8.22 (1H, s), 8.53 (2H, d, J = 8.6 Hz), 13.46 (1H, s).
O CH 1H-NMR (DMSO-D6) δ: 0.36 (2H, td, J = 5.2, 3.9 Hz), 0.56-0.60 (2H, m), 1.23-1.30 (1H, m), 1.38 (6H, s), 2.21 (3H, s), 3.91 (2H, d, J = 6.7 1-175 Hz), 4.34 (2H, d, J = 5.8 Hz), 6.97 (1H, d, J = 535 533 8.6 Hz), 7.29 (1H, dd, J = 8.3, 1.9 Hz), 7.47 HO N 3 3 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 1.9 Hz), 8.08-8.14 (2H, m), 8.61 (1H, t, J = 5.8 Hz). 【0772】 【Table 1-23】 1H-NMR (DMSO-D6) δ: 0.30 (2H, td, J = 5.3, O CH 4.0 Hz), 0.56 (2H, ddd, J = 9.2, 5.3, 3.1 Hz), H C 1.22-1.27 (1H, m), 1.38 (6H, s), 2.29 (6H, s), 3.69 (2H, d, J = 7.0 Hz), 4.36 (2H, d, J = 5.8 1-176 549 547 Hz), 7.41 (1H, dd, J = 8.4, 1.9 Hz), 7.58 (1H, CH d, J = 8.4 Hz), 7.61 (1H, d, J = 1.9 Hz), 8.02 HO N (2H, s), 8.64 (1H, t, J = 5.8 Hz), 13.18 (1H, br F s). 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.4 Hz), 1.54 (3H, s), 1.83-1.98 (1H, m), 2.55 (2H, d, J = 7.3 Hz), 3.36 (3H, s), 4.31-4.45 1-177 (2H, m), 7.35 (2H, d, J = 8.3 Hz), 7.45 (1H, 523 521 dd, J = 8.1, 2.0 Hz), 7.60 (1H, d, J = 8.1 Hz), HO O 3 7.67 (1H, br s), 8.26 (2H, d, J = 8.3 Hz), 9.03 (1H, t, J = 6.2 Hz), 13.26 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.99 (6H, d, J = 6.4 Hz), 1.20-1.39 (4H, m), 1.96-2.13 (1H, m), 3.84 (2H, d, J = 6.4 Hz), 4.33 (2H, d, J = 6.0 1-178 Hz), 7.05 (2H, d, J = 9.1 Hz), 7.37 (1H, dd, J 521 519 N = 8.3, 2.0 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.60 HO N (1H, d, J = 2.0 Hz), 8.28 (2H, d, J = 9.1 Hz), O F 8.46 (1H, t, J = 5.8 Hz), 13.15 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.94 (3H, s), 0.95 (3H, s), 1.27-1.36 (2H, m), 1.38 (6H, s), 1.41- 1.49 (2H, m), 1.56-1.66 (2H, m), 1.80-1.89 (2H, m), 4.36 (2H, d, J = 5.7 Hz), 4.45-4.53 1-179 N 577 575 (1H, m), 7.07 (2H, d, J = 9.0 Hz), 7.40 (1H, HO N CH 3 dd, J = 8.2, 2.0 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.28 (2H, d, J = 9.0 F Hz), 8.63 (1H, t, J = 6.1 Hz), 13.13 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.3 Hz), 1.27-1.37 (2H, m), 1.38 (6H, s), 1.55- 1.64 (2H, m), 2.67 (2H, t, J = 7.7 Hz), 4.37 1-180 (2H, d, J = 6.0 Hz), 7.38 (2H, d, J = 8.2 Hz), 507 505 7.42 (1H, d, J = 8.4 Hz), 7.59 (1H, d, J = 8.4 HO N CH CH Hz), 7.64 (1H, s), 8.25 (2H, d, J = 8.2 Hz), 8.64 (1H, t, J = 6.0 Hz), 13.27 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.90 (3H, t, J = 7.7 Hz), 1.26-1.37 (2H, m), 1.54 (3H, s), 1.55- 1.64 (2H, m), 2.67 (2H, t, J = 7.7 Hz), 3.36 1-181 N (3H, s), 4.32-4.44 (2H, m), 7.38 (2H, d, J = 523 521 N CH 7.5 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.59 (1H, d, HO N O 3 J = 8.4 Hz), 7.66 (1H, s), 8.25 (2H, d, J = 7.5 Hz), 9.03 (1H, t, J = 6.2 Hz), 13.27 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.99 (6H, t, J = 6.0 Hz), 1.37 (6H, s), 2.00-2.10 (1H, m), 4.11 CH N (2H, d, J = 6.5 Hz), 4.34 (2H, d, J = 6.0 Hz), 6.88 (1H, d, J = 8.7 Hz), 7.30 (1H, dd, J = 8.1, 1-182 524 522 2.1 Hz), 7.48 (1H, d, J = 8.1 Hz), 7.57 (1H, d, HO N 3 3 J = 2.1 Hz), 8.47 (1H, dd, J = 8.7, 2.4 Hz), 8.60 (1H, t, J = 6.0 Hz), 9.02 (1H, d, J = 2.4 Hz). 1H-NMR (DMSO-D6) δ: 1.24 (6H, s), 2.32 (3H, d, J = 1.3 Hz), 2.59 (2H, q, J = 12.1 Hz), 4.34 (2H, d, J = 6.2 Hz), 7.32 (1H, t, J = 9.2 1-183 N Hz), 7.44 (1H, dd, J = 8.4, 2.0 Hz), 7.59 (1H, 497 495 N CH d, J = 8.4 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.19- 8.25 (1H, m), 8.28 (1H, d, J = 7.7 Hz), 8.35 (1H, t, J = 5.8 Hz), 13.33 (1H, br s). 【0773】 【Table 1-24】 1H-NMR (DMSO-D6) δ: 0.29-0.39 (2H, m), 0.47-0.55 (2H, m), 1.08-1.17 (1H, m), 1.32 (3H, d, J = 6.3 Hz), 1.38 (6H, s), 4.10-4.18 (1H, m), 4.36 (2H, d, J = 6.0 Hz), 7.05 (2H, d, 535 533 1-184 J = 8.8 Hz), 7.41 (1H, d, J = 8.0 Hz), 7.58 HO N CH (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.27 (2H, d, J = 8.8 Hz), 8.63 (1H, t, J = 6.0 Hz), 13.13 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.29-0.39 (2H, m), 0.47-0.55 (2H, m), 1.08-1.17 (1H, m), 1.32 (3H, d, J = 6.3 Hz), 1.38 (6H, s), 4.10-4.18 (1H, m), 4.36 (2H, d, J = 6.0 Hz), 7.05 (2H, d, 535 533 1-185 J = 8.8 Hz), 7.41 (1H, d, J = 8.0 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.27 (2H, d, HO N CH J = 8.8 Hz), 8.63 (1H, t, J = 6.0 Hz), 13.13 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.37 (6H, s), 2.28 (3H, d, J = 1.2 Hz), 4.33 (2H, d, J = 6.0 Hz), 7.15 (1H, t, J = 9.1 Hz), 7.22 (1H, dd, J = 8.4, 1-186 N 505 503 2.3 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.49 (1H, d, N F F O N F Na J = 2.3 Hz), 8.10-8.16 (1H, m), 8.19 (1H, dd, J = 8.1, 1.6 Hz), 8.59 (1H, t, J = 6.0 Hz). 3 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 3.75 (2H, s), 4.57 (2H, d, J = 5.7 Hz), 5.42 (1H, t, J = 5.7 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.53 (1H, 400 398 1-187 d, J = 8.4 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.71 (1H, s), 8.31 (2H, d, J = 8.8 Hz), 13.13 (1H, br HO OH s). 1H-NMR (DMSO-D6) δ: 1.45 (3H, d, J = 6.8 Hz), 1.49 (3H, s), 2.32 (3H, s), 3.33 (3H, s), .02-5.10 (1H, m), 7.32 (1H, t, J = 9.3 Hz), 1-188 513 511 3 7.60 (2H, s), 7.76 (1H, s), 8.18-8.24 (1H, m), HO N O 8.27 (1H, d, J = 6.8 Hz), 8.81 (1H, d, J = 8.4 H C CH Hz), 13.32 (1H, s). 1H-NMR (DMSO-D6) δ: 1.46 (3H, d, J = 6.8 H C Hz), 1.54 (3H, s), 2.31 (3H, s), 3.37 (3H, s), .02-5.11 (1H, m), 7.32 (1H, t, J = 9.2 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.61 (1H, d, J = 8.4 513 511 1 1-189 N CH HO N Hz), 7.72 (1H, s), 8.19-8.25 (1H, m), 8.28 H C CH (1H, d, J = 7.3 Hz), 8.83 (1H, d, J = 8.2 Hz), F 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.33-0.37 (2H, m), 0.56-0.62 (2H, m), 1.21-1.30 (1H, m), 2.85 (3H, br s), 2.90 (3H, br s), 3.94 (2H, d, J = 7.1 1-190 N O 455 453 Hz), 5.13 (2H, s), 7.09 (2H, d, J = 8.6 Hz), N N CH N H C 7.56-7.67 (2H, br m), 7.78 (1H, br s), 8.30 (2H, d, J = 8.6 Hz), 13.15 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.30-1.40 (9H, m), 1.44-1.55 (3H, m), 1.64-1.74 (2H, m), 1.80- 1.88 (2H, m), 2.63-2.70 (1H, m), 4.33 (2H, d, J = 6.0 Hz), 7.25 (1H, dd, J = 8.6, 2.1 Hz), 557 555 1-191 N 7.40-7.46 (3H, m), 7.52 (1H, d, J = 2.1 Hz), 8.25 (2H, d, J = 8.1 Hz), 8.59 (1H, t, J = 6.0 N CH Hz). 【0774】 【Table 1-25】 1H-NMR (DMSO-D6) δ: 0.35 (2H, dt, J = 7.9, 2.8 Hz), 0.57-0.61 (2H, m), 1.21-1.30 (1H, m), 3.94 (2H, d, J = 7.0 Hz), 1-192 7.09 (2H, d, J = 8.8 Hz), 398 396 7.77 (1H, d, J = 8.4 Hz), 8.09 (1H, dd, J = 8.4, HO OH 1.6 Hz), 8.30 (2H, d, J = 9.0 Hz), 8.33 (1H, s), 13.31 (1H, s). 1H-NMR (DMSO-D6) δ: 0.35 (2H, td, J = 5.2, 4.1 Hz), 0.56-0.62 (2H, m), 1.21-1.29 (1H, m), 3.94 (2H, d, J = 7.0 Hz), 7.08 (2H, d, J = 8.8 Hz), 7.58 (1H, s), 7.74 (1H, d, J = 8.4 Hz), 397 395 1-193 8.06 (1H, d, J = 8.4 Hz), 8.17 (1H, s), 8.27 HO NH (1H, d, J = 2.1 Hz), 8.31 (2H, d, J = 8.8 Hz), 13.14 (1H, s). 1H-NMR (DMSO-D6) δ: 0.35 (2H, q, J = 4.8 Hz), 0.57-0.61 (2H, m), 1.22-1.29 (1H, m), Cl 2.81 (3H, d, J = 4.4 Hz), 3.94 (2H, d, J = 7.0 1-194 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.75 (1H, d, J = 411 409 8.4 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.24 (1H, s), HO N 8.31 (2H, d, J = 8.8 Hz), 8.63-8.67 (1H, m), O CH 13.19 (1H, s). 1H-NMR (DMSO-D6) δ: 0.33-0.37 (2H, m), 0.57-0.61 (2H, m), 1.20-1.30 (1H, m), 2.95 (3H, s), 3.00 (3H, s), 3.94 (2H, d, J = 7.0 Hz), 1-195 7.09 (2H, d, J = 8.8 Hz), 7.63 (1H, d, J = 9.1 425 423 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.83 (1H, d, J = N CH HO N 1.9 Hz), 8.30 (2H, d, J = 9.1 Hz), 13.16 (1H, O CH H C CH 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.51 (6H, s), 3.05 (3H, s), 3.75 (2H, s), 4.65 (2H, 1-196 s), 7.10 (2H, d, J = 8.8 Hz), 7.41 (1H, d, J = 551 549 N CH 8.6 Hz), 7.61-7.66 (2H, m), 8.31 (2H, d, J = HO N CH 8.8 Hz), 13.15 (1H, br s).
H C CH 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 3.34 (3H, s), 3.75 (2H, s), 4.49 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.53 (1H, dd, J = 8.2, 2.0 Hz), 414 412 1-197 N 7.62 (1H, d, J = 8.2 Hz), 7.72 (1H, d, J = 2.0 Hz), 8.31 (2H, d, J = 8.8 Hz), 13.14 (1H, br s).
HO O 3 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 2.79 CH (2H, t, J = 6.6 Hz), 3.65 (2H, td, J = 6.6, 5.1 Hz), 3.75 (2H, s), 4.69 (1H, t, J = 5.1 Hz), 1-198 N 414 412 7.10 (2H, d, J = 8.8 Hz), 7.47 (1H, s), 7.54 OH (1H, d, J = 8.1 Hz), 7.63 (1H, s), 8.31 (2H, d, J = 8.8 Hz), 13.10 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 2.89 (2H, t, J = 6.5 Hz), 3.25 (3H, s), 3.58 (2H, t, J = 6.5 Hz), 3.75 (2H, s), 7.10 (2H, d, J = 8.8 1-199 N 428 426 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.65 (1H, d, J = 1.9 Hz), 8.31 (2H, d, N O CH J = 8.8 Hz), 13.10 (1H, s). 【0775】 【Table 1-26】 H C CH 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.45 (3H, d, J = 7.1 Hz), 1.49 (3H, s), 3.33 (3H, s), 3.75 (2H, s), 5.02-5.11 (1H, m), 7.09 (2H, d, J 1-200 567 565 2 = 8.8 Hz), 7.58 (2H, s), 7.76 (1H, s), 8.29 (2H, N CH d, J = 8.8 Hz), 8.82 (1H, d, J = 8.2 Hz), 13.14 HO N O H C CH (1H, br s).
H C CH 3 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.47 (3H, d, J = 7.1 Hz), 1.54 (3H, s), 3.37 (3H, s), 3.75 (2H, s), 5.02-5.11 (1H, m), 7.09 (2H, d, J = 8.2 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.59 (1H, 567 565 2 1-201 N d, J = 8.4 Hz), 7.72 (1H, s), 8.31 (2H, d, J = HO N O 8.2 Hz), 8.83 (1H, d, J = 8.2 Hz), 13.15 (1H, H C CH F br s). 1H-NMR (DMSO-D6) δ: 1.48 (6H, s), 4.29 (2H, d, J = 6.0 Hz), 7.08 (1H, t, J = 7.6 Hz), 7.21 (2H, t, J = 7.6 Hz), 7.30 (2H, d, J = 8.4 1-202 H 459 457 HO N CH Hz), 7.33-7.41 (2H, m), 7.52-7.60 (3H, m), 7.68 (1H, t, J = 7.2 Hz), 8.03 (1H, t, J = 6.0 Hz), 8.34 (2H, d, J = 8.1 Hz), 13.33 (1H, br s).
H C 1H-NMR (DMSO-D6) δ: 1.00 (9H, t, J = 16.5 Hz), 1.29 (6H, s), 2.80 (2H, t, J = 7.0 Hz), 3.30 (4H, s), 3.34 (3H, q, J = 6.7 Hz), 3.73 N CH 1-203 (2H, s), 7.07 (2H, d, J = 8.8 Hz), 7.37 (1H, dd, 551 549 N N F F J = 8.4, 2.0 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.57 HO O (1H, d, J = 2.1 Hz), 8.00 (1H, t, J = 5.6 Hz), 8.29 (2H, d, J = 8.8 Hz), 13.10 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.89 (6H, d, J = 6.7 3 Hz), 1.02 (9H, s), 1.81-1.91 (1H, m), 3.25 (2H, d, J = 6.5 Hz), 3.75 (2H, s), 4.53 (2H, s), 1-204 456 454 7.10 (2H, d, J = 8.8 Hz), 7.54 (1H, d, J = 8.4 N CH Hz), 7.62 (1H, d, J = 8.1 Hz), 7.73 (1H, s), HO O CH 8.31 (2H, d, J = 8.8 Hz), 13.12 (1H, s). 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.3 Hz), 1.02 (9H, s), 1.28-1.37 (2H, m), 1.55- 1.62 (2H, m), 2.65 (2H, t, J = 7.7 Hz), 3.75 (2H, s), 7.10 (2H, d, J = 9.1 Hz), 7.43 (1H, d, 426 424 1-205 J = 8.1 Hz), 7.53 (1H, d, J = 8.1 Hz), 7.61 N CH (1H, d, J = 2.1 Hz), 8.31 (2H, d, J = 9.1 Hz), 13.09 (1H, s). 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.6 Hz), 1.51 (6H, s), 1.84-1.95 (1H, m), 2.55 (2H, d, J = 7.3 Hz), 3.05 (3H, s), 4.65 (2H, s), 1-206 521 519 7.35 (2H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.2 HO N CH 3 Hz), 7.62-7.66 (2H, m), 8.26 (2H, d, J = 8.4 O Hz), 13.26 (1H, br s).
H C CH 3 1H-NMR (DMSO-D6) δ: 1.01 (9H, s), 3.75 (2H, s), 4.67 (2H, d, J = 5.5 Hz), 5.55 (1H, t, J = 5.5 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.73 (1H, 1-207 F 434 432 d, J = 7.9 Hz), 7.78 (1H, s), 7.90 (1H, d, J = 7.9 Hz), 8.29 (2H, d, J = 8.8 Hz), 13.21 (1H, br s).
HO OH 【0776】 【Table 1-27】 H C CH O 1H-NMR (DMSO-D6) δ: 1.01 (9H, s), 1.39 (6H, s), 3.74 (2H, s), 4.44 (2H, d, J = 6.0 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.57 (1H, d, J = 8.1 1-208 571 569 Hz), 7.68 (1H, s), 7.88 (1H, d, J = 8.1 Hz), 8.28 (2H, d, J = 8.6 Hz), 8.69 (1H, t, J = 6.0 HO N CH Hz), 13.23 (1H, br s).
H C 1H-NMR (CDCl3) δ: 1.07 (9H, s), 1.12 (3H, t, Cl H C CH J = 5.8 Hz), 1.48 (9H, br s), 3.27 (2H, br s), N CH 3.70 (2H, s), 4.48 (2H, s), 7.02 (2H, d, J = 8.6 527 525 1-209 Hz), 7.41 (1H, br s), 7.50 (1H, d, J = 8.1 Hz), HO N 7.89 (1H, s), 8.50 (2H, d, J = 8.4 Hz). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.23 Cl (3H, t, J = 7.2 Hz), 2.99 (2H, dt, J = 19.7, 7.2 Hz), 3.76 (2H, s), 4.23 (2H, t, J = 6.0 Hz), 427 425 1-210 N 7.13 (2H, d, J = 9.1 Hz), 7.74 (2H, s), 7.97 HO N (1H, s), 8.33 (2H, d, J = 9.1 Hz), 9.05 (2H, s). 1H-NMR (DMSO-D6) δ: 1.00-1.32 (5H, m), 1.51 (6H, s), 1.61-1.85 (6H, m), 3.05 (3H, s), 3.89 (2H, d, J = 6.2 Hz), 4.65 (2H, s), 7.08 1-211 N 577 575 N (2H, d, J = 9.0 Hz), 7.40 (1H, d, J = 8.2 Hz), N CH 7.61-7.65 (2H, m), 8.30 (2H, d, J = 9.0 Hz), HO N CH 3 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 3.24 (2H, q, J = 9.5 Hz), 3.75 (2H, s), 3.86 (2H, s), 1-212 7.10 (2H, d, J = 8.6 Hz), 7.54-7.63 (2H, m), 481 479 H 7.74 (1H, s), 8.32 (2H, d, J = 8.6 Hz), 13.11 HO N F (1H, s). 1H-NMR (DMSO-D6) δ: 1.30-1.41 (3H, m), 1.44-1.56 (9H, m), 1.65-1.73 (2H, m), 1.81- 1.88 (2H, m), 2.66-2.73 (1H, m), 3.05 (3H, s), 1-213 571 569 4.65 (2H, s), 7.42 (1H, d, J = 8.6 Hz), 7.54 N (2H, d, J = 8.4 Hz), 7.62-7.66 (2H, m), 8.30 HO N CH (2H, d, J = 8.4 Hz), 13.36 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.09 (6H, s), 2.72 (2H, s), 3.75 (2H, s), 4.40 (1H, 1-214 s), 7.10 (2H, d, J = 8.8 Hz), 7.44 (1H, d, J = 442 440 8.8 Hz), 7.53 (1H, d, J = 8.1 Hz), 7.61 (1H, s), N OH 8.31 (2H, d, J = 8.8 Hz), 13.10 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.10 3 (6H, s), 2.81 (2H, s), 3.17 (3H, s), 3.75 (2H, s), 7.10 (2H, d, J = 8.8 Hz), 7.41 (1H, dd, J = 1-215 456 454 8.5, 1.7 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.58 N O CH (1H, d, J = 1.7 Hz), 8.31 (2H, d, J = 8.8 Hz), 13.10 (1H, s). 【0777】 【Table 1-28】 1H-NMR (DMSO-D6) δ: 1.00 (9H, s), 1.06 (3H, d, J = 6.3 Hz), 2.68 (2H, d, J = 6.0 Hz), 3.73 (2H, s), 3.82-3.88 (1H, m), 4.60 (1H, d, J 1-216 = 4.9 Hz), 7.09 (2H, d, J = 9.1 Hz), 7.42 (1H, 428 426 d, J = 9.3 Hz), 7.51 (1H, d, J = 8.1 Hz), 7.59 N OH (1H, s), 8.30 (2H, d, J = 9.1 Hz), 13.08 (1H, H C CH 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.20 (9H, s), 2.36 (2H, t, J = 7.6 Hz), 2.86 (2H, t, J = 7.6 Hz), 3.75 (2H, s), 7.10 (2H, d, J = 8.8 497 495 1-217 Hz), 7.40-7.46 (2H, m), 7.53 (1H, d, J = 8.2 HO Hz), 7.61 (1H, s), 8.31 (2H, d, J = 8.8 Hz), 13.11 (1H, br s).
O CH H C CH H C CH O 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 2.66 (2H, t, J = 7.6 Hz), 2.81 (3H, s), 2.87 (2H, t, J = 7.6 Hz), 2.95 (3H, s), 3.75 (2H, s), 7.10 (2H, 1-218 N 469 467 d, J = 8.8 Hz), 7.46-7.56 (2H, m), 7.66 (1H, d, J = 2.0 Hz), 8.31 (2H, d, J = 9.0 Hz), 13.11 HO CH N (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 0.89 (6H, d, J = 6.5 Hz), 1.30-1.40 (3H, m), 1.46-1.55 (3H, m), 1.65-1.73 (2H, m), 1.80-1.90 (3H, m), 2.67- 2.72 (1H, m), 3.25 (2H, d, J = 6.5 Hz), 4.53 1-219 476 474 (2H, s), 7.54 (2H, d, J = 8.4 Hz), 7.57 (1H, d, J = 1.6 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.73 N CH N (1H, s), 8.31 (2H, d, J = 8.4 Hz), 13.33 (1H, br HO O CH 1H-NMR (DMSO-D6) δ: 1.51 (6H, s), 3.06 (3H, s), 4.65 (2H, s), 7.42 (1H, d, J = 8.4 Hz), 1-220 N CH 465 463 7.56 (2H, t, J = 7.7 Hz), 7.62-7.69 (3H, m), HO N CH CH 8.34 (2H, d, J = 7.7 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.24 (9H, s), 3.02 (3H, s), 4.62 (2H, s), 7.40 (1H, dd, J = 8.4, 1.8 465 463 1-221 N CH Hz), 7.56 (2H, t, J = 7.6 Hz), 7.61-7.69 (3H, HO CH m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.01 (1.8H, d, J = Cl 6.7 Hz), 1.04 (4.2H, d, J = 6.7 Hz), 2.84 (0.9H, s), 2.84-2.88 (0.3H, m), 2.90-2.97 1-222 (0.7H, m), 3.01 (2.1H, s), 4.57 (1.4H, s), 4.71 397 395 N CH (0.6H, s), 7.42 (1H, dd, J = 8.3, 1.9 Hz), 7.57 HO N CH (2H, t, J = 7.6 Hz), 7.60-7.69 (3H, m), 8.34 3 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.37 3 (9H, s), 2.79 (3H, s), 3.75 (2H, s), 4.50 (2H, s), 7.11 (2H, d, J = 8.9 Hz), 7.55 (1H, dd, J = 1-223 533 531 N O CH 8.1, 1.6 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.72 S CH (1H, s), 8.31 (2H, d, J = 8.9 Hz), 13.17 (1H, br HO N CH s). 【0778】 【Table 1-29】 1H-NMR (DMSO-D6) δ: 0.97-1.05 (3H, m), 2.34-2.43 (2H, m), 2.85 (0.9H, s), 2.96 (2.1H, 1-224 s), 4.57 (1.4H, s), 4.65 (0.6H, s), 7.44 (1H, d, 383 381 N CH J = 8.4 Hz), 7.54-7.69 (5H, m), 8.34 (2H, d, J HO N = 8.4 Hz), 13.35 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 0.84-0.93 (3H, m), N 1.50-1.60 (2H, m), 2.31-2.38 (2H, m), 2.84 (0.9H, s), 2.96 (2.1H, s), 4.57 (1.4H, s), 4.66 397 395 1-225 N CH (0.6H, s), 7.41-7.46 (1H, m), 7.54-7.69 (5H, HO N m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 0.87-0.93 (6H, m), 1.99-2.10 (1H, m), 2.22-2.28 (2H, m), 2.84 (0.9H, s), 2.97 (2.1H, s), 4.58 (1.4H, s), 4.66 1-226 411 409 N CH (0.6H, s), 7.40-7.46 (1H, m), 7.56 (2H, t, J = HO N 7.6 Hz), 7.60-7.70 (3H, m), 8.34 (2H, d, J = O CH 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.43 3 (6H, s), 2.88 (2H, t, J = 7.5 Hz), 3.03 (3H, s), 3.55 (2H, t, J = 7.5 Hz), 3.74 (2H, s), 7.09 Cl F N F (2H, d, J = 9.0 Hz), 7.45 (1H, dd, J = 8.0, 2.0 565 563 1-227 N H C CH Hz), 7.55 (1H, d, J = 8.0 Hz), 7.64 (1H, d, J = 2.0 Hz), 8.30 (2H, d, J = 9.0 Hz), 13.11 (1H, HO O br s). 1H-NMR (DMSO-D6) δ: 1.46-1.86 (8H, m), 2.83 (0.9H, s), 2.96-3.10 (1H, m), 3.01 (2.1H, s), 4.57 (1.4H, s), 4.72 (0.6H, s), 7.42 (1H, d, 423 421 1-228 N CH J = 8.3 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.60-7.69 HO N (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.33 (1H, O br s). 1H-NMR (DMSO-D6) δ: 1.10-1.43 (5H, m), 1.58-1.77 (5H, m), 2.56-2.68 (1H, m), 2.81 (0.9H, s), 3.01 (2.1H, s), 4.56 (1.4H, s), 4.70 1-229 437 435 N CH (0.6H, s), 7.38-7.43 (1H, m), 7.56 (2H, t, J = HO N 7.6 Hz), 7.59-7.69 (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.87-2.97 (3H, m), 4.54 (0.8H, s), 4.75 (1.2H, s), 7.39-7.51 (5.4H, m), 7.54-7.61 (2.6H, m), 7.62-7.70 431 429 1-230 N CH (2.4H, m), 7.74-7.83 (0.6H, m), 8.35 (2H, d, J = 7.6 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.79 (3H, t, J = 7.4 Hz), 1.19 (6H, s), 1.64 (2H, q, J = 7.4 Hz), 1-231 3.02 (3H, s), 4.61 (2H, s), 7.43 (1H, d, J = 8.3 425 423 N CH Hz), 7.56 (2H, t, J = 7.6 Hz), 7.61-7.69 (3H, HO N CH 3 m), 8.34 (2H, d, J = 7.6 Hz), 13.33 (1H, br s).
O CH 【0779】 【Table 1-30】 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.7 Hz), 1.35 (9H, s), 1.84-1.95 (1H, m), 2.55 (2H, d, J = 7.4 Hz), 2.90 (3H, s), 3.77 (2H, s), 1-232 467 465 7.35 (2H, d, J = 8.1 Hz), 7.41 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 8.3 Hz), 7.62 (1H, s), HO CH N CH 8.26 (2H, d, J = 8.1 Hz), 13.24 (1H, br s).
H C CH 1H-NMR (DMSO-D6) δ: 0.75-0.84 (6H, m), 1.33-1.46 (2H, m), 1.47-1.60 (2H, m), 2.62- 2.71 (1H, m), 2.88 (0.9H, s), 3.03 (2.1H, s), 425 423 1-233 N CH 4.61 (1.4H, s), 4.72 (0.6H, s), 7.41-7.47 (1H, HO N CH m), 7.56 (2H, t, J = 7.6 Hz), 7.61-7.69 (3H, m), 8.33 (2H, d, J = 7.6 Hz), 13.35 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.37 (6H, s), 2.78 (0.6H, br s), 3.14 (3H, s), 3.23 (2.4H, br s), 4.59 (1.6H, s), 5.09 (0.4H, br s), 7.45 (1H, d, J 1-234 427 425 3 = 7.9 Hz), 7.56 (2H, t, J = 7.9 Hz), 7.61-7.69 HO N CH (3H, m), 8.33 (2H, d, J = 7.9 Hz), 13.33 (1H, O O CH br s). 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 1.12 (3H, t, J = 6.8 Hz), 1.50 (6H, s), 3.42 (2H, br F s), 3.75 (2H, s), 4.66 (2H, s), 7.09 (2H, d, J = 565 563 1-235 N O 8.8 Hz), 7.40 (1H, d, J = 8.3 Hz), 7.61 (1H, d, N CH HO N CH J = 8.3 Hz), 7.62 (1H, s), 8.30 (2H, d, J = 8.8 H C Hz), 13.14 (1H, s). 1H-NMR (DMSO-D6) δ: 1.21 (6H, s), 3.04 (2H, s), 4.41 (2H, s), 7.48 (1H, d, J = 8.6 Hz), 395 393 1-236 N 7.57 (2H, t, J = 7.6 Hz), 7.64-7.71 (3H, m), 8.35 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.48 (6H, s), 2.45 (3H, br s), 4.55 (2H, br s), 7.18 (1H, t, J = 7.2 1-237 3 Hz), 7.22-7.26 (2H, m), 7.28-7.34 (2H, m), 473 471 HO N CH 7.41 (1H, br s), 7.53-7.68 (5H, m), 8.35 (2H, d, J = 8.1 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.56-1.67 (4H, m), 2.08-2.17 (2H, m), 2.37-2.46 (2H, m), 3.02 (3H, s), 4.65 (2H, s), 7.39 (1H, d, J = 8.3 Hz), 491 489 1-238 N CH HO N 7.55 (2H, t, J = 8.0 Hz), 7.60-7.68 (3H, m), 8.34 (2H, d, J = 8.0 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.23 (6H, s), 3.02 (3H, s), 3.20 (3H, s), 3.43 (2H, s), 4.63 (2H, 1-239 CH 441 439 HO N CH s), 7.42 (1H, d, J = 8.3 Hz), 7.54-7.70 (5H, m), 8.34 (2H, d, J = 7.6 Hz), 13.36 (1H, br s). 【0780】 【Table 1-31】 1H-NMR (DMSO-D6) δ: 1.07 (6H, s), 1.83 (2H, t, J = 6.9 Hz), 3.21 (2H, t, J = 6.9 Hz), 1-240 4.44 (2H, s), 7.42 (1H, d, J = 8.3 Hz), 7.57 409 407 (2H, t, J = 7.6 Hz), 7.62-7.69 (3H, m), 8.34 HO N (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.15 (6H, s), 1.64- N 1.69 (2H, m), 1.74-1.81 (2H, m), 3.26 (2H, t, J = 6.0 Hz), 4.53 (2H, s), 7.42 (1H, d, J = 8.1 423 421 1-241 Hz), 7.56 (2H, t, J = 7.4 Hz), 7.60-7.69 (3H, HO N m), 8.35 (2H, d, J = 7.4 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.61 (3H, s), 2.82 (0.6H, br s), 3.23 (2.4H, s), 3.37 (3H, s), 4.64 (1.6H, s), 4.87-5.12 (0.4H, m), 7.46 (1H, d, J 1-242 N CH 481 479 3 CH = 8.3 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.63-7.71 HO N O 3 (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.61 (3H, s), 2.82 (0.6H, br s), 3.23 (2.4H, s), 3.37 (3H, s), 4.64 (1.6H, s), 4.87-5.12 (0.4H, m), 7.46 (1H, d, J 481 479 1-243 N CH 3 CH = 8.3 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.63-7.71 CH (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.18-1.31 (3H, m), 1.46-1.59 (3H, m), 1.63-1.72 (2H, m), 2.51- 2.58 (2H, m), 3.15 (3H, s), 4.71 (2H, s), 7.43 CH 505 503 1-244 N (1H, dd, J = 8.1, 1.8 Hz), 7.56 (2H, t, J = 7.5 HO N Hz), 7.63-7.69 (3H, m), 8.34 (2H, d, J = 7.5 Hz), 13.36 (1H, br s).
Cl 1H-NMR (DMSO-D6) δ: 0.81 (3H, t, J = 7.4 Hz), 1.15-1.25 (8H, m), 1.54-1.60 (2H, m), 1-245 N CH 3.02 (3H, s), 4.61 (2H, s), 7.42 (1H, d, J = 8.6 439 437 HO N CH Hz), 7.56 (2H, t, J = 7.4 Hz), 7.60-7.69 (3H, O m), 8.34 (2H, d, J = 7.4 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.88 (0.9H, s), 3.04- N 3.22 (6.1H, m), 3.63-3.77 (1H, m), 4.62 (1.4H, s), 4.80 (0.6H, s), 7.42-7.48 (1H, m), 7.52- 471 469 1-246 N CH 7.58 (2H, m), 7.60-7.69 (3H, m), 8.34 (2H, d, HO N J = 7.9 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.14-1.36 (5H, m), 1.38-1.50 (3H, m), 1.89-1.97 (2H, m), 3.37 (2H, s), 4.36 (2H, d, J = 6.0 Hz), 4.75 (1H, br 1-247 453 451 s), 7.49 (1H, d, J = 8.3 Hz), 7.53-7.59 (3H, HO N m), 7.64-7.70 (2H, m), 8.09 (1H, t, J = 6.0 O OH Hz), 8.34 (2H, d, J = 7.4 Hz), 13.32 (1H, br s). 【0781】 【Table 1-32】 1H-NMR (DMSO-D6) δ: 1.26-1.37 (3H, m), 1.42-1.50 (1H, m), 1.59-1.71 (6H, m), 3.02 (2H, s), 4.40 (2H, s), 7.47 (1H, dd, J = 8.1, 2.1 435 433 1-248 Hz), 7.56 (2H, t, J = 7.9 Hz), 7.63-7.69 (3H, HO N m), 8.34 (2H, d, J = 7.9 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.21 (6H, s), 2.94 (2H, s), 3.11 (3H, s), 4.63 (2H, s), 7.06-7.10 N CH (2H, m), 7.11-7.16 (1H, m), 7.16-7.22 (2H, 1-249 453 451 HO N CH m), 7.39 (1H, dd, J = 7.9, 1.8 Hz), 7.55 (2H, t, J = 7.4 Hz), 7.59-7.67 (3H, m), 8.34 (2H, d, J = 7.4 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.71 (6H, t, J = 7.4 Hz), 1.51 (4H, q, J = 7.4 Hz), 3.47 (2H, d, J = 4.0 Hz), 4.34 (2H, d, J = 5.7 Hz), 4.62 (1H, br 1-250 441 439 N CH s), 7.48 (1H, d, J = 7.7 Hz), 7.53-7.61 (3H, HO N CH 3 m), 7.64-7.71 (2H, m), 8.11 (1H, t, J = 5.7 Hz), 8.34 (2H, d, J = 7.3 Hz), 13.34 (1H, br s).
O OH 1H-NMR (DMSO-D6) δ: 0.87 (6H, t, J = 7.4 Hz), 1.52-1.63 (4H, m), 3.01 (2H, s), 4.40 (2H, s), 7.49 (1H, d, J = 8.3 Hz), 7.57 (2H, t, J 423 421 1-251 = 7.9 Hz), 7.64-7.72 (3H, m), 8.34 (2H, d, J = 7.9 Hz), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (0.6H, br s), 1.17 (2.4H, t, J = 6.9 Hz), 1.62 (3H, s), 2.81 (0.6H, s), 3.25 (2.4H, s), 3.54-3.67 (2H, m), 4.63 (1.6H, s), 4.90-5.17 (0.4H, m), 7.45 (1H, 495 493 1-252 CH N CH HO N O dd, J = 8.2, 1.8 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.63-7.69 (3H, m), 8.34 (2H, d, J = 7.6 Hz), F 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.02 (0.6H, br s), 1.17 (2.4H, t, J = 6.9 Hz), 1.62 (3H, s), 2.81 (0.6H, s), 3.25 (2.4H, s), 3.54-3.67 (2H, m), 1-253 CH 4.63 (1.6H, s), 4.90-5.17 (0.4H, m), 7.45 (1H, 495 493 N CH HO N O dd, J = 8.2, 1.8 Hz), 7.56 (2H, t, J = 7.6 Hz), 7.63-7.69 (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.51-1.55 (6H, m), 1.86-1.95 (2H, m), 3.46 (2H, s), 4.35 (2H, d, J = 6.0 Hz), 4.99 (1H, br s), 7.47 (1H, dd, J = 439 437 1-254 8.4, 2.0 Hz), 7.54-7.60 (3H, m), 7.64-7.69 HO N (2H, m), 8.12 (1H, t, J = 6.0 Hz), 8.34 (2H, d, J = 7.7 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.53-1.68 (4H, m), 1.77-1.89 (4H, m), 3.17 (2H, s), 4.42 (2H, s), 1-255 7.47 (1H, dd, J = 8.3, 2.1 Hz), 7.56 (2H, t, J = 421 419 7.6 Hz), 7.64-7.69 (3H, m), 8.35 (2H, d, J = HO N 7.6 Hz). 【0782】 【Table 1-33】 1H-NMR (DMSO-D6) δ: 0.69 (3H, d, J = 6.2 Cl Hz), 0.85-0.98 (2H, m), 1.06-1.28 (3H, m), 1.42-1.50 (2H, m), 2.05-2.12 (2H, m), 3.28 1-256 (2H, s), 4.36 (2H, d, J = 6.0 Hz), 4.73 (1H, br 467 465 s), 7.49 (1H, d, J = 8.1 Hz), 7.53-7.59 (3H, HO N m), 7.63-7.69 (2H, m), 8.10 (1H, t, J = 6.0 O OH Hz), 8.34 (2H, d, J = 7.9 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.89 (3H, d, J = 5.5 Hz), 1.33-1.46 (3H, m), 1.51-1.62 (4H, m), 1.87-1.94 (2H, m), 2.94 (2H, s), 4.39 (2H, s), 449 447 3 1-257 N 7.47 (1H, dd, J = 8.3, 2.3 Hz), 7.56 (2H, t, J = HO N CH 3 7.9 Hz), 7.63-7.69 (3H, m), 8.34 (2H, d, J = 7.9 Hz), 13.33 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.34 (6H, s), 4.99 (2H, s), 6.97 (1H, d, J = 7.6 Hz), 7.05 (1H, t, J N = 7.6 Hz), 7.20 (1H, t, J = 7.6 Hz), 7.39 (1H, 1-258 d, J = 7.6 Hz), 7.48 (1H, dd, J = 8.3, 1.8 Hz), 457 455 7.55 (2H, t, J = 7.6 Hz), 7.59-7.68 (2H, m), HO N 7.75 (1H, d, J = 1.8 Hz), 8.29 (2H, d, J = 7.6 Hz), 13.32 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.77 (6H, t, J = 7.3 Hz), 1.03-1.19 (4H, m), 1.36-1.50 (4H, m), N 3.46 (2H, s), 4.33 (2H, d, J = 6.0 Hz), 4.62 N H C 3 (1H, br s), 7.47 (1H, d, J = 8.4 Hz), 7.53-7.60 469 467 1-259 (3H, m), 7.61-7.69 (2H, m), 8.12 (1H, t, J = HO N CH 6.0 Hz), 8.34 (2H, d, J = 7.6 Hz), 13.35 (1H, O OH br s). 1H-NMR (DMSO-D6) δ: 0.84 (6H, t, J = 7.2 Hz), 1.14-1.29 (2H, m), 1.30-1.58 (6H, m), 3.02 (2H, s), 4.39 (2H, s), 7.48 (1H, dd, J = N CH 1-260 451 449 8.3, 2.1 Hz), 7.57 (2H, t, J = 7.9 Hz), 7.64- 7.70 (3H, m), 8.34 (2H, d, J = 7.9 Hz), 13.36 O CH (1H, br s). 1H-NMR (DMSO-D6) δ: 0.96-1.06 (3.9H, m), 1.10 (2.1H, t, J = 7.2 Hz), 2.31 (0.6H, q, J = 7.2 Hz), 2.42 (1.4H, q, J = 7.2 Hz), 3.29-3.35 1-261 397 395 N CH (2H, m), 4.56 (1.4H, s), 4.63 (0.6H, s), 7.45 HO N (1H, d, J = 8.3 Hz), 7.54-7.69 (5H, m), 8.34 (2H, d, J = 7.9 Hz), 13.33 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 1.28 (3H, s), 2.75 (2H, d, J = 15.7 Hz), 3.36 (2H, d, J = 15.7 Hz), 4.37 (2H, d, J = 6.0 Hz), 7.06-7.11 (2H, 1-262 m), 7.14-7.18 (2H, m), 7.44 (1H, dd, J = 8.3, 471 469 2.1 Hz), 7.52-7.62 (4H, m), 7.66 (1H, t, J = HO N 7.4 Hz), 8.34 (2H, d, J = 7.4 Hz), 8.41 (1H, t, J O CH = 6.0 Hz), 13.32 (1H, br s).
Cl 1H-NMR (DMSO-D6) δ: 1.13 (3H, t, J = 6.9 Hz), 1.50 (6H, s), 3.42 (2H, br s), 4.66 (2H, 1-263 N CH s), 7.41 (1H, dd, J = 8.3, 1.8 Hz), 7.56 (2H, t, 479 477 HO N CH J = 7.9 Hz), 7.61-7.69 (3H, m), 8.34 (2H, d, J O = 7.9 Hz), 13.33 (1H, br s). 【0783】 【Table 1-34】 1H-NMR (DMSO-D6) δ: 1.31 (3H, s), 2.91 (2H, d, J = 16.0 Hz), 3.04 (3H, br s), 3.51 (2H, N d, J = 16.0 Hz), 4.66 (2H, br s), 7.11-7.15 (2H, m), 7.17-7.21 (2H, m), 7.45 (1H, dd, J = 485 483 1-264 N CH 8.3, 2.1 Hz), 7.54 (2H, t, J = 7.9 Hz), 7.61- 7.67 (3H, m), 8.33 (2H, d, J = 7.9 Hz), 13.33 O CH (1H, br s). 1H-NMR (DMSO-D6) δ: 1.34-1.42 (2H, m), 1.40 (9H, s), 1.53-1.63 (2H, m), 1.96 (2H, t, J = 6.8 Hz), 2.86-3.00 (2H, m), 3.25 (2H, t, J = HO N 1-265 6.8 Hz), 3.78-3.87 (2H, m), 4.46 (2H, s), 7.42 550 548 N O (1H, dd, J = 8.3, 2.1 Hz), 7.54-7.59 (2H, m), 7.60-7.69 (3H, m), 8.34 (2H, d, J = 7.7 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.83 (9H, s), 0.90- 0.99 (1H, m), 1.41-1.67 (6H, m), 1.96-2.03 (2H, m), 2.92 (2H, s), 4.38 (2H, s), 7.47 (1H, 1-266 491 489 N CH dd, J = 8.3, 1.8 Hz), 7.56 (2H, t, J = 7.6 Hz), HO N CH 7.63-7.69 (3H, m), 8.34 (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.48-1.65 (4H, m), 1.67-1.77 (2H, m), 1.82-1.91 (2H, m), 3.03 (2H, s), 3.21 (3H, s), 3.23-3.29 (1H, m), 4.40 465 463 5 1-267 (2H, s), 7.48 (1H, dd, J = 8.1, 1.8 Hz), 7.56 HO N O (2H, t, J = 7.6 Hz), 7.63-7.70 (3H, m), 8.34 O (2H, d, J = 7.6 Hz), 13.34 (1H, br s). 【0784】 【Table 2-1】 Example Structure NMR MS(M+H) MS(M-H) Note 1H-NMR (DMSO-D6) δ: 2.24 (6H, s), 7.21 (2H, d, J = 7.6 Hz), 7.37 (1H, t, J = 7.6 Hz), 2-1 3 346 344 7.91 (2H, d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.35 (1H, br s).
HO H C 1H-NMR (CDCl3) δ: 2.34 (6H, s), 7.17 (2H, d, J = 7.7 Hz), 7.33 (1H, t, J = 7.7 Hz), 7.49 2-2 278 276 (2H, t, J = 7.7 Hz), 7.60 (1H, t, J = 7.7 Hz), 8.52 (2H, dd, J = 7.7, 1.2 Hz), 11.87 (1H, s).
HO H C 1H-NMR (CDCl3) δ: 2.32 (6H, s), 2.72 (3H, s), 7.17 (2H, d, J = 7.7 Hz), 7.34 (1H, t, J = 2-3 360 358 3 7.7 Hz), 7.53-7.56 (2H, m), 8.12-8.16 (1H, m), 11.29 (1H, s).
HO H C 1H-NMR (DMSO-D6) δ: 3.84 (3H, s), 7.25 (2H, d, J = 8.3 Hz), 7.59 (1H, t, J = 8.3 Hz), 2-4 N 382 380 7.92 (2H, d, J = 8.3 Hz), 8.51 (2H, d, J = 8.3 Hz), 13.59 (1H, br s).
HO O 1H-NMR (DMSO-D6) δ: 2.22 (6H, s), 5.22 (2H, s), 7.13-7.21 (2H, m), 7.32-7.37 (2H, m), 2-5 N 384 382 7.38-7.43 (2H, m), 7.46-7.48 (2H, m), 8.28- 8.32 (2H, m), 12.98 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 2.20 (6H, s), 6.86 (2H, dt, J = 9.4, 2.4 Hz), 7.17 (2H, d, J = 7.7 2-6 Hz), 7.32 (1H, t, J = 7.6 Hz), 8.19 (2H, dt, J = 294 292 9.5, 2.3 Hz), 10.32 (1H, br s), 12.87 (1H, br HO H C H C CH 1H-NMR (DMSO-D6) δ: 1.32 (9H, s), 2.22 (6H, s), 7.20 (2H, d, J = 7.7 Hz), 7.35 (1H, t, J 2-7 H C 334 332 = 7.7 Hz), 7.56 (2H, d, J = 8.5 Hz), 8.28 (2H, d, J = 8.5 Hz), 13.08 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 1.23 (6H, d, J = 7.3 Hz), 2.22 (6H, s), 2.90-3.05 (1H, m), 7.20 2-8 (2H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.7 Hz), 320 318 N 7.41 (2H, d, J = 8.3 Hz), 8.27 (2H, d, J = 8.3 Hz), 13.09 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.24 (6H, s), 7.19 (2H, d, J = 7.7 Hz), 7.34 (1H, t, J = 7.7 Hz), 2-9 3 364 362 F N 7.73 (1H, d, J = 8.1 Hz), 7.85 (1H, d, J = 10.7 Hz), 8.24 (1H, t, J = 7.9 Hz), 13.42 (1H, br s). 【0785】 【Table 2-2】 1H-NMR (DMSO-D6) δ: 7.50 (1H, t, J = 8.8 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.67-7.73 (1H, 2-10 370 368 m), 7.94 (2H, d, J = 8.1 Hz), 8.51 (2H, d, J = 8.1 Hz), 13.90 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.24 (6H, s), 7.20 (2H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.7 Hz), 2-11 7.45-7.47 (3H, m), 7.59-7.63 (2H, m), 7.71 378 376 (2H, dd, J = 6.9, 2.0 Hz), 8.37 (2H, dd, J = N N CH 6.9, 2.0 Hz), 13.20 (1H, br s).
H C 1H-NMR (DMSO-D6) δ: 2.22 (6H, s), 2.89- 3.00 (4H, m), 7.16-7.29 (7H, m), 7.33 (1H, d, 2-12 382 380 J = 7.7 Hz), 7.38 (2H, d, J = 8.4 Hz), 8.24 N N CH (2H, d, J = 8.4 Hz), 13.09 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.23 (6H, s), 2.39 (3H, s), 7.20 (2H, d, J = 7.6 Hz), 7.35 (1H, t, J 2-13 292 290 N = 7.6 Hz), 7.40-7.48 (2H, m), 8.11-8.18 (2H, m), 13.14 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.23 (6H, s), 3.83 (3H, s), 7.18-7.24 (3H, m), 7.36 (1H, t, J = 7.8 2-14 308 306 N Hz), 7.45 (1H, t, J = 7.8 Hz), 7.83-7.86 (1H, m), 7.94 (1H, d, J = 7.8 Hz), 13.17 (1H, br s).
F 1H-NMR (DMSO-D6) δ: 2.23 (6H, s), 7.21 (2H, d, J = 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 2-15 7.47-7.53 (1H, m), 7.57-7.63 (1H, m), 8.00- 296 294 8.05 (1H, m), 8.19 (1H, dt, J = 7.9, 1.3 Hz), 13.27 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 6.97 (1H, dd, J = 8.1, 0.7 Hz), 7.05 (1H, dd, J = 8.1, 0.7 Hz), 2-16 7.39 (1H, t, J = 8.1 Hz), 7.90 (2H, d, J = 8.4 368 366 Hz), 8.50 (2H, d, J = 8.4 Hz), 10.74 (1H, br s), N 13.38 (1H, br s).
HO HO 1H-NMR (DMSO-D6) δ: 1.20 (3H, t, J = 7.0 Hz), 4.12 (2H, q, J = 7.0 Hz), 7.21 (2H, d, J = 2-17 N 8.3 Hz), 7.55 (1H, t, J = 8.3 Hz), 7.91 (2H, d, J 396 394 = 8.3 Hz), 8.50 (2H, d, J = 8.3 Hz), 13.53 (1H, HO O br s). 1H-NMR (DMSO-D6) δ: 1.31-1.40 (3H, m), 1.45-1.54 (3H, m), 1.65-1.72 (2H, m), 1.81- 1.88 (2H, m), 2.22 (6H, s), 2.67-2.71 (1H, m), 2-18 384 382 7.20 (2H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.7 N N CH Hz), 7.51 (2H, dd, J = 6.7, 1.9 Hz), 8.29 (2H, dd, J = 6.7, 1.9 Hz), 13.16 (1H, br s). 【0786】 【Table 2-3】 1H-NMR (DMSO-D6) δ: 2.29 (3H, s), 7.38- 7.41 (1H, m), 7.47-7.52 (2H, m), 7.92 (2H, d, 2-19 366 364 N J = 8.1 Hz), 8.52 (2H, d, J = 8.1 Hz), 13.61 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.80 (3H, t, J = 7.3 Cl Hz), 1.55-1.63 (2H, m), 4.02 (2H, t, J = 6.3 Hz), 7.22 (2H, t, J = 8.3 Hz), 7.55 (1H, t, J = 410 408 2-20 8.3 Hz), 7.90 (2H, d, J = 8.3 Hz), 8.50 (2H, d, HO O J = 8.3 Hz), 13.54 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.18 (6H, d, J = 6.0 Hz), 4.65-4.71 (1H, m), 7.20 (1H, d, J = 8.4 2-21 Hz), 7.25 (1H, d, J = 8.4 Hz), 7.54 (1H, t, J = 410 408 N 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz), 8.50 (2H, d, J = 8.4 Hz), 13.49 (1H, br s). 1H-NMR (DMSO-D6) δ: 3.59-3.62 (2H, br m), 4.09 (2H, t, J = 5.0 Hz), 4.81 (1H, br s), 2-22 7.24 (2H, t, J = 8.3 Hz), 7.56 (1H, t, J = 8.3 412 410 N Hz), 7.92 (2H, d, J = 8.4 Hz), 8.52 (2H, d, J = HO O 8.4 Hz), 13.49 (1H, s). 1H-NMR (DMSO-D6) δ: 1.71-1.77 (2H, m), 3.39 (2H, t, J = 6.2 Hz), 4.14 (2H, t, J = 6.2 Hz), 4.45 (1H, br s), 7.23 (1H, d, J = 8.3 Hz), 2-23 426 424 7.24 (1H, d, J = 8.3 Hz), 7.56 (1H, t, J = 8.3 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.52 (2H, d, J = HO O 8.4 Hz), 13.56 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.23 (6H, s), 7.20 (2H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.7 Hz), 2-24 296 294 7.60 (2H, d, J = 8.6 Hz), 8.34 (2H, d, J = 8.6 Hz), 13.21 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 2.23 (6H, s), 7.20 (2H, d, J = 7.6 Hz), 7.35 (1H, t, J = 7.6 Hz), 2-25 312 310 7.60 (2H, d, J = 8.6 Hz), 8.34 (2H, d, J = 8.6 Hz), 13.21 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 2.22 (6H, s), 2.40 (3H, s), 7.20 (2H, d, J = 7.5 Hz), 7.32-7.37 2-26 N 292 290 (3H, m), 8.23 (2H, d, J = 8.2 Hz), 13.08 (1H, N br s).
HO H C H C O 1H-NMR (DMSO-D6) δ: 2.22 (6H, s), 3.85 (3H, s), 7.07 (2H, d, J = 9.0 Hz), 7.19 (2H, d, 2-27 N 308 306 J = 7.6 Hz), 7.34 (1H, t, J = 7.6 Hz), 8.31 (2H, d, J = 9.0 Hz), 12.98 (1H, s). 【0787】 【Table 2-4】 1H-NMR (DMSO-D6) δ: 2.24 (6H, s), 7.21 (2H, d, J = 7.7 Hz), 7.37 (1H, t, J = 7.7 Hz), 2-28 7.80 (1H, t, J = 7.9 Hz), 8.03 (1H, d, J = 7.9 346 344 Hz), 8.57 (1H, s), 8.62 (1H, d, J = 7.9 Hz), 13.33 (1H, br s).
O 1H-NMR (DMSO-D6) δ: 2.22 (6H, s), 5.19 (2H, s), 7.20 (2H, d, J = 7.5 Hz), 7.27-7.42 2-29 N 384 382 (5H, m), 7.43-7.49 (3H, m), 7.92-7.96 (2H, m), 13.17 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 2.22 (6H, s), 6.99- 7.03 (1H, m), 7.20 (2H, d, J = 7.7 Hz), 7.30- 2-30 294 292 N 7.37 (2H, m), 7.76-7.80 (2H, m), 9.69 (1H, s), 13.12 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 0.76 (3H, t, J = 7.4 Hz), 1.22-1.31 (2H, m), 1.53-1.60 (2H, m), 4.07 (2H, t, J = 6.2 Hz), 7.23 (2H, dd, J = 8.4, 2-31 424 422 2.2 Hz), 7.56 (1H, t, J = 8.4 Hz), 7.92 (2H, d, J HO O = 8.4 Hz), 8.51 (2H, d, J = 8.4 Hz), 13.56 (1H, br s). 1H-NMR (DMSO-D6) δ: 5.24 (2H, s), 7.35- 7.24 (7H, m), 7.57 (1H, t, J = 8.3 Hz), 7.93 2-32 458 456 N (2H, d, J = 8.2 Hz), 8.52 (2H, d, J = 8.2 Hz), 13.66 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.80 (6H, d, J = 6.7 Cl Hz), 1.82-1.92 (1H, m), 3.83 (2H, d, J = 6.0 Hz), 7.20 (2H, dd, J = 8.3, 3.5 Hz), 7.54 (1H, 424 422 2-33 t, J = 8.3 Hz), 7.90 (2H, d, J = 8.4 Hz), 8.50 O CH (2H, d, J = 8.4 Hz), 13.56 (1H, br s). 1H-NMR (DMSO-D6) δ: 3.12 (3H, s), 3.53 (2H, t, J = 4.5 Hz), 4.18 (2H, t, J = 4.5 Hz), 2-34 7.24 (2H, dd, J = 8.3, 3.8 Hz), 7.55 (1H, t, J = 426 424 8.3 Hz), 7.90 (2H, d, J = 8.4 Hz), 8.50 (2H, d, HO O J = 8.4 Hz), 13.54 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 3.83 (3H, s), 5.22 Cl (2H, s), 7.16 (2H, d, J = 8.8 Hz), 7.22 (2H, d, 2-35 J = 8.8 Hz), 7.37-7.32 (1H, m), 7.43-7.38 (2H, 420 418 N m), 7.50-7.45 (2H, m), 7.61-7.53 (1H, m), HO O 8.28 (2H, d, J = 8.8 Hz), 13.17 (1H, s). 1H-NMR (DMSO-D6) δ: 4.90 (2H, q, J = 8.7 Hz), 7.38 (2H, dd, J = 8.4, 2.4 Hz), 7.64 (1H, 2-36 450 448 t, J = 8.4 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.51 HO O F (2H, d, J = 8.2 Hz), 13.68 (1H, br s). 【0788】 【Table 2-5】 1H-NMR (DMSO-D6) δ: 0.99-1.10 (2H, m), 1.13-1.30 (3H, m), 1.61-1.83 (6H, m), 2.20 3 (6H, s), 3.86 (2H, d, J = 6.3 Hz), 7.04 (2H, d, 2-37 N 390 388 J = 9.1 Hz), 7.17 (2H, d, J = 7.7 Hz), 7.32 N (1H, t, J = 7.7 Hz), 8.26 (2H, d, J = 9.1 Hz), HO H C 12.95 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.28 (6H, d, J = 6.0 Hz), 2.20 (6H, s), 4.70-4.76 (1H, m), 7.02 2-38 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 7.6 Hz), 336 334 7.32 (1H, t, J = 7.6 Hz), 8.26 (2H, d, J = 8.8 Hz), 12.94 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.4 Hz), 1.84-1.94 (1H, m), 2.23 (6H, s), 2.54 2-39 3 (2H, d, J = 6.9 Hz), 7.20 (2H, d, J = 7.7 Hz), 334 332 7.30-7.38 (3H, m), 8.26 (2H, d, J = 8.5 Hz), 13.09 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 1.35 (3H, t, J = 6.9 Hz), 2.22 (6H, s), 4.13 (2H, q, J = 6.9 Hz), 2-40 N 7.05 (2H, d, J = 8.8 Hz), 7.20 (2H, d, J = 7.5 322 320 Hz), 7.34 (1H, t, J = 7.5 Hz), 8.29 (2H, d, J = 8.8 Hz), 12.97 (1H, br s).
HO H C H C 1H-NMR (DMSO-D6) δ: 0.99 (3H, t, J = 7.4 Hz), 1.71-1.80 (2H, m), 2.22 (6H, s), 4.03 2-41 N (2H, t, J = 6.6 Hz), 7.06 (2H, d, J = 9.0 Hz), 336 334 7.20 (2H, d, J = 7.5 Hz), 7.34 (1H, t, J = 7.5 Hz), 8.29 (2H, d, J = 9.0 Hz), 12.98 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 0.99 (6H, d, J = 6.8 Hz), 2.01-2.08 (1H, m), 2.22 (6H, s), 3.85 2-42 (2H, d, J = 6.6 Hz), 7.06 (2H, d, J = 8.8 Hz), 350 348 7.20 (2H, d, J = 7.5 Hz), 7.35 (1H, t, J = 7.5 Hz), 8.29 (2H, d, J = 8.8 Hz), 12.97 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 1.58 (3H, d, J = 6.4 3 Hz), 2.19 (6H, s), 5.66 (1H, q, J = 6.4 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.17 (2H, d, J = 7.7 2-43 3 398 396 N Hz), 7.23-7.28 (1H, m), 7.30-7.37 (3H, m), 7.41-7.43 (2H, m), 8.20 (2H, d, J = 9.0 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.58 (3H, d, J = 6.4 Hz), 2.19 (6H, s), 5.66 (1H, q, J = 6.4 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 7.7 N CH 2-44 398 396 N Hz), 7.24-7.28 (1H, m), 7.30-7.37 (3H, m), 7.41-7.43 (2H, m), 8.20 (2H, d, J = 9.0 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 5.32 (2H, s), 7.34- 7.27 (4H, m), 7.57 (1H, t, J = 8.2 Hz), 7.71 2-45 459 457 F (1H, td, J = 7.7, 1.7 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.55-8.51 (3H, m), 13.74 (1H, s). 【0789】 【Table 2-6】 1H-NMR (DMSO-D6) δ: 1.23-1.32 (1H, m), 3 1.35-1.57 (5H, m), 1.68-1.75 (2H, m), 1.92- 1.98 (2H, m), 2.22 (6H, s), 4.47-4.51 (1H, m), N CH 2-46 3 376 374 7.06 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 7.6 Hz), 7.34 (1H, t, J = 7.6 Hz), 8.27 (2H, d, J = 8.8 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.94 (6H, d, J = 4.2 H C Hz), 1.26-1.35 (2H, m), 1.41-1.48 (2H, m), 1.56-1.65 (2H, m), 1.81-1.87 (2H, m), 2.22 N CH 2-47 3 (6H, s), 4.46-4.50 (1H, m), 7.06 (2H, d, J = 404 402 8.8 Hz), 7.19 (2H, d, J = 7.5 Hz), 7.34 (1H, t, J = 7.5 Hz), 8.27 (2H, d, J = 8.8 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.23 (6H, s), 5.31 (2H, s), 7.19-7.23 (2H, m), 7.32-7.43 (4H, m), 2-48 7.48-7.53 (2H, m), 7.63 (1H, d, J = 8.4 Hz), 418 416 7.97 (1H, dd, J = 8.4, 1.7 Hz), 8.10 (1H, d, J = 1.7 Hz), 13.22 (1H, br s).
HO H C 1H-NMR (DMSO-D6) δ: 0.99 (3H, t, J = 7.5 Cl Hz), 2.55 (2H, q, J = 7.5 Hz), 5.22 (2H, s), 7.07 (1H, t, J = 6.8 Hz), 7.16 (1H, d, J = 6.8 Hz), 7.22 (1H, t, J = 6.8 Hz), 7.27 (1H, d, J = 2-49 486 484 F N 8.2 Hz), 7.31 (1H, d, J = 6.8 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.60 (1H, t, J = 8.2 Hz), 7.91 (2H, d, J = 8.6 Hz), 8.48 (2H, d, J = 8.6 Hz), 13.63 (1H, s). 1H-NMR (DMSO-D6) δ: 1.30-1.38 (2H, m), 1.50-1.65 (4H, m), 1.74-1.82 (2H, m), 2.22 N CH (6H, s), 2.29-2.36 (1H, m), 3.95 (2H, d, J = 2-50 376 374 7.1 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.20 (2H, d, J = 7.7 Hz), 7.34 (1H, t, J = 7.7 Hz), 8.28 (2H, d, J = 8.8 Hz), 12.97 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.81-1.94 (4H, m), 2.05-2.12 (2H, m), 2.22 (6H, s), 2.70-2.78 (1H, m), 4.05 (2H, d, J = 6.6 Hz), 7.06 (2H, d, N CH 2-51 362 360 J = 8.8 Hz), 7.20 (2H, d, J = 7.5 Hz), 7.34 (1H, t, J = 7.5 Hz), 8.29 (2H, d, J = 8.8 Hz), 12.97 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.38 (3H, t, J = 6.9 Hz), 2.22 (6H, s), 4.19 (2H, q, J = 6.9 Hz), N CH 3 7.19 (2H, d, J = 7.6 Hz), 7.34 (1H, t, J = 7.6 2-52 N Cl 356 354 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.92 (1H, dd, J O OH = 8.3, 1.7 Hz), 7.96 (1H, d, J = 1.7 Hz), 13.19 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.18 (3H, s), 5.18 (2H, s), 7.04 (1H, t, J = 7.4 Hz), 7.16-7.09 F N O (2H, m), 7.21 (1H, d, J = 7.9 Hz), 7.28 (1H, d, 2-53 472 470 J = 7.4 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.57- 7.49 (1H, m), 7.88 (2H, d, J = 8.4 Hz), 8.47 (2H, d, J = 8.4 Hz), 13.63 (1H, s). 1H-NMR (DMSO-D6) δ: 1.20 (3H, t, J = 7.5 Hz), 2.23 (6H, s), 2.80 (2H, q, J = 7.5 Hz), CH 7.21 (2H, d, J = 7.6 Hz), 7.36 (1H, t, J = 7.6 2-54 340 338 Cl N Hz), 7.58 (1H, d, J = 8.4 Hz), 8.17 (1H, dd, J = 8.4, 2.0 Hz), 8.29 (1H, d, J = 2.0 Hz), 13.20 H C OH (1H, br s). 【0790】 【Table 2-7】 1H-NMR (DMSO-D6) δ: 2.11 (3H, s), 5.17 (2H, s), 7.04 (1H, d, J = 7.7 Hz), 7.17-7.06 (3H, m), 7.25 (1H, d, J = 8.3 Hz), 7.29 (1H, d, F N O 2-55 472 470 J = 8.3 Hz), 7.57 (1H, t, J = 8.3 Hz), 7.91 (2H, F N CH d, J = 8.1 Hz), 8.52 (2H, d, J = 8.1 Hz), 13.64 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.22 (3H, s), 5.16 (2H, s), 7.06 (2H, d, J = 7.9 Hz), 7.20 (2H, d, F N O J = 7.9 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.28 2-56 F 472 470 (1H, d, J = 7.9 Hz), 7.55 (1H, t, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.49 (2H, d, J = 8.4 Hz), 13.62 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.34-1.23 (2H, m), 1.62-1.38 (6H, m), 1.72-1.63 (2H, m), 1.86- 1.77 (2H, m), 2.00-1.88 (1H, m), 2.22 (6H, s), N CH 2-57 3.86 (2H, d, J = 6.8 Hz), 7.06 (2H, d, J = 8.8 404 402 Hz), 7.20 (2H, d, J = 7.6 Hz), 7.34 (1H, t, J = OH 7.6 Hz), 8.28 (2H, d, J = 8.8 Hz), 12.97 (1H, br s). 3 1H-NMR (DMSO-D6) δ: 1.01 (9H, s), 2.22 (6H, s), 3.74 (2H, s), 7.07 (2H, d, J = 8.8 Hz), H C N CH 2-58 3 3 364 362 7.20 (2H, d, J = 7.7 Hz), 7.35 (1H, t, J = 7.7 H C O N Hz), 8.29 (2H, d, J = 8.8 Hz), 12.97 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.24 (6H, s), 5.46 (2H, s), 7.02 (1H, d, J = 8.8 Hz), 7.20 (2H, d, N CH 2-59 J = 7.7 Hz), 7.31-7.41 (4H, m), 7.46-7.49 (2H, 385 383 m), 8.53 (1H, dd, J = 8.8, 2.0 Hz), 9.10 (1H, d, J = 2.0 Hz), 13.13 (1H, br s). 1H-NMR (DMSO-D6) δ: 5.30 (2H, s), 7.28 (1H, d, J = 7.9 Hz), 7.30-7.35 (2H, m), 7.59 (1H, t, J = 8.4 Hz), 7.73 (1H, dt, J = 7.9, 1.5 2-60 459 457 F Hz), 7.93 (2H, d, J = 8.4 Hz), 8.48 (1H, dd, J = 4.9, 1.5 Hz), 8.51 (2H, d, J = 8.4 Hz), 8.56 (1H, d, J = 1.5 Hz), 13.67 (1H, br s). 1H-NMR (DMSO-D6) δ: 5.33 (2H, s), 7.23- 7.32 (4H, m), 7.57 (1H, t, J = 8.4 Hz), 7.94 2-61 459 457 (2H, d, J = 8.4 Hz), 8.48 (2H, d, J = 5.3 Hz), 8.54 (2H, d, J = 8.4 Hz), 13.72 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.00 (9H, s), 3.73 H C CH Cl (2H, s), 5.30 (2H, s), 7.08 (2H, t, J = 4.5 Hz), 7.30-7.20 (3H, m), 7.33 (1H, d, J = 7.7 Hz), 2-62 477 475 O 7.52 (1H, t, J = 8.1 Hz), 7.69 (1H, td, J = 7.7, 1.7 Hz), 8.28 (2H, d, J = 8.8 Hz), 8.53-8.49 (1H, m), 13.27 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.01 (9H, s), 1.46 (3H, d, J = 6.2 Hz), 3.74 (2H, s), 5.60 (1H, q, CH Cl CH CH J = 6.2 Hz), 7.04-7.11 (3H, m), 7.17 (1H, d, J 2-63 = 7.7 Hz), 7.27 (1H, dd, J = 7.0, 5.1 Hz), 7.37- 491 489 7.44 (2H, m), 7.72 (1H, t, J = 7.0 Hz), 8.30 OH (2H, d, J = 8.8 Hz), 8.51 (1H, d, J = 4.2 Hz), 13.32 (1H, br s). 【0791】 【Table 2-8】 1H-NMR (DMSO-D6) δ: 1.01 (9H, s), 1.47 H C CH Cl (3H, d, J = 6.3 Hz), 3.74 (2H, s), 5.60 (1H, q, J = 6.3 Hz), 7.13-7.02 (3H, m), 7.18 (1H, d, J O = 7.7 Hz), 7.27 (1H, dd, J = 7.1, 5.2 Hz), 7.48- 491 489 2-64 7.36 (2H, m), 7.72 (1H, t, J = 7.1 Hz), 8.31 (2H, d, J = 8.8 Hz), 8.51 (1H, d, J = 4.2 Hz), 13.32 (1H, br s).
H C CH 1H-NMR (DMSO-D6) δ: 1.01 (9H, s), 1.40 CH CH (3H, d, J = 6.2 Hz), 3.74 (2H, s), 5.62 (1H, q, 2-65 490 488 J = 6.2 Hz), 7.05-7.15 (4H, m), 7.21-7.41 (6H, m), 8.31 (2H, d, J = 8.8 Hz), 13.21 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.99 (6H, d, J = 6.6 H C Cl 3 Hz), 2.04 (1H, td, J = 13.3, 6.6 Hz), 3.86 (2H, d, J = 6.6 Hz), 5.31 (2H, s), 7.08 (2H, d, J = 2-66 O N 8.8 Hz), 7.31-7.21 (3H, m), 7.34 (1H, d, J = 463 461 7.7 Hz), 7.57-7.48 (1H, m), 7.70 (1H, td, J = 7.7, 1.6 Hz), 8.30 (2H, d, J = 8.8 Hz), 8.53 (1H, d, J = 4.9 Hz), 13.29 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.00 (6H, d, J = 6.6 Hz), 1.48 (3H, d, J = 6.6 Hz), 2.09-2.02 (1H, H C Cl m), 3.87 (2H, d, J = 6.6 Hz), 5.61 (1H, q, J = N 6.2 Hz), 7.14-7.04 (3H, m), 7.19 (1H, d, J = 2-67 477 475 7.9 Hz), 7.31-7.25 (1H, m), 7.48-7.37 (2H, m), 7.73 (1H, td, J = 7.9, 1.6 Hz), 8.32 (2H, d, J = 9.0 Hz), 8.53 (1H, d, J = 4.9 Hz), 13.33 (1H, br s).
H C CH Cl 1H-NMR (DMSO-D6) δ: 1.02 (9H, s), 3.74 3 (2H, s), 5.40 (2H, s), 7.08 (2H, d, J = 8.8 Hz), 2-68 7.24 (2H, d, J = 7.7 Hz), 7.44 (1H, t, J = 4.9 478 476 N Hz), 7.51 (1H, br s), 8.27 (2H, d, J = 8.8 Hz), 8.78 (2H, d, J = 4.9 Hz), 13.19 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.88 (3H, t, J = 7.2 Hz), 1.31-1.42 (4H, m), 1.69-1.76 (2H, m), 2.21 (6H, s), 4.05 (2H, t, J = 6.5 Hz), 7.04 N CH 2-69 364 362 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 7.4 Hz), 7.33 (1H, t, J = 7.4 Hz), 8.27 (2H, d, J = 8.8 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.92 (3H, t, J = 7.3 H C H C Hz), 1.38-1.48 (2H, m), 1.67-1.74 (2H, m), 2.21 (6H, s), 4.06 (2H, t, J = 6.5 Hz), 7.05 2-70 350 348 N (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 7.7 Hz), 7.33 (1H, t, J = 7.7 Hz), 8.27 (2H, d, J = 8.8 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.92 (6H, d, J = 6.6 Hz), 1.63 (2H, q, J = 6.6 Hz), 1.72-1.82 (1H, m), 2.21 (6H, s), 4.08 (2H, t, J = 6.6 Hz), 7.05 N CH 2-71 364 362 O N (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 7.4 Hz), 7.33 (1H, t, J = 7.4 Hz), 8.27 (2H, d, J = 8.8 Hz), 12.96 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.98 (6H, d, J = 6.5 Hz), 2.00-2.07 (1H, m), 2.19 (3H, s), 3.84 H C Cl (2H, d, J = 6.5 Hz), 5.31 (2H, s), 7.05 (2H, d, N O CH 2-72 J = 8.8 Hz), 7.20-7.26 (2H, m), 7.40 (1H, d, J 477 475 = 8.1 Hz), 7.50-7.57 (2H, m), 8.23 (2H, d, J = 8.8 Hz), 8.33 (1H, d, J = 3.7 Hz), 13.25 (1H, br s). 【0792】 【Table 2-9】 1H-NMR (DMSO-D6) δ: 0.90 (6H, t, J = 7.4 H C Hz), 1.60-1.69 (4H, m), 2.22 (6H, s), 4.36- N CH 2-73 4.42 (1H, m), 7.06 (2H, d, J = 8.8 Hz), 7.20 364 362 (2H, d, J = 7.5 Hz), 7.35 (1H, t, J = 7.5 Hz), 8.28 (2H, d, J = 8.8 Hz), 12.97 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.31-0.35 (2H, m), 0.55-0.59 (2H, m), 1.20-1.27 (1H, m), 2.21 (6H, s), 3.91 (2H, d, J = 7.0 Hz), 7.04 (2H, d, N CH 2-74 348 346 O N J = 8.8 Hz), 7.18 (2H, d, J = 7.4 Hz), 7.33 (1H, t, J = 7.4 Hz), 8.27 (2H, d, J = 8.8 Hz), 12.95 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.94-1.80 (4H, m), 2.11-2.03 (2H, m), 2.76-2.69 (1H, m), 4.05 (2H, d, J = 6.7 Hz), 5.29 (2H, s), 7.07 (2H, d, J = 8.8 Hz), 7.29-7.23 (3H, m), 7.32 (1H, d, J 475 473 2-75 = 7.9 Hz), 7.56-7.48 (1H, m), 7.71-7.66 (1H, m), 8.28 (2H, d, J = 8.8 Hz), 8.52-8.50 (1H, m), 13.28 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.40-1.31 (3H, m), Cl 1.54-1.45 (3H, m), 1.73-1.65 (2H, m), 1.88- 1.80 (2H, m), 2.73-2.66 (1H, m), 5.31 (2H, s), 2-76 7.31-7.25 (3H, m), 7.33 (1H, d, J = 7.7 Hz), 497 495 7.57-7.51 (3H, m), 7.70 (1H, td, J = 7.7, 1.7 Hz), 8.30 (2H, d, J = 8.4 Hz), 8.52 (1H, d, J = 4.6 Hz), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.30-0.99 (5H, m), Cl 1.83-1.60 (6H, m), 3.87 (2H, d, J = 6.3 Hz), .29 (2H, s), 7.06 (2H, d, J = 8.8 Hz), 7.29- 7.23 (3H, m), 7.32 (1H, d, J = 7.7 Hz), 7.55- 503 501 2-77 N N 7.49 (1H, m), 7.68 (1H, t, J = 7.7 Hz), 8.27 (2H, d, J = 8.8 Hz), 8.51 (1H, d, J = 4.9 Hz), 13.27 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.90 (3H, t, J = 7.3 Hz), 1.27 (3H, d, J = 6.0 Hz), 1.47-1.31 (2H, m), 1.60-1.51 (1H, m), 1.72-1.63 (1H, m), H C 4.65-4.59 (1H, m), 5.31 (2H, s), 7.06 (2H, d, J 477 475 2-78 = 9.0 Hz), 7.31-7.24 (3H, m), 7.34 (1H, d, J = 7.7 Hz), 7.53 (1H, t, J = 7.7 Hz), 7.70 (1H, td, J = 7.7, 1.5 Hz), 8.28 (2H, d, J = 9.0 Hz), 8.53 (1H, d, J = 4.2 Hz), 13.28 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.90 (3H, t, J = 7.3 Hz), 1.27 (3H, d, J = 6.0 Hz), 1.47-1.33 (2H, H C Cl m), 1.61-1.51 (1H, m), 1.72-1.62 (1H, m), H C N O 4.65-4.59 (1H, m), 5.31 (2H, s), 7.06 (2H, d, J 477 475 2-79 = 9.0 Hz), 7.31-7.24 (3H, m), 7.34 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.9 Hz), 7.72-7.68 (1H, m), 8.28 (2H, d, J = 9.0 Hz), 8.53 (1H, d, J = 4.0 Hz), 13.28 (1H, br s). 1H-NMR (DMSO-D6) δ: 5.31 (2H, s), 7.30- 7.25 (3H, m), 7.33 (1H, d, J = 7.7 Hz), 7.47- N O 7.43 (3H, m), 7.54 (1H, t, J = 8.5 Hz), 7.62- 2-80 491 489 7.57 (2H, m), 7.73-7.67 (3H, m), 8.36 (2H, d, OH J = 8.4 Hz), 8.52 (1H, d, J = 4.0 Hz), 13.56 (1H, br s). 【0793】 【Table 2-10】 1H-NMR (DMSO-D6) δ: 1.76-1.54 (6H, m), 2.04-1.95 (2H, m), 2.95-2.88 (1H, m), 5.31 2-81 (2H, s), 7.34-7.25 (4H, m), 7.58-7.51 (3H, m), 483 481 7.70 (1H, td, J = 7.7, 1.8 Hz), 8.29 (2H, d, J = 8.4 Hz), 8.54-8.52 (1H, m), 13.53 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.81-0.76 (2H, m), 0.96-0.90 (2H, m), 1.64-1.55 (1H, m), 5.31 N O (2H, s), 7.33-7.25 (4H, m), 7.58-7.50 (3H, m), 2-82 455 453 7.70 (1H, td, J = 7.7, 1.7 Hz), 8.28 (2H, d, J = 8.4 Hz), 8.53 (1H, d, J = 4.0 Hz), 13.52 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.31-1.40 (3H, m), 1.45-1.54 (3H, m), 1.65-1.72 (2H, m), 1.81- 1.87 (2H, m), 2.67-2.72 (1H, m), 5.44 (2H, s), 2-83 565 563 7.25-7.30 (2H, m), 7.51-7.56 (4H, m), 8.14 F (1H, d, J = 8.2 Hz), 8.29 (2H, d, J = 8.6 Hz), 8.94 (1H, s), 13.52 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.94 (6H, d, J = 4.2 Hz), 1.35-1.25 (2H, m), 1.49-1.40 (2H, m), 1.66-1.55 (2H, m), 1.89-1.79 (2H, m), 4.53- 4.44 (1H, m), 5.30 (2H, s), 7.07 (2H, d, J = 517 515 2-84 N N 8.8 Hz), 7.31-7.21 (3H, m), 7.34 (1H, d, J = 7.7 Hz), 7.56-7.48 (1H, m), 7.70 (1H, t, J = 7.1 Hz), 8.27 (2H, d, J = 8.8 Hz), 8.53 (1H, d, J = 4.6 Hz), 13.28 (1H, s). 1H-NMR (DMSO-D6) δ: 5.38 (2H, s), 7.28 (1H, d, J = 8.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.47-7.40 (5H, m), 7.55 (1H, d, J = 8.4 Hz), 2-85 491 489 N 7.61-7.57 (2H, m), 7.72 (2H, d, J = 8.8 Hz), 7.88-7.84 (1H, m), 8.36 (2H, d, J = 8.8 Hz), 8.58 (1H, d, J = 4.4 Hz). 1H-NMR (DMSO-D6) δ: 1.51 (3H, d, J = 6.4 Hz), 5.65 (1H, q, J = 6.4 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 7.7 Hz), 7.32 (1H, 2-86 505 503 N N dd, J = 6.9, 5.4 Hz), 7.50-7.41 (5H, m), 7.63- 7.59 (2H, m), 7.81-7.73 (3H, m), 8.40 (2H, d, J = 8.6 Hz), 8.55 (1H, d, J = 4.2 Hz). 1H-NMR (DMSO-D6) δ: 2.53 (3H, s), 5.40 (2H, s), 7.30 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.42-7.35 (2H, m), 7.49-7.44 (3H, 2-87 505 503 N N m), 7.64-7.56 (3H, m), 7.73 (2H, d, J = 8.8 Hz), 7.91-7.88 (1H, m), 8.37 (2H, d, J = 8.8 Hz). 1H-NMR (CDCl3) δ: 5.50 (0.90H, s), 5.60 (1.10H, s), 7.43-7.30 (5.45H, m), 7.69-7.54 (5.00H, m), 7.90-7.78 (2.00H, m), 8.05 2-88 482 480 (0.45H, d, J = 7.9 Hz), 8.71-8.60 (2.55H, m), 8.88 (0.55H, d, J = 4.2 Hz), 11.44 (0.45H, s), 14.69 (0.55H, br s). 1H-NMR (DMSO-D6) δ: 0.38-0.32 (2H, m), 0.62-0.56 (2H, m), 1.30-1.20 (1H, m), 3.93 (2H, d, J = 6.8 Hz), 5.32 (2H, s), 7.08 (2H, d, 2-89 461 459 J = 7.5 Hz), 7.36-7.24 (4H, m), 7.54 (1H, t, J = 8.4 Hz), 7.71 (1H, t, J = 7.6 Hz), 8.29 (2H, d, J = 7.5 Hz), 8.53 (1H, d, J = 4.6 Hz). 【0794】 【Table 2-11】 1H-NMR (DMSO-D6) δ: 0.32-0.35 (2H, m), 0.55-0.59 (2H, m), 1.20-1.25 (1H, m), 2.79 (3H, s), 2.91 (3H, s), 3.91 (2H, d, J = 7.0 Hz), N O CH 2-90 4.98 (2H, s), 7.05 (2H, d, J = 8.8 Hz), 7.16 455 453 O N N (1H, d, J = 8.4 Hz), 7.23 (1H, d, J = 8.4 Hz), O CH 7.51 (1H, t, J = 8.4 Hz), 8.26 (2H, d, J = 8.8 Hz), 13.15 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.76-1.53 (6H, m), Cl 2.05-1.93 (2H, m), 2.95-2.88 (1H, m), 5.36 (2H, s), 7.28 (1H, dd, J = 7.9, 0.7 Hz), 7.30 2-91 (1H, d, J = 7.9 Hz), 7.43-7.36 (2H, m), 7.59- 483 481 7.50 (3H, m), 7.81 (1H, td, J = 7.7, 1.8 Hz), HCl 8.29 (2H, d, J = 8.6 Hz), 8.57 (1H, dq, J = 5.0, 0.8 Hz). 1H-NMR (DMSO-D6) δ: 1.41-1.30 (3H, m), 1.56-1.45 (3H, m), 1.74-1.64 (2H, m), 1.89- 1.80 (2H, m), 2.74-2.65 (1H, m), 5.37 (2H, s), 2-92 7.28 (1H, dd, J = 8.0, 0.6 Hz), 7.31 (1H, d, J = 497 495 8.0 Hz), 7.46-7.40 (2H, m), 7.59-7.52 (3H, m), 7.85 (1H, td, J = 7.8, 1.6 Hz), 8.29 (2H, d, J = 8.6 Hz), 8.59-8.58 (1H, m). 1H-NMR (DMSO-D6) δ: 0.33-0.37 (2H, m), 0.54-0.59 (2H, m), 1.23-1.30 (1H, m), 4.21 N O (2H, d, J = 7.3 Hz), 5.23 (2H, s), 6.97 (1H, d, 2-93 461 459 J = 8.8 Hz), 7.23-7.35 (7H, m), 7.55 (1H, t, J = 8.0 Hz), 8.48 (1H, dd, J = 8.8, 2.2 Hz), 9.05 (1H, d, J = 2.2 Hz), 13.41 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.31 (9H, s), 5.38 (2H, s), 7.28 (1H, d, J = 8.2 Hz), 7.31 (1H, d, H C N O J = 8.2 Hz), 7.47-7.41 (2H, m), 7.52 (2H, d, J 2-94 H C 471 469 H C N N = 8.8 Hz), 7.56 (1H, t, J = 8.4 Hz), 7.86 (1H, td, J = 7.7, 1.5 Hz), 8.29 (2H, d, J = 8.8 Hz), 8.59 (1H, dd, J = 5.0, 0.8 Hz). 1H-NMR (DMSO-D6) δ: 5.38 (2H, s), 7.39- 7.34 (2H, m), 7.46-7.43 (3H, m), 7.54 (1H, d, J = 7.9 Hz), 7.61-7.57 (2H, m), 7.66 (1H, d, J 2-95 525 523 = 8.6 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.82-7.76 OH (2H, m), 8.34 (2H, d, J = 8.4 Hz), 8.56 (1H, d, J = 4.9 Hz). 1H-NMR (DMSO-D6) δ: 5.25 (2H, s), 7.36- 7.24 (8H, m), 7.46 (1H, ddd, J = 7.8, 4.9, 1.0 Hz), 7.57 (1H, t, J = 8.3 Hz), 7.72 (1H, dt, J = 2-96 N 491 489 7.8, 1.0 Hz), 7.79 (2H, d, J = 8.6 Hz), 7.90 (1H, td, J = 7.8, 1.8 Hz), 8.40 (2H, d, J = 8.6 Hz), 8.65 (1H, dq, J = 4.9, 0.9 Hz). 1H-NMR (DMSO-D6) δ: 5.40 (2H, s), 7.30 (1H, dd, J = 8.2, 0.7 Hz), 7.33 (1H, d, J = 8.2 Hz), 7.51-7.43 (3H, m), 7.58 (1H, t, J = 8.2 2-97 N Hz), 7.75 (1H, dt, J = 7.8, 1.0 Hz), 7.80 (2H, 492 490 dd, J = 6.7, 1.9 Hz), 7.95-7.87 (2H, m), 8.40 HCl HCl (2H, dd, J = 6.7, 1.9 Hz), 8.61 (1H, d, J = 5.0 Hz), 8.66 (1H, dq, J = 5.0, 0.9 Hz). 1H-NMR (DMSO-D6) δ: 2.48 (3H, s), 5.37 (2H, s), 7.23 (1H, d, J = 7.3 Hz), 7.28 (1H, d, J = 7.3 Hz), 7.48-7.45 (3H, m), 7.56 (1H, d, J 2-98 N 539 537 = 7.9 Hz), 7.64-7.59 (2H, m), 7.67 (1H, d, J = 8.6 Hz), 7.82-7.72 (4H, m), 8.35 (2H, dd, J = 6.8, 2.0 Hz). 【0795】 【Table 2-12】 1H-NMR (DMSO-D6) δ: 2.41 (3H, s), 5.30 (2H, s), 7.09 (1H, d, J = 7.7 Hz), 7.14 (1H, d, J = 7.7 Hz), 7.51-7.45 (3H, m), 7.54 (1H, d, J 2-99 N = 7.7 Hz), 7.60 (1H, t, J = 7.7 Hz), 7.66-7.64 540 538 (3H, m), 7.78 (1H, d, J = 8.2 Hz), 7.81 (1H, dd, J = 8.2, 0.8 Hz), 8.61 (1H, dd, J = 8.2, 0.8 Hz), 9.40-9.39 (1H, m), 13.78 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.50 (3H, s), 5.41 (2H, s), 7.29-7.24 (1H, m), 7.35 (2H, dd, J = CH F 4.9, 1.1 Hz), 7.43-7.39 (2H, m), 7.56 (2H, dd, 2-100 539 537 N N J = 7.7, 4.2 Hz), 7.67 (1H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.86-7.78 (2H, m), 8.36 (2H, d, J = 8.6 Hz), 8.59-8.57 (1H, m). 1H-NMR (DMSO-D6) δ: 2.34 (3H, s), 5.41 (2H, s), 7.27 (1H, d, J = 7.7 Hz), 7.34 (1H, t, J H C F 3 = 7.7 Hz), 7.43-7.39 (4H, m), 7.56 (1H, d, J = 2-101 7.7 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.72 (2H, 539 537 dd, J = 6.7, 1.9 Hz), 7.87-7.78 (2H, m), 8.35 (2H, dd, J = 6.7, 1.9 Hz), 8.59 (1H, d, J = 4.4 Hz). 1H-NMR (DMSO-D6) δ: 2.35 (3H, s), 5.40 (2H, s), 7.27 (2H, d, J = 7.9 Hz), 7.42-7.37 (2H, m), 7.49 (2H, d, J = 7.9 Hz), 7.56 (1H, d, 2-102 H C N J = 7.9 Hz), 7.67 (1H, d, J = 8.6 Hz), 7.71 539 537 (2H, d, J = 8.6 Hz), 7.85-7.77 (2H, m), 8.34 (2H, d, J = 8.6 Hz), 8.58 (1H, dq, J = 4.9, 0.9 Hz). 1H-NMR (DMSO-D6) δ: 5.39 (2H, s), 7.39- F F F 7.35 (2H, m), 7.56 (1H, d, J = 7.9 Hz), 7.69- N O 7.64 (2H, m), 7.72 (2H, dd, J = 6.7, 1.9 Hz), 2-103 593 591 7.83-7.75 (3H, m), 7.89-7.85 (2H, m), 8.39 (2H, dd, J = 6.7, 1.9 Hz), 8.57 (1H, d, J = 4.9 Hz). 1H-NMR (DMSO-D6) δ: 5.40 (2H, s), 7.40- 7.36 (2H, m), 7.56 (1H, d, J = 7.9 Hz), 7.67 N (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 7.9 Hz), 2-104 N 593 591 7.84-7.76 (5H, m), 7.92 (1H, d, J = 7.7 Hz), HCl 7.99 (1H, br s), 8.37 (2H, dd, J = 6.8, 2.0 Hz), 8.57 (1H, dq, J = 4.9, 0.9 Hz). 1H-NMR (DMSO-D6) δ: 5.40 (2H, s), 7.41- 7.36 (2H, m), 7.56 (1H, d, J = 7.9 Hz), 7.68 F N O 2-105 F N (1H, d, J = 8.6 Hz), 7.84-7.77 (8H, m), 8.37 593 591 F N N (2H, dd, J = 6.7, 1.9 Hz), 8.57 (1H, d, J = 4.9 Hz). 1H-NMR (DMSO-D6) δ: 5.40 (2H, s), 7.41- 7.36 (2H, m), 7.51-7.45 (3H, m), 7.57 (1H, d, J = 7.7 Hz), 7.64-7.60 (2H, m), 7.68 (1H, d, J 2-106 N 543 541 = 8.4 Hz), 7.84-7.79 (3H, m), 8.10 (1H, dd, J F OH HCl = 10.5, 1.4 Hz), 8.19 (1H, dd, J = 8.2, 1.5 Hz), 8.57 (1H, dq, J = 4.9, 0.9 Hz). 1H-NMR (DMSO-D6) δ: 2.54 (3H, s), 5.45 (2H, s), 7.30 (1H, td, J = 7.6, 1.1 Hz), 7.44- 7.35 (3H, m), 7.56-7.50 (1H, m), 7.58 (1H, d, 2-107 557 555 N N J = 7.9 Hz), 7.71-7.67 (2H, m), 7.75 (2H, dd, J = 6.7, 1.9 Hz), 7.81 (1H, t, J = 7.9 Hz), 7.92 (1H, br s), 8.36 (2H, dd, J = 6.7, 1.9 Hz). 【0796】 【Table 2-13】 1H-NMR (DMSO-D6) δ: 2.52 (3H, s), 5.43 (2H, s), 7.33 (1H, d, J = 7.7 Hz), 7.38 (1H, d, Cl F J = 7.7 Hz), 7.43 (1H, td, J = 7.7, 1.4 Hz), 7.48 (1H, td, J = 7.7, 1.9 Hz), 7.57 (1H, d, J = 2-108 N N 573 571 8.0 Hz), 7.63 (1H, dd, J = 8.0, 1.2 Hz), 7.68 (1H, d, J = 8.3 Hz), 7.76-7.72 (3H, m), 7.81 (1H, t, J = 8.3 Hz), 7.90-7.84 (1H, m), 8.37 (2H, dd, J = 6.7, 1.9 Hz). 1H-NMR (DMSO-D6) δ: 2.51 (3H, s), 3.88 H C F 3 (3H, s), 5.41 (2H, s), 7.00 (1H, td, J = 7.5, 0.9 Hz), 7.12 (1H, d, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 7.5 Hz), 7.43 (1H, 2-109 569 567 OH ddd, J = 8.8, 7.1, 1.3 Hz), 7.52 (1H, dd, J = 7.5, 1.7 Hz), 7.57 (1H, d, J = 7.9 Hz), 7.69- 7.66 (3H, m), 7.85-7.78 (2H, m), 8.34 (2H, dd, J = 6.8, 2.0 Hz). 1H-NMR (DMSO-D6) δ: 2.24 (3H, s), 2.49 (3H, s), 5.41 (2H, s), 7.22 (1H, br s), 7.31 2-110 (1H, br s), 7.46-7.43 (3H, m), 7.60-7.57 (3H, 553 551 N N CH m), 7.72-7.68 (3H, m), 7.82 (1H, t, J = 8.3 Hz), 8.33 (2H, dd, J = 6.7, 1.8 Hz). 1H-NMR (DMSO-D6) δ: 5.42 (2H, d, J = 1.6 Hz), 7.42-7.48 (4H, m), 7.54 (1H, t, J = 4.2 N O F 2-111 Hz), 7.59-7.63 (2H, m), 7.64-7.73 (3H, m), 543 541 7.81 (2H, d, J = 4.2 Hz), 8.29 (2H, d, J = 8.6 Hz), 8.35-8.37 (1H, m).
F 1H-NMR (DMSO-D6) δ: 5.37 (2H, s), 7.37 (1H, d, J = 8.3 Hz), 7.44-7.48 (3H, m), 7.55 (1H, d, J = 7.6 Hz), 7.58-7.66 (3H, m), 7.73 2-112 N 559 557 (2H, d, J = 8.6 Hz), 7.79 (1H, t, J = 8.1 Hz), 7.88 (1H, dd, J = 8.6, 2.3 Hz), 8.34 (2H, d, J = 8.6 Hz), 8.59 (1H, d, J = 2.3 Hz). 1H-NMR (DMSO-D6) δ: 2.27 (3H, s), 5.43 (2H, s), 7.35 (1H, s), 7.39 (1H, d, J = 5.8 Hz), 2-113 7.44-7.48 (3H, m), 7.57-7.63 (3H, m), 7.69- 539 537 N N CH 7.75 (3H, m), 7.83 (1H, t, J = 8.1 Hz), 8.35 (2H, d, J = 8.3 Hz), 8.51 (1H, d, J = 5.3 Hz). 1H-NMR (DMSO-D6) δ: 7.36 (1H, d, J = 7.9 Hz), 7.44-7.48 (3H, m), 7.56 (1H, d, J = 7.9 2-114 Hz), 7.59-7.63 (2H, m), 7.66-7.75 (4H, m), 539 537 OH 7.79 (1H, t, J = 8.1 Hz), 8.34 (2H, d, J = 8.6 Hz), 8.44 (1H, s).
F 1H-NMR (DMSO-D6) δ: 5.36 (2H, s), 7.41 (1H, dd, J = 8.8, 4.4 Hz), 7.44-7.48 (3H, m), 7.55 (1H, d, J = 7.9 Hz), 7.58-7.63 (2H, m), 2-115 543 541 7.65-7.75 (4H, m), 7.79 (1H, t, J = 8.1 Hz), 8.34 (2H, d, J = 8.6 Hz), 8.53 (1H, d, J = 3.0 Hz).
F 1H-NMR (DMSO-D6) δ: 2.53 (3H, s), 5.44 (2H, s), 7.54-7.30 (6H, m), 7.58 (1H, d, J = 2-116 7.7 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.74 (2H, 557 555 dd, J = 6.8, 1.8 Hz), 7.81 (1H, t, J = 8.0 Hz), HCl H C 3 7.90 (1H, br s), 8.35 (2H, dd, J = 6.8, 1.8 Hz). 【0797】 【Table 2-14】 1H-NMR (DMSO-D6) δ: 2.51 (3H, s), 5.42 (2H, s), 7.33-7.29 (3H, m), 7.37 (1H, d, J = 2-117 7.9 Hz), 7.57 (1H, d, J = 7.9 Hz), 7.69-7.65 557 555 OH (3H, m), 7.72 (2H, dd, J = 6.8, 1.8 Hz), 7.89- HCl H C 7.78 (2H, m), 8.34 (2H, dd, J = 6.8, 1.8 Hz). 1H-NMR (CDCl3) δ: 3.87 (3H, s), 5.27 (2H, s), 6.61 (1H, d, J = 8.2 Hz), 6.86 (1H, d, J = 7.3 Hz), 7.31 (1H, d, J = 8.6 Hz), 7.35-7.39 2-118 555 553 (3H, m), 7.43-7.51 (2H, m), 7.53-7.60 (3H, m), 7.64 (2H, d, J = 8.4 Hz), 8.50 (2H, d, J = 8.4 Hz).
F 1H-NMR (DMSO-D6) δ: 5.10 (2H, s), 6.16- 6.32 (2H, m), 7.32-7.38 (1H, m), 7.44-7.48 2-119 (3H, m), 7.54-7.63 (4H, m), 7.70-7.75 (2H, 541 539 m), 7.77-7.84 (1H, m), 8.34 (2H, d, J = 8.6 Hz). 1H-NMR (DMSO-D6) δ: 3.89 (3H, s), 5.48 (2H, s), 7.20-7.26 (2H, m), 7.44-7.49 (3H, m), 2-120 7.58-7.64 (3H, m), 7.69-7.75 (3H, m), 7.84 555 553 N N O OH CH (1H, t, J = 8.2 Hz), 8.33 (2H, d, J = 8.6 Hz), 8.56 (1H, d, J = 6.0 Hz). 1H-NMR (DMSO-D6) δ: 5.47 (2H, s), 7.44- 7.48 (3H, m), 7.55-7.63 (4H, m), 7.68 (1H, d, 2-121 J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.78- 593 591 OH 7.84 (2H, m), 8.03 (1H, t, J = 8.1 Hz), 8.35 (2H, d, J = 8.6 Hz), 13.58 (1H, br s). 1H-NMR (DMSO-D6) δ: 5.47 (2H, s), 7.44- N O 7.51 (4H, m), 7.56-7.63 (3H, m), 7.67-7.74 2-122 593 591 (4H, m), 7.82 (1H, t, J = 8.1 Hz), 8.34 (2H, d, N N F OH F J = 8.6 Hz), 8.83 (1H, d, J = 5.1 Hz). 1H-NMR (DMSO-D6) δ: 2.50 (3H, s), 5.40 (2H, s), 7.29 (1H, d, J = 7.7 Hz), 7.33 (1H, d, Cl F J = 7.7 Hz), 7.59-7.46 (4H, m), 7.68 (1H, d, J 2-123 573 571 N N = 8.4 Hz), 7.71-7.69 (1H, m), 7.75 (2H, dd, J = 6.7, 1.9 Hz), 7.84-7.78 (2H, m), 8.36 (2H, dd, J = 6.7, 1.9 Hz).
F 1H-NMR (DMSO-D6) δ: 2.49 (3H, s), 5.39 (2H, s), 7.26 (1H, d, J = 7.5 Hz), 7.31 (1H, d, J = 7.5 Hz), 7.53 (2H, dt, J = 8.7, 2.2 Hz), Cl N 2-124 7.56 (1H, d, J = 7.9 Hz), 7.63 (2H, dt, J = 8.7, 573 571 2.2 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.74 (2H, dd, J = 6.7, 1.9 Hz), 7.83-7.76 (2H, m), 8.35 (2H, dd, J = 6.7, 1.9 Hz). 1H-NMR (DMSO-D6) δ: 2.50 (3H, s), 3.80 CH F (3H, s), 5.40 (2H, s), 7.03 (1H, dq, J = 8.6, 1.2 Hz), 7.19-7.14 (2H, m), 7.29 (1H, d, J = 7.3 2-125 Hz), 7.39-7.32 (2H, m), 7.57 (1H, d, J = 7.9 569 567 Hz), 7.67 (1H, d, J = 8.6 Hz), 7.73 (2H, dd, J = 6.7, 1.9 Hz), 7.85-7.77 (2H, m), 8.34 (2H, dd, J = 6.7, 1.9 Hz). 【0798】 【Table 2-15】 1H-NMR (DMSO-D6) δ: 2.49 (3H, s), 3.81 (3H, s), 5.40 (2H, s), 7.01 (2H, dt, J = 9.5, 2.4 Hz), 7.28 (1H, d, J = 6.8 Hz), 7.32 (1H, d, J = 2-126 569 567 7.5 Hz), 7.57-7.53 (3H, m), 7.70-7.66 (3H, m), HCl 7.80 (2H, t, J = 7.9 Hz), 8.33 (2H, dd, J = 6.8, 2.0 Hz). 1H-NMR (DMSO-D6) δ: 2.35 (3H, s), 2.51 (3H, s), 5.42 (2H, s), 7.27 (2H, d, J = 7.7 Hz), 7.32 (1H, d, J = 7.7 Hz), 7.36 (1H, d, J = 7.7 H C N 2-127 553 551 Hz), 7.49 (2H, d, J = 8.2 Hz), 7.57 (1H, d, J = 7.7 Hz), 7.72-7.66 (3H, m), 7.88-7.77 (2H, m), 8.33 (2H, dd, J = 6.7, 1.9 Hz). 1H-NMR (DMSO-D6) δ: 1.19 (3H, t, J = 7.5 F Hz), 2.52 (3H, s), 2.65 (2H, q, J = 7.6 Hz), .43 (2H, s), 7.30 (2H, d, J = 8.4 Hz), 7.34 H C N O (1H, d, J = 7.7 Hz), 7.39 (1H, d, J = 7.7 Hz), 2-128 567 565 N 7.52 (2H, d, J = 8.4 Hz), 7.57 (1H, d, J = 7.7 Hz), 7.72-7.67 (3H, m), 7.81 (1H, t, J = 8.3 HCl H C Hz), 7.87 (1H, br s), 8.33 (2H, dd, J = 6.7, 1.9 Hz).
F F F F F 1H-NMR (DMSO-D6) δ: 2.51 (3H, s), 5.42 (2H, s), 7.32 (1H, d, J = 7.1 Hz), 7.37 (1H, d, 2-129 N J = 7.7 Hz), 7.63-7.48 (4H, m), 7.72-7.67 (3H, 623 621 m), 7.89-7.77 (3H, m), 8.37 (2H, dd, J = 6.8, H C 2.0 Hz). 1H-NMR (DMSO-D6) δ: 2.55 (3H, s), 5.47 F F F (2H, s), 7.40 (1H, d, J = 7.1 Hz), 7.48-7.43 F N O (3H, m), 7.58 (1H, d, J = 7.7 Hz), 7.69 (1H, d, 2-130 623 621 J = 8.5 Hz), 7.77-7.72 (4H, m), 7.82 (1H, t, J = 8.5 Hz), 7.95 (1H, br s), 8.35 (2H, dd, J = 6.7, 1.9 Hz). 【0799】 【Table 3-1】 Example Structure NMR MS(M+H) MS(M-H) Note 1H-NMR (DMSO-D6) δ: 2.19 (6H, s), 2.30 3 (3H, s), 7.01 (2H, s), 7.90 (2H, d, J = 8.4 Hz), 360 358 8.51 (2H, d, J = 8.4 Hz), 13.26 (1H, br s).
N CH 1H-NMR (DMSO-D6) δ: 3.72 (3H, s), 4.59 (2H, d, J = 5.5 Hz), 5.41 (1H, t, J = 5.5 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 8.4 412 410 3-2 N Hz), 7.92 (2H, d, J = 8.4 Hz), 8.53 (2H, d, J = 8.4 Hz), 13.70 (1H, br s).
HO O OH 1H-NMR (DMSO-D6) δ: 2.31 (3H, s), 3.71 Cl (3H, s), 7.36 (1H, d, J = 8.4 Hz), 7.49 (1H, d, 3-3 396 394 J = 8.4 Hz), 7.93 (2H, d, J = 8.3 Hz), 8.53 (2H, d, J = 8.3 Hz), 13.67 (1H, br s).
HO O 1H-NMR (DMSO-D6) δ: 1.09 (3H, t, J = 7.0 Hz), 2.30 (3H, s), 3.94 (2H, q, J = 7.0 Hz), 3-4 7.34 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 8.2 410 408 Hz), 7.93 (2H, d, J = 8.2 Hz), 8.53 (2H, d, J = HO O CH 8.2 Hz), 13.66 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.91 (3H, s), 3.74 (3H, s), 4.32 (2H, d, J = 5.8 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.92 453 451 (2H, d, J = 8.4 Hz), 8.42 (1H, t, J = 5.8 Hz), HO O N 8.53 (2H, d, J = 8.4 Hz), 13.73 (1H, br s).
CH CH 1H-NMR (DMSO-D6) δ: 2.17 (3H, s), 4.55 (2H, d, J = 5.1 Hz), 5.35 (1H, t, J = 5.2 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.4 396 394 Hz), 7.91 (2H, d, J = 8.6 Hz), 8.51 (2H, d, J = N 8.6 Hz), 13.61 (1H, br s).
HO OH 1H-NMR (DMSO-D6) δ: 1.90 (3H, s), 2.21 (3H, s), 4.28 (2H, d, J = 5.7 Hz), 7.41 (1H, d, 3-7 J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.91 437 435 (2H, d, J = 8.2 Hz), 8.37 (1H, t, J = 5.8 Hz), HO H C N 8.51 (2H, d, J = 8.2 Hz), 13.62 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.16 (9H, s), 2.21 (3H, s), 4.27 (2H, d, J = 5.7 Hz), 7.34 (1H, d, 3-8 J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.91 479 477 (2H, d, J = 8.2 Hz), 8.09 (1H, t, J = 5.6 Hz), HO H C N CH 8.51 (2H, d, J = 8.2 Hz), 13.64 (1H, br s).
O CH 【0800】 【Table 3-2】 1H-NMR (DMSO-D6) δ: 2.32 (3H, s), 3.47 (2H, t, J = 4.9 Hz), 3.88 (2H, t, J = 4.8 Hz), 4.70 (1H, br s), 7.34 (1H, d, J = 8.1 Hz), 7.47 426 424 N (1H, d, J = 8.1 Hz), 7.92 (2H, d, J = 8.4 Hz), HO O CH 8.51 (2H, d, J = 8.4 Hz), 13.56 (1H, br s). 1H-NMR (DMSO-D6) δ: 1.33 (9H, s), 2.22 (3H, s), 4.30 (2H, d, J = 6.0 Hz), 7.52-7.54 3-10 (2H, m), 7.60 (1H, d, J = 8.4 Hz), 7.91 (2H, d, 515 513 J = 8.4 Hz), 8.51 (2H, d, J = 8.4 Hz), 13.65 HO H C N (1H, br s).
H C CH 1H-NMR (DMSO-D6) δ: 3.79-3.87 (3H, m), 7.28 (1H, dd, J = 9.3, 3.7 Hz), 7.67 (1H, t, J = 3-11 N 400 398 9.2 Hz), 7.93 (2H, d, J = 8.6 Hz), 8.51 (2H, d, J = 8.6 Hz), 13.68 (1H, br s).
HO O 1H-NMR (DMSO-D6) δ: 3.82 (3H, s), 5.22 (2H, s), 7.17 (2H, d, J = 9.0 Hz), 7.24-7.27 Cl F (1H, br m), 7.35 (1H, t, J = 7.2 Hz), 7.41 (2H, 3-12 438 436 t, J = 7.3 Hz), 7.47 (2H, d, J = 7.1 Hz), 7.63- 7.66 (1H, br m), 8.28 (2H, d, J = 9.0 Hz), 3 13.26 (1H, br s). 1H-NMR (DMSO-D6) δ: 2.36 (3H, s), 5.01 Cl CH 3 (2H, s), 7.11-7.15 (1H, m), 7.22 (1H, d, J = 7.7 Hz), 7.39 (1H, d, J = 8.4 Hz), 7.52 (1H, d, 3-13 473 471 J = 8.4 Hz), 7.60 (1H, td, J = 7.7, 1.7 Hz), F N N 7.86 (2H, d, J = 8.4 Hz), 8.31 (1H, d, J = 4.0 Hz), 8.41 (2H, d, J = 8.4 Hz), 13.61 (1H, br s).
H C 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.6 Hz), 1.41 (6H, s), 1.83-1.95 (1H, m), 2.19 (3H, s), 2.54 (2H, d, J = 7.3 Hz), 4.33 (2H, d, 3-14 521 519 J = 5.5 Hz), 7.28-7.38 (3H, m), 7.46 (1H, d, J HO H C N CH = 8.4 Hz), 8.24 (2H, d, J = 8.2 Hz), 8.52-8.60 O (1H, m), 13.35 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.88 (6H, d, J = 6.6 H C Hz), 1.18 (3H, t, J = 7.1 Hz), 1.83-1.94 (1H, m), 2.19 (3H, s), 2.54 (2H, d, J = 7.1 Hz), 4.02 (2H, q, J = 7.1 Hz), 4.21 (2H, d, J = 5.7 3-15 455 453 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.46 (1H, d, J = 8.2 Hz), 7.69-7.75 HO H C N (1H, m), 8.24 (2H, d, J = 8.4 Hz), 13.33 (1H, O CH br s). 1H-NMR (DMSO-D6) δ: 0.91 (3H, t, J = 7.3 H C Cl N Hz), 1.37 (6H, s), 1.60-1.67 (2H, m), 2.33 N CH (3H, s), 2.62 (2H, t, J = 7.6 Hz), 4.31 (2H, d, J 507 505 3-16 N F F HO N F = 5.7 Hz), 7.30-7.38 (3H, m), 7.52 (1H, s), 8.10-8.15 (2H, m), 8.48 (1H, t, J = 5.7 Hz). 【0801】 【Table 3-3】 1H-NMR (DMSO-D6) δ: 0.35 (2H, dt, J = 8.0, 2.9 Hz), 0.59 (2H, ddd, J = 9.1, 5.0, 2.9 Hz), 1.20-1.29 (1H, m), 1.38 (6H, s), 2.35 (3H, s), N CH 3 3.93 (2H, d, J = 7.0 Hz), 4.32 (2H, d, J = 5.6 535 533 3-17 Hz), 7.05 (2H, d, J = 8.8 Hz), 7.44 (1H, s), HO NH CH 7.56 (1H, s), 8.29 (2H, d, J = 8.8 Hz), 8.49 F F (1H, t, J = 5.6 Hz), 13.08 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.99 (6H, d, J = 6.6 Hz), 1.41 (6H, s), 1.98-2.10 (1H, m), 2.18 (3H, s), 3.85 (2H, d, J = 6.6 Hz), 4.32 (2H, d, 3-18 J = 5.7 Hz), 7.06 (2H, d, J = 8.4 Hz), 7.30 537 535 N (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 8.2 Hz), HO H C N CH 8.27 (2H, d, J = 8.4 Hz), 8.52-8.59 (1H, m), F 13.23 (1H, br s). 1H-NMR (DMSO-D6) δ: 0.35 (2H, td, J = 5.2, Cl 4.1 Hz), 0.57-0.62 (2H, m), 1.24-1.27 (1H, m), 3-19 2.61 (3H, s), 3.94 (2H, d, J = 7.2 Hz), 7.09 412 410 N CH (2H, d, J = 8.8 Hz), 7.64 (1H, s), 8.27 (1H, s), OH 8.30 (2H, d, J = 8.8 Hz), 13.20 (2H, br s). 1H-NMR (DMSO-D6) δ: 0.35 (2H, td, J = 5.1, 4.1 Hz), 0.58-0.60 (2H, m), 1.22-1.30 (1H, m), 2.45 (3H, s), 3.94 (2H, d, J = 7.2 Hz), 7.09 411 409 3-20 (2H, d, J = 9.1 Hz), 7.56 (2H, s), 7.81 (1H, s), N CH 7.85 (1H, s), 8.32 (2H, d, J = 8.8 Hz), 13.06 HO NH (1H, br s). 1H-NMR (DMSO-D6) δ: 0.35 (2H, td, J = 5.2, 4.0 Hz), 0.57-0.62 (2H, m), 1.22-1.27 (1H, m), 2.42 (3H, s), 2.77 (3H, d, J = 4.7 Hz), 3.94 425 423 3-21 N CH (2H, d, J = 7.0 Hz), 7.09 (2H, d, J = 9.1 Hz), 7.56 (1H, s), 7.77 (1H, s), 8.31 (2H, d, J = 9.1 HO N Hz), 8.32 (1H, s), 13.09 (1H, br s).
O CH 1H-NMR (DMSO-D6) δ: 0.35 (2H, td, J = 5.6, 4.4 Hz), 0.57-0.61 (2H, m), 1.21-1.29 (1H, m), 2.28 (3H, s), 2.81 (3H, s), 3.02 (3H, s), 3.93 3-22 439 437 N CH (2H, d, J = 7.2 Hz), 7.08 (2H, d, J = 9.1 Hz), N CH 7.59 (1H, s), 7.62 (1H, s), 8.30 (2H, d, J = 9.1 HO N Hz), 13.10 (1H, br s).
O CH O 1H-NMR (DMSO-D6) δ: 0.35 (2H, td, J = 5.3, 4.0 Hz), 0.57-0.61 (2H, m), 0.90 (3H, t, J = Cl 7.3 Hz), 1.20-1.30 (2H, m), 1.30-1.40 (2H, m), 1.46-1.53 (2H, m), 2.41 (3H, s), 3.24 (2H, q, J N CH CH 467 465 3-23 3 3 N = 6.9 Hz), 3.94 (2H, d, J = 7.2 Hz), 7.09 (2H, HO N d, J = 9.1 Hz), 7.56 (1H, s), 7.74 (1H, s), 8.31 (2H, d, J = 9.1 Hz), 8.37 (1H, t, J = 5.5 Hz), 13.09 (1H, br s). 【0802】 Experimental Example 1: Evaluation of human mPGES-1 enzyme inhibitory activity The human mPGES-1 enzyme inhibitory activity of a test article was evaluated according to the report of Xu et al. (XU, D et al. MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazolyl)- 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). That is, the amount of PGE2 produced by human mPGES-1 in the presence of a test article was measured by the HTRF (homogeneous time resolved fluorescence) method, based on which the human mPGES-1 enzyme inhibitory activity of the test article was determined. 【0803】 1) Preparation of human mPGES-1 expressing cell microsome fraction A DNA fragment containing human mPGES-1, which is added with a BamHI recognition cleavage sequence immediately before the translation initiation codon and an EcoRI recognition cleavage sequence immediately after the translation termination codon was amplified by the PCR (Polymerase Chain Reaction) method using a human mPGES-1 expression plasmid DNA (pME- 18S/iPGES-1) prepared in-house as a template. The purified DNA fragment was digested with BamHI and EcoRI, and ligated to pcDNA3.1(+) (Invitrogen, model number V790-20), similarly digested with BamHI and EcoRI, by using a DNA Ligation kit ver.2.1 (Takara Bio, model number 6022). The human mPGES-1 expression plasmid DNA was isolated from Escherichia coli DH5α (TOYOBO, model number DNA-903) transformed with the obtained ligation product. The base sequence of human mPGES-1 cloned to a vector was determined by the Dye Terminator method by using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, #4337455). The determined sequence was identical with the sequence of the protein translational region 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-derived cells (FreeStyle CHO-S Cell, Invitrogen, #R800-07) by using a transgene reagent (FreeStyle MAX Reagent (Invitrogen, #16447-100)), and cultured with shaking (8% CO , 37 C) in a medium containing 8 mmol/L L- glutamine (GIBCO FreeStyle CHO Expression Medium, Invitrogen, #12651-022) for 48 hr.
The 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, #1873580)). Using an ultrasonic disruptor UD-201 (Tomy Seiko), the suspended cells were disrupted at output:3, duty cycle:50 for 30 seconds. 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 obtained 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 give a microsome fraction.
The protein concentration of the microsome fraction was measured by the Bradford method (Protein Assay Kit, Bio-Rad).
The microsome fraction was rapidly frozen in liquid nitrogen and preserved at -80 C. Human mPGES-1 in the microsome fraction was detected by Western Blot using rabbit anti-mPGES-1 polyclonal antibody (ThermoFisher Scientific, #PA1-10264). 【0804】 2) Evaluation of human mPGES-1 enzyme inhibitory activity A test article solution diluted with 0.1 mol/L potassium phosphate, pH 7.4 (hereinafter to be referred to as KPB) or DMSO (Nacalai Tesque, #13407-45) was added at 5 μL/well to 96 well V-bottom plate (Corning, #3363). The final DMSO concentration during the reaction was set to 2%(v/v).
Furthermore, a microsome fraction of CHO-S cells expressing human mPGES-1, which was diluted with reduced GSH (12.5 mmol/L KPB solution, SIGMA, #G6529-25G) such that the protein concentration was 5 μg/mL, was added at 20 μL/well. The amount of the microsome fraction used is the amount of microsome fraction within a range where the amount of PGE2 produced under the reaction conditions shown below and the amount of microsome fraction used show linearity. To the blank was added reduced GSH (12.5 mmol/L KPB solution) at 20 μL/well. After stirring at room temperature for 10 min, PGH2 (PGH2 dissolved in cold acetone to 100 μg/mL and diluted with D-PBS(-) (Nikken biomedical laboratory, #CM6201) to 10 μg/mL, Cayman Chemical, #17020) was added at 25 μL/well, and the mixture was stood at room temperature for 45 seconds. Tin(II) chloride dihydrate (2 mg/mL 10 mmol/L citric acid solution, Wako Pure Chemical Industries, Ltd., #204-01562) was added at 50 μL/well, and the plate was gently shaken to discontinue the enzyme reaction.
The concentration of PGE2 in the above-mentioned enzyme reaction mixture was measured using Prostaglandin E2 assay (CISbio Bioassays, #62P2APEC) according to the manual. As the reference standard for analytical curve, PGE2 (Cayman Chemical, #14010) was used. Using RUBYstar (BMG Labtech), the time- resolved fluorescence at 620 nm and 665 nm relative to the excitation light at 337 nm was measured. PGE2 concentration was extrapolated from the PGE2 analytical curve. Average of the PGE2 concentrations of the respectively-treated wells was used as the data.
The mPGES-1 enzyme inhibitory activity (%) of the test article was calculated according to the following formula 1. [formula 1] mPGES-1 enzyme inhibitory activity (%) = (PGE2 - PGE2 )/(PGE2 A X A - PGE2 ) x 100 PGE2 : PGE2 concentration of vehicle-treated well PGE2 : PGE2 concentration of blank well PGE2 : PGE2 concentration of test article-treated well The IC value (50% inhibitory concentration) of the test article was calculated according to the following formula 2. [formula 2] {log10(D / E) × (50 – G) / (F – G) + log10(E)} IC50 value = 10 D: concentration of test article that shows activity of not less than 50% inhibition between two points across 50% inhibition E: concentration of test article that shows activity of not more than 50% inhibition between two points across 50% inhibition F: mPGES-1 enzyme inhibitory activity (%) when concentration of test article is D G: mPGES-1 enzyme inhibitory activity (%) when concentration of test article is E The results are shown in Table 4-1 to Table 4-9. 【0805】 【Table 4-1】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 1-1 1-18 1-35 0.813 0.114 0.022 1-2 1-19 1-36 0.138 0.411 0.0007 1-3 1-20 1-37 0.164 0.0016 0.0008 1-4 1-21 1-38 0.025 0.988 0.0015 1-5 1-22 1-39 0.672 0.0027 0.0019 1-6 1-23 1-40 0.163 0.134 2.231 1-7 1-24 1-41 0.652 0.0006 0.0023 1-8 1-25 1-42 27.0 0.108 0.0010 1-9 1-26 1-43 0.601 0.018 0.0020 % inhibition 1-10 1-27 1-44 0.0010 0.0006 (at 30 μM) 42% inhibition 1-11 1-28 1-45 0.0006 0.138 (at 30 μM) 1-12 1-29 1-46 0.015 0.0011 0.0007 1-13 1-30 1-47 0.397 0.0006 0.043 1-14 1-31 1-48 1.413 0.0010 0.0009 1-15 1-32 1-49 0.0074 0.0007 0.0009 1-16 1-33 1-50 0.010 0.0008 0.0009 1-17 1-34 1-51 0.735 0.0059 0.0010 【0806】 【Table 4-2】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 1-52 1-69 1-86 0.0006 0.0003 0.0058 1-53 1-70 1-87 0.0045 0.0007 0.0008 1-54 1-71 1-88 0.0009 0.0025 0.0012 1-55 1-72 1-89 0.0011 0.0013 0.0009 1-56 1-73 1-90 0.0006 0.0006 0.0004 1-57 1-74 1-91 0.0005 0.0006 0.0004 1-58 1-75 1-92 0.0005 0.0067 0.0005 1-59 1-76 1-93 0.0006 0.0017 0.0007 1-60 1-77 1-94 0.0004 0.0009 0.0046 1-61 1-78 1-95 0.0007 0.0022 0.0021 1-62 1-79 1-96 0.0010 0.0012 0.081 1-63 1-80 1-97 0.0005 0.0031 0.0091 1-64 1-81 1-98 0.0019 0.0006 0.0009 1-65 1-82 1-99 0.0086 0.0008 0.0007 1-66 1-83 1-100 0.0041 0.011 0.0009 1-67 1-84 1-101 0.0010 0.0006 0.0058 1-68 1-85 1-102 0.0003 0.0005 0.0009 【0807】 【Table 4-3】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 1-103 1-120 1-137 0.0013 0.048 0.0005 1-104 1-121 1-138 0.0015 0.0012 0.0005 1-105 1-122 1-139 0.0007 0.0013 0.0006 1-106 1-123 1-140 0.0007 0.0023 0.0005 1-107 1-124 1-141 0.0012 0.0009 0.0011 1-108 1-125 1-142 0.0006 0.0008 0.0005 1-109 1-126 1-143 0.0025 0.0008 0.0010 1-110 1-127 1-144 0.0009 0.0008 0.0009 1-111 1-128 1-145 0.0012 0.0013 0.0005 1-112 1-129 1-146 0.0009 0.0006 0.0004 1-113 1-130 1-147 0.0009 0.009 0.0008 1-114 1-131 1-148 0.0059 0.0009 0.0017 1-115 1-132 1-149 0.0006 0.0003 0.0008 1-116 1-133 1-150 0.0020 0.0005 0.0004 1-117 1-134 1-151 0.0016 0.004 0.0004 1-118 1-135 1-152 0.0019 0.0005 0.0004 1-119 1-136 1-153 0.0010 0.0005 0.0005 【0808】 【Table 4-4】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 1-154 1-171 1-188 0.0005 0.0005 0.0016 1-155 1-172 1-189 0.0035 0.017 1.1 1-156 1-173 1-190 0.0041 0.0054 0.047 1-157 1-174 1-191 0.0007 0.0031 0.015 41% inhibition 1-158 1-175 1-192 0.012 0.0013 (at 30 μM) 1-159 1-176 1-193 0.0007 0.0018 8.7 1-160 1-177 1-194 0.0014 0.0013 10.5 1-161 1-178 1-195 0.0013 0.0014 6.0 1-162 1-179 1-196 0.0012 0.016 0.042 1-163 1-180 1-197 0.0010 0.0041 0.289 1-164 1-181 1-198 0.0037 0.0024 0.014 1-165 1-182 1-199 0.0009 0.0016 0.031 1-166 1-183 1-200 0.0011 0.0013 0.010 1-167 1-184 1-201 0.0019 0.0019 0.306 1-168 1-185 1-202 0.0021 0.0017 0.0082 1-169 1-186 1-203 0.0020 0.0014 0.020 1-170 1-187 1-204 0.0015 0.0053 0.034 【0809】 【Table 4-5】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 1-205 1-222 1-239 0.367 0.165 0.428 1-206 1-223 1-240 0.014 0.007 0.428 1-207 1-224 1-241 0.0043 5.8 0.278 1-208 1-225 1-242 0.016 4.2 0.082 1-209 1-226 1-243 0.059 2.2 0.120 1-210 1-227 1-244 0.288 0.050 0.021 1-211 1-228 1-245 0.063 0.672 0.108 1-212 1-229 1-246 0.032 0.532 0.307 1-213 1-230 1-247 0.088 0.750 0.011 1-214 1-231 1-248 0.024 0.045 0.016 1-215 1-232 1-249 0.452 0.521 0.226 1-216 1-233 1-250 0.039 0.848 0.012 1-217 1-234 1-251 0.126 1.0 0.018 1-218 1-235 1-252 0.070 0.070 0.511 1-219 1-236 1-253 0.041 0.263 0.791 1-220 1-237 1-254 0.016 1.3 0.030 1-221 1-238 1-255 0.079 0.0074 0.045 【0810】 【Table 4-6】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity （μM） activity （μM） activity （μM） 28% inhibition 1-256 2-6 2-23 0.098 0.155 (at 30 μM) 1-257 2-7 2-24 0.017 3.5 2.4 1-258 2-8 2-25 1.9 1.9 0.249 1-259 2-9 2-26 0.176 6.4 2.7 1-260 2-10 2-27 0.147 0.073 7.7 44% inhibition 1-261 2-11 2-28 0.0060 3.7 (at 30 μM) 1-262 2-12 2-29 0.007 0.141 0.503 43% inhibition 1-263 2-13 2-30 0.702 23.1 (at 30 μM) 1-264 2-14 2-31 0.163 14.3 0.031 1-265 2-15 2-32 0.056 16.4 0.014 1-266 2-16 2-33 0.011 0.412 0.102 1-267 2-17 2-34 0.150 0.039 0.163 2-1 2-18 2-35 0.283 0.0080 0.017 2-2 2-19 2-36 21.3 0.211 0.053 2-3 2-20 2-37 14.7 0.052 0.041 2-4 2-21 2-38 0.066 0.341 1.0 2-5 2-22 2-39 0.101 0.219 0.450 【0811】 【Table 4-7】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 2-40 2-57 2-74 1.3 0.025 0.424 2-41 2-58 2-75 0.429 0.145 0.0037 2-42 2-59 2-76 0.239 0.095 0.0058 2-43 2-60 2-77 0.570 0.121 0.0037 2-44 2-61 2-78 0.563 0.092 0.0068 2-45 2-62 2-79 0.012 0.0093 0.0037 2-46 2-63 2-80 0.494 0.259 0.0016 2-47 2-64 2-81 0.295 0.012 0.0027 2-48 2-65 2-82 0.019 0.151 0.0017 2-49 2-66 2-83 0.014 0.016 0.051 2-50 2-67 2-84 0.061 0.027 0.017 2-51 2-68 2-85 0.090 0.672 0.0016 2-52 2-69 2-86 0.100 0.084 0.0022 2-53 2-70 2-87 0.011 0.158 0.0018 2-54 2-71 2-88 0.170 0.172 0.0020 2-55 2-72 2-89 0.010 0.283 0.018 2-56 2-73 2-90 0.018 0.402 2.1 【0812】 【Table 4-8】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity （μM） activity （μM） activity （μM） 2-91 2-108 2-125 0.0016 0.0064 0.0043 2-92 2-109 2-126 0.0044 0.0028 0.0046 2-93 2-110 2-127 0.038 0.0074 0.0062 2-94 2-111 2-128 0.0041 0.0044 0.013 2-95 2-112 2-129 0.0050 0.0059 0.032 2-96 2-113 2-130 0.021 0.0051 0.035 2-97 2-114 3-1 0.0089 0.0049 0.484 2-98 2-115 3-2 0.0037 0.0030 0.148 2-99 2-116 3-3 0.0017 0.0055 0.141 2-100 2-117 3-4 0.0056 0.0047 0.202 2-101 2-118 3-5 0.0065 0.0071 0.341 2-102 2-119 3-6 0.0059 0.0018 0.056 2-103 2-120 3-7 0.010 0.0041 0.019 2-104 2-121 3-8 0.018 0.014 0.0010 2-105 2-122 3-9 0.018 0.015 0.776 2-106 2-123 3-10 0.0050 0.012 0.016 2-107 2-124 3-11 0.0038 0.012 0.093 【0813】 【Table 4-9】 Human mPGES-1 Human mPGES-1 Human mPGES-1 Example enzyme inhibitory Example enzyme inhibitory Example enzyme inhibitory activity μM activity μM activity μM （ ） （ ） （ ） 3-12 3-16 3-20 0.028 0.0021 1.1 3-13 3-17 3-21 0.034 0.0008 0.611 3-14 3-18 3-22 0.002 0.0012 6.9 3-15 3-19 3-23 0.0051 24.6 0.041 【0814】 Experimental Example 2: Evaluation of action of mPGES-1 inhibitor on normal intraocular pressure of Macaca fascicularis This test was performed using male Macaca fascicularis.
To eliminate interindividual difference and an influence of the difference in administration days, a crossover test was used for the evaluation as shown in Table 5. 【0815】 【Table 5】 Animal No. First course Second course Third course test article SX1M01 reference article vehicle mg/kg test article SX1M02 reference article vehicle mg/kg test article SX1M03 reference article vehicle mg/kg test article SX1M04 vehicle reference article mg/kg test article SX1M05 vehicle reference article mg/kg 【0816】 To exclude the influence of the remaining test article, a 1-week washout period was set between tests. On the day of test, the monkeys were fed after the final measurement.
The test article (compound of Examples 2-98) was suspended in 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.), and administered by gavage by using a polypropylene syringe (sterilized disposable product, Nipro Corporation) and a stomach catheter (nelaton type A No. 9, Izumo health). The dose was set to 10 mg/kg/5 mL (N=1) or 30 mg/kg/5 mL (N=4) based on the body weight of each individual the day before the administration. To the vehicle group was administered the vehicle (0.5% methylcellulose (MC)) by a method similar to that for the test article. As a reference article, Xalatan (registered trade mark) ophthalmic solution 0.005% (Pfizer Inc., general name: latanoprost) was used. The reference article was administered by instillation of 20 μL thereof to one eye by using a micropipette. After instillation, the lacrimal part was lightly fixed by gently pressing the lower eyelid for about 15 seconds. The opposite eye was treated in the same manner. The intraocular pressure was measured immediately before administration, and 2, 4, 8, 12 and 24 hr after administration. Before measurement of the intraocular pressure, the animal was fixed on a monkey chair, and topically anesthetized by instillation of an ophthalmic surface anesthetic (Benoxyl (registered trade mark) ophthalmic solution 0.4%, Santen Pharmaceutical Co., Ltd., general name: oxybuprocaine hydrochloride). A lid rectactor (Handaya Co., Ltd.) was set, and the intraocular pressure of the both eyes was measured using a pneumatic applanation tonometer (Model30 Classic, Reichert Inc.).
To confirm disappearance of the test article, after an intraocular pressure measurement at 24 hr after the third course administration, blood samples (1 mL) were collected from the femoral vein under unanesthetized condition by using polypropylene syringe and 23 gauge injection needle (both sterilized disposable products) treated with heparin sodium, and the concentration of unaltered compound in the plasma containing the test article was measured.
An intraocular pressure difference (D mmHg; in first decimal place) from the value immediately before administration was determined for each measurement eye at each measurement time point, an average of the both eyes was calculated and taken as the evaluation data of the individual. The mean and standard deviation (in second decimal place) of the intraocular pressure difference was calculated for each group, and the test article administration group or reference article administration group was subjected to a homoscedasticity test (significance level 5%) based on F-test with the vehicle group.
When the dispersion was equal, Student’s t-test was performed and, when the dispersion was not equal, Aspin-Welch’s t-test was performed. In addition, the maximum ocular hypotensive effect (D mmHg; maximum descent value from value immediately before administration, in first decimal place) was determined for each group, and the groups were compared in the same manner.
The two-sided test was performed. It is a significant variation when a difference from the vehicle group was found at a 5% significance level and shown in Fig. 1 separately as 5% and 1%. Since the test article 10 mg/kg administration group contained only one animal, it was excluded from the statistical analysis. 【0817】 The intraocular pressure of Macaca fascicularis used for this test before administration of a test article was 19.6±1.7 mmHg. After the measurement of intraocular pressure at 24 hr after the third course administration, the concentration of an unaltered test article in the plasma of the vehicle group and the reference article administration group was less than the lower detection limit. The results are shown in Fig. 1. 【0818】 Experimental Example 3: Evaluation of effect on prostaglandin composition in guinea pig aqueous humor A test article was dissolved in saline containing 0.5% polysorbate80 (Fluka) and 0.003% ophthalmic solution (pH 7.0 - 8.0) was prepared. The test article was administered to Hartley male guinea pig by instillation of 20 μL thereof to one eye by using a micropipette. After instillation, the lacrimal part was lightly fixed by gently pressing the lower eyelid for about 15 seconds. The opposite eye was treated in the same manner. To the vehicle group was administered the medium (0.5% polysorbate-containing saline) by a method similar to that for the test article. After 23 hr from the instillation, Mydrin P (registered trade mark) 0.5% ophthalmic solution (Santen Pharmaceutical Co., Ltd., general name: tropicamide/phenylephrine hydrochloride) was dropwisely added by one drop to the both eyes of a guinea pig to cause mydriasis.
The guinea pig was anesthetized with Escain (registered trade mark) inhalation anesthetics (Pfizer Inc., general name: isoflurane), the cornea of the both eyes was tapped with a 30G injection needle, and the leaked aqueous humor (primary aqueous humor) was collected. One hour later (24 hr after instillation), the guinea pig was anesthetized again with isoflurane, and the secondary aqueous humor was collected in the same manner. The concentration of prostaglandins in the secondary aqueous humor obtained from each group (4 guinea pigs, 8 eyes) was measured by the LC/MS/MS system (Ultra high performance liquid chromatography: Nexera (registered trademark) manufactured by Shimadzu Corporation, mass spectrometer: AB SCIEX manufactured by QTRAP (registered trademark) 5500), and the concentration ratio of each prostaglandin concentration relative to the total of all prostaglandin concentrations was calculated. The results are shown in Table 6. 【0819】 【Table 6】 6-keto- Example PGE2 (%) PGF2α (%) PGD2 (%) TXB2 (%) PGF1α (%) vehicle 80.8 7 6.8 4.7 0.7 1-51 50.7 14 21.7 13.2 0.4 1-81 60 9.8 15.7 13.2 1.3 1-98 38 14.2 31.2 16.3 0.3 1-109 29.5 14.1 37.5 18.9 0.1 1-122 37.3 11.7 27.7 23 0.2 1-128 36.2 13.9 29.7 19.3 0.8 1-129 62.5 10.2 18.1 9.2 0 1-130 73.6 8 11.2 6.2 1 1-131 42.9 9.8 27.9 18.8 0.6 1-135 56.1 12.7 19.4 10.9 0.9 1-136 66.7 7.9 17.3 7.4 0.7 1-137 49.5 11.3 24.8 14.1 0.3 1-150 69 8.9 14 8 0.2 1-169 28.7 13.5 40.3 17 0.5 1-178 30 13 36.6 20.1 0.3 1-184 57 10.3 21.2 10.7 0.8 1-185 50 11 25.4 12.1 1.6 2-98 37.8 14.8 27.3 20.1 0 【0820】 Experimental Example 4: Evaluation of action of mPGES-1 inhibitor on normal intraocular pressure of Macaca fascicularis This test is performed using male Macaca fascicularis.
To eliminate interindividual difference and an influence of the difference in administration days, a crossover test is used for the evaluation as shown in Table 7. 【0821】 【Table 7】 Animal No. First course Second course Third course Fourth course test article + SX1M01 vehicle test article reference article reference article test article + SX1M02 test article vehicle reference article reference article test article + SX1M03 reference article test article vehicle reference article test article + SX1M04 test article vehicle reference article reference article test article + SX1M05 vehicle reference article test article reference article test article + SX1M06 test article vehicle reference article reference article 【0822】 To exclude the influence of the remaining test article, a 1-week washout period is set between tests. On the day of test, the monkeys are fed after the final measurement.
A test article is dissolved in saline containing 0.5% polysorbate80 (Fluka) and 0.1% ophthalmic solution (pH 7.9 - 8.1) is prepared. To the vehicle group is administered the medium (0.5% polysorbate-containing saline) by a method similar to that for the test article. As a reference article, Xalatan (registered trademark) ophthalmic solution 0.005% (Pfizer Inc., general name: latanoprost) is used. The test article is administered by instillation of 30 μL thereof to one eye 5 times and 1 time of vehicle at 5-min intervals by using a micropipette (total 6 times instillation for each eye). Each of vehicle and reference article is adiministered 1 time and then vehicle is instilled 5 times (total 6 times instillation for each eye). In the test article+reference article combination group, the test article is instilled 5 times after instillation of the reference article (total 6 times instillation for each eye). After instillation at each time, the lacrimal part is lightly fixed by gently pressing the lower eyelid for about 15 seconds. The intraocular pressure is measured immediately before administration, and 2, 4, 8, 12 and 24 hr after administration. Before measurement of the intraocular pressure, the animal is fixed on a monkey chair, and topically anesthetized by instillation of an ophthalmic surface anesthetic (Benoxyl (registered trademark) ophthalmic solution 0.4%, Santen Pharmaceutical Co., Ltd., general name: oxybuprocaine hydrochloride). A lid rectactor (Handaya Co., Ltd.) is set, and the intraocular pressure of the both eyes is measured using a pneumatic applanation tonometer (Model30 Classic, Reichert Inc.).
An intraocular pressure difference (D mmHg; in first decimal place) from the value immediately before administration is determined for each measurement eye at each measurement time point, an average of the both eyes is calculated and taken as the evaluation data of the individual. The mean and standard deviation (in second decimal place) of the intraocular pressure difference is calculated for each group, and the test article administration group or reference article administration group is subjected to a homoscedasticity test (significance level 5%) based on F-test with the vehicle group. When the dispersion is equal, Student’s t-test is performed and, when the dispersion is not equal, Aspin-Welch’s t-test is performed. In addition, the maximum ocular hypotensive effect (D mmHg; maximum descent value from value immediately before administration, in first decimal place) is determined for each group, and the groups are compared in the same manner. The two-sided test is performed.
It is a significant variation when a difference from the vehicle group is found at a 5% significance level. 【0823】 The Formulation Examples of the present invention include the following formulations. However, the present invention is not limited by such Formulation Examples.
Formulation Example 1 (Production of capsule) 1) compound of Example 1-86 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 in a gelatin capsule.
Formulation Example 2 (Production of tablet) 1) compound of Example 86 10 g 2) lactose 50 g 3) cornstarch 15 g 4) carmellose calcium 44 g ) magnesium stearate 1 g The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is tableted by a tableting machine. In this way, 1000 tablets containing 10 mg of the compound of Example 1-86 per tablet are obtained.
Formulation Example 3 (production of eye drop) in 100 mL of eye drop 1) compound of Example 1-86 100 mg 2) polysorbate80 500 mg 3) sodium chloride 900 mg 4) sodium hydroxide q.s. ) sterilized purified water q.s.
The above components are aseptically blended to pH 7.9 - 8.1 to give an eye drop.
Formulation Example 4 (production of eye drop) in 100 mL of eye drop 1) compound of Example 1-86 100 mg 2) polysorbate80 100 mg 3) sodium dihydrogen phosphate dehydrate 100 mg 4) sodium chloride 900 mg ) benzalkonium chloride 5 mg 6) sodium hydroxide q.s. 7) sterilized purified water q.s.
The above components are aseptically blended to pH 7.9 - 8.1 to give an eye drop.
Formulation Example 5 (production of eye drop) in 100 mL of eye drop 1) compound of Example 1-86 100 mg 2) boric acid 700 mg 3) borax q.s. 4) sodium chloride 500 mg ) sodium edetate 0.05 mg 6) benzalkonium chloride 0.0005 mg 7) sterilized purified water q.s.
The above components are aseptically blended to pH 7.9 - 8.1 to give an eye drop.
INDUSTRIAL APPLICABILITY 【0824】 Since the compound of the present invention and a pharmaceutically acceptable salt thereof have an mPGES-1 inhibitory activity, they can afford a medicament effective for the prophylaxis or treatment of pain, rheumatism, osteoarthritis, fever, Alzheimer’s disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer including colorectal cancer and diseases for which suppression of PGE2 production is effective.
This application is based on a patent application No. 2014-031035 filed in Japan on February 20, 2014, the contents of which are incorporated in full herein.

Claims (26)

1. A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof: ( R ) [ I ] wherein X is CH or N, ring Cy is the formula: the formula: {wherein R is (1) halogen, (2) C alkyl, (3) cyano or (4) haloC1-4 alkyl, R is (1) halogen, (2) hydroxy, (3) carboxy, (4) C1-6 alkyl, (5) C alkoxy, (6) haloC alkoxy, (7) haloC alkyl, (8) C alkyl-carbonyl, a1 a2 a1 a2 (9) -C(O)NR R (R and R are each independently hydrogen or C alkyl) or (10) -(C H )-R n 2n (n is 1, 2, 3 or 4, -(C H )- may be straight or branched n 2n chain, and R is (a) hydroxy, (b) carboxy, (c) C alkoxy, (d) C alkyl-carbonyloxy, b1 b2 b1 b2 (e) -C(O)NR R (R and R are each independently hydrogen or C alkyl), b3 b4 b3 b4 (f) -OC(O)NR R (R and R are each independently hydrogen or C alkyl), b5 b6 b7 b5 b6 b7 (g) -NR C(O)NR R (R , R and R are each independently hydrogen or C alkyl), b8 b9 b8 b9 (h) -NR R (R and R are each independently hydrogen, C alkyl or haloC alkyl), 1-6 1-4 b10 b11 b10 b11 (i) -NR S(O) R (R and R are each independently hydrogen, C1-6 alkyl or C3-7 cycloalkyl), b12 b13 b12 (j) -NR C(O)OR (R is hydrogen or C1-6 alkyl, and R is C alkyl), b14 b15 b14 (k) -NR C(O)R (R is hydrogen or C alkyl, and R is (i) C aryl, 6-10 (ii) C alkyl (said C alkyl is optionally 1-8 1-8 substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, haloC alkyl, C alkoxy and 1-4 1-6 C aryl), 6-10 (iii) adamantyl or (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2, 3 or 4 substituents selected from the group consisting of C1-6 alkyl, halogen, hydroxyl C1-6 alkyl and halo C1-4 alkyl, and/or optionally form a fused ring with a benzene ring), or b14 b15 R and R optionally form a 4-, 5- or 6-membered lactam together with the nitrogen atom that R is bonded to and the carbon atom that R is bonded to (said lactam is optionally substituted by 1, 2 or 3 C alkyls, and/or optionally form a fused ring with a benzene ring), (l) the formula: b 1 6 ( R ) wherein m2 and m3 are each independently 1, 2 or 3, m4 is 0, 1, 2, 3 or 4, R is C alkyl or C alkoxy, and when m4 is 1-6 1-6 2, 3 or 4, each R is selected independently or (m) the formula: N b 1 7 wherein m5 and m6 are each independently 1, 2 or 3, and R is C alkyl or C alkoxy), 1-6 1-6 R is (1) halogen, (2) hydroxy, (3) C alkyl or (4) -OR {R is C alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f); (a) halogen, (b) hydroxy, (c) C alkoxy, c1 c2 c1 c2 (d) -C(O)NR R (R and R are each independently hydrogen or C alkyl), (e) C6-10 aryl (said C6-10 aryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl)}, and R is (1) hydrogen, (2) halogen, (3) C alkyl or (4) C alkoxy}, R is (1) halogen, (2) hydroxy, (3) C1-6 alkylsulfanyl, (4) C1-6 alkyl (said C1-6 alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, C aryl and C alkoxy), 6-10 1-6 (5) C cycloalkyl, (6) -OR {R is (a) C alkynyl, (b) C cycloalkyl optionally substituted by 1, 2 or 3 C alkyls or (c) C alkyl (said C alkyl is optionally substituted 1-8 1-8 by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v); (i) halogen, (ii) C6-10 aryl, (iii) C1-6 alkoxy, (iv) C cycloalkyl (said C cycloalkyl is optionally 3-7 3-7 substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl), and 1-6 1-4 (v) 4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said saturated heterocyclyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C alkyl and haloC alkyl))} or 1-6 1-4 (7) the formula: wherein R is (a) C alkyl, (b) C cycloalkyl, (c) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms, or (d) C aryl (said C aryl is optionally substituted 6-10 6-10 by 1, 2 or 3 substituents selected from the group consisting (i) halogen, (ii) C alkyl, (iii) haloC alkyl, (iv) C alkoxy, and (v) haloC alkoxy), and m1 is 0, 1, 2 or 3 and, when m1 is 2 or 3, each R is selected independently, excluding 4,6-bis-(2,5-dimethyl-phenyl)-1,3,5-triazinol.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring Cy is the formula: 1 2 4 wherein R , R and R are as defined in claim 1.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring Cy is the formula: 1 3 4 wherein R , R and R are as defined in claim 1.
4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X is CH.
5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X is N.
6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R is (1) chloro, (2) methyl, (3) cyano or (4) trifluoromethyl.
7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
8. The compound according to any one of claims 1, 2 and 4 to 7 or a pharmaceutically acceptable salt thereof, wherein R -(CnH2n)-R (n is 1 or 2, -(CnH2n)- may be straight or branched chain, and R is b1 b2 (a) -C(O)NR R , b5 b6 b7 (b) -NR C(O)NR R , b10 b11 (c) -NR S(O)2R or b14 b15 (d) -NR C(O)R b1 b2 b5 b6 b7 b10 b11 b14 b15 (R , R , R , R , R , R , R , R , and R are as defined in claim 1)).
9. The compound according to claim 8 or a pharmaceutically 2 b b acceptable salt thereof, wherein R is -CH -R (R is as defined in claim 8).
10. The compound according to any one of claims 1 and 3 to 9 or a pharmaceutically acceptable salt thereof, wherein R is (1) halogen, (2) hydroxy, (3) C alkyl or (4) -OR {R is C alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f) (a) halogen, (b) hydroxy, (c) C alkoxy, c1 c2 c1 c2 (d) -C(O)NR R (R and R are each independently hydrogen or C alkyl), (e) phenyl (said phenyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl), and (f) pyridyl (said pyridyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C alkyl, (iv) C alkoxy, and (v) haloC alkyl)}.
11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein m1 is 1, R is the formula: wherein R is as defined in claim 1.
12. A compound according to claim 1, selected from the following formulas: HO N CH O CH H C F H C N H C C H H C F H O N H C Cl H C F H O N C H HO N CH N F F H O N O C H N F F H O N F O C H N CH N CH N CH HO N O CH HO N CH N CH HO CH N C H N N O N CH or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 1 having the following formula: or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 1 having the following formula: or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 having the following formula: N N O N CH or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 1 having the following formula: or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 1 having the following formula:
18. A compound according to claim 1 having the following formula:
19. A compound according to claim 1 having the following formula:
20. A compound according to claim 1 having the following formula:
21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. An mPGES-1 inhibitor comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
23. A therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer’s disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma or cancer, comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
24. A therapeutic or prophylactic agent for glaucoma or ocular hypertension, comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and one or more kinds of other therapeutic agents for glaucoma in combination.
25. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for the production of an mPGES-1 inhibitor.
26. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for the production of a therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer’s disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma or cancer.
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JP2014031035 2014-02-20
PCT/JP2015/054519 WO2015125842A1 (en) 2014-02-20 2015-02-19 Triazine compound and use thereof for medical purposes

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