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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • 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
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  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to saturated-ring-fused dihydropyrimidinone or dihydrotriazinone compounds, or pharmaceutically acceptable salts thereof, having ROR ⁇ antagonist activity, pharmaceutical compositions comprising the same, and pharmaceutical use thereof.
• ROR ⁇ i.e., Retinoid-related Orphan Receptor gamma
• ROR ⁇ t is also known as a splicing variant of ROR ⁇ (Non patent literature 1).
• ROR ⁇ and ROR ⁇ t differ only in their N-terminal domains and share the same ligand-binding domain and DNA-binding domain. It is reported that ROR ⁇ is expressed in other tissues besides Th17 cells (Non Patent Literature 1).
• IL-17 produced in Th17 cells is involved in the induction of a variety of chemokines, cytokines, metalloproteases, and other inflammatory mediators and the migration of neutrophil, and therefore, inhibition of IL-17 may lead to inhibit such induction and migration (Non Patent Literatures 2 and 3).
• Th17 cells are involved in autoimmune diseases (such as rheumatoid arthritis, psoriasis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, systemic lupus erythematosus (SLE), Behcet's disease, sarcoidosis, Harada disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, graft-versus-host disease, alopecia areata, and vitiligo), allergic diseases, dry eye, fibrosis (such as lung fibrosis and primary biliary cirrhosis), and cancers (such as malignant melanoma and prostate cancer).
• autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, systemic lupus erythematos
• ROR ⁇ in adipose tissues is related to the regulation of adipogenesis and inhibition of ROR ⁇ can ameliorate insulin resistance (Non Patent Literature 4). It is known that adipose tissues are involved in metabolic diseases (such as hepatic steatosis).
• IL-17 and Th17 cells are involved in ischemia, cardiomyopathy, hypertension, and periodontitis.
• Non Patent Literature 5 it is reported that administration of anti-IL-17 antibody can ameliorate swelling and joint destruction associated with collagen-induced arthritis. It is also reported that swelling and joint destruction associated with collagen-induced arthritis can be ameliorated in experiments using IL-17-deficient mice (Non Patent Literature 6).
• Non Patent Literature 7 As for psoriasis, it is reported that administration of anti-IL-17 antibody is effective in treating psoriasis in clinical trials (Non Patent Literature 7). Anti IL-17 antibodies have been placed on the market for use in psoriasis (Non Patent Literature 8).
• Non Patent Literature 9 As for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, adaptive transfer of T cells derived from ROR ⁇ -KO mice does not increase IL-17 in the mucosa in a colitis model induced by the adaptive transfer of T cells, thereby the onset of colitis can be inhibited (Non Patent Literature 9). It is also reported that an anti-IL-23 antibody, an antibody against IL-23 which activates Th17 cells, was effective in treating Crohn's disease in clinical trials (Non Patent Literature 20).
• Non Patent Literature 10 the disease state of a mouse experimental autoimmune encephalomyelitis model which is an animal model of multiple sclerosis can be inhibited in ROR ⁇ -KO mice. It is also reported that an anti-IL-17A antibody can ameliorate MRI observation in relapsing remitting multiple sclerosis in clinical trials (Non Patent Literature 21).
• Non Patent Literature 11 As for systemic lupus erythematosus, it is reported that administration of anti-IL-17 antibody can inhibit onset of GBM nephritis model in ROR ⁇ t-KO mice which is an animal model of glomerulonephritis. Administration of anti-IL-17 antibody potentially inhibits nephritis associated with SLE as well (Non Patent Literature 12).
• Non Patent Literature 13 As for ankylosing spondylitis, it is reported that administration of anti-IL-17 antibody is effective in treating ankylosing spondylitis (Non Patent Literature 13).
• Non Patent Literature 7 As for uveitis, it is reported that administration of anti-IL-17 antibody is effective in treating uveitis associated with Behcet's disease, sarcoidosis, and Harada disease (Non Patent Literature 7).
• Non Patent Literature 14 As for type I diabetes, administration of anti-IL-17 antibody can inhibit progression of disease states in a NOD mouse model which is a type I diabetes model. Efficacy of anti-IL-17A antibody is currently assessed in clinical trials (Non Patent Literature 22).
• Non Patent Literature 19 As for graft-versus-host disease, it is reported that transfection of ROR ⁇ -KO-mouse-derived cells can ameliorate survival rates and rejections in a host in a mouse transplant model (Non Patent Literature 19).
• Non Patent Literature 25 As for alopecia areata, efficacy of anti-IL-17A antibody is currently assessed in clinical trials (Non Patent Literature 25).
• Non Patent Literature 34 As for vitiligo, increases of IL-17 and Th17 cells are recognized in patient sera and pathological tissues, respectively.
• Non Patent Literature 15 As for allergic diseases such as asthma, attenuated eosinophilic pulmonary inflammation, the reduced number of CD4+ lymphocytes, and the decrease of Th2 cytokines/chemokines levels are exhibited in ROR ⁇ -KO mice in an OVA-sensitized model, which then allergic reactions 21 can be inhibited (Non Patent Literature 15). Efficacy of anti-IL-17A antibody is currently assessed in clinical trials for atopic dermatitis (Non Patent Literature 23). Efficacy of anti-IL-23 antibody is currently assessed in clinical trials for asthma (Non Patent Literature 24).
• administering can inhibit inflammation and fibrosis in lung and extend survival of animals in a bleomycin-induced lung fibrosis model which is an animal model of lung fibrosis (Non Patent Literature 17).
• Non Patent Literature 18 As for primary biliary cirrhosis, it is reported that Th17 cells increase in the lesion area of patients with primary biliary cirrhosis, and efficacy of anti-IL-23 antibody is currently assessed in clinical trials (Non Patent Literature 18).
• Non Patent Literatures 26 and 27 As for malignant melanoma, efficacy of anti-TL-17 antibody is currently assessed in clinical trials (Non Patent Literatures 26 and 27).
• Non Patent Literature 29 As for hepatic steatosis, it is recognized that anti-IL-17 antibody ameliorated steatosis on pathological tissues in an alcoholic liver-disease model (Non Patent Literature 29).
• Non-alcoholic fatty liver disease As for non-alcoholic fatty liver disease, it is recognized that anti-IL-17 antibody treatment improved liver function, attenuated hepatic lipid accumulation, suppressed Kupffer cells activation, and decreased pro-inflammatory cytokines levels in a high fat diet-induced non-alcoholic fatty liver disease model (Non Patent Literature 30).
• Non Patent Literature 31 As for ischemia and cardiomyopathy, it is reported that IL-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. It is recognized that anti-IL-17A antibody treatment or IL-17A knockout reduced infarct size, improved cardiac function, and thus, ameliorated ischemia/reperfusion injury (Non Patent Literature 31).
• Non Patent Literature 32 As for hypertension, it is reported that treatment with antibody against IL-17A or IL-17RA suppressed increased blood pressure by administration of angiotensin II (Non Patent Literature 32).
• ROR ⁇ antagonists are deemed to be beneficial for preventing or treating autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers (such as malignant melanoma and prostate cancer), metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• Non Patent Literature 1 JETTEN, “Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism”, Nucl. Recept. Signal., 7: e003 (2009).
• Non Patent Literature 2 KOENDERS, et al., “Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis”, Ann. Rheum. Dis., 65: iii29-33 (2006).
• Non Patent Literature 3 SCHMIDT-WEBER, et al., “Th17 cells in the big picture of immunology”, J. Allergy Clin. Immunol., 120: 247-54 (2007).
• Non Patent Literature 4 MEISSBURGER, et al., “Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma”, EMBO Mol. Med., 3: 637-51 (2011).
• Non Patent Literature 5 KELCHTERMANS et al., “Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon- ⁇ and counteraction by interferon- ⁇ ”, Arthritis Res. Ther., 11(4): R122 (2009).
• Non Patent Literature 6 NAKAE, et al., “Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice”, J. Immunol., 171: 6173-6177 (2003).
• Non Patent Literature 7 HUEBER et al., “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”, Sci. Transl. Med., 2(52): 52ra72 (2010).
• Non Patent Literature 9 LEPPKES, et al, “ROR ⁇ -Expressing Th17 Cells Induce MurineChronic Intestinal Inflammation via Redundant Effects of TL-17A and IL-17F”, Gastroenterology, 136(1): 257-267 (2009).
• Non Patent Literature 10 IVANOV et al., “The Orphan Nuclear Receptor ROR ⁇ t Directs the Differentiation Program of Proinflammatory IL-17+T Helper Cells”, Cell, 126(6): 1121-1133 (2006).
• Non Patent Literature 11 STEINMETZ et al., “The Th17-Defining Transcription Factor ROR ⁇ t Promotes Glomerulonephritis”, J. Am. Soc. Nephrol., 22(3): 472-483 (2011).
• Non Patent Literature 12 CRISPIN et al., “Interleukin-17-producing T cells in lupus”, Curr. Opin. Rheumatol., 22(5): 499-503 (2010).
• Non Patent Literature 13 BAETEN et al., “Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial”, Lancet, 382(9906): 1705-1713 (2013).
• Non Patent Literature 14 EMAMAULLEE et al., “Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice”, Diabetes, 58: 1302-1311 (2009).
• Non Patent Literature 15 TILLEY, et al., “Retinoid-Related Orphan Receptor ⁇ Controls Immunoglobulin Production and Th1/Th2 Cytokine Balance in the Adaptive Immune Response to Allergen”, J. Immunol., 178: 3208-3218 (2007).
• Non Patent Literature 16 U.S. NATIONAL INSTITUTES OF HEALTH, “The Effects of a Single Intravenous Administration of Secukinumab (AIN457) or Canakinumab (ACZ885) in Dry Eye Patients”, ClinicalTrials.gov information for Clinical Trials Identifier NCT01250171 (Dec. 4, 2012).
• Non Patent Literature 17 M I et al., “Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF- ⁇ 1-Dependent and -Independent Mechanisms”, J. Immunol., 187: 3003-3014 (2011).
• Non Patent Literature 18 U.S. NATIONAL INSTITUTES OF HEALTH, “A Study of Efficacy and Safety of Ustekinumab in Patients With Primary Biliary Cirrhosis (PBC) Who Had an Inadequate Response to Ursodeoxycholic Acid”, ClinicalTrials.gov information for Clinical Trials Identifier NCT01389973 (Apr. 2, 2015).
• Non Patent Literature 19 FULTON et al., “Attenuation of Acute Graft-versus-Host Disease in the Absence of the Transcription Factor ROR ⁇ t”, J. Immunol., 189(4): 1765-1772 (2012).
• Non Patent Literature 20 Brian G Feagan et al., “Induction therapy with the selective interleukin-23 inhibitor risankizuab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study”, The Lancet, 389(10080): 1699-1709 (2017).
• Non Patent Literature 21 Eva Havrdova et al., “Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-23 concept study”, J. Neurol., 263(7): 1287-1295 (2016).
• Non Patent Literature 22 U.S. NATIONAL INSTITUTES OF HEALTH, “Study of Secukinumab in Patients With Newly-diagnosed Type 1 Diabetes Mellitus”, ClinicalTrials.gov information for Clinical Trials Identifier NCT02044848.
• Non Patent Literature 23 U.S. NATIONAL INSTITUTES OF HEALTH, “Secukinumab for Treatment of Atopic Dermatitis”, ClinicalTrials.gov information for Clinical Trials identifier NCT02594098.
• Non Patent Literature 24 U.S. NATIONAL INSTITUTES OF HEALTH, “Efficacy and Safety of BI 655066/ABBV-066 (Risankizumab) in Patients With Severe Persistent Asthma”, ClinicalTrials.gov information for Clinical Trials Identifier NCT02443298.
• Non Patent Literature 25 U.S. NATIONAL INSTITUTES OF HEALTH, “A Study of Secukinumab for the Treatment of Alopecia Areata”, ClinicalTrials.gov information for Clinical Trials Identifier NCT02599129.
• Non Patent Literature 26 U.S. NATIONAL INSTITUTES OF HEALTH, “An Open-Label, Proof-of-Concept Study of Ixekizumab in the Treatment of Pyoderma Gangrenosum”, ClinicalTrials.gov information for Clinical Trials Identifier NCT03137160.
• Non Patent Literature 27 U.S. NATIONAL INSTITUTES OF HEALTH, “Single-arm Study to Assess a Potential Effect of Anti-IL-17 (Secukinumab) in the Treatment of Pyoderma Gangrenosum”, ClinicalTrials.gov information for Clinical Trials Identifier NCT02733094.
• Non Patent Literature 28 Q Zhang et al., “Targeting Th17-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model”, Prostate, 77(8): 888-899 (2017).
• Non Patent Literature 29 W Shi et al., “Anti-IL-17 Antibody Improves Hepatic Steatosis by Suppressing Interleukin-17-Related Fatty Acid Synthesis and Metabolism”, Clin. Dev. Immunol., Volume 2013, Article ID 253046 (2013).
• Non Patent Literature 30 R Xu et al., “Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice”, Acta Biochim. Biophys. Sin. (Shanghai), 45(9): 726-733 (2013).
• Non Patent Literature 31 Y. H. Lial et al., “Interleukin-17A Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Cardiomyocyte Apoptosis and Neutrophil Infiltration”, J. Am. Coil. Cardiol. 59(4): 420-429 (2012).
• Non Patent Literature 32 M. A. Saleh et al., “Inhibition of Interleukin 17-A but not Interleukin-17F Signaling Lowers Blood Pressure and Reduces End-organ Inflammation in Angiotensin II-induced Hypertension”, JACC Basic Transl. Sci. 1(7): 606-616 (2016).
• Non Patent Literature 33 N. Dutzan et al., “A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans”, Sci. Transl. Med. 10(463): eaat0797 (2016).
• Non Patent Literature 34 R Speeckaert et al., “The many faces of interleukin-17 in inflammatory skin diseases”, Br. J. Dermatol. 175(5): 892-901 (2016).
• the present invention provides saturated-ring-fused dihydropyrimidinone or dihydrotriazinone compounds, or pharmaceutically acceptable salts thereof, having ROR ⁇ antagonist activity, pharmaceutical compositions comprising the same, and their medical use.
• One aspect of the present invention includes the following illustrative embodiments.
• R 1 is (1) C 1-8 alkyl, (2) halo-C 1-8 alkyl, (3) C 3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from Group A 1 , or (4) C 3 -A cycloalkyl-C 1-4 alkyl wherein the C 3-8 cycloalkyl moiety may be optionally substituted with the same or different 1 to 3 substituents selected from Group A,
• each variable is defined as defined in Item 1, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound according to any one of Items 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• An ROR ⁇ antagonist comprising a compound according to any one of Items 1 to 12 or a pharmaceutically acceptable salt thereof.
• a therapeutic or preventive agent for a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising a compound according to any one of Items 1 to 12 or a pharmaceutically acceptable salt thereof.
• a compound according to any one of Items 1 to 12 or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic or preventive agent for a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• [Item 22]A commercial package comprising a pharmaceutical composition according to Item 13 and a package insert concerning the pharmaceutical composition describing that the pharmaceutical composition can be used for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• kits comprising a pharmaceutical composition according to Item 13 and a package insert concerning the pharmaceutical composition describing that the pharmaceutical composition can be used for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• halogen includes fluoro, chloro, bromo, and iodo.
• a preferable “halogen” is fluoro, chloro, or bromo.
• C 1-4 alkyl means a straight- or branched-chain saturated hydrocarbon group with 1 to 4 carbon atoms.
• the “C 1-4 alkyl” group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
• C 1-8 alkyl means a straight- or branched-chain saturated hydrocarbon group with 1 to 8 carbon atoms.
• the “C 1-8 alkyl” group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2-ethylbutyl, n-heptyl, 5-methylhexyl, 4-methylhexyl, 4,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 2,3-dimethylpenty
• C 1-8 alkylene means a divalent group derived from straight- or branched-chain saturated hydrocarbon with 1 to 8 carbon atoms.
• the “C 1-8 alkylene” group includes, for example, the following groups:
• halo-C 1-4 alkyl means the “C 1-4 alkyl” group substituted with 1 to 5 halogen atoms independently selected from the group of the term “halogen”.
• the “halo-C 1-4 alkyl” group includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, and 4,4,4-trifluorobutyl.
• halo-C 1-8 alkyl means the “C 1-9 alkyl” group substituted with 1 to 9 halogen atoms independently selected from the group of the term “halogen”.
• the “halo-C 1-8 alkyl” group includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4,4-trifluorobutyl, 5-fluoropentyl, 5,5,5-trifluoropentyl, 4,4,5,5,5-pentafluoropentyl, 3,3,4,4,5,5,5-heptaflu
• cyano-C 1-4 alkyl means the “C 1-4 alkyl” group substituted with one cyano group.
• the “cyano-C 1-4 alkyl” group includes, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 4-cyanobutyl, and 2-cyano-2-methylpropyl.
• C 1-4 alkoxy means those which the “C 1-4 alkyl” group binds to an oxygen atom and the group binds to another group via the oxygen atom.
• the “C 1-4 alkoxy” group includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
• C 3-8 cycloalkyl means a monocyclic saturated hydrocarbon group with 3 to 8 carbon atoms.
• the “C 3-8 cycloalkyl” group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• C 3-8 cycloalkyl-C 1-4 alkyl means the “C 1-4 alkyl” group substituted with one cycloalkyl group selected from the group of the “C 3-8 cycloalkyl”.
• the “C 3-8 cycloalkyl-C 1-4 alkyl” group includes, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 2-cyclooctylethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 1-cycloheptylethyl, 1-cyclo
• C 3-8 cycloalkylene means a divalent group derived from a monocyclic saturated hydrocarbon group with 3 to 8 carbon atoms.
• the “C 3-8 cycloalkylene” group includes, for example, the following groups:
• bridged C 5-8 cycloalkylene means a divalent group derived from a bridged cyclic saturated hydrocarbon group with 5 to 8 carbon atoms.
• the “bridged C 5 -s cycloalkylene” group includes, for example, the following groups:
• C 6-14 aryl means an aromatic hydrocarbon group with 6 to 14 carbon atoms.
• the “C 6-14 aryl” group includes, for example, phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthryl, and pentalenyl.
• C 6-14 aryl-C 1-4 alkyl means the “C 1-4 alkyl” group substituted with one aryl group selected from the group of the “C 6-14 aryl”.
• the “C 6-14 aryl-C 1-4 alkyl” group includes, for example, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, anthracen-1-ylmethyl, anthracen-2-ylmethyl, and anthracen-9-ylmethyl.
• C 6-14 arylene means a divalent group derived from an aromatic hydrocarbon group with 6 to 14 carbon atoms.
• the “C 6-14 arylene” group includes, for example, the following groups:
• C 3-8 cycloalkyl optionally substituted with the same or different 1 to 3 substituents selected from Group A 1 ” in R 1 means unsubstituted C 3-8 cycloalkyl or a group where any of replaceable hydrogen atoms in C 3-8 cycloalkyl are substituted with the same or different 1 to 3 substituents selected from Group A 1 , i.e., the group consisting of (1) halogen, (2) C 1-4 alkyl, and (3) halo-C 1-4 alkyl.
• a substituted C 3-8 cycloalkyl group includes, for example, the following groups:
• Compound [I] is a compound of Formula [IT]:
• Embodiments of partial structures and substituents of Compound [I] and Compound [II] are illustrated as below, but each partial structure or substituent of Compound [I] and Compound [II] is not limited to those embodiments; Compound [II] and Compound [II] include any combinations of two or more embodiments optionally selected from the embodiments in each partial structure or substituent.
• a preferable structure is any of the following partial structures:
• a more preferable one is any of the following partial structures:
• a further preferable one is any of the following partial structures:
• a preferable structure is any of the following partial structures:
• a more preferable one is any of the following partial structures:
• a further preferable one is any of the following partial structures:
• Such a partial structure means either of the following partial structures:
• a preferable one is any of the following partial structures:
• a more preferable one is any of the following partial structures:
• a further preferable one is any of the following partial structures:
• R 1 is preferably C 1-8 alkyl, or C 3-8 cycloalkyl substituted with the same or different 1 to 3 substituents selected from Group A 1 , and is more preferably C 1-8 alkyl.
• Group A 1 is preferably halogen and C 1-4 alkyl.
• X 1 is preferably a bond.
• a partial structure of —X 1 —R 1 is preferably any one of the following structures:
• R 2 is preferably halogen and more preferably chloro.
• R 3 is preferably —Y 3 —COO—R 30 .
• Y 3 is preferably C 1-8 alkylene, C 1-8 cycloalkylene, or bridged C 5-8 cycloalkylene, and more preferably C 3-8 cycloalkylene or bridged C 5-8 cycloalkylene.
• C 1-8 alkylene in Y 3 is preferably any one of the following groups:
• C 3-8 cycloalkylene in Y 3 is preferably the following group:
• Bridged C 5-8 cycloalkylene in Y 3 is preferably any one of the following groups:
• C 6-14 arylene in Y 3 is preferably the following group:
• R 30 is preferably hydrogen or ethyl, and more preferably hydrogen.
• R 4 is preferably hydrogen or methyl, and more preferably hydrogen.
• R 5 and R 6 are preferably each independently hydrogen, C 1-4 alkyl, cyano-C 1-4 alkyl, or C 1-4 alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —COO—R 52 , —N(R 71 ) (R 72 ), —CO—N(R 73 ) (R 74 ), —N(R 75 ) —CO—R 62 , and —O—S(O) 2 —R 63 and are more preferably each independently hydrogen or C 1-4 alkyl.
• R 5 and R 6 are selected from the following options:
• (A) both are hydrogen; (B) one is hydrogen and the other is C 1-4 alkyl, preferably methyl; (C) both are C 1-4 alkyl, preferably methyl for both; (D) one is hydrogen and the other is cyano-C 4 alkyl, preferably cyanomethyl; or (E) one is hydrogen and the other is C 1-4 alkyl, preferably methyl or ethyl, substituted with one substituent selected from the group consisting of —O—R 51 , —COO—R 52 , —N(R 71 ) (R 72 ), —CO—N(R 73 )(R 74 ), —N(R 75 ) —CO—R 62 , and —O—S(O) 2 —R 63 .
• R 7 and R 8 are preferably each independently hydrogen, halogen, cyano, C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkyl substituted with —O—R 51 , and more preferably, both of them are hydrogen.
• R 7 and R 8 are selected from the following options:
• both are hydrogen;
• both are halogen, preferably fluoro for both;
• C both are C 1-4 alkyl, preferably methyl for both; or
• R 9 and R 10 are preferably each independently hydrogen or C 1-4 alkyl, and more preferably, both of them are hydrogen.
• R 9 and R 10 are selected from the following options:
• X 2 is ⁇ N— and R 3 is hydrogen.
• X 2 is ⁇ C(R 4 )— and R 3 is —Y 3 —COO—R 3 .
• pharmaceutically acceptable salt may be any salts without excess toxicity known in the art. Specifically, it includes, for example, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases.
• salts with inorganic acids include, for example, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases.
• Various forms of pharmaceutically acceptable salts are well known in the art and are listed, for example, in the following references:
• Compound [I] may be reacted with an inorganic acid, organic acid, inorganic base, or organic base to give each pharmaceutically acceptable salt thereof.
• Such salts with inorganic acids include, for example, salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid.
• Preferable salts include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.
• Such salts with organic acids include, for example, salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, camphor acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycollylarsanilic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galacta
• Preferable salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.
• Such salts with inorganic bases include, for example, salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium.
• Preferable salts include salts with sodium, potassium, calcium, magnesium, and zinc.
• Such salts with organic bases include, for example, salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, and lysine.
• Preferable salts include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, and lysine.
• a preferable “pharmaceutically acceptable salt” includes hydrochloride and sodium salt.
• Compound [I] or a pharmaceutically acceptable salt thereof may exist in a solvate form.
• solvate means Compound [I] or a pharmaceutically acceptable salt thereof coordinate with a solvent molecule and includes a hydrate.
• a solvate is preferably a pharmaceutically acceptable solvate and includes hydrates, ethanolates, and solvates with dimethylsufoxide of Compound [I] or a pharmaceutically acceptable salt thereof.
• such a solvate includes a hemihydrate, monohydrate, dihydrate, or monoethanolate of Compound [I], or a monohydrate of a hydrochloride salt of Compound [I] or a 2/3 ethanolate of a dihydrochloride salt thereof.
• Such a solvate may be obtained according to known methods.
• Compound [I] or a pharmaceutically acceptable salt thereof may exist in its tautomeric form. Such Compound [I] or a pharmaceutically acceptable salt thereof may exist in each tautomeric form or in the form of a mixture of its tautomers.
• Compound [I] or a pharmaceutically acceptable salt thereof may have stereoisomers recognized as cis/trans isomers. Such Compound [I] or a pharmaceutically acceptable salt thereof may exist in its cis or trans form, or in the form of a mixture of its cis and trans isomers.
• Compound [I] or a pharmaceutically acceptable salt thereof may have one or more asymmetric carbon atoms. Such Compound [I] or a pharmaceutically acceptable salt thereof may exist in a single enantiomeric form or a single diastereomeric form, or in the form of a mixture of its enantiomers or diastereomers.
• Compound [I] or a pharmaceutically acceptable salt thereof may exist in its atropisomeric form. Such Compound [I] or a pharmaceutically acceptable salt thereof may exist in each atropisomeric form or in the form of a mixture of its atropisomers.
• Compound [I] or a pharmaceutically acceptable salt thereof may simultaneously comprise multiple structural features responsible for the above isomers.
• Compound [I] or a pharmaceutically acceptable salt thereof may comprise the above isomers in any ratios.
• a diastereomeric mixture may be separated into each diastereomer by conventional methods such as chromatography and crystallization.
• Each diastereomer may also be prepared with a stereochemically-single starting material or by synthetic methods with stereoselective reactions.
• An enantiomeric mixture may be separated into each single enantiomer by methods well known in the art.
• an enantiomeric mixture may be reacted with a substantially pure enantiomer that is known as a chiral auxiliary to form a diastereomeric mixture, followed by separation from the diastereomeric mixture by ordinary methods such as fractional crystallization and chromatography to give a single diastereomer with an enhanced isomeric ratio or a substantially pure single diastereomer. Then, the separated diastereomer may be converted into a desired enantiomer by removal of the added chiral auxiliary in a cleavage reaction.
• An enantiomeric mixture may also be directly separated into each enantiomer by chromatography methods with a chiral stationary phase well known in the art.
• either of enantiomers may be obtained with a substantially-pure optically-active starting material or by stereoselective synthesis, i.e., asymmetric induction, for a prochiral intermediate with a chiral auxiliary or asymmetric catalyst.
• Absolute configurations may be determined by X-ray crystallography for crystalline products or intermediates. Crystalline products or intermediates derivatized with a reagent with a known configuration and an asymmetric center may optionally be used in the determination.
• Compound [I] or a pharmaceutically acceptable salt thereof may be labelled with an isotope atom such as 1 H, 3 H, 14 C, and 35 S.
• the ethyl group includes —CD 2 CD 3 and —CT 2 CT 3 besides —CH 2 CH 3 .
• Compound [I], or a pharmaceutically acceptable salt thereof is preferably Compound [I], or a pharmaceutically acceptable salt thereof, substantially purified. More preferable one is Compound [I], or a pharmaceutically acceptable salt thereof, having 80% or more of purity.
• a pharmaceutical composition herein may be prepared by, for example, mixing Compound [1] or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carrier(s) in an appropriate amount.
• the content (also referred to as “a therapeutically effective amount” herein) of Compound [I] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies depending on dosage forms and doses and is, for example, 0.1 to 100% by weight of the composition.
• a dosage form of Compound [I] or a pharmaceutically acceptable salt thereof includes an oral preparation such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions and a parenteral preparation such as external preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.
• an oral preparation such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions
• a parenteral preparation such as external preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.
• pharmaceutically acceptable carrier includes various conventional organic or inorganic carrier substances for formulation materials such as excipients, disintegrants, binders, fluidizers, and lubricants in solid formulations; solvents, solubilizing agents, suspending agents, tonicity agents, buffers, and soothing agents in liquid formulations; and bases, emulsifying agents, wetting agents, stabilizers, stabilizing agents, dispersants, plasticizers, pH regulators, absorption promoters, gelators, preservatives, fillers, solubilizers, solubilizing agents, and suspending agents in semisolid formulations.
• a preserving agent, an antioxidant agent, a colorant, or a sweetening agent may also be optionally used as an additive.
• Such an “excipient” includes, for example, lactose, white soft sugar, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and gum arabic.
• Such a “disintegrant” includes, for example, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose.
• Such a “binder” includes, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, white soft sugar, dextrin, starch, gelatin, carmellose sodium, and gum arabic.
• Such a “fluidizer” includes, for example, light anhydrous silicic acid and magnesium stearate.
• Such a “lubricant” includes, for example, magnesium stearate, calcium stearate, and talc.
• Such a “solvent” includes, for example, purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil, and olive oil.
• Such a “solubilizing agent” includes, for example, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.
• Such a “suspending agent” includes, for example, benzalkonium chloride, carmellose, hydroxypropyl cellulose, propyleneglycol, povidone, methylcellulose, and glyceryl monostearate.
• Such a “tonicity agent” includes, for example, glucose, D-sorbitol, sodium chloride, and D-mannitol.
• Such a “buffer” includes, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.
• Such a “soothing agent” includes, for example, benzyl alcohol.
• Such a “base” includes, for example, water, animal or vegetable oils such as olive oil, corn oil, arachis oil, sesame oil, and castor oil, lower alcohols such as ethanol, propanol, propylene glycol, 1,3-butylene glycol, and phenol, higher fatty acids and esters thereof, waxes, higher alcohols, polyalcohols, hydrocarbons such as white petrolatum, liquid paraffin, and paraffin, hydrophilic petrolatum, purified lanolin, absorptive ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose, synthetic polymers such as carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, and polyvinylpyrrolidone, propylene glycol, macrogol such
• Such a “preserving agent” includes, for example, ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
• Such an “antioxidant agent” includes, for example, sodium sulfite and ascorbic acid.
• Such a “colorant” includes, for example, food dye such as Food Red No. 2 and No. 3, and Food Yellow No. 4 and No. 5, and ⁇ -carotene.
• Such a “sweetening agent” includes, for example saccharin sodium, dipotassium glycyrrhizate, and aspartame.
• a pharmaceutical composition herein may be administered orally or parenterally such as locally, rectally, intravenously, intramuscularly, and subcutaneously to human as well as mammals other than human such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys.
• a dose may vary depending on subjects to be administered, diseases, symptoms, dosage forms, routes of administration, etc.
• the dose of Compound [I] the active ingredient, ranges generally from about 0.01 mg to about 1 g per day, which may be administered once or several times in a divided amount.
• kits for administration, treatment, and/or prevention a package such as packaged goods, and a set and/or case of medicine which comprises a pharmaceutical composition comprising Compound [I] or a pharmaceutically acceptable salt thereof as the active ingredient or active agent and a written matter concerning the composition indicating that the composition may or should be used for treatment and/or prevention are also useful.
• a kit, package, and set of medicine may comprise one or more containers filled with the pharmaceutical composition or one or more active ingredients and other drugs or medicines (or ingredients) used for the composition.
• Examples of such a kit, package, and set of medicine include commercial kits, commercial packages, and commercial medicine set for appropriate use in the treatment and/or prevention of intended diseases.
• kit, package, and set of medicine includes a cautionary note or package insert in the form designated by the government organization that regulates manufactures, use, or sales of pharmaceutical or biological products which ensures an approval by the government organization on manufactures, use, or sales of products concerning administration to humans.
• the kit, package, and set of medicine may include packaged products as well as structures configured for appropriate administration steps and configured so as to be able to achieve more preferable medical treatment and/or prevention including treatment and/or prevention of intended diseases.
• Compound [I] or a pharmaceutically acceptable salt thereof has ROR ⁇ antagonism and is useful for an ROR ⁇ antagonist.
• ROR ⁇ antagonist activity means that the function of ROR ⁇ is antagonized, preferably specifically antagonized, to disappear or reduce its activity, and includes, for example, antagonizing, preferably specifically antagonizing, the function of ROR ⁇ according to the conditions described in Test Example 1 below.
• ROR ⁇ antagonist means any substances that antagonize the function of ROR ⁇ , preferably any substances that specifically antagonize the function of ROR ⁇ .
• ROR ⁇ is preferably “human ROR ⁇ ”.
• Compound [I] or a pharmaceutically acceptable salt thereof has ROR ⁇ antagonism, and is expected to be effective against diseases that involve the function of ROR ⁇ .
• Compound [I] or a pharmaceutically acceptable salt thereof is expected to be useful for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease.
• autoimmune diseases means a generic name of diseases where an immune system of a subject overreacts to and attacks even normal cells and tissues thereof to cause symptoms, and includes, specifically, rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus (SLE), Behcet's disease, sarcoidosis, Harada disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, graft-versus-host disease, alopecia areata, and vitiligo.
• allergic diseases means diseases derived from the condition where an immune reaction excessively occurs against a certain antigen, and includes, specifically, atopic dermatitis, allergic rhinitis such as pollen allergy, allergic conjunctivitis, allergic gastroenteritis, asthma such as bronchial asthma and infantile asthma, food allergy, medication allergy, and hives.
• fibrosis means a condition with increased fibroconnective tissues, and includes, specifically, lung fibrosis and primary biliary cirrhosis.
• cancer includes malignant melanoma and prostate cancer.
• metabolic disease means a disease caused by abnormality of metabolic turnover or a disease which includes metabolic abnormality as an element that constitutes pathogenesis, and includes, for example, diabetes such as type I diabetes and type II diabetes, hepatic steatosis, and non-alcoholic fatty liver disease.
• treating also includes ameliorating symptoms, preventing from becoming severe, maintaining remission, preventing exacerbation, and preventing relapse.
• preventing means suppressing pathogenesis of symptoms.
• a general method of preparing Compound [I] or a pharmaceutically acceptable salt thereof is illustrated as below.
• a method of preparing Compound [I] or a pharmaceutically acceptable salt thereof is not intended to be limited thereto. Salts of each compound in the general method may be selected from the above “pharmaceutically acceptable salt” unless otherwise specified.
• Each compound obtained in each step may be isolated and/or purified by known methods such as distillation, recrystallization, and column chromatography, if necessary, but each reaction may optionally proceed to a sequential step without isolation and/or purification.
• the room temperature herein means a temperature under no control, and includes 1° C. to 40° C. as one embodiment.
• IPA Isopropyl alcohol Hex.: n-Hexane DMSO: Dimethyl sulfoxide NOE: Nuclear overhauser effect DsPhSO 3 N 3 : p-Dodecylbenzenesulfonylazide DMEAD: Di-2-methoxyethyl azodicarboxylate TBAI: Tetrabutylammonium iodide PPTS: Pyridinium p-toluenesulfonate
• DIBAL-H Diisobutylaluminum hydride TFA: Trifluoroacetic acid NaHMDS: Sodium bis(trimethylsilyl)amide
• HMDS Bis(trimethylsilyl)amine
• TEMPO 2,2,6,6-Tetramethylpiperidin-1-oxyl TBAF: Tetrabutylammonium fluoride
• Compound [I] wherein X 2 is ⁇ C(R 4 )—, or a salt thereof, may be obtained by, for example, the following Preparation method 1.
• R 1 , R 2 , R 3 , R 4 , X 1 , X 3 , X 4 , and X 5 are defined as defined above, and
• L 1 is halogen, for example, selected from chloro, bromo, and iodo.
• Compound [13] or a salt thereof may be prepared by reaction of Compound [11] with Compound [12] or a salt thereof in a solvent in the presence of an organometallic reagent and Lewis acid.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• hydrocarbon solvents such as toluene
• a mixed solvent of any of them etrahydrofuran.
• Such an organometallic reagent includes, for example, n-butyllithium and tert-butyllithium.
• a preferable organometallic reagent herein is n-butyllithium.
• Such Lewis acid includes a boron trifluoride-diethyl ether complex.
• the reaction temperature herein ranges, for example, from ⁇ 102° C. to ⁇ 69° C., preferably from ⁇ 78° C. to ⁇ 70° C.
• Compound [11] is commercially available or may be prepared by known methods from commercially available products.
• Compound [12] or a salt thereof may be prepared by, for example, any of Preparation methods 1A to 1R below.
• Compound [14] or a salt thereof may be prepared by reduction of Compound [13] or a salt thereof in a solvent in the presence of a metal reagent and an acid.
• Such a metal reagent includes, for example, zinc and iron.
• a preferable metal reagent herein is zinc.
• Such an acid includes, for example, acetic acid, trifluoroacetic acid, hydrochloric acid, and sulfuric acid.
• a preferable acid herein is acetic acid or hydrochloric acid.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; alcohol solvents such as methanol; water; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• alcohol solvents such as methanol
• water such as water
• a mixed solvent of any of them etrahydrofuran, methanol, or water.
• the reaction temperature herein ranges, for example, from 0° C. to 80° C., preferably from room temperature to 80° C.
• Compound [14] or a salt thereof may also prepared by hydrogenation of Compound [13] or a salt thereof in a solvent in the presence of a catalytic amount of palladium.
• a solvent includes, for example, ether solvents such as tetrahydrofuran; alcohol solvents such as ethanol; ester solvents such as ethyl acetate; and a mixed solvent of any of them.
• a preferable solvent herein is tetrahydrofuran, ethanol, or ethyl acetate.
• the reaction temperature herein is room temperature.
• Compound [16] or a salt thereof may be prepared by reaction of Compound [14] or a salt thereof with Compound [15] or a salt thereof in a solvent.
• Such a solvent includes, for example, hydrocarbon solvents such as toluene; ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• hydrocarbon solvents such as toluene
• ether solvents such as tetrahydrofuran
• halogenated solvents such as dichloromethane
• a mixed solvent of any of them includes, for example, hydrocarbon solvents such as toluene; ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• a preferable solvent herein is toluene, tetrahydrofuran, or dichloromethane.
• the reaction temperature herein ranges, for example, from 0° C. to 80° C., preferably from 0° C. to room temperature.
• the reaction may also be carried out with optional addition of triethylamine.
• Compound [I-1] or a salt thereof may be prepared by oxidation of Compound [16] or a salt thereof in a solvent in the presence of an oxidizing agent, followed by cyclization.
• Such a solvent includes, for example, halogenated solvents such as chloroform; ester solvents such as ethyl acetate; nitrile solvents such as acetonitrile; ether solvents such as cyclopentyl methyl ether; carboxylic acid solvents such as acetic acid; and a mixed solvent of any of them.
• a preferable solvent herein is dichloromethane, chloroform, cyclopentyl methyl ether, or acetic acid.
• Such an oxidizing agent includes, for example, 2-azaadamantan-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-oxyl radical, and Dess-Martin reagent.
• the reaction may also be carried out with optional addition of a co-oxidizing agent such as (diacetoxyiodo)benzene and sodium hypochlorite.
• a preferable oxidizing agent herein is a mixture of 2,2,6,6-tetramethylpiperidin-1-oxyl radical and (diacetoxyiodo)benzene.
• An acid in the cyclization includes hydrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
• a preferable acid herein is trifluoroacetic acid.
• the reaction temperature herein ranges, for example, from 0° C. to 80° C., preferably from 0° C. to room temperature.
• R 1 , R 2 , R 3 , X 1 , X 3 , X 4 , and X 5 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12a] or a salt thereof obtained in Preparation method 1A as follows, instead of Compound [12] or a salt thereof in Preparation method 1.
• X 3 , X 4 , and X 5 are defined as defined above.
• Compound [A2] or a salt thereof may be prepared by oxidation of Compound [A1] or a salt thereof in a solvent.
• Such a solvent includes, for example, ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; sulfoxide solvents such as dimethyl sulfoxide; ether solvents such as tetrahydrofuran; and halogenated solvents such as chloroform.
• ester solvents such as ethyl acetate
• hydrocarbon solvents such as toluene
• sulfoxide solvents such as dimethyl sulfoxide
• ether solvents such as tetrahydrofuran
• halogenated solvents such as chloroform.
• a preferable solvent herein is chloroform or dichloromethane.
• the oxidizing agent herein includes, for example, 2,2,6,6-tetramethypiperidin-1-oxyl radical, dimethyl sulfoxide, a sulfur trioxide-pyridine complex, iodoxybenzoic acid, pyridinium chlorochromate, and Dess-Martin reagent.
• a preferable oxidizing agent herein is 2,2,6,6-tetramethylpiperidin-1-oxyl radical.
• the reaction temperature herein ranges, for example, from ⁇ 78° C. to room temperature, preferably from 0° C. to room temperature.
• the reaction may also be carried out with optional addition of (diacetoxyiodo)benzene.
• Compound [A3] or a salt thereof may be prepared by reaction of Compound [A2] or a salt thereof with hydroxylamine hydrochloride in a solvent.
• Such a solvent includes, for example, alcohol solvents such as ethanol; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; ether solvents such as tetrahydrofuran; amide solvents such as dimethylformamide; nitrile solvents such as acetonitrile; water; and a mixed solvent of any of them.
• alcohol solvents such as ethanol
• hydrocarbon solvents such as toluene
• halogenated solvents such as dichloromethane
• ether solvents such as tetrahydrofuran
• amide solvents such as dimethylformamide
• nitrile solvents such as acetonitrile
• water and a mixed solvent of any of them.
• a preferable solvent herein is ethanol, toluene, tetrahydrofuran, or water.
• the reaction temperature herein ranges from room temperature to 120° C.
• the reaction may also be carried out with optional addition of sodium acetate.
• Compound [12a] or a salt thereof may be prepared by cyclization of Compound [A3] or a salt thereof in a solvent in the presence of an oxidizing agent.
• Such an oxidizing agent includes, for example, (diacetoxyiodo)benzene, sodium hypochlorite, chloramine T, and N-chlorosuccinimide.
• a preferable oxidizing agent herein is (diacetoxyiodo)benzene or sodium hypochlorite.
• an acid is used for an additive.
• an acid includes trifluoroacetic acid.
• a solvent used herein includes, for example, alcohol solvents such as methanol; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• a preferable solvent herein is methanol or dichloromethane.
• the reaction temperature herein ranges from 0° C. to room temperature.
• a base is used for an additive.
• a base includes, for example, triethylamine and pyridine.
• a preferable base herein is triethylamine.
• a solvent used herein includes, for example, halogenated solvents such as dichloromethane; alcohol solvents such as ethanol; nitrile solvents such as acetonitrile; ether solvents such as tert-butyl methyl ether; and a mixed solvent of any of them.
• a preferable solvent herein is dichloromethane.
• the reaction temperature herein ranges, for example, from 0° C. to room temperature and is preferably room temperature.
• R 1 , R 2 , R 3 , X 1 , and X 3 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12b] or a salt thereof obtained in Preparation method 1B as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• X 3 is defined as defined above, and
• G 1 is a protective group of carboxy, for example, selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl.
• Compound [B3] or a salt thereof may be prepared by reaction of Compound [B1] with Compound [B2] or a salt thereof in a solvent or without any solvents in the presence of a catalyst.
• Such a solvent includes, for example, halogenated solvents such as dichloromethane; ester solvents such as ethyl acetate; ether solvents such as diethyl ether; hydrocarbon solvents such as benzene; and a mixed solvent of any of them.
• halogenated solvents such as dichloromethane
• ester solvents such as ethyl acetate
• ether solvents such as diethyl ether
• hydrocarbon solvents such as benzene
• a mixed solvent of any of them e.g., no solvent or dichloromethane is preferable.
• Such a catalyst includes, for example, rhodium (II) acetate dimer dihydrate, indium (III) chloride, and iron (III) chloride.
• a preferable catalyst herein is rhodium (II) acetate dimer dihydrate.
• the reaction temperature herein is room temperature.
• Compound [B4] or a salt thereof may be prepared by reduction of Compound [B3] or a salt thereof in a solvent.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; hydrocarbon solvents such as toluene; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• halogenated solvents such as dichloromethane
• hydrocarbon solvents such as toluene
• a mixed solvent of any of them includes, for example, ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; hydrocarbon solvents such as toluene; and a mixed solvent of any of them.
• a preferable solvent herein is tetrahydrofuran, dichloromethane, or toluene.
• a reducing agent used herein includes, for example, diisobutylaluminum hydride, and lithium aluminum hydride.
• a preferable reducing agent herein is diisobutylaluminum hydride.
• the reaction temperature herein ranges, for example, from ⁇ 78° C. to room temperature, preferably from ⁇ 78° C. to 0° C.
• Compound [B5] or a salt thereof may be prepared from Compound [B4] or a salt thereof in a similar manner to Step 1A-2.
• Compound [12b] or a salt thereof may be prepared from Compound [B5] or a salt thereof in a similar manner to Step 1A-3.
• R 1 , R 2 , R 3 , X 1 , and X 3 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12c] or a salt thereof obtained in Preparation method 1C as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• X 3 and G 1 are defined as defined above.
• R 6D is C 1-4 alkyl
• R 7D and R OD are each independently hydrogen or C 1-4 alkyl
• R 1 , R 2 , R 3 , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12d] or a salt thereof obtained in Preparation method ID as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• G 1 , R 6D , R 7D , and R 6D are defined as defined above.
• R 1 , R 2 , R 3 , X 1 , X 3 , and X 4 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12e] or a salt thereof obtained in Preparation method 1E as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• X 3 and X 4 are defined as defined above.
• Compound [E3] may be prepared by reaction of Compound [E1] with Compound [E2] in a solvent in the presence of a base.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; alcoholic solvents such as methanol; amide solvents such as dimethylformamide; sulfoxide solvents such as dimethylsulfoxide; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• hydrocarbon solvents such as toluene
• alcoholic solvents such as methanol
• amide solvents such as dimethylformamide
• sulfoxide solvents such as dimethylsulfoxide
• a mixed solvent of any of them includes, for example, ether solvents such as tetrahydrofuran.
• Such a base includes, for example, sodium hydride, sodium hydroxide, sodium tert-butoxide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, and n-butyllithium.
• a preferable base herein is sodium hydride.
• the reaction temperature herein ranges, for example, from 0° C. to 14C° C., preferably from 0° C. to room temperature.
• Compound [E4] may be prepared by treatment of Compound [E3] in a solvent in the presence of an acid.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; halogen solvents such as dichloromethane; alcoholic solvents such as methanol; water; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• halogen solvents such as dichloromethane
• alcoholic solvents such as methanol
• water and a mixed solvent of any of them.
• a preferable solvent herein is tetrahydrofuran or water.
• Such an acid includes, for example, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, boron trifluoride-diethyl ether complex, trimethylsilyl iodide, iodine, and ion-exchange resin.
• a preferable acid herein is hydrochloric acid.
• the reaction temperature herein ranges, for example, from 0° C. to 120° C. and is preferably 60° C.
• Compound [E5] or a salt thereof may be prepared from Compound [E4] in a similar manner to Step 1A-2.
• Compound [12e] or a salt thereof may be prepared from Compound [E5] or a salt thereof in a similar manner to Step 1A-3.
• R 9F and R 10F are each independently hydrogen or C 1-4 alkyl
• R 1 , R 2 , R 3 , R 6D , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12f] or a salt thereof obtained in Preparation method 1F as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R 6D , R 9F , and R 00F are defined as defined above.
• R 1 , R 2 , R 3 , X 1 , X 3 , X 4 , and X 5 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12a] or a salt thereof obtained in Preparation method 1G as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R G1 and R G2 each independently C 1-4 alkyl, and X 3 , X 4 , and X 5 are defined as defined above.
• Compound [G3] or a salt thereof may be prepared by reaction of Compound [G1] or a salt thereof with Compound [G2] in a solvent in the presence of a base.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; sulfoxide solvents such as dimethyl sulfoxide; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• hydrocarbon solvents such as toluene
• sulfoxide solvents such as dimethyl sulfoxide
• a mixed solvent of any of them includes, for example, ether solvents such as tetrahydrofuran.
• Such a base includes sodium hydride and lithium diisopropylamide.
• the reaction temperature herein ranges, for example, from ⁇ 78° C. to 110° C., preferably from ⁇ 78° C. to 65° C.
• the reaction may also be carried out with optional addition of 18-crown-6-ether.
• Compound [G5] or a salt thereof may be prepared by protection of a carbonyl group of Compound [G3] or a salt thereof with Compound [G4] in a solvent in the presence of an acid.
• Such a solvent includes, for example, hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; nitrile solvents such as acetonitrile; and a mixed solvent of any of them.
• hydrocarbon solvents such as toluene
• halogenated solvents such as dichloromethane
• nitrile solvents such as acetonitrile
• a mixed solvent of any of them includes, for example, hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; nitrile solvents such as acetonitrile; and a mixed solvent of any of them.
• a preferable solvent herein is toluene.
• Such an acid includes, for example, p-toluenesulfonic acid and pyridinium p-toluenesulfonate.
• a preferable acid herein is p-toluenesulfonic acid.
• the reaction temperature herein ranges, for example, from room temperature to 120° C., preferably from 100° C. to 120° C.
• Compound [G6] or a salt thereof may be prepared by reduction of Compound [G5] or a salt thereof in a solvent.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• hydrocarbon solvents such as toluene
• halogenated solvents such as dichloromethane
• a mixed solvent of any of them includes, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• a preferable solvent herein is tetrahydrofuran or toluene.
• a reducing agent used herein includes, for example, lithium aluminum hydride and diisobutylaluminum hydride.
• a preferable reducing agent herein is diisobutylaluminum hydride.
• the reaction temperature herein ranges, for example, from ⁇ 78° C. to 65° C., preferably from ⁇ 78° C. to room temperature.
• Compound [G8] or a salt thereof may be prepared by Mitsunobu reaction of Compound [G6] or a salt thereof with Compound [G7] in a solvent.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; hydrocarbon solvents such as toluene; and a mixed solvent of any of them.
• ether solvents such as tetrahydrofuran
• halogenated solvents such as dichloromethane
• hydrocarbon solvents such as toluene
• a mixed solvent of any of them includes, for example, ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; hydrocarbon solvents such as toluene; and a mixed solvent of any of them.
• a preferable solvent herein is tetrahydrofuran or dichloromethane.
• a reagent used in Mitsunobu reaction includes, for example, a mixture of triphenylphosphine or tributylphosphine with diethyl azodicarboxylate or dipiperidineamide azodicarboxylate.
• a preferable reagent used in Mitsunobu reaction is a mixture of triphenylphosphine with diethyl azodicarboxylate.
• the reaction temperature herein ranges, for example, from 0° C. to 80° C., preferably from 0° C. to room temperature.
• Compound [G9] or a salt thereof may be prepared by removal of a phthaloyl group of Compound [G8] or a salt thereof in a solvent.
• Such a solvent includes, for example, alcohol solvents such as ethanol; halogenated solvents such as dichloromethane; ether solvents such as diethyl ether; and a mixed solvent of any of them.
• alcohol solvents such as ethanol
• halogenated solvents such as dichloromethane
• ether solvents such as diethyl ether
• a mixed solvent of any of them e.g., ethanol or dichloromethane.
• a reagent used for removal of the phthaloyl group includes, for example, methylhydrazine, hydrazine, and ethanolamine.
• a preferable reagent used for removal of the phthaloyl group is methylhydrazine or hydrazine.
• the reaction temperature herein ranges, for example, from 0° C. to 100° C., preferably from room temperature to 100° C.
• Compound [12a] or a salt thereof may be prepared by removal of an acetal group of Compound [G9] or a salt thereof in a solvent in the presence of an acid, followed by intramolecular cyclization in the presence of a base.
• Such a solvent includes, for example, alcohol solvents such as methanol; ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• alcohol solvents such as methanol
• ether solvents such as tetrahydrofuran
• halogenated solvents such as dichloromethane
• a mixed solvent of any of them e.g., a solvent for example, alcohol solvents such as methanol; ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; and a mixed solvent of any of them.
• a preferable solvent herein is methanol or tetrahydrofuran.
• Such an acid includes, for example, hydrochloric acid, acetic acid, and p-toluenesulfonic acid.
• a preferable acid herein is hydrochloric acid or p-toluenesulfonic acid.
• Such a base includes, for example, potassium carbonate, sodium acetate, and triethylamine.
• a preferable base herein is potassium carbonate.
• the reaction temperature herein ranges, for example, from 0° C. to 120° C., preferably from 0° C. to room temperature.
• R 7H is C 1-4 alkyl
• R 1 , R 2 , R 3 , R 6D , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12h] or a salt thereof obtained in Preparation method 1H as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R 6D , R 7H , and G 1 are defined as defined above.
• R 1 , R 2 , R 3 , R 6D , R 7H , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12i] or a salt thereof obtained in Preparation method 1I as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R 6D , R 7H , and G 1 are defined as defined above.
• R 41 is C 1-4 alkyl
• R 1 , R 2 , R 3 , X 1 , X 3 , X 4 , and X 5 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12j] or a salt thereof obtained in Preparation method 1J as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• X 3 , X 4 , X 5 , and R 4J are defined as defined above.
• R 6K is: (1) halo-C 1-4 alkyl, (2) cyano-C 1-4 alkyl, or (3) C 1-4 alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —CO—R 61 , —COO—R 52 , —N(R 71 ) (R 72 ), —CO—N(R 73 ) (R 74 ), —N(R 75 ) —CO—R 62 , —N(R 76 ) —COO—R 53 , and —O—S(O) 2 —R 63 , and
• R 1 , R 2 , R 3 , X 1 , X 4 , and X 5 are defined as defined above, or a part of salts thereof, may be obtained by, for example, using Compound [12k] or a salt thereof obtained in Preparation method 1K as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1, or by converting a benzyl ether moiety of the resulting compound into various substituents.
• X 4 , X 5 , and G 1 are defined as defined above.
• R 1 , R 2 , R 3 , R 9 , R 10 , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12m] or a salt thereof obtained in Preparation method 1M as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R 9 and R 10 are defined as defined above.
• halo-C 1-4 alkyl (2) cyano-C 1-4 alkyl, or (3) C 1-4 alkyl substituted with one substituent selected from the group consisting of —O—R 51 , —CO—R 61 , —COO—R 52 , —N(R 71 ) (R 72 ), —CO—N(R 73 ) (R 74 ), —N(R 73 ) —CO—R 62 , —N(R 76 ) —COO—R 53 , and —O—S(O) 2 —R 63 , and X 4 is a bond (Compound [I-1N]):
• R 1 , R 2 , R 3 , R 6 , X 1 , and X 5 are defined as defined above, or a part of salts thereof, may be obtained by, for example, using Compound [12n] or a salt thereof obtained in Preparation method 1N as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1, or by converting a benzyl ether moiety of the resulting compound into various substituents.
• X 5 and G 1 are defined as defined above.
• R 1 , R 2 , R 3 , R 11 , X 1 , and X 3 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12p] or a salt thereof obtained in Preparation method 1P as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R 11 , X 3 , and G 1 are defined as defined above.
• Compound [P2] or a salt thereof may be prepared from Compound [P1] or a salt thereof in a similar manner to Step 1B-2.
• Compound [P3] or a salt thereof may be prepared from Compound [P2] or a salt thereof in a similar manner to Step 1A-2.
• Compound [12p] or a salt thereof may be prepared from Compound [P3] or a salt thereof in a similar manner to Step 1A-3.
• R 50 is C 1-4 alkyl
• R 1 , R 2 , R 3 , R 6D , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12q] or a salt thereof obtained in Preparation method 1Q as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• R 5Q and R 6D are defined as defined above.
• R 1 , R 2 , R 3 , X 1 , and X 1 are defined as defined above, or a salt thereof, may be obtained by, for example, using Compound [12r] or a salt thereof obtained in Preparation method 1R as follows, instead of Compound [12] or a salt thereof in the above Preparation method 1.
• X 3 and G 1 are defined as defined above.
• R 1 , R 2 , X 1 , and L 1 are defined as defined above, may be prepared by, for example, cross-coupling reaction of Compound [S1] shown as follows, when X 1 is a bond, R 1 is C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 3-8 cycloalkyl-C 1-4 alkyl (i.e., Compound [11s] or [11t]).
• R 2 and L 1 are defined as defined above,
• L 2 is halogen (e.g., iodo) or trifluoromethanesulfonyloxy,
• R 18 is C 1-8 alkyl, optionally substituted C 3-8 cycloalky, or optionally substituted C 3-8 cycloalkyl-C 1-4 alkyl,
• R W1 is boronic acid, boronic acid ester, or trifluoroborate
• R W2 is zinc, or zinc halide
• R 1T is C 2-9 alkyl, or optionally substituted C 3-8 cycloalkyl-C 2-4 alkyl, and
• R 100T is trimethylsilyl or a straight- or branched-chain saturated hydrocarbon with 1 to 6 carbon atoms.
• Such a cross-coupling reaction includes methods described in literatures such as F. Diederich, P. J. Stang (1998). Metal-catalyzed Cross-coupling Reactions, Weinheim, Germany, Wiley-VCH, which includes Suzuki coupling, Negishi coupling, and Sonogashira coupling.
• Compound [S1] is preferably a compound wherein L 1 is bromo and L 2 is iodo, more preferably a compound shown as follows.
• Compound [S2], Compound [S3], and Compound [S4] for example, commercially available products such as isobutylboronic acid, 1-hexylboronic acid pinacol ester, potassium (3,3-dimethylbutyl)trifluoroborate, butylzinc bromide, and cyclohexylacetylene may be used, or these compounds may be prepared from corresponding commercially available compounds with chloro, bromo, or iodo, such as 1-chloro-3,3-dimethyl-butane and bromomethyl-cyclohexane, according to known methods.
• commercially available products such as isobutylboronic acid, 1-hexylboronic acid pinacol ester, potassium (3,3-dimethylbutyl)trifluoroborate, butylzinc bromide, and cyclohexylacetylene may be used, or these compounds may be prepared from corresponding commercially available compounds with chloro, bromo, or io
• Compound [S2] wherein R W1 is boronic acid may be prepared by preparation of a Grignard reagent from commercially available compounds such as R 1 —Br and magnesium, followed by reaction with, for example, trimethyl borate or triisopropyl borate.
• Compound [S2] wherein R W1 is boronic acid ester may be prepared by, for example, reaction of a boronic acid compound with pinacol.
• Compound [S2] wherein R W1 is trifluoroborate may be prepared by, for example, reaction of a boronic acid compound with potassium hydrogen fluoride.
• Compound [S3] may be prepared from, for example, commercially available compounds such as R 1 —I and zinc.
• An activating agent for zinc includes iodine, trimethylsilyl chloride, and 1,2-dibromoethane, and these agents can be used alone or in combination with any two or more of them.
• a preferable activating agent is trimethylsilyl chloride or 1,2-dibromoethane.
• Compound [11t] may be obtained by catalytic hydrogenation of an alkynylene compound obtained in Sonogashira reaction with a catalyst such as palladium carbon, platinum carbon, and rhodium-alumina to convert into an alkyl compound.
• a catalyst such as palladium carbon, platinum carbon, and rhodium-alumina to convert into an alkyl compound.
• the solvent in each step includes tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.
• a preferable solvent herein is tetrahydrofura or N,N-dimethylacetamide.
• the reaction temperature in each step includes room temperature to 80° C.
• a preferable reaction temperature herein is room temperature.
• Compound [15] or a salt thereof may be a commercially available product such as ethyl 6-isocyanato-hexanoate, methyl 2-isocyanato-2-methyl-propionate, methyl 3-isocyanato-propionate, ethyl 3-isocyanato-propionate, methyl 4-isocyanato-cyclohexanecarboxylate, and ethyl 4-isocyanatobenzoate, or may also be obtained by, for example, Preparation method 1Z shown as follows.
• R 3 is defined as defined above.
• Compound [15] or a salt thereof may be prepared by azidation reaction of Compound [Z1] such as a commercially available product such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-(methoxycarbonyl)bicyclo[2.1.1]pentane-1-carboxylic acid, 1-(2-methoxy-2-oxcethyl)-5-oxopyrrolidine-3-carboxylic acid, and 3-[1-(ethoxycarbonyl)cyclopropyl]propanoic acid, or a salt thereof, in the presence of a base in a solvent, followed by Curtius rearrangement.
• a commercially available product such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-(methoxycarbonyl)bicyclo[2.1.1]pentane-1-carboxylic acid, 1-(2-methoxy-2-oxcethy
• Such a solvent includes, for example, benzene, toluene, xylene, tetrahydrofuran, and a mixed solvent of any of them.
• a preferable solvent herein is toluene.
• the azidation agent herein includes, for example, diphenylphosphoryl azide.
• Such a base includes, for example, triethylamine and diisopropylethylamine.
• a preferable base herein is triethylamine.
• the reaction temperature herein ranges, for example, from 0° C. to 140° C., preferably from 100° C. to 120° C.
• Compound [I-1] wherein R 30 is hydrogen may be obtained by preparation of Compound [I-1] wherein R 30 is C 1-4 alkyl from the aforementioned Compound [15] or a salt thereof in Preparation method 1, followed by hydrolysis under known methods.
• Compound [I] wherein X 2 is ⁇ N—, X 3 is —C(R 5 ) (R 6 )—, R 3 is hydrogen, and R 5 is hydrogen (Compound [I-2A]), or a salt thereof, may be obtained by, for example, Preparation method 2 as follows.
• R 1 , R 2 , R 6 , X 1 , X 4 , X 5 , and L 1 are defined as defined above.
• Compound [22] or a salt thereof may be prepared by oxidation of Compound [21] or a salt thereof in a solvent.
• a solvent includes, for example, ether solvents such as tetrahydrofuran; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; nitrile solvents such as acetonitrile; and a mixed solvent of any of them.
• a preferable solvent herein is dichloromethane.
• An oxidizing agent used herein includes, for example, sulfur trioxide-pyridine complex, dimethyl sulfoxide, pyridinium chlorochromate, and Dess-Martin reagent.
• a preferable oxidizing agent herein is sulfur trioxide-pyridine complex.
• the reaction temperature herein ranges, for example, from ⁇ 60° C. to 60° C., preferably from 0° C. to room temperature.
• Compound [24] or a salt thereof may be prepared by reaction of Compound [22] or a salt thereof with Compound [23] or a salt thereof in a solvent in the presence of a base.
• Such a solvent includes, for example, alcohol solvents such as ethanol; halogenated solvents such as chloroform; hydrocarbon solvents such as chlorobenzene; and a mixed solvent of any of them.
• a preferable solvent herein is ethanol or water.
• Such a base includes, for example, sodium hydrogen carbonate and triethylamine.
• a preferable base herein is sodium hydrogen carbonate.
• the reaction temperature herein ranges, for example, from ⁇ 10° C. to 100° C., preferably from 0° C. to room temperature.
• Compound [26] or a salt thereof may be prepared by reaction of Compound [24] or a salt thereof with Compound [11] or a salt thereof in a solvent.
• Such a solvent includes, for example, ether solvents such as tetrahydrofuran.
• ether solvents such as tetrahydrofuran.
• a preferable solvent herein is tetrahydrofuran or diethyl ether.
• a reagent used herein includes, for example, organometallic reagents such as n-butyllithium and Grignard reagents such as magnesium.
• organometallic reagents such as n-butyllithium and Grignard reagents such as magnesium.
• a preferable reagent herein is n-butyllithium.
• the reaction temperature herein ranges from ⁇ 78° C. to room temperature.
• Compound [I-2A] or a salt thereof may be prepared by oxidation of Compound [26] or a salt thereof in a solvent.
• Such a solvent includes halogenated solvents such as dichloromethane.
• a preferable solvent herein is dichloromethane.
• An oxidizing agent used herein includes m-chloroperoxybenzoic acid.
• the reaction temperature herein is room temperature.
• reaction solution was slowly cooled to room temperature, and then, to the reaction solution was added a mixed solution of 3-methylsulfanyl-6,7-dihydro-5H-cyclopenta[1,2,4]triazine (100 mg) in tetrahydrofuran (2 mL).
• the reaction solution was stirred at room temperature for 1 day.
• aqueous ammonium chloride solution and ethyl acetate under ice cooling and the reaction solution was separated.
• the organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate.
• 2,2-Dimethyl-5-oxo-cyclopentanecarboxylic acid methyl ester (3.58 g) was mixed in ethylene glycol (1.76 mL) and toluene (40 mL) under nitrogen gas, and thereto was added para-toluenesulfonic acid monohydrate (200 mg) at room temperature.
• the reaction solution was stirred under heating at 140° C. for 3 hours to remove water. The resultant was slowly cooled to room temperature. Then, to the reaction solution were added 1M aqueous sodium carbonate solution (1.1 mL) and ethyl acetate, and the solution was separated. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed with a filter, and then the filtrate was concentrated under reduced pressure to give a crude product of the title compound (4.24 g).
• Lithium aluminum hydride (1.6 g) and tetrahydrofuran (30 mL) were mixed under nitrogen gas, and thereto was added a mixed solution of 7,7-dimethyl-1,4-dioxa-spiro[4.4]none-6-carboxylic acid methyl ester (4.24 g) in tetrahydrofuran (10 mL) under ice cooling.
• the reaction solution was stirred at room temperature for 1 hour. Then, thereto were added sequentially water (1.6 mL), 2N aqueous sodium hydroxide solution (1.6 mL), and water (4.8 mL) under ice cooling.
• Hydroxylamine hydrochloride (910 mg) was mixed in ethanol (10 mL) and water (2.5 mL), and thereto was added dropwise 4N aqueous solution of sodium hydroxide (3.35 mL) for 20 minutes under ice cooling. The resulting organic layer was added thereto, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed sequentially with water and saturated aqueous sodium chloride solution and then concentrated under reduced pressure.
• the mixture was extracted with chloroform, and the organic layer was dried over magnesium sulfate. Magnesium sulfate was removed with a filter, and then the filtrate was concentrated under reduced pressure.
• the resulting residue was mixed in cyclopentyl methyl ether (5 mL), and thereto was added 4N hydrogen chloride/cyclopentyl methyl ether solution (0.137 mL) under ice cooling. The mixture was stirred under ice cooling for 2 hours and then stirred at room temperature for 1 hour. The mixture was stirred under heating at 40° C. for 1 hour, and then the reaction solution was concentrated under reduced pressure.
• aqueous ammonium chloride solution 125 mL
• water 60 mL
• ethyl acetate/n-hexane 1/3
• Combined organic layers were washed with water (three times) and brine, and then dried over magnesium sulfate. Magnesium sulfate was removed with a filter, and then concentrated under reduced pressure.
• 2,2,3-Trimethylpent-4-en-1-ol (4.2 g) and triethylamine (7.2 mL) were mixed in chloroform (50 mL) under argon gas, and thereto was added dropwise a mixed solution of methanesulfonyl chloride (3.8 mL) in chloroform (15 mL) under ice cooling.
• the reaction solution was stirred under ice cooling for 5 minutes, and then warmed to room temperature.
• the reaction solution was stirred at room temperature for 3 hours, and then thereto was added water (13 mL).
• the solution was stirred at room temperature, and then thereto was added ethyl acetate (20 mL). The solution was separated.
• the aqueous layer was extracted with ethyl acetate (20 mL) once.
• the organic layer was washed with 1N hydrochloric acid (12 mL), saturated sodium hydrogen carbonate (12 mL), and saturated aqueous sodium chloride solution (12 mL) and dried over magnesium sulfate. Magnesium sulfate was removed with a filter, and then the filtrate was concentrated under reduced pressure to give the title compound (7.1 q).
• 2,2,3-Trimethyl-pent-4-en-1-ol methanesulfonic acid ester (7.1 g) and N-methylpyridone (65 mL) were mixed under nitrogen gas, and thereto was added sodium iodide (24 g) at room temperature.
• the reaction solution was heated at 140° C. for 4 hours 20 minutes. Then, thereto was added 20 w/w % aqueous sodium thiosulfate solution (31 mL) at room temperature, and the mixture was stirred for 1 hour.
• the organic layer was washed with water (21 mL) twice, 20 w/w % aqueous sodium thiosulfate solution (21 mL), and saturated aqueous sodium chloride solution (21 mL) and dried over magnesium sulfate. Magnesium sulfate was removed with a filter, and then the filtrate was concentrated under reduced pressure to give the title compound (5.4 g).
• 3,3,4-Trimethylhex-5-enal (1.8 g) was mixed in ethanol (30 mL) and water (15 mL) under argon gas, and thereto were added sodium acetate (7.4 g) and hydroxylamine hydrochloride (3.1 g) at room temperature.
• the reaction solution was stirred under heating at 60° C. for 1 day.
• the reaction solution was concentrated under reduced pressure, and thereto were added ethyl acetate and water.
• the solution was separated.
• the aqueous layer was extracted with ethyl acetate.
• the organic layer was washed with saturated aqueous sodium chloride solution (twice) and dried over sodium sulfate.
• Heptan-6-al oxime (1.7 g) and methanol (34 mL) were mixed under nitrogen gas, and thereto was added trifluoroacetic acid (0.25 mL) under sodium chloride-ice cooling, followed by addition of (diacetoxyiodo)benzene (5.1 g) over 40 minutes.
• the reaction solution was stirred under ice cooling for 20 minutes and at room temperature for 35 minutes.
• saturated aqueous sodium hydrogen carbonate solution 17.
• sodium sulfite (0.75 g) under ice cooling
• the reaction solution was concentrated under reduced pressure.
• the aqueous layer was extracted with ethyl acetate (10 mL, twice).
• Preparative apparatus Recycling Preparative Liquid Chromatograph LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd.
• Mobile phase: n-hexane/2-propanol 92/8 Flow rate: 10.0 mL/min
• Hept-6-en-1-ol (150 g) and (diacetoxyiodo)benzene (508 1C g) were mixed in chloroform (1500 mL) under nitrogen gas, and thereto was added a mixed solution of 2,2,6,6-tetramethylpiperidin-1-oxyl radical (20.5 g) in chloroform (20.0 mL) at room temperature. The reaction solution was stirred at room temperature for 3 days. Then, thereto was added an aqueous solution (1500 mL) of sodium carbonate (278 g) and sodium thiosulfale (208 g) under water cooling, and the mixture was stirred at room temperature for 1 hour, and then separated.
• Hept-6-enal (214 g, 46.4 w % of iodobenzene inclusive) was mixed in water (1149 mL) and ethanol (2298 mL) under nitrogen gas, and then thereto were added sodium acetate (151 g) and hydroxylamine hydrochloride (107 g) at room 2C temperature.
• the reaction solution was stirred at room temperature for 2 days.
• the reaction solution was concentrated under reduced pressure, and thereto were added ethyl acetate and water.
• the solution was separated.
• the aqueous layer was extracted with ethyl acetate (twice).
• the organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure.
• Hept-6-enal oxime (203 g, 24.5 w % of ethyl acetate, 2.5 w % of ethanol, and 9.2 w % of iodobenzene inclusive) and methanol (2333 mL) were mixed under nitrogen gas, and thereto was added trifluoroacetic acid (17.5 mL) under salt-ice cooling, followed by addition of (diacetoxyiodo)benzene (384 g) over 1 hour. The reaction solution was stirred at room temperature for 3 hours.
• the resulting residue was mixed in ethyl acetate (1000 mL) and 28 w/w % ammonia water (140 mL), and the mixture was separated.
• the organic layer was washed with 20 w/w % aqueous sodium carbonate solution (200 mL) and saturated aqueous sodium chloride solution and dried over sodium sulfate.
• Sodium sulfate was removed with a filter, and then the filtrate was concentrated under reduced pressure to give a crude product of the title compound (99.6 g).
• the organic layer was washed with 20 w/w % aqueous sodium carbonate solution (135 mL for the first round and 50 mL for the second round), 13 w/w % aqueous sodium chloride solution (130 mL), and saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed with a filter, and then the filtrate was concentrated under reduced pressure to give the title compound (25.5 g).
• Measurement apparatus HPLC system, Shimadzu Corporation, High-Performance Liquid Chromatograph Prominence Column: Daicel CHIRALPAK OZ-3R 0.46 cm ⁇ 15 cmL Column temperature: 40° C.
• Flow rate 1.0 mL/min
• the mixture was stirred at room temperature for 4 hours, and then thereto were added (diacetoxyiodo)benzene (1.20 g) and 2,2,6,6-tetramethylpiperidin-1-oxyl radical (0.527 g) at room temperature.
• the mixture was stirred at room temperature for 17 hours, and then thereto were added 20 w/w % aqueous sodium sulfite solution (200 mL) and 20 w/w % aqueous sodium carbonate solution (30 mL) at room temperature.
• the mixture was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed with a filter, and then the filtrated was concentrated under reduced pressure.
• Absolute configuration of the asymmetric carbon of the title compound was determined by single-crystal X-ray structural analysis.
• Ethyl 5,5-difluoro-2-oxo-cyclohexanecarboxylate (4.45 g) and toluene (53 mL) were mixed under nitrogen gas, and thereto were added ethylene glycol (1.45 mL) and p-toluenesulfonic acid monohydrate (205 mg) at room temperature.
• the reaction solution was stirred under heating at 140° C. with dehydration for 1 day.
• a mixed aqueous solution of sodium carbonate 114 mg
• water (18 mL) under ice cooling, and the mixture was separated.
• the aqueous layer was extracted with ethyl acetate (twice).
• Lithium aluminum hydride (886 mg) and tetrahydrofuran (12 mL) were mixed under argon gas, and thereto was added dropwise a mixed solution in tetrahydrofuran (18 mL) of ethyl 8,8-difluoro-1,4-dioxa-spiro[4.5]decane-6-carboxylate (2.92 g) azeotroped with toluene over 1 hour under ice cooling.
• the reaction solution was stirred under ice cooling for 20 minutes and stirred at room temperature for 4 hours.

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