US20190359575A1 - Dihydropyrimidin-2-one compounds and medical use thereof - Google Patents

Dihydropyrimidin-2-one compounds and medical use thereof Download PDF

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US20190359575A1
US20190359575A1 US16/228,448 US201816228448A US2019359575A1 US 20190359575 A1 US20190359575 A1 US 20190359575A1 US 201816228448 A US201816228448 A US 201816228448A US 2019359575 A1 US2019359575 A1 US 2019359575A1
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compound
formula
acid
alkyl
reaction solution
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Masahiro Yokota
Taku Ikenogami
Eiichi Watanabe
Noriyoshi Seki
Takayuki Sakai
Shingo Fujioka
Makoto Shiozaki
Katsunori SUWA
Yosuke Ogoshi
Masato Noguchi
Katsuya Maeda
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Japan Tobacco Inc
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Japan Tobacco Inc
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Priority to US16/228,448 priority Critical patent/US20190359575A1/en
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Priority to US16/902,935 priority patent/US20210130300A1/en
Priority to US18/085,466 priority patent/US20230373932A1/en
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Definitions

  • the present invention relates to dihydropyrimidin-2-one compounds or pharmaceutically acceptable salts thereof which have inhibitory actions against Retinoid-related Orphan Receptor gamma (ROR ⁇ ), pharmaceutical compositions comprising the same, and medical uses thereof.
  • ROR ⁇ Retinoid-related Orphan Receptor gamma
  • ROR ⁇ is a nuclear receptor which is important for the differentiation and activation of Th17 cells.
  • ROR ⁇ t is also known as a splice variant of ROR ⁇ (Nonpatent 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 (Nonpatent literature 1).
  • Th17 cells By inhibiting ROR ⁇ , the differentiation and activation of Th17 cells can be inhibited.
  • 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, hence, the inhibition of IL-17 may lead to the inhibition of such induction and migration (Nonpatent literatures 2 and 3).
  • ROR ⁇ in adipose tissues is related to the regulation of adipogenesis, and by inhibiting ROR ⁇ , insulin resistance can be improved (Nonpatent literature 4).
  • 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, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic diseases; dry eye; and fibrosis such as pulmonary fibrosis and primary biliary cirrhosis. It is known that adipose tissues are involved in metabolic diseases.
  • Nonpatent literature 5 As for rheumatoid arthritis, for example, it is reported that the administration of anti-IL-17 antibody can improve swelling and joint destruction associated with collagen-induced arthritis (Nonpatent literature 5). Moreover, it is reported that swelling and joint destruction associated with collagen-induced arthritis can be improved in experiments using IL-17-deficient mice (Nonpatent literature 6).
  • Nonpatent literature 7 As for psoriasis, it is reported that in a clinical trial, the administration of anti-IL-17 antibody is effective in treating psoriasis (Nonpatent literature 7). Anti IL-17 antibodies have been placed on the market for use in psoriasis (Nonpatent literature 8).
  • Nonpatent literature 11 As for systemic lupus erythematosus, it is reported that the onset of GBM nephritis model which is an animal model of glomerulonephritis can be inhibited in ROR ⁇ t-KO mice (Nonpatent literature 11). Nephritis associated with SLE may also be suppressed (Nonpatent literature 12).
  • polymyalgia rheumatica As for polymyalgia rheumatica, an efficacy of anti-IL-17 antibody in treatment of polymyalgia rheumatica is currently tested in a clinical trial.
  • type I diabetes the disease state of NOD mice which is a type I diabetes model can be suppressed by the administration of anti-IL-17 antibody (Nonpatent literature 14).
  • fibrosis in a bleomycin-induced pulmonary fibrosis model which is an animal model of pulmonary fibrosis, the administration of anti-IL-17 antibody can inhibit inflammation and fibrosis in lung and can increase survival of the animal (Nonpatent literature 17).
  • Th17 cells in the lesion area of a patient with a primary biliary cirrhosis increase, and an efficacy of an antibody to IL-23 which activates Th17 cells is currently tested in a clinical trial (Nonpatent literature 18).
  • ROR ⁇ antagonists are thought to be useful for preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic diseases such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic diseases such as diabetes.
  • autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and
  • Nonpatent literature 1 Anton. 2009 NRS 7, 1-32
  • Nonpatent literature 2 Koenders et al. 2006 Ann Rheum Dis 65 (Suppl III), iii29-iii33
  • Nonpatent literature 3 Carsten et al. 2007 J Allergy Clin Immunol 120, 247-54
  • Nonpatent literature 4 Bettina et al. 2011 EMBO Mol Med 3, 1-15
  • Nonpatent literature 5 Hilde et al. 2009 Arthritis Research & Therapy 11: R122
  • Nonpatent literature 6 Susumu et al. 2003 J. Immnol 171, 6173-6177
  • Patent literature 7 discloses et al.
  • Nonpatent literature 8 Sci Transl Med 2, 52ra72 [Nonpatent literature 8] Sanford et al. Drugs (2015) 75: 329-338 [Nonpatent literature 9] Moritz et al. 2009 Gastroenterology 136, 257-67 [Nonpatent literature 10] Ivaylo et al. 2006 Cell 126, 1121-1133 [Nonpatent literature 11] Oliver et al. 2011 J Am Soc Nephrol 22: 472-483 [Nonpatent literature 12] Jose et al. 2010 Curr Opin Rheumatol 22, 499-503 [Nonpatent literature 13] Anthony et al. Lancet 2013, 382(9906): 1705 [Nonpatent literature 14] Juliet et al.
  • Nonpatent literature 15 Stephen et al. 2007 J. Immnol 178, 3208-18
  • An object of the present invention is to provide dihydropyrimidin-2-one compounds or pharmaceutically acceptable salts thereof which have inhibitory actions against ROR ⁇ , pharmaceutical compositions comprising the same, and medical uses thereof.
  • the present invention relates to compounds which would inhibit differentiation and activation of T helper 17 (Th17) cells by an inhibitory action for Retinoid-related Orphan Receptor gamma: ROR ⁇ and inhibit interleukin-17 (IL-17) production.
  • Th17 T helper 17
  • ROR ⁇ Retinoid-related Orphan Receptor gamma
  • the present invention is also directed to provide an agent for preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes.
  • autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and
  • the present inventors have found dihydropyrimidin-2-one compounds which are ROR ⁇ antagonists, thereby have completed the present invention.
  • the present invention includes the following embodiments.
  • n is an integer of 0, 1 or 2, provided that when n is 2, each R 2 may be different with each other; or R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6 alkyl;
  • R 3h is hydrogen or methyl; R 3w is methyl or fluoro; n x is an integer of 0 or 2; n w is an integer of 0, 1, 2 or 3; R 3 is C 1-6 alkyl optionally substituted with one hydroxy, C 1-6 alkyl substituted with one C 1-4 alkoxy or C 3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group X b ; R 5B is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or trifluoromethyl; and the other symbols have the same meanings as defined in [01]. [12] The compound of [01], selected from the group consisting of the following formulae, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • An ROR ⁇ antagonist comprising the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • An agent for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof.
  • the agent of [15] wherein the disease is autoimmune disease.
  • autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
  • the agent of [15], wherein the disease is metabolic disease.
  • the agent of [18], wherein the metabolic disease is diabetes.
  • [20] A method of inhibiting ROR ⁇ , comprising administering to a mammal a therapeutically effective amount of the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof.
  • the method of [21], wherein the disease is autoimmune disease.
  • autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
  • the disease is metabolic disease.
  • the metabolic disease is diabetes.
  • [29] The use of [28], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
  • [30] The use of [27], wherein the disease is metabolic disease.
  • the use of [30], wherein the metabolic disease is diabetes.
  • a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
  • the compound of [33], wherein the disease is autoimmune disease, or a pharmaceutically acceptable salt thereof.
  • autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease, or a pharmaceutically acceptable salt thereof.
  • the disease is metabolic disease, or a pharmaceutically acceptable salt thereof.
  • metabolic disease is diabetes, or a pharmaceutically acceptable salt thereof.
  • Dihydropyrimidin-2-one compounds and pharmaceutically acceptable salts thereof of the present invention is useful as an agent for prevention or treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease, allergic diseases such as asthma, dry eye, fibrosis such as pulmonary fibrosis and primary biliary cirrhosis, and metabolic diseases such as diabetes.
  • autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyal
  • Halogen includes fluoro, chloro, bromo or iodo.
  • a preferable “halogen” is fluoro or chloro.
  • Alkyl means a straight or branched chain saturated hydrocarbon gorup, and includes, for example, “C 1-3 alkyl”, “C 1-4 alkyl”, “C 1-5 alkyl”, “C 1-6 alkyl”, “C 4-6 alkyl”, “C 4-8 alkyl”, and “C 5-8 alkyl”, each of which means alkyl with 1 to 3 of carbon atom(s), 1 to 4 of carbon atom(s), 1 to 5 of carbon atom(s), 1 to 6 of carbon atom(s), 4 to 6 of carbon atoms, 4 to 8 of carbon atoms, and 5 to 8 of carbon atoms, respectively.
  • C 1-3 alkyl includes, for example, methyl, ethyl, propyl, and isopropyl.
  • a preferable “C 1-3 alkyl” is methyl.
  • C 1-4 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and 1-methylpropyl.
  • a preferable “C 1-4 alkyl” is methyl or ethyl.
  • C 1-5 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, and 1-ethylpropyl.
  • a preferable “C 1-5 alkyl” is methyl.
  • C 1-6 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • C 1-6 alkyl is methyl, ethyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, I-methylpropyl or 1,1-dimethylbutyl.
  • C 4-6 alkyl includes, for example, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • a preferable one is isobutyl or isopentyl.
  • C 4-8 alkyl includes, for example, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl, I-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl.
  • a preferable one is butyl, isobutyl, pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.
  • C 5-8 alkyl includes, for example, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, I-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl.
  • a preferable one is pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.
  • C 1-6 alkyl optionally substituted with one hydroxy means “C 1-6 alkyl substituted with one hydroxy” or “unsubstituted C 1-6 alkyl”.
  • C 1-3 alkyl substituted with one hydroxy means “alkyl”, with 1 to 3 of carbon atom(s), substituted at any position with one hydroxy. In particular, it includes, for example, hydroxymethyl.
  • C 5-8 alkyl substituted with one hydroxy means “alkyl”, with 5 to 8 of carbon atoms, substituted with at any position with one hydroxy. In particular, it includes, for example, 3,3-dimethyl-3-hydroxypropyl, 3,3-dimethyl-2-hydroxybutyl, and 3,3-dimethyl-4-hydroxybutyl.
  • C 5-8 alkyl substituted with one halogen means “alkyl”, with 5 to 8 of carbon atoms, substituted with at any position with one halogen. In particular, it includes, for example, 3-fluoro-3-methylbutyl.
  • C 3-7 alkyl substituted with one trifluoromethyl means “alkyl”, with 3 to 7 of carbon atoms, substituted at any position with one trifluoromethyl. In particular, it includes, for example, 4,4,4-trifluorobutyl and 4,4,4-trifluoro-3,3-dimethylbutyl.
  • Alkenyl means a straight or branched chain unsaturated hydrocarbon group with one or more double bond(s) between carbon atoms, and includes, for example, “C 2-3 alkenyl” and “C 4-8 alkenyl” which “C 2-3 alkenyl” means alkenyl with 2 to 3 of carbon atoms and “C 4-8 alkenyl” means alkenyl with 4 to 8 of carbon atoms.
  • a preferable “C 4-8 alkenyl” is “C 4-6 alkenyl” with one double bond between carbon atoms.
  • C 2-3 alkenyl includes, for example, ethenyl and isopropenyl. A preferable one is isopropenyl.
  • C 4-8 alkenyl includes, for example, 2-methyl-prop-1-enyl, 3,3-dimethyl-but-1-enyl, and 3-methyl-but-2-enyl.
  • a preferable one is 2-methyl-prop-1-enyl or 3,3-dimethyl-but-1-enyl.
  • Alkynyl means a straight or branched chain unsaturated hydrocarbon group with one or more triple bond(s) between carbon atoms, and includes, for example, “C 4-8 alkynyl” which means alkynyl with 4 to 8 carbon atoms.
  • C 4-8 alkynyl is “C 4-6 alkynyl” with one triple bond between carbon atoms.
  • C 4-8 alkynyl includes, for example, 3,3-dimethyl-but-1-ynyl, 3-methyl-but-1-ynyl, and 3-ethyl-pent-1-ynyl.
  • a preferable one is 3,3-dimethyl-but-1-ynyl.
  • Alkoxy means a group where a straight or branched chain saturated hydrocarbon group attaches to oxygen atom, and includes, for example, “C 1-3 alkoxy”, “C 1-4 alkoxy”, “C 2-4 alkoxy”, “C 3-6 alkoxy”, and “C 2-7 alkoxy”, each of which means alkoxy with 1 to 3 of carbon atom(s), 1 to 4 of carbon atom(s), 2 to 4 of carbon atoms, 3 to 6 of carbon atoms, and 2 to 7 of carbon atoms, respectively.
  • C 1-3 alkoxy includes, for example, methoxy, ethoxy, propoxy, and isopropoxy.
  • a preferable one is methoxy or ethoxy.
  • C 1-4 alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferable one is methoxy.
  • C 2-4 alkoxy includes, for example, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferable one is isopropoxy or tert-butoxy.
  • C 3-6 alkoxy includes, for example, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy, and hexyloxy.
  • a preferable one is isobutoxy, isopentyloxy, neopentyloxy or 3,3-dimethylbutoxy.
  • C 2-7 alkoxy includes, for example, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferable one is isopropoxy or tert-butoxy.
  • C 2-7 alkoxy substituted with one trifluoromethyl means “alkoxy”, with 2 to 7 carbon atoms, substituted at any position with one “trifluoromethyl”. Its illustrative example includes, for example, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 7,7,7-trifluoroheptyloxy, and 8,8,8-trifluorooctyloxy. A preferable one includes, for example, 3,3,3-trifluorpropoxy.
  • C 1-3 alkyl substituted with one C 1-3 alkoxy means “alkyl”, with 1 to 3 of carbon atom(s), substituted at any position with one C 1-3 alkoxy. In particular, it includes, for example, methoxymethyl.
  • C 1-6 alkyl substituted with one C 1-4 alkoxy means “alkyl”, with 1 to 6 of carbon atom(s), substituted at any position with one C 1-4 alkoxy. In particular, it includes, for example, 2-methoxyethyl, 1-methyl-2-methoxyethyl, 2-methoxypropyl, 4-methoxy-2,2-dimethylbutyl, and 3-tert-butoxypropyl.
  • Cycloalkyl means a monocyclic saturated hydrocarbon group, and includes, for example, “C 3-6 cycloalkyl” and “C 4-6 cycloalkyl”, each of which means cycloalkyl with 3 to 6 of carbon atoms, and 4 to 6 of carbon atoms, respectively.
  • C 3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 4-6 cycloalkyl includes, for example, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3-6 cycloalkyl substituted with one C 1-3 alkoxy means “cycloalkyl”, with 3 to 6 of carbon atoms, substituted at any position with one C 1-3 alkoxy. In particular, it includes, for example, 3-methoxycyclobutyl.
  • C 3-6 cycloalkyl substituted with one C 1-3 alkoxy-C 1-3 alkyl means “cycloalkyl”, with 3 to 6 of carbon atoms, substituted at any position with one C 1-3 alkoxy-C 1-3 alkyl. In particular, it includes, for example, 1-methoxymethylcyclopropyl and 3-methoxymethylcyclobutyl.
  • Cycloalkenyl means a monocyclic unsaturated hydrocarbon group with one or more double bond(s) between carbon atoms, and includes, for example, “C 5-6 cycloalkenyl”, which means cycloalkenyl with 5 to 6 of carbon atoms.
  • C 5-6 cycloalkenyl is “C 5-6 cycloalkenyl” with one double bond between carbon atoms.
  • C 5-6 cycloalkenyl includes, for example, cyclopentenyl and cyclohexenyl.
  • a preferable one is cyclopent-1-enyl or cyclohex-1-enyl.
  • “Spiro cycloalkyl” means a cyclic saturated hydrocarbon group with one spiro atom, and includes, for example, “spiro C 6-11 cycloalkyl”, which means spiro cycloalkyl with one spiro atom and 6 to 11 of carbon atoms.
  • spiro C 6-11 cycloalkyl includes, for example, spiro [3.3]heptyl, spiro [4.4]nonyl, and spiro [5.5]undecyl.
  • a preferable one is spiro [3.3]heptyl.
  • Alkylcarbonyl means “alkyl”-attached carbonyl, and includes “C 1-3 alkylcarbonyl”.
  • C 1-3 alkylcarbonyl includes carbonyl which attaches to the “C 1-3 alkyl”.
  • a preferable one is methylcarbonyl.
  • Alkylsulfanyl means “alkyl”-attached sulfanyl, and includes “C 4-6 alkylsulfanyl”.
  • C 4-6 alkylsulfanyl includes sulfanyl which attaches to the “C 4-6 alkyl”.
  • a preferable one is isobutylsulfanyl or isopentylsulfanyl.
  • Alkylsulfinyl means “alkyl”-attached sulfinyl, and includes “C 4-6 alkylsulfinyl”.
  • C 4-6 alkylsulfinyl includes sulfinyl which attaches to the “C 4-6 alkyl”.
  • a preferable one is isobutylsulfinyl or isopentylsulfinyl.
  • Alkylsulfonyl means “alkyl”-attached sulfonyl, and includes “C 1-3 alkylsulfonyl”, “C 1-4 alkylsulfonyl”, and “C 4-6 alkylsulfonyl”.
  • C 1-3 alkylsulfonyl includes sulfonyl which attaches to the “C 1-3 alkyl”.
  • a preferable one is methylsulfonyl.
  • C 1-4 alkylsulfonyl includes sulfonyl which attaches to the “C 1-4 alkyl”.
  • a preferable one is methylsulfonyl.
  • C 4-6 alkylsulfonyl includes sulfonyl which attaches to the “C 4-6 alkyl”.
  • a preferable one is isobutylsulfonyl or isopentylsulfonyl.
  • C 1-6 alkyl substituted with one C 1-4 alkylsulfonyl means “alkyl”, with 1 to 6 of carbon atom(s), substituted at any position with one C 1-4 alkylsulfonyl. In particular, it includes, for example, 2-methylsulfonylethyl.
  • Alkoxycarbonyl means carbonyl which attaches to “alkoxy”, and includes, for example, “C 1-3 alkoxycarbonyl”.
  • C 1-3 alkoxycarbonyl includes, for example, methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. A preferable one is ethoxycarbonyl.
  • Cycloalkylsulfanyl means “cycloalkyl”-attached sulfanyl, and includes “C 3-6 cycloalkylsulfanyl”.
  • C 3-6 cycloalkylsulfanyl includes sulfanyl which attaches to the “C 3-6 cycloalkyl”.
  • a preferable one is cyclopentylsulfanyl.
  • Cycloalkylsulfinyl means “cycloalkyl”-attached sulfinyl, and includes “C 3-6 cycloalkylsulfinyl”.
  • C 3-6 cycloalkylsulfinyl includes, for example, sulfinyl which attaches to the “C 3-6 cycloalkyl”.
  • a preferable one is cyclopentylsulfinyl.
  • Cycloalkylsulfonyl means “cycloalkyl”-attached sulfonyl, and includes “C 3-6 cycloalkylsulfonyl”.
  • C 3-6 cycloalkylsulfanyl includes sulfonyl which attaches to the “C 3-6 cycloalkyl”.
  • a preferable one is cyclopentylsulfonyl.
  • Alkylene means a divalent group derived from straight or branched chain saturated hydrocarbon, and includes, for example, “C 1-3 alkylene” and “C 1-6 alkylene”, each of which means alkylene with 1 to 3 of carbon atom(s) and 1 to 6 of carbon atom(s), respectively.
  • C 1-3 alkylene includes, for example, methylene, ethylene, trimethylene, and —C(C 1-3 ) 2 —.
  • a preferable one is methylene or ethylene.
  • C 1-6 alkylene includes, for example, methylene, ethylene, trimethylene, butylene, pentylene, hexylene, —C(CH 3 ) 2 —, —C(CH 3 ) 2 —CH 2 —, —(CH 2 ) 2 —CH(CH 3 )—, —CH 2 —C(CH 3 ) 2 —CH 2 —, —(CH 2 ) 3 —C(CH 3 ) 2 —, and —(CH 2 ) 2 —C(CH 3 ) 2 —.
  • a preferable one is methylene, ethylene, trimethylene, butylene, —C(C 3 ) 2 —, —C(CH 3 ) 2 —CH 2 —, —(CH 2 ) 2 —CH(CH 3 )—, —CH 2 —C(CH 3 ) 2 —CH 2 —, —(CH 2 ) 3 —C(CH 3 ) 2 — or —(CH 2 ) 2 —C(CH 3 ) 2 —.
  • C 1-6 alkylene optionally substituted with one hydroxy means “C 1-6 alkylene substituted with one hydroxy” or “unsubstituted C 1-6 alkylene”.
  • Cycloalkylene means a divalent group derived from monocyclic saturated hydrocarbon, and includes, for example, “C 3-6 cycloalkylene”, which means cycloalkylene with 3 to 6 of carbon atoms.
  • C 3-6 cycloalkylene includes, for example, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.
  • a preferable “C 3-6 cycloalkylene” is “C 4-6 cycloalkylene”.
  • Cross-linked cycloalkylene means a divalent group derived from polycyclic saturated hydrocarbon with a cross-linked structure of carbon atoms, and includes, for example, “cross-linked C 5-8 cycloalkylene”, which means cross-linked cycloalkylene with 5 to 8 of carbon atoms.
  • cross-linked C 5-8 cycloalkylene includes, for example, bicyclo[1.1.1]pentylene, bicyclo[2.1.1]hexylene, bicyclo[2.2.1]heptylene, and bicyclo[2.2.2]octylene.
  • a preferable “cross-linked C 5-8 cycloalkylene” is “cross-linked C 5-6 cycloalkylene”, in paricular bicyclo[1.1.1]pentylene or bicyclo[2.1.1]hexylene.
  • Phenylene substituted with one halogen means phenylene substituted at any position with one halogen. In particular, it includes, for example, 2-fluorophenylene and 4-fluorophenylene.
  • Phenylene substituted with one C 1-3 alkyl means phenylene substituted at any position with one C 1-3 alkyl. In particular, it includes, for example, 2-methylphenylene and 3-methylphenylene.
  • Phenylene substituted with one C 1-3 alkoxy means phenylene substituted at any position with one C 1-3 alkoxy. In particular, it includes, for example, 2-methoxyphenylene and 3-methoxyphenylene.
  • Phenylene substituted with one trifluoromethyl means phenylene substituted at any position with one trifluoromethyl. In particular, it includes, for example, 3-trifluorophenylene.
  • “Pyrrolidinediyl substituted with one carboxy” means pyrrolidinediyl substituted at any position with one carboxy. In particular, it includes, for example, 3-carboxypyrrolidine-1,4-diyl.
  • “Pyrrolidinediyl substituted with one C 1-3 alkylcarbonyl” means pyrrolidinediyl substituted at any position with one C 1-3 alkylcarbonyl. In particular, it includes, for example, 1-methylcarbonylpyrrolidine-3,4-diyl.
  • “Pyrrolidinediyl substituted with one C 1-3 alkylsulfonyl” means pyrrolidinediyl substituted at any position with one C 1-3 alkylsulfonyl. In particular, it includes, for example, 1-methylsulfonylpyrrolidine-3,4-diyl.
  • “Pyrazolediyl substituted with one C 1-3 alkyl” means pyrazolediyl substituted at any position with one C 1-3 alkyl. In particular, it includes, for example, 1-methylpyrazole-3,5-diyl.
  • a preferable “C 4-8 alkyl” in R 1 particularly includes butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl.
  • a further preferable one is butyl, isobutyl, pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.
  • C 4-8 alkenyl in R 1 is “C 4-6 alkenyl”, and particularly includes 2-methyl-propenyl, 3,3-dimethyl-but-1-enyl, and 3-methyl-but-2-enyl. A further preferable one is 2-methyl-propenyl or 3,3-dimethyl-but-1-enyl.
  • C 4-8 alkynyl in R 1 is “C 1-6 alkynyl”, and particularly includes 3,3-dimethyl-but-1-ynyl, and 3-methyl-but-1-ynyl.
  • a further preferable one is “C 6 alkynyl”, in particular 3,3-dimethyl-but-1-ynyl.
  • a preferable “C 3-7 alkyl substituted with one trifluoromethyl” in R 1 is “C 3-5 alkyl substituted with one trifluoromethyl”, and particularly includes 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, and 4,4,4-trifluoro-3,3-dimethylbutyl.
  • a further preferable one is 4,4,4-trifluorobutyl or 4,4,4-trifluoro-3,3-dimethylbutyl.
  • a preferable “C 1-4 alkyl” in “C 1-4 alkyl substituted with one substituent selected from Group X a1 ” in R 1 is “C 1-2 alkyl”, in particular methyl or ethyl.
  • a preferable “C 3-6 alkoxy” in R 1 is “C 4-6 alkoxy”, and particularly includes propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy, and hexyloxy.
  • a further preferable one is isobutoxy, isopentyloxy, neopentyloxy or 3,3-dimethylbutoxy.
  • a preferable “C 2-7 alkoxy substituted with one trifluoromethyl” in R 1 is “C 2 alkoxy substituted with one trifluoromethyl”, in particular 3,3,3-trifluoropropoxy.
  • a preferable “C 1-3 alkoxy” in “C 1-3 alkoxy substituted with one substituent selected from Group X a2 ” in R 1 is “C 1-2 alkoxy”, in particular methoxy or ethoxy.
  • a preferable “C 4-6 cycloalkyl” in R 1 is in particular cyclobutyl, cyclopentyl or cyclohexyl.
  • a preferable “C 3-6 cycloalkyl substituted with one to two C 1-4 alkyl” in R 1 is “C 3-6 cycloalkyl substituted with the same or different one or two C 1-4 alkyl”, more preferably “cyclopropyl or cyclohexyl substituted with the same or different one or two methyl, isopropyl or tert-butyl”. In particular, it is 2-isopropylcyclopropyl, 2-tert-butylcyclopropyl or 3,3-dimethylcyclohexyl.
  • a preferable “C 5-6 cycloalkenyl optionally substituted with one to two C 1-4 alkyl” in R 1 is “C 5-6 cycloalkenyl optionally substituted with the same or different two C 1-4 alkyl”, more preferably “1-cyclopentenyl or 1-cyclohexenyl, optionally substituted with the same or different two methyl”.
  • it is 1-cyclopentenyl, 1-cyclohexenyl, 3,3-dimethylcyclohex-1-enyl or 4,4-dimethylcyclohex-1-enyl.
  • a preferable “spiro C 6-11 cycloalkyl” in R 1 is “spiro C 6-8 cycloalkyl”, more preferably “spiro C 7 cycloalkyl”. In particular, it is spiro [3.3]heptyl.
  • a preferable “C 1-3 alkoxycarbonyl” in R 1 is “C 1-2 alkoxycarbonyl”, more preferably ethoxycarbonyl.
  • a preferable “halogen” in R 2 is fluoro or chloro.
  • a preferable “C 1-6 alkyl” in R 2 is “C 1-2 alkyl”, more preferably methyl.
  • a preferable “C 1-3 alkoxy optionally substituted with phenyl” in R 2 is “C 1-2 alkoxy optionally substituted with phenyl”, more preferably benzyloxy.
  • n is an integer of 0 to 2.
  • n is an integer of 1 or 2.
  • R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6 alkyl” includes, when “n” is 1, the following embodiments.
  • a preferable “—Y b —COO—R 30 ” in R 3 is —(C 3-5 alkylene)-COOH or —C 4 cycloalkylene-COOH, in particular —C(CH 3 ) 2 —COOH, —C(CH 3 ) 2 —CH 2 —COOH, —C(CH 3 ) 2 —(CH 2 ) 2 —COOH or -cyclobutylene-COOH.
  • C 1-6 alkyl optionally substituted with one hydroxy in R 3 is “C 1-6 alkyl substituted with one hydroxy” or “unsubstituted C 1-6 alkyl”.
  • a preferable “C 1-6 alkyl substituted with one hydroxy” is “C 6 alkyl substituted with one hydroxy”.
  • An illustrative example of “C 1-6 alkyl optionally substituted with one hydroxy” includes methyl, ethyl, isopropyl, isobutyl, tert-butyl, I-methylpropyl, isopentyl, neopentyl or 4-hydroxy-1,1-dimethylbutyl.
  • a preferable “C 3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group X b ” in R 3 is “C 3-6 cycloalkyl optionally substituted with the same or different one to two substituent(s) selected from fluoro or methyl”, in particular cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 3,3-difluorocyclobutyl or cyclohexyl.
  • R 3 is —Y b —COO—R 30 , and includes any of the following structures.
  • R 3 is —Y b —COO—R 30 wherein Y b is
  • one preferable embodiment of Formula [I] includes an embodiment having the following structure.
  • a preferable R 4 is hydrogen.
  • C 1-6 alkylene optionally substituted with one hydroxy” in Y c in “—Y—COO—R 50 ” in R 5 includes, for example, methylene, ethylene, trimethylene, butylene, (CH 2 ) 2 —CH(CH 3 ), CH(CH 3 )—(CH 2 ) 2 , (CH 2 ) 2 —C(CH 3 ) 2 , CH 2 —C(CH 3 ) 2 —CH 2 , C(CH 3 ) 2 —(CH 2 ) 2 , (CH 2 ) 3 —C(CH 3 ) 2 , and (CH 2 ) 2 —CH(OH).
  • a preferable m is an integer of 0 to 2
  • a preferable w is an integer of 0 to 1.
  • a preferable “(CH 2 ) m —Y c1 —(CH 2 ) w ” in Y c in “—Y c —COO—R 50 ” in R 5 is Y c1 , Y c1 —CH 2 , CH 2 —Y c1 , CH 2 —Y c1 —CH 2 , (CH 2 ) 2 —Y c1 or (CH 2 ) 2 —Y c1 —CH 2 .
  • a preferable “C 3-6 cycloalkylene optionally substituted with one C 1-3 alkyl” in Y c1 is “cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, optionally substituted with one methyl”.
  • a preferable “cross-linked C 5-8 cycloalkylene” in Y c1 is “cross-linked C 5 cycloalkylene”, and for example has the following structure.
  • one preferable embodiment of Formula [I] includes embodiments having the following structures in the case where m is 0 and w is 0.
  • a preferable R 50 is hydrogen or methyl.
  • one preferable embodiment of Formula [I] includes an embodiment having the following structure in the case where m is 0 and w is 0.
  • a preferable R 50 is hydrogen or methyl.
  • one preferable embodiment of Formula [I] includes an embodiment having the following structure in the case where m is 0 and w is 0.
  • a preferable R 50 is hydrogen or methyl.
  • a preferable “C 1-4 alkyl optionally substituted with one C 1-3 alkoxy” in R 5 is “C 1-3 alkyl optionally substituted with one C 1-3 alkoxy”, more preferably “ethyl or isopropyl, optionally substituted with one methoxy”. In particular, it is methoxyethyl or isopropyl.
  • a preferable “C 3-6 cycloalkyl optionally substituted with one hydroxy-C 1-4 alkyl” in R 5 is “cyclobutyl optionally substituted with one hydroxymethyl”. In particular, it is cyclobutyl or 3-hydroxymethylcyclobutyl.
  • R 5 is —Y—COO—R 50 , and includes any of the following structures.
  • a preferable R 6 is methyl.
  • R 5 is (1) —Y c —COO—R 5 .
  • a compound of Formula [I] includes any compound of the following Formula [II], [III] or [VI].
  • One preferable embodiment of the compound of Formula [I] includes the compounds of the following general formulae.
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [I],
  • R 1 is (1) C 4-8 alkyl, (2) C 4-6 alkenyl, (3) C 4-6 alkynyl, (4) C 3-5 alkyl substituted with one trifluoromethyl, (5) C 1-4 alkyl substituted with one substituent selected from Group X a1 , (6) C 3-6 alkoxy, (7) C 2-7 alkoxy substituted with one trifluoromethyl, (8) C 1-3 alkoxy substituted with one substituent selected from Group X a2 , (9) C 4-6 cycloalkyl, (10) C 3-6 cycloalkyl substituted with one to two C 1-4 alkyl, (11) C 5-6 cycloalkenyl optionally substituted with one to two C 1-4 alkyl, (12) spiro C 6-8 cycloalkyl or (13) C 1-3 alkoxycarbonyl;
  • n is an integer of 0, 1 or 2, provided that when n is 2, each R 2 may be different with each other; or R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6 alkyl;
  • R 5 is —Y c —COO—R 50
  • Y c is (CH 2 ) m —Y c1 —(CH 2 ) w , m and w are 0, and Y c1 is phenylene, then R 6 is methyl; and either R 3 or R 5 or both of them have “—COO—”.
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [I],
  • R 1 is (1) C 4-8 alkyl, (2) C 4-6 alkenyl, (3) C 6 alkynyl, (4) trifluoromethyl-C 3-5 alkyl, (5) C 1-2 alkyl substituted with one substituent selected from Group X a1 , (6) C 4-6 alkoxy, (7) trifluoromethyl-C 2 alkoxy, (8) C 1-2 alkoxy substituted with one substituent selected from Group X a2 , (9) C 4-6 cycloalkyl, (10) C 3-6 cycloalkyl substituted with one to two C 1-4 alkyl, (11) C 5-6 cycloalkenyl optionally substituted with one to two C 1-4 alkyl, (12) spiro C 7 cycloalkyl or (13) ethoxycarbonyl;
  • n is an integer of 0, 1 or 2, provided that n is 2, each R 2 may be different with each other; or R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl optionally substituted with two methyl;
  • R 5 is —Y c —COO—R 50 , Y c is (ethylene)-Y c1 -(methylene), and Y c1 is phenylene, then R 6 is methyl; and either R 3 or R 5 or both of them have “—COO—”.
  • R 2 is fluoro or chloro;
  • n is 1;
  • R 3 is C 1-6 alkyl;
  • a more preferable embodiment of the compound of Formula [I] is a compound of Formula [II-A] which R 6 is methyl in Formula [II]:
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [II-B] which R 4 is hydrogen and R 6 is methyl in Formula [II]:
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [ITT]:
  • R 2 is fluoro or chloro;
  • n is 1;
  • Y b is C 1-6 alkylene;
  • a more preferable embodiment of the compound of Formula [I] is a compound of Formula [III-A] which R 6 is methyl in Formula [III]:
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [III-B] which R 4 is hydrogen and R 6 is methyl in Formula [III]:
  • a more preferable embodiment of the compound of Formula [I] is a compound of Formula [IV-A] which R 6 is methyl in Formula [IV]:
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [IV-B] which R 4 is hydrogen and R 6 is methyl in Formula [IV]:
  • a more preferable embodiment of the compound of Formula [I] is a compound of Formula [E-IV-A] which R 6 is methyl in Formula [E-IV]:
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [E-IV-B] which R 4 is hydrogen in Formula [E-IV-A.]:
  • a particularly preferable embodiment of the compound of Formula [E-IV] is a compound of the following formula:
  • Another embodiment of the compound of Formula [V] is the following compound:
  • R 3a and R 3b may combine together with the carbon atom to which they attach to form (1) a C 3-6 cycloalkane ring optionally substituted with the same or different one to three substituent(s) selected from the group consisting of hydroxy, halogen, hydroxycarbonyl, and C 1-3 alkoxycarbonyl, (2) a tetrahydropyran ring or (3) a 1-methanesulfonylazetidine ring;
  • R 3c is (1) hydrogen or (2) C 1-6 alkyl; and the other symbols have the same meanings as defined in [01], provided that when R 5 is —Y c —COO—R 50 , Y c is (CH 2 ) m —Y c1 —(CH 2 ) w , m and w are 0, and Y c1 is phenylene, then R 6 is methyl; either a structure of the formula:
  • a more preferable embodiment of the compound of Formula [V] includes the compounds of the following general formulae.
  • a further preferable embodiment of a compound of Formula [I] is any one of compounds of the following formulae:
  • R 3h is hydrogen or methyl; R 3w is methyl or fluoro; n x is an inter of 0 or 2; n w is an integer of 0, 1, 2 or 3; and the other symbols have the same meanings as defined in [01].
  • a more preferable one is any one of compounds wherein R 2 is chloro or trifluoromethyl.
  • a still more preferable one is any one of compounds of Formula [IV-B-A] to [ITV-B-D] wherein
  • Y c is C 1-6 alkylene, phenylene, cross-linked C 5-8 cycloalkylene or pyridinediyl.
  • Another further preferable embodiment of a compound of Formula [I] is any one of compounds of the following formulae:
  • R 3 is C 1-6 alkyl optionally substituted with one hydroxy, C 1-6 alkyl substituted with one C 1-4 alkoxy or C 3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group X b ;
  • R 5B is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or trifluoromethyl; and the other symbols have the same meanings as defined in [01].
  • C 4-8 alkyl C 3-7 alkyl substituted with one trifluoromethyl, C 1-5 alkyl substituted with one substituent selected from Group X a1 , C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl, C 1-3 alkoxy substituted with one substituent selected from Group X a1 , C 4-6 cycloalkyl, C 3-6 cycloalkyl substituted with the same or different one to two C 1-5 alkyl, C 5-6 cycloalkenyl optionally substituted with the same or different one to two C 1-4 alkyl, cyclohexylidenemethyl optionally substituted with the same or different one to two C 1-3 alkyl, tetrahydropyran-4-ylidenemethyl, C 3-6 cycloalkyl substituted with one to the same two halogen or C 5-6 cycloalkenyl substituted with one to the same two halogen; and R 2 is fluoro, chloro or tri
  • C 3-7 alkyl substituted with one trifluoromethyl C 1-5 alkyl substituted with one substituent selected from Group X a1 , C 3-6 alkoxy, C 4-6 cycloalkyl substituted with the same or different one to two C 1-5 alkyl, C 5-6 cycloalkenyl optionally substituted with the same or different one to two C 1-4 alkyl, C 6 cycloalkyl substituted with one to the same two halogen or C 6 cycloalkenyl substituted with one to the same two halogen; and R 2 is chloro or trifluoromethyl.
  • R 1 is any one of the following substituents.
  • Another embodiment of the present invention also includes the following embodiments.
  • n is an integer of 0, 1 or 2, provided that when n is 2, each R 2 may be different with each other; or R 1 and R 2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6 alkyl;
  • [05a] The compound of any one of [01a] to [04a], wherein R 6 is methyl, or a pharmaceutically acceptable salt thereof.
  • [06a] The compound of any one of [01a] to [05a], wherein R 4 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • [07a] The compound of any one of [01a] to [06a], wherein n is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof.
  • [08a] The compound of any one of [01a] to [07a], wherein R 2 is halogen, or a pharmaceutically acceptable salt thereof.
  • [09a] The compound of [08a], wherein R 2 is chloro or fluoro, or a pharmaceutically acceptable salt thereof.
  • [12a] A pharmaceutical composition comprising the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • An ROR ⁇ antagonist comprising the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
  • the agent of [14a] wherein the disease is autoimmune disease.
  • [19a] A method of inhibiting ROR ⁇ , comprising administering to a mammal a therapeutically effective amount of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
  • [20a] A method of treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to a mammal an effective amount of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
  • a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to a mammal an effective amount of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
  • [26a] Use of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treatment or prevention of a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
  • a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
  • [27a] The use of [26a], wherein the disease is autoimmune disease.
  • [28a] The use of [27a], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uvcitis, polymyalgia rheumatica, and type I diabetes.
  • [29a] The use of [26a], wherein the disease is metabolic disease.
  • [30a] The use of [29a], wherein the metabolic disease is diabetes.
  • [31a] A compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for use as an ROR ⁇ antagonist.
  • [32a] A compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for use as an agent for treatming or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
  • a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
  • the compound of [32a], wherein the disease is autoimmune disease, or a pharmaceutically acceptable salt thereof.
  • the compound of [32a] wherein the disease is metabolic disease, or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt may be any salts without excess toxicity known in the art.
  • a salt with an inorganic acid includes, for example, a salt with an organic acid, a salt with an inorganic base, and a salt with an organic base.
  • a salt with an organic acid includes, for example, a salt with an organic acid, a salt with an inorganic base, and a salt with an organic base.
  • Various forms of pharmaceutically acceptable salts are well known in the art, and are listed in the following references, for example.
  • the salt with an organic acid or inorganic acid includes a salt with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, 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, hexylresorcylic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid
  • a preferable salt with an organic acid includes a salt with oxalic acid, malcic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid or pamoic acid.
  • a salt with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid is illustrated.
  • a preferable salt with an inorganic acid includes a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid.
  • the salt with an organic base includes a salt with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine.
  • a preferable salt with an organic base includes a salt with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine.
  • the salt with an inorganic base includes a salt with ammonium, aluminum, barium, bismuth, calcium, lithium, magnesium, potassium, sodium or zinc.
  • a preferable salt with an inorganic base includes a salt with sodium, potassium, calcium, magnesium or zinc.
  • each pharmaceutically acceptable salt may be obtained by reacting a compound of Formula [I] with an inorganic base, an organic base, an inorganic acid or an organic acid.
  • a preferable salt of a compound of Formula [I] includes a salt with sodium, potassium or calcium.
  • Another preferable salt of a compound of Formula [I] includes a salt with sodium, potassium, L-lysine, tris(hydroxymethyl)methylamine, diethylamine, piperazine or dicyclohexylamine.
  • a compound of Formula [I] or a pharmaceutically acceptable salt thereof may exist in its solvate.
  • solvate means a compound where a solvent molecule is coordinated with a compound of Formula [I] or a pharmaceutically acceptable salt thereof, and includes a hydrate.
  • a pharmaceutically acceptable solvate is preferred as the solvate, and includes, for example, a hydrate, an ethanolate, and a dimethylsulfoxidate of a compound of Formula [I] or a pharmaceutically acceptable salt thereof.
  • it includes, for example, a hemihydrate, 1 hydrate, 2 hydrate or 1 ethanolate of a compound of Formula [I], or a monohydrate of a sodium salt of a compound of Formula [I] or a 1 ⁇ 2 ethanolate of dihydrochloride thereof.
  • the solvates may be obtained.
  • a compound of Formula [I] may exist as a tautomer.
  • a compound of Formula [I] may exist as an individual tautomer or a mixture of tautomers.
  • a compound of Formula [I] may have a carbon-carbon double bond.
  • a compound of Formula [I] may exist as an E-isomer, a Z-isomer or a mixture of E- and Z-isomers.
  • a compound of Formula [I] may exist as a stereoisomer which should be recognized as a cis/trans isomer.
  • a compound of Formula [I] may exist as a cis-isomer, a trans-isomer or a mixture of cis- and trans-isomers.
  • a compound of Formula [I] may have one or more asymmetric carbon atom(s).
  • a compound of Formula [I] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.
  • a compound of Formula [I] may exist as an atropisomer.
  • a compound of Formula [I] may exist as an individual atropisomer or a mixture of atropisomers.
  • a compound of Formula [I] may simultaneously have multiple structural features which can provide the above isomers.
  • a compound of Formula [I] may also contain the above isomers in any ratios.
  • Diastereomer mixtures may be isolated into each diastereomer by a conventional method such as chromatography or crystallization. Each diastereomer may be also prepared by using a starting material which is a single isomer in terms of stereochemistry or by a synthetic method using a stereoselective reaction.
  • a mixture of enantiomers may be isolated into each single enantiomer by a well known method in the art.
  • a mixture of enantiomers may be reacted with a substantially pure enantiomer which is known as a chiral auxiliary to form a mixture of diastereomers, which may be then isolated into a diastereomer with an enhanced isomeric ratio or a substantially pure single diastereomer by a common method such as fractionated crystallization or chromatography.
  • the added chiral auxiliary may be removed from the isolated diastereomer by a cleavage reaction to give a desirable enantiomer.
  • a mixture of enantiomers may be also directly separated by a well known chromatography in the art using a chiral stationary phase.
  • either of enantiomers may be also obtained by using a substantially pure and optically active starting material or a stereoselective synthesis (i.e., asymmetric induction) from a prochiral intermediate with a chiral auxiliary or asymmetric catalyst.
  • a stereoselective synthesis i.e., asymmetric induction
  • An absolute configuration may be determined by X-ray crystallographic analysis of a crystalline product or intermediate.
  • a crystalline product or intermediate which is induced by an agent having an asymmetric center with a known configuration may be used if needed.
  • a compound of Formula [I] may be labeled with an isotope atom such as 2 H, 3 H, 14 C, and 35 S.
  • a compound of Formula [I] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of Formula [I] or pharmaceutically acceptable salt thereof.
  • a more preferable one is a compound of Formula [I] or a pharmaceutically acceptable salt thereof purified in an 80% or more purity.
  • a pharmaceutical composition in the present invention may be prepared by optionally mixing a compound of Formula [I] or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carrier(s) in any amount.
  • a content of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition depends on dosage forms and doses, and is for example 0.1 to 100% by weight of the composition.
  • a dosage form of a compound of Formula [I] or a pharmaceutically acceptable salt thereof includes an oral preparation such as a tablet, a capsule, a granule, a powder, a lozenge, a syrup, an emulsion, and a suspension or an parenteral preparation such as an external preparation, a suppository, an injection, an eye drop, a nasal preparation, and a pulmonary preparation.
  • pharmaceutically acceptable carrier includes various common organic or inorganic carrier substances as a formulation material, and includes excipients, disintegrants, binders, fluidizers, and lubricants in a solid formulation, solvents, solubilizing agents, suspending agents, tonicity agents, buffers, and soothing agents in a liquid formulation, 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 a semisolid formulation.
  • a preserving agent, an antioxidant agent, a colorant or a sweetening agent may be also optionally used as an additive.
  • excipient includes, for example, lactose, white soft sugar, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethylstarch, low substituted hydroxypropylcellulose, and gum arabic.
  • disintegrant includes, for example, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose.
  • binder includes, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, white soft sugar, dextrin, starch, gelatin, carmellose sodium, and gum arabic.
  • fluidizer includes, for example, light anhydrous silicic acid and magnesium stearate.
  • lubricant includes, for example, magnesium stearate, calcium stearate, and talc.
  • solvent includes, for example, purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil, and olive oil.
  • solubilizing agent includes, for example, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.
  • sustained release agent includes, for example, benzalkonium chloride, carmellose, hydroxypropylcellulose, propyleneglycol, povidone, methylcellulose, and glyceryl monostearate.
  • tonicity agent includes, for example, glucose, D-sorbitol, sodium chloride, and D-mannitol.
  • buffer includes, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.
  • smoothing agent includes, for example, benzyl alcohol.
  • 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 acid and an ester 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, hydroxyethylcellulose, and hydroxypropylcellulose, synthetic polymers such as carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, and polyvinylpyrrolidone, propylene glycol, macrogol such as macrogol
  • preserving agent includes, for example, ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
  • antioxidant agent includes, for example, sodium sulfite and ascorbic acid.
  • 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.
  • sweetening agent includes, for example saccharin sodium, dipotassium glycyrrhizate, and aspartame.
  • a pharmaceutical composition in the present invention may be administered 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 orally or parenterally such as locally, rectally, intravenously, intramuscularly, and subcutaneously. While a dose may vary depending on subjects, diseases, symptoms, dosage forms, routes of administration and the like, for example when it is administered orally to an adult patient the dose of a compound of Formula [I] as the active ingredient ranges generally from about 0.01 mg to about 1 g per day, which may be administered once to several times in a divided amount.
  • a compound of Formula [I] or a pharmaceutically acceptable salt thereof has an inhibitory activity of Retinoid-related Orphan Receptor ⁇ (ROR ⁇ ), and is useful for treating or preventing various diseases or conditions which are expected to be improved by adjusting the ROR ⁇ inhibitory activity, e.g.
  • autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease, allergic diseases such as asthma, dry eye, fibrosis such as lung fibrosis and primary biliary cirrhosis, and metabolic diseases such as diabetes.
  • SLE systemic lupus erythematosus
  • ROR ⁇ antagonist means a compound having an ability which inhibits the function of Retinoid-related Orphan Receptor ⁇ (ROR ⁇ ) to make the activity thereof disappear or reduced.
  • inhibit ROR ⁇ means that a function of ROR ⁇ is inhibited to make the activity thereof disappear or reduced, which includes, for example, the function of ROR ⁇ is inhibited according to Test Example 1 described hereafter.
  • To “inhibit ROR ⁇ ” preferably includes “inhibiting human ROR ⁇ ”. Inhibiting the function or disappearing or reducing the activity may be preferably carried out during clinical indication in human.
  • ROR ⁇ inhibitor means any substance which inhibits ROR ⁇ , and may be a low molecular compound, a nucleic acid, polypeptide, protein, antibody, vaccine and the like.
  • a preferable “ROR ⁇ inhibitor” is “human ROR ⁇ inhibitor”.
  • treating includes improving symptoms, preventing severe diseases, maintaining a remission, preventing exacerbation as well as preventing relapse.
  • preventing means suppressing pathogenesis of symptoms.
  • autoimmune disease means a genric name of diseases where an immune system overreacts to and attacks normal cells and tissues thereof to cause symptoms, and in particular, includes rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, Behcet's disease, sarcoidosis, Harada disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
  • allergic disease means a disease derived from the condition where an immune reaction excessively occurs against a certain antigen, and in particular, includes atopic dermatitis, allergic rhinitis such as pollen allergy, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, infantile asthma, food allergy, medication allergy, and hives.
  • fibrosis means a condition with increased fibroconnective tissues, and in particular, includes lung fibrosis and primary biliary cirrhosis.
  • metabolic disease means a disease caused by abnormity 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 or type II diabetes.
  • the proposal of preferences and options in respect of different features of the compounds, methods, uses, and compositions comprises the proposal of combinations of those preferences and options for the different features, insofar as they are combinable and compatible.
  • Methods for preparing a compound of Formula [I] or a pharmaceutically acceptable salt thereof are illustrated as below.
  • a method for preparing a compound of Formula [I] or a pharmaceutically acceptable salt thereof is not however intended to be limited thereto.
  • 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 a reaction may optionally proceed to a sequential step without isolation and purification.
  • a compound of Formula [I] may be prepared according to the following Preparation Methods 1 to 5, for example:
  • P 1 is for example C 1-4 alkyl
  • R 3q1 is for example —Y b —CH 2 OP 2 (in which P 2 is a protective group such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS)), C 1-6 alkyl optionally substituted with hydroxy protected with one P 2 , C 3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group X b , 4-tetrahydropyranyl or I-methanesulfonyl-3-azetidinyl;
  • TMS trimethylsilyl
  • TDMS tert-butyldimethylsilyl
  • Y b is for example C 1-6 alkylene or C 3-6 cycloalkylene
  • Group X b is for example halogen or C 1-6 alkyl
  • R 5q is for example —Y c —COO—R q50 (in which R q50 is C 1-4 alkyl), hydrogen, C 1-4 alkyl optionally substituted with one C 1-3 alkoxy or C 3-6 cycloalkyl optionally substituted with hydroxy-C 1-4 alkyl protected with one P 2 ;
  • Y c is C 1-6 alkylene optionally substituted with hydroxy protected with one P 2 , CH 2 —CH 2 —O—CH 2 or (CH 2 ) m —Y c1 —(CH 2 ) w ;
  • n is an integer of 0, 1 or 2;
  • w is an integer of 0, 1 or 2;
  • Y c1 is for example C 3-6 cycloalkylene optionally substituted with one C 1-3 alkyl, phenylene, cross-linked C 5-8 cycloalkylene or
  • a compound of Formula [Q-102] may be prepared from a compound of Formula [Q-101a] by a rearrangement reaction with diacetoxyiodobenzene (e.g. a method described in Chem. Pharm. Bull., 1985, 33, 1097-1103).
  • a compound of Formula [Q-101a] may be prepared by Preparation Method 6 described below.
  • a compound of Formula [Q-103] may be prepared from a compound of Formula [Q-102] by hydrolysis with a base.
  • the base includes sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • a preferable base is sodium hydroxide.
  • a solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, and water, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is a mixed solvent with ethanol and water.
  • a reaction temperature includes from room temperature to 100° C.
  • a preferable reaction temperature is room temperature.
  • a compound of Formula [Q-105] may be prepared by a condensation reaction of a compound of Formula [Q-103] with a compound of Formula [Q-104].
  • a condensation agent includes aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), and carbonyldiimidazole (CDI).
  • WSC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • DCC N,N′-dicyclohexylcarbodiimide
  • DPPA diphenylphosphoryl azide
  • CDI carbonyldiimidazole
  • 1-hydroxy-1H-benzotriazole monohydrate HBt.H 2 O
  • DMAP 4-dimethylaminopyridine
  • a preferable condensation agent is a mixture of aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 4-dimethylaminopyridine (DMAP).
  • WSC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • DMAP 4-dimethylaminopyridine
  • a solvent includes toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is dichloromethane.
  • a reaction temperature includes from 0° C. to 100° C.
  • a preferable reaction temperature is room temperature.
  • a compound of Formula [Q-104] may be prepared by Preparation Method 7-1 described below.
  • a compound of Formula [Q-106] may be prepared from a compound of Formula [Q-105] in the presence of a base and a chlorosilane compound by Ireland Claisen rearrangement reaction (e.g. a method described in Org. Lett., 2007, 9, 4431-4434).
  • the base includes lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide (LiTMP).
  • LDA lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • LiTMP lithium 2,2,6,6-tetramethylpiperidide
  • a preferable base is lithium diisopropylamide (LDA).
  • the chlorosilane compound includes trimethylsilyl chloride and tert-butyldimethylsilyl chloride.
  • a preferable chlorosilane compound is trimethylsilyl chloride.
  • Hexamethylphosphoric triamide HMPA
  • N,N′-dimethylpropyleneurea DMPU
  • a solvent includes an ether type solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane.
  • a preferable solvent is tetrahydrofuran.
  • a reaction temperature includes from ⁇ 78° C. to 80° C.
  • a preferable reaction temperature is from ⁇ 78° C. to room temperature.
  • a compound of Formula [Q-107] may be prepared from a compound of Formula [Q-106] in the presence of a base by an azidation reaction followed by Curtius rearrangement reaction.
  • An azidation agent includes DPPA.
  • the base includes triethylamine and diisopropylethylamine.
  • a preferable base is triethylamine.
  • a solvent includes benzene, toluene, and xylene.
  • a preferable solvent is toluene.
  • a reaction temperature includes from 0° C. to 140° C.
  • a preferable reaction temperature is 110° C.
  • a compound of Formula [Q-109] may be prepared from a compound of Formula [Q-107] and a compound of Formula [Q-108].
  • a compound of Formula [Q-108] is hydrochloride, one or more equivalent(s) of a base such as triethylamine may be optionally added.
  • a solvent inludes benzene, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is tetrahydrofuran.
  • a reaction temperature includes from 0° C. to 80° C.
  • a preferable reaction temperature is from 0° C. to room temperature.
  • a compound of Formula [Q-108] may be prepared by Preparation Method 8-2 described below.
  • a compound of Formula [Q-110] may be prepared by an oxidative cleavage reaction of exo-olefin of a compound of Formula [Q-109], followed by a cyclization reaction with an acid.
  • the oxidative cleavage reaction includes ozone oxidation by reductive treatment.
  • a reducing agent used in the oxidative cleavage reaction includes dimethyl sulfide and triphenylphosphine.
  • a preferable reducing agent is dimethyl sulfide.
  • the acid used in the cyclization reaction includes hdyrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
  • a preferable acid is hdyrochloric acid.
  • the acid used in the cyclization reaction may be mixed with reactants from the beginning or may be added to the reaction system after completion of the oxidative cleavage reaction.
  • a solvent includes methanol, ethanol, isopropyl alcohol, tert-butanol, dichloromethane, and chloroform, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is methanol, or a mixed solvent of methanol with dichloromethane.
  • a reaction temperature includes from ⁇ 100° C. to 80° C.
  • a preferable reaction temperature is from ⁇ 78° C. to room temperature.
  • a compound of Formula [I] may be prepared from a compound of Formula [Q-110] by the following method.
  • a compound which R 3 or R 5 has a hydroxyl group as a substituent in a compound of Formula [I] and the hydroxyl group is protected with P 2 may be prepared by a deprotection reaction of P 2 .
  • the deprotection reaction may be carried out from the compound obtained in the cyclization reaction by a method described in a reference (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 165-215).
  • the reaction may be carried out under an acidic condition simultaneously with the cyclization reaction.
  • a compound which R 3 has a carboxyl group as a substituent in a compound of Formula [I] may be prepared by oxidizing a compound which R 3q1 has a primary hydroxyl group as a substituent with Dess-Martin reagent to an aldehyde (e.g. a method described in J. Org. Chem., 2000, 65, 5498-5505), followed by an oxidation reaction of the aldehyde with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and chlorous acid (e.g. a method described in J. Org. Chem., 1999, 64, 2564-2566).
  • an aldehyde e.g. a method described in J. Org. Chem., 2000, 65, 5498-5505
  • TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl
  • chlorous acid e.g. a method described in J. Org. Chem., 1999, 64, 2564-2566.
  • a compound which R 3 has a carboxyl group as a substituent may be prepared from a compound which R 3q1 has an ester as a substituent by a hydrolysis reaction.
  • the hydrolysis reaction may be carried out by a method of the above Step 2 or a hydrolysis reaction with an acid such as trifluoroacetic acid.
  • a compound which R 5 has a carboxyl group as a substituent in a compound of Formula [I] may be prepared by an oxidation reaction of a hydroxyl group or a hydrolysis reaction of an ester according to the Preparation Method of the compound which R 3 has a carboxyl group as a substituent.
  • R 5 is “—Y c —COO—R 50 ”
  • the compound may be prepared by the following hydrolysis reaction:
  • R 50 is for example C 1-4 alkyl and the other symbols have the same meanings as defined above.
  • R 3 is “—Y b —COO—R 30 ”
  • the compound may be prepared by the following hydrolysis reaction:
  • R 30 is for example C 1-4 alkyl and the other symbols have the same meanings as defined above.
  • R 3 is “—Y b —COO—R 30 ” in which R 30 is hydrogen
  • the compound may be prepared by the following oxidation reaction:
  • a compound of Formula [I] may be also prepared from a compound of Formula [Q-201] prepared from a compound of Formula [Q-101b] according to Preparation Method 1.
  • R q1 is for example bromo, iodo or benzyloxy
  • R 3q is for example —Y b —COO—R a30 (in which R q30 is C 1-4 alkyl), C 1-4 alkyl optionally substituted with one C 1-3 alkoxy or C 3-6 cycloalkyl optionally substituted with hydroxy-C 1-4 alkyl protected with one P 2
  • the other symbols have the same meanings as defined above.
  • a compound which R 1 is C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2 in Formula [I] may be prepared by the following method.
  • Bn is benzyl
  • X q1 is a leaving group such as halogen or a hydroxyl group
  • R 12 is a substituent (e.g. C 3-6 alkyl) which combines together with the oxygen atom on the benzene ring to form C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2
  • R 1 is for example C 3-6 alkoxy or C 2-7 alkoxy substituted with one trifluoromethyl, and the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-202] may be prepared by deprotecting the benzyl group of a compound of Formula [Q-201a] according to a method described in a reference (e.g. a method described in Peter G. M. Wuts (2007) Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, p 102-120).
  • the benzyl group may be removed by a reaction in the presence of Lewis acid in the step.
  • Lewis acid includes boron tribromide, boron trichloride, and trimethylsilyl iodide.
  • a preferable Lewis acid is boron tribromide.
  • a solvent includes benzene, toluene, dichloromethane, and chloroform.
  • a preferable solvent is dichloromethane.
  • a reaction temperature includes from ⁇ 78° C. to 80° C.
  • a preferable reaction temperature is ⁇ 78° C.
  • a compound of Formula [Q-204] may be prepared from a compound of Formula [Q-202] and a compound of Formula [Q-203].
  • a compound of Formula [Q-202] may be coupled with a compound of Formula [Q-203] in the presence of a base to give a compound of Formula [Q-204].
  • the base includes sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogencarbonate.
  • a preferable base is cesium carbonate.
  • a solvent includes diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, methylene chloride, chloroform, ethyl acetate, acetone, N,N-dimethylformamide, and dimethylsulfoxide.
  • a preferable solvent is N,N-dimethylformamide.
  • a reaction temperature is from room temperature to 120° C.
  • a preferable reaction temperature is 100° C.
  • a compound of Formula [Q-202] may be subjected under Mitsunobu reaction with a compound of Formula [Q-203] in a solvent in the presence of bis(2-methoxyethyl)azodicarboxylate and triphenylphosphine to give a compound of Formula [Q-204].
  • the solven includes methylene chloride, chloroform, tetrahydrofuran, and toluene.
  • a preferable solvent is tetrahydrofuran.
  • a reaction temperature includes from 0° C. to 100° C.
  • a preferable reaction temperature is from room temperature to 60° C.
  • a compound of Formula [I] may be prepared from a compound of Formula [Q-204] according to Preparation Method 1 Step 8.
  • a compound which R 1 is, for example, C 4-8 alkyl or C 1-4 alkyl substituted with one substituent selected from Group X a1 in Formula [I] may be prepared from a compound of Formula [Q-201b] by a cross coupling reaction or an insertion reaction of carbon monoxide:
  • R q2 is for example bromo, iodo or trifluoromethane sulfonyloxy and the other symbols have the same meanings as defined above.
  • the cross coupling reaction includes a method described in a reference (e.g. a method described in F. Diederich, P. J. Stang (1998). Metal-catalyzed Cross-coupling Reactions, Weinheim, Germany, Wiley-VCH), and the insertion reaction of carbon monoxide includes a method described in a reference (e.g. M. Schlosser (1994). Organometallics in Synthesis, Weinheim, Germany, Wiley-VCH).
  • R 1 is for example C 4-8 alkyl or C 1-4 alkyl substituted with one substituent selected from Group X a1 (provided that R 1 is not C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2 ),
  • R 10 is for example C 2-6 alkyl, M 1 is boronic acid, boronic acid ester or trifluoroborate salt, M 2 is zinc or zinc halide, and the other symbols have the same meanings as defined above.
  • a commercially available product e.g. isobutylboronic acid, 1-hexylboronic acid pinacol ester, potassium (3,3-dimethylbutyl)trifluoroborate, butylzinc bromide, cyclohexylacetylene
  • R 1 —X qq e.g. 1-chloro-3,3-dimethyl-butane, bromomethyl-cyclohexane; X qq is chloro, bromo or iodo
  • a compound of Formula [Q-202a] may be prepared by the following method.
  • a compound which M 1 is boronic acid may be prepared by preparing Grignard reagent from a commercially available compound such as R 1 —Br and magnesium to react with trimethyl borate, triisopropyl borate, for example.
  • a compound which M 1 is boronic acid ester may be prepared by reacting a boronic acid compound with pinacol.
  • a compound which M 1 is trifluoroborate salt may be prepared by reacting a boronic acid compound with potassium hydrogen fluoride.
  • a compound of Formula [Q-202b] may be prepared from a commerically available compound such as R 1 —I and zinc.
  • An activating agent of zinc includes iodine, trimethylsilyl chloride and 1,2-dibromoethane, and may be used alone or by mixture of two or more of them.
  • a preferable activating agent is trimethylsilyl chloride or 1,2-dibromoethane.
  • a solvent includes tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.
  • a preferable solvent is tetrahydrofuran or dimethylacetamide.
  • a reaction temperature includes from room temperature to 80° C.
  • a preferable reaction temperature is room temperature.
  • a commerically available product such as 3,3-dimethyl-1-butyne, cyclohexylacetylene, and phenylacetylene may be used for a compound of Formula [Q-202c].
  • An alkynylene compound of Formula [I] obtained by Sonogashira reaction may be converted into an alkyl compound by a catalytic hydrogen addition reaction with a catalyst such as palladium on carbon, platinum on carbon, and rhodium-alumina.
  • a compound of Formula [Q-201b] may be reacted in an alcohol solvent such as ethanol to convert into an ester corresponding to the alcohol.
  • a compound which R 3 or R 5 has a hydroxyl group as a substituent a compound which R 3 has a carboxyl group as a substituent or a compound which R 5 has a carboxyl group as a substituent may be prepared according to Preparation Method 2-1 Step 3.
  • a compound which R 6 is hydrogen in a compound of Formula [I] may be prepared by Biginelli reaction.
  • R 6 is hydrogen and each symbol has the same meaning as defined above.
  • a compound of Formula [I] may be prepared by reacting a compound of Formula [Q-301], a compound of Formula [Q-302], and a compound of Formula [Q-303] in the presence of an acid.
  • the acid includes hdyrochloric acid, acetic acid, trimethylchlorosilane, and p-toluenesulfonic acid.
  • a preferable acid is trimethylchlorosilane.
  • a solvent includes toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them.
  • a preferable solvent in the reaction is a mixed solvent of acetonitrile and N,N-dimethylformamide.
  • a reaction temperature includes from 0° C. to 140° C.
  • a preferable reaction temperature is from room temperature to 120° C.
  • a compound of Formula [Q-301] may be prepared by Preparation Method 6 described below.
  • a compound of Formula [Q-302] may be prepared by Preparation Method 7-2 described below.
  • a compound of Formula [Q-303] may be prepared by Preparation Method 8-3 described below.
  • a compound which R 3 or R 5 has a hydroxyl group as a substituent, a compound which R 3 has a carboxyl group as a substituent or a compound which R 5 has a carboxyl group as a substituent in a compound of Formula [I] may be prepared according to Preparation Method 2-1 Step 3.
  • R 3 is for example —Y b —CH 2 OP 3 (in which P 3 is a protective group such as tert-butyldiphenylsilyl (TBDPS) and benzyl), C 1-6 alkyl optionally substituted with a hydroxyl group protected with one P 3 , C 3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group X b , 4-tetrahydropyranyl or 1-methanesulfonyl-3-azetidinyl; R 5 is for example tert-butyl; and the other symbols have the same meanings as defined above.
  • P 3 is a protective group such as tert-butyldiphenylsilyl (TBDPS) and benzyl
  • TDPS tert-butyldiphenylsilyl
  • R 5 is for example tert-butyl
  • the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-403] may be prepared by reacting a compound of Formula [Q-401a] and a compound of Formula [Q-402] in the presence of Lewis acid according to a method described in a reference (e.g. a method described in G. K. Datta; J. A. Ellman, J. Org. Chem. 2010, 75, 6283-6285).
  • An illustrative example of a compound of Formula [Q-402] includes the following compound.
  • Lewis acid includes Lewis acid such as tetraalkyl orthotitanate.
  • a preferable Lewis acid is tetraethyl orthotitanate.
  • a solvent includes benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and cyclopentylmethyl ether.
  • a preferable solvent is cyclopentylmethyl ether.
  • a reaction temperature includes from room temperature to 120° C.
  • a preferable reaction temperature is 110° C.
  • a commercially available product may be used for a compound of Formula [Q-401a] or it may be prepared by known methods or Preparation Method 6.
  • a compound of Formula [Q-405] may be prepared by reacting a compound of Formula [Q-403] and a compound of Formula [Q-404] in the presence of a base according to a method described in a reference (e.g. a method described in T. P. Tang; J. A. Ellman, J. Org. Chem. 2002, 67, 7819-7832).
  • the base includes lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide (LiTMP).
  • LDA lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • LiTMP 2,2,6,6-tetramethylpiperidide
  • a preferable base is lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS).
  • a solvent includes benzene, toluene, xylene, hexane, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is tetrahydrofuran.
  • a reaction temperature includes from ⁇ 78° C. to room temperature.
  • a preferable reaction temperature is from ⁇ 78° C. to 0° C.
  • an additive such as titanium (IV) chlorotriisopropoxy may be also added.
  • An equivalent amount of the base includes from 1 to 3 equivalent(s).
  • a preferable amount is 2.1 equivalents.
  • a commercially available product may be used for a compound of Formula [Q-404] or it may be prepared by known methods or Preparation Method 6.
  • a compound of Formula [Q-406] may be prepared by reacting a compound of Formula [Q-405] with a reducing agent.
  • the reducing agent includes diisobutylaluminum hydride, lithium aluminum hydride, and lithium borohydride.
  • a preferable reducing agent is diisobutylaluminum hydride.
  • a solvent includes toluene, dichloromethane, diethyl ether, and tetrahydrofuran.
  • a preferable solvent is toluene.
  • a reaction temperature includes from ⁇ 78° C. to room temperature.
  • a preferable reaction temperature is from ⁇ 78° C. to 0° C.
  • a compound of Formula [Q-407] may be prepared by hydrolyze a compound of Formula [Q-406] under an acidic condition.
  • the acid includes hdyrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
  • a preferable acid is hdyrochloric acid.
  • a solvent includes tetrahydrofuran, methanol, ethanol, and isopropyl alcohol, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is methanol.
  • a reaction temperature includes from 0° C. to 60° C.
  • a preferable reaction temperature is from 0° C. to room temperature.
  • a compound of Formula [Q-409] may be prepared from a compound of Formula [Q-407] and a compound of Formula [Q-408].
  • a solvent includes benzene, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is tetrahydrofuran.
  • a reaction temperature includes from 0° C. to 80° C.
  • a preferable reaction temperature is from 0° C. to room temperature.
  • a compound of Formula [Q-410] may be prepared by an oxidation reaction of a compound of Formula [Q-409], followed by a cyclization reaction.
  • the oxidizing agent includes 2-azaadamantane-N-oxyl (AZADO), 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO), and Dess-Martin reagent (DMP). Diacetoxyiodobenzene or sodium hydrochlorite, for example, may be optionally added as a co-oxidizing agent.
  • a preferable oxidizing agent in the reaction is a mixture of 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) and diacetoxyiodobenzene.
  • the acid in the cyclization reaction includes hdyrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
  • a preferable acid is trifluoroacetic acid.
  • a solvent includes tert-butanol, benzene, toluene, dichloromethane, chloroform, ethyl acetate, and acetonitrile.
  • a preferable solvent in the reaction is dichloromethane or chloroform.
  • a reaction temperature includes from 0° C. to 80° C.
  • a preferable reaction temperature is from 0° C. to room temperature.
  • a compound which R 3 or R 5 has a hydroxyl group as a substituent, a compound which R 3 has a carboxyl group as a substituent or a compound which R 5 has a carboxyl group as a substituent in a compound of Formula [IV-D] may be prepared according to Preparation Method 1 Step 8.
  • the following compound of Formula [E-IV-D] may be prepared using an enantiomer (i.e., a compound of Formula [E-Q-402]) of a compound of Formula [Q-402] according to Preparation Method 4.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-401 b] and a compound of Formula [Q-402] according to Preparation Method 4.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-501] according to the following Preparation Method 5-1 or 5-2.
  • a compound of Formula [Q-503] which R 1 is C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2 in Formula [IV-D] may be prepared by the following method.
  • R 1 is C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2 , and the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-501a] may be prepared from a compound which R q1 is a benzyl ether group in a compound of Formula [Q-401b] according to Preparation Method 4.
  • a compound of Formula [Q-503] may be prepared from a compound of Formula [Q-501a] according to Preparation Method 2-1.
  • R q1 is for Example Bromo, Iodo or Trifluoromethanesulfonyloxy Group in a Compound of Formula [Q-501]:
  • a compound which R 1 is a substituent such as C 4-8 alkyl and C 1-4 alkyl substituted with one substituent selected from Group X a1 in Formula [IV-D] may be prepared from a compound of the following Formula [Q-501 b] by a cross coupling reaction or an insertion reaction of carbon monoxide.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-501b] according to Preparation Method 2-2.
  • Preparation Method 5-2 (Suzuki coupling) is for example as follows.
  • a compound of Formula [R 1 -M 1 ] may be synthesized by a common procedure.
  • GrubbsCat.2nd means a second-generation Grubbs catalyst, (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)-ruthenium, and the other symbols have the same meanings as defined above.
  • a compound which R 1 is C 3-6 alkylsulfanyl, C 3-6 alkylsulfinyl, C 3-6 alkylsulfonyl, C 3-6 cycloalkylsulfanyl, C 3-6 cycloalkylsulfinyl or C 3-6 cycloalkylsulfonyl in Formula [IV-D] may be prepared by the following method.
  • R 1s is C 3-6 alkyl or C 3-s cycloalkyl
  • R 1 is C 3-6 alkylsulfanyl or C 3-6 cycloalkylsulfanyl
  • R 5q is —Y c —COOR q50 wherein Y c is C 1-6 alkylene optionally substituted with one hydroxy and R q50 is hydrogen or C 1-4 alkyl
  • R 5 is —Y c —COOH
  • R 6 is methyl
  • the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-504] may be prepared from a compound of Formula [Q-401c] using Preparation Method 5.
  • a compound of Formula [Q-506] may be prepared by a coupling reaction of a compound of Formula [Q-504] and a compound of Formula [Q-505] according to a method described in a literature such as a method described in Org. Lett. 2004, 6, 4587-4590, for example.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-506] according to Preparation Method 1 Step 8.
  • R 1s is C 3-6 alkyl or C 3-6 cycloalkyl
  • R 1 is C 3-6 alkylsulfinyl or C 3-6 cycloalkylsulfinyl
  • R 5q is —Y c —COOR q50 wherein Y c is C 1-6 alkylene optionally substituted with one hydroxy and R q50 is hydrogen or C 1-4 alkyl
  • R 5 is —Y c —COOH
  • R 6 is methyl
  • the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-507] may be prepared by an oxidation reaction of sulfide of a compound of Formula [Q-506].
  • An oxidizing agent includes hydrogen peroxide, peracetic acid, hydroperoxide, permanganate, meta-chloroperbenzoic acid, and sodium hypochlorite.
  • a preferable oxidizing agent is meta-chloroperbenzoic acid.
  • a solvent includes benzene, dichloromethane, acetonitrile, and water, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is dichloromethane.
  • a reaction temperature includes from ⁇ 78° C. to room temperature.
  • a preferable reaction temperature is ⁇ 78° C.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-507] according to Preparation Method 1 Step 8.
  • R 1s is C 3-6 alkyl or C 3-6 cycloalkyl
  • R 1 is C 3-6 alkylsulfonyl or C 3-6 cycloalkylsulfonyl
  • R 5q is —Y c —COOR q50 wherein Y c is C 1-6 alkylene optionally substituted with one hydroxy and R q50 is hydrogen or C 1-4 alkyl
  • R 5 is —Y c —COOH
  • R 6 is methyl
  • the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-508] may be prepared by an oxidation reaction of sulfide of a compound of Formula [Q-506].
  • An oxidizing agent includes oxone, meta-chloroperbenzoic acid, and potassium permanganate.
  • a preferable oxidizing agent is meta-chloroperbenzoic acid.
  • a solvent includes benzene, dichloromethane, acetonitrile, and water, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is dichloromethane.
  • a reaction temperature includes from ⁇ 78° C. to room temperature.
  • a preferable reaction temperature is room temperature.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-508] according to Preparation Method 1 Step 8.
  • a compound of Formula [Q-520] may be prepared from a compound of Formula [Q-401a] according to Preparation Method 4.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-520] using cross-coupling reaction.
  • R 3q3 is —Y b —COOR q30 wherein Y b is phenyl and R q30 is hydrogen or C 1-4 alkyl, R 6 is methyl, and the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-511] may be prepared by reacting a compound of Formula [Q-403] with a compound of Formula [Q-510] under a basic condition.
  • a base includes lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide (LiTMP).
  • LDA lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • LiTMP 2,2,6,6-tetramethylpiperidide
  • a preferable base is lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS).
  • a solvent includes benzene, toluene, xylene, hexane, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is tetrahydrofuran.
  • a reaction temperature includes from ⁇ 78° C. to room temperature.
  • a preferable reaction temperature is from ⁇ 78° C. to 0° C.
  • an additive such as chlorotriisopropoxy titanium (IV) may be further added.
  • An equivalent amount of a base includes from 1 to 3 equivalent amount(s).
  • a preferable equivalent amount is 2.1 equivalent amounts.
  • a commercially available product such as 3-hydroxy-propionic acid methyl ester, 3-hydroxy-propionic acid ethyl ester, and 3-hydroxy-propionic acid t-butyl ester may be used.
  • a compound of Formula [Q-512] may be prepared by hydrolyzing a compound of Formula [Q-511] under an acidic condition.
  • An acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid.
  • a preferable acid is hydrochloric acid.
  • a solvent includes tetrahydrofuran, methanol, ethanol, and isopropyl alcohol, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is methanol.
  • a reaction temperature includes from 0° C. to 60° C.
  • a preferable reaction temperature is from 0° C. to room temperature.
  • a compound of Formula [Q-513] may be prepared by protecting a compound of Formula [Q-512] with tert-butyldiphenylsilyl (TBDPS) according to a method described in a literature (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 141-144).
  • TDPS tert-butyldiphenylsilyl
  • a compound of Formula [Q-514] may be prepared by reacting a compound of Formula [Q-513] with p-nitrophenyl chloroformate under a basic condition.
  • a base includes triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, and potassium carbonate.
  • a preferable base is triethylamine.
  • a solvent includes chloroform, dichloromethane, toluene, tetrahydrofuran, and acetonitrile.
  • a preferable solvent is chloroform.
  • a reaction temperature includes from 0° C. to 85° C.
  • a preferable reaction temperature is 0° C.
  • a compound of Formula [Q-516] may be prepared by reacting a compound of Formula [Q-514] with a compound of Formula [Q-515] under a basic condition.
  • a base includes triethylamine and diisopropylethylamine.
  • a preferable base is triethylamine.
  • a solvent includes chloroform, dichloromethane, and tetrahydrofuran.
  • a preferable solvent is chloroform.
  • a reaction temperature includes from room temperature to 60° C.
  • a preferable reaction temperature is 60° C.
  • a compound of Formula [Q-517] may be prepared by deprotecting tert-butyldiphenylsilyl (TBDPS) of a compound of Formula [Q-516] according to a method described in a literature (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 142-143).
  • TDPS tert-butyldiphenylsilyl
  • a compound of Formula [Q-518] may be prepared from a compound of Formula [Q-517] according to Preparation Method 4 Step 6.
  • a compound of Formula [Q-519] may be prepared by deprotecting tert-butyl ester from a compound of Formula [Q-518] wherein P 1 is for example tert-butyl according to a method described in a literature (e.g. a method described in Peter G. M. Wuts. Protective Groups in Organic Synthesis Third Edition, Wiley-Interscience, 406-407).
  • a compound of Formula [Q-520] may be prepared by brominating a compound of Formula [Q-519] according to a method described in a literature (e.g. a method described in A. J. Zych; H. Wang; S. A. Sakwa, Tetrahedron Lett. 2010, 51, 5103-5105).
  • a compound of Formula [Q-522] may be prepared from a compound of Formula [Q-520] and a compound of Formula [Q-521] according to Preparation Method 2-2 (including cross-coupling).
  • a compound of Formula [IV-D] may be prepared for example by hydrolyzing a compound of Formula [Q-522].
  • Step 11 coupling reaction
  • Step 12 hydrolysis reaction
  • R 6 is methyl, and the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-536] may be prepared from a compound of Formula [Q-401a] using Preparation Methods 4 and 5-4.
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-536] by a cyclization reaction under a basic condition, a reduction reaction using Schwartz's reagent, an oxidation reaction using Dess-Martin reagent into an aldehyde compound, followed by Pinnic Oxidation into a carboxylic acid compound.
  • Y b is C 3-6 cycloalkylene
  • R 3 is —Y b —COOH
  • R 6 is methyl
  • TBDMS tert-butyldimethylsilyl
  • TBDPS tert-butyldiphenylsilyl
  • MOM methoxymethyl
  • a compound of Formula [Q-403] may be prepared from a compound of Formula [Q-401a] according to Preparation Method 4 Step 1.
  • a compound of Formula [Q-531] may be prepared from a compound of Formula [Q-403] and a compound of Formula [Q-530] according to Preparation Method 4 Step 2.
  • a compound of Formula [Q-530] may be commercially available or synthesized by a method described in a literature (e.g. a method described in WO 2009/019174).
  • a compound of Formula [Q-403] may be prepared from a compound of Formula [Q-401a] according to Preparation Method 4 Step 4.
  • a compound of Formula [Q-533] may be prepared by protecting a compound of Formula [Q-532] with tert-butyldimethylsilyl (TBDMS) according to a method described in a literature (e.g. a method described in Peter G. M. Wuts. Protective Groups in Organic Synthesis Third Edition, Wiley-Interscience, 127-131).
  • TDMS tert-butyldimethylsilyl
  • a compound of Formula [Q-534] may be prepared from a compound of Formula [Q-533] according to Preparation Method 5 Step 5.
  • a compound of Formula [Q-536] may be prepared from a compound of Formula [Q-534] and a compound of Formula [Q-535] according to Preparation Method 5 Step 6.
  • a compound of Formula [Q-537] may be prepared by cyclizing a compound of Formula [Q-536] according to a method described in a literature (e.g. a method described in R. Patino-Molina; I. Cubero-Lajo; M. J. P. Vega; M. T. Garcia-Lopez, Tetrahedron Lett. 2007, 48, 3615-3616).
  • a compound of Formula [Q-538] may be prepared by reducing a compound of Formula [Q-537] with Schwartz's reagent according to a method described in for example S. R. Dandepally; R. Elgoummadi; A. L. Williams, Tetrahedron Lett. 2013, 54, 925-928.
  • a compound of Formula [Q-539] may be prepared by oxidizing a compound of Formula [Q-538] with Dess-Martin reagent (e.g. a method described in E. Vedejs; D. W. Piotrowski; F. C. Tucci, J. Org. Chem. 2000, 65, 5498-5505).
  • Dess-Martin reagent e.g. a method described in E. Vedejs; D. W. Piotrowski; F. C. Tucci, J. Org. Chem. 2000, 65, 5498-5505
  • a compound of Formula [IV-D] may be prepared from a compound of Formula [Q-539] by Pinnick oxidation (e.g. a method described in G. A. Kraus; B. Roth, J. Org. Chem. 1980, 45, 4825-4830).
  • Preparation Method 5-5 is illustrated in the following reactions when chemical name: (3-methoxymethoxymethyl-cyclobutyl)-acetic acid methyl ester is used as a compound of Formula [Q-530] and chemical name: 3,3-difluoro-cyclobutylamine is used as a compound of Formula [Q-535]
  • R 6 is methyl, and the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-101b], Formula [Q-301a] or [Q-401b] which is a starting material of Preparation Method 2 or 5 is represented by the following general formula:
  • U 1 is formyl, acetyl or ethylcarbonyl (which means each embodiment of —(C ⁇ O)—H, —(C ⁇ O)—R 6 or —(C ⁇ O)—CH 2 —R 6 wherein R 6 is hydrogen or methyl, respectively), and the other symbols have the same meanings as defined above.
  • a commercially available product e.g. 4-bromo-3-chloro-benzaldehyde, 1-(4-bromo-3-chloro-phenyl)-ethanone, 1-(4-bromo-3-chloro-phenyl)-propan-1-one
  • a compound of Formula [Q-602] may be prepared by a condensation reaction of a compound of Formula [Q-601] with N,O-dimethylhydroxylamine or N,O-dimethylhydroxylamine hydrochloride.
  • the condensation agent includes aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), and carbonyldiimidazole (CDI).
  • WSC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • DCC N,N′-dicyclohexylcarbodiimide
  • DPPA diphenylphosphoryl azide
  • CDI carbonyldiimidazole
  • 1-hydroxy-1H-benzotriazole monohydrate HBt.H 2 O
  • DMAP 4-dimethylaminopyridine
  • a preferable condensation agent in the step is a mixture of aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 1-hydroxy-1H-benzotriazole monohydrate (HOBt.H 2 O).
  • a solvent includes toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them.
  • a preferable solvent in the reaction is N,N-dimethylformamide or acetonitrile.
  • a compound of Formula [Q-101b] or Formula [Q-401b] may be prepared by reacting a compound of Formula [Q-602] with Grignard reagent such as MeMgX and EtMgX (wherein X is chloro or bromo).
  • a solvent includes an ether solvent such as diethyl ether, tetrahydrofuran (THF), and 1,2-dimethoxyethane (DME).
  • ether solvent such as diethyl ether, tetrahydrofuran (THF), and 1,2-dimethoxyethane (DME).
  • DME 1,2-dimethoxyethane
  • a preferable solvent is THF.
  • a compound of Formula [Q-301a] may be prepared by reacting a compound of Formula [Q-602] with a reducing agent such as diisobutylaluminum hydride (DIBAL-H).
  • DIBAL-H diisobutylaluminum hydride
  • a compound which U 1 is formyl or ketone may be also prepared from a commercially available compound such as 2,2-dimethyl-indane-5-carboxylic acid in place of a compound of Formula [Q-601] by the above Steps 1 and 2.
  • U 1 is formyl, acetyl or ethylcarbonyl and each symbol has the same meaning as defined above.
  • a compound of Formula [Q-101a], a starting material of Preparation Method 1, a compound of Formula [Q-301], a starting material of Preparation Method 3, and a compound of Formula [Q-401a], a starting material of Preparation Method 4, are represented by the following general formula:
  • the above compound may be for example prepared according to the following method.
  • a compound of Formula [Q-101a], Formula [Q-301] or Formula [Q-401a] wherein R 1 is C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2 may be prepared from a compound of Formula [Q-101b1] or Formula [Q-401b1] via a compound of Formula [Q-603].
  • Step 1 a deprotection reaction of benzyl group
  • Step 2 a reaction with a compound of Formula [Q-203]
  • a compound of Formula [Q-101a], Formula [Q-301] or Formula [Q-401a] wherein R 1 is C 4-8 alkyl or C 1-4 alkyl substituted with one substituent selected from Group X a1 but R 1 is not C 3-6 alkoxy, C 2-7 alkoxy substituted with one trifluoromethyl or C 1-3 alkoxy substituted with one substituent selected from Group X a2 may be prepared from a compound of Formula [Q-101b2] or Formula [Q-401b2].
  • a cross-coupling reaction using palladium may be carried out according to Preparation Method 2-2.
  • U 1 is acetyl or ethylcarbonyl, and each symbol has the same meaning as defined above.
  • a compound of Formula [Q-102b] may be prepared from 2-(3-chloro-4-trifluoromethanesulfonyloxy-phenyl)-propionic-acid-methyl-ester prepared from known 2-(3-chloro-4-hydroxy-phenyl)-propionic-acid-methyl-ester or a compound of the following Formula [Q-101b2] according to Preparation Method 1 Step 1.
  • a compound of Formula [Q-102] may be prepared from a compound of Formula [Q-102b] according to Preparation Method 2-2.
  • R 11 is for example C 2-4 alkyl, and the other symbols have the same meanings as defined above.
  • a compound of Formula [Q-604] a commercially available compound such as (4-bromo-3-chloro-phenyl)-methanol, (4-bromo-3,5-dimethyl-phenyl)-methanol, and (4-bromo-2-methoxy-phenyl)-methanol may be used.
  • a compound of Formula [Q-605] may be prepared by reacting a compound of Formula [Q-604] with a commercially available compound such as R 11 —Br in the presence of a base such as sodium hydride.
  • a solvent includes N,N-dimethylformamide.
  • a compound of Formula [Q-605] wherein R 11 is tert-butyl may be prepared by reacting a compound of Formula [Q-604] with di-tert-butyl dicarbonate in the presence of magnesium perchlorate (e.g. a method described in Org. Lett., 2005, 7, 427-430).
  • a compound of Formula [Q-606] may be prepared from a compound of Formula [Q-605] according to an insertion reaction of carbon monoxide in Preparation Method 2-2.
  • a solvent includes a mixed solvent of toluene and water.
  • the corresponding formyl, acetyl or ethylcarbonyl compound of Formula [Q-101a], [Q-301] or [Q-401a] may be prepared from a compound of Formula [Q-606] according to Preparation Method 6-1.
  • each symbol has the same meaning as defined above may be also prepared by a formation reaction of carbon-carbon bond of a compound of the following Formula [Q-607] and the compound having ketone or formyl.
  • a commercially available product such as 4-bromo-2-chloro-1-iodobenzene, 5-bromo-1,3-difluoro-2-iodobenzene, 4-bromo-2-ethyliodobenzene, and 5-bromo-2-iodo-m-xylene may be used.
  • 2-benzyloxy-4-bromo-1-iodo-benzene which a commercially available 5-bromo-2-iodophenol is benzylated by a known method is also illustrated.
  • the compound having ketone or formyl includes the compound having ketone such as spiro-C 6-11 cycloalkanone and C 4-6 cycloalkanone or the compound having formyl such as C 4-8 alkylaldehyde.
  • a compound of Formula [Q-607] may be reacted as follows to prepare a compound of the following Formula [Q-612].
  • a compound of Formula [Q-609] may be prepared by a halogen-metal exchange reaction of a compound of Formula [Q-607] with isopropylmagnesium chloride and the like, followed by an addition reaction with a compound of Formula [Q-608].
  • a solvent includes THF and DME.
  • a reaction temperature includes from ⁇ 45° C. to room temperature.
  • a compound of Formula [Q-610] may be prepared by a mesylation reaction of a compound of Formula [Q-609] in the presence of a base.
  • a mesylating agent includes methanesulfonyl chloride.
  • a base includes triethylamine and diisopropylethylamine.
  • a preferable base is triethylamine.
  • a catalytic amount of trimethylamine hydrochloride and the like may be added if needed.
  • a solvent includes benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, and acetone.
  • a preferable solvent is toluene.
  • a reaction temperature includes from 0° C. to 60° C.
  • a preferable reaction temperature is from 0° C. to room temperature.
  • a compound of Formula [Q-611] may be prepared by a catalytic hydrogenation of a compound of Formula [Q-610] in the presence of a catalyst.
  • a catalyst includes palladium carbon, platinum carbon, rhodium carbon, and rhodium-alumina.
  • a preferable catalyst is rhodium carbon.
  • a solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, 1,2-dimethoxyethane, and ethyl acetate, and may be used alone or by mixture of two or more of them.
  • a preferable solvent is a mixed solvent of methanol and tetrahydrofuran.
  • a compound of Formula [Q-611] may be also prepared by reducing a compound of Formula [Q-609] in the presence of Lewis acid.
  • Lewis acid includes boron trifluoride diethyl ether.
  • a reducing agent includes triethylsilane.
  • a solvent includes dichloromethane and tetrahydrofuran.
  • a preferable solvent is dichloromethane.
  • a reaction temperature includes from ⁇ 78° C. to room temperature.
  • a preferable reaction temperature is from ⁇ 78° C. to room temperature.
  • a compound of Formula [Q-612] may be prepared from a compound of Formula [Q-611] according to an insertion reaction of carbon monoxide in Preparation Method 6-3.
  • the corresponding formyl, acetyl or ethylcarbonyl compound of Formula [Q-101a], [Q-301] or [Q-401a] may be prepared from a compound of Formula [Q-612] according to Preparation Method 6-1.
  • the following compound may be prepared with a ketone compound of “C 3-6 cycloalkyl substituted with the same or different one to two C 1-5 alkyl”, e.g. 3-isopropyl-cyclobutanone, as described above.
  • a compound of Formula [Q-102], an intermediate of Preparation Method 1, e.g. a compound of Formula [Q-617] wherein R 2 is chloro and R 6 is methyl and the like, may be prepared by the following method.
  • a compound of Formula [Q-614] may be prepared by esterifying a compound of Formula [Q-613]. For example, when thionyl chloride and methanol are used, methyl ester may be obtained.
  • a compound of Formula [Q-613] a commercially available product such as 2-(4-hydroxy-phenyl)-propionic acid may be used.
  • a compound of Formula [Q-615] may be prepared by chlorination of a compound of Formula [Q-614] with N-chlorosuccinimide (NCS) and the like.
  • a solvent includes acetonitrile and N,N-dimethylformamide.
  • a preferable solvent is N,N-dimethylformamide.
  • a compound of Formula [Q-616] may be prepared by reacting a compound of Formula [Q-615] with trifluoromethanesulfonic anhydride in the presence of a base.
  • a base includes triethylamine and pyridine.
  • a preferable base is pyridine.
  • a solvent includes toluene, dichloromethane, chloroform, and tetrahydrofuran.
  • a preferable solvent is dichloromethane.
  • a reaction temperature includes from 0° C. to room temperature.
  • a preferable reaction temperature is 0° C.
  • a compound of Formula [Q-617] may be prepared from a compound of Formula [Q-616] by a cross-coupling reaction (e.g. Suzuki reaction and Sonogashira reaction) as described in Preparation Method 2-2.
  • a cross-coupling reaction e.g. Suzuki reaction and Sonogashira reaction
  • the resulted alkynylene compound may be converted into an alkylene compound by a catalytic hydrogenation with a catalyst such as palladium carbon, platinum carbon, and rhodium-alumina.
  • a compound of Formula [I] wherein R 2 is chloro and R 6 is methyl and the like may be prepared with a compound of Formula [Q-617] by the reactions described in Preparation Method 1.
  • a compound of Formula [Q-702] may be prepared from a compound of Formula [Q-701] and alkylphosphonic diester such as triethyl phosphonoacetate under Homer-Wadsworth-Emmons Reaction.
  • a compound of Formula [Q-104] may be prepared from a compound of Formula [Q-702] by DIBAL reduction according to Preparation Method 6-1 Step 2.
  • a commercially available aldehyde such as 2-methylpropylaldehyde, isovaleraldehyde, 3,3-dimethylbutylaldehyde, and 4-methylpentylaldehyde may be used, which may be alternatively prepared by a known method.
  • a compound of Formula [Q-701a] may be prepared from a compound of Formula [Q-703].
  • a compound of Formula [Q-704] may be prepared by protecting a hydroxyl group of a compound of Formula [Q-703] (e.g. a commerically available compound such as 2,2-dimethyl-3-hydroxypropanoic acid methyl ester, 4-hydroxy-2,2-dimethyl-butanoic acid methyl ester, and 5-hydroxy-2,2-dimethyl-pentanoic acid methyl ester) with trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS) and the like according to a method described in a literature (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 165-215).
  • TMS trimethylsilyl
  • TBS tert-butyldimethylsilyl
  • a compound of Formula [Q-705] may be prepared from a compound of Formula [Q-704] under DIBAL reduction according to Preparation Method 6-1 Step 2.
  • a compound of Formula [Q-701a] may be for example prepared by Parikh-Doering oxidation reaction of a compound of Formula [Q-705] with SO 3 .Py.
  • a compound of Formula [Q-701b] may be also prepared from C 3-6 cycloalkanone optionally substituted with the same or different one to three substituent(s) selected from Group X b and Wittig reagent according to a method described in a literature (e.g. a method described in Bioorg. Med. Chem. Lett. 2004, 14(20), 5199-5203).
  • a literature e.g. a method described in Bioorg. Med. Chem. Lett. 2004, 14(20), 5199-5203.
  • R 3q1 is cyclohexyl
  • a commerically available aldehyde or ketone such as 3,3-dimethyl-butylaldehyde, 4-methyl-pentanal, cyclohexyl-acetaldehyde, and 2-butanone may be used, which may be alternatively prepared by a known method.
  • a compound of Formula [Q-302] wherein R 4 is H i.e., an aldehyde compound
  • R 4 i.e., an aldehyde compound
  • a compound of Formula [Q-701] under a carburation reaction according to a method described in a literature (e.g. a method described in Bioorg. Med. Chem. Lett. 2004, 14 (20), 5199-5203).
  • a compound of Formula [Q-302] wherein R 4 is methyl may be prepared from a compound of Formula [Q-701] under a carburation reaction according to a method described in a literature (e.g. a method described in Tetrahedron Lett. 2009, 50, 1276-1278).
  • a commerically available ester such as 3-methyl-butanoic acid methyl ester, 4-methylvaleric acid methyl ester (i.e., 4-Methyl-pentanoic acid methyl ester), and 5-methylhexanoic acid methyl ester may be used, which may be alternatively prepared by a known method.
  • a methyl ester of a compound of Formula [Q-404] may be replaced with an ethyl ester.
  • the ester compound may be, for example, prepared from a compound where a hydroxyl group of C 3-6 cycloalkanone optionally substituted with the same or different one to three substituent(s) selected from Group X b or a commerically available product such as 1-hydroxypropan-2-one, 1-hydroxybutan-2-one, and 1-hydroxypentan-2-one is protected with TBDPS, benzyl and the like under Horner-Wadsworth-Emmons Reaction and the like using alkylphosphonic diester.
  • a compound of Formula [Q-404a] may be synthesized by the following preparation method.
  • a compound of Formula [Q-707] may be prepared from a compound of Formula [Q-706] by a protecting reaction of alcohol according to Preparation Method 7-1.
  • a compound of Formula [Q-708] may be prepared from a compound of Formula [Q-707] under Horner-Wadsworth-Emmons Reaction according to Preparation Method 7-1 Step 1.
  • a compound of Formula [Q-404a] may be prepared from a compound of Formula [Q-708] by 1,4-addition reaction with methyllithium in the presence of a copper catalyst (e.g. a method described in J. Am. Chem. Soc. 2009, 131(44), 16016-16017).
  • a compound of Formula [Q-408] may be prepared by the following method.
  • a compound of Formula [Q-408] may be prepared from a compound of Formula [Q-801] (e.g. a commerically available product such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 1-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylic acid, and 3-[1-(ethoxycarbonyl)cyclopropyl]propanoic acid) by an azidation reaction, followed by Curtius rearrangement reaction according to Preparation Method 1 Step 5.
  • a compound of Formula [Q-801] e.g. a commerically available product such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 1-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylic acid, and 3-[1-(ethoxycarbonyl)cyclopropyl]prop
  • a commercially available product such as methyl 3-aminopropanoate, methyl 3-aminocyclopentanecarboxylate, tert-butyl 2-(2-aminoethoxy)acetate, ethyl 4-aminobenzoate, and methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride may be used, which may be alternatively prepared by a known method.
  • a compound of Formula [Q-108] may be prepared by reacting a compound of Formula [Q-408] with benzyl alcohol or t-BuOH to protect an amino group with tert-butoxycarbonyl group (Boc group) or benzyloxycarbonyl group (Cbz group), followed by deprotection of the Boc group or Cbz group according to a known method (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 725-735, 748-756).
  • a known method e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 725-735, 748-756).

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Abstract

A compound of Formula [I] or a pharmaceutically acceptable salt thereof:
Figure US20190359575A1-20191128-C00001
wherein each symbol is defined as in the specification.

Description

    TECHNICAL FIELD
  • The present invention relates to dihydropyrimidin-2-one compounds or pharmaceutically acceptable salts thereof which have inhibitory actions against Retinoid-related Orphan Receptor gamma (RORγ), pharmaceutical compositions comprising the same, and medical uses thereof.
    • BACKGROUND ART
  • RORγ is a nuclear receptor which is important for the differentiation and activation of Th17 cells. RORγt is also known as a splice variant of RORγ (Nonpatent literature 1). RORγ and RORγt differ only in their N-terminal domains, and share the same ligand-binding domain and DNA-binding domain. It is reported that RORγ is expressed in other tissues besides Th17 cells (Nonpatent literature 1).
  • By inhibiting RORγ, the differentiation and activation of Th17 cells can be inhibited. 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, hence, the inhibition of IL-17 may lead to the inhibition of such induction and migration (Nonpatent literatures 2 and 3).
  • RORγ in adipose tissues is related to the regulation of adipogenesis, and by inhibiting RORγ, insulin resistance can be improved (Nonpatent literature 4).
  • It is known that 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, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic diseases; dry eye; and fibrosis such as pulmonary fibrosis and primary biliary cirrhosis. It is known that adipose tissues are involved in metabolic diseases.
  • As for rheumatoid arthritis, for example, it is reported that the administration of anti-IL-17 antibody can improve swelling and joint destruction associated with collagen-induced arthritis (Nonpatent literature 5). Moreover, it is reported that swelling and joint destruction associated with collagen-induced arthritis can be improved in experiments using IL-17-deficient mice (Nonpatent literature 6).
  • As for psoriasis, it is reported that in a clinical trial, the administration of anti-IL-17 antibody is effective in treating psoriasis (Nonpatent literature 7). Anti IL-17 antibodies have been placed on the market for use in psoriasis (Nonpatent literature 8).
  • As for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, in a colitis model induced by the adaptive transfer of T-cells, the adaptive transfer of T-cells derived from RORγ-KO mice does not increase IL-17 in the mucosa, thereby the onset of colitis can be suppressed (Nonpatent literature 9).
  • As for multiple sclerosis, the disease state of mouse experimental autoimmune encephalomyelitis model which is an animal model of multiple sclerosis can be suppressed in RORγt-KO mice (Nonpatent literature 10).
  • As for systemic lupus erythematosus, it is reported that the onset of GBM nephritis model which is an animal model of glomerulonephritis can be inhibited in RORγt-KO mice (Nonpatent literature 11). Nephritis associated with SLE may also be suppressed (Nonpatent literature 12).
  • As for ankylosing spondylitis, it is reported that the administration of anti-IL-17 antibody is effective in treating ankylosing spondylitis (Nonpatent literature 13).
  • As for uveitis, it is reported that the administration of anti-IL-17 antibody is effective in treating uveitis associated with Behcet's disease, sarcoidosis and Harada disease (Nonpatent literature 7).
  • As for polymyalgia rheumatica, an efficacy of anti-IL-17 antibody in treatment of polymyalgia rheumatica is currently tested in a clinical trial.
  • As for type I diabetes, the disease state of NOD mice which is a type I diabetes model can be suppressed by the administration of anti-IL-17 antibody (Nonpatent literature 14).
  • As for graft versus host disease, it is reported in a mouse transplant model that a survival rate and a rejection in a host would be improved by transfecting RORγKO mouse-derived cells (Nonpatent literature 19).
  • As for allergic disease such as asthma, in OVA-sensitized model, the attenuated eosinophilic pulmonary inflammation, the reduced numbers of CD4+ lymphocytes, and the decrease of Th2 cytokines/chenokines level are exhibited in RORγ-KO mice, that is, the allergenic reaction can be inhibited in RORγ-KO mice (Nonpatent literature 15).
  • As for dry eye, it is reported that the Th17 cells increases in an animal model of dry eye, and an efficacy of anti-IL-17 antibody in dry eye patient is currently tested in a clinical trial (Nonpatent literature 16).
  • As for fibrosis, in a bleomycin-induced pulmonary fibrosis model which is an animal model of pulmonary fibrosis, the administration of anti-IL-17 antibody can inhibit inflammation and fibrosis in lung and can increase survival of the animal (Nonpatent literature 17).
  • As for primary biliary cirrhosis, it is reported that Th17 cells in the lesion area of a patient with a primary biliary cirrhosis increase, and an efficacy of an antibody to IL-23 which activates Th17 cells is currently tested in a clinical trial (Nonpatent literature 18).
  • As for metabolic disease, the insulin resistance which is induced by feeding a high-fat diet can be suppressed in RORγ KO mice (Nonpatent literature 4).
  • On the basis of these findings, RORγ antagonists are thought to be useful for preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic diseases such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic diseases such as diabetes.
    • LIST OF NONPATENT LITERATURES
  • [Nonpatent literature 1] Anton. 2009 NRS 7, 1-32
    [Nonpatent literature 2] Koenders et al. 2006 Ann Rheum Dis 65
    (Suppl III), iii29-iii33
    [Nonpatent literature 3] Carsten et al. 2007 J Allergy Clin Immunol
    120, 247-54
    [Nonpatent literature 4] Bettina et al. 2011 EMBO Mol Med 3, 1-15
    [Nonpatent literature 5] Hilde et al. 2009 Arthritis Research &
    Therapy 11: R122
    [Nonpatent literature 6] Susumu et al. 2003 J. Immnol 171, 6173-6177
    [Nonpatent literature 7] Wolfgang et al. 2010 Sci Transl Med 2, 52ra72
    [Nonpatent literature 8] Sanford et al. Drugs (2015) 75: 329-338
    [Nonpatent literature 9] Moritz et al. 2009 Gastroenterology 136,
    257-67
    [Nonpatent literature 10] Ivaylo et al. 2006 Cell 126, 1121-1133
    [Nonpatent literature 11] Oliver et al. 2011 J Am Soc Nephrol 22:
    472-483
    [Nonpatent literature 12] Jose et al. 2010 Curr Opin Rheumatol 22,
    499-503
    [Nonpatent literature 13] Dominique et al. Lancet 2013, 382(9906): 1705
    [Nonpatent literature 14] Juliet et al. 2009 Diabetes 58: 1302-1311
    [Nonpatent literature 15] Stephen et al. 2007 J. Immnol 178, 3208-18
    [Nonpatent literature 16] ClinicalTrials.gov Identifier: NCT01250171
    [Nonpatent literature 17] Su et al. 2011 J. Immnol 187
    [Nonpatent literature 18] ClinicalTrials.gov Identifier: NCT01389973
    [Nonpatent literature 19] Fulton LM et al. 2012 J. Immunol 15;
    189(4): 1765-1772
    • SUMMARY OF INVENTION
  • An object of the present invention is to provide dihydropyrimidin-2-one compounds or pharmaceutically acceptable salts thereof which have inhibitory actions against RORγ, pharmaceutical compositions comprising the same, and medical uses thereof.
  • In particular, the present invention relates to compounds which would inhibit differentiation and activation of T helper 17 (Th17) cells by an inhibitory action for Retinoid-related Orphan Receptor gamma: RORγ and inhibit interleukin-17 (IL-17) production.
  • The present invention is also directed to provide an agent for preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes.
  • The present inventors have found dihydropyrimidin-2-one compounds which are RORγ antagonists, thereby have completed the present invention.
  • That is, the present invention includes the following embodiments.
  • [01] A compound of Formula [I] or a pharmaceutically acceptable salt thereof:
  • Figure US20190359575A1-20191128-C00002
  • wherein
    • R1 is
  • (1) C4-8 alkyl,
    (2) C3-8 alkyl substituted with one hydroxy,
    (3) C4-8 alkyl substituted with one halogen,
    (4) C4-8 alkenyl,
    (5) C4-8 alkynyl,
    (6) C3-7 alkyl substituted with one trifluoromethyl,
    (7) C1-5 alkyl substituted with one substituent selected from Group Xa1,
    (8) C3-6 alkoxy,
    (9) C2-7 alkoxy substituted with one trifluoromethyl,
    (10) C1-3 alkoxy substituted with one substituent selected from Group Xa2,
    (11) C4-6 cycloalkyl,
    (12) C3-6 cycloalkyl substituted with the same or different one to two C1-5 alkyl,
    (13) C5-6 cycloalkenyl optionally substituted with the same or different one to two C1-4 alkyl,
    (14) spiro C6-11 cycloalkyl,
    (15) C1-3 alkoxycarbonyl,
    (16) C3-6 alkylsulfanyl,
    (17) C3-6 alkylsulfinyl,
    (18) C3-6 alkylsulfonyl,
    (19) C3-6 cycloalkylsulfanyl,
    (20) C3-6 cycloalkylsulfinyl,
    (21) C3-6 cycloalkylsulfonyl,
    (22) cyclobutylidenemethyl,
    (23) cyclopentylidenemethyl,
    (24) cyclohexylidenemethyl optionally substituted with the same or different one to two C1-3 alkyl,
    (25) tetrahydropyran-4-ylidenemethyl,
    (26) C3-6 cycloalkyl substituted with one to the same two halogen, or
    (27) C5-6 cycloalkenyl substituted with one to the same two halogen;
    • Group Xa1 is
  • (a) C3-6 cycloalkyl optionally substituted with the same or different one to three C1-5 alkyl,
    (b) C3-6 cycloalkyl substituted with the same or different one to two halogen,
    (c) phenyl,
    (d) C2-4 alkoxy,
    (e) trimethylsilyl,
    (f) carboxy, and
    (g) tetrahydropyran-4-yl;
    • Group X2 is
  • (a) C3-6 cycloalkyl,
    (b) phenyl, and
    (c) C1-4 alkoxy;
    • R2 is
  • (1) halogen,
    • (2) C1-6alkyl,
  • (3) C1-3 alkoxy optionally substituted with phenyl, or
    (4) trifluoromethyl;
    n is an integer of 0, 1 or 2, provided that when n is 2, each R2 may be different with each other; or
    R1 and R2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C1-6 alkyl;
    • R3 is
  • (1) —Yb—COO—R30,
    (2) C1-6 alkyl optionally substituted with one hydroxy,
    (3) C1-6 alkyl substituted with one C1-4 alkoxy,
    (4) C1-6 alkyl substituted with one C1-4 alkylsulfonyl,
    (5) C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb,
    (6)
  • Figure US20190359575A1-20191128-C00003
  • (7)
  • Figure US20190359575A1-20191128-C00004
  • (8) phenyl,
    (9)
  • Figure US20190359575A1-20191128-C00005
  • or
    (10) C2-3 alkenyl;
    • Yb is
  • (a) C1-6 alkylene,
    (b) C3-6 cycloalkylene,
    (c) phenylene,
    (d) pyridinediyl or
    (e)
  • Figure US20190359575A1-20191128-C00006
    • R30 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • Group Xb is
  • (a) halogen,
    (b) C1-6 alkyl,
    (c) C1-3 alkyl substituted with one hydroxy,
    (d) C1-3 alkyl substituted with one C1-3 alkoxy, and
    (e) C1-3 alkoxy;
    • R4 is
  • (1) hydrogen or (2) methyl;
    • R5 is
  • (1) —Yc—COO—R50,
    (2) hydrogen,
    (3) C1-4 alkyl optionally substituted with one C1-3 alkoxy,
    (4) C1-4 alkyl substituted with one amide,
    (5) (C1-3 alkyl substituted with one C3-6 cycloalkyl substituted with the same or different two halogen,
    (6) C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl,
    (7) C3-6 cycloalkyl substituted with one C1-3 alkoxy,
    (8) C3-6 cycloalkyl substituted with one C1-3 alkoxy-C1-3 alkyl,
    (9) C3-6 cycloalkyl substituted with the same or different one to two halogen,
    (10) C3-6 cycloalkyl substituted with the same or different one to two C1-3 alkyl,
    (11) tetrahydropyran-4-yl or
    (12) pyridin-4-yl;
    • Yc is
  • (a) C1-6 alkylene optionally substituted with one hydroxy,
    (b) CH2—CH2—O—CH2 or
    (c) (CH2)m—Yc1—(CH2)w;
    m is an integer of 0, 1, or 2;
    w is an integer of 0, 1 or 2;
    • Yc1 is
  • (a) C3-6 cycloalkylene optionally substituted with one C1-3 alkyl,
    (b) phenylene,
    (c) phenylene substituted with one halogen,
    (d) phenylene substituted with one C1-3 alkyl,
    (e) phenylene substituted with one C1-3 alkoxy,
    (f) phenylene substituted with one trifluoromethyl,
    (g) cross-linked C5-8 cycloalkylene,
    (h)
  • Figure US20190359575A1-20191128-C00007
  • (i)
  • Figure US20190359575A1-20191128-C00008
  • (j) spiro[3.3]heptanediyi,
    (k) pyrrolidinediyl,
    (l) pyrrolidinediyl substituted with one carboxy,
    (m) pyrrolidinediyl substituted with one C1-3 alkylcarbonyl,
    (n) pyrrolidinediyl substituted with one C1-3 alkylsulfonyl,
    (o) pyridinediyl,
    (p) isoxazolediyl or
    (q) pyrazolediyl substituted with one C1-3 alkyl;
    • R50 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • R6 is
  • (1) hydrogen or (2) methyl;
    provided that
    when R5 is —Yc—COO—R50, Yc is (CH2)m—Yc1—(CH2)w, m and w are 0, and Yc1 is (b) phenylene,
    (c) phenylene substituted with one halogen, (d) phenylene substituted with one C1-3 alkyl, (e) phenylene substituted with one C1-3 alkoxy or (f) phenylene substituted with one trifluoromethyl, then R6 is methyl; and
    either R3 or R5 or both of them have “—COO—”.
    [02] The compound of [01], wherein the compound of Formula [I] is a compound of Formula [II], or a pharmaceutically acceptable salt thereof:
  • Figure US20190359575A1-20191128-C00009
  • wherein
    • R3 is
  • (1) C1-6 alkyl optionally substituted with one hydroxy,
    (2) C1-6 alkyl substituted with one C1-4 alkoxy,
    (3) C1-6 alkyl substituted with one C1-4 alkylsulfonyl,
    (4) C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb,
    (5)
  • Figure US20190359575A1-20191128-C00010
  • (6)
  • Figure US20190359575A1-20191128-C00011
  • (7) phenyl,
    (8)
  • Figure US20190359575A1-20191128-C00012
  • or
    (9) C2-3 alkenyl; and the other symbols have the same meanings as defined in [01].
    [03] The compound of [01], wherein the compound of Formula [I] is a compound of Formula [III], or a pharmaceutically acceptable salt thereof:
  • Figure US20190359575A1-20191128-C00013
  • wherein
    • R5 is
  • (1) hydrogen,
    (2) C1-4 alkyl optionally substituted with one C1-3 alkoxy,
    (3) C1-4 alkyl substituted with one amide,
    (4) C1-3 alkyl substituted with one C3-6 cycloalkyl substituted with the same or different two halogen,
    (5) C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl,
    (6) C3-6 cycloalkyl substituted with one C1-3 alkoxy,
    (7) C3-6 cycloalkyl substituted with one C1-3 alkoxy-C1-3 alkyl,
    (8) C3-6 cycloalkyl substituted with the same or different one to two halogen,
    (9) C3-6 cycloalkyl substituted with the same or different one to two C1-3 alkyl,
    (10) tetrahydropyran-4-yl or
    (11) pyridin-4-yl; and the other symbols have the same meanings as defined in [01].
    [04] The compound of [01], wherein the compound of Formula [I] is a compound of Formula [IV], or a pharmaceutically acceptable salt thereof:
  • Figure US20190359575A1-20191128-C00014
  • wherein each symbol has the same meaning as defined in [01].
    [05] The compound of any one of [01] to [04], wherein R6 is methyl, or a pharmaceutically acceptable salt thereof.
    [06] The compound of any one of [01] to [05], wherein R4 is hydrogen, or a pharmaceutically acceptable salt thereof.
    [07] The compound of any one of [01] to [06], wherein n is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof.
    [08] The compound of any one of [01] to [07], wherein R2 is halogen or trifluoromethyl, or a pharmaceutically acceptable salt thereof.
    [09] The compound of any one of [01], [02], [04] to [07] or [08], wherein Yc is
    (a) C1-6 alkylene or
    (b) (CH2)m—Yc1—(CH2)w;
    in is an integer of 0 or 1;
    w is an integer of 0 or 1;
    • Yc1 is
  • (a) C3-6 cycloalkylene optionally substituted with one C1-3alkyl,
    (b) phenylene,
    (c) phenylene substituted with one halogen,
    (d) phenylene substituted with one C1-3 alkyl,
    (e) phenylene substituted with one C1-3 alkoxy,
    (f) phenylene substituted with one trifluoromethyl,
    (g) cross-linked C5-8 cycloalkylene,
    (h) pyridinediyl or
    (i) pyrazolediyl substituted with one C1-3 alkyl; and
    • R3 is
  • (1) C1-6 alkyl optionally substituted with one hydroxy,
    (2) C1-6 alkyl substituted with one C1-4 alkoxy or
    (3) C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb, or a pharmaceutically acceptable salt thereof.
    [10] The compound of [02], wherein R50 is hydrogen, or a pharmaceutically acceptable salt thereof.
    [11] The compound of [01], wherein the compound of Formula [I] is any one of the compounds of Formulae [IV-B-A] to [IV-B-N], or a pharmaceutically acceptable salt thereof:
  • Figure US20190359575A1-20191128-C00015
    Figure US20190359575A1-20191128-C00016
    Figure US20190359575A1-20191128-C00017
  • wherein
    R3h is hydrogen or methyl;
    R3w is methyl or fluoro;
    nx is an integer of 0 or 2;
    nw is an integer of 0, 1, 2 or 3;
    R3 is C1-6 alkyl optionally substituted with one hydroxy,
    C1-6 alkyl substituted with one C1-4 alkoxy or
    C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb;
    R5B is hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy or trifluoromethyl; and
    the other symbols have the same meanings as defined in [01].
    [12] The compound of [01], selected from the group consisting of the following formulae, or a pharmaceutically acceptable salt thereof.
  • Figure US20190359575A1-20191128-C00018
    Figure US20190359575A1-20191128-C00019
    Figure US20190359575A1-20191128-C00020
    Figure US20190359575A1-20191128-C00021
    Figure US20190359575A1-20191128-C00022
    Figure US20190359575A1-20191128-C00023
  • [13] A pharmaceutical composition comprising the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
    [14] An RORγ antagonist comprising the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
    [15] An agent for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof.
    [16] The agent of [15], wherein the disease is autoimmune disease.
    [17] The agent of [16], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
    [18] The agent of [15], wherein the disease is metabolic disease.
    [19] The agent of [18], wherein the metabolic disease is diabetes.
    [20] A method of inhibiting RORγ, comprising administering to a mammal a therapeutically effective amount of the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof.
    [21] A method of treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to a mammal an effective amount of the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof.
    [22] The method of [21], wherein the disease is autoimmune disease.
    [23] The method of [22], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
    [24] The method of [21], wherein the disease is metabolic disease.
    [25] The method of [24], wherein the metabolic disease is diabetes.
    [26] Use of the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof for the manufacture of an RORγ antagonist.
    [27] Use of the compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
    [28] The use of [27], wherein the disease is autoimmune disease.
    [29] The use of [28], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
    [30] The use of [27], wherein the disease is metabolic disease.
    [31] The use of [30], wherein the metabolic disease is diabetes.
    [32] A compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof for use as an RORγ antagonist.
    [33] A compound of any one of [01] to [12] or a pharmaceutically acceptable salt thereof for use as an agent for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
    [34] The compound of [33], wherein the disease is autoimmune disease, or a pharmaceutically acceptable salt thereof.
    [35] The compound of [34], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease, or a pharmaceutically acceptable salt thereof.
    [36] The compound of [33], wherein the disease is metabolic disease, or a pharmaceutically acceptable salt thereof.
    [37] The compound of [36], wherein the metabolic disease is diabetes, or a pharmaceutically acceptable salt thereof.
  • Dihydropyrimidin-2-one compounds and pharmaceutically acceptable salts thereof of the present invention is useful as an agent for prevention or treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease, allergic diseases such as asthma, dry eye, fibrosis such as pulmonary fibrosis and primary biliary cirrhosis, and metabolic diseases such as diabetes.
    • DESCRIPTION OF EMBODIMENTS
  • Definitions of terms used herein are as follows.
  • “Halogen” includes fluoro, chloro, bromo or iodo. A preferable “halogen” is fluoro or chloro.
  • “Alkyl” means a straight or branched chain saturated hydrocarbon gorup, and includes, for example, “C1-3 alkyl”, “C1-4 alkyl”, “C1-5 alkyl”, “C1-6 alkyl”, “C4-6 alkyl”, “C4-8 alkyl”, and “C5-8 alkyl”, each of which means alkyl with 1 to 3 of carbon atom(s), 1 to 4 of carbon atom(s), 1 to 5 of carbon atom(s), 1 to 6 of carbon atom(s), 4 to 6 of carbon atoms, 4 to 8 of carbon atoms, and 5 to 8 of carbon atoms, respectively.
  • An illustrative example of “C1-3 alkyl” includes, for example, methyl, ethyl, propyl, and isopropyl. A preferable “C1-3 alkyl” is methyl.
  • An illustrative example of “C1-4 alkyl” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and 1-methylpropyl. A preferable “C1-4 alkyl” is methyl or ethyl.
  • An illustrative example of “C1-5 alkyl” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, and 1-ethylpropyl. A preferable “C1-5 alkyl” is methyl.
  • An illustrative example of “C1-6 alkyl” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. A preferable “C1-6 alkyl” is methyl, ethyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, I-methylpropyl or 1,1-dimethylbutyl.
  • An illustrative example of “C4-6 alkyl” includes, for example, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. A preferable one is isobutyl or isopentyl.
  • An illustrative example of “C4-8 alkyl” includes, for example, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl, I-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl. A preferable one is butyl, isobutyl, pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.
  • An illustrative example of “C5-8 alkyl” includes, for example, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, I-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl. A preferable one is pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.
  • “C1-6 alkyl optionally substituted with one hydroxy” means “C1-6 alkyl substituted with one hydroxy” or “unsubstituted C1-6 alkyl”.
  • “C1-3 alkyl substituted with one hydroxy” means “alkyl”, with 1 to 3 of carbon atom(s), substituted at any position with one hydroxy. In particular, it includes, for example, hydroxymethyl.
  • “C5-8 alkyl substituted with one hydroxy” means “alkyl”, with 5 to 8 of carbon atoms, substituted with at any position with one hydroxy. In particular, it includes, for example, 3,3-dimethyl-3-hydroxypropyl, 3,3-dimethyl-2-hydroxybutyl, and 3,3-dimethyl-4-hydroxybutyl.
  • “C5-8 alkyl substituted with one halogen” means “alkyl”, with 5 to 8 of carbon atoms, substituted with at any position with one halogen. In particular, it includes, for example, 3-fluoro-3-methylbutyl.
  • “C3-7 alkyl substituted with one trifluoromethyl” means “alkyl”, with 3 to 7 of carbon atoms, substituted at any position with one trifluoromethyl. In particular, it includes, for example, 4,4,4-trifluorobutyl and 4,4,4-trifluoro-3,3-dimethylbutyl.
  • “Alkenyl” means a straight or branched chain unsaturated hydrocarbon group with one or more double bond(s) between carbon atoms, and includes, for example, “C2-3 alkenyl” and “C4-8 alkenyl” which “C2-3 alkenyl” means alkenyl with 2 to 3 of carbon atoms and “C4-8 alkenyl” means alkenyl with 4 to 8 of carbon atoms. A preferable “C4-8 alkenyl” is “C4-6 alkenyl” with one double bond between carbon atoms.
  • An illustrative example of “C2-3 alkenyl” includes, for example, ethenyl and isopropenyl. A preferable one is isopropenyl.
  • An illustrative example of “C4-8 alkenyl” includes, for example, 2-methyl-prop-1-enyl, 3,3-dimethyl-but-1-enyl, and 3-methyl-but-2-enyl. A preferable one is 2-methyl-prop-1-enyl or 3,3-dimethyl-but-1-enyl.
  • “Alkynyl” means a straight or branched chain unsaturated hydrocarbon group with one or more triple bond(s) between carbon atoms, and includes, for example, “C4-8 alkynyl” which means alkynyl with 4 to 8 carbon atoms. A preferable “C4-8 alkynyl” is “C4-6 alkynyl” with one triple bond between carbon atoms.
  • An illustrative example of “C4-8 alkynyl” includes, for example, 3,3-dimethyl-but-1-ynyl, 3-methyl-but-1-ynyl, and 3-ethyl-pent-1-ynyl. A preferable one is 3,3-dimethyl-but-1-ynyl.
  • “Alkoxy” means a group where a straight or branched chain saturated hydrocarbon group attaches to oxygen atom, and includes, for example, “C1-3 alkoxy”, “C1-4 alkoxy”, “C2-4 alkoxy”, “C3-6 alkoxy”, and “C2-7 alkoxy”, each of which means alkoxy with 1 to 3 of carbon atom(s), 1 to 4 of carbon atom(s), 2 to 4 of carbon atoms, 3 to 6 of carbon atoms, and 2 to 7 of carbon atoms, respectively.
  • An illustrative example of “C1-3 alkoxy” includes, for example, methoxy, ethoxy, propoxy, and isopropoxy. A preferable one is methoxy or ethoxy.
  • An illustrative example of “C1-4 alkoxy” includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferable one is methoxy.
  • An illustrative example of “C2-4 alkoxy” includes, for example, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferable one is isopropoxy or tert-butoxy.
  • An illustrative example of “C3-6 alkoxy” includes, for example, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy, and hexyloxy. A preferable one is isobutoxy, isopentyloxy, neopentyloxy or 3,3-dimethylbutoxy.
  • An illustrative example of “C2-7 alkoxy” includes, for example, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A preferable one is isopropoxy or tert-butoxy.
  • “C2-7 alkoxy substituted with one trifluoromethyl” means “alkoxy”, with 2 to 7 carbon atoms, substituted at any position with one “trifluoromethyl”. Its illustrative example includes, for example, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 7,7,7-trifluoroheptyloxy, and 8,8,8-trifluorooctyloxy. A preferable one includes, for example, 3,3,3-trifluorpropoxy.
  • “C1-3 alkyl substituted with one C1-3 alkoxy” means “alkyl”, with 1 to 3 of carbon atom(s), substituted at any position with one C1-3 alkoxy. In particular, it includes, for example, methoxymethyl.
  • “C1-6 alkyl substituted with one C1-4 alkoxy” means “alkyl”, with 1 to 6 of carbon atom(s), substituted at any position with one C1-4 alkoxy. In particular, it includes, for example, 2-methoxyethyl, 1-methyl-2-methoxyethyl, 2-methoxypropyl, 4-methoxy-2,2-dimethylbutyl, and 3-tert-butoxypropyl.
  • “Cycloalkyl” means a monocyclic saturated hydrocarbon group, and includes, for example, “C3-6 cycloalkyl” and “C4-6 cycloalkyl”, each of which means cycloalkyl with 3 to 6 of carbon atoms, and 4 to 6 of carbon atoms, respectively.
  • An illustrative example of “C3-6 cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • An illustrative example of “C4-6 cycloalkyl” includes, for example, cyclobutyl, cyclopentyl, and cyclohexyl.
  • “C3-6 cycloalkyl substituted with one C1-3 alkoxy” means “cycloalkyl”, with 3 to 6 of carbon atoms, substituted at any position with one C1-3 alkoxy. In particular, it includes, for example, 3-methoxycyclobutyl.
  • “C3-6 cycloalkyl substituted with one C1-3 alkoxy-C1-3 alkyl” means “cycloalkyl”, with 3 to 6 of carbon atoms, substituted at any position with one C1-3 alkoxy-C1-3 alkyl. In particular, it includes, for example, 1-methoxymethylcyclopropyl and 3-methoxymethylcyclobutyl.
  • “Cycloalkenyl” means a monocyclic unsaturated hydrocarbon group with one or more double bond(s) between carbon atoms, and includes, for example, “C5-6 cycloalkenyl”, which means cycloalkenyl with 5 to 6 of carbon atoms.
  • A preferable “C5-6 cycloalkenyl” is “C5-6 cycloalkenyl” with one double bond between carbon atoms.
  • An illustrative example of “C5-6 cycloalkenyl” includes, for example, cyclopentenyl and cyclohexenyl. A preferable one is cyclopent-1-enyl or cyclohex-1-enyl.
  • “Spiro cycloalkyl” means a cyclic saturated hydrocarbon group with one spiro atom, and includes, for example, “spiro C6-11 cycloalkyl”, which means spiro cycloalkyl with one spiro atom and 6 to 11 of carbon atoms.
  • An illustrative example of “spiro C6-11 cycloalkyl” includes, for example, spiro [3.3]heptyl, spiro [4.4]nonyl, and spiro [5.5]undecyl. A preferable one is spiro [3.3]heptyl.
  • “Alkylcarbonyl” means “alkyl”-attached carbonyl, and includes “C1-3 alkylcarbonyl”.
  • An illustrative example of “C1-3 alkylcarbonyl” includes carbonyl which attaches to the “C1-3 alkyl”. A preferable one is methylcarbonyl.
  • “Alkylsulfanyl” means “alkyl”-attached sulfanyl, and includes “C4-6 alkylsulfanyl”.
  • An illustrative example of “C4-6 alkylsulfanyl” includes sulfanyl which attaches to the “C4-6 alkyl”. A preferable one is isobutylsulfanyl or isopentylsulfanyl.
  • “Alkylsulfinyl” means “alkyl”-attached sulfinyl, and includes “C4-6 alkylsulfinyl”.
  • An illustrative example of “C4-6 alkylsulfinyl” includes sulfinyl which attaches to the “C4-6 alkyl”. A preferable one is isobutylsulfinyl or isopentylsulfinyl.
  • “Alkylsulfonyl” means “alkyl”-attached sulfonyl, and includes “C1-3 alkylsulfonyl”, “C1-4 alkylsulfonyl”, and “C4-6 alkylsulfonyl”.
  • An illustrative example of “C1-3 alkylsulfonyl” includes sulfonyl which attaches to the “C1-3 alkyl”. A preferable one is methylsulfonyl.
  • An illustrative example of “C1-4 alkylsulfonyl” includes sulfonyl which attaches to the “C1-4 alkyl”. A preferable one is methylsulfonyl.
  • An illustrative example of “C4-6 alkylsulfonyl” includes sulfonyl which attaches to the “C4-6 alkyl”. A preferable one is isobutylsulfonyl or isopentylsulfonyl.
  • “C1-6 alkyl substituted with one C1-4 alkylsulfonyl” means “alkyl”, with 1 to 6 of carbon atom(s), substituted at any position with one C1-4 alkylsulfonyl. In particular, it includes, for example, 2-methylsulfonylethyl.
  • “Alkoxycarbonyl” means carbonyl which attaches to “alkoxy”, and includes, for example, “C1-3 alkoxycarbonyl”.
  • An illustrative example of “C1-3 alkoxycarbonyl” includes, for example, methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. A preferable one is ethoxycarbonyl.
  • “Cycloalkylsulfanyl” means “cycloalkyl”-attached sulfanyl, and includes “C3-6 cycloalkylsulfanyl”.
  • An illustrative example of “C3-6 cycloalkylsulfanyl” includes sulfanyl which attaches to the “C3-6 cycloalkyl”. A preferable one is cyclopentylsulfanyl.
  • “Cycloalkylsulfinyl” means “cycloalkyl”-attached sulfinyl, and includes “C3-6 cycloalkylsulfinyl”.
  • An illustrative example of “C3-6 cycloalkylsulfinyl” includes, for example, sulfinyl which attaches to the “C3-6 cycloalkyl”. A preferable one is cyclopentylsulfinyl.
  • “Cycloalkylsulfonyl” means “cycloalkyl”-attached sulfonyl, and includes “C3-6 cycloalkylsulfonyl”.
  • An illustrative example of “C3-6 cycloalkylsulfanyl” includes sulfonyl which attaches to the “C3-6 cycloalkyl”. A preferable one is cyclopentylsulfonyl.
  • “Alkylene” means a divalent group derived from straight or branched chain saturated hydrocarbon, and includes, for example, “C1-3 alkylene” and “C1-6 alkylene”, each of which means alkylene with 1 to 3 of carbon atom(s) and 1 to 6 of carbon atom(s), respectively.
  • An illustrative example of “C1-3 alkylene” includes, for example, methylene, ethylene, trimethylene, and —C(C1-3)2—. A preferable one is methylene or ethylene.
  • An illustrative example of “C1-6 alkylene” includes, for example, methylene, ethylene, trimethylene, butylene, pentylene, hexylene, —C(CH3)2—, —C(CH3)2—CH2—, —(CH2)2—CH(CH3)—, —CH2—C(CH3)2—CH2—, —(CH2)3—C(CH3)2—, and —(CH2)2—C(CH3)2—. A preferable one is methylene, ethylene, trimethylene, butylene, —C(C3)2—, —C(CH3)2—CH2—, —(CH2)2—CH(CH3)—, —CH2—C(CH3)2—CH2—, —(CH2)3—C(CH3)2— or —(CH2)2—C(CH3)2—.
  • “C1-6 alkylene optionally substituted with one hydroxy” means “C1-6 alkylene substituted with one hydroxy” or “unsubstituted C1-6 alkylene”.
  • “Cycloalkylene” means a divalent group derived from monocyclic saturated hydrocarbon, and includes, for example, “C3-6 cycloalkylene”, which means cycloalkylene with 3 to 6 of carbon atoms.
  • An illustrative example of “C3-6 cycloalkylene” includes, for example, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. A preferable “C3-6 cycloalkylene” is “C4-6 cycloalkylene”.
  • “Cross-linked cycloalkylene” means a divalent group derived from polycyclic saturated hydrocarbon with a cross-linked structure of carbon atoms, and includes, for example, “cross-linked C5-8 cycloalkylene”, which means cross-linked cycloalkylene with 5 to 8 of carbon atoms.
  • An illustrative example of “cross-linked C5-8 cycloalkylene” includes, for example, bicyclo[1.1.1]pentylene, bicyclo[2.1.1]hexylene, bicyclo[2.2.1]heptylene, and bicyclo[2.2.2]octylene. A preferable “cross-linked C5-8 cycloalkylene” is “cross-linked C5-6 cycloalkylene”, in paricular bicyclo[1.1.1]pentylene or bicyclo[2.1.1]hexylene.
  • “Phenylene substituted with one halogen” means phenylene substituted at any position with one halogen. In particular, it includes, for example, 2-fluorophenylene and 4-fluorophenylene.
  • “Phenylene substituted with one C1-3 alkyl” means phenylene substituted at any position with one C1-3 alkyl. In particular, it includes, for example, 2-methylphenylene and 3-methylphenylene.
  • “Phenylene substituted with one C1-3 alkoxy” means phenylene substituted at any position with one C1-3 alkoxy. In particular, it includes, for example, 2-methoxyphenylene and 3-methoxyphenylene.
  • “Phenylene substituted with one trifluoromethyl” means phenylene substituted at any position with one trifluoromethyl. In particular, it includes, for example, 3-trifluorophenylene.
  • “Pyrrolidinediyl substituted with one carboxy” means pyrrolidinediyl substituted at any position with one carboxy. In particular, it includes, for example, 3-carboxypyrrolidine-1,4-diyl.
  • “Pyrrolidinediyl substituted with one C1-3 alkylcarbonyl” means pyrrolidinediyl substituted at any position with one C1-3 alkylcarbonyl. In particular, it includes, for example, 1-methylcarbonylpyrrolidine-3,4-diyl.
  • “Pyrrolidinediyl substituted with one C1-3 alkylsulfonyl” means pyrrolidinediyl substituted at any position with one C1-3 alkylsulfonyl. In particular, it includes, for example, 1-methylsulfonylpyrrolidine-3,4-diyl.
  • “Pyrazolediyl substituted with one C1-3 alkyl” means pyrazolediyl substituted at any position with one C1-3 alkyl. In particular, it includes, for example, 1-methylpyrazole-3,5-diyl.
  • Embodiments of each group in the above formulae are illustrated as below.
  • A preferable “C4-8 alkyl” in R1 particularly includes butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl. A further preferable one is butyl, isobutyl, pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.
  • A preferable “C4-8alkenyl” in R1 is “C4-6 alkenyl”, and particularly includes 2-methyl-propenyl, 3,3-dimethyl-but-1-enyl, and 3-methyl-but-2-enyl. A further preferable one is 2-methyl-propenyl or 3,3-dimethyl-but-1-enyl.
  • A preferable “C4-8 alkynyl” in R1 is “C1-6 alkynyl”, and particularly includes 3,3-dimethyl-but-1-ynyl, and 3-methyl-but-1-ynyl. A further preferable one is “C6 alkynyl”, in particular 3,3-dimethyl-but-1-ynyl.
  • A preferable “C3-7 alkyl substituted with one trifluoromethyl” in R1 is “C3-5 alkyl substituted with one trifluoromethyl”, and particularly includes 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, and 4,4,4-trifluoro-3,3-dimethylbutyl. A further preferable one is 4,4,4-trifluorobutyl or 4,4,4-trifluoro-3,3-dimethylbutyl.
  • A preferable “C1-4 alkyl” in “C1-4 alkyl substituted with one substituent selected from Group Xa1” in R1 is “C1-2 alkyl”, in particular methyl or ethyl.
  • A preferable “C3-6 alkoxy” in R1 is “C4-6 alkoxy”, and particularly includes propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy, and hexyloxy. A further preferable one is isobutoxy, isopentyloxy, neopentyloxy or 3,3-dimethylbutoxy.
  • A preferable “C2-7 alkoxy substituted with one trifluoromethyl” in R1 is “C2 alkoxy substituted with one trifluoromethyl”, in particular 3,3,3-trifluoropropoxy.
  • A preferable “C1-3 alkoxy” in “C1-3 alkoxy substituted with one substituent selected from Group Xa2” in R1 is “C1-2 alkoxy”, in particular methoxy or ethoxy.
  • A preferable “C4-6 cycloalkyl” in R1 is in particular cyclobutyl, cyclopentyl or cyclohexyl.
  • A preferable “C3-6 cycloalkyl substituted with one to two C1-4 alkyl” in R1 is “C3-6 cycloalkyl substituted with the same or different one or two C1-4 alkyl”, more preferably “cyclopropyl or cyclohexyl substituted with the same or different one or two methyl, isopropyl or tert-butyl”. In particular, it is 2-isopropylcyclopropyl, 2-tert-butylcyclopropyl or 3,3-dimethylcyclohexyl.
  • A preferable “C5-6 cycloalkenyl optionally substituted with one to two C1-4 alkyl” in R1 is “C5-6 cycloalkenyl optionally substituted with the same or different two C1-4 alkyl”, more preferably “1-cyclopentenyl or 1-cyclohexenyl, optionally substituted with the same or different two methyl”. In particular, it is 1-cyclopentenyl, 1-cyclohexenyl, 3,3-dimethylcyclohex-1-enyl or 4,4-dimethylcyclohex-1-enyl.
  • A preferable “spiro C6-11 cycloalkyl” in R1 is “spiro C6-8 cycloalkyl”, more preferably “spiro C7 cycloalkyl”. In particular, it is spiro [3.3]heptyl.
  • A preferable “C1-3 alkoxycarbonyl” in R1 is “C1-2 alkoxycarbonyl”, more preferably ethoxycarbonyl.
  • A preferable “halogen” in R2 is fluoro or chloro.
  • A preferable “C1-6 alkyl” in R2 is “C1-2 alkyl”, more preferably methyl.
  • A preferable “C1-3 alkoxy optionally substituted with phenyl” in R2 is “C1-2 alkoxy optionally substituted with phenyl”, more preferably benzyloxy.
  • A preferable “n” is an integer of 0 to 2. In Formula [I], the following partial structure:
  • Figure US20190359575A1-20191128-C00024
  • includes the following embodiments.
  • Figure US20190359575A1-20191128-C00025
  • A further preferable “n” is an integer of 1 or 2. In Formula [I], the following partial structure:
  • Figure US20190359575A1-20191128-C00026
  • includes the following embodiments.
  • Figure US20190359575A1-20191128-C00027
  • In the above embodiments, when R2 is halogen, the following moieties are illustrated.
  • Figure US20190359575A1-20191128-C00028
  • The above structure also includes the following embodiments
  • Figure US20190359575A1-20191128-C00029
  • An embodiment of “R1 and R2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C1-6 alkyl” includes, when “n” is 1, the following embodiments.
  • Figure US20190359575A1-20191128-C00030
  • A preferable “—Yb—COO—R30” in R3 is —(C3-5 alkylene)-COOH or —C4 cycloalkylene-COOH, in particular —C(CH3)2—COOH, —C(CH3)2—CH2—COOH, —C(CH3)2—(CH2)2—COOH or -cyclobutylene-COOH.
  • “C1-6 alkyl optionally substituted with one hydroxy” in R3 is “C1-6 alkyl substituted with one hydroxy” or “unsubstituted C1-6 alkyl”. A preferable “C1-6 alkyl substituted with one hydroxy” is “C6 alkyl substituted with one hydroxy”. An illustrative example of “C1-6 alkyl optionally substituted with one hydroxy” includes methyl, ethyl, isopropyl, isobutyl, tert-butyl, I-methylpropyl, isopentyl, neopentyl or 4-hydroxy-1,1-dimethylbutyl.
  • A preferable “C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb” in R3 is “C3-6 cycloalkyl optionally substituted with the same or different one to two substituent(s) selected from fluoro or methyl”, in particular cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 3,3-difluorocyclobutyl or cyclohexyl.
  • One preferable embodiment of R3 is —Yb—COO—R30, and includes any of the following structures.
  • Figure US20190359575A1-20191128-C00031
  • Another preferable embodiment of R3 is —Yb—COO—R30 wherein Yb is
  • Figure US20190359575A1-20191128-C00032
  • and in this case, one preferable embodiment of Formula [I] includes an embodiment having the following structure.
  • Figure US20190359575A1-20191128-C00033
  • A preferable R4 is hydrogen.
  • An illustrative example of “C1-6 alkylene optionally substituted with one hydroxy” in Yc in “—Y—COO—R50” in R5 includes, for example, methylene, ethylene, trimethylene, butylene, (CH2)2—CH(CH3), CH(CH3)—(CH2)2, (CH2)2—C(CH3)2, CH2—C(CH3)2—CH2, C(CH3)2—(CH2)2, (CH2)3—C(CH3)2, and (CH2)2—CH(OH).
  • A preferable m is an integer of 0 to 2, and a preferable w is an integer of 0 to 1.
  • A preferable “(CH2)m—Yc1—(CH2)w” in Yc in “—Yc—COO—R50” in R5 is Yc1, Yc1—CH2, CH2—Yc1, CH2—Yc1—CH2, (CH2)2—Yc1 or (CH2)2—Yc1—CH2.
  • A preferable “C3-6 cycloalkylene optionally substituted with one C1-3 alkyl” in Yc1 is “cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, optionally substituted with one methyl”.
  • A preferable “cross-linked C5-8 cycloalkylene” in Yc1 is “cross-linked C5 cycloalkylene”, and for example has the following structure.
  • Figure US20190359575A1-20191128-C00034
  • When Yc1 is
  • Figure US20190359575A1-20191128-C00035
  • one preferable embodiment of Formula [I] includes embodiments having the following structures in the case where m is 0 and w is 0.
  • Figure US20190359575A1-20191128-C00036
  • In this case, a preferable R50 is hydrogen or methyl.
  • When Yc1 is “pyrazolediyl substituted with one C1-3 alkyl”, one preferable embodiment of Formula [I] includes an embodiment having the following structure in the case where m is 0 and w is 0.
  • Figure US20190359575A1-20191128-C00037
  • In this case, a preferable R50 is hydrogen or methyl.
  • When Yc1 is “isoxazolediyl”, one preferable embodiment of Formula [I] includes an embodiment having the following structure in the case where m is 0 and w is 0.
  • Figure US20190359575A1-20191128-C00038
  • In this case, a preferable R50 is hydrogen or methyl.
  • A preferable “C1-4 alkyl optionally substituted with one C1-3 alkoxy” in R5 is “C1-3 alkyl optionally substituted with one C1-3 alkoxy”, more preferably “ethyl or isopropyl, optionally substituted with one methoxy”. In particular, it is methoxyethyl or isopropyl.
  • A preferable “C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl” in R5 is “cyclobutyl optionally substituted with one hydroxymethyl”. In particular, it is cyclobutyl or 3-hydroxymethylcyclobutyl.
  • One preferable embodiment of R5 is —Y—COO—R50, and includes any of the following structures.
  • Figure US20190359575A1-20191128-C00039
  • A preferable R6 is methyl.
  • In [01], the expression “when R5 is —Yc—COO—R50, Yc is (CH2)m—Yc1—(CH2)w, m and w are 0, and Yc1 is phenylene, then R6 is methyl” means an embodiment where R6 is methyl when R5 moiety attaches to a dihydropyrimidine ring via phenylene. An illustrative example includes the following embodiment.
  • Figure US20190359575A1-20191128-C00040
  • In [01], the expression “either R3 or R5 or both of them have “—COO—” includes the following embodiments.
  • An embodiment where when R3 is (1) —Yb-coo-R30, then R5 is
  • (1) Yc—COO—R50,
    (2) hydrogen,
    (3) C1-4 alkyl optionally substituted with one C1-3 alkoxy or
    (4) C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl; or
  • an embodiment where when R3 is
  • (1) C1-6 alkyl optionally substituted with one hydroxy,
    (2) C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb,
    (3)
  • Figure US20190359575A1-20191128-C00041
  • or
    (4)
  • Figure US20190359575A1-20191128-C00042
  • then R5 is (1) —Yc—COO—R5.
  • A compound of Formula [I] includes any compound of the following Formula [II], [III] or [VI].
  • Figure US20190359575A1-20191128-C00043
  • One preferable embodiment of the compound of Formula [I] includes the compounds of the following general formulae.
  • Each symbol in the following each formula has the same meaning as defined in the above [01] unless otherwise specified.
  • Figure US20190359575A1-20191128-C00044
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [I],
  • wherein R1 is
    (1) C4-8 alkyl,
    (2) C4-6 alkenyl,
    (3) C4-6 alkynyl,
    (4) C3-5 alkyl substituted with one trifluoromethyl,
    (5) C1-4 alkyl substituted with one substituent selected from Group Xa1,
    (6) C3-6 alkoxy,
    (7) C2-7 alkoxy substituted with one trifluoromethyl,
    (8) C1-3 alkoxy substituted with one substituent selected from Group Xa2,
    (9) C4-6 cycloalkyl,
    (10) C3-6 cycloalkyl substituted with one to two C1-4 alkyl,
    (11) C5-6 cycloalkenyl optionally substituted with one to two C1-4 alkyl,
    (12) spiro C6-8 cycloalkyl or
    (13) C1-3 alkoxycarbonyl;
    • Group Xa1 is
  • (a) C3-6 cycloalkyl optionally substituted with the same or different one to three C1-5 alkyl,
    (b) phenyl,
    (c) C2-4 alkoxy, and
    (d) trimethylsilyl;
    • Group Xa2 is
  • (a) C3-6 cycloalkyl,
    (b) phenyl, and
    (c) C1-4 alkoxy;
    • R2 is
  • (1) halogen,
    (2) C1-6 alkyl or
    (3) C1-3 alkoxy optionally substituted with phenyl;
    n is an integer of 0, 1 or 2, provided that when n is 2, each R2 may be different with each other; or
    R1 and R2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C1-6 alkyl;
    • R3 is
  • (1) —Yb—COO—R30,
    (2) C1-6 alkyl optionally substituted with one hydroxy,
    (3) C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb,
    (4)
  • Figure US20190359575A1-20191128-C00045
  • or
    (5)
  • Figure US20190359575A1-20191128-C00046
    • Yb is
  • (a) C1-6 alkylene or (b) C4-6 cycloalkylene;
    • R30 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • Group Xb is
  • (a) halogen and
    (b) C1-6 alkyl;
    • R4 is
  • (1) hydrogen or (2) methyl;
    • R5 is
  • (1) —Yc—COO—R50,
    (2) hydrogen,
    (3) C1-4 alkyl optionally substituted with one C1-3 alkoxy or
    (4) C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl;
    • Yc is
  • (a) C1-6 alkylene optionally substituted with one hydroxy,
    (b) CH2—CH2—O—CH2 or
    (c) (CH2)m—Yc1—(CH2)w;
    m is an integer of 0, 1 or 2;
    w is an integer of 0, 1 or 2;
    • Yc1 is
  • (a) C4-6 cycloalkylene optionally substituted with one C1-3 alkyl,
    (b) phenylene,
    (c) cross-linked C5-6 cycloalkylene or
    (d)
  • Figure US20190359575A1-20191128-C00047
    • R50 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • R6 is
  • (1) hydrogen or (2) methyl,
    provided that
    when R5 is —Yc—COO—R50, Yc is (CH2)m—Yc1—(CH2)w, m and w are 0, and Yc1 is phenylene, then
    R6 is methyl; and
    either R3 or R5 or both of them have “—COO—”.
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [I],
  • wherein R1 is
    (1) C4-8 alkyl,
    (2) C4-6 alkenyl,
    (3) C6 alkynyl,
    (4) trifluoromethyl-C3-5 alkyl,
    (5) C1-2 alkyl substituted with one substituent selected from Group Xa1,
    (6) C4-6 alkoxy,
    (7) trifluoromethyl-C2 alkoxy,
    (8) C1-2 alkoxy substituted with one substituent selected from Group Xa2,
    (9) C4-6 cycloalkyl,
    (10) C3-6 cycloalkyl substituted with one to two C1-4 alkyl,
    (11) C5-6 cycloalkenyl optionally substituted with one to two C1-4 alkyl,
    (12) spiro C7 cycloalkyl or
    (13) ethoxycarbonyl;
    • Group Xa1 is
  • (a) C3-6 cycloalkyl optionally substituted with one to two methyl,
    (b) phenyl,
    (c) C3-4 alkoxy, and
    (d) trimethylsilyl;
    • Group Xa2 is
  • (a) cyclohexyl,
    (b) phenyl, and
    (c) methoxy;
    • R2 is
  • (1) fluoro or chloro,
    (2) C1-6 alkyl or
    (3) methoxy optionally substituted with phenyl;
    n is an integer of 0, 1 or 2, provided that n is 2, each R2 may be different with each other; or
    R1 and R2 may combine together with the benzene ring to which they attach to form indanyl optionally substituted with two methyl;
    • R3 is
  • (1) —Yb—COO—R30,
    (2) C1-6 alkyl optionally substituted with one hydroxy,
    (3) C3-6 cycloalkyl optionally substituted with the same or different one to two substituent(s) selected from Group Xb,
    (4)
  • Figure US20190359575A1-20191128-C00048
  • or
    (5)
  • Figure US20190359575A1-20191128-C00049
    • Yb is
  • (a) C3-5 alkylene or (b) C4 cycloalkylene;
    R30 is hydrogen;
    • Group Xb is
  • (a) fluoro and
    (b) methyl;
    • R4 is
  • (1) hydrogen or (2) methyl;
    • R5 is
  • (1) —Yc—COO—R50,
    (2) hydrogen,
    (3) C2-3 alkyl optionally substituted with one C1-3 alkoxy or
    (4) C4 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl;
    • Yc is
  • (a) C1-6 alkylene optionally substituted with one hydroxy,
    (b) CH2—CH2—O—CH2 or
    (c) (CH2)m—Yc1—(CH2)w;
    m is an integer of 0, 1 or 2;
    w is an integer of 0 or 1;
    • Yc1 is
  • (a) C3-6 cycloalkylene optionally substituted with one methyl,
    (b) phenylene,
    (c) cross-linked C5 cycloalkylene or
    (d)
  • Figure US20190359575A1-20191128-C00050
    • R50 is
  • (a) hydrogen or (b) methyl;
    • R6 is
  • (1) hydrogen or (2) methyl,
    provided that
    when R5 is —Yc—COO—R50, Yc is (ethylene)-Yc1-(methylene), and Yc1 is phenylene, then R6 is methyl; and
    either R3 or R5 or both of them have “—COO—”.
  • Another preferable embodiment of the compound of Formula [I] is a compound of the following Formula [II]:
  • Figure US20190359575A1-20191128-C00051
  • wherein
    • R1 is
  • (1) C4-8 alkyl,
    (2) C3-6 alkoxy or
    (3) C5-6 cycloalkenyl optionally substituted with one to two C1-4 alkyl;
    R2 is fluoro or chloro;
    n is 1;
    R3 is C1-6alkyl;
    • R4 is
  • (1) hydrogen or (2) methyl;
    Yc is C1-6 alkylene;
    • R50 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • R6 is
  • (1) hydrogen or (2) methyl.
  • A more preferable embodiment of the compound of Formula [I] is a compound of Formula [II-A] which R6 is methyl in Formula [II]:
  • Figure US20190359575A1-20191128-C00052
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [II-B] which R4 is hydrogen and R6 is methyl in Formula [II]:
  • Figure US20190359575A1-20191128-C00053
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [ITT]:
  • Figure US20190359575A1-20191128-C00054
  • wherein
    • R1 is
  • (1) C4-8 alkyl,
    (2) C3-6 alkoxy or
    (3) C5-6 cycloalkenyl optionally substituted with one to two C1-4 alkyl;
    R2 is fluoro or chloro;
    n is 1;
    Yb is C1-6 alkylene;
    • R30 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • R4 is
  • (1) hydrogen or (2) methyl;
    • R5 is
  • (1) hydrogen,
    (2) C1-4 alkyl optionally substituted with one C1-3 alkoxy or
    (3) C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl;
    • R6 is
  • (1) hydrogen or (2) methyl.
  • A more preferable embodiment of the compound of Formula [I] is a compound of Formula [III-A] which R6 is methyl in Formula [III]:
  • Figure US20190359575A1-20191128-C00055
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [III-B] which R4 is hydrogen and R6 is methyl in Formula [III]:
  • Figure US20190359575A1-20191128-C00056
  • Another preferable embodiment of the compound of Formula [I] is a compound of the following Formula [IV]:
  • Figure US20190359575A1-20191128-C00057
  • A more preferable embodiment of the compound of Formula [I] is a compound of Formula [IV-A] which R6 is methyl in Formula [IV]:
  • Figure US20190359575A1-20191128-C00058
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [IV-B] which R4 is hydrogen and R6 is methyl in Formula [IV]:
  • Figure US20190359575A1-20191128-C00059
  • Another more preferable embodiment is a compound of the following formula:
  • Figure US20190359575A1-20191128-C00060
  • Another preferable embodiment of the compound of Formula [I] is a compound of Formula [IV-D] which R4 is hydrogen in Formula [IV]:
  • Figure US20190359575A1-20191128-C00061
  • Another preferable embodiment of the compound of Formula [I] is a compound of the following Formula [E-IV]:
  • Figure US20190359575A1-20191128-C00062
  • A more preferable embodiment of the compound of Formula [I] is a compound of Formula [E-IV-A] which R6 is methyl in Formula [E-IV]:
  • Figure US20190359575A1-20191128-C00063
  • Another more preferable embodiment of the compound of Formula [I] is a compound of Formula [E-IV-B] which R4 is hydrogen in Formula [E-IV-A.]:
  • Figure US20190359575A1-20191128-C00064
  • A particularly preferable embodiment of the compound of Formula [E-IV] is a compound of the following formula:
  • Figure US20190359575A1-20191128-C00065
  • Another preferable embodiment of the compound of Formula [I] is a compound of the following Formula [V]:
  • Figure US20190359575A1-20191128-C00066
  • wherein
    • R3a is
  • (1) hydrogen or
    (2) C1-6 alkyl optionally substituted with the same or different one to three substituent(s) selected from the group consisting of hydroxy, halogen, hydroxycarbonyl, and C1-3 alkoxycarbonyl;
    • R3b is
  • (1) hydrogen or (2) C1-6 alkyl;
    • R3c is
  • (1) hydrogen or (2) C1-6 alkyl; and the other symbols have the same meanings as defined in [01],
    provided that
    when R5 is —Yc—COO—R50, Y is (CH2)m—Yc1—(CH2)w, m and w are 0, and Yc1 is phenylene, then R6 is methyl; and
    either a structure of the formula:
  • Figure US20190359575A1-20191128-C00067
  • or R5 or both of them have “—COO—”.
  • Another embodiment of the compound of Formula [V] is the following compound:
  • Figure US20190359575A1-20191128-C00068
  • wherein
    R3a and R3b may combine together with the carbon atom to which they attach to form
    (1) a C3-6 cycloalkane ring optionally substituted with the same or different one to three substituent(s) selected from the group consisting of hydroxy, halogen, hydroxycarbonyl, and C1-3 alkoxycarbonyl,
    (2) a tetrahydropyran ring or
    (3) a 1-methanesulfonylazetidine ring;
    R3c is (1) hydrogen or (2) C1-6 alkyl; and the other symbols have the same meanings as defined in [01],
    provided that
    when R5 is —Yc—COO—R50, Yc is (CH2)m—Yc1—(CH2)w, m and w are 0, and Yc1 is phenylene, then R6 is methyl;
    either a structure of the formula:
  • Figure US20190359575A1-20191128-C00069
  • or R5 or both of them have “—COO—”.
  • A more preferable embodiment of the compound of Formula [V] includes the compounds of the following general formulae.
  • Figure US20190359575A1-20191128-C00070
  • Another preferable embodiment of the compound of Formula [I] is a compound of the following Formula [VI]:
  • Figure US20190359575A1-20191128-C00071
  • A further preferable embodiment of a compound of Formula [I] is any one of compounds of the following formulae:
  • Figure US20190359575A1-20191128-C00072
  • wherein
    R3h is hydrogen or methyl;
    R3w is methyl or fluoro;
    nx is an inter of 0 or 2;
    nw is an integer of 0, 1, 2 or 3; and
    the other symbols have the same meanings as defined in [01].
  • In the Formulae [IV-B-A] to [IV-B-D], a more preferable one is any one of compounds wherein R2 is chloro or trifluoromethyl.
  • In the Formulae [IV-B-A] to [IV-B-D], a still more preferable one is any one of compounds wherein
    • Yc is
  • (a) C1-6 alkylene optionally substituted with one hydroxy or
    (b) (CH2)mYc1—(CH2)w—;
    m is an integer of 0, 1 or 2;
    w is an integer of 0, 1 or 2; and
    • Yc1 is
  • (a) C3-6 cycloalkylene optionally substituted with one C1-3 alkyl,
    (b) phenylene,
    (c) phenylene substituted with one halogen,
    (d) phenylene substituted with one C1-3 alkyl,
    (e) phenylene substituted with one C1-3 alkoxy,
    (f) phenylene substituted with one trifluoromethyl,
    (g) cross-linked C5-8 cycloalkylene,
    (h) pyrrolidinediyl,
    (i) pyrrolidinediyl substituted with one carboxy,
    (j) pyrrolidinediyl substituted with one C1-3 alkylcarbonyl,
    (k) pyrrolidinediyl substituted with one C1-3 alkylsulfonyl or
    (l) pyridinediyl.
  • A still more preferable one is any one of compounds of Formula [IV-B-A] to [ITV-B-D] wherein
  • Yc is C1-6 alkylene, phenylene, cross-linked C5-8 cycloalkylene or pyridinediyl.
  • Another further preferable embodiment of a compound of Formula [I] is any one of compounds of the following formulae:
  • Figure US20190359575A1-20191128-C00073
    Figure US20190359575A1-20191128-C00074
  • wherein
    R3 is C1-6alkyl optionally substituted with one hydroxy,
    C1-6 alkyl substituted with one C1-4 alkoxy or
    C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s)
    selected from Group Xb;
    R5B is hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy or trifluoromethyl; and
    the other symbols have the same meanings as defined in [01].
  • In the Formulae [IV-B-A] to [IV-B-N], a more preferable one is any one of compounds wherein
    • R1 is
  • C4-8 alkyl,
    C3-7 alkyl substituted with one trifluoromethyl,
    C1-5 alkyl substituted with one substituent selected from Group Xa1,
    C3-6 alkoxy,
    C2-7 alkoxy substituted with one trifluoromethyl,
    C1-3 alkoxy substituted with one substituent selected from Group Xa1,
    C4-6 cycloalkyl,
    C3-6 cycloalkyl substituted with the same or different one to two C1-5 alkyl,
    C5-6 cycloalkenyl optionally substituted with the same or different one to two C1-4 alkyl,
    cyclohexylidenemethyl optionally substituted with the same or different one to two C1-3 alkyl, tetrahydropyran-4-ylidenemethyl,
    C3-6 cycloalkyl substituted with one to the same two halogen or
    C5-6 cycloalkenyl substituted with one to the same two halogen; and
    R2 is fluoro, chloro or trifluoromethyl.
  • In the Formulae [IV-B-A] to [IV-B-N], a still more preferable one is any one of compounds wherein
    • R1 is C4-8alkyl,
  • C3-7 alkyl substituted with one trifluoromethyl,
    C1-5 alkyl substituted with one substituent selected from Group Xa1,
    C3-6 alkoxy,
    C4-6 cycloalkyl substituted with the same or different one to two C1-5 alkyl,
    C5-6 cycloalkenyl optionally substituted with the same or different one to two C1-4 alkyl,
    C6 cycloalkyl substituted with one to the same two halogen or
    C6 cycloalkenyl substituted with one to the same two halogen; and
    R2 is chloro or trifluoromethyl.
  • In a still more preferable embodiment of the Formulae [IV-B-A] to [IV-B-N], R1 is any one of the following substituents.
  • Figure US20190359575A1-20191128-C00075
  • Another embodiment of the present invention also includes the following embodiments.
  • [01a] A compound of Formula [I] or a pharmaceutically acceptable salt thereof:
  • Figure US20190359575A1-20191128-C00076
  • wherein
    • R1 is
  • (1) C4-8 alkyl,
    (2) C4-8 alkenyl,
    (3) C4-8 alkynyl,
    (4) C3-7 alkyl substituted with one trifluoromethyl,
    (5) C1-4 alkyl substituted with one substituent selected from Group Xa1,
    (6) C3-6 alkoxy,
    (7) C2-7 alkoxy substituted with one trifluoromethyl,
    (8) C1-3 alkoxy substituted with one substituent selected from Group Xa2,
    (9) C4-6 cycloalkyl,
    (10) C3-6 cycloalkyl substituted with one to two C1-4 alkyl,
    (11) C5-6 cycloalkenyl optionally substituted with one to two C1-4 alkyl,
    (12) spiro C6-11 cycloalkyl or
    (13) C1-3 alkoxycarbonyl;
    • Group Xa1 is
  • (a) C3-6 cycloalkyl optionally substituted with the same or different one to three C1-5 alkyl,
    (b) phenyl,
    (c) C2-4 alkoxy, and
    (d) trimethylsilyl;
    • Group Xa2 is
  • (a) C3-6 cycloalkyl,
    (b) phenyl, and
    (c) C1-4 alkoxy;
    • R2 is
  • (1) halogen,
    (2) C1-6 alkyl, or
    (3) C1-3 alkoxy optionally substituted with phenyl;
    n is an integer of 0, 1 or 2, provided that when n is 2, each R2 may be different with each other;
    or
    R1 and R2 may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C1-6 alkyl;
    • R3 is
  • (1) —Yb—COO—R30,
    (2) C1-6 alkyl optionally substituted with one hydroxy,
    (3) C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb,
    (4)
  • Figure US20190359575A1-20191128-C00077
  • or
    (5)
  • Figure US20190359575A1-20191128-C00078
    • Yb is
  • (a) C1-6 alkylene or (b) C3-6 cycloalkylene;
    • R30 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • Group Xb is
  • (a) halogen and
    (b) C1-6 alkyl;
    • R4 is
  • (1) hydrogen or (2) methyl;
    • R5 is
  • (1) —Yc—COO—R50,
    (2) hydrogen,
    (3) C1-4 alkyl optionally substituted with one C1-3 alkoxy or
    (4) C3-6 cycloalkyl optionally substituted with one hydroxy-C1-4 alkyl;
    • Yc is
  • (a) C1-6 alkylene optionally substituted with one hydroxy,
    (b) CH2—CH2—O—CH2 or
    (c) (CH2)m—Yc1—(CH2)w;
    m is an integer of 0, 1 or 2;
    w is an integer of 0, 1 or 2;
    • Yc1 is
  • (a) C3-6 cycloalkylene optionally substituted with one C1-3 alkyl,
    (b) phenylene,
    (c) cross-linked C5-8 cycloalkylene or
    (d)
  • Figure US20190359575A1-20191128-C00079
    • R50 is
  • (a) hydrogen or (b) C1-4 alkyl;
    • R6 is
  • (1) hydrogen or (2) methyl;
    provided that
    when R5 is —Yc—COO—R50, Y is (CH2)m—Yc1—(CH2)w, m and w are 0, and Yc1 is phenylene, then R6 is methyl; and
    either R3 or R5 or both of them have “—COO—”.
    [02a] The compound of [01a], wherein the compound of Formula [I] is a compound of Formula [II], or a pharmaceutically acceptable salt thereof.
  • Figure US20190359575A1-20191128-C00080
  • [03a] The compound of [01a], wherein the compound of Formula [I] is a compound of Formula [III], or a pharmaceutically acceptable salt thereof.
  • Figure US20190359575A1-20191128-C00081
  • [04a] The compound of [01a], wherein the compound of Formula [I] is a compound of Formula [IV], or a pharmaceutically acceptable salt thereof.
  • Figure US20190359575A1-20191128-C00082
  • [05a] The compound of any one of [01a] to [04a], wherein R6 is methyl, or a pharmaceutically acceptable salt thereof.
    [06a] The compound of any one of [01a] to [05a], wherein R4 is hydrogen, or a pharmaceutically acceptable salt thereof.
    [07a] The compound of any one of [01a] to [06a], wherein n is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof.
    [08a] The compound of any one of [01a] to [07a], wherein R2 is halogen, or a pharmaceutically acceptable salt thereof.
    [09a] The compound of [08a], wherein R2 is chloro or fluoro, or a pharmaceutically acceptable salt thereof.
    [10a] The compound of [02a], wherein R50 is hydrogen, or a pharmaceutically acceptable salt thereof.
    [11a] The compound of [03a], wherein R30 is hydrogen, or a pharmaceutically acceptable salt thereof.
    [12a] A pharmaceutical composition comprising the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
    [13a] An RORγ antagonist comprising the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
    [14a] An agent for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
    [15a] The agent of [14a], wherein the disease is autoimmune disease.
    [16a] The agent of [15a], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes.
    [17a] The agent of [14a], wherein the disease is metabolic disease.
    [18a] The agent of [17a], wherein the metabolic disease is diabetes.
    [19a] A method of inhibiting RORγ, comprising administering to a mammal a therapeutically effective amount of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
    [20a] A method of treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to a mammal an effective amount of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof.
    [21a] The method of [20a], wherein the disease is autoimmune disease.
    [22a] The method of [21a], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes.
    [23a] The method of [20a], wherein the disease is metabolic disease.
    [24a] The method of [23a], wherein the metabolic disease is diabetes.
    [25a] Use of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for the manufacture of an RORγ antagonist.
    [26a] Use of the compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treatment or prevention of a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
    [27a] The use of [26a], wherein the disease is autoimmune disease.
    [28a] The use of [27a], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uvcitis, polymyalgia rheumatica, and type I diabetes.
    [29a] The use of [26a], wherein the disease is metabolic disease.
    [30a] The use of [29a], wherein the metabolic disease is diabetes.
    [31a] A compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for use as an RORγ antagonist.
    [32a] A compound of any one of [01a] to [11a] or a pharmaceutically acceptable salt thereof for use as an agent for treatming or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
    [33a] The compound of [32a], wherein the disease is autoimmune disease, or a pharmaceutically acceptable salt thereof.
    [34a] The compound of [33a], wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes, or a pharmaceutically acceptable salt thereof.
    [35a] The compound of [32a], wherein the disease is metabolic disease, or a pharmaceutically acceptable salt thereof.
    [36a] The compound of [35a], wherein the metabolic disease is diabetes, or a pharmaceutically acceptable salt thereof.
  • The term “pharmaceutically acceptable salt” may be any salts without excess toxicity known in the art.
  • In particular, it includes, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, and a salt with an organic base. Various forms of pharmaceutically acceptable salts are well known in the art, and are listed in the following references, for example.
    • (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)
  • The salt with an organic acid or inorganic acid includes a salt with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, 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, hexylresorcylic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic 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), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, nitric acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, phosphoric acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, asparaginic acid or glutamic acid.
  • A preferable salt with an organic acid includes a salt with oxalic acid, malcic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid or pamoic acid. Alternatively, a salt with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid is illustrated.
  • A preferable salt with an inorganic acid includes a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid.
  • The salt with an organic base includes a salt with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine.
  • A preferable salt with an organic base includes a salt with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine.
  • The salt with an inorganic base includes a salt with ammonium, aluminum, barium, bismuth, calcium, lithium, magnesium, potassium, sodium or zinc.
  • A preferable salt with an inorganic base includes a salt with sodium, potassium, calcium, magnesium or zinc.
  • According to known methods, each pharmaceutically acceptable salt may be obtained by reacting a compound of Formula [I] with an inorganic base, an organic base, an inorganic acid or an organic acid.
  • A preferable salt of a compound of Formula [I] includes a salt with sodium, potassium or calcium.
  • Another preferable salt of a compound of Formula [I] includes a salt with sodium, potassium, L-lysine, tris(hydroxymethyl)methylamine, diethylamine, piperazine or dicyclohexylamine.
  • A compound of Formula [I] or a pharmaceutically acceptable salt thereof may exist in its solvate.
  • The term “solvate” means a compound where a solvent molecule is coordinated with a compound of Formula [I] or a pharmaceutically acceptable salt thereof, and includes a hydrate.
  • A pharmaceutically acceptable solvate is preferred as the solvate, and includes, for example, a hydrate, an ethanolate, and a dimethylsulfoxidate of a compound of Formula [I] or a pharmaceutically acceptable salt thereof.
  • In particular, it includes, for example, a hemihydrate, 1 hydrate, 2 hydrate or 1 ethanolate of a compound of Formula [I], or a monohydrate of a sodium salt of a compound of Formula [I] or a ½ ethanolate of dihydrochloride thereof.
  • According to known methods, the solvates may be obtained.
  • A compound of Formula [I] may exist as a tautomer. In that case, a compound of Formula [I] may exist as an individual tautomer or a mixture of tautomers.
  • A compound of Formula [I] may have a carbon-carbon double bond. In that case, a compound of Formula [I] may exist as an E-isomer, a Z-isomer or a mixture of E- and Z-isomers.
  • A compound of Formula [I] may exist as a stereoisomer which should be recognized as a cis/trans isomer. In that case, a compound of Formula [I] may exist as a cis-isomer, a trans-isomer or a mixture of cis- and trans-isomers.
  • A compound of Formula [I] may have one or more asymmetric carbon atom(s). In that case, a compound of Formula [I] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.
  • A compound of Formula [I] may exist as an atropisomer. In that case, a compound of Formula [I] may exist as an individual atropisomer or a mixture of atropisomers.
  • A compound of Formula [I] may simultaneously have multiple structural features which can provide the above isomers. A compound of Formula [I] may also contain the above isomers in any ratios.
  • Formulae, chemical structures or chemical names without specifying a stereochemistry herein include all the above isomers which may exist, unless otherwise specified.
  • Diastereomer mixtures may be isolated into each diastereomer by a conventional method such as chromatography or crystallization. Each diastereomer may be also prepared by using a starting material which is a single isomer in terms of stereochemistry or by a synthetic method using a stereoselective reaction.
  • A mixture of enantiomers may be isolated into each single enantiomer by a well known method in the art.
  • For example, a mixture of enantiomers may be reacted with a substantially pure enantiomer which is known as a chiral auxiliary to form a mixture of diastereomers, which may be then isolated into a diastereomer with an enhanced isomeric ratio or a substantially pure single diastereomer by a common method such as fractionated crystallization or chromatography. The added chiral auxiliary may be removed from the isolated diastereomer by a cleavage reaction to give a desirable enantiomer.
  • A mixture of enantiomers may be also directly separated by a well known chromatography in the art using a chiral stationary phase.
  • Alternatively, either of enantiomers may be also obtained by using a substantially pure and optically active starting material or a stereoselective synthesis (i.e., asymmetric induction) from a prochiral intermediate with a chiral auxiliary or asymmetric catalyst.
  • An absolute configuration may be determined by X-ray crystallographic analysis of a crystalline product or intermediate. In that case, a crystalline product or intermediate which is induced by an agent having an asymmetric center with a known configuration may be used if needed.
  • A compound of Formula [I] may be labeled with an isotope atom such as 2H, 3H, 14C, and 35S.
  • A compound of Formula [I] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of Formula [I] or pharmaceutically acceptable salt thereof. A more preferable one is a compound of Formula [I] or a pharmaceutically acceptable salt thereof purified in an 80% or more purity.
  • According to known methods in the art of pharmaceutical formulation, a pharmaceutical composition in the present invention may be prepared by optionally mixing a compound of Formula [I] or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carrier(s) in any amount. A content of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition depends on dosage forms and doses, and is for example 0.1 to 100% by weight of the composition.
  • A dosage form of a compound of Formula [I] or a pharmaceutically acceptable salt thereof includes an oral preparation such as a tablet, a capsule, a granule, a powder, a lozenge, a syrup, an emulsion, and a suspension or an parenteral preparation such as an external preparation, a suppository, an injection, an eye drop, a nasal preparation, and a pulmonary preparation.
  • The term “pharmaceutically acceptable carrier” includes various common organic or inorganic carrier substances as a formulation material, and includes excipients, disintegrants, binders, fluidizers, and lubricants in a solid formulation, solvents, solubilizing agents, suspending agents, tonicity agents, buffers, and soothing agents in a liquid formulation, 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 a semisolid formulation.
  • A preserving agent, an antioxidant agent, a colorant or a sweetening agent may be also optionally used as an additive.
  • The term “excipient” includes, for example, lactose, white soft sugar, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethylstarch, low substituted hydroxypropylcellulose, and gum arabic.
  • The term “disintegrant” includes, for example, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose.
  • The term “binder” includes, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, white soft sugar, dextrin, starch, gelatin, carmellose sodium, and gum arabic.
  • The term “fluidizer” includes, for example, light anhydrous silicic acid and magnesium stearate.
  • The term “lubricant” includes, for example, magnesium stearate, calcium stearate, and talc.
  • The term “solvent” includes, for example, purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil, and olive oil.
  • The term “solubilizing agent” includes, for example, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.
  • The term “suspending agent” includes, for example, benzalkonium chloride, carmellose, hydroxypropylcellulose, propyleneglycol, povidone, methylcellulose, and glyceryl monostearate.
  • The term “tonicity agent” includes, for example, glucose, D-sorbitol, sodium chloride, and D-mannitol.
  • The term “buffer” includes, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.
  • The term “soothing agent” includes, for example, benzyl alcohol.
  • The term “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 acid and an ester 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, hydroxyethylcellulose, and hydroxypropylcellulose, synthetic polymers such as carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, and polyvinylpyrrolidone, propylene glycol, macrogol such as macrogol 200 to 600, and a combination of two or more of them.
  • The term “preserving agent” includes, for example, ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
  • The term “antioxidant agent” includes, for example, sodium sulfite and ascorbic acid.
  • The term “colorant” includes, for example, food dye such as Food Red No. 2 and No. 3, and Food Yellow No. 4 and No. 5, and β-carotene.
  • The term “sweetening agent” includes, for example saccharin sodium, dipotassium glycyrrhizate, and aspartame.
  • A pharmaceutical composition in the present invention may be administered 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 orally or parenterally such as locally, rectally, intravenously, intramuscularly, and subcutaneously. While a dose may vary depending on subjects, diseases, symptoms, dosage forms, routes of administration and the like, for example when it is administered orally to an adult patient the dose of a compound of Formula [I] as the active ingredient ranges generally from about 0.01 mg to about 1 g per day, which may be administered once to several times in a divided amount.
  • A compound of Formula [I] or a pharmaceutically acceptable salt thereof has an inhibitory activity of Retinoid-related Orphan Receptor γ (RORγ), and is useful for treating or preventing various diseases or conditions which are expected to be improved by adjusting the RORγ inhibitory activity, e.g. autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease, allergic diseases such as asthma, dry eye, fibrosis such as lung fibrosis and primary biliary cirrhosis, and metabolic diseases such as diabetes.
  • The term “RORγ antagonist” means a compound having an ability which inhibits the function of Retinoid-related Orphan Receptor γ (RORγ) to make the activity thereof disappear or reduced.
  • To “inhibit RORγ” means that a function of RORγ is inhibited to make the activity thereof disappear or reduced, which includes, for example, the function of RORγ is inhibited according to Test Example 1 described hereafter. To “inhibit RORγ” preferably includes “inhibiting human RORγ”. Inhibiting the function or disappearing or reducing the activity may be preferably carried out during clinical indication in human.
  • The term “RORγ inhibitor” means any substance which inhibits RORγ, and may be a low molecular compound, a nucleic acid, polypeptide, protein, antibody, vaccine and the like. A preferable “RORγ inhibitor” is “human RORγ inhibitor”.
  • The term “treating” used herein includes improving symptoms, preventing severe diseases, maintaining a remission, preventing exacerbation as well as preventing relapse.
  • The term “preventing” used herein means suppressing pathogenesis of symptoms.
  • The term “autoimmune disease” means a genric name of diseases where an immune system overreacts to and attacks normal cells and tissues thereof to cause symptoms, and in particular, includes rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, Behcet's disease, sarcoidosis, Harada disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease.
  • The term “allergic disease” means a disease derived from the condition where an immune reaction excessively occurs against a certain antigen, and in particular, includes atopic dermatitis, allergic rhinitis such as pollen allergy, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, infantile asthma, food allergy, medication allergy, and hives.
  • The term “fibrosis” means a condition with increased fibroconnective tissues, and in particular, includes lung fibrosis and primary biliary cirrhosis.
  • The term “metabolic disease” means a disease caused by abnormity 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 or type II diabetes.
  • Herein, the proposal of preferences and options in respect of different features of the compounds, methods, uses, and compositions comprises the proposal of combinations of those preferences and options for the different features, insofar as they are combinable and compatible.
  • Methods for preparing a compound of Formula [I] or a pharmaceutically acceptable salt thereof are illustrated as below. A method for preparing a compound of Formula [I] or a pharmaceutically acceptable salt thereof is not however intended to be limited thereto.
  • 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 a reaction may optionally proceed to a sequential step without isolation and purification.
  • In particular, a compound of Formula [I] may be prepared according to the following Preparation Methods 1 to 5, for example:
  • Figure US20190359575A1-20191128-C00083
  • Each definition of each substituent in schemes in each Preparation Method is illustrative and is not limited thereto.
  • Preparation Method 1
  • A method for preparing dihydropyrimidin-2-one compounds via Claisen reaction (1)
  • Figure US20190359575A1-20191128-C00084
    Figure US20190359575A1-20191128-C00085
  • In the formula,
  • P1 is for example C1-4alkyl;
  • R3q1 is for example —Yb—CH2OP2 (in which P2 is a protective group such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS)), C1-6 alkyl optionally substituted with hydroxy protected with one P2, C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb, 4-tetrahydropyranyl or I-methanesulfonyl-3-azetidinyl;
  • Yb is for example C1-6 alkylene or C3-6 cycloalkylene;
  • Group Xb is for example halogen or C1-6 alkyl;
  • R5q is for example —Yc—COO—Rq50 (in which Rq50 is C1-4 alkyl), hydrogen, C1-4 alkyl optionally substituted with one C1-3 alkoxy or C3-6 cycloalkyl optionally substituted with hydroxy-C1-4 alkyl protected with one P2;
  • Yc is C1-6 alkylene optionally substituted with hydroxy protected with one P2, CH2—CH2—O—CH2 or (CH2)m—Yc1—(CH2)w;
  • m is an integer of 0, 1 or 2;
  • w is an integer of 0, 1 or 2;
  • Yc1 is for example C3-6 cycloalkylene optionally substituted with one C1-3 alkyl, phenylene, cross-linked C5-8 cycloalkylene or
  • Figure US20190359575A1-20191128-C00086
  • and
    the other symbols have the same meanings as defined in [01].
    • Step 1
  • A compound of Formula [Q-102] may be prepared from a compound of Formula [Q-101a] by a rearrangement reaction with diacetoxyiodobenzene (e.g. a method described in Chem. Pharm. Bull., 1985, 33, 1097-1103).
  • A compound of Formula [Q-101a] may be prepared by Preparation Method 6 described below.
    • Step 2
  • A compound of Formula [Q-103] may be prepared from a compound of Formula [Q-102] by hydrolysis with a base.
  • The base includes sodium hydroxide, potassium hydroxide, and lithium hydroxide. A preferable base is sodium hydroxide.
  • A solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, and water, and may be used alone or by mixture of two or more of them. A preferable solvent is a mixed solvent with ethanol and water.
  • A reaction temperature includes from room temperature to 100° C. A preferable reaction temperature is room temperature.
    • Step 3
  • A compound of Formula [Q-105] may be prepared by a condensation reaction of a compound of Formula [Q-103] with a compound of Formula [Q-104].
  • A condensation agent includes aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), and carbonyldiimidazole (CDI). For example, 1-hydroxy-1H-benzotriazole monohydrate (HOBt.H2O) or 4-dimethylaminopyridine (DMAP) may be optionally added thereto. A preferable condensation agent is a mixture of aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 4-dimethylaminopyridine (DMAP).
  • A solvent includes toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them. A preferable solvent is dichloromethane.
  • A reaction temperature includes from 0° C. to 100° C. A preferable reaction temperature is room temperature.
  • A compound of Formula [Q-104] may be prepared by Preparation Method 7-1 described below.
    • Step 4
  • A compound of Formula [Q-106] may be prepared from a compound of Formula [Q-105] in the presence of a base and a chlorosilane compound by Ireland Claisen rearrangement reaction (e.g. a method described in Org. Lett., 2007, 9, 4431-4434).
  • The base includes lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide (LiTMP). A preferable base is lithium diisopropylamide (LDA).
  • The chlorosilane compound includes trimethylsilyl chloride and tert-butyldimethylsilyl chloride. A preferable chlorosilane compound is trimethylsilyl chloride.
  • Hexamethylphosphoric triamide (HMPA) or N,N′-dimethylpropyleneurea (DMPU) may be added as an additive.
  • A solvent includes an ether type solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from −78° C. to 80° C. A preferable reaction temperature is from −78° C. to room temperature.
    • Step 5
  • A compound of Formula [Q-107] may be prepared from a compound of Formula [Q-106] in the presence of a base by an azidation reaction followed by Curtius rearrangement reaction.
  • An azidation agent includes DPPA.
  • The base includes triethylamine and diisopropylethylamine. A preferable base is triethylamine.
  • A solvent includes benzene, toluene, and xylene. A preferable solvent is toluene.
  • A reaction temperature includes from 0° C. to 140° C. A preferable reaction temperature is 110° C.
    • Step 6
  • A compound of Formula [Q-109] may be prepared from a compound of Formula [Q-107] and a compound of Formula [Q-108]. When a compound of Formula [Q-108] is hydrochloride, one or more equivalent(s) of a base such as triethylamine may be optionally added.
  • A solvent inludes benzene, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from 0° C. to 80° C. A preferable reaction temperature is from 0° C. to room temperature.
  • A compound of Formula [Q-108] may be prepared by Preparation Method 8-2 described below.
    • Step 7
  • A compound of Formula [Q-110] may be prepared by an oxidative cleavage reaction of exo-olefin of a compound of Formula [Q-109], followed by a cyclization reaction with an acid.
  • The oxidative cleavage reaction includes ozone oxidation by reductive treatment. A reducing agent used in the oxidative cleavage reaction includes dimethyl sulfide and triphenylphosphine. A preferable reducing agent is dimethyl sulfide.
  • The acid used in the cyclization reaction includes hdyrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid is hdyrochloric acid. The acid used in the cyclization reaction may be mixed with reactants from the beginning or may be added to the reaction system after completion of the oxidative cleavage reaction.
  • A solvent includes methanol, ethanol, isopropyl alcohol, tert-butanol, dichloromethane, and chloroform, and may be used alone or by mixture of two or more of them. A preferable solvent is methanol, or a mixed solvent of methanol with dichloromethane.
  • A reaction temperature includes from −100° C. to 80° C. A preferable reaction temperature is from −78° C. to room temperature.
    • Step 8
  • A compound of Formula [I] may be prepared from a compound of Formula [Q-110] by the following method. For example, a compound which R3 or R5 has a hydroxyl group as a substituent in a compound of Formula [I] and the hydroxyl group is protected with P2 may be prepared by a deprotection reaction of P2. The deprotection reaction may be carried out from the compound obtained in the cyclization reaction by a method described in a reference (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 165-215). Alternatively, the reaction may be carried out under an acidic condition simultaneously with the cyclization reaction.
  • A compound which R3 has a carboxyl group as a substituent in a compound of Formula [I] may be prepared by oxidizing a compound which R3q1 has a primary hydroxyl group as a substituent with Dess-Martin reagent to an aldehyde (e.g. a method described in J. Org. Chem., 2000, 65, 5498-5505), followed by an oxidation reaction of the aldehyde with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and chlorous acid (e.g. a method described in J. Org. Chem., 1999, 64, 2564-2566). Alternatively, a compound which R3 has a carboxyl group as a substituent may be prepared from a compound which R3q1 has an ester as a substituent by a hydrolysis reaction. The hydrolysis reaction may be carried out by a method of the above Step 2 or a hydrolysis reaction with an acid such as trifluoroacetic acid.
  • A compound which R5 has a carboxyl group as a substituent in a compound of Formula [I] may be prepared by an oxidation reaction of a hydroxyl group or a hydrolysis reaction of an ester according to the Preparation Method of the compound which R3 has a carboxyl group as a substituent.
  • For example, when R5 is “—Yc—COO—R50”, the compound may be prepared by the following hydrolysis reaction:
  • Figure US20190359575A1-20191128-C00087
  • wherein R50 is for example C1-4 alkyl and the other symbols have the same meanings as defined above.
  • For example when R3 is “—Yb—COO—R30”, the compound may be prepared by the following hydrolysis reaction:
  • Figure US20190359575A1-20191128-C00088
  • wherein R30 is for example C1-4 alkyl and the other symbols have the same meanings as defined above.
  • For example, when R3 is “—Yb—COO—R30” in which R30 is hydrogen, the compound may be prepared by the following oxidation reaction:
  • Figure US20190359575A1-20191128-C00089
  • wherein each symbol has the same meaning as defined above.
  • An example of Preparation Method 1 is as follows.
  • Figure US20190359575A1-20191128-C00090
    • Preparation Method 2 A Method for Preparing Dihydropyrimidin-2-One Compounds Via Claisen Reaction (2)
  • A compound of Formula [I] may be also prepared from a compound of Formula [Q-201] prepared from a compound of Formula [Q-101b] according to Preparation Method 1.
  • Figure US20190359575A1-20191128-C00091
  • In the formula, Rq1 is for example bromo, iodo or benzyloxy, R3q is for example —Yb—COO—Ra30 (in which Rq30 is C1-4 alkyl), C1-4 alkyl optionally substituted with one C1-3 alkoxy or C3-6 cycloalkyl optionally substituted with hydroxy-C1-4 alkyl protected with one P2, and the other symbols have the same meanings as defined above.
    • Preparation Method 2-1
  • A compound which R1 is C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2 in Formula [I] may be prepared by the following method.
  • Figure US20190359575A1-20191128-C00092
  • In the formula, Bn is benzyl, Xq1 is a leaving group such as halogen or a hydroxyl group, R12 is a substituent (e.g. C3-6 alkyl) which combines together with the oxygen atom on the benzene ring to form C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2, R1 is for example C3-6 alkoxy or C2-7 alkoxy substituted with one trifluoromethyl, and the other symbols have the same meanings as defined above.
    • Step 1
  • A compound of Formula [Q-202] may be prepared by deprotecting the benzyl group of a compound of Formula [Q-201a] according to a method described in a reference (e.g. a method described in Peter G. M. Wuts (2007) Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, p 102-120). For example, the benzyl group may be removed by a reaction in the presence of Lewis acid in the step.
  • Lewis acid includes boron tribromide, boron trichloride, and trimethylsilyl iodide. A preferable Lewis acid is boron tribromide.
  • A solvent includes benzene, toluene, dichloromethane, and chloroform. A preferable solvent is dichloromethane.
  • A reaction temperature includes from −78° C. to 80° C. A preferable reaction temperature is −78° C.
    • Step 2
  • A compound of Formula [Q-204] may be prepared from a compound of Formula [Q-202] and a compound of Formula [Q-203].
  • When Xq1 is a leaving group such as halogen (alkylation reaction):
  • A compound of Formula [Q-202] may be coupled with a compound of Formula [Q-203] in the presence of a base to give a compound of Formula [Q-204].
  • The base includes sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogencarbonate. A preferable base is cesium carbonate.
  • A solvent includes diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, methylene chloride, chloroform, ethyl acetate, acetone, N,N-dimethylformamide, and dimethylsulfoxide. A preferable solvent is N,N-dimethylformamide.
  • A reaction temperature is from room temperature to 120° C. A preferable reaction temperature is 100° C.
  • When Xq1 is a hydroxyl group (Mitsunobu reaction):
  • A compound of Formula [Q-202] may be subjected under Mitsunobu reaction with a compound of Formula [Q-203] in a solvent in the presence of bis(2-methoxyethyl)azodicarboxylate and triphenylphosphine to give a compound of Formula [Q-204].
  • The solven includes methylene chloride, chloroform, tetrahydrofuran, and toluene. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from 0° C. to 100° C. A preferable reaction temperature is from room temperature to 60° C.
    • Step 3
  • A compound of Formula [I] may be prepared from a compound of Formula [Q-204] according to Preparation Method 1 Step 8.
  • An example of Preparation Method 2-1 is as follows.
  • Figure US20190359575A1-20191128-C00093
    • Preparation Method 2-2
  • A compound which R1 is, for example, C4-8alkyl or C1-4 alkyl substituted with one substituent selected from Group Xa1 in Formula [I] (provided that R1 is not C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2) may be prepared from a compound of Formula [Q-201b] by a cross coupling reaction or an insertion reaction of carbon monoxide:
  • Figure US20190359575A1-20191128-C00094
  • wherein Rq2 is for example bromo, iodo or trifluoromethane sulfonyloxy and the other symbols have the same meanings as defined above.
  • The cross coupling reaction includes a method described in a reference (e.g. a method described in F. Diederich, P. J. Stang (1998). Metal-catalyzed Cross-coupling Reactions, Weinheim, Germany, Wiley-VCH), and the insertion reaction of carbon monoxide includes a method described in a reference (e.g. M. Schlosser (1994). Organometallics in Synthesis, Weinheim, Germany, Wiley-VCH).
  • Figure US20190359575A1-20191128-C00095
  • In the formula, R1 is for example C4-8 alkyl or C1-4 alkyl substituted with one substituent selected from Group Xa1 (provided that R1 is not C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2), R10 is for example C2-6 alkyl, M1 is boronic acid, boronic acid ester or trifluoroborate salt, M2 is zinc or zinc halide, and the other symbols have the same meanings as defined above.
  • For compounds of Formula [Q-202a], Formula [Q-202b], and Formula [Q-202c], a commercially available product (e.g. isobutylboronic acid, 1-hexylboronic acid pinacol ester, potassium (3,3-dimethylbutyl)trifluoroborate, butylzinc bromide, cyclohexylacetylene) may be used or they may be for example prepared from a commercially available R1—Xqq (e.g. 1-chloro-3,3-dimethyl-butane, bromomethyl-cyclohexane; Xqq is chloro, bromo or iodo) according to known methods.
  • For example, a compound of Formula [Q-202a] may be prepared by the following method.
  • A compound which M1 is boronic acid may be prepared by preparing Grignard reagent from a commercially available compound such as R1—Br and magnesium to react with trimethyl borate, triisopropyl borate, for example.
  • A compound which M1 is boronic acid ester may be prepared by reacting a boronic acid compound with pinacol.
  • A compound which M1 is trifluoroborate salt may be prepared by reacting a boronic acid compound with potassium hydrogen fluoride.
  • For example, a compound of Formula [Q-202b] may be prepared from a commerically available compound such as R1—I and zinc.
  • An activating agent of zinc includes iodine, trimethylsilyl chloride and 1,2-dibromoethane, and may be used alone or by mixture of two or more of them. A preferable activating agent is trimethylsilyl chloride or 1,2-dibromoethane.
  • A solvent includes tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide. A preferable solvent is tetrahydrofuran or dimethylacetamide.
  • A reaction temperature includes from room temperature to 80° C. A preferable reaction temperature is room temperature.
  • For example, a commerically available product such as 3,3-dimethyl-1-butyne, cyclohexylacetylene, and phenylacetylene may be used for a compound of Formula [Q-202c].
  • An alkynylene compound of Formula [I] obtained by Sonogashira reaction may be converted into an alkyl compound by a catalytic hydrogen addition reaction with a catalyst such as palladium on carbon, platinum on carbon, and rhodium-alumina.
  • In the insertion reaction of carbon monoxide, a compound of Formula [Q-201b] may be reacted in an alcohol solvent such as ethanol to convert into an ester corresponding to the alcohol.
  • In a compound of Formula [I], a compound which R3 or R5 has a hydroxyl group as a substituent, a compound which R3 has a carboxyl group as a substituent or a compound which R5 has a carboxyl group as a substituent may be prepared according to Preparation Method 2-1 Step 3.
  • An example of Preparation Method 2-2 is as follows.
  • Figure US20190359575A1-20191128-C00096
    • Preparation Method 3 A Method for Preparing Dihydropyrimidin-2-One Compounds Via Biginelli Reaction
  • A compound which R6 is hydrogen in a compound of Formula [I] may be prepared by Biginelli reaction.
  • Figure US20190359575A1-20191128-C00097
  • In the formula, R6 is hydrogen and each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [I] may be prepared by reacting a compound of Formula [Q-301], a compound of Formula [Q-302], and a compound of Formula [Q-303] in the presence of an acid.
  • The acid includes hdyrochloric acid, acetic acid, trimethylchlorosilane, and p-toluenesulfonic acid. A preferable acid is trimethylchlorosilane.
  • A solvent includes toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them. A preferable solvent in the reaction is a mixed solvent of acetonitrile and N,N-dimethylformamide.
  • A reaction temperature includes from 0° C. to 140° C. A preferable reaction temperature is from room temperature to 120° C.
  • A compound of Formula [Q-301] may be prepared by Preparation Method 6 described below.
  • A compound of Formula [Q-302] may be prepared by Preparation Method 7-2 described below.
  • A compound of Formula [Q-303] may be prepared by Preparation Method 8-3 described below.
  • A compound which R3 or R5 has a hydroxyl group as a substituent, a compound which R3 has a carboxyl group as a substituent or a compound which R5 has a carboxyl group as a substituent in a compound of Formula [I] may be prepared according to Preparation Method 2-1 Step 3.
    • Preparation Method 4 A Method for Preparing Dihydropyrimidin-2-One Compounds Using Optically Active Sulfinyl Amide (1)
  • A compound of Formula [TV-D] wherein R4 is hydrogen in a compound of Formula [I]:
  • Figure US20190359575A1-20191128-C00098
  • may be prepared under an asymmetric synthesis with optically active sulfinyl amide.
  • Figure US20190359575A1-20191128-C00099
  • In the formula, R3 is for example —Yb—CH2OP3 (in which P3 is a protective group such as tert-butyldiphenylsilyl (TBDPS) and benzyl), C1-6 alkyl optionally substituted with a hydroxyl group protected with one P3, C3-6 cycloalkyl optionally substituted with the same or different one to three substituent(s) selected from Group Xb, 4-tetrahydropyranyl or 1-methanesulfonyl-3-azetidinyl; R5 is for example tert-butyl; and the other symbols have the same meanings as defined above.
    • Step 1
  • A compound of Formula [Q-403] may be prepared by reacting a compound of Formula [Q-401a] and a compound of Formula [Q-402] in the presence of Lewis acid according to a method described in a reference (e.g. a method described in G. K. Datta; J. A. Ellman, J. Org. Chem. 2010, 75, 6283-6285).
  • An illustrative example of a compound of Formula [Q-402] includes the following compound.
  • Figure US20190359575A1-20191128-C00100
  • Lewis acid includes Lewis acid such as tetraalkyl orthotitanate. A preferable Lewis acid is tetraethyl orthotitanate.
  • A solvent includes benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and cyclopentylmethyl ether. A preferable solvent is cyclopentylmethyl ether.
  • A reaction temperature includes from room temperature to 120° C. A preferable reaction temperature is 110° C.
  • A commercially available product may be used for a compound of Formula [Q-401a] or it may be prepared by known methods or Preparation Method 6.
    • Step 2
  • A compound of Formula [Q-405] may be prepared by reacting a compound of Formula [Q-403] and a compound of Formula [Q-404] in the presence of a base according to a method described in a reference (e.g. a method described in T. P. Tang; J. A. Ellman, J. Org. Chem. 2002, 67, 7819-7832).
  • The base includes lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide (LiTMP). A preferable base is lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS).
  • A solvent includes benzene, toluene, xylene, hexane, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and may be used alone or by mixture of two or more of them. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from −78° C. to room temperature. A preferable reaction temperature is from −78° C. to 0° C.
  • To improve diastereoselectivity, an additive such as titanium (IV) chlorotriisopropoxy may be also added.
  • An equivalent amount of the base includes from 1 to 3 equivalent(s). A preferable amount is 2.1 equivalents.
  • A commercially available product may be used for a compound of Formula [Q-404] or it may be prepared by known methods or Preparation Method 6.
    • Step 3
  • A compound of Formula [Q-406] may be prepared by reacting a compound of Formula [Q-405] with a reducing agent.
  • The reducing agent includes diisobutylaluminum hydride, lithium aluminum hydride, and lithium borohydride. A preferable reducing agent is diisobutylaluminum hydride.
  • A solvent includes toluene, dichloromethane, diethyl ether, and tetrahydrofuran. A preferable solvent is toluene.
  • A reaction temperature includes from −78° C. to room temperature. A preferable reaction temperature is from −78° C. to 0° C.
    • Step 4
  • A compound of Formula [Q-407] may be prepared by hydrolyze a compound of Formula [Q-406] under an acidic condition.
  • The acid includes hdyrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid is hdyrochloric acid.
  • A solvent includes tetrahydrofuran, methanol, ethanol, and isopropyl alcohol, and may be used alone or by mixture of two or more of them. A preferable solvent is methanol.
  • A reaction temperature includes from 0° C. to 60° C. A preferable reaction temperature is from 0° C. to room temperature.
    • Step 5
  • A compound of Formula [Q-409] may be prepared from a compound of Formula [Q-407] and a compound of Formula [Q-408].
  • A solvent includes benzene, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from 0° C. to 80° C. A preferable reaction temperature is from 0° C. to room temperature.
    • Step 6
  • A compound of Formula [Q-410] may be prepared by an oxidation reaction of a compound of Formula [Q-409], followed by a cyclization reaction.
  • The oxidizing agent includes 2-azaadamantane-N-oxyl (AZADO), 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO), and Dess-Martin reagent (DMP). Diacetoxyiodobenzene or sodium hydrochlorite, for example, may be optionally added as a co-oxidizing agent. A preferable oxidizing agent in the reaction is a mixture of 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) and diacetoxyiodobenzene.
  • The acid in the cyclization reaction includes hdyrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid is trifluoroacetic acid.
  • A solvent includes tert-butanol, benzene, toluene, dichloromethane, chloroform, ethyl acetate, and acetonitrile. A preferable solvent in the reaction is dichloromethane or chloroform.
  • A reaction temperature includes from 0° C. to 80° C. A preferable reaction temperature is from 0° C. to room temperature.
    • Step 7
  • A compound which R3 or R5 has a hydroxyl group as a substituent, a compound which R3 has a carboxyl group as a substituent or a compound which R5 has a carboxyl group as a substituent in a compound of Formula [IV-D] may be prepared according to Preparation Method 1 Step 8.
  • The following compound of Formula [E-IV-D] may be prepared using an enantiomer (i.e., a compound of Formula [E-Q-402]) of a compound of Formula [Q-402] according to Preparation Method 4.
  • Figure US20190359575A1-20191128-C00101
    • Preparation Method 5 A Method for Preparing Dihydropyrimidin-2-One Compounds Using Optically Active Sulfinyl Amide (2)
  • Alternative method for preparing a compound of Formula [IV-D]A compound of Formula [Q-501] may be prepared from a compound of Formula [Q-401 b] and a compound of Formula [Q-402] according to Preparation Method 4. A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-501] according to the following Preparation Method 5-1 or 5-2.
  • Figure US20190359575A1-20191128-C00102
  • In the formula, each symbol has the same meaning as defined above.
    • Preparation Method 5-1 When Rq1 is for Example a Hydroxyl Group in a Compound of Formula [Q-501]:
  • For example, a compound of Formula [Q-503] which R1 is C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2 in Formula [IV-D] may be prepared by the following method.
  • Figure US20190359575A1-20191128-C00103
  • In the formula, R1 is C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2, and the other symbols have the same meanings as defined above.
  • A compound of Formula [Q-501a] may be prepared from a compound which Rq1 is a benzyl ether group in a compound of Formula [Q-401b] according to Preparation Method 4.
  • A compound of Formula [Q-503] may be prepared from a compound of Formula [Q-501a] according to Preparation Method 2-1.
    • Preparation Method 5-2 When Rq1 is for Example Bromo, Iodo or Trifluoromethanesulfonyloxy Group in a Compound of Formula [Q-501]:
  • A compound which R1 is a substituent such as C4-8 alkyl and C1-4 alkyl substituted with one substituent selected from Group Xa1 in Formula [IV-D] (provided that R1 is not C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2) may be prepared from a compound of the following Formula [Q-501 b] by a cross coupling reaction or an insertion reaction of carbon monoxide.
  • Figure US20190359575A1-20191128-C00104
  • In the formula, each symbol has the same meaning as defined above.
  • Figure US20190359575A1-20191128-C00105
  • In the formula, each symbol has the same meaning as defined above.
  • A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-501b] according to Preparation Method 2-2.
  • In particular, Preparation Method 5-2 (Suzuki coupling) is for example as follows. A compound of Formula [R1-M1] may be synthesized by a common procedure.
  • Figure US20190359575A1-20191128-C00106
  • In the formula, GrubbsCat.2nd means a second-generation Grubbs catalyst, (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)-ruthenium, and the other symbols have the same meanings as defined above.
    • Preparation Method 5-3 When Rq1 is Bromo in a Compound of Formula [Q-501] (i.e., a Compound of Formula [Q-504]):
  • A compound which R1 is C3-6 alkylsulfanyl, C3-6 alkylsulfinyl, C3-6 alkylsulfonyl, C3-6 cycloalkylsulfanyl, C3-6 cycloalkylsulfinyl or C3-6 cycloalkylsulfonyl in Formula [IV-D] may be prepared by the following method.
  • Figure US20190359575A1-20191128-C00107
  • In the formula,
    R1s is C3-6 alkyl or C3-s cycloalkyl,
    R1 is C3-6 alkylsulfanyl or C3-6 cycloalkylsulfanyl,
    R5q is —Yc—COORq50 wherein Yc is C1-6 alkylene optionally substituted with one hydroxy and
    Rq50 is hydrogen or C1-4 alkyl,
    R5 is —Yc—COOH,
    R6 is methyl, and the other symbols have the same meanings as defined above.
  • A compound of Formula [Q-504] may be prepared from a compound of Formula [Q-401c] using Preparation Method 5.
    • Step 1
  • A compound of Formula [Q-506] may be prepared by a coupling reaction of a compound of Formula [Q-504] and a compound of Formula [Q-505] according to a method described in a literature such as a method described in Org. Lett. 2004, 6, 4587-4590, for example.
    • Step 2
  • A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-506] according to Preparation Method 1 Step 8.
  • For example, an illustrative example of Preparation Method 5-3 includes the following reactions:
  • Figure US20190359575A1-20191128-C00108
    • Preparation Method 5-3-A
  • Figure US20190359575A1-20191128-C00109
  • In the formula,
    R1s is C3-6 alkyl or C3-6 cycloalkyl,
    R1 is C3-6 alkylsulfinyl or C3-6 cycloalkylsulfinyl,
    R5q is —Yc—COORq50 wherein Yc is C1-6 alkylene optionally substituted with one hydroxy and
    Rq50 is hydrogen or C1-4 alkyl,
    R5 is —Yc—COOH,
    R6 is methyl, and the other symbols have the same meanings as defined above.
    • Step 1
  • A compound of Formula [Q-507] may be prepared by an oxidation reaction of sulfide of a compound of Formula [Q-506].
  • An oxidizing agent includes hydrogen peroxide, peracetic acid, hydroperoxide, permanganate, meta-chloroperbenzoic acid, and sodium hypochlorite. A preferable oxidizing agent is meta-chloroperbenzoic acid.
  • A solvent includes benzene, dichloromethane, acetonitrile, and water, and may be used alone or by mixture of two or more of them. A preferable solvent is dichloromethane.
  • A reaction temperature includes from −78° C. to room temperature. A preferable reaction temperature is −78° C.
    • Step 2
  • A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-507] according to Preparation Method 1 Step 8.
    • Preparation Method 5-3-B
  • Figure US20190359575A1-20191128-C00110
  • In the formula,
    R1s is C3-6 alkyl or C3-6 cycloalkyl,
    R1 is C3-6 alkylsulfonyl or C3-6 cycloalkylsulfonyl,
    R5q is —Yc—COORq50 wherein Yc is C1-6 alkylene optionally substituted with one hydroxy and
    Rq50 is hydrogen or C1-4 alkyl,
    R5 is —Yc—COOH,
    R6 is methyl, and the other symbols have the same meanings as defined above.
    • Step 1
  • A compound of Formula [Q-508] may be prepared by an oxidation reaction of sulfide of a compound of Formula [Q-506].
  • An oxidizing agent includes oxone, meta-chloroperbenzoic acid, and potassium permanganate. A preferable oxidizing agent is meta-chloroperbenzoic acid.
  • A solvent includes benzene, dichloromethane, acetonitrile, and water, and may be used alone or by mixture of two or more of them. A preferable solvent is dichloromethane.
  • A reaction temperature includes from −78° C. to room temperature. A preferable reaction temperature is room temperature.
    • Step 2
  • A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-508] according to Preparation Method 1 Step 8.
    • Preparation Method 5-4
  • Preparation Method of Dihydropyrimidin-2-One Compounds Using Optically Active Sulfinylamide (4) (i.e., an Alternative Method for Preparing a Compound of Formula [IV-D] Using p-Nitrophenyl Chloroformate)
  • A compound of Formula [Q-520] may be prepared from a compound of Formula [Q-401a] according to Preparation Method 4. A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-520] using cross-coupling reaction.
  • Figure US20190359575A1-20191128-C00111
    Figure US20190359575A1-20191128-C00112
    Figure US20190359575A1-20191128-C00113
  • In the formula, R3q3 is —Yb—COORq30 wherein Yb is phenyl and Rq30 is hydrogen or C1-4 alkyl, R6 is methyl, and the other symbols have the same meanings as defined above.
    • Step 1
  • The reaction is carried out in a similar way to Preparation Method 4 Step 1.
    • Step 2
  • A compound of Formula [Q-511] may be prepared by reacting a compound of Formula [Q-403] with a compound of Formula [Q-510] under a basic condition.
  • A base includes lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide (LiTMP). A preferable base is lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS).
  • A solvent includes benzene, toluene, xylene, hexane, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and may be used alone or by mixture of two or more of them. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from −78° C. to room temperature. A preferable reaction temperature is from −78° C. to 0° C.
  • To improve a diastereoselectivity, an additive such as chlorotriisopropoxy titanium (IV) may be further added.
  • An equivalent amount of a base includes from 1 to 3 equivalent amount(s). A preferable equivalent amount is 2.1 equivalent amounts.
  • As a compound of Formula [Q-510], a commercially available product such as 3-hydroxy-propionic acid methyl ester, 3-hydroxy-propionic acid ethyl ester, and 3-hydroxy-propionic acid t-butyl ester may be used.
    • Step 3
  • A compound of Formula [Q-512] may be prepared by hydrolyzing a compound of Formula [Q-511] under an acidic condition.
  • An acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid is hydrochloric acid.
  • A solvent includes tetrahydrofuran, methanol, ethanol, and isopropyl alcohol, and may be used alone or by mixture of two or more of them. A preferable solvent is methanol.
  • A reaction temperature includes from 0° C. to 60° C. A preferable reaction temperature is from 0° C. to room temperature.
    • Step 4
  • A compound of Formula [Q-513] may be prepared by protecting a compound of Formula [Q-512] with tert-butyldiphenylsilyl (TBDPS) according to a method described in a literature (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 141-144).
    • Step 5
  • A compound of Formula [Q-514] may be prepared by reacting a compound of Formula [Q-513] with p-nitrophenyl chloroformate under a basic condition.
  • A base includes triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, and potassium carbonate. A preferable base is triethylamine.
  • A solvent includes chloroform, dichloromethane, toluene, tetrahydrofuran, and acetonitrile. A preferable solvent is chloroform.
  • A reaction temperature includes from 0° C. to 85° C. A preferable reaction temperature is 0° C.
    • Step 6
  • A compound of Formula [Q-516] may be prepared by reacting a compound of Formula [Q-514] with a compound of Formula [Q-515] under a basic condition.
  • A base includes triethylamine and diisopropylethylamine. A preferable base is triethylamine.
  • A solvent includes chloroform, dichloromethane, and tetrahydrofuran. A preferable solvent is chloroform.
  • A reaction temperature includes from room temperature to 60° C. A preferable reaction temperature is 60° C.
    • Step 7
  • A compound of Formula [Q-517] may be prepared by deprotecting tert-butyldiphenylsilyl (TBDPS) of a compound of Formula [Q-516] according to a method described in a literature (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 142-143).
    • Step 8
  • A compound of Formula [Q-518] may be prepared from a compound of Formula [Q-517] according to Preparation Method 4 Step 6.
    • Step 9
  • A compound of Formula [Q-519] may be prepared by deprotecting tert-butyl ester from a compound of Formula [Q-518] wherein P1 is for example tert-butyl according to a method described in a literature (e.g. a method described in Peter G. M. Wuts. Protective Groups in Organic Synthesis Third Edition, Wiley-Interscience, 406-407).
    • Step 10
  • A compound of Formula [Q-520] may be prepared by brominating a compound of Formula [Q-519] according to a method described in a literature (e.g. a method described in A. J. Zych; H. Wang; S. A. Sakwa, Tetrahedron Lett. 2010, 51, 5103-5105).
    • Step 11
  • A compound of Formula [Q-522] may be prepared from a compound of Formula [Q-520] and a compound of Formula [Q-521] according to Preparation Method 2-2 (including cross-coupling).
    • Step 12
  • A compound of Formula [IV-D] may be prepared for example by hydrolyzing a compound of Formula [Q-522].
  • In Preparation Method 5-4, Step 11 (coupling reaction) and Step 12 (hydrolysis reaction) are illustrated as follows.
  • Figure US20190359575A1-20191128-C00114
  • In the formula, R6 is methyl, and the other symbols have the same meanings as defined above.
    • Preparation Method 5-5 Preparation Method of Dihydropyrimidin-2-One Compounds Using Optically Active Sulfinylamide (5) (i.e., an Alternative Method for Preparing a Compound of Formula [IV-D])
  • A compound of Formula [Q-536] may be prepared from a compound of Formula [Q-401a] using Preparation Methods 4 and 5-4. A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-536] by a cyclization reaction under a basic condition, a reduction reaction using Schwartz's reagent, an oxidation reaction using Dess-Martin reagent into an aldehyde compound, followed by Pinnic Oxidation into a carboxylic acid compound.
  • Figure US20190359575A1-20191128-C00115
    Figure US20190359575A1-20191128-C00116
  • In the formula, Yb is C3-6cycloalkylene, R3 is —Yb—COOH, R6 is methyl; and the other symbols have the same meanings as defined above.
  • Protective groups in the formula may be optionally changed. For example, TBDMS (tert-butyldimethylsilyl) may be replaced with TBDPS (tert-butyldiphenylsilyl), and MOM (methoxymethyl) may be replaced with methyl.
    • Step 1
  • A compound of Formula [Q-403] may be prepared from a compound of Formula [Q-401a] according to Preparation Method 4 Step 1.
    • Step 2
  • A compound of Formula [Q-531] may be prepared from a compound of Formula [Q-403] and a compound of Formula [Q-530] according to Preparation Method 4 Step 2. A compound of Formula [Q-530] may be commercially available or synthesized by a method described in a literature (e.g. a method described in WO 2009/019174).
    • Step 3
  • A compound of Formula [Q-403] may be prepared from a compound of Formula [Q-401a] according to Preparation Method 4 Step 4.
    • Step 4
  • A compound of Formula [Q-533] may be prepared by protecting a compound of Formula [Q-532] with tert-butyldimethylsilyl (TBDMS) according to a method described in a literature (e.g. a method described in Peter G. M. Wuts. Protective Groups in Organic Synthesis Third Edition, Wiley-Interscience, 127-131).
    • Step 5
  • A compound of Formula [Q-534] may be prepared from a compound of Formula [Q-533] according to Preparation Method 5 Step 5.
    • Step 6
  • A compound of Formula [Q-536] may be prepared from a compound of Formula [Q-534] and a compound of Formula [Q-535] according to Preparation Method 5 Step 6.
    • Step 7
  • A compound of Formula [Q-537] may be prepared by cyclizing a compound of Formula [Q-536] according to a method described in a literature (e.g. a method described in R. Patino-Molina; I. Cubero-Lajo; M. J. P. Vega; M. T. Garcia-Lopez, Tetrahedron Lett. 2007, 48, 3615-3616).
    • Step 8
  • A compound of Formula [Q-538] may be prepared by reducing a compound of Formula [Q-537] with Schwartz's reagent according to a method described in for example S. R. Dandepally; R. Elgoummadi; A. L. Williams, Tetrahedron Lett. 2013, 54, 925-928.
    • Step 9
  • A compound of Formula [Q-539] may be prepared by oxidizing a compound of Formula [Q-538] with Dess-Martin reagent (e.g. a method described in E. Vedejs; D. W. Piotrowski; F. C. Tucci, J. Org. Chem. 2000, 65, 5498-5505).
    • Step 10
  • A compound of Formula [IV-D] may be prepared from a compound of Formula [Q-539] by Pinnick oxidation (e.g. a method described in G. A. Kraus; B. Roth, J. Org. Chem. 1980, 45, 4825-4830).
  • Preparation Method 5-5 is illustrated in the following reactions when chemical name: (3-methoxymethoxymethyl-cyclobutyl)-acetic acid methyl ester is used as a compound of Formula [Q-530] and chemical name: 3,3-difluoro-cyclobutylamine is used as a compound of Formula [Q-535]
  • Figure US20190359575A1-20191128-C00117
  • In the formula, R6 is methyl, and the other symbols have the same meanings as defined above.
    • Preparation Method 6 Methods for Preparing Starting Materials of Preparation Methods 1 to 5 Preparation Method 6-1
  • A compound of Formula [Q-101b], Formula [Q-301a] or [Q-401b] which is a starting material of Preparation Method 2 or 5 is represented by the following general formula:
  • Figure US20190359575A1-20191128-C00118
  • wherein U1 is formyl, acetyl or ethylcarbonyl (which means each embodiment of —(C═O)—H, —(C═O)—R6 or —(C═O)—CH2—R6 wherein R6 is hydrogen or methyl, respectively), and the other symbols have the same meanings as defined above. A commercially available product (e.g. 4-bromo-3-chloro-benzaldehyde, 1-(4-bromo-3-chloro-phenyl)-ethanone, 1-(4-bromo-3-chloro-phenyl)-propan-1-one) may be used for the compound or it may be prepared by known methods.
  • For example, it may be prepared by the following method.
  • Figure US20190359575A1-20191128-C00119
  • In the formula, each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [Q-602] may be prepared by a condensation reaction of a compound of Formula [Q-601] with N,O-dimethylhydroxylamine or N,O-dimethylhydroxylamine hydrochloride.
  • The condensation agent includes aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), and carbonyldiimidazole (CDI). For example, 1-hydroxy-1H-benzotriazole monohydrate (HOBt.H2O) or 4-dimethylaminopyridine (DMAP) may be optionally added. A preferable condensation agent in the step is a mixture of aqueous carbodiimide (WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 1-hydroxy-1H-benzotriazole monohydrate (HOBt.H2O).
  • A solvent includes toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, and may be used alone or by mixture of two or more of them. A preferable solvent in the reaction is N,N-dimethylformamide or acetonitrile.
    • Step 2
  • A compound of Formula [Q-101b] or Formula [Q-401b] may be prepared by reacting a compound of Formula [Q-602] with Grignard reagent such as MeMgX and EtMgX (wherein X is chloro or bromo).
  • A solvent includes an ether solvent such as diethyl ether, tetrahydrofuran (THF), and 1,2-dimethoxyethane (DME). A preferable solvent is THF.
  • A compound of Formula [Q-301a] may be prepared by reacting a compound of Formula [Q-602] with a reducing agent such as diisobutylaluminum hydride (DIBAL-H).
  • For example, a compound which U1 is formyl or ketone may be also prepared from a commercially available compound such as 2,2-dimethyl-indane-5-carboxylic acid in place of a compound of Formula [Q-601] by the above Steps 1 and 2.
  • Figure US20190359575A1-20191128-C00120
  • In the formula, U1 is formyl, acetyl or ethylcarbonyl and each symbol has the same meaning as defined above.
    • Preparation Method 6-2 Preparation Method 6-2A Synthesis of the Starting Material in Preparation Method 1, 3 or 4
  • A compound of Formula [Q-101a], a starting material of Preparation Method 1, a compound of Formula [Q-301], a starting material of Preparation Method 3, and a compound of Formula [Q-401a], a starting material of Preparation Method 4, are represented by the following general formula:
  • Figure US20190359575A1-20191128-C00121
  • wherein each symbol has the same meaning as defined above.
  • The above compound may be for example prepared according to the following method.
  • Figure US20190359575A1-20191128-C00122
  • In the formula, each symbol has the same meaning as defined above.
    • Step 1 to Step 2
  • For example, a compound of Formula [Q-101a], Formula [Q-301] or Formula [Q-401a] wherein R1 is C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2 may be prepared from a compound of Formula [Q-101b1] or Formula [Q-401b1] via a compound of Formula [Q-603].
  • Each Step may be carried out according to Preparation Method 2-1 Step 1 (a deprotection reaction of benzyl group) and Step 2 (a reaction with a compound of Formula [Q-203]).
    • Step 3
  • For example, a compound of Formula [Q-101a], Formula [Q-301] or Formula [Q-401a] wherein R1 is C4-8 alkyl or C1-4 alkyl substituted with one substituent selected from Group Xa1 but R1 is not C3-6 alkoxy, C2-7 alkoxy substituted with one trifluoromethyl or C1-3 alkoxy substituted with one substituent selected from Group Xa2 may be prepared from a compound of Formula [Q-101b2] or Formula [Q-401b2].
  • In the step, a cross-coupling reaction using palladium (including Suzuki reaction) may be carried out according to Preparation Method 2-2.
    • Preparation Method 6-2B
  • Figure US20190359575A1-20191128-C00123
  • In the formula, U1 is acetyl or ethylcarbonyl, and each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [Q-102b] may be prepared from 2-(3-chloro-4-trifluoromethanesulfonyloxy-phenyl)-propionic-acid-methyl-ester prepared from known 2-(3-chloro-4-hydroxy-phenyl)-propionic-acid-methyl-ester or a compound of the following Formula [Q-101b2] according to Preparation Method 1 Step 1.
    • Step 2
  • A compound of Formula [Q-102] may be prepared from a compound of Formula [Q-102b] according to Preparation Method 2-2.
    • Preparation Method 6-3
  • A compound of Formula [Q-101a], [Q-301] or [Q-401a] which is a starting material of Preparation Method 1, 3 or 4:
  • Figure US20190359575A1-20191128-C00124
  • wherein each symbol has the same meaning as defined above
    may be prepared by the following method, for example.
  • Figure US20190359575A1-20191128-C00125
  • In the formula, R11 is for example C2-4 alkyl, and the other symbols have the same meanings as defined above.
    • Step 1
  • As a compound of Formula [Q-604], a commercially available compound such as (4-bromo-3-chloro-phenyl)-methanol, (4-bromo-3,5-dimethyl-phenyl)-methanol, and (4-bromo-2-methoxy-phenyl)-methanol may be used. A compound of Formula [Q-605] may be prepared by reacting a compound of Formula [Q-604] with a commercially available compound such as R11—Br in the presence of a base such as sodium hydride.
  • A solvent includes N,N-dimethylformamide.
  • A compound of Formula [Q-605] wherein R11 is tert-butyl may be prepared by reacting a compound of Formula [Q-604] with di-tert-butyl dicarbonate in the presence of magnesium perchlorate (e.g. a method described in Org. Lett., 2005, 7, 427-430).
    • Step 2
  • A compound of Formula [Q-606] may be prepared from a compound of Formula [Q-605] according to an insertion reaction of carbon monoxide in Preparation Method 2-2.
  • A solvent includes a mixed solvent of toluene and water.
  • The corresponding formyl, acetyl or ethylcarbonyl compound of Formula [Q-101a], [Q-301] or [Q-401a] may be prepared from a compound of Formula [Q-606] according to Preparation Method 6-1.
    • Preparation Method 6-4
  • A compound of Formula [Q-101a], [Q-301] or [Q-401a] which is a starting material of Preparation Method 1, 3 or 4:
  • Figure US20190359575A1-20191128-C00126
  • wherein each symbol has the same meaning as defined above
    may be also prepared by a formation reaction of carbon-carbon bond of a compound of the following Formula [Q-607] and the compound having ketone or formyl.
  • As a compound of Formula [Q-607], a commercially available product such as 4-bromo-2-chloro-1-iodobenzene, 5-bromo-1,3-difluoro-2-iodobenzene, 4-bromo-2-ethyliodobenzene, and 5-bromo-2-iodo-m-xylene may be used. Alternatively, 2-benzyloxy-4-bromo-1-iodo-benzene which a commercially available 5-bromo-2-iodophenol is benzylated by a known method is also illustrated.
  • The compound having ketone or formyl includes the compound having ketone such as spiro-C6-11 cycloalkanone and C4-6 cycloalkanone or the compound having formyl such as C4-8 alkylaldehyde.
  • For example, when spiro-C6-11 cycloalkanone as the compound having ketone or formyl is spiro[3.3]heptan-2-one, a compound of Formula [Q-607] may be reacted as follows to prepare a compound of the following Formula [Q-612].
  • Figure US20190359575A1-20191128-C00127
  • In the formula, each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [Q-609] may be prepared by a halogen-metal exchange reaction of a compound of Formula [Q-607] with isopropylmagnesium chloride and the like, followed by an addition reaction with a compound of Formula [Q-608].
  • A solvent includes THF and DME. A reaction temperature includes from −45° C. to room temperature.
    • Step 2
  • A compound of Formula [Q-610] may be prepared by a mesylation reaction of a compound of Formula [Q-609] in the presence of a base.
  • A mesylating agent includes methanesulfonyl chloride.
  • A base includes triethylamine and diisopropylethylamine. A preferable base is triethylamine. A catalytic amount of trimethylamine hydrochloride and the like may be added if needed.
  • A solvent includes benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, and acetone. A preferable solvent is toluene.
  • A reaction temperature includes from 0° C. to 60° C. A preferable reaction temperature is from 0° C. to room temperature.
    • Step 3
  • A compound of Formula [Q-611] may be prepared by a catalytic hydrogenation of a compound of Formula [Q-610] in the presence of a catalyst.
  • A catalyst includes palladium carbon, platinum carbon, rhodium carbon, and rhodium-alumina. A preferable catalyst is rhodium carbon.
  • A solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, 1,2-dimethoxyethane, and ethyl acetate, and may be used alone or by mixture of two or more of them. A preferable solvent is a mixed solvent of methanol and tetrahydrofuran.
  • A compound of Formula [Q-611] may be also prepared by reducing a compound of Formula [Q-609] in the presence of Lewis acid.
  • Lewis acid includes boron trifluoride diethyl ether.
  • A reducing agent includes triethylsilane.
  • A solvent includes dichloromethane and tetrahydrofuran. A preferable solvent is dichloromethane.
  • A reaction temperature includes from −78° C. to room temperature. A preferable reaction temperature is from −78° C. to room temperature.
    • Step 4
  • A compound of Formula [Q-612] may be prepared from a compound of Formula [Q-611] according to an insertion reaction of carbon monoxide in Preparation Method 6-3.
  • The corresponding formyl, acetyl or ethylcarbonyl compound of Formula [Q-101a], [Q-301] or [Q-401a] may be prepared from a compound of Formula [Q-612] according to Preparation Method 6-1.
  • The following compound may be prepared with a ketone compound of “C3-6 cycloalkyl substituted with the same or different one to two C1-5 alkyl”, e.g. 3-isopropyl-cyclobutanone, as described above.
  • Figure US20190359575A1-20191128-C00128
    • Preparation Method 6-5
  • A compound of Formula [Q-102], an intermediate of Preparation Method 1, e.g. a compound of Formula [Q-617] wherein R2 is chloro and R6 is methyl and the like, may be prepared by the following method.
  • Figure US20190359575A1-20191128-C00129
    • Step 1
  • A compound of Formula [Q-614] may be prepared by esterifying a compound of Formula [Q-613]. For example, when thionyl chloride and methanol are used, methyl ester may be obtained. As a compound of Formula [Q-613], a commercially available product such as 2-(4-hydroxy-phenyl)-propionic acid may be used.
    • Step 2
  • A compound of Formula [Q-615] may be prepared by chlorination of a compound of Formula [Q-614] with N-chlorosuccinimide (NCS) and the like.
  • A solvent includes acetonitrile and N,N-dimethylformamide. A preferable solvent is N,N-dimethylformamide.
    • Step 3
  • A compound of Formula [Q-616] may be prepared by reacting a compound of Formula [Q-615] with trifluoromethanesulfonic anhydride in the presence of a base.
  • A base includes triethylamine and pyridine. A preferable base is pyridine.
  • A solvent includes toluene, dichloromethane, chloroform, and tetrahydrofuran. A preferable solvent is dichloromethane.
  • A reaction temperature includes from 0° C. to room temperature. A preferable reaction temperature is 0° C.
    • Step 4
  • A compound of Formula [Q-617] may be prepared from a compound of Formula [Q-616] by a cross-coupling reaction (e.g. Suzuki reaction and Sonogashira reaction) as described in Preparation Method 2-2.
  • When Sonogashira reaction is carried out, the resulted alkynylene compound may be converted into an alkylene compound by a catalytic hydrogenation with a catalyst such as palladium carbon, platinum carbon, and rhodium-alumina.
  • Steps after Step 4
  • A compound of Formula [I] wherein R2 is chloro and R6 is methyl and the like (i.e., a compound of Formula [I-Ca]) may be prepared with a compound of Formula [Q-617] by the reactions described in Preparation Method 1.
    • Preparation Method 7 A Method for Preparing Starting Materials (1) Preparation Method 7-1
  • As a compound of Formula [Q-104]:
  • Figure US20190359575A1-20191128-C00130
  • wherein each symbol has the same meaning as defined above,
    a commercially available compound such as 4-methyl-2-pentan-1-ol, 4-methyl-2-hexen-1-ol, 4,4-dimethyl-2-penten-1-ol, and 2,4-dimethyl-2-penten-1-ol may be used, which may be alternatively prepared by the following method.
  • Figure US20190359575A1-20191128-C00131
  • In the formula, each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [Q-702] may be prepared from a compound of Formula [Q-701] and alkylphosphonic diester such as triethyl phosphonoacetate under Homer-Wadsworth-Emmons Reaction.
    • Step 2
  • A compound of Formula [Q-104] may be prepared from a compound of Formula [Q-702] by DIBAL reduction according to Preparation Method 6-1 Step 2.
  • As a compound of Formula [Q-701], a commercially available aldehyde such as 2-methylpropylaldehyde, isovaleraldehyde, 3,3-dimethylbutylaldehyde, and 4-methylpentylaldehyde may be used, which may be alternatively prepared by a known method.
    • A Method for Preparing a Compound of Formula [Q-701] (1)
  • For example, a compound of Formula [Q-701a] may be prepared from a compound of Formula [Q-703].
  • Figure US20190359575A1-20191128-C00132
  • In the formula, each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [Q-704] may be prepared by protecting a hydroxyl group of a compound of Formula [Q-703] (e.g. a commerically available compound such as 2,2-dimethyl-3-hydroxypropanoic acid methyl ester, 4-hydroxy-2,2-dimethyl-butanoic acid methyl ester, and 5-hydroxy-2,2-dimethyl-pentanoic acid methyl ester) with trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS) and the like according to a method described in a literature (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 165-215).
    • Step 2
  • A compound of Formula [Q-705] may be prepared from a compound of Formula [Q-704] under DIBAL reduction according to Preparation Method 6-1 Step 2.
    • Step 3
  • A compound of Formula [Q-701a] may be for example prepared by Parikh-Doering oxidation reaction of a compound of Formula [Q-705] with SO3.Py.
    • A Method for Preparing a Compound of Formula [Q-701] (2)
  • Figure US20190359575A1-20191128-C00133
  • A compound of Formula [Q-701b] may be also prepared from C3-6 cycloalkanone optionally substituted with the same or different one to three substituent(s) selected from Group Xb and Wittig reagent according to a method described in a literature (e.g. a method described in Bioorg. Med. Chem. Lett. 2004, 14(20), 5199-5203). For example, when R3q1 is cyclohexyl, the following is illustrated.
  • Figure US20190359575A1-20191128-C00134
    • Preparation Method 7-2
  • As a compound of Formula [Q-302]:
  • Figure US20190359575A1-20191128-C00135
  • wherein each symbol has the same meaning as defined above,
    a commerically available aldehyde or ketone such as 3,3-dimethyl-butylaldehyde, 4-methyl-pentanal, cyclohexyl-acetaldehyde, and 2-butanone may be used, which may be alternatively prepared by a known method. For example, a compound of Formula [Q-302] wherein R4 is H (i.e., an aldehyde compound) may be prepared from a compound of Formula [Q-701] under a carburation reaction according to a method described in a literature (e.g. a method described in Bioorg. Med. Chem. Lett. 2004, 14 (20), 5199-5203). For example, a compound of Formula [Q-302] wherein R4 is methyl (i.e., a ketone compound) may be prepared from a compound of Formula [Q-701] under a carburation reaction according to a method described in a literature (e.g. a method described in Tetrahedron Lett. 2009, 50, 1276-1278).
    • Preparation Method 7-3
  • As a compound of Formula [Q-404]:
  • Figure US20190359575A1-20191128-C00136
  • wherein each symbol has the same meaning as defined above,
    a commerically available ester such as 3-methyl-butanoic acid methyl ester, 4-methylvaleric acid methyl ester (i.e., 4-Methyl-pentanoic acid methyl ester), and 5-methylhexanoic acid methyl ester may be used, which may be alternatively prepared by a known method.
  • A methyl ester of a compound of Formula [Q-404] may be replaced with an ethyl ester.
  • Figure US20190359575A1-20191128-C00137
  • The ester compound may be, for example, prepared from a compound where a hydroxyl group of C3-6 cycloalkanone optionally substituted with the same or different one to three substituent(s) selected from Group Xb or a commerically available product such as 1-hydroxypropan-2-one, 1-hydroxybutan-2-one, and 1-hydroxypentan-2-one is protected with TBDPS, benzyl and the like under Horner-Wadsworth-Emmons Reaction and the like using alkylphosphonic diester.
  • For example, a compound of Formula [Q-404a] may be synthesized by the following preparation method.
  • Figure US20190359575A1-20191128-C00138
  • In the formula, each symbol has the same meaning as defined above.
    • Step 1
  • A compound of Formula [Q-707] may be prepared from a compound of Formula [Q-706] by a protecting reaction of alcohol according to Preparation Method 7-1.
    • Step 2
  • A compound of Formula [Q-708] may be prepared from a compound of Formula [Q-707] under Horner-Wadsworth-Emmons Reaction according to Preparation Method 7-1 Step 1.
    • Step 3
  • A compound of Formula [Q-404a] may be prepared from a compound of Formula [Q-708] by 1,4-addition reaction with methyllithium in the presence of a copper catalyst (e.g. a method described in J. Am. Chem. Soc. 2009, 131(44), 16016-16017).
    • Preparation Method 8 A Method for Preparing Starting Materials (2) Preparation Method 8-1
  • As a compound of Formula [Q-408]:
  • Figure US20190359575A1-20191128-C00139
  • wherein each symbol has the same meaning as defined above,
    a commercially available product such as 6-isocyanate-hexanoic acid ethyl ester, 2-isocyanate-2-methyl-propionic acid methyl ester, 3-isocyanate-propionic acid methyl ester, 4-isocyanate-cyclohexanecarboxylic acid methyl ester, and 4-isocyanatebenzoic acid ethyl ester may be used, which may be alternatively prepared by a known method.
  • For example, a compound of Formula [Q-408] may be prepared by the following method.
  • Figure US20190359575A1-20191128-C00140
  • In the formula, each symbol has the same meaning as defined above.
  • A compound of Formula [Q-408] may be prepared from a compound of Formula [Q-801] (e.g. a commerically available product such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 1-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylic acid, and 3-[1-(ethoxycarbonyl)cyclopropyl]propanoic acid) by an azidation reaction, followed by Curtius rearrangement reaction according to Preparation Method 1 Step 5.
    • Preparation Method 8-2
  • As a compound of Formula [Q-108]:
  • Figure US20190359575A1-20191128-C00141
  • wherein each symbol has the same meaning as defined above,
    a commercially available product such as methyl 3-aminopropanoate, methyl 3-aminocyclopentanecarboxylate, tert-butyl 2-(2-aminoethoxy)acetate, ethyl 4-aminobenzoate, and methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride may be used, which may be alternatively prepared by a known method.
  • For example, a compound of Formula [Q-108] may be prepared by reacting a compound of Formula [Q-408] with benzyl alcohol or t-BuOH to protect an amino group with tert-butoxycarbonyl group (Boc group) or benzyloxycarbonyl group (Cbz group), followed by deprotection of the Boc group or Cbz group according to a known method (e.g. a method described in Peter G. M. Wuts (2007). Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 725-735, 748-756).
  • Figure US20190359575A1-20191128-C00142
  • In the formula, each symbol has the same meaning as defined above.
    • Preparation Method 8-3
  • As a compound of Formula [Q-303]:
  • Figure US20190359575A1-20191128-C00143
  • wherein each symbol has the same meaning as defined above,
    a commerically available urea compound such as ureido-acetic acid ethyl ester, 2,2-dimethyl-3-ureido-propionic acid ethyl ester, 3-ureido-cyclohexanecarboxylic acid ethyl ester, and 4-ureido-benzoic acid ethyl ester may be used, which may be alternatively prepared by a known method.
  • For example, a compound of Formula [Q-303] may be prapred by the following method.
  • Figure US20190359575A1-20191128-C00144
  • In the formula, each symbol has the same meaning as defined above.
  • A compound of Formula [Q-303] may be prepared from a compound of Formula [Q-108] and trimethylsilyl isocyanate.
  • A base includes triethylamine, diisopropylethylamine, and dimethylaminopyridine (DMAP), and may be used alone or by mixture of two or more of them. A preferable base is a mixture of triethylamine and dimethylaminopyridine.
  • A solvent includes benzene, toluene, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, and acetonitrile. A preferable solvent is tetrahydrofuran.
  • A reaction temperature includes from under ice cooling to 120° C. A preferable reaction temperature is 80° C.
    • Preparation Method 9
  • A racemate of Formula [I] obtained in Preparation Method 1, 2 or 3 or a racemate of Formula [Q-110] or Formula [Q-201], an intermediate, of a compound of Formula [I], may be separated into a desirable enantiomer by liquid chromatography using a chiral stationary phase.
  • Figure US20190359575A1-20191128-C00145
  • For example, a racemate [Q-901] which “R6 is methyl” and “R5 is —Yc—COO—C2H5” in the following formula may be separated and isolated into a compound of Formula [Q-902] and a compound of Formula [Q-E-902] by liquid chromatography using a chiral stationary phase, followed by hydrolysis of each isolated enantiomer to give a desirable compound.
  • Figure US20190359575A1-20191128-C00146
  • A separation condition is for example any of the followings. A mobile phase may be optionally adjusted depending on polarities of compounds and a mixing ratio of each solvent may be modified.
    • Separation Condition A:
  • Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.
    Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm
    Mobile phase; hexane:2-propanol=90:10
    Flow rate; 10.0 mL/min
    • Detection; UV (254 nm)
  • Separation condition B:
    Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.
    Column; Japan Analytical Industry Co., Ltd. JAIGEL-ODS-AP, SP-120-10, 2.0 cmφ×25 cm
    Mobile phase; acetonitrile:H2O:formic acid=90:10:0.1
    Flow rate; 10.0 mL/min
    • Detection; UV (220 nm)
  • The following abbreviations may be for example used herein:
  • DMF: dimethylformamide
    TBAF: tetrabutylammonium fluoride
    • NMP: N-methylpyrrolidone
  • Grubbs Cat. 2nd: (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium
    PdCl2(dppf): dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium
    • EXAMPLES
  • In particular, a method for preparing a compound of Formula [I] or a pharmaceutically acceptable salt thereof is illustrated by Examples. A method for preparation of a compound of Formula [I] or a pharmaceutically acceptable salt thereof is however not limited to the method for preparation.
  • For example, to “purify through silica gel column chromatography (ethyl acetate:hexane=1:50->1:5)” means a procedure for elution with a mixed solution with a mixed ratio of 1:50 (ethyl acetate:hexane), followed by elution with a mixed solution with a mixed ratio of 1:5 (ethyl acetate:hexane) in a purification through silica gel column chromatography. “d.r.” means a diastereomer ratio. A melting point is determined by a melting point determination apparatus (Yanaco MP-500D, manufactured by Yanagimoto Seisakujo).
    • Example 5 Preparation of 4-{5-tert-butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoic Acid (Optically Active Compound) Step 1 3-chloro-4-(2,2-dimethylpropoxy)-benzaldehyde
  • Figure US20190359575A1-20191128-C00147
  • 3-Chloro-4-hydroxybenzaldehyde (5 g) and 1-iodo-2,2-dimethylpropane (8.5 mL) were mixed in N,N-dimethylformamide (25 mL). To the reaction solution was added cesium carbonate (4.43 g), and the reaction solution was stirred at 100° C. overnight. To the reaction solution was added water, and then the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (4.82 g).
    • Step 2 4-Carbamoylaminobutanoic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00148
  • 4-Aminobutyric acid ethyl hydrochloride (3.00 g), triethylamine (2.49 mL), and 4-dimethylaminopyridine (218 mg) were mixed in tetrahydrofuran (40 mL). To the reaction solution was added trimethylsilyl isocyanate (2.37 mL), and the reaction solution was stirred at 80° C. for 3.5 hours. To the reaction solution was added ethyl acetate under ice cooling. After removing an insoluble on a filter, the filtrate was concentrated under reduced pressure. The solid precipitated by adding diisopropylether to the resulted residue was filtered to give the titled compound (2.48 g).
    • Step 3 4-{5-tert-Butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoic Acid Ethyl Ester (Optically Active Compound)
  • Figure US20190359575A1-20191128-C00149
  • 3-Chloro-4-(2,2-dimelhylpropoxy)-benzaldehyde (510 mg) and 4-carbamoylaminobutanoic acid ethyl ester (261 mg) were mixed in acetonitrile (1.6 mL) and N,N-dimethylformamide (0.8 mL). To the reaction solution was added trimethylchlorosilane (0.19 mL), and the reaction solution was stirred for 30 minutes. To the reaction solution was added 3,3-dimethylbutylaldehyde (0.19 mL), and the reaction solution was stirred at 80° C. for 2.5 hours. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was sequentially washed with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel chromatography (ethyl acetate:chloroform=1:2), followed by thin layer silica gel chromatography (ethyl acetate:chloroform=1:2), to give a racemate of the titled compound (147.4 mg). The racemate was separated and purified by recycling preparative chromatograph.
  • The titled compound (64.5 mg) was obtained as a compound in a fraction eluted earlier in recycling preparative chromatograph (separation condition A1). The compound was analyzed by analytical column DAICEL CHIRALPAK IA-3 (analytical condition B1) to determine 6.6 min as the retention time and >99% ee as the optical purity.
  • An enantiomer of the titled compound (i.e., an ethyl ester of Example 6) was obtained as a compound in a fraction eluted later in recycling preparative chromatograph (separation condition A1). The compound was analyzed by analytical column DAICEL CHIRALPAK IA-3 (analytical condition B1) to determine 9.5 min as the retention time and >99% ee as the optical purity.
  • The separation condition was as follows.
    • (Separation Condition A1)
  • Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.
    Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm
    Mobile phase; hexane:2-propanol=70:30
    Flow rate; 10.0 mL/min
    • Detection; UV (220 nm)
  • The analytical condition used in the chiral column was as follows.
    • (Analytical Condition B1)
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; hexane:2-propanol=80:20
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Step 4 4-{5-tert-Butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoic Acid (Optically Active Compound)
  • Figure US20190359575A1-20191128-C00150
  • 4-{5-tert-Butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoic acid ethyl ester (63 mg) obtained in Step 3 was mixed in ethanol (0.5 mL). To the reaction solution was added 4M aqueous lithium hydroxide solution (0.07 mL), and the reaction solution was stirred at room temperature for 3.5 hours. To the reaction solution were added 2M aqueous hydrochloric acid solution and water under ice cooling, which was then extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. To the resulted residue was added a mixed solvent of hexane-diisopropylether (1:1), and the precipitated solid was filtered to give the titled compound (47.8 mg).
  • The resulted compounds were analyzed with a chiral column to determine 13.5 min as the retention time and >99% ee as the optical purity of the relsuted enantiomer compound. The retention time of the other enantiomer was 16.7 min.
  • The analytical condition used in the chiral column was as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AS-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:trifluoroacetic acid=30:70:0.1
    Flow rate; 0.5 mL/min
    • Detection; UV (220 nm) Example 87 Preparation of 3-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl})-propionic Acid A Method for Preparation Using an Optically Active Sulfinamide Step 1 4-Bromo-3-chloro-N-methoxy-N-methyl-benzamide
  • Figure US20190359575A1-20191128-C00151
  • 4-Bromo-3-chloro-benzoic acid (100 g), N,O-dimethylhydroxylamine hydrochloride (49.7 g), 1-hydroxybenzotriazole monohydrate (13.0 g), and diisopropylethylamine (103.8 mL) were mixed in acetonitrile (800 mL). To the reaction solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97.6 g) in four batches under ice cooling, and the reaction solution was stirred at room temperature overnight. To the reaction solution were added toluene (1 L) and water (500 mL), and the mixture was separated, and then the aqueous layer was extracted with toluene (500 ml) twice. The resulted organic layer was collected and washed sequentially with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (115.8 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 3.36 (s, 3H), 3.55 (s, 3H), 7.47 (dd, J=8.32, 1.85 Hz, 1H), 7.66 (d, J=8.32 Hz, 1H), 7.81 (d, J=1.85 Hz, 1H)
    • Step 2 1-(4-Bromo-3-chloro-phenyl)-ethanone
  • Figure US20190359575A1-20191128-C00152
  • 4-Bromo-3-chloro-N-methoxy-N-methyl-benzamide (115 g) was mixed in tetrahydrofuran (575 mL). To the reaction solution was added dropwise 1 M methylmagnesium bromide/tetrahydrofuran solution (516 mL) under ice cooling, and the reaction solution was stirred for 2 hours under ice cooling. To the reaction solution was added dropwise 1M hydrochloric acid (550 mL) under ice cooling, and then to the mixture was added ethyl acetate (500 ml). The mixed solution was separated, and the aqueous layer was then extracted with ethyl acetate. The resulted organic layer was collected and washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. To the resulted residue were added diisopropylether and hexane, and the precipitated solid was filtered to give the titled compound (91.5 g).
  • 1H-NMR (400 MHz, CDCl3) 2.59 (s, 3H), 7.68 (dd, J=8.32, 1.85 Hz, 1H), 7.74 (d, J=8.32 Hz, 1H), 8.02 (d, J=1.85 Hz, 1H)
    • Step 3 1-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-ethanone
  • Figure US20190359575A1-20191128-C00153
  • 1-(4-Bromo-3-chloro-phenyl)-ethanone (78 g), triethylamine (390 mL), 3,3-dimethyl-but-1-yne (53.2 mL), and copper iodide (6.4 g) were mixed in N,N-dimethylformamide (46 mL) under argon gas. To the reaction solution was added bis(triphenylphosphine)palladium (II) dichloride (23.5 g), and the reaction solution was stirred at 90° C. for 2 hours. To the reaction solution were added saturated ammonium chloride water, a mixed solution of ethyl acetate-hexane (1:1), and Celite at room temperature, and the mixture was stirred for 10 minutes. After removing an insoluble on a filter, the filtrate was extracted with a mixed solution of ethyl acetate-hexane (1:1). The organic layer was sequentially washed with aqueous saturated ammonium chloride solution, 0.5M hydrochloric acid, water, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filler, the filtrated was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:30->1:13) to give the titled compound (75.37 g).
  • 1H-NMR (400 MHz, CDCl3) 1.35 (s, 9H), 2.58 (s, 3H), 7.49 (d, J=7.97 Hz, 1H), 7.74 (dd, J=7.97, 1.69 Hz, 1H), 7.95 (d, J=1.69 Hz, 1H)
    • Step 4 1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-ethanone
  • Figure US20190359575A1-20191128-C00154
  • 1-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-ethanone (22.3 g) was mixed in tetrahydrofuran (112 mL) and methanol (112 mL). To the reaction solution was added 5 w/w % rhodium/alumina (2.23 g), and the reaction solution was stirred for 8.5 hours under hydrogen gas at ordinary pressure. After removing rhodium/alumina on a filter, the filtrate was concentrated under reduced pressure. The procedure was repeated two more times, and the resulted residue was collected and purified through silica gel chromatography (ethyl acetate:hexane=1:50) to give the titled compound (58.0 g).
  • 1H-NMR (400 MHz, CDCl3) 0.98 (s, 9H), 1.45-1.48 (m, 2H), 1.54 (s, 3H), 2.57 (s, 3H), 2.72-2.76 (m, 2H), 7.31 (d, J=7.92 Hz, 1H), 7.76 (dd, J=7.92, 1.79 Hz, 1H), 7.92 (d, J=1.79 Hz, 1H)
    • Step 5 (S)-2-Methyl-propane-2-sulfinic acid [1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-eth-(E)-ylidene]-amide
  • Figure US20190359575A1-20191128-C00155
  • 1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-ethanone (56.1 g) and (S)-(−)-2-methyl-propane-2-sulfinic acid amide (29.05 g) were mixed in cyclopentylmethyl ether (234 mL). To the reaction solution was added tetraethyl orthotitanate (98.3 mL), and the reaction solution was stirred at 110° C. for 4.5 hours. The solution was added dropwise to a mixed solution of 10 w/w % aqueous ammonium chloride solution (300 mL)-ethyl acetate (200 mL) under ice cooling, and the mixed solution was stirred at room temperature for 30 minutes. To the mixed solution was added Celite, and the mixed solution was stirred for additional 30 minutes at room temperature. After removing an insoluble on a filter, the filtrate was washed sequentially with 30 w/w % aqueous ammonium chloride solution and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:50->1:33->1:20->1:10->1:5) to give the titled compound (69.86 g).
  • 1H-NMR (400 MHz, CDCl3) 0.99 (s, 9H), 1.32 (s, 9H), 1.45-1.47 (m, 2H), 2.70-2.75 (m, 2H), 2.73 (s, 3H), 7.26 (d, J=8.09 Hz, 1H), 7.68 (dd, J=8.09, 1.74 Hz, 1H), 7.84 (d, J=1.74 Hz, 1H)
    • Step 6 (R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00156
  • Diisopropylamine (52.7 mL) was mixed in tetrahydrofuran (341 mL) under argon gas. To the reaction solution was added dropwise 1.63 M n-butyllithium/hexane solution (220 mL) at −78° C., and the reaction solution was stirred at −78° C. for 40 minutes. To the reaction solution was added dropwise a mixed solution of 3-methyl-butanoic acid methyl ester (45 mL) in tetrahydrofuran (34 mL), and the reaction solution was stirred at −78° C. for additional 1 hour. To the reaction solution was added dropwise 1 M chloro titanium (IV) triisopropoxide/hexane solution (682 mL), and the reaction solution was stirred at −78° C. for additional 30 minutes. To the reaction solution was added dropwise a mixed solution of (S)-2-methyl-propane-2-sulfinic acid [1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-eth-(E)-ylidene]-amide (60.73 g) in tetrahydrofuran (34 mL), and the reaction solution was stirred at −78° C. for 10 minutes, then at −40° C. for additional 2 hours. The reaction solution was cooled to −78° C. and was dropped under ice cooling to aqueous ammonium chloride solution. The resulted mixed solution was stirred under ice cooling for 1 hour, and then an insoluble was removed on a filter. The filtrate was separated, and the organic layer was washed sequentially with ammonium chloride water and aqueous sodium chloride solution and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20->1:10->1:4->1:3) to give the titled compound (64.91 g) as a mixture of diastereomers generated by isopropyl group at α-position of ester (d.r.=90:10).
  • 1H-NMR (400 MHz, CDCl3) 0.72 (d, J=6.82 Hz, 0.3H), 0.92 (d, J=2.31 Hz, 2.7H), 0.93 (d, J=2.31 Hz, 2.7H), 0.98 (s, 8.1H), 0.99 (s, 0.9H), 1.01 (d, J=6.82 Hz, 0.3H), 1.25 (s, 8.1H), 1.34 (s, 0.9H), 1.44-1.49 (m, 2H), 1.86 (s, 0.3H), 1.89 (s, 2.7H), 2.01-2.11 (m, 1H), 2.46 (d, J=3.93 Hz, 0.1H), 2.63-2.72 (m, 2H), 2.83 (d, J=3.93 Hz, 0.9H), 3.59 (s, 2.7H), 3.70 (s, 0.3H), 5.04 (brs, 0.9H), 5.42 (brs, 0.1H), 7.13-7.27 (m, 2H), 7.39 (d, J=2.08 Hz, 0.9H), 7.43 (d, J=1.85 Hz, 0.1H)
    • Step 7 (S)-2-Methyl-propane-2-sulfinic acid {(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide
  • Figure US20190359575A1-20191128-C00157
  • (R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoic acid methyl ester (54.9 g) was mixed in toluene (384 mL) under argon gas. To the reaction was added dropwise 1 M diisobutylaluminum hydride/toluene solution (415 mL) at −78° C., and the reaction solution was stirred at −78° C. for 50 minutes, then gradually warmed to 0° C. to stirr for 3 hours. To the reaction solution was added dropwise under ice cooling methanol, then aqueous Rochelle salt solution. To the mixed solution was added ethyl acetate, and then the mixture was stirred at room temperature for 3 hours. The resulted solution was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. To the resulted residue was added diisopropylether, and the precipitated solid was filtered to give the titled compound (42.0 g, d.r.=95:5).
  • 1H-NMR (400 MHz, CDCl3) 0.70 (d, J=7.06 Hz, 3H), 0.75 (d, J=7.06 Hz, 3H), 0.99 (s, 9H), 1.15 (s, 9H), 1.17-1.26 (m, 1H), 1.47-1.52 (m, 2H), 1.94 (s, 3H), 2.04-2.09 (m, 1H), 2.65-2.71 (m, 2H), 3.91-3.96 (m, 1H), 3.99-4.06 (m, 1H), 4.75 (s, 1H), 6.63 (s, 1H), 7.17 (d, J=8.04 Hz, 1H), 7.23 (dd. J=8.04, 1.91 Hz, 1H), 7.40 (d, J=1.91 Hz, 1H) (for the major isomer)
  • An absolute configuration of the quaternary asymmetric carbon in the titled compound was determined by purification of the major isomer of the titled compound (i.e. the following compound), followed by single crystal X-ray structural analysis thereof.
  • Figure US20190359575A1-20191128-C00158
    • Step 8 (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol
  • Figure US20190359575A1-20191128-C00159
  • (S)-2-Methyl-propane-2-sulfinic acid {(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide (41.4 g) was mixed in methanol (207 mL) and tetrahydrofuran (21 ml). To the reaction solution was added dropwise 2M hydrogen chloride/methanol solution (193 mL) under ice cooling, and the reaction solution was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and chloroform was added to the residue. An aqueous sodium carbonate solution was added to the mixed solution under ice cooling so that the aqueous layer was adjusted to pH 10. The mixed solution was extracted with chloroform. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (29.0 g, d.r.=95:5) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 0.80 (d, J=7.00 Hz, 3H), 0.85 (d, J=7.00 Hz, 3H), 0.98 (s, 9H), 1.35-1.42 (m, 1H), 1.43-1.49 (m, 2H), 1.60 (s, 3H), 1.86-1.91 (m, 1H), 2.65-2.70 (m, 2H), 3.70 (dd, J=11.59, 3.38 Hz, 5H), 3.92 (dd, J=11.59, 9.18 Hz, 1H), 7.21-7.22 (m, 2H), 7.36 (d, J=1.69 Hz, 1H) (for the major isomer)
    • Step 9 3-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00160
  • (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol (29.0 g) was mixed in tetrahydrofuran (203 mL). To the reaction solution was added 3-isocyanatopropionic acid ethyl ester (11.8 mL) under ice cooling, and the reaction solution was stirred at room temperature for 100 minutes. To the reaction solution was added 3-isocyanatopropionic acid ethyl ester (1.18 mL) under ice cooling, and the reaction solution was stirred at room temperature for 75 minutes. To the reaction solution was added 3-isocyanatopropionic acid ethyl ester (0.59 mL) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. To the mixed solution was added N,N,N′-trimethylethylenediamine (1.73 mL), and the mixture was stirred at room temperature for 40 minutes. To the reaction solution was added 0.1M hydrochloric acid, which was extracted with ethyl acetate. The organic layer was washed sequentially with water, aqueous saturated sodium chloride solution, and aqueous sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel column chromatography (ethyl acetate:chloroform=1:10->1:5->1:3) to give the titled compound (41.6 g, d.r.=95:5).
  • 1H-NMR (400 MHz, CDCl3) 0.77 (d, J=6.94 Hz, 3H), 0.83 (d, J=6.94 Hz, 3H), 0.98 (s, 9H), 1.25 (t, J=7.03 Hz, 3H), 1.48 (dt, J=9.02, 4.05 Hz, 2H), 1.52-1.58 (m, 1H), 1.71-1.74 (m, 1H), 1.79 (s, 3H), 2.33-2.45 (m, 2H), 2.63-2.68 (m, 2H), 2.82 (brs, 1H), 3.31 (q, J=6.17 Hz, 2H), 3.80 (d, J=11.10 Hz, 1H), 3.90-3.95 (m, 1H), 4.12 (q, J=7.03 Hz, 2H), 4.49 (t, J=6.01 Hz, 1H), 7.13 (brs, 1H), 7.16 (d, J=8.15 Hz, 1H), 7.25 (dd, J=8.15, 2.03 Hz, 1H), 7.38 (d, J=2.03 Hz, 1H) (for the major isomer)
    • Step 10 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00161
  • 3-(3-((R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl)-ureido)-propionic acid ethyl ester (17.1 g) and iodobenzene diacetate (13.3 g) were mixed in dichloromethane (143 mL). To the reaction solution was added a mixed solution of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (17.5 mg) in dichloromethane (2 ml) under ice cooling, and the reaction solution was stirred at room temperature for 18 hours. To the reaction solution was added trifluoroacetic acid (10.78 mL) under ice cooling, and then the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added aqueous sodium sulfite solution under ice cooling, and then thereto was added aqueous potassium hydrogen carbonate solution. The resulted mixed solution was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20->1:9->1:7->1:4->1:3) to give the titled compound (18.3 g).
  • 1H-NMR (400 MHz, CDCl3) 0.71 (d, J=6.94 Hz, 3H), 0.98 (s, 9H), 1.04 (d, J=6.94 Hz, 3H), 1.28 (t, J=7.17 Hz, 4H), 1.41-1.48 (m, 2H), 1.68 (s, 3H), 1.83-1.90 (m, 1H), 2.64-2.69 (m, 4H), 3.78 (t, J=6.59 Hz, 2H), 4.16 (q, J=7.17 Hz, 3H), 4.61 (s, 1H), 5.90 (s, 1H), 7.16 (d, J=8.04 Hz, 1H), 7.24 (dd, J=7.94, 2.02 Hz, 1H), 7.38 (d, J=2.02 Hz, 1H)
    • Step 11 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00162
  • 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester (34.8 g) obtained by repeating Example 87 (a method for preparation using an optically active sulfinamide) Steps 1 to 10 was mixed in ethanol (350 mL). To the reaction solution was added dropwise 4M aqueous sodium hydroxide solution (38.7 mL) under ice cooling, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then water was added to the residue. To the mixed solution was added 6M hydrochloric acid (25.8 mL) under ice cooling. The precipitated solid was dissolved in ethyl acetate, and then extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and then dried over magnesium sulfate. After removing sodium sulfate on a filter, the reaction solution was concentrated under reduced pressure. To the resulted residue was added ethanol (500 mL), which was again concentrated under reduced pressure. The resulted residue was mixed in water (600 mL). To the reaction solution was added 4M aqueous sodium hydroxide solution (26.85 mL) under ice cooling. To the reaction solution was added 6M hydrochloric acid (17.9 mL) under ice cooling, and the reaction solution was stirred under ice cooling for 30 minutes. Then 6M hydrochloric acid was added to the solution so that the reaction solution was adjusted to pH 2, and the reaction solution was stirred under ice cooling for 30 minutes. The precipitated solid was filtered and dried to give the titled compound (28.9 g).
  • A specific optical rotation of the resulted compound was [α]D 25=+112.6° (c=1.00, methanol).
  • The resulted compound was analyzed with a chiral column, and the retention time of the resulted titled compound (S-enantiomer) was 9.0 minutes, the optical purity of which was >99% ee.
  • The analytical condition using a chiral column was as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid=30:70:0.1
    Flow rate; 0.5 mL/min
    • Detection; UV (220 nm)
  • The resulted solid (20 mg) was mixed in a mixed solvent of 2-propanol-water (1:20, 0.21 mL), and the suspension was stirred at 60° C. for 1.5 hours. The suspension was cooled to room temperature over 1 hour, and then the precipitated solid was filtered to give a crystal of the titled compound (18 mg). The melting point of the crystal was 117.5-118.7° C.
    • Example 87 Preparation of 3-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid A Method for Preparation Using Cleisen Reaction Step 1 2-(4-Hydroxy-phenyl)-propionic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00163
  • 2-(4-Hydroxyphenyl)propionic acid (75 g) was mixed in methanol (750 mL). To the reaction solution was added dropwise thionyl chloride (49 mL), and the reaction solution was stirred at 60° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (97 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.45 (d, J=7.40 Hz, 3H), 3.64-3.66 (m, 4H), 5.08 (s, 1H), 6.75-6.78 (m, 2H), 7.14-7.15 (m, 2H)
    • Step 2 2-(3-Chloro-4-hydroxy-phenyl)-propionic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00164
  • 2-(4-Hydroxy-phenyl)-propionic acid methyl ester (97.0 g) was mixed in N,N-dimethylformamide (450 mL). To the reaction solution was added N-chlorosuccinimide (60.1 g), and the reaction solution was stirred at 80° C. for 4 hours. To the reaction solution was added water, which was then extracted with toluene. The organic layer was washed with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrated was concentrated under reduced pressure to give the titled compound (101.5 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.45 (d, J=7.17 Hz, 3H), 3.61-3.66 (m, 4H), 5.58 (s, 1H), 6.95 (d, J=8.55 Hz, 1H), 7.09 (dd, J=8.44, 1.97 Hz, 1H), 7.25 (d, J=8.55 Hz, 1H)
    • Step 3 2-(3-Chloro-4-trifluoromethanesulfonyloxyphenyl)propionic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00165
  • 2-(3-Chloro-4-hydroxy-phenyl)-propionic acid methyl ester (101.5 g) was mixed in methylene chloride (600 mL) and pyridine (73 mL) under argon gas. To the reaction solution was added dropwise trifluoromethanesulfonic anhydride (91 mL) under ice cooling, and the reaction solution was stirred at room temperature for 6.5 hours. Then to the reaction solution was added trifluoromethanesulfonic anhydride (11.4 mL), and the reaction solution was stirred at room temperature overnight. To the reaction solution was added water, which was then extracted with chloroform. The organic layer was washed sequentially with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (156.69 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.50 (d, J=7.17 Hz, 3H), 3.67-3.71 (m, 4H), 7.27-7.28 (m, 1H), 7.46 (d, J=1.85 Hz, 1H)
    • Step 4 2-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-propionic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00166
  • 2-(3-Chloro-4-trifluoromethanesulfonyloxyphenyl)propionic acid methyl ester (60 g), tetrabutylammonium iodide (128 g), 3,3-dimethyl-but-1-yne (42.4 mL), triethylamine (60 mL), bis(triphenylphosphine)palladium (II) dichloride (12.2 g), and copper iodide (9.88 g) were mixed in N,N-dimethylformamide (300 mL) under argon gas. The reaction solution was stirred at 70° C. for 1 hour. To the reaction solution was added water, which was then extracted with toluene. The organic layer was washed sequentially with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and saturated sodium chloride water, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:30->1:20) to give the titled compound (37.15 g).
  • 1H-NMR (400 MHz, CDCl3) 1.31 (s, 9H), 1.45 (d, J=7.17 Hz, 3H), 3.62-3.67 (m, 4H), 7.08 (dd. J=7.86, 1.85 Hz, 1H), 7.29 (d, J=1.62 Hz, 1H), 7.34 (d, J=8.09 Hz, 1H)
    • Step 5 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00167
  • 2-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-propionic acid methyl ester (18.5 g) was mixed in methanol (185 mL). To the mixed solutoin was added 5 w/w % platinum/activated carbon (1.85 g), and the reaction solution was stirred for 9 hours under hydrogen gas at 4 atm. Removal from the reaction solution platinum/activated carbon on a filter gave a filtrate (referred to as Filtrate A hereinafter).
  • According to the reduction procedure, 2-[3-chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-propionic acid methyl ester (18.5 g) was treated to give a filtrate (referred to as Filtrate B hereinafter).
  • Filtrate A and Filtrate B were combined and concentrated under reduced pressure to give a residue (34.08 g/referred to as Residue C hereinafter).
  • Residue C was analyzed (1H-NMR measurement), which showed that the reduction reaction was not completed (i.e. a starting material was existed), and the reduction reaction was repeated.
  • Residue C (34 g) was divided into two halves of Residue D (17 g) and Residue E (17 g). Residue D (17 g) was mixed in methanol (185 mL). To the mixed solution was added 5 w/w % platinum/activated carbon (1.85 g), and the reaction solution was stirred for 5 hours under hydrogen gas at 4 atm. Then platinum/activated carbon was removed from the reaction solution on a filter to give a filtrate (referred to as Filtrate F hereinafter).
  • Residue E (17 g) was treated according to the reduction procedure to give a filtrate (referred to as Filtrate G hereinafter).
  • The resulted Filtrate F and Filtrate G were combined and concentrated under reduced pressure to give the titled compound (35.06 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 0.97 (s, 9H), 1.42-1.48 (m, 5H), 2.63-2.68 (m, 2H), 3.65-3.66 (m, 4H), 7.10 (dd, J=7.85, 1.81 Hz, 1H), 7.16 (d, J=7.97 Hz, 1H), 7.26-7.27 (m, 1H)
    • Step 6 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic Acid
  • Figure US20190359575A1-20191128-C00168
  • 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid methyl ester (35.0 g) was mixed in tetrahydrofuran (110 mL) and methanol (110 ml). To the reaction solution was added dropwise 4M aqueous sodium hydroxide solution (93 mL) under ice cooling, and the reaction solution was stirred at room temperature for 2 hours. Then to the reaction solution was added dropwise 2M hydrochloric acid (186 mL) under ice cooling, and the resulted mixed solution was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride water, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. To the resulted residue was added a mixed solution of hexane-diisopropylether (10:1), and then the precipitated solid was filtered. The resulted filtrate was concentrated under reduced pressure, and to the residue was added again a mixed solution of hexane-diisopropylether (10:1), and the precipitated solid was filtered. The resulted solid was collected to give the titled compound (30.4 g).
  • 1H-NMR (400 MHz, CDCl3) 0.96 (s, 9H), 1.42-1.44 (m, 2H), 1.48 (d, J=7.17 Hz, 3H), 2.63-2.65 (m, 2H), 3.67 (q, J-=7.17 Hz, 1H), 7.11 (dd, J=7.98, 1.73 Hz, 1H), 7.15 (d, J=8.09 Hz, 1H), 7.28 (d, J=1.85 Hz, 1H)
    • Step 7 (E)-4-Methyl-pent-2-en-1-ol
  • Figure US20190359575A1-20191128-C00169
  • (E)-4-Methyl-pent-2-enoic acid methyl ester (16.72 g) was mixed in dichloromethane (50 mL). To the reaction solution was added dropwise 1M diisobutylaluminum hydride/dichloromethane solution (300 mL) at −78° C., and the reaction solution was stirred at −78° C. for 1 hour. The reaction solution was added dropwise to 1.5M aqueous sulfuric acid solution (350 mL) under ice cooling, and then the mixed solution was stirred under ice cooling for 1.5 hours. The reaction solution was extracted with dichloromethane, and the organic layer was washed sequentially with 1M aqueous sulfuric acid solution, water, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound in dichloromethane solution (73.3 w/w %, 18.81 g).
  • 1H-NMR (400 MHz, CDCl3) 1.00 (d, J=6.94 Hz, 6H), 1.25 (s, 1H), 2.31 (td, J=13.58, 6.78 Hz, 1H), 4.09 (d, J=5.78 Hz, 2H), 5.59 (tdd, J=10.63, 5.20, 0.89 Hz, 1H), 5.67 (ddt, J=15.26, 6.17, 0.90 Hz, 1H)
    • Step 8 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid (E)-4-methyl-pent-2-enyl Ester
  • Figure US20190359575A1-20191128-C00170
  • 73.3 w/w % of (E)-4-methyl-pent-2-en-1-ol/dichloromethane solution (5.33 g), 2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid (10.0 g), and 4-dimethylaminopyridine (1.36 g) were mixed in chloroform (150 mL). To the reaction solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.7 g) under ice cooling, and the reaction solution was stirred at room temperature overnight. To the reaction solution were added ethyl acetate and 1 M hydrochloric acid, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water, aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (13.0 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 0.92-1.04 (m, 10H), 1.37-1.51 (m, 5H), 1.56 (s, 3H), 2.22-2.33 (m, 1H), 2.59-2.72 (m, 2H), 3.61-3.70 (m, 1H), 4.42-4.60 (m, 2H), 5.45 (tt, J=10.87, 3.38 Hz, 1H), 5.65 (dd, J=15.45, 6.52 Hz, 1H), 7.08-7.17 (m, 2H), 7.27-7.30 (m, 1H)
    • Step 9 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-isopropyl-2-methyl-pent-4-enoic Acid
  • Figure US20190359575A1-20191128-C00171
  • Diisopropylamine (10.9 mL) was mixed in tetrahydrofuran (130 mL). To the reaction solution was added dropwise 1.64M n-butyllithium/hexane solution (45.2 mL) at −78° C., and the reaction solution was stirred at −78° C. for 20 minutes. To the reaction solution was added dropwise a mixed solution of 2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid (E)-4-methyl-pent-2-enyl ester (13.0 g) in tetrahydrofuran (130 mL) over 30 minutes at −78° C., and the reaction solution was stirred under ice cooling for 60 minutes. Then thereto was added dropwise chlorotrimethylsilane (9.87 mL) at −78° C., and the reaction solution was stirred at −78° C. for 30 minutes, which was then stirred under ice cooling for 130 minutes, then at room temperature for 150 minutes. To the reaction solution was added 1 M hydrochloric acid under ice cooling, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel chromatography (ethyl acetate:hexane=1:30->1:15->1:7) to give the titled compound (14.49 g). 1H-NMR (400 MHz, CDCl3) 0.67 (d, J=6.94 Hz, 2H), 0.74 (d, J=6.70 Hz, 2H), 0.83 (d, J=6.70 Hz, 1H), 0.95 (t, J=4.05 Hz, 10 OH), 1.39-1.47 (m, 3H), 1.58 (s, 3H), 2.60-2.65 (m, 2H), 2.79-2.83 (m, 1H), 4.69 (dd, J=16.88, 2.08 Hz, 0.3H), 4.83 (dd, J=10.17, 2.08 Hz, 0.3H), 5.12 (dd, J=7.86, 2.31 Hz, 0.7H), 5.16 (s, 0.7H), 5.31 (dt, J=19.34, 8.44 Hz, 0.3H), 5.65-5.74 (m, 0.7H), 7.09 (d, J=8.09 Hz, 0.3H), 7.15 (d, J=8.32 Hz, 0.3H), 7.19 (dd, J=8.21, 1.97 Hz, 0.3H), 7.31 (dt, J=12.10, 4.28 Hz, 0.3H), 7.43 (d, J=2.08 Hz, 0.3H)
    • Step 10 2-Chloro-1-(3,3-dimethyl-butyl)-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene
  • Figure US20190359575A1-20191128-C00172
  • 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-isopropyl-2-methyl-pent-4-enoic acid (12.0 g) and triethylamine (7.2 mL) were mixed in toluene (120 mL). To the reaction solution was added diphenyl phosphoryl azide (11.1 mL), and the reaction solution was stirred at 120° C. for 7.5 hours. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel chromatography (ethyl acetate:hexane=1:30) to give the titled compound (9.6 g).
  • 1H-NMR (400 MHz, CDCl3) 0.64 (d, J=6.70 Hz, 2H), 0.67 (d, J=6.94 Hz, 1H), 0.82 (d, J=6.94 Hz, 1H), 0.84 (d, J=6.70 Hz, 2H), 0.98 (s, 6H), 0.98 (s, 3H), 1.46 (m, 2H), 1.62 (s, 1H), 1.74 (s, 2H), 1.99-2.01 (m, 0.65H), 2.17-2.20 (m, 1H), 2.35 (brs, 0.35H), 2.64-2.70 (m, 2H), 4.88-4.93 (m, 0.65H), 5.12-5.17 (m, 1H), 5.34-5.36 (m, 0.35H), 5.60-5.64 (m, 0.65H), 5.81-5.88 (m, 0.35H), 7.15-7.15 (m, 1H), 7.17-7.18 (m, 1H), 7.31-7.32 (m, 0.65H), 7.35-7.36 (m, 0.35H)
    • Step 11 3-{3-[1-(3-Chloro-4-(3,3-dimethyl-butyl)-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00173
  • 2-Chloro-1-(3,3-dimethyl-butyl)-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene (400 mg) and 3-amino-propionic acid ethyl ester hydrochloride (194 mg) were mixed in 1,4-dioxane (4 mL). To the reaction solution was added triethylamine (0.18 mL), and the reaction solution was stirred at 60° C. for about 40 minutes. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel column chromatography (methanol:chloroform=1:99->2:98->4:96) to give the titled compound (478 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.21-0.26 (m, 0.33H), 0.54-0.60 (m, 0.67H), 0.70-0.75 (m, 0.67H), 0.80-0.84 (m, 0.33H), 0.97-0.99 (m, 9H), 1.40-1.53 (m, 2H), 1.66-1.69 (m, 2H), 1.79-1.82 (m, 1H), 1.64-1.83 (m, 3H), 1.84-2.04 (m, 1H), 2.25-2.45 (m, 2H), 2.61-2.72 (m, 2H), 3.22-3.38 (m, 2H), 4.01-4.14 (m, 2H), 4.35-4.59 (m, 1H), 4.87-5.41 (m, 1H), 5.53-5.88 (m, 1H), 7.10-7.43 (m, 2H)
    • Step 12 3-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00174
  • 3-{3-[1-(3-Chloro-4-(3,3-dimethyl-butyl)-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionic acid ethyl ester (478 mg) was mixed in methanol (8 mL). The reaction solution was stirred at −78° C. for 30 minutes under ozone flow. Then the reaction solution was stirred at −78° C. for 3 minutes under nitrogen flow. Then to the reaction solution were added methylsulfide (0.76 mL) at −78° C. and methanol (4 mL) at room temperature. The reaction solution was concentrated under reduced pressure, and to the residue was added 2M hydrogen chloride/methanol solution (1 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel chromatography (methanol:chloroform=4:96) twice to give the titled compound (191 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.67-0.72 (m, 3H), 0.96 (s, 9H), 1.00-1.05 (m, 3H), 1.22-1.29 (m, 3H), 1.40-1.46 (m, 2H), 1.67 (s, 3H), 1.80-1.89 (m, 1H), 2.62-2.69 (m, 4H), 3.74-3.79 (m, 2H), 4.11-4.18 (m, 2H), 4.61 (brs, 1H), 5.88 (s, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.35-7.37 (m, 1H)
    • Step 13 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00175
  • 3-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester (racemate/191 mg) was purified using a recycling preparative chromatograph to give 61 mg as a fraction compound eluted later (analytical column DAICEL CHIRALPAK IA-3, retention time 7.1 minutes) and 58 mg as a fraction compound eluted earlier (analytical column DAICEL CHIRALPAK IA-3, retention time 4.9 minutes).
  • The separation condition by the recycling preparative chromatograph is shown as follows.
  • Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.
    Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm
    Mobile phase; hexane:2-propanol=90:10
    Flow rate; 10.0 mL/min
    • Detection; UV (254 nm)
  • The analytical condition using a chiral column is as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; hexane:2-propanol=90:10
    Flow rate; 1.0 mL/min
    • Detection; UV (254 nm)
  • The ethyl ester compound obtained as a fraction eluted later was converted into a carboxylic acid compound in the next step (Step 14, hydrolysis reaction). The retention time and NMR spectrum of the carboxylic acid compound in a chiral column coincided with those in a chiral column of the carboxylic acid compound (S-enantiomer) obtained in the method using the optically active sulfinamide.
  • The ester compound obtained as a fraction eluted later was thus estimated as an S-enantiomer.
    • (S-Enantiomer)
  • 1H-NMR (400 MHz, CDCl3) 0.67-0.72 (m, 3H), 0.96 (s, 9H), 1.00-1.05 (m, 3H), 1.22-1.29 (m, 3H), 1.40-1.46 (m, 2H), 1.67 (s, 3H), 1.80-1.89 (m, 1H), 2.62-2.69 (m, 4H), 3.74-3.79 (m, 2H), 4.11-4.18 (m, 2H), 4.61 (brs, 1H), 5.88 (s, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.35-7.37 (m, 1H)
    • (R-Enantiomer)
  • 1H-NMR (400 MHz, CDCl3) 0.67-0.72 (m, 3H), 0.96 (s, 9H), 1.00-1.05 (m, 3H), 1.22-1.29 (m, 3H), 1.40-1.46 (m, 2H), 1.67 (s, 3H), 1.80-1.89 (m, 1H), 2.62-2.69 (m, 4H), 3.74-3.79 (m, 2H), 4.11-4.18 (m, 2H), 4.61 (brs, 1H), 5.88 (s, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.35-7.37 (m, 1H)
    • Step 14 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00176
  • 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester (57 mg) was mixed in methanol (2 mL). To the reaction solution was added 2M aqueous sodium hydroxide solution (0.25 mL), and the reaction solution was stirred at 60° C. The reaction solution was concentrated under reduced pressure, and then water was added thereto. To the resulted mixed solution was added 2M hydrochloric acid (0.25 mL), which was then stirred at room temperature. The precipitated solid was filtered to give the titled compound (49 mg).
  • The resulted compound was analyzed by a chiral column, and the retention time of the resulted titled compound (S-enantiomer) was 9.0 minutes, the optical purity of which was >99% ee. The analytical condition in the chiral column was as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid=30:70:0.1
    Flow rate; 0.5 mL/min
    • Detection; UV (220 nm) Example 86 (the Enantiomer of Example 87) 3-{(R)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00177
  • 3-{(R)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester obtained in Example 87 Step 13 was treated according to the reaction in Example 87 Step 14 to give the titled compound (36 mg). The retention time of the resulted enantiomer (R-enantiomer) was 6.0 minutes.
  • The analytical condition in a chiral column was as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid=30:70:0.1
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Example 116 Preparatin of 3-{(S)-4-[3-chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid A Method for Preparation Using an Optically Active Sulfinamide Step 1 (S)-2-Methyl-propane-2-sulfinic acid [1-(4-bromo-3-chloro-phenyl)-eth-(E)-ylidene]-amide
  • Figure US20190359575A1-20191128-C00178
  • 1-(4-Bromo-3-chloro-phenyl)-ethanone (20 g) prepared according to Example 87 (a method for preparation using an optically active sulfinamide) Steps 1 to 2 and (S)-(−)-2-methyl-propane-2-sulfinic acid amide (11.4 g) were mixed in cyclopentylmethyl ether (100 mL). To the reaction solution was added tetraethyl orthotitanate (23.3 mL), and the reaction solution was stirred at 100° C. for 5 hours. To the reaction solution was added 25 w/w % aqueous citric acid solution under ice cooling, and the mixed solution was stirred at room temperature. After removing an insoluble on a filter, the filtrate was extracted with toluene. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and then concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20->1:10->1:5) to give the titled compound (23 g).
  • 1H-NMR (400 MHz, CDCl3) 1.30 (s, 9H), 2.72 (s, 3H), 7.56-7.61 (m, 1H), 7.66 (d, J=8.55 Hz, 1H), 7.91 (d, J=2.08 Hz, 1H)
    • Step 2 (R)-3-(4-Bromo-3-chloro-phenyl)-2-isopropyl-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00179
  • Diisopropylamine (21.1 mL) was mixed in THF (138 mL) under argon gas. To the reaction solution was added dropwise 1.63M n-butyllithium/hexane solution (88 mL) at −78° C., and the reaction solution was stirred at −78° C. for 20 minutes. To the reaction solution was added dropwise 3-methyl-butanoic acid methyl ester (18 mL), and the reaction solution was stirred at −78° C. for 30 minutes. To the reaction solution were added dropwise 1M chloro titanium (IV) triisopropoxide/hexane solution (100 mL) and then a mixed solution of chloro titanium (IV) triisopropoxide (48.7 g) in tetrahydrofuran (80 mL), and the reaction solution was stirred at −78° C. for 30 minutes. To the reaction solution was added dropwise a mixed solution of (S)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-3-chloro-phenyl)-eth-(E)-ylidene]-amide (23 g) in THF (138 mL), and the reaction solution was stirred at −78° C. for 75 minutes and then at −45° C. for 2 hours. The reaction solution was added dropwise saturated aqueous Rochelle salt solution. The mixed solution was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:10) to give the titled compound (16 g) as a mixture of diastereomers generated by the isopropyl group at α-position of ester (d.r.=72:28).
  • 1H-NMR (400 MHz, CDCl3) 0.75-1.01 (m, 6H), 1.25 (s, 6H), 1.33 (s, 3H), 1.87-1.88 (m, 3H), 2.04-2.12 (m, 1H), 2.46 (d, J=4.11 Hz, 0.3H), 2.80 (d, J=3.86 Hz, 0.7H), 3.60 (t, J=6.64 Hz, 2H), 3.71 (s, 1H), 5.13 (s, 0.7H), 5.42 (s, 0.3H), 7.14-7.22 (m, 1H), 7.52-7.56 (m, 1H), 7.57-7.59 (m, 1H)
    • Step 3 (S)-2-Methyl-propane-2-sulfinic acid [(R)-1-(4-bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]amide
  • Figure US20190359575A1-20191128-C00180
  • (R)-3-(4-Bromo-3-chloro-phenyl)-2-isopropyl-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoic acid methyl ester (16 g) was mixed in toluene (160 mL) under argon gas. To the reaction solution was added dropwise 1.01M diisobutylaluminum hydride/toluene solution (140 mL) at −78° C., and the reaction solution was stirred at −78° C. for 30 minutes, and then gradually warmed to 0° C., and then stirred for 1 hour. To the reaction solution were added dropwise methanol and then aqueous Rochelle salt solution under ice cooling, and then the mixed solution was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:5->1:3->1:1, then ethyl acetate only, then methanol:chloroform=1:20) to give the titled compound (11.5 g).
  • 1H-NMR (400 MHz, CDCl3) 0.66-0.85 (m, 6H), 1.13 (s, 7H), 1.29 (s, 2H), 1.69-1.81 (m, 2H), 1.89-2.00 (m, 3H), 2.01-2.12 (m, 1H), 3.83-4.12 (m, 2H), 5.06-5.28 (m, 1H), 6.81-6.93 (m, 1H), 7.12-7.23 (m, 1H), 7.50-7.62 (m, 2H)
    • Step 4 (R)-3-Amino-3-(4-bromo-3-chloro-phenyl)-2-isopropyl-butan-1-ol
  • Figure US20190359575A1-20191128-C00181
  • (S)-2-Methyl-propane-2-sulfinic acid [(R)-1-(4-bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]amide (11.5 g) was mixed in methanol (66 mL). To the reaction solution was added dropwise 2M hydrogen chloride/methanol solution (54 mL) under ice cooling, and the reaction solution was left to stand at room temperature overnight. The reaction solution was concentrated under reduced pressure, and aqueous sodium carbonate solution was added to the residue so that the aqueous layer was adjusted to pH 10, and then the reaction solution was extracted with chloroform. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (14 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 0.66-0.89 (m, 6H), 1.34-1.49 (m, 1H), 1.58-1.61 (m, 3H), 1.62-1.76 (m, 1H), 1.83-1.88 (m, 1H), 3.65-3.72 (m, 1H), 3.87-4.00 (m, 1H), 7.12-7.25 (m, 3H), 7.48-7.55 (m, 1H), 7.55-7.63 (m, 1H)
    • Step 5 3-{(3-[(R)-1-(4-Bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]-ureido}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00182
  • (R)-3-Amino-3-(4-bromo-3-chloro-phenyl)-2-isopropyl-butan-1-ol (14 g) was mixed in tetrahydrofuran (50 mL). To the reaction solution was added a mixed solution of 3-isocyanate-propionic acid ethyl ester (3.56 mL) in tetrahydrofuran (50 mL) under ice cooling, and the reaction solution was stirred under ice cooling for 1.5 hours. To the reaction solution was added water, which was then extracted with ethyl acetate. The organic layer was washed sequentially with 0.1 M hydrochloric acid, water, and aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:10->1:5->1:3->1:1, then methanol:chloroform=1:20) to give the titled compound (13.7 g).
  • 1H-NMR (400 MHz, CDCl3) 0.26-0.80 (m, 3H), 0.80-0.97 (m, 3H), 1.23-1.31 (m, 3H), 1.46-1.55 (m, 1H), 1.64-1.71 (m, 1H), 1.79-1.90 (m, 3H), 2.38-2.48 (m, 2H), 3.28-3.39 (m, 2H), 3.76-3.85 (m, 1H), 3.88-3.99 (m, 1H), 4.08-4.18 (m, 2H), 4.55-4.71 (m, 1H), 7.06-7.13 (m, 1H), 7.14-7.22 (m, 1H), 7.43-7.58 (m, 2H)
    • Step 6 3-[(S)-4-(4-Bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00183
  • 3-{3-[(R)-1-(4-Bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]-ureido}-propionic acid ethyl ester (9.49 g) and iodobenzene diacetate (7.26 g) were mixed in dichloromethane (95 mL). To the reaction solution was added 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (319 mg) under ice cooling, and the reaction solution was stirred at room temperature for 3.5 hours. To the reaction solution was added TFA (6.1 mL) under ice cooling, and the reaction solution was stirred at room temperature for 3.5 hours. To the reaction solution were added 20 w/w % aqueous sodium sulfite solution and 25 w/w % aqueous potassium hydrogen carbonate solution, and then the mixed solution was extracted with chloroform. The organic layer was washed sequentially with 25 w/w % aqueous potassium hydrogen carbonate solution and aqueous saturated sodium chloride solution, and then dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:6->1:3->1:2) to give the titled compound (7.77 g).
  • 1H-NMR (400 MHz, CDCl3) 0.68-0.74 (m, 3H), 1.00-1.07 (m, 3H), 1.26 (s, 3H), 1.68 (s, 3H), 1.80-1.89 (m, 1H), 2.60-2.67 (m, 2H), 3.72-3.78 (m, 2H), 4.08-4.19 (m, 2H), 4.82 (brs, 1H), 5.91 (s, 1H), 7.15-7.21 (m, 1H), 7.47-7.51 (m, 1H), 7.53-7.58 (m, 1H)
    • Step 7 3-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00184
  • 3-[(S)-4-(4-Bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic acid ethyl ester (58.1 g) prepared according to Example 116 (a method for preparation using an optically active sulfinamide) Steps 1 to 6, 3-[(S)-4-(4-bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic acid ethyl ester obtained in the previous step 6 (2.9 g), 2-(4,4-dimethyl-1-cyclohexenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (48.9 g), and tripotassium phosphate (87.7 g) were mixed in 1,2-dimethoxyethane (777 mL) and water (194 mL) under argon gas. To the reaction solution was added bis(triphenylphosphine)palladium (II) dichloride (5.6 g), and the reaction solution was stirred at 100° C. for 4 hours. To the reaction solution was added ethyl acetate at room temperature, and then an insoluble was removed on a filter. The filtrate was extracted with ethyl acetate, washed with aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified twice through silica gel chromatography to give the titled compound (48.3 g).
  • 1H-NMR (400 MHz, CDCl3) 0.73 (d, J=6.76 Hz, 3H), 1.00 (s, 6H), 1.05 (d, J=7.00 Hz, 3H), 1.27 (t, J=7.00 Hz, 2H), 1.50 (t, J=6.52 Hz, 2H), 1.69 (s, 3H), 1.85-1.92 (m, 1H), 1.95-1.97 (m, 2H), 2.28-2.32 (m, 2H), 2.67 (t, J=6.64 Hz, 2H), 3.78 (t, J=6.64 Hz, 2H), 4.13-4.19 (m, 2H), 4.62 (s, 1H), 5.58-5.61 (m, 1H), 5.91 (s, 1H), 7.11 (d, J=7.97 Hz), 7.25 (dd, J=7.97, 1.93 Hz, 1H), 7.38 (d, J=1.93 Hz, 1H)
    • Step 8 3-{((S)-4-[3-Chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00185
  • 3-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester (48.3 g) was mixed in ethanol (480 mL). To the reaction solution was added 4M aqueous sodium hydroxide solution (51 mL) under ice cooling, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then thereto was added water (960 mL). To the reaction solution was added 2M hydrochloric acid (102 mL) under ice cooling, and the reaction solution was stirred under ice cooling for 3 hours. The precipitated solid was filtered to give the titled compound (41 g) as a crystal. The specific optical rotation of the resulted compound was [α]D 25=+106.1° (c=1.00, methanol). The melting point of the resulted crystal was 90-95° C.
  • The resulted compound was analyzed using a chiral column, and the retention time of the resulted titled compound (S-enantiomer) was 9.2 minutes, the optical purity of which was >99% ee.
  • The analytical condition in the chiral column is shown as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid=30:70:0.1
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Example 116 Preparation of 3-{(S)-4-[3-chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid A Method for Preparation Using Cleisen Reaction Step 1 4-Bromo-3-chloro-N-methoxy-N-methylbenzamide
  • Figure US20190359575A1-20191128-C00186
  • 4-Bromo-3-chlorobenzoic acid (25.0 g), N,O-dimethylhydroxylamine hydrochloride (12.4 g), 1-hydroxybenzotriazolemonohydrate (19.5 g), and triethylamine (22.2 mL) were mixed in N,N-dimethylformamide (100 mL). To the reaction solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.4 g) under ice cooling, and the reaction solution was stirred at room temperature overnight. To the reaction solution was added 5 w/v % aqueous sodium hydrogen carbonate solution, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (31 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 3.36 (d, J=1.16 Hz, 3H), 3.55 (d, J=0.92 Hz, 3H), 7.47 (dt, J=8.17, 1.50 Hz, 1H), 7.66 (dd, J=8.32, 1.16 Hz, 1H), 7.81 (t, J=1.50 Hz, 1H)
    • Step 2 1-(4-Bromo-3-chloro-phenyl)-propan-1-one
  • Figure US20190359575A1-20191128-C00187
  • 4-Bromo-3-chloro-N-methoxy-N-methylbenzamide (31 g) was mixed in tetrahydrofuran (60 mL). To the reaction solution was added dropwise 0.97M ethylmagnesium bromide/tetrahydrofuran solution (141 mL) under ice cooling, and the reaction solution was stirred at room temperature for 1.5 hours. To the reaction solution was added 2M hydrochloric acid (140 mL) under ice cooling, which was then extracted with toluene. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (26.80 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.22 (t, J=7.17 Hz, 3H), 2.96 (q, J=7.17 Hz, 2H), 7.68 (dd, J=8.44, 1.97 Hz, 1H), 7.72 (d, J=8.32 Hz, 1H), 8.02 (d, J=1.85 Hz, 1H)
    • Step 3 2-(4-Bromo-3-chloro-phenyl)-propionic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00188
  • 1-(4-Bromo-3-chloro-phenyl)-propan-1-one (26.80 g) and iodobenzene diacetate (36.9 g) were mixed in trimethyl orthoformate (250 mL). To the reaction solution was slowly added concentrated sulfuric acid (11.1 mL) under water cooling, and the reaction solution was stirred at 60° C. for 3 hours. To the reaction solution was added water, which was then extracted with ethyl acetate. The organic layer was washed sequentially with aqueous sodium sulfite solution, water, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (55.3 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.48 (d, J=7.17 Hz, 3H), 3.23 (dd, J=7.40, 0.46 Hz, 1H), 3.67 (d, J=0.46 Hz, 3H), 7.06 (dd, J=8.32, 2.08 Hz, 1H), 7.40 (d, J=2.08 Hz, 1H), 7.55 (d, J=8.32 Hz, 1H)
    • Step 4 2-(4-Bromo-3-chloro-phenyl)-propionic Acid
  • Figure US20190359575A1-20191128-C00189
  • 2-(4-Bromo-3-chloro-phenyl)-propionic acid methyl ester (55.3 g) was mixed in tetrahydrofuran (100 mL) and methanol (100 mL). To the reaction solution was added 2M aqueous sodium hydroxide solution (150 mL), and the reaction solution was stirred at 60° C. for 1.5 hours. To the reaction solution was added 2M aqueous sodium hydroxide solution (50 mL), and the reaction solution was further stirred for 3.5 hours. The reaction solution was concentrated under reduced pressure, and to the resulted residue was added hexane (150 mL), which was separated. The aqueous layer was washed again with hexane (150 mL), and then thereto was added 2M hydrochloric acid (200 mL), which was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, a mixed solution which toluene was added to the filtrate was concentrated under reduced pressure to give the titled compound (21.6 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.51 (d, J=7.17, 3H), 3.70 (q, J=7.17 Hz, 1H), 7.08 (dd, J=8.21, 2.20 Hz, 1H), 7.42 (d, J=2.08 Hz, 1H), 7.57 (t, J=6.01 Hz, 1H), 10.63 (s, 1-H)
    • Step 5 (E)-4-Methyl-pent-2-en-1-ol
  • Figure US20190359575A1-20191128-C00190
  • (E)-4-methyl-pent-2-enoic acid methyl ester (20.7 g) was mixed in dichloromethane (50 mL). To the reaction solution was added dropwise 1M diisobutylaluminum hydride/dichloromethane solution (300 mL) at −78° C., and the reaction solution was stirred at −78° C. for 1 hour. To the reaction solution was added methanol (45 mL), and then the reaction solution was warmed to room temperature. The reaction solution was added dropwise to 1M aqueous sulfuric acid solution (150 mL), and then extracted with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound in dichloromethane solution (35.1 w/w %, 57.3 g).
  • 1H-NMR (400 MHz, CDCl3) 1.00 (d, J=6.94 Hz, 6H), 1.25 (s, 1H), 2.31 (td, J=13.58, 6.78 Hz, 1H), 4.09 (d, J=5.78 Hz, 2H), 5.59 (tdd, J=10.63, 5.20, 0.89 Hz, 1H), 5.67 (ddt, J=15.26, 6.17, 0.90 Hz, 1H)
    • Step 6 2-(4-Bromo-3-chloro-phenyl)-propionic acid (E)-4-methyl-pent-2-enyl Ester
  • Figure US20190359575A1-20191128-C00191
  • 35.1 w/w % of (E)-4-methyl-pent-2-en-1-ol/dichloromethane solution (28.8 g) and 4-dimethylaminopyridine (11.4 g) were mixed in dichloromethane (200 mL). To the reaction solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.9 g) under ice cooling, and the reaction solution was stirred for 30 minutes. To the reaction solution was added a mixed solution of 2-(4-bromo-3-chloro-phenyl)-propionic acid (22.0 g) in dichloromethane (100 mL), and the reaction solution was stirred at room temperature overnight. To the reaction solution was added water (200 mL), which was then extracted with chloroform. The organic layer was washed sequentially with 1M aqueous hydrochloric acid solution, 5 w/v % aqueous sodium hydrogen carbonate solution, water, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel chromatography (toluene:hexane=1:2) to give the titled compound (20.8 g).
  • 1H-NMR (400 MHz, CDCl3) 0.97 (d, J=6.47 Hz, 6H), 1.48 (d, J=7.17 Hz, 3H), 2.28 (td, J=13.35, 6.70 Hz, 1H), 3.66 (q, J=7.24 Hz, 1H), 4.51 (dd, J=6.59, 3.35 Hz, 2H), 5.44 (dtd, J=15.45, 6.36, 1.35 Hz, 1H), 5.66 (ddt, J=15.49, 6.47, 1.18 Hz, 1H), 7.07 (dd, J=8.32, 2.08 Hz, 1H), 7.41 (d, J=2.08 Hz, 1H), 7.55 (d, J=8.09 Hz, 1H)
    • Step 7 2-(4-Bromo-3-chloro-phenyl)-3-isopropyl-2-methyl-pent-4-enoic Acid
  • Figure US20190359575A1-20191128-C00192
  • 2-(4-Bromo-3-chloro-phenyl)-propionic acid (E)-4-methyl-pent-2-enyl ester (17.5 g) was mixed in tetrahydrofuran (200 mL). To the reaction solution was added dropwise 1.17M lithium hexamethyldisilazane/tetrahydrofuran solution (45.3 mL) at −41° C., and the reaction solution was stirred at −41° C. for 1 hour. To the reaction solution was added dropwise chlorotrimethylsilane (12.8 mL), and then the reaction solution was stirred at −41° C. for 30 minutes and then stirred at room temperature overnight. To the reaction solution was added 1M aqueous hydrochloric acid solution, which was then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give the titled compound (18.0 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 0.71 (d, J=6.70 Hz, 2.01H), 0.76 (d, J=6.70 Hz, 2.01H), 0.86 (d, J=6.70 Hz, 0.99H), 0.96 (d, J=6.70 Hz, 0.99H), 1.57 (ddd, J=13.47, 6.65, 3.99 Hz, 0.67H), 1.60 (s, 2.01H), 1.61 (s, 0.99H), 1.78 (ddd, J=13.47, 6.65, 3.99 Hz, 0.33H), 2.78 (dd, J=9.13, 2.89 Hz, 0.33H), 2.81 (dd, J=10.06, 2.66 Hz, 0.67H), 4.71 (dd, J=16.88, 1.62 Hz, 0.33H), 4.87 (dd, J=10.17, 2.08 Hz, 0.33H), 5.15 (dd, J=13.87, 2.31 Hz, 0.67H), 5.18 (dd, J=7.28, 2.20 Hz, 0.67H), 5.31 (dt, J=19.42, 8.50 Hz, 0.33H), 5.70 (dt, J=19.19, 8.38 Hz, 0.67H), 7.17 (dd. J=8.32, 2.31 Hz, 0.33H), 7.28 (dd, J=8.67, 2.43 Hz, 0.67H), 7.48 (d, J=2.31 Hz, 0.33H), 7.50 (d, J=8.55 Hz, 0.33H), 7.57 (d. J=8.55 Hz, 0.67H), 7.59 (d. J=2.31 Hz, 0.67H), 10.3 (s, 1H)
    • Step 8 1-Bromo-2-chloro-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene
  • Figure US20190359575A1-20191128-C00193
  • 2-(4-Bromo-3-chloro-phenyl)-3-isopropyl-2-methyl-pent-4-enoic acid (18.0 g) and triethylamine (10.6 mL) were mixed in toluene (300 mL). To the reaction solution was added diphenyl phosphoryl azide (16.3 mL), and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel chromatography (chloroform:hexane=1:4) to give the titled compound (15.5 g).
  • 1H-NMR (400 MHz, CDCl3) 0.69 (d, J=6.47 Hz, 1.05H), 0.70 (d, J=6.94 Hz, 1.95H), 0.83 (d, J=6.94 Hz, 1.05H), 0.86 (d, J=6.94 Hz, 1.95H), 1.40-1.48 (m, 0.35H), 1.63 (s, 1.05H), 1.76 (s, 1.95H), 1.99-2.06 (m, 0.65H), 2.16 (dd, J=10.17, 2.31 Hz, 0.65H), 2.20 (dd, J=9.94, 2.54 Hz, 0.35H), 4.88 (dd, J=16.99, 1.97 Hz, 0.65H), 5.13 (dd, J=10.29, 1.97 Hz, 0.65H), 5.18 (dd, J=16.88, 2.08 Hz, 0.35H), 5.38 (dd, J=10.29, 1.97 Hz, 0.35H), 5.60 (dt, J=19.27, 8.50 Hz, 0.65H), 5.84 (dt, J=19.03, 8.44 Hz, 0.35H), 7.10 (dd, J=8.55, 2.31 Hz, 0.65H), 7.14 (dd, J=8.55, 2.31 Hz, 0.35H), 7.45 (d, J=2.31 Hz, 0.65H), 7.51 (d, J=2.31 Hz, 0.35H), 7.55 (d, J=8.32 Hz, 0.65H), 7.59 (d, J=8.32 Hz, 0.35H)
    • Step 9 3-{3-[1-(4-Bromo-3-chloro-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00194
  • 1-Bromo-2-chloro-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene (13.76 g) and triethylamine (11.2 mL) were mixed in tetrahydrofuran (100 mL). To the reaction solution was added 3-amino-propionic acid ethyl ester hydrochloride (7.4 g) under ice cooling, and the reaction solution was stirred at room temperature overnight. To the reaction solution was added 1M aqueous hydrochloric acid solution (100 mL), which was then extracted with ethyl acetate. The organic layer was washed sequentially with 1M hydrochloric acid, 5 w/v % aqueous sodium hydrogen carbonate solution, water, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give the titled compound (18.5 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 0.32 (d, J=6.70 Hz, 1.02H), 0.59 (d, J=6.70 Hz, 1.98H), 0.76 (d, J=6.70 Hz, 1.98H), 0.84 (d, J=6.94 Hz, 1.02H), 1.25 (t, J=7.05 Hz, 1.98H), 1.25 (t, J=7.17 Hz, 1.02H), 1.45-1.53 (m, 1H), 1.71 (s, 1.98H), 1.83 (s, 1.02H), 1.98 (dd, J=10.52, 1.97 Hz, 0.66H), 1.99 (dd, J=10.52, 1.50 Hz, 0.34H), 2.38 (td, J=5.84, 1.77 Hz, 1.32H), 2.42 (t, J=5.90 Hz, 0.68H), 3.25-3.41 (m, 2H), 4.11 (q, J=7.17 Hz, 1.32H), 4.11 (q, J=7.17 Hz, 0.68H), 4.57 (t, J=6.01 Hz, 0.66H), 4.66 (t, J=6.13 Hz, 0.34H), 4.93 (s, 1H), 5.07 (dd, J=16.88, 1.85 Hz, 0.34H), 5.22 (dd, J=17.34, 2.54 Hz, 0.66H), 5.26 (dd, J=10.87, 2.31 Hz, 0.34H), 5.37 (dd, J=10.06, 1.97 Hz, 0.66H), 5.59 (dt, J=19.50, 8.44 Hz, 0.34H), 5.79 (dt, J=19.42, 8.50 Hz, 0.66H), 7.09 (dd, J=8.55, 2.31 Hz, 0.34H), 7.20 (dd, J=8.32, 2.31 Hz, 0.66H), 7.41 (d, J=2.31 Hz, 0.34H), 7.51 (d, J=2.31 Hz, 0.66H), 7.53 (d, J=8.32 Hz, 0.34H), 7.56 (d, J=8.32 Hz, 0.66H)
    • Step 10 3-[4-(4-Bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00195
  • 3-{3-[1-(4-Bromo-3-chloro-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionic acid ethyl ester (18.5 g) was mixed in methanol (100 mL) and dichloromethane (50 mL). The reaction solution was stirred at −78° C. for 3 hours under ozone flow. The reaction solution was then stirred at −78° C. for 30 minutes under nitrogen flow. To the reaction solution was added methylsulfide (15 mL) at −78° C., and the reaction solution was warmed to room temperature. To the reaction solution was added ethanol (50 mL), and the mixed solution was concentrated under reduced pressure. To the resulted residue was added 2M hydrogen chloride/ethanol solution (50 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel chromatography (ethyl acetate:chloroform=1:4) and then recrystallized from a mixed solution of hexane-diisopropylether (1:1) to give the titled compound (6.19 g).
  • 1H-NMR (400 MHz, CDCl3) 0.68-0.74 (m, 3H), 1.00-1.07 (m, 3H), 1.26 (s, 3H), 1.68 (s, 3H), 1.80-1.89 (m, 1H), 2.60-2.67 (m, 2H), 3.72-3.78 (m, 2H), 4.08-4.19 (m, 2H), 4.82 (brs, 1H), 5.91 (s, 1H), 7.15-7.21 (m, 1H), 7.47-7.51 (m, 1H), 7.53-7.58 (m, 1H)
    • Step 11 3-{4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00196
  • 3-[4-(4-Bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic acid ethyl ester (200 mg), 2-(4,4-dimethyl-1-cyclohexenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (160 mg) and tripotassium phosphate (287 mg) were mixed in 1,2-dimethoxyethane (4 mL) and water (1 mL) under argon gas. To the reaction solution was added bis(triphenylphosphine)palladium (II) dichloride (16 mg), and the reaction solution was stirred at 100° C. overnight. To the reaction solution was added ethyl acetate at room temperature, and then an insoluble was removed on a filter. The filtrate was washed sequentially with water and aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel chromatography (ethyl acetate:hexane=1:3), followed by thin layer silica gel chromatography (methanol:chloroform=1:30) to give the titled compound (180 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.73 (d, J=6.76 Hz, 3H), 1.00 (s, 6H), 1.05 (d, J=7.00 Hz, 3H), 1.27 (t, J=7.00 Hz, 2H), 1.50 (t, J=6.52 Hz, 2H), 1.69 (s, 3H), 1.85-1.92 (m, 1H), 1.95-1.97 (m, 2H), 2.28-2.32 (m, 2H), 2.67 (t, J=6.64 Hz, 2H), 3.78 (t, J=6.64 Hz, 2H), 4.13-4.19 (m, 2H), 4.62 (s, 1H), 5.58-5.61 (m, 1H), 5.91 (s, 1H), 7.11 (d, J=7.97 Hz, 1H), 7.25 (dd, J=7.97, 1.93 Hz, 1H), 7.38 (d, J=1.93 Hz, 1H)
    • Step 12 3-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00197
  • 3-{4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester (racemate/190 mg) was purified with recycling preparative chromatograph to give 71 mg as a fraction compound eluted later (analytical column DAICEL CHIRALPAK IA-3, retention time 6.4 minutes) and 75 mg as a fraction compound eluted earlier (analytical column DAICEL CHIRALPAK IA-3, retention time 4.1 minutes).
  • The separation condition in the recycling preparative chromatograph is shown as follows.
  • Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.
    Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm
    Mobile phase; hexane:2-propanol=90:10
    Flow rate; 10.0 mL/min
    • Detection; UV (254 nm)
  • The analytical condition in a chiral column is shown as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; hexane:2-propanol=90:10
    Flow rate; 1.0 mL/min
    • Detection; UV (254 nm)
  • The retention time of the compound obtained in the next step by hydrolysis of the compound as a fraction eluted later in a chiral column coincided with that in the chiral column of the compound obtained by the method using the optically active sulfinamide in Example 116 Step 8. The compound obtained as a fraction eluted later was thus estimated as an S-enantiomer.
    • Step 13 3-{(S)-4-[3-Chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00198
  • 3-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester (25 mg) was mixed in tetrahydrofuran (0.5 mL) and methanol (1 mL), and thereto was added 1 M aqueous sodium hydroxide solution (0.16 mL) at room temperature. The reaction solution was stirred at 50° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and then thereto was added water. To the mixed solution was added 1M hydrochloric acid (0.2 mL) under ice cooling, and then the mixed solution was stirred at room temperature. The precipitated solid was filtered to give the titled compound (19 mg). The resulted compound was analyzed by a chiral column, and the retention time of the resulted titled compound (S-enantiomer) was 9.2 minutes, the optical purity of which was >99% ee.
  • The analytical condition in the chiral column is shown as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid-30:70:0.1
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Example 115 (the Enantiomer of Example 116) 3-{(R)-4-[3-Chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-i-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00199
  • 3-{(R)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid ethyl ester obtained by Example 116 Step 12 was treated according to Example 116 Step 13 to give the titled compound (25 mg). The retention time of the resulted enantiomer (R-enantiomer) was 6.0 minutes.
  • The analytical condition in the chiral column is shown as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid=30:70:0.1
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Example 130 Preparation of 4-{4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-methyl-pentanoic Acid (an Optically Active Compound) Step 1 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanoic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00200
  • Diisopropylamine (14.3 mL) and tetrahydrofuran (70 mL) were mixed under argon gas. To the reaction solution was added dropwise 1.55M n-butyllithium/hexane solution (65.8 mL) at −78° C., and the reaction solution was stirred for 10 minutes under ice cooling. To the reaction solution was added dropwise a mixed solution of isobutanoic acid ethyl ester (13.6 mL) in tetrahydrofuran (70 mL) at −78° C., and the reaction solution was stirred at −78° C. for 1.5 hours. To the reaction solution was added dropwise a mixed solution of 3-bromopropoxy-tert-butyldimethylsilane (23.9 mL) in tetrahydrofuran (30 mL) at −78° C. and the reaction solution was stirred at −78° C. for 5.5 hours and then stirred at room temperature for 3 days. To the reaction solution was added aqueous saturated ammonium chloride solution, which was then extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20) to give the titled compound (26.4 g).
  • 1H-NMR (400 MHz, CDCl3) 0.04 (s, 6H), 0.89 (s, 9H), 1.17 (s, 6H), 1.24 (t, J=7.25 Hz, 3H), 1.41-1.50 (m, 2H), 1.56-1.51 (m, 2H), 3.58 (t, J=6.45 Hz, 2H), 4.11 (q, J=6.85 Hz, 2H)
    • Step 2 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentan-1-ol
  • Figure US20190359575A1-20191128-C00201
  • 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanoic acid ethyl ester (26.5 g) was mixed in tetrahydrofuran (200 mL) under argon gas. To the reaction solution was added dropwise 1M diisobutylaluminum hydride/toluene solution (210 mL) at −78° C., and the reaction solution was stirred at −78° C. for 40 minutes. To the reaction solution were added ethyl acetate and 1 M aqueous Rochelle salt solution (500 mL), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed sequentially with 0.5M hydrochloric acid (2×200 mL), water (2×200 mL), saturated aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated to give the titled compound (24.3 g).
  • 1H-NMR (400 MHz, CDCl3) 0.06 (s, 6H), 0.87 (s, 6H), 0.90 (s, 9H), 1.25-1.29 (m, 2H), 1.46-1.56 (m, 2H), 3.32 (s, 2H), 3.60 (t, J=6.45 Hz, 2H)
    • Step 3 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanal
  • Figure US20190359575A1-20191128-C00202
  • 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentan-1-ol (24.3 g) and triethylamine (38.2 mL) were mixed in dichloromethane (100 mL). To the reaction solution was added dropwise a mixed solution of sulfur trioxide pyridine complex (20.1 g) in DMSO (130 mL) under ice cooling, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (100 mL), which was then extracted with ethyl acetate. The organic layer was washed sequentially with 0.5M hydrochloric acid (3×200 mL), water (150 mL), saturated aqueous sodium hydrogen carbonate solution (100 mL), and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated to give the titled compound (25.2 g).
  • 1H-NMR (400 MHz, CDCl3) 0.04 (s, 6H), 0.89 (s, 9H), 1.05 (s, 6H), 1.47-1.41 (m, 2H), 1.54-1.48 (m, 2H), 3.59 (t, J=6.45 Hz, 2H), 9.45 (s, 1H)
    • Step 4 (E)-7-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enoic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00203
  • Sodium hydride (60 w/w %) (4.40 g) was mixed in tetrahydrofuran (100 mL) under argon gas. To the reaction solution was added dropwise ethyl diethylphosphonoacetate (21.8 mL) under ice cooling, and the reaction solution was stirred at room temperature for 40 minutes. To the reaction solution was added dropwise a mixed solution of 5-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanal (21.9 g) in tetrahydrofuran (50 mL) under ice cooling, and the reaction solution was stirred at room temperature for 75 minutes. To the reaction solution was added aqueous saturated ammonium chloride solution (150 mL) under ice cooling, which was extracted with ethyl acetate. The organic layer was washed sequentially with water (150 mL) and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20) to give the titled compound (27.1 g).
  • 1H-NMR (400 MHz, CDCl3) 0.04 (s, 6H), 0.89 (s, 9H), 1.05 (s, 6H), 1.29 (t, J=7.05 Hz, 3H), 1.36-1.47 (m, 4H), 3.56 (t, J=6.04 Hz, 2H), 4.19 (q, J=7.25 Hz, 2H), 5.72 (d, J=16.12 Hz, 1H), 6.90 (d, J=16.12 Hz, 1H)
    • Step 5 (E)-7-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-en-1-ol
  • Figure US20190359575A1-20191128-C00204
  • (E)-7-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enoic acid ethyl ester (27.1 g) was mixed in tetrahydrofuran (200 mL) under argon gas. To the reaction solution was added dropwise 1M diisobutylaluminum hydride/toluene solution (190 mL) at −78° C., and the reaction solution was stirred at −78° C. for 1.5 hours. To the reaction solution was added 0.5M hydrochloric acid (200 mL), which was then extracted with ethyl acetate (500 mL). The organic layer was washed sequentially with 0.5M hydrochloric acid (2×150 mL), water (150 mL), saturated aqueous sodium hydrogen carbonate solution (100 mL), and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated to give the titled compound (23.6 g).
  • 1H-NMR (400 MHz, CDCl3) 0.04 (s, 6H), 0.89 (s, 9H), 0.99 (s, 6H), 1.22 (brs, 1H), 1.31-1.27 (m, 2H), 1.40-1.48 (m, 2H), 3.56 (t, J=6.85 Hz, 2H), 4.11 (d, J=5.24 Hz, 2H), 5.53 (dt, J=15.72, 5.64 Hz, 1H), 5.63 (dt, J=15.72, 0.81 Hz, 1H)
    • Step 6 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic Acid (E)-7-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enyl Ester
  • Figure US20190359575A1-20191128-C00205
  • 2-[3-Chloro-4-(3,3-dimethylbutyl)phenyl]propionic acid (21.3 g), 7-(tert-butyldimethylsilyloxy)-4,4-dimethyl-2-heptenol (21.6 g), and 4-dimethylaminopyridine (11.6 g) were mixed in dichloromethane (250 mL). To the reaction solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.2 g) under ice cooling, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added water (150 mL), which was then extracted with ethyl acetate (500 mL). The organic layer was washed sequentially with water (150 mL) and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20) to give the titled compound (40.1 g).
  • 1H-NMR (400 MHz, CDCl3) 0.04 (s, 6H), 0.89 (s, 9H), 0.95 (s, 6H), 0.97 (s, 9H), 1.23-1.27 (m, 2H), 1.35-1.47 (m, 4H), 1.47 (d, J=7.25 Hz, 3H), 2.63-2.67 (m, 2H), 3.55 (t, J=6.45 Hz, 2H), 3.66 (q, J=7.12 Hz, 1H), 4.52 (dt, J=6.45, 1.21 Hz, 2H), 5.38 (dt, J=15.72, 6.45 Hz, 1H), 5.59 (dt, J=15.72, 1.21 Hz, 1H), 7.11 (dd, J=7.66, 1.61 Hz, 1H), 7.15 (d, J=8.06 Hz, 1H), 7.28 (d, J=1.61 Hz, 1H)
    • Step 7 7-(tert-Butyl-dimethyl-silanyloxy)-2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2,4,4-trimethyl-3-vinyl-heptanoic Acid
  • Figure US20190359575A1-20191128-C00206
  • Diisopropylamine (22.7 mL) was mixed in tetrahydrofuran (200 mL) under argon gas. To the reaction solution was added dropwise 1.55M n-butyllithium/hexane solution (100 mL) at −78° C., and the reaction solution was stirred under ice cooling for 20 minutes. To the reaction solution was added dropwise a mixed solution of 2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid (E)-7-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enyl ester (40.1 g) in tetrahydrofuran (250 mL) at −78° C., and the reaction solution was stirred under ice cooling for 1 hour. To the reaction solution was added chlorotrimethylsilane (20.8 mL) at −78° C., and the reaction solution was stirred at −78° C. for 1.5 hours and then stirred at room temperature for 19.5 hours. To the reaction solution was added 1M hydrochloric acid (312 mL) under ice cooling, which was then extracted with ethyl acetate (500 mL). The organic layer was washed sequentially with 18 w/v % aqueous sodium chloride solution (300 mL) and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:4) to give the titled compound (14.5 g).
  • 1H-NMR (400 MHz, CDCl3) 0.03 (s, 3.0H), 0.05 (s, 3.0H), 0.51 (s, 1.5H), 0.78 (s, 1.5H), 0.89 (s, 4.5H), 0.90 (s, 4.5H), 0.93 (s, 1.5H), 0.95 (s, 4.5H), 0.97 (s, 4.5H), 1.02 (s, 1.5H), 1.20-1.60 (m, 6.0H), 1.71 (s, 1.5H), 1.72 (s, 1.5H), 2.59-2.67 (m, 2.0H), 3.07-3.11 (m, 1.0H), 3.45 (t, J=6.85 Hz, 1.0H), 3.57 (t, J=7.25 Hz, 1.0H), 4.56 (dd, J=16.92, 2.01 Hz, 0.5H), 4.74 (dd, J=10.28, 2.22 Hz, 0.5H), 5.13-5.17 (m, 1.0H), 5.24-5.34 (m, 0.5H), 5.84-5.93 (m, 0.5H), 7.07 (d, J=8.06 Hz, 0.5H), 7.13 (d, J=8.46 Hz, 0.5H), 7.28-7.24 (m, 0.5H), 7.39 (d, J=2.01 Hz, 0.5H), 7.46 (dd, J=8.46, 2.01 Hz, 0.5H), 7.58 (d, J=2.01 Hz, 0.5H)
    • Step 8 tert-Butyl-(5-{1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-isocyanatoethyl}-4,4-dimethyl-hept-6-enyloxy)-dimethyl-silane
  • Figure US20190359575A1-20191128-C00207
  • 7-(tert-Butyl-dimethyl-silanyloxy)-2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2,4,4-trimethyl-3-vinyl-heptanoic acid (7.17 g) and triethylamine (2.86 mL) were mixed in toluene (100 mL). To the reaction solution was added diphenyl phosphoryl azide (4.42 mL), and the reaction solution was stirred at 110° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:60) to give the titled compound (5.12 g).
  • 1H-NMR (400 MHz, CDCl3) 0.02 (s, 3.0H), 0.04 (s, 3.0H), 0.53 (s, 1.5H), 0.75 (s, 1.5H), 0.81 (s, 1.5H), 0.88 (s, 4.5H), 0.89 (s, 4.5H), 0.91 (s, 1.5H), 0.98 (s, 4.5H), 0.98 (s, 4.5H), 1.12-1.48 (m, 6.0H), 1.60 (s, 1.5H), 1.81 (s, 1.5H), 2.34-2.42 (m, 1.0H), 2.64-2.69 (m, 2.0H), 3.36-3.41 (m, 1.0H), 3.49 (t, J=6.45 Hz, 1.0H), 4.77 (dd, 3=17.13, 1.81 Hz, 0.5H), 5.06-5.12 (m, 1.0H), 5.29 (dd, J=10.07, 2.01 Hz, 0.5H), 5.74-5.83 (m, 0.5H), 5.88-5.98 (m, 0.5H), 7.28-7.13 (m, 2.0H), 7.33 (d, J=2.01 Hz, 0.5H), 7.37 (d, J=2.01 Hz, 0.5H)
    • Step 9 {6-(tert-Butyl-dimethyl-silanyloxy)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3,3-trimethyl-3-vinyl-hexyl}-urea
  • Figure US20190359575A1-20191128-C00208
  • tert-Butyl-(5-{-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-isocyanatoethyl}-4,4-dimethyl-hept-6-enyloxy)-dimethyl-silane (552 mg) was mixed in tetrahydrofuran (10 mL). To the reaction solution was added 2M ammonia/methanol solution (3.18 mL), and the reaction solution was stirred at room temperature for 18.5 hours. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel column chromatography (ethyl acetate:hcxane=2:1) to give the titled compound (574 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.02 (s, 3.0H), 0.03 (s, 3.0H), 0.51 (s, 1.5H), 0.74 (s, 1.5H), 0.76 (s, 1.5H), 0.84 (s, 1.5H), 0.88 (s, 4.5H), 0.88 (s, 4.5H), 0.97 (s, 4.5H), 0.98 (s, 4.5H), 1.13-1.48 (m, 6.0H), 1.84 (s, 1.5H), 1.88 (s, 1.5H), 2.22 (d, J=10.48 Hz, 0.5H), 2.34 (d, J=10.88 Hz, 0.5H), 2.63-2.69 (m, 2.0H), 3.35-3.41 (m, 1.0H), 3.46 (t, J=5.91 Hz, 1.0H), 3.95 (s, 1.0H), 4.15 (s, 1.0H), 4.85 (dd, J=17.13, 1.81 Hz, 0.5H), 5.09 (dd, J=10.07, 2.01 Hz, 0.5H), 5.23-5.31 (m, 1.0H), 5.39-5.43 (m, 1.0H), 5.70-5.80 (m, 0.5H), 5.94-6.04 (m, 0.5H), 7.13-7.20 (m, 1.5H), 7.36-7.32 (m, 1.0H), 7.49 (d, J=1.61 Hz, 0.5H)
    • Step 10 4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-(4-hydroxy-1,1-dimethyl-butyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one (Optically Active Compound)
  • Figure US20190359575A1-20191128-C00209
  • {6-(tert-Butyl-dimethyl-silanyloxy)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3,3-trimethyl-3-vinyl-hexyl}-urea (574 mg) was mixed in methanol (10 mL). The reaction solution was stirred at −78° C. for 1 hour under ozone flow. To the reaction solution were added dimethylsulfide (0.785 mL) at −78° C. and then 2M hydrochloric acid/methanol solution (1.06 mL) under ice cooling. The reaction solution was stirred overnight, which was then concentrated. To the resulted residue was added saturated aqueous sodium hydrogen carbonate solution, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated. The resulted residue was purified through silica gel column chromatography (methanol:chloroform=1:10) to give a racemate of the titled compound (257 mg).
  • The racemate was separated and purified by a recycling preparative chromatograph.
  • The titled compound (103 mg) was obtained as a comound in a fraction eluted later in a recycling preparative chromatograph (separation condition A2).
  • The compound was analyzed in the analytical condition B2, and the retention time was 5.6 minutes and the optical purity was >99% ee.
  • The enantiomer of the titled compound was obtained as a compound in a fraction eluted earlier in a recycling preparative chromatograph (separation condition A2).
  • The compound was analyzed in the analytical condition B2, and the retention time was 3.8 minutes.
  • The separation condition is shown as follows.
    • (Separation Condition A2)
  • Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan
    • Analytical Industry Co., Ltd.
  • Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm
    Mobile phase; hexane:2-propanol=80:20
    Flow rate; 10.0 mL/min
    • Detection; UV (254 nm)
  • The analytical condition in the chiral column is shown as follows.
    • (Analytical Condition B2)
  • Measuring instrument: HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm
    Column temperature: 40° C.
    Mobile phase; hexane:2-propanol=80:20
    Flow rate; 1.0 mL/min
    • Detection; UV (254 nm)
  • 1H-NMR (400 MHz, CDCl3) 0.84 (s, 3H), 0.97 (s, 3H), 0.98 (s, 9H), 1.24-1.48 (m, 6H), 1.84 (s, 3H), 2.65-2.69 (m, 2H), 3.55-3.45 (m, 2H), 4.66 (s, 1H), 6.07 (d, J=5.24 Hz, 1H), 6.60 (s, 1H), 7.17 (d, J=8.06 Hz, 1H), 7.31 (dd, J=8.06, 2.01 Hz, 1H), 7.46 (d, J=2.01 Hz, 1H)
    • Step 11 4-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-butyl)-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-methyl-pentanal (Optically Active Compound)
  • Figure US20190359575A1-20191128-C00210
  • 4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-(4-hydroxy-1,1-dimethyl-butyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one (22.6 mg) obtained in the previous step was mixed in chloroform (2.0 mL). To the reaction solution was added Dess-Martin Periodinane (67.7 mg) under ice cooling, and the reaction solution was stirred under ice cooling for 1 hour. To the reaction solution were added 10 w/v % aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution, which was then extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated to give the titled compound (25.1 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.86 (s, 3H), 0.98 (s, 9H), 0.99 (s, 3H), 1.27-1.19 (m, 1H), 1.42-1.47 (m, 2H), 1.49-1.56 (m, 1H), 1.84 (s, 3H), 2.24-2.32 (m, 2H), 2.65-2.69 (m, 2H), 4.62 (s, 1H), 6.07 (d, J=5.24 Hz, 1H), 6.43 (s, 1H), 7.17 (d, J=8.06 Hz, 1H), 7.30 (dd, J=8.06, 2.01 Hz, 1H), 7.46 (d, J=2.01 Hz, 1H), 9.66 (t, J=1.21 Hz, 1H)
    • Step 12 4-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-methyl-pentanoic acid (Optically Active Compound)
  • Figure US20190359575A1-20191128-C00211
  • 4-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-methyl-pentanal (25.1 mg) obtained in the previous step, 2-methyl-2-butene (0.0588 mL), and 1M aqueous sodium dihydrogenphosphate solution (0.555 mL) were mixed in tert-butanol (1.5 mL) and acetonitrile (3.0 mL). To the reaction solution was added 0.166M aqueous sodium chlorite solution (0.500 mL), and the reaction solution was stirred at room temperature for 2.5 hours. To the reaction solution were added 10 w/v % aqueous sodium sulfite solution and 1 M hydrochloric acid, which was then extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated. The resulted residue was purified through thin layer silica gel chromatography (methanol:chloroform=1:9) to give the titled compound (13.4 mg).
    • Example 154 Preparation of 3-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylic Acid Step 1 4-Benzyloxy-butylaldehyde
  • Figure US20190359575A1-20191128-C00212
  • 4-Benzyloxy-butan-1-ol (5.0 g), potassium bromide (0.66 g), and 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (43.1 mg) were mixed in toluene (15 mL), ethyl acetate (15 mL), and water (3 mL). To the reaction solution were added dropwise a mixed solution of potassium hydrogen carbonate (5.55 g) in water (15 mL) and then 15 w/w % aqueous sodium hypochlorite solution (16.5 mL) under ice cooling. The reaction solution was stirred under ice cooling for 1.5 hours. To the reaction solution was added 15 w/w % aqueous sodium hypochlorite solution (4 mL), and the reaction solution was stirred for additional 2 hours. The reaction solution was extracted with toluene. The organic layer was washed sequentially with water, a mixed solution of potassium iodide (73 mg) in 1M hydrochloric acid (5 mL), a mixed solution of sodium thiosulfate (2.3 g) and potassium carbonate (4.02 g) in water (8.3 mL), and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (4.08 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.91-1.99 (m, 2H), 2.55 (td, J=7.05, 1.62 Hz, 2H), 3.51 (t, J=6.13 Hz, 2H), 4.49 (s, 2H), 7.15-7.37 (m, 5H), 9.79 (t, J=1.62 Hz, 1H)
    • Step 2 1-((E)-4-Benzyloxy-but-1-enyl)-piperidine
  • Figure US20190359575A1-20191128-C00213
  • 4-Benzyloxy-butylaldehyde (4.08 g) and Molecular Sieves 4A (15.8 g) were mixed in toluene (55 mL). To the reaction solution was added a mixed solution of piperidine (1.36 mL) in toluene (15 mL) under ice cooling, and the reaction solution was stirred at room temperature overnight. After removing an insoluble on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (5.24 g) as a crude product.
  • 1H-NMR (400 MHz, DMSO-D6) 1.38-1.65 (m, 6H), 2.13-2.20 (m, 2H), 2.69 (t, J=5.09 Hz, 4H), 3.35 (t, J=7.05 Hz, 2H), 4.17-4.25 (m, 1H), 4.44 (s, 2H), 5.86 (d, J=13.87 Hz, 1H), 7.14-7.36 (m, 5H)
    • Step 3 3-(2-Benzyloxy-ethyl)-2-piperidin-1-yl-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00214
  • 1-((E)-4-Benzyloxy-but-1-enyl)-piperidine (5.24 g) and hydroquinone (13.2 mg) were mixed in acetonitrile (3.45 mL). To the reaction solution was added ethyl acrylate (1.89 mL), and the reaction solution was stirred at 85° C. overnight. The reaction solution was concentrated under reduced pressure to give the titled compound (6.45 g) as a crude product.
  • 1H-NMR (400 MHz, DMSO-D6) 1.15 (t, J=7.05 Hz, 3H), 1.30-2.35 (m, 16H), 2.65-2.79 (m, 1H), 3.36-3.45 (m, 3H), 4.00-4.08 (m, 2H), 4.42 (s, 2H), 7.16-7.36 (m, 5H)
    • Step 4 3-(2-Benzyloxy-ethyl)-cyclobut-1-enecarboxylic Acid
  • Figure US20190359575A1-20191128-C00215
  • 3-(2-Benzyloxy-ethyl)-2-piperidin-1-yl-cyclobutanecarboxylic acid ethyl ester (6.45 g) was mixed in methyl p-toluenesulfonate (1.92 mL). The reaction solution was stirred at 105° C. for 1 hour. The reaction solution was cooled to 50° C., and water (13.5 mL) was added thereto. To the reaction solution was added potassium hydroxide (3.04 g, 85%) under ice cooling, and then the reaction solution was stirred at 45° C. overnight. The reaction solution was washed sequentially with diethylether and a mixed solution of diethylether-hexane solution (1:1). Concentrated hydrochloric acid was added to the aqueous layer under ice cooling so that the aqueous layer was adjusted to pH 1, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (4.57 g) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.82-1.88 (m, 8H), 2.50 (t, J=7.17 Hz, 1H), 2.84-2.93 (m, 2H), 3.51-3.56 (m, 2H), 4.51 (s, 3H), 6.98 (d, J=0.92 Hz, 1H), 7.26-7.38 (m, 5H)
    • Step 5 trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic Acid
  • Figure US20190359575A1-20191128-C00216
  • 3-(2-Benzyloxy-ethyl)-cyclobut-1-enecarboxylic acid (4.57 g) and zinc (4.17 g) were mixed in tetrahydrofuran (53 mL) and water (21.2 mL). To the reaction solution was added dropwise concentrated hydrochloric acid (31.8 mL) under ice cooling, and the reaction solution was stirred at room temperature for 2.5 hours. Tetrahydrofuran was distilled away under reduced pressure, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (acetone:hexane=1:9->1:6) to give the titled compound (2.93 g).
  • 1H-NMR (400 MHz, CDCl3) 1.78 (q, J=6.73 Hz, 2H), 1.92-2.01 (m, 3H), 2.38-2.59 (m, 5H), 3.09-3.17 (m, 1H), 3.43 (t, J=6.73 Hz, 2H), 4.48 (s, 2H), 7.26-7.36 (m, 5H)
    • Step 6 trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00217
  • trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic acid (2.93 g), 4-dimethylaminopyridine (0.15 g), 1-hydroxybenzotriazole monohydrate, and ethanol (0.86 mL) were mixed in chloroform. To the reaction solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.84 g) under ice cooling, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and water was added to the resulted residue, which was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:16) to give the titled compound (2.37 g).
  • 1H-NMR (400 MHz, CDCl3) 1.26 (t, J=7.13 Hz, 4H), 1.78 (q, J=6.82 Hz, 2H), 1.89-1.96 (m, 2H), 2.35-2.44 (m, 2H), 2.47-2.54 (m, 1H), 3.03-3.11 (m, 1H), 3.42 (t, J=6.82 Hz, 2H), 4.14 (q, J=7.13 Hz, 3H), 4.48 (s, 2H), 7.24-7.36 (m, 1H)
    • Step 7 trans-3-(2-Hydroxy-ethyl)-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00218
  • trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic acid ethyl ester (2.37 g) was mixed in tetrahydrofuran (24 mL). To the reaction solution was added 10 w/w % palladium hydroxide/activated carbon (0.24 g), and the reaction solution was stirred at room temperature for 3.5 hours at an ordinary pressure under hydrogen gas. After removing palladium hydroxide/activated carbon on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:4->1:3->1:1.5) to give the titled compound (1.24 g).
  • 1H-NMR (400 MHz, CDCl3) 1.19 (brs, 1H), 1.26 (t, J=7.17 Hz, 3H), 1.74 (q, J=6.94 Hz, 2H), 1.87-1.97 (m, 2H), 2.37-2.45 (m, 2H), 2.46-2.55 (m, 1H), 3.04-3.13 (m, 1H), 3.57-3.64 (m, 2H), 4.14 (q, J=7.17 Hz, 3H)
    • Step 8 trans-3-Carboxymethyl-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00219
  • trans-3-(2-Hydroxy-ethyl)-cyclobutanecarboxylic acid ethyl ester (1.24 g) and 2,2,6,6-tetramethylpiperidine-1-oxyl free radical (39 mg) were mixed in acetonitrile (12 mL) and 1M phosphate buffer (5.5 mL). To the reaction solution were added sodium chlorite (0.91 g) and 15 w/w % aqueous sodium hypochlorite solution (74 μL) under ice cooling, and the reaction solution was stirred under ice cooling for 5 minutes and then stirred at room temperature for 4 hours. To the reaction solution was added aqueous sodium sulfite solution under ice cooling, and the reaction solution was stirred at room temperature for 30 minutes. An aqueous potassium hydrogensulfate solution was added to the reaction solution so that the aqueous layer was adjusted to pH 2, which was then extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (methanol:chloroform-1:20) to give the titled compound (1.18 g).
  • 1H-NMR (400 MHz, CDCl3) 1.26 (t, J=7.17 Hz, 4H), 1.98-2.05 (m, 2H), 2.46-2.53 (m, 2H), 2.61-2.65 (m, 1H), 2.67-2.71 (m, 1H), 2.75-2.87 (m, 1H), 3.06-3.14 (m, 1H), 4.15 (q, J=7.17 Hz, 2H)
    • Step 9 trans-3-(Benzyloxycarbonylaminomethyl)-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00220
  • trans-3-Carboxymethyl-cyclobutanecarboxylic acid ethyl ester (1.18 g), benzylalcohol (1.05 mL), and triethylamine (3.8 mL) were mixed in toluene (12 mL). To the reaction solution was added diphenyl phosphoryl azide (1.6 mL) under ice cooling, and the reaction solution was stirred at room temperature for 15 minutes, then at 100° C. for 1 hour, and then at 70° C. for 7 hours. To the reaction solution was added water at room temperature, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water, aqueous potassium hydrogensulfate solution, aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:9->1:4->1:3) to give the titled compound (0.85 g).
  • 1H-NMR (400 MHz, CDCl3) 1.25 (t, J=7.17 Hz, 3H), 1.93-2.00 (m, 2H), 2.33-2.40 (m, 2H), 2.50-2.55 (m, 1H), 3.06-3.13 (m, 1H), 3.27-3.31 (m, 2H), 4.14 (q, J=7.17 Hz, 3H), 4.72 (brs, 1H), 5.10 (s, 2H), 7.30-7.38 (m, 5H)
    • Step 10 trans-3-Aminomethyl-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00221
  • trans-3-(Benzyloxycarbonylaminomethyl)-cyclobutanecarboxylic acid ethyl ester (400 mg) was mixed in ethanol. To the reaction solution was added 10 w/w % palladium/activated carbon (60 mg), and the reaction solution was stirred at room temperature overnight at an ordinary pressure under hydrogen gas overnight. After removing palladium/activated carbon on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (232 mg) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.26 (t, J=7.17 Hz, 3H), 1.92-1.98 (m, 2H), 2.34-2.43 (m, 3H), 2.76-2.79 (m, 2H), 3.04-3.12 (m, 1H), 4.15 (q, J=7.17 Hz, 3H)
    • Step 11 trans-3-Isocyanatomethyl-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00222
  • 3-Aminomethyl-cyclobutanecarboxylic acid ethyl ester (232 mg) was mixed in dichloromethane (5.5 mL) and saturated aqueous sodium hydrogen carbonate solution (5.5 mL). To the reaction solution was added triphosgene (134 mg) under ice cooling, and the reaction solution was stirred under ice cooling for 3 hours. The reaction solution was extracted with chloroform. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (236 mg) as a crude product.
  • 1H-NMR (400 MHz, CDCl3) 1.27 (t, J=7.11 Hz, 3H), 2.01-2.08 (m, 2H), 2.37-2.45 (m, 2H), 2.58-2.68 (m, 1H), 3.04-3.13 (m, 1H), 3.36 (d, J=6.70 Hz, 2H), 4.16 (q, J=7.11 Hz, 2H)
    • Step 12 3-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureidomethyl)-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00223
  • (R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol (130 mg) obtained according to Example 87 (a method for preparation using an optically active sulfinamide) Steps 1 to 8 was mixed in tetrahydrofuran (0.5 mL). To the reaction solution was added a mixed solution of trans-3-isocyanatomethyl-cyclobutanecarboxylic acid ethyl ester (56 mg) in tetrahydrofuran (0.5 mL) under ice cooling, and the reaction solution was stirred at room temperature overnight. To the reaction solution was added N,N,N′-trimethylethylenediamine (10 μl), which was then concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (acetone:chloroform=1:6) to give the titled compound (128 mg, d.r.=79:21).
  • 1H-NMR (400 MHz, CDCl3) 0.22 (d, J=6.94 Hz, 0.69H), 0.75 (d, J=6.94 Hz, 2.31H), 0.80 (d, J=6.94 Hz, 2.31H), 0.95 (d, J=6.94 Hz, 0.69H), 0.97 (s, 2.07H), 0.98 (s, 6.93H), 1.25 (t, J=7.17 Hz, 3H), 1.40-1.49 (m, 2.77H), 1.64-1.87 (m, 6.23H), 2.14-2.40 (m, 3H), 2.63-2.69 (m, 2H), 2.94-3.19 (m, 3H), 3.71-4.03 (m, 3H), 4.09-4.15 (m, 2H), 7.15-7.21 (m, 1H), 7.24-7.30 (m, 1H), 7.35-7.43 (m, 2H)
    • Step 13 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00224
  • 3-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureidomethyl)-cyclobutanecarboxylic acid ethyl ester (128 mg) and iodobenzene diacetate (90 mg) were mixed in dichloromethane (1.3 mL). To the reaction solution was added 2,2,6,6-tetramethylpiperidine-1-oxyl free radical (2 mg) under ice cooling, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added trifluoroacetic acid (0.74 μl), and the reaction solution was stirred for 1 hour. To the reaction solution was added dropwise aqueous sodium sulfite solution under ice cooling, and then thereto was added dropwise aqueous sodium hydrogen carbonate solution so that the aqueous layer was adjusted to pH 6. The resulted mixed solution was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:3), followed by purification by recycling preparative chromatograph to give the titled compound (72 mg).
  • The separation condition is shown as follows.
  • Separation instrument; Recycling preparative chromatograph LC-9225 NEXT SERIES Japan
    • Analytical Industry Co., Ltd.
  • Column; DAICEL CHIRALPAK IA-3 2.0 cmφ×25 cm
    Mobile phase; hexane:2-propanol=90:10
    Flow rate; 10.0 mL/min
    • Detection; UV (220 nm)
  • 1H-NMR (400 MHz, CDCl3) 0.72 (d, J=6.82 Hz, 3H), 0.98 (s, 9H), 1.05 (d, J=6.82 Hz, 3H), 1.26 (t, J=7.13 Hz, 3H), 1.42-1.47 (m, 2H), 1.68 (s, 3H), 1.86-1.94 (m, 1H), 2.04-2.11 (m, 2H), 2.35-2.42 (m, 2H), 2.63-2.77 (m, 3H), 3.09-3.18 (m, 1H), 3.58 (d, J=7.63 Hz, 2H), 4.15 (q, J=7.09 Hz, 2H), 4.62 (brs, 1H), 5.81 (s, 1H), 7.16 (d, J=8.04 Hz, 1H), 7.23 (dd, J=8.04, 1.91 Hz, 1H), 7.37 (d, J=1.81 Hz, 1H)
    • Step 14 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylic Acid
  • Figure US20190359575A1-20191128-C00225
  • 3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylic acid ethyl ester (72 mg) was mixed in tetrahydrofuran (360 μl) and methanol (360 μl). To the reaction solution was added dropwise 2M aqueous sodium hydroxide solution (296 μl) under ice cooling, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and thereto was added water. To the mixed solution was added 1M hydrochloric acid (590 μl) under ice cooling, and then the mixed solution was stirred at room temperature. The precipitated solid was filtered to give the titled compound (59 mg).
  • The specific optical rotation of the resulted compound was [α]D 25=+141.20 (c=0.05, methanol).
  • The resulted compound was analyzed by a chiral column, and the retention time of the resulted titled compound was 10.1 minutes.
  • The analytical condition in the chiral column is shown as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid=30:70:0.1
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Example 159 Preparation of 4-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoic Acid Step 1 (S)-2-Methyl-propane-2-sulfinic acid {(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide
  • Figure US20190359575A1-20191128-C00226
  • (R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-3-((S)-2-methyl-propane-sulfinylamino)-butyric acid methyl ester (3.39 g) prepared according to Example 87 (a method for preparation using an optically active sulfinamide) Steps 1 to 6 was mixed in tetrahydrofuran (30 mL). To the reaction solution was added dropwise 1M isobutylaluminum hydride/toluene solution (22.4 mL) at −78° C., and the reaction solution was stirred under ice cooling for 2.5 hours. To the reaction solution was added saturated aqueous Rochelle salt solution, which was then extracted with ethyl acetate. The organic layer was washed sequentially with aqueous saturated sodium chloride solution and water, and then concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:2) to give the titled compound (3.01 g).
    • Step 2 (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol
  • Figure US20190359575A1-20191128-C00227
  • (S)-2-Methyl-propane-2-sulfinic acid {(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide (3.0 g) was mixed in methanol (15 mL). To the reaction solution was added 2M hydrogen chloride/methanol solution (11.2 mL) under ice cooling, and the reaction solution was left to stand at room temperature overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added saturated sodium carbonate solution under ice cooling so that the aqueous layer was adjusted to be alkaline. The mixed solution was extracted with chloroform, and the organic layer was dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (2.37 g) as a crude product.
    • Step 3 4-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-benzoic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00228
  • (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol (100 mg) was mixed in tetrahydrofuran (1.5 mL). To the reaction solution was added 4-isocyanatebenzoic acid ethyl ester (59 mg) under ice cooling, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 4-isocyanatebenzoic acid ethyl ester (34 mg), and the reaction solution was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (methanol:chloroform=5:95) to give the titled compound (139 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.74-0.83 (m, 3H), 0.83-0.88 (m, 3H), 0.92-1.01 (m, 9H), 1.30-1.49 (m, 5H), 1.85-2.03 (m, 5H), 2.54-2.67 (m, 1H), 3.76-4.02 (m, 1H), 4.28-4.40 (m, 2H), 6.24-6.42 (m, 1H), 7.10-7.56 (m, 5H), 7.85-8.03 (m, 2H)
    • Step 4 4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoic Acid Ethyl Ester
  • Figure US20190359575A1-20191128-C00229
  • 4-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-benzoic acid ethyl ester (139 mg) and iodobenzene diacetate (182 mg) were mixed in dichloromethane (3.0 mL). To the reaction solution was added 2,2,6,6-tetramethylpiperidine 1-oxyl (4.0 mg) under ice cooling, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution was added saturated aqueous sodium sulfite solution under ice cooling, which was then extracted with chloroform. The organic layer was dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=3:1) to give the titled compound (33 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.70-0.78 (m, 3H), 0.97 (s, 9H), 1.06-1.12 (m, 3H), 1.34-1.41 (m, 3H), 1.42-1.49 (m, 2H), 1.79 (s, 3H), 1.92-2.03 (m, 1H), 2.63-2.71 (m, 2H), 4.30-4.42 (m, 2H), 5.07 (brs, 1H), 6.18 (s, 1H), 7.13-7.23 (m, 1H), 7.27-7.34 (m, 1H), 7.38-7.49 (m, 3H), 8.00-8.11 (m, 2H)
    • Step 5 4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoic Acid
  • Figure US20190359575A1-20191128-C00230
  • 4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoic acid ethyl ester (33 mg) was mixed in ethanol (1.0 mL) and tetrahydrofuran (1.0 mL). To the reaction solution was added 2M aqueous sodium hydroxide solution (0.132 mL), and the reaction solution was stirred at room temperature for 90 minutes, and then stirred at 70° C. so that the reaction solution became cloudy. The reaction solution was concentrated under reduced pressure, and then thereto was added 2M aqueous hydrochloric acid solution (0.132 mL). The precipitated solid was filtered to give the titled compound (21 mg).
  • The specific optical rotation of the resulted compound was [α]D 25=+87.5° (c=0.25, methanol).
  • The resulted compound was analyzed by a chiral column, and the retention time of the resulted titled compound was 16.2 minutes.
  • The analytical condition in a chiral column is shown as follows.
  • Measuring instrument; HPLC system Shimadzu Corporation high-performance liquid chromatograph prominence
    Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm
    Column temperature; 40° C.
    Mobile phase; water:acetonitrile:formic acid-30:70:0.1
    Flow rate; 1.0 mL/min
    • Detection; UV (220 nm) Example 226 Step 1 4-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-2-methoxy-benzoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00231
  • (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol (181 mg, corresponding to 0.5 mmol) prepared according to Example 159 (a method for preparation using an optically active sulfinamide) Steps 1 to 2 was mixed in tetrahydrofuran (5.0 mL), and thereto was added 4-isocyanate-2-methoxy-benzoic acid methyl ester (114 mg) under ice cooling. A cooling bath was removed, and the reaction solution was stirred at room temperature overnight. The resulted solution was then concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=4:1) to give the titled compound (139 mg).
    • Step 2 4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-2-methoxy-benzoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00232
  • 4-(3-{((R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-2-methoxy-benzoic acid methyl ester (139 mg) and dichloromethane (2.0 mL) were mixed, and thereto were added 2,2,6,6-tetramethylpiperidine 1-oxyl (4.0 mg) and iodobenzene diacetate (92 mg) under ice cooling. A cooling bath was removed, and the reaction solution was stirred for about 3 hours. Then trifluoroacetic acid (119 mg) was added to the reaction solution. The reaction solution was stirred at room temperature for 80 minutes, and then thereto were added saturated aqueous sodium sulfite solution and chloroform, which was separated. The organic layer was dried over sodium sulfate. After filtered through sodium sulfate, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=2:3), followed by prufication by thin layer silica gel chromatography (ethyl acetate:hexane=1:1) to give the titled compound (81 mg).
    • Step 3 4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-2-methoxy-benzoic Acid
  • Figure US20190359575A1-20191128-C00233
  • 4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-2-methoxy-benzoic acid methyl ester (68 mg), methanol (2.0 mL), and tetrahydrofuran (1.0 mL) were mixed. To the reaction solution was added 2M aqueous sodium hydroxide solution (0.2 mL) at room temperature, which was stirred at 70° C. for about 3 hours. The reaction solution was concentrated under reduced pressure, and then thereto was added 2M aqueous hydrochloric acid solution (0.2 mL). The precipitated solid was filtered and dried at 60° C. to give the titled compound (58 mg).
    • Example 229 Step 1 cis-(3-Hydroxymethyl-cyclobutyl)-acetic Acid Tert-Butyl Ester
  • Figure US20190359575A1-20191128-C00234
  • cis-3-tert-Butoxycarbonylmethyl-cyclobutanoic acid (10.0 g) was mixed with tetrahydrofuran (100 mL), and thereto was added dropwise 0.85M borane-tetrahydrofuran/tetrahydrofuran solution (82 mL) at −16° C. The reaction solution was stirred for 23 hours with naturally warming to room temperature, and then thereto was added 6M hydrochloric acid (20 mL). The reaction solution was concentrated, and then thereto were added ethyl acetate and water, which was separated. The organic layer was washed sequentially with water (3 times) and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (8.93 g).
  • 1H-NMR (400 MHz, CDCl3) 1.43 (s, 9H), 1.45-1.51 (m, 2H), 2.18-2.25 (m, 2H), 2.29 (d, J=7.25 Hz, 2H), 2.36-2.43 (m, 1H), 2.58-2.48 (m, 1H), 3.55 (d, J=6.45 Hz, 2H)
    • Step 2 cis-(3-Hydroxymethyl-cyclobutyl)-acetic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00235
  • cis-(3-Hydroxymethyl-cyclobutyl)-acetic acid tert-butyl ester (1.25 g) was mixed with chloroform (6.0 mL), and then thereto was added trifluoroacetic acid (3.0 mL) at room temperature. The mixture was stirred for 71 hours, and then thereto was added trifluoroacetic acid (3.0 mL). The mixture was stirred at 60° C. for 1.5 hours, and then concentrated. After azeotropy with toluene (twice), the residue was mixed with methanol (9.0 mL), and thereto was added 2M trimethylsilyldiazomethane n-hexane solution (9.4 mL). The reaction solution was stirred for 1 hour at room temperature, and then thereto was added acetic acid (80 mL), which was concentrated. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:20->1:10->1:5->1:2->1:1)) to give the titled compound (983 mg).
  • 1H-NMR (400 MHz, CDCl3) 1.43-1.52 (m, 2H), 2.18-2.27 (m, 2H), 2.34-2.46 (m, 3H), 2.52-2.62 (m, 1H), 3.55 (d, J=6.28 Hz, 2H), 3.65 (s, 3H)
    • Step 3 cis-(3-Methoxymethoxymethyl-cyclobutyl)-acetic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00236
  • cis-(3-Hydroxymethyl-cyclobutyl)-acetic acid methyl ester (500 mg) was mixed with chloroform (5.0 mL), and thereto were added chloromethyl methyl ether (0.323 mL) and diisopropylethylamine (0.739 mL) under ice cooling. The reaction solution was stirred for 20 hours at room temperature, and then thereto were added ethyl acetate and 0.5M hydrochloric acid, which was separated. The organic layer was washed sequentially with 0.5N hydrochloric acid, water, aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:15->1:10) to give the titled compound (364 mg).
  • 1H-NMR (400 MHz, CDCl3) 1.44-1.53 (m, 2H), 2.22-2.29 (m, 2H), 2.39 (d, J=7.25 Hz, 2H), 2.43-2.49 (m, 1H), 2.52-2.62 (m, 1H), 3.35 (s, 3H), 3.44 (d, J=6.45 Hz, 2H), 3.65 (s, 3H), 4.60 (s, 2H)
    • Step 4 (R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-methoxymethyl-cyclobutyl)-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00237
  • Diisopropylamine (0.280 mL) was mixed in tetrahydrofuran (1.0 mL) under argon gas. To the reaction solution was added dropwise 1.63M n-butyllithium/hexane solution (1.20 mL) at −78° C., and the reaction solution was stirred at 0° C. for 10 minutes. To the reaction solution was added dropwise a mixed solution of (3-methoxymethoxymethyl-cyclobutyl)-acetic acid methyl ester (363 mg) in tetrahydrofuran (2.0 mL) at −78° C., which was stirred at −20° C. for additional 1.5 hours. To the reaction solution was added dropwise 1M chloro titanium (IV) triisopropoxide/hexane solution (3.70 mL) at −78° C., which was stirred at −78° C. for additional 1 hour. To the reaction solution was added dropwise a mixed solution of (S)-2-methyl-propane-2-sulfinic acid [1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-eth-(E)-ylidene]-amide (307 mg) in tetrahydrofuran (2.0 mL), which was stirred at −78° C. for 4 hours. To the reaction solution was added acetic acid (0.212 mL) at −78° C. To the reaction solution were added 10 wt/v % aqueous citric acid solution and ethyl acetate at room temperature, which was separated. The organic layer was washed sequentially with 10 wt/wt % aqueous citric acid solution and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:2->1:1->2:1) to give the titled compound (429 mg) as a diastereomer mixture.
  • 1H-NMR (400 MHz, CDCl3) 0.97-0.98 (m, 9H), 1.28-1.34 (m, 9H), 1.42-1.52 (m, 3H), 1.74-1.83 (m, 3H), 1.85-1.91 (m, 1H), 2.01-2.11 (m, 1H), 2.28-2.55 (m, 2H), 2.61-2.71 (m, 3H), 2.85-2.96 (m, 1H), 3.29-3.35 (m, 5H), 3.53-3.65 (m, 3H), 4.53-4.60 (m, 2H), 5.03-5.28 (m, 1H), 7.12-7.21 (m, 2H), 7.41-7.37 (m, 1H)
    • Step 5 (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00238
  • (R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-methoxymethoxymethyl-cyclobutyl)-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoic acid methyl ester (315 mg) was mixed with methanol (3.0 mL), and thereto was added 2M hydrogen chloride/methanol solution (0.458 mL) under ice cooling. The reaction solution was stirred at room temperature for 21 hours, and then thereto were added 2N aqueous sodium hydroxide solution (0.910 mL) and saturated aqueous sodium hydrogen carbonate solution under ice cooling. To the reaction solution was added ethyl acetate, which was separated. Then the organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=2:1->4:1->ethyl acetate:methanol=20:1) to give a diastereomer compound A of the titled compound (57.5 mg) and a diastereomer compound B of the titled compound (60.3 mg), respectively.
    • (Diastereomer Compound A of the Titled Compound)
  • 1H-NMR (400 MHz, CDCl3) 0.81-0.89 (m, 1H), 0.97 (s, 9H), 1.39-1.49 (m, 7H), 1.93-2.01 (m, 1H), 2.13-2.21 (m, 1H), 2.46-2.53 (m, 1H), 2.64-2.68 (m, 2H), 2.79 (d, J=9.27 Hz, 1H), 3.37 (d, J=6.04 Hz, 2H), 3.68 (s, 3H), 7.14 (d, J=8.06 Hz, 1H), 7.25 (dd, J=8.06, 2.01 Hz, 1H), 7.47 (d, J=2.01 Hz, 1H)
    • (Diastereomer Compound R of the Titled Compound)
  • 1H-NMR (400 MHz, CDCl3) 0.97 (s, 9H), 1.41-1.46 (m, 7H), 2.00-2.15 (m, 2H), 2.30-2.41 (m, 1H), 2.63-2.68 (m, 3H), 2.81 (d, J=9.67 Hz, 1H), 3.41 (s, 3H), 3.50 (d, J=6.04 Hz, 2H), 7.13 (d, J=8.06 Hz, 1H), 7.22 (dd, J=8.06, 2.01 Hz, 1H), 7.40 (d, J=2.01 Hz, 1H)
    • Step 6 (R)-3-Amino-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00239
  • The diastereomer compound A of (R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoic acid methyl ester (57.0 mg) was mixed with dimethylformamide (1.0 mL), and thereto were added t-butyldimethylchlorosilane (34.3 mg) and imidazole (15.5 mg) at room temperature. The mixture was stirred for 16.5 hours, and then thereto were added ethyl acetate and water, which was separated. The organic layer was washed sequentially with water (3 times) and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:4) to give a diastereomer compound A of the titled compound (68.6 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.04 (s, 6H), 0.79-0.88 (m, 1H), 0.85 (s, 9H), 0.97 (s, 9H), 1.29-1.36 (m, 1H), 1.40 (s, 3H), 1.42-1.50 (m, 3H), 1.84-1.92 (m, 1H), 2.06-2.15 (m, 1H), 2.38-2.49 (m, 1H), 2.63-2.67 (m, 2H), 2.78 (d, J=9.67 Hz, 1H), 3.31 (d, J=5.64 Hz, 2H), 3.68 (s, 3H), 7.13 (d, J=8.06 Hz, 1H), 7.26-7.24 (m, 1H), 7.45 (d, J=2.01 Hz, 1H)
  • The diastereomer compound B of (R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoic acid methyl ester (60.0 mg) was treated in a similar way to the diastereomer compound A of (R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoic acid methyl ester to give a diastereomer compound B of the titled compound (65.0 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.02 (s, 6H), 0.89 (s, 9H), 0.97 (s, 9H), 1.38-1.45 (m, 6H), 1.50-1.58 (m, 1H), 1.92-2.03 (m, 2H), 2.24-2.32 (m, 1H), 2.57-2.66 (m, 3H), 2.79 (d, J=9.67 Hz, 1H), 3.40 (s, 3H), 3.44 (dd, J=5.64, 1.61 Hz, 2H), 7.12 (d, J=8.06 Hz, 1H), 7.22 (dd, J=8.06, 2.01 Hz, 1H), 7.40 (d, J=2.01 Hz, 1H)
    • Step 7 (R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(4-nitro-phenoxycarbonylamino)-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00240
  • The diastereomer compound A (31.3 mg) and the diastereomer compound B (28.0 mg) of (R)-3-amino-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-butanoic acid methyl ester were mixed with chloroform (1.5 mL), and thereto were added diisopropylethylamine (0.0434 mL) and a solution of chloroformic acid p-nitrophenyl ester (50.4 mg) in chloroform (0.5 mL) at room temperature. The reaction solution was stirred for 3 hours, and then concentrated under reduced pressure. The resulted residue was purified through thin layer silica gel column chromatography (ethyl acetate:hexane=1:6) to give the titled compound (51.4 mg).
    • Step 8 (R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(3-fluoro-3-methyl-cyclobutyloxycarbonylamino)-butanoic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00241
  • (R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(4-nitro-phenoxycarbonylamino)-butanoic acid methyl ester (51.4 mg) was mixed with chloroform (1.0 mL), and thereto were added 3,3-difluorocyclobutylamine hydrochloride (32.9 mg) and triethylamine (0.0478 mL). The reaction solution was stirred for 17.5 hours at 60° C., and then concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=1:8->1:6) to give the titled compound (51.3 mg).
    • Step 9 (R)-5-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-6-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(3,3-difluoro-cyclobutyl)-6-methyl-dihydro-pyrimidine-2,4-dione
  • Figure US20190359575A1-20191128-C00242
  • (R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(3-fluoro-3-methyl-cyclobutyloxycarbonylamino)-butanoic acid methyl ester (51.3 mg) was mixed with tetrahydrofuran (2.0 mL) under argon gas, and thereto was added potassium t-butoxide (12.8 mg) under ice cooling. The reaction solution was stirred for 40 minutes under ice cooling, and then thereto was added water. To the reaction solution was added ethyl acetate, which was separated. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through thin layer silica gel chromatography (ethyl acetate:hexane=1:4) to give the titled compound (36.0 mg) as a mixture of diastereomers.
  • 1H-NMR (400 MHz, CDCl3) −0.03-0.04 (m, 6H), 0.85-0.91 (m, 9H), 0.97-0.98 (m, 9H), 1.40-1.65 (m, 6H), 1.76-2.23 (m, 3H), 2.54-2.89 (m, 6H), 3.05-3.19 (m, 1H), 3.29-3.52 (m, 4H), 4.70-4.98 (m, 1H), 5.40 (brs, 1H), 7.28-7.06 (m, 3H)
    • Step 10 (S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-(3,3-difluoro-cyclobutyl)-5-(3-hydroxymethyl-cyclobutyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one
  • Figure US20190359575A1-20191128-C00243
  • Bis(cyclopentadienyl)zirconiun (IV) chloride hydride (73.6 mg) was mixed with tetrahydrofuran (3.0 mL) under argon gas. To the suspension was added a solution of (R)-5-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-6-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(3,3-difluoro-cyclobutyl)-6-methyl-dihydro-pyrimidine-2,4-dione (36.0 mg) in tetrahydrofuran (6.0 ml) at room temperature, which was then stirred. To the reaction solution was added bis(cyclopentadienyl)zirconium (IV) chloridehydride (75.0 mg), and the mixture was stirred for 20 hours. To the reaction solution was added 2N hydrochloric acid (1.0 mL) at room temperature. The reaction solution was stirred for 3 days, and then thereto were added ethyl acetate and water, which was then separated. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through thin layer silica gel chromatography (methanol:chloroform=1:15) to give the titled compound (10.6 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.98 (s, 9H), 1.34-1.47 (m, 3H), 1.58-1.70 (m, 5H), 2.09-2.28 (m, 2H), 2.39-2.48 (m, 1H), 2.65-2.69 (m, 2H), 2.76-2.89 (m, 2H), 2.93-3.03 (m, 2H), 3.49 (d, J=5.64 Hz, 2H), 4.76-4.70 (m, 1H), 4.87 (s, 1H), 5.89 (d, J=1.21 Hz, 1H), 7.17 (d, J=8.06 Hz, 1H), 7.20 (dd, J=8.06, 1.61 Hz, 1H), 7.34 (d, J=1.61 Hz, 1H)
    • Step 11 3-[(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-(3,3-difluoro-cyclobutyl)-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-cyclobutanoic Acid
  • Figure US20190359575A1-20191128-C00244
  • (S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-(3,3-difluoro-cyclobutyl)-5-(3-hydroxymethyl-cyclobutyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one (10.6 mg) was mixed with chloroform (0.5 ml), and thereto was added Dess-Martin reagent (15.9 mg) under ice cooling. The reaction solution was stirred for 20 minutes under ice cooling, and then thereto were added 10 wt/v % aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution, then ethyl acetate. After separation, the organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The residue was mixed with t-butanol (0.7 mL) and acetonitrile (1.4 mL), and thereto were added 1M aqueous sodium dihydrogenphosphate solution (0.22 mL) and an aqueous solution (0.25 mL) of 2-methyl-2-butene, sodium chlorite (3.8 mg) at room temperature. The reaction solution was stirred for 15.5 hours at room temperature, and then thereto were added sequentially 10 wt/v % aqueous sodium sulfite solution and 2N hydrochloric acid, then ethyl acetate. Aftere separation, the organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through thin layer silica gel column chromatography (methanol:chloroform=1:10) to give the titled compound (7.5 mg).
    • Example 258 Step 1 1-(4-Bromo-2-chloro-phenyl)-3-isopropyl-cyclobutanol
  • Figure US20190359575A1-20191128-C00245
  • 4-Bromo-2-chloro-1-iodobenzene (3.68 g) was mixed in tetrahydrofuran (17.8 mL). To the reaction solution was added dropwise 2M isopropylmagnesium chloride/tetrahydrofuran (5.8 mL) at −30° C., and the reaction solution was stirred at −30° C. for 40 minutes. To the reaction solution were added dropwise 0.6M lanthanum chloride bis(lithium chloride) complex/tetrahydrofuran (4.5 mL) and then a mixed solution of 3-isopropyl-cyclobutanone (1.00 g) in tetrahydrofuran (8.9 mL), and the reaction solution was stirred at −30° C. for 4 hours. To the reaction solution was added 20% aqueous ammonium chloride solution, which was then extracted with tert-butylmethylether. The organic layer was washed sequentially with 20% aqueous ammonium chloride solution, water, and 20% aqueous sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acctate:hexane=0:100->10:90) to give the titled compound (2.72 g) as a mixture of cis- and trans-isomers.
    • Step 2 4-Bromo-2-chloro-1-(3-isopropyl-cyclobut-1-enyl)-benzene
  • Figure US20190359575A1-20191128-C00246
  • 1-(4-Bromo-2-chloro-phenyl)-3-isopropyl-cyclobutanol (2.42 g) and pentatluoroanilinium trifluoromethanesulfonate (133 mg) were mixed in toluene (16.0 mL). The reaction solution was stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel column chromatography (hexane) to give the titled compound (2.02 g).
  • 1H-NMR (400 MHz, CDCl3) 0.95 (d, J=6.70 Hz, 3H), 0.98 (d, J=6.47 Hz, 3H), 1.59-1.68 (m, 1H), 2.42-2.52 (m, 2H), 2.91 (dd, J=12.72, 4.39 Hz, 1H), 6.74 (s, 1H), 7.12 (d. J=8.32 Hz, 1H), 7.34 (dd, J=8.32, 1.97 Hz, 1H), 7.50 (d, J=1.97 Hz, 1H)
    • Step 3 4-Bromo-2-chloro-1-(3-isopropyl-cyclobutyl)-benzene
  • Figure US20190359575A1-20191128-C00247
  • 4-bromo-2-chloro-1-(3-isopropyl-cyclobut-1-enyl)-benzene (2.02 g) was mixed in a mixed solution of tetrahydrofuran (10.0 mL) and methanol (10.0 mL). To the reaction solution was added 5 w/w % rhodium/activated carbon (203 mg), and the reaction solution was stirred for 3 hours at 1 atm under hydrogen gas. After removing rhodium/activated carbon on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (hexane) to give the titled compound (1.94 g). The relative configurations of substituents on the cyclobutane ring were estimated as cis-configuration by NOESY measurement.
  • 1H-NMR (400 MHz, CDCl3) 0.83 (d, J=6.70 Hz, 6H), 1.37-1.46 (m, 1H), 1.59-1.68 (m, 2H), 1.85-1.96 (m, 1H), 2.46-2.54 (m, 2H), 3.39-3.48 (m, 1H), 7.11 (d, J=8.27 Hz, 1H), 7.34 (dd, J=8.27, 2.03 Hz, 1H), 7.46 (d, J=2.03 Hz, 1H)
    • Step 4 1-[3-Chloro-4-(3-isopropyl-cyclobutyl)-phenyl]-ethanone
  • Figure US20190359575A1-20191128-C00248
  • 4-Bromo-2-chloro-1-(3-isopropyl-cyclobutyl)-benzene (1.85 g), palladium acetate (30 mg) and 1,3-bis(diphenylphosphino)propane (103 mg) were mixed in 2-ethoxyethanol (13.0 mL) under argon gas. The reaction solution was stirred at room temperature for 10 minutes, and then to the reaction solution were added N,N-diisopropylethylamine (2.8 mL) and ethyleneglycol monovinyl ether (1.8 mL). The reaction solution was stirred at 145° C. (for 2.5 hours. To the reaction solution was added 6M hydrochloric acid (3.2 mL) under ice cooling, and the reaction solution was stirred at room temperature overnight. To the reaction solution was added water, which was then extracted with tert-butylmethylether. The organic layer was washed sequentially with water and 25% aqueous sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:hexane=0:100->10:90) to give the titled compound (1.24 g).
  • 1H-NMR (400 MHz. CDCl3) 0.84 (d, J=6.70 Hz, 61H), 1.43 (d, J=34.91 Hz, 1H), 1.70 (d, J=36.07 Hz, 2H), 1.94 (d. J=42.08 Hz, 1H), 2.54-2.58 (m, 2H), 2.57 (s, 3H), 3.50-3.59 (m, 1H), 7.35 (d, J=7.98 Hz, 1H), 7.80 (dd, J=7.98, 1.74 Hz, 1H), 7.89 (d, J=1.74 Hz, 1H)
    • Step 5 3-{(S)-4-[3-Chloro-4-(3-isopropyl-cyclobutyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic Acid
  • Figure US20190359575A1-20191128-C00249
  • 1-[3-Chloro-4-(3-isopropyl-cyclobutyl)-phenyl]-ethanone was treated as a starting material in a similar manner to Example 87 (a method for preparation using an optically active sulfinamide) Steps 5 to 11 to give the titled compound (73 mg).
    • Example 271 Step 1 4-(3,3-Dimethyl-but-1-ynyl)-3-trifluoromethyl-benzoic Acid
  • Figure US20190359575A1-20191128-C00250
  • 4-Bromo-3-trifluoromethyl-benzoic acid (5.2 g), bis(triphenylphosphine)palladium (II) dichloride (678 mg), and copper iodide (185 mg) were mixed in N-methylpyrrolidone (32 mL) under argon gas. The reaction system was vacuated to replace with argon three times, and then thereto were added diisopropylamine (10.9 mL) and 3,3-dimethyl-but-1-yne (3.55 mL). The reaction solution was stirred at 60° C. overnight, and then warmed to room temperature, and to the reaction solution was added toluene (30 mL). Then thereto were added 2M aqueous sodium hydroxide solution (12 mL) and water, which wash then extracted with toluene. The resulted aqueous layer was acidified by adding 6M aqueous hydrochloric acid solution (20 mL), and ethyl acetate was added thereto, and the mixture was separated. The organic layer was washed with brine, and then dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through silica gel column chromatography (ethyl acetate:methanol-90:10). Hexane was then added to the resulted solid, and the resulted slurry was stirred and then filtered to give the titled compound (2.4 g). The filtrate was concentrated under reduced pressure, and purified through silica gel column chromatography (ethyl acetate:hexane=1:9->10:0) to give the titled compound (1.47 g).
  • 1H-NMR (400 MHz, CDCl3) 1.33 (s, 9H), 7.57-7.62 (m, 1H), 8.12-8.17 (m, 1H), 8.32-8.35 (m, 1H)
    • Step 2 4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzoic Acid
  • Figure US20190359575A1-20191128-C00251
  • 4-(3,3-Dimethyl-but-1-ynyl)-3-trifluoromethyl-benzoic acid (3.9 g) was mixed in methanol (40 mL). To the mixed solution was added 5 w/w/o platinum/activated carbon (1.16 g), and the reaction solution was stirred for two days overnight at 1 atm under hydrogen gas. After removing platinum/activated carbon on a filter from the reaction solution, the filtrate was concentrated under reduced pressure to give the titled compound (7.32 g).
  • 1H-NMR (400 MHz, CDCl3) 0.97 (s, 9H), 1.44-1.52 (m, 2H), 2.76-2.84 (m, 2H), 7.39-7.45 (m, 1H), 8.12-8.18 (m, 1H), 8.34 (brs, 1H)
    • Step 3 4-(3,3-Dimethyl-butyl)-N-methoxy-N-methyl-3-trifluoromethyl-benzamide
  • Figure US20190359575A1-20191128-C00252
  • 4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzoic acid, a crude product, (3.78 g), N,O-dimethylhydroxylamine hydrochloride (1.48 g), 1-hydroxybenzotriazolemonohydrate (211 mg), and sodium hydrogen carbonate (1.28 g) were mixed in N,N-dimethylformamide (22 mL). Then thereto was added WSC.HCl (3.04 g), and the mixture was stirred at room temperature for 3 hours and then left to stand at room temperature overnight. To the reaction solution were added water, hexane, and ethyl acetate, which was then separated, and then the aqueous layer was extracted with ethyl acetate twice. After azeotropy of the organic layer with a denatured ethanol solution, the resulted residue was purified through silica gel chromatography (ethyl acetate:hexane=8:92->1:1) to give the titled compound (4.29 g).
  • 1H-NMR (400 MHz, CDCl3) 0.96 (s, 9H), 1.44-1.50 (m, 2H), 2.72-2.79 (m, 2H), 3.36 (s, 3H), 3.54 (s, 3H), 7.31-7.36 (m, 1H), 7.76-7.81 (m, 1H), 7.95-7.98 (m, 1H)
    • Step 4 1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-phenyl]-ethanone
  • Figure US20190359575A1-20191128-C00253
  • 4-(3,3-Dimethyl-butyl)-N-methoxy-N-methyl-3-trifluoromethyl-benzamide (4.29 g) was mixed in tetrahydrotfuran (25 mL). To the reaction solution was added dropwise 0.91M methylmagnesium bromide/tetrahydrofuran solution (22.3 mL) under ice cooling, and the reaction solution was stirred under ice cooling for 40 minutes. To the reaction solution were added dropwise 1M hydrochloric acid (32 mL) and water under ice cooling, and then thereto was added ethyl acetate. After the mixed solution was separated, the aqueous layer was extracted with ethyl acetate. The resulted organic layer was dried over magnesium sulfate. After removing magnesium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (3.6 g).
    • Step 5 4-{(S)-4-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoic Acid
  • Figure US20190359575A1-20191128-C00254
  • 1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-phenyl]-ethanone was treated as a starting material in a similar manner to Example 87 (a method for preparation using an optically active sulfinamide) Steps 5 to 11 to give the titled compound (29 mg).
    • Example 281 Step 1 (R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butylamine
  • Figure US20190359575A1-20191128-C00255
  • (R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol (1.98 g) obtained according to Example 159 (a method for preparation using an optically active sulfinamide) Steps 1 to 2 was mixed with dimethylformamide (50 ml), and to the mixed solution were mixed chloro-t-butyldiphenylsilane (2.36 ml) and imidazole (620 mg) under ice cooling. The reaction solution was stirred at room temperature for 20 hours. To the reaction solution were added ethyl acetate and water, which was then separated. The organic layer was washed with water and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the reaction solution was concentrated under reduced pressure, and the resulted residue was purified through silica gel column chromatography (ethyl acetate:n-hexane) to give the titled compound (2.77 g).
  • 1H-NMR (400 MHz, CDCl3) 0.79 (d, J=7.25 Hz, 3H), 0.81 (d, J=7.25 Hz, 3H), 0.98 (s, 9H), 1.06 (s, 9H), 1.37 (s, 3H), 1.43-1.47 (m, 2H), 1.68-1.75 (m, 1H), 1.79-1.82 (m, 1H), 2.62-2.67 (m, 2H), 3.81 (d, J=5.24 Hz, 2H), 7.10 (d, J=8.06 Hz, 1H), 7.18 (dd, J=8.06, 2.01 Hz, 1H), 7.37-7.46 (m, 7H), 7.69-7.66 (m, 4H)
    • Step 2 6-(4-Nitro-phenoxycarbonylamino)-nicotinic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00256
  • 6-Amino-nicotinic acid methyl ester (100 mg) was mixed with dichloromethane (5.0 mL) and tetrahydrofuran (3.0 mL). To the mixed solution were added p-nitrophenyl chloroformate (146 mg) and pyridine (0.0798 mL) under ice cooling, which was then stirred for 1 hour. The mixture was stirred at room temperature for 15 minutes, and then a solid was filtered. The resulted solid was washed sequentially with water, tetrahydrofuran, and n-hexane, and then dried under reduced pressure to give the titled compound (57.3 mg).
  • 1H-NMR (400 MHz, DMSO-D6) 3.76 (s, 3H), 6.45 (dd, J=8.87, 0.81 Hz, 1H), 6.93 (td, J=6.35, 3.90 Hz, 2H), 7.82 (dd, J=8.87, 2.82 Hz, 1H), 8.12 (td, J=6.35, 3.90 Hz, 2H), 8.50 (dd, J=2.42, 0.81 Hz, 1H), 11.04 (s, 1H)
    • Step 3 6-(3-{(R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butyl}-ureido)-nicotinic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00257
  • (R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butylamine (71.7 mg) was mixed with chloroform (1.5 ml), and to the mixed solution were added 6-(4-nitro-phenoxycarbonylamino)-nicotinic acid methyl ester (57.3 mg) and triethylamine (0.0252 ml) at room temperature. The reaction solution was stirred at 60° C. for 3 hours, and then concentrated. The residue was purified through thin layer silica gel chromatography (chloroform:methanol=20:1) to give the titled compound (105 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.97 (s, 9H), 0.99 (s, 9H), 1.04 (d, J=6.85 Hz, 3H), 1.21 (d, J=6.85 Hz, 3H), 1.34-1.39 (m, 2H), 1.78 (s, 3H), 1.98-2.01 (m, 1H), 2.11-2.18 (m, 1H), 2.53-2.66 (m, 2H), 3.47 (dd, J=10.88, 4.03 Hz, 1H), 3.67 (dd, J=10.88, 8.87 Hz, 1H), 3.93 (s, 3H), 6.36 (d, J=8.87 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H), 7.07 (dd, J=8.06, 1.61 Hz, 1H), 7.26-7.30 (m, 3H), 7.33-7.42 (m, 4H), 7.48 (dd, J=8.06, 1.61 Hz, 2H), 7.57 (dd, J=7.66, 1.61 Hz, 2H), 8.03 (dd, J=8.87, 2.01 Hz, 1H), 8.66 (s, 1H), 8.73 (d, J=2.01 Hz, 1H), 10.05 (s, 1H)
    • Step 4 6-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-nicotinic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00258
  • 6-(3-{(R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butyl}-ureido)-nicotinic acid methyl ester (105 mg) was mixed with tetrahydrofuran (1.0 ml). To the mixed solution was added at room temperature an 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.191 ml). The mixture was stirred for 15 hours at room temperature, and then concentrated. The residue was purified through thin layer silica gel column chromatography (chloroform:methanol=20:1) to give the titled compound (62.0 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.93 (d, J=6.85 Hz, 3H), 0.96 (s, 9H), 1.15 (d, J=6.85 Hz, 3H), 1.43 (dd, J=8.87, 8.46 Hz, 2H), 1.87-1.90 (m, 1H), 1.92 (s, 3H), 2.12-2.19 (m, 1H), 2.58-2.71 (m, 2H), 3.61-3.72 (m, 2H), 3.93 (s, 3H), 6.39 (d, J=8.46 Hz, 1H), 7.16 (d, J=8.06 Hz, 1H), 7.23 (dd, J=8.06, 2.01 Hz, 1H), 7.39 (d, J=2.01 Hz, 1H), 8.05 (dd, J=8.46, 2.42 Hz, 1H), 8.79 (d, J=2.42 Hz, 1H), 8.97 (s, 1H), 10.20 (s, 1H)
    • Step 5 6-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-nicotinic Acid Methyl Ester
  • Figure US20190359575A1-20191128-C00259
  • 6-(3-{(R)-I-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-nicotinic acid methyl ester (62.0 mg) and iodobenzene diacetate (43.6 mg) were mixed in dichloromethane (1.0 mL). To the reaction solution was added 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (1.9 mg) under ice cooling, and the reaction solution was stirred at room temperature for 18 hours. To the reaction solution was added trifluoroacetic acid (0.0182 mL) under ice cooling, which was then stirred at room temperature for 4.5 hours. To the reaction solution were added aqueous sodium sulfite solution and then aqueous sodium hydrogen carbonate solution at room temperature. The resulted mixed solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure. The resulted residue was purified through thin layer silica gel column chromatography (chloroform:methanol=20:1).
  • The resulted compound was mixed with chloroform, and thereto was added trifluoroacetic acid. The reaction solution was stirred at 50° C. for 3.5 hours, and then concentrated. The residue was mixed with ethyl acetate, and washed sequentially with aqueous sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over sodium sulfate. After removing sodium sulfate on a filter, the filtrate was concentrated under reduced pressure to give the titled compound (22.5 mg).
  • 1H-NMR (400 MHz, CDCl3) 0.84 (d, J=6.85 Hz, 3H), 0.98 (s, 911), 1.17 (d, J=6.85 Hz, 3H), 1.42-1.46 (m, 2H), 1.81 (s, 3H), 1.95-2.02 (m, 1H), 2.65-2.69 (m, 2H), 3.95 (s, 3H), 5.22 (s, 1H), 7.19 (d, J=8.06 Hz, 1H), 7.30 (dd, J=8.06, 2.01 Hz, 1H), 7.39 (s, 1H), 7.44 (d, J=2.01 Hz, 1H), 8.12 (d, J=8.87 Hz, 1H), 8.25 (dd, J=8.87, 2.42 Hz, 1H), 9.01 (d, J=2.42 Hz, 1H)
    • Step 6 6-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-nicotinic Acid Hydrochloride
  • Figure US20190359575A1-20191128-C00260
  • 6-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-nicotinic acid methyl ester (22.5 mg) was mixed with ethanol (1.0 mL) and tetrahydrofuran (0.25 mL). To the reaction solution was added dropwise 2M aqueous sodium hydroxide solution (0.0465 mL) at room temperature, and the reaction solution was stirred at room temperature for 14.5 hours. To the reaction solution was added 2M hydrochloric acid at room temperature, which was then concentrated. To the residue was added a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=10:1), and an insoluble was removed on a filter. The filtrate was concentrated to give the titled compound (22.0 mg).
    • Examples 263 and 264
  • According to the following reaction scheme, the compounds of Examples 263 and 264 were prepared. In the reaction scheme, 3-[(S)-4-(4-bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic acid ethyl ester was synthesized in Example 116 Step 6.
  • Figure US20190359575A1-20191128-C00261
  • In the formula, GrubbsCat.2nd means a second-generation Grubbs catalyst, (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)-ruthenium.
    • Example 273
  • The compound of Example 273 was prepared using an optically active sulfinic acid as follows.
  • Figure US20190359575A1-20191128-C00262
    Figure US20190359575A1-20191128-C00263
    Figure US20190359575A1-20191128-C00264
    • Example 292
  • The compound of Example 292 was prepared according to the following reaction scheme.
  • Figure US20190359575A1-20191128-C00265
    • Examples 293 and 294
  • The compounds of Examples 293 and 294 were prepared using the bromo product obtained in Step 10 of the method using Cleisen reaction in Example 116 and 2-methyl-but-3-yn-2-ol.
  • Figure US20190359575A1-20191128-C00266
    • Example 296
  • The compound of Example 296 was prepared according to the following reaction scheme.
  • Figure US20190359575A1-20191128-C00267
    • Example 298
  • The compound of Example 298 was prepared according to the following reaction scheme. In the following reaction scheme, 3-[(S)-4-(4-bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionic acid ethyl ester was synthesized in Example 116 Step 6.
  • Figure US20190359575A1-20191128-C00268
    • Example 316
  • The compound of Example 316 was prepared using (3,3-difluoro-cyclobutyl)-acetic acid methyl ester as follows according to the method of Example 229.
  • Figure US20190359575A1-20191128-C00269
    • Example 320
  • The compound of Example 320 was prepared using (3,3-difluoro-cyclobutyl)-acetic acid methyl ester as follows according to the method of Example 271.
  • Figure US20190359575A1-20191128-C00270
  • According to the method of Example 87, Example 116, Example 154 or Example 159 using an optically active sulfinic acid amide (i.e., (S)-(−)-2-methyl-propane-2-sulfinic acid amide), the following Example compounds were prepared.
    • Example 38, Example 113, Example 125, Example 126, Example 127, Example 137, Example 140, Example 147, Example 150, Example 157, Example 158. Example 161, Example 162, Example 163, Example 164, Example 165, Example 173, Example 175, Example 176, Example 177, Example 178, Example 179, Example 183, Example 185, Example 189
  • According to the method using the reaction of an optically active sulfinic acid amide the following Example compounds were prepared.
  • Example 190 to Example 357, other than Example 190, Example 191, Example 197, Example 198, Example 199, Example 200, Example 205, Example 212, Example 213, and Example 312
  • According to the method of Example 87, Example 116 or Example 130 using Cleisen reacton, the following Example compounds were prepared.
    • Example 9, Example 12, Example 13, Example 14, Example 15, Example 16, Example 17, Example 18, Example 19, Example 20, Example 21, Example 22, Example 23, Example 24, Example 25, Example 26, Example 27, Example 28, Example 29, Example 30, Example 31, Example 32, Example 33, Example 34, Example 35, Example 36, Example 37, Example 38, Example 39, Example 40, Example 41, Example 42, Example 43, Example 44, Example 45, Example 46, Example 47, Example 48, Example 49, Example 50, Example 51, Example 52, Example 53, Example 54, Example 55, Example 56, Example 57, Example 58, Example 59, Example 60, Example 61, Example 63, Example 64, Example 65, Example 66, Example 67, Example 68, Example 69, Example 70, Example 71, Example 72, Example 73, Example 74, Example 75, Example 76, Example 77, Example 78, Example 79, Example 80, Example 81, Example 82, Example 83, Example 84, Example 85, Example 86, Example 88, Example 89, Example 90, Example 91, Example 92, Example 93, Example 94, Example 95, Example 96, Example 97, Example 98, Example 99, Example 100, Example 103, Example 104, Example 105, Example 106, Example 107, Example 108, Example 109, Example 110, Example 111, Example 112, Example 114, Example 115, Example 117, Example 118, Example 119, Example 120, Example 121, Example 122, Example 123, Example 124, Example 128, Example 129, Example 131, Example 132, Example 133, Example 134, Example 135, Example 136, Example 138, Example 139, Example 141, Example 142, Example 143, Example 144, Example 145, Example 146, Example 148, Example 149, Example 151, Example 152, Example 153, Example 155, Example 156, Example 160, Example 166, Example 167, Example 168, Example 169, Example 170, Example 171, Example 172, Example 174, Example 180, Example 181, Example 182, Example 184, Example 186, Example 188
  • According to the method using the Cleisen reaction, the following Example compounds were prepared.
    • Example 190, Example 191, Example 197, Example 198, Example 199, Example 200, Example 205, Example 312
  • When an Example compound is an optically active product, a desirable enantiomer was obtained by a chiral column separation and purification of a racemate intermediate (e.g. an ethyl ester intermediate).
  • For example, the following example is illustrated (see Example 87, Steps 13 and 14, a method for preparation using Cleisen reaction).
  • Figure US20190359575A1-20191128-C00271
  • Each absolute configuration of each enantiomer was estimated on the basis of the followings:
  • 1) A consistency of the retention times in a chiral column of an optically active product obtained in the method using an optically active sulfinic acid amide and an optically active product obtained by the method using Cleisen reaction and a separation using a chiral column;
    2) A certain regularity in the retention times in a chiral column of a methyl ester intermediate or an ethyl ester intermediate of a compound in the present invention and the like;
    3) A certain regularity in the strength of the biological activity value of each enantiomer of a compound in the present invention (Test Example 1); and/or
    4) Results of X-ray structural analysis of a co-crystal of a compound having an RORγ antagonist activity (i.e. a related compound having the same 4-phenyl-3,4-dihydro-1H-pyrimidin-2-one skeleton as the compound of the present invention) and RORγ.
  • Absolute configurations of parts of Example compounds and the intermediates were determined by single crystal X-ray structural analysis.
  • According to Example 5, the of following Example compounds were prepared using Biginelli reaction.
    • Example 1, Example 2, Example 3, Example 4, Example 6, Example 7, Example 8, Example 10, Example 11, Example 62, Example 101, Example 102, Example 187
  • Chemical structures and structural information of Example compounds prepared as above are shown in the following tables.
  • In the tables, i) refers to a stereochemistry of the Example compound, ii) refers to physical data (such as the retention time in a chiral column) and analytical conditions for the Example compound, or physical data (such as the retention time in a chiral column) and analytical conditions for a precursor or intermediate such as an ester of the Example compound.
  • In the tables,
  • “Chiral column IA-3” refers to CHIRALPAK IA-3 0.46 cmφ×15 cm manufactured by DAICEL Corporation, “Chiral column IC” refers to CHIRALPAK IC 0.46 cmφ×25 cm manufactured by DAICEL Corporation, “Chiral column IF-3” refers to CHIRALPAK IF-3 0.46 cmφ×15 cm manufactured by DAICEL Corporation, “Chiral column AD-3R” refers to CHIRALPAKAD-3R 0.46 cmφ×15 cm manufactured by DAICEL Corporation, and “Chiral column AS-3R” refers to CHIRALPAKAS-3R 0.46 cmφ×15 cm manufactured by DAICEL Corporation.
  • In the tables, “JAIGEL-ODS-AP-A” refers to an analytical column JAIGEL-ODS-AP-A, SP-120-10, 96×25 cm of Japan Analytical Industry Co., Ltd.
  • In the tables, for example, “Chiral column IC, IPA/Hexane=3/7, 1 ml/min, Retention time 8.1 min” refers to “Chiral column, Mobile phase, Flow rate, Retention time, used in the measurement”. “IPA” refers to isopropanol. “Hex” or “hexane” refers to n-hexane. “TFA” refers to trifluoroacetic acid.
  • In the tables, for example, “the optical purity of a methyl ester of Example 32 was >99% ee” refers to “HPLC analysis using a chiral column for a methyl ester, a synthetic precursor, of Example 32 showed that the optical purity was >99% ee”.
  • Figure US20190359575A1-20191128-C00272
  • In the tables, HPLC analyses of Examples 38, 87, and 116 using a chiral column were determined with samples synthesized by a method using Cleisen reaction.
  • The specific optical rotations were determined with samples synthesized by a method using an optically active sulfinic acid amide.
  • In the tables, Example 64, Example 278, Example 279, and Example 280 are different with each other and any one of the following isomeric compounds, respectively.
  • Figure US20190359575A1-20191128-C00273
  • TABLE 1
    Example Chemical Structural Formula Structural Information
     1
    Figure US20190359575A1-20191128-C00274
         		i) Racemate
     2
    Figure US20190359575A1-20191128-C00275
         		i) Racemate
     3
    Figure US20190359575A1-20191128-C00276
         		i) Racemate
     4
    Figure US20190359575A1-20191128-C00277
         		i) Racemate
     5
    Figure US20190359575A1-20191128-C00278
         		i) Optically active product of Example 1 Enantiomer of Example 6 ii) Optical purity was >99% ee Chiral column AS-3R, H2O/MeCN/TFA = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 13.5 min
     6
    Figure US20190359575A1-20191128-C00279
         		i) Optically active product of Example 1 Enantiomer of Example 5 ii) Optical purity was >99% ee Chiral column AS-3R, H2O/MeCN/TFA = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 16.7 min
     7
    Figure US20190359575A1-20191128-C00280
         		i) Racemate
     8
    Figure US20190359575A1-20191128-C00281
         		i) Racemate
     9
    Figure US20190359575A1-20191128-C00282
         		i) Racemate
     10
    Figure US20190359575A1-20191128-C00283
         		i) Optically active product of Example 8 Enantiomer of Example 11 ii) Optical purity was >99% ee Chiral column AS-3R, H2O/MeCN/TFA = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 13.6 min
     11
    Figure US20190359575A1-20191128-C00284
         		i) Optically active product of Example 8. Optical purity was >99% ee Enantiomer of Example 10 ii) Chiral column AS-3R, H2O/MeCN/TFA = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 12.6 min
     12
    Figure US20190359575A1-20191128-C00285
         		i) Optically active product of Example 9 Enantiomer of Example 13 ii) Optical purity of methyl ester of Example 12 was 99.9% ee Chiral column IC, IPA/hexane = 30/70, 1 ml/min, Retention time 7.1 min
     13
    Figure US20190359575A1-20191128-C00286
         		i) Optically active product of Example 9 Enantiomer of Example 12 ii) Optical purity of methyl ester of Example 13 was 98.9% ee Chiral column IC, IPA/hexane = 30/70, 1 ml/min, Retention time 8.1 min
     14
    Figure US20190359575A1-20191128-C00287
         		i) Enantiomer of Example 15 ii) Optical purity was >99% ee Chiral column AS-3R, H2O/MeCN/TFA = 40/60/0.1, Flow rate = 0.5 ml/min, Retention time 11.4 min
     15
    Figure US20190359575A1-20191128-C00288
         		i) Enantiomer of Example 14 ii) Optical purity was >99% ee Chiral column AS-3R, H2O/MeCN/TFA = 40/60/0.1, Flow rate = 0.5 ml/min, Retention time 12.7 min
     16
    Figure US20190359575A1-20191128-C00289
         		i) Racemate
     17
    Figure US20190359575A1-20191128-C00290
         		i) Racemate
     18
    Figure US20190359575A1-20191128-C00291
         		i) Racemate
     19
    Figure US20190359575A1-20191128-C00292
         		i) Single enantiomer Example 19, Example 20, and Example 21 are diastereomers with each other ii) 96.7% d.e Chiral column IC, IPA/hexane/TFA = 3/7/0.1, 1 ml/min, Retention time 5.8 min,
     20
    Figure US20190359575A1-20191128-C00293
         		i) Single enantiomer Example 19, Example 20, and Example 21 are diastereomer with each other ii) 96.2% d.e. Chiral column IC, IPA/hexane/TFA = 3/7/0.1, 1 ml/min, Retention time 5.3 min
     21
    Figure US20190359575A1-20191128-C00294
         		i) A mixture of two diastereomers Example 19, Example 20, and Example 21 are diastereomer with each other ii) Chiral column IC, IPA/hexane/TFA = 1/9/0.1, 1 ml/min, Retention time 12.9 min, 13.3 min
     22
    Figure US20190359575A1-20191128-C00295
         		i) Racemate
     23
    Figure US20190359575A1-20191128-C00296
         		i) Racemate
     24
    Figure US20190359575A1-20191128-C00297
         		i) A mixture of two diastereomers ii) Methyl ester of Example 24 analytical condition Chiral column IF-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.6 min, 8.7 min
     25
    Figure US20190359575A1-20191128-C00298
         		i) A mixture of two diastereomers ii) Methyl ester of Example 25 analytical condition Chiral column IF-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 12.5 min, 13.3 min
     26
    Figure US20190359575A1-20191128-C00299
         		i) Racemate
     27
    Figure US20190359575A1-20191128-C00300
         		i) Racemate
     28
    Figure US20190359575A1-20191128-C00301
         		i) Racemate
     29
    Figure US20190359575A1-20191128-C00302
         		i) Racemate
     30
    Figure US20190359575A1-20191128-C00303
         		i) Racemate
     31
    Figure US20190359575A1-20191128-C00304
         		i) Enantiomer of Example 32 ii) Optical purity of methyl ester of Example 31 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 3.7 min
     32
    Figure US20190359575A1-20191128-C00305
         		i) Enantiomer of Example 31 ii) Optical purity of methyl ester of Example 32 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 4.6 min
     33
    Figure US20190359575A1-20191128-C00306
         		i) A mixture of two diastereomers ii) Chiral column AS-3R, H2O/MeCN/TFA = 40/60/0.1, 0.5 ml/min, Retention time 12.60 min
     34
    Figure US20190359575A1-20191128-C00307
         		i) A mixture of two diastereomers ii) Chiral column AS-3R, H2O/MeCN/TFA = 40/60/0.1, 0.5 ml/min, Retention time 13.25 min, 14.05 min
     35
    Figure US20190359575A1-20191128-C00308
         		i) Enantiomer of Example 36 ii) Optical purity was >99.5% ee Chiral column IA-3, IPA/Hex/TFA = 5/95/0.1, 1 ml/min, Retention time 4.91 min
     36
    Figure US20190359575A1-20191128-C00309
         		i) Enantiomer of Example 35 ii) Optical purity was >99.5% ee Chiral column IA-3, IPA/Hex/TFA = 5/95/0.1, 1 ml/min, Retention time 8.08 min
     37
    Figure US20190359575A1-20191128-C00310
         		i) Enantiomer of Example 38 ii) 92% ee Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 6.5 min
     38
    Figure US20190359575A1-20191128-C00311
         		i) Enantiomer of Example 37 ii) >99% ee Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 10.0 min [α]D 25 = +106° (C = 1.00, MeOH)
     39
    Figure US20190359575A1-20191128-C00312
         		i) Enantiomer of Example 40 ii) Optical purity of methyl ester of Example 39 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 6.32 min
     40
    Figure US20190359575A1-20191128-C00313
         		i) Enantiomer of Example 39 ii) Optical purity of methyl ester of Example 40 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 9.27 min
     41
    Figure US20190359575A1-20191128-C00314
         		i) Enantiomer of Example 42 ii) Optical purity of methyl ester of Example 41 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.8 min
     42
    Figure US20190359575A1-20191128-C00315
         		i) Enantiomer of Example 41 ii) Optical purity of methyl ester of Example 42 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 10.2 min
     43
    Figure US20190359575A1-20191128-C00316
         		i) Enantiomer of Example 44 ii) Analytical condition of methyl ester of Example 43 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.0 min
     44
    Figure US20190359575A1-20191128-C00317
         		i) Enantiomer of Example 43 ii) Analytical condition of methyl ester of Example 44 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.0 min
     45
    Figure US20190359575A1-20191128-C00318
         		i) Enantiomer of Example 46 ii) Optical purity of methyl ester of Example 45 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.4 min
     46
    Figure US20190359575A1-20191128-C00319
         		i) Enantiomer of Example 45 ii) Optical purity of methyl ester of Example 46 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.7 min
     47
    Figure US20190359575A1-20191128-C00320
         		i) Enantiomer of Example 48 ii) Optical purity of methyl ester of Example 47 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.3 min
     48
    Figure US20190359575A1-20191128-C00321
         		i) Enantiomer of Example 47 ii) Optical purity of methyl ester of Example 48 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.3 min
     49
    Figure US20190359575A1-20191128-C00322
         		i) Enantiomer of Example 50 ii) Optical purity of methyl ester of Example 49 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 5.3 min
     50
    Figure US20190359575A1-20191128-C00323
         		i) Enantiomer of Example 49 ii) Optical purity of methyl ester of Example 50 was >99% ee Chiral Column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 7.3 min
     51
    Figure US20190359575A1-20191128-C00324
         		i) Enantiomer of Example 52 ii) Optical purity of methyl ester was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.0 min
     52
    Figure US20190359575A1-20191128-C00325
         		i) Enantiomer of Example 51 ii) Optical purity of methyl ester of Example 52 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.9 min
     53
    Figure US20190359575A1-20191128-C00326
         		i) Racemate
     54
    Figure US20190359575A1-20191128-C00327
         		i) Enantiomer of Example 55 ii) Optical purity of methyl ester of Example 54 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 3.65 min
     55
    Figure US20190359575A1-20191128-C00328
         		i) Enantiomer of Example 54 ii) Optical purity of methyl ester of Example 55 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 6.01 min
     56
    Figure US20190359575A1-20191128-C00329
         		i) Enantiomer of Example 57 ii) Optical purity of methyl ester of Example 56 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.8 min
     57
    Figure US20190359575A1-20191128-C00330
         		i) Enantiomer of Example 58 ii) Optical purity of methyl ester of Example 57 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.5 min
     58
    Figure US20190359575A1-20191128-C00331
         		i) Enantiomer of Example 59 ii) Optical purity of methyl ester of Example 57 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.2 min
     59
    Figure US20190359575A1-20191128-C00332
         		i) Enantiomer of Example 58 ii) Optical purity of methyl ester was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.1 min
     60
    Figure US20190359575A1-20191128-C00333
         		i) Enantiomer of Example 61 ii) Optical purity of methyl ester of Example 60 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.1 min
     61
    Figure US20190359575A1-20191128-C00334
         		i) Enantiomer of Example 60 ii) Optical purity of methyl ester of Example 61 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 9.6 min
     62
    Figure US20190359575A1-20191128-C00335
         		i) Racemate
     63
    Figure US20190359575A1-20191128-C00336
         		i) Single enantiomer Stereochemistry of cyclopentane ring not determined ii) Optical purity of methyl ester of Example 63 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.3 min
     64
    Figure US20190359575A1-20191128-C00337
         		i) Single enantiomer Stereochemistry of cyclopentane ring not determined Examples 64, 278, 279, and 280 are a diastereomer with each other ii) Optical purity of methyl ester of Example 64 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.3 min Optical purity of Example 64 was >99% ee Analytical condition of Example 64 JAIGEL-ODS-AP-A,
    MeCN/H2O/HCO2H = 90/10/0.1, Flow
    rate 1 ml/min, Retention time 9.6 min.
     65
    Figure US20190359575A1-20191128-C00338
         		i) Racemate
     66
    Figure US20190359575A1-20191128-C00339
         		i) Enantiomer of Example 67 ii) Optical purity of methyl ester of Example 66 was >98% ee Chiral column IF-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 8.69 min
     67
    Figure US20190359575A1-20191128-C00340
         		i) Enantiomer of Example 66 ii) Optical purity of methyl ester of Example 67 was >98% ee Chiral column IF-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 10.26 min
     68
    Figure US20190359575A1-20191128-C00341
         		i) Enantiomer of Example 69 ii) Optical purity of methyl ester of Example 68 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.3 min
     69
    Figure US20190359575A1-20191128-C00342
         		i) Enantiomer of Example 68 ii) Optical purity of methyl ester of Example 69 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.4 min
     70
    Figure US20190359575A1-20191128-C00343
         		i) Racemate
     71
    Figure US20190359575A1-20191128-C00344
         		i) Enantiomer of Example 72 ii) Optical purity of methyl ester of Example 71 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.2 min
     72
    Figure US20190359575A1-20191128-C00345
         		i) Enantiomer of Example 71 ii) Optical purity of methyl ester of Example 72 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.5 min
     73
    Figure US20190359575A1-20191128-C00346
         		i) Diastereomer mixture ii) Analytical condition of methyl ester of Example 73 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 3.6 min, 4.6 min, 7.0 min, 7.7 min Example 73 was prepared by hydrolysis of two diastereomer mixtures with 7.0 min and 7.7 min of retention times among the isomers.
     74
    Figure US20190359575A1-20191128-C00347
         		i) Enantiomer of Example 75 ii) Optical purity of methyl ester of Example 74 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 3.8 min
     75
    Figure US20190359575A1-20191128-C00348
         		i) Enantiomer of Example 74 ii) Optical purity of methyl ester of Example 75 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.0 min
     76
    Figure US20190359575A1-20191128-C00349
         		i) Enantiomer of Example 77 ii) Optical purity of methyl ester of Example 76 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 3.7 min
     77
    Figure US20190359575A1-20191128-C00350
         		i) Enantiomer of Example 76 ii) Optical purity of methyl ester of Example 77 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.1 min
     78
    Figure US20190359575A1-20191128-C00351
         		i) Enantiomer of Example 79 ii) Optical purity of methyl ester of Example 78 was >99.5% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 5.27 min
     79
    Figure US20190359575A1-20191128-C00352
         		i) Enantiomer of Example 78 ii) Optical purity of methyl ester of Example 79 was >99.5% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1 ml/min, Retention time 9.25 min
     80
    Figure US20190359575A1-20191128-C00353
         		i) Racemate
     81
    Figure US20190359575A1-20191128-C00354
         		i) Racemate
     82
    Figure US20190359575A1-20191128-C00355
         		i) Enantiomer of Example 83 ii) Optical purity of methyl ester of Example 82 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 4.2 min
     83
    Figure US20190359575A1-20191128-C00356
         		i) Enantiomer of Example 82 ii) Optical purity of methyl ester of Example 83 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 6.3 min
     84
    Figure US20190359575A1-20191128-C00357
         		i) Racemate
     85
    Figure US20190359575A1-20191128-C00358
         		i) Racemate
     86
    Figure US20190359575A1-20191128-C00359
         		i) Enantiomer of Example 87 ii) Optical purity of ethyl ester was >99% ee Analytical condition of ethyl ester of Example 86 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.9 min Optical purity of Example 86 was >99% ee Analytical condition of Example 86 Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 6.0 min
     87
    Figure US20190359575A1-20191128-C00360
         		i) Enantiomer of Example 86 ii) Optical purity of ethyl ester was >99% ee Analytical condition of ethyl ester of Example 87 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.1 min Optical purity of Example 87 was >99% ee Analytical condition of Example 87 Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min Retention time 9.0 min
    [α]D 25 = +112.6° (C = 1.00, MeOH)
     88
    Figure US20190359575A1-20191128-C00361
         		i) Diastereomer of Example 89 ii) Optical purity of methyl ester of Example 88 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 3.7 min
     89
    Figure US20190359575A1-20191128-C00362
         		i) Diastercomer of Example 88 ii) Optical purity of methyl ester of Example 89 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 5.6 min
     90
    Figure US20190359575A1-20191128-C00363
         		i) Racemate
     91
    Figure US20190359575A1-20191128-C00364
         		i) Enantiomer of Example 92 ii) Optical purity of methyl ester of Example 91 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 4.5 min
     92
    Figure US20190359575A1-20191128-C00365
         		i) Enantiomer of Example 91 ii) Optical purity of methyl ester of Example 92 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 7.5 min
     93
    Figure US20190359575A1-20191128-C00366
         		i) Enantiomer of Example 94 ii) Optical purity of methyl ester of Example 93 was >99% ee Chiral column IA-3, hexane/IPA = 90/1.0, Flow rate 1 ml/min, Retention time 5.3 min
     94
    Figure US20190359575A1-20191128-C00367
         		i) Enantiomer of Example 93 ii) Optical purity of methyl ester of Example 94 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.8 min
     95
    Figure US20190359575A1-20191128-C00368
         		i) Enantiomer of Example 96 ii) Analytical condition of methyl ester of Example 95 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.0 min
     96
    Figure US20190359575A1-20191128-C00369
         		i) Enantiomer of Example 95 ii) Analytical condition of methyl ester of Example 96 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 9.7 min
     97
    Figure US20190359575A1-20191128-C00370
         		i) Enantiomer of Example 98 ii) Optical purity of ethyl ester of Example 97 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.2 min
     98
    Figure US20190359575A1-20191128-C00371
         		i) Enantiomer of Example 97 ii) Optical purity of ethyl ester of Example 98 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.2 min
     99
    Figure US20190359575A1-20191128-C00372
         		i) Enantiomer of Example 100 ii) Optical purity of methyl ester of Example 99 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 4.3 min
    100
    Figure US20190359575A1-20191128-C00373
         		i) Enantiomer of Example 99 ii) Optical purity of methyl ester of Example 100 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 8.9 min
    101
    Figure US20190359575A1-20191128-C00374
         		i) Enantiomer of Example 102 ii) Analytical condition of methyl ester of Example 101 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 7.3 min
    102
    Figure US20190359575A1-20191128-C00375
         		i) Enantiomer of Example 101 ii) Analytical condition of methyl ester of Example 102 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 7.9 min
    103
    Figure US20190359575A1-20191128-C00376
         		i) Enantiomer of Example 104 ii) Optical purity of methyl ester of Example 103 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.7 min
    104
    Figure US20190359575A1-20191128-C00377
         		i) Enantiomer of Example 103 ii) Optical purity of methyl ester of Example 104 was >99% ee Chiral column IA-3 hexane/IPA = 90/1.0, Flow rate 1 ml/min, Retention time 12.4 min
    105
    Figure US20190359575A1-20191128-C00378
         		i) Racemate
    106
    Figure US20190359575A1-20191128-C00379
         		i) Racemate
    107
    Figure US20190359575A1-20191128-C00380
         		i) Enantiomer of Example 108 ii) Optical purity of methyl ester of Example 107 was >99% ee Chiral column IA-3, hexane/IPA = 80/10, Flow rate 1 ml/min, Retention time 3.4 min The relative configuration of substituents on the cyclobutane ring was estimated as trans-isomer
    108
    Figure US20190359575A1-20191128-C00381
         		i) Enantiomer of Example 107 ii) Optical purity of methyl ester of Example 108 was >99% ee Chiral column IA-3, hexane/IPA = 80/10, Flow rate 1 ml/min, Retention time 4.9 min
    109
    Figure US20190359575A1-20191128-C00382
         		i) Enantiomer of Example 110 ii) Analytical condition of methyl ester of Example 109 Chiral column IA-3, hexane/IPA = 90/10 Flow rate 1 ml/min, Retention time 5.7 min
    110
    Figure US20190359575A1-20191128-C00383
         		i) Enantiomer of Example 109 ii) Analytical condition of methyl ester of Example 110 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 9.3 min
    111
    Figure US20190359575A1-20191128-C00384
         		i) Enantiomer of Example 112 ii) Optical purity of methyl ester of Example 111 was 86.6% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 3.8 min
    112
    Figure US20190359575A1-20191128-C00385
         		i) Enantiomer of Example 111 ii) Optical purity of ethyl ester of Example 112 was 98.8% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.3 min
    113
    Figure US20190359575A1-20191128-C00386
         		i) Optically active product (optical purity not determined)
    114
    Figure US20190359575A1-20191128-C00387
         		i) Racemate
    115
    Figure US20190359575A1-20191128-C00388
         		i) Enantiomer of Example 116 ii) Optical purity was >99% ee Analytical condition of ethyl ester of Example 115 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.1 min Analytical condition of Example 115 Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 6.0 min
    116
    Figure US20190359575A1-20191128-C00389
         		i) Enantiomer of Example 115 ii) Optical purity was >99% ee Analytical condition of ethyl ester of Example 116 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.4 min Analytical condition of Example 116 Chiral column AD-3R, H2O/MeCN/HCOOH =30/70/0.1, Flow rate 0.5 ml/min, Retention time 9.2 min [α]D 25 = +106.1° (C = 1.00, MeOH)
    117
    Figure US20190359575A1-20191128-C00390
         		i) Enantiomer of Example 118 ii) Prepared by hydrolysis of ethyl ester of Example 117 Analytical condition of ethyl ester Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.1 min
    118
    Figure US20190359575A1-20191128-C00391
         		i) Enantiomer of Example 117 ii) Synthesized by hydrolysis of ethyl ester of Example 118 Analytical condition of ethyl ester Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.4 min
    119
    Figure US20190359575A1-20191128-C00392
         		i) Enantiomer of Example 120 ii) Analytical condition of ethyl ester of Example 119 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.8 min
    120
    Figure US20190359575A1-20191128-C00393
         		i) Enantiomer of Example 119 ii) Analytical condition of ethyl ester of Example 120 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.9 min
    121
    Figure US20190359575A1-20191128-C00394
         		i) Enantiomer of Example 122 ii) Analytical condition of ethyl ester of Example 121 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.7 min
    122
    Figure US20190359575A1-20191128-C00395
         		i) Enantiomer of Example 121 ii) Analytical condition of ethyl ester of Example 122 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.8 min
    123
    Figure US20190359575A1-20191128-C00396
         		i) Enantiomer of Example 124 ii) Analytical condition of ethyl ester of Example 123 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.2 min
    124
    Figure US20190359575A1-20191128-C00397
         		i) Enantiomer of Example 123 ii) Analytical condition of ethyl ester of Example 124 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.7 min
    125
    Figure US20190359575A1-20191128-C00398
         		i) Optically active product (optical purity not determined)
    126
    Figure US20190359575A1-20191128-C00399
         		i) Optically active product (optical purity not determined)
    127
    Figure US20190359575A1-20191128-C00400
         		i) Optically active product (optical purity not determined)
    128
    Figure US20190359575A1-20191128-C00401
         		i) Enantiomcr of Example 129 ii) Analytical condition of ethyl ester of Example 128 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.1 min
    129
    Figure US20190359575A1-20191128-C00402
         		i) Enantiomer of Example 129 ii) Analytical condition of ethyl ester of Example 128 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 11.1 min
    130
    Figure US20190359575A1-20191128-C00403
         		i) Optically active product (optical purity not determined)
    131
    Figure US20190359575A1-20191128-C00404
         		i) Enantiomer of Example 132 ii) Analytical condition of ethyl ester of Example 131 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.0 min
    132
    Figure US20190359575A1-20191128-C00405
         		i) Enantiomer of Example 131 ii) Analytical condition of ethyl ester of Example 132 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.7 min
    133
    Figure US20190359575A1-20191128-C00406
         		i) Enantiomer of Example 134 ii) Analytical condition of ethyl ester of Example 133 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.4 min
    134
    Figure US20190359575A1-20191128-C00407
         		i) Enantiomer of Example 133 ii) Analytical condition of ethyl ester of Example 134 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.9 min
    135
    Figure US20190359575A1-20191128-C00408
         		i) Enantiomer of Example 136 Prepared by reduction of ethyl ester of Example 133 ii) Analytical condition of ethyl ester of Example 135 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.4 min
    136
    Figure US20190359575A1-20191128-C00409
         		i) Enantiomer of Example 135 Prepared by reduction of ethyl ester of Example 134 ii) Analytical condition of ethyl ester of Example 136 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.9 min
    137
    Figure US20190359575A1-20191128-C00410
         		i) Optically active product ii) Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min Retention time 9.2 min [α]D 25 = +113.4° (C = 0.5, MeOH)
    138
    Figure US20190359575A1-20191128-C00411
         		i) Enantiomer of Example 139 ii) Optical purity of methyl ester of Example 138 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.9 min
    139
    Figure US20190359575A1-20191128-C00412
         		i) Enantiomer of Example 138 ii) Optical purity of methyl ester of Example 139 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.7 min
    140
    Figure US20190359575A1-20191128-C00413
         		i) Optically active product (optical purity not determined)
    141
    Figure US20190359575A1-20191128-C00414
         		i) Enantiomer of Example 142 ii) Analytical condition of ethyl ester of Example 141 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.1 min
    142
    Figure US20190359575A1-20191128-C00415
         		i) Enantiomer of Example 141 ii) Analytical condition of ethyl ester of Example 142 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.5 min
    143
    Figure US20190359575A1-20191128-C00416
         		i) Enantiomer of Example 144 ii) Analytical condition of ethyl ester of Example 143 Chiral column. IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.0 min
    144
    Figure US20190359575A1-20191128-C00417
         		i) Enantiomer of Example 143 ii) Analytical condition of ethyl ester of Example 144 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 11.1 min
    145
    Figure US20190359575A1-20191128-C00418
         		i) Enantiomer of Example 146 ii) Optical purity of methyl ester of Example 145 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.1 min
    146
    Figure US20190359575A1-20191128-C00419
         		i) Enantiomer of Example 145 ii) Optical purity of methyl ester of Example 146 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.6 min
    147
    Figure US20190359575A1-20191128-C00420
         		i) Optically active product (optical purity not determined)
    148
    Figure US20190359575A1-20191128-C00421
         		i) Enantiomer of Example 149 ii) Analytical condition of ethyl ester of Example 148 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.9 min
    149
    Figure US20190359575A1-20191128-C00422
         		i) Enantiomer of Example 148 ii) Analytical condition of ethyl ester of Example 149 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.7 min
    150
    Figure US20190359575A1-20191128-C00423
         		i) Optically active product (optical purity not determined)
    151
    Figure US20190359575A1-20191128-C00424
         		i) Optically active product ii) Analytical condition of ethyl ester of Example 151 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Prepared from a fraction with 6.1 min of retention time among fractions with retention times of 4.2 min and 6.1 min
    152
    Figure US20190359575A1-20191128-C00425
         		i) Optically active product ii) Analytical condition of ethyl ester of Example 152 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.1 min
    153
    Figure US20190359575A1-20191128-C00426
         		i) Optically active product ii) Analytical condition of ethyl ester of Example 153 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.5 min
    154
    Figure US20190359575A1-20191128-C00427
         		i) Optically active product ii) Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 12.1 min [α]D 25 = +141.2° (C = 0.05, MeOH)
    155
    Figure US20190359575A1-20191128-C00428
         		i) Enantiomer of Example 156 Same absolute configuration as Example 148 (prepared by reduction of ethyl ester of Example 148)
    156
    Figure US20190359575A1-20191128-C00429
         		i) Enantiomer of Example 155 Same absolute configuration as Example 149 (prepared by reduction of ethyl ester of Example 149)
    157
    Figure US20190359575A1-20191128-C00430
         		i) Optically active product (optical purity not determined)
    158
    Figure US20190359575A1-20191128-C00431
         		i) Optically active product (optical purity not determined)
    159
    Figure US20190359575A1-20191128-C00432
         		i) Optically active product ii) Chiral column AD-3R, H2O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 16.2 min [α]D 25 = +87.5° (C = 0.25, MeOH)
    160
    Figure US20190359575A1-20191128-C00433
         		i) Optically active product (optical purity not determined
    161
    Figure US20190359575A1-20191128-C00434
         		i) Optically active product (optical purity not determined)
    162
    Figure US20190359575A1-20191128-C00435
         		i) Optically active product (optical purity not determined)
    163
    Figure US20190359575A1-20191128-C00436
         		i) Optically active product (optical purity not determined)
    164
    Figure US20190359575A1-20191128-C00437
         		i) Optically active product (optical purity not determined)
    165
    Figure US20190359575A1-20191128-C00438
         		i) Optically active product (optical purity not determined)
    166
    Figure US20190359575A1-20191128-C00439
         		i) Single enantiomer Example 166 and Example 167 are a diastereomer with each other ii) Ethyl ester of Example 166 was prepared by reduction of ethyl ester of Example 151 (Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, the compound in a fraction with 6.9 min of retention time). Prepared from the ethyl ester (Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, the compound in a fraction of 3.8 min with retention time)
    167
    Figure US20190359575A1-20191128-C00440
         		i) Single enantiomer Example 166 and Example 167 are a diastereomer with each other ii) Ethyl ester of Example 167 was prepared by reduction of ethyl ester of Example 151 (Chiral column IA-3, hexane/IPA = 90/1.0, Flow rate 1 ml/min, the compound in a fraction with 6.9 min of retention time). Prepared from the ethyl ester (Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, the compound in a fraction with 4.6 min of retention time)
    168
    Figure US20190359575A1-20191128-C00441
         		i) Optically active product (optical purity not determined)
    169
    Figure US20190359575A1-20191128-C00442
         		i) Single enantiomer Stereochemistry of the cyclopropane ring was estimated as trans-isomer Example 169 and Example 170 are a diastereomer with each other ii) Analytical condition of ethyl ester of Example 169 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.7 min
    170
    Figure US20190359575A1-20191128-C00443
         		i) Single enantiomer Stereochemistry of the cyclopropane ring was estimated as trans-isomer Example 169 and Example 170 are a diastereomer with each other i) Analytical condition of ethyl ester of Example 170 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.1 min
    171
    Figure US20190359575A1-20191128-C00444
         		i) Optically active product ii) Analytical condition of ethyl ester of Example 171 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Prepared from a fraction with 6.6 min of retention time among fractions with 4.8 min and 6.6 min of retention times.
    172
    Figure US20190359575A1-20191128-C00445
         		i) Optically active product (optical purity not determined)
    173
    Figure US20190359575A1-20191128-C00446
         		i) Optically active product (optical purity not determined)
    174
    Figure US20190359575A1-20191128-C00447
         		i) Single enantiomer Stereochemistry of the cyclopropane ring was estimated as trans-isomer ii) Analytical condition of ethyl ester of Example 174 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 14.5 min
    175
    Figure US20190359575A1-20191128-C00448
         		i) Optically active product (optical purity not determined)
    176
    Figure US20190359575A1-20191128-C00449
         		i) Optically active product (optical purity not determined)
    177
    Figure US20190359575A1-20191128-C00450
         		i) Optically active product (optical purity not determined)
    178
    Figure US20190359575A1-20191128-C00451
         		i) Optically active product (optical purity not determined)
    179
    Figure US20190359575A1-20191128-C00452
         		i) Diastereomer mixture of 3-{(S)-4-[3- chloro-4-((S)-1,3,3-trimethyl-butyl)- phenyl]-5-isopropyl-4-methyl-2-oxo- 3,4-dihydro-2H-pyrimidin-1-yl}- propionic acid and 3-{(S)-4-[3-chloro-4-((R)-1,3,3- trimethyl-butyl)-phenyl]-5-isopropyl-4- methyl-2-oxo-3,4-dihydro-2H- pyrimidin-1-yl}-propionic acid
    180
    Figure US20190359575A1-20191128-C00453
         		i) Optically active product (optical purity not determined)
    181
    Figure US20190359575A1-20191128-C00454
         		i) Optically active product (optical purity not determined)
    182
    Figure US20190359575A1-20191128-C00455
         		i) Optically active product (optical purity not determined)
    183
    Figure US20190359575A1-20191128-C00456
         		i) Optically active product (optical purity not determined)
    184
    Figure US20190359575A1-20191128-C00457
         		i) Optically active product (optical purity not determined)
    185
    Figure US20190359575A1-20191128-C00458
         		i) Optically active product (optical purity not determined)
    186
    Figure US20190359575A1-20191128-C00459
         		i) Optically active product (optical purity not determined) ii) Na salt of Example 77
    187
    Figure US20190359575A1-20191128-C00460
         		i) Racemate
    188
    Figure US20190359575A1-20191128-C00461
         		i) Racemate
    189
    Figure US20190359575A1-20191128-C00462
         		i) Optically active product (optical purity not determined)
  • TABLE 2
    Example Chemical Structural Formula Structural Information
    190
    Figure US20190359575A1-20191128-C00463
         		i) Optically active product (optical purity not determined) ii) Analytical condition Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 4.7 min
    191
    Figure US20190359575A1-20191128-C00464
         		i) Optically active product (optical purity not determined) ii) Analytical condition Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 10.7 min
    192
    Figure US20190359575A1-20191128-C00465
         		i) Optically active product (optical purity not determined)
    193
    Figure US20190359575A1-20191128-C00466
         		i) Optically active product (optical purity not determined)
    194
    Figure US20190359575A1-20191128-C00467
         		i) Optically active product (optical purity not determined)
    195
    Figure US20190359575A1-20191128-C00468
         		i) Optically active product (optical purity not determined)
    196
    Figure US20190359575A1-20191128-C00469
         		i) Optically active product (optical purity determined)
    197
    Figure US20190359575A1-20191128-C00470
         		i) Optically active product (optical purity not determined) ii) Optical purity of alcohol, a synthetic precursor, was >99% ee Analytical condition of alcohol of Example 197 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 6.3 min
    198
    Figure US20190359575A1-20191128-C00471
         		i) Optically active product (optical purity not determined)
    199
    Figure US20190359575A1-20191128-C00472
         		i) Optically active product (optical purity not determined) ii) Optical purity of alcohol, a synthetic precursor, was >99% ee Analytical condition of alcohol of Example 199 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 5.7 min
    200
    Figure US20190359575A1-20191128-C00473
         		i) Optically active product (optical purity not determined) ii) Optical purity of alcohol, a synthetic precursor, was >99% ee Analytical condition of alcohol of Example 200 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 6.0 min
    201
    Figure US20190359575A1-20191128-C00474
         		i) Optically active product (optical purity not determined)
    202
    Figure US20190359575A1-20191128-C00475
         		i) Optically active product (optical purity not determined)
    203
    Figure US20190359575A1-20191128-C00476
         		i) Optically active product (optical purity not determined)
    204
    Figure US20190359575A1-20191128-C00477
         		i) Optically active product (optical purity not determined)
    205
    Figure US20190359575A1-20191128-C00478
         		i) Optically active product (optical purity not determined) ii) Analytical condition of methyl ester of Example 205 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 8.8 min
    206
    Figure US20190359575A1-20191128-C00479
         		i) Optically active product (optical purity not determined)
    207
    Figure US20190359575A1-20191128-C00480
         		i) Optically active product (optical purity not determined)
    208
    Figure US20190359575A1-20191128-C00481
         		i) Optically active product (optical purity not determined)
    209
    Figure US20190359575A1-20191128-C00482
         		i) Optically active product (optical purity not determined)
    210
    Figure US20190359575A1-20191128-C00483
         		i) Optically active product (optical purity not determined)
    211
    Figure US20190359575A1-20191128-C00484
         		i) Optically active product (optical purity not determined)
    212
    Figure US20190359575A1-20191128-C00485
         		i) Enantiomer of Example 213 ii) Optical purity of ethyl ester was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 5.2 min
    213
    Figure US20190359575A1-20191128-C00486
         		i) Enantiomer of Example 212 ii) Optical purity of ethyl ester was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 8.3 min
    214
    Figure US20190359575A1-20191128-C00487
         		i) Optically active product (optical purity not determined)
    215
    Figure US20190359575A1-20191128-C00488
         		i) A mixture of two diastereomers
    216
    Figure US20190359575A1-20191128-C00489
         		i) Optically active product (optical purity not determined)
    217
    Figure US20190359575A1-20191128-C00490
         		i) A mixture of two diastereomers
    218
    Figure US20190359575A1-20191128-C00491
         		i) Optically active product (optical purity not determined)
    219
    Figure US20190359575A1-20191128-C00492
         		i) Optically active product (optical purity not determined)
    220
    Figure US20190359575A1-20191128-C00493
         		i) Optically active product (optical purity not determined)
    221
    Figure US20190359575A1-20191128-C00494
         		i) Optically active product (optical purity not determined)
    222
    Figure US20190359575A1-20191128-C00495
         		i) Optically active product (optical purity not determined)
    223
    Figure US20190359575A1-20191128-C00496
         		i) A mixture of two diastereomers
    224
    Figure US20190359575A1-20191128-C00497
         		i) Optically active product (optical purity not determined)
    225
    Figure US20190359575A1-20191128-C00498
         		i) Optically active product (optical purity not determined)
    226
    Figure US20190359575A1-20191128-C00499
         		i) Optically active product (optical purity not determined)
    227
    Figure US20190359575A1-20191128-C00500
         		i) Optically active product (optical purity not determined)
    228
    Figure US20190359575A1-20191128-C00501
         		i) Optically active product (optical purity not determined)
    229
    Figure US20190359575A1-20191128-C00502
         		i) Optically active product (optical purity not determined)
    230
    Figure US20190359575A1-20191128-C00503
         		i) Optically active product (optical purity not determined)
    231
    Figure US20190359575A1-20191128-C00504
         		i) Optically active product (optical purity not determined)
    232
    Figure US20190359575A1-20191128-C00505
         		i) Single enantiomer (optical purity not determined) Example 232 and Example 233 are a diastereomer with each other
    233
    Figure US20190359575A1-20191128-C00506
         		i) Single enantiomer (optical purity not determined) Example 232 and Example 233 are a diastereomer with each other
    234
    Figure US20190359575A1-20191128-C00507
         		i) Optically active product (optical purity not determined)
    235
    Figure US20190359575A1-20191128-C00508
         		i) Optically active product (optical purity not determined)
    236
    Figure US20190359575A1-20191128-C00509
         		i) Optically active product (optical purity not determined)
    237
    Figure US20190359575A1-20191128-C00510
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the pyrrolidine ring was estimated as trans-isomer
    238
    Figure US20190359575A1-20191128-C00511
         		i) Optically active product (optical purity not determined) Stereochemistry of the pyrrolidine ring was estimated as trans-isomer
    239
    Figure US20190359575A1-20191128-C00512
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the pyrrolidine ring was estimated as trans-isomer
    240
    Figure US20190359575A1-20191128-C00513
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the pyrrolidine ring was estimated as trans-isomer
    241
    Figure US20190359575A1-20191128-C00514
         		i) Optically active product (optical purity not determined)
    242
    Figure US20190359575A1-20191128-C00515
         		i) Single enantiomer optical purity not determined) Stereochemistry of the cyclopentane ring was estimated as trans-isomer Example 242 and Example 243 are a diastereomer with each other
    243
    Figure US20190359575A1-20191128-C00516
         		i) Single enantiomer optical purity not determined) Stereochemistry of the cyclopentane ring was estimated as trans-isomer Example 242 and Example 243 are a diastereomer with each other
    244
    Figure US20190359575A1-20191128-C00517
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the pyrrolidine ring was estimated as trans-isomer Example 244 and Example 245 are a diastereomer with each other
    245
    Figure US20190359575A1-20191128-C00518
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the pyrrolidine ring was estimated as trans-isomer Example 244 and Example 245 are a diastereomer with each other
    246
    Figure US20190359575A1-20191128-C00519
         		i) Optically active product (optical purity not determined)
    247
    Figure US20190359575A1-20191128-C00520
         		i) Optically active product (optical purity not determined)
    248
    Figure US20190359575A1-20191128-C00521
         		i) Optically active product (optical purity not determined)
    249
    Figure US20190359575A1-20191128-C00522
         		i) Optically active product (optical purity not determined)
    250
    Figure US20190359575A1-20191128-C00523
         		i) Optically active product (optical purity not determined)
    251
    Figure US20190359575A1-20191128-C00524
         		i) Optically active product (optical purity not determined)
    252
    Figure US20190359575A1-20191128-C00525
         		i) Optically active product (optical purity not determined)
    253
    Figure US20190359575A1-20191128-C00526
         		i) Optically active product (optical purity not determined)
    254
    Figure US20190359575A1-20191128-C00527
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclohexane ring was estimated as trans-isomer Example 254, Example 255, Example 256, and Example 257 are a diastereomer with each other ii) Optical purity of Example 254 was >99% ee Analytical condition of Example 254 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 10.2 min.
    255
    Figure US20190359575A1-20191128-C00528
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclohexane ring was estimated as cis-isomer Example 254, Example 255, Example 256, and Example 257 are a diastereomer with each other ii) Optical purity of Example 255 was >99% ee Analytical condition of Example 255 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 13.2 min.
    256
    Figure US20190359575A1-20191128-C00529
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclohexane ring was estimated as trans-isomer Example 254, Example 255, Example 256, and Example 257 are a diastereomer with each other ii) Optical purity of Example 256 was >99% ee Analytical condition of Example 256 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 11.7 min.
    257
    Figure US20190359575A1-20191128-C00530
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclohexane ring was estimated as cis-isomer Example 254, Example 255, Example 256, and Example 257 are a diastereomer with each other ii) Optical purity of Example 257 was >99% ee Analytical condition of Example 257 JAIGEL ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 14.0 min.
    258
    Figure US20190359575A1-20191128-C00531
         		i) Optically active product (optical purity not determined)
    259
    Figure US20190359575A1-20191128-C00532
         		i) Optically active product (optical purity not determined)
    260
    Figure US20190359575A1-20191128-C00533
         		i) Optically active product (optical purity not determined)
    261
    Figure US20190359575A1-20191128-C00534
         		i) Optically active product (optical purity not determined)
    262
    Figure US20190359575A1-20191128-C00535
         		i) Optically active product (optical purity not determined)
    263
    Figure US20190359575A1-20191128-C00536
         		i) Optically active product (optical purity not determined)
    264
    Figure US20190359575A1-20191128-C00537
         		i) Optically active product (optical purity not determined)
    265
    Figure US20190359575A1-20191128-C00538
         		i) Optically active product (optical purity not determined)
    266
    Figure US20190359575A1-20191128-C00539
         		i) Optically active product (optical purity not determined)
    267
    Figure US20190359575A1-20191128-C00540
         		i) Optically active product (optical purity not determined)
    268
    Figure US20190359575A1-20191128-C00541
         		i) Optically active product (optical purity not determined)
    269
    Figure US20190359575A1-20191128-C00542
         		i) Optically active product (optical purity not determined)
    270
    Figure US20190359575A1-20191128-C00543
         		i) Optically active product (optical purity not determined)
    271
    Figure US20190359575A1-20191128-C00544
         		i) Optically active product (optical purity not determined)
    272
    Figure US20190359575A1-20191128-C00545
         		i) Optically active product (optical purity not determined)
    273
    Figure US20190359575A1-20191128-C00546
         		i) Optically active product (optical purity not determined)
    274
    Figure US20190359575A1-20191128-C00547
         		i) Optically active product (optical purity not determined)
    275
    Figure US20190359575A1-20191128-C00548
         		i) Optically active product (optical purity not determined)
    276
    Figure US20190359575A1-20191128-C00549
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclobutane ring not determined
    277
    Figure US20190359575A1-20191128-C00550
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclobutane ring not determined
    278
    Figure US20190359575A1-20191128-C00551
         		i) Single enantiomer Stereochemistry of the cyclopentane ring not determined Examples 64, 278, 279, and 280 are a diastereomer with each other ii) Optical purity of Example 278 was >99% ee Analytical condition of Example 278 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 9.1 min.
    279
    Figure US20190359575A1-20191128-C00552
         		i) Single enantiomer Stereochemistry of the cyclopentane ring not determined Examples 64, 278, 279, and 280 are a diastereomer with each other ii) Optical purity of Example 279 was >99% ee Analytical condition of Example 279 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 10.4 min.
    280
    Figure US20190359575A1-20191128-C00553
         		i) Single enantiomer Stereochemistry of the cyclopentane ring not determined Examples 64, 278, 279, and 280 are a diastereomer with each other ii) Optical purity of Example 280 was >99% ee Analytical condition of Example 280 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 90/10/0.1, Flow rate 1 ml/min, Retention time 10.8 min.
    281
    Figure US20190359575A1-20191128-C00554
         		i) Optically active product (optical purity not determined)
    282
    Figure US20190359575A1-20191128-C00555
         		i) Optically active product (optical purity not determined)
    283
    Figure US20190359575A1-20191128-C00556
         		i) Optically active product (optical purity not determined)
    284
    Figure US20190359575A1-20191128-C00557
         		i) Optically active product (optical purity not determined)
    285
    Figure US20190359575A1-20191128-C00558
         		i) Optically active product (optical purity not determined)
    286
    Figure US20190359575A1-20191128-C00559
         		i) Optically active product (optical purity not determined)
    287
    Figure US20190359575A1-20191128-C00560
         		i) Optically active product (optical purity not determined)
    288
    Figure US20190359575A1-20191128-C00561
         		i) Optically active product (optical purity not determined)
    289
    Figure US20190359575A1-20191128-C00562
         		i) Optically active product (optical purity not determined)
    290
    Figure US20190359575A1-20191128-C00563
         		i) Optically active product (optical purity not determined)
    291
    Figure US20190359575A1-20191128-C00564
         		i) Optically active product (optical purity not determined)
    292
    Figure US20190359575A1-20191128-C00565
         		i) Optically active product (optical purity not determined)
    293
    Figure US20190359575A1-20191128-C00566
         		i) Optically active product (optical purity not determined)
    294
    Figure US20190359575A1-20191128-C00567
         		i) Optically active product (optical purity not determined)
    295
    Figure US20190359575A1-20191128-C00568
         		i) Optically active product (optical purity not determined)
    296
    Figure US20190359575A1-20191128-C00569
         		i) Optically active product (optical purity not determined)
    297
    Figure US20190359575A1-20191128-C00570
         		i) Optically active product (optical purity not determined)
    298
    Figure US20190359575A1-20191128-C00571
         		i) Optically active product (optical purity not determined)
    299
    Figure US20190359575A1-20191128-C00572
         		i) Single enantiomer Example 299 and Example 300 are a diastereomer with each other ii) Optical purity of Example 299 was >99% ee Analytical condition of Example 299 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 80/20/0.1, Flow rate 1 ml/min, Retention time 14.7 min.
    300
    Figure US20190359575A1-20191128-C00573
         		i) Single enantiomer Example 299 and Example 300 are a diastereomer with each other ii) Optical purity of Example 300 was >99% ee Analytical condition of Example 300 JAIGEL-ODS-AP-A, MeCN/H2O/HCO2H = 80/20/0.1, Flow rate 1 ml/min, Retention time 15.3 min.
    301
    Figure US20190359575A1-20191128-C00574
         		i) Optically active product (optical purity not determined)
    302
    Figure US20190359575A1-20191128-C00575
         		i) Optically active product (optical purity not determined)
    303
    Figure US20190359575A1-20191128-C00576
         		i) Optically active product (optical purity not determined)
    304
    Figure US20190359575A1-20191128-C00577
         		i) Optically active product (optical purity not determined) Diastereomer mixture
    305
    Figure US20190359575A1-20191128-C00578
         		i) Single enantiomer (optical purity not determined) Example 305 and Example 306 are a diastereomer with each other
    306
    Figure US20190359575A1-20191128-C00579
         		i) Single enantiomer (optical purity not determined) Example 305 and Example 306 are a diastereomer with each other
    307
    Figure US20190359575A1-20191128-C00580
         		i) Single enantiorner (optical purity not determined) Example 307 and Example 308 are a diastereomer with each other
    308
    Figure US20190359575A1-20191128-C00581
         		i) Single enantiomer (optical purity not determined) Example 307 and Example 308 are a diastereorner with each other
    309
    Figure US20190359575A1-20191128-C00582
         		i) Optically active product (optical purity not determined)
    310
    Figure US20190359575A1-20191128-C00583
         		i) Single enantiomer (optical purity not determined) Example 310 and Example 311 are a diastereomer with each other
    311
    Figure US20190359575A1-20191128-C00584
         		i) Single enantiomer (optical purity not determined) Stereochemistry of hydroxyl not determined
    312
    Figure US20190359575A1-20191128-C00585
         		i) Single enantiomer, >99% ee Analytical condition of Example 312 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 8.8 min
    313
    Figure US20190359575A1-20191128-C00586
         		i) Optically active product (optical purity not determined)
    314
    Figure US20190359575A1-20191128-C00587
         		i) Optically active product (optical purity not determined)
    315
    Figure US20190359575A1-20191128-C00588
         		i) Optically active product (optical purity not determined)
    316
    Figure US20190359575A1-20191128-C00589
         		i) Optically active product (optical purity not determined)
    317
    Figure US20190359575A1-20191128-C00590
         		i) Optically active product (optical purity not determined)
    318
    Figure US20190359575A1-20191128-C00591
         		i) Optically active product (optical purity not determined)
    319
    Figure US20190359575A1-20191128-C00592
         		i) Optically active product (optical purity not determined)
    320
    Figure US20190359575A1-20191128-C00593
         		i) Optically active product (optical purity not determined)
    321
    Figure US20190359575A1-20191128-C00594
         		i) Optically active product (optical purity not determined)
    322
    Figure US20190359575A1-20191128-C00595
         		i) Optically active product (optical purity not determined)
    323
    Figure US20190359575A1-20191128-C00596
         		i) Optically active product (optical purity not determined)
    324
    Figure US20190359575A1-20191128-C00597
         		i) Optically active product (optical purity not determined)
    325
    Figure US20190359575A1-20191128-C00598
         		i) Optically active product (optical purity not determined)
    326
    Figure US20190359575A1-20191128-C00599
         		i) Optically active product (optical purity not determined)
    327
    Figure US20190359575A1-20191128-C00600
         		i) Optically active product (optical purity not determined)
    328
    Figure US20190359575A1-20191128-C00601
         		i) Optically active product (optical purity not determined)
    329
    Figure US20190359575A1-20191128-C00602
         		i) Optically active product (optical purity not determined)
    330
    Figure US20190359575A1-20191128-C00603
         		i) Optically active product (optical purity not determined)
    331
    Figure US20190359575A1-20191128-C00604
         		i) Optically active product (optical purity not determined)
    332
    Figure US20190359575A1-20191128-C00605
         		i) Optically active product (optical purity not determined)
    333
    Figure US20190359575A1-20191128-C00606
         		i) Optically active product (optical purity not determined)
    334
    Figure US20190359575A1-20191128-C00607
         		i) Optically active product (optical purity not determined)
    335
    Figure US20190359575A1-20191128-C00608
         		i) Optically active product (optical purity not determined)
    336
    Figure US20190359575A1-20191128-C00609
         		i) Optically active product (optical purity not determined)
    337
    Figure US20190359575A1-20191128-C00610
         		i) Optically active product (optical purity not determined)
    338
    Figure US20190359575A1-20191128-C00611
         		i) Optically active product (optical purity not determined)
    339
    Figure US20190359575A1-20191128-C00612
         		i) Optically active product (optical purity not determined)
    340
    Figure US20190359575A1-20191128-C00613
         		i) Optically active product (optical purity not determined)
    341
    Figure US20190359575A1-20191128-C00614
         		i) Optically active product (optical purity not determined)
    342
    Figure US20190359575A1-20191128-C00615
         		i) Optically active product (optical purity not determined)
    343
    Figure US20190359575A1-20191128-C00616
         		i) Optically active product (optical purity not determined)
    344
    Figure US20190359575A1-20191128-C00617
         		i) Single enantiomer (optical purity not determined) Stereochemistry of the cyclobutane ring was estimated as cis-isomer
    345
    Figure US20190359575A1-20191128-C00618
         		i) Optically active product (optical purity not determined)
    346
    Figure US20190359575A1-20191128-C00619
         		i) Optically active product (optical purity not determined)
    347
    Figure US20190359575A1-20191128-C00620
         		i) Optically active product (optical purity not determined)
    348
    Figure US20190359575A1-20191128-C00621
         		i) Optically active product (optical purity not determined)
    349
    Figure US20190359575A1-20191128-C00622
         		i) Optically active product (optical purity not determined)
    350
    Figure US20190359575A1-20191128-C00623
         		i) Optically active product (optical purity not determined)
    351
    Figure US20190359575A1-20191128-C00624
         		i) Single enantiomer (optical purity not determined) Example 351 and Example 352 are a diastereomer with each other
    352
    Figure US20190359575A1-20191128-C00625
         		i) Single enantiomer (optical purity not determined) Example 351 and Example 352 are a diastereomer with each other
    353
    Figure US20190359575A1-20191128-C00626
         		i) Optically active product (optical purity not determined)
    354
    Figure US20190359575A1-20191128-C00627
         		i) Optically active product (optical purity not determined)
    355
    Figure US20190359575A1-20191128-C00628
         		i) Optically active product (optical purity not determined)
    356
    Figure US20190359575A1-20191128-C00629
         		i) Optically active product (optical purity not determined)
    357
    Figure US20190359575A1-20191128-C00630
         		i) Optically active product (optical purity not determined)
  • In the following table, compounds of Examples 38, 87, and 116 were synthesized by a preparation method using Claisen reaction and measured.
  • TABLE 3
    MS
    M + H M − H
    or or
    Example 1H-NMR M − Na + H M − Na − H
    1 (400 MHz, CDCl3) 0.98 (s, 9H), 1.06 (s, 9H), 437 435
    1.88-2.04 (m, 2H), 2.32-2.44 (m, 2H), 3.37-3.44 (m, 1H),
    3.61 (s, 2H), 3.69-3.76 (m, 1H), 4.82 (d, J = 2.65 Hz,
    1H), 5.75-5.81 (m, 1H), 6.09 (s, 1H), 6.82 (d,
    J = 8.60 Hz, 1H), 7.06 (dd, J = 8.49, 2.32 Hz, 1H),
    7.23 (d, J = 2.21 Hz, 1H)
    2 (400 MHz, DMSO-D6) 0.96 (s, 3H), 1.02 (s, 9H), 381 379
    1.20 (s, 3H), 3.68 (s, 2H), 4.72 (d, J = 3.24 Hz, 1H), 6.22 (d,
    J = 5.32 Hz, 1H), 7.06 (t, J = 8.21 Hz, 2H), 7.14 (dd,
    J = 8.32, 2.08 Hz, 1H), 7.26 (d, J = 2.08 Hz, 1H), 8.21 (s,
    1H), 12.14 (s, 1H)
    3 (400 MHz, CDCl3) 0.98 (s, 9H), 1.14-1.31 (m, 3H), 477 475
    1.49-1.59 (m, 2H), 1.64-1.78 (m, 8H),
    1.90-2.03 (m, 2H), 2.32-2.45 (m, 2H), 3.39-3.46 (m, 1H),
    3.68-3.75 (m, 1H), 4.03 (t, J = 6.73 Hz, 2H), 4.82 (d,
    J = 2.65 Hz, 1H), 5.58 (d, J = 2.21 Hz, 1H), 6.09 (s, 1H),
    6.85 (d, J = 8.38 Hz, 1H), 7.06 (dd, J = 8.49, 2.10 Hz,
    1H), 7.22 (d, J = 1.98 Hz, 1H)
    4 (400 MHz, DMSO-D6) 0.88 (s, 3H), 1.02 (s, 9H), 395 393
    1.08 (s, 3H), 2.15 (d, J = 13.87 Hz, 1H), 2.29 (d, J = 14.33 Hz,
    1H), 3.68 (s, 2H), 4.77 (d, J = 3.24 Hz, 1H), 6.15 (d,
    J = 5.32 Hz, 1H), 7.03 (s, 1H), 7.05 (d, J = 8.55 Hz, 1H),
    7.19 (dd, J = 8.44, 2.20 Hz, 1H), 7.33 (d, J = 2.08 Hz,
    1H), 8.09 (d, J = 3.24 Hz, 1H), 11.92 (s, 1H)
    5 (400 MHz, CDCl3) 0.98 (s, 9H), 1.06 (s, 9H), 437 435
    1.90-2.03 (m, 2H), 2.32-2.45 (m, 2H), 3.38-3.45 (m, 1H),
    3.61 (s, 2H), 3.68-3.75 (m, 1H), 4.82 (d, J = 2.65 Hz,
    1H), 5.62 (brs, 1H), 6.09 (s, 1H), 6.82 (d, J = 8.16 Hz,
    1H), 7.05 (dd, J = 8.49, 2.32 Hz, 1H), 7.23 (d,
    J = 2.21 Hz, 1H)
    6 (400 MHz, CDCl3) 0.99 (s, 9H), 1.07 (s, 9H), 437 435
    1.91-2.03 (m, 2H), 2.33-2.45 (m, 2H), 3.39-3.46 (m, 1H),
    3.62 (s, 2H), 3.69-3.76 (m, 1H), 4.82 (d, J = 2.65 Hz,
    1H), 5.50-5.60 (brm, 1H), 6.09 (s, 1H), 6.83 (d,
    J = 8.38 Hz, 1H), 7.05 (dd, J = 8.38, 2.21 Hz, 1H),
    7.23 (d, J = 2.21 Hz, 1H)
    7 (400 MHz, DMSO-D6) 0.72 (s, 3H), 0.96 (s, 3H), 409 407
    1.00 (s, 9H), 1.37-1.46 (m, 1H), 1.61-1.69 (m, 1H),
    1.95-2.10 (m, 2H), 3.68 (s, 2H), 4.64 (d, J = 3.24 Hz, 1H),
    6.08 (d, J = 5.32 Hz, 1H), 7.01 (s, 1H), 7.05 (d,
    J = 8.44 Hz, 1H), 7.19 (dd, J = 8.44, 2.20 Hz, 1H),
    7.32 (d, J = 2.31 Hz, 1H), 8.14 (d, J = 4.86 Hz, 1H), 11.96 (s,
    1H)
    8 (400 MHz, CDCl3) 0.97 (s, 9H), 0.98 (s, 9H), 435 433
    1.24-1.30 (m, 2H), 1.41-1.46 (m, 2H), 1.89-2.02 (m, 2H),
    2.36-2.40 (m, 2H), 2.62-2.67 (m, 2H),
    3.37-3.44 (m, 1H), 3.68-3.75 (m, 1H), 4.84 (d, J = 2.87 Hz, 1H),
    5.82 (brs, 1H), 6.10 (s, 1H), 7.04 (dd, J = 7.72, 1.76 Hz,
    1H), 7.16 (d, J = 7.94 Hz, 1H), 7.20 (d, J = 1.76 Hz, 1H)
    9 (400 MHz, DMSO-D6) 0.73 (d, J = 6.94 Hz, 3H), 437 435
    1.03 (s, 9H), 1.05 (d, J = 6.94 Hz, 3H), 1.61 (s, 3H),
    1.65-1.76 (m, 2H), 1.92-1.99 (m, 1H), 2.19 (t, J = 7.40 Hz,
    2H), 2.40-2.50 (m, 1H), 3.40-3.50 (m, 1H), 3.70 (s,
    2H), 6.05 (s, 1H), 6.98 (s, 1H), 7.07 (d, J = 8.79 Hz,
    1H), 7.27 (dd, J = 8.67, 2.43 Hz, 1H), 7.37 (d,
    J = 2.31 Hz, 1H), 12.07 (s, 1H)
    10 (400 MHz, DMSO-D6) 0.92 (s, 9H), 0.93 (s, 9H), 435 433
    1.34-1.38 (m, 2H), 1.62-1.79 (m, 2H), 2.18 (t, J = 7.40 Hz,
    2H), 2.57-2.61 (m, 2H), 3.11-3.18 (m, 1H),
    3.59-3.66 (m, 1H), 4.76 (d, J = 3.01 Hz, 1H), 6.25 (s, 1H),
    7.13 (dd, J = 7.86, 1.62 Hz, 1H), 7.16 (d, J = 3.24 Hz,
    1H), 7.25 (d, J = 7.86 Hz, 1H), 7.28 (d, J = 1.85 Hz, 1H),
    12.05 (brs, 1H)
    11 (400 MHz, DMSO-D6) 0.92 (s, 9H), 0.93 (s, 9H), 435 433
    1.34-1.38 (m, 2H), 1.62-1.78 (m, 2H), 2.18 (t, J = 7.40 Hz,
    2H), 2.57-2.61 (m, 2H), 3.11-3.18 (m, 1H),
    3.59-3.66 (m, 1H), 4.76 (d, J = 3.01 Hz, 1H), 6.25 (s, 1H),
    7.13 (dd, J = 7.86, 1.62 Hz, 1H), 7.16 (d, J = 3.24 Hz,
    1H), 7.25 (d, J = 7.86 Hz, 1H), 7.28 (d, J = 1.85 Hz, 1H),
    12.05 (brs, 1H)
    12 (400 MHz, DMSO-D6) 0.72 (d, J = 6.76 Hz, 3H), 437 435
    1.00 (d, J = 13.28 Hz, 9H), 1.04 (d, J = 6.76 Hz, 3H), 1.60 (s,
    3H), 1.66-1.73 (m, 2H), 1.95 (dd, J = 13.52, 6.76 Hz,
    1H), 2.19 (t, J = 7.49 Hz, 2H), 3.27-3.34 (m, 1H),
    3.41-3.48 (m, 1H), 3.69 (s, 2H), 6.04 (s, 1H), 6.97 (s, 1H),
    7.06 (d, J = 8.69 Hz, 1H), 7.26 (dd, J = 8.57, 2.29 Hz,
    1H), 7.37 (d, J = 2.41 Hz, 1H), 12.06 (s, 1H)
    13 (400 MHz, DMSO-D6) 0.72 (d, J = 7.00 Hz, 3H), 437 435
    1.02 (s, 9H), 1.04 (t, J = 5.80 Hz, 3H), 1.60 (s, 3H),
    1.66-1.73 (m, 2H), 1.91-1.97 (m, 1H), 2.19 (t, J = 7.49 Hz,
    2H), 3.27-3.34 (m, 1H), 3.41-3.48 (m, 1H), 3.69 (s,
    2H), 6.04 (s, 1H), 6.97 (s, 1H), 7.06 (d, J = 8.69 Hz,
    1H), 7.26 (dd, J = 8.57, 2.29 Hz, 1H), 7.37 (d,
    J = 2.41 Hz, 1H), 12.06 (s, 1H)
    14 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 435 433
    0.95 (s, 9H), 1.04 (d, J = 6.70 Hz, 3H), 1.36-1.40 (m, 2H),
    1.61 (s, 3H), 1.66-1.73 (m, 2H), 1.94-2.01 (m, 1H),
    2.17 (t, J = 7.63 Hz, 2H), 2.56-2.66 (m, 2H),
    3.25-3.35 (m, 1H), 3.41-3.48 (m, 1H), 6.05 (s, 1H),
    7.01 (s, 1H), 7.26 (dd, J = 7.98, 1.73 Hz, 1H), 7.29 (d,
    J = 8.09 Hz, 1H), 7.35 (d, J = 1.62 Hz, 1H), 12.08 (s, 1H)
    15 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 435 433
    0.94 (s, 9H), 1.04 (d, J = 6.70 Hz, 3H), 1.36-1.40 (m, 2H),
    1.61 (s, 3H), 1.65-1.73 (m, 2H), 1.94-2.01 (m, 1H),
    2.17 (t, J = 7.40 Hz, 2H), 2.60-2.67 (m, 2H),
    3.25-3.35 (m, 1H), 3.41-3.48 (m, 1H), 6.05 (s, 1H),
    7.01 (s, 1H), 7.26 (dd, J = 7.98, 1.73 Hz, 1H), 7.29 (d,
    J = 8.09 Hz, 1H), 7.35 (d, J = 1.62 Hz, 1H), 12.08 (s, 1H)
    16 (400 MHz, DMSO-D6) 0.76 (d, J = 7.00 Hz, 3H), 449 447
    1.01 (s, 9H), 1.07 (d, J = 6.40 Hz, 3H), 1.60 (s, 3H),
    1.98-2.05 (m, 1H), 2.22-2.31 (m, 2H), 2.35-2.40 (m, 2H),
    2.70-2.78 (m, 1H), 3.69 (s, 2H), 4.65-4.74 (m, 1H),
    6.26 (s, 1H), 7.06 (s, 1H), 7.09 (s, 1H), 7.24 (dd,
    J = 8.69, 2.41 Hz, 1H), 7.34 (d, J = 2.41 Hz, 1H), 12.22 (s,
    1H)
    17 (400 MHz, DMSO-D6) 0.78 (d, J = 7.49 Hz, 3H), 449 447
    1.03 (s, 9H), 1.09 (d, J = 6.76 Hz, 3H), 1.60 (s, 3H),
    1.95-2.02 (m, 1H), 2.24-2.30 (m, 2H), 2.46-2.54 (m, 2H),
    2.88-2.90 (m, 1H), 3.69 (s, 2H), 4.92-5.01 (m, 1H),
    6.32 (s, 1H), 7.07 (t, J = 4.35 Hz, 2H), 7.24 (dd, J = 8.57,
    2.29 Hz, 1H), 7.33 (d, J = 2.17 Hz, 1H), 12.25 (s, 1H)
    18 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 451 449
    1.01 (s, 9H), 1.03 (d, J = 7.00 Hz, 3H), 1.47-1.48 (m, 4H),
    1.60 (s, 3H), 1.91-1.98 (m, 1H), 2.24 (t, J = 6.64 Hz,
    2H), 3.25-3.32 (m, 1H), 3.41-3.44 (m, 1H), 3.69 (s,
    2H), 6.05 (s, 1H), 6.93 (s, 1H), 7.06 (d, J = 8.69 Hz,
    1H), 7.26 (dd, J = 8.69, 2.41 Hz, 1H), 7.36 (d,
    J = 2.41 Hz, 1H), 11.99 (s, 1H)
    19 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 451 449
    1.00 (s, 9H), 1.02 (d, J = 6.70 Hz, 4H), 1.08 (d, J = 6.94 Hz,
    3H), 1.47 (td, J = 13.76, 7.32 Hz, 1H), 1.58 (s, 3H),
    1.79 (td, J = 13.70, 7.24 Hz, 1H), 1.89-1.95 (m, 1H),
    2.28 (dt, J = 16.49, 4.74 Hz, 1H), 3.32-3.43 (m, 1H),
    3.68 (s, 2H), 6.02 (s, 1H), 6.95 (s, 1H), 7.05 (d, J = 8.79 Hz,
    1H), 7.25 (dd, J = 8.55, 2.31 Hz, 1H), 7.35 (d,
    J = 2.31 Hz, 1H), 12.11 (s, 1H)
    20 (400 MHz, DMSO-D6) 0.71 (d, J = 6.70 Hz, 3H), 451 449
    1.00 (s, 9H), 1.02 (d, J = 6.70 Hz, 3H), 1.07 (d, J = 6.94 Hz,
    3H), 1.47-1.50 (m, 1H), 1.58 (s, 3H), 1.75-1.79 (m,
    1H), 1.95-1.97 (m, 1H), 2.26-2.28 (m, 1H),
    3.20-3.27 (m, 1H), 3.47-3.54 (m, 1H), 3.67 (s, 2H),
    6.01 (s, 1H), 6.96 (s, 1H), 7.04 (d, J = 8.79 Hz, 1H), 7.24 (dd,
    J = 8.55, 2.31 Hz, 1H), 7.35 (d, J = 2.31 Hz, 1H), 12.11 (s,
    1H)
    21 (400 MHz, DMSO-D6) 0.70 (dd, J = 6.94, 3.24 Hz, 3H), 451 449
    1.00 (s, 9H), 1.02 (d, J = 7.40 Hz, 3H), 1.07 (dd, J = 6.94,
    4.16 Hz, 3H), 1.42-1.53 (m, 1H), 1.58 (s, 3H),
    1.73-1.84 (m, 1H), 1.89-1.98 (m, 1H), 2.23-2.33 (m, 1H),
    3.17-3.57 (m, 2H), 3.68 (s, 2H), 6.02 (d, J = 3.70 Hz,
    1H), 6.96 (d, J = 4.86 Hz, 1H), 7.05 (dd, J = 8.67,
    2.20 Hz, 1H), 7.25 (dt, J = 8.79, 2.14 Hz, 1H), 7.35 (d,
    J = 2.31 Hz, 1H), 12.11 (s, 1H)
    22 (400 MHz, DMSO-D6) 0.94 (s, 9H), 0.94 (s, 9H), 449 447
    1.36-1.40 (m, 2H), 1.70-1.72 (m, 2H), 1.78 (s, 3H),
    2.19 (t, J = 7.46 Hz, 2H), 2.60-2.64 (m, 2H), 3.26-3.28 (m,
    1H), 3.48-3.55 (m, 1H), 6.23 (s, 1H), 6.85 (s, 1H),
    7.27 (s, 2H), 7.36 (s, 1H), 12.09 (brs, 1H)
    23 (400 MHz, DMSO-D6) 0.82 (s, 9H), 0.94 (s, 9H), 463 461
    1.35-1.39 (m, 2H), 1.54 (s, 3H), 1.65-1.69 (m, 2H),
    1.79 (d, J = 4.16 Hz, 2H), 2.13 (t, J = 7.46 Hz, 2H),
    2.59-2.63 (m, 2H), 3.25-3.27 (m, 1H), 3.43-3.50 (m, 1H),
    6.06 (s, 1H), 7.13 (s, 1H), 7.24-7.27 (m, 2H), 7.34 (d,
    J = 1.73 Hz, 1H), 12.06 (brs, 1H)
    24 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 449 447
    0.90-0.98 (m, 9H), 1.05-1.07 (m, 6H), 1.36-1.40 (m, 2H),
    1.47-1.50 (m, 1H), 1.61 (s, 3H), 1.76-1.83 (m, 1H),
    1.95-2.01 (m, 1H), 2.26-2.31 (m, 1H),
    2.60-2.64 (m, 2H), 3.23-3.27 (m, 1H), 3.35-3.54 (m, 1H),
    6.04 (d, J = 4.39 Hz, 1H), 7.02 (d, J = 5.78 Hz, 1H),
    7.23-7.32 (m, 2H), 7.34 (d, J = 1.62 Hz, 1H), 12.12 (s, 1H)
    25 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 449 447
    0.90-0.98 (m, 9H), 1.05-1.07 (m, 6H), 1.36-1.40 (m, 2H),
    1.47-1.50 (m, 1H), 1.61 (s, 3H), 1.76-1.83 (m, 1H),
    1.95-2.01 (m, 1H), 2.26-2.31 (m, 1H),
    2.60-2.64 (m, 2H), 3.23-3.27 (m, 1H), 3.35-3.54 (m, 1H),
    6.04 (d, J = 4.39 Hz, 1H), 7.02 (d, J = 5.78 Hz, 1H),
    7.23-7.32 (m, 2H), 7.34 (d, J = 1.62 Hz, 1H), 12.12 (s, 1H)
    26 (400 MHz, CDCl3) δ: 0.70 (t, J = 6.65 Hz, 3H), 401 399
    0.94 (d, J = 12.89 Hz, 9H), 1.05 (q, J = 3.49 Hz, 3H),
    1.45-1.50 (m, 2H), 1.72 (d, J = 9.67 Hz, 3H), 1.92 (dd,
    J = 10.88, 6.85 Hz, 3H), 2.37 (t, J = 6.85 Hz, 2H),
    2.53-2.57 (m, 2H), 3.55 (q, J = 6.31 Hz, 2H), 5.36-5.49 (m,
    1H), 5.78 (s, 1H), 7.14 (d, J = 8.46 Hz, 2H), 7.31 (dd,
    J = 8.26, 4.23 Hz, 2H).
    27 (400 MHz, CDCl3) δ: 0.71 (dd, J = 12.69, 6.65 Hz, 421 419
    3H), 0.93 (dd, J = 14.51, 11.69 Hz, 6H), 1.06 (dd,
    J = 20.75, 13.90 Hz, 3H), 1.48 (dt, J = 17.19, 7.45 Hz,
    2H), 1.61 (td, J = 13.30, 6.85 Hz, 1H), 1.69 (d, J = 14.10 Hz,
    3H), 1.87-1.94 (m, 3H), 2.38 (t, J = 6.85 Hz, 2H),
    2.67-2.71 (m, 2H), 3.55 (dq, J = 25.39, 6.58 Hz, 2H),
    5.47 (s, 1H), 5.80 (d, J = 11.69 Hz, 1H), 7.17 (d, J = 8.06 Hz,
    1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H), 7.37 (d,
    J = 2.01 Hz, 1H).
    28 (400 MHz, CDCl3) δ: 0.72 (d, J = 6.85 Hz, 3H), 407 405
    0.94 (t, J = 7.25 Hz, 3H), 1.06 (d, J = 6.85 Hz, 3H), 1.37 (t,
    J = 7.45 Hz, 2H), 1.57 (dd, J = 15.51, 7.86 Hz, 2H),
    1.72 (s, 3H), 1.93 (dt, J = 18.67, 6.95 Hz, 3H), 2.41 (t,
    J = 6.85 Hz, 2H), 2.71 (t, J = 7.66 Hz, 2H), 3.58 (dd,
    J = 7.66, 5.64 Hz, 2H), 4.97 (s, 1H), 5.81 (s, 1H),
    7.19 (d, J = 7.66 Hz, 1H), 7.23 (d, J = 2.01 Hz, 1H), 7.38 (d,
    J = 1.61 Hz, 1H).
    29 (400 MHz, DMSO-D6) 0.74 (d, J = 6.94 Hz, 3H), 475 473
    0.94 (s, 9H), 1.06 (d, J = 6.94 Hz, 3H), 1.34-1.43 (m, 4H),
    1.54-1.65 (m, 7H), 1.95-2.05 (m, 3H),
    2.20-2.27 (m, 1H), 2.59-2.64 (m, 2H), 4.03-4.09 (m, 1H),
    6.13 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H),
    7.29 (d, J = 8.09 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H),
    12.05 (s, 1H)
    30 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 475 473
    0.94 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.24-1.25 (m, 1H),
    1.38 (dt, J = 10.33, 3.41 Hz, 2H), 1.44-1.60 (m, 9H),
    2.02-2.13 (m, 3H), 2.60-2.62 (m, 2H),
    4.07-4.09 (m, 1H), 5.91 (s, 1H), 7.03 (s, 1H), 7.23 (dd, J = 7.98,
    1.97 Hz, 1H), 7.29 (d, J = 7.86 Hz, 1H), 7.33 (d,
    J = 1.85 Hz, 1H)
    31 (400 MHz, CDCl3) 0.87-0.94 (m, 2H), 0.96 (s, 9H), 475 473
    1.02-1.18 (m, 4H), 1.41-1.45 (m, 2H),
    1.47-1.59 (m, 3H), 1.67 (s, 3H), 1.68-1.79 (m, 2H),
    1.87-1.94 (m, 2H), 2.35 (t, J = 6.94 Hz, 2H), 2.63-2.68 (m, 2H),
    3.52 (t, J = 6.47 Hz, 2H), 5.20 (s, 1H), 5.76 (s, 1H),
    7.15 (d, J = 8.09 Hz, 1H), 7.21 (dd, J = 7.98, 1.97 Hz, 1H),
    7.35 (d, J = 1.85 Hz, 1H)
    32 (400 MHz, CDCl3) 0.89-0.95 (m, 2H), 0.96 (s, 9H), 475 473
    1.04-1.17 (m, 4H), 1.41-1.45 (m, 2H),
    1.47-1.59 (m, 3H), 1.68 (s, 3H), 1.70-1.79 (m, 2H),
    1.89-1.96 (m, 2H), 2.38 (t, J = 6.94 Hz, 2H), 2.64-2.68 (m, 2H),
    3.55 (t, J = 6.59 Hz, 2H), 5.05 (s, 1H), 5.77 (s, 1H),
    7.16 (d, J = 8.09 Hz, 1H), 7.21 (dd, J = 8.09, 2.08 Hz, 1H),
    7.35 (d, J = 2.08 Hz, 1H)
    33 (400 MHz, DMSO-D6) 0.38 (t, J = 7.34 Hz, 1.5H), 449 447
    0.61 (d, J = 6.82 Hz, 1.5H), 0.83 (t, J = 7.34 Hz, 1.5H), 0.94 (s,
    4.5H), 0.95 (s, 4.5H), 1.02 (d, J = 6.70 Hz, 1.5H),
    1.04-1.06 (m, 1H), 1.24-1.31 (m, 0.5H), 1.37 (dt, J = 12.48,
    5.12 Hz, 2H), 1.42-1.49 (m, 0.5H), 1.58 (s, 1.5H),
    1.61 (s, 1.5H), 1.69-1.71 (m, 3H), 2.17-2.18 (m,
    2H), 2.61-2.63 (m, 2H), 3.23-3.53 (m, 3H), 5.93 (s,
    0.5H), 5.96 (s, 0.5H), 7.00 (s, 0.5H), 7.02 (s, 0.5H),
    7.26-7.28 (m, 2H), 7.34 (d, J = 1.62 Hz, 0.5H), 7.35 (d,
    J = 1.50 Hz, 0.5H), 12.09 (brs, 1H)
    34 (400 MHz, DMSO-D6) 0.38 (t, J = 7.28 Hz, 1.5H), 449 447
    0.61 (d, J = 6.82 Hz, 1.5H), 0.83 (t, J = 7.34 Hz, 1.5H), 0.94 (s,
    4.5H), 0.95 (s, 4.5H), 1.02 (d, J = 6.82 Hz, 1.5H),
    1.05-1.07 (m, 1H), 1.24-1.31 (m, 0.5H), 1.36-1.39 (m,
    2H), 1.42-1.49 (m, 0.5H), 1.58 (s, 1.5H), 1.61 (s,
    1.5H), 1.69-1.72 (m, 3H), 2.17-2.19 (m, 2H),
    2.61-2.63 (m, 2H), 3.23-3.53 (m, 3H), 5.93 (s, 0.5H),
    5.97 (s, 0.5H), 7.00 (s, 0.5H), 7.02 (s, 0.5H),
    7.26-7.28 (m, 2H), 7.34 (d, J = 1.62 Hz, 0.5H), 7.35 (d, J = 1.50 Hz,
    0.5H), 12.10 (brs, 1H)
    35 (400 MHz, DMSO-D6) 0.76 (d, J = 6.82 Hz, 3H), 463 461
    0.87 (s, 3H), 0.89 (s, 3H), 0.94 (s, 9H), 1.04 (d, J = 6.82 Hz,
    3H), 1.35-1.40 (m, 2H), 1.61 (s, 3H), 2.02-2.07 (m,
    3H), 2.60-2.64 (m, 2H), 3.17 (d, J = 13.99 Hz, 1H),
    3.56 (d, J = 13.99 Hz, 1H), 6.08 (s, 1H), 7.17 (bs, 1H),
    7.29-7.29 (m, 2H), 7.39 (s, 1H), 12.09 (bs, 1H)
    36 (400 MHz, DMSO-D6) 0.76 (d, J = 6.82 Hz, 3H), 463 461
    0.87 (s, 3H), 0.89 (s, 3H), 0.94 (s, 9H), 1.04 (d, J = 6.82 Hz,
    3H), 1.35-1.40 (m, 2H), 1.61 (s, 3H), 2.02-2.07 (m,
    3H), 2.60-2.64 (m, 2H), 3.17 (d, J = 13.99 Hz, 1H),
    3.56 (d, J = 13.99 Hz, 1H), 6.08 (s, 1H), 7.17 (bs, 1H),
    7.29-7.29 (m, 2H), 7.39 (s, 1H), 12.09 (bs, 1H)
    37 (400 MHz, DMSO-D6) 0.72-0.79 (m, 6H), 0.95 (s, 449 447
    9H), 1.35-1.40 (m, 2H), 1.45-1.50 (m, 1H),
    1.55-1.58 (m, 4H), 1.65-1.72 (m, 3H), 2.16 (t, J = 7.51 Hz,
    2H), 2.60-2.64 (m, 2H), 3.27-3.31 (m, 1H),
    3.42-3.48 (m, 1H), 5.94 (s, 1H), 7.05 (s, 1H),
    7.25-7.28 (m, 2H), 7.35 (d, J = 1.73 Hz, 1H), 12.08 (brs, 1H)
    38 (400 MHz, DMSO-D6) 0.73-0.76 (m, 6H), 0.95 (s, 449 447
    9H), 1.35-1.40 (m, 2H), 1.45-1.49 (m, 1H),
    1.55-1.58 (m, 4H), 1.68-1.70 (m, 3H), 2.16 (t, J = 7.51 Hz,
    2H), 2.60-2.64 (m, 2H), 3.27-3.30 (m, 1H),
    3.41-3.48 (m, 1H), 5.94 (s, 1H), 7.05 (s, 1H),
    7.25-7.28 (m, 2H), 7.35 (d, J = 1.73 Hz, 1H), 12.08 (brs, 1H)
    39 (400 MHz, DMSO-D6) 0.69 (d, J = 6.70 Hz, 3H), 451 449
    0.95 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.38 (dt, J = 8.79,
    3.73 Hz, 2H), 1.61 (s, 3H), 1.93-1.96 (m, 1H),
    2.62 (dt, J = 10.40, 3.73 Hz, 2H), 3.44-3.62 (m, 4H),
    3.92 (s, 2H), 6.12 (s, 1H), 7.02 (bs, 1H), 7.27-7.30 (m,
    2H), 7.34-7.36 (m, 1H)
    40 (400 MHz, DMSO-D6) 0.69 (d, J = 6.70 Hz, 3H), 451 449
    0.95 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.38 (dt, J = 8.79,
    3.73 Hz, 2H), 1.61 (s, 3H), 1.93-1.96 (m, 1H),
    2.62 (dt, J = 10.40, 3.73 Hz, 2H), 3.44-3.62 (m, 4H),
    3.92 (s, 2H), 6.12 (s, 1H), 7.02 (bs, 1H), 7.27-7.30 (m,
    2H), 7.34-7.36 (m, 1H)
    41 (400 MHz, DMSO-D6) 0.67-0.79 (m, 3H), 0.94 (s, 447 445
    9H), 1.03-1.13 (m, 3H), 1.32-1.43 (m, 2H),
    1.54-1.61 (m, 3H), 1.93-2.05 (m, 1H), 2.14-2.35 (m, 5H),
    2.54-2.69 (m, 2H), 4.83-4.99 (m, 1H), 6.27 (s, 1H),
    6.99 (s, 1H), 7.17-7.35 (m, 3H)
    42 (400 MHz, DMSO-D6) 0.67-0.79 (m, 3H), 0.94 (s, 447 445
    9H), 1.03-1.13 (m, 3H), 1.32-1.43 (m, 2H),
    1.54-1.61 (m, 3H), 1.93-2.05 (m, 1H), 2.14-2.35 (m, 5H),
    2.54-2.69 (m, 2H), 4.83-4.99 (m, 1H), 6.27 (s, 1H),
    6.99 (s, 1H), 7.17-7.35 (m, 3H)
    43 (400 MHz, DMSO-D6) 0.74-0.77 (m, 6H), 0.94 (s, 463 461
    9H), 1.01-1.10 (m, 1H), 1.14-1.23 (m, 1H),
    1.38-1.41 (m, 3H), 1.57 (s, 3H), 1.63-1.71 (m, 3H),
    1.83-1.90 (m, 1H), 2.14 (t, J = 7.46 Hz, 2H), 2.60-2.64 (m,
    2H), 3.25-3.27 (m, 1H), 3.40-3.47 (m, 1H), 5.94 (s,
    1H), 7.05 (s, 1H), 7.24 (dd, J = 7.98, 1.85 Hz, 1H),
    7.29 (d, J = 7.98 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H), 12.08 (brs,
    1H)
    44 (400 MHz, DMSO-D6) 0.74-0.77 (m, 6H), 0.94 (s, 463 461
    9H), 1.02-1.06 (m, 1H), 1.15-1.21 (m, 1H),
    1.38-1.41 (m, 3H), 1.57 (s, 3H), 1.64-1.68 (m, 3H),
    1.84-1.88 (m, 1H), 2.13 (t, J = 7.46 Hz, 2H), 2.60-2.64 (m,
    2H), 3.25-3.27 (m, 1H), 3.40-3.47 (m, 1H), 5.94 (s,
    1H), 7.05 (s, 1H), 7.24 (dd, J = 8.03, 1.79 Hz, 1H),
    7.29 (d, J = 8.09 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H)
    45 (400 MHz, DMSO-D6) 0.69-0.77 (m, 3H), 0.93 (s, 447 445
    9H), 1.02-1.10 (m, 3H), 1.30-1.43 (m, 2H), 1.61 (s,
    3H), 1.95-2.06 (m, 1H), 2.18-2.39 (m, 5H),
    2.57-2.65 (m, 2H), 2.66-2.77 (m, 1H), 4.59-4.73 (m, 1H),
    6.25 (s, 1H), 7.09 (s, 1H), 7.17-7.33 (m, 3H),
    12.23 (brs, 1H)
    46 (400 MHz, DMSO-D6) 0.69-0.77 (m, 3H), 0.93 (s, 447 445
    9H), 1.02-1.10 (m, 3H), 1.30-1.43 (m, 2H), 1.61 (s,
    3H), 1.95-2.06 (m, 1H), 2.18-2.39 (m, 5H),
    2.57-2.65 (m, 2H), 2.66-2.77 (m, 1H), 4.59-4.73 (m, 1H),
    6.25 (s, 1H), 7.09 (s, 1H), 7.17-7.33 (m, 3H),
    12.23 (brs, 1H)
    47 (400 MHz, DMSO-D6) 0.64-0.72 (m, 3H), 0.93 (s, 449 447
    9H), 1.00-1.05 (m, 3H), 1.31-1.40 (m, 2H),
    1.40-1.51 (m, 4H), 1.59 (s, 3H), 1.90-2.00 (m, 1H),
    2.18-2.25 (m, 2H), 2.55-2.65 (m, 2H), 3.21-3.28 (m, 1H),
    3.38-3.46 (m, 1H), 6.04 (s, 1H), 6.95 (brs, 1H),
    7.21-7.29 (m, 2H), 7.31-7.34 (m, 1H), 11.94 (brs, 1H)
    48 (400 MHz, DMSO-D6) 0.64-0.72 (m, 3H), 0.93 (s, 449 447
    9H), 1.00-1.05 (m, 3H), 1.31-1.40 (m, 2H),
    1.40-1.51 (m, 4H), 1.59 (s, 3H), 1.90-2.00 (m, 1H),
    2.18-2.25 (m, 2H), 2.55-2.65 (m, 2H), 3.21-3.28 (m, 1H),
    3.38-3.46 (m, 1H), 6.04 (s, 1H), 6.95 (brs, 1H),
    7.21-7.29 (m, 2H), 7.31-7.34 (m, 1H), 11.94 (brs, 1H)
    49 (400 MHz, DMSO-D6) 0.47-0.54 (m, 3H), 497 495
    0.86-0.91 (m, 3H), 0.94 (s, 9H), 1.33-1.42 (m, 2H),
    1.54 (s, 3H), 1.75-1.88 (m, 1H), 2.57-2.65 (m, 2H),
    2.81-2.90 (m, 2H), 3.49-3.59 (m, 1H), 3.70-3.81 (m,
    1H), 5.78 (s, 1H), 6.96 (s, 1H), 7.09-7.15 (m, 1H),
    7.21-7.27 (m, 1H), 7.27-7.34 (m, 3H),
    7.80-7.86 (m, 2H), 12.75 (brs, 1H)
    50 (400 MHz, DMSO-D6) 0.47-0.54 (m, 3H), 497 495
    0.86-0.91 (m, 3H), 0.94 (s, 9H), 1.33-1.42 (m, 2H),
    1.54 (s, 3H), 1.75-1.88 (m, 1H), 2.57-2.65 (m, 2H),
    2.81-2.90 (m, 2H), 3.49-3.59 (m, 1H), 3.70-3.81 (m,
    1H), 5.78 (s, 1H), 6.96 (s, 1H), 7.09-7.15 (m, 1H),
    7.21-7.27 (m, 1H), 7.27-7.34 (m, 3H),
    7.80-7.86 (m, 2H), 12.75 (brs, 1H)
    51 (400 MHz, DMSO-D6) 0.15-0.19 (m, 1H), 447 445
    0.51-0.41 (m, 3H), 0.79 (s, 3H), 0.94 (s, 9H),
    1.36-1.40 (m, 2H), 1.66-1.71 (m, 2H), 1.74 (s, 3H), 2.16 (t,
    J = 7.49 Hz, 2H), 2.60-2.64 (m, 2H), 3.16-3.27 (m,
    1H), 3.47-3.55 (m, 1H), 6.25 (s, 1H), 7.08 (s, 1H),
    7.27 (d, J = 0.97 Hz, 2H), 7.38 (s, 1H), 12.05 (brs, 1H)
    52 (400 MHz, DMSO-D6) 0.16-0.19 (m, 1H), 447 445
    0.41-0.51 (m, 3H), 0.79 (s, 3H), 0.94 (s, 9H),
    1.36-1.40 (m, 2H), 1.66-1.71 (m, 2H), 1.73 (s, 3H),
    2.19-2.13 (m, 2H), 2.60-2.64 (m, 2H), 3.18-3.25 (m, 1H),
    3.47-3.55 (m, 1H), 6.25 (s, 1H), 7.08 (s, 1H), 7.27 (s, 2H),
    7.38 (s, 1H), 12.04 (brs, 1H)
    53 (400 MHz, CDCl3) δ: 0.72 (d, J = 6.85 Hz, 3H), 421 419
    0.90 (t, J = 6.85 Hz, 3H), 1.06 (d, J = 6.85 Hz, 3H), 1.35 (t,
    J = 3.63 Hz, 4H), 1.60 (t, J = 7.45 Hz, 2H), 1.73 (d,
    J = 8.06 Hz, 3H), 1.93 (tt, J = 17.93, 5.31 Hz, 3H),
    2.41 (t, J = 7.05 Hz, 2H), 2.70 (t, J = 7.66 Hz, 2H), 3.58 (td,
    J = 6.55, 3.49 Hz, 2H), 5.06 (s, 1H), 5.82 (s, 1H),
    7.18 (d, J = 8.06 Hz, 1H), 7.23 (d, J = 2.01 Hz, 1H), 7.38 (d,
    J = 2.01 Hz, 1H).
    54 (400 MHz, DMSO-D6) 0.70 (d, J = 6.82 Hz, 3H), 463 461
    0.95 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.12 (s, 6H),
    1.36-1.40 (m, 2H), 1.60 (s, 3H), 1.63-1.68 (m, 2H),
    1.97-1.98 (m, 1H), 2.60-2.64 (m, 2H), 3.27-3.41 (m, 4H),
    6.00 (s, 1H), 7.00 (bs, 1H), 7.26 (dd, J = 8.09, 1.85 Hz,
    1H), 7.30 (d, J = 8.09 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H),
    12.18 (bs, 1H)
    55 (400 MHz, DMSO-D6) 0.70 (d, J = 6.82 Hz, 3H), 463 461
    0.95 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.12 (s, 6H),
    1.36-1.40 (m, 2H), 1.60 (s, 3H), 1.63-1.68 (m, 2H),
    1.97-1.98 (m, 1H), 2.60-2.64 (m, 2H), 3.27-3.41 (m, 4H),
    6.00 (s, 1H), 7.00 (bs, 1H), 7.26 (dd, J = 8.09, 1.85 Hz,
    1H), 7.30 (d, J = 8.09 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H),
    12.18 (bs, 1H)
    56 (400 MHz, CDCl3) 0.20-0.26 (m, 1H), 0.27-0.32 (m, 433 431
    1H), 0.38-0.45 (m, 1H), 0.60-0.67 (m, 1H),
    0.86-0.92 (m, 1H), 0.98 (s, 9H), 1.42-1.47 (m, 2H), 1.80 (s, 3H),
    1.89-1.96 (m, 2H), 2.39 (t, J = 7.05 Hz, 2H),
    2.65-2.69 (m, 2H), 3.54 (ddd, J = 6.85, 6.85, 2.82 Hz, 2H), 5.09 (s,
    1H), 5.65 (d, J = 1.61 Hz, 1H), 7.19 (d, J = 8.06 Hz, 1H),
    7.27 (dd, J = 4.43, 2.01 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H)
    57 (400 MHz, CDCl3) 0.20-0.26 (m, 1H), 0.27-0.32 (m, 433 431
    1H), 0.38-0.45 (m, 1H), 0.60-0.67 (m, 1H),
    0.86-0.92 (m, 1H), 0.98 (s, 9H), 1.42-1.47 (m, 2H), 1.80 (s, 3H),
    1.89-1.96 (m, 2H), 2.39 (t, J = 7.05 Hz, 2H),
    2.65-2.69 (m, 2H), 3.54 (ddd, J = 6.85, 6.85, 2.82 Hz, 2H), 5.09 (s,
    1H), 5.65 (d, J = 1.61 Hz, 1H), 7.19 (d, J = 8.06 Hz, 1H),
    7.27 (dd, J = 4.43, 2.01 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H)
    58 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 447 445
    1.52-1.67 (m, 3H), 1.64 (s, 3H), 1.69-1.76 (m, 1H),
    1.80-1.88 (m, 1H), 1.92-2.03 (m, 3H), 2.40 (t,
    J = 7.25 Hz, 2H), 2.51-2.59 (m, 1H), 2.64-2.68 (m, 2H),
    3.57 (ddd, J = 14.91, 12.89, 8.06 Hz, 2H), 5.32 (s, 1H),
    5.77 (d, J = 1.21 Hz, 1H), 7.16 (d, J = 8.06 Hz, 1H),
    7.20 (dd, J = 8.06, 2.01 Hz, 1H), 7.34 (d, J = 1.61 Hz, 1H)
    59 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 447 445
    1.52-1.67 (m, 3H), 1.64 (s, 3H), 1.69-1.76 (m, 1H),
    1.80-1.88 (m, 1H), 1.92-2.03 (m, 3H), 2.40 (t,
    J = 7.25 Hz, 2H), 2.51-2.59 (m, 1H), 2.64-2.68 (m, 2H),
    3.57 (ddd, J = 14.91, 12.89, 8.06 Hz, 2H), 5.32 (s, 1H),
    5.77 (d, J = 1.21 Hz, 1H), 7.16 (d, J = 8.06 Hz, 1H),
    7.20 (dd, J = 8.06, 2.01 Hz, 1H), 7.34 (d, J = 1.61 Hz, 1H)
    60 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.45 (m, 2H), 407 405
    1.46 (d, J = 1.61 Hz, 3H), 1.70 (s, 3H), 1.90-1.97 (m,
    2H), 2.40 (t, J = 6.85 Hz, 2H), 2.65-2.69 (m, 2H),
    3.55 (t, J = 6.85 Hz, 2H), 5.04 (s, 1H), 5.76 (d, J = 1.21 Hz,
    1H), 7.21-7.20 (m, 2H), 7.36 (d, J = 1.61 Hz, 1H)
    61 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.45 (m, 2H), 407 405
    1.46 (d, J = 1.61 Hz, 3H), 1.70 (s, 3H), 1.90-1.97 (m,
    2H), 2.40 (t, J = 6.85 Hz, 2H), 2.65-2.69 (m, 2H),
    3.55 (t, J = 6.85 Hz, 2H), 5.04 (s, 1H), 5.76 (d, J = 1.21 Hz,
    1H), 7.21-7.20 (m, 2H), 7.36 (d, J = 1.61 Hz, 1H)
    62 (400 MHz, DMSO-D6) 1.02 (s, 9H), 1.89-2.01 (m, 393 391
    3H), 2.14-2.20 (m, 1H), 2.63-2.72 (m, 1H),
    2.75-2.81 (m, 1H), 3.69 (s, 2H), 4.66 (s, 1H), 5.95 (d,
    J = 4.35 Hz, 1H), 7.01 (s, 1H), 7.08 (d, J = 8.69 Hz, 1H),
    7.13 (dd, J = 8.45, 1.93 Hz, 1H), 7.25 (d, J = 1.69 Hz,
    1H), 8.11 (d, J = 3.38 Hz, 1H)
    63 (400 MHz, DMSO-D6) 0.68-0.77 (m, 3H), 0.93 (s, 461 459
    9H), 1.00-1.08 (m, 3H), 1.32-1.40 (m, 2H), 1.59 (s,
    3H), 1.66-1.91 (m, 4H), 1.91-2.06 (m, 2H),
    2.57-2.64 (m, 2H), 2.67-2.79 (m, 1H), 4.63-4.77 (m, 1H),
    6.18 (s, 1H), 7.02 (s, 1H), 7.19-7.37 (m, 3H),
    12.21 (brs, 1H)
    64 (400 MHz, DMSO-D6) 0.68-0.77 (m, 3H), 0.93 (s, 461 459
    9H), 1.00-1.08 (m, 3H), 1.32-1.40 (m, 2H), 1.59 (s,
    3H), 1.66-1.91 (m, 4H), 1.91-2.06 (m, 2H),
    2.57-2.64 (m, 2H), 2.67-2.79 (m, 1H), 4.63-4.77 (m, 1H),
    6.18 (s, 1H), 7.02 (s, 1H), 7.19-7.37 (m, 3H),
    12.21 (brs, 1H)
    65 (400 MHz, CDCl3) δ: 0.70 (t, J = 7.66 Hz, 3H), 0.98 (d, 415 413
    J = 7.25 Hz, 9H), 1.05 (d, J = 6.85 Hz, 3H), 1.28 (d,
    J = 15.72 Hz, 2H), 1.37-1.42 (m, 2H), 1.72 (d, J = 5.24 Hz,
    3H), 1.88-1.98 (m, 3H), 2.29 (s, 3H), 2.41 (t,
    J = 6.85 Hz, 2H), 2.51-2.55 (m, 2H), 3.57 (ddd,
    J = 14.81, 8.36, 5.94 Hz, 2H), 5.12 (s, 1H), 5.78 (s, 1H),
    7.08 (d, J = 7.66 Hz, 1H), 7.16 (d, J = 7.66 Hz, 2H).
    66 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 475 473
    0.94 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.24-1.25 (m, 1H),
    1.38 (dt, J = 10.33, 3.41 Hz, 2H), 1.44-1.60 (m, 9H),
    2.02-2.13 (m, 3H), 2.60-2.62 (m, 2H),
    4.07-4.09 (m, 1H), 5.91 (s, 1H), 7.03 (s, 1H), 7.23 (dd, J = 7.98,
    1.97 Hz, 1H), 7.29 (d, J = 7.86 Hz, 1H), 7.33 (d,
    J = 1.85 Hz, 1H)
    67 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 475 473
    0.94 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.24-1.25 (m, 1H),
    1.38 (dt, J = 10.33, 3.41 Hz, 2H), 1.44-1.60 (m, 9H),
    2.02-2.13 (m, 3H), 2.60-2.62 (m, 2H),
    4.07-4.09 (m, 1H), 5.91 (s, 1H), 7.03 (s, 1H), 7.23 (dd, J = 7.98,
    1.97 Hz, 1H), 7.29 (d, J = 7.86 Hz, 1H), 7.33 (d,
    J = 1.85 Hz, 1H)
    68 (400 MHz, CDCl3) 0.93 (t, J = 7.25 Hz, 3H), 0.98 (s, 421 419
    9H), 1.42-1.47 (m, 2H), 1.59-1.68 (m, 1H), 1.69 (s,
    3H), 1.91-1.84 (m, 1H), 1.99-1.92 (m, 2H), 2.40 (t,
    J = 7.05 Hz, 2H), 2.69-2.64 (m, 2H), 3.58 (t, J = 6.45 Hz,
    2H), 5.06 (s, 1H), 5.71 (t, J = 1.61 Hz, 1H), 7.18 (d,
    J = 8.06 Hz, 1H), 7.22 (dd, J = 7.66, 2.01 Hz, 1H),
    7.35 (d, J = 1.61 Hz, 1H)
    69 (400 MHz, CDCl3) 0.93 (t, J = 7.25 Hz, 3H), 0.98 (s, 421 419
    9H), 1.42-1.47 (m, 2H), 1.59-1.68 (m, 1H), 1.69 (s,
    3H), 1.91-1.84 (m, 1H), 1.99-1.92 (m, 2H), 2.40 (t,
    J = 7.05 Hz, 2H), 2.69-2.64 (m, 2H), 3.58 (t, J = 6.45 Hz,
    2H), 5.06 (s, 1H), 5.71 (t, J = 1.61 Hz, 1H), 7.18 (d,
    J = 8.06 Hz, 1H), 7.22 (dd, J = 7.66, 2.01 Hz, 1H),
    7.35 (d, J = 1.61, Hz, 1H)
    70 (400 MHz, CDCl3) δ: 0.72 (d, J = 6.85 Hz, 3H), 391 389
    0.91 (q, J = 8.19 Hz, 3H), 1.06 (d, J = 6.85 Hz, 3H),
    1.30-1.40 (m, 2H), 1.57 (dt, J = 16.12, 7.05 Hz, 2H), 1.72 (d,
    J = 9.67 Hz, 3H), 1.93 (td, J = 13.00, 6.45 Hz, 3H),
    2.39 (t, J = 6.85 Hz, 2H), 2.61 (t, J = 7.66 Hz, 2H),
    3.49-3.60 (m, 2H), 5.33 (s, 1H), 5.81 (s, 1H), 7.11 (dq, J = 24.48,
    6.18 Hz, 3H).
    71 (400 MHz, DMSO-D6) 0.61-0.72 (m, 5H), 0.93 (s, 461 459
    9H), 0.98-1.04 (m, 5H), 1.32-1.40 (m, 2H), 1.59 (s,
    3H), 1.61-1.67 (m, 2H), 1.87-1.98 (m, 1H),
    2.57-2.65 (m, 2H), 3.44-3.58 (m, 2H), 5.93 (s, 1H),
    6.95 (s, 1H), 7.22-7.31 (m, 2H), 7.31-7.39 (m, 1H),
    12.09 (brs, 1H)
    72 (400 MHz, DMSO-D6) 0.61-0.72 (m, 5H), 0.93 (s, 461 459
    9H), 0.98-1.04 (m, 5H), 1.32-1.40 (m, 2H), 1.59 (s,
    3H), 1.61-1.67 (m, 2H), 1.87-1.98 (m, 1H),
    2.57-2.65 (m, 2H), 3.44-3.58 (m, 2H), 5.93 (s, 1H),
    6.95 (s, 1H), 7.22-7.31 (m, 2H), 7.31-7.39 (m, 1H),
    12.09 (brs, 1H)
    73 (400 MHz, CDCl3) 0.68-0.75 (m, 3H), 0.95 (s, 9H), 449 447
    0.99-1.07 (m, 3H), 1.13-1.28 (m, 3H),
    1.37-1.48 (m, 2H), 1.65 (s, 3H), 1.72-1.98 (m, 4H),
    2.19-2.36 (m, 1H), 2.58-2.68 (m, 2H), 4.56 (brs, 1H), 5.82 (s,
    1H), 7.08-7.22 (m, 2H), 7.32-7.39 (m, 1H)
    74 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 0.94 (s, 477 475
    9H), 0.98 (s, 6H), 1.01-1.09 (m, 3H), 1.26-1.45 (m,
    6H), 1.59 (s, 3H), 1.91-2.03 (m, 1H), 2.59-2.66 (m,
    2H), 3.14-3.23 (m, 1H), 3.36-3.47 (m, 1H), 6.01 (s,
    1H), 6.92 (s, 1H), 7.23-7.32 (m, 2H), 7.33-7.39 (m,
    1H)
    75 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 0.94 (s, 477 475
    9H), 0.98 (s, 6H), 1.01-1.09 (m, 3H), 1.26-1.45 (m,
    6H), 1.59 (s, 3H), 1.91-2.03 (m, 1H), 2.59-2.66 (m,
    2H), 3.14-3.23 (m, 1H), 3.36-3.47 (m, 1H), 6.01 (s,
    1H), 6.92 (s, 1H), 7.23-7.32 (m, 2H), 7.33-7.39 (m,
    1H)
    76 (400 MHz, DMSO-D6) 0.63-0.72 (m, 3H), 0.93 (s, 459 457
    9H), 0.98-1.05 (m, 2H), 1.30-1.43 (m, 2H), 1.57 (s,
    3H), 1.89-1.99 (m, 1H), 2.06 (brs, 6H),
    2.57-2.68 (m, 2H), 5.93 (s, 1H), 6.94 (brs, 1H), 7.19-7.35 (m,
    3H)
    77 (400 MHz, DMSO-D6) 0.63-0.72 (m, 3H), 0.93 (s, 459 457
    9H), 0.98-1.05 (m, 2H), 1.30-1.43 (m, 2H), 1.57 (s,
    3H), 1.89-1.99 (m, 1H), 2.06 (brs, 6H),
    2.57-2.68 (m, 2H), 5.93 (s, 1H), 6.94 (brs, 1H), 7.19-7.35 (m,
    3H)
    78 (400 MHz, DMSO-D6) 0.74 (d, J = 6.94 Hz, 3H), 475 473
    0.94 (s, 9H), 1.06 (d, J = 6.94 Hz, 3H), 1.34-1.43 (m, 4H),
    1.54-1.65 (m, 7H), 1.95-2.05 (m, 3H),
    2.20-2.27 (m, 1H), 2.59-2.64 (m, 2H), 4.03-4.09 (m, 1H),
    6.13 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H),
    7.29 (d, J = 8.09 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H),
    12.05 (s, 1H)
    79 (400 MHz, DMSO-D6) 0.74 (d, J = 6.94 Hz, 3H), 475 473
    0.94 (s, 9H), 1.06 (d, J = 6.94 Hz, 3H), 1.34-1.43 (m, 4H),
    1.54-1.65 (m, 7H), 1.95-2.05 (m, 3H),
    2.20-2.27 (m, 1H), 2.59-2.64 (m, 2H), 4.03-4.09 (m, 1H),
    6.13 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H),
    7.29 (d, J = 8.09 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H),
    12.05 (s, 1H)
    80 (400 MHz, DMSO-D6) 0.72 (d, J = 6.82 Hz, 3H), 461 459
    0.94 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.37 (dt, J = 8.71,
    3.67 Hz, 2H), 1.60 (s, 3H), 1.88-2.01 (m, 3H),
    2.12-2.15 (m, 2H), 2.62 (dt, J = 10.17, 3.67 Hz, 2H),
    2.97-3.00 (m, 1H), 3.26-3.28 (m, 1H), 3.62 (dd, J = 13.64,
    7.40 Hz, 1H), 6.11 (s, 1H), 7.01 (bs, 1H), 7.24 (dd,
    J = 8.09, 1.85 Hz, 1H), 7.28 (d, J = 8.09 Hz, 1H), 7.32 (d,
    J = 1.85 Hz, 1H), 12.06 (bs, 1H)
    81 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.46 (m, 2H), 526 524
    1.64 (s, 3H), 1.93-2.00 (m, 2H), 2.40 (t, J = 7.25 Hz,
    2H), 2.65-2.69 (m, 2H), 2.80 (s, 3H), 2.88-2.96 (m,
    1H), 3.29 (t, J = 7.25 Hz, 1H), 3.45 (t, J = 7.66 Hz, 1H),
    3.50-3.57 (m, 1H), 3.63-3.70 (m, 1H), 3.84 (d,
    J = 7.66 Hz, 2H), 5.57 (s, 1H), 6.03 (s, 1H), 7.20 (s,
    2H), 7.33 (s, 1H)
    82 (400 MHz, DMSO-D6) 0.52-0.57 (m, 3H), 497 495
    0.89-0.92 (m, 3H), 0.94 (s, 9H), 1.31-1.42 (m, 2H),
    1.55 (s, 3H), 1.78-1.89 (m, 1H), 2.58-2.64 (m, 2H),
    3.05-3.18 (m, 2H), 3.50-3.59 (m, 1H), 3.61-3.70 (m,
    1H), 5.77 (s, 1H), 6.94 (s, 1H), 7.15-7.24 (m, 2H),
    7.25-7.34 (m, 3H), 7.36-7.45 (m, 1H),
    7.77-7.84 (m, 1H), 12.91 (brs, 1H)
    83 (400 MHz, DMSO-D6) 0.52-0.57 (m, 3H), 497 495
    0.89-0.92 (m, 3H), 0.94 (s, 9H), 1.31-1.42 (m, 2H),
    1.55 (s, 3H), 1.78-1.89 (m, 1H), 2.58-2.64 (m, 2H),
    3.05-3.18 (m, 2H), 3.50-3.59 (m, 1H), 3.61-3.70 (m,
    1H), 5.77 (s, 1H), 6.94 (s, 1H), 7.15-7.24 (m, 2H),
    7.25-7.34 (m, 3H), 7.36-7.45 (m, 1H),
    7.77-7.84 (m, 1H), 12.91 (brs, 1H)
    84 (400 MHz, DMSO-D6) 0.66 (d, J = 6.94 Hz, 3H), 373 371
    0.88 (L J = 7.40 Hz, 3H), 1.03 (d, J = 6.94 Hz, 3H), 1.28 (qt,
    J = 7.40, 7.20 Hz, 2H), 1.53 (tt, J = 7.63, 7.20 Hz, 2H),
    1.61 (s, 3H), 1.70 (tt, J = 7.40, 6.80 Hz, 2H), 1.94 (sep,
    J = 6.94 Hz, 1H), 2.18 (t, J = 7.40 Hz, 2H), 2.54 (t,
    J = 7.63 Hz, 2H), 3.31 (dt, J = 13.60, 6.80 Hz, 1H),
    3.43 (dt, J = 13.60, 6.80 Hz, 1H), 5.99 (s, 1H), 6.87 (s, 1H),
    7.14 (d, J = 8.32 Hz, 2H), 7.29 (d, J = 8.32 Hz, 2H),
    12.07 (brs, 1H)
    85 (400 MHz, CDCl3) δ: 0.61 (d, J = 6.85 Hz, 3H), 479 477
    0.92 (t, J = 7.25 Hz, 3H),
    1.01 (d, J = 6.85 Hz, 3H), 1.36 (d, J = 7.25 Hz, 2H),
    1.69 (s, 3H),
    1.96 (d, J = 6.45 Hz, 3H), 2.42 (t, J = 6.65 Hz, 2H),
    2.66 (s, 2H),
    3.58 (d, J = 6.45 Hz, 2H), 4.82 (s, 1H), 5.08 (d, J = 7.25 Hz,
    2H), 5.74 (s, 1H),
    6.92 (d, J = 6.45 Hz, 2H), 7.11 (d, J = 8.46 Hz, 1H),
    7.38 (dt, J = 13.70, 5.84 Hz, 5H).
    86 (400 MHz, DMSO-D6) 0.66-0.71 (m, 3H), 0.94 (s, 421 419
    9H), 1.00-1.07 (m, 3H), 1.34-1.43 (m, 2H), 1.60 (s,
    3H), 1.86-1.99 (m, 1H), 2.38-2.46 (m, 2H),
    2.59-2.66 (m, 2H), 3.46-3.56 (m, 1H), 3.56-3.66 (m, 1H),
    6.11 (s, 1H), 7.01 (s, 1H), 7.23-7.31 (m, 2H),
    7.32-7.35 (m, 1H), 12.27 (brs, 1H)
    87 (400 MHz, DMSO-D6) 0.66-0.71 (m, 3H), 0.94 (s, 421 419
    9H), 1.00-1.07 (m, 3H), 1.34-1.43 (m, 2H), 1.60 (s,
    3H), 1.86-1.99 (m, 1H), 2.38-2.46 (m, 2H),
    2.59-2.66 (m, 2H), 3.46-3.56 (m, 1H), 3.56-3.66 (m, 1H),
    6.11 (s, 1H), 7.01 (s, 1H), 7.23-7.31 (m, 2H),
    7.32-7.35 (m, 1H), 12.27 (brs, 1H)
    88 (400 MHz, DMSO-D6) 0.65-0.73 (m, 2H), 0.95 (s, 451 449
    9H), 1.00-1.07 (m, 2H), 1.34-1.42 (m, 2H),
    1.54-1.68 (m, 4H), 1.84-2.01 (m, 2H), 2.59-2.66 (m, 2H),
    3.40-3.52 (m, 2H), 3.77-3.88 (m, 1H), 6.04 (s, 1H),
    7.01 (s, 1H), 7.23-7.32 (m, 2H), 7.32-7.37 (m, 1H)
    89 (400 MHz, DMSO-D6) 0.65-0.73 (m, 2H), 0.95 (s, 451 449
    9H), 1.00-1.07 (m, 2H), 1.34-1.42 (m, 2H),
    1.54-1.68 (m, 4H), 1.84-2.01 (m, 2H), 2.59-2.66 (m, 2H),
    3.40-3.52 (m, 2H), 3.77-3.88 (m, 1H), 6.04 (s, 1H),
    7.01 (s, 1H), 7.23-7.32 (m, 2H), 7.32-7.37 (m, 1H)
    90 (400 MHz, CDCl3) 0.80 (d, J = 7.25 Hz, 3H), 0.97 (s, 449 447
    9H), 1.14 (d, J = 7.25 Hz, 3H), 1.42-1.47 (m, 2H),
    1.65 (s, 3H), 1.84-1.91 (m, 2H), 2.04-1.96 (m, 1H), 2.00 (s,
    3H), 2.36 (t, J = 6.85 Hz, 2H), 2.68-2.64 (m, 2H),
    3.78-3.61 (m, 2H), 5.52 (s, 1H), 7.16 (d, J = 8.06 Hz, 1H),
    7.24 (dd, J = 8.06, 1.61 Hz, 1H), 7.37 (d, J = 1.61 Hz, 1H)
    91 (400 MHz, CDCl3) 0.93-1.02 (m, 2H), 0.98 (s, 9H), 477 475
    1.29-1.39 (m, 1H), 1.42-1.47 (m, 2H), 1.51-1.76 (m,
    2H), 1.71 (s, 3H), 1.90-1.96 (m, 2H), 2.37 (t,
    J = 7.25 Hz, 2H), 2.64-2.69 (m, 2H), 3.08 (dd, J = 12.09,
    11.69 Hz, 1H), 3.29 (dd, J = 11.69, 12.49 Hz, 1H),
    3.48-3.61 (m, 2H), 3.80 (dd, J = 11.69, 3.63 Hz, 1H),
    3.95 (dd, J = 11.28, 2.82 Hz, 1H), 5.65 (s, 1H), 5.86 (s, 1H),
    7.18 (d, J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz,
    1H), 7.38 (d, J = 1.61 Hz, 1H)
    92 (400 MHz, CDCl3) 0.93-1.02 (m, 2H), 0.98 (s, 9H), 477 475
    1.29-1.39 (m, 1H), 1.42-1.47 (m, 2H), 1.51-1.76 (m,
    2H), 1.71 (s, 3H), 1.90-1.96 (m, 2H), 2.37 (t,
    J = 7.25 Hz, 2H), 2.64-2.69 (m, 2H), 3.08 (dd, J = 12.09,
    11.69 Hz, 1H), 3.29 (dd, J = 11.69, 12.49 Hz, 1H),
    3.48-3.61 (m, 2H), 3.80 (dd, J = 11.69, 3.63 Hz, 1H),
    3.95 (dd, J = 11.28, 2.82 Hz, 1H), 5.65 (s, 1H), 5.86 (s, 1H),
    7.18 (d, J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz,
    1H), 7.38 (d, J = 1.61 Hz, 1H)
    93 (400 MHz, DMSO-D6) 0.60-0.68 (m, 3H), 0.93 (s, 407 405
    9H), 0.98-1.02 (m, 3H), 1.31-1.40 (m, 2H), 1.63 (s,
    3H), 1.85-1.96 (m, 1H), 2.57-2.66 (m, 2H),
    3.91-4.02 (m, 1H), 4.05-4.15 (m, 1H), 6.06 (s, 1H),
    7.05 (s, 1H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H),
    7.43-7.48 (m, 1H), 12.41-12.73 (m, 1H)
    94 (400 MHz, DMSO-D6) 0.60-0.68 (m, 3H), 0.93 (s, 407 405
    9H), 0.98-1.02 (m, 3H), 1.31-1.40 (m, 2H), 1.63 (s,
    3H), 1.85-1.96 (m, 1H), 2.57-2.66 (m, 2H),
    3.91-4.02 (m, 1H), 4.05-4.15 (m, 1H), 6.06 (s, 1H),
    7.05 (s, 1H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H),
    7.43-7.48 (m, 1H), 12.41-12.73 (m, 1H)
    95 (400 MHz, DMSO-D6) 0.93 (s, 9H), 1.21-1.23 (m, 495 493
    1H), 1.34-1.38 (m, 2H), 1.54 (s, 3H), 2.21-2.32 (m,
    3H), 2.52-2.63 (m, 7H), 2.64-2.66 (m, 1H),
    4.92-4.96 (m, 1H), 6.38 (s, 1H), 7.20-7.22 (m, 2H),
    7.29 (d, J = 8.09 Hz, 1H), 7.31 (d, J = 1.85 Hz, 1H)
    96 (400 MHz, DMSO-D6) 0.93 (s, 9H), 1.21-1.23 (m, 495 493
    1H), 1.34-1.38 (m, 2H), 1.54 (s, 3H), 2.23-2.32 (m,
    3H), 2.51-2.66 (m, 7H), 2.84-2.90 (m, 1H),
    4.90-4.98 (m, 1H), 6.38 (s, 1H), 7.21 (dd, J = 7.98, 1.97 Hz,
    1H), 7.23 (s, 1H), 7.29 (d, J = 8.09 Hz, 1H), 7.31 (d,
    J = 1.85 Hz, 1H)
    97 (400 MHz, DMSO-D6) 0.65-0.69 (m, 3H), 447 445
    0.86-0.91 (m, 2H), 0.93 (s, 9H), 0.99-1.06 (m, 5H),
    1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.91-2.01 (m, 1H),
    2.57-2.64 (m, 2H), 3.65-3.74 (m, 2H), 6.26 (s, 1H),
    7.02 (s, 1H), 7.21-7.30 (m, 2H), 7.32-7.36 (m, 1H),
    12.38 (brs, 1H)
    98 (400 MHz, DMSO-D6) 0.65-0.69 (m, 3H), 447 445
    0.86-0.91 (m, 2H), 0.93 (s, 9H), 0.99-1.06 (m, 5H),
    1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.91-2.01 (m, 1H),
    2.57-2.64 (m, 2H), 3.65-3.74 (m, 2H), 6.26 (s, 1H),
    7.02 (s, 1H), 7.21-7.30 (m, 2H), 7.32-7.36 (m, 1H),
    12.38 (brs, 1H)
    99 (400 MHz, CDCl3) 0.93-1.05 (m, 2H), 0.98 (s, 9H), 489 487
    1.35-1.47 (m, 3H), 1.56-1.77 (m, 2H), 1.70 (s, 3H),
    2.56-2.69 (m, 6H), 3.00-3.05 (m, 1H), 3.10 (t,
    J = 11.69 Hz, 1H), 3.30 (t, J = 11.28 Hz, 1H), 3.81 (d,
    J = 12.09 Hz, 1H), 3.96 (d, J = 11.28 Hz, 1H),
    4.99-5.08 (m, 1H), 5.61 (s, 1H), 6.06 (s, 1H), 7.18 (d, J = 8.06 Hz,
    1H), 7.24 (d, J = 10.07 Hz, 1H), 7.37 (s, 1H)
    100 (400 MHz, CDCl3) 0.93-1.05 (m, 2H), 0.98 (s, 9H), 489 487
    1.35-1.47 (m, 3H), 1.56-1.77 (m, 2H), 1.70 (s, 3H),
    2.56-2.69 (m, 6H), 3.00-3.05 (m, 1H), 3.10 (t,
    J = 11.69 Hz, 1H), 3.30 (t, J = 11.28 Hz, 1H), 3.81 (d,
    J = 12.09 Hz, 1H), 3.96 (d, J = 11.28 Hz, 1H),
    4.99-5.08 (m, 1H), 5.61 (s, 1H), 6.06 (s, 1H), 7.18 (d, J = 8.06 Hz,
    1H), 7.24 (d, J = 10.07 Hz, 1H), 7.37 (s, 1H)
    101 (400 MHz, CDCl3) 0.97 (s, 9H), 1.01 (s, 9H), 447 445
    1.41-1.45 (m, 2H), 2.62-2.69 (m, 6H), 3.06-3.13 (m, 1H),
    4.77 (d, J = 2.90 Hz, 1H), 4.91-5.00 (m, 1H),
    5.31-5.36 (m, 1H), 6.27 (s, 1H), 7.02 (dd, J = 7.85, 1.81 Hz,
    1H), 7.15 (d, J = 7.73 Hz, 1H), 7.17 (d, J = 1.69 Hz, 1H)
    102 (400 MHz, CDCl3) 0.97 (s, 9H), 1.01 (s, 9H), 447 445
    1.41-1.45 (m, 2H), 2.62-2.68 (m, 6H), 3.05-3.12 (m, 1H),
    4.77 (d, J = 3.14 Hz, 1H), 4.91-5.00 (m, 1H), 5.39 (d,
    J = 2.41 Hz, 1H), 6.27 (s, 1H), 7.02 (dd, J = 7.73, 1.93 Hz,
    1H), 7.15 (d, J = 7.97 Hz, 1H), 7.17 (d, J = 1.93 Hz, 1H)
    103 (400 MHz, DMSO-D6) 0.70-0.77 (m, 3H), 0.93 (s, 465 463
    9H), 1.03-1.10 (m, 3H), 1.33-1.42 (m, 2H), 1.61 (s,
    3H), 1.85-1.95 (m, 1H), 2.17-2.29 (m, 2H),
    2.36-2.47 (m, 2H), 2.55-2.63 (m, 2H), 2.81-2.89 (m, 1H),
    4.88-5.01 (m, 1H), 6.26 (s, 1H), 6.98 (s, 1H),
    7.11-7.20 (m, 1H), 7.27-7.33 (m, 1H), 12.18 (brs, 1H)
    104 (400 MHz, DMSO-D6) 0.70-0.77 (m, 3H), 0.93 (s, 465 463
    9H), 1.03-1.10 (m, 3H), 1.33-1.42 (m, 2H), 1.61 (s,
    3H), 1.85-1.95 (m, 1H), 2.17-2.29 (m, 2H),
    2.36-2.47 (m, 2H), 2.55-2.63 (m, 2H), 2.81-2.89 (m, 1H),
    4.88-5.01 (m, 1H), 6.26 (s, 1H), 6.98 (s, 1H),
    7.11-7.20 (m, 1H), 7.27-7.33 (m, 1H), 12.18 (brs, 1H)
    105 (400 MHz, DMSO-D6) 0.68 (d, J = 6.45 Hz, 3H), 429 427
    1.03 (d, J = 6.45 Hz, 3H), 1.61 (s, 3H), 1.66-1.74 (m, 2H),
    1.93 (qq, J = 6.45, 6.45 Hz, 1H), 2.18 (t, J = 7.45 Hz, 2H),
    2.71-2.83 (m, 2H), 3.27-3.34 (m, 1H),
    3.39-3.46 (m, 1H), 4.18 (t, J = 5.84 Hz, 2H), 6.00 (s, 1H), 6.87 (s,
    1H), 6.91 (d, J = 8.87 Hz, 2H), 7.31 (d, J = 8.87 Hz, 2H)
    106 (400 MHz, DMSO-D6) 0.63 (d, J = 6.85 Hz, 3H), 373 371
    0.84 (d, J = 6.45 Hz, 6H), 1.02 (d, J = 6.85 Hz, 3H), 1.62 (s,
    3H), 1.66-1.74 (m, 2H), 1.80 (tsep, J = 6.45, 7.25 Hz,
    1H), 1.94 (qq, J = 6.85, 6.85 Hz, 1H), 2.18 (t, J = 7.66 Hz,
    2H), 2.42 (d, J = 7.25 Hz, 2H), 3.28-3.34 (m, 1H),
    3.40-3.47 (m, 1H), 5.99 (s, 1H), 6.89 (s, 1H), 7.10 (d,
    J = 8.46 Hz, 2H), 7.29 (d, J = 8.46 Hz, 2H), 12.07 (brs,
    1H)
    107 (400 Mz, DMSO-D6) 0.76 (d, J = 6.76 Hz, 1H), 0.96 (d, 461 459
    J = 12.56 Hz, 9H), 1.09 (d, J = 6.76 Hz, 1H),
    1.35-1.40 (m, 2H), 1.60 (s, 3H), 1.86-1.89 (m, 2H),
    2.00-2.03 (m, 1H), 2.34-2.43 (m, 5H), 2.61-2.65 (m, 2H),
    4.87-4.89 (m, 1H), 6.30 (s, 1H), 7.05 (s, 1H), 7.22-7.24 (m,
    1H), 7.29-7.31 (m, 2H).
    108 (400 Mz, DMSO-D6) 0.76 (d, J = 6.76 Hz, 1H), 0.96 (d, 461 459
    J = 12.56 Hz, 9H), 1.09 (d, J = 6.76 Hz, 1H),
    1.35-1.40 (m, 2H), 1.60 (s, 3H), 1.86-1.89 (m, 2H),
    2.00-2.03 (m, 1H), 2.34-2.43 (m, 5H), 2.61-2.65 (m, 2H),
    4.87-4.89 (m, 1H), 6.30 (s, 1H), 7.05 (s, 1H), 7.22-7.24 (m,
    1H), 7.29-7.31 (m, 2H),
    109 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 433 431
    1.04 (d, J = 6.70 Hz, 3H), 1.57-1.84 (m, 8H), 1.61 (s, 3H),
    1.94-2.04 (m, 3H), 2.17 (t, J = 7.51 Hz, 2H),
    2.20-2.28 (m, 1H), 2.56 (dd, J = 8.79, 6.94 Hz, 2H),
    3.27-3.34 (m, 1H), 3.42-3.49 (m, 1H), 6.05 (s, 1H),
    6.99 (s, 1H), 7.27 (s, 2H), 7.35 (s, 1H), 12.04 (s, 1H)
    110 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 433 431
    1.04 (d, J = 6.70 Hz, 3H), 1.57-1.84 (m, 8H), 1.61 (s, 3H),
    1.94-2.05 (m, 3H), 2.17 (t, J = 7.51 Hz, 2H),
    2.20-2.26 (m, 1H), 2.56 (dd, J = 8.67, 6.82 Hz, 2H),
    3.27-3.34 (m, 1H), 3.42-3.49 (m, 1H), 6.05 (s, 1H),
    7.00 (s, 1H), 7.27 (s, 2H), 7.35 (s, 1H), 12.06 (s, 1H)
    111 (400 MHz, DMSO-D6) 0.70-0.78 (m, 3H), 0.93 (s, 461 459
    9H), 1.02-1.09 (m, 3H), 1.30-1.42 (m, 5H), 1.60 (s,
    3H), 1.96-2.12 (m, 3H), 2.50-2.54 (m, 2H),
    2.58-2.67 (m, 2H), 4.78-4.95 (m, 1H), 6.30 (s, 1H),
    7.11 (s, 1H), 7.18-7.35 (m, 3H), 12.32 (brs, 1H)
    112 (400 MHz, DMSO-D6) 0.70-0.78 (m, 3H), 0.93 (s, 461 459
    9H), 1.02-1.09 (m, 3H), 1.30-1.42 (m, 5H), 1.60 (s,
    3H), 1.96-2.12 (m, 3H), 2.50-2.54 (m, 2H),
    2.58-2.67 (m, 2H), 4.78-4.95 (m, 1H), 6.30 (s, 1H),
    7.11 (s, 1H), 7.18-7.35 (m, 3H), 12.32 (brs, 1H)
    113 (400 MHz, DMSO-D6) 0.64 (d, J = 6.70 Hz, 3H), 371 369
    1.01 (d, J = 6.70 Hz, 3H), 1.09 (s, 3H), 1.10 (s, 3H), 1.60 (s,
    3H), 1.89 (sep, J = 6.70 Hz, 1H), 2.45 (t, J = 6.94 Hz, 2H),
    2.62-2.67 (m, 4H), 3.52 (dt, J = 14.00, 6.94 Hz, 1H),
    3.62 (dt, J = 14.00, 6.94 Hz, 1H), 6.03 (s, 1H), 6.86 (s,
    1H), 7.09 (d, J = 7.86 Hz, 1H), 7.12 (d, J = 7.86 Hz, 1H),
    7.19 (s, 1H), 12.24 (s, 1H)
    114 (400 MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 409 407
    1.04 (d, J = 6.85 Hz, 3H), 1.31 (t, J = 7.25 Hz, 3H), 1.64 (s,
    3H), 1.96 (qq, J = 6.85, 6.85 Hz, 1H), 2.45 (dd, J = 6.85,
    6.85 Hz, 2H), 3.51 (dt, J = 13.50, 6.85 Hz, 1H), 3.65 (dt,
    J = 13.50, 6.85 Hz, 1H), 4.32 (q, J = 7.25 Hz, 2H), 6.15 (s,
    1H), 7.16 (s, 1H), 7.46 (dd, J = 8.06, 2.01 Hz, 1H),
    7.50 (d, J = 2.01 Hz, 1H), 7.77 (d, J = 8.06 Hz, 1H)
    115 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 445 443
    0.98 (s, 6H), 1.03 (d, J = 6.76 Hz, 3H), 1.45 (t, J = 6.52 Hz,
    2H), 1.61 (s, 3H), 1.92-1.99 (m, 3H), 2.21-2.26 (m,
    2H), 2.45 (t, J = 7.00 Hz, 2H), 3.49-3.56 (m, 1H),
    3.58-3.65 (m, 1H), 5.54-5.56 (m, 1H), 6.12 (s, 1H),
    7.04 (s, 1H), 7.19 (d, J = 7.97 Hz, 1H), 7.29 (dd, J = 7.97,
    1.93 Hz, 1H), 7.36 (d, J = 1.93 Hz, 1H), 12.25 (brs, 1H)
    116 (400 MHz, DMSO-D6) 0.71 (d, J = 7.00 Hz, 3H), 445 443
    0.98 (s, 6H), 1.03 (d, J = 6.76 Hz, 3H), 1.46 (t, J = 6.52 Hz,
    2H), 1.61 (s, 3H), 1.92-1.99 (m, 3H), 2.22-2.26 (m,
    2H), 2.45 (t, J = 7.00 Hz, 2H), 3.49-3.56 (m, 1H),
    3.59-3.66 (m, 1H), 5.54-5.56 (m, 1H), 6.13 (s, 1H),
    7.04 (s, 1H), 7.19 (d, J = 7.97 Hz, 1H), 7.29 (dd, J = 8.09,
    1.81 Hz, 1H), 7.36 (d, J = 1.93 Hz, 1H), 12.26 (brs, 1H)
    117 (400 MHz, DMSO-D6) 0.69 (d, J = 6.76 Hz, 3H), 447 445
    0.94 (s, 3H), 0.97 (s, 3H), 1.03 (d, J = 7.00 Hz, 3H),
    1.29-1.37 (m, 2H), 1.42-1.49 (m, 2H), 1.55-1.60 (m, 7H),
    1.90-1.97 (m, 1H), 2.45 (t, J = 7.00 Hz, 3H),
    2.76-2.84 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H),
    6.11 (s, 1H), 7.02 (s, 1H), 7.30 (dd, J = 7.97, 1.93 Hz,
    1H), 7.34 (d, J = 1.93 Hz, 1H), 7.39 (d, J = 8.21 Hz, 1H),
    12.26 (brs, 3H)
    118 (400 MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 447 445
    0.94 (s, 3H), 0.97 (s, 3H), 1.03 (d, J = 5.80 Hz, 3H),
    1.29-1.37 (m, 2H), 1.45-1.48 (m, 2H), 1.55-1.58 (m, 4H),
    1.60 (s, 3H), 1.90-1.97 (m, 1H), 2.45 (t, J = 7.00 Hz,
    2H), 2.76-2.84 (m, 1H), 3.48-3.55 (m, 1H),
    3.58-3.65 (m, 1H), 6.11 (s, 1H), 7.02 (s, 1H), 7.30 (dd,
    J = 8.09, 1.81 Hz, 1H), 7.34 (d, J = 1.93 Hz, 1H), 7.39 (d,
    J = 8.21 Hz, 1H), 12.26 (brs, 1H)
    119 (400 MHz, DMSO-D6) 0.68 (d, J = 6.94 Hz, 3H), 433 431
    1.03 (d, J = 6.70 Hz, 3H), 1.07-1.19 (m, 2H), 1.42-1.60 (m,
    6H), 1.61 (s, 3H), 1.71-1.81 (m, 3H), 1.93 (t,
    J = 6.70 Hz, 1H), 2.45 (t, J = 6.94 Hz, 2H), 2.65-2.69 (m,
    2H), 3.54 (dd, J = 13.76, 6.82 Hz, 1H), 3.62 (dd,
    J = 13.76, 6.82 Hz, 1H), 6.11 (s, 1H), 7.02 (s, 1H),
    7.27 (dd, J = 7.98, 1.73 Hz, 1H), 7.30 (d, J = 8.09 Hz, 1H),
    7.35 (d, J = 1.62 Hz, 1H), 12.30 (s, 1H)
    120 (400 MHz, DMSO-D6) 0.68 (d, J = 6.94 Hz, 3H), 433 431
    1.02 (d, J = 6.70 Hz, 3H), 1.06-1.19 (m, 2H), 1.46-1.58 (m,
    6H), 1.60 (s, 3H), 1.70-1.80 (m, 3H), 1.89-1.96 (m,
    1H), 2.44 (t, J = 7.05 Hz, 2H), 2.64-2.68 (m, 2H),
    3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H), 6.10 (s, 1H),
    7.01 (s, 1H), 7.26 (dd, J = 8.09, 1.85 Hz, 1H), 7.29 (d,
    J = 8.09 Hz, 1H), 7.34 (d, J = 1.62 Hz, 1H), 12.33 (s, 1H)
    121 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 419 417
    1.03 (d, J = 6.94 Hz, 3H), 1.57-1.66 (m, 4H), 1.60 (s, 3H),
    1.75-1.82 (m, 2H), 1.90-1.97 (m, 1H),
    1.97-2.05 (m, 2H), 2.24 (t, J = 7.74 Hz, 1H), 2.30-2.36 (m, 2H),
    2.56 (t, J = 7.86 Hz, 2H), 3.45-3.54 (m, 1H),
    3.55-3.64 (m, 1H), 6.11 (s, 1H), 6.97 (s, 1H), 7.26 (d,
    J = 0.92 Hz, 2H), 7.33 (s, 1H), 12.44 (s, 1H)
    122 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 419 417
    1.03 (d, J = 6.70 Hz, 3H), 1.57-1.66 (m, 4H), 1.60 (s, 3H),
    1.79 (dt, J = 12.02, 5.20 Hz, 2H), 1.94 (dd, J = 12.72,
    5.55 Hz, 1H), 1.98-2.02 (m, 2H), 2.24 (t, J = 7.74 Hz,
    1H), 2.29-2.36 (m, 2H), 2.56 (dd, J = 12.95, 4.86 Hz,
    2H), 3.45-3.54 (m, 1H), 3.55-3.64 (m, 1H), 6.11 (s,
    1H), 6.96 (s, 1H), 7.26 (d, J = 0.92 Hz, 2H), 7.33 (s,
    1H), 12.35 (s, 1H)
    123 (400 MHz, DMSO-D6) 0.67 (d, J = 6.94 Hz, 3H), 435 433
    0.84 (s, 9H), 1.02 (d, J = 6.70 Hz, 3H), 1.17-1.23 (m, 2H),
    1.47-1.55 (m, 2H), 1.60 (s, 3H), 1.93 (t, J = 7.05 Hz,
    1H), 2.35-2.44 (m, 2H), 2.63 (t, J = 7.74 Hz, 2H),
    3.52 (dd, J = 14.10, 6.94 Hz, 1H), 3.60 (dd, J = 14.10, 6.94 Hz,
    1H), 6.10 (s, 1H), 7.00 (s, 1H), 7.26 (dd, J = 7.60,
    1.40 Hz, 1H), 7.29 (d, J = 7.60 Hz, 1H), 7.35 (d,
    J = 1.39 Hz, 1H), 12.40 (s, 1H)
    124 (400 MHz, DMSO-D6) 0.67 (d, J = 6.70 Hz, 3H), 435 433
    0.84 (s, 9H), 1.02 (d, J = 6.94 Hz, 3H), 1.20 (dd, J = 11.10,
    5.78 Hz, 2H), 1.47-1.55 (m, 2H), 1.60 (s, 3H),
    1.92 (dd, J = 11.79, 4.86 Hz, 1H), 2.43 (t, J = 7.05 Hz, 2H),
    2.63 (t, J = 7.63 Hz, 2H), 3.51 (dd, J = 13.87, 6.94 Hz,
    1H), 3.61 (dd, J = 13.87, 6.94 Hz, 1H), 6.10 (s, 1H),
    7.02 (s, 1H), 7.27 (dd, J = 8.09, 1.62 Hz, 1H), 7.29 (d,
    J = 8.09 Hz, 1H), 7.35 (d, J = 1.39 Hz, 1H), 12.39 (s, 1H)
    125 (400 MHz, CDCl3) 0.67-0.73 (m, 3H), 1.00 (s, 9H), 437 435
    1.02-1.06 (m, 3H), 1.69 (s, 3H), 1.75-1.81 (m, 2H),
    1.82-1.91 (m, 1H), 2.61-2.68 (m, 2H),
    3.70-3.84 (m, 2H), 4.04-4.11 (m, 2H), 5.45 (s, 1H), 5.85 (s,
    1H), 6.83-6.91 (m, 1H), 7.27-7.30 (m, 1H),
    7.41-7.43 (m, 1H)
    126 (400 MHz, CDCl3) 0.68-0.74 (m, 3H), 423 421
    1.01-1.06 (m, 3H), 1.08 (s, 9H), 1.69 (s, 3H), 1.82-1.90 (m,
    1H), 2.63-2.71 (m, 2H), 3.64 (s, 2H), 3.71-3.82 (m,
    2H), 5.24 (s, 1H), 5.86 (s, 1H), 6.81-6.87 (m, 1H),
    7.22-7.28 (m, 1H), 7.39-7.44 (m, 1H)
    127 (400 MHz, CDCl3) 0.65-0.73 (m, 3H), 411 409
    1.00-1.06 (m, 3H), 1.68 (s, 3H), 1.80-1.90 (m, 1H),
    2.59-2.69 (m, 2H), 3.47 (s, 3H), 3.72-3.78 (m, 2H),
    3.78-3.83 (m, 2H), 4.13-4.20 (m, 2H), 5.32-5.52 (m, 1H),
    5.84 (s, 1H), 6.87-6.92 (m, 1H), 7.26-7.30 (m, 1H),
    7.40-7.44 (m, 1H)
    128 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 447 445
    1.02 (d, J = 6.85 Hz, 3H), 1.61 (s, 3H), 1.72-1.80 (m, 2H),
    1.93 (qq, J = 6.85, 6.85 Hz, 1H), 2.22-2.35 (m, 2H),
    2.44 (dd, J = 6.85, 6.85 Hz, 2H), 2.76 (t, J = 7.86 Hz, 2H),
    3.52 (dt, J = 13.50, 6.85 Hz, 1H), 3.62 (dt, J = 13.50,
    6.85 Hz, 1H), 6.11 (s, 1H), 7.03 (s, 1H), 7.30 (dd,
    J = 8.06, 1.61 Hz, 1H), 7.33 (d, J = 8.06 Hz, 1H), 7.38 (d,
    J = 1.61 Hz, 1H)
    129 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 447 445
    1.02 (d, J = 6.85 Hz, 3H), 1.61 (s, 3H), 1.72-1.80 (m, 2H),
    1.93 (qq, J = 6.85, 6.85 Hz, 1H), 2.22-2.35 (m, 2H),
    2.44 (dd, J = 6.85, 6.85 Hz, 2H), 2.76 (t, J = 7.86 Hz, 2H),
    3.52 (dt, J = 13.50, 6.85 Hz, 1H), 3.62 (dt, J = 13.50,
    6.85 Hz, 1H), 6.11 (s, 1H), 7.04 (s, 1H), 7.30 (dd,
    J = 8.06, 1.61 Hz, 1H), 7.33 (d, J = 8.06 Hz, 1H), 7.38 (d,
    J = 1.61 Hz, 1H)
    130 (400 MHz, DMSO-D6) 0.73 (s, 3H), 0.92 (s, 3H), 421 419
    0.95 (s, 9H), 1.27-1.35 (m, 1H), 1.36-1.41 (m, 2H),
    1.66-1.72 (m, 1H), 1.74 (s, 3H), 1.98-2.13 (m, 2H),
    2.59-2.64 (m, 2H), 6.00 (d, J = 5.24 Hz, 1H), 6.77 (d,
    J = 2.01 Hz, 1H), 7.28 (s, 2H), 7.36 (s, 1H), 8.22 (dd,
    J = 5.24, 2.42 Hz, 1H), 11.96 (br s, 1H)
    131 (400 MHz, CDCl3) 0.24-0.30 (m, 4H), 0.71 (d, 419 417
    J = 6.76 Hz, 3H), 1.05 (d, J = 6.76 Hz, 3H), 1.12 (s, 3H),
    1.47-1.51 (m, 2H), 1.71 (s, 3H), 1.85-1.92 (m, 1H),
    2.69 (t, J = 6.40 Hz, 2H), 2.76-2.80 (m, 2H), 3.77 (t,
    J = 6.52 Hz, 2H), 5.89 (s, 1H), 6.00 (brs, 1H), 7.17 (d,
    J = 8.21 Hz, 1H), 7.23 (dd, J = 7.97, 1.93 Hz, 1H),
    7.35 (d, J = 1.93 Hz, 1H)
    132 (400 MHz, CDCl3) 0.24-0.29 (m, 4H), 0.72 (d, 419 417
    J = 7.00 Hz, 3H), 1.05 (d, J = 7.00 Hz, 3H), 1.12 (s, 3H),
    1.47-1.52 (m, 2H), 1.72 (s, 3H), 1.86-1.93 (m, 1H),
    2.70 (t, J = 6.40 Hz, 2H), 2.76-2.80 (m, 2H), 3.77 (t,
    J = 6.52 Hz, 2H), 5.90 (s, 1H), 6.31 (brs, 1H), 7.18 (d,
    J = 7.97 Hz, 1H), 7.22 (dd, J = 7.97, 1.93 Hz, 1H),
    7.34 (d, J = 1.93 Hz, 1H)
    133 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 417 415
    1.03 (d, J = 6.76 Hz, 3H), 1.60-1.65 (m, 5H), 1.67-1.73 (m,
    2H), 1.92-1.99 (m, 1H), 2.11-2.16 (m, 2H),
    2.20-2.24 (m, 2H), 2.45 (t, J = 6.88 Hz, 3H), 3.48-3.56 (m,
    1H), 3.58-3.65 (m, 1H), 5.62-5.65 (m, 1H), 6.12 (s,
    1H), 7.04 (s, 1H), 7.18 (d, J = 8.21 Hz, 1H), 7.29 (dd,
    J = 7.97, 1.93 Hz, 1H), 7.36 (d, J = 1.93 Hz, 1H),
    12.26 (brs, 1H)
    134 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 417 415
    1.03 (d, J = 6.76 Hz, 3H), 1.61-1.65 (m, 5H), 1.67-1.73 (m,
    2H), 1.92-1.99 (m, 1H), 2.12-2.16 (m, 2H),
    2.20-2.24 (m, 2H), 2.45 (t, J = 6.88 Hz, 2H), 3.49-3.56 (m,
    1H), 3.58-3.65 (m, 1H), 5.62-5.64 (m, 1H), 6.12 (s,
    1H), 7.04 (s, 1H), 7.18 (d, J = 7.97 Hz, 1H), 7.29 (dd,
    J = 8.09, 1.81 Hz, 1H), 7.36 (d, J = 1.93 Hz, 1H),
    12.26 (brs, 1H)
    135 (400 MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 419 417
    1.02 (d, J = 6.76 Hz, 3H), 1.19-1.44 (m, 5H), 1.60 (s, 3H),
    1.70-1.81 (m, 5H), 1.90-1.97 (m, 1H), 2.45 (t,
    J = 7.00 Hz, 3H), 2.85-2.91 (m, 1H), 3.48-3.55 (m,
    1H), 3.58-3.65 (m, 1H), 6.11 (s, 1H), 7.01 (s, 1H),
    7.31-7.32 (m, 2H), 7.34 (d, J = 1.69 Hz, 1H),
    12.26 (brs, 1H)
    136 (400 MHz, DMSO-D6) 0.69 (d, J = 6.76 Hz, 3H), 419 417
    1.02 (d, J = 6.76 Hz, 3H), 1.18-1.44 (m, 5H), 1.60 (s, 3H),
    1.70-1.81 (m, 5H), 1.90-1.97 (m, 1H), 2.45 (t,
    J = 6.88 Hz, 2H), 2.85-2.91 (m, 1H), 3.48-3.55 (m,
    1H), 3.58-3.65 (m, 1H), 6.11 (s, 1H), 7.01 (s, 1H),
    7.31-7.32 (m, 2H), 7.34 (d, J = 1.45 Hz, 1H),
    12.26 (brs, 1H)
    137 (400 MHz, DMSO-D6) 0.72 (d, J = 6.28 Hz, 3H), 435 433
    0.76 (d, J = 6.28 Hz, 3H), 0.95 (s, 9H), 1.36-1.40 (m, 2H),
    1.42-1.52 (m, 2H), 1.55 (s, 3H), 1.62-1.68 (m, 1H),
    2.44 (t, J = 6.76 Hz, 2H), 2.60-2.64 (m, 2H),
    3.48-3.55 (m, 1H), 3.58-3.64 (m, 1H), 5.99 (s, 1H),
    7.06 (s, 1H), 7.25 (dd, J = 7.97, 1.69 Hz, 1H), 7.28 (d,
    J = 7.97 Hz, 1H), 7.33 (d, J = 1.69 Hz, 1H)
    138 (400 MHz, DMSO-D6) 0.67 (d, J = 6.76 Hz, 3H), 447 445
    0.86-0.96 (m, 2H), 1.02-1.04 (m, 4H), 1.16-1.21 (m, 4H),
    1.40-1.43 (m, 2H), 1.60 (s, 3H), 1.66-3.74 (m, 4H),
    1.89-1.96 (m, 1H), 2.45 (t, J = 6.88 Hz, 2H),
    2.64-2.68 (m, 2H), 3.48-3.65 (m, 2H), 6.10 (s, 1H), 7.02 (s, 1H),
    7.26-7.27 (m, 2H), 7.34 (s, 1H), 12.30 (br s, 1H).
    139 (400 MHz, DMSO-D6) 0.67 (d, J = 6.76 Hz, 3H), 447 445
    0.86-0.96 (m, 2H), 1.02-1.04 (m, 4H), 1.16-1.21 (m, 4H),
    1.40-1.43 (m, 2H), 1.60 (s, 3H), 1.66-1.74 (m, 4H),
    1.89-1.96 (m, 1H), 2.45 (t, J = 6.88 Hz, 2H),
    2.64-2.68 (m, 2H), 3.48-3.65 (m, 2H), 6.10 (s, 1H), 7.02 (s, 1H),
    7.26-7.27 (m, 2H), 7.34 (s, 1H), 12.30 (br s, 1H).
    140 (400 MHz, DMSO-D6) 0.70 (d, J = 6.85 Hz, 3H), 449 447
    1.02 (d, J = 6.85 Hz, 3H), 1.60 (s, 3H), 1.92 (qq, J = 6.85,
    6.85 Hz, 1H), 2.45 (dd, J = 6.85, 6.85 Hz, 2H),
    2.76-2.87 (m, 2H), 3.52 (dt, J = 13.50, 6.85 Hz, 1H), 3.63 (dt,
    J = 13.50, 6.85 Hz, 1H), 4.27 (t, J = 5.84 Hz, 2H), 6.10 (s,
    1H), 7.01 (s, 1H), 7.14 (d, J = 8.46 Hz, 1H), 7.29 (dd,
    J = 8.46, 2.42 Hz, 1H), 7.38 (d, J = 2.42 Hz, 1H)
    141 (400 MHz, DMSO-D6) 0.67 (d, J = 6.94 Hz, 3H), 447 445
    1.01 (s, 3H), 1.02 (d, J = 6.01 Hz, 3H), 1.09 (s, 3H), 1.38 (dd,
    J = 11.68, 8.67 Hz, 2H), 1.57-1.65 (m, 2H), 1.60 (s,
    3H), 1.81 (td, J = 8.84, 2.77 Hz, 2H), 1.92 (dd, J = 8.90,
    4.51 Hz, 1H), 2.16 (t, J = 8.09 Hz, 1H), 2.45 (t,
    J = 6.94 Hz, 2H), 2.56 (t, J = 7.74 Hz, 2H), 3.53 (dd,
    J = 13.76, 6.82 Hz, 1H), 3.61 (dd, J = 13.76, 6.82 Hz, 1H),
    6.10 (s, 1H), 7.02 (s, 1H), 7.26 (d, J = 1.16 Hz, 2H),
    7.34 (s, 1H), 12.25 (s, 1H)
    142 (400 MHz, DMSO-D6) 0.67 (d, J = 6.94 Hz, 3H), 447 445
    1.01 (s, 3H), 1.02 (d, J = 5.78 Hz, 3H), 1.09 (s, 3H), 1.38 (dd,
    J = 11.44, 8.90 Hz, 2H), 1.57-1.65 (m, 2H), 1.60 (s,
    3H), 1.81 (dt, J = 13.18, 4.16 Hz, 2H), 1.92 (dd, J = 9.02,
    4.62 Hz, 1H), 2.16 (t, J = 8.21 Hz, 1H), 2.45 (dd, J = 9.02,
    5.09 Hz, 2H), 2.56 (dd, J = 10.06, 5.43 Hz, 2H), 3.53 (q,
    J = 6.86 Hz, 1H), 3.61 (dd, J = 13.76, 6.82 Hz, 1H),
    6.10 (s, 1H), 7.02 (s, 1H), 7.26 (d, J = 1.16 Hz, 2H), 7.34 (s,
    1H), 12.25 (s, 1H)
    143 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 441 439
    1.04 (d, J = 6.70 Hz, 3H), 1.61 (s, 3H), 1.93 (dd, J = 11.10,
    4.39 Hz, 1H), 2.45 (dd, J = 9.83, 4.28 Hz, 2H), 2.85 (dd,
    J = 9.83, 5.90 Hz, 2H), 2.96 (dd, J = 9.71, 5.55 Hz, 2H),
    3.53 (t, J = 6.82 Hz, 1H), 3.63 (t, J = 6.94 Hz, 1H),
    6.11 (s, 1H), 7.03 (s, 1H), 7.17-7.23 (m, 3H),
    7.26-7.29 (m, 4H), 7.38 (d, J = 1.39 Hz, 1H), 12.30 (s, 1H)
    144 (400 MHz, DMSO-D6) 0.69 (d, J = 6.70 Hz, 3H), 441 439
    1.03 (d, J = 6.94 Hz, 3H), 1.60 (s, 3H), 1.90-1.97 (m, 1H),
    2.29-2.35 (m, 2H), 2.84 (dd, J = 9.71, 5.55 Hz, 2H),
    2.94 (dd, J = 9.59, 5.43 Hz, 2H), 3.53 (t, J = 6.82 Hz, 1H),
    3.63 (t, J = 6.94 Hz, 1H), 6.11 (s, 1H), 6.98 (s, 1H),
    7.16-7.21 (m, 3H), 7.23-7.29 (m, 4H), 7.37 (d, J = 1.62 Hz,
    1H), 12.50 (s, 1H)
    145 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 483 481
    1.68 (s, 3H), 1.93-2.07 (m, 3H), 2.08-2.18 (m, 1H),
    2.32-2.46 (m, 4H), 2.60-2.69 (m, 3H), 3.67-3.53 (m,
    2H), 5.20 (s, 1H), 5.85 (d, J = 1.21 Hz, 1H), 7.20 (s,
    2H), 7.36 (s, 1H)
    146 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 483 481
    1.68 (s, 3H), 1.93-2.07 (m, 3H), 2.08-2.18 (m, 1H),
    2.32-2.46 (m, 4H), 2.60-2.69 (m, 3H), 3.67-3.53 (m,
    2H), 5.20 (s, 1H), 5.85 (d, J = 1.21 Hz, 1H), 7.20 (s,
    2H), 7.36 (s, 1H)
    147 (400 MHz, DMSO-D6) 0.64-0.71 (m, 3H), 423 421
    0.99-1.04 (m, 3H), 1.22 (s, 9H), 1.59 (s, 3H),
    1.87-1.96 (m, 1H), 2.40-2.46 (m, 2H), 3.42-3.56 (m, 1H),
    3.56-3.69 (m, 1H), 4.42 (s, 2H), 6.09 (s, 1H), 7.02 (s, 1H),
    7.27-7.38 (m, 2H), 7.40-7.49 (m, 1H), 12.24 (brs,
    1H)
    148 (400 MHz, DMSO-D6) 0.72 (d, J = 6.70 Hz, 3H), 403 401
    1.04 (d, J = 6.70 Hz, 3H), 1.61 (s, 3H), 1.90-1.98 (m, 3H),
    2.42-2.53 (m, 4H), 2.67-2.72 (m, 2H),
    3.48-3.55 (m, 1H), 3.62 (dd, J = 13.87, 6.94 Hz, 1H), 6.13 (s, 1H),
    6.14-6.16 (m, 1H), 7.05 (s, 1H), 7.30 (dd, J = 8.21,
    1.73 Hz, 1H), 7.33 (d, J = 7.86 Hz, 1H), 7.38 (d,
    J = 1.62 Hz, 1H), 12.26 (s, 1H)
    149 (400 MHz, DMSO-D6) 0.72 (d, J = 6.94 Hz, 3H), 403 401
    1.03 (d, J = 6.70 Hz, 3H), 1.61 (s, 3H), 1.95 (dt, J = 20.88,
    6.59 Hz, 3H), 2.42-2.51 (m, 4H), 2.69 (td, J = 7.51,
    2.00 Hz, 2H), 3.48-3.55 (m, 1H), 3.59-3.66 (m, 1H),
    6.13 (s, 1H), 6.15 (dd, J = 4.16, 2.31 Hz, 1H), 7.05 (s,
    1H), 7.30 (dd, J = 8.21, 1.73 Hz, 1H), 7.33 (d,
    J = 8.09 Hz, 1H), 7.38 (d, J = 1.62 Hz, 1H), 12.31 (s, 1H)
    150 (400 MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 423 421
    0.93 (d, J = 6.45 Hz, 6H), 1.02 (d, J = 6.85 Hz, 3H), 1.59 (s,
    3H), 1.63 (dt, J = 6.65, 6.70 Hz, 2H), 1.81 (tsep, J = 6.70,
    6.45 Hz, 1H), 1.92 (qq, J = 6.85, 6.85 Hz, 1H), 2.44 (dd,
    J = 7.05, 7.05 Hz, 2H), 3.51 (dt, J = 13.50, 7.05 Hz, 1H),
    3.62 (dt, J = 13.50, 7.05 Hz, 1H), 4.06 (t, J = 6.65 Hz,
    2H), 6.09 (s, 1H), 6.98 (s, 1H), 7.10 (d, J = 8.87 Hz,
    1H), 7.27 (dd, J = 8.87, 2.42 Hz, 1H), 7.35 (d,
    J = 2.42 Hz, 1H)
    151 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 445 443
    1.03 (s, 6H), 1.03 (d, J = 6.76 Hz, 3H), 1.46-1.49 (m, 2H),
    1.61 (s, 3H), 1.68-1.74 (m, 2H), 1.91-1.98 (m, 1H),
    2.16 (t, J = 5.92 Hz, 2H), 2.45 (t, J = 6.88 Hz, 2H),
    3.48-3.55 (m, 1H), 3.59-3.66 (m, 1H), 5.37 (s, 1H),
    6.12 (s, 1H), 7.04 (s, 1H), 7.16 (d, J = 7.97 Hz, 1H), 7.29 (dd,
    J = 7.97, 1.45 Hz, 1H), 7.36 (d, J = 1.21 Hz, 1H),
    12.24 (brs, 1H)
    152 (400 MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 391 389
    1.03 (d, J = 6.76 Hz, 3H), 1.61 (s, 3H), 1.75-1.82 (m, 1H),
    1.90-2.10 (m, 4H), 2.30-2.37 (m, 2H), 2.45 (t,
    J = 7.00 Hz, 2H), 3.48-3.55 (m, 1H), 3.59-3.74 (m,
    2H), 6.11 (s, 1H), 7.02 (s, 1H), 7.31-7.33 (m, 2H),
    7.37 (d, J = 8.93 Hz, 1H), 12.26 (brs, 1H)
    153 (400 MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 391 389
    1.03 (d, J = 6.76 Hz, 3H), 1.60 (s, 3H), 1.75-1.82 (m, 1H),
    1.90-2.10 (m, 4H), 2.30-2.36 (m, 2H), 2.45 (t,
    J = 7.00 Hz, 2H), 3.48-3.55 (m, 1H), 3.59-3.74 (m,
    2H), 6.11 (s, 1H), 7.02 (s, 1H), 7.32 (dd, J = 7.49,
    1.69 Hz, 1H), 7.33 (s, 1H), 7.37 (d, J = 8.69 Hz, 1H),
    12.25 (brs, 1H)
    154 (400 MHz, DMSO-D6) 0.72 (d, J = 6.82 Hz, 3H), 461 459
    0.94 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.37 (dt, J = 8.71,
    3.67 Hz, 2H), 1.60 (s, 3H), 1.88-2.01 (m, 3H),
    2.12-2.15 (m, 2H), 2.62 (dt, J = 10.17, 3.67 Hz, 2H),
    2.97-3.00 (m, 1H), 3.26-3.28 (m, 1H), 3.62 (dd, J = 13.64,
    7.40 Hz, 1H), 6.11 (s, 1H), 7.01 (bs, 1H), 7.24 (dd,
    J = 8.09, 1.85 Hz, 1H), 7.28 (d, J = 8.09 Hz, 1H), 7.32 (d,
    J = 1.85 Hz, 1H), 12.06 (bs, 1H)
    155 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 405 403
    1.03 (d, J = 6.70 Hz, 3H), 1.50-1.57 (m, 2H), 1.61 (s, 3H),
    1.61-1.70 (m, 2H), 1.72-1.81 (m, 2H),
    1.90-2.02 (m, 3H), 2.44 (t, J = 6.94 Hz, 2H), 3.28-3.34 (m, 1H),
    3.52 (q, J = 7.01 Hz, 1H), 3.61 (dd, J = 13.87, 6.94 Hz,
    1H), 6.11 (s, 1H), 7.01 (s, 1H), 7.29 (dd, J = 8.21,
    1.97 Hz, 1H), 7.35 (d, J = 1.95 Hz, 1H), 7.35 (d,
    J = 8.21 Hz, 1H), 12.27 (s, 1H)
    156 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 405 403
    1.03 (d, J = 6.94 Hz, 3H), 1.47-1.57 (m, 2H), 1.60 (s, 3H),
    1.62-1.70 (m, 2H), 1.73-1.79 (m, 2H),
    1.93-2.00 (m, 3H), 2.35-2.41 (m, 2H), 3.28-3.34 (m, 1H),
    3.51 (dd, J = 13.87, 7.17 Hz, 1H), 3.59 (dd, J = 13.87, 7.17 Hz,
    1H), 6.12 (s, 1H), 6.98 (s, 1H), 7.29 (dd, J = 8.09,
    1.85 Hz, 1H), 7.35 (d, J = 1.94 Hz, 1H), 7.35 (d,
    J = 8.21 Hz, 1H), 12.39 (s, 1H)
    157 (400 MHz, CDCl3) 0.67-0.75 (m, 3H), 409 407
    1.00-1.08 (m, 3H), 1.21-1.28 (m, 6H), 1.70 (s, 3H),
    1.82-1.95 (m, 1H), 2.60-2.66 (m, 2H), 3.68-3.82 (m, 3H),
    4.56 (s, 2H), 5.40-5.66 (m, 1H), 5.88 (s, 1H),
    7.31-7.42 (m, 2H), 7.45-7.52 (m, 1H)
    158 (400 MHz, CDCl3) δ: 0.03 (d, J = 2.82 Hz, 9H), 437 435
    0.70 (d, J = 6.85 Hz, 3H), 0.81-0.85 (m, 2H), 1.04 (d, J = 6.85 Hz,
    3H), 1.70 (s, 3H), 1.83-1.90 (m, 1H), 2.67 (dt,
    J = 14.78, 5.44 Hz, 4H), 3.71-3.82 (m, 2H), 5.50 (s,
    1H), 5.87 (s, 1H), 7.20 (d, J = 8.06 Hz, 1H), 7.25 (d,
    J = 2.01 Hz, 2H), 7.37 (d, J = 2.01 Hz, 1H),
    159 (400 MHz, DMSO-D6) 0.73-0.78 (m, 3H), 0.96 (s, 469 467
    9H), 1.07-1.13 (m, 3H), 1.35-1.44 (m, 2H), 1.72 (s,
    3H), 2.01-2.09 (m, 1H), 2.60-2.70 (m, 2H), 6.39 (s,
    1H), 7.30-7.40 (m, 2H), 7.41-7.47 (m, 3H),
    7.54-7.59 (m, 1H), 7.91-7.96 (m, 2H)
    160 (400 MHz, CDCl3) 0.79 (s, 3H), 0.90 (m, 9H), 479 477
    1.04 (d, J = 9.02 Hz, 3H), 1.11-1.39 (m, 3H), 1.43 (m, 2H),
    1.94 (s, 3H), 2.19 (m, 1H), 2.27-2.34 (m, 1H),
    2.61-2.65 (m, 2H), 3.38 (mz, 4H), 3.48-3.54 (m, 2H),
    6.11 (s, 1H), 6.66 (s, 1H), 7.11 (d, J = 8.09 Hz, 1H), 7.25 (m,
    2H), 7.38 (d, J = 1.85 Hz, 1H)
    161 (400 MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 461 459
    1.03 (d, J = 6.85 Hz, 3H), 1.59 (s, 3H), 1.95 (qq, J = 6.85,
    6.85 Hz, 1H), 2.44 (dd, J = 6.85, 6.85 Hz, 2H), 3.50 (dt,
    J = 13.50, 6.85 Hz, 1H), 3.64 (dt, J = 13.50, 6.85 Hz, 1H),
    5.12 (s, 2H), 6.12 (s, 1H), 7.09 (s, 1H), 7.22 (dd,
    J = 12.40, 2.50 Hz, 2H), 7.25 (dd, J = 2.50, 1.41 Hz, 2H),
    7.34-7.40 (m, 3H), 7.43-7.46 (m, 2H)
    162 (400 MHz, DMSO-D6) 0.71 (d, J = 6.85 Hz, 3H), 490 488
    0.95 (s, 9H), 1.03 (d, J = 6.85 Hz, 3H), 1.36-1.40 (m, 2H),
    1.62 (s, 3H), 1.98 (qq, J = 6.85, 6.85 Hz, 1H),
    2.26-2.32 (m, 1H), 2.60-2.65 (m, 2H), 2.65-2.71 (m, 1H),
    3.35-3.38 (m, 1H), 3.67-3.72 (m, 1H), 3.85 (d,
    J = 17.33 Hz, 1H), 4.07 (d, J = 17.33 Hz, 1H),
    5.02-5.09 (m, 1H), 6.22 (s, 1H), 7.19 (s, 1H), 7.27 (dd, J = 8.06,
    2.01 Hz, 1H), 7.30 (d, J = 8.06 Hz, 1H), 7.35 (d,
    J = 2.01 Hz, 1H)
    163 (400 MHz, DMSO-D6) 0.73 (d, J = 6.85 Hz, 3H), 490 488
    0.95 (s, 9H), 1.07 (d, J = 6.85 Hz, 3H), 1.36-1.41 (m, 2H),
    1.62 (s, 3H), 1.98 (qq, J = 6.85, 6.85 Hz, 1H),
    2.18-2.24 (m, 1H), 2.60-2.65 (m, 2H), 2.67-2.74 (m, 1H),
    3.35-3.39 (m, 1H), 3.68-3.73 (m, 1H), 3.83 (d,
    J = 17.73 Hz, 1H), 4.10 (d, J = 17.73 Hz, 1H),
    5.03-5.09 (m, 1H), 6.28 (s, 1H), 7.21 (s, 1H), 7.25 (dd, J = 8.06,
    2.01 Hz, 1H), 7.31 (d, J = 8.06 Hz, 1H), 7.34 (d,
    J = 2.01 Hz, 1H)
    164 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 441 439
    1.02 (s, 9H), 1.03 (d, J = 6.85 Hz, 3H), 1.60 (s, 3H), 1.97 (qq,
    J = 6.85, 6.85 Hz, 1H), 2.43 (dd, J = 7.05, 7.05 Hz, 2H),
    3.50 (dt, J = 13.50, 7.05 Hz, 1H), 3.64 (dt, J = 13.50,
    7.05 Hz, 1H), 3.73 (s, 2H), 6.13 (s, 1H), 7.09 (s, 1H),
    7.21 (dd, J = 12.49, 2.42 Hz, 1H), 7.25 (dd, J = 2.42,
    1.21 Hz, 1H)
    165 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 455 453
    0.94 (s, 9H), 1.03 (d, J = 6.85 Hz, 3H), 1.60 (s, 3H), 1.67 (t,
    J = 7.45 Hz, 2H), 1.97 (qq, J = 6.85, 6.85 Hz, 1H),
    2.44 (dd, J = 6.85, 6.85 Hz, 2H), 3.50 (dt, J = 13.50, 6.85 Hz,
    1H), 3.64 (dt, J = 13.50, 6.85 Hz, 1H), 4.09 (t,
    J = 7.45 Hz, 2H), 6.13 (s, 1H), 7.09 (s, 1H), 7.22 (dd,
    J = 12.29, 2.22 Hz, 1H), 7.26 (dd, J = 2.22, 1.41 Hz, 1H)
    166 (400 MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 447 445
    0.93 (s, 3H), 1.01 (s, 3H), 1.02 (d, J = 7.00 Hz, 3H),
    1.17-1.35 (m, 3H), 1.38-1.46 (m, 2H), 1.55-1.74 (m, 6H),
    1.89-1.96 (m, 1H), 2.45 (t, J = 6.76 Hz, 2H),
    3.07-3.15 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H),
    6.11 (s, 1H), 7.02 (s, 1H), 7.28-7.34 (m, 3H),
    12.25 (brs, 1H)
    167 (400 MHz, DMSO-D6) 0.69 (d, J = 6.76 Hz, 3H), 447 445
    0.93 (s, 3H), 1.01 (s, 3H), 1.02 (d, J = 6.76 Hz, 3H),
    1.15-1.35 (m, 3H), 1.38-1.46 (m, 2H), 1.54-1.74 (m, 6H),
    1.89-1.96 (m, 1H), 2.45 (t, J = 6.76 Hz, 3H),
    3.08-3.17 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H),
    6.11 (s, 1H), 7.01 (s, 1H), 7.28-7.34 (m, 3H),
    12.25 (brs, 1H)
    168 (400 MHz, CDCl3) 0.97 (s, 9H), 1.41-1.50 (m, 2H), 463 461
    1.63 (s, 3H), 1.76-1.96 (m, 3H), 2.03-2.18 (m, 1H),
    2.24-2.35 (m, 1H), 2.38-2.51 (m, 1H),
    2.61-2.71 (m, 2H), 2.74-2.88 (m, 1H), 3.38 (s, 3H),
    3.53-3.60 (m, 2H), 3.61-3.75 (m, 2H), 5.08-5.42 (m, 1H),
    5.93 (s, 1H), 7.12-7.24 (m, 2H), 7.35-7.39 (m, 1H)
    169 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 433 431
    0.86-0.94 (m, 3H), 0.90 (s, 9H), 1.02 (d, J = 6.94 Hz, 3H),
    1.59 (s, 3H), 1.90-1.95 (m, 1H), 1.99-2.05 (m, 1H),
    2.44 (t, J = 6.70 Hz, 2H), 3.47-3.54 (m, 1H),
    3.58-3.65 (m, 1H), 6.11 (s, 1H), 6.97 (d, J = 8.55 Hz, 1H),
    6.98 (s, 1H), 7.23 (dd, J = 8.21, 1.97 Hz, 1H), 7.33 (d,
    J = 2.08 Hz, 1H), 12.28 (s, 1H)
    170 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 433 431
    0.85-0.94 (m, 3H), 0.90 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H),
    1.59 (s, 3H), 1.94 (t, J = 6.94 Hz, 1H), 1.99-2.04 (m,
    1H), 2.35-2.40 (m, 2H), 3.50 (dd, J = 13.99, 6.82 Hz,
    1H), 3.59 (dd, J = 13.99, 6.82 Hz, 1H), 6.11 (s, 1H),
    6.96 (d, J = 8.28 Hz, 1H), 6.97 (s, 1H), 7.22 (dd, J = 8.09,
    1.85 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H), 12.35 (s, 1H)
    171 (400 MHz, CDCl3) 0.30-0.40 (m, 2H), 0.51 (m, 1H), 433 431
    0.78 (s, 3H), 0.92-1.00 (m, 9H), 1.40-1.45 (m, 2H),
    1.79 (s, 4H), 2.65 (m, 5H), 3.67-3.78 (m, 1H),
    5.31 (s, 1H), 6.11 (s, 1H), 7.14 (d, J = 8.09 Hz, 1H), 7.21 (d,
    J = 2.08 Hz, 1H), 7.24 (m, 1H), 7.37 (d, J = 2.08 Hz, 1H)
    172 (400 MHz, CDCl3) 0.85 (s, 3H), 0.97 (s, 9H), 1.13 (s, 463 461
    3H), 1.21 (d, J = 4.84 Hz, 3H), 1.23 (d, J = 4.84 Hz, 3H),
    1.34-1.39 (m, 1H), 1.42-1.46 (m, 2H), 1.97 (s, 3H),
    2.12-2.25 (m, 2H), 2.35-2.27 (m, 1H), 2.66-2.62 (m,
    2H), 4.59-4.52 (m, 1H), 6.16 (s, 1H), 6.58 (s, 1H),
    7.13 (d, J = 8.06 Hz, 1H), 7.23 (dd, J = 8.06, 2.01 Hz,
    1H), 7.36 (d, J = 2.01 Hz, 1H)
    173 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 431 429
    1.02 (d, J = 6.70 Hz, 3H), 1.60 (s, 3H), 1.77-2.04 (m, 7H),
    2.12 (t, J = 6.82 Hz, 2H), 2.38-2.47 (m, 4H),
    3.46-3.56 (m, 2H), 3.62 (dt, J = 13.60, 6.80 Hz, 1H), 6.11 (s,
    1H), 7.01 (s, 1H), 7.28-7.33 (m, 3H), 12.27 (brs, 1H)
    174 (400 MHz, DMSO-D6) 0.70 (d, J = 6.70 Hz, 3H), 419 417
    0.78-0.88 (m, 2H), 0.88-0.95 (m, 1H), 0.98 (d, J = 6.70 Hz,
    3H), 1.02 (t, J = 6.13 Hz, 6H), 1.14-1.21 (m, 1H),
    1.59 (s, 3H), 1.93 (dd, J = 12.37, 6.13 Hz, 2H),
    2.35-2.43 (m, 2H), 3.50 (dd, J = 13.76, 6.59 Hz, 1H), 3.59 (dd,
    J = 13.76, 7.05 Hz, 1H), 6.11 (s, 1H), 6.93 (d, J = 8.32 Hz,
    1H), 6.96 (s, 1H), 7.22 (dd, J = 8.21, 1.97 Hz, 1H),
    7.33 (d, J = 2.08 Hz, 1H), 12.46 (s, 1H)
    175 (400 MHz, DMSO-D6) 0.71 (d, J = 6.85 Hz, 3H), 439 437
    0.95 (s, 9H), 1.03 (d, J = 6.85 Hz, 3H), 1.31-1.35 (m, 2H),
    1.60 (s, 3H), 1.97 (qq, J = 6.85, 6.85 Hz, 1H), 2.43 (dd,
    J = 6.85, 6.85 Hz, 2H), 2.64-2.69 (m, 2H), 3.50 (dt,
    J = 13.50, 6.85 Hz, 1H), 3.63 (dt, J = 13.50, 6.85 Hz, 1H),
    6.14 (s, 1H), 7.09 (s, 1H), 7.12 (dd, J = 11.08, 1.81 Hz,
    1H), 7.24 (dd, J = 1.81, 1.01 Hz, 1H)
    176 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 405 403
    0.93 (s, 9H), 1.02 (d, J = 6.85 Hz, 3H), 1.38-1.42 (m, 2H),
    1.60 (s, 3H), 1.94 (qq, J = 6.85, 6.85 Hz, 1H), 2.44 (dd,
    J = 6.85, 6.85 Hz, 2H), 2.52-2.55 (m, 2H), 3.51 (dt,
    J = 13.50, 6.85 Hz, 1H), 3.62 (dt, J = 13.50, 6.85 Hz, 1H),
    6.09 (s, 1H), 6.99 (s, 1H), 7.07 (dd, J = 11.89, 2.01 Hz,
    1H), 7.12 (dd, J = 8.06, 2.01 Hz, 1H), 7.23 (dd, J = 8.06,
    4.03 Hz, 1H)
    177 (400 MHz, DMSO-D6) 0.65 (d, J = 6.82 Hz, 3H), 421 419
    0.84 (t, J = 7.51 Hz, 6H), 1.02 (d, J = 6.82 Hz, 3H),
    1.20-1.30 (m, 4H), 1.53-1.56 (m, 1H), 1.61 (s, 3H),
    1.88-1.95 (m, 1H), 2.45 (t, J = 6.80 Hz, 2H), 2.59 (d, J = 7.17 Hz,
    2H), 3.52 (dt, J = 14.00, 6.80 Hz, 2H), 3.62 (dt, J = 14.00,
    6.80 Hz, 2H), 6.09 (s, 1H), 7.04 (bs, 1H), 7.24 (d,
    J = 8.09 Hz, 2H), 7.27 (dd, J = 8.09, 1.74 Hz, 2H),
    7.35 (d, J = 1.74 Hz, 1H), 12.31 (bs, 1H)
    178 (400 MHz, DMSO-D6) 0.63 (d, J = 6.94 Hz, 3H), 449 447
    0.81 (t, J = 6.70 Hz, 6H), 1.01 (d, J = 6.94 Hz, 3H),
    1.13-1.35 (m, 8H), 1.61 (s, 3H), 1.67-1.70 (m, 1H),
    1.87-1.94 (m, 1H), 2.45 (t, J = 6.80 Hz, 2H), 2.59 (d, J = 7.17 Hz,
    2H), 3.53 (dt, J = 14.00, 6.80 Hz, 1H), 3.62 (dt, J = 14.00,
    6.80 Hz, 1H), 6.08 (s, 1H), 7.05 (bs, 1H), 7.23 (t,
    J = 3.93 Hz, 1H), 7.25-7.29 (m, 1H), 7.35 (d,
    J = 1.85 Hz, 1H), 12.29 (bs, 1H)
    179 (400 MHz, DMSO-D6) 0.598 (d, J = 7.20 Hz, 1.5H), 435 433
    0.600 (d, J = 7.20 Hz, 1.5H), 0.99 (d, J = 6.70 Hz, 3H),
    1.11 (d, J = 7.20 Hz, 1.5H), 1.12 (d, J = 7.20 Hz, 1.5H),
    1.46 (ddd, J = 14.05, 3.93, 0.92 Hz, 1H), 1.58 (s, 3H),
    1.75 (dd, J = 14.05, 8.79 Hz, 1H), 1.87-1.90 (m, 1H),
    2.42-2.44 (m, 2H), 2.48-2.49 (m, 1H), 3.51 (dt,
    J = 14.00, 6.80 Hz, 1H), 3.61 (dt, J = 14.00, 6.80 Hz, 1H),
    6.06 (s, 1H), 6.98 (s, 0.5H), 7.00 (s, 0.5H),
    7.27-7.31 (m, 2H), 7.36-7.38 (m, 1H)
    180 (400 MHz, CDCl3) 0.90 (s, 3H), 0.96-1.02 (m, 18H), 505 503
    1.29-1.52 (m, 4H), 3.80 (s, 3H), 2.51-2.72 (m, 8H),
    2.96-3.10 (m, 1H), 3.44-3.60 (m, 2H),
    4.94-5.06 (m, 1H), 5.07-5.18 (m, 1H), 6.16 (s, 1H),
    7.13-7.20 (m, 2H), 7.21-7.28 (m, 1H), 7.40-7.45 (m, 1H)
    181 (400 MHz, CDCl3) 0.82 (s, 3H), 0.96 (s, 9H), 1.15 (s, 533 531
    3H), 1.36-1.47 (m, 2H), 1.99 (s, 3H), 2.18-2.36 (m,
    2H), 2.50-2.78 (m, 8H), 2.97-3.10 (m, 1H), 3.72 (s,
    3H), 4.77-4.90 (m, 1H), 6.24 (s, 1H), 7.02 (brs, 1H),
    7.08-7.14 (m, 1H), 7.17-7.21 (m, 1H),
    7.31-7.33 (m, 1H)
    182 (400 MHz, CDCl3) 0.77 (s, 3H), 0.94 (s, 9H), 1.13 (s, 505 503
    3H), 1.33-1.50 (m, 3H), 1.97 (s, 3H), 2.07-2.50 (m,
    6H), 2.57-2.71 (m, 2H), 3.70-3.75 (m, 2H),
    4.78-4.89 (m, 1H), 6.31 (s, 1H), 6.91 (brs, 1H),
    7.07-7.13 (m, 1H), 7.13-7.21 (m, 1H), 7.29-7.35 (m, 1H)
    183 (400 MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 409 407
    0.99 (d, J = 6.45 Hz, 6H), 1.02 (d, J = 6.85 Hz, 3H), 1.59 (s,
    3H), 1.92 (qq, J = 6.85, 6.85 Hz, 1H), 2.03 (tscp, J = 6.45,
    6.45 Hz, 1H), 2.45 (dd, J = 7.05, 7.05 Hz, 2H), 3.52 (dt,
    J = 13.50, 7.05 Hz, 1H), 3.62 (dt, J = 13.50, 7.05 Hz, 1H),
    3.81 (d, J = 6.45 Hz, 2H), 6.09 (s, 1H), 6.98 (s, 1H),
    7.07 (d, J = 8.87 Hz, 1H), 7.26 (dd, J = 8.87, 2.42 Hz,
    1H), 7.36 (d, J = 2.42 Hz, 1H)
    184 (400 MHz, CDCl3) 0.85 (d, J = 15.26 Hz, 3H), 0.96 (s, 475 473
    9H), 1.10 (s, 6H), 1.24-1.77 (m, 8H), 1.90 m, 2H),
    2.14-2.31 (m, 2H), 2.61-2.65 (m, 2H), 4.72 (m, 1H),
    6.08 (s, 1H), 6.30 (s, 1H), 7.12 (d, J = 7.63 Hz, 1H),
    7.21 (t, J = 3.93 Hz, 1H), 7.25 (t, J = 1.50 Hz, 1H),
    7.35 (s, 1H)
    185 (400 MHz, DMSO-D6) 0.64-0.70 (m, 3H), 475 473
    0.98-1.03 (m, 3H), 1.16 (s, 6H), 1.58 (s, 3H),
    1.60-1.67 (m, 2H), 1.85-1.99 (m, 1H), 2.35-2.42 (m, 2H),
    2.66-2.74 (m, 2H), 3.43-3.55 (m, 1H), 3.55-3.65 (m,
    1H), 6.10 (s, 1H), 7.00 (s, 1H), 7.21-7.39 (m, 3H)
    186 (400 MHz, DMSO-D6) 0.64-0.70 (m, 3H), 0.94 (s, 459 457
    9H), 0.99-1.04 (m, 3H), 1.33-1.41 (m, 2H), 1.58 (s,
    3H), 1.85-2.00 (m, 7H), 2.58-2.64 (m, 2H),
    4.00-4.15 (m, 1H), 5.93 (s, 1H), 6.86 (s, 1H),
    7.19-7.34 (m, 3H)
    187 (400 MHz, CDCl3) 0.97 (s, 9H), 1.33 (s, 9H), 431 429
    1.90-2.03 (m, 2H), 2.32-2.45 (m, 2H), 3.40-3.47 (m, 1H),
    3.67-3.74 (m, 1H), 4.84 (d, J = 2.87 Hz, 1H),
    5.50-5.59 (brm, 1H), 6.11 (s, 1H), 7.05 (dd, J = 7.94, 1.76 Hz,
    1H), 7.25 (d, J = 1.76 Hz, 1H), 7.38 (d, J = 7.94 Hz, 1H)
    188 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 371 369
    1.03 (d, J = 6.85 Hz, 3H), 1.63 (s, 3H), 1.67-1.74 (m, 2H),
    1.82 (s, 3H), 1.87 (s, 3H), 1.96 (qq, J = 6.85, 6.85 Hz,
    1H), 2.18 (t, J = 7.45 Hz, 2H), 3.28-3.34 (m, 1H),
    3.40-3.47 (m, 1H), 6.01 (s, 1H), 6.24 (s, 1H), 6.91 (s, 1H),
    7.18 (d, J = 8.46 Hz, 2H), 7.34 (d, J = 8.46 Hz, 2H)
    189 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 437 435
    1.04 (d, J = 6.85 Hz, 3H), 1.11 (s, 9H), 1.61 (s, 3H), 1.98 (qq,
    J = 6.85, 6.85 Hz, 1H), 2.44 (dd, J = 7.05, 7.05 Hz, 2H),
    3.51 (dt, J = 13.50, 7.05 Hz, 1H), 3.64 (dt, J = 13.50,
    7.05 Hz, 1H), 6.14 (s, 1H), 6.29 (d, J = 16.52 Hz, 1H),
    6.44 (d, J = 16.52 Hz, 1H), 7.13 (s, 1H), 7.17 (dd,
    J = 12.29, 1.81 Hz, 1H), 7.28 (d, J = 1.81 Hz, 1H)
  • TABLE 4
    MS
    M + H M − H
    or or
    Example 1H-NMR M − Na + H M − Na − H
    190 (400 MHz, CDCl3) 0.90 (s, 3H), 0.97 (s, 9H), 1.00 (s, 519 517
    3H), 1.24-1.40 (m, 2H), 1.40-1.51 (m, 3H), 1.79 (s,
    3H), 2.56-2.73 (m, 6H), 3.00-3.11 (m, 1H),
    3.43-3.60 (m, 2H), 3.73 (s, 3H), 4.48-4.53 (m, 1H),
    4.89-5.03 (m, 1H), 6.14 (s, 1H), 7.14-7.18 (m, 1H),
    7.24-7.29 (m, 1H), 7.42-7.46 (m, 1H)
    191 (400 MHz, CDCl3) 0.90 (s, 3H), 0.97 (s, 9H), 1.00 (s, 519 517
    3H), 1.24-1.40 (m, 2H), 1.40-1.51 (m, 3H), 1.79 (s,
    3H), 2.56-2.73 (m, 6H), 3.00-3.11 (m, 1H),
    3.43-3.60 (m, 2H), 3.73 (s, 3H), 4.48-4.53 (m, 1H),
    4.89-5.03 (m, 1H), 6.14 (s, 1H), 7.14-7.18 (m, 1H),
    7.24-7.29 (m, 1H), 7.42-7.46 (m, 1H)
    192 (400 MHz, DMSO-D6) 0.73-0.79 (m, 3H), 489 487
    0.88-0.93 (m, 6H), 1.05-1.11 (m, 3H), 1.55-1.63 (m, 2H),
    1.70 (s, 3H), 1.77-1.88 (m, 1H), 2.02-2.13 (m, 1H),
    4.05-4.11 (m, 2H), 6.35 (s, 1H), 7.27-7.38 (m, 4H),
    7.51-7.55 (m, 1H), 7.85-7.91 (m, 2H)
    193 (400 MHz, DMSO-D6) 0.72-0.78 (m, 3H), 1.01 (s, 489 487
    9H), 1.06-1.10 (m, 3H), 1.70 (s, 3H), 2.03-2.12 (m,
    1H), 3.73-3.75 (m, 2H), 6.33 (s, 1H), 7.24-7.36 (m,
    4H), 7.46-7.52 (m, 1H), 7.82-7.89 (m, 2H)
    194 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 427 425
    0.99 (d, J = 6.45 Hz, 6H), 1.03 (d, J = 6.45 Hz, 3H), 1.60 (s,
    3H), 1.93-2.05 (m, 2H), 2.44 (t, J = 7.05 Hz, 2H),
    3.50 (dt, J = 13.50, 7.05 Hz, 1H), 3.64 (dt, J = 13.50, 7.05 Hz,
    1H), 3.83 (d, J = 6.25 Hz, 2H), 6.13 (s, 1H), 7.09 (s,
    1H), 7.21 (dd, J = 12.29, 2.22 Hz, 1H), 7.25 (dd, J = 2.22,
    1.41 Hz, 1H)
    195 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 441 439
    0.92 (d, J = 6.85 Hz, 6H), 1.03 (d, J = 6.85 Hz, 3H),
    1.57-1.62 (m, 2H), 1.60 (s, 3H), 1.78-1.88 (m, 1H),
    1.93-2.00 (m, 1H), 2.44 (t, J = 6.85 Hz, 2H), 3.50 (dt, J = 13.50,
    6.85 Hz, 1H), 3.64 (dt, J = 13.50, 6.85 Hz, 1H), 4.07 (t,
    J = 6.45 Hz, 2H), 6.13 (s, 1H), 7.09 (s, 1H), 7.22 (dd,
    J = 12.29, 2.22 Hz, 1H), 7.26 (dd, J = 2.22, 1.41 Hz, 1H)
    196 (400 MHz, DMSO-D6) 0.71-0.77 (m, 3H), 523 521
    1.06-1.11 (m, 3H), 1.14-1.18 (m, 6H), 1.61-1.69 (m, 2H),
    1.72 (s, 3H), 2.01-2.09 (m, 1H), 2.68-2.77 (m, 2H),
    6.39 (s, 1H), 7.36-7.40 (m, 2H), 7.41-7.49 (m, 3H),
    7.55-7.58 (m, 1H), 7.91-7.95 (m, 2H), 12.86 (brs,
    1H)
    197 (400 MHz, CDCl3) 0.83 (s, 3H), 0.97 (s, 9H), 1.14 (s, 505 503
    3H), 1.33-1.40 (m, 1H), 1.41-1.48 (m, 2H), 1.97 (s,
    3H), 2.11-2.34 (m, 3H), 2.34-2.46 (m, 3H),
    2.46-2.57 (m, 1H), 2.59-2.69 (m, 2H), 3.26 (s, 3H),
    3.97-4.04 (m, 1H), 4.77-4.87 (m, 1H), 6.22 (s, 1H),
    6.81 (brs, 1H), 7.10-7.15 (m, 1H), 7.19-7.22 (m, 1H),
    7.32-7.35 (m, 1H)
    198 (400 MHz, DMSO-D6) 0.81 (s, 3H), 0.94 (s, 9H), 519 517
    0.98 (s, 3H), 1.35-1.40 (m, 3H), 1.74 (s, 3H),
    1.76-1.83 (m, 1H), 1.93-1.99 (m, 2H), 2.04-2.08 (m, 2H),
    2.25-2.40 (m, 3H), 2.59-2.63 (m, 2H), 3.28 (s, 3H),
    3.40 (d, J = 6.45 Hz, 2H), 4.88-4.80 (m, 1H), 6.34 (s, 1H),
    6.92 (s, 1H), 7.22 (dd, J = 8.06, 2.01 Hz, 1H), 7.27 (d,
    J = 8.06 Hz, 1H), 7.32 (d, J = 2.01 Hz, 1H)
    199 (400 MHz, CDCl3) 0.77-0.91 (m, 2H),
    0.96-0.99 (m, 9H), 1.40-1.49 (m, 2H), 1.61-1.66 (m, 3H),
    1.69-1.76 (m, 1H), 1.77-1.94 (m, 2H), 2.09-2.19 (m,
    1H), 2.27-2.37 (m, 1H), 2.43-2.53 (m, 1H),
    2.61-2.71 (m, 1H), 2.78-2.92 (m, 1H), 3.47-3.57 (m, 2H),
    4.01-4.11 (m, 2H), 4.51-4.63 (m, 1H), 5.12 (brs,
    1H), 5.96 (brs, 1H), 7.15-7.19 (m, 2H),
    7.33-7.34 (m, 1H)
    200 (400 MHz, CDCl3) 0.98 (s, 9H), 1.41-1.47 (m, 2H), 489 487
    1.62-1.66 (m, 3H), 1.79-1.98 (m, 3H),
    2.09-2.21 (m, 1H), 2.39-2.54 (m, 5H), 2.62-2.71 (m, 2H),
    2.81-2.92 (m, 1H), 3.26-3.30 (m, 3H), 3.99-4.06 (m,
    1H), 4.84-4.90 (m, 1H), 4.92-5.02 (m, 1H),
    5.98-6.00 (m, 1H), 7.14-7.23 (m, 2H), 7.33-7.36 (m, 1H)
    201 (400 MHz, CDCl3) 0.74-0.85 (m, 6H), 1.05 (s, 9H), 455 453
    1.47-1.63 (m, 2H), 1.66-1.75 (m, 4H),
    2.61-2.68 (m, 2H), 3.59-3.66 (m, 2H), 3.67-3.77 (m, 2H),
    5.30 (brs, 1H), 5.79 (s, 1H), 6.56-6.62 (m, 1H),
    7.03-7.10 (m, 1H)
    202 (400 MHz, CDCl3) 0.74-0.85 (m, 6H), 455 453
    0.91-1.01 (m, 6H), 1.45-2.09 (m, 9H), 2.60-2.69 (m, 2H),
    3.68-3.78 (m, 2H), 4.00-4.07 (m, 2H), 5.19 (brs, 1H),
    5.79 (s, 1H), 6.58-6.65 (m, 1H), 7.03-7.12 (m, 1H)
    203 (400 MHz, DMSO-D6) 0.75-0.80 (m, 3H), 471 469
    1.09-1.13 (m, 3H), 1.24 (s, 9H), 1.74 (s, 3H),
    2.03-2.13 (m, 1H), 4.45 (s, 2H), 6.41 (s, 1H), 7.41-7.54 (m,
    5H), 7.58-7.62 (m, 1H), 7.92-7.97 (m, 2H),
    12.88 (brs, 1H)
    204 (400 MHz, DMSO-D6) 0.64-0.72 (m, 3H), 0.94 (s, 483 481
    9H), 0.98-1.03 (m, 3H), 1.35-1.38 (m, 2H),
    1.96-2.05 (m, 3H), 2.57-2.65 (m, 2H), 4.48-4.57 (m, 1H),
    4.70-4.79 (m, 2H), 6.14 (s, 1H), 7.17-7.36 (m, 6H),
    7.84-7.89 (m, 2H), 12.88 (brs, 1H)
    205 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.34-1.41 (m, 489 487
    2H), 1.43-1.51 (m, 1H), 1.51-1.54 (m, 3H),
    1.57-1.67 (m, 2H), 2.02-2.15 (m, 2H), 2.23-2.34 (m, 4H),
    2.58-2.65 (m, 2H), 2.84-2.95 (m, 1H),
    3.23-3.28 (m, 2H), 4.32-4.37 (m, 1H), 4.88-4.99 (m, 1H),
    6.17 (s, 1H), 7.12-7.14 (m, 1H), 7.18-7.24 (m, 1H),
    7.26-7.31 (m, 2H), 12.24 (brs, 1H)
    206 (400 MHz, CDCl3) 0.94-1.01 (m, 9H), 477 475
    1.40-1.49 (m, 2H), 1.53-1.68 (m, 5H), 2.05-2.17 (m, 1H),
    2.17-2.29 (m, 1H), 2.29-2.43 (m, 1H), 2.58-2.69 (m,
    5H), 3.20-3.24 (m, 2H), 3.27-3.30 (m, 3H),
    3.66-3.79 (m, 1H), 3.79-3.90 (m, 1H), 5.53-5.64 (m, 1H),
    5.79-5.82 (m, 1H), 7.12-7.23 (m, 2H),
    7.31-7.36 (m, 1H)
    207 (400 MHz, DMSO-D6) 0.68-0.72 (m, 3H), 0.96 (s, 487 485
    9H), 1.03-1.09 (m, 3H), 1.37-1.43 (m, 2H), 1.73 (s,
    3H), 1.98-2.08 (m, 1H), 2.61-2.69 (m, 2H), 6.20 (s,
    1H), 7.32-7.46 (m, 3H), 7.46-7.49 (m, 1H),
    7.51-7.56 (m, 1H), 7.65-7.72 (m, 1H), 7.72-7.78 (m, 1H)
    208 (400 MHz, CDCl3) 0.68-0.79 (m, 3H), 0.98 (brs, 487 485
    9H), 1.03-1.09 (m, 3H), 1.39-1.49 (m, 2H),
    1.72-1.80 (m, 3H), 1.87-2.00 (m, 1H), 2.61-2.72 (m, 2H),
    5.51-5.77 (m, 1H), 6.00-6.10 (m, 1H),
    7.00-7.12 (m, 1H), 7.14-7.24 (m, 1H), 7.28-7.35 (m, 1H),
    7.37-7.51 (m, 2H), 7.84-7.99 (m, 1H)
    209 (400 MHz, DMSO-D6) 0.75-0.79 (m, 3H), 541 539
    0.79-0.83 (m, 3H), 0.95 (s, 9H), 1.34-1.44 (m, 4H),
    1.66 (s, 3H), 1.84-1.95 (m, 2H), 2.60-2.67 (m, 2H),
    3.15 (s, 3H), 3.24-3.29 (m, 2H), 6.39 (s, 1H),
    7.32-7.36 (m, 2H), 7.41-7.44 (m, 2H), 7.44-7.46 (m, 1H),
    7.64-7.69 (m, 1H), 7.91-7.97 (m, 2H)
    210 (400 MHz, DMSO-D6) 0.96 (s, 9H), 1.35-1.43 (m, 485 483
    2H), 1.69 (s, 3H), 1.96-2.09 (m, 1H), 2.13-2.22 (m,
    1H), 2.60-2.69 (m, 2H), 3.12 (s, 3H), 3.18-3.29 (m,
    2H), 6.39 (s, 1H), 7.32-7.39 (m, 2H), 7.42-7.48 (m,
    3H), 7.63-7.67 (m, 1H), 7.90-7.97 (m, 2H),
    12.89 (brs, 1H)
    211 (400 MHz, CDCl3) 0.98 (s, 9H), 1.40-1.48 (m, 2H), 437 435
    1.68 (s, 3H), 1.84-1.95 (m, 1H), 2.00-2.11 (m, 1H),
    2.59-2.70 (m, 4H), 3.14-3.27 (m, 5H),
    3.67-3.88 (m, 2H), 5.53 (brs, 1H), 5.91-5.93 (m, 1H),
    7.15-7.19 (m, 1H), 7.22-7.26 (m, 1H), 7.37-7.39 (m, 1H)
    212 (400 MHz, DMSO-D6) 0.72 (d, J = 6.94 Hz, 3H), 417 415
    0.92 (s, 9H), 1.03 (d, J = 6.94 Hz, 3H), 1.32-1.38 (m, 2H),
    1.61 (s, 3H), 1.91-1.98 (m, 1H), 2.43-2.49 (m, 4H),
    3.45-3.52 (m, 1H), 3.61-3.69 (m, 1H), 3.75 (s, 3H),
    6.08 (s, 1H), 6.87 (dd, J = 7.74, 1.73 Hz, 1H),
    6.89-6.92 (m, 2H), 7.05 (d, J = 7.86 Hz, 1H), 12.24 (s, 1H)
    213 (400 MHz, DMSO-D6) 0.72 (d, J = 6.94 Hz, 3H), 417 415
    0.92 (s, 9H), 1.03 (d, J = 6.94 Hz, 3H), 1.32-1.38 (m, 2H),
    1.61 (s, 3H), 1.94 (t, J = 6.70 Hz, 1H), 2.43-2.49 (m,
    4H), 3.45-3.52 (m, 1H), 3.62-3.69 (m, 1H), 3.75 (s,
    3H), 6.08 (s, 1H), 6.87 (dd, J = 7.74, 1.73 Hz, 1H),
    6.89-6.92 (m, 2H), 7.05 (d, J = 7.86 Hz, 1H), 12.26 (s, 1H)
    214 (400 MHz, CDCl3) 0.70 (d, J = 6.94 Hz, 3H), 1.03 (t, 425 423
    J = 5.20 Hz, 6H), 1.06 (d, J = 6.70 Hz, 6H), 1.88 (tt,
    J = 19.19, 6.40 Hz, 2H), 2.66 (t, J = 6.24 Hz, 2H), 2.80 (d,
    J = 6.94 Hz, 2H), 3.76 (t, J = 6.47 Hz, 2H), 5.19 (s, 1H),
    5.86 (s, 1H), 7.18 (d, J = 8.32 Hz, 1H), 7.28 (dd, J = 8.44,
    1.97 Hz, 1H), 7.39 (d, J = 2.08 Hz, 1H)
    215 (400 MHz, CDCl3) 0.69 (t, J = 6.59 Hz, 3H), 1.06 (d, 441 439
    J = 6.70 Hz, 6H), 1.20 (d, J = 6.70 Hz, 6H), 1.88 (dt,
    J = 19.34, 6.70 Hz, 2H), 2.60 (tt, J = 17.11, 5.39 Hz, 2H),
    2.83 (dd, J = 12.95, 9.94 Hz, 2H), 3.76 (ddd, J = 44.74,
    20.46, 12.60 Hz, 2H), 5.69 (d, J = 27.51 Hz, 1H), 5.91 (s,
    1H), 7.45 (dd, J = 18.84, 1.73 Hz, 1H), 7.58 (ddd,
    J = 20.29, 8.38, 1.79 Hz, 1H), 7.86 (dd, J = 10.52,
    8.21 Hz, 1H)
    216 1H-NMR (CDCl3) δ: 0.71 (d, J = 6.94 Hz, 3H), 0.87 (t, 471 469
    J = 3.24 Hz, 6H), 1.07 (d, J = 6.94 Hz, 6H),
    1.51-1.68 (m, 2H), 1.86 (dd, J = 13.64, 6.70 Hz, 2H), 2.58 (dt, J = 8.71,
    3.29 Hz, 2H), 3.36-3.40 (m, 2H), 3.69-3.85 (m,
    2H), 5.82 (s, 1H), 5.92 (s, 1H), 7.54 (dd, J = 8.32, 1.85 Hz,
    1H), 7.63 (d, J = 1.85 Hz, 1H), 8.06 (d, J = 8.32 Hz,
    1H).
    217 (400 MHz, CDCl3) 0.71 (d, J = 6.94 Hz, 3H), 0.87 (t, 455 453
    J = 3.24 Hz, 6H), 1.07 (d, J = 6.94 Hz, 6H),
    1.51-1.68 (m, 2H), 1.86 (dd, J = 13.64, 6.70 Hz, 2H), 2.58 (dt,
    J = 8.71, 3.29 Hz, 2H), 3.36-3.40 (m, 2H),
    3.69-3.85 (m, 2H), 5.82 (s, 1H), 5.92 (s, 1H), 7.54 (dd, J = 8.32,
    1.85 Hz, 1H), 7.63 (d, J = 1.85 Hz, 1H), 8.06 (d,
    J = 8.32 Hz, 1H)
    218 (400 MHz, CDCl3) 0.70 (d, J = 6.70 Hz, 3H), 0.93 (d, 439 437
    J = 6.70 Hz, 6H), 1.04 (d, J = 6.94 Hz, 3H), 1.57 (dd,
    J = 15.37, 6.82 Hz, 5H), 1.72-1.89 (m, 2H), 2.66 (t,
    J = 6.36 Hz, 2H), 2.92 (t, J = 7.74 Hz, 2H), 3.76 (td,
    J = 6.30, 2.62 Hz, 2H), 5.24 (s, 1H), 5.86 (s, 1H),
    7.19 (d, J = 8.32 Hz, 1H), 7.29 (dd, J = 8.32, 2.08 Hz, 1H),
    7.40 (d, J = 1.85 Hz, 1H)
    219 (400 MHz, CDCl3) 0.71 (d, J = 6.94 Hz, 3H), 457 455
    0.99-1.08 (m, 9H), 1.83-1.90 (m, 3H), 2.18-2.28 (m, 2H),
    2.52-2.60 (m, 2H), 3.28 (d, J = 6.47 Hz, 2H), 3.67-3.86 (m,
    2H), 5.92 (d, J = 5.32 Hz, 2H), 7.54 (dd, J = 8.44,
    1.73 Hz, 1H), 7.62 (d, J = 1.85 Hz, 1H), 8.07 (d,
    J = 8.32 Hz, 1H)
    220 (400 MHz, DMSO-D6) 0.61-0.77 (m, 3H), 0.95 (s, 483 481
    9H), 0.99-1.10 (m, 3H), 1.35-1.43 (m, 2H), 1.71 (s,
    3H), 2.02-2.18 (m, 4H), 2.60-2.69 (m, 2H),
    5.91-6.04 (m, 1H), 6.95-7.05 (m, 1H), 7.18-7.45 (m, 3H),
    7.46-7.49 (m, 1H), 7.62-7.67 (m, 1H),
    7.67-7.75 (m, 1H)
    221 (400 MHz, DMSO-D6) 0.65-0.70 (m, 3H), 0.94 (s, 499 497
    9H), 1.00-1.06 (m, 3H), 1.36-1.43 (m, 2H), 1.71 (s,
    3H), 1.95-2.05 (m, 1H), 2.60-2.68 (m, 2H), 3.87 (s,
    3H), 5.98 (s, 1H), 7.29-7.36 (m, 3H), 7.37-7.44 (m,
    1H), 7.52-7.60 (m, 3H), 13.03 (brs, 1H)
    222 (400 MHz, CDCl3) 0.71-0.77 (m, 3H), 0.98 (s, 9H), 495 493
    1.03-1.10 (m, 3H), 1.40-1.49 (m, 2H), 1.71 (s, 3H),
    1.87-1.97 (m, 1H), 2.63-2.72 (m, 2H),
    4.17-4.26 (m, 3H), 4.27-4.35 (m, 3H), 5.35 (brs, 1H), 5.91 (s,
    1H), 7.14-7.21 (m, 1H), 7.23-7.28 (m, 1H),
    7.38-7.41 (m, 1H)
    223 (400 MHz, CDCl3) 0.66 (dd, J = 9.02, 6.94 Hz, 3H), 453 451
    1.05 (dd, J = 6.82, 1.50 Hz, 3H), 1.31-2.07 (m, 20H),
    2.61-2.67 (m, 2H), 3.42 (t, J = 7.86 Hz, 1H),
    3.70-3.84 (m, 2H), 5.53 (d, J = 15.95 Hz, 1H), 5.90 (d,
    J = 3.24 Hz, 1H), 7.44 (dd, J = 17.57, 1.85 Hz, 1H),
    7.54 (tt, J = 13.18, 3.74 Hz, 1H), 7.78 (dd, J = 10.06, 8.21 Hz,
    1H)
    224 (400 MHz, CDCl3) 0.70 (d, J = 6.94 Hz, 3H), 1.04 (d, 437 435
    J = 6.94 Hz, 3H), 1.54-1.89 (m, 0H), 2.10 (t, J = 7.86 Hz,
    2H), 2.67 (t, J = 6.24 Hz, 2H), 3.76 (t, J = 6.24 Hz, 2H),
    5.19 (s, 1H), 5.87 (s, 1H), 7.28 (t, J = 2.08 Hz, 2H),
    7.39 (s, 1H)
    225 (400 MHz, CDCl3) 0.97 (s, 9H), 1.41-1.49 (m, 2H), 485 483
    1.71 (s, 3H), 2.63-2.70 (m, 2H), 3.39 (s, 3H),
    3.54-3.63 (m, 3H), 3.82-3.95 (m, 1H), 5.43-5.55 (m, 1H),
    6.44 (s, 1H), 6.96-7.01 (m, 2H), 7.15-7.21 (m, 1H),
    7.25-7.30 (m, 1H), 7.43-7.46 (m, 1H),
    7.83-7.87 (m, 2H)
    226 (400 MHz, CDCl3) 0.76-0.81 (m, 3H), 0.99 (s, 9H), 499 497
    1.10-1.14 (m, 3H), 1.42-1.49 (m, 2H), 1.82 (s, 3H),
    1.95-2.04 (m, 1H), 2.66-2.72 (m, 2H), 4.11 (s, 3H),
    4.93 (brs, 1H), 6.23 (s, 1H), 7.00-7.05 (m, 1H),
    7.20-7.25 (m, 1H), 7.29-7.34 (m, 1H), 7.36-7.40 (m, 1H),
    7.45-7.48 (m, 1H), 8.20-8.25 (m, 1H)
    227 (400 MHz, CDCl3) 0.70 (d, J = 6.94 Hz, 3H), 1.07 (d, 469 467
    J = 6.70 Hz, 3H), 1.64 (d, J = 7.17 Hz, 5H), 1.83 (dt,
    J = 17.42, 7.63 Hz, 4H), 2.05 (t, J = 11.33 Hz, 2H),
    2.57 (dd, J = 9.13, 6.59 Hz, 2H), 3.77 (ddd, J = 25.72, 13.24,
    6.65 Hz, 2H), 4.07 (t, J = 7.40 Hz, 1H), 5.83 (s, 1H),
    5.91 (s, 1H), 7.50-7.54 (m, 1H), 7.62 (d, J = 1.85 Hz,
    1H), 8.06 (d, J = 8.32 Hz, 1H)
    228 (400 MHz, CDCl3) 0.74 (d, J = 6.85 Hz, 3H), 447 445
    0.96-1.10 (m, 4H), 0.98 (s, 9H), 1.07 (d, J = 6.85 Hz, 3H),
    1.46-1.42 (m, 2H), 1.68 (s, 3H), 1.87-1.93 (m, 1H),
    2.64-2.69 (m, 2H), 2.72 (s, 2H), 5.45 (s, 1H), 5.98 (s, 1H),
    7.18 (d, J = 8.06 Hz, 1H), 7.21 (dd, J = 8.06, 1.61 Hz,
    1H), 7.33 (d, J = 1.61 Hz, 1H)
    229 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 495 493
    1.64 (s, 3H), 1.81-1.92 (m, 2H), 2.09-2.17 (m, 1H),
    2.28-2.38 (m, 1H), 2.45-2.54 (m, 1H),
    2.65-2.69 (m, 2H), 2.78-2.91 (m, 3H), 2.94-3.04 (m, 2H),
    4.66-4.76 (m, 1H), 4.99 (s, 1H), 5.95 (s, 1H),
    7.21-7.17 (m, 2H), 7.34 (s, 1H)
    230 (400 MHz, CDCl3) 0.98 (s, 9H), 1.14-1.19 (m, 6H), 421 419
    1.40-1.48 (m, 2H), 1.67 (s, 3H), 1.99-2.11 (m, 1H),
    2.13-2.37 (m, 3H), 2.61-2.70 (m, 2H),
    4.59-4.70 (m, 1H), 5.83 (s, 1H), 5.90 (s, 1H), 7.13-7.22 (m,
    2H), 7.32-7.37 (m, 1H)
    231 (400 MHz, MeOH-D4) 1.01 (s, 9H), 1.44-1.51 (m, 456 454
    2H), 1.84 (s, 3H), 2.19-2.38 (m, 4H), 2.70-2.76 (m,
    2H), 6.50 (s, 1H), 7.27-7.33 (m, 1H), 7.38-7.43 (m,
    1H), 7.48-7.51 (m, 1H), 7.56-7.60 (m, 2H),
    8.49-8.55 (m, 2H)
    232 (400 MHz, DMSO-D6) 0.70-0.76 (m, 3H), 0.93 (s, 487 475
    9H), 1.03-1.07 (m, 3H), 1.32-1.41 (m, 2H), 1.57 (s,
    3H), 1.91-2.26 (m, 9H), 2.57-2.63 (m, 2H),
    4.46-4.59 (m, 1H), 6.15 (s, 1H), 7.01 (brs, 1H),
    7.19-7.23 (m, 1H), 7.25-7.32 (m, 2H)
    233 (400 MHz, DMSO-D6) 0.69-0.75 (m, 3H), 0.93 (s, 487 485
    9H), 1.02-1.08 (m, 3H), 1.32-1.40 (m, 2H), 1.58 (s,
    3H), 1.84-2.20 (m, 9H), 2.56-2.64 (m, 2H),
    4.46-4.58 (m, 1H), 6.14 (s, 1H), 7.00 (brs, 1H),
    7.18-7.24 (m, 1H), 7.24-7.31 (m, 2H)
    234 (400 MHz, CDCl3) 0.75 (d, J = 6.85 Hz, 3H), 0.98 (s, 461 459
    9H), 1.08 (d, J = 6.85 Hz, 3H), 1.42-1.46 (m, 2H),
    1.71 (s, 3H), 1.74-1.89 (m, 3H), 1.94-2.11 (m, 4H),
    2.63-2.68 (m, 2H), 2.80 (td, J = 8.46, 8.06 Hz, 1H), 4.89 (td,
    J = 7.25, 8.06 Hz, 1H), 5.27 (s, 1H), 5.93 (s, 1H),
    7.17 (d, J = 8.06 Hz, 1H), 7.23 (dd, J = 8.06, 2.01 Hz, 1H),
    7.36 (d, J = 2.01 Hz, 1H)
    235 (400 MHz, DMSO-D6) 0.65 (d, J = 6.85 Hz, 3H), 475 473
    0.95 (s, 9H), 1.01 (d, J = 6.85 Hz, 3H), 1.22-1.46 (m, 5H),
    1.55 (s, 3H), 1.57-1.67 (m, 3H), 1.69-1.78 (m, 1H),
    1.79-1.94 (m, 2H), 2.45-2.53 (m, 1H),
    2.60-2.65 (m, 2H), 4.11-4.26 (m, 1H), 6.10 (s, 1H), 6.79 (s,
    1H), 7.26 (dd, J = 8.06, 1.61 Hz, 1H), 7.29 (d,
    J = 8.06 Hz, 1H), 7.34 (d, J = 1.61 Hz, 1H)
    236 (400 MHz, DMSO-D6) 0.67-0.74 (m, 3H), 0.95 (s, 435 433
    9H), 1.01-1.06 (m, 3H), 1.14-1.20 (m, 3H),
    1.34-1.42 (m, 2H), 1.58 (s, 3H), 1.87-1.99 (m, 1H),
    2.52-2.57 (m, 2H), 2.58-2.66 (m, 2H), 4.55-4.70 (m, 1H),
    6.11 (s, 1H), 6.93-6.96 (m, 1H), 7.23-7.32 (m, 2H),
    7.32-7.36 (m, 1H), 12.21 (brs, 1H)
    237 (400 MHz, DMSO-D6) 0.65-0.73 (m, 3H), 0.95 (s, 562 560
    9H), 1.02-1.07 (m, 3H), 1.35-1.40 (m, 2H), 1.42 (s,
    9H), 1.56-1.64 (m, 3H), 1.86-1.97 (m, 1H),
    2.59-2.66 (m, 2H), 3.24-3.43 (m, 4H), 3.45-3.56 (m, 1H),
    3.56-3.67 (m, 1H), 4.85-5.03 (m, 1H),
    6.18-6.30 (m, 1H), 7.11-7.18 (m, 1H), 7.23-7.39 (m, 3H),
    12.63 (brs, 1H)
    238 (400 MHz, DMSO-D6) 0.65-0.73 (m, 3H), 0.95 (s, 462 460
    9H), 1.02-1.08 (m, 3H), 1.35-1.42 (m, 2H),
    1.59-1.68 (m, 3H), 2.59-2.66 (m, 2H), 3.25-3.52 (m, 5H),
    3.58-3.68 (m, 1H), 4.77-5.03 (m, 1H),
    6.20-6.29 (m, 1H), 7.24-7.42 (m, 4H), 8.87-9.22 (m, 1H)
    239 (400 MHz, DMSO-D6) 0.64-0.71 (m, 3H), 0.94 (s, 504 502
    9H), 1.00-1.07 (m, 3H), 1.32-1.41 (m, 2H),
    1.56-1.63 (m, 3H), 1.83-1.96 (m, 4H), 2.57-2.65 (m, 2H),
    3.30-3.36 (m, 1H), 3.39-3.64 (m, 2H),
    3.66-3.89 (m, 2H), 4.80-5.13 (m, 1H), 6.13-6.32 (m, 1H),
    7.10-7.16 (m, 1H), 7.22-7.39 (m, 2H), 12.62 (brs, 1H)
    240 (400 MHz, DMSO-D6) 0.65-0.72 (m, 3H), 0.93 (s, 540 538
    9H), 1.00-1.06 (m, 3H), 1.33-1.41 (m, 2H), 1.60 (s,
    3H), 1.86-2.00 (m, 1H), 2.57-2.64 (m, 2H),
    2.91-2.96 (m, 3H), 3.08-3.26 (m, 2H), 3.38-3.52 (m, 2H),
    3.52-3.59 (m, 1H), 4.81-5.02 (m, 1H), 6.19 (s, 1H),
    7.08-7.15 (m, 1H), 7.22-7.31 (m, 2H),
    7.31-7.37 (m, 1H)
    241 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.30-1.40 (m, 463 461
    3H), 1.48-1.59 (m, 2H), 1.52 (s, 3H), 2.02-2.09 (m,
    2H), 2.35-2.43 (m, 3H), 2.60-2.64 (m, 2H), 3.22 (d,
    J = 5.64 Hz, 2H), 3.48-3.55 (m, 1H), 3.57-3.65 (m,
    1H), 6.03 (s, 1H), 7.02 (s, 1H), 7.22 (dd, J = 8.06,
    2.01 Hz, 1H), 7.28 (d, J = 8.06 Hz, 1H), 7.31 (d,
    J = 2.01 Hz, 1H)
    242 (400 MHz, DMSO-D6) 0.68-0.73 (m, 3H), 0.95 (s, 461 459
    9H), 1.02-1.07 (m, 3H), 1.33-1.42 (m, 2H),
    1.47-2.00 (m, 9H), 2.53-2.57 (m, 2H), 2.58-2.66 (m, 2H),
    4.67-4.78 (m, 1H), 6.04-6.08 (m, 1H),
    6.90-6.95 (m, 1H), 7.22-7.36 (m, 3H)
    243 (400 MHz, DMSO-D6) 0.68-0.73 (m, 3H), 0.95 (s, 461 459
    9H), 1.02-1.07 (m, 3H), 1.33-1.42 (m, 2H),
    1.47-2.00 (m, 9H), 2.53-2.57 (m, 2H), 2.58-2.66 (m, 2H),
    4.67-4.78 (m, 1H), 6.04-6.08 (m, 1H),
    6.90-6.95 (m, 1H), 7.22-7.36 (m, 3H)
    244 (400 MHz, CDCl3) 0.85-0.89 (m, 3H), 0.97 (s, 9H), 490 488
    1.08-1.13 (m, 3H), 1.29-1.35 (m, 3H),
    1.40-1.47 (m, 2H), 1.85 (s, 3H), 2.59-2.69 (m, 2H),
    3.28-3.66 (m, 5H), 3.77-3.92 (m, 1H), 4.20-4.30 (m, 2H),
    4.30-4.38 (m, 1H), 5.95 (s, 1H), 7.12-7.20 (m, 1H),
    7.28-7.36 (m, 1H), 7.60-7.69 (m, 1H), 8.66 (brs, 1H),
    11.57 (brs, 1H)
    245 (400 MHz, CDCl3) 0.78-0.82 (m, 3H), 0.97 (s, 9H), 490 488
    1.04-1.12 (m, 3H), 1.22-1.35 (m, 3H),
    1.38-1.52 (m, 2H), 1.80 (s, 3H), 2.57-2.72 (m, 1H),
    3.36-3.71 (m, 5H), 3.72-3.91 (m, 1H), 4.20-4.30 (m, 2H),
    4.35-4.47 (m, 1H), 5.95 (s, 1H), 7.03-7.10 (m, 1H),
    7.13-7.20 (m, 1H), 7.23-7.26 (m, 1H), 7.30-7.35 (m,
    1H), 8.79 (brs, 1H), 10.94 (brs, 1H)
    246 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.35-1.40 (m, 523 521
    2H), 1.53 (s, 3H), 1.58-1.70 (m, 2H), 1.74-2.11 (m,
    9H), 2.23-2.31 (m, 1H), 2.55 (d, J = 9.27 Hz, 1H),
    2.60-2.64 (m, 2H), 2.73-2.82 (m, 1H), 4.27-4.20 (m,
    1H), 5.97 (s, 1H), 7.18 (s, 1H), 7.21 (dd, J = 7.86,
    1.81 Hz, 1H), 7.29 (d, J = 8.06 Hz, 1H), 7.31 (d,
    J = 2.01 Hz, 1H)
    247 (400 MHz, DMSO-D6) 0.67-0.73 (m, 3H), 0.92 (s, 435 433
    9H), 1.01-1.06 (m, 3H), 1.13-1.19 (m, 3H),
    1.32-1.41 (m, 2H), 1.58 (s, 3H), 1.89-2.01 (m, 1H),
    2.50-2.54 (m, 2H), 2.56-2.67 (m, 2H), 4.54-4.69 (m, 1H),
    6.10 (s, 1H), 6.92-6.98 (m, 1H), 7.21-7.29 (m, 2H),
    7.29-7.35 (m, 1H), 12.16 (brs, 1H)
    248 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.46 (m, 2H), 509 507
    1.63 (s, 3H), 1.82-1.91 (m, 2H), 2.11 (q, J = 10.21 Hz,
    1H), 2.29-2.55 (m, 5H), 2.61-2.72 (m, 4H),
    2.81-2.90 (m, 1H), 3.63 (d, J = 7.25 Hz, 2H), 5.09 (s, 1H),
    5.83 (s, 1H), 7.18-7.16 (m, 2H), 7.32 (s, 1H)
    249 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.36-1.40 (m, 476 474
    2H), 1.53 (s, 3H), 1.70 (t, J = 10.00 Hz, 2H),
    1.89-1.96 (m, 1H), 2.18-2.25 (m, 1H), 2.29-2.35 (m, 2H),
    2.43-2.53 (m, 1H), 2.60-2.75 (m, 3H), 3.49-3.56 (m,
    1H), 3.58-3.66 (m, 1H), 6.03 (s, 1H), 6.86 (s, 1H),
    7.06 (s, 1H), 7.23 (dd, J = 1.61, 8.06 Hz, 1H), 7.29 (d,
    J = 8.06 Hz, 1H), 7.31 (d, J = 2.01 Hz, 1H), 7.37 (s, 1H)
    250 (400 MHz, DMSO-D6) 0.72-0.85 (m, 4H), 0.95 (s, 489 487
    9H), 1.35-1.40 (m, 2H), 1.52 (s, 3H), 1.67 (q,
    J = 10.21 Hz, 1H), 1.73-1.81 (m, 1H), 1.91 (q,
    J = 10.07 Hz, 1H), 2.21-2.29 (m, 1H), 2.46-2.53 (m,
    1H), 2.60-2.64 (m, 2H), 2.72-2.78 (m, 1H), 3.28 (s,
    3H), 3.34-3.44 (m, 2H), 5.93 (s, 1H), 7.03 (s, 1H),
    7.21 (dd, J = 2.01, 8.06 Hz, 1H), 7.29-7.27 (m, 2H)
    251 (400 MHz, CDCl3) 0.98 (s, 9H), 1.17 (s, 3H), 1.21 (s, 487 485
    3H), 1.42-1.46 (m, 2H), 1.62 (s, 3H), 1.83-1.97 (m,
    4H), 2.10-2.18 (m, 3H), 2.28-2.36 (m, 1H),
    2.44-2.52 (m, 1H), 2.63-2.68 (m, 2H), 2.80-2.89 (m, 1H),
    4.79-4.88 (m, 1H), 5.27 (s, 1H), 6.06 (s, 1H), 7.15 (d,
    J = 8.06 Hz, 1H), 7.19 (dd, J = 8.06, 1.61 Hz, 1H),
    7.33 (d, J = 1.61 Hz, 1H)
    252 (400 MHz, CDCl3) 0.98 (s, 9H), 1.41-1.48 (m, 2H), 517 515
    1.79 (s, 3H), 1.98-2.24 (m, 2H), 2.32-2.57 (m, 2H),
    2.61-2.74 (m, 3H), 5.45 (brs, 1H), 6.20 (s, 1H),
    7.20-7.24 (m, 1H), 7.26-7.31 (m, 1H), 7.40-7.55 (m, 3H),
    8.05-8.20 (m, 2H)
    253 (400 MHz, DMSO-D6) 0.64 (d, J = 6.70 Hz, 3H), 387 385
    0.93 (s, 9H), 1.01 (d, J = 6.70 Hz, 3H), 1.42 (dt, J = 8.55,
    4.16 Hz, 2H), 1.60 (s, 3H), 1.86-1.94 (m, 1H),
    2.42-2.54 (m, 4H), 3.48-3.56 (m, 1H), 3.57-3.65 (m, 1H),
    6.05 (s, 1H), 6.90 (s, 1H), 7.14 (d, J = 8.09 Hz, 2H),
    7.28 (d, J = 8.09 Hz, 2H), 12.26-12.29 (m, 1H)
    254 (400 MHz, DMSO-D6) 0.67-0.73 (m, 3H), 0.93 (s, 475 473
    9H), 1.00-1.06 (m, 3H), 1.32-1.54 (m, 4H),
    1.55-1.66 (m, 4H), 1.70-1.81 (m, 1H), 1.83-2.02 (m, 3H),
    2.56-2.63 (m, 2H), 2.74-2.80 (m, 1H),
    4.21-4.33 (m, 1H), 6.09 (s, 1H), 6.94 (s, 1H), 7.19-7.25 (m,
    1H), 7.25-7.29 (m, 1H), 7.30-7.33 (m, 1H),
    12.18 (brs, 1H)
    255 (400 MHz, DMSO-D6) 0.68-0.74 (m, 3H), 0.93 (s, 475 473
    9H), 1.01-1.07 (m, 3H), 1.31-1.44 (m, 4H),
    1.44-1.54 (m,2H), 1.55-1.67 (m, 4H), 1.70-1.81 (m, 1H),
    1.83-2.02 (m, 3H), 2.57-2.64 (m, 2H),
    4.22-4.33 (m, 1H), 6.10 (s, 1H), 6.94 (s, 1H), 7.19-7.24 (m,
    1H), 7.24-7.29 (m, 1H), 7.29-7.33 (m, 1H),
    12.19 (brs, 1H)
    256 (400 MHz, DMSO-D6) 0.67-0.73 (m, 3H), 0.93 (s, 475 473
    9H), 1.00-1.06 (m, 3H), 1.32-1.54 (m, 4H),
    1.55-1.66 (m, 4H), 1.70-1.81 (m, 1H), 1.83-2.02 (m, 3H),
    2.56-2.63 (m, 2H), 2.74-2.80 (m, 1H),
    4.21-4.33 (m, 1H), 6.09 (s, 1H), 6.94 (s, 1H), 7.19-7.25 (m,
    1H), 7.25-7.29 (m, 1H), 7.30-7.33 (m, 1H),
    12.18 (brs, 1H)
    257 (400 MHz, DMSO-D6) 0.68-0.74 (m, 3H), 0.93 (s, 475 473
    9H), 1.01-1.07 (m, 3H), 1.31-1.44 (m, 4H),
    1.44-1.54 (m, 2H), 1.55-1.67 (m, 4H), 1.70-1.81 (m, 1H),
    1.83-2.02 (m, 3H), 2.57-2.64 (m, 2H),
    4.22-4.33 (m, 1H), 6.10 (s, 1H), 6.94 (s, 1H), 7.19-7.24 (m,
    1H), 7.24-7.29 (m, 1H), 7.29-7.33 (m, 1H),
    12.19 (brs, 1H)
    258 (400 MHz, DMSO-D6) 0.69 (d, J = 6.70 Hz, 3H), 433 431
    0.80 (d, J = 6.70 Hz, 6H), 1.02 (d, J = 6.70 Hz, 3H),
    1.37-1.48 (m, 1H), 1.60-1.69 (m, 2H), 1.60 (s, 3H),
    1.83-1.97 (m, 2H), 2.38-2.48 (m, 4H), 3.37-3.46 (m, 1H),
    3.52 (ddd, J = 6.80, 7.20, 14.00 Hz, 1H), 3.62 (ddd, J = 6.80,
    7.20, 14.00 Hz, 1H), 6.11 (s, 1H), 7.03 (s, 1H),
    7.29-7.34 (m, 3H), 12.30 (brs, 1H)
    259 (400 MHz, CDCl3) 0.75 (d, J = 6.85 Hz, 3H), 0.98 (s, 449 447
    9H), 1.04 (d, J = 6.85 Hz, 3H), 1.42-1.47 (m, 2H),
    1.56 (s, 3H), 1.58 (s, 3H), 1.67 (s, 3H), 1.90-1.97 (m, 1H),
    2.64-2.69 (m, 2H), 3.11 (d, J = 14.51 Hz, 1H), 3.19 (d,
    J = 14.91 Hz, 1H), 4.97 (s, 1H), 6.16 (s, 1H), 7.18 (d,
    J = 8.06 Hz, 1H), 7.25 (dd, J = 2.01, 8.06 Hz, 1H),
    7.38 (d, J = 2.01 Hz, 1H)
    260 (400 MHz, CDCl3) 0.71 (d, J = 6.94 Hz, 3H), 0.98 (s, 437 435
    6H), 1.05 (d, J = 6.94 Hz, 3H), 1.49-1.54 (m, 2H),
    1.70 (s, 3H), 1.84-1.91 (m, 1H), 2.70-2.65 (m, 4H),
    3.40 (s, 2H), 3.75-3.77 (m, 2H), 5.28 (s, 1H), 5.87 (s, 1H),
    7.19 (d, J = 8.09 Hz, 1H), 7.26 (dd, J = 8.09, 1.85 Hz,
    1H), 7.38 (d, J = 1.85 Hz, 1H)
    261 (400 MHz, CDCl3) 0.99 (d, J = 6.94 Hz, 3H), 451 449
    1.13-1.11 (m, 6H), 1.16 (s, 3H), 1.39-1.66 (m, 2H), 1.80 (s,
    3H), 1.91-1.96 (m, 1H), 2.14-2.23 (m, 1H),
    2.53-2.58 (m, 1H), 3.31-3.19 (m, 2H), 3.96-4.00 (m, 1H),
    6.12 (s, 1H), 6.66-6.69 (m, 1H), 7.13-7.16 (m, 1H),
    7.26 (s, 1H)
    262 (400 MHz, DMSO-D6) 0.68-0.76 (m, 3H), 0.93 (s, 489 487
    9H), 0.99-1.10 (m, 5H), 1.32-1.40 (m, 2H),
    1.46-1.62 (m, 7H), 1.63-1.81 (m, 3H), 1.94-2.03 (m, 1H),
    2.07-2.11 (m, 2H), 2.57-2.64 (m, 2H),
    3.99-4.10 (m, 1H), 6.13 (s, 1H), 6.97 (brs, 1H), 7.20-7.29 (m,
    2H), 7.29-7.33 (m, 1H)
    263 (400 MHz, CDCl3) 0.69 (d, J = 6.85 Hz, 3H), 1.05 (d, 419 417
    J = 6.85 Hz, 3H), 1.17-1.26 (m, 2H), 1.50-1.56 (m,
    2H), 1.62-1.68 (m, 4H), 1.70 (s, 3H), 1.84-1.91 (m,
    1H), 2.13-2.21 (m, 1H), 2.66 (t, J = 6.25 Hz, 2H),
    2.71 (d, J = 7.25 Hz, 2H), 3.70-3.84 (m, 2H), 5.28 (s, 1H),
    5.86 (s, 1H), 7.17 (d, J = 8.06 Hz, 1H), 7.26-7.24 (m,
    1H), 7.38 (d, J = 2.01 Hz, 1H)
    264 (400 MHz, CDCl3) 0.71 (d, J = 6.85 Hz, 3H), 1.05 (d, 417 415
    J = 6.85 Hz, 3H), 1.68-1.77 (m, 4H), 1.71 (s, 3H),
    1.85-1.92 (m, 1H), 2.45 (t, J = 7.05 Hz, 2H), 2.53 (t,
    J = 6.85 Hz, 2H), 2.67 (t, J = 6.25 Hz, 2H), 3.84-3.71 (m,
    2H), 5.30 (s, 1H), 5.87 (s, 1H), 6.55 (t, J = 2.01 Hz, 1H),
    7.29 (dd, J = 8.06, 2.42 Hz, 1H), 7.39 (d, J = 8.87 Hz,
    1H), 7.41 (d, J = 2.01 Hz, 1H)
    265 (400 MHz, CDCl3) 0.98 (s, 9H), 1.44-1.48 (m, 2H), 455 453
    1.67 (s, 3H), 2.65-2.70 (m, 2H), 2.72 (t, J = 6.04 Hz,
    2H), 3.91-3.75 (m, 2H), 5.49 (s, 1H), 6.25 (s, 1H),
    6.87 (dd, J = 8.06, 1.61 Hz, 2H), 7.25-7.14 (m, 5H),
    7.38 (d, J = 2.01 Hz, 1H)
    266 (400 MHz, DMSO-D6) 0.69-0.76 (m, 3H), 0.94 (s, 483 481
    9H), 1.04-1.10 (m, 3H), 1.34-1.42 (m, 2H), 1.70 (s,
    3H), 1.96-2.09 (m, 1H), 2.43-2.53 (m, 3H),
    2.60-2.67 (m, 2H), 6.29 (s, 1H), 7.06-7.18 (m, 2H),
    7.29-7.39 (m, 2H), 7.40-7.46 (m, 2H), 7.64-7.75 (m, 1H)
    267 (400 MHz, CDCl3) 0.71 (d, J = 6.85 Hz, 3H), 1.05 (d, 431 429
    J = 6.85 Hz, 3H), 1.54-1.69 (m, 6H), 1.71 (s, 3H),
    1.86-1.93 (m, 1H), 2.22 (t, J = 5.64 Hz, 2H), 2.30 (t,
    J = 5.64 Hz, 2H), 2.65 (t, J = 6.25 Hz, 2H), 3.71-3.82 (m,
    2H), 5.45 (s, 1H), 5.88 (s, 1H), 6.18 (s, 1H), 7.18 (d,
    J = 8.06 Hz, 1H), 7.28 (dd, J = 8.06, 1.61 Hz, 1H),
    7.41 (d, J = 1.61 Hz, 1H)
    268 (400 MHz, CDCl3) 0.69 (d, J = 6.85 Hz, 3H), 433 431
    0.95-0.98 (m, 2H), 1.04 (d, J = 6.85 Hz, 3H), 1.13-1.22 (m, 3H),
    1.60-1.68 (m, 6H), 1.70 (s, 3H), 1.84-1.91 (m, 1H),
    2.58 (d, J = 6.85 Hz, 2H), 2.64 (t, J = 6.45 Hz, 2H),
    3.83-3.70 (m, 2H), 5.49 (s, 1H), 5.86 (s, 1H), 7.12 (d,
    J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H),
    7.38 (d, J = 2.01 Hz, 1H)
    269 (400 MHz, DMSO-D6) 0.68-0.74 (m, 3H), 0.94 (s, 487 485
    9H), 1.00-1.06 (m, 3H), 1.31-1.46 (m, 4H),
    1.46-1.53 (m, 2H), 1.57 (s, 3H), 1.71-1.81 (m, 2H),
    1.81-1.91 (m, 2H), 1.99-2.05 (m, 1H), 2.08-2.19 (m, 2H),
    2.56-2.64 (m, 2H), 6.09 (s, 1H), 6.80 (brs, 1H),
    7.20-7.31 (m, 2H), 7.31-7.37 (m, 1H)
    270 (400 MHz, DMSO-D6) 0.62-0.69 (m, 3H), 0.93 (s, 455 453
    9H), 0.99-1.05 (m, 3H), 1.36-1.43 (m, 2H), 1.63 (s,
    3H), 1.84-1.94 (m, 1H), 2.39-2.45 (m, 2H),
    2.62-2.69 (m, 2H), 3.45-3.54 (m, 1H), 3.57-3.67 (m, 1H),
    6.13 (s, 1H), 7.07 (s, 1H), 7.38-7.43 (m, 1H),
    7.54-7.61 (m, 2H), 12.28 (brs, 1H)
    271 (400 MHz, DMSO-D6) 0.70-0.74 (m, 3H), 0.93 (s, 503 501
    9H), 1.06-1.12 (m, 3H), 1.36-1.44 (m, 2H), 1.75 (s,
    3H), 1.98-2.08 (m, 1H), 2.63-2.72 (m, 2H), 6.42 (s,
    1H), 7.42-7.50 (m, 3H), 7.60-7.63 (m, 1H),
    7.65-7.70 (m, 2H), 7.90-7.96 (m, 2H), 12.89 (brs, 1H)
    272 (400 MHz, DMSO-D6) 0.67-0.73 (m, 3H), 0.95 (s, 473 471
    9H), 1.01-1.06 (m, 3H), 1.34-1.43 (m, 2H), 1.60 (s,
    3H), 1.62-1.84 (m, 8H), 1.95-2.06 (m, 1H),
    2.59-2.66 (m, 2H), 5.91 (s, 1H), 6.90 (brs, 1H),
    7.22-7.37 (m, 3H)
    273 (400 MHz, CDCl3) 0.98 (s, 9H), 1.44-1.48 (m, 2H), 485 483
    1.71 (s, 3H), 2.66-2.71 (m, 2H), 3.41 (s, 3H),
    3.57-3.61 (m, 3H), 3.88-3.94 (m, 1H), 5.46 (s, 1H),
    6.35 (s, 1H), 7.01 (dt, J = 8.46, 2.01 Hz, 1H), 7.19-7.30 (m,
    3H), 7.45 (d, J = 2.01 Hz, 1H), 7.74 (t, J = 1.61 Hz, 1H),
    7.90 (dt, J = 7.66, 1.41 Hz, 1H)
    274 (400 MHz, DMSO-D6) 0.94 (s, 9H), 1.32-1.41 (m, 489 487
    2H), 1.55 (s, 3H), 1.73-1.84 (m, 6H), 3.85-1.89 (m,
    2H), 1.90-1.99 (m, 1H), 2.01-2.12 (m, 1H),
    2.57-2.64 (m, 2H), 3.10 (s, 3H), 3.11-3.25 (m, 2H),
    5.93 (s, 1H), 7.04 (brs, 1H), 7.22-7.27 (m, 1H),
    7.27-7.32 (m, 1H), 7.32-7.36 (m, 1H), 12.30 (brs, 1H)
    275 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.38-1.43 (m, 486 484
    2H), 1.62 (s, 3H), 2.64-2.68 (m, 2H), 3.28 (s, 3H),
    3.41-3.53 (m, 3H), 3.80-3.87 (m, 1H), 6.79 (s, 1H),
    7.34 (dd, J = 8.06, 1.61 Hz, 1H), 7.37 (d, J = 8.46 Hz,
    1H), 7.47 (d, J = 1.21 Hz, 1H), 7.54 (s, 1H), 7.71 (t,
    J = 2.22 Hz, 1H), 8.39 (d, J = 1.61 Hz, 1H), 8.85 (d,
    J = 1.21 Hz, 1H)
    276 (400 MHz, CDCl3) 0.97 (s, 9H), 1.39-1.48 (m, 2H), 511 509
    1.71-1.84 (m, 5H), 2.07-2.23 (m, 2H),
    2.63-2.71 (m, 2H), 2.83-2.96 (m, 1H), 3.17 (s, 3H),
    3.76-3.85 (m, 1H), 5.45 (brs, 1H), 6.19-6.22 (m, 1H),
    7.16-7.22 (m, 1H), 7.23-7.29 (m, 1H), 7.38-7.44 (m, 1H),
    7.46-7.53 (m, 2H), 8.08-8.16 (m, 2H)
    277 (400 MHz, CDCl3) 0.98 (s, 9H), 1.41-1.48 (m, 2H), 511 509
    1.48-1.58 (m, 1H), 1.72-1.81 (m, 4H),
    1.90-2.00 (m, 1H), 2.01-2.13 (m, 1H), 2.39-2.49 (m, 1H),
    2.63-2.71 (m, 2H), 3.16 (s, 3H), 3.52-3.64 (m, 1H),
    5.33 (s, 1H), 6.17-6.21 (m, 1H), 7.18-7.23 (m, 1H),
    7.26-7.31 (m, 1H), 7.40-7.43 (m, 1H), 7.47-7.52 (m,
    2H), 8.07-8.14 (m, 2H)
    278 (400 MHz, DMSO-D6) 0.70-0.75 (m, 3H), 0.93 (s, 461 459
    9H), 1.01-1.07 (m, 3H), 1.32-1.41 (m, 2H),
    1.51-1.66 (m, 4H), 1.66-1.92 (m, 4H), 1.92-2.05 (m, 2H),
    2.57-2.64 (m, 2H), 2.69-2.80 (m, 1H),
    4.65-4.77 (m, 1H), 6.18 (s, 1H), 7.03 (brs, 1H), 7.19-7.26 (m,
    1H), 7.25-7.34 (m, 2H), 12.17 (brs, 1H)
    279 (400 MHz, DMSO-D6) 0.67-0.74 (m, 3H), 0.93 (s, 461 459
    9H), 1.01-1.09 (m, 3H), 1.30-1.41 (m, 2H),
    1.53-1.64 (m, 4H), 1.67-1.93 (m, 4H), 1.93-2.05 (m, 2H),
    2.56-2.64 (m, 2H), 2.69-2.81 (m, 1H),
    4.65-4.78 (m, 1H), 6.19 (s, 1H), 7.02 (s, 1H), 7.19-7.34 (m,
    3H), 12.20 (brs, 1H)
    280 (400 MHz, CDCl3) 0.71-0.78 (m, 3H), 0.97 (s, 9H), 461 459
    1.03-1.10 (m, 3H), 1.40-1.49 (m, 2H),
    1.64-1.76 (m, 4H), 1.81-1.99 (m, 3H), 2.04-2.16 (m, 2H),
    2.23-2.34 (m, 1H), 2.61-2.71 (m, 2H), 2.91-3.03 (m,
    1H), 4.82-4.96 (m, 1H), 5.63 (brs, 1H), 5.86 (brs,
    1H), 7.14-7.19 (m, 1H), 7.20-7.25 (m, 1H),
    7.34-7.38 (m, 1H)
    281 (400 MHz, DMSO-D6) 0.76 (d, J = 6.85 Hz, 3H), 470 468
    0.95 (s, 9H), 1.12 (d, J = 6.85 Hz, 3H), 1.36-1.40 (m, 2H),
    1.74 (s, 3H), 2.06-2.13 (m, 1H), 2.62-2.66 (m, 2H),
    7.29 (s, 1H), 7.32-7.36 (m, 2H), 7.41 (s, 1H), 7.91 (s,
    1H), 8.06 (dd, J = 8.87, 0.81 Hz, 1H), 8.22 (dd, J = 8.87,
    2.42 Hz, 1H), 8.90 (dd, J = 2.42, 0.81 Hz, 1H), 13.20 (s,
    1H)
    282 (400 MHz, CDCl3) 0.68 (d, J = 6.85 Hz, 3H), 1.05 (d, 441 439
    J = 6.85 Hz, 3H), 1.71 (s, 3H), 1.83-1.90 (m, 1H),
    2.22-2.34 (m, 2H), 2.47-2.56 (m, 1H), 2.58-2.69 (m,
    4H), 2.90 (d, J = 7.66 Hz, 2H), 3.82-3.70 (m, 2H),
    5.68 (s, 1H), 5.87 (s, 1H), 7.13 (d, J = 8.06 Hz, 1H), 7.29 (dd,
    J = 8.06, 2.01 Hz, 1H), 7.42 (d, J = 2.01 Hz, 1H)
    283 (400 MHz, DMSO-D6) 0.69-0.75 (m, 3H), 0.94 (s, 537 535
    9H), 1.05-1.10 (m, 3H), 1.34-1.42 (m, 2H), 1.71 (s,
    3H), 1.97-2.08 (m, 1H), 2.59-2.68 (m, 2H), 6.38 (s,
    1H), 7.30-7.39 (m, 2H), 7.42-7.45 (m, 1H),
    7.46-7.72 (m, 4H)
    284 (400 MHz, DMSO-D6) 0.69 (d, J = 12.49 Hz, 1H), 519 517
    0.80 (s, 3H), 0.91 (s, 3H), 0.94 (s, 9H), 1.07 (s, 3H),
    1.09-1.23 (m, 2H), 1.12 (s, 3H), 1.32-1.37 (m, 2H),
    1.53 (d, J = 12.09 Hz, 1H), 1.61 (s, 3H), 1.99-2.06 (m, 1H),
    2.44 (t, J = 6.85 Hz, 2H), 2.61-2.65 (m, 2H),
    3.51-3.62 (m, 2H), 6.06 (s, 1H), 7.09 (s, 1H), 7.29 (d,
    J = 8.06 Hz, 1H), 7.32 (dd, J = 8.06, 1.61 Hz, 1H),
    7.40 (d, J = 1.61 Hz, 1H)
    285 (400 MHz, CDCl3) 0.70 (d, J = 6.85 Hz, 3H), 0.98 (s, 459 457
    6H), 1.04 (d, J = 6.85 Hz, 3H), 1.34 (t, J = 6.25 Hz, 2H),
    1.46 (t, J = 6.25 Hz, 2H), 1.69 (s, 3H), 1.85-1.92 (m,
    1H), 2.24 (t, J = 6.04 Hz, 2H), 2.32 (t, J = 6.04 Hz, 2H),
    2.63 (t, J = 6.45 Hz, 2H), 3.68-3.82 (m, 2H), 5.80 (s,
    1H), 5.87 (s, 1H), 6.19 (s, 1H), 7.18 (d, J = 8.06 Hz,
    1H), 7.27 (dd, J = 8.06, 2.01 Hz, 1H), 7.40 (d,
    J = 2.01 Hz, 1H)
    286 (400 MHz, CDCl3) 0.68 (d, J = 6.85 Hz, 3H), 0.87 (s, 461 459
    3H), 0.88 (s, 3H), 1.03 (d, J = 6.85 Hz, 3H),
    1.08-1.23 (m, 4H), 1.33-1.36 (m, 2H), 1.45-1.56 (m, 3H),
    1.68 (s, 3H), 1.83-1.90 (m, 1H), 2.60-2.63 (m, 4H),
    3.67-3.82 (m, 2H), 5.85 (s, 1H), 5.86 (s, 1H), 7.12 (d,
    J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H),
    7.37 (d, J = 2.01 Hz, 1H)
    287 (400 MHz, DMSO-D6) 0.93 (s, 9H), 1.02 (d, 487 485
    J = 6.24 Hz, 1H), 1.12, (s, 3H), 1.14 (s, 3H), 1.22 (s,
    1H), 1.34-1.38 (m, 2H), 1.48 (s, 3H), 1.83-1.85 (m,
    2H), 1.89-2.05 (m, 4H), 2.22-2.25 (m, 1H),
    2.59-2.63 (m, 2H), 2.79 (t, J = 8.55 Hz, 1H), 3.52 (brs, 1H),
    4.65-4.74 (m, 1H), 6.15 (s, 1H), 7.07 (s, 1H),
    7.14-7.16 (m, 1H), 7.25-7.26 (m, 2H)
    288 (400 MHz, CDCl3) 0.71 (d, J = 6.85 Hz, 3H), 1.04 (d, 403 401
    J = 6.85 Hz, 3H), 1.70 (s, 3H), 1.84-1.91 (m, 1H),
    2.08-2.17 (m, 2H), 2.67 (t, J = 6.25 Hz, 2H), 2.92 (t,
    J = 7.66 Hz, 2H), 2.99 (t, J = 8.06 Hz, 2H), 3.71-3.83 (m,
    2H), 5.28 (s, 1H), 5.87 (s, 1H), 6.41 (t, J = 2.22 Hz, 1H),
    7.26-7.27 (m, 2H), 7.40 (d, J = 1.21 Hz, 1H)
    289 (400 MHz, CDCl3) 0.72 (d, J = 6.85 Hz, 3H), 1.06 (d, 433 431
    J = 6.85 Hz, 3H), 1.72 (s, 3H), 1.93-1.87 (m, 1H),
    2.37 (t, J = 5.04 Hz, 2H), 2.44 (t, J = 5.04 Hz, 2H), 2.66 (t,
    J = 6.25 Hz, 2H), 3.67 (t, J = 5.44 Hz, 2H), 3.75-3.82 (m,
    4H), 5.34 (s, 1H), 5.89 (s, 1H), 6.30 (s, 1H), 7.17 (d,
    J = 8.06 Hz, 1H), 7.29 (dd, J = 8.46, 2.42 Hz, 1H),
    7.44 (d, J = 2.01 Hz, 1H)
    290 (400 MHz, CDCl3) 0.69 (d, J = 6.85 Hz, 3H), 1.05 (d, 435 433
    J = 6.85 Hz, 3H), 1.33-1.43 (m, 2H), 1.50-1.54 (m,
    2H), 1.71, (s, 3H), 1.81-1.91 (m, 2H), 2.61-2.67 (m,
    4H), 3.33 (td, J = 11.69, 1.61 Hz, 2H), 3.76 (dt, J = 20.42,
    7.25 Hz, 2H), 3.94 (dd, J = 11.28, 2.82 Hz, 2H), 5.56 (s,
    1H), 5.87 (s, 1H), 7.13 (d, J = 8.06 Hz, 1H), 7.27 (dd,
    J = 8.06, 2.01 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H)
    291 (400 MHz, CDCl3) 0.68 (d, J = 6.85 Hz, 3H), 1.04 (d, 405 403
    J = 6.85 Hz, 3H), 1.69 (s, 3H), 1.71-1.77 (m, 2H),
    1.81-1.90 (m, 3H), 1.99-2.08 (m, 2H), 2.60-2.68 (m,
    3H), 2.80 (d, J = 7.66 Hz, 2H), 3.70-3.83 (m, 2H),
    5.32 (s, 1H), 5.86 (s, 1H), 7.12 (d, J = 8.06 Hz, 1H), 7.24 (dd,
    J = 8.06, 2.01 Hz, 1H), 7.38 (d, J = 2.01 Hz, 1H)
    292 (400 MHz, CDCl3) 0.96 (s, 12H), 1.40-1.45 (m, 2H), 419 417
    1.66 (s, 3H), 1.80 (s, 3H), 2.61-2.71 (m, 4H),
    3.69-3.87 (m, 2H), 4.45 (s, 1H), 4.69 (s, 1H), 5.23 (s, 1H),
    6.24 (s, 1H), 7.14 (d, J = 7.86 Hz, 1H), 7.22 (dd, J = 7.86,
    1.62 Hz, 1H), 7.36 (d, J = 1.62 Hz, 1H)
    293 (400 MHz, CDCl3) 0.71 (d, J = 6.88 Hz, 3H), 1.05 (d, 423 421
    J = 6.88 Hz, 3H), 1.26 (s, 1H), 1.30 (s, 6H), 1.70 (s,
    3H), 1.71-1.76 (m, 2H), 1.85-1.92 (m, 1H),
    2.59-2.72 (m, 2H), 2.76-2.81 (m, 2H), 3.69-3.82 (m, 2H),
    5.46 (s, 1H), 5.87 (s, 1H), 7.19 (d, J = 8.07 Hz, 1H),
    7.26 (dd, J = 8.07, 2.09 Hz, 1H), 7.38 (d, J = 2.09 Hz, 1H)
    294 (400 MHz, CDCl3) 0.70 (d, J = 6.88 Hz, 3H), 1.05 (d, 425 423
    J = 6.88 Hz, 3H), 1.40 (s, 3H), 1.46 (s, 3H), 1.71 (s,
    3H), 1.84-1.93 (m, 3H), 2.66 (t, J = 6.28 Hz, 2H),
    2.79-2.84 (m, 2H), 3.71-3.84 (m, 2H), 5.40 (brs, 1H),
    5.88 (s, 1H), 7.20 (d, J = 8.07 Hz, 1H), 7.28 (dd, J = 8.07,
    2.09 Hz, 1H), 7.40 (d, J = 1.79 Hz, 1H)
    295 (400 MHz, DMSO-D6) 0.73 (d, J = 6.82 Hz, 3H), 460 458
    0.95 (s, 9H), 1.10 (d, J = 6.82 Hz, 3H), 1.35-1.41 (m, 2H),
    1.73 (s, 3H), 2.02-2.10 (m, 1H), 2.61-2.67 (m, 2H),
    6.79 (s, 1H), 7.30-7.41 (m, 4H), 8.01 (s, 1H)
    296 (400 MHz, CDCl3) 0.98 (s, 9H), 1.41-3.46 (m, 2H), 517 515
    1.66 (s, 6H), 1.67 (s, 3H), 2.66-2.71 (m, 2H), 3.39 (s,
    3H), 3.56-3.65 (m, 3H), 3.74-3.81 (m, 1H), 5.15 (s,
    1H), 6.23 (s, 1H), 6.80 (s, 1H), 7.09 (s, 1H), 7.19 (d,
    J = 8.06 Hz, 1H), 7.28 (dd, J = 8.06, 2.01 Hz, 1H),
    7.43 (d, J = 1.61 Hz, 1H)
    297 (400 MHz, DMSO-D6) 0.70 (d, J = 6.90 Hz, 3H), 473 471
    0.94 (s, 9H), 1.05 (d, J = 6.90 Hz, 3H), 1.36-1.41 (m, 2H),
    1.71 (s, 3H), 2.61-2.66 (m, 2H), 3.55 (s, 3H), 6.11 (s,
    1H), 6.32 (brs, 1H), 7.35 (brs, 2H), 7.43 (brs, 1H),
    7.67 (brs, 1H)
    298 (400 MHz, CDCl3) 0.72 (d, J = 6.94 Hz, 3H), 1.05 (d, 419 417
    J = 6.94 Hz, 3H), 1.10 (s, 3H), 1.28 (s, 3H), 1.70 (s,
    3H), 1.85-1.92 (m, 3H), 2.21-2.26 (m, 2H), 2.69 (t,
    J = 6.24 Hz, 2H), 3.66-3.83 (m, 3H), 5.20 (brs, 1H),
    5.88 (s, 1H), 7.25 (d, J = 8.21 Hz, 1H), 7.30 (dd, J = 8.21,
    2.08 Hz, 1H), 7.36 (d, J = 2.08 Hz, 1H)
    299 (400 MHz, CDCl3) 0.61-0.71 (m, 3H), 0.95 (s, 9H), 435 433
    0.99-1.06 (m, 3H), 1.11-1.17 (m, 3H),
    1.38-3.47 (m, 2H), 1.67 (brs, 3H), 1.78-1.90 (m, 1H),
    2.59-2.67 (m, 2H), 2.72-2.85 (m, 1H), 3.46-3.60 (m, 1H),
    3.62-3.75 (m, 1H), 5.76-5.85 (m, 2H),
    7.11-7.17 (m, 1H), 7.21-7.25 (m, 1H), 7.33-7.38 (m, 1H)
    300 (400 MHz, CDCl3) 0.61-0.71 (m, 3H), 0.95 (s, 9H), 435 433
    0.99-1.06 (m, 3H), 1.11-1.17 (m, 3H),
    1.38-1.47 (m, 2H), 1.67 (brs, 3H), 1.78-1.90 (m, 1H),
    2.59-2.67 (m, 2H), 2.72-2.85 (m, 1H), 3.46-3.60 (m, 1H),
    3.62-3.75 (m, 1H), 5.76-5.85 (m, 2H),
    7.11-7.17 (m, 1H), 7.21-7.25 (m, 1H), 7.33-7.38 (m, 1H)
    301 (400 MHz, CDCl3) 0.71 (d, J = 6.94 Hz, 3H), 1.05 (d, 451 449
    J = 6.94 Hz, 3H), 1.58-1.67 (m, 4H), 1.71 (s, 3H),
    1.80-1.91 (m, 3H), 1.94-2.04 (m, 4H), 2.68 (t, J = 6.24 Hz,
    2H), 2.86-2.90 (m, 2H), 3.72-3.83 (m, 2H), 5.24 (s,
    1H), 5.88 (s, 1H), 7.21 (d, J = 8.09 Hz, 1H), 7.27 (dd,
    J = 8.09, 2.08 Hz, 1H), 7.40 (d, J = 2.08 Hz, 1H)
    302 (400 MHz, DMSO-D6) 0.65-0.71 (m, 3H), 0.79 (s, 447 445
    9H), 0.99-1.03 (m, 3H), 1.58 (s, 3H), 1.68-1.81 (m,
    2H), 1.87-1.97 (m, 1H), 2.04-2.15 (m, 1H),
    2.17-2.33 (m, 4H), 3.30-3.40 (m, 1H), 3.40-3.50 (m, 1H),
    3.51-3.61 (m, 1H), 6.10 (s, 1H), 6.91 (brs, 1H),
    7.27-7.32 (m, 3H)
    303 (400 MHz, DMSO-D6) 1.03 (s, 9H), 1.36-1.41 (m, 485 483
    2H), 1.61 (s, 3H), 2.03-2.11 (m, 1H), 2.21-2.29 (m,
    1H), 2.46 (t, J = 7.17 Hz, 2H), 2.61-2.65 (m, 2H),
    2.92 (s, 3H), 2.93-2.98 (m, 1H), 3.15-3.22 (m, 1H),
    3.48-3.65 (m, 2H), 6.16 (s, 1H), 7.20 (s, 1H), 7.26 (dd,
    J = 8.09, 1.85 Hz, 1H), 7.31 (d, J = 8.09 Hz, 1H), 7.37 (d,
    J = 1.85 Hz, 1H), 12.26 (brs, 1H)
    304 (400 MHz, CDCl3) 0.83 (s, 9H), 0.96-1.03 (m, 3H), 477 475
    1.65-1.69 (m, 3H), 1.70-1.84 (m, 3H),
    1.91-2.06 (m, 1H), 2.08-2.21 (m, 1H), 2.24-2.36 (m, 2H),
    2.58-2.66 (m, 2H), 2.89-3.05 (m, 1H), 3.14-3.18 (m,
    3H), 3.35-3.48 (m, 1H), 3.66-3.88 (m, 2H),
    5.66-5.72 (m, 1H), 5.93-5.99 (m, 1H), 7.20-7.24 (m, 1H),
    7.27-7.32 (m, 1H), 7.35-7.38 (m, 1H)
    305 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 451 449
    0.95 (s, 9H), 1.35-1.41 (m, 2H), 1.58 (s, 3H),
    1.90-2.00 (m, 1H), 2.45 (t, J = 6.94 Hz, 2H), 2.60-2.66 (m, 2H),
    3.08 (t, J = 9.02 Hz, 1H), 3.21 (s, 3H), 3.46-3.65 (m,
    2H), 6.11 (s, 1H), 7.07 (s, 1H), 7.25-7.31 (m, 2H),
    7.33-7.36 (m, 1H)
    306 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.02 (d, 451 449
    J = 6.94 Hz, 3H), 1.34-1.40 (m, 2H), 1.60 (s, 3H),
    1.93-2.02 (m, 1H), 2.42 (t, J = 7.05 Hz, 2H), 2.56-2.66 (m,
    3H), 2.85 (t, J = 9.36 Hz, 1H), 2.90 (s, 3H),
    3.48-3.63 (m, 2H), 6.08 (s, 1H), 7.05 (s, 1H), 7.26-7.31 (m,
    2H), 7.36 (s, 1H)
    307 (400 MHz, DMSO-D6) 0.73 (d, J = 6.94 Hz, 3H), 499 497
    0.95 (s, 9H), 1.37-1.43 (m, 2H), 1.69 (s, 3H),
    2.05-2.11 (m, 1H), 2.63-2.68 (m, 2H), 3.19 (t, J = 8.90 Hz, 1H),
    3.23 (s, 3H), 3.33-3.37 (m, 2H), 6.30 (s, 1H), 7.17 (d,
    J = 8.32 Hz, 2H), 7.33-7.46 (m, 4H), 7.83 (d,
    J = 8.32 Hz, 2H)
    308 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.09 (d, 499 497
    J = 6.70 Hz, 3H), 1.36-1.41 (m, 2H), 1.73 (s, 3H),
    2.08-2.14 (m, 1H), 2.62-2.71 (m, 3H), 2.92 (s, 3H),
    2.96 (t, J = 9.13 Hz, 1H), 6.37 (s, 1H), 7.33-7.48 (m, 5H),
    7.58 (s, 1H), 7.91-7.94 (m, 2H)
    309 (400 MHz, DMSO-D6) 0.69 (d, J = 6.82 Hz, 3H), 461 459
    0.87 (s, 9H), 1.02 (d, J = 6.82 Hz, 3H), 1.32 (d, J = 6.70 Hz,
    2H), 1.60 (s, 3H), 1.65 (d, J = 32.60 Hz, 2H), 1.93 (sep,
    J = 6.82 Hz, 1H), 2.28-2.40 (m, 1H), 2.43-2.46 (m,
    2H), 2.48-2.54 (m, 2H), 3.44-3.56 (m, 2H),
    3.62 (ddd, J = 6.80, 7.20, 14.00 Hz, 1H), 6.11 (s, 1H),
    7.01 (s, 1H), 7.29-7.33 (m, 3H), 12.32 (brs, 1H)
    310 (400 MHz, DMSO-D6) 0.73 (d, J = 6.82 Hz, 3H), 437 435
    0.91 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.61 (s, 3H),
    1.93-2.00 (m, 1H), 2.36-2.46 (m, 3H), 2.93-2.98 (m, 1H),
    3.47-3.55 (m, 1H), 3.58-3.66 (m, 1H), 4.38 (brs,
    1H), 6.12 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 7.98,
    1.97 Hz, 1H), 7.31-7.34 (m, 2H)
    311 (400 MHz, DMSO-D6) 0.73 (d, J = 6.82 Hz, 3H), 437 435
    0.91 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.61 (s, 3H),
    1.92-2.00 (m, 1H), 2.36-2.45 (m, 3H), 2.96 (dd, J = 13.76,
    1.50 Hz, 1H), 3.47-3.55 (m, 1H), 3.58-3.66 (m, 1H),
    4.39 (brs, 1H), 6.12 (s, 1H), 7.00 (s, 1H), 7.24 (dd,
    J = 8.09, 1.85 Hz, 1H), 7.31-7.35 (m, 2H)
    312 (400 MHz, CDCl3) 0.97 (s, 9H), 1.39-1.47 (m, 2H), 503 501
    1.52-1.68 (m, 5H), 2.07-2.26 (m, 2H),
    2.36-2.47 (m, 1H), 2.56-2.68 (m, 6H), 2.98-3.08 (m, 1H),
    3.46-3.51 (m, 2H), 3.72 (s, 3H), 4.64-4.69 (m, 1H),
    4.89-5.01 (m, 3H), 5.90-5.94 (m, 1H), 7.12-7.21 (m,
    2H), 7.32-7.35 (m, 1H)
    313 (400 MHz, CDCl3) 0.98 (s, 9H), 1.12 (s, 9H), 541 539
    1.37-1.74 (m, 6H), 1.80 (s, 3H), 2.65-2.73 (m, 2H),
    3.19-3.29 (m, 2H), 5.15 (s, 1H), 6.18 (s, 1H),
    7.19-7.33 (m, 2H), 7.42-7.52 (m, 3H), 8.07-8.13 (m, 2H)
    314 (400 MHz, DMSO-D6) 0.66-0.71 (m, 3H), 0.94 (s, 507 505
    9H), 1.02-1.07 (m, 3H), 1.37-1.44 (m, 2H), 1.65 (s,
    3H), 1.78-1.82 (m, 2H), 1.81-1.87 (m, 4H),
    1.91-1.96 (m, 2H), 1.96-2.05 (m, 1H), 2.64-2.71 (m, 2H),
    5.96 (s, 1H), 7.04 (s, 1H), 7.40-7.47 (m, 1H),
    7.56-7.63 (m, 2H), 12.27 (brs, 1H)
    315 (400 MHz, DMSO-D6) 0.79 (s, 9H), 1.68 (s, 3H), 511 509
    1.70-1.81 (m, 2H), 1.96-2.08 (m, 1H), 2.08-2.17 (m,
    2H), 2.17-2.28 (m, 2H), 3.11 (s, 3H), 3.16-3.44 (m,
    3H), 6.38 (s, 1H), 7.32-7.48 (m, 5H), 7.61-7.65 (m,
    1H), 7.89-7.96 (m, 2H), 12.86 (brs, 1H)
    316 (400 MHz, DMSO-D6) 0.93 (s, 9H), 1.33-1.40 (m, 507 505
    2H), 1.54 (brs, 3H), 2.15 (brs, 6H), 2.17-2.27 (m,
    2H), 2.38-2.46 (m, 2H), 2.58-2.64 (m, 2H),
    2.65-2.77 (m, 1H), 6.01 (brs, 1H), 7.14 (brs, 1H),
    7.18-7.24 (m, 1H), 7.27-7.33 (m, 2H)
    317 (400 MHz, DMSO-D6) 0.66 (d, J = 6.94 Hz, 3H), 417 415
    1.02 (d, J = 6.94 Hz, 3H), 1.30 (s, 9H), 1.61 (s, 3H),
    1.89-1.95 (m, 1H), 2.45 (t, J = 6.94 Hz, 2H), 3.48-3.67 (m,
    2H), 6.12 (s, 1H), 7.10 (s, 1H), 7.31 (dd, J = 8.09,
    1.85 Hz, 1H), 7.43 (d, J = 8.09 Hz, 1H), 7.43 (d,
    J = 1.85 Hz, 1H), 12.25 (brs, 1H)
    318 (400 MHz, DMSO-D6) 0.81 (d, J = 6.70 Hz, 6H), 497 495
    1.38-1.49 (m, 1H), 1.63-1.69 (m, 2H), 1.69 (s, 3H),
    1.84-1.96 (m, 1H), 1.99-2.08 (m, 1H), 2.13-2.23 (m, 1H),
    2.40-2.48 (m, 2H), 3.13 (s, 3H), 3.20-3.29 (m, 2H),
    3.44 (tt, J = 9.66, 7.33 Hz, 1H), 6.39 (s, 1H),
    7.35-7.44 (m, 3H), 7.46 (dt, J = 8.94, 2.20 Hz, 2H), 7.65 (s, 1H),
    7.94 (dt, J = 8.94, 2.20 Hz, 2H), 12.91 (brs, 1H)
    319 (400 MHz, CDCl3) 0.96 (s, 9H), 1.40-1.46 (m, 2H), 469 467
    1.89-2.16 (m, 3H), 2.26-2.45 (m, 2H),
    2.56-2.70 (m, 4H), 3.69-3.78 (m, 1H), 3.78-3.88 (m, 1H),
    5.65 (brs, 1H), 5.89-5.93 (m, 1H), 7.13-7.22 (m, 2H),
    7.33-7.36 (m, 1H)
    320 (400 MHz, DMSO-D6) 0.94 (s, 9H), 1.33-1.41 (m, 518 516
    2H), 1.69 (s, 3H), 2.14-2.36 (m, 2H), 2.56-2.67 (m,
    3H), 2.75-2.90 (m, 1H), 3.23-3.44 (m, 1H),
    7.23-7.35 (m, 3H), 7.39-7.42 (m, 1H), 7.97-8.03 (m, 2H),
    8.19-8.25 (m, 2H), 8.87-8.92 (m, 1H)
    321 (400 MHz, DMSO-D6) 0.23-0.32 (m, 2H), 443 441
    0.32-0.40 (m, 1H), 0.54-0.62 (m, 1H), 0.87-0.94 (m, 1H),
    0.97 (s, 6H), 1.41-1.47 (m, 2H), 1.67 (s, 3H),
    1.90-1.94 (m, 2H), 2.20-2.26 (m, 2H), 2.34-2.42 (m, 2H),
    3.40-3.50 (m, 1H), 3.51-3.62 (m, 1H),
    5.52-5.55 (m, 1H), 5.92-5.96 (m, 1H), 7.11-7.15 (m, 1H),
    7.15-7.17 (m, 1H), 7.17-7.20 (m, 1H), 7.27-7.33 (m,
    1H), 7.35-7.39 (m, 1H)
    322 (400 MHz, DMSO-D6) 0.64-0.69 (m, 3H), 0.93 (s, 493 491
    9H), 1.00-1.05 (m, 3H), 1.36-1.42 (m, 2H), 1.64 (s,
    3H), 1.90-1.98 (m, 1H), 2.28 (s, 6H), 2.62-2.71 (m,
    2H), 5.99 (s, 1H), 7.12 (brs, 1H), 7.39-7.45 (m, 1H),
    7.52-7.61 (m, 2H), 12.41 (brs, 1H)
    323 (400 MHz, DMSO-D6) 0.95 (s, 9H), 1.38-1.46 (m, 519 517
    2H), 1.73 (s, 3H), 1.98-2.10 (m, 1H), 2.13-2.24 (m,
    1H), 2.66-2.73 (m, 2H), 3.09 (s, 3H), 3.16-3.25 (m,
    2H), 6.42 (s, 1H), 7.41-7.46 (m, 2H), 7.46-7.51 (m,
    1H), 7.66-7.74 (m, 3H), 7.91-7.96 (m, 2H)
    324 (400 MHz, DMSO-D6) 0.92 (s, 9H), 1.35-1.43 (m, 523 521
    2H), 1.60 (s, 3H), 1.74-1.79 (m, 2H), 1.79-1.83 (m,
    4H), 1.87-1.91 (m, 2H), 1.91-1.99 (m, 1H),
    2.03-2.13 (m, 1H), 2.62-2.70 (m, 2H), 3.06 (s, 3H),
    3.08-3.21 (m, 2H), 5.97 (s, 1H), 7.10 (brs, 1H),
    7.38-7.44 (m, 1H), 7.53-7.59 (m, 1H), 7.60-7.65 (m, 1H),
    12.27 (brs, 1H)
    325 (400 MHz, DMSO-D6) 0.94 (s, 9H), 1.30-1.44 (m, 525 523
    4H), 1.49-1.57 (m, 2H), 1.56-1.64 (m, 5H),
    1.91-2.05 (m, 3H), 2.07-2.24 (m, 2H), 2.63-2.71 (m, 2H),
    3.09 (s, 3H), 3.10-3.25 (m, 2H), 3.96-4.09 (m, 1H),
    6.16 (s, 1H), 7.18 (brs, 1H), 7.40-7.44 (m, 1H),
    7.54-7.59 (m, 1H), 7.61-7.64 (m, 1H), 12.07 (brs, 1H)
    326 (400 MHz, CDCl3) 0.69-0.76 (m, 3H), 0.97 (s, 9H), 529 527
    1.04-1.10 (m, 3H), 1.42-1.50 (m, 2H), 1.76 (s, 3H),
    1.84-1.94 (m, 1H), 2.68-2.77 (m, 2H),
    4.19-4.27 (m, 3H), 4.28-4.35 (m, 3H), 5.18 (brs, 1H), 5.94 (s,
    1H), 7.28-7.32 (m, 1H), 7.52-7.58 (m, 1H),
    7.62-7.67 (m, 1H)
    327 (400 MHz, DMSO-D6) 0.72 (d, J = 6.94 Hz, 3H), 453 451
    1.04 (d, J = 6.94 Hz, 3H), 1.62 (s, 3H), 1.93-1.99 (m, 1H),
    2.10-2.20 (m, 2H), 2.45 (t, J = 6.82 Hz, 2H),
    2.66-2.75 (m, 2H), 3.48-3.66 (m, 2H), 5.54-5.58 (m, 1H),
    6.13 (s, 1H), 7.06 (s, 1H), 7.23 (d, J = 8.09 Hz, 1H),
    7.32 (dd, J = 8.09, 2.08 Hz, 1H), 7.39 (d, J = 2.08 Hz,
    1H), 12.25 (brs, 1H)
    328 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 455 453
    1.03 (d, J = 6.94 Hz, 3H), 1.61 (s, 3H), 1.63-1.70 (m, 2H),
    1.83-1.87 (m, 2H), 1.91-2.15 (m, 5H), 2.45 (t,
    J = 6.94 Hz, 2H), 3.03-3.11 (m, 1H), 3.48-3.65 (m,
    2H), 6.12 (s, 1H), 7.03 (s, 1H), 7.30-7.38 (m, 3H),
    12.25 (brs, 1H)
    329 (400 MHz, DMSO-D6) 0.80 (d, J = 6.58 Hz, 6H), 507 505
    1.40-1.45 (m, 1H), 1.55 (s, 3H), 1.62-1.67 (m, 2H),
    1.85-1.90 (m, 1H), 2.22-2.28 (m, 3H), 2.41-2.45 (m, 3H),
    2.55-2.60 (m, 4H), 2.69-2.75 (m, 1H), 2.88 (t,
    J = 9.87 Hz, 1H), 3.37-3.46 (m, 1H), 4.91-5.01 (m,
    1H), 6.41 (s, 1H), 7.25 (s, 1H), 7.27-7.35 (m, 3H),
    12.23 (s, 1H)
    330 (400 MHz, DMSO-D6) 0.80 (d, J = 6.70 Hz, 6H), 501 499
    1.38-1.48 (m, 1H), 1.57 (s, 3H), 1.60-1.70 (m, 2H),
    1.77-1.99 (m, 6H), 1.83 (s, 4H), 2.04-2.13 (m, 1H),
    2.39-2.47 (m, 2H), 3.12 (s, 3H), 3.13-3.19 (m, 1H),
    3.20-3.27 (m, 1H), 3.37-3.47 (m, 1H), 5.94 (s, 1H),
    7.06 (s, 1H), 7.28-7.36 (m, 3H), 12.30 (brs, 1H)
    331 (400 MHz, DMSO-D6) 0.98 (s, 6H), 1.46 (t, 461 459
    J = 6.40 Hz, 2H), 1.58 (s, 3H), 1.86-1.95 (m, 3H),
    2.03-2.11 (m, 1H), 2.21-2.27 (m, 2H), 2.44 (t, J = 6.94 Hz,
    2H), 3.12-3.28 (m, 5H), 3.47-3.62 (m, 2H),
    5.54-5.56 (m, 1H), 6.07 (s, 1H), 7.14 (s, 1H), 7.19 (d,
    J = 7.98 Hz, 1H), 7.29 (dd, J = 7.98, 1.85 Hz, 1H),
    7.37 (d, J = 1.85 Hz, 1H), 12.24 (brs, 1H)
    332 (400 MHz, DMSO-D6) 0.98 (s, 6H), 1.46 (t, 509 507
    J = 6.36 Hz, 2H), 1.70 (s, 3H), 1.91-1.96 (m, 2H),
    2.01-2.10 (m, 1H), 2.15-2.28 (m, 3H), 3.12 (s, 3H),
    3.20-3.29 (m, 2H), 5.55-5.58 (m, 1H), 6.40 (s, 1H),
    7.25 (d, J = 7.91 Hz, 1H), 7.40 (dd, J = 7.91, 1.97 Hz, 1H),
    7.44-7.49 (m, 3H), 7.67 (s, 1H), 7.91-7.96 (m, 2H),
    12.90 (brs, 1H)
    333 (400 MHz, DMSO-D6) 0.98 (s, 6H), 1.46 (t, 539 537
    J = 6.36 Hz, 2H), 1.70 (s, 3H), 1.92-1.95 (m, 2H),
    2.00-2.08 (m, 1H), 2.13-2.28 (m, 3H), 3.12 (s, 3H),
    3.20-3.30 (m, 2H), 3.82 (s, 3H), 5.55-5.58 (m, 1H),
    6.39 (s, 1H), 6.96 (dd, J = 8.32, 1.85 Hz, 1H), 7.07 (d,
    J = 1.62 Hz, 1H), 7.25 (d, J = 7.86 Hz, 1H), 7.40 (dd,
    J = 7.98, 1.97 Hz, 1H), 7.48 (d, J = 1.85 Hz, 1H), 7.62 (s,
    1H), 7.66 (d, J = 8.55 Hz, 1H), 12.50 (s, 0H)
    334 (400 MHz, DMSO-D6) 0.98 (s, 6H), 1.46 (t, 510 508
    J = 6.36 Hz, 2H), 1.70 (s, 3H), 1.91-1.95 (m, 2H),
    2.05-2.13 (m, 1H), 2.19-2.27 (m, 3H), 3.14 (s, 3H),
    3.22-3.26 (m, 2H), 5.55-5.57 (m, 1H), 7.17 (s, 1H),
    7.23 (d, J = 8.04 Hz, 1H), 7.37 (dd, J = 8.04, 1.91 Hz, 1H),
    7.45 (d, J = 1.91 Hz, 1H), 7.81-7.86 (m, 2H), 8.14 (dd,
    J = 8.67, 2.03 Hz, 1H), 8.81 (d, J = 2.03 Hz, 1H)
    335 (400 MHz, DMSO-D6) 0.92-1.03 (m, 2H), 449 447
    1.09-1.18 (m, 3H), 1.50-1.68 (m, 9H), 1.85-1.93 (m, 1H),
    2.00-2.09 (m, 1H), 2.44 (t, J = 6.94 Hz, 2H), 2.56 (d,
    J = 6.94 Hz, 2H), 3.05-3.12 (m, 4H), 3.15-3.22 (m,
    1H), 3.47-3.63 (m, 2H), 6.06 (s, 1H), 7.11 (s, 1H),
    7.22-7.28 (m, 2H), 7.36 (d, J = 1.39 Hz, 1H),
    12.25 (brs, 1H)
    336 (400 MHz, DMSO-D6) 0.95-1.05 (m, 2H), 497 495
    1.10-1.17 (m, 3H), 1.53-1.70 (m, 9H), 1.99-2.07 (m, 1H),
    2.13-2.21 (m, 1H), 2.58 (d, J = 6.70 Hz, 2H), 3.10 (s,
    3H), 3.13-3.28 (m, 2H), 6.39 (s, 1H), 7.28-7.31 (m,
    1H), 7.35-7.37 (m, 1H), 7.45-7.49 (m, 3H), 7.64 (s,
    1H), 7.92-7.96 (m, 2H), 12.89 (s, 1H)
    337 (400 MHz, DMSO-D6) 0.96-1.03 (m, 2H), 527 525
    1.10-1.18 (m, 3H), 1.53-1.71 (m, 9H), 1.98-2.06 (m, 1H),
    2.12-2.20 (m, 1H), 2.58 (d, J = 6.70 Hz, 2H), 3.10 (s,
    3H), 3.12-3.28 (m, 2H), 3.82 (s, 3H), 6.38 (s, 1H),
    6.93-6.97 (m, 1H), 7.05-7.07 (m, 1H), 7.30 (d,
    J = 8.15 Hz, 1H), 7.37 (dd, J = 8.15, 2.14 Hz, 1H),
    7.46 (d, J = 2.14 Hz, 1H), 7.59 (s, 1H), 7.63-7.67 (m, 1H)
    338 (400 MHz, DMSO-D6) 0.93-1.04 (m, 2H), 498 496
    1.09-1.18 (m, 3H), 1.52-1.72 (m, 9H), 2.02-2.11 (m, 1H),
    2.17-2.26 (m, 1H), 2.57 (d, J = 6.00 Hz, 2H), 3.11 (s,
    3H), 3.21 (d, J = 14.57 Hz, 2H), 7.24-7.34 (m, 3H),
    7.42 (d, J = 1.85 Hz, 1H), 7.95 (s, 1H), 8.04 (dd, J = 8.79,
    0.69 Hz, 1H), 8.22 (dd, J = 8.79, 2.54 Hz, 1H),
    8.87-8.89 (m, 1H)
    339 (400 MHz, DMSO-D6) 0.88-1.03 (m, 2H), 0.91 (s, 447 445
    9H), 1.09-1.18 (m, 3H), 1.52-1.69 (m, 6H), 1.77 (s,
    3H), 2.41-2.47 (m, 2H), 2.55 (d, J = 6.45 Hz, 2H),
    3.47-3.54 (m, 1H), 3.71-3.64 (m, 1H), 6.29 (s, 1H),
    6.85 (s, 1H), 7.20 (d, J = 8.06 Hz, 1H), 7.25 (dd, J = 8.46,
    2.01 Hz, 1H), 7.35 (d, J = 2.01 Hz, 1H)
    340 (400 MHz, DMSO-D6) 0.94 (s, 9H), 1.37-1.44 (m, 509 507
    2H), 1.61 (s, 3H), 1.87-1.98 (m, 1H), 2.02-2.13 (m,
    1H), 2.25 (s, 6H), 2.64-2.72 (m, 2H), 3.05-3.14 (m,
    4H), 3.14-3.22 (m, 1H), 6.03 (s, 1H), 7.20-7.24 (m,
    1H), 7.42-7.47 (m, 1H), 7.54-7.59 (m, 1H),
    7.59-7.64 (m, 1H), 12.49 (brs, 1H)
    341 (400 MHz, CDCl3) 0.96 (s, 9H), 1.41-1.48 (m, 2H), 541 539
    1.70 (s, 3H), 1.87-2.13 (m, 2H), 2.28-2.44 (m, 2H),
    2.50 (s, 6H), 2.57-2.68 (m, 1H), 2.68-2.76 (m, 2H),
    5.18 (brs, 1H), 5.86 (s, 1H), 7.27-7.32 (m, 1H),
    7.44-7.50 (m, 1H), 7.57-7.61 (m, 1H)
    342 (400 MHz, CDCl3) 0.98 (s, 9H), 1.44-1.51 (m, 2H), 551 549
    1.84 (s, 3H), 1.96-2.24 (m, 2H), 2.37-2.57 (m, 2H),
    2.63-2.81 (m, 3H), 5.44 (brs, 1H), 6.24 (s, 1H),
    7.32-7.40 (m, 1H), 7.45-7.54 (m, 2H), 7.55-7.63 (m, 1H),
    7.67-7.72 (m, 1H), 8.08-8.18 (m, 2H)
    343 (400 MHz, CDCl3) 0.96-1.00 (m, 9H), 503 501
    1.42-1.50 (m, 2H), 1.71 (s, 3H), 1.88-2.13 (m, 2H),
    2.29-2.45 (m, 2H), 2.59-2.67 (m, 2H), 2.68-2.77 (m, 2H),
    3.69-3.75 (m, 1H), 3.75-3.88 (m, 2H), 5.81 (brs, 1H),
    5.95 (s, 1H), 7.28-7.33 (m, 1H), 7.48-7.54 (m, 1H),
    7.60-7.63 (m, 1H)
    344 (400 MHz, CDCl3) 0.82 (s, 9H), 1.65-1.69 (m, 3H), 515 513
    1.71-1.85 (m, 3H), 1.85-1.97 (m, 2H),
    1.98-2.03 (m, 3H), 2.03-2.18 (m, 6H), 2.24-2.37 (m, 2H),
    3.14-3.26 (m, 5H), 3.35-3.47 (m, 1H), 4.88 (brs, 1H),
    5.84 (s, 1H), 7.18-7.28 (m, 2H), 7.32-7.37 (m, 1H)
    345 (400 MHz, CDCl3) 0.73-0.78 (m, 3H), 0.96 (s, 9H), 533 531
    1.09-1.14 (m, 3H), 1.43-1.49 (m, 2H), 1.85 (s, 3H),
    1.90-2.00 (m, 1H), 2.69-2.78 (m, 2H), 4.10 (s, 3H),
    4.92 (s, 1H), 6.24 (s, 1H), 6.99-7.04 (m, 1H),
    7.30-7.37 (m, 2H), 7.56-7.62 (m, 1H), 7.69-7.72 (m, 1H),
    8.18-8.25 (m, 1H), 10.44-10.67 (m, 1H)
    346 (400 MHz, CDCl3) 0.97 (s, 9H), 1.41-1.49 (m, 2H), 547 545
    1.78 (s, 3H), 1.97-2.26 (m, 2H), 2.33-2.59 (m, 2H),
    2.62-2.76 (m, 3H), 4.10 (s, 3H), 4.98 (brs, 1H),
    6.19-6.23 (m, 1H), 7.00-7.07 (m, 1H), 7.20-7.29 (m, 2H),
    7.30-7.34 (m, 1H), 7.42-7.45 (m, 1H),
    8.20-8.26 (m, 1H), 10.51 (brs, 1H)
    347 (400 MHz, CDCl3) 0.16-0.24 (m, 1H), 431 429
    0.25-0.32 (m, 1H), 0.33-0.43 (m, 1H), 0.56-0.65 (m, 1H),
    0.82-0.91 (m, 1H), 0.91-1.06 (m, 2H), 1.09-1.30 (m,
    4H), 1.55-1.76 (m, 6H), 1.79 (s, 3H), 2.54-2.65 (m,
    4H), 3.65-3.81 (m, 2H), 5.66 (brs, 1H),
    5.70-5.72 (m, 1H), 7.11-7.15 (m, 1H), 7.25-7.29 (m, 1H),
    7.40-7.44 (m, 1H)
    348 (400 MHz, DMSO-D6) 0.94 (d, J = 6.47 Hz, 6H), 519 517
    1.63 (t, J = 6.82 Hz, 2H), 1.67 (s, 3H), 1.76-1.86 (m, 1H),
    2.21-2.40 (m, 2H), 2.56-2.67 (m, 3H), 4.09 (t,
    J = 6.59 Hz, 2H), 6.49 (d, J = 0.92 Hz, 1H), 7.16 (d,
    J = 8.79 Hz, 1H), 7.36 (dd, J = 8.67, 2.43 Hz, 1H),
    7.47 (d, J = 2.54 Hz, 1H), 7.50-7.53 (m, 2H), 7.67 (s, 1H),
    7.94-7.96 (m, 2H), 12.90 (brs, 1H)
    349 (400 MHz, DMSO-D6) 0.93 (d, J = 6.47 Hz, 6H), 509 507
    1.55 (s, 3H), 1.65-1.60 (m, 2H), 1.75-1.86 (m, 1H),
    2.18-2.28 (m, 2H), 2.32 (s, 6H), 2.42-2.55 (m, 2H),
    2.66-2.75 (m, 1H), 4.07 (t, J = 6.59 Hz, 2H), 6.03 (d,
    J = 1.16 Hz, 1H), 7.13 (d, J = 8.70 Hz, 1H), 7.21 (s, 1H),
    7.24 (dd, J = 8.70, 2.43 Hz, 1H), 7.35 (d, J = 2.43 Hz,
    1H), 12.46 (brs, 1H)
    350 (400 MHz, DMSO-D6) 0.12-0.16 (m, 2H), 517 515
    0.41-0.46 (m, 2H), 0.81-0.89 (m, 1H), 1.64 (t, J = 6.47 Hz,
    2H), 1.68 (s, 3H), 2.21-2.37 (m, 2H), 2.54-2.74 (m,
    3H), 4.12 (t, J = 6.47 Hz, 2H), 6.49 (d, J = 0.92 Hz, 1H),
    7.16 (d, J = 8.70 Hz, 1H), 7.37 (dd, J = 8.70, 2.50 Hz,
    1H), 7.47 (d, J = 2.50 Hz, 1H), 7.50-7.53 (m, 2H),
    7.67 (s, 1H), 7.93-7.97 (m, 2H), 12.90 (brs, 1H)
    351 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 503 501
    0.95 (s, 9H), 1.35-1.41 (m, 2H), 1.56-1.77 (m, 11H),
    1.99-2.06 (m, 1H), 2.61-2.65 (m, 2H), 3.11 (t,
    J = 8.90 Hz, 1H), 3.22 (s, 4H), 5.93 (s, 1H), 6.91 (s,
    1H), 7.25-7.35 (m, 3H)
    352 (400 MHz, DMSO-D6) 0.95 (s, 10H), 1.03 (d, 503 501
    J = 6.70 Hz, 3H), 1.35-1.40 (m, 2H), 1.61-1.79 (m,
    11H), 2.00-2.06 (m, 1H), 2.61-2.67 (m, 3H),
    2.86-2.91 (m, 1H), 2.93 (s, 3H), 5.90 (s, 1H), 6.95 (s, 1H),
    7.25-7.32 (m, 2H), 7.37 (d, J = 1.85 Hz, 1H)
    353 (400 MHz, DMSO-D6) 1.03 (s, 9H), 1.67 (s, 3H), 519 517
    2.38-2.21 (m, 2H), 2.54-2.79 (m, 3H), 3.72 (s, 2H),
    6.49 (d, J = 0.92 Hz, 1H), 7.12 (d, J = 8.79 Hz, 1H), 7.36 (dd,
    J = 8.55, 2.31 Hz, 1H), 7.47 (d, J = 2.31 Hz, 1H),
    7.50-7.53 (m, 2H), 7.67 (s, 1H), 7.93-7.97 (m, 2H),
    12.90 (brs, 1H)
    354 (400 MHz, DMSOD6) 0.16-0.12 (m, 2H), 507 505
    0.45-0.41 (m, 2H), 0.81-0.88 (m, 1H), 1.56 (s, 3H),
    1.61-1.67 (m, 2H), 2.19-2.28 (m, 2H), 2.32 (s, 6H),
    2.44-2.57 (m, 2H), 2.66-2.74 (m, 1H), 4.10 (t, J = 6.47 Hz,
    2H), 6.03 (d, J = 1.16 Hz, 1H), 7.12 (d, J = 8.79 Hz, 1H),
    7.21 (s, 1H), 7.24 (dd, J = 8.67, 2.43 Hz, 1H), 7.35 (d,
    J = 2.54 Hz, 1H), 12.44 (brs, 1H)
    355 (400 MHz, DMSO-D6) 1.02 (s, 9H), 1.55 (s, 3H), 509 507
    2.28-2.19 (m, 2H), 2.32 (s, 6H), 2.44-2.52 (m, 2H),
    2.66-2.74 (m, 1H), 3.70 (s, 2H), 6.04 (d, J = 1.16 Hz, 1H),
    7.08 (d, J = 8.55 Hz, 1H), 7.21 (s, 1H), 7.23 (dd, J = 8.55,
    2.31 Hz, 1H), 7.35 (d, J = 2.31 Hz, 1H), 12.44 (brs, 1H)
    356 (400 MHz, DMSO-D6) 0.70-0.76 (m, 3H), 0.94 (s, 453 451
    9H), 1.06-1.11 (m, 3H), 1.37-1.46 (m, 2H), 1.71 (s,
    3H), 2.02-2.10 (m, 1H), 2.52-2.61 (m, 2H), 6.26 (s,
    1H), 7.14-7.21 (m, 3H), 7.21-7.27 (m, 1H),
    7.27-7.34 (m, 1H), 7.34-7.37 (m, 1H), 7.80-7.87 (m, 2H)
    357 (400 MHz, DMSO-D6) 1.55 (s, 3H), 1.73-1.64 (m, 521 519
    2H), 1.76-1.87 (m, 4H), 2.01-2.08 (m, 2H),
    2.17-2.28 (m, 2H), 2.32 (s, 6H), 2.41-2.51 (m, 3H),
    2.66-2.74 (m, 1H), 3.98 (t, J = 6.47 Hz, 2H), 6.03 (d,
    J = 1.16 Hz, 1H), 7.09 (d, J = 8.79 Hz, 1H), 7.21 (s, 1H),
    7.23 (dd, J = 8.67, 2.43 Hz, 1H), 7.34 (d, J = 2.31 Hz,
    1H), 12.45 (brs, 1H)
  • Formulation examples of the present invention include for example the following, but the present invention should not be construed as being limited thereto.
    • Formulation Example 1 (Preparation of a Capsule)
  • 1) Compound of Example 1 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 (Preparation of a Tablet)
  • 1) Compound of Example 1 10 g
    2) Lactose 50 g
    3) Corn starch 15 g
    4) Carmellose calcium 44 g
    5) Magnesium stearate  1 g
  • The entire amounts of 1), 2) and 3) and 30 g of 4) arc mixed with water and dried in vacuo and then granulated. The granulated powder is mixed with 14 g of 4) and 1 g of 5) and tableted by a tableting machine. In this way, 1000 tablets can be obtained, each of which contains 10 mg of Compound of Example 1.
    • Test Example 1
  • Pharmacological effects of the typical compounds of the present invention were observed.
    • In Vitro Assay of Inhibitory Effect Against RORγ Transcriptional Activity
  • Inhibitory effect of a test article on transcriptional activity of RORγ was measured by means of the following reporter gene assay.
  • cDNA encoding human and mouse RORγ ligand binding domain (LBD) were obtained based on the sequences of human RORγ (Genebank registered number NM_005060.3) and mouse RORγ (Genebank registered number NM_011281.2) (LBD sequence: human RORγ, from Ser253 to Lys518; mouse RORγ, from Ile251 to Lys516).
  • The LBD cDNA of human or mouse RORγ was inserted into pFA-CMV vector (Strategene), which expresses GAL4-DNA binding domain fusion protein. The resulting plasmids are hereinafter referred to as GAL4-hRORγ plasmid and GAL4-mRORγ plasmid, respectively.
  • GAL4-hRORγ plasmid or GALA4-mRORγ plasmid was transiently co-transfected into Chinese hamster ovary cells (CHO cells) with pG5-Luc (Promega), a reporter plasmid expressing firefly luciferase depending on GAL4.
  • TransIT (Registered trademark) CHO transfection reagent (Mirus) was used to co-transfect GAL4-hRORγ plasmid or GAL4-mRORγ plasmid into CHO cells with pG5-Luc plasmid. One day before the assay, CHO cells were suspended in HAM F-12 Nutrient medium containing 10 v/v % fetal bovine serum and seeded at 6×106 cells per 175 cm2 cell culture flask. Fifty four micro litters of TransIT (Registered trademark) CHO reagent was added into a 15 ml tube containing 1.16 mL of HAM F-12 Nutrient medium without fetal bovine serum, and mixed and incubated at room temperature for 10 min. Thirty six micro litters of plasmid solution containing the GAL4-hRORγ plasmid (400 ng), pG5-Luc plasmid (9000 ng) and pcDNA3 plasmid (8600 ng) were added into the tube and mixed gently. In case of mouse assay, a plasmid solution containing the GAL4-mRORγ plasmid (250 ng), pG5-Luc plasmid (9000 ng) and pcDNA3 plasmid (8750 ng) was added, instead. The mixture was incubated at room temperature for 10 min. Nine micro litters of CHO Mojo Reagent were then added into each tube and mixed gently. The mixture was incubated at room temperature for 10 min. The resultant transfection reagent was applied to the cell culture. After incubation at 37° C., 5% CO2 for 4 hours, the plasmid-transfected CHO cells were harvested with a trypsin treatment. The collected cells were resuspended in HAM F-12 Nutrient medium supplemented with 10 v/v % fetal bovine serum and plated into a 384-well-white plate at 8,000 cells/50 μL/well. The plate was incubated at room temperature for 1 hour and then further incubated at 37° C., 5% CO2 for 3 hours. The test articles were dissolved in dimethylsulfoxide (DMSO) to obtain a concentration of 10 mM. The resulting solution was diluted with a medium just before use and added to the cells in the plate to prepare 8 different concentrations of the test article. The final concentration of DMSO was 0.2 v/v %. After the addition of the test articles, the cells were incubated at 37° C., 5% CO2 for 2 days.
  • Cell viability was tested by a fluorescence method using Resazurin (invitrogen). Two days after the addition of the test article, Resazurin was diluted with a medium to make the 20 μM resazurin solution. Ten micro litters of the diluted Resazurin solution was added into the 384-well-plate. Then, the fluorescence was measured immediately at 615 nm with the excitation wavelength of 570 nm (0 hr reading). After incubation at 37° C., 5% CO2 for 2 hours, the fluorescence was measured at 615 nm with the excitation wavelength of 570 nm again (2 hour reading). The fluorescence counts (2 hr-0 hr) were calculated by subtracting the 0 hr readings from the 2 hr readings. The luminescence count (2 h-0 h) in the cells treated with 0.2% DMSO alone was defined as 100%, and the cell viability in the test article was calculated as a percentage (%-of-control) based on the value of 0.2% DMSO alone. When the cell viability is 70% or less, it was judged that the test article has cytotoxicity.
  • RORγ transcriptional activity was detected as the intracellular luciferase activity using SteadyLite HTS Reporter Gene Assay System (Perkin Elmer). StedyLite Reagent was diluted five-fold into a solution containing Extension reagent (10 mM Tricine, 0.2% w/v BSA, 0.02% v/v Tween-20) to obtain the luciferase substrate solution. After the measurement of the cell viability using Resazurin, the culture media in the plate were removed, and then the luciferase substrate solution was added into each well. After the incubation at room temperature for 10 minutes, luminescence of each well was measured by a microplate reader. The luciferase activity derived from the luminescence count in the vehicle-control well treated with 0.2% DMSO alone was defined as 100%, and the luciferase activity in the test article was calculated as a percentage (%-of-control) based on the value of the vehicle-control. EC50 value of test article was calculated by curve fitting with GraphPad Prism. The luminescence counts at the concentration of the test article where the cytotoxicity was observed were excluded from the data analysis.
  • The results are shown in the table below.
  • The values with % is the activity of the test article which was calculated as a percentage (%-of-control) based on the value of the vehicle-control treated with 0.2% DMSO alone (100%).
  • In the following table, compounds of Examples 38, 87, and 116 were synthesized by a preparation method using Claisen reaction and measured.
  • TABLE 5
    LUC EC50 (μM)
    Example hRORγ mRORγ
    1 0.088 0.060
    2 >20 13.060 
    (55%)
    3 0.182 0.061
    4 1.443 0.675
    5 0.034 0.024
    6 >8 >8
    (76%) (75%)
    7 0.152 0.110
    8 0.021 0.022
    9 0.055 0.032
    10 0.009 0.017
    11 >8 >8
    (87%) (79%)
    12 0.023 0.017
    13 6.572 5.926
    14 >8 >8
    (69%) (59%)
    15 0.012 0.012
    16 0.362 0.137
    17 0.206 0.153
    18 0.051 0.028
    19 2.285 1.209
    20 2.935 2.519
    21 0.019 0.024
    22 0.017 0.029
    23 0.042 0.041
    24 2.938 2.934
    25 <0.032   <0.032  
    26 0.364 0.217
    27 0.025 0.016
    28 0.187 0.082
    29 0.036 0.049
    30 0.060 0.047
    31 3.074 >3.2
    (52%)
    32 0.026 0.046
    33 0.435 0.617
    34 0.013 0.021
    35 >3.2 >3.2
    (51%) (52%)
    36 0.021 0.024
    37 0.154 0.282
    38 0.011 0.015
    39 0.020 0.026
    40 0.152 0.198
    41 >8 >8
    (59%) (61%)
    42 0.031 0.028
    43 0.564 0.835
    44 0.051 0.090
    45 7.330 7.508
    46 0.017 0.016
    47 1.103 0.764
    48 0.012 0.016
    49 0.983 0.832
    50 0.007 0.013
    51 1.181 1.083
    52 0.010 0.015
    53 0.036 0.021
    54 >8 >8
    (92%) (81%)
    55 0.022 0.026
    56 5.163 4.291
    57 0.031 0.022
    58 1.249 1.654
    59 0.012 0.020
    60 15.270  12.430 
    61 0.143 0.046
    62 0.665 0.520
    63 >8 >8
    (51%) (70%)
    64 0.019 0.016
    65 0.028 0.021
    66 3.609 2.681
    67 0.023 0.017
    68 1.236 1.756
    69 0.020 0.017
    70 0.251 0.133
    71 0.505 0.758
    72 0.013 0.017
    73 0.803 0.657
    74 0.986 1.103
    75 0.296 0.316
    76 3.472 6.358
    77 0.015 0.024
    78 6.490 10.760 
    79 0.016 0.018
    80 0.016 0.017
    81 2.579 2.487
    82 0.980 0.790
    83 0.040 0.043
    84 0.746 0.502
    85 0.545 0.368
    86 6.770 >8
    (51%)
    87 0.011 0.015
    88 0.443 0.422
    89 0.016 0.016
    90 0.015 0.018
    91 0.539 1.152
    92 0.013 0.020
    93 2.144 2.544
    94 0.152 0.142
    95 >3.2 5.685
    (66%)
    96 0.033 0.026
    97 1.344 3.097
    98 0.013 0.018
    99 1.507 2.886
    100 0.020 0.035
    101 0.032 0.021
    102 >8 >8
    (76%) (76%)
    103 >3.2 >3.2
    (65%) (50%)
    104 0.050 0.031
    105 2.792 1.691
    106 1.162 0.616
    107 3.930 1.976
    108 0.016 0.021
    109 >8 >8
    (60%) (67%)
    110 0.011 0.010
    111 0.405 0.481
    112 0.021 0.019
    113 3.031 1.399
    114 14.880  10.960 
    115 >8 >8
    (110%) (100%)
    116 0.015 0.022
    117 >3.2 >8
    (106%) (76%)
    118 0.019 0.017
    119 >8 >8
    (74%) (76%)
    120 0.061 0.014
    121 >8 >8
    (62%) (85%)
    122 0.028 0.015
    123 >3.2 >3.2
    (109%) (100%)
    124 >0.512 0.030
    (54%)
    125 <0.032   <0.032  
    126 0.037 0.027
    127 2.940 1.950
    128 >20 >20
    (66%) (54%)
    129 0.047 <0.032
    130 0.010 0.019
    131 >8 >8
    (77%) (81%)
    132 0.018 0.014
    133 >8 >8
    (71%) (88%)
    134 0.070 0.027
    135 >8 >8
    (90%) (84%)
    136 0.094 0.049
    137 0.015 0.011
    138 >8 >8
    (85%) (96%)
    139 >0.512 0.027
    (110%)
    140 0.209 0.139
    141 >8 >8
    (57%) (52%)
    142 >0.512 0.049
    (102%)
    143 >8 >8
    (90%) (100%)
    144 >0.512 0.037
    (60%)
    145 2.038 3.973
    146 0.014 0.012
    147 0.059 0.030
    148 >8 >8
    (57%) (69%)
    149 1.014 0.245
    150 0.021 0.012
    151 0.018 0.023
    152 >20 >20
    (56%) (57%)
    153 0.327 0.116
    154 0.010 0.014
    155 >8 >8
    (83%) (81%)
    156 0.520 0.166
    157 0.497 0.255
    158 0.030 0.023
    159 0.021 0.023
    160 0.015 0.040
    161 0.154 0.047
    162 0.172 0.275
    163 0.143 0.267
    164 0.018 0.011
    165 0.027 0.017
    166 0.014 0.029
    167 0.065 0.049
    168 0.012 0.018
    169 0.008 0.015
    170 0.058 0.040
    171 0.012 0.014
    172 0.013 0.018
    173 0.022 0.011
    174 0.014 0.011
    175 0.009 0.012
    176 0.022 0.013
    177 0.017 0.017
    178 0.019 0.021
    179 0.064 0.027
    180 0.032 0.050
    181 0.018 0.032
    182 0.027 0.076
    183 0.118 0.078
    184 0.011 0.022
    185 0.009 0.014
    186 0.091 0.116
    187 0.172 0.063
    188 2.606 1.129
    189 0.030 0.022
  • TABLE 6
    LUC EC50(μM)
    Example hRORγ mRORγ
    190 >8 >8
    (74%) (66%)
    191 0.045 0.071
    192 0.017 0.011
    193 0.018 0.019
    194 0.058 0.028
    195 0.018 0.012
    196 0.009 0.017
    197 0.013 0.023
    198 0.012 0.026
    199 0.070 0.136
    200 0.014 0.023
    201 0.060 0.051
    202 0.087 0.052
    203 0.030 0.021
    204 0.014 0.017
    205 0.281 0.427
    206 0.081 0.117
    207 0.009 0.018
    208 0.021 0.040
    209 0.051 0.074
    210 0.006 0.007
    211 0.011 0.008
    212 >8 >8
    (68%) (81%)
    213 0.131 0.056
    214 0.169 0.100
    215 >20 >20
    (77%) (70%)
    216 >20 >20
    (86%) (76%)
    217 >20 >20
    (90%) (77%)
    218 0.376 0.122
    219 >20 >20
    (88%) (86%)
    220 0.022 0.029
    221 0.025 0.024
    222 0.020 0.040
    223 >20 >20
    (78%) (70%)
    224 0.343 0.123
    225 0.101 0.072
    226 0.017 0.020
    227 >20 >20
    (89%) (87%)
    228 0.032 0.032
    229 0.009 0.018
    230 0.225 0.076
    231 0.692 0.458
    232 0.015 0.019
    233 0.069 0.072
    234 0.964 0.534
    235 >3.2 1.610
    (70%)
    236 0.020 0.015
    237 0.719 0.673
    238 0.715 0.666
    239 4.562 3.065
    240 0.108 0.147
    241 0.112 0.247
    242 0.078 0.058
    243 1.219 0.543
    244 0.176 0.269
    245 0.261 0.301
    246 0.010 0.022
    247 0.018 0.016
    248 0.010 0.021
    249 0.412 0.779
    250 0.042 0.114
    251 0.013 0.028
    252 0.020 0.028
    253 0.075 0.034
    254 0.028 0.028
    255 0.273 0.296
    256 0.022 0.026
    257 0.165 0.115
    258 0.022 0.016
    259 0.057 0.043
    260 0.439 0.492
    261 >20 >20
    (90%) (100%)
    262 0.022 0.022
    263 0.026 0.018
    264 0.045 0.033
    265 0.037 0.071
    266 0.012 0.017
    267 0.030 0.033
    268 0.015 0.014
    269 0.019 0.023
    270 0.052 0.026
    271 0.043 0.047
    272 0.017 0.036
    273 0.025 0.075
    274 0.008 0.008
    275 0.542 1.215
    276 0.028 0.047
    277 0.023 0.038
    278 0.013 0.013
    279 0.016 0.022
    280 0.026 0.042
    281 0.014 0.021
    282 0.378 0.187
    283 0.018 0.028
    284 2.785 1.503
    285 1.353 0.030
    286 0.270 0.038
    287 0.036 0.034
    288 1.491 0.917
    289 1.117 0.773
    290 0.463 0.259
    291 1.085 0.138
    292 0.089 0.073
    293 1.095 1.019
    294 0.068 0.034
    295 0.134 0.366
    296 3.721 4.533
    297 0.044 0.061
    298 0.022 0.018
    299 0.011 0.016
    300 0.010 0.014
    301 0.027 0.010
    302 0.028 0.030
    303 1.399 1.308
    304 0.021 0.019
    305 0.003 0.006
    306 0.063 0.027
    307 0.005 0.013
    308 0.032 0.025
    309 >3.2 0.071
    (63%)
    310 0.476 0.277
    311 0.086 0.094
    312 0.248 0.538
    313 0.260 0.366
    314 0.038 0.032
    315 0.013 0.019
    316 0.018 0.019
    317 0.040 0.024
    318 0.017 0.014
    319 0.013 0.014
    320 0.023 0.027
    321 0.060 0.048
    322 0.021 0.019
    323 0.051 0.023
    324 0.047 0.036
    325 0.174 0.060
    326 0.032 0.036
    327 0.058 0.040
    328 0.035 0.019
    329 0.074 0.050
    330 0.019 0.014
    331 0.014 0.008
    332 0.012 0.013
    333 0.023 0.013
    334 0.022 0.014
    335 0.026 0.011
    336 0.010 0.007
    337 0.022 0.014
    338 0.013 0.012
    339 0.017 0.015
    340 0.123 0.043
    341 0.067 0.032
    342 0.043 0.028
    343 0.038 0.019
    344 0.013 0.012
    345 0.042 0.023
    346 0.026 0.018
    347 0.109 0.035
    348 0.046 0.039
    349 0.063 0.045
    350 0.109 0.052
    351 0.004 0.011
    352 0.063 0.051
    353 0.059 0.045
    354 0.239 0.144
    355 0.113 0.052
    356 0.021 0.015
    357 0.034 0.029
    • INDUSTRIAL APPLICABILITY
  • The compound of Formula [I] or a pharmaceutically acceptable salt thereof is useful in treating or preventing autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic disease such as asthma: dry eye: fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes.

Claims (21)

1-37. (canceled)
38: A method of inhibiting RORγ, comprising administering to a mammal a therapeutically effective amount of a compound selected from the group consisting of:
Figure US20190359575A1-20191128-C00631
Figure US20190359575A1-20191128-C00632
or a pharmaceutically acceptable salt of any of the foregoing.
39: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00633
or a pharmaceutically acceptable salt thereof.
40: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00634
or a pharmaceutically acceptable salt thereof.
41: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00635
or a pharmaceutically acceptable salt thereof.
42: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00636
or a pharmaceutically acceptable salt thereof.
43: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00637
or a pharmaceutically acceptable salt thereof.
44: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00638
a pharmaceutically acceptable salt thereof.
45: The method of claim 38, wherein the compound is:
Figure US20190359575A1-20191128-C00639
or a pharmaceutically acceptable salt thereof.
46: A method of treating a disease selected from the group consisting of allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to a mammal an effective amount of a compound selected from the group consisting of:
Figure US20190359575A1-20191128-C00640
Figure US20190359575A1-20191128-C00641
or a pharmaceutically acceptable salt of any of the foregoing.
47: The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00642
or a pharmaceutically acceptable salt thereof.
48: The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00643
or a pharmaceutically acceptable salt thereof.
49: The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00644
or a pharmaceutically acceptable salt thereof.
50: The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00645
or a pharmaceutically acceptable salt thereof.
51: The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00646
or a pharmaceutically acceptable salt thereof.
52: The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00647
or a pharmaceutically acceptable salt thereof.
53. The method of claim 46, wherein the compound is:
Figure US20190359575A1-20191128-C00648
or a pharmaceutically acceptable salt thereof.
54: The method according to any one of claims 46 to 53, wherein the disease is allergic disease.
55: The method according to any one of claims 46 to 53, wherein the disease is dry eye.
56: The method according to any one of claims 46 to 53, wherein the disease is fibrosis.
57: The method according to any one of claims 46 to 53, wherein the disease is metabolic disease.
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