TW200401778A - Oxazolidinone derivatives - Google Patents

Abstract

The present invention relates to an oxazolidinone derivative of the following formula (I), (II) or (III), [wherein, R1 and R2: a substituted phenyl group etc.; R3 and R4: H, a lower alkyl group etc.; R5: a lower alkyl group, a lower alkylsulfinyl-lower alkyl group, a lower alkylsulfonyl-lower alkyl group etc.; R6: a lower alkyl group etc.; m is an integer of 0-2; n is an integer of 1-6] or the pharmaceutically acceptable salt, ester or other derivative thereof, having an excellent Th1 selective immunosuppressor effect.

Description

200401778 发明 Description of the invention (The description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and the drawings are briefly explained. The oxazolidinone derivative, its pharmacologically acceptable salt, its ester or other derivative, and medicine containing it as an active ingredient. [Previous technology] In the past, in the treatment of rheumatism and other autoimmune diseases, immune-related diseases have been treated with anti-inflammatory drugs such as steroids. Therefore, there is no fundamental treatment for this disease. And reports on the immune system abnormality in the development of diabetes and nephritis [Kidney International, 51, 94 (1997), Journal of Immunology, 1 5 7, 4 6 9 1 (1 9 9)] have not been found so far Eliminate abnormalities. The helper-T cells that play a central role in the immune response are divided into two different subgroups, SP type 1 helper T cells (hereinafter referred to as T h 1 cells) and type 2 helper T cells (hereinafter referred to as T h 2 cell).

Thl cells produce cytokines such as interleukin 2 (hereinafter referred to as IL-2), interferon-γ ^ (hereinafter referred to as IFN-γ), and TNF-α, which are mainly related to cellular immunity. On the other hand, Th2 cells produce cytokines such as interleukin 4 (hereinafter referred to as IL-4), interleukin 10 (hereinafter referred to as IL-10), and are mainly related to humoral immunity (JI mmu η ο 1., V ο 1 1 3 6, 2 3 4 8-2 3 5 7, 1 9 8 6). I F N-γ produced by T h 1 cells can inhibit the function of T h 2 cells. In contrast, IL-4 and IL-10 produced by Th2 cells can inhibit the function of Th1 cells. In the normal immune function of the human body, the balance between T h 1 fine 200401778 cells and T h 2 cells is very important. In recent years, it has been understood that the abnormal balance of Thl / Th2 cells is associated with various diseases associated with the immune system. The report states that T h 1 cell imbalance is associated with chronic rheumatoid arthritis and chronic inflammatory diseases and organ-specific autoimmune diseases [eg, diabetes, multiple sclerosis, inflammatory bowel disease (eg, ulcerative colitis , Crohn's disease), glomerulonephritis, hepatitis, liver disease, autoimmune hemolytic anemia, leukocytopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Edison's disease, Hypoparathyroidism, pernicious anemia, limited ileitis, atrophic gastritis, gluten allergic enteritis, Goodpasture syndrome, post-streptococcal nephritis, myasthenia gravis, rheumatic fever, virality Cardiomyopathy, uveitis, sympathetic ophthalmia, pemphigus vulgaris, vesicular pemphigus, psoriasis], while Th2 cell imbalance is associated with allergic diseases and systemic autoimmune diseases (Immunol Today, V ο 1. 16, 3 4-3 8, 1 9 9 5; Science V ο 1. 260, 54 7- 549, 1 9 9 3; Immunity, Vol. 3, 1 7 1-1 7 4, 1 9 9 5 ; J. Exp. Med, Vol 1 9 0, 995-1003, 19 99, Kidney Int., Vol 52, 52-59, 1 9 9 7; I. Exp. Med "Vol. 185, 65-70, 1997). In immune-related diseases, each of its symptoms has been proved to be assisted by -T cells are involved in various cytokinins, and it is believed that inducing or inhibiting the production of these cytokinins is effective for the treatment of immune-related diseases. To date, compounds known to increase IL-4 in the body have been known, For example, 1, 2 5-dihydroxyvitamin D 3, but its effect is only indirect [j ο ιη · η a 1 of I mmu η ο 1 ogy, 1 6 0, 5 3 1 4 (1 9 9 8) ]. It is also known that gold and D-penicillamine also have the same effect, these effects are weak, and the direct induction of IL-4 production by 200401778 has not been proven [C 1 inica 1 E xperimenta 1 I mmu η ο 1 〇gy 5 438, 108 (1997)] In addition, compounds known to increase IL-10 in the body, such as 2 5 4 -dinitrochlorobenzene, but its effect is directly IL-1 0 The induction effect has not been proven [I mmu η ο 1 〇gy 5 8 9, 5 0 2 (1 9 6)]. Based on the above background, there is a choice Induction of IL-4 and / or IL-10 as a positive electrode to produce a compound to be developed. For example, compounds that selectively induce the production of IL-4 and / or IL-10 are disclosed in Japanese Patent Laid-Open Nos. 2000-11015. In this bulletin, compounds having the structure of 1-P 萼 -3,8-diacspiro [4.5] dec-2-one are disclosed, but the compounds having specific substituents in the structure are not specifically disclosed. [Summary of the Invention] The present inventors have intensively investigated the results of the selective inhibition of the Th 1 cell immune activity selective inhibitory effect on the production of IL-4 and / or IL-10 produced by Th2 cells, and the present invention The oxazolidinone derivative has excellent IL-4 and / or IL-1 0 inducing effect, and can be effectively used as chronic rheumatoid arthritis of chronic inflammatory diseases and diseases, and organ-specific autoimmune diseases [eg , Diabetes, multiple sclerosis, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), glomerulonephritis, hepatitis, liver disease, autoimmune hemolytic anemia, leukopenia, thrombocytopenia , Allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Edison's disease, hypoparathyroidism, malignant anemia, localized ileitis, atrophic gastritis, gluten-sensitive enteritis, Goodpasci Syndrome, nephritis after streptococcal infection, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, cross 200401778 Sensitive ophthalmia, pemphigus vulgaris, vesicular pemphigoid, psoriasis) (should Chronic rheumatoid arthritis or organ-specific autoimmune diseases, most preferably ulcerative colitis, Crohn's disease or hepatitis) are therapeutic and / or preventive agents, and are compatible with previous IL-4 and / or IL-1 Compared with the production-inducing agent, the compound of the present invention has high water solubility, high oral absorption, and has a rapid effect, high mobility to target organs or target cells, low mobility in the brain, low side effects, and safe use ( It has a wide concentration difference in pharmacological effects and toxicity, and excellent in vivo dynamics (long half-life in plasma, high AUC, low tissue accumulation, etc.), and completed the present invention. (1) The present invention relates to a pharmaceutical composition containing the compound of the following general formula (I), its pharmacologically acceptable salt, its ester or other derivative as an active ingredient.

R 1 and R 2 are the same or different, and each is a phenyl substituted with 1 to 3 groups selected from the substituent group a; R 3 and R 4 are the same or different; each is hydrogen or a lower alkyl; or R 3 and R 4 200401778 The common table is ethylene, R5 is hydrogen, lower alkyl, lower sulfinyl sulfonium lower alkyl, lower alkanesulfonyl lower alkyl, lower alkyl group containing 1 to 3 oxygen atoms in the carbon chain, and carbon chain Low alkyl groups containing 1 to 3 sulfur atoms, low alkyl groups containing 1 to 3 nitrogen atoms in the carbon chain, substituted with 1 to 3 groups selected from the substituent group b, and 1 to 3 in the carbon chain A low alkyl group of an oxygen atom, a sulfur atom, or a nitrogen atom or formula -C0-R 7 (wherein R 7 is a group selected from the substituent group b), R 6 is a low alkyl group or contains one in the carbon chain Low alkyl of oxygen atom, | m is an integer of 0 ~ 2, η is an integer of 1 ~ 6, and the substituent group a is selected from halogen atom, lower alkyl, halogen lower alkyl, lower alkoxy, and halogen lower Alkoxy, lower alkylthio, hydroxy, amine, nitro and cyano, the substituent group b is selected from aryl and heteroaryl groups, and is selected from 1 to 3 substituted aryl groups of the substituent group a And a heteroaryl substituted with 1 to 3 groups selected from the substituent group a, but when the general formula I), R3 and R4 are simultaneously hydrogen, R5 is hydrogen, lower alkyl and _ the carbon chain other than lower alkyl group containing 1 oxygen atoms]. The above is preferably (2) as described in (1) above, which contains a compound of general formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof, and (3) as described in (1) above, which contains a general formula ( II) a compound, a burial allowable salt thereof, an ester or other derivative thereof, (4) as described in the above (1) or (3) compound or a pharmacologically acceptable salt thereof, m is 0, (5) as described in (1) or ( 3) a compound or a pharmacologically acceptable salt thereof, m is a number of 2,401,007,778, (6) the compound or a pharmacologically acceptable salt thereof according to any one of (1) to (5) above, wherein R3 and R4 are hydrogen, ( 7) The compound or a pharmacologically acceptable salt thereof according to any one of the above (1) to (5), wherein R3 and R4 are collectively expressed as ethylidene, (8) As described in any one of the above (1) to (5) Compound or a pharmacologically acceptable salt thereof, wherein R3 and R4 are the same or different and each is a low alkyl group, (9) The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (5) above, wherein R 3 And R 4 are the same or different, each is a C _ 2 alkyl group, (10) the compound or a pharmacologically acceptable salt thereof according to any one of (1) to (5) above, wherein R 3 and R 4 are the same or different , Each for methyl, (1 1 ) The compound according to any one of (1) to (5) above, or a pharmacologically acceptable salt thereof, wherein R3 and R4 are hydrogen, (1 2) The compound according to any one of (1) to (10) above, or A pharmacologically acceptable salt thereof, wherein R5 is a low alkyl group, (1 3) A compound as described in any one of (1) to (10) above, or a pharmacologically acceptable salt thereof, wherein R 5 is a C! _4 alkyl group, ( 14) The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (1 0) above, wherein R5 is methyl or ethyl, and (1 5) is any of (1) to (1 0) above A compound of one item or a pharmacologically acceptable salt thereof, wherein R5 is a low alkyl group containing one oxygen atom in the carbon chain, (16) the compound of any one of the above (1) to (10) or a pharmacologically acceptable salt thereof, Wherein R 5 is a C 4 alkyl group containing one oxygen atom in the carbon chain, (1 7) a compound or a pharmacologically acceptable salt thereof as described in any one of (1) to (] 0) above 200401778, wherein R 5 is in the carbon chain A C2_3 alkyl group containing 1 oxygen atom, () 8) The compound according to any one of (1) to (1 0) above or a drug burying salt thereof, wherein R5 is a methoxy group or a 2-methoxyethyl group , () 9) The combination of any one of (1) to (1 0) above Or a pharmacologically acceptable salt thereof, in which R 5 is a lower alkylsulfinyl sulfonyl lower alkyl group, a lower alkyl sulfinyl sulfonyl lower alkyl group, (2 0) the compound according to any one of (1) to (1 0) above, or Pharmacologically acceptable salts, where R 5 is c 1 _ 2 alkanesulfinyl fluorene C! _ 2 alkyl or C! _ 2 alkane sulfinyl fluorene C! _ 2 alkyl, (2 1) as described above (1) to (1 0) The compound according to any one or a pharmacologically acceptable salt thereof, wherein R5 is methylsulfinylmethyl or methylsulfonylmethyl, (2 2) The compound according to any one of (1) to (1 0) above Or a pharmacologically acceptable salt thereof, wherein R5 is a low alkyl group having 2 to 3 oxygen atoms in the carbon chain, a low alkyl group having 1 to 3 sulfur atoms in the carbon chain, and one having 1 to 3 nitrogen atoms in the carbon chain A lower alkyl group or a lower alkyl group having 1 to 3 substitutions selected from the substituent group b, and a carbon chain containing 1 to 3 oxygen atoms, sulfur atoms, or nitrogen atoms, (2 3) are as described in (1) to ( 1) The compound of any one of 10) or a pharmacologically acceptable salt thereof, wherein R5 is a low alkyl group having 2 to 3 oxygen atoms in the carbon chain, and a low alkyl group or carbon chain having 1 to 3 sulfur atoms in the carbon chain A low alkyl group containing 1 to 3 nitrogen atoms, (2 4) as in any one of (1) to (1 0) above A compound or a pharmacologically acceptable salt thereof, wherein R5 is (:! Containing 2 to 3 oxygen atoms in the carbon chain) _4 alkyl group, low alkyl group containing 1 to 3 sulfur atoms in carbon chain or C 4 alkyl group containing 1 to 3 nitrogen atoms in carbon chain, (2 5) as in (1) to (1 0) above The compound of any one or a pharmacologically acceptable salt thereof, wherein R 5 is a C 2 _ 3 alkyl group having 2 to 3 oxygen atoms in the carbon chain, and an alkyl or carbon chain having 200 401778 1 to 3 sulfur atoms in the carbon chain C 2-3 radicals containing 1 to 3 nitrogen atoms, (26) The compound according to any one of (1) to (10) above or a pharmacologically acceptable salt thereof, wherein R 5 is 1 to 3 in the carbon chain A C2_3 alkyl group having a sulfur atom, (2 7) the compound or a pharmacologically acceptable salt thereof according to any one of (1) to (1 0) above, wherein R 5 is methylthiomethyl or 2-methylthioethyl, (2 8) The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (1 0) above, wherein R5 is a group of the formula -CO-R7 (wherein, R7 is a group selected from the substituent group b) ), (29) The compound or pharmacologically acceptable salt thereof as described in (28) above, wherein R7 is an aryl group, a heteroaryl group, or an aryl group substituted with 1 to 3 groups selected from the substituent group a, (3 0) The compound (2 8) or a pharmacologically acceptable salt thereof as described above, wherein R 7 is phenyl, furyl, thio A phenyl group or a phenyl group substituted with 1 to 3 groups selected from the substituent group a, (3 1) A compound as described above (2 8) or a pharmacologically acceptable salt thereof, wherein R 7 is phenyl, furyl, or thiophene Or a phenyl group substituted with 1 to 3 groups (the substituent may be selected from the group consisting of a halogen atom, a low-density group, and a low-oxyl group (3 2) as described above (2 8) or a pharmacologically acceptable compound Salt, wherein R 7 is phenyl or phenyl having 1 to 3 substituents (the substituent may be selected from the group consisting of fluorine, chlorine, C 2 alkyl and lower alkoxy), (3 3) is as described above ( 28) a compound or a pharmacologically acceptable salt thereof, wherein R 7 is a 1-3 substituted phenyl group having a low alkoxy group, (34) as described in (1) above, which is a compound containing the general formula (III), which Pharmacologically tolerable salt, its ester or other derivative, (3 5) The compound (3 4) as described above or its pharmacologically acceptable salt, in which R 6 is C!-4 -14- 200401778 alkyl or 1 in the carbon chain Cj. 4 alkyl group with 3 oxygen atoms, (3 6) The compound of the above (3 4) or a pharmacologically acceptable salt thereof, wherein R 6 is a C! _ 2 alkyl group or a C2_3 alkyl group with 1 oxygen atom in the carbon chain (3 7) A compound as described in (3 4) above or its A physiologically acceptable salt, wherein R 6 is methyl, ethyl, methoxymethyl, or 2-methoxyethyl, (38) the compound according to any one of (1) to (37) above, or a pharmacologically acceptable salt thereof, Wherein R 1 and R 2 are the same or different, and each is selected from the group consisting of a halogen atom, a lower alkyl group, a lower halogen group, a C 1-2 group oxygen group, a C 1 _ 2 group thio group, a nitro group, and an amino group Z 1 to 3 A phenyl group substituted with (3 9) the compound according to any one of (1) to (3 7) or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 are the same or different and each is selected from a halogen atom, A compound having a lower alkyl group, a lower halogen group, a nitro group and a Z 1 to 3 group substituted with a Z group 5 (4 0) as described in any one of (1) to (3 7) above, or a pharmacologically acceptable salt thereof, Wherein R 1 and R 2 are the same or different, and each is a phenyl group substituted with 1 to 3 groups selected from a halogen atom, a C 2 alkyl group, a halogen C 2 alkyl group, a nitro group, and a cyano group, (4 1) such as The compound of any one of the above (1) to (3 7) or a pharmacologically acceptable salt thereof, wherein R1 and R2 are the same or different, and each is fluorine, chlorine, methyl, trifluoromethyl, nitro, and cyano Phenyl substituted with 1 to 3 groups, (4 2) as described in (1) to (3 7) A compound or a pharmacologically acceptable salt thereof according to any one of the above, wherein R 1 and R 2 are the same or different, and each is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl , 4-chlorophenyl, 3-tolyl, 3-trifluorotolyl, 3-nitrophenyl, 3,4-xylyl, 2,3-difluorophenyl, 2,4-difluorophenyl , 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-ditrifluorotolyl, 3-cyanophenyl or 4-cyanophenyl 200401778 (43) The compound or pharmacologically acceptable salt thereof according to any one of (1) to (37) above, wherein R 1 and R 2 are the same or different, and each is 3-fluorophenyl, 4-fluorophenyl, 3 -Trifluorotolyl, 4-trifluorotolyl, 3-cyanophenyl or 4-cyanophenyl. (4 4) The compound or a pharmacologically acceptable salt thereof according to any one of (1) to (4 3) above, wherein η is 2, (4 5) As described in any one of (1) to (4 3) above A compound or a pharmacologically acceptable salt thereof, wherein η is 3, (4 6) The compound or a pharmacologically acceptable salt thereof as described in (1) above, which is 8-{2-[bis- (4-fluorophenyl) methoxy] Ethyl ethyl 3-methylthiomethyl-1-fluorene-3,8-diacspiro [4,5] dec-2-one, 8- {3- [bis- (4-fluorophenyl) methoxy ] Propylbutan-3-methylthiomethyl-1-fluorene-3, 8-diazepi [4,5] dec-2-one, 8- {2- [bis- (4-fluorophenyl) methoxy [Ethyl] ethylbulspirin [(8 -azinebicyclo [3 2 1] octane) -3 5 5 '-(3 -methylthiomethyl) -oxazolidine] -2' -one, 8-{3- [Bis- (4-fluorophenyl) methoxy] ethylspiro [(8-azinebicyclo [3 2 1] octane) -3,5 '-(3-methylthiomethyl) -D, etc. ] -2 '-Ketone, _ 8-{2-[bis- (3-trifluorotolyl) methoxy] ethylbu 3 -methanesulfinylmethyl-1 -fluorene-3,8 -diazine Spiro [4,5] dec-2-one, 8-{2-[bis- (3 -trifluorotolyl) methoxy] ethyl}-3 -methylthiomethyl-butan-3, 8- Bisacyl [4,5] dec-2-one, 8-{3-[ -(3 -trifluorotolyl) methoxy] propyl}-3 -methylthiomethyl-1-MDA-3,8 -diacryl [4,5] dec-2-one, 8-{ 3-[(3 -Cyanophenyl) (3 ^ trifluorotolyl) methoxy] propyl 3-methylthiomethyl-1-_-3,8 -di-arylene [4,5] dec- 2-keto, -1 6-200401778 8-{2-[(4-cyanophenyl) (4 I -trifluorotolyl) methoxy] ethyl}-3 -methylthiomethyl-1 -fluorene- 3,8 -diPY spiro [4,5] dec-2-one, 8-[3-(4-fluorophenoxy) -3-(4-fluorophenyl) propyl] -1 -fluorene-3 , 8-Diacryl [4,5] dec-2-one, 8- [3-(3-trifluorotolyloxy) -3-(3-trifluorotolyl) propyl 1-D 萼- 3,8-Diacyl [4 5 5] dec-2-one, 8- [3-(3 -trifluorotolyloxy) -3-(3 -trifluorotolyl) propyl] -3 -formyl Thiomethyl-1 -pyrene-3 5 8 -dipyridyl [4,5] dec-2-one, 8-{2-[bis (3-trifluorotolyl) methoxy] ethylbuspiro [(8-Ρ Bibicyclo [3.2.1.octane) -3 5 5'-oxazolidine] -2'-one, 8- [3- (3-cyanophenoxy) -3- ( 3 -fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2-one, 8- [3- (4- Phenoxy) -3- (4- ^ phenyl) propyl] -1-fluorene-3,8-oneyolspiro [4,5] dec-2-one, 8- [3-(3- Cyanophenoxy) -3-(3-trifluorotolyl) propyl] -1 -fluorene-3,8-diacryl [4,5] dec-2-one, 8- [3- (4- Cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2-one, 8-[3-(2- Fluorophenoxy) -3-(4-fluorophenyl) propyl] -1-fluorene-3,8-diazaspiro [4,5] dec-2-one and 8- {3-[(3- Cyanophenyl) (3 ^ trifluorotolyl) methoxy] propyl} -3-ethyl-1-oxo-3,8-diazelop [4,5] dec-2-one, (4 7) — A medicinal composition containing the compound according to any one of (1) to (4 6) above, its pharmacologically acceptable salt, its ester or other derivative as an active ingredient, 200401778 (4 8) such as (4 7 ) The medicinal composition according to (4) can selectively inhibit the immune activity of T h] cells, (4 9) The medicinal composition according to (4 7), which can promote the production of IL-4, (50) such as (4 7) The medicinal composition according to (4 7), which can promote the production of IL-10, (5 1) The medicinal composition according to (4 7), for prevention or treatment Chronic inflammatory diseases, organ-specific autoimmune diseases, or inflammatory bowel diseases, (5 2) The pharmaceutical composition as described in (4 7), used to prevent or treat chronic rheumatoid arthritis, diabetes, multiple sclerosis Disease, ulcerative colitis, Crohn's disease, glomerulonephritis, hepatitis, liver disease, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis , Edison's disease, hypoparathyroidism, malignant anemia, limited ileitis, atrophic gastritis, gluten-induced enteritis, Good Paster syndrome, nephritis after streptococcal infection, myasthenia gravis, Rheumatic fever, viral cardiomyopathy, uveitis, sympathetic ophthalmia, pemphigus vulgaris, vesicular pemphigus, or psoriasis, (5 3) The pharmaceutical composition as described in (4 7), used to prevent or treat chronic Rheumatoid arthritis or organ-specific autoimmune diseases, (5 4) The pharmaceutical composition according to (4 7), for preventing or treating ulcerative colitis, Crohn's disease or hepatitis, (5 5) — The purpose of manufacturing a pharmaceutical composition is to use a compound according to any one of (1) to (4 6), a pharmacologically acceptable salt, an ester or other derivative thereof, (5 6), such as (5 5), wherein medicine The composition selectively inhibits the immune activity of Th 1 cells, (5 7) The use of (5 5), wherein the pharmaceutical composition is used to prevent or treat chronic 200401778 inflammatory diseases, organ-specific autoimmune diseases or inflammation Intestinal diseases, (5 8) Uses such as (5 5), wherein the pharmaceutical composition can be used to prevent or treat chronic rheumatoid arthritis, diabetes, multiple sclerosis, ulcerative colitis, Crohn's disease, glomeruli Nephritis, Hepatitis, Liver Disease, Autoimmune Hemolytic Anemia, Leukopenia, Thrombocytopenia, Allergic Encephalitis, Demyelination, Hashimoto's Thyroiditis, Edison's Disease, Hypoparathyroidism, Malignant Anemia, localized ileitis, atrophic gastritis, gluten allergic enteritis, Good Paster syndrome, streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, Sensitive ophthalmia, pemphigus vulgaris, vesicular pemphigus, or psoriasis, the use of (5 9) such as (5 5), wherein the pharmaceutical composition can be used to prevent or treat chronic rheumatoid arthritis or organ-specific autoimmunity Disease, (60) Uses such as (5 5), wherein the pharmaceutical composition can be used to prevent or treat ulcerative colitis, Crohn's disease or hepatitis, (6 1) — a method for preventing or treating disease, which is administered Warm-blooded animals use a pharmacologically effective amount of a compound described in any one of (1) to 4 6), a pharmacologically acceptable salt, an ester or other derivative thereof, (6 2) a method such as (6 1), wherein the disease is chronic Inflammatory diseases, organ-specific autoimmune diseases, or inflammatory bowel diseases, (6 3) The method of (6 1), wherein the diseases are chronic rheumatoid arthritis, diabetes, multiple sclerosis, ulcerative colitis , Crohn's disease, glomerulonephritis, hepatitis, liver disease, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Edison's disease, A Hypoparathyroidism , Pernicious anemia, limited to 200401778 local ileitis, atrophic gastritis, gluten allergic enteritis, Good Paster syndrome, streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uve membrane Inflammation, sympathetic ophthalmia, pemphigus vulgaris, vesicular pemphigus, or psoriasis, (6 4) A method such as (6 1), wherein the disease is chronic rheumatoid arthritis or an organ-specific autoimmune disease, ( 6 5) The method according to (6 1), wherein the disease is ulcerative colitis, Crohn's disease, or hepatitis, (6 6) The method according to any one of (6 1) to (6 5), wherein the warm-blooded animal Be human. ® In the above formula, the "low alkyl" in the definition of R3, R4, R5, R6 and the substituent group a may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second Butyl, third butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl Methyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Dimethyl butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl, etc. straight φ or branched C! _ 6 Alkyl, R 3, R 4 and substituent group a are preferably C! _4 alkyl, more preferably C ^ 2 alkyl, most preferably methyl, and R5 and R6 are preferably Cm alkyl, more preferably Ci_2 is preferably methyl or ethyl. In the above formula, "lower alkylsulfinyl sulfoalkyl" in the definition of R5 is a group in which the above "low alkyl" is combined with sulfinyl sulfinyl (for example, methylsulfinyl, ethylsulfinyl, propylene Sulfonyl, Isosulfinyl, Isosulfinyl, Isosulfinyl, Isobutylsulfinyl, Isobutylsulfinyl, Isosulfinyl, Isosulfinyl, Isosulfinyl, Isosulfinyl Fluorenyl, 2-methylbutylsulfinylfluorenyl, neopentylsulfinylfluorenyl, -20- 200401778 1-ethylpropylsulfinylfluorenyl, hexamethylenesulfinyl, or isohexamethylenesulfinyl, and the above-mentioned " "Low alkyl" bonded groups, for example, methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, isopropylsulfinylmethyl, butylsulfinylmethyl, isobutylsulfinyl Stilbene methyl, second sulphinyl stilbene methyl, third sulphin sulphonium stilbene methyl, sulphenyl sulphonium sulphonium methyl, isopresylsulphonium sulphonium methyl, 2 -methyl sulphinium sulphonium methyl, neopentyl Sulfenylmethyl, 1-ethylpropylsulfinylmethyl, hexamethylenesulfinylmethyl, isohexylsulfinylmethyl, 2- (methylsulfinyl) ethyl, 2- (ethylsulfinyl) Yl) ethyl, 2- (propylsulfinylfluorenyl) ethyl, 2- (isopropylsulfinyl) ethyl, 2- (butylsulfinyl) ethyl, 2- (isobutylsulfinyl) ethyl, 2- (second butylsulfinyl) ethyl, 2- (third butylsulfinyl) Ethyl, 2- (pentylsulfinyl) ethyl, 2- (isopentylsulfinyl) ethyl, 2- (2-methylbutylsulfinyl) ethyl, 2- (neopentyl) Sulfonyl) ethyl, 2- (1-ethylpropanesulfinyl) ethyl, 2- (hexanesulfinyl) ethyl, 2- (isohexylsulfinyl) ethyl, 3- (Methylsulfinyl) propyl, 3- (ethylsulfinyl) propyl or 3- (propylsulfinyl) propyl, preferably (111-4 sulfinyl) More preferably, it is a sulfinylfluorenyl ^ '1-2 alkyl group, most preferably methylsulfinylmethyl or 2- (methylsulfinyl) ethyl. In the above formula, R5 is defined as "low "Alkylsulfonyl-lower alkyl" is a group in which the above-mentioned "low alkyl" is combined with sulfonium (for example, methanesulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butanesulfonyl, isopropyl Butanesulfonyl, second butanesulfonyl, third butanesulfonyl, pentosulfonyl, isopentylsulfonyl, 2-methylbutsulfonyl, neopentylsulfonyl, 1-ethylpropanyl Sulfonyl, Hexylsulfonyl, or Heterogeneous Fluorenyl, a group obtained by combining with the above-mentioned "low alkyl", for example, methylsulfonylmethyl, ethylsulfonylmethyl, sulfonylmethyl, isopropylsulfonylmethyl, butylsulfonylmethyl, isopropyl Butanesulfonylmethyl, second butanesulfonylmethyl, third butanesulfonylmethyl, pentamidine 200401778 Methyl, 1-ethylpropanesulfonylmethyl, hexanesulfonylmethyl, isohexylsulfonylmethyl, 2- (methylsulfonyl) ethyl, 2- (ethylsulfonyl) ethyl, 2-( Propanesulfonyl) ethyl, 2- (isopropylsulfonyl) ethyl, 2- (butylsulfonyl) ethyl, 2- (isobutylsulfonyl) ethyl, 2- (second butylsulfonyl) Fluorenyl) ethyl, 2- (third butylsulfonyl) ethyl, 2- (pentylsulfonyl) ethyl, 2- (isopentylsulfonyl) ethyl, 2- (2-methylbutyl Sulfonyl) ethyl, 2- (neopentylsulfonyl) ethyl, 2- (1-ethylpropanesulfonyl) ethyl, 2- (hexylsulfonyl) ethyl, 2- (isopropyl Sulfonyl) ethyl, 3- (methylsulfonyl) propyl, 3- (ethylsulfonyl) propyl or 3- (propanesulfonyl) propyl, preferably Cm ® Base, more preferably Ci_2 Sulfo group glycosyl Ci_2 hospital, most suitably methyl or sulfonylurea methyl 2 - (methanesulfonamide acyl) ethyl. In the above formula, the "low alkyl group containing 1 to 3 oxygen atoms in the carbon chain" in the definition of R5 is a group containing 1 to 3 oxygen atoms in the low alkyl carbon chain (excluding the group containing oxygen atoms at the end of the carbon chain) ), For example, methoxy, 2-methoxyethyl, 2-methoxypropyl, 3-methoxybutyl, ethoxymethyl, 2- (ethoxy) ethyl, 2- (ethoxy ) Propyl, 3- (ethoxy) butyl, propoxymethyl, 2- (propoxy) ethyl or 2- (propoxy) propyl, etc., as low as 1 oxygen atom in the carbon chain Alkyl, 2- (methoxy) ethoxymethyl, 2- (ethoxy) ethoxymethyl or 2- [2- (methoxy) ethoxy] ethyl have 2 carbon chains Low alkyl of oxygen atom, 2-[2-(methoxy) ethoxy] ethoxymethyl or 2-{2-[2-(methoxy) ethoxy] ethoxy} ethyl etc. A low alkyl group containing 3 oxygen atoms in the carbon chain is preferably a C 4 alkyl group containing 1 to 3 oxygen atoms in the carbon chain, and more preferably a C 2 _ 3 alkyl group containing 1 to 3 oxygen atoms in the carbon chain. The C2_3 alkyl group containing 1 oxygen atom in the carbon chain is most preferably a methoxymethyl group or a 2-methoxyethyl group. -22- 200401778 In the above formula, the "low alkyl group containing 3 to 3 sulfur atoms in the carbon chain" in the definition of R5 is a group containing 1 to 3 sulfur atoms in the low alkyl carbon chain (excluding the end of the carbon chain) Sulfur atom), for example, methylthio, 2-methylthioethyl, 2-methylthiopropyl, 3-methylthiobutyl, ethylthiomethyl, 2- (ethylthio) ethyl, 2- (Ethylthio) propyl, 3- (ethylthio) butyl, ethylthiomethyl, 2- (ethylthio) ethyl or 2- (ethylthio) propyl contain 1 sulfur in the carbon chain Atomic lower alkyl, 2- (methylthio) ethylthiomethyl, 2- (ethylthio) ethylthiomethyl, or 2- [2- (methylthio) ethylthio] ethyl in the carbon chain Low alkyl with 2 sulfur atoms, 2-[2-(methylthio) ethylthio] ethylthiomethyl or 2-{2-[2-(methylthio) ethylthio] ethylthio} Low alkyl with 3 oxygen atoms in carbon chains such as ethyl, preferably C 4 alkyl with 1 to 3 sulfur atoms in the carbon chain, more preferably C with 1 to 3 sulfur atoms in the carbon chain A 2_3 alkyl group or a C 2_3 alkyl group containing 1 sulfur atom in the carbon chain is most preferably a methylthiomethyl group or a 2-methylthioethyl group. In the above formula, the "low alkyl group containing 1 to 3 nitrogen atoms in the carbon chain" in the definition of R 5 is a group containing 1 to 3 nitrogen atoms in the low alkyl carbon chain (excluding those containing a nitrogen atom at the end of the carbon chain) Group), for example, methylaminomethyl, 2-methylamineethyl, 2-methylaminepropylφ, 3-methylaminobutyl, ethylaminomethyl, 2- (ethylamino) ethyl, 2-( Ethylamino) propyl, 3- (ethylamino) butyl, ethylaminomethyl, 2- (propylamino) ethyl or 2- (ethylamino) propyl Low alkyl, 2- (methylamino) ethylaminomethyl, 2- (ethylamino) ethylaminomethyl, or 2- [2- (methylamino) ethylamino] ethyl containing 2 in the carbon chain Low alkyl with 2 nitrogen atoms, 2-[2-(methylamino) ethylamino] ethylamine methyl or 2-{2-[2-(methylamino) ethylamino] ethylamino) ethyl Low alkyl with 3 nitrogen atoms in the carbon chain, preferably 0 ^ 4 alkyl with 1 ~ 3 nitrogen atoms in the carbon chain, more preferably C2_3 alkyl with 1 ~ 3 nitrogen atoms in the carbon chain -23- 200401778, a C 2 _ 3 alkyl group containing one nitrogen atom in the carbon chain, most preferably methylamine methyl or 2-methylamine ethyl. In the above formula, in the definition of R5, "a lower alkyl group selected from 1 to 3 substitutions in the substituent group b, a carbon chain containing 1 to 3 oxygen atoms, sulfur atoms, or nitrogen atoms" is "Low alkyl with 1 to 3 oxygen atoms", "Low alkyl with 1 to 3 sulfur atoms in the carbon chain" or "Low alkyl with 1 to 3 nitrogen atoms in the carbon chain" 1 to 3 substituted groups from the substituent group b, for example, 4-methoxybenzyloxymethyl, 4-methylthiobenzyloxymethyl, 4-dimethylamine benzyloxymethyl, or 2- (4-methyl Oxybenzyloxy) ethyl. In the above formula, the "low alkyl group containing 1 oxygen atom in the carbon chain" in the definition of R6 is, "the low alkyl group containing 1 to 3 oxygen atoms in the carbon chain" is "1 oxygen atom in the carbon chain" The "low alkyl" part is synonymous. In the above formula, the "halogen atom" in the definition of the substituent group a is F, C1,

Br or I is preferably F or C1, and most preferably F. In the above formula, the "halo-lower alkyl group" in the definition of the substituent group a is a group in which the above-mentioned "low-alkyl group" is substituted with a halogen atom, for example, trifluoromethyl, trichloromethyl, dichloromethyl, dichloro Methyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl Halo Ci_6 alkyl group, such as 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, or 2,2-dibromoethyl, is more preferred. Ci_2 ^ 1 group, and more preferably fluorine C! _2 alkyl chloride (^ _2 alkyl group, most preferably trifluoromethyl group. In the above formula, the "low alkoxy group" in the definition of the substituent group a is the above " A "low alkyl" group bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, -24-200401778 Tributoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1-ethylpropyl, 2-ethylpropoxy, neopentyloxy, hexyloxy, 4-methyl Pentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, methylbutyl Straight, branched, straight-branched Ch6 alkanoyl groups such as 2-_methylbutanyl, 1,3-dimethylbutoxy, or 2,3-dimethylbutoxy, etc. are preferably Ci_4 courtyards The oxy group 5 is more preferably Ci_2 alkoxy group. Most preferably, it is a methyl group. In the above formula, the "halo-lower alkoxy group" in the definition of the substituent group a is that the "low-alkoxy group" has a halogen atom substituted group. , For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2-iodoethoxy, 3-chloropropoxy, 4-fluoro Halo Cm alkoxy, such as butoxy, 6-iodohexyloxy, or 2,2-dibromoethoxy, is preferably halogen Ci_4 and oxygen, more preferably halogen, Ci_2, and oxygen. 1_2 oxo group Ci_2 oxo group is most preferably digas methyl group. In the above formula, the "low alkylthio group" in the definition of the substituent group a is the group in which the above "low alkyl group" is combined with a sulfur atom, For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, second butylthio, third Butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methyl Pentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-^ __ • methylbutylthio, Straight or branched Ci-6 alkylthio, such as 1,3-methylbutylthio, or 2,3-methyl thiosulfate, is preferably C! _4 alkylthio, more preferably In the above formula, the "aryl group" and "there are 1 to 3 substituted Zs selected from the substituent group a." The aryl moiety of "aryl" is, for example, a C 6 ^ aromatic hydrocarbon such as' benzyl, indenyl or naphthyl, preferably phenyl or naphthyl, and most preferably phenyl. In the above formula, the heteroaryl portion in the definition of "heteroaryl" and "having 1 to 3 substituted heteroaryl groups selected from substituent group a" in the definition of substituent group b contains 1 to 3 sulfur atoms, oxygen 5 to 7 membered aromatic heterocyclic group of atom and / or nitrogen atom, for example, furyl, thienyl, pyrilyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl , Heterothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, datralyl, pyrimidinyl, or pyridyl Ring group, and the above heteroaryl group can be fused with other rings such as benzene ring, for example, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, fluoracinyl, indolyl Or isoindolyl, etc., is preferably a 5- to 6-membered heteroaryl group, and most preferably furanyl or thienyl. In the above formula, specific examples of "there are 1 to 3 substituted phenyl groups each selected from the substituent group a" in the definitions of R 1 and R 2 are, for example, 2-fluorophenyl group, 3-fluorophenyl group, 4- Fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-trifluorotolyl, 3-trifluorotolyl , 4-trifluorotolyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoro Fluoromethoxyphenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl , 3-cyanophenyl, 4-cyanophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3 , 5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5 > dichlorophenyl, 3,4-dichlorophenyl, 3,5-di Chlorophenyl, 2,3-di-trifluorotolyl, -26- 200401778 2,4-di-trifluorotolyl '2,5-di-trifluorotolyl, 3,4-di-trifluorotoluene Base, 3; 5-di-trifluorotolyl, 3,4,5-trifluorophenyl, 354,5-tri Chlorophenyl, 2,4-dimethoxyphenyl or 3 5 5 -dimethoxyphenyl are preferably selected from the group consisting of halogen, t-lower, halo-lower, C1- 2 Halo C 1 _ 2 alkoxy, C 1 _ 2 alkylthio, nitro and cyano 1 to 3 substituted phenyl, more preferably selected from halogen atoms, lower alkyl, halogen lower alkyl, 1 to 3 substituted phenyl groups of nitro and cyano groups; more preferably 1 to 3 substituents selected from halogen atom, C 1 _ 2 group, halogen C 1-2 group, nitro group and cyano group The phenyl group is more preferably a phenyl group having 1 to 3 substituents selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, nitro and cyano, and more preferably 2-fluorophenyl, 3- Fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-tolyl, 3-trifluorotolyl, 3-nitrophenyl, 3,4-xylyl, 2, 3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-di-triphenyl Fluorotolyl, 3-cyanophenyl or 4-cyanophenyl, most preferably 3-fluorophenyl, 4-fluorophenyl, 3-trifluorotolyl, 4-trifluorotolyl, 3-cyanophenyl Or 4-cyanophenyl. In the above formula, in the definition of the substituent group b, “there are 1 to 3 substituted aryl groups each arbitrarily selected from the substituent group a”, for example, the above “has 1 to 3 arbitrarily selected from the substituent group a Substituted phenyl groups ", 5-fluoroindene-3 -yl, 5-chloroindene-3 -yl, 5-methylindene-3-yl, 5-methoxyindene-3-yl, 5-fluoroindene-2 -Yl, 5-chlorobenzyl-2-yl, 5-methylbenz-2-yl, 5-methoxybenzyl-2-yl, 5-chrysene-2-yl, 5-chloronaphthalen-2-yl, 5- Menadiene-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoronaphthalene-phenyl, 5-naphthalene-1-yl, 5-methylnaphthalene-1-yl, 5-methylnaphthalene-1 -Yl, 5-benz-3-yl, 5-hydroxynaphthalen-2-yl, or 5-hydroxynaphthalen-1-yl, preferably 1 to 3 substituted phenyl groups selected from the substituent group a, more Preferably it is a phenyl group having 1 to 3 substituents (the -27- 200401778 substituent is a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group), and more preferably 1 to 3 substituents The phenyl group (the substituent is a group selected from the group consisting of fluorine, chlorine, C! _2 alkyl, and a lower alkoxy group) is most preferably a phenyl group having 1 to 3 substituents selected from a lower alkoxy group. "The pharmacologically acceptable salt" refers to a salt prepared by reacting the compound of the general formula (I), (11) or (111) of the present invention with an acid such as an amine group when it has a basic group. Its salts are preferably hydrohalates such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodate; inorganic salts such as nitrate, perchlorate, sulfate, and phosphate; methanesulfonic acid; Salts, trifluoromethanesulfonate, ethanesulfonate and other low-alkane sulfonates, benzenesulfonate, p-toluenesulfonate and other aromatic sulfonates, acetate, malate, fumarate, Organic acid salts such as succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine, lysine, spermine, ornithine , Glutamate, aspartate and the like, most preferably inorganic or organic acid salts (especially fumarate or maleate). The compounds of the general formula (I), (π) or (111) of the present invention, their pharmacologically acceptable salts, their esters or other derivatives may have various isomers due to the presence of asymmetric carbon atoms in the molecule. The isomers and mixtures of the isomers of the compounds of the present invention are represented by a single formula, that is, general formula (I), (Π) or (IΠ). Therefore, the present invention also includes isomers and mixtures of isomers in any ratio. When the compound of the general formula (I), (Π) or (III) of the present invention, its pharmacologically acceptable salt, its ester or other derivative is left or recrystallized in the atmosphere, it may absorb water, adsorb water, and form hydrates. Such hydrates are also included in the salts of the present invention. 200401778 The above "ester" means that when the compound (I), (Π) or (III) of the present invention has a hydroxyl group, it is esterified and expressed as an ester. The hydroxyl group can be referred to as "general protecting group" or "in vivo. Such "esters or other derivatives" can be obtained by protecting the protecting groups cleaved by biological methods such as hydrolysis. "General protective group" refers to a protective group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis. The `` general protecting group '' in `` hydroxyester '' is preferably methylamyl, ethylamyl, propionyl, butylamyl, isobutylamyl, pentamyl, special fluorenyl, pentamyl, isopentamyl, octyl, nonyl Fluorenyl, decylfluorenyl, 3-methylnonylfluorenyl, 8-® methylnonylfluorenyl, 3-ethyloctylfluorenyl, 3,7-dimethyloctylfluorenyl, undecylfluorenyl, dodecylfluorenyl, decyl Trimethyl, tetradecyl, pentadecyl, hexadecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13, 13-dimethyltetradecanyl, ten Heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylhexadecyl, 19-decyl, icosyl, and 21-yl, ethyl chloride Haloyl carbonyls such as fluorenyl, dichloroethenyl, trichloroethyl fluorenyl, trifluoroethyl fluorenyl, alkoxyalkyl carbonyls such as methoxy fluorenyl, propylene fluorenyl, propynyl fluorenyl, methyl φ propylene fluorenyl "Substitutable aliphatic fluorenyl groups" such as butenefluorenyl, isobutylenefluorenyl, (E)-2 -methyl-2-butenefluorenyl and other unsaturated alkylcarbonyl groups (preferably as low as C! _ 6 Aliphatic fluorenyl); benzyl fluorenyl, α-naphthyl fluorenyl, β-naphthyl fluorenyl, etc. Haloarylcarbonyl such as 2-bromobenzyl, 4-chlorobenzylfluorenyl, low alkylarylcarbonyl such as 2,4,6-trimethylbenzylfluorenyl, 4-tolylfluorenyl, etc. Alkoxyarylcarbonyl, 4-nitrobenzylfluorenyl, 2-nitrobenzylfluorenyl and other nitroarylcarbonyl groups, 2- (methoxycarbonyl) benzylfluorenyl and other lower alkoxycarbonylated arylcarbonyl groups, 4-phenylbenzylfluorenyl and the like "Substitutable aromatic fluorenyl" such as arylcarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl-29- 200401778, butoxycarbonyl, second butoxycarbonyl, third butoxycarbonyl, isopropyl Low alkoxycarbonyl groups such as butoxycarbonyl, halogens such as 2,2 5 2 -trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or "alkoxycarbonyl" substituted with low alkoxycarbonyl groups such as trioxanesilyl •, Tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydro "Tetrahydropyranyl or tetrahydrothiopyranyl" such as thiopyran-4-yl; "Tetrahydrofuranyl or tetrahydrothiofuranyl" such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl; trimethyl Silyl, triethylsilyl, isopropylsilyl, tert-butyl Tri-lower silyl groups such as dimethylsilyl, methyldiisopropylsilyl, methyltrisuccinic, triisopropylsilyl, dibenzosilyl, diphenylsilyl, diphenyl "Silyl" such as isopropylsilyl, phenyldiisopropylsilyl and the like, substituted with 1 to 2 aryl groups and lower alkylsilyl; methoxymethyl, 1,1-dimethyl-1-methoxymethyl Low alkoxymethyl such as ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, and third butoxymethyl; low alkoxylated low alkoxy such as 2-methoxyethoxymethyl Methyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, etc. "haloalkoxymethyl" and other "alkoxymethyl"; 1 -ethoxyethyl, 1 -Lower alkoxylated ethyl such as (isopropoxy) ethyl, "substituted ethyl" such as halogenated ethyl such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl , Benzyl, Trityl, α-Naphthyl, 9-Onion methyl, etc. 1 to 3 aryl substituted low alkyl; 4-methylbenzyl, 2,4,6-trimethyl Benzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, Low-radicals such as 4-chlorobenzyl, 4-bromobenzyl, and 4-pyridyl; low-oxyl, nitro, halogen, and amino-substituted aromatic rings substituted with 1 to 3 aryl-substituted lower alkyl groups "Aralkyl"; Vinyloxy group, dipropoxyfluorenyl group; "burning oxycarbonyl group"; carbohydrazone, 4-methoxy-30- 200401778 benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl 1 to 2 lower alkoxy groups such as 2-nitrobenzyloxycarbonyl, 4-benzyloxycarbonyl, or nitro groups, such as nitro, may have substituted "aralkoxycarbonyl groups", which may be substituted low aliphatic fluorenyl groups . "Protection group in vivo that can be cleaved by biological methods such as hydrolysis" refers to a protective group that can be cleaved in the human body by biological methods such as hydrolysis to form a free acid or its salt. After the experimental arteriovenous injection, the animal body fluid, the original compound, or its pharmacologically acceptable salt can be detected and determined. "Hydroxyesters" and "protective groups that can be cleaved by biological methods such as hydrolysis in vivo" are preferably methylamoxymethyl, ethylammonium methyl, dimethylamine ethylammonium methyl, propylammonium methyl, butanidine Oxymethyl, pivalamyloxymethyl, pentamyloxymethyl, isoamyloxymethyl, hexamethyleneoxymethyl, 1-methylammonyloxyethyl, 1-acetamyloxyethyl, 1-propylammonium Oxyethyl, 1-butyryloxyethyl, 1-tetramethyleneoxyethyl, 1-pentamethyloxyethyl, 1-isopentyloxyethyl, 1-hexamethyleneoxyethyl, 1-formamidine Oxypropyl, 1-acetamyloxypropyl, 1-propanyloxypropyl, 1-butamyloxypropyl, 1-pentamyloxypropyl, 1-pentamyloxypropyl, 1-isoamyl Oxypropyl, 1-hexamethyleneoxypropyl, 1-acetamidobutyl, 1-propanophenoxybutyl, 1-butanophenoxybutyl, 1-pentaphenoxybutyl, 1-acetamido Pentyl, 1-propanyloxypentyl, 1-butanyloxypentyl, 1-tetrapentyloxypentyl, 1-tetrapentyloxyhexyl, etc. 1-("lower aliphatic fluorenyl" oxy) " "Lower alkyl", cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexanecarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl '1 -cyclohexyl Carbooxypropyl, 1-ring 1-("cycloalkyl" carbonyloxy) "lower alkyl", such as carbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl, 1-("aromatic alcohol" oxy " "Low courtyard base" Temple 1-(Baking gas base) "Low courtyard base", methyl gas 200401778 carbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxy Carbonyloxymethyl, isobutoxycarbonyloxymethyl, pentoxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1-( Methoxycarbonyloxy) ethyl, 1-(ethoxycarbonyloxy) ethyl, 1-(propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1-(but Oxycarbonyloxy) ethyl, 1-(isobutoxycarbonyloxy) ethyl, 1-(third butoxycarbonyloxy) ethyl, i-(pentoxycarbonyloxy) ethyl, 1- ( Hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1-(cyclopentyloxycarbonyloxy) propyl, 1-(cyclohexyloxycarbonyloxy) propyl, 1- (Cyclopentyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycurtoxy) ethyl, 1- (ethoxyloxy) propyl, 1 -(Methoxyloxy) propyl , 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (pentoxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1 -(Ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (Isobutoxycuryloxy) butyl, methoxy-based oxy) pentyl, 1- (ethoxylockoxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy Base) Hexyl and other (low alkoxy-based gas-based) radicals; (5-benzyl-2 -oxo-1,3 -dendronyl-4 -yl) methyl, [(5- (4-methylbenzyl Radical) -2 -Ga-1,3-phenylene-4-yl) methyl, [(5- (4-methylaminophenyl) -2 -oxo-1,3-phenylene-4,4-yl ) Methyl, [(5-(4-fluorophenyl) -2 -oxo-1,3-dioxo-4, -yl) methyl, [(5-(4-chlorophenyl)-2-oxo -1,3-Dioxo-4, 4-yl) methyl, (2-oxo-1,3-di-D, 4-fluorenyl 4-methyl) methyl, (5-methyl-2 -oxo-1, 3-Shinjimao-4-base) , (5-ethyl-2 -oxo-1; 3-dioxofluoren-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxofluoren-4-yl) methyl (5--32- 200401778 isopropyl-2-oxo-1,3 -dioxo-4-octyl) methyl, (5-butyl-2-oxo)> 153- 4-Carboxyloxyalkyl group

} Phthalyl group> Monophthaloyl group and monomethoxyphthaloyl group phthaloyl group j) Low aliphatic aliphatic fluorenyl group J 5 that can be taken by the above-mentioned factory 5 Aromatic fluorenyl group j succinic acid half ester residue that the above-mentioned factory can replace Ethyl J y Phosphate Pro J3XL Residue J 5 Ester of Ethyl Amino Acid, etc. Residue j 9 Carbamate has 1 or 2 lower alkyl substituted carbamates > Oxygen γαι m-based plant 1-(醯 _ L-based): courtyard: executive: m: radical J 5 should be a replaceable low-aliphatic fluorenyl or succinate half ester residue. Other derivatives of the plant J are When the compound VII, (II) or (II I) of the present invention contains; when there is an amine group 5 Derivatives other than the above-mentioned pharmacologically tolerable salt J and the above-mentioned ester j of the same are represented by their derivatives. It can be an amino group derivative such as a low amino group, aryl • γ, behenyl) K amino group or a heteroarylγ, behenyl) K amino group. The present invention-general formula ⑴, (II) or 丨 (III ) Specific examples of compounds-Division is as follows: " r Compound 1 described in Table 1 and Table 3, but the present invention is not limited to litification △ Mouth 0 and compounds of Table 1, Table 2 and Table 3 each have formula (I), ( The structural formulas of Π) and (I II;). The abbreviations in the table are as follows: Et ethyl 9 M (^ * methyl, Ph phenyl 9 Fu r (2) furan-2- .yl Fu r (3) furan -3-group 5 Th] (2) thiophene 2--group? T hi (3) thiophene 3-group. 200401778 [Table 1]

No. Ri R2 R3 R4 R5 n 1 -1 3-F-Ph 3-F-Ph HH-CH2-SOMe 2 1 -2 3-F-Ph 3-F-Ph HH-(CH2) 2-SOMe 2 1 -3 3-F-Ph 3-F-Ph HH-CH 「SOMe 3 1-4 3-F-Ph 3-F-Ph HH-(CH2) 2-SOMe 3 1-5 3-F-Ph 3- F-Ph HH-CHrS02Me 2 1 -6 3-F-Ph 3-F-Ph HH-(CH2) 2-S02Me 2 1-7 3-F-Ph 3-F-Ph HH-CH factory S02Me 3 1- 8 3-F-Ph 3-F-Ph HH-(CH2) rS02Me 3 1-9 3-F-Ph 3-F-Ph HH -CH2-0- (CH2) 2-OMe 2 1 -10 3-F -Ph 3-F-Ph HH-CHrO-(CH2) 2-OMe 3 1-11 3-F-Ph 3-F-Ph HH-CH 「SMe 2 1 -12 3-F-Ph 3-F-Ph HH-CHrSMe 3 1-13 3-F-Ph 3-F-Ph HH-(CH2) 2-SMe 2 1 -14 3-F-Ph 3-F-Ph HH-(CH2) 2-SMe 3 1- 15 3-F-Ph 3-F-Ph HH -CHrNHMe 2 1-16 3-F-Ph 3-F-Ph HH -CHr_e 3 1-17 3-F-Ph 3-F-Ph HH -CO-Ph 2 1-18 3-F-Ph 3-F-Ph HH -CO-Ph 3 200401778 1-19 3-F-Ph 3-F-Ph HH -C〇- (2-Me〇-Ph) 2 1- 20 3-F-Ph 3-F-Ph HH -C0- (2-MeO-Ph) 3 1-21 3-F-Ph 3-F-Ph HH -CO- (3-MeO-Ph) 2 Bu 22 3-F-Ph 3-F-Ph HH -CO- (3-MeO-Ph) 3 1-23 3-F-Ph 3-F-Ph HH-C0- (4_Me0_Ph) 2 1-24 3-F- Ph 3-F-Ph HH -CO- (4-MeO-Ph) 3 1-25 3-F-Ph 3-F-Ph HH -C0- (2,4-diMe0 ~ Ph) 2 1-26 3-F-Ph 3-F-Ph HH -CO-(2,4-diMeO-Ph) 3 1-27 3 -F-Ph 3-F-Ph HH CO-Fur (2) 2 1-28 3-F-Ph 3-F-Ph HH -CO_Fur (2) 3 1-29 3-F-Ph 3-F-Ph HH -CO-Fur (3) 2 1-30 3-F-Ph 3-F-Ph HH _C0-Fur (3) 3 1-31 3-F-Ph 3-F-Ph HH -C0-Thi (2 ) 2 1-32 3-F-Ph 3-F-Ph HH -C0-Thi (2) 3 1 ~ 33 3-F-Ph 3-F-Ph HH-C0-Thi (3) 2 1-34 3 -F-Ph 3-F-Ph HH -CO-Thi (3) 3 1-35 3-F-Ph 3-F-Ph Me Me H 2 1-36 3-F-Ph 3-F-Ph Me Me H 3 1-37 3-F-Ph 3-F-Ph-(ch2) 2 one H 2 1-38 3-F-Ph 3-F-Ph-(ch2) 2 one H 3 1-39 3-F -Ph 3-F-Ph-(ch2) -CHrSMe 2 1-40 3-F-Ph 3-F-Ph-(ch2) 2 one-CHrSMe 3 1-41 3-F_Ph 3-F-Ph-(ch2 ) 2 One-(CH2) 2-SMe 2 1-42 3-F-Ph 3-F-Ph-(ch2) 2 One-(CH2) 2-SMe '3 1-43 3 ~ F-Ph 3-F -Ph-(ch2) 2 one-CO-Ph 2 1-44 3-F-Ph 3-F-Ph-(ch2) 1 one- COHPh 3 1-45 3-F-Ph 3-F-Ph-( ch2) 2—-C0- (2-MeO-Ph) 2 1-46 3-F-Ph 3-F-Ph-(ch2) 2— -C0- (2-Me0-Ph) 3 1-47 3- F-Ph 3-F-Ph-(ch2) 'Γ -CO-Fur (2) 2 200401778

1-48 3-F-Ph 3-F-Ph-(CH2) 2--CO-Fur (2) 3 1-49 3-F-Ph 3-F-Ph-(CH2) 2--CO-Thi ⑵ 2 1-50 3-F * ~ Ph 3-F-Ph-(ch2) 1 -CO-Thi ⑵ 3 1-51 4-F-Ph 4 ~ F-Ph HH -CHrSOMe 2 1-52 4- F-Ph 4-F-Ph HH-(CH2) Plant SOMe 2 1-53 4-F-Ph 4-F-Ph HH-CH2-SOMe 3 1-54 4-F-Ph 4-F-Ph HH- (CH2) rSOMe 3 1-55 4-F ~ Ph 4-F-Ph HH-CH2-S02Me 2 1-56 4-F-Ph 4-F-Ph HH-(CH2) rS02Me 2 1-57 4-F -Ph 4-F-Ph HH-CH2-S02Me 3 1-58 4-F-Ph 4-F-Ph HH ~ (CH2) rS02Me 3 1-59 4-F-Ph 4-F-Ph HH-CH2- 〇- (CH2) 2-OMe 2 1-60 4-F-Ph 4-F-Ph HH -CHr0- (CH2) r0Me 3 Bu 61 4-F-Ph 4-F-Ph HH-CH2_SMe 2 1-62 4-F-Ph 4_F-Ph HH -CHrSMe 3 1-63 4-F-Ph 4-F ~ Ph HH-(CH2) rSMe 2 1-64 4-F-Ph 4-F-Ph HH-(CH2) 2-SMe 3 1-65 4-F-Ph 4-F-Ph HH -CHrNHMe 2 1-66 4 ~ F ~ Ph 4-F-Ph HH -CHrNHMe 3 1-67 4-F-Ph 4-F- Ph HH-(CH2) rNHMe 2 1-68 4-F-Ph 4-F-Ph HH-(CH2) rNHMe 3 1-69 4-F-Ph 4-F-Ph HH _C〇-Ph 2 1-70 4-F-Ph 4-F-Ph HH -CO-Ph 3 1-71 4-F-Ph 4-F-Ph HH-C0- (2-MeO-Ph) 2 1-72 4-F-Ph 4 ~ F ~ Ph HH -CO- (2-MeO-Ph) 3 1-73 4-F-Ph 4-F-Ph HH-CO- (3-_-Ph) 2 1-74 4-F-Ph 4-F-Ph HH -C0- (3-Me0-Ph) 3 1-75 4-F-Ph 4-F-Ph HH _C0_ (4 ~ M6〇-Ph) 2 1-76 4-F-Ph 4-F-Ph HH -C〇- (4-Me〇-Ph) 3 -36- 200401778 1-77 4-F_Ph 4-F-Ph Η H -CO- (2,4-diMeO-Ph) 2 1-78 4-F-Ph 4-F-Ph Η H -C0- ( 2,4-diMe0-Ph) 3 1-79 4-F-Ph 4 ~~ F ~ Ph Η H -CO- (3,5-diMeO-Ph) 2 1-80 4-F-Ph 4-F- Ph Η H -C〇- (3? 5-diMe〇-Ph) 3 1-81 4-F-Ph 4-F-Ph Η H -CO-Fur (2), 2 1-82 4-F-Ph 4-F-Ph Η H -CO-Fur (2) 3 1-83 4-F-Ph 4-F_Ph Η H -CO-Fur (3) 2 1-84 4-F-Ph 4-F-Ph Η H -CO-Fur (3) 3 1-85 4-F-Ph 4 ~ F_Ph Η H -CO-Thi (2), 2 1-86 4-F-Ph 4-F_Ph Η H-CO-Thi (2 ) 3 1-87 4-F-Ph 4-F-Ph Η H -CO-Thi (3) 2 1-88 4 ~ F ~~ Ph 4-F-Ph Η H-CO-Thi (3) 3 1 -89 4-F-Ph 4-F-Ph Me Me H 2 1-90 4-F-Ph 4-F-Ph Me Me H 3 1-91 4-F-Ph 4-F-Ph-(CH2) 2- H 2 1-92 4-F-Ph 4-F-Ph-(CH2) 2- H 3 1-93 4-F-Ph 4-F-Ph-(CH2) 2--CH2-SMe 2 1 -94 4 ~ F ~ Ph 4-F-Ph-(CH2) r ~ CHrSMe 3 1-95 4-F-Ph 4_F-Ph-(CH2) 2--(CH2) rSMe 2 1-96 4-F- Ph 4_F-Ph-(CH2) 2 ~-(CH2) r SMe 3 1-97 4-F-Ph 4-F-Ph-(ch2) 2--CO, 2 1-98 4-F-Ph 4-F-Ph-(CH2) 2- -CO-Ph 3 1 -99 4-F-Ph 4 ~ F ~ Ph-(CH2) 2--CO- (2-MeO-Ph) 2 1-100 4-F-Ph 4-F-Ph-(CH2) 2--CO -(2-MeO-Ph) 3 1-101 4-F-Ph 4-F-Ph-(CH2) 2--CO-Fur⑵ 2 1-102 4-F-Ph 4-F-Ph (CH2) f -CO-Fur (2) 3 1-103 4_F_Ph 4 ~ F ~ Ph-(CH2) • Factory-CO-Thi ⑵ 2 1-104 4-F-Ph 4-F-Ph-(ch2) 2- -CO -Thi ⑵ 3 1-105 3-Cl-Ph 3-Cl-Ph Η H -CHrSMe 2 1-106 3-Cl-Ph 3-Cl-Ph HH-(CH2) 2_SMe 1-107 3-Cl-Ph 3 -C Ph HH -CO-Ph 1-108 3-Cl-Ph 3-C Ph HH -CO- (2-MeO-Ph) 1-109 3-Cl-Ph 3-C Ph PhHH -C0_Fur ( 2) 1-110 3-Cl-Ph 3-Π-Ph HH -CO-Thi (2) 1-111 3-C Ph 3-Cl-Ph Me Me H 1-112 3-Cl-Ph 3-Cl -Ph-(ch2) 2 ~ H 1-113 4-Cl-Ph 4 ~ C1-Ph HH -CHrSMe 1-114 4-C Ph 4-Cl-Ph HH-(CH2) 2-SMe 1-115 4 -Cl-Ph 4-Cl-Ph HH -CO-Ph 1-116 4-Cl-Ph 4-Cl-Ph HH -CO- (2-Me〇-Ph) 1-117 4-Π -Ph 4-Cl -Ph HH -CO-Fur (2) 1-118 4-Cl-Ph 4-Cl-Ph HH-CO_Thi (2) 1-119 4-C Ph 4-Cl-Ph Me Me H 1-120 4- Cl-Ph 4-Cl-Ph-(ch2) 2-H 1-121 3-Me-Ph 3 -Me-Ph HH-CHrSMe 1-122 3-Me-Ph 3-Me-Ph HH-(CH2) rSMe 1-123 3-Me-Ph 3-Me-Ph HH -CO-Ph 1-124 3 ~ Me -Ph 3-Me-Ph HH-C0- (2-MeO-Ph) 1-125 3-Me-Ph 3-Me-Ph HH -CO-Fur ⑵ 1-126 3-Me-Ph 3-Me-Ph HH -CO ~ Thi (2) 1-127 3-Me-Ph 3_Me-Ph Me Me H 1-128 3-Me-Ph 3-Me-Ph-(ch2) 2 -H 1-129 4-Me-Ph 4-Me-Ph HH-CH 「SMe 1-130 4 ~ * Me-Ph 4-Me-Ph HH-(CH2) rSMe 1-131 4-Me-Ph 4-Me-Ph HH -CO-Ph 1- 132 4-Me-Ph 4-Me-Ph HH -C0- (2-Me0-Ph) 1-133 4-Me-Ph 4-Me-Ph HH -CO-Fur⑵ 1-134 4-Me-Ph 4- Me-Ph HH -C0-Thi (2) 1-135 4-Me-Ph 4-Me-Ph Me Me H 1-136 4-Me-Ph 4-Me-Ph-(CH2) r H 2 1-137 3-CF3-Ph 3-CF3-Ph HH-CHrS0Me 2 1-138 3-CF, ~ Ph O 3-CF3-Ph HH-(CH2) 2-SOMe 2 1-139 3-CF3-Ph 3-CFrPh HH -CHrS0Me 3 1-140 3-CF3-Ph 3-CF3-Ph HH-(CH2) rSOMe 3 1-141 3_CF3-Ph 3-CF3-Ph HH -CHrS02Me 2 1-142 3-CF3-Ph 3-CF3- Ph HH-(CH2) 2-S02Me 2 1-143 3-CF3_P1i 3-CF2-Ph HH-CHrS02Me 3 1-144 3-CF3-Ph 3-CF3-Ph HH-(CH2) rS02Me 3 1-145 3- CFs-Ph 3-CF3-Ph HH-CH2-0-(CH2) 2_OMe 2 1-146 3-CF3-Ph 3-CF3 ~ Ph HH -CHr0- (CH2) r0Me 3 1-147 3-CF2-Ph 3-CF3-Ph HH -CHrSMe 2 1-148 3-CFs-Ph 3- CF3_Ph HH -CHrSMe 3 1-149 3-CFs-Ph 3-CF3-Ph HH-(CH2) 2_SMe 2 1-150 3-CF3-Ph 3-CF3-Ph HH-(CH2) rSMe 3 1-151 3- CF3-Ph 3-CFs-Ph HH ~ CHrNHMe 2 1-152 3-CF3-Ph 3-CF3-Ph HH -CHrNHMe 3 1-153 3-CF3-Ph 3-CF3-Ph HH-(CH2) rNHMe 2 1 -154 3-CF3_Ph 3-CF2-Ph HH-(CH2) rNHMe 3 1-155 3-CF3-Ph 3-CF3-Ph HH -CHr〇-CHrPh 2 1-156 3-CFs-Ph 3-CF3_Ph HH- CHr〇-CHrPh 3 1-157 3-CFs-Ph 3-CF3-Ph HH -CHr0-CHr (4-Cl-Ph) 1-158 3-CFs-Ph 3-CFrPh HH -CH2_0-CH2-(4- Cl -Ph) 1-159 3-CF3-Ph 3-CF3_Ph HH -CO-Pb 2 1-160 3-CF3-Ph 3-CF3-Ph HH -CO-Ph 3 1-161 3-CF2-Ph 3- CF3-Ph HH -C0- (2 ~ Me0-Ph) 2 1-162 3-CF3-Ph 3-CF2-Ph HH -C0- (2-Me0-Ph) 3 1-163 3-CF3-Ph 3- CF3-Ph HH -C0- (3-Me0-Ph) 2 2200401778 1-164 3-CF3-Ph 3-CF3-Ph Η H -C0- (3-Me0-Ph) 1-165 3-CF3-Ph 3 -CF3-Ph Η H-CO-(4-_-Ph) 1-166 3-CF3_Ph 3-CF3-Ph Η H-CO-(4-MeO-Ph) 1-167 3-CFrPh 3-CF3-Ph Η H -CO- (2,4-diMeO-Ph) 1-168 3-CFs-Ph 3-CF3-Ph Η H -CO-(2,4-diMeO-Ph) 1-169 3-CF3-Ph 3- CFs-Ph Η H -CO-Fur (2) 1-170 3-CF3-Ph 3-CF3-Ph Η H -CO ~ Fur (2) 1-171 3-CF3-Ph 3-CF3-Ph Η H- C〇-Fur (3) 1-172 3-CF3-Ph 3-CF3-Ph Η H -CO-Fur (3) 1-173 3-CF3-Ph 3-CF3-Ph Η H -CO-Thi (2 ) 1-174 3-CFs-Ph 3-CF3-P1i Η H-C0-Thi (2) 1-175 3-CF3-Ph 3-CF3-Ph Η H -CO-Thi (3) 1-176 3- CF3-Ph 3-CF3-Ph Η H -CO-Thi (3) 1-177 3-CF3-Ph 3-CFs-Ph Me Me H 1-178 3-CF3-Ph 3-CF3_Ph Me Me H 1-179 3-CF3-Ph 3-CF3-Ph-(CH2) 2-H 1-180 3-CF3-Ph 3-CF3-Ph _ (ch2) 2-H 1-181 3-CF3-Ph 3-CF3-Ph -(ch2) 2--CHrSMe 1-182 3-CF 「Ph 3-CF3-Ph-(ch2) 2--CH2-SMe 1-183 3-CF3-Ph 3-CF3_Ph-(CH2) 2--( CH2) rSMe 1 -184 3-CF3-Ph 3-CF3-Ph-(CH2) 2- ~ (CH2) rSMe 1-185 3-CF3-Ph 3-CF3-Ph-(CH2) r -CO-Ph 1 -186 3-CF3-Ph 3-CF3-Ph-(CH2) 2 "-CO, 1-187 3-CFrPh 3-CF3-Ph ~ (CH2) r -CO- (2-MeO_Ph) 1-188 3- CF3-Ph 3-CF3-Ph ~ (CH,) r 1 (2-MeO-Ph) 1 -189 3-CF3-Ph 3-CF3-Ph-(CH 2) 2- -CO-Fur (2) 1-190 3-CF3-Ph 3-CF3-Ph ~ (ch2) 2- -CO-Fur⑵ 1-191 3-CF3-Ph 3-CF3-Ph-(CH2 ) 2--CO-Thi (2) 1-192 3-CF3-Ph 3-CF3-Ph-(ch2) 2- -CO-Thi (2) -4 0- 3 2 3 2 3 2 3 2 3 2 3 2 3

2 3 2 3 2 3

2 3 2 3 2 3 2 3 200401778 1-193 4-CF3_Ph 4-CFrPh HH-CH Factory SOMe 2 1-194 4-CF,-Ph υ 4-CF3-Ph HH ~ (CH2) rSOMe 2 1-195 4 -CF3-Ph 4-CFrPh HH -CH 「SOMe 3 1-196 4-CF3-Ph-4-CFrPh HH-(CH2) 2-SOMe 3 1-197 4-CF3-Ph 4-CF3-Ph HH -CH2 ~ S02Me 2 1-198 4-CF3-Ph 4-CFrPh HH-(CH2) 2-S02Me 2 1-199 4-CF3-Ph 4-CF3-Ph HH-CH2-S02Me 3 1-200 4-CF3-Ph 4-CF3-Ph HH-(CH2) rS〇2Me 3 1-201 4-CF3-Ph 4-CF3-Ph HH -CH2-0- (CH2) 2-OMe 2 1-202 4-CF3-Ph 4- CF3-Ph HH-CH2-〇 ~~ (CH2) 2-〇Me 3 1-203 4-CF3-Ph 4-CF3-Ph HH-CH2_SMe 2 1-204 4-CF3-Ph 4-CF3-Ph HH- CHrSMe 3 1-205 4-CF3-Ph 4-CFrPh HH-(CH2) rSMe 2 1-206 4-CF3-Ph 4-CF3-Ph HH-(CH2) 2-SMe 3 1-207 4-CF3-Ph 4-CF3 ~ Ph HH -CHrNHMe 2 1-208 4-CF3-Ph 4-CF3-Ph HH -CHrNHMe 3 1-209 4-CF3-Ph 4-CF3-Ph HH-(CH2) 2-NHMe 2 1- 210 4-CF3-Ph 4-CF3-Ph HH-(CH2) 2-Li Me 3 1-211 4-CF3-Ph 4-CF3-Ph HH -CO-Ph 2 1-212 4-CF3-Ph 4- CF3-Ph HH -CO-Ph 3 1-213 4-CF 「Ph 4-CF3HPh HH -C0- (2-Me0-Ph) 2 1-214 4-CF3-Ph 4-CF3-Ph HH-CO-(2 * ~ Me0-Ph) 3 215 4-CF3 ~ Ph 4-CF3-Ph HH ~ C0 ~ (3 ~ Me0_Ph) 2 1- 216 4-CFrPh 4-CF3-Ph HH -C0- (3-Me0-Ph) 3 1-217 4-CF3-Ph 4-CFrPh HH -CO- (4-MeO-Ph) 2 1-218 4-CFrPh 4-CF 「Ph HH-CO-(4-MeCHPh) 3 1-219 4-CF3-Ph 4-CF3-Ph HH -CO- (2,4-diMe (HPh) 2 1-220 4-CF3-Ph 4-CF3-Ph HH-CO- (2,4-diMeO-Ph) 3 1-221 4-CFs-Ph 4-CF3-Ph HH ~ X0-Fur (2) 2 -4 1 >

200401778

1-222 4-CF3-Ph 4-CFrPh Η H -C0-Fur (2) 3 1-223 4-CF3-Ph 4-CF3_Ph Η H -CO-Fur (3) 2 1-224 4-CF3-Ph 4-CF3-Ph Η H ~ C〇-Fur (3) 3 1-225 4_CFrPh 4-CF3-Ph Η H -CO- 丁 hi (2) 2 1-226 4-CF3 ~~ Ph 4-CF3-Ph Η H -CO-Thi ⑵ 3 1-227 4-CF3-Ph 4-CF3-Ph Η H -CO-Thi (3) 2 1-228 4-CF3-Ph 4-CF3-Ph Η H -CO-Thi ⑶ 3 1-229 4-CF3-Ph 4-CF3-Ph Me Me Η 2 1-230 4-CF3-Ph 4-CF3-Ph Me Me Η 3 1-231 4-CFrPh 4-CF3-Ph-(CH2 ) 2-Η 2 1-232 4-CF3-Ph 4-CF3-Ph-(ch2) 2- Η 3 1-233 4-CFfPh 4-CF3-Ph-(ch2) 2--CHrSMe 2 1-234 4 -CF3-Ph 4_CF3-Ph-(ch2) 2--CHrSMe 3 1-235 4-CF3-Ph 4-CF3-Ph-(CH2) f-(CH2) rSMe 2 1-236 '4-CF3-Ph 4 -CF3-Ph-(CH2) 2--(CH2) 2-SMe 3 1-237 4-CFs-Ph 4-CF3-Ph-(CH2) 2- -CO-Ph 2 1-238 4-CF3-Ph 4-CFrPh-(CH2) 2--CO ~ Ph 3 1-239 4-CF3-Ph 4-CF3-Ph-(CH2) 2--CO- (2-MeO-Ph) 2 1-240 4-CF3 -Ph 4-CF3-Ph-(ch2) 2- -C0 ~ (2-Me0-Ph) 3 1-241 4-CF3-Ph 4-CF3-Ph-(ch2) 2--CO-Fur (2) 2 1-242 4-CF3-Ph 4_CF3-Ph-(CH2) 2--CO-Fur (2) 3 1-243 4-CF3-Ph 4-CF3-Ph-(CH2) 2- -CO-Thi (2) 2 1-244 4-CF3-Ph 4-CF3-Ph-(CH2) 2- -CO-Thi (2) 3 1-245 3 -Me〇-Ph 3-MeO-Ph Η Η-CH2-SMe 2 1-246 3-MeO-Ph 3-MeO-Ph Η Η-(CH2) plant SMe 2 1-247 3-MeO-Ph 3-MeO -Ph Η Η -C〇-Ph 2 1-248 3-MeO-Ph 3-MeO-Ph Η CO -CO- (2_MeO-Ph) 2 1-249 3-MeO-Ph 3-MeO-Ph Η Η- CO-Fur (2) 2 1-250 3-MeO-Ph 3-MeO-Ph Η Η -CO-Thi (2) 2 -42 1-251 3-MeO-Ph 3-MeO-Ph Me Me H 1- 252 3-Me〇-Ph 3-MeO-Ph-(ch2) ιΓ H 1-253 4-Me〇-Ph 4-Me〇-Ph HH ~ CH2 ~ SMe 1-254 4-Me〇-Ph 4 ~- M6〇 * ~ Ph HH-(CH2) rSMe 1-255 4-MeO-Ph 4-Me〇-Ph HH -CO_Ph 1-256 4-MeO-Ph 4-Me〇-Ph HH -C〇- (2- Me〇-Ph) 1-257 4-Me〇-Ph 4-MeO-Ph HH -C〇-Fur (2) 1-258 4-MeO-Ph 4-MeO-Ph HH -CO-Thi (2) 1 -259 4-MeO-Ph 4-MeO-Ph Me Me H 1-260 4 ~ Me〇-Ph 4-MeO-Ph-(CH2) 2-H 1-261 3-MeS-Ph 3-MeS-Ph HH _CH2-SMe 1-262 3-MeS-Ph 3-MeS-Ph HH-(CH2) rSMe 1-263 3-MeS-Ph 3-MeS-Ph HH -CO-Ph 1-264 3-MeS-Ph 3- MeS-Ph HH-C0- (2-Me0-Ph) 1-265 3-MeS-Ph 3-MeS-Ph HH -CO-Fur (2) 1-266 3-MeS-Ph 3-MeS-Ph HH-CO-Thi (2) 1-267 3-MeS-Ph 3-MeS-Ph Me Me H 1-268 3-MeS-Ph 3-MeS-Ph-(ch2) 2 ~ H 1 -269 4-MeS-Ph 4-MeS-Ph HH -CH2 ~ SM6 1-270 4-MeS-Ph 4-MeS-Ph HH-(CH2) rSMe 1-271 4-MeS-Ph 4-MeS-Ph HH -CO-Ph 1-272 4-MeS-Ph 4-MeS-Ph HH-CO- (2-MeO-Ph) 1-273 4-MeS-Ph 4-MeS-Ph HH -CO-Fur (2) 1 -274 4-MeS-Ph 4-MeS-Ph HH -C (KThi (2) 1-275 4-MeS-Ph 4-MeS-Ph Me Me H 1-276 4-MeS-Ph 4-MeS-Ph- (CH2) 2-H 1-277 3-F-Ph 3-CN-Ph HH ~ CH2 ~ SM6 1-278 3-F-Ph 3-CN-Ph HH-(CH2) rSMe 1-279 '3-F -Ph 3-CN-Ph HH -CO-Ph 1-280 3-F-Ph 3-CN-Ph 1-281 3-F-Ph 3-CN-Ph 1-282 3-F-Ph 3-CN- Ph 1-283 3-F-Ph 3_CN-Ph 1-284 3-F-Ph 3-CN-Ph 1-285 3-F-Ph 3-CN-Ph 1-286 3-F ~~ Ph 3-CN -Ph 1-287 4-F-Ph 4-CN-Ph 1-288 4-F-Ph 4-CN-Ph 1-289 4-F-Ph 4-CN-Ph 1-290 4-F-Ph 4 -CN-Ph 1-291 4-F-Ph 4-CN-Ph 1-292 4-F-Ph 4-CN-Ph 1-293 4-F-Ph 4-CN-Ph 1-294 4-F- Ph 4-CN-Ph 1-295 4-F-Ph 4-CN-Ph 1-296 4-F-Ph 4-CN-Ph 1-297 3-CF3-Ph 3-CN, 1-298 3-CF3 -Ph 3-CN-Ph BU299 3-CF3-Ph 3-CN-Ph 1-300 3-CF3-Ph 3-CN-Ph 1- 301 3-CFs-Ph 3-CN-Ph 1-302 3-CF3-Ph 3-CN-Ph 1-303 3-CF3-Ph 3-CN-Ph 1-304 3-CF 「Ph 3-CN-Ph 1-305 3-CF3-Ph 3-CN-Ph BU306 3-CF3-Ph 3-CN-Ph 1-307 3-CFs-Ph 3-CN-Ph 1-308 3-CF3-Ph 3-CN- Ph HH -C (H2-MeO-Ph) HH -CO-Fur (2) HH -CO-Thi (2) Me Me Η Me Me Η-(ch2) Η-(CH2) 2- Η HH-CH2-SMe HH-(CH2) 2-SMe HH • -CO-Ph HH-CO_ (2-MeO-Ph) HH -CO-Fur (2) HH -CO-Thi (2) Me Me H Me Me H-(ch2) 2 -H-(ch2) 2 -HH Η-CH2-SMe H Η-CH 「SMe H Η-(CH2) rSMe H Η -CO-Ph H Η-CO- (2-MeO-Ph) H Η-CO -(2-Me (HPh) H Η-CO- (4-MeO-Ph) H Η -C0 ~ (4-Me0 ~ Ph) H Η -CO-Fur (2) H Η _C0-Fur (2) H Η -CO-Thi (2) H Η -CO-Thi (2) 200401778 1-309 3-CF3-Ph 3-CN-Ph Η H -CHr〇-CHrPh 1-310 3-CF3_Ph 3-CN-Ph Η H-CH2-〇- CH2-Ph 1-311 3-CF3-Ph 3-CN-Ph Η H-CH2_0- (CH2) 2-OMe 312 3-CF3-Ph 3-CN-Ph Η H-CH2- 〇_ (CH2) 2-OMe 1-313 3-CF3-Ph 3-CN-Ph Me Me H 1-3L4 3-CF3-Ph 3-CN-Ph Me Me H 1-315 3-CF3-Ph 3- CN-Ph-(CH2) 2-H 1-316 3-CF2-Ph 3-CN-Ph-(CH2) 2-H 1-317 4-CF3-Ph 4-CN-Ph Η Η -CH2-SMe 1-318 4-CF3-Ph 4-CN -Ph Η Η-(CH2) factory SMe 1-319 4-CF3-P1i 4-CN-Ph Η Η -CO-Ph 1-320 4-CF3-Ph 4-CN-Ph Η C -C〇- (2 -Me〇-Ph) 1-321 4-CFs-Ph 4-CN-Ph Η Η -CO-Fur (2) 1-322 4-CF3-Ph 4-CN-Ph Η Η-C0-Thi (2) 1-323 4-CF3-Ph 4-CN-Ph < Me Me H 1-324 4-CF3-Ph 4-CN-Ph Me Me H 1-325 4-CF3-Ph 4-CN-Ph-(ch2 ) 2- H 1-326 4-CF3-Ph 4-CN-Ph-(CH2) 2- H 1-327 3-F-Ph 3-N0rPh HH -CH 「SMe 1-328 3-F-Ph 3- N0rPh Η H-(CH2) 2-SMe 1-329 3-F-Ph 3-N0rPh Η H -CO, 1-330 3-F-Ph 3-N0rPh Η H -CO- (2-MeO-Ph) 1 -331 3-F ~ Ph 3-N0rPh Η H -CO-Fur (2) 1-332 3-F-Ph 3-N0rPh Η H -C0-Thi (2) 1-333 3-F-Ph 3-N0rPh Me Me H 1-334 3-F-Ph 3-N0rPh Me Me H 1-335 3-F-Ph 3-N0rPh-(CH2) r H 1-336 3-F-Ph 3-N0rPh-(CH2) 2 -H 1-337 4_F-Ph 4-N0rPh Η H-CH2-SMe 200401778 1-338 4-F-Ph 4-N0rPh Η H-(CH2) rSMe 2 1-339 4 ~ F ~ Ph 4-N0rPh Η H -CO-Ph 2 1-340 4-F-Ph 4-N0rPh Η H -C0- (2-Me0-Ph) 2 1-341 4-F_Ph 4-N0rPh H -CO-Fur (2) 2 1-342 4-F-Ph 4-N0rPh Η H -CO- 丁 hi⑵ 2 1-343 4-F-Ph 4-N0rPh Me Me H 2 1-344 4 ~ F ~ Ph 4-N0rPh Me Me H 3 1-345 4-F-Ph 4-N0rPh-(CH2) 2-H 2 1-346 4-F_Ph 4-N0rPh-(ch2) 2- H 3 1-347 3-CF3 -Ph 3-N0 「Ph HH -CHrSMe 2 1-348 3-CF3-Ph 3-N0rPh Η H-(CH2) 2-SMe 2 1-349 3-CF3-Ph 3-N0rPh Η H -CO-Ph 2 1-350 3-CF3-Ph 3-N0rPh Η H -CO- (2_MeO-Ph) 2 1-351 3-CFfPh 3-N0rPh Η H -CO-Fur (2) 2 1-352 3-CF3-Ph 3 -N02-Ph Η H-CO-Thi (2) 2 1-353 3-CF3-Ph 3-N0rPh Me Me H 2 1-354 3-CF3-Ph 3-N02-Ph Me Me H 3 1-355 3 -CF3-Ph 3-N0rPh-(CH2) 2-H 2 1-356 3-CF3-Ph 3 ~ N0rPh-(CH2) 2-H 3 1-357 4-CF 「Ph 4-N0rPh Η Η -CHrSMe 2 1-358 4-CF3-Ph 4-N0rPh Η Η-(CH2) 2-SMe 2 1-359 4-CF3-Ph 4-N0rPh Η CO -CO-Ph 2 1-360 4-CF3-Ph 4-N0rPh Η Η -C0- (2-Me0-Ph) 2 1-361 4-CF3_Ph 4-N0rPh Η CO -CO-Fur (2) 2 1-362 4_CF3 ~ Ph 4-N0 「Ph Η Η -C0-Thi ( 2) 2 1-363 4-CF3-Ph 4-N0rPh Me Me H 2 1-364 4-CF3_Ph 4-N02-Ph Me Me H 3 1-365 4-CF3-Ph 4-N0rPh-(CH2 ) 2- H 2 1-366 4-CF3-Ph 4-N02-Ph-(CH2) 2- H 3 -4 6- 200401778

1-367 3 ~ CF3〇-Ph 3-CF30-Ph Η Η H [Table 2]

R R2— (CH2) m—〇 R3〉 ~ (CH2) n

(Π)

No. R1 R2 R3 R4 R5 n in

2-1 3-F-Ph 3-F-Ph HHH 2 2-2 3-F-Ph 3-F-Ph HHH 3 2-3 3-F-Ph 3-F-Ph HH-CH ^ SOMe 2 ( 2-4 3-F-Ph 3-F-Ph HH-(CH2) rSOMe 2 0 2-5 3-F-Ph 3-F-Ph HH-CH2-SOMe 3 (2-6 3-F-Ph 3 -F-Ph HH-(CH2) 2-SOMe 3 0 2-7 3-F-Ph 3-F-Ph HH ~ CH2 ~ S02Me 2 0 2-8 3-F-Ph 3-F-Ph HH-( CH2) rS02Me 2 0 2-9 3-F-Ph 3-F-Ph HH-CHrS02Me 3 0 2 -10 3-F-Ph 3_F-Ph HH-(CH2) 「S02Me 3 0 2-11 3-F- Ph 3-F-Ph HH-CHrO- (CH2) 2- -OMe 2 0 2-12 3-F-Ph 3-F-Ph HH -CH2-0_ (CH2) 2_ -OMe 3 0 2-13 3- F-Ph 3-F-Ph HH-CH2-SMe 2 i 2 -14 3-F-Ph 3-F-Ph HH _CH2 ~ SM6 3 i 2-15 3-F-Ph 3-F-Ph HH-( CH2) rSMe 2 C 200401778 2-16 3-F-Ph 3-F-Ph Η H-(CH2) rSMe 2-17 3-F-Ph 3-F-Ph Η H-CH'r_e 2-18 3- F-Ph 3-F-Ph Η H-CO, 2-19 3-F-Ph 3-F-Ph Η H -CO-Ph 2-20 3_F-Ph 3-F-Ph Η H -CO- (2 -MeO-Ph) 2-21 3-F-Ph 3-F-Ph Η H -C〇- (2-Me〇-Ph) 2-22 3-F-Ph 3-F-Ph Η H -CO- (3-MeO-Ph) 2-23 3 + Ph 3-F-Ph Η H -C0- (3-Me0-Ph) 2-24 3-F-Ph 3-F-Ph Η H -CO- (4 -MeO-Ph) 2-25 3-F-Ph 3-F-Ph Η H-C〇- (4-Me〇-Ph) 2-26 3-FP h 3-F-Ph Η H -CO- (2,4-diMeO-Ph) 2-2-7 3-F-Ph 3-F-Ph Η H -CO- (2,4-diMeO-Ph) 2 -28 3-F-Ph 3-F-Ph Η H -CO-Fur (2) 2-29 3-F-Ph 3-F-Ph Η H -CO-Fur (2) 2-30 3-F- Ph 3-F-Ph Η H -CO-Fur (3) 2-31 3-F-Ph 3-F-Ph Η H -CO-Fur (3) 2-32 3-F-Ph 3-F-Ph Η H-CO-Thi (2) 2-33 3-F-Ph 3-F-Ph Η H -CO-Thi (2) 2-34 3-F-Ph 3-F-Ph Η H -CO-Thi (3) 2-35 3-F-Ph 3-F-Ph Η H -CO-Thi (3) 2-36 3-F-Ph 3-F-Ph Me Me H 2-37 3-F-Ph 3 -F-Ph Me Me H 2-38 3-F-Ph 3-F-Ph-(CH2) 2- H 2-39 3-F-Ph 3-F-Ph-(CH2) r H 2-40 3 -F-Ph 3-F-Ph-(CH2) 2 ~ -CE Factory SMe 2-41 3-F-Ph 3-F-Ph-(CH2) 2--(CH2) 2-SMe 2-42 3- F-Ph 3-F-Ph _ (CH2) 2--CO-Ph 2-43 3-F-Ph 3-F-Ph-(CH2) r -CO- (2-MeO_Ph) 2-44 3-F -Ph 3-F-Ph-(CH2) r -CO-Fur (2) 200401778 2-45 3-F-Ph 3-F-Ph-(CH2) 2--CO- 丁 Hi (2) 2 0 2 -46 3-F-Ph 3-F-Ph HHH 2 1 2-47 3-F-Ph 3-F-Ph Me Me H 2 1 2-48 3-F-Ph 3-F-Ph-(CH2) 2-H 2 1 2-49 4-F-Ph 4-F-Ph HHH 2 0 2-50 4-F-Ph 4-F-Ph HHH 3 0 2-51 4-F-Ph 4-F-Ph HH ~ CH2 ~ S0M6 2 0 2-52 4-F-Ph 4-F-Ph HH-(C H2) rS0Me 2 0 2-53 4-F-Ph 4-F-Ph HH-CH2-SOMe 3 0 2-54 4-F-Ph 4-F-Ph HH-(CH2) 2-SOMe 3 0 2- 55 4-F-Ph 4-F-Ph HH-CHrS02Me 2 0 2-56 4-F-Ph 4-F-Ph HH-(CH2) rS02Me 2 0 2-57 4-F-Ph 4-F-Ph HH -CHrS02Me 3 0 2-58 4-F-Ph 4-F-Ph HH-(CH2) 2 ~ so2M6 3 0 2-59 4-F-Ph 4-F-Ph HH -CH2-0-(CH2) 2-OMe 2 0 2-60 4_F-Ph 4-F-Ph HH -CHr0- (CH2) r0Me 3 0 2-61 4-F-Ph 4-F-Ph HH -CHrSMe 2 0 2-62 4-F -Ph 4-F-Ph HH -CHrSMe 3 0 2-63 4-F-Ph 4-F-Ph HH-(CH2) 2-SMe 2 0 2-64 4-F-Ph 4-F ~ Ph HH- (CH2) 2-SMe 3 0 2-65 4-F-Ph 4-F-Ph HH _CHr_e 2 0 2-66 4-F-Ph 4-F-Ph HH -CO-Ph 2 0 2-67 4- F-Ph 4-F-Ph HH -CO-Ph 3 0 2-68 4-F-Ph 4-F-Ph HH -CO- (2-MeO-Ph) 2 0 2-69 4-F-Ph 4 ~ F ~ Ph HH -C0 ~ (2 ~ M6〇 ~ Ph) 3 0 2-70 4-F-Ph 4-F-Ph HH-C0- (3-MeO-Ph) 2 0 2-71 4-F -Ph 4-F-Ph HH -CO- (3-MeO-Ph) 3 0 2-72 4-F-Ph 4-F-Ph HH -C0- (4-Me0-Ph) 2 0 2-73 4 -F-Ph 4-F-Ph HH -C0- (4-Me0-Ph) 3 0

-49- 200401778 2-74 4-F-Ph 4-F-Ph Η H -CO- (2,4-diMeO-Ph) 2 0 2-75 4-F-Ph 4-F-Ph Η H -C (H2,4-diMeO_Ph) 3 0 2-76 4 ~~ F_Ph 4_F-Ph Η H -C0_Fur (2) 2 0 2-77 4-F-Ph 4-F-Ph Η H -CO-Fur (2) 3 0 2-78 4-F-Ph 4_F ~ Ph Η H -CO-Fur (3) 2 0 2-79 4-F-Ph 4-F-Ph Η H -CO-Fur (3) 3 0 2- 80 4-F-Ph 4-F-Ph Η H -C0_Thi (2) 2 0 2-81 4-F ~ Ph 4-F-Ph Η H-CO-Thi (2) 3 0 2-82 4-F -Ph 4-F-Ph Η H -CO-Thi (3) 2 0 2-83 4-F ~ Ph 4_F-Ph Η H-CO-Thi (3) 3 0 2-84 4-F-Ph 4- F-Ph Me Me H 2 0 2-85 4-F-Ph 4-F-Ph Me Me H 3 0 2-86 4-F-Ph 4-F-Ph-(CH2) 2- H 2 0 2- 87 4-F-Ph 4-F-Ph-(CH2) 2-H 3 0 2-88 4-F-Ph 4-F-Ph-(CH2) 2- Me 2 0 2-89 4-F-Ph 4-F-Ph-(CH2) f Me 3 0 2-90 4-F-Ph 4-F-Ph-(CH2) 2- -CH2-SMe 2 0 2-91 4-F-Ph 4-F- Ph-(ch2) 2_-(CH2) rSMe 2 0 2-92 4-F-Ph 4-F-Ph-(CH2) r -CO-Ph 2 0 2-93 4-F-Ph 4-F_Ph-( ch2) 2- -CO- (2-MeO-Ph) 2 0 2-94 4 ~ F-Ph 4-F-Ph-(ch2) 2- -CO-Fur (2) 2 0 2-95 4-F -Ph 4-F-Ph-(CH2) 2--CO-Thi (2) 2 0 2-96 4_F ~ Ph 4-F-Ph Η Η H 2, 1 2-97 4-F-Ph 4-F -Ph Me Me H 2: 1 2-98 4-F-Ph 4_F-Ph-(ch2) Plant H 2 1 2-99 3-C P Ph 3-Cl-Ph Η Η H 2: 0 2-100 3-Cl-Ph 3-Cl-Ph Η CH -CH2-SMe 2 0 2-101 3-Cl-Ph 3-Cl-Ph Η Η-(CH2) rSMe 2 0 2-102 3-Cl-Ph 3-Cl-Ph Η Η -CO-Ph 2: 0

-50 ^ 200401778 2-103 3-Cl-Ph 3-C Bu Ph HH-C0- (2-MeO-Ph) 2 0 2-104 3-Cl-Ph 3-C Bu Ph HH -CO-Fur (2 ) 2 0 2-105 3-Cl-Ph 3-C Pl Ph HH -CO-Thi ⑵ 2 0 2-106 3-C Pl Ph 3-C Pl Me Me H 2 0 2-107 3 ~ C1-Ph 3-Cl-Ph-(CH2) r H 2 0 2-108 3 ~ C1-Ph 3-Cl-Ph HHH 2 1 2-109 3-Cl-Ph 3-Cl-Ph Me Me H 2 1 2-110 3-Cl-Ph 3-Cl-Ph-(CH2) 2-H 2 1 2-111 4-Cl-Ph 4-Cl-Ph HHH 2 0 2-112 4-Cl-Ph 4-Cl-Ph HH- CH2 " SM6 2 0 2-113 4-C Bu Ph 4-Cl-Ph HH-(CH2) 2-SMe 2 0 2-114 4-Cl-Ph 4-CHPh HH -CO ~ Ph 2 0 2-115 4 -Cl-Ph 4-Cl-Ph HH-C0- (2-MeO-Ph) 2 0 2-116 4-Cl-Ph 4-Cl-Ph HH -CO-Fur (2) 2 0 2-117 4- Cl-Ph 4-Cl-Ph HH -CO-Thi (2) 2 0 2-118 4 ~ C1-Ph 4-Cl-Ph Me Me H 2 0 2-119 4-Cl-Ph 4-Cl-Ph- (ch2) 2-H 2 0 2-120 4-C Ph 4-Cl-Ph HHH 2 1 2-121 4-Cl-Ph 4-Cl-Ph Me Me H 2 1 2-122 4-Cl-Ph 4-CHPh-(CH2) 2- H 2 1 2 -123 3-Me-Ph 3-Me-Ph HHH 2 0 2-124 3-Me-Ph 3-Me-Ph HH -CHrSMe 2 0 2-125 3 -Me-Ph 3-Me-Ph HH-(CH2) 2-SMe 2 0 2-126 3-Me-Ph 3-Me-Ph HH -CO-Ph 2 0 2-127 3-Me-Ph 3-M e-Ph HH-C0- (2-MeO-Ph) 2 0 2-128 3-Me-Ph 3-Me-Ph HH -CO-Fur (2) 2 0 2-129 3-Me-Ph 3-Me -Ph HH -CO-Thi (2) 2 C 2-130 3-Me-Ph 3-Me-Ph Me Me H 2 C 2-131 3-Me-Ph 3-Me-Ph-(CH2) 2- H 2 0

200401778 2-132 3-Me-Ph 3-Me-Ph HHH 2 1 2-133 3-Me-Ph 3-Me-Ph Me Me H 2 1 2-134 3-Me-Ph 3-Me-Ph-( CH2) 2-H 2 1 2-135 4-Me-Ph 4-Me-Ph HHH 2 0 2-136 4-Me-Ph 4-Me-Ph HH-CH2-SMe 2 0 2-137 4-Me- Ph 4-Me-Ph HH-(CH2) 2-SMe 2 0 2-138 4-Me-Ph 4-Me-Ph HH -C0-Ph 2 0 2-139 4-Me-Ph 4-Me-Ph HH -CO- (2-Me〇-Ph) 2 0 2-140 4-Me-Ph 4-Me-Ph HH -CO-Fur (2) 2 0 2-141 4-Me-Ph 4-Me-Ph HH -C0-Thi (2) 2 0 2-142 4-Me-Ph 4-Me-Ph Me Me H 2 0 2-143 4-Me-Ph 4-Me-Ph-(CH2) 2- H 2 0 2 -144 4-Me-Ph 4-Me-Ph HHH 2 1 2-145 4-Me-Ph 4-Me-Ph Me Me H 2 1 2-146 4-Me-Ph 4-Me-Ph-(ch2) 2- H 2 1 2-147 3-CF3-Ph 3-CF3-Ph HHH 2 0 2-148 3-CF3-Ph 3-CF3_Ph HHH 3 0 2-149 3-CF3-Ph 3-CF3-Ph HH- CHrSOMe 2 0 2-150 3-CF3_Ph 3-CF3_Ph HH-(CH2) 2-SOMe 2 0 2-151 3-CF3-Ph 3-CF3-Ph HH-CH 「SOMe 3 0 2-152 3-CF2-Ph 3-CF 「Ph HH-(CH2) rSOMe 3 0 2-153 3-CF3-Ph 3-CF3-Ph HH-CH2-S02Me 2 0 2-154 3-CF3-Ph 3-CF3-Ph HH-(CH2 ) 2-S02Me 2 0 2-155 3-CF3-Ph 3-CF3-Ph HH-CH2-S02Me 3 0 2-156 3-CF3-Ph 3-CFs-Ph HH-(CH2) 2-S02Me 3 0 2-157 3-CF3-Ph 3-CF3-Ph HH -CH2-〇- (CH2) 2-OMe 2 0 2-158 3-CF3-Ph 3-CF3-Ph HH -CH2-0- (CH2) 2-OMe 3 0 2-159 3-CF3-Ph 3-CF3-Ph HH -CHrSMe 2 0 2-160 3 -CF3-Ph 3-CFs-Ph HH -CHrSMe 3 0

200401778 2-161 3-CF3-Ph 3-CF3-Ph 2-162 3-CF3-Ph 3-CF3-Ph 2-163 3-CFs-Ph 3-CF3-Ph 2-164 3-CF3_Ph 3-CF3- Ph 2-165 3-CF3-Ph 3-CF3-Ph 2-166 3-CF3-Ph 3-CF3-Ph 2-167 3-CF3-Ph 3-CF3-Ph 2-168 3-CF3_Ph 3-CFs- Ph 2-169 3-CF3-Ph 3-CF3-Ph 2-170 3-CF3-Ph 3-CF3-Ph 2-171 3-CF3-Ph 3-CF3-Ph 2-172 3-CF3_Ph 3-CF3- Ph 2-173 3-CF3-Ph 3-CF3-Ph 2-174 3-CF3-Ph 3-CF3-Ph 2-175 3_CF3_Ph 3-CF3-Ph 2-176 3-CFfPh 3-CF3-Ph 2-177 3-CF3-Ph 3-CF3-Ph 2-178 3-CF3-Ph 3-CF3-Ph 2-179 3-CF3-Ph 3-CF3-Ph 2-180 3-CF3-Ph 3-CF3-Ph 2 -181 3_CF3_Ph 3-CF3-Ph 2-182 3 ~ CF3- ~ Ph 3-CF3-Ph 2-183 3-CF3-Ph 3-CF3-Ph 2-184 3-CF3-Ph 3-CFs-Ph 2- 185 3-CFs-Ph 3-CF2-Ph 2-186 3-CF3-Ph 3-CF3-Ph 2-187 3-CF3-Ph 3-CF3-Ph 2-188 3-CF3-Ph 3-CF2-Ph 2-189 3-CF3-Ph 3-CF2-Ph

HH-(CH2) rSMe HH-(CH2) rSMe HH-CHr_e HH -CO-Ph HH -CO-Ph HH-C0- (2-Me〇-Ph) HH -CO ~ (2-MeO-Ph) HH- CO- (3-Me〇-Ph) HH-CO- (3-MeO-Ph) HH -C0- (4-Me0-Ph) HH -CO- (4-MeO-Ph) HH ~ C0 ~ (2, 4 ~ diM6〇 ~ Ph) HH -CO- (2,4-diMeO-Ph) HH -CO-Fur (2) HH -CO-Fur (2) HH _C0-Fur (3) HH -CO-Fur (3 ) HH -CO-Thi⑵ HH-C0-Thi (2) HH -CO-Thi (3) HH -CO-Thi (3) Me Me H Me Me H-(CH2) r Η-(CH2) 2- Η- (CH2) r -CHrSMe-(CH2) f-(CH2) 2-SMe-(CH2) Factory_C0-Ph-(CH2) r -C0- (2-Me0-Ph) 200401778 2-190 3-CF3- Ph 3-CF3-Ph-(CH2) 2- -CO-Fur (2) 2 0 2-191 3-CF, _Ph ο 3-CF3-Ph-(CH2) 2- -CO-Thi (2) 2 0 2-192 3-CF3-Ph 3-CF3 ~ Ph HHH 2 2-193 3-CFs-Ph 3 ~ CFS-Ph Me Me H 2 2-194 3-CF3-Ph 3-CF3-Ph _ (CH2) 「 H 2 1 2-195 4-CF3_Ph 4-CF3-Ph HHH 2 2-196 4-CF3-Ph 4-CF3-Ph HHH 3 2-197 4-CF3_Ph 4-CF3-Ph HH -CHrS0Me 2 (2-198 4-CF3-Ph 4-CF3-Ph HH ~ (CH2) rS0Me 2 0 2 -199 4-CF3-Ph 4-CF3-Ph HH -CHrS0Me 3 (2-200 4-CFrPh 4-CF3 ~ Ph HH-( CH2) rS0Me 3 0 2- 201 4-CF3-Ph 4-CFrPh HH-CH2-S02Me 2 0 2-202 4-CF3-Ph 4-CFrPh HH ~ (CH2) 2 ~ S02M6 2 0 2-203 4-CF3-Ph 4-CF3-Ph HH -CH2-S02Me 3 0 2-204 4-CFrPh 4-CF3-Ph HH-(CH2) 2 ~ so2M6 3 0 2-205 4-CF3-Ph 4-CF3-Ph HH-CH〗-. -(CH2) 2-OMe 2 0 2-206 4-CF3-Ph 4 ~ CF3 ~~ Ph HH -CHr0- (CH2) rOMe 3 0 2-207 4_CF3 ~ Ph 4-CF3-Ph HH -CH2 ~ SM6 2 (2-208 4-CF3-Ph 4-CF3-Ph HH -CHrSMe 3 (2-209 4-CF3-Ph 4-CFfPh HH-(CH2) 2-SMe 2 0 2-210 4-CF3-Ph 4- CF3-Ph HH-(CH2) 2-SMe 3 0 2-211 4-CF3-Ph 4-CF3-Ph HH -CHrNHMe 2 (2-212 4-CF3-Ph 4-CFs-Ph HH -C0 ~ Ph 2 2-213 4-CF3-Ph 4-CF 「Ph HH -CO-Ph 3 2-214 4-CF3-Ph 4-CF3-Ph HH -CO- (2-MeO-Ph) 2 2-215 4-CF3 -Ph 4-CF3-Ph HH ~ C0- (2-Me0-Ph) 3 2-216 4-CF3-Ph 4-CF3-Ph HH -CO- (3-MeO-Ph) 2 2-217 4-CF3 -Ph 4-CF3-Ph HH -C0- (3-Me0-Ph) 3 2-218 4-CFrPh 4-CF3-Ph HH -CO- (4-Me〇-Ph) 2 54-

2-219 4-CF3-Ph 2-220 4-CFs-Ph 2-221 4-CF3-Ph 2-222 4-CF3-Ph 2-223 4-CF3-Ph 2-224 4-CF3-Ph 2- 225 4-CFrPh 2-226 4-CF3-Ph 2-227 4-CF3-Ph 2-228 4-CF3-Ph 2-229 4-CF3-Ph 2-230 4-CF3-Ph 2-231 4-CF3 -Ph 2-232 4-CF3-Ph 2-233 4-CF3-Ph 2-234 4-CF3_Ph, 2-235 4-CF3-Ph 2-236 4-CF3-Ph 2-237 4-CF3-Ph 2 -238 4-CF3-Ph 2-239 4-CFfPh 2-240 4-CF3-Ph 2-241 4-CF3-Ph 2-242 2-243 3-MeO-Ph 2-244 3-MeO-Ph 2- 245 3-Me〇-Ph 2-246 3-MeO-Ph 2-247 3-MeO-Ph 4-CF3-Ph '4-CF3-Ph

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph. Η H

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph Η H

4-CF3-Ph Η H 4-CF3-Ph Me Me 4-CF3-Ph Me Me 4-CF3-Ph-(CH2) r 4-CF3-Ph-(CH2) r 4-CF3-Ph-(CH2) r 4-CF3-Ph-(CH2) 2-4-CF3-Ph-(CH2) 2- 4-CF3-Ph-(CH2) r 4-CFs-Ph-(CH2) r 4-CF3-Ph-( CH2) 2-

4-CF3-Ph Η H 4-CF3-Ph Me Me-(CH2) 2-

3-MeO-Ph HH 3-MeO-Ph HH 3 ~ M6〇-Ph HH 3-Me〇-Ph HH 3-MeO-Ph HH _C0- (4-MeO-Ph)-C0- (2,4-diMe0 -Ph)-CO-(2,4-diMeO-Ph) -CO-Fur (2) -CO-Fur (2) -CO-Fur (3) -CO-Fur (3) -CO-Thi (2) -CO-Thi (2) -CO-Thi (3) -⑶-Thi (3)

H

H

H

H -CHrSMe-(CH2) rSMe -CO-Ph -C0- (2-Me0-Ph) -CO-Fur ⑵ -CO-Thi (2)

H

H

H

H-CH2-SMe-(CH2) 2-SMe -CO-Ph -CO- (2-MeO-Ph) 200401778

2-248 3-Me〇-Ph 3-MeO-Ph HH -CO-Fur (2) 2 0 2-249 3-Me〇-Ph 3-MeO-Ph HH -CO-Thi (2) 2 0 2- 250 3-MeO-Ph 3-MeO-Ph Me Me H 2 0 2-251 3-Me〇-Ph 3-MeO-Ph-(CH2) 2- H 2 0 2-252 3-MeO-Ph 3-MeO -Ph HHH 2 1 2-253 3-Me〇-Ph 3-MeO-Ph Me Me H 2 1 2-254 3-Me〇-Ph 3-MeO-Ph-(CH2) 2- H 2 1 2-255 4-MeO-Ph 4-MeO-Ph HHH 2 0 2-256 4-MeO-Ph 4-MeO-Ph HH-CHrSMe 2 0 2-257 4-Me〇-Ph 4-MeO-Ph HH-(CH2) rSMe 2 0 2-258 4-MeO-Ph 4-MeO-Ph HH -CO-Ph 2 0 2-259 4-Me〇-Ph 4-MeO-Ph HH, -CO- (2-Me〇-Ph) 2 0 2-260 4-MeO-Ph 4-MeO-Ph HH -CO-Fur (2) 2 0 2-261 4-MeO-Ph 4-MeO-Ph HH -CO-Thi (2) 2 0 2- 262 4-Me〇-Ph 4-MeO-Ph Me Me H 2 0 2-263 4-MeO-Ph 4-MeO-Ph-(ch2) 2-H 2 0 2-264 4-MeO-Ph 4-MeO -Ph HHH 2 1 2-265 4-MeO-Ph 4-Me〇-Ph Me Me H 2 1 2-266 4-MeO-Ph 4-MeO-Ph-(CH2) 2-H 2 1 2-267 3 -MeS-Ph 3-MeS-Ph HHH 2 0 2-268 3-MeS-Ph 3-MeS-Ph HH ~ CHrSMe 2 0 2-269 3-MeS-Ph 3-MeS-Ph HH-(CH2) rSMe 2 0 2-270 3-MeS-Ph 3-MeS-Ph HH -CO-Ph 2 0 2-271 3-MeS-Ph 3-MeS-Ph HH -CO- (2-M eO-Ph) 2 0 2-272 3-MeS-Ph 3-MeS-Ph HH -CO-Fur (2) 2 0 2-273 3-MeS-Ph 3-MeS-Ph HH -CO-Thi (2) 2 0 2-274 3-MeS-Ph 3-MeS-Ph Me Me H 2 0 2-275 3-MeS-Ph 3-MeS-Ph ~ (CH2) r H 2 0 2-276 3-MeS-Ph 3 -MeS-Ph HHH 2 1 o6- 200401778

2-277 3-MeS-Ph 3-MeS-Ph Me Me H 2-278 3-MeS-Ph 3-MeS-Ph-(CH2) 2-H 2-279 4-MeS-Ph 4-MeS-Ph HHH 2-280 4-MeS-Ph 4-MeS-Ph HH -CH2-SMe 2-281 4-MeS-Ph 4-MeS-Ph HH-(CH2) rSMe 2-282 4-MeS-Ph 4-MeS-Ph HH -CO-Ph 2-283 4-MeS-Ph 4-MeS-Ph HH -CO- (2-Me〇-Ph) 2-284 4-MeS-Ph 4-MeS-Ph HH -CO-Fur (2 ) 2-285 4-MeS-Ph 4-MeS-Ph HH -C0-Thi (2) 2-286 4-MeS-Ph 4-MeS-Ph Me Me H 2-287 4-MeS-Ph 4-MeSHPh- (CH2) 2- H 2-288 4-MeS-Ph 4-MeS-Ph HHH 2-289 4-MeS-Ph 4-MeS-Ph Me Me H 2-290 4-MeS-Ph 4-MeS-Ph- (ch2) 2- H 2-291 3-F-Ph 3-CN-Ph HHH 2-292 3-F-Ph 3-CN-Ph HHH 2-293 3_F-Ph 3-CN-Ph HH -CHrSMe 2- 294 3-F ~ Ph 3-CN-Ph HH-(CH2) 2-SMe 2-295 3-F-Ph 3-CN-Ph HH -CO-Ph 2-296 3-F-Ph 3-CN-Ph HH-CO-(2-MeCHPh) 2-297 3-F-Ph 3-CN-Ph HH -CO-Fur (2) 2-298 3-F-Ph 3-CN-Ph HH -C0-Thi (2 ) 2-299 3-F-Ph 3-CN-Ph Me Me H 2-300 3-F-Ph 3-CN-Ph-(ch2) 2- H 2-301 3-F-Ph 3-CN-Ph HHH 2-302 3-F-Ph 3-CN-Ph Me Me H 2-303 3-F_Ph 3-CN-Ph-(ch2) 2- H 2-304 4-F-Ph 4-CN-Ph HHH 2 -305 4 ~ F_ Ph 4-CN-Ph HHH 200401778 2-306 4_F ~ Ph 4-CN-Ph HH _CH2_SM6 2-307 4-F_Ph 4-CN-Ph HH-(CH2) 2-SMe 2-308 4_F-Ph 4-CN- Ph HH -CO, 2-309 4-F-Ph 4-CN-Ph HH -CO-(2--Ph) 2-310 4_F-Ph 4-CN-Ph HH -CO-Fur (2) 2-311 4-F-Ph 4-CN-Ph HH -CCKThi ⑵ 2-312 4-F-Ph 4-CN-Ph Me Me Η 2-313 4-F-Ph 4-CN-Ph-(CH2) r Η 2 -314 4-F-Ph 4-CN-Ph HH Η 2-315 4-F-Ph 4-CN-Ph Me Me Η 2-316 4-F-Ph 4-CN-Ph one (CH2) 2-Η 2-317 3-CF3-Ph 3-CN-Ph HH Η 2-318 3-CFs-Ph 3-CN-Ph HH Η 2-319 3-CFs-Ph 3-CN-Ph HH-CHrSMe 2-320 3 -CF3-Ph 3-CN-Ph HH-(CH2) 2-SMe 2-321 3-CF3-Ph 3-CN-Ph HH -CO-Ph 2-322 3-CF3-Ph 3-CN-Ph HH- CO- (2-MeO-Ph) 2-323 3-CF3-Ph 3-CN-Ph HH -C0_Fur (2) 2-324 3-CF3-Ph 3-CN-Ph HH -CO-Thi (2) 2 -325 3-CF3-Ph 3-CN-Ph HH -CH2-〇- (CH2) 2-〇Me 2-326 3 ~~ CF3-Ph 3-CN-Ph HH -CH · Factory 0- (CH2) 「 OMe 2-327 3-CF3-Ph 3-CN-Ph Me Me H 2-328 3-CF 「Ph 3-CN-Ph-(ch2) 2-H 2-329 3-CF3-Ph 3-CN-Ph -(CH2) r H 2-330 3-CF3-Ph 3-CN-Ph HHH 2-331 3-CF3-Ph 3-CN-Ph Me Me H 2- 332 3-CF3-Ph 3-CN-Ph-(CH2) r H 2-333 4-CF3-Ph 4-CN-Ph HHH 2-334 4-CF ^ Ph 4-CN-Ph HH -CH, -SMe 200401778 2-335 4-CF3 ~ Ph 4-CN-Ph HH-(CH2) factory SMe 2-336 4-CF3-Ph 4-CN-Ph HH -C〇-Ph 2-337 4-CF3-Ph 4- CN-Ph HH -CO-(2-Ph) 2-338 4-CF3-Ph 4-CN-Ph HH -CO-Fur (2) 2-339 4-CFrPh 4-CN-Ph HH -CO-Thi (2) 2-340 4-CF3-Ph 4-CN-Ph Me Me H 2-341 4-CF 「Ph 4-CN-Ph-(ch2) 2- H 2-342 4-CF3-Ph 4-CN -Ph HHH 2-343 4-CF3-Ph 4-CN-Ph Me Me H 2-344 4-CF3-Ph 4-CN-Ph-(CH2) 2- H 2-345 3-F-Ph 3-N0rPh HHH 2-346 3-F-Ph 3-N0rPh HH _CH2-SMe 2-347 3-F-Ph 3-N0rPh HH-(CH2) rSMe 2-348 3-F-Ph 3-N0rPh HH -CO-Ph 2 -349 3-F-Ph 3-N02-Ph HH -CO- (2-MeO-Ph) 2-350 3-F-Ph 3-N0rPh HH -CO-Fur (2) 2-351 3-F-Ph 3-N0rPh HH -C0-Thi (2) 2-352 3-F-Ph 3-N0rPh Me Me H 2-353 3-F-Ph 3_N02_Ph-(CH2) 2- H 2-354 3-F-Ph 3 -N0rPh HHH 2-355 3-F-Ph 3-N0rPh Me Me H 2-356 3-F-Ph 3-N0rPh-(CH2) 2-H 2-357 4-F-Ph 4-N0rPh HHH 2-358 4-F-Ph 4-N0rPh HH-CH2-SMe 2-359 4-F-Ph 4-N02 ~ Ph HH-(CH2) rSMe 2-360 4-F-Ph 1 4-N0rPh HH -CO, 2-361 4-F-Ph 4-N0rPh HH _C0- (2-MeO-Ph) 2-362 4-F-Ph 4-NOrPh HH -CO-Fur (2) 2-363 4-F-Ph 4-N0rPh HH -CO-Thi (2) 200401778

2-364 4-F-Ph 4-N0rPh Me Me H 2-365 4-F-Ph 4-N0rPh-(CH2) 2-H 2-366 4-F-Ph 4-N0 'Factory Ph HHH 2-367 4-F-Ph 4-N0rPh Me Me H 2-368 4 + Ph 4-N0rPh-(CH2) 2-H 2-369 3-CF3-Ph 3-N02-Ph HHH 2-370 3 ~ CF3-Ph 3 -N0rPh HH -CHrSMe 2-371 3-CF3_Ph 3-N0rPh HH-(CH2) rSMe 2-372 3-CF3_Ph 3-N0rPh HH -CO-Ph 2-373 3-CF3-Ph 3-N02-Ph HH-C0 -(2-MeO-Ph) 2-374 3-CFs-Ph 3-N0rPh HH -CO-Fur (2) 2-375 3-CF3-Ph 3-N0rPh HH -CO-Thi (2) 2-376 3 -CFrPh 3 ~ N0rPh Me Me H 2-377 3-CF3-Ph 3-N0rPh-(CH2) 2-H 2-378 3-CF3-Ph 3-N0rPh HHH 2-379 3-CFrPh 3-N0rPh Me Me H 2-380 3-CF3-Ph 3-N0rPh-(CH2) 2- H 2-381 4-CF3-Ph 4-N02-Ph HHH 2-382 4-CF3-Ph 4-N0rPh HH -CHrSMe 2-383 4 -CF3-Ph 4-N0rPh HH-(CH2) rSMe 2-384 4-CFrPh 4-N0rPh HH -CO-Ph 2-385 4-CF3-Ph 4-N0rPh HH-CO-(2 ·,) 2-386 4-CFrPh 4-N02-Ph HH -CO-Fur (2) 2-387 4-CFrPh 4-N02-Ph HH -CO-Thi (2) 2-388 4-CF3-Ph 4-N0rPh Me Me H 2 -389 4-CF3_Ph 4-N0rPh-(CH2) 2-H 2-390 4-CF3-Ph 4-NOrPh HHH 2-39 1 4-CF3-Ph 4-N0rPh Me Me H 2-392 4-CF3-Ph 4-N0rPh-(CH2) r H 200401778 2-393 2-394 2-395 2-396 2-397 2-398 2- 399 2-400 2-401 2-402 2-403 2-404 2-405 2-406 2-407 2-408 2-409 2-410 2-411 2-412 2-413 2-414 2-415 2 -416 2-417 2-418 2-419 2-420

2-421 3-F-Ph 4-F-Ph HHH 3 + Ph 4-F-ph HHH 3-F-Ph 4-F-Ph HHH 3-F-Ph 4-F ~ * Ph HHH 3-F- Ph 4_CF3-Ph HHH 3-F-Ph 4-CF3-Ph HHH 3-F-Ph 4-CF3-Ph HHH 3-F-Ph 4-CF3_Ph HHH 4-F-Ph 2-F-Ph HHH 4-F -Ph 2-F-Ph HHH 4-F-Ph 2-F_Ph HHH 4 ~ F ~ Ph 2-F-Ph HHH 4-F-Ph 3-F-Ph HHH 4-F-Ph 3-F-Ph HHH 4-F_Ph 3-F-Ph HHH 4-F-Ph 3-F-Ph HHH 4-F-Ph 4-Cl-Ph HHH 4-F-Ph 4-Cl-Ph H 'j HH 4-F-Ph 4-C Bu Ph HHH 4-F-Ph 4-C Bu Ph HHH 4-F-Ph 3-CF3-Ph HHH 4-F-Ph 3-CF3-Ph HHH 4-F-Ph 3-CF3-Ph HHH 4-F-Ph 3-CF3-Ph HHH 4 ~ F_Ph 4-CF3-Ph HHH 4 ~ F ~ Ph 4-CFrPh HHH 4-F-Ph 4-CF3-Ph HHH: 4-F-Ph 4-CF3- Ph HHH 4-F-Ph 3-CN-Ph HHH

2 0

-6 1- 200401778

2-422 4-F-Ph 3-CN-Ph HHH 2-423 4-F_Ph 3-CN-Ph HHH 2-424 4-F-Ph 3-CN-Ph HHH 2-425 3-CF3-Ph 2- F-Ph HHH 2-426 3-CF3_Ph 2-F-Ph HHH 2-427 3-CF3-Ph 2-F-Ph HHH 2-428 3-CF3-Ph 2-F-Ph HHH 2-429 3-CF3 -Ph 3-F-Ph HHH 2-430 3-CF3-Ph 3-F-Ph HHH 2-431 3-CFa-Ph 3-F-Ph HHH 2-432 3-CF3-Ph 3-F-Ph HHH 2-433 3-CFs-Ph 4-F-Ph HHH 2 ~ 434 3-CF3-Ph 4-F-Ph HHH 2-435 3-CFrPh 4-F-Ph HHH 2-436 3-CF3-Ph 4- F-Ph HHH 2-437 3-CF3-Ph 4-Cl-Ph HHH 2-438 3-CF3-Ph 4-Cl-Ph HHH 2-439 3-CFs-Ph 4-Cl-Ph HHH 2-440 3 -CF3-Ph 4-Cl-Ph HHH 2-441 3-CF3-Ph 4-CF3-Ph HHH 2-442 3-CF3-Ph 4-CF3-Ph HHH 2-443 3-CF3-Ph 4-CF3- Ph HHH 2-444 3-CF3-Ph 4-CF3_Ph HHH 2-445 3-CF3-Ph 4-CN-Ph HHH 2-446 3-CFfPh 4-CN-Ph HHH 2-447 3-CF3-Ph 4- CN-Ph HHH 2-448 3-CF3-Ph 4-CN-Ph HHH 2-449 3-CF3-Ph 2,3-diF-Ph HHH 2-450 3-CF〇-Ph 2,4-diF-Ph HHH

2 0

-62- 200401778 2-451 3-CF3-Ph 3,5-diF-Ph HHH 2-452 3-CF3-Ph 3,4-diF-Ph HHH 2-453 3-CF 「Ph 2,6-diF- Ph HHH 2-454 3-CF3-Ph Ph HHH 2-455 3-CF3-Ph 3-Cl-Ph HHH 2-456 2 ~ F-Ph 4-CF3-Ph HHH 2-457 4-F-Ph 2- Cl-Ph HHH 2-458 4-F-Ph Ph HHH 2-459 4-CN-Ph 3-CF3-Ph HHH 2-460 4-CN-Ph 4-CF3-Ph HHH 2-461 4-Cl-Ph 3-CF3-Ph HHH 2-462 4-Cl-Ph 4-CN-Ph HHH 2-463 4-Cl-Ph 4-F-Ph HHH 2-464 4-C Ph 3-F-Ph HHH 2- 465 4-MeO ~ Ph 4-CN-Ph HHH 2-466 4-MeO ~ Ph 4-CF3-Ph HHH 2-467 3-CF3-Ph 4-CN-Ph HH Me 2-468 · 3-CF3-Ph 4-CN-Ph HH Et 2-469 3-CF ^ Ph 4-CN-Ph HH-CH? -SMe

【table 3 ]

-63- 200401778 R1 R2 R6 n 3-1 3-F-Ph 3-F-Ph Me 3-2 3-F-Ph 3-F-Ph Me 3-3 3-F-Ph 3-F-Ph Et 3-4 3-F-Ph 3-F-Ph Et 3-5 3-F-Ph 3-F-Ph -CHr0Me 3-6 3-F-Ph 3-F-Ph-CH2-0Me 3-7 3 -F-Ph 3-F-Ph-(CH2) factory OMe 3-8 3-F-Ph 3-F-Ph-(CH2) rOMe 3-9 4-F-Ph 4-F-Ph Me 3-10 4-F-Ph 4-F ~ Ph Me 3-11 4-F-Ph 4-F-Ph Et 3-12 4-F_Ph 4-F-Ph Et 3-13 4-F_Ph 4-F-Ph -CHrOMe 3-14 4-F-Ph 4-F-Ph -CHrOMe 3-15 4-F-Ph 4-F-Ph-(CH2) 2-OMe 3-16 4-F-Ph 4-F-Ph-( CH2) rOMe 3-17 3-CF3-Ph 3-CF3-Ph Me 3-18 3-CF3-Ph 3-CF3_Ph Me 3-19 3-CF3-Ph 3-CF3-Ph Et 3-20 3-CF3- Ph 3-CF3-Ph Et 3-21 3-CF3-Ph 3-CF3-Ph-CH2-OMe 3-22 3_CF3-Ph 3-CF3-Ph -CHrOMe 3-23 3-CF3-Ph 3-CF3-Ph -(CH2) 2-OMe 3-24 3-CF3-Ph 3-CF3-Ph-(CH2) rOMe 3-25 4-CF3-Ph 4-CF3-Ph Me 3-26 4-CF, -Ph 4- CFrPh Me

2 3 -64- 200401778

3-27 4-CF3-Ph 4-CF3-Ph Et 3-28 4-CF3-Ph 4-CF3-Ph Et 3-29 4-CF3-Ph 4-CF3-Ph -CHr0Me 3-30 4-CF3- Ph 4-CF3_Ph-CH2-OMe 3-31 4-CF3-Ph 4-CF3-Ph-(CH2) rOMe 3-32 4-CF3-Ph 4-CF3 ~ Ph-(CH2) 2-OMe 3-33 3 -F-Ph 3-CN-Ph Me 3-34 3-F-Ph 3-CN-Ph Me 3-35 3-F-Ph 3-CN-Ph Et 3-36 3-F-Ph 3-CN- Ph Et 3-37 3-F-Ph 3-CN-Ph -CHrOMe 3-38 3-F-Ph 3-CN-Ph -CHrOMe 3-39 3-F-Ph 3-CN-Ph-(CH2) rOMe 3-40 3-F-Ph 3-CN-Ph-(CH2) rOMe 3-41 4-F-Ph 4-CIHPh Me 3-42 4-F-Ph 4-CN-Ph Me 3-43 4-F -Ph 4-CN-Ph Et 3-44 4-F-Ph 4-ClHPh Et 3-45 4-F-Ph 4-CIHPh -CHrOMe 3-46 4-F-Ph 4-CN-Ph-CH2-OMe 3-47 4-F-Ph 4-CN-Ph-(CH2) rOMe 3-48 4-F-Ph 4-CN-Ph-(CH2) rOMe 3-49 3-CF3-Ph 3-CN-Ph Me 3-50 3-CFs-Ph 3-CN-Ph Me 3-51 3-CF3-Ph 3-CN-Ph Et 3-52 3-CF3-Ph 3-CN-Ph Et 3-53 3-CF3-Ph 3-CN-Ph -CHrOMe 3-54 3-CFs-Ph 3-CN-Ph -CHrOMe 3-55 3-CF3-Ph 3-CN-Ph-(CH2) rOMe -6 5-200401778

3-56 3_CFfPh 3-CN-Ph-(CH.Z) r0Me 3-57 4-CF3-Ph 4-CN-Ph Me 3-58 4-CF3-Ph 4-CN-Ph Me 3-59 4-CF3 -Ph 4-CN-Ph Et 3-60 4-CF3-Ph 4-CN-Ph Et 3-61 4-CF3-Ph 4-CN-Ph -CHr0Me 3-62 4-CF3-Ph 4-CN-Ph -CH2 ~ 0M6 3-63 4-CF3-Ph 4-CN-Ph-(CH2) 2-0Me 3-64 4-CF3_Ph 4-CN-Ph-(CH2) r0Me 3-65 3-F-Ph 3- N02-Ph Me 3-66 3-F-Ph 3-N0 「Ph Me 3-67 3-F-Ph 3-N0rPh Et 3-68 3-F-Ph 3-N0rPh Et 3-69 3-F-Ph 3-N0rPh -CH factory OMe 3-70 3-F-Ph 3-N0rPh-CH factory OMe 3-71 3-F-Ph 3-N0rPh-(CH2) 2-OMe 3-72 3-F-Ph 3- N0rPh-(CH2) 2-OMe 3-73 4-F-Ph 4-N0rPh Me 3-74 4_F_Ph 4-N0rPh Me 3-75 4-F-Ph 4-N0rPh Et 3-76 4-F-Ph 4- N0rPh Et 3-77 4-F-Ph 4-N0rPh -CH2-〇Me 3-78 4-F-Ph 4-N0rPh -CHrOMe 3-79 4-F-Ph 4-N0rPh-(CH2) 2-OMe 3 -80 4-F-Ph 4-NO Factory Ph-(CH2) rOMe 3-81 3-CF3 ~ Ph 3-N0rPh Me 3-82 3-CF3 ~ Ph 3-N0rPh Me 3-83 3-CF3-Ph 3 -N0rPh Et 3-84 3-CF3-Ph 3-N0rPh Et -66- 200401778 3-85 3-CF3-Ph 3 ~ N0rPh -CHr0Me 3-86 3-CF3-Ph 3-N0rPh ~ CH2_0Me 3-87 3- CF3-Ph 3-N0rPh-(CH2) 2-OMe 3-88 3-CF3-Ph 3- N0_Factory Ph-(CH2) r0Me 3-89 4-CF3-Ph 4-N0rPh Me 3-90 4-CF3-Ph 4_N〇2-Ph Me 3-91 4-CF3-Ph 4-N0rPh Et 3-92 4 ~ CF3 ~ Ph 4_N02 ~ Ph Et 3-93 4-CFrPh 4-N0rPh -CH2-OMe 3-94 4-CFrPh 4-N0rPh -CH Factory OMe 3-95 4-CF3-Ph 4-N0rPh-(CH2) 2 ~ 〇Μθ 3-96 4-CF3-Ph 4-N0rPh-(CH2) 2-OMe 3-97 3,4-diF-Ph 3,4-diF-Ph Me 3-98 3,4-diF-Ph 3,4-diF-Ph Me 3-99 3,4-diF-Ph 3,4-diF-Ph Et 3-100 3,4-diF-Ph 3,4-diF-Ph Et 3-101 3,4 -diF-Ph 3,4-diF-Ph -CHrOMe 3-102 3,4-diF-Ph 3,4-diF-Ph-CH2-OMe 3-103 3,4-diF-Ph 3,4-diF- Ph-(CH2) 2-OMe 3-104 3,4-diF-Ph 3,4-diF-Ph-(CH2) 2-〇Me

3 In Tables 1 to 3, the numbers of the exemplified compounds are preferably 1-9 to 12, 12, 19 to 34, 37 to 40, 43 to 50, 59 to 62, 1 to 65, 1 -66, 1 -69 to 1 -88, 1 to 91 to 1 to 94, 1 to 97 to 1 to 105, Bu 107 to 1-110, Bu 112, 1-113, 1-115 to Bu 118, 1- 120 '1 — 137, 1 — 139, 1 — 141, 1 — 143, 1-145 to 1-148, 1-151, 1-152, Bu 155 to 1-176, Bu 179 to M82, Bu 185 to 1 -192, Bu 201 ~ 1-204, 1-207, 1-67-200401778 208, Bu 211 ~ 1-228, Bu 231 ~ 1-234, Bu 237 ~ 1-245, Bu 277, Bu 279 ~ 1 —282, 1—285 to Bu 292, Bu 295 to 1-298, Bu 300 to Bu 312, Bu 315 to Bu 317, Bu 319 to 1 —322, Bu 325 to 1-327, Bu 329 to Bu 332, Bu 335 ~ 1-337, Bu 339 ~ Bu 342, Bu 345 ~ Bu 347, 1-349, 1 -35 1, Bu 352, Bu 355 ~ Bu 357, Bu 359 ~ Bu 362, Bu 365, Bu 366, 2- 1, 2-2, 2-13, 2-14, 2-17 ~ 2-35, 2_38 ~ 2-40, 2_42 ~ 2-45, 2-49, 2-50, 2-59 ~ 2-62, 2-65 ~ 2-83, 2-90, 2-92 ~ 2-95, 2-100, 2-102 ~ 2-105, 2-107, 2-111, 2-112, 2-114 ~ 2- 117, 2-11 9, 2-147, 2-148, 2-159, 2-160, 2-163 to 2-181, 2-184 to 2-186, 2-188 to 2-192, 2-195, 2-196, 2-205, 2-208, 2-211 ~ 2-227, 2-232 ~ 2-234, 2-236 ~ 2-239, 2-291 ~ 2-293, 2-295 ~ 2-300, 2- 304 ~ 2-306, 2-308 ~ 2-311, 2-317 ~ 2-319, 2-321 ~ 2-326, 2-328, 2-329, 2-333, 2-334, 2-336 ~ 2-339, 2-341, 2-345, 2-346, 2-348 ~ 2-351, 2-353, 2-357, 2-358, 2-360 ~ 2-363, 2-365, 2- 369, 2-370, 2- 372 ~ 2-375, 2-377, 2-381, 2-382, 2-384 ~ 2-387, 2-389, 2-393, 2-395, 2-397, 2-399, 2-401, 2-403, 2-405, 2-407, 2-409, 2-411, 2-413, 2-415, 2-417, 2- 419, 2-421, 2- 423, 2-425, 2-427, 2-429, 2-431, 2-433, 2-435, 2-437, 2-439, 2 4 4-1 5 2-4 4 3, 2-445, 2-447, 3-1 to 3-64 and 3-97- 3-104, preferably the exemplified compound number 1-6 1: 8-{2-[bis- (4-fluorophenyl) methoxy] Ethyl} -3 -methylthiomethyl-1-D 萼 -3, 8 -diaciro [4 5 5] dec-2-one, exemplified compound number 1-6 2: 8-{3-[bis- (4-fluorophenyl) methoxy] propyl} -3 -methylsulfide -1-B 萼 -3, 8-bis-diaspiro [4,5] dec-2-one, exemplified compound number 1-9 3: 8-{2-[bis- (4-fluorophenyl) formyl Oxy] ethyl} -spiro [(8-azinebicyclo [3.2.1.octane) -3,5 '-(3-methylthiomethyl) -Doxazolidine] -2 1-one, Exemplified compound number 1-94 · 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -spiro [(8-azinebicyclo [3 2 1] octane) -3,5 Μ 3 -methylthiomethyl) -oxazolidine] -2 '-200401778 Ethyl Plant 3 -methylsulfinylmethyl-1-fluorene-3,8-dimethylacetone [4,5] dec-2- Ketone, exemplified compound number 1-147. 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl}-3 -methylthiomethyl-1 -fluorene-3,8-diazine Spiro [4,5] dec-2-one, exemplified compound No. 1-148: 8-丨 3- [bis- (3-trifluorotolyl) methoxy] propyl 3-methylthiomethyl-1 -Fluorene-3, 8-diacspiro [4,5] dec-2-one, exemplified compound number 1-2 9 8: 8-{3-[(3 -cyanophenyl) (3 '-trifluorotoluene )] Methoxy] propyl} -3 -methylthiomethyl-1 -fluorene-3,8 -diacspiro [4,5] dec-2-one, exemplified compound number 1-3 1 7: 8-丨 2-[(4-Cyanophenyl) (4 | -Trifluorotolyl) methoxy] ethyl 3-methylthiomethyl-1 -fluorene-3,8-diaciro [4 5 5] dec-2-one, exemplified compound numbers 2-4 9: 8-[3-(4 -fluorophenoxy) -3-(4-fluorophenyl) propyl] -b 噚 -3,8-diazepi [4,5] dec-2-one, exemplary compounds Number 2-1 4 7: 8-[3-(3 -trifluorotolyloxy) -3-(3 -trifluorotolyl) propyl 1 -fluorene-3 5 8 -diacridyl [4,5 ] Dec-2-one, exemplified compound number 2-1 5 9: 8-[3-(3 -trifluorotolyloxy) -3-(3 -trifluorotolyl) propyl] -3 -methylthiomethyl -1-P 萼 -3,8-bisacryl [4,5] dec-2-one, exemplified compound number 2-1 8 4 ·· 8-{2-[bis (3 -trifluorotolyl) Methoxy] ethyl} -spiro [([卩 丫 Bicyclo [3.2.1] octane) -3,5 ^ oxazolidine] -2'-one, exemplified compound number 2-2 9 1: 8 -[3-(3 -cyanophenoxy) -3-(3 -fluorophenyl) propyl 1-fluorene-3,8 -diaciro [4,5] dec-2-one, exemplified compound number 2-3 0 4: 8-[3-(4 -cyanophenoxy) ~ 3-(4 -fluorophenyl) propyl] -1 -fluorene-3,8 -diacryl [4,5] dec -2 -ketone, Shows the compound number 2-3 1 7. 8-[3-(3 -cyanophenoxy) -3-(3 -trifluorotolyl) propyl]-]-fluorene-3,8 -diphosphonium spiro [ 4,5] dec-2-one, exemplified compound number 2-333 f [3- (4-cyanophenoxy) -3- (3-trifluorotoluene-6 9- 200401778) propyl; l ·] -Fluorene-3,8-diaciro [4,5] dec-2-one, e.g. compound number 2-4 0 1 8-[3-(2-^ this gas group)-3-(4-this 8- {3-[(3-cyanophenyl) ( 3'-trifluorotolyl) methoxy] propyl} -3 -ethyl-1 -fluorene-3,8-diacryl [4,5] dec-2-one The present general formula (I), The compound of (11) or (ΠI) can be easily prepared by the following method. Method A is a method for preparing compound (I), (11) or (ΠI). Method A

R R 1a 2〉 —〇— (CH2) n (IV)

R1

(VI)

A 2nd Project> —〇 一 (CHyn i—N * X0 Ah. Or% —0— (CH2) n ~ N Vr ° Nine NVa R2 Nine V (Ia) (lb) X ~ R5a (Vila) r2 or X —R5b (Vllb)

(V) R4

〇 〇 Project A4 y 2a-

Or 5c X — R5c (vile) or χ—R5b (vnb)

, 5b 200401778

In the above formula, R1, R2, R3, R4, R5, m and η are as defined above, R1 a and R2a are amine groups other than the substituents in the R1 and R2 groups and / or hydroxyl groups are amine groups that can be protected and / Except for hydroxyl or hydroxyl, as defined for R 1 and R 2, R 5 a is a lower alkyl group, a lower alkylsulfinyl sulfonium lower alkyl group, a lower alkyl sulfonyl fluorene lower alkyl group, and a carbon chain containing 1 to 3 oxygen atoms. Low alkyl, low alkyl with 1 to 3 sulfur atoms in the carbon chain, low alkyl with 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 groups selected from the substituent group b, And a low alkyl group containing 1 to 3 oxygen atoms, sulfur atoms, or nitrogen atoms in the carbon chain [but in compound (la), when R3 and R4 are hydrogen, R5a is a low radical or a carbon bond contains 1 oxygen A base other than the radical of the original t] ^ b is a base of the formula -C0-R 7 (wherein R 7 is as defined above), R 5 e is a low alkyl group, a low alkylsulfinyl fluorene low alkyl group, Low alkanesulfonyl low alkyl, low alkyl with 1 to 3 oxygen atoms in the carbon chain, low alkyl with 1 to 3 sulfur atoms in the carbon chain, and low 1 to 3 nitrogen atoms in the carbon chain Alkyl or substituted with 1 ~ 3 groups selected from the substituent group b, and the carbon chain contains 1 ~ 3 oxygen atoms, sulfur atoms or nitrogen Low alkyl, Q is not specific as long as it is the radical of a conventional nucleophilic residue, and should be C1, 200401778

Halogen atoms such as Br and I; trihalomethoxy groups such as trichloromethoxy; lower alkylsulfonyloxy groups such as methylsulfonyloxy and ethylsulfonyloxy; trifluoromethanesulfonyloxy and pentafluoroethanesulfonyl Haloalkanesulfonyloxy, such as fluorenyloxy; arylsulfonyloxy, such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-toluenesulfonyloxy, etc., most preferably a halogen atom or lowalkanesulfonyl Oxygen; X is a halogen atom. In the above, the "protecting group" in the "protectable amine group" in the definition of Rla & R2a is a conventional amine group protecting group in the field of organic synthetic chemistry, and is not particularly limited. For example, the above-mentioned "general protecting group for hydroxy esters" "Aliphatic fluorenyl"; "aromatic fluorenyl"; "alkoxycarbonyl"; "enoxycarbonyl", "aralkoxycarbonyl"; "silyl"; or "aralkyl" group, or N 5 N-dimethylamine methylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, sulfenyl, 5-chlorosulfenyl, diphenylmethylene, (5-chloro- 2-Methoxyphenyl) benzylidene and other "methylene groups forming Schiff base", preferably aliphatic fluorenyl, alkoxycarbonyl or enoxycarbonyl, more preferably alkoxycarbonyl, most preferably methoxycarbonyl Or ethoxycarbonyl. In the above, the "protecting group" in the "protectable hydroxyl group" in the definition of Rla and R2a is a conventional hydroxyl protecting group in the field of organic synthetic chemistry, and is not particularly limited. For example, the "general protecting group for hydroxyl ester" is exemplified above. , Preferably an aliphatic fluorenyl group, an aromatic fluorenyl group or a silane type, more preferably a silane type, and most preferably a trimethylsilyl group or a triethylsilyl group. Process A 1 is a process for preparing a compound of general formula (VI). In an inert solvent and in the presence of a base, a compound of general formula (IV) and a compound of general formula (V) or an acid addition salt thereof (for example, hydrochloride) , Nitrate, sulfate, etc.). The inert solvent used in the above reaction is not specific as long as it does not affect the reaction and can dissolve the raw materials -72-200401778 and the reagents. It can use aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; benzene, toluene, xylene And other aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane institute, chloroform, carbon tetrachloride, dichloromethane institute, 1,2 dichloroethane institute, and dichlorobenzene; ethyl formate, propyl acetate, and butyl acetate , Diethyl carbonate and other esters; ethers, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; acetone, methyl isopentanone, 4-methyl -2-Ketones such as amyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane and n-benzene; nitriles such as acetonitrile and isobutyronitrile; formamide, N, Amines such as N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidone, hexamethylphosphonium triamine Dimethylphosphine®, cyclobutene®, etc .; preferably ketones, amidines, ethers or nitriles, most preferably ketones or amidines. Examples of the base used in the above reaction include alkali metal iodides such as lithium iodide, sodium iodide, and potassium iodide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; bases such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate Metal bicarbonates; a combination of alkali metal hydrides such as Li Η, Na Η, K Η, or inorganic bases such as lithium fluoride, sodium fluoride, potassium fluoride and other alkali bases, or N- Memorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpyridine, 4-pyrrolidinopyridine, picolin, 4-(Ν, Ν- Dimethylamino) pyridine, 2,6-bis (third butyl) -4-methylpyridine, Ν, Ν-dimethylaniline, N, Ν-diethylaniline, 1,4-diazine bicyclic ring [4 3 · 0] octane (DABC〇), 1, 8-diazine bicyclic [5 4 0]-7-undecene and other organic amines; preferably a combination of metal iodide and alkali metal carbonate. The reaction temperature varies depending on the type of the raw material compound, the inert solvent used, and the base, and is usually 0 ° C: ~ 250 ° C (preferably 70t ~ 170 ° C). The reaction time varies depending on the starting compound, the inert solvent used, the type of base, and the reaction temperature, but it is usually 15 minutes to 48 hours (preferably 2 to 24 hours). After the reaction is completed, the target compound (VI) of the present reaction can be prepared from the reaction mixture by a conventional method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering off, add an unmixed organic solvent such as water and ethyl acetate, and separate the organic layer containing the target compound with anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous carbonic acid. It is obtained by distilling off the solvent after drying sodium hydrogen and the like. The obtained target compound is appropriately combined with a usual method such as recrystallization, reprecipitation, and the usual methods for separating and purifying organic compounds, if necessary, by column chromatography, elution with an appropriate eluent, separation, and purification. Project A 2 is the preparation of compound (I), (i) R 5 is a low compound, a low compound, a low acid compound, a low compound, a low compound, and a low compound. The carbon chain contains 1 to 3 oxygen atoms. Low alkyl, low alkyl with 1 to 3 sulfur atoms in the carbon chain, low alkyl with 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 groups selected from the substituent group b, And a low alkyl group containing 1 to 3 oxygen, sulfur or nitrogen atoms in the carbon chain [but when R3 and R4 are hydrogen, R5 is other than a low alkyl group or an alkyl group containing 1 oxygen atom in the carbon chain []] Compound (I a) or (ii) R 5 is a compound of formula -C0-R 7 (wherein R 7 is as defined above) compound (I b). The compound (I a) can be prepared in the presence or absence of an inert solvent (preferably in the presence), and the compound (VI) is reacted with a compound of general formula (Vila) by using a base, metal or organometallic reagent, and if necessary Rla and R2a can be removed by removing the amine group and / or hydroxyl protecting group. 200301778 The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene can be used. ; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloromethane,], 2-dichloroethane, dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; Ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; bases such as pyridine and triethylamine; formamidine, N, N-dimethylformamide Amidines, such as amidine, N, N-dimethylacetamide, etc .; preferably amidines or ethers. The bases used in the above reactions are alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate and potassium carbonate; sodium bicarbonate and carbonate Alkali metal bicarbonates such as potassium hydrogen; pyridine, triethylamine, triisopropylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, picolin, 4-dimethylamine pyridine, 1 Organic amines such as 4,4-diazine bicyclo [2.2 2] octane, 1,8-diazine bicyclo [5.4 40b 7-undecene; etc .; preferably an alkali metal hydride. The metal used in the above reaction is preferably lithium, potassium or sodium. The organometallic reagents used in the above reactions are, for example, butyllithium, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, lithium diisopropylamide, ethyl bromide Magnesium or isopropyl magnesium bromide. In this project, catalysts such as tetrabutylammonium iodide, potassium iodide or sodium iodide can be used to promote the reaction. The reaction temperature varies depending on the types of raw material compounds, inert solvents used, alkalis, metals, and organometallic reagents, and is usually-~] OOt: (preferably 0 ~ room temperature). -75- 200401778 The reaction time varies depending on the type of raw material compound, the inert solvent used, the base, the metal, the organometallic reagent, and the reaction temperature. It is usually 5 minutes to 48 hours (preferably 15 minutes to 24 hours). The deprotection of the amine and / or hydroxyl protecting group may depend on the type, and may be based on the deprotection reaction commonly used in organic synthetic chemistry, for example, TW Green (Protective Groups in Organic Synthesis), John Wiley & Sons: JFW Me 〇mis, (Protective Groups in Organic Chemistry), Plenum Press said that the method has been carried out. When the amine-protecting group is a silane group, it can generally be removed by treating tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid ·· pyridine, potassium fluoride and other compounds that generate fluoride ions. The inert solvent used in the above reaction is not specific as long as it does not affect the reaction, and ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether can be used. The reaction temperature and reaction time are not particularly limited, and the reaction temperature is generally 0 t to 50 ° C, and the reaction time is 10 hours to 18 hours. When the amine protecting group is an aliphatic fluorenyl group, an aromatic fluorenyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, it can be removed by treatment with an acid or a base in an aqueous solvent. The acid used in the above reaction is not particularly limited to the acid conventionally used for removing the above-mentioned amine-protecting group. For example, an inorganic acid such as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, or nitric acid is preferably hydrochloric acid. The base used in the above reaction is a base conventionally used for removing the above-mentioned amine protecting group, and is not particularly limited. It is preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, and hydroxide. ib Potassium and other alkali metal hydroxides 7 6- 200401778; alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, and potassium third butoxide; or ammonia such as ammonia, concentrated ammonia-methanol. The non-inert solvents used in the above reaction are, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclic Alcohols such as hexanol, 2-methoxyethanol; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; water; or water and the above organic solvents Mixed solvents; alcohols (most preferably ether). The reaction temperature and reaction time may vary depending on the raw material compounds, solvents, and acids or bases used. There is no particular limitation. In order to suppress side reactions, the reaction temperature is usually 0 ° C ~ 150 ° C, and the reaction time is 1 hour ~ 1. 〇Hour. When the amine-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is generally in an inert solvent, and can be contacted with a reducing agent (suitable for catalytic reduction at room temperature) for removal or removal with an oxidizing agent. The solvent used to remove by contact reduction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. Aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether, etc. can be used; benzene, toluene, xylene, etc. Aromatic hydrocarbons; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate and other esters; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol Alcohols such as 2-methoxyethanol; organic acids such as acetic acid; water; or mixed solvents of the above solvents; preferably alcohols, ethers, organic acids or water (most preferably alcohols or organic acids). -77- 200401778 The catalyst used for the contact reduction is preferably Pcl / c, Ruanlai nickel, uranium oxide, platinum black, rhodium-alumina, triphenylphosphine-rhodium oxide, palladium-barium sulfate. The reaction pressure is not specific, but is usually 1 to 10 atmospheres. The reaction temperature and reaction time vary depending on the starting compounds, catalysts, inert solvents, etc. Generally, the reaction temperature is ot ~ loot, and the reaction time is 5 minutes to 24 hours. The inert solvent used for removal by oxidation is not specific as long as it does not affect the reaction, and it is preferably an aqueous organic solvent. These organic solvents are, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dioxane Ethers such as ethylene glycol dimethyl ether; Ketones such as acetone; Methylamines such as formamidine, dimethylformamide, dimethylacetamide, and hexamethylphosphonium triamine; or dimethylformene , Cyclobutane and other sub-maples; preferably halogenated hydrocarbons, ethers or sub-mills (most preferably halogenated hydrocarbons or sub-maples). The oxidant used in the above reaction is oxidant capable of removing the above-mentioned amine-protecting group, but it is not particularly limited. It is preferably potassium persulfate, sodium persulfate, ammonium nitride (CAN) or 2,3-dichloro-5,6-dicyano- Paraquinone (DDQ). The reaction temperature and reaction time vary depending on the raw material compound, oxidant, inert solvent, etc. Generally, the reaction temperature is 0T: ~ 150t, and the reaction time is 10 minutes to 24 hours. When the protecting group of the amine group is an aralkyl group, the protecting group can be removed by an acid. The acid used in the above reaction is not specific as long as it is a conventional acid for removing the above-mentioned amine protecting group such as aralkyl. For example, HC1, hydrochloric acid, sulfuric acid, phosphoric acid and other inorganic acids; acetic acid, formic acid, oxalic acid, methanesulfonic acid, and p-toluenesulfonic acid. Acid, sulfonic acid, -78- 200401778 Trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids such as Bronsted acid; zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, tribromo Lewis acids such as boron chloride; or acidic ion exchange resins; preferably inorganic or organic acids (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid). The inert solvents used in the foregoing first-stage reaction are not specific as long as they do not affect the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; chloroform and dichloride Methane, 1,2-dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate and other esters; ether, isopropyl ether, * Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, third butanol, isopropyl alcohol Alcohols such as pentanol, diethylene glycol, glycerol, octanol, cyclohexanol, 2-methoxyethanol; formamidine, dimethylformamide, dimethylacetamide, hexamethylphosphonium Amines such as amines; water; or a mixed solvent of the above solvents; preferably ethers, alcohols, or water (most preferably dioxane, tetrahydrofuran, ethanol, or water). The reaction temperature varies depending on the raw material compound, the acid used, and the solvent, and is usually φ -2 0 ° C to the boiling point (preferably 0 ° C to 100 ° C). The reaction time varies depending on the raw material compound, the acid used, the inert solvent, and the reaction temperature, and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours). When the protective group of an amine group is an alkenyloxycarbonyl group, generally, the removal conditions when the protective group of the aforementioned amine group is an aliphatic fluorenyl group, an aromatic fluorenyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, Remove with alkali treatment. In addition, in the case of an aryloxycarbonyl group, it is preferable to use palladium and triphenylphosphine or nickel tetracarbonyl nickel to remove it. The method is simple and has few side reactions. -79- 200401778 When the hydroxy-protecting group is a fluorenyl group, it is generally treated with tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride to generate a fluoride anion, or with hydrochloric acid, hydrobromic acid, Inorganic acids such as sulfuric acid or perchloric acid and phosphoric acid or organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid are removed by treatment. When treated with a fluoride anion, the reaction can be promoted by adding organic acids such as acetic acid, formic acid, and propionic acid. The inert solvent used in the above reaction is not specific as long as it does not affect the reaction, and is preferably ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, isobutyronitrile Other nitriles; organic acids such as acetic acid; water; or mixed solvents of the above solvents. The reaction temperature and reaction time vary depending on the raw material compounds, catalysts, inert solvents, etc., usually the reaction temperature is 0 ° C ~ 100 ° C (preferably 10 ° C ~ 50 ° C), and the reaction time is 1 hour ~24 hours. When the hydroxy-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is generally removed by contacting with a reducing agent in an inert solvent (preferably under a catalyst and at room temperature by contact reduction) to remove it or using an oxidizing agent. The inert solvent used in the contact reduction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. Aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether can be used; aromatic hydrocarbons such as benzene, toluene, and xylene Types; esters such as ethyl acetate, propyl acetate; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, Alcohols such as isopropanol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, 2-methoxyethanol, and methane-8 0- 200401778 Amines such as amines, dimethylformamide, dimethylacetamide, N-methyl-2-pyridine, hexamethylphosphonium triamine; fatty acids such as formic acid and acetic acid; water; or the above solvents Mixed solvents; alcohols (most preferably methanol or ethanol). The catalyst used in the contact reduction is preferably not specific to those who are used to remove the hydroxy protecting group by the contact reduction, for example, P d / C, Raney nickel, platinum oxide, uranium black, rhodium-alumina, triphenylphosphine-rhodium oxide, Palladium-barium sulfate, preferably P d / C. The reaction pressure is not specific, but is usually 1 to 0 atmosphere. The reaction temperature and reaction time vary depending on the raw material compounds, catalysts, inert solvents, etc. Generally, the reaction temperature is 0 ° C ~ 100 ° C (preferably 20 ° C ~ 7 ot:) ®, and the reaction time is 5 Minutes to 48 hours (preferably 1 to 24 hours). The inert solvent used for removal by oxidation is not specific as long as it does not affect the reaction. It is preferably an aqueous organic solvent, such as ketones such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; nitriles such as acetonitrile; ether, Ethers such as tetrahydrofuran and dioxane; sulfonamides such as dimethylformamide, dimethylacetamide, and hexamethylphosphonium triamine; or acylamines such as dimethylarsine. The oxidant used in the above reaction is an oxidant capable of removing the above-mentioned hydroxyl protecting group. It is not specific, and is preferably potassium persulfate, sodium persulfate, ammonium nitride (CAN) or 2 5 3 -dichloro-5,6 -dicyanide- Paraquinone (DDQ). The reaction temperature and reaction time vary depending on the starting materials, oxidant, inert solvent, etc. Generally, the reaction temperature is 0 ° C to 150 ° C, and the reaction time is 10 minutes to 24 hours. Can also be used in liquid ammonia or methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol 'cyclohexanol, Alcohols such as 2-methoxyethanol are removed at -7 8 t to 0 t: alkali metals such as metal 200401778 lithium and sodium metal are removed. It can also be removed in a solvent with a halogenated alkylsilyl group such as aluminum chloride-sodium iodide or trimethylsilyl iodide. The solvent used in the above reaction is not specific as long as it does not participate in the reaction, and halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; nitriles such as acetonitrile; or a mixed solution of the above solvents. The reaction temperature and reaction time vary depending on the starting compound, inert solvent, etc. Generally, the reaction temperature is 0 ° C ~ 5 (TC, the reaction time is 5 minutes to 7 2 hours. When the reaction substrate has s atoms, aluminum chloride- Sodium iodide. _ When the hydroxy-protecting group is an aliphatic fluorenyl group, an aromatic fluorenyl group, or an aralkyloxycarbonyl group, it is removed by treatment with a base in an inert solvent. The base used in the above reaction is a base that can remove the hydroxy-protecting group. Not specific, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; alkali metal carbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; lithium hydroxide, sodium hydroxide, and potassium hydroxide, etc. Alkali metal hydroxides; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, and potassium third butoxide; or ammonia such as ammonia φ water, concentrated ammonia-methanol; preferably alkali metal hydroxides Type, metal alkoxy type or ammonia type (most preferably alkali metal hydroxide type or metal alkoxy type). The non-inert solvent used in the above reaction is used by hydrolysis reactions and is not particularly limited. For example, ether, isopropyl Propyl ether, tetrahydrofuran, dioxane, dimethyl Ethers such as ethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol, diethylene glycol, glycerin, Alcohols such as octanol, cyclohexanol, 2-methoxyethanol; water; or a mixed solvent of water and the above organic solvents. -82- 200401778 The reaction temperature and reaction time vary depending on the raw material compound, the base used, and the inert solvent. It can inhibit side effects, usually, the reaction temperature is -20t: ~ 150 ° C, the reaction time is 1 hour ~ 10 hours. The hydroxy protecting group is alkoxymethyl, tetrahydropyranyl, tetrahydrosulfide In the case of pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or substituted ethyl, it is usually removed by treatment with an acid in an inert solvent. The acid used in the above reaction is not specific as long as it is a conventional acid for removing the above-mentioned hydroxy-protecting group, and it can be generally used. Bronsted acid or Lewis acid, preferably HC 1, hydrochloric acid, sulfuric acid, nitric acid and other inorganic acids; or acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and other organic acids such as Bronsted acid; Luisic acid such as boron trichloride, etc. Doowe X 50W Acidic cation exchange resin. The inert solvent used in the above reaction is not specific as long as it does not affect the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methyl chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; Ethers such as diethyl ether, isopropyl φ ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, Tertiary butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, 2-methoxyethanol and other alcohols; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone Ketones, such as cyclohexanone; water; or a mixed solvent of the above solvents; preferably ethers or alcohols (most preferably tetrahydrofuran or methanol). The reaction temperature and reaction time vary depending on the starting compound, the acid used, and the inert solvent. Generally, the reaction temperature is -10t: ~ 200T: (preferably Ot: ~ 150t) -83- 200401778, and the reaction time is 5 minutes ~ 48 hours (preferably 30 minutes to 0 hours). When the protecting group for an alkoxy group is an alkenoxycarbonyl group, the removal conditions for the same protective group as the above-mentioned hydroxyl group are usually an aliphatic fluorenyl group, an aromatic fluorenyl group, and an alkoxycarbonyl group, and they are removed by alkali treatment. When the protecting group is an aryloxycarbonyl group, it is more convenient to remove it by using Pd and triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphoric acid. And fewer side reactions. R 5 in compound (I a) is a low alkyl compound containing 1 sulfur atom in the carbon chain, in an inert solvent (preferably water or ketone), and using an oxidizing agent (for example, * potassium permanganate, two Manganese compounds such as manganese oxide; chromic acids such as chromium oxide, dichromic acid, pyridinium chlorochromate, and pyridinium dichromate; hungry oxidants such as starium tetraoxide; oxidants such as ruthenium tetraoxide; hydrogen peroxide, third butyl Peroxyacids and peroxides such as hydrogen peroxide, cumene hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and dimethyldioxocene; organic compounds such as dimethylimide and benzoquinone for oxidation; use of oxygen And ozone to oxidize; Selenium dioxide, sodium hypochlorite, bromine, chlorine and other selenium, halogen-based oxidants; use microorganisms as oxidants, preferably peracid or peroxidation), at -78 ° C ~ 1000 ° C (Preferably -20 t: ~ room temperature), the reaction is performed for 5 minutes to 48 hours (preferably 15 minutes to 24 hours), and the compound in which R5 is a low alkanesulfonyl low alkyl group can be prepared by other methods. In this reaction, the removal reaction of the above-mentioned amine group and / or hydroxyl protecting group can be performed sequentially in different orders. (ii) Preparation method of compound (lb) Compound (I b) can be used in the presence or absence (preferably) of an inert solvent to make compound (VI) and general formula (Vllb) by using a base, an organometallic reagent or a metal. After the compound is reacted, the Rla and R2a amine groups and / or the hydroxyl-84-200401778 protecting group are removed as necessary to prepare the compound. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials without affecting the reaction. For example, the users of the compound (VI) and the compound (Vila) reaction in the A2 process of the above method A are preferably ethers, hydrocarbons or tritium. Amines are most preferably ethers. The organometallic reagent and metal used in the above reaction can be, for example, users of the reaction of the compound (V I) and the compound (V I I a) in the above-mentioned A, A 2 process of the method, and are preferably butyllithium. The reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of reagent, and is usually -7 8 ° C ~ close to room temperature (preferably -20 ° C ~). The reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, and it is usually 5 minutes to 98 hours (preferably 5 minutes to 24 hours). The method for removing R 1 a and R 2 a amine groups and / or hydroxyl protecting groups may be carried out as described above for the method for removing amine groups and / or hydroxyl protecting groups, if necessary. After the reaction is completed, the target compound (I a) or (I b) of the present reaction can be prepared from the reaction mixture by a conventional method. For example, neutralize the reaction mixture appropriately. If there are insoluble substances, add immiscible organic solvents such as water and ethyl acetate after filtering off, and separate the organic layer containing the target compound with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous After the sodium bisulfate is dried, the solvent is distilled off. If necessary, the obtained target compound is appropriately combined according to a conventional method, for example, recrystallization, reprecipitation, and other conventional methods for separating and purifying organic compounds, and is usually combined with column chromatography and eluted with an appropriate eluent for separation and purification. Process A 3 is a process for preparing a compound of the general formula (IX). The compound of the general formula (VII), the compound (V) or its -85- 200401778 acid addition salt is reacted in an inert solvent and in the presence of a base. For implementation, this project can be carried out in the same way as the A1 project in Method A above. The A4 project is to prepare compound (II), in which (i) R5 is a low alkyl group, a low alkylsulfinyl fluorene low alkyl group, a low alkyl sulfonyl fluorene low alkyl group, and a low alkyl group having 1 to 3 oxygen atoms in the carbon chain. Group, a low alkyl group containing 1 to 3 sulfur atoms in the carbon chain, a low alkyl group containing 1 to 3 nitrogen atoms in the carbon chain, or 1 to 3 groups selected from the substituent group b, and the carbon A low alkyl compound (Π a) containing 1 to 3 oxygen, sulfur or nitrogen atoms in the chain, or (ii) a compound (11 b) in which R 5 is a group of the formula -C 0-R 7.法 Method for preparing compound (Π a) Compound (Π a) can be used in the presence or absence of an inert solvent (preferably in the presence) to make compound (IX) and general formula (Vile) using an alkali, metal or organometallic reagent. After the compound is reacted, if necessary, the amine and / or hydroxyl protecting groups of Rla and R2a are removed to prepare. This process can be performed in a manner similar to the method for preparing compound (I a) in the above process A 2 of process A. (ii) Preparation method of compound (Π b) Compound (11 b) can be used in the presence or absence (preferably) of an inert solvent to make compound (IX) and general formula ( Vllb) After the compound is reacted, if necessary, the amine and / or hydroxyl protecting groups of Rla and R2a are removed and prepared. This process can be performed in a manner analogous to the method for preparing compound (I b) in the above process A2, process A2. The A5th process is a process for preparing a compound (11c) in which R < is hydrogen, and the amine group and / or the hydroxyl protecting group of Rla and R2a in the compound (IX) are removed, and this project N The method is similar to the method of removing the amine-8-6-200401778 and / or the hydroxyl protecting group in the A2 process of the above-mentioned A method. Π) Process A6 of the preparation method of compound (Ila) is a process for preparing compound (III). In the presence or absence of an inert solvent (preferably the presence), the compound (VI) is made by using an alkali, metal or organometallic reagent. The compound (VI a) in which R 1 a and R 2 a are hydrogen is reacted with a compound of general formula (X), and the amine and / or hydroxyl protecting groups of Rla and R2a are removed as needed to prepare. The method for preparing compound (I b) in the above-mentioned process A2 of method A is performed. Method B is a method for preparing the raw material compound (IV) of the method A described above. Method B R1a—X (XI) R2a—CHO (XII) Project B 1

Section B 2 (XIII)

Process B 3 (XIV) HO— (CH2) n —Q (XV) R1 R2a > —〇— (CH2) n— 〇 (IV)

〇 一 (CH2) n 一 〇 (IV)

R1a \ B4 project > --OH-^ 2a /

R H〇 一 (CH2) n-Q (XIII) (XV)

R 2a " Project B 5 -OH-^ A 32a / (XIII)

Q (XVI) (XVII) Process B 6 R1i R2a (XVIII) R :: V〇-o-s.彳 x—so2r r (XIX) (IVa) In the above formula, R 1 a, R 2 a, n, Q and X are as defined above, and R 8 is lower alkyl, halo lower alkyl or phenyl, p-tolyl P-nitrophenyl, etc. may be a low alkyl-87-200401778 group or a nitro group of 1 to 3 substituted Z aryl groups. Process B1 is a process for preparing the general formula (XIII). In the presence or absence of an inert solvent (preferably the presence), a metal or organometallic reagent is used to react the compound of the general formula (XI) with the compound of the general formula (XII). Come on. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reactants without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether. Ethers; ethers, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like; preferably ethers. The metal or organometallic reagent used in the above reaction may be the same as that used in the above-mentioned A, A2 project of the method. The reaction temperature varies depending on the starting compound, the inert solvent used, and the type of reagent, but it is usually -100 ° C to room temperature (preferably -90 ° to 0 ° C). The reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, and it is usually 5 minutes to 98 hours (preferably 15 minutes to 1 hour). Process B 2 is a process for preparing a compound of general formula (X I V), and the hydroxyl group of the compound (X Π I) is converted into a functional group with a nucleophilic residue detached for execution. The conversion method of the hydroxy functional group may vary depending on the intended functional group, and can be carried out according to a method generally known in organic synthetic chemistry. When the target functional group is a halogen atom, it can be carried out by reacting the compound (XII) with a halogenating agent in the presence or absence (preferably) of an inert solvent. The inert solvent used in the above reaction is not specific as long as it can dissolve raw materials and reagents without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, methylene chloride, 1,2-Dichloroethyl-8 8- 200401778 Halogenated hydrocarbons such as alkane, dichlorobenzene; organic acids such as acetic acid, formic acid, propionic acid; formamide, N, N -dimethylformamide, N, N -Amines such as dimethylacetamide; water; preferably aromatic hydrocarbons, halogenated hydrocarbons or water. Examples of the halogenating agent used in the above reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, and hydroiodic acid; halogens such as bromine and chlorine; phosphorus trichloride, phosphorus tribromide, phosphorus pentabromide, phosphorus pentachloride, and oxygen chloride Phosphorous reagents such as phosphorus; sulfinic acid such as sulfenyl chloride, sulfenyl bromide, tosylsulfonium chloride; or sulfonic acid reagents, preferably phosphorus reagents. The reaction temperature varies depending on the raw material compound, the inert solvent used, and the type of halogenating agent, and is usually -78 ° C ~ 200 ° C (preferably -78 ° C ~ 100 ° C). The reaction time varies depending on the raw material compound, the inert solvent used, the halogenating agent, and the reaction temperature, and is usually 5 minutes to 48 hours (preferably 15 minutes to 10 hours). When the target functional group is a alkanesulfonyloxy group, a haloalkanesulfonyloxy group or an arylenesulfonyloxy group, the compound (X Π I) can be used in the presence or absence (preferably) of an inert solvent. The corresponding base is reacted with the relative halogen or anhydride to perform this reaction. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reactants without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, etc .; methylene chloride, chloroform, carbon tetrachloride, methylene chloride, Halogenated hydrocarbons such as 1,2-dichloroethane and dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; ether, isopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethyl Ethers such as alkane, diethylene glycol dimethyl ether; organic bases such as pyridine, triethylamine; formamidine, N, N-dimethylformamide, N, N-dimethylacetamide, etc. Amines are preferably halogenated hydrocarbons or organic bases. The base used in the above reaction is the same as that used in the A2 project of the above-mentioned A method, and is preferably an organic amine. The halogen halides or anhydrides used in the above reaction may be aliphatic halides such as acetyl chloride, acetam bromide, and propyl chloride, fatty anhydrides such as acetic anhydride, propionic anhydride, and sulfonium halides such as methanesulfonyl chloride and toluenesulfonyl chloride. Sulfuric anhydride, such as methanesulfonic anhydride and trifluoromethanesulfonic anhydride, is preferably chloro. The reaction temperature varies depending on the raw material compound, the inert solvent used, the halogen, and the type of anhydride, and is usually -80T: ~ loot: (preferably -80t ~ room temperature). The reaction time varies depending on the raw material compound, the inert solvent used, halogen halide, anhydride, and reaction temperature, and is usually 5 minutes to 98 hours (preferably 15 minutes to 3 hours). Process B 3 is a process for preparing a compound (I V), which is carried out by reacting a compound (X I V) with a compound of general formula (X V) using an acid and a catalyst in the presence or absence of an inert solvent (preferably the presence). The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reactants without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether. Ethers; ethers, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and the like; preferably ethers. 0 The acid used in the above reaction is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid and other inorganic acids; acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoroacetic acid, and three Bronsted acids such as organic acids such as fluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins; preferably organic acid. The reaction temperature varies depending on the starting compound, the inert solvent used, and the type of acid, and is usually 0 ° C to 200 ° C (preferably 20 ° C to 150 ° C). The reaction time varies depending on the starting compound, the type of inert solvent used, the type of acid, and the reaction temperature of -9 0-200401778, and it is usually 5 minutes to 48 hours (preferably 30 minutes to 12 hours). And when using a Dean-Stark type dehydration device, the reaction can also be accelerated. Project B 4 is another way to prepare compounds of general formula (IV). In the presence or absence of an inert solvent (preferably the presence), an acid and a catalyst are used to react the compound (X 111) with the compound (XV). Come on. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reactants without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether can be used. Ethers; ethers, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; preferably aromatic hydrocarbons. The acid used in the above reaction is the same as that used in the B3 project of Method B above, and is preferably an organic acid. The reaction temperature varies depending on the starting compound, the inert solvent used, and the type of acid, and is usually 0 ° C to 200 ° C (preferably 20 ° C to 150 ° C). The reaction time varies depending on the starting compound, the type of inert solvent used, the type of acid, and the reaction temperature, and is usually 15 minutes to 48 hours (preferably 30 minutes to 15 hours). And when Dea η-S t a r k type dehydration device is used, the reaction can also be accelerated. Project B 5 is a process for preparing a compound of general formula (XVII). In the presence or absence of an inert solvent (preferably the presence), the compound (X 111) is reacted with a compound of general formula (XVI) in the presence of a base. Come on. The inert solvent used in the above reaction is not specific as long as it can dissolve raw materials and reagents without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, methylene chloride, 1,2 dichloroethyl 200401778 Halogenated hydrocarbons such as alkane, dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Ethers such as alkane, diethylene glycol dimethyl ether; organic bases such as pyridine, triethylamine; formamidine, N 5 N -dimethylformamide, N, N -dimethylacetamide, etc. Amines; preferably amines or ethers. The base used in the above reaction may be the same as that used in the A2 project of the above method A, and is preferably an organic amine or an alkali metal hydride. The reaction temperature varies depending on the starting compound, the type of inert solvent and base used, and it is usually 7 8 ° C to 100 ° C (preferably -50 ° C to room temperature). ® The reaction time varies depending on the starting compound, the type of inert solvent used, the type of base, and the reaction temperature. It is usually 5 minutes to 48 hours (preferably 15 minutes to 1 hour). Project B 6 is a process for preparing a compound of general formula (XV 111). In the presence or absence of an inert solvent (preferably, it is present), the compound (XV 11) is boronized with a boronizing agent and sequentially oxidized. . The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, etc .; methylene chloride, chloroform, carbon tetrachloride, methylene chloride. , Dichloroethane, dichlorobenzene and other halogenated hydrocarbons; hexane, heptane, petroleum spirit, petroleum ether and other aliphatic hydrocarbons; diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, two Ethers such as ethylene glycol dimethyl ether; preferably ethers. The boronating reagent used in the above reaction is a boronizing reagent such as borane-dimethylsulfide complex, borane-tetrahydrofuran complex, 9-borane bicyclo [3. 3 1] nonane (9-BBN), 9-Rane bicyclo [3 3 1] nonane (9-BBN) is preferred. The oxidation treatment of the above reaction can be performed by hydrogen peroxide-sodium hydroxide according to the method commonly used in organic synthetic chemistry-92-200401778, for example, the method described in Org Syn Gol 1 vol VII259. The reaction temperature varies depending on the starting compound, the inert solvent used, and the boronating reagent, and is usually -78 ° C to 100 ° C (preferably 0 ° C to room temperature). The reaction time varies depending on the raw material compound, the inert solvent used, the boronating reagent, and the reaction temperature, and is usually 5 minutes to 48 hours (preferably 30 minutes to 24 hours). Project B7 is a process for preparing a compound of general formula (IVa). The compound (XV 111) is reacted with a compound of general formula (XIX) in the presence or absence of an inert solvent, preferably in the presence of an inert solvent. Execute. Xin The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane, chloroform, carbon tetrachloride, dichloromethane , 1,2 dichloroethane, dichlorobenzene and other halogenated hydrocarbons; hexane, heptane, petroleum spirit, petroleum ether and other aliphatic hydrocarbons; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane Ethers such as alkane and diethylene glycol dimethyl ether; Organic bases such as pyridine and triethylamine • Formamidine, N, N-dimethylformamide, N, N-dimethylacetamide, etc. Amidine g; preferably halogenated hydrocarbons or organic bases. The base used in the above reaction may be the same as that used in the A2 project of the above method A, and is preferably an organic amine. The reaction temperature varies depending on the starting compound, the inert solvent and the base used, and it is usually -78 ° C to 100 ° C (preferably -50 eC to room temperature). The reaction time varies depending on the starting compound, the inert solvent, base, and reaction temperature used, and it is usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours). After the reaction is completed, the target compound of each process of the above-mentioned method B can be prepared from the -93-200401778 reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering off, add an unmixed organic solvent such as water and ethyl acetate, and separate the organic layer containing the target compound with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous carbonic acid. It is obtained by distilling off the solvent after drying sodium hydrogen and the like. If necessary, the obtained target compound is appropriately combined according to a conventional method such as recrystallization, reprecipitation, and other conventional methods for separating and purifying ordinary organic compounds, and is subjected to column chromatography to elute and separate with a suitable eluent for separation and purification. Process C is a process for preparing the raw material compound-compound (V 111) in the above process A. Method C R1a " ^ (CH2) n-Q (XX) Project C 1

OH / ^ (CH2) n —Q (XXI) Project C 2 R2a— (CH2) m-〇H (XXII)

(CH2) n-Q R2a— (CH2) m-0 (VIII) In the above formula, Rla, R2a, m, n and Q are as defined above. Process C 1 is a process for preparing a compound of general formula (X X I), which is performed by reducing the compound of general formula (X X) in an inert solvent. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane, chloroform, carbon tetrachloride, dichloromethane, Halogenated hydrocarbons such as 1,2 dichloroethane and dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; ether, isopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane And other ethers such as diethylene glycol dimethyl ether; organic bases such as pyridine and triethylamine; carbon tetrachloride, N, N-dimethylformamide, N, N-dimethylacetamide and the like -94- 200401778 amines; alcohols such as methanol and ethanol, preferably alcohols. The reducing agents used in the above reaction can be alkali metal borohydrides such as sodium borohydride, lithium borohydride, cyanoborohydride, aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride, lithium aluminum triethoxylate, and tellurium hydride. Hydrogenation reagents such as hydrogenating organic reducing agents such as sodium, diisobutylaluminum hydride, and sodium (dimethoxyethoxy) aluminum hydride, etc., and alkali metals such as sodium and lithium are preferably alkali metal borohydrides. The reaction temperature varies depending on the starting compound, the type of inert solvent and reducing agent used, and is usually -20 ° C to 8 (ΓC (preferably 0 ° C to room temperature). The reaction time depends on the starting compound and the inert solvent used. The type of reducing agent and reaction temperature vary, usually 5 minutes to 48 hours (preferably 15 minutes to 3 hours). Project C 2 is a process for preparing compound (V 11 I) in an inert solvent. The compound (XXI) and the compound of general formula (XX Π) are subjected to photocondensation using a phosphine-based reagent and an azodicarboxylic acid-based reagent to perform condensation. As long as the inert solvent used in the above reaction can dissolve the raw materials and the reagent without affecting the reaction, No specific, can use aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, carbon tetrachloride, dichloromethane, 1,2 dichloroethane, dichlorobenzene and other halogenated hydrocarbons; hexane , Heptane, petroleum spirit, petroleum ether and other aliphatic hydrocarbons; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; pyridine, triethylamine, etc. Bases; carbon tetrachloride, N, N-dimethylformamide, N N-dimethylacetamide and other amines; preferably aromatic hydrocarbons or ethers. The phosphine-based reagent used in the above reaction is, for example, tributylphosphine or triphenylphosphine, preferably triphenylphosphine. -95 -200401778 The azodicarboxylic acid reagent used in the above reaction is, for example, azodicarboxylic acid esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; i, r-azo Azodicarboxylic acid amines such as bis (dimethylformamide); preferably azodicarboxylic acid esters. The reaction temperature varies depending on the raw material compound, the type of inert solvent and reagent used, and is usually -7. 8 ° C ~ 1 2 0 ° C (preferably 0 ° C ~ room temperature). The reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, usually between 5 minutes and 4 to 8 hours. (It is preferably between 15 minutes and 2 hours). After the reaction is completed, the target compound of each process in the above method C can be prepared from the reaction mixture according to the usual method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, After filtering off, add unmixed organic solvents such as water and ethyl acetate, and separate the organic layer containing the target compound with anhydrous sulfur. Magnesium, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc. are dried, and then the solvent is distilled off. The obtained target compound is obtained by ordinary methods such as recrystallization, reprecipitation, and other conventional methods for separating and refining organic compounds, if necessary. Chromatography, dissolution and separation with an appropriate eluent, and purification. Method D is a method for preparing the compound (V) and the compound (V) in which R 3 and R 4 are hydrogen in the raw material of the method A above. 200401778 Method D

R3 D1 Project W-ch2c〇2r10 (XXIV) (XXV)

〇The D 5th project) ^ \ OH The D 2nd project R9—V / V-co, R4

(XXVIIa) (Va) In the above formula, R3 and R4 are as defined above, and R9 is a lower alkoxycarbonyl group (the above-mentioned "lower alkoxy group" is a group bonded to a hydroxyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, φdibutoxycarbonyl, third butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, neopentyloxycarbonyl, hexane An oxycarbonyl group is preferably C, an alkoxycarbonyl group, and most preferably a third butoxycarbonyl group.), R] ^ is a carboxy protecting group (can be a general carboxy protecting group for organic synthetic learning, and is not particularly limited, and is preferably Low alkyl.), W is lithium, sodium or potassium. Project D 1 is a process for preparing a compound of general formula (XXV). In the presence or absence (preferably the presence) of an inert solvent, a metal or organometallic reagent is used to make the compound of general formula (XX Π I) and the general formula (XXIV). ) Compounds are reacted to apply -97- 200401778. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane, chloroform, carbon tetrachloride, dichloromethane, Halogenated hydrocarbons such as 1,2 dichloroethane and dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; ether, isopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane Ethers such as dimethyl ether, diethylene glycol dimethyl ether; bases such as pyridine, triethylamine; carbon tetrachloride, N, N-dimethylformamide, N, N-dimethylacetamide, and other amines Class; should be amidines or ethers. _ The metal or organometallic reagent used in the above reaction can be the same as that used in the above method A2A project. The reaction temperature varies depending on the starting compound, the type of inert solvent and reagent used, and is usually -1 2 (TC ~ room temperature (preferably -7 8 ° C ~ 0T :). The reaction time depends on the starting compound, the inert solvent used The type of reagent and reaction temperature vary, usually between 5 minutes and 48 hours (preferably between 15 minutes and

Between 1 hour). The first D 2 project is a method for preparing a compound of general formula (X X V I). The deprotection of the carboxyl protecting group can be performed according to the methods commonly used in organic synthetic chemistry, for example, T. W. Green (Protective Groups in Organic Synthesis),

John Wiley & Sons: J. F. W. McO mis, (Protective Groups Organic Organic Chemistry), Plenum Press stated the method to carry out. For example, when the carboxy-protecting group is a lower alkyl group, the compound (X X V) is treated with a base and the ester group is converted with a carboxyl group in the presence or absence of an inert solvent (preferably the presence thereof). -98- 200401778 The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as dichloromethane, 1,2 dichloroethane, and dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, and petroleum ether; ether, isopropyl ether, tetrahydrofuran, dioxane, dioxane Ethers such as methoxyethane and diethylene glycol dimethyl ether; bases such as pyridine and triethylamine; carbon tetrachloride, N 5 N -dimethylformamide, N 5 N -dimethylacetamidine Amines such as amines; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, 2 -Alcohols such as methoxyethanol; water; mixed solvents of water and the above organic solvents; preferably alcohols or mixed solvents of water and alcohols. The base used in the above reaction may be the same as that used in the A2 project of the above method A, and is preferably an alkali metal hydroxide. The reaction temperature varies depending on the type of the starting compound, the inert solvent used, and the type of base, and is usually -20 ° C to the boiling point (preferably C to the boiling point). The reaction time varies depending on the starting compound, the type of inert solvent used, the type of base, and the reaction temperature, but it is usually 5 minutes to 48 hours (preferably 15 minutes to 5 hours). Process D 3 is a method for preparing a compound of general formula (XXVII) of the Curtius reaction. In the presence or absence of an inert solvent (preferably in the presence), the compound (XXVI) is treated in the presence of a base and carried out with an azide reagent. . The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane, chloroform, carbon tetrachloride, dichloromethane, Halogenated hydrocarbons such as dichloroethane, dichlorobenzene, hexane, heptane, petroleum spirit, petroleum ether, etc. 9 9-200401778 aliphatic hydrocarbons; ether, isopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; bases such as pyridine and triethylamine; carbon tetrachloride, N, N-dimethylformamide, N, N-dimethylethyl Amidines such as amidines; preferably aromatic hydrocarbons. The base used in the above reaction may be the same as that used in the A2 process of the above method A, and is preferably an organic amine. The azide reagent used in the above reaction is, for example, a diarylphosphonium azide derivative such as diphenylphosphonium azide; a trialkylsilane azide such as trimethylsilazide, triethylsilane azide, or sodium azide Alkali metal salts such as potassium and azide are preferably diphenylphosphonium azide. The reaction temperature varies depending on the type of the starting compound, the inert solvent and the base used, and is usually -20 ° C to the boiling point (preferably (TC to the boiling point). The reaction time depends on the starting compound, the type of the inert solvent, the base, The reaction temperature varies, usually 5 minutes to 48 hours (preferably 15 minutes to 1 hour). The D4th project is a process for preparing the compound (V). The compound (XXV 11) is treated in an inert solvent to Acid, remove R 9 group for implementation. As long as the inert solvent used in the above reaction can dissolve the raw materials and reagents without affecting the reaction, it can be used as aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether, etc. ; Benzene, toluene, xylene and other aromatic hydrocarbons; chloroform, dichloromethane, 1,2 dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; methyl acetate, ethyl acetate, propyl acetate, butyl acetate Esters such as esters and diethyl carbonate; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropyl Alcohol, n-butanol, isobutanol, tertiary butanol, isoamyl alcohol Diethylene glycol, glycerol, octanol-1 00-200401778, cyclohexanol, 2-methoxyethanol and other alcohols; carbon tetrachloride, dimethylformamide, dimethylacetamide, hexamethyl Phosphonium triamine and other amines; water; water or mixed solvents of the above solvents; preferably alcohols, ethers or mixed solvents of alcohols and ethers. The acid used in the above reaction is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid , Perchloric acid, phosphoric acid and other inorganic acids; acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids such as Bronsted acid; chloride Lewis acids such as zinc, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins, preferably inorganic or organic acids (most preferably Lu hydrochloric acid, acetic acid or trifluoroacetic acid) The reaction temperature varies depending on the raw material compound, the acid used, and the inert solvent, and is usually -20 ° C to the boiling point (preferably (TC ~ 100t :). The reaction time depends on the raw material compound, the acid and the inert solvent used. The reaction temperature varies, usually between 15 minutes and 48 hours (preferably between 30 minutes and 15 hours). The D 5 process is a process for preparing the compound (V a). In an inert solvent, the compound of the general formula (XXVIIa) is treated with an acid and the R9 group is removed for execution. After the reaction is completed, the target compound of each process of the above D method can be prepared from the reaction mixture according to the usual method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering off, add water and ethyl acetate, etc. The mixed organic solvent is separated from the organic layer containing the target compound and dried with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., and the solvent is distilled off. The obtained target compound is obtained by ordinary methods such as recrystallization and recrystallization if necessary. Precipitation and other commonly used methods for the separation and purification of organic compounds in 200401778 are appropriately combined, and column chromatography is used to dissolve them with a suitable eluent for separation and purification. Method E is another way to prepare compounds (la), (lb), (Ila), (lib), and (III) in method A. E method R2a —〇— (CH2) n—〇 E 1 project (IV)

R1a>>-(CH2) n-〇R a — (CHgJm—0 E2 project R3 N. r3 \ (VIII) HN XT. Or HN xr R4, r5c (XXVIIIc) R 'V (XXVIIIb) In the above formula , R1, R1a, R2, R2a, R3, R4, R5a, R5b, r5c, R6, m, n and Q are as defined above.

R11 or R2 — (CH2) m-0

Ya 0, R5b R2a (IV)

> -〇- (CH2) n-Q

200401778 Project E 1 is another way to prepare compound (I a) or (I b) in method A. In an inert solvent and in the presence of a base, make compound (IV) and the general formula (XXV 111 a) or ( XXV 111 b) After the compound or its acid addition salt (such as an inorganic acid salt such as hydrochloride, nitrate, sulfate, etc.) is reacted, R 1 a and R 2a 2 amine groups and / or hydroxyl protecting groups are removed and implemented as necessary. . The reaction of the compound (IV) with the compound (XX VIII a) or (XX villb) or its acid addition salt can be performed in a manner similar to the method of the A1 project of the above method A, and if necessary, the amine group and / or hydroxyl group of Rla and R2a The reaction for removing the protecting group may be performed in a manner similar to the method for removing the amine group and / or the hydroxyl protecting group in the A2 process of the above method A. Process E 2 is another way to prepare the compound (11 a) or (11 b) in method A. In an inert solvent and in the presence of a base, the compound (V 111) and the general formula (XXVIIIc) or (XXVIIIb) After the compound or its acid addition salt is reacted, the amine group and / or the hydroxyl protecting group of RIa and R2a are removed as needed to perform the operation. . The reaction of the compound (V 111) with the compound (XXV 111 c) or (XXV 111 b) or an acid addition salt thereof can be performed similarly to the method of the A1 project of the above method A, and if necessary, the amine groups of Rla and R2a and / Or the reaction for removing the hydroxyl protecting group can be performed in a manner similar to the method for removing the amine group and / or the hydroxyl protecting group in the A2 process of the above method A. Project E 3 is another way to prepare compound (111) in method A. Compound (IV) is reacted with a compound of general formula (XXIX) or an acid addition salt thereof in an inert solvent and under a base. Rla and R2a are removed by removing the amine group and / or the hydroxyl protecting group. . The reaction of the compound (IV) with the compound (XXIX) or an acid addition salt thereof can be performed similarly to the method of the A1 project of the above method A, and if necessary, the amine group and / or the hydroxyl protecting group of R 1 a and R 2 a can be removed. The reaction can be performed in a manner similar to the method of removing -10 3-200401778 deamino group and / or hydroxyl protecting group in the above-mentioned A2 project of method A. After the reaction is completed, the target compound of each process of the above-mentioned E method can be prepared from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering off, add an unmixed organic solvent such as water and ethyl acetate, and separate the organic layer containing the target compound with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous carbonic acid. It is obtained by distilling off the solvent after drying sodium hydrogen and the like. If necessary, the obtained target compound is appropriately combined according to a conventional method such as recrystallization, reprecipitation, and other conventional methods for separating and purifying ordinary organic compounds, and is subjected to column chromatography to elute and separate with a suitable eluent for separation and purification. The F method is a method for preparing the starting compounds (X X V 111 a), (X X V 111 b), (XXVIIIc), and (XXIX) in the above E method. F method

R9 —N

F1 Project X-R5a (Vila) NH (XXVII)

(XXVIIIa)

F 2nd project X—R5b (Vllb) F 3th project x—r5c (Vile)

(XXVIIIb)

r-n / 0r ° -NH

(XXVIIa) F 4th Project X — R6 (X)

(XXIX) nr6 200401778 In the above formula, R3, R4, R5a, R5b, R5c, R6, R9 and X are as defined above. The F1 project is a process for preparing a compound (XXV 111 a). In the presence or absence of an inert solvent (preferably the presence), the compound (XXV 11) and the compound (V 11 are used) a) After the reaction, the R 9 group is removed and carried out. The reaction of the compound (XXV 11) and the compound (V 11 a) can be performed similarly to the reaction method of the compound (IV) and the compound (V 11 a) in the A 2nd process of the above method A. The method of removing the R9 group can be similar to the above D Method D4. * Project F 2 is a process for preparing compound (XXVI Π b). In the presence or absence of an inert solvent (preferably the presence), the use of an alkali, metal or organometallic reagent is used to make compound (XXV 11) and compound (V 11 b) After the reaction, the R 9 group is removed to perform. The reaction of the compound (XXV 11) and the compound (V 11 b) can be performed similarly to the reaction method of the compound (IV) and the compound (V 11 b) in the A2 process of the above method A. The method of removing the R9 group can be similar to the above D Method D 4 of the project. @ 第 F 3 Project is a process for preparing compound (XXV III c). In the presence or absence of an inert solvent (preferably the presence) 7 use test, metal or organometal reagents to make compound (XXVII) and compound (Vile) After the reaction, the R9 group was removed and carried out. The reaction of the compound (XXV 11) and the compound (V 11 c) can be performed similarly to the reaction method of the compound (IV) and the compound (V 11 c) in the A4 process of the A method described above. The method for removing the R9 group can be similar to the above D Method D 4 of the project. The F4th project is a process for preparing the compound (XXIX). In the presence or absence of (-105-200401778) of an inert solvent, a base is used to react the compound (X xv 11 a) with the compound (X). , R 9 group is removed for implementation. The reaction of the compound (XXV 11 a) and the compound (X) can be performed in a manner similar to the reaction method of the compound (Via) and the compound (X) in the A6 process of the above method. Engineering methods to implement. After the reaction is completed, the target compound of each process of the above-mentioned F method can be prepared from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering off, add an unmixed organic solvent such as water and ethyl acetate, and separate the organic layer containing the target compound with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous carbonic acid. It is obtained by distilling off the solvent after drying sodium hydrogen and the like. If necessary, the obtained target compound is appropriately combined according to a conventional method such as recrystallization, reprecipitation, and other conventional methods for separating and purifying ordinary organic compounds, and is subjected to column chromatography to elute and separate with a suitable eluent for separation and purification. The G method is a method for preparing the compound (X X I a) in which η is 2 among the intermediate compounds (X X I) of the C method. Law G (XXX) Project G 1-X-ch2co2r10 (XXXI)

OH -31a- xo2r 10 Project G2

(XXXIII) (XXXII)

The G 3rd project r 丨 v, Q (XXIa) In the above formula, Rla, RlG, X and Q are defined as above. Project G 1 is a method for preparing compound (XXX 11). In the presence or absence of an inert solvent (preferably the presence), a metal or organometallic reagent is used to make the compound of general formula (XXX) and general formula (XXXI) Compound reaction-] 0 6-200401778. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane, chloroform, carbon tetrachloride, dichloromethane, 1 , 2-dichloroethane, dichlorobenzene and other halogenated hydrocarbons; hexane, heptane, petroleum spirit, petroleum ether and other aliphatic hydrocarbons; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane And other ethers such as diethylene glycol dimethyl ether; organic bases such as pyridine and triethylamine; formamide, N, N-dimethylformamide, N, N-dimethylacetamide and the like Amines; preferably amines or ethers. The metal or organometallic reagent used in the above reaction may be the same as that used in the above-mentioned A, A2 project of the method. The reaction temperature varies depending on the types of raw materials, inert solvents and reagents used, but it is usually -120 ° C to 12CTC (preferably room temperature to 100 ° C). The reaction time varies depending on the raw material compound, the inert solvent used, the type of reagent, and the reaction temperature, and is usually between 5 minutes and 48 hours (preferably between 15 minutes and 1 hour). _ The G 2 project is a process for preparing a compound of general formula (X X X 111). The compound (X X X 11) is reduced with a reducing agent in an inert solvent. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reactants without affecting the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, etc .; methylene chloride, chloroform, carbon tetrachloride, methylene chloride, Halogenated hydrocarbons such as 1,2-dichloroethane, dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane, petroleum spirit, petroleum ether; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether; organic bases such as pyridine and triethylamine-107-200401778; formamide, N 5 N -dimethylformamide, N 5 N -dimethyl Ethylamines such as methylacetamide; alcohols such as methanol and ethanol; preferably ethers. The reducing agents used in the above reaction can be alkali metal borohydrides such as sodium borohydride, lithium borohydride, cyanoborohydride, aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride, lithium aluminum triethoxylate, and tellurium hydride. Sodium, diisobutylaluminum hydride, sodium hydride (methoxyethoxy) aluminum hydride and other hydrogenating organic reducing agents and other hydrogenating reagents, and alkali metals such as sodium and lithium are preferably aluminum hydride compounds. The reaction temperature varies depending on the type of the raw material compound, the inert solvent and the reducing agent used, and is usually -20 ° C ~ 8 (ΓC (preferably (TC ~ room temperature). The reaction time depends on the raw material compound, the inert solvent, The type of the reducing agent and the reaction temperature vary, but it is usually between 5 minutes and 48 hours (preferably between 15 minutes and 24 hours). The G 3rd project is to convert the hydroxyl group of the compound (XXX 111) into an active compound. The engineering of the compound of general formula (XXIa) with functional groups having nucleophilic residues detached can be carried out in the same way as the method B and B 2 of the above method. After the reaction is completed, the target compound of each method of the above G method can be used in accordance with ordinary methods. The reaction mixture is prepared. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering off, add unmixed organic solvents such as water and ethyl acetate, and separate the organic layer containing the target compound with anhydrous magnesium sulfate and anhydrous. After drying, sodium sulfate, anhydrous sodium bicarbonate, etc., it is obtained by distilling off the solvent. If necessary, the obtained target compound can be appropriately combined according to ordinary methods, for example, recrystallization, reprecipitation and other conventional methods for separating and purifying organic compounds. Chromatography, dissolved in a suitable eluent out separation and purification method of an optically active substance [eta] Method C Method for the preparation of the above intermediate compound (XXI) of -108- 200401778 (XXI-asym) of. [Eta] Method

R

(Chyn — 〇 Project # 1 ---

QH R1a ^^ (CH2) n-Q (XX) (XXI-asym) In the above formula, Rla & Q is as defined above. The first project is a process for preparing a compound of general formula (X X I-a s y m), and the compound of general formula (X X) is subjected to asymmetric reduction in an inert solvent. The inert solvent used in the above reaction is not specific as long as it can dissolve the raw materials and reagents without affecting the reaction, and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used; dichloromethane institute, chloroform, carbon tetrachloride, methylene chloride , 15 2 -dichloroethane, dichlorobenzene and other halogenated hydrocarbons; hexane, heptane, petroleum spirit, petroleum ether and other aliphatic hydrocarbons; ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether; bases such as pyridine and triethylamine; formamidine, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, etc. Amines; alcohols such as methanol and ethanol; preferably ethers. The asymmetric reducing agent used in the above reaction is a conventional reducing agent and is not limited. For example,

Organoboron reagents such as bicyclo [3 3 1] nonane, oxazole borane, etc .; aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride, lithium triethoxy aluminum hydride, and binaphthylene glycol, 2,2 '- Asymmetric aluminum reagents modified with asymmetric ligands such as bis (diphenylphosphine) -1,1′-binaphtyl; Rare earth metals such as Ru, Rh and asymmetric matching with 2,2f-bis (diphenylphosphine) Body-modified metal catalysts; yeast and other enzymes; preferably organic boron reagents. -109- 200401778 The reaction temperature varies depending on the raw material compound, the type of inert solvent and asymmetric reducing agent used, usually -78t: ~ 80t ( It should be -25t ~ room temperature.) The reaction time varies depending on the raw material compound, the type of inert solvent used, the type of asymmetric reducing agent, and the reaction temperature, usually between 5 minutes and 7 to 2 hours (preferably between 15 minutes and 2 After 4 hours). At the end of the reaction, the compound (XXI-asym) of the Η1 project can be prepared from the reaction mixture according to the usual method. For example, the reaction mixture is appropriately neutralized. If there is insoluble matter, after filtering, add water Organic solvents such as ethyl acetate and ethyl acetate The layer is obtained by drying anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., and then distilling off the solvent. The obtained target compound is obtained by ordinary methods, such as recrystallization, reprecipitation, and other conventional methods for separating and purifying common organic compounds, if necessary. Appropriate combination, column chromatography, elution with appropriate eluent, separation and purification. Raw material compounds (V 11 a), (V 11 b), (V 11 c), (X) ~ (X 11), (XV) , (XVI), (XIX), (XX), (XXII) to (XXIV), (XXX), and (XXXI) are conventional compounds, or can be easily prepared according to known methods or similar methods. [Example J For example, J .〇1. G C hem., 5 8, 1 1 0 9-1 1 1 7 (1 9 9 3); J. 0 rg · Che m, 66, 2 1 8 1-2 1 8 2 (2 0 0 1); IACS, 95, 3 0 5 0 (1 9 7 3), etc.] [Effects of the invention] The present invention contains the oxazolidinone of the general formula (I), (Π) or (π I) above Derivatives, their pharmacologically acceptable salts, their esters, or other derivatives have excellent IL-4 and / or IL-10 induction, and thus can be used as Th 1 immunosuppressive agents [specifically, chronic inflammatory diseases such as chronic wind Arthritis, viscera-specific autoimmune disease (eg, diabetes, multiple sclerosis), inflammatory bowel disease -110- 200401778 (eg, ulcerative colitis, Crohn's disease), glomerulonephritis, hepatitis , Liver disease, liver disorder, autoimmune hemolytic anemia, leukocytopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Edison's disease, parathyroidism, malignancy Anemia, localized ileitis, atrophic gastritis, gluten-sensitive enteritis, Good Paster syndrome, streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, sympathetic Ophthalmitis, Pemphigus Vulgaris, Pemphigus Vulgaris, Psoriasis] (It should be chronic rheumatoid arthritis or an organ-specific autoimmune disease, most preferably ulcerative colitis, Crohn's disease or hepatitis) Compared with conventional IL-4 and / or IL-10 production inducers, the compounds of the present invention have higher water solubility, higher oral absorption, and have a rapid effect on target organs. High mobility of organs or target cells, low mobility in the brain, low side effects, safe area (difference in concentration between drug effect and toxicity), wide in vivo dynamics (long half-life in plasma, high AUC, low tissue accumulation, etc.) ). [Industrial Applicability] The present invention contains the oxazolidinone derivative of the general formula (I), (11), or (I Π), a pharmacologically acceptable salt, an ester or other derivative thereof, and acts as a treatment for the above diseases. When used as an agent or preventive agent, it can be used alone or mixed with appropriate pharmaceutical acceptable excipients, diluents, etc., for example, lozenges, capsules, granules, powders, or syrups, etc. Oral administration. This formulation can use excipients (for example, sugar derivatives such as lactose, white sugar, glucose, mannose, sorbose; corn starch, potato starch, alpha starch, dextrin and other starch derivatives; cellulose derivatives such as crystalline cellulose A 200401778 organic excipients such as rubber, polydextrose, polytriglucose, etc .; and silicon derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium aluminum metasilicate, etc .; hydrogen phosphate Phosphates such as calcium; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate; slip agents (for example, stearic acid metal salts such as stearic acid, calcium stearate, and magnesium stearate; Talc, colloidal silica, propolis, cetyl wax and other waxes; sulfates such as boric acid, adipic acid, sodium stearate; ethylene glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; Dodecyl sulfate such as dodecyl sulphate, dodecyl magnesium sulfate; silicic acids such as silicic anhydride, silicic acid hydrate; and the above starch derivatives), binding agents (for example, hydroxypropyl cellulose, hydroxypropyl Methylcellulose, polyvinylpyrrolidone, polyethylene glycol and the foregoing Excipients, etc.), disintegrating agents (for example, cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and internally bridged carboxymethyl cellulose sodium; carboxymethyl starch Chemically modified starch cellulose such as sodium carboxymethyl starch, bridged polyvinylpyrrolidone, etc.), stabilizers (parabens such as methylparaben, propylparaben, etc .; chloroprene Alcohols, benzyl alcohol, phenethyl alcohol, etc .; benzyl ammonium chloride; phenols such as phenol, cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (for example, conventional sweeteners, sour flavors, spices Etc.); Additives such as diluents are manufactured according to customary methods. The dosage varies according to symptoms and age. For example, when taken orally, the lower limit for adults is 0.1 mg (preferably 0.5 mg) and the upper limit is 4 000 mg (preferably 4,000 mg). When administered intravenously, the lower limit for adults per day is 0.01 mg (preferably 0.05 mg), the upper limit is 500 mg (preferably 300 mg), and 1 ~ 6 administrations. 200401778 [Embodiment] Examples, reference examples, and test examples are described in detail below, but the present invention is not limited thereto. Example 1 8-{2-[bis- (3-trifluorotolyl) methoxy] ethyl}-3-(thiophene-2-ylcarbonyl) -1 -flf -3,8 -diacryl [ 4 5 5] dec-2-one and its oxalate (exemplified compound number 1-1 7 3) (1 &) 8- [2-bis- (3-trifluorotolyl) methoxyethyl] -1 -Fluorene-3,8-diacylspiro [4,5] dec_2-ketone · The 1-fluorene-3,8-diacridino [4,5] dec-2-one hydrochloride prepared in Reference Example 1 Salt 150 mg (0.78 mmol), bis- (3-trifluorotolyl) methyl 2-chloroethyl ether prepared in Reference Example 2 (298 mg (0.78 mmol)), sodium carbonate 289 mg (2.72 mmol) And 12 mg of sodium iodide (0.0 7 8 mmol) was dissolved in 8 ml of methyl isobutyl ketone, and heated under reflux for 18 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloro φ methane: methanol = 9 9: 1) to obtain the target compound 287 mg (73%) as white crystals. NMR spectrum (400MHz, CD30D) (5ppm: 7.76 (2H, s), 7.5h7.66 (6H, in), 5.65 (1H, s), 3.65 (2H, t, J-5.6Hz), 3.34 (2H , s), 2.53-2.80 (6H, m), 1.78-1.98 (4H, m) Infrared absorption spectrum vniax cnr1 (KBr): 3269, 2925, 2830, 1753, 1 330, 1256, 1 1166, 1125, 1074 ° (1 b) 8-{2-[bis- (3-trifluorotolyl) methoxy] ethyl}-3-(thiophene-2-ylcarbonyl) -I -fluorene-3,8 -diacryl [4,5] dec-2 is called ketone 200401778 8- {2-[bis- (3-trifluorotolyl) methoxy] ethyl}-1 -fluorene-3 prepared in Example (1 a), 8-Diaciro [4; 5] dec-2-one 0 2 5 g (0 4 9 8 mmol) was dissolved in 50 ml of tetrahydrofuran, and 2-decanoyl chloride 0 1 1 ml (0 9 9 5 Mmol), n-butyllithium (1.59 N, 0.4 7 ml (0.746 mmol)), and stirred under ice-cooling for 5 hours. After the reaction was completed, water was added to the reaction solution, and ethyl acetate was added. Ester extraction. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) , Winning the combination 0 · 24 g (82.8% yield) oily substance. (Lc) 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3- (thiophene- 2-ylcarbonyl) -1 -fluorene-3 5 8 -diaciro [4 5 5] dec-2-one ketooxalate The 8- {2-[bis- (3- Trifluorotolyl) methoxy] ethyl}-3-(thiophene-2 -ylcarbonyl) -bufa-3,8 -diazelop [4,5] dec-2 -one 0.2 4 g ( 0.4 1 1 mol) was dissolved in 5 ml of ethyl acetate, 0.037 g (0.4 1 1 mol) of oxalic acid was added, and left to stand overnight. The target compound was crystallized to obtain 0.1 2 g (0.12 g). 4 3.3%). NMR spectrum (400MHz, CDC13) ppm: 7.29-7.24 (m, 6H), 7.03-6.98 (m, 2H), 5.29 (s, 1H), 3. 47-3. 44 (m, 2H), 3. 35-3.29 (m, 2H), 3.25 (s, 2H), 2.54-2. 46 (m, 6H), 1.97-1.63 (m, 6H), 1.15 (t, 3H, J = 7.15 Hz) Infrared absorption spectrum v max cnT1 (KBr): 1748, 1 604, 1 507, 1 223 Mass analysis (FAB) m / z 4 4 5 ((M + H) +, free body). Example 2 [Bis- (3-dichlorotolyl) methylamino] ethyl} -3-methylthiomethyl-1-sue-3, 8-diacryl [4,5] dec-2-one And its fumarate (exemplified compound number 200401778 code 1-1 4 7) (2a) 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl 3-methylsulfide Methyl-l-fluorene-3,8-diacspiro [4,5] dec-2-one The 8- [2-bis- (3-trifluorotolyl) methoxy group prepared in Example (1a) Ethyl] -1 -fluorene-3,8-diacylspiro [4 5 5] dec-2-one 1 3.0 g (25.9 mmol) dissolved in N 5 N -dimethylformamidine 130 ml of amine, added Na Η 1.2 4 g (content 60.0%, 3 1 · 1 mmol), tetrabutylammonium iodide 1. 91 (5 · 18 mmol) ), 5.2 ml of methylthiomethyl chloride (38.81 mmol), and stir at room temperature for 5 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate ® layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 9.30 g of the target compound (yield 63.7%) as an oily substance. (2b) 8- {2- [Bis- (3-trifluorotolyl) methoxy] ethyl 3-methylthiomethyl-1-fluorene-3,8-diacylspiro [4,5] dec -2-ketofumarate The 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl}-3 -methylthiomethyl prepared in Example (2 a) 1- 噚 -3,8-di-saccharo [4,5] dec-2-one-9.30 g (16. 6 φ mmol) was dissolved in 50 ml of ethyl acetate, and transbutene was added. 192 g of diacid (16.6 millimoles) was left overnight. 9.25 g (82. 4%) of the target compound was obtained from the precipitated crystals. Nuclear magnetic resonance spectrum (4QQMHz, CD30D) (5 ppm: 7.76-7.54 (ηι, 8Η), 5.73 (s, 1Η), 3.80 (t, 2H, J = 5.34Hz), 3.52 (s, 2H) , 3. 33-3.21 (m, 8H), 2.20-2. 07 (m, 7H) infrared absorption spectrum vmax cr1 (KBr): 1753, 1615, 1430, 1331, 1 255, 1166, 1125, 1073, 984 mass (FAB) m / z 5 6 3 ((M + H) +, free body). 200401778 Example 3 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl)- 3-(thiophene-2-ylcarbonyl) -1 -Pin-3; 8-diaciro [4,5] dec-2-one and its oxalate (exemplified compound number 1-1 7 4) (3 a) 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl 1-fluorene-3,8-diacryl [4,5] dec-2-one was prepared in Reference Example 1 1-fluoren-3, 8-diaciro [4,5] dec-2-one hydrochloride 8.9 mg (0.4 6 mmol) and the bis- (3-trifluorotolyl group) prepared in Reference Example 3 ) Methyl 3-chloropropyl ether 167 mg (0.42 mmol) dissolved in 2 ml of N, N-dimethylformamide, potassium carbonate 145 mg (1.0 mmol) and iodinated Sodium 6 mg (0.0 4 mmol), stirred at 1 3 (TC for 4 hours. Cool at room temperature The solution was added with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried and concentrated. The residue was purified by layered thin-layer chromatography (eluent: dichloromethane: methanol = 0: 1 ) 156 mg (72%) of the target compound was obtained. (3b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl) -3- (thien-2-ylcarbonyl) ) -1 -fluorene-3,8-bisacylspiro [4,5] dec-2-one_ 8-{3-[bis- (3 -trifluorotolyl) methyl) prepared using Example (3 a) Oxy] propyl 1-fluorene-3,8-diacillyl [4,5] dec-2-one 2 0 mg (0 3 9 mmol) and 2-decyl chloride 6 2 μl ( 0.58 millimolar), the reaction and purification were performed in the same manner as in Example (1b), and the target compound 235 mg (97%) was obtained. (3 c) 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl plant 3-(thiophene-2 -ylcarbonyl) -1-P 萼 -3,8 -di 卩 yal Spiro [4,5] dec-2-one ketooxalate The 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl}-3-(thiophene) prepared in Example (3b) -2 -ylcarbonyl) -1-fluorene-3,8-diaciro [4.5] dec-2-one 2 0 200401778 mg (0.35 mmol) was dissolved in 3 ml of ethyl acetate, Added 32 mg of oxalic acid (0.35 mmol) and left at room temperature overnight. The crystals were collected by filtration to obtain 122 mg (48%) of the target compound as white crystals. NMR spectrum (400MHz, DMSO-d6) 0ppm: 8.00_7.94 (2H, m), 7.79 (2H, in), 7.74-7.60 (6H, in), 7.22-7. 19 (1H, m), 5.77 (1H, s), 3.96 (2H, s), 3.48 (2H, t, J = 5.9Hz), 3.21-2.87 (6H, m), 2. 19-1.87 (6H, m) infrared absorption spectrum vmax cuf1 ( KBr): 2493, 1786, 1651, 1330, 1123 Mass analysis (FAB) m / z 6 2 7 ((M + H) +, free body) Elemental analysis 値 (C32H3 () F6N 2 0 8 S-1 / 2H20 ) Calculated 値: C: 52.97; H: 4.31; F: 15.71; N: 3.86; S..4.42 Measured 値: C: 5 2.7 5; H: 4 · 3 0; F ·· 1 5 · 4 4; N : 3 · 9 5; S: 4. 3 1. Example 4 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (2-methoxybenzylfluorenyl) -1 -fluorene-3, 8-diacryl [4,5] dec-2-one and its oxalate (exemplified compound number 1-1 6 2) (4 a) 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl }-3-(2 -methoxybenzyl ginsyl) -1 -pinen-3,8 -diazelop [4,5] dec-2-one, 8- {3 prepared using Example (3 a) -[Bis- (3-trifluorotolyl) methoxy] propyl) -1 -fluorene-3,8-diacryl [4,5] dec-2 -one 2 0 mg (0 3 9 1 Mol) and 80 microliters of 2-methoxybenzidine chloride (0.58 mol), the reaction and purification of Example (1 b) can be carried out to obtain 250 mg (99%) of the target compound. (4 b) 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl) -3-(2 -methoxybenzylfluorenyl) -1 -fluorene-3,8 -difluorene Acyl [4,5] dec-2-one ketooxalate The 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 200401778 group prepared in Example (4a)}-3 -(2-Methoxybenzyl) -1 -fluorene-3 5 8 -diaciro [4,5] dec-2-one 2 0 mg (0.37 mmol) dissolved in ethyl acetate 3 ml, added 33 mg (0.37 mmol) of oxalic acid, and left at room temperature overnight. The crystals were collected by filtration to obtain 155 mg (62%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) (5 ppm: 7.79 (2Η, s), 7.75-7.73 (2Η, m), 7.68-7. 60 (4Η, m), 7. 48-7 44 (1Η, m), 7. 33-7. 31 (1H, m), 7. 08-6.99 (2H, di), 5.77 (1H, s), 3.96 (2H, s), 3.48 (2H, d, J = 5.9Hz), 3.32-2.97 (6H, m), 2.1 6-1.9K6H, m) Infrared absorption spectrum cnr 丨 (KBr): 2947, 2498, 1 793, 1331, 1123 Wide mass analysis (FAB) ηι / z 6 5 1 ((Μ + Η) +, free body). Example 5 8- {3- [bis- (3-Dichlorotolyl) methoxy] propyl} -3 -ethyl-1-Dfluorene-3,8-diacryl [4,5] dec -2 -ketone and its oxalate (exemplified compound number 3-2 0) (5a) 8- {3- [bis- (3-diphenylmethylbenzyl) methoxy] propyl} -3 -ethyl -1-shu-3,8-diacridyl [4,5] dec-2-one was prepared using the 8- {3-[bis- (3-trifluorotolyl) methoxy group prepared in Example (3a) ] Propyl 1-pyrene-3,8-diacryl [4,5] dec-2-one 2 0 mg (0 3 9 mmol) Tyl and ethyl iodide 4 7 μl (0.5 8 millimolar), the reaction and purification of Example (2a) can be performed to obtain the target compound 168 mg (80%). (5b) 8- {3- [Bis- (3-trifluorotolyl) methoxy] propyl} -3 -ethyl-1-isopropyl-3,8-diacylspiro [4,5] dec -2-Ketooxalate Dissolve 160 mg (0 2 9 mmol) of the compound prepared in Example (5 a) in 3 ml of ethyl acetate, and add 26 mg (0 2 9 mmol) of oxalic acid. And left at room temperature overnight. The crystals were collected by filtration to obtain 145 mg (78%) of the target compound as white crystals. -1 1 8- 200401778 Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7.87 (2H, s), 7.74-7 · 59 (6Η, κι), 5.77 (1Η, s) 3.47 (2Η , T,]: 6.0 · 0Ηζ), 3.37 (2Η, s), 3.19 (2Η, q, J: 7.2Hz), 3. 16-2.92 (6Η, m), 2. 03-1. 87 ( 6Η, m), 1.06 (3Η, t, J = 7.2Hz) Infrared absorption spectrum vmax cnr 丨 (KBr): 2929, 2563, 1743, 1 332, 1 1 25 Mass analysis (FAB) m / z 5 4 5 ( (Μ + Η) +, free body) Elemental analysis 値 (C29H32F6N207) Calculate 値: C: 54 · 89; Η: 5.08; F: 17.96; N: 4.41 Measured 値: C: 54.65; Η: 4.82; F: 18 57; Ν: 4.46〇 Example 6

I 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl) -3- (2-methoxyethoxymethyl ^ -1) -1 -fluorene-3 5 8 -diacryl [4,5] Dec-2-one and its oxalate (Exemplified compound 5 Tiger code 1-1 4 6) (6a) 8- {3- [bis- (3-trifluorotolyl) methoxy] Propyl} -3- (2-methoxyethoxymethyl) -1 -fluorene-3, 8-diacryl [4,5] dec-2-one was prepared using Example 8- {8- { 3-[Bis- (3-trifluorotolyl) methoxy] propyl 1-fluorene-3,8-diacryl [4, 5] dec-2-one 300 mg (0.58 mmol) and 80 microliters of 2-methoxyethoxymethyl chloride (0.70 millimolar) were used in the same manner as in Example (2a), and 165 mg (47%) of the target compound was obtained after extensive reaction and purification. (6b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1 -fluorene-3,8-diazine Spiro [4 5 5] dec-2-one keto fumarate 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl} prepared in Example (6 a)- 3-(2 -methoxyethoxymethyl) -1 -fluorene-3,8 -diaciro [4,5] dec-2-one 1 5 5 mg (〇2 6mmol) dissolved in ethyl acetate 3 ml of the ester, 30 mg of fumaric acid (0 26 mmol) was added, and it was left at room temperature overnight. The crystals were collected by filtration to obtain 149 mg (80%) of 200401778 white crystals of the target compound. NMR spectrum (400MHz, DMS〇-d6) δ ppm: 7.77 (2Η, s), 7.71-7.58 (6H, m), 6.6K2H, s), 5.74 (1H, s), 4.64 (2H, s ), 3.52-3.39 (6H, m), 3.38 (2H, s), 3.24 (3H, s), 2.49-2.37 (6H, m), 1. 82-1. 67 (6H, m) infrared absorption spectrum v max cm—1 (KBr): 2928, 2493, 1757, 1 330, 1123 Mass analysis (FAB) m / z 6 0 5 ((M + H) +, free body) Elemental analysis (C33H4 () F6N209-1 / 2H20) Calculate 値: C: 54 · 17; Η: 5.65; F: 15.58; Ν: 3. 83 Measured 値: C: 54.16; Η: 4.95; 'F: 14.18; Ν: 3.75. Example 7 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (4-chlorobenzyloxymethyl) -1 -fluorene-3,8-diacryl [4,5] Dec-2-one and its fumarate (exemplified compound number 1-1 5 8) (7a) 8- {3- [bis- (3-trifluorotolyl) methoxy ] Propyl} -3- (4-chlorobenzyloxymethyl) _ 丨 _ 噚 -3,8-diaciro [4,5] dec-2-one, 8- {prepared using Example (3a) 3-[bis- (3-trifluorotolyl) methoxy] propyl}-1 -fluorene-3,8 -diacryl [4 5 5] dec-2 -one 3.0 mg (0.5 8 millimoles) and 122 mg (0.64 millimoles) of 4-chlorobenzylchloromethyl ether. The reaction and purification of Example (2a) were carried out to obtain the target compound 175 mg (45%). (7 b) 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl;}-3-(4-chlorobenzyloxymethyl) -1 -fluorene-3,8 -di Acryl [4,5] dec-2-one keto fumarate The 8- {3-[bis- (3-trifluorotolyl) methoxy] propyl 3 prepared in Example (7 a) -(4-chlorobenzyloxymethyl) -1 -fluorene-3,8-diacylspiro [4,5] dec-2-oneone 160 mg (0.24 mmol) dissolved in ethyl acetate 3 ml, added fumaric acid 2 8 -1 20- 200401778 mg (0.24 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 122 mg (60%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) δ ppm: 7.79 (2H, s), 7.77-7 · 58 (6H, m), 7.4K2H, d, J = 8.4Hz), 7.36 (2H, d, J = 8.4Hz), 6.6K2H, s), 5.74 (1H, s), 4.72 (2H, s), 4.47 (2H, s), 3.46 (2H, d, J = 6.2Hz), 3.37 (2H, s ), 2.47-2.35 (6 H, m), 1. 80 ~ 1.62 (6H, m)

Infrared absorption spectrum vmax cur1 (KBr): 2930, 2492, 1759, 1 330, 11M Mass analysis (FAB) m / z 671 ((M + H) +, free body) Elemental analysis 値 (C37H37C1F6N208-1 / 2H20) Calculation値: C: 55. 82; Η: 4.81; Cl: 4. 45; F: 14. 32; N: 3. 52 Found 値 C: 55.  81; H: 4.4; Cl: 4.  46; F: 14. 12; N: 3.  42. Example 8 8- {3-[(3-cyanophenyl) (3f-trifluorotolyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-噚 · 3 , 8-Diacridyl [4,5] dec-2-one and its oxalate (exemplified compound number 1-3 1 2) (8a) 8- {3-[(3-cyanophenyl) (3 ' -Trifluorotolyl) methoxy] propyl 1-fluorene-3,8-diacryl [4 5 5] dec-2-one. 3-[(3-cyanophenyl) prepared in Reference Example 4 (3'-trifluorotolyl) methoxy] propanol 3 0 0 mg (0. 8 9 mmol) was dissolved in 3 ml of dichloromethane, and 187 µl of triethylamine (1. 34 millimoles) and 90 microliters of mesylate chloride (1.  16 millimoles). After stirring for 30 minutes under ice-cooling, rinse with water and saturated saline in this order. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained methanesulfonic acid- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} ester 370 mg (0. 89 millimoles) dissolved in 5 ml of N, N-dimethylformamide, and added 1-pyrene-3,8-diacridyl spiro [4. 5] dec-2 -one hydrochloride -121- 200401778 207 mg (1. 07 millimoles), potassium carbonate 247 mg (1. 87 millimolar) and potassium iodide 15 mg (0. 0 9 mmol), and stirred at 100 ° C for 10 hours. After the reaction was completed, water was added at room temperature, and extraction was performed twice with ethyl acetate. The organic layers were combined, washed sequentially with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash chromatography (eluent: methanol: dichloromethane = 5: 95) to obtain the target compound 283 mg (67%). (8b) 8- {3-[(3-cyanophenyl) (3 ^ trifluorotolyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-fluorene-3 8- {3-[(3-Cyanophenyl) (3 · -trifluorotolyl) methoxy] prepared in Example (8a) using 8,8-diasciro [4,5] dec-2-one Propyl-1-fluorene-3, 8-diacryl [4,5] dec-2-one 300 mg (0. 63 mmol) and 2-methoxyethoxymethyl chloride 110 μl (0. 95 millimolar), the reaction and purification of Example (2a) were carried out to obtain the target compound 283 mg (67%). (8c) 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-Pf- 3,8-Diacridyl [4,5] dec-2-one oxalate The 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) prepared in Example (8b) Methoxy] propyl} -3- (2-methoxyethoxymethyl) -1-fluorene-3, 8-diacspiro [4,5] dec-2-one 270 mg (0. 48 mmol) dissolved in 3 ml of ethyl acetate, and 43 mg of oxalic acid (0.  48 mmol), and left overnight at room temperature. The crystals were collected by filtration to obtain 188 mg (60%) of the target compound as white crystals. Nuclear fe resonance spectrum (400MHz, DMS〇-d6) δ ppm: 7. 94 (lH, s), 7.79-7.72 (4Η, m), 7. 67-7. 56 (3Η, m), 5. 7K1H, s) 4. 66 (2H, s), 3. 53 (2H, d? J = 4.  0Hz), 3.  49-3. 42 (6H, m), 3. 25 (3H, s), 3. 19 ~ 2.  93 (6H, m), 2.  06-1.  88 (6H, m) Infrared absorption spectrum cur1 (KBr): 2928, 2496, 1757, 1329, 1122 Mass analysis 0 8 8) 111/2 562 ((^ 4 + 11) +, free body) -122- 200401778 Element Analysis of 値 (C31H36F3N30rl / 2H20) Calculate 値: C: 56. 36; Η: 5. 65; F: 8. 63; Ν: 6. 36 Measured 値: C: 56 · 51; Η: 5.  41; F: 8.  79; Ν: 6.34. Example 9 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 3-benzyloxymethyl-1 -fluorene-3,8-diacryl [4,5] Dec-2-one and its fumarate (exemplified compound numbers 1-3 1 0) (9a) 8- {3-[(3-cyanophenyl) (3f-trifluorotoluene ) Methoxy] propyl} -3-benzyloxymethyl-1 -fluorene-3,8-diacspiro [4,5] dec-2-one, 8- {3 prepared using Example (8a) -[(3-Cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 1-fluorene-1,3,8-diacryl [4,5] dec-2-one 200 mg (0 . 42 millimoles) and 70 microliters of chloroform (0. 5 1 millimolar), the reaction and purification of Example (2a) were carried out to obtain 165 mg (66%) of the target compound. (9b) 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} -3-benzyloxymethyl-bucarpine-3,8-diacryl [4,5] dec. 2-ketofumarate The 8- {3-[(3 -cyanophenyl) (3 '-trifluorotolyl) methoxy group prepared in Example (9 a) ] Propyl 3-benzyloxymethyl-1-fluorene-3, 8-diacirospiro [4,5] dec-2-one 160 mg (0. 27 mmol) dissolved in 3 ml of ethyl acetate, and 3 mg of fumaric acid (0.1 mg 27 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 87 mg (47%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7. 94 (1H, s), 7.77-7 · 70 (4Η, m), 7. 66-7 · 55 (3Η, m), 7. 37-7 · 27 (5Η, m), 6.61 (2Η, s), 5.68 (1Η, s) 4.73 (2Η, s), 4. 48 (2H, s), 3. 45 (2H, d, J = 6. 7Hz), 3. 37 (2H, s), 2. 47-2. 36 (6H, m), 1. 7 9- 1.62 (6Η, m) Infrared absorption spectrum vmax cur1 (KBr): 2932, 2501, 1759, 1329, 1124 200401778 Mass analysis "8 8) 111/2 594 ((^ / [+:«) + , Free body) Elemental analysis (C37H38F3N30rH20) Calculation: C: 61. 07; Η: 5. 54; F: 7. 83; N: 5. 77 Found 値: C: 60 · 89; Η: 5.  17; F: 7. 94; Ν: 5.83. Example 1 〇3-ethyl-8- {3-[(3-trifluorotolyl) (3'-cyanophenyl) methoxy] propyl} -1 -fluorene-3,8-diacryl [4,5] dec-2-one and its fumarate (exemplified compound number 3-5 2) (10a) 3-ethyl-8- {3-[(3-trifluorotolyl) ( 3f-cyanophenyl) methoxy] propylbu 1-fluorene-3,8-diacylspiro [4,5] dec-2-one, 8- {3-[( 3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 1-fluorene-3, 8-diacryl [4,5] dec-2-one 1030 mg (2. 17 millimoles) and 336 microliters of ethyl iodide (4. 2 millimoles), the reaction and purification of Example (2a) can be performed to obtain the target compound 869 mg (80%). (10b) 3-ethyl-8- {3-[(3-trifluorotolyl) (3 · -cyanophenyl) methoxy] propylbu 1-fluorene-3,8-diazelop [ , 5] dec-2-one keto fumarate The 3-ethyl-8- {3-[(3-trifluorotolyl) (3 '-cyanophenyl) prepared in Example (10a) ) Methoxy] propyl bu 1-fluorene-3, 8-diaciro [4,5] dec-2-one 469 mg (0. 95 millimolar) and 10 ml of ethyl acetate, 108 mg of fumaric acid (0.  95 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 461 mg (80%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7. 95 (lH, s), 7. 52-7. 81 (7H, m), 6. 60 (2H, s), 5. 68 (1H, s), 3. 45 (2H, t, J = 5Hz), 3. 2'9 (2H, s), 3. 17 (2H, q, I = 7Hz), 2. 36 ~ 2. 60 (8H, m), 1.  65-1.  86 (4H, m), 1.  05 (3H, t, J = 7Hz) -124- 200401778 Infrared absorption spectrum Max cut1 (KBr): 1751, 1330, 1165, 1123, 1074 Mass analysis (FAB) m / z 502 ((Μ + Η) +, free Volume) Elemental analysis of plutonium (C31H34F3N30rQ · 5H20) Calculation of plutonium: C: 59. 44; Η: 5. 63; Ν: 6.  71 Found 値: C: 59.  17; Η: 5. 43; Ν: 6. Example 40 1 1 8- {2- [Bis ((3-trifluorotolyl) methoxy) ethyl] 3-methylsulfinamidinylmethyl-1 -fluorene-3,8-diacylspiro [ 4,5] dec-2-one and its fumarate (exemplified compound number 1-1 4 1) # (lla) 8- {2- [bis- (3-trifluorotolyl) methoxy ] Ethyl 3-methylsulfinylmethyl-1-fluorene-3, 8-diazepi [4,5] dec-2-one The 8- {2- [bis- (3-Trifluorotolyl) methoxy] ethyl 3-methylthiomethyl-1 -fluorene-3,8-diacryl [4,5] dec-2-one 4 grams (0.  7 1 1 millimolar) was dissolved in 8 ml of acetone / water (1/1), and ox one 0 was added under ice-cold stirring. 4 4 g (0.  7 1 1 millimolar), and stirred for 1 hour. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: dichloromethane / methanol = 1 0/1) to obtain the target compound.  1 4 5 g (yield 3 4.  3%) oily substance. (llb) 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3-methanesulfenylmethyl-1 -fluorene-3 5 8 -diacylspiro [4, 5] Dec-2-one keto fumarate. 8- {2-[bis- (3-trifluorotolyl) methoxy] ethyl}-3 -methyl prepared in Example (1 1 a) Sulfenylmethyl-1 -fluorene-3 5 8 -diaciro [4 5 5] dec-2-one 145 grams (0. 244 mmol) dissolved in 5 ml of ethyl acetate, added fumarate-125-200401778 diacid 0.  0 2 8 g (0.24 4 mmol) was left overnight. The crystals were filtered to obtain the target compound.  〇 7 9 grams (4 5.  7%). Nuclear magnetic resonance spectrum (400MHz, CD3OD) (5 ppm: 7. 76-7 · 54 (π, 8H), 5. 73 (s, 1H), 4. 66 (s, 2H), 3. 790, 2H, J = 5. 34 Hz), 3. 73 (s, 2H), 3. 33-3. 21 (m, 8H), 2.  99 (s, 3H), 2. 20-2.  03 (m, 4H) Infrared absorption spectrum vmax cnf1 (KBr): 1 756, 1435, 1331, 1166, 1126, 1073, 983 Mass analysis (FAB) m / z 595 ((M + H) +, free body). Example 1 2 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3 -methanesulfinylmethyl-1 -fluorene-3,8-diacylspiro [4 , 5] dec-2-one and its fumarate (exemplified compound number 1-1 3 7) (12a) 8- {2- [bis- (3_trifluorotolyl) methoxy] ethyl Gib 3-methanesulfinylmethyl-1 -fluorene-3,8-diacirospiro [4,5] dec-2-one. The 8- {2- [bis- (3) prepared in Example (2a) -Trifluorotolyl) methoxy] ethyl}-3 -methylthiomethyl-1-fluorene-3,8 -diacryl [4,5] dec-2 -one 0. 4 grams (0.  7 1 1 millimolar) was dissolved in 4 ml of acetone / water (1/1), and 0 × 〇n e 0. 2 1 9 grams (0. 3 5 6 mmol), stir for 30 minutes. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: dichloromethane / methanol = 5 0/1) to obtain the target compound 0.156 g (yield 38.0%) as an oily substance. (12b) S- {2- [Bis ((3-trifluorotolyl) methoxy) ethyl] 3-methylsulfinylmethyl-1 -fluorene-3,8-diacylspiro [4,5 ] Dec-2-one ketofumarate-126- 200401778 8- {2-[bis- (3 -trifluorotolyl) methoxy] ethyl 3 prepared in Example (1 2 a) -Methanesulfenylmethyl-1-fluorene-3,8-diaciro [4,5] dec-2-one 156 grams (0. 270 mmol) dissolved in 5 ml of ethyl acetate, added fumaric acid 0.  0 3 1 g (0.  270 mmol), and left overnight. The crystals were filtered to obtain the target compound.  〇9 grams (48 · 1%). Nuclear magnetic resonance spectrum (4_Hz, CD30D) δ ppm: 7. 76-7 · 54 (π, 8H), 5. 72 (s, 1H), 4. 57 (d, 1H, J = 13. 6 Hz), 4. 43 (d, 1H, J = 13. 6 Hz), 3. 78 (t, 2H, J = 5. 16 Hz), 3.  71 (q, 2H, J = 8.  71 Hz), 3. 22 (t, 4H, J = 5.  16 Hz), 3. 15-3.  04 (m, 2 H), 2. 67 (s, 3H), 2. 24-2. 01 (m, 4H) Infrared absorption spectrum vmax cnf1 (KBr): 1750, 1435, 1331, 1 259, 1 1 66, 1 1 24, 1073, 983 Mass analysis (FAB) m / z 579 ((M + H) +, Free body). Example 1 3 3 -Methyl- [bis- (4-fluorophenyl) methoxy] ethyl 1-fluorene-3, 8-diazepi [4,5] dec-2-one and its grass Acid salt (Exemplified compound number 3-9) (13a) 8- [2-bis (4-fluorophenyl) methoxyethyl] -1-fluorene- 3,8-diazepi [4,5] 2-ketone using 1-pyrene-3 5 8 -diaciro [4 5 5] dec-2-one ketone hydrochloride 800 mg (4. 15 mmol) and bis- (4-fluorophenyl) methyl 2-chloroethyl ether 1 prepared in Reference Example 5.  2 9 grams (4. 56 mmol), reaction and purification in the same manner as in Example (1 a), and 1.24 g (74%) of the target compound were obtained. (13b) 3-methyl-8- {2- [bis- (4-fluorophenyl) methoxy] ethyl 1-fluorene-3,8-diacryl [4,5] dec-2-2 The ketone prepared the 8- {2-[bis- (4-fluorophenyl) methoxy] ethyl} prepared in Example (1 3 a) -1 -P 萼 -3,8-diacylspiro [4,5 ] Dec-2-2 ketone 118 mg (0.29 mmol) and methyl-127-200401778 20 microliters of base iodine (0. 32 millimoles), and the reaction and purification were performed in the same manner as in Example (2a), and 75 mg (60%) of the target compound was obtained. (13c) 3-methyl-8- {2- [bis- (4-fluorophenyl) methoxy] ethyl 1-fluorene-3,8-diacryl [4,5] dec-2- The ketooxalate salt is 3-methyl 8- {2- [bis- (4-fluorophenyl) methoxy] ethyl 1-fluorene-3,8-diacryl [ 4,5] dec-2-one 75 mg (0. 18 mmol) dissolved in 5 ml of ethyl acetate, 16 mg of oxalic acid (0. 18 millimoles) and left overnight at room temperature. The crystals were collected by filtration to obtain 74 mg (80%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (4_Hz, DMS〇-d6) δ ρρη: 7.34-7 · 46 (4Η, m), 7.12_7. 25 (4Η, m), 5. 56 (1Η, s), 3. 62 (2Η, t, J = 5Hz), 3. 35 (2H, s), 2. 92-3. 38 (4H, m), 2. 75 (3H, s), 2. 50 (2H, t), 1.  86-2.  03 (4H, m), infrared absorption spectrum vmax cnf1 (KBr): 1754, 1603, 1507, 1408, mass analysis (? 8) 111/2417 ((1 ^ +: «) +, free body) elemental analysis 値(C25H28F2N20?) Calculate 値: C: 59. 28; Η: 5. 57; N: 5. 53 Found 値: C: 58. 52; Η: 5. 34; N: 5. 48〇 Example 1 4 8- {2- [Bis- (4-fluorophenyl) methoxy] ethylbspiro [(8-azinebicyclo [3. 2. 1] octane) -3,5 1-oxazolidine] -2 ′ -one (exemplified compound number 1-9 1) Spiro [(8 -azine bicyclic [3.  2 .  1] octane) · 3,5 ′ -oxazolidine] -2f -one 103 mg (0. 47 mmol) and 133 mg of bis (4-fluorophenyl) methyl 2-chloroethyl ether prepared in Reference Example 5 (0. 47 millimoles), and reacted and purified in the same manner as in Example (1a) to obtain 110 mg (55%). -128- 200401778 Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) (5ppn): 7. 19-7. 48 (4H, in), 6. 96-7. 10 (4H, m), 5. 33 (1H, s), 5. 30 (1H, s), 3. 54 (2H, t, J = 6Hz), 3. 18-3. 54 (4H, m), 2. 63 (2H, t, J = 5Hz), 1.  84-2.  22 (8H, m) Infrared absorption spectrum vmax cnf1 ⑽r): 1740, 1508, 1260, 1222, 1079 Mass analysis (FAB) m / z 429 ((M + H) +, free body). Example 1 5 8- {2- [Bis ((3-trifluorotolyl) methoxy) ethyl] spiro [(8-azinebicyclo [3.  2 · 1] octane) -3,5 ′ -oxazolidine] -2 ′ -one (Exemplified compound number 1-1 7 9) Spiro [(8 -azine bicyclic [3.  2 .  1] octane) -3,5 1 -oxazolidine; 1-2 '-one 1240 mg (1. 32 millimoles) and 600 mg of bis (3-trifluorotolyl) methyl 2-chloroethyl ether prepared in Reference Example 2 (1. 32 millimoles), the reaction and purification were performed in the same manner as in Example (1a) to obtain the target compound 62 2 mg (49%). Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 67-7. 42 On, 8H), 5. 46 (s, 1H), 5. 12 (s, 1H), 3. 65-3. 53 (m, 2H), 3.  36-3. 20 (m, 4H), 2.  73-2. 58 (m, 2H), 2.  24-1.  81 (m, 8H) Infrared absorption spectrum vmax cm · 1 (CDC13) :, Π50, 1489, 1449, 1420, 1331 Mass analysis (FAB) m / z 5 2 9 ((M + H) +, free body). Example 1 6 8- {3-[(3-cyanophenyl) (3f-trifluorotolyl) methoxy] propylbu 3-methyl-1-oral-3,8-diacryl [ 4,5] dec-2-one and its oxalate (exemplified compound number 3-5 0) (16a) 8- {3-[(3-cyanophenyl) (3 ^ trifluorotolyl) methoxy ] Propylbu 3-methyl-1 -fluorene-3,8-diaciro [4,5] dec-2-one A 3-[(3-cyanophenyl) (3'- Trifluorotolyl) methoxy] propanol 300 mg (0.  90 mmol) was dissolved in 3 ml of dichloromethane, and 188 µl of triethylamine (1. 35 millimoles) and 90 microliters of mesylate (1.  17 millimoles). After stirring under ice-cooling for 30 minutes, it was sequentially washed with water and saturated brine. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained methanesulfonic acid- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} ester 372 mg (0. 90 millimoles) dissolved in 5 ml of dimethylacetamide, and added to the 3-methyl-1 -fluorene-3,8-diacridyl [4,5] dec-2-one hydrochloride prepared in Reference Example 6 222 mg of salt (1. 07 millimoles), potassium carbonate 248 mg (1. 80 millimolar) and potassium iodide 15 mg (0. 0.01 millimolar), stirred at 10 Ot: 6 hours. After the reaction was completed, water was added at room temperature and extraction was performed twice with ethyl acetate. The organic layer was combined, washed with water and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash chromatography (eluent: methanol: dichloromethane = 5: 95) to obtain the target compound 246 mg (56%). (16b) 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 3-methyl-1 -fluorene-3,8-diacryl [4 5 5] dec-2-one ketooxalate The 8- {3-[(3-cyanophenyl) (3 ~ trifluorotolyl) methoxy] propyl} -3-prepared in Example (16a) Ethyl-1-pyrene-3,8-diazepi [4,5] dec-2-one 240 mg (0. 49 millimoles) dissolved in 3 ml of ethyl acetate, 44 mg of oxalic acid (0.  4 9 mmol), and left overnight at room temperature. The crystals were collected by filtration to obtain 235 mg (82%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) ό ppm: 7. 94 (2H, η), 7. 79-7.  56 (6H, m), 5. 70 (1H, s), 3. 52 ~ 3. 40 (2H, m), 3. 36 (2H, s), 3. 22-2. 91 (6H, m), 2. 75 (3H, s), 2. 03-1. 86 (6H, m) Infrared absorption spectrum cnf1 (KBr): 2501, 1756, 1405, 1329, 1121 Mass analysis (FAB) m / z 4 8 8 ((M + H) +, free body) -130- 200401778 element Analyze 値 (c28h3 () f3n3o?) Calculate 値: C: 58. 23; H: 5. 24; F: 9. 87; Ν: 7 · 28 Found: C: 58. 00; Η: 5.13; F: 9. 89; Ν: 6. 67. Example 1 7 8- {2- [Bis ((3-trifluorotolyl) methoxy) ethyl] 3-methyl-1-methyl-3,8-diacylspiro [4,5] dec- 2-ketones and their acid salts (Exemplified Compound Number 3.  1 7) (17a) 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3-methyl-1-fluorene-3,8-diacylspiro [4,5 ] Dec-2 -one The bis- (3-trifluorotolyl) methyl 2-chloroethyl ether prepared in Reference Example 2 260 mg (0. 68 millimoles) dissolved in 5 ml of dimethylacetamide, and 3-methyl-1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride prepared in Reference Example 6 Salt 168 mg (0. 81 millimoles), potassium carbonate 188 mg (1.36 millimoles), and potassium iodide 15 mg (0. 0.01 millimolar), and stirred at 100 ° C for 10 hours. After the reaction was completed, water was added at room temperature and extraction was performed twice with ethyl acetate. Combine the organic layers, rinse with water, saturated brine, and dry under sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash chromatography (eluent: methanol: dichloromethane = 5: 95) to obtain the target compound 318 mg (91%). (17b) 8- {2- [Bis- (3-trifluorotolyl) methoxy] ethyl 3-, 1-methyl-1-fluorene-3,8-diacylspiro [4 5 5] dec-2 -Ketooxalate 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl 3-, 3-methyl-triazole-3, 8-diazine prepared in Example (17a) Spiro [4,5] dec-2-one 310 mg (0. 60 mmol) was dissolved in 3 ml of ethyl acetate, and 54 mg (0.5 mg) of oxalic acid was added. 60 mM) and left at room temperature overnight. The crystals were collected by filtration to obtain 3 1 1 mg (85%) of the target compound as white crystals. 200401778 Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) (5 ppm: 7. 80 (2H, jn), 7.  73-7. 60 (6H, m), 5. 82 (1H, s), 3. 67 (2H, t, J = 5. 2Hz), 3. 34 (2H, s), 3. 14-2. 87 (6H, m), 2.  75 (3H, s), 1. 97-1.  85 (4H, m) Infrared absorption spectrum vmax cuf1 (KBr): 2928, 2501, 1 755, 1331, 1123 Mass analysis (FAB) m / z 517 ((M + H) +, free body) Elemental analysis (C27H28F6N207) ) Calculate 値 · C: 53_47; Η: 4. 65; F: 18. 79; N: 4.  62 Found 値: C: 53. 33; H: 4.  54; F: 20.  39; N: 4.63. Example 1 8 3- (2-methoxyethyl) -8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -1-fluorene-3,8-diacryl [4,5] Dec-2-one and its oxalate (exemplified compound number 3-23) (18a) 3- (2-methoxyethyl) -8- {2- [bis- (3-trifluoro Tolyl) methoxy] ethyl 1-fluorene-3 5 8 -diacylspiro [4,5] dec-2-one, 8- {2- [bis- (3- Trifluorotolyl) methoxy] ethyl 1-fluorene-3,8-diacylspiro [4,5] dec-2-one 158 mg (0. 31 millimoles) and 58 microliters of 2-methoxyethyl bromide (0. 54 millimolars), the reaction of Example (2a) was performed and purified to obtain 85 mg (49%) of the target compound. (18b) 3- (2-methoxyethyl) -8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl}-1-fluorene-3,8-diacryl [ 4,5] Dec-2-one ketooxalate The 3- (2-methoxyethyl) -8- {2- [bis- (3-trifluorotolyl) methoxy group prepared in Example (18a) Yl] ethyl} -1-fluoren-3, 8-diazepi [4,5] dec-2-one 85 mg (.  15 millimoles) and left overnight at room temperature. The crystals were collected by filtration to obtain 77 mg (78%) of the target compound as white crystals. -132- 200401778 Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) δ ppm: 7. 60-7. 80 (8H, m), 5. 82 (1H, s), 3. 68 (2H, t, J = 5Hz); 3. 46 (2H? T? J = 5Hz), 3. 40 (2H, s), 3. 31 (2H, t, J = 5H z), 3. 25 (3H, s), 2.  90-3. 25 (6H, m), 1.  85-2.  00 (4H, m) Infrared absorption spectrum vmax cnr1 (KBr): 1754, 1331, 1167, 1122 Mass analysis (FAB) m / z 561 ((M + H) +, free body) Elemental analysis 値 (C29H32F6N207) Calculation 値C: 53.54; Η: 4. 96; Ν: 4. 31 Found 値: C: 53. 44; Η: 4.  90; Ν: 4.24. Example 1 9 8- {3- [Bis ((4-fluorophenyl) methoxy] propyl) 3-ethyl-1-fluorene-3,8-diacyl ^ spiro [4,5] dec- 2-ketone and its oxalate (exemplified compound number 3-12) (19 &) 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -bumin-3,8- Diazaspiro [4,5] dec-2-one was prepared using 1-fluorene-3,8-diasciro [4,5] dec-2-one ketone hydrochloride 86 mg (0. 45 mmol) and bis- (4-fluorophenyl) methyl 3-chloropropyl ether prepared in Reference Example 7 (1.4 mg) 4 9 1 mol), the reaction and purification were carried out in the same manner as in Example (1 a) to obtain 11 1 mg (60%) of the target compound. φ (19b) 8- {3- [bis- (4-fluorophenyl) methoxy] propylbuthyl 3 · ethyl-buthyl-3,8-diacryl [4,5] dec-2- The ketone uses 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-fluorene-3, 8-diazelop [4,5] decane prepared in Example (19a) -2-one 0. 15 grams (0. 36 mmol), tetrabutylammonium iodide 13. 3 mg (0. 036 mmol) and ethyl iodide 0. 0432 ml (〇.  54 millimolars), and the reaction was performed in the same manner as in Example (2a) and purified to obtain the target compound 83 mg (51. 8%). -133- 200401778 (19c) 8- {3- [bis- (4-fluorophenyl) methoxy] propylbutan 3 -ethyl-1-fluorene- 3,8-diazepiro [4,5] Dec-2 -one ketooxalate The 8- {3- [bis- (4-fluorophenyl) methoxy] propyl) -3-ethyl-1-fluorene- 3, 8-Diacyl [4,5] dec-2-one 83 mg (0. 187 mmol) was dissolved in 3 ml of ethyl acetate, and oxalic acid 17 was added.  8 mg (0.  1 8 7 mol) and left at room temperature overnight. The crystals were collected by filtration to obtain the target compound 61 1 mg (59. 5%). Nuclear magnetic resonance spectrum (400MHz ^ CD30D) δ ppm: 7.  40-7.  33 (m, 4H), 7.  09-7.  01 (m, 4H), 5. 42 (s, 1H), 3.  61-3.  30 (m, 3H), 3. 45 (s, 2H), 3. 35-3. 20 (m, 8H), 2. 18-2. 05 (m, 6H), 1. 16 (t, 3H, J = 7. 29 Hz) Infrared absorption spectrum vmax cnf1 (KBr): 1741, 1729, 1604, 1 506, 1221 Mass analysis (FAB) m / z 445 ((M + H) +, free body). Example 2 0 8- {3- [Bis ((4-fluorophenyl) methoxy) propyl] 3-methylthiomethyl-1-Pfluorene-3,8-diazepi [4,5] Decane-2 -one and its oxalate (exemplified compound numbers 1-6 2) (20a) 8- {3- [bis- (4-fluorophenyl) methoxy] propyl 3-methylthiomethyl -1- 噚 -3 5 8 -diacspiro [4,5] dec-2-one, using 8- {3- [bis- (4-fluorophenyl) methoxy] propyl, prepared in Example (19a) Gib 1- 噚 -3, 8-dipyrospiro [4,5] dec-2-one 0. 15 grams (0. 36 millimoles), tetrabutylammonium iodide 1 3.3 mg (0.036 millimoles) and methylthiomethyl chloride 0 · 0 4 5 3 milliliters (0. 54 millimoles), and reacted and purified in the same manner as in Example (2a) to obtain 60 mg (51. 8%) of the target compound. (20b) 8_ {3- [bis- (4-fluorophenyl) methoxy] propyl} -3-methylthiomethyl-bucarpine-3,8-bisacylspiro [4,5] dec-2 -Ketooxalate-134- 200401778 8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -3 -methylthiomethyl-1 -fluorene prepared in Example (20a) -3,8-Diaciro [4,5] dec-2-one-6 mg (0 · 1 2 6 mmol) was dissolved in 3 ml of ethyl acetate, and oxalic acid was added 1 1.  3 mg (0.  1 2 6 mol)) and left at room temperature overnight. The crystals were collected by filtration to obtain 39 mg (54.7%) of colorless crystals of the target compound. Nuclear magnetic resonance spectrum (400MHz, CD3OD) 0ppm: 7. 39-7. 33 (m, 4H), 7. 09-7. 02 (in, 4H), 5. 43 (s, 1H), 4. 42 (s, 2H), 3. 63-3. 45 (m, 4H), 3. 35-3. 20 (in, 6H), 2. 22-2 · 05 (ηι, 9H) Infrared absorption spectrum vmax cur1 (KBr): 1753, 1604, 1 507, 1427, 1405, 1 252, 1 2 2 2 钃 Mass analysis (FAB) m / z 477 ((M + H) +, free body). Example 2 1 8- {2- [Bis- (4-fluorophenyl) methoxy] ethylbu 3 -ethyl-1-fluorene-3, 8-diacylspiro [4,5] dec-2 -Ketone (Exemplified compound number 3-1 1) 8- [2-bis (4-fluorophenyl) methoxyethyl] -1-fluorene-3, 8-diacryl prepared in Example (13a) [ 4,5] dec-2-one 15 grams (0. 371 mmol), tetrabutylammonium iodide 13.8 mg (0. 037 mmol) and ethyl iodide 0. 045 ml (0. 49 millimoles), the reaction was carried out in the same manner as in Example (2a), and the target compound 123 mg (63. 4%) was purified. Nuclear magnetic resonance spectrum (400MHz, CDCl3) 5ppm: 7. 52-7. 25 (m, 6H), 7. 04-6. 98 (m, 2H), 5. 33 (s, 1H), 3. 56 (t, 2H, J = 5.89 Hz), 3. 32 (q, 2H, J 2 7 · 28 Hz), 3.  25 (s, 2H), 2. 71 (t, 2H, J = 5. 89 Hz), 2.  62-2. 55 (m, 4H), 1.  95-1.  72 (m, 4H), 1. 15 (t, 3H, J = 7. 28 Hz) Infrared absorption spectrum vmax cnT1 (CDC13): 1 748, 1604, 1507, 1222 Mass analysis (FAB) m / z 431 ((M + H) +, free body). -135- 200401778 Example 2 2 3 -Methyl-8-{3-[bis- (4-fluorophenyl) methoxy] propyl 1-fluorene-3, 8 -diacylspiro [4,5 ] Dec-2-one and its oxalate (exemplified compound number 3-1 0) (22a) 3-methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1-Hydroxy-3,8-diacspiro [4,5] dec-2-one was prepared using 8- {3- [bis- (4-fluorophenyl) methoxy] propane prepared in Example (19a) Gib 1 -fluorene-3 5 8 -diaciro [4 5 5] dec-2 -one 197 mg (0.47 mmol) and methyl iodide 4 4 microliters (0. 7 1 millimolar), reaction and purification were performed in the same manner as in Example (2a) to obtain 122 mg (60%). (22b) 3-methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl 1-fluorene-1,3,8-diacylspiro [4,5] dec-2- Ketooxalate is prepared from the methyl 3-methyl-8- {3- [bis- (4-fluorophenyl) methoxy] propyl group 1-fluorene-3, 8-diazine prepared in Example (22a). Spiro [4,5] dec-2-one 122 mg (0. 28 mmol) dissolved in 10 ml of ethyl acetate, 26 mg of oxalic acid (0. 28 millimoles) and left overnight at room temperature. The crystals were collected by filtration to obtain 95 mg (64%) of white crystals of the target compound. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7.  35-7. 45 (4H, m), 7. 12-7. 23 (4H, m), 5. 51 OH, s); 3. 42 (2H? T? J = 5Hz), 3. 38 (2H, s), 3. 00-3. 21 (4H, m), 2. 76 (3H, s), 2. 50 (2H, t, J = 5Hz), 1. 90-2. 10 (6H, m) Infrared absorption spectrum vmax cnfi (KBr): 1748, 1604, 1505, 1440, 1408 Mass analysis (FAB) m / z 431 ((M + H) +, free body) Elemental analysis 値 (C24H28F2N203, 1 3 / 9C2H204) Calculate 値: C: 57. 62; H: 5. 55; N: 5.  00 Actual measurement: C: 57. 78; H: 5. 50; N: 4.  59〇200401778 Example 2 3 3- (2-Methoxyethyl) -8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -BuH-3,8-diazine Spiro [4,5] dec-2-one and its oxalate (exemplified compound number 3-16) (23a) 3- (2-methoxyethyl) -8- {3- [bis- (4-fluoro Phenyl) methoxy] propyl} -1 -fluorene-3,8-diacylspiro [4,5] dec. 2-ketone 8- {3- [bis- (4) prepared using Example (19a) -Fluorophenyl) methoxy] propylbu 1-P-N-3,8-diaciro [4,5] dec-2-one 225 mg (0. 54 millimoles) and 5-methoxyethyl bromide 56 microliters (0.5 60 millimolars), 50 mg (20%) of the target compound were reacted and purified in the same manner as in Example (2a). (23b) 3- (2-methoxyethyl) -8- {3- [bis- (4-fluorophenyl) methoxy] propyl} -1 -fluorene-3 5 8 -diacryl [VII 5] dec-2-ketooxalate The 3-(2-methoxyethyl) -8-{3-[bis- (4-fluorophenyl) methoxy] propane prepared in Example (2 3) Base} -1-fluorene-3, 8-diacspiro [4,5] dec-2-one 50 mg (0.11 mmol) was dissolved in 5 ml of ethyl acetate, and 9 mg of oxalic acid (0 · 1 1 mol), and left at room temperature overnight. The crystals were collected by filtration to obtain 84 mg (74%) of white crystals of the target compound. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) 0ppin: 7. 35-7. 45 (4H, m), 7. 12-7. 20 (4H, m), 5. 49 (1H, s), 3. 46 (2H, t, J = 5Hz), 3. 36-3. 42 (5H, m), 3. 31 (2H, t5 J = 5Hz), 3. 26 (2H, s), 2. 90-3. 20 (6H, m), 2. 5K2H, t, J = 5Hz), 1. 80-1.  98 (4H, m) Infrared absorption spectrum vmax cr1 (KBr): 1746, 1728, 1506, 1221, 1117 Mass analysis (FAB) m / z 47 5 ((M + H) +, free body) Elemental analysis 値 (C26H32F2N204 , 5 / 4C2H204) Calculate 値: C: 58. 31; H: 5. 92; N: 4. 77 Found 値: C: 58. 60; H: 5.  56; N: 4.  75〇200401778 Example 2 4 8- {3- [Bis ((3-trifluorotolyl) methoxy) propyl] 3-methyl-1-fluorene- 3,8-diazepi [4,5 ] Dec-2-one and its oxalate (exemplified compound number 3-1 8) (24a) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 3-methyl 1- 噚 -3,8-diacryl [4,5] dec-2-one The 8- {3- [bis- (3-trifluorotolyl) methoxy] prepared in Example (19a) Propyl} -1-fluorene-3, 8-diacryl [4,5] dec-2-one 300 mg 58 millimoles) and 54 microliters of methyl iodide (0. 87 millimolar), the reaction was performed in the same manner as in Example (2a), and the target compound was 253 mg (82%). (24b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3 -methyl-1-fluorene-3 5 8 -diacryl [4,5] dec- 2-ketooxalate The 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 3-methyl-1-fluorene-3 prepared in Example (2 4 a), 8-Diacillyl [4,5] dec-2-one 240 mg (0. 45 mmol) dissolved in 3 ml of ethyl acetate, 41 mg of oxalic acid (0. 45 millimolar) and left at room temperature overnight. The crystals were collected by filtration to obtain 217 mg (77%) of the target compound as white crystals. . Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7. 87 (2H, s), 7.74-7.59 (6Η, m), 5. 76C1H, s) 3.47 (2Η, t, 5 · 8Ηζ), 3.36 (2Η, s), 3.2 · 2.9 (89Η, m), 2. 7 5 (3H, s), 2. 00-1. 87 (6H, m) Infrared absorption spectrum vmax cnf1 (KBr): 2926, 2505, 1 755, 1330, 1123 Mass analysis (FAB) m / z 531 ((M + H) +, free body) Elemental analysis 値 (C28H3 () F with 207) Calculation 値: C: 54. 20; Η: 4. 87; F: 18. 37; N: 4. 51 Found 値: C: 53 · 78; Η: 4.68; F: 18. 08; N: 4. 51. 200401778 Example 2 5 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1 -fluorene-3,8-diazine Spiro [4,5] dec-2-one and its oxalate (exemplified compound number 1-1 6 9) (25a) 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl } -3- (furan-2-ylcarbonyl) -1 -fluorene-3,8-diacspiro [4,5] dec-2-one, 8- {2- [bis -(3-trifluorotolyl) methoxy] ethyl} -1-fluorene-3, 8-diacryl [4,5] dec-2-one 200 mg (0. 39 millimoles) and 59 microliters of propidium chloride 58 millimoles), the reaction was performed in the same manner as in Example (lb) and the target compound was purified by 234 mg (98%). (25b) 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-fluorene-3,8-diazelopi [ 4,5] Dec-2-one oxalate The 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl group prepared in Example (25a) 3-(furan-2- Carbonyl) -1 -fluorene-3,8-diacryl [4,5] dec-2-one (220 mg 37 millimoles) was dissolved in 3 ml of ethyl acetate, and 33 mg of oxalic acid (0.08 mg) was added.  37 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 165 mg (65%) of the target compound as white crystals. Nuclear fe resonance spectrum (400MHz, DMS〇-d6) δ ppm: 8. 00 (1H, d, J = 1. 8Hz), 7. 81 (2H, s), 7. 74-7. 61 (4H, m), 7. 46 (1H, d, J = 3. 5Hz), 6. 71 (1H, dd, J = 1. 8 Hz, 3. 5Hz), 5. 83 (1H, s), 3. 95 (2H, s), 3. 69 (2H, t, J = 5. 0Hz), 3. 15-2. 83 (6H, m), 2. 14-1.  96 (4H, m) Infrared absorption spectrum vmax cnf1 (KBr): 2499, 1789, 1 667, 1330, 1123 Mass analysis (FAB) m / z 597 ((M + H) +, free body) Elemental analysis 値 (C31H28F6N209 ) Calculate 値: C: 54. 23; Η: 4. 11; F: 16. 60; N: 4.  08 Found: C: 53. 85; H: 4. 01; F: 16. 37; N: 4.  05. 200401778 Example 2 6 8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethylbu 3 -ethyl-1-fluorene-3, 8-diacylspiro [4,5 ] Dec-2-one (Exemplified Compound Numbers 3-9 9) (26 &) 8- {2- [bis- (354-difluorophenyl) methoxy] ethyl} -1-fluorene-3,8 -Bis-spiro [4,5] dec-2--one Ketone 1-prepared using Reference Example 1-螺 · 3,8-bis-acryl [4,5] dec-2--one hydrochloride 150 mg (0. (78 mmol) and (3, 4-difluorophenyl) benzyl 2-chloroethyl ether 220 mg (0. 78 millimolars), the reaction was performed in the same manner as in Example (1a) and purified to obtain the target compound 232 mg (74%). (261〇8- {2- [bis- (3,4-difluorophenyl) methoxy] ethyl} -3-ethyl-1-fluorene-3 5 8 -diazepi [4,5] Dec-2 -one was used as the 8- {2- [bis- (3,4-difluorophenyl) methoxy] ethyl} prepared in Example (26a). [4,5] Dec-2-one 0. 20 grams (0. 45 millimolar), tetrabutylammonium iodide 16. 8 mg (45. 6 mmol) and ethyl iodide 0. 055 ml (0. 68 millimoles), followed by reaction and purification of Example (2a) to obtain the target compound 130 mg (61.  1 % ). Nuclear magnetic resonance spectrum (400MHz, CDC13) 5 ppm: 7.15-6. 95 (ιη, 6H), 5. 28 (s, 1H), 3. 60 (br s, 2H), 3. 32 (q, 2H, I = 7. 27 Hz), 3. 27 (s, 2H), 2. 90-2. 43 (m, 4H), 2. 00-1. 40 (m, 6H), 1.  16 (t, 3H, J = 7. 27 Hz) Infrared absorption spectrum vmax cnf 丨 (CDC13): 1749, 1611, 1515, 1434, 1279 Mass analysis (FAB) m / z 467 ((M + H) +, free body). Example 2 7 8- {2- [Bis- (3,4-difluorophenyl) methoxy] ethylb 3-methoxymethyl-1-fluorene-3,8-diacylspiro [4, 5] Dec-2-one (Exemplified compound number 3-1 0 1) -140- 200401778 Using 8- {2- [bis- (3,4-difluorophenyl) methoxy group prepared in Example (26 a) [Yl] ethylfluoren-3, 8-diacylspiro [4,5] dec-2-one 20 grams (0. 45 millimolar), 168 mg tetrabutylammonium iodide 6 mmol) and chloromethyl methyl ether 0. 052 ml (0. 68 millimoles), the reaction was performed in the same manner as in Example (2a), and the target compound was 103 mg (46. 8%). Nuclear magnetic resonance spectrum (400 MHz, CDC13) 5 ppm: 7. 2 Bu 6. 95 (m, 6H), 5. 28 (s, 1H), 4. 69 (s, 2H), 3. 59 (br s, 2H), 3. 39 (s, 3H), 3. 34 (s, 2H), 2. 91-2. 49 (m, 4H), 2.  05-1.  40 (m, 6H) Infrared absorption spectrum vmax cnf1 (CDC13): 1 754, 1611, 1515, 1434, 1278 Mass analysis (FAB) m / z 483 ((M + H) +, free body). Example 2 8 8- {2- [bis- (3-cyanophenyl) (3f-trifluorotolyl) methoxy] ethyl} -3- (furan-2-ylcarbonyl) -1-fluorene- 3, 8-Diaciro [4,5] dec-2-one (Exemplified compound number 1-3 0 5) (28a) 8- {2- [bis- (3-cyanophenyl) (3'-tri Fluorotolyl) methoxy] ethyl} -1 -fluorene-3,8-diacylspiro [4,5] dec-2-one, 1-fluorene-3,8-diacridyl, prepared in Reference Example 1 [4,5] Decane-2-one hydrochloride 204 mg (1. 06 millimoles) and (3-cyanophenyl) (3 * -trifluorotolyl) methyl 2-chloroethyl ether 300 mg (0. 88 millimoles), and the reaction was performed in the same manner as in Example (1a) and purified to obtain 130 mg (32%) of the target compound. Nuclear magnetic resonance spectrum (400MHz, CDC13) ό ppm: 7. 69 (1H, S), 7. 60 (1H, s), 7. 43 -5. 59C6H, m), 5. 34 (1H, s), 3. 59 (2H, t, J = 5. 7 Hz), 3. 34 (2H, s), 2. 7K2H, t, J = 5. 7 Hz), 2. 55-2. 67 (4H, m), 1.  95-2.  03 (2H, m), 1. 75-1.  84 (2H, m) Infrared absorption spectrum vmax cnf1 (KBrh 3268, 2923, 2330, 1750, 1328, 1126 Mass analysis 0 8 6) 111 / 246〇 (("+:«) +, free body) -141- 200401778 Elemental analysis 値 (c24h24f3n3o5) Calculate 値: C: 62. 74; H: 5. 27; N: 9.  15; F: 12. 40 Found 値: C: 62. 52; Η: 5. 08; Ν: 8. 60; F: 12. 34〇 (28b) 8- {2- [bis- (3-cyanophenyl) (3 ~ trifluorotolyl) methoxy] ethyl} -3-(furan-2-ylcarbonyl) -1-噚-3,8-Diacyl [4,5] dec-2-one was prepared using 8- {2- [bis- (3-cyanophenyl) (3'-trifluorotolyl)) prepared in Example (28a). Methoxy] ethyl} -1-fluoren-3,8-diacryl [4,5] dec-2-one 0,100 g (0. 211 millimoles), n-butyllithium (1. 59N), 0. 20 ml (0. 317 mmol) and 2-decanoyl chloride.  〇4 1mL (〇. 422mmol), the reaction was performed in the same manner as in Example (1b) and the target compound 65 was purified. 0 mg (5 4. 2 % ). Nuclear magnetic resonance spectrum (400M 谱 ζ, 0) (: 13) δρρη: 7.66-7 · 41 (ιη, 10Η), 6.58-6 · 5 7 (m, 1H), 5. 41 (s, 1H), 3. 92 (s, 2H), 3. 61-3. 47 (m, 2H), 3. 10-2. 55 (m, 4H), 2.  32-1. 61 (m, 8H) Infrared absorption spectrum vniax cnf1 (CDC13): 1 785, 1 674, 1470, 1377, 1330, 1 229, 1165, 1124 Mass analysis (FAB) m / z 568 ((M + H) +, Free body). Example 2 9 3 -Ethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl 1-fluorene-3, 8-diazelop [4,5] dec- 2-ketone and its oxalate (exemplified compound number 3-19) (29a) 3-ethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl 1-fluorene -3 5 8 -Diaciro [4 5 5] dec-2 -one 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl prepared in Example (2 5 a) 210 mg of pyrene-3, 8-diacspiro [4,5] dec-2-one (0_42 mmol) and 67 μl of ethyl iodide (0.  84 millimolar), the reaction was performed in the same manner as in Example (2a) -142-200401778, and the target compound was purified in an amount of 196 mg (88%). (29b) 3-Ethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -1-fluorene-3,8-diazelop [4,5] dec- 2-ketooxalate The 3-ethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl}-1 -fluorene-3,8 prepared in Example (29a) -Diacron [4,5] dec-2-one 196 mg (0.  38 mmol) was dissolved in 2 ml of methanol, and 33 mg of oxalic acid (0. 38 mmol), isopropanol, and left at room temperature overnight. The crystals were collected by filtration to obtain 180 mg (79%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) δ ppm: 7.60-7.80 (8Η, m), 5. 83 (1H, s), 3.  68 (2H, t, J = 5Hz), 3. 35 (2H, s), 3.  18 (2H, q, J = 7Hz), 2. 90-3. 20 (4H, m), 2. 5K2H, t, J = 5Hz), 1. 87-2. 00 (4H, m), 1. 06 (3H, t, J = 7Hz) Infrared absorption spectrum / max ciif1 (KBr): 1 755, 1331, 1167, 1123, 1074 Mass analysis (FAB) m / z 531 ((M + H) +, free body ) Elemental analysis (C27H3 () F & N207) Calculation: C: 54. 20; Η: 4. 87; N: 4. 51 Found 値: C: 54. 01; Η: 4.  61; N: 4.48. Example 3 Ο 8- {3- [bis- (3-trifluorotolyl) methoxy] propylbutan 3-methoxymethyl-1-fluorene-3, 8-diazepi [4,5] Dec-2-one and its oxalate (exemplified compound number 3-22) (30 a) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3-methoxy Methyl-1 -fluorene-3,8-diΠΥspiro [4 5 5] dec-2-one, using 8- {3- [bis- (3-trifluorotolyl) methoxy, prepared from Example (3a) Propyl] propylbu 1-fluorene-3, 8-diacylspiro [4,5] dec-2-one 30 grams (0. 581 millimolar) -143- 200401778, tetrabutylammonium iodide 21. 0 mg (58. 1 mmol) and chloromethyl methyl ether 0. 13 ml (1. 47 millimoles), reaction and purification were performed as in Example (2a) to obtain 124 mg (38.  1 %). (30b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3-methoxymethyl-1 -fluorene-3 5 8 -diacylspiro [4 5 5] Decano-2-ketooxalate The 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 3-methoxymethyl-1- prepared in Example (30a) PQ-3, 8-diacillyl [4,5] dec-2-one 124 mg (0.  2 2 1 mole) dissolved in 5 ml of ethyl acetate, and added oxalic acid 19.  9 mg (0.  2 2 1 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 99 mg (68 · 8%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (40 MHz, CD3OD) (5 ppm: 7.75-7.53 (ιη, 8H), 5. 66 (s, 1H), 4. 87 (s, 3H), 4. 67 (s, 2H), 3.  64-3.  47 (m, 6H), 3.  38-3. 21 (m, 4H), 2. 25-2.  08 (m, 6H) Infrared absorption spectrum vmax cnf 丨 (KBr): 1759, 1617, 1435, 1404, 1332, 1280, 1256, 1166, 1123, 1093, 1074 Mass analysis (FAB) m / z 561 ((M + H) +, free body). Example 3 1 8- {3- [Bis ((3-trifluorotolyl) methoxy) propyl] 3-methylthiomethyl-1-fluorene-3,8-diacylspiro [4,5] Decane-2 -one and its oxalate (Exemplified Compound No. 1-148) (31 a) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 3-methylthiomethyl -1 -fluorene · 3,8-diacryl [4,5] dec-2-one was prepared using the 8- {3-[bis- (3-trifluorotolyl) methoxy group prepared in Example (3 a). [Propyl] propyl}-1 -fluorene-3,8 -diacryl [4,5] dec-2 -one 0.30 g (0.5 8 1 mmol) -144- 200401778 Butyl ammonium 21. 0 mg (58. 1 micromole) and methylthiomethyl chloride 15 ml (1. 74 millimolar), the reaction was performed in the same manner as in Example (2a), and the target compound was 22 mg (66.  3%). (31b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propylmethylthiomethyl-1-Pf -3,8 -diacryl [4,5] dec-2- Ketooxalate prepared 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3} -methylthiomethyl-1-fluorene-3, 8 prepared in Example (31a) -Diazepi [4,5] dec-2-one 222 mg (0.385 mol) was dissolved in 5 ml of ethyl acetate, and oxalic acid 34 was added. 7 mg (0. 3 8 5 mmol), and left at room temperature overnight. The crystals were collected by filtration, and the target compound was obtained as white crystals of 157 mg (6 1.  2 % ). Nuclear magnetic resonance spectrum (4QOMHz, CD3OD) 5 ppm: 7. 73-7 · 53 (ιη, 8H), 5. 67 (s, 1H), 4. 43 (s, 2H), 4. 67 (s, 2H), 3.  66-3.  47 (m, 4H), 3.  35-3. 22 (m, 7H), 2.  25-2.  08 (m, 6H) Infrared absorption spectrum vmax cnf1 (KBr): 1750, 1616, 1431, 1331, 1255, 1165, 1123, 1092, 10 7 4 Mass analysis (? 8) 111/2 577 ((1 ^ + 1 ^) +, free body). Example 3 2 φ 8- {2- [bis- (3-cyanophenyl) (3'-trifluorotolyl) methoxy] ethyl} -3- (thiophen-2-ylcarbonyl) -1- Pyrene-3,8-diacspiro [4,5] dec-2-one and its oxalate (exemplified compound number 1-3 0 7) (32a) 8- {2- [bis- (3-cyanobenzene (3 ~ trifluorotolyl) methoxy] ethyl} -3- (oxphen-2-ylcuryl) -1-P 萼 -3, 8. · ** spiro [4,5] dec -2-Wake 8- {2-[bis- (3-cyanophenyl) (3′-trifluorotolyl) methoxy] ethyl 1- 噚 -3 prepared in Example (2 8 a) , 8-Diacillyl [4,5] dec-2-one 300 g -145- 200401778 (0. 2111 millimoles), n-butyllithium (1. 59N), 0.60 mg (0. 950 mmol) and 2 -decanoyl chloride.  1 4 ml (1.  27 mmol), the reaction was carried out in the same manner as in Example (1 b) and purification was carried out to obtain 259 mg (79%) of the target compound. (32b) 8- {2- [bis- (3-cyanophenyl) (3'-trifluorotolyl) methoxy] ethyl} -3-(thiophene-2-ylcarbonyl) -1 -fluorene- 3,8-Diacridyl [4,5] dec-2-one ketooxalate The 8- {2- [bis- (3-cyanophenyl) (3'-trifluorofluorene) prepared in Example (32a) Phenyl) methoxy] ethyl} -3- (tidophen-2-ylcuryl) -1-B department-3, 8-spiro [4,5] dec-2-one 259 mg (0. 444 mmol) dissolved in 5 ml of ethyl acetate and added oxalic acid 40. 0 mg (0. 4 4 4 mmol), freeze-dried. The crystals were collected by filtration to obtain 273 mg of the target compound as white crystals (9 1.  3%). Nuclear magnetic resonance spectrum (400MHz, CD3OD) 0ppm: 7. 97-7. 50 (in, 10H), 7. 18-7. 13 (m, 1H), 5. 65 (s, 1H), 4. 02 (s, 2H), 3.  70-3. 50 (m, 4H), 3. 40 ~ 3. 27 (m, 4H), 2. 3 8-2.  08 (m, 6H) Infrared absorption spectrum vmax cnf1 (KBr): 1786, 1652, 1417, 1382, 1330, 1229, 1164, 1123 Mass analysis (FAB) m / z 5 8 4 ((M + H) +, free body). Example 3 3 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (4-methoxybenzylfluorenyl) -1-fluorene-3,8-diazine Spiro [4,5] dec-2-one and its oxalate (exemplified compound number 1-1 6 6) (33a) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl } -3- (4-methoxybenzylfluorenyl) -1 -fluorene-3,8-diacylspiro [4,5] dec-2-one. 8- {3- [prepared in Example (30a) Bis- (3-trifluorotolyl) methoxy] ethyl) -1-fluorene-3,8-diacryl [4,5] dec-2-one 300 grams (0. 581 milli -146- 200401778 mole), n-butyl lithium (1. 59N), 0. 55 mg (0. 871 mmol) and 4-methoxybenzyl chloride 198 ml (0. 871 millimolars), reacted and purified in the same manner as in Example (lb) to obtain 360 mg (95. 3%). (33b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (4-methoxybenzylfluorenyl) -1-fluorene-3, 8-diacryl [4,5] Dec-2-one oxalate 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (4 prepared in Example (33 a) -Methoxybenzyl) -1-fluoren-3, 8-diacylspiro [4,5] dec-2-one 360 mg (0. 553 mmol) dissolved in 5 ml of ethyl acetate, added oxalic acid 49. 8 mg (0.  5 5 3 millimolar) and left at room temperature overnight. The crystals were collected by filtration to obtain 220 mg (53.7%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD30D) 5ppm: 7. 72-7. 53 (m, 10H), 6,98-6. 93 (m, 2H), 5. 67 (s, 1H), 3. 99 (s, 2H), 3. 86 (s, 3H), 3. 64-3. 50 (ηι, 4H), 3. 38-3. 2 7 (m, 4H), 2.38-2. 09 (ιη, 6H) Infrared absorption spectrum vmax cm-i ®r): 1785, 1654, 1605, 1513, 1330, 1258, 1171, 1124 Mass analysis (FAB) m / z 651 ((M + H) +, free body). Example 3 4 φ 8- {2- [bis- (3-cyanophenyl) (3'-trifluorotolyl) methoxy] ethyl} -3- (2-methoxybenzylfluorenyl) -1 -Fluorene-3,8-diaciro [4,5] dec-2-one and its oxalate (exemplified compound number 1-3 0 1) (34a) 8- {2- [bis- (3-cyano Phenyl) (3'-trifluorotolyl) methoxy] ethyl} -3-(2-methoxybenzylfluorenyl) -1 -fluorene-3,8 -diazelop [4,5] dec- 2-ketone using 8- {2- [bis- (3-cyanophenyl) (3 ^ trifluorotolyl) methoxy] ethyl 1-fluorene-3, 8-prepared in Example (28a) Bisacyl [4,5] dec-2-one 300 g -147- 200401778 (0. 211 millimoles), n-butyllithium (1. 59N), 0. 60 mg (0. 950 mmol) and 2-methoxyoctyl chloride 17 ml (1. 27 millimoles), the reaction was carried out in the same manner as in Example (lb) and purified to obtain the target compound 281 mg (72.  3%). (34b) 8- {2- [bis- (3-cyanophenyl) (3 ^ trifluorotolyl) methoxy] ethyl} -3- (2-methoxybenzylfluorenyl) -1-fluorene- 3, 8-Diaciro [4,5] dec-2-one oxalate The 8- {2- [bis- (3-cyanophenyl) (3'-trifluorotoluene) prepared in Example (34a) ) Methoxy] ethyl} -3- (2-methoxybenzylfluorenyl) -1-fluorene-3, 8-diazepi [4,5] dec-2-one 2 8 1 mg (0 · 4 6 3 mmol) dissolved in 5 ml of ethyl acetate, and 4 1 oxalic acid was added.  6 mg (0. 4 6 3 mmol), freeze-dried. The crystals were collected by filtration to obtain 268 mg (83 · 0%) of the target compound. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 82-6. 95 (m, 12H), 5. 64 (s, 1Η), 4.  00 (s, 2H), 3. 81 (s, 3H), 3.  65-3. 52 (m, 4H), 3.  41-3. 25 (m, 4H), 2. 32-2.  19 (m, 4H), 2. 18-2.  08 (m, 2H) Infrared absorption spectrum vmx cmH _r): 1793, 1685, 1603, 1332, 1250, 1165, 1122 Mass analysis (FAB) m / z 608 ((M + H) +, free body). Example 3 5 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (2,4-dimethoxybenzylfluorenyl) -1 -fluorene-3,8 -Bisacyl [4,5] dec-2-one and its oxalate (exemplified compound 5 Tiger code 1-1 6 8) (35a) 8- {3- [bis- (3-trifluorotolyl) Methoxy] propyl} -3- (2,4-dimethoxybenzylfluorenyl) -1 -fluorene-3 5 8 -diacspiro [4,5] dec-2-one Example (3 3 a) Prepared 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 1-fluorene-3,8-diacryl [4,5] dec-2-one 3 0 0 grams (0.  5 8 1 milli -148- 200401778 mole), n-butyl lithium (1. 59N), 0.55 mg (0.5 871 mmol) and 2,4-dimethoxybenzidine chloride 2 3 2 ml (0.  8 7 1 mol), the reaction and purification were carried out in the same manner as in Example (1 b) to obtain the target compound 3 5 3 mg (8 9.  3%). (35b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (2,4-dimethoxybenzylfluorenyl) -1 -fluorene-3,8- Diazepi [4,5] dec-2-one ketooxalate The 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl}-prepared in Example (3 5 a) 3- (2,4-Dimethoxybenzylfluorenyl) -1-fluorene-3,8-diacryl [4,5] dec-2-one 3 5 3 mg (0.  5 1 9 mmol) dissolved in 3 ml of ethyl acetate and added oxalic acid 4 6. 7 mg (0.  5 1 9 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 5 2 1 mg of the target compound as white crystals (1 3.  0%). Nuclear magnetic resonance spectrum (4 Hz, CD30D) δ ppm: 7.73-7.53 (ιη, 8H), 7. 33 (d, 1H, J = 8. 16 Hz), 6. 59-6. 54 (m, 2H), 5. 67 (s, 1H), 3. 98 (s, 2H), 3. 85 (s, 3H), 3.  79 (s, 3H), 3. 65-3. 58 (m, 4H), 3.  38-3. 27 (m, 4H), 2.  31 ~ 2.  08 (m, 6H) Infrared absorption spectrum vmax cnf1 ⑽r): 1789, 1673, 1608, 1331, 1165, 1123 Mass analysis (FAB) m / z 681 ((M + H) +, free body). Example 3 6 8- {2- [bis- (3-trifluorotoluyl) methoxy) ethyl] -3- (2-methoxybenzylfluorenyl) -1-fluorene-3, 8-di Azuron [4,5] dec-2-one and its oxalate (exemplified compound number 1-1 6 1) (36a) 8- {2- [bis- (3-trifluorotolyl) methoxy] Ethyl} -3- (2-methoxybenzylfluorenyl) -1 -fluorene-3,8-diacylspiro [4,5] dec-2-one. 8- {2- [Bis- (3-trifluorotolyl) methoxy] ethyl 1-fluorene-3,8-diacryl [4,5] dec-2-one 200 mg (0. 40 millimoles) and 67 microliters of 2-methoxybenzyl chloride (0. 44 millimoles), the reaction of Example-lb-2004-01778 was carried out and purification was carried out to obtain 193 mg (76%) of the target compound. (36b) 8- {2- [Bis- (3-trifluorotolyl) methoxy] ethyl} -3- (2-methoxybenzylfluorenyl) -1-fluorene-3,8-diazaspiro [4 5 5] Decane-2-ketooxalate The 8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -3- (2 prepared in Example (36a) -Methoxybenzyl) -1-fluoren-3, 8-diazepi [4,5] dec-2-one 193 mg (0. 30 millimolar) dissolved in 2 ml of ethyl acetate, 27 mg of oxalic acid (0.  30 mmol), isopropanol, and left at room temperature overnight. The crystals were collected by filtration to obtain the target compound as white crystals (124 mg, 56%). Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) ό ppm: 7. 60-7. 75 (8H, in), 7.46 (1Η, · dt, J = 1. 5Hz, 7Hz), 7. 31 (m, dt, J = 1. 5Hz, 7Hz), 7. 07 (lH, d, 8Hz), 7. 03 (1Η, t, 8Hz), 5. 83 (1H, s), 3. 94 (2H, s), 3. 75 (3H, s), 3. 70 (2H, t, 5Hz), 2.  95-3. 25 (4H, m), 2. 50 (2H, t, 5Hz), 2.  00-2. 15 (4H, m) Infrared absorption spectrum vlnax cnfl (KBr): 1792, 1331, 1 252, 1166, 1123 Mass analysis (FAB) m / z 637 ((M + H) +, free body) Elemental analysis 値 (C32H3 () F6N205 · 1 · 6C2H204) Calculate 値: C: 53. 95: H: 4. 27; N: 3. 56 Cut and see: C: 53. 97; H: 4. 37; N: 3. 77. ® Example 3 7 3-methoxymethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -l-fluorene-3,8-bisacylspiro [4, 5] dec-2-one and its oxalate (exemplified compound number 3-21) (37a) 3-methoxymethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] Ethyl} -1 -fluorene-3,8-diacryl [4 5 5] dec-2-one, 8- {2- [bis- (3-trifluorotolyl) methyl) prepared in Example (la) Oxy] -150- 200401778 Ethyl} -l-fluorene- 3,8-diacryl [4,5] dec-2-one 206 mg (0.41 mmol) and chloromethyl methyl ether 62 micro Liter (0. 82 millimolars), the reaction and purification of Example (2a) were carried out to obtain 160 mg (71%) of the target compound. (37b) 3-methoxymethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl} -1 -fluorene-3,8-diacylspiro [4,5] Decyl-2 -ketooxalate The 3-methoxymethyl-8- {2- [bis- (3-trifluorotolyl) methoxy] ethyl group 1-fluorene prepared in Example (37a) -3,8-Diaciro [4,5] dec-2-one 160 mg (0. 29 millimoles) dissolved in 2 ml of methanol, 26 mg of oxalic acid (0. 29 mmol), isopropanol, and left at room temperature overnight. The crystals were collected by filtration to obtain 138 mg (74%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS (H16) δ ppm: 7.60-7.77 (8H, m), 5.82 (1H, s), 4. 73 (2H, s), 3. 67 (2H, t, J = 5Hz), 3. 44 (3H, s), 3. 21 (2H, s), 2. 88-3. 17 (4H, in), 2. 5K2H, t, J = 5Hz), 1.  90-2.  05 (4H, m) · Infrared absorption spectrum vmax cm · 1 (KBr): 1703, 1331, 1165, 1120, 1074 Mass analysis (FAB) m / z 547 ((M + H) +, free body) Elemental analysis 値(C28H3 {) F6N208) Calculate 値: C: 52. 83; Η: 4.75; NM. 40 φ measured 値: C: 52. 73; Η: 4. 65; Ν: 4. 44. Example 3 8 3- (2-methoxyethyl) -8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -1-fluorene-3 5 8-diacryl [4,5] Dec-2-one and its oxalate (exemplified compound number 3-24) (38a) 3- (2-methoxyethyl) -8- {3- [bis- (3-trifluoro Tolyl) methoxy] propyl}-1 -fluorene-3 5 8 -diacylspiro [4,5] dec-2-one 200401778 8-{3-[bis- (3-trifluorotolyl) methoxy] propyl 1-fluorene-3,8-diacryl [4,5] dec-2-one 1 6 5 mg (0.32 mmol) and 60 μl of 2-methoxyethyl bromide (0. 642 millimolars), the reaction was performed in the same manner as in Example (2a), and 90 mg (49%) of the target compound was purified. (38b) 3- (2-methoxyethyl) -8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -1-fluorene-3,8-diacryl [ 4,5] dec-2-one oxalate The 3- (2-methoxyethyl) -8- {3- [bis- (3-trifluorotolyl) formyl) prepared in Example (3 8 a) Oxy] propylbu 1-fluorene-3, 8-diacryl [4,5] dec-2-one 90 mg (0. 15 mmol) dissolved in 3 ml of methanol, and 14 mg of oxalic acid (0. 15 · mol), isopropanol, and left at room temperature overnight. The crystals were collected by filtration to obtain 81 mg (78%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) (5ppm: 7. 58-7. 82 (8H, ni), 5. 76 (lH, s), 3. 40-3. 51 (4H, m), 3. 4K2H, s) 3 3. 32 (2H, t, J = 5Hz), 3. 26 (3H, s), 2. 85-3. 20 (4H, m), 2. 5K2H, t, J = 5Hz), 1. 85-2. 00 (4H, m) Infrared absorption spectrum vmax cur1 ®): 1734, 1 702, 1333, 1166, 1123 Mass analysis (FAB) m / z 575 ((M + H) +, free body) Elemental analysis 値 (C3QH34F6N208 ) # Calculate 値: C: 53. 30; Η: 5. 30; N: 4. 03 Actual measurement: C: 52. 86; Η: 5. 07; N: 4. 18. Example 3 9 [Bis- (3-trifluorotolyl) methoxy] propyl} -3- (2-furfuryl) -1-fluorene-3,8-diacryl [4,5] dec -2-ketone and its oxalate (exemplified compound number 1-170) (39a) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (2-fur Fluorenyl) -152- 200401778 -1 -fluorene-3,8-diBYspiro [4,5] dec-2-one used 8- {3- [bis- (3-trifluoro) prepared in Example (3a) Tolyl) methoxy] propyl} -1 -fluorene-3,8-diacylspiro [4,5] dec-2-one 4 7 0 mg (0.  9 1 millimolar) and 2-furfuryl chloride 1300 microliters (1.  (0 9 mmol), the reaction was performed in the same manner as in Example (1 b), and the target compound was obtained as 490 mg (88%). (39b) 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3- (2-furfuryl) -1 -fluorene-3 5 8 -diacylspiro [4 , 5] dec-2-one ketooxalate 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl 3- (2-furfuran) prepared in Example (39a) Acyl) -1-fluorene- 3,8-diacryl [4,5] dec-2-one 490 mg  8 1 mmol) was dissolved in 5 ml of ethyl acetate, and 72 mg (0.5 mg) of oxalic acid was added.  81 1 mol), and left at room temperature overnight. The crystals were collected by filtration to obtain the target compound as white crystals (4.33 mg, 77%). Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) (5ppin: 8. 01 (lH, d, I = lHz), 7. 60-7 · 77 (8H, m), 7.46 (1Η, d, 1 = 3.5Ηζ), 6.72 (1Η, dd, J = ΙΗζ, 3.5Ηζ), 5.77 (1Η, s ), 3.  96 (2Η, s), 3. 47 (2Η, t, J = 5Hz), 2.  90-3.  25 (4Η, m), 2. 47-2.  52 (4H, m), 1. 90-2. 20 (4H, m) Infrared absorption spectrum vmax cm · 1 (KBr): 1791, 1331, 1229, 1166, 1123 φ Mass analysis (FAB) m / z 611 ((M + H) +, free body) Elemental analysis 値(C3QH28F6N205 · 7 / 6C2H204) Calculate 値: C: 54. 27; H: 4. 27; N: 3. 91 Found 値: C: 54. 47; H: 4. 16; N: 4. 01. Example 4 0 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} -3-methylthiomethyl-1-fluorene-3, 8-di Acryl [4,5] dec-2-one and its oxalate (exemplified compound -153- 200401778 number 1-2 9 8) (40a) 8- {3-[(3-cyanophenyl) (3f- Trifluorotolyl) methoxy] propyl} -3-methylthiomethyl-1 -fluorene-3,8-diacirospiro [4,5] dec-2-one 8 prepared using Example (8a) -{3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 1-fluorene-3, 8-diacryl [4,5] dec-2-one 200 Mg (0. 42 millimoles) and methylthiomethyl chloride 5 3 microliters (0.  63 millimolars), the reaction was carried out in the same manner as in Example (2a), and the target compound was 142 mg (63%). (40b) 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} -3-methylthiomethyl-1 -fluorene-3, 8-diazine Spiro [4,5] dec-2-ketooxalate The 8- {3-[(3-cyanophenyl) (3f-trifluorotolyl) methoxy] propyl group prepared in Example (40a) 3-methylthiomethyl-1-pyrene-3,8-diacryl [4,5] dec-2-one 130 mg (0. 24 millimoles) dissolved in 3 ml of ethyl acetate, 22 mg of oxalic acid (.  2 4 mmol) and left at room temperature overnight. The crystals were collected by filtration to obtain 118 mg (78%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) δ ρρη: 7.94 (1Η, m), 7.79-7.72 (4Η, m), 7. 67-7.  56 (3Η, m), 5. 7K1H, s) 4.  42-4.  36 (2H, m), 3. 50-3.  41 (4H, m), 3. 3 4-2. 9K6H, m)? 2. 08 (3H, s), 2. 04-1. 88 (6H, m) Infrared absorption spectrum v max cuf1 (KBr): 2493, 1754, 1430, 1330, 1123 Mass analysis (FAB) m / z 534 ((M + H) +, free body) Elemental analysis 値 (C29H32F3N307S ) Calculate 値: C: 55 · 85; Η: 5.17; F: 9 · Η; N: 6.72; S: 5. 14 Found 値: C: 55. 54; Η: 4.95; F-. 8. 97; Ν: 6. 72; S: 5. 18〇 Example 4 1 8- {3-[(3-cyanophenyl) (3f-trifluorotolyl) methoxy] propyl} -3- (2-methoxy200401778 ethyl) -1 -3,8. Diaciro [4,5] dec-2-one and its oxalate (exemplified compound number 3-5 6) (41a) 8- {3-[(3-cyanophenyl) (3 '-Trifluorotolyl) methoxy] propyl} -3- (2-methoxyethyl) -1 -fluorene-3,8-diacryl [4 5 5] dec-2-one (8 a) Preparation of 8-{3-[(3 -cyanophenyl) (3 1 -trifluorotolyl) methoxy] propyl 1-fluorene 1 -3,8 -diacylspiro [4,5 ] Dec-2-one 200 mg (0. 42 millimoles) and 60 microliters of 2-bromoethyl methyl ether (0.63 millimoles) were reacted and purified in the same manner as in Example (2a) to obtain 161 mg (72%) of the target compound. (41b) 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} -3- (2-methoxyethyl) -1-fluorene-3, 8-Diaciro [4,5] dec-2-one oxalate The 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy [Propyl] propyl} -3- (2-methoxyethyl) -1-fluorene-3,8-diaciro [4,5] dec-2-one 150 mg 28 millimoles) dissolved in 3 ml of ethyl acetate, 2.5 mg of oxalic acid (0.5 mg 28 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 97 mg (56%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) a ppm: 7. 94 (lH, in), 7.85-7.72 (4Η, m), 7. 67-7. 56 (3H, m), 5. 71 (1H, s) 3.50-3. 43 (4H, m), 3. 41 (2H, s), 3.32 (2H, t, J = 5. 3Hz), 3. 26 (3H, s), 3. 20-2.  93 (6H, m), 2.  03-1.  87 (6H, m) Infrared absorption spectrum vmax cr1 ⑽r): 2928, 2498, 1753, 1329, 1121 Mass analysis (FAB) m / z 532 ((M + H) +, free body) Elemental analysis 値 (C3QH34F3N308) Calculation値: C: 57. 97; H: 5. 51; F: 9. 17; N: 6. 76 Found 値: C: 57 · 56; H: 5. 16; F: 8. 83; N: 6. 48. -155- 200401778 Example 42 8- {3-[(3-Cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 3-methoxymethyl-1-fluorene-3, 8 -Bisacyl [4,5] dec-2-one and its oxalate (exemplified compound number 3-5 4) (42a) 8- {3-[(3-cyanophenyl) (3f-trifluorotoluene (Methoxy) methoxy] propylbutan 3-methoxymethyl-1 -fluorene-3,8-diaciro [4 5 5] dec-2-one, 8- {3 prepared using Example (8 a) -[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl} -1_ 噚 -3, 8-diacryl [4,5] dec-2-one 500 mg ( 1. 06 mmol) and 120 μl of chloromethyl methyl ether (1. 58 millimoles), the reaction was performed in the same manner as in Example (2a), and the target compound was obtained as 225 mg (40%). (42b) 8- {3-[(3-Cyanophenyl) (3'-trifluorotolyl) methoxy] propylbutanyl 3-methoxymethyl-1-fluorene-3, 8-diacryl [4,5] Dec-2-one oxalate The 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl group prepared in Example (42a) 3-Methoxymethyl-1-fluorene-3, 8-diazepi [4,5] dec-2-one 210 mg (0. 40 millimolar) dissolved in 3 ml of ethyl acetate, 36 mg of oxalic acid (0.  40 millimolar) and left at room temperature overnight. The crystals were collected by filtration to obtain 191 mg (78%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ρρπκ7 · 94 (1Η, m), 7.85-7 · 72 (4Η, m), 7.  67-7. 56 (3Η, m), 5. 70 (1H, s), 4. 59 (2H, s), 3. 50-3. 42 (4H, m), 3. 22 (3H, s), 3.  18-2. 87 (6H, m), 2.  06-1. 83 (6H, m) Infrared absorption spectrum vmax cnT1 (KBr): 2497, 1758, 1403, 1329, 1121 Mass analysis 0 8 3) 111/2 518 ((1 ^ +? 1) +, free body) Elemental analysis 値(C29H32F3N30rH20) Calculate 値: C: 55. 68; Η: 5.48; F: 9. 11; N: 6. 72 Found 値: C: 55 · 68; H: 5. 17: F · 9 · 21; N: 6.  34. 200401778 Example 43 8- {2- [bis- (3-cyanophenyl) (3f-trifluorotolyl) methoxy] ethyl} -3- (4-methoxybenzylfluorenyl-1 -fluorene- 3, 8-Diaciro [4,5] dec-2-one (Exemplified Compound No. 3 0 3) 8- {2-[bis- (3-cyanophenyl) prepared using Example (2 8 a) ) (3'-trifluorotolyl) methoxy] ethylbu 1-fluorene-3, 8-diacryl [4,5] dec-2-one 0. 100 g (0. 211 millimoles), n-butyllithium (1. 59N), 0. 20 mg (0. 317 mmol) and 4-trimethoxybenzyl chloride 072 g (0. 422 millimolars), the reaction was carried out in the same manner as in Example (lb), and the target compound was 138 mg (100%). Nuclear magnetic resonance spectrum (400MHz, CDC13) (5 ppm: 7.70-7. 42 (m, 10H), 6. 96-6. 88 (m, 2H), 5. 43 (s, 1H), 3. 91 (s, 2H), 3. 87 (s, 3H), 3. 55 (s, 2H), 3. 11 ~ 2. 40 (m, 4H), 2. 16-1.  51 (m, 8H) Infrared absorption spectrum vmax cnT1 (CDC13): 1781, 1677, 1606, 1513, 1329, 1 258, 1169, 1126 Mass analysis (FAB) m / z 608 ((M + H) +, free body ). Example 4 4 8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diazelop [4, 5] dec-2 -Ketone and its fumarate (exemplified compound number 2-49) (44a) 8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1- Pyrene-3,8-diacylspiro [4,5] dec-2-one 3-chloro-1- (4-fluorophenyl) propyl 4-fluorophenyl ether 190 mg (0. 67 millimoles) dissolved in 5 ml of dimethylformamide, and 155 mg of 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride (0 . 81 millimoles), potassium bicarbonate 112 mg (1. 34 millimoles) and potassium iodide 200401778 1 5 mg (0.  0.01 mmol), and stirred at 100 ° C for 8 hours. Warm to room temperature, add water, and extract twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in that order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 9/1) to obtain 250 mg (92%) of the target compound. (441〇- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2 -Ketofumarate 8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3 prepared in Example (4 4a), 8-Diacillyl [4,5] dec-2-one 240 mg (0. 60 millimolar) _ dissolved in 3 ml of ethyl acetate, added 6 mg of fumaric acid (0. 60 mM) and left at room temperature overnight. The crystals were collected by filtration to obtain 213 mg (69%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) ό ppm: 7.  47-7 · 41 (2H, m), 7.  19-7. 13 (2H, m), 7.  07-7.  00 (2H, m), 6.  92-6.  86 (2H, m), 6. 62 (2H, s), 5.  36-5.  33 (1H, m), 3. 22 (2H, s), 2.  56-2.  45 (6H, m), 2. 17-2.  05 (1H, m), 1.  96-1.  88 (1H, m), 1.  87-1.  70 (4H, m) 'Infrared absorption spectrum vmax cm " 1 (KBr): 1753. 1 505. 1 260. 1207 Lu Mass analysis (FAB) m / z 403 ((M + H) +, free body) Elementary analysis (C26H28F2N207) Calculation: C: 60. 23; Η: 5. 44; F: 7. 33; N: 5. 40 IJ 値: C: 59. 90; H: 5. 07; F: 7. 21; N: 5. 41. Example 5 2-ketone and its fumarate (exemplified compound number 2-413) -158- 200401778 (45a) 8- [3- (3-trifluorotolyloxy) -3- (4-fluorophenyl) Propyl] -1-fluorene- 3,8-diacryl [4 5 5] dec-2-one The 3-chloro-1- (4-fluorophenyl) propyl 3-trifluoro prepared from Reference Example 22 Toluyl ether 306 mg (0. 92 millimoles) and 1-fluorene-3, 8-diacylspiro [4,5] dec-2-one hydrochloride 212 mg (1. 1 millimolar), reaction and purification were carried out in the same manner as in Example (44a) to obtain 358 mg (86%) of the target compound. (45b) 8- [3- (3-trifluorotolyloxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4 5 5] dec-2 -Ketofumarate The 8- [3-(3-trifluorotolyloxy) -3-(4-fluorophenyl) propyl prepared in Example (4 5 a): 1-1-1 -3,8-Di DY Spiral [4,5] dec · 2__ 350 mg (0. 77 mmol) dissolved in 3 ml of ethyl acetate, 90 mg of fumaric acid (0. 77 mmol) and left overnight at room temperature. The crystals were collected by filtration to obtain 308 mg (70%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7.48-7.  42 (3Η, m), 7.23-7. 12 (5H, m) 3 6. 63 (2H, s), 5. 55-5. 52 (1H, m), 3. 23 (2H, s), 2. 62-2. 50 (6H, m), 2.  21-2. 12 (1H, m), 2.  03-1.  93 (1H, m), 1.  87-1. 70 (4H, m) Infrared absorption spectrum vmax cm— (KBr): 1751, · 1 329, 1226, 1127 Mass analysis (FAB) m / z 453 ((M + H) +, free body) Elemental analysis 値 (C27H28F4N207 ) Calculate 値: C: 57. 04; Η: 4. 96; F: 13. 37; N: 4. 93 Found 値: C: 56. 38; H: 4. 36; F: 13. 40; N: 4. 85. Example 4 6 8- [3- (3-cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3, 8-diacryl [4,5] dec- 2-ketone and its fumarate (exemplified compound number 2-3 1 7) -159- 200401778 (46a) 8- [3- (3-cyanophenoxy) -3- (3-trifluorotoluene Propyl] -propyl] -bucarpine- 358-diazepi [4,5] dec-2-one The 1- 噚 -3 5 8-diazepi [4,5] dec-2-2 prepared in Reference Example 1 Ketohydrochloride 150 mg (0. 774 mmol), 3- (3-cyanophenoxy) -3- (3-trifluorotolyl) propyl mesylate prepared in Reference Example 309 mg (0. 774 mmol) dissolved in 5 ml of N, N-dimethylacetamide, and 214 mg of potassium carbonate (1. 55 mmol), potassium iodide 26 mg (0. 155 mmol), molecular sieve 4 A 0. 46 grams were stirred at 10 ° C for 16 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth and washed with ethyl acetate several times. Water was added to the organic layer, extracted with ethyl acetate, and sodium sulfate. It was dried under reduced pressure, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0Π) to obtain the target compound 172 mg (yield 99.7%) as an oily substance. (46b) 8- [3- (3-cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec- 2-ketofumarate 8- [3- (3-cyanophenoxy) -3- (3-trifluorotolyl) propyl prepared in Example (46a); 1-1-1 -3, 8-Diacillyl [4,5] dec-2-one 172 mg (0. 374 milligrams @ mol) dissolved in 5 ml of ethyl acetate, added 43 mg of fumaric acid (0. 374 mol)) and left overnight. The crystals were collected by filtration to obtain the target compound 9 3.  0 mg (43. 3%) of white crystals. Nuclear magnetic resonance spectrum (400 MHz, CD30D) δ ppm: 7.76-7 · 17 (in, 8H), 5. 62-5. 57 (m, 1H), 3. 41 (s, 2H), 3. 36-3. 03 (m, 7H), 2. 48-2. 35 (m, 1H), 2. 35-2. 22 (m, 1H), 2. 19-1. 97 (m, 4H) Infrared absorption spectrum ymax cnf1 Q (Br): Π59, 1329, 1 256, 1166, 1127, 1074, 983 -160- 200401778 Mass analysis (FAB) m / z 460 ((M + H) + , Free body). Example 4 7 8- [3- (4-cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene- 3,8-diacryl [4 5 5] dec- 2-ketone and its fumarate (exemplified compound number 2-4 4 5) (47a) 8- [3- (4-cyanophenoxy) -3- (3-trifluorotolyl) propyl ] -1- 噚-3,8-Diaciro [4 5 5] dec-2-one The 1-fluoren-3,8-diaciro [4,5] dec-2-one produced in Reference Example 1 Hydrochloride 190 mg (1. 01 mmol), 3- (4-cyanophenoxy) -3- (3-trifluorotolyl) propyl mesylate prepared in Reference Example 21 432 mg 774 mmol) dissolved in 5 ml of N, N-dimethylacetamide, and potassium carbonate 278 mg (2. 01 mmol), potassium iodide 33 mg (0. 201 millimoles), molecular sieve 4 A 0. 6 2 grams, stir at 100 ° C for 16 hours. After the reaction was completed, it was filtered through celite and washed several times with ethyl acetate. Water was added to the organic layer, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 252 mg (yield 99.7%) as an oily substance. (47b) 8- [3- (4-cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3,8 · diacspiro [4,5] dec-2 -Ketofumarate 8- [3-(4-cyanophenoxy) -3-(3-trifluorotolyl) propyl] -1-fluorene prepared in Example (4 7 a) 3,8-Diaciro [4,5] dec-2-one 252 mg (0. 549 mmol) dissolved in 5 ml of ethyl acetate, added fumaric acid 0. 0 6 4 g (0.  3 7 4 millimoles) and left overnight. The crystals were collected by filtration to obtain 162 mg (51 · 3%) of the target compound as white crystals. 200401778 Nuclear magnetic resonance spectrum (400MHz, CD30D) (5 ppm: 7. 75-7. 52 (m, 6H), 7.05-λ 00 (m, 2H), 5. 65-5. 60 (m, 1H), 3. 41 (s, 2H), 3. 37-3. 05 (m, 7H), 2. 49-2. 38 (m, 1H), 2. 38-2. 25 (m, 1H), 2. 19-1. 98 (m, 4H) Infrared absorption spectrum v max cm · 1 (KBr): 1753, 1604, 1 506, 1330, 1 250, 1173, 1 1 2 7, 1074, 983 Mass analysis (FAB) m / z 4 6 0 ((M + H) +, free body). Example 4 8 8- [3- (4-chlorophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3, 8-diacylspiro [4,5] dec- 2-ketone and its fumarate (exemplified compound numbers 2-4 3 7) ^ (48a) 8- [3- (4-chlorophenoxy) -3- (3-trifluorotolyl) propene 1-fluorenyl-3,8-diazepi [4,5] dec-2-one prepared from Reference Example 1 Hydrochloride 1 37 mg (0.  7 0 9 mmol), Reference Example 16 3-(4-chlorophenoxy) -3- (3-trifluorotolyl) propyl 290 mg (0. 709 mmol) dissolved in 5 ml of N, N-dimethylacetamide, and 196 mg of potassium carbonate (1. 42 mmol), potassium iodide 24 mg (0. 142 mmol), molecular sieve 4 A 0. 43 grams, stirred at 100 ° C for 16 hours. After the reaction was completed, it was filtered through celite and washed several times with ethyl acetate. Water was added to the organic layer, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 280 mg (yield 84. 2%) as an oily substance. (48b) 8- [3- (4-chlorophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2 -Ketofumarate 8- [3- (4-chlorophenoxy) -3- (3-trifluorotoluene-162- 200401778-based) propyl] -1 prepared in Example (48 a) -Fluorene-3,8-diacillyl [4,5] dec-2-one 280 mg (0. 597 mmol) dissolved in 5 ml of ethyl acetate, added fumaric acid 0. 0 6 9 mg (0.  5 9 7 mmol) and left overnight. The crystals were collected by filtration to obtain the target compound 183 mg (52. 4%) of white crystals. Nuclear magnetic resonance spectrum (400MHz, CD30D) (5 ppm: 7.72-7 · 52 On, 4H), 7.20-7 · 14 (m, 2H), 6. 89-6. 82 (m, 2H), 5. 50-5. 43 (m, 1H), 3. 41 (s, 2H), 3. 37-3. 03 (m, 7H), 2. 42-2. 32 (m, 1H), 2. 32-2. 21 (m, 1H), 2. 19-2. 00 (m, 4H) Infrared absorption spectrum vmax cnf1 (KBr): 1758, 1490, 1 329, 1235, 1168, 1127, 9 8 3 Mass analysis (FAB) m / z 469 ((M + H) +, free body ). Example 4 9 8- [3- (2-Fluoro-phenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diazaspiro [4,5] Dec-2 -one and its fumarate (exemplified compound number 2-425) (49a) 8- [3- (2-fluoro-phenoxy) -3- (3-trifluorotolyl)- Propyl] -1-fluorene-3, 8-diacylspiro [4,5] dec-2-one The 1-fluorene-3,8-dicridino [4,5] dec-2 produced in Reference Example 1 -Ketohydrochloride 142 mg (0. 789 mmol), 3- (2-fluorophenoxy) -3- (3-trifluorotolyl) propyl mesylate prepared in Reference Example 290 mg (0. 789 mmol) dissolved in 5 ml of N, N-dimethylacetamide, and 204 mg of potassium carbonate (1. 48 millimoles), potassium iodide 25 mg (0. 148 mmol), molecular sieve 4 A 0. 43 grams, stirred at 100 ° C for 16 hours. After the reaction was completed, it was filtered through celite and washed several times with ethyl acetate. Water was added to the organic layer, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by -1 63- 200401778 silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1) to obtain the target compound of 260 mg (yield 77.8%) as an oily substance. (49b) 8- [3- (2-Fluoro-phenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diacryl [4,5] dec -2-ketofumarate 8- [3- (2-fluoro-phenoxy) -3- (3-trifluorotolyl) -propyl] -1- 噚 prepared in Example (49a) -3, 8-Diaciro [4,5] dec-2-one 260 mg (0. 575 mmol) dissolved in 5 ml of ethyl acetate, added fumaric acid 0. 0 6 7 g (0. 5 7 5 millimoles) and left overnight. The crystals were collected by filtration to obtain the target compound 262 mg (80.  1%) of white crystals. φ nuclear magnetic resonance spectrum (400MHz, CD3OD) (5ppin: 7. 77-7. 51 (in, 4H), 7. 1H7. 02 (m, 1H), 6. 96-6. 85 (m, 3H), 5. 52-5. 48 (m, 1H), 3. 41 (s, 2H), 3. 38-3. 05 (m, 7H), 2. 50-2. 39 (m, 1H), 2. 34-2. 22 (m, 1H), 2. 19-1. 99 (m, 4H) Infrared absorption spectrum v max cnf1 (KBr): 1754, 1503, 1330, 1258, 1199, 1169, 1126, 1074 Mass analysis (FAB) m / z 453 ((M + H) +, free body ). Example 5 8- [3- (3-Fluorophenoxy) -3- (3-trifluorotolylpropyl] -1-fluorene-3, 8-diacridyl #spiro [4,5] dec- 2-ketone and its fumarate (exemplified compound number 2-4 2 9) (50a) 8- [3- (3-fluorophenoxy) -3- (3-trifluorotolyl) -propane Base] -bubi- 3,8-diazepi [4 5 5] dec-2-one The 1- 噚 -3 5 8-diazepi [4,5] dec-2-one produced in Reference Example 1 Hydrochloride 113 mg (0. 586 millimolar), 3- (3-propenyloxy) -3- (3-trifluorotolyl) propyl mesylate prepared in Reference Example 230 (0. 586 mmol) dissolved in 5 ml of N, N-dimethylacetamide, and potassium carbonate 1 6 2 -164- 200401778 mg (1. 17 millimoles), 19 mg potassium iodide (0. 117 mmol), molecular sieve 4 A 0. 34 grams, stirred at 100 ° C for 16 hours. After the reaction was completed, it was filtered through celite and washed several times with ethyl acetate. Water was added to the organic layer, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 165 mg (yield 62. 2%) of an oily substance. (50b) 8- [3- (3-Fluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diacylspiro [4,5] dec- 2-ketofumarate The 8- [3_ (3-fluorophenoxy) -3- (3-trifluorotolylpropyl) prepared in Example (50a): l. -Diacron [4,5] dec-2-one 165 mg (0. 365 mmol) dissolved in 5 ml of ethyl acetate, added fumaric acid 0. 042 grams (0. 365 mmol), and left overnight. The crystals were collected by filtration to obtain 3 mg (54.6%) of the target compound Η as white crystals. Nuclear magnetic resonance spectrum (40 (^ take, 00300) 0? 111: 7 75-7. 52 (111, 4) 1), 7. 22-7. 13 (m, 1H), 6. 72-6. 59 (m, 3H), 5. 52-5.  48 (m, 1H), 3. 41 (s, 2H), 3. 38-3. 02 (in, 7H), 2. 42-2. 31 (m, 1H), 2. 31-2. 21 (hi, 1H), 2. 18-1. 98 (m, 4H) Infrared absorption spectrum vmax cm-1 (KBr): 1757, 1610, 1 593, 1489, 1330, 1 262, 1 1 6 7, 1135, 983 Mass analysis (FAB) m / z 453 (( M + H) +, free body). Example 5 1 8- [3- (4-trifluorotolyloxy) -3- (3-trifluorotolyl) -propyl] -1-B- 3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified compound number 2-441) (51a) 8- [3- (4-trifluorotolyloxy) -3- (3-trifluorotolyl) -Propyl] -1- -165- 200401778 hydrazone-3,8-diazolo [4,5] dec-2-one Ketone-3,8-diasciro [4,5] prepared in Reference Example 1 ] Dec-2-one ketone hydrochloride 115 mg (.  5 9 9 mmol), 3-(4-trifluorotolyloxy) _3_ (3-trifluorotolyl) propyl propionate 265 mg (0. 599 mmol) dissolved in 5 ml of N, N-dimethylacetamide, and 166 mg of potassium carbonate (1. 20 millimoles), potassium iodide 20 mg (0. 120 millimolar), molecular sieve 4 A 0. 38 grams were stirred at 1000 ° C for 6 hours. After the reaction was completed, it was filtered through celite and washed several times with ethyl acetate. Water was added to the organic layer, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 254 mg (yield 84. 4%) of an oily substance. (51b) 8- [3- (4-trifluorotolyloxy) -3- (3-trifluorotolyl) -propyl] -bucarpine-3,8-diacryl [4,5] dec- 2-ketofumarate The 8- [3- (4-trifluorotolyloxy) -3- (3-trifluorotolyl) -propyl] -1-sulfone prepared in Example (51a) -3,8-Diaciro [4,5] dec-2-one 245 mg (0.506 mmol) was dissolved in 5 ml of ethyl acetate, and fumaric acid 0 was added. 059 mg (0.  5 0 6 mol), and left overnight. The crystals were collected by filtration to obtain 184 mg (58 · 8%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (gallop, CD30D) δ ppm: 7. 78-7. 47 (m, 6Η), 7. 05-7. 00 (m, 2H), 5. 62-5.  58 (m, 1H), 3. 42 (s, 2H), 3. 42-3. 08 (m, 7H), 2. 49-2. 38 (in, 1H), 2. 38-2. 26 (m, 1H), 2. 20-2. 01 (m, 4H) Infrared absorption spectrum vmax cm-1 (KBr): 1757, 1614, 1330, 1247, 1166, 1115, 1069, 983 Mass analysis (FAB) m / z 503 ((M + H) +, free body). -166- 200401778 Example 5 2 8- [3- (4-fluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diacylspiro [4 , 5] dec-2-one and its fumarate (exemplified compound number 2-4 3 3) (52a) 8- [3- (4-fluorophenoxy) -3- (3-trifluoro Tolyl) -propyl] -1-fluorene- 3,8-diazelop [4,5] dec-2-one methanesulfonic acid 3-(4-fluorophenoxy)- 3-[3-(trifluoromethyl) phenyl] propyl 270 mg (0. 69 millimoles) and 1-fluorene-3, 8-diaciro [4,5] dec-2-one hydrochloride 159 mg (0. 83 mmol), the reaction was carried out in the same manner as in Example (44a) and the target compound was purified 2 8 3 mg (91%) ° (52b) Trifluorotolyl) -propyl] -1-fluorene-3, 8-diacylspiro [4,5] dec-2-one keto fumarate The 8- [3- (4-Fluorophenoxy) -3- (3-trifluorotolyl) propylpyrene-3, 8-diazepi [4,5] dec-2-one 270 mg 60 mmol) was dissolved in 3 ml of ethyl acetate, and 69 mg (0.6 mg) of fumaric acid was added.  60 mmol) and left at room temperature overnight. The crystals were collected by filtration to obtain 244 mg (72%) of white crystals of the target compound. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) 5ppin: 7. 76-7. 57 (4H, in), 7. 07-7. 01 (2H, m), 6.  96-6.  89 (2H, m), 6. 6K2H, s), 5. 50 ~ 5. 46 (1H, m), 3. 22 (2H, s), 2.  55-2.  39 (6H, m), 2. 17-2.  06 ClH, m), 2.  03-1.  92 (1H, m), 1.  87-1.  67 (4H, m) Infrared absorption spectrum v max cnr1 (KBr): 1755, 1 505, 1 329, 1204, 1126 Mass analysis (FAB) m / z 453 ((M + H) +, free body) Elemental analysis 値(C27H28F4N207) Calculate 値: C: 57. 04; Η: 4. 96; F: 13. 37; N: 4. 93 Measured 値 · C: 56 · 38; Η: 4. 36; F: 13. 40; N: 4.85. 200401778 Example 5 3 8- [3- (3-trifluorotolyloxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene- 3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified compound number 2-147) (53a) 8- [3- (3-trifluorotolyloxy) -3- (3-trifluorotolyl) Propyl] -1-fluorene-3,8-diacspiro [4,5] dec-2-one was prepared using 3- [3- (trifluoromethyl) phenoxy] methanesulfonic acid prepared in Reference Example 24- 3- [3- (trifluoromethyl) phenyl] propyl ester 287 mg (0. 65 millimolar) and 1-fluorene-3,8-diacillyl [4,5] dec-2-one ketone hydrochloride prepared in Reference Example 1 150 mg (0.5 78 millimolars), the reaction and purification were carried out in the same manner as in Example (4a) to obtain 286 mg (88%) of the target compound. (53b) 8- [3- (3-trifluorotolyloxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec- 2-ketofumarate 8- [3- (3-trifluorotolyloxy) -3- (3-trifluorotolyl) propyl] -1-fluorene prepared in Example (53a) 3, 8-Diacillyl [4,5] dec-2-one 280 mg (0. 56 mmol) was dissolved in 3 ml of ethyl acetate, and 65 mg of fumaric acid (0.5 mg 5 6 mmol) and left at room temperature overnight. The crystals were collected by filtration to obtain 245 mg (71%) of white crystals of the target compound. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ρρπι: 7.82 (1Η, S), 7. 78-7. 73 (1H, in), 7.  57-7.  67 (2Η, m), 7.  49-7.  43 (1H, m), 7.  28-7.  20 (3H, m), 6. 6K2H, s), 5. 72-5. 65 (1H, m) 3 3. 2K2H, s), 2. 55-2. 37 (6H, m), 2.  23-2. 12 (1H, m), 2. 06-1. 97 (1 H, m), 1. 83-1.  65 (4H, m) Infrared absorption spectrum i / max cm · 1 (KBr): 1 756, 1 328, 1167, 1125, 1072 Mass analysis (FAB) m / z 5 0 3 ((M + H) +, free body). 200401778 Elemental analysis of plutonium (c28h28f6n2o7) Calculation of plutonium: C: 53 · 59; plutonium: 4. 66; F: 18. 16; N: 4. 46 Found 値: C: 53. 61; Η: 4. 42; F: 17. 68; N: 4.40. Example 5 4 (3S) -8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -l-Pf-3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2 to 4 9) (54a) (3S) -8- [3- (4-fluorophenoxy) -3- (4-Fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4 5 5] dec. 2-one The (1 R)-3 -chloro-1- (4-fluorophenyl) -1 -propanol 1 3.  1 g (69 mmol) was dissolved in 130 ml of toluene, and 4-fluorophenol 9 was added. 3 grams (83. 0 millimolar), triphenylphosphine 2 1.8 grams (8 3.  1 millimolar) and 40% diethyl azodicarboxylate-toluene solution 36 ml (82. 7 millimoles) and stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/9) to obtain (1S) -3-chloro-1- (4-fluorophenyl) propyl. 4-fluorophenyl ether 1 4. 3 grams. Add the resulting compound 1 4. 3 g of 280 g of dimethylacetamide were added, and 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride prepared in Reference Example 1 was added 11. 7 grams (60. 7 millimoles), sodium bicarbonate 8. 5 g (101 mmol) and potassium iodide 760 mg (4.  5 7 mmol), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The organic layer was sequentially washed with water, saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 9/1) to obtain 17 · 1 g (84%) of the target compound. 200401778 (54b) (3S) -8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -l-Bf-3,8-diazepron ] Dec-2-one ketofumarate The (3 S)-8-[3-(4-fluorophenoxy) -3-(4-fluorophenyl) prepared in Example (5 4 a) Propyl] -1-fluorene- 3,8-diacryl [4,5] dec-2-one 1 gram (42. 5 mmol) dissolved in 180 ml of ethyl acetate, added fumaric acid 4. 93 mg (42. 5 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 17 · 1 g (78%) of white crystals of the target compound. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) ό ppm: 7.  47-7 · 41 (2H, m), 7. 19-7. 13 (2H, m), 7. 05-7.  00 (2H, m), 6.  91-6.  86 (2H, in), 6. 6K2H, s), 5.  35-5.  32 (1H, _ m), 3. 2K2H, s), 2.  46-2.  42 (6H, m), 2.  13-2.  05 (1H, m), 1.  95-1. 86 (1H, m), 1.  8 2-1. 6 8 (4 H? M) Infrared absorption spectrum vmax cnfi (KBr): 1754, 1504, 1 222, 1204 Mass analysis (FAB) m / z 403 ((M + H) +, free body). Elemental analysis of plutonium (C26H28F2N207) Calculation of plutonium: C: 6, 0 · 23; plutonium: 5. 44; F: 7. 33; N: 5. 40 Found 値: C: 60. 16; H: 5. 23; F: 7. 53; N: 5. 46 Specific rotation [a] 25D-0. 37 ° (cl. 0, MeOH). ❿ Example 5 5 (3S) -8- [3- (3-trifluorotolyloxy) -3- (4-fluorophenyl) propyl] -1- 噚-3,8-diazepi [4 , 5] dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 1 3) (55a) (3S) -8- [3- (3-trifluorotolyloxy ) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diacylspiro [4,5] dec-2-one, according to the method of Example 5, 4 using (1 R)- 3-Chloro-1-(4-fluorophenyl) -1 -prop-170-200401778 alcohol 300 mg (1. 59 mmol) and trifluorocresol 309 mg (2. (03 mmol), and (lS) -3 -chloro-1- (4-fluorophenyl) propyl 3-trifluorom-phenylene ether (21 mg, 42%) was obtained. The obtained compound 2 2 1 mg (0. 6 6 mmol) and 1-fluorene-3,8-diacillyl [4,5] dec-2-one ketone hydrochloride prepared in Reference Example 1 15 mg (0. 7.9 millimolar) was synthesized to obtain 241 mg (80%) of the target compound. (55b) (3S) -8- [3- (3-trifluorotoluyloxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3, 8-diacylspiro [4,5 ] Dec-2-one fumarate The (3 S) -8- [3- (3-trifluorotolyloxy) -3- (4- φ fluorobenzene) prepared in Example (5 5 a) )] Propyl] -1-fluorene-3, 8-diacryl [4,5] dec-2-one 241 mg (0. 53 mmol) dissolved in 3 ml of ethyl acetate, 62 mg of fumaric acid (0.  5 3 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 236 mg (78%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7.  49-7 · 42 (3Η, m), 7. 22-7. 15 (5H, m), 6. 6K2H, s), 5. 55-5.  52 (1H, m), 3. 22 (2H, s), 2. 48-2. 33 (6H, m), 2.  18-2. 11 (1H, m), 1.  99-1. 91 (1H, m), 1. 82-1.  68 (4H, m) Infrared absorption spectrum vmax cnf1 (KBr): 1750, 1328, 1226, 1126 # Mass analysis (FAB) m / z 453 ((M + H) +, free body) Specific rotation [a] 25D + 5. 14 ° (c 1. 0, MeOH). Example 5 6 8- [3- (2,3-difluorophenoxy) -3- (3-trifluorotolyl) -propylbuimidine-1,3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified compound number 2-4 4 9) (56a) 8- [3- (2,3-difluorophenoxy) -3- (3 -tri Fluorotolyl) -propyl] -1-fluorene 200401778-3, 8-diacylspiro [4,5] dec-2-one. The methanesulfonic acid 3-hydroxy-3-(3- Trifluorotolyl) -propyl ester 300 mg (0.  10 millimolar) was dissolved in 6 ml of toluene, and 140 mg of 2,3-difluorophenol (1. 11 millimoles), 290 milligrams of triphenylphosphine (1. 11 mmol), diethyl azodicarboxylate 0.1 174 ml (11 11 mol), stir at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 3- (2,3-difluorophenoxy) -3- (3-trifluorotolyl mesylate). ) -Propyl ester 265 mg. ® Dissolve 2 6 5 mg of the obtained compound in 5 ml of dimethylacetamide, and add 1-fluorene-3,8-diaciro [4 5 5] dec-2-one ketone hydrochloride 1 prepared in Reference Example 1. 2 4 mg (0. 646 mmol), potassium carbonate 179 mg (1. 29 millimoles) and potassium iodide 21 mg (0.  1 2 9 mmol), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The organic layer was combined, washed successively with water, saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / φmethanol = 1 0/1) to obtain the target compound (205 mg, 67.5%). (56b) 8- [3- (2,3-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diacylspiro [4,5 ] Dec-2-one fumarate The 8- [3-(2,3-difluorophenoxy) -3-(3-trifluorotolyl)-prepared in Example (5 6 a)- Propyl; 1-l-fluorene-3,8-diacryl [4,5] dec-2-one 205 mg (0. 4 3 6 mmol) dissolved in 3 ml of ethyl acetate, and 5 1 mg of fumaric acid (0. 4 3 6 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 159 mg (62 · 1%) of the target compound as white crystals. -172- 200401778 Nuclear magnetic resonance spectrum (400_, CD30D) δ ppm: 7. 75 (s, 1H), 7. 70 (d, 1H, J = 7. 5 Hz), 7. 65-7. 55 (m, 2H), 6. 96-6. 68 (m? 3H), 5. 58 (dd, 1H, I = 3. 9 Hz, 8. 8 Hz), 3. 42 (s, 2H), 3. 40-3. 06 (m, 7H), 2. 54-2. 42 (m, 1H), 2. 37-2. 2 5 (in, 1H), 2. 20-2. 00 (m, 4H) Infrared absorption spectrum vmax cnri (KBr): 1745, 1620, 1511, 1479, 1 330, 1 254, 1168, 1127, 1073, 983, 804, 768, 728, 705, 648 Mass analysis (FAB ) m / z471 ((M + H) +, free body). Example 5 7 8- [3- (2,4-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-^-3,8-diazaspiro [4, 5] dec-2-one and its fumarate (exemplified compound number 2-4 5 0) (57a) 8- [3- (2,4-difluorophenoxy) -3- (3 -Trifluorotolyl) -propyl] -1-fluorene-3,8-diacryl [4,5] dec-2-one. The methanesulfonic acid 3-hydroxy-3-(3 prepared from Reference Example 15 -Trifluorotolyl) -propyl ester 300 mg (1.  〇1mmol) was dissolved in 6 ml of toluene, and 140 mg of 2,4-difluorophenol (1. 11 millimoles), triphenylphosphine 290 mg (1.11 millimoles), diethyl azodicarboxylate 0.1 174 ml (1. 11 millimoles), and stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 3- (2,4-difluorophenoxy) -3- (3-trifluorotolyl mesylate). ) -Propyl ester 225 mg. 225 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride prepared in Reference Example 1 was added 106 mg (0. 548 millimoles), potassium carbonate 152 mg (1. 10 millimoles) and potassium iodide 18 mg (0 · 110 millimoles), and stirred at 10 for 8 hours. After returning to temperature -173- 200401778 to room temperature, water was added and extraction was performed twice with ethyl acetate. The organic layer was combined, washed with water and saturated brine in this order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 185 mg (7 1.  1 % ). (57b) 8- [3- (2,4-difluorophenoxy) -3- (3-trifluorotolyl) -propylbu 1-fluorene-3,8-diacylspiro [4,5] Decano-2-ketofumarate 8- [3- (2,4-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] prepared in Example (57a) -1- 噚 -3, 8-Diacillyl [4,5] dec-2-one 185 mg (0.39 mol) was dissolved in 3 ml of ethyl acetate, and fumaric acid 4 6 mmol was added ® g (0.  3 9 3 millimolar) and left at room temperature overnight. The crystals were collected by filtration to obtain 105 mg (45.5%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 74 (s, 1H), 7. 69 (d, 1H, I = 7. 5 Hz), 7. 65-7. 54 (m, 2H), 6. 99-6. 87 (m, 2H), 6. 77-6. 68 (m, 1H), 5. 4 6 (dd, 1H, I = 3. 9 Hz, 8. 8 Hz), 3. 42 (s, 2H), 3. 40-3. 07 7H), 2. 53-2. 4 0 (m, 1H), 2. 36-2. 23 (m, 1H), 2. 20-2. 01 (m, 4H) Infrared absorption spectrum vmax cnr1 (KBr): 1756, 1508, 1330, 1258, 1 208, 1168, 1127, 1074, 982, 966, 805, 706, 647 Mass analysis (FAB) m / z471 ((M + H) +, free body). Example 5 8 8- [3- (3, 5 -difluorophenoxy) -3- (3 -trifluorotolyl) -propyl] -bucarpine-3, 8-diacylspiro [4 5 5 ] Dec-2-one and its fumarate (exemplified compound number 2-451) (58a) 8- [3- (3,5-difluorophenoxy) -3- (3-trifluorotoluene Propyl) -propyl] -1-fluorene-3,8-diacryl [4,5] dec-2-one-174- 200401778 methanesulfonic acid 3-hydroxy-3-(3 prepared from Reference Example 15 -Trifluorotolyl) -propyl ester 300 mg (1.  01 millimolar) dissolved in 6 ml of toluene, and stirred at room temperature and added 140 mg (1 · 11 mmol) of 3,5-difluorophenol and 290 mg of triphenylphosphine (1. 11 mmol), diethyl azodicarboxylate 0.1 174 ml (1. 11 millimoles), and stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 3- (3,5-difluorophenoxy) -3- (3-trifluorotolyl mesylate). ) -Propyl 257 mg. 257 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-0 萼 -3,8-diaciro [4,5] dec-2-one hydrochloride 121 mg (0.5 626 millimoles) ^, potassium carbonate 177 mg (1. 29 mmol) and potassium iodide 21 mg (0. 125 millimoles), stirred at 10 (TC for 8 hours. After warming to room temperature, add water and extract twice with ethyl acetate. Combine the organic layers, rinse with water and saturated brine, and then sulphate The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 201 mg (68. 2 % ). (58b) 8- [3- (3,5-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1- 噚 φ-3,8-diacylspiro [4 5 5] Dec-2-one keto fumarate 8- [3- (3,5-difluorophenoxy) -3- (3-trifluorotolyl) -propion prepared in Example (58a) Yl] -1-fluorene-3, 8-diacspiro [4,5] dec-2-one 201 mg (0. 4 2 7 mmol) dissolved in 3 ml of ethyl acetate, 50 mg of fumaric acid (0. 4 2 7 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 164 mg (65 · 3%) of the target compound as white crystals. -175- 200401778 Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 74 (s, 1H), 7. 69 (d, 1H, J = 7. 4Hz), 7. 66-7. 56 (m, 2H), 6. 58-6. 44 (m, 3H), 5:20 (dd, lH. J = 4. 1 Hz, 8. 3 Hz), 3. 41 (s, 2H), 3. 36-3. 21 (m, 3H), 3. 21-3. 01 (m, 4H), 2. 44-2. 3 2 (m, 1H), 2. 32-2. 21 (m, 1H), 2. 18-1. 99 (m, 4H) Infrared absorption spectrum vmax cm · 1 (KBr): 1739, 1 624, 1600, 1471, 1 329, 1 1 70, 1146, 1118, 1073, 992, 966, 842, 805, 705, 647 Mass analysis (FAB) m / z471 ((M + H) +, free body). Example 5 9 8- [3- (3? 4-one win phenoxy) -3- (3 -diwin tolyl) -propyl] -1-shu-3, 8-diacryl [4, 5] dec-2-one and its fumarate (exemplified compound number 2-452) (59a) 8- [3- (3,4-difluorophenoxy) -3- (3-trifluoro Tolyl) -propyl] -1-fluorene-3,8-diacryl [4 5 5] dec · 2-ketone The methanesulfonic acid 3 -hydroxy-3-(3 -trifluoro) prepared in Reference Example 15 Tolyl) -propyl ester 300 mg (1.  Ο 1 millimolar) was dissolved in 6 ml of toluene, and 3,4-difluorophenol 140 mg (1. 11 millimolar), triphenylphosphine 290 mg (1. 11 mmol), diethyl azodicarboxylate 0.1 174 ml (1.11 mmol) was stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 3- (3,4-difluorophenoxy) -3- (3-trifluorotolyl mesylate). ) -Propyl ester 211 mg. 1 mg of the obtained compound 21 was dissolved in 5 ml of dimethylacetamide, and 1-fluorene-3,8-diacyl [4,5] dec-2-one hydrochloride 99 · prepared in Reference Example 1 was added. 1 mg (0. 514 mmol), potassium carbonate 142 mg (1. 03 millimoles) and potassium iodide 17 mg (0.  103 mmol), and stirred at 100 ° C for 8 hours. After warming to -176- 200401778, add water and extract twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in this order, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1) to obtain 194 mg (80. 2%) of the target compound. (59b) 8- [3- (3,4-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diazepiro [4,5 ] Dec-2-one ketofumarate 8- [3- (3,4-difluorophenoxy) -3- (3-trifluorotolylpropyl) prepared in Example (59a): 1-1- 噚 -3, 8-Diacillyl [4,5] dec-2-one 194 mg (0. 412 mmol) was dissolved in 3 ml of ethyl acetate, and 48 φ mg of fumaric acid (0.1 mg  4 1 2 mmol), and left overnight at room temperature. The crystals were collected by filtration to obtain 150 mg of the target compound as white crystals (62. 0%). Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 73 (s, 1H), 7. 69 (d, 1H, J = 7. 4 Hz), 7. 65-7. 55 (m, 2H), 7. 13-7. 03 (m, 1H), 6. 89-6. 81 (in, 1H), 6. 74 -6. 63 (m, 1H), 5. 46 (dd, 1H, J = 4. 1 Hz, 8. 7 Hz), 3. 42 (s, 2H), 3. 38-3. 23 (m, 3H), 3. 23-3. 04 (m, 4H), 2. 43-2. 32 (m, 1H), 2. 32-2. 21 (m, 1H), 2. 19-2.  01 (m, 4H) Infrared absorption spectrum V] nax cm-i (KBr): 1 756, 1515, 1330, 1 256, 1210, 1159, φ 1126, 1074, 982, 803, 706, 647 Mass analysis (FAB) m / z 471 ((M + H) +, free body). Example 6 0 8- [3- (2,6-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] -lJW-3,8-diazelop [4,5] Decane-2 -one and its fumarate (exemplified compound number 2-4 5 3) (60a) 8- [3- (2,6-difluorophenoxy) -3- (3-difluoro Tolyl) -propyl] -1-Harmonica-3 5 8 -Diacyl [4,5] dec-2 -one-17 7- 200401778 The methanesulfonic acid 3-hydroxy-3-prepared in Reference Example 15 (3-trifluorotolyl) -propyl ester 300 mg (1.  0 1 mmol) was dissolved in 6 ml of toluene, and 140 mg of 2,6-difluorophenol (1. 11 millimoles), 290 milligrams of triphenylphosphine (1. 11 mmol), diethyl azodicarboxylate 0.1 174 ml (1. 11 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 3- (2,6-difluorophenoxy) -3- (3-trifluorotolyl mesylate). ) -Propyl ester 292 mg (70.1% yield). The obtained compound 29.2 mg (0. 7 1 2 mmol) was dissolved in 5 ml of dimethylacetamide, and 137 mg of 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride was added (0. 712 mmol), potassium carbonate 197 mg (1. 42 mmol) and potassium iodide 24 mg (0.  1 4 2 mmol), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The combined organic layers were washed with water and saturated brine in this order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 225 mg (67 · 2%). (60b) 8- [3- (2,6-difluorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diacylspiro [4,5 ] Dec-2-one ketofumarate 8- [3- (2,6-difluorophenoxy) -3- (3-trifluorotolyl) -propion prepared in Example (60 &) Base] -1 -fluorene-3,8-diacryl [4,5] dec-2-one 2 2 5 mg (0. 478 mmol) was dissolved in 3 ml of ethyl acetate, and 56 mg (0.5 mg of fumaric acid) was added.  4 7 8 millimolar) and left at room temperature overnight. The crystals were collected by filtration, and the target compound was obtained as white crystals 1.55 mg (55. 2 % ). -178- 200401778 Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 76 (s, 1H), 7. 67 (d, 1H, J = 7. 7 Hz), 7. 61 (d, 1H, J 2 7. 7 Hz), 7. 53 (t, 1H, J = 7. 7Hz), 7. 06-6. 95 (m, 1H), 6. 93-6. 84 (m, 2H), 5. 42 (dd, 1H, J = 4. 3 Hz, 8. 7 Hz), 3. 42 (s5 2H), 3. 40-3. 25 (m, 3H), 3. 25-3. 07 (m, 4H), 2. 63-2. 52 (m, 1H), 2. 34-2. 24 (m, 1H), 2. 20-2. 01 (m, 4H) Infrared absorption spectrum vmax or1 (KBr): 1 756, 1495, 1476, 1330, 1291, 1168, 1126, 1074, 1006, 983, 780, 733, 705, 648 Mass analysis (FAB) m / z471 ((M + H) +, free body). Example 6 1 8- {2- [bis- (3-trifluoromethoxyphenyl) methoxy] ethyl 1-fluorene-3, 8-diaciro [4,5] dec-2- Ketones and their fumarate (Exemplified Compound Numbers 1-3 6 7) (61a) 8- {2- [bis- (3-trifluoromethoxyphenyl) methoxy] ethyl 1- 噚-3,8-Diacridyl [4,5] dec-2-one 170 mg (2-chloroethyl- (3, 3'-ditrifluoromethoxyphenyl) methyl ether obtained in Reference Example 26 (0 . 41 millimoles) was dissolved in 5 mg of dimethylacetamide, and 1-fluorene-3 5 8-diacridyl [4,5] dec-2-one hydrochloride, 79 mg, prepared in Reference Example 1 was added ( 0. 41 millimoles), 113mg potassium carbonate (0. 82 millimolar) and potassium iodide 14 mg (820 micromolar), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The combined organic layers were washed with water and saturated brine in this order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5/1) to obtain 220 mg (100%) of the target compound. (61b) 8- {2- [bis- (3-trifluoromethoxyphenyl) methoxy] ethyl} -1-fluorene- 3,8-diazelop [4,5] dec-2-one The fumarate was prepared from the (6-la) 8- {2- [bis- (3-trifluoromethoxyphenyl) methoxy-179-200401778-yl] ethylbenzene 1-fluorene-3, 220 mg of 8-diasciro [4,5] dec-2-one (0.41 mmol) was dissolved in 3 ml of ethyl acetate, and 48 mg of fumaric acid (0.5 4 1 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 180 mg (67 · 4%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (40 drawing 2, 00300) 5 mouth 111: 7. 47 (12) 1, 1 = 2. Take 0), 7.49 (d, 2H, J = 8. 0 Hz), 7. 34 (s, 2H), 7. 22 (dd, 2H, J = 1. 4 Hz, 8. 0 Hz), 5. 64 (s, 1H), 3. 81 (t, 2H, I = 5. 1 Hz), 3. 41 (s, 2H), 3. 39-3. 25 (m, 4H), 3. 25-3. 14 (m, 2H), 2. 19-2. 01 (m, 4H) Infrared absorption spectrum vmax cm · 1 ⑽r): 1760, 1 259, 1215, 1165, 1082, 983 Mass analysis (FAB) m / z 535 ((M + H) +, free body). Example 62 8- [3- (phenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diazepi [4,5] dec-2-one And its fumarate (exemplified compound number 2-4 5 4) (62 &) 8- [3- (phenoxy) -3- (3-trifluorotolyl) -propyl] -1- Pyrene-3,8-diacylspiro [4,5] dec-2-one was prepared from Reference Example 15 methanesulfonic acid 3-hydroxy-3-(3.trifluorotolyl) -propyl ester 300 mg (1 . 01mmol) dissolved in 6ml of toluene, and 99mg of phenol (1. 06 millimoles), 320 mg triphenylphosphine (1. 21 mmol), diethyl azodicarboxylate 0.1  190 ml (1.  2 1 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 3- (phenoxy) -3- (3-trifluorotolyl) -propyl mesylate 227 mg. Oily substance. The obtained compound 2 2 7 mg was dissolved in 5 ml of dimethylacetamide, and 1-P-3, 8-diaciro [4,5] dec.-2-one hydrochloride 117 mg (0. 626 millimolar) -180- 200401778, potassium carbonate 168 mg (1. 21 millimoles) and potassium iodide 20 mg (0. 121 mmol), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The combined organic layers were washed with water and saturated brine in this order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 1 2 4 mg (4 7.  1 % ). (6213) 8- [3- (phenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diazepi [4 5 5] dec-2-one The fumarate was the 8- [3 · (phenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-di prepared in Example (62 a). Azuron [4,5] dec-2-one 124 mg (0. 285 mmol) dissolved in 3 ml of ethyl acetate, added 33 mg of fumaric acid (0. 427 millimolar) and left at room temperature overnight. The crystals were collected by filtration to obtain the target compound as white crystals 110 mg (7 (K 1%). Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 73 (s, 1H), 7. 69 (d, 1H, J 2: 7. 2 Hz), 7. 6 Bu 7. 53 (m, 2H), 7. 23-7. 15 (m, 2H), 6. 92-6. 85 (m, 3H), 5.49 (dd, 1H, J = 4. 0 Hz, 8. 7 Hz), 3.42 (s, 2H), 3. 45-3. 07 (m, 7H), 2. 43-2 · 22 (m, 2H), 2. 19-2. 00 (m, 4H) Infrared absorption spectrum v max cnTi (KBr): 1759, 1740, 1539, 1490, 1 329, 1 232, 1 168, 1 125, 1073, 982, 805, 756, 705, 648 Mass analysis ( FAB) m / z 435 ((M + H) +, free body). Example 6 3 8- [3- (3-chlorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diazelop [4,5] dec -2 -ketone and its fumarate (exemplified compound number 2-4 5 5) (63a) 8- [3- (3-benzylbenzyl) -3- (3-dibenzylbenzyl) -Propyl-200401778 3 5 8 -Diaciro [4,5] dec-2-one, 3-hydroxy-3-(3-trifluorotolyl) -propyl methanesulfonate prepared from Reference Example 15 300 mg (1. 01 mmol) was dissolved in 6 ml of toluene, and 136 mg of 3-chlorophenol (1. 21 millimoles), 320 mg triphenylphosphine (1. 11 millimoles), diethyl azodicarboxylate 0.190 ml (1.  2 1 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain methanesulfonic acid 3-(3-chlorophenoxy) -3-(3-trifluorotolyl)- Propyl 3 8 5 mg oily substance. 385 mg of the obtained compound was dissolved in 5 ml of dimethylacetamide, and 1-fluorene-3, 8-diacyl [4,5] dec-2-one hydrochloride 189 mg (0.5 981 mmol), potassium carbonate 271 mg (1. 96 millimolar) and potassium iodide 33 mg (0. 196 mmol), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The combined organic layers were washed with water and saturated brine in this order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 0/1) to obtain the target compound 262 mg (57 · 0%). (63b) 8- [3- (3-chlorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene- 3,8-diazelop [4,5] dec- 2-keto fumarate 8- [3- (3-chlorophenoxy) -3- (3-trifluorotolyl) -propyl prepared in Example (63a); -3,8-Diacyl [4,5] dec-2-one 262 mg (0. 559 mmol) was dissolved in 3 ml of ethyl acetate, and 65 mg (0.5 mg of fumaric acid) was added.  5 5 9 millimoles) and left at room temperature overnight. The crystals were collected by filtration to obtain 220 mg of the target compound as white crystals (67.  3%). -1 82- 200401778 Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 73 (s, 1H), 7. 69 (d, 1H, J = 7. 4 Hz), 7. 64-7. 55 (m, 2H), 7. 19-7. 14 (m, 1H), 6. 97-6. 87 (m, 2H), 6. 8 4-6. 78 (in 1H), 5. 56 (dd, 1H, J = 4. 0 Hz Hz, 8. 7 Hz), 3. 41 (s, 2H), 3. 38-3.  05 (m, 7H), 2. 43-2. 22 (m, 2H), 2. 20-2. 00 (m, 4H) Infrared absorption spectrum vmax cm-i (KBr): 1739,1591,1477,1 329,1240,1167, 1124,1072,981 Mass analysis (FAB) m / z 469 ((M + H) +, Free body). Example 6 4 8- [3- (4-trifluorotolyloxy) -3- (2-fluorophenyl) propyl; 1-1-1 hydrazone-3, 8-diacylspiro [4 5 5] dec -2 -ketone and its fumarate (exemplified compound number 2-4 5 6) (64a) 8- [3- (4-trifluorotoluyloxy) -3- (2-fluorophenyl) propane [] Yl] -1-fluorene- 3,8-diacylspiro [4,5] dec-2-one following the method of Example (3 a), the methanesulfonic acid 3-[4-( Trifluoromethyl) phenoxy] -3- (2-fluorophenyl) propyl 372 mg (0. 95 millimolar) and 1 · ， -3,8-diaciro [4,5] dec-2-one ketone hydrochloride prepared in Reference Example 1 212 mg (1. 11 millimolar), and the target compound was 349 mg (82%) ° (64b) 8- [3- (4-trifluorotolyloxy) -3- (2-fluorophenyl) propyl]- 1-fluorene- 3,8- diaciro [4,5] dec-2-one fumarate The 8- [3- (4-trifluorotolyloxy)- 3- (2-fluorophenyl) propyl] -1-shu-3,8-dioxospiro [4,5] dec-2-one 349 mg (0. 77 mmol) dissolved in 3 ml of ethyl acetate, 89 mg of fumaric acid (0. 77 mmol) and left overnight at room temperature. The crystals were collected by filtration to obtain 36.5 mg (83%) of the target compound as white crystals. -1 83- 200401778 Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ρρη: 7.60 (2H, d, J = 9Hz), 7.49 (1 Η, s), 7.  42-7.  48 (1Η, in), 7.  32-7.  38 (1H, m), 7. 16 ~ 7.  28 (2H, m), 7. 06 (2H, d, J = 9Hz), 6. 63 (2H, s), 5. 72 ~ 5. 78 (1H, m), 3. 22 (2H, s), 2. 47-2. 60 (6H, m), 2.  12-2. 22 (1H, m), 2.  02-2.  18 (1H, m), 1.  67 ~ 1.  85 (4H, m) Infrared absorption spectrum vmax cnf1 (KBr): 1750, 1329, 1 249, 1164, 1068 Mass analysis (FAB) m / z 453 ((M + H) +, free body) Elemental analysis 値 (C23H24F4N20r4 / 3C4H404) Calculate 値: C: 56. 05; Η: 4. 84; N: 4. 61 Found 値: C: 56.  28; Η: 4. 81; N: 4. 85. Example 6 5 8- [3- (2-Chlorophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene- 3,8-diazepi [4,5] dec-2 -Ketone and its fumarate (exemplified compound number 2-4 5 7) (65a) 8- [3- (2-chlorophenoxy) -3- (4-fluorophenyl) propyl]- BU 萼 3-3,8-Diacyl [4,5] dec. 2-ketone followed the method of Reference Example 12 and the 3-chloro-1-(4-fluorophenyl)- 1-propanol 300 mg (1. 59 mmol) and 165 μl of 2-chlorophenol (1. 59 millimolars) was synthesized to obtain 3 1 9 mg of 3-chloro-1- (4-fluorophenyl) propyl-2-chlorophenyl ether. 219 mg of the obtained compound and 1-fluorene-3,8-diaciro [4,5] dec-2-one ketone hydrochloride prepared in Reference Example 1 2 4 6 mg (1.28 mmol) Synthesis was carried out to obtain 386 mg (86%) of the target compound. (65b) 8- [3- (2-chlorophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2- Keto-fumarate was prepared from Example (6 5 a) 8-[3-(2 -chlorophenoxy) -3-(4-fluorophenyl) -184- 200401778 propyl] -1- Pyrene-3, 8-diacillyl [4,5] dec-2-one 386 mg (0. 92 mmol) dissolved in 3 ml of ethyl acetate, 107 mg of fumaric acid (0. 92 millimoles) and left at room temperature overnight. The crystals were collected by filtration to obtain 3,52 mg (71%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (40 MHz, DMS0-d6) δ ppm: 7.49-7. 44 (2H, m), 7. 25-7. 14 (3H, m), 6. 99-6. 85 (3H, m), 6. 6K2H, s), 5. 48 ~ 5. 43 (1H, m), 3. 22 (2H, s), 2.  45-2.  4K6H, m), 2.  14 ~ 2.  05 (1H, m), 1.  96-1.  87 (1H, in), 1.  82-1. 69 (4H, m) Infrared absorption spectrum vmax cm-ι (κΒγ): 1751 · 1591 · 1226 · 1075 · 981 Mass analysis (FAB) m / z419 ((M + H) +, free body). Example 6 6 8- [3 -Phenoxy-3-(4-fluorophenyl) propyl] -1-fluorene-3, 8-diazepi [4,5] dec-2 Butenedioic acid salt (exemplified compound number 2-4 5 8) (66a) 8- [3-phenoxy-3 (4-fluorophenyl) propyl] -1-fluorene-3,8-diazine Spiro [4,5] decan-2-one followed the method of Reference Example 12 and 300 mg of 3-chloro-1- (4-fluorophenyl) -1-propanol prepared in Reference Example 1 (1. 59 millimoles) and 150 mg of phenol (1. 59 millimoles), and 230 mg of 3-chloro-1- (4-fluorophenyl) propylphenyl ether was obtained. The obtained compound 230 mg and 1-fluorene-3,8-diacylspiro [4,5] dec-2-one hydrochloride 201 mg (1. 04 millimoles) was synthesized to obtain the target compound 286 mg (86%). (6613) 8- [3-phenoxy-3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diazepi [4,5] dec-2-one keto-butenedi The 8- [3-phenoxy- 3- (4-fluorophenyl) propyl] -1-fluorene-3, 8-diacryl [4,5] dec- 2-keto 286 mg (0. 74 millimolar) dissolved in 3 ml of acetic acid -185- 200401778 ethyl acetate, added 86 mg of fumaric acid (0.  74 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 271 mg (73%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) ό ppm: 7. 48-7. 42 (2H, m), 7. 22-7. 13 (4H, m), 6. 89-6. 83 (3H, m), 6. 61 (2H, s), 5. 41-5. 37 (1H, m), 3. 22 (2H, s), 2.  48-2. 43 (6H, m), 2. 15-2.  05 (1H, m), 1.  96-1. 87 (1H, m), 1.  82-1. 69 (4H, m) Infrared absorption spectrum v max cnf1 (KBr): 1753, 1597, 1510, 1226, 1080 Mass analysis (FAB) m / z 385 ((M + H) +, free body). Example 6 7 8-[(3S) -3- (4-chlorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diacylspiro [4 , 5] dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 3 7) (67a) 8-[(3S) -3- (4-chlorophenoxy) -3- (3-trifluorotolyl) -propylbu 1-fluorene-3,8-diaciro [4,5] dec-2-one The 3- (4-methanesulfonic acid) prepared in Reference Example 51 Chlorophenoxy) -3- (3-trifluorotolyl) -propyl ester 1. 82 grams (4. 45 mmol) dissolved in 20 ml of dimethylacetamide, and 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride 0. 49 grams (4. 90 mmol), potassium carbonate 0. 75 grams (8. 90 millimoles) and potassium iodide 0. 15 grams (0. 89 millimoles) and stirred at 10 for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in that order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5/1) to obtain 1 · 4.5 g (69 · 3%) of the target compound. (67b) 8-[(3S) -3- (4-chlorophenoxy) -3- (3-trifluorotolyl) -propyl] -1-200401778 hydrazone-3,8-diazaspiro [4 , 5] dec-2-one keto fumarate 8-[(3S) -3- (4-chlorophenoxy) -3- (3-trifluorotolyl) prepared in Example (67a) -Propyl] -1-fluorene-3, 8-diacryl [4,5] dec-2-one 351 mg (0.  7 4 8 mmol) dissolved in 5 ml of ethyl acetate, added fumaric acid 87 mg (0. 7 4 8 millimolar) and left overnight. The crystals were collected by filtration to obtain 204 mg of the target compound (46.  6%) of white crystals. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 72 (s, 1H), 7. 68 (d, 1H, J = 7. 3 Hz), 7. 66-7. 56 (m, 4H), 7. 18 (d, 1H, J = 8. 6 Hz), 6. 87 (d, 1H, J = 8. 6 Hz), 5. 48 (dd, 1H, J = 3. 6 Hz, 8. 5 Hz), 3. 42 (s, 2H), 3. 50-3. 03 On, 7H), 2. 46-2. 20 (m5 2H), 2. 20-1. 95 (m, 4H) Infrared absorption spectrum vmax cufi ⑽r): 1761, 1490, 1 329, 1 233, 1169, 1126, 1073, 981 Mass analysis (FAB) m / z 469 ((M + H) +, free body ) Specific rotation [a] 25D + 3. 44 ° (c 0. 30, MeOH). Example 6 8 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diacylspiro [4 , 5] dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 4 5) (68a) 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3,8-diaciro [4,5] dec-2-one. The methanesulfonic acid (3 S) prepared in Reference Example 53 -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl ester 2. 66 grams (6. 66 millimoles) dissolved in 20 ml of dimethylacetamide, and 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride was added 1. 41 grams (7. 33 millimoles), sodium bicarbonate 1. 12 grams (13. 3 millimolar) and potassium iodide 0. 22 grams -187- 200401778 (1.  3 3 mmol), and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in this order, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5/1) to obtain the target compound 2. 0 0 g (6 5.  4%). (68b) 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3, 8-diacylspiro [4, 5] Dec-2-one keto fumarate The 8-f (3 S)-3-(4-cyanophenoxy) -3-(3-trifluorotoluene) prepared in Example (6 8 a) Propyl) -propyl; 1-l-fluoren-3,8-diacryl [4,5] dec-2-one 3 0 8 mg (0. 670 mmol) was dissolved in 5 ml of ethyl acetate, and 78 mg of fumaric acid (0.5 mg) was added. 670 mmol), and left overnight. The crystals were collected by filtration to obtain 222 mg (57.5%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD3OD) δ ppm: 7. 75 (s, 1H), 7. 69 (d, 1H, J = 7. 4 Hz), 7. 64-7. 53 (m, 4H), 7. 07-7. 01 (m, 2H), 5. 64 (dd, 1H, J = 4. 0 Hz, 8. 7 Hz), 3. 42 (s, 2H), 3. 45-3. 07 (m, 7H), 2. 50-2. 37 (m, 1H), 2. 37-2. 2 7 (m, 1H), 2. 20-2. 02 (m, 4H) Infrared absorption spectrum vmax cur 丨 (KBr): 1761, 1604, 1506, 1329, 1250, 1172, 1 127, 1074, 982, 837, 805, 706, 647 Mass analysis (FAB) m / z 460 ((M + H) +, free body). (68c) 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -1-fluorene-3 5 8 -diacylspiro [4, 5] dec-2-one ketone hydrochloride 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propion prepared in Example (6 8 a) Yl] -1-fluorene-3, 8-diacspiro [4,5] dec-2-one 100 mg (0. 2 1 8 mmol) dissolved in 5 ml of ethyl acetate, added 1 N hydrochloric acid / ether to dissolve -188- 200401778 solution 0. 2 2 ml (0. 2 2 millimoles) and left overnight. The crystals were collected by filtration to obtain 97 mg (89 · 9%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 77 (s, 1H), 7. 72 (d, 1H, J = 7. 5 Hz), 7. 64-7. 53 (m, 4H), 7. 08-7. 02 (m, 2H), 5. 67 (dd, 1H, J = 3. 8 Hz, 8. 7 Hz), 3. 45 (s, 2H), 3. 75-3. 15 (m, 7H), 2. 56-2. 32 (m, 2H), 2. 34-2.  06 (m, 4H) Infrared absorption spectrum vinax cnf1 (KBr): 1759, 1604, 1506, 1329, 1 250, 1172, 1126, 1074 Mass analysis (? 8 8) 〇 1/2 460 ((1 ^ + 11) +, Free body) specific rotation [〇t] 25D-10. 4 ° (c 0. 20, H20). Example 6 9 8- [3- (3-trifluorotolyloxy) -3- (4-cyanophenyl) -propyl] -1-fluorene-3J-diacylspiro [4,5] dec-2 -Ketone and its fumarate (exemplified compound number 2-4 5 9) (69a) 8- [3- (3-trifluorotolyloxy) -3- (4-cyanophenyl) -propyl ] -1- 噚 -3, 8-Diacridyl [4,5] dec-2-one was prepared in the same manner as in Example (3 a). The methanesulfonic acid 3-[3-(tri Fluoromethyl) phenoxy] -3- (4-cyanophenyl) propyl 420 mg (1. 05 millimoles) and 1-fluorene-3,8 · diacillyl [4,5] dec-2-one ketone hydrochloride 2 3 3mg (1.2mimoles) to obtain the target compound 4 0 9 mg (85%). (69b) 8- [3- (3-trifluorotolyloxy) -3- (4-cyanophenyl) -propyl] -1-fluorene-3, 8-diacylspiro [4,5] dec- 2-ketofumarate The 8- [3- (3-trifluorotolyloxy) -3- (4-cyanophenyl) propyl] -bumin-3 prepared in Example (69a), 8-Diacillyl [4,5] dec-2-one 409 mg (0. (89 mmol) was dissolved in 4 ml of ethyl acetate, 103 mg (0.89 -189-200401778 mmol) of fumaric acid was added, and it was left at room temperature overnight. The crystals were collected by filtration to obtain 375 mg (73%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) (5 ppm: 7. 83 (2H, d, J = 8Hz), 7.64 (2 H, d, J = 8Hz), 7. 43-7. 50 (2H, m), 7. 16-7. 27 (3H, m), 6. 6K2H, s), 5. 62-5. 6 8 (1H, m), 3. 2K2H, s), 2.  36-2.  55 (6H, m), 2.  06-2. 17 (1H, m), 1.  93-2.  05 (1H, m), 1. 6 4-1. 8 0 (4 H5 m) Infrared absorption spectrum vmax cnf1 (KBr): 1758, 1452, 1328, 1126 Mass analysis (FAB) m / z 460 ((M + H) +, free body) Elemental analysis 値 (C24H24F3N3〇r6 / 5C4H404) Calculation: C: 57. 77; Η: 4. 85; Ν: 7. 02 Found 値: C: 57 · 93; Η: 4. 82; Ν: 7. 18〇 Example 7 〇 8- [3- (4-trifluorotolyloxy) -3- (4-cyanophenyl) propyl] -1-fluorene-3,8-diacylspiro [4,5] Dec-2-one and its fumarate (exemplified compound numbers 2-4 6 0) (70a) 8- [3- (4-trifluorotoluyloxy) -3- (4-cyanophenyl) Propyl 1-pyrene-3,8-diacryl [4,5] dec-2-one was used to imitate the method of Example (3a), and the methanesulfonic acid 3-[4-( Trifluoromethyl) phenoxy] -3- (4-cyanophenyl) propyl 391 mg and -3, 8-diacspiro [4,5] dec-2-one hydrochloride 217 mg (1. 13 millimolars) was synthesized to obtain the target compound 3 2 3 mg (72%). (70b) 8- [3- (4-trifluorotolyloxy) -3- (4-cyanophenyl) -propyl] -1-fluorene-3, 8-bisacylspiro [4,5] dec- 2-ketofumarate 8- [3- (4-trifluorotolyloxy) -3- (4-cyanophenyl) propyl] -1-fluorene prepared in Example (70a) -3, 8-Diacillyl [4,5] dec-2-one 323 mg 71 mmol -190- 200401778 ear) was dissolved in 4 ml of ethyl acetate, and 82 mg of fumaric acid (0.  7 1 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 347 mg (86%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) (5 ppm: 7. 83 (2H, d, J = 8Hz), 7. 62 (2H, d, J = 8Hz), 7. 58 (2H, d, J = 9Hz), 7. 48 (1H, s), 7. 08 (2H, d, J = 9Hz), 6.  61 (2H, s), 5.  62-5.  68 (1H, m), 3. 2K2H, s), 2.  36-2.  56 (6H, m), 2.  06-2. 17 (1H, m), 1. 93-2.  05 (1H, m), 1.  64-1.  80 (4H, m) Infrared absorption spectrum v max cur 丨 (KBr): 1759, 1328, 1178, 1113, 1068 Mass analysis (FAB) m / z 4 6 0 ((M + Hr, free body) Elemental analysis 値 ( C24H24F3N303-5 / 4C4H404) Calculation: C: 57. 62; H: 4. 84; N: 6. 95 Found 値: C: 57. 74; H: 4. 77; N: 7.20. Example 7 1 8-{(3S) -3- (4-chlorophenyl) -3- [3- (trifluoromethyl) phenoxy] propylbu 1-fluorene-3,8-diacryl [4,5] Dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2 to 4 6 1) (71a) 8-{(3S) -3- (4-chlorophenyl ) -3- [3- (trifluoromethyl) phenoxy] propyl} -1 -fluorene-3 5 8 -diacspiro [4,5] dec-2-one was prepared from (1S) using Reference Example 37 ) -3 -chloro-1- (4-chlorophenyl) propyl 3- (trifluoromethyl) phenyl ether 192. 4 mg (0. 5510 mmol) and 1-fluorene-3, 8-diacspiro [4,5] dec-2-one hydrochloride prepared in Reference Example 1 16. 8 mg (0. 6 0 6 3 mmol), the reaction and purification of Example (3 a) were performed to obtain the target compound 1 77. 0 mg (69% yield) of a light yellow oily substance. (71b) 8-{(3S) -3- (4-chlorophenyl) -3- [3- (trifluoromethyl) phenoxy] propyl} -191- 200401778 -1 -fluorene-3,8 -Diaciro [4,5] dec-2-one keto fumarate The 8-{(3 S) -3- (4-chlorophenyl) -3- [prepared from Example (7 la) 3- (trifluoromethyl) phenoxy] propyl-bubbin-3, 8-diacryl [4,5] dec-2-one 170. 3 mg (0. 3632 mmol) dissolved in methanol and added fumaric acid 42. 2 mg (0. 3 6 4 mmol), isopropyl ether, and filtered to crystallize to obtain the target compound 1 78. 3 mg (83% yield) of white powder. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 43-7. 35 (m, 5H), 7. 18 (d, 1H, J = 8. 1 Hz), 7. 14 (s, 1H), 7. 10 (dd, 1H, J = 2. 2 Hz, 8. 1 Hz), 5.47 (dd, 1H, J = 4. 1 Hz, 8. 5 Hz), 3. 41 (s, 2H), 3. 31-3. 30 (m, 2H), 3. 16-2. 91 (m, 4H), 2. 39-2. 31 (m, 1H), 2. 27-2. 20 (m, 1H), 2. 15-2. 11 (m, 2H), 2. 07-L 96 (m, 2H) Infrared absorption spectrum vmax ceT1 (KBr): 3246, 2931, 2555, 1 756, 1592, 1492, 1453, 1328, 1169, 1127, 983 Mass analysis (FAB) m / z 469 ( (M + H) +, free body) Elemental analysis 値 (C27H28C1F3N207) Calculate 値: C: 55. 44; Η: 4. 82; Cl: 6. 06; F: 9. 74; N: 4. 79 Found 値: C: 54 · 94; H: 4. 62; Cl: 5. 80; F: 9. 29; N: 4. 73. Example 7 2 8-{(33) -3- (4-chlorophenyl) -3- [4-cyanophenoxy] propyl} -1-fluorene-3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 6 2) (72a) 8-{(3S) -3- (4-chlorophenyl) -3- [4 -Cyanophenoxy] propyl} -1-fluorene-3, 8-diacryl [4,5] dec-2-one was prepared using (1S) -3 -chloro-1- (1-S 4-Chlorophenyl) propyl 4-cyanophenyl ether 203. 5 mg (0. 6646 millimolar) and 1- 噚--192- 200401778 3,8-diacridyl [4,5] dec-2-one hydrochloride 147 mg (0. 763 mmol), the reaction of Example (3 a) and purification to obtain the target compound 224. 9 mg (79% yield) of a pale yellow oily substance. (72b) 8-{(3S) -3- (4-chlorophenyl) -3- [4-cyanophenoxy] propyl} -1-fluorene-3, 8-diacylspiro [4,5] The dec-2-ketofumarate was prepared from the 8-{(3S) -3- (4-chlorophenyl) -3- [4-cyanophenoxy] propyl group prepared in Example (72a). 1-fluorene-3, 8-diacillyl [4,5] dec-2-one 202. 2 mg (0. 4747 mmol) dissolved in methanol and added fumaric acid 55. 1 mg (0.  4 7 5 mmol) and isopropyl ether, the crystals were collected by filtration to obtain the target compound 2 36. 7.3 mg (83% yield) of milky white powder. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. 58-7. 55 (m, 2H), 7. 41-7. 3 6 (m, 4H), 7. 03-7. 00 (m, 2H), 5. 50 (dd, 1H, J = 4. 4 Hz, 8. 1 Hz), 3. 31-3. 3 0 (m, 2H), 3. 30-3. 05 (m 6H), 2. 35 (m, 1H), 2. 23 (m, 1H), 2. 14-2. 11 (m, 2 H), 2. 07-1. 99 (in, 2H) Infrared absorption spectrum v max cur1 (KBr): 3248, 2930, 2556, 2225, 1757, 1604, 1505, 1250, 1173, 1088, 983 Mass analysis (FAB) m / z426 ((M + H ) +, Free body) Lu elemental analysis 値 (c27H28cm3o7) Calculate 値 ·· C: 59 · 83; Η: 5. 21; Cl: 6. 54; N: 7. 75 Found 値: C: 58. 87; Η: 5. 69; Cl: 6. 20; N: 7.50. Example 7 3 8-[(38) -3- (4-chlorophenyl) -3- (4-chlorophenoxy) propyl] -1-fluorene-3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified optically active compound of compound number 2-1 1 1) -193- 200401778 (73a) 8-[(3S) -3- (4-chlorophenyl ) -3- (4-chlorophenoxy) propyl] -1-fluorene-3, 8-diacryl [4 5 5] dec-2-one, (lS) -3 -chlorine prepared using Reference Example 39 -1- (4-chlorophenyl) propyl 4-chlorophenyl ether 1 7 5.  9 mg (0.  5 5 7 3 mmol) and 1- 噚 -3 5 8 -diaciro [4,5] dec-2-one hydrochloride 1 2 3 mg (0.63 9 mmol) prepared in Reference Example 1. (Ear)), the reaction was performed in the same manner as in Example (3a) and the target compound was purified. 7 mg (68% yield) of a yellow oily substance. (7 3 b) 8-[(3 S)-3-(4 -chlorophenyl) -3-(4-chlorophenoxy) propyl] -1 -fluorene-3, 8 -diacylspiro [4 , 5] dec-2-one keto fumarate The 8-[(3 3) -3- (4-chlorophenyl) -3- (4-chlorophenoxy) prepared in Example (73 &) ) Propyl; 1-1 -pyrene-3,8 -diaciro [4,5] dec-2-one 1 5 3 · 7 mg (0 · 3 5 3 1 mmol) dissolved in methanol, add Butenedioic acid 41. 0 mg (0. 353 mmol) and isopropyl ether. The crystals were collected by filtration to obtain the target compound 175.  5 mg (90% yield) of white powder. Nuclear magnetic resonance spectrum (400 MHz, CD30D) δ ppm: 7. 39-7. 36 (m, 4H), 7. 35-7. 1 6 (m, 2H), 6. 86-6. 82 (m, 2H), 5. 35 (dd, 1H, I = 4. 4 Hz, 8. 5 Hz), 3. 31-3. 0 5 (m, 8H), 2. 33-2. 12 (m, 4H), 2. 07-2. 03 (m, 2H) Infrared absorption spectrum v max cnf1 (KBr): 3236, 2932, 2533, 1752, 1703, 1582, 1489, 1235, 1172, 1090, 982 Mass analysis (FAB) m / z 435 ((M + H) +, free body) Elemental analysis 値 (C26H28C12N207) Calculation 値 ·· c: 56. 63; H: 5. 12; Cl: 12. 86; N: 5. 08 Found 値: C: 55. 96; H: 5. 09; Cl: 12. 56; N: 5.04. • 194- 200401778 Example 7 4 8-[(3S) -3- (4-chlorophenyl) -3- (4-fluorophenoxy) propyl] -1-fluorene-3,8-diacryl [4,5] Dec-2-one and its fumarate (exemplified optically active compound of compound number 2-463) 3- (4-Fluorophenoxy) propyl] -1-fluorene-3, 8-diacspiro [4 5 5] dec-2-one was prepared using (1S) -3 -chloro-1 from Reference Example 40 -(4-chlorophenyl) propyl 4-chlorophenyl ether 1 6 1.  9 mg (0.  5 4 1 2 mmol) and 1-fluorene-3,8-diaciro [4,5] dec-2-one ketone hydrochloride 1 1 6 mg (0. 6 0 2 millimoles), the reaction and purification of Example (3 a) were performed to obtain the target compound 183. 2 mg (81% yield) of light yellow oily substance. (74b) 8-[(3S) -3- (4-chlorophenyl) -3- (4-fluorophenoxy) propyl] -1-fluorene-3, 8-diacryl [4,5] Dec-2-one fumarate will be 8-[(3S) -3- (4-chlorophenyl) -3- (4-fluorophenoxy) propyl prepared in Example (74a); l · 1-fluorene-3,8-diacryl [4,5] dec-2-one 1 7 4 · 3 mg (0 · 4 1 6 1 1 mmol) dissolved in methanol and added fumaric acid 48. 3 mg (0. 416 mmol) and isopropyl ether, the crystals were collected by filtration to obtain the target compound 190. 4 mg (86.6% yield) of white powder. Nuclear magnetic resonance spectrum (400MHz, CD30D) 5ppm: 7. 4 (M. 34 (m, 4H), 6. 94-6. 8 2 (m5 4H), 5. 31 (dd, 1H, J = 4. 4 Hz, 8. 8 Hz), 3. 33-3. 05 (m, 8H), 2. 40-2. 0 3 (m, 6H) Infrared absorption spectrum vmax cnf1 (KBr): 3422, 3253, 2929, 2642, 2560, 1744, 1681, 1616.  1504, 1203, 1089, 983 Mass analysis (FAB) m / z 419 ((M + H) +, free body) -195- 200401778 Elemental analysis 値 (C26H28C1FN207) Calculation 値: C: 58. 37; H: 5. 28; C1: 6. 63; F: 3. 55; N: 5. 24 Found 値: C: 57. 87; Η: 4. 88; C1: 6. 48; F: 3. 59; Ν: 5. 41. Example 7 5 8-[(3S) -3- (4-chlorophenyl) -3- (3-fluorophenoxy) propyl] -l-fluorene- 3,8-diacylspiro [4,5 ] Dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 6 4) (75a) 8-[(3S) -3- (4-chlorophenyl) -3- (3-Fluorophenoxy) propyl] -1-shu-3,8. Diaciro [4 5 5] dec-2-one was prepared using (lS) -3 -chloro-1- ( 4-Chlorophenyl) propyl 3-fluorophenyl ether 204. 9 mg (0. 6849 mmol) and 1- 噚 -3 8-diaciro [4,5] dec-2-one hydrochloride 146 mg (0. 758 millimoles), the reaction was performed in the same manner as in Example (3a), and the target compound 2 3 2 · 9 mg (yield 81%) was obtained as a pale yellow oily substance. (75b) 8-[(3S) -3- (4-chlorophenyl) -3- (3-fluorophenoxy) propyl] -1-fluorene-3, 8-diacylspiro [4,5] The dec-2-one fumarate was prepared in Example (7 5 a) 8-[(3 S)-3-(4-chlorophenyl) -3-(3-fluorophenoxy) propane Group; 1-l-fluoren-3, 8-diazepi [4,5] dec-2-one 217. 7 mg (0. 5197 mmol) dissolved in methanol and added fumaric acid 48. 3 mg (0. 416 mmol) and isopropyl ether, and the crystals were collected by filtration to obtain the target compound 2 37. 9 mg (86.6% yield) of light yellow powder. Nuclear magnetic resonance spectrum (400MHz, CD30D) (5 ppm: 7.  4 Bu 7.  35 (m, 4H), 7.  20-7 · 1 4 (m, 1H), 6. 70-6. 60 (m, 3H), 5. 39 (dd, 1H, J = 4. 4 Hz, 8. 1 Hz), 3. 31-3. 3 〇 (m, 2H), 3. 22-2. 91 (m, 6H), 2. 35-2. 00 (m, 6H) 200401778 Infrared absorption spectrum Max cr! ((M + H) +, free body) Elemental analysis 値 (C26H28C1FN207) Calculate 値: C: 58. 37; Η: 5. 28; C1: 6. 63; F: 3. 55; Ν: 5. 24 Found 値 C: 57. 85; Η: 4. 94; C1: 6. 04; F: 3. 92; Ν: 5. 37. Example 7 6 8-[3-(4-Cyanophenoxy) -3-(4-methoxyphenyl) propyl] -1 -fluorene-3; 8 -Diacylspiro [4,5] dec- 2-ketone and its fumarate (exemplified compound numbers 2-4 6 5) (76 &) 8- [3- (4-cyanophenoxy) -3- (4-methoxyphenyl) propane The method of Example 1-1-fluoren-3,8-diacspiro [4,5] dec-2-one followed the method of Example (3a), and the methanesulfonic acid 3-(4-cyanocyanide) prepared in Reference Example 4 5 was used. 200 mg of phenoxy) -3- (4-methoxyphenyl) propyl ester and 1-Pf -3, 8 -diaciro [4,5] dec-2-one ketone hydrochloride 192 mg (1. 21 millimoles), and the target compound was 185 mg (82%, 2% engineering). (7613) 8- [3- (4-cyanophenoxy) -3- (4-methoxyphenyl) propyl] -1-fluorene-3,8-di-II-spirospira [4 5 5] dec-2 -Ketofumarate 8- [3- (4-cyanophenoxy) -3- (4-methoxyphenyl) propyl] -1-fluorene-3 prepared in Example (76a), 8-Diacillyl [4,5] dece-2-one 185 mg (0. 40 millimolar) dissolved in 2 ml of ethyl acetate, 46 mg of fumaric acid (0. 40 millimolar) and left at room temperature overnight. The crystals were collected by filtration to obtain 110 mg (47%) of the target compound as white crystals. 200401778 Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7.66 (2H, d,] = 9Ηζ), 7.47 (1H, s), 7. 33 (2H, d, J = 9Hz), 7. 08 (2H, d5 J = 9Hz), 6. 90 (2H, d, J = 9Hz), 6.  58 (2H, s), 5. 45-5. 52 (1H, m), 3. 72 (3H, s), 3. 2K2H, s), 2. 32-2. 50 (6H, m), 2.  08-2.  20 (1H, m), 1. 85-1.  95 (1H, m), 1.  64-1.  84 (4H, m) Infrared absorption spectrum vmx cnf1 ⑽r): 1756, 1 603, 1506, 1250, 1173 Mass analysis (FAB) m / z 422 ((M + H) +, free body). Example 7 7 8- [3- (4-trifluorotolyloxy) -3- (4-methoxyphenyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec -2-ketone and its fumarate (exemplified compound number 2-466) (77a) 8- [3- (4-trifluorotolyloxy) -3- (4-methoxyphenyl) propane [I]]-l-fluorene-3,8-diacryl [4,5] dec-2-one following the method of Example (3a), the 3- (4-trifluoromethanesulfonate) prepared in Reference Example 48 Toluyloxy) -3- (4-methoxyphenyl) propyl 290 mg and 1-fluorene-3,8-diacryl [4,5] dec-2-one hydrochloride 164 mg (0. 85 millimolar) was synthesized to obtain the target compound 224 mg (68%, 2 works). (77b) 8- [3- (4-trifluorotolyloxy) -3- (4-methoxyphenyl) propyl] -1-fluorene-3, 8-diacylspiro [4,5] dec 2-ketofumarate The 8- [3- (4-trifluorotolyloxy) -3- (4-methoxyphenyl) propyl prepared in Example (77a); 1-1-1 Pyrene-3, 8-diacillyl [4,5] dec-2-one 224 mg (0. 48 mmol) dissolved in 2 ml of ethyl acetate, and 56 mg of fumaric acid (0. 4 8 mmol), and left at room temperature overnight. The crystals were collected by filtration to obtain 230 mg (82%) of the target compound as white crystals. -198- 200401778 Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7. 55 (2H, d, J = 9Hz), 7.48 (1H, s), 7. 33 (2H, d, I = 9Hz), 7. 06 (2H, d, J = 9Hz), 6. 90 (2H, d, J = 9Hz), 6.  61 (2H, s), 5. 45-5. 52 (1H, m), 3. 72 (3H, s), 3. 22 (2H, s), 2. 32-2. 50 (6H, m), 2.  08-2. 20 (1H, m), 1.85—1.95 (1Η, m), 1.64-1. 84 (4H, m) Infrared absorption spectrum vmax cnf1 (KBr): 1 752, 1613, 1515, 1329, 1250 Mass analysis (FAB) m / z 465 ((M + H) +, free body) Elemental analysis 値 (C24H27F3N204_6 / 5C4H404) Calculate 値: C: 57. 29; Η: 5. 31; N: 4. 64 Found 値 C: 57 · 28; Η: 5. 21; Ν: 5. 〇 · Example 7 8 8- [3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] 3-methyl-1-fluorene-3,8-di Azuron [4,5] dec-2-one and its fumarate (exemplified compound number 2-467) (78a) 8- [3- (4-cyanophenoxy) -3- (3- Trifluorotolyl) -propyl] -3-methyl-1-3,8-diacylspiro [4 5 5] dec-2-one The 3- (4-cyano mesylate) prepared in Reference Example 21 Phenoxy) -3- (3-trifluorotolyl) -propyl ester 373 mg (0. 934 millimoles) dissolved in 5 milliliters of dimethylacetamide, and 3-methyl-1-fluorene-3, 8-diacryl [4,5] dec-2-one prepared in Reference Example 6 was added Hydrochloride 212 mg (1. 03 millimoles), sodium bicarbonate 157 mg (1. 87 mmol) and potassium iodide 16 mg (93. 4 micromolar) and stirred at 100 ° C for 8 hours. After warming to room temperature, water was added and extraction was performed twice with ethyl acetate. Combine the organic layers, rinse with water and saturated brine, and dry under sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5/1) to obtain the target compound 4 4 1 mg (9 9.  9 % ). -199- 200401778 (78b) 8- [3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -3-methyl-1 -fluorene-3, 8 -di Acron [4,5] dec-2-one keto fumarate 8- [3- (4-cyanophenoxy) -3- (3-trifluorotolyl) prepared in Example (78a) -Propyl] -3 -methyl-1-fluorene-3,8-diacryl [4,5] dec-2-one 441 mg (0. 931 mmol) dissolved in 5 ml of ethyl acetate, added 106 mg of fumaric acid (0. 9 3 1 mol)) and left overnight. The crystals were collected by filtration to obtain 301 mg (54 · 8%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD30D) δ ppm: 7. S0 (s, 1H), 7. 76-7. 56 On, 5H), 7. 13-7. 07 (m, 1H), 5. 69 (dd, 1H, J = 5. 5 Hz, 14. 0 Hz), 3. 29 (s, 2H), 2. 73 (s, 3H), 2. 55-2. 32 (m, 7H), 2. 22-2. 10 (m, 1H), 2. 07-1. 94 (m, 1H), 1.  81-1. 67 (m, 4H) Infrared absorption spectrum vmax cm · 1 (KBr): 1752, 1604, 1505, 1329, 1250, 1172, 1125, 1073, 1033, 983 Mass analysis (FAB) m / z 4 74 ((M + H) +, free body). Example 7 9 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -3-ethyl-1-fluorene-3,8- Diazaspiro [4,5] dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 6 8) (79a) 8-[(3S) -3- (4- Cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -3-ethyl-1 -fluorene-3 5 8 -diazelop [4 5 5] dec-2-one 6 7 prepared 8-[(3 S)-3-(4 -cyanophenoxy) -3-(3 -trifluorotolyl) -propyl] -1-fluorene-3, 8 -diacylspiro [ 4,5] dec-2-one 300 mg (0. 653 mmol) dissolved in 6 ml of dimethylformamide, and NaH 0 was added under stirring at room temperature. 029 g (content 60. 0%, 0. 718 millimolar), tetrabutylammonium iodide 24mg -200- 200401778 (65. 3 micromolar), ethyl iodine 0. 063 ml (0. 784 mmol), and stirred at room temperature for 9 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5/1) to obtain the target compound 230 mg (7 2.  3%). (7 91 ^) 8-[(33) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -3-ethyl-1 -fluorene-3,8 -Diaciro [4,5] dec-2-one ketofumarate The 8-[(3 S)-3-(4-cyanophenoxy) -3 prepared in Example (7 9 a) -(3 -trifluorotolyl) -propyl] -3 -ethyl-1-fluorene-3, 8 -diaciro [4,5] dec-2 · one 230 ml (0. 472 mmol) was dissolved in 3 ml of ethyl acetate, and fumaric acid 5 5 mg (0. 4 7 2 mmol), and left overnight at room temperature. The crystals were collected by filtration to obtain 184 mg (64.6%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) 5ppm: 7. 81 (s, lH), 7. 75-7. 57 (m, 5H), 7. 13-7. 07 (m, 2H), 5. 70 (dd, 1H, J = 5. 5 Hz, 14. 0 Hz), 3. 29 (s, 1H), 3. 16 (q, 2H, J = 7. 4 Hz), 2. 60-2. 35 (m, 7H), 2. 22-2. 10 (m, 1H), 2. 08-1. 9 5 (m, 1H), 1. 82-1. 68 (m, 4H), 1. 05 (t, 3H, J = 7. 4 Hz) Infrared absorption spectrum vmax cur1 (KBr): 1748, 1605, 1506, 1 329, 1 250, 1172, 1 125, 1073, 983, 836, 803, 760, 706, 647 Mass analysis (FAB) m / z 488 ((M + H) +, free body). Example 8 0 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) · propyl] -3-methylthiomethylfluorene-3, 8-di Azuron [4,5] dec-2-one and its fumarate (exemplified optically active compounds of compound numbers 2-4 6 9) (80a) 8-[(3S) -3- (4-cyano Phenoxy) -3- (3-trifluorotolyl) -propyl] -3- 200401778 methylthiomethyl-1 -fluorene-3,8-diacryl [4,5] dec-2-one 8-[(3 S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propylbu 1-fluorene-3, 8-diacryl prepared in Example 68 [ 4,5] dec-2-one 300 mg (0. 653 mmol) dissolved in 6 ml of dimethylformamide, and 29 mg of NaH (content 60. 0%, 0. 718 millimolar), tetrabutylammonium iodide 0. 024 g (65. 3 micromolar), methylthiomethyl chloride 0.1 066 ml (0. 784 mmol), and stirred at room temperature for 9 hours. After the reaction was completed, water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 200 mg (yield 59.0%) of the target compound as an oily substance. (80b) 8-[(3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl] -3-methylthiomethyl-1-fluorene- 3,8 Diaciro [4,5] dec-2-one fumarate The 8-[(3S) -3- (4-cyanophenoxy) prepared in Example (80a) · 3 · (3 -Trifluorotolyl) -propyl] -3 -methylthiomethyl · 1 -fluorene-3,8 -diaciro [4,5] dec-2-one, 200 ml (0. 385 mmol) was dissolved in 3 ml of ethyl acetate, 45 mg (0.385 mmol) of fumaric acid was added, and it was left overnight. The crystals were collected by filtration to obtain the target compound 191 mg (78. 0%). Nuclear magnetic resonance spectrum (40_ζ, Hall 0-d6) (5 ppm: 7. 79 (s, 1Η), 7. 78-7. 55 (m, 5H), 7. 13-7. 07 (m, 1H), 6. 73-6. 65 (m, 1H), 5. 70 (dd, 1H, J = 5. 50 Hz, 14.  0 Hz), 4. 37 (s, 2H), 3. 37 (s, 1H), 2. 58-2. 34 (m, 7H), 2. 22-2. 10 (m, 1H), 2. 05 (s, 3H), 2. 10-1. 95 (m, 1H), 1. 82-1. 65 (m, 4H) Infrared absorption spectrum vmax cur1 (KBr): 1754, 1604, 1506, 1431, 1329, 1251, 1 173, 1127, 1073, 984 Mass analysis (FAB) m / z 520 ((M + H) +, Free body). -202- 200401778 Reference Example 1 1- 噚 -3,8-Diacillyl [4 5 5] dec-2-one ketone hydrochloride  Med.  Che m. , 38,3772-3779 (1995) Synthesis of 2-oxo-1 -fluorene-3,8-diaciro [4,5] dec-8-carboxylic acid tert-butyl ester 2.50 g (9 .  75 mmol) dissolved in 2.5 ml of ethanol, and 4 N H C 1 / dioxane 2. 8 ml, stirred at room temperature for 20 hours, the solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol / ether to obtain white crystals of the target compound 1.  1 g (59%). Infrared absorption spectrum VmaxCm'KBr): 3227, 2970, 1762, 1 565, 1 43 1,1274 Mass analysis (EI) m / zl56 (M +, free body) Elemental analysis 値 (C7H12N 2 0 2 -HC1 (%)) Calculate 値: C: 43. 64; H: 6. 80; N: 14. 54; Cl: 18. 40 Measured 値: C: 4 3 · 5 9; Η: 6.  8 7; N: 1 4 · 6 5; C 1: 1 7. 5 0. Reference Example 2 Bis- (3-trifluorotolyl) methyl 2-chloroethyl ether Bis- (3-trifluorotolyl) methanol was 0.1%. 5 grams (1. 56 mmol) and 2-chloroethanol.  6 ml was dissolved in 5 ml of toluene, and a catalyst amount of p-toluenesulfonic acid monohydrate was added and heated under reflux for 5 hours. After cooling at room temperature, the solution was extracted with a saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate layer was washed with saturated common salt water, dried, and concentrated to obtain the target compound 0. 55 grams (92%) of an oily substance. Nuclear magnetic resonance spectrum (400MHz, CDCl3) 5ppm: 7. 45-7. 70 (8H, no, 5. 52 (lH, s), 3. 70-3. 78 (4H, m). -203- 200401778 Reference Example 3 Bis- (3-trifluorotolyl) methyl 3-chloropropyl ether Bis- (3-trifluorotolyl) methanol 249 mg (0. 78 millimoles) and 2 ml of 3-chloro-1 -propanol were dissolved in 4 ml of toluene. A catalytic amount of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 12 hours. After cooling at room temperature, the solution was extracted with a saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 50: 1) to obtain the target compound 2 94 mg (92%) as an oily substance. Reference Example 4 3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propanol Reference Example (4a) 3-cyanophenyl-3'-trifluorotolylmethanol 3- 20 grams of bromobenzotrifluoride (8 8.  8 millimolar) was dissolved in 2000 ml of tetrahydrofuran, and 6 ml of n-butyllithium (1. 56 mol / L in hexane 97. 7 millimoles). After stirring at -78 ° C for 30 minutes, 3-cyanobenzaldehyde 1 1 was added dropwise over 30 minutes.  7 grams (8 8.  8 mmol) in tetrahydrofuran (50 ml). After stirring at -78 ° C for 1 hour, warm to room temperature and stir for 1 hour. The reaction solution was added with water and extracted twice with ethyl acetate. The organic layer was combined, washed with water and saturated brine in this order, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 15:85) to obtain 3-cyanophenyl-3'-trifluorotolyl methanol 16. 3 grams (6 6%). Nuclear magnetic resonance spectrum (400MHz, CDC13) δ ppm: 7. 71 (1H, s), 7.66 (1H, s), 7. 54-7.72 (3Η, m), 7. 45-7 · 52 (3Η, m), 5.92 (1Η, s). -204- 200401778 Reference Example (4b) 3-[(3-cyanophenyl) (3f -trifluorotolyl) methoxy] propanol The 3-cyanophenyl-3'- prepared from Reference Example (4a) Trifluorotolyl methanol 16. 3 grams (58. 8 mmol) dissolved in 160 ml of N, N-dimethylformamide. Add NaH under ice cold 2. 8 grams (55% content, 64. 7 millimoles), stir for 30 minutes, and add allyl bromide 8 dropwise between 5 minutes.  9 ml (7 0.  6 millimoles). After stirring for 30 minutes under ice-cooling, the temperature was returned to room temperature and stirred for 1 hour. The reaction solution was added with water and extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in this order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 170 ml of tetrahydrofuran. Add 9-borabicyclo [3,3,1] nonane (948 ^ 0. 5 mol / L tetrahydrofuran solution 141 ml (70. 6 millimoles), warm to room temperature and stir for 16 hours. Under ice cooling, 27 ml of ethanol and 27 ml of a 6N-NaOH solution were sequentially added, and 27 ml of 30% hydrogen peroxide was added dropwise over 30 minutes. After stirring for 30 minutes under ice-cooling, water was added and extraction was performed twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in this order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash chromatography (eluent: ethyl acetate: n-hexane = 3 5: 6 5) to obtain the target compound 13.8 g (70%). Nuclear magnetic resonance spectrum (400MHz, CDCl3) 0ppm: 7. 65 (lH, s), 7. 55-7. 59 (4H, in), 7. 48-7. 5K3H, m), 5. 42 (1H, s), 3. 82 (2H, t, J = 6. 0 Hz), 3. 62 (2H, t, J = 6. 0 Hz), 1. 87-1. 93 (2H, m) 〇 Reference Example 5 Bis (4-fluorophenyl) methyl 2-chloroethyl ether Bis (4-fluorophenyl) methanol 18. 4 g (84 mmol) and 2-chloroethanol 1 1.  2 ml, followed by the reaction and purification of Reference Example 2 to obtain the target compound 1 2.  4 -205- 200401778 g of oily substance. Reference example 6 3 -methyl-1 -fluorene-3 5 8 -diaciro [4,5] dec-2-one ketone hydrochloride (6 &): 8-second butoxyfluorenyl-3 -Methyl-1-pyrene-3,8-monospiro [4,5] dec-2-one will be 8-thirdbutoxycarbonyl-1-fluorene-3,8-diacylspiro [4,5] 5 grams of dec-2-one (27. 3 mmol) dissolved in 70 ml of dimethylformamide, and methyl iodide was added 2. 55 ml (4 1. 0 millimoles). Add HaH 1 under ice cooling. 3 grams (30. 0 millimoles). Stir for 30 minutes under ice-cooling and then for 1 hour at room temperature. Pour into water and extract twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine in this order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 7 5: 2 5) to obtain 6.9 g (93%) of the target compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CDC13) δ ppm: 3.88-3 · 73 (2H, Hi), 3. 30-3. 17 (4H, m), 2.85 (3H, m), 1. 88-1. 80 (2H, m), 1. 67-1. 56 (2H, m), 1.41 (9H, s). Reference Example (6 b) ·· 3 -methyl-1 -fluorene-3,8 -diaciro [4,5] dec-2-one hydrochloride 6 g (22 mmol) of -1- · -3, 8 · diactil [4,5] dec-2-one was dissolved in 60 ml of ethanol, and 4N-hydrochloride di Pinane 5 5 ml. After stirring for 30 minutes under ice cooling, it was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the crystals were recrystallized from methanol-ether to obtain the target compound as white crystals 3.  8 grams (83%). Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) δ ppm: 3. 37 (2H, s), 3. 20-3. 13 (2H,

Bi), 3.09-3.01 (2H, m), 2.73 (3H, m), 1.99-1.96 (4H, m). -206- 200401778 Reference Example 7 Bis (4-fluorophenyl) 3-chloropropyl ether 1.5 g (6.81 mmol) of bis- (4-fluorophenyl) methanol and 1.1 ml of 3-chloropropanol The reaction was performed in the same manner as in Reference Example 2 and purified to obtain 2.02 g (99%) of the target compound as an oily substance. Reference Example 8 (3,4-difluorophenyl) benzyl 2-chloroethyl ether (3,4-difluorophenyl) benzyl alcohol 0.88 g (4.00 mmol) and 2-chloroethanol 0.5 5 4 Ml, reacted and purified following Reference Example 2 to obtain the target compound 1.12 g (99%) ° Nuclear magnetic resonance spectrum (400MHz, CDCl3) 5ppni: 6.90-7.3 5 (8H, m), 5.39 (1H5 s) 5 3 · 65-3 · 75 (4Η, m). Reference Example 9 (3-cyanophenyl) (3f-trifluorotolyl) methyl 2-chloroethyl ether Reference Example (9a): 3-cyanophenyl-3 trifluorotolylmethanol 3-bromobenzotrifluoro 20 g (88.8 mmol) and 3-cyanobenzaldehyde | 2.9 g (88.8 mmol) were reacted and purified in the same manner as in Reference Example (4a) to obtain 16 · 3 g (66%) of the target compound. Nuclear magnetic resonance spectrum (400MHz, CDC13) ppm: 7.71 (1H, s), 7.66 (1H, s), 7.54-7.72C3H, m), 7.45-7.52 (3H, m), 5.92 (1H, s) 〇Reference Example (9b): (3-cyanophenyl) (3'-trifluorotolyl) methyl 2-chloroethyl ether (3-cyanophenyl) (3trifluorotolyl) prepared from Reference Example (9a) ) 576 mg (2.08 mmol) of methanol was dissolved in 5 ml of dichloromethane, 230 ml (3.12 mmol) of sulfenyl chloride was added, and 1 drop of dimethylformamide was added. Stir at room temperature -207- 200401778 for 3 hours, evaporate the solvent under reduced pressure, and azeotropize twice with ether. The obtained residue was dissolved in 5 ml of 2-chloroethanol, 40 mg (0.2 1 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 120 ° C for 4 8 hours. After the reaction was completed, the temperature was returned to room temperature, water was added and the mixture was extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash chromatography (eluent: ethyl acetate: n-hexane = 5: 95) to obtain the target compound 46 1 mg (65%). Nuclear magnetic resonance spectrum (400MHz, CDCl3) 3ppm: 7.42-7.74 (8Η5 m), 5.50 (1H, s), 3.60-3 · 75 (4Η, m). Reference Example 1 0 Bis [(8 -azinebicyclo [3 · 2 · 1] octane) -3,5 '-(Pfazole)]-2 ketone Reference Example (10a): 3 -Third-Butane Oxycarbonylmethyl-3 · hydroxy-8-azinebicyclo [3.2.1] Lithium tert-butyl acetate 5.07 which will be synthesized by the method described in JACS, 95, 3050 (1973) G (4 1.6 mmol) / toluene solution, add 20 ml of toluene solution of 7.2 g (3 2.0 mmol) of N-butoxycarbonyl nortropine dropwise while stirring under ice cooling, and stir at the same temperature for 1 hour . After the reaction was completed, 1 N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 5.8 g of unrefined target compound as white crystals. Reference Example (10b) .. 3-Carboxymethyl-3 -hydroxy-8-acylbicyclo [3.2.1] Octane-8-carboxylic acid tert-butyl ester was prepared from Reference Example (10a) 3-Third-butoxycarbonylmethyl-3-hydroxy-8-azinebicyclo [3 · 2 · 1] octane-8-carboxylic acid tert-butyl ester 5. 8 9 g (about 17 · 3 mmol Ear) dissolved-208- 200401778 50 ml of ethanol, 50 ml of a 1 NN a a solution was added while stirring at room temperature. Stir for 1.5 hours at 100 ° C. After the reaction was completed, the reaction solution was weakly oxidized with 1 N hydrochloric acid under ice-cooling stirring, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the unrefined target compound as white crystals (4.92 g). Reference Example (10c): Spiro [(8-Third-butoxycarbonyl-8-azinebicyclo [3.2.1] octane) -3,3 1- (Panidine)]-2 1-one 4.92 g (approximately 17.3 mmol) of 3-carboxymethyl-3-hydroxy-8-acylbicyclo [3.2.1] octane-I carboxylic acid third butyl ester prepared in Reference Example (10b) was dissolved In 90 ml of toluene, 4.8 ml (34.5 mmol) of triethylamine and 7.4 ml (3 4.5 mmol) of diphenylphosphonium azide were added under stirring at room temperature, and heated under reflux for 30 minutes. After the reaction was completed, the reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/4) to obtain 4.64 g of the target compound (yield: 95. 3%). White crystals. Nuclear magnetic resonance spectrum (400MHz, CDCl3) (5ppm: 4.79 (lH, br.s.), 4.16 {40 (2 Η, m), 3.27 (2Η, s), 1.82-2 · 24 (8Η, m) ， 1 · 46 (9s, s). Reference Example (10 d): Bis [(8 -Acridinebicyclo [3 · 2 · 1] octane) -3,5 '-(oxazolidine)]-2 ^ The ketone spiro [(8-third-butoxycarbonyl-8-acylbicyclo [3.2.1.octane) -3-5 3 '-(oxanidine)]-2 prepared in Reference Example (10c) -2 '-Ketone 7 3 4 mg (2.6 mmol) was dissolved in 7.0 ml of dichloromethane, and 7 ml of trifluoroacetic acid was added under stirring at room temperature, followed by stirring at room temperature for 1 hour. After the reaction was completed, saturated bicarbonate was used. Neutralize with sodium solution. Extract the organic layer with a mixed solvent of chloroform / methanol = 3/1 to obtain the target compound 3 41 mg (yield 71.9%) as white crystals. -209- 200401778 Nuclear magnetic resonance spectrum (400MHz, CD30D ) (5 ppm: 3.57-3 · 49 (m, 2H), 3.26 (s, 2 Η), 2.19-2.11 (m, 2Η), 2.16 (s, 1Η), 2.14 (s, 1H), 1.92 -1.88 (m, 1H), 1.88-1.85 (m, 1H), 1.83-1.76 (m, 3H) Infrared absorption spectrum vmax cr1 (KBr): 1774,1484,1406,1385,1331,1259 Mass analysis (FAB) m / z 182 ((M + H) +, free body). Example 1 1 3 -Chloro-1- (4-phenylene) -1-propanol Dissolve 2 g (10.7 mmol) of 3-chloro-4'-fluoropropanone in 10 ml of tetrahydrofuran and ethanol 10 ml, sodium borohydride 4.05 mg (1 0.7 mmol) was added under cooling. After stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. 2 The organic layer was combined, washed sequentially with water, saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/4 ) To obtain 1.75 g (87%) of the target compound. Nuclear magnetic resonance spectrum (400 MHz, DMS0-d6) (5 ppm: 7.38-7 · 31 (2H, m), 7.08-7 · 02 (2H , m)? 4.99-4. 93 (1H, m), 3. 78-3. 70 (1H, m), 3.59-3. 51 (1H, m), 2.27-2.17 (1H, m), 2.1 Bu 2.02 (1H, m). Reference Example 1 2 3-chloro-1- (4-fluorophenyl) propyl 4-fluorophenyl ether 3-chloro-1-(4-fluorophenyl) -1 -propanol 2 prepared in Reference Example 1 1 0 0 mg (1.06 mmol) was dissolved in 5 ml of toluene, and 118 mg (1.06 mmol) of 4-fluorophenol and 310 mg (1.06 mmol) of triphenylphosphine were added. Add 186 microliters (1.16 mmol) of diethyl azodicarboxylate and stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-210-200401778: n-hexane = 1: 9) to obtain 190 mg (64%) of the target compound. Nuclear magnetic resonance spectrum (400MHz, DMSO-d6) (5ppm: 7.34-7.30 (2H, ni), 7.06-7.01 (2H, m), 6. 90-6. 84 (2H, m), 6. 79-6. 75 (2H, m), 5. 30 ~ 5.25 (1H, in), 3.83-3.77 (1H, m), 3.61 -3.55 (1Η, in), 2.49-2.39 (lH, in) m2.20- 2 · 11 (1Η, m). Reference Example 1 3 3 -Hydroxy-3-(3 -trifluorotolyl) propionic acid ethyl ester 25.0 g (144 mmol) of 3-trifluoromethylbenzaldehyde was dissolved in tetrahydrofuran 300 ml, 23.9 ml (215 mmol) of ethyl bromoacetate and 14.1 g (215 mmol) of zinc powder were added under stirring at room temperature, and heated under reflux for 1 hour. After the reaction was completed, the reaction solution was 1 N hydrochloric acid was added, and the organic layer was extracted with ethyl acetate. After the organic layer was dried under sodium sulfate, the solvent was distilled off under reduced pressure to obtain the target compound 39.1 g as an oily substance. Reference Example 1 4 1- (3 -Trifluorotolyl · propane-1,3-diol The 3-hydroxy- (3-trifluorotolyl) propionic acid ethyl ester prepared in Reference Example 13 39.1 g (14 4 mmol) Dissolve in 300 ml of ether, and add 8.17 g (144 mmol) of lithium aluminum hydride-ether (100 ml) under ice-cold stirring. After stirring at room temperature for 1 hour, cool in ice Under stirring, 8 ml of water, 1 NN a 0 Η aqueous solution, 8 ml of water, and 16 ml of water were added successively, and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered through celite and washed with ethyl acetate several times. The organic layer was removed by distillation, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain the target compound 23.6 g (yield 7 4.8%) as an oil. Reference Example 1 5 3-Hydroxy-3-(3-trifluorotolyl) propyl mesylate 200401778 1- (3-trifluorotolyl) -propane-1,3-diol prepared from Reference Example 1 4 2.00 g (9.88 mmol) was dissolved in 30 ml of dichloromethane, 0.70 ml (9.08 mmol) of methanesulfonyl chloride and 2.54 ml (18.2 ml) of triethylamine were added while stirring at 40 ° C. After the reaction was completed, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain the target compound 2 44 mg (yield 89,9%) as an oily substance. Nuclear magnetic resonance spectrum (400MHz CDC13) δ ppm: 7.69-7.44 On, 4H), 5 · (Π-4 · 96 (m, 1H), 4.58-4.49 (m, 1H), 4.37-4.25 (m, 1H), 3.02 (s , 3H), 2.10-2.03 On, 2H). Reference Example 16 3- (4-chlorophenoxy) -3- (3-trifluorotolyl) propyl methanesulfonate 300 mg (1.0 mg mol) of 3-hydroxy-3-(3-trifluorotolyl) propyl sulfonate was dissolved in 6 ml of toluene, and 142 mg of p-chlorophenol (1.11) was added under stirring at room temperature. Mmol), 317 mg (1.21 mmol) of triphenylphosphine, 0.19 ml (1.21 mmol) of diethyl azodicarboxylate, and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 290 mg (yield 7 0.5%) of the target compound as an oily substance. NMR spectrum (400MHz, CDC13) ppm: 7.62-7,44 (m, 4H), 7.15-7. 10 (m 1Η), 6.92-6 · 88 (ιη 1H), 6.84- 6.82 (ιη 1H), 6.72-6 · 69 (ιη 1H), 5.39-5.35 (m, 1 Η), 4.58-4.42 (m, 1H), 4.38-4 · 32 On, 1H), 2 97 (s, 3H), 2.4 b 2.03 (m, 2H). Reference Example 1 7 3- (2 · fluorophenoxy) -3- (3-trifluorotolyl) propyl mesylate 2 12- 200401778 3-hydroxy-3 methanesulfonic acid prepared in Reference Example 15 -(3-Trifluorotolyl) propyl 300 mg (1.01 mmol) was dissolved in 6 ml of toluene, and 124 mg (1.11 mmol) of orthofluorophenol and 317 mg (1.21) of triphenylphosphine were added under stirring at room temperature. Mmol), diethyl azodicarboxylate (1.9 ml, 1.2 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 290 mg (yield 73.5%) of the target compound as an oily substance. Reference Example 1 8 3- (3-fluorophenoxy) -3- (3-trifluorotolyl) propyl mesylate The 3-hydroxy-3-(3 -trimethane mesylate) prepared in Reference Example 15 300 mg (1.01 mmol) of fluorotolyl) propyl ester was dissolved in 6 ml of toluene, and 124 mg (1.11 mmol) of metafluorophenol, 317 mg (1.21 mmol) of triphenylphosphine were added under stirring at room temperature, Diethyl azodicarboxylate 0.19 ml (1.21 mmol) was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 230 mg (yield 58.3%) of the target compound as an oily substance. Reference Example 1 9 3- (4-trifluorotolyloxy) -3- (methanesulfonyl) propyl mesylate The 3-hydroxy-3 -methanesulfonic acid mesylate prepared in Reference Example 15 was prepared. 300 mg (1.01 mmol) of trifluorotolyl) propyl ester was dissolved in 6 ml of toluene, and 4-hydroxybenzotrifluoride (179 mg, 1.1 mmol) was added under stirring at room temperature. Phenylphosphine 3 17 mg (1.21 mmol) and 0.19 ml (1.21 mmol) of diethyl azodicarboxylate were stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate -213- 200401778 ester = 4/1) to obtain the target compound 265 mg (yield 5 9.6%) as an oily substance. Reference Example 2 0 3- (3-Cyanophenoxy) -3- (3-trifluorotolyl) propyl mesylate The 3 -hydroxy-3-(3 -trimethane mesylate) prepared in Reference Example 15 300 mg (1.01 mmol) of fluorotolyl) propyl ester was dissolved in 6 ml of toluene, and 3-cyanophenol 132 mg (1.11 mmol) and triphenylphosphine 317 mg (1.21 mmol) were added under stirring at room temperature. 1. 0.19 ml (1.21 mmol) of diethyl azodicarboxylate, and stir at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 309 mg (yield 7 6.9%) of the target compound as an oily substance. Reference Example 2 1 3- (4-Cyanophenoxy) -3- (3-trifluorotolyl) propyl mesylate The 3-hydroxy-3-(3 -trimethane mesylate) prepared in Reference Example 1 300 mg (1.01 mmol) of fluorotolyl) propyl ester was dissolved in 6 ml of toluene, and 4-cyanophenol 132 mg (1.11 mmol) and triphenylphosphine 317 mg (1.21 mmol) were added under stirring at room temperature. 1. Diethyl azodicarboxylate 0.19 ml (1.21 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain an oily substance of 35 mg (yield 83. 3%) of the target compound. Reference Example 2 3 3-Chloro-1- (4-fluorophenyl) propyl 3-trifluorotoluene Using 3-chloro-1-(4-fluorophenyl) -1-propanol prepared in Reference Example 1 1 200 mg (1.06 mmol) and 172 mg (1.06 mmol) of 3-hydroxybenzotrifluoride were reacted and purified in the same manner as in Reference Example 12 to obtain the target compound 3 06 mg (87%). -214- 200401778 NMR spectrum (400MHz, CDCl3) 5ppm: 7.57-7.52 (lH, m), 7.42-7.33 (3H, m), 7.10-7. 03 (2H, m), 6. 98-6. 93 (1H, in), 6. 83-6. 80 (1H, m), 5. 56-5.50 (1H, m), 3.93-3.85 (lH, m), 3. 66-3.59 (1H, m) 5 2. 61-2. 51 (1H, m), 2. 27-2.17 (1H, m) o Reference Example 2 3 3- (4-fluorophenoxy) methanesulfonic acid-3- [3- (trifluoro Methyl) phenyl] propyl ester was prepared using Reference Example 15 3-hydroxy-3-[3- (trifluoromethyl) phenyl] propyl ester 360 mg (1.21 mmol) as reference example 16 The reaction and purification were performed to obtain 294 mg (62%) of the target compound. Nuclear magnetic resonance spectrum (400MHz, CDC13) (5 ρρΐϋ: 7.63-7 · 46 (4Η, m), 6.94-6.74 (4Η, m), 5. 32-5. 27 (1H, m), 4. 57 -4. 49 (1H, m), 4. 40-4. 33 (1H, m), 2.97 (3H, s), 2. 42-2. 22 (2H, m). Reference Example 24 Methanesulfonic acid 3 -[3- (trifluoromethyl) phenoxy] -3 · [3- (trifluoromethyl) phenyl] propyl ester methanesulfonic acid 3-hydroxy-3 prepared in Reference Example 15-[3- (Trifluoromethyl) phenyl] propyl 360 mg (1.21 mmol) and 3-hydroxybenzotrifluoride 149 mg (1.2 1 mmol) were reacted and purified in the same manner as in Reference Example 19 Target compound 3 2 6 mg (61%). Nuclear magnetic resonance spectrum (400MHz, CDC13) δ ppm: 7.65-7 · 49 (4Η, m), 7.34-7 · 20 (1Η, m), 7.22-7 16 (1Η, m), 7.14-7.10 (1Η, m), 6. 99-6. 95 (1H, m), 5. 45-5. 49 (1H, m), 4.55-4.48 (lH, m ), 4.39-4.34 (lH, in), 2.98 (3H, s), 2.45-2.26 (2H, m). Reference Example 2 5 (lR) -3-chloro-1- (4-fluorophenyl) -1 -Propanol Dissolve 3 -chloro- -fluoropropanone (108 mM) in tetrahydrofuran 400 mM -215- 200401778 liters and add (+)-B -Chloroisoisopine at -78 ° C Alkylborane 4 0 g (1 2 5 mmol). After stirring at -7 8 ° C for 30 minutes, place at -2 (TC for 15 hours. Add 2 ml (2 19 mmol) of diethanolamine and stir at room temperature. 2 hours. Add 400 ml of diethyl ether to the reaction solution, filter off insoluble matter, evaporate the mother liquor under reduced pressure, and purify the residue by silica gel column chromatography (eluent: toluene / n-hexane = 4/1) The compound was recrystallized from n-hexane to obtain 13.1 g (65%) of the target compound.

Peripheral analysis: Optically active HPLC column [Chiral Pak 0J (0.4 6cm X 25cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 1.0 ml / min] was measured for optical purity Confirmed to be 99.1% ee. Nuclear magnetic resonance spectrum (400MHz, CDCl3) (5ppm: 7.38-7.31 (2H, in), 7.08-7.02 (2H, m), 4.99-4. 93 (1H, m), 3. 78-3. 70 (1H, m), 3.59-3. 51 (1H, m), 2. 27-2.17 (1H, m), 2. 11-2. 02 (1H, m). Reference Example 2 6 2-chloroethyl- (3 1,3'-di-trifluoromethoxyphenyl) methyl ether 1.20 g (4.98 mmol) of 3-trifluoromethoxybromobenzene was dissolved in 2 ml of tetrahydrofuran, and added dropwise at 1-8 ° C with stirring. 5 7 N n-butyllithium (hexane solution) 3.20 ml (4.98 mmol), stirred at -78 ° C for 5 minutes, then added 1.20 g of 3-trifluoromethoxybenzaldehyde (3. 3 2 mmol), and stirred under ice cooling for 3 hours. After the reaction was completed, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. Solvent. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 0/1) to obtain 675 mg of the target compound (yield 43.5%) as an oil. Compound 6.5 mg (2.17 mmol) was dissolved in tetrahydrofuran 14 mmol 200401778 liters, and acetic anhydride 0.4 ml (4.3 3 mmol) was added under ice-cooled stirring. Mol), 0.90 ml (6.52 mmol) of triethylamine, 0.13 g (1.09 mmol) of 4-dimethylaminopyridine, and stirred at room temperature for 2 hours. After the reaction was completed, water was added to the reaction solution, and acetic acid Ethyl acetate extraction. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 5/1) 480 mg of the target compound (yield 53.3%) was obtained as an oily substance. 480 mg (1.22 mmol) of the obtained compound was dissolved in 7.2 ml of toluene and stirred at room temperature. Add 0.3 3 ml of 2-chloroethanol (4.87 mmol) and 23 mg (0.12 2 mmol) of p-toluenesulfonic acid monohydrate, and stir at 100 t for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 0/1) to obtain 170 mg of the target compound (yield 33.7). %) Oily substance. Reference Example 2 7 3-Hydroxy-3- (2-fluorophenyl) -propionic acid ethyl ester Following the procedure of Reference Example 13, 4.55 g (36.7 mmol) of 2-fluorobenzaldehyde was used. ,bromine Acid ethyl ester 6.1 2 g (6.7 3 mmol) of the reaction, the desired compound can be obtained 7.6 5 g of an oily substance. It was used in the next reaction without purification. Reference Example 2 8 1- (2-Fluorophenyl) -propan-1,3-diol was prepared using 3-hydroxy-3- (2-fluorophenyl) -propionic acid ethyl ester prepared in Reference Example 27 7. 6 5 G, imitating the method of Reference Example 14 to prepare 5.17 g of the target compound (yield 83%, 2 works) as an oily substance. 200401778 NMR spectrum (400MHz, CDCl3) 5ppm: 7.52-7.57 (m, lH), 7.22-7.2 9 (m, 1H), 7.13-7.18 (m, 1H), 6.98-7.05 (m, 1H), 5.26- 5.32 (m5 1H), 3.86-3.93 (m, 2H), 2.91-2.97 (m, 1H), 2.13-2.17 (m, 1H), 2.01 (t, 2H, J = 5Hz). Reference Example 2 9 Methanesulfonate 3-hydroxy-3- (2-fluorophenyl) propyl acid 1- (2-fluorophenyl) -propane-1,3-diol prepared in Reference Example 2 8 5.0 g (2 9.4 milligrams) Moore), following the method of Reference Example 15 to obtain 6.8 g (yield 93%) of the target compound as an oily substance. NMR spectrum (_MHz, CDCl3) 5ppm: 7.45-7.52 (m, lH), 7.26_7.3 2 (m, 1H), 7.14-7.20 (m, 1H), 7.01-7.08 (m, 1H), 5.13- 5.23 (m, 1H), 4.48-4.55 (in, 1H), 4.30-4.37 (in, 1H), 3.02 (s, 3H), 2.10U6 (m, 3H). Reference Example 3 0 3- [4- (trifluoromethyl) phenoxy] -3- (2-fluorophenyl) propyl mesylate Following the procedure of Reference Example 16 using 3-hydroxy-methanesulfonic acid, 315 mg (1.27 mmol) of 3- (2-fluorophenyl) propyl and 246 mg (1.52 mmol) of 4-hydroxybenzyltribromo were reacted to obtain 373 mg of the target compound (75% yield) ). Nuclear magnetic resonance spectrum (400MHz, CDCl3) 6ppm: 7.47 (d, 2H, J = 9Hz), 7.27-7.3 8 (hi 2H), 7.07-7.15 (m, 2H), 6.15 (d, 2H, J = 9Hz), 5.58-5.73 (m, 1H), 4.46 -4.54 (m, 1H), 4.34-4.42 (in, 1H), 2,97 (s, 3H), 2.35-2.47 (in, 2H). Reference Example 3 1 3 -Hydroxy-3-(4-cyanophenyl) -propionic acid ethyl ester The method of Reference Example 13 was used in the same manner as in Example 13. Using 4-cyanobenzaldehyde 4.65 g (3.5 4 mmol), bromine Ethyl acetate 4.60 g (27.5 mmol) was reacted to obtain 5.06 g (65%) of the target compound as an oily substance. -218- 200401778 NMR spectrum (400MHz, DMS〇-d6) δ ppm: 7.66 (2H, d, J = 8Hz), 7.51 (2 H, d, J = 8Hz), 5.15-5.21 (1H, m), 4.20 (2H, q, J = 7Hz), 3.56 (1H, d, J = 4Hz), 2.65-2 · 76 (2Η, m), 1.27 (3H, t, J = 7Hz). Reference Example 3 2 1- (4-Cyanophenyl) -propane-1,3-diol Using 3-hydroxy-3- (f cyanophenyl) -propionic acid ethyl ester prepared in Reference Example 31 5.06 g According to the method of Reference Example 14, an oily substance of 2.90 g (yield 71%) of the target compound can be obtained. NMR spectrum (400MHz, CDC13) δ ppm: 7.66 (2H, d, J = 8Hz), 7.45 (2 H, d, J = 8Hz), 5.03-5.68 (1H, m), 3.85-3.95 (2H, m ), 3.28-3.31 (1H, m), 1. 93-2.03 (3H, m). Reference Example 3 3 3-hydroxy-3- (4-cyanophenyl) propyl mesylate was prepared using Reference Example 3 2 1-(4-cyanophenyl) -propane-1,3-diol 2.90 g (1 6.4 mmol), the method of Reference Example 15 can be used to obtain the target compound 2 · 2 3 g (product Rate 5 4%) oily substance. NMR spectrum (400MHz, CDC13) δ ppm: 7.67 (2H, d, I = 9Hz), 7.51 (2 H, d, J = 9Hz), 4.97-5.02 (1H, m), 4.51-4.59 (1H, m ), 4.29-4.36 (1H, m), 3. 05 (3H, s), 2.00-2.18 (3H, m). Reference Example 3 4 3- [3- (trifluoromethyl) phenoxy methanesulfonate ] -3- (4-Cyanophenyl) propyl was used in the same manner as in Reference Example 16 using 3-hydroxy-3- (4-cyanophenyl) propyl mesylate prepared in Reference Example 3 300 (1.17 Mol)) and 2-18 mg (1.34 mol) of 3-hydroxybenzyltribromo were reacted to obtain 420 mg of the target compound (yield 89%). -219- 200401778 NMR spectrum (400MHz, CDC13) δ ppm: 7.68 (2H, d, J = 9Hz), 7.50 (2H, d, J = 9Hz), 7.31 (1H, dd, J = 7 Hz, 8 Hz), 7.195 (1H, d, J = 7Hz), 7.09 (1H, s), 6.94 (1H, dd, J = 8Hz, 2Hz), 5.39-5.44 (1H, m), 4.47-4.55 (1H, m), 4.35 -4.22 (1H, m), 2.99 (3H, m), 2.26-2.42 (2H, m). Reference example 3 5 3- [4- (trifluoromethyl) benzene mesylate Oxyoxy] -3- (4-cyanophenyl) propyl was used in the same manner as in Reference Example 16 using 3-hydroxy-3- (4-cyanophenyl) propyl mesylate prepared in Reference Example 33. (1.21 millimoles) and 4--2.5 mg (1.39 millimoles) of pentyltribromide were reacted to obtain 391 milligrams of the target compound. It was used in the next reaction without purification. Reference Example 3 6 (lR) -3-chloro-1- (4-chlorophenyl) propan-1-ol Followed the method of Reference Example 2 5 using 3,4 f -dichloropropanone 5. 5 1 G (27. 1 mmol), (+)-B-chlorodiisospinnamylphenylborane 9.13 g (28.5 mmol) was reacted to obtain the target compound 3. 40 g (61% yield) of a colorless oily substance.

The optical purity was measured using an optically active HPLC column for analysis [ChiralPak 0J (0.46cm X 25cm), manufactured by Daicel, elution solvent: Zhengjiyuan / 2-propanol = 90/10, flow rate: 0.7 ml / mi η], Confirmed to be 9 7 · 1% ee. NMR spectrum (400MHz, CDC13) δ ppm: 7.34-7.29 (m, 4H), 4.94 (dt, 1H, J = 4.4 Hz, 8.1 Hz), 3.74 (ddd, 1H, J = 5.9 Hz, 8.5 Hz, 11.0 Hz), 3. 54 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.24-2.15 (m, 1H), 2.09-2.00 (m, 1H), 1.98 (d, 1H, J = 4.4 Hz) Mass analysis 01) 111/2 2 04 (^^ +, free body). -220- 200401778 Reference Example 3 7 (lS) -3 -chloro-1- (4-chlorophenyl) propyl 3- (trifluoromethyl) phenyl ether (1R) -3-chloro prepared using Reference Example 36 201.4 mg of 1- (4-chlorophenyl) propan-1-ol (0.9821 mmol). The target compound 2 4 1 · 4 mg (yield 70%) can be obtained by following the method of Reference Example 12. Colorless oil substance. NMR spectrum (400MHz, CDC13) ppm: 7.34-7.26 (m, 5H), 7.16-7.1 0 (m, 2H), 6,95 (dd, 1H, J = 2.2 Hz, 8.1 Hz), 5.40 (dd , 1H, J = 4.4 Hz, 8. 8 Hz), 3.79 (ddd, 1H, J = 5. 1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5. 1 Hz, 5.9 Hz, 11.0 Hz), 2.50-2.41 (m, 1H), 2.22-2.14 (m, 1H) Mass analysis (El) m / z 348 (M +, free body). Reference Example 3 8 (lS) -3 -chloro-1- (4-chlorophenyl) propyl 4-cyanophenyl ether (1R) -3-chloro-1- (4-chlorophenyl) prepared using Reference Example 36 ) Propanol-1-alcohol 2 0 4.7 mg (0.9 9 81 1 mol), following the method of Reference Example 12 to obtain the target compound 2 45.1 mg (80% yield) as a colorless oily substance. NMR spectrum (400MHz, CDC13) (5 ppm: 7.50 (d, 2H, J = 8.8 Hz), 7. 36-7.26 (m, "0, 6.89 (d, 2H, J = 8.8 Hz), 5.44 (dd , 1H, J = 4.4 Hz, 8.1 Hz), 3.77 (ddd, 1H, J = 5.1 Hz, 8 · 8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5 · 1

Hz, 5.9 Hz, 11.0 Hz), 2.51-2.43 (m, 1H), 2.24-2.16 (m, 1H) Mass analysis (El) m / z 305 (M +, free body). Reference Example 3 9 (lS) -3 -chloro-1- (4-chlorophenyl) propyl-chlorophenyl ether Using (1 R)-3 -chloro-1-(4-chlorobenzene 2) Propyl-butanol 20 1.5 mg (0.9 8 2 5 mmol), the target compound 2 1 9 8 · 3 mg (yield 64%) can be obtained by following the method of Reference Example 12 as a colorless oil. substance. 200401778 NMR spectrum (400MHz, CDC13) ppm: 7.34-7.25 (m, 4H), 7.11 (d, 2Η, I = 8.8 Hz), 6.75 (d, 2H, J = 8.8 Hz), 5.31 (dd , 1H, J = 4.4 Hz, 8.8 Hz), 3.78 (ddd, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 11.0 Hz), 2.46- 2.38 (m, 1H), 2.19-2.11 (m, 1H) Mass analysis (EI) m / z314 (M +, free body). Reference Example 4 0 (lS) -3 -chloro-1- (4-chlorophenyl) propyl 4-fluorophenyl ether (lR) -3-chloro-1- (4-chlorophenyl) prepared using Reference Example 36 ) Propanol-1-alcohol 20 0 2.7 mg (0.9 9 84 mmol), the method of Reference Example 12 can be used to obtain the target compound 189.7 mg (64% yield) as a colorless oily substance. NMR spectrum (400MHz, CDC13) (5 ppm: 7.34-7.25 (m, 4H), 6.89-6.8 5 (m, 2H), 6.77-6 · 74 (in, 2H), 5.27 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.79 (dd d, 1H, J = 5. 1 Hz, 8.8 Hz, 11.0 Hz), 3.58 (ddd, 1H, J = 5. 1 Hz, 5.9 Hz, 1 1 · 0 Hz), 2.46-2.35 (m, 1H), 2.19-2 · 10 On, 1H). Reference Example 4 1 (lS) -3 -chloro-1- (4-chlorophenyl) propyl 3-fluorophenyl ether (lR) -3-chloro-1- (4-chlorophenyl) prepared using Reference Example 36 ) Propan-1-ol 2 18.1 mg (1.03 mmol), the method of Reference Example 12 can be used to obtain the target compound 2 2 4 · 8 mg (yield 7 1%) as a colorless oil. Like substance. Nuclear magnetic resonance spectrum (400MHz, CDC13) ppm: 7.34-7.30 On, 2H), 7.04-6 · 9 9 (m, 2H), 6.77-6 · 71 (m, 4H), 5.24 (dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.80 (dd d, 1H, J = 5.1 Hz, 8.8 Hz, 11.0 Hz), 3.59 (ddd, 1H, J = 5.1 Hz, 5.9 Hz, 1 1.0 Hz), 2.46—2.38 (m , 1H), 2.18-2.10 (m, 1H). Reference Example 4 2 3- (Third-butyrylsilyloxy) -1- (4-methoxyphenyl) -propan-1-ol 1- (4-methoxyphenyl) -propan-1,3 -Diol (Bioorg · Chem · Let · 8, -222- 200401778 1998, 2967-2972) 4.0 g (21.9 mmol), tertiary dimethylsilyl chloride 3.16 g (21.0 mmol), 1.58 g of imidazole (23.2 mmol) was dissolved in 100 ml of dichloromethane and stirred at room temperature for 1.5 hours. Water was added and the mixture was extracted with a hexane-ethyl acetate mixture. The extract was washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (75 g, 15% ethyl acetate-hexane) to obtain the target compound (4.71 g, 67%) as an oily substance. NMR spectrum (400MHz, DMS0-d6) ppm: 7.30 (2H; d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 4.88-4.93 (1H, m), 3.80-3.87 ( 2H, m), 3.80 (3H, s), 1.87-1.97 (2H, m), 0.93 (9H, s), 0.09 (6H, s). Reference Example 4 3 4-[(3-Third-butanesilyloxy) -1- (4-methoxyphenyl) -propoxy] benzonitrile 3 »(Third-butane Silyloxy) 1- (4-methoxyphenyl) -propan-1-ol 260 mg (0.90 mmol) was dissolved in tetrahydrofuran-DMF (4 ·· 1, 2.5 ml), and NaH was added under ice-cooling 39 mg (0.90 mmol). After stirring for 1 hour, 4-fluorobenzonitrile 4 9 3 · 1 (1.5 mmol) was added at the same temperature, and the mixture was stirred at 80 ° C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Rinse with water, saturated saline. After drying, it was concentrated to give 450 mg of an oily substance. It was used in the next reaction without purification. Reference Example 44 4-[(3-Hydroxy) -1- (4-methoxyphenyl) -propoxy] benzonitrile will contain 4-[(3 -tertiary succinic acid) prepared in Reference Example 4 3 450 mg of a 1- (4-methoxyphenyl) -propoxy] benzonitrile mixture was dissolved in 10 ml of tetrahydrofuran, and 2 ml of a 1 M-tetrabutylammonium fluoride solution was added. After stirring for 1 hour, -223- 200401778 was added to the reaction solution, and extracted with ethyl acetate. Rinse with water, saturated salt water. After drying and concentrating, the residue was purified by silica gel column chromatography (20 g, 45% ethyl acetate-hexane) to obtain 150 mg (59%, 2 engineering) of the target compound as an oily substance. Nuclear magnetic resonance spectrum (400MHz, DMS〇-d6) δ ρριικ 7.47 (2H, d, J = 9Hz), 7.26 (2H, d, J = 9Hz), 6.90 (2H, d, J = 9Hz), 6.87 (2H, d, J = 9Hz), 5.37-5.42 (1H, m), 3.82-3.88 (1H, m), 3.80 (3H, s), 3.71-3.78 (1H, m), 2.23-2. 33 (1H, m ), 2.02-2.08 (1H, m). Reference Example 4 5 3- (4-cyanophenoxy) -3- (4-methoxyphenyl) propyl methanesulfonate 4- [Prepared in Reference Example 44 (3-Hydroxy) -1- (4-methoxyphenyl) -propoxy] 150 mg (0.53 mmol) of benzonitrile was dissolved in 3 ml of dichloromethane, and pyridine 6 4 · 1 ( 0.7 9 millimoles), mesylate chloride 6 1 · 1 (0.7 9 millimoles). After stirring at the same temperature for 1 hour, the reaction solution was added with a 1 N aqueous hydrochloric acid solution. It was extracted with ethyl acetate, washed with water, saturated sodium carbonate solution, and saturated brine in this order. After drying, 200 mg of oily substance was obtained. It can be used in the next reaction without purification. Reference Example 4 6 The third butyl- [3- (4-methoxyphenyl) -3- (4-trifluorotolyloxy) propoxy] dimethylsilane was used in the same manner as in Reference Example 4 3, using 3- (Third-butyrylsilyloxy) -1-(4-methoxyphenyl) -propan-1-ol 386 mg (1.30 mmol), 4-trifluoromethylfluorobenzene 5 0 7 · 1 (4.0 Millimoles), to obtain 5 1 4 mg of oily substance. It can be used in the next reaction without purification. -224- 200401778 Reference Example 4 7 3- (4-methoxyphenyl) -3- (4-trifluorotolyloxy) -prop-butanol Follow the method of Reference Example 44 using the third method prepared in Reference Example 46 Butyl- [3- (4-methoxyphenyl) -3- (4-trifluorotoluyloxy) propoxy] dimethylsilane, the target compound can be obtained 2 3 1 mg (55%, 2 engineering) Oily substance. Nuclear magnetic resonance spectrum (400MHz, DMS0-d6) δ ppm: 7.43 (2H, d, J = 9Hz), 7.27 (2H, d, J = 9Hz), 6.91 (2H, d, J = 9Hz), 6.87 ( 2H, d, J = 9Hz), 5.36-5.41 (1H, m), 3.84-3.90 (1H, m), 3.78 (3H, s), 3.75-3.80 (1H, m), 2.24-2.30 (1H, m ), 2.02-2.11 (1H, m). Reference Example 4 8 3- (4-trifluorotolyloxy) -3- (4-methoxyphenyl) propyl methanesulfonate. Using 3- (4-methoxyphenyl) -3- (4-trifluorotolyloxy) -propan-1-ol prepared in Reference Example 47, 290 mg of an oily substance was obtained. It was used in the next reaction without purification. Reference Example 4 9 3- (Third-butyrylsilyloxy) -1- (3-trifluorotolyl) -propan-1-one The 1- (3-trifluorotolyl) prepared in Reference Example 1 4 -Propylene-1,3-diol 4.00 g (18. 2 mmol) was dissolved in 80 ml of dichloromethane, and under ice-cooling and stirring, 2.74 g of tertiary dimethylchlorosilane was added ( 18.2 millimoles), 1.48 grams (21.8 millimoles) of imidazole, and stirred for 1 hour under ice cooling. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/10/1) to obtain 4.4 4 g of TB ether as an oily substance. -225- 200401778 2.0 g (5.88 mmol) of the obtained compound was dissolved in 12 ml of dichloromethane, and under stirring with ice cooling, 105 mg of tetrapropylammonium perruthenate (0.5 mg 2 9 9 mmol), 4-methylmorpholine N-oxide 1.05 g (8.99 mol), molecular sieve 4 A 3 g, and stirred for 1 hour under ice cooling. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was washed with dichloromethane, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 0/1) to obtain the target compound 1.76 g (yield 8 8.4%) as an oily substance. NMR spectrum (400MH2, CDC13) δ ppm.; 8,20 (s; 1H); 8.13 (d; 1H? J = 8.06), 7.79 (d, 1H J = 7.33 Hz), 7.58 (t, 1H , J 2 7.70 Hz), 4.05 (t, 2H, J = 6.59 Hz), 3.18 (t, 2H, J = 6.59 Hz), 0.82 (s, 9H), 0.02 (s, 6H) infrared absorption Spectrum vmx cnfi (KBr): 2956, 2930, 2858, 1732, 1 689, 1613, 1 330, 1256, 1 172, 1 1 36, 1098, 836 Mass analysis (FAB) m / z 333 ((M + H) +, Free body). Reference Example 5 Ο (3S) l- (Third-Butylsilyloxy) -3- (4-chlorophenoxy) _3- (3-trifluorotolyl) -propane (+)-B-chloro Dissolve 3.93 g (12.2 mmol) of bis-isospinnamylphenylborane in 10 ml of a THF solution, and stir at -78 ° C to add the 3- (third butanesilyl oxide) prepared in Reference Example 49 ) -1- (3-trifluorotolyl) -propan-butanone 3.70 g (5.49 mmol), and left at -2 Ot for 16 hours. After the reaction was completed, 2.5 7 ml (26.8 millimoles) of diethanolamine was added under ice-cooling stirring, and the mixture was stirred for 1 hour. The reaction solution was diluted with ether and filtered. The filtrate was evaporated under reduced pressure. Purification by chromatography (eluent: toluene / hexane = 5/1 to hexane / ethyl acetate = 5/1), a crude reduced product of 2.88 g of -226-200401778 was obtained. Nuclear fe resonance spectrum (400MHz, CDC13) δ ppm: 7.58 (s, 1H), 7.50 (d, 1H, J = 8.1 Hz), 7.43 (d, 1H, J = 7. 3 Hz), 7.12 (d, 1H , J = 8.8 Hz), 5.36 (dd, 1H, J = 4.8 Hz, 8.4 Hz), 3.87-3.78 (m, 1H), 3.72-3. 58 (m, 1H), 2.22-2.12 (m, 1H) , 2.00-1.75 (m, 1H), 0.87 (s, 9H), 0.01 (s, 3H), -0.02 (s, 3H) infrared absorption spectrum vniax cmH (KBr): 2955, 2930, 2858, 1490, 1 330 , 1237, 1169, 1132, 10 94 Mass analysis (FAB) m / z 445 ((M + H) +, free body). Reference Example 5 1 ^ (3S) -3- (4-chlorophenoxy) -3- (3-trifluorotolyl) -propyl ester The (3S) l- (second Butyl dimethyl ethoxy) -3- (4-chlorophenoxy) -3- (3-trifluorotolyl) -propane 2.47 g (5.55 mmol) was dissolved in 2.5 ml of ether, Under warm stirring, 10 ml of a 4 N aqueous hydrochloric acid solution was added. Stir at room temperature for 3 hours. After the reaction was completed, it was neutralized with 4N NaOH aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: hexane / ethyl acetate = 3/2) to obtain 1.81 Φ of TBS salt. 1.18 g (5.4 7 mmol) of the obtained compound was dissolved in 18 ml of methylene chloride, and 0.5 ml (6.5 mmol) of trimethylsulfonium chloride was added under ice-cooling stirring. Amine 1.2 ml (8.2 mmol) was stirred for 2 hours under ice cooling. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain the target compound 1.82 g (yield 81.1.1%) as an oily substance. -227- 200401778 NMR spectrum (4_Hz, CDC13) δ ppm: 7.68-7.45 (m, 4H), 7.16 (d, 2Η, J = 9.2 Hz), 6.76 (d5 2H, J = 9.2 Hz), 5.32 (dd, 1H, J = 4.0 Hz, 8.4 Hz), 4.56-4.47 (m, 1H), 4.40-34.31 (m, 1H), 2.97 (s, 3H), 2.39-2.21 (m, 2H) infrared absorption spectrum vmax cuf 丨 (KBr): 1490, 1330, 1 235, 1176, 1134 Mass analysis (FAB) m / z 408 (M +, free body). Reference Example 5 2 (3S) l- (Third-butyldimethylsilyloxy) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propane (+)-B- 4.25 g (13.2 millimoles) of chlorodiisospinnamyl phenylborane was dissolved in 11 ml of a THF solution, and stirred at -7 8 ° C, and 3- (third butyl dimethyl) prepared in Reference Example 4 9 was added. Silyloxy) -1- (3-trifluorotolyl) -propan-1-one 4.00 g (1 2.0 mmol) was left at -20 ° C for 16 hours. After the reaction was completed, 2.31 ml (24.1 mmol) of diethanolamine was added under ice-cooling stirring, and the mixture was stirred for 1 hour. The reaction solution was diluted with ether and filtered. The filtrate was distilled off under reduced pressure. Purified by silica gel column chromatography (eluent: toluene / hexane = 5/1 to hexane / ethyl acetate = 5/1) to obtain a crude reduced product of 3.6 g of an oily substance. 3.46 g (10.4 mmol) of the prepared reduction was dissolved in 17 ml of toluene, and 4-cyanophenol 1.4.8 g (12. 4 mmol) and triphenylphosphine 3 were added at room temperature with stirring. 26 g (12. 4 mol) and 5.4 ml of diethyl azodicarboxylate (12. 4 mol) were stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7/1) to obtain the target compound 4.06 g (yield 8 9.9%) as an oily substance. 200401778 NMR spectrum (400MHz, CDC13) δ ppm: 7.61-7.45 (m, 6H), 6.92 (d, 1H, J = 8.8 Hz), 5.49 (dd, 1H, J = 4.8 Hz, 8.4 Hz), 3.89-3.81 (in, 1H), 3.67-3.61 (m, 1H), 2.28-2.18 (m, 1H), 2.09-1.95 (m, 1H), 0.90 (s, 9H), 0.02 (s, 3H ), 0.00 (s, 3H) Infrared absorption spectrum vmax cm · 1 (KBr): 2955, 2930, 2227, 1 605, 1 506, 1330, 1253, 1191, 1133 Mass analysis (FAB) m / z 436 ((M + H) +, free body). Reference example 5 3 (3S) -3- (4-cyanophenoxy) -3- (3-trifluorotolyl) -propyl ester The (3 S) 1-( Tributydimethylsilyloxy) -3-(4-cyanophenoxy) -3- (3-trifluorotolyl) -propane 4.06 g (9.32 mmol) dissolved in 40 ml of ether at room temperature 20 ml of a 4N aqueous hydrochloric acid solution was added with stirring. Stir at room temperature for 3 hours. After the reaction was completed, it was neutralized with 4N NaOH aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: hexane / ethyl acetate = 1/1), and 2.85 g of de-TBS salt was obtained. 2.68 g of the obtained compound was dissolved in 30 ml of dichloromethane, and 0.97 ml (12.5 mmol) of methanesulfonyl chloride and 2.1 ml (15.0 mmol) of triethylamine were added under ice-cold stirring. It was stirred for 2 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain the target compound (2.66 g, yield: 79.7%) as an oily substance. -229- 200401778 NMR spectrum (400MHz, CDC13) (5 ppm: 7.62-7.45 (m, 6H), 6.91 (d, 1H, J = 8.8 Hz), 5.49 (dd, 1H, J = 4.4 Hz, 8.8 Hz ), 3.95-3.86 (m, 1H), 3. 78-3.71 (m, 1H), 2.33-2.22 (m, 1H), 2.13-2.02 (m, 1H) infrared absorption spectrum v max cnf1 (KBr): 2228 , 1732, 1605, 1 506, 1330, 1254, 1171, 1133, 1073, 1048, 835 Mass analysis (? 8: 8) 111/2 332 (1 ^ +, free body). Test Example 1 T cells of mice Induction of IL-10 production by strain DIO. G 4.1 cells (1) IL-10 production determination The mouse T cell strain D10.G 4.1 cells were cultured in RPMI containing 10% bovine fetal blood pupa and 5 μM 2 -thiol ethanol. 1640 medium (manufactured by Life Technologies) was injected into a 96-well flat-bottom plate (manufactured by Corning) at 25,000 cells / 0.2 ml. At the same time, a predetermined concentration of compound was added. A positive control group that induced IL-10 production The anti-mouse CD3e antibody (manufactured by BD Biosciences) was lysed to a final concentration of 0.4 μg / ml, and adsorbed to a 96-well flat-bottomed plate. Similarly, D 1 0. G 4. 1 cells 2 5 0 0 0 cells / 0.2 ml After 24 hours of incubation, IL-10 was produced in the culture supernatant. IL-10 in the culture supernatant can be measured by ELISAKIT (manufactured by GenzymeTechne). (2) Evaluation of the induction of IL-10 production by each compound The induction effect of IL-10 production can be calculated from the semi-logarithmic curve of IL-10 production and the concentration of each compound, and the concentration of IL-10, which is 30% of the amount of positive control group, is induced to be ED3. The results are shown in Table 4 〇-23 0- 200401778 [Table 4] Compound ED30 (μg / ml) Example 2 0 · 02 1 Example 2 1 0 .05 4 Example 5 2 0, .03 0 Example 5 3 0.. 03 3

The above results clearly show that the compounds of the present invention have excellent IL-10 inducing effects.

-23 1-

Claims (1)

200401778, patent application scope 1 · A compound of the following formula (I), (11) or (III), its pharmacologically acceptable salt, its ester or other derivative, R1 ") > —〇 一 (CH2) n R2 One N N-R5 (I) 〇 R1 and R2 are the same or different, each is 1 to 3 substituted phenyl groups selected from the substituent group a, R3 and R4 are the same or different, each is hydrogen or a lower alkyl group, or R3 and R4 are collectively shown as Ethyl group, R5 is hydrogen, lower alkyl, lower alkylsulfinyl fluorene lower alkyl, lower alkyl sulfonyl fluorene lower alkyl, low alkyl group containing 1 ~ 3 oxygen atoms in carbon chain, and 1 ~ Low alkyl with 3 sulfur atoms, low alkyl with 1 to 3 nitrogen atoms in the carbon chain, substituted with 1 to 3 groups selected from the substituent group b and 1 to 3 oxygen atoms in the carbon chain, Sulfur atom or nitrogen atom with low alkyl group or formula -C 0-R 7 (where R 7 is a group selected from substituent group b), -232- 200401778 R6 is low alkyl group or contains 1 oxygen in carbon chain Atom low alkyl, m is an integer of 0 ~ 2, η is an integer of 1 ~ 6, and the substituent group a is selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkyl group, a lower alkyl group, a lower alkyl group, and a lower alkyl group. Group, low alkylthio group, via group, amine group, nitro group and cyano group are substituted group b which is selected from aryl group and heteroaryl group, and is substituted by 1 ~ 3 groups selected from substituent group a. And heteroaryl substituted with 1 to 3 groups selected from substituent group a, but When R3 and R4 in the formula (I) are both hydrogen, R5 is hydrogen, a lower alkyl group and a group other than a lower alkyl group containing one oxygen atom in the carbon chain]. 2. The compound according to item 1 of the scope of patent application, which is a compound of formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof. 3. The compound according to item 1 of the scope of patent application, which is a compound of formula (11), a pharmacologically acceptable salt thereof, an ester thereof or other derivatives. 4. The compound or pharmacologically acceptable salt thereof according to any one of items 1 or 3 in the scope of patent application, wherein m is 0. 5. The compound or pharmacologically acceptable salt thereof according to any one of items 1 or 3 in the scope of patent application, wherein m is an integer of 1 or 2. 6. A compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 5 of the scope of the patent application, wherein R3 and R4 are hydrogen. 7. A compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 5 of the scope of patent application, wherein R3 and R4 are co-expressed as ethyl. 8. The compound or the pharmacological capacity of any one of the items 1 to 5 of the scope of the applied patent -23 3- 200401778 Xu salt, wherein R3 and R4 are the same or different and each is a low alkyl group. 9. A compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 5 of the scope of patent application, wherein R3 and R4 are the same or different and each is a C! _2 alkyl group. 10. The compound or the pharmacologically acceptable salt thereof according to any one of items 1 to 5 of the scope of patent application, wherein R3 and R4 are the same or different and each is a methyl group. 1 1. The compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof, wherein R5 is hydrogen. 1 2. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is a lower alkyl group. 1 3. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is a C! _4 alkyl group. 14. The compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof, wherein R5 is methyl or ethyl. 15. The compound or any of its pharmacologically acceptable salts according to any one of claims 1 to 10 in the scope of patent application, wherein R5 is a low alkyl group containing one oxygen atom in the carbon chain. 16. A compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is a C! _4 alkyl group containing 1 oxygen atom in the carbon chain. 17. A compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of the patent application, wherein R5 is a C2_3 alkyl group containing one oxygen atom in the carbon chain. 18. The compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof, wherein R5 is methoxy or 2-methoxyethyl. 19. A compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of the patent application, wherein R 5 is a lower alkylsulfinyl sulfonium lower alkyl group, or a lower alkyl sulfonyl fluorenyl lower alkyl group. -234- 200401778 2 0. If the compound or any of its pharmacologically acceptable salts according to any of items 1 to 10 of the scope of patent application, wherein R5 is c! _2 alkylsulfinyl sulfonium C 2 alkyl, C! _2 alkylsulfonyl sulfonium ci_2 alkyl. 2 1. The compound or a pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is methanesulfenylmethyl or methanesulfonylmethyl. 2 2. The compound or any pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is a low alkyl group containing 2 to 3 oxygen atoms in the carbon chain and 1 to 3 carbon atoms in the carbon chain Low alkyl group of sulfur atom, low alkyl group containing 1 to 3 nitrogen atoms in carbon chain, or 1 to 3 substitutions selected from substituent group b, and 1 to 3 oxygen atoms, sulfur in carbon chain A lower alkyl atom or nitrogen atom. 2 3. The compound or any of its pharmacologically acceptable salts according to any one of items 1 to 10 in the scope of the patent application, wherein R5 is a low alkyl group containing 2 to 3 oxygen atoms in the carbon chain, and 1 to 3 members in the carbon chain A low alkyl group of a sulfur atom or a low alkyl group containing 1 to 3 nitrogen atoms in the carbon chain. 2 4. If any one of the compounds in the scope of patent application 1 to 10 or a pharmacologically acceptable salt thereof, wherein R5 is a carbon chain containing 2 to 3 oxygen atoms (^ _4 alkyl, carbon chain containing 1 to A low alkyl group of 3 sulfur atoms or a Ci_4 group containing 1 to 3 nitrogen atoms in the carbon chain. 2 5. For example, a compound or a pharmacologically acceptable salt thereof according to any of items 1 to 10 in the scope of patent application, where R5 It is a C2_3 alkyl group having 2 to 3 oxygen atoms in the carbon chain, a C i_4 alkyl group having 1 to 3 sulfur atoms in the carbon chain, or a C2.3 alkyl group having 1 to 3 nitrogen atoms in the carbon chain. 2 6. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is a C2.3 alkyl group containing 1 to 3 sulfur atoms in the carbon chain. -23 5-200401778 2 7. The compound or any pharmacologically acceptable salt thereof according to any one of items 1 to 10 in the scope of patent application, wherein R5 is methylthiomethyl or 2-methylthioethyl. 2 8. The scope of application is 1 to 10 The compound according to any one of the above items, or a pharmacologically acceptable salt thereof, wherein R5 is a group of the formula -CO-R7 (where R7 is a group selected from the substituent group b). 2 9. The compound as claimed in item 28 of the scope of patent application Or its pharmacologically acceptable salt, Wherein R 7 is an aryl group, a heteroaryl group or an aryl group having 1 to 3 substituents selected from the substituent group a. 3 0.0. The compound or a pharmacologically acceptable salt thereof according to item 28 of the patent application range, wherein R 7 is Phenyl, furyl, thienyl, or 1 to 3 substituted phenyls selected from substituent group a. 3 1. The compound or the pharmacologically acceptable salt thereof according to item 28 of the patent application, wherein R7 is phenyl , Furyl, thienyl or phenyl with 1 to 3 substitutions (the substituent may be selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group). 3 2. A compound or a pharmacologically acceptable salt thereof, wherein R7 is a phenyl group or a phenyl group having 1 to 3 substitutions (the substituent may be selected from the group consisting of fluorine, chlorine, an alkyl group, and a lower alkoxy group). 3 3. The compound of scope item 28 or a pharmacologically acceptable salt thereof, wherein R7 is 1 to 3 substituted phenyl groups having a low alkoxy group. 3 4. As the compound of scope item 1 of the patent application, it is formula (111) Compound, its pharmacologically acceptable salt, its ester or other derivative. 35. For example, the compound of claim 34 or its pharmacologically acceptable salt, which R6 is a Ci.4 alkyl group or a Cm alkyl group containing one oxygen atom in the carbon chain. 3 6. If the compound or the pharmacologically acceptable salt of the item 34 in the patent application scope, its -23 6- 200401778 is Ci_2 An alkyl group or a C2_3 alkyl group containing one oxygen atom in the carbon chain. 37. For example, a compound or a pharmacologically acceptable salt thereof according to item 34 of the scope of patent application, wherein R6 is methyl, ethyl, methoxymethyl or 2 -Methoxyethyl. 3 8. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 37 in the scope of patent application, wherein R1 and R2 are the same or different and each is selected from a halogen atom, a low radical, Halogenated phenyl, C 1-2 oxy, C 1 _ 2 thio, nitro and cyano substituted with 1 to 3 groups. 39. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 37 in the scope of patent application, wherein R1 and R2 are the same or different, and each is selected from the group consisting of a halogen atom, a lower alkyl group, a lower halogen alkyl group, a nitrate 1 to 3 groups substituted with phenyl and cyano. 40. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 37 in the scope of patent application, wherein R1 and R2 are the same or different, and each is selected from the group consisting of a halogen atom, a Cu alkyl group, and a halogen C] _2 alkane A phenyl group substituted with 1 to 3 groups of phenyl, nitro and cyano. 41. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 37 in the scope of patent application, wherein R1 and R2 are the same or different, and each is selected from fluorine, chlorine, methyl, trifluoromethyl, Nitro and cyano are substituted by 1-3 phenyl groups. 4 2. The compound or pharmacologically acceptable salt thereof according to any one of items 1 to 37 in the scope of patent application, wherein R1 and R2 are the same or different, and each is 2-fluorophenyl, 3-fluorophenyl, 4-fluoro Phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-tolyl, 3-trifluorotolyl, 3-nitrophenyl, 3,4-xylyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, -23 7- 200401778 3, 5-difluorophenyl, 3,5-ditrifluorotolyl , 3-cyanophenyl, or 4-cyanophenyl. 4 3. The compound or any of its pharmacologically acceptable salts according to any one of items 1 to 37 in the scope of patent application, wherein R1 and R2 are the same or different and each is 3-fluorophenyl, 4-fluorophenyl, 3-triphenyl Fluorotolyl, 4-trifluorotolyl, 3-cyanophenyl or 4-cyanophenyl. 4 4. The compound or the pharmacologically acceptable salt thereof according to any one of claims 1 to 4 in the scope of patent application, wherein η is 2. 4 5. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4 in the scope of patent application, wherein n is 3. 46. The compound or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, which is selected from: 8- {2- [bis- (4-p-phenyl) methoxy] ethyl} -3-methylthiomethyl Phenyl-1-Π 萼 _ 3,8-bisacylspiro [4 5 5] dec-2-one, 8- {3- [bis- (4-fluorophenyl) methoxy] propyl 3-methyl Thiomethyl-1-fluorene-3,8-bisacylspiro [4,5] dec-2-one, 8- {2- [bis- (4-fluorophenyl) methoxy] ethylbuspiro [ (8-azinebicyclo [3 · 2 · 1] octane) -3,5 '-(3-methylthiomethyl) -oxazolidine] -2'-one, 8- {3- [bis- (4 -Fluorophenyl) methoxy] ethylbulspirin [(8-azinebicyclo [3.2.1] octane) -3,5 1-(3-methylthiomethyl) -oxazolidine] -2 '- Ketone, 8- {2- [bis- (3-trifluorotolyl) methoxy] ethylbull 3-methylsulfinylmethyl-1 -fluorene-3,8-diacylspiro [4,5] Dec-2 -one, 8- {2- [bis- (3-trifluorotolyl) methoxy] ethylbuthyl 3-methylthiomethyl-1-fluorene-3,8-diacylspiro [4, 5] dec-2-one, -23 8- 200401778 8- {3- [bis- (3-trifluorotolyl) methoxy] propyl} -3-methylthiomethyl-1-fluorene-3, 8-bisacryl [4,5] dec-2-one, 8- {3-[(3-cyanophenyl) (3'-trifluorotolyl) methoxy] propyl 3-methylthiomethyl-1 -fluorene · 3,8-diacylspiro [4,5] dec-2-one, 8- {2-[(4-cyanophenyl) (4 (-trifluorotolyl) ) Methoxy] ethylbuthyl 3-methylthiomethyl-1 -fluorene-3,8-diacspiro [4,5] dec-2-one, 8- [3- (4-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2-one, 8- [3 · (3-trifluorotolyloxy) -3- (3-trifluorotolyl) propyl] -oxan-3, 8-diacryl [4,5] dec-2-one, 8- [3- (3 · trifluorotolyloxy) -3- (3-trifluorotolyl) propyl] -3 -methylthiomethyl-1 -fluorene-3, 8 · diacspiro [4,5] dec-2-one, 8- {2- [ Bis (3-trifluorotolyl) methoxy] ethylbulspirin [(8-azinebicyclo [3.2.1.octane) -3 5 5f-oxazolyl] -2'-one, 8 -[3- (3 -cyanophenoxy) -3- (3-fluorophenyl) propyl] -1-fluorene-3,8-diacryl [4,5] dec-2-one, 8- [3- (4-Cyanophenoxy) -3- (4-fluorophenyl) propyl] -1-fluorene-3,8-diazelop [4,5] dec-2-one, 8- [ 3- (3-cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene- 3,8-diacryl [4,5] dec-2-one, 8- [ 3- (4-cyanophenoxy) -3- (3-trifluorotolyl) propyl] -1-fluorene-3,8- Azuron [4 5 5] dec-2-one, 8- [3 · (2-fluorophenoxy) -3- (4-fluorophenyl) propyl] -1 · 噚-3,8-diazine Spiro [4,5] dec-2-one and -23 9- 200401778 8- {3-[(3-cyanophenyl) (3f-trifluorotolyl) methoxy] propyl 3-ethyl- 1-fluorene-3,8-diacylspiro [4,5] dec-2-one. 47. A pharmaceutical composition containing the compound according to any one of claims 1 to 46 of the scope of patent application, a pharmacologically acceptable salt, an ester or other derivative thereof as an active ingredient. 48. The pharmaceutical composition according to item 47 of the scope of patent application, which can selectively suppress the immune activity of T h 1 cells. 49. If the pharmaceutical composition in the scope of patent application No. 47 is applied, it can promote the production of IL-4. 50. If the pharmaceutical composition under the scope of patent application No. 47 is applied, it can promote the production of IL-10. 51. The pharmaceutical composition according to item 47 of the scope of patent application, which can be used to prevent or treat chronic inflammatory diseases, organ-specific autoimmune diseases, or inflammatory bowel diseases. 5 2. The pharmaceutical composition according to item 47 of the scope of patent application, which can be used to prevent or treat chronic rheumatoid arthritis, diabetes, multiple sclerosis, ulcerative colitis, Crohn's disease, glomerulonephritis, hepatitis , Liver disease, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Edison's disease, hypoparathyroidism, malignant anemia, limitation Ileitis, atrophic gastritis, gluten-sensitive enteritis, Goodpasture syndrome, post-streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, sympathetic ophthalmia, Pemphigus vulgaris, vesicular pemphigus, or xerophobia. -240- 200401778 5 3. The pharmaceutical composition according to item 47 of the patent application scope, which can be used to prevent or treat chronic inflammatory diseases or organ-specific autoimmune diseases. 54. The pharmaceutical composition according to item 47 of the scope of patent application, which can be used to prevent or treat ulcerative colitis, Crohn's disease or hepatitis. 5 5 .—A kind of application for manufacturing a pharmaceutical composition, which uses a compound such as any one of items 1 to 46 of the scope of patent application, a pharmacologically acceptable salt thereof, an ester thereof, or other derivatives. 56. As described in claim 55 of the scope of patent application, the pharmaceutical composition selectively inhibits the immune activity of Th1 cells. 57. The use of item 55 in the scope of patent application, wherein the pharmaceutical composition can be used to prevent or treat chronic inflammatory diseases, organ-specific autoimmune diseases or inflammatory bowel diseases. 58. According to the application of the scope of patent application No. 55, the pharmaceutical composition can be used to prevent or treat chronic rheumatoid arthritis, diabetes, multiple sclerosis, ulcerative colitis, Crohn's disease, glomerulonephritis, Hepatitis, liver disease, autoimmune hemolytic anemia, leukocytopenia, thrombocytopenia, allergic encephalitis, demyelinating disease, Hashimoto's thyroiditis, Edison's disease, hypoparathyroidism, malignant anemia, Limited ileitis, atrophic gastritis, gluten-sensitive enteritis, Good Paster syndrome, post-streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, sympathetic ophthalmia Pemphigus vulgaris, vesicular pemphigus, or psoriasis. 59. If the application of the scope of patent application No. 55, the pharmaceutical composition can be used to prevent or treat chronic rheumatoid arthritis or organ-specific autoimmunity -241- 200401778 epidemic disease. 60. According to the application of the scope of application for item 55, the pharmaceutical composition can be used to prevent or treat ulcerative colitis, Crohn's disease or hepatitis. 61. A method for preventing or treating diseases, which is administered to a warm-blooded animal in a pharmacologically effective amount, such as a compound according to any one of claims 1 to 46, a pharmacologically acceptable salt thereof, an ester thereof, or other derivatives thereof. 62. The method according to item 61 of the scope of patent application, wherein the disease is a chronic inflammatory disease, an organ-specific autoimmune disease, or an inflammatory bowel disease. 63. The method according to item 61 of the scope of patent application, wherein the disease is chronic rheumatoid arthritis, diabetes, multiple sclerosis, ulcerative colitis, Crohn's disease, glomerulonephritis, hepatitis, liver disease, autologous Immune hemolytic anemia, Leukopenia, Thrombocytopenia, Allergic encephalitis, Demyelinating disease, Hashimoto's thyroiditis, Edison's disease, Hypoparathyroidism, Malignant anemia, Limited ileitis, Atrophy Gastritis, gluten allergic enteritis, Goodpasture syndrome, streptococcal nephritis, myasthenia gravis, rheumatic fever, viral cardiomyopathy, uveitis, sympathetic ophthalmia, pemphigus vulgaris, Vesicular pemphigoid or xerophobia. 64. The method according to item 61 of the scope of patent application, wherein the disease is chronic rheumatoid arthritis or an organ-specific autoimmune disease. 65. The method according to item 61 of the scope of patent application, wherein the disease is ulcerative colitis, Crohn's disease or hepatitis. 6 6. The method according to any one of claims 61 to 65 in the scope of patent application, wherein the warm-blooded animal is a human. -242- 200401778 Lu, (a), the designated representative of the case is: Figure _ (b), the representative symbols of the representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please disclose the most unobvious features Chemical formula: R3 ⑺〇 一 (CH2) η — R5 R4 〇R3 ⑼ (III)