TW200808724A - Piperidine derivative and use thereof - Google Patents

Abstract

sThe present invention relates to a compound represented by the formula: wherein Ar is a phenyl group optionally having substituent (s), R1 is a hydrogen atom, a hydrocarbon group optionally having substituent (s), an acyl group or a heterocyclic group optionally having substituent (s), R2 is a hydrogen atom, a C1-6 alkyl group optionally having substituent (s) or a C3-6 cycloalkyl group optionally having substituent (s), Z is a methylene group optionally having a C1-6 alkyl group, ring A is a piperidine ring optionally further having substituent (s), ring B and ring C are benzene rings optionally further having substituent (s), and R2 optionally form a ring together with the adjacent substituent on the ring B, except the compounds represented by the formula: and or a salt thereof. The compound of the present invention has a superior tachykinin receptor antagonistic action, particularly a substance P receptor antagonistic action, and is useful as a pharmaceutical agent, for example, tachykinin receptor antagonist, an agent for the prophylaxis or treatment of lower urinary tract symptoms, gastrointestinal diseases or central nerve diseases.

Description

200808724 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a novel pyridine derivative having excellent antagonism to a tachykinin receptor and uses thereof. [Prior Art]

Tachykinin is a generic term for a group of neuropeptides. The substances p(Sp), neurokinin A and neurokinin B are known in mammals, and these peptides are well known to bind to corresponding receptors present in vivo (neurokinin 1, neurogenic Peptide-2, as well as neurokinin-3), thus showing various biological activities. * Among these neuropeptides, SP has the longest history and has been studied in detail. In 1931, it was confirmed that the extract from the intestine of the horse had the presence of sp, and in 1971, its structure was determined. Sp is a peptide consisting of 11 amino acids. , SP, 'should knives in the central and peripheral nervous system, and in addition to the function as a conductive substance of the first sensory neurons, there are enhancements such as vasodilation, contraction of smooth muscle, excitation of neurons, Various physiological activities such as salivation, diuretic enhancement, and immune enhancement. In particular, it is well known that Sp is caused by a pain pulse (pain transmits a message of pain to a second neuron, whereby the tip of the spine (dorsal root) angle is released' and the SP released from the peripheral tip causes an inflammatory reaction at its receptor. This is a disorder involving various disorders (for example, pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, cardiovascular regulation, chronic inflammatory diseases such as chronic rheumatoid arthritis, including asthma Or over (4) 318921 6 200808724 Rhinorrhea, respiratory diseases, intestinal inflammatory diseases including ulcerative colitis and Crohn's disease, eye damage and ocular inflammatory disease, proliferative vitreoretinopathy, intestinal depression, frequent urination, Psychosis, vomiting, etc. [Reference, for example, Physiological Review, Vol. 73, pp. 229-308 (1993); Journal of Autonomic Pharmacology, Vol. 13, 23-93 K (1993)]. Currently, the following compounds are known to have SP receptors. Antagonistic activity. European Patent EP-A-436,334 discloses compounds of the formula

Etc., the patent W092/17449 discloses a compound represented by the following formula

Etc., Patent W0 9 5 /1 6 6 7 9 discloses a compound of the formula: 7 318921 200808724

Japanese Patent Publication No. JP-A-9-263585 discloses a heterocyclic compound or a salt thereof as shown in the following formula

Wherein the cyclic oxime heterocyclic ring, wherein XZZ:.Y&lt; is -N=C&lt;, -CO-N< or -CS-N<; Rln Rb is bonded to each other to form a ring A, or the same or different a substituent independently representing a hydrogen atom or a cyclic oxime; the cyclic oxime and the cyclic oxime independently represent, if necessary, a substituted homocyc lie ring or a heterocyclic ring, and at least one of them is optionally substituted The heterogeneous J exhibits that the polar C is a homologous or heterogeneous as needed, the ring Z is a homocyclic ring or a heterocyclic ring that needs to be substituted; and the η is an integer of 1 to 6. Patent WO 03/1 01 964 describes a compound having a tachykinin receptor antagonistic activity or a salt thereof, as shown in the following formula 8 318921 200808724

Wherein Ar is an aryl group, an aralkyl group, or an aromatic heterocyclic group, each of which may be substituted, a hydrogen atom, a nicotine group to be substituted, an acid group or, if necessary, a substituted =_% group, X system An oxygen atom or an optionally substituted imine group, z is selected as the substituted fluorenylene group, and ring A is substituted with the desired piperidine %, and the ring B is optionally substituted. An aromatic ring, when #z is a methylene group substituted by a mercapto group, Ri is not a mercapto group, and when z is a methyl group substituted by a methyl group, the ring B is a substituted aromatic ring. SUMMARY OF THE INVENTION The object of the present invention is to provide a chemical structure having an antagonistic activity against a tachykinin receptor or the like, which has a chemical structure different from that of a known chemical substance including the above compound (including a derivative). A drug commonly used in the prevention or treatment of urinary tract function. The inventors of the present invention have conducted extensive research in view of the above circumstances, and as a result, it has been unexpectedly found that a piperidine derivative represented by the following formula (1) or a salt thereof has an excellent chemical structure excellent for tachykinin receptors. Antagonism (especially

Antagonism of the sp receptor) and fully satisfied as a pharmaceutical agent. The present inventors have completed the present invention based on these proposals. Specifically, the present invention provides the following compound: U] a compound represented by the following formula (hereinafter sometimes referred to simply as the compound (I)) or its 318921 9 200808724

I A I C

RrN^J^\Ar wherein, Ar is a phenyl group which may have a substituent, and R1 is a hydrogen atom, optionally a hydrocarbon group having a substituent, a fluorenyl group or a heterocyclic group having a substituent as required, and an R 2 hydrogen atom; If necessary, a Ch alkyl group having a substituent or a C3-6 cycloalkyl group having a substituent, Z is optionally a methylene group having a C!-6 alkyl group, and the ring A is optionally a substituent having a substituent. The pyridine ring, the ring B and the ring C are optionally a benzene ring having a substituent, and R 2 is required to form a ring together with a substituent adjacent to the ring B; the compound represented by the following formula is excluded.

And

[2] A compound such as [1], as shown in formula (11): 10 318921 200808724 f

Wherein the symbol in the formula is as defined in [l]; [3] the compound as in [1], as shown in formula (11 a)

Wherein the symbol in the formula is as defined in [1]; [4] The compound according to any one of (8) wherein R is a hydrogen atom or a stilbile group; (3) + a compound of the formula - wherein the r2 is a hydrogen atom or [6] The compound of any one of [1] to [3], wherein z is a methylene group having a methyl group as desired; m is a compound of [3] ,Ar system depends on f to have! Up to 3 phenyl groups of atomic atoms; R system (1) chlorine atom, (2) Cl-6 alkyl-carbonyl group, optionally having 1 or 2 substituents selected from the group consisting of: (1) amine group (ii) Cl 6 methoxyl, (out) C16 leuko-carbonylamino (iv) C1-6 alkoxy-carbonylamino, (v) Ci6 alkyl sulfhydryl amine '(vi) as needed a 5- or 6-membered nitrogen-containing heterocyclic group having 1 to 5 substituents selected from the group consisting of a C alkyl group and a ketone group of 11 318921 200808724, which may be optionally combined with cyclopentene or cyclohexane. Together form a spiro ring '(vii)Ci-6 alkyl-monooxy, (viii) hydroxy and (ix) amine fluorenyl, (3) Ci-6 alkoxy-carbonyl, (4) Cl-6 Anthranyl-based, (5) C1 -6 alkyl, (6) Amino-Wittyl, (7) (^-6 alkylamino-carbonylcarbonyl, (8) di- Ci-6 alkylamino-monomethyl, or (9) piperidin-4-ylcarbonyl, optionally having ! or 2 substituents selected from the group consisting of: (i) Ci-e alkyl-carbonyl , if necessary, has a 5- or 6-membered nitrogen-containing heterocyclic group (the heterocyclic group optionally has an anthracene or two keto groups), (ii) a Ci6 alkoxy-carbonyl group, an alkylsulfonyl group, (iv) Ci _e alkyl-carbonylamino-Ch alkyl-carbonyl, (v) di-Cl_e alkyl-amine sulfhydryl and (vi) keto group; R2 system (1) hydrogen atom or (2) optionally having! to 3 halogen atoms Ci6 alkyl; Z is optionally a methylene group having a methyl group; Ring A is a piperidine having no further substituents. Ring B is required to form a step (4) atom or a combination of R2 and R2. , 3-dihydrobenzo-cough % ring; and 'sub-cloth B ring C-type benzene ring, which optionally has 1 or 2 # 芙 · & z z 迷 from the following group of substitutions (1) cyano, 318921 12 200808724 (2) Tip group, (3) halogen atom, (4) Ci-6 alkyl group having 1 to 3 halogen atoms as needed, (5) Ci-6 alkynyl group, (6) 1 to 1 as needed Ci-6 alkoxy groups of three halogen atoms, (7) Ci-6 alkylthio group, (8) Cl-6 alkylsulfonate group, (9) ^--C 1 -6 alkylamino group, (1 0 ) C 1 -6 alkyl-prison base (11) Cl-6 alkyl-prison amino group, (12) 匕-6 alkoxy-carbonyl and (13) amine sulfhydryl; [8 a compound represented by the formula: or a salt thereof:

among them

Ar is preferably a phenyl group having 1 to 3 halogen atoms; R1 is a (1) hydrogen atom, and (2) a Ch alkyl-carbonyl group, which optionally has i or 2 substituents selected from the group consisting of: i) an amine group, (ii) a Cl_6 alkoxy group, (iii) a Ci-6 alkyl-carbonylamino group, (ιν). -6 alkoxy-carbonylamino, (v) Ci-6 alkylsulfonylamino '(V1) optionally has from 1 to 5 substituents selected from the group consisting of Cl-6 alkyl groups and the group of 318921 13 200808724 a 5- or 6-membered nitrogen-containing heterocyclic group which, if desired, forms a spiro ring with cyclopentane or cyclohexane, (vii) Ci6 alkyl-carbonyloxy, (¥^hydroxyl and (1)乂) Aminomethyl sulfhydryl, (3) Cl-6 alkoxy-alkyl, (4) 匕-6 alkyl sulfonyl, (5) Amino-based, (6) Ci-6 alkylamino a carbonylcarbonyl group, (7) a di-Ci-6 alkylamino-monoyl group, or a (8) piperidin-4-ylindenyl group, optionally having or a substituent selected from the group consisting of (OHh alkyl-carbonyl, which optionally has a 5- or 6-membered nitrogen-containing heterocyclic group (the heterocyclic group optionally has an anthracene or two keto groups), (ii) a c alkoxy-carbonyl group , (iiOc^alkylsulfonyl, (iv) Ci 6 alkyl-carbonylamino-Ch alkyl-carbonyl, (v) di-Ch alkyl-amine sulfhydryl and (vi) keto; R2 (1) a hydrogen atom or (2) a Ci-β alkyl group having 丨 to 3 halogen atoms as needed; ^ Z is an anthracene group having a fluorenyl group as needed; a π-ring of a substituent of a substituent; a benzene ring or a ring of β and R which together have a halogen atom or a Ci e-alkyl group to form a 2,3-dihydrobenzopyrene ring; and a quinone C-type benzene a ring which optionally has hydrazine or two substituents selected from the group consisting of (1) cyano, (2) nitro, 318921 14 200808724 (3) halogen atom, (4) 1 to 3 halogens as needed Ch group of an atom, (5) (^-6 alkynyl, (6) Ci-6 alkoxy having 1 to 3 halogen atoms as needed, (7) Cl-6 :): a terminal thio group, (8) Ci-6:J: complete base, (9) di-Ci-6 alkylamino group, (10) Cl-6 alkyl-based, (1 1 )Cl-6 alkyl- a few amino groups, (12) Ci-6 alkoxy-and a few groups and (13) an amine carbenyl group; [9] N-{2-[(3R,4S)-4-({[4'-chloro) -4-(Trifluoromethoxy)biphenyl-3-yl]fluorenyl}amino)-3-phenylpiperidin-1-yl]-2-ketoethyl}. acetamidine, 3' - [({(3R,4S)-:l-[(5,5-Dimethyl-2,4-diketo-1,3-oxazolidin-3-yl)ethinyl]-3-benzene Piperidine-4-yl}amino)methyl]-2-fluoro-4, mono(trifluorodecyloxy)biphenyl-4-carbonitrile, 2-fluoro-3'-({[(3R, 4S)-1-ethanol thiol 3-phenylphenylpyridin-4-yl]amino} fluorenyl)-4'-(trifluorodecyloxy)biphenyl-4-indolecarbonitrile, 3'-[U(3R,4SM-[(1- Ethyl (tetra)-4-yl) benzyl]-3-phenylpyridin-4-yl}amino) fluorenyl]-2-fluoro-4-, mono(trifluoromethoxy)biphenyl-4 Nitrile, 3'-[({(3R,4S)+[(2,6-dione-based brigade bit 4_yl))]]phenylphenyl brigade + fluorene)f-based]_2_fluorine _4'heptafluoromethoxy)carbonitrile, 318921 15 200808724 2- [(3R,4S)-4-({[4'-cyano-2,-fluoro-4-one (trifluorodecyloxy)) Phen-3-yl]methyl}amino)-3-phenylpiperidin-1-yl]-2-oxoacetamide, 3-{2-[(3R,4S)-4-({[ 4'-Chloro-4-(trifluoromethoxy)biphenyl-3-yl]methyl}amino)-3-phenylpiperidine-}-yl]-2-one-one ethyl b 5, 5 Di-nonyl-1,3-anthracene-2,4-dione, 4- U(3R' 4S)-4-({[4'-chloro-2'-fluoro-4-(trifluorof) Oxy)biphenyl_3__yl]indenyl}amino)-3-peptidylpiperidine-fluorenyl]carbonyl hydrazine piperidine-2,6-dione, 3'-[({(3143)-1- [(5,5-Dimercapto-2,4-dione-1,3-oxazolidin-3-yl)ethenyl]-3-phenylperidine _4_ yl} amino) methyl] _4, _ (three gas methyloxy) biphenyl-4-carbonitrile, or a salt thereof; [1 square] before the compound [1] of the drug. [11] A pharmaceutical agent comprising the compound of [1] or a prodrug thereof. [12] The agent according to [11], which is a tachykinin receptor antagonist. [13] The agent according to [11] is a prophylactic or therapeutic agent for urinary tract symptoms, digestive diseases or central nervous system diseases. [14] The agent according to [11] is associated with bladder hyperactivity, symptoms of lower urinary fistula associated with benign prostatic hyperplasia, visceral pain of the pelvis, lower urinary tract symptoms associated with chronic prostatitis, and interstitial cystitis. An agent for the prevention or treatment of lower urinary tract symptoms, intestinal depression, inflammatory bowel disease, vomiting, nausea, depression, anxiety neurosis, anxiety or sleep disorders (insomnia). [15] A method of preventing or treating a lower urinary tract symptom, a digestive disorder disease, or a central nervous system disease, which comprises administering to a mammal an effective amount of a compound 318921 16 200808724 [1] or a prodrug thereof. The use of j^ sigma or its stagnation for the manufacture of a prophylactic or therapeutic agent for lower urinary tract disease, sputum organ disease or central nervous system disease. The &amp; month compound (1) and its salts and prodrugs have an antagonistic effect on tachykinins, and the antagonism of the substance ρ, and the low carbon number toxicity is safe as a pharmaceutical agent. Therefore, the compound (1) and the bean salt of the present invention and the prodrug thereof are used for the prevention and treatment of an abnormality such as a lower urinary tract function, which is used as a pharmaceutical product, for example, a tachykinin receptor. [Embodiment] [Best Mode for Carrying Out the Invention]

Ar is a phenyl group which has a substituent as needed. As the substituent of the phenyl group, for example, 1 to 3 substituents selected from the group consisting of (1) A atom (for example, fluorine, chlorine, bromine, iodine, etc.), (2) Ch-alkylene can be mentioned. An oxy group (for example, a methylenedioxy group, an ethylenedioxy group, etc.), (3) a nitro group, a (4) cyano group, (5) a ruthenium-based ruthenium group, and (6) Halogenated Ch alkenyl, (7) as desired, C26 alkynyl, (8) halogenated Ch cycloalkyl, (WC6, aryl (eg, phenyl, 1 nephi, 2-na Base, biphenyl, 2-indenyl, etc.), (10) alkoxy groups which are halogenated as desired, (11) Ci ealkylthio or anthracenyl group which is toned as required, (12) hydroxyl group, (13) Amino, (14) mono-c!-6 alkylamino (eg, methylamino, ethylamino, etc.), (15) mono-indenyl arylamine (eg, phenylamino, 1-nylamino group, 2-naphthylamino group, etc.), (16) di-Ci6 alkylamino group (for example, an arylamino group, a diethylamino group, etc.), (17) bismuth to aryl Amino group (for example, diphenylamino group, etc.), (18) mercapto group, (19) mercaptoamine group, (20) mercapto 318921 17 200808724 oxy group, 21) A 5- to 7-membered cyclic amino group having a substituent, (22) a 5-membered aromatic heterocyclic group (for example, a 2- or 3-thienyl group, a 2-, 3-=4 ratio). Indenyl, 2-, 3-, 4-, 5- or 8-quinolinyl, 1-, 3-, 4- or 5-isoquinolinyl +, 1-, 2- or 3-indenyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]tetramyl, etc., (23)sulfonic acid, (24)c(i)4aryloxy (eg 'phenoxy, (naphthyloxy group, etc.), (25) a group formed by a combination of 1 to 3 groups of the above (1) to (24), etc. "The above-mentioned need is an alkyl group, for example, There may be mentioned a Cw alkyl group having 1 to 5, preferably up to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) as desired (e.g., fluorenyl, ethyl, propyl, iso) a propyl group, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, a hexyl group, etc.), etc. Specific examples include methyl, chloromethyl, difluoroindenyl, trichloroindenyl, and tris. Fluoromethylethyl, 2-&gt; stinyl ethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, =, 3, 3, 3-trifluoropropyl, isopropyl, butyl , 4,4,4_trifluorobutyl, different Base, second butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5.5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc. As the Ch-alkenyl group, for example, a C2-6 alkenyl group having 1 to 5, preferably fluorene to 3 halogen atoms (for example, fluorine, chlorine, /odor, iodine, etc.) may be mentioned. For example: vinyl, allyl, isopropenyl, butenyl, nonenbutyl, second butenyl, etc.), etc. Specific examples include vinyl, allyl, isopropenyl, butenyl, Isobutenyl, second butenyl, 3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl and the like. The above-mentioned need for a dentate Ch alkynyl group, for example, may be mentioned as having 1 to 5, preferably 丨 to 3 halo atoms (for example, fluorine, gas, 18 318921 200808724 indifferent, broken, etc.). A C2-6 block group (e.g., a 1-hexynyl group, etc.), etc. can be described. A base, a butyl group, a 1-hexyl group, a trifluoro-1-butenyl group, etc. • an ethyl group, a fast propyl group And the specific examples include ethynyl group, C3 3'3 difluoro-1 propyl block, 4, 4, and the above-mentioned c3-6 cycloalkyl group, as described above, for example, If necessary, it has a C3 base (for example, cyclopropyl, cyclobutyldipentyl, cyclohexyl, etc.) of a tooth, such as a tooth, a moth, etc., and 齅 every &gt; - /, slave examples include propyl propyl, cyclobutyl, fluorene, 4, dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like. In the above, it is necessary to halogenate the U-oxy group. For example, C&quot; having 1 to 5, preferably i to 3, functional atoms (for example, gas, chlorine, bromine, iodine, etc.) may be mentioned as needed. Alkoxy (eg: foxyoxy, isopropoxy, butoxy, visible) Lactobacillus c ^ 丞 丞 虱 虱 、 、, second butoxy, pentyloxy hexyloxy, etc.). Specific examples include methoxy, difluoromethoxy, chaotic methoxy, ethoxy, 2, 2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4 , 4, 4-trifluorobutoxy, isobutoxy, second butoxy, pentyloxy, hexyloxy and the like. The above-mentioned need to dentate the Ch alkylthio group, for example, may have 1 to 5, preferably 1 to 3, halogen atoms (for example, fluorine, chlorine/odor, etc.) as needed. Ci_6 alkylthio group (e.g., p-thio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, second butylthio group, tert-butylthio group, etc.) Wait. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, 318921 19 200808724 butadiene; 4,4-difluorobutylthio, pentylthio, hexylthio, and the like. The above-mentioned "mercapto group, for example, may be described - (〇0)-R3, -(〇s)-R3, 'rR3, -SO-R3, -(P=〇)(10)4)(〇r4,)( R3 is a chlorine atom, a hydrocarbon group optionally having a substituent, an amine group optionally having a substituent, a hydroxyl group optionally having a substituent or a heterocyclic group optionally having a substituent, and the oxime and R are the same or similar Each is a hydrogen atom or a hydrocarbon group optionally having a substituent, etc. A hydrocarbon group optionally having a substituent represented by R, R and R4', including, for example, as indicated by R1 described later herein The "fety group" of the substituent is the same group. The "substituent" of the "amino group having a substituent as necessary" as defined by R includes, for example, a hydrocarbon group having a substituent as necessary, and a substituent having a substituent as necessary. a cyclyl group, a hydroxy group, a fluorenyl group or the like having a substituent, if necessary, as an "amino group having a substituent as required, and a "hydrocarbyl group having a substituent" as required, including For example, the same as the hydrocarbon group having a substituent as required by R1, which is described later in the text, is the same. , the "heterocyclic group optionally having a substituent, which is represented by R3," the "hydrocarbyl group of the substituent optionally having a substituent, and includes, for example, a hydrocarbon group having a substituent as required in the present specification. And, the same group. As the "amino group which has a substituent as required, which is represented by R3, the "hydroxyl group of a substituent which may have a substituent, if necessary, includes, for example, (1) a mercapto group (11) Cl~6 alkoxy (eg methoxy, ethoxy, propoxy, iso 318921 20 200808724 propoxy, butoxy, second genus I # 禾 虱 寻), aryloxy (eg ·· This milk base, naphthyl, etc.), (·,

Clv) formazan or Ch alkyl-carbonyloxy (J, ethyl ethoxy, propionic acid # 13 虱 虱 #) and (v) Ch4 aryl-carbonyl oxo-. Oxy, naphthyl and. View base (for example, the United States is good for the foundation, etc.). The thiol group of the t-milyl group, the ethyl lactyl group, the propyl sulfonyl group, and the isopropoxy group includes, for example, -(C = 〇)-R,, -= as the "amino group having a substituent as required" represented by R3 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Is a hydrogen atom or, if necessary, a nicotine group having a substituent, R is a hydrogen atom or a lower alkyl group G such as a Cl_e alkyl group such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group. a base, a second butyl group, a tert-butyl group, a pentyl group, a hexyl group or the like, and particularly preferably a Ch alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or the like, etc. The hydrocarbon group having a substituent is required, and includes, for example, the same group as the "hydrocarbon group optionally having a substituent" represented by R1 described later herein. "Amine group having a substituent as necessary" , the "substituent" of the "hydroxyl group having a substituent, as exemplified, "Ci6 alkoxy", "C6-h aryloxy,", "methyloxy", "Ci 6 alkane" Base-carbonyloxy" and "C6-H aryl" The carbonyloxy group may be further substituted with a hydrocarbon group having a substituent as indicated by R1 which will be described later, and the "substituent" is substituted with the same group or the like, and the substituents are preferably used. a halogen atom (for example, fluorine, chlorine, molybdenum, etc.), etc. 318921 21 200808724 R3 represents an amine group having a substituent as required (for example, having 1 to 3 hetero atoms (except for a nitrogen atom, a 5- to 9-membered cyclic amine group of a sulfur atom or the like (for example, Νι咯 pyridine = each bite group), N-hexa-amp; (tetra)-based, N-hexahydronaphthyl group N-Foline, etc.) and so on. R3 represents "having a substituent-based group as needed, for example, including a disk = as described in the nucleus as a table of R3 (4)" "Amine-based substituents having a substituent as needed. White spoons are required to have a substituent group having a substituent. ,, are the same group, etc. R is a heterocyclic group which may have a substituent as necessary, and includes, for example, the same group as the m-(tetra) "heterocyclic group which is to have a substituent" as described hereinafter. The above-mentioned amino group, For example, a brewing amine group, a C&quot; a home base-several base wire (4) such as a B-group #), a heterocyclic group 4 alkyl group-a few earth bases (for example, a ketone group) may be mentioned. N_hexahydropyridyl-acetamido group, etc.), C3-7 cycloalkyl-arylamino group (for example, cyclopropylamino group, etc.), Ce_&quot; aryl-carbonylamino group (for example, phenyl group) a arylamino group, a naphthylamino group, etc.), a heterocyclic arylamino group (for example, a fluorenylamino group, a fluorenylamino group, a pyrenyl amide group, etc.), C !-6 alkoxy-carbonylamino group (for example: methoxydecylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, butoxycarbonyl group, etc.) α-nonyloxy-carbonylamino group (e.g., phenoxycarbonylamino group, naphthyloxy "amine group, etc."), heterocyclic oxyalkylamino group, 6 fluorenyl arylamino group (e.g., methylsulfonylamino group, ethyl group) Sulfhydrylamino group, etc., C6-H arylsulfonylamino group (example) ··Phenylsulfonylamino, 2-naphthylsulfonium 318921 22 200808724, amine, naphthyl glycerylamine, etc., heterocyclylamino, glandyl, mono or mono C1-6 a ureido group (for example, a guanylureido group, a dimercaptoadenyl group, etc.), a mono- or a di-U group-gland group (for example, a phenyl gland group, a triphenyl gland, etc., an oxime group of the upper oxime, ' For example, an alcoholic oxy group, a Ch alkyl-oxy group (e.g., an ethoxylated group, a propionic acid oxy group, etc.), a heterocyclic group-Ch-alkylcarbonyloxy group, a Cw cycloalkyl-carbonyloxy group may be mentioned. a group (for example, a cyclopropylcarbonyloxy group, etc.), a C6]4 aryl-carbonyloxy group (for example, a benzylideneoxy group, a naphthylcarbonylcarbonyl group, etc.), a heterocyclic carbonyloxy group (for example, nicotine) Mercaptooxy alkoxy, oxy group (eg methoxyoxyoxy, f, oxy oxy, butoxy oxy m "aryloxy"; &quot; Spicy base, miscellaneous Cycloalkoxy-monooxyl, mono-c&quot;alkyl-amine methoxy (e.g., methylamine-methoxyl, ethylamine-mercaptooxy, etc.) An oxy group (e.g., dimethylamine ii yloxy group, 3-amino amine I oxy group, etc.) "Aryl-amine-methyl fluorenyloxy (for example: native amine formazan &amp; oxy group, naphthylamine, decyloxy group, etc.), etc. 2 in the text: as a heterocyclic group - Cl-6 a number of amino-amino groups, heterocyclic carbonyl groups, heterocyclic groups - county amine groups, heterocyclic sulfonyl silks, heterocyclic filaments, heterocyclic filaments (10) county oxy- several. For example, one to four groups selected from the group consisting of oxygen atoms and sulfur atoms other than carbon atoms may be used: 'and if necessary, i or 2 ketone groups, etc. to &quot Non-aromatic heterocyclic groups of members (preferred 'better 5_ or 6-members) (eg: fluorenyl, tetradecyl, tetraarsenyl, hexahydrocardyl 318921 23 200808724 Piperanyl, morpholinyl, thiomorpholinyl, hexahydropyridyl) or an aromatic heterocyclic group (eg, fluorenyl, fluorenyl, ton. Each group, anthracenyl, fluorenyl, isodecyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, indole, 2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-D, etc. diazolyl, furazyl, l 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2,3-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, hydrazine, pyrimidinyl, pyridyl, triterpene, and the like. The above-mentioned "5- to 7-membered cyclic amine group having a substituent, 5- to 7-membered cyclic amine group", for example, may be mentioned as a 5- to saturated saturated amine group such as N - morpholinyl group, N-thiofolfolinyl group, π chen teng -1 - group, n - hexahydroanthracene group having a substituent, π ratio 嘻 — -1 - group, etc. to 7-membered ring "Substituent,", for example, i to 3 substituents selected from Group 4 below. Cl_6 alkyl (eg, fluorenyl, ethyl, propyl, iso-yl, butyl, iso) Butyl, t-butyl, tert-butyl, pentyl, hexyl,), ^6_14 aryl (eg phenyl, naphthyl, 2-naphthyl, biphenyl, 2-monopropyl, etc.) 5 to aroma a heterocyclic group (for example, 2- or 3-thienyl, 2,-, 3- or 4-pyridyl, 2,3,4,5- or δ-carboline, b, 3 - , 4 or 5 a porphyrin group, a b, a 2- or 3-mercapto group, a 2-benzothiazolyl group, a 2-benzo[b]-phenyl group, a benzo[b]furanyl group, etc.). The ruthenium is a phenyl group having a halogen atom (for example, a fluorine atom), and a phenyl group which is preferably substituted by a fluorine atom in the para position. Particularly preferred is an unsubstituted phenyl group. i is a hydrocarbon group having a substituent of a hydrogen atom, a mercapto group or a heterocyclic group optionally having a substituent. And 318921 24 200808724 means "has a substitute for, for example, a hydrocarbyl group of a group of lavans, a monocyclic saturated group; a di-, a group, an ', etc., preferably a one-carbon atom. As the group hydrocarbon group, an alkyl group, an alkenyl group, an alkene group, or a clay group can be used. Specifically, for example, a fluorenyl group, a %# group group, and a aryl group. "Alkyl group, for example, ^^^^^ For example: base, ethyl: low, alkyl, etc., for example, a second butyl group, a: dimercapto 1, propyl, butyl, isobutyl, butyl-butyl, pentyl, hexyl Etc. etc. are widely used. Examples: For example, a lower alkylene group or the like is preferable, for example, a soil field of 1. vinyl group, propylene group, allyl group, isopropyl group, butenyl group, =butenyl group, etc.) Etc. is widely used. The alkynyl group, for example, a lower alkynyl group or the like is preferably a group, a propargyl group, a propenyl group or the like, etc., and a s group, for example, a low carbon number cycloalkyl group or the like is preferable. For example, c "cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like are widely used. - "Aryl", for example, Ce-14 aryl (e.g., phenyl, naphthyl, 2-nonyl such as strepyl, 2-indenyl, etc.) and the like are preferred, and, for example, phenyl or the like is widely used. The "hydrocarbyl group" of the hydrocarbon group which may have a substituent represented by R, may have, for example, a (fluorene atom) atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), (2) Nitro(3) cyano (4) hydroxy (5) a lower alkyl group which is dentated as needed (for example, a Cl_6 alkyl group which may be halogenated as required, for example: methyl, chloromethyl, difluorodecyl, Trichloroindolyl, trifluorodecyl, ethyl, 2-&gt; stinyl ethyl, 2, 2, 2-tris-arylethyl, pentafluoroethyl, propyl, 3, 3, 3-triternal 31891125 2008 200824 II propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, 4, 4, 4-difluorobutyl, pentyl, isopentyl, neopentyl, 5, 5 , trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.), (6) halogenated as desired (: 2-6 alkenyl, (7) halogenated CM alkynyl, (8) A halogenated C3-6 cycloalkyl group is required, (9) a lower alkoxy group which is optionally converted (for example, a 匕~6 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, or an isopropyl group) Oxyl, butoxy, isobutoxy, pentyloxy, hexyloxy, etc.), (1〇)醯a group, (11) a halogenated Ci-6 alkylthio or thio group, (12) fluorenyl, (丨3) amine, (14) a mono-lower alkylamino group (for example: Mono-[nonalkylamino group, such as methylamino, ethylamino, etc.), (15) di-lower alkylamino (eg, di-Ch alkylamino, eg dimethylamine) a group, a diethylamino group, etc.), (16) a mono-(Vh arylamino group (for example, a phenylamino group, a fluorenylnaphthylamino group, a 2-naphthyl group), (17) -Ce-H arylamino group (e.g., diphenylamino group, etc.), (18) mercaptoamine group, (19) carboxyl group, (2〇) aryl group (e.g., aryl group, such as phenyl, naphthalene) Base, biphenyl, 2-onion, etc.), (21) aryloxy (eg, G-η aryloxy, such as phenoxy, naphthyloxy, etc.), (22) low halogenation as needed Alkylalkyl-carbonylamino group (for example, an alkyl-carbonylamino group which is optionally dentated, such as an ethyl fluorenylamino group, a trifluoroethenylamino group, etc.), (23) is preferably halogenated as needed Alkylalkylsulfonylamino group (for example, if desired, a halogenated Cl-6 alkylsulfonyl group, such as methylsulfonium) Alkylamino, trifluoroheptylamino group, etc.), (24) a halogenated lower alkoxycarbonylamino group if desired (for example, a certain amount of Cl-6 alkoxylate to be deuterated) Amino group, for example, methoxycarbonylamino group, trifluoromethoxycarbonylamino group, etc.), (25) keto group, (26) 5- to 7-membered cyclic amine group having a substituent, if necessary, (27) a heterocyclic group, 318921 26 200808724 (28) Cl-3 alkylene dioxy (for example: methylenedioxy, ethylenedioxy, etc.), (29) aminyl (30) from the above (1) A group to the combination of (3) to 3 groups can be used. The hydrocarbon group having a substituent, if desired, the "hydrocarbyl group" may have 1 i 5 'preferably i to 3 of the above substituents at the substitutable position of the hydrocarbyl group. § Substituent number! Two or more The respective substituents may be the same or different. The "acid group" of the "substituent hydrocarbon group" as defined by R, for example, includes a fluorenyl group, a Ci6 alkyl group - a few groups (such as: Ethyl, propyl, etc.), heterocyclic _Ci ealkyl-carbonyl, Ch ring (4) such as cyclopropyl-carbon, etc., C6i4 aryl (eg phenylcarbonyl, naphthyl, etc.) , a heterocyclic carbonyl group (for example, nicotine sulfhydryl group, etc.), Gy alkoxy-m-yloxy group (for example, methoxy group, ethoxy group, propoxy group, succinyl group: butoxy group, etc.) ), Ce i4 aryloxy, group (eg, phenoxy, naphthyloxy, etc.), heterocyclyloxy-aryloxy, Ci 6 calcined base (9) such as: mercapto, B Exact base, etc., C6_i4 aryllithinyl group (for example: phenyl 4 fluorenyl, 2-naphthylsulfonyl, naphthylsulfonyl, etc.), heterocyclylsulfonyl fluorenylsulfinate (for example: ? A lysine, ethyl arsenate, a propyl sulfhydryl group, a butyl sulfinamide group, etc., a G(mono) 4 aryl sulfonate group (for example, a phenyl arylene, a naphthyl sulphate) Stirring base, etc., amine methyl thiol, thiamine methyl sulfhydryl, mono-monoalkyl-amine ketone group (for example, methylaminocarbamic acid group, mercaptocarbamyl group, etc.), di-Ch alkyl group - an amine methyl sulfhydryl group (for example: dimethylamine oxime, diethylamine mercapto, etc.), "aryl-aminomethyl thiol (for example: phenylamine-based, naphthylamine) And the like. In the present invention, a heterocyclic group of a heterocyclic group 318921 27 200808724 C]-6-alkyl-carbonyl, a heterocyclic carbonyl group or a heterocyclic oxy group is, for example, a carbonaceous atom, One of the group consisting of an oxygen atom and a sulfur atom to two, a helium atom, a sub, and, if necessary, a right run #m to 1 to 4 miscellaneous

代 代基, such as _子, as needed, the C factory is more than two, _, etc. 5 - to 14 - members (preferably 5 to 9: 6 more &lt; soil is 5_ I 6_ member) Non-aromatic heterocyclic group (for example: tetrakisyl, tetrachlorophosphonyl, hexachloropurine, tetra:, yl, bis: "like, hexamethyl fluorenyl" or aromatic heterocyclic (eg: , porphinyl, pyrrolyl, oxime, isoxazolyl, iso(tetra)yl, imi-4, unfilament, monoazolyl, 1,3,4'diazolyl, furazyl, l 2, 3_thiadiazolyl, &quot;dioxahydrazide, i,3,4m trifilament, u-heart three, four-wire&quot; than silk, pin-based K-base, base, third, etc. can be used. ^ And R represents a hydrocarbon group having a substituent, and the term "substituted ethoxylate," and "bristylamino" as used herein includes, for example, "phenyl", The "substituent," recited "wound oxy, and decylamino" are the same group. R1 represents "the hydrocarbon group optionally having a substituent, the "substituent," as exemplified" 5_ to 7-membered cyclic amine groups having a substituent, as needed, For example, it is the same group as the "membered cyclic amine group" which has a substituent represented by "the substituent of "phenyl", which is represented by the above-mentioned Ar, and has the same substituent. Hydrocarbyl group, the "substituent," 318921 28 200808724 exemplified by "heterocycle, 彳丨a ~, for example, may include a group of selected, ..., ruthenium atoms and sulfur atoms in addition to carbon atoms. One to one member of the group from 5 to 14 (more than 1 to 4 g W, 乂1 to 4 5 to 9-, more preferably 5- or 6-:): two = silk (for example ············································ 2,4,monozolyl, u 1,2,3-thiadiazolyl,]? / sub-division, 1 W &quot; sulphate, u, "salt-salt, brigade, earth, : 4 oxadiazolyl, tetrazolyl, pyridyl, fluorenyl, hexamethyl, non-fragrant heterocyclic (for example: pyrromethene%: its south base, tetracycline , hexahydrogen ratio bite base, tetraterpene thiol, horse brown lindi, thiofolene, six The chlorine-heterocyclic heterocyclic group may be further fused with other non-aromatic ih ', non-aromatic or non-aromatic homo- or heterocyclic rings. The "hetero atom" such as a halogen atom ^ has a substituent, etc. 兀 〇 6 6 alkoxy group, ketone R1 represents a "sulfhydryl group" including the "substituent" of the "phenyl" group represented by the red phase t! II and the above group. The same meaning, Q, "if necessary, a heterocyclic ring 2 having a substituent, for example, one of a group of a fusible and a sulfur atom in addition to a carbon atom can be mentioned to a self-deuterium atom, an oxygen source: a hetero atom 5 to "member (more than two cars, monocyclic or bicyclic) heterocyclic group and so on. For example, in addition to the furnace to 2%, from the nitrogen, oxygen and sulfur atoms, including the selected group of 1 to 4 heteroatoms 318921 29 200808724 5-membered ring group, such as 2 or 3 —thienyl, 2- or 3-furanyl, i- 2 — or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or oxazolyl, 3-, 4- or 5- Isomorphine, 2, 4 or 5 ring, 3'4- or 5_ carbazolyl, 3-, 4- or 5-kissinyl, 2, 3 or 4 ton sulfhydryl, 2_4- or base 'base, 1&gt; 2, 4_triple, ^ or 2h_tetrasyl, etc.: except for a carbon atom, contains 1 to 4 groups selected from a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. a 6-membered ring group of a hetero atom, for example, a 2- 3 - or 4-mercapto group, an N-oxy 2, 3 - or 4_ntba group, a 2, 4 or 5 - (tetra) group, and a N-lact-2- can be used. 4- or 5--yl, thiofarpine, ifolin, N-hexachloropyridyl, 2-, 3- or 4-hexahydropyridyl, thiol-meryl 1 , U-(tetra)-based, hexa-(tetra)-based, triterpene-based or well-based 4-[indolyl], pyridinyl, Ν''oxy-3- or 4-indole, etc.; From nitrogen, oxygen and sulfur Group of 4 to 2 2-atom bicyclic or tricyclic fusion ring groups, such as fluorenyl, benzopyrene, oxime, benzoyl, benzo-salt, sulfanyl, aliton:: Base, mouth-based, linyl, phenyl, phenyl, phenyl, dibenzo, scent, scent, ff, morphine, morphine, etc. (preferably, by the above ^Bei nucleus and - or two 5- or 6-membered rings (except for carbon atoms = 1 to 4 heteroatoms in groups of atoms and sulfur atoms) = where 'preferably tweezers, excluding a heterocyclic group of a nitrogen atom, a 5- to 7-membered member of the group of 1 to 3 hetero atoms (a quaternary 1k is a 5- or 6-membered member), "a heterocyclic group having a substituent as required, The "heterocyclic group," the substitution 318921 30 200808724 may have a substituent similar to the above "hydrocarbyl group having a substituent," a "hydrocarbyl group", a similar group, for example, may be used ( 1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (2) a lower alkyl group (e.g., a Ci 6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, iso) Butyl, second butyl, third (, pentyl, hexyl, etc.), (3) cycloalkyl (Example 1: C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (4) low sarcophagus Alkynyl (eg, C26 alkynyl, eg, ethynyl, 1-propynyl, propargyl, etc.) '(5) lower alkyl alkenyl (eg, &lt;2 6 alkenyl, eg, vinyl, propenyl, Isopropenyl, butenyl, isobutenyl, etc., (6) aralkyl (for example, 〇-&quot; aralkyl, such as benzyl, methylbenzyl, phenethyl, etc.), (7 &gt; aryl (e.g., Ce core aryl, such as phenyl, naphthyl, etc., preferably phenyl, etc.) '(8) lower alkoxy group (e.g., Cie alkoxy group, such as hydrazine) An oxy group, an oxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxide group, a second butoxy group, etc.), (9) an aryloxy group (for example, Ch). An aryloxy group such as a phenoxy group, etc. '(10) a stilbene group (for example, a formic acid group, a low carbon number-and a few groups (Ch alkyl-carbonyl group, such as ethyl ketone group, propyl fluorenyl group, butyl sulfhydryl group, isobutyl group)醯, etc.) 'Arylcarbonyl (for example: C6_u aryl-carbonyl, such as benzamidine, etc.), amine methyl sulfonate, sulfonic acid group, sulfinic acid group, phosphonic acid group, amine sulfonyl group , a lower alkyl alkylsulfinyl group (for example, C. alkyl sulfinyl, such as methyl sulphate, ethyl sulphate, propyl sulphate, butyl sulphite An aryl group, such as a fluorenyl group, for example, a phenyl sulfenyl group, a naphthyl arsenate group, or the like, a low carbon number kiln base (for example, : Ch Hoxasulfonyl, such as methylsulfonyl, ethylsulfonyl, propyl fluorenyl, butyl tartrage, etc., aryllithinyl (eg: C6, aryl 318921 31 200808724 Two bases [e.g., phenyl lysyl, naphthyl base, etc.), single-molecular amines, such as: mono-Cl_6 leucine lysyl, such as arylamine, N-ethylamine gamma, N_ Propylamine lysyl, μ Base base, Ν-butylamine, etc.) 'dialkylamino gamma (for example: di-I-alkylamine sulfonyl group, such as N, N-dimethylamine sulphate, n, n Monoethylamine, N,N-dipropylaminesulfonyl, N,N-dibutylaminesulfonyl, etc.), =) carboxyl (1 -oxy (eg: gf oxygen) Base, low carbon (tetra)-based alkaloids (for example: Ch-based-severyloxy, such as ethoxylated, propyloxy, butyloxy, #丁醒oxy, etc.), aryl a methoxy amide "aryl-f-group, a group such as benzoic acid oxy, naphthyloxy, etc.), a low-carbon anatomyl group (for example, a c a 6 alkoxy-carbonyloxy group such as methoxy Alkylcarbonyl, ethyl carbylcarbyl, propoxy, isopropyloxy, butoxy, isobutoxy, tributoxy, etc., aryloxy- a few groups (for example, a C?-!5 aralkoxy-carbonyl group such as a benzyloxycarbonyl group, etc.), (13) a one, two or three teeth-low carbon number alkyl group (for example: one _, two _ or Sannan-CM alkyl, such as chloromethyl, dichloromethyl, trifluoromethyl, 2, 2, 2_tris, etc.), ((4)嗣(15) A sulfonyl group, (16) an imido group, ((7) an amine group, ((8) a mono-low carbon number amine group (for example: a H-amino group, such as a methylamino group, an amine group, a propylamino group, an isopropylamino group, a butylamino group, etc.), (19) a mono-lower alkylamino group (for example, a di-Cw alkylamino group, such as a dimethylamino group, two Ethylamino, dipropylamino, diisopropylamino, dibutyl benzyl, methyl ethylamino, etc.), (2G) SI-based amine, (21) 3- to 6- The % of the amine group optionally contains, in addition to the carbon atom and a nitrogen atom, one to three hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom (for example: 318921 32 200808724 3- to 6-membered cyclic amine group, such as azir idiny 1 , azetidin, σ ratio, σ ratio 17 1#, σ 嘻 、, 咪 17 σ 吐 吐 、, imidazolidinyl, hexahydropyridyl, morpholinyl, dipyridinium, tetrahydro σ ratio thiol, fluorenyl-fluorenyl hexahydropyrene, hydrazine-ethyl hexahydro π 啡 啡 等 等 , , , , 比 比 比 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Oxyl, ethylenedioxy, etc.), (23) hydroxy (24) nitro (25) cyano (26) thiol (27) alkylthio (Cw alkylthio, such as methylthio , ethylthio, propylthio, isopropylthio, butylthio, second butylthio, tert-butylthio, etc.), (28) arylthio (eg Ghfang) a thio group such as a phenylthio group, a naphthylthio group or the like, (29) a group derived from a combination of 1 to 3 groups in the above (1) to (28), and the like. As used herein, "mercapto", "decyloxy" and "decylamino" may be used as the "substituent" of the "hydrocarbyl group" of the above-mentioned hydrocarbon group optionally having a substituent, as exemplified. a group, a "nonyloxy group" and a "nonylamino group" are similar groups. A heterocyclic group having a substituent, if necessary, a "heterocyclic group" may have 1 at a substitutable position of the heterocyclic group. Up to 5 substituents. When the number of substituents is two, it may be the same or different. 5, preferably 1 to 3, two or more, each substituent R is preferably a halogen atom Or an acid group. The acid group is preferably a group represented by the following formula.

A hydroxyl group having a substituent is required, and "a group of - (OO)-R5, -S〇2-R5 or ~ (c = a hydrocarbon group which requires a substituent, #318921 200808724 needs to be substituted a heterocyclic group of the group, including, for example, a group represented by the above, "an amine which is also known as a ruthenium, a substituent having a substituent "having a substituent (tetra) group" and "optional basis" The heterocyclic group is the same group. The hydrocarbon group having a substituent as required, (1)/ΪΙ, preferably, 1; ;f (for example, methyl group), if necessary, is selected from the group consisting of Group = 2 substituents (1) amine, ((1) Ci_6 alkoxy (eg methoxy), ((1)) methyl (iv) G16 (tetra) j-based (, followed by - « amine (eg methoxy) Amino group B:: base tetylene diyl), (VI) C1_6 alkylsulfonylamino group (methylsulfonylamino), (t ring group (for example: 5- or 6-membered aromatic or Non-aromatic 'salt earth (eg, hexapyridinyl, ketohexahydropyridinyl=yl TM trisalyl, dihydrotrimethylene dipyridinium, pyrrolidinyl, etc.) in addition to carbon atoms, =),: Original: One pound into a group - to two of the two There are 1 to 5 substituents selected from the group of T. Chromatography (for example: methyl, isopropyl), thiol, methionyl (for example, acetamino group), full two f The female m has to have 1 or 2 ketone groups, and the decarburization base is still combined with cyclopentene or cyclohexane to form a spiro (tetra)oxy group (for example, ethyl ethoxy), (5) silk and (1) Amine = (2) C" loop wire (for example: cyclohexyl), which may be grouped as needed: (1) silk, (5) Gi 6 silk base (for example: lower armor ~ oxygen 318921 34 200808724 base) / (111) Mercaptoamine group, (iv) Ch alkyl-carbonylamino group (for example: oxime-based amine group), (ν) (^_6 alkoxy-carbonylamino group (for example: decyloxyamino group) Monobutoxycarbonylamino), (Vi) (^_6 alkylsulfonylamino (eg /methylsulfonylamino), (vii) heterocyclic (5 or 6-membered aromatic or Non-fragrant heterocyclic group (for example: hexahydropyridinyl, keto hexahydropyridyl, piperidinyl, imidazolyl, tetrazolyl, trisal, dihydrotrisyl, sulfhydryl) 'Imidazolidinyl, tetrahydropyrimidinyl, pyrrolidinyl, etc.) comprises a nitrogen atom selected from the group consisting of One or two of the sulfur atoms are in groups of two to four heteroatoms), optionally having a group selected from the group consisting of: to five substituents: an alkyl group (eg, sulfhydryl group, Isopropyl), hydroxy, methyl, monoalkyl-carbonyl (eg ethyl carbyl), formamidine and Cie alkyl-carbonylamino (eg, ethylamine), and optionally Having i or 2 fluorenyl groups, saponin 6-alkyloxy (for example: ethoxylated), thiol and (X) carbamoyl, etc., (3 melyl 14 aryl (phenyl) Further, if necessary, it has a substituent selected from the group consisting of (1) a mercaptoamine group and (ii) a GH alkyl group. And B is preferably an amine group, preferably an amine group having a substituent, as represented by Cl-6垸 γ,

Cl-6 an amine group, a bis-amine group, and the like. The "hydroxy group having a substituent" as the V represents an oxy group. R5 means "having a substituent - a ring group, if necessary, than a scorpion" or a nitrogen atom of 5 or 6 _ non-aromatic:; = soil (especially), hexahydrogen. 4_hexahydro(tetra)yl, hexahydrobenzyl) 318921 200808724 and optionally 1 or 2 substituents selected from the group consisting of (i)Ch alkyl (eg methyl, ethyl, propyl, isopropyl) And, if necessary, substituted with a substituent selected from the group consisting of: a fluorenyl group, a hydrazine-alkyl-carbonyl group (for example, an ethyl group), an alkoxy group (for example, a methoxyl group). Isopropyloxycarbonyl), amidino and mono- or di-C1_6 alkyl-amine-methyl hydrazino such as: dimethyl hydrazide, (ii) formazan (uOCh alkyl-carbonyl (eg, acetamidine) Substituted, if necessary, substituted with a substituent selected from the group consisting of: (a) a mercaptoamine group, (b) a c(mono)alkyl-carbonylamino group (e.g., an ethenyl group) and a compound 5 _ or 6_ member non-aromatic or aromatic, a heterocyclic group (for example: tetra. stil, trifilament, dihydrotrisyl, etc.) in addition to carboniferous: external 'containing a nitrogen atom, an oxygen atom and a sulfur atom One of the groups to one 4 heteroatoms, and optionally having 2 or 2 keto groups, (iV) Cl-6 alkanesulfonyl (methylsulfonyl), optionally substituted with substituents selected from the group consisting of: (4) a mercaptoamine group, (8) a pyrylamino group such as an ethylamine group, and ((:) 5_ or 6_M a non-aromatic or aromatic heterocyclic ring, such as a tetradentate group, a sigma sigma group, two Hydrogen triterpene, etc., in addition to carbon atoms, the package 3 is extended from a group of nitrogen atoms, oxygen atoms and sulfur atoms - to two to one of four heteroatoms' and optionally 1 or 2 The same group, (v) Ch alkoxy-singyl (for example: methoxyl group, third-butane =) is optionally substituted with a substituent selected from the group consisting of: (I^Cw alkyl-carbonylamino group (for example: acetamino group) and or non-family or aromatic heterocyclic group (for example: tetrafilament, trisal, hydrazine-saltyl, etc.) 'In addition to a carbon atom, it contains a group selected from a nitrogen atom, an oxygen atom, and a sulfur atom of 318921 36 200808724—having two or four BenQ, one to four heteroatoms, and as needed a substituent such as a heterocyclic group (Example: 5 - one to m ~ from a group of rat atoms, oxygen atoms and sulfur atoms, etc. - 1 to 4 heteroatoms), if necessary, have 1 or 2 keto groups:: see fragrant = base (Hymene heterocyclic group (for example: 5- or &quot; non-aromatic, including from the second son = plant - wind cough 2 (3fl),) 'except broken atom', oxygen group and sulfur atom group 1 to 4 heteroatoms of one to two )), (VHi) di-Cl_6 alkyl-amine carbaryl: di(ix) ketone group, etc. f makeup r I group) Among them, R1 is (1) a wind atom, a base group, which optionally has a group selected from the group consisting of: (1) an amine group, (1) a melon 6 alkoxy group, (lli) a CH compound base: a soil Nvwa, (lv)Cl-6 alkoxy-monoamine, (v) Ci'6 炫 醯 : : ::: V1) 5 or a member of a nitrogen-containing heterocyclic group (such as · · four Azolyl, triazole = dihydrotrisyl, sulphate, sulphate, tetrahydronyl, piperidinyl, etc., optionally having a group selected from Gi-meso and keto groups Up to 5 substituents, which are optionally formed together with cyclopentene or cyclohexane to form a spiro ring, (6)) Cl aryl-monooxy, Ιιι) thiol and (IX) Aminomethyl thiol, 318921 37 200808724 (3) Cl-6 Institute of Oxygen 1 - Prison, (OCh alkylamino-carbonyl, (5) C 1 - 6 ' (6) Amino-based keto, (7) C 1 -6 alkylamino-monomethyl, (8) - - Ci_6 alkylamino-peptidyl, or = (tetra) + silk , if necessary, having a group selected from the group consisting of: (1) c "alkyl-carbonyl" optionally having a 5- or 6-membered nitrogen-containing heterocyclic group (eg, tetradecyl, tri-salt, _ &amp; one having 1 or 2 ketone groups, (1) melon (tetra)yl group, etc.), if desired, (iv) CH-alkyl-filaria-based n(v) bis-diylalkyl-aminocarboxamidine and (Vi) ketone groups and the like. The above "if necessary, a group of 1 to 6: a group of substituents 5 - or 6-S nitrogen-containing trans-group, the oxime or cyclohexanthene together form a spiro ring," 5_ or 6_ member contains nitrogen and represents % group, and may include a 5- or 6-membered heterocyclic group (for example: tetrazolyl, tri-dihydrotris-salt, acridinyl) And a tetrahydro(tetra)yl group: a disulfide, a pyrrolidinyl group, or the like, which comprises, in addition to a nitrogen atom and a carbon atom, one selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom to a dihetero atom. &lt; i to 3 beautiful,, = "5 or 6-membered nitrogen-containing heterocyclic ring having 1 or 6 ketone groups as needed", and may be mentioned as 5-a Or a 6-membered oxygen-containing &amp; base (for example: tetrazolyl, triazolyl, dihydrotrimu), containing an atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to an i atom and a carbon atom. 318921 38 200808724 Group = one to two of 1 to 3 heteroatoms. ' 中 R车乂 is C1-6 alkoxy-Cl-6 yard base-several base,

Alkyl-carbonylamino-G oxime I 6 alkyl-rebel, CH alkoxy-carbonyl or W(:alkyl-daily)piperidine~4~yl. R is a chlorine atom, a C&quot; alkyl group having a substituent or a CM cycloalkyl group having a substituent as necessary. R, which is optionally a C6 alkyl group having a substituent, and a "alkyl group", for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a butyl group, a dibutyl group, or a Tributyl, pentyl, hexyl and the like. Among these, a C-dialkyl group such as a methyl group, an ethyl group or the like is preferable and a methyl group is more preferable. R represents a C3_6 cycloalkyl group having a substituent, and a "C3-6 cycloalkyl group", for example, can be used as a butyl group, a butyl group, a cyclopentyl group. Bad U storm. R represents a C&quot;alkyl group having a substituent, or a "substituent ring having a substituent, as needed," and includes, for example, "for the above Ri" The "hydrocarbyl group" of the substituent "the substituent" is the same group. Among them, it preferably has 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.). R2 is preferably A hydrogen atom or a Gh group having a substituent. Among them, 'preferably has ～ alkyl groups as required to three tooth atoms (for example, gas, chlorine, bromine, iodine, etc.). Further, it is a Ci6 alkyl group and is particularly preferably a methyl group. Z is optionally a group (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, second butyl group, and the like). Methylene group of tributyl, pentyl, hexyl, etc. 318921 39 200808724 z The early father is a fluorene-based fluorene-based fluorenyl group. 1 to 8 substituents A are as needed, except for R1, len- and Ar. The hexahydropyridine ring having a substituent, if desired, "A group similar to the substituent of "phenyl" in the above Ar may be mentioned. Ring A preferably has no substituted hexahydrogen port ratio ring ring other than Rl, off-and red. %/ and % C are benzene rings further having a substituent as needed. In addition to the rings c ' 0-R 2 and Z-, the ring B may further have from 1 to 3 substituents: in addition to the ring β, the ring C may have 1 to 5 substituents. The ring/and ring C may have a "substituent," and a group similar to the substituent of the "phenyl" of Ar described above may preferably be mentioned as further having a halogen atom as needed. Or a benzoquinone of a Ci_6 alkyl group, or a ring B and R2 together form a 2,3-dihydrobenzenefuran. The ring c preferably has a fluorene or two substituents selected from the group below (1). a gas base, (2) a stone base, (3) a halogen atom, (4) a Ci-e alkyl group having 1 to 3 halogen atoms as needed, (5) a Ci-6 block group, (6) having 1 as needed Alkoxy group to 3 halogen atoms, (7) Ci6 alkylthio group, (8) c^ alkylsulfonyl group, (9) di-Cl-6 alkylamine group, (1Q)Ci-6 alkyl group- Carbonyl, (inc!-6 alkyl-carbonylamino, (12)Cl-6 alkoxy-carbonyl and amine In particular, it is preferred to have a benzene ring having one or two substituents selected from the group consisting of (1) a cyano group, (2) a tooth atom, and (3) optionally having 1 to a C atom of 3 halogen atoms and (4) a ch alkoxy group. 318921 40 200808724 Compound (I), preferably a compound represented by formula (11)

Wherein the symbol is the above definition, and particularly preferred is a compound having the structure shown below (Ila)

The symbol is the above definition. More specifically, the compound (LIa), wherein preferably

Ar is available as needed! Phenyl group to 3 halogen atoms, R1 is (1) a hydrogen atom, (2) a C-alkyl group, optionally having 1 or 2 substituents selected from the group consisting of: an amine group, (ii) Ci-6 alkoxy, alkyl-carbonylamino, (iv)^6 alkoxy-carbonylamino, (v) Ci 6 alkylsulfonylamino, (νι) 5- or 6-member a nitrogen-containing heterocyclic group, optionally having 1 to 5 substituents selected from the group consisting of a C 6 alkyl group and a keto group, which are optionally formed together with cyclopentane or cyclohexane to form a spiro ring, (vii Ci 6 alkyl-carbonyloxy, (viii) hydroxy and (ix) amine fluorenyl, (3) Cl-6 alkoxy-slow, (4) Ci-6 alkylamino carbon, 41 318921 200808724 (5) Ci-6 alkylsulfonyl, (6) amino-based thiol, (7) -6 alkylamino-carbonylcarbonyl, (8) di-Cl-6 alkylamino- a benzyl group, or (9) piperidin-4-ylcarbonyl, optionally having a group selected from the group consisting of: or two substituents: (ί)(^6 alkyl-carbonyl, which optionally has a 5- or 6-membered nitrogen-containing heterocyclic group (the heterocyclic group optionally has an anthracene or two keto groups), (ii) a c alkoxy-carbonyl group, (iii) a C1-6 alkylsulfonyl group, Iv) Ci_6 alkane - carbonylamino-CH alkyl-carbonyl, (v) bis-Cl_6 alkyl-amine fluorenyl and (vi); i) oxime to three halogen atoms (^6 alkane R is (1) a hydrogen atom Or (2) having 1 group as needed; Z is a fluorenylene group having a methyl group as needed; and ring A is a hexahydropyridyl group B having no further substituent, further having an _ atom or ^ as needed

...forms the formation of 2,3-dihydrophenylpyran; and the alkene ring of the ketone or the B ring of the B ring is a benzene ring, which is required to be formed from the group or the following group as needed. (1) cyano, (2) nitro, (3) halogen atom, (4) if desired, i to 3 halo (5) Ci-6 alkynyl, alkyl, (6) as needed CVS alkoxy group of 3 halobutyl 318921 42 200808724 (7) Cl-6 alkylthio group, (8) C 1 -6 alkyl base, (9) di-Cl-6 alkylamino group (10) Cl-6 alkyl-based, (11) Cl-6 alkyl-decylamine, (12) Ci-6 alkoxy-enactivator and (13) aminyl. More preferably, the compound (Ila) wherein Ar is a phenyl group; R is aCh alkoxy-Ch alkyl-carbonyl group, Cb alkyl-carbonylamino group_Cl_6 alkyl-carbonyl group, Cu alkoxy-carbonyl group or p (Cl_6 alkyl-carbonyl) piperidine_4_ yl group; ring A is a hexahydro σ ratio bite ring having no further substituent; R 2 is a Ci6 alkyl group having 1 to 3 halogen atoms as needed; a benzene ring having no further substituent; and ring c is a benzene ring, optionally having a group or two substituents selected from the group consisting of: (1) a cyano group, (2) a halogen atom, (3) A Ch alkyl group having up to 3 halogen atoms and (4) aCh alkoxy group as needed. Further, as the compound (I), a compound represented by the formula (IIa) can be mentioned as a preferred specific example.

318921 43 200808724 where

Ar is a phenyl group having 1 to 3 halogen atoms as needed; R1' is (1) a hydrogen atom, and (2) a Ch alkyl-carbonyl group, if necessary, having ι or 2 selected from the group shown below Substituent (ammonium, (ii) Ci 6 alkoxy, (iii) Ci 6 alkyl-carbonylamino, (ivMi-6 alkoxy-carbonylamino, (v) Ci6 alkylsulfonate Alkylamino, (vi) 5- or 6-membered nitrogen-containing heterocyclic group optionally having 1 to 5 substituents selected from the group consisting of an alkyl group and a keto group, optionally having a cyclopentyl group Burning or cyclohexane together to form a spiro ring, (vi i)Ch-alkyl-aryloxy, (viii)hydroxyl and (ix)aminocarbazinyl, (3) Cl-6 alkoxy-. (4) C1 - 6 base base, (5) Amino-based, (6) C 1 -6 alkylamino-Wei-based, (7) Di-Cl-6 alkylamine a base-dyl-yl, or (8) piperidin-4-ylcarbonyl, optionally having 1 or 2 substituents selected from the group consisting of: (i) (^-6 alkyl-carbonyl) , if necessary, having a 5- or 6-membered nitrogen-containing heterocyclic group (the heterocyclic group optionally has 1 or 2 keto groups), (ii) Ci-e alkoxy-prison, (iii) Ci- e burned stone jaundice, (iv) u finished - phenylamino-Ci_6 alkyl-based, (V) di-Ci-6 alkyl-amine-branth and (vi) keto; R2' is (1) a hydrogen atom or (2) as needed a Ch alkyl group having 1 to 3 halogen atoms; Z' is a fluorenylene group having a fluorenyl group as needed; 318921 44 200808724 Ring A' is a hexahydropyridine ring having no further substituent; ring ^ is required as needed - a benzene ring having a tooth atom or a Ci_6 wire or a combination of R and R to form 2,3-dihydrobenzenefuran; _ ring C' is a benzene ring, which optionally has a substituent selected from the group shown below. 2 (1) cyano, (2) nitro, (3) halogen atom, (4) Cl_6 alkyl having 1 to 3 halogen atoms as needed, (5) Ch alkynyl, (6) as needed Ci-6 alkoxy group of 1 to 3 halogen atoms, (7) Cl-6 alkylthio group, (8) Cl-6 alkylsulfonyl group, (9) di-C!-6 alkylamino group , (10) Cl-6 alkyl-based, (11) Cl-6 alkyl-monoamine, (12) Ci-6 alkoxy-alkyl and (13) amine sulfhydryl. Compound (I), the salts of the following examples 1 to 13 can be mentioned as preferred embodiments. In particular, shame [2-((3R, 4S)-4-{[ (4,-cyano- 4-decyloxybiphenyl-yl)methyl]amino}-3-phenylpiperidin-1 -yl)-2-ketoethyl]acetamide (Example 10), N~[2 -((3R,4S)-4-{[(4'-Cyano-2'-fluoro-4-indolyl phenyl) - 318921 45 200808724 methyl]amino}-3-phenyl 嚷An example of u), —yl)-2-ketoethyl]acetamidamine (implementing N-[2~((3R, 4S)-4-{Γ^ a ^ ^ A} 3 I, r ~ i [( 4 _ disorder-4-methoxybiphenyl-3-yl)methyl]amine basic group 疋+yl)-2,ylethyl]acetic acid amine (Example 15), N-[2-((3R ,4S)-4-{[(4, - n —4 审^ 1 at #K4齓_4-methionylbiphenyl-3-yl)methyl]amino-3-diyl yawn + base) _2, phenylethyl]ethinamine (Example (8), Ν-[2 body 4-{[(&quot;oxy-, methylbiphenyl)-yl)methyl]-amino- 3-phenyl brigade bite + base) 2- 2-ketoethyl]acetic acid amine (Example 17), N-{2—[(3R,4S)-4-({[4一甲_//4 4-methylamino-4] (Difluoromethyl)biphenyl-3-yl]methyl}amino)-3-phenylpitrile +yl]_2-ketoethyl}acetic acid amine (Example 18), Ν-[2-( (3Ε,48)-4-{{(4-^^_3-|,-4-ΤΑ^,^-3^) fluorenyl]amino}}phenyl phenyl] 2-ketoethylethylacetic acid amine (Example 21), hydrazide}-3-phenylbendone + yl)_2-ketoethyl]ethanoamine (Example 23), N_[2_ ((^'4S) + {[(4'-bromo-4-ylbiphenyl-3-yl)methyl]amino}-3-phenyl brigade + base)_2,ylethyl]B Amine (Example 22), N-[2-(10),4S)-4-{[(4,-ethynyl+methoxybiphenyl-3-yl)-N-{2-[(3R'4S) )-4-({[4'-cyano+(trifluorofoxy)biphenyl_3_yl]methyl}amino)-3-phenyl brig.乙基基]_2_g同基ethyl}acetamide (Example 24), ^[2-((3艮43)-4-{[(4'-Cyano-4-methoxy-2, —Methylbiphenyl-3,318921 46 200808724 yl)methyl]aminopyr-3-phenylpiperidinyl+yl)_2-ketoethyl]acetamide (Example 25), 4曱oxy-3 -({[(3R,4S)-:l-(methoxyethenyl)_3_phenylpyridin-4-yl]amino}methyl)biphenyl-4-ylcarbonitrile (Example 32) , 2fluoro-4-methoxy-3 -({[(3R,4S)-l-(decyloxyethyl)_3_phenylpiperidin-4-yl]amino}methyl)biphenyl_4 - carbonitrile (Example 33), 3-[({(3艮48)-1-[(i-ethylpiperidinyl-4-yl)carbonyl]]-3-phenylpiperidin-4-yl}amino)曱]], 4, _ methoxybiphenyl _4_ decyl nitrile (Example 35), 3 -[({(3R,4S)-1-[(1-() a few bases]_3_phenyl bunge-4-yl}amino)methyl]m-methoxybiphenyl + methyl eye (Example 36), , (3{〇-3-(ethinylamine) Base) - 4 - ((祁, 4幻_4_{[(4,_cyano_4_decyloxybenz-3-yl)methyl]aminophenyl) 3_phenyl 1唆+yl)— [Ketyl butylamine (Example 41), 3-[U(3R,4S)-1-[(2,6-diketopiperidinyl)) ]]-3-phenylene bite + mercaptoamino)methyl]-4,-methoxybiphenyl + a guess (Example 42), '4 - A battle base-3, -({[( 3R,4S)-3-phenyl+(1H-tetras-s-ethylhexyl)piperidin-4-yl]amino}methyl)biphenyl- 4-carbonitrile (Example 43), 4-A Oxy-3, -[({(3R,4S)-1 -[(5-keto-4,5-dihydro-1H-1,2,4-diazole-3-yl)ethenyl] 3- phenylpiperidin-4-ylphosphonium) fluorenyl]biphenyl-4-carbonitrile (Example 44), N-{2-[(3R,4S)-4-({[4, -chloro-4-(tris-methoxy)biphenyl_3_yl] 318921 47 200808724 fluorenyl}amino)_3-phenylpiperidine-fluorenyl]-2-ketoethyl}acetamide (Example 72), ' 3 -[({(3R,4S)-l-[(5, 5-Dimercapto-2, 4-dione-1,3-1,3-oxazolidine-3-yl) Ethyl hydrazide]-3-phenylpiperidine-4-ylindolyl)methyl]-2-fluoroin-4, mono(difluorodecyloxy)biphenyl-4-indenecarbonitrile (Example 96, 97), 2-Fluoro-3'-({[(3R,4S)-1-ethanolindol-3-phenylpiperidin-4-yl]amino} fluorenyl)-4'-(trifluoroanthracene) Oxy)biphenyl-4-oxonitrile (Example 1〇〇), 3 -[({(3R,4S)-1-[(1-acetamidine) (piperidin-4-yl)carbonyl]-3-phenylpiperidin-4-yl}moon-female)]]-fluoro-4'-(trifluoromethoxy)biphenyl-4 Formonitrile (Example 101), 3 -[({(3R,4S)-l-[(2,6-diketo)-4-ylpiperidin-4-yl)carbonyl]-3-phenylpiperidin-4-yl }Amino)methyl]-2-fluoro-4'-(trifluorodecyloxy)biphenyl-4-carbonitrile (Example 102), 2- [(3R,4S)-4" ({ [4 '-Cyano-2'-fluoro-4-(trifluorodecyloxy)biphenyl-3-yl]fluorenyl}amino)-3-phenylpiperidine-1 -yl μ2-ketoacetamide (Example 104), 3-{2-[(31^'48)-4-({[4-chloro-4-(trifluorodecyloxy)biphenyl-3-yl]methyl}amino) 3-phenylpiperidinyl-diyl]-2-oxoethylethyl 5,5-di-decyl-1,3-indan-2,4-dione (Example 116), 4- {[(3R,4S)-4-({[4'-gas-2'-fluoro-4-(trifluoromethoxy)biphenyl-3-yl]methyl}amino)-3-phenyl) Piperidine-fluorenyl]carbonyl}piperidine-2,6-dione (Example 132) and 3'-[({(3R,4S)-1-[(5, 5-didecyl- 2, 4-diketo-l-3-oxazolidine-3-yl)ethinyl]-3-phenylpiperidin-4-yl}amino)methyl]-4, (Trifluoromethyl 31892148 200 808 724 methoxy) biphenyl-4-carbonitrile (Example 137), its salts and the like. The salts of the compound (I) include, for example, metal salts, ammonium salts, salts with organic tests, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. . Suitable examples of metal salts include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; Suitable examples of salts with organic bases include with tridecylamine, triethylamine, acridine, mercaptopyridine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, bicyclo A salt such as hexylamine, N,N,-diphenylfluorene or ethylenediamine. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, sulfonic acid , salts of benzenesulfonic acid, p-toluenesulfonic acid, and the like. Suitable examples of salts with basic amino acids include those with arginine, lysine, ornithine. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Among them, preferred are pharmaceutically acceptable salts. For example, if the compound has an acidic group, it is preferably an inorganic salt such as an alkali metal salt (for example, a sodium salt, a potassium salt, etc.), an alkaline earth metal salt (for example, a calcium salt, a magnesium salt, a barium salt, etc.), ammonium. Salt and so on. If the compound has a basic acting group, it is preferably an inorganic acid salt such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like, or an organic acid salt such as acetic acid, citric acid, fumaric acid or oxalic acid. ',,, talc, maleic acid, citric acid, succinic acid, sulfonic acid, acid, and the like. ', Yin, 318921 49 200808724 The prodrug of the compound (1) of the present invention or a salt thereof, the compound is emulsified, transported, hydrolyzed by a reaction with an enzyme, a gastric acid, etc. under human conditions, that is, an enzyme white t Etc;; gastric acid hydrolysis, etc., conversion of the compound (I). The prodrug of the compound (1) of the present invention includes a compound wherein the amine group of the compound is modified by a mercapto group, an alkyl group or a phosphonium group (for example, an amine group of the compound (1): by: ten (tetra), propylamine, pentylamine: Rebel (5 methyl-2-keto-L3 -dioxole__4_yl)methoxy, tetrahydrofuranyl, pyrrolidinylmethyl, trimethylacetoxy" or: three a compound modified by a butyl group or the like; wherein the compound of the present invention (1) is a compound modified by a mercapto group, an alkyl group, a phosphoric acid or a boric acid (for example, wherein the compound (1) of the present invention is represented by an yttrium, a ten (tetra) group, or a propyl group. a compound modified with a saccharide group, a trimethyl sulfhydryl group, an amber fluorenyl group, a transbutylidene group, an propylamino group or a dimethylaminomethyl group (tetra); wherein the carboxyl group of the compound (1) of the present invention is modified to an ester or a compound of decylamine (for example, wherein the carboxyl group of the compound (I) of the present invention is modified to an ethyl ester, a phenyl ester, a carboxymethyl ester, a dimethylaminomethyl ester, a trif-yl (10) oxymethyl group , ethoxy (tetra)oxy = hydrazine, fluorenyl ^, (5-royl-2- keto-13 dioxo a pentene _4-yl) decyl ester, a compound such as hexyloxycarbonylethyl ester or methyl decylamine, etc. The prodrugs are known from the compound (1) of the present invention as such. Further, the prodrug of the compound (I) of the present invention may be a compound which is physiologically converted to the compound (I) of the invention and is described in

Pharmaceutical Research and Development&quot;, V〇l. 7 318921 50 200808724 ((iv) 11), PP. i63_198 (1990), pubiished by Hirokawa PUbHshing c〇. The hydrate of the heart, for example, a hydrate of a compound represented by the formula (丨) and a salt thereof are all included in the scope of the present invention. The compound represented by the formula (I) can be labeled with an isotope (e.g., 3H, HC, 35S, (2), etc.). In the case where the compound (1) of the present invention has a palm center, an isomer such as, for example, a mirror image isomer or a non-image isomer may be present. This isomer is included in the scope of the present invention together with it. Further, there may be an example, i.e., a case arises by the formation of a rainbow, but such an isomer or a mixture thereof is contained in the compound (1) of the present invention or a salt thereof. The compound (1) is preferably a cis isomer. The method for producing the compound (1) of the present invention or a salt thereof will be explained below. The chemical (I) and its salts of this month can be prepared according to the preparation method described in 卯 (10) / 101964. In particular, they can be prepared using the following Process a, Method B, Method C or Method D. [Method A] The compound represented by the formula (10) or a salt thereof (referred to as R2)

(lb) wherein each symbol is as defined above, and is prepared by reacting with a compound represented by the formula (π&quot; or a salt thereof (hereinafter referred to as compound 318921 51 200808724 (111)) or a reactive derivative, Rla-〇 H (Hi) and the right side of the flank of the nicotine group having a substituent, a awake base or, if necessary, a substituted heterofilament, similar to the example of w. A reactive derivative of the compound (III), for example, A compound represented by the compound (Ilia) or a salt thereof (hereinafter referred to as the reaction (Ilia)) can be used:

Rla-L (III' wherein L· is a leaving group and p is the same as defined above. The leaving group represented by L includes, for example, a functional atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.), substituted a sulfonyloxy group (for example, a thiol group ii oxy group such as an anthracene oxy group, an acetaminophen oxy group, etc.; ^―&quot; an arylsulfonyloxy group such as a benzenesulfonyloxy group, a p-toluenesulfonyloxy group Base, etc., an aromatic sulfonyloxy group such as a benzyloxy group, an acidoxy group, an ethoxylated oxy group, a benzoic acid oxy group, a carbonate, a trichloroethylene imidic acid vinegar, or a oxalic acid , phosphite (eg methyl phosphite, etc.), penta-coordinated phosphorus compound (Phosphorane), heterocyclic or aryl (butylimine, benzotriazole, quinoline, 4-nitrophenyl ester) The substituted oxy group, the hetero ring (imidazole, etc.), etc. The reaction using the above reactive derivative as a burning agent can be carried out by reacting the reaction compound (lb) with a reactive derivative, usually in the presence of a base. The solvent includes, for example, an alcohol such as methanol, ethanol, propanol or the like; an ether such as dimethoxyethane, dioxane, tetrahydrofuran or the like; Ketones such as 318921 52 200808724 acetone, etc.; nitriles such as acetonitrile, etc.; 醯月女, 石石风 such as dimethyl sapite, etc., ϋ N,N-dimethylformamidine. For example, the right unequal, which may be suitable for mixing J-barbaric base such as Ertian... monomethylmorpholine, pyridine, picoline,: female, diethylamine, N-computer such as potassium carbonate, sodium carbonate,氡 gasification - methyl aniline, etc.; and in an amount relative to a 1 molar matrix, for example, potassium, sodium aroxide, etc. The base is preferably from about 1 to about 丨〇 molar equivalent /,,, from 1 to about 100 Molar equivalents, reactive derivatives include, sulphuric acid vinegar or sulphate (for example:: (for example: chlorine, bromine, angstroms. The amount of reactive derivatives is about 3 moles relative to 1) Ear equivalents.. 4 1 to about 5 mole equivalents, preferably about 1 to J. The addition of an additive to the field promotes the reaction. This includes, for example, moth compounds such as Weiner, potassium moth, etc., and: phase: 1 旲 基 贝 is about G. 1 to about 1 G molar equivalents, preferably 'to about 5 molar equivalents. 巧〕 υ. 1 reaction temperature is usually from about one muscle to about 20 (TC Preferably, it is about 〇 〇 〇, and the reaction time is usually from about 0.5 to about 48 hours, from about 0.5 to about 16 hours. The slave soil is a reaction based on the reactivity of using the above reactive derivative as a oximation agent. The type of derivative or matrix 'is usually carried out in a solvent. If necessary, a suitable base can be added to promote the reaction. Solvents include, for example, hydrocarbons such as benzene, / benzene, etc.; , tetrahydrogenated biting, etc., esters such as ethyl acid, etc., halogenated hydrocarbons such as chloroform, dichloroftane, etc., esters such as acesulfame 318921 200808724 acid B; Pyridine or the like; water or the like, which can be used as a suitable compound, a quaternary amine, or an anthracene. In addition, from the package, such as 'test metal hydroxides such as chlorinated bicarbonate such as sodium bicarbonate, hydrogen carbonate"; carbon (tetra) =, sodium, potassium carbonate, etc., acetates such as sodium sulphate, etc.; Amine II: triethylamine, N-methyl, etc.; aromatic amines ～:; The ratio of base mouth to bite-dimethylaniline is about 1 to about 1 丨 with respect to 丨:r ° molar equivalents, preferably about! to about heart deuterated agents including, for example, tannic acid, sulfonic acid, meals, carbonic acid or pelvic, biological (eg · acid complex, sour liver, mixed acid liver, activation (d), isocyanate, isothiocyanate, etc. The amount of the brewing agent is usually from about ! to about 10 mole equivalents, preferably from about i to about 3 mole equivalents per 1 mole of matrix. The reaction temperature is usually about 〇 〇 c to about 1, preferably from about Qt: to about mt:, and the reaction time is usually from about 15 minutes to about 24 hours, preferably from about 3 minutes to about 16 hours. The compound (ib) as a starting compound can be produced by deuteration of a compound represented by the formula (ia) obtained by the following *B or the method C or a salt thereof. The chemistry can be carried out according to known methods, for example, the method described in Theodora Ψ. Greene, Peter GM Wuts, "Protective Groups ln 〇 gan gangan Synthesis, Third Edition, (] 999) π! 吖 InterSclence, or the like. The reaction is usually carried out in the presence of an acid or a base, if necessary, according to the kind of the compound (la), at 54 318921 200808724, without adversely affecting the solvent of the reaction. The acid is preferably a mineral acid (hydrochloric acid, hydrazine bromine). Acid, sulfuric acid, etc.), carboxylic acid (acetic acid, trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acid (methanesulfonic acid, toluenesulfonic acid, etc.), Lewis acid (aluminum chloride, tin dichloride, zinc bromide, etc.) And etc. If necessary, a mixture of one or more kinds may be used. The amount of the acid varies depending on the kind of the solvent and other reaction conditions, but is usually about mole or more with respect to the i mole compound (5), and the acid can be used. As a solvent, = is preferably an inorganic test (test metal hydroxide such as hydroxide steel, ammonia-oxygenated carbonic acid - 'chlorine chloride off-load, etc., test = month 1 and so on), or organic test (amine such as trimethylamine, Triethylamine, isopropyl isopropyl: methylamine -etc.), etc., and the type and other anti-accumulation. The amount of the test is usually based on the solvent of the about mole compound (10) through the ear, preferably about 〇·! to about 5 1 without adversely affecting The solvent of the reaction includes: alcohol, ethanol, propanol, 2_two sax, butyl sulphate, such as A · ν - Benzene butyl butyl alcohol, butyl alcohol, butyl alcohol, such as benzene, Toluene?, butanol search; burned, burned, etc.. Six, several, known as the moon, such as the scorpion temple, toothed hydrocarbons, such as dichloro, such as diethyl ether, iso-diether, tert-butyl / hole Imitate special '·ethers, dimethoxyacetamidine, etc. · soil... tetrahydrofuran, di-alkane, finder, nitrile, such as acetonitrile oxime, acetonide, etc.; carboxylic acid, you u ^, , g 曰 pain For example, ethylamine acetate, dimethyl: and the like; amine amines such as N,N-dimethylmethyl 1 acetamide; anthraquinones, water, and the like. The solvent can be used in a high A wind jaw such as dimethyl sulfoxide, etc.; a mixture of two or more is used at an appropriate ratio 318921 55 200808724 0 The reaction temperature is 'for example, about -5 〇t: to about 2〇〇〇c, which varies from 5 degrees to loot, and is, for example, from about G 5 to about just hours, from about y to about 24 hours. J υ· 5 [MethodΒ]

Each of these symbols is as defined above. The compound (IV) as a starting compound in this method can be produced by the production method described in WO03/1 01964 and the like.豕 (Step 1) In this step, a compound represented by the formula (IV) (hereinafter referred to as a conversion to an imine or a form) is subjected to reduction to give a formula represented by the formula (ν) (hereinafter referred to as an amine compound (V)). The σ y compound (10) can be converted into an imine or a monthly loss by a known method. For example, the reaction can be carried out using a variety of amines in a solvent inert to the reaction. Amines can be mentioned, ammonia, such as ammonia, Amine chloride, for example, amine, 0-methyl-amine, hydrazine-terminated amine, etc.; class: such as benzylamine, aminodiphenylmethane, phenylethylamine, etc. 318921 56 200808724, etc. may also be used in the form of a salt, for example, an aqueous solution thereof, an amine used in the amount of a dibasic salt disulfate, or the like, or may be, for example, from about 丄 to about 50 mol, compared to the compound (10) of H. Examples of solvents which are inert to the reaction include from 1 to about 10 moles of toluene, xylene, etc.; aliphatic "...] such as 'fragrant aromatic hydrocarbons, such as, for example, gas, 1 formazan, such as gargene, burned, · Halogenated hydrocarbons, 4, _, such as (three), tetra-U, di-alkane, etc.; alcohols, such as methanol, four Liao, etc.; guess, examples Such as B guess, etc. = butanol, benzyl alcohol, etc. This solvent can be mixed in an appropriate ratio: methyl (tetra) dimethyl sulfoxide agent package: to: as the reaction: effective treatment by adding a catalyst. For example, heat engine acid (for example: hydrochloric acid, hydrochloric acid, carboxylic acid (for example: formic acid, acetic acid, propionic acid, three liters, methanesulfonic acid, p-toluenesulfonic acid, etc.) - 夂 Temple, (for example. ^ j Lewis acid (for example: 翕 each such as ^,, words, zinc bromide, San Gu 测 、,> 虱 虱 铝 虱 虱 虱 虱 虱 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Etc.), molecular sieve (for example: sub-&quot; such as ^ 曰酉 dehydration agent (such as · · magnesium sulfate, A, 5A search), the character of the temple) the amount of catalyst specific to a mole of stolen goods (to For example, from about 0.01 to about 10 to about 10 moles, the hopper soil is about 0. 1 and the reaction temperature is usually about 0. 〇 to about 15 (ΓΓ, day m mU0C ' is preferably about 2 (TC) To C and the reaction time is usually from about 0.5 to about 4 δ + 3 ± about 0.5 to 24 hours. 0 48 small days, preferably with a reduction of the inert solvent in the transition (4)曰 Ό 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此Wind i compounds include, you are a gentleman's mouth, * Guanri / μ Lux, such as sodium bismuth boride, lithium borohydride, hydrogen boron 2 zinc, cyanoguanidine U, triethyl hydrazine, cyano chlorination: , Suihua-Dingshao, hydrogenated Shao, hydrogenation (four), occupational complex (employment = material ^ burning tea test, etc.), etc. The metal chloride preferably includes hydrogen deletion:: diammonium, triethylene oxime Hydrogenation of the metal, etc. Metal hydrogenation = imine dissociation relative to -mole, for example, from about 1 to about 5 moles, preferably from about 1 to about 10 moles. , by the reduction reaction of metal hydride - generally the reaction is inert to the field # μ square incense without hydrocarbons, such as toluene, one of the original, aliphatic hydrocarbons, such as geng, gas, - animal farm has Alkane, agglomerated hydrocarbons, such as the etc. rr bond, such as ethylene, tetrahydrofuran, dioxin: broad, such as methanol, ethanol, 2, alcohol, butanol, benzene; :::::acetonitrile temple , N'N-dimethyl ketoamine; dimethyl cation can be used in a suitable ratio of the mixture. The reaction temperature is usually from about -8 (rc to about 8 (rc, more than two OC' and the reaction time is usually from about 5 minutes to two to about 1 to 24 hours.) The catalyst hydrogenation reaction can be carried out in hydrogen. Environment and preparation of compounding compounds such as bismuth: 寻, nickel compounds, such as Raney nickel catalyzed palladium uranium, peak earning, such as the amount of imine or bismuth in the ear is about 0.001 Up to about 0.5 moles, 々1 mole, preferably about 〇. 〇1 318921 58 200808724 Catalyst hydrogenation reaction is usually carried out in a solvent inert to the reaction including, for example, an alcohol such as methanol , ethanol, two alcohols, hydrocarbons, such as stupid, hyperthyroidism, - A 婪 Chu · A, 卞 ,, —. 斤 曱 曱 , ,, halogenated hydrocarbons, such as dichloro decane, imitation, etc.; ethers, for example Ether, diterpene, tetrakis: hydrazines such as succinic acid, etc.; for example, N,N-dimethyl ketones § carboxylic acid, such as acetic acid, etc.; water or a mixture thereof. The hydrogen pressure at the time of the reaction treatment is usually about! to about 5 Torr and the atmospheric pressure is from about 1 to about 10 atm. The reaction temperature is usually about 〇. Preferably, it is about 2 (TC to about 10 (rc), and the reaction time is usually from about 5 minutes to about 72 hours, preferably from about 0.5 to about 40 hours. In this step, the amine compound 〇 〇 can also be directly prepared from the preparation, and at the same time the preparation and reduction of the imine or the monthly loss of the reaction, not divided into clothing =: or. In this case, the reaction mixture _ cross is preferably about γ (step 2) in this step In the case where the amine compound (ν) is alkylated or further compound (la), the transfer to the k-form can be carried out by a method known per se. (V) and (VI) a compound or a salt thereof (hereinafter, the following compound (VI)) or a reactive derivative thereof: 曰-化R2

318921 59 (VI) 200808724 Each of these symbols is the same as defined above and is a burning agent. The reactive bamboo organism of the compound (VI) is, for example, a compound represented by the formula (v I &amp;) or a salt thereof (hereinafter referred to as a reactive derivative (VIa)).

Where L is the leaving group and the other symbols are as defined above. The leaving group represented by L includes, for example, a south atom (for example, a chlorine atom, a sub, an iodine atom), a substituted sulfooxy group (for example, a 6 alkyl sulfonium oxy group such as hydrazine) With an oxy group, anthraquinone, an oxy group, etc.; an aryl sulfo group = an oxy group: for example, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, etc.; (: a 7-16 fluorite fluorenyloxy group, such as a benzyl group Sulfomethoxy group; c&quot; alkoxy lyoxy group, such as methoxysulfonyloxy group, etc.), - when the reaction is carried out using compound (VI) or the above reactive derivative (via) as a deuteration agent' Depending on the type of the compound (VI) or the reactive derivative (Vh) and the amination of the substance, it generally comprises reacting the reaction compound (Chlor or a reactive derivative (Via) with an amine compound (v) in the presence of a base. Reaction in a solvent. Ethers such as diethyl ether, dioxane, tetrahydrogen, etc., nitriles, such as acetonitrile, guanamines, etc., sulfoxides, such as dimethyl sulfoxide, etc., , alcohols, such as methanol, ethanol, etc. tetrahydrofuran, etc.; ketones, such as acetone, such as hydrazine, hydrazine-dimethylformamide, etc. Water, etc., which can be appropriately mixed with _ such as diethyl ether, second-order pine, ^4. _______ ' '. 318921 60 200808724 Included, for example, 'organic tests, such as trimethylamine, triethylamine, &quot; ... compared to hydrazine, methyl M, N, N' xylamine, etc., and inorganic tests, such as carbonic acid unloading, sodium carbonate, potassium argon oxide, sodium hydroxide, etc. The amount of the test relative to the amine compound of the 旲-ear (7) For example, it is preferably from about 1 to about 10 moles of about i. The Wudou reactive derivative (10)) includes 'for example, a tooth (for example, a vapor, a bromide, an ethide, etc.), a sulfate, or a stone. Yellow vinegar (for example, pyrite, p-toluene, benzoic acid, etc.), and the like, and especially for the compound: (π) or reactive derivative (na) relative to - The molar amine compound (7) 'for example, is from about! to about 5 moles, preferably from about i to about 3 moles. If necessary, an additive may be added to promote the reaction. This additive includes, for example, moth compounds, for example Mothium, material (4) and relative to the chemical, the amount of the substance (V) is from about 0.1 to about 1 mole, preferably from about 5 to about 5 moles. The reaction temperature is usually -1 (rc to about 20 (rc, preferably about 110 C' and the reaction time is usually about 〇. 5 to about 48 hours 5 5 to about 16 hours. The soil is immersed. A method in which alkylation can be known per se = amine compound 00 can be reacted with a compound represented by formula or a salt thereof (hereinafter referred to as compound (VII)):

318921 61 (VII) 200808724

Preparation of imine or sub-face from early Fengan # ^ and other symbols are as defined above,

The reaction of L does not separate the pH of the intermediate reaction mixture from the product imine or imine ion. In this case, it is from about 4 to about 5. (Step 3) In the reaction (la), the compound (IV) is subjected to reductive amination to obtain a compound. This reaction can be carried out in a manner known per se. For example, the compound (IV) can be reacted with a compound represented by the formula (VI (1) or a salt thereof (hereinafter referred to as - the compound (VIII)): ...,

Each of these symbols is as defined above, and the resulting imine or imine ion is reduced. The reaction for preparing an imine or imine ion and its reduction can be carried out in accordance with the method described in Step 1. In this step, the compound (la) can also be directly reacted from the compound (manufactured by the hydrazine, and reacted with the acetamide to reduce the imine or imine ion, without separating the intermediate imine or imine ion of the 318921 62 200808724. In the case of about 4 to about 5. The pfi of the reaction mixture is preferred [Method C] 51a-

(IX) ^1a one

〆, 〆天, 等, etc., or substituted stone 妒 妒 知 #, for example, trigaster (tetra) oxy, etc., and other symbols are the same as the above: the basis of this reaction, the compound represented by the formula (10) or a salt thereof The two compounds (10)) and the plant represented by the formula (1) are obtained as the compound (Ia) · · · · · · · · · · · · · · · · · · · · · · · · · · · · The compound (IX) in this method is a starting compound which can be produced according to the preparation method described in 101,964 or the like. This = can be performed by methods known per se [eg: cheraicalReviews, voi. 95, p 2457 (i99 in the presence of transition metal reminders (4) and in the presence of no =, solvent. The use of j reactions The transition metal catalyzes the southern forge, the chlorinated, and the tetrakis(triphenylphosphine) ruthenium, for example, a catalyst for the injection of a catalyst (% of palladium acetate), a nickel catalyst (such as nickel chloride), and the like. 318921 63 200808724 If necessary, a ligand (triphenylphosphine, tri-tert-butylphosphine, etc.) or a metal oxide (copper oxide, silver oxide, etc.) may be used as a cocatalyst Ccocatalyst). The amount of the catalyst to be used varies depending on the kind of the catalyst, and is generally from about 〇·(10) to about 1 mole per mole of the mole compound (IX), preferably from about 0.01 to about 5% molar equivalent. The amount of the ligand used is generally from about 0.0001 to about 4 moles per mole of the compound (IX) = 'more (four) about Q. Q1 to about 2 mole equivalents, and the use of the cocatalyst For each compound (Ιχ), it is generally about 1 to about 4 moles, preferably about 1 to about 2 moles. Field tests, such as 'can be mentioned organic amines (tridecylamine, triethylamine, di-, propylamine?-methylmorpholine, U-diazabicyclo[5.4·〇] eleven_7_ ^ ^ ^ Τ本amine Temple), alkali metal salts (sodium strontium carbonate, carbon-xenon potassium, sodium carbonate, carbonic acid clock, sodium sulphate, phosphate slag, sputum: all genus =: _, etc.), metal Hydrides (potassium hydride, sodium hydride, etc.), two genera: emulsions (sodium methoxide, ethanol steel, copper butoxide, third potassium butoxide), alkali diazide azide (di-doped h-potassium)笪 ^ ^ i and 虱 Li 矽 矽 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮. Among them, it is preferably a mountain 4&amp;, ^ m ^ ~ a genus of a genus such as potassium carbonate, sodium carbonate, potassium phosphate, etc., such as strontium-butyric acid, such as sodium tributoxide. , the second brother of potassium, etc.; organic amines such as the amount of Sanyitian 斟 斟 替 替 7 7 7 7 7 女 女 女 女 7 7 7 7 7 7 7 7 The base is made of T in the mother-mole compound (amount, compared to 1 stone of the rex rabbit, from about 1 to about 10 moles of the earth, and 'spoon 1 to about 5 moles equivalent. For example, hydrocarbons (benzene, = Helu can be used, and U-dichloroethane, etc.), nitriles (:, &quot;A) stupid, etc., can be used.臆^ Nitrile finder), ethers (dimethoxyethane, 318921 64 200808724 tetrahydrofuran, etc.) 'alcohols (sterols, ethanol, etc.), aprotic polar solvents (U bis-yl 'decylamine, two F-kia, hexamethylphosphonium, etc.), water or a mixture thereof. The reaction temperature is usually from about -lot to about 2 Torr (rc, preferably from about 〇匕 to about 15 (TC' and the reaction time is usually from about 5 to about 48 hours, more preferably from about 0.5 to about 16 hours. [Method D]

(XI) The parent is the same as the above definition. In the reaction, the compound represented by the formula (XI) or a salt thereof (hereinafter referred to as the second compound (9)) is represented by the compound represented by the formula α(1) or (IV) thereof to give a compound (la):

Each of these symbols is identical to the above definition, which can be performed by a method similar to that described in the method [. 101m ^ (XI) In this method, the starting compound can be produced according to the production method described in W003/101964. In the above method, the optically active compound represented by the formula (Va) by using -V "V, 士^, 0" (hereinafter referred to as the compound (5)) is used as the starting compound: 318921 65 200808724

(Va) wherein each of the symbols is the same as defined above, and the amine compound (V) is substituted to prepare the optically active compound (I). Compound (Va) In this method, the starting compound can be produced according to the preparation method described in WO03/101964 or the like. When the compound (I) is obtained as a free compound in the above method, for example, an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (for example, sulfonic acid, benzenesulfonic acid, toluenesulfonic acid, Oxalic acid, anti-butyric acid, cis-conoic acid, tartaric acid, etc.), inorganic test (for example: metal, such as sodium, unloading, alkaline earth metals, such as magnesium, aluminum, ammonium, etc.), or organic base ( For example, salts such as trimethylamine, triethylamine, % pyridine, methylpyridine, ethanolamine, diethanolamine, diethanolamine, dicyclohexylamine, N,N-diphenylmethylethylenediamine, etc. Prepared in a conventional manner. When the compound (〗) is obtained in the form of a salt, the compound can be converted into a free compound or other salt in a conventional manner. Further, in each of the above reactions, when the starting compound forms a salt, the compound may be a salt. Such salts include, for example, those which are salts of the compound (I). The compound (1) thus prepared can be isolated and purified by a typical separation method such as d-day, distillation, chromatography or the like. The object (1) contains an optical isomer, a stereoisomer, a domain phenotype or a female isomer, and these are also included in the compound (the synthesis and the fraction known per se, according to it, 1J····, %, solvent extraction, 318921 66 200808724 column chromatography, recrystallization, etc.) can be obtained as a single product. For example, human: ^) optical isomers' optical isomers decomposed by this compound: the same as: 匕* 3 1 匕 &amp; [I]. The optical isomers can be produced in a manner known per se. Specifically, an optically active synthetic intermediate is used, or an optical isomer is obtained by optically separating the obtained racemic product according to an ordinary method. The method of optical resolution may be a method known per se, such as a segmental recrystallization method, a chiral column method, a non-image isomer method, and the like. ^(Fractional recrystallization method) A method of separation by hunting recrystallization, in which racemic t has an optically active compound (for example: (1)-mandelic acid, (a)-bitter; 1 酉: (1)-tartaric acid, (a)-tartaric acid , (1) + phenethylamine, (a) _ ethylamine, cinchonine, (a) one nai ^ ^ ^) contend for the formation of T, Ma Xuzi, etc.), and if necessary, can obtain free optics by neutralization step Isomer. 2) Chiral column method The racemate or a salt thereof can be applied to a column as an optical isomer (hand column) to provide separation. For example, in liquid chromatography, a mixture of photoisomers is applied to a chiral f-column, such as the leg nti (tetra) frequency (manufactured by 〇s〇h C〇rporati〇n), CHIRAL series (by

Manufactured by Chemlcal Industries, Ltd., etc., alone or in combination with water, a buffer (for example, a citrate buffer, etc.) and an organic solvent (for example, ethyl decyl alcohol, isopropanol, acetonitrile, trifluoromethane) Acetic acid, diethylamine, etc.) are developed to separate optical isomers. In the case of gas chromatography, the column Μ—(10) is manufactured by the heart of le_Ine.) (d) in 318921 67 200808724 3 ) The non-image isomer method is used to make a racemic mixture by chemical reaction with an optically active agent. A method of non-mirrored mixture, which is obtained by a typical separation method (for example, a piecewise recrystallization method, a layer f), and a chemistry, such as hydrolysis, to separate the optically active agent portion to obtain an optical structure. For example, when Compound (1) contains a primary or secondary amino group in the molecule, the compound and the optically active organic acid OiTOAU-methoxy A (trifluoromethyl)phenylacetic acid], (I)-menthoxyacetic acid Etc.), etc. Concentrated soils should be obtained in the form of (iv) or in the form of a captanamine. The second == has a carboxylic acid group, and the compound and the optically active amine or alcohol reagent are used to convert the non-image isomers which are obtained by the knife to the optical isomer of the original compound by acid hydrolysis or alkali hydrolysis. ^ Compound (I) may be in the form of a crystal. The crystal of the compound (1) can be produced by crystallization of the compound (I) by a crystallization method known per se. Examples of the crystallization method include a crystallization method from a solution, a crystallization method from steam, a crystallization method from melts, and the like. The crystallization method from solution, which is a typical factor related to the solubility of a compound (solvent composition, pH, temperature, ionization, = state) or the amount of solvent, can be converted from unsaturated state to supersaturated state. Concentration method, cooling method, reaction method heart, 7 heart growth method, pass I method, and the like. Examples of usable solvents include aromatic 318921 68 2UU^U8724 aromatic hydrocarbons (for example, benzene, methyl chloroform, chloroform, etc.), saturated hydrocarbons; =) 'toothed hydrocarbons (for example: burning, etc.), _ (For example: B shout, Li Bing ^ such as: hex, g-burn, cyclohexonitrile (such as: acetonitrile, etc.), 酉 similar;, examples: .,: hydrogen: husband, two, finished, etc.) Kia stone wind, etc.), amine amines (for example, 1 two classes, etc.) 'sub-stone types (for example: classes (for example: cool acid, etc.), alcohols (·=: dimethyl f, A (four), etc. ), 酉 等, etc.) 'Water, etc. These solvents may be used alone as I, ethyl or isopropanol (for example:: [.( s τ or a suitable combination of two or seed crystals. h100 (volume ratio)). If necessary, use The "if gas two-crystallization method" is, for example, a vaporization method (a sealing method, a gas removal method; a gas phase reaction method, a chemical transport method, etc.), a method, a w sequence from a itch, for example, Normal solidification method (Chai/differential gradient and Bryce's evil and floating zone method, etc.), protection of the mouth and the domain melting method (zone melting-induced hook, inch length method (VLS method and liquid phase epitaxy method) Etc.) etc. The crystallization method is more than the material "(4) to 12fl degrees to find the second (), such as: alcohol, such as methanol, ethanol, etc.), and the transferred solution is not higher than the solvent, w 7 port P to % A method of m four P (for example, a degree 0 of 0 to 5 (rc, preferably 〇2 0 C ). The analysis of the crystal obtained by the present invention is obtained by powder X-ray winding by the method of _ 斫The method of analyzing the shots, and the method of the twin crystal can be described by a mechanical method, an optical method, etc. The compound (1) crystal obtained by the above production method (hereinafter referred to as The crystal of the invention)) has high purity and high product f, exhibits low hygroscopicity, and even after long-term preservation invariability under normal conditions, and the stability is very excellent, 318921 69 200808724. In addition, superior in biological properties (drug power) Learning (absorption, distribution, metabolism, excretion) and efficacy, etc.), therefore, it is particularly useful for pharmaceuticals. In this specification, specific optical rotation ([a]D) means 'for example, using a spinner (jASCO, P-1 030 square light ·0.ΑΡ_2)) The specific rotation of the measurement is in this specification, the melting point means use, for example, the micro melting point instrument crying (Yanako, MP500D) or DSC (differential scanning calorimeter) instrument (seik〇EXSTAR6000) In this specification, the peak value of the powder x-ray diffraction is used, for example, Jane mtil„a+_(Rlgaku. 败扣(8), etc., with Cu-Κα ray as the source of radiation. (4) and the value of ♦ diffraction by powder χ ray varies depending on the measurement conditions of the measuring instrument. The crystals in this specification may exhibit different values due to the (4) and powder χ ray diffraction of the towel. Measuring instrument varies As long as they fall within the general error range. The compound of the present invention has excellent antagonism against tachykinin receptors, and is also a substance Ρ receptor antagonism, including anaerobic inhibition of capsaicin and neurogenic receptors. The inhibitory effect of increased tracheal vascular permeability, the compound has low toxicity and is therefore safe. χ / Therefore, the compound of the present invention has excellent antagonism against substance p receptor and nerve stimulating receptor, and can be used as a safe drug. For the treatment of the following diseases associated with substance sputum in mammals (eg, mice, rats, hamsters, scorpions, dogs, cows, sheep, wolves, humans, etc.): disease. , 318921 70 200808724 Symptoms, _ heart =:::: gland (2) digestive diseases [eg · large, sputum, disease, inflammatory bowel disease, x-infected disease, spiral urea-positive Gram ^ Diseases caused by sexual sputum (eg, Helicobacter pylori, etc.) (eg: stomach two-day temple), gastric cancer, posterior gastric tube disease, digestive sound a, , / shell * colon polyps, cholelithiasis, pruritus, digestion 4 T ulcer, pancreatitis, vomiting, nausea, etc.]. For bei ulcer, reactive ileitis, vomiting (3) limbs or allergic diseases [eg: allergic rhinitis, allergies, hay fever, systemic allergic reactions, monthly cancer treatment, cognac, bronchitis, cough: py axis) , dermatitis, post-inflammatory, swollen, pharyngitis 'cystitis, ::: 2: after and trauma (4) Shaoguan ^ fine m fire, inflammatory eye disease, etc.]. It is a disease [eg rheumatoid arthritis * deformed arthritis, rheumatoid myelitis, Guan Langyan), education, fracture, re-fracture, soft, abnormal cell disease, etc.]. ,,,,, and woven damage and similar (5) respiratory diseases [eg cold disease, inflammation, pneumonitis, lung ablation, pulmonary sputum, wide sputum and lungs 1 Sarcoma, tuberculosis, interstitial pneumonia, Shixia, adult respiratory disorder syndrome, chronic lung epidemic, &amp; main, / by giant,,,,,,,,,,,,,,,, Viral infectious diseases caused by viruses, etc., 318921 71 200808724 gram-infected diseases, bacterial infections, Helicobacter pylori infection, value: disease, K. pneumonia, invasive staphylococcal transmission, infectious diseases, tuberculosis, membranous inflammation , AIDS encephalitis, 跄^7 Λ ^ w sex,, 囷 囷 脑 」 」 」 」 」 内 内 内 内 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休 休Cancer, anal cancer), brain tumor, head and neck cancer (tonal cancer, pharyngeal cancer, larynx::: cancer: colon cancer, uterine cancer (uterine body cancer, uterine cancer 2: sing $cyst cancer) skin Cancer, hemangioma, malignant lymphoma, dermatitis, 庐# heart, "melanin thyroid cancer, osteoma, Tumor fibroma, retinal pediatric solid tumor, Kaposi's sarcoma, Kappo II caused by brush, histiocytoma 'leioraroma' striated tendon α' remnant lunomas, osteoblastoma, bone cancer, cartilage Meat, cancerous mesothelioma, tumors such as leukemia, Hodgkin's disease, etc.] Putian (8) central nervous system diseases [eg · neurodegenerative diseases (eg: Azi, per mole, money, Parkinson's disease, CJD, amyotrophic lateral sclerosis (ALS), 柷Dunton's disease, diabetic neuropathy, multiple sclerosis, etc., mental illness (eg schizophrenia, depression, mania, Anziety neur〇sis, compulsive mental function^(〇bSessive-c(10)pulsiveneur〇sis), panic disorder, epilepsy, alcohol dependence, anxiety symptoms, anxiety mental state, etc.), central and peripheral neurological diseases (eg : head trauma, spinal cord injury, cerebral edema, sensory dysfunction, 318921 72 200808724 sensation of the effect of Xingwan, autonomic dysfunction and autologous neck ^ vibration injury, etc.), memory impairment (eg Such as: Alzheimer's disease, health L j blood stasis, etc.) 'cerebral vascular disorders (for example: due to intracerebral hemorrhage, matter &quot; Zhang blocking, late effects and / or complications, asymptomatic big two, eve, short brain Ischemic seizures, hypertensive cerebral palsy, premature rupture of blood and brain screens, and recurrence of late cerebral vascular accidents (for example, neurological symptoms, mental disorders, conscious symptoms, activities of daily living, etc.), the posterior brain &amp; closed. Central g can be insufficient, cerebral circulation and / or renal dysfunction y or abnormal, sleep disorders (insomnia), etc.. % disease [eg · acute coronary syndrome (eg · acute heart only Wang Ji Not%, angina, etc.), peripheral arterial obstruction, Raynaud's disease, cypress, disease, sacral artery treatment (coronary balloon dilatation (PTCA), guided coronary resection (DCA), stent, etc.) Restenosis, coronary stenosis after surgery, stenosis, treatment (vascular angioplasty, atherectomy, stent, etc.), or sputum or other peripheral arterial bypass surgery, ischemic heart disease (heart dysfunction, etc.) , myocarditis, intermittent Sexual claudication, ventricular infarction, arteriosclerosis (eg, atherosclerosis, etc.), heart failure (acute heart failure, ^ 14 visceral failure with hyperemia), arrhythmia, atherosclerosis, thrombosis, hypertension, high Blood pressure, tinnitus, hypotension, etc.]. (1 (eight) pain [eg migraine, neuralgia, pelvic organ pain including bladder pain, etc.] 〇 (11) autoimmune diseases [eg · collagen disease, systemic lupus erythematosus, more dermatological arteritis, Myasthenia gravis, multiple sclerosis, Sjogren's disease, Bethel's disease, etc.] 318921 73 200808724 ((2) Liver disease [eg hepatitis (disease], etc.), cirrhosis, interstitial liver (W pancreas) Dirty diseases [example ((4) kidney disease f such as · renal pelvis, pancreatitis, etc.]. ^ ^ ^ month bonfire, kidney glomerulonephritis, sputum "total sorrow, occlusion microvascular, (c) blood g-ball sclerosis Radiation caused by kidney disease, sugar: 'month complications, organ disorders including 'uree urinary nephropathy, etc.'. (15) metabolic diseases [such as complication, diabetes (Insulin-dependent diabetes, diabetic neuropathy) Etc., abnormal glucose tolerance, hypertrophy of diabetes, sexual dysfunction, etc.]

(16) Endocrine diseases [A cell tumor, inflammation, Lin's disease, Cushing's syndrome, black hair, 14 preparations, hyperlipidemia, etc. 1 (17) Other diseases such as: rejection after transplantation, excessive red blood cells after migration, 1, sputum, sling, increased adhesion of white blood cells, increased blood viscosity, :: jade hyperplasia, vascular purple spot, autoimmune hemolytic Anemia, scattered blood 5 internal coagulopathy (10), multiple myelopathy, etc.] (^) gynecological diseases [eg, menopausal disorders, pure poisoning, endometrial uterine fibroids, ovarian disease, breast disease, etc.] () Skin diseases [eg, edema, hemangioma, dryness, scrapie, etc.] (e) Eyelid disease. Disease [eg glaucoma, ocular hypertension, etc.] Houke disease [eg: Meniere's disease (Menue 1) Syndrome), 74 318921 200808724 Tinnitus, taste disorders, dizziness, imbalance, difficulty swallowing, etc. (g) Diseases caused by environmental and/or occupational factors (eg radiation diseases, diseases caused by ultraviolet light, infrared light, laser light) , high altitude disease, etc. (h) exercise disorders (i) chronic fatigue / among these diseases, the compounds of the present invention are particularly useful as a body antagonist to promote lower urinary tract symptoms such as frequent urination, urinary incontinence, etc. Lower urinary tract disease The pharmaceutical preparation containing the compound of the present invention may be any solid form such as a powder, a suspension, a sac, a suppository, or the like, and any liquid form such as a syrup, an emulsion, an injection, a suspension, etc. The medicine containing the compound of the present invention The preparation can be produced by any common method, for example, mixing, kneading, granulating, spinning, coating, sterilizing, emulsifying the temple: according to the type of the formulation. The manufacture of the pharmaceutical preparations, examples can be tested Japanese music program for each of the general rules of the formula. It trming pharmaceutical preparations can be formulated into active ingredients and substances: a sustained release preparation of a knife-polymerized compound. The sustained release preparation JP-A-9 Processed in the method described in -263545. In the pharmaceutical preparation of the formula, the ingredients of the compound of the present invention or the salts thereof are according to the type of the formula (4), but the amount to the (four) amount per preparation is preferably about 〇·5 to 20 % by weight. Further, when the compound of the present invention is used in the above-mentioned pharmaceutical preparation, it may be used alone or in a suitable carrier for a suitable carrier, for example, 318921 75 200808724 For example: starch, lactose, sucrose, binder (for example, temple powder, gum arabic, anti =, dish _, etc.), vegan, crystalline venetian / alumina, acesulfame, hydroxypropyl fiber lubricant ( Stearic acid, stearic acid _, disintegrant (for example: methyl cellulose _, talc release water for injection, physiological saline, etc.) and if necessary 卞 dilution W, for example: agents, preservatives, colorants, fragrances 2K, for example: stability of you, six ^ „ / endeavors, emulsifiers, embroidery:, temple, etc.), etc. can be formulated as solid preparations such as powder,: granules, tablets, capsules, etc., or liquid preparations For example, injections, etc., are administered orally or parenterally. The dosage of the pharmaceutical preparations of the invention is not according to the present invention, and is affected by the salt, the route of administration, the symptoms of the patient and the age of the patient. The oral dose of the pharmaceutical preparation for difficult adult patients is generally from ^^•00 hair = human kilograms per day, more preferably from about 0.2 to 4 milligrams per body of body weight/mother day, according to the compound of the present invention, can be administered one day a day Two or three parts. 2 When the pharmaceutical preparation of the present invention is a sustained-release preparation, the dosage is based on the type of the compound (1), the prescription, the release of the drug, and the administration of the animal (for example, mammals such as humans, rats, mice, cats, dogs, rabbits, Cattle, etc.), and the purpose of the drug varies. For example, when the drug is administered in a non-oral manner, it is released from the preparation by about 0.4% to about 100 mg of the compound (1). 1 The compound of the present invention can be used as a mixture or in an appropriate ratio in combination with other active ingredients 318921 76 200808724. The compound of the present invention can have the following excellent effects in combination with other pharmaceutically active ingredients: (1) Compared with the compound of the present invention or other pharmaceutically active ingredients, the back J can be reduced by J. More specifically, when the compound of the present invention is combined with an anti-parasympathetic nerve agent or an NK-2 receptor antagonist, the dose can be reduced when administered separately from the anti-parasympathetic agent or the Li-2 X antagonist, and thus, It can reduce side effects such as dry mouth; (2) According to the patient's symptoms (slight symptoms, severe symptoms, etc.), a drug that can be combined with the compound of the present invention can be selected; (3) Other medical activities having different mechanisms of activity from the compounds of the present invention can be selected. The ingredient 'may be designed to be longer during the treatment; the 1 mechanism of the sexual mechanism (5) combines the compound of the present invention with other pharmaceutically active ingredients, such as the synergistic effect (synergic effect). The drug to be mixed or combined with the compound of the present invention includes the following: a drug (hereinafter, simply referred to as a combination (1) for treating a diabetic agent insulin preparation (for example, an animal extracted from bovine or swine sputum, an enterobacteria or yeast) Humans synthesized by genetic engineering technology; zinc insulin; protamine zinc insulin; Tengdao-^ or any organism (eg · iNS-η &gt; a ^ a ^ r &gt; ) insulin sensitizer (for example: Pili g, 曲格列留, Roggliet κ, maleate, 318921 77 200808724 JTT 5G1^MCC-555, YM-44G, GI-26257G, KRP-297, FK-614, CS-011 Temple ) 'α-glucosidase inhibitors (eg · voglibose, apo-figogliol, amylin, etc.), double veins (eg phenidate, 曱 胍: 才田明, etc.), Shihuang stuffed urea (such as ································································································ Urea, etc.) and other prostaglandin secretagogues (eg · repaglinide's serotonin, MiG or salt hydrate, GUM, I3, 歹J, etc. ), peptide peptidase jy inhibitors (eg, liver P-Dpp I, PT-100, P32/98, etc.), $3 agonists (eg · CL-316243, f586U-A, UL-TG-307, AJ —9677, AZ-40140 f ), amyloid stimulating effect W (such as linlin peptide, etc.), sarcosal acid glutamate serotonase inhibition (such as gentry, etc.) 'glucose regeneration inhibitor (eg · liver Glycosylphosphatase inhibits β « ^st SI # φ] #J . ^ # ^ #] # } , SGLT (^ 匍 匍 共 co-transporter) inhibitors (eg · T-1095, etc.), etc. (2 An aldose reductase inhibitor for the treatment of diabetic complications (eg, to 1 rest a, epalrestat, zenarestat, sabolina (z') Lrestat), non-darseta (SNK_86〇), mirtastat (10) 509), CT-112, etc.) 'neurotrophic factors (eg ngf, nt_3, etc.), hall inhibitors (eg ALT-945, Pima Pimagedine, pyratoxathine, N_ desertified benzene 嗟嗤 ( (ALT-766), then _226, etc. 'Active oxygen scavenger (eg: lipoic acid (th1〇CtlCaGid) )), brain vasodilator (eg: tiapuride, etc.), etc., 318921 78 200808724 (3) Anti-lipidemia agents statins inhibit cholesterol synthesis (eg, pravastatin, simvastatin, 洛Slovastatin, atorvastatin, fluvastatin, cevastatin (atin) or its salts (eg sodium salt, etc.), squalene synthase Inhibitors or fibrate compounds have reduced activity of triglycerides such as bezaf ibrate, ci〇f inrate, simfibrate, kleley Bet (clinofibra1:e), etc.). (4) hypotensive agents angiotensin-converting enzyme inhibitors (eg, captopril (03?1: (^1'11), enalapril (61131叩1^1), dilapril (^ 1叩1^1), etc., blood stasis hormone antagonists (eg, losartan, candesatan cilexetil, etc.), calcium antagonists (eg, manidipine ( Manidipine), nifedipine, amlodipine, effluentine (^〇111 (111^), nicardipine (nicardipine), etc., cl〇nidine). 5) Anti-obesity agents that act on the central nervous system (eg, deXfenfluramine, fenfluramine, phentermine, sibutramine, ampoules) Nonfepramone, dexamphetamine, mazindol, phenylpr〇pan〇lamine, cloxazepine (c 1 〇benz〇rex), etc., pancreas A lipase inhibitor (eg, Ollie ^ 318921 79 200808724 (1Stat) f ), no 3 agonists (eg CL - 31 6243, SR 586U A, UL-TG-307, AJ, 77, AZ40140, etc.), anorexia peptide (eg leptin neptln) 'CNTF (hairy neurotrophic factor), etc.), = cholecysin stimulating effect I Tetrast (1) ntitript), FpL-i leakage, etc.) Cannabinoid CB1 fork antagonist (eg, rimonabant (heart sputum), etc. (6) diuretic • xanthine derivative (eg · · theobromine Theobromine sodium salicylate, 1,2:he〇br〇mine calcium salicylate, diuretic preparations (eg, ethiazide, cyclopentalin) Iazide), trichlormethiazide, hydrochlotothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penf lutizide ), 泊 哄 thia thia 〇 meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth Agent (for example, acetazolamide) ), chlorhexidine yellow amine formulation (eg chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide ( Isosorbide), ethacrynic acid, piritanide, bumetanide, furosemide, and the like. 318921 80 200808724 (7) chemotherapeutic burning agents (for example: cyclophosphamide, ifosamide, etc.), metabolic antagonists (for example, aminomethoate (methotrexate), 5 - fluorourine. (5-Π nor our aci 1), etc., anti-tumor antibiotics (eg mitomycin (mit (10) yCin), adrimycin (3 (11 ^ 311 ^ (: 11) etc.), derived from plant anti-tumor agents (eg, vincristine, vindesirie, taxol, etc.), cisplatin, carboplatin Carb〇platin), etoposide, etc. Among them, 5-fluorouracil derivatives such as FurtuIon and neo-fluoroiron do-Furtulor® are preferred. (8) Immunotherapeutic agents Indica or bacterial-derived components (eg, muramyl dipeptide deriviativess, Picibanil, etc.), immune restorer polysaccharides (eg, lentinan) , schizophyllan, krestin special) genetically engineered cells (e.g., interferon, interleukin (IL), etc.), colony stimulating factor (granule stimulator stimulating factor, erythropoietin, etc.), among others, preferably IL-i, iL-2, IL-12, etc. (9) Identification of therapeutic agents for improving cachexia in animal models or clinically implemented luteinizing hormone derivatives (eg, megestrol acetate) [J0urnal 〇f Clinical 〇nc〇iogy, ν〇1· 12 2/3-225, 1994] 'Metoclopramide (Post (4) ah (10) (4)) Medicine', = Hydrocannabinol (tetrahydrocannabinol), 荦吖μ, +, two, Shiyanxi I 318921 81 200808724 This two music category] 'obesity metabolism improving agent (such as eicosapentanoic acid) [British Journal of Cancer, vol 68, PP · 314-318, 1 993], growth hormone, IGF- 1 and antibodies against cachexia-producing factors such as TNF-α, LIF, IL-6 and oncostatin 〇 (10) anti-inflammatory steroids (eg dexamethas 〇ne), hyaluronic acid Nano, cyclooxygenase inhibitors (eg, indomethacin (indomethacin), ketopro (ketoprof en), loxoprofen (1 OXOprof en), meloxicam, ampiroxicam, celecoxib, rofecoxib, etc. (11) Miscellaneous cooling inhibitors (eg, ALT-711, etc.), nerve regeneration promoting drugs (eg, Y-128, VX853, prosaptide, etc.), drugs acting on the central nervous system (eg : anti-depressants such as de-propanol-flavor ((16310^11^116), amitriptyline (_11:]^? seven 711116), imipramine, fluoxetine, paro West, din (paroxetine), doxepin (doxepin), duloxet, duloxetine, venlafaxine, etc., anti-caries agents (for example, lamotrigine, Carbamazepine, gabapentin) Antiarrhythmic drugs (eg mexiletine), acetylcholine receptor ligands (eg ABT-, endothelin receptors) Body antagonists (eg ABT-627), monoamine uptake inhibitors (eg tramadol), indoleamine uptake inhibitors (eg #西318921 82 200808724 buckle 1 with etine), paroxet; T(parGxetine)), an anesthetic analgesic (eg morphine), non-narcotic analgesic (eg butyl morphine (bUprenorphine) Isomal f (ax(10)ad〇i)), gaba receptor agonist 'GABA uptake inhibitor (eg: gabbins), receptor agonist κ, eg, codonidine ), local analgesics (eg · capsaicin) 'protein kinase c inhibitors (eg · ·), anti-anxiety drugs (eg: bemz〇diazepines), phosphodiesterase inhibitors ( For example: sildenafi", dopamine receptor-promoting dorsal] (eg, apomorphine (Qiu (10) sinking in)), dopamine receptor antagonists (eg · haloperidol) , serum-stimulating receptor receptor (eg, tandospironecitrate, souma; L. (sumatryptan), tegaser (dgaser)), serum-stimulating hormone receptor Antagonists (eg, cypr〇heptadine hydrochloride, ondansetron ((10), for example (10)), serotonin uptake inhibitors (eg, fluvoxamine maleate) , fluoxetine ^ ribs to form ^ paroxetine P oxetine)), lure (for example: three D sitting (t Riaz〇iam), zolpidem, xiaomian (eg, rametidine), anti-parasympathetic agent, alpha receptor blocker (eg tamsulosin) ), urapidil, naftopidil, siloxine (sil〇d〇sin), for the treatment of overactive bladder J (eg · cytosine hydrochloride (f iav〇xate hydrochloride) )), muscles, sputums (eg, baci〇f en), potassium channel openers (eg, nicorandil), calcium channel blockers (Example 83) 318921 200808724 =·nifedipine), chloride channel opener (activation f such as lubiPr〇stone), prevention and/or treatment of Amer disease agents (eg · donepezil) , rivastigmine, galanthamine, for the treatment of Parkinson's disease (eg L-dopa), prevention and / or treatment of multiple sclerosis (eg interferon / 3 - la) , histamine H1 receptor inhibitors (eg ··············· 1^〇11161;11&amp;2丨116|^(^〇(:]:11〇1^仏)), proton pump inhibitors (eg lans〇praz〇le, Ogilvy saliva) (omeprazole)), antithrombotic agents (aspirin, cilostazol), NK-2 receptor antagonists, NK-3 receptor antagonists (eg telnetant) ), treatment of HIV-infected agents (eg, saquinavir, zidovudine, lamivudine, nevirapine) for the treatment of chronic obstructive pulmonary disease (eg · Shami) Salix〇i, thiotropium br(10)ide, cii〇milast, diuretic (eg furosemide), antidiuretic (eg vascular plus) Vasopressin V2 receptor agonist), etc. Anti-choling agents include, for example, atr〇pine, scopolamine, homatropine, tropicamide, cyclopentolate, Butyl scopolamine bromide, propanthel ine bromide, methylbenactyzium bromide, mepenz〇la1:e bromide, pirenzepine Pirenzepine), ipratropium bromide 318921 84 200808724 (ipratropium bromide), trihexyphenidyl, oxybutynin, pr〇piverine, darifenacin, care Tolterodine, sol ifenacin, temiverine, trospium or its salts (eg atropine sulfate, scopolamine hydrobromide, hydrobromic acid) Matropine, cyclopentaine hydrochloride, pirenzepine hydrochloride, trihexyphenidate hydrochloride, oxybutynin hydrochloride, tolterodine tartrate, succinyl succinyl, etc., preferably oxybutynin, propylene Lin, dafinaxin, tolterodine, vegetarian Fen new, temiverine, trospium chloride or a salt thereof (e.g.: oxybutynin hydrochloride, tolterodine tartrate, succinate new prime Lifen etc.). Further, an acetaminophenase inhibitor (e.g., distimmide or the like) or the like can be used. NK-2 receptor antagonists include, for example, tourism derivatives such as GR159897, GR149861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL1 05212A, ZD602, MDL1 05172A , SCH205528, SCH62373, R-1 1 3281, etc., perhydroisoindole derivatives such as RPR-1 06145, etc., quinoline derivatives such as SB-414240, etc., pyrroloindole derivatives such as ZM-253270 Etc., peptoid derivatives such as MEN11420 (nepadutant), SCH217048, L-659877, PD-147714 (CAM-2291), MEN1 0376, S16474, etc., others such as GR100679, DNK333, GR94800, UK-224671 , MEN10376, MEN1 0627, or its salts. A pharmaceutical composition comprising a mixture or composition of a compound of the invention and a group of 85 318921 200808724, a pharmaceutical and a combination medicament, which may be formulated as (1) as a single formulation containing a compound of the invention and a composition of the composition, or The city (2) includes the compound of the present invention and the combination drug as a separate formulation. Hereinafter, it is generally referred to simply as a combined preparation of the present invention. The combination preparation of the present invention can be used in the same manner as the method of producing a pharmaceutical preparation containing the compound of the present invention by separating or simultaneously mixing the active ingredient of the compound of the present invention and the combination drug, either by itself or in a pharmaceutical form. Formulated. The dosage per ounce of the combined preparation of the present invention varies depending on the severity of the symptoms, age, sex, body weight, sensitivity of the administered individual, time, administration interval, characteristics, formulation and type of the pharmaceutical preparation, type of active ingredient, and the like. , but not particularly limited. The dose of the compound of the present invention is not particularly limited insofar as it does not cause side effects. In the case of oral administration, the daily dose is administered; for each kilogram of mammalian body weight, about 〇 5 to 1 〇〇 mg, preferably 0.05 to 50 mg, and more preferably about 〇 2 to 3 〇mg, can be scored once a day or divided into two or three parts a day. The dose of the compound or combination of the invention may be set at a target which does not cause side effects. The daily dose of the compound or combination preparation of the present invention depends on the severity of the symptoms, age, sex, body weight, and sensitivity of the individual to be administered, the daily interval, the characteristics, the formulation and type of the pharmaceutical preparation, and the type of the active ingredient. It varies, but is not particularly limited. In the case of oral administration, the daily dose is usually in the range of about 0.001 to 2000 mg per kg of mammalian body weight, preferably about 〇1 to 5 mg, 318921 86 200808724 and more preferably About 0.1 to 100 mg can be administered once a day or two or four parts a day. In the administration of the combination preparation of the present invention, the compound of the present invention and the combination drug may be administered simultaneously or in combination, and the drug may be administered before administration of the compound of the present invention, and vice versa. In the case of staggered administration, the time interval varies depending on the active ingredient of the administration, the formulation, and the pitching path. For example, if the combination drug is administered first, the compound of the present invention can be administered from 1 minute to 3 days after administration of the combination drug, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour. If the compound of the present invention is administered first, the combination drug can be administered from 1 minute to 1 day after administration of the compound of the present invention, and the ginseng VIII (four) and the uncle sputum are administered at a dose of 10 minutes to 6 hours, more preferably 15 minutes to 1 minute. Dosing in hours. In a preferred method of administration, about 0 001 to _ n of the drug is formulated as an oral preparation for oral administration, and after about 15 minutes "; to (10) mg / kg of the compound of the present invention; a dose of one day for oral administration. In the combined preparation of the present invention, the present invention is in the form of a formula, and the content of the sigma is 4 m. The combination of the sigma and the preparation of the yoghurt is in the order of 〇.〇1 to Preferably, the ratio is 0.1 to 5 θ θ. / main uo weight, main 50 reset %, and more preferably 〇·5 to [Example] υ垔里%. The present invention further refers to the reference example, / example is detailed Description, wonderful. Clothing only examples and experiments. The scope of each of the Ming can be modified. And in the absence of toughness, tolerance, in the following reference examples and examples, column chromatography (TLC) was carried out by inspecting. Thin layer chromatography 318921 87 200808724 The ceremonial order was carried out using a TLC sheet of 6〇f254 manufactured by Merck, and used as a solvent for the elution solvent in the f-column chromatography as an elution. It was tested using a uv detector. The tannin of the column chromatography method used silicone rubber 60 (70 to 230 mesh) manufactured by Merck. The "room temperature", General Department of 1〇 C to 35 ° C. The extract was dried using sodium sulfate or magnesium sulfate. The abbreviations used in the following examples and reference examples are as follows: LC · Liquid chromatography MS : Mass spectrometry ESI : Electrospray ionization FAB : Rapid atomic impact Μ: Molecular ion peak NMR : Nuclear magnetic resonance Hz · Hertz J · Fuhe Constant m: multiple peak q: quadruple peak t: triplet d: doublet s: single peak br: wide dt: double triple brs · see early peak ·

Au ··T-butyl B〇c ··Tertoxycarbonyl 88 318921 200808724

Rt: residence time N: equivalent concentration MPa: million Pawt%: wt% DMF: N,N-dimethyl decylamine THF: tetrahydrofuran DMS0: diterpenoid IPE: diisopropyl ether TFA · Barium trifluoroacetate · H2O · 1-Phenylbenzotriazine hydrate WSHUC1: Buethyl-3-(didecylaminopropyl) carbodiimide hydrochloride

NaBH(0Ac)3: sodium triethoxyborohydride Pd (PPh〇4: hydrazine (triphenylphosphine) palladium £3N: triethylamine in the examples and reference examples LC-MS under the following conditions Determination: LC-MS analytical measuring instrument: LC-MS system, Waters HPLC part: HP 110 0, Ag i ent Technology Co., Ltd. MS part: Micromass ZMD HPLC condition column: CAPCELL PAK, Cl8UG120, (S- 3//m, 1.5x35 mm (Shiseido Co., Ltd.) Solvent: Solution A; water containing 0. 05% TFA, solution B; containing 0. 05% 89 318921 200808724 TFA acetonitrile gradient cycle ·············· Solution A / solution 90/10), 2. 00 minutes (solution A / solution Β = 5 / 95), 2 · 75 minutes (solution A / solution B = 5 / 95) ' 2 · 76 minutes (solution a / solution b=9Q/10), 3·60 minutes (solution A/solution B=90/10) Injection volume: 2// L, flow rate: 〇. 5 mL/min, detection method: UV 220rnn MS conditional ionization method: ESI '

Chiral HPLC conditions (measured in the case of Reference Example 1 for non-imagewise heterogeneous values and excess image isomerization transcendental values) Columns · CHIRALCEL OD-RH 4.6 mm ID x 150 mm Solvent · 50 mM potassium dihydrogen phosphate (pH 8.0) / acetonitrile = 85 /15 Injection volume: 2 0 // L· Flow rate: 0·3 mL/min Temperature: 40 ° C Detection method: UV 220 nm In the examples, the reaction was carried out by microwave on the following instruments. Instrument: Biotage, Emrys Optimizer Reference Example 1 N-{2-[(3R,4S)-4-Amino-3-phenyl π-bite-i-yl]-2-ketoethyljacetamide The sulfonate Ν-B glycerol (6.44 g) was suspended in acetonitrile (12 〇 mL). 3-Phenyl bucky-4-one monohydrochloride (10. 58g), Et3N (5. 06g) and 318921 90 200808724 WSC · HC1 (11·50g) were added in sequence, and the mixture was stirred at 50 °C. hour. The mixture was cooled to 25 ° C, and a mixture of brine/3N hydrochloric acid (1:1) (40 mL) was added. The aqueous layer was extracted again with acetonitrile (60 mL). The organic layer was combined and the mixture was washed twice with brine (5N sodium hydroxide solution (1:1) mL) and brine (40 mL). The organic layer was concentrated under reduced pressure and concentrated with ethyl acetate. Ethyl acetate (150 mL) and Shiqi gum (1 Qg) were added to the residue. The mixture was heated to 7 G °C and scrambled for 3 Q. The mixture was heated and the oxime gel was washed twice with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and concentrated with EtOAc. Toluene (1 〇 OmL) was added to the residue, and the residue was evaporated to reflux. After allowing to cool to 25 ° C, the precipitated crystals were collected by filtration and washed twice with toluene (20 mL). Drying under reduced pressure gave N-[2-keto-2 (4-keto-3-phenylpiperidin-1 -yl)ethyl]ethylamine (8·70 g) as a white crystal. -[2-Ketyl-2-(4-keto-3-phenylpiperidin-1yl)ethyl]acetamide (10 g) was suspended in toluene (5 mL). (s)-Phenylethylamine (6·63 g) and p-quinonesulfate benzene monohydrate (〇·35 g) were sequentially added. After refluxing for 3 hours at 〇1 ° C, the water was separated by a Dean-stark apparatus. The mixture was cooled to 25 °C. Raney nickel catalyst (30 mL), ethanol (5〇11^) and 5; 1:31^ (3.69 g) were added. The reduction reaction is carried out at 5 Torr at a hydrogen pressure of 至·5 to IMPa until the hydrogen absorption stops. The reaction mixture was filtered under pressure under a nitrogen stream, and Raney nickel was catalyzed by washing with ethanol (1 〇 mL) twice. The filtrate and washing solution were concentrated under reduced pressure. Water (OO mL) was added to the residue and the mixture was refluxed for 3 min. After cooling to room temperature, seed crystals were added and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration and washed twice with water (50 mL). 6 在 in a vacuum. 〇 Drying 3 small 318921 91 200808724 to give white crystals of N-[2-keto-2((3R,4S)-3-phenyl-4 {[(IS)-1-phenylethyl]amino} Amino-1-yl)ethyl]ethinamine (H. 64 g). The resulting N-[2-keto-2((3R,4S)-3-phenyl-4{[(1S)-1-phenylethyl]amino}piperidinyl-ethyl)ethyl] Indoleamine (10 g) was dissolved in ethanol (200 mL). 1% by weight of palladium carbon (water wet) (5 g) was added and the reduction reaction was carried out under a hydrogen pressure of 50 t:, 0.5 to 1 MPa until the absorption of hydrazine was stopped. The reaction mixture was filtered, and the palladium carbon was washed twice with ethanol (2 mL). The filtrate and the washing liquid were subjected to N-{2-[(3R,4S)-4-amino-3-phenylpiperidin-1-yl]-2-ketoethyl}acetamide (7) under reduced pressure. ·〇〇克). The N-{2-[(3R,4S)-4-amino-3-phenyl-l-yl-1-yl]-2-oxanylethyl}acetamide (7.0 g) was added to ethanol ( 75 mL), refluxing 30 minutes to dissolve the mixture. After cooling to 65 ° C, methanesulfonic acid (2.53 was added. After cooling to 25 ° C, ethyl acetate (15 mL) was added. The crystals of the precipitate were collected by filtration and washed with ethanol/ethyl acetate ( 1 : 3) (4 〇 mL) was washed twice. Drying under reduced pressure gave white crystals (9· 〇 7 g). Ethanol (75 mL) was added and refluxed for 30 minutes to dissolve the mixture. After cooling to 25 ° C, The mixture was stirred for 3 hours, and ethyl acetate (15 mL) was added. The precipitated crystals were collected by filtration and washed twice with ethanol/ethyl acetate (1:3) (4〇1111). The title compound (8. 84 g) was obtained as white crystals. H NMR (300MHz, DMSO-de): (5 1.83-1.91 (2H, m), 1.88 (3H, s), 2·33 (3H, s), 3 · 15 (1H, br), 3.58-4.06 (7H, m), 7·30'7·4〇 (5H? m), 7.78 (3H? br), 7.96-8.03 (1H? m) 318921 92 200808724 MS (FAB): 372CM+H) Elemental analysis: C16H25N3 〇5S · L 5H2 〇 C, 48.12; H,7·00; N, 10.59; S,8·27 Calculated C, 48.23; H, 7.08; N , 10.55 ; S, 8.05 Non-mirror heterogeneous transcendence: 99. 8% de mirror heterogeneous transcendence: 99. 7% Ee Reference Example 2 Μ-(2-{(3R,4S)-4-[(5-Bromo-2-indolylphenyl)amino]- 3-phenylphenyl- -1-yl}- 2-(ketoethyl)acetic acid amine amide compound (6·2g), 5-bromo-2-methoxybenzaldehyde (3.3g) and acetic acid (2mL) in dichlorodecane (90mL) NaBH (OAcM 9.7 g) was added, and the mixture was stirred at room temperature for 16 hr. A saturated aqueous solution of sodium hydrogen sulfate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Washed with brine, dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title compound (4 68 g, 6 〇%). MSCESI + ) : 474, 476 (M+H) Reference Example 3 4-methoxy-2'-(methylthio)biphenyl-3-carboxylate 5-bromo -2-decyl benzhydrazide (1) g), [2-methylthio]phenyl]-decanoic acid (7.8 g), Pd(PPh3)4 (1.6 g) and carbonic acid _(12.(8) A mixture of "(2/l) (15 〇 mL) was heated under reflux for 7 hours under nitrogen. After cooling, the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and 318921 93 200808724 water. The organic layer was washed with aq. aq. sodium hydrogen sulfate and then brine. The residue was purified by EtOAc EtOAcjjjjjjjj 1 side (3_112, CDCh): 5 2·36 (3Η, s), 3·96 (3Η, s), 7.04 (1Η, d, &gt; 8·5Ηζ), 7·19 (1Η, d, J: 3.6Hz), 7·25 —7·36 (3H,m),7·64 (1H,dd,J:8.5,2·4Ηζ), 7·89 dH,d,J = 2· 4Hz), 1〇 · 5 (1H, s) Reference Example 4 4~Methoxy-2'-(methylsulfonyl)benzaldehyde The compound obtained in Reference Example 3 (8.5 g) &amp; m-chloroperoxybenzoic acid (!3· lg) A solution of dichloromethane (1 mL) was stirred at room temperature for 4 hours. Ethanol (1 mL), ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous potassium carbonate solution, a saturated aqueous sodium hydrogen carbonate solution, and brine, and dried and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc

Elemental analysis: C15Hh〇4S Measured value C, 61·89 ; H, 4· 79 Calculated value C, 62· 05 ; H, 4· 86 Reference examples 5 to 7, using (3-methylindolyl-4-oxo) Benzophenyl)boronic acid and bromobenzene derivatives (1 acetylene benzene in Reference Example 5, 4_bromo-2-fluorobenzazole in Reference Example 6, 318921 94 200808724 5 to 7: and 4-bromo -3-Methylbenzene is speculated that the reference phase &amp; Reference Example 5 was obtained as described in Reference Example 3. Reference Example 5 4-Ethynyl-4-methoxybiphenyl-3-furfural elemental analysis· · CuH12〇2 · 〇· 5H2〇 Measured value C, 78. 39 ; 5 03 Calculated value C, 78. 35; H, 5 34 Reference Example 6 3-Fluoro-3'-methylindole-4-oxo Elemental analysis of phenyl phthalonitrile: C^HnFNOz measured value C, 7〇·24 ; Η, 3.95; N, 5·29 Calculated value C, 70·58; Η, 3.95; Ν, 5.49 Reference example 7 3 Elemental analysis of - mercapto-4-methoxy-2-mercaptobiphenyl-4-onecarbonitrile: C16H13NO2 · 〇· 3^2〇 measured value C, 74·86 ; Η, 5·14; Ν, 5.10 Calculated C, 74·87; Η, 5· 34 ; Ν, 5. 46 Reference Example 8 3-Mercapto-4-(trifluoromethoxy)biphenyl-4-ylcarbonitrile-isopropylamine ( 3 5 mL) In a solution of THF (50 mL), a solution of 1.6 mol/L η-butyllithium in hexane (i5raL) was added to the solution. After cooling the reaction mixture to -78 ° C, 1-bromo- 4-(Trifluoromethoxy)benzene (6·〇g), the mixture was stirred for 2 hours. Then, wortene citric acid was added (8 to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to residue and mixed 318921 95 200808724 The extract was extracted with EtOAc. EtOAc (EtOAc m. 30% ethyl acetate/hexane) gave 5-bromo-2(trifluorodecyloxy)benzofural (5·04 δ, 75%) as a colorless oil. 5-br. Benzoaldehyde (4.2g), (4-cyanophenyl)boronic acid (2.3g), Pd(PPh3)4 (541mg) and potassium carbonate (4.3g) in THF/water (2/1) A mixture of 60 mL) was heated under reflux for 12 hours in a nitrogen atmosphere. After cold potassium, the reaction mixture was concentrated, and ethyl acetate and saturated aqueous sodium carbonate solution were added to the residue for extraction. The organic layer was washed with brine and then with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc Elemental analysis: C15H8F3NO2 Measured value C, 61 · 92 ; H, 2 · 91 ; N, 4 · 96 Calculated value C, 61. 86 ; H, 2. 77 ; N, t 81 Cang test case 9 [3-({ [(3R,4S)-1-(N-Ethylglycine)-3-Phenyl-p--4-yl]amino}indolyl-4-yl]boronic acid obtained in Reference Example 1 Add a solution of the compound (2·〇4g), (3-methylindolyl-4-methoxyphenyl)boronic acid (0.9g) and acetic acid (0.4mL) in dichloromethane (4〇mL), add NaBH ( 〇AcM3·2g), the mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with water. The aqueous layer was purified with EtOAc EtOAc EtOAc (EtOAc). 318921 96 200808724 MS (ESH): 440CM+H) The compounds in Reference Examples 1 to 9 are shown below (Table 1). 97 318921 200808724 Table 1 Reference example number Structure 1 Howling 2 CHsD^ 〇广H3C Population fly NJ_O X. 3 c^cVKii ?Μβ ohcA^, 4 sojyie 5 r〇^ B 7 8 9 Τυί j Lb, oh l 98 318921 200808724 Reference example ίο 4'-Ethyl-4-methoxybenzazole-3-carbaldehyde is synthesized using 4'-bromobenzene and the same compound (3_bromo-methoxyphenyl). Obtained by the method described in Reference Example 3. Melting point: 136-138 ° C ^ ^ Reference Example 11 N-(3'-Mercapto-4'-nonyloxybiphenyl-4-yl)acetamide using 4 - &gt; odor-ethylaniline and hydrazine 3 — ψ ^ | _ τ w T ® Dishyl~4-methoxyphenyl)boronium, the title compound was obtained by the method described in Reference 3. Elemental analysis · · Cl6Hl5N〇3 · 〇 · 5H2 〇 measured value C, 69.11 ; H, 5.4 〇; N, 4 96 Calculated value C, 69. 05 ; H, 5. 79 ; N, 5. 〇 3 Reference example 12 '4-Ter Butyl-4-methoxybiphenyl_3_carboxylic acid was obtained using Buqin-4-t-butylbenzene and (3), and the title compound was obtained by the method described in Reference Example 3. = soil native) Elemental analysis: Cl8H2 0〇2 · 〇· 2H2 〇 亍 measured value C, 79. 24 ; H, L 22 Calculated value C, 79. 50 ; Η, 56 Reference Example 13 4~(dimethyl Amino)-4-methoxybiphenyl-3-carbaldehyde is 4-bromo-indole, fluorenyl-diphenylaniline and (3-methyl+oxy)boronic acid, and the title compound is described by reference example 3. The melting point of the soil: 113-115 〇 C method. 318921 99 200808724 Cang test Example 1 4 4 -Methoxy-4 (methyl stellate) biphenyl-3 to A lightly using 4-bromophenylmethylhydrazine and (3_decanoic acid), title The compound was obtained by the hydrazine method described in Reference 3. The soil base was measured for C, 62. 00; t L 82 Calculated C, 62.05; H, 4.86 Reference Example 15 3 -Fluoro-5'-formamidine Base-4, monomethoxybiphenyl~4~carbonitrile (Step 1) Yueji lang~3-gas-2, thiophene (6.57g) and carbon; bow = Yu Bingming (20 The methyl hard (3.77 mL) was added at a temperature, and the mixture was added with hydrazine under reflux. The mixture was extracted with ethyl acetate. The mixture was dried and concentrated with water. Shi Xi: = analytical purification (solvent gradient; 10 to 17% of ethyl acetate crystallized 5-bromo-Ifluoro-methoxybenzaldehyde (3.6;;; M ^ C^)-4.10 (3H, d, , 7δ), , 4δ 2·4^ — —Η,, (Step 2) The compound obtained in Step 1 was obtained by the method described in Reference Example 3 # and 4-cyanophenylboronic acid. Title 318921 100 200808724 ^-NMR (300MHz, CDCls) : δ 4:. IS r^u , called, d, J = 3Hz) 7 R8 (1 H, dd, = 13, 2Hz), 7.64 - 7.68 (2H, 8

5 7. 73-7 77 C2H m),7·86 (1H,dd,J = 2,1 Hz), i〇4ς ·&quot;(10), Reference Example 16 Ester-based ~4-methoxyphenyl)boron The method is obtained. 3'-Mercapto-4'-methoxybiphenyl-4-carboxylic acid hydrazine using methyl 4-bromobenzoate and (3-carboxylic acid, the title compound was analyzed by the element described in Reference Example 3: Cl6Hl4〇 4 · 〇. 1 H2 〇 measured value C, 70· 32 ; H, 5. 18 鲁 十异值 C, 70·63 ; H, 5.26 Reference Example 17 4'-Chloro-4-methoxy-2-indole Base Benzene 3- oxime light * 2-bromochloropyridinium benzene and (3_decanoyl decyloxyphenyl) linonic acid, the compound compound was analyzed by the method described in Reference Example 3: C15H13CIO2 ι. ιη2〇 Measured value C, 68. 45 ; Η, 4 « 96 Calculated value C, 68. 63 ; Η, 5. 07 Reference Example 18 4'-Bromo-4-methoxy-3'-(Trifluoro Methyl)biphenyl-3-carbaldehyde uses 2,5-dibromobenzotrifluoride and (3-fluorenyl-methoxy)

Phenyl)boronic acid, the title compound was obtained by the method described in Reference Example 3. · Ci5Hi〇BrF3〇2 · 〇. ihQ Measured value C, 51. 07 ; H, 3"5 Calculated value C, 49. 91 H,2, 85 318921 101 200808724 Reference Example 19 2'-Fluoro-3'-mercapto-4'-methoxybiphenyl-4-indenecarbonitrile (Step 1) 4-Chloro-3-fluorobenzoquinone A solution of the ether (9·Og) in THF (20 mL) was added to EtOAc EtOAc (EtOAc) DMF (6.5 mL) was added to the reaction mixture, and the mixture was evaporated. mjjjjjjjjjjjjjjjj Monofluoro-6-methoxy-benzazole (7.6 g). 'H-NMR (300 MHz, CDCh): δ 3. 94 (3Η5 s), 6. 76 (1Η, dd5 J = 9,2Hz) , 7·51 -7·57 (1H, m), 10.40 (1H, d, J = lHz) (Step 2) Step 1 Obtained compound (1.3 g), 4-cyanophenylboronic acid (1.3 g) , palladium (II) acetate (0· 046g), 2-(di-t-butylphosphino)biphenyl (〇. i2g) and potassium carbonate (1.43g) in water (5mL) and THF (25mL) The mixture solution was heated under reflux for 2 hours under argon. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and concentrated to give white powder. The title compound (0. 81g, 46%) 〇^-NMR (300MHz, CDCh): δ 4. 00 (3H, s), 6. 91 (1H, dd ** = 9,1·5Ηζ),7· 57-7·63(3Η, ηι), 7·71-7·75(2Η, πι), 10.49 (1H, d, J=1.2Hz) Reference Example 20 3'-Indolyl-4'-nonyloxy-2(trifluoromethyl)biphenyl-4-carbonitrile 318921 102 200808724 4-chloro-3-(trifluoromethyl)benzonitrile And (3_曱醯基_4_曱氧

The phenyl group) acid-deleted title compound was obtained by the method described in Referential Example 3. Melting point: 116-118 ° C Reference Example 21 3'-Mercapto-4'-methoxybiphenyl-4-formamide using 4-bromophenylamine and (3 fluorenyl- 4-A) Oxyphenyl)boronic acid, the title compound was obtained by the method described in Reference 3. Elemental analysis: C15H13NO3 Determination C, 70·46; Η, 5·09; N, 5.49 Calculated C, 70·58; Η, 5·13; N, 5.49 Reference 22 2'-Fluor-5'-A Mercapto-4'-methoxybiphenyl- 4-carbonitrile (Step 1) 4-Chloro-2-methoxybenzoic acid (1.7 g) in acetic acid (2 〇) solution at room temperature Bromine (〇.56 mL) was added, and the mixture was stirred for 2 hours, and water was added until the reaction mixture 'precipitate was collected by water and collected by water to obtain 5-bromo-4-fluoro-2-methoxybenzoic acid as a white powder. 2·38g, 96%). 4- earn (3_z, CDCl3): e 4·〇7 (3Η, s), 6·86 (ιη, d, J = 9.6Hz), 8.39 (1H, d, J = 7.8Hz) (Step 2 γ 1 1 3 又 又 化合物 1 1 1 1 1 1 1 1 1 ν ν ν ν ν ν ν 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 The material was collected by filtration through water and THF. The resulting precipitate was dissolved in a solution of NaBH4 (1.08 g) in water (12 mL), and the mixture was stirred at room temperature 318921 103 200808724 for one hour. 1N Hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue obtained was purified by EtOAc (EtOAc) (EtOAc: EtOAc (EtOAc) Phenyl) decyl alcohol (2.33 g, 1% by weight). Η-NMR (300MHz, CDC13): 5 3·84(3Η, s), 4·62(2Η, s), 6.68 (1Η? d, J = 1〇.5Hz)5 7.46 ( 1 Η5 d5 J^7 8 Hz) (Step 3) A solution of the compound obtained in Step 2 (2·24 g) in toluene (3 〇mL) was added to a short (1.77 g) mixture at room temperature and stirred for 2 days. The insoluble material was filtered off and the filtrate was concentrated. The residue obtained was purified by (4) column chromatography (ethyl acetate / hexanes (10)) to afford white benzene (1.86 g, 84%). 4-Li R (3G0MHz, CDCh): ^ J = 9· 9Hz), 8. 03 (1H, d, J (Step 4) 5-bromo-4-fluoro-2-methoxy 3·93 3H, s), 6.79 (1H, d, = δ · ΙΗζ), ΐ〇β 30 (1Η, s) The compound obtained using the step 3 and (4 compound obtained by the method described in Reference Example 3 obtained W-NMR (30〇miz, CDCM: 5 J = 12·3Ηζ), 7·62-7·95 (4H, 10.42 (1H, s) Refer to Example 23-Cyanophenyl)boronic acid, titled 4. 00 (3H ,s),6· 84 (1H,d, n),7· 99 (1H,d,J = 9·0Hz), methylbiphenyl~a guess 5'-cartosyl-4'-methoxy a 2, (Step 1) 318921 104 200808724 4-bromo-3-methylanisole (2·〇g) and dichloromethane (3〇mL) in dichloromethyl methyl ether (1·lmL) The solution was added to a solution of titanium tetrachloride (1.3 mL), and the mixture was stirred at 0 C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the mixture and the product was extracted with ethyl acetate. Sodium dry:!: stayed and concentrated to give 5-bromomethoxy-bu-methylbenzaldehyde (0.73 g, 32%) as a white powder. 4-NMR (300匪2, CDC13): 3 2·45 (3H,s ), 3· 91 (3H, s), 6·87 (1H, s), 7·94 (1H, s), 1〇·33 (1H, s) (Step 2) The compound obtained using Step 1 and 4-cyanophenyl)boronic acid, the title compound was obtained by the method described in Referential Example 3. !Η-·R (300MHz, CDC13): 5 2· 33 (3Η, s), 3· 98 (3Η, s) , 6.91 (1H, s), 7.38-7.42 (2H, m), 7.68-7.72 (3H? m), 10.44 (1H, s) 'Reference Example 24 3-indolyl-4' - via phenylene 4-indene nitrile (step 1) 5-bromosulfanal (6·03g) and 2,6-lutidine (5.2mL) in di-methane (100mL) solution, add trifluoromethyl at a 78 art Triisopropyl sulfonate sulfonate (9·7 mL), the mixture was stirred at -3 (rc) for 3 hr. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the product was extracted with ethyl acetate. Drying over anhydrous sodium sulfate and concentrating. The obtained residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Propyl decyloxy) benzene 318921 105 200808724 Formaldehyde (7·21 g, 67%).沱-NMR (300MHz, CDCh): 5 1·12 (18H,d,J = 7.2Hz), 1.29-1·56 (3H,m),6·79 (1H,d,J = 7.9Hz),7.51 (1H, dd, J: 8.7, 2.7 Hz), 7·81 (1H, d, &gt; 2·7Ηζ), 1〇·44 (1H, s) (Step 2) Compound obtained in Step 1 (1.6 g , (4-cyanophenyl)boronic acid (0.73 g), Pd(PPh3)4 (0.16 g) and potassium carbonate (〇·83⁄4) in THF/water (13/1) (21. 5 mL) The mixture was heated under reflux for 14 hours under a nitrogen atmosphere. After cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) W-NMR (300MHz, CDCh): 5 7·1 Bu 7·14 (1H, m), 7·64-7·79 (6Η, m), 9·99 (1Η, s), 11.10 (1Η, s Reference Example 25 3'-Methylmercapto-4'-methoxy-2'-mercaptobiphenyl-4-indenecarbonitrile (Step 1) 4-Bromo-3-indolylanisole (1〇· lg And dichloromethyl methyl ether (5.4 mL) was added to a solution of tetramethylamine (6.6 mL) in a gas-fired (150 mL) solution. The mixture was stirred at 0 ° C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the mixture and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc Formaldehyde (〇. 56g, 5%). 2·64 (3H, s), 3·9〇 (3h, s), 7·67 (1H, d, J = 9· 3Hz), l〇· 54 !H-NMR (300MHz, CDCls): 6 · 75 (1H, d, J = 8·7 Hz), (1H, s) (Step 2) Using the compound obtained in Step 1 and (4-nitrophenyl), the title compound is described by Reference Example 3. obtain. Ifi-NMR (300AtHz, CDCl3): 6· 92 (1H, d, J = u· 4Hz), (2H, m), l〇· 68 (1H, s) Reference Example 26 occupies 2·41 (3H, s ),3· 95 (3H, s), 7· 32-7· 38 (3H,m),7·β8 — 7· 72 4 (7-Fe-based 2,3-dihydro-indole-benzofuran) a 5-benzyl) benzonitrile (step 1) 2,3-dihydrobenzofuran (6. 〇§) dissolved in acetonitrile (15 〇乩), which is added to the dream of the imine (9. 8g), the mixture was given for 2 hours at 〇t. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography (yield: ethyl acetate / hexanes) eluted with EtOAc (yield: EtOAc). ^NMR (300MHz, CDCh): ^ 3. 20 (2H, t, J=8. 7Hz), 4.57 H,t, J-8. 6Hz), 6. 66 (1H,d,J=9. 〇Hz ), 7.19 (1H, dd J=8. 7, 2.3Hz), 7. 28 (1H,m) ' (Step 2) The compound obtained in Step 1 and (4-cyanophenyl)boronic acid 318921 107 200808724 4_(2,3-Dihydro-1-benzofuran-5-yl)benzonitrile was obtained by the method described in Reference Example 3. !H-NMR (300MHz, CDCh) : ^ 3. 29 (2H? J = 8. 6Hz), 4.65 (2H,t,J = 8· 7Hz), 6· 88 (1H,d,J 2·8·3Hz ), 7.35 (1H, dd, J = 8.3, 2.2 Hz), 7.44 (1H, d, J = 1.5 Hz), 7.60-7.70 (4H5 m) (Step 3) Compound obtained using Step 2, title compound Obtained by the method described in the first step of Example 2 3 . 'H-NMR (300MHz, CDCh): 5 3. 34 (2H5 t5 J = 8. 6Hz), 4.83

(2H, t, J = 8.7 Hz), 7.64 - 7.67 (3H, m), 7.71 - 7.74 (2H m), 7. 84 (1H, m), 10 · 27 (1H, s) Reference Example 27 3 - Brewing base-4 (2, 2,2-trifluoroethoxy)biphenyl-4-carbonitrile (Step 1) 5-bromosulfanal (〇.81g) in DMF (8 mL) at room temperature Sodium telluride (NaH) (60% in oil, 〇. I9g) was added and the mixture was stirred for 3 。. Thereafter, a solution of 2,2,2-trifluoroethyl difluoromethanesulfonate (1.1 §) in DMF (8 mL) was added, and the mixture was stirred at 65 ° C for 2 hours. Ice water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by hydrazine column chromatography (solvent gradient: 5 to 30% ethyl acetate /hexane) to afford 5-bromo-2-(2,2,2-difluoroethoxy)benzene as colorless oil. Capric acid: (ι. jealous, μ%) Ή-NMR (300MHZ, CDCh): ^ 4.48 (2H, q, j.7.7Hz) 318921 108 200808724 6·86 —6· 89 (1H,m),7 · 66 — 7.70 (1H, m), 8· 00 (1H, d, J=2·7Hz), 1〇·41 (1H, s) (Step 2) The compound obtained in step 1 and (4-cyano) Phenyl)boronic acid, the title compound was obtained by the method described in Reference 3. NMR (300MHz, CDCh): 5 4· 57 (2H, q, J = 7· 5Hz), 7·1〇(1H,d,] = 8·7Ηζ),7·67-7·85 (5H,m ), 8·15 (1H, d, J = 2.3 Hz), 10.54 (1H, s) Reference Example 28 2-Fluoro-3'-methylindole- 4'-(trifluorodecyloxy)benzonitrile (Step 1) In a known method (Bioorganic &amp; Medicinal Chemistry

Letters, 9 (1 999), 1311-1316) 5-bromo-2(trifluoromethoxy)benzofural (5·38 g), dipentaboron (5·lg), potassium acetate (5·) 9g) and hj bis(diphenylphosphine)iron ruthenium]palladium (ruthenium) dichloride (PdCh(dppf)) (〇.65g) in DMF (35mL), stirred at 90 ° C in argon atmosphere ΐβ hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by hydrazine column chromatography (solvent gradient: 5 to 20% ethyl acetate /hexane) to afford 5-U,4,5,5-tetradecyldioxabenzene as a white powder. 2-yl)-2-(trifluoromethoxy)benzaldehyde (3e2 g, 51%). The crude product obtained was used in the next step without further purification. (Step 2) Compound obtained in Step 1 (1.6 g), 4-chloro-3-fluorobenzonitrile 318921 109 200808724 (〇·78g), Pd(PPh3)4(0·I7g) and nitrite &amp;

A solution of a mixture of potassium citrate (1.4 g) in THF (20 mL) and water (10 mL) was stirred at &lt;RTI ID=0.0&gt;&gt; Pour water into the reaction mixture and mix it with α, this. The material was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (solvent gradient: EtOAc: EtOAc: EtOAc: EtOAc: C15H7F4NO2

Found C, 58·06; H, 2.46 ·, N, 4.70 Calculated C, 58·26; H, 2.28; N Reference Example 29 4'-Chloro-2'-fluoro-4-(trifluoromethoxy) Biphenyl-3-formaldehyde using 5-bromo-2(trifluoromethoxy)-cagexin $/pure T虱丞; Benmethod and 4-chloro-2-fluorophenylboron, title The compound was obtained by the method described in reference to 3 above. Melting point: 4 b 42 ° C Further in Reference Example 30: -(Trifluoromethoxy)-4,-(trifluoromethyl)biphenyl-3-formaldehyde using 5-bromo-2(trifluoromethoxy) The benzaldehyde and 4-(trifluoromethyl)phenylboronic acid were obtained by the method described in Reference Example 3. ]H-NMR (300MHz, CDCh) : , 5 7.48 (1H, d/J^〇Hz) 7.68-7.75 (4H, q like), 7.89 (1H, d, jl6. 〇Hz)&gt;8;18 ( 1H, s), 10.43 (1H, s) Reference Example 31 4-Chloro-4-(trifluoromethoxy)biphenyl-3-furfural using 5-bromo-2-(trifluoromethoxy) Benzaldehyde and 4~chlorophenylboronic acid, 318921 110 200808724 The title compound was obtained by the method described in Reference 3. Η-NMR (300MHz, CDC13): 3 7·42 —7·53 (5H,m), 7.8, 7.84 (1Η, m), 8.14 (1Η, s), 1〇42 (1Η, s) Reference 32 4-Gas-4-(trifluoromethoxy)biphenyl-3 tocarboxylic acid using 5/odor 2 (difluoromethoxy)benzaldehyde and 4-fluorophenylboronic acid, the title compound is described by reference Example 3. The method is obtained. V 臓 (10) MHz, CDci 3) j 7.12_718 ... d, J = 6.0 Hz), 7 53-7 57 Γ 9 Η . , .53 7.57 (currently 0, 7.81 (1H, d, 1=6._, 8. 11 (1H, s), i〇. 41 (1H, s) Reference Example 33, 4 Chlorine 4 (two rats) Methoxy)biphenyl-g-methyl was used as 5-bromo 2-(difluoromethoxy)benzaldehyde and 24,2-dicarboxylic acid, and the title compound was obtained by the method described in Referential Example 3.

Melting point · 62-63 ° C Reference Example 34 2,4'-difluoro-4_(trifluoromethoxy)biphenyl_3-formaldehyde using 5-bromo~2-(trifluoromethoxy)benzoic acid and a base -1,3,2~Dioxaborolan-2-yl)-1,2,,Bu 4//Not obtained by the method described in Reference Example 3. 1 book, title text points: 3 9 - 41. . Reference Example 35 2'Chloro-3'-methylindenyl (trifluoromethoxy) group was used in Reference Example 28, step! The compound obtained in the nitrile and 318921 111 200808724 qibenjia guess' title compound was obtained by the method described in Tea Test Example 3. Melting point: 134 ° C Reference Example 3 6 2'-Chloro-4'-fluoro-4-(trifluoromethoxy)biphenyl_3_formaldehyde using 5-bromo-2-(trifluoromethoxy)benzaldehyde The title compound was obtained by the method of Reference Example 3 and 2-chloro-4-fluorophenyl.

Melting point · 64 ° C Reference Example 37 4 -(Difluoromethoxy)- 3'-formylbiphenyl-4-indenonitrile (Step 1) 5-bromosulfanal and 4-cyanophenylboronic acid , crude 3, _mercapto-hydroxybiphenyl-4-carbonitrile, obtained as described in Reference Example 3, obtained as a crude product, which was used in the next step without further purification. (Step 2) Step 1 Obtain a solution of the compound (1.0 g) in dichloromethane (4 〇), and add to a 50% aqueous potassium hydroxide solution (5 〇) to tetrabutylammonium bromide (1.22). this). Rat (monofluoro) broth gas (halocarbon 22) was blown into the mixture. 5 knives of 4 chloro (monofluoro) methyl sulphur gas were further blown into the mixture and mixed for 3 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with hydrazine sulphuric acid and concentrated. The residue was purified by EtOAc EtOAc. ^-NMR (300MHz, CDCh): d 6·74 (1H, t, J = 72.2Hz), 7.39 (1H? d, J-8.5Hz) 5 7.63-7.80 (4H, m), 7.85 (1H, 318921 112 200808724 dd,] = 2·5,8·7Ηζ),8·17(1Η,d,J=2.5Hz), 10.46 (1H, brs) Reference Example 38 3'-Acetyl-4'-methoxy Biphenyl-phthalonitrile (Step 1) Synthesis of 3'-carbamimido-4'-methoxybiphenyl-4-carbonitrile (〇.47g) in THF (10 mL) by a known method (W002/26710) A solution of 3 mercapto magnesium chloride in diethyl ether (1 mL) was added at -78 ° C, and the mixture was stirred at room temperature for 2 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by column chromatography (solvent gradient: 1 EtOAc to EtOAc / hexane) Biphenyl-4 -indoleonitrile (〇.46 g, 91%). Elemental analysis · c16h15n〇2 measured value C, 75· 51 ; H, 5 · 91 ; N, 5 · 39 Calculated value C, 75 · 87 ; H, 5 · 97 ; N, 5 · 53 (Step 2) To a solution of the compound (2·g) obtained in the step 1 in dichloromethane (7 mL) was added EtOAc (2··········· The reaction mixture was treated with silicone and the reaction solution was concentrated. The residue was purified by gelatin column chromatography (solvent gradient; 1 Torr to (10) acetic acid)

The title compound (1.53 g, 92%) was obtained. Melting point: l 〇 2 ° C Reference Example 39 318921 113 200808724 3' - Mercapto-2 - fluorenyl-4'-(tris-decyloxy)biphenyl-4-indenecarbonitrile was obtained using Step 1 of Reference Example 28. The title compound was obtained by the method described in Reference Example 3, and 4-bromo-3-mercaptobenzonitrile. Elemental analysis: Cl6Hl 〇F3N 〇 2 Measured value C, 63. 19 ; H, 3. 60 ; N, 4. 19 Calculated value C, 62 · 96 ; H, 3 · 30 ; N, 4. 59 Description Reference example The compounds of 10 to 39 are shown below (Tables 2 to 3). 114 318921 200808724 Table 2 Reference example No. Structure 10

11

12

13

-H* 14 15

twenty four

N 115 318921 200808724 Table 3 Reference example No. Structure 25 ch3i OHC*

26

27

28

CF3O. OHC'

31

OHC

34

35

OHC

36

CF30. OHl

116 318921 200808724 Example 1 (3R,4S)-4-({[4-methoxy-2'-(indolylsulfonyl)biphenyl-3-yl]methyl}amino)-3-benzene (3R,4S)-4-Amino-3-phenylpiperidine-1-carboxylic acid tert-butyl ester synthesized by a known method (W003/1 01964) (912 mg), a solution of the compound (871 mg) and EtOAc (3 mL) (m. hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was purified by EtOAc EtOAcjjjjjjjj MSCESI + ) : 551CM+H) Examples 2 to 3 using (3 R,4 S)-4-amino-3-phenyl oxime-1 -dibutylic acid tert-butyl ester and each relative benzoquinone Aldehyde derivative (3,-mercapto-4,-methoxybiphenyl-4-indenecarbonitrile synthesized by the known method (w〇〇2/2671〇) as Example 2 and known method (W002 /26710) is 2-fluoro-3,-fluorenyl-4'-methoxybiphenyl-4-indenecarbonitrile synthesized in Example 3, and the compounds of Examples 2 to 3 were obtained as in the method described in Example 1. . Example 2 (3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)methyl]amino}-3-phenyl dentate-1 Third butyl ester MSCESI+) : 498CM+H) 318921 117 200808724 Example 3 (3R,4S)-4-{ [(4'-Cyano-2'-fluoro-4-methoxybiphenyl-3-yl) )methyl]amino} -3phenyl σ bottom bite-1 - retinoic acid tert-butyl ester MSCESI+) : 516CM + H) Example 4 (3R, 4S)-N-{[4-methoxy-2 '-(Methylsulfonyl)biphenyl-3-yl]fluorenyl}-3-phenylpyrazine-4-amine dihydrochloride. Example 1 gave compound (1.2 g) in ethanol (1 〇) A solution of 4N hydrogen chloride / ethyl acetate (10 mL) was added to a solution of &lt The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 3 The obtained compound, the compounds of Examples 5 to 6 were obtained as in the method described in Example 4. Example 5 4'-Methoxy-3'-({[(3R,4S)-3-phenylpiperidin-4-yl]aminopurinemethyl)biphenyl-4-phthalonitrile dihydrochloride MS (ESI + ): 398CM-2HCHH) Example 6 2-fluoro-4'-methoxy-3'-({[(3R,4S)-3-phenylpiperidin-4-yl]amino} Indenyl)biphenyl-4-anthraquinone hydrochloride MS (ESH): 416CM-2HC1+H) 318921 118 200808724 Example 7 N-[2-((3R,4S)-4-{[(4- Methoxybiphenyl-3-yl)indenyl]amino}mono-3-phenylpiperidin-1-yl)-2-ketoethyl]acetamide The compound obtained in Reference Example 1 (4〇8 mg) Adding NaBH (〇Ac) to a solution of (W020〇5/GG5415) 4-methoxybiphenyl + f _12mg) and acetic acid (0.1 mL) in dichlorodecane (i〇mL) synthesized by a known method 3 G 〇〇 mg), the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine and evaporated The residue was purified by EtOAc EtOAc (EtOAc (EtOAc) 74%). MS (ESH): 472CM+H) Examples 8 to 11 The compound obtained in Reference Example 1 and the corresponding phenylfurfural derivative were respectively used (Reference Example 3 is the compound obtained in Example 8, and Reference Example 4 is Example 9). A known compound, which is a known method (w〇〇2/2671 〇), is a 3'-methylindole- 4'-nonyloxybiphenyl-4-methylcarbonitrile synthesized in Example 1 by a known method. (WOO 2/26710) is 2-fluoro-3, monomethyl-4, methoxybiphenyl-4-carbonitrile synthesized in Example π, and the compounds of Examples 8 to u are as described in Example 7. The method was obtained (the compounds of Examples 8 and 9 were each treated with 1 equivalent of hydrogen chloride/ethyl acetate and separated as hydrogen chloride). Example 8 N-{2-[(3R,4S)-4-({[4-methoxy-2'-(methylthio)biphenyl-3-yl] 318921 119 200808724 methyl}amino group -3-phenylpiperidin-1-yl]-2-ketoethyl hydrazide monohydrochloride MSCESI+) : 518CM-HC1+H) Example 9 N-{2-[ (3R, 4S) )-4-({[4-methoxy-2'-(methylsulfonyl)biphenyl-3-yl]indolyl}amino)-3-phenylpiperidin-1-yl]-2 -ketoethylethyl hydrazide monohydrochloride MS (ESI + ) : 550 (M-HC1+H)

Example 1Q N-[2-((3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)methyl]amino}-3-phenylene Benzo-1-yl)-2-ketoethyl]ethinamine MS (ESH): 497CM+H) Example 11 N-[2-((3R,4S)-4- {[(4'-Cyanide Benzyl-2'-fluoro-4-hydroxybiphenyl-3-yl)indenyl]amino}-3-phenylpiperidin-1-yl)-2-oneylethyl]acetamide MSCESI+) : 515CM+H) Example 12 N-[2-((3R,4S)-4-{[(4, 4'-dimethoxybiphenyl-3-yl)indolyl]amino}-3 - Phenyl benzylidene-1-yl)-2-ketoethyl]ethanoamine Reference Example 2 Obtained compound (475 mg), (4-methoxyphenyl)boronic acid (152 mg), Pd(PPh3)4 (35 mg And a mixture of potassium carbonate (276 mg) in THF/water (2/1) (18 mL), 15 min. Water extraction. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and washed with brine 318921 120 200808724, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (solvent gradient; 50 to 100%) Ethyl acetate/hexane) and from ketone/ The title compound (2) 54%) was obtained as white crystals. MSCESI+): 502CM+H) Examples 13 to 18 The compounds obtained in Reference Example 2 were used, and each corresponding to a commercially available phenylboronic acid derivative, and the compounds of Examples 13 to 18 were as described in Example 12. obtain. Example 13 N-{2-[(3R,4S)-4-({[4-methoxy-4,-(trismethoxy)biphenyl-3-yl]methyl}amino)- 3-phenylpiperidine-1-yl;]-2-ketoethyl}acetamimid MS (ESH): 556CM+H) Example 14 N - [2 - ((3R, 4S)-4-{ [(4-Methoxy-4,-nitrobiphenyl-%)indenyl]amino}-3-phenylpiperidin-1-yl)-2-oneethyl)acetamimid MS ( ESI+): 517(M+H) Example 15 N-[2-((3R,4S)-4- 4-[[(4'-)-4-methoxybiphenyl-3-yl]indenyl}amine ))-3-phenylanthene-1-yl)-2-ketoethyl]acetamide MSCESI+) : 506CM+H) Example 16 N-[2-((3R,4S)-4_{[ (4'-Fluoro-4-decyloxybiphenyl-3-yl]indenyl}amino)-3-phenylpiperidin-1-yl)-2-oneylethyl]acetamidamine 318921 121 200808724 MS (ESH): 490CM+H) Example 17 N-[2-((3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -Phenylpiperidin-1-yl)-2-ketoethyl]acetamide MSCESI+): 486CM+H) Example 18 N-{2-[(3R,4S)-4-({[4- Methoxy-4'-(trimethylmethyl)biphenyl-3-yl]fluorenyl}amino)-3-phenylpiperidine-;[-yl;|_2_keto丨acetamide MSCESI + ) : 540CM+H) Example 19 N [2-((3R,4S)-4-{[(2'-Cyano-4-indolylbiphenyl-3-yl)) Amino]-3-phenylpiperidin-1 -yl)-2-ketoethyl]acetamide The compound obtained in Reference Example 1 (4 〇 9 mg) was synthesized by a known method (W002/26710) 3'-Methylmercapto-4,-nonyloxybiphenyl- 2-indene nitrile (237 mg) and acetic acid (0·2ιηΐ〇 in dichlorodecane (7 mL) in a solution of ί^Βϋ(ΟΑ〇 3 (636 π^), the mixture was stirred at room temperature for 12 hours. Saturated carbon 酉 氲 氲 水 ' 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷 谷The title compound was obtained as white crystals (yield: EtOAc (EtOAc: EtOAc) 45〇mg, 9〇%) MS(ESI + ) : 497(M+H) Examples 20 to 25 The compound obtained from the wheat test example 1 and the corresponding corresponding benzaldehyde derivative 318921 122 200808724 (by known methods) (W002/26710) is Example 3: Synthesis of 3,-decanoyl-4'-decyloxybiphenyl-3-carbonitrile, Reference Example 6 is the compound obtained in Example 21, and the known method (WO02/2671 0) is taken as an example. 22, 4,-bromo-4-nonyloxybiphenyl-3-furfural, Reference Example 5 is the compound obtained in Example 23, Reference Example 8 is the compound obtained in Example 24, and Reference Example 7 is an example. The compound obtained in Example 25), the compound of Example 2 to 25 was obtained as in the method described in Example 19. Example 20 N-[2-((3R,S)-4-{[(3'-Cyano-4-methoxybiphenyl-3-yl)indolyl]amino}-3-phenylphene Pyridin-1-yl)-2-ketoethyl]acetamimid MS (ESIi): 497CM+H) Example 21 N-[2-((3R,4S)-4-{[(4'-Cyanide Benzyl-3'-fluoro-4-hydroxybiphenyl-3-yl)methyl]aminopurin-3-phenylpiperidine-1-yl)-2-ketoethyl]acetamide MSCESI+) : 515CM+H) Example 22 1^-[2-((31^,43)-4-{[(4'-Bromo-4-methoxybiphenyl-3-yl)indenyl]amino) _Phenylpiperidin-1-yl)-2-ketoethyl]acetamide MSCESI + ) : 550, 552CM+H) Example 23 N-[2-((3R,4S)-4-{[ (4'-ethynyl-4-methoxybiphenyl-3-yl)methyl]aminopurin-3-phenylpiperidine-i-yl)-2-ketoethyl]acetamidamine MSCESI+) : 496CM+H) Example 24 3Ϊ8921 123 200808724 N-{2-[(3R,4S)-4-({[4'-Cyano-4-(trifluoromethoxy)biphenyl-3-yl]] (amino)-3-phenylpiperidin-1 -yl]-2-ketoethyl}ethinamine monohydrochloride MS (ESI + ): 55KM-HC1 + H) Example 25 N-[ 2-((3R,4S)-4-{[(4'-Cyano-4-methoxy-2'-fluorenylbiphenyl-3-yl) Methyl]amino]-3-phenylpiperidine-1-yl]-2-ketoethylethylamineamine monohydrochloride MSCESI + ) : 51KM-HC1+H) Example 26 N-[2 -((3R,4S)-4-{[(4-methoxy-3',5'-dimercaptobiphenyl-3-yl)methyl]amino}-3-phenylpiperidine-1 -yl)-2-ylketoethyl]acetamide monohydrochloride The compound obtained in Reference Example 9 (44 mg), 1-bromo-3,5-dimethylbenzene (186 mg), Pd(PPh3)4 (35 mg) and potassium carbonate (276 mg) were stirred in THF / water (2 / 1) (18 mL) After cooling, the reaction mixture was concentrated, and the residue was subjected to ethyl acetate for extraction and aqueous sodium hydrogen carbonate. The organic layer was washed with saturated aqueous The residue was purified by silica gel column chromatography (solvent gradient: 5 〇 to 1 〇〇% of ethyl acetate / hexane) to give one equivalent of 4 N hydrogen chloride / ethyl acetate. The title compound (32 〇mg, 6 〇%) was added to the white crystals by filtration. MSCESI+) : 500CM-HC1+H) Example 27 124 318921 200808724 ^{2-[(3148)-4-({[4-曱oxy-3',5'-贰(trifluoromethyl)biphenyl) -3-yl]T-amino}amino)-3-phenylpitrien-1-yl]-2-S-ylethylethyl acetamide The compound obtained in Reference Example 9 and 1-bromo-3, 5 were used. The compound of Example 3 was softened as in Example 26 (no treatment with 1 equivalent of hydrogen chloride/ethyl acetate, and the obtained compound was in free form). (ESH): 608CM+H) Example 28 [2-((3R,4S)-4-{[(4-Cyano-4-methoxybiphenyl-yl)methyl]amino}-3- Phenylpiperidin-1-yl)-2-ketoethyl]carbamic acid tert-butyl ester The compound obtained in Example 5 (154 mg), Et3N (148 // L) and N-Boc-glycine (38 mg) In a solution of THF (5 mL), wsc············· The reaction mixture was added to water, and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and dried and evaporated. The residue obtained was purified by EtOAc EtOAcjjjj( MSCESI+): 455 (MB〇c+2H) Example 2 9 [2-((3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)methyl) Amino]-3-phenylpiperidin-1-yl)-2-hydroxyethyl]amino p-acid tert-butyl ester The compound obtained in Example 28 (〇· 18 g) was obtained from ethyl acetate (1 mL) 318921 125 200808724 / in the trough solution was added 4N hydrogen chloride / ethyl acetate (3 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness crystals crystals crystals MS (ESI+): 455 (M-2HC1 + H) Example 3 0 N-[2-((3R,4S)-4-{[(4'-Cyano-4- phenoxybiphenyl-3) Alkyl}amino}-3-phenylpyridin-1-yl)-2- ketoethyl]pyridinium guanidinamine The compound obtained in Example 29 and EtW (266 // L) Methanesulfonyl chloride (45/L) was added to a solution of THF (5 mL), and the mixture was stirred at room temperature for 14 hours, the reaction mixture was added to water, and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and dried and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc: MS (ESI + ): 533CM+H) Example 31 (3R,4S)-1 -(methylmercaptoethyl)-N-{[4-methoxy-2,-(methylsulfonyl) Biphenyl-3-yl]hydrazino}-3-phenyl ct-4-amino monohydrochloride The compound obtained in Example 4 (400 mg), Et3N (154 mg) and methoxyacetic acid (103 mg) in DMF To a solution of (5 mL), WSC·HC1 (218 mg) and HOBt················ The organic layer was washed with a saturated aqueous solution of sodium sulfate and brine and dried over magnesium sulfate. The residue obtained was purified by hydrazine column chromatography (solvent gradient; 126 318 921 2008 087 24 50 to 100% ethyl acetate / hexane) and i equivalent of 4N hydrogen hydride / ethyl acetate. The title compound (240 mg, 60%) was obtained. MS (ESH): 523 (M-HC1 + H) Examples 32 to 33 used methoxyacetic acid and the corresponding corresponding n-heptane derivative (Example 5 is the compound obtained in Example 32, and Example 6 is The compound obtained in Example 33 was obtained by the method described in Example 31 (the compound was not obtained in 1 equivalent of hydrogen chloride / ethyl acetate, obtained in free form). Example 32 4 -decyloxy-3'-({ [(3R,4S)-1-(decyloxyethyl)- 3 -phenylpiperidin-4-yl]amino}methyl)biphenyl 4- 4-carbonitrile MSCESI+): 470CM+H) Example 3 3 2Fluoro-4-oxooxy-3~({[(3R,4S)-1-(methoxyethyl)-3-stupid Isopiperidin-4-yl]amino}mercapto)biphenyl-4-indene nitrile MS (ESH): 488 (M+H) Example 3 4 (3R,4S)-1-[(1-ethylhydrazine) 5-piperidinyl-4-yl)carbonyl]-n-{[4-methoxy-2'-(methyl sulphate)biphenyl-3-yl]indolyl 3 A solution of the compound obtained in Example 4 (400 mg), Ei:3N (154 mg) and ethylpiperidine-4-carboxylic acid (195 mg) in DMF (5 mL) was added 127 318921 200808724 WSC HCl (218 mg) and hydrazine H20 (175 mg) were stirred at room temperature for 8 hours. Water was poured into the reaction mixture and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The residue obtained was purified by hydrazine column chromatography (solvent gradient; 50 to 100% ethyl acetate / hexane). The precipitate was collected by chromatography to give crystal crystal crystal crystal crystal crystal MS (ESI+): 604 (M-HC1+H) Examples 35 to 36 using 1-ethylhydrazinopiperidine- 4-carboxylic acid and the corresponding corresponding piperidine derivatives (Example 5) The compound of Example 35, and Example 6 were obtained as the compound of Example 36), and the compound of Examples 35 to 36 was obtained by the method described in Example 34 (the compound was not treated with 1 equivalent of ruthenium chloride/ethyl acetate. Obtained in free form). Example 35 3'-[({(3R,4S)-1-[(1-Ethylpiperidine-4-yl)carbonyl]-3-phenylpiperidin-4-yl}amino)methyl -4,-methoxybiphenyl-4-oxonitrile MS (ESI + ) ·· 551 (M+H) Example 36 3' - [({(3R,4S)-1-[(1 - B) Mercaptopiperidin-4-yl)carbonyl]-3-phenylpiperidin-4-yl}amino)indolyl]- 2-fluoro-tetra-, 4-decyloxybiphenyl- 4-carbonitrile MS (ESI +) ·· 569(M+H) Example 37 4-(((3R' 4S)-4-{[(4'-Cyano-4-indolylbiphenyl-3-yl)methyl]amine 128 318921 200808724 base}-3-phenyl brigade-1-yl) thiol] ketone-1-acidic acid tert-butyl ester compound obtained in Example 5 (257 mg), EtsN (248 // L) and 1 -(Secondoxybutyryl) π- bottom 唆- 4-acidic acid (163 mg) in THF (5 mL), WSC · HCl (173 mg) and HOBt · H2 〇 (139 mg), mixture in the room Stir for 16 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and evaporated. The residue obtained was purified by EtOAc EtOAcjjjjj: MS (ESH): 509 (M-Boc+2H) Example 38 4 -decyloxy-3 -({[(3R,4S)-3-phenyl-1-) The title compound was obtained by the method described in Example 29, using the compound obtained in Example 37. MSCESI+) : 509CM-2HC1+H) Example 39 4Methoxy-3 -{[((3R,4S)-1-{[1 -(methylsulfonyl)piperidine-4-yl]carbonyl X-Phenylpiperidin-4-yl)amino]indenyl}biphenyl-4-oxonitrile The compound obtained in Example 38 was obtained using the title compound. MSCESI+): 587CM+H) Example 4 0 N (2 {4-[(3R,4S)-4-{[(4'-Cyano-4-indolylbiphenyl-3-yl) 318921 129 200808724 Methyl]aminobenz-3-biphenylyl-p-butyl)-based ketone-pyridyl-2-ketoethyl)acetamide monohydrochloride The compound obtained in Example 38 and N-acetic acid were used. The glycine acid, the title compound was obtained as described in Example 31. MS (ESH): 608 (M-HC1 + H) Examples 41 to 44 The compound obtained in Example 5 and the corresponding corresponding tauric acid derivative (Examples 41 and 43 are commercially available acid-lowering derivatives). Example 42 is an example of a 2,6-dione-based 唆4_carboxylic acid synthesized by a known method (e.g., journal 〇f (1973), 38(14), pages 2489-96). 44 is 5-keto-4,5-dihydro-111-1,2 synthesized by a known method (for example, Austral 〇 J〇urnal of Chemistry (1979), 32(1), i61_5). 4-Triazole-triyl)acetic acid, the compounds of Examples 41 to 44 were obtained as described in Example 31 (this compound was not treated with one equivalent of hydrogenated hydrogen/ethyl acetate and was obtained in free form) . Example 41 (3R)-3-(Ethylamino)-4-((3R,4S)-4-{[(4,-cyano-4-yloxy)] alkyl]amino group }-3-笨基阿辰咬_1_基)_4_ketobutylamine MSCESI + ) : 554CM+H) Example 42 3' - [({(3R,4S)-1-[(2, 6-diketopiperidin-4-yl)carbonyl]-3-phenylimididin-4-yl}amino)methyl]-4'-decyloxybiphenyl-4-is-cause MSCESI+) : 537CM +H) Example 43 318921 130 200808724 4-decyloxy-3-({[(31^,48)-3-phenyl-1-(1{]-tetra-n-yl-1-ylethendyl)唆-4-yl]amino}methyl)biphenyl- 4-carbonitrile MSCESI + ) : 508 (M+H) Example 44 4'-decyloxy-3' - [({(3R, 4S) )-1-[(5-keto-4,5-dihydro-1H- 1,2,4-oxadiazol-3-yl)ethenyl]-3-phenylpiperidin-4-yl}amine Benzyl]benzil-4-indene nitrile MS (ESIi): 523CM+H) Example 45 (3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3 -yl)indolyl]amino}-3-phenylanthine-1-restroxenate The compound obtained in Example 5 (137?) and ΕΪ3Ν(2〇6//丨) in THF (5 mL) Add methyl chlorodecanoate (34 / / L) to the solution, and stir the mixture at room temperature for 16 hours. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried, and then evaporated. The residue was purified by EtOAc (EtOAc:EtOAc) MSCESI+): 456CM+H) Example 46 (3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)methyl]amino}-N-indenyl To the solution of the compound (I73 mg) in THF (5 mL). Reaction mixture 318921 131 200808724 The compound was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) The compounds described in Examples 1 to 4 are as shown below (Tables 4 to 7). 132 318921 200808724 Table 4 R2

133 318921 200808724 Table R2

134 318921 200808724 Table 6

135 318921 200808724 Table 7 R2

Example 47 N-[2-((3R,4S)-4-{[(4'-acetoxy-4-methoxybiphenyl-3-yl)indolyl]amino}-3-phenyl Benzo-1-yl-2-mercaptoethyl)ethinamine monohydrochloride 136 318921 200808724 The compound obtained in Reference Example i and the compound obtained in Reference Example 1 were reacted and purified as described in Example 7. get on. The product obtained was treated with 1 equivalent of ruthenium chloride/ethyl acetate to give the titled character MSCESI+): 514CM-HC1+H) Example 48 N-{3'-[({(3R'4S) + [(ethyl) Amino)ethylamino]_3_phenyl benzylidene-4-yl}amino) fluorenyl]-4'-nonyloxybiphenyl+yl}acetamide-antimonic acid hydrazine using the compound obtained in Reference Example 1 And the chemical, the reaction and the purification obtained in Reference Example u were carried out as described in Example 7. The product obtained was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. MS (ESH): 529CM-HC1+H) Example 49 1^[2-((3_-4-{[(4,------------------- Amino}-3-phenylpiperidin-1-yl)-2-ketoethyl]acetamide monohydrochloride | The compound obtained in the study of the test sample 1 and the compound obtained in Reference Example 12 were reacted and Purification was carried out as in the method described in Example 7. The obtained product was obtained from EtOAc EtOAc EtOAc (EtOAc) , 4S)-4-({[4,-(dimethylamino)_4-methoxybiphenyl_3_yl]methyl}amino)-3-phenyl-l-yl;|_2__ The ketoethyl}acetamide dihydrochloride salt was subjected to the compound obtained in Reference Example 1 and the compound 318921 137 200808724 obtained in Reference Example 13, and the reaction and purification were carried out in the same manner as described in Example 7. The product obtained was treated with 2 eq. of hydrogen chloride / ethyl acetate to give the title compound =, MS (ESI+): 515CM-2HC1-+H) Example 51 decyl)biphenyl-3 - N-{2-[(3R, 4S)-4-({[4-曱oxy-4'-(methyl-stone-ylethyl}acetamido]methyl}amino)-3-phenyl 唆-1-yl] 1-2- Using the compound obtained in Reference Example 1 and the compound obtained in Reference Example 14, the title compound was obtained by the reaction 3 and purification as described in Example 7. &quot; MS (ESI+): 550 CM+H) Example 52 + cyano-5-fluoro+methoxybiphenyl-3-yl) fluorenyl]amino}-3phenylpiperidin-1-yl)-2-ketoethyl]acetamide 1 The obtained compound and the compound obtained by reference to 15 are obtained, and the title compound is obtained by the reaction and purification as described in Example 7. "MSCESI+": 515CM+H) Example 53 3'-({[(3143)-1-(^Ethylglycine))-3-phenylpiperidin-4-yl]amino}indenyl -4'-methoxybiphenyl- 4-carboxylic acid decyl ester The compound obtained in the study of the first example and the compound obtained in Reference Example 16 were used, and the title compound was obtained by the reaction and purification as described in Example 7. MS (ESH): 530 (M+H) 318921 138 200808724 Example 54 N-[2-((3R'4S) + {[(4, 'Gas + Methoxy-2, Methylbiphenyl) _ ) ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用The title compound was obtained by the reaction and purification as described in Example 7. MS (ESI+): 520 (M+H) Example 5 5 N-{2-[(3R' 4S)_4_({[4, _Bromo+methoxy-3, _(trifluoromethyl)biphenyl-3-yl]methyl}amino)-3-phenylpiperidin-indole-yl]-2-ylketoethyl}B The compound obtained in Reference Example 1 and the compound obtained in Reference Example 18 were used as the decylamine, and the title compound was obtained by the reaction and purification as described in Example 7. ^ MSCESI+) : 618, 620CM+H) Example 5 6 N-[2-((3R,4S)-4_U(4,-Cyano-2_fluoro+methoxybiphenyl-3-yl)methyl Amino}-3-phenylpiperidin-1-yl)-2-mercaptoethyl]acetamide-using the compound obtained in Reference Example 1 and the compound obtained in Reference Example 19, the title compound The method described in 7 was carried out by reaction and purification. MS (ESI+): 515CM+H) Example 57 N-{2-[(3R,4S)-4-({[4'-Cyano-4-methoxy] Base ~2, mono(trifluoromethyl) 318921 139 200808724 ~ ketoethyl} after the compound biphenyl-3-yl]methyl}amino) 1-phenyl-n-yl-1-yl μ2 The reaction of the guanamine method and the use of the compound obtained in Reference Example 1 and the reference Example 2 were obtained, and the title compound was obtained by the purification of the product as described in Example 7. MSCESI+): 565CM+H) Example 58 3'- ({[(3R,4S)-1-(Ν-Ethylglycine))~3~Benzene/4Acyl}indenyl)-4-decyloxybiphenyl-4-ylindole The compound obtained in Reference Example 1 and the compound obtained in Reference Example 21 were used as the amine, and the title compound was obtained by the method as described in Example 7. Obtained by reaction and purification. μ MSCESI+) : 515CM+H) Example 5Θ N-〇((3R'4S)-4_U(4-cyano-6-fluoro-4-decyloxybiphenyl-3) Obtained by purifying methyl]amino}-3phenylpiperidin-1-yl)-2-ketoethyl]acetamide. MSCESI+): 515CM+H) Example 60 Using the compound obtained in Reference Example 1 and the compound obtained in Reference Example 22, the title compound was reacted by the method as described in Example 7 and

...4 - 丞 丞 斗 肀 肀 肀 ^ ^ 甲基 甲基 甲基 甲基 } } } } } } } } 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用The obtained compound was reacted with the method described in Reference Example 23, 318921 140 200808724, and the compound was obtained by purification as in the example. MSCESI + ) : 51KM+H) Example 61 N-[2-((3R,4S)-4-U(4,Cyano+hydroxyl-phenyl)-3-phenylpiperidin-1-yl)_2 - Ketoethylethyl]acetamidine soil The compound obtained in Reference Example 1 and the compound obtained in Reference Example 'The title compound were obtained by the reaction and purification as described in Example 7. ^ MS (ESH): 483CM+H) Example 62 ^[^(([(4'-Cyano-4-indolyl-2-methylbiphenyl-3-yl)indenyl]amino}-3 -Phenylpitrile +yl)_2-ketoethyl]acetic acid amine The compound obtained in the test example 1 and the compound obtained in Reference Example 25 were used, and the title compound was obtained by the reaction and purification as described in Example 7. MS (ESI + ): 51KM+H) Example 63 l[2K(3R,4S)-4-{[Bu(4'-Cyano-4-indolylbiphenyl-3-yl)ethyl] Amino}-3phenylpiperidin-1-yl)_2-ketoethyl]acetamide (non-figomer mixture) The compound obtained in Reference Example 1 (1.86 g) at room temperature, reference example 38. The obtained compound (〇·63g) and Et3N (0·76g) in dichloromethane (60mL) were added to titanium tetrachloride (0.24g) Dihydromethane (i〇mL) was dissolved in 141 318921 200808724 and the mixture was mixed for 2 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane was evaporated. NaBH3CN (0.47 g) was added to the reaction / broth at room temperature, and the mixture was allowed to stand for 3 minutes. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and dried and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc MS (ESI+): 511 (M+H) (m.). Ethyl]amino]amino}-3phenylpiperidin-1-yl)-2-oneethyl]acetamide (short residence time) Example 6 3 Non-imagewise mixture obtained (〇 . 4 〇g) Purified by chiral column chromatography. The title compound (〇·22g) was obtained as a colorless solid. MSCESI + ) : 51KM+H) [a ]d25+46· l°(c 〇· 51, sterol) Mirror surrogate excess: 99.7% de Purification conditions by chiral column chromatography

Column CHIRALPAK AD 50mmIDx500mmL Solvent··hexane/IPE/diethylamine=75/25/0.2 Flow rate: 80mL/min Temperature: 4Q°C Measurement method: UV 260nm 318921 142 200808724 Example 65 N-[2-( (3R,4S)-4-{[1-(4'-Cyano-4-methoxybiphenyl-3-yl)ethyl]amino}-3-phenylpiperidine-1-yl)- 2-ketoethylethylacetamide (longer residence time) Purified by chiral column chromatography as described in Example 64, obtained from a long-term retention day-to-day separation of the liquid to obtain a colorless amorphous solid. The title compound (0.086g) 〇MS(ESH): 51KM+H) [a]d25-5· 6 ° (c 0· 51, sterol) Mirror overshoot: 99. 7% de chiral column chromatography The purification conditions were the same as those described in Example 64. Example 66 Hydro-1-benzoxanthylethyl} N-{2-[(3R,4S)-4-({[5-(4-cyanophenyl)-2,3-difuran-7 -Alkylamino)amino-3-phenylpiperidinyl-acetamide The compound obtained in Reference Example 1 and the compound obtained in Reference Example 26 were used, and the title compound was obtained by the method as described in Example 7. Obtained by reaction and purification. Dingxin MS (ESI + ): 509CM+H) Example 67: {2-K3R,4S)-4—({[4,-Cyano-4_(2, 2, trifluoroethoxy) Methyl]amino}amino)-3-phenyl pi. Ding [-based] t-ketoethyl}acetic acid amine monohydrochloride 318921 143 200808724 using the compound obtained in Reference Example 1 and Reference Example 27 Compounds, reaction and purification were carried out in the same manner as described in Example 7. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Trifluoromethoxy)-mono-ketoethyl}ethyl N-{2-[(3R,4S)-4-({[4'-cyano-2'~fluoro-phenyl-3-yl] fluorenyl) The compound obtained in Reference Example 1 and the compound obtained in Reference Example 28 were obtained by the reaction and purification as described in Example 7. ~ MS(ESH): 569(M+H) Example 6 9 N-{2-[(3R'4S)-4-({[4'-Cyano-2'-methyl~4__(trifluoro) Methoxy)biphenyl-3-yl]methylindolyl)-3_phenylpiperidine-hydrazinyl]_2-ketoethyl} Ethylamine soil using the compound obtained in Reference Example 1 And the compound obtained in Reference Example 39, the title compound was obtained by the reaction and purification as described in Example 7. &quot; MSCESI+): 565CM+H) Example 70 Fluoromethoxy)biphenylphenethyl) Ethyl N-{2-[(3R,4S)-4-({[4'-chloro-2'-fluoro-4(tri-3-yl)methyl)amino)-3-phenylpiperidine -1 - group]~amine 318921 144 200808724 The compound obtained using Reference Example 1 and the compound '4 compound obtained in Reference Example 29 were obtained by the reaction and purification as described in Example 7. MSCESI+) : 578 CM+H) Example 71 N-{2-keto-2-[(3R,4S)-3-phenyl-4-({[4-(trifluoromethoxy)-tetra-(difluoromethyl)biphenyl) -3-yl] fluorenyl}amino) π- bottom oxime - I-yl]ethyl} acetamidine The compound obtained in Reference Example 1 and the compound obtained in Reference Example 'title compound by the method as described in Example 7 It is obtained by carrying out a reaction and purification. MSCESI + ) : 594CM+H) Example 72 N-{2-[(3R,4S)-4-({[4'-chloro-4-(trifluorodecyloxy)biphenyl-3-yl] oxime The compound (557 mg), the compound obtained in Reference Example 31 (451 mg), Et3N ((()))). A solution of 304 mg) and acetic acid (〇· imL) in ethyl acetate (8 mL) was stirred at 45 ° C for 10 minutes. NaBH (0 AcM 954 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with aq. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 318921 145 200808724

Elemental analysis: C29H29C 1 F3N3O3 · H2O Determination C, 60· 66 ; H, 5.19 ; Ν, 7 · 1 〇 calculated C, 60 · 26 ; H, 5 · 41 ; N, 7 · 27 MS (ESH : 560 (M+H) Example 73 N-{2-[(3R,4S)-4-({[4'-fluoro-4(trifluoromethoxy)biphenyl-3-yl]methyl) The compound obtained by the reference example 1 and the compound obtained in Reference Example 32 were used as the title compound by the same procedure as in Example 7, using the compound obtained in Reference Example 1 and the compound obtained in Reference Example 32. The method described is obtained by reaction and purification. MSCESI+): 544CM+H) Example 74 N-{2-[(3R,4S)-4-({[2',4'-dichloro-4-(trifluorodecyloxy)biphenyl-3- The compound obtained in Reference Example 1 and the compound obtained in Reference Example 3 3 were used for the title of the compound obtained by the reference Example 1 and the title of the title compound. The compound was obtained by the method described in Example 7 by reaction and purification. MSCESI+): 594CM+H) Example 75 N-{2-[(3R,4S)-4-[2',4'-difluoro-4-(trifluoromethoxy)biphenyl-3-yl]曱 } 胺 胺 } } } 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 318 The title compound was obtained by the reaction and purification as described in Example 7. ~ MS (ESH): 562CM+H) Example 76 N-{2-[(3R,4S)-4-({[2'-chloro-4'-cyano-4dfoxy)biphenyl-3 -yl]methyl}amino)-3-phenylpiperidine-fluorenyl- 2,2-ketoethyl oxime oxime A compound obtained by the method of the test of Example 1 and a compound obtained in Reference Example 35, the title compound It was obtained by carrying out the reaction and purification as described in Example 7. MS (ESI+): 585 (M+H) </RTI> </RTI> </RTI> N-{2-[(3R,4S)-4-({[2,-chloro-4,-fluoro-4-(trifluoro-f-oxy)) The compound obtained in Reference Example 1 and the compound obtained in Reference Example 36, the title compound, were used for the biphenyl-3-yl]methyl}amino)-3-phenylpiperidine-indenyl] ketoethyl}acetamide. It was obtained by carrying out the reaction and purification as described in Example 7. MS (ESI+): 578 (M+H) (m.). Methyl}amino)-3-phenylpiperidine-1-yl]- 2-ketoethyloximeacetamide The compound obtained in Reference Example 1 and the compound obtained in Reference Example 37, the title compound Obtained by the method described in Example 7 and obtained by purification of 318921 147 200808724. MSCESI+): 533CM+H) Example 79 2-((3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)methyl]amino}- The compound obtained in Example 5 (155 mg), Et3N (184 / / L) and acetic acid oxy acetic acid (47 mg) in THF (5 mL) To the solution, WSC·HCl (97 mg) and HOBt·H2 (76 mg) were added, and the mixture was stirred at room temperature for an hour. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) +H) Example 80 -4,-methoxybiphenyl-4-carbonitrile &quot; Using the compound obtained in Example 5 and glycolic acid, the title compound was obtained by reaction and purification as described in Example 79. . 9 MS (ESI + ): 456 MH+H) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Oxybiphenyl}-3-phenylpiperidin-1-yl)-4-ketobutylamine The compound obtained in Example 5 and succinic acid 318921 148 200808724 were carried out by the method as described in Example 79. Reaction and purification. MSCESI + ) : 497CM + H) Example 82 3' -({[(3R,4S)-1-Ethyl-3-phenylpiperidin-4-yl]aminopurine -4 -decyloxybiphenyl-4-carbonitrile monohydrochloride at 0 C, the compound obtained in Example 5 (i72 mg) and Εΐ3Ν (204 // L) in THF (5 mL) Ethylene gas (3 〇 / / L) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and the product was taken up in ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine and dried and evaporated. The residue obtained was purified by silica gel column chromatography (50% ethyl acetate /hexane). The product obtained is treated with i equivalent of hydrogen chloride / ethyl acetate to give the title compound. MS (ESH): 440CM-HC1+H) Example 83 4'-decyloxy-3'-({[(3R,4S)-1-(methylsulfonyl)-3-phenylpiperidine- 4-yl]amino}methyl)biphenyl-4-carbonitrile was added to a solution of the compound obtained in Example 5 (177%) and Et3N (21〇#L) in THF (5 mL) at 〇 ° C. Sulfonyl chloride (33 / / L), the mixture is mixed until 2 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and evaporated. The residue was purified by EtOAc EtOAcEtOAcEtOAc MSCESI + ) : 476CM+H) Example 84 318921 149 200808724

—{Te嗤-1-yl-methoxy-3’-{[((31^,48)-3-phenyl-;[acetic acid))-4-yl]. The compound obtained in Example 38 and 1H__tetrazole-indole-acetic acid were reacted and purified as in the method described in Example 79. . The obtained product was treated with 1 hr of hydrogen chloride / ethyl acetate to give the title compound. MSCESI+): 619 (M-HC1+H) Example 85 4 -decyloxy-3' - ({[(3R,48)-1-({1-[(5-keto--4,5-II) Hydrogen-1H-1,2,4-triazol-3-yl)ethenyl]piperidine-4-yl-carbonyl)_3_phenyl brio σ疋-4-yl]amino}indenyl)biphenyl a 4-indene nitrile monohydrochloride salt using the compound obtained in Example 38 and (5-fluorenyl- 4 4 - one gas-111-1,2,4-triazol-3-yl)acetic acid, reaction and purification This was carried out as described in Example 79. The product obtained was treated with hydrazine hydrochloride/EtOAc to afford title compound.

Mb(ESI + ) · t&gt;34(M-HC1+H) Example 8δ 4-[{(3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3- Methyl]amino}-3-phenylpiperidine-1-yl}carbonyl]-N,N-dimercaptopiperidine-monodecylamine using the compound obtained in Example 38 and didecylamine Chlorine was brewed and the title compound was obtained by reaction and purification as described in Example 83. MSCESI+): 580CM+H) Example 87 318921 150 200808724 4' -Methoxy-3'-{[((3R,4S)-3-phenyl-i-) 2,4-triazol-1-yl Ethyl)piperidin-4-yl]carbonyl}piperidine-4-yl)amino]methyl 1 biphenyl-4-indanonitrile monohydrochloride The compound obtained in Example 38 and (丨肜丨, 2,4_Triazole_ι_yl)acetic acid, reaction and purification were carried out as described in Example 79. The obtained product was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. MS (ESI+): 618 (M-HC1+H) Example 88 3 [({(3R,4S)-1-[(5, 5-dimethyl- 2, 4-dione-1,3- Oxazolidin-3-yl)ethinyl]-3-phenylpiperidin-4-yl}amino)indenyl]- 4,-methoxybiphenyl-4-carbonitrile soil using Example 5 The obtained compound and (5, 5-dimercapto-2,4-dione-1,3-1,3-oxazolidine-3-yl)acetate synthesized by a known method (w〇2〇〇6/ 030975) The title compound was obtained by the reaction and purification as described in Example 79. MSCESI + ) : 567 (MfH) Example 89 (3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)methyl]amino} - 3-( 3-butylphenyl 4-fluorophenyl)piperidinecarboxylate (Step 1) 3-(4-Fluorophenyl)-4-one synthesized by a known method (W003/1 01964) under argon atmosphere Piperidine-polycarboxylic acid tert-butyl ester (6·〇g), (S)-l-phenylethylamine (3.7 g) and aluminum chloride (〇·14 g) in toluene (4〇mL) The solution was stirred for 14 hours, and concentrated using a Dean-stark trap at 14 (rc 151 318921 200808724: dehydration reaction mixture under reduced pressure. Renilu ((10)) as a compound... Add the reaction obtained from the above, The sub-mixture was turbulent at 25 ° C under a hydrogen pressure of MPa 5 MPa.: By: removing the Raney nickel 'supernatant concentrated under reduced pressure. The owing 2 was purified by ruthenium column chromatography. (solvent gradient; 〇 〇 to 5 (10) acetonitrile acetate / hexane) to give a pale yellow oil (6. lg). mixture of the obtained residue, 'bar weight, lg) and ethanol (5 〇mL) at 0.5 MPa The mixture was stirred for 30 hours under hydrogen pressure. The carbon was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by Shixi rubber column chromatography (solvent gradient; hexane: acetic acid ethyl acetate = 2: 1 monoacetic acid ethyl acetate alone - acetic acid ethyl acetate: methanol = 2: 1) to obtain a colorless powder (3R' 4S)-4-Amino-3-(4-fluorophenyl)piperidine- I-tert-butyl tert-butylate (4.3 g, 71%). Elemental analysis·· C16H—〇2 Measured value C, 65·36 ; H,7·77 ; Ν,9·34 Calculated value C,65· 28 ; Η, 7· 88 ; Ν,9· 52 (Step 2) Step 1 obtained compound (1.2 g), 3, -mercapto-4, monomethoxybiphenyl- 4-carbonitrile (0.95 g) and acetic acid (〇·8 mL) in dichloromethane (3 mL) To the solution was added NaBH (0 AcM 2 · 5 g), and the mixture was stirred at room temperature for 4 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then brine, dried and evaporated. The residue was purified by EtOAc (EtOAc EtOAc (EtOAc) 31S921 152 200808724 Elemental analysis·· C31H34FN3O3 ·孖2〇8. 21 8. 01 Determination C, 71.05, · H, 6.6δ ; N, calculated C, 70.97 ; fj,6&gt;72;n)' MSCESI + ) : 516CM+H) 'Example 90 3 ({[(3R,4S) 3-(4-fluorophenyl))- 4-yl]amino}methyl)-4,-methoxy linkage Benzene-4-carbonitrile dihydrochloride The compound obtained in Example 89 was used, and the title compound was obtained by the reaction and purification as described in Example 4. MSCESI+): 416CM-2HC1+H) Example 91 N {2 [(3R,4S)-4-{[(4'-Cyano-4-methoxybiphenyl-3-yl)-methyl]amino 3-(4-Fluorophenyl)pyrene +yl]-2-indenylethylethene using the compound obtained in Example 90 and (tetra) glycerol, the title character was as described in Example 79 Inverse MSCESI + ) : 515CM + H) Example 92 3'-({[(31^) + [(1-Ethyl) ketone _4_yl)] phenyl) money-4 The compound obtained in Example 90 and the title compound were obtained by the purification as described in Example 79. /, Reaction and MS (ESH): 569CM+H) Example 93 318921 153 200808724 (3R,4S)-4-({[4'-Cyano-2'-fluoro-4-(trifluoromethoxy) (Biphenyl_3_yl)methyl}amino)-3-phenyl succinyl 17-decreasing acid tert-butyl ester using (3R,4S)-4-amino-3-phenyl brigade. The title compound was obtained by the reaction and purification as described in Example 7, and the title compound was obtained by the method described in Example 7. MSCESI+): 570CM+H) Example 94 2-Fluoro-3'-({[(3R,4S)-3-phenylbend π-1,4-yl]amino}indenyl)-4, one (three) Fluoromethoxy)biphenyl-4-carbonitrile dihydrochloride The compound obtained in Example 93 was used, and the title compound was obtained by the reaction and purification as described in Example 4. MSCESI+): 470CM-2HC1+H) Example 95 2-Fluoro-3'-({[(3R,4S)-3-phenyl)-4-yl]amino}indenyl)-4, one (1) Trifluoromethoxy)biphenyl-4-carbonitrile bis(trifluoroacetate) A solution of the compound (4. lg) obtained in Example 93 in TFA (10 mL). The reaction solution was concentrated under reduced pressure to give the title compound. MSCESI+) : 470CM-2TFA+H) Example 9 6 3 -[({(3R,4S) -1-[(5,5-dimercapto-2,4-diindolyl-1,3-) σ 坐 σ -3- -3- ) 基 基 基 -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- - - - - - - - - - - - - - - - - - - 4-carbonitrile The compound obtained in Example 94 (325 mg), Et3N (182 mg), and (5, 5-dimercapto-2, 4-dione-1,3-pyridin-3-yl)acetic acid ( 168 mg) 318921 154 200808724 In a solution of DMF (6 mL), WSC· HCl (173 mg) and HOBt·H2 〇 (138 mg) were added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and evaporated The residue was purified by EtOAc EtOAc (EtOAc) elute Elemental analysis: C33H3 〇F4N4〇5· 〇.31^〇 Measured value C, 61. 63 ; Η, 80 ; N, 72 Calculated value C, 61 · 54 ; H, 4 · 79 ; N, 8. 70 MS ( ESI + ) ·· 639 (M+H) Example 97 3' - [({(3R,4S)-:l-[(5,5-Dimethyl-2, 4-dione-l-l,3 —oxazolidin-3-yl)ethinyl]-3-phenylpiperidine-4-yl}amino)methyl]-2-fluoro- 4'-(trifluoromethoxy)biphenyl-4 -Methyl carbonitrile monohydrochloride The compound obtained in Example 96 (78 mg) was obtained eluted with EtOAc (EtOAc)

Melting point: 1 98-200 ° C Elemental analysis · · C33H31CIF4N4O5 · O.5H2O Measured value C, 58 · 02 ; H, 4 · 58 ; N, 8. 16 Calculated value C, 57 · 94 ; H, 4 · 71 ; N,8. 19 MS(ESI+): 639 (M-HC1+H) Example 9 8 318921 155 200808724 3-{[((3R,4S)-1-{[(4S)-2, 5-dione Imidazolidin-4-yl]ethenyl}-3-phenylpiperidin-4-yl)amino]pyridyl 2-fluoro-4, -(trifluorodecyloxy)biphenyl-4-methyl The nitrile was subjected to the compound obtained in Example 94 and [(4S)-2, 5-one-keto-π-sodium sulphate synthesized by a known method (Journal of the American Chemical Society (1 947) ^ 69 ^ (1382)). -4 -yl]acetic acid, the title compound was obtained by EtOAc m. 2,5-Diketopylimidazolidinyl-1-yl)ethinyl]-3-phenylpiperidin-4-yl}amino)indolyl]-2-fluoroin-4, mono(trifluoromethoxy) Biphenyl-4-phthalonitrile The compound obtained in Example 94 was used and known by the method (Journal of the Chemical Society, Perkin Transactions 1 · Organic and Bio-〇rganic Chemistry (1972-1999) ( 1 988), (12), 3175-82) Synthesis of (2,5-dioneimidazolidinyl-i-yl)acetic acid, the title compound was obtained by reaction and purification as described in Example 79. MSCESI+): 610 (M+H) Example 100 2-Fluoro-3 -({[(3R,4S)-1-ethanolindolino-3-phenylu-n- s--4-yl]amino} A (4) _(trifluorodecyloxy)biphenyl-4-oxancarbonitrile Compound obtained in Example 94 (325 mg), Et3N (1, 82 mg), and hexanes 318921 156 200808724 acid (92 mg) in DMF (6 mL) To the solution, WSC · HCi (173 mg) and HOBt · H 2 (138 mg) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried and evaporated. The residue was purified by EtOAc (EtOAc) elute

Melting point: 132-134 ° C Elemental analysis · C28H25F4N3O3 calcd. C, 63·72; Η, 4·84; N, 7.84 Calculated C, 63.75; H, 4.78; N, 7.97 MS (ESI) + ) : 528CM+H) Example 101 3 -[({(3R,4S)-1-[(1-Ethylpiperidin-4-yl)carbonyl]- 3-phenylpiperazin-4-yl Amino)methyl]- 2-fluoro-4'-(trifluorodecyloxy)biphenyl-4-ylcarbonitrile The compound obtained in Example 94 (325 mg), Et3N (182 mg), and ethyipiperidine To a solution of -4-carboxylic acid (154 mg) in EtOAc (EtOAc)EtOAc. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Elemental analysis: C34H34F4N4O3· 〇·2Η2〇157 318921 200808724 Measured value C, 65· 29 ; Η, 5· 70 ; Ν, 8· 54 Calculated value C, 65· 21 ; Η, 5· 54 ; Ν, 8. 95 MS (ESH): 623 CM+H) Example 102 3'-[({(3R,4S)-l-[(2,6-diketopiperidin-4-yl)carbonyl]-3-phenyl Phenyridin-4-yl}amino)methyl]-2-fluoro-4, -(trifluoromethoxy)biphenyl- 4-carbonitrile. Compound obtained in Example 94 (325 mg), El: 3N (182 mg And a solution of 2,6-diketopiperidine-4-carboxylic acid (141 mg) in DMF (6 mL), EtOAc (EtOAc) hour. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine and dried and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Elemental analysis: C32H28F4N4O4 found C, 62·78; H, 4. 94; N, &amp; 92 Calculated C, 63·15; H, 4.64; N, 9. 21 MS (ESI+): 609CM+H Example 103 3 -[({(3R,4S)-1-[(2,4-dione-i,3-oxazolidin-3-yl)ethenyl]-3phenylpiperidine- The compound obtained in Example 94 and (2, 4-diketone-oxime) were used in the 4-amino}amino)methyl]-2-fluoro-4,-(trifluorodecyloxy)biphenyl-4-indolecarbonitrile. , 3_噚318921 158 200808724, oxazin-3-yl)acetic acid, the title compound was obtained by reaction and purification as described in Example 79. MSCESI+): 611CM+H) Example 104 2-[(3R,4S)-4-({[4,-Cyano-2,-fluoro+tris-methoxy]biphenyl-3-yl}methyl) Amino]-3-phenylpiperidine-i-yl]_2-ketoacetamide The compound obtained in Example 94 (38 mg), Et3N (213 mg), and physic acid (94 mg) in DMF (6niL) To the solution, wsc·HC1 (2〇1 mg) and HOBt·H20 (161 mg) were added, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and evaporated and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc: Melting point: 142-144t Elemental analysis····················· 37 MS(ESI + ): 54KM+H) Example 105 2-[(3R,4S)-4-({[4'-Cyano-2'-fluoro-4-(trifluoromethoxy)) Phen-3-yl]methyl}amino)- 3-phenylpiperidin-1-yl]H~dimethyl-2-oxanylethane with amine The compound obtained in Example 94 and N,N~2 Methylglycine-title compound was obtained by purification as described in Example 79 and purification by 318921 159 200808724. MSCESI+): 569CM+H) Example 106 3[({(3R,4S)-1-[(2, 4-dione-3,4-dihydro-n-butyl) ethinyl]-3benzene The compound obtained in Example 94 and (2, 4-di) were used as the base compound of the formula: 4-amino}amino)methyl]-2-fluoro- 4-(tris-methoxy)biphenyl-4-carbonitrile. The keto-3,4-dihydro-2H-pyrimidin-1-yl)acetic acid, title compound was obtained by the reaction and purification as described in Example 79. MS (ESH): 622 (M+H): s. 5-diketopylimidin-1-yl)ethinyl]piperidine-4-yl}amino)indenyl]-4, mono(trifluorodecyloxy)biphenyl-4-carbonitrile-hydrochloric acid Salt (Step 1) 60% NaH (1·68 g) was added to a solution of 1,5,5-trimethylhydantoin (4·98 g) in DMF (30 mL) at 0 ° C, and the mixture was stirred for 30 min. . A solution of benzyl bromoacetate (8·Og) in DMF (10 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours. The reaction mixture was poured into water and the product was taken up in ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) A mixture of the obtained oil (7.3 g), 1% by weight of saturated carbon (%) and ethanol (130 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere (〇·1 MPa) at 318921 160 200808724. The catalyst was removed and the filtrate was concentrated under reduced pressure to give (3,4&apos;&lt;~&gt;&gt; Melting point: 130-132 ° C (Step 2) Using the compound obtained in Example 94 and the compound obtained in the step, the reaction and purification were carried out as described in Example 79. The obtained product was treated with 1 equivalent of hydrogen chloride / ethyl acetate to afford titled. MS (ESH): 652 (M-HC1+H) Example 108 2 solitude ({[4'-cyano-2, prepared 4_(trifluoromethoxy)biphenylmethyl-2-]] Indoleamine monohydrochloride The title compound MSCESI+ was obtained by the procedure described in Example 79 using the compound obtained in Example 94 and the succinic acid mono succinic amine. The reaction and purification were carried out in the same manner as described in Example 79. : 555(M-HC1+H) Example 109 1 [({(31^)-1-[(2,6-dione-yl). Amino)methyl]_2_fluoro_4'-(tricarbonitrile-hydrochloride 4, the compound obtained in Example 94 and (2,6-n-bito-yl)acetic acid, reacted and purified as the obtained product The title compound is obtained by the following method: i. The title compound is obtained by the following procedure: 318921 161 200808724 2-Fluoro-3 - ({[( 3R,4S)-3-phenylpiperidin-4-yl]amino}methyl)-4-(difluorodecyloxy)biphenyl-4-onecarbonitrile dihydrochloride (332mg), (2, 6 Diketopiperidin-1-yl)acetic acid (128 mg), WSC·HCl (144 mg), HOBt·M) (115 mg), triethylamine (152 mg) Mixture of DMF (6mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over magnesium sulfate, and then evaporated. The residue obtained was purified by column chromatography (solvent gradient: 50 to 100% ethyl acetate /hexane). The obtained product was treated with hydrogen chloride / ethyl acetate. The obtained residue was crystalljjjjjjjjjj ,

Melting point·· 223°C Elemental analysis······································· (ESH): 623 (M~HC1+H) Example 110 (3R,4S)-4-[4'-Cyano-2'-fluoro-4-(trifluorodecyloxy)-linked stupid~3-one · fluorenyl}amino)-N-methyl-3-phenyl π-decyl- 1 -decylamine - The compound obtained in Example 94 and methyl isocyanate were used to characterize the character by way of example 83 The method described was carried out by reaction and purification, and π&quot; MS (ESI + ): 52KM+H) was transmitted only. Example 111 3' - [U(3R,4S)-Bu [(4,4-Dimethyl- 2, 5-dioneimidazole # 疋i-yl: 318921 162 200808724 Ethyl]-3-benzene The use of the compound obtained in Example 94 and (4) of piperidine-4-yl}amino)methyl]_2-fluoro-tetrazide, mono(trifluoromethoxy)-benben-4-pyrano-hydrochloride , 4-Dimercapto-2, 5-dioneimidazolidinyl-1-yl)acetic acid, reaction and purification were carried out as described in Example 79. The obtained product was treated with EtOAc (EtOAc/EtOAc) 'MS(ESI+): 638CM-HC1+H) Example 112 2-fluoro-3 -[({(3R,4S)-1-[(3-keto-2-azaspiro[4·5]癸) —2-yl) ethinyl]-3-phenylpiperidin-4-yl}amino)indolyl]-4-(trifluoromethoxy)biphenyl-4-indanonitrile monohydrochloride (step 1) using 2-azaspiro[4.5.nonan-3-one, (3-keto-2-noxa[4.5]indol-2-yl)acetic acid as described in Example 1 The method is carried out by reaction and purification, step 1. Melting point: 122-124 ° C (Step 2) The compound obtained in Example 94 and the compound obtained in the step , were reacted and purified as described in Example 79. The resulting product was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. MSCESI + ) : 663 (M-HC1+H) Example 113 3' - [({(3R,4S)-l-[(2, 4-Dimercapto-1,3-diazaspiro[4] · 壬-3-yl)ethyl aryl]-3 phenylpiperidin-4-yl}amino)methyl] one gas a 4, 318921 163 200808724 (difluoromethoxy)biphenyl-4-carbonitrile The hydrochloride salt was obtained using the compound obtained in Example 94 and (2,4-diketo-j,3-diazaspiro[4. 4]indol-3-yl)acetic acid, and reacted and purified as described in Example 79. The method is carried out. The product obtained was treated with 1N hydrogen chloride / ethyl acetate. MSCESI+): 664CM-HC1+H) Example 114 (3R,4S)-4-[4'-chloro-4-(trifluoromethoxy)biphenyl-3-yl]methylindenyl)-3 -Phenyl brigade. The compound obtained by the reference example 31 was used as the title compound in the same manner as in the tert-butyl decanoic acid tert-butyl ester (3R,4S)-4-amino-3-phenylpiperidine-hydrazine-carboxylic acid tert-butyl ester. The method described in Example 7 was carried out by carrying out the reaction and purification. MSCESI + ) : 56KM+H) Example 115 (3R,4S)-N-{[4'-chloro-4-(trifluoromethoxy)biphenyl-3-yl]indenyl}-3-phenyl A solution of the compound (2.g.) obtained from m.p. The reaction solution was concentrated under reduced pressure and the residue was dissolved in EtOAc EtOAc. The organic layer was washed with brine, dried and evaporated and evaporated. The residue was taken up in EtOAc (EtOAc m. MS (ESI + ) ·· 461 (M-2HC1+H) Example 116 3-{2-[(3R,4S)-4-({[4'-chloro-4-(trifluoromethoxy)) Benzene-3-yl] 318921 164 200808724 methyl}amino)-3-phenylpiperidine-1-yl]-2-oxoethylethyl 5,5-dimethyl-1,3-Dcarbazole The compound obtained in Example 115 (267 mg), E: t3N (152 mg) and (5, 5-dimethyl-2, 4-dione-1,3- To a solution of oxazolidine-3-yl)acetic acid (14 mg) in DMF (6 mL), EtOAc (EtOAc) The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, and evaporated. The residue obtained was purified by hydrazine column chromatography (solvent gradient: EtOAc - EtOAc). The product obtained was treated with 1 equivalent of hydrogen chloride / ethyl acetate to give the title compound. MS (ESI+) · 630 (M-HC1+H) Example 1 Π 4-{[(3R,4S)-4-({[4,-chloro-4(trifluorodecyloxy)biphenyl-3) The compound obtained in Example 115 and the 2,6-dione group were used as the amino group]-3-aminopiperidin-1-yl]carbonylpiperidinyl-2,6-dione monohydrochloride. Piperidine-4-carboxylic acid, reaction and purification were carried out as described in Example 79. The product obtained was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. That is, the title compound was obtained by the following procedure. (3R,4S) - N-{[4'-chloro-4-(trifluoromethoxy)biphenyl-3-yl]indenyl}-3phenylpiperidin-4-aminodihydrochloride ( a mixture of 267 mg), 2,6-diketopiperidine-4-carboxylic acid (118 mg), WSC · HCl (144 mg), HOBt · H2 (l15 mg), diethylamine (152 mg) and DMF (6 mL) Spoiled for 14 hours at room temperature. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was dried over magnesium sulfate with a saturated aqueous solution of 318. The obtained residue was purified by chromatography on silica gel column chromatography (solvent gradient: 20 to 50% ethyl acetate / hexane) to give an amorphous solid of {[(3R, 4S)-4-({[4, - 4-(tris-f-oxy) phenyl-3-yl]methyl}amino)-3-phenylpiperidine-fluorenyl]carbonyl}piperidine-2,6-dione. The resulting amorphous solid was treated with 4N hydrogen chloride / ethyl acetate (3 mL) and the mixture was concentrated under reduced. The obtained residue was crystallized from crystal crystal crystal crystal crystal crystal

Melting point: 153 ° C

Elemental analysis · · CnHsoChF—Or O.5H2O Measured value C, 57.75 ; H,4· 92 ; N,6· 50 Calculated value C,57· 68 ; H,4· 84 ; N,6· 51 MSCESI+) : 600CM-HC1+H) Example 118 (3R,4S)-1-[(1-Ethylpiperidine-4-yl)carbonyl]-N-{[4,-chloro-4-yl (trifluoroindole) Oxy)biphenyl-3-yl]methylpyrimidin-3-phenylpiperidine-4-amine monohydrochloride The compound obtained in Example 115 and 1-ethylhydrazinium-4-one acid were reacted. Purification was carried out as described in Example 79. The obtained product was obtained as a title compound. MSCESI+): 614CM-HC1+H) Example 119 (3R,4S)-4-({[2'-chloro-4'-cyano-4-(trifluorodecyloxy)biphenyl-3-yl]曱基}Amino)- 3 -Phenylpyrazine-1 -Resinic acid tert-butyl ester 318921 166 200808724 ▲Use (3R,4S)-4-amino-3-phenyl(tetra)+acid acid third vinegar And the compound obtained in Example 35, the title compound was obtained by the reaction and purification as described in Example 7. MSCESI + ) : 586CM+H) Example 120 2-Chloro-3-({[(3R,4S)-3-phenylpiperidin-4-yl]amino}methyl)-4, one (two) Fluoromethoxy)biphenyl-4-carbonitrile dihydrochloride The compound obtained in Example 119 was used, and the title compound was obtained by reaction and purification as described in the only example 115. MS (ESH): 486CM-2HC1+H) Example 121 2-chloro-3'-[({(3R,4S)-1-[(5,5-didecyl-2, 4-dione-) 1,3-indolizin-3-yl)ethinyl]-3-phenylnidyl-4-yl}amino)indolyl]-4,-trifluoromethoxy)biphenyl-4-indrene The monohydrochloride salt was obtained using the compound obtained in Example 120 and (5,5-dimercapto-2,4-dione-1,3-1,3-oxazolidin-3-yl)acetic acid, and reacted and purified as in Example 79. The method described is carried out. The product obtained was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. MS (ESI+): 655CM-HC1+H) </RTI> </RTI> <RTIgt; </RTI> 2-chloro-3'-[({(3R,4S)-1-[(2,6-dionepiperidin-4-yl)carbonyl] 3-phenylpiperidin-4-yl}amino)indolyl]- 4, mono(trifluorodecyloxy)biphenyl-4-phthalonitrile monohydrochloride using the compound obtained in Example 110 2,6 - dioxin base. Qualification - 4 - 167 318921 200808724 Carboxylic acid, reaction and purification The product described in Example 79 was treated with 1 equivalent of hydrogen chloride / ethyl acetate to give the title product (ESI + ) ·· 625 ( M-HC1+H) ° ° Example 123 3'-[({(3R,4S)-1-[(1-Ethyl)pyridin-4-yl) 赛美]3 # 唆-4- The compound obtained in Example 120 and the compound obtained by the use of Example 120 and the ethylidene D-Chen-4 were used as the amine. The acid, reaction and purification were carried out as described in Example 79. The obtained product was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. , MS (ESI+): 639 (M-HC1+H) Example 124 (3R,4S)-4-({[2,,4,-dichloro-4-(trifluoromethoxy)biphenyl) (3R,4S)-4-amino-3-phenylpiperidine]-carboxylic acid, third, 3-yl]methyl}amino)-3-phenyl dentate-1-carboxylic acid tert-butyl ester The butyl ester and the compound 'reference compound obtained in Reference Example 33 were obtained by the reaction and purification as described in Example 7. MSCESI+): 595CM+H) Example 125 4~(Trifluoromethoxy)biphenyl-3-yl]methyl(3R,4S)-N - {[2,,4,-dichloro-ylbu 3- The phenylpiperidin-4-amine dihydrochloride salt was obtained using the compound obtained in Example 124. The title compound was obtained by the reaction as described in Example 115 and pure &amp; MS (ESI+) * 495 (M~2HC1 + H) 318921 168 200808724 Example 126 3 - {2-[(3R,4S)-4-({[2',4'-dichloro-4-(trifluoro) Methoxy)biphenyl-3-yl]methyl}amino)-3-phenylpiperidine-; ι-yl]-2-ketoethyl}-5, 5-dimethyl-1,3 - oxazolidine-2,4-dione monohydrochloride using the compound obtained in Example 125 and (5, 5-dimethyl-2,4-diindenyl-1,3-oxazolidine-3 -Acetylacetic acid, reaction and purification were carried out as described in Example 79. The product obtained was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. MS (ESH): 664CM-HC1+H) Example 127 4-{[(3R,4S)-4-({[2',4'-dichloro-4-(trifluoromethoxy)biphenyl) 3 —yl]methyl}amino)_3 -benyl-denyl-1-yl]-based 丨 ^ — -2 6 - _ _ _ the same hydrochloride using the compound obtained in Example 125 and 2, 6- The keto group, 4-carboxylic acid, was reacted and purified as described in Example 79. The product obtained was treated with 1N hydrogen chloride / ethyl acetate to give the title compound. MS (ESI+): 634 (M-HC1+H) Example 12 δ (3R,4S)-1-[(1-Ethyl acetylidene-4-yl)-yl]- ν- {[2,4, - - = -4-(trifluoromethoxy)biphenyl-3-yl]indolyl}-3-phenylpiperidine-4-monoamine 1 hydrochloride The compound obtained in Example 1.25 and 丨~B The hydrazine- 4-acid-acid reaction and purification were carried out as described in Example 79. The product obtained was treated with 1 gasification of nitrogen/acetic acid ethyl acetate to give the title compound < 318921 169 200808724 MS (ESH): 648CM-HCHH) Example 129 (3R, 4S)-4-({[4' -Chloro-2'-fluoro-4-(tridecyloxy)biphenyl-3-yl]methyl}amino)-3-phenyl brigade-1-decanoic acid tributyl hydrazine (3R, 4S The compound of the title compound was obtained by the method described in Example 7 and deuterated by the method described in Example 7. MS (ESH): 579 MH+H) (m.) </RTI> (3,,,,,,,,,,,, The title compound was obtained by the reaction and purification as described in Example 115. MS (ESH): 479CM-2HC1+H) Example 131 3-{2-[(3R,4S)-4-(U4,-chloro-2, _fluoro_4_(trifluoromethoxy)biphenyl- 3-yl]methyl}amino)-3-phenyl(tetra)+yl]_2-ketoethylhydrazine-5, 5-dimethyl-1,3-oxazolidine-2,4-dione The hydrochloride salt was obtained using the compound obtained in Example I30 and (5, 5-dimethyl-2,4-dioneyl1,3-1,3-oxazolidine-3-yl)acetic acid, and reacted and purified as in Example 79. The trick is to proceed. The obtained product was treated with EtOAc (EtOAc m. MSCESI + ) : 648CM-HC1+H) Example 132 318921 170 200808724 4-{[(3R,4S)-4-({[4'-Chloro-2'-fluoro-4-(trifluoromethoxy)) Biphenyl-3~yl]methyl}amino)-3-phenylindan-1-yl]yl}Nippon Bite-2,6-dione monohydrochloride Compound obtained in Example 130 (276 mg) , Et3N (152mg) and 2,6-diketopiperidine-4-carboxylic acid (118mg) in DMF (6mL), WSC · HC1 (144mg) and HOBt · H20 (115mg), mixture room temperature Stir for 14 hours. The reaction mixture was poured into water and the product was extracted ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried and evaporated. The resulting residue was purified by hydrazine column chromatography. (solvent gradient, 50-100% ethyl acetate / hexane). The product obtained was treated with 1 equivalent of nitrochloride / acetic acid to give the title compound. Melting point: 162-164°c Elemental analysis·· C31H29CI2F4N3O4·1·3Ή2〇 Measured value C, 54· 93 ; Η, 4· 85 ; Ν, 5· 92 计 值 C, 54·92·, Η, 4.70; Ν, 6.20 MS (ESI+): 6i8 (M-HCl+H) Example 133 2-[(3R,4S)-4-({[4' - gas-2'-fluoro-4-(trifluoroanthracene) The compound obtained in Example 130 and glycolic acid were used as the title compound in the same manner as in Example 79. The method described is obtained by reaction and purification. MSCESI+): 537CM+H) ^ Example 134 (3R,4S)-1-[(i-p- yl-piperidine-4-yl)carbonyl]-N-{[4,-gas- 318921 171 200808724 fluoro-4 The compound obtained in Example 130 and the ethyl hydrazide piperidine _4 were used as a compound of the compound obtained in Example 130: tris(methoxy)biphenyl-3-yl]methyl-3-phenylpiperidin-4-amine-monohydrochloride The carboxylic acid, reaction and purification were carried out as described in Example 79. The obtained product was treated with 1N hydrogen chloride / ethyl acetate to afford the title compound. MS (ESH): 632CM-HC1+H) Example 135 (3R,4S)-4-({[4'-Cyano-4-(trifluoromethoxy)biphenyl-l-yl]-yl)}amine (3), phenyl-branched bite-l-rebel acid butyl vinegar (3R, 4S)-4-amino-3-phenylpyrazine-1-butyric acid tert-butyl ester and reference example 8狻The obtained compound, the title compound was obtained by the reaction and purification as described in Example 7. MSCESI+): 552CM+H) Example 136 3'-({[(3R,4S)-3-phenylpiperidin-4-yl]amino}indolyl)-4, mono(trifluoromethoxy) Biphenyl-4-phthalonitrile dihydrochloride The compound obtained in Example 135 was used, and the title compound was obtained by reaction and purification as described in Example 115. MS (ESI+): 452 (m. 3-oxazolidin-3-yl)ethinyl]-3-phenylpiperidin-4-yl}amino)indenyl]-4,-(trifluorodecyloxy)biphenyl-4-indole The compound obtained by the nitrile monohydrochloride salt of Example 136 (262 mg), Et3N (152 mg), and 318921 172 200808724 (5, 5-dimethyl-2, 4-dione-i, 3-oxazolidine-3) A solution of acetic acid (womg) in DMF (6 mL) was added wsc················· The reaction mixture was poured into water. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine and evaporated. The residue obtained was purified by hydrazine column chromatography (solvent gradient: EtOAc - EtOAc). The product obtained was treated with 1N hydrogen chloride / ethyl acetate to give the title compound.

Melting point: 197-199 ° C

Elemental analysis: C33H32ClF3N4〇5 · 〇· 5H2O Measured C, 59.78; H, 4.85; N, 8.42 Calculated C, 59.50; H, 4.99; N, 8.41 MS (ESI+): 620 (M~HC1+H) The compounds described in Examples 4 to 13 7 are as follows (Table 8 14) 〇 318921 173 200808724 Table 8 R2

174 318921 200808724 Table R2

Example No. Ar z ) Additive MS (ESI) 60 XX (3«, 4S) X) ch2 ch3〇q^ ^CN 511 (M+H)+ 61 XX (3R4S) Xs ch2 Η0χχα ; N 483 (Μ+ ΗΓ 62 XX (3R.4S) Ό ch2 CH3〇y^j 511 (M+H)+ 63 0 〇::: (3R.4S) Ό C(CH3)H (1:1 non-image mixture) y *CN 511 (M+Hf 64 .〇::: (3R.4S) j〇CH3CV, C(CH3)H Everyone (shorter residence time) y CN 511 (M+H)+ 65 XX (3R. 4S) X) CH3〇s^s?Nj c(ch3)h (longer residence time) u CN 511 (M+H)+ 66 cH^¥ry XX (3R,4S) X) 0Hz 4 509 (M+ Hf 67 XX (3R,4S) X) CH2 ^CN Hydrochloric acid 585 + (M-HCI+H broad 68 ch/^Y (3«,4S) Ό CHz ^3°3⁄4 CN 559 (M+H)+ 69 XX X) CHz CF^( ZH 565 (M+Hf 70 0 CH3A¥TV XX (3Rt4S) X) ch2 Z\ 578 (Μ+ΗΓ 71 CH人Ύ XX (3RAS) Ό CH2 ^3 594 (_)+ 72 XX (3R,4S) Xi Cht CFsCV^ 580 (M+H)+ 175 318921 200808724 Table ίο

R1 Example No. R1 4 Ar z Additive MS (ESI) 73 XX: (3R4S) Force 544 (M+H 疒74 0 Aα: (3R.4S) X) ch2 594 (M+H)+ 75 XX ( 3) ) : : : : : : : : : : : (3R.4S) .乂) ch2 .3⁄4 578 (Wl+H)+ 78 ch3A^ XX (3R.4S) X) OHz gas 533 (M+H)+ 79 .〇::: (3/=?, 4S) j〇CHj CH3〇^ 498 (M+H)+ 80 H0T one (3R,4S) X) CHa CH30-produced 456 (M+H)+ 81 h2n person^ (3R4S) X) ch2 497 (_疒82 Η3〇γ^· 'Ο::: (3R.4S) X) ch2 hydrochloric acid 440 (M-HCI+H)* 83 h3c\ .oc (3R,4S) X) ch2 CH3〇Nj{^ 476 (_ ♦ B4 XX (3R4S) JO ch2 CH3〇y^ Hydrochloric acid 619 (M-HCI+ΗΓ 85 ( -Ο·*,, (3R.4S) X) ch2 'N Hydrochloric acid 634 (M-HCI+H)+ 176 318921 200808724 Table 11 R2 Example y No. 4 AT z &quot;°B0 Additive f MS (ESI) 86 Ο One 〇:: (3R4S) X) CH2 CH30 丫, ON 580 (M+H)+ 87 XX (3R .4S) X) ch2 CH3〇Y^j| ZH Hydrochloric acid 618 (M-HCI+H, 86 plus one Ο: (3R.4S) X) ch2 557 (M+H)+ 89 h3c^d^ 〆〇: (3R.4S) XrF CHa :N 516 (M+H 广90 H 〆〇:: (3R,4S) OrF CHj CH3〇vvs\ ; 2 hydrochloric acid 416 (Μ-2ΗΟΙ+ΗΓ 91 XX (3R.4S) XrF CHj CH%A :N 515 (M+ H)+ 92 H3C and N〇vo 〆〇:: (3R,4S) ;〇rF ch2 CH3cy^ :N 559 (M+H}+ 93 H9C^J〇^ h^X (3H.4S) X) ch2 CF^ ;N 570 (M+Hf 94 H 〆〇:: (択,4S) /0 ch2 :N 2 hydrochloric acid 470 (M-2HCI+H)4 95 H XX: (3R,4S) Force ch2 :N 2TFA 470 (M-2TFA+H)+ 96 XX X) ch2 rH 639 (M+H)+ 97 XX: (3R,4S) j〇CHj CF^ JN hydrochloric acid 639 (M-HCH-Hf 98 XX (3R4S) X ) ch2 : N 610 (M+H)+ 177 318921 200808724 Table 12

Example No. R1 Ar z R2-] I Additive MS (ESI) 99 XX: (3R-4S) Ό ch2 CFsO^ CN 610 (M+Hf 100 π〇γ XX: (3R4S) X) ch2 CFaOj CN 528 ( M+Hf 101 XX: (3«,4S) X) CHjs CFsOs^ 3Ν 623 (M+Hf 102 〇Ar 0 XX: (3R,4S&gt; Force ch2 CFaO^ 609 (Μ+ΗΓ 103 XX: (3R.4S X) ch2 :Ν 611 (Μ+ΗΓ 104 Η2Ν^ν .〇: (3Rf4S) X) ch2 CF3〇v^ :Ν 541 (Μ+Η 广105 Η3(λΝ人]^ ch3o P ruler, 4S&gt; X CH2 CF3〇^ 589 (Μ+Η 疒106 0 .〇:: (3R.4S) X) CHjj cf3o^ ίΑ :Ν 622 (Μ+Η)+ 107 XX force ch2 Ια :Ν hydrochloric acid 652 (M-HCi +H)+ 108 ★ XX (3R.4S) X) CHz CFs〇X :Ν Hydrochloric acid 556 (M-HCI+H)* 109 XX (3R4S) JO ch2 :Ν Hydrochloric acid 623 (M-HCI+ΗΓ 110 h3cnV XX (3R4S) X) ch2 CF3〇Vj^ ίχχ :Ν 527 (Μ+Η)+ 111 I (3R4S) j〇ch2 cf:3^C ίΑ :Ν hydrochloric acid 638 (M-HCI+H)+ 178 318921 200808724 13

179 318921 200808724

R2

180 318921 200808724 Example 138 3'-[({(3148)-1-[(2,6-diketopiperidinyl-1-yl)ethenyl]-3-phenylpiperidin-4-yl} Amino)methyl]-2-fluoro-4,-(trifluoromethoxy)biphenyl-4-indenecarbonitrile-maleate saturated aqueous sodium hydrogencarbonate solution was added to the compound obtained in Example 丨〇9 (0·35g). The resulting mixture was extracted with ethyl acetate. The extract is dried from anhydrous sulphur sulphur and dried under reduced pressure to give a colorless solid 3, one [[(3r,4s) -1-[(2,6-dione-piperidin-1-) Ethylamino)-3-phenylpiperidine-4-yl}amino)methyl]-2-fluoro-4'-(trifluorodecyloxy)biphenyl-4-carbonitrile. The obtained colorless solid (0.05 g) was dissolved in ethanol (2 mL) and acetone (4 mL), and then succinic acid (0. 0 095 g) was added. The resulting mixture was stirred at room temperature for 14 hours. A mixture of hexane and diisopropyl ether was added and the solid which was precipitated was collected by chromatography to give the title compound (q. MS (ESI + ) : 623 (M-116+H) Elemental Analysis·································· 4·64; N,7·58 Example 139 3'-[({(3R,4S)-1-[(2,6-diketopiperidin-1-yl)ethinyl]-3-benzene 3'-[[B]-based 4-amino}amino)methyl]-2-fluoro-4'-(tris-methoxy)biphenyl- 4-carbonitrile-fumarate salt as a colorless solid ({(3R,4S)-1-[(2,6-diketopipridin-1-yl)ethenyl]-3-phenylpyrylene-4-yl}amino)methyl]-2 -Fluoro-4,-(trifluoromethoxy)biphenyl-4-indene nitrile (〇·〇5g) is dissolved in ethanol (2mL) and acetone (3mL), then fumaric acid is added (〇·〇 〇95g). The resulting mixture was 181 31892] 200808724 and stirred at room temperature for 14 hours. The title compound (〇·〇 52g) was obtained as a white powder. MSCESI+) : 623CM-116+H) Elemental analysis: C37H34N4 〇8F4 calc. C, 59·74; H, 4. 57; N, 7.26 Calculated C, 60·16 ; H,4· 64 ; 7. 58 Example 140 4' - {[(3R,4S)-4-({[4'-chloro-4-(trifluoromethoxy)biphenyl-3-yl]methyl}amino)- 3-phenylpiperidin-1-yl]carbonyl}piperidine-2,6-dione monohydrate (3R,4S)-N-{[4'-chloro-4-(trifluorodecyloxy) linkage Benzyl-3-yl]methyl}-3-phenylpiperidin-4-aminodihydrochloride (9.8 g), 2,6-diketopiperidine-4-carboxylic acid (5·Og) A mixture of WSC, HC1 (6· lg), HOBt · H 2 〇 (4.9 g), triethylamine (6.4 g) and DMF (200 mL) was stirred at room temperature for η hr. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium carbonate and brine and dried over magnesium sulfate. The residue obtained was purified by hydrazine column chromatography (solvent gradient; 20-50% ethyl acetate / hexane) to give the amorphous solid 4-{[(3R,4S)-4-({[4' - Chloro-4-(trifluorodecyloxy)biphenyl-3-yl]methyl}amino)-3-phenylpiperidin-1-yl]carbonyl}piperidine-2,6-dione (11.5 g ). The obtained amorphous solid (8 g) was dissolved in ethanol (6 liters), and water (15 mL) was added. The resulting mixture was stirred at room temperature for 14 hours until crystallization occurred. The crystals were collected by filtration, washed with water and dried to afford white crystals crystals crystalssssssssssssssssssss

Elemental analysis · · C31H29N3O4CIF3 · H2O Measured value C, 60. 02 ; H, 4. 96 ; N, 6. 72 Calculated value C, 60. 24 ; H, 5 · 06 ; N, 6. 80 Example 141 4' - {[(3R,4S)-4-({[4'-chloro-4-(trifluorodecyloxy)biphenyl-3-yl]methyl}amino)-3 -phenyl brigade 17 - 1 -yl]subunit} π bottom bite-2,6-dione-maleate The compound obtained in Example 140 was dissolved in toluene (丨·5 mL). To the solution was added a solution of 1,4-butyloxane (0.06 g) in 1,4-dioxane. The resulting mixture was stirred at room temperature; then stirred and concentrated under reduced pressure. The residue was treated with toluene to give a crude solid (yel. 36g). The obtained solid ((····························· Elemental analysis: C35H33N3O8CIF3 calcd for C, 58.48; H, 4.51; N, 5.83 Calculated C, 58.70; H, 4.64; N, 5.87 Example 142 4' -{[(3R,4S)-4-[4' - Chloro-4-(trifluoromethoxy)biphenyl-3-yl]indenyl}amino)-3-phenylbendidin-1-yl]carbonyl}piperidine-2,6-dione-reverse The compound obtained in the enedic acid salt of Example 140 was dissolved in toluene (151111 Torr.) a solution of maleic acid (0.66 g) in 1,4-dioxane was added to the solution, and the resulting mixture was stirred at room temperature. The residue was concentrated under reduced pressure. EtOAc EtOAc (EtOAc: Compound: · 16g, yield 57%). Elemental analysis: C35H33N3O8CIF3 Measured C, 58.47; H,4·56; N, 5· 86 Calculated C, 58.70; H, 4. 64 ; N, 5. 87 Example 143 2-Fluoro-3'-({[(3R,4S)-1 -(3-methyl-1,2,4-thiadiazol-5-yl)-3-phenylpiperidin-4 -amino]amino}methyl)-4'-(trifluoromethoxy)biphenyl-4-carbonitrile monohydrochloride at -10 ° C, acetamidine salt A stirred mixture of (21 g) and perchloromethyl mercaptan (37 g) in di-methane (180 mL) was added dropwise aqueous sodium hydroxide (44 g, 6 7 mL) over 1 hour. The mixture was stirred at room temperature 2 After the hour, the filtrate was washed with water, dried over anhydrous magnesium sulfate and then distilled (47 ° C / 10 mmHg) to give 5-chloro-3 decyl-1,2, 4-indole (12 g) as a colorless oil. 2-fluoro-3,-({[(3R,4S)-3-phenylpiperidin-4-yl]amino}methyl)-4'-(trifluoromethoxy) at 〇 °C Add a mixture of biphenyl-4-carbonitrile dihydrochloride (〇·27g) and triethylamine (0.15g) in ethanol (5mL), add 5-chloro-3-methyl-1' 2,4 - sigh Dioxane (〇·〇81 g). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The mixture was washed with EtOAc EtOAc (EtOAc m. [(3R 4S) -1-(3-methyl-1,2,4-thiadiazol-5-yl) 3-Phenylpiperidine-4-yl]amino} 318921 184 200808724 Methyl)-4'-(trifluorodecyloxy)-biphenyl-4-carbonitrile. The obtained compound was treated with 4N hydrogen chloride / ethyl acetate solution and concentrated under reduced pressure. The residue was crystallized from ethanol / diisopropyl ether to give the title compound (yield: 23 g, yield: 75%) 〇 Elemental analysis: C29H26N5OSCIF4 · 0. 5H2 〇 measured value C, 56· 41 ; H, 4· 50 ; N,11· 38 Calculated C, 56.81; H, 4.44; N, 11.42 Example 14 4 [(3R,4S)-4-({[4'-Cyano-2'-fluoro-4-(3) Fluoromethoxy)biphenyl-3-yl]methyl}amino)-3-phenylpiperidin-1yl](keto)acetic acid ethyl ester at 0 C,2-fluoro-3 -({[ 3R,4S)-3-phenyl π-bottom-4-yl]amino}methyl)-4-(difluoromethoxy)biphenyl- 4-carbonitrile dihydrochloride (2. 〇g) And a mixture of triethylamine (0.75 g) in THF (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned water and ethyl acetate. The organic layer was washed with EtOAc EtOAc. The residue was purified by EtOAc EtOAc (EtOAc) elute Elemental analysis································· 145 3'(U(3R'4S) + (3'3-dimercapto-2, butyl aryl)_3_phenylpiperidin-4-yl]aminoindenyl)_2_fluoro_4'_ (trifluoromethoxy)biphenyl + carbonitrile 318921 185 200808724 monohydrochloride 2-fluoro-3'-({[(3R,4S)-3-phenylpiperidin-4-yl]amino} -4'-(Trifluorodecyloxy)biphenyl-4-indenitrile dihydrochloride (〇·27g), 3,3-dimercapto-2-ketobutyrate sodium salt (〇·l 〇g) and triethylamine (〇·i5g) in a mixture of DMF (6 mL), HOBt · Η2〇 (0·12g) and WSC · HC1 (0·14g) were added. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford 3' -({[(3R,4S)-1 -(3,3-didecyl-2-ketobutyl))-3 -Phenylpiperidin-4-yl]amino}methyl)-2-fluoro-4'-(trifluorodecyloxy)biphenyl-4-carbonitrile. The obtained compound was treated with 4N hydrogen chloride / ethyl acetate solution and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether / EtOAc (EtOAc (EtOAc) Elemental analysis · C32H32N3O3CIF4 Measured value C, 61. 89 ; H, 5. 55 ; N, 6. 46 Calculated C, 62. 19 ; H, 5. 22 ; N, 6. 80 Example 146 (3R, 4S )-4-({[ 4' -cyano-2'-fluoro-4-(trifluoromethoxy)biphenyl-3-yl] fluorenyl}amino)-3-phenyl-1,4' - two mouth bite - 1 ' - slow acid third butyl ester 2' -fluoro-3' - ({[(3R,4S)-3-phenylpiperidin-4-yl]amino} fluorenyl) - 4'-(Trifluorodecyloxy)biphenyl- 4-indolonitrile dihydrochloride (0.11 g), l-Boc-piperidone (4·Og) and acetic acid in DMFAHF (1:10, llmL) NaBH(0Ac)3 (2. lg) was added to the mixture. The resulting mixture was stirred at room temperature for 16 186 318921 200808724 hours. The reaction mixture was distributed in water and ethyl acetate. The organic layer was washed sequentially with a pad of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) MS (ESI+): 653 (M+H) Example 147 3 ({[(3R,4S)-1'-ethyl-branyl-3-phenyl-1,4'-linked sigma-4-yl] Amino}methyl)-2-fluoro-4,-(trifluorodecyloxy)biphenyl-4-carbonitrile The compound obtained in Example 146 (〇·88 g) and 4 Ν Ν 氲5小时。 The mixture was stirred at 60 ° C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give 2-[3,3-(3)-({[(3R,4S)-3-phenyl-1,4'-bipiperidin-4-yl]amino} Base) - 4, -(Trifluorodecyloxy)biphenyl-4-indonitrile dihydrochloride (〇·82 g). To a mixture of the amorphous solid ((K33g) and triethylamine (0.20g) in THF (7mL) was added at 〇 ° C, and acetonitrile (〇·〇 47g) was added. The mixture was given at the same temperature. After the mixture was stirred for 2 hours, the reaction mixture was combined with water and ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated. Purification of the title compound (0·23 g ' yield 77%). MS (ESI+): 595 (M+H) Elemental analysis: C33H34N3〇2F4·0.5H2〇 65. 58 ; H, 5 · 84 ; N, 8. 93 Calculated C, 65 · 66 ; H, 5 · 84 ; N, 9. 28 187 318921 200808724 The compounds described in Examples 138 to 147 are below (Table 15). Table 15

Example No. R1 Ar 2 R2HDs Θ Additive MS (ESI) 13B 〆〇:: (3R.4S) X9 ch2 of, CXN Maleic acid 623 (M-116+H)4 138 όςτ XX (3R.4S X) ch2 CF3〇^ Fumarate 623 (Μ-11β+Η)+ 140 XV •XX (3R.4S) X) ch2 Water 600 (Μ+Η)+ 141 ο .〇::: (3R .4S) ch2 CF, maleic acid βοο (Μ-116+ΗΓ 142 A-(3R.4S) 乂) ch2 )ci Fumaric acid 600 (Μ-11β.Η&gt;+ 143 .〇:: : (3R,4S) 乂) C«2 cf30^ XN Hydrochloric acid 568 (M-HCkHf 144 XX JO CH2 cf3o^ ^CN 570 (Μ+Η)+ 145 XX (3R.4S) X) ch2 cf3o^ ^XJN Hydrochloric acid 562 (M-HCI+H^ 146 XX (3R.4S) X) CHi cf3o^ 653 (Μ+ΗΓ 147 HaC^rO^ @R,4S) 乂) CK2 ^CN 595 (Μ+Η 卜 Preparation Example 1 ( 1) Compound 1 of Example 1 Omg (2) Lactose 60 mg (3) Corn starch 35 mg (4) Hydroxypropyl decyl cellulose 3 mg 188 200808724 (5) Magnesium stearate η 2 mg Compound obtained in Example 1 (10ing a mixture of lactose (6 mg) and corn starch (35 mg) using 1% by weight of aqueous hydroxypropyl methylcellulose solution (3 mg of hydroxypropyl methylcellulose) Granulation, followed by 4 〇. Drying under the sputum and sieving. The obtained granules were mixed with magnesium stearate (2 mg) and compressed. Uncoated tablets were obtained as icing sugar, titanium dioxide, talc and gum arabic as a sugar coating. «. Secret coated tablets and smooth surface layer to obtain the final coated tablets. Preparation Example 2 (1) Compound of Example 1 70 mg 50 mg 7 mg 3 mg (2) Lactose (3) Corn powder (4) Soluble starch (5) Magnesium stearate yoke yoke obtained in Example 1 (10 mg) and magnesium stearate (3 Å) granulated with aqueous solution of amylose (7 mL, 7 mg, soluble starch), dried and The sugar (7〇mg) and the corn starch (5〇) are mixed. The mixture is compressed to obtain a tablet. Reference Preparation Example 1

5. Omg 20·Omg to a total volume of 2mL (1) Rof ecoxib (2) Sodium chloride (3) Distilled water (5. Omg) and sodium chloride (2 〇. 〇mg) dissolved in Distilled water and water was added to a total volume of 2 mL. The solution was filtered and filled under sterile conditions to 318921 189 200808724 ampoules (2 mL). The ampoules are sterilized solution. Then break the seal to obtain the reference preparation for injection. Example 2 (1) Cocoa _ (2) Lactose 50 mg (3) Corn starch 34 mg 1 〇·6 mg Γ) ΤΠ nr (4) Corn powder (paste) (5) Magnesium stearate u iug 0. 4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg or more The above (1) to (6) are mixed according to a general method and obtained by tableting. 'Mechanical ingot Preparation Example 3 The formulation prepared in Preparation Example 1 or 2 was combined with the formulation prepared in Reference Preparation Example i or 2. Test Example 1 Radioligand receptor binding inhibitory activity (Receptor for binding inhibitory activity is derived from human mother lymphocyte (IM-9)) Method of M. A. Cascieri et al. [M〇lecuiar Pharmac〇1〇 Gy, Volume 42, page 458 (1 992)] was modified for use. This receptor was prepared from human mother lymphocytes (IM-9). IM-9 cells (2x1 〇5 cells/mL) were cultured for 3 days (1 liter)' and then centrifuged at 500 x G for 5 minutes to obtain cell pellets. The obtained cell pellet was washed once with phosphate buffer (Flow Laboratories, CAT. 28 28-1 03-05), followed by Polytron homogenizer 190 318921 200808724 (Kinematika, Germany) in 30 mL of 50 mM Tris-HC1. Buffer (pH 7.4' contains 120 mM sodium chloride, 5 mM potassium chloride, 2 // g/mL chymase, 40//g/mL bacitracin, 5//g/mL phosphoryl dipeptide ( Phosphoramidon), 〇·5ιηΜphenylsulfonylsulfonium fluoride and lmM ethylenediaminetetraacetate) were homogenized and centrifuged at 40, 000 x G for 2 minutes. The residue was washed twice with 30 mL of the above buffer, followed by cold; the east was stored (-8 〇. 〇) as a sample of the receptor.

The sample was in reaction buffer (5 mM Tris-HCl buffer (pH 7.4), 0.02% bovine serum albumin, phenylmethyl sulfonium fluoride, g/mL chymase, 40// The g/mL bacitracin and 3 mM manganese chloride were suspended to obtain a protein of 0. 5 mg/mL and the 1 q〇# 1 portion of the suspension was used in the reaction. After the sample and BHSP (0·46 KBq) were added, the reaction was carried out in a reaction buffer of 25 ° C '0·2 mL for 30 minutes. The amount of non-specific binding was determined by adding a substance p having a final concentration of 2 x 1 〇 6 m. After the reaction, a cell harvester (290 PHD, Cambridge Technology, Inc., UeS. A) was used, via glass filter paper (GF/B,

Whatman, U.S. )·) was filtered and the filter paper was immersed in 〇·1% polyethyleneimine for 24 hours and allowed to dry. After washing three times with 250 // 1 50 mM Tris-HCl buffer (pH 7.4) containing 〇·02% bovine serum albumin, the residual radioactivity was determined on a filter paper by gamma. The antagonistic activity of the compound obtained in each of the examples was determined by measuring the concentration necessary for 50% inhibition (1C5.) in the above case, and the results are shown in the table (Table 16). 〇191 318921 200808724 Table 16 Example No. IC50 (nM) 10 0.019 11 0.016 15 0.020 16 0.031 17 0.022 18 0.036 21 0.019 22 0.018 23 0.015 24 0.021 25 0.018 32 0.015 33 0.015 35 0.017 36 0.017 41 0.019 42 0.014 43 0.015 , 44 0.015 72 0.023 96 0.021 97 0.023 100 0.015 101 0.024 102 0.013 104 0.019 116 0.058 132 0.140 137 0.042 192 318921 200808724 Radioligand means the substance p labeled [125ι]. From Table 16, it is understood that the compounds of the present invention possess excellent antagonism against the substance P receptor. The present invention is hereby incorporated by reference in its entirety by reference in its entirety in its entirety in the the the the the the the the the the 193 318921

Claims (1)

200808724 X. Patent application scope: 1. A compound of the formula (I) or a salt thereof: Wherein Ar is a phenyl group which may have a substituent, and R1 is a hydrogen atom, a hydrocarbon group optionally having a substituent, a fluorenyl group or a hetero ring optionally having a substituent, and an R 2 -based hydrogen atom, optionally having a substituent - a 6 alkyl group or a C3-6 cycloalkyl group optionally having a substituent, Z is optionally a fluorenylene group having an anthracene-6 group, and the ring A is a piperidine ring further having a substituent, a ring B and a ring. C is a benzene ring further having a substituent as needed, and R2 forms a ring as needed with a substituent adjacent to the B ring, but excludes a compound represented by the following formula: And: 2. The compound of claim 1 is as shown in formula (11): 194 318921 (II) 200808724 R2 The symbol in the formula is as defined in the application. Show: ^ Compound of the first item, which is, for example, the formula (na) γ γ^ύ, \ν,, R1-N\^&gt;Ar The symbols in the formula are as defined in item 1 of the scope of the patent application. A compound according to any one of the claims to the third aspect of the invention, wherein the 'R is a mouse atom or a brewing group. The compound according to any one of the items 1 to 3, wherein R is a hydrogen atom or an alkyl group optionally having a substituent. 6. The compound according to any one of claims 1 to 3, wherein z is a methylene group having a methyl group as needed. 7. The compound of claim 3, wherein Ar is optionally a phenyl group having 1 to 3 halogen atoms; F is a (1) hydrogen atom, and (2) Ci-6 leuko-yl Optionally having 1 or 2 substituents selected from the group consisting of: (i) an amine group, (ii) a Ci-6 alkoxy group, (1^) (^_6 alkyl-monoamino group, (iv) Ci-e alkoxy-arylamino, (ν) (^.6 alkyl 318921 195 200808724 sulphate, (vi) 5- or 6-membered nitrogen-containing heterocyclic group, which has 1 to 5 substituents selected from the group consisting of Ch alkyl and fluorenyl, which together with a cyclopentyl or cyclohexyl group form a spiro ring, (vii) Ci-6^-&amp;oxy , (viii) mercapto and (χ) carbamic acid groups, (3) (^-6 alkoxy-carbonyl, (4) Cl-6 dhamido-yl, (5) C1 - 6 Stuffed base, (6) aminocarbonylcarbonyl, (7) Ci_6-andylamino-monomethyl, (8)--Ci-6 alkylamino-monomethyl, or (9) piperidine- a 4-ylcarbonyl group which optionally has i or 2 groups selected from the group consisting of: (1) optionally having a nitrogen-containing 5- or 6-membered heterocyclic group (the heterocyclic group optionally has 1 or 2) a keto group of Cie alkyl _ carbonyl CiOCh alkoxy-carbonyl, (iii) Ci (; alkyl sulfonyl, alkyl-monoamino-Ch-alkyl group, (v) two Cie alkyl-aminocarboxy group and (vi) ketone group; Ci R system of 1 to 3 halogen atoms (1) fluorene atom or (2) alkyl group if necessary; Z system may have methyl group as needed Ring A is a piperidine ring having no further substituent; : 裒c further has a tooth atom or a Ci6 yard T: a 2,3-dichlorobenzopyrene ring; and % C is a ring, Potted clouds | in ancient base: /, depending on the group of 1 or 2 selected from the following groups 318921 196 200808724 (1) cyano, (2) nitro, (3) halogen atom, (4) A Cl_6 alkyl group having 1 to 3 halogen atoms, (5) (^-6 alkynyl group, (6) a Ch alkoxy group having 1 to 3 halogen atoms, (7) a Ch alkylthio group, (8) (^-6 alkylsulfonyl, (9) di-Cl-6 alkylamino, (10) Cl-6 alkyl-based, (11) Cl-6 alkyl-amine a group, (12) a Ci-6 alkoxy-carbonyl group and (13) an amine fluorenyl group. 8. A compound of the formula (Ila) or a salt thereof: f Wherein Ar is a phenyl group having 1 to 3 halogen atoms as needed; R1 is a (1) fluorene atom, and a group of '6' 6 aryl (2) (^-6 alkyl-carbonyl), if necessary 1 or 2 substituents selected from the group (i) amine group, (ii) Cl-6 alkoxy group, (iii) Ci-carbonylamino group, (iv)-6 alkoxy-carbonylamino group, (v) Ci_ 318921 197 200808724 Sulfhydrylamino, (vi) 5- or 6-membered nitrogen-containing heterocyclic group, replenished! "One selected from the group consisting of substituents: Ci_6 alkyl and:: The heterocyclic group may form a spiro ring together with cyclopentane or cyclohexane as needed, (\^: 666 alkyl-weiloxy, (^)^1)_ at 111 W and (1) anthracenyl, (3) Cl-6 alkoxy-based, (4) Cl-6 alkyl sulfhydryl, (5) aminocarbonylcarbonyl, (6) Ci~6 dadyl - a few benzyl, (7) - anthranyl-singyl-based, or (8) bridging -4-yl-based, JL condensate clouds and my ancient, eight wishes to have 1 to 2 a substituent selected from the group consisting of: (1) a 5- to 6- or nitro nitrogen-containing heterocyclic group (IV), if desired, a Ci6 alkyl group having 1 or 2 ketone groups, Base-county, (ilu-based sulfonyl, (4)! 2(1) hydrogen atom or (2) Ch z having a tooth atom as needed is a methylene group optionally having a methyl group; ring A is a group having no further substituent Piperidine ring; % B is a ring or a ring of the D (8) Μ 口 T butyl group, if necessary, to form a 2,3-dihydrobenzopyran ring; and ring C is a ring, as needed Substituent: Instead of having 1 or 2 selected from the group consisting of (1) mercapto, 31892} 198 200808724 (2) nitro, (3) halogen atom, (4) 1 to 3 halo as needed Alkyl Cl_6 alkyl, (5) Ch alkynyl, (6) Cl_6 alkoxy having 1 to 3 atomic atoms, (7) Cl-6 alkylthio, (8) Cl-6 alkyl Sulfhydryl, (9) di-Cl-6 alkylamino, (10) Cl-6 alkyl-based, (11) Cl-6 alkyl-amine, (12) C!-6 Alkoxy-carbonyl and (13) aminocarboxamyl. 9. A compound or a salt thereof: N-{2-[(3R,4S)-4-({[4'-chloro-4-(trifluoro)) Methoxy)biphenyl-3-yl]fluorenyl}amino)-3phenylpiperidin-1yl]-2-ketoethyloxime, 3 -[({(3R,4) S)-1 -[(5,5-Dimethyl- 2,4-dione-1,3-azinosyl-3-yl)ethyl δ&amp; yl]- 3-based 4-Amino}amino)indenyl]-2-fluoro-4'-(trifluoromethoxy)biphenyl-4-carbonitrile, 2-fluoro-3'-({[(3R,4S)-) 1-ethanolindol-3-phenylpiperidin-4-yl]amino}methyl)-4'-(trifluoromethoxy)biphenyl ▼, 3 -[({(3R,4S)- 1-[(1-乙乙基基口定-4-4) Prison]] 3-Phenyl-Butyl-4-yl}amino)methyl]-2-fluoro-4,-(trifluoromethyl) Oxy)biphenyl-4-carbonitrile, 318921 199 200808724 3 -[({(3R,4S)-1-[(2,6-di-ketopiperidin-4-yl)carbonyl]- 3-phenylphene Pyridin-4-yl}amino)indenyl]-2fluoro-tetra-, 4-(trifluoroindolyl)biphenyl-4-carbonitrile, 2+-[(3R,4S)-4-({[ 4'-Cyano-2'-fluoro-4-(trifluoromethoxy)biphenyl-3-yl]indolyl}amino)-3-phenylpiperidine-fluorenyl]-2-keto Acetamide, 3-{2-[(3R,4S)-4-({[4'-chloro-4-(trifluoromethoxy)biphenyl-3-yl]] yl}amino)-3 -Stupylpiperidine-1 mono-]2- 2-ketoethyl b 5,5-methyl-1,3-oxazole bite-2, 4-dione 4-{[(3R,4S)-4-({[4'-Chloro-2'-fluoro-4-(trifluorodecyloxy)biphenyl-3-yl]fluorenyl)amino)-3benzene Gibberidine-fluorenyl-carbonyl]piperidine u-dione, ' ^ [((3R'4S)-1 -[(5, 5-dimethyl- 2, 4-diindole-yl 1 , 3 萼疋 3 )) 酉 酉 amp amp 基 一 一 一 一 一 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 。 。 。 。 。 。 。 。 。 。 。 。 。 10. Prescription of the compound of the third paragraph of the patent scope of the patent application. u·: a kind of pharmaceutical agent' includes a compound of the first application of the patent scope or a pharmaceutical agent of the first 7 Τ \ ° patent model, which is a tachykinin-accepting agent. • A pharmaceutical agent according to item u of the scope of patent application, which is a preventive or remedy for urinary tract disease, digestive diseases or central nervous system diseases. ', 14. For example, the pharmaceutical agent of the scope of patent application, which is under the bladder hyperactivity, 318921 200 200808724 benign prostatic hyperplasia related pain, chronic prostatitis related symptoms, pelvic visceral pain related Urinary tract symptoms, large: sputum, worry camp, anxiety psychosis 1 2, = intestinal disease, vomiting, lg this disease, anxiety or sleep loss, sleep, prevention or treatment of drugs. ^ (Lost 15 · - urinary tract symptoms, digestive crying official ^, into σ. 5 disease or central nervous system prevention or treatment methods, including the effective dose of the mammal to apply for the application of Yuan Li range 1 The compound or a prodrug thereof. The use of the compound of the first aspect of the patent application or the prodrug thereof is for the manufacture of a medicament for the prevention or treatment of lower urinary tract symptoms, digestive diseases or central nervous diseases. 318921 201 200808724 VII. Designated representative map: None (1) The representative representative figure of this case is: ( ). (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: R2 I 318921