TW200813007A - Substituted pyrrole derivatives - Google Patents

Abstract

The present invention provides novel pyrrole derivatives represented by formula (I): wherein R1 represents a hydrogen atom, cyano, optionally halogenated C1-6 alkyl or an optionally substituted C1-6 alkoxy-carbonyl; R2 and R4 may be the same or different and represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl substituted with an optionally substituted hydroxy, an optionally substituted or oxidized thiol, etc.; R3 represents an optionally substituted thiazolyl, an optionally substituted pyrazolyl, an optionally substituted oxazolyl, etc.; and R5 represents an optionally substituted phenyl having a cyano at the 4- or 3-position, and androgen receptor antagonists containing the same.

Description

200813007 IX. Description of the invention: [Technical field to which the present invention pertains] The present invention relates to novel pyrrole derivatives and to the above-described androgen receptor antagonists, and more particularly to a novel pyrrole derivative which is dependent on androgen (a male hormone) a disease which exerts a prophylactic and/or therapeutic effect by inhibiting the androgen receptor (AR) and is not affected by mutation or the like, and exhibits androgen receptor antagonism, and the male hormone containing the above effects Body antagonist. [Prior Art]

Journal of Medicinal Chemistry (1986), 29(11), 2298-2315 discloses a pyrrole derivative having a male receptor binding inhibition effect; in addition, for example, WO 97/49709 and JP 11-255651 A disclose the use of androgen receptor binding. Inhibitors treat benign prostatic hyperplasia. The applicant's application WO 03/57669 discloses an androgen receptor antagonist comprising a pyrrole derivative which is effective for the prevention and treatment of prostate cancer (this is one of the most serious diseases of androgen dependent diseases), and hormones. Non-dependent stage treatment of prostate cancer. WO 02/02524 discloses azole derivatives as effective therapeutic agents for AIDS. SUMMARY OF THE INVENTION The main object of the present invention is to provide a pyrrole derivative which is novel and can exert excellent androgen receptor antagonism even if they belong to the category of pyrrole derivatives of WO 03/57669. The present invention has a pyrrole derivative containing an androgen receptor antagonism and has been found to have an optionally substituted (tetra) group, a substituted (tetra) group, and a substituted group on the nitrogen atom of the ring. ^ Sitting on the base can be replaced by [1, 2♦ than ° base, can be replaced! , 2,3·three saliva A, can be taken U, 4 records or can be substituted when the base material derivative (4) _ the excellent vegan receptor antagonist side, excellent rate dynamics, etc. The toxicity is delayed, so the present invention is completed. Therefore, the present invention provides: [1] a compound represented by the formula (I) or a salt thereof:

Wherein R1 represents (1) a halogen atom, (2) a cyano group, (3) a halogenated group which is optionally halogenated or (4) a Cw alkoxy group-carbonyl group which is optionally substituted; and R2 and R4 are the same or different, And (1) hydrogen atom, (2) alkyl group, (3) C: 3·6 cycloalkyl, (4) trifluoromethyl, (5) amino-Ci 6 alkyl, (6) single or two Substituted amine group _(^_6 alkyl, (7) optionally halogenated c. 1 - 6 alkyl group, which is substituted by a hydroxyl group optionally substituted, (8) C2_6 alkenyl group, which is optionally Substituted substituted, (9) Cu alkyl group, which is optionally substituted and optionally substituted with an oxidized thiol, (10) cyano, (1 fluorene) fluorenyl, (12) substituted as needed Oxazolyl or (13) 1,3-dioxopenta-2-yl; R3 represents (1) a substituted thiazolyl group, (2) a substituted pyrazolyl group, (3) A substituted oxazolyl group, (4) an oxazole which is substituted as needed 319299 6 200813007 [1,2-dipyridyl, (5) optionally substituted triazolyl, (6) substituted as needed 1,2,4-triazolyl or (7) optionally substituted tetrazolyl; R5 represents phenyl , which has a cyano group at the 4 or 3 position and can be further substituted, except for 4-(4-cyanophenyl)-1-((4-cyano-β1,3-thiazole-2-yl)methyl) -2,5-Dimethyl-1Η-pyrrole-3·carboxylate, 4_,('cyanophenyl 2,5-monomethyl-1_((1-di-p-methyl-1Η-1) , 2,3-tris-7-yl)methyl-ΐΗ-σpyr-3-indene nitrile and 4-(4-cyanophenyl)-2,5-dimethyl_ι_(ιη-1 , 2,3-trioxa-4-ylmethyl)-1Η-pyrrole-3-carbonitrile (hereinafter referred to as the compound (1)); [2] The compound according to [1], wherein the meaning 1 is (1) a ruthenium atom, (2) a cyano group or (3) a halogenated C!-6 alkyl group; [3] a compound according to [1], wherein R2 and R4 are the same or different and are different Represents (1) a halogen atom, (2) optionally a c1-6 alkyl group via a radical, (3) a C3-6 cycloalkyl group, (4) a trifluoromethyl group, (5) a cyano group or (6) an anthracene. [4] The compound according to [1], wherein R3 is (1) a pyrazolyl group which is optionally substituted, (2) an optionally substituted oxazolyl group, and (3) optionally substituted. Imidazole [l,2-a]%b bite, (4) 1,2,4_trisyl or (5) as needed [4] The compound according to [1], wherein R3 is an optionally substituted fluorenyl group; [6] The compound according to [1], wherein R3 is optionally substituted [1] The compound according to [1], wherein R5 is 4-cyanophenyl, 3-cyanophenyl, 4-cyano-3 (trifluoroanthracene) Phenyl, 4-IIyl-2-indenylphenyl or 3-ox-4-ylphenyl; 7 319299 200813007 [8] (i) 4-(2,5-Dimethyl+trifluoro Methyl)_m_indazole _5_yl]methyl}-1 Η-11 bilo-3-yl) bet gambling, (ii) 3-(4-cyanophenyl)-5-methyl ·(Trifluoromethyl)_1Η_π比azole_5_yl]methyl}-111-吼嘻-2-carbonitrile, (iii) 5_{[3-(4-cyanophenyl)-5-ethyl Base_1Η_σpyryl]methyl}-111-pyrazole-3-carbonitrile, (iv)4·[2-methyltriazole_5_ylmethyl)_5_(triyl)-1Η-α ratior-3 -yl]benzonitrile, (7)2-{[3·cyano-4-(4-cyanophenyl)_2,5-dimethyl·m_pyrrole+yl]methyl}-1,3-thiazole_ 4_carbonitrile, 1 -(vi) 4 ·(4.cyanophenyl)_2,5 dif group small {[4_(trifluoromethyl..."set-2-yl]methyl}-111- 〇比略-3 -carbonitrile, (vii) 2-{[3_cyano-4_(4 cyano) Base)_2,5-dimethyl-_m_epyr+ylindenyl}-1,3_喔sa·4-carbonitrile, (iv) cyanophenyl phenyl bromazole ^ small pyridine base ^^-Dimethyl-1Η-pyrrole-3_indenenitrile or 'I(iX)4_(H[3_(1-trans-l-l-methylethyl)-1 heart-to-salt-4)] a radical of 2,5-dimethyl-1H-pyridin-3-yl)benzonitrile, or a salt thereof; ' [9] a prodrug of a compound according to [1]; [10] a compound (I) Or a salt or a prodrug thereof; [11] The drug according to [1G], which is a male receptor antagonist; [4, wherein the drug is administered, wherein the androgen receptor is A normal male receptor and a mutant male receptor; the drug according to (10), which is a preventive or therapeutic agent for steroid-dependent stage cancer and/or non- 319299 8 200813007 激素 Ρό 激素; The drug 'which is a prophylactic or therapeutic agent for prostate cancer; the method of the receptor' includes administering an effective amount of the δ substance (1) or a salt thereof or a prodrug thereof to the mammal; [16] for pre-I or treating the male A method of hormone-sensitive cancer in a phase-dependent manner, comprising administering a mammalian compound (I) or a method or a prodrug thereof; Π7| a method for pre-treatment of prostate cancer, comprising administering a compound (I) or a salt thereof or a prodrug thereof effective in administration to a mammal; [18] a compound (1) or a salt thereof or a compound thereof Use of a drug for the manufacture of a male receptor antagonist; 〇 [ [19] The use of the compound (1) or a salt thereof or a prodrug thereof for the manufacture of a medicament for preventing or treating an androgen-dependent stage and/or a non-dependent stage hormone-sensitive cancer [20] The use of the compound (I) or a salt thereof or a prodrug thereof for the manufacture of a medicament for preventing or treating prostate cancer; [21] The compound according to (1), wherein Ri represents (1) a chlorine atom, (7) a group, (3) a halogenated Cw alkyl group or (4) optionally substituted c alkoxy-carbonyl group, !"6 R and R4 are the same or different, and respectively represent (1) a hydrogen atom, a base, (3) G: 3·6 cycloalkyl, (4) trifluoromethyl, (5) amino-c 6 alkyl, (6) mono- or di-substituted amino-Cl_6 alkyl, (7) A halogenated Cw alkyl group which is optionally substituted with a hydroxyl group which is optionally substituted, (8) a C2_6 alkenyl group which is substituted with a hydroxyl group which is optionally substituted, and (9)^alkyl group From the thiol which is optionally substituted and optionally oxidized, 319299 9 200813007, (10) cyano, (11) fluorenyl, (12) optionally substituted oxazolyl or (13) 1,3- Dioxapentan-2-yl; R3 represents (1) pyrazolyl which may be substituted as desired, (2) optionally substituted, and (3) substituted as desired [1, 2 -a] fluorenyl, (4) 1,2,4-trientyl substituted as desired or (5) tetrazolyl which may be substituted as desired; and R5 represents a phenyl group having a position at 4 or 3 The compound of the above [1], wherein R1 represents (1) a halogen atom, (2) a cyano group, (3) a Cu alkyl group which is required to be i| (4) A Cu-alkoxy-substituted group which is substituted as needed, and R2 and R4 are the same or different and each represents (1) a hydrogen atom, (2) (^6 alkyl group, (3) C3_6 cycloalkyl group, (4) trifluoromethyl, (5) amino-C^ alkyl, (6) mono- or di-substituted aminoalkyl, (7) optionally halogenated CN6 alkyl, which is optionally a substituted hydroxy-substituted, (8) C2_6 alkenyl group substituted with a hydroxy group optionally substituted, (9) an alkyl group, Substituted and optionally oxidized thiol substituted, (10) cyano, (11) fluorenyl, (12) optionally substituted oxazolyl or (13) 1,3-dioxopentane Or a phenyl group, and R 5 represents a phenyl group which has a cyano group at the 4 or 3 position and which may be further substituted; [23] The compound according to [1] or a salt thereof a class, wherein R1 represents (1) a halogen atom, (2) a Cu alkyl group which is required to be toothed, or (3) a Cu 10 319299 which is optionally substituted; 200813007 alkoxy-alkyl; R2 and R4 are the same or Different, and respectively represent (1) a hydrogen atom, (7). _ alkyl, (3) C3-6 cycloalkyl, (4) trifluoromethyl, (5) amino-c16 alkyl, (6) mono or disubstituted amine _Ci_6 alkyl, If desired, the C"alkyl group, which is substituted by a trans group which is optionally substituted, (8) C2-6 alkenyl group, which is substituted with a hydroxy group which is optionally substituted, (9) Cl 6 alkyl group, Substituted by thiol which is optionally substituted and optionally oxidized, (10) cyano, (11) fluorenyl, (12) optionally substituted oxazolyl or (13) 1,3-dioxane Alkane-2-yl; soil r3 represents optionally substituted l52,3-triazolyl; and R5 represents phenyl which has a cyano group at the 4 or 3 position and can be further substituted; and the invention further provides, [24 The compound according to [1], wherein R1 represents (1) a hydrogen atom, ("cyano group, (3) optionally halogenated (^_6 alkyl or (4) optionally selected from a substituent group 1 to 5 substituents of Group A substituted by Ci_6 alkoxy-carbonyl, substituent group A consists of (1,) keto, (2,) argon atom, (3,) Ci 3 alkylene Oxyl, (4,) nitro, (5,) cyano, (6,) as needed C2·6-thinyl group to 3 halogen atoms, (7')carboxyl C2_6 alkenyl group, (8') CM alkynyl group having 1 to 3 halogen atoms as needed, (9,) optionally have! to 3 C3_6 cycloalkyl group of a halogen atom, (1 〇') c6-14 aryl group, (11 ') Ck alkoxy group having 1 to 3 halogen atoms, (12') 0^_6 alkoxy group - Base - c16 alkoxy, (13,) hydroxy, (14,) C6-14 aryloxy, (15,) C7-16 aralkyloxy, (16') fluorenyl, (17,) A Cu alkylthio group having 1 to 3 halogens 319299 11 200813007, (18') C6_14 arylthio group, (19') C7_16 aralkylenethio group, (20,) amine group, (21) ,) a single C!_6 alkylamino group, (22,) mono C6_14 arylamino group, (23,) di-Cw alkylamino group, (24,) di-C6_14 arylamino group, (25,) Mercapto, (26,)carboxy, alkyl-carbonyl, (28')C3-6 cycloalkyl-carbonyl, (29')(^6 alkoxy-carbonyl, (30')C6_14 aryl-based , (31') C7-i6 arylalkyl-aryl, (32') C6-i4 aryloxy-yl, ( 33') C7-16 aralkyloxy-carbonyl, (34,) 5 or 6 membered heterocyclic-carbonyl group, wherein the heterocyclic ring includes, in addition to a carbon atom, 1 to 3 selected from #1 from nitrogen A hetero atom of a group consisting of an atom, a sulfur atom and an oxygen atom, (35,) an amine carbenyl group, (36,) a thiocarbamyl group, (37,) a mono(^-6 alkyl-amine formazan) , (38) bis-Cw alkyl-amine-methyl-based, (39') mono- or di-CfM aryl-amine carbaryl, (40') mono or di-5 or 6 member heterocyclic-amine A a mercapto group, wherein the heterocyclic ring includes, in addition to a carbon atom, 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, (4ΐ,) (^_6 alkylsulfonyl, ( 42,) (^_6 alkylsulfinyl, (43,) (: 4 arylsulfonyl, (44,) C6_i4 arylsulfinyl fluorenyl, (45') formazanyl, (46,) Ci_6 alkyl-carbonylamino group, (ο,). " aryl-carbonylamino, (48') (^_6 alkoxy-carbonylamino, (49,)Ci_6 alkyl fluorenylamino, (50') C6_14 arylsulfonylamino, (51,)Ci_6 alkyl·carbooxy, (520(:^4 arylcarbonyloxy, (53,)Ci_6 alkoxy-carbonyloxy, (54)mono-Cualkyl-amine-methyl oxo) , (55,) bis-Ci_6 alkyl-amine methyl methoxy, (56') C6_; u aryl-amine oxiranoxy, (57,) nicotine decyloxy (niC〇tin〇yl〇 Xy), (58,) 5 to 7 membered saturated cyclic amine groups, optionally having 1 to 3 substituent halogen atoms formed from the following groups, (2,,) having 1 to 3 as needed The Ch group of the atomic atom, (3,,) as required 319299 12 200813007 (1 to 3 halogen atoms, (4,6) C6_14 aryl and (5,,)) a Cw alkoxy group of 1 to 3 halogen atoms, a (59,) 5 to 10 membered aromatic heterocyclic group, which includes, in addition to a carbon atom, 1 to 3 groups selected from a nitrogen atom, a sulfur atom and an oxygen atom. The group of heteroatoms is composed of (6〇,) acid groups. R2 and R4 are the same or different And respectively represent (丨)氲 atom, (2) Cw alkyl group, (3) C3_6 cycloalkyl group, (4) trifluoromethyl group, (5) amine group _c1-6 alkyl group, (6) amine group- a Cw alkyl group, wherein the amine group is mono- or disubstituted with a substituent selected from the group consisting of a Cm alkyl group and a Cw alkyl-carbonyl group, and (7) a Ci6 alkyl group which is halogenated as needed, which is derived from a hydroxyl group. Substituting 'the meal group may be substituted with a substituent selected from the group of substituents B consisting of: (a) ci-6 alkyl group, which is optionally selected from 1 to 5 groups of substituents A Substituent substituted, (b) C2_6 alkenyl, which is optionally substituted with 1 to 5 substituents selected from substituent group A, (c) C2_6 alkynyl, which may be worked up to 5 as needed Substituted by a substituent selected in the group A, (d) a C3_6 cycloalkyl group, which is optionally substituted with 1 to 5 substituents selected from the substituent group A, (e; ^6^4) An aryl group which is optionally substituted with from j to 5 substituents selected from the substituent group A and (1) a C7 i6 aralkyl group, optionally having 1 to 5 substituents selected from the substituent group a Substituted, (8) C2_6 alkenyl, which Substituted by a radical, the hydroxyl group may be substituted with a substituent selected from the group of substituents B, and (9) a C1-6 alkyl group substituted by 1 to 3 groups as shown by the following chemical formula: _s(0) nR6, wherein R6 represents a hydrogen atom or a group selected from the group of substituents B and η is 〇, 13 319299 200813007 1 or 2^0) cyano group, (1)) thiol group represented by a chemical formula: _c (five) R7, = ONR R9, _c〇Rl. Or _(c=s)_NrUr12, wherein r7, r8, represent a hydrogen atom or a group selected from the group of substituents B, and R8 and R, RuARl2 may form a 5 or 6 member impurity together with an adjacent nitrogen atom. a ring group comprising, in addition to a carbon atom, U 3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom and may have a substituent selected from the group of substituents B, (10) optionally selected Substituted oxazolyl or (13) 1,3 dioxopenta-2-yl group from substituent group A (except keto group); R3 represents (1) as needed (iv) from substituent group A (---- keto group) and the substituent of the substituent group B are substituted with oxime, and (7) are optionally substituted by a substituent selected from the group A of the substituent (excluding the keto group) and the substituent group b. a salivary group, (3) optionally, a ruthenium substituted by a substituent selected from the group of substituents A (except for a keto group; and a substituent group B), and (4) optionally selected from the group of substituents a (only Excluding fluorenyl): and substituents substituted with substituents of group B, imidazolium n,2_a]pyridyl, (5) optionally selected from group A (excluding keto groups) and substituent group B Substituent substituted u, 3_triazolyl, (6) 1,2,4. triazole substituted by a substituent selected from substituent group A (except for keto group) and substituent group B as needed Or (7) a tetrazolyl group which is optionally substituted with a substituent selected from the group of substituents A (except for a keto group) and the group of substituents B; and R5 represents a phenyl group which has a cyanide at the 4 or 3 position. a group, and further substituted by a substituent selected from the group of substituents A; 319299 14 200813007 [25] A compound according to π], wherein R1 represents (1) a hydrogen atom, (7) an aryl group or (3) Ci_6 alkyl group having 1 to 3 halogen atoms as needed; R is a U) hydrogen atom, (2) Cu alkyl group, (3) C3 6 cycloalkyl group, (4) tri-3 fluoromethyl group, (5) a hydroxy-substituted Ci_6 alkyl group or a (6) cyano group; R is (1) a thiazolyl group optionally substituted with 1 or 2 substituents selected from the group consisting of (1, C1_6 alkyl groups) , which is optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxyl group, (2,) an aminomethyl group and a (3,) cyano group, and (2) as needed 1 selected from the group below a substituent substituted with pyrazolyl GDCk alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxyl group, (2,)Ci_6 alkoxy-carbonyl, (3,) a carboxyl group, (4,) an amine carbenyl group, a (5,) mono-Cl_6 alkyl-amine-carbamyl group, and a (6') cyano group, (3) optionally 1 or 2 selected from the group below The oxazolyl group substituted by a substituent consisting of: (1,) Ci 6 alkyl, which is optionally substituted, (2') aminyl and (3,) cyano, (4) Saliva [l,2-a]%b pyridine, (5) C, 1-6 alkyl substituted 1 , 2, 3-trisyl, (6) 1 as needed, optionally having 1 to 3 halogen atoms , 2,4-trisal or (7) tetrasal; R4 is (1) a hydrogen atom, (2) a Cu alkyl group, which is optionally substituted with a substituent selected from the group consisting of a hydroxyl group and a ketone group. And (3) a trifluoromethyl group or a (4) cyano group; R5 represents a phenyl group having a cyano group at the 4 or 3 position, and may further be Cm selected from (1) optionally having 1 to 3 halogen atoms. Substituents of the group consisting of an alkyl group and (2) a halogen atom are substituted. 15 319299 200813007 In the present invention, the compound (1) or a salt thereof is structurally asymmetric: an atom, an optically active compound, and a racemic compound are all included in the present invention, and the compound or a salt thereof may be a hydrate. Or anhydrate. The compound of the present month (I) or its salt, not only has an effective antagonistic activity against the natural type of androgen receptor, but also has high antagonistic activity against the mutated androgen receptor, and the compound can be orally administered, and the toxicity It is extremely low, so it can be used as a drug with androgen receptor antagonism, which is effective against, for example, prostate cancer in a non-hormone-dependent stage. [In the embodiment], in the compound (I), R1 represents (1) a hydrogen atom, (2) a cyano group, (3) a Cw alkyl group which is optionally halogenated or (4) a Ci6 alkoxy group which is optionally substituted. Carbonyl. Examples of the "halogenated Cu alkyl group" include a c1-6 alkyl group (e.g., fluorenyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, second butyl group, second butyl group). , pentyl and hexyl), if necessary, having 1 to 5, preferably 1 to 3, halogen atoms (for example, fluorine, chlorine, bromine, and iodine), and particularly including methyl, chloromethyl, difluoroanthracene , trichloroindolyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3_trifluoropropyl, Isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, t-butyl, dibutyl, pentyl, isopentyl, neopentyl, 5,5,5-three Dentyl, hexyl, 6,6,6-trifluorohexyl. Examples of the Ci_6 alkoxy-alkyl group of the "Substituted substituted Cu-oxy-carbonyl group" include an anthraceneoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxy group. Carbonyl group, second butoxycarbonyl group, third butoxide 16 319299 200813007 Carbonyl group, pentyloxy group, hexyloxycarbonyl group and the like. The Cw alkoxy-carbonyl group may have a substituent group at the substitutable position, preferably: one:: lower:: when the number of substituents is equal to or greater than 2, each substituent group of substituents A·· Same. (1) a ketone group, (2) a halogen atom (such as fluorine, chlorine, bromine, and iodine), (3) a Cw alkylenedioxy group (such as a methylenedioxy group, a thiophene, etc.), and a soil Ruthenium (4) nitro, (5) cyano, (6) CM alkenyl (such as ethylene, propylene, butene, pentene, hexene, etc.), which may have 1 to 3 halogen atoms (such as fluorine, chlorine, etc.) Moments and sentences, (7) carboxyl C2·6 alkenyl (such as 2-carboxyethylene, 2-carboxymethylethylene, etc.), (8) Cw fast radicals (such as B, propyne, butyne, pentyne, hexyne, etc.) ), if necessary, having 1 to 3 halogen atoms (such as fluorine, chlorine, bromine, and iodine), (9) C3_6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), It is required to have 1 to 3 halogen atoms (such as fluorine, gas, bromine and iodine), (10) C6_M aryl (such as phenyl, 1β naphthyl, 2-naphthyl, 2-phenylbiphenyl, biphenyl, 4 -biphenyl, 2_fluorenyl, etc.), (11) C^6 alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Dibutoxy, tert-butoxy, pentyloxy, etc.) 'It has 1 to 3 halogen atoms as needed ( Such as fluorine, chlorine, bromine and broken), 319299 17 200813007 (12) (^_6 alkoxy-carbonyl alkoxy (such as ethoxycarbonylmethoxy), (13) hydrogen, (14) C6_14 aryloxy (e.g., phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc.), (15) C7_16 aryl: !: aralkyloxy (such as benzyloxy, phenethyloxy, etc.), (16) a base, (17) a Cu alkylthio group (such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, etc.), which has 1 to 3 halogen atoms (such as fluorine, gas, bromine and broken), (18) C6_14 arylthio (such as phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), (19) C7_16 aralkylthio (such as benzylthio, phenethylthio, etc.), (20) amine, (21) monoalkylamine (such as mercaptoamine, ethyl) Amino group, etc.), (22) mono C6_14 arylamino group (such as phenylamino group, 1-naphthylamino group, 2-naphthylamino group, etc.), (23) di-Ci -6 alkyl group (for example) Dimethylamino, diethylamino, ethyl decylamino, etc., (24) di-C6_14 arylamine (such as diphenyl) Amino group, etc.), (25) fluorenyl group, (26) carboxyl group, (27) Cu alkyl-carbonyl group (e.g., ethyl fluorenyl group, propyl fluorenyl group, etc.), (28) C3_6 cycloalkyl-carbonyl group (such as cyclopropyl) Alkylcarbonyl, cyclopentylcarbonyl, cyclohexane 18 319299 200813007 carbonyl, etc., (29) Ck alkoxy-carbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) Etc), (30) Ον" aryl group (such as benzamidine, naphthylmethyl, 2_cathene, etc.), (31) Cn6 arylalkyl-based (such as phenylacetate, 3_ Phenylpropionyl group, etc., (32) C6-!4 octaoxy group (such as phenoxy group, etc.), (33) C7-16 aralkyloxy-carbonyl (such as benzoic acid) An oxycarbonyl group, a phenethyloxycarbonyl group, or the like, a (34) 5 or 6 membered heterocyclic-carbonyl group, wherein the heterocyclic ring includes, in addition to a carbon atom, 1 to 3 members selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. a group of heteroatoms (eg, an alkali-based base, a different thiol group, a fluorenyl group, a mercaptomethyl group, a morpholine carb〇nyl group, a thiomorpholine group) (thiomorpholinocarbonyl), phenazine] benzyl, pyrrole _1 _ carbonyl, etc.), (35) Aminomethyl thiol, (36) Thiocarbamyl, (37) Mono Cw alkyl-amine methyl thiol (eg methylamine thiol, ethylamine A)醯, etc.), (38) — Cw alkyl-amine-methyl sulfhydryl (eg dimethylamine-methyl hydrazino, diethylamine-methyl hydrazino, N-ethyl-N-decylamine carbhydryl, etc.) , (39) mono or di Cl_6 aryl-amine carbaryl (such as phenylamine fluorenyl, naphthylamine carbaryl, 2-naphthylamine fluorenyl, etc.), (4 〇) single or two 5 or 6-member heterocycle-county, wherein the heterocyclic ring is in addition to an atom, 319299 19 200813007 includes 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom (eg 2-pyridylamine A) Sulfhydryl, 3_pyridylaminocarboxamidine, 4-pyridylaminecarbamyl, 2-thienylmethyl indenyl, indolyl thiophenemethylcarbendyl, etc., (41) alkylsulfonyl (such as methyl) Sulfhydryl, ethylsulfonyl, etc., (42) C!-6 alkylsulfinyl (such as methylsulfinyl, ethylsulfinyl, etc.), ', , (43) C6_14 Arylsulfonyl (such as phenylsulfonyl, cyanosulfonyl, 2-naphthyl, etc.), (44) C6_H arylsulfin Base (such as phenylsulfinyl, i-naphthyl fluorenyl, 2-naphthyl fluorenyl, etc.), (45) decylamino, (46) C -6 carbyl-carbonyl Amino group (e.g., ethenylamino group, etc.), (47) C6-U aryl-carbonylamino group (e.g., benzhydrylamino group, naphthoylamino, etc.), (48) Cw alkane Oxy-carbonylamino group (such as methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, butoxycarbonylamino group, etc.), (49) C -6-6 Amino group (such as methyl sulphate, ethyl sulphate, etc.), (50) CVh aryl succinyl amine group (such as phenyl fluorenylamino group, naphthyl fluorenylamino group, 1- Naphthylsulfonylamino group, etc., (51) C -6 alkyl-peroxy (such as ethoxylated, propyloxy), (52) C6-]4 aryl-carbonyloxy (e.g., benzhydryloxy, naphthylcarbonyloxy, etc.), (53) C _6 alkoxy-oxyl (e.g., methoxyoxy, ethoxyoxy, 319299 20 200813007 propoxy a carbonyloxy group, a butoxycarbonyloxy group, etc.), (54) a monoCl4 group, an amine, a fluorenyloxy group (e.g., an fluorenylmethoxymethyl methoxy group, etc.), Female (55) di Cl.6-siloxy (such as dimethylamine-methoxyl, hydrazinyloxy, etc.), mono-(10)% aryl-amine-methoxyl (such as phenylamine) Methoxy, naphthyl roWt χτί « \ 丨 (57) final test oxime (nic〇tin〇yi〇x force, (10) 5 to 7 member saturated cyclic amine group, which optionally has m selected from the following groups Substituents: (1,) a halogen atom, (2u group (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyldipentyl and hexyl) Etc.), if necessary, has 1 to 3 south atoms (such as fluorine, chlorine, bromine, and iodine), (3,) 〇: 3 όcycloalkyl (such as cyclopropane, cyclobutane, cyclopentane, Cyclohexane, etc.), if desired; to 3+ halogen atoms (eg, chlorine, bromine, and angstrom), (4,)C6]4 aryl (eg, phenyl, 1-nyl, 2-naphthyl) , 2—biphenyl, 3•biphenyl, biphenyl: 2-indenyl, etc.) and (5,)Ci_doxy (eg methoxy, ethoxy, propoxy, isopropoxy, Butyl, iso-yl, t-butyl, t-butyl, pentyl, etc., if desired, have 1 to 3 halogen atoms (such as fluorine, (25) 5 to 1G member aromatic heterocyclic group includes, in addition to a carbon atom, a hetero atom selected from the group consisting of a milk atom, a sulfur atom and an oxygen atom (such as 2-thiophene). , 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolinyl, 5-quinolinyl, quinolinyl, 319299 21 200813007 1-Isoquinolyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 1-indenyl, 2-indenyl, 3-indenyl, 2 -benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.; 60) Acid base. R1 is preferably (1) a hydrogen atom, (2) a cyano group or (3) a halogenated c1-6 alkyl group; more preferably a (1) hydrogen atom, (2) a cyano group or a (3) trifluoro group. Sulfhydryl; and preferably cyano. R and R4 are the same or different and each represents (1) a hydrogen atom, (2) c, <alkyl, (3) c3_6 cycloalkyl, (4) trifluoromethyl, (5) amine-Cu Alkyl, (6) mono- or di-substituted amino-C1-6 alkyl, (7) Ci 6 alkyl as desired, which is substituted by a hydroxy group optionally substituted, (8) c2- a 6 alkenyl group which is substituted by a hydroxy group which is optionally substituted, (9) a Cl4 alkyl group which is optionally substituted and optionally substituted with an oxidized thiol, (10) a cyano group, a (11) fluorenyl group, 12) An oxazolyl group or a (13) 1,3-dioxopenta-2-yl group which may be substituted as needed. Examples of the "Cw alkyl group" represented by R2 and R4 include an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, a hexyl group and the like. Examples of the R C3:6 cycloalkyl group represented by R2 and R4 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the "amino-Cw alkyl group" represented by R and R include an aminomethyl group, an aminoethyl group, an aminopropyl group, an aminobutyl group and the like. Examples of the "mono or disubstituted amino-Ci_6 alkyl group" represented by R2 and R4 include an amino group-substituted Ci_6 alkyl group (e.g., methyl group, ethyl group, propyl group, 319299 22 200813007 isopropyl group, butyl group). Base, isobutyl, t-butyl, tert-butyl, pentyl, hexyl, etc.), the amine group having 1 or 2 substituents selected from the group consisting of alkyl groups such as methyl and ethyl , propyl, isopropyl, butyl, isobutyl, t-butyl, di-dibutyl, pentyl, hexyl hydrazine) and Cl-6 alkyl-based (eg, ethyl, ethyl carbonyl, A propylcarbonyl group, an isopropylcarbonyl group, a butylcarbonyl group, an isobutylcarbonyl group, a second butylcarbonyl group, a tert-butylcarbonyl group, a pentyl group, a hexylcarbonyl group, and the like. Examples of the substituents of the "optional substituted transradyl" which are represented by R2 and R4 as "required red substituted by a hydroxyl group which is optionally substituted" include (UCw alkyl (such as A) Base, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, hexyl, etc.), (2) c26 alkenyl (eg vinyl, propenyl, Isopropenyl, alkenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-mercaptopropenyl, 2·methyl-1 propyl-yl), (3) C2_6 alkynyl (such as ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.), (4) Cw cycloalkyl (such as cyclopropyl) , cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) C6 i4 aryl (such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, biphenyl, 'biphenyl , 2_fluorenyl, etc.) and (6) C7_10 aralkyl (such as benzyl, phenethyl, diphenylmethyl, naphthylmethyl, 2-naphthylmethyl, 2,2-diphenyl) a group, a phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, etc.). The substitutions may have from 1 to 5, preferably based on the substitutable position. 1 to 3 substituents selected from the substituent group A, and when the number of the substituents is 2 or more, each substituent may be the same or different. In addition, R2 and R4 are represented by "as needed" The substituted hydroxyl group is taken as 319299 23 200813007, and the recrystallized alkyl group in the as-received Cu alkyl group as needed includes an alkyl group (e.g., methyl group, ethyl group, propyl group, and the like). a propyl butyl group, an isobutyl group, a dibutyl group, a tert-butyl group, a pentyl group, a hexyl group, etc., which may have 1 to 5, preferably fluorene to 3 halogen atoms (such as fluorine, chlorine, etc.) as needed. Bromine and iodine), and particularly including methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, Pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, second butyl, tert-butyl , pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc. R2 and R4 represent "hydroxyl as desired Substitution of "optionally substituted hydroxy" in substituted C26 alkenyl" Examples are the substituent examples of the "optionally substituted hydroxy group" in the "i-substituted alkyl group which is substituted by a radical which is optionally substituted by the above-mentioned R and R", and "C: 2·6" Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-mercapto-2 propenyl, 1-methyl-2-propene Examples of the group, 2-methyl-1 propenyl group, etc. R and R4 represent "C 6 alkyl group substituted by thiol which is optionally substituted and optionally substituted with oxidized thiol", and includes Ci6 alkyl group (such as methyl group, B group). Base, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, hexyl, etc.) having from 1 to 3 groups represented by the formula _s(〇)nR6 a group wherein R6 represents (1) a halogen atom, (2) a Ci6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, A pentyl group, a hexyl group, etc., which has 1 to 5 (more than 1 to 3) L substituents selected from the substituent group a, and (3) a C2_6 alkenyl group (e.g., 24 319299 200813007). Vinyl, propylene, different Propylene, 1-butenyl, 2-butenyl, 3-butene, 2-methyl-2-propenyl, 2-methyl-2-propenyl, 2-methyl"propenyl temple), which can be substituted as needed The position has 4 5 (preferably 43) substituents selected from the substituent group A, and (4) C2 6 alkynyl groups (e.g., an alkenyl group, a propynyl fluorenyl-butyl group, a 2-butynyl group, a 3-butyl group) An alkynyl group, a hexyl group, etc., which may have from i to 5 (preferably to 3) of the substituents of the substituent group A, and (5) a c3_6 cycloalkyl group at the substitutable position. For example, a cyclopropenyl group, a cyclobutanyl group, a cyclic nucleus group, a cyclohexyl group #), which has 1 to 5 (preferably 1 to 3) selected from the substituent group A as needed. Substituent, (6) C6_"aryl (such as phenyl, naphthyl, 2_cainyl, 2-biphenyl, 3'biphenyl, 4_biphenyl, 2_:€基#) There are 1 to 5 in the replaceable position (preferably! Up to 3) a substituent selected from the substituent group a or (7) a C7_I6 aryl group (eg, benzyl, phenethyl, diphenylmethyl, naphthylmethyl, 2-naphthylmethyl, 2, 2_) Diphenylethyl, 3-phenylpropyl, "phenylbutyl, 5-phenylene, etc.", which has to be worked up to 5 (preferably! to 3) in the replaceable position a substituent from a group of substituents; and η is not 0, 1 or 2. Examples of "aryl" of tf in R and R include a group as shown in the formula: -COOR7, _C0NRV, _COR1〇 or _(c=s)_NRllRl2, wherein R1 represents (1) a hydrogen atom, (7) a Ci6 alkyl group (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl) , pentyl, hexyl, etc.), optionally having from 5 (preferably from 3 to 3) substituents selected from substituent group a, at the substitutable position, (3) C2_6 alkenyl (such as vinyl) , acryl, isopropyl, dibutyl, 319299 25 200813007

Sit3: butyl group, 2_methyl-2 propyl group, 1 propyl group, earth county, etc., which has 1 to 5 ^ 3 at the substitutable position as required) a substituent, (4) a C2_6 block (such as an ethyl group, a propynyl group, a W block group, a 2-butynyl group, a 3-butanyl group, a 1-hexyl group, etc.) 1 to 5 (preferably a substituent from the substituent group A, (5) C3·6 cycloalkyl (such as Yi's soil & Dingyuan, cyclopentyl, cyclohexyl, etc. And optionally having from j to 5 (preferably i to 3) substituents selected from the group of substituents A, (6) Q "aryl (9) stupid ^ Cai Ji ^ - Cai Ji, 2 a biphenyl group, a 3-biphenyl group, a 4-biphenyl group, a 2-phenyl group, etc., which optionally has from 1 to 5 (preferably from 1 to 3) at a substitutable position selected from the group of substituents A Substituents or (7) C7 i6 aromatics (eg benzyl, phenethyl, diphenyl f methyl, 1-naphthylmethyl, 2_naphthylmethyl, 2,2-diphenylethyl, 3_ Benzene propyl 4-phenylbutyl, 5-phenylpentyl, etc.), if necessary, in the substitutable position of 1 to 5 (preferably! to 3) a substituent selected from the substituent group a; or R8 and R9 and Rif may form a cyclic group together with an adjacent nitrogen atom (eg, a 5- or 6-membered heterocyclic ring including 1 to 3 hetero atoms selected from the group consisting of a milk atom, a sulfur atom and an oxygen atom), optionally having 1 to 3 substituents selected from the group consisting of: (1 core 6 alkyl group (eg methyl group, B) Base, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, hexyl, etc.) which have from i to 5 (preferably 1 in the substitutable position) as desired Up to 3) substituents selected from substituent group A, (7) C2_6 dilute groups (eg, ethyl, propyl, isopropenyl, 1-butenyl, 2-butanyl, 319299 26 200813007 3-=ene Base, 2-methyl-2-propenyl, iota-2-propenyl, 2-indolyl d-propyl, etc., which may have from 5 to 3 (preferably from 3 to 3) in the position of substitution. a substituent selected from the substituent group A, (3) a C26 block group (e.g., an ethylidene propynyl group, a 1-butynyl group, a 2-indolyl group, a 3-butanyl group, a hexyl group, etc.), It has ~ to 5 (preferably ii) in the replaceable position as needed 3) selected from substituents substituting f group A, (4) ring filaments (such as cyclopropyl, cyclobutyl, % pentyl, cyclohexyl, etc.), which may have up to 5 in the substitutable position as needed ( Preferably, it is a substituent selected from the group of substituents a, and (5) a CVU aryl group (e.g., phenyl, h-naphthyl, 2-naphthyl, 2-biphenyl, % biphenyl 4 % phenyl, 2-enyl, etc.), which may have up to 5 (preferably 1 to 3) substituents selected from the substituent group A at the substitutable position, (6) C6_10 aryl _ Ci 3 alkyl (such as benzyl, p-tolyl, phenylethyl, phenylpropyl, 丨-naphthylmethyl, 2-naphthylmethyl, etc.) It is necessary to have i to 5 substituents from the substituent group at the substitutable position, (7)% aryl group = thiophene group, stone-phenethyl group, etc., as needed in the substitutable position There are 1 to 5 (preferably 丨 to 3) substituents selected from the substituent group A. Especially for the "mercapto" represented by R and R4, c" alkane groups (such as methyl, ethyl, propyl, butyl, isobutyl, pentanoate, isovaleryl, trimethyl Pival (yl), hexyl, etc., alkenyl (alkenyl), such as acryl, methacryl, croto^noyl, isocroton, etc. C4 7 cycloalkyl group (such as cyclopropylcarbonyl, % butylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc. c7 i5 aryl fluorenyl (such as benzamidine, p-tolylhydrazino, bnaphthalene) Sulfhydryl, 2_naphthoquinone 319299 27 200813007 610 square base C2·4 burn && base (such as phenylethyl phenyl, phenylpropionic acid, hydratropoyl, phenylbutyl yl (phenylbutylyl) ))) aryl _C3 5 dilute sulfhydryl groups (such as cinnamon syrup (in sen & yi), 2 _ phenyl propyl fluorene (atropoy 1), etc.) are all examples. The substituent of the substituted oxime group is exemplified by the group in which the substituent group is a ketone group, and the oxazole has 丨 to 5 based on the substitutable position ( It is preferably 丨 to 3) substituents, and when the number of the substituents is 2 or more, each substituent may be the same or different. R and R may be the same or different, and each is preferably a hydrogen atom, If desired, Cw alkyl having a hydroxyl group, ο: % 6 cycloalkyl, trifluoromethyl, cyano or decyl, and more preferably Cl-6 alkyl, trifluoromethyl or cyano. ' Preferred is a hydrogen atom, a fluorenyl group, a hydroxymethyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a cyano group or a decyl group, and more preferably a methyl group, an ethyl group, or a third group. Fluoromethyl or cyano. R and §, preferably a nitrogen atom, a methyl group, a methyl group, a methyl group, a propyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a cyano group or a decyl group. More preferably, it is a methyl group or a cyano group. R3 represents (1) a thiazolyl group which is optionally substituted, (2) a pyrazolyl group which is optionally substituted, (3) an optionally substituted oxazolyl group, (4) If desired, substituted imidazo[l,2-a]acridinyl, (5) as needed, substituted i, 2,3-triwaxyl, (6) substituted 1,2,4-trid, as needed Azolyl or (7) substituted as desired, R3 means "according to the need "thiazolyl", "optionally substituted carbazolyl", "optionally substituted oxazolyl", "replaced 319299 28 200813007 as needed, 2♦ than bite", "as needed Examples of substituents in substituted saliva, "1,2,4-trisyl optionally substituted" and "tetrasyl optionally substituted" include (1) excluding thiol, substituent group A a group, an alkyl group (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl, hexyl, etc.), which may be ^ Generation position has 1 to 5 (preferably! Up to 3) selected from the group A of the substituent, (3) C2_6 alkenyl (such as vinyl, acryl, isopropyl, b, butenyl, 2-butenyl, 3-but Alkenyl, 2-methyl-2-propenyl, 2-methyl-2-propenyl, 2-methyl-1propenyl, etc., optionally having 1 to 5 (preferably 1 to 3) at a substitutable position a substituent selected from the substituent group A, (4) a C 2-6 alkynyl group (e.g., ethynyl, propynyl, 丨-butynyl, azetidinyl, 3-butynyl, 1-hexyne) a base or the like which has, as needed, at a substitutable position [to 5 (preferably 1 to 3) substituents selected from the substituent group A, (5) c3 6 cycloalkyl (e.g., cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, etc., which have a need of 6 to 5 (preferably i to 3) substituents selected from substituent group A, (6) C6_14 Base (such as phenyl, naphthyl, 2_tea, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2_g, etc.), potted as needed in the substitutable position! to 5 (more Preferably, it is selected from the group consisting of substituents of substituent group A, (7) Qi aryl group & burn group (such as benzyl) P-tolyl (p_t〇lyl), phenylethyl, phenylpropylphosphonylmethyl, 2-naphthylmethyl, etc., optionally in the substitutable position and 1 to 5 (preferably + 1 to 3) a substituent selected from the group of substituents A, and () 610 aryl C2·4 (for example, α-phenethyl, stone-styryl, etc.), "can be substituted as needed The position has 1 to 5 (preferably u 3) 319299 29 200813007 substituents from the substituent group A, and may have the above 1 to 3 substituents at the substitutable position and the number of substituents is 2 Or more, the individual substituents may be the same or different. Among them, the preferred substituents are methyl, thiol, oxime-ethyl, 1-hydrazin-1-ylethyl, trifluoromethyl a carboxyl group, a methoxycarbonyl group, an amine fluorenyl group, an N-methylamino fluorenyl group, a cyano group or a decyl group; more preferably the substituent is hydrazine-hydroxy-1-methylethyl, trifluoromethyl or More specifically, particularly preferred R3 comprises 5-{3 fluorotrifluoromethylpyrazolyl, 5-{3_(cyanopyrazolyl, 5_i沁込2•hongtriazolyl, 2 Thiazolyl, 2-(4-trifluoromethyl)thiazolyl, 2_(' Ethylzolyl, 4-{3-(1.hydroxy-1-indenylethyl)indolylpyrazinyl, and imidazo[丨,2_&]pyridyl. R5 represents phenyl, which The cyano group may have a cyano group at the 4 or 3 position and may be further substituted. For the further substituent of the phenyl group, the substituent group A is exemplified except for the ketone group. For the R5', it is preferably 4-cyanophenyl group, 3_. Cyanophenyl, 4-cyano-3-(trifluoromethyl)phenyl, 4·cyano-2-methylphenyl or 3-chloro-4-cyanophenyl; and particularly preferably 4-cyano Phenylphenyl, 3-cyanophenyl or 4-aryl-3-((d)methyl)phenyl. The compound (I) is preferably as shown below. (la): Compound (1) wherein 'R1 is (1) a hydrogen atom, (2) a cyano group, (3) a Cw alkyl group which is optionally halogenated, or (4) a substituted d_6 alkoxy group if necessary Carbonyl 319299 30 200813007; R2 and R4 are the same or different and are (1) a hydrogen atom, (2) a Ci 6 alkyl group, a (3) C3·6 cycloalkyl group, a (4) trifluoromethyl group, (5) Aminoalkyl, (6) mono- or di-substituted amino-Ci_6 alkyl, (7) optionally halogenated Ci 6 alkyl 'substituted by optionally substituted hydroxy, (8) c2_6 alkenyl , which is substituted by a hydroxy group which is optionally substituted, (9) Cw alkyl group, which is substituted by an oxidized thiol as needed, and optionally substituted with an oxidized thiol, (10) cyano group, (11) fluorenyl group, (12) A substituted oxazolyl group or (13) 1,3-dioxopentacycloalkyl group; R3 is (1) a pyrazolyl group optionally substituted, (2) an optionally substituted oxazolyl group, 3) an imidazole which is substituted as needed [U-ap is pyridyl, (4) 1,2,4-dijunyl which may be substituted as desired or (5) a tetrazolyl which is optionally substituted; and r5 represents benzene a base having a cyano group at the 4 or 3 position and further substituted; (lb) : compound I), wherein R1 is (1) a hydrogen atom, (2) a cyano group, (3) a Cu alkyl group which is required to be normalized, or (4) a c1-6 alkoxy-carbonyl group R 2 having a substituent R4 is the same or different and is respectively (1) a hydrogen atom, (2) a Ci 6 I) alkyl group, (3) a C3_6 cycloalkyl group, (4) a trifluoromethyl group, (5) an amine group - a C 6 alkyl group, (6) a mono- or di-substituted amino-Ci_6 alkyl group, (7) a halogenated group which is optionally substituted by a hydroxyl group which is optionally substituted, (8) c26 alkenyl group, which is optionally Substituted hydroxy-substituted, (9) alkyl group, which is optionally substituted and optionally substituted by oxidized thiol, (1 〇) cyano, (11) fluorenyl, (12) as desired An oxazolyl or (13) 1,3-dioxopentane-2-yl group; r3 is an optionally substituted thiazolyl group; and R5 represents a phenyl group which may have a cyano group at the 4 or 3 position and may be further Substituting; (lc) : 319299 31 200813007 C1 ·6 force base or (3) as needed to replace c #像子, (2) as needed to be functionalized I·6 oxy group _ group; R2 fish R4

Compound (i) wherein Ri is (1) a 1,2,3-diazolyl group of a hydrogen atom, and R5 represents a phenyl group which may have a cyano group at the 4 or 3 position and may be further substituted; (Id): a compound (I), wherein R1 is (1) a hydrogen atom, (2) a cyano group or (3) a C 1-6 alkyl group which is optionally halogenated; R 2 and R 4 are the same or different and each are (1) a fluorene atom, (ii) Cu alkyl, (out) 〇3_6 cycloalkyl, (iv) trifluoromethyl, (v) amino-Cw alkyl, wherein the amine group is mono- or disubstituted by Cw alkyl, (vi Halogenated (^_6 alkyl, which is substituted by a hydroxy group which may be substituted by a C1 -6 leumino group, (vii) a C2-6 fine group which is substituted by a group, and (viii) a Ci_6 alkyl group. Substituted by a thiol, and the thiol can be substituted by a C!-6 alkyl group and can be oxidized, (ix) cyano, (χ) (^_6 驴 、, (xi). oxasyl or (χϋ) , 3-dioxopenta-2-yl; R3 is (1) a substituted thiazolyl group, (ii) optionally substituted pyrazolyl, (iii) optionally substituted oxazolyl, (iv Substituted imidazo[1,2-a]acridinyl, (v) 1,2,3-triazole as needed Base, (vi) 1,2,4-triazolyl or (vii) optionally substituted by 32 319299 200813007 ^; and R5 is 4-cyanophenyl, 3-cyanophenyl , 4-cyano-3(trifluoromethyl)phenyl, 4-cyano-2-methylphenyl or 3-chloro-4-yl-2-phenyl; (Ie) ·· 4 mouth (1) 'R is a hydrogen atom, a cyano group or a trifluoromethyl group; R2 and R are the same or different' and each is a hydrogen atom, optionally a Ci-6 alkyl C3_6% alkyl group having a hydroxyl group, a trifluoromethyl group, a cyano group Or a thiol group; r3 is a thiosaltyl group, a decyl group, a sulphonyl group, a sulphonic [ua]pyridinyl group, a fluorene bistriazole group, a 1,2,4-triazolyl group or a tetrazolyl group, and each may have 2 to 3 substituents selected from the group consisting of (1) methyl, (2) hydroxymethyl, (3) 1-hydroxyethyl, (4) hydroxy" methylethyl, (5) trifluoromethyl a group, a (6) a group, a (7) methoxy group, (8) an amine group, a (9) N-nonylamino group, a (1) cyano group and a (u) fluorenyl group; Phenylphenyl, 3-cyanophenyl, 4·cyano-3-trifluoromethyl)phenyl, 4-cyano-2-methylphenyl or 3-chloro-4-cyanophenyl. If): Compound (I), wherein R1 is (1) hydrogen a (2) cyano group or (3) a Cu alkyl group having 1 to 3 halogen atoms as needed; R is (1) a Cu alkyl group, (2) a C3_6 cycloalkyl group, (3) a trifluoromethyl group, (4) a Ci_6 alkyl group substituted by a hydroxy group or (5) a cyano group; R3 is (1) optionally substituted with 1 or 2 substituents selected from the group consisting of the substituents selected from the group consisting of ')d-6 alkyl group, which is optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxyl group, (2,) an amine carbenyl group, and a (3,) cyano group (2) π-pyrazolyl group optionally substituted with one substituent selected from the group consisting of (1,)c _6 alkane 33 319299 200813007 base 'as needed 1 to 3 Substituted by a substituent comprising a group of a pertinoid atom and a radical group, (2,) Ck alkoxy-mono, (3') tracing, (4') amidyl, (5') a group of C "alkyl-amino decanoic acid group and (6') cyano group; (3) σ oxalyl group optionally substituted by 1 or 2 substituents selected from the group selected from the group consisting of (1') (^_6 alkyl, which can be substituted by a hydroxyl group, (2,) an amine a group of a fluorenyl group and a (3,) cyano group; (4) an imidazole n, 2_a] pyridine group, (5) 1,2,3-triazolyl, optionally having up to 3 halogen atoms as needed Substituted by Ci-6, (6) 1,2,4-triwaxyl or (7) tetrasqually; R is a (1) alkyl group, optionally selected from the group consisting of a hydroxyl group and a ketone group Substituent substitution, (2) trifluoromethyl and (4) cyano, and R5 represent phenyl, which may have a cyano group at the 4 or 3 position, and may further include (1) as desired. Substituted to a group of three halogen atoms of Ci6 alkyl group and (2) a halogen atom. (Ig) · · Compound (I) wherein R1 is a hydrogen atom, a cyano group or a trifluoromethyl group, which is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group or a trimethyl group. , cyano or fluorenyl; R3 is thiazolyl, σ-bisazolyl, oxazolyl, imidazo[Ha]pyridyl, 1,2,3-triazolyl, limenazolyl or tetrazolyl, individually There are 1 to 3 substituents selected from the group consisting of (1) 1-hydroxyl-methyl/ethyl, (2) trifluoromethyl and (3) cyano, and R4 is a hydrogen atom, Base, ethyl, propyl: isopropyl, cyclopropyl, trifluoromethyl, cyano or decyl; and R5 is 3-cyanophenyl, 'aryltrifluoromethyl)phenyl, 3' Gas | alkyl phenyl, 4-cyano-24 phenyl or 4-cyanophenyl. Particularly preferred is (1) 4_(2,5, dimethyl small {[3_(trifluoromethyl) beast 319299 34 200813007 oxazol-5-yl]methyl}-1 Η-pyrrol-3-yl)benzonitrile, (9) 3-(4-cyanophenyl)-5•methyl small (1) fluorenylmethyl)m5_yl] fluorenyl}-1Η-ϋ ratio σ each-2 -曱 guess, (iii) 5-{[3- (4-cyanophenyl)_5•ethyl-2-methyl]yl]methyl}-111-° than 嗤-3-indene nitrile, (iv) 4_[2_methyl small GHH3·triazole_ 5_ylmethyl)_5_(trifluoromethylpyrrole_3_yl)benzonitrile, (7)2-{[3-cyano-o-cyanophenyl)_2,5-diindenyl squara ] 曱 }}-1,3-° stopper -4-carbonitrile, (10)4·(4-cyanophenyl)_2,5-dimethyl squad (trifluoromethyl...-indol-2-yl)曱基}-ΐΗ-吼 各 each 3-carbonitrile, (4)) 2·{[3-cyano_4_(4-cyanophenyl)_2,5-dimethyl·ΐΗ“比心心·基] mercapto}-1,3-oxazol-4-indene nitrile, (V111) 4-(4-cyanophenyl)_;[_imidazole [LLap pyridine-5-indenyl)_ 2 5_ Methyl-1H-pyrrole_3_indenenitrile or soil, I.(5)4·(1_{[3_(tetra)yl sulfhydrylethyl sitting _4 yl] fluorenyl fluorenyl-1H-fluorenyl _3_yl) Benzimidonitrile, or a salt thereof. ^ The salt of the compound (1) in the present invention, for example, Examples of salts, amines, organic salts, inorganic acid salts, organic acid salts, or acidity = acid salts, etc. Preferred examples of the metal salts include anathopantic metal-dina salt and Potassium salt; soil salt of soil-testing group such as: _ salt, magnesium salt and lock salt; Ming salt, etc. Preferred examples of organic salt include trimethylamine, triethylamine, ratio; methyl I疋, 2,6- a salt of a diterpene group, an ethanolamine, a diethanolamine, a triethanolamine, a hexylamine, a dicyclohexylamine, an N,N,-diphenylmethylethylidene diamine, etc. 319299 35 200813007 Class. Inorganic acid Preferred examples of the salt include salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred examples of the salts of the organic acid include formic acid, acid, trifluoroacetic acid, phthalic acid, and antibutanic acid. Salts of oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, p-toluene, etc. Preferred examples of salts of a test amino acids Including arginine: salts of amidic acid, ornithic acid, and the like, and preferred examples of salts of acidic amino acids include aspartic acid, face acid, and the like Salts. In the above examples, pharmaceutically acceptable salts are preferred. For example, those having acidic functional groups in the compounds are inorganic salts such as metal salts (such as sodium salts, potassium salts, etc.) and alkalis. Examples include earth metal salts (such as calcium salts, magnesium salts, barium salts, etc.), and amine salts, etc. In addition, those having an inactive functional group in the compound are salts of inorganic acids such as hydrochloric acid, hydrogen acid, and acid. a salt of a sulfuric acid, a sulphuric acid or the like or a salt of an organic acid such as acetic acid, phthalic acid, antibutanic acid, tartaric acid, methic acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, etc. The salt is an example. & The compound (1) of the present invention means that the compound can be converted into a compound in the physiological state of the living body, the lower jaw is reacted by an enzyme or a gastric acid, and the compound is converted into a compound by an enzyme oxidation, reduction, hydrolysis or the like. σ) or μ converts the compound into a compound by hydrolysis by gastric acid or the like. Examples of the prodrug of the substance (1) include a compound in which the amine of the compound (I) is enthalpy: pit-formed or dish-acidified (for example, the amine of the compound (1) is a di- or di-propyl group, a pentylamino group. , (5-methyl-2-retentive-1,3-::: cyclopental-4-boxoxy group, tetrahydrocarbamate, pyrrolidylmethylated, neopentyloxy Methylation 319299 36 200813007 (pivaloyloxymethylated) or a compound such as a third butylation; wherein the hydroxyl group of the compound (I) is deuterated, alkylated, phosphorylated or converted to a borate compound (eg, The hydroxyl group of the compound (I) is acetylated, palmylated, glycerolated, neopentylated, amberated, butylated, propylamine or decylaminocarbonylcarbonyl. And a compound wherein the carboxyl group of the compound (1) is esterified or amided (for example, wherein the carboxyl group of the compound (1) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylamine Methyl esterification, neopentyloxycarbonyl group S, ethoxylated ethoxyethyl ester, thiol esterification, (5-methyl a compound such as 2-keto-1,3-dioxol-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification or methylammonium amide. (1) It is prepared by a known method by itself. Further, the compound (I) may be a compound which can be converted into the compound (I) under physiological conditions, such as "Development of Drugs", Volumn 7, Molecular Design, Hirokawa Shoten, 1990, pages 163-198. Next, a method of preparing the compound (I) and salts thereof will be described. In the following preparation methods, an alkylation reaction, a hydrolysis reaction, an amination reaction, and an esterification reaction are carried out. , amidoximation reaction, etherification reaction, oxidation reaction, reduction reaction, etc., such reactions are carried out in a manner known per se. Examples of such methods include as in "ORGANIC FUNCTIONAL GROUP PREPARATION, 2nd edition, ACADEMIC PRESS INC .?published in 1989"", "Comprehensive Organic Transformations, VCH Publishers Inc" published in 1999" 37 319299 200813007, etc. Further, the product can be dissolved in the reaction The form is used for the subsequent reaction, or it can be used as a crude product, but it can also be separated from the reaction by the method of self-determination, and the general separation method (such as re-knot, bamboo, mouth) Days, retort, layering, and easy to produce. (3) Aji) The compound (1) of the present invention or a salt thereof can be obtained by a known method or the like in addition to the method shown in the following reaction scheme or the like. The compound shown can be obtained by reacting a compound represented by the formula (?) with a compound represented by the formula (m). The compound represented by the formula (ν) itself is contained in the compound represented by the formula (1). .../ by a method known per se or a similar method (for example: reduction reaction, catalytic hydrogenation reaction, deuteration reaction, oxidation reaction, alkylation reaction, hydrolysis reaction, hydrazide reaction, dehydration reaction, decarboxylation reaction, dealkylation) The carbonyl group reaction, the sulfurization reaction, the trifluoromethylation reaction, and the like) are carried out by functional group conversion of the compound represented by the formula (IV), and the compound contained in the formula (1) can be derived. Further, when the protecting group is bonded to the compound represented by the formula (??), it can be removed by a method known per se or the like to obtain a compound represented by the formula (1). The compound of the formula (VI) or a salt thereof can be obtained by reacting a compound represented by the formula with a compound represented by the formula (V), and further, by a method known per se or the like (for example) ·Reduction reaction, catalytic hydrogenation reaction, brewing reaction, oxidation reaction, alkylation reaction, hydrolysis reaction, guanidine reaction, dehydration reaction, decarboxylation reaction, dealkyloxycarbonyl reaction, sulfurization reaction, trifluoromethylation reaction The compound represented by the formula (VI) or a salt thereof can be derived by performing a functional group conversion of the compound represented by the formula (VI). 38 319299 200813007 Further, a compound represented by the formula (VII) and a compound represented by the formula (VI) can be subjected to a cyclization reaction by a method as described in the following documents or the like, whereby the formula (IV) can be obtained. The compound shown. This document is (Chem. Pharm. Bull. 1979, Vol. 27? pp 793 ^ Heterocycles 1987, Vol. 26, pp 947, Tetrahedron 1994, Vol. 60, pp 901 and J. Am. Chem. Soc. 1982, Vol. Pp4461). Reaction diagram 1

In the reaction of each of the compounds of Figure 1, X represents a leaving group such as a halogen, R3' represents an optionally substituted thiazolyl group, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted. Imidazole [l,2-a] pyridyl, optionally substituted 1,2,3-triazolyl, optionally substituted 1,2,4-triazolyl or optionally substituted tetrazolyl And the R3's "optionally substituted carbazolyl", "optionally substituted pyrazolyl", "optional 39 319299 200813007 substituted oxazolyl", "optionally substituted pyridine" "", "1,2,3-trisyl group as needed", "l,2,4-triazolyl as required" and "tetrazolyl as appropriate" As the substituent, a substituent similar to the above R3 can be used. R3'' and R3'" denote a substituent which is converted to R3 by a cyclization reaction, for example, an optionally substituted C _ 6 alkyl group, a decyl group, an optionally substituted fluorenyl group, an optionally substituted amine A thiol group, a thioamine group, etc.; and the "C--6 alkyl group which is substituted as needed", "the thiol group which is optionally substituted" and the "amino group which is substituted as needed" As the "substituent", a substituent similar to the above R3 may be used. Others are as defined above, but may be protected by a protecting group commonly used for organic synthesis, if necessary. The compound in the reaction diagram includes the case of forming a salt. Examples of the salts include those similar to those exemplified for the compound (1), etc. Compounds („), (111), and (1¥) which are isolated materials can be known by known methods (for example, Japanese dragon fan 3_252854). Or a synthetic method thereof, and, for example, can be produced by the method described in the following Reference Examples; in addition, the commercial product can also be used as it is commercially available. Reaction Scheme> In a known manner, the compound (IV) or: = can be formed by the compound (11) and the compound (the ruthenium compound (7), and the alkali metal hydride metal ruthenium amine such as aminated sodium is included in the sample. , Carbonate II test = money... Compound (9) about!.. to .... Mo 4 4 = Use! For each kiss, fight 4 is about 1·0 to 2·〇莫耳. 319299 40 200813007 Compound (III) or The compound (V) is used in an amount of from about L0 to about H) mole per 10 moles of the compound (Π). Preferably, it is from about h〇 to 2〇m. The reaction temperature is usually from about -70 ° C to about 1 Torr. Oh, preferably about 〇. The reaction time is usually from about 5 minutes to about 48 hours, and preferably from about 5 minutes to about 20 hours. This reaction usually acts in an organic solvent which does not adversely affect the reaction. The organic solvent which does not adversely affect the reaction, for example, ethers such as diethyl ether, dioxane and tetrahydrofuran (THF), saturated hydrocarbons such as calcined and pentane, toothed hydrocarbons For example, methylene chloride and chloroform, guanamines such as N,N-methylmethanoamine (DMF), aromatic carbonium compounds such as benzene and toluene are available; and the solvents may be used alone or in appropriate Mix two or more types in proportion. In the reaction scheme 1, in the case where the protecting group is 1> butyl, triphenylmethyl, t-butoxycarbonyl, phenoxycarbonyl, or the like, the deprotection reaction can give the compound (IV) It is carried out by acid treatment and is carried out in a solvent which does not adversely influence the reaction. Examples of the solvent include ethers, hydrocarbons, halogenated hydrocarbons, ketones, nitriles, acid amines, esters, and organic acids; preferred solvents are ethers, carbonium compounds, and halogenated carbonium compounds. These solvents may be used singly or in combination of two or more kinds in an appropriate ratio. For the acid, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; organic acids such as citric acid, acetic acid, trifluoroacetic acid (TFA) and p-toluene citrate; Lewis acid (Lewis acid) can be used. The tribromide and the oxime gum may be used singly or in combination of two or more. The amount of the acid to be used is usually from 1 to 41 319299 200813007 1 〇 0 to /5 Torr per 1 mole of the compound (IV), but the excess may also be used as a solvent. When the anti-banking is 2, the suspension is from 72° 〇 to 1 〇 (rC and preferably 旳 to 6crc. The reverse 间 吊 is 0.5 00 hours and preferably 〇 5 to 48 hours. The oxycarbonyl group, the benzyl group or the benzyloxymethyl hydrazine can be hunted by performing catalytic hydrogenation under conditions similar to those described above, and when the protecting group is neopentyloxymethyl group, etc., stand! The hydrolysis reaction is carried out on the several groups of compounds under the foregoing conditions: the original reaction 14 is removed by the burning reaction. (4) The original reaction can be carried out using a reducing agent generally used for organic synthesis, for example, monohydrogenation, murine base Sodium hydride, triethyl oxime side, sodium hydride; hydrogen hydride clock and hydrogenated clock, and can be added with metal salts such as chlorination. The use of reduction d is 1 per mole of compound (Iv) Or (V) about 1.0 to 10 moles, preferably 10 to 5 moles. The reaction temperature is usually from about -70X; to about 1〇〇t, preferably from about 吖 to about 50C. The reaction time is usually It is from about 3 minutes to about 5 hours, and preferably from about 30 minutes to about 20 hours. The soil reaction usually acts in an organic solvent which does not adversely affect the reaction. An organic solvent which does not adversely influence the reaction, for example, an alcohol such as methanol, ethanol and 2-propanol, an ether such as diethyl ether, dioxane and tetrahydrofuran (THJF), a saturated hydrocarbon such as Hexane and pentane and aromatic hydrocarbons such as benzene and toluene may be used, and the solvents may be used singly or in combination of two or more kinds in appropriate proportions. The catalytic hydrogenation reaction can be generally used for organic synthesis. In the presence of a metal catalyst, react with hydrogen to carry out 'palladium carbide and platinum carbide, and add mineral 329299 42 200813007. Acids such as hydrochloric acid and organic acids such as acetic acid. The metal catalyst is usually used in a compound per h0 mole (ιν) Or (VI) is used in an amount of from about 0.01 to about 1 mole equivalent, preferably from about 1 to about 2. The reaction temperature is usually from about -1 (rc to about 10 (rc and preferably about 〇.〇). To about 50 ° C; the reaction time is usually from about 30 minutes to about 5 hours and from about 30 minutes to about 20 hours. The soil reaction is usually carried out in an organic solvent which does not adversely affect the reaction. Affected organic solvents, examples Alcohols, alcohols and 2-propanol, ruthenium bis, di 〇xane and tetrahydroanthracene (THF), and hydrocarbons #己烧和戊烧Aromatic carbonium compounds such as benzene and toluene may be used, and the solvents may be used alone or in combination of two or more in an appropriate ratio. The deuteration reaction can be generally carried out for organic synthesis, for example, · The use of a hydrating agent such as an organic acid, a halogenated sulfhydryl group and an acid can be carried out in the presence of a base. For example, an alkali metal salt such as sodium nitride, carbonic acid, sodium carbonate or hydroxide can be removed. Sodium hydroxide, and organically, triethylamine, diisopropylethylamine and pyridine are available. The acidifying agent is usually used in an amount of from 1 to 2 G mole equivalent, preferably from 2 to 1 (mole equivalent) per LG mole of the compound (IV) or (VI). For use in the test, for each 1.0 mole of compound (IV) or (νι), use 丨 to (7) mole, which is 1 to 5 mole equivalents; and the excess amount can be regarded as a solvent. The reaction temperature is usually from about 0 ° C to about 12 (TC, preferably about 2 (TC to 319299 43 200813007 about loot: the reaction time is usually about 0.5 to 1 hour, and preferably about 1 to 48 hours). The reaction is usually carried out in an organic solvent which does not adversely affect the reaction. Examples of the organic solvent which does not adversely affect the reaction include a scorpion, a carbonitride, a functional hydrocarbon, a hydrazine, a guess, and a brew. Amines, _ = aromatic amines, heterocyclics, etc.; preferred solvents are Guan, carbonitrides, functional hydrocarbons, guanamines, aromatic amines and heterocyclics. These solvents can be used alone/ Or mixing two or more kinds in an appropriate ratio. Oxidation reaction is usually carried out in a solvent which does not adversely influence the reaction, using an oxidizing agent generally used for organic synthesis, for example, a compound such as potassium perchlorate and dioxide A chromium compound such as chromic acid, a bromine compound such as nitric acid (IV) and a sulfide such as dimethyl hydrazine may be used in the presence of an acid or a test if necessary. Examples of the solvent include water and hydrocarbon. Compound, toothed carbon ruthenium compound, alcohol Classes, ketones, organic acids, guanamines, esters and sulfoxides. Preferred solvents are water, hydrogen barrier compounds, halogenated carbon and chlorine compounds, terpenoids, organic acids, guanamines, esters and sulfoxides. Or the appropriate ratio (4) combined with two kinds of ❹. ^ Early use of the acid alone, for example, sulphuric acid such as sulfuric acid and organic acids such as acetic acid can be used. For the base, for example, the test metal salts For example, potassium hydroxide and sodium hydroxide and amines such as triethylamine, diisopropylethylamine and (tetra) (10) eridine may be used; in addition, if necessary, a dehydrating agent such as dicyclohexylcarbodiimide (dleyciQhexylearbGdiimide) may be used. And can also add grass 醯 chlorine (〇x mail c loride), pyridine sulfur trioxide, etc. The amount of oxidant used is usually every L0 mole of compound (IV) or (νι) 319299 44 200813007 use 1 to 20 Mo The ear, preferably i to 1 Torr, and the excess amount can be regarded as a solvent; the acid and base are usually used in an amount of 1 to 2 moles per mole of the compound (ι & or (VI) 1 to 2 moles Preferably, it is i to 1 mole. In addition, the amount of the additive is usually every L0 mole. The substance (IV) or (νι) uses i < to 20 mol, preferably 1 to 1 mol. The reaction temperature is usually from -7 to 12 (rc, preferably from 7 to 1 C). The reaction time is usually from 〇 to 1 〇M, and preferably from 1 to μ hours. The sintering reaction can be carried out by a conventional method, and the compound (IV) or (VI) and the compound are present in the presence of (d). (V) The reaction proceeds.

Examples of the base include hydrogenated metal such as sodium hydride and chloride, and metal amide such as sodium amination, potassium carbonate and the like. The base is usually used in an amount of from L0 to 10 mol, preferably from work to 2.0 mol, per U of the mole of the compound (IV) or (VI). The compound (V) is usually used in an amount of from 1.0 to 10 moles per (VI), and preferably the reaction temperature is usually from about -70 ° C to about 50 ° C. The reaction time is usually Approximately 5 minutes from about 5 minutes to about 20 hours. Molar compound (IV) or 1·〇 to 2.0 moles. About 100C, preferably about 〇. 〇 to knife ginger to about 48 hours, and preferably + The Chinese material is suspended in an organic solvent which does not adversely affect the reaction, and has no adverse effect on the reaction, for example, (4) + B, di X di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di di Compounds such as hexidine and glutinous L compounds such as diterpenoids: such as hydrazine, aromatic compounds such as benzene and toluene: 319299 45 200813007 and so on ~ = used alone, or mixed in appropriate proportions of two or more. The burning reaction of the σ substance can be carried out by reacting a certain group of compounds with a domesticizing agent in a solvent which does not adversely influence the reaction, and if necessary, an additive may be present. 'Ten pairs of burning ^ example, Lv, organic magnesium reagent such as burning Magnesium dentate, and organic clock compounds such as a burn-in clock are available. Examples of solvents include hydrocarbons. Hexyl, hydrazines such as diethyl ether, ethers. The solvent may be used singly or in combination of two or more in an appropriate ratio. The organomagnesium reagent or the organic clock compound is usually used in an amount of 1 mole per mole of the compound ( IV) or (VI) using mo motes, preferably from ! to 10, the reaction temperature is usually from about -7 (rc to about 10 (rc, preferably from about Wei to about 50 C: reaction time is usually about 5 hours) Up to about 24 hours. The hydrolysis reaction can be carried out using an acid or an assay generally used for organic synthesis. ^ For the acid, for example, a mineral acid such as hydrochloric acid, a Lewis acid, a Lewis acid and a thiol (10) 1) or a group of sulphide (such as 1 touch) and organic acids such as TFA and p-toluene can be used. For example, metal hydroxides such as potassium hydroxide, hydroxide 2 and barium hydroxide; Salts such as sodium carbonate and carbonic acid unloading; metal-burning oxides such as nail carvings, etc. are available. There are compounds such as diethylamine, saliva and alkali which are usually used per mole of compound called Ge (four) • to about 50 moles, preferably from about 1 to about 20 moles. 319299 46 200813007 Medium class = pass, acting on the opposite An organic solvent which does not adversely affect the organic solvent 2 reaction without adverse effects, for example, an alcohol, an aromatic hydrocarbon, an aliphatic chlorocarbon, a dentate carbon hydrazine, water, or two or more of the above A wide variety of mixtures can be used. The reaction time is usually from about 1 G minutes to about 5 M, and from 30 minutes to about 2 hours. The reaction temperature is usually about 〇. 〇 to about 2 (9), preferably about 20 °C to about 12 〇. The amination reaction can be carried out by means of a method generally used for organic synthesis to activate a living organism and then react with an aromatic (tetra)amine or an aliphatic amine, if necessary, in the presence of a evasive . Alternatively, it may be carried out by the action of a acetamide derivative, acetaminophen or an aliphatic amine, if any, in the presence of a reaction. * The material or additive is exemplified for the activator, and the chlorinating agent chlorine used for organic synthesis, the oximation agent generally used for organic synthesis, such as acid ox (four) under-vaporized, is generally used. Organically synthesized condensing agents such as 13-bis = diimine oxime-ethyl _3_(3'-dimethylaminopropyl) carbonization = amine 14 diethyl cyanophosphate or the like can be used. For the purpose of this additive, N_ _ its ugly - lysine or the like is available. &Basic open two Jun and N·经基獍 For the test example, organic tests such as diisopropyl and pyridine are available. The amount of activator used is usually red. The molar compound is used in an amount of from 1 to 10 mol, preferably from J to 5 ^ ^ A ^ 1 π ^ ^ , of me. The amount of the additive used is entangled as the mother. The compound (IV) or (VI side is used! to 20 moles, preferably 319299 47 200813007 is preferably 2 to 10 moles. The amount of the base is usually per i or (5) Use! To 10 moles, preferably compound σν) can be used as a solvent. Mohr, and the excess amount of reaction time is usually from about 10 minutes to about 5 hours, and is from /knife clock to 35u*. The reaction temperature is usually about, preferably from about 20 to about 80 t:. J 100C, the reaction is usually applied to the organic dissolution of the reaction without adversely affecting the reaction, #, = input, toothed hydrocarbons, steroids, human weathering a 鲈社~今丨*,...,I private class, heterocyclic class. Two ==, carbon gas compound side gas compounds and fermented slopes. The reaction can be carried out by using the organic solvent in the form of a dehydrating agent such as a sulfhydryl halide disk, if it is used alone or in an appropriate ratio of two or more. ^, Yu Wenxuan has no adverse effect on the reaction _, gas-breaking compounds 4 carbon oxides, _ Γ (four), hydrogen-absorbing compounds, and second class. Preferred solvents are hydrazine heterocycles. These two are: combined with: alkaloids, aromatic amines or more. Use, or mix two kinds of strontium carbonate in an appropriate ratio. Illustrative metal salts such as sodium hydride, carbonic acid unsalted fish = triethylamine, diisopropylethylamine (4) are available:

Dehydrated/used animal use A uses 1 to 20 grass: i:, 'mother. 〇 mol compound (iV) or (Vi) 4 ears, preferably 1 to W mole. The amount of the test is usually 319299 48 200813007 == Compound (IV) or (VI) is used to the ear to 1 to 5 moles and the excess amount can be used as a solvent. = The temperature should be usually from 吖 to 12 Qt, preferably from reaction day: usually from 55 to 50 hours, and preferably from 〇5 to ::,. The devitrification reaction can be carried out by the compound (IV) and (νι) in the presence of an organic compound which is not adversely affected or in the presence of a counter or metal salt: : = : if necessary, can be used in the acid, Examples of the π ° x / combined oxime include ethers, hydroreactivator 5, ketones, nitriles, guanamines, esters, organic acids and sulfonic acids. Preferred solvents are ethers, furnaces, water, compounds and sulphur, etc., and the hydrogenated hydrogenation of the teeth is used in the early days, or in appropriate proportions or in the appropriate proportions. In other words, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, and organic acids such as toluene acid can be used. For the whole hydrochloric acid ratio bite and the use of salts such as sodium chloride are available. In other words, the amount of the use of the test metal acid is usually from 0 to 耳, preferably from the heart to the % of the ear, and the amount of the super (four) can be used. The amount of the metal salt is usually 1 per gt; The synthesis of the ear is 30 moles, preferably +1 to 1 mole. The reaction temperature is usually crc to 200. 〇, preferably 〇. 〇 to 17 generations. The reaction time is usually 0.5 00 hours, and It is preferably from 〇5 to private hours. The sulfidation reaction can be carried out by using, for example, phosphorus pentasulfide or Lawesson's reagent.

This reaction is usually carried out in an organic solvent which does not adversely affect the enthalpy and preparation of the iridium I. 319299 49 200813007. The solvent (s), an aromatic hydrocarbon, an aliphatic hydrocarbon, a halogenated hydrocarbon, or a mixture of two or more of the above may be used. Five stone melon-disc or Lawson reagents are usually used in an amount of σν per i Q mole of the compound or (5) using 〇5 to 3 Torr, preferably 〇.5 to ι〇. The reaction temperature is usually It is about (rc to about 15 (rc, preferably about 2 to about 12 (TC. The reaction time is usually from 1 minute to about 5 hours, and preferably from about 30 minutes to about 12 hours.) The fluoropurification reaction can be carried out by using a trifluoromethylating agent in the presence of an aromatic compound or a bromide and a metal reagent, and if necessary, in the presence of a common method for organic synthesis. For metal reagents, for example, copper reagents such as copper chloride, copper desert, copper iodide and copper metal, and palladium reagents such as dichlorobis (triphenylph〇sphine palladium) are available. For the trifluoromethylation reagent, for example, an anthrone reagent such as triethyltrifluoromethyl calcin (tnethyltriflu〇rGmethylsilane) and a g-like derivative such as ethyl chlorodifluoroacetate and fluorosulfonyl (second) Methyl fluoroacetate is available for use. For basic examples, basic metal salts such as potassium carbonate and carbonic acid Sodium and plated potassium and organic tests such as triethylamine, diisopropylethylamine and (iv) are available. The amount of the metal reagent is usually 1 mole per mole of compound (ιν) or (VI). Up to 10 moles, preferably i to 5 moles. The amount of the trifluoromethyl landscaping reagent is from 1 to 20 moles per mole of the compound (ιν) or (Μ) of the G mole. It is 2 to 1 mole. The amount of base used is usually used per mole of compound (iv) or (VI)! to 1 mole, preferably ι to '5 319299 50 200813007 mole, and beyond The amount of the main reaction can be used as a solvent. The main reaction time is usually from 10 minutes to about 50 hours, and preferably about 5% of the turmeric, ', spoon 12 hours τ. The reaction temperature is usually from about 〇 to about 1 〇〇, Fortunately, it is about 20 ° C to about 80 ° C. 'The present reaction is usually applied to an organic solvent which does not adversely affect the reaction. The organic solvent which does not adversely affect the reaction is exemplified by ethers and hydrocarbons. , halogenated hydrocarbons, ketones, nitriles, decylamines, heterocyclics, etc., preferred solvents are ethers, hydrocarbons, deuterated hydrocarbons and decylamine These solvents may be used singly or in combination of two or more in appropriate proportions. - In the example, I is produced in the free form by the above-mentioned reaction product, and can be converted in a conventional manner. Salt-forming, and if the target product obtained is produced as a salt, it can be converted into a free form or other salts in a conventional manner. The compound (1) obtained by the above preparation method or its salt can be used for π/ Knowing means to isolate or purify, for example, solvent extraction, liquid conversion, conversion solvation, crystallization, recrystallization and chromatography. When compound (I) or its salts have optical isomers, stereoisomers, structures An isomer (regi0is0mer) or a rotational isomer (isoal isomer), which is also contained in the compound (1) or a salt thereof, and each of which can be obtained by a synthesis method and/or a separation method known per se, respectively. As an f-compound. For example, when the optical isomer of the compound or its salt has an optical isomer, the optical isomer derived from the compound is also contained in the compound (1) or a salt thereof. Here, the optical isomer can be produced by a method known per se. 319299 200813007 The compound (i) or a salt thereof may be a hydrate or a non-hydrate. The compound (1) or a salt thereof can be labeled with an isotope (e.g., bis, etc. U C and 35S) The compound (I) or a salt thereof can be a crystal.

The compound (1) or a salt thereof can be subjected to a crystal known per se to prepare a crystal of the compound (1) or a salt thereof (referred to as a crystal of the present invention). In the case of the male sensitizer, which contains the compound (1) of the present invention or a salt thereof, the agent (hereinafter sometimes referred to as "the male antagonist of the present invention" antagonism" has low and no side effects. = as a t-king of music and a male receptor antagonist. The pharmaceutical and composition of the male receptor receptor antagonist of the lactating invention is a mammal: L animal (for example: mouse, rat, hamster, rabbit, I Miao, dog, cow, and sheep have excellent male receptor antagonism and/or inhibit prosta specific antigen (psa) production, which has excellent (oral) absorption and (metabolic) stability; It can be used as a therapeutic or prophylactic agent for dihalite-related diseases, for example, hormone-sensitive diseases at the second and/or male-independent stages, in the male-dependent phase and/or the male-independent phase. = sensitive cancer (such as prostate cancer (such as · hormone-dependent prostate cancer, stimulating, etc.), uterine cancer, breast cancer (including progressive breast cancer, r ' / / adenocarcinoma, non-invasive gland Intraductal cancer, inflammation Sexual breast cancer, etc.), f tumor, liver cancer (for example, primary liver cancer, extrahepatic cholangiocarcinoma, etc.), 4 sensitive diseases such as benign prostatic hyperplasia, endometriosis, uterus 319299 52 200813007 smooth muscle Tumor, early maturity, menstrual pain, no menstrual disease, premenstrual syndrome and polypoid ovarian syndrome (pleuritis 〇varian Syndr〇me), and can be used as contraceptive (or if there is a rebound effect after interruption of the drug as a preventive or treatment Infertility). In particular, the compound (1) or a salt thereof of the present invention is antagonistic to normal male and/or mutant male receptors, and may be in a male-dependent phase. And/or male hormone-independent stages of hormone-sensitive cancers exert excellent preventive or therapeutic effects. Among male and female receptor antagonists, male vocal tracts with antagonistic mutations (4) drugs or male receptors with increased sensitivity Any of the antagonists can be used as a prophylactic or therapeutic agent for hormone-sensitive cancers in the male-dependent phase and/or the male-supplementary stage. ', x contains the androgen receptors of the present invention. Medicine for anti-drugs _ Oral or parenteral μ (such as topical administration of rectal administration, intravenous administration; and the male receptor receptor antagonist of rt invention) and the pharmaceutical composition, For example: tablets (including sugar-coated ingots and film-coated tablets), powders, soft gels #), miscellaneous water,,,:): y* X "; capsules (including sharp sacs) for water main squirt, suppository or persistence The release may be via intravenous administration, intramuscular administration, subcutaneous administration> ejaculation, or direct administration to the target. The pharmaceutical composition which can be used in the preparation of the present invention is exemplified by various conventional examples. The formulation is mixed with the label, in the solid formulation =: = inorganic loading, examples and solvents in the liquid formulation, the solution solution 319299 53 200813007 buffer and mitigating agent ( Soothing agent). Further, if necessary, general additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, and the like can be used in an appropriate amount. Examples of the excipients include lactose, white sugar, D-mannitol, coagulum, corn starch, crystalline cellulose, light anhydrous citric acid (light silicic acid, etc.) and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal stone, and the like. y Examples of binders include crystalline cellulose, white sugar, mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene tetrahydrofuranone, starch, sucrose, gelatin, methylcellulose, and fluorenyl. Cellulose and so on. Examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose oxime, methylidene starch, L-propylcellulose, and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like. Examples of the co-solvent include polyethylene glycol, propylene glycol, D-mannitol, benzoquinone, methazine, ethanol, trisamin 〇 inethane, cholesterol, diethanolamine, sodium carbonate, sodium citrate, and the like. Examples of suspending agents include interfacial active agents such as octadecyl triethanolamine, sodium dodecyl sulfate, dodecylaminopropionic acid, lecithin, benzalconium chloride, and benzethonium chloride. , glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, thiol cellulose, carboxymethyl cellulose, carbonyl ethyl cellulose, carbonyl propyl cellulose Wait. 54 319299 200813007 Examples of mannose agent include glucose, mountain (10), gasification sodium, glycerin, D-, etc. Buffering examples include phosphate, acetate, carbonic acid, salt, and citric acid. Examples of hydrazine are benzyl alcohol. Chlorobutanol, benzyl alcohol #Preservatives include, for example, p-oxybenzoic acid phenylethyl alcohol, dehydrated acetic acid, sorbic acid, and the like. The oxidizing agent is exemplified by sulfite, ascorbic acid, α-fertility, and the like. The male drug receptor antagonist of the present invention contained in the drug composition of the present invention is a second embodiment: administration to a subject, administration route, disease, and the like. Although it will be based on the basic two: the same 'but the usual amount, for example, the total amount of the preparation is the foundation, about 0. 01 to 100 weight is preferably 0.5-20% by weight. ^ is 50% by weight, and the dosage form is different, but based on the total amount of the preparation, the content of the additive (such as a carrier) contained in the second embodiment is usually from about 1 to 9.99% by weight, preferably from 10 to 90% by weight. use. : The male steroidal antagonist has low toxicity, so it can be safely used, and the dosage of the male receptor receptor can be different depending on the type of compound, the second year, the dosage form, the administration method, etc., however, 10 hang. 1 to about 1000 mg / kg, preferably about 0.01;, to: ? , _ , ] ι > · 1 to about 5 〇 mg / kg, especially # >,. Ming male receptor; heart two: about 6 〇 kg) of each intravenous administration; Second: cancer patients ( In the case of _ human or district fractional dose 319299 55 200813007 As mentioned above, the dosage will vary depending on the conditions, in some cases, a small dose may be sufficient, and in some cases the required dose may exceed The above-mentioned range of drugs which can be used in combination with the androgen receptor antagonist of the present invention, for example, hormone therapeutic drugs, anticancer drugs (eg, chemotherapy drugs, immunotherapy drugs (including vaccines), antibodies, gene therapy drugs a drug which inhibits the action of a cell growth factor and its receptor, or a drug which inhibits angiogenesis, etc. (hereinafter referred to as a concomitant drug) can be used in combination. Although the compound of the present invention has an effective anticancer activity when used alone, Its efficacy can be enhanced by further use of one or more combinations of the above concomitant drugs (combination of multiple drugs).

For the "hormone therapy", for example, the female test, vinyl female, chlorotrianisene, medroxyprogesterone acetate, megestrol Acetate, chloride Chlormadinone acetate, cyproterone acetate, danazol, dienogest, progesterone receptor modulator (asoprisnil), allylestrol, pregnancy Gestrinone, nomegestrol, tadenan, mepartricin, raloxifene, ormeloxifene, dextromethorphan Levormeloxifene), anti-estrogen (such as tamoxifen citrate, tremifene citrate, etc.), ER down-regulator (such as fulvestrant) Etc., human menopausal gonadotropin, follicle stimulating hormone, oral contraceptive preparation, mepitiostane, testrolactone, aminoglutetethimide, LH-RH 56 319299 200813007 derivatives ( Such as : LH-RH agonist (such as: goserelin acetate, buserelin, leuprorelin acetate, etc.), LH-RH antagonist), Quluo Droloxifene, epitiostolol, ethinylestradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, comedy) Oral (letrozole), exemestane, vorozole, formestane, etc., anti-androgen (eg, flutamide, bicalutamide, Nilutamide, etc., 5 α -reductase inhibitors (eg, finasteride, dutasteride, epristeride, etc.), corticosteroids (eg: Dexamethasone, predonisolone, betamethasone, triamcinolone, etc., and male synthesis inhibitors (eg, abiraterone, etc.) Visual pigment and slowing Pigment metabolism of drugs (such as: Lia saliva (liarozole), etc.) available for use. For the "chemotherapeutic drugs", for example, an alkylating drug, an antimetabolite, an anticancer antibiotic, a plant-derived anticancer drug, and other chemotherapeutic drugs are available. For the "alkylating drug", for example, nitrogen mustard, hydrochloric acid mustard-N-oxide, nitrogen mustard butyric acid, cyclophosphamide, ifosfamide, thiotepa , carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, dibromomannitol 57 319299 200813007 (mitobronitol), amphetamine Acid mustard, dacarbazine, ranimustine, estazolam sodium, tri-ethyl melamine, carmustine, lomustine, streptozoto Streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaplatin Oxalplatin, Altretamine, ambamustine, dibrospidium hydrochloride, florol, fotemustine, prednimustine , pumitepa, Ribosumtin, temozolomide, treosulfan, trophosphamide, zinostatin stimalamer, Adozelesin, Cystemustine, bizelesin, etc. are available. For the "anti-metabolite", for example, mercaptopurine, 6_mercaptopurine riboside, thioinosine, methotrexate, ennotebine (enocitabine) ), cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (such as · fluoride urea, tegafur ( Tegafur), UFT, dexifluridine, carmofor, gallocitabine, emmitefur, etc., aminopterin, chrysanthemum folic acid | (calcium leucovorin), sulphur guanine 58 319299 200813007 (tabloid), 17 votes new (butocine), folinate calcium, levofolinatecalcium, cladribine, 乙口Emitefur, fludarabine, gemcitabine (86111 (^& 1311^), basal gland (11}^(11*0\}^&1^&1111< ^), pentostatin, piritrexim, idoxur Idine), mitoguazone, tiazofurine, ambamustine, etc. For the "anticancer antibiotic", for example, actinomycin D, actinomycin C, mitogen microtin C, color microtin A3, Bleomycin hydrochloride, Bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, Doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, Mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, hydrochloric acid Idarubicin hydrochloride and the like are available. For example, the "plant-derived anticancer drug", etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate (vincristine) Sulfate, vindesine sulfate, tenipophene 59 319299 200813007 (teniposide), paclitaxel, docetaxel, vinorelbine, irinotecan ), topotecan, etc. are available. For the example of the "other chemotherapy drugs", sobuzoxane and the like are available. For the example of the "immunotherapy drug (BRM)", Picibanil, krestin, sizofiran, lentinan, and uranium (ubenimex), interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin ), lymphotoxin, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, etc. are available. In addition, vaccines such as BVG vaccine, PROVENGE, Onyvax-P, PROSTVAC-VF, GVAX, DCVax-Prostate, SAPOIMMUNE, VPM-4-001 are available. For antibodies, antibodies against EpiCAM, antibodies against PSCS, and antibodies against PSMA are available. For the "cell growth factor" which is a "drug which inhibits the action of the cell growth factor and its receptor", any substance which promotes cell growth can be used. In general, a factor which can be used is a peptide having a molecular weight of 20,000 or less, and which acts upon binding to a receptor at a low concentration, and specific examples include (1) EGF (epidermal growth factor) or substantially the same activity. Substance [eg: 60 319299 200813007 EGF, neuroregulin-1 (heregulin), TGF-α, HB-EGF, etc.]; (2) insulin (insulin) or substances with substantially the same activity [such as insulin, IGF ( Insulin-like growth factor, ILGF-2, etc.; (3) FGF (fibroblast growth factor) or substance with substantially the same activity [eg, acidic FGF, basic FGF) , KGF (keratinocyte growth factor), FGF-10, etc.; (4) other cell growth factors [eg CSF (community stimulating factor), EPO (erythropoietin), IL-2 (interleukin) -2), NGF (neural cell growth factor), PDGF (platelet-derived growth factor), TGF cold (transformation growth factor yS), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), and the like. The "cell growth factor receptor" may be any receptor having the ability to bind to the above-mentioned cell growth factor, and specific examples include HER2, HER3 and HER4 (which are EGF receptors and receptors belonging to the same family). Insulin receptor, IGF receptor, FGF receptor_1, FGF receptor-2 and the like. Examples of the "drug that inhibits the action of a cell growth factor" include Herceptin (Herceptin (trademark); HER2 antibody), imatinib mesylate, ZD1389 or cetuximab ( Cetuximab), gefitinib, erlotinib, and the like. For "anti-angiogenesis drugs", VEGF antibodies (such as bevacitumab), antibodies to VEGF receptors, VEGF receptor kinase inhibitors (such as SU11248), PDGF receptor kinase inhibitors, Tie2 receptors Kinase inhibitors, thalidomide, etc. are available. In addition to the above drugs, L-aspartate indolease 61 319299 200813007 (L-asparaginase), aceglatone, procarbazine hydrochloride, protoporphyrin cobalt (protoporphyrin cobalt) Complex), mercury hematoporphyrin sodium, differentiation inducer (such as retinoid, vitamin D group, etc.), α-blocker (α _blocker) (such as tamsulosin hydrochloride ( Tamsulosin hydrochloride, naftopidil, urapidil, alfuzosin, terazosin, prazosin, siropin D〇sin), etc., a serine sulphate kinase inhibitor, an endothelin receptor antagonist (such as atrasentan, etc.), a proteasome inhibitor (such as bortezomib) , Hsp90 inhibitors (such as 17-AAG, etc.), spironolactone, minoxidil, 11 α-hydroxyprogesterone, bone resorption inhibitors and anti-metastatic drugs (antimetastatic agent) (such as zoledronic acid (z Iedr〇nic acid), alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid Clodronic acid), etc. are available for use. Among them, as a preferred concomitant drug, an LH-RH derivative or the like can be represented. The LH-RH derivative includes, by way of example, an LH-RH derivative or a salt thereof, which is effective against a hormone-dependent disease, particularly a sex hormone-dependent cancer (such as prostate cancer, uterine cancer, breast cancer, pituitary tumor, liver cancer, etc.). , sex hormone-dependent diseases such as benign prostatic hyperplasia, endometriosis, uterine leiomyoma, precocious puberty, menstrual pain, no menstrual disease, premenstrual syndrome, polycystic ovary 62 319299 200813007 syndrome, and contraception (or if the drug is interrupted After the rebound effect caused infertility). Further, an LH-RH derivative or a salt thereof which is effective for LH-RH-sensitive but non-hormone-dependent benign or malignant tumors is also exemplified. Specific examples of the LH-RH derivative or a salt thereof include the peptide described in the following, for example, Treatment with GnRH analogs: Controversies and prespectives (published by Parthenon Publishing Group Ltd. inl996), JP-A H03- 503165, JP-A H03-101695, JP-A H07-97334 and JP-A H08-259460. For the LH_RH derivative, an LH-RH agonist or an LH_RH antagonist is exemplified. The LH-RH antagonist exemplifies a physiologically active peptide or a salt thereof represented by the following formula: X_D2Nal_D4ClPhe-D3Pal_Ser-AB-Leu-C_Pro_DAlaNH2 wherein X represents N(4H2-furanylmethyl)Gly or NAc, respectively. , A represents a residue selected from the group consisting of NMeTyr, Tyr, Aph (Atz) and NMeAph (Atz); B represents a residue selected from the group consisting of DLys (NiC), DCit, DLys (AzaglyNic), DLys (AzaglyFur), DhArg (Et2), DAph (Atz) and DhCi, and C represents Lys (Nisp), Arg or hArg (Et2). The LH-RH agonist is exemplified by a physiologically active peptide or a salt thereof represented by the following formula: 5·keto-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z wherein Respectively denotes Y represents a residue selected from the group consisting of DLeu, DAla, DTrp, DSer(tBu), D2Nal and DHis (ImBzl), and Z represents NH-C2H5 or Gly-NH2. In particular, Y is Dleu and Z is NH-C2H5 (ie, peptide A is 5-keto 63 319299 200813007 -Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pr〇. NH- C H # - · Liu Bolin (le-0_n)) peptide or its salts (such as acetate 2 5 ::; contains the male receptor receptor antagonist of the present invention and accompanying the compound ^ soil. The medicament of the composition of the invention accompanying medicament has: poison: lower: two =) by:: or enteral (such as topical administration, rectal administration, intravenous technique, puddle, mixed by the known method) The above-mentioned concomitant drug and the pharmaceutically acceptable carrier composition 'e.g., a tablet (including a sugar-coated key and a film-coating) = a pellet, a capsule (including a soft capsule), a syrup, and an injection-release injection can be passed through Intravenous administration, intramuscular administration, intra-injection (intraorganica), or direct administration to the target. This can be used to prepare the pharmaceutically acceptable carrier of the concomitant drug of the present invention: An organic or inorganic carrier of the formulation material, (iv) a thief-shaped agent, a lubricant, a binder, and a solvent in the disintegration formulation in the formulation Solubilizers, suspending agents, isotonic agents, 7 doses and mitigating agents. Even worse, if necessary, appropriate dosages, wetting agents, etc. 匕月] colorants, sweeteners, adsorption agents Examples include lactose, dinosaur powder, crystalline cellulose, light anhydrous mannitol, temple powder, corn soil, etc. Months exemplified by 3 magnesium stearate, calcium stearate, talc, sheng 矽 = mixture examples include crystalline cellulose , white sugar, d_mannitol, dextrin, cellulose, propylmethylcellulose, polyethylene ketone, 319299 64 200813007 powder, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc. Examples of the solvent include water for injection, alcohol, propylene glycol, and poly Ethylene glycol, sesame oil, corn oil, eucalyptus oil, etc. Examples of cosolvents include polyethylene glycol, propylene glycol, D-mannitol, benzoyl benzoate, ethanol, triamine methane, cholesterol, triethanolamine, sodium carbonate, Sodium citrate, etc. Suspension > Sexual agents such as octadecyl triethanolamine, sodium dodecyl sulfate, dodecylaminopropionic acid, lecithin, chlorinated benzalkonium chloride, benzammonium, glyceryl monostearate, etc.; hydrophilic polymers such as Polyvinyl alcohol, polypyridylpyrrolidone, sodium carboxymethylcellulose, sulfhydryl cellulose, carbonyl fluorenyl cellulose, carbonyl ethyl cellulose, carbonyl propyl cellulose, etc. Examples of isoparametric agents include glucose, Sorbitol, sodium chloride, glycerin, D·, etc. The buffering agent includes, for example, a disc acid salt, a curric acid salt, a Wei salt, and a sulphate acid mitigating agent, which comprises, for example, stupid methanol, etc. Examples of phenylethyl alcohol rot include p-oxybenzene. Formate, chlorobutanol, benzyl alcohol, Benyi: water, acid, sorbic acid, etc. Examples of π antioxidants are Xiao & = + > In the present invention, accompanying salts, ascorbic acid, fertility, and the like. The proportion of concomitant drugs can be adapted to the male androgen receptor antagonists and the like. Although it may be different depending on the preparation 2: depending on the individual to be administered, the route of administration, and the disease, but usually the amount of the antagonist of 319299 65 200813007 is based on the total amount of the agent in the accompanying drug of the present invention, about 〇.〇 1 to "A heavy / wide, to the weight%, more preferably 0.5 to 2 weight 0 / 〇. 〇乂 preferably is from 0.1 to 50 (four) form differently. In the concomitant agent of the present invention, the content of the P music is often (four), based on the total amount of the preparation, the medium agent is as in the present invention, and the money war (four) 3 is usually The weight %' is preferably from 10 to 9 % by weight based on the total amount of the preparation. And, from 1 to 99.98, the male receptor antagonist and the companion substance of the present invention are % of clothing, and the same content can be used. Agent. The burdocks can be produced according to known methods for producing a formulation process. The male and female receptor antagonists or concomitant drugs may be 14 dispersing agents (such as TWeen 80 (by ATRAS p〇WDER, Meipu 6〇 (NIKK〇CHEMICAL c〇, wd), poly ^ = Alcohol, = methyl cellulose, sodium alginate, methyl cellulose, dextrin, etc.), stabilizers (such as ascorbic acid, sodium metabisulfite, etc.), surfactants (such as MSI alcohol) ), etc., cosolvents (such as glycerin, ethanol, etc.), buffers (such as phosphoric acid and its basic metal salts, citric acid and alkaline metal salts, etc.), isotonic agents (such as sodium chloride, potassium chloride, nectar) Alcohol, sorbitol, glucose, etc.), pH adjusters (such as hydrochloric acid, sodium hydroxide, etc.), preservatives (such as ethyl p-oxybenzoate, benzene T acid, methylparabene, p-phenylpropyl) (pr〇pyiparabene), benzyl alcohol, etc., 319299 66 200813007 1 sword (such as concentrated glycerin, grape W (meghimine), white sugar, etc.), mitigating agents (such as glucose, "alcohol, etc.", etc. = (such as C, water Intravascular injection, or oily blood vessel injection by :: _ with: emulsified in a co-solvent such as vegetable oil (such as olive oil Sesame:, two suspensions are not oil) or propylene glycol to prepare an injectable injection. Sputum oil and jade are prepared for oral administration; starch, etc.), disintegration South] (such as lactose, sugar, Two primary gums, methine cellulose, polyethyl ether __丄 = can be, etc.), lubricants (such as talc, _ Lai # / propyl cellulose into the invention / gold W / Ethyl alcohol 6 〇〇 〇, etc.), etc., and the method of adding knowledge, and then use the known side of the body to achieve the taste of the mask or provide the intestinal (four) sex d two Z preparation. The coating agent, for example, _ TW =, Methyl cellulose, propyl cellulose acetal ρΜ^ΓΤ Ψ ^ (cellulose acetic acid (4):: ♦ o-F phthalic acid by propyl methyl cellulose, succinic acid eutrophic acid, Eudragit (by German r〇 Hm, (3) l system ', methyl propyl acid-acrylic acid polymer), coloring agent (such as heart = 1 dioxin, etc.) can be used. Oral preparation can be rapid release 诏 and sustained release preparation Any one of the above-mentioned male receptor receptors or the music can be made into oily or by a method known per se. Sexual solids, semi-solids. Suppositories. Examples of oily substrates used in the above compositions include glycerides of two fatty acids (such as cocoa butter, chasing by ladders 319299 67 200813007 (Ultepsols) (Dynamiten〇belc, Germany) 〇·Preparation), etc., medium fatty acids (such as Migri〇ls (manufactured by dynamite N〇BEL (3)·), vegetable oils (such as sesame oil, soybean oil, cotton oil, etc.). Further, examples of the soil bottom include polyethylene glycol and propylene glycol, and aqueous gel substrates include, for example, natural gums, cellulose derivatives, ethylene polymers, and the like. Examples of sustained release preparations include sustained release microcapsule preparations. Although there are known methods for preparing sustained release microcapsules, the formulation of the four soil performance release preparations is administered as described in the following [2]. The male antagonist of the present invention is preferably molded into a solid preparation (e.g., powder, granule, lozenge, and capsule) or a rectal administration of a suppository. Among them, oral preparations are preferred. The concomitant drug can be prepared as the above dosage form depending on the type of the drug. Agent 2] after secret, [1] the male receptor of the present invention antagonizes symplectic morphism (4) and its preparation method; [2] the male agent of the present invention; Γ;;: Γ drug rapid release preparation and holding (four) Sublingual androgen receptor antagonist or concomitant drug (9), buccal or intraoral disintegrating agent of the present invention and preparation method thereof. LJ Xueguanzhuang ejector and its preparation anti-drug ==!; preferably is where 'the male receptor receptor of the present invention is included herein: benzoate and/or salicylate in water 3 In this vascular injection. The blood test; the main injection can be dissolved in water 319299 68 by using the present invention, the ☆ accompanying drug, and the methionate and/or salicylate. Obtained in 200813007. The salts of the formic acid and salicylic acid include basic metal salts such as sodium and genus such as dianthine and magnesium, sulphate, glucosamine salt, and organic acid salts such as amines; and male receptor antagonists of the present invention Or concomitant drug concentration in blood (four) is about. The concentration of .5 to 50 w/v%, preferably 3 to the present formate and/or salicylate is G.5 to 5 GW/V%, preferably 3% to 20 w/v%. two two! It is known that an additive for an injectable injection can be appropriately blended into a solution such as a stabilizer (such as ascorbic acid, sodium metabisulfite surfactant (polysorbate 8), wheat (=rog〇al), etc. ), cosolvents (such as glycerin, ethanol, etc.), buffers (such as alkali metal salts, citric acid and its alkali metal salts), isotonic sodium, potassium chloride, etc.), dispersants (such as Cellulose, dextrin, etc.) (such as hydrochloric acid, sodium hydroxide, etc.), preservatives (such as parabenate: B, benzoic acid, etc.), solvent (such as concentrated sugar: by: A Amine, etc.), co-solvent (such as propylene glycol, white sugar, etc.), dexamethasone, benzyl alcohol, etc., etc. The additive is blended with - (examples of melon for blood injections, preferably with a pH adjuster for angi injections) The positive value is adjusted to 12, preferably 2.5 to 8.0, and the main = tube (4) can be antagonized by the male receptor of the present invention, if necessary, the benzoate and/or salicylate, and = ~Universal 'The above additives are obtained by dissolving in water. The dissolution procedure 319299 69 200813007 can be entered in any order According to the conventional method of blood official injection, the method of the squirting solution is preferably warm, and the method, the high-pressure twisting and reducing bacteria, the HI ejector T using filtration, and the solid-solid method For example, the blood vessels are sterilized. The same method as for hearing correction / M ] C * The liquid is preferably sterilized by high heat, and is subjected to the conditions of 5 to 3 minutes after the war. For example, It can be made into a product, a substance, a * pole, and from Ning, the Luo liquid has anti-microbial / it can be used for multiple separate administrations. [2] Continuous release preparation or rapid release preparation and its preparation method is preferably continuous The sexual release preparation, wherein t, the sputum contains the androgen receptor antagonist or concomitant drug of the present invention, and is coated with a coating agent as needed, such as a water-insoluble substance, a swelling polymer or the like. For example, a once-a-day oral administration of a sustained release preparation is preferred. Examples of the water-insoluble substance used for the coating agent include cellulose ethers such as ethyl cellulose, butyl cellulose, and the like, and cellulose. Esters such as cellulose acetate, vitamin vinegar, etc. g such as polyethylene vinegar, polybutyl vinegar, etc., acrylic polymer such as acrylic acid / methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl ethoxylate / sub-propyl Dilute acid cinnamon vinegar / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethyl methacrylate, alkyl methacrylate copolymer, poly (methacrylic acid, polymethacrylate, poly-f-group A acrylamide salt, an aminoalkyl methacrylate copolymer, a poly(methacrylic anhydride), a f-based propylene acrylate copolymer, in particular, Eudragit (ROHM, CO. LTD., manufactured) such as JEudragit 70 319299 200813007 RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-ΡΟ (ethyl acrylate / methyl methacrylate / tridecyl acrylate / ethyl ammonium copolymer) , Eudragit NE-30D (methyl methacrylate / ethyl acrylate copolymer), hardened oil such as hardened castor oil (such as Lovely Wax (FrointInds), etc.), waxes such as palm wax, fatty acid glycerides, paraffin, etc. Polyglycerol fatty acid esters and the like. With regard to the expanded polymer, it is preferred to have an acidic separable group and a pH-dependent swelling polymer, that is, an acidic separating group in which an acidic region such as a small swelling in the stomach is in the middle. Sexual regions such as polymers which swell in the small or large intestine are preferred. A polymer having an acidic separating group and a pH-dependent swelling, and examples thereof include a crosslinked polyacrylic acid polymer such as Carbomer 934P, 940, 941, 974P, 980 and 1342, and polycarbophil. ), polycarbophil calcium (manufactured by BF GOODRICH COM.) and High Bis Wako 103, 1〇4, l〇5 and 304 (manufactured by WAKO_CHEM). The coating agent for the sustained release preparation may further comprise a hydrophilic substance. The hydrophilic substance exemplifies a polysaccharide having a sulfate group such as pullulan, a dextrin and a metal alginate, and a burnt group or a carboxyl group such as hydroxypropylcellulose or hydroxypropyl. a polysaccharide of ketone-based fibrin with sodium carboxymethylcellulose, thioglycolic cellulose, polyethylene η-pyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like. The water-insoluble substance content in the sustained release preparation coating agent is about 319299 71 200813007 30 to about 90% (w/w), preferably ❸% to about 8% (w/w), and more preferably From about 40 to about 75% (w/w); the expanded polymer content is from about 约 to about 3 〇 = /w), and preferably from about 3 to about 15% (w/w). The coating agent can be fed into the hydrated material of the two 11 and in the case of the towel, the hydrophilic substance is about 50% or less in the coating agent, and the sputum is Μ 〇 〇 〇 , , , , , , It is from about 5 to about 40 Å/o (w/w), and more preferably from about 5 to about 35% (w/w). Here, the weight % of the coating composition, i.e., is applied to the coating solution (e.g., water, lower alcohol such as methanol, ethanol, etc.). Call or performance release Ao Mi system, a ... clothing, 'prepare the core of the drug, pick up the coating agent solution coated with or swell polymer to 埶, 容 solution, non-water soluble The substance is initially H or dissolved or dissolved in a solvent. J. Preparation of a core containing a drug A coating agent is used, and the core of the drug is contained, and the core of the product (hereinafter referred to as "the core j" is not particularly limited" granule or fine granule. The terracotta is in the form of granules, such as when the core is granules or fine granules, the average particle size is less than 2,000 microns (private call; ',,,,', secret, and 1 soil is about 50 〇 Up to 1,400 micrometers (vm). Core preparation can be carried out according to the general potential, one dose, in the sentence, 4, σ method, for example, a suitable shaped sheet 黏J binder, disintegrant, 涧, 典Rabbit 丨. ^ With the,, f 刎, stabilizer and other drugs mixed with the sputum by wet rubbing granule method 戋 six according to the drug in the core containing = 5 granules to prepare the preparation. ao 〇 / o (w /w), , 〇 铨 铨, 々 30 to about 70% (w/w). About lactose, mannitol, grape (four), Γ contained in the core, for example, 'sugars such as white sugar, 蠃 powder , cellulose, calcium phosphate, corn 319299 72 200813007 Temple powder can be used. Among them, crystalline cellulose and corn starch are preferred. For the adhesive, for example, examples can be used. · Polyvinyl alcohol, hydroxypropyl fiber Prime, xjx, B-fermented, poly-B fine σ, slightly burnt, piUr〇nic F68, gum arabic, gelatin, temple powder, etc. Preferred examples of disintegrants Wei methylcellulose #5 (ECG5〇5), crocinnellose sodium, cross-linked polyvinylpyrrolidone (Cr〇Sp〇vidone), Low-substituted hydroxypropylcellulose (L-HPC), etc. Among them, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferred. For glidants and anti-agglomerates For example, talc, magnesium stearate and its inorganic salts are available, and for lubricants, for example, ethyl alcohol can be used. For stabilizers, acids such as tartaric acid, citric acid, succinic acid, and anti-butene Diacids and maleic acid are available. In addition to the above preparation methods, the core can be further subjected to rolling granulation u (which is carried out when the spray is dissolved in an aqueous solvent such as water or a lower alcohol (such as A) , B, etc.) adhesive to the inert carrier particles to prepare the core center % 'small 1 small amount of drug or drug mixed flow agent, etc.), pot coating method, maternal pregnancy, + t For example, the granules are used in the following examples: (4) granulation method. For inerts or preparations; =, lactose, crystalline fiber U500 micron ((4). The average particle size is preferably about 1 〇〇 to separate the coating protection agent contained in the core for the self-coating agent, and the ancient water-insoluble material is exemplified for the protective agent. Available = hydrophilic substance, danic or sulphate polysaccharide is ethylene glycol and has been treated with propylmethylcellulose and hydroxy 319299 73 200813007 = base cellulose. The protective agent may contain acid as a stabilizer Such as tartaric acid, bar acid, succinic acid, succinic acid and fumaric acid, and glidants, such as / moonstone. When using a protective agent, the coating amount is about the core work

Up to about 15% (w/w), preferably from about 1 to about 10 Torr, more preferably about 8% (w/w) 〇, the protective agent can be applied by a general coating method, especially It is spray coated onto the core by a fluid bed coating method, a pan coating method or the like. II. Coating a Core Sustained Release Formulation with a Coating Agent The core obtained by the above τ can be produced by using a coating agent, wherein the above-mentioned water-insoluble substance, ρΗ depends on σ 兵 亲水 hydrophilic substance f can be heated to dissolve or dissolve or dissolve in the solvent ten? A core coating method using rt (tetra) h solution, such as a spray coating method. " 二水广: Biomass, PH-dependent swelling polymer or hydrophilic substance in coating == coverage is based on core (excluding protection; U5 to: 9°% (w/w), preferably More preferably from about 5 to about 35% (w/w). For the solvent of the coating solution, or as a mixture thereof. When using two =: for use alone (water/organic solvent: weight ratio) It can be mixed in i = organic solvent, preferably) to about 鸠. The organic = two 100% of the variable garden is not limited to 4 inches, as long as its 319299 74 200813007 soluble non-aqueous; gluten and low alcohol such as methanol, ethanol, isopropanol and n-butanol, low Carkanesones such as acetone, acetonitrile, chloroform and dichloromethane are preferred; among them, lower alcohols are preferred, and ethanol and isopropanol are particularly preferred. A mixture of water and water and an organic solvent is particularly suitable for use as a solvent for coating agents. At this time, if necessary, an acid such as tartaric acid, citric acid, amber bismuth, maleic acid, and fumaric acid to a coating agent solution may be added to stabilize the coating agent solution. # If the coating operation by spray coating can be carried out by a general coating method and = ' using a fluidized bed coating method, a bread coating method, etc., the coating agent solution is mainly applied to the core. At this time, if necessary, talc, dioxin, magnesium stearate, stearic acid _, light non-cut acid, etc. can be added as a glidant, 2 glycerin fatty acid vinegar, hardened sesame oil, triethyl citrate, cetyl wax Alcohol, octadecyl alcohol, etc. may be added as a plasticizer. After the application of the coating agent, an antistatic agent such as talc may be mixed in as needed. The body = sexual release preparation may be a liquid (solution, suspension, emulsion, etc.) or hemostatic, 4 doses, tablets, etc.). Although oral preparations and parenteral preparations such as B/priming agents are available, oral preparations are preferred. The carrier rapid release preparation, in addition to the active ingredient of the drug, the general inclusion f preparation = and the excipient (hereinafter referred to as the excipient short) are both pharmaceutical and bismuth users. The excipients used in the preparation are not particularly limited to those in which the excipients are removed. Oral solid coffee (AWCe; Η = contains lactose, temple powder, ... grain, Gan = Bu by slow fine coffee. Preparation), sugar powder, sugar... light hot water tannic acid, magnesium carbonate, calcium carbonate, l• cysteine Amino acid 319299 75 200813007, etc., preferably corn starch, mannitol or the like. These excipients may be used singly or in combination of two or more. The excipient content is, by way of example, based on the total amount of the fast release formulation, from about 4.5 to about 99.4 w/w%, preferably from about 20 to about 98.5 w/w%, more preferably from about 30 to about The drug content in the 97 w/w% sessile release formulation is suitably selected from the range of about 0.5 to 95%, preferably about 1 to 60%. In the case where the quick release preparation is an oral solid preparation, a disintegrant is generally contained in addition to the above components. For example, the disintegrator includes carboxymethyl cellulose calcium (ECG-505, manufactured by GOTOKU CHEMICAL CO. LTD.), and crosslinked hydroxyindole cellulose (Ac-Di-Sol, manufactured by ASAHI KASEI CORP.). , crospovidone (such as Kollidone CL, manufactured by BASF), low-substituted hydroxypropyl cellulose (produced by SHIN_ETSU CHEMICAL CO. LTD.), carboxy-based starch (MATSUTANI CHEMICAL INDUSTRY CO. LTD.), Wei Weiji Lot粉纳 (Explotab, prepared by KIMURA SANGYO CO· LTD·), some α 殿 powder (PCS, prepared by ASAHI KASEI CORP·), and can be used by, for example, water absorption, swelling or formation of channels (active ingredients and shaping at the core) The agent is a disintegrant that causes the disintegrating particles to come into contact with water. These disintegrants may be used singly or in combination of two or more. The amount of the disintegrant compound may be appropriately selected depending on the kind of the drug to be used or the mixture f and the release design of the preparation, and is based on the total amount of the quick release preparation, which is about 〇·〇5 to about 30 w/w. ° / 〇 and preferably from about 0.5 to about 15 w / w 〇 / 〇. When the immediate release preparation is an oral solid preparation, the above composition is 76 319299 200813007 2 : ί: force: the step includes 'as required for the solid preparation of the addition of the ",, and the addition Examples include bonding 'soil, 'cutting vitamins, polyvinylpyrrolidone, pullulan, 生, raw w such as sodium sulphate, nonionic == polyoxyethylene - polyoxyethylene sorbitol = two :: knitting derivatives, etc.), coloring agents (such as tar pigment, coke (such as sweetener (10) Qfiavin chest needs, cover (four)), adsorbents, preservatives, wetting agents, anti-static dilute two materials such as (four), lemon System, (4), ^ for the description of the adhesive, preferably propyl cellulose, polyethylene glycol, λ 乙 稀 ° 各 各 各 各 各 各 。 。 。 。 。 。 。 。 。 。 。 。 。 。 It can be shaped according to the needs of further pharmaceutical manufacturing techniques. The above mixing can be carried out according to the method of hanging, for example, mixing, kneading, etc. Specifically, for example, the release coating of the product is granulated by compression molding. In the case of the agent, the components can be used as a granulator or a general kneader (HATA IR0N W0RKS C0 W) D raw ^), flow bed granulator FD_5S (produced by p〇WREXc〇Rp.), etc., mixed with a preparation method similar to:: 'sex release preparation core, and then wet squeezing method, flow bed granulation Granulation or the like to prepare granules. The immediate release preparation and the sustained release preparation as defined above are prepared by using 319299 77 200813007 with appropriate excipients, respectively, and the two preparations obtained can be administered simultaneously: administration, Or the two preparations may be formulated with appropriate excipients, etc.; orally, the preparations (such as granules, fine granules, troches, capsules, etc.) may also be formulated as granules or fine granules. And filling a capsule as an oral dosage form.,, [3] sublingual lozenge, buccal or intraoral disintegration preparation and its preparation sublingual lozenge, buccal or intraoral rapid collapse, suspect, or Oral mucosa film. Fine clothing (4) solid preparations such as eight for sublingual tablets, buccal or intraorbital disintegration preparations, including: the male antagonist of the present invention or the preparation of the concomitant drug and excipient Comparison: In addition, it may contain adjuvants such as flow aids, infiltration agents, hydrophilic carriers, dispersion, polymers and It may also contain ^dextrin or bioavailability. The simpleness of the clothing can make absorption easier and the above-mentioned excipients include lactose, white sugar, D_mannitol, powder, pigment, light There is no forest acid, etc. The glidant example includes stearic acid town, =:, talc, colloidal stone, etc., and especially magnesium stearate and colloid! ". The isotonic agent includes sodium chloride and glucose as an example. Fructose, glycerol, glycerol, glutinous rice, glutinous, glycerin, urinary casting, and particularly preferred. The hydrophilic carrier is exemplified by an expandable carrier such as crystalline fiber t, \ethyl cellulose, Cross-linked polyethylene, lang, light, anhydrous, 夕^ # ^#",;" ^ ^'* ^(in^ ^ ^ ' 7 Examples of dispersive polymers include gums (such as tragacanth Tragacam), Arab # (acacia gum), Guaya gum (4)), 319299 78 200813007 Alginate (such as sodium alginate), cellulose derivatives (such as methyl cellulose, carboxymethyl cellulose, hydroxyl Methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, water-soluble powder, polyacrylic acid (such as carbomer), polymethyl Acrylic acid, polyvinyl alcohol, polyethylene glycol, polyethylene pipirone, polycarbophil, ascorbyl palmitate, etc., and propylmethylcellulose, polyacrylic acid, algae The acid salt, gelatin, sulfhydryl cellulose, polyethylene σ pirone, polyethylene glycol and the like are preferred. It is especially preferred to use propylmethylcellulose. Examples of the stabilizer include cysteine, thiosorbitol, tartaric acid, ruthenium rubber, sodium carbonate, ascorbic acid, glycine, nitrosyl halide, etc., and citric acid and ascorbic acid are preferred. The sublingual lozenge, buccal or intraoramiral disintegrating preparation can be prepared by using a known method of the heart & an orthotropin antagonist or concomitant drug and excipient of the present invention. Further, adjuvants such as glidants, isotonic agents, hydrophilic carriers, dissolvable polymers, stabilizers, colorants, sweeteners, preservatives and the like may be blended as needed. The ingredients may be mixed at the same time or at intervals of time, followed by a pressure-sensitive tablet, a buccal tablet or an intra-oral disintegration agent. To obtain a suitable hardness, a solvent such as water or ethanol can be used before or after the tableting to adjust the wettability or humidity, and the mixture can be dried after m-die. In the example of the film for forming a mucosa, the male anti-agent or the accompanying substance of the present invention, the soluble polymer (the cellulose-based cellulose), and the excipient are dissolved in a solvent such as water: The mold was prepared to prepare a film. Also, add additives, loser "proper elasticity, may include glycols such as polyethylene glycol or C 319299 79 200813007 diol, = and adhesion to increase the adhesion of the drug film to the inner layer of the oral mucosa The polymer (such as polycarbophil and the ruthenium can be used to pour the solution to the non-attached, / car opoi) ° cast sheet) is dispersed into a uniform thickness (preferably (four) = surface, coated (four) dried to prepare medicine The formed film is then dried at room temperature and cut to the desired surface area. Receptor antagonism: a morphologically and water-soluble or water-dispersible carrier which is inert to the male (=) male antagonist or the concomitant drug. The reticular body can be formed by a solid composition which is a solution. Obtained by sublimation of a solvent, wherein the androgen receptor antagonist or the concomitant drug of the present invention is dissolved in a suitable solvent. / In the composition of the intraorally rapidly disintegrating preparation, in addition to the androgen receptor antagonist of the present invention or accompanying In addition to the drug, it is preferably included (1) 忒 matrix forming agent for example includes gelatin, dextrin and animal or plant protein = such as Daxian, wheat and psyllium, rubber materials such as gum arabic, gum (guar) gUm), agar and gum (xanthan), · brewed $, alginic acid; carboxymethyl cellulose; carrageenan; polydextrose; pectin, synthetic polymers such as poly Vinyl pyrrolidone, a substance derived from a lunar-arabino complex, etc. In addition, sugars such as mannitol, glucose, lactose, galactose and saccharide (trehal〇se); cyclic sugars such as cyclodextrin 'inorganic salts such as Sodium hydride, sodium chloride and sulphate; and amino acids with 2 to 12 carbon atoms such as glycine, L-alanine, L_aspartate, 319299 80 200813007 L- lysine, hydrazine Amino acid (hyd y prQiine), l-isoleucine, l leucine and L-phenylalanine, etc. are included. ▲ or = matrix forming agent can be used to solidify the precursor solution or suspension, ΰ海The base shelling agent may or may not contain a surfactant. The matrix shape or: 1:: base: outside ' The present invention supports the androgen receptor antagonists s, Sile contention was maintained dispersed state in a solution or suspension.

The beta composition may contain secondary ingredients such as preservatives, antioxidants, interfacial agents, thickeners, colorants, pH modifiers, flavoring:::agents. Examples of suitable coloring agents include red, black and yellow L _ such as ELUS ANDEBERALD manufactured by FD including thin farmland: soil and FD & C red 40. Examples of suitable flavoring agents include aroma tomb, 'photograph, liquorice, citrus, lemon, grapefruit, caramel, and examples including = acid glucoside. Suitable pH adjusters are .A /酉I, y acid, hydrochloric acid and fumaric acid. Examples include 1, umatin) # ° Appropriate taste masking agent Absorption =::: ion exchange resin, cyclodextrin cage compound, octopus cystatinized apomorphine. Preferably, the agent is a sputum/male bismuth antagonist or concomitant drug. And the system = the aforementioned tongue rotten, buccal preparation), which dissolves within 9〇% 6〇 minutes (the monthly biotin receptor buckling agent or concomitant drug is about 1 to about 2 to about 5 minutes) = 交佳 ^ about 1 to about 15 minutes, more preferably, the internal speed of the preparation of the preparation can be placed in the mouth, 319299 81 200813007 about 1 to about 60 seconds collapse ^ ^ i to about 10 seconds. , from about 1 to about 3. seconds, more preferably about 99% by weight of the above thief-shaped agent, preferably based on the content of about 10 to about cyclodextrin derivative =: (4) Dextrin or 々 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To the person and the car father is about 1 to about 5% by weight. The isotonic agent content, based on the total amount of the preparation, is about 10 to about 70% by weight of the tablet. Tough water., ',, two % by weight, and preferably about, about (U to about 5. The weight is based on the total amount of the preparation, % by weight, and preferably from about 10 to about 30% by weight. The content of the diterpene polymer, to the formulation Based on the total amount, about 0.1 and (4) about 1G to about 25 % by weight, based on the total amount of the preparation, is from about 5% to about 5% by weight, preferably about 5% by weight. The preparation may further comprise additives such as colored enamel, sweeteners and preservatives. The concomitant drug dosage may vary depending on the type, age, weight, symptoms, dosage form, administration method, administration period, and the like of the compound (1), however, in some cases, it is usually about 0.01 to about 1000 mg/kg, preferably about = (10) mg / kg, more preferably about (U to about i (9) mg / kg, particularly preferably '" spoon 0.1 to about 50 mg / kg 'especially about i · 5 to about 3 〇 mg / kg is the male hormone of the present invention A daily dose of a body antagonist or concomitant drug for a patient with prostate cancer (adult, weighing about 60 kg) can be _ times or zone: several doses. As mentioned above, the dose will vary depending on different conditions. In some cases, a small dose is sufficient, and the dose required in some cases or 319299 82 200813007 is outside the above range. As long as there are no troublesome side effects, the amount of music can be /', 疋. The daily dose depends on the degree of symptoms, the weight of the target, the sensitivity Difference, period of administration, interval of administration: different nature, type of preparation, type of active ingredient, etc., not protective: Limit 'but' mammalian oral dose W inch ^ to about 2_ ± 服通通吊母1公斤重量Preferably, it is from about 〇·01 to about 500 mg, more preferably about iOOmg, and the amount is usually divided into one to four times a day. In the case of drug administration, two The preparation may simultaneously be administered with "$I administered concomitant drug, and then administered to the present invention = or, when the male receptor receptor anti-reagent of the present invention is administered in a certain (four) interval, the time difference depends on the activity to be administered. The knife back type is different from the method of administration. For example, when the drug is used, the suspension of the invention in the accompanying Chinese (4) invention is administered to the % A-forked body antagonist within 1 minute to 3 days, preferably 10 minutes to 1 day, and better day:, Lucus Up to 1%. When the male receptor receptor antagonist of the present invention is administered first, the male receptor receptor antagonist of the invention can be administered after administration! The administration of the accompanying drug in minutes to 8% is preferably from 1 minute to 6 hours, more preferably from 15 minutes to 1 hour. For example, the ten pairs of #乂佳投乐方法, for oral administration of about 0 01 to about 2 (9) g/kg with or without drugs, are administered orally, and then about two spoonfuls of 0.05 to about i〇0. The oral preparation in which the parental dose of mg/kg of the androgen receptor antagonist of the present invention is administered orally is administered orally. EXAMPLES 319299 83 200813007 The present invention will be described in detail with reference to the embodiments, the examples, the formulation examples and the method of the test examples, which are not intended to be limiting. "Room temperature" generally means from about 10 to about 351 in the reference examples. "%" is a percentage by weight unless otherwise specified. The yield is expressed in mol/mol % (mol/mol %). The NMR spectrum was proton NMR and was measured on a 200 MHz or 300 MHz spectrometer with tetramethylsilane as an internal standard and the value is expressed in ppm. In the present specification, a melting point means using a Mico melting point apparatus (Model B, 545, Buchi, manufactured by Yanaco Analytical Instruments Crop) or a differential scanning calorimeter (DSC, SEIKO, EXSTAR 6000). The measured melting point. In general, the melting point is occasionally different depending on the measuring equipment and the measurement conditions. The crystal of the present invention may be different from the melting point of the crystal contained in the present specification as long as the difference is within the general error range. Other abbreviations used in this specification are listed below: s: singlet (singlet) brs · wideband singlet d (double) t: triplet q: four peaks dd: doublet ddd: double doublet dt ·· Shuangsanfeng 84 319299 200813007 td : Sanshuangfeng m: Multi-bee br: Broadband (board) CDC13: Deuterated gas-like DMS〇-d6: Deuterated Diterpenoid 飒 iH-NMR: Proton NMR

Me : 曱基

Et: ethyl i-Pr · isopropyl boc · · third butoxycarbonyl THF : tetrahydroanthracene TFA : trifluoroacetic acid AIBN : 2,2'-azobis(isobutyl) DMF ·· N N-dimercaptodecylamine NMP: mercaptopyrrolidone NBS: N-bromosuccinimide [Reference Example 1] 1-triphenylmethyl-1H-pyrazole-3- Carboxaldehyde

/CHO

Further, 1H_carbazole_3_carboxaldehyde (5.31 g) was dissolved in DMF (50 ml), 85 319299 200813007 potassium carbonate (13.8 g) and triphenylchloromethane (15.62 g). The reaction solution was stirred at room temperature for 40 hours, diluted with water and extracted with ethyl acetate. The organic chips were washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was washed with diisopropyl ether to give the title compound (1······ 1H-NMR (CDC13) 5 : 6·78 (1Η, (1), 7·11-7·35 (15Η m), 7.39 (lH, d), 9.97 (lH, s)· ? [Reference Example 2 Triphenylmethylpyrazol-3-yl)methanol

The compound (10.00 g) obtained from Reference Example 1 was suspended in methanol (100 ml) and THF (100 ml). The mixture is cooled to 〇. Strontium borate (1.10 g) was added, and the reaction solution was stirred at the same temperature for 30 minutes and concentrated, and water was added to the residue. The precipitate was collected by filtration and washed with water, ethyl acetate (diethyl ether) and diisopropyl ether to afford the title compound (9·4 g) as colorless crystals. tNMI^CDCW : 1.97 (lH, t), 4.69 (2H, d), 6.22 (lH, d), 7.11-7.32 (16H5m).

[Reference Example 3] 3-(brominated methyl)-1-tritylmethyl_111-pyrazole 319299 86 200813007

Br A mixture of the compound obtained in Reference Example 2 (2.72 g), triphenylphosphine (2.30 g) and methylene chloride (30 ml) was cooled in an ice bath and NBS (1.57 g) was added. After the reaction mixture was stirred at room temperature for 3 minutes, a saturated aqueous solution of dicarbonate was added to the reaction mixture and the dichloro(tetra) layer was separated, and the methylene chloride layer was purified by column chromatography (hexane-ethyl acetate). The title compound (2.00 g). ^NMRCCDCl^ : 4.52 (2H? s), 6.30 (1H5 d)? 7.11.7.35 (16H, m)· [Reference Example 4] Methyl-1 Η-pyrrole-i-carboxylic acid tert-butyl ester 3- Bromo-4-cyano-2,5-diindole

319299 87 200813007 Crystallized from ethyl acetate to obtain the desired product (2.66 g) crystals: NMR (CDC13) δ: 1.62 (9 Η, s), 2.37, (machine S)' 2·56 (3Η, s)· The following product was obtained by the same procedure as in Reference Example 4, 4-bromo-2,5-didecyl-1H-pyrrole-1,3-diacid. - Di Sanding

3->Smelly-5·Cyano-2,4_Dimethyl-l-1_Damic acid third-party

4-NMR (CDC13) δ: 1·65 (9Η, s), 2·20 (3Η, s), 2·50 (3Η, s)· [Reference Example 5]

5_({[T-butyl(diindenyl)indenyl]oxy}methyl)-3-(trifluoromethyl)-lH mouth than wow 319299 88 200813007

Incorporating the monomethylaminopyridine (1.41 g), triethylamine (14·g) and the first butyl chloride (monodecyl) Shikijik into the [3_ synthesized by a known method] a solution of (difluoromethyl; ^zirconazole-5-yl)nonanol (191 g) in THF (2% liter), and the mixture was stirred at room temperature for 14 hr. The mixture was extracted with EtOAc.

[Reference Example 6] 4_Bromo-2,5-dimethylbiquinone·3_dibasic acid tert-butyl ester

2,5-Dimethyl_ιη·pyrrole_3·carboxylic acid tert-butyl ester (9.65 g) and NBS (9.24 g) in DMF (50 ml) were stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine (1 mL) and evaporated. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (EtOAc-EtOAc) (CDCI3) δ: 1 < 57 (9H, s), 2.18 (3η " 〇 8.20 (1Η, S). , 2·44 (3Η, s), [Reference Example 7] 4-bromo-3,5 -Dimethyl-1^!-吼洛_2-carbonitrile

Prepare a solution of 3,5-dimethylacid (6 56 g) with n, guanyl diimidazole (5.86 g) in butyl 1 (5〇1111). 〇: Stir for 3 minutes, and add ammonia water, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine (100 ml) and evaporated. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. A solution of the residue and pyridine (1 mL) in EtOAc (EtOAc) (EtOAc) Ethyl acetate and sodium dicarbonate solution were added to the reaction mixture and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford crystals of the desired product (3.59 g). ^-NMR (CDC13) δ: 2.17 (3Η, s) , 2.26 (3Η, s) f 8.72 (1H, S).

[Reference Example 8] [1_(Tertidinoxycarbonyl)-4-cyano-2,5-diindenyl-1 fluorene--3-yl]-fat acid 90 319299 200813007

A solution of butyllithium in hexane (1.6 mol/l, 12.5 liters) was added dropwise at -78 C to the 3-bromo-4-yl group, 5-indenyl-pyridyl- A solution of 1 - citric acid Tributyl (5.0 g) in THF (75 mL). The reaction mixture was stirred at the same temperature for 30 minutes on the bench' and a solution of tridecyl borate (20 ml) dissolved in THF (210 liters) was added, and the mixture was stirred for 1 hour. A mixture of water (20 ml) and decyl alcohol (20 liters) was added to the reaction mixture, and the mixture was allowed to warm to room temperature. Saturated brine (1 (10 ml) was added to the reaction mixture' and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium The residue was crystallized from ethyl acetate ethyl acetate to afford titled product (4·93 g).

^NMR (CDCls) δ: 1.6-1.7 (2h, br s)^ le64 (3H, s), 2·60 (3H, s)· (9H, s), 2.54 Using the same method as in Reference Example 8, The following products were obtained. [1,4-bis(second butoxycarbonyl)dimethylpyrrole-3-yl]boronic acid 91 319299 200813007

(3H, s) f [1-(Tertidinoxycarbonyl)-5-cyano-2,4·dimethyl-1H--pyrrol-3-yl]boronic acid OH /

^-NMR (CDC13) δ: 1.58 (9Η, s) r 2.19 (3H, s) , 2.50 (3H, s) f 7·93 (1H, s)· [Reference Example 9] 4-[4-Cyanide 3-(trifluoromethyl)phenyl]-2,5-dimercapto-lH-upyrrol-3-carbonitrile

[1-(Secondoxybutyryl)-4-ylyl-2,5-diindenyl-111-.嘻-3_ yl] acid (6.0 g), 4-bromo-2-(trifluoromethyl)-benzonitrile (5.68 g), potassium fluoride (4.62 g), tri-tert-butylphosphine (0.36 mo) A mixture of 1/1 calcined solution, 3.2 mM 92 319299 200813007 liters, ginseng (diphenylmethyleneacetone) dipalladium (〇·42 g) and THF (50 ml) was stirred at room temperature for 20 hours. Saturated brine (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium The residue was purified by silica gel column chromatography (ethyl acetate-hexane), and crystallised from ethyl acetate to give 3 cyano- 4-(4- oxy- yl) 2,5- dimethyl The acidified third butyl ester (4.00 g) crystals. 3-cyano-4-(4-cyanophenyl)_2,5-dimethylpyrrole-1-carboxylic acid tert-butyl ester (4.00 g), potassium carbonate (3.55 g), water (3〇 The mixture was stirred with EtOAc (30 mL). The magnesium was dried and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (2·74 g). s. R (CDCl3) δ: 2·34 (3H, s), 2·46 (3h, ^ 7卜 7.8 (machine m), 7·88 (1H, d), 8.25 (1H, br s)· ester Using the same procedure as in Reference Example 9, the following product 4-(3-chloro-4-cyano) was obtained. Phenyl)-2,5-dimethylpyrrolecarboxylic acid third -

2·50 (3Η, s), d), 8·〇8 (1Η, 4-NMR (CDC13) δ: 1·33 (9H, s), 2·12 (3h, * 7.21 - 7·26 (1Η) , in), 7·39 (1Η, d), 7·62 (1Η, 319299 93 200813007 4-(3 -Chloro-4-ylphenyl)-3,5-dimethyl-1Η_ϋ比洛-2 - A guess

^-NMR (CDCI3) δ: 2·2〇(3H, s), 2·29 (3H, s), 7.33 - 7.40 (2Η, m), 7·71 (1Η, d), 8·60 (1Η , s). 4-(4-Hero-2-methylphenyl)-2,5-dimercapto--A guess

^-NMR (CDCI3) δ: 2·07 (3H, s), 2·28 (3H, s), 2·44 (3H, s), 7.2-7.4 (1Η, ία), 7·4-7· 55 (1Η, rri), 7·55-7·7 (1Η, m)r 8·20 (1H, s).

[Reference Example 10] 4-(3-cyanophenyl)_2,5-diindenyl-1H-pyrrole-3-indoleonitrile

94 319299 200813007 3-Bromo-4-cyano-2,5-dimercapto-purin-π ratio (2.45 g), 3-cyanophenylboronic acid (2.16 g), hydrazine (triphenylphosphine) A mixture of palladium ((6 gram), anhydrous potassium carbonate (3.90 g), DMF (90 ml) and water (π ml) was heated at 13 (rc for 20 h then cooled to room temperature. The reaction mixture was added with EtOAc EtOAc (EtOAc m. It was purified by hexanes and crystallized from ethyl acetate to give the desired product (0.91 g) crystals. "NMR (CDC13) δ: 2.29 (3 Η, s) , 2.41 (3 Η, s) , 7.4-7.5 (2 Η. m ) 7·6-7·8 (2H, m), 8·30 (1H, br [Reference Example 11] 2-Chloro-4-(2,5-dimercapto-1H-pyrrol-3-yl) Benzoonitrile

Mixture of 4-(3-chloro-4.cyanophenyl)-2,5-diamidino-3-butyric acid tert-butyl ester (2.4 g) with TFA (10 ml) at room temperature 4 hour. A saturated aqueous sodium dicarbonate solution and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with saturated brine, dried (anhydrous sulfate) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford crystals of desired product (0.72 g). 95 319299 200813007

[Reference Example 12] 1-Ethyl-5-mercaptoic acid ethyl ester

Acetic anhydride (3.06 g) was added to a solution of ethyl 3-mercapto-1 -pyrazol-5-carboxylate (3.08 g) in pyridine (4 mL). After the reaction mixture was concentrated, the residue was crystalljjjjjjjlili The crystal precipitated from the residue was finely powdered in hexane, and filtered to obtain a target product (2.51 g) crystals. h-NMR (CDC13) δ: 1·41 (3Η, t), 2·61 (3Η, d), 2·78 (3Hr s), 4·22 (2H, q), 6·61 (1H, d [Reference Example 13] 1-Ethyl-5-(indenyl bromide)·ιΗ-pyrazole-3-carboxylic acid ethyl ester

Add NBS (246 g) to a solution of ethyl 1-ethylindol-5-mercapto-1 -pyrazole-3-carboxylate (2.35 g) in tetra 96 319299 200813007 gasified carbon (72 ml) Aibn (197 liters) and the mixture was refluxed for 3 hours. The precipitate was removed by filtration and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford product (2·23 g) as an amorphous powder.

U2 (2Η, S), 6.97 (1H, s) · [Reference Example 14] 1-{[(2,2-dimethylpropenyl)oxy]methyl b 5-methyl-111-pyridyl Azole _3-oleic acid ethyl ester

Add sodium hydride (6 〇 % dispersion) to a solution of ethyl 3-methyl-1 Η-pyrazole-5-carboxylate (7·71 g) in dehydrated DMF (150 mL) under argon with EtOAc. In the oil, 2.3 g), and the mixture was stirred for 3 minutes. A solution of chloromethyl chloroformate (8. 66 g) in DMF (10 ml) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford the object product (9.2 g) as an oil. 'H-NMR (CDC13) δ: 1.19 (9Η, s), 1.39 (3H, t), 2.36 (3Hf s), 4.40 (2H, q), 6.CM (2H, s), 6·59 (1H , s)· [Reference Example 15] 319299 97 200813007 5·(Bromomethyl)-1-{[(2,2·dimethylpropenyl)oxy]methyl b ih_ -3-carboxylic acid B Ester ^

COOEt is in 1-{[(2,2-dimethylpropenyl)oxy]methyl}·5_methyl sin. NBS (3.07 g) and hydrazine (246 ml) were added to a solution of ethyl bromide-3-carboxylate (4.03 g) in carbon tetrachloride (9 mL), and the mixture was rinsed for two hours. The precipitate was removed by filtration and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford product (yield: 3.79 g) as an oil. .../ 4-Li R (CDC13) δ·· 1·20 (9Η, S), 1·4〇(3H, t), 4·4ι (2Η, (1), 4·62 (2Η, s), 6.15 ( 2Η, s), 6·85 (1Η, s)e [Reference Example 16] [(Benzyloxy)methyl]-5-methyl-1Η_σ is more than saliva-3-supplemented vinegar

COOEt Add sodium hydride (6 〇% dispersion) to a solution of 3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (7.71 g) in dehydrated DMF (150 ml) under argon and ice. In the oil, 2.3 g), and the mixture was stirred for 30 minutes. A solution of benzylmethyl chloromethyl ether (9.0 g) in DMF (10 mL) was added to the mixture, and the mixture was stirred at 319 299 98. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford product (5·2 g) as an oil. ^NMR (CDC13) δ: 1.40 (3Η, t) , 2.38 (3Η, s) , 4.,1 {2Η, q), 1 (2Η, s), 5·58 (2Η, s), 6.61 (1Η, s), 7·25-7.35 (5H, m)· [Reference Example 17] {1 [(本methoxy)indolyl]-5-methyl-ΐΗ-σ-嗤-3-yl Sterol

Add 1 [(present methoxy) A) to a suspension of lithium aluminum hydride (680 mg) in dehydrated THF (359 ml) under argon at 10,000 ° C or below. a solution of dehydroethetyl ethoxide (4.92 g) in dehydrated THF (25 ml), and the mixture was stirred at the same temperature for 10 min and stirred at room temperature 2 ·5 hours. After ice cooling again, the reaction was quenched by the addition of a saturated aqueous solution of sodium sulfate. The reaction mixture was neutralized with 1 Ν salt and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate The resulting product was used for subsequent procedures without further purification of 'H-NMRCCDCIs. 5 : 2.26 (1H? t)? 2.33(3H? s)9 4.50(2H9 s)? 4·65(2Η,d),5·44 (2Η, s), 6·08 (1Η, s) 5 7·25_7·37 (5Η, m). 319299 99 200813007 [Reference Example 18] 1_[(Benzyloxy)methyl]-3-( Iodinyl)-5-methyl-1H_pyrazole

Ch2i under ice cooling and stirring, in {1-[(benzyloxy)indolyl]-5-fluorenyl-1!1-pyrazol-3-yl}methanol (3.82 g) in ethyl acetate (164 ml Diisopropylethylamine (8.5 ml) was added to the solution, and then sulphuric acid sulphuric acid (2.55 ml) was added to the mixture, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Sodium iodide (24. 64 g) was added to a solution of the residue in acetone (64 ml), and the mixture was refluxed for 15 hours. After the reaction mixture was concentrated, the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjj Shape. The resulting product was used in the subsequent work without further purification. : ^-NMR (CDCI3) 5: 2.30 (3H, s) , 4.37 (2H, s), 4.49 (2H, s), 5.42 (2H, s), 6.12 (1H, s), 7.24-7.40 (5H, n).

[Reference Example 19] 1 -[(本methoxy)methyl]-4-methylH-indole-3-hydroxyethyl ester 319299 100 200813007

(4.22 g) Sodium hydride (1. 38 g in 6% dispersion oil) was added to a solution of dehydrated DMF (90 ml), and the mixture was stirred for 3 hr. Next, a solution of benzyl chloromethyl group (4 g) in DMF (5 ml) was added to the mixture, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford product (3·25 g) as an oil. ^NMR (CDCI3) δ: 1.42 (3Η, t) , 2.31 (3Η, s) , 4.42 (2Η, q), 4.52 (2Η, s), 5.52 (2Η, s), 7.23^7.37 (5Η, m) , 7;42 (1Η, s).

[Reference Example 20] {1-[(Indolyloxy)indenyl]_4·indolyl-1Η-indolepyr-3-yl}nonanol

Add 1-[(this methoxy) fluorenyl group to a suspension of lithium aluminum hydride (408 mg) in dehydrated THF (215 ml) with stirring under argon at rt. ]-4 -Mercapto-1HH3-acidified ethyl ester (2. 95 g) in dehydrated THF (15 ml), and the mixture was stirred at the same temperature for 319299 101 200813007 for 10 minutes at room temperature. Mix for 2 hours. After the reaction mixture was cooled again with ice, the reaction was quenched with a saturated aqueous sodium sulfate solution, and the mixture was neutralized with 1 EtOAc. The organic layer was washed with EtOAc (EtOAc m. The resulting product was used in the post-production process without further purification. lH~NMR (C〇Cl3) 2·09 (3Η, s), 2.10 (1H, br s), 4.51 (2H, s), 4·67 (2H, d), 5·40 (2H, s)/ 7,25-7.40 (6H, m)· [Reference Example 21] 1-[(Benzyloxy)indolyl]-3-(iodomethyl)_4_methyl-1Hj-pyrazole

CHJ was stirred under ice-cooling in {1_[(phenylhydroxy)indolyl]_4_methyl_1H_pyridin-3-yl} decyl alcohol (2.40 g) in ethyl acetate (1 mL) To the solution were added diisopropylethylamine (8.5 ml) and decanesulfonium chloride (2.55 ml), and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was re-read and brine washed, dried over anhydrous sulfuric acid steel and concentrated. Sodium hydride (15.48 g) was added to a solution of the residue in propylene (1 〇 3 (4)), and the mixture was refluxed for 15 hr. After the mixture was concentrated, the residue was partitioned between EtOAc EtOAc EtOAc EtOAc EtOAc. For subsequent procedures and no 319299 102 200813007 for further purification. 4-NMR (CDC13) δ: 2·05 (3H, s), 4.39 (2H, s), 4_49 (2H, s), 5·37 (2Η, s), 7·24-7·39 (6Η, m)· [Reference Example 22] 3 -(difluorojmethyl)-1Η _ϋ ratio σ sit-5-decanoic acid

A mixture of [3-(trifluoromethyl)-1H-indazol-5-yl]nonanol (15.0 g), manganese dioxide (150 g) and DMF (200 ml) was stirred at 60 ° C for 14 hours. Saturated brine was added to the reaction mixture, and the insoluble material was removed by filtration. After extracting the filtrate with ethyl acetate, the extract was washed with saturated brine, dried and concentrated. The residue was suspended in diisopropyl ether-hexane and filtered to give the title compound (9.75 g). 1H NMR (DMSO-d6) δ: 7.50 (lHf s) r 9.88 (1H, s) / 14.94 (1H, s) · [Reference Example 23] 4-(4-disorganylphenyl)-2,5- Dimethyl-r-butanoic acid

103 319299 200813007 A solution of potassium hydroxide (10.44 g) and tributyl acetacetate (63. 2 ml) in dry THF (350 ml) was stirred at room temperature for 3 min and fractionated under ice cold. 4_[(1E)_2-Nitroprop-1-enyl]benzonitrile (35·0 g) was added to the reaction solution, and stirred for more than 3 minutes. After a minute, the reaction solution was poured into EtOAc (EtOAc) The organic layer was washed with brine (200 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was used to carry out the subsequent work without further purification. Methanol (100 ml), water (14.2 ml) and TFA (14.2 ml) were added to the residue, and the mixture was between 75 and 78. Stir under the arm for an hour. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (250 ml) and washed sequentially with water (3 ml), saturated aqueous sodium bicarbonate (200 ml x 2) and saturated brine (50 ml). After the solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the target product (23·7 g) was crystallized to crystals. The product was filtered, rinsed with a small amount of diisopropyl ether, and dried.

Hi-NMR (CDCls) δ: 1.30 (9H, s), 2.10ΟΗ, s), 2.50(3H, s), 7.33(2H, d), 7.61(2H, d), 8.07(lHf s).

[Reference Example 24] 4_(2,5·Dimercapto-1H-pyrrole-3-yl)benzonitrile 319299 104 200813007

a mixture of 4-(4-cyanophenyl)_2,5-> fluorenyl-indole-pyrrolidine 3-carboxylic acid terpene (2 〇.1 g) and TFA (5 〇 unopened) in the chamber The residue obtained by concentrating the reaction solution was diluted with ethyl acetate. The residue was diluted with ethyl acetate, and then washed with saturated sodium chloride and dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate-hexane) to afford (U3 g) crystals. H-NMR (CDC13) δ: 2·27 (3H, s), 2·40 (3H, s), 6·〇4 (lH, (1) 7·46 (2H, d), 7·61 (2H, d ), 7·76 (iH, br s)· [Reference Example 25] 4~(4-cyanophenyl)_l_{2_[methoxy(indenyl)amino]_2-ketoethyl, group }-2,5-dimethyl-m·pyrrole-3-carboxylic acid tert-butyl ester soil

Under ice cooling, 4-(4-cyanophenyl)_2,5-dimethyl-1H-pyrrole 319299 105 200813007-3-carboxylic acid tert-butyl ester (〇·60 g) in DMF (15 ml) Sodium hydride (60% dispersion oil, 0. 10 g) was added to the solution. The reaction mixture was stirred at room temperature for 30 minutes, and 2-chloromethoxymethylacetamide (33 g) was added to the mixture, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (ethyl acetate-hexane:) to afford the title compound (63. ^NMR (CDC13) δ: 2.01 (3H, s), 2.48 (3H, s), 3.25 (3H; s), 3.80 (3H, s)r 4.76 (2 H, s), 7.34 (2 H, d) , 7.61 (2 H/ d).

[Reference Example 26] 2,5-Dimethyl-1-(2-ketopropyl)_'phenylpyrrole-3-carboxylic acid tert-butyl ester

319299 106 200813007. Citric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate·hexane) to afford title compound (637 mg). ^-NMR (CDCI3) δ: 1.96 (3Η, s) , 2.21 (3Η, s) r 2.44 (3H, s), 4·62 (2 H, s), 7·33 (2 H, d), 7.63 (2H, d)· [Reference Example 27] 4-(2,5-Dimethyl-1H)pyr-3-yl)-2-(trifluoromethyl)benzoonitrile

[1,4-Bis(tert-butoxycarbonyl)-2,5-dimethyl-111-°pyrrol-3-yl] octanoic acid (7·7 g), 4-bromo-2-(three Fluorinyl) benzonitrile (7.38 g), potassium fluoride (4.62 g), di-dibutyl lin (〇·36 mo 1/1 hexyl solution, 3 · 2 ml), ginseng (dibenzylideneacetone) A mixture of dipalladium (0.42 g) and THF (50 ml) was stirred at room temperature for 20 hr. Saturated brine (1 Torr) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The water was dried over magnesium sulfate and concentrated. The mixture of residue and TFA (i 〇 ml) was stirred for 6 hours at "1. Saturated sodium dicarbonate/salt and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with saturated brine, dried over magnesium sulfate sulfate and evaporated. The residue was purified by silica gel chromatography (acetic acid B 107 319299 200813007 ester-hexane) to obtain the desired product (148 g) crystals s), 6.07 (1H, d) ΓΓΙ) ^ 7.85 (1H, s). .^-NMR (CDCI3) δ: 2.27 (3H, S), 2.42 (3h^7·59 - 7·67 (1H, called, 7.72 - 7·8〇 (2H, [Reference Example 28] 4 -(4-cyanophenyl)_2_methyl-1H_pyrrole-3-carboxylic acid tert-butyl ester

4-[(Ε)-2-Nitrovinyl]benzonitrile (11.47 g) synthesized by a known method and tributyl acetacetate (π·47 liter) in decyl alcohol (18 ml) To the solution was added sodium decoxide (918 mg), and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 2 Μ ammonia-methanol solution (18 liters), and the mixture was stirred at room temperature for 20 hr. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate and aqueous 10% EtOAc. The organic layer was washed with an aqueous solution of citric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with diisopropyl ether to give the aimed product (4.49 g). ^-NMR (CDCI3) δ: 1.40 (9Η, s), 2.53 (3H, s) f 6,60^6.61 (ih m), 7·45-7·48 (2H, m), 7·58-7.61 (2H, m), 8.33, (1H, s)· [Reference Example 29] 4_(4-Alkylphenyl)-2-indenyl-1 Η-σ ratio 319299 108 200813007

Add TFA (1.1 ml) to 4-(4-cyanophenyl)-2-mercapto-1H·-pyrrolidine carboxylic acid tributyl vinegar (327 mg), stir at room temperature for 1 hour. . After the reaction solution was concentrated at a low pressure, the residue was poured into a mixed THF-acetic acid-acetic acid-saturated solution of sodium chlorate and separated. The organic sound was washed with a saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was washed with isopropyl_1 to obtain the target product (17 2 mg) as a solid.

4-plane R (DMS〇-d6) δ: 2·19 (3H, s), 6·22 (1H, s), 7.27 (1H t), 7·66 (4Η, dd), 1〇·93 ( 1Η, s)· [Reference Example 30] 3-(4-cyanophenyl)-5-methylpyrrole_2-carbonitrile

逐 dropwise in a mixture of 4-(4-cyanophenyl)-2-methyl-1Η-pyrrole (3 〇7 g), DMF (3.1 ml) and acetonitrile (12 ml) at 〇 °C A mixture of 109 319299 200813007 chlorosulfonium isocyanate (1·6 ml) and acetonitrile (6 ml) was added. After stirring for 30 minutes at 〇 °C. This mixture was added to a sodium dicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and purified by silica gel column chromatography (ethyl acetate-hexane) to afford crystals of the desired product (1.49 g). ^-NMR (CDC13) δ: 2.36 (3Η, s), 6.27 (1H, dd), 7.59 (2h, d) ^ 7·76 (2H, d), 8·74 (1H, s)· [Reference Implementation Example 31] 3-(broken methyl)-1•triphenylmethyl-1H-^

〇_Triphenylsulfonyl-1 hydrazin-3-yl)methanol (1.16 g), triphenylphosphine (1.07 g), iodine (1.04 g), imidazole (0.28 g) and THF (20 liters) The mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium dicarbonate solution and ethyl acetate were added to the reaction mixture, and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was suspended in diethyl ether and filtered to obtain a target product (1·g) crystal. Η~NMR (CDC13) δ: 4·44 (2H, s), 6·26 (1H, d), 7el_7.2 (6 H, ' 7·24 (1H, s), 7·31 (9 H, m)· [Reference Example 32] Dimethylpropionyl)oxy]indolyl 4_methyl_1H-pyrazole-3-carboxyl 110 319299 200813007 Ethyl acetate

COOEt Add hydride (in 6% dispersion oil) to a solution of 4_mercapto-iHib π-tetrate ethyl ester (7·71 g) in dehydrated DMF (150 ml) under argon 'ice cooling' 2·^克)' and the mixture was stirred for 30 minutes. A solution of neodecanoic acid methyl vinegar (8.66 g) in DMF (7.5 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by hydrazine column chromatography (ethyl acetate-hexane) and crystallized from ethyl acetate (hexanes) to obtain the desired product (12·7 g) crystals. ^NMR (CDCls) δ: 1.17 (9Η, s), 1.41 (3H, t), 2.27 (3H, S) f 4.41 (2H, q), 5.99 (2H, s), 7.47 (lRr s).

[Reference Example 33] M bromomethyl)-M[(2,2-dimercaptopropyl)oxy]methyl}_ιΗ_σ 嗤 _3·carboxylic acid ethyl ester

In the presence of 1-{[(2,2-dimethylpropionyl)oxy]indolyl 4-indolyl-1Η-. NBS (6.14 g) and hydrazine (492 ml) were added to a solution of sal -3- oxalate (8 〇 5 g) in carbon tetrachloride 〇 8 〇 ml, and the mixture was refluxed. 3 hours. The precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (ethyl acetate-hexane) to afford product (5·88 g) as an oil. ^H-NMR (CDCI3) δ: 1.18 (9H, 3), 1.44 (3Η, t), 4.46 (2Η, q), 4.68 (2Ηλ s), 6.02 (2Hf s), 7.80 (1H, s).

[Reference Example 34] l-{[(2,2-Dimercaptopropyl)oxy]indolyl iodonium)-1]9[_pyrazole 3-carboxylic acid ethyl ester

In 5-(bromomethyl)-l-{[(2,2-dimethylpropionyl)oxy]methyl}_1Hβ> pyrazole-3-carboxylic acid ethyl ester (2·39 g) in acetone The solution in (68. 8 ml) was added to hardened sodium (10.3 g) and refluxed for 1.5 hours. After concentrating the reaction mixture, the residue was crystallised from EtOAcjjjjjjjjjjjjjjjj It is a crystalline powder. The resulting product was used in the subsequent work without further purification. Η-NMR (CDC13) δ: 1·20 (9Η, s), 1·39 (3Η, t), 4.41 (2Η, q)r 4·53 (2H, s), 6·12 (2H, s) , 6·83 (1H, s)· [Reference Example 35] 319299 112 200813007 4-mercapto-1-triphenylindenyl-1^1_. ratio. Sitting _3-Resin ethyl ester r

COOEt

Add triethylamine (1 〇 9 ml) to a solution of 4-mercapto-1H-pyrazole-3-carboxylic acid ethyl ester (1 mM) in dehydrated DMF (19.5 liters). Diphenylchlorodecane (2.17 g) and dimercaptoamine pyridine (79 mg) were stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc (EtOAc) elute ^-NMR (CDC13) 7·〇5 (1H, s), q) / δ: U (3Η, t), 2·23 (3Η, S), 4·33 (2η, 7·11-7·15 (6Η, m), 7.27-7.31 (9Η, m)· [Reference Example 36] (4·methyl_1_二本曱基) than salivary_3_yl)methanol

A mixture of ch2oh borohydride (525 gram), chlorinated (77 gram mg), and thf (27 7 ml ethanol (13.8 liters) was stirred at room temperature for 1 minute, and: The human 4_f-based tris-trimethyl group was mixed with _3_ oxacillin (ι·ι克) and the mixture was stirred at room temperature for 22 hours. The reaction mixture was 319299 113 200813007. After pouring ice water, 1 hydrochloric acid was added (ΐ3· 9 ml). THF-ethanol was removed by distillation, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and filtered from crystal (900 mg) crystal. Η-NMR (CDC13) δ: 1·92 (1, t), 2·03 (3H, s), 4.63 (2H, d),. 7·〇4 (1H, s), 7.11-7·ΐ6 (6H, m), 7.25-7·31 (9H, m)· [Reference Example 37] 3-(iodohydrazino)_4_mercaptotriphenylindolyl_iH_pyrazole rN\

Ch2i in the ice drop, '((4-methyl-1-triphenyl)-111-° than saliva-3-yl) sterol (〇·9g) in dichloromethane (9〇 ml) A solution of saliva (19 〇 gram), triphenylphosphine (730 mg) and iodine (707 mg) was added to the solution, and the mixture was stirred at the same temperature for 1.5 hours. The insoluble matter was removed by filtration. The filtrate was washed with aqueous sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) and crystallised from ethyl acetate. & job (CDC13) δ·· 1·99 (3Hr s), 4·41 (2Η, S), 7.00 (1Η, S), 7·12-7·15 (6Η, m), 7·26- 7·32 (9Η, m)· [Reference Example 38] 3-formic acid-1-tritylmethylpyr-4-carboxylate methyl ester 319299 114 200813007 ohcVn\ N-butyl rt h3cooc Under ice cooling, To a solution of methyl 3-mercapto-1H-pyrazole-4-carboxylate (1.18 g) in dehydrated DMF (53.6 ml), triethylamine (1.35 mL) and triphenylchloromethane (2.24) (g), and stirred at room temperature for 63 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (ethyl acetate-hexane), h-NMR (CDC13) δ: 3·85 (3H, s), 7·10-7·14 (6H, m), 7·31 - 7·36 (9Η, m), 7·92 (1Η, s 〉, 10.34 (1Η, s)· [Reference Example 39] Methyl 3-(hydroxymethyl)-1-trityl-1H-pyrazole-4-carboxylate N-Trt

H3COOC 3-carboyl-1·triphenylmethyl-1H-indazole-4-glycolic acid ester (1.74 g) in decyl alcohol-THF mixture (1:1, 70 ml) with ice-cooling and stirring Sodium borohydride (182 mg) was added to the solution and the mixture was stirred for 30 min. Ice water and 0.1 N hydrochloric acid (48 ml) were added to the reaction mixture, and the mixture was concentrated. The residue was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. 115 319299 200813007 ^-NMR (CDCIb) δ: 3.79 (3H, s) , 4.05 (1H, t), 4.79 (2H, d) 7.10-7.15 (6H, m), 7·25-7·34 (9H, m), 7.80 (ih, s)· [Reference Example 40] 3-(E-methyl)-1_tritylmethyl-11^ than spit-4_ oleic acid methyl vinegar N-Trt

H3COOC

Under ice cooling and stirring, a solution of 3-methylhydroxymethyl>1 triphenylsulfonyl-1?-??carbazole-4-carboxylic acid methyl ester (1.7 g) in dichloromethane (9 mL) was added. Imidazole (336 mg), triphenylphosphine (129 g) and iodine (1.25 g) were stirred at the same temperature for 2 hours. The insoluble matter was removed by filtration. The filtrate was treated with sulphurite; sodium sulphate: turbid solution was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane), and crystallised from ethyl acetate to give the desired product (1 〇 6 g) crystals. lH one calendar (CDCl3>δ: 3·82 (3H, s)' 4.67 (2H, s), 7·1〇_7·13 (6η m)/ 7·28"7·34 (9Η, m), 7.78 (1ΗΑ s).

[Reference Example 41] 4_Cyano-1Η_σ-biszole-4 oleic acid ethyl ester

EtOOC

NC

NH. Hydroxylamine hydrochloride (219 mg) was added to a solution of 4_carboxylic acid-1-indole-pyrazole-3, ethyl acid (5 〇5 mg) in nmp (6 liters). C was stirred for 6 hours. The reaction mixture was cooled with ice and added with sulfinium chloride 116 319299 200813007 (1·〇8 g). Mix at room temperature! After an hour, the reaction mixture was poured and water m-acetic acid was extracted. The organic layer was re-read and brine washed, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate to give crystals of the objective product (356 mg). 4.35 (2Hf q), 8.69 (iH, 'H-NMR (DMSO-d6) δ: 1.31 (3 Η, t) [Reference Example 42] 4-cyano-1-trityl-1H-pyrazole 3-carboxylic acid ethyl ester

Add hydride (6% by weight dispersion oil) to a solution of ethyl 4-cyano-1H-pyrazole-3-carboxylate (1.94 g) in DMF (117 mL) under argon with ice-cooling. 517 house grams), and the mixture was stirred for a few hours. Burn (10) g) in a solution of _ ml), and mix for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give the objective product (4.09 g) as an amorphous powder. W (CDC13) δ: 1.,1 (3Η, t), 4.43 (2H, ,) , 7.〇6^1〇(6Η, top), 7·30-7·37 (9Η, m), 7 ·77 (1Η, s>· [Reference Example 43] 3_(Hydroxymethyl)-1-triphenylmethyl-1H-pyrazole_4-indenecarbonitrile 319299 117 200813007 N-Trt

NC Under a argon atmosphere, a mixture of sodium borohydride (1.89 g), chlorination (2.78 g), THF (100 ml) and ethanol (50 ml) was stirred at room temperature for 30 min and 4-cyano- Ethyl 1-triphenylhydrazin-1H-pyrazole-3-carboxylate (4·7 g) was stirred at room temperature for 14 hours. Ice water and 1 Torr hydrochloric acid (45 ml) were added to the mixture and the mixture was concentrated. The residue was partitioned between ethyl acetate and water, and ethyl acetate layer was washed with saturated brine, The residue was crystallized from ethyl acetate to give the desired product (3·26 g) crystals. H,R (CDCl3) δ: 2·18 (1H, br s), 4·79 (2Η, s), · 7·〇7-7·1〇(6Η, m), 7·31·7·36 (9Η, m), 7.73 (1Η, s)· [Reference Example 44] 3-(Moth methyl)-1_tritylpyrazolecarbonitrile 丨^VN\ J^/a Trt

NC was added to a solution of 3-(hydroxymethyl)-1-triphenylindenyl-1H-pyrazole 4A (2 g) in a dichlorocarbyl (11 ml) solution under ice cooling and stirring. Oxazole mr), triphenylene (1·58 g) and broken (1.53 g), and at the same temperature / cold t 7 2 j蛉. The insoluble matter was removed by filtration. The filtrate was washed with sulphuric acid sulphuric acid and brine, and purified with ethyl sulfate (ethyl acetate-hexane), and crystallised from ethyl acetate 319299 118 200813007 to obtain the desired product (1.89 g) crystals. H NMR (CDC13) δ: 4.44 (2Η, s), 7.07-7.14 (6H, m)·, 7.28 7·37 (9H, m), 7·68 (1H, s)· [Reference Example 45] 5 -Cyano-111-pyrazole-3-carboxylic acid

C〇2ch3 To a solution of methyl 5-formic acid-1H-pyrazolecarboxylate (14.79 g) in hydrazine (192 liters), hydroxylamine hydrochloride (7 gram) was added at 100 ° C. Stir for 6 hours. The reaction mixture was cooled with ice and sulfoxide (34.53 g) was added. After stirring at room temperature for a few hours, the mixture was poured into ice water' and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Dream Glue Chromatography (ethyl acetate-hexane) and crystallized from ethyl acetate to give the desired product (12 4 2 g) crystals. 4-NMR (CDC13) δ: 3·99 (3H, s), 7·21 (iH, s), ii: 6i (ih, ^ s).

[Reference Example 46] 5-cyano-1 -trityl-pyranyl-l-3-methyl acid methyl ester 319299 119 200813007

Co2ch3 sodium hydride (60% dispersion) was added to a solution of methyl 5-cyano-indole-3-carboxylic acid methyl ester (9·07 g) in DMF (300 ml) under argon with ice-cooling. In oil, 2.64 g), and stirred for 1 hour. A solution of triphenylchloromethane (17.56 g) in DMF (100 ml) was added and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The crystals deposited from the residue were powdered in ethyl acetate and filtered to obtain a target product (18.57 g) crystals. Ifi-NMR (CDC13) δ: 3.08 (3Η, s), 7.03-7.16 (6H, m) Λ 7.27- 7.37 (9H, m), 7·42 (1H, s)· [Reference Example 47] 3· (hydroxyindole)_1-trityl-1H-pyrazole-5-indole nitrile rt

NC

^-OH Under argon, a mixture of sodium hydride (4·73 g), chlorinated (6.99 g), THF (250 ml) and ethanol (125 ml) was stirred at room temperature for 30 min. Further, decyl 5-cyano-1-trityl-1H-pyrazole-3-carboxylate (9.84 g) was added, and the mixture was stirred at room temperature for 22 hr. In the reaction mixture 120 319299 200813007 Ice water and 1N hydrochloric acid (100 ml) were added and the mixture was concentrated. The residue was mixed with acetic acid and the ethyl acetate was washed with saturated brine, and then dried and concentrated with anhydrous sulfuric acid. The residue was crystallized from ethyl acetate to give crystals of the desired product (yield: 7 4 g). ^-NMR (CDC13) δ: 1.94 (1Η, t) , 4.68 (2H, d) e Q/ 'L94 (iHf s) 7.12-7.17 (6Hf m) f 7.29-7.35 (9H, m).

[Reference Example 48] 3_(O-Methyl)-1-tritylmethyl-indole-σ ratio salivation-5-carbonitrile

3-(hydroxymethyl)-^-trityl-1H-pyrazole-5·carbonitrile (7·31 g) in dichloromethane (15 mL) in ice bath and mixing To the solution were added imidazole (1.50 g), triphenylphosphine (5·77 g) and iodine (5·58 g), and the mixture was stirred at the same temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was washed with a sulfur-sodium sulfate aqueous solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate·hexane) and ethyl acetate ethyl acetate to afford crystals of the desired product (7·36 g). H^NMR (CDCls) δ: 4.34 (2Hf s) , 6.95 (1H, s), 7.13-7.16 (6H, m), 7·31-7·34 (9H, m)· ' [Reference Example 49] Bromotrityl-1H-port is more than 319299 121 200813007

The same procedure as in Reference Example 1 was carried out using 4-bromo-1H-pyrazole to obtain the title compound (4 〇 2 g) as a colorless crystal. h-NMR (CDCl3) 5: 7·1〇-7·39 (16Η, m>, 7.62 (1H, s)· [Reference Example 50] ι_trityl-m-pyrazole-4-carboxylate aldehyde

OHC

The solution of the compound obtained in Reference Example 49 (11 g) was evaporated to EtOAc (t EtOAc), and the solution of n-butyl lithium in hexane (1.6 mmol, 9.5 ml) was added dropwise dropwise. . After stirring for a few hours at the same temperature, DMF (4.7 ml) was added and the mixture was stirred for a few hours. An aqueous solution of ammonium chloride was added to the reaction mixture, and after warming to room temperature, the solution was diluted with water. Filtration and collection of the precipitate (4), followed by rinsing with water, ethanol and diethylamine, and sub-drying to obtain the title compound (7.9 g) as colorless 'H-NMR (CDCls) δ: 7.11^7.37 (1 Η, s ), 9· 85 (1H, s) · (15Hf m) r 7.97 (1H, s), 8.12 [Reference Example 51] 319299 122 200813007 (1_trityl-1Η-η than salivation 4-yl Methanol

The compound obtained from the reference _5 ( (53 g 实施 实施 实施 & 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 相同 4.8 4.8 4.8 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 (1h, % (15H, m), 7.39 (1H, S), 7.67 (iH, s), [Ref. 52] 4-(Bromomethyl)_1-tritylmethyl_11^pyrazole

▲ J "V only pays < compound (1.4g), each of the same as the example of the third example of the reaction plate green / only 'J reaction and purification # to obtain titled> (1·ΐ g), which is a colorless, amorphous solid. ^NMR (CDCla) δ; 4.43 (2Η, s), (1H, S)· 7·10-7·48 (16H, called,

[Reference Example 53] (Difluoromethyl)_lH-u than wow_4_carboxylic acid ethyl ester 319299 123 200813007

p02Et N Η 2-(ethoxymethylene)-4,4,4-trifluoro-1H-pyrazole-4-ketobutanoic acid acetamidine (4·80 g)>Valley in ethanol (50 ml) ), and added hydrazine monohydrate ( 1.20 g). The reaction mixture was heated at reflux for 16 h and concentrated. The residue was dissolved in aq. EtOAc (EtOAc)EtOAc. ^NMR (CDCls) δ: 1.38 (3Η, t) , 4.36 (2Η, q) , 8.23 (1Η, s).

[Reference Example 54] Ethyl 3-(difluoromethyl)-1-trityl-1H-indazole-4-carboxylate

319299 124 200813007 ^-NMR (CDC13) δ: 1.32 (3H, t) , 4.29 (2H, g) , 7.〇7-7>38 (15H, m), 7·92 (1H, s) · [Reference Example 55] [3-(Trifluoromethyl)-1-tritylmethyl "^·pyrazole-4-yl]methanol

Lithium aluminum hydride (0.34 g) was suspended in THF (50 mL) and cooled to EtOAc. A solution of the compound (4.00 g) obtained in Reference Example 54 in THF (120 mL) was added dropwise to the suspension. The reaction solution was stirred at room temperature for 16 hours and cooled in an ice bath. Water (〇····················· The title compound (3.80 g) was obtained as a colorless crystal. \ '职(10)〇ΐ3)δ: 1>65 (1H, t), 4.64 (2η,(1),7.〇8_7·ΐ3 (6η, d7.34 (9H, m), 7.38 (ιη, * ' [Reference Example 56] 4-(Methylmethyl)-3-(trifluoromethyl)"-tritylmethyl.carbazole

The title compound (i62 g) was obtained as a colorless crystals. 'face ((10)3) δ: 4.42 (2H, s), to (a) 』(6HU28- 7·35 (9H, m), 7·41 (1H, s)· [Reference Example 57] (2E)-3- (4-cyanophenyl) acrylate

Under a cold portion, a solution of phenylhydrazine (dimethoxyphosphino)acetate (2 g) and p-cyanobenzofural (10.0 g) in THF (90 ml) was added dropwise sodium hydride (60) A suspension of 3.1 g of THF (120 ml) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into EtOAc (EtOAc m. The residue was crystallized from diethyl ether to obtain crystals of desired product (20.0 g). 4-; NMR (CDC13) δ·· 5·27 (2H, s), 6·56 (1H, d), 7·33 - 7·46 (5Η' m)/ 7·58 - 7·73 (5Η m)· The following compound was obtained in the same manner as in Reference Example 57. (2E)-3-butyl 4-(4-cyanophenyl)acrylate 126 319299 200813007

Η ^-NMR (CDC13) δ: 1.54 m). (9Η, s), 6·45 (1Η, d), 7.5··7 (5H, [Ref. 58] 4_(4-cyanophenyl) -5-methyl_m_tr than _3_ carbonitrile

Under ice cooling, 4 sides of _2-cyanoethylene]benzophenone (μ4 g) and ι-[(ι-heteroylethyl)sulfonate]_4·indene (2 〇9 g) A solution of sodium hydride (60% dispersion oil, 〇48 g) in THF (20 mL) was added dropwise to a solution in thf (5 mL), and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated brine (1 mL) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford crystals of the desired product (0.60 g). 7·55 (2H, d), H-NMR (CDC13) δ: 2.37 (3Η, s); 7.29 (1h/d) 7·72 (2H, d)r 8·63 (1H, br s)· 319299 127 200813007 The following compounds were obtained in the same manner as in Reference Example 58. 4-(4-cyanophenyl)-5-methyl-1H-pyrrole-3-carboxylic acid benzyl ester

^-NMR (CDC13) δ: 2·18 (3Hr s), 5·14 (2H, s), 7·20 (2H, dd,), 7·28 - 7·34 (3Η, m), 7· 38 (2Η, d), 7·44 (1Η, d), 7·57 (2 Η, d) , 8·41 (1Η, s〉 4·(4-cyanophenyl)-5-fluorenyl- 1Η-pyrrole-3-carboxylic acid tert-butyl ester

XH-NMR (CDC13>δ: 1·37 (9Η, s), 2 · 18 (3Η, s), 7 · 34 (1Η, d), 7.41 (2H, d), 7.65 (2H, d), 8.39 (1H, s).

[Referential Example 59] 4-(4-oxophenyl)-2·Moth-5-mercapto-1Η-dehydrazol-3 _ decanoic acid second butyl

128 319299 200813007 4-(4 • Oxyphenyl)-5 -methyl-1 Η_σ 嘻-3-glycolic acid tert-butyl ester (4 79 g) and hydrazine-iodinated dimethylene iodide (4.21 g) The solution in DMF (50 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into EtOAc EtOAc. The residue was purified by a silica gel column chromatography (ethyl acetate-hexane), and crystallised from ethyl acetate to afford crystals of the desired product (5.83 g). ^NMR (CDCI3) δ: 1-31 (9H/m)A 2.15 (3Η, S) , 7.3〇^ 7.35 (2Hr in), 7.61 - 7·67 (2H,in), 8.49 (1H, s)· The following compounds were obtained in the same manner as in Reference Example 59. 4-(4-cyanophenyl)-2-iodo-5-methyl_1H_pyrrole-3-carboxylic acid benzoic acid

[Reference Example 60] 4-(4-Cyanophenyl)-5-methyl-2-(trifluoromethyl)pyrene-3-3 = butyl acid butyl 319299 129 200813007

4-(4_Analylphenyl)-2-Moth-5-fluorenyl-t-butyl tributyl acrylate (1.06 g), methyl fluorosulfonyl (difluoro)acetate (0.99 ml) and a solution of copper (25 g) in DMF (15 ml) was stirred at 80 ° C for 14 hours. The reaction mixture was poured into EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) elut ^-NMR (CDCI3) δ: 1.39 (9Η, s) , 2.18 (3Η, s) r 7.37 (2Hf d), 7·67 (2H, d), 8·77 (1H, br s)· [Reference Implementation Example 61] 2-fL-based 4-(4-carbylphenyl)-5-mercapto-1 Η-σ-pyrrol-3-benzyl benzoate

A mixture of chloro-iso-isocyanate (1.01 ml) and acetonitrile (5 130 319299 200813007 ml) was added dropwise at 4 ° C to 4·(4-cyanophenyl)·5-methyl-1Η_„ a mixture of -3·carboxymethyl carboxylate (3.09 g), DMF (2.25 ml) and acetonitrile (15 ml). After stirring at 0 ° C for 30 min, the mixture was poured into aqueous sodium bicarbonate and Ester extraction. The extract was washed with saturated brine and purified by silica gel column chromatography (ethyl acetate) to give the desired product (27 g) crystals. ^ (CDCl3) δ: 2·14 (3H, s) , 5·15 (2 η, 3), 7·17 to dd), 7.26 - 7.33 (3H, m) , 7.44 (2 H, d) f 7.75 (2 ^ d)' 13.17 (1H, s).

[Reference Example 62] 2-cyano-4-(4-cyanophenyl)-5-methyl-lH-u ratio tr____-acid

4-(4-Cyanophenyl)-5-methyl-2-cyano-1Η_σ 咯 _3_ phthalic acid benzyl ester (2.50 g), 10% palladium carbon (7jc content 50%, 250 mg ), a mixture of TiiF (1 ml) and decyl alcohol (10 ml) was given 3" in hydrogen and room temperature. The catalyst was removed by filtration using celite, followed by washing with methanol. The side washing liquid was combined with the mother liquid, and then condensed with ethyl acetate to obtain the target product (1.47 g) crystals. ^ ^-NMR (DMSO-d6) δ: 2.14 (3Hf s) , 7.47 (2H, d), 7.81 (2H d)r 8.62 (1H, S). 319299 131 200813007 [Reference Example 63] 4- [2-Methyl-5-(trifluoromethyl)_1H_pyrrole Iyl]benzonitrile

4 (4 乱 phenyl) _5_methyl _2 (trifluoromethyl each · third township 7 mg), sodium chloride (9 〇 mg) and dimethyl: milliliters) mixture at 17 吖Mix for 48 hours. The catalyst was removed by filtration using Shixiazao soil, followed by rinsing with methanol. This washing liquid was combined with a mother liquid, concentrated, and then washed with ethyl acetate to obtain a target product (147 g) crystals. The reaction mixture was poured into saturated brine (2 g ml) and extracted with ethyl acetate. The layer of acetic acid (10) was rinsed with brine and dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) and crystallised from ethyl acetate. HNMR (CDC13) δ: 2.45 (3H, s), 6·71 (1H, d), 7·45 - 7·51 (2 H, m), 7.61 ^ 7.72 (2 Hf m), 8.43 (1H, s The following compound was obtained by the same procedure as Reference Example 63 using the compound obtained in Reference Example 62. 4 (4-cyano basic group)_5_methyl ratio each _2_曱carbonitrile 132 319299 200813007

Earn (CDCl3) δ: 2·46 (3H, s), 6·97 (1H, (1), 7.46 (2 H, (1) 7·69 (2 H, d), 8·75 (1H, s).

[Reference Example 6 4 ] 4-(4-Cyano basic)-2,5-dimethyl-111-° than 嘻-3_ phthalic acid benzoquinone

A mixture of benzylacetate (152.8 g), potassium hydroxide (14. 8 g) and THF (495 ml) was stirred at room temperature for 2 min and cooled to 〇 C. 4-[(1Ε)-2_Nitroprop-1-enyl]benzonitrile (50 g) was added, and the mixture was stirred at 〇C for 1 hour. The reaction mixture was poured into aq. EtOAc. A mixture of the oil, decyl alcohol (13.9 ml), water (13.9 ml) and hydrochloric acid (13.9 ml) was stirred at 75 ° C for 2 hours. The reaction solution was allowed to cool to room temperature and concentrated, and the residue was partitioned between acetic acid and water. The organic layer was washed with aq. sodium bicarbonate and saturated brine, dried over EtOAc EtOAc EtOAc The crystals precipitated were filtered, and washed with a small amount of diisopropyl ether to give 4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid benzyl ester (34.1 g).工布丽R (CDC13) δ: 2·10 (3H, s), 2·53 (3H, s), 5.07 (2H, S), 7·03 — 7·〇6 (2Η, m), 7· 22 — 7·29 (5H, m)r 7·47 (2H, d), 8·〇ΐ (1Η, s) · [Reference Example 65] 4-(4-cyanophenyl)_5_fluorenyl -2-propyl_1H-pyrrole-3-carboxylic acid

A mixture of benzyl 3-ketohexanoate (6.40 g), potassium oxychloride (776 mg) and THF (50 ml) synthesized by a known method was stirred at room temperature for 20 minutes and cooled to 〇. °C. 4-(2-Nitropropen-1-yl)cyanobenzene (2.66 g) synthesized by a known method was added to the mixture, and the mixture was stirred for 1 hour at 〇 ° C. The mixture was poured into saturated brine, and The extract was extracted with EtOAc. EtOAc (EtOAc) 75X: Stirred for 2 hours. The reaction solution was allowed to cool to room temperature and concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate. The residue was chromatographed on silica gel column (ethyl acetate-hexane) to obtain 4-(4-cyano 319299 134 200813007 phenyl)-5-mercapto-2-propyl-1H-pyrrole-3-carboxylate Acid stupid methyl ester. The resulting compound was used in the subsequent procedure without further purification. 4-(4-cyanophenyl)-5-methyl-2-propylcarboxylic acid benzyl ester, 10% palladium on carbon (water content 5〇%, 294 mg), THF (1 〇 5 ml) and methanol ( A mixture of 35 ml) was stirred at room temperature for 3 hours under argon. The catalyst was removed by filtration using celite, followed by rinsing with methanol. The lotion was combined with the mother liquor, concentrated and then rinsed with ethyl acetate to obtain the product: (2.42 g) crystals. 1β54'1β66 (2Hf in), 2.05 )' 7·70 (2H, d), 11_14 ^-NMR (DMSO-de) δ: 0.90 (3Η, t), (3H, s), 2·80 (2H, t), 7·35 (2H, (1H, s) A 11.35 (1H, br. s). • The same compound as in Reference Example 65 gave the following compound _(4-cyanophenyl)- 2-cyclopropyl-5-methyl

NC

Η R (DMSO-d6) δ: 0·78-0·83 (2Η, m) 2.02 (3H, s), 2·65-2·74 (1H, m), 7·35 10.63 (1H, s )···〇·89~〇·95(2h, d), 7.73 (2H, m), (2H, d)f 4-(4-cyanophenyl)_ 5 -ethyl-2-anthracene Base - lH-n than each mouth j, know _ 竣 319299 135 200813007

七 --NMR (DNSO-de) δ: 1.07 (3H, t) , 2.37 (2H, q) , 2.41 (3H, s), 7·34 (2H, d), 7·72 (2H, d), 10·98 (1H, s), 11.19 (1H, s). 4_(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic acid

Η ^-NMR (DMSO-de) δ: 2.05 (3H, s) , 2,39 (3H, s) , 7.35 (2H, d), 7·71 (2H, d), 11·22 (1Η, s ), 11.43 (lHr s)· 4-(4-cyanophenyl)-2-ethyl-5-mercapto-1H-indole-3-carboxylic acid

Hexa-NMR (DMSO-de) δ: 1.17 (3Η, t) , 2.06 (3Η, s), 2.84 (2Η, q), 7·37 (2Η, d), 7·73 (2Η, d), 11 19 (Ifi, s). 136 319299 200813007 [Reference Example 66] This (2-methyl-5-propyl-1H-pyrrol-3-yl)benzonitrile

Mixture of 4-(4-cyanophenyl)-5-mercapto-2-propyl-1H-pyrrole-3"carboxylic acid (2.42 g) and TFA (5 ml) was stirred at room temperature 40 minute. The residue obtained by concentrating the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford crystals of the desired product (1.97 g).

(2H, m) , 7 · 57- Li R (CDC13) δ: 0·99 (3H, t), ι·γ s), 2.55 (2H, t), 6.05 (lHf d) 7.61 (2H, m) , 7·78 (1H, br.s)· Method The following compounds were obtained. Benzocarbonitrile

The same 4-(5-cyclopropyl·2-methyl-1H-pyrrole-3-NC as in Example 6 6

Η - NMR (CDC13) δ: 0.61-0.67 (2H,

1.75-1.82 (1Η, m), 2·39 (3Η, s), 5·99 7.60 (2H, d), 7·89 (1H, s) · 319299 137 200813007 4-(2-ethyl-5- Mercapto-1H-pyrrol-3-yl)benzonitrile

^-NMR (DNSO-d6) δ: 1.18 (3Η, t) , 2.59 (3H, q〉, 5.94 (1H, d), 7.45 (2H, d), 7·71 (2H, d) 4-(2 ,5-Dimethyl-1H-pyrrol-3-yl)benzonitrile s), 2.69 (2H, 10.64 (1H, s).

,6·04 . (1H, d), ^-NMR (CDCls) δ: 2.27 (3H, s), 2.40 (3H, s 7·46 (2H, d), 7·61 (2H, d), 7 ·76 (1H, br s). 4-(5-ethyl-2-mercapto-1H-° than 嘻-3-yl) benzocanca

4-NMR (CDCls) δ: 1·27 (3Η, t), 2.41 (3Η, s) 6.06 (1Η, d) r 7.46-7.49 (2Hf m) f 7.59-7.62 (1H, br.s). 2·62 (2H, q), (2H, m), 7·80 138 319299 200813007 [麦考贯例6 7 ] 3-(4-cyanophenyl)-5-methyl-2-(three Fluoromethyl)_Hn ratio

Stir at room temperature 4-(4-cyanophenyl) 2_mercapto-1Η_σ pyrrole (1 〇 1 g) with Ν_ molybdenum diimide (1.31 g) in DMF (25 ml) The solution was diluted with ethyl acetate. EtOAc (EtOAc)EtOAc. 3-(4-Cyanophenyl)-5-methyl-2-iodo-1H-pyrrole (1.17 g) is obtained as a mixture with by-products. In the mixture (7 g) Molybdenum copper (476 mg) and methim flu〇r〇sulf〇nyl (difluoro) acetate (1.92 ml) were added to the solution in DMF (12 liter). The mixture was heated to a temperature of 1 Torr: the reaction solution was allowed to cool to room temperature, poured into water and extracted with ethyl acetate (5 mL). The organic layer was washed with water and saturated brine. The residue was purified by EtOAc (EtOAc) elute (CDC13) δ: 2.34 (3Hf S) f 6.09-6.10 (1H, m) , 7.53 (2H, d), 7_65 (2H, d), 8·40 (ih, s) [Reference Example 68] 3_( 4-cyanophenyl)_ 5-mercapto-2-carboxyl-out-purine 139 319299 200813007

Vilsmeier reagent (337 mg) was added to 4-(4-cyanophenyl)-2-methyl-1H-portpyr (200 g) in DMF under ice cooling. The solution was (3.0 halo) and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into a saturated aqueous solution of sodium dicarbonate (2 liter) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried The residue was purified by silica gel column chromatography (ethyl acetate hexane), and crystals crystals crystals Η-NMR (CDC13) δ: 2·42 (3H, s), 6·21 (1H, d〉, 7·58 (2H, d), 7·72 (2Η, d), 9·50 (1Η, s), 10·07 (1Η, s)· [Reference Example 69] 4_(Bromomethyl)-1-(4-methoxybenzyltrifluoromethyl, 2,3_3

P-methoxybenzylazide (3.35 140 319299 200813007 g), 4,4,4-trifluorobutynoic acid ethyl ester (ethyl 4,4,4-trifluorobut-2- A mixture of ynoate (2.90 g) and toluene (30 mL) was stirred at EtOAc to 20 hr. The reaction mixture was poured into a saturated aqueous solution of EtOAc. The residue was purified with EtOAc EtOAc (EtOAc) A mixture of sodium borohydride (1. 27 g), calcium chloride (2.8 g), THF (40 ml) and ethanol (20 ml) was stirred at room temperature for 30 minutes, and the obtained oil was added (5· 53 g), the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into aq. EtOAc (EtOAc)EtOAc. A mixture of the obtained oil (2·11 g), NBS (1.57 g), triphenylphosphine (2·31 g) and THF (20 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine, and ethyl acetate was evaporated. The residue was purified by EtOAc EtOAc (EtOAc) ^-NMR (CDC13) δ: 3.80 (3Η, s), 4.59' (2Hf s) f 5.57 (2H, S), 6·88 (2H, d), 7.25 (2H, d)· [Reference Example 70 ]-oxy-4-(4-(yl)phenyl)-2,5-dimethyl-1Η-p-pyrrol-1-yl]ethanoamine 141 319299 200813007

4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole_3_carbonitrile (2〇·〇克), iodoacetamide (84.0 g) and potassium carbonate (62.5 g) The solution in 〇]\^ (150 ml) was stirred at 120 ° C for 20 hours. The reaction mixture was poured into EtOAc EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) and crystallised from ethyl acetate to afford the desired product (18·8 g). H NMR (DMSO-de) δ: 2.12 (3Η, s), 2.25 (3H, s) r 4.55 (2H, s)/ 7.34 (1H, s) r 7.48 (2H, d), 7.65 (1H, s) , 7.86 (2H, d).

[Reference Example 71] 厶[3-Cyano-4-(4-cyanophenyl)-2,5-dimethyl_1H_n ratio _;[_yl]ethane sulfate

319299 142 200813007 2-[3-Cyano-4-(4-cyanophenyl)-2,5·dimethyl-1H-pyrrol-1-yl] Ethylene &amine (8·〇克) A solution of Lawesson's reagent (7.5 g) in THF (250 mL) was stirred at 8 Torr for 2 h. The reaction mixture was poured into saturated brine, and ethyl acetate was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) and crystallised from ethyl acetate and diethyl ether to afford crystals of the desired product (63.5 g). 4-year (CDC13) δ: 2·26 (3H, s), 2·42 (3H, s), 4·95 (2H, s), β·56 (1Η, s), 7·2-7.4 ( 3Η, m), 7·72 (2Η, d)· [Reference Example 72] [2-(Trifluoromethyl)_;i,3-thiazolyl]methanol

2-(trifluoromethyl)-indole, thiazole|carboxylic acid ethyl ester (2.62 g) in dehydrated thf under argon at a temperature of 1 ° C or lower. A solution of lithium aluminum hydride (441 mg) in dehydrated THF (116 ml) was added, and the mixture was stirred at the same temperature for 2 hrs and further stirred at room temperature for 1 hour. After ice-cooling again, the reaction was quenched by the addition of a saturated aqueous sodium sulfate solution, and the mixture was neutralized with 1N hydrochloric acid and then ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The resulting product was used in the subsequent work without further purification. 143 319299 200813007

Br s), 4·97 (2H, s), 7·82 (1H, [Reference Example 73] 3 - σ stopper cr sitting 4-(iodomethyl)-2-(trifluoromethyl)^

Add diisopropylethylamine (4·81 ml) to <4-yl]methanol (2.6 g) in ethyl acetate methanesulfonyl chloride (2.65 g) in ethyl acetate (11 chilled and stirred under ice) , into a solution of [2·"(difluoromethyl)-1,3-sand (116 ml) t, a solution of 1 liter) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into water' and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate Sodium iodide (17.4 g) was added to a solution of the residue in acetone (yield: 74 ml) and the mixture was refluxed for 1.5 hr. After concentrating the reaction mixture, the residue was partitioned between ethyl acetate-water, and then evaporated, evaporated. The resulting product was used in the subsequent procedure without further purification. ^-NMR (CDC13) δ: 4.66 (2Hf s) r 7.89 (1H, s).

[Reference Example 74]

5-mercapto-1,3-thiazole-2-carboxylic acid ethyl ester OHC RC〇2Et 144 319299 200813007 Ethylamino (thioketo) acetate (31.6 g) dissolved in 1,2-dimethoxy B-burn (450 house liters)' and added bromomomalonaldehyde (35.8 g). The reaction mixture was stirred at room temperature for 68 hours and concentrated, and the residue was dissolved in ethyl acetate and saturated aqueous sodium sulfate. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate (MgSO4). Things. ^-NMR (CDC13) δ: 1.47 (3Η, t) , 4.52 (2Η, q) , 8.56 (1Η, s) f 10.13 (1H, s)· [Reference Example 75] 5-(Hydroxyfluorenyl)- Ethyl 1,3-thiazole-2-carboxylate

A solution of the compound obtained in Reference Example 74 (6·90 g) in ethanol (200 ml) was cooled to 〇 ° C, and sodium borohydride (yield 71 g) was added. The reaction solution was stirred at the same temperature for 30 minutes and concentrated, and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated, dried over anhydrous magnesium 4-; NMR (CDC13) δ: 1·44 (3Hr t), 2·13 (1H, t), 4·48 (2Η, q), 4·96 (2Η, d), 7·88 (1Η, s)· [Reference Example 76] ethyl 5-(bromomethyl)-1,3-thiazole-2-carboxylate 145 319299 200813007

C02Et The title compound (1.87 g) was obtained as a colorless crystal, using the compound obtained from Reference Example 75 (yield: 81 g). ^-NMR (CDCI3) δ: 1.44 (3Η, t) , 4.47 (2Η, σ) 4 *7ΐ , ’ 'ι•'丄 (2Η 7.94 (1Η, s).

[Reference Example 77] Methyl 2-(bromomethyl)-1,3-oxazol-2-carboxylate

C02Me 2-methyl-1,3- sulphur-4-carboxylic acid methyl ester [1·83 g, as described in

Tetrahedron 1^, 38, 331, (1997) method synthesis],]^8 (6.90 g), 2,2'-azobis(isobutyronitrile) (0.40 g) and carbon tetrachloride (4 〇 ml) The mixture was heated under reflux for 14 hours, diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extracted ethyl acetate layer was dried over anhydrous magnesium sulfate (MgSO4). h-NMR (CDC13) δ: 3·93 (3H, s), 4·48 (2H, s), 8·25 (1H, s)· [Reference Example 78] 4_(4-cyanophenyl) 1-(2-hydroxyethyl)-2,5-dimercapto-indole-n-pyrrol-3-carbonitrile 146 319299 200813007

NC

The solution of hydrogenated sodium (60% dispersion oil, 〇·44 g) in dmf (15 ml) was cooled in an ice bath' and 4-(4-carbophenyl)-2,5-diindenylpyrene was added. 3-indene nitrile (1.99 g). The reaction mixture was stirred at the same temperature for a few minutes and 2-ethyl acetate (1.1 ml) was added and the mixture was allowed to stand at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The residue was dissolved in methanol (50 ml) and potassium carbonate (2············· The residue was dissolved in ethyl acetate and f, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and further evaporated. The residue was purified by column chromatography (ethyl acetate) to afford compound (yel. ^ ^ 丑 (c陶δ: i72 (1H, (4), 2·3ι (3h, s), 2.46 yang, 3.88-3.94 (2H, m), 4 shoulders (2H,...7.49 (2h, (1), 7.7 q (Machine [Reference Example 79] . H4-cyanophenyl)_2,5-dimethyl small (2__ethylethylcarbonitrile 319299 147 200813007

The solution of the chloroform (0.068 ml) in dioxane (1 ml) was cooled to -70 C, and dimercaptosulfoxide (12 ml) was added. The reaction mixture was stirred at the same temperature for 20 minutes, and a solution of the compound obtained from Reference Example 78 (88 g) in dichloromethane (1 ml) was added, and then dimethyl hydrazine (0.50 liter) was added. ). The reaction mixture was slowly heated to -3 Torr and cooled again to -70 °C. Triethylamine (〇·32 ml) was added to the reaction mixture, and the mixture was heated to 0 ° C, stirred at the same temperature for a few hours, and water and ethyl acetate were added to the reaction solution. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. h-NMR (CDC13) δ: 2·18 (3H, s), 2·34 (3H, s), 4·79 (2H, s), 7·5〇 (2Η, d〉, 7·7〇 ( 2Η, d〉, 9·75 (1Η, s).

[Reference Example 80] Helium methyl)-2-methyl-1,3-oxazole

Mixture of acetaminophen (60.0 g) and dichloro-2-propanone (26.0 g) 148 319299 200813007 loot: heated for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium dicarbonate and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated with anhydrous sulfuric acid, and then the residue was distilled (100 to 13 〇〇 c / 4 Torr to 6 〇 mm Hg (mmHg)). The obtained crude title compound was purified by EtOAcjjjjjjjj H-NMR (CDC13) δ·· 2.47 (3Η, s), 4·48 (2Η, s), 7·54 (1H, s)· [Reference Example 81] 4-decyl-1-triphenyl Methyl-1;[^pyrazole-3-carboxylic acid ethyl ester will Ν

Ph--Ph

Ph 4-Acetyl-indole-oxime-3-carboxylic acid ethyl ester (5·g), triphenylchlorodecane (8·71 g), triethylamine (6.2 ml) synthesized by the known method A mixture of 4-didecylaminopyridine (0.38 g) and dichloromethane (5 liters) was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was washed with EtOAc EtOAc. b-NMR (CDC13) δ: 1·39 (3Η, t), 4·42 (2Η, q), 7·08 - 7.15 (6H, m), 7·31 (1H, s), 7·32 - 7·37 (,8 H, m), 7·96 (1H, s), 1〇·39 (1H, s)· [Reference Example 82] 149 319299 200813007 4-(Hydroxymethyl)-1-III Ethyl benzoyl-1H-pyrazole-3-carboxylate

Ph--ph Ph A mixture of the compound (4.0 g) synthesized from Reference Example 81, sodium hydrogen halide (45 g), THF (20 ml) and methanol (20 ml) was given at ot. 1 hour. The reaction mixture was poured into a bar acid aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with EtOAc (EtOAc m. ^-NMR (CDCI3) δ: 1.37 (3Η, t), 3.75 (1Η, t), 4.38 (2H, q), U2 (2H, d), 7·10 - 7·16 (6H, m), 7·24 (1H, s), 7·32 (muscle td).

[Reference Example 83] mercapto)-1-tritylmethylpyroxyethyl ester

Ph--Ph Ph 0^- compound synthesized from Reference Example 82·61 g) iodine (1.56 g), imidazole (0 42. phantom-,., 曰V g) and dichloromethane (2 〇 ml) The guilty 150 319299 200813007 was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium dicarbonate and ethyl acetate were added to the reaction solution, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was washed with saturated brine, dried over anhydrous The residue was suspended in diethyl ether and filtered to afford title compound (2 g). ^-NMR (CDCI3) δ: 1.40 (3Η, t), 4.39 (2H, q) r 4.59 (2H, s), 7·08 - 7·15 (6H, m), 7·32 (9H, td) , 7.37 (1H, s) [Reference Example 84], 4_(2_Mercapto-5-methyl-1H-pyrrol-3-yl)benzonitrile

Wellsmeyer reagent (1·72 g) was dissolved in DMF (17 ml) and added with a small amount of 4-(4-cyanophenyl)-2-methyl-1H-ton over 20 min. (1.02 g). The reaction mixture was stirred at room temperature for 1 hr, water (1 mL) was added and the mixture was stirred for 45 min. The reaction mixture was poured into a sodium bicarbonate solution and extracted three times with ethyl acetate. The organic layer was washed with water and aq. The residue was purified by silica gel chromatography chromatography eluting ^-丽R (CDC13) δ··2·39 (3H, s), 6·20 (1H, d), 7·57 (2ΗΛ d), 7·72 (2Η, d), 9·41 (1Η , brs), 9·51 (1Η, s)· 319299 151 200813007 [Reference Example 8 5 ] 4-(2-methyl-1H-pyrrolyl)benzonitrile

ΊΤΑ (7.3 ml) was added 4_(4-cyanophenyl)-5-methyl-1H-pyridinium_3_carboxylic acid tert-butyl ester (4〇9·3亳g) and the mixture was at room temperature Stirred for 3 hours. The reaction solution was diluted with benzene and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) XH-NMR (CDCls) δ: 2.44 (3H, s) f 6.38 (1H, t), 6.73 (1H, t), 7.50 (2H, d), 7·63 (2H, d), 8·〇7 ( 1H, brs). * [Reference Example 86] 4-(5-Mercapto-2-methyl-1H-indolyl-3-yl)benzonitrile

Η

CHO 4-(2-methyl-1H-pyrrole-3-yl)benzonitrile (144·7 mg) was dissolved in DMF (1.6 ml), and a small amount of Wilmer Meyer reagent (203.52) was added under ice cooling. Pen gram). The mixture was stirred at room temperature for 45 minutes, poured into di-substrate and further stirred for 15 minutes. The organic layer was extracted with a saturated aqueous solution of sodium bicarbonate (3 ml), and then extracted four times with ethyl acetate. Organic, layer; 152 319299 200813007 Washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut "H-NMR (CDCls) 5: 2.50 (3H, s), 7.08 (lHf d) , 7 50 \^nr a), 7·69 (2H, d), 9.48 (1H, s).

[Example 1] 4-(4-cyanophenyl)_2,5-dimethyl small (1Η-indoleazole-3-ylmethyl)_研_吼rr-3-carbonitrile

The suspension of sodium hydride (60% dispersion oil, 400 mg) in DMF (13 liters) was added in an ice bath and 4-(4-cyanophenyl)-2,5-dimethyl-111 was added. - Pyrrole-3-carbonitrile (1·3 () g). The reaction mixture was dropped at the same temperature for 30 minutes and the compound obtained from Reference Example 3 (2 〇 () g) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (hexane-ethyl acetate) to afford 4-(4-cyanophenyl)-2,5-dimethyl-1-[(1-triphenylhydrazinyl-1 More specific than saliva _3_yl) fluorenyl]-1 Η-pyrroleonitrile (2.27 g) crystals. 4_(4-cyanophenyl)_2,5-dimercaptotriphenylhydrazinyl azole 153 319299 200813007-3-yl)mercapto]-1H-pyrrole-3-carbonitrile (2.27 g), pyridine hydrochloride A mixture of the salt (1·g) and methanol/THF (3/1, 70 ml) was heated at 80 °C for 4 hours and concentrated, and ethyl acetate and water were added to the residue. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by EtOAc EtOAcjjjjjjjj -Li R (CDC13) δ: 2.31 (3H, s), 2·47 (3H, s), 5·11 (2H, s), 6·08 (1Η, d), 7·51 (2Η, d) , 7·56 (1Η, d), 7·69 (2Η, d), 1〇·〇8 (1Η, s).

[Example 2] 4-(4-cyanophenyl)_2,5-didecylmethyl-1H.pyrazol-3-yl)methyl]-1Η-pyrrole-3-carbonitrile

NC

From the mixture of the compound obtained in Example 1 (〇·49 g), potassium carbonate (〇·45 g) and DMF (4 ml), methyl iodide (〇.l〇 ml) was added. The reaction mixture was stirred at room temperature for a little hour, diluted with water and ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 3H, s) f 2.48 (3H, s)A 3.88 (3H, s) r 5·〇4 (2H, s), 5·90 (1H, d), 7.30 (1H, d), 7·5〇 ( 2H, d), 7.69 (2H, d).

[Example 3] 4-(4-cyanophenyl)-2,5-dimercapto-1-[(1-methyl-1H-indazol-5-yl)methyl]-1H-pyrrole- 3-carbonitrile

NC

The reaction of Example 2 was carried out and purified by column chromatography to give the title compound (0.10 g). h-NMR (CDC13) δ: 2·22 (3H, s), 2·37 (3H, s), 3·89 (3H, s), 5·06 (2Η, s), 5·66 (lHf d ), 7·4〇(1Η, d), 7·51 (2Η, d), 7·72 (2Η, d).

[Example 4] 4-(4-cyanophenyl)-2,5-diindenyl-1-{[5-(trifluoromethyl)-1Η-oxazol-3-yl]methyl}- 1Η-pyrrole-3-indoleonitrile 155 319299 200813007

NC

Sodium hydride (60% dispersion oil, 4.87 g) was added to 5-({[t-butyl(diindenyl)fluorenyl)oxy}methyl (trifluoromethyl) under ice cooling. _1H_ a solution of saliva (33.0 g) in DMF (318 ml). The reaction mixture was stirred at room temperature for 30 min, and phenyl hydrazinyl chloride (19.1 g) was added, and the mixture was stirred at room temperature 6 The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then purified. The residue was purified by silica gel column chromatography (ethyl acetate-hexane). An oil (34.38 g) was obtained. The oil obtained from the above reaction (48 g) was dissolved in THF (50 ml), and tetrabutylammonium fluoride (3·38 g) was added. The reaction solution was stirred at room temperature for 30 minutes and concentrated. ethyl acetate and water were added to the residue. The ethyl acetate layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to afford § )克). A mixture of the resulting oil (3.80 g), triphenylphosphine (3. 66 g) and dichloromethane (20 liters) in an ice bath The temperature was lowered and NBS (2 49 g) was added. After the reaction mixture was stirred at room temperature for 30 minutes, a saturated aqueous sodium dicarbonate solution was added to the mixture and the methylene chloride layer was separated. Ethyl acetate) Purify the dichloromethane layer to obtain 1-[(benzyloxy)methyl 319299 156 200813007 yl]-3-(bromomethyl)-5-(trifluoromethyl)-1 Η "Biazole and 1- a mixture of [(phenylhydroxy)indolyl]-5-(bromomethyl)-3-(trifluoromethyl)-l-pyrazole (about 1:1) as a colorless oil (3·70)克). Using the obtained oil (3.70 g), sodium hydride (60% dispersion oil, 0.52 g) and 4-(4-cyanophenyl)-2,5-dimethyl-1 fluorene-fluorene -3 -phthalonitrile (2.21 g) The same reaction and purification procedure as in Example 1 was carried out to obtain 1 {[1 [(present methoxy)methyl]-5-(triponyl)_; Η_σ ratio -3-yl] fluorenyl-(4-cyanophenyl)_2,5-diindenyl fluorene _3_indenitrile and [(benzyloxy)methyl]-3·(three Fluorinyl)-1Η_σ-bisazolyl]methyl 4-(4-cyanophenyl)_2,5-dimethyl-lH-n than 嘻-3-carbonitrile (about 1: 1, 3.83 g) A mixture of colorless crystals. The obtained colorless crystals (3.44 g) were dissolved in methanol / hexanes (5:1, 6 liters) and 10% palladium carbon (1.00 g) was added, and the mixture was stirred at room temperature under hydrogen for 2 hours. The catalyst was removed by filtration. After that, the filtrate was concentrated and the residue was dissolved in ethyl acetate. ethyl acetate was washed with 10% aqueous sodium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated. Ethyl ester) was purified to give the title compound (0.22 g) as colorless crystal. ^NMR (CDCI3) δ: 2.28 (3Η, s), 2.45 (3Η/ s), 5.15 (2Η, s), 6.36 (1Η, s), 7.50 (2Η, d), 7.71 (2η, d)^ 10.3 〇.10.5〇(1Η, br s) · [Example 5] 4-[4_Akyl-3_(trifluoromethyl)phenyl]_2,5-dimethyl small {[5_(trifluoromethyl) )-1Η_pyrazol-3-yl]methyl}·ιη-pyrrole A guess 319299 157 200813007

^Sodium hydride (60% dispersion oil, 〇·085 g) was added to 4 [4 cyano | (difluoroindolyl) phenyl] 2,5 dimethyl _ ή 吡 _ _ _ 3 • A guess = 45 grams) in DMF (5 liters) solution. After the reaction mixture was allowed to stand at room temperature for 30 minutes, hydrazine (benzyloxy)methyl]-5-(bromomethyl)-3-(trifluoromethyl)-1 Η-pyrazole and I[( A mixture of benzyloxy)indenyl]-%(bromoindolyl)-5-(trifluoromethyl)-1 -pyrazole (〇·58 g) was stirred at room temperature for 14 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 1-{[1_[(benzyloxy)methyl]-3-(violent fluoromethyl)-lH-nH5 - Methyl}-4-(4.cyanophenyl)_2,5-dimethyl-111-°Pilo-3-carbonitrile with 1-{[1-[(benzyloxy)methyl) ]_5-(trifluoromethyl) 1H- °biazole _3_yl]methyl}_4_(4-cyanophenyl)_2,5-dimethyl-oxime-port ratio 17-3-acetonitrile Mixture (3·65 g). 2 mol/L (m〇l/l) boron tribromide was added to a mixture of the above two isomers (〇·7 g) and dichloromethane (20 ml) at 0 °C. Dichlorosilane solution (2.2 ml). After stirring at room temperature for 2 hours, the reaction mixture 319299 158 200813007 was poured into a saturated aqueous solution of sodium dicarbonate (1 mL) and extracted with ethyl acetate. The acetate layer was re-read and rinsed with brine, dried with anhydrous sulfuric acid and concentrated. The residue was purified by column chromatography (ethyl acetate) and crystallised from diethyl ether to afford crystals of the title compound (42 g). 2.46 (3Η, s), 5.17 (2Η, s), f 7.89 (1H, d)r 10.79 (1H, 4 NMR (CDC13) δ·· 2·30 (3H, s) 6·37 (lHf s), 7·70 — 7·82 (2Η [Example 6] 4-(3-cyanophenyl)-2,5-dimethylene>soil"-{[3-(dimethylmethyl)-ΐΗ -σ比哇-5_基]methyl}-1Η-^嘻-3 - carbonitrile

FF uses 4-(3-cyanophenyl)_2 枓^ ^ ^ /.IC . α ... dimercapto-111_pyrrole-3_carbonitrile as the material, according to the same formula of Example 5, The title compound is available in the set. ^-NMR (CDCI3) δ: 2.25 (3Η 6·37 (1Η, s), 7·53 - 7·68 (4 2·44 (3H, S), 5·16 (2H, S), 10·58 (1H, s>· [Example 7] 2'Chloro-4_(2,5-dimethylfluoromethyl)_m-pyrazol-5-yl]oxime 319299 159 200813007 base}-111-吼3 -benzonitrile

The title compound was obtained in the same manner as in Example 5, using 2-?-?-(2-(2,5-dimethyl-1?七-丽R (CDC13) δ: 2.24 (3Η, s) , 2.32 (3H, s) , 5.14 (2H, s), 6·13 (1H, s), 6·36 (1H, s), 7· 33 (1H, dd), 7·48 (1H, d), 7.63 (1H, d).

[Example 8] 3 - {[ 3 -Gasyl-4 -(4 oxyphenyl)_ 2,5 -didecyl-1Η-σBilo-1 -yl]indolyl 1Η-pyrazole -5_carboxylic acid ethyl ester

Ν ΝΗ COOEt 160 319299 200813007 4-(4-cyanophenyl)-2,5-dimethyl-1H-portoprol-3-carbonitrile (ι·45 g) under argon and ice cooling Sodium hydride (60% dispersion oil, 300 mg) was added to a solution of dehydrated DMF (19.6 ml), and the mixture was stirred 30 hr. Further, a solution of 'Iacetic acid group_5_(bromomethyl)_ιη-π ratio η sit-3-carboxylic acid ethyl ester (2.07 g) in dehydrated DMF (3 ml) was added to the mixture, and the mixture was stirred at room temperature. hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute (CDC13) δ·· 1·39 (3H, t), 2·31 (3H, s), 2·37 (3H, s), 4·39 (2Η, q)r 5·11 (2Η, s) , 6·54 (1Η, s), 7·51. (2Η, d), 7.70 (2Hf d), 10.80 (1H, s).

[Example 9] 4-(4-cyanophenyl)_i_{[5-(methyl)-oxime-吼sa-3-yl]methyl b 2,5-dimethyl·1Η_pyrrole- 3-carbonitrile

A mixture of sodium borohydride (120 mg), calcium chloride (175 mg), THF (12.6 ml) and ethanol (6.3 ml) was stirred at room temperature for 30 minutes, and 319299 161 200813007 was added to the mixture 3{[3 -Cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-indol-1-yl]indolyl}-1Η-pyrazole-5-carboxylic acid ethyl ester (235 mg The mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into ice water and 1N hydrochloric acid (3. The reaction mixture was extracted with EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) iH-NMR (DMSO-d6) δ: 2·31 (3H, s), 2·44 (3H, s), 4·42 (2H, d), 5·09 (2Η, s), 5·24 ( 1Η, t), 6·02 (1Η, s), 7·52 (2Η, d), 7·89 (2Η, d), 12·66 (1Η, s)·· [Example 10] 3-{ [3—Cyano-4-(4-cyanophenyl)-2,5-diindenyl-111-° than 嘻-1-yl]methyl} _ 1H-12 than jun-5-carboxylic acid

a solution of 4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-indanonitrile (1.77 g) in dehydrated DMF (24 mL) EtOAc. Sodium hydride (60% dispersion oil, 368 mg) was added and the mixture was stirred for 30 minutes. Further, 5-(bromomethyl)-1-{[(2,2-dimethylpropionyl)oxy]anthracene 162 319299 200813007 base}_111-pyrazole-3-carboxylic acid ethyl ester (3.20 g) A solution in dehydrated DMF (5 ml) was added and the mixture was stirred at room temperature for 3 hr. The ruthenium mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Shih-Hui gel chromatography (ethyl acetate-hexane) to obtain 5-{[3-cyano-4 gas 4-cyanophenyl)-2,5-dimethyl-1H- Ethyl pyrrol-1-yl]methyldimethylpropionyl)oxy]indolyl}-indole-pyrazole-5-carboxylate (3.12 g), which was a crystalline powder. In 5_{[3-cyano-4-(4-cyanophenyl)_2,5-dimethylpyrrole-i-yl]indenyl}-1_{[(2,2-dimethylpropenyl) Ethyl]methyl bromide bismuthazole | ethyl acetoacetate (1.05 g) in a solution of hydrazine (9. 7 ml) was added 1 N oxyhydrogen solution = sodium aqueous solution (6.45 ml) and methanol (9· 7 ml), the reaction mixture was stirred at ~μ for 26 hours. After distilling off the sterol and THF, the residue was diluted with X and neutralized with 1N hydrochloric acid (6·45 mL). After extracting with ethyl acetate, the organic layer was washed with brine sat. Filter the sink; the temple is immersed in _ rinsed and dried to obtain the title compound pi? 毫 2.29 (3H, s) r 2,43 (3H, 6·64 (1H, s), 7·55 (2H, d) , s), 3.81 (1H, 7.90 (2H, d)· ifi-NMR (DMSO-d6) δ s), 5·20 (2Η, s〉, [Example 11] {[3] 4-(4 -cyanophenyl)_2,5-dimethyl--indolyl]methyl b 1H-carbazole-3_formamide 163 319299 200813007

3-{[3-Cyano(4-cyanophenyl)-2,5-monomethyl-1H-pyrrolyl]methyl b 1H-pyrazole-5-carboxyl under ice cooling and stirring Add oxazole (225 mg) and DMF (-drop) to the solution of the acid (2〇4 mg)^ dehydrated THF solution (1.8 ml), and wait until the reaction temperature is warmed to room temperature, and further stir the mixture. 2 hours. After concentration, the acid chl〇ride of THF was added to a mixed solution of concentrated ammonia (2.5 ml) THF (1.25 liters) under ice cooling and stirring, and the reaction temperature was obtained. The mixture was warmed to room temperature, and the mixture was further stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sulphur, and dried with magnesium. Purification by column chromatography (ethyl acetate / hexanes) eluted elute elut elut elut elut elut elut elut elut elut elut elut elut DMS〇-d6) δ: 2·29 (3h, s), 2·44 (3h, 3), 6.65 (1H, s)/ 7.42 (lHf br s), 7.53 (2H, br s), 7.89 (2H,d), 13·45 (1H, br S) · [Example 12] {[Cyano 4 (4-cyano basic)_2,5-dimethylpyryl]曱319299 164 200813007 S} -N-methyl-1H-pyrazole_3-carboxamide

In ice cooling and stirring, in 3_{[3_cyano_4_(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole+yl]methyl}_m_pyrazole_5_ Add oxazolyl (225 mg) and DMF (-drop) to a solution of carboxylic acid (2 〇 4 mg) in dehydrated THF (1.8 mL), and then warm to room temperature and stir the mixture 2 hour. After concentrating, the chlorous acid dissolved in THF was added to a solution of 21 V [mercaptoamine in THF (10 ml), and the mixture was warmed to room temperature, and the mixture was further stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium The residue was purified by EtOAc EtOAc (EtOAc) ^-NMR (DMSO-d6) δ: 2.28 (3Η, s) r 2.43 (3H, s) , 2.72 (3Hf d)f 5.19 (2H, s) f 6.59 (lHf s)f 7.54 (2Hf d) f 7.89 (2Hf d) r 8.31 (1H, br s), 13.47 (lHf br s).

[Example 13] 165 319299 200813007 4·(4-cyanophenyl)_2,5-diindenyl-m-n-pyrazole-3-yl)methyl]-1Η-dehydrazin-3-carbonitrile

4-(4-cyanophenyl)-2,5-diindenyl-m-pyrrole-3-carbonitrile (1·πg) in dehydrated dmf (15 ml) under argon and ice-cooling Sodium hydride (60% dispersion oil, 23 〇 mg) was added to the solution, and the mixture was stirred for 3 Torr. A solution of [((benzyloxy)methyl]-3-(iodomethyl)-5-mercapto-1H-pyrazole (1.97 g) in dehydrated DMF (3 mL) The mixture was stirred for 3·5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) eluting eluting Η{1_[(phenylhydroxy)methyl b-5-methyl lH-u-pyrazol-3-yl}methyl)-en ('cyanophenyl)_2,5-dimethyl-yl-1Η_pyrrole- Formonitrile (1·87 g). Under ice cooling and stirring, Η{Η(benzyloxy)indolyl]-5-fluorenyl 1 Η is more than 3-yl}methyl)_4-(4-cyanophenyl)_2,5_2 Methyl]&, a solution of tris-carbonitrile (131 g) in monochloromethane (3 ml), 319299 166 200813007, a solution of tribromination in methylene chloride (5.25 ml), The mixture was mixed for 2 hours. The reaction mixture was poured into ice water and neutralized with a saturated aqueous sodium carbonate solution, followed by fractionation. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The crystals obtained from the residue were purified by methanol, filtered, and purified by EtOAc (EtOAc). H-NMR (CDC13) δ: 2·30 (6H, s), 2·46 (3H, s), 5·02 (2H, s) 5.76 (1Η, s), 7.49 (2H, d), 7.68 ( 2H, d), 9.63 (1H, br s).

[Example 14] 4-(4-cyanophenyl)-2,5-dimethylmethyl-1 Η-σ-biazole _3_yl) fluorenyl]_1 Η-° pyrrole-3-carbonitrile

4-(4-cyanophenyl)-2,5-diindenyl-1H-pyrrole-3-cyano (1 Ug) in dehydrated DMF (15 mL) Sodium hydride (60% dispersion oil, 23 〇 mg) was added and the mixture was stirred for 1 min. Further, a solution of ^[(phenylhydroxy)indolyl]-3_(iodomethyl)-4-methyl-1H-pyrazole (1.97 g) in dehydrated DMF (3 ml) was added to the mixture The mixture was stirred at elevated temperature for 3.5 hours. The reaction mixture was poured into water and taken up in acetonitrile acetate at 319299 167 200813007. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc (EtOAc-EtOAc) eluting eluting [(Benzyloxy)methyl]_4_methyl-1H-indazole-3-yl}methyl)-4-(4-cyanophenyl)_2,5-diindenyl-1H-pyrrole- Formonitrile (1.83 g). Under ice cooling and stirring, [(benzyloxy)methylcyclomethyl-1Η-σ is more than 嗤3_yl}methyl)-4-(4-cyanophenyl)-2,5 -Dimethyl-iH-latole-3-acetonitrile (1.62 g) in a solution of methylene chloride (37.2 ml) was added 2M boron dibromide in dichloromethane (6 · 51 ml) The solution was stirred and the mixture was stirred for 3 hours. The reaction mixture was poured into ice water and neutralized with a saturated aqueous sodium carbonate solution, followed by fractionation. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) "^-NMR (CDCla) δ: 1.99 (3Η, s) , 2.26 (3Η, s) , 2.43 (3Η, s), 5·04 (2Η, s), 7·32 (1Η, s), 7 ·49 (2Η, d), 7·67 (2Η, d), 9·96 (1H, br s)· [Example 15] 4-(2,5-monomethyl-1·{[3-( Trifluoromethyl)-ΐΗ_σΛsup-5-yl]indolyl ih_ "birol-3-yl)benzonitrile 319299 168 200813007

Synthesis Method 1: 3-(Trifluoromethyl)-1^^ is compared with sal-5-carbonic acid (〇&1^&1(16113^(16) (9.75 g), triphenylchlorodecane ( Mixture of ι 6·6 g), triethylamine (12. 2 ml), 4-didecylaminopyrrolidine (0.55 g) and dichloromethane (300 ml) was stirred at room temperature for 24 hours. The mixture was poured into aq. EtOAc (EtOAc) (EtOAc m. A mixture of sodium (4.05 g), THF (300 ml) and methanol (300 ml) was stirred at 0<0>C for 1 hour and then at room temperature for 3 hours. The reaction mixture was poured into aqueous citric acid and The mixture was extracted with EtOAc. EtOAc (EtOAc m. m. And adding imidazole (215 g), triphenylphosphine (8·26 g) and iodine (8·00 g), and stirring the mixture under 〇t: The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. Alkyl) purification to obtain 5-(moth methyl)->(dimurazolyl)_1-trityl-1H-indole and 3-(moth 319299 169 200813007 base)_5-(trifluoromethyl )_丨_triphenyl fluorenyl hydrazide mixture (Μ·% g) solid. Under ice cooling, in 3_(4-cyanophenyl)_2> dimethyl_11{_pyrrole (360 house) To a solution of DMF (10 ml), sodium hydride (6% disperse oil, 88 mg) was added. The mixture was stirred at room temperature for 3 Torr, and then the above 5-(iodomethyl)-3_ ( Trifluoromethyl)-}•tritylpyrazole with 3 (decomplexed)_5-(difluoromethyltrityl-indole-indole mixture (〇·95 g) at room temperature The mixture was stirred for 14 hours. The reaction mixture was poured with EtOAc EtOAc. Purification of alkane to obtain 4_(2,5-dimethyl-1-{[3-(trifluoromethyltriphenylmethyl-1Η-indolyl)methylpyr 1H-indol-3-yl)benzene a mixture of a nitrile and 4_(2,5-diindenyl (dimethylmethyl)-1-triphenylindenyl-1Η_σΐ^τ7?-3-yl]hydrazinyl 1 Η-pyrrol-3-yl)benzonitrile ( 31 mg) solid. The mixture (293 mg) was dissolved in TFA (2 ml), and the mixture was stirred at room temperature for 10 min. ethyl acetate and sodium bicarbonate water were added to the reaction mixture and the mixture was separated. Water layer and organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) 50% Method 2·2,5-Dimercapto-1-(2-ketopropyl)-4-(4-cyanophenyl; MH-pyrrole-3-carboxylic acid tert-butyl ester (350 mg) a mixture of sodium hydride (28% in methanol, 0.24 ml) and 1,2-dimethoxyethane (3 ml) was stirred at room temperature for 30 min and ethyl trifluoroacetate (〇 14 ml) Then, the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into saturated brine, 319299 170 200813007 and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. (ml) and hydrazine monohydrate (0.25 ml), and the mixture was stirred at 8 ° C for 30 minutes. Ethyl acetate and sodium dicarbonate solution were added to the reaction mixture, and the mixture was separated into water. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from diethyl ether to give 4-(4-cyanophenyl)-2,5-dimethyl-1- [3-(Trifluoromethyl)-1Η-indazol-5-yl]fluorenyl}-1Η-pyrrole-3-carboxylic acid tert-butyl ester (276 mg) crystals in 4-(4-cyanobenzene) Base>2,5- Dimercapto-1-{[3-(trifluoromethyl)-1Η-b-azol-5-yl]indolyl}-1Η-pyrrole_3_tert-butyl tert-butyl ester (223 mg) in ethyl acetate 4N hydrochloric acid/acetic acid ethyl acetate was added to the solution in (2 · 5 liters), and the mixture was stirred at 40 ° C for 14 hours. Ethyl acetate and sodium dicarbonate aqueous solution were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with EtOAc (EtOAc m. .

Melting point 147-149°C 4 calendar (CDC13) δ: 2.24 (3H, S), 2·31 (3H, s), 5·14 (2H, S), 6·13 (1Η, S), 6·35 (1Η, s), 7·43 (2Η, d), 7·63 (2Η, d), 10.40 (1H, s).

[Example 16] 4-[2,5-Dimethyl_l_(1H_l52,3-triazole-N-ylmethyl)-;111-pyrrolyl]_2-(trifluoromethyl)benzonitrile 171 319299 200813007

A mixture of triazole-4-carboxylic acid ethyl ester (20.2:...g), triphenylchloromethane (40 g), triethylamine (24 ml) and DMF (140 ml) synthesized by a known method at room temperature The mixture was mixed for 20 hours. The reaction mixture was poured into saturated brine (100 ml) and evaporated. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to afford a colorless solid (52·1 g). A mixture of terbinahydride (6.9 g), chlorination (15 g), THF (120 ml) and ethanol (60 ml) was stirred at room temperature for 3 min, and the solid obtained from the above reaction was added to the mixture (3 5 g) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate The solid obtained by the above reaction (24.0 g) was dissolved in DMF (300 ml), and NBS (131 g) and triphenylphosphine (19.4 g) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (EtOAc EtOAc). a mixture of bromomethyldiazole derivatives (2Mg) solid. The obtained product is a mixture of two different two: 319299 172 200813007 without further purification. # , ▲ # 1 J is used in the following reaction. 3_"4 cyanide The title compound can be obtained in the same manner as in the synthesis method 1 of Example 15 as the material of the formula 3-(trifluoroindolyl)phenyl]-2,5-dimethyl]-yl-indole-pyrrole. ^H-NMR (CDC13) 6·12 (1H, s), m), 11·91 (1Η, s)' 2·39 7'60 (1Η, (3Η, d), s)' 5.18 (2Η, s), 7·71 - 7.84 d δ: 2·30 (3Η, 7·42 (1Η, s), s).

[Example 17] 4-(3-Chloro-4cyanophenyl)_3,5-dimethylindole-5-yl]methylMHH2-carbonitrile small {[3_(trifluoromethyl)_1H- ° ratio

Using 4-(3· and 5-(ironmethyl)-3-(trifluoromethyl)succinimide=base_1H "Bilo_2_carbonitrile to synthesize the same method as in Example 15! The same ^_1Η· Π is the material of the saliva, the leg (CDCl3) δ·· 2.20 (3H, s), 2·3〇 (3 付超化口7·38 (1H, d), 7·71 (1H, d), 8·5 (3H, S)' 7·23 (1Η, dd), 丄A s)· [Example 18] 3-(4-cyanophenyl)-5-mercapto-(trimethyl) )-lH-pyrazole-5-yl] A 319299 173 200813007 Base each 2__ guess

NC

Add 3-(4-cyanophenyl)-5-indole to a solution of sodium hydride (60% dispersion oil, 〇·〇3g) in MF (3.00 liters) under the ice Base-1Η-吼甲猜(〇·14g). The reaction mixture was stirred at room temperature for 30 minutes and h[(benzyloxy)methyl]-5-(bromomethyl)-3_(ffluoromethyl)_ 1Η-σ as described in the example A mixture of azole and 丨_[(phenylhydroxy)indenyl](bromoindolyl)-5(difluoroindolyl) 1H-pyrazole (0.26 g) in DMF (1.0 = liter) The mixture was added, and the mixture was stirred at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Purification by silica gel column chromatography (ethyl acetate·hexane) and crystallization from hexane to obtain crystals of intermediate product (316 mg). Next, the compound obtained above (3 〇 8 mg) To a solution of dichloromethane (10 liters), boron tribromide (1 〇 in dichloromethane (2·27 ml) was added dropwise, and the mixture was stirred for a few hours. The water and saturated aqueous solution of sodium dicarbonate were added. The reaction solution was poured, and the mixture was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate-hexane), and the title compound of 319299 174 200813007 was obtained by the test method, and the chromatographic method (acetic acid B) The ester was purified and crystallized from ethyl acetate·diisopropyl ether. X-title compound (48 mg) crystal

Melting point: 189-190°C 5·40 (2H, s), 93 (2H, d)· 6.55 (1H, 4-Li R (DMSO-d6) δ: 2·32 (3H, s), 6·59 (1Η, s), 7·85 (2Hr d) [Example 19] 4-[2,5-Dimethylpyrazole-5-ylcarbonitrile;)-1Η-吼-3-yl]benzene

Under ice cooling, in a solution of 4-(4-cyanophenyl)-2,5-dimethylpyrrolidine-3-carboxylate (440 mg) in DMF (10 mL) Sodium hydride (60% dispersion oil, 98 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes, and 5-(iododecyl)-1-trityl-1H-pyrazole (? 73 g) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in TFA (10 mL). Ethyl acetate and sodium dicarbonate aqueous solution were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over EtOAc EtOAc EtOAc EtOAc EtOAc The residue was purified by silica gel column chromatography (ethyl acetate_hexane), and blackened with diethyl ether w only ρ μ _ λ %, σ day to obtain the title compound (12 mg ) Crystal. (2H, (2Hr s), d), ¥ (CDCl3) δ: 2·28 (3h, s), 2.36 (3h, s), 5·〇9 6·〇3 (1H, S), 6· 08 (1H, s), 7·3〇(1H, s), 7·45 7·51 (1H, d), 7·60 (2 H, ci) · [Example 20] 4-{[3- Cyano-4-(4-cyanophenyl)-2,5-dimethyl-exo^ββ1-yl]fluorenyl} -1Η - ° ratio σ sitting -3 _ acid

4-(4-cyanophenyl)-2,5-dimethyl-1Η- under argon and ice cooling. To a solution of azole-3-carbonitrile (1.77 g) in dehydrated DMF (24 ml) was added sodium hydride (60% dispersion oil, 368 mg), and the mixture was stirred for 3 min. Further, 4-(bromomethyl)-1-{[(2,2-dimethylpropenyl)oxy]indolyl}-111^biszole-3-carboxylic acid ethyl ester (3.81 g, purity : 84%) A solution in dehydrated DMF (5 ml) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 4-{[3-cyano 176 319299 200813007 -4-(4-cyanophenyl)-2,5-dimethyl Biorrol-1-yl]methyl}-1-{[(2,2-dimethylpropenyl)oxy]methyl}-1Η-carbazole_3_hyalacid ethyl ester (1.86 g), It is a crystalline powder. '{[3-Cyano-4-(4-cyanophenyl)-2,5-dimethyl-1Η-σ is more than 嘻-1 -yl]methyl}-1-{[(2,2 -Dimethylpropionyl)oxy]methyl}_1Η-pyrazole_3_carboxylic acid ethyl ester (1.06 g) in THF (97 ml) was added 1 NaOH aqueous solution (6.45 liters) The mixture was stirred at room temperature for 26 hours with methanol (9.7 mL). After distilling off the alcohol and THF, the residue was diluted with water and neutralized with 1N hydrochloric acid (6 45 ml). After extraction with ethyl acetate, the organic layer was washed with saturated salt, dried with anhydrous sulfur and concentrated to dry. The crystallized powder was rinsed with diethyl ether and dried to give the title compound ( 490 mg). ^ ° ^-NMR (DMSO-d6) s〉, 7.29 (1H, s) [Example 21] δ· 2·20 (3H, s), 2·35 (3H, s), 7·58 (2Η, d), 7.93 (2Hf d). 5.29 (2Η, 4-{[3-cyano-4-(4-cyano; #1, 乂暴本基)-2,5-dimercapto-11^pyrrole small US 1 methyl}-111-pyrazole_3-carbenamide

319299 177 200813007 4-{[3-Cyano-4_('cyanophenyl)-2,5-dimethyl-1H- under ice cooling and stirring. Add oxalic acid chloride (245 mg) and DMF (-drip) to a solution of dehydrated THF (1.9 liter) in a dehydrated THF (1.9 liter) solution. The reaction temperature was allowed to warm to room temperature and the reaction mixture was further disturbed for 2 hours. After concentration, under ice cooling and stirring, the acid dissolved in THF is added to a mixed solution of concentrated ammonia (2.5 ml) and thf (i 25 ml), and the reaction temperature is warmed to room temperature, and further The reaction mixture was stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from ethyl acetate-methanol toield

Ih-NMR (DMSO - d6) s), 7.2 4 (1H, §) br s), 7·90 (2h, [Example 22] δ: 2·19 (3Η, s), 2.34 (3Η, s) , 5·33 (2Η, 7·33 (1Η, br s)' 7·56 (2Η, d), 7·70 (0·5Η, d), 7·97 (〇·5Η, br s), 13.23 (1Η, br s〉·4 {[3Cyano-4-(4-cyanophenyl)-2,5-dimethyl-ΐΗ_σpyr-l-yl]methyl}·Ν-methylpyrazole Guanamine

319299 178 200813007 Under ice cooling and stirring, at 4 kg jin {[3-cyano_4-(4-cyanophenyl-methyl-1Η_σ than 嘻-1-yl]-' _ 丞 Τ Τ base卜1Η “Bizotung carboxylic acid (216 克克) in the dehydrated THF solution (1.9 liters), 办 产 丌 、 、 、 、 、 、 、 、 、 245 245 245 245 245 245 245 245 245 245 245 245 245 245 245 245 245 -Drip), sample 幡, w Λ, /u 7 wait for the reaction temperature to warm to room temperature, and further disturb the reaction mixture for 2 hours. After concentration, under ice cooling and (4), dissolve again in the chloric acid Add to the solution of 2M methylamine in (10) ml) and return to the reaction mixture for 3 hours. The reaction mixture is poured into water and extracted with ethyl acetate. Organic The layer was washed with EtOAc (EtOAc m. m. $mg) crystals.

^NMR (DMSO-de) δ: 2.20 (3Η, s) , 2.34 (3H, s)f 2.76 (3H d), 5.35 (2H, s), 7.27 (1H, s), 7.56 (2H, d) , 7.90 (2Hf d) 8.19 (lHf q), 13.22 (lHf br s).

[Example 23] 4-(4-cyanophenyloxindole)_1Η-σ-biazole-4-yl]indolyl 2,5-dimethyl-1Η·υ比略-3_carbonitrile

Mix a mixture of sodium hydride (272 mg), calcium chloride (400 mg), THF (14.4 179 319299 200813007 house liter) and ethanol (7.2 ml) at room temperature and add 4-{ [3-Cyano-4-(4-cyanophenyl)-2,5-dimethyl-1Η-pyrrole, 丨-美曱基}-1-{[(2,2-dimercaptopropene) Ethyl]oxy]fluorenyl}_1Η_pyrazole_3_carboxyxan-2-acetate (704 mg) was stirred at room temperature for 13.5 hours. The mixture was poured into ice water and 1 Ν hydrochloric acid (7.2 ml) was added. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from ethyl acetate-methanol to afford crystals of the title compound (338 mg). 4-Li R (DMSO-d6+TFA) δ: 2·25 (3Η, s), 2·39 (3Η \ η/ s) , 4.50 (2Η, S), 5·ΐ〇(2Η, s), 7.27 (1Η, s〉, 7.57 (2Η, d), 7·91 (2Η d) . [Example 24] 4-(4-cyanophenyl)-1-{[3-(1-) -methylethyl)-1;^-. 峻 -4--4-yl]methyl b 2,5-dimethyl-1H-pyrrole-3-carbonitrile

In argon at -70 ° C, at 4_{[3-cyano-4-(4-cyanophenyl)-2,5-diindenyl-1H-indol-1-yl]methyl} Ethyl-1-([(2,2-dimethylpropionyl)oxy]methylpyrazole-3-carboxylate (521 mg) in dehydration Τηρ (5·21 319 299 180 200813007 liters) A solution of 1 M methylmagnesium bromide in THF (3.18 mL) was added to the solution. The reaction mixture was allowed to stand at the same temperature for 3 minutes and then left at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was poured into the hydrazine 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 (ethyl acetate-hexane), and the precipitate was further purified by column chromatography (ethyl acetate-hexane) with NH oxime (manufactured by Fuji Siiysia Chemical Ltd.). And recrystallized from ethyl acetate-ether to give the title compound (171 mg). (3Η, 7.59 H-NMR (DMSO-d6) δ: 1.49 (9Η, s), 2.21 (3Η, s), 2.34 s), 5·19 (2Η, s), u◦一5·3〇 (1Η , & s), 6·76 (ιη, (2Η'(1)'7·92 (2Η'(1), 12.37 (1Η, br s)· [Example 2 5 ] 5 {[3-4_(4-Cyano) Phenyl)_2,5-didecyl_1Η-吼d d•yl]methyl bJR·pyrazole-3-carboxylic acid ethyl ester

Under argon and ice-cooling, 4-(4-cyanophenyl)-2,5-dimethyl-1Η_3 竣酉夂2 竣酉夂 (297 mg) in dehydrated DMF (5 mL) 319299 181 200813007 Sodium hydride (44% in 60% dispersion oil) was added to the solution, and the mixture was stirred for 30 minutes. Further, M[(2,2-dimethylpropanoyl)oxy]methyl}-5-(block methyl)-iH-pyrazolecarboxylic acid ethyl acetate (475 mg) in dehydrated DMF (5 ml) The solution was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 5-{[3-t-butoxycarbonyl-4-(4-cyanophenyl)_2 as a non-crystalline powder. ,5-dimethyl]pyryl]methyl b-{{(2,2-dimethylpropenyl)oxy]methyl}-111-pyrazole-3-carboxylic acid ethyl ester (126 Mg). A mixture of sodium borohydride (74 mg), calcium chloride (108 mg), thf (3.9 ml) and ethanol (1.95 ml) was stirred at room temperature for 3 min, and 5-{[3-(third Butoxycarbonyl)-4_(ζμcyanophenyl)_2,5-dimethyl-1Η_吼r-l-yl]indolyldidecylpropenyl)oxy]methyl-MH-carbazole Ethyl carboxylate (222 mg), and the mixture was stirred at room temperature for 20 hours. After 1N hydrochloric acid (195 ml) was added, and ethyl acetate was evaporated and evaporated. The residue was purified by NH-hydrazine gel column chromatography (ethyl acetate-hexane) to give 5-{[3-(t-butoxycarbonylcyanophenyl)-2,5-dimethyl-l-indole- Pyrrolyl-1-yl]methylpyrazole-3-diol carboxylate (97 houser) and 4·(4-cyanophenyl)-1_{[3_(hydroxymethyl)_1Η_pyrazole_5_ Tertyl] fluorenyl}_2,5-dimercapto-1 Η-pyrrole-3-carboxylic acid tert-butyl ester (4 〇 mg), which is an amorphous powder. 5-{[3-苐dibutoxymethyl_4_(4-cyanophenyl)-2,5-didecyl 319299 182 200813007 -1H-pyrrol-1-yl]methyl bm_pyrazole _3_acetic acid ethyl vinegar (η mg) was dissolved in TFA (0.3 liters) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a solution of chloroform and sodium dicarbonate, and the mixture was dissolved. The organic layer was washed with EtOAc (EtOAc m. m. (8 mg) crystal. ^H-NMR (CDCI3) δ: 1.37 (3Η, t), 2.28 (3Η, s) 4·36 (2Η,q)' 5·1〇(2Η, s), 6·09 (1Η, s), 7 · 45 (2Η,d), 7·61 (2Η, d)· 2.36 (3Hr 6.49 (1H,

[Example 26] 4-(l-{[3-(hydroxyindenyl)_1Η_σ-bisazolyl]indolyl 2,5-diindenyl·ih_pyrrole-3-yl)benzonitrile

4 (4-cyano basic)_1_"[3-(radiomethyl)_ιη-π than wow_5_yl] methyl b 2,5-dimethyl-1Η-pyrrole_3_carboxylic acid third The butyl ester (33 mg) was dissolved in TFA (0.5 mL) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate 183 319299 200813007 The residue was purified by EtOAc EtOAc (EtOAc) H-KIMR (CDC13) δ: 2·25 5.04 (2Η, s), 5.RP.

5 (3H, s), 2·34 (3H, s), 4·68 / ~ (1H' s), 6·〇6 (1H, s), 7·42

[Example 27] hydroxyethyl)_1Η-indolozolyl]methyl b 2,5-dimethyl-1H-pyrrole_3_yl)benzonitrile

4-(4-Cyanophenylhydroxymethylpyrazole-5-yl)indolyl}_2,5-dimethyl-1H-pyrrole-3-carboxylic acid tert-butyl ester (186 mg) in dichloromethane Manganese dioxide (794 mg) was added to the solution (18.3 ml), and the mixture was stirred at room temperature for 22 hours. The insoluble material was filtered off with celite and rinsed with dichloromethane. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 4-(4-cyanophenyl)-l-{[3-mercapto-1H-pyrazole-5-yl] Mercapto}_2,5-dimercapto_1H-pyrrole_3_carboxylic acid tert-butyl (90 mg), which is a crystalline powder. At 4 〇 ° C, '4_(4-cyanobenzene) Base)_1][3_mercapto_1Η-σ-pyrazole 319299 184 200813007 -5-yl]fluorenyl}_2,5-dimethyl 11:TL, soil-1H-.pyrrol-3-carboxylic acid The third butyl ester (79 mg) was added to a solution of 1M methylmagnesium bromide in THF (0.7 mL) in THF (2.9 mL). After the temperature is restored from room temperature to room temperature, the mixture is placed at the same temperature for 30 minutes, and the mark +_ _ is then placed in the hour; The reaction mixture was poured into a mixture of gasified pine, six or six liters of water, and the mixture was extracted with ethyl acetate. The organic layer was further washed with a saturated salt, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (acetic acid ethyl acetate _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 1 - Material - 3-carboxylic acid terpene vinegar (28 mg), which is a crystalline powder. 4·(4-cyanophenylethyl)-1-indole-pyrazole-1-yl]methyl}-2,5-dimethyl-1Η-pyrrole_3_carboxylic acid tert-butyl ester (43 mg) is soluble TFA (0.157 liter) and spoiled the mixture for 15 hours at room temperature. Methylene chloride and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute Η-NMR (CDC13> δ: 1·52 (3Η, d), 2·28 (3Η, s), 2·36 (3Η, s), 4.96 (lHf q) r 5,04 (2H, s) r 5.82 (1h, s) , 6.07 (1H, s), 7·44 (2H, d)r 7.60 (2H, d)· [Example 28] 5_{[3-(4- gas base)-2, 5 - monomethyl-1 Η-ϋ 咯 -1- -1- 基 基 基 i i i i i i i 319 319299 185 200813007

Tetrabutyl 4-(4-cyanophenylcarbazyl-1H-indazole-5-yl)methyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (138 mg To the solution in NMP (3.4 liter) was added hydrochloric acid (28.4 mg), and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by oxime column chromatography (ethyl acetate-hexane) to give 4-(4-cyanophenyl) small ({3_[(EH hydroxyimino)methyl)-1 Η·- ratio Salicin-5-yl}methyl)_2,5-dimethyl-1]9[-pyrrole-3-carboxylic acid tert-butyl vinegar (116 mg), which is an amorphous powder. In 4-(4-cyanophenyl; (hydroxyimino)methyl]_1H_ than 5-(yl)methyl)-2,5-dimethyl-1H-pyro-3-carboxylic acid tert-butyl Add pyridine (155 mg) and cyanuric chl〇ride (1〇9 mg) to a solution of diester (83 g) in dioxane (Π·84 ml) at room temperature The mixture was given for 2.5 hours. The precipitate was removed by filtration and washed with dioxane, thinking solution and washings; The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 319299 186 200813007) to give 4-(4-cyanophenyl)cyano-1H-pyrazole-5-yl)methyl]-2 , 1,3-mercapto-1H-pyrrole-3-carboxylic acid tert-butyl ester (37 mg), which is a crystalline powder. ^... 4_(4_Cyano-phenyl)-i_[(3-cyanosin-5-yl)methyl]_2,5-monomethyl-1Η-pyrrole-3-decanoic acid tert-butyl ester (36 mg Soluble in tfa (〇139 ml and stir the mixture at room temperature for a few hours. Add methyl chloride and sodium dicarbonate solution to the reaction mixture, and dissolve the mixture. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) elute (3H, s), 2.30 (3H, s), 5.15 (2H, s) dH, s), 7·43 (2H, d), 7·63 (2H, d), β·14 (1H, S) , 6.51 1〇·50 (1H, s)· [Example 29] 4-{2,5-monomethylmethyl-1H-pyrazole-5-yl)methyl]-1H-pyrrole_3_yl} Benzoonitrile

Under argon and ice cooling, at 4_(4-cyanophenyl)_2,5-dimethyl_iH_ 319299 187 200813007 pyrrole-3-carboxylic acid tert-butyl ester (2〇8 mg) in dehydrated dmf Hydrogen Xian (60% dispersed oil, 3G gram) was added to the solution in (5 ml) and the mixture was dropped for 30 minutes. Further, a solution of 3_(broken methyl)_4_methyl + trityl- _ _: azole (330 gram) in dehydrated DMF (5 ml) was added to the mixture, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. (4) 4_(4-cyanophenyl)_2,5-dimethyl 4-((4-methyl-)- (4-methyl-(-)- 1-tritylmethyl.吼峻_3_基}Methyl Mh" than tert-butyl tartrate (392 mg). 4-(4-cyanophenyl)_2,5-dimethyl small ({4_Methyltrityl 1H is more than 3_yl}methyl)_1Hn3_Resined third vinegar (39〇 mg) dissolved in TFA (4.74 ml) and mixed at room temperature for four hours Add chloroform and sodium dicarbonate in μ t·s, and dissolve the mixture. The organic layer is washed with saturated brine, dried with anhydrous sulfur and concentrated. The residue is chromatographic column chromatography ( The title compound (16 mg) was obtained crystals eluted eluted eluted elut elut elut elut elut elut elut elut elut 1·94 (3H, s), 2·25 (3H, s) 5·〇3 (2Η, S), 6·07 (1Η, s), 7·3〇 (1Η, % 7.59 (2Hf d).

[Example 30] 1H-pyridyl 4-{5-ethyl_2-fluorenylmethyl "Η-. than salivation_3_yl) methyl group 17-3-yl}benzonitrile 319299 188 200813007

Under argon and ice cooling, tributyl butyl 4-(4-cyanophenyl)-2-ethyl-5-methyl•1H-pyrrolecarboxylate (217 mg) was dehydrated dmf (5 liters) Sodium hydride (60% dispersion oil, 3 〇 mg) was added to the solution and the mixture was stirred for a few minutes. Further, a solution of 3-(iodomethyl)>4-methyl-1·trityl-1H-pyrazole (330 g) in dehydrated thf (5 ml) was added to the mixture at room temperature. The mixture was stirred for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. Purification of hexane) to give 4-(4-cyanophenyl)-2-ethyl-5-fluorenyl-1 ((4-methyl-1-diphenylmethyl-ij^pyrazole-3-yl) }Methyl)_1H_pyrrole-3_carboxylic acid tert-butyl ester (370 mg), which is an amorphous powder. 4-(4-Cyano basic)-2-ethyl-5-methyl_1_({ 4-methyl-1_trityl-1H-pyrazol-3-yl}fluorenyl)-iH-pyrrole-3-carboxylic acid tert-butyl ester (365 mg) was dissolved in TFA (4.31 mL). The mixture was stirred at room temperature for 4 hours. To the reaction mixture was added dichloromethane and aqueous sodium bicarbonate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purified by chromatography (ethyl acetate-hexane) with methanol - The title compound (8 mg) crystal was obtained by crystallization. 319299 189 200813007 h-NMR (CDC13) δ: 1·26 (3H, t)r 1·93 (3H, s), 2.32 (3H, s), 2· 57 (2H, q), 5·04 (2H, s), 6·09 (H s), 7·29 (1H, s), 7.45 (2H, d), 7·59 (2H, d)· [ Example 31] 3-{[3-(4-murylphenyl)-2,5-dimethyl--111-'7-specific-1-yl]fluorenyl}-111- 吼嗤-4 -methyl formic acid

Under argon, in 4-(4-cyanophenyl)-2,5-dimethyl-111-° 嘻-3·carboxylic acid tert-butyl ester (581 mg) in dehydrated DMF (15 mL) Sodium hydride (80% dispersion oil, 83 mg) was added to the solution, and the mixture was stirred for 30 minutes under ice cooling. Further, a solution of methyl 3-(iodomethyl)-1-tritylpyrazole-4-carboxylate (1·5 g) in dehydrated DMF (35 ml) was added to the mixture and stirred at room temperature. The mixture was 21 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by celite column chromatography (ethyl acetonitrile-hexane), and crystallised from ethyl acetate to give 3-{Π 三 tributoxycarbonyl) ice (4-cyanophenyl)- 2,5-Dimercaptol-indole-pyrrole-7-yl)methyl-m-phenylmethyl-1H-pyrazole-4-carboxylic acid methyl ester (1.11 g) crystals. & 319299 190 200813007 3-{[3_(Tertibutoxycarbonyl)_4_(4-cyanophenyl)-2,5-dimethyl-1H-pyryl)A under ice cooling and stirring a solution of methyl iodide-trityl-m-pyrazole-4-carboxylate (Mg) in dichloromethane (16. 2 ml), iMITA in methylene chloride (24) • The solution in 3 ml) was added in three portions and the mixture was mixed at the same temperature for 4 hours. Methylene chloride and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 3-{[3-(t-butoxycarbonyl)-4-(4-cyanophenyl)-2,5- Methyl dimethyl hydrazino-pyrrolidyl]methyl bromide-pyrazole-4-carboxylic acid methyl ester (598 mg), which is an amorphous powder. 3_{[3-(Tertibutoxycarbonyl)>4_('cyanophenyl>2,5-didecyl_1Η_ϋ ratio 17 each_1-yl]methyl}·1Η-pyrazole-4 - carboxylic acid oxime ester (541 mg) was dissolved in TFA (〇·96 ml), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and sodium dicarbonate aqueous solution were added to the reaction emulsion A, and the mixture was divided into valleys. The organic layer was washed with EtOAc (EtOAc m. Crystal. H NMR (CDC13) δ: 2.22 (3Η, s), 2.29 (3H, s), 3.90 (3Hf s), 5·37 _ s), 6·13 (1H, s), 7·45 ( 2H, d), 7·61 (2H, d)r 9·86 (1H, br s).

[Example 32] 4_(1_{[4_(radiomethyl)_1Η-π-pyrazol-3-yl]fluorenyl}-2,5-dimethyl-ih-pyrrol-3-yl)benzonitrile 191 319299 200813007

A mixture of sodium borohydride (170 mg), calcium chloride (252 g), THF (9 ml) and ethanol (4.5 ml) was stirred at room temperature for 30 min, and 3-{[3- (4 - murine base) -2,5-dimethyl ratio _ yl] fluorenyl sulfonate (1 mg) and spoiled the mixture for 5 days at room temperature. The reaction mixture was poured into ice water, and 1N hydrochloric acid (4.5 ml The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (4 mg) as crystal powder. h-NMR (CDC13) δ: 2·26 (3H, s), 2·32 (3H, s), 4.43 (2H, s), 5·17 (2Η, s〉, 6·11 (1Η, s) , 7.44 (2Η, d), 7·53 (.1Η, s), 7· 61 (2Η, d)· [Example 33] 3_{[3-(4-Cyanophenyl)-2,5_ Dimercapto-based _111_pyrrol-1-yl]hydrazino}_111- mouth than salivary-4-carbonitrile 192 319299 200813007

N under argon and ice cooling, 4_(4-cyanophenyl)-2,5-diindenyl-111-sucking-3-butyric acid tert-butyl ester (462 mg) in dehydrated dmf (11.7 Sodium hydride (60% in 60% dispersion oil) was added to the solution of HCl, and the mixture was stirred for 30 minutes. Further, a solution of 3·(iodomethyl)>tritylpyrazole-4-carbonitrile (817 mg) in dehydrated DMF (15 ml) was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. EtOAc was evaporated. Crystallization of ethyl acetate gave 4-(4-cyanophenyl)-b ("4-cyano-1-triphenylmethyl-1H-pyrazol-3-yl}methyl)-2,5-dimethyl Pyrrole-3-carboxylic acid tert-butyl ester (1·〇g) crystals. Under ice cooling and stirring, in '(4-cyanophenylcyanoel_triphenylmethyl)pyrazine|yl}f group) a solution of 1MTFA in dichloromethane (23.25 ml) in a solution of 1-2,5-dimethyl-p-butanylcarboxylic acid tert-butyl ester (1.0 g) in dichloromethane (15 mL) Add in three portions, and ride the mixture at the same temperature for 4 hours. Add a mixture of di-methane and sodium dicarbonate to the reaction mixture, and dissolve the mixture. The organic layer is washed with saturated 319299 193 200813007 brine. The residue was dried over anhydrous sodium sulfate (MgSO4). 4_Cyano-1H-indazol-3-yl)methyl]-2,5-dimethyl-1Η-pyrrole-3-carboxylic acid tert-butyl ester (231 mg) crystals 4-(4-cyano) Phenyl) small [(4-cyanobisazol-3-yl)indenyl]_2,5-dimethyl-1H.pyrrole_3_carboxylic acid tert-butyl ester (230 mg) dissolved in TFA (〇. The mixture was stirred at room temperature for 1 hour and 5 hours. Ethyl acetate and sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating, the residue was purified by EtOAc EtOAcjjjjjjjjj 3Η, s), 2.36 (3Η, s), 5.18 (2Η, s), 6·11 (1Η, s), 7·43 (2Η, d), 7·60 (2Η, d), 7·94 ( 1Η, s) f 1〇·32 (1H, br s)· [Example 34] 3-{[3-(4-Cyanophenyl)_5_ethyl_2-methyl]Η- π 嘻Small base] Yl} -111- ° Yue than olfactory -5- carbonitrile

319299 194 200813007 Under the argon and ice cooling, '(cyananophenylethyl methyl m-pyrrolidine carboxylic acid tert-butyl ester (1.55 g) in dehydration 〇 MF (37.5 ml) Sodium hydride (60% dispersion oil, 220 mg) was added to the solution, and the / lysate was stirred for 30 minutes. Further, 3-(iodomethyl)-1-trityl-1H-pyrazolecarbonitrile ( 2.66 g) The solution was added to a mixture of dehydrated dmf (i5 ml), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. And concentrated. Add ethyl acetate and ether to the residue and refine the crystal, then filter, rinse with ether, and further dry to obtain 4-(4-cyanophenyl)-1-({5-cyano-1) Phenylhydrazyl-1^^biazole-3-yl}methyl)_2-ethyl-5-methyl-111_pyrrole-3-carboxylic acid tert-butyl ester (2·78 g) crystal. With stirring, 4-(4-cyanophenyl)-indole-({5-cyano-1_trityl-1-indole-α-salt-3-yl}methyl>2-ethyl- 5_曱基^沁pyrrole_3_carboxylic acid tert-butyl ester (987 mg) in dichlorodecane In a solution of 15 ml), a solution of 1 MTFA in dichloromethane (22. 5 ml) was added in three portions, and the mixture was stirred at the same temperature for 2.5 hours. A gas burned and two were added to the reaction mixture. An aqueous solution of sodium carbonate was added, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate 4-(4-cyanophenyl) small [(5-cyano-1Η-pyrazol-3-yl)indolyl]_2-ethyl-5-methyl-1H-pyrrole-3-carboxylic acid The third butyl ester (422 mg) crystals. 4_(4_ Unterylphenyl)-1_[(5-cyano-biquinone-3-yl)methyl b 2_ethyl-5-methyl-1Η- Pyrrol-3-carboxylic acid tert-butyl ester (323 mg) in ethyl acetate 4 Ν hydrogen chloride (7.78 ml) in a solution of 丨 液 4 4 4 4 319 319 319 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The aqueous solution of sodium dicarbonate was neutralized and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate) The title compound (75 mg) was obtained crystals from crystals eluted eluted elute

Melting point; 159-160 ° C & face (CDCl3 > δ: !·27 (3H, t), 2·29 (3h, s), 2·53 (3), (1), 5·15 (2Η, s) '6.15 UHf s), 6.51 (1H, s), in 45 (3), (1), 7.63 (2Η, d)f 10.02 (1H, br S). ' [Example 35] 4-(4-cyanyl basic)-2, 5_Dimethyl-saltylmethyl)_^^吼--3-carbonitrile 1

N

NH used the compound obtained in Reference Example 52 (1·1 () g), gasified steel (60% dispersion oil, 〇·2 gram) and 4-(4-cyanophenyl)-2, 5_Dimercapto-1Η_pyrrole-3-carbonitrile (0·66 g), the same reaction and purification operation as in Example 执行 was carried out to obtain 4-(4-cyanophenyl)-2,5-dimethyl Base-ΐγι: benzoquinone-1Η-ϋ ratio σ sitting _4_ 曱 ))-11^-1? 比略_3 - A guess (〇·51 grams), the pot is a colorless amorphous solid. 319299 196 200813007 Using the obtained solid (0. 51 g), the same reaction and purification procedures were used to give the title compound (24 g) as colorless crystals / H-NMR (CDC13) δ: 2.28 ( 3Η, s), 2.44 (3Η, s), 5.01 (2η人37 (2Η, s), 7·49 (2Η, d), 7·69 ((2Ή,(1)· [Example 36] 4_(4- Cyanophenyl)_2,5-dimethyl-methyl-m-pyrazolyl)methyl]_1H-pyridin-3-carbonitrile

NC

The title compound (1) 3 mg) was obtained as the colorless crystals. 3·88 (3H, s), 7·50 (2H, d), ^NMR (CDCI3) δ: 2.28 (3Η, s) f 2.44 (3Hr 4·95 (2H, s), 7·07 (1H, s), 7·3〇(1^ s) 7·7〇(2H, d)· [Example 37] 4_(4-oxyphenyl)-2,5-dimethyl-1_(『3 丞丄二乱 methyl)-1H-pyrazole-4 yl]methyl}_1H-pyrrole-3_indenecarbonitrile 319299 197 200813007

NC used the compound obtained from Reference Example 56 (1·4 g), sodium hydride (60% dispersion oil, 014 g) and 4-(4-cyanophenyl)-2,5-dimethyl·1Η -pyrrole-3-carbonitrile (〇·66 g), the same reaction and purification operation as in Example 1 was carried out to obtain 4-(4-cyanophenyl)-2,5-dimethyltrifluoromethyl>; 1-Diphenylmethyl_1H-pyrazol-4-yl]nonylpyrrole-3-carbonitrile (1.69 g), which is a colorless crystal. Using 4-(4-cyanophenyl)-2,5-dimethyl_;μ{[3-(trifluoromethyl)-1_triphenylindol-1H-pyrazol-4-yl]methyl The reaction of the same procedure as in Example 1 was carried out to give the title compound (yield: 75 g) as colorless crystals. H-tiMR (CDCI3) δ: 2·24 (3Hr s)f 2·40 (3Hf s), 5·08 (2Hr s)r 6.95 (1H, s), 7.50 (2H, d) r 7.71 (2h, f χ〇.43 (1H, brs).

[Example 38] 4-[2-Mercapto-1_(1H_1,2,3-triazol-4-ylmethyl>5-(trifluoromethyl>1H-pyrrol-3-yl]benzonitrile 319299 198 200813007

Add sodium hydride to a solution of 4-[2-indolyl-5-(trifluoromethyl)-1H-pyrrole-3-ylbenzonitrile (284 mg) in DMF (10 mL) (60% in 60% dispersed oil). After the reaction mixture was stirred at room temperature for 30 minutes, a mixture of bromomethyltriazole derivative (550 mg) which was synthesized by the method of Example 16 was added to the mixture, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in methanol (5 ml) and THF (5 ml), and p-toluenesulfonic acid monohydrate (0.43 g) was added, and the mixture was stirred at 60 ° C for 2 hours. Ethyl acetate and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut 'H-NMR (CDCls) δ: 2.40 (3Η, s), 5.34 (2H, s), 6.75 (1H, s), 7·43 (2H, d), 7·52 (1H, s), 7· 66 (2H, d), 11·81 (1H, s)· [Example 39] 4_(2,5-Dimethyl-1-{[5-(trifluoromethyl)-1) is more than saliva-4 -yl]methyl}_111-199 319299 200813007 °pyr-3-yl)benzonitrile

Adding sodium chloride (10) to a solution of 3-(4-cyanophenyl)-2,5-dimethyl-1Η·α pyrrole (86 mg) in DMF (10 mL) % of the oil, 26 house gram). After the reaction mixture was stirred at room temperature for 3 minutes, 4-(iodomethyl)-5-(trifluoromethyl)trityl-1H-pyrazole (21 g) was added at room temperature. The mixture was stirred for 14 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to <> residue dissolved in methanol (1 mL) &<""&&&&&&&&&&&&&&&&&&&&& The mixture was stirred at 6 Torr for 2 hours. Ethyl acetate and sodium dicarbonate aqueous solution were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) elute 2.30 (3H, s), 5.03 (2Hr s), 6.10 (lHr s), 6.88 (1H, s), 7.45 (2H, d), 7.63 (2H, d), 10· 64 (1H, s) · ' [Example 40] 3-(4-cyanophenyl)-5-methyl-1-(111-1,2,3-triazol-4-ylindenyl)-111-oral ratio-2- Nitrile

A mixture of 3-(4-nitriphenyl)-5-fluorenyl-2-methylpyrazine and the bromodecyltriazole derivative described in Example 16 was used as a material in the same manner as in Example 39. The title compound was obtained. 4-Li R (CDC13) δ: 2.42 (3Η, s), 5.36 (2H, s), 6.27 (1H, s), 7.66 - 7·71 (2H, m), 7·72 - 7.77 (3H, m ) [Example 41] 4 - (4 _ murine phenyl) _ 5 - fluorenyl-1 - (1H_1, 2, 3 - 2 12 - 4 - yl fluorenyl) · 1 Η - σ ratio -2- A guess 201 319299 200813007

N using 4-(4-cyanophenyl)-5 oxime to give a mixture of 9 glutonitrile and the bromomethyltriazole derivative described in Example 16 as an example, and Example 39 The title compound was obtained in the same manner. XH-NMR (CDC13) δ: 2.48 (3Η, s), 5.39 (2Η, Λ 6 · 94 (1Η, s) Λ 7·41 (2H, d), 7·68 (2H, d), 7·76 (1H, s), 1Ί ... ·97 (1Η, s).

[Example 42] 4-(4-cyanophenyl)-5-mercapto-1-(ιΗ-12,3-di 4 4 #-ylmethyl)_1H^tb-r--3-carbonitrile

N Η using 4-(4-cyanophenyl)_5-methyl-oxime-oral 夂1 m, one of the 3-carbonitrile and the bromine and methyl triads described in Example 16 The mixture was obtained as a material, and the title compound was obtained in the same manner as in Example 319299 202 200813007 39. ^-NMR (CDCI3) δ: 2.30 (3Η, s) , 5.34 (2Η, s), 7.56 (2Η, d), 7·82 (1H, s), 7·92 (2H, d)A 15·12 (1H, s).

[Example 43] 4-[2,5-Dimercapto-1-(1H-1,2,3-triazol-4-ylmethyl)-1Η-pyrrol-3-yl]benzonitrile

A mixture of 3-(4-cyanophenyl)-2,5-diindenyl-1H-pyrrole and the bromomethyltriazine derivative described in Example 16 was used as the material, which was the same as in Example 39. The title compound was obtained by the method. ^-NMR (CDCI3) δ: 2.23 (3Η, s) , 2.31 (3Η, s), 5.14 (2Η, s), 6·13 (1H, s), 6·35 (1H, s)r 7·44 (2H, d〉, 7·63 (2H, d), 10.54 (1H, s).

[Example 44] 4-[5-ethyl-2-methyl-1-(111_1,2,3-triazol-4-ylmethyl)-111-pyrrole-3-yl]benzonitrile 203 319299 200813007

Adding sodium hydride in a mixture of 4-(4- gas base)-"5-ethyl-2-methyl- ΐΗ-σ bilo (200 mg) and DMF (4 ml) at room temperature (6 〇% disperse oil, 57 mg). After stirring the reaction mixture for 10 minutes, 4-(indiyl)-N-triphenylsulfonyl-111_1,2,3-triazole (461 mg) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into aq. EtOAc. The residue was purified by a gel column chromatography (ethyl acetate-hexane) to give an oil. A mixture of the oil, p-toluenesulfonic acid monohydrate (272 mg), THF (4 ml) and methanol (4 ml) was stirred at 6 hr for 5 hours. The reaction mixture was placed > The mixture was poured into a saturated aqueous solution of sodium dicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. Purification by ethyl acetate-hexanes afforded the title compound (45 mg). , 5·19 (2Hr s), 6·09 (1Η, s), 7·38 (1Η, s), 7·43_7·46 (2Η, claw), 204 319299 200813007 7.58-7.62 (2H, m), 12·6-13·6 (1H, br s)· [Example 45] each)-3- 4-[2-methyl-5-propyl-disialylmethyl]benzonitrile

Add sodium chloride (6〇) to a mixture of 4-(4-cyanophenyl 2- 曱 ς ^ , 丞 propyl ΐΗ ΐΗ σ ( ( 50 50 50 50 50 50 50 50 50 50 % dispersion oil, 13 mg). After stirring the reaction mixture for 10 minutes, add 4_(bromomethyl called triphenylsulfonyl-(1) mountain to Wang Jun (9) mg hydrazine and stir the mixture for 1 hour at room temperature. The mixture was extracted with brine and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain oil. A mixture of the oil, p-toluenesulfonic acid monohydrate (64 mg), THF (1 ml) and methanol (1 ml) was stirred at 6 (TC) for 2 hr. The mixture was poured into a saturated aqueous solution of sodium dicarbonate and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography 205 319299 Purified by the title compound (45 mg). It is amorphous. π 'H-NMR (CDCls) δ: 1.00 (3Η, t); 1.66 (2H, sextet), 2.35 s), 2.56 (2H, t) r 5.19 (2Hf s), 6.09 (1H, s), 7.36 (iH^ s) 7·43-7.46 (2H, m), 7·59-7·62 (2H, m)· [Example 46]

4-[5_cyclopropyl_2_indolyl-1-(ιη-1,2,3-triazol-4-ylmethyl)_1Ή-3-yl]benzonitrile N

NC

ν, ν, νη 4-(5-cyclopropyl-2-methyl ratio was added to a solution of sodium hydride (60% dispersion oil, 0 〇 8 g) in DMF (8 mL) Slightly _3_ base) benzonitrile (〇·35 g). The reaction mixture was stirred at room temperature for % min' and 4-(bromomethyl)-indole-trityl-triazole (ο·6 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water' and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was dissolved in a THF-methanol mixed solution (1:1·4·〇 ml), and tosylic acid monohydrate (0.6 g) was added and the mixture was stirred at 6 ° C. hour. After the solvent of the reaction solution was distilled off under reduced pressure, the residue was evaporated to ethyl acetate. EtOAc EtOAc (EtOAc) The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc , 0· 83-0· 89 (2H, m), m), 2.36 (3H, s), 5.37 (2H, s), 5.99 (1H, s) 7.42 (2H, d) , 7.60 (2h d 12.02 (1H, br s) The following compound was obtained in the same manner as in Example 46. [Example 47] 4-[5-mercapto-1-(1H-1,2,3-triazole-4) ,pyrrolid-3-yl]benzoquinone fluorenyl)-2_(trifluoromethyl)β1Η_

NC

Η h-NMR (CDC13) δ: 2·33 (3Η, s), 5, 33 \ f ▽·43 (2Η, c〇, 7·52 (1Η, d), 7·63 d) [Example 48 s)f 5·99 (iH, s), 11.91 (lHf br s). 4-[2-ethyl-5-methyl-1-(111-1,2,3-triyl)benzonitrile Olfactory-4-ylindenyl)-ιη-πBilo_3_ 319299 207 200813007

NC

Η s), 2·74 (2H, q), s), 7.45 (2H, d), 4-NMR (CDC13) δ: 1·20 (3H, t), 2.24 (3H, 5·19 (2H, s), 6_1〇(1H, s), 7·35 (1H, 7·62 (2H, d), 12·05 (1H, br s)· [Example 49] 4-ylindenyl)-lH- Pyrrole

4-[2-mercapto-5-mercapto-1-(1H-1,2,3-triazole·-3-yl)benzoquinone NC

0 V

\N Η s) , 6.16 (1H, s), ), 9·50 (1H, s), ^-NMR (CDC13) δ: 2.50 (3H, s) , 5.72 (2H, 7.49 (2H, d), 7·69 (2H, d), 7.7 6 (1H, 12.27 (1H, br s).

[Example 50] 1H-pyrrol-3-yl]phenylhydrazine 4-[5-mercapto-1-(1H_1,2,3-triazol-4-ylindenyl) nitrile 208 319299 200813007

\N

H ^-NMR (DMSO~d6) δ: 2.32 (3H, S),, 6.29 (iHr 7·68 (2H, d), 7.78 (in, s). 'azole-4_ylindenyl)_4_ (Trifluoroanthracene s), 7·41 (2H, d), 7·61 (2H, d), [Example 51] 4_[2,5-Dimethyl-1-(1H,1,2,3 -三基)·1Η_吼咯-3_yl]benzonitrile

Add hydrogenated di(6〇/刀刀) to a solution of 4-(4-iododifluorenyl-1H_pyrrole_3_bean)benzonitrile (250 mg) in DMF (5 mL) In oil, 28 grams). The reaction mixture was stirred at room temperature for 3 Torr, and a mixture (10) of the bromomethyltrisal derivative described in Example 8 was added to the mixture, and the mixture was stirred at room temperature for an hour. The reaction mixture 209 319299 200813007 was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (7) ethyl acetate-hexane to give 4-{4-iodo-2,5-didecyl <-[(^-triphenylmethyl--1,2, 3-triazole _4_yl) fluorenyl]_1 Η Π Π 嘻 基 基 基 基 基 基 基 基 糊 糊 糊 糊 糊 糊 糊 糊 糊 糊 将 将 将 将 将 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4比Bylo-3-yl}benzonitrile (343 mg), a mixture of ruthenium dihydrofolate (302 mg) and copper iodide (1) (111 g) in Π 80t: stirred 14 hour. Ethyl acetate and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallised from diethyl ether to give 4-{2,5-didecyl- 4 -(trifluoromethyl)-1-[(1) -triphenylmethyl-1H-1,2,3-triazol-4-yl)methyl]_1H_pyrrol-3-yl}benzonitrile (130 mg) solid 4_{2,5-dimethyl- 4-(Trifluoromethyl)-1-[(1_tritylmethyl-1H-1,2,3-triazol-4-yl)indolyl]-ih-pyrrol-3-yl}benzonitrile ( 130.0 mg) was dissolved in methanol (2 liters) and THF (2 mL), and aq. To the reaction mixture were added an aqueous solution of ethyl acetate and sodium chlorate, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate). NMR (CDC13) δ: 2·14 (3H, s), 2·42 (3H, s), 5·19 (2H, s), 7·36 (2Η, d), 7·47 (1Η, s), 7·64 (2 Η, d), 11·85 (1Η, s)· 210 319299 200813007 [Example 52] 4-(2,5-diindolyl small {[5-(trifluoro-fyl) )-;111yi 2,3' triazole|yl]methyl b 1H·吼 _3_yl)benzonitrile

Add hydrazine to a solution of 4-(4-cyanophenyl)-2,5-dimethylpyrrolidine-3-carboxylic acid benzyl ester (600 mg) in DMF (10 mL) Sodium (60% dispersed oil, 1 〇〇 mg). The reaction mixture was stirred at room temperature for 30 minutes, and 4-(bromomethyl)-1-(4-decyloxybenzyl)-5-(difluoromethyl)-1; 2,3-Sanjun (0.64 g), and stirred at room temperature; the mixture was mixed for 14 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was then dried over anhydrous sulfuric acid and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 4-((c-cyanophenyl phenyloxy)methyl)-5-(trifluoromethyl)-ml, 2, 3- Triazol-4-yl]methyl 2,5-dimercapto-1H-pyrrole-3-carboxylic acid benzyl ester (599 mg) as a solid. 4-(4-cyanophenylmethoxybenzyl)_5-(trifluoromethyl)-1H-1,2,3-triu-n-yl-4-yl]methyl}-2,5_diindole Base-1 Η-σ ratio each -3- tacrotic acid 211 319299 200813007 The original S (350 mg); the valley in TFA (3 house liters) and disturbed the mixture at 60 ° C for 3 hours. A solution of ethyl acetate and sodium dicarbonate in water was added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in methanol and palladium on carbon (yield) and the mixture was stirred at room temperature under hydrogen for 3 hours. After the insoluble material was removed by filtration and concentrated, residue was dissolved in TFA (3 ml), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc EtOAc) 4-leg (CDC13) δ: 2.25 (3H, S), 2_32 (3H, S), 5·22 (2H, s), 6·13 (1H, s)r 7·45 (2Hf d), 7· 61 (2H, d), 1ΐ·97 (1H, s)· [Example 53] 4-(4-cyanophenyl) 2,5-diindenyl^-{[b (trifluoromethyl)" Η",〗,,: 嗤·4-基]曱基}-iH_ 口比嘻-3 -曱carbonitrile

Under ice β σρ 'in 4-(4-cyanophenyl)_ 2,5-dimethyl-lH-indole 212 319299 200813007 -3-carbonitrile (250 g) in DMF (3 ml) Ammonium hydride (60% dispersion oil, 68 mg) was added to the solution. After the reaction mixture was stirred at room temperature for 30 minutes, 4-(bromomethyl)_ι &lt; 4-methoxybenzyltrifluoromethyl)-1 -1,2,3-diazole (0.21 g) ), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in TFA (3 liters) and the mixture was stirred at 60 C for 3 hours. Ethyl acetate and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut ^-NMR (CDC13) δ· 2 . 3' ... 2·26 (3H, s), 2.44 (3H, s), 5.24 (2H, s), 7.51 (2H, d), 7.70 (2Hf d), 12.53 (1H, s). 54] 4-(4-cyanophenyl)_ 2,5-diindenyl)-1Η-pyrrole-3-carbonitrile

Ethyl 1H-1,2,4-triazole-5-carboxylate (4.00 g), triphenylchlorodecane 213 319299 200813007 (8.77 g), triethylamine (5.2 mL) and DMF (30) The mixture of ML) was stirred at room temperature for 14 hours. The reaction mixture was poured into saturated brine (1 mL) and evaporated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate]]]]] A mixture of sodium borohydride (2.06 g), calcium chloride (4.52 g), THF (80 ml) and ethanol (40 ml) was stirred at room temperature for 3 hr. Intermediate product i G 0.02 g) was added to the mixture and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to afford intermediate 2 (8.61 g). The obtained intermediate 2 (2 〇 5 g) was dissolved in methylene chloride (m.sub.2), and methanesulfonium chloride (yield: 56 ml) and triethylamine (us) were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was saturated with brine (1 mL) and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in acetone (2 mL) and EtOAc (EtOAc) was then applied. The reaction mixture was poured into saturated brine (100 ml The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from diethyl ether to give a moth methyltris-trisamine (0.94 g) solid. This product is a mixture of two isomers and can be used without further purification: the following reactions. The title was obtained by the same method as that of Example 39 except that the above-mentioned moth methyl samarium bio-heart (4) nitrogen I phenyl monomethyl-1 Η-pyrrole 3-carbonitrile was used as the starting material and pyridine hydrochloride was used as the acid. Compound. lH· (CDCl3) δ·· 2·33 (machine S), 2·48 (3H, s), 5·25 (2H, s), 7.53 (2Η, d)f 7.90 (2Η, d), 8.47 ( 1Η, 5), 14.05 (1, s) 319299 214 200813007 [Example 55] 4-[2,5-Dimethyl-1-(111-1,2,3-triazol-4-ylmethyl) -11^pyrrole-3_yl]benzonitrile

A mixture of 1H-tetrazole-5-carboxylic acid ethyl ester sodium salt (5·28 g), triphenylchloromethane (8.97 g) and DMF (30 ml) was stirred at room temperature for 14 hr. The reaction mixture was poured into saturated brine (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to afford ethyl 1-triphenylhydrazyl-1H-tetrazol-5-carboxylate (m. A mixture of sodium borohydride (1.89 g), calcium chloride (4.15 g), THF (80 ml) and ethanol (40 ml) was stirred at room temperature for 30 min. Ethyl 1-tritylmethyl_ih_tetrazole-5-carboxylate (9·58 g) was added to the mixture and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to afford (1-triphenylmethyl)indole-tetras-sodium-5-yl)methanol (7·76 g). The obtained (1-tritylmethyl-1 fluorene-tetrazol-5-yl)methanol (2.06 g) was dissolved in dichloromethane (20 liters), and then added with methanesulfonyl chloride (〇56 ml) and three Ethylamine (1·25 house liter), and the mixture was stirred at room temperature for 14 hours. The reaction was combined with 215 319299 EtOAc (EtOAc). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in acetone (20 liters) and sodium iodide (1·8 gram) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated brine (1 mL) and ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from diethyl ether to give 5-methane iodomethyltriphenylmethyl_111_tetrasole (2.25 g). Fu(峨methyl)-1_trityl-1Η_tetrazole and 4-(4-cyanophenyl)· 2,5-dimethyl-1H-pyrrole-3- obtained by the above reaction The title compound was obtained in the same manner as in Example 39. , W (CDC13) δ: 2.27 (3Η, s), 2.45 (3H, s), 5.59 (2H, s)f 7·55 (2H, d), 7·92 (2H, d). ' [Example 56] 4-(4-cyanophenyl)·2,5-dimethyl·^[4-(trifluoromethyl*h,3_thiazol-2-yl]fluorenyl}-111-11 ratio-3 -carbonitrile

2-[3-Cyano-4-(4-cyanophenyl)·2,5-dimethyl-ΐΗ_σ 嘻 嘻 ]] ethylamine (1.5 g) and 3-de-trifluoroacetone (〇 · 79 ml) A solution of the solution in B 319299 216 200813007 nitrile (30 ml) was stirred at 80 t for hr. The reaction mixture was poured into saturated brine and extracted withEtOAc. The ethyl acetate layer was dried with anhydrous sulfuric acid and condensed. Residues were chromatographed on silica gel column (ethyl acetate-hexane)

Purification and crystallization from diethyl ether gave the title compound (355 mg). Melting point: 180-182°C 丄Η 匪 (CDCl3) δ: 2·32 (3H, s), 2·49 (3h, s), I% (2h, s), 7·31 (2H, d〉, 7.72 (2H, d), 7.79 (1H, s)· [Example 57] 2-{[3-Cyano-4-(4-cyanophenyl)-2,5-dimethyl_m •吼吼•yl]methyl}-1,3-indole-4-carboxylic acid amine

Under ice cooling, from 2_[3-cyano_4_(4-cyanophenyl)_2,5-didecyl-1Η·吼小基] ethionamide and bromopyruvate as in the examples Preparation of 2·{[3-cyano-o-nitrophenyl)_2,5-dimethyl•1 Η 各 」 基 } } } } } } } } 4 4 4 4 4 4 4 4 4 4 4 4 4 4 To the mixture of ([〇毫升) and DMF (2 drops), grass-brewed chlorine (〇43 ml) was added, and the mixture was stirred at room temperature for 3 minutes. The reaction mixture was added dropwise to aqueous ammonia (10 liters) under ice cooling, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate and saturated brine were added to the reaction mixture, and the mixture was dissolved. There was 319299 217 200813007 and the layers were washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 2·5〇(3H, s), 5·% (2h, s), 5.78 (1H, s), 7.01 (in, s) f 7.51 (2H, d) , 7.72 (2H, d), 8.16 (1H , s).

[Example 58] 2-{[3-Cyano-4-(4-cyanophenyl)_2,5-diindenyl-yl]-pyrrol-i-yl]methyl}-1,3-嗟嗤-5-nonylamine

2-[3-Cyano-4-(4-cyanophenyl)-2,5-diindenyl-1H-portpyr-l-yl]ethionamide (1.00 g), 1-chloro-1 -(ethoxycarbonyl)_2-ketoethane hydride (potassium 1 - chioro-1 - (ethoxycarbonyl) 2 - ox. ethanide) (〇·68 g) and acetic acid (0.23 ml) in ethanol (5 ml) The solution was stirred at 8 rc for 14 hr. EtOAc was evaporated. _Hexane) was purified and crystallized from diethyl ether to obtain 218 319299 200813007 dimethyl-1 Η _. 嘻 1 1 - yl] 曱

2- {[3-Cyano-4-(4-cyanophenyl)-2,5-yl}-1,3- sorrow-5- oxoacetate (589 % -4-(4-cyanide) The solution in phenyl) 2,5-dimethyl alcohol (2 ml) was stirred at 5 rc for hrs. The reaction mixture was poured into 1N hydrochloric acid (4 liters) and extracted with ethyl acetate. The layer was dried over anhydrous magnesium sulfate and concentrated. EtOAc m. [10-{[3-Cyano-4-(4-cyanophenyl)-2,5-] The title compound was obtained in the same manner as Example 57. NMR (CDC13) δ: 2·31 (3H, s), 2.48 ( 3H, s), 5·34 (2H, 5·81 (2Η, s), 7·51 (2Η, d), 7·72 (2Η, d〉, 8·ιι (ίϋ. s)· [Example 59] 2_{[3 -Cyano-4_(4-carbylphenyl)-2,5-dimethylindol-1-yl]methyl}-1,3-嗟0 sits -4-曱 guess

319299 219 200813007 Synthetic Method 1 : Add sodium hydride to a solution of ping (ping cyanophenyl) _ 2,5-dimethyl gamma (〇·6 g) in dmf (i5 ml) under ice cooling (60% dispersed oil, 〇·16g). The reaction mixture was stirred at room temperature for 3 hrs and 2 -(bromomethyl s s s carbonitrile (1 gram) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into saturated brine and The mixture was extracted with ethyl acetate. EtOAc EtOAc m. Crystals. Synthesis Method 2 ············································································· The mixture was stirred at room temperature for a few hours. Ethyl acetate and sodium bicarbonate aqueous solution were added to the mixture, and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography (ethyl acetate-hexanes)

Melting point: 183-185°C b Position (CDC13) δ: 2·31 (3H, s), 2·48 (3H, s), 5_37 (2H, s), 7.55 (2H, d), 7·72 ( 2Η, d), 8·03 (1Η, s)· [Example 60] 4-(4-cyanophenyl)-2,5-dimethyl-l-(l,3_thiazole_2_ Methyl)-lH-pyrrole_3_carbonitrile 220 319299 200813007

Using 4-(4-carbylphenyl)-2,5-dimercapto-1Η-σΛ^-3- bet and 2-(&gt;odor methyl)-1,3 -pyrene as material] The title compound was obtained in the same manner as in the the the the NMR (CDC13) δ: 2.31 (3Η, s), 2.48 (3Η, s) r 5.37 (2H, s), 7·55 (2H, d), 7·72 (2H, d), 8.03 (1H, s ).

[Example 61] 2-{[3-Cyano-4-(4-cyanophenyl)-2,5-diindenyl-1H-pyrrole-1-yl]A Sit-5-曱 guess

The title compound was obtained by the same method as the compound of the compound of the compound of the compound of the compound of 289 319299. H NMR (CDCI3) δ: 2·30 (3h, s), 2.48 (3H 7.51 (2Η, d), 7·73 (2Η, d), 8.25 (1Η, s) s), 5.39 (2H, s) r [Example 02] 2-{[3-Cyano-4-(4-cyano-2-methylphenyl)_2,5-dimethyl-4-pyrrole-buyl]fluorenyl}-l, 3-thiazole-4-indoleonitrile

The title compound was obtained by the same method as the the the the the the the the the the ^ NMR (CDC13.) δ: 2·〇6 (3Η, s), 2·26 (3Η, s), 5·36 (2H, s), s). Industrial 〆7·3 (1H' m), 7.4-7·7 (2H, 2.46 (3H, s), m), 8.02 (1H, [Example 03] 2-({3-cyano·4_[4-amino-3_(tri-l-yl) Phenyl]A5·dimethyl·1Η·Pylolyl}曱曱&gt;1,3, sputum carbonitrile 222 319299 200813007

4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-diindenyl-1H-pyrrole-3-carbonitrile was used in the same manner as in Synthetic Method 1 of Example 59. The title compound was obtained. NMR NMR (CDC13) δ: 2.33 (3Hf s), 2.50 (3Hf s) r 5.38 (2Hf s) f 7·7-7·8 (2H, m), 7·90 (1H, d), 8.03 (1H , s)· [Example 64] 4-(4-cyanophenylhydroxy-1-indolylethyl)-1,3-thiazol-2-yl]methyl b 2,5-dimethyl-1H -pyrrole-3-indoleonitrile

Under ice cooling, from 2-[3·cyano-4-(4-cyanophenyl)-2,5-difluorene 223 319299 200813007 base 1 Η-pyrrole-1 yl] ethionamide and Ethyl bromopyruvate was prepared in the same manner as in the Example to give 2-{[3-cyano·4 cyanophenyl) 2,5-dimethyl-111-pyrrol-1-yl]methyl bromide. 3_ Thiazole-4-carboxylic acid ethyl ester (1% mg) in THF (5 ml) was added to the solution of methylated methyl (3 μl solution, 〇 · 63 ml), and the mixture was in the room Stir for 3 minutes. Ethyl acetate and an aqueous citric acid solution were added to the reaction mixture, and the mixture was separated. The organic layer was purified by EtOAc (EtOAc) eluting elut elut elut ...,, 口曰曰^-NMR (CDC13) 2.50 (3H, s), 7·71 (2H, d)· δ: 1·61 (6H, S), 2·33 (3H, s), 5_32 ( 2Η, s), 7.13 (1Η, s), 2.48 (1H, s), 7·51 (2H' d), [Example 05] 4-(4-cyanophenyl)·ΐ-{[5- (hydroxymethyl)-4_(trifluoromethyl hydrazine) octagonal 2 yl]methyl}-2,5-monomethyl-1 Η ϋ ϋ 洛 -3- -3- carbonitrile

2-[3-Cyano-4-(4-cyanophenyl)-2,5-dimethyl "oxime, pyrrolyl] ethionamide (1.07 g), 2_gas-4, 4,4-trifluoro_3_oxybutyric acid acetate 319299 224 200813007 (ethyl 2-chloro-4,4,4-trifluoro-3_ oxobutanoate) (0.87 g), diethylamine (〇·8 ml) and sub The thiopurine chloride (〇·32 ml) was taken in acetonitrile (15 ml) in EtOAc (1 mL). The residue was purified by silica gel column chromatography (ethyl acetate-hexane) eluting with diethyl ether to afford 2 -{[3-cyano-cyanophenyl&gt; 5_Dimethyl-1,4-pyrrolidinyl]methyl 4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid ethyl (397 gram) crystal. Sodium borohydride (66 mg) a mixture of calcium chloride (13 mg), THF (6 liters) and ethanol (3 ml) at room temperature for a minute 'and add cyano-4-(4-cyanophenyl)-2,5 · Dimercapto-1H-pyrrole-1·yl]fluorenyl}- aryl (trifluoromethyl) 4,3-thiazole-5-carboxylic acid ethyl ester (254 mg) and stirred at ambient temperature The reaction mixture was poured into an aqueous solution of citric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate and evaporated. Purification of the ester-hexanes and crystallization from EtOAc (EtOAc) (2H, s) r 7.50 (2H, d), 7.71 (2H, d).

[Example 66] 2-{[3_(4-cyanophenyl)_2,5-dimercaptopyryl]methylthiazole-4-carboxamide 319299 225 200813007

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Conh2 using 2 (polymethyl)-UK4-carboxylic acid ethyl acetate (3.00 g), sodium hydride (6 〇% dispersion oil, 〇.52 g) and M4-cyanophenyl)_2,5-dimethyl -1 Η - σ ratio each -3- oxic acid awkward > formazan (4.29 gram), the same reaction and purification operation as in Example 1 was carried out and the value * 1 1 ^ - 乍 乍 2 «3_[(Benzyloxy)carbonyl]-4-(4-cyanide stupid) 'Methyl-specific small base> 曱基卜口口口冬魏魏酸乙醋(4·51克) crystal . 2-{[3_[phenoxy(mono)]-4-(4-cyanophenyl)-2,5-diindenyl·1Η, Π each small group] mercaptothiazole_4_carboxylic acid A mixture of ethyl ester (4.45 g), ethanol (m.) and 2N sodium hydroxide (m.sub.1) was stirred at room temperature and concentrated. The pH of the residue was adjusted to S1 with 3N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extracted layer is dried in anhydrous form, magnesium sulfate and concentrated to obtain 2_{[3_[(benzene-oxy-oxy)- 4-(4-cyanophenyl)-2,5-dimethyl-1Η_Π比比_丨_ Methyl bromide, 3-carbazole·4-carboxylic acid (4.27 g) crystal. 2_{[3_[(benzyloxy)carbonyl]_heart (4_ylphenyl)-2,5_ Difyl]methylbu^•嗟峻_4_weilic acid (425 g top, f in THF (70 liters), and added dropwise to the grass chloroform (26 ml). Stirring reaction at f to /m After 3 minutes, the solvent was distilled off under reduced pressure. The residue was dissolved in THF (40 mL) and the solution was added dropwise to 28% aqueous ammonia (1〇〇319299 226 200813007 liters) and THF (50 halo) The mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate. ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to afford 1-{[4-(aminoamino) hydrazine, 3 _嗔 _2_2_yl]methyl}-4-(4-cyano basic)·2,5-monomethyl-1H- π 嘻 嘻 嘻 嘻 ( (4·25 g), which is non- Crystalline solid. Under ice cooling, in ι_{[4-aminocarbonyl)-1,3-thiazol-2-yl]methyl}-4-(4-cyanophenyl)_2,5-dimethyl •1Η-pyrrole-3_carboxylic acid Methyl chloroform (2 mM) was added dropwise to a solution of dimethyl ester (4.20 g) and pyridine (2. 2 ml) in DMF (20 liters). The mixture was stirred at the same temperature for 0.5 hr. It was diluted with water and extracted with ethyl acetate. The extract layer was washed successively with 1N hydrochloric acid, water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. Purification with ethyl acetate) to give 4-((cyanocyanophenylcyano-1,3-thiazol-2-yl)methyl]_2,5-dimethylpyrrole-3-carboxylic acid benzyl ester (3.30 g) Crystal. Heart (4_cyanophenyl)_;[_[(heart cyano),&gt; sedo-2-yl) methyl]-2,5-dimethyl-1H-pyrrolecarboxylic acid benzo A solution of the ester (2·8 g) in dichlorofane (30 ml) was cooled in an ice bath and a solution of 2? After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was extracted with 2N aqueous sodium hydroxide, and the pH of the sodium hydroxide layer was adjusted to be added with concentrated hydrochloric acid. And with ethyl acetate The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate-ethyl acetate EtOAc) to afford (amino). , 3_thiazole-2-yl]methyl}_4_(4_ylyl = yl)-2,5-dimethyl·1Η" is n-acid (1〇7g), which is colorless non-crusted 319299 227 200813007 Shaped solid. 1-{[4.(Aminocarbonyl)-i,3-thiazol-2-yl]methyl-4-(4-cyanophenyl)-2,5-diindenyl-1H-pyrrole-3- The carboxylic acid (0.90 g) was dissolved in TFA (10 mL) and mixture was stirred at room temperature for 2 s and further concentrated. Ethyl acetate and a saturated aqueous solution of sodium dicarbonate were added to the residue, and the mixture was partitioned. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (0.60 g). ^H-NMR (CDCls) δ: 2.29 (3Η, s), 2.37 (3H, s), 5.29 (2H, s), 5.65 (1H, s s), 6.13 (1H/s), 7.07 (1H/ br s) / 7.45 (2H, d), 7·63 (2H, d), 8·09 (1H, s).

[Example 67] 2_{[3-(4-cyanophenyl)-2,5-dimethyl-in-fluorenyl]methylthiazole-4-carbonitrile ’

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CHc

</ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 4-NMR (CDC13) δ: 2.27 (3Η, 6·13 (1H, s), 7·44 (2Η, d), s), 2.34 (3H, 7.62 (2H, d), s>' 5.32 (2H , t7·93 UH, s)·s), 319299 228 200813007 [Example 68] 2-{[2-Cyano-3_(4-cyanophenyl)methyl"Η-σ 咯 小 small base]曱}}-1,3-0 sputum-4-carboxamide

Add 3-(4-cyanophenyl) _methyl_ιη_pyrrole to a solution of sodium hydride (6 〇 % dispersion oil, 〇〇 3 g) in DMF (3.0 liters) under ice cooling. 2-carbonitrile (〇·14 g). After stirring the reaction mixture for 3 minutes at room temperature, 2-(bromomethyl)-indole, 3-thiazolcarbonitrile (19 g) in dmf (1 〇 4 liters) / 谷液' The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (ethyl acetate-hexane) to afford intermediate (217 m.). Next, 28% aqueous ammonia (5.0 ml) was added to the mixture of the above-obtained compound (125 mg) in THF (2.5 ml), and the mixture was stirred at room temperature for 88 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate. The organic layer was washed with water and saturated brine, evaporated The residue was crystallized from ethyl acetate to afford crystals of the title compound (76 g). 319299 229 200813007 4R (DMSO-d6) δ: 7·62 (2HA br h, 2.38 (3H, s), 5.65 -, d) ' 7.84 (2H, d) , 7· 92

[Example 69] 4-(Carnerylcyanophenyl)*&quot;2,5-Dimethyl-l-{[2_(trifluoromethyl)_1,3"pyrazolyl]fluorenyl}-1Η_ Pyrrole _3_ carbonitrile

4-(4-cyanophenyl)-2,5-dimethyl-1Ή-pyrrole-3-indene nitrile (443 g) in dehydrated DMF (2 mL) under argon and ice-cooling Sodium hydride (60% dispersion in 60% dispersion oil) was added to the solution, and the mixture was stirred for 30 minutes. Further, a solution of 4_(iododecyl)-2-(trifluoromethyl)thiazole (88 mmol) in dehydrated DMF (2 ml) was added to the mixture, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Η-deleted R (CDC13) δ: 2·31 (3H, s), 2·, λ 7.50 (2Η, d) r 7.69 (1H, s), 7.72 319299 230 200813007 [Example 70] 4-(4- Cyanophenyl)-2,5-dimethylpyrrole_3_indole

4-Chloromethyl-1,3-sigh (2.00 g) was dissolved in acetone (100 ml) and sodium iodide (5·00 g) was added. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was dissolved in ethyl acetate and saturated aqueous sodium dicarbonate. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated to give s.

4-iodomethyl-1,3-thiazole (1. gram), sodium hydride (0.2% in 6% dispersion oil) and 4-(4-cyanophenyl)_2,5_2 Methyl·1Η_pyrrole_3•indoleonitrile (1·〇〇克) The same reaction and purification procedure as in Example i was carried out.

'h-NMR (CDC13) δ: 2.30 (3Η, 6.88 (1Η, d), 7.51 (2H, d), [Example 71] s)' 2·47 (3H, S), 5·24 (2h, 7·7〇(2H, d), 8·84 (1H, d)· 4_(4_Alitylphenyl)·2,5-dimethyl small (UH5-ylmethylHh) Formonitrile 319299 231 200813007

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Using 5-gasmethyl-1,3-thiazole, 5-iodomethyl-1,3-thiazole was obtained in the same manner as in Example 67. The reaction of s utilizes 5-iodomethyl_1,3-thiazole (1·13 g), sodium hydride (6 〇% octa, 〇·17 g) and 4-(4-cyanophenyl)_2,5 _Dimethyl-1H_indole was slightly succinimide (60 g), and the same reaction and purification procedure as in Example 1 was carried out to give the title compound (0.22 g) as colorless crystals. Pieces to ^-NMR (CDC13) δ: 2.31 (3Hf s), 2.48 (3H, s)f 5.28 (2H 7.49 (2H, d), 7.65 (IH. s), 7.71 (2H, d) , 8.81 (lH , s / ^ ^ [Example 72] 4-(4-Cyanophenyl)-1-{[2-(hydroxymethyl)_1,3_thiazole-5-yl]-methyl}}2-decyl- 1H·pyrrole·3·曱nitrile soil '5_

NC

The compound obtained from Reference Example 76 (1,87 g), sodium hydride 319299 232 200813007 (0.64 g in a dispersion oil, 0.44 g) and 4_(4-cyanophenyl)_2,5-dimethyl _1H. pyrrole-3-carbonitrile (2 21 g), the same reaction as in Example 1 was carried out and purified to give 5-([3-cyano-4-(4-cyanophenyl)-2 ,5-Dimethyl·1Η_Πbyr-1-yl]methyl b-U-thiazole-2-carboxylic acid ethyl ester (132 g), which is a colorless crystal 5·{[3'cyano_4-(4 ·Cyanophenyl)_2,5-dimethyl-1Η-pyrrolyl]methyl}-1,3-yttrium-2-carboxylic acid ethyl ester (0.50 g) in THF (14 ml) To: (:, add calcium carbonate (33 g) and sodium borohydride (〇 ii), and add ethanol (7 ml) dropwise. The reaction mixture was stirred at room temperature for 16 hours and diluted with water. The extract was extracted with EtOAc. EtOAc (EtOAc m. It is a colorless crystal. s), 2.47 (3H, S), 3.11 (1H, br s)' 7·46 (1H, s), 7·48 (2H, d), ^-NMR (CDC Ls: 2.31 (3Η s), 4.91 (2Η, s), 5·23 (2η 7.70 (2Η, d).

[Example 73] S{[3-cyano-4-(4-cyanophenyl)_2,5-diindenyl-m_pyrrole-yl]methyl}-1,3-thiazole-2 -Procarbamide

NC

319299 233 200813007 Using 5_{f3-cyano-4-(4-cyanophenyl$yl"p--17-specific-1-yl]F-based}-I,3-thiazole-2-carboxylic acid ethyl ester ( 〇·5 gram), the same reaction and purification operation as in Example % was carried out to obtain cyanide-4-(4-cyanophenyl)-2,5-dimethyl-1H_pyrroleyl]methyl卜^嚓嗤^carboxylic acid...(4) g), which is a colorless crystal. In 5_{[3-cyano-4-(4 cyanophenyl)_2,5-difyl-1Η_ϋ比咯小基] _ 嗟 嗟 嗟 -2- 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓 缓Triethylamine (0. 14 ml) was added to the mixture. The reaction mixture was stirred at room temperature for 7 hours, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. Concentration. The residue was suspended in ethyl acetate. EtOAc was obtained eluted elut elut elut elut elut elut (2H, s), 6·62 (1H, br s), 7·19 (1H, br s), 7·49 (2H (1) 7.55 (1H, s), 7.71 (2Hf d).

[Example 74] 2_{[3-cyano-4-(4-cyanophenyl)-2,5-dimethyl]methyl}-1,3-oxazole-4-carboxamide

NC

CONH2 319299 234 200813007 The compound obtained from Reference Example 77 (1 〇 5 g), '0·20 g in sodium hydride oil, and 4·(4-cyanophenyl)-2,5-dimethyl -1H-: 17-methyl eye (1.06 g), the same reaction as in Example 1 was carried out and purified, and 2_{[3_cyano-4-(4-cyanophenyl)- 2,5-Dimethyl-1 Η-pyridyl m]methyl}_i, 3h4 acid vinegar (1·3 gram), which is a colorless crystal using 2][3H4-(4-cyanophenyl)- 2,5-Dimethyl-indole-l-l-yl]methyl}-l, 3 m methyl decanoate (115 g) was subjected to the same reaction and purification procedure as in Example 66 to give 2-{[3- Cyano 4-(4-cyanophenyl)_2,5-diindenyl]zirpyrrole]yl]hydrazinyl oxazolidine _4•carboxylic acid hydrazine 5 g), which is a colorless crystal. Using 2-{[3-cyano-4-(4-cyanophenyl)-2,5-dimethylpyryl-1-yl]methylindole, 3-oxazole-4-carboxylic acid (0.85 The title compound (〇·62 g) was obtained as colorless crystals. b-NMR (CDC13) δ: 2·36 (3Η, s), 2·54 (3Η, s), 3·16 (2Η, s)r 5.55 (1Η, br s) , 6.70 (iHf br s) f 7.49 (2Rr d)f 7.7i (2H, d), 8·23 (1H, s)· [Example 75] 2-{|&gt;Cyano-4-(4-cyanophenyl)_2,5 -dimercapto-111_11pyrrol-1-yl]fluorenyl}-1,3-oxazole-4-carbonitrile 235 319299 200813007

Using the compound (0.42 g) obtained in Example 74, the same reaction and purification procedure as in the the the

Melting point·· 188-189°C ^-NMR (CDC13) δ: 2.35 (3Η, s) , 2.53 (3H, S) ς i 19 f2R. 7.47 (2H, d), 7·70 (2H, d), 8·18 (1H, s).

[Example 76] 4-(4-Cyanophenyl)-l-{[4-(hydroxymethyl)-153-oxazol-2-yl]indolyl 2 Hong dimethyl-1H_pyrrole-3 _carbonitrile soil

EXAMPLES Compounds obtained from Reference Example 77 were used (0.28 of the same ones were synthesized by the same reaction and purification procedure to give 28 g of J, and I and the title compound 319299 236 200813007 (0.16 g) crystals were carried out. 'H-NMR (CDC13 δ: 2.35 (3Η, s), 2.51 (3H, s), 4.56 (2h 5.14 (2H, s), 7·48 (2H, d), 7·61 (1H, s〉, 7·68 (2H) , d> [Example 77] 4-(4-Cyanophenyl)-2,5-dimercapto-1-(13-oxazol-5-ylmethylbromo-3-indoleonitrile)

NC

The compound obtained in Example 78 (9 mg) was dissolved in methanol (4 ml), and potassium carbonate (97 mg) and &lt;&quot;&gt; . After concentrating the reaction mixture, the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (EtOAc-EtOAc) 'Make ((10)3) δ: 2.34 (3H, s), 2·51 (3H, s), 5·〇9 (2H, s), 7·02 (1H/ S)' 7·48 (2H, d) f 7.68 (2H, d), 7·87 (1H, s)· [Example 78] 4-(4-cyanophenyl)-2,5-dimethyl small [(2_methyl-bite I Methyl]-1Η-吼洛_3-carbonitrile 237 319299 200813007

NC

Test the same method as in Example 31, and then π U to obtain 2-methyl-4-iodomethyl-1,3-oxazole (1·43 g). Using 2-methyliodomethyloxazole (ι 3 g), sodium hydride (6 〇% in political oil, 〇·24 g) and 4 from cyanophenyl p's dimethyl quinone "birar 3 carbonitrile The title compound (0.98 g) was obtained as a colorless crystal. m.p.: NMR (CDC13) δ: 2·33 (3H, s), 2.45 (3h, s), 2·49 (machine (7) 4.91 (2Hf s), 7.26 (1H, s) r 7.50 (2H, d), 7.70 (2Hf d).

[Example 79] 4-(4-cyanophenyl)-1_{[5·(hydroxymethyl)-2-mercapto-1,3-oxazol-4-yl]methyl}-2'5 -monomethyl-1Η_σ ratio σ each-3-carbonitrile

- Ν HO^-O \&gt;-CH3 319299 238 200813007 The solution of the compound obtained in Example 78 (221 mg) in thf (6 mL) was cooled to -78. (:, and a solution of n-butyllithium in hexane (16 mol/l, 〇·44 ml) was added dropwise. The reaction mixture was stirred at the same temperature for 15 minutes, and DMF (0.40 ml) was added at the same temperature. The mixture was stirred for 2 hours, and further stirred at room temperature for 2 hours. Water and ethyl acetate were added to the mixture, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated. Purification of ethyl ester-methanol to give 4-(4-cyanophenyl)-1-{[5-methylindenyl-2-methyl-1,3-oxazol-4-yl]indolyl}-2, 5_Dimethyl-1H-indole-3-carbonitrile (75 mg) as a colorless, non-crystalline solid. The same reaction and purification procedure as in Reference Example 75 was carried out using the colorless solid (75 mg). The title compound (35 mg) was obtained as colorless H NMR (CDCI3) δ: ..73 (lH, t), 2.34 (3 Η, s), 2.42 (3Η. 2.50 (3Η, s), 4.41 (2Hf d ), 4.94 (2Η, S), 7.50 (2Η, 7·69 (2Η, d)· [Example 80] 4-(4-cyanophenyl)-ΐ · (Imidazole Hay than pyridine-5_ 曱Base)_2,5-dimethyl-1H-pyrrole-3-carbonitrile

NC ^〇Ν h3C^^ch3

239 319299 200813007 Sodium [l,2-a]ab^-5-ylmethanol (〇·76 g) was suspended in THF (20 mL), and sulphur chloride (1.2 mL) was added. The reaction mixture was shaken at room temperature for 1 · 5 hours, and the residue was suspended in ethyl acetate and filtered to obtain 5-(chloromethyl)imidazole [i'la]pyridine hydrochloride. 〇·〇〇克). Using 5-(chloromethyl)imidazolium [丨,2_a]pyridine hydrochloride (〇·33 g), sodium hydride (60% dispersion oil, 〇·14 g) and 4-('cyanophenyl)_2 5- dimethyl-1 oxime-pyrrole-3-carbonitrile (0.29 g) was subjected to the title compound (0.19 g).

Melting point·· 276-278°C ^-NMR (CDC13) δ: 2.23 (3Η, s), 2.40 (3H, s)r 5.21 (2H, s), 5.92 (1H, d), 7.19 (1H, dd) , 7.56-7.58 (3H, m), 7.68-7.76 (3H, m), 7·86 (1H, s)·, [Example 81] 4-(4-ethoxyphenyl)-1 _(mouth) σ sits [1,2-a] ^ σ 曱 曱 ))), 2,5-dimethyl carbonitrile

NC

Imidazo[l,2-a]acridin-8-ylmethanol (0.89 g) was suspended in THF (20 mL), and then sulphur chloride (1. The reaction mixture was stirred at room temperature for 319299 240 200813007 for 2 hours and concentrated to give 8-(chloromethyl)imidazole [^ "pyridyl gull salt (1.20 g). n using 8-(chloromethyl)imidazole^,24 Pyridine hydrochloride (1.2 g), sodium gasification (60% dispersion oil, 〇·72 g) and 4_(4-cyanophenyl)_2,5-dimethyl-1Η-pyrrole_ 3-carbonitrile (1·00 g), the same reaction and purification procedure as in Example i was carried out to give the title compound (0.50 g) crystals., 4- (CDC13) δ: 2·23 (3H, s ) / 2·39 (3H, s), 5·5 , 'η, s) r 6.21 (1Η, d)f 6.75 (1H, d) , 7.56 (2H, d) , 7.70-7.75 (4H/ m) , 8 · 13 (1H, d) · [Example 82] 4-(4-cyanophenyl)-; i_(imidazopyridinyl)-2,5-diindenyl-1H-pyrrole_3_ Nitrile

Sodium sulphate [l, 2-ap was suspended in THF (14 ml) than bit _6_ benzyl alcohol (0. 74 g) and thionium chloride (1.1 ml) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was suspended in diisopropyl ether and filtered to obtain 6-(chloromethyl)methane π sitting [i, 2_a]n than biting hydrochloride (1 · gram). Using 6-(chloromethyl)imidine [l,2-a]hydrazine hydrochloride (1·(8) g), hydrogenation 319299 241 200813007 sodium (60% dispersion oil, 〇6 gram) and 4-( 4-cyanophenyl)·2,5-didecyl

[Example 83] 4-(1-{[3-(1-hydroxydecylethyl)_1Η-pyrazolyl]methyl b 2,5-didecyl-111_pyrrole-3-yl)benzamide Nitrile

Under ice cooling, 4-(4-cyanophenyl)_2,5-dimethyl-1Η-indole-3-carboxylic acid second butyl ester (〇·6 g) in DMF (1 mL) Sodium hydride (60% dispersion oil, 〇·12 g) was added to the solution. After the reaction mixture was stirred at room temperature for 30 minutes, 4-(iodomethyl)-trityl-1-indole-pyrazole-3-carboxylic acid ethyl acetate (m.) was added to the mixture at room temperature. The mixture was stirred for 14 days π. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium The obtained colorless solid (yield: 76 g) was dissolved in TFA (5 ml), and the mixture was stirred at room temperature for 3 hours at 319 299 242. Ethyl acetate and an aqueous solution of sodium dicarbonate were added to the reaction mixture, and the mixture was dissolved. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by hydrazine column chromatography (ethyl acetate-hexane) and crystallised from diethyl ether to afford 4-{[3_(4-cyanophenyl)-2,5-dimethyl- Crystals of ethyl 1-methyl]methylpyrazole-3-carboxylate (246 mg). '4_{[3-(4-Cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl]methyl}-1Η-pyrazole-3-carboxyl at 〇 °C A solution of 3M methylmagnesium bromide in diethyl ether (0.3 mL) was added to a solution of EtOAc (EtOAc). The mixture was placed at the same temperature for 1 hour. A saturated aqueous solution of citric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate·hexane), and the precipitate was further chromatographed with NH-gel (manufactured by Fuji Silysia Chemical Ltd.) (ethyl acetate·hexane). Purification and recrystallization from ethyl acetate-ether to give the title compound (30 mg).

Melting point: 164-166°C Η-NMR (CDC13) δ: 1·68 (6H, s), 2.21 (3H, s), 2·30 (3H, s), 5·〇6 (2Η, s), 6·09 (1ΗΛ s), 6.67 (1Η, s), 7.45 (2Η, d)r 7·61 (2Η, d)· [Example 84] 4_[2-(hydroxymethyl)·5- Mercapto-1-(11^1,2,3-triazol-4-ylmethyl)-111·pyrrol-3-yl]benzoquinone 243 319299 200813007

Ethanol (2.0 ml) was added to a solution of sodium borohydride (31 mg) and calcium chloride (46 g) in THF (2.0 liters) and the mixture was stirred for 2 min. 4-[2-Methyl fluorenyl-5-methylmethyl)-1 hydrazin-3-yl]benzonitrile (80 mg) was added to the mixture and mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate was rinsed with water and brine, dried with anhydrous sulfur and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (37 mg) as pale yellow solid. Lower ^-NMR (DMSO-de) 5: 2.27 (3H, s), 4.53 (2h, s), 5.28 (2h/s) 6·08 (lH, s), 7·61 dd), 7·78 ( 2H, d) · · [Example 85] 4-(2-m-methylmethyl)-5-fluorenyl-^[3-(trifluoromethyl)-lH_n-biazole-5-yl]methyl}_1H_ Puroro-3-yl)benzonitrile

319299 244 200813007 4-(2-indolyl_5-methyl-1H4-yl-3-yl) anthracene nitrile (767·9 mg) was dissolved in DMF (12.2 mL). Sodium (60.2% dispersion oil, 210.2 mg). The reaction mixture was sanded at the same temperature for 30 minutes and 5-(iodomethyl)-3-(trifluoromethyl)-trityl-111-oxime (2.08 g) was added. The reaction mixture was scrambled at room temperature for 3 Torr, poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (ethyl acetate-hexane). The obtained oil was added with diethyl ruthenium crystals, and the crystals were washed with diethyl ether to obtain 4-(2-carboxylic acid group 5-methyl-1-([3-(difluoroindolyl)). _ base] methyl bιη_ 吼嘻-3_yl) benzonitrile (2·98 g) which is a colorless crystal. The obtained 4-(2-carbamimido-5-methyl-1·{ [3_(trifluoromethyltriphenylmethyl-1Η♦ 坐·5_yl]methyl}_1Η_吼口____) benzene f guess (165 g) dissolved in acetonitrile, cooled in nitrogen and ice Next, a 1 μ solution of TFA in acetonitrile was added by other methods. The reaction mixture was stirred at the same temperature for 25 minutes, poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine. Drying with anhydrous sulfur (tetra) and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 4-(2-mercapto-5-methyltrifluoromethyl)-1Hn5 _基]Methyl}-111-吼-r--3-yl)benzonitrile with 4_[9-hydroxy-6-methyl-2-trifluoromethyl)-4H, 9H-n than saliva [l, 5_a] A mixture of 吼 and [Μ. 比哄·8-yl] benzophenone (694.1 mg). The mixture (649·1 mg) was dissolved in methanol (9 7 ml) under ice cooling, and sodium borohydride (87.9 g) was added. The reaction mixture was stirred at the same temperature for 319299 245 200813007: for 20 minutes, and a saturated aqueous solution of chlorine (10) was added, and the mixture was washed with ethyl acetate and EtOAc. The residue was purified by column chromatography (ethyl acetate), and recrystallized to obtain the title compound (3,5 mg, and the second crystal: 56.5 g), which was a colorless crystal. NMR (DMSO-d6) δ··2·18 (3H, s)f 6.13 (1H, s)f 6.40 (1H, s)r [Example 86] S), 4·48 (2H, S), 5 ·29 (2H, 7·62 (2H, d), 7·80 (2H, d). 4-(5-(hydroxymethylmethyl·trifluoromethyl)-exazole (5-yl) A }}-1Η-πpyr-3-yl)benzonitrile

4-(5-Methyl-2-ylindolyl-1H-indole-3-yl)benzazole (130.1 mg) was dissolved in DMF (2·; Sodium (6〇Z is '35·7 faint in bulk oil). The reaction mixture was stirred at the same temperature for 15 minutes&apos; and 5-(mothenyl)-3-(trifluoromethyl)steatriene was added to the saliva (352.86 mg). The reaction mixture was stirred at room temperature for 2 minutes, poured into water and extracted twice with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by Shih Hose column chromatography 319299 246 200813007 (acetic acid ethyl Si_hexane). The obtained oil was crystallized from diethyl ether, and the crystal was washed with a binary singe to obtain a 4-(5-methylaminomethyl "-([l(trifluoromethyl)-1-3-triphenylhydrazinyl] Η σ ratio. Azole-5_yl]methyl b 1H_pyrrole_3_yl)benzonitrile (269.1 mg), which is a colorless crystal. The obtained 4-(5-methylindenyl 1 fluorenyl small {[ 3-(trimethylsulfonyl)]_tritene &amp; _1H_pyrazole-5-yl]methyl}-1H_pyrrole_3_yl)benzonitrile (141.9 mg) is dissolved in acetonitrile, and Under nitrogen and ice cooling, a solution of 1 M TFA in acetonitrile prepared by other methods was added. The reaction mixture was stirred under the same degree for 20 minutes, poured into a saturated aqueous solution of sodium dicarbonate and extracted with an organic layer. The mixture was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated. Base 2_methyl_1-{[3·(trifluorocarbazole·5_yl]methyl}_ΐΗ_σ ratio _3_yl) benzonitrile (77·5 mg). 4_(5_ Methyl hydrazino 2_methyl small {[3_(三敦methylΗη" bisazol-5-yl j methyl ΐΗ ΐΗ pyrrolyl Benzoonitrile (5.64 mg) was suspended in methanol (9.7 ml), and under ice cooling, sodium borohydride (1 mM 9 mg) was added and the reaction mixture was stirred at the same temperature for 15 minutes, poured into water, and treated with acetic acid. The organic layer was extracted with EtOAc (EtOAc m. The alkane was recrystallized to obtain the title compound (first carcass·20.3 pg 'second crystal ······················································ (4) Legs (DMS〇-d6) δ··2·31 (3Η, s), 4·47 (2Η, &gt;)' 6·30 (1Η, s), 6·45 (1Η, s), 7 ·53 (2Η, (1), 319299 247 200813007 [Example 87] 3·(4-cyanophenyl)·5_(ylaminomethyl H_{[3_(trimethylmethyl-5-yl)methyl} ·1 H-11 than slightly 2-indene nitrile

Add cerium (IV) ammonium nitrate (2·74 g) to 3-(4-cyanophenyl)-5-methyl-1_{[3-(trifluoromethyl)-1Η-ϋ at room temperature A solution of biszinocarbyl]methyl ih_pyr-2-pyrimonitrile (0.36 g) in acetonitrile (3 mL) and water (5 mL). The reaction mixture was stirred at the same temperature for 3 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with EtOAcq. The brown solid (0. 18 g) was suspended in THF (2 mL) and ethyl alcohol (2 mL). The reaction mixture was stirred at the same temperature for 3 hours. A saturated aqueous solution of citric acid was poured and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was crystallized from ethyl acetate-diethyl ether to afford the title compound (j. ^NMR (DMSO-d6) δ : 4.55 (2H, s), 5.48 (2H, s) / 6.56 (1H, s), 6.74 (1H, s), 7.86 (2H, d), 7·94 ( 2H, d)· [Example 88] 248 319299 200813007 4-(5-(Alkylmethyl)_ι__([5_(1_hydroxydecylethyl)_m"pyrazole-4-yl] fluorenyl}- 2-mercapto-lH-u ratio -3-yl) benzoquinone

Sodium hydride (87 mg in 60% dispersion oil) was added to a solution of the compound (381.3 mg The reaction mixture was stirred at room temperature for 3 minutes, and ethyl (iodomethyl)-1-trityl-1-indazole-3-carboxylate (1 g) was added. The reaction mixture was stirred at room temperature for 14 hours, poured into saturated brine and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sulphuric acid and concentrated to give colorless solid (1····· The resulting colorless solid (1.00 g) was dissolved in EtOAc (25 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate·hexane), and crystallised from diisopropyl ether to give 4_{[3_(4-cyanophenyl)-5-methylamino-2-yl Crystals of ethyl-ih_pyrrole small group]methyl}_111_pyrazole-5-carboxylate (292 mg). Sodium borohydride (25.2 mg) was added to 4-{[3_(4-cyanophenyl)-5-methylcarbonylmethyl嘻-1_yl}methyl}-ΐΗ_π than saliva 319299 at 〇 °C 249 200813007 -5-A solution of carboxylic acid ethyl acetate (200·6 mg) in ethanol (5 ml). The reaction mixture was lion at the same temperature for 3 hours. The reaction mixture was combined with a saturated aqueous solution of chloroacetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate The residue was suspended in diethyl ether and filtered to obtain 4-{[3-(4-cyanophenyl)_5_(hydroxyindenyl)_2_indolyl-1 Η^pyr-1-yl]hydrazinyl 1 Η- Ethyl pyrazole-5-carboxylate (198.5 mg). Add 3 {{[3_(4-cyanophenyl)_5_(hydroxyindenyl; decylpyrrole-1βyl)methyl}-111 to a solution of 3 Μ Μ Μ 镁 镁 magnesium in diethyl ether (〇·82 ml) a solution of _pyrazole-5-carboxylic acid ethyl ethane (9 〇·ΐ mg) in THF (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was combined with a saturated aqueous solution of ammonium chloride. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. Crystallization gave the title compound (46.5 mg). m.p.: 167-168:: NMR (DMSO-d6) δ: 1.50 (6 Η, s)f 2.21 (3H, s) , 4.35 (2Hf d)' 4.94 (1H, s), 5·02 (1H, s), 5·22 (2H, s), 6·29 (1H, s)f 6·57 (lHf s), 7·55 (2H, d), 7·77 (2H, (1), ι2·ΐ8 (ih, s)· The compounds obtained in the above examples are summarized in Table 1 below. 319299 250 200813007

251 319299 200813007

252 319299 200813007 20 CN Me ho2c η Me NC, 21 CN Me X, h2noc h Me NC, c 22 CN Me MeHNOC H Me NC, c 23 CN Me ho^/^n Me NC, c 24 CN Me Me IL / OH Me NCXi 25 H Me 丫, NH N OH Me NC^ 0 \ 26 H Me NH w C02Et Me NC^ 0 \ 27 H Me 丫, NH ) — OH Me Me 28 H Me V\h CN Me NCOk 29 H Me V\h &gt;-/ Me Me NC\ 0 \ 30 H Et V\h Jw Me Me NC, 0 \ 31 H Me 丫, H Me02C Me NC, D \ 253 319299 200813007 32 Η Me 丫, H Me NC1X 33 Η Me 丫, NH NC Me NC, c 34 Η Et 丫, H CN Me NCxx 35 CN Me Me NC^ a 36 CN Me N\ Me Me NC, 37 CN Me )0N CF〆H Me NC&lt; c \ 38 Η CF3 T&gt; Me NC, 0 \ 39 Η Me CF3X h Me NC) a 40 Η Me Y&gt; CN NC^ 0 \ 41 Η CN Y&gt; Me NC^ 0 42 CN H T&gt; Me N. , 0 43 Η Me Y&gt; Me NC\ D \ 254 319299 200813007

255 319299 200813007

256 319299 200813007

257 319299 200813007

258 319299 200813007

[Formulation Example 1] 259 319299 200813007 (1) Compound of Example 9 50 mg (2) Lactose 34 mg (3) Corn starch (4) Corn house powder (paste) 1 〇 · 6 gram 5 mg (5 Magnesium stearate (6) About 曱······················································ . [Formulation Example 2] (1) Compound of Example 41 50 mg (2) Lactose 34 mg (3) Corn starch (4) Corn powder (paste) 10·ό mg 5 mg (5) Magnesium stearate 〇·4 mg (6) Rebel-based cellulose|Bow 20 mg total amount 120 mg The above components (1) to (6) were mixed by a conventional method and pressed by a tablet machine to obtain a tablet. [Formulation Example 3] (1) Compound of Example 80 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5 mg 319299 260 200813007 (5) Stearic acid Magnesium strontium·4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg By the conventional method, the above components (1) to (6) are mixed and pressed by a tablet machine to obtain a tablet. Test Example 1: AR binding inhibition test (wild type, LNCaP type) 3 nM radiolabeled mibolerone and 1 // were added to a solution containing a wild type or LNCaP type mutant male receptor (AR). The compound was sputum, and after the solution was incubated at 4 ° C for 3 hours, B (binding) / F (free) separation was carried out by a polydextrose / carbon method. The amount of labeling of B was measured and the inhibition rate of individual compounds was calculated. The results are shown in Table A. Table A 1 / z 抑制 inhibition rate Compound number wild type LNCaP type 1 97 94 4 96 92 14 101 101 34 89 95 43 93 96 56 99 94 59 97 94 60. 93 88 70 100 94 71 90 86 75 99 93 80 89 80 Bicalutamide 88 63 From the results shown in Table 明显, it is apparent that the compound of the present invention has a strong affinity for the wild type and the LNCaP type mutant male receptor. 261 319299 200813007 Test Example 2: Compound of the present application inhibits prostate specific antigen (PSA) production in different (including mutant) prostate cancer cells. Human prostate cancer cell LNCaP-FGC is cultured in a 96-well plate, cells The number is 5000 cells / 100 / / L / well. Testosterone and 1//Μ compound were added at a final concentration of 1 ng/mL every other day. After three days of addition, the PSA concentration in the culture supernatant was measured by ELISA, and the inhibition rate of PSA production was calculated to assume that the inhibition rate of the group in which no testosterone was added was 100%, and the inhibition rate of the group to which the testosterone was added was observed. 0%. The results are shown in Table B. Table B 1 // Inhibition rate at the time of hydrazine Compound number Inhibition rate (%) 584836901 113345567 00197 9 881 999999999 5 9 Amine card ratio From the results shown in Table 明显, it is apparent that the compound of the present invention has potent PSA production inhibitory activity. Test Example 3: AR transcriptional inhibition test In a flask, 5,000,000 Cos-7 cells were seeded and cultured in 262 319299 200813007 (DMEM + 10% polyglucose charcoal (DCC) - fetal bovine serum (FBS) + Incubate for 24 hours in 2 mM branic acid). The vector DNA inserted into the mutant AR (W741C) and the luciferase gene are then ligated to the vector DNA downstream of the androgen reaction promoter by a liposome method. 2 hours, change the medium. After 3 hours of incubation, DHT (dihydrotinosterone) at a final concentration of 〇·〇4 // 与 and test compound at a final concentration of 0.1//Μ were added. After 24 hours of culture, luciferase activity was measured, and the transcriptional inhibitory activity of the test compound against AR was examined. The results are shown in Table C, expressed as the inhibition rate (%) of the control group. Table C 0.1 // Inhibition rate at 化合物 Compound number inhibition rate (%) 1 42 4 51 9 39 14 60 15 29 34 47 38 23 56 29 60 33 70 43 75 51 80 29 Bicalutamide-72 From Table C As is apparent from the results, bicalutamide has little transcriptional inhibitory activity against mutant AR (W741C), but the compound of the present invention has excellent transcriptional inhibitory activity. 263 319299 200813007 Test Example 4: Rat prostate weight reduction test After castration of three-week-old male rats, subcutaneous injection of 1.5 mg/kg propionate propionate was administered orally with compound 5 mg/kg/A (the same If there is a card, the amine is 5. mg / kg / day;) 7 days. On the day after the completion of the administration, the front knee was reset. The weight reduction rate of the sultan gland is assumed to be 〇% measured by the undoes, and the 启 埶 曰丄 曰丄 曰丄 曰丄 曰丄 々 々 测量 , , , , , , , , , , , , , , , , , , , , , , , , , to

(Industrial Applicability) The compound of the present invention (1) or its _^ mutated receptor has excellent antagonism, "sex hormone receptor and/or synaptophysin-dependent phase and/or male use and can be effectively used as In the anti-magents and / or therapeutic agents. 1 Pre-stage hormone-sensitive cancer pre-319299 264

Claims (1)

200813007 X. Patent application scope: 1. A compound or a salt thereof as shown in formula (I): Wherein R1 represents (1) a hydrogen atom, (2) a cyano group, (3) a Ci_6 alkyl group which is optionally dentated or (4) a C1-6 alkoxy group-carbonyl group which is optionally substituted; R2 and R4 are The same or different, and respectively represent (1) a hydrogen atom, (2) a Ci6 alkyl group, (3) a C3_6 cycloalkyl group, (4) a trifluoromethyl group, (5) an amine group, an alkyl group, a (6) single Or a substituted amino group π&quot; alkyl group, (7) a halogenated C1 -6 alkyl group which is optionally substituted with a trans group, a (8) 6 alkenyl group, which is optionally substituted a hydroxy-substituted, (9) Cle6 alkyl group which is optionally substituted and optionally substituted with an oxidized thiol, (丨〇) a gas group, (11) a stilbene group, (12) a substituted sit group or (I?) 〗 3_monooxygen pentazol-2-yl, R3 represents (1) thiazolyl which is optionally substituted, (2) oxazolyl which is optionally substituted, and (3) substituted as needed Oxazolyl, (4) imidazole [l,2-a]pyridyl optionally substituted, (5) optionally substituted oxime, 2,3_trisal, (6) optionally substituted 1 , 2,4-triazolyl or (7) as needed. a sitting group; and R5 represents a phenyl group having a cyano group at the 4 or 3 position and further substituted; 319299 265 200813007 except for the 4 gas-c-cyanophenyl)-1-((4-cyano-1,3) · Thiazol-2-yl)indenyl) 2,5-dimethyl-1Η-pyrrole-3-carboxylic acid methyl ester, 4-(4-cyanophenyl)-2,5*&quot;dimethyl- 1-((1-triphenylindenyl-1H-1,2,3-triazol-4-yl)indolyl-1H-indole-3-indene nitrile and 4-methyl 4-cyanophenyl)-2 , 5-Dimethyl-1-(111-152,3-triazole-4-ylmethyl)-111-pyrrole-3-indolecarbonitrile. 2. A compound according to claim 1, wherein Ri is a halogen atom, a cyano group or a Cl_6 alkyl group which is optionally dented. 3. The compound of claim 1, wherein R2 and R4 are the same or different 'and represent (1) a hydrogen atom, (2) a Cw alkyl group optionally having a hydroxyl group, and (3) (^^ ring An alkyl group, a (4) trifluoromethyl group, a (5) cyano group or a (6) aryl group. 4. The compound of claim 1, wherein R3 is (1) a substituted π-pyrazole a base, (2) an oxazolyl group which is optionally substituted, (3) an imidazole [12^]pyridyl group which is optionally substituted, (4) a 1,2,4-triazolyl group which is optionally substituted or (5) And a tetrazolyl group which is substituted as required. 5. The compound of claim 1, wherein R3 is a thiazolyl group which is optionally substituted. 6. The compound of claim 1 wherein R3 is The 1,2,3-triazolyl group is optionally substituted. 7. The compound of claim 1, wherein R5 is 4-cyanophenyl, 3-cyanophenyl, 4-cyano_ 3-(Trifluoromethyl)phenyl, 4-cyano-Imethylphenyl or 3-chloro-4-cyanophenyl. 8. A compound or a salt thereof (·) 4 -(2,5-dimethyl+{[3-(trifluoromethyl)qH-nbiazole-5-yl]曱丨-出-吼咯^基) 266 319299 200813007 benzonitrile, (ii) 3_(4-cyanophenyl)-5-methyl·1_{[3-(trifluoromethyl)-1Η-η ratio Zyrid-5-yl]methyl} -1Η - 0 洛洛_ 2 - Acha, (iii) 5-{[3-(4-cyanophenyl)-5-ethyl-2-methyl-111 - fluoren-1-yl] fluorenyl}-1 Η-pyrazole-3-indolecarbonitrile, (iv) 4-[2-mercapto-1-(1Η-1,2,3-triazole-5-yl)曱5)(5-(trifluoromethyl)-1Η. 嘻-3 -yl]benzoquinone, 〇) 2-{[3-cyano-4-(4-cyanophenyl)-2,5 -Dimethyl-1Η-吼-r--1-yl, hydrazinyl 1,3-thiazole-4-indrene, (vi) 4-(4-cyanophenyl)_2,5-dimethyl- 1-{[4-(Trifluoromethyl)-1,3-thiazol-2-yl]indolyl 1H_pyrrole-3-carbonitrile, (vii) 2-{[3-cyano-4-(( 4-cyanophenyl)-2,5-dimethyl-1H-portpyr-1-yl]fluorenyl}-1,3-oxazol-4-indrene, (viii) 4-(4- Cyanophenyl)-1-(imidazole [l,2-appyridin-5-ylfluorenyl)-2,5-dimethyl-111-fluorenyl-3-carbonitrile or (ix) 4-(1 -{[3-(1-hydroxy_1_mercaptoethyl)·1Η-.Bizozol-4yl]曱./ .. base} 2,5-dimethyl-1Η-dehydrazo-3 Base) Benzene bet. 9. A prodrug of a compound as claimed in claim 1. 10. A drug containing a compound of the formula (I) or a salt thereof or a prodrug thereof: ρ.1 267 319299 200813007 wherein 'R1 represents (1) a hydrogen atom, (2) a cyano group, (3) a C!-6 alkyl group optionally halogenated or (4) a Cw alkoxycarbonyl group optionally substituted; R2 R4 is the same or different and represents (1) a hydrogen atom, (2) a q 6 alkyl group, (3) a C3-6 cycloalkyl group, (4) a trimethyl group, and (5) an amine group-Cu. a (6) mono- or di-substituted amino-C!-6 alkyl group, (7) optionally halogenated Cu alkyl group, which is substituted with a hydroxy group optionally substituted, (8) c2 6 alkenyl group , which is substituted by a hydroxyl group which is optionally substituted, (9) C!_6 alkyl group, which is substituted by an oxidized thiol as needed, if necessary, (1 〇) gas group, (11) fluorenyl group, 12) A substituted oxazolyl or (13) ι,3-dioxopenta-2-yl group; R3 represents (1) a substituted thiazolyl group, (2) optionally substituted. More than a thiol group, (3) a thiol group which is optionally substituted, (4) an imidazole [l,2-a]pyridyl group which is optionally substituted, (5) an ι, 2,3-three which may be substituted as needed Azolyl, (6) substituted 1,2,4-triazolyl or (7) optionally substituted tetrazole And R represent a phenyl group having a cyano group at the 4 or 3 position and may be further substituted, except for 4-(4-cyanophenyl)-1-((4-cyano-1,3-thiazole) _2_yl)methyl)-2,5-dimercapto-1H- ° than 嘻-3 - oleic acid ester, 4-(4-cyanophenyl)_2,5-dimercaptotriphenylhydrazine Base-m_l,2,3-triazole_4_yl)methyl-1H_pyrrole-3-carbonitrile and 4_(4-cyanophenyl)_2,5-dimethyl small (1H-1,2 , 3_Triazol-4-ylmethyl)-1Η-pyrrole_3-carbonitrile. U. The drug of claim 10, which is a male hormone receptor antagonist. 12. The medicament according to claim 11, wherein the androgen receptor 319299 268 200813007 is a normal androgen receptor or a mutant androgen receptor. 13. A medicament according to the first aspect of the patent scope, which is a preventive or therapeutic agent for a hormone-sensitive cancer which is in the male-dependent P white slave and/or non-dependent stage. /, shows ' 14. as claimed in the patent scope f 1〇, which is a therapeutic agent for prostate cancer. A method for antagonizing an androgen receptor, which comprises administering a compound of the formula (1) or a salt thereof or a prodrug thereof to a mammal: Wherein R1 represents (1) a hydrogen atom, (2) a cyano group, (3) a Ci_6 alkyl group which is optionally halogenated or (4) an optionally substituted c!_6 alkoxy-carbonyl group; R is the same as R4 Or different, and respectively represent (1) a hydrogen atom, (2) ^ 6 alkyl group, (3) C3_6 cycloalkyl group, (4) trifluoromethyl group, (5) amine group. 16 alkyl, (6) mono- or di-substituted amino-Cw alkyl, (7) optionally halogenated c 6 · 6 alkyl ' which is substituted by a base which is optionally substituted, (g) c26 a dilute group, which is substituted by a trans group which is optionally substituted, a (9) c! 6 alkyl group which is optionally substituted with an oxidized thiol as desired, (10) oxy, (11) Base, (12) 喔 喔 或 或 or (I]) 〗 〖, 一 氧 五 -2- -2- -2- , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Substituting 319299 269 200813007 Pyrazolyl, (3) oxazolyl, optionally substituted, (4) imidazole [l,2-a]pyridyl optionally substituted, (5) optionally substituted i, 2,3_triazolyl, (6) as desired, substituted iota, 2,4-triazolyl or (7) optionally substituted tetrastone; and R5 represents phenyl, which is in the 4 or 3 position Has a cyano group and can be further substituted; except for 4-(4-cyanophenylcyano q, thiathiazole-2-yl)methyl)_2,5-dimethyl-iH_pyrrole , 4_(4-cyanophenyl)-2,5-dimethyl-1_((1_trityl-1H-1,2,3-triazole_4_yl) ) methyl-lH-u ratio slightly-3·carbonitrile and 4_('cyanophenyl>2,5-dimethyl-1-(111-1,2,3_triazole-4_yl group) a pyridyl-3-carbonitrile. 16. A method for preventing or treating a hormone-sensitive cancer in a male-dependent phase and/or a non-dependent phase, which comprises administering an effective amount to a mammal (I a compound or a salt thereof or a prodrug thereof: R3 wherein R1 represents (1) a hydrogen atom, (2) a cyano group, (3) an alkyl group which may be optionally converted, or (4) a C1-6 alkoxycarbonyl group which may be optionally substituted; R and R are The same or different, and respectively represent (1) a hydrogen atom, I) &lt;^6裱 alkyl, (4) trifluoromethyl, (5) amine-c beauty, mouth ^6 % soil early or two Substituted amino-Cw alkyl, (7) optionally substituted by CZ alkyl 319299 270 200813007, which is substituted by a hydroxy group optionally substituted, (8) c26, which is optionally substituted Substituted, (9) C1-6 leukoxyl, which is substituted by an oxidized thiol as needed, (10) cyano, (11) fluorenyl, (12) optionally substituted oxazole Or (13) 1, dioxopenta-2-yl; R3 represents (1) optionally substituted thiazolyl, (2) optionally substituted pyrazolyl, (3) optionally substituted Oxazolyl, (4) imi-substituted [1,2-a] fluorenyl, (5) as needed, substituted, ι, 2, 3 _ trisyl, (6) as needed Substituting 1,2,4-triazolyl or (7) optionally substituted tetradecyl; and R5 a group having a cyano group at the 4 or 3 position and which may be further substituted; except for 4-(4-cyanophenyl)-1-((4-cyano-; i, 3-thiazole!) fluorenyl -2,5-dimercapto-111-pyridin-3-carboxylic acid, 4-(4-cyanophenyl)-2,5-dimethyltriphenylmethyl _11^1,2, 3_Triazol-4·yl)methyl-1H-pyrrole-3-carbonitrile and 4-(4-cyanophenyl)-2,5-diindenyl_1_(1Η&gt;1,2,3- $ Triazol-4-ylmethyl)_1Η·pyrrole-3-carbonitrile. 17. A method for preventing or treating prostate cancer comprising administering to a mammal an effective amount of a compound of the formula (I) or a salt thereof or a prodrug thereof: 271 319299 200813007 wherein R1 represents (1) a hydrogen atom, (2) a cyano group, (3) a Cw alkyl group optionally halogenated or (4) a CN6 alkoxy-carbonyl group optionally substituted; R2 and R4 are The same or different and respectively represent (1) a hydrogen atom, (2) a Cle6 alkyl group, (3) a C3_6 cycloalkyl group, (4) a trifluoromethyl group, (5) an amine group - a C1-6 alkyl group, (6) a single or a second Substituted amine-C -6 alkyl, (7) optionally substituted Cu alkyl, which is optionally substituted by a substituted hydroxy group, (8) c2_6 alkenyl, which is optionally substituted a hydroxy-substituted, (9) C1-6 alkyl group, which is substituted by an oxidized thiol as needed, optionally substituted, (1) an aryl group, (11) fluorenyl group, (12) an optionally substituted Azolyl or (13) ι,3-dioxapenta-but-2-yl; R3 represents (1) a substituted thiazolyl group as desired, (2) a pyrazol group optionally substituted, and (3) as needed Substituted oxazolyl, (4) imidazole [l,2-a]pyridyl optionally substituted, (5) optionally substituted anthracene, 2,3-triazolyl, (6) as needed Substituted 1,2,4-triazolyl or (7) tetrasubstituted as desired; R 5 represents a phenyl group which has a cyano group at the 4 or 3 position and can be further substituted; and, except for the exclusion of 4-(4-cyanophenyl H-((4-cyano-u-thiazole-2-yl) ) mercapto)-2,5-dimethyl "pyrrole"|methyl carboxylate, 4_(4-cyanophenyl)-2,5-dimethyl]-((1_triphenylfluorene) Fantasy-triazole methyl-1H-tonole-3-3 carbonitrile and guanidinium cyanophenyldiphenylmethyl-1-(1H_1,2,3-triazole-4-phenylsulfonylcarbonitrile). Soil 18, the use of a compound of the formula (1) or a salt thereof or a prodrug thereof for the manufacture of a male receptor antagonist: 319299 272 200813007 And 2 in R3 f represents (1) a halogen atom, (2) a cyano group, (7) a C^6 alkane which is required to be dentate or (4) a cw alkoxy group-carbonyl group which is optionally substituted; R2 and R4 are the same or different and each represents (1) a hydrogen atom, (7) C "alkyl group, (3) C3_6 ke group, (4) tridecyl group, (7) amine group -6 group, (6) mono or di substituted Amino-Ci 6 alkyl, (7) optionally a C4 alkyl group substituted with a hydroxy group optionally substituted, an alkenyl group substituted with a hydroxy group optionally substituted, (9) a Cw alkyl group, Substituted and optionally oxidized thiol substituted, (10) cyano, (11) fluorenyl, (12) optionally substituted oxazolyl or (13) 1,3-dioxopentane -2-yl; R represents (1) a thiazolyl group which is optionally substituted, (2) a carbazolyl group which is optionally substituted, (3) an oxazolyl group which is optionally substituted, and (4) an imidazole which is optionally substituted [l, 2-a]pyridyl, (5) optionally substituted iota, 2,3-triazolyl, (6) optionally substituted i, 2,4-trisal or (7) optionally substituted a phenyl group, which has a phenyl group which has a cyano group at the 4 or 3 position and which may be further substituted; except for 4-(4-cyanophenyl)-1-((4-cyano-1), 3-thiazole_2-yl)indolyl)_2,5-dimethyl-1H-port ratios -3 -s-acid oxime esters, 4-(4-cyanobenzene 273 319299 200813007 u, 2,3-Tris-7-yl) A small (1H_12 /indene nitrile and 4·(4·glyphenyl)·2,5·dimethyl 19. A methyl group as in formula (1) • I. The use of a compound or a salt thereof or a prodrug thereof for the manufacture of a pre-wide 1: 'dioxin-dependent phase and/or a non-dependent hormone-sensitive cancer agent: \r3 R2 wherein 'R' is not (1) a hydrogen atom, (2) a cyano group, (3) a Cw alkyl group optionally halogenated or (4) a Ci6 alkoxy group-carbonyl group optionally substituted; R2 and R4 are the same or different And respectively represent (1) a hydrogen atom, (2) a Ci6 alkyl group, (3) a CV6 cycloalkyl group, (4) a trifluoromethyl group, (5) an amine group &lt;16 alkane, a group, (6) a single or a substituted amino-Ci-6 alkyl group, (7) a halogenated Cu alkyl group which is optionally substituted with a transsubstituted, (8) c2 6 alkenyl group, which is optionally substituted a hydroxy-substituted, (9) c1-6 leukoxyl group which is substituted by an oxidized thiol as needed, (10) a cyano group, a (11) fluorenyl group, and (12) an oxime which is optionally substituted An oxazolyl or a dioxapentane-2 group; R3 represents (1) a substituted thiazolyl group, (2) a pyrazol group optionally substituted, (3) an optionally substituted oxazolyl group, (4) If necessary, replace the mouth of the rice σ sit [1,2 - a] ° ratio σ base, (5) as needed to replace 1, 2 3 - three 0 sit 319299 274 200813007 base, (6) as needed Substituted, 2,4-triazolyl or (7) substituted as needed Azolyl; and R5 represents phenyl which has a cyano group at the 4 or 3 position and can be further substituted; except 4-(4-cyanophenylindole-((4-cyano-1,3-thiazole)- 2-yl)methyl)-2,5-dimethyl-1Η_pyrrole_3_carboxylic acid methyl ester, 4-gas 4-cyanophenyl)-2,5-dimethyl 4-((1- Trityl-1Η-1,2,3-triazol-4-yl)indolyl-1Η-pyrrole-3-carbonitrile and 4_(4-cyanophenyl)_2,5-dimethyl_1_ (1Η-1,2,3-triazole_4_ylmethyl)·1Η_pyrrole_3_carbonitrile. 20. A compound of the formula (1) or a salt thereof or a prodrug thereof for prevention of production Or the use of a medicament for treating prostate cancer: R\R1 4 /, medium, R represents (1) a hydrogen atom, (2) a cyano group, (3) a Ci-6 alkyl group which is halogenated as needed, or (4) as needed Substituted Ci_6 alkoxy-carbonyl; R2 and R4 are the same or different and represent (1) a hydrogen atom, (2) a Ci 6 alkyl group, a (3) Cl6 alkyl group, and (4) a trifluoromethyl group, respectively. Aminoalkyl, (6) mono- or di-substituted amino-Cw alkyl, (7) optionally halogenated Cw alkyl, substituted by optionally substituted hydroxy, (8) Cw alkenyl Substituted by as needed Generation, (9) ◦ i 6 burned by the need to be replaced as needed and oxidized thiol as needed) cyanide 319299 275 200813007 base, (1 1) brewing base, (12) is considered to be replaced by evil Oxazolyl or), 3_dioxapenta-2-yl-2-; R is not (1) depending on the acoustic substitution, (2) as needed, pyrazol, (3) as needed Oxazolyl, (i.e., imidazole [l,2-a]pyridyl, (5) optionally substituted anthracene substituent, (6) substituted 1,2,4-triazole as needed Or (7) as needed; &lt; azole tetracycline, · ·, face substitution R5 represents phenyl, which has a cyano group at the 4 or 3 position and can be substituted; ~ 赉缒坻 only exclude 4- (4-cyanide Phenyl)-1-((4-cyano-i,3-thiasole,yl)-2,5-dimethyl-ih-pyrrole-3-carboxylic acid methyl ester, 4&lt;4, base) Methyl: Dimercaptotriphenyl fluorenyl _111-1, 2, 3 _ three noisy I vegetable -1H-pyrrole _3-carbonitrile and 4-(4-cyanophenyl)^5 moxibustion) +(111-1,2,3-trimethyl-4-methylmethylcarbonitrile. A | 3l9299 276 200813007 VII. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4 319299