TW201114741A - Substituted pyrrolidine derivatives and use thereof - Google Patents

Abstract

Provision of a novel pyrrolidine derivative and a medicament containing the derivative. A compound represented by the formula (I) wherein R1 is cyanophenyl optionally having substituent (s); R2 is (1) a hydrogen atom or (2) C1-6 alkyl; R3 is a hydrogen atom; R4 is (1) an aromatic ring group optionally having substituent (s), (2) -NRa-X-(CH2)n-Y-Rb wherein Ra is (1') a hydrogen atom or (2') C1-6 alkyl; X is (1') a bond, (2') -CO-, (3') -CONH- or (4') -SO2-; n is an integer of 0 to 3; Y is (1') a bond, (2') -O-, (3') -NH-, (4') -NHCO-, (5') -NHSO2- or (6') -CH=CH-; Rb is a cyclic group optionally having substituent (s); or (3) -O-Z-Rc wherein Z is (1') a bond, (2') -CH2- or (3') -CONH-; Rc is a cyclic group optionally having substituent (s); R5 is (1) a hydrogen atom, (2) hydroxy or (3) C1-6 alkoxy optionally having substituent (s); R6 is (1) a hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom; R7 is (1) a hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom; R8 is (1) a hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom; and R9 is (1) a hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom; excluding 18 compounds, or a prodrug thereof.

Description

201114741 VI. Description of the Invention: [Technical Field] The present invention relates to novel pyrrolidine derivatives and androgen receptor antagonists containing the same, and in particular, the present invention relates to androgen-dependent diseases A novel pyrrolidine derivative having a prophylactic/therapeutic effect, the effect of which is derived from the inhibition of the androgen (male hormone) receptor (AR), and exhibits androgen receptor antagonism which is not affected by mutation or the like, and includes the derivative Androgen receptor antagonist. φ [Prior Art] Patent References 1 to 4 of the present applicant disclose substituted pyrrolidine derivatives having male hormone receptor accommodation. Further, Patent Documents 5 to 10 and Non-Patent Documents 1 to 3 describe substituted pyrrolidine derivatives similar to the compounds described in the present specification. [Prior Technical Documents] [Patent Documents] Patent Document 1: US-A-2006/0106067 • Patent Document 2: WOWO2007/015567 Patent Document 3: PCT/JP07/073057 Patent Document 4: JP Application No. 2007-299658 Document 5: W020G6/044454 Patent Document 6: W02005/115975 Patent Document 7: W020G2/092093 Patent Document 8: US Patent No. US 6,376,472 Patent Document 9: W098/57638 6 321538 201114741 Patent Document 10: WO2006/123725 [ Non-Patent Document] Non-Patent Document 1: J. 〇rg. Chem. 2007, 72, 2030-2039 Non-Patent Document 2: Bioorg. Med. Chem. 11 (2003) 145-157 Non-Patent Document 3: J. Med. Chem. 1972, 15(8), 827-836 SUMMARY OF THE INVENTION The main object of the present invention is to provide a novel n-rhoquinone derivative exhibiting superior androgen receptor antagonism. The present inventors have conducted studies on various pyridoxine derivatives having androgen receptor antagonism and found that the novel pyrrolidine derivatives described below unexpectedly exhibit excellent androgen receptor antagonism, excellent pharmacokinetics, etc., or Reduced toxicity leads to the completion of the present invention. Accordingly, the present invention provides a compound represented by the formula (I) (hereinafter sometimes abbreviated as the compound (I) or a salt thereof

Wherein R1 is a cyanophenyl group optionally having a substituent; R2 is a (1) hydrogen atom or an OCw alkyl group; R3 is a hydrogen atom; R4 is 7 321538 201114741 (1) An aromatic ring group having a substituent, if necessary, (2) -NRa-X-(CH2)n-γ-Rb, wherein RKl') hydrogen atom or (2,)Cl_6 alkyl group; X is (1) bond, (2')-C0 one, ( 3, )_c〇NH_ or (4, )_s〇2_ . η is an integer from 0 to 3; , (3')-NH-, (4')-NHC0-, (5,) Υ is (Γ) Bond, (2, -NHS〇2- or (6')-CH=CH-

R is a ring group having a substituent as needed; or (3) -〇-Z-Rc, wherein, (Γ) bond, (2,)_CH2— or (3,)_c〇nh1; R is a view A ring group having a substituent; 2(1) a hydrogen atom, (2) a hetero or an alkyl group of a (3) reversible substituent; (1) a hydrogen atom, (2) a picture atom, (3) a group via a carbon atom, (^ a group derived from a ^ group) (5) a group via an oxygen atom or (6) a group via a sulfur; y is (1) a hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, a group of (a group, (5) a group via an oxygen atom, or (8) a group of:;:: (10) atom, (2) a tooth atom, (3) a group via a carbon atom, a money of 2, a group of (5) (tetra) oxy or (6) a group via a sulfonium; and a hydrogen atom; (2) "Sub, (3) a group via a carbon atom, (4 nitrogen, a group of a sub, a group of (5) via an oxygen atom or (6) via a sulphate 321538 8 201114741; except the following 18 compounds are excluded:

[s] 9 321538. The compound of the above [1], wherein R4 is optionally an aromatic ring group having a substituent, or a ring group having a substituent as required or Re is a phenyl group, a ratio σ Fixed base, 吼α sitting base,. Rice beta, naphthyl, ° plug. Sitrate, oxime-sigma, isoindolyl, sulfhydryl, benzothiazolyl, benzimidazolyl, acridinyl, thienyl, piperidinyl or morpholinyl, each having a substituent; [3] The compound of the above [1], which is a compound represented by the formula (la) (hereinafter sometimes abbreviated as a compound (I a))

(ia)

In the formula, the ring 3 is a benzene ring further having a substituent as needed; the ring Ba is an aromatic hydrocarbon ring optionally having a substituent, an aromatic hetero ring optionally having a substituent, or a non-aromatic ring optionally having a substituent ;

-N(CH3)---N(CH3)CH2---N(CH3)C0---N(CH3)S〇2---0CH2- or -0C0NH-; R2a is a hydrogen source or a Cw alkane 10; 321538 201114741 R is a hydrogen atom, a hydroxyl group or a Cl_e alkoxy group; 2 L is a bond, and the ring is an aromatic ring having a substituent as desired or an aromatic hetero ring having a substituent in the south; :] The compound of the above-mentioned [3] wherein the ring Aa is a benzene ring which further has a substituent of a halogen atom and a substituent of an alkoxy group as needed; [3] a compound in which ring β3 is a benzene ring, a #biting ring

Wow wah ring, naphthalene ring, ° plug ring, ring, hetero ring, ° bow, ring, benzo (tetra) ring, benzo W ring, cough, 2, 3-dihydrobenzopyrene ring And (4) a ring or a light ring, each having a substituent as required; [6] The compound of the above [3], wherein the ring further has a Ci 6 group selected from a halogen atom, optionally having a _ atom, and C] the phenyl ring of the substituent of the oxy group, and the soil f Ba is the benzene ring " than the e ring " than the salivary ring, the taste ring, the naphthalene ring, the sputum ring, 噚. Ring, isoindole, ten rings, benzopyrene, benzo-salt ring, _cough%, 2' 3-dihydrobenzopyrene ring, clever. a ring or an oxime ring, which has a substituent; and [7] a compound of the above [1], which is a compound represented by the formula (Ib) (hereinafter referred to as a compound (lb)

11 321538 [S] 201114741 Formula t, the soil Ab is a benzene ring having a substituent selected from a tooth atom and optionally a Cl-6 alkyl group having a tooth atom as needed; the ring β is further substituted as necessary定n ring;

Lb is a bond or -NHC0-; R is (1) an amine carbenyl group having a substituent selected from a Ci6 alkyl group and a cycloalkyl group optionally having a hydroxyl group, (2) a cyano group, and (3) A pyrrolidinyl group having a pendant oxy group or (4) an oxadiazolyl group having a Cm alkyl group as required; _R2b is a Ch alkyl group; and R5b is a hydrogen atom or a via group); [8] a compound in which (1) is a bond, a ring ore is a pyridine ring, a monoalkylamine, a (b) a mono G-6 cycloalkylamine, a (c) cyano group, ((1) a pyrrolidinyl group having a pendant oxy group as desired or (e) an oxadiazolyl group having a Ch alkyl group as required; or a ruthenium (2) L being a ~NHC0-, a ring furnace having a 2-pyridine ring, 1^ (&) optionally having a light-based Cm alkyl group or (b) optionally having a c!-6 alkyl group; [9] 5 [(2S,3R)-l-(3-chloro- 4-like phenyl)-3_yl-2-methylindole, each of which is -3-yl]·~Ν-cyclopropylpyridine-2-decylamine, or a salt thereof; [10] 5 [ (2S,3R)~1-(3-Chloro-4-cyanophenyl)-3-yl-2-methylindole-3-yl]-n-(i-methylethyl)pyridine -2-carboxamide, or a salt thereof; [11] 5-{(2S,3R)-1-[4-cyano-3-(three Methyl)phenyl]-3-hydroxy-2-methyl η 洛 _ _ _ _ _ _ _ _ _ _ _ _ _ η η 曱醯 曱醯 曱醯 曱醯 、 、 、 、 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] -l-(4-cyano-3-fluorophenyl)-3-hydroxy-2-methyl 321538 12 201114741 pyrrolidin-3-yl]-N-decylpyridin-2-carboxamide, or a salt thereof ; [13] 2-Gas-4-{(2S,3R)-3-yl) | Methyl_3_[6_(2_ side-oxyl oxime Turn to 唆]-based} Benzene gambling, or its salt [14] 5-[(2S,3RH-U-cyanophenyl)-3_-yl- 2-methylpyrene-bito-3-yl ] 吼 ° -2- carbonitrile, or a salt thereof; [(5) 2-fluoro-4-K2S, 3R) _ 3-trans group + methyl _ 3 Lu (5-methyl salt; Π 6] Ke 2S, 3S) + (3_Chloro-Cyanophenyl)|Methyl-based biting base ^Met's methyl propyl group ^Beat ^Jimamine BCj £ · , salt, [17] N-[(2S'3S )-l-(3-gas + cyanophenyl) _2 base material bite _3_ yl] + (5-methyl), 3'4, diazole-2-yl) pyridine * formamide, or a salt thereof [18] The prodrug of the compound of the above [1]; [19] The agent comprising the compound of the above (1), or a salt thereof or a prodrug thereof, wherein the agent of the above [19] is an androgen receptor antagonist Agent; 'androgen receptor is positive a hormonal and/or canine-type androgen receptor; a drug of W [19] which is in an androgen-dependent phase and/or a pharmaceutical agent; a prophylactic or therapeutic agent for cancer resistant to hormones; 4] The agent 'prophylactic or therapeutic drug for prostate cancer 321538 13 201114741 [24] A method for antagonizing androgen receptor, comprising administering an effective amount of the above compound or a salt thereof or a prodrug thereof to a mammal; A method for preventing or treating a hormone-sensitive cancer in a male hormone-dependent phase and/or an androgen-independent phase, comprising administering an effective amount of the compound of the above [1] or a salt thereof or a prodrug thereof to A method for preventing or treating prostate cancer, comprising administering an effective amount of the compound of the above [1] or a salt thereof or a prodrug thereof to a mammal; [27] a compound of the above [1] or a salt thereof Or a prodrug thereof for use in the manufacture of an androgen receptor antagonist; (8) the use of the compound of the above (1) or a salt thereof or a prodrug thereof for use in an androgen-dependent phase and/or Or prevention in the androgen-independent phase or An agent for treating a cancer susceptible to cancer; and a use of a compound of the case <1^1] or a salt thereof or a prodrug thereof for use in the prevention or treatment of prostate cancer by Ik. F-formation compound (I) or its salt right-handed tb

"Halogen atom" means a fluorine atom, a gas atom, 321538 14 201114741 or a moth atom. In the present specification, examples of the "group passing through an atom" include (1) a cyano group, (2) an alkyl group (Ch alkyl group) having a substituent as necessary, and (3) an alkenyl group having a substituent as necessary. (C2-6 alkenyl), (4) an alkynyl group having a substituent (C2-6 alkynyl group), (5) a cycloalkyl group having a substituent (C3-8 cycloalkyl group), (6) If necessary, a cycloalkenyl group having a substituent (C3-8 cycloalkenyl group), ^ (7) an optionally substituted aryl group (Ce-ioaryl group), (8) anthracenyl group, (9) as needed A heterocyclic group having a substituent (which has a bond at a carbon atom) or the like. Examples of the "Ci-6 alkyl group" of the above "Cm alkyl group having a substituent optionally" include an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, and a third group. Butyl, pentyl, hexyl and the like.的 Examples of the "substituent" of the above-mentioned "Ci-6 alkyl group having a substituent as necessary" include a substituent selected from the following substituent group A. The number of the substituent is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3. Substituent group A: a group of substituents consisting of (1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.); (2) a cyano group; (3) a nitro group; ) hydroxy; [s] 15 321538 201114741 (5) A C38 cycloalkyl group having an atom (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.) as required; (8) ^See Ce-丨° aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.) having 1 to 3 substituents of a selected (iv) atom and a cyano group; a hydrazine selected from a halogen atom, a C6_1Q aryl group (for example, a phenyl group), an n-methyl^-(2-pyrylene)amino group, and a 2-quinolyl group to three substituents

Cl_6 alkoxy (eg, decyloxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.); earthy (8) 1 to 3 as needed C26 ethoxyl group of a halogen atom (for example: ethyleneoxy, propyleneoxy, butenyloxy, pentenyloxy, hexenyloxy, etc.); (8) C2_6 alkyne having J to 3 atom as needed a group (e.g., an epoxy group, a propynyloxy group, a butynyloxy group, a pentynyloxy group, a hexynyloxy group, etc.); (10) a Cw cycloalkyl group having 1 to 3 halogen atoms as needed —oxy (e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.); ^ • (11) C 3 8 cycloalkenes having 1 to 3 halogen atoms as needed An oxy group (for example: cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, etc.); (12) an aryloxy group having up to 3 deuterium atoms as needed (for example, Phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc.); (13) G_8 cycloalkylalkoxy having up to 3 halogen atoms, if desired (for example: cyclopropylmethoxy, cyclopropane Ethyloxy, cyclobutyloxy, pentylmethoxy, cyclohexyl Base methoxy, cyclohexyl ethoxy, etc.); < (14) Having it as needed! G_8 cycloalkenyl group to three halogen atoms _Ci e alkoxy group (for example, cyclopentenyl methoxy group, cyclohexenyl methoxy group, cyclohexenyl group) 16 [S3 321538 201114741 base, ring Hexylpropyloxy group, etc.; aryl-Cl-6 alkoxy group (15) optionally having 1 to 3 atoms per unit (for example: phenylmethoxy, phenylethoxy, etc.) (*16) C4 group-amine such as a group (e.g., methylamine sulfonyl group, ethylamine sulfhydryl group, propylamine sulfonyl group, etc.); (10) broad. Lithylene-amine yellow wine base (for example: dimethylamine sulphate, diethylamine sulfonyl, dipropylamine, etc.); (18) amine carbaryl; (19) amine thiol (10) 1 to 3, if desired, one of the following substituents, an alkyl-amino group (for example: methylamine, ethylamine, ethylamine, propylamine, isopropylamine) Anthracenyl, butylamine, butylamine, isobutylamine, tributylamine, etc.) (4) tooth atom (for example, fluorine atom, etc.), (6) meridine, (6) if necessary ! 2 minus C oxime (for example: methoxy 'ethoxy, etc.), (4) "calling aryl (eg phenyl, etc.), (6) optionally having 1 Ci 6 alkoxy-based (eg - a 5- or 6-membered aromatic heterocyclic group (for example, a furyl group, a carbazolyl group, an acridinyl group, etc.), (f) an amine carbenyl group, (g) a di- C!-6 alkylamino group (for example: dimethylamino group, etc.), (h) cyclic amine group (for example, morpholinyl group, etc.), (i) optionally having one hydroxyl group "6 cycloalkyl group (for example) : cyclopentyl hydrazine), (j) Ci-e alkylthio (for example, methylthio group, etc.), (k) Cn succinyl (for example, methyl sulphate, etc.) 1) a C16 alkyl group sulfhydryl group (e.g., fluorenylsulfonyl group, etc.), (m) a cl_6 alkyl group, an amine group (e.g., methyl group), and (n) a Ci-eoxy group. Cutting base (eg methoxy methoxy, 321538 17 201114741 ethoxycarbonyl, etc.); (21) C3-6 cycloalkyl-amine sulfhydryl (eg cyclopropylamine sulfhydryl, cyclopentylamine) (2) A di-Cm alkane having one (:1-6 alkoxy group (for example, an anthraceneoxy group, etc.) as needed Amino-amino group (for example: dimethylaminocarbamyl, diethylaminoindenyl, N-ethyl-N-decylamine fluorenyl, etc.); (23) 1 Ch as needed a C6-1D aryl-amine-methyl fluorenyl group (for example, a decylamino group, etc.) of an alkyl group (for example, a fluorenyl group, etc.); (24) (having one selected from (a) a cyano group, if necessary, And (b) a 5- or 6-membered heterocyclic ring having 1 to 3 halogen atoms (for example, a fluorine atom) as needed (isoxazolyl, 嗔σ sitting group, °Sepi-β-based, dihydro-sehage , ° ratio. Base, 11 σ 坐 base)) - Aminomethyl, (25) Having a G-6 alkyl group selected from (a) a hydroxyl group, (b) optionally having one hydroxyl group (for example: Amidino, ethyl, etc.), (c) aminyl, (¢1): -0-6, a group of amine groups (for example, dinonylamino group, etc.), (6) pendant oxy group, and (f) a cyclic amine sulfhydryl group having 1 or 2 substituents of a C6-10 φ aryl group (for example, a phenyl group, etc.) (for example, azacyclobutylcarbonyl group, N-pyrrolidinylcarbonyl group, N-morpholinylcarbonyl group, N-thiolanyl quinolyl, fluorenyl, etc., (26) di-Ch alkyl-amine thiol (eg dimethylamine hydrazine) (2) a methyl fluorenyl group; (27) a hydrazino group or a benzyl group (eg, an ethyl group, an ethyl group, a propyl group); (29) C2-6 alkenyl-carbonyl (eg, vinylcarbonyl, propylenecarbonyl, butyl [s] 18 321538 201114741 alkenylcarbonyl, pentenylcarbonyl, hexenyl (30) C2-6 alkynyl-carbonyl (for example: ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl, etc.); (31) C3-8 ring Alkyl-carbonyl (for example: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); (32) C3-8 cycloalkenyl-carbonyl (for example: cyclopropenylcarbonyl, cyclobutene) a carbonyl group, a cyclopentenylcarbonyl group, a cyclohexenylcarbonyl group, or the like; (33) a C6-1D aryl-carbonyl group (for example, a benzoinyl group, a 1-naphthylcarbonyl group, a 2-naphthylcarbonyl group, etc.); (34) C3-8 cycloalkyl-G-6 alkyl-carbonyl (for example: cyclopropylcarbonylcarbonyl, cyclopropylethylcarbonyl, cyclobutylmethylcarbonyl, cyclopentylmethylcarbonyl, cyclohexylmethyl) Carbonyl, cyclohexylethylcarbonyl (35) C3-8 cycloalkenyl-Ch alkyl-carbonyl (for example: cyclopentenylmethylcarbonyl, cyclohexenylcarbonylcarbonyl, cyclohexenylethylcarbonyl, cyclohexenylpropane羰 (36) C6-1Q aryl-Ch alkyl-carbonyl (eg benzylcarbonyl, phenyl acetaminophen Rebellion J, (37) 5 or 6 membered monocyclic aromatic heterocyclic group a carbonyl group (e.g., a furylcarbonyl group, a thiophenecarbonyl group, a fluorenylcarbonyl group, a carbazolylcarbonyl group, an isoxazolylcarbonyl group, a thiazolylcarbonyl group, an isothiazolylcarbonyl group, an imidazolylcarbonyl group, a pyridylcarbonyl group, . (3) 8 to 12 member condensed aromatic heterocyclic group-carbonyl group (for example, benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothiophenylcarbonyl, Mercaptocarbonyl, isodecylcarbonyl, 1H-carbazolylcarbonyl, benzene [s] 19 321538 201114741 and imidazolylcarbonyl, benzoxanthylcarbonyl, etc.; (39) 5 or 6 member non-aromatic heterocyclic ring Alkyl-carbonyl (for example: oxacyclopropylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl, thiaheptylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, thicyclopropyl a carbonyl group, a piperidinylcarbonyl group, a morpholinylcarbonyl group, etc.; (40) a Ci-6 burnt. a basestone yellow base (for example, a methyl stellite base, an ethyl stellite base, etc.), (41) C2-6 a dilute acid group (for example, an ethylene group, a propyl group, etc.); # (42) a C2-6 alkynylsulfonyl group (for example, an ethynylsulfonyl group, a propynylsulfonyl group) (43) C3-8 cycloalkylsulfonyl (for example: cyclopropylsulfonyl, cyclobutyl), butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl, etc. Sulfonyl group, etc.) (44) C3-8 cycloalkenyl group sulfo acyl (e.g.: sulfo acyl cyclopropenyl, cyclobutenyl stuffed sulfo group); (45) Cm. An arylsulfonic acid group (for example, phenylsulfonyl group, etc.); φ (46) C3-8 cycloalkyl-C!-6 alkyl-sulfonyl group (for example, cyclopropylsulfonylsulfonyl group, etc.) (47) C3-8 cycloalkenyl-C!-6 alkyl-sulfonyl (for example: cyclopentenylmethylsulfonyl, etc.); (48) C6-1D aryl-Cl-6 alkyl - Renewed base (for example: benzyl group, etc.), (49) 5 or 6 membered monocyclic aromatic heterocyclic-sulfonyl (for example: furylsulfonyl, π-sequenyl fluorenyl, '° (50) 8 to 12 members of the condensed aromatic heterocyclic-sulfonyl group (for example, benzofuranylsulfonyl, isobenzofuranylsulfonyl, etc.); ] 20 321538 201114741 (51) 5 or 6 beifangxiangzao--continuous base (for example: oxifenyl, azetidinylsulfonyl, etc.); (52) amine group; (53) Mono-Ci-6 alkylamino group (for example: mercaptoamine, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butyl Amino group, etc.; (54) Di-C!-6 alkylamino group (for example: dimethylamino, diethylamino, dipropylamino, diisopropylamino, two Amino group, diisobutylamino group, ♦ di-t-butylamino group, etc.; (55) Cm alkoxy-carbonylamino group (for example: second butoxycarbonylamino group, etc.); (56) a mono(Ch alkyl-carbonyl)amino group having 1 to 3 halogen atoms as needed (for example, an ethyl fluorenylamino group, an ethylcarbonylamino group, a propylcarbonylamino group, a tert-butylcarbonylamino group, etc.) (57) a mono(C3-8 cycloalkyl-carbonyl)amino group (for example, a cyclopropylcarbonylamino group, a cyclobutylcarbonylamino group, a cyclopentylcarbonylamino group, a cyclohexylcarbonylamino group, etc.); φ (58) A mono(C6-1D aryl-carbonyl)amine group having 1 to 3 halogen atoms as required (for example, benzhydrylamino group, etc.); (59) Single (5 or 6 membered monocyclic aromatic) Heterocyclyl-carbonyl)amino group (for example: furylcarbonylamino group, thienylcarbonylamino group, fluorenylcarbonylamino group, carbazolyl group 1k-amino group, iso-indolyl-carboxylamino group, Alkylamino, isodecylcarbonylamino, imidazolylcarbonylamino, pyridylcarbonylamino, „bazolylcarbonylamino, etc.; (60) Single (8 to 12 member condensed aromatic heterocyclic group) -carbonyl)amino group (for example: And furanylcarbonylamino, isobenzofuranylcarbonylamino, benzothienyl [s] 321538 21 201114741 carbonylamino, iso-p-thylthiocarbonyl, etc.); (10) single (5 or 6 members non-fragrance) (heterocyclyl-monoamino)aminoheteroyl, etc.) (62) sulfhydryl group = arylamino group, azetidinyl benzylamino oxetanyl Si (63) Ch alkylthio group (Example #: Methylthio, ethylthio, etc.; (64) C4 based thio (eg vinylthio, propylthio, etc.).

Alkynylthio (eg, ethynylthio, propynylthio, butynyl sulfenyl, pentynylthio, hexynylthio, etc.); (66) C3 8% alkylthio (eg : cyclopropylthio, cyclobutylthio, etc. =) c" ring thiol (for example: cyclopropyl thio, cyclobutylthio (68) Ce-io arylthio (eg benzene) (69) C3-8 cycloalkyl-Cl_6 alkyl-thio group (for example: cyclopropylmethylthio group, etc.); (70) C3-8 ring group _Cl_6 silk-sulfanyl group (e.g., cyclopentyl thiolthio group, etc.); (71) optionally having (a) a hydroxyl group, (... optionally having a halogen atom (e.g., a fluorine atom, etc.) and a meridine; to 3 Substituent CM stimuli (eg, decyl, ethyl, propyl, isopropyl, tert-butyl, etc.), (c) C36 cycloalkyl (eg cyclopentyl, etc.), (d) cyanide a group, (e) an amine carbenyl group, (f) c^ an alkyl-amine methyl sulfhydryl group (for example, methylamine carbaryl) and (g) a cyclic amine carbaryl group (for example, morpholinylcarbonyl) a 5- or 6-membered monocyclic aromatic heterocyclic group of one substituent (eg, furyl, thienyl, pyrrolyl, oxazolyl, Diazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl, 321538 22 201114741 triazolyl, etc.; (72) 8 to 12 member condensed aromatic heterocyclic group (eg: Benzofuranyl, isobenzohexanyl, benzo-11, phenanthrenyl, isobenzobenzophenanyl, 11 π phenyl, iso-B, 1,H-carbazolyl, benzimidazolyl , benzoxazolyl, etc.); (73) 5 or 6 membered non-aromatic heterocyclic groups having pendant oxy groups (eg, oxetanyl, azetidinyl, oxetanyl, sulfur) Heterocyclic butyl, pyridyl D-decyl, tetrahydrofuranyl, thioheteropropyl, phenyl, hydrazino, dihydro 0-pyridyl, etc.; • (74) 5 or 6 membered single ring Aromatic heterocyclic-oxyl (eg: furyloxy, thienyloxy, °ryloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy) , imidazolyloxy, π-pyridyloxy, «bisazolyloxy, pyrimidinyloxy, etc.;; (75) 8 to 12 membered condensed aromatic heterocyclic-oxy (eg benzofuranyloxy) Base, isobenzofuranyloxy, benzothiazide Alkoxy group, isobenzothiophenyloxy group, mercaptooxy group, isodecyloxy group, monoterpene-oxazolyloxy group, benzene φ-meridinooxy group, benzoindoleoxy group, etc. (76) 5 or 6 membered non-aromatic heterocyclic-oxy groups (eg, oxacyclopropyloxy, azetidinyloxy, oxetanyloxy, thioheterobutyloxy) a group, a phenoxy group, a tetrakilyloxy group, a thioheteropropyloxy group, a π-butoxy group, etc. (77) a pendant oxy group; (78) a Ci-6 alkyl sulfinic acid Sulfhydryl (eg, methylsulfinyl, ethylsulfinyl, etc.); (79) C2-6 alkenylsulfinyl (eg, vinylsulfinyl, propenyl [s] 23 321538 201114741 sulfonyl, etc.; (80) C2-6 alkynyl sulfinyl (eg ethynyl sulfinyl, propynyl sulfhydryl, butynyl sulfinyl, pentynyl) a sulfonyl group, a hexynyl group, a fluorenyl group, etc.; (81) a C3-8 cycloalkyl sulfinyl group (eg, a cyclopropylsulfinyl group, a cyclobutylsulfinyl group, etc.); C3-8 ring-thin sub-continuous thiol group (for example: cyclopropenyl sulfonyl, cyclobutenyl sulfhydryl, etc.) (83; Ce-io aryl arylene (eg, phenyl sulfhydryl, etc.); (84) C3-8 cycloalkyl-Cm alkyl-sulfinyl (eg, cyclopropyl fluorenyl) Sulfosyl, etc.; & (85) Ch cycloalkenyl-Cl_e alkyl-sulfinyl (for example: cyclopentenylmethylsulfinyl, etc.); 1 (86) Ch alkyl-amine a thiocarbonyl group (for example, a mercaptoaminothiocarbonyl group, an ethylaminothiocarbonyl group, a propylaminothiocarbonyl group, etc.); (87) a di-Ch alkyl-aminothiocarbonyl group (for example, two Methylaminothiocarbonyl, diethylaminothiocarbonyl, dipropylaminothiocarbonyl, etc.); (88) carboxyl group; (10)) Cm silk group_county (for example: methoxy group, ethoxy group, C Oxyl-based, isopropoxycarbonyl, oxy-, isobutoxy-based, tert-butoxycarbonyl, etc.; (90) C2-6, oxy-county (eg, ethyleneoxy , acryloxy group, butene A base, (iv) oxy-aryl, hexene oxide, etc.); (91) C2-6 blockoxy-yl group (for example: ethoxylated oxy group, Propyloxycarbonyl 321538 24 201114741 base, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl (92) C3-8 ring-based oxy-aryl (eg, cyclopropyloxy, butyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.) (93) C3-8 cycloalkenyloxy-carbonyl (for example: cyclopropenyloxycarbonyl, cyclobutoxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl, etc.); (94) C6 -i. An aryloxy-yl group (eg, phenoxy, 1-naphthyloxy, 2-naphthyloxycarbonyl, etc.); (95) G-8 cycloalkyl-Ch alkoxy-carbonyl (eg : cyclopropylmethoxycarbonyl#, cyclopropylethoxycarbonyl, cyclobutyloxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexylmethoxycarbonyl, cyclohexylethoxycarbonyl, etc.) (96) C3-8 cycloalkenyl-Ch alkoxy-carbonyl (for example: cyclopentenyl methoxycarbonyl, cyclohexenyl fluorenyloxycarbonyl, cyclohexenyl ethoxycarbonyl, cyclohexane) Base propyloxy prisoner, etc.); (97) C6-!. Aryl-G-6 alkoxy-carbonyl (e.g., phenyl fluorenyloxycarbonyl, phenylethoxycarbonyl, etc.); φ (98) optionally has two alkoxy groups (e.g., decyloxy, etc.) An aromatic heterocyclic group (e.g., tri-negative, etc.)-amino-aminocarbazinyl; (99) optionally having 1 or 2 selected from a Cw alkyl group (e.g., methyl group, etc.) and a pendant oxy group a substituent of a C2-3 alkyleneoxy group (for example, an ethoxy group, etc.), a (100) Ch alkylenedioxy group (for example, a methylenedioxy group, etc.); (101) having a side as needed a C2-4 alkylene group of an oxy group (for example, a triadenylene group, a tetramethylene group, or the like); (102) optionally having 1 or 2 selected from a C alkyl group (for example, a fluorenyl group) and a pendant oxy group. a C2-4 alkyleneoxy group of a substituent (for example, an exopropenyloxy group [si 25 321538 201114741, etc.); (10)) optionally having a (4) mercapto group, (6) a Cl-6 group (methyl group), and c: a cyclic amine group of 1 to 3 substituents of a pendant oxy group (indolyl group, morphinyl group); and (104) an amine sulfonyl group. The above-mentioned "Ch-alkenyl group having a substituent as required" Examples include vinyl, acryl, butyl, The "substituent = examples of the above-mentioned "Gw filaments having a substituent as necessary" include a substituent selected from the substituent group A. The number of substituents is not particularly limited as long as a specified number of substitutions The base may be substituted, but is preferably 1 to 5, more preferably 1 to 3. The number of the octa substituent is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably It is from 1 to 5, more preferably from 3 to 3. The above-mentioned examples of the C26 block having a substituent as required include an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexene group. The above-mentioned "as required to have a substituent of the filament": the example includes a substituent selected from the substituent group U. The substitution ^ is preferably from 1 to 5, more preferably from 1 to 3. The cycloalkylene f"?: subunit includes a cyclopropyl group, a cyclobutyl group, a cyclofilament, a cycloalkyl group, a cyclooctyl group, etc. m. Examples of the above-mentioned "optional having a substituent" Including (1) as needed (4) from the "sub and cyano group to take 3 generations of base to take 321538 26 201114741 generation of Cl-6 base (for example: thiol, B a group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, etc.), and (2) a substituent selected from the substituent group A (excluding the pendant oxy group). The number of substituents is not particularly The limitation is that a specified number of substituents may be substituted, but it is preferably from 1 to 5, more preferably from 1 to 3. The above-mentioned "C3-8 cycloalkenyl group having a substituent C3-8" Examples of the 8-cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, etc. The above "C3-8 ring having a substituent as necessary" Examples of the "substituent" of the alkenyl group include (1) a Cl-6 alkyl group having 1 to 3 substituents selected from a halogen atom and a cyano group as required (for example, anthracenyl group, ethyl group, propyl group, and iso group). A propyl group, a butyl group, an isobutyl group, a tert-butyl group, etc.), and (2) a substituent selected from the substituent group A (excluding the pendant oxy group). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3 Å. The above-mentioned "Ce-IG aryl group having a substituent as necessary" Examples of the "C6-10 aryl group" include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like. Examples of the "substituent" of the above-mentioned "Cho aryl group having a substituent" as required include (1) a Cl-6 ray group having 1 to 3 substituents selected from a halogen atom and a cyano group as needed (for example: A a group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, etc.), and (2) a substituent selected from the substituent group A (excluding the pendant oxy group). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3. [s] 27 321538 201114741 In the present specification, "mercapto" includes (1) a decyl group, (2) an alkyl-carbonyl group (匕-6 alkyl-carbonyl group) having a substituent as necessary, and (3) An alkenyl-carbonyl group having a substituent (C2-6 alkenyl-carbonyl group), (4) an alkynyl-carbonyl group having a substituent as desired (C2-6 alkynyl-carbonyl group), (5) optionally having a substituent Cycloalkyl-carbonyl (C3-8 cycloalkyl-carbonyl), (6) cycloalkenyl-carbonyl (C3-8 cycloalkenyl-carbonyl) optionally having a substituent, (7) optionally having a substituent Aryl-carbonyl (Cwo aryl-carbonyl), 0 (8) optionally heterocyclic-carbonyl group having a substituent, (9) carboxyl group, (10) alkoxy-carbonyl group optionally having a substituent (Ch) Alkoxy-carbonyl), (11) alkenyloxy-carbonyl (C2-6 alkenyloxy-carbonyl) optionally having a substituent, (12) alkynyloxy-carbonyl having a substituent as desired (C2-6) Alkynyloxy-carbonyl group), (13) cycloalkyloxy-carbonyl group having a substituent as desired (C3-8 cycloalkyloxy group), (14) cycloolefin having a substituent as needed Oxy-carbonyl (C3-8 cycloalkenyloxy-rebel), ( 15) a cycloalkynyloxy-carbonyl group having a substituent (C3-8 cycloalkynyloxy group), (16) an optionally substituted aryloxy-carbonyl group (Cm aryloxy-carbonyl group), [s] 28 321538 201114741 (17) A heterogeneous group having a substituent, oxy group, or (18) an amine group having a substituent, if necessary, and the like.

I = ", if necessary, a k-silk with a substituent, a group", and the oxime includes an ethyl group, an ethyl group, a propyl group, a isopropyl butyl group, an isobutyl carboxyl group, a butyl carbonyl group, and a silk. County, Ji Xuji and so on. ^

^ 克 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝 丝1 to 5, more preferably 1 to 3. The above-mentioned % of the C2-6 alkenyl-cutting group having a substituent includes acetylene, (4) ketone, butyl substrate, pentyl carbonyl, and Alkenylcarbonyl and the like. Examples of the "substituted soil" of the above-mentioned "substituent group having a substituent" include a substituent selected from the substituent group A. The number of the substituents is not particularly limited as long as the substituent of the silky wire is replaceable, it is preferably from 1 to 5, more preferably from 1 to 3. Examples of the "c26 alkynyl-carbonyl group" of the above-mentioned "Cm alkynyl-carbonyl group having a substituent" include ethynylcarbonyl group, propyne county, penicillin, and W-shirt. ^ Examples of the "substituent" of the above "C2-6 alkynyl-carbonyl group optionally having a substituent" include a substituent selected from the substituent group A. The number of substituents is not particularly (four)' as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3. 321538 29 201114741 Examples of the "c3 8 cycloalkyl-carbonyl group" of the above-mentioned "Cw cycloalkyl-carbonyl group having a substituent" include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, Cycloheptylcarbonyl, cyclooctylcarbonyl and the like. Examples of the "substituent" of the above-mentioned "Cw cycloalkyl group-carbonyl group having a substituent" include (1) a Cl_6 alkyl group having i to 3 substituents selected from the group consisting of a _ atom and a cyano group, for example (for example) : methyl, ethyl, propyl, isopropyl,

Butyl, isobutyl, tert-butyl, etc.), and (2) a substituent selected from the substituent group A (excluding the pendant oxy group). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3. ~ Examples of the "c"^-base-" of the above-mentioned "CM ring-based group having a substituent, a base" include cyclopropenyl, cyclocycline, cyclopentenyl, cyclohexenyl Carbonyl, cycloheptyl, cyclooctylcarbonyl, and the like. The above "take a base of a substituent - a carbonyl group as needed"

Examples of the _alkenyl group include (1) a Cw alkyl group having a U 3 substituent selected from a halogen atom and an aryl group, if necessary (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl) , a third butyl group, etc.), and (2) a substituent selected from the group A of the substituent group (excluding the pendant oxy group). The number of the substituents is not particularly limited as long as the specified number of substituents are achievable, but the health is from 5 to 5, more preferably from 1 to 3. "Examples of the "^. aryl group-singyl group" of the above-mentioned "aryl group, group" having a substituent include the phenyl ketone group, the naphthalene group, the 2-layer extract, and the like. The above-mentioned "area substitution" of the "aryl group" having a substituent [321538 30 201114741: Take::: sub-comprising (1) optionally having a halogen atom and a green (1): a substituent of a Cl_6 alkyl group ( For example, a substituent of a methyl group, an ethyl group, or a propyl group, a pendant oxy group. Substituent: The substituent group A, the number of the t group is not particularly limited, as long as the group is replaceable, But it is preferably 1 to 5,

Examples of the above-mentioned "heterocyclic group-subunit having a substituent as necessary" include (1) a 5- or 6-membered monocyclic aromatic heterocyclic ring (for example, a thiophene, a porphin: = each, _, a different (four), a material, a foreign material, M (m) homing), (2) 8 to 12 members of condensed aromatic heterocycles (eg · benzofuran, iso-, benzophenone, iso-benzopyrene, ah, iso-, 1H, Benzimidazole , benzoxazole, etc., -, L 3 temple '(3) 5 or 6 shell non-aromatic heterocycle (eg: hetero (tetra), _butane, oxetane, pyrrolidine' tetrapyran , thiazepine, brigade, etc.). Examples of the "substituent sense #" of the above-mentioned "heterocyclic group having a substituent" include (1) optionally having a substituent selected from a _ atom and a cyano group to a CH-based substituent of three earth substituents (for example: A Base, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.), and (2) a ground-removing group selected from the group of substituents A (excluding pendant oxy groups). The number of the groups is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 5 to more than 3. The above-mentioned "Ci-oxyl group having a substituent as needed" Examples of the % 6 -oxy-indenyl group include Toxy County, Ethoxy County, Propoxydecyl 'Isopropoxy-yl, Butoxy County, Isobutoxy Group, and 321538 31 201114741 Dibutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxy, and the like. Examples of the "substituent" of the above "C!-6 alkoxy-carbonyl group having a substituent as necessary" include a substituent selected from the substituent group A. The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3. Examples of the "rC2_6 alkenyloxy-carbonyl group" of the above-mentioned "CM alkenyloxy-carbonyl group having a substituent" include an ethyleneoxycarbonyl group, a propyleneoxycarbonyl group, a butenyloxycarbonyl group, a penteneoxycarbonyl group, a hexene group. Oxycarbonyl group and the like. Examples of the "substituent group" of the above-mentioned "C2_6 alkenyloxy group having a substituent" include a substituent selected from the substituent group A. The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5', more preferably from 1 to 3. Examples of the "c2 6 alkynyloxy-carbonyl group" of the above-mentioned "匕6-alkynyloxy-carbonyl group having a substituent" include an acetyleneoxycarbonyl group, a propynyloxycarbonyl group, a butyloxycarbonyl group, a pentyne group. An oxycarbonyl group, a hexenyloxycarbonyl group or the like. The above "Example of the substituent j of the alkynyloxy group-carbonyl group having a substituent" includes a substituent selected from the substituent group A. The number of the substituents is not particularly limited as long as the specified number of substituents is The substitution is 'but it is preferably from 1 to 5, more preferably from 1 to 3. " "Cw cycloalkyloxy-carbonyl" of the above-mentioned "Gw cycloalkyloxy-carbonyl group having a substituent" Examples include a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a cycloheptyloxycarbonyl group, a cyclooctyloxy group, a carbon group and the like. 321538 32 201114741 "Examples of the above-mentioned "desired earth having a G-8 cycloalkyloxy-carbonyl group having a substituent"" includes (1) optionally having 1 to 3 substituents selected from a halogen atom and a cyano group. a Cl 6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, third τ, etc.), and (2) a substituent selected from the group of substituents, ' Exclude the side oxy). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5' and more preferably from 1 to 3.瘫s The above "c3_8 = olefinic oxygen, -carbonyl group" of the above-mentioned "C3-8 cycloalkenyloxy-yl group having a substituent" includes a cyclopropyloxy group, a cyclobutoxy group, The base of the material, the ring has a silk group, a cycloheptenyloxy group, a cyclooctenyloxycarbonyl group and the like. Examples of the "substituent" of the above-mentioned "cycloalkenyloxy group-substituted group having a substituent" include (1) optionally having 1 to 3 substituents selected from a halogen atom and a chlorine group (for example, A Base, ethyl, propyl, isopropyl,

a butyl isobutyl group, a second butyl group, etc.), and (2) a substituent selected from the group of substituents A (excluding the pendant oxy group). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 5 to 5, more preferably from 1 to 3. Examples of the above-mentioned cyclic polyoxyl group of C"ring blockoxy group having a substituent include a cyclopropyloxy group, a cyclobutoxy group, a ring block. An oxymethyl group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctynyloxycarbonyl group or the like. Examples of the "substituent" of the above-mentioned "C3-8 ring-blockoxy-poly group having a substituent" include (1) optionally having a halogen atom and an aryl group, and m 321538 33 201114741 3 substitutions. The base c]-6 alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.), and (2) selected from the group: Substituent (excluding pendant oxy group). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is preferably from 〗 1 to 1, more preferably from 1 to 3. Examples of the "aryloxy-carbonyl group" of the above-mentioned "aryloxy group" having a substituent include a phenoxycarbonyl group, a naphthyloxycarbonyl group, a quinoneoxy group, and the like. Examples of the "substituent" of the above-mentioned "C6, aryloxy group, and the substituent having a substituent" include (1) a nutrient (4) from the (tetra) sub and a cyano group of 1 to 3 substituents of a C 6 alkyl group (for example: A a group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, etc.), and (2) a substituent selected from the substituent group a (excluding a pure group). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, but it is more preferably from 1 to 3. Examples of the "hetero%" of the above-mentioned "heterocyclic group-oxyl group having a substituent" include (1) a 5- or 6-membered monocyclic aromatic heterocyclic ring (for example, a bite, a porphin, a turn, a (4), different shots, Mi Jun, ^ Ding. than saliva, etc.), (2) 8 to 12 members condensed aromatic heterocycles (eg benzopyrene, isophthalonitrile, benzopyrene, isophenylene, Ah, different (four), ih_ ^ sit: benzo, benzo-, etc.), (3) 5 or 6 non-aromatic miscellaneous: gas heterocyclic cyanine, azetidin, oxetane, material Biting, tetrahydrofuran, thietane, piperidine, etc.). Examples of the "take 321538 34 201114741 substituent" of the above-mentioned "heterocyclic group-oxygen-based carbon group having a substituent" include (1) optionally having a oxime selected from a tooth atom and a cyano group to three substituents. C!-6 alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.), and (2) substituent selected from substituent group A (excluded Side oxy). The number of the substituents is not particularly limited as long as the specified number of substituents are replaceable, and it is preferably more preferably from 1 to 3. The above-mentioned "amine-containing mercapto group having a substituent as necessary" is optionally contained in an alkyl group (Ci-6 alkyl group) having a substituent as required, and optionally having a substituent (one county), optionally having a substitution. Alkynyl group (6)-alkynyl group, cycloalkyl group (匕S cycloalkyl group) having a substituent, optionally a substituent group having 2 substituents, and optionally an aryl group (α) -, aryl) i or 2 substituents of the amine mercapto group. The above-mentioned "heterocyclic group optionally having a substituent (which has a bond at a carbon atom) includes an aromatic heterocyclic group (for example, a monocyclic aromatic heterocyclic group, a condensed aromatic heterocyclic group), and a non-aromatic heterocyclic group ( For example, a monocyclic non-aromatic heterocyclic group, a non-aromatic heterocyclic group, etc. Examples of the monoterpene aromatic heterocyclic group include, in addition to a carbon atom, 丨 to 4, which are selected from an oxygen atom, a sulfur atom, and a nitrogen atom (tetra) The atom as a ring constitutes a 5- to 7-membered monocyclic aromatic heterocyclic group of the atom. Specific examples of the monocyclic aromatic heterocyclic group include a furyl group (for example, 2-furan=, 3-furyl group), a thienyl group (for example, ··· 2 _Thienyl, 3-tertiphenyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidine) Base, 6-pyrimidinyl), morphine-based, such as 3-mercapto, 4-mercapto, pyridinyl (eg, pyridyl), 321538 35 201114741. Sitting base, 4_„米吐基,5♦坐基), 対基^基, 4'°比嗤基), (四)基 (eg: 2-嗟 嗟 、, 4 寺 soxazolyl), isoindole, Azolyl (eg, oxazolyl, ": base, 5 sylvestris), sessile, di-salt (eg, yl, 1 yl), stilbene, thiol - 基), 三哇基 (for example: l 2, 4_三唾_卜基, ^^令...-三好仏四端 such as: four; ^:, base), three tillage, etc. ^ Condensed aromatic Examples of the ring group include a hetero atom having an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to a face, and a 5- to 7-membered monocyclic aromatic heterocyclic ring having an atomic group, and the disk is prepared as a dressing garden. a condensing group of a group with a C6, an aryl group or the like, a condensing group of the above 5- to 7-membered monocyclic aromatic heterocyclic group, etc. Specific examples of the group = an aromatic heterocyclic group include a cylinyl group (for example, 2_base 3) Material base, 4_(tetra) base, heterogeneous base], sputum-based base (example two Lin - Gui (four) base, 4-base material base), material scare base (example m two lions! Such as: 2_benzene and butterfly 2 Anthracenyl (for example, 2-benzobenzophene, 3-benzone)

Base (for example: 2-benzoxyl), benzo (tetra), C, 5-benzoxanyl, 6-benzoxanyl, benzox-2-yl, benzo Saliva (4) soil (for example: base, ah + base, accompanied by · (4) 3- 36 [s] 321538 201114741 (for example: πίϋ and [4,5_bMm 绍"

HtUr County (10): (4) Butterfly (1) 吼 并 and ^ Γ Γ base, three records, Μ bite base, than sit thiophene, pyrazole and three tillage. Examples of the monocyclic non-aromatic heterocyclic group include 3 to 8 members (more) and/or (and preferably saturated) monocyclic non-aromatic heterocyclic groups. Specific examples of the sub-native fluorene heterocyclic group include oxacyclopropyl, azametry, diindenyl, thiacyclobutylidene, tetradentate, tetrahydrotetrazole, tetrahydrotetrazole, Cyclohexyl, thiol^diyl, maixin, azepanyl, oxetan, bis, heptazep, thiazepine, thiazepine Base, dioxaoxazacyclooctyl, thia 5 4 fused ^! (4) sub (10) face 1 or 2 nitrogen atoms ^ 鱼 苯 51 51 51 ··thiophene) =: a ring obtained by hydrazine (which may be partially saturated with J, etc.) and a ring equivalent to a 4- to 7-membered monocyclic non-aromatic heterocyclic group such as: 2: non-disaccharide heterocyclic group Examples include dichloro, iL HL), dihydroisoyl (for example: ^ - bis: ke =; yl), dihydrogen] '4 ~ benzo: oxa^ = = hexene ), monohydrobenzodioxepene 321538 37 201114741 m. its 3 dioxin 2,5-benzodioxanyl), tetrahydrogen, for example, 4,5,6,7 a tetrahydro-1 benzofuran-3-yl), a spray = such as a dilute - 2 -yl group, a dienyl group, a diene group (example - Bu, One wind "~2ίί~ pentene-2-yl), dihydroquinolinyl (eg ··· 1,2-^喧琳-4~ base), tetrahydrogen base (eg ··· U,3, 4 - tetrahydrofuran 14-hetero-based group (for example: 1,2-: hydrogen hetero- 4_ group), tetrahydro (J such as 1,4-hydrogen blowing q and 4-yl), etc. t "There is a case where the rf is required to have a sufficiency (the syllabus has a bond and a substituent), and (1) a Cl_e alkyl group having 1 to 3 substituents selected from a halogen atom and a murine group as needed (for example: A Methyl, propylidene, isopropyl, butyl, isobutyl, tert-butyl, etc.) and (2) substituents of group A (10) in addition to pendant oxy). The number of substituents is not limited to 'as long as the specified number of substituents are replaceable, but it is preferably from 1 to 5, more preferably from 1 to 3. In the book (4), the "(4) base of the nitrogen material" includes (1) the group II has one or two of the above-mentioned "bases via a carbon atom". In the present specification, the example of the "group via an oxygen atom" includes the subtraction of one of the above-mentioned "groups via a carbon atom" as needed. The group that wants the sulfur atom"_子 includes as needed! One of the above-mentioned "groups via a carbon atom" or the above-mentioned "group of a molecule", and the group can be oxidized. 'In the book towel, the "aromatic ring base" of 321538 38 201114741 can be described as an aromatic hydrocarbon group or an aromatic heterocyclic group (for example, a single ring aromatic) Heterocyclic group, condensed aromatic heterocyclic group) and the like. Examples of the aromatic hydrocarbon group include an aryl group and the like. Specifically, a phenyl group, a 1-naphthyl group, a 2-naphthyl group or the like can be mentioned. Examples of the monocyclic aromatic heterocyclic group include a 5- to 7-membered monocyclic aromatic heterocyclic group having, in addition to a carbon atom, another j to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring-constituting atom. Specific examples of the monocyclic aromatic heterocyclic group include a furyl group (for example, 2-furyl group, 3-furyl group), a thienyl group (for example, 2-thienyl group, a thiophenyl group), and a pyridine group (for example, 2-oxime). Bite base y base, 4_π specific filament), (4) base (eg. 2n base, 4-ray base, 5-debase, 6-ray base), tower base such as · 3" combined well base, 4 tower Base), π is more than sulfhydryl (for example: & thiol), such as imidazolyl, 2-imidazolyl, 4-imidazolium (for example: babi salivyl, 3_吼like 4 base 5 ten sitting Base), ° than spyryl 2-*^ Λ , ^ sityl, 4-pyrazolyl), thiazolyl (eg: stagnation, 4-hydrazino, 5-sex, g such as: " Azole A, 4 yl) iso(tetra)yl, oxime (example)

Am f-salt), iso-saltyl, indenyl (for example: 1, 2, 4^ two „ sitting _5_ base, soil 7 sitting two sitting base (for example: 1,3, 4-mercapto } Tris-s--1-yl, f, di-salyl (eg: 1,2,4- _ k 0 - sitting d-base, 1,2,3-triazole-buff,] 9 q di-salt-2- a base, a 1-base 1,2,3-yl group, a tetradec-5-yl group, a triterpene group, etc.. A tetradyl group (for example, an example of a tetras--1-condensed aromatic heterocyclic group includes an additional 1S4 It is selected from the group consisting of oxygen atoms and :: a hetero atom such as an atom other than a carbon atom and a ruthenium atom. 321538 39 201114741 A 5- to 7-member member of a ring-constituting atom obtains its own circle, and its base is aryl and aryl. In the group, the straw is obtained by kneading the above 5 to the group obtained. Specific examples of the fragrant heterocyclic group such as the scented scented heterocyclic group include 噎琳基 (for example: 2_啥琳" quinolinyl, 4 喧琳基, 啥 啥 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基Benzene tallow base), benzopyrene (for example, ······················^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ : =Miwa + base, benzopyrene I base, benzopyrene such as Finance, Wengji, ah cited;: soil, mouth mouth wood-6-base), ten seat base (for example, · 1H - mouth Inducing saliva "a base" " than the mouth and 7 1H kiss each offense, 3 training 哄 __ base, ih ^ each, b > 哄 _6_ base), (four) and. More than thiol (such as carbazole [4, 5-bMt2_ base, 1 Η _ _ _ _ _ [4, 5 _ _ _ _ _ _ base), mouth rice bite and Na, (for example: 1 Η 咪 咪 咪[4,5 clocks than Sakai-2_base), stupid and heterosexual base, called um, called the end base drink, in this specification '"Aromatic ring with substituents as needed" The column includes (1) optionally having 1 to 3 selected from the group consisting of a halogen atom, an aryl group, a thiol group, a methyl group, a silk yam, and a cyclofilament (for example, a di(tetra) thio- morphine, a trans-base, etc.). Substituted Ci 6 alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.), 321538 40 201114741 to have one basis group (for example: 3_methyl + butyl rare earth, (3) if necessary, having i radicals & fast radicals (for example: ^: . ) C26 olefins having a Cho aryl group (eg phenyl, etc.) E., et al.), the C6, aryl group optionally has a C-alkyl group (eg, #土, s" C丨'6 alkyl as required to have 1 to 3 halogen atoms (for example: gas atom Etc. 'and (6) a substituent selected from substituent group A. The number of substituents is not It is not limited as long as it is a substitutable number. The pot is preferably from 1 to 5, more preferably from 1 to 3. ', # In the present specification, the atmosphere of "the phenyl group having a substituent as needed" The phenyl group includes a 2-cyanophenyl group, a 3-cyanophenyl group, and a 4-cyanophenyl group. In the present specification, examples of the "substituent group" of the "cyanophenyl group having a substituent as necessary" include (1) A Cm alkyl group having from i to 3 substituents selected from a ruthenium atom and a gas group (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, etc.) And (2) a substituent selected from the substituent group A (excluding the pendant oxy group). The number of the substituent is not particularly limited as long as it is a substitutable number, preferably 丨 to 4, more preferably The compound (I) is explained in detail below. In the compound (I), 'R1 is a cyanophenyl group which may have a substituent as necessary. The substituent of the "cyanophenyl group having a substituent as necessary" is Preferably, one or two substituents selected from the group consisting of (halogen atom, (2) Ci6 alkyl having i to 3 halogen atoms, and (3) Ci6 morphoxy are preferred. In particular, One or two substituents selected from the group consisting of (1) a gas atom, (2) a fluorine atom, (3) an fluorenyl group having 1 to 3 fluorine atoms, (4) a methoxy group, and (5) an ethoxy group as necessary More preferably. 321538 41 201114741 About R1, 4-cyanophenyl, 3-chloro-4-cyanophenyl, 5-chloro-4-cyano-2-fluorophenyl, 5-chloro-4-cyano- 2-methylphenyl '4-cyano-3-fluorophenyl, 4-cyano-3-methoxyphenyl, 4-cyano-3-methoxyphenyl, 2-cyano-5 A phenyl group and a 4-cyano-3-(trifluoromethyl)phenyl group are preferred. In the compound (I), 'R2 is a (1) hydrogen atom or (2) a Ci_e alkyl group (for example, a mercapto group) , ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl, hexyl, etc.). R2 is preferably a hydrogen atom or a methyl group. In the compound (I), R3 is a hydrogen atom. In the compound (I), R4 is (1) an aromatic ring group having a substituent as needed, and (2) -NRa-X-(CH2)nY-Rb, wherein *^ is a (1,) hydrogen atom or ( 2,) C -6 alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl, hexyl, etc.); X Is (1) bond, (2,)-C0-, (3,)-c〇NH- or (4,), S〇2-; η is an integer from 〇 to 3; Υ is (1) bond , (2,)-〇-, (3,, (4,)_NHC〇_, (5')-NHS〇2- or (6,)-CH=CH-; ^ is a ring optionally having a substituent Or (3) -〇-Z-Rc, wherein Z is a (1,) bond, (2')-CH2- or (3,)-C0NH_; Γ is a ring group having a substituent as needed. Examples of the "cycloalkyl group having a substituent as necessary" of R or R include "a non-aromatic ring group having a substituent as required by [S] 321538 42 201114741" and the above-mentioned "aromatic ring group having a substituent as necessary". Examples of the "non-aromatic ring group" having a non-aromatic ring group having a substituent include a non-aromatic homocyclic group and a non-aromatic heterocyclic group (for example: a ring non-aromatic heterocyclic group, a condensed non-aromatic heterocyclic group, etc. Examples of the non-aromatic homocyclic group include 3 to 8 members (preferably 5 or 6 members) saturated or unsaturated (preferably saturated). Aromatic homocyclic fluorenyl, specifically C3-8 cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, #cycloheptyl, cyclooctyl, etc.) and C3-8 cycloalkenene a group (for example, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, etc.). Examples of the monocyclic non-aromatic heterocyclic group include 3 to 8 members ( Preferably 5 or 6 members) a saturated or unsaturated (preferably saturated) monocyclic non-aromatic heterocyclic group, specifically an oxacyclopropyl, azetidinyl, oxetanyl, thioheterocycle Butyl, pyroline, tetrahydrofuranyl, thioheteropropyl, butyl, tetrahydroindolyl, thiacyclohexyl, morpholinyl, thiomorpholinyl, piperidinyl, nitrogen heterocycle φ heptyl, oxetanyl, thiaheptyl, oxazepine, thiazepine, azacyclooctyl, oxetanyl, thicyclooctyl, Oxazacyclooctyl, thia a heterocyclic octyl group, a dioxolyl group, etc. Examples of the condensed non-aromatic heterocyclic group include a 5- or 6-membered aromatic heterocyclic ring selected from the group consisting of 1 or 2 nitrogen atoms by condensation (for example: ° ratio ρ , sigma squat, ° ratio ° sitting, 〇 than well, π bite, bite), a 5-membered aromatic heterocyclic ring containing one atomic atom (eg thiophene) and one or two rings of the benzene ring a group derived from a ring (which may be partially saturated), a ring equivalent to a 4- to 7-membered monocyclic non-aromatic heterocyclic group, etc., specifically a dihydroindenyl group (for example, 2,3-dihydrogen) -1Η-吲哚-1- [s] 43 321538 201114741 base)~dihydroisoyl (for example: dihydrogen I 啊 虱 虱 开 呋 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Hydrobenzodioxanyl (e.g., 2,3-propanol: 5:yl), dicyclohexyl), dihydrobenzo-indole, 4 stupid and dioxa 9Η Milky heterocycloheptyl (for example: 3 4 -. -2Η-1,5-bensodioxenyl), tetram 4, 5, 6, 7-tetrahydro + benzofuran: methane Base (for example: -2-yl, 2Η-yl), dihydrogen (for example: 4Η, blame? It is a steroidal alkenyl group (for example: 3, 4-dihydro-2H-spray: upper 2-dihydroisophthalocyanine-4_yl), tetrahydroisoindolinyl (diyl 2, (two) The base is selected from the group consisting of a dentate atom, an aryl group, and a non-aromatic ring group having a substituent as required. a Cl-6 alkyl group having 1 to 3 substituents of a base group, an amine/ankyl-based imide group, and a cyclic amine group (10), a thiol group (for example, methyl group, ethyl group, and ethyl group). a base, a propylene glycol, a butyl group, etc.), (2) a C2-6 alkenyl group having a group (for example, a 3-methyl group, a butene group, etc.), and (3) a base group as needed ^ Block base (for example: 3_methyl + butyl block + base, etc.), (4) C: aryl-Cl_6 炫 (for example, stupid methyl, etc.), (5) C ^ group (for example, phenyl, etc.) as needed a q 6-dilute group (e.g., ethylidene group, etc.), which is required to have a Cl_6 alkyl group (e.g., a methyl group, etc.), and the monoalkyl group optionally has i S 3 functional atoms (for example, a fluorine atom) And (6) a substituent of the substituent group A. The number of substituents is not particularly limited as long as [S] 321538 44 201114741 It may be a substitutable number. It is preferably i to 5, more preferably i to 3. R "optionally substituted aromatic ring group" and ^ or ^ "optionally substituted" Each of the ring groups" is preferably a styryl group, a pyridyl group, a pyrazolyl group, an imidazolyl group, a naphthyl group, a thiazolyl group, a carbazolyl group, an isoxazolyl group, a fluorenyl group, a stupid oxime group, and a benzo flavor. Wow, 嗓, 嗟, 基, 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基Alpha-1()aryl (stupyl): (Ό halogen atom (fluorine atom, chlorine atom, bromine atom), (2) Cw alkoxy (methoxy), (3) Ci-e slate Astragalus (methyl stellite), (4) Ci-e alkoxy-carbonyl (ethoxycarbonyl), (5) carboxyl, (6) amine carbaryl and (Ό Ci-e alkyl-amine Mercapto (methylamine-methyl), (B), if necessary, has one substituent (pyrazolyl, imidazolyl, pyridyl) selected from the group consisting of: 5 or 6-membered aromatic heterocyclic ring (1) Halogen atom (bromine atom), (2) cyano group, (3) as needed Cl_e alkyl group having one hydroxyl group (methyl, isopropyl), (4) CM alkenyl group having 1 hydroxyl group as needed (3-methylbutene-(5) C2- having 1 hydroxyl group as needed 6 alkynyl (3-fyl-1-butyne-j 321538 45 201114741 base), (6) Ce ifl aryl (phenyl) having one halogen atom (fluorine atom) as needed, (7) C! -6 alkoxy-carbonyl (methoxycarbonyl, ethoxycarbonyl), (8) carboxyl group, (9) amine carbenyl group, (10) optionally having 1 to 3 Cl_6 alkane selected from the following substituents Amino-aminomethyl thiol (methylamine carbaryl, ethylamine, isopropylamine, isopropylamine, butylamine, butylamine, butylamine): (a) Halogen atom (fluorine atom), (b) hydroxyl group, (C)c]_e-yardoxy group (methoxy group), (d) cyclic amine group (morphine group), (e) c!_6 alkyl group-amine group A Mercapto (methylamine carbaryl) and (5-membered aromatic heterocyclic carbazolyl) having 1 Ci-6 alkoxy-carbonyl (ethoxycarbonyl), (11) C3— 6-cycloalkyl-amine-mercapto (cyclopropylamine sulfhydryl), (12) di-Ch alkyl-amine-mercapto (dimethylamine-methyl), (13) 5 or 6 membered heterocyclyl-aminocarboxamido (isoxazolylamine oxime) having 1 substituent selected from (&) cyano and (b) Ci 6 alkyl (fluorenyl) φ as needed Base, thiadiazolylcarbamyl, dihydrothiazolylamine, pyrazolylmethylguanidinyl, tetrahydropyranylamine, mercapto, tetrahydrothiomethaneamine Dioxido tetrahydrothiopipetanylcarbamyl), (14) cyclic amidino (pyrrolidinylcarbonyl, morpholinylcarbonyl), (15) di-Cw alkylamine (two) Methylamino), (16) Cm alkoxy-carbonylamino (t-butoxycarbonylamino), (1) A cyclic amine group having 1 to 3 substituents selected from the group consisting of卩, 卩, etc., 琳琳基): [s] 46 321538 201114741 (a) Hydroxy, (bK, -6 alkyl (methyl) and (c) pendant oxy, (18) 1 if necessary a 5-membered aromatic heterocyclic group (oxadiazolyl, imidazolyl, U-pyrazolyl) selected from the group consisting of: (a) a cyano group, (b) optionally having a halogen atom (a fluorine atom) and a hydroxyl group. 1 to 3 substituents of Ch alkyl (indenyl, ethyl, isopropyl), (c Aminomethyl sulfhydryl, (d) Ci 6 alkyl-amine carbaryl (decylamine f decyl, isobutylamine carbaryl) having one hydroxy group, if desired, and (e) cyclic amine fluorenyl (morpholino group), gin (10) 6-membered non-aromatic heterocyclic group (indoline) having a pendant oxy group, and (20) Cw alkyl-carbonylamino group (methylcarbonylamino group), ( C) optionally having a functional atom (fluorine atom) of Ce...aryl(phenyl)-amino group, (9) optionally having 1 or 2 C61Q aryl groups (phenyl, phenyl) selected from the following substituents - aminylamino group: φ (1) a halogen atom (a fluorine atom, a gas atom), (2) a murine group, (3) optionally having a halogen atom (a fluorine atom), a transamidiamine group, and a cyclic amine group. (two-side oxythio- morphinyl) 丨 to three substituents of the Ch-yard (methyl, ethyl, tert-butyl), (4) C6-1Q aryl (phenyl), (5 Ce-ioaryl-carbonyl (benzhydryl), (6) optionally having a halogen atom (fluorine atom) and a!. 1 to 3 substituents of aryl (phenyl), Ch alkoxy (methoxy), m 321538 47 201114741 (7). An aryloxy group (phenoxy group), (8) a 6-membered aromatic heterocyclic group - a pendant oxy group (pyrimidinyloxy group), (9) an amine carbenyl group, do) optionally have 1 to 3 halogen atoms ( Fluorine atom) Cl-6 alkyl-amine sulfhydryl (ethylamine methyl sulfhydryl), (11) di-C!-6 alkylamino group (dimethylamino), (12) Cm alkyl a carbonylamino group (methylcarbonylamino group), (13) a cyclic amine group having one pendant oxy group (pyrrolidinyl group, morpholinyl group), (14) an amine continuation base, (15) -Cm alkylamine sulfonyl (dipropylamine sulfonyl), and (16) 5-membered aromatic heterocyclic group ("specific"), (E) Cw cycloalkyl (cyclohexyl)-carbonylamine The base (F) optionally has 1 or 2 c^ selected from the following substituents. Aryl (phenyl)-methylcarbonylamino group: φ (1) from an atom (fluorine atom, chlorine atom), (2) cyano group, (3) having 1 to 3 halogen atoms (fluorine atom) as needed Ci_e alkyl (methyl, tert-butyl), (4) C6-1D aryl (phenyl), =)) an alkoxy group having 1 C6-le aryl (phenyl) as desired (methane) (6) aryloxy (phenoxy), (7) di-Ch-hosylamino (dimethylamino), 321538 48 201114741 (8) Ci-e competitive base (methyl sulphate) Stuffed base), and (9) C2-3 extended alkyloxy group (extended ethoxy group), (G) optionally having 1 Cl-6 alkyl group (methyl aryl (phenyl)-ethylcarbonyl group An amine group, the Cl-6 group may have 1 to 3 halogen atoms (fluorine atoms), (H) Ce-io square (phenyl)-propylamino group, (I) 1 if necessary C6H aryl (phenyl)-vinylcarbonylamino group of one halogen atom (fluorine atom), (1) C61 having one halogen atom (fluorine atom) as needed. Aryl (phenyl)-oxymethylcarbonylamine Base, contiguous need to have C ^ which is selected from the following substituents. Aryl (phenyl) ureido: (1) Halogen (fluorine atom, chlorine atom), (2) cyano group, (3) 16 alkyl group (methyl group, tert-butyl group) having 1 to 3 halo κ 囷 千 千 (齓 atom) as needed = CH alkoxy (methoxy) having 1 to 3 (tetra) atoms (fluorine atom), (5) Ch, aryloxy (phenoxy), (6) Ci-6 alkoxy-carbonyl (B) Oxycarbonyl), (7) di-Cm alkylamino (dimethylamino), and (8) Cm alkyloxy (ethyloxy), Cm of the following substituents. aryl (benzene Base)-(L) optionally has one selected from methylureido groups: [s] 321538 49 201114741 (1) Halogen atoms (fluorine atoms, chlorine atoms), and (2) Cl-6 morphoxy groups (methoxyl) The aryl (phenyl) monomethylamino group having i substituents selected from the group consisting of: (1) a halogen atom (a fluorine atom), (2) a cyano group, and (3) optionally having 1 to 3 atoms (gas atom) of c]-6 alkyl (methyl, tert-butyl), (4) α6 alkoxy (methoxy;), (5) C6-1D aryloxy (phenoxy), (6) Ci-6 alkoxy-carbonyl (methoxycarbonyl), (7) Cm alkyl-carbonylamino (A) a carbonylamino group, and (8) a 6-membered aromatic heterocyclic group (n to a butyl group), and a fluorene-based (methoxy group) having 1 Cl 6 alkoxy group (N-) C6, aryl(phenyl)-methyl)amino group, (*〇) optionally has a GeiQ aryl group selected from the group consisting of: (1) a halogen atom (a fluorine atom) , chlorine atom), (2) cyano group, (3) Ci6 alkyl (methyl, tert-butyl), (4) C6-U) aryl group having 1 to 3 halogen atoms (fluorine atoms) Phenyl), =) optionally having one to three _ atoms (fluorine atoms), an alkoxy group (decyloxy group), 321538 50 201114741 (6) Cm alkyl-carbonylamino group (mercaptocarbonylamino group) And (7) C1 2-3 4 5 alkyloxy (ephthyloxy), (P) optionally has 1 (^-6 7 8 alkyl (t-butyl) b ((: 6-aryl (phenyl)-alkyl)-N-Ci-ealkyl (indenyl)amine, (Q) optionally having a C61() aryl group (phenyl) selected from the following substituents )_ Methylsulfonylamino group: (1) a halogen atom (a fluorine atom), and (2) 1 to 3 halogen atoms (a fluorine atom) as needed Ci6 alkyl (methyl), 00 Cno aryl (phenyl)-aminomethylcarbonylamino, (8) optionally having 5 or 6 membered aromatic heterocyclic groups selected from the group consisting of the following substituents ,·基,异曙丝"米唾基,定定基)_几基胺

a Cu alkoxy group of a halogen atom (a fluorine atom) (a 321538 51 1 halogen atom (a fluorine atom, a chlorine atom, a bromine atom), a 2 cyano group, and 3 (3) optionally have a terminal atom (a fluorine atom) and a cyclic amine group. (1,3 substituents of the alkyl group (methyl, ethyl), 4 =) aryl group C having a halogen atom (say atom, gas atom), ^ 5 (5) ) having 1 to 3 oxy groups, ethoxy groups, and 6 as needed. Aryloxy (phenoxy), 7-Cycloamino (morpholinyl), 8-aminomethylindenyl, 201114741 (9) Cie alkyl-aminocarboxamide (methylamine-methyl hydrazide) having 1 hydroxy group as needed a group, a butyl group, a butyl group, a butyl group, a butyl group, a butyl group, a hydroxy group, a hydrazinyl group (11) a carboxyl group, (12) a Ci-e alkoxy-carbonyl group (methoxycarbonyl group), (13) a 5- or 6-membered aromatic heterocyclic group having 1 Cl_e alkyl group (methyl group) as needed (卩f (oxadiazolyl, pyridyl), _(14)amine fluorenyl, and (15) di-Ci-e alkylamine sulfonyl (didecylamine fluorenyl), (T) N-(5 or 6-membered aromatic heterocyclic group (π-pyridylcarbonyl)_[Ci6 alkyl(methyl)amino group, (U) condensed aromatic heterocyclic group having 1Ch alkyl group (fluorenyl group) as needed , benzothiazolyl, benzimidazolyl, acridinylcarbonylamino, (V) 5 or 6 membered aromatic heterocyclic φ groups having 1 Cm aryl (phenyl) as desired (thienyl, imidazolyl, Thiazolyl, pyridyl)-fluorenylcarbonylamino group,

The Ce-ni aryl group optionally has one halogen atom (chlorine atom), (W) a 6-membered non-aromatic heterocyclic group (morpholinylfluorenylcarbonylamino group, (X) 6 membered aromatic heterocyclic group (π-pyridine) Ethylcarbonylamino, (Υ) 6 member non-aromatic heterocyclic (piperidinyl)-ethylcarbonylamino, (Ζ) 5 or 6 membered aromatic heterocyclic group (imidazolyl, β-pyridyl) Vinylcarbonylamino, (ΑΑ) 6-membered aromatic heterocyclic pyridyl)-carbonylaminocarbonylcarbonylamino, (fluorene) condensed aromatic heterocyclic (fluorenyl)-methylcarbonylamino, [ S3. 52 321538 201114741

(cc) condensed aromatic heterocyclic group (stupid imidazolyl, benzo-bisazolyl)-ethylcarbonylamino group, I (DD) 5-membered aromatic heterocyclic group (thienyl)-sulfonylaminomethyl A carbonylamino group, an (EE) 6-membered aromatic heterocyclic group, a pyridyl group, a ureido group, (FF), if desired, a 6-membered aromatic heterocyclic group having 0 cyclic amino group (pyrrolidinyl group). The mercaptoamine group and the earth (GG) optionally have one substituent selected from the following substituents. Aryl(phenyl)-indenyloxy: (1) a halogen atom (chlorine atom), (2) a carboxyl group, (3) a Cm alkoxy-carbonyl group (methoxycarbonyl group), and (4) a Ci-e alkyl group - Amidino (methylamine sulfhydryl), (HH) optionally has 1 aryl (1) aryl (phenyl) monoaminooxy group selected from the group consisting of: (1) optionally 1 hydroxyl. 6 alkyl (isopropyl), ^ (2) fluorenyl, (3) Ci-e alkoxy-carbonyl (decyloxycarbonyl), (4) amine-branth, and (5) Ch-alkyl- Amine-based (decylamine sulfhydryl), (1) if necessary, has 1 (four) from the lower hemp base (° ratio biting) -oxy group: ^heteroyl group (1) 丨 a hydroxyl group as needed 6 alkyl (isopropyl), (2) carboxyl, '(3) Cm alkoxy-carbonyl (methoxycarbonyl), 321538 53 201114741 (4) amine carbaryl, and (5) Ch alkyl- The amine fluorenyl group (methylamine carbaryl group) and the aromatic heterocyclic group (JJ) optionally have 6 members (pyridyl)-decyloxy group selected from the following substituents: (1) 1 if necessary a hydroxyl group of Cl_e alkyl (isopropyl), (2) an amine formazan, and

(3) Ch alkyl-amine-mercapto-methyl (methylamine-methyl fluorenyl group. In particular, R 4 is preferably a group: a Ce(1) aryl group selected from the following substituents (stupid (A) optionally has a 1 to a group) : (1) a halogen atom (a fluorine atom, a gas atom, a bromine atom), (2) a Cm alkoxy group (methoxy group), (3) a Ci-e basestone xanthyl group (methyl sallow base), (4) Ci-e alkoxy-carbonyl (ethoxycarbonyl), (5) carboxyl, (6) amine indenyl, and (7) Cm alkyl-amine indenyl (methylamine methyl), The aromatic heterocyclic ring (8) optionally has a 5- or 6-membered group (pyrazolyl, imidazolyl, pyridyl) selected from the following substituents: (1) a halogen atom (bromine atom), (2) a cyano group, (3) If necessary, have one base group of Cm alkyl (indenyl, isopropyl), =)) Gw alkenyl having one hydroxyl group as needed (3_methylbutene, 1 321538 54 201114741 (5) There are; j 录 其 „ „ „ 1 is a hydroxyl group C: 2-6 alkynyl (3_methyl q-butyne-diyl), (6) as needed, a southern 囟 atom (fluorine Atomic) C6-ID aryl (phenyl), (7) Ci-6 alkoxy-mono(methoxyl, B a benzyl group, (8) a carboxyl group, (9) an amine carbenyl group, (10) optionally having 1 to 3 Ci6 alkylamino-mercaptomethyl groups (methylamine methyl fluorenyl group, selected from the group consisting of Ethylamine (tetra), isopropylamine, isobutylamine, mercapto, and butylamine, (t-butylamine), (a) halogen atom (fluorine atom), (6) trans group, (6) Ci 6 (methoxy), (4) cyclic amine (morphine), (e) Cl_6, alkalyl (amino), and (f) 1 Cm alkoxy, if desired - 5-membered aromatic heterocyclic group (°-carbazolyl) of carbonyl (ethoxycarbonyl), (11) C3-6 cycloalkyl-aminecarbamyl (cyclopropylamine fluorenyl), (12) di- Ci-e alkyl-amine-mercapto (dimethylammonium), φ (13) optionally has 5 or 6 membered heterocyclyl-aminocarboxamidines (isoindole) selected from the group consisting of the following substituents Carbazolylhydrazinyl, thiadiazolylaminocarbazyl, dihydrothiazepine amine, π-thylaminodecyl, tetrahydropyranylamine, tetrahydrogen a piperidylamine sulfhydryl group, a tetrahydrothiopiperidylamine sulfhydryl group): (a) a cyano group and (b) a C 1 - 6 group (methyl group) , (14) a cyclic amidino group (oxaridinylcarbonyl, morpholinylcarbonyl), (15) a di-Ci-6 alkylamino group (didecylamino group), (16) a Ci-e alkane Oxy-carbonylamino group (second butoxycarbonylamino group), 55 321538 201114741 (17) If necessary, it has 1 to 3 cyclic amine groups selected from the following substituents (pyrrole, azetoin, or (Linyl): (a) a hydroxyl group, (10Ch alkyl (fluorenyl) and (c) pendant oxy group, (18) a 5-membered aromatic heterocyclic group having a substituent selected from the group consisting of: , σ米β, and σ to succinyl): (a) a cyano group, (b) a Cm alkyl group having one to three substituents selected from a halogen atom (a fluorine atom) and a hydroxyl group, if necessary (methyl, Ethyl, isopropyl), (imaine-aminomethyl), (d) Ci 6 alkyl-aminoindenyl (mercaptoamine-based, isobutylamine-methyl fluorenyl) having one hydroxyl group as needed And (4) a cyclic amine-brenyl group (mlyl carbonyl group), (19) a 6-membered non-aromatic heterocyclic group having a pendant oxy group (dichlorotonyl dimethyl group), and (20) a Cm alkyl-carbonylamino group ( Methylcarbonylamino), «as required" a halogen atom ( Atom) of Ce〗. The aryl(phenyl)-amino group, =), is required to have i or 2 substituents selected from the following substituents. Aryl (phenyl 'lower) - mercapto amine group: (1) a halogen atom (a fluorine atom, a chlorine atom), (2) a cyano group, having a /+ atom from a * atom (a fluorine atom), a imine And a ring amine group (= group: dailyl group) of li3 substituents, ethyl, tert-butyl;), (4) C6-1Q aryl (phenyl), (5) Cew fang a benzyl group (benzhydryl group), 321538 56 [201114741 (6) A Cl 1 alkane having 1 to 3 substituents selected from a halogen atom (a fluorine atom) and a c6-1Q aryl group (phenyl group) as needed Oxy (methoxy), (7) Ch. Aryloxy (phenoxy), (8) 6-membered aromatic heterocyclic group - pendant oxy (pyrimidinyloxy (9) amine carbenyl, (10) optionally having 1 to 3 halogen atoms (fluorine atom) ) 6 alkyl monoamine methyl thiol (ethylamine methyl sulfhydryl), οι) di-c!-1 alkylamino (didecylamino), (12) C!-1 alkyl- a carbonylamino group (methylcarbonylamino group), (13) a cyclic amine group having one pendant oxy group, if necessary, (14) (15) (16)

An amine stone, an I-Ch alkyl sulfonyl group (dipropylamine sulfonyl), and a 5-membered aromatic heterocyclic group (n-l-l- yl),

Or two C selected from the group consisting of a substituent (1) a halogen atom (a fluorine atom, a chlorine atom), (2) a chaotic group, and (3) a ci6 group having 丨 to three tooth atoms (a gas atom) as needed, Third butyl), τ (4) C1-idyl (phenyl), =, if necessary, a C6_1D aryl (stupid) k-Wei (Methane 321538 57 1

Cm aryloxy (phenoxy), 201114741 (7) Di-Cl-6 alkylamino (didecylamino), (8) Ci-6 alkyl base (methyl stellite) And (9) C2-3 extended alkyloxy (ephthyloxy), (F) optionally having one Ci-e entertainment; (m) Cm aryl (phenyl) __ethyl A carbonylamino group, the Cw alkyl group optionally having 丨 to 3 atoms (fluorine atoms), '(G) Ce-ioaryl(phenyl)-propylamino group, (H) having 1 if necessary The aryl (phenyl)-ethylamino group of the halogen atom (fluorine atom), (I) optionally has one halogen atom (fluorine atom). The aryl(phenyl)-oxymethylcarbonylamino group, i (7) optionally has one Ce selected from the following substituents. Aryl (phenyl)-ketone group (1) halogen atom (fluorine atom, chlorine atom), (2) cyano group,

(3) A group having 1 to 3 halogen atoms (fluorine atoms) as needed, a third butyl group,

Cl-6 base (A

Ci-6 alkoxy group (methyl (4) optionally has 1 to 3 halogen atoms (oxygen atom)), (5) C6-1() aryloxy (phenoxy), (6) Ch Alkoxy-carbonyl (ethoxycarbonyl), (7) di-Cl-6 alkylamino (dimethylamino), and (8) Cw alkyloxy (ethylene), CK) 1(d) from the following substituents "filament (benzene phantom 321538 58 201114741 methylurea: U) halogen atom (fluorine atom, gas atom), and (2) Cm alkoxy (decyloxy), (L) It is required to have a methylamino group: one selected from the group consisting of an aryl group (phenyl)_(1) a halogen atom (a fluorine atom), (2) a cyano group,

(3) G-6 alkyl having 1 to 3 groups, a third butyl group, and a halogen atom (fluorine atom) as desired (曱(4)Cm alkoxy (methoxy), (5) C6-lfl aryloxy (phenoxy), (6) Ci-e, oxime-carbonyl (methoxycarbonyl), (Ό G-6 alkyl-carbonylamino), and (8) 6 members Aromatic heterocyclic group (π-pyridyl),

00 is optionally required to have 12 groups of Cl-6 alkoxy groups (methoxy groups) -N-CCm. Aryl (phenyl) monomethyl) amine, N-Cw alkyl (methyl (A) optionally has an acid group amine group: 1 Ce-I selected from the following substituents. Aryl (phenyl) _ (3 4 5) If necessary, have 1 base, tert-butyl), C]_6 alkoxy (a 321538 59 1 halogen atom (fluorine atom, gas atom), 2 cyano group, 3 to 3 s atom Ci6 courtyard based on (fluorine atom) (A 4

Ce-u) aryl (phenyl), 5, if necessary, has 1 to 3 tooth atoms (fluorine atom) of 201114741 oxy), (6) C]-1 2 alkyl-carbonylamino group (mercaptocarbonylamine) And (7) C2-3 alkyloxy (ephthyloxy), (〇) optionally have 1 (^-2 alkyl (t-butyl) aryl (phenyl sulfonate) The base hN-Ci-e alkyl (methyl) amine group, CP) optionally has one Ce selected from the following substituents: aryl (phenyl)-methylsulfonylamino group: (1) tooth atom (fluorine atom), and (2) a Cie alkyl group (fluorenyl group) having i to 3 deuterium atoms (fluorine atom), (Q) a-lfl aryl group (phenylamino mercaptocarbonylamino group, 00 optionally has 5 or 6 membered aromatic heterocyclic groups (thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridyl) selected from the group consisting of: (1) a halogen atom ( a fluorine atom, a chlorine atom, a bromine atom), • (2) a cyano group, (3) a Cl_e alkyl group having 1 to 3 substituents selected from a halogen atom (a fluorine atom) and a cyclic amino group (i. (methyl, ethyl), (^) as needed, having one halogen atom (fluorine atom) , gas atom) c beautiful (phenyl), ^ = 1 to 3 (tetra) atom (10) sub-oxy (methyl (6) Ce-io aryloxy (phenoxy), (7) cyclic amine (morpholine) Base), 60 1 2 321538 201114741 (8) Aminomethyl sulfhydryl, (9) If necessary, have a base of c] _6 yard base, a waking base (methylamine carbaryl, isobutylamine formazan) Base, tert-butylamine methyl sulfhydryl), (10) Cycloamine (N_Merlinyl, N-piperidinylcarbonyl), a (11) carboxyl group, (12) Ci-6 alkoxy-carbonyl (methoxycarbonyl), (13) 5- or 6-membered aromatic heterophenyl (oxadiazolyl, acridinyl) having a complete (methyl) group, if necessary, 14) Aminesulfonyl, and (15) hexaalkylamine sulfonyl (dimethylamine sulfonyl), (8) hydrazine or 6-membered aromatic heterocyclic ((tetra)yl)-carbonyl) n-alkyl (methyl) An amine group, (7) a condensed aromatic heterocyclic group having a Cl s group (methyl group) (., a fluorenyl group, a benzofluorene, a benzoic acid group. , Lu 00 as needed to have "solid ^. aryl (phenyl) 5 or 6 member aromatic heterocyclic group (° thiophene, Mixian, - , a base group)-methyl(tetra)amine group, the C6-〗Q aryl group optionally has one halogen atom (gas atom), 00 6 S material base group, sulfhydryl amino group, (7) 5 or 6 member aromatic Cyclic group (imidinary "bitenyl)_ethenylamine (1)6 carbaryl heterocyclic (biting wire) _ carbonyl silk methylamino group, (7) condensation ^ heterocyclic group (, base)曱 曱 丝 胺, 缩 。 芳香 芳香 芳香 芳香 芳香 芳香 芳香 芳香 芳香 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 (Thienyl)-sulfonylaminomethylcarbonylamino group, (BB) 6-membered aromatic heterocyclic group (β-pyridyl)-ureido group, (CC) optionally having 1 cyclic amine group (pyrrolidinyl group) a 6-membered aromatic heterocyclic group (pyridyl)-methylamino group, '^(DD) optionally has a Ce iD aryl group selected from the following substituents (phenylphenoxy: ' (1) letter Atom (gas atom), ruthenium (2) carboxyl group, (3) Cm alkoxy-carbonyl group (decyloxycarbonyl group), and (4) Ci-e alkyl-amine methylmercapto group (methylamine methyl sulfhydryl group), (EE) A C6_i() aryl group having a substituent selected from the group consisting of phenylamine-based aryl oxygen : U) A Cm alkyl group (isopropyl group) having one hydroxyl group, (2) a suspending group, φ (3) a Ci-e alkoxy-carbonyl group (methoxycarbonyl group), and (4) an amine And (5) Ci-e alkyl-amine fluorenyl (decylamine carbhydryl), (FF) optionally has 6 members of an aromatic heterocyclic group selected from the following substituents (° ratio σ base group) )-oxyl: (1) 16-alkyl (isopropyl), (2) carboxyl, (3) Ci-e alkoxy-carbonyl (methoxycarbonyl), (1) 4) Aminomethyl thiol, and 321538 62 201114741 (5) Ci-e alkyl-amine carbaryl (methylamine carbaryl), and (GG) optionally have 6 members selected from the following substituents Aromatic heterocyclic group (. Pyridyl)-methoxy: & (1) Cm alkyl (isopropyl) having 1 hydroxy group as desired, (2) amine T thiol, and (3) Ci-6 alkyl-amine A Mercapto (methylamine methyl sulfhydryl). In the compound (1), 'R5 is (1) a hydrogen atom, (2) a hydroxyl group or (3) a C--6 alkoxy group having a substituent (methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, Isobutoxy, second butoxy, tert-butoxy, pentyloxy, hexyloxy). Examples of the "substituent" in the "L alkoxy group having a substituent as necessary" in R5 include a substituent selected from the substituent group A. The number of substituents is not particularly limited as long as it is a substitutable number, preferably up to 5, more preferably 1 to 3. Regarding R, a hydrogen atom, a hydroxyl group or a decyloxy group is preferred.

In the compound (I), R6 is (1) a hydrogen atom, (2) atom, (3) a group derived from a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom, or (6) a sulfur atom. Group. Regarding R6, a hydrogen atom is preferred. (2) a halogen atom, (3) a group, (5) in the compound (1) via an oxygen atom, and R7 is a group in which (1) a hydrogen atom is a group of a carbon atom, and (4) is a group via a nitrogen atom. a group or (6) a base of a sulfur atom. Regarding R7, a hydrogen atom is preferred. (2) a halogen atom, (3) in the compound (I), R8 is (1) a hydrogen atom 321538 63 201114741 a group derived from a carbon atom, (4) a group via a nitrogen atom, and (5) a group via an oxygen atom a group or (6) a group via a sulfur atom. It is preferred that R ' is a halogen atom. In the compound (I), R9 is (1) a hydrogen atom, (2) atom, (3) a group via a stone anti-atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom. It is preferred that R ' is a hydrogen atom.

The compound (I) is preferably a compound wherein R* is optionally selected from the group consisting of (1) atom and (2) if necessary; To the atomic alpha group, and (3) the oxime or the substituent of the two substituents; R is a hydrogen atom or a methyl group; R is a gas atom; the following substituents. Aryl (stupid (A) optionally has 1 to 3 selected from _ groups): U) _ atom (fluorine atom, gas atom, bromine atom), (2) Cl-6 s. oxy (methoxy) (3) Ci-e basestone xanthyl (methyl sulphate), (4) Ci-e oxy-mono(ethoxy), (5) thiol, (6) amine Sulfhydryl and (Ό Ci-e alkyl-aminoindenyl (methylamine-methyl), aromatic heterocyclic (B) optionally have 5 or 6 members selected from the following substituents 321538 64 201114741 ( Carbazolyl, imidazolyl, π-pyridyl) (1) halogen atom (bromine atom), (2) gas group, (3) Ch group having U_ group, isopropyl group if necessary), (4)视 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 稀 CM 稀 CM CM CM CM CM CM CM CM CM CM CM CM CM CM ), (6) Ch. The aryl group (phenyl) optionally has a u@ tooth atom (a gas atom), (7) a Cm alkoxy group - a carbonyl group (methoxycarbonyl group, an ethoxycarbonyl group), (8) a carboxyl group, and (9) an amine formazan. (10) If necessary, there are 1 to 3 Ch-alkyl-amine T-methyl groups selected from the group consisting of methylaminocarbenyl, ethylamine, mercapto, isopropylamine, and Butylamine decyl, tert-butylamine fluorenyl): _(4), atom (fluorine atom), (b) thiol, (c) Ci4oxy (methoxy), (d)% <amine ( morpholinyl), (e) Ci_6 alkyl-amine methyl hydrazino. (decylamine fluorenyl) f (f) optionally has a Ci e alkoxy group - carbonyl (ethoxycarbonyl group) 5-membered aromatic heterocyclic group (carbazolyl), (U) Cw cycloalkyl-monomethylcarbamyl (cyclopropylamine fluorenyl), (12) di-Ch alkyl-amine carbhydryl (dimethyl胺 醯 ) ) 、 ( 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视Base, thiazolidine oxime group (1) ratio, succinylamine, sulphide, sulphonate, 321538 65 201114741 tetrahydrothiopiperidylamine sulfhydryl, tetrahydrothiopiperidylamine sulfhydryl): (a) cyano and (b) C!-6 alkyl (methyl), (14 Cyclocarbamyl (π 洛 咬 、, 吗 基 )), (15) di-Cm alkylamino (dimethylamino), (16) C!-6 alkoxy - a carbonylamino group (second butoxycarbonylamino group), (17) optionally having 1 to 3 cyclic amine groups (pyrrolidinyl, oxazolidinyl, morpholinyl) selected from the group consisting of: Qin (a) a transradical group, a (6)-indenyl group (methyl group), and (c) a pendant oxy group, (18) a 5-membered aromatic heterocyclic group (U oxadiazole group, imidazole) having one substituent selected from the group consisting of , pyrazolyl): (a) cyano group, (b) optionally having a halogen atom (fluorine atom) and a hydroxyl group from jade to three substituents of a C 6 alkyl group (methyl, ethyl, isopropyl) And (c) an amine sulfhydryl group, (d) a Cl_6 alkyl group having one hydroxyl group, if desired, a methylaminomethyl group, an isobutylamine methyl sulfhydryl group, and (4) a cyclic amine group (Norline carbonyl group), (19) 6-membered non-aromatic heterocyclic group (dihydropyridyl) having a pendant oxy group as needed And (20) a Ci-6 alkyl-carbonylamino group (mercaptocarbonylamino group), (C) a Ce heart aryl (phenyl)-amino group having one halogen atom (fluorine atom), if necessary, (9) It is desirable to have 1 or 2 alpha selected from the following substituents. Aryl (phenyl, naphthyl)-monoamino group: (1) atom (fluorine atom, gas atom), 321538 66 201114741 (2) cyano group, (3) optionally having a south atom (fluorine atom), One of the one to three substituents of the imido group and the cyclic amine group (the two-side oxythio- phenanthyl group) (alkyl, ethyl, tert-butyl), (4) C6-10 Aryl (phenyl), (5) Ce-i. An aryl-mono(phenyl) group, (6) optionally having a Cm alkoxy group (methoxy group) selected from the group consisting of a tooth atom (a fluorine atom) and a C6, aryl (phenyl) group of 1 to 3 substituents , Pan (7) Ch. An aryloxy group (phenoxy group), (8) a 6-membered aromatic heterocyclic group - a pendant oxy group (pyrimidinyloxy group), (9) an amine carbenyl group, an anthracene) having 1 to 3 halogen atoms as needed ( a fluorine atom) of a Ci 6-amino-mercapto (ethylamine-methyl) group, (11) a di-Ci-6 alkylamino group (dimethylamino), 02) a Ch-carbonylamine a group (methylcarbonylamino group), Φ (13), if desired, a cyclic amine group having one pendant oxy group (bite group, morpholinyl group), (14) amine sulfonyl group, (15) one-Ci -ealkylamine thiol (dipropylamine fluorenyl), and (16) 5-membered aromatic heterocyclic group (π-pyryl), (E) CM cycloalkyl (cyclohexyl)-carbonylamino group, ( F) A core aryl (phenyl)-methylcarbonylamino group having 1 or 2 substituents selected from the group consisting of: (1) a halogen atom (fluorine atom, chlorine atom), 321538 67 201114741 (2) cyanide Base, (3) Ci ealkyl (methyl, tert-butyl) having 1 to 3 tooth atoms (fluorine atom), (4) C6-1Q aryl (phenyl), (5) Need to have 1 Ce-i. Cie alkoxy (methoxy), (6) α丨〇 aryloxy (phenoxy), aryl (phenyl),

(7) bis-Cm alkylamino (dimethylamino), (8) Ci-e sylvestreyl (methyl stellite), and (9) C2-3 alkyloxy (extension) Ethoxy), (G) optionally has one CW complete (methyl) Ce i as needed. Aryl (phenyl)-ethylcarbonylamino group The group optionally has from i to 3 self atoms (gas atom), (H) C6-1G aryl (phenyl)-propylcarbonylamino group,

Cwd aryl (phenyl)- (I) A vinylcarbonylamino group having one halogen atom (fluorine atom) as needed, (J) optionally having one halogen atom (oxymethylamino group, gas) C6-1G aryl (phenyl) of the atom - Ch of the following substituent. The aryl (phenyl)-(K) optionally has one selected from the group consisting of urea groups: (1) a halogen atom (a fluorine atom, a chlorine atom), (2) a cyano group, (3) a 1 to 3 group, if necessary, Third butyl), a halogen atom (fluorine atom)

Ci-6 alkyl (A 321538 68 201114741 (4) as desired oxy), Cl-6 alkoxy having 1 to 3 atoms (fluorine atoms) (methyl(5) C6-1D aryloxy ( Phenoxy), (6) Ci-e alkoxy-condensyl (ethoxylated), (7)--Ci-e alkylamino (dimethylamino), and (8) Cm Alkyloxy (ethyloxy), Ce-H aryl (phenyl) of the following substituents

(L) optionally having one selected from the group consisting of methylureido groups: (1) a halogen atom (a fluorine atom, a chlorine atom), and (2) a 匕-6 alkoxy group (a methoxy group), (8) optionally having one C aryl (phenyl)-methylamino group selected from the group consisting of: (1) a halogen atom (a fluorine atom), (2) a cyano group, and (3) having 1 to 3 (four) sub- Fluorine atom) c] ritual (曱•., butyl), (4) 匕-6 alkoxy (decyloxy), (5). Aryloxy (phenoxy), (6) Cm alkoxy-carbonyl (methoxycarbonyl), (7) Cw alkyl-arylamino (methyl amide), and (8) 6-membered aromatic a ring group (D is a pyridyl group), (N) a Cl_6 alkyl (methyl) aryl (phenylmethyl) amine group having one Ch alkoxy group (methoxy group), if necessary, (O) Ce_i() aryl (phenyl) having a substituent selected from the group consisting of the following substituents: 69 321538 201114741 Anthraquinone: (1) a halogen atom (a fluorine atom, a chlorine atom), (2) a cyano group, (3) An alkyl group having 1 to 3 groups, a third butyl group, and a halogen atom (fluorine atom) as desired (Cm alkoxy group of a halogen atom (fluorine atom) (A)

(4) Ce-i. Aryl (phenyl), (5) optionally having 1 to 3 oxy), (6) C]-6 alkyl-carbonylamino (methylcarbonyl saddle)' and (7) C2-3 extension (Ethyloxy), (8) optionally having 1 Cl_6 succinyl (t-butyl). ))-sulfonyl)-NC b 6 alkyl (methyl) amine US, earth (1) halogen atom (fluorine atom), and 2 if necessary, have 1 to 3 halogen atoms (fluorine atoms) (8) C6-!. An aryl(phenyl)-aminomethylamino group, if desired, a 5- or 6-membered aromatic heterocyclic thiophene group, a sulphur-based group, a hetero- , a sulfhydryl group, a sulfhydryl group, a chiral amine (1) a halogen atom (a fluorine atom, a chlorine atom, a bromine atom), (2) a cyano group, and (3) optionally having a ring atom (say atom) and a cyclic amine group ( [321538 70 201114741 1 to 3 substituents of Cm alkyl (methyl, ethyl), (4) If necessary, have one halogen atom (fluorine atom, chlorine atom) & (1) (Phenyl), (5) Ci 6 alkoxy (methoxy, ethoxy) having 1 to 3 halogen atoms (fluorine atom), (6) Ce-io aryloxy (phenoxy) (), anthracenylamino (morpholinyl), (8) aminocarboxylidene, ruthenium (9), if desired, has one carboxylic acid group, a sulfonyl group, a carbamic acid group Butylamine-methyl hydrazino, tert-butylamino fluorenyl), (10) cyclyl hydrazino morpholinylcarbonyl, N-piperidinylcarbonyl, 1 hydroxy group, (11) carboxyl group, (12) alkoxy-carbonyl (methoxycarbonyl), (13) as needed There are 1 Cl_6 alkyl (indenyl) 5- or 6-membered aromatic heterocyclic-yl (succinyl, indole), (14) sulfonyl, and (15) di-Ci-e Amine thiol (didecylamine fluorenyl), (T) N-(5 or 6 member aromatic heterocyclic (acridinyl)-carbonyl)-N_Ci_6 alkyl (methyl) amine group, (U) A condensed aromatic heterocyclic group having one C!-6 alkyl (methyl) group (indenyl, benzothiazolyl, benzimidazolyl, acridinyl)-carbonylamino group, (V) is required as needed a C61 aryl (phenyl) 5- or 6-membered aromatic heterocyclic group (thienyl, imidazolyl, thiazolyl, pyridylmethylcarbonylamino, = 321538 71 201114741 c6-]. The aryl group optionally has _A atom (chlorine atom), (W) 6-membered non-aromatic heterocyclic group (morpholinyl)-fluorenylcarbonylamino group, (X) 6-membered aromatic heterocyclic group (acridinylethyl ethylamino group, ( Y) 6-membered non-aromatic heterocyclic (piperidinyl)-ethylcarbonylamino group, (Z) 5- or 6-membered aromatic heterocyclic group (imidazolyl, π-pyridylvinylcarbonylamino, (ΑΑ) 6 Aromatic heterocyclic group condensed aromatic with pyridylcarbonylaminomethylcarbonylamino, \ΒΒ) Heterocyclic group (fluorenylmethylcarbonylamino group, (CC) δ-aromatic heterocyclic group (benzimidazolyl, benzona-n-azolyl)-ethylcarbonylamino group, (10)) 5-membered aromatic heterocyclic group (嗟 基 ) _ _ 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 6 6 6 6 6 6 6 6 6 6 6 6 6 彡 彡 杂环 杂环 杂环 杂环 ° 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视 视An atom (chlorine atom), (2) a carboxyl group, (3) a Cm alkoxy group (methoxycarbonyl group), and (4) a Cw alkyl-amine methyl group (methylamine methyl group), ( A C6-1D aryl (phenyl)-aminol-yloxy group selected from the following substituents: & (U optionally has one hydroxy group, 6 alkyl group (isopropyl group) ), (2) carboxyl group, . 321538 72 201114741 (3) Ci-e oxy-carbonyl (methoxyl), (4) amine sulfhydryl, and (5) Ci-e alkyl-amine A Sulfhydryl (methylamine carbaryl), (II) optionally has one substituent selected from the group consisting of the following substituents: (Acridine)-oxyl: $ (1) Cl-6 alkyl (isopropyl), (2) carboxyl, (3) Ci-e methoxy-carbonyl (methoxy) having 1 hydroxyl group as needed a carbonyl group), an I(4) aminyl fluorenyl group, and (5) a Ci-e alkyl-amine fluorenyl group (methylamine carbaryl group), and (JJ) optionally have 6 members selected from the following substituents Aromatic heterocyclic (n-pyridyl)-decyloxy: (1) 匕-6-alkyl (isopropyl), (2) aminyl, and (3) Ci-, optionally having one hydroxy group Ealkyl-aminoindenyl (methylamine fluorenyl); Φ R5 is hydroxy or decyloxy; R is a nitrogen atom; R is a chlorine atom; R is a gas atom; and R is a hydrogen atom. Particularly, as the compound (I), preferred are the following compounds, among which are 4-cyanophenyl, 3-chloro-4-cyanophenyl, 5-chloro-4-cyano-2-fluorophenyl, 5 -chloro-4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 4-cyano-3-methoxyphenyl, 4-cyano-3-ethoxybenzene Or 4-cyano_3_(trifluoromethyl 321538 73 201114741)phenyl; R 2 is a hydrogen atom or a methyl group; R 3 is a hydrogen atom; R 4 is (A) optionally has 1 to 3 selected from a group) · The following substituents of c6-1G aryl (benzene (1) halogen atom (fluorine atom, chlorine atom, atom), (2) Cm alkoxy (methoxy), (3) Ci-e alkyl sulfonate Sulfhydryl (τ-sulfonyl), (4) Ci-e alkoxy-carbonyl (ethoxycarbonyl), (5) carboxyl, (6) aminecarboxamide and (7) Cm alkyl-amine A Amidino (methylamine-methyl sulfhydryl), (8) optionally has 5 or 6 member bases selected from the following substituents (° ratio 0 sit-base, mito-based, η-mercapto group): 『%% (1) a halogen atom (bromine atom), (2) a cyano group, a -6 alkyl group (methyl group, an isopropyl group), a C2-6 group (3-methyl-1-butene (3), if necessary, has one Base (4) as needed a base of a radical group, (5) a C2_6 alkynyl group having one hydroxyl group as needed (3-methyl-oxime-butynyl group), and (6) having one halogen atom (fluorine atom) as needed Indyl aryl (phenyl), (7) Cw alkoxy-carbonyl (methoxycarbonyl, ethoxycarbonyl), 321538 74 201114741 (8) Rebel, (9) Aminomethyl, (10) If desired, there are 1 to 3 Ch alkyl-amine fluorenyl groups selected from the group consisting of methylamino fluorenyl, ethylamine carbaryl, isopropylamine decyl, isobutylamine formazan Base, tert-butylamine fluorenyl): (a) a halogen atom (a fluorine atom), (b) a hydroxyl group, (ocw alkoxy group), (d) a cyclic amino group (morpholinyl group), (e) Cl_6 alkyl monoamine carbenyl (methylamine carbenyl) and (f) 5-membered aromatic heterocyclic carbazole with 1 Cl_e alkoxy-carbonyl (ethoxycarbonyl), if desired (11) C3-e cycloalkyl-amine-brenyl (cyclopropylamine), (12) bis-Ci-6 alkyl-amine fluorenyl (didecylamine fluorenyl), (13) A 5- or 6-membered heterocyclic group having a substituent selected from the group consisting of the following substituents - isoxazolylamine Sulfhydryl, thiadiazolylamine, sulfhydrylamine, hydrazinyl hydrazide

Tetrahydrothiomethaneamine ketone group, tetramethyl thioxanthyl amide group): (a) cyano group and (oCh alkyl (methyl), (14) cyclic amine mercapto group („Byrrolidinylcarbonyl, morpholinylcarbonyl), (15) bis-Ci-6 alkylamino (dimethylamino), (16) Cm alkoxy-carbonylamino (second butoxy a carbonylamino group), (17) optionally having 5 ring amine groups (oxaridinyl, oxazolidinyl, morpholinyl) selected from the group consisting of: (a) a hydroxyl group, (b)^- 6 alkyl (methyl) and (c) pendant oxy group, (10) optionally having 5 members of an aromatic heterocyclic group selected from the following substituents 321538 75 201114741 (% · σ stagnation, taste sulphate, η ratio σ 坐 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) And (c) an amine methyl sulfhydryl group, (4) if desired, i having a thiol group, an amine group (methylamine f-branched group, isobutylamine?), and (e) a cyclic amine^醯-based (Nallidyl), (19) 6-membered non-aromatic heterocyclic group (dichloropyrene) And (20) Cm alkyl-monoamino (methylaminoamino), (C) Cei having one tooth atom (fluorine atom) as needed. Aryl (phenyl)-amino group, (9) If necessary, or two c(tetra)aryl (phenyl, naphthyl)-carbonylamino groups selected from the group consisting of: (1) a halogen atom (a fluorine atom, a chlorine atom), (2) a cyano group, and a ruthenium (3) Any one of 1 to 3 substituents (methyl, ethyl) having a terminal atom (oxygen atom), a transamidiamine group, and a cyclic amine group (two-sided oxythiophenanthyl group) as needed , a third butyl group, (4) an aryl group (phenyl), (5) a C6-1() aryl-carbonyl group (benzhydryl group), (8) optionally having a halogen atom (a fluorine atom) and Cei. 1 to 3 substituents of aryl (phenyl) Ci-6 alkoxy (decyloxy), (7) C6-1 () aryloxy (phenoxy), (8) 6 members Aromatic heterocyclic group - pendant oxy group (pyrimidinoxy), 321538 76 201114741 (9) Aminomethyl sulfhydryl, (10) Ci6 alkyl monoamine A having 1 to 3 halogen atoms (fluorine atoms) as needed Mercapto (ethylamine sulfhydryl), (11) di-Cl-6-homo-amino (dimethylamino), (12) Cm alkyl-carbonylamino group (methylcarbonylamino group), (13) a cyclic amine group having one pendant oxy group as required (π ratio biting group, morphine group), (14) amine sulfonate Sulfhydryl, ^(15)diphenyl 1-6 alkylamine sulfonyl (dipropylamine sulfonyl), and (16) 5-membered aromatic heterocyclic (α-pyryl), (Ε) as needed Q w aryl (phenyl)-methylcarbonylamino group having 1 or 2 substituents selected from the group consisting of: (1) a halogen atom (a fluorine atom, a chlorine atom), (2) a cyano group, (3) as needed c]_6 alkyl group having 1 to 3 halogen atoms (fluorine atom), (4) Cm aryl group (phenyl group), (5) 1 C6-1Q as needed Cl_6 alkoxy (methyl group) of aryl (phenyl), (6) C6-1D aryloxy (phenoxy), (7) di-Cl-6 alkylamino (dimethylamino) ), (8) Ci-e basestone xanthine base (sulfenyl yellow base), and (9) (Vs alkyloxy group), (F) 1 C, 6 alkane as needed Base (mercaptoaryl) to ethyl 77 [S] 321S38 201114741 arylamino group, which has 1 to 3 halogen atoms (fluorine atoms), (G) Ce-H) aryl (phenyl)-propylamino group, (8) C61 having an i atom ((iv)) as needed. Aryl (phenyl)-vinylcarbonylamino group, (1) C61 having i functional atoms (fluorine atoms) as needed. An aryl(phenyl)-oxymethylcarbonylamino group, (7) an aryl (phenyl)-ureido group optionally having one substituent selected from the group consisting of: (1) S atom (fluorine atom, gas atom) (2) Cyano group, (3) Cl4 group (methyl group, tert-butyl group) having 1 to 3 tooth atoms (gas atom) as needed, (4) optionally having 3 to 3 tooth atoms (fluorine atom) Ethoxy (methoxy), (5) Οδ-ίο ^ gas (phenoxy), (6) Ci-e alkoxy-carbonyl (ethoxycarbonyl), (7) di-C]- 6 alkylamino (dimethylamino), and (8) Cm alkyloxy (ethyloxy), (1) optionally having 1 (tetra)aryl (phenyl) selected from the following substituents _ Methylurea group: (1) Self-atoms (fluorine atoms, gas atoms), and (2) Cm alkoxy groups (methoxy groups), α) optionally have a Cei selected from the following substituents. (Editor's 321538 78 201114741 Methylamino group: (1) Halogen atom (fluorine atom), (2) Cyano group, (3) Ci6 alkyl group (methyl) having 1 to 3 tooth atoms (fluorine atom) as needed , tert-butyl), (4) Cw alkoxy (τ oxy), (5) C6-1 D^ gas group (phenoxy), • (6) Ci-e alkoxy-mono(indenyloxy), (7) Ci-e alkyl-carbonylamino (methylcarbonylamino), and (8) 6-membered aromatic heterocyclic group (D to bite base), «) n-Ch alkyl (f-based) N-(C6-lfl square group) (meth)amino group, (N) optionally has one Ce selected from the following substituents: aryl (phenyl)-sulfonylamino group: (1) halogen atom (fluorine atom, chlorine atom) , % (2) cyano group, (3) as needed, to 3 teeth (fluorine atom) c]_6 alkyl (methyl, tert-butyl), (4) C6-lfl aryl (phenyl) (^) Ci6 morphoxy (methoxy) having 1 to 3 halogen atoms (fluorine atom) as desired, (6) Cw alkyl-carbonylamino group (methylcarbonylamino group), and (7) CM alkyloxy (ephthyloxy), (〇) as desired, has a monoalkyl group (tertiary butyl group) ((: 6 丨. aryl (benzene 79 [s] 321538 201114741 base) - Continued fluorenyl) - ni6 silk (methyl) amine group, one selected from the group consisting of the following (tetra) group (stupid - (1) halogen atom (fluorine atom), and To one of three tooth atoms (gas atoms), (8) C6' aryl (phenyl)-aminomethyl drum amine group, ^ see that it is necessary to have f 1 selected from the following substituents 5 or 6-membered aromatic heterocyclic ring: wire-based, heterophilic, mercapto, π-bito)-carbonylamino: U) halogen atom (fluorine atom, gas atom, bromine atom), (2) cyano group, . , μ (3) Having two or three substituents selected from the group consisting of a _ atom (a fluorine atom) and a cyclic amine group (a core group), a Cl_e alkyl group (methyl group, ethyl group), (4) optionally having c (tetra)aryl φ (phenyl) of one tooth atom (fluorine atom, chlorine atom), (5) 6 alkoxy group (methoxy group, ethoxy group) having 1 to 3 halogen atoms (fluorine atom) as needed ), (6) C6-1() aryloxy (phenoxy), (7) cyclic amino group (morpholinyl), (8) aminic acid group, (9) having one hydroxyl group as needed -6-alkyl-aminoindenyl (decylamine decyl, isobutylamine sulfhydryl, tert-butylamine fluorenyl), (10) Cycloamine fluorenyl having 1 hydroxy group as needed (N_morpholinyl group, 80 321538 201114741 base group), (11) carboxyl group, (12) Cm alkoxy-carbonyl (decyloxycarbonyl), (13) 5 or 6 membered aromatic heterocyclic group having 1 Ch alkyl group (fluorenyl group), if desired, 14) Amines, and (15) di-C!-6 alkylamine sulfonyl (dioxylsulfonyl), (S) N- (5 or 6 member aromatic heterocyclic (σ ratio) °定))--)-N-Ci-6 alkyl (meth)ylamino, (T) condensed aromatic heterocyclic group having 1 G-6 alkyl (fluorenyl) as desired , stupid and thiazolyl, benzimidazolyl, pyridyl)-carbonylamino, (U) 5 or 6 membered aromatic heterocyclic group having 1 Cho aryl (phenyl) as desired (thienyl, imidazolyl) , thiazolyl, pyridyl)-methylcarbonylamino group, the C6-1D aryl group optionally has one halogen atom (chlorine atom), (V) 6 member aromatic heterocyclic group (° ratio bite group)-ethyl group Alkylamino, φ (W) 5 or 6 membered aromatic heterocyclic (imidazolyl, acridine)-vinylcarbonylamino, (X) 6-membered aromatic heterocyclic pyridyl)-carbonylamino Alkylcarbonylamino group, (Y) condensed aromatic heterocyclic group (fluorenyl)-fluorenylcarbonylamino group, (Z) condensed aromatic heterocyclic group (benzene) And imidazolyl, benzoxazolyl)-ethylcarbonylamino, (AA) 5-membered aromatic heterocyclic group (π-sepeno) _ scutane-based amine fluorenylamino, (ΒΒ) 6 Aromatic heterocyclic (acridinyl)-ureido, (CC) 6-membered aromatic heterocyclic group having 1 cyclic amino group (pyrrolidinyl) as desired [s] 81 321538 201114741 Οpyridyl)-曱The amino group, (DD) optionally has one Ce selected from the following substituents. Aryl (phenyl)-methoxy: (1) a halogen atom (a gas atom), (2) a carboxyl group, (3) a Ci-e alkoxy group (a methoxy group), and (4) Cm alkyl-aminoindenyl (decylamine fluorenyl), (EE) optionally has 1 aryl aryl (phenyl)-aminoloxy group selected from the group consisting of: (1) Cl-6 group (isopropyl) optionally has one hydroxyl group, (2) carboxyl group, (3) Ci-6-oxyl-carbonyl group (methoxyl group), (4) amine-methyl group, And (5) Ci-e alkyl-amine mercapto (mercaptoamine), aromatic heterocyclic group

(FF) optionally has 1 (pyridyl)-oxy group selected from the following substituents: (1) CNe alkyl (isopropyl) having 1 hydroxyl group, (2) carboxyl group, (3) a Ci-e alkoxy-carbonyl (methoxycarbonyl) group, (4) an amine carbaryl group, and (5) a Cw alkyl-amine carbaryl group (methylamine carbaryl group), and (10) optionally have 1 member selected from the following substituents

(°-pyridyl)-indoyl··9 miscellaneous JG) Cl_e alkyl (isopropyl) having one hydroxyl group as needed, 321538 82 201114741 (2) Amine group, and =) Cw alkyl -Aminocarboxamyl (methylamine fluorenyl); R is hydroxy or methoxy; the ruthenium is a hydrogen atom; R is a hydrogen atom; R8 is a hydrogen atom; and R9 is a hydrogen atom. More specifically, the following compounds and salts thereof are preferred. t3H2S'3R)_1-(3-Chlorocyanophenyl)-3,yl-2-indole 3:yl]|cyclopropylfin-2-ylamine (Example 26) pyridine, 3J;:S, 3R) + (3_ gas '4-indolylphenyl)-3-hydroxy-2-mercaptopyrrole (3) '~(1_methylethyl)pyridine-2-ylamine (Example 27) ~2~甲其(2S' 3RH —[4_Nitro-3~(trifluoromethyl)phenyl]I via the group (4) II ratio " each bite '3 - kib ethyl Π ratio. Brewing amine (Example 34) biting q !2S,3R)-1_(4-nitro-3-fluorophenyl)-3'-yl-2-methyl-0 ratio (5) ^] winter methyl ° Bisyl 1 amide (Example 1 〇 5). each. 〜4'{(2S,3R)_3_ thiol'2-methyl-3~[6-(2_sideoxyl ratio (6) pyridine I-based] pyrrolidine + fluorenylbenzonitrile (implementation Example 112) Group ~2S,3R)~1_(4-cyanophenyl)~3-hydroxy-2-methylpyrrolidine-3-(?) bite ''2''carbonitrile (Example 113) 4' iL2'4'{(2S,3R>3~^&'2~ ψ ^-3~[6-(5~ ψ *-1, 3, 114) sitting 2~yl)pyridine-3-yl]pyrrole Pyridylbenzonitrile (Example Γ f 9〇' 3S)-l-(3-chloro-4-cyanophenyl)- 2-methyl. Biropyridine 3:321538 83 201114741 base]-N-(2-hydroxy-2-mercaptopropyl)pyridine_2, 5-diamine (Example 316) (9) N-[(2S' 3S)-l-(3-chloro-4-cyanophenyl)-2-methylpyrrolidine_3_yl]-5-(5-methyl-1,3,4-protonadiazol-2-yl Pyridyl-2-monodecylamine (Example 318) ' In a specific embodiment of the present invention, among the above compounds (I), the compound (I a ) is preferred. In the compound (ia), the ring is a benzene ring further having a substituent as needed. Examples of the "substituent" of the benzene ring having a substituent as required include the substituents exemplified as the "substituent" of the above-mentioned "cyanophenyl group having a substituent as necessary". With respect to the substituent, it is preferred to have one or three or two or more substituents selected from 1 to 3 halogen atoms as necessary. In particular, 1 or a group selected from the group consisting of (丨) a gas atom, (2) a fluorine atom, (3) an fluorenyl group having i to 3 fluorine atoms, (4) a methoxy group, and (5) an ethoxy group, as desired Two substituents are preferred. Spring € Preferably, the benzene ring having a substituent selected from a halogen atom, a Ch alkyl group having a halogen atom, and a C -6 alkoxy group is optionally required. Regarding ring Aa, 4-cyanophenyl, 3-gas-4-nitrophenyl, 5-chloro-4-indolyl-2-fluorophenyl, 5-chloro-4-Ilyl-2-methylbenzene , 4-cyano-3-3 phenyl, 4-aryl-3-methoxyphenyl, cyano | ethoxyphenyl, 2-amino-5-fluorophenyl and 4-cyano -3-(trimethylmethyl)phenyl is a preferred substituent. "In the compound (5)" ring is an aromatic moiety having a substituent as needed, an aromatic heterocyclic ring optionally having a substituent or a substituent having a substituent, 321538 84 201114741 Non-aromatic ring. "Aromatic hydrocarbon ring having a substituent if necessary Examples of the "aromatic hydrocarbon ring" include an aromatic hydrocarbon ring corresponding to the aromatic hydrocarbon group exemplified as the "aromatic ring group" of the above-mentioned "aromatic ring group having a substituent as necessary". The aromatic hydrocarbon ring is preferably a benzene ring or a naphthalene ring. Examples of the "aromatic heterocyclic ring" of the "aromatic heterocyclic ring having a substituent as necessary" include the "aromatic heterocyclic group" exemplified as the "aromatic cyclic group" as described above in the "aromatic cyclic group having a substituent as necessary". Aromatic heterocycle. About ® Aromatic Heterocycle, π ratio Jun ring ° ring, ° thiophene ring, 嘻σ ring, isoindole 0 ring, β plug ring, π bite ring. Lead π ring, bow and ring, benzene and sell σ ring, benzene and meter. The seat ring and the ankle ring are preferred. Examples of the "non-aromatic ring" of the "non-aromatic ring having a substituent having a substituent" include a non-aromatic ring group exemplified as the "ring group" of the above-mentioned "ring group having a substituent as necessary". Aromatic ring. With regard to the non-aromatic ring, a cyclohexane ring, a piperidine ring, a morpholine ring and a 2,3-dihydrobenzofuran ring are preferred. Ring Ba is preferably a benzene ring, a 吼π-ring ring, a ° ratio β ring, a azo ring, a naphthalene ring, a thiazole ring, a carbazole ring, an isoxazole ring, an anthracene ring, a benzothiazole ring, a benzo ring. mum. The ring, the bite ring, the 2,3-dihydrobenzopyrene ring, the oxime ring or the celene ring, each having a substituent as needed, more preferably a pyridine ring having a substituent as needed. Examples of the "substituent" of the "aromatic hydrocarbon ring having a substituent, if necessary", the "aromatic heterocyclic ring having a substituent as necessary", and the "non-aromatic ring having a substituent as necessary" include the above-mentioned "replacement as needed" Substituents exemplified by "substituents" of the aromatic cyclic group of the group. [s] 85 321538 201114741 The "substituent" of the "aromatic hydrocarbon ring optionally having a substituent" is preferably: (1) a halogen atom (a fluorine atom, a chlorine atom or a bromine atom), and (2) if necessary 16 alkoxy (methoxy) of i to 3 substituents selected from a halogen atom (a fluorine atom) and a Ce heptaaryl (phenyl group), (3) a Ci6-based waking group (methyl sulfhydryl group), 4) C!-6 alkoxy-carbonyl (methoxycarbonyl, ethoxycarbonyl), (5) a suspending group, (6) an amine carbenyl group, (7) having i to 3 tooth atoms (gas atoms) as needed Cw alkyl-amine-mercapto-based (decylamine sulfhydryl, ethylamine-methyl fluorenyl), (8) cyano group, (9) optionally having a halogen atom (fluorine atom), a hydroxyimino group, and The oxime of the cyclic amino group (two-sided oxythiomorpholinyl group) to three substituents = alkyl (methyl, ethyl, isopropyl, tert-butyl), (i) Cei. Square (phenyl), (1) melon. Aryl-based (benzoquinone), (1) known. Aryloxy (phenoxy), (13) 6-membered aromatic heterocyclic group - pendant oxyblymidyloxy), (14) di-C!-6 alkylamino (dimethylamino) , (15) (: 1_6 alkyl-carbonylamino group (methyldecylamino), (6) optionally having a fluorenylamino group (pyrrolidinyl, morpholinyl), (17) amine sulfonate Sulfhydryl, (18) bis-Ch-alkanyl ylamine fluorenyl (dipropylamine), (10) 5- or 6-membered aromatic heterocyclic + (p-pyrrolyl, pyridyl), (2) Cl_6 alkylsulfonyl (methylsulfonyl) and (21) C2-3 alkyloxy (ethyloxy). "Substituent" of "aromatic heterocyclic ring having a substituent as necessary", Preferably, (1) a halogen atom (a fluorine atom, a chlorine atom, a bromine atom), a guanidinium group, or (3) optionally has a group selected from the group consisting of a (tetra) (fluoro atom), a silk, and a cyclic amino group (an pyridine group). 3 substituents of c, _e alkyl (methyl, ethyl, isopropyl), (4) Cz_6 alkenyl (3_methylbutene <_ base) having 1 hydroxyl group as needed, (5) CM alkynyl group having 1 hydroxyl group as needed (3_methylbutyne 321538 86 201114741 -1-yl), (6 If necessary, it has one halogen atom (a fluorine atom, a chlorine atom) (: _ aryl (phenyl), (7) k alkoxy-carbonyl (methoxycarbonyl, ethoxycarbonyl), (8) carboxyl, ( 9) Aminomethyl sulfhydryl, (1 〇), if necessary, has up to 3 base-amines of the following substituents (methylamine, ethylamine, isopropylamine) Anthracenyl, isobutylamine, mercaptomethyl, tert-butylamine, mercapto): (a) a halogen atom (a fluorine atom), (b) a hydroxyl group, (c) a G 6 alkoxy group (methoxy group), (d) a cyclic amino group (morpholinyl group), (e) a Cl_6 alkyl-monomethylcarbamyl group (roradylcarbamyl group), and (f) optionally having one C!-6 alkoxy-carbonyl group ( 5-membered aromatic heterocyclic group of ethoxycarbonyl) (α-saltyl), (丨1)c3 6-cycloalkyl-aminecarboxylidene (cyclopropylaminecarbamyl), (12): _Ci 6 alkane a 5-aminomethylamino group (di-F-aminocarbamoyl), (13) optionally having 5 or 6 members of a heterocyclic group-aminoindenyl group (isoxazolylamine formamidine) selected from the group consisting of the following substituents Base, thiadisthylamine, hydrazinyl hydrazino, π-thylsulfanyl, tetrahydropyranyl Amine thiol, tetrahydrothiopiperidylamine methyl sulfonyl, tetrahydrothiopiperidylamine methyl sulfhydryl) (a) cyano group and (b) Cl 6 alkyl group (fluorenyl group), # ( 14) A cyclic sulfhydryl group having 1 hydroxy group (pyrrolidinylcarbonyl, morphinylcarbonyl, N-piperidinylcarbonyl), (15) di-Ci-6 alkylamino group (dimethylamine), if necessary (6) (16) (^-6 alkoxy-carbonylamino (t-butoxycarbonylamino), (Π) optionally has 1 to 3 cyclic amine groups (pyrrolidine) selected from the following substituents Base, 1 sulphonyl, morphinyl): (a) thiol, (b) Ci-6 alkyl (methyl) and (c) pendant oxy, (18) optionally having one selected from the group consisting of a 5- or 6-membered aromatic heterocyclic group (oxadiazolyl, imidazolyl, π-pyrazolyl, "pyridinyl"): (a) a cyano group, (b) optionally having a halogen atom (fluorine atom) And a Ci-alkyl group having 1 to 3 substituents of a hydroxyl group (fluorenyl group, ethyl group, isopropyl group), (c) aminyl group, IS] 87 321538 201114741 (d) 1 base group as needed Cm alkyl-amine sulfhydryl (decylamine carbaryl, isobutylamine methyl) and (e) cyclic amine thiol (drinking) (19) 6-membered non-aromatic heterocyclic group (dihydropyridyl) having a pendant oxy group, (20) Ci_6 alkyl-carbonylamino group (methylaminoamino group), (21) A Cu alkoxy group (decyloxy group, ethoxy group) having 1 to 3 halogen atoms (fluorine atoms), and (22) Ce-i, if necessary. An aryloxy (phenoxy) group, (23) an amine sulfonyl group, (24) a di-c-b 6 carbyl retinoic acid group (didecylamine fluorenyl group), and (25) % of having 1 C6m of a halogen atom (chlorine atom). Aryl (phenyl). In the compound (la), I/ is a bond, -〇-, ~ with -, -nhcH2-, -NHC0---NHC0CH2---NHC0NH->-NHC0(CH2)2---NHCOCH2O-, -NHCOCH2NHCO-, -NHC0(CH2)3-, -NHC0CH=CH-, -NHC0NHC0-, -NHCOCH2NH-, -NHCOCH2NHSO2-, -NHC0NHCH2-, -NHSO2-, -NHSO2CH2-'-N(CH3)- > -NCCH3)CH2- '-N(CH3)C0- '-N(CH3)S〇2-, -〇CH2- or -OCONH-. Regarding La, a bond and -NHCO- are preferred. In the compound (la), R 2a is a hydrogen atom or a 0-6 alkyl group (for example, mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, Amyl, hexyl, etc.). As for R2a, a ruthenium atom and a ruthenium group are preferred. In the compound (la), R5a is a hydrogen atom, a hydroxyl group or a C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Dibutoxy, tert-butoxy, pentyloxy, hexyloxy, etc.). R5a ' is preferably a hydrogen atom, a hydroxyl group or a decyloxy group. Preferable examples of the compound (Ia) include the following compounds, wherein: ring Aa 88 321538 201114741 is a benzene ring further having a substituent selected from a halogen atom, a Cw alkyl group having a halogen atom, and a Cw alkoxy group, if necessary, And the ring Ba is a benzene ring, a pyridazine ring, and a ratio of °. Sitting ring, taste. Ring, naphthalene ring, ° plug ° ring, 唁σ ring, sigma ring, anthracycline, benzothiazole ring, benzimidazole ring, acridine ring, 2,3-dihydrobenzindole The ring of the ring, the ring of the ring, or the ring of the porphyrin, each having a substituent as needed. With respect to the compound (la), the following compounds are preferable, wherein: the ring 43 is a benzene ring (1) halogen atom having 1 or 2 substituents selected from the group consisting of, and (2) having 1 to 3 halogens as necessary. Atom G-6 alkyl β group, (3) Ch alkoxy; ring Ba is a benzene ring, a naphthalene ring, a π ratio ring, a σ-mist ring, a porphin ring, a saliva ring, an isoxazole ring, a thiazole Ring, pyridine ring, anthracene ring, indazole ring, benzothiazole ring, stupid imidazole ring, acridine ring, cyclohexane ring, piperidine ring, morpholine ring or 2,3-diphenylbenzofuran ring , each having a substituent; I/ is a bond, _0-, _NH-, _NHCH2_, -NHC0_, -NHCOCIL·-, -NHC0NH-, -.C0(CH2)2-, -Li COCH2〇-,- NHCOCHWHCO-, φ -NHC0(CH2)3---NHCOCH-CH---NHC0NHC0---NKOCHzNH-, -NHCOCH2NHS〇2-, -NHC0NHCH2-, -NHS〇2---NHSO2CH2- '-N(CH3 )---N(CH3)CH2---N(CH3)C0---N(CH3)S〇2---OCH2- or -0(3)NH-; R2a is a hydrogen atom or a methyl group; and R53* hydrogen atom , hydroxy or decyloxy. Particularly, as the compound (la), the following compounds are preferred, wherein: cyclopentane 3 is 4-cyanophenyl, 3-chloro-4-cyanophenyl, 5-chloro-4-cyano-2-fluoro Phenyl, 5-chlorocyano-2-indenylphenyl, cyano-3-fluorophenyl, 4-89 321538 201114741 cyano-3-methoxyphenyl, 4-cyano-3-ethoxy a phenyl group, a 2-cyano-5-fluorophenyl group or a 4-cyano-3-(difluoro-Tyl)phenyl group as a substituent on a nitrogen atom; the ring Ba is: (1) having 1 as needed To three benzene rings or naphthalene rings selected from the group consisting of: (1) a functional atom (a fluorine atom, a chlorine atom, a bromine atom), (a pseudoscopic need to have a halogen atom (a fluorine atom) and a Ce-nonyl group ( 1 to 3 substituents of phenyl), Cl-6 alkoxy (methoxy), (3) indol-6 alkylsulfonyl (methylsulfonyl), (4) (1-6) An oxy-carbonyl group (methoxycarbonyl group, ethoxycarbonyl group), (5) a carboxyl group, (6) an amine carbenyl group, (7) a C-alkyl group having from 1 to 3 halogen atoms (fluorine atoms) as needed - Aminomethyl sulfhydryl (methylamine methyl sulfhydryl, ethyl amine fluorenyl), (8) cyano group, (9) optionally having an atomic group (fluorine atom), hydroxyl group And a cyclic amino group (two-sided oxythiomorpholinyl) oxime to three substituents of Ci_6 alkyl (methyl, ethyl, isopropyl, tert-butyl), (1 〇) c (tetra) aryl (phenyl), πύα-1D aryl-carbonyl (benzoyl), (12) C6_i() aryloxy (phenoxy), (13) 6-membered aromatic heterocyclic-side oxy ( Pyrimidinyloxy), (14) mono-Ci-e alkylamino (dimethylamino), (15) Ci-alkyl-carbonylamino (methylcarbonylamino), (16) as needed a cyclic amine group having one pendant oxy group (σ ratio thiol group, morphine group), (17) amine continuation base, (m alkyl amide yellow wine base (dipropylamine sulfonyl)), 19) 5- or 6-membered aromatic heterocyclic group (tI than aryl, pyridyl), (20) (^-6 alkylsulfonyl (methylsulfonyl), and (21) (: 2_3 Alkyloxy (ethyleneoxy); (ii) pyrazole ring, imidazole ring, thiophene ring, indazole ring, isoxazole ring, thiazole ring, pyridine ring, anthracene ring, indazole ring, benzothiazole Ring, benzo-I-[s] 321538 90 201114741 The ring or the ruthenium has j to 3 substituents selected from the following: (1) Halogen (fluorine atom, chlorine atom, bromine atom), (2) cyano group, (3) Cl_6 alkyl group having 1 to 3 substituents selected from the group consisting of a _ atom (a fluorine atom), a thiol group and a cyclic amine group (fluorenyl group) Base, ethyl, isopropyl), (4) as desired, having a C2_6# group (3-methyl-di-butyl), (5) having one alkyne group in one county as needed (3- Methyl + butyl fast + base), (6) Ce i having a halogen atom (fluorine atom, chlorine atom) as needed. Aryl (phenyl), (7) C!-6 alkoxy-carbonyl ( Methoxycarbonyl, ethoxycarbonyl), (phantom carboxyl, (9) amine carbenyl, (1〇) optionally have from 1 to 3 C selected from the following substituents, - 6 alkyl-amine formazan Alkylamine, ethylamine, isopropylidene, isobutylamine, butylamine, and butylamino): (a) a halogen atom (fluorine atom), (b) hydroxy, (c) Ci6 alkoxy (methoxy), (4) alanine (Merlinyl), (e) Ci6 alkyl-aminocarboxamide (methylamine methyl) f ( f) 5-membered aromatic heteropoly group having 1 Cl_e alkoxy-carbonyl (ethoxycarbonyl) as desired ((silk) ), (1) melon 6-ring alkyl group - amine methyl sulfhydryl group (cyclopropylamine ke group) (12) - Ci-e alkyl group - amine aryl group (dimethylamine carbaryl), (13) If desired, a 5- or 6-membered heterocyclyl-amine-branched group selected from the group consisting of the following substituents ((4)-methylamine-methyl fluorenyl group, hydrazine di- s- yl yl yl yl yl Amine amide, tetrazolium succinylcarbamyl, tetrahydrothioglycolylcarbamyl, tetrahydrothiopiperidylamine, fluorenyl (a) cyano and (b) Cl_6 alkyl (methyl), (14) cycloamine fluorenyl (pyrrolidinylcarbonyl, morpholinylcarbonyl, N-piperidinylcarbyl)' (15) di-Chane as needed Amino group (didecylamino group), (16) Ci 6 alkoxy-carbonylamino group (second butoxycarbonylamino group), (17) optionally having j 321538 91 201114741 to 3 selected from the following Substituent ring amine group (pyrrole sigma, carbazole c group, morpholinyl group): (a) hydroxy group, (WCh alkyl group) and (c) side oxy group, (18) 1 if necessary a 5- or 6-membered aromatic heterocyclic group selected from the group consisting of oxadiazolyl, imidazolyl, Azolyl, n-pyridyl) (a) cyano, (b) optionally having a halogen atom (fluorine atom) and 1 to 3 substituents of the radical, c, _6 alkyl (fluorenyl, Ethyl, isopropyl), (c) aminomethyl sulfhydryl, (d) Ci-6-homo-indenyl group (nonylamine oxime, isobutylamine oxime) having 1 hydroxy group as needed And (e) a cyclic aminyl (morpholinocarbonyl) group, optionally having 6 pendant non-aromatic heterocyclic groups (dihydrogen 11 to bite), (2〇) (^_6) The alkoxy group (methoxy group, ethoxy group) having 1 to 3 halogen atoms (fluorine atoms), if necessary, is a carbonyl group (methylcarbonylamino group). Aryloxy (phenoxy), (23) aminesulfonyl, (24) di-Ci-6 alkylamine sulfonyl (dimylamine sulfonyl) and (25) 1 halogen as needed a C6_1D aryl (phenyl) group of an atom (chlorine atom); or (iii) a cyclohexane ring, a piperidine ring, a morpholine ring or a 2,3-dihydrobenzofuran sigma ring; I/ is a bond, -〇---ΝΗ---NHCH2---NHC0---NHC0CH2-, -NHC0NH---NHC〇CCH2)2---NHCOCH2O---NHCOCH2NHCO- '-NHCO(CH2)3---NHC0CH =CH---NHC0NHC0---NHC0CH2NH-, -NHCOCH2NHSO2---NHCONHCH2---NHSO2---NHSO2CH2- '-N(CH3)---N(CH3)CH2---N(CH3)C0- -N(CH3)S〇2---0CH2- or -0CONH-[particularly a bond or _NHC〇_]; R2a is a ruthenium atom or a ruthenium group; and R5a is a nitrogen atom, a hydroxyl group or a ruthenium group. . [s] 92 321538 201114741 In another embodiment of the present invention, in the above compound (i), the compound (lb) is preferred. In the compound (lb), the ring Ab is a benzene ring which is further substituted with a substituent selected from a halogen atom and, if necessary, a C!-6 alkyl group having a halogen atom, as needed. With respect to the ring Ab, it is preferred to further have a benzene ring having a substituent selected from the group consisting of (1) a chlorine atom, (2) a fluorine atom, and (3) an fluorenyl group having 1 to 3 fluorine atoms as necessary. Regarding the ring Ab, 4-cyanophenyl, 3-chloro-4-cyanophenyl, 4-cyano-3-hydroxyphenyl or 4-cyano-3-(trifluoromethyl)phenyl Substituents on the nitrogen atom are preferred. In the compound (lb), the ring is a pyridine ring further having a substituent as needed. The pyridine ring having no substituent other than the substituent Rb is preferred for the ring Bb ', and the substituent is not substituted except for the substituent fluorene, and the pyridine ring in which the Lb is bonded to the 2-position or the 3-position is more preferable. In the compound (lb), Lb is a bond or -NHC0-. In the compound (lb), (1) an amine methyl group selected from a substituent having a Ci6 alkyl group and a C3-6 cycloalkyl group, if necessary, and (2) a cyano group, (3) If necessary, the ratio of the side of the oxy group is determined by the ratio of σ or (4) if necessary, the ruthenium of the Cu group. With respect to R', (1) optionally has a C1-6 alkyl group (e.g., anthracenyl, ethyl, isopropyl, isobutyl) and a Ch cycloalkyl group (e.g., a ring) selected from a hydroxyl group as needed. An alkyl group of a substituent of a propyl group, (2) an aryl group, (3) a pyrrolidinyl group having a pendant oxy group as required, and (4) a ruthenium (for example, a fluorenyl group) if necessary The dimercapto group is preferably a cyclopropylamine methyl sulfonyl group, an isopropylamine oxime group, an ethylamine fluorenyl group, a decylamine oxime, 2 93 m 321538 201114741 side oxypyrrolidine-1 More preferably, a cyano group, a cyano group, a 5-nonyl oxadiazole-2-yl group and a 2-hydroxy-2-methylpropyl group. In the compound (ib), hydrazine is a Cl_e alkyl group. Regarding RZb, a fluorenyl group is preferred. In the compound (lb), P is a hydrogen atom or a hydroxyl group. Preferred examples of the compound (I b ) include: (1) wherein, Lb is a bond, the ring shovel is a 3-azidine ring (wherein, the pyridine ring bonded at the 3_ position), and! ^ is: (phantom monoCi_6 alkylamine carbenyl, (b) mono Cw cycloalkylamine sulfhydryl, (c) cyano, (purine needs to have a pendant oxypurine or (e) a compound having a oxadiazolyl group having a Cu alkyl group; and (2) wherein Lb is -NHC0-, a cyclic oxime is a 2_π-pyridyl ring (wherein ^ is a 2-position bonded pyridine ring), and ^ Is a compound having a hydroxyl group or (b) an oxadiazolyl group having a Cl_e alkyl group as necessary. With respect to the compound (lb), the following compounds are preferred, wherein % A is further 丨 as needed a benzoquinone selected from the group consisting of (1) a chlorine atom, (2) a fluorine atom, and (3) a methyl group optionally having from 5 to 3 fluorine atoms; and % Bb having no substituent other than the substituent fluorene Pyridine ring;

Lb is a bond or -NHC0-; ;^ is (1) optionally having a Ci6 alkyl group (e.g., methyl, ethyl, isopropyl, isobutyl) having a hydroxyl group as desired, and a C36 ring-burning An amidino group of a substituent such as a cyclopropyl group, (2) a cyano group, (3) a pyrrolidinyl group optionally having a pendant oxy group or (4) optionally having a Ci 6 alkyl group (for example:曱[S] 321538 94 201114741 噚 oxadiazolyl; R 2b is methyl; and R _ is a hydrogen atom or a hydroxyl group. Particularly, as the compound (lb), a compound is preferred, wherein: % Ab is 4-cyanophenyl, 3-vapor-4-cyanophenyl, 4-cyanofluorophenyl or 4-cyano (trifluoro) a methyl)phenyl group as a substituent on a nitrogen atom; a ring B is an alpha specific anthracene ring having no substituent other than the substituent r, wherein '1^ is bonded to a 2-position or a 3-position; Lb is a bond or -NHC0-;

Rb is cyclopropylamine sulfhydryl, isopropylamine carbhydryl, ethylamine carbhydryl, decylamine decyl, 2-sided oxypyrrolidin-1 yl, cyano, 5-A -1'3, 4-oxaindole-2-yl or 2-yl-2-ylpropyl; R2b is methyl; and Rb is a hydrogen atom or a base. Examples of the salt of the compound (I) in the present invention include a metal salt, a salt recorded, a salt formed by an organic base, a salt with an inorganic acid, a salt with an organic acid, and a basic or acidic salt. a salt formed by an amino acid or the like. Preferable examples of the metal salt include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; aluminum salts and the like. Preferable examples of the salt with an organic base include dimethylamine, triethylamine, „比咬, 曱基^ ratio σ, 2, lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine. a salt formed by dicyclohexylamine, hydrazine, hydrazine fluorene-ethylidene diamine or the like. Preferred examples of the salt formed with the inorganic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and acid acid. Preferred salts of the salt formed by the organic acid include a 95, 321538 201114741 酉, acetic acid, difluoroacetic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid a salt formed of citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-behenic acid, etc. Preferred examples of the salt formed with the test amino acid include arginine, Preferable examples of the salt formed by the amine acid, ornithic acid, and the like and the salt formed with the succinic acid include salts with aspartic acid, face acid, and the like. An acceptable salt is preferred. For example, when the compound has an acidic ensemble, an inorganic salt such as an alkali metal salt can be mentioned (for example) Such as: sodium salt, potassium salt, etc.), alkaline earth metal salts (such as: calcium salts, magnesium salts, barium salts), ammonium salts, etc.. In addition, the compounds have a basic palace based on which can be described And, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like, or with an organic acid such as acetic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, and maleic acid. a salt formed by a diacid, citric acid 'succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. The prodrug of the compound (I) refers to a reaction of a protease, gastric acid, etc. in a physiological environment in a living body. The compound which is converted into the compound (1), that is, the compound which is converted into the compound (1) by oxidation, reduction, hydrolysis or the like, and the compound which is converted into the compound (1) by hydrolysis or the like due to gastric acid or the like. Examples of the prodrug include deuteration, alkylation or phosphorylation of an amine group in the compound (1) (for example, oxiranylation, propylation of an amine group in the compound (ί), Pentylaminocarbonylation, (5-methyl-2-sideoxy-oxime, 3-12 Obtained by a heterocyclic penten-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrroleylmethylation, trimethylacetoxythiolation or a compound obtained by third butylation The compound 丨 makes the carboxylic acid in the compound (I) 321538 96 201114741

Liquefaction, burning, acidification or shed acidification (for example: transmethylation, palmitoylation, propylation, and trimethylethylation of the compound (i) a compound obtained by a compound obtained by transbutenyl dimerization, propylamine enrichment or dimethylaminocarbonyl methylcarbonylation; esterification or guanamine of a carboxyl group in a human (I) (for example, ethyl esterification, strepyl esterification, carboxyl thioesterification, dimethylamine methyl esterification, trimethylacetoxymethyl group in the compound (丨) Esterification, ethoxycarbonyloxyethyl esterification, mercaptoesterification, (5-fluorenyl-2-oxo-1,3-dioxolan-4-yl) sulfhydryl vinegar A compound obtained by, for example, a compound obtained by a cyclohexyloxymethyl group or a methyl alanation or the like. These compounds can be produced from the compound (I) according to a method known per se. Prodrugs of Compound (I) can also be converted to compounds under physiological conditions as described in IYAKUHIN no KAUUI'SU, Development of Pharmaceuticals, Vol. 7, Design of Molecules, p. 163-198, HIROKAWA SHOTEN, 1990. (I). The method for producing the compound (I) or a salt thereof is explained below. In the following production methods, when an alkylation reaction, a hydrolysis, an amination reaction, a cooling reaction, a brewing amination reaction, an etherification reaction, an oxidation reaction, a reduction reaction, or the like is carried out, the above reaction is carried out according to a method known per se. . Such

Examples of the method include the methods described in ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC., 1989; Comprehensive Organic Transformations, VCH Publishers Inc., 1989, and the like. Further, the obtained product can be used as a reaction mixture or a crude purified product. [s] 97 321538 201114741 Next reaction. It can also be isolated early from the reaction mixture according to a conventional method, and can be simply obtained by a general separation means chromatography or the like.冉,,. Reading, ρ is shown by the method shown in the following or a method similar thereto. The second method and the like are obtained by the method (1) or 』. The compound represented by the formula (VI) is encompassed by the formula (1). 匕 = by a method known per se or a method analogous thereto (for example, 1 original reaction, brewing reaction, bis-denation reaction, oxidation reaction) , burning a few == solution: brewing amination reaction, deuteration reaction, dehydration reaction, de-W; W, dealkoxycarbonylation reaction, sulfurization reaction, trifluoromethyl H, etc.) conversion formula (IV) The functional group of the compound can also be obtained as a compound encompassing two: (1). When the compound (5) has a protecting group, the protecting group can be eliminated by a known method or the like to obtain the compound 9(1). Examples of the method of production include the ethyl H-burning and the four-air biting in the method. Examples of the saturated hydrocarbon include hexane, pentane and the like. In the method, examples of the halogenated hydrocarbon include dichlorosilane, gas imitation, and the like. In the = method, an example of an amine is Baoqing-dimethylacetochlor and the like. Examples of the aromatic hydrocarbons in the process include benzene, methyl stupid, and the like. In the coating method, examples of the alcohol include methanol and B. In n, examples of the ketone include acetone and methyl ethyl s. In the known method, examples of the nitrile include acetonitrile and the like. In the method of the coating 4, examples of the ester include ethyl acetate and the like. In the production method + ancient Chinese, examples of the aromatic amine include aniline and the like. 321538 98 201114741 In the process of the production process, examples of the hetero ring include pyridine and the like. Examples of the organic acid in the & method include formic acid, acetic acid, and the like. Examples of the Aachen in the K-way include the dimethyl sapphire and the like. In the reaction of the compound of Figure 1, each symbol is: R4, a carbocyclic group optionally having a substituent, and R4'· is ~(CH2)nY-Rb' wherein n is an integer from 〇 to 3 and is required by contempt a ring group having a substituent. Further, γ is a genus of atoms χ2 is a radical atom, a gas, an isocyanate, a chloroformyl group or a fluorenyl group, χ3 is a halogen atom or an isocyanate group, a hydroxyl group, and a hydrazine is a halogen atom. Further, the other symbols are as defined above, and if necessary, they can be protected by a protecting group generally used for organic synthesis or the like. The compound in the reaction diagram includes a salt' and examples of the salt include those similar to the salt of the compound (I) and the like. 321538 99 201114741 Reaction diagram l

(V) may be according to a known method or its method (1) Na, (10), (7), ) and (1)', for example, the method 4 shown in the reference example described below.

In addition, when the compound is commercially available, such products can be used as they are. [Step AJ] The compound (VI) can be synthesized by a reaction compound (j) and a compound (νπ) according to a conventional method, wherein R4 is an aromatic ring group which optionally has a substituent and R5 is a hydroxyl group. When the compound (VII) is commercially available, the commercially available product can be used as it is 100 321538 201114741. When the compound is not commercially available, it can be reacted with an aromatic halide compound such as Dinglu, Grenner reagent (GHgnard) or the like by a known method or a similar method thereof, or The compound (VII) is synthesized by reacting a compound such as: butane, diisopropylguanidinium, etc. with an aromatic compound. The amount of the compound (VII) to be used is 1 to 0 mol of the compound (π), and about 1 is used. 0至3. 0摩尔。 0 to about 10 mol, light 4 && 隹 is about 1. 0 to 3. 0 mol.

The reaction temperature is usually about πην* ? & s 1 ΛΛ〇 ^ C to about 2 〇〇〇 c ' is preferably about -78 ° C • clock to about 48 hours, preferably to about 100 ° C. The reaction temperature is usually from about 5 minutes to about 5 minutes to about 24 hours. This reaction is carried out in an organic solvent which does not adversely influence the reaction. #男贱岭剂, can use ether, saturated hydrocarbons, fragrant hydrocarbons, etc. These solvents may be used alone or in a suitable ratio of a mixture of two or more thereof. [Step B] When the compound <^111) is a 24 atom, a bromine atom or an iodine atom, the compound (1) π and the compound (νιπ) may be subjected to a suitable metal catalysis according to a conventional method. ) _ combined reaction to synthesize its "quote, b compound (b). By the literature (Xleet, a1·, J. 〇rg. Chem. 2006, Vol. 71' pp. 6522 or Maet, al., j. Aro Chem. Sqc. 1998, ν〇1· 120, ρρ· 12459 The method described in the method or the method similar thereto is carried out. The reaction temperature is about 2 (TC to about 15 "c, preferably about 6 "c to about 12 〇 321538 [S3 101 201114741 ° C. The reaction time is generally from about 5 minutes to about 48 hours, preferably about 5 minutes. To about 24 hours. When X2 of the compound (VIII) is a carboxyl group, 'the compound (VIII) is activated by treatment with an activator, and if necessary, the compound is reacted with the compound (III) in the presence of a base or an additive, according to the general The method for organic synthesis can synthesize R4 into -ΝΓ-ί:0~·((:Η2)η-Υ-Κ^κ(vi). Examples of activators include chlorinating agents generally used in organic synthesis. Such as arsenic chloride, grass 醯 chlorine, etc., generally used in organic synthesis of oximation agents such as: sorrow, sulphur-based gas, etc., commonly used in organic synthesis of condensing agents such as: 1,3-dicyclohexyl carbon Diimine, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, diethylsulfonyl cyanide, hydrazine, hydrazine-carbonyldiimidazole, chlorinated 4-( 4,6-Dimethoxy-1,3,5-tris-2-yl)-4-methylmorphin-4-indole, etc. Examples of additives include hydroxybenzotriazole, N-hydroxyamber醯imine, etc. Examples of tests include The test is as follows: diisopropylethylamine, triethylamine, »bipyridine, etc. The amount of the compound (ΠΙ) used is generally 每. 5 to 5. 0 per 〇mol of the compound (VIII). The amount of the activator used is generally from 8. 8 to 2.0 mol. The amount of the activator used is generally from 1 to 10 mol, preferably from 1 to 5 mol, per 1 mol of the compound (νιπ). It is generally used in an amount of from 1 to 2 mol, preferably from 2 to 10 mol, per 1 mol of the compound (νίπ). The amount to be used is generally from 1 to 1 μm〇 per 1 of the compound, preferably. It is 1 to 5 mol' and its excess amount can also be used as a solvent. 102 321538 201114741 The reaction 03⁄4 is generally from about 1 minute to about hour, preferably from about go minute to about 12 hours. The reaction temperature is generally about 0. To about 1 Torr, preferably from about 20 to about 80 ° C. The reaction is generally carried out in an organic solvent which does not adversely influence the reaction. Examples of the organic solvent which does not adversely influence the reaction include ethers, hydrocarbons, halogenated hydrocarbons. , ketone, nitrile, decylamine 'heterocyclic ring, etc. Preferred solvents include ethers, hydrocarbons, halogenated hydrocarbons and captanamines. Mixing or using a mixture of two or more thereof in an appropriate ratio. When X2 of the compound (VIII) is a chloro group, if necessary, it is combined with a compound in the presence of a base according to a method generally used for organic synthesis. (ill). Reaction ' can synthesize R4 to -NRa-CO-CCHOn-Y-R1^ compound (vi). Examples of bases include organic bases such as diisopropylethylamine, triethylamine, 11-pyridinium and many more. The amount of the compound (III) to be used is generally 对. 5 to 5.0 mol, preferably 〇. 8 to 2. 〇 m〇l, per mol of the compound (Vni). The amount to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1.0 mol of the compound (viii), and an excess amount thereof can also be used as a solvent. The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 3 minutes to about 12 hours. The reaction temperature is usually from about Torr to about 1 Torr, preferably from about 20 to about 80 °C. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. Examples of organic > gluten agents which do not adversely affect the reaction include test, smoke, smouldering, ketone, nitrile 'guanamine, heterocyclic ring and the like. Preferred solvents include ethers, hydrocarbons, halogenated hydrocarbons 321538 103 201114741 and guanamine. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. According to a conventional method, a compound (VHI) in which ruthenium 2 is a fluorine atom, an isocyanate group or a gas sulfonyl group is reacted with a compound (丨I丨) in the presence of a suitable base to synthesize ρ as -NRa_Rb, _NRa_c〇NH_(CH2)n_Y_Rb or -NRa-S〇2-(CH2)nY-Rb compound (νι) Examples of the β base include alkali metal salts such as sodium hydride, potassium carbonate, sodium carbonate, potassium hydroxide, hydrogen Sodium oxide or the like, and an organic base such as triethylamine, diiso-propylethylamine, pyridine, and the like. The amount of the compound (VIII) to be used is generally from 0.5 to 5. 0 mol, preferably from 〇·8 to 2. 〇 mol, per 10 m of the compound (III). The amount of the base to be used is generally a compound (ΠΙ) per 1 〇 m〇1, and is used up to 10 mol', preferably U to 5 mol equivalents. When an organic test such as triethylamine, diisopropylethylamine "bite is used, the excess amount can also be used as a solvent. The reaction temperature is usually from 0 to 12 ° C, preferably from 20 to 1 Torr. Hey. The reaction time is usually from 0.5 to 100 hours, preferably from 1 to 48 hours. This reaction is generally carried out in an organic spray that responds to the reaction. Examples of the organic solvent which does not adversely influence the reaction include a sulphur, a saturated smouldering hydrocarbon, an aromatic hydrocarbon, an anthracene, a quiz, a tartamine, a arylamine, a heterocyclic ring and the like. Preferred solvents are hydrocarbons, functional hydrocarbons, decylamines, aromatic amines and heterocycles. These solvents may be used alone or in a suitable ratio of one or more of their mixtures. According to the method of S, 'X-methyl-based compound (VHI) is catalyzed by 321538 104 201114741 (I11) and a reducing agent such as sodium borohydride, sodium triethyl sulfonium hydride or cyano hydride By reductive amination reaction, a compound (VI) wherein R4 is -NRa-(CH2)nY-Rb can be synthesized. The amount of the compound (III) to be used is generally 〇. 5 to 5. 0 mol', preferably 〇. 8 to 2. 0 mol, per mole of the compound (VIII)'. The amount of the reducing agent to be used is generally from 1 to 10 mol, preferably from 1 to 5 mol equivalents per mol of the compound (VIII). The reaction temperature is generally from 〇 to 12〇t:, preferably from 20 to 10〇 (Tc. The reaction time is generally from 0.5 to i〇〇 hours, preferably from 丨 to 48 hours. Generally, there is no adverse effect on the reaction. The reaction is carried out in an organic solvent. Examples of the organic solvent which does not adversely influence the reaction include decylamine, ether, saturated hydrocarbon, aromatic hydrocarbon, alcohol, organic acid, etc. Preferred solvents are decylamine, ether, alcohol and organic. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. [Step C] A compound in which X3 is a halogen atom or an aryl group in the presence of a suitable base according to a conventional method (IX) The compound (VI) wherein R4 is -0-Z-RC can be synthesized by a coupling reaction with the compound (IV). Examples of the base include alkali metal salts such as sodium hydride, potassium carbonate, sodium carbonate, potassium hydroxide, The amount of the compound (IV) is generally 0. 5 for each 1.0 mol of the compound (IV) '. 0 〇 , , 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 碱 碱 碱 碱 碱 碱 碱 碱 碱 碱 碱 碱l compound (IV), using i to 1 〇 105 321538 201114741 mol 'preferably! to 5 moer # amount. When using organic tests such as: triethylamine, ', propyl ethylamine, than "疋, etc. The excess amount can also be used as a solvent. The reaction temperature is usually from 0 to 12 crc, preferably from 20 to (10) C. The reaction time is usually from 0.5 to 100 hours, preferably from 228 to 48 hours. The reaction is carried out by an organic solvent which does not adversely affect the reaction. Examples of the organic solvent which does not adversely influence the reaction include a salt, a saturated hydrocarbon, a toothed hydrocarbon, an aromatic hydrocarbon, a ketone, a nitrile, an amine, a cis, an aromatic amine, a heterocyclic ring, etc. Preferred solvents are _, a hydrocarbon, a halogenated hydrocarbon, a brewing amine, an aromatic amine, and a heterocyclic ring. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. In the phosphine compound and the azobishypoacid compound , or a compound (VI) which can synthesize or -0-Re by reacting a compound (IX) wherein X is a trans group with a compound (IV) by a Mitsunobu reaction in the coexistence of a compound of a scale compound. Examples include triarylphosphines such as triphenylphosphine, etc. a phosphine such as: tributylphosphine, etc., an alkylarylphosphine such as dicyclohexylphenylphosphine, etc., a resin-supported phosphine reagent such as a diphenylphosphino-polystyrene resin, etc., etc. For the compound (IV) per 10 m〇1, from about 1.0 to about 10 mol, preferably about; [· 〇 to 3. 〇m〇1. 'Examples of azodicarboxylic acid compounds include A nitrogen dicarboxylic acid ester such as diethyl azodicarboxylate such as azodicarboxylate amide such as 1,1,-azobis(N,N-dimercaptomethylamine), etc. The amount of the azodicarboxylic acid compound or the phosphine compound used in the compound β described in the literature (Tsunoda et al., Tetrahedron. Lett. 1996, Yol. 37, t S3 106 321538 201114741 pp2759) can be mentioned. 0 至0. 0 mol。 For each 1.0 mol of the compound (IV), using from about 1.0 to about 10 mol, preferably from about 1. 0 to 3. 0 mol. 0至3. 0摩尔。 The amount of the compound (I) is 0. 5 to 3. 0 mol. The reaction temperature is from about 20 ° C to about 150 ° C, preferably from about 60 ° C to about 120 ° C. The reaction time is from about 1 hour to about 50 hours. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. Examples of the organic solvent which does not adversely influence the reaction include ethers, saturated hydrocarbons, aromatic hydrocarbons and the like. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. [Step D] According to a conventional method, a compound (X) wherein X4 is a chlorine atom, a bromine atom or an iodine atom is subjected to a coupling reaction with the compound (V) in the presence of a suitable metal catalyst such as palladium, copper or the like. Compound (VI) can be synthesized. By the method described in the literature (Xie et al., J. Org. Chem. 2006, Vol. 71, pp. 6522 or Ma et al., J. Am. Chera. Soc. 1998, Yol. 120, pp. 12459) Or a similar method can be used for the reaction. The reaction temperature is from about 20 ° C to about 150 ° C, preferably from about 60 ° C to about 120 ° C. The reaction time is usually from about 5 minutes to about 48 hours, preferably from about 5 minutes to about 24 hours. The compound (VI) can be synthesized by a surface reaction with the compound (v) by subjecting [4] 107 321538 201114741 compound (x) to a fluorine atom in the presence of a suitable base in the presence of a suitable base. Examples of the base include alkali metal salts such as sodium hydride, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like, and organic bases such as triethylamine, diisopropylethylamine, pyridine and the like. The amount of the compound (X) to be used is generally from 1 to 10 mol, preferably from 1 to 5 mol equivalents per mol of the compound (V). The amount of the base to be used is generally from 1 to 10 mol, preferably from 1 to 5 mol equivalents per 1.0 mol of the compound (V). When an organic base such as triethylamine, diisopropylethylamine, pyridine or the like is used, an excess amount thereof can also be used as a solvent. The reaction temperature is usually from 0 to 120 ° C, preferably from 20 to 100 ° C. The reaction time is usually from 0.5 to 100 hours, preferably from 1 to 48 hours. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. Examples of the organic solvent which does not adversely influence the reaction include ethers, saturated hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ketones, nitriles, decylamines, esters, aromatic amines, heterocyclic rings, sulfoxide g, and the like. Preferred solvents are ethers, hydrocarbons, halogenated hydrocarbons, amines, aromatic amines, heterocycles, sulfoxides. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. [Function-based conversion] A reducing agent generally used for organic synthesis such as sodium borohydride, sodium cyanoborohydride, sodium triethyl sulfonium borohydride, lithium borohydride, lithium aluminum hydride or the like can be used for the reduction reaction, and A metal salt such as calcium chloride or the like may be added. 0 至 0. 0 mol。 The amount of the compound is 0. 0 to 5. 0 mol. The amount of the metal salt used is about 0.5 to about 10 mol, preferably about 1. 0 to 3. 0 mol 1, per [1.0] 321538 201114741 per 1.0 mol of the compound (VI). The reaction temperature is usually from about -70 ° C to about 10 ° C, preferably from about 0 ° C to about 50 ° C. The reaction time is usually from about 30 minutes to about 50 hours, preferably from 30 minutes to about 20 hours. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. As the organic solvent which does not adversely influence the reaction, for example, an alcohol, an ether, a saturated hydrocarbon, an aromatic hydrocarbon or the like can be used. These solvents may be used singly or as a mixture of one or more of an appropriate ratio of ® . The deuteration reaction can be carried out according to a method generally used for organic synthesis, using a deuteration agent such as an organic acid, a mercapto halide, an acid anhydride or the like, if necessary in the presence of a base. For the test, for example, metal salts such as sodium hydride, potassium carbonate, sodium carbonate, potassium hydroxide, sodium ruthenium oxide, and the like, and organic tests such as triethylamine, diisopropylethylamine, pyridine, and the like can be used. The amount of the hydrating agent to be used is generally 1 to 20 mole equivalents, preferably 2 to 10 moles per mole of the compound (VI). The amount of the base to be used is generally from 1 to 10 mol, preferably from 1 to 5 mol equivalents per mol of the compound (VI). When an organic base (e.g., triethylamine, diisopropylethylamine, °, β, etc.) is used, an excess amount thereof can also be used as a solvent. The reaction temperature is usually from 0 to 120 ° C, preferably from 20 to 100 ° C. The reaction time is usually from 0.5 to 100 hours, preferably from 1 to 48 hours. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. As the organic solvent which does not adversely influence the reaction, for example, an ether, a saturated hydrocarbon, a halogenated hydrocarbon, an aromatic hydrocarbon, a ketone, a nitrile, a catalyzed amine, a chiral amine, an aromatic amine, a heteropoly [s] 109 321538 201114741 ring or the like can be used. Preferable examples thereof include ethers, hydrocarbons, halogenated hydrocarbons, decylamines, aromatic amines and heterocyclic rings. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio.

The oxidation reaction may be carried out in a solvent which does not adversely influence the reaction, using an oxidizing agent generally used for organic synthesis such as a manganese compound (for example, potassium permanganate, manganese dioxide, etc.), a chromium compound (for example, chromic acid, etc.). A sulfur compound (for example, dimercaptosulfoxide or potassium peroxysulfate) or a ruthenium compound (for example, diammonium nitrate (IV) or the like) is carried out in the presence of an acid or a base, if necessary. Examples of the solvent include water, saturated hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, organic acids, decylamines, hydrazines, hydrazines, nitriles and the like. Preferable examples thereof include water, hydrocarbons, halogenated hydrocarbons, ketones, organic acids, decylamines, esters, hydrazines, and nitriles. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. As the acid, for example, a mineral acid such as sulfuric acid or the like, an organic acid such as acetic acid or the like can be used. For the test, for example, a metal salt such as potassium hydroxide, sodium hydroxide or the like, an amine such as triethylamine, diisopropylethylamine, piperidine or the like can be used. If necessary, a dehydrating agent such as dicyclohexylcarbodiimide, grass chloroform, sulfur trioxide pyridine or the like may be added. The amount of the oxidizing agent to be used is generally from 1 to 20 mol, preferably from 1 to 10 mol, per 1.0 mol of the compound (VI). When dimethyl sulfoxide is used, its excess amount can also be used as a solvent. The amount of the acid or base to be used is generally from 1 to 20 mol, preferably from 1 to 10 mol, per mol of the compound (VI). The amount of the other additives used is generally from 1 to 20 mol, preferably from 1 to 10 mol, per mol of the compound (VI). The reaction temperature is usually -70 to 120 ° C, preferably -70 to 100 ° C. 01至48小时。 The reaction time is generally from 0.1 to 100 hours, preferably from 0.1 to 48 hours. According to a conventional method, the reaction compound (VI) can be subjected to a hospitalization reaction with a burning agent such as a halogenated compound in the presence of a base. For the test, for example, a metal hydride such as sodium hydride or potassium hydride; an alkali metal amine such as sodium amine or the like; potassium third potassium hydride, potassium carbonate or the like can be used. The amount of the base used is from 1.0 to about 10 mol, preferably from about 1.0 to 2.0 mol, per 1.0 mol of the compound (VI). 0至2. 0摩尔。 The amount of the amount of the compound is 0. 0 to 2. 0 mol. The reaction temperature is usually from about -70 ° C to about 100 ° C, preferably from about 0 ° C to about 50 ° C. The reaction time is usually from about 5 minutes to about 48 hours, preferably from about 5 minutes to about 20 hours. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. As the organic solution strain which does not adversely influence the reaction, for example, an ether, a saturated hydrocarbon, a halogenated hydrocarbon, a decylamine, an aromatic hydrocarbon or the like can be used. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. If necessary, the reaction compound (VI) may be reacted with a sintering agent in the presence of an additive such as chlorinated (111) in a solvent which does not adversely influence the reaction to carry out an alkylation reaction of a carbonyl group. As the alkylating agent, for example, an organomagnesium reagent such as an alkylmagnesium halide or the like; an organolithium reagent such as an alkyllithium or the like, or the like can be used. As the solvent, for example, a hydrocarbon, an ether or the like can be used. These solvents may be used singly or as a mixture of one or more of them in an appropriate ratio. The amount of the organomagnesium reagent or organolithium reagent used is generally from 1 to 20 mol, preferably from 1 to 10 mol, per 1.0 [S] 111 321538 201114741 mol of the chelate compound (VI). The amount of the additive used is generally 0.1 to 10 mol, preferably 1. 0 to 5. 0 mol per 1.0 mol of the compound (VI). The reaction temperature is usually from about -70 to about 100 ° C, preferably from about -70 to about 50 °C. 5至约24小时。 The reaction time is generally from about 0.5 to about 24 hours. Hydrolysis is carried out using an acid or a base generally used for organic synthesis.

As the acid, for example, a mineral acid such as hydrochloric acid or the like; a Lewis acid such as boron tribromide or the like; a combination of Lewis acid and a mercaptan or a sulfide; an organic acid such as trifluoroacetic acid, Toluene continued acid, etc., etc. As the base, for example, a metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide or the like; an alkaline salt such as sodium carbonate, potassium carbonate or the like; a metal alkoxide such as sodium decoxide or ethanol can be used. Sodium, potassium butoxide, etc.; organic bases such as: triethylamine, imidazole, formazan, etc., and the like. The amount of the acid or base to be used is generally from 0.1 to about 50 mol, preferably from about 1 to about 20 mol, per 1.0 mol of the compound (VI). This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. As the organic solvent which does not adversely influence the reaction, for example, an alcohol, an ether, an aromatic smoke, a saturated hydrocarbon, a halogenated hydrocarbon, an imipen, water or a mixture of one or more thereof can be used. The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 30 minutes to about 12 hours. The reaction temperature is usually from about 0 to about 200 ° C, preferably from about 20 to about 120 ° C. The amidation or deuteration reaction can be carried out by an activator according to a method generally used for organic synthesis (a compound containing a slow acid derivative [s] 112 321538 201114741 biogroup in the substituents R4 to R9 (ιν) The activation is carried out and the derivative is carried out with an aromatic or aliphatic amine or a hydrazine derivative, if necessary in the presence of a base or an additive. Further, the ester derivative (the compound (IV) having a substituent R4 to an ester derivative group) can be reacted with an aromatic or aliphatic amine, if necessary in the presence of a base or an additive. As the activator, for example, a gasifying agent generally used for organic synthesis such as sulfite gas, grass ruthenium chloride or the like; a oximation agent generally used for organic synthesis such as an acid anhydride, mercapto chloride or the like; Organically synthesized condensing agents such as: 13-monohexylcarbodiimide, 1-ethyl-3-(3,-dimethylaminopropyl)carbodiimide, diethylphosphonium cyanide, N , N-carbonyldiimidazole, 4-(4,6-monomethoxy-1,3,5-trian-2-yl)-4-methylmorpholine _4-oxime, etc., etc. As the additive, for example, N-hydroxybenzotriazole, N-hydroxycypanelimimine or the like can be used. As the base, for example, an organic base such as diisopropylethylamine, triethylamine, hydrazine or the like can be used. The amount of the aromatic or aliphatic amine to be used is generally 0.5 to 5.0 m〇l, preferably 〇 8 to 2· 〇 m〇1, per 1 〇 m〇1 of the compound (VI). The amount of the activator used is generally the compound (VI) per lG m〇l, and the amount of the additive used is preferably 为mol', preferably from 5 to 5 ffl, per 1.0 mol of the compound (VI).丨 to 2〇卽丨, preferably 2 to 10(10). The amount of the base to be used is usually from 1 to 10 m〇i, preferably from 1 to 5 mol, per 1.0 mol of the compound (VI). Further, the excess amount can also be used as a solvent. The reaction time is generally from about 1 minute to about 5 hours, preferably from about 321538 113 to 201114741 to about loot: preferably from minute to about 12 hours. The reaction temperature is usually from about 20 to about 80 °C. This reaction is generally carried out in response to the reaction. As the organic solvent which does not adversely influence the reaction, for example, hydrazine, a halogen, a halogenated hydrocarbon, a litrile, a nitrile, a brewing amine, a heterocyclic ring or the like can be used. Preferred examples thereof include hydrazine, smoke, toothed hydrocarbons and _. These solvents may be used alone or in a mixture of one or more of (d) in proportions. The dehydration reaction can be carried out in a solvent which does not adversely influence the reaction, by a method generally used for organic synthesis, using a dehydrating agent such as a base tooth, a liver, an oxygen gas (4), and the like, if necessary. Examples of the solvent include mystery, light, halogenated hydrocarbon, ketone, nitrile, decylamine, vinegar, aromatic amine, heterocyclic ring and the like. Preferred solvents include ethers, hydrocarbons, dentate hydrocarbons, decylamines, aromatic amines and heterocycles. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio.

As the base, for example, a metal salt such as sodium nitride or carbonic acid can be used.

Sodium carbonate, etc., or organic tests such as: triethylamine, diisopropylethylamine K, and the like. The amount of the dehydrating agent to be used is generally from 1 to 20 mol, preferably from 1 to 1 mol, per 10 mol of the compound (VI). The amount of the base to be used is generally from 1 to 10 mol of the compound (VI), from 丨 to 1 〇 m 〇 1, preferably from i to 5 mol, and the excess amount thereof can also be used as a solvent. The reaction temperature is usually from 0 to 1203⁄4, preferably from 〇 to 1〇〇. Hey. The reaction time is usually from 0.5 to 100 hours, preferably from 5 to 48 hours. The cyanation reaction can be generally used in an organic synthesis method to make an aromatic moth 321538 114 201114741 compound, bromide or chloride (in the compound (IV), the substituent ^(cyanophenyl) through a chlorine atom, a bromine atom or an iodine atom. Substituting, or substituents R to R9 are aryl "aromatic heterocyclic groups, or having such amine groups, hydroxyl groups or sulfhydryl groups" substituted with a chlorine atom, a desert atom or a read atom, and a metal cyanide, if necessary in a metal catalyst In the presence of. As the metal catalyst, for example, a palladium reagent such as ruthenium (triphenylphosphine) palladium or the like can be used. &

As the metal cyanide, for example, zinc cyanide, copper cyanide, sodium cyanide, potassium cyanide or the like can be used. The amount of the metal catalyst used is generally from 0.1 to 0.2 m〇l, preferably from 0.05 to 〇. i m〇1, per 1 〇 m〇1 of the compound (VI). The amount of metal cyanide used is generally from 1 to 20 mol', preferably from 2 to 10 m〇i, per 1 〇 m〇1 of the compound (νι). The reaction time is usually from about 10 minutes to about 50 hours, preferably from about several minutes to about 12 hours. The reaction temperature is usually from about Torr to about 1 Torr.匚, from about 20 to about 80 ° C. 'Parent is generally carried out in an organic solvent which does not adversely influence the reaction. For the organic solvent which does not adversely affect the reaction, examples of use include: a., a halogen, a halogenated hydrocarbon, a ketone, a nitrile, a decylamine, a heterocyclic ring. Wait. Preferred examples are hydrocarbons, halogenated hydrocarbons and decylamine. These solvents may be used singly or as a mixture of one or more of the quotient rolls. The ratio of the field can be generally used in the organic synthesis method by the aromatic substituent R4 or the aromatic heterocyclic group. The aromatic iodide, bromide or chloride (the compound (IV) to R9 is a chlorine atom, An aryl group substituted with a bromine atom or an iodine atom 321538 115 201114741, or having such an amine group, a hydroxyl group or a whale group, and carbon monoxide, if necessary in the presence of a metal catalyzed hydrazine and a base, and in an alcohol such as sterol, It is carried out in the presence of ethanol or the like. As the metal catalyst, for example, a palladium reagent such as acetic acid or the like may be used in combination with a suitable ligand such as bis(diphenylphosphino)ferrocene or the like. As the base, for example, an organic base such as triethylamine, diisopropylethylamine, Dtb bite or the like can be used. With regard to carbon monoxide, gaseous carbon monoxide can be directly introduced into the reaction system. In addition, a reagent for generating carbon monoxide in the system such as hexacarbonyl molybdenum or the like can also be used. The amount of the metal catalyst and the ligand to be used is generally 0.01 to 0.5 mol, preferably 〇 J to 〇 3 mol, per 1 〇 m 〇 1 of the compound (VI)'. The amount of the alcohol and the base to be used is generally from 1 to 20 mol, preferably from 2 to 10 mol, per mol of the compound (VI). The reaction time is usually from about 10 minutes to about 50 hours, preferably from about 3 minutes to about 12 hours. The reaction temperature is usually from about Torr to about 1 Torr. Preferably, it is from about 20 to about 80 °C. This reaction is carried out in an organic solvent which does not adversely influence the reaction. As the organic solvent which does not adversely influence the reaction, for example, an ether, a hydrocarbon, a halogenated hydrocarbon, a ketone, a nitrile, a decylamine, a heterocyclic ring or the like can be used. Preferable examples thereof include ethers, hydrocarbons, halogenated hydrocarbons and decylamine. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. The Curtius rearrangement reaction can be used in the organic synthesis method as a method of 116 321538 201114741, which makes the aromatic tetacid (in the compound (ιν), the substituents R4 to R9 are the decanoic acid derivative groups. a substituted aryl or aromatic heterocyclic group, or having such an amine group, a hydroxyl group or a fluorenyl group) and an azide compound such as diphenylphosphoryl azide, etc., if necessary in the presence of a base The reaction is carried out in the presence of an alcohol. As the base, for example, an organic base such as triethylamine, diisopropylethyl: pyridine or the like can be used. As the alcohol, for example, 2-methyl-2-propanol, ^ethanol, benzodecyl alcohol or the like can be used. The amount of the abundance compound to be used is generally from 1 to 5.0 mol, preferably from 1 to 2. 〇 m〇1, per 1 〇 m〇1 of the compound (Π). The amount of the base to be used is generally from 1 Torr to 1 〇mol, preferably from 1.0 to 3.0 m, per 1.0 mole of the compound (VI). The amount of the alcohol used is generally from 1.0 Torr to 5 〇 m 〇1, preferably from 〇 to 10 mol, per 1.0 mol of the compound (VI). The reaction time is generally from about 1 minute to about 5 M, preferably from about 3 minutes to about 12 hours. The reaction temperature is usually from about Torr to about 1 Torr, preferably from about 20 to about 80 °C. This reaction is generally carried out in an organic solvent which does not adversely influence the reaction. As the organic solvent which does not adversely influence the reaction, for example, an ether, a hydrocarbon, a dentate hydrocarbon, a ketone, a nitrile, a decylamine, a heterocyclic ring or the like can be used. Preferable examples thereof include hydrocarbons, dentate hydrocarbons and decylamine. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. The vulcanization reaction of the compound (VI) is carried out using phosphorus pentasulfide, Lawesson reagent or the like. 321538 117 201114741 This reaction can be carried out in a solution that reacts to the reaction. As the solvent, for example, hydrazine, an aromatic hydrocarbon, a saturated hydrocarbon, a southern hydrocarbon or a mixture of one or more thereof, or the like can be used. The amount of phosphorus pentasulfide, Lawson's reagent, and the like used is generally 5 to 1 〇 m 〇 1 , preferably 〇 5 to 3 〇, i for each compound (VI) of ι. The reaction temperature is generally from about 〇 to about 15 (rc, preferably from about 2 Torr to about 12 ° C. The reaction time is generally from 1 () minutes to about 5 () hours, preferably from about minutes to about 12 hours. When the protecting group is tert-butyl, triphenyl T-based, tert-butylbenzyloxycarbonyl, tetrahydropyranyl, 4-methoxybenzyl, 2::, oxybenzene When the methyl group is used, for example, the compound (9) can be subjected to a deprotection reaction by treating the compound (9) with an acid which does not adversely influence the reaction. For the solvent, for example, 34, a saturated hydrocarbon, an aromatic hydrocarbon, a toothed hydrocarbon, or the like can be used. Guess, amine, vinegar, organic acid, etc. Preferred examples thereof include _, a hydrocarbon, and a halogenated hydrocarbon. These solvents may be used singly or in a mixture of one or more of them in an appropriate ratio. For the acid, for example, Mineral acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, acid, etc.; organic acids such as: formic acid, acetic acid, trifluoroacetic acid, p-toluene acid, etc.; Lewis acid such as boron tribromide; and tannins. The acid may be used singly or as a mixture of one or more of them. The amount of the acid used is generally a compound per 1 〇m〇1 (VI), using 1 to 100 mol, preferably 丨 to 5 〇 m 〇 1. In addition, the excess amount thereof can also be used as a solvent. The reaction temperature is generally -72 to i 〇〇 t, preferably 〇 to 6 (rc. The reaction time is generally 0.5 to 1 hour, preferably 〇. 5 to 48 hours. 321538 118 201114741 When the protecting group is a benzomethoxycarbonyl group, a benzyl group, a benzoquinoneoxy group, etc. Deprotection can be carried out by catalytic hydrogenation of compound (VI). In the presence of a metal catalyst generally used for organic synthesis, such as palladium-carbon, platinum-carbon, etc., by compound (VI) with hydrogen The reaction is carried out to carry out a catalytic hydrogenation reaction. Further, a mineral acid (for example, hydrochloric acid or the like), an organic acid (for example, acetic acid, etc.), or the like may be added. The amount of the metal catalyst used is generally a compound (VI) per 1. 〇mo 1 . It is used in an amount of from about 1 to about 1 mole equivalent, preferably from about 1 to about 5 molar equivalents. The amount of mineral acid (for example, hydrochloric acid), organic acid (for example, acetic acid), etc. used is generally l. 〇mol of the compound (VI), using from about 1 Torr to about 5 〇 molar equivalents, preferably from about 1 〇 to 5 〇 The molar reaction temperature is generally from about 10 CTC, preferably from about 〇.〇 to about 5 (TC. The reaction time is generally from about 3 minutes to about 5 hours, preferably from 30 minutes to about 20 hours. .

The organic solvent which does not adversely affect the reaction is subjected to this reaction == an adversely affected organic solvent, which may be, for example, an alcohol or an ether, which may be separately or (d) appropriately transferred to a known method according to a known method: In the form, the method converts it into a free form or the like... by the above-mentioned manufacturing method according to the conventional method | Known means such as solvent extraction of the compound (1) or a salt thereof by liquid phase conversion, phase transfer, Crystallization, recombination 321538 119 [201114741 crystal, chromatography, etc. isolated and purified. When the compound (I) or a salt thereof contains a filament isomer, a stereoisomer, a positional isomer or a rotamer, it is also encompassed in the compound G) and can be synthesized by a synthesis method known per se and The product obtained by the separation method is: - when the compound (1) or a salt thereof contains an optical isomer: the optical isomer of the compound is also included in the compound (1) or its salt, and can be Optically known isomers are produced by methods known per se. The compound (I) or a salt thereof may be a solvate or an unsolvate. The σ (I) or its salt can be isotopically (for example: %, hydrazine,

Etc. W Compound (I) or a salt thereof may be crystalline. The compound (I) or a salt thereof may be a co-crystal. Crystallization of a compound (1) or a salt thereof to crystallize the compound (1) or a salt thereof (hereinafter sometimes referred to simply as the compound (1) of the present invention or a salt thereof according to the present invention. Shows excellent androgen = medical material 'low toxicity and low fortune, seal (four) as a safe 4 music product, androgen receptor antagonist, etc. - excellent m has the pharmaceutical composition of the compound (1) or its salt = excellent = sex hormone receptor antagonism and / or in Wei animals (for example: small (oral) absorbent rats, stagnation, rabbits, juveniles, dogs, cattle, sheep, monkeys, humans, etc.) Sexual antigen (PSA) produces an inhibitory effect and exhibits excellent (metabolic) stability and the like, which can be used as a prophylactic or [S] 32J538 120 201114741 treatment of male steroid receptor-related (four) (four) 胄n-dependent stages and/or male knees Non-dependent Stages of Nurturing: : Disease 'Don't be in the androgen-dependent phase and/or male: hormone-sensitive stage A hormone-induced cancer (eg prostate 2; eg hormone-dependent frontier Lin Zi, μ # Guan Urea cancer (example, etc.) Μ, 5 non-refractory prostate cancer, Lu cancer, cancer (including progressive breast cancer such as: invasive ductal carcinoma, in situ s cancer, inflammatory breast cancer, etc.), pituitary tumor, liver cancer, for example, liver cancer, extrahepatic cholangiocarcinoma Etc.), etc., sexual hormone-sensitive diseases such as pre-hypertrophy, endometriosis, uterine fibroids, precocious puberty, menstrual pain, arrhythmia, premenstrual syndrome and polycystic ovarian syndrome#, contraceptives II = Le When there is a rebound effect after the substance, as a medicine for preventing or treating infertility) Terrin, because the compound (1) of the present invention or a salt thereof antagonizes normal males and/or money 24 (four), the pair is male. Hormone-sensitive cancers in the segment and/or androgen-independent phases exhibit excellent prophylactic or therapeutic effects. Among the male agonist antagonists, the mutant androgen receptors are shown to be (tetra) and exhibit enhanced sensitivity to the heterohormone receptor. Anti-allergic drugs are also useful as ribs or agents for the treatment of cancers in the androgen-dependent phase and/or androgen-independent phase. An agent containing the compound (1) of the present invention or a salt thereof, for example, a drug composition obtained by mixing an androgen receptor antagonist of the present invention and a pharmaceutically acceptable carrier according to a method known per se, such as a key agent (including a sugar-coated spin) Membrane

[SJ 321538 12] 201114741 Ingots, powders, granules, capsules (including soft capsules), liquids, injections, lotions, sustained release agents, etc., can be safely administered orally or parenterally (eg local Administration, rectal administration, intravenous administration, etc.) injection can be administered intrapulmonary, intramuscularly, subcutaneously or intradermally or directly to the lesion. Examples of pharmaceutically acceptable carriers which can be used in the manufacture of the agents of the present invention include a variety of organic or inorganic carriers which are conventionally used as formulation materials. For example, excipients, lubricants, binders and disintegrating agents for solid preparations, or solvents, solubilizers, suspending agents, isotonic agents, buffers, palliatives and the like for liquid preparations can be mentioned. Further, if necessary, an appropriate amount of a conventional preservative, an antioxidant, a coloring agent, a sweetener, an adsorbent, a wetting agent and the like can be suitably used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous citric acid and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, bauxite and the like. " Examples of binders include crystalline cellulose, radish, sugar ' 〇 mannitol, dextrodextrin, propyl cellulose, propyl methyl cellulose, polyglycoside, = powder, sucrose , Mingsheng, methyl cellulose, slow methyl cellulose and so on. Examples of the disintegrator include: temple powder, methine cellulose, dimethylcellulose, kievone powder, L-propylcellulose, and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, polyethylene glycol (ffiaCr〇g〇1), sesame oil, corn oil, eucalyptus oil, and the like. Examples of the co-solvent include polyethylene glycol, propylene glycol, D-mannitol, benzene fg benzamidine, ethanol, diamine methyl (salt is (four) thin sleeve Qian), cholesterol, triethanolamine, sodium carbonate, sodium citrate Wait. [s] 321538 122 201114741 Examples of suspending agents include surfactants such as: stearin triethanolamine, sodium dodecyl sulfate, dodecylaminopropionic acid, egg structure, chlorinated benzalkonium chloride ), gasification of benzethonium chloride, glyceryl monostearate, etc. 'Hydrophilic polymers such as: polyvinyl alcohol, polyvinylpyrrolidone, carboxy-f-cellulosic steel, methyl cellulose, Hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like. Examples of the isotonizing agent include glucose, D-sorbitol, sodium carbonate, glycerin, D-mannitol, and the like. Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. Examples of the mitigating agent include benzyl alcohol and the like. Examples of the preservative include p-hydroxybenzoic acid ester, butyl alcohol, benzyl alcohol, phenylethyl alcohol, dehydrated acetic acid, sorbic acid, and the like. Examples of antioxidants include sulfites, anti-success, and fertility. The content of the compound (1) or monoterpene of the present invention in the agent of the present invention can be appropriately determined by administration to an individual, administration route, disease, etc., based on the entire formulation, which is usually (four). 〇1 to preferably about 0.1. Up to 50% by weight, more preferably about 随着 it varies with the form of the definition. 0% 1% 'however' the additive in the pharmaceutical composition of the present invention is changed, for example, in the form of a preparation, and the content of the entire preparation A is exaggerated to 99.99% by weight, preferably about 10 to 2, which is usually It is about 1% by weight on yu. 321538 123 201114741 The compound (i) of the present invention or a salt thereof is low in toxicity and can be used safely. The daily dose varies depending on the kind of the compound, the age, weight and condition of the patient, the dosage form, the administration method, and the like. For the purpose of, for example, treating prostate cancer, intravenous administration to a patient, the daily dose of an adult (weight about kg) is from about 0.01 to about 1000 mg/kg, preferably from about 1 to about mg/kg, more preferably. It is preferably from about 0.1 to about 100 mg/kg 'especially from about 1 to about 50 mg/kg, especially from about 1.5 to about 30 mg/kg, which is administered once a day intravenously or several times a day. Intravenous administration. The dose does not need to be explained as the above various conditions change. Thus, a dose less than the aforementioned dose may be sufficient, or in some cases an excessive dose is necessary. A drug which can be used together with the compound (I) of the present invention or a salt thereof, for example, a hormone therapeutic agent, an anticancer agent (for example, a chemotherapeutic agent, an immunotherapeutic agent (including a vaccine), an antibody, a gene therapy drug, An agent that inhibits the action of cell growth factors and its receptors, a drug that inhibits angiogenesis, and the like (hereinafter referred to as a concomitant drug). Although the compound (I) or a salt thereof in the present invention exhibits an excellent anticancer effect even when it is used as a single agent, it can be enhanced by using it in combination with one or more of the above-mentioned co-concomitants (multi-dose co-injection) ^) For examples of "hormone therapeutics", it is possible to use phosphoestrone, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate (megestrol) Acetate), chlormadinone acetate, cyproterone acetate, up to 124 321538 201114741 danazol, dienogest, dilopridone. Asoprisnil), allylestrenol, gestrinone, nomegestrol, tadenan, mepartricin, raloxifene, Ogilvy Ormeloxifene, levomeloxifene, antiestrogens (eg tamoxifen citrate, toremifene citrate), ER down-regulation Control agents (eg, fulvestrant, etc.), human menopausal gonadotropins, folHtropin, oral contraceptive preparations, mepitiostane, and Taishou

(testrolactone), aminoglutethimide, LH-RH derivatives (eg, LH-RH agonists (eg, goserelin acetate, buserelin, Liu Bolin) (leuprorelin), etc., LH-RH antagonists, droloxifene, epitiostanol, block estradiol; ethenylestradiol sulfonate, aromatase inhibitors (eg: Fadrozole hydrochloride, anastrozole, retrozole, exemestane, vorozole, formestane, etc., anti-male Hormones (eg, flutamide, bicartamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, dutasteride) (dutasteride), epristeride, etc., adrenal corticosteroids (eg dexamethasone, bonniesone [s] 321538 125 201114741 (prednisolone), betamethasone, beta Triamcinolone Etc., an androgen synthesis inhibitor (e.g., abiraterone, etc.), a retinoid, a drug that slows down the metabolism of retinoids (e.g., liarozole, etc.), and the like. As examples of "chemotherapeutic agents", alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and other chemotherapeutic agents can be used. The "burning agent" includes nitrogen mustard, nitrogen mustard oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, Carboquone, improsuifan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan ( Meiphalan), dacarbazine, ranimustine, sodium estramustine phosphate, tri-ethyl melamine, carmustine, lomustine , streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, Oxaliplatin, aitretamine, ambamustine, dibrospidium hydrochloride, fumtemustine, prednisolone Prednimustine (pumitepa), ribomustin, temoz〇i〇mide, 曲奥舒凡 [S3 126 321538 201114741 (treosulphan), chlorophosphine, tro Zinostatin stimalamer, adozelesin, cystemustine, bizelesin, etc. "Antimetabolites" include mercaptopurine, 6-drug nucleus 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine Sodium (cytarabine ocfosfate), ancitabine hydrochloride, 5-FU drugs (eg, fluorided urea, tegafur, UFT, dexifluridine, carmofur ( Carmofor), gallocitabine, emitefur, etc., aminopterin, leucovorin calcium, tabloid, butocine ), folic acid caicium, left arbor Fresh lev〇f〇l inate calcium, cladribine, emitefur, fiudarabine, gemcitabine, hydroxycarbamide, spray Pentostatin, piritrexim, idoxuridine, mitoxantrone (m; [t〇guazone), alpha stopper. Take thiazophrine, aminoxie > 'ambamustine' and so on. "Anticancer antibiotics" include actinomycin 邛, actinomycin _c, mitogen micronuclides nC, chromosomal-A3, bieomyCin hydrochloride, bieomyCin suifate ), [si 321538 127 201114741

Peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, oral pirarubicin Hydrochloride (pirarubicin hydrochloride), epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, Mittane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like. "Anti-cancer agents derived from plants" include etoposide, etoposide, vinblastine sulfate, vincristine sulfate, and diammonium sulphate. Salt (vindesine sulfate), teniposide, paclitaxel, docetaxel, vinorelbine, irinotecan, topotecan, and the like. For "other chemotherapeutic agents", for example, sobuzoxane or the like can be used. "Immunotherapy (BRM)" includes picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, Interleukin, giant [s] 128 321538 201114741 phagocytic community stimulating factor, granulocyte cell stimulating factor, erythropoietin, lymphotoxin, Corynebacterium parvum, levamisole, Multi-vinegar K, procodazole and the like. For vaccines, use BCG vaccine, PR0VENGE, Onyvax-P, PR0STVAC-VF, GVAX, DCVax_

Prostate, SAPOIMMUNE, VPM-4-001, etc. As the "antibody", an antibody against EpiCAM, an antibody against PSCA, an antibody against PSMA, or the like can be used. "Cell growth factor" in "a drug that inhibits the activity of a cell growth factor or a cell growth factor receptor" includes any substance that promotes cell proliferation, which is generally a peptide having a molecular weight of not more than 20,000, and which can be Bonding to the receptor and exhibiting activity at low concentrations, the receptor comprises (1) EGF (epidermal growth factor) or a substance having substantially the same activity [eg EGF, heregulin, TGF-α, HB -EGF, etc.], (2) Tengdaosu or substances with substantially the same activity [eg insulin, IGF (insulin-like growth)

_ factor (insul in-1 ike growth factor)-1, IGF-2, etc.], (3) FGF (fibroblast growth factor) or substances with substantially the same activity [eg acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-l〇, etc., (4) other cell growth factors [eg CSF (community stimulating factor), EP0 (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF/9 (transformation growth factor), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), etc. "Cell growth factor receptor" includes any receptor capable of binding to the aforementioned cell growth [S] 129 321538 201114741, and specifically, EGF receptor and HER2, HER3 and HER4 (which are belonging to the same family) Body, insulin receptor, IGF receptor, FGF receptor-1, FGF receptor_2 and the like. "Drugs that inhibit cell growth factor activity" include trastuzumab (Herceptin (trademark): (HER2 antibody)), imatinib mesylate, ZD1839, cetuximab ( Cetuximab), gefitinib, erlotinib, etc. φ Β Γ For the agent for inhibiting angiogenesis, an antibody against VEGF (for example, l3evacizumab), an antibody against VEGF receptor, a VEGF receptor kinase inhibitor (for example, SU11248, etc.), PDGF can be used. Receptor kinase inhibitor, Tie2 kinase inhibitor, fhaiid〇mide, and the like. In addition to the aforementioned drugs, L-aspartate indolease, aceglatone, procarbazine hydrochloride, pro-purine inverterate (pr〇t〇p) may be used. 〇rphyrin-cobalt _ complex salt), mercuric hematoporphyrin-sodium, differentiation inducer (eg retinoid, vitamin D, etc.), α_blocker (a_bl〇cker) (eg, tamsuiosin hydrochloride, naftopidil, urapidii, alfuzosin, teraz〇sin, Slightly sitting on praz〇sin, silodosin, etc., a serine/threonine kinase inhibitor, an endothelin receptor antagonist (eg, atazantan, etc.) , protein body inhibitors (eg, bortezomib, etc.), Hsp 90 inhibition [S3 321538 130 201114741 preparation (eg: 17-AAG, etc.), spironolactone, minoxidil , 11 α -progesterone (11 α -hydroxyprogesterone), bone resorption inhibition • metastasis Formulations (eg, zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic (ibandronic) Acid), clodronic acid, and the like. ^ Particularly preferred co-concomitant drugs are, for example, LH-RH derivatives and the like. The LH-RH derivative includes an LH-RH derivative or a salt thereof, which is effective against a hormone-dependent disease, particularly a sex hormone-dependent disease such as a sex hormone-dependent cancer (for example, prostate cancer, uterine cancer) , breast cancer, pituitary tumor, liver cancer, etc.), prostatic hypertrophy, endometriosis, uterine fibroids, early maturity, menstrual pain, no menstrual disease, premenstrual syndrome, multi-room ovarian syndrome, etc., and contraception (or application Infertility in the rebound effect after drug interruption). Further, it includes an LH-RH derivative or a salt thereof which is effective against a benign tumor or a malignant tumor which is sexually non-hormone-dependent and LH-RH-sensitive. Specific examples of the LH-RH derivative or a salt thereof are included in "Treatment

Wl_th GnRH analogs: Controversie and perspectives" issued in 1996 by The Parthenon Publishing Group, pct Japanese translation patent publications 3_5〇3165, Jp_A 3_

The peptides described in 101695, JP-A 7-97334, and JP-A 8-259460, and the like. LH-RH derivatives include LH-RH agonists and LH-RH antagonists. The LH-RH antagonist is, for example, a physiologically active peptide as shown in the following formula: m 131 321538 201114741 X-D2Nal-D4ClPhe-D3Pal-Ser-AB-Leu-C-Pro-DAlaNH2 [where X is N (4H2) -furanyl)Gly or NAc, A is a residue selected from the group consisting of 丽 e yr, Tyr, Aph (Atz) and NMeAph (Atz), and B is selected from the group consisting of DLys (Nic), DCit, DLys (AzaglyNic), DLys ( Residues of AzaglyFur), DhArg(Et2), DAph(Atz) and DhCi, and C is Lys(Nisp), Arg or hArg(Et2)] or a salt thereof. The LH-RH agonist includes, for example, a physiologically active peptide represented by the formula: 5-sided oxy-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z Lu [where Y is selected from Residues of DLeu, DAla, DTrp, DSer(tBu), D2Nal, and DHis (ImBzl) and Z are NH-C2H5 or Gly-NH2] or a salt thereof, and particularly 'appropriately, γ is DLeu, and Z Is a peptide of NH-C2H5 (ie, peptide A represented by 5-sided oxy-pro-His-Trp-Ser-Tyr_DLeu-Leu-Arg-Pro-NH-GH5; peptide of UUproreiin) Or a salt thereof (for example: acetate). For example, according to a method known per se, a male pharmaceutically acceptable carrier of the present invention is mixed with a pharmaceutically acceptable carrier such as a tablet (including a sugar-coated tablet and a film-coated tablet). ), a powder, a granule, a capsule (including a soft capsule), a liquid, an injection, a suppository, a sustained release agent, and the like, and a compound containing the compound (1) of the present invention or a salt thereof and a combined drug (hereinafter, The combination drug of the present invention is a low toxicity and can be safely administered orally or parenterally (for example, topical administration, rectal administration, intravenous administration, etc.). The injection can be administered intravenously, intramuscularly, subcutaneously or intra-organically, or directly to the lesion. A pharmaceutically acceptable carrier which can be used in the manufacture of the combination of the present invention. [s] 321538 132 201114741 ^Examples of various organic or inorganic materials for use in solid preparations, lubricated as a formulation material Agents, binders Solvents, cosolvents for liquid preparations. · Tanning agents, slow side, relief materials. Further, if necessary, a suitable conventional preservative, antioxidant, humectant or the like can be suitably used. Examples of the coloring agent, sweetener, adsorbent, and excipient include lactose, Yan sugar, mannitol, house powder, corn starch, crystalline cellulose, light anhydrous anthracite, and the like. Examples of bauxite 2' mooncakes include magnesium stearate, stearic acid dance, 'talc, and colloidal binders, including crystalline cellulose, curtain sugar, mannitol, dextrin' (tetra) cellulose, and C. Examples of disintegrants such as methylcellulose, polyethylene ketone, starch, co-gelatin, methylcellulose, and m-methylcellulose steel include Cong 1 methylcellulose and slow methyl fibril Approximately, a terpenyl starch, a l-(tetra)-based cellulose, and the like. # > Examples of the solvent include water for injection, alcohol, propylene glycol, polyglycol diol, sesame oil, corn oil, olive oil, and the like. Examples of solubilization include polyethyl b, D-mannitol methyl benzoate, ethanol, triamine methane, cholesterol, sodium triethoxide, sodium citrate, and the like. Examples of suspending agents include interface-active swords such as: hard waxed triethanolamine dodecyl sulfate steel, dodecylaminopropionic acid, (tetra) lipid, chlorinated dimethicin, fresh ethyl, single hard rot vinegar Etc., hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, decyl cellulose 321538 133 201114741 light methyl cellulose, 35 ethyl cellulose, propyl fiber And so on. Examples of the isotonizing agent include glucose, D_sorbitol, gasified sodium, glycerin, D-mannitol, and the like. Examples of the buffering agent include buffer solutions such as Wei salt, acetate, carbonate, citrate, and the like. Examples of the mitigating agent include stupid methanol and the like.

"Examples of preservatives include p-benzoic acid, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydrated acetic acid, sorbic acid, etc. Examples of antioxidants include sulfite, ascorbic acid, and fertility diseases, etc. The present male antagonist and the co-concomitant drug may be mixed according to the male hormone of the present invention in the administration of the individual, the administration route, and the combination drug. The content of the agent is dependent on the form of the preparation. The body entanglement is usually from about 0.1% by weight to 9q%, and is relative to the entire formulation by weight%, more preferably two = preferably from about 约. In the present invention, the group of people is... weight%. Form and et change, and the phase of the drug with the drug (four) 'with the preparation to 99.9_: two = agent? Often from about 〇. 1« from about 〇. 5wt% to 2() by weight χ. 1% by weight to 50% by weight 'better, agent: to 99% by weight of shoulder, preferably, ^ is about 10% by weight to 90% by weight %. 321538 134 201114741 When the androgen receptor antagonists and co-compounds of the present invention are separately formulated, the same content can be employed. These preparations can be produced by a method known per se which is generally used in a pharmaceutical manufacturing process. For example, the androgen receptor antagonist and co-concomitant of the present invention may be combined with a dispersing agent (for example, Tween 80 (manufactured by Atlas Powder, US), HC0 60 (manufactured by Nikko Chemicals Co., Ltd.), polyethylene. Alcohol, stearyl cellulose, sodium alginate, hydroxypropyl decyl cellulose, dextrin, etc.), ampoules (eg ascorbic acid, sodium metabisulfite, etc.), surfactants (eg polysorbate 80) , polyethylene glycol, etc.), solubilizers (eg, glycerol, ethanol, etc.), buffers (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, chlorination) Sodium, potassium chloride, mannitol, sorbitol, glucose, etc.), pH adjusters (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl p-hydroxybenzoate, benzoic acid, p-hydroxybenzoic acid) a methylparaben, a propyl benzoate, a benzoquinone, etc., a dissolution agent (for example, concentrated glycerin, meglumine, etc.), a cosolvent (for example, propylene glycol, sucrose, etc.), Relief (eg glucose, benzyl alcohol, etc.), etc. Preparing an injection such as an aqueous injection, or by dissolving, suspending or emulsifying the androgen receptor antagonist of the present invention and a co-adjuvant drug in vegetable oils such as olive oil, sesame oil, cotton oil, corn oil, etc. A cosolvent such as propylene glycol is used to prepare an oily injection having the androgen receptor antagonist of the present invention and a co-compound. In the case of the orally administered preparation, the androgen receptor antagonist of the present invention and the concomitant drug can be obtained by adding an excipient [s] 135 321538 201114741 lactose sucrose, starch, etc. according to a method known per se. Decomposing agents (eg, powder, calcium, etc.), adhesives (eg, powder, gum arabic, buffered cellulose, polyethylene phase, propyl cellulose, etc.), lubricants (eg: Code: „Polyethylene glycol_〇, etc.) to the compound of the present invention or the accompanying drug β, and compact and mold the mixture, and if necessary, for the purpose of concealing intestinal characteristics or sustained release, by itself Known methods = Π: 曱:: Formulations resulting in oral administration. Film-forming agents include propyl, ethyl cellulose, methyl cellulose, cellulose 2, "ethyl diol, Tween 80, Plur0nic F68, fiber weixin test ϊή酉曰 酉夂酉曰, search for propyl methyl cellulose vinegar, thiol:: 素,, _, Eudragit (methyl acrylate / acrylic acid = _Manufacture), pigment (for example: iron oxide red, dioxide: special). The oral administration preparation may be a rapid release preparation or a sustained release preparation, for example, 'in the case of a suppository', the androgen receptor anti-half drug of the present invention can be produced into an oily or aqueous solid W solid or liquid according to a method known per se. Suppository. The oily substrate used in the above composition includes, for example, a glyceride of a southern fatty acid [e.g., cocoa butter, (10) 〇is (by

Dmmite Nobel (manufactured by DE), etc., and the middle key, such as (8) (10) core (manufactured by D Qing ite N〇bel, DE), or vegetable oil (for example, sesame oil, soybean oil, cottonseed oil, etc.). Further, the aqueous substrate includes, for example, polyethylene glycol and propylene glycol, and the aqueous colloid substrate includes, for example, a natural rubber, a vitamin derivative, a vinyl polymer, an acrylic polymer, or the like. The above sustained release preparations include sustained release of microcapsules and the like. 321538 136 201114741 In order to obtain sustained release microcapsules, a method known per se can be employed. For example, it is preferably molded to the sustained release preparation shown in the following [2]. The androgen receptor antagonist of the present invention is preferably molded into an oral administration preparation such as a solid preparation (e.g., powder, granule, lozenge, capsule, etc.) or the like, or molded into a rectal administration preparation such as a suppository. In particular, oral administration of the preparation is preferred. The co-concomitant drug can be made into the above-mentioned drug form with the drug type. Specifically, the injection of the compound (I) or a salt thereof or a co-compound drug thereof in the present invention and the method for producing the same, and the compound (I) or a salt thereof or a concomitant drug thereof in the present invention are specifically shown below. A quick release preparation or a sustained release preparation and a process for the preparation thereof, and [3] a sublingual lozenge, a buccal or intraoral rapid disintegrating agent of the compound of the present invention or a salt thereof or a concomitant drug, and a process for the preparation thereof. [1] Injection and preparation thereof The injection is preferably prepared by dissolving the compound (I) of the present invention or a salt thereof or a concomitant thereof in water. The injection may also contain a benzoate and/or a salicylate. The injection is obtained by dissolving the compound (I) of the present invention or a salt thereof or a co-compound thereof, and, if necessary, a benzoate and/or a salicylate into water. The above-mentioned salts of benzoic acid and salicylic acid include, for example, alkali metal salts such as sodium, bell, etc., face metal salts such as: mother, magnesium, etc., ammonium salts, meglumine salts, and temmi (tromethamol) salt and the like. The concentration of the compound (I) or a salt thereof or a concomitant drug thereof in the present invention is from 0.5 w/v% to 50 w/v%, preferably from about 3 w/v% to about 20 w/v%. The concentration of the benzoate or/and the salicylate is from 0.5 w/v% to 50 w/v%, [s] 137 321538 201114741 is preferably from 3 w/v% to 20 w/v%. . A conventional additive to be used in an injection solution can be appropriately added to the preparation of the present invention. Examples of the additives include stabilizers (for example, ascorbic acid, sodium metabisulfite, etc.), surfactants (for example, polysorbate 80, polyethylene glycol, etc.), solubilizers (for example, glycerin, ethanol, etc.), buffers ( For example: phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc., isotonic agents (for example: sodium chloride, potassium chloride, etc.), dispersants (for example: hydroxypropyl decyl cellulose, dextrin ), a pH adjuster (for example, hydrochloric acid, sodium hydroxide, etc.), an antiseptic agent (for example, ethyl p-hydroxybenzoate, benzoic acid, etc.), a dissolving agent (for example, concentrated glycerin, melomin, etc.), A solvent (for example, propylene glycol, sucrose, etc.), a mitigating agent (for example, glucose, benzoquinone, etc.), or the like. The above additives are mixed in a usual ratio which is generally used in an injection solution. 5之间为优选。 By adding a pH adjusting agent to control the pH of the pH of 2 to 12, preferably 2. 5 to 8. 0 is advantageous. By injecting the compound (I) of the present invention or a salt thereof or a co-concomitant drug, and φ, if necessary, a salt of a benzoic acid and/or a salt of salicylic acid, and if necessary, an injection of the above-mentioned additive into water . It may be dissolved in any order, and may be appropriately dissolved in the same manner as the conventional method of producing an injection. The aqueous solution for the injection solution is preferably heated, or, for example, can be subjected to filter sterilization, high-pressure heat sterilization or the like in the same manner as that of the general injection solution to provide an injection solution. The aqueous solution for the injection solution is preferably subjected to autoclaving for 5 minutes to 30 minutes at 100 ° C to 121 ° C. Further, a formulation to which the antibacterial property of the solution is imparted can be produced, so that [s] 138 321538 201114741 can be used as a separate and multiple-administered preparation. [2] a sustained release preparation or a rapid release preparation, and a preparation thereof, preferably a sustained release preparation, which is coated with a film forming agent such as a water-insoluble substance, a swellable polymer or the like (if necessary) The compound (I) or a salt thereof or a core of a co-concomitant drug is obtained. For example, a sustained release preparation which is orally administered once a day is preferred. Water-insoluble substances for the film forming agent include, for example, cellulose ethers such as ethyl cellulose, butyl cellulose, and the like; cellulose esters such as cellulose acetate, cellulose propionate, and the like; Vinyl esters such as: polyvinyl acetate, polyvinyl butyrate, etc.; acrylic polymers such as: acrylic acid/mercaptoacrylic acid copolymer, methyl methacrylate copolymer; ethoxylated ethoxyethyl acrylate / methacrylic acid cassia Ethyl ethoxide/aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, alkyl decyl methacrylate copolymer, poly(decyl methacrylate), polydecyl acrylate, polymethyl Acrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic anhydride), methacrylic acid@glycidyl acrylate copolymer, specifically Eudragit (manufactured by Rohm Pharma) such as Eudragit RS-100, RL -100, RS-30D, RL-30D, RL-P0, RS-P0 (ethyl acrylate/methyl methacrylate/trimethyl sulphate methyl acrylate/ethyl ammonium copolymer), Eudragit NE-30D (methacrylic acid methyl methacrylate / acrylic acid copolymer) Hydrogenated oils such as: hydrogenated castor oil (e.g.: Lovely overstep (Freund Corporation) and the like) and the like; worthy as: Ge brown wax, fatty acid glycerides, paraffin and the like; polyglycerol fatty acid esters and the like. The swellable polymer is preferably a polymer having an acidic dissociative group and a pH-dependent swelling property, and the polymer having an acidic dissociative group swells less in the acidic [s] 139 321 538 201114741 region (eg, stomach), but Neutral areas (eg, small intestine or large intestine) are greatly inflated. The polymer having an acidic dissociation group and pH-dependent swelling characteristics includes, for example, a crosslinkable polypropylene-based polymer such as Carbomer 934P, 940, 941, 974P, 980, 1342, etc. 'polycarbophil (p〇) _ycarbophil), polycarbophil calcium (all manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all by Wako Pure Chemical Industries,

Ltd. manufacture) and so on. The film forming agent used in the sustained release preparation may further contain a hydrophilic substance. The hydrophilic substance includes, for example, a polysaccharide having a sulfate group as needed, such as: pullulan, dextrin, an alkali metal alginate, etc.; a group having a group of 11⁄2 alkyl or an alkyl group such as: a polysaccharide such as propylcellulose, propylmethylcellulose or several fluorenylcellulose steel; mercaptocellulose; polyvinylpyrrolidone; polyvinyl alcohol; polyethylene glycol; The content of the water-insoluble substance in the film-forming agent of the sustained release preparation is from about 30% (w/w) to about 90% (w/w), preferably from about 35% (w/w) to about 80% ( w/w), and more preferably from about 40% (w/w) to about 75% (w/w). The swellable polymer is present in an amount from about 3% (w/w) to about 3 G% (w/w), preferably from about /w) to about 15% (w/w). The film forming agent may further contain a hydrophilic substance, and in this example, the content of the hydrophilic substance in the film forming agent is about w/w) or less, preferably from about 5% (w/w) to about 4 (10). (w/w), and more preferably from about 5% (w/w) to about 35% (w/w). This % (w/w) refers to a film forming agent group obtained by removing a solvent (4) such as water, a low carbon number alcohol such as decyl alcohol, ethanol, or the like from a film forming agent liquid [S3 321538 140 201114741 as a reference) % by weight. By preparing a drug-containing core, followed by coating with a film forming agent liquid (by heating and dissolving a water-insoluble substance, a swellable polymer, or the like, or by dissolving or dispersing in a solvent exemplified below) The core can be used to make sustained release formulations. I. The method of preparing a drug-containing core is not particularly limited to a form of a drug-containing core to be coated with a film forming agent (hereinafter sometimes referred to simply as a core), and it is preferred to form the core into particles such as granules m ^ or Fine particles. When the core is composed of granules or fine particles, the average particle size thereof is preferably from about 15 0 to about 2,000 /z m, more preferably from about 500 /z m to about 1,400 // m. A suitable excipient, a binder, a disintegrant, a lubricant, a stabilizer, etc. may be mixed with a drug by a conventional method, and the mixture may be subjected to a wet extrusion granulation method or a fluidized bed granulation method or the like. Prepare the core. The content of the drug in the core is from about 0.5% (w/w) to about 95% | (w/w), preferably from about 5.0% (w/w) to about 80% (w) /w), more preferably from about 30% (w/w) to about 70% (w/w). Excipients contained in the core include, for example, sugars such as sucrose, lactose, mannitol, glucose, etc., starch, crystalline cellulose, calcium phosphate, corn starch, and the like. Among them, crystalline cellulose and corn starch are preferred. The binder includes, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyethylene π ratio, sigma ketone, P1 uron i c F 6 8, gum arabic, gelatin, starch, and the like. Disintegrators include, for example, strontium methylcellulose calcium (ECG 505), cross-linking: croscarmel lose sodium [s] 141 321538 201114741 (Ac-Di-Sol), crosslinkable polyvinylpyrrole Helium

Post-twined J (crospovidone), low-substituted propyl cellulose (in sputum, hydroxypropyl cellulose, polyvinylpyrrolidine and low-grade. Cellulose is preferred. Lubricant or aggregation inhibition The agent includes, for example, <^@magnesium citrate and inorganic salts thereof. The lubricant includes polyethylene glycol, etc. The bone stone, hard acid such as: tartaric acid, citric acid, succinic acid, anti-butyric acid _ private ampoules include Acid, etc. 1 acid, butadiene dilute, in addition to the above manufacturing method, can also be dissolved by, for example, jltiL. (dissolved in a suitable solvent such as water, low carbon number alcohol (for example, J. Jiaxheng, 7 ▲, etc., the binder is added to the inert carrier particles (which is & 〃 & , )), and the flat bottom is added to the mixture of the drug, the excipient, the moisturizing agent, the alcoholic agent, and the like. The core is prepared by a pan coating method, a fluidized bed coating method, or a molten teaching method. The inert carrier particles include, for example, sugarcane, pouch, starch, 100 crystalline cellulose or The wax is prepared, and its average particle size is preferably from about νπι to about 1,500 μπι. In order to be contained in the core For the purpose of separating the substance from the film forming agent, the surface of the core may be coated with a protective agent, for example, the above-mentioned hydrophilic substance, water-insoluble substance, etc. The protective agent includes polyethylene glycol, and has a hydroxy group. Or a carboxyalkyl group polysaccharide, more preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose. The protective agent may contain a stabilizer such as an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, cis Butic acid, etc., and lubricants such as: talc, etc. When a protective agent is used, the coating amount is from about 1°/〇(w/w) to about 15% (w/w) based on the core. Preferably, it is from about 1% (W/W) to about 10% (w/w), more preferably from about 2% (w/w) to about 8% (w/w). 142 321538 201114741 The coating of the protective agent is carried out by a usual coating method, and specifically, the protective agent may be sprayed to the core by a fluidized bed coating method, a flat pan coating method, or the like to perform coating. This is obtained by a film forming agent liquid (by heating and dissolving the above water-insoluble substance with a pH-dependent expandable polymer, and a hydrophilic substance, or by dissolving or dispersing it in a solvent) Applying the core of 0 obtained in the above step to obtain a sustained release preparation. The method of coating the film with the film forming agent liquid includes, for example, a spray coating method, etc. 'Appropriate selection of the film forming agent liquid The composition ratio of the water-insoluble substance, the expandable polymer, and the hydrophilic substance is such that the content of the component in the coating film is respectively the above content. The coating amount of the film forming agent is core (excepting the coating of the protective agent) The amount of cloth is from about 1% (W/W) to about 90% (w/w), preferably from about 5% (w/w) # to about 50% (w/w), More preferably, it is from about 5% (w/w) to 35% (w/w). The solvent in the film forming agent liquid includes water or an organic solvent, either individually or as a compound thereof. In the example of use in the mixture, the mixing ratio of water to organic solvent (water/organic > cereal. weight ratio) may vary from 1 to 1%, and preferably to about 30%. The organic solvent is not particularly limited as long as it can dissolve the water-insoluble substance, and includes, for example, a low carbon number alcohol such as decyl alcohol, ethanol, isopropanol, n-butanol or the like, and a low carbon number alkyl ketone such as acetone. Ethyl acetate, gas imitation, dichlorodecane, etc. Among them, a lower carbon number is preferred, and ethyl alcohol and isopropanol are particularly preferred. It is preferred to use water, and a mixture of water and an organic solvent as 143 [S] 321538 201114741 as a solvent for the film forming agent. In this case, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid or the like may be added to the film forming agent liquid to stabilize the film forming agent liquid. The coating operation by spray coating can be carried out by a conventional coating method, and specifically, the coating film forming agent liquid can be sprayed to the core by, for example, a fluidized bed coating method, a flat pan coating method, or the like. . In this case, if necessary, talc, titanium oxide, magnesium stearate 'calcium stearate, light anhydrous citric acid, etc. may be used as a lubricant, and glycerin fatty acid ester, hydrogenated castor oil, or ® may also be added. Triethyl citrate, hexadecanol, stearyl alcohol, etc. are used as plasticizers. After coating with a film forming agent, an antistatic agent such as talc or the like may be mixed as necessary. The quick release formulation can be a liquid (solution, suspension, emulsion, etc.) or a solid (granules, pills, lozenges, etc.). It may be an oral administration agent or a parenteral administration agent such as an injection solution or the like, and is preferably an oral administration agent. The quick release preparation may usually contain, in addition to the active ingredient drug, a carrier, an additive, and an excipient (hereinafter sometimes referred to simply as an excipient) which are conventionally used in the field of the formulation. The formulation excipients used are not particularly limited as long as they are excipients which are generally used as excipients for the preparation. For example, excipients for oral solid preparations include lactose, powder, corn powder, crystalline cellulose (Avicel PH101, manufactured by Asahi Kasei Corporation, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous acid, Carbonic acid, carbonic acid, L-cysteine, etc., and preferably corn starch and mannitol. These excipients may be used singly or in combination of two or more. The amount of the excipient is, for example, from about [s] 144 321538 201114741 4. 5 w/w% to about 99.4 w/w%, preferably from about 2 〇w, based on the total amount of the quick release preparation. /w% to about 98. 5 w/w%, more preferably from about 30 w/w% to about 97 w/w%. The content of the drug in the rapid release preparation may be appropriately selected in the range of from about 5% to about 95%', preferably from about 1% to about 60%, based on the total amount of the rapid release preparation. When the rapid release preparation is an oral solid preparation, it usually contains a disintegrating agent in addition to the above ingredients. The disintegrator includes, for example, carboxymethyl cellulose (ECG-505, manufactured by GOTOKU CHEMICAL COMPANY LTD.), and thioglycol (for example: acjizol, by Asahi Kasei).

Made by Corporation), crospovidone (for example: colidone CL, manufactured by BASF), low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), slow-twisting starch (by Matsutani Chemical) Manufactured by Industry Co., Ltd.), ketamine powder (Exprotab 'manufactured by Kimura Sangyo Co., Ltd.), part of α-starch (PCS, manufactured by Asahi Kasei Corporation), and the like, and for example, φ includes Contact with water absorbs water, causes swelling, or creates a channel between the active ingredients constituting the core and the excipient to disintegrate the particles. These disintegrants may be used singly or in combination of two or more. The amount of the disintegrant used is appropriately selected depending on the kind and amount of the drug to be used, the formulation design for the release characteristics, and the like, and is, for example, from about 0.05 w/w based on the total straightness of the rapid release shoulder β彳. % to about 30 w/w%, preferably from about 0.5 w/w% to about 15 w/w%. When the rapid release preparation is an oral solid preparation, it may further contain, if necessary, an additive for a solid preparation other than the above ingredients. Such additives as [S] 145 321538 201114741 include, for example, binders (for example: sucrose, gelatin, acacia powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, slow methyl cellulose, Polyethylene (pyrrolidone, pullan, dextrin, etc.), lubricants (eg polyethylene glycol, magnesium stearate, talc, light anhydrous citric acid (eg: aerosil (Nippon Aerosil)), interface Active agent (for example: anionic surfactants such as sodium alkyl sulfate, nonionic surfactants such as: polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.) , coloring agents (for example: tar color, caramel, iron oxide red, titanium oxide, riboflavin), if necessary, flavoring agents (eg sweeteners, spices, etc.), adsorbents, preservatives, wetting agents Antistatic agent, etc. Further, stabilizers such as organic acids such as tartaric acid, citric acid, succinic acid, fumaric acid, etc. may be added. The above binder preferably includes hydroxypropyl cellulose and polyethylene. Alcohol and polyethylene n than rididone and the like.

The quick release preparation can be prepared by mixing the above ingredients and, if necessary, further kneading the mixture according to the technique of conventionally preparing the preparation and molding. The above mixing is carried out by a generally used method such as mixing, kneading or the like. Specifically, when the formed rapid release preparation is, for example, a granule, it can be used according to the same method as the above-described method for preparing a core of the sustained release preparation, by using a vertical granulator, a universal kneader (universal kneader) )(by

HataIr°nW°rksC°., Ltd.), a fluidized bed granulator FD-5S (manufactured by Powrex Corporation) and other mixed air knives, after which the mixture was subjected to wet extrusion granulation, flow bed It is prepared by a granulation method or the like. The thus obtained rapid release preparation and the continuous release preparation itself can be made into a product by 321538 146 201114741, or can be appropriately prepared separately from the preparation excipients and the like by a usual method, and then simultaneously, simultaneously Administration or administration may be carried out in any combination of administration intervals, or may be made into an oral administration preparation (for example, granules, fine granules, troches, capsules, etc.) or together with preparation excipients and the like. Oral administration of the preparation. It may also be allowed to be granulated or granulated and filled in the same capsule to be used as an oral administration preparation. [3] Sublingual, buccal or intraoral disintegrating agent and its preparation sublingual, buccal or intraorbital disintegrating agent may be a solid preparation such as a key agent, or may be a mucosal patch (membrane) . The sublingual, buccal or intraoral disintegrating agent is preferably a preparation containing the androgen receptor antagonist or co-concomitant drug and excipient of the present invention. It may also contain adjuvants such as lubricants, isotonic agents, hydrophilic carriers, water-dispersible polymers, stabilizers, and the like. Further, in order to facilitate absorption and increase the bioavailability, a cyclodextrin or a /3-cyclodextrin derivative (e.g., hydroxypropyl-/5-cyclodextrin) may be contained. The above excipients include lactose, Yan sugar, D-mannitol, temple powder, crystalline cellulose, light anhydrous citric acid and the like. Lubricants include magnesium stearate, calcium stearate, talc, colloidal alumina, and the like, and particularly preferred are magnesium stearate and colloidal alumina. The isotonic agent includes sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, sucrose, glycerin, urea, etc., and particularly preferably mannitol. The hydrophilic carrier includes a swellable hydrophilic carrier such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous citric acid, citric acid, calcium diphosphate, calcium carbonate, and the like, and Particularly preferred is crystalline cellulose (for example, microcrystalline cellulose or the like). Water-separable polymers include gums (eg, gum tragacanth, arabic [S1 147 321538 201114741 gel, gums), alginate (eg sodium alginate), cellulose derivatives (eg, sulfhydryl fibers) , carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl fluorenyl cellulose), gelatin, aqueous starch, polyacrylic acid (eg Carbomer), polyacrylic acid, polyvinyl alcohol , polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbate, ruthenium palmitate, etc., and preferably hydroxypropyl methylcellulose, polyacrylic acid, alginate, gelatin, carboxymethyl Cellulose, polyvinylpyrrolidone, polyethylene glycol, etc., particularly preferably hydroxypropyl fluorenyl cellulose. Stabilizers include cysteine, thiosorbitol, wine ® stearic acid, citric acid, sodium sulphate, ascorbic acid, glycine, sodium sulfite, etc., and particularly preferred are citric acid and ascorbic acid. The sublingual, buccal or intraoral fast-disintegrating agent can be produced by mixing the androgen receptor antagonist or the co-concomitant drug and excipient of the present invention by a method known per se. Further, if necessary, auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a coloring agent, a sweetener, a preservative, and the like may be mixed. The sublingual, buccal or intraoral rapid fast disintegrating agent is obtained by simultaneously mixing the above ingredients or mixing the above ingredients at time 0 intervals, followed by subjecting the mixture to compression molding under pressure. In order to obtain an appropriate hardness, it is also allowed to use a solvent such as water, alcohol or the like before and after the tableting process, and after molding, the material is dried to obtain a product. In the case of molding a mucosal patch (membrane), the androgen receptor antagonist or co-compound drug of the present invention and the above water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylguanidine) The base cellulose), an excipient or the like is dissolved in a solvent such as water or the like, and the resulting solution is cast to obtain a film. In addition, [S3 148 321538 201114741 additives such as: plasticizers, elixirs 'antioxidants, preservatives, colorants, buffers, sweeteners, etc. may also be added. In order to give the film appropriate elasticity, it may contain a diol such as polyethylene glycol, propylene glycol, etc. or may contain a bioadhesive polymer (for example, polycarbophil, kappabo (in order to improve the adhesion of the mucosal lining in the sputum). Carbopol)). In the mold, the solution is poured onto a non-adhesive surface, and the solution is dried by a coating tool such as a doctor blade or the like to a uniform thickness (preferably about 1 μm to about 1, 微米). A film is formed. It is preferred to dry the thus formed film at room temperature or under heating for a predetermined area. The internal disintegration agent is preferably a water-repellent body comprising an androgen receptor antagonist or a concomitant drug of the present invention, and a water-soluble or inert to the androgen steroid inhibitor or co-compound of the present invention. A solid-state rapid diffusion administration formulation comprising a water-diffusing carrier. The mesh is obtained by sublimating a solvent which is a composition consisting of a solution prepared by dissolving the male hormone receptor antagonist of the present invention or a co-compound drug in a suitable solvent. The composition of the intraoral rapid fast disintegrating agent preferably contains a matrix forming agent and a second component in addition to the male #hormone receptor antagonist or co-concomitant drug of the present invention. The matrix forming agent includes animal protein or plant protein such as: gelatin, dextrin, soybean, wheat, and psyllium (tetra) protein, etc.; rubber materials such as: gum arabic, guar gum, acacia, sanxian gum, etc.; Vinegar; alginic acid; slow-twisting cellulose; carrageenan; poly-grass; pectin; synthetic polymers such as: polyethylene, etc.; derived from the daily turnover of _ arabic compound. Further, it includes sugars such as: mannitol, glucose, lactose, galactose, trehalose, etc.; ring_such as: cyclodextrin; inorganic salts such as: scale [S] 321538 149 201114741 sodium, sodium chloride and cesium Aluminum acid or the like; an amino acid having 2 to 12 carbon atoms such as: glycine, L-alanine, L-aspartic acid, L- faceamine, l-hydroxyproline, L-iso white Amine acid, l-leucine, L-phenylalanine, and the like. One or more matrix forming agents may be introduced into the solution or suspension prior to curing. These matrix formers may be present in addition to the surfactant, or such matrix formers may be excluded from the surfactant. In addition to forming a matrix, the matrix forming agent can also help to maintain the diffusion of the androgen receptor antagonist or co-compound drug of the present invention in a solution or suspension. The composition may contain a second component such as a preservative, an antioxidant, an surfactant, a thickener, a coloring agent, a pH controlling agent, a flavoring agent, a sweetener, a food flavoring coating, and the like. Suitable coloring agents include red, black and yellow iron oxide, and FD&C dyes manufactured by Eli and Eberald such as FD&CBlue2, FD & C Red 40 and the like. Examples of suitable end-flavoring agents include peppermint, raspberry, licorice, citrus, lemon, grapefruit, caramel, vanilla, cherry, vine seasoning, and combinations thereof. Examples of suitable pH control agents include citric acid, tartaric acid, acid-filled, hydrochloric acid, and maleic acid. Examples of suitable sweeteners include aspartame, vinegar lactone K, and thaumatine. Examples of suitable food flavoring agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbent materials, and microencapsulated apomorphine formulations generally containing from about 0.1% by weight to about 50% by weight, preferably from about 0.1% by weight to about 30% by weight of the androgen receptor antagonist or co-compound of the present invention, and preferably from about 丨 minutes to about 6 〇. Minutes, preferably from about 1 minute to about 15 minutes, more preferably from about 2 minutes to about 5 minutes. 321538 150 201114741 ^Intravenous or more of the male gonadotropin receptor antagonist or partner of the present invention The preparation of the music (to the water) (such as the sublingual agent, the lining, etc.), after being placed in the oral cavity, is 1 second to 6 sec, preferably 4 30 sec, more preferably 1 to 10 sec. An intra-sigma rapid disintegration preparation that disintegrates within the range. The above excipients are present in the entire formulation in an amount of from about 10% by weight to 99% by weight, preferably from about 3% by weight, about 9% by weight. The content of the square-cyclodextrin or the 10,000-cyclodextrin derivative in the whole body is from 〇 to about 5% by weight. The content of the flux of the entire shot is about 1% by weight, preferably from about 5% by weight to about 5% by weight. The content of the isotonic agent in the entire formulation is from about 0% by weight to about 9% by weight, more preferably from 10% by weight to about 70% by weight. The hydrophilic carrier in the entire formulation: from about 0.1% by weight to about 50, preferably from about 1% by weight to about 30% by weight. The water-dispersible polymer of the entire formulation Yin contains 0 from about 0.1 to about 30% by weight, preferably from about 1% by weight to about Μ: the content of the stabilizer in the entire formulation is from about From 1% by weight to about 1% by weight, preferably from about 1% by weight to about 5% by weight. The above-mentioned preparation may further contain additives such as a coloring agent, a sweetener, a preservative, etc., if necessary. The dose of the combined preparation of the present invention varies depending on the kind, age, body weight, condition, drug form, administration method, administration period, and the like of the compound (1) of the present invention... and, for example, for a prostate cancer patient (adult, body weight: about =) 'Respectively for the androgen receptor antagonist or co-adjuvant drug of the present invention, 'about 0_01 to about! , _? ~ / day, preferably from about 〇 to about (10) mg / kg / day, more preferably from about 1 to about 1 〇 is about "." to about (10) Μ, especially about U to about 3 flm ^ [S] 321538 151 201114741 days dose, one or several divided into several times a day intravenously administered combination preparation. Of course, since the above dosages vary with a variety of conditions, it may sometimes be sufficient to administer less than the above dosages, and in addition, it may be necessary to administer more amounts. The amount of co-concomitant drug can be set at any value unless there is a question about side effects. As far as companion drugs are concerned, the daily dose varies with the severity of the symptoms, age, sex, body weight, individual sensitivity, time and interval of administration, characteristics, type of prescription and pharmaceutical preparation, type of active ingredient, etc. The medicinal dose is usually from about 0.001 mg to 2,000 mg, preferably from about 0.01 mg. From mg to 500 mg, more preferably from about 0.1 mg to 100 mg, which is usually administered in divided portions from once a day to four times. When the combination preparation of the present invention is administered, the androgen receptor antagonist of the present invention may be administered after administration of the co-concomitant drug, or the co-concomitant drug may be administered after administration of the androgen receptor antagonist of the present invention. However, these can also be φ at the same time. When administered at time intervals, the length of the interval will vary depending on the active ingredient to be administered, the form of the drug, and the method of administration. For example, when the co-concomitant drug is administered first, the administration time is from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour after administration of the co-concomitant drug. An androgen receptor antagonist of the invention. When the androgen receptor antagonist of the present invention is administered first, from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to administration of the androgen receptor antagonist of the present invention. Co-concomitant drugs were administered over a one hour time frame. In a preferred method of administration, for example, a daily dose of about 0.001. [si 152 321538 201114741 mg / kg to 200 mg / kg orally to prepare a co-administration of the oral administration preparation, and 15 minutes Thereafter, the androgen receptor antagonist of the present invention prepared as an orally administered preparation is orally administered at a daily dose of from about 005 mg/kg to 100 mg/kg. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Reference Examples, Examples, Modulation Examples, and Experimental Examples, which are not intended to be construed as limiting. In the structural formula of the compound described in the examples, "-N-" sometimes shows "-M-". • "Room" usually represents a temperature from about 10 ° C to about 35 ° C, and "%" represents % by weight. The yield is expressed in mol/mol%. The NMR spectrum showed proton Li, which was measured using tetradecyl decane as an internal standard and a 200 MHz or 300 MHz spectrometer, and the value of 5 was expressed in ppm. Other abbreviations used in the manual are as follows. s : Single peak Lu brs : Wide single peak d : Double peak dd : Double double peak ddd : Double double peak td · · Three double peaks t : Three peaks dt : Double three peaks q : Four peaks m : Multi peaks 153 321538 201114741 CDC13 : Atmosphere Chloroform DMS0-d6 : Deuterated dimethyl sulfoxide CD3 〇 D : Deuterated decyl alcohol ^-NMR : Proton nuclear magnetic resonance THF : Tetrahydrofuran DMF : N, N-dimethyl decylamine DMS0 : Dimercapto sulfoxide WSC: 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride® DMT-MM: 4-(4,6-methoxy-1,3, 5-trin-2-yl)-4-methyloran-4-iron HOBt : 1-hydroxybenzotriazole NMP : N-decylpyrrolidone HPLC: high performance liquid chromatography reference example 1 2-Chloro-4-(3-ylpyrrolidine-l-yl)benzophenone

2-Chloro-4-fluorobenzonitrile (10.0 g), pyrrolidin-3-ol (5. 60 g) and lithium carbonate (7.12 g) were suspended in DMSOUOO ml) at 100 ° C The mixture was stirred for 3 hours. The reaction mixture was diluted with water, and the resulting crystals were collected by filtration and dried. The title compound (9. 56 g) was obtained as a brown crystal. 154 321538 201114741 ^-NMR (CDCh) 5 : 1.68C1H, d), 2. 00-2. 30(2H, m), 3.25- 3. 36(1H, m), 3. 37-3.49(1H, m ), 3.49-3. 64(2H, m), 4. 55-4. 80C1H, m), 6.41(1H, dd), 6.56C1H, d), 7. 42(1H, d). Reference example 2 2 -Chloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]benzonitrile

(4S, 5S)-4-Hydroxy-5-methylpyrrolidin-2-one (7.0 g) was dissolved in THF (120 ml), and the mixture was cooled to 5 °C. A solution of bis(2-methoxyethoxy)aluminum hydride in benzene (59. 7 ml) was slowly added to the reaction mixture, and the mixture was stirred at 70 ° C for 3 hours. The reaction mixture was cooled to 5 ° C, sodium carbonate decahydrate (26.1 g) was added, and the mixture was further stirred at room temperature for 16 hours. The reaction mixture was diluted with THF, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue obtained was dissolved in EtOAc (EtOAc). Lithium carbonate (8.99 g) and 2-chloro-4-fluorobenzonitrile (9.46 g) were added to the solution, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated and dried over anhydrous sulfate. The solvent was evaporated and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj !Η-Li R (CDC13) 5 : 1.18 (3H, d), 1.75 (1H, d), 1.99-2. 16 155 321538 201114741 m), 3.39-, m), 6. 43 (1H, m)' 2.23-2.4K1H,m),3.17-3.31(ιΗ, 3.54(1H, m), 3. 87-4. 00(1H, m), 4. 36-4. 58〇H (1H, Dd),6·56(1Η,d),7·42(1Η,d) Reference Example 3 4-[(2S, 3S)-3, thiol_2_benzonitrilemethylpyrrolidin-1-yl] a 2 trifluoromethyl)

The test article methylbenzonitrile was used as a starting material, and the title compound was obtained in the same manner as in the spring. ^mr ccdcio d)j L88(1Hj dx 2 〇3_2 ig

2 26-2.39(lH, m), 3.23-3.35(1H, m), 3.48-•57(1H, m), 3.93-4.05C1H, m), 4.43^57(1H, ra), 6.65 (1H, Dd), 6.80(1H,d), 7.57(1H,d). Reference Example 4 2-Chloro-4-(3-o-oxypyrrolidine-i-yl)benzonitrile

0 NC. α Add chloroform (2.94 ml) to dichlorohydrazine (80 ml) and cool the mixture to -78 C. A solution of DMS0 (3. 35 ml) diluted with chloranil (20 ml) was added. The reaction mixture was stirred for 30 minutes, and a solution of the compound obtained in Example 1 321 538 156, 201114741 (3.00 g) in methylene chloride (100 ml) was slowly added, and the mixture was stirred at -40 ° C for 30 minutes. Triethylamine (13.1 ml) was added to the reaction mixture, and the mixture was further stirred at 0 ° C for 20 minutes. An aqueous solution of ammonium chloride was added to the reaction mixture, diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, the~~~~~~~~~~ Ή-NMR (CDCh) 5 : 2.82 (2H, t), 3. 74-3. 85(4H, m), 6.52 ^ C1H, dd), 6. 67(1H, d), 7. 52(1H, d). Reference Example 5 2-Chloro-4-[(2S)-2-methyl-3-oxooxypyrrolidin-1-yl]benzonitrile NC Cl

The compound obtained in Reference Example 2 (7.00 g) and triethylamine (33.0 ml) were dissolved in DMSO (100 ml), and a sulfur trioxide bite complex (23.5 g) was added and stirred at room temperature. The mixture was 1 hour. The reaction mixture was diluted with ethyl acetate and water. The solvent was evaporated, the~~~~~~~~~~~~~~~~~~~~ CdCh) δ : 1.34(3H, d), 2. 68-2. 89(2H, m), 3.63-3.86C2H, m), 4. 03(1H, q), 6.56C1H, dd), 6. 70 (1H, d), 157 321538 201114741 7. 50C1H, d). Reference Example 6 4-[(2S)-2-Methyl-3-oxooxypyrrolidin-1-yl]-2-(trifluoromethyl) Benzoquinone

Using the compound obtained in Reference Example 3 as a starting material, the title compound was obtained in the same manner as in the the the !H-NMR (CDCh) 5 : 1. 36(3H, d), 2. 76- 2. 87(2H, m), 3. 70-3.88C2H, m), 4.09(1H, q), 6. 79(1H, dd), 6.94(1H, d), 7. 67(1H, d). Reference Example 7 4- [(2S)-2-Mercapto-3-yloxylpyrrolidine-1 - Benzoonitrile

A sulfur trioxide pyridine complex (9. 49 g) was added to a solution of the compound obtained in Reference Example 49 (4.02 g) and triethylamine (22.17 ml) in DMSO (50 ml) at room temperature The mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc. EtOAc m. The residue was purified by EtOAc EtOAcjjjjjjj 158 321538 201114741 沱-NMR (CDCl3) 5 : 1.34(3H,d), 2.78(2H,m), 3.74C2H, m), 4.05(1H, q), 6. 67(2H, d), 7.54 (2H, d). Reference Example 8 2-Chloro-4-[(2R, 3R)-3-yl-2-methyln ratio p 唆-i-yl] phenyl

Cl

Add 70% solution (12 ml) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene to (4R,5R)-4-hydroxy-5-methyl η ratio under ice cooling a suspension of π each of 2-ketone (1.40 g) in THF (60 ml), and a mixture of 7 (TC) for 3 hours. The reaction mixture was cooled with ice, sodium carbonate decahydrate (5.22 g) was added, and The mixture was stirred overnight at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in the crystals of M.sub.2 (25 ml), and lithium carbonate (1.79 g) and 2-chloro-4-fluorophenylhydrazine were added. Nitrile (1.89 g), and the mixture was stirred at 1 °C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by EtOAc (m.p.h.hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh 1. 94 g). !H-NMR (CDCh)^ : 1.18(3H, d), 1.83(1H, d), 2.02-2.16 (1H, m), 2.23-2.39(lH, m), 3. 16-3.33(1H, m ), 3.39-3. 55(1H, m), 3. 87-4. 01 (1H, m), 4. 39-4. 56(1H, m), 6.43 (1H, dd), 6.56(1H, d), 7.41 (1H, d). Reference Example 9 2-Gas-4-[(2R)-2-indolyl-3-sideoxy 0 to B 唆-1-yl]benzonitrile 159 321538 201114741

Using the compound obtained in Reference Example 8 as a starting material, the title compound was obtained in the same manner as in the the the The W-NMR data was consistent with the data of the compound obtained in Reference Example 2. Reference Example 10 ° (2S,3=)-3-hydroxy-2-methylpyrrolidine-benzoic acid benzyl ester

Add 70% solution of bis(2-methoxyethoxy)aluminum hydride in toluene (6 〇mi) to (4S,5S)-4-hydroxy-5-methylpyrrolidine under ice cooling A suspension of 2-ketone (7.0 g) in THF (12 mL) and at 7 Torr. The mixture was stirred for 4 hours. The reaction mixture was ice-cooled, sodium carbonate decahydrate (22.2, g) was added, and the mixture was stirred at room temperature overnight. The sediment was removed by filtration, Φ and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (120 ml), and diethylamine (12.71 ml). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aq. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H-NMR (CDCh) (5: 1. 15-1. 30(3H, m), 1. 66(1H, d), 1. 82-1.97(1H, m), 2.00-2. 15(1H , m), 3.40-3. 55(2H, m), 160 321538 201114741 3. 90-4. 00(1H, m), 4. 29-4. 39(1H, m), 5. 05-5. 22(2H, m), 7. 30-7. 40(5H, m). Reference Example 11 2-Chloro-5-|1-4-[(25,33)-3-yl-2-ylmethyl '1 to 57 each set _1_ base benzoquinone

w A mixture of the compound obtained in Reference Example 10 (2.92 g), 10% palladium/carbon (120 mg) and methanol (70 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hours. The palladium catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (30 ml) 'added lithium carbonate (1.1 g) and 2-chloro-4, 5-difluorobenzonitrile (2. 58 g), and stirred at 10 ° C 5小时。 Mixture 1. 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by EtOAc EtOAcjjjjjjjj Ή-NMR (CDCh) (5: 1.19C3H, d), 1. 72(1H, d), 1.94-2.09 (1H, m), 2. 11-2.25 (1H, m), 3.31-3.45 (1H, m), 3.65-3.80(1H, m), 4. 05-4. 22(1H, m), 4. 39-4, 51 (1H, m), 6.62 (1H, d), 7. 19(1H , d). Reference Example 12 2-lacto-5-fluoro-4-[(2S)-2-methyl-3-oxirane oxime ratio _ 基 基 321 321 321 321 321538 161 201114741

Using the compound obtained in Reference Example 11 as a starting material, the title compound was obtained in the same manner as in the the ^-NMR (CDCh) (5: 1.23C3H, d), 2. 60-2. 87(2H, m), 3.64-3.85(2H, m), 4. 26-4. 41 (1H, in), 6.80(1H, d), 7. 29C1H, d). Citation Reference Example 13 2-Fluoro-4-[(2S, 3S)-3-hydroxy-2-methylpyrrolidin-1-yl]benzonitrile

Using the compound obtained in Reference Example 10 and 2, 4-difluorobenzonitrile as a starting material, the title compound was obtained from 'H-NMR (CDCh) (5: 1. 18(3H, d), 1. 74(1H, d), 2.05-2.15 φ (1H, ra), 2. 25-2. 35(1H, m) , 3. 18-3. 28(1H, m), 3.40-3.50C1H, m), 3. 85-3. 95(1H, m), 4. 42-4. 52(1H, m), 6.25 ( </ RTI> </ RTI> <RTIgt; -benzonitrile

The compound obtained in Reference Example 13 was used as a starting material to participate in reference to 162 321538 201114741

, m), 3. 66~ 2-chloro-5-methyl-4_[(2S)_2_ f-based (2S)-2-f-yl-3-oxo-pyrrolidinyl-phenyl] benzene), 6.46 (1H, dd), Reference Example 15

Npl 2 -chloro-4 -[(2S,3S)-3-hydroxy-2-methylpyrrolidinium]-5-methylbenzonitrile as a starting material, the same title as in Reference Example 7 Compound. &amp; H-NMR (CDC13) c5 : 1.05 (3H, d), 2. 28(3H, s), 2.57-2 78 (2H, m), 3. 19-3. 33(1H, m), 3 66-3. 81 (1H, m), 3. 93(iH, q), 6. 97(1H, s), 7. 43(1H, s). 'Lu Reference Example 16 [(3S)-1 -(3-chloro-4-cyanophenyl)n ratio u each bite _3_yl] aminic acid tert-butyl

Stirring (3S)-pyrrolidin-3-ylamine decanoic acid tert-butyl (4.82 g), 2-chloro-4-fluorobenzonitrile (4.83 g), lithium carbonate (3) at 100 °C A mixture of 82 g) and DMSO (50 in 1) for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, The residue was purified by EtOAc EtOAc (EtOAc) elute ^-NMRCCDCh)^ : 1.46(9H, s), 1. 95-2. 05(1H, m), 2.25-2.90(1H, m), 3.20C1H, dd), 3. 35-3. 50(2H , m), 3. 64(1H, dd), 4. 30-4. 42C1H, m), 4. 60-4. 72(1H, m), 6.40(1H, dd) 6.55(1H, d), 7.42 (1H, d). Reference Example 17 4-[(3S)-3-Aminopyrrolidin-1-yl]-2-benzoquinone nitrile hydrochloride NC-^Λ-Ν^Ί hci, h2 A mixture of the compound obtained in Reference Example 16 (7.55 g), a 10% hydrogenated hydroquinone solution (40 ml), and decyl alcohol (80 ml) was stirred at 50 ° C for 20 hours. The reaction mixture was concentrated under reduced EtOAc. Lu! H-NMR (DMSO-de) (5: 2. 10-2. 20(1H, m), 2. 20-2. 38(1H, m), 3.38-3. 68(4H, in), 3. 90-4. 00(1H, m), 6. 62(1H, dd), 6.77C1H, d), 7. 65(1H, d), 8.46(3H, brs). Reference 18 [(31 〇-1-(3-chloro-4-cyanophenyl)1» ratio 1; each 11 _3_yl] carboxylic acid tributyl hydrazine

Using the (3R)-pyrrolidin-3-ylamine decanoic acid tert-butyl ester and 2-chloro-4-fluoro 164 321538 201114741 benzonitrile as a starting material, the title compound was obtained in the same manner as in the the the The ^-NMR data was consistent with the data of the compound obtained in Reference Example 16. Reference Example 19 4_[(3R)-3_Aminopyrrolidine 11 1-1 yl]-2_chlorobenzaldehyde gamma hydrochloride

CI

Using the compound obtained in Reference Example 18 as a starting material, the title compound was obtained in the same manner as in Reference Example 17. The H-NMR data was consistent with the data of the compound obtained in Reference Example 17. Reference Example 20 (2S,3S)-3-Hydroxy-2-indolylpyrrolidine-1-carboxylic acid tert-butyl ester

Add 70% solution (60 ml) of sodium bis(2-decyloxyethoxy)aluminum hydride in toluene to (4S,5S)-4-hydroxy-5-methylpyrrolidine under ice cooling A suspension of 2-ketone (7.5 g) in THF (120 ml) was stirred and the mixture was stirred at 70 ° C for 4 hr. The reaction mixture was ice-cooled, sodium carbonate decahydrate (52.2 g) was added, and the mixture was stirred at room temperature overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (120 ml). EtOAc (EtOAc m. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and saturated brine and dried with &lt;RTI ID=0.0&gt;&gt; The residue was purified by silica gel column chromatography (EtOAc-EtOAc). H-NMR (CDC13) (5: 1. 18(3H, d), 1.46 (9H, s), 1.55-1.62 (1H, m), 1.78-1.92 (1H, m), 1.98-2. 10(1H , m), 3.32-3-47(2H, m), 3. 80-3. 93(1H, m), 4. 26-4. 36(1H, m). Reference example 21 Lu (2S, 3S) -2-methyl-3-[(methylsulfonyl)oxy]pyrrolidine-dicarboxylic acid tert-butyl ester

0. p chlorosulfonate (〇·598 ml) was added to a solution of the compound obtained in Reference Example 20 (1. 〇3 g) and triethylamine (1. 〇7 ml) in THF (25 ml). The mixture was stirred at room temperature for 2 hours under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate The residue was purified to silica gel elute elut elut elut elut elut elut H-NMR (CDCh) (5: 1. 20-1. 30(3H, m), 1. 47(9H, s), 2. 12- 2·22(2Η, m), 3.06(3H, s) , 3. 41-3. 51 (2H, m), 4.05-4.15 C1H, m), 5. 10(1H, q). Reference 22 (2S,3R)-3-azido-2-methyl . Bilo bite-i_carboxylic acid tert-butyl ester 321538 166 201114741 〇, ^ \ Vn The compound obtained in Reference Example 21 (1.33 g), sodium azide (0.43 g) and DMF (25 ml) were stirred at 100 °C. The mixture was 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H-NMR (CDCh) (5: 1.20(3H, d), 1.47(9H, s), 1.90-2.00 (1H, id), 2. 10-2. 22(1H, m), 3.40-3. 55(2H, m), 3.70-4. 00(2H,m). Reference Example 23 (2S,3R)-3-Amino-2-mercaptopyrrolidine-1-carboxylic acid tert-butyl ester 〇, A / nh2 A mixture of the compound (0. 85 g) obtained in Reference Example 22, 10% palladium/carbon (45 mg) and decyl alcohol was stirred under a hydrogen atmosphere at room temperature for 2 hours, and the catalyst was removed by filtration under reduced pressure. The filtrate was concentrated to give the title compound (0. <RTI ID=0.0># </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1. 55-1. 70C1H, in), 2. 02-2. 15(1H, m), 3. 12-3. 18(1H, m), 3. 30-3. 65(3H,m)· Reference Example 24 [s] 167 321538 201114741 (2S,3R)-3-{[(4-Fluorophenyl)carbonyl]aminobi-2-pyridylpyrrolidine-1-carboxylic acid tert-butyl ester

4-Fluorobenzylidene chloride (0.171 ml) was added to a solution of the compound obtained in Reference Example 23 (242 mg) and triethylamine (0.254 ml) in THF (10 ml). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAcjjjjjjjli ]H-NMR (CDCh) (5: 1.29 (3H, d), 1.47 (9H, s), 1.85-2.00 (1H, m), 2.23-2.38 (1H, m), 3.40-3. 60 (2H, m), 3.70-3.90(1H, m), 4.25-4.35(1H, m), 6. 05-6. 20(1H, ra), 7.05-7. 15(2H, m), 7. 70-7 80(2H, m). Reference Example 25 (2S,3R)-3-{[(4-fluorophenyl)ethenyl]amino}-2-methylpyrrolidine-1-carboxylic acid III Butyl ester

Using the compound obtained in Reference Example 23 and (4-fluorophenyl)ethyl chlorobenzene as a starting material, the title compound was obtained in the same manner as the the the 168 321538 201114741 H-NMR (CDCh) 5 : 1.19(3H, d), 1.45(9H, s), 1.65-1.80 OH, m), 2. 10-2. 25(1H, m), 3. 20- 3. 45(2H, m), 3.51(2H, s), 3. 55-3. 65(1H, m), 4. 03-4. 13(1H, m), 5. 45- 5. 55( 1H, m), 6. 98-7. 08(2H, m), 7. 18-7. 26(2H, m). Reference Example 26 (2S,3R)-2-methyl[(phenylcarbonyl) Oxypyrrolidine-polycarboxylic acid tert-butyl ester

A solution of diethyl azodicarboxylate in 2.2 m〇l/L of toluene (3.77 ml) was added to the compound obtained in Reference Example 20 (丨.39 g), benzoic acid (1〇1 g). And a solution of diphenylphosphine (2. Π g) in thF (30 ml), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced EtOAc. ^-NMR (CDC13) (5: 1.27 (3H, d), 1.47 (9H, s), 2.05-2.35 (2H, ra), 3.45-3.65 (2H, m), 3.88-4. 15(1H, m ), 5.12-5.20C1H, m), 7.40-7.50(2H, m), 7.50-7.60(1H, m), 8. 02(2H, d). Reference 27 (2S,3R)-3-hydroxy- 2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of the compound obtained in Reference Example 26 (1. 60 g), hydrogen oxygen 169 321538 201114741 lithium monohydrate (264 mg) and water/methanol (10 ml / 20 ml) was stirred at room temperature for 2 hours. Spoiled at 50 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). lE-MR (CJ) CU) δ : 1.14C3H, d), 1.47(9H, s), 1.55-1.65 (1H, m), 1.80-1.90(1H, m), 2. 00-2. 15(1H , m), 3.4〇-3. 90(3H, m), 4. 00-4. 10(1H, m). Reference Example 28 (2S, 3R)-2-indolyl-3-[(fluorenylsulfonate) Mercapto)oxy]pyrrolidine-butyl carboxylic acid tert-butyl ester

Using the compound obtained in Reference Example 27 as a starting material, the title compound was obtained in the same manner as in the the the / ^-NMRCCDCh)^ : 1.15-1.25C3H, m), 1.47C9H, s) 2 15-2.30(2H, ra), 3.05(3H, s), 3. 45-3. 60(2H, m), 4.00-4.15 (1H, m), 4.87-4. 93(1H,in). Reference 29

(2S,3S)-3-azidomethylpyrrolidine-1-carboxylic acid terpene vinegar The compound obtained in Reference Example 28 was stirred at UG ° C (3. 58 g), stack 321538 170 201114741 sodium nitride A mixture of (1. 25 g) and DMF (60 ml) was used for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was purified to silica crystal elut elut elut elut elut elut elut H-NMR CCDCh): 1. 12-1. 22C3H, in), 1.46C9H, s), 1 90- 2.00(1H,m), 2.08-2. 18(1H, m)' 3.30-3· 50( 2H, m), 3. 90-4. 05(2H, m). ' ' Reference Example 30 Despite (2S,3S)-3-amino-2-methyl piroxicam-i-acid retardation Ο-Ο Using the compound obtained in Reference Example 29 as a starting material, the title compound was obtained in the same manner as in Reference Example 23. ^ &gt; !H-NMR (CDCh) (5 : 1.09(3H, d), 1. 30-1. 50(2H, m), ! 46 (9H, s), 1.60-1. 72(1H,m ), 1.98-2. l〇(1H,m), '3 22_ 3. 50(3H, m), 3. 70-3. 90(1H, m). Refer to Example 31 (2)(10) as from fluorophenyl Hejib 曱基^ each bite-acid tributyl acrylate

The compound obtained in Reference Example 30 and 4-fluorobenzoic acid chloride were used as the starting material of '321538 171 201114741, in the same manner as in Reference Example 24 (10), Π), 2.20-2.30 (1 Η, m), 3 ') ' 1 shoulder - 1.95 : 2r(i;, r55 — 4.., — (2H, m), 7. 75-7. 82(2H, m). ' 18 Reference 32 (2S, 3S)-3—丨[([Fluorophenyl)ethyl]aminodibu 2-methylate bite_butyl carboxylic acid tert-butyl ester

The title compound was obtained in the same manner as in the 24 Reference Example, using the compound obtained in Reference Example 29 and (4-diphenyl)ethylamine chloride as a starting material. H-NMR (CDCh) (5: 0.86 (3H, d), 1.44C9H, s), 1.50-1.70 OH, m), 1.98-2. 13(1H, m), 3. 20-3. 40 (2H , m), 3. 56(2H, s), 4. 00-4. l〇(lH, ra), 4. 35~4. 45(1H, in), 5.30(1H, d), ^•〇 〇-7.10(2H, m), T.20-7.25(2H, m). Reference Example 33 (2S' 3S) 1-(3-Chloro-4-cyanophenyl), 2-decylpyrrolidinium_3 _ sulfonic acid

2 gas-4-[(2S'3S)~3m-2-mercapto group was used. Called bite-1-base] 172 321538 201114741 This bet is used as a starting material to compound. The title j-NMR (CDC13) 6 : 1. 25 (3H, (3H, s), 3.27-3.37 (lH, m ^ d), 2.30-2. 52 (2H, m) was obtained in the same manner as in Reference Example 21. ), 3.11 m), 3.50-3. 60(1H, m), 4.15- 4.25(1H, m), 5. 12-5. 22(1H, m), 6.45(1H, dd), 6. 58(1H, d), 7.44C1H, d). Reference 34

4-((2S, 3R)-3-azido-2-indenyl bromidino-i-yl]-2 monochlorobenzonitrile The compound obtained in Reference Example 33 was stirred at 120 ° C (12. 18 g The mixture of sodium azide (3.77 g) and DMF (100 ml) was added for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) elute 3H, d), 2. 15-2. 25(1H, m), 2.30-2.43(1H, m), 3. 35-3. 55(2H, m), 3.85(1H, q), 3.96(1H , d), 6.44C1H, dd), 6.57(1H, d), 7.44(1H, d). Reference 35 [(2S,310-1-(3-chlorocyanophenyl)-2-indenyl) Ind-3-yl]-tert-butyl carboxylic acid 173 321538 201114741

Tri-n-butylphosphine (10.45 ml) was added to a solution of the compound (9. 95 g) obtained from the title compound THF (100 ml), and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction mixture, and the mixture was stirred for 1 hour. Sodium carbonate (6. 04 g) and di-tert-butyl dicarbonate (16.60 g) were added and the mixture was stirred for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate Φ. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc) elute ^-NMR (CDCh) 5 : 1.23(3H, d), 1.44(9H, s), 1.95-2.05 (1H, m), 2.33-2.48C1H, m), 3. 32-3. 52(2H, m ), 3.81(1H, q), 3.95-4.05(1H, m), 4. 63(1H, brs), 6.43C1H, dd), ^ 6.56C1H, d), 7.42C1H, d). Reference 36 4 -[(2S,3R)-3-amino-2-methylpyrrolidin-1-yl]-2-chlorobenzonitrile salt:

Using the compound obtained in Reference Example 35 as a starting material, the title compound was obtained in the same manner as in Reference Example 17.丽 R (DMS0-d〇5 : 1.15(3H,d), 2. 05-2.20(lH,m), [s] 174 321538 201114741 2. 40-2. 50(1H, m), 3. 45- 3. 55(2H, m). 3. 64(1H, brs), 4. 05(1H, q), 6.64(1H, dd), 6.77(1H, d), 7. 65C1H, d), 8.27C3H , brs). Reference Example 37 4-[(2S,3S)-3-Laminated 2-methylindole ratio p 唆-1-yl]-2-chlorobenz

CI

The compound obtained in Reference Example 29 (5.11 g) and trifluoroacetic acid (10 ml) were mixed under ice cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was combined with lithium carbonate (7 21 g), 2-dichloro- 4-fluorobenzonitrile (3.34 g) and MS (25 ml), and mixture hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous EtOAc. The residue was purified by silica gel column chromatography elution elution elution elution elution elution elution elution elution elution elution elution ), 2.32- 2.42C1H, ra), 3.25-3.35C1H, m), 3.45-3.55(1H, m), 4. 00-4.22(2H, m), 6.43(1H, dd), 6.56(1H, d ), 7.43(1H, d). Reference Example 38 [(2S,3S)-l-(3-chloro+cyanophenyl)+methyl^each bit I]]butyl butyl citrate 321538 175 201114741

Cl

Using the compound obtained in Reference Example 37 as a starting material, the title compound was obtained in the same manner as in the title compound 35. ^-NMR (CDCh) 5 : 1.06 (3H, d), 1.47 (9H, s), 1.85-2.00 (1H, m), 2.25-2.40C1H, in), 3. 20-3.30 (1H, m), 3.35-3.45C1H, m), 4. 10-4.30(2H, in), 4. 60-4. 72(1H, m), • 6.43(1H, dd), 6.56(1H, d), 7.42(1H , d). Reference Example 39 4-[(2S,3S)-3-Amino-2-methylpyrrolidin-1-yl]-2-chlorobenzonitrile nitrile hydrochloride

CI

HCI / vnh2 The title compound was obtained in the same manner as the the the the _ Leg R (DMS0-d〇6 : 1· 13(3H,d), 2.05-2·35(2Η,m), 3. 15-3. 35(1H, m), 3. 45-3. 55 (1H, m), 3. 70-3. 80(1H, ra), 4. 10-4. 20(1H, m), 6. 63(1H, dd), 6. 74(1H, d), 7. 64(1H, d), 8. 55(3H, brs). Reference Example 40 3-(4-Fluorophenyl)pyridine-2-carboxylic acid

176 321538 201114741 Mixing 3-{[(三 Itmethyl) 醯 醯 ] 氧基 氧基 氧基 咬 咬 -2- -2- -2- -2- 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 A mixture of 4-fluorophenylboronic acid (2.17 g), hydrazine (triphenylphosphine)palladium (292 mg) and toluene (80 ml) was used for 6 hours. The reaction mixture was filtered to remove insolubles. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen sulfate and EtOAc. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford ethyl 3-(4-fluorophenyl)pyridine-2-carboxylate (1.49 g). At 50. (: 3-(4-fluorophenyl) acridine-2-carboxylic acid methyl ester (i.48g), THF/decyl alcohol (l〇ml/l〇ml) and 1 mol/L hydrogen obtained by stirring A mixture of sodium hydroxide aqueous solution (13 ^1) was added for 1 hour. Water was added to the reaction mixture, and the aqueous layer was washed with diisopropyl ether, acidified with hydrochloric acid and extracted with a mixed solvent of THF / ethyl acetate. Anhydrous sulphuric acid was dried over EtOAc (EtOAc m.jjjjjjjjj ), 7. 31-7. 35(2H, m), φ 7.63(1H, dd), 7.79(1H, dd), 8.63(1H, d). Reference 41 4 - [(2'2, 2 2 Oxyethyl)amine-based benzoic acid

Add oxalic acid chloride (4.4 ml) to a solution of 4-(methoxycarbonyl)benzoic acid (9.0 g) and DMF (3 drops) in THF (250 ml). 2 hours. The reaction mixture was concentrated under reduced pressure and the residue 321 538 177 201114741 was dissolved in N,N-dimethylacetamide (5 〇 mi). Thereafter, a solution of 2,2,2-trifluoroethylamine (4.7 ml) in N,N-didecylacetamide (50 ml) was added, and the mixture was stirred for 15 hr. The reaction mixture was concentrated under reduced pressure. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was dissolved in methanol, a 4 mol/L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was acidified with (10) hydrochloric acid and evaporated. The title compound (丨丨.3〇 g) was obtained as a colorless solid. ^-NMR (DMSO-de): 4. 05-4. 17(2H, m), 7. 96-8. 06(4H, m), 9.26-9.28(lH, m), 13.27(1H, brs) Reference example 42

4-[(lE)-N-hydroxyethylimino]benzoic acid ho, N Ο (Step D: Hydroxylamine hydrochloride (14.5 g) and sodium acetate (17.1 g) were added to 4-glycidylbenzene A solution of ethyl formate (20.0 g) in EtOAc (EtOAc) (EtOAc). Drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The precipitate was collected by filtration and washed with hexane to afford ethyl 4-[(1E)-N-hydroxyethylimido]benzoic acid (21. 6 g (Step 2) A 1 m〇i/L aqueous sodium hydroxide solution (212 mi) was added to a solution of the compound (21.6 g) obtained in Step 1 [s] 178 321538 201114741 in decyl alcohol (100 ml), and The mixture was stirred at room temperature for 1 hour. The reaction mixture was dried with EtOAc EtOAc. The title compound (19·〇g) was obtained as a white solid. ???H-NMR (DMSO-de): 2. 18 (3H, s), 7. 77 (2H, d), 7 . 95(2H, d), 11.49( 1H, s), 13.00 (1H, s). Reference Example 43 4-[(2S,3S)-3-Hydroxy-2-indolylpyrrolidinyl]-methoxybenzoonitrile

PH

The title compound was obtained in the same manner as in Example 2, using 4-fluoro-2-methoxybenzonitrile as a starting material. Li R (CDC13) (J : ..., Λ 1 / 1 峨 峨 d), 1.91 (1H, d), 丨 99_2 η (, m), · 4-2.34 (1Η, m), 3.19_3·32 (1Η, 3.53 (1H, ffi), 3.88 (3H, s), 3.91 - 4. G1 (lH, · 4. 54 (lH, m), 5. 98 (lfl α β Reference Example 44 Η, dX 6·14〇Η&gt ; ddX 7·32^^ 2-methoxy-4-[(2S), 2, methyl I-side oxy (10). 定_卜基]Benzyl guess 321538 】79 201114741

Using the compound obtained in Reference Example 43 as a starting material, the title compound was obtained in the same manner as in φ ^-NMR (CDCh) 5 : 1. 35(3H, d), 2. 73-2. 82(2H, in), 3. 68-3.82C2H, m), 3. 92(3H, s), 4. 05(1H, q), 6. 11(1H, d), 6.25C1H, dd), 7.40(1H, d). Reference 45 2-Hydroxy-4-[(3R)-3-hydroxyindole Pyridin-1-yl]benzonitrile

Using (3R)-3-hydroxypyrrolidine as a starting material, the title compound was obtained in the same manner as in Reference Example 1. !H-NMR (CDCls)^ : 1.8K1H, d), 2. 10-2. 25(2H, m), 3.32 (1H, d), 3. 39-3.47(lH, m), 3. 50- 3. 60(2H, ra), 4.64-4. 70(1H, in), 6.41(1H, dd), 6. 55(1H, d), 7.40(1H, d). 180 321538 201114741 Reference example 46 2 -Chloro-4-[(3S)-3-hydroxyindole-Butyl-1-yl]benzoquinone ^ PH month

N The title compound was obtained in the same manner as in Reference Example 1 using (3S)-3-hydroxypyrrolidine as a starting material. • H-NMR CCDCh)^ : 1.88(1H, d), 2. 09-2. 25(2H, m), 3.32 (1H, d), 3.38-3.47(lH, m), 3. 50-3. 60 (2H, m)! 4.67(1H, s), 6.4K1H, dd), 6.54(1H, d), 7.39(1H, d). Refer to Example 47 4-(Amino thiol group is 0 -3- Acid ethyl acetate hydrochloride

r Disperse 4-methylmercapto-1Η-β-pyrazole-3-acid ethyl ester (8. 26 g), 0-fluorenylhydroxylamine hydrochloride (5.102 g), hydrogencarbonate at 80 °C A mixture of sodium (3.14 g), THF (82 ml) and water (82 ml) was taken for 3 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, and then filtered and evaporated. The obtained residue was suspended in diethyl ether and collected by filtration to give 4-[(E)-(methoxyimino)f-yl]-1H-pyrazole-3-carboxylic acid as a colorless powder. a mixture of -[(Z)-(methoxyimino)methyl]-1 Η-β than salicylic acid ethyl ester (8. 744 g). The obtained mixture (8. 30 g) was dissolved in ethanol (200 ml), 10% palladium-carbon (0-83 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 48 hours. The insoluble material was filtered off, and the filtrate was concentrated. The residue was suspended in diisopropyl ether-EtOAc (EtOAc m. —'H-NMR (CDCh)^ : 1.32(3H, t), 4. 06-4. 17(2H, m), 4.31 (2H, q), 7. 96(1H, s)8.34(3H, s 13.68 (1H, s). Reference Example 48 2-Chloro-4-[(2S,3S)-2-methyl-3-(decylamine oxime)pyrrolidin-1 -yl]benzonitrile Acid salt

The compound obtained in Reference Example 5 (327. 4 mg) and decylamine (2 mol/L THF solution, 2.80 ml) were dissolved in THF (7 ml), and sodium triethylsulfonylborohydride (1.56 g) was added. ). The reaction mixture was stirred at room temperature for 1 hour and poured into aqueous sodium sulfate. The organic layer was washed with water and brine, evaporated The residue obtained was purified by column chromatography (hexane-ethyl acetate). The resulting product was dissolved in ethyl acetate, and a 4 mol/L solution of hydrogen chloride in ethyl acetate was added, and a mixture of 182 321 538 201114741 was obtained to obtain the title compound (10).9 as a white powder. • H-NMR (CDaOD) d : 1.23 (3H, d), 2. 20-2. 32(1H, m), 2.51-2.68C1H, m), 2.86(3H, s), 3. 34-3. 49(1H, m), 3.55-3.70 (1H, m), 3.74-3.90(lH, m), 4. 28-4. 46(1H, m), 6.68(1H, dd), 6. 79(1H , d), 7.56(1H, d). Reference 49 = C[(2S,3S)-3-hydroxy-2-indolylpyrrolidine q-yl]benzonitrile • 0 N—v ,,·〇

OH Using 4-fluorobenzonitrile as a starting material, the title compound was obtained in the same manner as in Reference Example 2. INMIUCDCIOcS : 1.1_,d),mu·,heart,2 22_ 2.37(1H, m), 3. 16-3. 31(1H, m), 3.40-3. 54(1H, m), p 3.38-4.02 (lH, m), 4. 39-4. 54(1H, n〇, 6. 50-6. 56(2H, m), 7.42-7.48(2H, m). Reference 50 Cyano-N,N - Dimercapto n-bite-3-continued amine

6-Cyanobenzoate-3-chlorohydrazine hydrochloride ("ο mg) was added to 50% aqueous dimethylamine (5 mi) and the mixture was stirred at room temperature for 2 hr. The residue obtained was washed with water to give the title compound 321 538 183 201114741 (235 mg) as a yellow powder. H-NMR (DMS0-de) 5 : 2.7K6H, s), 8.31-8. 36 (1H, m), 8. 40-8.46(1H, m), 9.09(1H, dd). Reference Example 51 (2S)-2-Mercapto-3-yloxypyrrolidine-1-carboxylic acid phenyl decyl ester

The compound obtained in Reference Example 10 (13.51 g) was dissolved in acetonitrile (100 ml), and molecular sieve 4A (13.3 g), 4-mercaptomorpholine-N-oxide (10.0 g) and tetrapropyl peroxydecanoate were added. Ammonium (0.40 g) and the mixture was stirred at room temperature for 20 h. The solvent was evaporated, ethyl acetate was added to the residue, and the insoluble material was filtered. The filtrate was concentrated, EtOAcjjjjjjjjjj !H-NMR (CDCh) 5 : 1. 34(3H, d), 2. 50-2. 70(2H, m), 3.60-3.75(1H, m), 3. 90-4. 10(2H, m), 5. 15(1H, d), 5.20(1H, d), 7.30-7.40(5H, m). Reference 52 (2S,3R)-3-(6-bromopyridin-3-yl)- 3-hydroxy-2-methylpyrrolidine-1-carboxylic acid benzoate 184 321538 201114741

2,5-Dibromopyridine (2.64 g) was dissolved in diethyl ether (165 ml) and the mixture was cooled to -78. Butyllithium (1.6 mol/L hexane solution, 7.0 ml) was added to the reaction mixture, and the mixture was stirred for 30 minutes. A solution of the compound obtained in Example 51 (2.00 g) in THF (30 ml) was added dropwise to the reaction mixture, and the mixture was further stirred for 30 minutes and warmed to room temperature. The reaction mixture was diluted with an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj !H-NMR (CDC13) 5 : 1. 27-1. 33(3H, in), 2. 13-2. 26(3H, m), 3. 60-3. 76(2H, in), 3. 91-4. 06(1H, in), 5. 08-5. 22(2H, m), appeal 7. 29-7. 39(5H, m), 7.44-7.49(1H, m), 7.63(1H , dd), 8.50C1H, d). Reference Example 53 5-{(2S, 3R)-1-[(Benzyloxy)carbonyl]-3-hydroxy-2-methylpyrrolidin-3-ylindolepyridine Methyl 2-carboxylate [s] 185 321538 201114741

C02Me The compound (1.52 g) obtained in Reference Example 52, [l,l-bis(monophenylphosphino)ferrocene]dichloropalladium(η) dichloromethane complex (310 mg) under a carbon monoxide atmosphere. And triethylamine (0.65 mi) was suspended in methanol (2 mL) and the suspension was stirred at 60 C for 14 hours. The reaction mixture was concentrated, ethyl acetate was added, and insoluble material was filtered. The filtrate was concentrated, and the residue was purified mjjjjjjjjjjjj ^^13), 5:1.30(3^d), 2.17^31(2H m) 2 62 C1H, s), 3.63-3.76C1H, ra), 4. 〇〇(3H, s)4.〇M. ;〇(1H m), 5.09-5.2K2H, m), 7. 30~7. 39(5H, ra), 7. 92(1H M) B.10C1H, dd), 8.85(1H, dd). ' Example 1 2-Gas-4-(3-hydroxy-3-phenylpyrrolidinyl)benzonitrile 321538 186 201114741

The compound obtained in Reference Example 4 (208 mg) was dissolved in THF (10 ml), and the mixture was cooled to 5 °C. A 1 mol/L solution of phenylmagnesium bromide in THF (3.52 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) !H-NMR (CDCh) (5: 1.99 (1H, s), 2. 33-2. 45(1H, ra), 2.46-2. 61(1H, in), 3. 50-3. 83C4H, m ), 6.44 (1H, dd), 6.59 (1H, wd), 7. 29-7. 47(4H, in), 7. 48-7. 56(2H, m). Example 2 2-Chloro-4 -[3-(4-fluorophenyl)-3-hydroxyindole-1-yl]benzonitrile [si 187 321538 201114741

F The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 4 and 4-fluorophenyl magnesium bromide as a starting material. 'H-NMRCCDCls)^ : 2.04(1H, s), 2. 29-2. 60(2H, m), 3.53-3·87(4Η, in), 6.44C1H, dd), 6. 58(1H, d), 7. 05-7. 17(2H, m), 7.43C1H, d), 7.46-7.55(2H,m). Example 3

4-[3-(6-Bromopyridin-3-yl)-3-hydroxypyrrolidine-i-yl]_2_gasbenzonitrile 2,5-dibromopyridine (558 mg) dissolved in THF (30 ml ), and the solution = 郃 to -78 Ό. Butyllithium (1.6 mol/L hexane solution, l 47 ml) was slowly added to the reaction mixture, and the mixture was stirred for a few minutes. A solution of the compound (400 mg) obtained in Reference Example 4 321538 188 201114741 in THF (5 ml) was added dropwise to the reaction mixture and the mixture was further stirred for 30 minutes and warmed to room temperature. The reaction mixture was diluted with an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) !H-NMR (DMSO-de) δ : 2. 17-2. 48(2Η, πι), 3. 54-3. 71(4Η, m), 5.83C1H, s), 6. 62(1Η, dd ), 6. 79(1Η, d), 7. 58- 7. 72(2Η, m), 7.92(1Η, dd), 8.59(1Η, d). Example 4 4-[ 3-(6-bromo) Pyridin-2-yl)-3-hydroxypyrrolidine-i-yl]-2- gas benzonitrile

The title compound was obtained in the same manner as in Example 3, using the compound obtained in Reference Example 4 and the ratio of 2, 6 - 2 to the ratio of α as the starting material. ^-MRiCdC^S : 2.24-2.68(2H, m), 3. 52-3. 89(4H, m), 4. 05-4. 15(1H, m), 6.43(1H, dd), 6. 57(1H, d), 7.38-7. 55(3H, m), 7. 59-7. 70(1H, m). Example 5 189 321538 201114741

5-[ 1-(3-Chloro-4-cyanophenyl)-3-hydroxypyrrolidin-3-yl]pyridine-2-methyzine in a nitrogen atmosphere at 12 (TC, using DMF (5 ml) as solvent The compound obtained in Example 3 (100 mg), zinc cyanide (15.5 mg) and hydrazine (triphenylphosphine)palladium (15 mg) were mixed for 4 hours. The reaction mixture was diluted with aqueous ammonia and ethyl acetate. The organic layer was separated, dried over EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Compound (28 mg) m), 2.39-2. 48(1H, m), 丽 R (DMSO-ώ) (5: 2. 20-2. 35C1H, 3.56-3. 76(4H, in), 6 〇〇(ih, s), 6. 63(1H, dd), 6. 80(1H, d), 7.63(1H, d), 8.08(1H, dd), 8.21(1H, dd), 8.95- 8. 99(1H, m). Example 6 2-Chloro-4-[3-(4-chlorophenyl)-3-hydroxypyrrolidine [1-yl]Benzene 321538 190 201114741

Using the compound obtained in Reference Example 4 and 4-phenylphenylmagnesium bromide as a starting material, the title compound was obtained in the same manner as in Example 1. ^NMRCCDCls)^ : 2.04(1H, s), 2.28^2.6l(2H, m), 3.53- 3.86C4H, m), 6.43(1H, dd), 6.58(1H, d), 7. 35-7. 54(5H, m). Example 7 [3 (3-Bromo-2' 6-difluorophenyl)_3_hydroxypyrrolidine, 丨_基卜2_chlorobenzonitrile

Using the compound obtained in Reference Example 4 and 1-bromo-24-difluorobenzene as 321538 191 201114741 as a starting material, the title compound was obtained in the same manner as in Example 3. tmUCDClOr 2.42(lH,s), 2.5G_2.68(1H m), 2 79- 2. 92(1H,m), 3.51-3. 73(2H,m),3.80( 1H d) 3 97- 4.08C1H , ra), 6.48C1H, dd), 6. 62(1H, d), 6. 87^ 96〇H m), 7.44(1H, d), 7. 51-7. 62(1H, m). ' Example 8

2-disorder 4-[3-(4-chlorobenzyl)-3-perylene π ratio u each base] benzoic acid production

CI uses CHIRALPAK AD (5(10) IDx5〇cm υ as the column, is burned: ethanol = 50:50 as the mobile phase, and at a flow rate of 6 〇ml/min, temperature 3 (TC, the 2 chloro obtained in Example 6) _4_[3_(4_Phenylphenyl)-3-carbyl-trans-biting +-base]Benzyl guess (4〇) optical resolution. Concentrated first φ first obtained from the column and differentiated to obtain 19 mg. CHIRALPAK AD-HU.6 mm IDx250 Lai υ as a column, n-hexane: ethanol = 50:50 as the mobile phase, and the flow rate 〇 5m ^ min 'temperature 30 〇 C, UV absorption (254 nm), concentration 〇 5 mg/rnl, injection amount of 0. 010 龃 under the analysis conditions, peaks were displayed at 3 minutes. Example 9 2-Ga-4-[3-(4-Phenylphenyl)-3-hydroxypyrrolidine ―卜基】benzonitrile 321538 192 201114741

Using CHIRALPAK AD as a column, n-hexane:ethanol = 50:50 as the mobile phase, and the 2-chloro-4-[3-() obtained in Example 6 at a flow rate of 60 ml/min and a temperature of 30 °C. Optical resolution of 4-chlorophenyl)-3-hydroxylahydroidin-1-yl]benzonitrile (40 mg). Concentrate the second difference from the column and φ to obtain I9 mg. This distinction is made in CHIRALPAK AD-H (4.6 mm IDx250 mm 1) as a column, Zhengxuan > ethanol = 50: 50 as the mobile phase, and the UV absorption is detected at a flow rate of 0.5 ml/min and a temperature of 30 °C. (254 nm), concentration 0. 5 mg / ml, injection amount of 0. 010 ml of the analysis conditions, showing the wave enthalpy in Example 3.10 2-chloro-4-[(2S,3R)-3- (4-fluorophenyl)-3-hydroxy-2-hydrazinopyrrolidinyl--:[-yl]benzonitrile

193 321538 201114741 标题 Using the compound obtained in Reference Example 5 as a starting material, the title compound was obtained in the same manner as in Example 1. /, lfI-臓(10)013)^ : 1.32(3H,d), 1.99(1H 9 C2H, m), 3.15-3.30C1H, m), 3.56-3.69(1Η ^ ' --αΗ, dd), ,62 (]fl&gt; d), ,(;7Η;;;〇;2;^η· T. 31-7. 41(2H, m)s 7. 45(ih, d). m), Example 11 2 -chloro-4-K2S, -i-yl]benzonitrile T-pyrrolidine

The title compound was obtained in the same manner as in Example 1 except that σ was used as a starting material. 'Fiber (CDCIOS: UK3JJ,d), 2 G2( ^ ^ 3.16-3.32(1H, ra), 3.55-3.70OH, 4 Q), 6.48(1H,dd),6.61(1H,d) '仙3( 7.45(1H,d). *d8(4H&gt; i Example 12 4 Russian ruthenium bromide w_yl)_3, yl i methyl η&quot; 321538 194 201114741 -1-yl]_2_chlorobenzonitrile

Μ ' c丨

Using the compound obtained in Reference Example 5 as a starting material, the title compound was obtained in the same manner as in Example 3. ^-NMR (CDCh)^ : 1.33C3H, d), 2. 19(1H, s), 2.29-2.40 (1H, ra), 2.41-2.54(1H, m), 3. 21-3.35(1H, m ), 3.62-3. 73(1H, m), 4. 01(1H, q), 6.49(1H, dd), 6.62C1H, d), 7.44-7. 51(2H, m), 7. 54- 7. 60(1H, m), 8. 38-8. 41 (1H, m). Example 13 5-[(2S,310-1-(3-chloro-4-cyanophenyl)-3-hydroxyl Ethyl 2-methylindrolridin-3-yl]pyridine-2-carboxylate 195 321538 201114741

Cl b

The compound obtained in Example 12 (250 mg), palladium acetate (29 mg), 1, bis-bis(diphenylphosphino)ferrocene (71 mg) and triethylamine (0) were obtained under a carbon monoxide atmosphere. 18 ml) was suspended in ethanol/DMF (2 ml/5 ml) and the suspension was stirred at 70 ° C for 16 hours. The reaction mixture was diluted with a sodium sodium carbonate aqueous solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, evaporated The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ^-NMR (CDC13) (5: 1.35 (3H, d), 1.44 (3H, t), 2.24 (1H, s), 2. 31-2.44 (1H, m), 2. 46-2. 59 (1H , m), 3. 22-3. 36(1H, m), 3. 61-3.74(1H, m), 4. 07(1H, q), 4.47(2H, q), 6.50 (1H, dd) , 6.63(1H, d), 7. 47(1H, d), 7.88(1H, dd), 8.13 (1H, d), 8. 72(1H, d). Example 14 5-[ (2S,3R -1 -(3-chloro-4-cyanophenyl)-3-hydroxy-2-methyloxaridin-3-yl]pyridine-2-carbonitrile [si 196 321538 201114741

Using the compound obtained in Example 12 as a starting material, the title compound was obtained in the same manner as in Example 5. /, 贝^MRCCDCh)^ : 1.34C3H, d), 2.32-2.45(lH ra) 2 4β 2.60(2H,m)&gt;3.24-3.39(lH,m), 3.64-3.80(lH,m; 4 04 (1H, q), 6.5K1H, dd), 6. 64(1H, d), 7.47(1H, d), 7.68 (1H, dd), 7_84(1H, dd), 8.77(1H, dd) 15 -1-methylethyl)pyridin Φ 2-chloro-4-K2S,3R)-3-hydroxy-3-[6-(i-pyridin-3-yl)-2-methyl ° Acridine-i-based benzonitrile 321538 197 201114741

Using the compound obtained in Example 13 and bismuth magnesium bromide as a starting material, the title compound was obtained in the same manner as in Example 1. ^-NMR (CDCls) (5: 1.34C3H, d), 1.53C6H, s), 2.03-2.16 (1H, m), 2. 29-2. 56(2H, m), 3.22-3. 35(1H , m), 3.61-3.73(1H, m), 4. 01-4. 11 (1H, ra), 4. 70-4.80(1H, m), 6. 47-6. 55(1H, m), 6. 57-6. 68(1H, m), 7. 38(1H, d), 7.47 (1H, d), 7. 67-7. 78(1H, m), 8.54(1H, d). _ Example 16 5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyridin-3-yl]pyridine-2-carboxylic acid 198 321538 201114741

The compound obtained in Example 13 (95 mg) was dissolved in THF/ethanol (3 ml / 3 ml), and 1 mol/L aqueous sodium hydroxide solution (0. 99 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1 mol/L hydrochloric acid, and the organic solvent was evaporated under reduced pressure. The residue was collected by EtOAc (EtOAc m. JH-NMR (CDCh) (5: 1. 18(3H, d), 2. 24-2. 47C2H, m), 3.15-3.34(1H, m), 3. 56-3. 72(1H, m) , 4. 15(1H, q), 6. 03(1H, brs), 6. 70(1H, dd), 6. 84(1H, d), 7. 63(1H, d), 7.91-7. 96(1H, in), 8.01C1H, d), 8.70(1H, d). Example 17 5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy- 2-indolylpyridin-3-yl]pyridin-2-ylamine 199 321538 201114741

The compound obtained in Example 16 (60 mg), WSC (64 mg), HOBt ammonium salt (51 mg) and diisopropylethylamine (0.06 ml) were suspended in DMF (3 ml) at room temperature The mixture was stirred for 72 hours. The reaction mixture was diluted with water and ethyl acetate. The residue was purified by EtOAc EtOAc (EtOAc) !H-NMR (CDCh) (5: 1.35 (3H, d), 2. 33 (1H, s), 2.35-2.57 (2H, m), 3. 26-3. 37(1H, m), 3. 65-3. 78(1H, m), 4. 08(1H, q), 5.55C1H, s), 6.51(1H, dd), 6.65(1H, d), 7.48(1H, d), 7. 77 (1H, s), 7. 90(1H, dd), 8. 17(1H, dd), 8.56-8. 59(1H, m). Example 18 4-[(2S,3R)-3- (6-Bromopyridin-3-yl)-3-indolyl-2-mercaptopyrrolidin-1-yl]-2-chlorobenzoanil 200 321538 201114741

Sodium hydride (67 mg) was suspended in DMF (15 ml) and the mixture was cooled to 5 °C. The compound obtained in Example 12 (600 mg) was added, and the mixture was stirred for 20 minutes. Methyl iodide (0.14 ml) was added to the reaction mixture and the mixture was warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine The residue was purified by EtOAc EtOAc (EtOAc) φ !H-NMR (CDCh)^ : 1.33(3H, d), 2. 27-2. 40( 1H, m), 2.51-2. 68(1H, m), 3. 10(3H, s), 3. 10-3. 20(1H, m), 3.46-3.56 (1H, in), 4. 11(1H, q), 6.42(1H, dd), 6. 56(1H, d), 7.42-7 52(3H, m), 8.26(1H, dd). Example 19 5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-methoxy-2-methyl Ethyl pyrrolidin-3-yl]pyridine-2-carboxylate [s] 201 321538 201114741

Using the compound obtained in Example 18 as a starting material, the title compound was obtained in the same manner as in Example 13. ^-NMR (CDCh)^ : 1.31-1.39 (3H, m), 1. 39-1. 49(3H, m), 2. 28-2. 48(1H, m), 2. 56-2. 79 (1H, m), 3. 03-3. 27(4H, m), 3.45-3. 68(1H, m), 4. 08-4. 31 (1H, m), 4. 39-4. 56 (2H, m), 6. 38-7. 23(2H, m), 7. 39-7. 62C1H, m), 7.67- 7. 82(1H, m), 8. 04-8. 20(1H , m), 8. 59-8. 72(1H, m). Example 20 5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methyl Pyryryryl-3-yl]-N-(2-methoxyethyl)pyridine-2-carboxamide 202 321538 201114741

The title compound was obtained in the same manner as in Example 17, using the compound obtained in Example 16 and 2-decyloxyethylamine as the starting material. JH-NMR (CDC13) 5 : 1.35 (3H, d), 2. 30-2. 43(1H, m), 2.44- 2. 57(1H, m), 2. 58(1H, s), 3. 20-3. 34(1H, m), 3. 39(3H, s), 3. 52-3. 60(2H, m), 3. 60-3. 74(3H, m), 4. 01- 4. 10(1H, m), 6.50C1H, dd), 6. 63(1H, d), 7.47(1H, d), 7.86(1H, dd), 8. 06-8. 12(1H, m) , 8.24 (1H, brs), 8.53 (1H, d). • Example 21 5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-methoxy-2- Mercaptopyridin-3-yl]pyridine-2-carboxylic acid 203 321538 201114741

Using the compound obtained in Example 19 as a starting material, the title compound was obtained in the same manner as in Example 16. !H-NMR (CDCh)^ : 1.37C3H, d), 2. 34-2. 50C1H, in), 2.58-2.78C1H, m), 3. 08-3. 27(1H, m), 3. 13 (3H, s), 3.49-3.62 (1H, m), 4. 17(1H, q), 6.45(1H, dd), 6.59C1H, d), 7.46 (1H, d), 7. 86(1H, Dd), 8.23 (1H, d), 8.54 (1H, d). Example 22 5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-methoxy-2 -mercapto-l-bromo-3-yl]pyridine-2-carboxamide [s] 204 321538 201114741

M

Using the compound obtained in Example 21 as a starting material, the title compound was obtained in the same manner as in Example 17. 'H-NMR (CDCh) 5 : 1.36(3H, d), 2. 32-2. 48(1H, m), 2.56-2.74(1H, m), 3.1K3H, s), 3. 11-3. 24(1H, m), 3.44-3.60 (1H, m), 4. 11-4.25(1H, ra), 5.55C1H, brs), 6.45(1H, dd), 6.58C1H, d), 7.45(1H, d), 7. 70-7. 85(2H, m), 8.20 (1H, d), 8.46(1H, d). Example 23 5-[(2S, 3R)-l-(3-chloro-4 -Cyanophenyl)-3-indolyl-2-indenylpyridin-3-yl]-N-decylpyridin-2-ylamine 205 321538 201114741

Using the compound obtained in Example 21 and methylamine (2 mol/L THF) as a starting material, the title compound was obtained in the same manner as in the Example.

H-NMR (CDCh) δ : 1. 36(3H, d), 2. 31-2. 46(1H, m), 2. 54. 2. M(1H,m), 3.02(3H,d), 3.08—3.2K1H,m), 3. l〇(3H, s), 3.46-3.58(lH, m), 4. 13-4. 26(1H, m), 6.44(1H, dd)! 6.58(1H , d), 7.45 (1H, d), 7.76 (1H, dd), 7.85-7.99 (1η, m), 8. 19 (1H, d), 8.41 (1H, d). Example 24 4- [(2S'3R)-3-(4-chlorophenyl)_3_hydroxy_2_decylpyrrolidinium-fluorenyl]-2~(trifluoromethyl)benzonitrile 321538 206 201114741

Using the compound obtained in Reference Example 6 and 4-chlorophenylmagnesium bromide as a starting material, the title compound was obtained in the same manner as in Example 1. ^-NMR CCDCh)^ : 1.32(3H, d), 2. 00(1H, s), 2.30-2.54 (2H, in), 3. 25-3.39C1H, m), 3. 64-3. 76( 1H, m), 4. 08(1H, q), 6.70(1H, dd), 6. 85(1H, d), 7. 31-7. 43(4H, m), 7.61 (1H, d). Example 25 5-[(2S,3R)-l-(3-Chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyrrolidin-3-yl]-N-ethylpyridine-2- Formamide

' Cl \ Μ

[S] 207 321538 201114741 Using the compound obtained in Example 16 and ethylamine as a starting material, the title compound was obtained in the same manner as in Example 17. !H-NMR (CDCh) 5 : 1.26(3H, t), 1.36(3H, d), 2.28-2.43 (1H, in), 2.45-2.62C1H, in), 2.76(1H, s), 3. 19 -3. 35( 1H, m), 3. 43-3. 56(2H, m), 3. 61-3. 75(1H, m), 4. 06C1H, q), 6. 50(1H, dd ), 6.63C1H, d), 7. 47(1H, d), 7.84(1H, dd), 7.89-7. 99(1H, m), 8.04(1H, dd), 8.46- 8.53(1H, m) Example 26 Weng 5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]-N-cyclopropylpyridine 2-carbamamine

The compound obtained in Example 16 (100 mg), WSC (107 mg), HOBt (75.5 mg), cyclopropylamine (0.039 ml) and diisopropylethylamine (0.11 ml) were dissolved in DMF. (5 ml), and the mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc. MS (ESI+, m/e): 397 (M+H).]H-NMR (CDCh) 5 : 0. 58-0. 69 (2H, m), 0. 81-0. 93 (2H, m) , 1.35(3H, d), 2.29-2.43(2H, m), 2.44-2. 58(1H, m), 2. 86-3. 02(1H, m), 3. 20-3. 35(1H , m), 3. 61-3. 75(1H, m), 4. 00-4. 12(1H, m), 6. 50(1H, dd), 6. 63(1H, d), 7.47( 1H, d), 7. 86(1H, dd), 7. 91-8. 00(1H, m), 8. 09-8. 15(1H, m), 8.45-8. 51(1H, m) Example 27 5-[(2S,3R)-l-(3-Chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyrrolidin-3-yl]-N-(l-fluorenyl) Ethyl)pyridin-2-decylamine

The compound obtained in Example 16 (100 mg), WSC (107 mg), H0Bt (75.5 mg), isopropylamine (0.048 ml), and diisopropylethylamine (〇·10 ml) were dissolved in DMF. (5 ml), and the mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with 209 321 538. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MSCESI+, m/e): 399CM+H). H-NMR (CDCh) ^ . 1. 27(6H, d), 1.35(3H, d), 2 29-2 43 (1H, m), 2. 45 -2. 59(1H, m), 2. 65(1H, s), 3.20-3 33(1H in), 3. 57-3. 76(1H, m), 3. 99-4. 11 (1H , m), 4. 17-4. 34(1H, m), 6.50(1H, dd), 6. 63(1H, d), 7.47(1H, d), 7 79(1H d), 7.87(1H , dd), 8. 08(1H, d), 8.48(1H, d) Example 28

-1-yl]-2-(trifluoromethyl)benzonitrile

Using the compound obtained in Reference Example 6 as a starting material, the title compound was obtained in the same manner as in Example 3. 'H-NMR (CDCh) 5 : 1.34(3H, d), 2. 17(1Η s), 2.32-2.56 321538 210 201114741 (2H, m), 3. 28-3.42(1H, m), 3. 68 -3.80(1H, m), 4.01-4. 10(1H, m), 6.71C1H, dd), 6.86(1H, d), 7. 47-7. 52(1H, m), 7. 55-7 67(2H, m), 8. 37-8. 42(1H, m). Example 29 5-{(2S, 3R)-l-[4-cyano-3-(trifluoromethyl)benzene Ethyl 3-hydroxy-2-indolylpyrrolidin-3-ylpyridinium-2-carboxylate

Using the compound obtained in Example 28 as a starting material, the title compound was obtained from !H-NMR (CDCh)^ : 1.36(3H, d), 1.43(3H, t), 2. 30(1H, s), 2. 36-2. 47(1H, m), 2. 48-2 62(1H, m), 3. 28-3. 42(1H, m), 3. 67-3. 81(1H, in), 4. 07-4. 19(1H, m), 4. 47 (2H, q), 6.72C1H, dd), 6.86C1H, d), 7. 63(1H, d), 7. 91(1H, dd), 8. 13(1H, d), 8. 72(1H , d). Example 30 5 -{(2S, 3R)-1-[4-Cyano-3-(trifluoromethyl)phenyl]-3-yl-2-methylpyrrolidin-3- }}pyridine-2-carbonitrile 211 321538 201114741

The title compound was obtained in the same manner as in Example 5, using the compound obtained in Example 28 as a starting material. lH-NMR(CDCl3)5: 1.35(3H,d), 2.35-2.62(3Η,m), 3.40 〇H, dt), 3.72-3.86(lH, m), 4. 10(1H, q) , 6. 73(1H, dd), 6.87(1H, d), 7.62(1H, d), 7. 69(1H, d), 7.88(1H, dd), 8.73-8. 80(1H, m) Example 31 Xin 5-{(2S,3R)-1,4-[4-cyano-3-(trifluoromethyl)phenyl]-3-hydroxyindenyl 0 to 0 each -3-yl} ton Bite_2-Rebel acid 321538 212 201114741

OH Using the compound obtained in Example 29 as a starting material, the title compound was obtained in the same manner as in Example 16. Ή-NMR (DMSO-de)^ : 1. 18(3H, d), 2.36-2.44(2H, ra), 3. 23-3. 50(2H, m), 3. 63-3. 78(1H , m), 4. 23C1H, q), 6.03 (1H, brs), 6.89-7. 05(2H, m), 7.8K1H, d), 7.92-8.06 (2H, ra), 8. 70-8. 77(1H, m). Example 32 5-{(2S,3R)-l-[4-Cyano-3-(trifluoromethyl)phenyl]-3-hydroxy-2-indolylpyrrolidine- 3-yl}pyridin-2-ylamine 213 321538 201114741

Using the compound obtained in Example 31 as a starting material, the title compound was obtained in the same manner as in Example 17. !H-NMR (CDCh) 5 : 1.36C3H, d), 2.38 (1H, s), 2.37-2.60 (2H, m), 3.39C1H, dt), 3. 69-3. 84(1H, m), 4. 13(1H, q), 5.57C1H, br. s. ), 6. 74(1H, dd), 6.88(1H, d), 7. 64(1H, d), 7.77C1H, br. s. ), 7. 91 (1H, dd), 8. 17(1H, dd), 8.59 (1H, d). Example 33 5-{(2S,3R)-l-[4-cyano-3-( Trifluoromethyl)phenyl]-3-lightyl-2-mercaptopyrrolidin-3-*}-N-decylpyridin-2-carboxamide [s] 214 321538 201114741

The solution of Example 31 was used as a starting material, compound.

The obtained compound and methylamine (2 jgoi / L THF obtained the title H-NMR (CDC13) (5: 1.37 (3H, d), 2. 32-2. 64 (2H, m) in the same manner as in Example (11·s), 3.02(3H,d),3.23-3.4K1H,m),3.66_3 8 ·= m), 4. 03-4. 18(1H,in),6.72(1H,dd ), 6. 87 (1H, d) 7 ,

C1H, d), 7.84C1H, dd), 7.91-7.96C1H, m), 8 Oinji ^ m 8-50(lH, d). dX Example 34 5'K2S,3R)-1-[4-cyano Trimethylmethyl)phenyl]-3_yl-ylpyrrolidin-3-ylbu-N-ethylpyridine-2-monoamine 321538 215 201114741

N F F

The compound obtained in Example 16 (200 mg), WSC (196 mg), HOBt (138 mg), ethylamine hydrochloride (83. 4 mg) and diisopropylethylamine (0. 18 ml) was dissolved in DMF (5 ml), and the mixture was stirred at room temperature for 72 hr. The reaction mixture was diluted with aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with water and saturated brine, evaporated The residue was purified by EtOAc EtOAc (EtOAc) elute MS (ESI+, m/e): 419 (M+H). NMR (CDH) ά : 1.26 (3H, t), 1.37 (3H, d), 2.31-2.63 (2H, m), 2. 88C1H , s), 3. 27-3. 39(1H, in), 3. 42-3. 56(2H, m), 3. 67-3. 81C1H, m), 4. 05-4. 19(1H , m), 6.72(1H, dd), 6.87C1H, d), 7. 63(1H, d), 7. 86(1H, dd), 7. 89-7. 99(1H, m), 8. 03(1H, dd), 8.49(1H, d). Example 35 5-{(2S, 3R)-1 -[4-nitro-3-(trifluoromethyl)phenyl]-3 - aryl- 2-曱216 321538 201114741

Pyryryryl-3-yl}-1 cyclopropylpyridine-2-decylamine

Using the compound obtained in Example 31 and cyclopropylamine as a starting material, the title compound was obtained in the same manner as in Example 17. H-NMR (CDC13) 5 : 0.59-0· 69(2H,m), 0.83-0. 93(2H,m), 1.37(3H, d), 2. 32-2. 46(1Η, m) , 2. 48-2. 62(1Η, m), 2.86 (1Η, s), 2. 87-2. 98(1H, m), 3.32(1H, dt), 3.64-3.81 # (1H, m) , 4. 12(1H, q), 6. 72(1H, dd), 6. 86(1H, d), 7.62 (1H, d), 7. 86(1H, dd), 7. 90-7. 99(1H, m), 8. 04(1H, d), 8.47(1H, d). Example 36 5-{(2S,3R)-l-[4-cyano-3-(trifluoromethyl) Phenyl]-3-hydroxy-2-methylpyrrolidinylmethylethyl)pyridine-2-carboxamide [s] 217 321538 201114741

Using the compound obtained in Example 31 and isopropylamine as a starting material, the title compound was obtained in the same manner as in Example 17.

'H-NMR (CDCh) (5: 1.27 (6H, d), 1.37 (3H, d), 2.31-2.63 (2H, m), 2.72 (1H, s), 3.34 (1H, dt), 3. 67 -3. 81 (1H, m), 4. 03-4. 36(2H, m), 6. 72(1H, dd), 6.87(1H, d), 7. 63(1H d), 7.74-7.83 (1H, m), 7.88(1H, dd), 8.07(1H, d), φ 8. 42-8. 52(1H, m). Example 37 4~[(28,38)-3-(5 - desert 0 to 0 to 2 - 2)-3-yl-2-yl group. slightly bite base] 2-chlorobenzonitrile

Br butyl lithium (i. 6 mol/L hexane dissolved m 218 321538 201114741 solution, 3.84 ml) was added dropwise to 2, 5-dibromopyridine (1) under an argon atmosphere at -78 °C. · 21 g) of toluene (1 〇〇 ml) solution. The mixture was stirred for 1 hour, and a toluene solution (1 ml) of the compound obtained in Reference Example 5 (1.00 g) was added dropwise. The mixture was stirred for 3 Torr and allowed to warm to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Evaporate the agent under reduced pressure, and purify the residue with a column and use hexane-acetic acid

Example 38: Boxing:

I

I 6-[(2S,3S)-l-(3-chlorocyan-3-yl)° ratio biting -3- citrate methyl vinegar

4-cyanophenyl)-3-hydroxy-2-methyl"pyrrolidine 〇 eight. /CH3 phenylphosphino)ferrocene}dichlorodecane complex "The obtained compound (800 mg) and tri-p-dichloropalladium {1,1'-bis (dimer (166 mg)) were added to the examples. 37 321538 219 201114741 Ethylamine (0.34 ml) in methanol (20 ml), and the mixture was stirred overnight at 60 ° C under a carbon monoxide atmosphere. After cooling to room temperature, water was added to the reaction mixture and acetic acid. The mixture was extracted with ethyl acetate. EtOAc EtOAc m. NMR (CDCh) d : 1.30 (3H, d), 2. 26-2. 38 (1H, m), 2.45-2.57 (1H, m), 3. 38-3. 50(1H, m), 3. 68-3.80(1H, m), _ 3. 89-4. 00(4H, m), 5.28(1H, s), 6.50C1H, dd), 6.63(1H, d), 7. 19(1H, dd ), 7.45 (1H, d), 8.3K1H, dd), 9. 16(1H, d). Example 39 6-[(2S, 3S)-l-(3-chloro-4-cyanophenyl)- 3-hydroxy-2-methyloxaridin-3-yl]pyridine-3-carboxylic acid

A 1 mol/L aqueous solution of sodium hydroxide (7. 40 ml) was added to a solution of the compound obtained in Example 38 (550 mg) in THF (13 ml)-ethanol (13 ml), and [s] 220 321538 201114741 at room temperature The mixture was stirred for 5 hours. Water was added to the reaction mixture, and the mixture was neutralized with 1 mol/L hydrochloric acid. The mixture was extracted with EtOAc. The solvent was evaporated under reduced pressure. j-NMR (DMS〇-d6) (5: 1.16 (3H, d), 2. 21-2.34C1H, m), 2. 44-2. 57(1H, m), 3. 25-3. 43( 1H, m), 3. 56-3. 69(1H, m), 4. 24(1H, q), 5.98(1H, s), 6. 63(1H, dd), 6.75(1H, d), Φ 7.57(1H, d), 7. 84(1H, dd), 8.29(1H, dd), 8.93C1H, dd), 13.33C1H, br. s.). Example 40 2-chloro-4-{( 2S,3S)-3-hydroxy-3-[5-(l-hydroxy-1-methylethyl)-pyridin-2-yl]-2-methylpyrrolidine-l-yl}benzonitrile N = Cl

A solution of the compound of Example 38 (80 mg) in THF (10 ml). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate 221 321538 201114741. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. !H-NMR (CDC13) (5: 1.29 (3H, d), 1.6K6H, s), 1.76 (1H, s), 2. 22-2. 33(1H, m), 2. 41-2. 54 (1H, in), 3. 37-3. 48(1H, m), 3. 66-3.77(1H, m), 3. 89(1H, q), 5. 54(1H, s), 6.49 ( 1H, dd), 6.63C1H, d), 7. 03(1H, d), 7.44(1H, d), 7.83 (1H, dd), 8.68(1H, d). βExample 41 6-[ (2S , 3S)-l-(3-Ga-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]pyridine-3-carbonitrile

The compound obtained in Example 37 (100 mg), zinc cyanide (18 mg) and hydrazine (triphenylphosphine) palladium (88 mg) in NMP (10 ml) were stirred under an argon atmosphere at 10 °C. The solution was 2.5 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified mjjjjjjjjjjjjjjjj The title compound (20 mg) was crystallized. 'H-NMR mSO-άΟδ : 1.16C3H, d), 2. 24-2.37(1H, m), 2.42-2. 55(1H, m), 3. 25-3. 38(1H, m), 3 55-3. 68(1H, m), 4.22C1H, q), 6. 10(1H, s), 6.62(1H, dd), 6. 74(1H, d), 7.57(1H, d), 7. 91(1H, d), 8.33(1H, dd), 8.91C1H, d). Example 42 6-[(2S,3S)-1_(3-chloro-4-cyanophenyl)-3-hydroxyl -2-mercapto. Pyrrolidine^-3-yl]pyridine-3-carboxamide

The compound obtained in Example 39 (60 mg), HOBt·NH3 (33 mg) and WSC (42 mg) in DMF (5 ml) was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the crystallite crystal crystal crystal crystal crystal crystal JH-NMR (CDCls) (5: 1. 28(3H, d), 2. 37-2. 49(2H, m), 3.36-3.50(1H, in), 3. 64-3. 78(1H, In), 4. 07(1H, q), 5.51(1H, [s] 223 321538 201114741 s), 6.30C1H, br. s. ), 6. 50(1H, dd), 6. 62(1H, d ), 7.41-7. 49C2H, m), 7. 52(1H, br. s. ), 8.24C1H, dd), 9. 03(1H, d). Example 43 6-[ (2S,3S)- L-(3-Chloro-4-cyanophenyl)-3-hydroxy-2-mercaptopyrrolidin-3-yl]-N-decylpyridin-3-indoleamine

Using the compound obtained in Example 39 and methylamine (2 mol/L THF) as a starting material, the title compound was obtained in the same manner as in Example 42. ^-NMR CCDCh) (5: 1. 29(3H, d), 2. 26-2. 37(1H, m), 2. 44-2.56(1H, m), 3. 05(3H, d), 3. 37-3. 50(1H, m), 3.67-3.78 (1H, in), 3. 93(1H, q), 5. 22C1H, s), 6. 11(1H, br. s.), 6.49C1H, dd), 6.63(1H, d), 7. 19(1H, d), 7.45(1H, d), 8. 10(1H, dd), 8.9K1H, s). Example 44 6-[ (2S,3S)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyridin-3-yl]-N-ethylpyridin-3-ylamine 224 321538 201114741

Using the compound obtained in Example 39 and ethylamine as a starting material, the title compound was obtained in the same manner as in Example 42. R (CDC13) 5 : 1.21-1. 33(6H,m), 2.25-2. 37(1H,m), 2.43-2. 56(1H,m),3,37-3.59(3H, Ιη), 3. 68-3. 78(1H,m), 3.93(1H, q), 5.23(1H,s), 6. 10(1H,br. s·),6.49(1H, dd), 6 63(1H, d), 7. 18(1H, d), 7.45C1H, d), 8. 10(1H, dd), 8. 91(1H, d). Example 45 Ester 2-chloro-4 -{(2S,3R)-3-hydroxy-2-indolyl-3-[6-(pyrrolidin-1-ylcarbonyl)σ butyl-3-yl]pyrrolidine-i-yl}benzonitrile

Mix a mixture of the compound obtained in Example 16 (1 〇〇mg), pyrrolidine (0. 070 ml), WSC (80 mg), H0Bt (57 mg) and DMF (5 ml) overnight. . Water was added to the reaction mixture, and 225 321538 201114741 was extracted with ethyl acetate. The extract was washed with aq. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut 'H-NMR (CDCh) (5: 1. 34(3H, d), 1. 85-2. 00(4H, m), 2.35 (1H, m), 2. 50(1H, m), 3. 25(1H, m), 3. 32(1H, s), 3.60-3.75(5H, m), 4.04(1H, q), 6.50(1H, dd), 6. 62(1H, d), 7.46( 1H, d), 7.65(1H, d), 7.74(1H, dd), 8.49(1H, d). Example 46 2-Chloro_4-{(2S, 3R)-3_Lightyl-2- Methyl-3~[6~(?) pyridine-3-yl]pyrrolidinyl-l-yl}benzonitrile

CI

Using the compound obtained in Example 16 and morpholine as a starting material, the title compound was obtained in the same manner as in Example 45. ^-NMR (CDCh)^ : 1.34(3H, d), 2. 35(1H, m), 2.50(1H, m), 2. 91(1H, s), 3. 30(1H, m), 3 60-3. 75(5H, m), 3.75-3.85(4H, m), 4. 04(1H, q), 6.49(1H, dd), 6. 63(1H, d), V. 47( 1H, d), 7. 60(1H, d), 7. 79(1H, dd), 8. 52(1H, d). Example 47 ' · 5~[ (2S, 3R)-1 -(3 -chloro-4-cyanophenyl)_3-trans-base_2_ τ group e ratio leptin-3-yl]-oxime, Ν-dimethylpyridine-2-carboxamide 321538 226 201114741

Using the compound obtained in Example 16 and dimethylamine (2 mol/L THF) as a starting material, the title compound was obtained in the same manner as in Example 45. !H-NMR (CDC13) (5: 1.33C3H, d), 2.30 (1H, ra), 2. 50 (1H, m), 3.04 (3H, s), 3. 13 (3H, s), 3. 25(1H, m), 3. 60(1H, s), 3. 65C1H, m), 4. 03(1H, q), 6. 49(1H, dd), 6. 62(1H, d), 7.40-7.50(2H, m), 7. 72(1H, dd), 8.45(1H, d). Example 48 5-[ (2S,3R)-l-(3-chloro-4-cyanophenyl) -3-hydroxy-2-mercapyryrrolidin-3-yl]-N-(2, 2, 2-trifluoroethyl) acridine-2-decylamine

Using the compound obtained in Example 16 and 2, 2, 2-trifluoroethylamine as a starting material, the title compound was obtained in the same manner as in Example 45. !H-NMR (CDC13) (5: 1.35C3H, d), 2. 33-2. 58(3H, m), 3.30 (1H, m), 3.70C1H, in), 4. 02-4. 17( 3H, m), 6.51(1H, dd), 6.64(1H, d), 7.47C1H, d), 7. 91(1H, dd), 8. 17(1H, dd), 8.29C1H, t), 8.58 C1H, dd). 227 321538 201114741 Example 49 2-Gas-4-{(23,31〇-3-hydroxy-2-methyl-3-[4-(methylsulfonyl)phenyl]σ ratio Pyridyl-l-yl}benzonitrile

(Step 1) A solution of [4-(decylsulfonyl)phenyl]cen bromide in THF® (4.5 ml) was added to the compound obtained in Reference Example 5 at -78 °C (469) A solution of mg in THF (10 ml), and the mixture was stirred at the same temperature for 5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aq. The residue was purified by EtOAc (EtOAc-EtOAc) Methyl-3-[4-lu(indolylsulfonyl)phenyl]pyrrolidinium-indole-benzonitrile (225 mg). (Step 2) Add mCPBA (25 〇昵) to the acetonitrile (1 〇ffil) solution of the compound obtained in Step i (225 mg) under ice cooling and stir the mixture at room temperature for 16 hours. To the reaction mixture, the mixture was extracted with ethyl hexanoate. The extract was washed with brine and dried over anhydrous sulphuric acid and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) elute !H-NMR (DMSO-de) 5 : i 〇 nr d), 2.25-2.45C2H, m),

LSI 321538 228 201114741 3. 19(3H, s), 3. 25-3. 35(1H, ra), 3. 60-3. 70(1H, m), 4.09 (1H, q), 5.90 (1H, s), 6. 69(1H, dd), 6.82(1H, d), 7.62 (1H, d), 7. 67(2H, d), 7. 89(2H, d). Example 50 2-Chlorine -4-[(2S, 3R)-3-carbyl-3-(4-decyloxyphenyl)-2-indolyl 0-pyridin-1-yl]benzonitrile

CI

A 0.5 mol/L solution (3.0 ml) of (4-nonyloxyphenyl)magnesium bromide in THF was added to THF (5 ml) obtained in Reference Example 5 in THF (5 ml) at -78 °C. And the mixture was stirred at the same temperature for 1.5 hours. Will be full

An aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aq. The residue was purified by EtOAc (EtOAc-EtOAc) 124 mg). Ή-NMR (CDCh) 5 : 1.3K3H, d), 1.91 (1H, s), 2.27-2.47 (2H, m), 3. 15-3. 25(1H, m), 3. 55-3. 65 (1H, m), 3. 80(3H, s), 4. 05(1H, q), 6.48(1H, dd), 6.6K1H, d), 6. 88(2H, d), 7. 29( 2H, d), 7.44C1H, d). Example 51 229 321538 201114741 [(,3R) 1 (3-Chlorocyanophenyl)_3-yl-based 2-methyl-methyl-pyridyl-3-yl]benzene Ethyl citrate

(Step 1) In a -78 c butyl ketone (1.6 m 〇 1 / L hexane solution, 〇 75 (4) spring to 1, 4 峨 benzene (33 〇 mg) of diethyl ether (5 (4) suspension and given 1 3 ^ knife knives were mixed. After that, the compound obtained in Reference Example 5 (235 mg) of THF (2 =, cold liquid was added to the reaction mixture and the mixture was stirred for 3 hr, and 16 (4) was observed at room temperature. Adding to the reaction mixture and extracting the mixture with Sa, extracting the extract with saturated brine, drying with anhydrous sulfur I magnesium and rolling under reduced pressure, followed by column chromatography (hexane Purify the residue by column chromatography (hexane __EtOAc) to afford 2-chloro-4-[(2S,3R)-3-yl-3- (1 ', Phenylmethylpyrrolidin-1-yl]benzonitrile (120 mg). [2] The hydrazine (120 mg) obtained in step 1 under stirring in a carbon monoxide atmosphere (TC), acetic acid Palladium (12 mg), 1,1,-bis(diphenylphosphino)ferrocene (30 ιπρΛ _, triethylamine (〇. 〇75 DMF/ethanol (2 ml/2 ml) 4 ί ·+·, hours. Add water to the reaction mixture and use acetic acid The extract was extracted. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and dried over EtOAc EtOAc EtOAc EtOAc The title compound (23 mg) was obtained as a colorless crystals: EtOAc (CD). , 1. 38(3H, t), 2. 05(1H, s), 2. 32-2. 50(2H, m), 3. 22-3, 32(1H, m), 3. 62-3 70(1H, m), 4. 07(1H, q), 4. 37(2H, q), 6.49(1H, dd), 6. 63(1H, d), 7. 42-7. 50( 3H, m), 8. 03(2H, d). Example 52 4-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indenylpyrrole Pyridine_3 -yl]benzoic acid C!

5小时。 Mixture of the compound obtained in Example 51 (0. 74 g), lithium hydroxide monohydrate (120 mg) and ethanol / THF / water (5 ml / 5 ml / 10 ml) 1. 5 hours And stirred at 50 ° C for 2 hours. The reaction mixture was diluted with aq. sodium hydroxide and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid, and extracted with a mixed solvent of ethyl acetate / methanol. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was crystallized from EtOAc (EtOAc) elute ^-NMR (DMSO-de) (5: 1. 16(3H, d), 2. 22-2.40(2H, m), 3. 15-3. 35(1H, m), 3. 55-3. 70(1H, m), 4. 07(1H, q), 5.79 (1H, s), 6.67C1H, dd), 6.81(1H, d), 7. 53(2H, d), 7.61 (1H, d ), 7. 89(2H, d), 12.88(1H, brs). 231 321538 201114741

Example 53 4-[ (2S,310 + (3-Gas_4_1phenyl)_3_-yl-1 methyl n-Bisto-3-yl]-N-methylbenzimidamide CI

- Using the compound obtained in Example 52 and methylamine (2 m 〇l / L THF) as a starting material, compound was obtained in the same manner as in Example 45. No face (DMS0-d6)d: 1.16(3H,d), 2.25-2.35(2Η,m), 2·76(3Η,d), 3.28-3.38(lH,m),3.55-3.65UH , m), '4. (n 〇H, q), 5.73C1H, s), 6. 67(1H, dd), 6.81(1H, d), 7.48 C2H, d), 7.60(1H, d), 7.77C2H, d), 8.35 (1H q) Example 54 '

44(2S,3R)-l-(3-Gas-4-cyanophenyl)_3_trans-base_2_ τ-based n-pyridyl~3-yl]benzamide Q

Using the compound obtained in Example 52 and the salt of the title compound (77:) as the starting material, the title compound 232 was obtained in the same manner as in Example 45 [S] 321538 201114741 • H-NMR (DMSO-de) ^ : 1.16C3H, d), 2. 25-2.40(2H, m), 3. 15-3. 35(1H, m), 3. 55-3. 65(1H, m), 4. 08(1H, q ), 5.73 (1H, s), 6.68 (1H, dd), 6.8K1H, d), 7. 31(1H, brs), 7. 47(2H, d), 7. 61(1H, d), 7 82(2H, d), 7. 89(1H, brs). Example 55 4-[(2S, 3R)-3-(6_Demonin-3-yl)-3-yl-2 -methyl n is more than bitten-1-yl]benzonitrile

Using the compound obtained in Reference Example 7 as a starting material, the title compound was obtained in the same manner as in Example 3. Ή-NMR (CDC13) (5: 1.32C3H, d), 2.25(1H, s), 2.27-2.37 (1H, in), 2.42-2. 53(1H, m), 3.22-3. 32(1H, m), 3.62-3. 72(1H, in), 4. 02(1H, q), 6. 59(2H, d), 7.46(1H, dd), φ 7. 50(2H, d), 7.57 (1H, dd), 8.39 (1H, dd). Example 56 4-[(2R, 3S)-3-(6-bromopyridin-3-yl)-3-hydroxy-2-indolylpyrrolidin-1 -yl]-2-chlorobenzonitrile

CI

233 321538 201114741 Using the compound obtained in Reference Example 9 as a starting material, the title compound was obtained in the same manner as in Example 12. The j-NMR data was consistent with the data of the compound obtained in Example 12. Example 57 2-Chloro-4-{(2S,3R)-3-[6-(4-fluorophenyl)° ratio acetyl-3-yl]-3-radio-2-methylpyrrolidine-l -benzonitrile

CI

The compound obtained in Example 12 (275 mg), (4-fluorophenyl)boronic acid (98 mg), hydrazine (triphenylphosphine)palladium (40 mg), and 2 mol/L sodium carbonate aqueous solution were stirred under microwave irradiation. A mixture of (2.1 ml) and 1,2-dimethoxyethane (7 ml) was stirred at 130 ° C for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) elution elution elution elution elution elution elution (54 mg). ^-NMR (CDC13) 6 : 1,36(3H,d),2·12(1H,s), 2.35-2.55 (2H, in), 3. 25-3. 35C1H, m), 3. 60- 3. 70(1H, m), 4. 10(1H, q), 6.5K1H, dd), 6. 64(1H, d), 7. 10-7. 20(2H, m), 7.47 (1H, d), 7. 68(1H, d), 7. 77(1H, dd), 7. 90- 8. 00(2H, in), 8.68C1H, d). 234 321538 201114741 Example 58 2-Chloro- 4-[(2S,3R)~3-hydroxy-2-methyl-3-(6-pyrrolidinyl-i-ylpyridin-3-yl)pyrrolidin-1-yl]benzonitrile

CI

The compound obtained in Example 12 was mixed under a light microwave shot of 18 0 C (275 Å), pyrrolidine (〇.〇58 1!11), 1,8-diazabicyclo[5.4.0] A mixture of -7-ene (0.105 ml) and 1-methyl-2-indrolridone (2 ml) was used for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate).

^-NMR (CDCh) (5: 1. 16(3H, d), 1. 85-l. 95(4H, m), 2. 15-2.35C2H, in), 3.05-3. 15(1H, m ), 3.25-3.35(4H, m), 3. 45-3. 55(1H, m), 4. 03(1H, q), 5. 50(1H, s), 6 4〇(lH d), 6.65 (1H, dd), 6.78 (1H, d), 7.51 (1H, dd)', 7··6〇(1Η'd), 7.99(1H, d). 'Example 59 2-chloro-4- {(2S,3R)-3-hydroxy-2-methyl-3__[6_(5-fluorenyl y 3 4 -yl 2,2-yl-2-yl) σ is more than -3-yl]. Bilo bite-i-based benzophene guess 321538 235 201114741

A mixture of the compound obtained in Example 16 (25 mg), acetonitrile (62 mg), WSC (161), _ (114 mg) and DMF (5 ml) was stirred at room temperature for 5 hours. Water was added to the inverse compound, and the mixture was transferred to a mixed solvent of ethyl acetate/clear. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Residue and 曱Ml_7mg), triethylamine (^ shoulder (4) and Qing (1) Hill mixed 5, and heated the mixture under reflux for 2M, add hydrate, and extract with ethyl acetate ... this is anhydrous sulfur The residue, the (4) extract, (methanol/ethyl acetate) and the basic egg were purified by (4) column chromatography, and the title compound (87 (4) was obtained as the title compound (b). Yellow solid W-NMR (CDC13) (5: 1.3? (train a 0. ΠΗ, Π), 2.47-, 6〇 (1Η;:;;;; 65 3 5 (1Β· 2·3-2.45 m), 3.65-3·75(1Η, m), 4 1〇( 'S)' 3·25—3·37(1Η, OH, d), ,48(1H, d), /^;;';;' 6-52(1H' dd&gt;- ^.65 (1H, dd). , ), 8.22 (1H, dd), 8.71 Example 60: benzyl-2-methyl-pyrrolidine. 5-[(2R' 3S)-l-(3-cyanocyanophenyl)-3~-3-yl]° ratio 曱醯-2-decylamine 321538 236 201114741

(Step D, in the same manner as in Example 13, from the compound (10 mg) obtained in Example 56, 5-[(10),3s)+(3-chloro-4-cyanophenyl)-3- Hydroxy-2-indenyl D is more than pyridyl]pyridine 2, acid ethyl ester (740 mg). ((4) 2) 5_[(2r,3s)+(3-chloro-4-cyanophenyl) was obtained as a pale yellow solid from the compound obtained in the step (74"g). 3-hydroxy-2-methylpyrrolidinyl]pyridine-2-carboxylic acid (687 mg). (Step 3) Compound (343 mg) obtained from Step 2 in the same manner as Example 45 HOBt ammonium salt (5 mg) gave the title compound ( 175 mg) as colorless crystals. H-NMR (DMSO-de) 5 : 1. 18 (3H, d), 2.25-2.45 (2H, m), 3. 18-3. 28(1H, m), 3. 55-3. 65(1H, in), 4. 16(1H, q), 6.00 OH, s), 6. 70(1H, dd), 6.85( 1H, d), 7. 60(1H, brs), 7. 63(1H, d), 7. 95-8. 02(2H, m), 8.09(1H, brs), 8.55C1H, s). Example 61 5-[(2R,3S)-l-(3-Chloro-4-cyanophenyl)-3-hydroxy, 2-methylpyrrolidin-3-yl]-N-methylpyridine-2-methyl Guanamine [S] 237 321538 201114741

The title compound was obtained in the same manner as in Example 45, using the compound obtained in Example 60, Step 2, and decylamine (2mol/L THF / mixture) as starting material. Ή-NMR CDMSO-dO, : M8 (3h&gt;d)&gt;2&gt;25.2&gt;45(2H, m)} 2· '9(3H,d;,3·18-3·28(1H,m) , 3 55_3. 7G(1H,m),4· 16 (1H' q),6.Q1(1H' s)' 6.7Q(1H,dd), 6.85(1H,d),7.63 〇H, d) , 7.90-8.00(2H, m), 8.56(1H, s), 8.75(1H, q). Example 62 5 [(2S' 3R) + (4-cyanophenyl)_3,yl-2-methyl Hip-hop bite _3_ base] ° bite 2-formamide

= υ υ 相同 相同 相同 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 , acid B 64 g) 〇 2 was added in the same manner as in Example 16 _ mode, obtained from the step =1 = 1. 64 g) to obtain a light brown solid 5_[(2S, 3 old _ (4_ atmosphere secret a compound obtained from the step 2 (323 mg) in the same manner as in Example 45, 321538 238 201114741 (Step 3) And the title compound (218 mg) was obtained as a colorless crystals of H.sub.2H. 2. 35-2. 47(1H, m), 3. 12-3. 25(1H, m), 3. 51-3. 65(1H, m), 4. 10(1H, q), 5.98( 1H, s), 6.72(2H, d), 7.56(2H, d), 7. 57(1H, brs), 7. 92-8. 00(2H, m), 8. 09(1H, brs), 8.52 (1H, s). @Example 63 5-[(2S,3R)-l-(4-Cyanophenyl)-3-hydroxy-2-methylindazin-3-yl]-N-A Pyridine-2-carboxamide

The title compound was obtained in the same manner as in Example 45, using the compound obtained from Example 62 and Step 2 and methyleneamine (2 mol/L THF). !H-NMR CDMSO-de)^ : 1.19(3H, d), 2.22-2.48(2H, m), 2.78(3H, d), 3.10-3. 25C1H, m), 3. 53-3. 63(1H, m), 4.09 (1H, q), 5. 98(1H, s), 6. 72(2H, d), 7. 56(2H, d), 7.95-8. 00C2H, m), 8.50 (1H, s), 8.75 (1H, q). Example 64 2-chloro-4-[(2S, 3R)-3-hydroxy-2-methyl-3-(6-morpholin-4-yl Pyridine [s] 239 321538 201114741 -3-yl)pyrrolidin-1-yl]benzonitrile hydrochloride α

• HCI The compound obtained in Example 12 (275 mg), morpholine (0. 061 ml), 1,8-diazabicyclo [5.4. 0] eleven-7-ene were stirred under microwave irradiation at 200 °C. (0. 105 ml) and a mixture of hydrazine-mercapto-2-pyrrolidone (2 ml) for 30 W. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sulphuric acid and concentrated under reduced pressure. The residue was purified by hydrazine column chromatography (hexane-ethyl acetate) and spectroscopy (H.sub.-ethyl acetate), and 4 m 〇i/L gasification gas acetic acid was added. The vinegar solution gave the title compound (1 mg) as a light brown crystal. !H-NMR (DMSO-de)^ : 1.15(3H, d), 2.22^2.40(2H m) • 3.15-3.30C1H, m), 3.50-3.65(4H, m), 3. 65-3. 80 (4H, mi 4.1〇-4.30(3H, brs), 4. 07(1H, q), 6.68(1H, dd), 6 82 OH, d), 7.20-7.32C1H, m), 7.63(1H, d ), 7. 82- 8. 00(2H.m). Example 6 5 ~3-yl]-3-yl-yl 2-py-4-{(2S, 3R)-3-[6-(diindole) Aminoamino)n-pyridyl-2-methylindolodine_i_ylbenzonitrile 321538 240 201114741

Using the compound obtained in Example 12 and dimethylamine hydrochloride as a starting material, the title compound was obtained in the same manner as in Example 64. tNMR (DMS0-d6) 5 : 1.15 (3H, d), 2.25-2.40 (2H, π 〇, 3.15- 3.25 UH' m), 3.18 (6H, s), 3.50-3.65 (lH, m), 4. OH; OH, q), 6.0i(lH, brs), 6. 69(1H, dd), 6.83(1H d) 7.15- 7.25UH,in),7·64(1Η,d),7.heart 7 22(1H,' m)' 7. 92-8. 02(1H, m). 'Example 66

4-([2S, 3S)-3-(6-invalid ratio σ-but-2-yl)-3-yl-1-yl]-2-chlorobenzonitrile Q

The methyl group was compared with 嘻 π using the compound obtained in Reference Example 5 and 2,6--, from u_~/one shoulder to pyridine (2.37 g) as a starting material to be in the same manner as in Example 12 Fang Nide title compound. ^-NMRCCDCla)^ : 1.3K3H, d), 2. 30-2. 4〇(iH, ra) 2 43_ 2.55(1H, ra), 3. 35-3. 45(1H, m), 3. 65 -3. 75(1H 3 93 (1H,q), 4.65(1H,s), 6.49(1H,dd), 6.62(1h' d)' 7·〇5 321538 241 201114741 (1H, dd), 7.43- 7. 50(2H, m), 7. 52-7. 60(1H, m). Example 67 6-[(2S,3S)-l-(3-chloro-4-cyanophenyl)-3-hydroxy -2-decylpyrrolidin-3-yl]pyridine-2-carbonitrile

A mixture of the compound (275 mg), zinc cyanide (80 mg), hydrazine (triphenylphosphine) (40 mg) and DMF (5 ml) obtained in Example 66 was stirred for 1 hour under 18 CTC microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (hexane-ethyl acetate) elution elution elution elution ). • 'H-NMR (CDCh) 5 : 1. 31(3H, d), 2. 32-2. 42C1H, in), 2. 45-2.55C1H, m), 3. 47-3. 57(1H, m), 3. 68-3. 78(1H, m), 3.96 (1H, q), 4. 51(1H, s), 6. 50C1H, dd), 6. 63(1H, d), 7.39 ( </ RTI> <RTIgt; Mercapto-3-[6-(1,3,4-oxadiazol-2-yl)pyridin-3-yl]pyrrolidinyl-l-yl}benzonitrile [S] 242 321538 201114741

The title compound was obtained in the same manner as in Example 59, using the compound obtained in Example 16 and toluene as a starting material. Mso-άθδ : 1.19C3H, d), 2.32-2.47(2H, m) 3·23-3·32(1Η,m), 3.57~3.72(1H,m), 4. 19(1H, q),6 〇7 • (1H, s), 6.710H, dd), 6.85(1H, d), 7.63(1H, d)! s! 03 (1H, dd), 8. 18(1H, d), 8.80(1H , d), 9.4i(iH s) * Example 69 ' · 5-[ (2S,3R)-1 -(3-Chloro-4-indolyl)-3 mono-based, 2-methylpyridinium bite -3-yl]-N-methyl 0-bito-2-carboxamide

- The title was obtained in the same manner as in Example 17 using the compound obtained in Example 16 and methylamine (2 butyl liver solution) as a starting material.

32153S 243 201114741 Compound. 'H-NMR (CDC13) (5: 1.36(3H, d) 9 〇^·30-2.43(1Η, m), 2.45-2.60(1Η, m), 2.78(1H, s), 3 0?rq„ ^ d), 3. 20-3. 34(1H, m), 3. 59-3. 75(1H,m), 4. 〇6(ih e Q), 6. 50(1H,dd),6.63 (1H, d), 7.47 (1H, d), 7·83 (1Η, dd), 7. 94(1H, brs), 8. 01-8. 06(1H, m), 8. 50( 1H, d) Example 70 5~[(25,31〇-Bu(5-chloro-4-cyano~2-|| floc 1, decyl)-3~hydroxy-2-methylpyrrolidine -3-yl]pyridine-2-carboxamide

CI

Step υ In the same manner as in Example 3, from the reference compound = 66g), the yellow (four) substance was called 2s, 3R) group) + minus -2m each bite] toluene (2.00 g). U II, step 2) In the same manner as in Example 13, 5_[(2s, 3r)-b (5-chloro) was obtained as a light brown solid from the compound 5 obtained in step i (2.00 g). +Cyano-2-fluorophenyl)-3-carbyl-2~methyl scale bite_3_yl> than bite a 2-ethyl citrate (1. 03 g). iStep 3) In the same manner as in Example 16, 5 [[2S, 3R), K5-chloro + cyano] 510 538 244 201114741 was obtained from the 5 (3 〇〇 mg) obtained in Step 2. 3-hydroxy-2-mercaptopyrrolidin-3-yl]pyridine-2-carboxylic acid' and the title compound was obtained as colorless crystals from the compound (H.sub. 60 mg). 'H-NMR (DMS0-d6) (5: 1.05 (3H, d), 2. 15-2. 25(1H, m), 2. 36-2. 48(1H, m), 3. 41-3 58(1H, m), 3. 86-4. 04(1H, m), 4. 19(1H, q), 5.84C1H, s), 7.04(1H, d), 7. 63(1H, brs ), 7. 77(1H, d), 8. 03(1H, d), 8. 08-8. 20(2H, m), 8. 78(1H, d). _ Example 71 5-[( 2S,3R)-l-(5-Chloro-4-cyano-2-fluorophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]-N-mercaptopyridine-2-carboxamidine Amine

The title compound was obtained in the same manner as in Example 70 and Step 3 using the compound obtained in Example 70 and Step 2 and decylamine (2 mol/L THF). ^-NMR mSO-άΟδ : 1.05(3H, d), 2. 13-2. 28(1H, m), 2.38-2.48C1H, m), 2. 82(3H, d), 3.42-3. 57( 1H, in), 3. 88-4. 06(1H, m), 4. 19(1H, q), 5. 83(1H, s), 7. 04(1H, d), 7. 77(1H , d), 8.01C1H, d), 8. 12(1H, dd), 8.71-8.82 (2H, in).

[S] 245 321538 201114741 Example 72 6_[(2S' 3S)-l-(3-Gas-4-cyanophenyl)~3-hydroxy-2-indolylpyrrolidin-3-yl]pyridine- 2-carbamide

(Step 1) In the same manner as in Example 13, the compound (1. 99 g) obtained from Example 66 gave 6-[(2S,3S)-l-(3-chloro-4) as a pale yellow solid. Ethyl cyanophenyl)-3-hydroxy-2-methylpyrrolidinyl-3-yl]pyridine-2-carboxylate (1.73 g). (Step 2) In the same manner as in Example 16, the compound (300 mg) obtained from the step 1 obtained chlorocyanophenyl)_3-hydroxy-2-methylindole π _ _ _ yl pyridine-2 The title compound (105 mg) was obtained as a colorless crystals of crystals from the title compound. —!H-NMR (DMS0-de) (5: 1.17(3H, d), 2.23-2.39(1H, m), 2.43-2. 56(1H,ro), 3. 19-3. 31(1H, m), 3. 56-3. 68(1H, m) 4.29(1H, q), 5.99(1H, s), 6.69(1H, dd), 6.80(1H, d), 7. 54-7. 63 (2H,m), 7. 76-7. 84(2H,m), 7. 88~7·94(1Η, m乂7. 95-8. 05(1H,m). Example 73 6~[ (2S,3S)-l-(3-Chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyrrolidin-3-yl]-N-methylpyridine_2-formamide 321538 246 201114741

N, CH3

Use example 72, steps! The obtained compound and methylamine (2m〇1/L THF solution) as the starting (four), and the real blue? 2. The title compound is obtained in the same manner as in step 2. 1H-face (DMS〇-d6) m8(3H,d), 2.24_2·38(1Η,m), 2.45 2. d7(1H, m), 2. 69(3H, d), 3. 15-3.31 (1H, m) 3.57-3.70UH, n〇' 4.28(1h,q),6 〇i(ih,s),6 7〇(汛dd), 6.84(1H, d), 7.63C1H, d), 7.80(1H, dd), 7. 90(1H, dd), 8.0K1H, t), 8.25C1H, q). Example 74 Hydroxy-2-methylpyrrole 5 [(2S,3R)-l-( 4-cyano-3-fluorophenyl-3-yl]pyridin-2-decylamine

F

(Step 1) In the same manner as in Example 3, 3-benzyl-3-methylpyrrole (2.42 g) was used.疋 基 : : : : : : : : : ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( [(2S,3R)-l-(4-Cyano-3-fluorophenyl)-3-hydroxy-2-methylpyrrolidinyl-3-yl]pyridine-2-carboxylic acid ethyl ester (1.66 g) 〇 (Step 3) In the same manner as in Example 16, the compound (330 mg) obtained from the step 2 was obtained as 5-[(2S,3 s s s s s s s s s The title compound (195 mg) was obtained as colorless crystals from the compound and the title compound (163 mg). -NMR (DMSO-de)^ : 1. 19(3H, d), 2.26-2.47(2H, m), 3. 15-3.29(1H, m), 3. 55-3. 68(1H, m) , 4. 13(1H, q), 6.00 (1H, s), 6. 58C1H, dd), 6.65(1H, dd), 7. 50-7. 66(2H, m). 7. 92-8. 04(2H, m), 8. 10(1H, brs), 8. 56(1H, s) Example 75 5-[(2S'3R)-l-(5-chloro-4-cyano-2- Nonylphenyl)_3_hydroxymethylpyrrolidin-3-yl]pyridin-2-decylamine

CI

(Step 1) 4-[(2),·3_(6-bromopyridine-3-yl) was obtained as a brown oil from the compound (0. 85 g) obtained from Reference 5 in the same manner as in Example 12. _3_Hydroxy-2-methylpyrrolidinyl-2-chloro-4-methylbenzonitrile (0.78 g). 'A (Step 2) was obtained in the same manner as in Example 13 from the 321538 248 201114741 compound (0.78 g) obtained in the step i to obtain a chloro-4-cyano-2-yl group as a light brown solid. Phenyl phenyl)-3-mono-yl-2-methylindole-3-yl]-pyridin-2-carboxylic acid ethyl ester (0.39 g). (Step 3) In the same manner as in Example 16, the compound (160 mg) obtained from the step 2 obtained 5-[(2S,3R)]n4_yloxy-2-methylphenyl)-3- The title compound (86 mg) was obtained as colorless crystals from the title compound. ® H-NMR (DMS0-de) (5 : 0.89 (3H, d), 2. 05-2. 15(1H, m), 2. 26(3H, s), 2. 39-2. 47(1H , m), 3. 22-3. 31 (1H, m), 3.97-4.18(2H, m), 5. 67(1H, s), 7.03C1H, s), 7.59(1h! s), 7.64( 1H, brs), 8.04(1H, d), 8. 11(1H, brs), 8.19 OH, dd), 8.87C1H, d). Example 76 5-[(2S,3R)-1 -(5- Chloro-4-cyano-2-methylphenyl)_3_hydroxy-2-methylcarboxyryl-3-yl]methylpyridine-2-monoamine α

The title compound was obtained in the same manner as in Example π, Step 3, using the compound obtained in Example 75 and Step 2, and methylamine (2 m / / / THF / THF) as starting materials. 249 321538 201114741 W-NMR (MS〇-d6) (5: 0·90 (3Η, d), 2.05-2. 15(1H,m), 2.26(3H, s), 2. 39-2. 48( 1H, m), 2. 83(3H, d), 3.20-3.3K1H, m), 3. 98-4. 17(2H, m), 5. 67(1H, s) 7 03(1H s), 7.59(1H, s), 8.03(1H, d), 8.20(1H, dd), 8.76(1H q), 8.87(1H, d). Example 77 4-{(2S, 3R)-3-hydroxy- 2-methyl-3-[6-(1,3,4-nordinary dis-2-yl)

B is 唆-3-yl]0 is more than 0--1 -yl-2-(trifluoromethyl)benzoquinone

a mixture of the compound (213 mg), formazan (82 mg), DMT-MM (379 mg), THF (4 ml) and isopropyl alcohol (4 ml) obtained in Example 31 at room temperature 6 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was dissolved in THF (10 ml), triethylamine (0.76 ml) and toluenesulfonium chloride (0. 52 g) were added, and the mixture was stirred at 70 ° C for 4 hours. The reaction mixture was diluted with water 250 321538 201114741 and ethyl acetate. The organic layer was separated, washed with brine sat. The residue obtained was purified by silica gel column chromatography (yield: hexanes) to give the title compound (102 mg) as a colorless solid. ^-NMRCCDCh)^ : 1.40(3H, d), 2. 41-2. 65(3H, m), 3.36-3.47(1Η, m), 3. 74-3. 87(1Η, m), 4. 11-4. 24(1Η, m), 6.76 (1Η, dd), 6.9K1H, d), 7. 66(1H, d), 8. 00(1H, dd), 8.29 (1H, dd), 8.58 C1H, s), 8.79 (1H, dd). Example 78 5-{5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indenyl Pyrrole σ--3-yl]0 is more than bite _2-kib 1,3, 4-曙2 0 sitting-2 -曱 guess

The compound obtained in Example 80 (86 mg), trifluoroacetic anhydride (0.042 ml) and triethylamine (0.056 ml) were dissolved in THF (5 ml), and the mixture was stirred at room 251 321538 f S] 201114741 hour. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogencarbonate. The organic layer was separated and dried over anhydrous sodium sulfate and solvent was evaporated. The residue was purified by EtOAc EtOAc (EtOAc) 'H-NMR (CDCh)^: 1.37C3H, d), 2.38(1H, s), 2.39-2.62 (2H, m), 3. 29-3. 41(1H, ra), 3. 68-3. 79(1H, m), 4. 10(1H, q), 6. 53(1H, dd), 6.66(1H, d), 7.49(1H, d), 7. 99(1H, dd), 8.3K1H , d), 8.83C1H, d). 0 Example 79 2-Chloro-4-[(2S, 3R)-3-hydroxy-2-indolyl-3-{6-[5-(trifluoromethyl) -1,3,4-oxadiazol-2-yl]pyridin-3-yl}pyrrolidin-1-yl]benzonitrile

N The compound obtained in Example 16 (211 mg), tributyl phthalate (0.20 g), DMT-MMC 0.41 g), THF (5 ml) and isopropyl alcohol (5 m) were stirred at room temperature. 1) The mixture is for 24 hours. The reaction mixture was diluted with water and ethyl acetate [s] 252 321538 201114741. The organic layer was separated, washed with saturated brine, dried over anhydrous The residue was dissolved in ethyl acetate (2 ml), EtOAc (EtOAc) The residue was suspended in ethyl acetate (1 mL), EtOAc (EtOAc) (EtOAc) The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with brine sat. The residue was purified to give the title compound (98 mg). 'H-NMRCCDCh)^ : 1.37(3H, d), 2. 38-2. 47(2H, m), 2.49-2.62(1H, m), 3.28-3.40C1H, m), 3.66-3. 78( 1H, m), 4. 03-4. 16(1H, m), 6.52(1H, dd), 6. 66(1H, d), 7.48(1H, d), 8. 00(1H, dd), 8.3K1H, dd), 8.81 (1H, dd). Example 80 5M5_[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy- 2-indolylpyrrolidine 3-mono]pyridin-2-yl}-1,3,4-oxadiazol-2-ylamine 321538 253 201114741

Using the compound obtained in Example 16 and 2-mercapto-2-oxoethoxyacetamide as a starting material, the title compound was obtained in the same manner as in Example 77. ^-NMR (DMS0-de) 5 : 1. 19(3H, d), 2. 33-2.46(2H, m), 3. 25-3. 38(1H, m), 3. 59-3. 72 (1H, m), 4. 13-4. 25(1H, m), 6.09C1H, s), 6. 67-6. 77(1H, m), 6.85(1H, s)7.63(1H, d), 8.07C1H, d), 8. 19-8. 34C2H, m), 8.70(1H, s), 8.83(1H, s). Example 81 5-[(2S,3R)-l-(4 -Cyano-3-fluorophenyl)-3-hydroxy-2-methyloxaridin-3-yl]pyridine-2-indolecarbonitrile 254 321538 201114741

N

Using the compound obtained in Example 74 as a starting material, the title compound was obtained in the same manner as Example 113. Ή-NMR (CDCh) 5 : 1.34 (3H, d), 2. 34-2. 44( 1H, m), 2.47-2.57(2H, m), 3. 26-3. 38(1H, ra), 3. 66-3. 75(1H, m&gt;, 4.03 (1H, d), 6.30-6.43C2H, m), 7.42(1H, dd, ), 7. 69(1H, d), 7.85(1H, dd ), 8. 77(1H, d). #Example 82 4 -{(2S,3R)-3-transyl-2-methyl-3-[6-(5-methyl-1, 3,4_唁2° sitting-2-yl) σΛσ定-3-yl]〇 0 0 each bite-1-yl丨-2-(trifluoromethyl)benzene 255 321538 201114741

NIN

Using the compound obtained in Example 31 and acetonitrile as a starting material, the title compound was obtained in the same manner as in Example 77. H-NMR (CDC13) (5: 1.38 (3H, d), 2. 39-2. 63 (3H, m), 2.65 (3H, s), 3. 34-3.43 (lH, m), 3. 67 -3. 84(1H, m), 4.11-4. 19(1H, m), 6.74C1H, dd), 6.89C1H, d), 7. 64(1H, d), 7. 97(1H, dd) , 8. 23(1H, dd), 8. 71(1H, dd). Example 83 2-fluoro-4-{(23,31〇-3-hydroxy-2-indolyl-3-[6-( 1,3,4-oxadiazol-2-yl)pyridin-3-yl]pyrrolidinyl-l-yl}benzonitrile 256 538538 201114741

Using the compound obtained in Example 104 and toluene as a starting material, the title compound was obtained in the same manner as in Example 59. ]H-NMR (CDCh) 5 : 1.37(3H, d), 2. 38-2. 47(2H, m), 2.49-2.60C1H, in), 3. 26-3.40(1H, m), 3. 66-3. 75(1H, m), 4. 06-4. 13(1H, m), 6. 31-6.45(2H, m), 7.43(1H, dd), # 7.95(1H, dd), 8. 25-8. 29(1H, m), 8.56(1H, s), 8. 78(1H, d). Example 84 4-[(2S, 3R)-3-(6-bromopyridine-3 -yl)-3-hydroxy-2-methylpyrrolidin-1-yl]_2-methoxybenzonitrile 257 321538 201114741

Using the compound obtained in Reference Example 44 as a starting material, the title compound was obtained in the same manner as in Example 12. !H-NMR (CDC13) (5: 1.33 (3H, d), 2.24 (1H, s), 2.27-2.37 (1H, m), 2.41-2. 54(1H, m), 3.24-3. 33( 1H, in), 3.63-3. 73(1H, in), 3. 89(3H, s), 4. 02(1H, q), 6. 02(1H, d), 6. 19(1H, dd ), 7. 37(1H, d), 7.43-7.49(1H, m), 7.54- 7.61(1H, m), 8.41C1H, dd). Example 85 4-[(2S,3R)-3 -[6-(methylaminocarbonylbipyridin-3-yl)-3-hydroxy-2-mercaptopyrrolidin-1-yl]-2-methoxybenzonitrile 258 321538 201114741 〇

y &amp; (Step 1) Using the compound obtained in Example 84 (5973 mg) as a starting material, 5-[(2S, cyano-3- methoxyphenyl) was obtained in the same manner as in Example 13. _3_Hydroxy-2-methylpyrrolidine_3_yl]pyridine-2-carbonyl acid ethyl ester (390. 〇mg). (Step 2) 5-[(2S,3R)-l-(4-cyano-3-indolyl phthalic acid) was obtained in the same manner as in Example 16 using the compound obtained in the step ( (384 4 mg). 3-)-3-yl-2-mercaptopyrrolidine-3-yl]pyridine-2-carboxylic acid (333. 5 mg). (Step 3) The title compound (40.4 mg) was obtained. ^-NMRCCDCh)^ :l.36(3H, d), 2. 30-2. 41 (1H, m), 2.46- 2. 56(2H' m),3· 〇2(3H,d),3 25-3. 34(1H,m),3.63-3.76 (1H, m), 3.89(3H, s)5 4. 05-4. 13(1H, m), 6. 04(1H, d), 6. 21(1H, dd), 7. 38(1H, d), 7. 86(1H, dd), 7. 96(1H, s), 8· 07-8. 13(1H,m),8 · 53(1H,d). 259 321538 201114741 Example 86 4-{(2S,3R)-3-hydroxy-2-methyl-3-[6-(1,3,4-oxadiazole-2- Base) -3_基]0 比洛°定_1~基}_2_曱oxybenzoquinone

The title compound was obtained in the same manner as in Example 59, using the compound obtained in Example 85 and Step 2 2. 62(1H, m), 2.65(1H, s), 3. 27-3. 39(1H, m), 3.66-3.78 (1H, m), 3.90(3H, s), 4. 06-4 .08(1H, m), 6. 05(1H, d), 6.22C1H, dd), 7. 38(1H, d), 7. 96(1H, dd), 8.24C1H, dd), 8.56C1H, s), 8.79 (1H, dd). Example 87 4-{(2S,3R)-3-[6-(5-ethyl-1,3,4-oxadiazol-2-yl). Bispin-3-yl]-3-hydroxy-2-methyl D-pyridyl-l-yl}-2-(trifluoromethyl)benzonitrile 260 321538 201114741 F p

CH3

Mixture of acid-repellent ml), WSC (43), Chi (10) mg) and DMF ([separate the organic layer, and release the reaction mixture with saturated water and red (iv). Dry and concentrate (hydroacetic acid ethyl acetate solution (3 ml _), add "1 1 chlorinated W)" and stir the mixture at room temperature for 1 hour and shrink. Dissolve the residue in Na (1Gml), add propylene Chlorine (0. kiss ml) and ml) 'and the mixture was stirred at room temperature for 2 hours. Green plus 曱 4 醯 (176 mg), ^ at 8 (rc lin mixture 2 () hours. The monohydrate (7 mg) was added to the reaction mixture, and the mixture was stirred at 10 ° C for 2 M. The organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , d), 1.45(3H, t), 2. 39(1h, s), 2.39-2.62(2H,m), 2.99(2H,q), 3. 31—3.46C1H,m), 261 321538 201114741 3 69-3. 84(1H, m), 4. 09-4. 23(1H, in), 6. 69-6. 79(1H, m), 6. 86-6. 91(1H, m), 7.64(1H, d), 7. 97(1H, dd), 8.25 (1H, d), 8.72(1H, d). Example 88 4_{(2S, 3R)-3-hydroxy-2-methyl-3-[6-(5-mercapto-1,3, 4_ Oxazol-2-yl)pyridin-3-yl]pyrrolidin-1-yl-2-phenyloxybenzonitrile

The title compound was obtained in the same manner as in Example 59, using the compound obtained in Example 85 and Step 2 and acetonitrile as a starting material. φ ^-NMR (CDCh) ά : 1. 37(3H, d), 2. 33-2. 47(2Η, m), 2. 48-2. 59(1Η, m), 2. 65(3Η, s), 3. 24-3. 41 (1Η, m), 3.61-3.79 (1H, m), 3. 90(3H, s), 4. 08-4. 16(1H, m), 6.05(1H , d), 6.22(1H, dd), 7. 38(1H, d), 7. 95(1H, dd), 8.2K1H, d), 8.73(1H, d). Example 89 5-[(2S ,3R)-l-(5-chloro-4-cyano-2-fluorophenyl)-3-carbyl-2-hydrazinopyrrolidin-3-yl]pyridine-2-carbonitrile 262 321538 201114741

Cl

Using the compound obtained in Example 70 as a starting material, the title compound was obtained in the same manner as Example 113. _ !H-NMR CCDCh) (5 : 1.20(3H, d), 2. 30-2. 38(2H, m), 2.42-2. 53(1H, m), 3. 47-3. 57(1H , m), 3. 99-4. 11 (1H, m), 4. 11-4. 20(1H, m), 6.72(1H, d), 7.27(1H, d), 7. 74(1H, d), 8. 02 (1H, dd), 8.89 (1H, d). Example 90 2-chloro-4-{(2S, 3R)-3-hydroxy-3-[6-(3-hydroxy-3) -mercapto-1-yn-1-yl-pyridin-3-yl]-2-indolylpyrrolidine-l-yl}benzonitrile

263 321538 201114741 The compound obtained in Example 12 (2q〇. 3 mg), 2-methylbut-3-yn-2-ol (0.050 ml), diisopropylamine (0.16 ml), A mixture of chlorobis(triphenylphosphine)palladium (35 mg), iron iodide (1) (9.5 mg) and THF (3 ml) was used for 20 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with brine sat. The residue was purified by EtOAc EtOAc (EtOAc) ^-NMR (CDCh)^ : 1.32C3H, d), 1.62(6H, s), 2.29-2.39 # (1H, m), 2.41-2.54(1H, m), 2. 64(1H, s), 2 72(1H, s), 3. 20-3. 30(1H, m)3. 58-3. 71(1H, in), 3. 96-4. 09(1H, m), 6.49(1H, Dd), 6.62(1H, d), 7. 38(1H, d), 7.45(1H, d), 7. 64(1H, dd), 8.59(1H, s). Example 91 5-[(2S , 310-1-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]-N-(2-morpholin-4-ylethyl)pyridine-2 - methotrexate 264 321538 201114741

Using the compound obtained in Example 16 and 2-morpholin-4-ylethylamine as a starting material, the title compound was obtained in the same manner as in Example 45. ^-NMR (CDCh) ¢5 : 1.35(3H, d), 2. 35-2. 45(1H, m), 2.46-2. 54(6H, m), 2. 60(2H, t), 3 27-3. 36(1H, m), 3. 58(2H, q), 3. 64-3. 77(5H, m), 4. 06-4. 18C1H, m), 6. 51(1H , dd), 6. 64(1H, d), 7.48C1H, d), 7. 86(1H, dd), 8. 13(1H, dd), 8. 26(1H, s), 8. 60( 1H, dd). Example 92 {5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indenyl. Bilobyl-3-yl]pyridin-2-yl}amine decanoate 265 321538 201114741

The compound obtained in Example 16 (0.67 g), diphenylphosphoryl azide (〇. 49 ml), triethylamine (0.39 ml) and 2-methyl- were stirred at 80 °C. A mixture of 2-propanol (6 ml) was used for 14 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous The residue was purified by EtOAc EtOAc (EtOAc) φ H_NMR (CDCl〇(5 : 1. 32(3H,d), 1. 52(9H,s), 2·21(1H, s), 2.31-2.47(2H, m), 3. 20-3. 30(1H, m), 3. 60-3. 69(1H, m), 4.02(1H, q), 6.48(1H, dd), 6.61(1H, d), 7.45(1H, d), 7.52( 1H, S), 7. 67(1H, dd), 7.92(1H, d), 8.25(1H d). 'Example 93 2-Chloro-4-{(2S,3R)_3-M-methyl- 3 Lu (2_ oxaoxy^ 3 -% oxazolidine-3-yl)pyridin-3-yl]pyrrolidinyl}benzonitrile 321538 266 201114741

Using the compound obtained in Example 12 and 1,3-oxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 112. JH-NMR (CDC13) (5: 1.34 (3H, d), 2. 27 (1H, s), 2.29-2.40 (1H, m), 2.42-2. 55(1H, m), 3. 18-3 31(1H, m), 3.64(1H, ddd), 4. 05(1H, q), 4. 20-4. 28(2H, m), 4. 46-4. 53(2H, m), 6.49C1H, dd), 6.62(1H, d), 7. 46(1H, d), 7. 79(1H, dd), 8. 19(1H, dd), 8. 25-8. 28(1H, m). Example 94 N-{5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylindyrridin-3-yl]pyridine- 2-yl}acetamide 267 321538 201114741

A mixture of the compound obtained in Example 92 (77.6 mg) and trifluoroacetic acid (1.5 ml) was stirred at room temperature for one hour. Trifluoroacetic acid was evaporated under reduced pressure, pyridine (2 ml) and ethyl acetate (0.0171 ml). The reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate. The title compound (29.2 mg) was obtained as a colorless powder. H-NMR (CDCh)^: l.33(3H, d), 2. 21(4H, s), 2.28-2.53 (2H, m), 3.22-3. 31(ih, m)5 3.61-3.69 ( 1H, in), 3.98- 4. 07(1H, m), 6. 49(1h, dd), 6. 62(1H, d), 7.46(1H, d), 7. 72(1H, dd), 7.96(1H, s), 8. 15(1H, s), 8.27(1H, d). Example 9 5 2-Chloro-4-[(2S' 3R)~3, Hydroxy_3_{6_[(2S ,3S)_3_hydroxyl_2_mercapto-5-sideoxy oxime 咬 丨 丨 基 基 基 ] _ _ _ 基 基 _ 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268 268

The compound obtained in Example 12 (177. 0 mg) and (4S, 5S)-4-((t-butyl(dimethyl)decyl)oxyb-5-methylpyrrolidine-2 The ketone (14.1 ml) was used as a starting material, and a pale yellow oil was obtained in the same manner as in Example 112. The obtained oil was dissolved in THF (1 ml), TBAF (1 ml, 1 The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and ethyl acetate. The residue obtained was purified by EtOAc (EtOAc-EtOAc) (dHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH d), 1. 90(1H, s), 2. 09-2. 19(1H, m), 2. 29-2. 40(1H, m), 2. 41-2. 54(1H, m) , 2. 67-2. 88(2H, m), 3. 20-3. 29(1H, in), 3. 60- 3. 69(1H, m), 4. 03-4. 12(1H, m), 4. 51-4. 67(1H, m), 4. 79(1H, q), 6.49(1H, dd), 6. 62C1H, d), 7. 46(1H, d), 7.77( 1H, dd), 8. 17(1H, d), 8. 31-8. 33(1H, m). Example 96 2-Chloro-4-[(2S,3R)-3-hydroxy-3-{ 6-[(lE) -3-hydroxy-3-methylbutyl 269 321538 201114741 -1-en-1-yl]σ is more than -3-yl}_2-methyl pi. D-i-yl]benzonitrile

咜c CH. The compound obtained in Example 12 (135. 4 mg), 2-mercaptobut-3-en-2-ol (0.045 ml), tris(o-tolyl) was stirred at 80 °C. Mixture of phosphine (21 mg), palladium acetate (38 mg), triethylamine (0.040 ml) and DMF (3 ral) for 3 hours, add 2-mercaptobut-3-en-2-ol (0.45 ml ), and the mixture was given 20 hours at 10 0 C. The reaction and the θ compound were diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous The residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane). _ W-NMR (CDCIOS: 1.33(3H,d), 1.43(6H,s),2·〇7(1η s), 2.30-2.4U2H,m),2.43-2.51(lH,m), 3.20~3.35 (1h m), 3.59-3.69C1H, m), 4. 02-4. 11 (1H, m), 6.48(ih, dd) 6.56-6.74(2H, m), 6.88(1H, d), 7.23- 7.28 (iH, 7·43-7.48 (1Η, m), 7. 66 (1H, dd), 8. 54 (1H, d). 'Example 97 5-[(2S,3R)-l-(3 -chloro-4-cyanophenyl)-3-hydroxy-2-methyl%habit-3-yl]-N-(5-mercaptoisoxazol-3-yl)pyridin-2-ylamine 321538 270 201114741 α

〇

Ch3 The title compound was obtained in the same manner as in Example 45, using the compound obtained from the compound of Example 16 and 3-amino--5- decyl isoindole as a starting material. ^-MR(CKh)d : 1.37(3H, d)5 2. 37^2. 47(4H, m), 2.48-2.6K1H, m), 3.07(1H, s), 3. 29-3. 38 (1H, m), 3.68-3.77 (1H, m), 4. 02-4. 12(1H, m), 6.53(1H, dd), 6. 66(1H, d), 6.86C1H, d), 7. 49(1H, d), 7. 83(1H, dd), 8.2K1H, d), 8.9K1H, d), 10.44(1H, s). Example 98 5_[ (2S, 3R)-1- (3-Chloro-4-nitrophenyl)-3-lightyl~2-indenyl ratio ° σ -3--3-]] Ν-[2-(methylamino)-2- oxo Ethyl&gt; than bite-2-carboxamide

N

N

D

〇 CH.

[S] 271 321538 201114741 The title compound was obtained in the same manner as in Example 45, using the compound obtained in Example 16 and N-mercaptoamineamine as the starting material. H-NMR (CDCh) (5: 1.35C3H, d), 2. 31-2. 45(1H, m), 2.46-2.60C1H, s), 2.83C3H, d), 2.93C1H, s), 3 22- 3. 36(1H, m), 3. 62-3. 76(1H, m), 4. 03-4. 11 (3H, m), 6. 13 (1H, s), 6.53C1H, s), 6.64 (1H, d), 7.47 (1H, d), 7.85 (1H, dd), 8.08 (1H, d), 8.53 (1H, s), 8. 61 (1H, d). Example 99 Weng 5-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyrrolidin-3-yl]-N-(2-hydroxy-2-indole Propyl-2-pyridineamine

Using the compound 16 obtained in the Example and 1-amino-2-methyl-2-propanol as a starting material, the title compound was obtained in the same manner as in Example 45. ^-NMR (CDCh) (5: 1.28C6H, s), 1.35(3H, d), 2.32-2.41 (1H, m), 2. 47-2. 58(2H, m), 2. 94(1H, s), 3. 22-3. 32(1H, m), 3.46(2H, d), 3. 62-3. 74(1H, ra), 4. 04-4. 16(1H, in), 6.5 K1H, dd), 6.64(1H, d), 7. 47(1H, d), 7. 86(1H, dd), 272 321538 201114741 8. 02-8. 07(1H, m), 8. 35( 1H, s), 8. 52(1H, d). Example 100 5-[(2S, 310-1-(3-chloro-4-cyanophenyl)-3-hydroxy-2-indolylpyrrolidine- 3-yl]-N-(2-hydroxy-2-mercaptopropyl)pyridin-2-indoleamine hydrochloride

The compound obtained in Example 99 (51.5 mg) was dissolved in ethyl acetate (1 m1), ethylamine ethyl acetate (3 m1) was added, and the mixture was stirred at room temperature for 30 minutes. And concentrated. The residue was suspended in diethyl ether and filtered to afford title compound (34.6 g). ^-NMR (DMS0-d6) (5: 1. 09(6H, s), 1. 18(3H, d), 2.25-φ 2.47C2H, ra), 3. 18-3. 34(3H, m) , 3.56-3. 72(1H, s), 4. 10-4. 23(1H, s), 6. 70(1H, dd), 6.84(1H, d), 7. 63(1H, d), 7. 97-8. 05(2H, m), 8.47(1H, s), 8.62(1H, s). Example 101 5-[(2S,3R)-l-(3-chloro-4-cyanobenzene ))-3-yl-yl-2-methyl 0 pirazol-3-yl]-Nl,3, 4-17-soxadiazol-2-ylpyridin-2-ylamine 273 321538 201114741

Using the compound obtained in Example 16 and 2-amino-1,3,4-thiadiazine as a starting material', the title compound was obtained in the same manner as in Example 45. !H-NMR (CDCh) (5: 1.43 (3H, d), 2. 37-2. 55 (1H, m), 2.55-2.72 (1H, m), 3.29-3. 51 (1H, m), 3. 69-3. 90C1H, m), 4. 03-4. 15(1H, in), 4. 49(1H, s), 6.56(1H, dd), 6. 69(1H, d), 7.50 (1H, d), 7.78C1H, dd), 8.26(1H, d), 8. 91(1H, s), 9.47C1H, s), 11.7K1H, s). Example 102 5- [ (2S, 3R )-1-(4-cyano-3-fluorophenyl)-3-transyl-2-meryl σ ratio 17 each 0--3-yl]0 ratio bitten-2-lower acid methyl ester

NC F

C〇2M6 274 321538 201114741 The compound obtained in Reference Example 52 (13.86 g) was dissolved in methanol (60 ml), 10% palladium carbon (0.50 g) was added, and the mixture was stirred at room temperature under a helium atmosphere for 3 hours. The insoluble material was filtered off, and the filtrate was concentrated. The residue obtained was dissolved in DMSO (120 ml), 2,4-difluorobenzonitrile (7.29) and lithium carbonate (6. 63 g) were added, and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was diluted with water and ethyl acetate. After separation of the organic layer, it was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (11.04 g). ^-NMR (CDCh) 5 : 1.35(3H, d), 2. 33-2. 43(1H, m), 2.47 (1H, s), 2. 49-2. 58(1H, m), 3.28( 1H, dt), 3. 61-3. 72(1H, m), 4. 00(3H, s), 4. 01-4. 10(1H, m), 6. 30-6. 43(2H, m), 7. 41(1H, dd), 7. 88(1H, dd), 8. 10-8. 15(1H, m), 8.71-8.75(1H, in). Example 103 I 5-[ (2S, 3R)-l-(2-Cyano-5-fluorophenyl)-3-carbo-2-indenyl oxime-3-yl]pyridine-2-carboxylic acid decyl ester

The title compound (1.34 g) was obtained as a pale yellow powder. 275 321538 201114741 ^-NMR (CDCh)d : 1.20(3H, d), 2. 31-2.4〇(1H 2.55(1H, m), 2.75(1H,s), 3.49-3.62(lH 2·42- , Hi), 4 n〇rqn s), 4. 13(1H,q), 4.35(1H, td),6·45(1h , , , as), 6 57fi h ddd), 7.5K1H, dd) , 8.06C1H, dd), 8. l6(lH 5 πh ' d), 8. 89 Example 104 5-[ (2S,3R)-l-(4-Cyano-3-fluorophenyl)-3_hydroxy-3 -yl]pyridine-2-carboxylic acid T-based tonic bite

Co2h The compound obtained in Example 102 (1 ().78 ml) and ethanol (10 ml) were added 'lmol/L cesium hydroxide_ml), and the solution was applied to the official, the field, and the chemical solution (6 to the composition). The mixture was incubated for 1 hour. Add l_/LBa acid (6|ml), and evaporate the organic solvent under reduced slabs. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -IVMR (DMS0-d6)5 : 1 3.19-3.32C1H ,) 3573' 2·31-2·45^ ^ nqnw , ' , . 3·67〇Η, m), 4.08-4. 19C1H, m): S, 6*55~6-68(2fl, m), 7.54-7.61(1H, m), 7.93-8.04C2H,m), 8.69(1H,dd). Example 105 321538 276 201114741 5-[( 2S,3R)-l-(4-Cyanido-3-fluorophenyl)-3-hydroxy-2-indenyl. Biropyridin-3-yl]-N-indenyl ratio bite-2_nonylamine H3CU'k

The compound obtained in Example 104 (2.82 g), decylamine (2 mol/L THF solution, 12.4 ml), WSC (1. 90 g), HOBt (1.34 g), and DMF (40) were stirred at room temperature. A mixture of ml) for 14 hours. The reaction mixture was diluted with water and ethyl acetate. After the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) The crystals obtained and the title compound (1. 00 g) obtained from the mixture were recrystallized to give the title compound (2. 67 g).

Melting point 196 to 197 ° C 2.62 (1H, m), 3.01C3H, d), 3. l〇(1H, s)&gt; 3. l8-3. 31 (1H, m), 3. 60-3. 72C1H, m), 4. 05(1H, q), 6. 32(1H dd) 6 39 UH,dd),7.40OH,dd),7·79(1Η,_,7|7 99(2h m) , 8.45-8.49 (lH, m). '321538 277 201114741 Example 106 5-[(2S,3R)-l-(3-Gas-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidine -3-yl]-N_(4-nitro-1Η-0 ratio ° sitting-3-yl) 0 to 0 _2-anthraquinone

Using the compound obtained in Example 16 and 3-amino-4-cyanopyrazole as a starting material, the title compound was obtained in the same manner as in Example 45. ^-NMR (DMSO-de)^ : 1. 20(3H, d), 2. 29-2.48(2H, in), 3. 18-3. 38(1H, m), 3. 58-3. 71 (1H, m), 4. 14-4. 26(1H, m), 6.09C1H, s), 6.72C1H, dd), 6.87(1H, d), 7.64(1H, d), 8. 02-8 15(2H, in), 8. 53(1H, s), 8.66(1H, d), 10.84(1H, ® s), 13. 54(1H, s). Example 107 N-Terylene -5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-hydrazinopyrrolidin-3-yl]pyridine-2-decylamine

278 321538 201114741 The title compound was obtained in the same manner as in Example 45, using the compound obtained in Example 16 and the butylamine as the starting material. !H-NMR (CDCh)^ : 1.35(3H, d), 1.47(9H, s), 2.31-2.41 (1H, m) 2.45-2.59(lH, m), 2.75(1H, s), 3.26(1H , dt), 3.67(1H, ddd), 4. 07(1H, q), 6.49(1H, dd), 6. 63(1H, d), 7. 47(1H, d), 7.87C2H, dd) , 8. 05(1H, dd), 8. 43-8. 46(1H, m). Example 108 ^^1^-T-butyl-5-[(28,31〇-1-(4- Cyan-3-fluorophenyl)-3-yl-2-methylpyrrolidin-3-yl]pyridine-2-carboxamide

F

Using the compound obtained in Example 104 and a butylamine as a starting material, the title compound was obtained in the same manner as in Example 45. ^-NMR (CDCh) 5 : 1.35(3H, d), 1.47(9H, s), 2.31-2.40 (1H, m), 2.47-2. 58(1H, m), 2.74(1H, s), 3 .26C1H, dt), 3. 66(1H, ddd), 4. 05(1H, q), 6. 29-6. 41 (2H, m), 7.4K1H, dd), 7. 84-7. 93 (2H, in), 8. 05(1H, dd), 8. 44-8. 47(1H, m). Example 109 [s] 279 321538 201114741

N_(2_Cylic acid 2-methylpropyl)-5-[(23,31〇-1-(4-cyano-3-fluorophenyl)-3-yl-2-methylπpyrrole) Acridine_3_yl]pyridine_2_formamide F

Using the compound obtained in Example 1 to 4 and hydrazine-amino-2-methyl-2-propanol as a starting material, a cult compound was obtained in the same manner as in Example 45! H-NMR (CDCh) 5 : 1.28(6H, s), 1. 36(3H, d) 9 〇〇, 1TT , Λ 28-2 43⁄4 (1H, m), 2.48-2.59C2H, m), 3. 08(1H, s), 3.26 (iH.

3.45(2H, d), 3. 66(1H,ddd), 4. 06(1H,q),6 3〇—6')), m)' 7·41(1Η,dd),7.85(1H, Dd), 8.01 (1H, dd) 8. 3 (2H's), 8. 51 (1H, dd)., 35〇H&gt; Example 110 [ ({5-[ (2S,3R)-l-( 3-chloro-4-cyanophenyl)-3~carbyl~2rrolidin-3-yl]pyridin-2-yl}carbonyl)amino]methylhh group ratio, sitting ~3 monocarboxylic acid 321538 280 201114741

Using the compound obtained in Example 16 and the compound obtained in Reference Example 47 as a starting material, the title compound was obtained in the same manner as in Example 45. !H-NMR (CDCh) (5: 1.34 (3H, d), 1.39 (3H, t), 2.27-2.39 (1H, m), 2.48-2.60 (1H, m), 2.88 (1H, s), 2 96(1H, s), 3. 17-3. 30(1H, m), 3. 59-3. 69(1H, id), 3. 99-4. U(1H, m), 4. 42C2H , q), 4. 72(2H, d), 6. 44-6. 51 (1H, m), 6.60(1H, d), 7. 39-7.45C1H, m), 7.68(1H, s), 7.82(1H, dd), φ 7. 97-8. 04(1H, m), 8.49(1H, d), 8.57-8. 65(1H, m). Example 111 2_Chloro_4-[( 2S, 3R)-3-carbyl-3-{6-[4-(l-ylamino-1-methylethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-2- Methyl pyrrolidine-1-yl]benzonitrile 321538 281 201114741

Q

(Step 1) In the same manner as in Example 112, the compound obtained in Example 12 (1.20 g) and ethyl 1H-pyrazole-4-carboxylate (0.51 g) was used as starting material to obtain l-{ 5-[(2S,3R)-i~(3_Chloro_4_cyanophenyl)_3_hydroxy-2-methyl-pyrrolidin-3-yl&gt;pyridin-2-yl}-丨11 - Pyrazole-4-carboxylic acid ethyl ester (852·1 mg). (Step 2) The compound obtained in the step 1 (〇. 2〇g) was dissolved in THF (20 ml), and the oxime (111) and the potassium oxalate (3 m〇1 / L ether) were added at 0 C. Solution; 1. 5 πι 1) 'and disturb the mixture for 1 hour. After further disturbing for 2 hours at room temperature, the reaction mixture was added dropwise to ice water, neutralized with citric acid, and the mixture was diluted with water and ethyl acetate. After separation of the organic layer, it was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)

!H-NMR (CDC13) (5: 1.35(3H, d), 1.61(6H, s)&gt; { 7g(1H s), 2. 29(1H,s), 2.33-2.43C1H,m), 2 56(1H m)' 3. 22-3.35C1H,m),3.61-3.73C1H,m),4·〇3,4 12(1H (10) 6.50C1H,dd),6.64C1H,d),7.46(1H , d), 7 73(1H,d) ' 7. 83-7.96(2H,m), 8.34(1H,dd),8.43(ih,d) ' 321538 282 201114741 Example 112

2-Chloro_4-{(2S,3R)-3,yl_2_ fluorenyl_3_[6_(2_p-oxyl-l-yl)pyridin-3-yl]pyrrolidinyl}benzonitrile The compound obtained in Example 12 (204. 4 mg), 2-pyrrolidone (0.047 ml), hydrazine, Ν'-dimercaptoethylenediamine (〇〇 11 ml), and tripotassium phosphate (〇 .22 g) and copper (I) iodide (10 mg) were suspended in toluene (10 mi) and the mixture was stirred at 80 C for 3 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous The residue obtained was purified by EtOAc EtOAc EtOAc EtOAc

Melting point 171 to 174 ° C !H-NMR (CDCh)^ : 1.33(3H, d), 2. 03-2. 20(2H, m), 2.26 (1H, s), 2. 30-2. 39 (1H, m), 2. 42-2. 53(1H, m), 2. 66(2H, t), 3.20-3.29C1H, m), 3. 63(1H, ddd), 4. 02-4 . 11 (3H, m) 6.48C1H, dd), 6. 62(1H, d), 7. 45(1H, d), 7. 76(1H, dd) B.3K1H, d), 8.37(1H, d). '321538 283 201114741 Example 113 5-[(2S,3R)-l-(4-cyanophenyl)-3-hydroxy-2-indolylpyridin-3-yl]pyridin-2-indole Nitrile

N

N The compound obtained in Example 62 (11. 7 mg) was dissolved in DMF (5 ml), EtOAc (0. 060 ml) and pyridine (0. 113 ml) were added, and the mixture was stirred at room temperature 2 hour. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Melting point 151 to 153 ° C !H-NMR (CDCh) (5 : 1.34 (3H, d), 2. 32-2. 43 (1H, m), 2.45-2.57C2H, m), 3. 26-3 . . . (6H, d) 7. 84(1H, dd), 8.77(1H, d). Example 114 284 321538 201114741 2-Fluoro-4-{(25,3 ft)-3-yl-2-methyl-3-[6 -(5-mercapto-1,34-oxadiazol-2-yl)pyridin-3-yl]pyrrolidin-1 -yl}benzonitrile

The compound obtained in Example 31 (15 3. 0 mg), acetamidine (6.70 mg), MT-MM (249. 0 mg), THF (5 ml) and isopropanol were taken at room temperature. A mixture of (5 ml) for 16 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous The residue obtained was dissolved in THF (15 ml), triethylamine (0.31 ml) and benzenesulfonium chloride (0.26 g) were added, and the mixture was stirred at 70 ° C for 24 hours. The reaction mixture was diluted with water and ethyl acetate. After the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Melting point 186 to 187 ° C 'H-NMR (CDCh) 5 : 1.37 (3H, d), 2.40 (1H, ddd), 2.50-2.6K1H, m), 2. 64-2. 66(4H, m) , 3. 25-3. 37(1H, m), 3.69 (1H, ddd), 4. 05-4. 13(1H, in), 6. 31-6. 44(2H, m), 7.42 (1H , dd), 7. 94(1H, dd), 8.20(1H, dd), 8. 71(1H, d). Example 115 285 321538 201114741 1 -{5-[(2S,3R)-l-( 3-chloro-4-cyanophenyl)-3-hydroxy-2-methylpyrrolidin-3-yl]pyridin-2-yl}-1{{-pyrazole-4-decylamine

(Step 1) The compound obtained in Example 111 'Step 1 (〇. 59 g) was dissolved in THF (2.6 ml) and ethanol (2.6 ml), and lm〇l/L aqueous sodium hydroxide solution was added. (2.6 ml), and the mixture was stirred at room temperature for 3 hours. 1 mol/L hydrochloric acid (2.6 ml) was added, and the reaction mixture was concentrated. The precipitated solid was collected by filtration and washed with diethyl ether to give 1-{5-[(2S,3R)-bromo-cyanocyanophenyl)-3-yl-2-methylpyrrol-3-yl]咐 (bite-2-yl} -1 Η-° than salivary-4-decanoic acid (574. 9 mg). Lu (Step 2) The compound obtained in Step 1 (120. 5 mg) was dissolved in DMF (3 ml) 'Add WSC (65. 4 mg) and HOBt salt (59.1 mg), and mix the mixture for 5 hours. Dilute the reaction mixture with water and ethyl acetate. After separation of the organic layer, wash with saturated brine. The residue was dried over EtOAc EtOAc (EtOAc) )d : 1.19C3H, d), 2.32-2.44(2H, m), 3. 24-3. 31(1H, m), 3.58-3. 70(1H, m), 4. 17(1H, q) , 5.96 ΠΗ, s), 6.70(1H, dd), 6.84C1H, d), 7.22(1H, s), 7.63 321538 286 201114741 (1H,d),7·79(1Η,s), 7. 87- 7. 96(1H,m), 8.00-8. 07(1H, m), 8. 11C1H, d, ), 8.49C1H, d), 9. 09(1H, d). Example 116 l-{5 -[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-3-hydroxy-2-methylindoleidine -3-yl]pyridin-2-S}-N-methyl-1H-pyrazole-4-decylamine α

In the same manner as in Example 45, the title compound was obtained using the compound obtained in Example 115, Step 1 and decylamine (2mol/L THF). 'H-NMR (DMSO-de)^ : 1.19C3H, d), 2. 32-2.44(2H, m), ® 2. 75(3H, d), 3. 21-3. 31(1H, m) , 3. 58-3. 70(1H, m), 4.17 (1H, q), 5.96C1H, s), 6.70(1H, dd), 6. 84C1H, d), 7.63 (1H, d), 7. 89-7. 95(1H, m), 8. 00-8. 06(1H, m), 8. 12(1H, d), 8.29(1H, d), 8.50(1H, d), 9. 05 (1H, d). Example 117 2-Chloro-4-[(2S,3R)-3-carbyl-2-methyl-3-{6-[4-(N-methyl-4-yl) -1Η-pyrazol-1-yl group&gt;pyridin-3-yl}pyrrolidin-1-yl]benzonitrile 287 321538 201114741

Cl

The title compound was obtained in the same manner as in Example 45, using the compound obtained in Example 115, Step i, and Marlin as starting material. Η-NMR (CDC13) 5. 1.36 (3H, d), 2.3h2.41 (lH, m), 2.47- 2. 58 (1H, m) 3. 00-3. 39C2H, m) 3. 60-3 86(9H, m), 4.04C1H, d), 6.49(1H, dd), 6. 63(1H, d), 7. 45(1H, d), 7.82-7.92 (3H, ra), 8. 33-8. 38(1H, m), 8. 62(1H, d). Example 118 l-{5-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-3 _Hydroxy-2-pyridylpyrrole and the like pyridine-3-yl]pyridin-2-yl}-N-(2-hydroxy-2-methylpropyl)-iH-pyrazole- 4-anthracene 288 321538 201114741

In the same manner as in Example 45, the title compound was obtained using the compound obtained in Example 115, Step 1 and 1-amino-2-mercapto-2-propanol as starting material. ^-NMR (DMS0-d6) (5: 1. 10(6H, s), 1.19(3H, d), 2.33-2.44(2H, m), 3.2K2H, d), 3. 26-3. 31 ( 1H, m), 3.58-3.70 (1H, d), 4. 17(1H, q), 4. 50(1H, s), 5. 96(1H, s), 6.70 (1H, dd), 6.84( 1H, d), 7. 63(1H, d), 7. 87-7. 96(1H, m), 8. 00-8. 08(1H, m), 8. 14-8. 21 (2H, m), 8.50(1H, d), 9.20 (1H, d). Example 119 2-Chloro-4-[(2S, 3R)_3-transyl-2_methyl_3_(1H-° than squat- 4-base) σ Bilo. Dec-1-yl]benzonitrile

[s] 289 321538 201114741

Add butyl hydride (1.6 mol/L hexane) to a solution of 4-bromo-1-trityl oxazole (1.82 g) in THF (30 ml) at -78 °C under argon. Solution, 3. 22 ml). The mixture was stirred for 1 hour, and a solution of the compound (1. 00 g. The mixture was stirred for 30 minutes and allowed to warm to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The mixture was stirred at 40 ° C for 2 hours. After cooling to (TC, the mixture was neutralized with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was purified to give the title compound ( 217 mg). 1H, m), 3. 42-3. 55(1H, m), 3. 93-4. 08(1H, m), 5.40C1H, s), 6.6K1H, dd), 6.73(1H, d), 7. 35-7. 62(3H, m), 12. 61(1H, br. s.). Example 120 2-Chloro-4-[(2S,3S)-3-hydroxy-3-(lH- Imidazolyl-2-yl)-2-methylpyrrole

Pyridin-1-ylbenzoquinone NC CI

Q N-n

HO%N

HNV In the same manner as in Example 119, m 290 321538 201114741 compound and 2-bromo-1-triphenylmethyl-title compound obtained in Reference Example 5 were used. 1 Ηm saliva was obtained as a starting material! H-NMR (DMS0-de) 5 : 1.18(3H, d) 9 〇〇2·23'2.38(1Η m) 2·43-2.56(1Η,m), 3.04- 3.20(lH Q m ' 4 N r Q9nu , c ' ' 3·42-3.54(1Η,m). 4.32(1H,q),5·92(1Η,s), 6.57(1ίί μ, n iUH,dd ), 6.67 (1H rn 6.72C1H, s), 7.02 (1H, s), 7.57 (lH, 11.97 (1H, br. Example 121)

4~yl)~2-methyl 0 to 0 each 2-gas-4-[(2S, 3S)-3-hydroxy-3-(lH-n „sept-1-yl]benzonitrile

In the same manner as in Example 119, the ruthenium reference compound and the 4-bromo+trityl substitute were used as the starting materials of the title compound. «(DMSO-dO^l.lS-l.^H, m), 2&gt;21^ 3.01-3.20(1H, m), 3. 41-3. 54(1H, m), 4&gt; 25_4 3 5.90( 1H, s), 6.57(1H, dd), 6.67(lHj d), 6 ?3 s·), 7.02UH, br. S.), 7.56UH, d), u.96(ih ^ 321538 291 201114741 Example 122 2_Chloro-4-[(2S,3R)-3-hydroxy-2-methyl-3-(1-indolyl-1H-pyrazol-4-yl)°Bilo bite-1 - Benzoonitrile

To a solution of the compound obtained in Example 119 (50 mg) in DMF (5 ml), hexanes (30 mg) and methane (0.013 ml) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and purified title crystals crystals crystals !H-NMR (CDCls) (5 : 1.3K3H, d), 1. 95 (1H, br. s. ), 2.21-2.3K1H, m), 2.38-2.5K1H, m), 3. 14-3.25 ( 1H, m), 3.49-3. 59(1H, m), 3.86(3H, s), 3.92(1H, q), 6.45C1H, dd), 6. 58(1H, d), 7. 25(1H , s), 7.41 (1H, s), 7.43 (1H, d). Example 123 2-chloro-4-[(2S,3S)-3-hydroxy-2-methyl-3-(1-methyl -1H-imidazole-2-292 321538 201114741 base&gt;bibrid-1-yl]benzonitrile

In the same manner as in Example 122, the compound obtained in Example 120 was used as starting material to give the title compound. MS (ESI+, m/e): 318 (M+H) </RTI> <RTIgt; </RTI> N-[(3S)-l-(3-chloro-4-cyanophenyl)pyridin-3-yl]-4-fluoro Benzylamine

4-It benzoquinone chloride (0.137 ml) was added to a solution of the compound (200 mg) obtained in Reference Example 17 and triethylamine (0.324 ml) in THF (5 ml). The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ^-NMR (DMSO-de) ^ : 2. 05-2. 15(1H, m), 2. 20-2. 32(1H, m), 3.28-3.55C3H, ra), 3. 67(1H, Dd), 4. 55-4. 70(1H, m), 6.6K1H, dd), 6. 75(1H, d), 7. 25-7. 33C2H, m), 7. 62(1H, d) , 7. 88-7. 98(2H, m), 8. 63(1H, d). Example 125 N-[(3S)-l-(3-chloro-4-cyanophenyl)pyrrolidine- 3-yl]-2-(4-fluorophenyl) Φ acetamide C!

In the same manner as in Example 124, using the compound obtained from the title compound and (4-fluorophenyl)ethylamine chloride as a starting material, the title compound was obtained. ♦ 1H_NMR (__d6) Π.85]. 9_ 讧2· 22(1H,m), 3. 17(1H, dd), 3. 30-3. 50(4H, m), 3.56(1H, dd), 4.32-

4. 42(1H, m), 6.59 (1H, dd), 6.74(1H, d) 7 〇5-7 i5(2H ra), 7.20-7.30C2H, m), 7.61(1H, d), S^ OCIH, d). Example 126 !H(3RH-(3-chloro-4-cyanophenyl)Bilo bite]-4_benzophenamide 321538 294 201114741

Cl

F The title compound was obtained in the same manner as in the the the the The W-NMR data was consistent with those obtained in Example 124. Example 127 N-[(3R)-l-(3-chloro-4-cyanophenyl &gt;byrrolyl-3-yl]_2_(4-fluorophenyl)acetamide

In the same manner as in Example 124, using the compound obtained in Reference Example μ and (4-fluorophenyl)acetamethylene as a starting material, the title compound was obtained. The H-NMR data was consistent with the compounds obtained in Example 125. Example 128 N_[(2S, 3R)-l-(3-Gas-4-cyanophenyl)-2-methylindolebi-3-yl]-4-fluorobenzamide

CI

F 321538 295 201114741 The compound obtained in Reference Example 24 (244 mg) was added to trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and lithium carbonate (280 mg), 2-chloro-4-fluorobenzonitrile (130 mg) and dimethyl sulfoxide (1 〇mi) were added to the residue, and at 100 ° The mixture was stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sulphuric acid, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAcjHHHHH ^-NMR (CDCh) 5 : 1. 31C3H, d), 2. 12-2. 22(1H, m), 2. 45-2. 60(1H, m), 3. 45-3. 60(2H , m), 3.96C1H, q), 4. 49(1H t), 6.45(1H, dd), 6. 55-6. 63(2H, m), 7. 02-7. 12(2H, m) 7. 29(1H, d), 7.75-7.85(2H, m). ' ' Example 129 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)_2-methyl-n Biha bite _3_ base]_2_ • (4-fluorophenyl)acetamide

In the same manner as in Example 128, the title compound was obtained using the compound obtained in Reference Example 25 =====. n,W,1.95-2.〇5(ih m) 2 Training 2·45(1Η,Ε),3·28—3·_,^·_,^=, 321538 296 201114741 q), 4. 26( 1H, t), 6·39 (1Η, dd), 6.51 (1H, d), 6.9〇_7 〇〇 (2H, m), 7. 18-7. 30(4H, m)· Example 130 ^ [(23,33) + (3-Ga-4-phenylphenyl)_2_methyltrans. _3_基]_4_ fluorobenzamide

The compound obtained in Reference Example 31 and 2-chloro-4-fluorobenzonitrile were used as a starting material in the same manner as in Example 128 to give the title compound. j-NMlUCDClOi^ · ll〇(3H,d), 2 〇5_2. 22(1H,m),2 4〇_ 2.50(1H, m), 3.28-3.40(ih, m), 3.45-3. 55( 1H, m), 4.30-4.43C1H, m), 4. 6Ο-4. 72(1H, m), 6. 16(1H, d), 6.46 (1H, dd), 6.60C1H, d), 7. L〇~7&gt;2〇(2H, m), 7.43(1H, d) φ 7. 75-7. 85(2H, m). 'Example 131 N-[(2S,3S)+(3-Chlorine .cyanophenyl (4-fluorophenyl)acetamide ci

In the same manner as in Example 128, the title compound was obtained using 321 538 297 201114741; It (C Si carbonitrile as starting material) obtained in the same manner as Example 128. 32 〇H, 3.33-3.43 (^,)// ^ ^ ^ e α β . ” 2 (1Η, m), 4.39-4.50C1H, m), two 39 (1H, dd), 6.53 (1H, d), U4-U2 (2H, m), 7.20 7.30 ( 2Η,m), 7. 41(ιη,廿) Example 132 '

N-[ (2S,3R)-l-(3~Chloro_4_cyanophenyl)_2~-Ν'-(4-fluorophenyl)urea CI

The methyl group ratio ρ -3- ] 基 ] 化合物 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 温 。 。 Concentrate the reaction mixture under reduced pressure, and leave the substance (2 (4). Add carbon _ 崎 异 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 Water is added to the reverse red compound, and the extract is read (4) after water washing, Μ(10)_drying, and (4) concentrated under pressure. After casting (4), the material is recrystallized from ethyl acetate to obtain ()diacetyl phthalic acid (4). Purification of residual mg). Such as chloroform (57 ^ Γ α ΓΓ 1 · 15 ^ dX ^ 85-2 · 00 ^ 11 · ^ 2.25-2.450H, m), , 30-, 40 (1H, m), , 42.3.52 (1H, m) 321538 298 201114741 3.85(1H, q), 3. 90-4. 00(1H, ra), 6.51(1H, d), 6. 65(1H, dd), 6. 79(1H, d), 6. 98-7. 10(2H, m), 7. 30-7. 40(2H, m), 7. 61(1H, d), 8.27(1H, s). Example 133 2- Chloro-4-{(2S,3R)-3-[(4-fluorobenzyl)amino]-2-methylpyrrolidinium-1-yl}benzonitrile hydrochloride

CI

A mixture of the compound obtained in Reference Example 35 (300 mg) and trifluoroacetic acid (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dichloromethane was evaporated. 4-Fluorobenzaldehyde (0.098 ml) and sodium triethylsulfonium borohydride (568 mg) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with EtOAc EtOAc. Purify the residue by nightmless column chromatography (hexane-acetic acid ethyl acetate) and basic sulphuric acid column chromatography (hexane-acetic acid ethyl acetate) to 4 mol / L gasification of ethyl acetate The solution was acidified and recrystallized from EtOAc (EtOAc) !H-NMR (DMSO-de)d : 1.16C3H, d), 2.30-2.60(2H, m), 3.40-3. 65(3H, m), 4. 18-4. 30(2H, m), 4. 35-4. 45(1H, m), 6.64(1H, dd), 6. 79(1H, d), 7.20-7. 32(2H, m), 7.55, 7. 70(3H, m) , 29. 29(2H, brs). 321538 299 201114741 Example 134 4-Chloro-N-[(3S)-l-(3-chloro-4-cyanophenyl)pyrrolidin-3-yl]benzene Sulfonamide

Add 4-chlorobenzene to Φ chloro (253 mg) in a solution of the compound (258 mg) and triethylamine (0.418 ml) in THF (10 ml). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel chromatography eluting elut elut elut elut eluting ^-NMR CCDC13) (5: 1. 95-2. 05(1H, m), 2. 18-2. 28(1H, m), 3.2K1H, dd), 3. 30-3. 50(2H, m), 3. 53(1H, dd), 3.98-4. 08(1H, in), 4.84(1H, d), 6.33(1H, dd), 6.47(1H, d), ^ 7. 38(1H , d), 7.52(2H, d), 7. 83C2H, d). Example 135 4-Chloro-N-[(3R)-l-(3-chloro-4-cyanophenyl)°-pyrrolidine- 3_yl]benzenesulfonamide

In the same manner as in Example 134, the title compound was obtained using the compound of 300 321538 201114741 and 4-chlorobenzenesulfonium chloride as the starting materials. The ^-NMR data was consistent with the compound obtained in Example 134. Example 136 N5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methylpyrrolidin-3-yl; h-pyridyl-2, 5-diindole amine

A mixture of methyl 6-amine pyridyl-3-carboxylate (180 mg), 1 mol/L aqueous sodium hydroxide solution (5 ml) and methanol/THF (5 ml/5 ml) was stirred at room temperature for 3 hours. . The reaction mixture was neutralized with hydrochloric acid, and the residue was dissolved in DMF (10 ml). The compound (272 mg), WSC (288 mg), HOBt (203 mg), and triethylamine (0. 418 ml) obtained in Reference Example 36 were added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. The title compound (240 mg) was obtained as crystals crystals. ^-NMR (DMS0-de) (5: 1.2K3H, d), 2. 03-2. 13(1H, m), 2. 35-2.45C1H, m), 3. 45-3. 55(2H, m), 3. 99(1H, q), 4. 20-4. 30(1H, m), 6.63(1H, dd), 6. 76(1H, d), 7. 60(1H, 301 321538 201114741 d), 7.76(1H, brs), 8. 09(1H, d), 8. 19(1H, brs), 8.32 (1H, dd), 8.88C1H, d), 8. 97(1H, d). Example 137 N5-[(2S, 3R)-l-(3-Gas-4-cyanophenyl)-2-methyl D-pyridyl-3-yl]-N2-decylpyridine-2, 5- Diamine

In the same manner as in Example 136, the title compound was obtained using the compound obtained from methyl (6-(methylamine-carbamoyl) pyridine-3-carboxylate and the compound obtained in Reference 36. !H-NMR (DMS0-de) (5: 1.21(3H, d), 2. 02-2. 12(1H, m), 2.37-2.47(lH, m), 2. 82(3H, d), 3. 40-3. 60(2H, m), 3.99 ^ (1H, q), 4. 20-4. 30(1H, m), 6. 63(1H, dd), 6. 76(1H, d ), 7.6K1H, d), 8. 08(1H, dd), 8.33(1H, dd), 8.80-8.90 (2H, m), 8.97C1H, dd). Example 138 2-chloro-4-{( 3R)-3-[(4-fluorophenyl)amino]pyrrolidin-1-yl}benzonitrile

The compound 302 321538 201114741 (500 mg) obtained in Reference Example 19 was basified with aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. Dry over anhydrous magnesium sulfate and concentrate under reduced pressure. PF-iodobenzene (430 mg), (diphenylarbenium acetonide) dipalladium (0) (89 mg), -(dicyclohexylphosphino)biphenyl (34 mg), tributoxy The residue was mixed with sodium (280 mg) and toluene (8 ml), and the mixture was stirred at 130 ° C under microwave irradiation for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by hydrazine gel column chromatography (hexane-ethyl acetate) (yield: hexane-ethyl acetate). The title compound (87 mg) was obtained as a pale yellow solid. • H-NMR (DMSO-de) 5 : 1. 90-2. 05(1H, m), 2. 20-2. 35(1H, in), 3. 18(1H, dd), 3. 35- 3. 55(2H, m), 3. 68C1H, dd), 4.05- 4. 15C1H, m), 5. 83(1H, d), 6. 55-6. 65(3H, m), 6. 75 (1H, d), 6. 88-6. 98(2H, m), 7. 60(1H, d). φ Example 139 2-chloro-4-{(2S, 3R)-3-[(4 -fluorophenyl)amino]-2-methylindenyryl-1-yl}benzonitrile

In the same manner as in Example 138, using the compound obtained in Reference Example 36 and 1-fluoro-4-iodobenzene as a starting material, the title compound was obtained. 303 321538 201114741 JH-NMR (DMS0-de) (5: i.20(3H, d), 1. 93-2. 03(1H, m), 2. 30-2.45C1H, m), 3. 35- 3. 55(2H, m), 3. 62-3. 70(1H, m) 3.83C1H, q), 5.80(1h, d)s 6.47-6. 62(3H, m), 6. 73(1H , d), 6.90-7.00 (2H, m), 7.58 (1H, d). Example 140 N-[(2S,3R)-1-(3-Gas-cyanophenyl)_2-methylhydrazine Pyridyl-3_yl]-3_phenylpropanamide

The DMF of the compound obtained in Reference Example 36 was mixed. 12 m〇1/L solution (0.500 ml), 0.144 mol/L solution of 3-phenylpropionic acid DMF (0·500 ml), dmf of triethylamine Then. 12m〇l/L solution (〇. 500 ml) Lu and WSC/HOBt DMF. 144mol/L solution (〇. 500 ml), and mix the mixture at room temperature for 24 hours. Ethyl acetate (3 ml) and a 2% aqueous sodium hydrogencarbonate solution (2 ml) were added to the mixture, and the mixture was extracted. After separating the organic layer through an upper layer of PhaseSeptube (manufactured by Wako Pure Chemical Industries, Ltd.), it was concentrated under reduced pressure. The residue was dissolved in DMSO / MeOH (0.5 ml / 0.5 ml) and preparative HPLC (PLC: High Yield Purification System, Gi Ison Inc., Column: YMC Combi Prep ODS-A S-5 // m, 19x50mm, solvent: solution A; 0. 1% water containing trifluoroacetic acid, solution B; 0. 1% acetonitrile containing trifluoroacetic acid, gradient cycle: 〇. 〇〇304 321538 201114741 min (solution A / solution B = 95 / 5), 1.00 min (solution A / solution B = 95 / 5), 5. 20 minutes (solution A / solution B = 5 / 95), 6. 40 minutes (solution A / Solution B=5/95), 6.50 minutes (solution A/solution B=95/5), 6.60 minutes (solution A/solution B=95/5), flow rate: 20 ml/min, detection method: UV 220 nm) Purification afforded the title compound. Yield: 17.3 mg MSCESI+, m/e): 368 (M+H) Example 141 N-[(2S, 3R)-1-(3-chloro-4-cyanophenyl)-2-indenyl σ Bilo 0--3-yl]-3-[4-(trifluoromethyl)phenyl]propanamide

The title compound was obtained from 3-[4-(trifluoromethyl)phenyl]propanoic acid in the same manner as Example 140. Yield: 17.9 mg of MS (ESI+, m/e): 436 (M+H) Example 142 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole base. Biloxidin-3-yl]-2-(4-fluorophenoxy)acetamide 305 321538 201114741

\ , CH3 b

The title compound was obtained from (4-fluorophenoxy)acetic acid in the same manner as in Example 140. Yield: 8. 4 mg of MS (ESI+, m/e): 388 CM+H) Example 143 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-mercaptopurine L-bromo-3-yl]-4-phenylbutyramine

The title compound was obtained from 4-phenylbutyric acid in the same manner as in Example 140. Yield: 14. 3 mg MSCESI+, m/e): 382 (M+H) Example 144 (2E)-N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2 -mercaptopurine-3-306 321538 201114741 base]-3_(4-fluorophenyl)propane-2_thin amine

The title compound was obtained from (2E)_3_(4-fluorophenyl)prop-2-enoic acid in the same manner as in Example 140. Yield: 14. 8 mg MSCESI+, m/e): 384 (M+H) Example 145 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole . Bilpyridin-3-yl]-2-(3-(phenyl)ethene

CI

The title compound was obtained from (3-fluorophenylacetic acid) in the same manner as Example 140. Yield: 14.2 mg MS (ESI+, m/e): 372 (M+H) Example 146 307 321538 201114741吼11 each bit -3-yl]-2- N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)~2 (3,4-dichlorophenyl)acetamidamine α

The title compound was obtained. Yield of 3, 4-dichlorophenylacetic acid: 14. lmg MSCESI+, m/e): 422 (M+H) Example 147 2-(biphenyl-4-yl)-indole-[(28, 3Ι〇~ι# Ί ~ 1~(3-chloro-4-cyanophenyl)-2-indolylpyrrolidin-3-yl]acetamidamine α

4-biphenylacetic acid was obtained in the same manner as in Example 140. Yield: 15. 5 mg 321538 308 201114741 MSCESI+, m/e): 430 (M+H) Example 148 2-[4-(benzyloxy)phenyl]-N-[(2S,3R)-l -(3-chloro-4-cyanophenyl)-2-mercaptopyrrolidin-3-yl]acetamide

Winter N The title compound was obtained from 4-benzophenoxyphenylacetic acid in the same manner as in Example 140. Yield: 16. lmg MSCESI+, m/e): 460CM+H) Example 149 φ N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indenylpyrrole Pyridin-3-yl]-2-(thiophen-2-yl)acetamide

309 321538 201114741 2-Thienylacetic acid was obtained in the same manner as in Example 140. Yield: 6. 3 mg MS (ESI+, ra/e): 360 (M+H) Example 150 2~Methylpyrrolidin-3-yl]-2- N-[(2S, 3R)-l-( 3-chloro-4-cyanophenyl) (1H-indol-3-yl)acetamide

In the same manner as in Example 140, the compound. Get title from 吲哚-3-acetic acid

Yield: 10.4 mg of MS (ESI+, m/e): 393 (M+H) Example 151 </ RTI> </ RTI> </ RTI> <RTIgt; (3-chloro-4-yl)benzamide

31〇 321538 201114741 The title compound was obtained from 4-chlorobenzoic acid in the same manner as in Example 140. Yield: 14. 2 mg MSCESI+, m/e): 374 (M+H) Example 152 N-[(2S, 3R)-1-(3-chloro-4-cyanophenyl)-2-mercaptopurine Carrrol-3-yl]-4-cyanobenzamide

The title compound was obtained from 4-cyanobenzoic acid in the same manner as in Example 140. Yield: 8. lmg MSCESI+, m/e): 365 (M+H) Example 153 4-t-butyl-N-[(2S,3R)-l-(3-chloro-4-cyanophenyl) )-2-indolyl-l-rhodium-3-yl]benzamide 311 321538 201114741

The title compound was obtained from 4-t-butylbenzoic acid in the same manner as in Example 140. Yield: 1. 9 mg MSCESI+, m/e): 396 (M+H) Example 154 4-(ethylamino)-N-[(2S,3R)-1-(3-chloro-4- Cyanophenyl)-2-mercaptopyrrolidin-3-yl]benzamide

The title compound was obtained from 4-acetamidobenzoic acid in the same manner as in Example 140. Yield: 2. 2 mg MS (ESI+, ra/e): 397 (M+H) Example 155 [si 312 321538 201114741 w3i〇«m cyanyl) ^methyl 吼 _ _3_ _] Trifluoromethyl)benzamide

4-(Trifluoromethyl)benzoic acid hydrazinopyridine each _3-yl] was obtained in the same manner as Example 140. Yield: 16.1 mg of MS (ESH, m/e): 408 (M+H) Example 156 N-[(2S, 3R)-l-(3-chloro-4-cyanophenylphenyl-4~ Amine

The 4-biphenylcarboxylic acid was obtained in the same manner as in Example 40. Yield: 13. 5 mg MSCESI+, m/e): 416 (M+H) 321538 313 201114741 Example 157 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2 -methyl. Biropyridin-3-yl]-4-amine sulfonylbenzamide

The title compound was obtained from 4-carboxybenzenesulfonamide in the same manner as in Example 140. Yield: 5. 7 mg MSCESI+, m/e): 419 (M+H) Example 158 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Ethrolidin-3-yl]-4-(trifluoromethoxy)benzamide

The title compound was obtained from 4-(trifluoromethoxy)benzoic acid in the same manner as in Example 140. Yield: 16.1 mg MSCESI+, ra/e): 424 (M+H) 314 321538 201114741 Example 159 Bu [(25'3--(3-chloro-4-cyanophenyl), 2_A Base _3_基]_4_ phenoxybenzamide

The title compound was obtained from phenoxybenzoic acid in the same manner as in Example 140. Yield: 16.6 mg of MS (ESI+, m/e): 432 (M+H) Example 160 N-[(2S, + + (phenylcarbonyl) benzamide

The title compound was obtained from 4-benzylidenebenzoic acid in the same manner as in Example 140. 321538 315 201114741 Yield: 16.9 mg MSCESI+, ra/e): 444CM+H) Example 161 4-(phenylhydroxy)-N-[(2S, 3R)-l-(3-gas-4- Cyanophenyl)-2-indenyl. Biloxidin-3-yl]phenylhydrazine

The title compound was obtained from 4-benzophenoxybenzoic acid in the same manner as in Example 140. Yield: 15.7 mg of MS (ESI+, m/e): 446 (M+H) Example 162 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Pyrrrolidin-3-yl]-4-(dipropylamine sulfonyl)benzamide 316 538538 201114741

Cl The title compound was obtained from 4-(dipropylaminesulfonyl) benzene benzoic acid in the same manner as in Example 140. Yield: 17. Omg MS (ESH, m/e): 503 (M+H) Example 163 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole Pyrrrolidin-3-yl]-4-nonyloxybenzamine

The title compound was obtained from 4-methoxybenzoic acid in the same manner as in Example 140. Yield: 11. 8 mg MSCESI+, m/e): 370 (M+H) Example 164 I [S] 317 321538 201114741 3-chloro-N-[(2S, 3R)-l-(3-chloro-4 -cyanophenyl)-2-methylπpiroxime-3-yl]benzamide

The title compound was obtained from 3-chlorobenzoic acid in the same manner as in Example 140. Yield: 9. Omg MS (ESI+, m/e): 374 (M+H) Example 165 2-chloro-N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl) -2-methyl. Bilpyridin-3-yl]benzamide η

The title compound was obtained from 2-chlorobenzoic acid in the same manner as in Example 140. Yield: 10. 6 mg MSCESI+, m/e): 374 (M+H) Example 166 318 321538 201114741 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2 - mercapto pyrrolidin-3-yl] _2, 4-difluorobenzamide

The title compound was obtained from 2,4-difluorobenzoic acid in the same manner as in Example 140. Lu yield: 10. 2 mg MSCESI+, m/e): 376 (M+H) Example 167 3-chloro-N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)- 2-methylindole-3-yl]-4-nonyloxybenzamide

The title compound was obtained from 3-chloro-4-methoxybenzoic acid in the same manner as in Example 140. Yield: 15. lmg MSCESI+, m/e): 404 (M+H) Example 168 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indolylpyrrole Pyridin-3-yl]-3,5-bis(trifluoromethyl)benzamide 319 321538 201114741

F F

The title compound was obtained from 3,5-bis(trifluoromethyl)benzenecarboxylic acid in the same manner as in Example 140. Yield: 13. 2 mg MS (ESI+, m/e): 476 (M+H) Example 169 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Pyryryryl-3-yl]-1H-indole-5-carboxamide

The title compound was obtained from 1H-indole-5-carboxylic acid in the same manner as in Example 140. Yield: 9. 1 mg of MS (ESI+, m/e): 379 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> Example 170 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Ratio 11 σ -3- group] 320 321538 201114741 -1H-吲哚-2-carboxamide

The title compound was obtained from 1H-indole-2-carboxylic acid in the same manner as in Example 140. Yield: 2. 2 mg Φ MS (ESH, ra/e): 379 (M+H) Example 171 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-曱基吼罗ridin-3-yl] _1,3_benzoquinone beta-c sitting_6_甲甲胺

The title compound was obtained from 1,3-benzothiazole-6-carboxylic acid in the same manner as in Example 140. Yield: 8. 6 mg MSCESI+, m/e): 397 (M+H) Example 172 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl 0 to 17 each π--3-yl]-1- 321 321538 201114741 thiol-1H-indole-2-carboxamide

The title compound was obtained from the indole-1H-indole-2-carboxylic acid in the same manner as in Example 140. Yield: 14.2 mg % MSCESI+, m/e): 393CM+H) Example 173. N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Purine-3-yl]naphthalene-1-decylamine

The title compound was obtained from naphthalene-1-carboxylic acid in the same manner as in Example 140. Yield: 13. 8 mg MSCESI+, m/e): 390CM+H) Example 174 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-mercaptopurine Pyridin-3-yl]naphthalene 322 321538 201114741 -2-decylamine

The title compound was obtained from naphthalene-2-carboxylic acid in the same manner as in Example 140. Yield: 15.8 mg of MS (ESI+, m/e): 390 (M+H) Example 175 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Mercaptopyrrolidin-3-yl&gt;pyridin-3-carboxamide trifluoroacetate

The title compound was obtained from pyridine-3-carboxylic acid in the same manner as in Example 140. Yield: 15.7 mg MS (ESI+, m/e): 341 MH+H) Example 176 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole . Birolidine _3-based &gt; ratio 323 321538 201114741

CF3C〇2H In the same manner as in Example 140, compound.

Pyridyl-2-carbamide trifluoroacetate

The title yield was obtained from pyridine-2-carboxylic acid: 8.7 mg MSCESI+, m/e): 34KM+H) Example 177 N-[(2S,3R)-1 (3-chloro-4-cyanyl) ~ pyridine-4-carbamide trifluoroacetate methyl -3--3-pyru

In the same manner as in Example 140, the compound was used. The title product was obtained as a carboxylic acid: 12. 0 mg MS (ESI+, m/e): 341 (M+H) Example 178 2~Methylpyrrolidine-3- 6-chloro-N-[ (2S, 3R) -l-(3-chloro~4, cyanogen) ^]pyridine-3-carboxamide trifluoroacetate 321538 324 201114741

• CF3C02H The title compound was obtained from 6-chloropyridine-3-carboxylic acid in the same manner as in Example 140. Yield: 12. 2 mg MSCESI+, m/e): 375 (M+H)

Example 179 4-Chloro-N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indolylpyrrolidin-3-yl]pyridin-2-indoleamine III Fluoroacetate

The title compound was obtained from 4-chloropi-pyridin-2-carboxylic acid in the same manners as in Example 140. Yield: 7. 8 mg MSCESI+, m/e): 375 (M+H) Example 180 2 -chloro-N-[(2S, 3R)-l-(3-chloro- 4-cyanophenyl)- 2-indenyl piperidine-3-yl]pyridin-4-guanamine trifluoroacetate 325 321538 201114741

The title compound was obtained from 2-chloropyridine-4-carboxylic acid in the same manner as in Example 140. Yield: 6. 6 mg MSCESI+, m/e): 375 (M+H) Example 181 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole Pyrrrolidin-3-yl]-1H-benzimidazole-5-decylamine trifluoroacetate

The title compound was obtained from 1H-benzimidazole-5-carboxylic acid in the same manner as in Example 140. Yield: 8.7 mg MSCESI+, m/e): 380 (M+H) Example 182 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole 0 口 〇 -3- -3- group]-2- [s] 326 321538 201114741 (pyridin-3-yl) acetamide trifluoroacetate

Cf3co2h The title compound was obtained from pyridin-3-ylacetic acid hydrochloride in the same manner as in Example 140. Yield: 11. 5 mg MSCESI+, m/e): 355 (M+H) Example 183 N-(2-{[(2S,3R)-l-(3-chloro-4-cyanophenyl)- 2-indolyl.Byrrolidin-3-yl]amino}-2-oxoethyl)pyridin-3-indoleamine trifluoroacetate

The title compound was obtained from N-(pyridin-3-ylcarbonyl)glycine in the same manner as Example 140. Yield: 7. 7 mg 327 321538 201114741 MSCESI+, m/e): 398 (M+H) Example 184 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2 -decylpyrrolidin-3-yl]-3-(pyridin-3-yl)propanamide trifluoroacetate

The title compound was obtained from 3-pyridin-3-ylpropanoic acid in the same manner as in Example 140. Yield: 11.2 mg MSCESI+, m/e): 369 (M+H) Example 185 (2E)-N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)- 2-indolylpyridin-3-yl]-3-(pyridin-3-yl)prop-2-enylamine trifluoroacetate

The title compound was obtained from (2E)-3-pyridin-3-ylprop-2-enoic acid in the same manner as Example 140. Yield: 11. 6 mg 328 321538 201114741 MS (ESI+, ra/e): 367CM+H) Example 186 (2E)-N-[(2S,31〇-Bu(3-chloro-4-cyanophenyl) -2-methylpyridin-3-yl]-3-(1Η-imidazol-4-yl)prop-2-enylamine trifluoroacetate

The title compound was obtained from (2?) -3 (1? Yield: 5. 2 mg of MS (ESH, m/e): 356 (M+H) Example 187 N-[(2S, 3R)-1-(3-chloro-4-cyanophenyl)-2- Mercaptopyrrolidin-3-yl]-2-(1H-imidazol-4-yl)acetamido trifluoroacetate

The title compound was obtained from hydrazine-micidin-4-yl acetate hydrochloride in the same manner as in Example 140. Yield: 5. 3 mg 329 321538 201114741 MSCESI+, m/e): 344CM+H) Example 188 3-(lH-benzimidazol-2-yl)-N-[(2S, 3R)-l-( 3-chloro-4-cyanophenyl)-2-mercaptopyrrolidin-3-yl]propanamide trifluoroacetate

The title compound was obtained from 3-(1H-benzom-yt-2-yl)propanoic acid in the same manner as Example 140. Yield: 11.3 mg of MS (ESI+, m/e): 408 (M+H) Example 189 N-[(2S, 3R)-1 - (3-chloro-4-cyanophenyl)-2-indole Pyrrrolidin-3-yl]lu-N2-phenylglycineguanamine trifluoroacetate

In the same manner as in Example 140, the compound of the title 330 321538 201114741 was obtained from N-phenylglycine. Yield: 6. 9 mg MSCESI+, m/e): 369 (M+H) Example 190 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Ethrolidin-3-yl]-3-(piperidin-1-yl)propanamide trifluoroacetate

The title compound was obtained from 3-piperidin-1-ylpropanoic acid in the same manner as in Example 140. Yield: 12. 9 mg MSCESI+, m/e): 375 (M+H) Example 191 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Ethrolidin-3-yl]-4-(dimethylamino)phenylguanamine trifluoroacetate

331 321538 201114741 4-(didecylamino)benzazole The title compound was obtained from the acid in the same manner as in the the the the the Yield: 19.9 mg MS (ESI+, m/e): 353 MH+H) Example 192 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl); Pyrrrolidin-3-yl1-2-[4-(dimethylamino)phenyl]ethanoamine_ri% difluoroacetate

Ν

vS ο ,c

• CF3C〇2H

h, c'Nsch, 4-(didecylamino)phenylmethyl. Biloxazin-3-yl]-4- The title compound was obtained from acetic acid in the same manner as in the the the the the compound. ® Yield · · 19. 4 mg MSCESI+, m/e): 397 (M+H) Example 193 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)~2 ( 1Η-^^-1-yl)benzamide 321538 332 201114741

The title compound was obtained from 4-(1Η-σ ratio p-1-yl)benzoic acid in the same manner as in Example 140. Yield: 1. 6 mg MSCESI+, m/e): 405 (M+H) Example 194 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Ethrolidin-3-yl]-6-fluoropyridine-2-carboxamide trifluoroacetate

* cf3co2h The title compound was obtained from 6-fluoropyridine-2-carboxylic acid [S] 333 321538 201114741 in the same manner as in Example 140. Yield: 5. 8 mg MSCESI+, m/e): 359 (M+H) Example 195 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Pyrrrolidin-3-yl]-1,8-naphthyridin-2-ylamine trifluoroacetate

The title compound was obtained from 1,8-naphthyridin-2-carboxylic acid in the same manner as in Example 140. Yield: 9. 1 mg ® MSCESI+, m/e): 392 (M+H) Example 196 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Pyryryryl-3-yl]-1,6-naphthyridin-2-ylamine trifluoroacetate [S] 334 321538 201114741

I naphthyridine-2-carboxylic acid gave the title compound. ® Yield: 8.7 mg MSCESI+, m/e): 392 (M+H) Example 197 N-[(2S,3R)-b (3-chloro- 4-cyanophenylmethylpyrrolidine-3 Monoyl]|(4-fluorophenyl)indolepyridin-2-indole trifluoroacetate

The title compound was obtained in the same manner as in Example 140. Yield: 12. 7 mg MS (ESI+, m/e): 435 (M+H) Example 198~2-methylpyrrolidine-3-yl] N-[(2S, 3R)-l-(3 -chloro-4-cyanophenyl) 321538 335 201114741 -6-(morpholin-4-yl)pyridine-2-carboxamide trifluoroacetate

The title compound was obtained from 6-morpholin-4-ylpyridine-2-carboxylic acid in the same manner as in Example 140.

Yield: 15. 6 mg of MS (ESI+, m/e): 426 (M+H) Example 199 5-chloro-N-[(2S,3R)-l-(3-chloro-4-cyanophenyl) )-2-T-based pyrrolidin-3-yl]pyridine-3-carboxamide trifluoroacetate

The title compound of the pyridine-3-carboxylic acid was obtained from 5-chloro in the same manner as in Example 140. Yield······················ Cyanophenyl)-2-methylpyrrolidin-3-yl]-6-phenoxypyridine-3-carboxamide trifluoroacetate

• cf3co2h The title compound was obtained from 6-phenoxypyridine-3-carboxylic acid in the same manner as in Example 140. Yield: 16.8 mg MSCESI+, ra/e): 433 (M+H) Example 201 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Ethrolidin-3-yl]-2-(morpholin-4-yl)pyridine-3-indolyl trifluoroacetate

In the same manner as in Example 140, the title compound was obtained from 2- y _ _ _ _ _ ntbβ _ _ _ carboxylic acid. Yield: 17. 6 mg 337 321538 201114741 MSCESI+, ra/e): 426 (M+H) Example 202 N-[(2S,3R)-l-(3- gas-4-cyanophenyl)-2 -mercapto-l-bromo-3-yl]-6-(morpholin-4-yl)pyridine-3-carboxamide trifluoroacetate

In the same manner as in Example 110, the title compound was obtained from 6 _ _ _ _ 4 ~ π π _ _ _ carboxylic acid. Yield: 12. 7 mg MS (ESI+, m/e): 426 (M+H) Example 203 φ N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2 -Methyl-pyridridin-3-yl]-θα-pyrrolidin-1-ylethyl)pyridine-3-carboxamide trifluoroacetate

In the same manner as Example 140, the title compound was obtained from 6-(2-[rho] ratio of 11-pyridin-1-ylethyl 338 321538 201114741 base &gt; pyridine-3-carboxylic acid. Yield: 15. 8 mg MSCESH , m/e): 438CM+H) Example 204 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indolylpyridin-3-yl]-2 -cyclohexylacetamide

The title compound was obtained from cyclohexylacetic acid in the same manner as in Example 140. Yield: 15. 0 mg MSCESI+, m/e): 360 (M+H) Example 205 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Ethrolidin-3-yl]-6-φ (2,2,2-trifluoroethoxy)indole J-pyridine-3-decylamine trifluoroacetate

The title compound was obtained from 6-(2,2,2-trifluoroethoxy 339 321538 201114741 base) pyridine-3-carboxylic acid in the same manner as in Example 140. Yield: 16.1 mg MSCESH, m/e): 439 (M+H) Example 206 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Purine-3-yl]-2-fluoropyridine-4-carboxamide trifluoroacetate

Eight The title compound was obtained from 2-fluoropyridine-4-carboxylic acid in the same manner as in Example 140. Yield: 5. 5 mg of MS (ESI+, m/e): 359 (M+H) Example 207 N-[(2S,3R)-1-(3-chloro-4-cyanophenyl)-2- Methyloxaridin-3-yl]_N-(2,2,2-trisylethyl)benzene_1,4-diterpenoid 340 321538 201114741

α The title compound was obtained from the chemical compound obtained in Reference Example 41 in the same manner as in Example 140. Yield: 15. 6 mg MSCESI+, ra/e): 465 (M+H) Example 208 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Ethrolidin-3-yl]-4-[(1E)-N-hydroxyethylimino]benzamide

N

The title compound was obtained from the compound obtained in Reference Example 42 in the same manner as in Example 140. Yield: 10. 9 mg 341 321538 201114741 MSCESI+, m/e): 397 (M+H) Example 209 N-[(2S, 3R)_l-(3-A. Methyl η 洛 _ _ 3 - yl] benzene - 1,4-dimethyl decylamine

〇

The title compound was obtained from 4-aminomercaptobenzoic acid in the same manner as in Example 140. Yield: 1. 5 mg MSCESI+, m/e): 383 CM+H) Example 210

N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-hydrazinopyrrolidinyl-3-yl]_2_(4-phenylphenyl)ethinamide α

Obtained from (4-chlorophenyl)acetic acid 321538 342 201114741 the title compound. Yield: 15. 0 mg MSCESI+, m/e): </RTI> </RTI> </RTI> <RTIgt; </RTI> </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> 211 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indenyl. Biloxidin-3-yl]Ια-methoxyphenyl) acetamide

The title compound was obtained from (4-methoxyphenyl) acetic acid in the same manner as in Example 140. Yield: 8. 3 mg MSCESI+, m/e): 384 (M+H) Example 212 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole Ethrolidin-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide 343 321538 201114741 α

The title compound was obtained from [4_(trimethylmethyl)phenylacetic acid in the same manner as in Example 14.

Yield: 14.4 mg of MS (ESI+, m/e): 422 (M+H) Example 213 Methylpyrrolidin-3-yl]-2-N-[(2S,3R)-l-(3 -chloro-4~ phenyl) (4-methylphenyl)acetamide

The title compound was obtained in the same manner as that of the compound (1). Yield: 13. 0 mg MS (ESI+, m/e): 368 (M+H) Example 214 N-[(2S, 344 321538 201114741 (4-phenoxyphenyl) ethylamine

The title compound was obtained from (4-phenoxyphenyl)acetic acid in the same manner as in Example 140. Yield: 17.3 mg MS (ESI+, m/e): 446 (M+H) Example 215 2-(4-t-butylphenyl)-N-[(2S, 3R)-l-(3 -chloro-4-cyanophenyl)-2-methylpyrrolidin-3-yl]acetamide

Q

345 321538 201114741 The title compound was obtained from (4-t-butylphenyl)acetic acid in the same manner as Example 140. Yield: 14. 8 mg MSCESI+, m/e): 410 (M+H) Example 216 N-[(2S, 3R)-1-(3-chloro-4-cyanophenyl)_2_methyl π ratio p each 0--3-yl]-2-[4-(indolylsulfonyl)phenyl]acetamide

The title compound was obtained from [4-(methylsulfonyl)phenyl] φ acetic acid in the same manner as in Example 140. Yield: 7. 9 mg of MS (ESI+, m/e): 432 (M+H) Example 217 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Mercaptopyridin-3-yl]anthracene-chlorophenyl) acetamidine 346 321538 201114741

V\u

The title compound was obtained from (3-chlorophenyl)acetic acid in the same manner as in Example 140. Yield: 14.4 mg MSCESI+, m/e): 388 (M+H) Example 218 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)~2~ . Bilidine _3_ kib 2 (2-chlorophenyl) ethanoamine

The title compound was obtained from (2-chlorophenyl)acetic acid in the same manner as in Example 140. Yield: 11.7 mg of MS (ESI+, m/e): 388 (M+H) Example 219 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2~ Methyl pyrrolidine _3_ kib (pyridin-3-yl)-1,3-thiazole _4_cartoamine trifluoroacetate soil 321538 347 201114741

The title compound was obtained in the same manner as in Example 40, from &lt;RTI ID=0.0&gt;&gt; Yield: 12. 2 mg of MS (ESI+, m/e): 424 </RTI> </RTI> <RTIgt; Pyrrrolidin-3-yl]-4-[(1,1-dithiocarbadolyl)indolyl]benzoguanamine trifluoroacetic acid

• cf3co2h The title compound was obtained from 4-[(1,1-dioxythios 348 321538 201114741 morpholin-4-yl)methyl]benzoic acid in the same manner as in Example 140. Yield: 14.1 mg MSCESI+, m/e): 487 (M+H) Example 221 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole ° ratio σ σ -3 -yl] -Ν2-(嗟-phen-2-yl aryl) glycamide

The title compound was obtained from hydrazine-(thiophen-2-ylsulfonyl)glycine in the same manner as in Example 140. Yield: 6. 8 mg MSCESI+, m/e): 439 (M+H) Example 222 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole ° ratio of each α--3-yl]-3-(2-o-oxypyrrolidin-1-yl)benzamide

349 321538 201114741 The title compound was obtained from 3-(2-oxo-pyridin-1-yl)benzoic acid in the same manner as in Example 140. Yield: 12. 0 mg of MS (ESI+, m/e): 423 (M+H) Example 223 N-[(2S, 3R)-1-(3-chloro-4-phenyl)-2- Methyl 0 to 11 each 0--3-yl]-4-(pyrimidin-2-yloxy)phenylamine

The title compound was obtained from 4-(pyrimidin-2-yloxy)benzoic acid in the same manner as Example 140. Yield: 6. 3 mg MSCESI+, m/e): 434 (M+H) Example 224 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole . Bilpyridin-3-yl]-2-(2,3-dihydro-1-benzophenanthrene-5-yl)Ethylamine 350 321538 201114741

The title compound was obtained from 2,3-dihydro-1-benzofuran-5-yl acetic acid in the same manner as in Example 140. Yield: 7. 9 mg φ MS (ESI+, m/e): 396 (M+H) Example 225 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2 -decylpyrrolidin-3-yl]-3-(4-chlorophenyl)isoxazole-5-decylamine

The title compound was obtained from 3-(4-chlorophenyl)isoxazole-5-carboxylic acid in the same manner as Example 140. Yield: 4. 3 mg MSCESI+, m/e): 44KM+H) Example 226 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indenyl Pyridin-3-yl]-2-[2-(4-chlorophenyl)-1,3-α. Sitting _4-base] ethylamine 351 321538 201114741

The title compound was obtained from [2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetic acid in the same manner as Example 140. Yield: 18. 0 mg MS (ESH, m/e): 471 (M+H) Example 227 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Methyl pyrrolidin-3-yl]-2-(morpholin-4-yl)acetamide trifluoroacetate

The title compound m 352 321538 201114741 was obtained from morpholin-4-yl acetic acid in the same manner as in Example 140. Yield: 10. 6 mg MSCESI+, m/e): 363 (M+H) Example 228 N-[(2S, 3R)-l-(3- gas-4-cyanophenyl)-2-indole Pyrrrolidin-3-yl]-3-(1H-indazol-1-yl)propanamide trifluoroacetate

In the same manner as in Example 140, the title compound was obtained from 3 - (1 Η - π π _ 1 - yl) propionic acid. Yield: 15.0 mg MS (ESI+, EtOAc): 422 (M+H) Methyloxaridin-3-yl]-4-(morpholin-4-yl)benzoguanamine trifluoroacetate [s] 353 321538 201114741

CF3C 〇 2H The title compound was obtained from 4-bromo-4-ylbenzoic acid in the same manner as in Example 140. Yield: 14. 6 mg MSCESI+, m/e): 425 (M+H) Example 230 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-indole ° ratio 0 each -3-yl]-2-(4-cyanophenyl)acetamide

The title compound was obtained from (4-cyanophenyl)acetic acid in the same manner as in Example 140. Yield: 7. 1 mg of MS (ESH, m/e): 379 (M+H) 354 321538 201114741 Example 231 1-[(2S,3R)-l-(3- gas-4-cyanophenyl) -2-decylpyrrolidin-3-yl]-3-(4-methoxyphenyl)urea

The solution obtained in Reference Example 36, a 0.12 mol/L solution of triethylamine in DMF (0.500 ml), and 4-methoxyphenyl isocyanate in DMF of 0. 144 mol/L solution (0. 500 ml) and DMF (0.50 ml), and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (3.5 ml) and 2 °/ were added to the reaction mixture. Aqueous sodium bicarbonate (1 ml) was added and the mixture was extracted. After separating the organic layer from the above layer of PhaseSeptube (manufactured by Wako Pure Chemical Industries, Ltd.), it was concentrated under reduced pressure. The residue was dissolved in DMSO/MeOH (0.5 ml / 0.5 ml) and preparative HPLC (PLC: High Yield Purification System, GiIson Inc., Column: YMC CombiPrep ODS-A S -5/zm, 9x50 mm, solvent: solution A; 0. 1% water containing trifluoroacetic acid, solution B; 0.1% acetonitrile containing trifluoroacetic acid, gradient cycle: 〇. 〇〇 minute (solution A/ Solution B=95/5), 1.00 min (solution A/solution B=95/5), 5.20 minutes (solution A/solution B=5/95), 6.40 minutes (solution A/solution B=5) /95), 6, 50 minutes (solution A / solution B = 95/5), 6. 60 minutes (solution A / solution B = 95/5), flow rate: 20 ml / min, test side [S] 355 321538 201114741 Method: UV 220 nm) was purified to give the title compound. Yield: 11.3 mg MS (ESI+, m/e): 385 (M+H) Example 232 4_({[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2 -Methyl 0, each of which is a 3-hydroxy]aminoindenyl}amino) benzoic acid ethyl ester

The title compound was obtained from ethyl 4-isocyanatobenzoate in the same manner as in Example 231. Yield: 19.2 mg MS (ESI+, m/e): 427 (M+H) Example 233 1-[(2S, 3R)-1-(3-chloro-4-cyanophenyl)-2曱基吼口 Each 1,3--3-]]3-[4-(trifluoromethyl)phenyl]urea 356 321538 201114741

F

The title compound was obtained from 4-(trifluoromethyl)phenyl isocyanate in the same manner as in Example 231. Yield: 14.4 mg MSCESI+, m/e): 423 (M+H) Example 234 1-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Ethrolidin-3-yl]-3-[4-(didecylamino)phenyl]urea %

ί^γΝ CHa 357 321538 201114741 The title compound was obtained from 4-(didecylamino)phenyl isocyanate in the same manner as in Example 231. Yield: 17. 0 mg of MS (ESI+, m/e): 398 (M+H) Example 235 1-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2- Mercaptopyridin-3-yl]-3-(4-methoxybenzyl)urea f • Cl&gt;n ν-4 In the same manner as in Example 231, from the isocyanate 4-decyloxy group The phenylhydrazine beta vinegar title compound was obtained. Yield: 6. 3 mg MSCESI+, m/e): 399CM+H) Example 236 1-(4-chlorobenzyl)-3-[(2S, 3R)-l-(3-chloro-4- Cyanophenyl)-2-mercaptopyrrolidin-3-yl]urea[s] 358 321538 201114741 Νι

The title compound was obtained from 4-chlorophenyl phthalocyanate in the same manner as in Example 231. Yield: 15.8 mg of MS (ESI+, m/e): 403 (M+H) Example 237 1-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Mercaptopyridin-3-yl]-3-(3-fluorophenylindenyl)urea %

The title compound was obtained from 3-fluorobenzyl isocyanate in the same manner as in Example 231. 359 321538 201114741 Yield: 7. 0 mg MS (ESI+, m/e): 387 (M+H) Example 238 1-[(2S,3R)-l-(3- gas-4-cyanophenyl) -2-decylpyridin-3-yl]-3-(4-fluorophenylindenyl)urea

,CH; 0

J The title compound was obtained from 4-fluorophenyl phthalocyanate in the same manner as in Example 231. Yield: 6. 7 mg φ MSCESI+, m/e): 387 (M+H) Example 239 1_[(2S,3R)-l-(3-chloro-4-dichlorophenyl)_2-indenyl More than 11 each.定-3_基]_3-(4-chlorophenyl)urea 360 321538 201114741

The title compound was obtained from 4-chlorophenyl isocyanate in the same manner as in Example 231. Yield: 13. 7 mg of MS (ESI+, m/e): 389 (M+H) Example 240 1-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Mercaptopyridin-3-yl]-3-(2,3-dihydro-1-benzoin-5-yl)urea

CI The title compound was obtained from 2,3-dihydro-1-benzofuran-5-yl isocyanate in the same manner as in Example 231. Yield: 7. 1 mg of MS (ESI+, m/e): 397 CM+H) Example 241 361 321538 201114741 1-[(2S,3R)-l-(3-chloro-4_cyanophenyl)_2-oxime吼17 each -3--3-yl]-3-(4-cyanophenyl)urea

# Title compound was obtained from 4-cyanophenyl isocyanate in the same manner as in Example 231. Yield: 9. 9 mg MSCESI+, m/e): 380 (M+H) Example 242 1-(4-t-butylphenyl)-3-[(2S, 3R)-l-(3 - Chloro-4-cyanophenyl)-2-indolyl-hlrolidin-3-yl]urea

The title compound was obtained from 4-t-butylphenyl isocyanate in the same manner as in Example 231. 362 321538 201114741 Yield: 14. 8 mg MSCESI+, m/e): 411 (M+H) Example 243 1-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2 - 曱基. Biropyridin-3-yl]indole butyl-3-yl)urea triacetate

The title compound was obtained from pyridine-3-isocyanate in the same manner as in Example 231. Yield: 3. 9 mg φ MSCESI+, m/e): 356 (M+H) Example 244 [[2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Pyrrrolidin-3-yl]-3-(4-phenoxyphenyl)urea 363 321538 201114741

The title compound was obtained from 4-phenoxyphenyl isocyanate # in the same manner as in Example 231. Yield: 8. 9 mg of MS (ESI+, m/e): 447 (M+H) Example 245 1-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-曱基. Biropyridin-3-yl]-3-

(3-chlorophenyl) urea Q

The title compound was obtained from 3-chlorophenyl isocyanate in the same manner as in Example 231. Yield: 13. 6 mg MSCESI+, m/e): 389 (M+H) 364 321538 201114741 Example 246 1 -[ (2S,3R)-1-(3-chloro-4-cyanophenyl)-2 -Methyl π ratio &quot;〇定-3-yl]-3-[4-(trifluorodecyloxy)phenyl]urea

CI

The title compound was obtained from 4-(trifluorophosphonio)phenyl isocyanate in the same manner as in Example 231. Yield: 8. 1 mg of MS (ESI+, m/e): 439 (M+H) Example 247 3 - gas-N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl) )-2-methyl 0 to 11 each bit -3-yl] benzenesulfonamide [s] 365 321538 201114741

N # mixed reference compound 36 obtained in Example 36 and triethylamine in DMF 0. 12 111〇1 solution (〇.5〇〇1111), 3-chlorobenzenesulfonium chloride in 1) swollen () 144111〇 A few solutions (0·500 ml) and triethylamine were added to a solution of MF (〇5 〇〇ml), and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (3 '5 ml) and 2% aqueous sodium hydrogencarbonate (1 ml) were added to the reaction mixture, and the mixture was extracted. After separating the organic layer from the above layer of PhaseSeptube (manufactured by Wako Pure Chemical Industries, Ltd.), it was concentrated under reduced pressure. The residue was dissolved in DMSO / MeOH (0.5 ml / 0.5 ml) and purified by preparative HPLC ( Instrument: High Yield Purification System, GiIson Inc., Column: YMC Combi Prep ODS-A S-5/ Zm, 19x50 mm, solvent: solution a; 0. 1% water containing trifluoroacetic acid, solution B; 0. 1% acetonitrile containing trifluoroacetic acid, gradient cycle: 0. 〇〇 minutes (solution A / solution B = 95/5), 1. 〇〇 minutes (solution A / solution B = 95 / 5), 5. 20 minutes (solution A / solution B = 5 / 95), 6. 40 minutes (solution A / solution B = 5 /95), 6. 50 minutes (solution A / solution B = 95/5), 6 · 60 minutes (solution A / solution B = 95 / 5) 'Flow rate: 2 〇 m 1 / min, detection method: UV Purification by 2 20 nm) gave the title compound. 321538 [s] 366 201114741 Yield: 7. 4 mg MSCESI+, m/e): 410 (M+H) Example 248 N_[(2S,3R)-l-(3-chloro-4-cyanophenyl) -2-methylpyrrolidin-3-yl]-4-methylbenzenesulfonamide

The title compound was obtained from 4-mercaptobenzenesulfonyl chloride in the same manner as in Example 247. Yield: 10.3 mg MSCESI+, m/e): 390 (M+H) Example 249 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indole 0 to π each 0--3-yl]-4-(trifluoromethyl)benzenesulfonamide 367 321538 201114741

The title compound was obtained from 4-(trifluoromethyl)sulfonium chloride in the same manner as in Example 247. Yield: 9. 3 mg MS (ESI+, m/e): 444 (M+H) Example 250 iK (2s'3io-im cyanyl), 2-methyl-methyl _3_yl]_4_ Fluorobenzenesulfonamide

The title compound was obtained from 4-fluorobenzenesulfonyl chloride in the same manner as in Example 247. Yield: 8. 9 mg 368 321538 201114741 MSCESI+, m/e): 394 (M+H) Example 251 4-chloro-N-[(2S, 3R)-l-(3-chloro-4-cyanobenzene Benzyl-2-methyl^ phenoxymethylamine

The title compound was obtained from 4-chlorobenzenesulfonium chloride in the same manner as in Example 247. Yield: 4. 2 mg of MS (ESI+, m/e): 410CM+H) Example 252 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl吼 啶 -3- -3- -3-yl]-4-(trifluorodecyloxy) benzoate decylamine 369 321538 201114741

The title compound was obtained from 4-(trifluorodecyloxy)benzenesulfonate® chlorobenzene in the same manner as Example 247. Yield: 12. 1 mg MSCESI+, m/e): 460 (M+H) Example 253 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl °Bilo?-3-3-yl]-2,3-dihydro-1-benzoindole. South-5-continuous amine

N

The title compound was obtained from 2,3-dihydro-1-benzofuran-5-sulfonyl chloride in the same manner as in Example 247. Yield: 1. 0 mg MS (ESI+, m/e): 418 (M+H) Example 254 370 321538 201114741 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl) -2-decylpyrrolidin-3-yl]-4-inorganic benzene

CI

N The title compound was obtained from 4-cyanobenzenesulfonium chloride in the same manner as in Example 247. Yield: 2. 5 mg MSCESI+, m/e): 40KM+H) Example 255 N-(4-{[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2- Methyloxaridin-3-yl]aminesulfonyl}phenyl)acetamide

[s] 371 321538 201114741 The title compound was obtained from 4-ethylaminophenylsulfonium chloride in the same manner as in Example 247. Yield: 2. 9 mg MSCESI+, m/e): 433 (M+H) Example 256 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Toxrolidin-3-yl]-4-nonyloxybenzenesulfonamide

Ci^V^ The title compound was obtained from 4-decyloxybenzenesulfonyl chloride in the same manner as in Example 247. Lu yield: 9. 7 mg MS (ESI+, m/e): 406 (M+H) Example 257 N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2 -methylpyrrolidin-3-yl]biphenyl-4_continued amine 372 321538 201114741

Cl

The title compound was obtained from 4-biphenylsulfonyl chloride in the same manner as in Example 247. Yield: 7, 0 mg MSCESI+, m/e): 452 (M+H) Example 258 N-[(2S, 3R)-l-(3-chloro-4-cyanophenyl)-2-methyl Ethrolidin-3-yl]-Ι-ί^-fluorophenyl) phthalocyanine

The title compound was obtained from 4-fluorophenylsulfonylsulfonium chloride in the same manner as in Example 247. Yield: 6. 8 mg 373 321538 201114741 MS (ESI+, m/e): 408CM+H) Example 259 N-[(2S, 3R)-l-(3-Gas-4-cyanophenyl)-2 Monomethylpyrrolidine_3_yl]-bu [4-(dimethylmethyl)phenyl]methanox

The title compound was obtained from 4-trifluoromethylbenzylsulfonyl chloride in the same manner as in Example 247. Yield: 4. 9 mg MSCESI+, m/e): 458 CM+H) Example 260: 1-[(2S,3S)-l-(3-chloro-4-1 phenyl)-2-methyl Than 嘻-3-yl]-3-(4-fluorophenyl)urea

The compound obtained in Reference Example 39 (100 mg), triethylamine (0.077 ml), 4-fluorophenyl isocyanate (〇. 〇 63 ml), and DMF (2 ml) 374 321538 201114741 were stirred at room temperature. The mixture was 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc. W-IMR (DMS0-d6) 6 :0·99(3Η,d), 1.90-2. 05(1H,m), 2. 15-2. 30(1H, m), 3. 15-3. 30 (1H, m), 3. 35-3. 45(1H, m), 4. 05-4. 15(1H, m), 4. 15-4. 30(1H, in), 6.49(1H, d ), 6.63 • (1H, dd), 6.75C1H, d), 7. 00-7. 12(2H, m), 7. 35-7. 45(2H, m), 7.60C1H, d), 8. 50(1H, s). Example 261 2-Chloro-4-{(2S,3S)-3-[(4-fluorophenylindenyl)amino]-2-indolylpyrrolidine-l-yl} Benzonitrile hydrochloride

α

• HCI

F

The compound obtained in Reference Example 39 (100 mg), 4-fluorobenzaldehyde (0.039 ml), triethylamine (0.077 ml), sodium triethylsulfonylborohydride (390 mg), and A mixture of THF/DMF (4 ml / 1 ml) was taken for 16 hours. The reaction mixture was diluted with EtOAc EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) elute The title compound (7 6 mg). !H-NMR (DMS0-de) (5: 1. 19(3H, d), 2. 18-2.33(1H, m), 2. 40-2. 55(1H, m), 2. 20-2 35(1H, m), 3. 45-3. 60(1H, m) 3. 70-3. 85(1H, m), 4. 15-4. 40(3H, m), 6. 62( 1H, d), 6.75 (1H, s), 7. 25-7. 35(2H, m), 7. 60-7. 75(3H, m), 9.55(1H, brs), 9.89(1H, brs Example 262 • 2-Chloro-4-{(2S,3R)-3-[(4-cyanobenzyl)amino]-2-methylpyrrolidine-l-yl}benzonitrile trifluoride Acetate

N The compound obtained in Reference Example 36 and triethylamine were mixed at room temperature under DMF φ.12111〇1 solution (0.50〇1111), 4-cyanobenzaldehyde at 0.14 mol/L of 〇11〇5'. Solution (0.5 ml), sodium triethylsulfonate hydride (38 mg) and DMF (0.500 ml). Ethyl acetate (3.5 ml) and a 2% aqueous sodium hydrogencarbonate solution (1 ml) were added to the mixture and the mixture was extracted. The above layer of PhaseSeptube (manufactured by Wako Pure Chemical Industries, Ltd.) was separated and concentrated under reduced pressure. The residue was dissolved in DMSO / MeOH (0.5 ml / 0.5 ml) and purified by preparative HPLC ( Instrument: High Yield Purification System, Gi 1 son Inc., 376 321538 201114741 Column: YMC CombiPrep O00-A S-5/zm, 19x50 mm, solvent: solution A; 0. 1% water containing trifluoroacetic acid, solution B; 0% acetonitrile containing trifluoroacetic acid, gradient cycle: 0. 00 minutes ( Solution A / solution B = 95 / 5), 1. 00 minutes (solution A / solution B = 95 / 5), 5.20 minutes (solution A / solution B = 5 / 95), 6. 40 minutes (solution A / solution B=5/95), 6. 50 minutes (solution A/solution B=95/5), 6.60 minutes (solution A/solution B=95/5), flow rate: 20 ml/min, detection method: Purification by UV 220 nm) gave the title compound. Lu yield: 7. 2 mg MS (ESI+, m/e): 35KM+H) Example 263 N-[4-({[(2S,3R)-l-(3-chloro-4-cyanophenyl) )-2-mercapto-l-pyridin-3-yl]amino}indenyl)phenyl]acetamidotrifluoroacetate π

The title compound was obtained from 4-ethylaminobenzaldehyde in the same manner as in Example 262. Yield: 4. 7 mg MSCESI+, m/e): 383 (M+H) Example 264: 4-({[(2S,3R)-l-(3-chloro-4-cyanophenyl)- 2-mercaptopurridin-3-yl]amino}mercapto)benzoate trifluoroacetate 377 321538 201114741

The title compound was obtained in the same manner as in Example 262. &quot;4~Methylmercaptobenzoic acid methyl ester Yield: 11. 4 mg MS (ESI+, m/e): 384 (M+H) Example 265 2-chloro-4-[(2S,3R)-2 -曱基_ t Each bite + base]Benzene guesses trifluoroethyl^one gas methyl)benzyl]amino}

4-(Trifluoromethyl)benzaldehyde The title compound was obtained in the same manner as in Example 262. Yield: 1. 9 mg MS (ESI+, m/e): 394 (M+H) Example 266 mi (3) phenoxy phenylmethyl) amide Salt [S3 321538 378 201114741

The title compound was obtained from 3-phenoxybenzazole in the same manner as in Example 262.

Yield: 12. 8 mg MSCESI+, m/e): 418CM+H) Example 267 4-{(2S,3R)-3-[(4--1-ylindole-2-chlorobenzonitrile Butylmethyl)amino]-2-methylpyrrolidine-acetate

• cf3co2h 4-tert-Butylbenzaldehyde was obtained in the same manner as Example 262. Yield: 14.1 mg MSCESI+, m/e): 382 (M+H) Example 268 2-chloro-4-{(2s'3R)mH(4n3_Aphenylmethyl)amino] &quot;Byrrolidine -1-yl}benzoquinone trifluoroacetate 321538 379 201114741

Cf3co2h The title compound was obtained from 4-(3-pyridyl)phenylfurfural φ in the same manner as in Example 262. Yield: 27. 1 mg of MS (ESI+, m/e): 403 CM+H) Example 269 2-chloro-4-[(2S, 3R)-2-mercapto-3-{[(6-pyrrolidine) -1-ylpyridin-2-yl) fluorenyl]amino}pyrrolidin-1-yl]benzonitrile trifluoroacetate

The title compound was obtained in the same manner as in Example 2 6 2 from pyridine-2-carbaldehyde. 380 321538 201114741 Yield: 25. 3 mg MSCESI+, m/e): 396CM+H) Example 270 N-[(2S, 3S)-l-(3-chloro-4-cyanophenyl)_2-fluorenyl Luo Luo. D--3-yl]-4-cyanobenzamide

The compound obtained in Reference Example 39 (104. 5 mg) and triethylamine (0.13 ml) were dissolved in THF (2 mL), and 4-cyanobenzoquinone chloride (69. Mg). The reaction mixture was stirred at room temperature for 30 min and poured into a saturated aqueous The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous acid, and concentrated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) ^-NMR (CDCh) d : 1. 11(3H, d), 2. 03-2. 23(1H, m), 2. 40-2.57(1H, m), 3. 26-3. 45(1H , m), 3. 53(1H, t), 4.29-4.44 (1H, m), 4. 57-4. 79(1H, m), 6. 22(1H, d), 6.47C1H, dd), 6.60C1H, d), 7.45(1H, d), 7. 79(2H, d), 7. 90(2H, d). Example 271 N-[(2S,3S)-l-(3-chloro- 4-cyanophenyl)-2-indolylpyridin-3-yl]-4- 381 321538 201114741 Fluorobenzene

In the same manner as in Example 270, the compound obtained by the reference example (96.5 mg) was used as a starting material, and 4-chlorobenzene (82.8 Torr) was used for the synthesis of 'from ethyl acetate-hexane. The title compound (49. 2 mg) was obtained as white crystals. ^α^ΙΟ,.-Ι.ΙΚΒΗ, d), !.83_2.〇2(111&gt; m), 3.〇9_ 3.24C1H, m), 3.37C1H, t), 3. 78^3. 93( 1H, m), 3.94-4.06 (1H, m), 4.69 (1H, d), 6.38 (1H, dd), 6 51 (1H, ^ 718_ 7.30 (2H, m), 7.42 (1H, d), 7 89-7. 96(2H m) Example 272 ' · (10)I[(10)SH-m cyanophenyl)_2-methyl(tetra)bita_3_IP-yl]-3-(4-fluorophenyl)prop-2-ene Guanamine

In the same manner as in Example 270, the compound (10).7 (IV) obtained in Reference Example (10) was used as a starting material, and ❹(10))-3-(4-fluorobenzyl)prop-2-enyl fluorenyl (83.6) The title compound (10)·i 321538 382 201114741 mg) was obtained as white crystals. ^-NMR CCDCh) 5 : 1. 10(3H, d) i 〇〇 2.50 (lH, in), 3.26-3.41 (lH, m), 3.5 〇 (iHUH, m), 2.35-(1H, m), 4.57-4.72(lH,m),5.7〇(1h ' 4. 25—4. 39 6. 47(2H,dd),7.06-7.15(2H 'd),6.38(1H,d), An, n〇, 7, 45 ( 7.57 (2H, in), 7.67 (1H, d). 5 d) &gt; Example 273 N-[(2S,3S)-l-(3-chloro-4-cyanide Stupid • [4-(Trifluoromethyl)phenyl]methanesulfonamide t-pyridin-3-yl]

CI

In the same manner as in Example 270, the compound of Reference Example % (1G 1.3 mg) was used as a starting material, and the synthesis was carried out using 4_1 benzoquinone chloride (115. 5 mg) from ethyl acetate-hexane. The title compound (48. 2 mg) was obtained as white crystals. 'H-NMR (CDCh) δ : 1. l〇(3H, d), 1. 82-2. 01(1Η, m), 2. 19-2.3Κ1Η, m), 3. 11-3. 25( 1H, m), 3. 38(1H, t), 3.71-3.86 (1H, m), 3.85-3.98(lH, m), 4.29(1H, d), 4.37(2H, s), 6.38(1H, Dd), 6. 52(1H, d), 7.42(1H, d), 7.56(2H, d), 7. 70(2H, d). Example 274 l-[ (2S, 3S)-l-( 3-ox-4-cyanophenyl)-2-methyl D-pyridin-3-yl] 383 321538 201114741 -3-(4-chlorophenyl)urea

In the same manner as in Example 270, the compound obtained in Reference Example 39 (102. 2 mg) was used as a starting material, and 4-chlorophenyl isocyanate (67. 8 mg) was used for the synthesis from acetic acid. The title compound (98. 0 mg) was obtained as white crystals. .Ή-NMR (CDCh) (5 : 0. 99(3H, d), 1. 88-2. 06(1H, m), 2. 12-2.24C1H, m), 3. 17-3. 28( 1H, m), 3.43(1H, t), 4.03-4.17 (1H, in), 4. 17-4. 32(1H, m), 6. 55(1H, d), 6. 63(1H, dd ), 6.75C1H, d), 7.28(2H, d), 7.44(2H, d), 7.60(1H, d), 8.62(1H, brs). Example 275 1-[(2S,3S)-l- (3-chloro-4-cyanophenyl)-2-indenyl "byrrolidin-3-yl]-3-Φ [4-(trifluorodecyloxy)phenyl]urea

CI

H3c The compound obtained in Reference Example 39 (100. 2 mg) was used as a starting material in the same manner as in Example 270, and 4-trifluoromethoxyphenyl isocyanate (66, 7//1) was used. The title compound (50. 7 mg) was obtained as white crystals. 384 321538 201114741 ]H-NMR (CDCh) (5 : 0. 99(3H, d), 1.84-2 〇8(1Η, πι)5 2.11-2. 31(1H, m), 3. 17-3. 30(1H, m), 3. 43(ih, t), 3.97-4.16 (1H, m), 4·18-4·33(1Η, m), 6.58(1H,d) 6. 64(1H, Dd), 6. 75(1H, brs), 7. 24(2H, d), 7. 51(2H, d), 7. 60〇H, d), 8. 70(1H, brs). 276 2- gas-4-{(2S,3S)-3-[(4-cyanophenyl)amino]- 2 - fluorenyl p-pyridin-1-yl}benzonitrile

α. re The compound (116 q mg) and triethylamine (65.8//1) obtained in Reference Example 39 were dissolved in THF (2.2 ml) and 4-cyanobenzaldehyde (62.0 mg) was added and Acetic acid (49·2//1). The mixture was stirred at room temperature for 5 minutes, and sodium triethylsulfonylborohydride (143, 9 mg) was added. The reaction mixture was stirred at room temperature for 2.5 hours, and sodium triethylsulfonylborohydride (319 9 mg), acetic acid-hexane was recrystallized to give the title compound (70. 1 mg;) as white crystals. 49.2// 1) and DMF (10. 5 ml). The reaction mixture was stirred at room temperature for 3 Torr and a saturated aqueous solution of sodium bicarbonate was poured, and the mixture was extracted with ethyl acetate. After the organic layer (10) and brine were washed, it was concentrated with anhydrous sulfur-dry y. By (4) Pipe Tomography 己 乂 乂 _ 纯 纯 纯 , , , , , , , 7 7 7 7 7 7 7 7 7 7 7 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 . . . ((2H, m), 2. 94-4. 07(1H, m), 6.41(1H, dd), 6.54(1H, d), 7.41(1H, d), 7. 50(2H, d), 7.64(2H, d). 277 N [(2S,3S)-l-(3-Gas-4-cyanophenyl)- 2-indenyl π ratio. Deuterium 2-carbylamine

In the same manner, the compound obtained in Reference Example 39 (152.7 mg) was used as a starting material, and pyridine-2-carbonyl chloride hydrochloride (149.8 mg) was used in the same manner as in Example 270, from acetic acid. The title compound (49. 5 mg) was obtained as white crystals. φ ^-NMR (CDCh)^ : 1.13(3H, d), 2. 08-2. 31 (1H, m), 2.37-2.59(1H, m), 3.23-3.43C1H, m), 3. 52( 1H, t), 4.19-4.43 OH, m), 4. 56-4. 85(1H, m), 6.46(1H, dd), 6. 60C1H, d), 7. 44(1H, d), 7.46 -7. 53(1H, m), 7. 83-7. 95(1H, m), 8.21 〇H, d), 8. 58(1H, d). Example 279 2-Qi-4-{( 2S, 3S)-2-methyl-3-[(3-phenoxyphenyl)amino]0-pyridyl-l-yl} 曱 曱 nitrile hydrochloride 386 321538 201114741

Cl

The compound obtained in Reference Example 39 (116.9 mg) and triethylamine (71. 0# 1) were dissolved in THF (1. 6 ml), and DMF of 3-phenoxybenzaldehyde (92. 8 mg) was added. (0.4 ml) solution and the mixture was stirred at room temperature for 10 minutes. Acetic acid (73. 3/z 1) was added, and the mixture was further stirred at room temperature for 10 minutes. After the mixing, a triethyl hydride was added (474. 1 mg). The reaction mixture was stirred at room temperature for 14 hr. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by hydrazine column chromatography (H.sub.-ethyl acetate), and the product obtained was dissolved in ethyl acetate. A solution of 4 mol/L of ethyl acetate in ethyl acetate was added, and the mixture was concentrated to crystals crystals crystals crystals crystals crystals crystals crystals , d), 2. 15-2. 31 (1H, m), 2. 42-2. 62C1H, m), 3. 17-3.30(1H, m), 3. 52C1H, t), 3. 66- 3. 87(1H, m), 4.24(2H, s), 4. 29-4. 43(1H, m), 6.61 (1H, dd), 6. 75(1H, d), 7. 00-7 10(3H, m), 7. 17(1H, t), 7. 31-7. 53(5H, in), 7. 67(1H, d), 9. 52(1H, brs), 9.86( 1H, brs). Example 280 2-Chloro-4-K2S, 3S)-3-[(4-fluorophenyl)amino]-2-methylpyrrolidin-1- [s] 387 321538 201114741 Benzene guess

The compound obtained in Reference Example 39 (206. 5 mg) was basified with aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was dissolved in anhydrous dimethyl acetamide (0.5 ml). 4-Fluoroiodobenzene, copper (I) iodide and acetic acid planer were added under an argon atmosphere. The mixture was stirred at 90 ° C for 2.5 days and poured into an aqueous ammonia solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by hydrazine column chromatography (hexane-ethyl acetate), and the obtained mixture was purified by preparative thin layer chromatography (H. The title compound (4.5 mg) was obtained as white crystals. Ή-NMR (CDCh) δ l. 04(3H, d), 1. 85-2. 17(1H, m), 2. 30-2.64(1H, m〇, 3. 25-3. 38(1H, m), 3.46(1H, t), 3; i 73(1H, brs), 3. 97-4. 12(1H, m), 4. 12-4. 25(1H, m), 6.45(1H, Dd), 6. 56-6. 62(3H, m), 6. 88-6. 97(2H, m), 7.43(1H, d). Example 281 N-[(2S, 3S)-1- (3 -Chloro- 4-cyanophenyl)-2-methyl 0-habita-3-yl]pyridin-3-carboxamide [s] 388 321538 201114741

In the same manner as in Example 270, the obtained compound (119. 2 mg) was used as a starting material, and the synthesis was carried out using pyridyl chloride hydrochloride (93. 6 mg) from ethyl acetate. The title compound (83. 2 mg) was obtained as white crystals. 'H-NMR (CDCh) δ : 1. 12(3Η, d), 2. 05-2. 28C1H, m), 2. 40-2. 59(1Η, m), 3. 28-3. 43( 1Η, m), 3. 53(1Η, t), 4.30-4.45 (1Η, m), 4. 58-4. 77(1H, m), 6. 26(1H, d), 6.47(1H, dd ), 6.6K1H, d), 7.40-7.49(2H, ffi)5 8. 07-8. 23(1H, m), 8.78 (1H, dd), 9.00C1H, d). ' * Example 282 N- [(2S,3S)-l-(3-chloro-4-cyanophenyl)_2-methylpyrrolidine_3_yl]pyridinium-4-carboxamide

In the same manner as in Example 270, the compound obtained in Reference Example 39 (115. 9 mg) was used as a starting material, and the synthesis was carried out using a bite-methyl-chloride hydrochloride (91.0 mg) from acetic acid. The ethyl ester-hexane was recrystallized to give the title compound (50.3 mg). Ή-NMR (CDCh) 5 : 1. 11C3H, d), 2. 08-2. 27(1H, m), 2. 39-2.60(1H, m), 3. 26-3. 43(1H, m ), 3. 53(1H, t), 4.29-4.45 (1H, m), 4. 58-4. 81C1H, m), 6.28(1H, d), 6.47(1H, dd), 6.60(1H, d ), 7.44(1H, d), 7. 63(2H, d), 8.8〇(2H, d). Example 283 N-[(2S, 3S)-l-(3-chloro-4-cyanophenyl) _2-Methyl-p-pyridin-3-yl]-N-methylpyridine-2-carboxamide

In the same manner as in Example 270, the obtained in Reference Example 48 was used.

2-Chloro-4-[(2S,3S)-2-methyl-3-(methylamino)pyrrole bite 4-yl] styrene nitrile hydrochloride (96.5 mg) as starting material and The title compound (28H iH.(CDCl3)m_, d), 2.26_2.41 (1H, m), 2.42_ 2. 63(1H, m), 3. 16 (3H) was obtained as a white solid. , s), 3. 24-3. 39(1H, m), 3.58(1H, t), 4. 49-4. 63(1H, m), 4. 68-4. 91 (in, m), 6.47(1H, d), 6.6K1H, s), 7. 34-7.47C2H, m), 7.65(1H, d), 7.78-7.86 (1H, in), 8.62(1H, d). Example 284 N -[(2S,3S)]-(3-gas-4-cyanophenylmethyl at b each bite_3_base] 321538 390 201114741

-5-(trifluoromethyl)pyridine_2-carbamamine CI

The compound obtained in Reference Example 39 (101. 8 mg), 5-trifluoromethyl ruthenium (86.0 mg), and triethylamine (〇·1〇mi) were dissolved in dmf (2 ml) and Add WSC (107. 5 mg) and HOBt (1. 1 mg). The reaction / WD compound was stirred at room temperature overnight, poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by EtOAc EtOAc EtOAcjjjjjj Ή-NMR (CDCL·) (5 : 1. 13(3H, d), 2. 12-2. 32(1H, m), 2. 41-• 2. 59(1H, m), 3. 28- 3. 43(1H, m), 3. 54(1H, t), 4.28-4.36 (1H, in), 4. 63-4. 79(1H, m), 6.47(1H, dd), 6. 60 (1H, d), 7.45C1H, d), 8. 11-8.20C2H, m), 8. 36(1H, d), 8.85(1H, d). Example 285 N-[(2S' 3S)- L-(3'-gas-4-cyanophenyl)_2-methylpyrrolidin-3-yl]_4_(trifluoromethyl) 0-butoxy-2-carbamide 391 321538 201114741 α

In the same manner as in Example 284, the compound m. 2 mg) obtained in Reference Example 39 was used as a starting material, and 4-trifluoromethyl hydrazine 1 (79. 4 mg) was used to obtain a white color. The title compound (μ. 8 mg). H-NMR (CDCh) (5: 1. 14(3H, d), 2. 08-2. 30(1H, m), 2.41-2. 56(1H, m), 3. 28-3. 45( 1H, m), 3. 53(1H, t), 4.21-4.41 (1H, m), 4. 62-4. 80(1H, m), 6.47(1H, dd), 6.60(1H, d), 7. 45(1H, d), 7. 72(1H, dd), 8. 15(1H, d), 8.46(1H, s), 8. 78(1H, d). Example 286 6-{ [(2S' 3S) + (3-Chloro-4-cyanophenyl)_2_methyl ♦ 唆 _3_ yl] oxy} pyridine-3-decylamine

N 321538 392 201114741 The compound obtained in Example 358 was used as a starting material compound in the same manner as in Example 115, Step 2. MMR (CDC1 eg: 1.〇9(10),d) 2 274^^4 2.47-2.6_,m)' 3·27~3·38(1Η,m),3 55(1H,",4.43UH, t) , 5.44-5.57(ih&gt; m)j 5&gt;85(2η^ s) 6&lt;47(1H, dd), 6.61 (1H,d)' 6.85(iH,d),7 44(ih' ' 8 〇9 (1H, dd), 8.61 (1H, d). ' ' Example 287

4_Terbutyl-N~[(2S,3R)-l-(3-Gas_4-cyanophenyl)-2-indolylpyrrole Benz-3-yl]benzoic acid amine

To the chilled portion, the compound obtained in Reference Example 36 (200 mg) and the tri-amine (165 々i) in THF (2 (4) solution were added with a third butyl beryllite-brown chlorine (2 g) and stirred at room temperature. The mixture was mixed for 2 hours. A 1 mol/L aqueous sodium hydroxide solution was added to the reaction product, and the mixture was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine and dried over anhydrous The residue was purified by EtOAc EtOAc EtOAc (EtOAc) elute (300 MHz, CDCh) (5: 1. 09(3H, d), 1.36(9H, s), 1. 91-2. 07(1H, m), 2. 23-2. 43(1H, m) , 3. 29-3. 46(2H, m), 3. 64-3. 76(2H, m), 4. 87(1H, d), 6.29C1H, dd), 6.42(1H, d), 7 32(1H, d), 7. 46-7. 56(2H, m), 7. 70-7. 84(2H, m). Example 288 2-chloro-4-K2S, 3R)-3- [(4-Methoxyphenyl)amino]-2-indenyl. Pyrrolidine-l-yl}benzonitrile

A solution of the compound obtained in Reference Example 36 (500 mg) and 4-# methoxybenzaldehyde (240/z 1) in DMF (5 ml) was stirred at room temperature for 6 hr. The reaction mixture was ice-cooled, sodium triethylsulfonyl hydride (1.30 g) was added, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, a 1 mol/L aqueous sodium hydroxide solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc elut elut elut Ή-NMR (300 MHz, CdCU) δ : 1. 16(3H, d), 1.98(1Η, dd), 394 321538 201114741 2. 18-2. 36(1H, m), 3. 16(1H, d ), 3. 30-3. 51 (2H, m), 3. 69-3. 84(1H, m), 3. 76(2H, s), 3. 79(3H, s), 6.40C1H, dd ), 6.53C1H, d), 6. 79-6. 89(2H, m), 7. 14-7. 25(2H, m), 7. 39(1H, d). Example 289 4-third Butyl-N-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-2-indenylpyrrole π3_yl]-N-mercaptobenzoic acid amine

Me Me XMe

0 N'Me

Carbonate (505 mg) was added to a solution of the compound (523 mg) obtained in Example 287 (d. A solution of methyl iodide (207 mg) in DMF (2 ml) was added and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, the mixture was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate-hexane toieldield !H-NMR (300 MHz, CdCh) 6 : 1. 18(3H, d), 1.37(9H, s), 1. 82-1. 97(1H, m), 2. 16-2. 35C1H, m ), 2. 67(3H, s), 395 321538 201114741 3.28-3.48C2H, m), 3. 63(1H, dt), 4. 36-4.45(1H, m), 6.32C1H, dd), 6.44C1H , d), 7.40(1H, d), 7. 51-7. 62(2H, m), 7. 69-7. 77(2H, m). Example 290 is more than 2-chloro-4- {( 2S,3R)-3-[(4-Methoxybenzyl)amino]_2-methylrrolidine-l-yl}benzonitrile trifluoroacetate

* CF3CO2H The title compound was obtained from 4-methoxybenzene in the same manner as in Example 262. Yield: 11.3 mg MS (ESI+, m/e): 356 (M+H) Example 291 6-{[(2S, 3S)-l-(4-cyanophenyl)~2~methyl Bilobidine _3_yl]oxy) 0-pyridyl-3-carboxamide

321538 396 201114741 The title compound was obtained using the compound obtained in Example 359. Ή-NMR (CDCh)^ : 1.09C3H, d), 2. 28-2. 42(1H, m), 2.47-2.57(1H, m), 3. 24-3. 39(1H, m), 3.49 -3. 62(1H, m), 4. 39-4.49(1H, m), 5.42-5. 60(1H, m), 5. 86(2H, s), 6. 54-6. 60(2H , m), 6. 85(1H, d), 7. 42-7. 53(2H, in), 8.09 (1H, dd), 8.6K1H, d). Example 292 Qin 4-tert-butyl- N-[(2S,3S)-1-(3-chloro-4-cyanophenyl)-2-methyloxaridin-3-yl]benzenesulfonamide

Me Me /-Me

To a solution of the compound obtained in Reference Example 39 (500 mg) and triethylamine (390 /i 1) in THF (5 ml) was added 4-t-butylbenzenesulfonium chloride (524 mg), The mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, the mixture was diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 397 321538 201114741 'H-NMR (300 MHz, CDC13) (5:1·11(3Η,d), 1.36(9H,s), 1. 86-2. 06(1H, m), 2. 08-2 . 25(1H, m), 3. 16(1H, dd), 3.34(1H, dd), 3. 72-3.89(1H, ra), 3. 88-4. 00(1H, m), 5.34( 1H, d), 6.36C1H, d), 6.47(1H, s), 7. 39(1H, d), 7. 56(2H, d), 7. 84(2H, d). Example 293 2- Gas-4-{(2S,3S)-3-[(4-decyloxyphenyl)amino]-2-indolylpyridol. Fixed-1 - quinone benzoquinone

_n, h

CN A solution of the compound obtained in Reference Example 39 (500 mg) and 4-?-p-oxyphenylfurfural (230 #1) in DMF (5 ml) was stirred at room temperature for 7 hr. The reaction mixture was ice-cooled, sodium triethylsulfonyl hydride (1.23 g) was added, and the mixture was stirred at room temperature for 14 hr. A 1 mol/L aqueous solution of sodium hydroxide was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous acid and concentrated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) ^-NMR (300 MHz, CDCh) 5 : 1. 12(3H, d), 1. 76-1. 98 (1H, 398 321538 201114741 m), 2.17-2.36UH, m), 3 3i (1h, m ), 3 29_3 m), 3. 77(2H, s), 3.81(3H, s), 3. 91-4. 07(1H, m), 6 4 (1H, d), 6.53(1H, s) , 6. 88(2H, d), 7.27(2H, d), 7 4 (1H, d). *40 Example 294 N-[(2S,3S)-1-(3H-Cyanophenyl)_2_A Base-to-bite + methoxyl ratio

〇

I ch3 was produced at room temperature (IV) Compound (10 mg) obtained in Reference Example 39, 2 to methoxy-5-pyridinecarboxylic acid (ιοί mg), wsc (158 mg), mg), diethylamine (192# 1) And a mixture of DMF (5 ml) for 4 hours D. The reaction mixture was diluted with aqueous ethyl acetate and aqueous ammonium sulfate, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, the crystallijjjjjlililililililililililililili H-NMR (300 MHz, DMS0-de) (5: 0. 96 (3H, d), 2. 15-2. 35 (2H, m), 3. 19-3. 38 (1H, m), 3. 43-3. 55(1H, m), 3. 92(3H, s), 4. 15-4. 28(1H, m), 4.39-4.53(1H, in), 6.65(1H, d) , 6. 76(1H, s), 6. 93(1H, d), 7. 61(1H, d), 8. 17(1H, dd), 321538 399 201114741 8.63C1H, d), 8. 71( 1H, d). Example 295 2-Chloro-4-{(2S, 3R)-3-[(4~ 曱I I~ T gas basic fluorenyl) (methyl)amino]-2- OMe methyl Pyrrolidine-l-yl}benzonitrile

^Ν'Me •f&gt;c,

To a solution of the compound (340%) obtained in the title compound (yield: 940 mg) and iodine (90/z), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was diluted with ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) 'H-NMR (300 MHz, CDCh) (5: 1. 19(3H, d), 2. 13(3H, s), 2. 15-2. 26(2H, m), 2. 91-3. 21 (1H, in), 3. 31-3. 54(4H, m), 3. 79(3H, s), 3. 94(1H, td), 6.42(1H, dd), 6.54(1H, d ), 6. 75-6. 89(2H, m), 7. 12-7. 22(2H, m), 7. 41(1H, d). Example 296 N5-[(2S,3S)-l -(3-chloro- 4-cyanophenyl)-2-mercaptopyrrolidin-3-yl]pyridine-2, 5-dimethylamine 400 321538 201114741

Mix a mixture of methyl 6-amine-mercaptopyridine-3-carboxylate (119 mg), 1® mol/L aqueous sodium hydroxide solution (5 ml), THF (5 ml) and methanol (5 ml) at room temperature After 1.5 hours, the mixture was neutralized with 1 mol/L hydrochloric acid and concentrated. A mixture of the obtained residue, the compound obtained in Reference Example 39 (150 mg), WSCC (158 mg), H0Bt (lll mg), triethylamine (192/z 1) and DMF (5 ml) was stirred at room temperature. 4 hours. The reaction mixture was diluted with ethyl acetate and aqueous ammonium chloride, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous succinic acid, and filtered through EtOAc. The solvent was concentrated, and the residue was evaporated,jjjjjjjj !H-NMR (300 MHz, DMS0-de) 5 : 0. 99(3H, d), 2. 17-2. 37(2H, m), 3. 21-3. 57(2H, ra), 4 19-4. 31 (1H, m), 4. 43-4. 58(1H, m), 6. 65(1H, dd), 6. 77C1H, d), 7. 61(1H, d), 7. 79(1H, br. s. ), 8. 15(1H, d), 8.24(1H, br. s. ), 8.41(1H, dd), 8. 97(1H, d), 9. 05C1H , d). Example 297 N5-[(2S, 3S)-l-(3-chloro-4-cyanophenyl)-2-methylindolyl-3-yl] [s] 401 321538 201114741

-N2-mercaptopyridine_2, 5-dimethylguanamine CI

In the same manner as in Example 296, methyl 6-(methylamine-mercapto)pyridiniumcarboxylate (128 mg), 1 m〇i/L aqueous sodium hydroxide solution (5 ml), THF (5 ml) , methanol (5 ml), the compound obtained in Reference Example 39 (150 mg), WSCC158 rag), H0Bt (lll mg), triethylamine (192//1), and DMF (5 ml) were used as starting materials. the remains. Residue obtained from MF_water to give the title compound ( 168 mg) as a white powder. 〇H-NMR (300 MHz, DMSO-de) (J · 0. 99 (3H, d), 2 16-2 37(2H m), 2. 84(3H, d), 3. 22-3. 38(1H, m), 3. 44-3. 56C1H, m), 4. 18-4. 30(1H, m ), 4. 43-4. 57(1H, m), 6. 65(1H, dd), 6.77(1H, d), 7. 61(1H, d), 8. 14(1H, d), 8.42 (1H, dd), 8.84-8.93 (1H, m), 8.97 (1H, d), 9.〇4(iH, d). Example 298 N-[(2S, 3S)_l-(3-gas- 4-cyanophenyl)-2-methyln ratio P each bite _3-based] cyanide ratio -3-amine 321538 [s] 402 201114741

N

φ In the same manner as in Example 294, the compound obtained in Reference Example 39 (150 mg), 6-cyanidine-3-carboxylic acid (97. 9 mg), wsc (158 mg), HOBtClll mg), Triethylamine (192//1) and DMF (5 ml) were used as starting materials to obtain the purified product. The title compound (127 mg) was obtained as a pale yellow powder. ^-NMR (300 MHz, DMSO-de) 5 : 0. 99 (3H, d), 2. 18-2. 35 (2H, m), 3. 21-3. 38 (1H, m), 3.44 3. 57(1H, m), 4. 17-4. 31(1H, m), 4.42-4. 57(1H, m), 6.65(1H, d), 6. 77(1H, s), 7.61 φ (1H, d), 8. 22(1H, d), 8.46(1H, dd), 9.07(1H, d), 9.16 (1H, s). Example 2 9 9 N-[(2&amp; 3S) -1-(3-chloro-4-cyanophenyl)-2-methyl 0-pyridyl~3-yl]-6-(trifluoromethyl)pyridine-3-decylamine 403 321538 201114741

In the same manner as in Example 294, 'for reference, for example, the obtained reference compound (150呃), 6-(trifluoromethyl)pyridine-3-carboxylic acid (126唣) 1% (158 mg), H0Bt (lll) Mg) 'Triethylamine (192# 1) and j) MF (5 ml) were used as starting materials to obtain the purified product. The obtained purified product was recrystallized from ethyl acetate to afford the title compound (89. 6 mg). ^-NMR C300 MHz, DMSO-de) ^ : 0. 99(3H, d), 2. 20-2. 35(2H, m), 3.23-3.4K1H, m), 3. 46-3. 56( 1H, m), 4. 18-4. 31 (1H, m), 4. 43-4. 58(1H, m), 6.65(1H, dd), 6. 77(1H, d), 7.62 (1H , d), 8. 09(1H, d), 8.5K1H, dd), 9. 06(1H, d), 9.18 • (1H,d)· Example 300 6-Chloro-N_[(2S,3S) -l-(3-chloro-4-cyanophenyl)-2-indolylpyridin-3-yl]pyridine-3-indolyl 404 321538 201114741

In the same manner as in Example 294, the compound (150 mg), 6-chloropyridine-3-carboxylic acid (1〇4 mg), WSC (158 mg), HOBt (lll mg) obtained in Reference Example 39 was used. Triethylamine (192/zl) and DMF (5 ml) were used as starting materials to obtain a purified product. The obtained purified product was recrystallized from THF-MeOH toield H-NMR (300 MHz, DMS0-d6) (5: 0. 97C3H, d), 2. 16-2. 34 (2H, 3. 21-3. 35(1H, m), 3. 44-3. 55(1H, m), 4. 16-4. 29(1H, m)' 4.40-4.55(lH,m), 6.64C1H,dd),6·76(1Η,d), 7.61 d), 7.69( 1H, d), 8. 29(1H, dd), 8. 86-8. 93(2H, m). Example 301 N~[(2S, 3S)-l-(3-gas-4-cyanide Phenyl)-2-methylpyrrolidin-3-yl]_6_fluoron-pyridin-3-carboxamide

321538 405 201114741 The compound obtained in Reference Example 39 (15〇11^), 6-fluoropyridine-3-carboxylic acid (93.3 11^), %8 (:(158 mg) was used in the same manner as in Example 294. , H0Bt (lll mg), triethylamine (192/zl), and DMF (5 ml) were used as starting materials to give the purified product. The purified product was recrystallized from THF-methanol . 0 mg). !H-NMR (300 MHz, DMSO-d6) (5:0. 98(3H, d), 2. 18-2. 34(2H, m), 3. 22-3. 35( 1H, m), 3. 45-3. 55(1H, in), 4. 17-4. 28(1H, m), 4. 41-4. 55C1H, in), 6. 65(1H, dd) , 6.76(1H, d), 7.34 • (1H, dd), 7. 61(1H, d), 8. 39-8. 48(1H, m), 8. 75(1H, d), 8.85C1H, d). Example 302 6-{[(2S,3S)-l-(3-Chloro-4-cyanophenyl)-2-methylindolizin-3-yl]aminoindenyl}acridine- Methyl 3-carboxylate

In the same manner as in Example 294, the compound obtained in Reference Example 39 (200 mg), 5-(methoxymethyl) hydrazinidine-2-carboxylic acid (159 mg), WSC (211 mg) HOBt (148 mg), triethylamine (256 /z 1) and DMF (5 ml) were used as starting materials to obtain purified products. The obtained purified product was recrystallized from ethyl acetate 406 321538 201114741 to give the title compound (152 rag) as white crystals. 'H-NMR (300 MHz, CDCh) (5: 1. 14(3H, d), 2. 14-2. 31 (1H, m), 2.43-2. 54C1H, m), 3. 30-3. 42(1H, m), 3.49-3.58C1H m), 4. 00C3H, s), 4. 26~4. 37(1H, m), 4. 63-4. 76(1H, m), 6.46C1H, Dd), 6. 60(1H, d), 7.44(1H, d), 8.23(1H, d), 8.29(1H, dd), 8.49(1H, dd), 9. 16(1H, dd). Example 303

5-Gas-N-[(2S,3S)-l-(3-Gas__4-cyanophenyl)_2-decylpyrrolidinyl-3-yl]pyridin-2-decylamine

CI

The compound obtained in Reference Example 39 (100 mg), 5-chloro-portion oxime-: citric acid (69.4 mg), WSCU 〇 5 mg) ' occupation (74 4 )), 三乙 (128# 1), and leaven (5 mi) as a starting material, treated in the same manner as in Example 294. 'Subsequent to column column chromatography (purification, acetic acid-hexane) purification and recrystallization from acetic acid to hexane The title compound was obtained as white crystals (69. 5 mg). Earn (10) 0 MHz, CDCl3M:1.l2(3Hd) 211_2 28(ii &quot;0, 2.40-2.52(lH,m), 3.30-3·41(1η ,...,3 47_3 57(] mX 4·24-4·35^, m), 4.60-4.74OH, m), 6.46(1H, dd: 321538 407 201114741 6·60(1Η, d), 7.44C1H, d), 7.87 (1H, dd)) 8.06 (1H, d), 8.17C1H, d), 8.52C1H, d). Example 304 6-{[(25,35)+(3-chloro-4-cyanide Phenyl)-2,methylpyrrolidine_3_yl]aminemethanyl}d than biting-3-acid alpha

The mixture of the compound obtained in Example 302 (189 mg), i mol/L aqueous sodium hydroxide (5 mi), and decyl alcohol (2 THF (3 ml) was stirred at room temperature for 4 hours, adjusted with 1 mol/L hydrochloric acid. To pH 4, and diluted with ethyl acetate. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and evaporated. The title compound (101 mg) was obtained as white crystals.]H-NMR (300 MHz, DMSO-de) (5: 0. 99 (3H, d), 2. 13-2. 26 (1H, m), 2. 40-2. 55(1H, m), 3. 21-3. 36(1H, m), 3. 44-3. 55(1H, m), 4. 16-4. 29(1H, m ), 4. 46-4. 61 (1H, m), 6.64C1H, dd), 6.76(1H, d), 7.61(1H, d), 8. 17(1H, dd), 8.47(1H, dd) , 9. 09-9. 16(2H,m), 13.76(1H,br. s.). 408 321538 201114741 Example 305 cyanophenyl)-2-f-pyrrolidine _3

4-Chloro-N-[(2S,3S)-l-(3'&quot;chloro-4-yl]pyridine-2-carboxamide α

Mg), H0Bt (74.4 mg), triethylamine (128#1) and DMF (5 ml) were used as starting materials to obtain a purified product. The obtained purified product was recrystallized from EtOAc (EtOAc) ]H-NMR (300 MHz, CDCh) (5: 1. 12(3H, d), 2. 11-2. 28(1H, φ m), 2. 41-2. 52(1H, m), 3 29-3. 41 (1H, m), 3. 47-3. 57(1H, m), 4. 24-4. 35(1H, in), 4. 61-4. 75(1H, m) , 6.46(1H, dd), 6.60C1H, d), 7.44(1H, d), 7.49(1H, dd), 8. 13(1H, d), 8.2K1H, d), 8.48(1H, d). Example 306 6-Chloro-N-[(2S,3S)-l-(3-Ga-4-cyanophenyl)-2-indolylpyrrolidin-3-yl]pyridine-2-carboxamide 409 321538 201114741 ci

In the same manner as in Example 294, the compound obtained in Reference Example 39 (1〇〇111§), 6-chloro-11, 0-but-2-butylic acid (69.4 11^), and ¥5〇 (1〇5) were used. φ mg), H0Bt (74.4 mg), triethylamine (128/zl) and DMF (5 ml) were used as starting materials to obtain purified products. The obtained purified product was recrystallized from EtOAc (methanol) (m. ^-NMR (300 MHz, CDC13) occupies: 1.12 (3H, d), 2.16-2. 33 (1H, m), 2.41-2. 53 (1H, m), 3.29-3. 41 (1H, m) , 3.48-3. 58(1H, m), 4. 27-4. 37(1H, m), 4. 58-4. 71 (1H, m), 6.46(1H, dd), 6.60(1H, d ), 7.44(1H, d), 7.52(1H, dd), 7.87(1H, t), 7.96(1H, d), 8. 15(1H, dd). #实施例307 N2-[(2S,3S )-l-(3-chloro-4-cyanophenyl)-2-indolylpyridin-3-yl&gt;pyridin-2,5-diamine [s] 410 321538 201114741 ci

The compound obtained in Example 3〇4 (70. 0 mg), WSC (52.3 mg), HOBt ammonium salt (41.5 mg), diethylamine (38.) was used in the same manner as in Example 296. 0 private 1) and DMF (3 ml) were used as starting materials to obtain a purified product. The obtained purified product was recrystallized from methanol to give the title compound (54.2 mg).曰之沱-Wake R (300 MHz, DMS0-d6) 6 :0·99(3Η,d) 9

..., B·14—25 25(1H in), 2.44-2. 54(1H, m), 3. 21-3. 34(1H, m) 〇 ,, ’

Λ d·44-3.54(1H m), 4. 16-4. 27(1H, m), 4. 46-4. 60(1H,m),6 64qh dd 6. 76(1H,d),7.61 C1H, d), 7. 77(1H, s), 8. u(lH' 8.32(1H, s), 8.4K1H, dd), 9. 04-9·1〇(2η,m) ' dd)' Example 308 'Indolyl 5-{[(2S,3S)-1-(3-chloro- 4-cyanophenyl)-2-carbo-n-yl]-amine] ntb.定-2 _缓酸酉 321538 411 201114741

Cl

In the same manner as in Example 296, the compound (100 mg), 6-(methoxycarbonyl)pyridine-3-decanoic acid (79. 8), WSC (105 mg), HOBt obtained in Reference Example 39 was used. (74. 4 mg), triethylamine (128#1) and Dmf (5 ml) were used as starting materials to obtain a purified product. The obtained purified product was recrystallized from THF (yield) to give the title compound (81. 4 mg). 'H-NMR (300 MHz, DMSO-de) (5:0. 99(3H, d), 2. 20-2. 36(2H, m), 3. 23-3. 36(1H, m), 3. 45-3. 56(1H, m), 3. 92(3H, s), 4. 17-4. 30(1H, m), 4.43-4. 57(1H, m), 6.65(1H, Dd), 6.77C1H, d), 7.61(1H, d), 8. 18(1H, d), 8.42(1H, dd), ® 9. 02(1H, d), 9. 13(1H, d) Example 309 N2-[(2S,3S)-l-(3-Galy-1,4-cyanophenyl)_2-methyl-pyridin-3-yl]-N5-Methyl-0 ratio bite-2, 5 -dimethylamine 412 321538 201114741

Cl

In the same manner as in Example 294, the compound obtained in Example 304 (55.0 mg), methylamine (2. 〇m〇i/LTHF solution, 85.7/z 1), WSC (41. 0 mg), H0Bt (28.9 mg), triethylamine (29. 8//1) and DMF (2 in 1) were used as starting materials to obtain purified products. The obtained purified product was recrystallized from EtOAc (m.) ^-NMR (300 MHz, DMSO-de) 5 : 0. 99 (3H, d), 2. 13-2. 25 (1H, m), 2.42-2.60 (lH, m), 2. 84 (3H, d), 3. 25-3. 36C1H, m), 3. 44-3.54(lH, m), 4. 15-4. 27(1H, m), 4. 45-4. 60(1H, m) , 6.64(1H, dd), 6.76(1H, d), 7. 61(1H, d), 8. 14(1H, d), • 8.38C1H, dd), 8.77-8. 84(1H, m) , 9.03-9. 10(2H, m). Example 310 N5-Terbutyl-NZ-[(2S,3S)_l-(3-Gas-4-cyanophenyl)-2-indenyl pi ratio L-bromo-3-yl]pyridine-2, 5-diguanamine 321538 413 201114741

Cl

The compound obtained in Example 304 (55.0 mg), the third butyl φ amine (18.1/1), WSC (41' 〇mg), n〇Bt (28.9 mg), three Ethylamine (29. 8 #1) and DMF (2 ml) were used as starting materials in the same manner as in Example 294, and then purified by preparative HPLC (acetonitrile-water, hydrazine. The title compound (8.3 mg) was obtained as a white powder. !11_ legs (300 MHz, CDC13) 5 : 113 (3H, d),! 51(9H,s), 2.13-2.30(lH,m),2.42-2.54(lH,m), 3.30-3.42(lH,m), 3.48-3.57(1H, m), 4. 25-4 36(1H, m), 4. 63-4. T6(1H, m), • 5.94C1H, s), 6.46C1H, dd), 6.60(1H, d), 7.44(1H, d), 8. 12-8. 27(3H, in), 8.92(1H, dd) Example 311 6_Bromo-N-[(2S,33)-1-(3-Gas~4-cyanophenyl)_2-methyl Pyrrolidine-3-yl]pyridine-3-carboxamide 414 321538 201114741

The compound obtained in Reference Example 39 (200 mg), 6-bromopyridine-3-carboxylate (178 mg), WSC (2 U mg), HOBt (148 mg), and triethylbenzene were used in the same manner as in Example 294. The amine (256//1) and DMF (5 ml) were used as the starting material to obtain the purified product. The obtained purified product was crystallized from ethyl acetate to afford the title compound (10 mg) as white crystals. H-NMR (300 MHz, CDCWd: uoqh, d), 2 〇6_2 23(ih, m), 2.43-2.54C1H, m), 3. 30-3. 41C1H, m), 3.48-3.57 (lH m) , 4.31-4.4K1H, m), 4. 60-4. 73(1H, m), 6. 15-6. 21 (1H,5 m), 6.46(1H,dd),6.60UH, d),7 45(1H,d), 7 63(ih,' dd), 7. 99(1H, dd), 8. 72-8. 75(1H, m). Example 312 ' *

2-bromo-N-[(2S, 3S)-l-(3-chlorocyano]-1,3-indole-4-methylamine

Phenyl)-2-methyl η piroxime _3_ is obtained by the same formulation as the tetra compound (30〇11^), 2-di-13~^- XI reference example 39 of Example 294. 4-carboxylic acid (275 mg), WSC (31 321538 415 201114741 mg), H0Bt (223 mg), triethylamine (384# 1), and DMF (l〇ml) were used as starting materials to obtain a purified product. The obtained purified product was crystallized from diisopropyl ether to give the title compound (353 mg). H-NMR (300 MHz, CDCh)^: 1.11 (3H, d), 2. 08-2. 26(1H, m), 2. 38-2. 50C1H, m), 3. 28-3. 39 (1H, m), 3. 47-3. 55(1H, m), 4. 23-4. 35(1H, m), 4. 56-4. 70C1H, m), 6.45C1H, dd), 6.59 (1H, d), 7.31(1H, d), 7.44(1H, d), 8. 10(1H, s). Example 313 孀^ N-[(2S, 3S)_l-(3-chloro-4 - gas phenyl) - 2 - fluorenyl group 0 洛 σ _ _ 3 _ base] - 1,3- ° plug α sit -4- 曱 amine

In the same manner as in Example 294, the compound obtained in Reference Example 39 (10 〇 111 运), 1,3-° 塞 ° 几 _ _ acid (56.9 111 旦), \^ (3 (105) Mg), HOBt (74. 4 mg), triethylamine (128/zl) and DMF (5 ml) were used as starting materials to obtain purified product. The obtained purified product was recrystallized from ethyl acetate to give a white powder. Title compound (63.0 mg). ^-NMR (300 MHz, CDCh)^: 1. 13 (3H, d), 2. 08-2. 25 (1H, m), 2.40-2. 52 (1H, m) , 3. 28-3. 40(1H, m), 3. 46-3. 56(1H, m), 4. 24-4. 36(1H, m), 4. 61-4. 75(1H, m), 6.46 (1H, dd), 416 321538 201114741 6.59C1H, d), 7.44C1H, d) 8.78(1H, d). Example 314 7·52(1Η,d), 8.22C1H, d), N -[(2S, 3S)-l-(3-chloro-4-3⁄4 stylyl) phenoxypyridine-3-decylamine 2~methylpyrrolidin-3-yl]_6

CI

In the same manner as in Example 2 94, the compound (100 mg), 6-phenoxypyridine

Using the ~3~saucy acid (94.8 11^), 匚 (105 mg), HOBt (74. 4 mg), triethylamine (128# 1), and DMF (5 ml) obtained in Reference Example 39 as a starting point Material to obtain a purified product. The obtained purified product was recrystallized from ethyl acetate to give the title compound (104 mg). !H-NMR (300 MHz, CDC13) (5: 1.09C3H, d), 2. 02-2. 19(1H, m), 2. 40-2. 52(1H, m), 3. 28-3 39(1H, m), 3. 45-3. 55(1H, in), 4. 29-4.40(lH, m), 4. 58-4. 72(1H, m), 6. 13(1H , d), 6.46C1H, dd), 6.59C1H, d), 6.99(1H, d), 7. 11-7. 19(2H, m), 7. 23-7. 30(1H, m), 7 39-7. 48(3H, m), 8. 15(1H, dd), 8. 58(1H, d). Example 315 N-[(2S,3S)-l-(3-gas-4 -Cyanophenyl)-2-methylpyrrolidin-3-yl]-6-(2,2,2-trifluoroethoxy)pyridine-3-decylamine 417 321538 201114741 ci

In the same manner as in Example 294, the compound obtained by the reference example (10 mg), 6-(2,2,2-trifluoroethoxy) π ratio _3_acid (97. 4 mg), WSCUG 5 mg), _ (74, 4 mg), triethylamine (10) and MK 5 ml) were used as starting materials to obtain a purified product. The obtained purified product was crystallized from ethyl acetate (yield) to give the title compound (76. d), 2.03-2. 21(1H, m), 3. 46-3. 57(1H, m), 4. 83(2H, q), d), 6.96(1H, d),

'H-NMR (300 MHz, CDCls): 1.10 (33⁄4 m), 2. 40-2. 53(1H, m), 3. 28-3. 41 Qjj m), 4. 29-4. 42(1H , m), 4.59-4.73(^ 6. 14(1H,d), 6.46(1H,dd),6.6〇(1h 7.44(1Η,d),8.09(1H,dd), 8.59(iH,d Example 316 N2-[(2S,3S)-Bu(3-chloro-4-cyanophenylmethylindolepyrrolidinyl-3-yl)-N5-(2-hydroxy-2-methylpropyl) Pyridine_2, 5, dimethyl hydrazine 321538 418 201114741

N I!

The compound obtained in Example 304 (80 mg), 1-amino-2-mercapto-2-propanol (37.0 mg), DMT-MM (91. 4 mg), THF (1) 5 ml) and a mixture of 2-propanol (1.5 ml) for 18 hours. The solvent was concentrated, and the residue was diluted with ethyl acetate and 1 mol/L aqueous hydrochloric acid, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the title compound was obtained from mjjjjjjjj

Melting point 203 to 205 ° C ^-NMR (300 MHz, CDCh)^ : 1. 13(3H, d), 1.33(6H, s), 1.82C1H, s), 2. 13-2.30C1H, m), 2.43-2. 54(1H, m), 3.30-3. 41(1H, m), 3. 49-3. 58(3H, m), 4. 26-4. 36(1H, ra), 4.63- 4. 76(1H, m), 6.46(1H, dd), 6. 60(1H, d), 6.63-6.7K1H, ra), 7.44C1H, d), 8. 17-8. 31 (3H, m ), 8.99-9.02 419 321538 201114741 (1H, m). Example 317 N-[(2S,3S)-l-(3-Gas-4-cyanophenyl)-2-methylpyrrolidin-3-yl ]-5-(1,3,4-oxadiazol-2-yl)pyridin-2-decylamine

CI

The compound obtained in Example 304 (100 mg), cesium formate (30. 1 mg), DMT-MM (138 mg), THF (2.5 ml), and 2-propanol (2.5 ml) were stirred at room temperature. a mixture of 20 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen sulfate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sulfuric acid. The solvent was evaporated, and the obtained residue, a mixture of 4-methylbenzenesulfonic acid monohydrate (47. 5 mg), diphenylbenzene (4 ml) and DMF (2 ml) was stirred at 150 ° C for 7 hours. The reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, EtOAc (EtOAc m. [s] 420 321538 201114741 Ή-NMR (300 MHz, CDCls) (5: 1. 15(3H, d), 2. 15-2. 32(1H, m), 2. 44-2. 55(1H, (m), 3. 31-3. 1H, m), 6.47(1H, dd), 6.6K1H, d), 7.45(1H, d), 8.20(1H, d), 8. 39(1H, dd), 8.55C1H, dd), 8. 59 (1H, s), 9.31 (1H, dd). Example 318 N-[(2S,3S)-l-(3-chloro-4-cyanophenyl)-2-methylpyrrolidin-3-yl] -δα-methyl-1,3,4-proton-2-indole-2-yl)

The compound obtained in Example 304 (1 mg), acetamidine (37.1 mg), DMT-MM (138 mg), TTHFU. 5 ml) and 2-propanol (2. Mixture of 5 ml) for 20 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogencarbonate and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue, a mixture of 4-methylbenzenesulfonic acid monohydrate (47. 5 rag), xylene (4 ml) and DMF (2 ml) was stirred for 7 hr. The reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified mjjjjjjjjjjjj

Compound (47. 5 mg). Melting point 207 to 208 ° C 丽 R (300 MHz, CDC10 5 : 1.15 (3H, d), 2. 14-2. 3K1H, m), 2.43-2. 55C1H, m), 2. 69(3H, s ), 3. 31-3. 43(1H, m), 3. 49-3. 59(1H, m), 4. 27-4. 38(1H, m), 4. 64-4. 78(1H , m), 6.47C1H, dd), 6.6K1H, d), 7.45(1H, d), 8. 19(1H, d), 8.35(1H, dd), 8.48(1H, dd), 9.24(1H, Dd). Example 319

N-j_(2S,3S)-l-(3-chloro-4-cyanophenyl)-2-indenyl n-yl]-5-(morpholin-4-ylcarbonyl)pyridin-2-indoleamine

The compound obtained in Example 304 (80. 0 mg), morpholine (21. 7/z 1), WSC (59. 7 mg), HOBt (42. 1 mg), triethylamine (43) were stirred at room temperature. 4 // 1) and a mixture of DMF (2 ml) for 4 days. The reaction mixture was diluted with ethyl acetate and 0.5 N hydrochloric acid, and organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjj d), 2. 12-2. 29(ih, 29~3.90(10H,m), 4.25-4.36 6. 46(1H,dd),6.60C1H,d), 8·15(1H, d), 8 27 (1H, dd), compound (65. 3 mg). j-NMR (300 MHz, CDCIO (5: m), 2.42-2.53 (lH, m), 3. (1H, m), 4. 62-4. 76(1H,m), 7.44C1H,d), 7. 92(1H,dd), 8.63C1H, dd). Example 320 N-[(2S, 3S) + (3-chloro+ cyanide] [(4-经基娘+基)) n fixed, 2_ an amine

化合物' In the same manner as in Example 319, the compound (10).0 mg), 4, _ (42 ()), Μ 韵 ΐ ΐ 5 mg), THF (1 ml) and 2- The title compound (48. 7 mg) was obtained as white crystals. d), 1.46-1, 77(2H, m), 2.42-2.53C1H, m), 3.99-4. 24(2H, m), 6.46(1H,dd), ^-NMR (300 MHz, CDCh) ^ : 1. 13(3H, m), 1. 80-2. 10(2H, m), 2.11-2.29(13⁄4 m), 3. 17-3. 42(2H, m), 3.47-3.? 2(3H m), 4. 26-4. 37(1H, m), 4. 63-4. 76(1H, 321538 423 201114741 7·91(1Η, dd), 8. 16(1H, d), 6.60(1H, d), 7.44C1H, d), 7 8.26C1H, dd), 8. 62(1H, dd) Example 3 21

-N -(2-hydroxy-1' 1 -mercaptoethyl)pyridine 2 5 -didecylamine N

The compound obtained in Example 3〇4 (80. 0 mg), 2-amino-2-indol-2-propanol (39·6# 1), DMT was used in the same manner as in Example 319. - MM (115 mg), THF (2 ml), and 2-propanol (2 ml) were obtained as the starting material. iH-NMR (300 MHz, CDC13) (5:1·13(3Η,d), 1.47(6H,s), 2. 13-2. 30(1H, m), 2. 42-2. 53C1H, m ), 3. 30-3. 42C1H, m), 3.49-3. 57(1H, m), 3. 60(1H, t), 3. 73C2H, d), 4.25-4.36 OH, m), 4. 63-4. 76(1H, m), 6.26(1H, s), 6.46C1H, dd), 6. 60(1H, d), 7. 44(1H, d), 8. 15-8. 21 ( 2H, m), 8.24-8.29 424 321538 201114741 (1H, m), 8.95C1H, dd). Example 322 N-[(2S,3S)-l-(3-chloro-4-cyanophenyl)-2 -methyl. Biropyridin-3-yl]-1,3-oxazol-4-decylamine

In the same manner as in Example 294 (purification using basic silicone), the compound obtained in Reference Example 39 (100 mg), 1,3-indazole-carboxylic acid (49. 8 mg), WSC ( 105 mg), H0Bt (74·4 mg), triethylamine (128 // 1) and DMF (5 ml) were used as starting materials to obtain purified products. The obtained purified product was recrystallized from ethyl acetate-hexane to afford titled compound (54.8 g). _ 'H-NMROOOMHz, CDCh) 5 : 1.11 (3H, d), 2. 06-2·23 (1Η, m), 2. 38-2. 50C1H, m), 3. 27-3. 39 ( 1H , ra), 3. 46-3. 55(1H, m), 4. 22-4. 33(1H, m), 4. 59-4. 72(1H, m), 6.45(1H, dd), 6.59(1H, d), 7.05(1H, d), 7.44(1H, d), 7. 90(1H, d), 8.28C1H, d). Example 323 N-[(2S,3S)-l- (3-Chloro-4-cyanophenyl)-2-indolylpyridin-3-yl]-1-methyl-1H-imidazole-4-carboxamide 425 321538 201114741

~N ch3 The compound obtained in Reference Example 39 (100 lI1g), 丨-methyl~ih imidazole-4-carboxylic acid (55·6 mg), WSC (105 mg), H0Bt (74 4 mg) ® diethylamine (丨28# 1) and DMF (5 ml) were used as starting materials, and purified product was obtained in the same manner as in Example 294 (purified using basic sapon.). The obtained purified product was recrystallized from ethyl acetate to give the title compound (51.6 g). ^-NMR (300 MHz, CDCh) (5: 1. l〇(3H, d), 2. 04-2. 21 (1H, m), 2. 36-2. 46(1H, m), 3. 25-3. 36(1H, m), 3. 43-3. 52(1H, m), 3. 76(3H, s), 4. 22-4. 33(1H, in), 4. 57- 4. 69(1H, ni), φ 6.44C1H, dd), 6.58(1H, d), 7. 18(1H, d), 7.39(1H, d), 7.42C1H, d), 7. 55C1H, d Example 324 1^-[(35)-1-(3-chloro-4-cyanophenyl) °birdin-3-yl]-6-fluoropyridine_3-carbamimid 426 321538 201114741

In the same manner as in Example 294, the compound obtained in Reference Example 17 (10〇11^), 6-fluoropyridine-3-carboxylic acid (65.4 1112), \^(:(111 mg), H0Bt (78) was used. 5 mg), triethylamine (134// hydrazine and mp. (5) (4) as the starting material to give the purified product. The obtained purified product was crystallised from ethyl acetate. 2 mg) H-NMR (300 MHz, CDCh) δ : 2. 15-2. 29(1H, m), 2. 40-2. 54 (1Η, m), 3. 36-3.45(1H, m ), 3.46-3. 63(2H, m), 3.75-3. 83(1H, m), 4. 82-4. 91(1H, m), 6.44(1H, dd), 6.51(1H, d) , 6.58(1H, d), 6. 99-7. 〇6(ih, m), 7. 37(1H, d), 8.21-8. 31(1H, m), 8.63(1H, d). Example 325 N-[(3R)-l-(3-chloro-4-cyanophenyl)pyrrolidine_3_yl]_6_fluoropyridine_3_decylamine

In the same manner as in Example 294, 321538 427 201114741 σ (100 mg) obtained by the reference example μ, 6-fluoro 0 ratio biting-3-acid acid (65·4 mg), WSC (111 mg), H〇Bt (78. 5 beer), triethylamine (134# 1) and DMF (5 ml) were used as starting materials to obtain a purified product. The obtained purified product was recrystallized from ethyl acetate to afforded the title compound (70. 4 mg). H-NMR (300 MHz, CDCl 〇 δ: 2. 16-2. 29C1H, m), 2.37-2.51 OH, m), 3. 38-3. 62(3H, m), 3. 74-3. 83 (1H, m), 4.82- 4. 93(1H, ra), 6.43(1H, dd), 6.56(1H, d), 6. 71(1H, d), 6.98-7.05C1H, m), 7.31( 1H, d), 8. 22-8. 32(1H, m), 8.66 • (1H, d). Example 326 N-[(2S,3S)-l-(3-chloro-4-cyanophenyl) )_2-mercaptopyrrolidine_3_yl]-1H-imidazole-4-carboxamide

N The compound obtained in Reference Example 39 (1 〇〇?), 1H-Nandrol-4-carboxylic acid (49.4 mg), WSC (105 mg), HOBt (74. 4 mg), triethylamine ( The purified product was obtained in the same manner as in Example 294 (purified by preparative HPLC (acetonitrile-water, containing ο. % tf a )). The obtained purified product was recrystallized from EtOAc (m.) 321538 428 201114741 Ή-NMR (300 MHz, CDCh)^ : 1. 12(3H, d), 2. 06-2. 23(1H, m), 2. 36-2. 48(1H, m), 3 25-3. 38(1H, in), 3. 44-3. 54(1H, m), 4. 23-4. 34(1H, m), 4. 59-4. 73(1H, m) , 6.45(1H, dd), 6. 59(1H, d), 7.43C1H, d), 7. 62-7. 65(1H, m), 7.71-7.75 (1H, m), 9.40(1H, brs Example 327 6-{[(3S)-l-(3-chloro-4-cyanophenyl>pyrrolidin-3-yl]aminemetholyl}pyridine-3-carboxylic acid decyl ester

The compound obtained in Reference Example 17 (250 mg) 5-(decyloxycarbonyl) D was used as the chito-2-acid (210 mg), WSC (278 mg), HOBt (196 mg), triethylamine (338). #1) and DMF (10 ml) were used as starting materials, and purified products were obtained in the same manner as in Example 294. The obtained purified product was recrystallized from ethyl acetate to give the title compound (196 mg). ^-NMR (300 MHz, CDC13) (5: 2. 16-2. 29 (1H, m), 2. 4 b 2. 55 (1H, m), 3. 36-3.44 (1H, m), 3.45 -3. 65(2H, m), 3.75-3. 83(1H, m), 3. 99C3H, s), 4. 77-4. 90(1H, m), 6.45(1H, dd), 6. 60(1H, d), 7.45(1H, d), 8.20(1H, d), 8.27(1H, dd), 8.47(1H, dd), 9. 12(1H, dd). Example 328 [s] 429 321538 201114741 6-{[(3R)-l-(3-Chloro-4-cyanophenyl)pyrrolidin-3-yl]aminoindenyl}pyridine-3-carboxylic acid methyl ester

w Using the compound obtained in Reference Example 19 (250 mg), 5-(methoxybenzyl) σ ratio bit-2-reacid (210 mg), WSC (278 mg), HOBt (196 mg), triethyl The purified product was obtained in the same manner as in Example 294, using amine (338 / / 1) and DMF (10 ml) as starting materials. The obtained product was recrystallized from ethyl acetate-hexane to give the title compound (285 mg). ^-NMR (300 MHz, CDCh) 5 : 2. 16-2. 30(1H, m), 2. 41-2. 55 φ (1H, m), 3.37-3.44C1H, m), 3. 45- 3.65(2H, m), 3.75-3.83(1H, m), 3. 99(3H, s), 4. 78-4. 89(1H, ra), 6.45(1H, dd), 6.60C1H, d) , 7.45(1H, d), 8.20(1H, d), 8. 27(1H, dd), 8.47(1H, dd), 9. 12(1H, dd). Example 329 6-{[(3S) -l-(3-chloro-4-cyanophenyl)pyrrolidin-3-yl]amine fluorenyl}acridine-3-carboxylic acid 430 321538 201114741

Cl

The gas of the gas ~$-cyanophenyl)pyrrolidin-3-yl]aminecarbenyl}pyridine-3-carboxylate obtained in Example 327 (1?3, 丄mol/L sodium hydroxide aqueous solution ( 3 ml), THF (5 ml) and methanol (mixture of 3 at room temperature for 1.5 hours, with lmc) 1 / L hydrochloric acid for 10 weeks to pH 4 ' and diluted with ethyl acetate. After separation of the organic layer, The title compound (161 mg) was obtained as a white powder. NMR (300 MHz, DMSO-de) 5: 2. 13-2. 36(2H, m), 3.35-3.48(2H, m)5 3.48-3. 60(1H, m), 3.62-3. 73(1H, m), 4. 61-4. 76(1H, m ), 6. 60(1H, dd), 6. 75(1H, d), 7. 62(1H, d), 8.16C1H, d), 8.41-8.50C1H, m)j 9. 〇9(1H, Brs), 9-2K1H, d), 13.7K1H, brs). Example 330 2-Chloro+{(2S,3S)-3-[(4-Gaphenethyl)oxy]_2_indenyl D ratio洛嘴_1-based benzonitrile 321538 431 201114741

Cl

Sodium hydride (30 mg) was added to a solution of the compound (118 mg. 4-Chlorobenzyl chloride (120 mg) and potassium iodide (1 mg) were added under ice cooling and the mixture was stirred for 16 hours. Water was added to the reaction mixture and water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj ^-NMR (CDCh) 5 : 1. 18(3H, d), 2. 05-2. 20C1H, m), 2. 25-2.35C1H, ra), 3. 15-3. 25(1H, m) , 3.40-3. 50(1H, m), 3.98-4. 18(2H, m), 4.50-4.60(2H, in), 6.4K1H, dd), 6.55C1H, d), 7.25-7.38 (4H, m), 7.42 (1H, d). Example 331 4_({[(2S,3S)-l-(3-chloro-4-cyanophenyl)-2-methyl-perylpyridine _3-yl ] oxomethyl)benzoic acid

432 321538 201114741

Compound. Using the starting material obtained in Reference Example 2, the title l), 2.07-2.22 (lH, m), 2.28- 3. 40-3. 50 (ih, m), 3. 93 4-65 (2H, s), 6.42C1H, dd), 7.43(2H,d), 8. 〇4(2H, d). H-iiMR(CDCl3)(5:1.19(3H,d),2〇7-2.38C1H, m ), 3. 15-3·27(1Η,m), 3.40 (3H, s), 4. 00-4. 20(2H, m), 4. 65(2H, 6.55C1H, d), 7.40(1H , d), 7.43Γ2Η Example 332 Lu 4-({[(2S,3S)-:l-(3-chloro-4-cyanophenyl)-2-methyl). σ 各 _ _3 _ ]oxy}indenyl)benzoic acid

A mixture of the compound obtained in Example 331 (203 mg), hydrogenated monohydrate (44 mg) and methanol/THF/water (2 ml / 2 ml / 2 ml) was stirred at 50 ° C for 30 min. The reaction mixture was acidified with hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was recrystallized from ethyl acetate / hexane toield 'H-NMR (DMSO-de) (5: 1.07 (3H, d), 1. 95-2. 12(1H, m), 2. 22-2. 35(1H, m), 3. 15-3 .28(1H, m), 3. 38-3. 50(1H, in), 4. 12-4. 32(2H, m), 4. 65(2H, s), 6. 62(1H, dd ), 6. 75 (1H, 433 321538 201114741 d), 7.48C2H, d), 7. 6K1H, d), 7. 94(2H, d), 12. 94(1H, brs). Example 333 4- ({[(2S,3S)-l-(3-chloro-4-cyanophenyl)-2-methylindoledin-3-yl]oxy}methyl)-N-methylbenzamide

The compound obtained in Example 332 (110 mg), decylamine (2m/l/L THF solution, 0. 223 ml), WSC (85 mg), HOBt (60 mg) and DMF (3 m 1 ) were stirred at room temperature. a mixture of 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) The extract was washed with saturated brine, dried over anhydrous magnesium sulfate The residue was crystallized from ethyl acetate / EtOAc (EtOAc) Ή-NMR (CDCh)^ : 1.19 (3H, d), 2. 05-2. 40(2H, m), 3.02 3H, d), 3. 15-3. 28(1H, m), 3. 40 -3. 50(1H, m), 4.00-4.20 2H, m), 4. 63(2H, s), 6. 13(1H, brs), 6.42(1H, dd), 6.55 434 321538 201114741 1H, d , 7. 38-7.48 (3H, m), 7.77 (2H, d). Example 334 6-{[(3R)-l-(3-chloro-4-chlorophenyl)nbi. Ding-3-yl]oxybbitidine-3-carboxylic acid methyl ester

The compound obtained in Reference Example 45 (240 mg) was dissolved in THF (15 ml), sodium hydride (60% in oily suspension, 0.20 g) was added, and the mixture was stirred at room temperature for 30 minutes. 5-Chloronicotinate decanoate (0.39 g) was added, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate The residue obtained was suspended in diethyl ether and filtered to afford title compound (531.1 mg). lE-MR(CdCh)d : 2. 34-2.45(2H, m), 3. 49-3. 61 (3H, m), 3.78C1H, dd), 3. 92(3H, s), 5. 78 -5. 85(1H, m), 6.43(1H, dd), 6.57(1H, d), 6. 74(1H, dd), 7.41-7.43(1H, m), 8. 17(1H, dd) , 8.83 (1H, dd). Example 335 435 321538 201114741 6-{[(38)-1-(3-Ga-4-cyanophenyl)pyrrolidin-3-yl]oxy}pyridine-3-carboxylate Oxalate

The title compound 臓(CDC13)(5: 2.34-2.46(2H,m), 3.49- was obtained by the method of the example compound using the exemplified compound and 5-chloronicotinate as the starting material. 3. 62(3H,m: 3.79C1H, dd), 3. 94(3H, s), 5.83(1H, d), 6.39-6 49(Π m), 6.56-6.62C1H, m), 6. 76 (1H) d), 7.41-7. 49 (1H, m: 8. 14-8. 21 (1H, m), 8. 85 (1H, dd) Example 336 2 chloro-terminated 2-yl decyloxy ^唆唆+基]Benzyl Geng

〇J^N

Ν, α u 321538 436 201114741 The compound obtained in Reference Example 45 (0.15 g) was dissolved in DMF (15 ml), sodium hydride (60% in oily suspension, 60 mg), and at room temperature The mixture was stirred for 30 minutes. 2-Chloropyridylpyridine hydrochloride (0.39 g) was added, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate The residue obtained was suspended in diethyl ether, and filtered to give the title compound (116. # Ή-NMR CCDCh) : 2. Π-2. 24(1H, m), 2. 30-2. 39(1H, m), 3. 44-3. 58(4H, m), 4. 39- 4. 45(1H, m), 4. 65-4. 76(2H, m), 6.42(1H, dd), 6.56(1H, d), 7. 23(1H, dd), 7. 40-7 46(2H, m), 7. 71C1H, td), 8. 56-8. 60C1H, m). Example 337 2-Chloro-4-[(3S)-3-(pyridin-2-ylindole) Pyrrolidin-1-yl]benzonitrile

The compound obtained in Reference Example 46 and 2-chloromethyl group were used in the same manner as in Example 336. The pyridine salt was used as the starting material to obtain the title [S] 437 321538 201114741. Participating in Xinjiang (10) (5) accounted for: 2. 11-2. 24 (1H, m), 2·3〇—2 39〇η, heart, 3. 44-3· 58(4Η,m), 4. 39-4. 45 (1Η,m), 4.65-4. 76(2Η,m), 6.42(1Η, dd), 6.56(1H, d), 7. 23(1H, dd), 7. 40-7. 46(2H, m), 7.71 (1H, td), 8.56-8. 60(1h,m) Example 338 6-{[(3R)-:l-(3-chloro-4-cyanophenyl)pyrrolidine_ 3_yl]oxy}pyridine-3_-acid

N The compound obtained in Example 334 (〇42 g) was dissolved in ethanol (2 ml, and 1 m 〇l/L aqueous sodium hydroxide solution (2 ml) was added. At 5 〇 it was stirred &quot;5 1 small k, and adding 1 mo 1 / L hydrochloric acid (2 m 1). The reaction mixture was diluted with acetonitrile and water. After separation of the organic layer, it was washed with saturated brine, dried over anhydrous sulfuric acid, and concentrated in B (10) The residue was collected by filtration to give the title compound (346. <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; 83(1H,s),5·77(1Η,s),6·63(1Η,dd), 6.79(1H, d &gt; 6-9K1H, d), 7.62C1H, d), 8. 15(1H, dd), 8. 75(1H, 13.1K1H, s). 321538 438 201114741 Example 339 6-{[(3S)-l-(3-chloro-4-cyanophenyl)pyrrolidine- 3-yl]oxypyridin-3·~ carboxylic acid

In the same manner as in Example 338, the title compound was obtained using the compound obtained in Example 335 as starting material. 'H-NMR (DMSO-de) 5 : 2. 20-2. 46(2H, m), 3. 43-3. 60(3H, m), 3. 72-3. 83(1H, m), 5. 77(1H, s), 6. 63(1H, d), 6. 79(1H, d), 6.88-6.92C1H, m), 7. 62(1H, d), 8. 15(1H, Dd), 8. 72-8. 75(1H, m), 13. 07(ih&gt; s) #Example 340 4-[({[(3R)-l-(3-chloro-4-cyanophenyl) &gt; Bipyridyl_3_yl]oxyindolecarbonyl) Amino]methyl benzoate 439 321538 201114741

In the same manner as in Example 334, the compound and the 4-isocyanatobenzoic acid methyl compound.

Using the ester obtained in Reference Example 45 as a starting material, the title leg was obtained (αχη with: 2.15-2.44 (2H, m), 3.34_3.6G (3H, m) 3. 62-3. 74(1H, m) , 3.81(3H, s), 5.44(1H, s), 6. 64(1H dd), 6.81(1H, d), 7.61(3H, dd), 86-7.91(2H, m) 10.15(1H, s Example 341: 4-[({[(38)-1-(3-chloro-4-cyanophenyl)pyrrolidin-3-yl]oxyindolecarbonyl)amino]benzoic acid methyl ester

440 321538 201114741 'H-NMR (CDCls) 5 : 2 3. 63-3. 73(1H, m), dd), 6.80(1H, d), 10. 16(1H, s). •15-2- 4〇(2H, m), 3.36-3.6K3H, m), 3,8K3H, SX 5·44(1Η, s)j 6.64(1H, 7.61(3H,dd),7.85-7.97(2H,m ),

Example 3426-{[(3R)-i decylamine ♦ chloro-4-cyanophenyl (tetra)-yl]oxybbit _3-

N In the same manner as in Example 115, Step 2, using the compound obtained in Example 338 and the salt of the salt as the starting material, the title compound was obtained. Ή-NMR (CDCh) (5: 2. 18-2.43 C2H, m), 3. 44-3. 57 (3H, m), 3.77 (1H, dd), 5.75 (1H, d), 6.62 (1H, Dd), 6.78 (1H, d), 6.87 (1H, d), 7.42 (1H, s), 7. 62 (1h, d), 7 99 (1H, s), 8. 14 (1H, dd), 8. 7K1H, d). 441 [s] 321538 201114741 Example 343 6-{ [(3S)-l-(3-Gas-4-cyanophenyl) ° ratio π each bite _3_ base]oxyb ϋ定-3-曱醯amine

The title compound was obtained by using the compound obtained in Example 339 and HOBt ammonium salt as a starting material in the same manner as in the the the 'H-NMRCCDCh)^ : 2.24-2.40C2H, m), 3. 44-3. 59(3H, m), 3.77(1H, dd), 5.75C1H, d), 6. 62(1H, dd), 6. 78(1H, d), 6.87(1H,d), 7.42C1H,s), 7.62(1H,d), 7.99(1H, s), ® 8. 14(1H, dd), 8.71 (1H, d). Example 344 6-{[(3R)-l-(3-chloro-4-cyanophenyl)pyrrolidin-3-yl]oxybu n-methyl hydrazine °-3-甲甲胺321538 442 201114741

In the same manner as in Example 45, using the compound obtained in Example 338 and decylamine (2 mol/L THF) as a starting material, the title compound was obtained. ^-NMR (CDCls)^ : 2.32-2.44(2H, m), 3.03(3H, d), 3.48-3. 63(3H, m), 3. 77(1H} dd), 5. 75-5. 80(1H, m), 6. 04(1H, s), 6.43(1H, dd), 6. 57(1H, d), 6. 75(1H, d), 7.43C1H, d), 7.99(1H , dd), 8.56 (1H, d). Example 345 φ 6-{[(3S)-l-(3-chloro-4-cyanophenyl)oxaridin-3-yl]oxybu N-A Pyridyl-3-guanamine

[s] 443 321538 201114741 In the same manner as in Example 45, the example coffee compound and the methylamine curry/L THF solution were used as the compound. Published the title of Ye Wei

iH.(CDCl3)m2.46(2H,m),3.〇4(3H 3.65C3H, m), 3.78(1H, dd), 5.8〇(1H, s), 6 〇9〇H ' 6.45(1H , dd), 6.59 (1H, d), 6.76C]H 7 , ' 8.0K1H, dd), 8.580H, d). '^ ^ ^ Example 346 2-Chloro-4-[(3R)-3- {[5-(P-hydroxy+methylethyl)pyridine-pyridrolidin-1-yl]benzonitrile

The compound obtained in Example 336 (76.9 mg) was dissolved in THF (5 ml), and the solution of sulphate (3 mol/L acetamidine solution; ο·?mi) was added to 〇C, and The mixture was stirred at room temperature for 5 hours. Chlorinated planer (η丨) was added, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was dripped into ice water, neutralized with citric acid, and diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ^MRCCDCls)^ : 1.6K6H, s), 1.73(1Η, s), 2.29-2.44 (2H, m), 3. 48-3. 62(3H, m), 3. 77(1H, dd) 5 73 (1H d) 6.44C1H, dd), 6. 58(1H, d), 6. 70(1H, dd), 7. 44(1H, d) 7. 75(1H, dd), 8. 24-8 31 (1H, m). 'Example 347 2-Chloro_4-[(3S)-3-{[5-(l-ylamino-1-methylethyl)0-pyridine-2-yl] Oxyl}° 洛 咬-1-yl]benzonitrile

L1 In the same manner as in Example 346, the compound of Φ obtained in Example 337 was used as starting material to give the title compound. H-NMR (CDCh) (5: 1.6K6H, s), 1.73 (1H, s), 2.31-2.45 (2H, m), 3.48-3. 62 (3H, id), 3.77 (1H, dd), 5. 70-5. 76(1H, m), 6.44(1H, dd), 6.58C1H, d), 6.70(1H, d), 7.44(1H, d), 7. 75(1H, dd), 8 27-8. 31 (1H, m). Example 348 4-[({[(3R)-l-(3-Ga-4-cyanophenyl) ° ratio n--3-yl]oxy丨 基) Amino] benzoic acid 321538 445 201114741

The same method as in embodiment 338

The title compound was obtained by using the compound obtained in Example 34(s) as a starting material. ^-NMR (DMSO-de) δ ' 2. 11-2 ά?ί9υ , ^·42(2Η, s), 3.35-3.59C3H, m) 3. 62-3. 75(1Η, in), 5.44C1H , s) 6 48 R e , ο. 4δ-6. 74(2Η, m), 6. 81 (1Η, d), 7. 51-7. 69(3Η, m) 7 rq 7 persons^83'7 91(2Η,m), l〇.l〇(1H s). 'Example 349 4-[({[(3S)-l-(3-chloro-4-cyanophenyl)amino]phenylhydrazine) acid

Barrol-3-yl]oxy}carbonyl) Obtained using Example 341 In the same manner as Example 338, 321538 446

The compound of II 201114741 was used as a starting material to obtain the title compound. W-iiimDMSO-c^j. 13-2.47(2H, s), 3.35-3. 60(3H' m), 3. 64-3. 74(1H, m), 5.44(1H, s), 6. 50-6. 74(2H, m), 6.81 (1H, d), 7. 53-7. 68(3H, m), 7. 84-7. 90(2H, ra), 10. 10(1H, s). Example 350 [4_(P-hydroxy-1-methylethyl)phenyl]amine decanoic acid (3{〇_1_(3_chloro-4-ylcyanophenyl)pyrrolidin-3-yl ester

The compound obtained in Example 340 was used as a starting material to give the title compound. ^-NMR (CDC13) (5: 1.59 (6H, s), 1. 72 (1H, s), 2.28-2.40 (2H, ra), 3. 49-3. 57(3H, m), 3. 70 (1H, dd), 5. 49-5. 54(1H, m), 6.44C1H, dd), 6.59(1H, d), 6. 65(1H, s), 7.30-7.38 (2H, m), 7. 43-7. 49(3H, m). Example 351 [4-(1-Hydroxy-1-methylethyl)phenyl]carbamic acid (3s)-i-(3-chloro-4-cyano 447 321538 201114741 Phenyl)pyrrolidin-3-yl ester

Using the same procedure as in Example 346, the compound obtained in Example 341 was used as a starting material to give the title compound. JH-NMR (CDC13) (5: 1.59 (6H, s), 1,71 (1H, s), 2.24-2.42 (2H, m), 3.46-3.56 (3H, m), 3. 67-3.73 (1H , m), 5.49-5. 54(1H, m), 6.45(1H, dd), 6. 55-6. 66(2H, m), 7. 37(2H s), 7. 43-7. 53 (3H, m). Example 352 (4-Aminoformylphenyl)aminecarboxylic acid (3R)-l-(3-Galy-4-cyanophenyl babi-has-3-yl ester 321538 448 201114741

Lu (IV) In the same manner as in Example 115, Step 2, using the compound obtained in Example 348 and H()Bt ammonium salt as a starting material, the title compound was obtained. σ

s), 3.43-3.58(3H m) 3-64-3.7Κ1Η, m), 5.43(1H, s), 6. 64(1H, dd), 6.81(1H 7.22C1H, S), 7.5K2H, d) , 7. 64(1H, d), 7.80(3H d), 9. 98(1H, s). Example 353 Spring [4-(decylamine decyl)phenyl]amine decanoic acid (3^4 —(3_chloro_4-cyanophenyl)pyrrolidin-3-yl ester 321538 449 201114741

In the same manner as in Example 45, using the compound obtained in Example 348 and methylamine (2mol/L THF) as a starting material, the title compound was obtained. ^-NMR (DMSO-de)^ : 2. 25(2H, s), 2. 76(3H, d), 3.36-3.59(3H, s), 3. 62-3. 76(1H, s), 5.43(1H, s), 6. 64(1H, dd), 6.8K1H, d), 7. 51(2H, d), 7. 64(1H, d), 7. 76(2H, d), 8.27 (1H, s), 9. 98(1H, s). Example 354 φ (4-Aminomethylphenyl)amine decanoic acid (3S)-l-(3-chloro-4-cyanophenyl)pyrrole Acridine _ 3 _

N

[S] 450 321538 201114741 The title compound was obtained by using the compound obtained in the Example and the saponin salt as a starting material. -Teng (DMSO-d grabs 2.13 - 2.43 (2H, m), 3.38_3 6i (3H, m), 3.59-3. 72 (1H, m), 5.43 (1H, s), 6.64 (lHs dd), 6.81 (1H, d), 7.2K1H, s), 7.5K2H, d), 7. 64(1H, d), 7 77.7 86 (3H, m), 9.98(1H, s).

Example 355 [4-(Methylamine-mercapto)phenyl]aminecarboxylic acid Pyrrolidin-3-yl ester

-C3-Chloro-4-cyanophenyl) The title compound was obtained using the compound obtained in Example 349 and methylamine (2m?? MMR (DMS0-d6)6:2.〇8~2.4_,s),2 76(3H,d), 3.36-3.58C3H, s), 3. 58-3. 73(2H, m), 5. 43(1H, s), 6 64 (1H, dd), 6.8K1H, d), T.51C2H, d), 7.64(1H, d), 7.71- 321538 451 201114741 7.78(2H, m), 8.28C1H, d), 9. 98(1H, s). Example 356 2-Oxo-4-[(2S,3S)-3-{[5-(l-hydroxy-1-indenyl)pyrazine-2 _ base] oxy}-2-fluorenyl. Pyrrolidinylbenzoylnitrile

(Step 1) In the same manner as in Example 336, using the compound (0.50 g) of 庐π and the oxime 5-chloronicotinate (ο.%) of Reference Example 2 as a wide material, 6-{K2S, 3S was obtained. Small (3-gas + phenyl) winter methyl hydrazine: methyl -3-yl]oxy}pyridine-3-carboxylate (549, 5).疋

(Step 2) A compound (75. 1 mg) was obtained in the same manner as in the s 346. u pull 铩 4 s), 1.71 (1H, 3·24-3.36 (1Η, 5.37-5.49(ίΗ, ΐΧ 7.43(1H, *H-NMR (CDCh)^ : 1. 〇8r〇H ,, d) , 1.60C6H, s), 2. 24-2. 42(1H, m), 2 44 o Cr^ , A ^.44-2.55(lH, m), m), 3.48-3.56C1H, m), 4.38 ^4.47(1H, m), m) '6.47UH'dd), 6.6()(1H,d), 6.74(iH, d), 7.77C1H, dd), 8.25(1Hj d) Example 357 452 [s ] 321538 201114741 4-[(2S,3S)-3-{[5-U-Pyridinylethyl)&gt;Bist 2_yl]oxy}-2-indolylpyrrolidin-1-yl Stupid carbonitrile

(Step 1) In the same manner as in Example 336, using the compound obtained in Reference Example 49 (0.50 g) and 5-chloro-ethyl acetate ( 〇 42 g) as starting materials to obtain e-UdSSH-U-氰 基 ) ) ) ) ) ) ) ) 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 604 (Step 2) The title compound (107.2 mg) was obtained. — INMIMCDCIOS :1·〇8(3Η,d), shoulder (10), s), 173(ih, s), 2. 25-2. 40(1H,m), 2. 44-2. 55(1H, m), 3.24-3. 37(1H, m), 3.48-3. 60(1H,m), 4. 39-4· 49(1H,m), 5. 38-5. 50(1H, m) , 6.54-6.60 (2H, m), 6.76 (1H, this), 7. 44-7.5 〇 (2H, m) 7. 76C1H, dd), 8.25(1H, d). ' ' Example 358 6-{ [(2S' 3S)-1_(3-chloro-4-cyanophenyl)~2_fluorenyl. Biryridyl]oxy}pyridine-3-carboxylic acid 321538 453 201114741

In the same manner as in Example 338, using Example 356, 6-{[(2S,3S)-l-(3-chloro-4-cyanophenyl)-2-methylindole obtained in Step 1 ® The decyl-3-yl]oxyindole pyridine-3-carboxylic acid decyl ester was used as a starting material to give the title compound. !H-NMR (CDCh) δ : 12(3H, d), 2. 32-2. 46(1H, m), 2. 51- 2.62(1H, m), 3.28-3.42(1H, m), 3 53-3. 62(1H, m), 4. 42-4. 52(1H, m), 5. 50-5. 64(1H, m), 6. 50(1H, dd), 6.63C1H, d), 6.89 (1H, d), 7.46 (1H, d), 8.28 (1H, dd), φ 8.93C1H, d). Example 359 6-{[(2S,3S)-l-(4-cyanide Phenyl)-2-methylindenidin-3-yl]oxyacridine-3-carboxylic acid [s] 454 321538 201114741

In the same manner as in Example 338, Step 1, using 6_{[(2S,3S)-1-(4-cyanophenyl)-2-indenyl-pyridinium obtained in Example 357, Step 1. The title compound was obtained as the starting material of 3-ethyl]oxy}pyridine-3-carboxylic acid decyl ester. 'H-NMRCCDCh)^ : 1.10(3H, d), 2. 29-2. 44(1H, m), 2.49-2.59C1H, ra), 3. 24-3.31 (1H, m), 3. 52- 3. 68(1H, m), 4. 41-4. 51(1H, m), 5. 48-5. 64(1H, m), 6. 58(2H, d), 6.86 (1H, d) , 7.44-7. 51(2H, in), 8. 26(1H, dd), 8.9K1H, d). Example 360 6-{[(2S, 3S)-l-(3-chloro-4-cyanide Phenyl)-2-methyl ° 嘻-3-yl]oxy}pyridine-3-carboxamide

455 321538 201114741 In the same manner as in Example 115, Step 2, 6-{[(2S,3S)-l-(3-cyanophenyl)-2-indolyl-pyridine obtained in Example 358 was used. 3-Amino]oxy}pyridine-3-carboxylic acid and HOBt ammonium salt were used as starting materials to give the title compound.

'H-NMRCCDCh)^ : 1.09C3H, d), 2. 27~2. 45(1H, m) 2 47-2.60(1H,m), 3.27-3.38(lH,m),3.55(1h,υ' , 4'43(1H t),5_51(1H,dt),5.85(2H,s),6·47(1η,'dd)',"i(iH' d), 6.85C1H, d), 7.44C1H , d), 8. 〇9(iH, dd), 8 61〇H • d). Example 361 6-{[(2S, 3S)-l-(4-cyanophenyl)-2-methyl. Bilobidine _3_yl]oxybbit

6-{K2S,3S)-l-(4-cyanophenyl)_2-methylpyrrolidine-3-yl]oxy} obtained in Example 359 was used in the same manner as in the step 2 of Example 115. The title compound was obtained as a starting material over the pyridine-3-carboxylic acid and HOBt ammonium salt. W-NMIUCDClOd : 1.09(3H,d), 2.28-2.42(lH' m), 2 47- 321538 456 201114741 2.57(1H, ra), 3.32C1H, td), 3. 50-3. 59(1H, m ), 4.39-4. 49(1H, m), 5.5K1H, dt), 5. 86(2H, brs), 6. 57(2H, m), 6.85(1H, d), 7.48(2H, m) , 8. 09(1H, dd), 8. 61(1H, d). Example 362 5-[(2S, 3R)-l-(4-Ga-3-trifluorophenyl)-3-yl-- 2-methyl t» than u each -3-yl]-N-ethylpyridin-2-decylamine

F

In the same manner as in Example 45, the title compound was obtained as colorless crystals from the compound obtained in Example 1-4 and ethylamine (2 mol/L THF). φ WRCCDCh)^ : 1.26(3H, t), 1.36(3H, d), 2.28-2 43 (1H,m), 2.46-2.6K1H,m),2·91(1Η,s),3·17_3. 35(1η m), 3.41-3.57C2H, m), 3. 59-3. 74(1H, m), 3.99-4.1l(iH q), 6.4K1H, d), 6. 34(1H, td) , 7. 41(1H, dd), 7. 83Q{j dd), 7. 94(1H, brs), 8.02(1H, dd), 8.49(ih, dd) 'Example 363 ' · 5-[( 2S,3R)-l-(4-cyano-3-fluorophenyl)-3-hydroxy-2-pyridylpyrrolidin-3-yl]-N-(tetrahydro-2H-pyran-4-yl) Pyridine.定_2-甲甲胺 疋 321538 457 201114741

F

: In the same manner as in Example 45, the example was used as the =::::...amine as ^-NMR (CDC13) (5:1·35 (3Η η, d), 1.55-1.70 (2Η, m),1 97 (2H,dd), 2.39(1H,dd),2 47 q π Λ "&gt;2.59(2H,m),3.21-3 35 (1H, m), 3.47-3.60C2H, m) q 0 , north m into 3.62-3·75 (1Η, m), 3. 96- U9(10), n), 6.25-6.48 (2H, ^ 7 7.97 (2H, n), 8.13 (1H, dd), 8 53 (ih, dd). · Example 364 • 5-[(2S,3R)-l-(4-cyanide~3~ gas cage scrambled base)-3-hydroxy-2-mercaptopyrrolidin-3- ]]-N-(tetrahydro-2H-thio D-butyl, 4-yl)pyridine-2-carboxamide

321538 458 201114741 Compound and tetrahydro-2H-thios-l-l-amine as starting material gave the title compound as colorless crystals. &amp; *''' ]H-NMR (CDC13) (5: 1.35 (3H, d), Ί L- ryUH, m), 2. 19- 2.44 (3H, m), 2.45-2. 60 (2H, m), 2. 63-2. 88(4H m) 3.21-3.35(1H, m), 3. 61-3. 73(1H, m), 3.88-4 15(2H m) 6.26-6.45C2H, m ), 7.42C1H, dd), 7.87(1H, dd), 7. 94(ih! d), 8. 11(1H, d), 8.53(1H, d). Example 365 • 5-[ (2S, 3R)-l-(4-cyano-3-fluorophenyl)-3-hydroxy-2-methylindole-3-yl]-N-(l,1-tetrahydro-2-H-thio旅基基) π than bite a 2_ methotrexate

F

An oxone (registered trademark; 0.27 g) aqueous solution (1.5 ml) was added to a decyl alcohol solution (15 ml). Methanol was removed under reduced pressure, water was added to the residue, and mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAcjjjjjjjjjjj 459 321538 201114741 'H-NMRCCDCh)^ : 1.19(3H, d), 2. 00-2. 48(6H, m), 3&gt; 〇〇_ 3.40(5H, s), 3. 55-3. 68( 1H, m), 4. 08-4. 26(2H, m) β 03 (1H, s), 6. 55-6. 70(2H, m), 7. 54-7. 63(1H, m) , 797-8. 06C2H, m), 8.49-8. 55(1H, m), 8.86(1H, d). Example 366 5-[(2S' 3R)-l-(4-Cyan-3-B Oxyphenyl)-3-hydroxy-methylpyrrole

Pyridin-3-yl]-N-decylpyridin-2-indoleamine CK

The compound obtained in Example 105 (119 mg) and sodium ethoxide (m.sub.4) was dissolved in DMSO (3 ml), and the mixture was stirred at 8 ° C for 4 hours. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elutcd H-swell (CDC13) (5: l.34(3H,d), 147(3H,t), 2.25_2 44 (2H, m), 2.49(1H, d), 3. 〇2(3H, d) , 3. 29(1H, q), 3.54-3. 79(1H, m), 3. 93-4. 33(3H, m), 6. 04(1H, d), 6.12-6.29 (1H, m ), 7. 38(1H, d), 7.87(1H, dd), 7. 94(1H, brs), 460 321538 201114741 8. 14(1H,dd), 8. 54(1H,dd) Example 367 -丞"Τ N-[(3S)-l-(3-chloro-4-cyanophenyl) ton 1 1,3,4=etc. di-bar-2-yl> ratio.~2~曱Guanamine

In the same manner as in Example 317, 6-{[(3S)-l-(3-gas-4-cyanophenyl) cores synthesized in Example 329 were used.定_3_基]胺甲基基} mouth bite-3-rebel acid (66.〇11^), B. (26.4 11^), 011|17'-1^ (105 mg), THF ( 2 ml), 2-propanol (2 ml), 4-methylbenzoic acid monohydrate (33.8 mg), diphenylbenzene (4 ml) and N-methyl. Bilo bite (2 mi) was used as the starting material to give the title compound (43·1 mg) as pale yellow crystals. Recrystallization was carried out using acetone-house. JH-NMR (CDCh) (5: 2. 18-2. 31 (1H, m), 2. 43-2. 56(1H, m), 2. 68C3H, s), 3. 38-3.45 (lH, m), 3.46-3. 66(2H, m), 3.76-3. 84(1H, m), 4.78-4. 90(1H, m), 6.46(1H, dd), 6.6K1H, d), 7.46 (1H, d), 8. 16(1H, d), 8. 34(1H, dd), 8.47(1H, dd), 9. 19(1H, dd). Example 368 461 321538 201114741 6-{[ (3R)-l-(3-chloro-4-cyanophenyl)pyrrolidin-3-yl]aminoindenyl}pyridine-3-carboxylic acid

6-{[(3R)-l-(3-chloro-4-nitrophenyl)pyrrolidin-3-yl]aminoindenyl}pyridine-3-carboxylic acid oxime ester synthesized in Example 328 (270 A mixture of 1 mg/L aqueous sodium hydroxide solution (5 ml), THF (5 ml) and methanol (5 ml) was stirred at room temperature for 2 hours, then adjusted to pH 4 with 1 mol/L hydrochloric acid and concentrated. Solvent. The residue obtained was washed with water to give the title compound (224 mg). !H-NMR (DMSO-de) 5 : 2. 13-2. 34(2H, m), 3. 36-3. 46(2H, m), ® 3. 48-3. 60(1H, in) , 3. 62-3. 72( 1H, ra), 4. 60-4. 76(1H, m), 6.60C1H, dd), 6.75(1H, d), 7. 62(1H, d), 8 14(1H, dd), 8.44C1H, dd), 9.08(1H, dd), 9. 20(1H, d), 13. 76(1H, brs). Example 369 N2-[(3S)-l -(3-chloro-4-cyanophenyl) °bipyridin-3-yl]-N5-(2-hydroxy-2-mercaptopropyl)pyridine-2, 5-diamine 462 321538 201114741

The 6-{[(3S)-l-(3-gas gin-4-cyanophenyl hydrazide. -3-yl]amine oxime babi-3 was synthesized in Example 329 at room temperature. - tempering acid (70. 〇mg), amidino-2-methylpropan-2-ol (33.6 mg), DMT-MM (111 mg), THF (1.5 ml) and 2-propanol The mixture was diluted with ethyl acetate and 1 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted elution : 1·32(6Η,s), 1.73(1H,s),219_2.3〇(lH,m),2.42-2.56(lH,m),3.36-3.43(lH,m),3.46- 3.63(4H , m), 3. 75-3. 83(1H, m), 4. 77-4. 87(1H, m), 6.45 (1H, dd), 6. 56-6. 63(2H, m), 7. 45(1H, d), 8.17(1H, d), 8. 20-8. 30(2H, m), 8. 95(1H, dd). Example 370 N2-[(3R)-l- (3-chloro-4-cyanophenyl)n-pyrrolidine_3_yl]_N5_(2-hydroxy-2-methylpropyl)pyrene than bite-2, 5-diamine m 321538 463 201114741

In the same manner as in Example 369, 6-{[(3R)-l-(3-chloro-4-cyanophenyl)pyrrolidinyl-3-yl]aminocarbamyl] synthesized in Example 368 was used. Pyridine-3-carboxylic acid (65.0 mg), amido-2-propenylpropan-2-ol (31_2 mg), DMT-MM (103 mg), THF (1.5 ml) and 2-propanol ( 1.5 ml) The title compound (32 8 mg) was obtained as white crystals.臓(CDClOd: 1.32(6H,s), i.73(1H,s), 2.18-2.30 (lH,m),2.42-2.56(lH,m),3.36-3.44(lH,m),3.47 -3.64C4H, m), 3. 76-3. 83(1H, ra), 4. 76-4. 89(1H, m), 6.45 _ (1H,dd),6.56-6.64(2H,m ), 7.45(1H,d), 8. n(lH,d), 8.20-8.30(2H, m), 8. 95(1H, dd). Example 3 71 N-[(3S)-l- (3-Chloro-4-cyanophenyl)pyrrolidine _3_yl]_5_[(4-hydroxypiperidin-1-yl)yl group&gt; than biting a 2~ guanamine 464 321538 201114741

N

In the same manner as in Example 369, 6-{[(3S)-l-(3-chloro-4-cyanophenyl)pyrrolidinyl-3-yl]aminocarbamyl] synthesized in Example 329 was used. Π-pyridine-3-carboxylic acid (100 mg), benzylidene-4-ol (54_4 mg), MT-MMC158 mg), THF (2 ml) and 2-propanol (2 ml) as starting materials. The title compound (67. 8 mg) was obtained as white crystals. Recrystallization was carried out using ethyl acetate-hexane. _ H-NMR (CDC13) (5 . 1.47-1. 74 (2H, m), 1.77-2. G9 (2H, m), 2.15-2.28 (1H' 2.39-2.55 (1H, m), 3 23 ( Ih, heart), 3.35-3.43C1H, m), 3. 44-3. 69(4H, m), 3. 74-3. 83(1H,,) 3.9δ_4.2Κ2Η,ffi), 4.76—4.89 ( Ih, m), 6.45 (1H, dd), 6.60 (1H, d), 7.45 C1H, d), 7.9 〇 nH w, . /, auuH, dd), 8.13(1H, d), 8.25C1H, d), 8. 57(1H, dd). Example 372 N-[ (3R)-l-(3-chloro-4-cyanobenzene ))3⁄4来— gluten, 3-yl]-5-[(4_hydroxypiped 321538 465 201114741.-1-yl) ruthenium]0 than bite-2-nonanoic acid amine

α α is the same as in Example 369, using the 6-{[(3R) + (3-chlorophenyl) old _3_yl]aminocarbazide} pyridine-3 -carboxylic acid (65?), piperidin-4-ol (35.4 11^), 010-1^ (103 mg), THF (1.5 ml) and 2-propanol (15 ml) as starting materials The title compound of the white salt Ba (23. 3 mg). Recrystallization was carried out using ethyl acetate-hexane. iH-NMRCCDClOs : 146_175(2H,ra), l 75_2.G7(2H,m), 2. 15-2. 28(1H, In)) 2. 40-2. 54(1H, m), 3. 23 (1H, brs), • 3-35-3.43(lH, m)j 3.44_3.67(4H, m), 3. 73-3. 83(1H, m), 3. 98-4. 22(2H , m)5 4. 77.4. 89(1H, m), 6. 45(1H, dd), 6.60(1H, d), 7.45(1H, d), 7. 90(1H, dd), 8. 13 (1H, d), 8.25(1H, dd), 8. 57(1H, dd). Example 373 N-[(3S)-l-(3~Chloro-4-cyanophenyl)pyrrolidinyl ,3_thiazole_4_carbamamine 321538 466 201114741

In the same manner as in Example 294, 4-[(10)-3-aminol t 唆+yl]-2-chlorobenzidine hydrochloride (1 〇〇 mg), 1 synthesized in Reference Example 17 was used. , 3-thiazole-4-carboxylic acid (60. 〇mg), WSCC 111 mg), Η0Βΐ (78·5 ru mg), triethylamine (135//1) and DMF (5 ml) as starting materials. The title compound (98. 2 mg) was obtained as a light crystal. Recrystallization was carried out using ethyl acetate to hexane. ^-NMR (CDCh) &lt;5: 2. 12-2. 26(1H, ra), 2. 39-2. 53(1H, m), 3. 32-3. 42(1H, m), 3 43-3. 62C2H, m), 3. 73-3. 82(1H, m), 4. 77-4. 88(1H, m), 6.44(1H, dd), 6. 59(1H, d ), 7.44 (1H, d), 7.50 (1H, d), 8.20 (1H, d), 8.75 (1H, d). 0 Example 374 1^-[(31〇-1-(3-Ga-4) -Cyanopyl)p-pyrrolidine-3-yl]_5_(5-methyl-1,3,4-flfdiazol-2-yl)u-pyridinyl-2-amine [s] 321538 467 201114741

Cl

6-{[(3R)-l-(3-chloro-4-cyanophenyl)pyrrolidine_3_yl]aminecarbenyl} ° than biting-3-carboxylic acid (65.〇11^) , acetamidine (25.9 11^), dragon 1'-1^ (103 mg), THF (1.5 ml), 2-propanol (1.5 ml), 4-mercaptobenzenesulfonic acid monohydrate (33. 3 mg), diphenylbenzene (4 ml) and hydrazine, decyl-didecylacetamide (2 ml). Recrystallization was carried out using acetone-hexane. JH-NMR (CDCh) 5 : 2. 18-2. 31(1H, m), 2. 42-2. 56(1H, m), Φ 2.68(3H, s), 3.37-3.66(3H, m) , 3.75-3.85(1H, m), 4. 80-4. 89(1H, m), 6.46(1H, dd), 6.6K1H, d), 7. 46(1H, d), 8. 16(1H , d), 8. 34(1H, dd), 8. 43-8. 50(1H, m), 9.19 (1H, dd). Example 3 7 5 !^-[(31〇-1-(3 -chloro-4-cyanophenyl)indoleidine-3-yl]~1,3-thiazole_4-monoamine [s] 468 321538 201114741

4-[(3R)-3-Aminopyrrolidin-1-yl]-2-chlorobenzonitrile hydrochloride (1 〇〇 mg) synthesized in Reference Example 19 was used in the same manner as in Example 294. ), 1,3-thiazole-4-carboxylic acid (60' 〇mg), WSC (111 mg), H0Bt (78. 5 ♦ mg}, triethylamine Cl35//i;) and DMF (5 ml) Starting material, the title compound (101 mg) was obtained as pale crystals. , 2. 39-2. 53(1H, m), 3. 33-3. 41 (1H, m), 3. 43-3. 62(2H, m), 3. 73-3. 81 (1H, (m), 4.76-4. 8.75 (1H, d). φ Example 376 N-[(2S,3S)-1-(3-chloro-4-cyanophenyl)-2-indolyl*»specific 唆-3-yl]- 5-amine sulfonyl pyridyl-2-guanamine

CI

a mixture of 5-aminosulfonylpyridine-2-carboxylate (76.2 mg), 1 mol/L hydrogen 469 321538 201114741 Aqueous sodium oxide solution (1 ml), THF (2 ml) and methanol (2 ml) After stirring at room temperature for 1 hour, it was adjusted to pH 4 with 1 mol/L hydrochloric acid. The solvent was concentrated and the residue obtained was stirred at room temperature, 4-[(2S,3S)-3-amino-2-methylindyrridin-1-yl]-2-chloride synthesized in Reference 39 A mixture of benzonitrile hydrochloride (80 mg), WSC (84. 5 mg), H0Bt (59.4 mg), triethylamine (102 #1) and DMF (5 ml) for 5 hours. The reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of ammonium sulfate, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by EtOAc EtOAc EtOAc. ^-NMR (CDCL·) δ : 1. 13(3H, d), 2. 12-2. 31(1Η, m), 2. 40-2.56(1Η, m), 3. 29-3.43(1Η, m), 3.49-3. 59C1H, m), 4. 26-4. 38(1H, m), 4. 62-4. 78(1H, m), 5. 00(2H, s), 6.47 (1H , dd), 6.60(1H, d), 7. 45(1H, d), 8. 11-8. 18(1H, m), φ 8.36-8.40(2H, m), 9. 09(1H, dd Example 377 N-[(2S, 3S)-l-(3-chloro-4-cyanophenyl)-2-methylpyrobityl-3-yl]-5-(didecylamine sulfonyl) Pyridin-2-guanamine

321538 470 201114741 6-cyano N,N-methyl η synthesized by reference example 50 was stirred at 5 ° under a nitrogen stream with a mixture of -3-glycoside (215 mg) and methanolic hydrogen chloride (20 ml). The mixture was concentrated for 20 hours, and the solvent was concentrated. After the obtained residue was suspended in water (10 ml), the mixture was adjusted to pH 8 with sodium carbonate and the mixture was stirred at room temperature for 30 minutes. Obtained a pale yellow powder (201 mg). A mixture of the obtained powder (86.! mg) ' lm 〇 1/L aqueous sodium hydroxide (1 ml), THF (2 mi) and methanol (2 ml) at room temperature After stirring for 30 minutes, the mixture was adjusted to ρίί 4 with im〇i/L hydrochloric acid. The solvent was concentrated and the residue obtained was stirred at room temperature. 4-[(2S,3S)-3- Amino-2-methylpyrrolidin-1-yl]-2-onebenzonitrile hydrochloride (80 mg), WSC (84.5 mg), HOBt (59.4 mg), triethylamine (102//1) and The mixture was diluted with ethyl acetate and a saturated aqueous solution of chlorination, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was obtained, and the obtained residue was purified by EtOAc EtOAc (EtOAc) CdCh)d : 1.14(3H, d), 2. 16-2. 30(1H, m), 2.43-2.54(1H, m), 2.81C6H, s), 3. 31-3. 42(1H, m ), 3.50-3.59 (1H, m), 4. 26-4. 37(1H, m), 4. 63-4. 77(1H, m), 6.47C1H, dd), 6.6K1H, d), 7.45 (1H, d), 8. 16(1H, d), 8.25(1H, dd), 8. 36-8. 41(1H, m), 8. 95(1H, dd). Example 378 2-Chlorine -4-K2S,3R)-3-hydroxy-2-methyl-3-[6-(2-methyl-1H-imidazole 321538 471 201114741

The same as that obtained in Example 12 was used in the same manner as in Example 112. The title compound was obtained as the starting material and 2 A (tetra) saliva. H-NMR(CDCl3) m(3H,d), 2 34_2.45(iH,m),25i_ 2.61(2H,m)' 3.25~3. 35(1H,m),3.51(1H,s),3 69(1H, ddd), 4. 08(1H, q), 6.52(1H, dd), 6.65(1H, d), 6. 95(1H, d), 7. 24(1H, d), 7 28(1H, dd)5 7.48(1H, d), 7. 84(1H, dd), 8. 55-8. 58(1H, m). Example 379

2-Chloro-4-[(2S,3R)-3~hydroxy-2-methyl-3-(2-sideoxy-2H-1,2'-bipyridyl-5'-yl)pyrrolidine -Based]

[S] 321538 472 201114741 In the same manner as in Example 112, the title compound was obtained using the compound obtained in Example 12 and the 2-light base ratio as the starting material. H-NMR (CDCh) (5 · 1.33(3H, d), 2. 30-2. 39(1H, m), 2.44-2. 55(1H, m), 3. 22-3.34(2H, m) , 3. 61-3. 73(1H, m), 4. 02-4. 11(1H,m), 6.24-6.36(1H, m), 6.49(1H,dd), 6. 62-6. 67 (2H, m), 7. 39-7. 48(2H, m), 7. 82-7. 90(3H, m) 8. 49(1H,dd). Example 380 Li 5-[(2ύ, 310 + (3-chloro-4-cyanophenyl)_3_transyl-2-methylpyrrolidin-3-yl]1(4' 5-dihydro-1' 3H2_yl) 吼_2_甲Indoleamine

The title compound was obtained in the same manner as in Example 45, using the compound obtained in Example 16 and 2-amino-1,3-indole as starting material. (D_-d is: U8(3H,d), 2 31_2 44(2H,m), 3.22-3.3K3H' m), 3.55~3.71(ih,m),3 7b3 85(211,m), 4. 10-4. 23(1H,m), 6.01C1H,s), 6.7 〇(1h,dd),6 84(1H, d)' 7. 63(1H,d),7·94- 8·〇4(1η,m),8 〇5 8 〇9(1H, m), 321538 473 201114741 8.68C1H, d), 10.30C1H, s).

[Preparation Example 1] (1) Compound of Example 316 50 mg (2) Lactose 34 mg (3) Corn starch 10. 6 mg (4) Corn starch (paste) 5 rag (5) Magnesium stearate 0.4 Rg (6) Carboxymethylcellulose calcium 20 mg Total amount 120 mg According to a conventional method, the above (1) to (6) are mixed and ingots are obtained by an ingot making mechanism. [Preparation Example 2] (1) Compound of Example 1 5.0 mg (2) Sodium chloride 20. 0 mg (3) Distilled water _

Total 2. 0 mL The compound of Example 1 (5.0 mg) and sodium chloride (20.0 mg) were dissolved in distilled water, and distilled water was added to a total amount of 2.0 mL. The solution was filtered and filled into ampoules (2 mL) under sterile conditions. The ampoule is sterilized and tightly sealed to obtain an injection. Experimental Example 1 AR binding inhibition assay (wild type, LNCaP type) Adding 3 nM radiation marker miboleron and final concentration in a solution containing an androgen receptor (AR) having a wild type or LNCaP type mutation 474 321538 201114741

Is a compound of l/z Μ, and the mixture is incubated at 4 ° C for 3 hours, and then B (binding) / F (Free) separation according to the polydextrose / charcoal method, the label of B is measured, and Calculate the inhibition rate of the compound. The results are shown in Table 1. [Table 1] Inhibition rate (%) at 1//M Table 1 Compound number wild type LNCaP type 26 94 97 27 98 97 34 97 89 35 99 92 45 77 49 48 97 90 83 46 56 105 57 46 112 99 92 113 21 46 114 10 14 281 93 65 313 86 59 316 95 63 318 96 88 Bicalutamide 92 85 It is clear from Table 1 that the compounds of the invention are wild type and 475 321538 201114741 LNCaP type mutant androgen receptor Shows strong affinity. Experimental Example 2 Inhibition of prostate specific antigen (PSA) production against various (including mutant) prostate cancer cells using the compound of the present application Human prostate cancer cell LNCaP-FGC was inoculated at 5000 cells/100 //L/well. A 96-well plate was placed and a final concentration of 1 ng/mL of testosterone and 1 // guanidine compound was added every other day. Three days after the addition, the PSA concentration in the culture supernatant was measured by EL ISA. As for the compound labeled with *, the human prostate cancer cell LNCaP-FGC was inoculated into a 24-well dish at 40,000 cells/1000 //L/well, and a final concentration of 0.1 ng/mL was added every other day. The same as 1 / Μ compound. Three days after the addition, the PSA concentration in the culture supernatant was measured by EL ISA. The inhibition rate of PSA production was calculated as 100% in the non-addition group of guanosterone and 0% in the testosterone-added group. The results are shown in Table 2.

[Table 2] Inhibition rate (« at 1//M

[s] 476 321538 201114741 Table 2 Compound number inhibition rate «) 26 69. 1 27 56. 3 34 57. 2 35 37. 5 45 57. 0 48 80. 5 63 23. 8 83* 100. 8 105* 83 3 113* 100. 6 114* 90. 5 316* 100. 5 Bicalutamide* 75. 0 It is apparent from Table 2 that the compound of the present invention exhibits potent PSA production inhibitory activity. Experimental Example 3 AR transcription inhibition assay Cos-7 (5,000,000 cells) was spread in a flask and cultured in medium (DMEM + 10% polydextrose charcoal (DCC) - fetal bovine serum (FBSH2 mM branic acid) The medium was cultured for 24 hours. The vector DNA inserted into the mutant AR (W741C) and the vector DNA having the luciferase bound to the androgen-responsive promoter were co-transfected by liposome method.培m 477 321538 201114741 养基' and culture the cells for 3 hours. Add a final concentration of 〇. 1 "DHT (dihydroanthracene) and a final concentration of 1 # μ. Culture cells for 24 hours, measure luciferin The enzyme activity, and the AR transcriptional inhibitory activity of the compound was examined. The results are shown in Table 3 with respect to the inhibition rate (%) of the control group (〇·丨 with elbow DHT). [Table 3] 1//M pair mutant Immortal inhibition rate (%) Table 3

Compound No. 26 27 34 35 45 48 63 83 105 112 113 114 281 313 316 318 Inhibition rate (%) 82 85 92 74 48 77 39 38 56 98 30 34 88 72 73 89 -12 Bicalutamide 321538 478 201114741 It can be clearly seen in 3 that bicalutamide is mutated from the transcriptional inhibitory activity. However, the compounds of the present application show activity. Industrial Applicability The compound (I) or a salt thereof of the present invention has an excellent antagonistic effect on a normal androgen receptor and/or a mutant androgen receptor, and is used as a heterotrophic hormone. A medicament for the prophylaxis or treatment of a hormone-sensitive cancer in a stage and/or a male-independent phase. • [Scheme 丨 simple description] None. [Main component symbol description]

Ml 〇

321538 479

Claims (1)

201114741 VII. Patent application scope: 1. A compound of the formula (I), or a salt thereof, or a salt thereof, or a salt thereof, or a salt thereof, or a salt thereof, or a salt thereof, or a salt thereof, R1 is a cyanophenyl group having a substituent as required; Is (1) a hydrogen atom or (2) (^-6 alkyl; R is a nitrogen atom; R4 is (1) an aromatic ring group optionally having a substituent, (2) -NRa-X-(CH2)nY- Rb, wherein ^ is (1') a hydrogen atom or (2,) Cn6 alkyl; X is a (Γ) linkage, (2,)-C0-, (3,)-C0NH- or (4,)- S〇2_; η is an integer from 0 to 3; Υ is (Γ) bond, (2,)-0-, (3,)-ΝΗ-, (4,)-NHC〇-, (5')-NHS〇2- or (6,)-CH= CH-; Rb* optionally as a ring group having a substituent; or (3)- wherein Z is a (1') bond, (2')-CH2- or (3,)-C〇NH-; A ring group having a substituent is required; 匕r5 having a substituent is (1) a hydrogen atom, (2) a hydroxyl group, or (3) an on-demand alkoxy group; 321538 480 201114741 R is (1) a hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom, or (6) a group via a sulfur atom; R7 is (1) a hydrogen atom, (2) a tooth atom, (3) via carbon a group of an atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom; R is a (1) hydrogen atom, (2) a halogen atom, 3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) a group via an oxygen atom or (6) a group via a sulfur atom; and R is a U) hydrogen atom, (2) a halogen atom, (3) a group via a carbon atom, (4) a group via a nitrogen atom, (5) via an oxygenogen a group of a subgroup or (6) a group via a sulfur atom; the following 18 compounds are excluded: 321538 481 201114741 2. A compound of claim 1 wherein R4 is required to have [S] 482 321538 201114741 a substituted aromatic ring group, mr optionally having a substituent base-based base, 〇 〇 Base, 0 to α sitting base, mouth rice π sitting group, Cai Ji, 嗟〇 基, 卩 oxazolyl, isoxazolyl, fluorenyl, benzothiazolyl, stupid and stilbene, bite base Or a thienyl group, a piperidinyl group or a morpholinyl group, which may optionally have a substituent. 3. If the patent application scope is j a compound of the formula, which is represented by the formula (la) Da) In the formula N, the benzene ring having a substituent in the step =1; the β β is an aromatic hydrocarbon ring optionally having a substituent, optionally having an aromatic heterocyclic ring or a non-aromatic ring having a substituent as necessary;纟:t,^ 〜ΝΗ---NHCH2---NHCO---NHCOCIL·-, nC0NH-, ~_c〇(CH2)2_, _NHC〇CH2〇_, _nhc〇CH2NHC〇_, nHC0(CH2) 3- &gt; -NHC0CH=CH---NHC0NHC0-, ~NHCOC:H2NH~, -NHCOCH2NHS〇2-, -NHC0NHCH2-, -NHS〇2-, --NHSO2CH2- &gt; ^N(CH3)--- N(CH3)CH2---N(CH3)C0-, ~N(CH3)S〇2', -0CH2- or -0CONH-; R is a hydrogen atom or a C1_6 alkyl group; R is a hydrogen atom, a hydroxyl group or a Ci_6 Alkoxy; 483 321538 201114741 $When, U is a bond, then ring Ba is an aromatic hydrocarbon ring optionally having a substituent or an aromatic hetero ring optionally having a substituent. 4. The compound of claim 3, wherein the ring V is a benzene ring having a substituent selected from the group consisting of a halogen atom, a group having a (iv) group, and a Ci-e alkoxy group, as needed. For example, the compound of the third item of the patent (4), wherein the ring is a benzene ring, a 2 ring ring, a salt ring, a taste ring, a naphthalene ring, a ring, a ring, a ring, a ring, a ring, a ring, a benzopyrrole ring, a benzo (tetra) ring, a cough ring: a 2,3-dihydrobenzofuran ring, an oxazole ring or a thiophene ring, which may have a substituent. 6.= Patent Application No. 3 a compound wherein ring Aa is a benzene ring having an optional (four) atom, optionally an alkyl group having a tooth atom, and a substituent of a Ch alkoxy group, and a ring Ba is a benzene ring as desired. The bite ring, the ring of the ring, the rice salt ring, the sputum ring, the word ring, the π ring, the stupid ring, the benzimidazole ring, the acridine ring, the 2, 3_ dihydrobenzofuran, , the phenocyclic ring, which may optionally have a substituent. For example, the compound of the first item, the compound of the formula (10), and the Rb (lb) formula, 321538 484 201114741, the ring Ab further has a C selected from a halogen atom and optionally a tooth atom as needed! a stupid ring of a -6 alkyl substituent; a ring B is a π ratio bite ring further having a substituent as needed; 1^ is a bond or -NHC0-; 1^ is (1) optionally having an optional a Cl_6 alkyl group of a hydroxyl group, an amine methyl group of a substituent of a Ge cycloalkyl group, (2) a cyano group, (3) a pyrrolidinyl group optionally having a pendant oxy group, or (4) optionally having c!-6 Alkyl oxadiazolyl; R2b is a Cl-6 substituent; and R is a hydrogen atom or a meridine. 8. The compound according to claim 7 wherein (1) Lb is a bond, ring Bb is a 3-3⁄4 pyridine ring, Rbg(a) a mono Cl_6 alkylamine carbazyl group, (b) a single C3- a 6 cycloalkylaminecarbamyl group, (c) a cyano group, ((1) a fluorenyl group having a pendant oxy group as desired or (e) an oxadiazole group having a Cu alkyl group, if necessary; or (2) L^-NHC0-, ring Bb is 2-pyridine ring, R^(a) optionally requires a C1-6 alkyl group having a hydroxyl group or (b) an oxadiazolyl group having a Ci-6 alkyl group as desired. a compound which is 5-[(2S,3R)-l-(3-chloro-4-cyanophenyl)-3-carto-2-pyridylpyrrolidin-3-yl]-N-cyclopropyl Pyridine-2-carbamide or a salt thereof 10. A compound which is 5-[(2S,3R)-l-(3-gas-4-cyanophenyl)-3-hydroxy-2-methyl Pyrroxy-3-yl]-N-(l-decylethyl)pyridin-2-indoleamine or a salt thereof 485 321538 201114741 11· A compound which is 5-{(2S,3R)~i- [4-Cyano-3-indanyl)phenyl]-3-hydroxy-2-methylpyrrolidin-3-ylbu N-methyl-2-indoleamine or a salt thereof.疋12. A compound which is 5-[(2S,3R)~i-(4_cyano_3-fluoro]-3-yl-2-yl-yl-l-yl-3-yl]~N -methylpyridine__2 a soil) or a salt thereof. "Metformin 13. a compound which is 2-chloro-4-{(2S,3R)-3-hydroxy-2, methyl-3-[6-(2-o-oxypyrrolidin-1-yl) Pyridine _ _ _ _ _ 比 比 。 。 。 } } } } } } } 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Pyrrrolidin-3-yl]pyridine-2-carbonitrile or a salt thereof. Working soil 15. A compound which is 2-fluoro-4-one {(2S,3R)-3 hydroxy 曱美-3-[6 -(5-fluorenyl-1,3,4-fluoren-2-yl-2-yl)pyridine-3-yl]npyridin-1-yl}benzonitrile or a salt thereof. N2-[(2S,3S)-l-(3-chlorocyanyl)-2-methylindole-3-yl]_N5_(2_transyl-2-methylpropyl)= 2, 5-diamine or a salt thereof. U. a compound which is N_[(2S,33)_1_(3_gas_4_cyanophenyl)-2-methyl- 0-p each 0疋3-yl]-5-(5-mercapto-1,3,4-indenyl sigma-2-yl)D-pyridin-2-indoleamine or a salt thereof. A prodrug of a compound of item 1. 19. An agent' includes a compound of claim 1 or a salt thereof or a prodrug thereof. 20. A pharmaceutical agent as claimed in claim 19 It is an androgen receptor antagonist 321 538 486 201114741. The agent according to claim 20, wherein the androgen receptor is a normal androgen receptor and/or a mutant androgen receptor. An agent according to claim 19, which is a medicament for the prophylaxis or treatment of a hormone-sensitive cancer in an androgen-dependent phase and/or an androgen-independent phase. A medicament for the prophylaxis or treatment of prostate cancer. The method for antagonizing the androgen receptor comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to breastfeeding 25. A method of preventing or treating a hormone-sensitive cancer in an androgen-dependent phase and/or an androgen-independent phase, comprising administering an effective amount of a compound of claim 1 or a salt or a prodrug thereof to a mammal. | 26. A method for preventing or treating prostate cancer, comprising administering an effective amount of a compound of claim 1 Or a salt thereof or a prodrug thereof to a mammal. 27. Use of the compound of claim 1 or a salt thereof or a prodrug thereof for the manufacture of an androgen receptor antagonist. Use of the compound of claim 1 or a salt thereof or a prodrug thereof for the manufacture of a medicament for preventing or treating a hormone-sensitive cancer in an androgen-dependent phase and/or androgen-independent phase . [s] 487 321538 201114741 29. Use of a compound of claim 1 or a salt thereof or a prodrug thereof for the manufacture of a medicament for preventing or treating prostate cancer. [S3 488 321538 201114741 IV. Designated representative map: There is no schema in this case. (1) The representative representative of the case is: () Figure (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. 5 321538