TW201029996A - Heterocyclic compound - Google Patents

Heterocyclic compound Download PDF

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TW201029996A
TW201029996A TW98129505A TW98129505A TW201029996A TW 201029996 A TW201029996 A TW 201029996A TW 98129505 A TW98129505 A TW 98129505A TW 98129505 A TW98129505 A TW 98129505A TW 201029996 A TW201029996 A TW 201029996A
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Taiwan
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1h
hz
2h
amino
ml
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TW98129505A
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Chinese (zh)
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TWI475018B (en
Inventor
Yoshihiro Banno
Ryoma Hara
Ryosuke Tokunoh
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Takeda Pharmaceutical
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Priority to PCT/JP2009/054095 priority patent/WO2009110520A1/en
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Abstract

Provision of a prophylactic or therapeutic agent for diabetes, which has superior efficacy. A compound represented by the formula: or wherein each symbol is as described in the specification, or a salt thereof.

Description

201029996 VI. Description of the Invention: - Technical Field of the Invention The present invention relates to a heterocyclic compound having a glycosidic antagonism, which is suitable as a prophylactic or therapeutic agent for diabetes and the like. [Prior Art] Glycosin is a linear peptide having 29 amino acids which is secreted by pancreatic α cells and promotes hepatic saccharide decomposition and glucose nascent in the liver. Patients with diabetes usually exhibit excessive secretion and reactivity of glycosides, which is one of the causes of hyperglycemia. Therefore, the glycoside receptor antagonist can inhibit the liver from producing excessive sugar by the action of turning off the glycoside, so it is suitable as a therapeutic drug for diabetes. Regarding the glycoside antagonist, the following compounds are known. 1) A compound of the formula:

[wherein, the cyclic oxime is a 6- to 10-membered aryl group, a 6- to 10-membered aromatic heterocyclic group, a 6-membered aryl group condensed with a 5- or 6-membered carbocyclic ring; and Ri, when it is present, is (a) halogen, OH, C〇2R4, S0PR5, CN, N〇2, C(0)NR6R7 or NR6R7, (b) CH alkyl, CCOXh alkyl or C(0)Ci-6 alkyl (substitutable by (a)) , (c) 6 3 321426 201029996 to 10 membered aryl, aryloxy or arylthio, or 5 to 1 member aromatic heterofluorenyl, aromatic heterocyclic-oxy or aromatic heterocyclic -thio groups (each may be substituted by (a) or (b); such groups may be further subjected to beta-pyrazole, sodium salivate, tetrazole, pyrrole, triazole, thiazole, furan, thiophene, thiadiazole or anthracene An azole (each may be substituted by (a) or (b)); r2 is η, or a substituent (a) or (b); x is _〇_, -s-, -(ccrWi-, -OC( R3) 2k(r3)2〇_; Rule 3 is H, or Ch. Alkyl, Cw alkenyl, aryl or aromatic heterocyclic groups (each may be substituted with (&) or (〇, one of which is not R3 Is Η or alkyl); R4 is II or G-6 alkyl; ❹!^5 is Cl-1G alkyl, aryl or aryl-Chg alkyl; R6 and R7 are each ruthenium or

Ci-3 炫基' p is 〇 to 2; Ra is CH2CH2CO2R4, CH2CH(OH)C〇2R4 or 5-tetrazolyl; and Rb is oxime, or substituent (a) or (b)] (Patent Document 1) : W02006/102067). 2) - A compound of the formula:

[wherein ' R1 is (a) C]-i fluorenyl, C2-i 〇 or C2-1. Fast radicals (each may be substituted)' or (b) aryl, aromatic heterocyclic or non-aromatic heterocyclic groups (each may be substituted); R2 is deuterium or R1; R3 and R4 are each deuterium or C! -]. Alkyl; R5 is fluorene or F; R6 is hydrazine, OH, F or G-3 alkyl, or R5 forms a pendant oxy group with R6; R8 is hydrazine or G-ioalkyl (substitutable phenyl, hydrazine H , OCh alkyl, C〇2H, CO2C1-6 alkyl, halogen substituted); m is 0 to 2; n is 1 to 6; when one of m and η is not 〇, Z is COR8, 5- Tetrazolyl or 5-(2-sided oxy 4 321426 201029996 -1,3,4-oxadiazolyl), and when both m and η are 〇, ζ is 5-tetrazed or 5 -(2~Sideoxy-1,3,4-anthracenyl)] (Patent Document 2: W02004/069158). 3) - a compound of the formula: ν .ζ

X R_ Ε I Ν 〆

D (I) Lu Φ

-S(0)2〇R5 "^N, yNH N=N

Wherein, V is -C(0)〇R2, -C(〇)NR2R3, -c(o)nr2ore on X5 R4 ' at 9 1,n is from ° to 3; r7 is H, Ci-6 alkyl, etc.; R8 and r9 are each; γ is -(10)-m or -bonding; is diyl=6-membered aromatic heterocyclic ring (each ri is Η or Cm alkyl; X is 321426 5 201029996 -^[CRVVtCH^- , (CR'VVWr · -Mo^jrWr·

Hey you "iiVtqtyr,

JL(DH^(CR^^O-tCiyr· »

X<CH*^

(CR^VVtc^fe- ❿ r is 0 or l; q and s are each 0 to independently H or Ci-6 alkyl; D is R12, R13, R14 and R15 each 321426 6 201029996

W is -0---S---S(0)2- or -NR2°-; W' is =CIT - or -N= ; R i20* ,16

R17, R18, and Riy are each independently Η, -(ΧΟ)Νί^1!^, -CCO)!^1, etc.; R, 18 |19 21n22 .21 »20 and 1^ are each 11, (1) An alkyl group, a fluorene 3-8 cycloalkyl group or a fluorene 3-8 cycloalkyl group - 〇1-6 alkyl group; each of R21 and R22 is H, -CF3, a C6 alkyl group, an aryl group, an aromatic heterocyclic group Etc.; and E is a 3- to 9-membered single or double ring that is optionally substituted (Patent Document 3: WO00/69810). 4) A compound of the formula:

Among them, A is

OH 7 321426 201029996 x is a bond, -CRf- or -NR1-; Y is >CR3- or >N-; R1, 1^2 and R3 are each independently H or Ci-e alkyl, or R] R2 forms a double bond as needed; E is c!, alkyl, or ο-,. Cycloalkyl, Cw cycloalkyl-Ci 6 alkyl, aryl, aromatic heterocyclic or aryl-C,-6 alkyl (these groups may each be substituted by halogen, C!-6 alkyl, etc. ) et al; b is

V4, , or vO^ ; Spring X is -N= or -CR8= ; Y' is -s 〇- or NR8-; R8 is Η, or Ci-6 alkyl or aryl (these groups can each be Halogen, Ci 6 alkyl, etc. substituted; R9 is hydrazine or Ch alkyl; D is aryl or aromatic heterocyclic (each may be halogen, C--i-alkyl, Cm alkoxy, Cw cycloalkyl , aryl (these rings may be substituted by halogen, Cl-io alkyl, etc.), etc.) (Patent Document 4: (9). Further, 'the following compounds are also known. 5) - A compound of the following formula:

Ra XR$ wherein, G is phenyl or (tetra); W is - (4) ((10) A-, -CH(6) NH-, - Tibetan Mastiff (5)-, genus| or ((4)Q; μ h or alkyl; 犷 ο, 1 Or 2; Rl is H, optionally substituted silk, optionally substituted y, if necessary, substituted by the family, if necessary, substituted: non-aromatic heterocyclic group substituted by cycloalkyl hydrazine ; _ Η 视 视 视 视 Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; H, optionally substituted alkyl, halogen, -CF3, -ORn OCFs, -0 core, etc.; I is -CF3, -OCF3, optionally substituted alkyl, wishing f substituted cycloalkyl a non-aromatic heterocyclic group m 视 which may be substituted, a substituted aryl group, an optionally substituted aromatic heterocyclic group, -OR!3, -c(=o)R13, -C〇 0) NR13R14, etc.; χ is _((>〇)仙_, one NH(〇〇)—, ~NH(C=0)0-, _S〇2NH-, _c〇2_ or one bond; H, wish for the substituted Cl-4 alkyl group, optionally substituted alkoxy group, if necessary, take 1 phenoxy group, a substituted cycloalkyl group, an optionally substituted fluorene aromatic heterocyclic group, an optionally substituted aryl group, an optionally substituted aromatic group, a heterocyclic group, etc., & and R5 may be bonded to each other. Forming a 5 or 6 membered ring; Rii, : and the heart are each independently a fluorene, optionally substituted by a substituted alkyl group, optionally substituted non-aromatic _ = listening to the substituted aromatic reduction requires a substituted aromatic _ ring · Depending on the need = 3; the compound is a inflammatory disease for the treatment of y-column compounds, especially under

(Patent Document 5: W02004/098528) Patent Document 1: W02006/102067 Patent Document 2: W02004/069158 Patent Document 3: WO00/69810 Gong 426 9 201029996 Patent Document 4: W02004/002480 ' Patent Document 5: W02004/098528 [ Disclosure of the Invention Problems to be Solved by the Invention It is desired to develop a compound which has excellent effects and is suitable for preventing or treating diabetes and the like. Means for Solving the Problems The inventors of the present invention have found a compound represented by the following formula (I) or a salt thereof (sometimes abbreviated as "compound (I)" in the present specification) and a compound represented by the formula (ΙΑ) or The salt (sometimes abbreviated as "compound (")" in the present specification) has an excellent glycosidic antagonism and has an excellent effect as a prophylactic or therapeutic agent for diabetes or the like. Based on this finding, the inventors of the present invention have conducted intensive studies and thus completed the present invention. Accordingly, the present invention relates to (1) a compound represented by the following formula or a salt thereof:

Wherein, the cyclic oxime is a benzene ring which is optionally substituted, or a 5- or 6-membered aromatic heterocyclic ring which is optionally substituted; the cyclic oxime is a 5-membered aromatic heterocyclic ring which is optionally substituted; the ring AC is optionally substituted a benzene ring, or a 5- or 6-membered aromatic heterocyclic ring which is optionally substituted; 10 321426 201029996 R is a C1-e alkyl group which is optionally substituted, and c3 which is substituted as preferred, and the naphthenic earth is to be substituted a heterocyclic group to be substituted by C6_l4 aryl or φ φ φ ^ 土 一 ;; R is a ruthenium atom or a Cl-6 alkyl group; RA5 is -(CH2)3-C00RA11 or -nrA6-crhCRA9rA10_c〇〇 rA11; RA6, RA7, RA8, rA9 and rA11 gas enthalpy are led to a ruthenium atom or a Ch alkyl group; Μ and R are a ruthenium atom, a c]-6 alkyl group or a meridine group;

(2) A compound according to the above item (1), wherein

» , and ring AA is a benzene ring or a 6-membered aromatic heterocyclic ring; the formula (IA) is of the following formula (IA,)

(3) a heterocyclic Cl-6 alkyl group as described in the above item (2), optionally substituted: a 5- or 6-membered heterocyclic group; RA4 is a hydrogen atom; wherein RA3 is optionally substituted C3 -i. a cycloalkyl group or, if necessary, R ^-(CH 2 ) 3 -C00RAn ^-NRA6-(CH 2 ) 2 -C00RA11 ; R is a hydrogen atom or a methyl group; and R is a hydrogen atom, a methyl group or an ethyl group; 4) +3-{[(4-{[cyclohexyl-fluorenyl- benzofuran-2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid or its salt (5) 3-{[(6-{[cyclohexyl(5-fluoro_3-methylbenzofuran-2-yl)) 321426 11 201029996 yl]amino}pyridin-3-yl)carbonyl]( Amidino)aminopropionic acid or a salt thereof; (6) 3-{[(4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl) Butyl]amino}phenyl)alkyl](methyl)amino}propionic acid or a salt thereof; (7) 3-[{[4-({1-[5-(cyclopropylmethoxy) a 3-methyl-;|monobenzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonylindole (methyl)amino]propionic acid or a salt thereof; (8) 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-benzofuran-2-yl]methyl}amino) Phenyl]carbonyl hydrazine (methyl)amino]propionic acid or a salt thereof; (9) 3-{[(5-·([cyclohexyl(5-fluoro-3-methyl-1-benzo-c-c-) 2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amine Propionate or a salt thereof; (10) 3-{[(4-{[cyclopentyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino}phenyl a (meth)amino}propionic acid or a salt thereof; (11) a compound of the formula: or a salt thereof:

R5 (I) wherein, cyclic oxime is a substituted benzene ring or a substituted 5 or 6-square-membered aromatic heterocyclic ring as required; ring B is a ratio of °. sit;

Rl=R2 are each independently a substituted hydrocarbyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or a fluorenyl group; R3 is a Ci6 alkyl group which is optionally substituted, and optionally substituted] . Cyclone 321426 12 201029996, optionally substituted C6-H aryl or optionally substituted heterocyclic group R4 is a hydrogen atom or a Cl-6 alkyl group; R5 is -(CHA-COOR11 or -NRLcrY-CRWO- Coor11 ; R, R, R8, R9 and R11 are each independently a hydrogen atom or a Ci group; and R is a hydrogen atom, a Cl-6 alkyl group or a meridine group, but does not contain N-[4-[[(l-benzene) -5-5-propyl-ΐΗ-π than sal-4_yl)methyl]amino]benzyl]alanine;

(12) A compound according to the above item (11), wherein

And ring A is a benzene ring or a 6-membered aromatic heterocyclic ring; 'The formula (I) is of the following formula (Π or

The compound according to the above item (11), wherein R1 is an optionally substituted Cm alkyl group, an optionally substituted aryl group, or an optionally substituted 5 or 6 membered aromatic heterocyclic group. ;

R is optionally substituted Cl-6 alkyl, optionally substituted Cl-6 alkoxy, or optionally substituted C3-1C) cycloalkyl; R3 is optionally substituted C]-6 An alkyl group, optionally substituted C3-1Q cycloalkyl, or a substituted 5- or 6-membered heterocyclic group; R4 is a hydrogen atom; R5 is -(CH^-COOR11 or -NV-CHz-CRVLcOOR11; R6 is a hydrogen atom or a methyl group; R9 is a hydrogen atom, a mercapto group or an ethyl group;

Rl° is a hydrogen atom, a mercapto group or an ethyl group; and 13 321426 201029996 R11 is a hydrogen atom, a mercapto group or an ethyl group; (14) 3-[({4-[(cyclohexyl){3-mercapto-1-[ 5-(Trifluoromethyl)pyridin-2-yl]-indole-n-pyrazol-4-yl}fluorenyl)amino]phenyl}carbonyl)amino]propionic acid or a salt thereof; (15) 3- [{[4-(indolylhexyl[1-(3-decyloxyphenyl)-3-methyl-1H-inden-4-yl]methyl}amino)phenyl]yl}} Methyl)amino; |propionic acid or its salt; (16) 3-[{[4-({cyclohexyl[1-(3-methoxyphenyl)-4-methyl-1H-吼鲁吐_3_yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid or a salt thereof; (17) a prodrug of a compound of the above item (1) or (11) (18) An agent comprising the compound of the above (丨) or (11) or a prodrug thereof; (19) The agent according to the above (18), which is a glycoside antagonist; (20) An agent according to the above item (18) which is a sugar production inhibitor; (21) an agent according to the above item (18) which is a preventive or therapeutic agent for diabetes; ❹(22) a mammal inhibiting sugar Method of production, the method comprising casting the mammal A compound according to the above item (1) or a prodrug thereof or a compound according to the above item (11) or a prodrug thereof; (23) a method for preventing a silky urine, comprising administering the mammal A compound of the above item (1) or a prodrug thereof or a compound of the above (11) or a prodrug thereof; (10) a compound of the above item (1) or a prodrug thereof or a compound of the above (1) The use of the prodrug thereof for the manufacture of a medicament for inhibiting the production of sugar; 321426 14 201029996 (25) - a compound of the above item (i) or a prodrug thereof or a compound according to the above item (11) or The use of its prodrugs is used to manufacture a preventive or therapeutic agent for diabetes; (Effect of the Invention) Since the compound of the present invention has a glycosidic antagonism and an excellent effect (inhibition of blood sugar increase, hypoglycemic action, etc.), it is suitable for preventing or treating diabetes and the like. ® [Embodiment] In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or a moth atom. In the present specification, examples of the rCl_1D alkyl group include mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl, isopentyl, new Pentyl, 1-ethylpropyl, hexyl, isohexyl, 1, dimethyl butyl, 2, 2-dimethylbutyl, 3, 3-dimeryl butyl, 2-ethyl butyl Base, heptyl, octyl, decyl, fluorenyl and the like. In the present specification, examples of the "C!-6 alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, and a different Pentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, hydrazine,] dimethyl butyl, 2, 2-dimethylbutyl, 3, 3-dimercaptobutyl, 2 -ethylbutyl and the like. In the present specification, examples of the "branched chain Cm alkyl group" include isopropyl, isobutyl, t-butyl, tert-butyl, isopentyl, neopentyl, oxime-ethylpropyl, isohexyl. 1,1-didecylbutyl, 2,2-didecylbutyl, 3, 3-321426 15 201029996 Dimercaptobutyl, 2-ethylbutyl, and the like. In the present specification, examples of "C2, alkenyl" include vinyl, propylidene, 2-propenyl, 2-methyl-dipropylbutenyl, 2-butenyl, 3, and Glycosyl, 3-mercapto-2-butenyl, b-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl+pentenyl, hexenyl 3_hexyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like. In the present specification, examples of "&6-thinyl" include ethylene group, 1-propenyl group, 2-propenyl group, 2-methyl-1-propenyl group, butenyl group, 2-butenyl group. , 3 = butenyl, 3-mercapto-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-mercapto-3-pentene Base, hexenyl, 3-hexenyl, 5-hexyl, and the like. In the present specification, examples of the "C^oalkynyl group" include an ethynyl group, a propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a pentynyl group. , 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, Heptynyl, 1-octynyl, and the like. In the present specification, examples of the "C2-6 block group" include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, and a 1- Pentyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexyne Base. Examples of 'Ci-e alkoxy group' in the present specification include a decyloxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, and a third. Butoxy and the like. In the present specification, examples of the "C2-6 alkenyloxy group" include vinyloxy 16321426 201029996 and the like. Examples of 'c3_1Q cycloalkyl group' in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2 21]heptyl, bicyclo [2.2.2 ] octyl, bicyclo [3. 2.1] octyl, bicyclo [3.2.2] fluorenyl, bicyclo [3.3. 1] fluorenyl, bicyclo [4·2· 1:] fluorenyl, bicyclo [4·3 ^ 癸Base, adamantyl and the like. In the present specification, examples of the "C3'6 cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like. The Ch ring filament and the "cyclofilament may form a fused ring group with a benzene ring, and examples of such fused ring group include a hydroquinone group, etc. In the present specification, an example of rC3, cycloalkenyl" includes a ring.乙妇基 (example t '2-cyclopropene + yl), cycline (for example, 2_cyclobutenyl-bu), pentylene (for example, 2-ring stalk-buji, 3_cyclopentyl) Rare-based, cyclohexyl: group (eg '2-cyclohexanyl}, 3-cyclohexene+yl), cycloheptyl (4) =, 2'-cycloheptene]-yl), cyclooctene The base (for example, 2-cyclooctane+ group) and the like. In the present specification, examples of the "Cw ring group" include a cyclopropyl group (example / 2 to cyclopropene + group), and a cyclobutanyl group (for example, 2-cyclobutylene+yl), pentylene group (five), such as 2-ring squara, 3 cyclyl, decyl (for example, 2-cyclohexene+yl, 3-cyclohexene) _Buji) and so on. The C, 6-ring aryl group may form a slight group with the benzene ring by the & c core ring, and examples of the _ ring group include dihydronaphthyl groups and the like. In the present specification, "Examples of "cycloalkylene group" include H-indene-ene+ group, 2'4-cyclohexadiene+ group, 2,5-cyclohexadiene + 321426 17 201029996 Base. The C4-10 cycloalkadienyl group may form a fused ring group with the benzene ring, and examples of such fused ring groups include a fluorenyl group and the like. In the present specification, examples of the "C6-H aryl group" include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, an anthracenyl group, a biphenyl group and the like. In the present specification, examples of the "C6-1.aryl group" include a phenyl group, a naphthyl group and the like. In the present specification, examples of the "C6-14 aryloxy group" include a phenyloxy group and a naphthyloxy group. ^ In the present specification, examples of the "O-n aralkyl group" include a phenylhydrazine group, a phenethyl group, a naphthylfluorenyl group, a biphenyl fluorenyl group and the like. In the present specification, examples of the "0-13 aralkyloxy group" include a benzoinyloxy group and the like. In the present specification, examples of the "C8-13 arylalkenyl group" include a styryl group and the like. In the present specification, examples of the "heterocyclic group" include the following aromatic heterocyclic Q groups and non-aromatic heterocyclic groups. In the present specification, examples of the "aromatic heterocyclic group" include 4 to 12 membered aromatic heterocyclic groups, for example, in addition to a carbon atom, 1 to 4 are selected from an oxygen atom and a sulfur atom (oxidized as needed) And a hetero atom of a nitrogen atom as a ring constituting an atom of 4 to 7 members (preferably 5 or 6 members) of a monocyclic aromatic heterocyclic group, and 8 to 12 members of a fused aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a condensed ring or the like, and are selected from a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms (for example, D to 17 each, σ Mazole 'pyrazole, pyridinium, pyridine, pyrimidine), 5 member aryl containing 1 sulfur atom 18 321426 201029996 Aromatic heterocyclic ring (such as · thiophene) and ring fused to U monocyclic aromatic heterocyclic group Ge. 2 Preferred examples of the aryl group corresponding to the aromatic heterocyclic group include a monocyclic aromatic heterocyclic group such as a furan fluorenyl group (e.g., an fluorenyl group). 3, for example, 2 kisses are based on small silk, 4 kiss base), silk (for example, pyrimidine, 4" dense, 5_♦ fixed base), base (for example, 2-4 tartar), Predicate base (for example, ^, 3" A π merging, - a 峨 ... called, for example, -2- mei, 4 - imi, (for example, saliva, basal, 3 kiss, base, (4), 5- (4), different (10) For example, ^: wow base, 5 side base Ο group: _) ~ base (for example: sitting base), disali (for example, !, 2, 4_三卜基, 124_3 2 m Base, triterpene I base 3 soil, I 2 '4' diterpene + base, = aromatic heterocyclic group 'such as 喧 butterfly, for example, 2_ meal 1 噎 Linlin, 6-噎琳基),噎琳基 (for example, 3_ 异唆琳基), 圭〇 sits on the Linke (for example, 2-啥U sits by him. u H like), D (four) Linji (for example, Kuiyou Linji, 6 Temple Ruolin Base), stupid and biting the base (for example, 2-benzene 321426 19 201029996 and biting the thiol group, 3-benzo sulfhydryl group), phenyl phenyl group (for example) 2_benzoxenyl, 3-benzothienyl), benzonfazolyl (for example, 2~benzoxazole benzene) isoindole (eg '7-benzoxanthyl), benzopyrene Salivation (for example, 2-open thiazolyl), benzimidazolyl (for example, benzimidazole-1 ke, = sani-yl-2-yl, benzo-sodium 5-amino), benzo Sanwaji (for example, benzotrisin-5-yl), ten bases (for example, "引嗓一卜基'

Residual 3_yl, ,,-5-yl),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 1'2- owe _3_base) " pheno-indenyl (eg " pheno[4 3Μρ pyrazole pyridyl (for example, 1 Η-pyrrole

Q

[U,4]^^)), etc. ^3 (for example, 1 block c] 〗 2 members == Examples of "non-aromatic heterocyclic groups" include 4 to 4 selected from oxygen atoms and 2 = atoms, A 4- to 7-member (preferably 5 or 6 member) group containing a 1 to atomic impurity as a non-aromatic argon atom and a nitrogen monocyclic non-aromatic argon atom. Examples of the non-aromatic two-membered and non-aromatic heterocyclic heterocyclic nucleus nucleus nucleus nucleus group #合团, among them, 登Α人' household, 3 shengsheng fused ring base Heterocycle (for example, each of the two or two nitrogen atoms of 5 or "aromatic each + sitting " than saliva " than the brown " than the bite, illusion, containing 321426 20 201029996 a sulfur atom of 5 members A heterocyclic ring (for example: porphin) and a benzene ring! or 2 « = corresponds to a ring of 4 to 7 membered monocyclic aromatic ring groups (further partially saturated if necessary). Non-aromatic heterocyclic ring Preferred examples of the group include a monocyclic non-aromatic heterocyclic group such as n fluorene-based propane group (for example, 3-epoxypropyl hydrazine, ruthenium (tetra), 2-quinone quinone), and slightly bite base (for example) , 卜基基,定基,3+定基,四—派基基), =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哄基基, 2_尔基, 3_派哄基), hexam=甲=胺基 (for example, hexamethyleneimine + group), a fixed group (for example, 3 oxazolidin-2-yl), thiazolidine (eg, thiazolidine-2-yl), diyl (eg, dichlorothio Pein + base, two gas sulfur two asthma one - Γ - 〇, taste sputum bite (for example, sputum bite _2_ base, mouth miwa bite _3 a base) φ 琳 基 (such as 胁 琳 琳 I base ) "Sermaline (for example, 嗟 琳 一 一 2 2 、 、 、 、 、 、 、 、 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( For example, 'i,3_dioxacyclopentanthene-4 (for example, 3,dioxol-4-yl), two temperament::戍4, 5:—虱-1, 2' 4 曙 ” ” 坐 基 基 基 派 派 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( a thiopyranyl group (for example, a 4-thio(tetra)yl group), a tetrahydrothiophenanthene group such as a 2-tetrahydrothiopiperidyl group, a 3-tetrahydrothiopiperidyl group, and a tetrahydrogen.石 代 四 ) ) 氧化 氧化 氧化 氧化 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四Desmodium-4-yl), tetrahydrofuranyl (eg, tetrahydro 322426 21 201029996 furan-3-yl 'tetrahydrofuran-2-yl), pyridinyl-), _ group (eg?:::二-〇'Πη(?Γ3四气务一卜基), 二气三哇基 (Example: 2,3-一虱-1Η-1,2,3-triazole-buji), tetrahydrogen - ΙίΜ, 2, 3-three wah + yl), etc.; gas dioxin (for example, 2, 3, 4,5-yl' such as dihydrogen (for example, 2,3-dihydroanthracene _2 password_2_ ——, 蓝, ^, 风, (, ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ^ = for example '3, dichloro 2H=i -3-yl), _ group (for example, (tetra)--3-yl), dihydropentenyl (eg H-decene hydroquine for example), 2 - 2 Hydrogen terminal 4 - group), di i, u, "hydrogen. bis 2 4 isoquinolin-4-yl", tetrahydroisoquinolinyl such as bis] '2 - fluorene dihydropyridyl (for example . =3'4-四虱异喧琳 In this specification, "5 or 6 members 11^ too 0 and -4_ base", etc.; = ring aromatic heterocyclic group and monocyclic non-aromatic 6 In the present specification, "5 or the corresponding scent from the above-mentioned aroma: the ring-shaped base m" is succinct and quot; sputum, 吼唆" 密唆, 塔哄"嗤 嗟 嗟 、 、 异 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 The ring of the 5-membered ring of the heterocyclic group, for example, bites 111 south. The phenotype, ° ratio ρ, σ meter ° sitting, π than saliva, ° plug β sitting, different ° plug. Sit, 卩琴° sit, 卩琴0 sit, mouth and other two bite, α plug two. Sitting, three saliva, four. Wait and wait. In the present specification, examples of the "4 to 12-membered aromatic heterocyclic-oxy group" include a group which bonds an oxy group to the above 4- to 12-membered aromatic heterocyclic group, for example, a quinone-based decyloxy group. Wait. ® In the present specification, examples of the "4 to 12 member non-aromatic heterocyclic group-oxy group" include a group which bonds an oxy group to the above 4- to 12-membered non-aromatic heterocyclic group, for example, > Π-decyloxy, tetrahydrothioσ-sodium decyloxy, 1,1-dihydrothiopiperidyloxy and the like. In the present specification, examples of the "4 to 12-membered aromatic heterocyclic group-carbonyl group" include a group which bonds a carbonyl group to the above 4- to 12-membered aromatic heterocyclic group, for example, a thiol group, a porphin A benzyl group, an 吼β-based group, an η-fluorenyl group, an isoxazolylcarbonyl group, an acridinylcarbonyl group, a thiazolylcarbonyl group, or the like. In the present specification, examples of the "4 to 12 member non-aromatic heterocyclic group-carbonyl group" include a group which bonds a carbonyl group to the above 4- to 12-membered non-aromatic heterocyclic group, for example, tetrahydrofuranylcarbonyl group, pyrrolidine Alkylcarbonyl, morpholinylcarbonyl, and the like. In the present specification, examples of the "G-6 alkyl-carbonyl group" include an ethyl group, a propyl group, a butyl group, an isobutyl group, a tert-butyl group, a amyl group, an isovaleryl group, a hexyl group, and the like. In the present specification, examples of the "Ch alkyl-carbonyloxy group" include ethyl hydrazine 23 321426 201029996 oxy group, propyl fluorenyloxy group, butyl fluorenyloxy group, isobutyl decyloxy group, tert-butyl decyloxy group, pentamidine group Oxyl, isoamyloxy, hexyloxy, and the like. In the present specification, examples of the "Cl-6 alkoxy-cut group" include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a third butoxycarbonyl group and the like. In the present specification, examples of the "C3-!. cycloalkyl-carbonyl group" include a cyclopropylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group and the like. In the present specification, examples of the "fluorene 14 aryl-carbonyl group" include a phenyl fluorenyl group and the like. ® In the present specification, examples of the "Cm alkylthio group" include a mercaptothio group, an ethylthio group, an isopropylthio group and the like. In the present specification, examples of the "C6-H arylthio group" include a phenylthio group, a naphthylthio group and the like. In the present specification, examples of the "〇-13 aralkylthio group" include a phenylhydrazinethio group and the like. In the present specification, examples of the "G-6 alkylsulfonyl group" include a mercaptosulfonylsulfonyl group, an ethylsulfonyl group, an isopropylsulfonyl group and the like. In the present specification, examples of the "Ce-nonylsulfonyl group" include a benzenesulfonyl group and the like. In the present specification, examples of the "C!-3 alkylenedioxy group" include a methylenedioxy group, an extended ethyldioxy group and the like. In the present specification, examples of the "hydrocarbon group which may be optionally substituted" include Cl-oxime which is optionally substituted. a C2-10 alkenyl group which is substituted, optionally substituted, a C2-1G alkynyl group which is optionally substituted, a C3-1G cyclodextant which is optionally substituted, a C3-10 ring dilute group which is optionally substituted, and A substituted C4-1D cyclodextadienyl group, 24 321426 201029996, and optionally substituted C6_]4 aryl group, optionally substituted Cm aryl group, optionally substituted "arylalkenyl group, etc." In the present specification, an example of "optionally substituted hydroxy group" includes a thiol group which is optionally substituted with a substituent selected from the group consisting of: (1) Ci iQ alkyl group which is optionally substituted (preferably as needed) Substituted C]6 alkyl), (2) C(tetra)alkenyl optionally substituted, G(3) optionally substituted cycloheterocycloalkyl, (4) optionally substituted fluorenylcycloalkenyl (5) a substituted aryl group, if desired, (6) a C7-13 aralkyl group optionally substituted, (descending a substituted Cm arylalkenyl group, (8) optionally substituted Ci 6 alkyl-carbonyl, (9) optionally substituted heterocyclic group, etc. In the present specification, the "Ch alkyl group which is optionally substituted", "as the case requires, the disubstituted Cl-1Q" G-6 alkyl, Ch. Alkyl, C2, "Alkenyl substituted as necessary", "Cm alkynyl substituted by hydrazine", and "% base which is optionally substituted" The -1 D alkenyl group, the Chq alkynyl group, and the Cm alkyl-carbonyl group optionally have from 丨 to 5 (preferably from 1 to 3) substituents at each substitutable position. Examples of such substituents include the following groups of substituents A: (Substituent Group A) (1) 匕~cycloalkyl; (2) ^(1)*aryl 321426 25 201029996 (a) If necessary, by hydrazine to 3 substituents selected from the following 1 to 3 halogen atoms substituted by a Ch alkyl group, (b) a hydroxyl group, (c) a Ch alkoxy group substituted by 1 to 3 halogen atoms, and (d) a halogen atom; (3) 1 if necessary 4 to 12 membered aromatic heterocyclic groups substituted with 3 substituents selected from the group consisting of: (a) a C alkyl group substituted with 1 to 3 halogen atoms, (b) a hydroxyl group, (c) 1 if necessary a Ch alkoxy group substituted with 3 halogen atoms, and (d) a halogen atom; (4) A 4 to 12 member non-aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of (a) 1 to 3 halogens as needed a substituted Cw alkyl group, (b) a hydroxyl group, (c) a C!-6 alkoxy group substituted with 1 to 3 elemental atoms, (d) a halogen atom, and (e) a pendant oxy group; 5) A mono- or di-substituted amine group (a) optionally substituted with 1 to 3 substituents selected from the following substituents (i) a halogen atom, and an oxy group, optionally substituted with a substituent selected from the group consisting of , 26 321426 201029996 (b) Ch alkyl• Daichi substituted by 1 to 3 halogen atoms, (c) Ci-6 alkoxy group substituted by 1 to 3 halogen atoms, if necessary, d) a Ch alkyl group which is substituted with 1 to 3 dentate atoms, if desired, (e) an amine sulfhydryl group which is mono- or di-substituted with a C!-6 alkyl group, if desired, wherein the Cm alkyl group Depending on the need to be substituted with 1 to 3 halogen atoms, and (f) 4 to 12 membered aromatic heterocyclic groups; (6) Cl_6 alkyl-carbonyl substituted with 1 to 3 halogen atoms as needed; (7) Ci 6 alkoxy-based (a) halogen atom '(b) Cl-6 alkoxy group, and (C) Ce-14 aryl group, if desired, substituted with 1 to 3 substituents selected from the group consisting of: (8) Cl-6 alkylsulfonyl substituted by 1 to 3 halogen atoms as needed; (9) as needed a mono- or di-substituted aminemethanyl group via Ci-e, wherein the Cl-6 alkyl group is optionally substituted with 1 to 3 halogen atoms; (10) optionally via a Cm alkyl group - or a bis-substituted amine (thioformamidine) group, wherein the Ch alkyl group is optionally substituted with up to 3 halogen atoms; (11) an amine sulfonyl group substituted by a Cm alkyl group as a single or a di-substituted group Wherein the C]-6 alkyl group is substituted by as needed to: 3; (12) carboxy; (13) hydroxy; 27 321426 201029996 (14) optionally 1 to 3 selected from the following Substituted substituted alkoxy (a) halogen atom, (b) slow group, (c) Cl-6 alkoxy group, (d) C3-6 cycloalkyl group, (e) 1 to 3 as needed C6-h aryl-substituted Ch alkoxy-carbonyl, (f) optionally mono- or di-substituted amine group selected from the group consisting of a Ch alkyl group and a Ch alkoxy-carbonyl group, (g) as needed 4 to 12 membered aromatic heterocyclic group (i) halogen atom substituted with 1 to 3 substituents selected from the group consisting of: (ii) Ch alkyl group, (h) optionally substituted with 1 to 3 Ch alkyl groups 4 to 12 members of non-aromatic heterocyclic groups, (〇Cl-6 sinter base, (j) Cl-6 alkyl sulphide And (k) a radical; (15) a C2-6 alkenyloxy group substituted with 1 to 3 halogen atoms as needed; (16) 0-13 aralkyloxy; (17) C6-u aryl (18) Ci-6 alkyl-decyloxy; (19) 4 to 12 28 321426 201029996 aromatic heterocyclic-oxygen substituted with 1 to 3 substituents selected from the group consisting of a group (i) a Ci-6 alkyl group substituted with 1 to 3 halogen atoms, and (ii) a cyano group; (20) a 4 to 12 member non-aromatic heterocyclic group-oxy group; (21) as needed a C6-h aryl-carbonyl (a) halogen atom substituted with 1 to 3 substituents selected from the group consisting of: (b) a Ch alkyl group optionally substituted with 1 to 3 halogen atoms; (22) 4 to 12 membered aromatic heterocyclic-carbonyl groups substituted with 1 to 3 substituents selected from Ci-6 alkyl groups, wherein the Ch alkyl group is optionally substituted with 1 to 3 halogen atoms; 4 to 12 membered non-aromatic heterocyclic-carbonyl groups substituted with 1 to 3 substituents selected from C!-6 alkyl groups, wherein the Cw alkyl group is optionally 1 to 3 halogen atoms Substituted; q (24) fluorenyl; (25) C!-6 alkyl substituted with 1 to 3 substituents selected from the group consisting of Thio group (a) halogen atom, and (b) Cw alkoxycarbonyl group; (26) Ch3 aralkylthio group; (27) C6-h arylthio group; (28) cyano group; (29) nitro group 29 321426 201029996 (30) Halogen atom; (31) (2) alkyl dioxy group. When two or more substituents are used, the respective substituents may be the same or different. In the present specification, the "optionally substituted benzene ring", "replaced C6-U aryl group", "Cho cycloalkenyl group as required", "C4-1G substituted as needed" a cycloalkyldienyl group, an optionally substituted aralkyl group, and an optionally substituted C8-13 arylalkenyl group, a benzene ring, a C6-U^ aryl group, a C3-1D ring-dilute group, The C4-10 cycloalkyl, Cm aryl, and C8-13 arylalkenyl groups each have 1 to 5 (preferably 1 to 3) substituents at the substitutable positions, respectively. Examples of such substituents include the following substituent group B: (Substituent Group B) (1) C3-H) cycloalkyl; (2) optionally substituted with 1 to 3 substituents selected from the group consisting of Ce-M aryl 0 (a) a G-6 alkyl group substituted with 1 to 3 halogen atoms, (b) a hydroxyl group, (c) a Ch alkoxy group substituted with 1 to 3 halogen atoms as required, And (d) a halogen atom; (3) a 4 to 12 membered aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of (a) optionally substituted with 1 to 3 prime atoms; -6 alkyl, (b) hydroxy, 30 321426 201029996 (c) G-6 alkoxy substituted by 1 to 3 halogen atoms, and (d) halogen atom; (4) 1 to 3 as needed 4 to 12 member non-aromatic heterocyclic groups substituted with a substituent selected from the group consisting of: (a) a Cm alkyl group substituted with 1 to 3 halogen atoms, (b) a hydroxyl group, (c) optionally 1 through a halogen atom substituted with a G-6 alkoxy group, (d) a halogen atom, and (e) a pendant oxy group; (5) an optionally substituted mono- or di-substituted amine group (a) a Cw alkyl (i) halogen former substituted with one to three substituents selected from the group consisting of And (ii) a C!-6 alkoxy group, (b) a G-6 alkyl-carbonyl group substituted with 1 to 3 halogen atoms as needed, (c) substituted with 1 to 3 halogen atoms as needed Ch alkoxy-carbonyl, (d) C!-6 alkylsulfonyl substituted by 1 to 3 halogen atoms, (e) optionally substituted by C!-6 alkyl or di-substituted Aminomercapto group, wherein the Ch alkyl group is optionally substituted with 1 to 3 halogen atoms, (〇4 to 12 membered aromatic heterocyclic group, 31 321426 201029996 (g) C6-U aryl-yl group ( For example, phenyl fluorenyl), (h) C6-u aryl sallow (for example, phenyl fluorenyl), and (i) C?-13 aryl (for example, benzyl); (6) a Cw alkyl-carbonyl group substituted with 1 to 3 halogen atoms as needed; (7) A C -6 alkoxy group having a substituent selected from the group consisting of the following: (a) a halogen atom , (b) Cl-6 alkoxy, and ® (C) Ce-i4 aryl; (8) Cl-6 alkylsulfonyl substituted by 1 to 3 dentate atoms as needed; (9) There is a need for a monomethyl or a di-substituted amine carbenyl group via a Ci-6 alkyl group, wherein the Ch alkyl group is optionally substituted with up to 3 halogen atoms; (10) a mono- or di-substituted amine (thiomethyl) group optionally substituted by Ci-δ, wherein the Ch alkyl group is optionally substituted with 1 to 3 halogen atoms; (11) Ci-6 as needed Alkyl mono- or di-substituted amine sulfonyl, wherein the ❹Ch alkyl group is optionally substituted with i to 3 halogen atoms; (12) carboxyl group; (13) hydroxyl group; (14) 1 if necessary & 6 alkoxy (a) halogen atom, (b) carboxyl group, (c) C, -6 alkoxy group, (d) C3-6 cycloalkyl group, substituted with 3 substituents selected from the group consisting of 321426 201029996 (e) Ch alkoxy-carbonyl substituted by 1 to 3 C6-h aryl groups as needed, (substituting a substituent selected from C!-6 alkyl and Cm alkoxy-carbonyl) a - or a di-substituted amine group, (g) a 4 to 12 membered aromatic heterocyclic group (i) halogen atom substituted with 1 to 3 substituents selected from the group consisting of, and (iUCH alkyl, ® ( h) 4 to 12 membered non-aromatic heterocyclic groups substituted with 1 to 3 Ch alkyl groups, (〇Cl-6 alkyl group, (j) C]-e alkylthio group, and 00 a hydroxyl group; (15) a C2-6 alkenyloxy group substituted with 1 to 3 halogen atoms as needed; (16) 0-13 aralkyloxy group; q (17) C6-14 aryloxy; (18) Cm alkyl-carbonyloxy; (19) 4 to 12 membered aromatic heterocyclic-oxy group substituted by 1 to 3 substituents selected from the group consisting of (i) Ci-6 alkyl substituted with 1 to 3 halogen atoms, and (indenyl) cyano; (20) 4 to 12 membered non-aromatic heterocyclic-oxy; (21) 1 to 3 C6-h aryl groups substituted with a substituent selected from the following substituents: 321426 201029996 - a carbonyl group (a) a halogen atom, and (b) a Ch alkyl group optionally substituted with 1 to 3 halogen atoms; (22) a 4- to 12-membered aromatic heterocyclic-yl group substituted with 1 to 3 substituents selected from a Ci alkyl group, wherein the Ci-e alkyl group is optionally substituted with 1 to 3 _ atoms (23) 4 to 12 members of a non-aromatic heterocyclic group-carbonyl group substituted by a substituent selected from a Ci-6 alkyl group as needed, wherein the Ci-e alkyl group is optionally subjected to 1 to Substituted by three _ atoms, (24) fluorenyl; (25) Ci-6 alkylthio (a) halogen atom substituted by 1 to 3 substituents selected from the group consisting of, and (b) Cm alkane Oxycarbonyl; (26) C7-13 aralkylthio; ❹ (27) C6-14 arylthio; (28) (29) a nitro group; (30) a halogen atom; (31) a Ci-3 alkyl dioxy group; (32) a Cm alkyl group substituted with 1 to 3 substituents selected from the group below (a) Halogen atom, (b) carboxyl group, (c) hydroxyl group, 34 321426 201029996 (d) Cl-6 alkoxy-rebel group (e) Ci- substituted by 1 to 3 Ci-e alkoxy groups as needed 6 alkoxy groups, and (in the case of an amine group which is substituted with a Ci-6 alkyl group or a di-substituted group; (33) a C2-6 alkenyl group substituted with 1 to 3 substituents selected from the group consisting of a) a halogen atom, (b) a ruthenium, (c) a meridine, (d) a Cl-6 alkoxy-alkyl group, (e) a Ci-6 alkoxy group, and (f) a Ci-e as needed An alkyl-mono- or di-substituted amino group; and (34) a C7_13 aralkyl group substituted with 1 to 3 substituents selected from the group consisting of: (a) optionally substituted with 1 to 3 halogen atoms. Alkyl, (b) a thiol group, a ruthenium (C) Cl-6 alkoxy group, and (d) a halogen atom. When two or more substituents are used, the respective substituents may be the same or different. In the present specification, the C3, cycloalkyl group of the "C3, cycloalkyl group which is optionally substituted" has a substituent of 1 to 5 (preferably 1 to 3) as needed. Examples of such substituents include the above substituent group β and a pendant oxy group. When two or more substituents are used, the respective substituents may be the same or different. 35 321426 201029996 In the 5th book of this book, the "heterocyclic group" of the "1 - /, if necessary, substituted 丞 = 5 or 6 member heterocyclic group to be substituted" = #香族In the case of _, the aromatic heterocyclic group has 1 to 5 (preferably 1 to 3) substitutional beauty. Or containing the above group of substituents. When two substituents are used, the respective substituents may be the same or different. 「 "If necessary, the "heterocyclic group which is substituted as necessary" or the "heterocyclic group" of the 6-membered heterocyclic group 6 (tetra) ring group and "5 when it is necessary for the aryl-aromatic heterocyclic group" Heterocyclyl. The substitutional position has from 1 to 5 (preferably from 3 to 3) groups which replace these substituents. When two 1ρ ι3 groups of the above substituents are used, as well as side oxygen or different. (d) or more In the case of a plurality of substituents, each of the substituents may be the same as the one described in the description of the heterocyclic ring, and the "5 or 6 member aromatic aromatic mixed soil and the 5 = substituted aromatic heterocyclic ring which are optionally substituted" 5 or 6 sets have 1 to 5 (more than the mm system, the substitutable substitutions include the "representative 纟R substituents. When these substituents are substituted (4) with a substituent, The group: the example of the base includes 'C〇~NRa, ^ S(0)3~rA'~s(〇)2~RA^-S(〇)_ra λ expressed by the following formula, = hour, na 2 is a wind atom, optionally substituted hydrocarbyl group, or 321426 36 201029996 to be substituted heterocyclic group. RA' and RB' are each independently a hydrogen atom, optionally substituted hydrocarbyl group, or need a heterocyclic group to be substituted, or RA' and RB' together with an adjacent nitrogen atom to form a nitrogen-containing non-aromatic heterocyclic ring which is optionally substituted. This is formed by "and RB" together with an adjacent nitrogen atom" Examples of the "nitrogen-containing non-aromatic heterocyclic ring" of the nitrogen-containing non-aromatic heterocyclic ring which is optionally substituted include a 5- to 7-membered nitrogen-containing non-aromatic heterocyclic ring which contains at least one nitrogen atom in addition to a carbon atom. The ring constitutes an atom, and further contains, if necessary, 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom (which may be oxidized), and a nitrogen atom. Preferred of such nitrogen-containing non-aromatic heterocyclic rings Examples include pyrrolidine, imidazole biting, beta bismuth, brigade bite, brigade, chlorpyrifos, thiophene, etc. The nitrogen-containing non-aromatic heterocyclic ring has 1 to 5 as needed in the substitutable position. (preferably 1 to 3) substituents. Regarding such substituents, the above substituent group oxime and pendant oxy group may be mentioned. When two or more substituents Q are used, each substituent may be the same Or different examples of "醯基" include (1) formazan; (2) thiol; (3) a 0-6 alkyl-carbonyl (a) halogen atom substituted with 1 to 3 substituents selected from the group consisting of: (b) a Ci-6 alkoxy-alkyl group, (C) a C6-H aryl group, and 37 321426 201029996 (d) Cm alkoxy; (4) Ci-6 azepine-based (a) halogen atom substituted with 1 to 3 substituents selected from the group below, (b) Ce-H An aryl group, and (c) a G-6 alkoxy group; (5) a C3-1D cycloalkyl-based group; (6) a C6-14 aryl-carbonyl group substituted with 1 to 3 halogen atoms as needed; (Substituting a mono- or di-substituted aminemethanyl group (a) which is optionally substituted with 1 to 3 Cm alkyl (i) halogen atoms substituted with a substituent selected from the group consisting of Ii) Ci-6 alkoxy-cut, (iii) C6-14 aryl, oxime (iv) Ci-6 alkoxy, and (v) 4 to 12 membered aromatic heterocyclic groups, (b) C3 -]. a cycloalkyl group, (c) a Ce_14 aryl (i) halogen atom substituted with 1 to 3 substituents selected from the group consisting of, and (ii) a c]-6 alkane substituted with 1 to 3 halogen atoms as needed And (iii) Ch alkoxy, and 321426 38 201029996 (d) 4 to 12 aryl aromatic heterocyclic; (8) optionally substituted with 1 to 3 substituents selected from the group consisting of: e sulfosulfonyl (a) a halogen atom, and (b) a C6-14 aryl group; (9) a Ce i4 arylsulfonyl group substituted with 1 to 3 halogen atoms as needed; Ο (10) as needed a mono- or di-substituted amine sulfonyl (a) halogen atom selected from the group consisting of: and (b) optionally 1 to 3 substituents selected from 4 to 12 member non-aromatic heterocyclic groups a substituted Cm alkyl group, wherein the 4 to 12 membered non-aromatic heterocyclic group is optionally substituted with a pendant oxy group; (11) an amine which is mono- or di-substituted with a substituent selected from a C1-e alkyl group, if necessary ( Thiosulfanyl) wherein the Cie is required to be substituted with 1 to 3 dentate atoms; (12) 4 to aromatic hybrids substituted with 1 to 3 substituents selected from the group consisting of Ch: Ring base H, the towel, the Gh base, 1 to 3 yarns as needed The substituted atoms; ⑽ ^ ^ ^ 1 to 3 substituents selected from a burn to the group substituted by the group to the 4 '^ group wherein the system optionally substituted with one Bin prime atoms; and the like. Next, the compound (1) will be explained. = a benzene ring which is optionally substituted or an aromatic or heterocyclic ring. 5 or 6 321426 39 201029996 5" or 6-membered aromatic heterocyclic ring is preferably acridine. 6-membered substituted benzene ring or optionally substituted 5 or shellfish steroids" "-, group" and "two-membered fragrant heterocyclic ring" ^ further in addition to the position of 詈it soil, also have 1 to 4 substituents depending on the position of the place. Ring A is preferably a benzene ring or a 5 β β-sub 6-membered aromatic heterocyclic ring (for example, a fluorene-based or a 6-membered aromatic heterocyclic ring (& 疋 human ❹ and does not have except --NR4-Ah, %疋), particularly preferably a benzene ring, a substituent group, and a group other than "-(4)5 ϋ", which is a part of benzene or a 6-membered aromatic heterocyclic ring A. The following

Preferably, the other symbols other than the ring U are as defined above as a ratio of e to e.

Specific examples of the pyrazole of ring B include 321426 40 201029996 wherein mz3 is: 1) 21 and z2 are nitrogen atoms, and z3 is a carbon atom or 2"2 and 23 are nitrogen atoms, and a carbon atom nR; Any of the alternative positions in the formula (I), the following contains the part of the ring B: R3

R3

R3 ❹

Better for or

R1-N

Each of the payment numbers is as defined above. R and R2 are έ έ έ 视 视 视 视 视 视 视 视 视 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 321426 41 201029996 R1 is preferably (1) a substituted C-alkyl group (eg, fluorenyl, 1,1-dimercaptopropyl), (2) a substituted C6-u aryl group as desired (eg , phenyl), or (3) a 5- or 6-membered aromatic heterocyclic group (for example, pyridyl) which is optionally substituted, more preferably (1) is optionally substituted with 1 to 3 substituents selected from the group consisting of Ch alkyl® (eg, fluorenyl, 1,1-dimethylpropyl) (a) a halogen atom (eg, fluoro), (b) a C6-h aryl (eg, phenyl), and (c) a G-6 alkoxy group (for example, a decyloxy group), (2) a C6-u aryl group (for example, a phenyl group) substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom ( For example, fluorine, chlorine, q (b), optionally substituted with 1 to 3 halogen atoms (eg, fluorine), C!-6 alkyl (eg, fluorenyl), and (c) 1 to 3 as needed a halogen atom (for example, fluorine) substituted with a G-6 alkoxy group (for example, a decyloxy group, an ethoxy group), or (3) optionally substituted with 1 to 3 substituents selected from the group consisting of 5 or 6 Aromatic heterocyclic group (for example, 11 to π group) (a) halogen atom (example) , fluorine, chlorine), (b) C!-6 alkyl (for example, methyl) substituted with 1 to 3 halogen atoms (for example, fluorine), and 42 321426 201029996 (C) as needed A halogen atom (for example, a decyloxy group) is substituted with 3 halogen atoms (for example, fluorine). R2 is preferably (1) a Cm alkyl group which is optionally substituted (for example, an anthracenyl group, an ethyl group, a tert-butyl group, a n-propyl group, an isopropyl group), (2) a substituted Cl-6 as needed An alkyl-substituted hydroxy group, that is, a Cm alkoxy group (for example, a methoxy group, an isopropoxy group) which is optionally substituted, or (3) a C3-1() cycloalkyl group which is optionally substituted (for example) , cyclopropyl, cyclohexyl); more preferably (1) C?-6 alkyl substituted with 1 to 3 substituents selected from the group consisting of (for example, methyl, ethyl, tert-butyl) , n-propyl, isopropyl) (a) a halogen atom (eg, fluorine, gas), (b) a C6-14 aryl group (eg, phenyl), (c) a G-6 alkoxy group (eg, hydrazine) Oxy), and (d) 4 to 12 membered non-aromatic heterocyclic groups (for example, N-morpholinyl), Q (2) optionally substituted with 1 to 3 substituents selected from the group consisting of Alkoxy (eg, decyloxy, isopropoxy) (a) halogen atom (eg, fluorine, gas), (b) C6-14 aryl (eg, phenyl), and (c) Ch alkoxy Base (for example, methoxy), or (3) C3_i. A cycloalkyl group (for example, cyclopropyl, cyclohexyl). R3 is a C1-6 alkyl group optionally substituted, a C3-]fluorene cycloalkyl group optionally substituted, a C6-H aryl group optionally substituted or a heterocyclic group optionally substituted. 43 321426 201029996 The "optionally substituted heterocyclic group" of R3 is preferably a 5- or 6-membered heterocyclic group which is optionally substituted. R3 is preferably (1) a substituted C-alkyl group (preferably a branched G-6 alkyl group (e.g., isopropyl, isobutyl, 1-ethylpropyl)), (2) A substituted C3-1() cycloalkyl group (eg, cyclopentyl, cyclohexyl), or (3) a substituted 5- or 6-membered heterocyclic group (eg, pyridyl, piperidinyl, Siqi sulfur brigade ° South base, 1_oxidized four gas sulfur brigade π Nanji, 1,1-dihydrotetrahydrothiopyranyl), more preferably (1) 1 to 3 as needed A G-6 alkyl group substituted with a substituent (preferably a branched chain G-6 alkyl group (for example, isopropyl, isobutyl, 1-ethylpropyl)) (a) is optionally subjected to 1 to 3 Cw alkoxy groups (e.g., methoxy) are taken as φ 0-6 alkoxy (e.g., methoxy, ethoxy, propoxy), (b) C6-h aryloxy ( For example, phenyloxy), (c) Cm aralkyloxy (eg, benzyloxy), (d) optionally substituted by Cl-6 (eg, 5 fluorenyl) mono- or di-substituted Amino group, (e) 4 to 12 membered non-aromatic heterocyclic group (for example, piperidinyl, morpholinyl), (f) Cl -6 alkyl group (for example, '曱Continued brewing group, an isopropyl group cornerstone yellow Pro), and 44 321426 201029996 (g) α-u aryl sulfonic acyl group (e.g., phenyl sulfonic acyl), (2) C3-l. a cycloalkyl group (for example, a cyclohexyl group), or (3) a 5- or 6-membered heterocyclic group substituted with 1 to 3 anthracene and a Uh square group (for example, a phenyl group) (for example, „ββ基基& ^ ^ 丞 啶 啶 、, tetrahydrothiopyranyl, 1- emulsified tetrahydrothiocarbenyl, 1 J _ - ''-emulsified tetrahydrothio-sodium) R is a hydrogen atom or Cm alkyl. R4 is preferably a hydrogen atom.

R5 is a group of -(CH2VC00R" or zhi_cr7r8_cr9r10_c, wherein R6, R7, R8, R9 κ and κ are each independently a ruthenium atom or a ruthenium group, and r is a hydrogen atom, a Ci_e group or R6 is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom. R7 is preferably a hydrogen atom. A methyl group or an ethyl group, more preferably a hydrogen atom methyl group or ethyl group, more preferably a hydrogen atom methyl group. Or an ethyl group, more preferably a hydrogen atom, R8 is preferably a hydrogen atom, R9 is preferably a hydrogen atom, RID is preferably a hydrogen atom, R11 is preferably a hydrogen atom, R5 is preferably -NR6-CR7R8-CR9R1Q-C00Rn2 in the compound (I). Preferred among them are the following compounds, wherein ^ is a substituted C _ 6 aryl group, optionally substituted with (9) aryl, and optionally substituted 5 or 6 membered aromatic heterocyclic groups; " i is to replace the t (^ channel, if necessary to replace the 6 oxo or as needed to replace. Cycloalkyl; ^ for, and the peak of the L channel, see f Substituting "cyclohexa" or optionally substituted 5 or 6 membered heterocyclic group; 323426 45 201029996 R is a hydrogen atom; is -(〇12)3-(10)R]] or, 6_CH2_CR9RiD_c〇〇Rll; R6 a hydrogen atom or a methyl group; R9 is a hydrogen atom, a methyl group or an ethyl group; R10 is a hydrogen atom, a methyl group or an ethyl group; and R is a hydrogen atom, a fluorenyl group or an ethyl group. ❹ ❹ When the ring A is a benzene ring or 6 Specific examples of the formula (1) include the following formulas )'), (Γ,), and (1,,,)

Or a symbol other than = ring is as defined above; the compounds represented by the above formulas (I), (1) and (I''') and salts thereof are also encompassed by the range of the compound (I) Inside. The formula (I) is more preferably the formula (I,). Preferred examples of the compound (I) include the following compounds. (Compound A) In the formula (I), the ring A of the compound or a salt thereof is a benzene ring or a 5- or 6-membered aromatic heterocyclic ring (preferably a specific bite); the ring B is β-ratio; R1 is ( 1) a C6_"aryl group (for example, phenyl), or a substituted C6 group (for example, methyl, 1, dicaptanylpropyl), or 321426 46 201029996 (3) 5 $6 aromatic heterocyclic groups (such as " thiol) as required; R2 is (1) Ci-e alkyl (e.g., methyl, Ethylene, t-butyl, n-propyl, isopropyl), (2) Ci- 6 calcined base (eg, methoxy, isopropoxy), or ' (3) ) C3_l which is substituted as needed. Cycloalkyl (eg, cyclohexyl). ® p3 soil'

XV (1) A C1-e alkyl group which is optionally substituted (preferably a branched chain 6 alkyl group (for example, 'isopropyl, isobutyl, 1-ethylpropyl (2)) is optionally substituted. a cycloalkyl group (for example, cyclopropyl, cyclohexyl), or (3) a 5- or 6-membered heterocyclic group which is optionally substituted (for example, pyridyl, piperidinyl, tetrahydrothioholanyl, I- Oxidized tetrahydrothiopyranyl, 1 l-dioxylated tetrahydrothiopiperidinyl); 'R4 is a hydrogen atom; and R5 is -(CH2)3-C00Rn or -NR6-(CH2)2-C00Rn (preferably -NR6-(CH2)2-C00Rn) wherein R is a hydrogen atom or a fluorenyl group (preferably a hydrogen atom), and R is a hydrogen atom, a fluorenyl group or an ethyl group (preferably a hydrogen atom). Compound A-1) A compound of the formula (1) which is a compound of the formula (I,) or U, () (preferably, formula (Γ)) or a salt thereof, 321426 47 201029996 wherein the bad A is a benzene ring or 6 members An aromatic heterocyclic ring (for example, " than a bite); R1 is (1) a Ci 6 alkyl group (e.g., 'mercapto, 1,1-dimethylpropyl) substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom (for example, fluorine), (b) a Ce-H aryl group (for example, a phenyl group) And (c) a Cl-6 alkoxy group (for example, a methoxy group), (2) a CeH4 aryl group V (for example, 'phenyl group) (a) substituted with 1 to 3 substituents selected from the group consisting of a halogen atom (for example, fluorine, chlorine), (b) a Cw alkyl group (for example, a fluorenyl group) substituted with 1 to 3 halogen atoms (for example, fluorine), and (c) 1 to 3 as needed a halogen atom (for example, 'fluoro) substituted with a Cl_6 alkoxy group (for example, a methoxy group), or (3) a 5- or 6-membered fluorene aromatic heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of the following: (for example, pyridyl) (a) a halogen atom (for example, fluorine, chlorine), (b) a Ch alkyl group (for example, a fluorenyl group) substituted with 1 to 3 halogen atoms (for example, fluorine), and c) a Ch alkoxy group (for example, a decyloxy group) substituted with 1 to 3 halogen atoms (for example, fluorine) as required; and R 2 is (1) optionally substituted with 1 to 3 substituents selected from the group consisting of Ch alkyl (eg 'mercapto, ethyl, tert-butyl, n-propyl, isopropyl) 48 321426 201029996 (a) Halogen atoms (eg, fluorine, nitrogen >, (b) Ce-H aryl (for example, stupid And (C) Cl-δ alkoxy (for example, formazan) (2) Cl-6 alkoxy group substituted with 1 to 3 substituents selected from the group consisting of oxime (for example, decyloxy group) , isopropoxy) (a) a halogen atom (for example, fluorine, chlorine, (b) Ce-14 aryl (for example, stupid), J, and

(c) C VIII 6 oxy (for example, methyst, (3) C3-1 fluorene (for example, cyclopropyl, R3 is blizzard, or cyclohexyl); ^ as needed 1 a Cl-6 alkyl group (preferably a branched chain group (hemp, needle base, ethyl ethyl propyl)) substituted with 3 substituents selected from the group consisting of 1 to 3 & w, alkane as needed An oxy group (e.g., methoxy) substituted with a C1-6 alkoxy group (e.g., a decyloxy group, an ethoxy group, a propoxy group), (b) a Ce-H aryloxy group (e.g., a phenyloxy group) And (c) a C7-u aralkyloxy group (e.g., benzyloxy), (d) an optionally substituted amino group with a Ch alkyl group (e.g., 'methyl), or e) 4 to 12 members of non-aromatic heterocyclic groups (for example, η-bottomyl, morphinyl), (f) Ci-e alkylsulfonyl (for example, mercaptosulfonyl, isopropylsulfonyl) And (g) α-nonylsulfonyl (for example, 'phenylsulfonyl), (2) C3-1G cycloalkyl (for example, cyclohexyl), or 49 321426 201029996 2 as needed 3 "aryl (for example, phenyl) substituted 5 or beryllium (eg "ttD-based K-based, tetrahydrosulfide Base, dihydrotetrazolidine, sulfonate, tetrahydrogen thiophenate; R is a hydrogen atom; and ^-(CH2)3-C00H ^-NR^(CH2)2- C00H ^ l^i^-Nr-(CH2)2-

+ U hydrogen #子 or methyl (preferably a hydrogen atom). (Compound A-2) It is a formula (I,), (I,,) or (1',,) (preferably a salt, a formula ( a compound of the formula I), a compound of the formula (I)) or a ring thereof wherein the ring A is a benzene ring or a 6-membered aromatic heterocyclic ring (for example, "比唆); (1) 1 to 3 substituents selected from the group consisting of Substituted Ci6 alkyl (eg, 'methyl, I dimethyl propyl) (a) halogen atom (eg, fluoro), © (t〇Ce-u aryl (eg, phenyl), and (c) Cm alkoxy (for example, decyloxy), (2) optionally substituted with 3 substituents selected from the group consisting of c... aryl (for example, phenyl) (a) halogen atom (for example, fluorine, gas) (), depending on the cesium to be replaced by 1 to 3 halogen atoms (for example, fluorine), _6 (eg, methyl), and cadaver (c), if necessary, to 3 dentate atoms (for example, Fluorine substituted ci 6 alkoxy (eg, methoxy, ethoxy), or 50 321426 201029996 (3) 5 or 6 membered aromatics substituted with 1 to 3 substituents selected from the group consisting of Ring group (for example, pyridyl) (a) halogen Sub (for example, fluorine, gas), • (b) Ch alkyl (eg, methyl) substituted with 1 to 3 halogen atoms (eg, fluorine), and _ (c) 1 to 3 as needed a halogen atom (for example, fluorine) is substituted for (^_6 alkoxy group (for example, methoxy group); and R2 is (for example, a Ci 6 alkyl group which is substituted with three substituents selected from the group consisting of the following substituents (for example, Methyl, ethyl, tert-butyl, n-propyl, isopropyl) (a) dentate atom (eg, fluorine, gas), (b) C6-14 aryl (eg, phenyl), (C Cl-6 alkoxy (eg, decyloxy), and (d) 4 to 12 member non-aromatic heterocyclic groups (eg, N_morpholinyl), (2) optionally selected to 3 selected Ci ealkyl alkoxy group substituted by the following substituents (for example, methoxy, isopropoxy) (a) halogen atom (for example, fluorine, gas), (b) Ce-ΐ4 aryl (for example, benzene) And (c) Cl-6 alkoxy (eg, decyloxy), or C3'10 cycloalkyl (eg, cyclopropyl, cyclohexyl); R3 is (1) 1 to 3 as needed a c--6 alkyl group substituted with a substituent selected from the group consisting of a branched chain Ch alkane (e.g., isobutyl, ethylidene) (a) 1 to 3 Cw alkoxy groups (e.g., 'methoxy), if desired, 51 321426 201029996 one of the alkoxy groups (eg, methoxy, Ethoxy, propoxy), (b) Ce~14 aryloxy (eg, phenyloxy), (c) Cm aralkyloxy (eg, benzyloxy), (4) It is required to have a C 6 alkyl group (for example, methyl group) or a di-amino group, (4) 4 to 12 members of a non-aromatic heterocyclic group (for example, (tetra), morphinyl), ruthenium (1) C, and a base stone (for example, , methyl aryl, isopropyl, and (g) Ce-u arylsulfonyl (for example, phenylsulfonyl), (2) Cs-iocycloalkyl (for example, cyclohexyl) Or, or () a 5- or y heterocyclic group substituted with 1 to 3 C6-]4 aryl groups (for example, phenyl group) (for example, '(tetra)yl, (tetra)yl, tetrahydrothiopyranyldi, Tetrahydrothio(tetra)yl;;[,]_tetrahydrothio(tetra)thioindole; R is a hydrogen atom; and ❹ K5 is -(CH2)3-, or 6_CH2_cr9r1. - CH2-CR9r-COORn ^ wherein R is a hydrogen atom or a methyl group (preferably a hydrogen atom), R is a hydrogen atom, a methyl group or an ethyl group (preferably a hydrogen atom), and R is a hydrogen atom, a methyl group or a A group (preferably a hydrogen atom), and R is a hydrogen atom, a methyl group or an ethyl group (preferably a hydrogen atom). (Compound A-3) 3 [(H-[(cyclohexyl{3-methyltrifluoromethyl)pyridine-2-yl]~1H~pyrazol-4-ylindolemethyl)amino]phenylindole Carbonyl)amino]propionic acid or a salt thereof; 321426 52 201029996 3-[{[4-(3-methoxyphenyl)-3-methyl-1H-D is sitting at 0- 4-yl]fluorenyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid or a salt thereof; or 3-[{[4-({cyclohexyl[1-(3-decyloxybenzene) — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Compound (IA) is illustrated below. The ring AA is a benzene ring which is optionally substituted or a 5 or 6 membered aromatic heterocyclic ring which is optionally substituted. The 5- or 6-membered aromatic heterocyclic ring of the e-ring AA is preferably pyridine. "Benzene ring" or "5 or 6 member aromatic heterocyclic ring" of "Auxiliary substituted ring or 5 or 6 membered aromatic heterocyclic ring" as required by ring AA, =: group" As well as the RA5 group, it is also necessary to further have ** to 4 substituted beauty in the replaceable position. The ring AA is preferably a benzene ring or a 5- or 6-membered aromatic: , more preferably a benzene ring or a 6-membered aromatic heterocyclic ring (% by way of example), and it has no other substitution except for the "-NR" group. In the formula (IA), when the ring AA is a benzene ring containing a part of the ring-shaped aromatic heterocyclic ring of the ring AA,

Preferably 321426 53 201029996

rA4 wherein each symbol except for the ring AA is as defined above. Ring AB is a 5-membered aromatic heterocyclic ring which is optionally substituted. The 5-membered aromatic heterocyclic ring of the ring AB is preferably a ratio of σ, fen, 吱, miso, or 口 0 0 ^ ΑΒ ΑΒ 视 视 视 视 视 视 视 视 视 视The "5-membered aromatic heterocyclic ring" has, in addition to having a "-ch(rA3)- group", further has 1 or 2 substituents at a substitutable position as needed. The ring AB is preferably a 5-membered aromatic heterocyclic ring which is optionally substituted with 1 to 3 substituents selected from the group consisting of D-Biro, π-phene, gnach, miso, β 峻 、, 〇 口Each of (a) an anthracene-6 alkyl group (for example, an anthracenyl group, an ethyl group) substituted with 1 to 3 substituents selected from a Ch alkoxy group (for example, an anthraceneoxy group, an ethoxy group), wherein Ch The Ch alkoxy group is optionally substituted with 1 to 3 C!-6 alkoxy groups (for example, methoxy group), (b) C3-1G cycloalkyl group (for example, cyclohexyl group), (C) A C6-H aryl group (for example, a phenyl group) having 1 to 3 G-6 alkyl groups (for example, a methyl group) as needed, wherein the C!-6 alkyl group is required to have 1 to 3 halogen atoms ( For example, fluoro) is substituted, (d) cyano, (e) C]-e alkoxy (eg, decyloxy), and 54 321426 201029996 (Ο halogen atom (eg, bromine atom). a substituted benzene ring or a substituted 5- or 6-membered aromatic heterocyclic ring as needed. The 5- or 6-membered aromatic heterocyclic ring of the ring AC is preferably pyridine. 6 members, AC "optionally substituted benzene" Ring or benzene which is optionally substituted 5 or alicyclic heterocyclic Or a "5 or 6 member aromatic heterocyclic ring" further has 1 to 4 substituents at a substitutable position. © Ring AC is preferably (1) Fu I"", and 1 to 3 are selected from The following substituent-substituted phenylcycloalkane ja) is optionally substituted with 3 dentate atoms (for example, fluorine) substituted with Cl 6 (for example, methyl, ethyl), (b) C3, cycloalkyl ( For example, 'cyclopropyl, cyclohexyl), alkoxy is now required to be substituted with 1 to 3 substituents selected from the group consisting of methoxy, ethoxy, propoxy, isobutoxy) hydrazine ( 1) Ch alkoxy (for example, methoxy), (ii) Ch cycloalkyl (for example, cyclopropyl), 4 to 12 (t) optionally substituted with 1 to 3 substituents selected from the following substituents Aromatic heterocyclic group (for example, carbazolyl, isoxazolyl, fluorene (1') halogen atom (for example, fluorine, chlorine), and (ii) Ci-s alkyl (for example, fluorenyl) And 4 to) (5) to 1 to 3 C1-6 Hyun (eg, methyl) to furazolyl), 12 to be non-aromatic heterocyclic (eg, propylene oxide, tetrahydrogen) 321426 55 201029996 (ν) Cl-6 alkyl radicals (eg a methyl group, (vi) a Ci-e thiol group (for example, a methylthio group), and (vii) a mesogenic group, (d) a halogen atom (for example, fluorine, chlorine), (e) Ct -uAralkyloxy (for example, benzyloxy), (〇4 to 12 member non-aromatic heterocyclic-oxy group (for example, tetrahydron tour)

a oxy group, a tetrahydrothiopyranyloxy group, a tetrahydrothiophenanthyloxy group, and a (g) optionally substituted with 1 to 3 substituents selected from the group consisting of To a 12-membered aromatic heterocyclic-oxy group (for example, B to a methoxy group) (i) a C1-6 alkyl group substituted with 1 to 3 halogen atoms (for example, fluorine) as needed (for example, methyl group) And (ii) a cyano group, (h) a C6-]4 aryl group (for example, a phenyl group), Ο (1) a 4 to 2 membered aromatic which is optionally substituted with 1 to 3 substituents selected from the group consisting of Heterocyclic group (for example, oxazolyl, oxazolyl, iso-nfazolyl, "•bazolyl, D-pyridyl") (i) Cl-6 alkyl (for example, fluorenyl), and (ii) Ci-6 An oxy group (for example, methoxy group), (j) a 4- to 12-membered non-aromatic heterocyclic group (for example, N-morpholinyl group, N-^ morpholino group), (k) Cm aralkyl group (for example, Benzyl), (l) cyano, (m) optionally substituted with a substituent selected from the following substituents _ or bis-substituted 56 321426 201029996 (i) depending on the number of 1 to 3 C-e Alkoxy (eg, methoxy) substituted Cl-δ alkyl (eg, decyl, ethyl), (ii) Ci-6 alkyl-carbonyl ( For example, an alkyl group), (iii) a C!-6 alkylsulfonyl group (for example, a mercaptosulfonyl group), (iv) optionally a Cl-6 alkyl group (for example, an ethyl group) _ or two a substituted amine fluorenyl group, (V) Ce-u aryl-based (for example, benzoinyl), fluorene (Vi) C6_14 arylsulfonyl (for example, phenylsulfonyl), and (vii a 0-13 aromatic group (for example, a benzyl group, and (n) a Ce-H arylsulfonyl group (for example, a phenylsulfonyl group); or (2) optionally 1 to 3 substituents selected from the group consisting of Substituted 5- or 6-membered aromatic heterocyclic ring (eg, pyridine) (a) Substituting one to three halogen atoms (eg, gas) for one of the alkyl groups (eg, methyl, ethyl), (b) (^-103⁄4 alkyl (for example, cyclohexyl), e Ci 6 alkoxy (e.g., decyloxy, ethoxy) substituted with 1 to 3 substituents selected from the following: (1) C! -6 alkoxy (for example, methoxy), and (ii) C3-6 cycloalkyl (for example, cyclopropyl), (4) halogen atom (for example, fluorine, chlorine, desert), (e) C7-] a 3-party alkyloxy group (for example, a benzyloxy group), and (1) a 4 to 12 member non-aromatic hybrid _ Oxy group (e.g., tetrazolium trip tetrahydrothiopyranyl group). In the formula (IA), the part represented by the formula 321 426 57 201 029 996

It is derived from a bicyclic group formed by ring AB and ring AC (one side of each ring is shared (i.e., condensed)). Here, the side of the ring AB which forms the double ring is bonded to the side of the ring AC by the same multiplicity. For example, in the formula (IA), the part represented by the following formula

When it is a group represented by the following formula

"-CH(RA3)- in the fused ring formed by ring AB and ring AC, the group" is present at any bondable position on ring AB. ❹ RA3 is optionally substituted Cialkyl, optionally substituted C3-i〇 cycloalkyl, optionally substituted C6-H aryl or optionally substituted heterocyclic. The "optionally substituted heterocyclic group" of RA3 is preferably a 5- or 6-membered heterocyclic group which is optionally substituted. RA3 is preferably (1) a substituted Cl-6 alkyl group (preferably a branched chain Cl-6 group (for example, isopropyl, isobutyl, 1-ethylpropyl)), (2) ) Gi replaced as needed. Cycloalkyl (eg, cyclopentyl, cyclohexyl), 58 321426 201029996 or (3) optionally substituted 5 or 6 membered heterocyclic group (eg, pyridinyl, piperidinyl, tetrahydrothio-branyl) , 1 - oxidized tetrahydrothiocarbenyl, 1,1 -dihydrothiocarbenyl), more preferably (1) G-substituted by 1 to 3 substituents selected from the group consisting of: 6 alkyl (preferably methyl, ethyl, butyl, hexyl, branched Cl-6 alkyl (eg, isopropyl, isobutyl, 1-ethylpropyl)) (a) as needed a 6 alkoxy group substituted with 1 to 3 Cw alkoxy groups (for example, methoxy group) (for example, a decyloxy group, an ethoxy group, a propoxy group), (b) a C6-H aryloxy group (for example) , phenyloxy), (c) C?-13 aralkyloxy (eg, benzyloxy), (d) optionally substituted by G-6 alkyl (eg, fluorenyl) mono- or di a substituted amino group, (e) a 4- to 12-membered non-aromatic heterocyclic group (for example, piperidinyl, morpholine Q-based), (f) a G-6 alkylsulfonyl group (for example, a mercaptosulfonyl group) Base, isopropylsulfonyl), (g) Ce-M arylsulfonyl (for example, phenylsulfonyl), and (h) Ci-e alkyl a thio group (for example, methylthio group), (2) a C3-indenyl group (for example, a cyclopentyl group, a cyclohexyl group), (3) optionally 1 to 3 C6-H aryl groups (for example, a phenyl) substituted 5- or 6-membered heterocyclic group (eg, 吼D-based, sigma-based, tetrahydrothio-branched sigma, 1- oxidized tetrachlorothio-branyl, 1,1-dioxide Hydrogenthiopyranyl), or 59 321426 201029996 (4) C6-u aryl (eg, phenyl). R is a halogen atom or a Cl-6 alkyl group. RA4 is preferably a hydrogen atom. R is -(tetra)·- or a subsidy i^r,r,RA6;5'RA8'RA9^Aii^^^ atom or ·= base' and r is a nitrogen atom, a group or a meridine. Filial piety is preferably a ruthenium atom or a methyl group, more preferably a hydrogen atom.

RA7 is preferably a hydrogen atom. RA8 is preferably a hydrogen atom. RA9 is preferably a hydrogen atom. RA1° is preferably a hydrogen atom. = preferably hydrogen, methyl or ethyl, more preferably a hydrogen atom. R is preferably -NRA6-CRA7RA8-CRA9RA1°-C〇〇RAu. Specific Formula (I) When the ring AA is a benzene ring or a 6-membered aromatic hetero ring, a good example includes the following formula (ΙΑ,)

(wherein, each symbol except the ring is as defined above). The compounds represented by the above formula (ΙΑ,) and salts thereof are also encompassed within the scope of the compound (ΙΑ). Preferably, it is a compound represented by the above formula (ΙΑ), wherein 321426 60 201029996 RA3 is an optionally substituted Ch alkyl group, optionally substituted Ca-. a cycloalkyl group or a substituted 5- or 6-membered heterocyclic group; RA4 is a hydrogen atom; RA5 is -(CH2)3-C00RA" or -NRA6-(CH2)2-C00RAU; R is a hydrogen atom or a And R 11 is a hydrogen atom, a methyl group or an ethyl group. Preferred examples of the compound (IA) include the following compounds. (Compound AA) In the formula (IA), '% of the compound or its salt AA is a ring or a 5- or 6-membered aromatic heterocyclic ring (for example, π 唆), · Ring AB is 5 members which are optionally substituted An aromatic heterocyclic ring (for example, pyrrole, thiophene, β-flour, sputum, sigma ratio); ring AC is a benzene ring which is optionally substituted, or a 5- or 6-membered aromatic heterocyclic ring which is optionally substituted (for example) , pyridine); RA3 is ® (1) optionally substituted Cm alkyl (preferably branched CH alkyl (eg 'isopropyl, isobutyl, 1-ethylpropyl)), (2) a substituted C3-1Q cycloalkyl group (e.g., cyclohexyl), or (3) a substituted 5- or 6-membered heterocyclic group (e.g., pyridyl, piperidinyl, tetrahydrothiopyran), if desired Base, 1~ oxidized tetrahydrothiopiperidyl, hydrazine, hydrazine-tetrahydrothiopiperidyl); RA4 is a hydrogen atom; and RA5 is -(ch2)3-coorA11 or A6-(ch2) 2-coorA11, preferably -NRA6__(CH2)2-C〇〇RAn 321426 61 201029996 wherein R is a hydrogen atom or a methyl group (preferably a nitrogen atom), and RAn is a hydrogen atom, a decyl group or an ethyl group (preferably) Is a hydrogen atom). (Compound AA-1) A compound of the formula (10) which is a compound of the formula (IA) or a salt thereof, wherein hydrazine is a benzene ring or a 6-membered aromatic heterocyclic ring (for example, D-pyridyl); Aromatic heterocyclic ring (for example, thiophene, furan, imidazole, pyrazole) substituted with 3 substituents selected from (a) Cl-6 alkyl (eg, methyl, ethyl), ( b) a C3-1Q cycloalkyl group (for example, a cyclohexyl group), and (C) a C6-14 group (for example, a phenyl group); the ring AC is (1) optionally having 1 to 3 substituents selected from the group consisting of Substituted benzene ring (a) ci 6 alkyl (eg, fluorenyl) substituted with 1 to 3 dentate atoms (eg, fluorine), 〇 3) C3-1Q cycloalkyl (eg, cyclohexyl) , (c) a Cl-6 alkoxy group (for example, a decyloxy group), and (d) a halogen atom (for example, fluorine), or (2) optionally substituted with 1 to 3 substituents selected from the group consisting of a 5- or 6-membered aromatic heterocyclic ring (for example, "biter") (a) an alkyl group (for example, a fluorenyl group) substituted with 1 to 3 halogen atoms (for example, fluorine), (b) a Cm cycloalkyl group (eg, cyclohexyl), (c) Ci-6 alkoxy For example, a decyloxy group, and (d) a halogen atom (for example, a system); 62 321426 201029996 RA3 is (1) optionally taken up to 3 substituents selected from the group consisting of (preferably a branched chain Cl_e alkyl group ( For example, a Cm alkyl group of isobutyl or ethylidene (a) is optionally taken up to 3. 6 alkoxy groups (for example, instead of a ethoxy group (for example, a methoxy group, an ethoxy group) (b) α丨4 aryloxy (for example, phenyloxy), earth, (c) Cm aralkyloxy (for example, benzyloxy), gin (d), if necessary, c!-6 a group (e.g., fluorenyl) mono- wu-amino group, and ~'' substituted (e) 4 to 12 member non-aromatic heterocyclic group (e.g., yl), alpha agridyl morpholine (f) Cl - 6 burnt stone xanthine base (for example, sulfhydryl aryl base 'isopropyl group'' and soil only (g) Ce-M arylsulfonyl (for example, phenylsulfonyl), (2) C3-1Q ring Alkyl (eg, cyclohexyl), or oxime (3) 6-membered heterocyclic group substituted with 1 to 3 Ce-H aryl groups (eg, phenyl) as desired (eg, pyridyl, piperidinyl, tetra Argon thiopyranime 1 or oxidized tetrahydrothiopiperidyl, 1,1-diox Tetrahydrothiopyrantoin R is a gas atom; and RA5 is '(CH2)3-C00H or -NRA6-(CH2)2-COOH, preferably, A6-C00H 'K, (CH〇2 / And R is a nitrogen atom or a methyl group (preferably a gas atom). (Compound AA-2) A compound of the formula (IA) which is a compound of the formula (IA') or a step thereof, wherein 321426 63 201029996 is a ring AA a benzene ring or a 6-membered aromatic heterocyclic ring (for example, a cyclized polypyridyl group is preferably a 5-membered aromatic heterocyclic ring (e.g., thiophene, furan, imidazole, pyrazole) substituted with 1 to 3 substituents selected from the following substituents. ), (a) depending on the order, working from 1 to 3 c, _6-yard oxy (for example, methoxy) substituted C!-6 alkyl (eg, methyl, ethyl), (b) a C3-i0 polar group (for example, cyclohexyl), and (C) a Ce-H aryl group (for example, a styl group); ❹ _ a ring AC is (1) optionally substituted with 1 to 3 substituents selected from the group consisting of a benzene ring") a c-quote (for example, methyl) substituted with 1 to 3 atoms (for example, fluorine), (b) a Cm cycloalkyl group (for example, cyclohexyl), as needed a Ch alkoxy group substituted with 1 to 3 substituents selected from the following (example) , methoxy, ethoxy) (i) Cm alkoxy (eg, decyloxy), and Gi) C3-6 cycloalkyl (eg, cyclopropyl), (d) halogen atom (eg, fluorine) ), (e) a C7-?3 aralkyloxy group (for example, a benzyloxy group), and a 12-membered non-aromatic heterocyclic group-oxy group (for example, tetrahydroπ-decyloxy) Or (2) 视·β, and a 5 or 6-membered aromatic heterocyclic ring (for example, pyridine) which is substituted with 1 to 3 substituents selected from the group consisting of 1 to 3 halogen atoms (eg, fluorine) substituted Ci6 alkyl (eg, methyl), 321426 64 201029996 (b) C3-1 () cycloalkyl (eg, cyclohexyl), / (c) 1 to 3 as needed c]-6 alkoxy (e.g., decyloxy, ethoxy) (i) Cm alkoxy (e.g., methoxy), and (ii) G-6 cycloalkyl (substituted) For example, cyclopropyl), (d) a halogen atom (for example, fluorine), (e) a C7-]3 aralkyloxy group (for example, a benzoinyloxy group), and a fluorene A 4 to 12 member non-aromatic hybrid Cyclo-oxy (for example, tetrahydropyranyloxy); RA3 is (1) as needed 1 (preferably, a branched bond propyl)) to a Ci 6 alkylCh alkyl group substituted with 3 substituents selected from the group consisting of: isopropyl, isobutyl, decyl ethyl, cH Up to 3 Cl'6-terminated oxy groups (eg, methoxy) take 6 alkoxy groups (eg, 'methoxy, ethoxy, propoxy)' (b) Ce-u aryloxy (eg, Phenyloxy), (c) Cm aralkyloxy (for example, phenylhydranyloxy), the amine group (4) is optionally substituted by el-6 silk (-, methyl) mono- or di-substituted

a 4- to 12-membered non-aromatic heterocyclic group (eg, a ketone group, a fluorenyl sulfonyl group, an isopropyl sulfonate (f), a Cl-6 alkyl group (eg, a group), and (g) c6-14 aryl sallow base (for example, phenyl fluorenyl), 321426 65 201029996 (2) Cho cycloalkyl (for example, cyclopentyl, cyclohexyl), or (3) 1 through 3 (6- or 6-membered heterocyclic groups substituted with a Vm aryl group (for example, phenyl) (for example, pyridyl, piperidinyl, tetrahydrothiopiperidyl, tetrahydrothiopiperidyl, 1 , 丨-tetrahydrothiopiperidyl); RA4 is a hydrogen atom; and R is -(CH〇3-COORa11 or ~NRA6-(CH2)2-COORAn, preferably -NRA6_(CH2)2- COORa11 wherein RA is a hydrogen atom or a methyl group (preferably a hydrogen atom), and rA11 is a hydrogen atom, a decyl group or an ethyl group (preferably a hydrogen atom). (Compound AA-3) A compound of the formula (IA), It is a compound of the formula (IA), or a salt thereof, wherein the ring AA is a benzene ring or a 6-membered aromatic heterocyclic ring (for example, acridine); and the ring AB is optionally substituted with 1 to 3 substituents selected from the group consisting of 5-membered aromatic (eg, pyrrole, thio , furan, imidazole, pyrazole, pyrrole) (a) Ci-e alkyl group substituted with 1 to 3 substituents selected from the group consisting of Cl_e alkoxy groups (for example, methoxy, oxime ethoxy), for example (for example) , methyl, ethyl), wherein the Ch alkoxy group is optionally substituted with 3 alkoxy groups (for example, a decyloxy group), (b) a C3-1G ring-based group (for example, a cyclohexyl group). (c) a c aryl group (for example, a phenyl group) having 1 to 3 Ci-e alkyl groups (for example, a methyl group) as needed, wherein the Ci-6 group base system may have 1 to 3 halogen atoms as needed. (for example, fluorine) substituted, (d) cyano, (e) Cm alkoxy (for example, methoxy), and 321426 66 201029996 (f) dentate atom (for example, bromine atom); 1) a benzene ring (e.g., a fluorenyl group) which is substituted with 1 to 3 substituents selected from the group consisting of the following substituents (for example, fluorenyl), b) a cycloalkyl group (for example, cyclopropyl, cyclohexyl), a (c) as desired, 1 to 3, a C decyloxy group substituted with a substituent selected from the group consisting of: methoxy, ethoxy Base, propoxy, isobutoxy) (i) Cl-6 alkoxy (for example, methoxy), (ii) C3-6 cycloalkyl (for example, cyclopropyl), (iii) optionally substituted with 1 to 3 substituents selected from the group consisting of To a 12-membered aromatic heterocyclic group (for example, carbazolyl, isoxazolyl, fluorenyl) (i) a halogen atom (for example, fluorine, gas), and (ii') Ci-6 alkyl (for example, hydrazine) base),

Gv) is taken from 1 to 3 G-6 alkyl groups (for example, fluorenyl groups) to 12 members of the non-fragrance group (for example, propylene oxide group, tetrahydro-schemandyl group), ( V) a Ci-e alkylsulfonyl group (for example, methylsulfonyl), (Vi) a Ch alkylthio group (for example, a mercaptothio group), and (vii) a hydroxyl group, (d) a halogen atom (for example) , fluorine, chlorine), (e) Oi-U aralkyloxy (eg, phenylhydranyloxy), ) 4 to 12 member of the non-fragrant heterocyclic-oxy group (eg, tetrahydro-n- bottom) Methane 321426 67 201029996 oxy (5) hydroxythiopyranyloxy, i'b dioxyloxy), & (§) 4 to 12 membered aromatic heterocyclic group-oxy groups substituted by 1 to 3 substituents selected from the following (for example, π-bitoyloxy group) (1 to 3 halogens are required for contempt) Atom (for example, fluorine) substituted C!-6 alkyl (for example, methyl), and (iΟcyano, (h) Ce-H aryl (for example, phenyl), (^) as needed 4 to 12 membered aromatic heterocyclic groups (for example, carbazolyl, isoxazolyl, pyridinyl) substituted with 3 substituents selected from the group consisting of (OCl-6 alkyl group (for example, methyl group) And (ii) C-e alkoxy (e.g., methoxy), (j) 4 to 12 member non-aromatic heterocyclic groups (e.g., N-morphinyl, N-thionapine) , (k) Cm aryl (for example, benzyl), (1) cyano,

On) as needed _ from the underlying singular _ or the second amino group (1) as needed, 1 to 3 L alkoxy (eg, methoxy) substituted Cl-6 alkyl (eg, methyl , B), (11) c 〗 〖6 alkyl group - several groups (for example, ethyl thiol), (ill) C〗 - 6 silk surface (for example, f-based continuation base), methyl sulfhydryl, (5) C6-6-yl (for example, ethyl) mono- or di-substituted amine 321426 68 201029996 (v) G-nonylaryl-carbonyl (for example, benzoinyl), (Vi) Ce-M aryl Sulfosyl (for example, phenylsulfonyl), and (vii) C?- 3 alkyl (for example, benzyl), and (n) Ce-u arylsulfonyl (for example, benzenesulfonate) a thiol group, or ii, a 5- or 6-membered heterocyclic ring (for example, a specific bite) substituted with 1 to 3 substituents selected from the group consisting of (a) optionally 1 to 3 halogen atoms (for example) , fluorine) substituted G 6 alkyl (for example, methyl), (b) C3-1. a cycloalkyl group (for example, a cyclohexyl group), (c) a c1-6 alkoxy group (for example, a methoxy group, an ethoxy group) substituted with 1 to 3 substituents selected from the group consisting of: (i) Ci- e alkoxy (for example, methoxy), and (ii) C3-6 cycloalkyl (for example, cyclopropyl), (d) halogen atom (eg 'fluorine, gas, bromine), (e) η An alkyloxy group (for example, phenylhydrazinyloxy group), and ©) 4 to 12 members of the non-fragrant heterocyclic group-oxy group (for example, tetraarhdyloxy); RA3 is (1) A 〇6 alkyl group substituted with 1 to 3 substituents selected from the group consisting of a methyl group, an ethyl group, a butyl group, a hexyl group, a branched chain fluorene group (for example, an isopropyl group, an isobutyl group) , 1-ethylpropyl)) (a) A Cm alkoxy group substituted with 1 to 3 Cm alkoxy groups (for example, an oxiranyl group) (for example, a decyloxy group, an ethoxy group, a propoxy group) ), (b) Ce-H aryloxy (eg, phenyloxy), 69 321426 201029996 (C) 0-]3 aralkyloxy (eg, benzyloxy), (d) Requires a c--6 alkyl (eg, methyl) mono- or di-substituted amine group, (e) 4 to 12 members non-aromatic Cycloalkyl group (e.g., piperidinyl, morpholinyl), (O Ci_6 acyl continued firing group (e.g., methyl acyl indeed, isopropyl indeed acyl), '

(g) Ce-u aryl fluorenyl (for example, phenylsulfonyl), and (h) Ci-6 thiol (for example, mercaptothio), (2) Cho cycloalkyl (for example, cyclopentyl) a cyclohexyl group, (3) a 5- or 6-membered heterocyclic group substituted with 1 to 3 α-fluorene aryl groups (for example, phenyl group) (for example, 'mercapto κ group, tetrahydrothio (tetra) group) Oxidized tetrahydrothio-indenyl, i'b-dihydrothio-bromyl), or (4) Ce-i4 aryl (eg, phenyl); RA4 is a hydrogen atom;

R is -(ch〇3-coo Guang or He 6-(CH2)2_c〇〇rA11 CCH2)2-C00RAn is preferably _NRA6- (compound AA-4) cyclohexyl (3_methyl + benzocytosis _2 benzyl) (meth)amino}propionic acid or its salt; "" 3 {[(6-{[cyclohexyl (5-fluoromethyl)-amino}pyridine-3- US)#其u#本开furan-2-yl)methyl]yl) radical](methyl)aminouric acid or its salt; 321426 70 201029996 3-{[(4-{[2-ethyl 1-(5-fluoro-3-indolyl-1-benzofuran-2-yl)butyl]amino fluorenylphenyl)carbonyl](methyl)amino}propionic acid or a salt thereof; 3 - [ {[4-({1-[5-(Cyclopropylmethoxy)-3-methyl-1-benzo[r-propan-2-yl]-2-mercaptopropyl}amino)phenyl) ]carbonyl}(methyl)amino]propionic acid or a salt thereof; or 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2H-pyran-4-yloxy) )-1-benzofuran-2-yl]fluorenyl}amino)phenyl]carbonylindole (fluorenyl)amino]propionic acid or a salt thereof. Lu (Compound AA-5) 3-{[(5-{[Cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]aminobipyridin-2-yl) )carbonyl](methyl)amino}propionic acid or a salt thereof; or 3 U(4-{[cyclopentyl(5-fluoro-3-indolyl-1-benzofluorenyl-2-yl)methyl) Amino}phenyl)carbonyl](indenyl)amino}propionic acid or a salt thereof. As the salts of the compounds (I) and (IA), preferred are pharmaceutically acceptable salts. Examples of such salts include salts formed with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt formed with the inorganic base include alkali metal salts such as sodium salts, potassium salts and the like, alkaline earth metal salts such as calcium salts, magnesium salts and the like; aluminum salts; ammonium salts and the like. Preferred examples of the salt formed with an organic base include a compound of the formula, a methyl group, a solution, an ethanolamine, a diethanolamine, a triethanolamine, an aminobutyrolol [paraxylmethylamine), a third butylamine. a salt formed by cyclohexylamine, benzylamine, dicyclohexylamine, N,N-diphenylmethylethylidene diamine or the like. 321426 71 201029996 Preferred examples of the salt formed with the inorganic acid include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acid filling and the like. Preferred examples of the salt formed with an organic acid include f acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, and frequency a salt formed from an acid, an oxime sulfonic acid, a benzenesulfonic acid, a p-toluenesulfonic acid or the like. Preferred examples of the salt formed with the tester amino acid include salts formed with arginine, amidic acid, ornithine and the like. Preferred examples of the salt formed with the acid amino acid include salts formed with aspartic acid, glutamic acid and the like. The compound (I) or (IA) prodrug means a compound which is converted to the compound (I) or (IA) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, 'enzymatic oxidation A compound which is converted into a compound (I) or (IA) by a reaction, a reduction reaction, a hydrolysis reaction or the like; or a compound which is converted into the compound (I) or (IA) by hydrolysis of gastric acid or the like. Examples of the compound (1) and the compound (IA) include: a compound obtained by subjecting an amine group in the compound (I) and the compound (IA) to a brewing, burning or acidification (for example, 'making a compound (I) And the amine group in the compound (IA) is oxidized, propylamined, pentylaminocarbonylated, (5-methyl-2-oxy 3_dioxol-4-yl) a compound obtained by oxycarbonylation, tetrahydromanocyanation, pyrrolidinylmethylation, trimethylacetoxymethylmethylation or tert-butylation); compound (I) and compound ( a compound obtained by deuteration, alkylation, phosphorylation or boronation of a hydroxy group in IA) (for example, by subjecting a hydroxyl group in the compound (I) and the compound (IA) to acetylation, hexadecanism or glycerination , 321426 72 201029996 dimethyl ethane brewing, amber fermentation, anti-butene dimerization, propylamine dimethylation or dimethylaminomethyl grouping to obtain compounds (丨) and compounds (IA a compound obtained by esterification or amide hydration in a compound (for example, esterifying a carboxyl group in the compound (I) and the compound (IA) with an ethyl group, Phenyl esterification, carboxymethyl esterification, dimercaptoalkyl sulfhydryl esterification, trimethylacetoxy oxime esterification, ethoxycarbonyloxyethyl esterification, mercapto esterification, (5-fluorenyl-2-oxo-1,3-dioxol-4-yl) thiol esterification, cyclohexyloxydecylethyl esterification or methyl amination The obtained compound), etc. These compounds can be obtained from the compound (I) and the compound (ΙΑ) according to a method known per se. The compound (I) and the compound (ΙΑ) may also be, for example, IYAKUHIN no KAIHATSU, Development Compounds of Compound (I) and Compound (IA) under physiological conditions as described in the Pharmaceuticals, Vol. 7, Design of Molecules, p. 163-198 (1990) (published by HIROKAWA SHOTEN). And (IA) and its 刖 (this compound is sometimes collectively referred to as "the compound of the invention" in the present specification) includes stereoisomers such as cis, trans isomers, and the like. An optically active form such as a racemate, an R compound, an S compound, etc. depending on the species of the ring (eg, ring A, etc.) 'Isolation can be produced by configuration' and such isomers are also included in the compounds of the invention. The compounds of the invention can be used with isotopes (eg, %, %, 14 (:, 35S, 125ι), etc. The compound of the present invention may be a hydrate, a non-hydrate, a solvate or an unsolvate. 321426 73 201029996 has a low mouth and sex, and thus it is a mixture of itself or a mixed with a medically acceptable mixture. The form of the composition can be used as a prophylactic or therapeutic agent for diseases such as horses and diseases in mammals (e.g., humans, mice, pigs, and monkeys). Examples of the carrier which can be used as a cross-linking agent herein include various organic or inorganic eliminating substances which are conventionally used as a layer material, which are added as an excipient, a slip agent, and a binder of a solid dosage form. Or a disintegrant; a solvent, a dissolution aid, a suspending agent, etc. as a liquid dosage form, a slow (four) and a flat (four)-thing agent; Formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like may also be used as needed. Preferred examples of the cleavage acid excipient include lactose, D, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low substituted hydroxypropyl cellulose, carboxy Methylcellulose sodium, gum arabic, pullulan, light anhydrous citric acid, synthetic aluminate metasilicate, and the like. ❹ The preferred examples of the talc include a magnesium stearate, a stearic acid dance, and a tannin oxide. Preferred examples of the binder include pregelatinized starch, sucrose, Mingsheng, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose crystallizable cellulose, sucrose, D-mannitol , secret sugar, dextrin, polytrimose, thioglycolic cellulose, (tetra)methylcellulose, and: ketone. Preferred examples of the diarrhea, sucrose, sucrose, sucrose, sputum, m-methyl cellulose, sputum methyl cellulose sodium, slow methyl: Temple 321426 74 201029996 sodium, Light anhydrous citric acid and low substituted hydroxypropyl cellulose. Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution (Ringer's solution), alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Preferred examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzoyl benzoate, ethanol, ginsyl methane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, Sodium salicylate and sodium acetate. Preferred examples of suspending agents include: surfactants such as stearin® triethanolamine, sodium lauryl sulfate, lauryl alanine, lecithin, benzalkonium chloride, benzethon Ammonium chloride (benzethonium chloride), glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, thiol cellulose, hydroxymethyl cellulose, hydroxy Ethyl cellulose, hydroxypropyl cellulose, etc.; polysorbate and polyoxyethylidene hydrogenated castor oil. Preferred examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, 0 D-sorbitol, and glucose. Preferred examples of the buffer include, for example, a phosphate buffer, an acetate buffer, a carbonate buffer, a citrate buffer, and the like. A preferred example of the smoothing agent comprises benzofuranol. Preferred examples of preservatives include p-benzoic acid ester, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid. Preferred examples of the antioxidant include sulfite, ascorbate and the like. Preferred examples of the coloring agent include water-soluble edible tar pigments (for example, food coloring materials such as food coloring red No. 2 and No. 3, food coloring yellow 4 75 321426 201029996 and No. 5, food coloring blue No. 1 and No. 2, etc. ), a water-insoluble lake pigment (for example, the salt of the above-mentioned water-soluble edible tar pigment) and a natural pigment (for example, cold-carotene, chlorophyll, red iron oxide). Preferred examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia. Examples of the dosage form of the above pharmaceutical composition include: oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets and orally disintegrable tablets), capsules (including soft capsules and microcapsules), granules, powders , tablets, syrups, ® emulsions, suspensions, films (for example, orally disintegrable films), and parenteral agents, such as injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections) , drip infusion), external preparations (for example, skin preparations, ointments), suppositories (for example, rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalation), ophthalmic preparations, and the like. These dosage forms can be administered safely by oral or parenteral route (e. g., topical, rectal, intravenous). Q These preparations may be release controlling preparations (for example, sustained release microcapsules) such as a quick release preparation, a sustained release preparation, and the like. The pharmaceutical composition can be produced according to a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia or the like. 1至十重量重量。 The dose of the compound of the present invention is, for example, about 0.1 to 100% by weight. If desired, a coating may be applied during the manufacture of the oral formulation for the purpose of masking taste, enteric properties or sustained release. Examples of the coated substrate used for the coating include a sugar-coated substrate, a water-soluble 76321426 201029996 film-coated substrate, an enteric film-coated substrate, and a sustained-release film-coated substrate. With regard to the sugar coated substrate, sucrose is used. Further, it may be used in combination with one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, polytriglucose, palm wax and the like. Examples of water-soluble film-coated substrates include: cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, mercaptohydroxyethylcellulose, and the like; synthetic polymers, For example, polyvinyl acetal® diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragi t E (trade name)], polyethyl hydrazine pipirone, and the like; Classes, such as polytriglucose and the like. Examples of enteric film-coated substrates include: cellulosic polymers such as hydroxypropyl decyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate Acrylic polymer, such as methacrylic acid copolymer L [Eudragit L (trade name)], 0 methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragi t S (trade name)]; and naturally occurring substances such as insects. Examples of the sustained release film-coated substrate include: a cellulose polymer such as ethyl cellulose; and an acrylic polymer such as an amino amide-based copolymer RS [Eudragit RS (trade name)], Ethyl propyl acrylate-methyl methacrylate copolymer suspension [Eudragi t NE (trade name)] and the like. The above two or more coated substrates may be used in 77 321426 201029996 after being mixed in an appropriate ratio. For example, a light shielding agent such as titanium oxide, ferric oxide or the like can be used for coating. The compounds of the present invention exhibit low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, bioavailability, cardiotoxicity, carcinogenicity) and little side effects. Therefore, it can be used as a prophylactic or therapeutic or diagnostic agent for various diseases in mammals (for example, humans, cows, horses, dogs, cats, monkeys, mice, rats). The compounds of the invention have excellent glycosidic antagonism. The compound of the present invention can improve the state associated with the excessive expression of x-glycoside by, for example, shutting down glycosidic effects (e.g., excessive glycogen production in the liver, excessive secretion of growth hormone, excessive inhibition of gastric motility, etc.). Therefore, the compound of the present invention can be used as a prostaglandin antagonist, a sugar production inhibitor, a prophylactic or therapeutic agent for a disease associated with excessive action of glycoside, and the like. Specifically, the compound of the present invention can be used as a prophylactic or therapeutic agent for obesity, diabetes (for example, type 1 diabetes, type 2 diabetes, column diabetes, obesity type diabetes), hyperlipidemia (eg, 0 hypertriglyceridemia, hypercholesterolemia, hypoHDL, postprandial hyperlipidemia), hypertension, heart failure, diabetic complications [eg, neuropathy, nephropathy, retinopathy, diabetes) Cardiomyopathy, cataract, macrovascular disease, osteopenia, hyperosmolar diabetes coma, infectious diseases (eg, respiratory infections, urinary tract infections, gastrointestinal infections, dermal soft tissue infections, lower limb infections), diabetic gangrene, dry mouth , hearing loss, cerebrovascular disease, peripheral blood circulation disorders], metabolic syndrome (containing three or more selected from high triglyceride (TG), HDL low cholesterol (HDL-C), hypertension , abdominal obesity and abnormal glucose tolerance), muscle loss 78 321426 201029996 disease. Put forward == diagnostic criteria, 曰本 Diabetes Association has been in the year = this: sue, diabetes is the following == sugar concentration (static g g oral glucose tolerance test (75 g OGTO 2 f concentration (intravenous blood) Grapes ^75 g QGTT) 2 small ❹ ❹ and non-fasting blood glucose concentration (static:; to: 2 1 not: Yu · He. The above symptoms of diabetes did not appear and ^ Tang Yuchen = 3 ==: fasting Blood glucose concentration (intravenous blood _

A condition of 2 W or 75 & ° glucose tolerance test (75 S dl - ^ glucose concentration in intravenous blood) below 14 〇 mg / dl" is called "marginal". In addition, the ship (American Diabetes Association) and WHO have also proposed new diagnostic criteria for diabetes in 1997 and 1998, respectively. In the blood, 'diabetes is a condition that shows the following symptoms: grapes in the fasting, the degree of glucose in the blood of the vein (intravenous blood glucose) is not lower than i2 "g blood two doses of glucose test for 2 hours (intravenous plasma)匍 糖 ;; 辰 )) not less than 200 mg / dl. rr root glucose financial abnormalities for the following symptoms, _ sugar concentration (intravenous blood glucose concentration) low g X and 75 g oral glucose resistance The concentration of glucose in the concentration test for 2 hours is not less than just _ but less than 200. 1. According to the ADA report, the glucose concentration in fasting blood (glucose concentration in blood of 321426 79 201029996) is not less than 110 mg. /dl but less than 126 mg/dl is called IFGUmpaired Fasting Glucose, fasting glucose abnormality) ° According to WHO report, IFGUmpaired Fasting heart ycymia, fasting glucose abnormality), oral administration of glucose tolerance and steep test for 2 hours A condition in which the concentration (intravenous plasma glucose concentration) is less than 140 mg/dl is called IFG (fasting blood glucose abnormality). - The compound of the present invention can also be used as described above. The new diagnostic criteria are anti-diabetic, marginal, impaired glucose tolerance, IFG (fasting glucose abnormality), and prophylactic or therapeutic agents for IFG (fasting blood glucose abnormality). In addition, the compounds of the present invention prevent edge type, Glucose tolerance abnormality, IFG (fasting glucose abnormality), or IFG (fasting blood glucose abnormality) develop into diabetes. Further, the compound of the present invention can also be used as a prophylactic or therapeutic agent for osteoporosis and cachexia (for example, Cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological malignant disease, endocrine disease cachexia, infectious disease cachexia, heart disease cachexia or cachexia caused by acquired plague deficiency syndrome, fatty liver, polycystic ovary syndrome, Kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerular sclerosis, renal syndrome, hypertensive nephrosclerosis, end stage renal disease), muscular dystrophy, myocardial infarction, angina, cerebrovascular disease (eg : cerebral infarction, stroke, ischemia, coronary heart disease , non-Q wave, muscle infarction (non-Q wave ΜI), congestive heart failure, ventricular hypertrophy, arrhythmia, intermittent claudication, peripheral arterial occlusive disease (eg 'peripheral artery abnormalities'), Alzheimer's disease (Alzheimer's) Disease), Parkinson's syndrome, anxiety, dementia, 姨 素 321 321 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 426 , leukemia, breast cancer, prostate cancer, skin cancer, epithelial cancer, adenoid keratosis), large intestine irritability, acute or chronic abdominal filling, inflammatory diseases (eg, chronic typhoid arthritis, spondylitis deformation, bone and joint Inflammation, low back pain, gout, gouty arthritis, postoperative or traumatic inflammation, swelling, neuralgia, pharyngitis, bladder inflammation, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammation Sexual bowel disease (including inflammatory colitis), ulcerative colitis, gastric membranous injury (including gastric mucosal damage caused by aspirin), Lyme disease (Lyme Vision, urticaria, dry arthritis, conjunctivitis, gastritis, chronic thyroid gland, chronic active hepatitis, Crohn's disease ((: 1_〇如, 3 (1:1 post, slippery) Membrane inflammation, ankylosing spondylitis), intestinal adhesion, malabsorption, dysfunction of testicular dysfunction, organ obesity syndrome, sarcopenia, macular degeneration, congenital hypoplasia, thrombocytopenia, multiple sclerosis, Periodontal disease, cutaneous tumor, pulmonary sarcoidosis, myasthenia gravis, Obiter's syndrome, influenza, cerebral malaria, silicosis, monthly reabsorption, fever, muscle pain, and multiple bones Tumor-associated bone disease, neurodegenerative disease caused by trauma, traumatic brain injury, giant disease, graft versus host response, transplant rejection, skin disorders (eg, scar tissue formation, eczema, atopic dermatitis) , contact dermatitis, urticaria, scleroderma, dryness), allergic or respiratory diseases (eg, asthma, respiratory distress syndrome, hay fever, allergic nose) Chronic pulmonary inflammatory disease (eg, chronic obstructive pulmonary disease (C0PD)), inflammation associated with autoimmune diseases (eg, systemic lupus erythematosus, Addison's 81 321426 201029996 disease), multi-gland function Low symptoms, Graves, disease, infectious diseases (eg 'sepsis, septic shock, bacillary pain, Helicobacter pylori), viral diseases (eg, simple herpes virus infection, huge Cellular virus infection, Epstein-Barr virus infection, human immunodeficiency virus infection, type A, type B, and hepatitis C virus infection, angiogenesis (eg, solid tumor, ocular neovascularization) , hemangioma, edema, analgesia, pain (eg, neuromuscular pain, headache, pain caused by cancer or surgery, toothache, arthritic pain), large intestine, leukemia, central nervous system disease (eg, by Cerebral ischemia, cerebral infarction, cerebral edema, etc.), renal fibrosis, liver fibrosis, fibrosis of the prostate, Fibrosis. Further, the compound of the present invention can also be used as an gastrointestinal motility function improving agent. The compounds of the present invention are also useful for secondary prevention as well as for inhibiting the development of various diseases as described above (e.g., secondary prevention and inhibition of cardiovascular events such as development of myocardial infarction, etc.). Although the administration object of the compound of the present invention is not particularly limited, it is preferably a mammal (e.g., 'mouse, rat, hamster, rabbit, u fine, dog, cow, sheep, monkey, human, etc.). Although the dose of the compound of the present invention varies depending on the administration subject, the administration route, the target disease, the symptoms, and the like, for example, when Q. spine R.W-t 艮 is administered to an adult diabetic patient, the single dose is usually About 0. 〇〗? Tongue, i'^lOOmg/kg body weight' is preferably 〇. 05 to 30 mg/kg body weight 'better 〇] w, A main 1U mg/kg ancestral weight; this dose can be administered daily as desired Up to 3 times. 321426 82 201029996 The compound of the present invention which is used to increase the effect of the compound of the present invention or to reduce the dose of the compound of the present invention can be used in combination with the following agents, for example, diabetes, diuretic, adenine, and the like. Diabetes complication therapeutics, hyperlipidemia treatment ^, anti-stress blood pressure agents, anti-obesity agents, diuretics, anti-thrombotic agents, etc. (hereinafter = simple, for combination drugs). Administration time of the compound of the present invention and combination drug

'It can be administered to the subject at the same time or administered to the subject in a staggered manner. Further, the compound of the present invention and the combination drug may be administered in two preparations containing one ingredient or as a single preparation containing both active ingredients. The dose of the combination drug can be appropriately determined depending on the dose for clinical use. Further, the mixing ratio of the three inventive compounds and the combination drug can be determined according to the target of the drug, the disease, the disease, the combination, and the like. 01至100重量份。 The amount of the compound of the present invention may be used in an amount of from 0.01 to 100 parts by weight. Examples of the therapeutic agent for diabetes include: an insulin preparation [for example, an animal Tetrandin preparation extracted from the pancreas of bovine or pig, using Escherichia coli aschendna coli) or a yeast human insulin preparation synthesized by genetic engineering technology; zinc phosphine Islandin; protamine zinc insulin; a fragment or derivative of insulin (for example, etc.), an oral insulin preparation), an insulin sensitizer (for example, piglitazone or a salt thereof) Salt strontium salt), TAK-379, Loctagsson (r〇sigutaz〇ne) or its cockroach; Optima maleate), tesaglitazar, Ragaglitazar, grazing Mura* (muragUtazar), Eli itazone, (etagi idasen), Naliboso 321426 83 201029996 (Naveglitazar), AMG-131, THR-0921), α-glycosidase inhibition Agents (eg, voglibose, acarbus, miglitol, emigiitate, biguanides (eg 'metformin', butyl) Buformin or a salt thereof (for example, hydrochloride) Oxalate, alkaloid)), Tengusu secretagogue [continued urea (eg 'tolbutamide, glibenclamide, gHciazide) Chlorpropamide, t〇iazamide, acetohexamide, glycipypyamide, glimepiride, gHpizide, lattice Cloth (glybuzole), lapaghin (repagHnide), 纳格奈

Glucose-dependent Tengdamycin secretagogue (eg, TAK-875)], dipeptide-based MSI such as 'agreline; butyl, saxagliptin, τ~·6666, AJ-9677), GPR40 Vildagliptin, sitagliptin, siglipin GLP-1MR 'ΝΝ-2211 λ AC-29i Aib(8, 35)hGLP-1 (7s 37)NH2 eg pramlintide bb6 , TS-021), mega 3 agonist (eg 't agent, GLP-1 receptor agonist [eg, GLP-Bu AC-2993 (exendin-4), BIM-51077,

For example, BVT-3498), lipostatin 84 321426 201029996 (adiponectin) or its agonist, IKK inhibitor (eg, AS-2868), alizarin resistance improving drug, somatostatin receptor agonist, grape A 糠 kinase activator (for example, Ro-28-1675), a GIP (glucose-dependent insulinotropic peptide), and the like. Examples of therapeutic agents for diabetic complications include: aldose reductase inhibitors (eg, tolrestat, epairestat, zenarestat, zopolrestat) , minalstatin (minalrestat), fidarestat (fidarestat), CT-112), neurotrophic factor and its promoting drugs (eg, NGF, NT-3, BDNF, described in WO01/14372 neurotrophic production and secretion Promoter (for example, 4-(4-hydroxyphenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]indazole)), TAK -583, a nerve regeneration enhancer (eg, y-128), a PKC inhibitor (eg, ruboxistaurin mesylate), an AGE inhibitor (eg, ALT946, pimagedine) , Biato Xianxin (pyrat〇xanthine), N-benzoquinone methylthiazole rust bromide (ALT766), ALT-711, EXO-226, Pyriorin, Pyrimin (Pyrid〇 Xamine)), active oxygen scavengers (eg 'lipoic acid'), cerebral vasodilators (eg 't iapr丨de, mexiletine), Somatostatin receptor agonists (e.g., BIM23190), apoptosis signal regulating kinase -i (ASK-l) inhibitors and the like. Examples of therapeutic agents for serotonemia include: statin compounds (eg, pravastatin, simvastatin, lovastatin (i〇vastatin), atostatin; Atorvastatin), fluvastatin, ruthenium statin 321426 85 201029996 (rosuvastatin), pitavastatin (ritavasta1:in) or its salt (eg, sodium salt, calcium salt), squalene synthetase inhibition Agent (for example, lapaquistat acetate or a salt thereof), a fibrate compound (for example, bezafibrate, clofibrate, simfibrate, Klee Clinofibrate), ACAT inhibitors (eg, Avasimibe, Eflucimibe), anion exchange resins (eg, colestyramine), probucol Acid test drugs (for example, nicomol, niceritrol), ethyl eicosapentaenoate, phytosterols (eg, soy sterol, T-glutenol) (γ -oryzanol)) and so on. Examples of anti-high jk pressure agents include: angiotensin-converting enzyme inhibits Qiqi (e.g., captopril, enalapril, deLapril), angiotensinΠ Antagonists (eg, candesartan ester (. & 11 (163 & 1^8110^16 and 61^1), losartan (1〇5&1^311), eprosartan, Valsartan, telmisartan, irbesartan, tassosartan, 1-[[2'-(2, 5-dihydro-5-sideoxy) -4H-1, 2, oxadiazol-3-yl)biphenyl-4-yl]indenyl]-2-ethoxy-1H-benzopyrene-7-carboxylic acid, TAK-491), calcium Antagonists (eg, manidipine, nifedipine, amlodipine, efenidipine, nicardipine), potassium channel openers (eg, left) Leccaromakalim, L-27152, AL 0671, NIP-121), clonidine 321426 86 201029996 (clonidine), etc. Examples of anti-obesity agents include: anti-obesity regular J (acting on the middle pole nervous system) For example, 'dexfenfiura (dexfenfiura) Mine), fenfluramine, phentermine, sibutramine, amfepramone (am; fepramone), dexamphetamine, mazind 〇i), phenylpropanolamine, clobenzorex; MCH receptor antagonist (for example, SB-568849; ❹ SNAP-7941; compounds described in WO01/82925 and W001/87834); neuropeptide Y antagonist (eg, CP-422935); cannabinoid receptor antagonist (eg 'SR-141716, SR-147778); ghrelin antagonist; 11-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498)), a lipase inhibitor (eg, orlistat, cetiiistat), a stone 3 agonist (eg, AJ-9677, AZ40140), appetite suppressant Peptides (eg, leptin, CNTF (ci 1 iary neurotropic O fact〇r), cholecystokinin agonist (eg, linterist (11111) :11:1^?1;)吋? 1^15849), a food repellent (for example, ?-57), etc. Examples of diuretics include xanthine derivatives (e.g., sodium salicylate theobromine, calcium salicylate), and thiazide preparations (e.g., ethiazide, cyclopentanene pi ( CyCi〇penthiazide), trichloromethyazide, hydrochlorothiazide, hydrofluoric acid, hydroflumethiazide, benzylhydrochlorothiazide 87 321426 201029996 (benzylhydrochlorothiazide), pentosene morphine ( Penflutizide), polythiazide, methyclothiazide, anti-ancoidosterone (eg, spironolactone, triamterene) , carbonic anhydrase enzyme inhibitors (eg, acetazolamide), chlorobenzene-branched amines (eg, chlortalidone, mefruside, indapamide © (indapamide) )), azosemide, isosorbide, ethacrynic acid, pi ratio pitatanide, bumetanide, and sigma Furosemide) and so on. Examples of antithrombotic agents include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarim (eg, warfarin potassium), anticoagulant drugs (eg, Aragatroban, dabigatran, thrombolytic agents (eg, urokinase, tisokinase, altplase, nataplase) Nateplase), monteplase, pamiteplase, platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol), twenty carbon Ethylpentaenoate, beraprost sodium, sarpogrelate hydrochloride, E5555, SHC 530348, prasugrel, FXa inhibitor gas (eg 'TAK-442, Rivaroxaban, apixaban, DU-176b, YM150). 321426 88 201029996 Two or more of the above combinations may be combined in an appropriate ratio. The method for producing the compound of the present invention is explained below. The compound of the present invention can be produced according to a method known per se, such as the method detailed below, or a method analogous thereto. In the following production methods, the starting material compound may be in the form of a salt, and examples of such salts include those similar to the salts of the compound (I) and the compound (IA). The compound obtained in each step of the following reaction formula can be used as the reaction mixture or the crude product in the next reaction, or can be isolated and purified by known methods (for example, concentration, concentration under reduced pressure, solvent extraction, crystallization). , recrystallization, phase transfer, chromatography, etc.) are used for isolation and purification for use in the next reaction. When the compound of the following formula is commercially available, such commercially available products can be used directly. In the following reactions, when the starting material compound has an amine group, a carboxyl group Q or a hydroxyl group as a substituent, these groups can be protected by a conventional protecting group such as peptide chemistry. In this case, the protecting group may be removed after the reaction as needed to obtain the target compound. Examples of the amine protecting group include: a brewing group, a Cl-6 group-yl group, a Cl-6 alkoxy group, a benzoic acid group, and a Cf-1. Aryl-based (for example, benzylcarbonyl), Oh aralkyloxy-carbonyl (for example, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), triphenylsulfonyl, ortho-benzene Dimercapto, N,N-diamidohydrazinyl, substituted alkylene (eg, trimethylsulfonyl, triethyldecyl, dinonylphenylphosphino, tert-butyl) Mercaptoalkyl, 89 321426 201029996 dibutylethylcylate, C2-6 thiol (eg, 1-allyl), and the like. These groups may be optionally substituted with 1 to 3 substituents selected from a halogen atom, a cv6 alkoxy group and a nitro group. Examples of the carboxy protecting group include: a Cl-6 alkyl group, a C7-n aralkyl group (e.g., benzyl group), a phenyl group, a trityl group, a substituted decyl group (e.g., trimethyldecyl group, triethyl group). A decyl group, a dimethylphenyl decyl group, a tert-butyldimethyl decyl group, a tert-butyldiethyl decyl group, a C2_6 alkenyl group (for example, 1-allyl), and the like. Examples of the hydrazine protecting group include: an alkyl group, a phenyl group, a trityl group, an O-io aralkyl group (e.g., 'benzyl group), a decyl group, a Ci 6 alkyl group, a carbonyl group, a benzoquinone group, Cm aryl-derivative (for example, phenylhydrazinocarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted decyl (for example, trimethyldecyl, diethyl decyl, di Methylphenyldecylalkyl, tert-butyldicylidenealkyl, tert-butyldiethyldecylalkyl, G6alkenyl (for example, allyl), and the like. These groups may be optionally substituted with from i to 3 substituents selected from the group consisting of a halogen atom, a Cm 0 alkyl group, a Ci-e alkoxy group, and a nitro group. The above protecting group can be removed according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980), and the like. Specifically, the use of acid, alkali, ultraviolet, hydrazine, benzamidine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsulfonium alkyl halide (for example) , a method such as trimethyl-breaking, tridecyl bromide, or the like, a reduction method, and the like. Further, in the following respective reactions, the introduction of a substituent can be carried out by a method known per se from the starting material, the intermediate and/or the obtained product to convert the reaction to 321426 90 201029996 and Lushui. Examples of the substituent conversion reaction include a method known per se, for example, converting the hydrazine to a thiol group, activating the sulfhydryl group to an amine group, and converting the thiol group to a hydroxymethyl group by reduction. Conversion of several groups to reduction or conversion to an alcohol compound, reductive amination of a few groups, use of a k-group, deuteration of an amine group, urearation, sulfonation or Alkylation, substitution or amination of an active halogen by an amine 'Amination of a nitro group by reduction reaction, burning of a base, substitution by a base and amination; nitrogen-containing Alkylation of a ring nitrogen atom of a heterocyclic ring, introduction of a substituent by a coupling reaction (for example, an aryl coupling reaction); substitution of a dentate by an amine, an alcohol or a thiol; The compound (I) can be produced, for example, by the method shown in the following reaction scheme. Reaction diagram 1

Wherein R is a Cl-6 alkyl group (e.g., decyl, ethyl, n-hexyl); Q is a leaving group (e.g., sulfonyloxy, p-toluenesulfonyloxy, element 91) 321426 201029996 Sub (eg 'chlorine, bromine)); R3M is an organometallic compound (to be mentioned later) 'and other symbols are as defined above. Step 1 The ruthenium (111) can be obtained by subjecting the starting material compound (π) to a reduction reaction. This reduction reaction can be carried out according to a conventional method using a reducing agent. Examples of the reducing agent include a metal hydrogen compound such as sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride (DIBALH) or the like; a metal hydrogen complex compound such as sodium borohydride or cyanamide Sodium hydride, lithium aluminum hydride, sodium hydride aluminum, etc.; The reducing agent is usually used in an amount of from 1 to 20 mol per 1 mol of the compound (π). This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and, for example, alcohols such as methanol, ethanol, lactone, iso-ol, butanol, isobutanol, and butanol may be mentioned. Halogenated hydrocarbons such as dichloromethane, chloroform, tetra-gasified carbon, tri-ethylene, etc.; aromatic hydrocarbons such as stupid, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc. Ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetra-furfuran, dioxane, dimethoxyethane, etc.; inorganic acids such as hydrochloric acid, sulfuric acid, etc.; organic acids such as citric acid, Acetic acid, propionic acid, trifluoroacetic acid, methyroic acid, etc.; water; Two or more of these solvents may be used in combination in an appropriate ratio. The reaction time is usually from 1 minute to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -l〇〇t: to 15〇. 〇, preferably ― 别 ^ to 1 〇〇 321426 92 201029996 °c. The compound (π) used as a starting material can be synthesized according to a method known per se. For example, the synthesis method described in WO2007/89031, ΕΡ94154, WO2003/99793 or ΕΡ1176140. Step 2 Compound (IV) can be produced by subjecting compound (111) to an oxidation reaction. This oxidation reaction can be carried out using an oxidizing agent according to a conventional method. Examples of the oxidizing agent include active manganese dioxide, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Dess-Martin periodinane, diterpene hard anhydride (for example, Acetic anhydride, difluoroacetic anhydride), diterpene hard-thinous sulfonium chloride, dimethyl sulfite, sulfur-containing chlorine, diterpenoid-oxalyl chloride, disulfoxide-chlorine, and acid (for example, Glycol in the presence of phosphoric acid, difluoroacetic acid, monochloroacetic acid; g-dicyclohexylcarbodiimide (DCC), and the like. The oxidizing agent is usually used in an amount of from 1 to 20 moles per 1 mole of the compound (?π). This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and are, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl-, tetrahydrofuran, anthracene, 4-dioxane, 1,2- a methoxy group or the like; a ketone such as a propyl group, a methyl ethyl ketone or the like; a halogenated hydrocarbon such as a gas-fired, chloroform, tetra-carbonated carbon, trichloroethylene or the like; an aromatic hydrocarbon such as benzene. Saturated tobacco, such as cyclohexane, hexane, etc.; amides, such as hydrazine, hydrazine, hydrazine, hydrazine, hydrazine, hexamethylene Amines and the like; inorganic acids such as hydrochloric acid, 321426 93 201029996 sulfuric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; water; Two or more of these solvents may be used in combination in an appropriate ratio. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -1 Torr (TC to 15 Torr. (:, preferably -2 (TC to 100 ° C. Step 3) The compound (VI) can be reacted with the organometallic compound (V) by reacting the compound (IV) with the organometallic compound (V). The reaction is carried out in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction can be carried out, and is, for example, an ether such as diethyl ether or tetrahydrofuran. 4-diazine or the like; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; etc. These solvents can be used in an appropriate ratio. Examples of the organometallic compound (V) include: a Grignard reagent (for example, a compound represented by the formula: R3MgBr), an organolithium reagent (for example, a compound represented by the formula: R3Li), and an organozinc reagent (for example, ' A compound represented by the formula: (R3)2Zn, wherein R3 is as defined above), etc. These compounds can be produced according to a method known per se, for example, "Jikken Kagaku Kouza (The Chemical Society Japaned.), 4th Edition , vol. 25, Synthesis by 0rganic M Etal Reagent" pp. 9-449, Maruzen Press 1992 The method described in the middle of the household, or a similar method. 32!426 94 201029996 The amount of the organometallic compound (V) is usually used per 1 mole of the compound (IV). The reaction time is usually 0.5. The reaction time is usually from 0.5 to 100 ° C, preferably from -20 ° C to 50 ° C. The reaction time is usually 0.5. Up to 20 hours. Step 4 Compound (VII) can be produced by converting the base group of compound (VI) to a leaving group. The conversion to a leaving group can be carried out according to a conventional method, for example, by It is reacted with methanesulfonyl chloride in the presence of a suitable base or by reaction with a sulfurous gas. Examples of the base used in this reaction include N,N-diisopropylethylamine (DIEA), triethyl Amine (TEA), pyridine, N,N-didecylaniline, etc. The amount of methotrexate or sulfinium chloride is usually from about 1 to 50 moles per 1 mole of compound (VI). Preferably, it is from about 1 to 10 moles. The base is usually used in an amount of from about 0 to 50 moles, preferably from about 1 to 10 moles per mole of the compound (VI). It is carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and are, for example, ethers such as ethylene, tetrahydrogen, and 1,4-dioxin. And the like; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; etc. These solvents may be used in combination in an appropriate ratio. The reaction temperature is usually -50 to 150 ° C, preferably -10 to 100 ° C. 5至二十小时。 The reaction time is usually 0.5 to 20 hours. Step 5 95 321426 201029996 Compound (I) can be compounded with compound (VIII) and compound (VIII) (for example, 3-{((4-aminophenyl)carbonyl)amino}ethyl propionate by the presence of a test. ) prepared by reaction. The acetic acid group of the obtained adduct can be hydrolyzed as needed. Examples of the base to be used in the reaction include: an alkali metal hydroxide such as lithium hydroxide, sodium ruthenium oxide, potassium hydroxide or the like; an alkaline earth metal hydroxide such as magnesium hydroxide, calcium hydroxide or the like; an alkali metal carbonate For example, sodium carbonate, potassium carbonate, carbonic acid strontium, etc.; metal hydrogencarbonate such as sodium hydrogencarbonate, potassium cesium carbonate, etc.; alkali metal alkoxide having 1 to 6 carbon atoms, such as sodium methoxide, ethanol Sodium, potassium butoxide, etc.; metal hydrides such as sodium hydride, potassium hydride, calcium hydride, etc.; This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and are: alcohols such as decyl alcohol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc.; ethers, for example 1, 4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethyl bromide, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, N-butyl acetate or the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; guanamines such as decylamine, N, N-dimercaptocarbamide, N,N-dimercaptoacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; sulfoxides such as dimethyl sulfoxide; cyclobutane; hexamethyl phosphate Triamine; and so on. Two or more of these solvents may be used in combination in an appropriate ratio. In this reaction, 1 equivalent to a large excess amount (preferably 1 to 10 equivalents) of a metal halide (for example, sodium molybdenum or the like) may be added to the compound (V11) as a reaction accelerator. 96 321426 201029996 A compound (VIII) is used in an amount of about 1 to 10 moles, preferably about 2 to 2 moles, per 1 mole of the compound (νΐί). S for? The amount of the compound (vίί) of the molar is usually from 1 to 〇 molar equivalent, preferably from 5 to 5 molar equivalents. The reaction temperature is usually from -30 to 20 {rc, preferably from 〇 to (10). c. The reaction time is usually from 〇5 to 20 hours. The base can be hydrolyzed according to a method known per se, for example, (4) heart (10)

The method described in in Organic Synthesis, Third Edition, Wiley-Spence (10) 9) or a method analogous thereto. The general method for producing the starting material compound and its reactive derivative used in the above method is explained below. Exhausted 2

Compound (VIII) can be based on, for example, the following reaction scheme 2

9 S h W Ml l W1 % and W2 are each independently an amine protecting group, and fla is a Cl inflammatory moiety. The alkyl group is as defined above. 321426 97 201029996 In this reaction, the compound is condensed with the compound (a2). Compound (a3-l). The condensation reaction can be carried out according to a conventional method, for example, a general winning coupling method. Examples of the method include a method comprising directly condensing a compound (al-oxime) with a compound (a2) using a condensing agent; a method comprising reacting a reactive derivative of the compound with the compound (a2): and the like. Examples of the condensing agent include: a carbodiimide condensation tester (for example, 'dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide (EDC;), f its hydrochloride, etc.; Wei condensing reagent, such as cyanophosphonic acid diacetic acid, diphenyl filled IUb Diphenylphosphoryl azide, etc.; several groups: imidazole, 2-chloro-1,3-dimethylimidazole rust tetrafluoroboric acid, 2_(7-aza-1H-benzobisazol-1-yl)-1, 1,3,3_tetramethylurea hexafluorophosphate (hats, etc. Examples of the solvent used in the condensation reaction include: guanamines such as hydrazine, [dimethyl decylamine, hydrazine, hydrazine-dioxin]乙乙_, 卜 methyl bites, etc.; © sub-hard types, such as diterpenoids; halogenated hydrocarbons, such as chloroform, dichloropyrene, etc.; ^ aromatic hydrocarbons, such as benzene, toluene, etc.; For example, tetrazole, diterpene, b test, dimethoxyethane, etc.; vinegar, such as acetic acid, ethyl acetate, etc.; nitrile 'such as B guess, C., etc.; water; etc. Solvents can be mixed in appropriate proportions. The compound (10) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles per 1 mole of the compound (al_1;). # Relative to each mole of the compound (Gentry), the condensing agent The amount used is usually from 0.1 to 10 mol, preferably from 3 to 3 mol. 321426 98 201029996 When a carbodiimide condensing agent is used as the condensing agent, an appropriate condensation accelerator can be used as needed (for example, 1 -Hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy quinone imine) to increase the efficiency of the reaction. When using HATU or a phosphoric acid condensation reagent as a condensation In the case of a reagent, the reaction efficiency can be improved by using an organic amine base (for example, triethylamine, N,N-diisopropylethylamine, etc.). Condensation per 1 mole of the compound (al-Ι) The polymerization agent or the organic amine base is usually used in an amount of from 0.1 to 10 moles, preferably from 0.3 to 3 moles. The reaction temperature is usually from -30 to 120 ° C, preferably from -10 to 100. The reaction time is usually 0.5 to 60 hours. Examples of the reactive derivative of the compound (al-1) include a mercapto halide (for example, a mercapto group) , 醯基漠), 11 m alpha sitide (imidazolide), mixed anhydride (for example, anhydride with decyl carbonate, ethyl carbonate, isobutyl carbonate), etc. For example, when using 醯 函, The reaction is usually carried out in the presence of a base in a solvent which does not adversely influence the reaction. Examples of the base include: amines such as triethylamine, pyridine, N-mercaptomorpholine, N,N-didecyl. Aniline, 4-diguanylidenepyridine, etc.; an alkali metal salt such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate or the like; Examples of the solvent which does not adversely affect the reaction include: guanamines such as N,N-didecylguanamine, N,N-dimercaptoacetamide, N-decylpyrrole 99 321426 201029996, etc. , _ _ members, such as dimethyl slate, etc.; southern smog, such as chloroform, dichloromethyl, aromatic _, such as benzene, toluene, etc.; ethers, such as tetrahydrofuran, two bismuth , Essence, dimethoxyethane, etc.; 酉 类 category, such as acetic acid methyl vinegar, acetic acid, vinegar, etc.; nitriles, such as B guess, C., etc.; water; These solvents can be used in combination in an appropriate ratio. When the above guanamine is used as a solvent, the reaction can be carried out without a test. (d) The compound sand is usually used in an amount of from 1 to 10 moles, preferably m moles, per mole of the mole compound (aH). The self-test is usually from 1 to 10 moles, preferably from 1 to 5 moles, per 1 mole of the compound (aH). 1 The reaction temperature is usually -3 Torr. (: to 12 (rc, preferably _1〇 to the discussion. c. The reaction time is usually 〇·5 to 3 hours. When using mixed acid, the compound (a) is in the presence of chlorine A carbonate (for example, 'gas methyl carbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) is oxime-reacted, and then reacted with compound (a2). Examples of tests for use in this reaction include the foregoing for use in a compound (al) -1) The exemplified by the reaction of the oxime base with the compound (10). The compound (10) is usually used in an amount of from 1 to 10 mol, preferably from ~5 mol, per 1 mol of the compound. The amount of chlorocarbonate used is 1 to 10 moles, preferably ! to 5 moles per 1 mole of iStAi $ in chemical (&1-1). 1 Moule, Ί ^ in ^ w ± 匕5 (al-1), the amount of the base is usually 1 to 10 旲, preferably 1 to 3 摩尔. 321426 100 201029996 The reaction temperature is usually -30 °C to 120 ° C, preferably -10 to 100 ° C. The reaction time is usually 0.5 to 20 hours. When using imidazolide, the compound (al-Ι) is related to, for example, Ν, Ν '-carbonyl mum (CDI) reaction, obtaining the corresponding imidazolide, and then further reacting with the compound (a2). The compound (a2) is usually used in an amount of from 1 to 10 mol per 1 mol of the compound (al-Ι). It is preferably 1 to 5 moles. The amount of N,N'-carbonyldiimidazole® (CDI) is usually 1 to 10 moles, preferably 1 per 1 mole of the compound (al-1). The reaction temperature is usually from -30 ° C to 120 ° C, preferably from -10 to 100 ° C. The reaction time is usually from 0.5 to 20 hours. About the compound (al-Ι) and the compound (a2) It can be obtained from a commercially available product, or can be obtained according to a method known per se or a similar method using a commercially available compound. Step la 0 Compound (a3-2) is a compound according to the same method as in Step 1 ( Al-2) is produced with the compound (a2). Regarding the compound (al-2), a commercially available product may be used, or a commercially available compound may be used according to a method known per se or the like. Step 2 Compound (a4) can be produced by subjecting compound (a3-l) to reduction reaction in the presence of a metal catalyst and a hydrogen source. Such reduction reactions can be carried out in a solvent which does not adversely affect the reaction according to a conventional method. 101 321426 201029996 Examples of metal catalysts used in this reaction include palladium-carbon, palladium black, chlorination, and oxidation. , m, Raney_nickel, Raney cobalt, etc. Examples of hydrogen sources include hydrogen, citric acid, ammonium formate, phosphinate, hydrazine, and the like. Examples of the solvent which does not adversely affect the reaction include: decyl alcohol, tetrahydrofuran, N,N-dimercaptoacetamide and the like. The amount of the metal catalyst is usually from 0.001 to 1000 mol, preferably from 〇1 to 1 mol, per 1 mol of the compound U3-1). The reaction temperature is usually -70 to 15 ° C, preferably -20 to 10 (TC. The reaction time is usually from 0.1 to 1 hour, preferably from 1 to 4 hours. In the presence of a reducing agent, it is carried out in a solvent which does not adversely affect the reaction. Examples of the reducing agent include iron oxide, zinc, tin, etc., and the compound (a4) φ can be obtained by "Jikken Kagaku Kouza (The Chemical Society of Japan ed.), 4th Edition, vol. 20, Organic Synthesis II Alcohol and Amine" pp. 279-280, Maruzen Press 1992, or a similar method. Step 3 Compound (a4) can be used by itself A method of removing the protecting group (W1) of the compound (a3-2) to produce a method such as that described in Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999) or the like. 102 321426 201029996 Step 4 The compound (VI11) can be produced by subjecting the compound (a4) or the compound (a9) to a reductive amination reaction. The reductive amination reaction can be carried out by a method known per se, for example, ^Jikken Kagaku Kouza (The Chemical Society of Ja Pan ed. ), 4th Edition, vol. 20. Organic Synthesis II Alcohol and Amine” pp. 300-302, method described by Maruzen Press 1992; Reductions in Organic Chemistry Second ❹

The method described in Edition, American Chemical Society (1996), pp. 187-189; or a method analogous thereto. Step 5 Compound (a7) can be synthesized by a Friedel-Crafts reaction using compound (a5) and glutaric anhydride (a6), and by a synthesis method as described in, for example, WO2004/45616 Or a similar method of synthesis. ❿Step 6 Compound (a8) can be obtained by removing the protecting group of compound (a7) by a method known per se, for example, as described in Protective Gro叩s in Organic Synthesis, Third Edition, Wiley-Interscience (1999). Method or the like. Step 7 Compound (a9) can be obtained by esterifying compound (a8) by a method known per se to prepare a method as described in, for example, Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999) 103 321426 201029996 Or a similar method. The compound (IA) can be produced, for example, by the method shown in the following Reaction Scheme A1. In the following Reaction Scheme A1, the compound (Bla) contains a compound in which the RAn in the compound (IA) is a Ci-6 alkyl group, and the compound (Bib) contains a compound in which the RAn in the compound (IA) is a hydrogen atom. Reaction diagram A1

(BVI) Step by step~

Wherein X is CH2 or NRA6, 1^113 is a G-6 alkyl group, and L is a leaving group (for example, a sulfonyloxy group, a p-toluenesulfonyloxy group, a halogen atom (for example, chlorine, bromine) )), as well as other symbols are as defined above. Step 1 The compound (BI11) can be produced, for example, by converting the hydroxyl group of the compound (BII) to 104 321426 201029996 as a leaving group. The conversion to the leaving group can be carried out according to a conventional method, for example, by reacting with sulfonium chloride, phosphonium chloride or acid chloride in the presence of a suitable base. Examples of the base include N,N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N,N-dimethylaniline and the like. The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (BII). The amount of the sulfonium chloride, the phosphonium chloride or the sulfinium chloride is usually from 1 to 10 moles, preferably from 1 to 5 moles, per 1 mole of the compound (BII). This reaction can be carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and there may be mentioned, for example, ethers such as an ethyl bond, a tetrazide, a 1,4-dioxene, etc.; a halogenated meridian such as a gas imitation; , dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; These solvents can be used in combination in an appropriate ratio. The reaction temperature is usually -80 to 200 ° C, preferably -10 to 150 ° C. The Q reaction time is usually from 10 minutes to 20 hours, preferably from 15 minutes to 24 hours. The compound (BII) can be obtained by the following reaction. Step 2 The compound (Bla) can be produced, for example, by reacting a compound (Bill) with a compound (BIV) in the presence of a base. Examples of the base include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; soil-measured metal hydroxides such as 4H hydroxide, calcium hydroxide, etc.; alkali metal carbonates such as sodium carbonate , potassium carbonate, carbonic acid 105 321426 201029996 铯, etc.; test metal hydrogencarbonate, such as sodium bicarbonate, z carbonic acid hydrogen clock, etc.; with 1 to 6 carbon atoms, metal oxide oxides, such as sodium methoxide, sodium ethoxide, a third butanol clock or the like; a metal hydride such as sodium hydride, potassium hydride, bismuth 4 bow, etc.; The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (Bill). This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol and the like; ethers, for example, 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl decyl ether, diisopropyl ether, ethylene glycol diterpene ether, etc.; esters such as ethyl citrate, acetic acid Ethyl ester, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichlorosilane, gas, carbon tetrachloride, trichloroethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; Amines such as decylamine, N,N-didecylguanamine, N,N-dimercaptoacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; anthraquinones such as diterpenes Sulfoxide and the like; sulfolane; hexamethylenephosphoric acid triamine; Two or more of these solvents may be used in combination in an appropriate ratio. In this reaction, an alkali metal woven compound (for example, a block of sodium, a potassium sulphate, or the like) may be added as a reaction accelerator, and the alkali metal iodide is usually added in an amount of 1 mole per mole of the compound (Bill). 1 to 20 moles, preferably 1 to 10 moles. The compound (BIV) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 3 moles, per mole of the compound (Bill). 106 321426 201029996 The reaction temperature is usually -80 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The compound (BIV) can be obtained by the following reaction. Step 3 The compound (Bla) can be obtained by reductive amination of the compound (BV) with the compound (BIV) by a method known per se, for example, Reductions in Organic Chemistry Second Edition, American Chemical Society (1996), pp. 187-189; Journal of Chemical Society Perkin Transactions 1, (2000), pp. 145-146, etc., or a method analogous thereto. The compound (BV) can be obtained by the following method. Step 4 Compound (BVII) can be produced, for example, by reacting compound (ΒΠΙ) with compound q (BVI) in the presence of a base according to the method for producing compound (Bla) from compound (ΒΙΠ). As the compound (BVI) ', a commercially available product can be used, or it can be produced from a commercially available compound by a method known per se or the like. Step 5 The compound (BVI I) can be produced, for example, by a reductive amination reaction of the compound (BV) with the compound (BVI) according to the method for producing the compound (Bla) from the compound (bv). Step 6 321426 107 201029996 The compound (BVI11) can be produced by hydrolyzing the compound (BVII) by a method known per se, for example, as described in Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999). Method or a similar method. Step 7 The compound (BIa) can be produced, for example, by condensing the compound (BVI 11) with the compound (BIX). The condensation reaction can be carried out according to a conventional method, for example, a general peptide coupling method. Examples of such methods include a method comprising directly condensing a compound (BVI II) with a compound (BIX) using a condensing agent; or a method comprising reacting a reactive derivative of the compound (BVIII) with a compound (BIX): and the like. Examples of the condensing agent include: a carbodiimide condensation reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-didecyl) Aminopropyl)carbodiimide (EDC) and its hydrochloride; phosphoric acid condensation reagents such as diethyl cyanophosphate, diphenylphosphonium azide, etc.; carbonyl diimidazole, 2-chloro -1,3-diamidazolium rust tetrafluoroborate, 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetradecylurea hexafluorophosphate (HATU )Wait. Examples of the solvent used in the direct condensation reaction using a condensing agent include: guanamines such as N,N-didecylguanamine, N,N-dimercaptoacetamide, N-decylpyrrole, and the like. Ammoniums such as diterpenoids; i-hydrocarbons such as chloroform, dichlorodecane, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons such as benzene, toluene, etc. Ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, tert-butyl methyl ether, etc.; esters, 108 321426 201029996 such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate Ester, etc. Nitriles such as acetonitrile, propionitrile, etc.; water; Two or more of these solvents may be mixed in an appropriate ratio. The condensing agent is usually used in an amount of from 1 to 10 mol', preferably from 1 to 5 mols, per 1 mol of the compound (10) (1). When a carbodiimide condensation reagent is used as the condensing agent, it is optionally used by using a suitable condensation accelerator (for example, hydroxy-> θ ❹ saliva, benzotris-tris-sodium, sulfonium, succinyl-imine, (d) Grade (iv) amine) to increase the efficiency of the reaction. When HATU or a dish acid condensation reagent is used as the condensation reagent, the reaction efficiency can be improved by making an organic test (e.g., triethylamine mpropylethylamine or the like). The amount of the individual used in the condensation accelerator or organic amine is usually calculated relative to 1 mole of the compound (10) (1)! To 1 mole, preferably Mo. The compound (10) is usually used in an amount of from 1 to 10 moles, preferably from 5 to 5 moles per mole of the compound (10) π). The reaction time is usually from 1 minute to 6 hours, preferably! The reaction temperature of the ring is usually -50 to 150 t, preferably -10 to 1 Torr (rc. Examples of the reactive derivative of the compound (BVIII) include a tanning base (for example, mercapto chloride, mercapto bromide), imidazolide a mixed acid anhydride (for example, an acid anhydride having methyl carbonate, ethyl carbonate, isobutyl carbonate or the like) or the like. When a brewing base halide is used as the reactive derivative of the compound (10) u), the reaction is usually carried out in the presence of τ, in the opposite Anti-Imperial Solvents are carried out. 321426 109 201029996 Examples of bases include amines such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N,N-dimethylaniline, 4-didecyl Aminopyridine or the like; an alkali metal salt such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate or the like; The amount used is usually from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the halogen compound per mole of the compound (BVIII). Examples of the solvent used in the reaction include: guanamines such as N,N-dimethyldecylamine, N,N-dimethylacetamide, N-decylpyrrolidone, etc.; For example, dimethyl sulfoxide or the like; halogenated hydrocarbons such as chloroform, dichlorosilane, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; Tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, tert-butyl decyl ether, etc.; esters such as decyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; nitriles, For example, acetonitrile, propionitrile, etc.; water; These solvents can be used in combination in an appropriate ratio. When the above guanamine is used as a solvent which is inert to the reaction, the reaction can be carried out without the presence of Q in the base. The compound (BIX) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the halogen compound per 1 mole of the compound (BVIII). The reaction temperature is usually -30 ° C to 150 ° C, preferably -10 to 100 ° C. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. When a mixed acid anhydride is used as the reactive derivative of the compound (BVI11), the compound (BVIII) is reacted with a chlorocarbonate (for example, chlorocarbonate, ethylene carbonate, isobutyl carbonate) in the presence of a base, followed by Reacts with compound 110 321426 201029996 (BIX). Examples of the base to be used in the reaction include the bases exemplified for the reaction of the mercapto halide of the above compound (BVIII) with the compound (BIX). The gas carbonate is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (BVIII). The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (BVI II). The compound (BIX) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (BVIII). The reaction temperature is usually -30 ° C to 120 ° C, preferably -10 to 100 ° C. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. As the compound (BIX), a commercially available product can be used, or it can be produced from a commercially available compound by a method known per se or the like. Q Step 8 The compound (Bib) can be produced, for example, by hydrolyzing an ester of the compound (Bla) according to the method for producing the compound (BVIII). The starting material compound of the reaction diagram A1: the compound (BII) and the compound (BV) can be obtained, for example, by the method shown in the following reaction scheme A2. 111 321426 201029996 Reaction diagram Α 2

Ο where ΧΑ1 ΜΑ14, 0, or S; RA12 is C 6 6 alkyl; Changchuan and rA14

a substituent which is independently a hydrogen atom or a ring of the above-mentioned ring AB as needed; RA3M is an organometallic compound (to be mentioned later); La1 is an illuminating group (for example, a halogen atom such as chlorine, bromine, etc.), And other symbols are as defined above. Step 1 ❹ Compound (2) can be produced by subjecting compound (1) to a reduction reaction. The reduction reaction can be carried out according to a conventional method using a reducing agent. Examples of the reducing agent include a metal hydrogen compound such as a bismuth metal hydrogen complex compound such as bis(2-methoxyethoxyethoxy)aluminum hydride or diisobutylaluminum hydride (DIBALH), such as sodium borohydride or cyanoborohydride. Sodium, yttrium aluminum hydride, sodium hydride, which hydrogenation, etc.; Phase, every! The molar compound (1), the reducing agent is usually used in an amount of from 1 to 20 mol, preferably from 1 to 10 mol.

This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and, for example, A 321426 112 201029996 alcohols such as decyl alcohol, ethanol, propanol, isopropanol, butanol, isobutanol, third Butanol or the like; halogenated hydrocarbons such as dioxane, chloroform, carbon tetrachloride, trichloroethylene, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, Heptane or the like; ethers such as diethyl ether, diisopropyl ether, tert-butyl decyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; water; Two or more of these solvents may be used in combination in an appropriate ratio. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -100 ° C to 150 ° C, preferably -20 ° C to 100 ° C. As the compound (1), a commercially available product can be obtained, or can be obtained from a commercially available compound by a method known per se or the like. Step 2 Compound (3) can be produced by subjecting compound (2) to an oxidation reaction. 0 The oxidation reaction can be carried out using an oxidizing agent according to a conventional method. Examples of the oxidizing agent include active manganese dioxide, chromic acid pyridine rust salt (PCC), dichromic acid pyridine salt (PDC), Dess-Martin oxidizing agent, diterpenoid-anhydride (for example, acetic anhydride, three Fluorine anhydride), disulfoxide-sulfur gas, diterpene sulphur-sulfur gas, dioxins, grass chlorin, dimethyl sulphate, chlorine, and acid (eg, phosphoric acid, Dioxenium sulfoxide-dicyclohexylcarbodiimide (DCC) or the like in the presence of trifluoroacetic acid or dichloroacetic acid. The oxidizing agent is usually used in an amount of from 1 to 100 moles, preferably from 1 to 50 moles, per mole of the compound (2). 113 321426 201029996 This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and there may be mentioned, for example, ethers such as ethyl bromide, diisopropyl-, diphenyl ether, tetrahydro-n-butyl, 1,4-dioxane, 1,2-dimethoxyethane, tert-butyl decyl ether, etc.; ketones such as acetone, mercaptoethyl ketone, etc.; halogenated hydrocarbons such as dioxane, chloroform, carbon tetrachloride, Trichloroethylene or the like; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as cyclohexane, hexane, etc.; guanamines such as N,N-dimethyldecylamine, N,N-di Methylacetamide, hexamethylphosphoric acid triamide, etc.; nitriles, such as acetonitrile, propionitrile, etc.; inorganic acids such as hydrochloric acid, sulfuric acid, etc.; organic acids such as citric acid, acetic acid, propionic acid, trifluoroacetic acid, Methanesulfonic acid, etc.; water; Two or more of these solvents may be used in combination in an appropriate ratio. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -100 to 150 ° C, preferably -20 to 100 ° C. Step 3 ❹ Compound (3) can be obtained, for example, by treating the compound (4) with a base and reacting the compound with a formazan reagent. Examples of the base to be used in the reaction include: an organolithium compound such as n-butyllithium, a second butyllithium, a third butyllithium or the like; and an alkali amide such as lithium diisopropylamide and hexamethyl (trimethyl) Lithium alkyl) amine lithium and the like. The base is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (4). Examples of the formazanization reagent include hydrazine, hydrazine-dimethyl decylamine, N-methylmercaptopiperidine, ethyl orthoformate and the like. 114 321426 201029996 Often a compound of Moh (4), the amount of the reagent used is usually from 10 to 10 moles, preferably from 1 to 5 moles. The reaction is preferably carried out in a solvent inert to the reaction, and is not particularly limited as long as the reaction can be carried out, and can be carried out, for example, two, four gas, (10), ether, diisopropyl scale. , ethylene glycol dimethyl test, etc.; smoke, for example, two, two:; Two or more of these solvents may be suitably mixed: the time is usually from lfl minutes to 4M, preferably from 5 minutes to the reaction temperature usually - just up to (10). C, preferably, to the compound (4), a commercially available product may be used, or it may be obtained from the commercially available method or the like by the step 4 σ. The compound (6) can be produced, for example, from a compound which is commercially available by, for example, a compound = method (a compound of the compound (5), a commercially available product, or a method known per se or the like). Step 5 Compound (8) can be obtained by reacting compound (7) with 2-chloro-methylethylammoniumamine according to the method for producing a compound (βΙ(1). 乳丞~ι\μ About compound (7) A commercially available product may be used, or may be obtained from a commercially available compound by a method known per se by 321426 115 201029996 or the like. Step 6 Compound (6) may be, for example, a compound ( 8) Prepared by reacting with a base. Examples of the base include: an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium oxychloride, etc.; soil test metal hydroxides such as hydroxide, calcium hydroxide, etc. Alkali metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal strontium carbonate salts, such as carbonic acid argon, argon carbonate clocks, etc.; metal oxide oxides having 1 to 6 carbon atoms, for example Sterol sodium, ethanol® , potassium butoxide, etc.; metal hydrides, such as sodium complexation, strontium clock, calcium hydride, etc.; organic bases, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU , 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (0 person 6 (:0), etc. The base is usually used in an amount of 1 to 10 moles, preferably 1 to 5 moles per 1 mole of the compound (8). The reaction is preferably carried out in a solvent inert to the reaction. These solubilizing agents are not particularly limited as long as the reaction can be carried out, and, for example, alcohols such as decyl alcohol, ethanol, 1-propanol, 2-propanol, tert-butanol and the like can be mentioned; Ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl decyl ether, diisopropyl ether, ethylene glycol dioxime ether, etc.; esters such as formic acid B Ester, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, triethylene glycol, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc. Amidoxime, such as formamide, N, N-dimethyl Amines, N,N-dimercaptoacetamides, etc.; nitriles such as acetonitrile, propionitrile, etc.; sulfoxides such as diterpenoids; cyclobutane; hexamethylene 116 321426 201029996 triamine phosphate; Two or more of these solvents may be used in an appropriate ratio. The reaction temperature is usually -80 ° C to 201 TC, preferably (^ to 15 (rc. The reaction time is usually 10 minutes to 48 minutes). Hour, preferably from 15 minutes to 24 hours. Step 7 Compound (3) can be produced by subjecting compound (6) to a reduction reaction according to the production method of compound (2). ❿ Step 8 Compound (BII) can be borrowed It is obtained by reacting the compound (3) with the organometallic compound (12). Examples of the organometallic compound (12) include: a Grignard reagent (for example, a compound represented by the formula: R3MgBr), an organolithium reagent (for example, a compound represented by the formula: R3Li), and an organozinc reagent (for example, by the formula: R3) a compound represented by 2zn, wherein R3 is as defined above and the like. Q These organometallic compounds can be produced by a method known per se, for example, "Jikken Kagaku Kouza (The Chemical Society of Japan ed.), 4th Edition, vol. 25, Synthesis by Organic Metal Reagent" pp. 9-449, The method described in Maruzen Press 1992 or a similar method. The organometallic compound (12) is usually used in an amount of from 1 to 10 moles, preferably from 1 to 5 moles, per mole of the compound (3). This reaction is carried out in a solvent inert to the reaction. These solvents are not particularly limited 'as long as the reaction can be carried out' and may be mentioned, for example, ether 117 321426 201029996, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.; aliphatic hydrocarbons such as hexane , heptane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; Two or more of these solvents may be used in an appropriate ratio. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -100 to 200 ° C, preferably -80 to 150 ° C. Step 9 Compound (BII) can be produced, for example, by treating compound (4) with a base and reacting the compound with compound (13). Examples of bases include those similar to those described in step 3. The base and the compound (13) are usually used in an amount of usually 1 to 10 moles, preferably 1 to 5 moles per 1 mole of the compound (4). This reaction is preferably carried out in a solvent inert to the reaction. Examples of the solvent include those similar to those described in Step 3. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -100 to 100 ° C, preferably -80 to 50 ° C. As the compound (13), a commercially available product can be used, or it can be produced from a commercially available compound by a method known per se or the like. Step 10 Compound (BII) can be produced, for example, by treating compound (9) with a base, and then reacting the compound with compound (13). 118 321426 201029996 Examples of the base include organolithium compounds such as n-butyllithium, lithium dibutylate, t-butyllithium and the like. The base and the compound (13) are usually used in an amount of usually 1 to 10 moles, preferably 1 to 5 moles per 1 mole of the compound (9). This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and for example, ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, and B can be mentioned. Diol dimethyl ether, etc.; hydrocarbons such as n-hexane, n-pentane, etc.; Two or more of these solvents may be used in combination in an appropriate ratio. The reaction time is usually from 10 minutes to 48 hours, preferably from 15 minutes to 24 hours. The reaction temperature is usually -100 to 100 ° C, preferably -80 to 50 ° C. As the compound (9), a commercially available product can be used, or it can be obtained from a commercially available compound by a method known per se or the like. Step 11 Compound (BV) can be produced according to Step 2 by, for example, subjecting Compound (BII) to an oxidation reaction. Step 12 The compound (BV) can be produced, for example, by reacting the compound (6) with the organometallic compound (12) according to the step 8. Step 13 The compound (BV) can be obtained by reacting the compound (4) with the Friedel-Crafts of the compound (10). 119 321426 201029996 Although this reaction is preferably carried out by adding ^ can be carried out without adding a catalyst, and then entering the lamp 'but /, also using the acid catalyst of this reaction. Such as sulfuric acid, anhydrous phosphoric acid, polyphosphoric acid, etc. only 匕1匕 contains: inorganic acids 'examples such as gasification, tin tetrachloride, tetrachloro-Lewis acid (Lewis acid), diethyl chloride, zinc chloride Etc. - 箸鈥 - gasification of boron, diethyl Ming, gasification, chlorinated diethyl ether, gasification = good land, the use of polyphosphoric acid, emulsified zinc 4 as an acid catalyst. The ruthenium phase may be used in an amount of from 1 to 50 moles, preferably from i to 20 moles, per 1 mole of the compound (4) acid catalyst. In some cases, an acid catalyst can also be used as a solvent. The compound (1 hydrazine) is usually used in an amount of from 1 to 20 mol, preferably from 1 to 1 mol, per 1 mol of the compound (4). This reaction can be carried out under the face of H, or can be carried out after dissolving or suspending in a solvent for the reaction mu. These solvents are not particularly limited, and it is sufficient to carry out the reaction, and mention may be made, for example, of hydrocarbons such as n-hexanol, benzene, toluene, etc.; _, for example, 1,4-dioxin, Tetrahydrocethane, diethyl ether, dimethoxyethane, tert-butyl decyl ether, diisopropyl ether, ethylene glycol dimethyl gas, etc.; hydrocarbons such as dichloromethane chloroform tetrachloride Fossil, diethylene, etc.; mercapto hydrocarbons, such as nitroguanidine, etc., nitriles such as acetonitrile, propionitrile, etc.; guanamines such as formamidine, N,N-dimethylformate , N, N-dimethylacetamide, etc.; sub-stone type 'such as dimethyl (tetra), etc.; cyclobutyl hard; hexamethylweitriamine; disulfide; Two 13⁄4 more views can be mixed and used. 321426 120 201029996 The reaction time is usually from 10 minutes to 48 hours', preferably from 15 minutes to 24 hours. The reaction temperature is usually -100 to 3 Torr. (: 'It is preferably 〇 to 2 〇〇 ° C. Regarding the compound (10), a commercially available product may be used, or may be obtained from a commercially available compound by a method known per se or the like. Step 14 ❹ & compound (10) can be obtained by reacting compound (1) with an organometallic reagent by (iv) (iv) 8. As the compound (11), a commercially available product may be used, or a commercially available compound may be obtained by a method known per se or the like. The starting material compound of the reaction scheme: Compound (BIV) can be obtained by the method shown in the following Reaction Scheme A3. Reaction diagram A3

Wherein, hydrazine is an amine protecting group, and other symbols are as defined above. Step 1 121 321426 201029996 The compound (10) can be produced according to the method for producing the compound (Bla) from the compound (10) (1): by, for example, condensing the compound (b1) with the compound, and using a commercially available product, or A method known per se or a similar method is obtained from a commercially available compound. Step 2

The compound (10) can be obtained by subjecting the compound (10) to a weak reaction under the action of the gold riding hydrogen. The material reduction reaction can be carried out according to a conventional method in the case of a spray which does not interfere with the body. Examples of the metal catalyst include, carbon, black, gas, platinum oxide, platinum black, platinum-palladium, nickel nickel, Raney cobalt, and the like. Examples of hydrogen sources include hydrogen, formic acid, ammonium citrate, hypophosphite, hydrazine, and the like. Examples of the solvent which does not adversely affect the reaction include methanol, tetrahydrofuran, n, n-dimethylacetamide and the like. The metal catalyst is usually used in an amount of from 0.001 to the surface mole per 1 mole of the compound (b2), preferably from 〇1 to (10) mole. The reaction temperature is usually -70 i 1 ζη<νΛ. Main 150 C, preferably -20 to 100 C. The reaction time is usually 〇 1 $ 1 ηη , 々.1 main 100 hours, preferably 〇. 1 to 40 hours. This reaction can also be carried out in the presence of a reduced rhodium ruthenium in a solvent which does not adversely affect the reaction. As the reducing agent, oxygen, iron, zinc, tin, etc. may be mentioned, and the compound (b3) 321426 122 201029996 may be based on "Jikken Kagaku Kouza (The Chemical Society of Japan ed.), 4th Edition, vol. 20 The reaction described in Organic Synthesis II Alcohol and Amine" pp. 279-280, Maruzen Press 1992 or a similar method. 1至20摩尔。 The reducing agent is usually used in an amount of from 0.1 to 20 moles per 1 mole of the compound (b2). Examples of the solvent which does not adversely affect the reaction include: alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol®, etc.; aromatic hydrocarbons such as benzene, Anthraquinone, dioxane, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, diisopropyl, tert-butyl decyl ether, tetrahydrofuran, dioxane, dimethoxy Ethane, etc.; vinegar, such as decyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate, etc.; guanamines, such as N,N-didecylamine, N,N-dimethyl Ethylamine, N_mercaptopurine, etc.; Two or more of these solvents may be used in combination in a suitable winter ratio. The reaction temperature is usually -70 to 15 (TC, preferably -20 to 1 Torr (Γ. The reaction time is usually 〇1 to 1 Torr, preferably 〇. 1 to 4 Torr). 3 The compound (BIV) can be produced by a reductive amination reaction of the compound (b3) with the compound (b4) according to the method for producing the compound (Bla) from the compound (BV). ' Regarding the compound (b4), it can be used. Commercially available products, or commercially available compounds by methods known per se or the like: 321426 123 201029996. Step 4 Compound (b7) can be synthesized according to the synthesis method described in WO2004/45616 or A similar method is prepared by reacting the compound (b5) with the Friedel-Crafts of glutaric anhydride (b6). Regarding the compound (b5), a commercially available product may be used, or it may be A known method or the like is prepared from a commercially available compound. Step 5 Compound (b8) can be obtained by removing a protecting group of compound (b7) by a method known per se, for example, Organic Synthesis, Third Edition. , the method described in Wiley-Interscience (1999) or A similar method. Step 6 Compound (b3) (RA7, RA8, RA9 and a hydrogen atom) can be obtained by esterifying compound (b8) by a method known to the present invention, for example, 'Protective Groups in Organic Synthesis, Third Edition, The method described in Wiley-Interscience (1999) or the like. Step 7 The compound (blO) can be produced according to the method for producing the compound (Bla) from the compound (BVIII) by, for example, the compound (b9) and the compound (BIX). For the compound (b9), a commercially available product can be used, or it can be obtained from a commercially available compound by a method known per se or the like. 124 321426 201029996. Step 8 Compound (b3) It can be obtained by removing the protecting group of the compound (blO) according to the method of the step ^, and the branching method. The compound (the following formula (10)-1) in the compound (10) [compound ( BIa-Ι)] can be prepared according to the following reaction chart A4. Reaction chart A4

Wherein R is a Ch alkyl group, an α14 aryl group, a 4 to 12 membered aromatic heterocyclic group (a group gj bonded via a carbon atom on the ring), and 4 i 12 a non-aromatic heterocyclic group (via a ring) A carbon atom-bonded group), or a cyano group, and other symbols are as defined above. Step 1 The compound (BI a-1) can be obtained by reacting a compound (BIa-2) with an organometallic reagent or a metal cyanide in the presence of a metal catalyst. Examples of the metal catalyst include: a palladium catalyst (for example, palladium (II) acetate, bis(dibenzylideneacetone) dipalladium (ruthenium), bis(dibenzylideneacetone)palladium (0), ruthenium (triphenylphosphine) Palladium (〇), [1, 丨,-bis(diphenylphosphino)ferrocene] dichloropalladium (II) dichloromethane adduct, bis(para-tert-butylphosphine) palladium (〇) )); nickel catalyst (for example, ruthenium (triphenylphosphine) nickel (ruthenium), dichloro [oxime, 2 bis (diphenylphosphino) ethane] nickel (II), dichloro [1, 3 - bis(diphenylphosphino)propane] nickel (II), dichloro[1,4-bis(diphenylphosphino)butane]nickel(II), etc.). The singularity of the singularity of the singularity of the singularity of the singularity of the singularity of the singularity of the singularity. Examples of the organometallic reagent include boric acid, boric acid ester, Grignard reagent, organotin reagent, organozinc reagent, and the like. Examples of the metal cyanide include zinc cyanide and the like. The organometallic reagent or metal cyanide is usually used in an amount of from 1 to 100 moles, preferably from 1 to 10 moles, per mole of the compound (BIa-2). This reaction can be carried out as needed in the presence of a base. Examples of such tests include metal oxides such as oxidized clocks, cerium oxide, potassium hydroxide, etc.; soil-measured metal hydroxides such as magnesium oxyhydroxide, calcium hydroxide, etc.; alkali metal carbonates, For example, sodium carbonate, potassium carbonate, carbonic acid planing, etc.; alkali metal hydrogencarbonate, such as sodium cesium carbonate, potassium hydrogencarbonate, etc.; metal oxide oxide having 1 to 6 carbon atoms, such as sodium methoxide, sodium ethoxide, third Potassium butoxide, etc.; The base is usually used in an amount of from 1 to 100 moles, preferably from 1 to 10 moles, per mole of the compound (BIa-2). This reaction can be carried out as needed in the presence of a ligand. Examples of such a ligand include: a phosphorus ligand (for example, triphenylphosphine, 1,3-bis(diphenylphosphino)propane, 1,3-bis(diphenylphosphino)propane, 2 , 2'-bis(diphenylphosphino)-1, fluorene-binaphthyl and 4,5-bis(diphenylphosphino)-9,9-diindenylxanthene, etc.). 01至一个摩尔。 The amount of the ligand is usually from 0.01 to 2 moles, preferably from 0. 02 to 1 mole. 126 321426 201029996 This reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out, and, for example, alcohols such as decyl alcohol, ethanol, propanol, isopropanol, butanol, butanol, etc.; ethers, For example, 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dioxime ether, etc.; esters such as ethyl formate, ethyl acetate , n-butyl acetate, etc.; _ hydrocarbons, such as dichlorosilane, chloroform, carbon tetrachloride, trichloroethylene, etc.; hydrocarbons, such as n-hexane, benzene, toluene, etc.; guanamines, such as ruthenium Amine, hydrazine, hydrazine-dimethyl decylamine, N,N-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; sulfoxides such as dimethyl hydrazine; sulfolane; Triammonium phosphate; water, etc. Two or more of these solvents may be used in combination in an appropriate ratio. The reaction temperature is usually -100 to 180 ° C, preferably -80 ° C to 150 ° C. The reaction time is usually from 0.1 to 48 hours, preferably from 0.1 to 24 hours. The compound (BIa-2) can be produced, for example, according to the method for producing the compound (Bla) in Reaction Scheme A1. In the compound (BV) described in Reaction Scheme A2, the compound [Compound (BV-1)] represented by the following formula (BV-1) can be produced according to the following Reaction Scheme A5. Reaction diagram A5

127 321426 201029996 wherein each symbol is as defined above. Step 1 Compound (BV-1) can be produced, for example, by reacting compound (7-1) with compound (7-2) in the presence of a base. Examples of the base include: an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide or the like; an alkaline earth metal hydroxide such as magnesium hydroxide, calcium hydroxide or the like; an alkali metal carbonate such as sodium carbonate, Potassium carbonate, carbonic acid, etc.; test metal hydrogencarbonate, such as sodium bicarbonate, cesium carbonate, etc.; with a metal oxide oxide with 1 to 6 carbon atoms, such as methanol, ethanol, and third butanol Potassium and the like; metal hydrides such as sodium hydride, hydrogenation and calcium hydride; organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- Diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (0 person 6 (:0), etc.; 1 molar compound (7-1), the base is usually used in an amount of 1 to 50 moles, preferably 1 to 20 moles. 0 relative to 1 mole of compound (7-1), compound (7) The amount of use of -2) is usually from 1 to 10 moles, preferably from 1 to 5 moles. The reaction is preferably carried out in a solvent inert to the reaction. These solvents are not particularly limited as long as the reaction can be carried out. Just do it, Mention may be made, for example, of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc.; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxy group Ethylene, tert-butyl decyl ether, diisopropyl ether, ethylene glycol diterpene ether, etc.; esters such as ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons , for example, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, etc.; 128 321426 201029996 dazzling class 'such as hexaplocarb, benzene, toluene, etc.; brewing amines, such as amide, N, N-didecyl Amidoxime, N,N-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; sulfoxides such as dimethyl sulfoxide; cyclobutane; hexamethylene sulphate. Two or more of these solvents may be used in an appropriate ratio. The reaction temperature is usually from -8 ° C to 20 (TC, preferably 〇. (: to 15 (rc. The reaction time is usually 10 minutes). To 48 hours, preferably 15 minutes to 24 hours. Compound (7-1) can be produced by a method known per se or the like. The β compound (7-2) can be used by itself. The known methods or similar methods. Of square (1), a compound represented by the following formula of [compound (1-1)] can be prepared according to the following reaction Μ FIG. Scheme Α6 ❹

(1-3) COjRA12 •ch3 Step 1

R^-OH (1-2a) Step 2l (1-2) (iv) c. (1-1) where 'RAA2 is a trace, and other symbols are as above. Step 1 ° Compound (1-2) can be produced, for example, by brominating compound (1-3). Examples of the desertification agent include chloramines, for example, (iv) succinimide, 1,3-dibromo-5,5-dimethylhydantoin, and the like. The amount of the desertifier used is usually from 1 to 100 moles, preferably from 1 to 10 moles, per 1 mole of the compound (Bu 3). This reaction can be carried out in the presence of a free radical initiator as desired. Examples of such radical initiators include azobisisobutylphosphonium, hydrazine peroxide and the like.月 月 月 笨 笨 曰 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基 自由基This reaction is preferably carried out in a solvent inert to the reaction.

The agent is not particularly limited as long as the reaction can be carried out, and the vinegar can be dissolved, such as ethyl formate, ethyl acetate, n-butyl acetate, and the like: for example, methylene chloride, chloroform, tetrachloride Carbon, trichloroethylene, etc., halogen halides such as acetonitrile, propionitrile, etc.; Two or more nitriles can be mixed in proportion to make hydrazine. 4小时得。 The temperature of the reaction time is usually from -100 to 18 (rc, preferably 〜80 。. The reaction time is usually 〇. 1 hour to 48 hours, more than I50 C. to 24 hours. 0. 1 hour The compound (1-3) can be produced by a method known per se or the like, or the alkali metal alkoxide compound (1 to 1) can be produced, for example, by reacting a compound (1). The compound (1-1) can also be obtained, for example, by reacting with a person (W and a reaction surface (1_2a) (IV). Examples of the alkali metal alkoxide include sodium decoxide, potassium decoxide, sodium ethoxide, ethanol, etc. 321426 130 201029996 The amount of metal oxide oxide used is usually from 1 to 50 moles, preferably from 1 to 10 moles per 1 mole of compound (1-2). Examples of bases include: metal detection Carbon-acid salts such as sodium carbonate, potassium carbonate, carbonic acid planing, etc.; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; metal hydrides such as sodium hydride, potassium hydride and calcium telluride; The base is usually used in an amount of from 1 to 50 moles, preferably from 1 to 10 moles per 1 mole of the compound (1-2). The amount of the compound (l-2a) to be used is usually from 1 to 50 mol, preferably from 1 to 10 mol, per 1 mol of the compound (1-2). The reaction is preferably carried out in response to the reaction. It is carried out in an inert solvent. These solvents are not particularly limited as long as the reaction can be carried out, and, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and third butanol can be mentioned. And the like; ethers, such as 1,4-dioxane, tetrahydroanion, hexagram, dimethoxyethane, tert-butyl decyl ether, diisopropyl ether, ethylene glycol dioxime ether, etc.; Esters, such as ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons, such as dichlorohydrazine, chloroform, tetrachloride, trichloroethylene, etc.; hydrocarbons, For example, n-hexane, benzene, toluene, etc.; guanamines such as decylamine, N,N-didecylguanamine, N,N-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc. Sulfoxides, such as disulfoxide, etc.; sulfolane; hexamethylenephosphoric acid triamine; etc. Two or more of these solvents may be used in admixture in an appropriate ratio. A metal-breaking compound (for example, mothium hydride, potassium hydride, etc.) is added as a reaction accelerator; the amount of the alkali metal iodide is usually 1 to 50 moles per 1 mole of the compound (1-2). The temperature is usually from -80 ° C to 200 ° C, preferably from 0 ° C to 150 ° C. The reaction time is usually from 0.1 to 48 hours. It is preferably from 0.1 to 24 hours. The compound (1 -2a) can be produced by a method known per se or the like. In the compound (Bla) of the reaction diagram A1, the following formula (BIa-3) is represented. a compound [compound (BIa-3)] and a compound represented by the formula (BIa-4) [Chemical Formula (BIa-4)], and a compound (Bib) of the reaction diagram A1, the following formula (BIb- The compound [BIb-Ι] represented by Ι) can be obtained, for example, by the method shown in the following Reaction Scheme A7. Reaction diagram A7

132 321426 201029996 wherein C.sub.1-6 alkyl substituted by (1) the following substituents is optionally 1 to 3 selected from (a) a halogen atom, (b) a mercapto group, (c) an anthracene-6 alkoxy group. , C3-6 cycloalkyl, group, (e) only need to be 1 to 3 "aryl substituted Cl_6 oxygenated carbon

1)) if necessary, an amine group selected from the group consisting of a Cl_6 alkyl group and a Cl-6 alkoxy group, which is an early or a di-substituted group, and the (S) is required to be i to 3 selected from the following Substituent substituted 4 to Z shell aromatic heterocyclic group (i) halogen atom, and (ii) Ch alkyl group, (h) 4 to 12 member non-substituted by 1 to 3 Ci-e alkyl groups as needed Ruthenium heterocyclic group, (i) indol-6 alkylsulfonyl, (j) Ci-e alkylthio, and (k) hydroxyl; (2) Cm aralkyl; (3) C6- "Aryl; (4) Ci-6 alkyl-based; (5) 4 to 12 members of the aromatic fluorenyl group 321426 133 201029996 (i) depending on the substitution of one or three substituents selected from the group consisting of a 〇6 alkyl group substituted with 1 to 3 halogen atoms, and (ii) a cyano group; (6) 4 to 12 members of a non-aromatic heterocyclic group-oxy group, LAel being a leaving group or a hydroxyl group, and other symbols It is as defined above. Examples of "departing groups" of LAei include fluorine atom, gas atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group. Base, trifluoromethanesulfonyloxy and the like. Step 1 In this step, for example, the compound (7-1-1) can be produced by reacting the compound (18) with the compound (19). When LAei is a leaving group, the reaction is carried out in the presence of a base in a solvent which does not adversely affect the reaction. Examples of the base include: amines such as triethylamine, N-diisopropylethylφamine, N-methylmorpholine, anthracene, fluorenyl-dimethylaniline, 4-didecylaminopyridine, and the like; Determination of metal salts, such as sodium bicarbonate, sodium carbonate, potassium carbonate, three hours of acid filling, etc.; metal oxides, such as sodium hydroxide, potassium hydroxide, hydroxide, etc.; soil test metal hydroxides, such as hydrogen Oxidizing town, oxidizing mother, hydroxide I shell, etc.; metal hydride, such as hydrogenation, sodium, etc.; metal Cl-6 burning oxide, such as sodium decoxide, sodium ethoxide, potassium butoxide, etc.; Wait. The base is usually used in an amount of from 1 to 1,000 moles, preferably from 1 to 5 moles, per mole of the compound (18). The compound (19) is used in an amount of from 1 to 1000 mol, preferably from 1 to 10 mol, per 1 mol of the compound (18). Examples of the solvent which does not adversely affect the reaction include: ethers such as sigma, tetrachlorine π, dioxin, etc.; halogenated tobaccos such as chloroform, di-methane, etc.; aromatic hydrocarbons, for example Benzene, toluene, diphenylbenzene, etc.; guanamines such as N,N-dimethylformamide, N,N-dimercaptoacetamide, etc.; sulfoxides such as dimethyl sulfoxide; ketones , for example, acetone, etc.; acetonitrile; water. These solvents can be used in combination in an appropriate ratio. The reaction temperature is usually -80 ° C to 150 ° C, preferably -10 ° C to 100 ❹〇Γ C. 5至二十小时。 The reaction time is usually 0.5 to 20 hours. When LAei is a hydroxyl group, the reaction is carried out by a method known per se, for example, the method described in Synthesis, page 1 (1981) or the like. That is, the reaction is usually carried out in the presence of a mechanical compound and an electrophilic agent in a solvent which does not adversely affect the reaction. Examples of the organophosphorus compound include triphenylphosphine, tributylphosphine, and the like. Examples of the Q electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1, fluorenyl-azodicarbonyldipiperidine, and the like. The organophosphorus compound and the electrophile are usually used in an amount of usually 1 to 1000 moles, preferably 1 to 5 moles per 1 mole of the compound (18). The compound (19) is usually used in an amount of from 1 to 1,000 moles, preferably from 1 to 5 moles, per mole of the compound (18). For solvents which do not adversely affect the reaction, reference may be made to those similar to those previously described. 135 321426 201029996 The reaction temperature is usually -80 to 150 ° C, preferably -10 to 100 ° C. The compound (18) and the compound (19) can be produced according to a method known per se, respectively. Step 2 In this step, for example, the compound (7-1-1) is reacted with the compound (7-2) in the presence of the test to obtain the compound (V-2). This reaction was carried out in the same manner as in the first step of Reaction Scheme A5. The compound (7-2) can be produced according to a method known per se. 〇 Step 3 In this step, for example, the compound (V-2) RAe] is removed to obtain a compound (BV-2). When RAei is a benzyl group, the reaction can be, for example, a metal catalyst (for example, palladium-carbon, palladium black, palladium-carbethylenediamine complex, palladium chloride, platinum oxide, platinum black, platinum-palladium, rees Nickel, Raney cobalt, etc., in the presence of a hydrogen source, are carried out in a solvent which does not adversely affect the reaction. 01至100摩尔。 The amount of the catalyst is usually from 0.001 to 1000 moles, preferably from 0.01 to 100 moles. Examples of hydrogen sources include hydrogen, citric acid, ammonium citrate, phosphinate, hydrazine, and the like. Examples of the solvent which does not adversely affect the reaction include: alcohols such as decyl alcohol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol, tert-butanol, and the like; Aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane 1,2-two 136 321426 201029996 methoxyethane, etc.; halogenated hydrocarbons, such as di-methane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.; Amidoxime, for example, N,N-dimethylformamide, N,N-dimercaptoacetamide, N-methylpyrrolidone, etc.; ethyl acetate, acetic acid, and the like. These solvents can be used in combination in an appropriate ratio. The reaction temperature is usually from 0 to 120 ° C, preferably from 10 to 80 ° C. 5至100小时。 The reaction time is usually from 0.5 to 100 hours. Step 4 In this step, for example, the compound (V-2) can be produced by reacting the compound 〇 (BV-2) with the compound (19). This step is carried out in the same manner as in the first step of this reaction. Step 5 In this step, for example, the compound (BII-1) can be produced by subjecting the compound (V-2) to a reduction reaction. This reaction was carried out in the same manner as in Step 1 of Reaction Scheme 1. Step 6 q In this step, for example, the compound (BI11-1) can be produced by converting the radical of the compound (BII-1) to a leaving group (L). This reaction was carried out in the same manner as in the first step of Reaction Scheme A1. Step 7 In this step, for example, the compound (BIa-3) can be produced by reacting the compound (BIII-1) with the compound (BIV) under the test. This reaction was carried out in the same manner as in Step 2 of Reaction Scheme A1. Step 8 In this step, for example, the compound (BV11-1) can be obtained by reacting the compound (B111-1) with the compound (BVI) in the presence of 137 321426 201029996. This reaction was carried out in the same manner as in the step 4 of Reaction Scheme A1. Step 9 In this step, for example, the compound (BVII1-1) can be produced by hydrolyzing an ester of the compound (BVI1-1). This reaction was carried out in the same manner as in the step 6 of Reaction Scheme A1. Step 10 In this step, for example, the compound (BIa-3) can be obtained by condensing the compound (BVIII-1) with the compound (BIX-1). This reaction was carried out in the same manner as in the step 7 of Reaction Scheme A1. As the compound (BIX-1), a commercially available product can be used, or it can be produced from a commercially available compound by a method known per se or the like. Step 11 In this step, for example, the compound (BIa-4) can be produced by removing the compound (BIa-3) i RAG1. This step is carried out in the same manner as in the third step of the reaction. Step 12 In this step, for example, the compound (BIa-3) can be produced by reacting the compound (BIa-4) with the compound (19). This step is carried out in the same manner as in step 1 of this reaction. Step 13 In this step, for example, the compound (BIb-1) can be obtained by hydrolyzing the ester of the compound (BIa-3) according to the method for producing the compound (BVIII) 138 321426 201029996. The starting material compound of Reaction Scheme A2: Compound (4-1) can be obtained, for example, by the method shown in the following Reaction Scheme A8. Reaction diagram A8

Ο (7-1-2) M*, 〇 7Β γ (1S) Step 1

ο (14) Ο o-vAc step

ο (16) 〇Sc Step R^l

(4-1) wherein, each of RK2 and RAG3 is a substituent which the aforementioned ring AC optionally has, and the other symbols are as defined above. Step 1 In this step, for example, the compound (14) can be produced by reacting the compound (7-1-2) with the compound (15) under basic conditions. This reaction was carried out in the same manner as in the first step of Reaction Scheme A5. Step 2 In this step, for example, the compound (16) can be produced by hydrolyzing the ester of the compound (14) according to the method for producing the compound (BVIII) in the reaction chart A1. Step 3 In this step, for example, the compound (4-1) can be produced by reacting the compound (16) in acetic anhydride. In this step, sodium acetate can be used as an additive. The sodium acetate is usually used in an amount of from 1 to 1,000 moles, preferably from 1 to 10 moles, per mole of the compound (16). The reaction temperature is usually -80 to 200 ° C, preferably -10 to 150 ° C. 5至二十小时。 139 321426 201029996 reaction time is usually 0. 5 to 20 hours. The compound (7-1-2) and the compound (15) can be produced according to a method known per se. In the compound (BIa-3) of Reaction Scheme A7, the compound [Compound (BIa-5)] represented by the following formula (BIa-5) can be produced, for example, by the method shown in the following Reaction Scheme A9. Reaction diagram A9 <17)

Wherein each symbol is as defined above. Step 1 In this step, for example, the compound (BIa-5) can be produced by reacting the compound φ (BIa-4) with the compound (17). This reaction is carried out in the presence of a base in a solvent which does not adversely affect the reaction. Examples of the base include: amines such as triethylamine, N,N-diisopropylethylamine, N-mercaptomorpholine, N,N-didecylphenylamine, 4-didecylaminopyridine, and the like An alkali metal salt such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate or the like; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like; an alkaline earth metal hydroxide such as magnesium hydroxide or hydroxide Calcium, barium hydroxide, etc.; metal hydrides, such as potassium hydride, sodium hydride, etc.; metal chloride -6 oxidized 140 321426 201029996, such as sodium methoxide, sodium ethoxide, potassium butoxide, etc.; The base is usually used in an amount of from 1 to 50 moles, preferably from 1 to 5 moles, per mole of the compound (BIa-4). The compound (17) is usually used in an amount of from 1 to 50 mol, preferably from 1 to 5 mol, per 1 mol of the compound (BIa-4). In this reaction, sodium iodide or potassium iodide may be further added to the solvent, and the amount of sodium iodide or potassium iodide is usually from 1 to 100 moles, preferably from 1 to 100 moles per 1 mole of the compound (Bla-4). It is 1 to 10 moles. Examples of the solvent which does not adversely affect the reaction include: ethers such as diethyl ether, tetrahydrofuran, diterpene, etc.; halogenated hydrocarbons such as chloroform, dichlorodecane, etc.; aromatic hydrocarbons such as benzene, Toluene, diphenylbenzene, etc.; guanamines such as N,N-dimethyldecylamine; sulfoxides such as disulfoxide; ketones such as acetone; acetonitrile; These solvents can be used in combination in an appropriate ratio. The reaction temperature is usually from 0 to 150 ° C, preferably from 0 to 100 ° C. 5至100小时。 The reaction time is usually from 0.5 to 100 hours. The compound (BIa-4) can be obtained according to Reaction Scheme A7. The compound (17) can be produced according to a method known per se. The compound (I) and the compound (IA) thus obtained can be isolated by a known separation and purification method (for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.) purification. Further, when the compound (I) and the compound (IA) are obtained as a free compound, they can be converted into a target salt of 141 321426 201029996 by a method known per se or the like. When the compound (I) and the compound (oxime) are obtained in the form of a salt, they can be converted into a free compound form or other target salt according to a method known per se or the like. When the compound (I) or the compound (oxime) contains an optical isomer, a stereoisomer, a positional isomer or a rotamer, these isomers are also encompassed by the compound (I) and the compound (ΙΑ). Within the scope, and can be obtained as a single product according to a synthesis method known per se and a separation method. For example, when the compound (I) and the compound (ΙΑ) have optical isomers, the optical isomers from which the compound is isolated are also encompassed within the range of the compound (I) and the compound (ΙΑ). Optical isomers can be produced according to methods known per se. Specifically, an optically active synthetic intermediate is used, or the final racemic product is optically analyzed according to a conventional method to obtain an optical isomer. The method of optical analysis may be a method known per se, such as separation recrystallization, palm column method, non-image isomer method, and the like. 1) Separation recrystallization method Q In this method, an optically active compound is formed (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+) Racemate salt of 1-phenylethylamine, (-)-Phenylethylamine, cinchonine, (-)-cinchonidine, brucine It is separated by separation and recrystallization, and a neutralization step is carried out as needed to obtain a free optical isomer. 2) Palm column method In this method, a racemate or a salt thereof is applied to a column (a palm column) for separating an optical isomer for separation. In the case of liquid chromatography, 142 321426 201029996 For example, a mixture of optical isomers is applied to a palm branch, such as ENANTI0-0VM (manufactured by Tosoh Corporation), CHIRAL series (by Daicel Chemical Industries, Ltd., etc., and bite separately with a water-based buffer (for example, a phosphate buffer, etc.) and an organic solvent (for example, decyl alcohol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) The mixture was developed as a mixture to separate the optical isomer. In the second gas chromatography, for example, the separation is carried out using a palm column such as CP-Chirasil-DeX CB (manufactured by 阢 Sciences Inc.). 3) Non-image isomer method In this method, a non-image mixture is prepared by chemically reacting a racemic mixture with an optically active agent, which is separated by a typical separation method (for example, separation) A crystallization method, a chromatography method, or the like is prepared as a single substance, followed by chemical treatment such as hydrolysis to separate the optically active agent portion to obtain an optical isomer. For example, when the compound (I) or the compound (IA) contains a hydroxyl group or a primary or secondary amine group in the molecule, the compound is reacted with an optically active organic acid (for example, ΜΤΡΑ[α-曱oxy_α) The condensation reaction is carried out by _(difluoromethyl)phenylacetic acid], methoxyacetic acid, or the like to obtain a non-image isomer of the ester compound or the guanamine compound, respectively. When the compound (I) has a rebel group, the compound is subjected to a condensation reaction with an optically active amine or an optically active alcohol to obtain a non-mirrible isomer of the guanamine compound or the ester compound, respectively. The isolated non-image isomer is converted to the optical isomer of the original compound by acid hydrolysis or base hydrolysis. EXAMPLES The present invention is illustrated in more detail by reference to the following Examples, Experimental Examples, and the accompanying Examples, which are not to be construed as limiting the invention. The j-NMR spectrum uses tetramethyl decane as the internal standard and Varian

Gemini 200 (200 MHz), 300 (300 MHz), Bruker 300 (300 MHz) spectrometers are measured' and all values are expressed in 卯m. Unless otherwise indicated, the value indicated by the mixed solvent is the volume mixing ratio of the individual solvents. Unless otherwise indicated, '% means % by weight. Further, the proportion of the solvent to be used in the Shixi hose column chromatography means the volume mixing ratio unless otherwise specified. In the present specification, the room temperature (ambient temperature) is from about 2 〇〇c to about 3 Torr. Each symbol in the embodiment has the following meanings. MSO: Dimethyl sulphate, CDCU: chloroform, S · early rh, d: doublet,

Four peaks

q dd : doublet, dt. double three bees,

Quint * Four, Π1 · Multimodal, brs I broad peak, J: coupling constant. In the examples, LC/MS analysis was carried out under the following conditions. Measuring device: Waters LC/MS system 144 321426 201029996

HPLC : Agilent HP1100 MS : Micromass ZMD Column: CAPCELL PAK C18UG120 S-3 micron (r/, 坩), 1 c m (mm) (manufactured by Shiseido Co., Ltd.) · bx35 millisolvent: solution A : 0 05 aqueous solution of trifluoroacetic acid, solution b fluoroacetic acid acetonitrile solution · 0. 04% three gradient cycle: 0 minutes (solution A / solution B = 90 / l 〇), 2% A / solution B = 5 / 95), 2.75 Minute (solution A / solution β ^ clock (solution minutes (solution Α / solution Β = 90/10), 3.60 minutes (dissolved, night 9, 2. 76 1 〇), Α / solution Β = 90 / injection volume : 2 μL, flow rate: 0.5 ml / min (mL / min), detection method: UV 220 nm (nm),

MS Conditional Freedom Method: ESI Column Conditions In the examples, the purification method using preparative HPLC was carried out. Instrument · Gilson Inc., High throughput purification system Column: YMC CombiPrep ODS-A S-5 micron, 50 x 20 mm; or CombiPrep Hydrosphere C18 S-5 micron, 50 x 20 mm Solvent: Solution A: 0.1% trifluoroacetic acid Aqueous solution, solution B: 0. 1% trifluoroacetic acid acetonitrile solution gradient cycle: 0 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. 40 145 321426 201029996 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), or 0 minutes (solution A / solution B = 98 / 2), 1.00 minutes (solution A / solution B = 98 / 2), 5.00 minutes (solution A / solution B = 0/100), 6.40 minutes (solution A / solution B = 0 / 100), 6.50 minutes (solution A / solution B = 98 / 2), 6. 60 minutes (solution A / solution B = 98 / 2) Flow rate: 20 ml / min,

Detection method: UV 220 nm Example 1 3-[({4-[(cyclohexyl){3-mercapto-1-[5-(trifluoromethyl)acridin-2-yl]-1H-oxime Zin-4-yl}indenyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3-[(4-Nitrophenylhydrazinyl)amino]propionic acid ethyl ester 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride ( 23.0 g) added to 4-nitrobenzoic acid (16.7 g), ethyl propylamine hydrochloride (18.4 g), 1-hydroxybenzotriazole monohydrate (18.4 g), A mixture of triethylamine (16.7 mL) and N,N-didecylguanamine (200 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc. Recrystallization from ethyl acetate-hexane gave the title compound (26.6 g, 100%). 146 321426 201029996 Ή NMR (300 MHz, CDCh) 5 ppra 1.29 (t, J=7. 2 Hz, 3H), 2.68 (t, j=6. 1 Hz, 2H), 3.76 (q, J=6.11) Hz, 2H), 4.19 (q5 J=7. 1 Hz, 2H), 7.03 (br. s. , 1H), 7.93 (d, J=9.11)

Hz, 2H), 8.29 (d, J=8. 7 Hz, 2H). (2) 3-{[(4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester [(4-Nitrophenylhydrazinyl)amino]propionic acid ethyl ester (26. 6 g), 5% palladium-carbon (8.9 g), tetrahydrofuran (15 〇mL) and ethanol hydrazine (150 mL) The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The 5% palladium-carbon was filtered off and the filtrate was concentrated under reduced pressure to give a white solid. The title compound (22. 6 g, 95%) was obtained from white crystals. !H NMR (300 MHz, CDCh) ^ ppm 1.27 (t, J=7.2 Hz, 3H), 2.63 (t, J=6.0 Hz, 2H), 3.70 (q, j=6. 〇Hz, 2H) , 3.94 (br. s., 2H), 4. 17 (q, J=7. 2 Hz, 2H), 6.66 (d, J=8. 7

Hz, 2H), 7. 60 (d, J=8. 7 Hz, 2H). q (3) Methyl 3-methyl-1H-pyrazole-4-carboxylate Ethyl acetate (30.0 g) A mixture with dimethyl decyl decanoic acid (3 4 · 7 niL) was disturbed at 10 0 C for 12 hours, and the mixture was allowed to cool. Ethanol (500 raL) and hydrazine monohydrate (12 6 mL) were added to the reaction mixture at room temperature, and the mixture was heated to reflux for 12 hours. The mixture was allowed to cool' and was reduced under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the title compound (22.3 g, 61%). ]H NMR (300 MHz, CDCls) (5 ppm 2.56 (s, 3H), 3.84 (s, 321426 147 201029996 3H), 7.96 (s, 1H). (4) 3-mercapto-1-phenyl-IH -0 is 0 to 0 - -4- oxic acid is applied to 0 C, and sodium hydride (1·9 g, 60% in oil) is added to the above-mentioned 3-methyl-1Η-η ratio 〇 sitting- 4- lyophilic vinegar (5.3 g) in a solution of dimethylformamide (70 mL) and stir the mixture for 1 min. Add 2-chloro-5-trifluorodecylpyridine (7.5 g) And the mixture was stirred overnight at room temperature. An aqueous solution of chlorinated solution was added to the reaction mixture, and the mixture was extracted with acetonitrile. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The title compound (3.3 g, 31%) was obtained as a pale yellow solid (yield: EtOAc: EtOAc: EtOAc: MHz, CDCh) δ ppm 2.57 (s, 3H), 3.87 (s, 3H), 7.97-8.17 (m, 2H), 8.63-8.74 (m, 1H), 9.00 (s, 1H). (5) 3- Mercaptotrifluoromethyl)pyridine_2_ylbu-1H_pyrazole-4-furfural _ The above-prepared 3-mercapto-1-phenyl-1H-pyrazole-4-carboxylic acid oxime ester ( 3 .3 g) Dissolved in tetrahydrofuran (10 mL), and the solution was added dropwise to a solution of nitrous acid (0.45 g) in tetrahydrofuran (2 mL) at 0 °C. The reaction mixture was stirred at 0 ° C for 30 min and water (0.45 mL) was carefully added dropwise. Next, a 1N aqueous solution of sodium hydroxide (2.3 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and residue was washed with THF (30 mL). The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (50 mL), and then the mixture was evaporated. After the mixture was cooled, 148 321426, 2010, s, s,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 1〇MR (3〇〇MH^ CDCl3)^.57 (3, 3H), 7.97-8 17 (m 2H), 8.63-8.74 (m,1H), 9. 〇〇(s,lH),9 95 (s, (8) (6) cyclohexyl {3-methyl-l-[5-(trifluoromethyl)pyridine m is more than β-s--4-yl}methanol, at 0C '1 Μ > odorized ring has been tetrahydrogen The argon solution (15) was added dropwise to the above-mentioned 3-mercapto-1-[5-(tri-i-methyl)0-bito- 2_yl]_1}1_pyrazole-4-carbaldehyde (2.6) g) in tetrahydrofuran (4 mL) solution. After stirring for 1 hour in 〇〇c, an aqueous solution of ammonium sulfate was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was applied The title compound (2.0 g, 36%) was obtained as a colorless solid. NMR (300 MHz, CDCls) δ ppm 0. -1. 93 (m, 11H), 2 36 (s, 3H), 3.62 (br. s., 1H), 4.44 (dd, J=7.2, 3.4 Hz, 0 W), 7· 91-8 . 07 (m, 2H), 8.43 (s, 1H), 8· 63 (s, 1H). (7) 3-[({4-[(cyclohexyl){3-indolyl-l-[5-( Trifluoromethyl) hydrazine bite 2_yl]-1H-pyrazol-4-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid at room temperature, stearous (0. 24 mL) was added to the above-prepared cyclohexyl {3-mercapto-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl} sterol ( 0. 75 g) of tetrahydrofuran solution (10 mL), and the mixture was stirred for 30 minutes. The reaction mixture was poured into aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the residue was dissolved in dimethylacetamide (15 mL) 321426 149 201029996, and sodium iodide (0.63 g), sodium carbonate (45 g) and 3-{[(4-Aminophenyl)carbonyl]amino}propionic acid ethyl acetate (0.75 g) synthesized in Example 1 (2). The mixture was stirred overnight at 80 ° C and allowed to cool. Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane =1:1). Purification, the title compound (876 mg) was obtained as ethyl ester. The title compound of the title compound was dissolved in ethanol (4 mL), and 1N hydrogen was added at room temperature. Aqueous solution of sodium (4 mL), and the mixture was stirred for 1 hour. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (4 mL) was added to residue. The title compound (0.78 g, 70%) was obtained as a white solid. JH NMR (300 MHz, CDCla) <5 ppm 0. 81-2. 23 (m, 11H), 2.34 (s, 3H), 2.50-2.68 (m, 2H), 3.43-3.74 (m, 2H), 4.20 (d, J=6.4 Hz, 1H), 6.47 (d, J=8.5 Hz, 2H), 6.68 (br. s., 1H), 7.51 (d, J=8. 5 Hz, 2H), 7.86- 8.05 (m, 2H), ❹ 8. 31 (s, 1H), 8.57 (s, 1H). Example 2 3-[({4-[(cyclohexyl){3-methyltrifluoromethyl)0 ratio啶_2_yl] -1H-° than salin-4-ylindenyl)amino]phenyl}carbonyl)(fluorenyl)amino]propionic acid

(1) 3-[Methyl(4-nitrobenzylidenyl)amino]propionic acid ethyl ester 150 321426 201029996 In the same manner as in Example 1 (1), 3-(indolyl)propionic acid B was used. The title compound (28 〇g, 1 〇〇H NMR (300 MHz, CDCh) d ppm l. 26 (t, J=7.1 Hz, 3H) , 2.51-2.78 (m, 2H), 2.99-3.10 (m, 3H), 3.46-3.86 (ra, 2H), 4.03-4.28 (m, 2H), 7.50-7.65 (m, 2H), 8.28 (d, J=8. 7 Hz, 2H). ❹(2) 3-{[(4-Aminophenyl)carbonyl](methyl)amino}ethyl propionate In the same manner as in Example 1 (2), The title compound (26·6 g, 90%) was obtained as an oil..H NMR (300 MHz, CDCh) δ ppm 1.26 (t, J=7.2 Hz, 3H), 2.64 (t, J= 6.4 Hz, 2H), 3.05 (s, 3H), 3.74 (t, J=7. 0 Hz, 2H), 3.85 (br. s., 2H), 4.14 (q, J=7.2 Hz, 2H), 6.59 -6.72 (in, 2H), 7.23-7.28 (m, 2H). (3) 3-[({4-[(cyclohexyl){3-methyl-l-[5-(trifluoromethyl)pyridine- 2-mercapto]-1H-pyrazol-4-ylindenyl)amino]phenyl}carbonyl)(indenyl)amino]propanoic acid The same procedure as in Example 1 (7) was used, using Example 1 (6) The synthesized cyclohexyl hydrazone 3- Base-1-[5-(tri-I-yl)n-ratio π-but-2-yl]-1H-d ratio "s--4-yl} decyl alcohol (0.75 g) and Example 2 (2) Synthesis of 3-{[(4-Aminophenyl)carbonyl](indenyl)amino}propanoic acid ethyl ester (0.80 g). H NMR (300 MHz, CDCL·) δ ppm 0. 95-2. 23 (m, 11H), 2.37 (s, 3H), 2.62-2.78 (m, 2H), 3.05 (s, 3H), 3.58-3.84 151 321426 201029996 (m, 2H), 4.21 (d, J=6. 1 Hz, 1H), 6.49 (d, J=8. 7 Hz, 2H), 7.24 (d, J=8. 7 Hz, 2H) , 7.90- 8.00 (m, 2H), 8.32 (s, 1H), 8.59 (s, 1H). Example 3 3-[({4-[(cyclohexyl){3-ethyl-1_[ 5-(3) Fluoromethyl)pyridinyl-2-yl]-1H-pyrazol-4-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3-Ethyl-1-[5-(trifluoromethyl)pyrenepyrimidin-2-yl]-1Η-πΛwow_4_ oxalic acid methyl hydrazine A mixture of (2.6 g) and dimercaptomethionine didecyl acetal (2.8 mL) was stirred at TC for 12 hours and allowed to cool. Ethanol (50 mL) and hydrazine monohydrate (1.1 mL) It was added to the reaction mixture φ, and the mixture was treated in the same manner as in Example 1 (3) to give a crude product of methyl 3-ethyl-1H-pyrazole-4-carboxylate. Potassium carbonate (4.2 g) and 2-gas-5-difluorodecyl acridine (3.6 g) were added to dimethyl decylamine (30 ml), and the mixture was stirred at i〇〇°c. The title compound (4.7 g, 79%) was obtained as a yellow solid in the same manner as in Example 1 (4). I^iMR (300 MHz, CDCI3) (5 ppm 1.33 (t, J = 7. 5 Hz, 3H) 3. 00 (q, J=7. 5 Hz, 2H), 3.87 (s, 3H), 7. 99-8. 18 (m 2H), 8. 68 (s, 1H) , 9. 00 (s, 1H). ' 321426 152 201029996 (2) 3-Ethyl-1-[5-(trifluoromethyl) σ-pyridyl-2-yl]qΗ-pyrazole_4_formaldehyde The above-mentioned synthesized 3-ethyl group was treated in the same manner as in Example 1 (5). 1-(5-(Trifluoroindolyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid decyl ester (4.7 g) afforded the title compound (1.1 g, 26 % ). NMR (300 MHz, CDCh) δ ppm 1. 35 (t, J=7. 6 Hz, 3H), 3. 00 (q, J-7. 6 Hz, 2H), 7. 98- 8. 23 (m, 2H), 8. 71 (s, 1H), 9.04 (s, 1H), 10.05 (s, 1H). (3) Cyclohexyl {3-ethyl-l-[5-(three Fluoromethyl)acridine-2-yl]pyran-4-yl}nonanol The above-prepared 3-ethyl-1-[5-(dimethylmethyl) was treated in the same manner as in Example 1 (6). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ br> 300 MHz, CDCI3) 5 ppm 0.80-2. 21 (m, 14H), 2.73 (q, J=7.3 Hz, 2H), 4.44 (dd, J=7.2, 3. 4 Hz, 1H), 7.87- ❹ 8.16 (m, 2H), 8.43 (s, 1H), 8.63 (s, 1H). (4) 3-[({4-[(J hexyl) {3-ethyl-i-[5- (trifluoromethyl) 0 is more than a group of -111-oxime-s--4-yl}methyl)amino]phenyl-hydroxy)amino]propanoic acid in the same manner as in Example 1 (7), The cyclohexyl {3ethyl_1-[5-(difluoromethyl)β ratio σ sec-2-yl] ratio synthesized as described above was used. _4-yl}sterol (0.55 g) and 3~{[(4-aminophenyl)carbonyl]aminopropionic acid ethyl ester (0.37 g) synthesized in Example 1 (2) were obtained. The title compound (0.32 g, 38%). NMR (300 MHz, CDCh) 5 ppm 0. 86-2. 〇〇(mj 11H)5 j 32 321426 153 201029996 (t,J=7. 5 Hz,3H), 2.38-2. 58 (ra,2H) , 2.70 (q, J=7. 5 Hz, 2H), 3.39-3.69 (m, 2H), 4.22 (d, J=6. 0 Hz, 1H), 6.47 (d, J=8.5 Hz, 2H), 6.68 (br. s., 1H), 7.51 (d, J=8.5 Hz, 2H), 7.85-8.08 (m, 2H), 8.30 (s, 1H), 8.56 (s, 1H). Example 4

3_[({4-[(cyclohexyl{3-ethyl-l-[5-(trifluoromethyl)pyridin-2-yl]-1 Η-pyrazole-4-ylindolemethyl)amino] Benzene}carbonyl)(fluorenyl)amino]propanoic acid The same procedure as in Example 1 (7) was carried out using the cyclohexyl {3-ethyltrifluoromethyl) oxime synthesized in Example 3 (3). 2-yl]-lH-ntb〇-4-yl} decyl alcohol (0.55 g) and 3-{[(4-aminophenyl)carbonyl] synthesized in Example 2 (2) The title compound (0. 35 g, 41%) was obtained as a white solid. 4 NMR (300 MHz, CDC10 d ppm 1.19-2·06 (m,11H), 1.35 (t, J=7.5 Hz, 3H), 2.60-2.81 (m, 4H), 3.05 (s, 3H), 3.72 (d, J=7.5 Hz, 1H), 4.24 (d, J=6. 2 Hz, 1H), 6.50 (d, J=8. 7 Hz, 2H), 7.26 (d, J=8. 7 Hz , 2H), 7.91-8.09 (m, 2H), 8.31 (s, 1H), 8.59 (s, 1H)· Example 5 3—[(H-[(cyclohexyl){3-propyl-l-[5 -(trifluoromethyl)D-pyridin-2-yl] 154 321426 201029996 -1H-Bizozol-4-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3-propyl-l-[5-(trifluoromethyl)pyridin-2-yl]-1H _ 〇 〇 竣 竣 竣 竣 竣 竣 将 将 将 将2.1 g) Mixture with dimethyl decyl hydrazide® (2.1 mL) at 1 Torr. (: stirring for 12 hours, and allowing the mixture to cool. Ethanol (50 mL) and hydrazine monohydrate (0.75 mL) were added to the reaction mixture. In the same manner as in Example 1 (3), 3 - C was obtained. Base yjj-° is a crude product which is brewed by 4-sodium acid. The crude product is dissolved in dimercaptoamine (20 ml), potassium carbonate (3.〇g) and 2_gas_5 are added. Trifluoropyridylpyridine (2.7 g), and the mixture was stirred for 2 hrs in EtOAc (3). %) H NMR (300 MHz, CDCh) in ppm 1. 〇2 (t, J=7 4 Hz 3H) 1.69-1.88 (m, 2H), 2.93 (d, J = 7.7 Hz, 2H), 3.87 ( s, 3H), 7.98-8.19 (m, 2H), 8.69 (s, 1H), 9.00 (s, 1H). (2) 3-propyl-l-[5-(trifluoromethyl)pyridine_2 _Base]_1H-pyrazole_4_furfural The above-prepared propyl-1-[5-(trifluoromethyl)indole-2-yl] was treated in the same manner as in Example 1 (5). _11 than saliva-4_ oxalic acid (3,3 g), the title compound (11 g,) was obtained as a yellow oil. 321426 155 201029996 R R (300 MHz, CDC13) (5 DM]] l P Κ 3 (t, J = 7. 3 Hz, 3H), 1.79 (m, 2H), 2.94 (d, J = 7 7 H7 9u \

Hz, 2H), 8.00-8.23 (m, 2H), 8.71 (s, 1H), 9.04 (s, 1ίη 1Λ 1H), 10.05 (s, 1H). (3) Cyclohexyl {3-propyl-1- [5-(Trifluoromethylsulfonyl) 3⁄4-pyridyl-2-yl]-1H_pyrazol-4-yl}methanol was treated in the same manner as in Example 1 (6). -propyl-1-[5-(trifluoromethyl)n ratio -2-yl]- IJJ-ntl· 4 &gt;1 J than furfural (1.1 g), obtained as a yellow oil The title target compound (1·3 g 95%). ° »H NMR (300 MHz, CDCls) c5 ppm 0. 80-2. 21 (m, i6〇H), 2. 67 (q, J=7.8Hz, 2H), 4.44 (dd, J=7.5 , 3.4 Hz! 1H), 7. 90- 8. 16 (m, 2H), 8.43 (s, 1H), 8.63 (s, 1H) (4) 3-[({4-[(cyclohexyl){3- Propyl-i-[5-(trifluoromethyl)indole ratio biting 2-yl]-1H-indole-4-yl}methyl)amino]phenyl phenylcarbonyl)amino]propionic acid In the same manner as in Example 1 (7), the above-mentioned synthesized cyclohexyl {3_propyl-1-[5-(disorganoyl)pyrene-2-yl]-1H-π ratio 〇4 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — The title compound (0.38 g, 39%) was obtained as a white solid. ]H NMR (300 MHz, CDCh) S ppm 1.03 (t, J=7. 4 Hz, 3H), 1.07-2.04 (m, 13H), 2. 49-2.74 (m, 4H), 3.52-3. (m, 2H), 4. 24 (d, J=6. 4 Hz, 1H), 6. 50 (d, J=8. 7 Hz, 2H), 6. 55-6. 68 (m, 1H) , 7. 53 (d, J=8. 7 Hz, 2H), 7. 86-8. 08 (m, 2H), 8.31 (s, 1H), 8.57 (s, 1H). Example 6 321426 156 201029996 3_[({4-[(cyclohexyl){3-propyl-l-[5-(trifluoromethyl)pyridine-2-yl]-1H-pyrazol-4-yl}indolyl)amino]benzene (carbonyl)(methyl)amine;|propionic acid

According to the same method as in Example 1 (7), the cyclohexyl {3-propyl-1-[5-(trifluoromethyl) "Bitter-2-yl]-1Η synthesized in Example 5 (3) was used. -η is more than 嗤-4-meryl} decyl alcohol (〇. 65 g) and 3-{[(4-aminophenyl)alkyl](indenyl)amine group synthesized in Example 2 (2)} The title compound (0.34 g, 34%) was obtained as a white solid. H NMR (300 MHz, CDCla) δ ppm 1.03 (t, J=7.2 Hz, 3H), 1.08-2.13 (m, 13H), 2.54-2.78 (m, 4H), 3.05 (s, 3H), 3.71 (t, J=6.2 Hz, 1H), 4.24 (d, J=5.7 Hz, 1H), 6.50 (d, J=8. 7 Hz, 2H), 7.26 (d, J=8. 7 Hz, 2H) , 7.87- 8.12 ^ (m, 2H), 8.31 (s, 1H), 8.59 (s, 1H). Example 7 3-[({4-[(cyclohexyl){3-(1-mercaptoethyl) -l-[5-(Trifluoromethyl)acridin-2-yl]-1H-pyrazol-4-yl}indenyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3-(1-Mercaptoethyl)-1-[5-(trifluoromethyl)pyrene-But-2-yl]-1Η-π ratio 157 321426 201029996 Oxazole-4-carboxylic acid oxime ester In the same manner as in Example 1 (3), 4-methyl-3-hydroxyacetic acid methyl ester (2.9 g), dimethylformamide dinonyl acetal (28 mL) and hydrazine monohydrate were used. (1.1 mL), a crude product of methyl 3-(1-mercaptoethyl)-ih-pyrazole-4-carboxylate was obtained. The crude product was dissolved in dimethyl decylamine (m 1), potassium carbonate (4.2 g) and 2-hexane-5-trifluoropyridylpyridine (3.6 g) were added, and the mixture was stirred at 100 ° C. 2 hours. The title compound (4.6 g, 73%) °H NMR (300 MHz, CDCh) δ ppm 1.36 (d, J = 6.8 Hz, 6H), 3.60 (quint, J=6.8 Hz, 1H), 3.87 (s, 3H), 7.99-8.99 Cm, 4H). (2) 3-(1-mercaptoethyl)-i-[5-( Trifluoromethyl <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Methyl) π ratio. Benz-2-yl]-1 Η-» 嗤 -4- 叛 叛 曱靡 (4.6 g), the title compound (17 g, 4 〇%) °H NMR (300 MHz, CDCh) δ ppm 1.38 (d, J=6. 8 Hz, 6H), 3.41-3.64 (m, 1H), 8.01-8.28 (m, 2H), 8.70 (s, 1H), 9-04 (s, 1H), 10.06 (s, 1H). (3) Cyclohexyl {3-(1-methylethyl)-1-[5-(trifluoromethyl)pyrene than bit-2-yl] - 1H-pyrazol-4-yl} sterol The 3-(1-methyl-158 321426 201029996-ethyl)-b [5-(trifluoromethyl) group was synthesized in the same manner as in Example 1 (6). Pyridine-2-yl]- 1H-pyrazole_4_furfural (1.7 g) mp mp (3 g) 00 MHz, CDCh) d ppm 0. 80-2. 21 (m, 17H), 3 01 (quint, J-6.9Hz, 1H), 4.45 (dd, J=7.5, 3.6 Hz, 1H), 7.90-8.10 (in, 2H), 8.43 (s, 1H), 8.62 (s, 1H). (4) 3-[({4-[(cyclohexyl){3-(1-methylethyl-(trifluoromethyl) Pyridin-2-yl]-111-pyrazole-4-ylindolemethyl)amino]phenyl}carbonyl)amino]®propionic acid The same procedure as in Example 1 (7) was used, using the ring synthesized above. Hexyl{3-(1-mercaptoethyl)-1-[5-(trifluoromethyl)pyridine-2-yl]_1H-pyrazol-4-yl}methanol (〇. 50 g) and Example 1 (2) The title compound (0. 11 g, 14%) was obtained as a pale yellow solid. ). !H NMR (300 MHz, CDCls) δ ppm 1. 20-2. 06 (m, 11H), 1.28 ❹—1.40 (m, 6H), 2.64 (t, J=4.5 Hz, 2H), 2. 91-3. 17 (m, 1H), 3. 54-3. 79 (m, 2H), 4. 29 (d, J=6. 2 Hz, 1H), 6. 43-6.65 (m, 3H) , 7.54 (d, J=8. 7 Hz, 2H), 7.86-8.11 (m, 2H), 8.30 (s, 1H), 8.58 (s, 1H). Example 8 3-[({4-[( Cyclohexyl {3-(1-methylethyl)-1-[5-(tripholinyl)&lt;7-indol-2-yl]-1H-indazol-4-yl}methyl)amino ]phenyl}carbonyl)(methyl)amino]propionic acid 159 321426 201029996

Using the same procedure as in Example 1 (7), the cyclohexyl {3-(1-methylethyl)-1-[5-(trifluoromethyl)pyridine-2-carboxylate synthesized in Example 7 (3) was used. -1H-pyrazol-4-yl} decyl alcohol (0.65 g) and the 3-{[(4-aminophenyl)carbonyl](fluorenyl)amine group synthesized in Example 2(2) The title compound (0.16 g, 21%) was obtained as a white solid. ]H NMR (300 MHz, CDCh) d ppm 1. 20-2. 05 (m, 11H), 1.32 -1.37 (m, 6H), 2.59-2.79 (in, 2H), 2.96-3.20 (m, 4H) , 3.73 (t, J=7. 5 Hz, 2H), 4.28 (d, J=6. 0 Hz, 1H), 6.52 (d, J=8. 7 Hz, 2H), 7.26 (d, J=8 7 Hz, 2H), 7.88-8.11 (m, 2H), 8.30 (s, 1H), 8.59 (s, 1H). Example 9 3-[({4-[(cyclohexyl){3-cyclopropyl -i-[5-(Trifluoromethyl)pyridin-2-yl]--lH-t-p--4-yl}indolyl)amino]phenyl}alkyl)amino]propionic acid

(1) 3-cyclopropyl-1-[5-(trifluoromethyl)pyridine_2-yl]_1H_pyrazole_4_carboxylic acid methyl ester The same method as in Example 1 (3), using 3_ Cyclopropyl-3-3-oxo-propionic acid methyl vinegar (2.8 g), dimethyl decylamine dimercapto acetal (2.8 and 160 321426 201029996 hydrazine monohydrate (1.1 raL), obtained 3 - crude product of cyclopropyl-1H-pyrazole-4-carboxylic acid vinegar. The crude product was dissolved in dimethylformamide (3 〇^1), potassium carbonate (4.2 g) and 2- Gasoline-trifluoropyridylpyridine (3.6 g), and the mixture was stirred at 100 ° C for 2 hours. The title compound was obtained as a white solid (4 g. , 77%). 'H NMR (300 MHz, CDCh) δ ppm 1. 02-1. 1〇(m, 4H), 2.55- 2. 70 (m, 1H), 3.89 (s, 3H), 8.00- 8. 03 (m, 2H), 8. 66 (s, 1H), 8.96 (s, 1H). ❹(2) 3-cyclopropyl-1 -[5-(trifluoromethyl)pyridine_2_ The above-prepared 3_cyclopropyl-1-[5-(trifluoromethyl)pyridin-2-yl group was treated in the same manner as in Example 1 (5). ]_1Η__pyrrole_4_ oleic acid methyl vinegar (4.8 g) to give the title compound as a white solid (1.5 g, 祁

Ppml.02~1.15(m,4H), 2.50- (m' 2H), 8.69 (s,1H),8·99

JH NMR (300 MHz, CDCh) d 2. 70 (m, 1H), 8. 00-8. 10 (s, 1H), 10.10 (s, 1H). (3) Cyclohexyl {3-cyclopropyl+ [5_(Tri-imethyl)m_2_yl]_ih_吼-4-yl}methanol was treated in the same manner as in Example 1 (6). The needle was synthesized in the same manner as in Example 1 (6).

Base-1-[5-(diindenyl)bite-2-yl η ltI oxime oxazole 4-formaldehyde (15 g) 'obtained as a white solid titled servant known compound (2.1 g, 99%). 4 丽R (300 MHz, CDCM 5 ppm 0 0 ... τ ”. 2. 10 (m, training), 4.48 (dd, J-7.3, 3.0 Hz, 1H), 7.90-8 mr 8· 10 Cm, 2H) , 8.40 (s, 321426 161 201029996 1H), 8.60 (s, 1H). (4) 3-[({4-[(cyclohexyl{3-cyclopropyltrifluoromethyl)pyridin-2-yl]- lH-t-4-yl}mercapto)amino]phenyl}alkyl)amino]propanoic acid The same procedure as in Example 1 (7) was used, using the cyclohexyl{3-cyclopropyl synthesized above. 1-[5-(Trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-yl} decyl alcohol (0.50 g) and the 3-{[ synthesized in Example 1 (2) (4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.32 g), m. (5 ppm 〇· 86-2. 07 (m,16H) 2 64 (t, J=5.5 Hz, 2H), 3.65 (q, J=5.9 Hz, 2H), 4.37 (d, J=6.4 Hz, 1H ), 6.54-6.70 (m, 3H), 7.53 (d, J=8.3 Hz, 2H), 7.93 (s, 2H), 8.28 (s, 1H), 8.56 (s, 1H). Example 10 3 -[({4-[(cyclohexyl{3-cyclopropyl-l-[5-(trimethyl)methyl)pyrimidin-2-yl]-1H-pyrazol-4-yl}indenyl)amine (phenyl)-propenyl)(methyl)amino]propionic acid

The cyclohexyl {3-cyclopropyl-1-[5-(trifluoromethyl)pyridine-2-yl]-1H-pyry synthesized in Example 9 (3) was used in the same manner as in Example 1 (7). Zin-4-yl} decyl alcohol (0.50 g) and 3-{[(4-aminophenyl)carbonyl](indenyl)amino}propionic acid ethyl ester (0.34 g) synthesized in Example 2 (2) ), the title compound (0.19 g, 25%) was obtained as white 162 321426 201029996. H NMR (300 MHz, CDCh) δ ppm 0. 92-2. 09 (m, 16H), 2.71 (t, J=6.2 Hz, 2H), 3.07 (s, 3H), 3.71 (t, J=6.4 Hz, 2H), 4.36 (d, J=6.4Hz, 1H), 6.54 (d, J=8. 7 Hz, 2H), 7.26 (d, J=8. 7 Hz, 2H), 7.94 (s, 2H ), 8.28 (s, 1H), 8.57 (s, 1H). Example 11 3-[({4-[(cyclohexyl){3-(2-phenylethyl)-l-[5-(trifluoro) Indole) acridine®-2-yl]-1H-pyrazol-4-yl}indenyl)amino]phenyl}alkyl)amino]propionic acid

(1) Ethyl 3-(2-phenylethyl(trifluoromethyl)acridin-2-yl]-1H-0 pyrazole-4-carboxylate was used in the same manner as in Example 1 (3). Ethyl 3-oxo-5-phenylpentanoate (5.8 g), dimethylformamide dimethyl acetal (3.6 mL) and hydrazine monohydrate (1.3 mL) - Crude product of ethyl 2-(2-phenylethyl)-lH-pyrazole-4-carboxylate. The crude product was dissolved in dimethylformamide (3 mL). And 2-chloro-5-trifluoromethylpyridine (4.8 g), and the title compound was obtained as a white solid (yield: m. 5. 2 g, 50 163 321426 201029996 R R (300 MHz, CDCh) 5 ppra i. 39 (t, J=7.2 Hz, 3H), 3. 00-3. 15 (m, 2U), 3. 22 -3· 39 (m, 2H), 4 34 (q, J=7 2

Hz, 2H), 7.15-7.38 (in, 10H), 7. 99-8. 17 (m, 2H), 8.69 (s, 1H), 9.01 (s, 1H). (2) 3-(2-Benzene Benzyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyridin-4-yl oxime. The above-mentioned synthesized 3_ was treated in the same manner as in Example 1 (5). 2-Phenylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-in-pyrazole-4-carboxylic acid ethyl ester (5.2 g) gave the title title as a white solid Compound (3. 〇g, 65 %) ° NMR (300 MHz, CDCh) δ ppm 2. 98-3. 17 (m, 2H), 3.22-3.41 (m, 2H), 7.11-7.47 (m, 5H) , 7.99-8.22 (m, 2H), 8.71 (s, 1H), 9.04 (s, 1H), 9.99 (s, 1H). (3) Cyclohexyl {3-(2-phenylethyl)-1- [5-(Trifluoromethyl)e-pyridyl-2-yl]-1H-0 is 0--4-yl}methanol φ The above-prepared 3-(2-phenylene) was treated in the same manner as in Example K6). Ethyl)-1-[5-(trifluoromethyl)-pyrimidin-2-yl]pyr-4-pyrene (1.5 g) gave the title compound as a white solid (17 g, s. (300 MHz, CDCL·) δ ppm 0. 83-2. 02 (m, 12H), 2.92 -3.23 (m, 4H), 4.28 (dd, J=7. 3, 2. 7 Hz, 1H), 7.15 -7.40 (in, 5H), 7. 93-8. 13 (m, 2H), 8. 42 (s, 1H), 8. 64 ( s, 1H). (4) 3-[({4-[(cyclohexyl){3-(2-phenylethyl))-(trifluoroindolyl).pyridin-2-yl]-lH -t-4-yl}hydrazino)amino]phenylindoles)amino] 321426 164 201029996 In the same manner as in Example 1 (7), the above-mentioned synthesized cyclohexyl {3-(2) was used. -Phenylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]~1H~吼〇-4-yl}methanol (0.50 g) and Example 1 (2) Synthesis of 3 勹[(4-aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.28 g), m. ) d ppm 0. 84-1. 97 (m, 11H) 2 45 - 2.64 (m, 2H), 2.87-3.18 (m, 4H), 3.49-3.67 (m, 2H), 4. 16(d, J =6. 0 Hz, 1H), 6.41 (d, J=8.7 Hz, 2H), 6.61 (br. s., 1H), 7.15-7.34 (m, 5H), 7.49 (d, J=8.7 Hz, 2H ), 7.87-8.10 (in, 2H), 8.31 (s, 1H), 8.57 (s, 1H). Example 12 3 [({4-[(cyclohexyl){3-(2-phenylethyl)-) I-[5-(tri-chaotic methyl) 0-biti-2-yl]-1H-pyrazol-4-yl}methyl)amino]phenyl phenylcarbonyl)(methyl)amino]

Using the same procedure as in Example 1 (7), the cyclohexyl {3-(2-phenylethyl)-bu [5-(trifluoromethyl) acridine-2-yl group synthesized in Example ii (3) was used. ] ~111~oxazol-4-yl}methanol (〇. 5〇g) and 3-U(4-aminophenyl)carbonyl](indenyl)amino}propyl synthesized in Example 2(2) The title compound (0.30 g, 41%) was obtained as a white solid. *H NMR (300 MHz, CDCh) (5 ppm 0. 93-2. 01 (m, 11H), 2.59 -2.74 (m, 2H), 2.89-3.20 (m, 7H), 3.71 (d, J=6 . 0 Hz, 2H), 4.18 (d, J=6. Hz, 1H), 6.43 (d, J=8. 7 Hz, 2H), 7.16-7.37 (m, 5H), 7.90-8.13 (m, 2H), 8.32 (s, 1H), 8. 60 (s, 1H). Example 13 3-{[(4_{[{3_T-butyl-1-[5-(trifluoromethyl)pyridine) -2-yl]-111-indol-4-yl}(cyclohexyl)methyl]amino}phenyl;) Prison base] Amino propyl propionate

(1) 3-tert-butyl-1-[5-(trifluoromethyl)pyridine-2-yl]- 1H-pyrazole-4-carboxylic acid oxime ester according to the same method as in Example 1 (3), Using 4,4-dimercapto-3-indolyl valeric acid ethyl ester (3.4 g), dimethylformamide-didecyl acetal (28 mL) and hydrazine monohydrate (1.1 mL) were obtained. The crude product of 3-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester. This crude product was dissolved in dimethyl decylamine (15 ml), potassium carbonate (1,2 g), and 2-dichloro-5-trifluoromethylpyridyl (17 g) were added, and the mixture was stirred overnight at room temperature. . The title compound (28 g, 43%) was obtained as a white solid. H NMR (300 MHz, CDC10 d ppm 丨38 (t, J=7 2 Hz, 3H), 321426 166 201029996 1.49 (s, 9Η), 4.32 (q, J = 7.2 Hz 2W, 2H), 8.68 (d, J=ll Hz,1H) 9 〇3 / 7. 98 -8.21 (m' (s,1H) (2) 3-tert-butyltrifluoromethyl)pyrr#; _4-formaldehyde b疋~2 -yl]-1Η-pyrazole The same procedure as in Example 1 (5) was used to treat the above-mentioned dibutyl-bu [5-(trifluoromethyl) ridge 2_yl]^ α ")' to give a white solid. Title target compound armor 93%) ° Ο ]H NMR (300 MHz, CDCh) &lt;5 ρηιη 1 4Q r ^ ηττ, ·49 (s,9H), 7. 98-8.21 (m,2H), 8.68 (d, J = L1 Hz, 1H) 9 fiQ r y. 09 (s, 1H), 10. 11 (s, 1H). (3) Cyclohexyl {3-t-butyl dioxin L3, fluorocarbon Base) acridine 2 -yl] -ΙΗ-η ratio 0 -4-yl} sterol oxime The above-prepared 3_t-butyl-1-[5] was treated in the same manner as in Example 1 (6). -(Difluoromethyl)pyridin-2-yl]-in-pyrazole-4-furanal (L 7 g) gave the title compound (M g 4) / /H NMR (300 MHz) , CDCh) 5 ppm 〇. 79_2. 2〇(m \ ^ ^ -- ^ -·〇ΗΖ, !H), ;H;3 8.52 (s, 1H), 8.62 (s, 1H). (4) 3-{[(4-{[{3-Ternyl butyl [5-(trifluoromethyl)pyridine-2-yl]-IP-pyrazol-4-yl} (cyclohexyl) Methyl]amino}phenyl)benzyl]amino}propionic acid The same procedure as in Example 1 (7) was used, using the cyclohexyl{3-t-butyl-i-[5- (trifluoromethyl)pyridine-2-yl]-1H-pyrazole-4-yl} 321426 167 201029996 Methanol (0.53 g) and the 3-{[(4-amine) synthesized in Example 1 (2) Ethyl phenyl) carbonyl]amino}ethyl propionate (0.32 g), ield title compound (0.12 g, 15%) as a white solid..H NMR (300 MHz, CDCh) ppm 1. 00-2. 00 (m, 11H), 1 27 (s, 9H), 2.57-2.61 (m, 2H), 3.17-3.59 (m, 2H), 4.44 (br. s., 1H), 6.31-6.51 (m, 2H ), 7.33-7.47 (m, 1H), 7. 49-7. 62 (m, 2H), 7. 74-8. 07 (m, 2H), 8. 32-8. 57 (m, 2H). ^Example 14 3-{[(4-{[{3-Ternyl-1-[5-(trifluoromethyl)pyrene)-111- 吼嗤-4-yl} (cyclohexyl)methyl]amino}phenyl)carbonyl](indenyl)amino}_propionic acid

Using the same procedure as in Example 1 (7), the cyclohexyl {3-t-butyl-i-[5-(trifluoromethyl)pyridin-2-yl]-1H synthesized in Example 13 (3) was used. -. 3-U(4-Aminophenyl)carbonyl](indenyl)aminopyridinium propionate (0.34) synthesized from "s--4-yl} decyl alcohol (0.52 g) and Example 2 (2) g) The title compound (013 g, 16%) lH NMR (300 MHz, CDCh) 5 ppm 0. 96-2. 00 (m, 11H), 1.42 (s, 9H), 2.61-2.81 (m, 2H), 3.08 (s, 3H), 3.72 (t, 168 321426 201029996 J=6.4Hz, 2H), 4.57 (d, J=6. 1 Hz, 1H), 6.54 (d, J=8. 7 Hz, 2H), 7.26 (d, J=8. 7 Hz, 2H), 7.89-8.13 (m, 2H), 8.40 (s, 1H), 8.59 (s, 1H). Example 15 3-({[4-({cyclohexyl][i-phenyl_3_(2- Phenylethyl)-ih-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}amino)propionic acid

(1) 1_Benyl-3-(2-phenylethyl to 0--4-acetic acid ethyl vinegar. 3-Ethoxy-5-phenylpentanoic acid ethyl ester (5.8 g) with dimethyl A mixture of mercaptoamine dimercaptoacetal (3.6 mL) was stirred at rt (TC was stirred overnight and the mixture was cooled to room temperature. Ethanol (30 mL) and phenylhydrazine (2.9 g) were added to the reaction mixture. Medium' and the mixture was stirred for an additional 8 hours at 10 ° C. © After cooling the mixture, the ethanol was evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc (EtOAc) (HHHHHHHH 1 g, 84%) NMR (300 MHz, CDCls) δ ppm 1.40 (t, J=7.2 Hz, 3H), 2.87 (dd, J=9.0, 6. 6 Hz, 2H), 3.15-3.32 (m, 2H), 4.36 (q, J=7. 2 Hz, 2H), 6.92-7.53 (m, J=7. 5, 3.8, 3.8, 3.5 169 321426 201029996

Hz, 10H), 8.05 (s, 1H). (2) 1-phenyl-3-(2-phenylethyl)-lH-. The above-prepared ethyl 1-phenyl-3-(2-phenylethyl)-1-indole-pyrazole-4-carboxylate was treated in the same manner as in Example 1 (5). 7. 1 g) gave the title compound (4.6 g, 75%).沱NMR (300 MHz, CDCI3) 5 ppm 2.87 (t, J=7. 8 Hz, 2H), 3.23 (t, J=7. 6 Hz, 2H), 6.84-7.58 (m, 10H), 8.07 (s , 1H), 9.93 (s, 1H). o (3) Cyclohexyl [1-phenyl-3-(2-phenylethyl)-IH-n ratio. The above-prepared p-phenyl-3-(2-phenylethyl)-1Η-pyrazole-4-furaldehyde (2.6 g) was treated in the same manner as in Example 1 (6). The title compound (2.9 g, 85%) was obtained as a white solid. ]H NMR (300 MHz, CDCla) &lt;5 ppm 0. 75-2. 19 (m, 12H), 2.46 -3. 17 (m, 4H), 4. 16 (dd, J=8. 3, 2 . 7 Hz, 1H), 6. 83- 7. 54 (m, 10H), 7.58 (s, 1H). ❿(4) 3-({[4-({cyclohexyl[1-phenyl-3- (2-Phenylethyl)_1H-pyrazol-4-yl]fluorenyl}amino)phenyl]alkyl}amino)propanoic acid The same procedure as in Example 1 (7) was carried out using the above-mentioned synthesis. Cyclohexyl [1-n-yl_3_(2-propenylethyl)-1Η-β than 嗤-4-yl]methanol (〇. 5〇g) and 3-{[ synthesized by Example 1(2) (4-Aminophenyl)carbonyl]amino-propionic acid ethyl ester (0-33 g). NMR (300 MHz, CDC13) (5 ppm 0.94-2. 03 (m, iiH), 2.40 - 2.56 (m, 2H), 2. 67 (t, J = 5 · 7 Hz, 2H), 2. 91-3 07 (m 321426 170 201029996 2H), 3.68 (q, J=5. 9 Hz, 2H), 4.20 (d, J=7. 0 Hz, 1H), 6.52-6.58 (m, J=8. 7 Hz, 3H), 6.82 (d, J=8. 6 Hz, 2H), 7.12-7.22 (m, 4H), 7.35-7.65 (m, 11H). Example 16 3-[ {[4-({ Cyclohexyl [1-phenyl-3-(2-phenylethylpyrazol-4-yl)

Using the same method as in Example 1 (7), the hexyl group [1_benyl-3-(2-phenylethyl-s--4-yl)methanol (0.50 g) synthesized in Example 15 (3) was used. 3-{[(4-Aminophenyl)carbonyl](indenyl)amino}propionic acid ethyl ester (0. 35 g) obtained in the title compound (2) 0·37 g, 47%). ❿ 4 NMR (300 MHz, CDCh) (5 ppm 0. 94-2· 08 (m, 11H), 2. 44 -2.59 (ra, 2H), 2.73 (d, J =6. 0 Hz, 2H), 2.91-3.05 (m, 2H), 3.09 (s, 3H), 3.73 (t, J=6.4 Hz, 2H), 4.19 (d, J=6. 8 Hz, 1H) , 6.53 (d, J=8. 7 Hz, 2H), 6.79-6.88 (m, 2H), 7.12-7.58 (m, 11H). Example 17 3-{[(4-·([cyclohexyl] -mercapto-1-phenyl-1H-indole "oxazol-4-yl)indolyl]amino}phenyl)alkyl]amino}propionic acid 321426 171 201029996

(1) 3-Methyl-1-phenyl-indole-π ratio 0--4-reoxazide 3-methoxy-1H-pyrazole-4-carboxylate synthesized in Example 1 (3) Methyl ester (14.4 g) was dissolved in dimethylacetamide (2 mL), phenylboronic acid (25.0 g), copper acetate (36.4 g) and pyridine (32 mL) were added. The mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered through celite, and 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ]H NMR (300 MHz, CDCh) &lt;5 ppm 2.56 (s, 3H), 3.86 (s, 3H), 7.26-7.70 (m, 5H), 8.34 (s, 1H). (2) 3-methyl -1 -Phenyl-1 jj-0 σ -44_曱 · · The above-mentioned synthesized 3-mercapto-p-phenyl-1H-pyrazole-4- was treated in the same manner as in Example 1 (5). The title compound (3.8 g, 39%) was obtained as a pale yellow solid. NMR (300 MHz, CDCh) δ ppm 2. 59 (s, 3H), 7. 27-7. 72 (m, 5H), 8.34 (s, 1H), 10.00 (s, 1H). (3) Cyclohexyl (3-Methyl-i-phenyl-indole-σ-pyrazole-4-yl)nonanol The above-prepared 3-mercapto-1-phenyl-1H- was treated in the same manner as in Example 1 (6). Pyrazole-4-furaldehyde (3.8 g) was obtained as a white solid title 321426 172. !H NMR (300 MHz, CDCh) δ ppm 0. 80-2. 20 (m&gt; jijj) 2 34 (s, 3H), 3.61 (brs, lH), 4.44 (d, J = 7.2 Hz 'lH) 7 20- 7.80 (m, 6H). ' (4) 3-{[(4-{[cyclohexyl(3-methyl-1-phenyl-1H~pyrazolyl)methyl]amino}phenyl Alkyl]amino}propionic acid The same procedure as in Example 1 (7) was carried out, using the cyclohexyl (3-indolyl + phenyl-1 Η-η than salicyl) methanol synthesized as described above (0·14 g). And ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (15 g), which is obtained as a white solid. 〇5 &amp; 31 % ) 〇' H NMR (300 MHz, CDCh) δ ppm 1. 04-2. 21 (m, 12H), 2 36 (s, 3H), 2.65 (br. s., 2H), 3.67 (br. s. , 2 H), 4.20 (d, J-6. 0 Hz, 1H), 6.49 (d, J=6. 0 Hz, 2H), 6.55-6.71 (m, 1H), 7. 14-7. 74 (m, 8H). ◎ Example 18 3 U(4-·([cyclohexyl(3-methylphenyl)-4-yl)indolyl]amino}phenyl)carbonyl] (mercapto)amino}propionic acid

In the same manner as in Example 1 (7), the cyclohexyl (3·decyl-1-phenyl-benzazol-4-yl) decyl alcohol (〇. 14 g) synthesized in Example 17 (3) was used. 173 321426 201029996 and 3-{[(4-aminophenyl)carbonyl](indenyl)amino}propionic acid ethyl acetate (0.15 g) synthesized as a white solid. Title target compound (0. 04 g, 23%). !H NMR (300 MHz, DMSO-de) d ppm 0.87-2.10 (m&gt; 12H), 2.25 (s, 3H), 2.47 (t, J=7.4 Hz, 2H), 2.89 (s, 3H), 3.51 ( t, J=7.4 Hz, 2H), 4.16 (t, J=7. 6 Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 6.58 (d, J=8.7 Hz, 2H), 7.10 ( d, J=8. 7 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 7. 43 (t J=8 0 Hz, 1H). 1 2 3 4 5 Example 19 3-({[4-({[1-(4-Chlorophenyl)-3-methyl-1Η-°bazol-4-yl](cyclohexyl) fluorenyl}amino)phenyl]carbonyl Amino)propionic acid

174 321426 1 1-(4-Chlorophenyl)-3-methyl-1H-0 is 0 -4- -4- 酸 酸 甲 甲 2 2 In the same manner as in Example 17 (1), Example 1 (3) was used. Methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g), 4-chlorophenylboronic acid 3 (13.9 g), copper acetate (16.3 g) and pyridine (14) The title compound (6.9 g, 62%) was obtained. 5 ]H NMR (300 MHz, DMSO-de) 5 ppm 2. 54 (s, 3H), 3. 85 (s, 3H), 7.43 (d, J=8.7 Hz, 2H), 7.62 (d, J= 8. 7 Hz, 2H), 8.31 (s, 1H). 201029996 (2) Bu (4-phenylphenyl)-3-indolyl-indole is the same as in Example 1 (5). The title compound of the title compound (4.1 g, 68%) was obtained as a pale yellow solid. °]H NMR (300 MHz, CDCh) δ ppm 2.58 (s, 3H), 7.46 (d, J=9. 0 Hz, 2H), 7.64 (d, J=9. 0 Hz, 2H), 8.31 ( s, 1H), 10.00 (s, 1H). (3) [1-(4-Chlorophenyl)-3-methyl-1H--pyrazol-4-yl](cyclohexyl)methanol hydrazine The above-prepared 1-(4-phenylphenyl)-3-indolyl-1H-pyrazole-4-carbaldehyde (4.2 g) was obtained to give the title compound (4.9) g, 85%). JH NMR (300 MHz, CDCls) &lt;5 ppm 0. 88-2. 00 (m, 11H), 2.32 (s, 3H), 3.59 (br. s., 1H), 4.43 (d, J = 7.2 Hz ,1H), 7.38 (d, J=9.0 Hz, 2H), 7.58 (d, J=9. 0 Hz, 2H), 7.76 (s, 1H). Q (4) 3-( {[4-( { [1-(4-chlorophenyl)-3-indolylpyran-4-yl](cyclohexyl)indolyl}amino)phenyl]carbonyl}amino)propanoic acid, in the same manner as in Example, Using the above-mentioned synthesized gas phenyl)-3_mercapto-1H-pyrazol-4-yl](cyclohexyl)nonanol (〇. 46 g) and the 3-{[ synthesized in Example 1 (2) (4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.35 g). NMR (300 MHz, DMSO-de) (5 ppm 〇86-2. 〇9 (m,12H) 2.24 (s, 3H), 2.41 (t, J=7_ j HZj 2h), 3.28-3.44 (m, 321426 175 201029996 2H), 4· 20 (t, J=7. 7 Hz, 1Η), 6· 33 (d, J=7. 9 Hz 1H) 6. 58 (d, J-8. 9 Hz, 2H) , 7.39-7. 60 (m, 4H) 7 73 (d J=9. 0 Hz, 2H), 7. 92-8. 09 (m, 1H), 8. 29 (s, 1H) Example 20

3-[{[4-({[Bu(4-Phenylphenyl)-3-methyl-1Η-ηBizozol-4-yl](cyclohexyl)methylammonium)phenyl]carbonyl} Methyl)amino]propionic acid

[1-(4-Phenylphenyl)-3-methyl-1H-0 啥-4-yl] (cyclohexyl) synthesized by the same method as in Example 1 (7) using Example ig (3) Ethyl alcohol (0. 46 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester (0.25 g) synthesized in Example 2 (2) 'The title compound was obtained as a white solid (0.41 g, 57%). NMR (300 MHz, DMSO-de) δ ppm 0. 75-2. 07 (m, 12H), 2.23 (s, 5H), 2.85 (br. s., 3H), 3.39-3.57 (m, 2H), 4.13 (br. s., 1H), 6.20 (d, J=7.0 Hz, 1H), 6.56 (d, J=8. 5 Hz, 2H), 7. 09 (d, J=8. 5 Hz, 2H ), 7. 46 (d, J=8. 7)

Hz, 2H), 7.71 (d, J=8. 7 Hz, 2H), 8.28 (s, 1H). Example 21 3-({[4-( {[ 1-(4-fluoro-2-fluorenyl) Phenyl)-3-mercapto-1Η-π ratio, sit-4-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}amino)propionic acid 176 321426 201029996

(1) 1-(4-Fluoro-2-indolylphenyl)-3-ylindolyl-1H-pyrazole-4-carboxylic acid hydrazine vinegar was used in the same manner as in Example 17 (1), using Example 1 ( 3) The synthesized 3_mercapto- 1Η_β-pyrazole-4-restroxate (6·25 g) and 4-fluoro-2-mercaptophenyl acid (13.9 g) were obtained as a white solid. The title compound (7.5 g, 68%). ]H NMR (300 MHz, CDCh) 5 ppm 2.26 (s, 3H), 2.54 (s, 3H), 3.85 (s, 3H), 6.80-7.35 (m, 3H), 7.97 (s, 1H). (2 1-(4-Fluoro-2-indolylphenyl)-3-indenyl-iH-f-pyrazole-4-carbaldehyde was treated in the same manner as in Example 1 (5) by 1-(4-) Fluor-2-mercaptophenyl)-3-indolyl-1H-indole-4-hyalonic acid vinegar (7.5 g) was obtained as the title compound (4.3 g, 83%). ]H NMR (300 MHz, CDCh) 5 ppm 2. 24 (s, 3H), 2.57 (s, 3H), 6. 90-7. 39 (m, 3H), 7.99 (s, 1H), 10.00 (s , 1H). (3) Cyclohexyl [1-(4-fluoro-2-indolyl)-3-fluorenyl-fluorenyl] decyl alcohol was treated in the same manner as in Example 1 (6). 1-(4-Fluoro-2-indolylphenyl)-3-indolyl-indole-sigma ratio, sulphonyl-4-pyrene (4 3 g), the title compound (6.1 g, 98%) ). HNMR (300 MHz, CDC13) (5 ppm 0.88-2. 〇〇(m,11H), 2.22 177 321426 201029996 (s,3H), 2.32 (s,3H),4·44 (dd,J= 7.3,3. 3 Hz 1H), 6.91-7.30 (m, 3H), 7.41 (s, 1H). (4) 3-({ [4_({ [1-(4-fluoro-2-methylphenyl) -3-mercapto-iH-n is exemplified by the same method as in Example 1 (7), using the same method as in Example 1 (7), (cyclohexyl) fluorenyl}amino)phenyl]carbonyl}amino)propionic acid. The above-mentioned cyclohexyl[1-(4-fluoro-2-indolylphenyl)-3-indolyl-1Η-πoxazol-4-yl]methanol (〇. 50 g) and Example 1 (2) Synthesis of 3-{[(4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.55 g). NMR (300 MHz, DMSO-de) δ ppm 0.87-2.00 (m, 12H), 2. 12 (s, 3H), 2.21 (s, 3H), 2. 34 (t, J=7. 1 Hz, 2H ), 3.22-3.45 (m, 2H), 4.21 (t, J=7.7 Hz, 1H), 6.31 (d, J=8.1 Hz, 1H), 6.59 (d, J=8. 9 Hz, 2H) , 7.10-7.31 (m, 3H), 7.51 (d, J=8.7 Hz, 2H), 7.76 (s, 1H), 8.11 (s, 1H). Example 22 3-[{[4-({[1 -(4-fluoro-2-methylphenyl)_3_indolyl_iH-pyrazol-4-yl](cyclohexyl)fluorenyl}amino) Phenyl]carbonyl}(indenyl)amino]propionic acid

OH 0 Cyclohexyl [l-(4-fluoro-2-indolylphenyl)-3-indolyl-1H synthesized by the method of Example 21 (3) using the same procedure as in Example 1 (7) ~. Ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester synthesized by the reaction of stil-4-yl] decyl alcohol (0.50 g) and Example 2 (2) (0.39 g) 'A title compound (0.48 g, 60%) *H NMR (300 MHz, DMSO-de) δ ppm 0.87-1.84 (m, 12H), 2. 10 (s, 3H), 2.22 (s, 3H), 2.48-2. 50 (m, 2H), 2.91 (s, 3H), 3.52 (in, 2H), 4.16 (d, J=9. 0 Hz, 1H), 6.59 (d, J=8.7 Hz, 2H), 7.00-7.32 (m, 6H), 7.75 ( s, 1H). ® Example 23 3-({[4-(4-methoxyphenyl)-3-methyl-lH-nbiazole-4-yl] fluorenyl Amino)phenyl]carbonyl}amino)propionic acid

❹(0 1_(4-methoxyphenyl)~3-methyl-iH-n is the same as that of Example 4 (1), and Example 1 (3) is used. Synthesis of 3-methyl-1H-pyrazole-4-carboxylic acid methyl ester (5.7 g) and 4-methoxyphenyl boronic acid (12.4 g) to give the title compound (6 5 g, 65%) ΐ NMR (300 MHz, CDCl 〇 ρρπ) 2·55 (s, 3H), 3 83 (s, 3H), 3.85 (s, 3H), 6.97 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 8.23 (s, 1H) 179 321426 201029996 (2) 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4 - furfural treatment in the same manner as in Example 1 (5). The above-mentioned 1~(4~methoxy-based)-3_mercapto-1Η_ο 0 _4_ 叛 甲 S ( (6. 6 g), the title compound (4.1 g, 78%) was obtained as a pale yellow solid.] H NMR (300 MHz, CDC10 (5 ppm 2.58 (s, 3H), 3.86 (s 3H), 6.99 (d, J = 9.0 Hz, 2H), 7.59 (d, J=8. 9 Hz, 2H) 8.24 (s, 1H), 9.98 (s, 1H). (3) Cyclohexyl [l-(4-decyloxyphenyl) -3-mercapto-1H-pyrazol-4-yl]carboxol was treated in the same manner as in Example 1 (6) by the above-mentioned synthesized 丨__(4 The title compound (7.1 g, 98%) was obtained as a white solid (yield: </ RTI> </ RTI> </ RTI> <RTIgt; CDCls) δ ppm 0. 88-1. 97 (m, 11H), 2 33 (s' 3H), 3.59 (br. s·, 1H), 3.83 (s, 3H), 4.43 (dd J=7. 3 , 3.0 Hz' 1H), 6.94 (d, J=9.0 Hz, 2H), 7·53 (d, q J=9.2 Hz, 2H), 7.70 (s, 1H). ' (4) 3-( {[4-({cyclohexyl[1-(4-methoxyphenyl)- 3 -indolyl__1H_indazol-4-yl]fluorenyl}amino)phenyl]carbonyl}amino) Propionic acid was synthesized in the same manner as in Example 1 (7) using the above-mentioned cyclohexyl[1-(4-methoxyphenyl)-3-indolyl-1H-pyrazol-4-yl]nonanol ( 68. 68 g) and the ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) of the title compound (1), 0.44 g, 39%). 12H), Li R (300 MHz, DMSO-d6) d ppm 0.89_2. 〇8 (m, 321426 180 201029996 2.22 (s,3H),2.34-2.45 (m,2H), 3.44-3. 60 (m, 2H)' 3.76 (s, 3H), 4.07-4.27 (m, 1H), 6.30 (d, J=9. 0 Hz, 1H), 6.58 (d, J=8. 9 Hz, 2H), 6.99 (d, J=9. 2 Hz, 2H), 7.51 (d, J=8. 9 Hz, 2H), 7.60 (d, J=9.2 Hz, 2H), 8.03 (br. s., 1H), 8 . 14 (s, 1H). Example 24 3-[{[4-({cyclohexyl[1-(4-methoxyphenyl)-3-methyl-lH-nbiazole-4_yl]) Amino)phenyl]carbonyl}(methyl)amino]propionic acid

Using the same procedure as in Example 1 (7), the cyclohexyl [1-(4-decyloxyphenyl)-3-indenyl-in-indole-4-yl] synthesized in Example 23 (3) was used. Hydroxide (0·68 g) and 3-{[(4-aminophenyl)carbonyl]phosphonium (methyl)amino}propionic acid ethyl ester (〇. 42 g) synthesized in Example 2 (2) The title compound (0. 28 g, 24%) was obtained as a white solid. H NMR (300 MHz, DMSO-de) δ ppm 0.87-2.10 (m, 12H) 2.23 (s, 3H), 2.45-2.50 (m, 2H), 2.90 (s, 3H), 3·44_ 3. 60 ( m, 2H), 3.77 (s, 3H), 4. 13-4. 15 (m, 1H), 6 21 (d, J-7. 7 Hz, 1H), 6· 58 (d, J=8. 7 Hz, 2H), 6. 99 (d J=9.0Hz, 2H), 7. 10(d, J=8. 7 Hz, 2H), 7.60 (d, J-9. 〇Hz, 2H), 8 . 14 (s, 1H). ' 321426 181 201029996 Example 25 3-[({4-[(cyclohexyl){3-methyl-1-[4-(trifluoromethoxy)phenyl) 1H 吼-4-yl}methyl)amino]]phenyl]#carbonyl)amino]propionic acid

(1) 3-methyl-1-[4-(trifluoromethoxy)phenyl]_1H-pyrazole-4-carboxylic acid vinegar vinegar was used in the same manner as in Example 17 (1), using Example 1 ( 3) Methyl 3-methyl-1H-pyrazole-4-carboxylate (6.8 g) and 4-trifluoromethoxyphenylboronic acid (20.0 g) were obtained as a white solid. Title target compound (3.9 g, 27%). H NMR (300 MHz, CDCh) δ ppm 2.55 (s, 3H), 3.86 (s, 3H), 7.32 (d, J = 9. 2 Hz, 2H), 7.71 (d, J = 9. 2 Hz, 2H), 8.32 (s, 1H). (2) 3-Methyl-l-[4-(trifluoromethoxy)phenyl]-ijj-»biazole-4-carbaldehyde according to Example 1 (5) The same method was used to treat the above-mentioned synthesized 3-methyl-1-[4-(trifluorodecyloxy)phenyl]-1H-indole than sino-4-indolyl ester (3.9 g) The title compound (2.3 g, 66%) was obtained as pale yellow solid. ]H NMR (300 MHz, CDCh) δ ppm 2.59 (s, 3H), 7.36 (d, J=9.0 Hz, 2H), 7.73 (d, J=9. 0 Hz, 2H), 8.32 (s, 1H) , 10.01 (s, 1H). (3) Cyclohexyl {3-mercapto-l-[ 4-(trifluorodecyloxy)phenyl]-1H-indazole 182 321426 201029996 -4-yl} sterol The same method as in Example 1 (6) was used to treat the above-mentioned synthesized 3__mercapto-1-[4-(disorganomethoxy)phenyl]_; [[}-〇 than sal-4-pyruic acid ( 2 6 g), the title compound (2.2 g, 72%). </ RTI> <RTIgt; 2 Hz, 2H), 7.66 (d, J=9. 2 Hz, 2H), 7.77 (s, 1H) (4)3-[({4-[(cyclohexyl){3-曱基+[4-(三一甲Oxy)phenyl]-lH-t-s-yl}methyl)amino]phenyl}-decyl)amino]propanoic acid The same procedure as in Example 1 (7) was used, using the ring synthesized above. Hexyl{3-mercapto-1-[4-(trifluoromethoxy)phenyl]-indole-pyrazole-4-yl} decyl alcohol (〇.59g) and the synthesis of Example 1(2) -{[(4-aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0. 55 g), m. , DMSO-de) (5 ppm 0.85-2. 11 (m, ΠΗ) φ 2.24 (s, 3H), 2.39 (t, J=7. 2 Hz, 2H), 3.30-3.43 (m, 2H), 4.20 (t, J = 7.6 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 8.3 Hz, 2H), 7.34-7. 61 (m, 4H), 7 82 (d J=9. 1 Hz, 2H), 8. 02 (br. s., 1H). Example 2 6 3-[({4_[(cyclohexyl){3-mercapto-1-[4-( Trifluoromethoxy)phenyl]]111-oxazol-4-yl}methyl)amino]phenyl}alkyl)(methyl)amino]propionic acid 321426 183 2010 29996

The cyclohexyl {3-methyl-1-[4-(trifluorodecyloxy)phenyl]-1 fluorene-pyrazole-4 synthesized in Example 25 (3) was used in the same manner as in Example 1 -Based on methanol (0.97 g) and 3-{[(4-aminophenyl)carbonyl](indolyl)aminopropionic acid ethyl ester (0.63 g) obtained in Example 2 (2). The title compound (1.3 g, 63%) was obtained as a white solid. H NMR (300 MHz, DMSO-de) d ppm 0.89-2.06 (m, 11H), 2.24 (s, 3H), 2.40 (t, J=7. 0 Hz, 2H), 3.28-3.45 (m, 5H), 4.20 (t, J=7.8 Hz, 1H), 6.34 (d, J=7. 6 Hz, 1H), 6.58 (d, J = 9.1 Hz, 3H) [(Cyclohexyl{3-fluorenyl-l-[4-(trifluoromethyl)phenyl]-1H_pywa-4-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3 曱 1 [4 (2 曱 曱) phenyl] 1 1 _ 〇 0 0 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 _ _ _ _ _ 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用3) Methyl 3-methyl-1 oxime-pyrazole-4-carboxylate synthesized (8.9 phantom crude product and 4_trifluoro 184 321426 201029996 nonylphenylboronic acid (13.3 g) gave the title as a white solid Target compound (2.0 g, 11%). H NMR (300 MHz, CDCls) δ ppm 2.56 (s, 3H), 3.87 (s, 3H), 7.72 (d, J = 9.2 Hz, 2H), 7.82 (d, J=9. 2 Hz, 2H), 8.41 (s, 1H). (2) 3-mercapto-l-[4-(trifluoromethyl)phenyl]-lH-e is sitting at 0 4-decanoic acid The above-prepared 3-mercapto-1-[4-(trifluoromethyl)phenyl]-1H-0-pyrazole-4-treazone was treated in the same manner as in Example 1 (5). The title compound (0.6 g, 30%) was obtained as a pale yellow solid..H NMR (300 MHz, CDCh) δ ppm 2.56 (s, 3H), 7.72 (d, J =9.0 Hz, 2H), 7.82 (d, J=9. 0 Hz, 2H), 8.40 (s, 1H), 9.98 (s, 1H). (3) Cyclohexyl {3-mercapto-1 - [4 -(Trifluoromethyl)phenyl]-1H-pyrazol-4-yl}nonanol The above-mentioned synthesized 3_mercaptopurine-1-[4-(two) was treated in the same manner as in Example 1 (6). Fluorinyl The title compound (0.7 g, 93%) was obtained as a pale yellow solid. H NMR (300 MHz, CDCh) δ ppm 0. 90-1. 98 (m, 11H), 2.34 (s, 3H), 3.53-3.69 (m, 1H), 4.46 (d, J=7. 〇Hz, 1H), 7.67 (d, J=9.0 Hz, 2H), 7.77 (d, J=9. 0 Hz, 2H), 7.85 (s, 1H). 5 (4) 3-[({4-[(cyclohexyl){3-indolyl-i_[ 4_(trifluoromethoxy) Phenyl]-1H-indole-4-yl}indenyl)amino]phenylindoleyl)amino]propanoic acid The same procedure as in Example 1 (7) was used, using the cyclohexyl 321426 synthesized as described above. 185 201029996 {3-mercapto-l_[4-(trifluoromethyl)phenyl]-1Η~〇 is synthesized by β-s--4-yl} decyl alcohol (0.36 g) and Example 1 (2) 3-{[(4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.33 g), m. (300 MHz, DMSO-de) δ ppm 0.90-2.12 (m, 11H), 2.26 (s, 3H), 2.41 (t, J=7.2 Hz, 2H), 3.23-3.44 (in, 2H), 4.22 (t, J=7. 6 Hz, 1H), 6.36 (d, J=7.9 Hz, 1H), 6.60 (d, J=8.9 Hz, 2H), 7.52-7.80 (m, 4H), 7.93 ( d, ® J=6.0 Hz, 2H), 7.97-8. 10 (s, 1H). Example 28 3-[({4-[(cyclohexyl{3-methyl-l-[4-(trifluoromethyl)phenyl]-1H-indazol-4-yl}fluorenyl)amino] Phenyl}carbonyl)(methyl)amino]propionic acid

Using the same procedure as in Example 1 (7), the cyclohexyl {3-methyl-1-[4-(trimethylmethyl)phenyl]-1H-0-by-azole _4 synthesized in Example 27 (3) was used. Base of decyl alcohol (0.36 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester (0.40 g) synthesized in Example 2 (2), The title compound (0.20 g, 35%) was obtained as a white solid. NMR NMR (300 MHz, DMSO-de) δ ppm 0.81-2.10 (m, 11H), 2.28 (s, 3H), 2.42-2.50 (m, 2H), 2. 90 (s, 3H), 3. 52 ( t, J=7.3 Hz, 2H), 4.18 (t, J=7. 5 Hz, 1H), 6.26 (d, 321426 186 201029996 J=7. 7 Hz, 1H), 6.59 (d, J=8. 7 Hz, 2H), 7.11 (d, J=8. 7 Hz, 2H), 7.80 (d, 2H), 7.94 (d, J=8. 5 Hz, 2H), 8.43 (s, 1H). Example 29 3-[({4-[(cyclohexyl){3_(methoxymethyl)-1-[5-(trifluoromethyl)acridin-2-yl]-1Η-Πΐ^σ sits _4_ base }methyl)amino]phenyl}alkyl)amino]propionic acid

(1) 3-(methoxymethyl)- 1-salt-4-s-acid oxime ester 4-methoxyacetamidineacetic acid methyl ester (25·0 g) and dimercaptocarhamamine dimethyl A mixture of acetal (22.9 mL) was stirred at 1 °C for 2 hours and the mixture was cooled to room temperature. Ethanol (250 mL) and hydrazine monohydrate (8.3 mL) Q were added to the reaction mixture and the mixture was heated to reflux for 12 hours. After the mixture was allowed to cool, the reaction mixture was concentrated under reduced pressure and water was added to residue. The mixture was extracted with ethyl acetate to give a crude product (25.08 g) of dec. This compound can be used directly in the next reaction. JH NMR (300 MHz, CDCh) δ ppm 3.51 (s, 3H), 3.84 (s, 3H), 4.85 (s, 2H), 7.99 (s, 1H). (2) 3-(methoxycarbonyl) -l-[5-(Trifluoromethyl)pyridin-2-yl: carbazole-4-carboxylic acid decyl ester 187 321426 201029996 In the same manner as in Example 1 (4), the above-mentioned synthesized 3_(oxygen) was used. The title compound (5.2 g, m.p.), m. 38%). H NMR (300 MHz, CDCh) d ppm 3.54 (s, 3H), 3.89 (s, 3H), 4.83 (s, 2H), 7.90-8.36 (in, 2H), 8.70 (s, 1H), 9.06 (s , 1H). (3) 3-(methoxydecyltrifluoromethyl)acridine-2-yl]-lH-° is treated in the same manner as in Example 1 (5). 3-(decyloxyindenyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid vinegar (5.2 g) synthesized as described above Light yellow solid, title compound 0.9 g, 40 !H NMR (300 MHz, CDCh) δ ppm 3.53 (s, 3H), 4.83 (s, 2H), 8.05-8.25 (m, 2H), 8.72 (s, 1H) , 9.11 (s, 1H), Q 10. 10 (s, 1H). (4) Cyclohexyl {3-(methoxymethyl)-l-[5-(trifluoromethylpyridin-2-yl) -1H-pyrazol-4-yl}methanol The above-prepared 3-(decyloxymethyl)_1-[5-(trifluoromethyl)pyridine-2 was treated in the same manner as in Example 1 (6). -1H-pyrazole-4-furaldehyde (1.9 g) gave the title compound (2.4 g, 99%) as an oil. NMR (300 MHz, CDCh) ppm 0.90-2. (m,11H),3.02 (d, J=6. 0 Hz, 1H), 3.46 (s, 3H), 4.43 (dd, J=7. 7, 6.0 Hz, 1H), 4.52-4.69 (m, 2H) ), 7.93-8.11 (m, 2H), 8.44 188 321426 20102999 6 (S,1H), 8. 65 (s,1H). (5) 3-[({4-[(cyclohexyl){3-(methoxymethylbu[5_(trifluoromethyl)) 〇 Pyridinium _2 基 心 比 唾 唾 ) ) ) ) ) ) 唾 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- (Methoxymethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl} decyl alcohol (1.2 g) and Example 1 (2) The title compound (0.19 g, 10%) was obtained as a white solid. NMR (300 MHz, DMSO-de) δ ppm 1. 90-2. 10 (m, 11H), 2.40 (t, J = 7. 2 Hz, 2H), 3.24-3.45 (m, 5H), 4.28-4.71 (m, 3H), 6.37 (d, J=8. 9 Hz, 1H), 6.64 (d, J=8. 9 Hz, 2H), 7. 51 (d, J=8. 9 Hz, 2H), 8. 00 (d, J=8. 9 Hz, 2H), 8. 33 (dd, J=9. 0, 2. 3 Hz, 1H). Example 30 〇3-[({4-[( Hexyl {3-(decyloxyindenyl)-l-[5-(trifluoromethyl)pyridin-2-yl]-1H-. Bisazo-4-yl}methyl)amino]phenyl}carbonyl)(indenyl)amino]

According to the same method as in Example 1 (7), the 189 321426 201029996 synthesized by the example 29 (4) was used. The cyclohexyl {3-(decyloxy fluorenyl)-l-[5-(trifluoromethyl group V bite- 2-yl]-1H-pyrazol-4-yl}methanol (1.2 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino group synthesized in Example 2(2)} Ethyl propionate (1. 〇S) gave the title compound (0. Π g, 8%) as a white solid. NMR (300 MHz, DMSO-de) δ ppm 0.89-2.09 (m, 11H), 2.40-2.52 (m, 2H), 2.89 (s, 3H), 3.33 (s, 3H), 3.51 Ct, J=7. 3 Hz, 2H), 4.28-4.74 (m, 3H), 6.27 (d, J =8.7 Hz, 1H), 6.64 (d, J=8.7 Hz, 2H), 7.09 (d, J=8. 7 Hz, ® 2H), 8.01 (d, J=8.9Hz, 1H), 8.33 (dd, J=9. 0, 2. 3 Hz, !H), 8.58 (s, 1H), 8.83 (s, 1H). Example 31 3~U(4-{[{l-[3-chloro-5- (Trifluoromethylpyridin-2-yl]-3-indenyl-1H-pyrazol-4-yl}(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino}propionic acid

(1) 1~[3-gas_5_(dimethylmethyl)π is 0-but-2-yl]-3_mercapto-1Η_ο than 0 decanoic acid methyl ester according to the same method as in Example 1 (4) Methyl-1H-pyrazole-4-carboxylate (3.8 g) and 2,3-dichloro-5-trifluoromethylpyridine (5.8 g) synthesized in Example 1 (3). The title compound (7. 〇g, 78%) was obtained as a pale yellow solid. 321426 190 201029996 ]H NMR (300 MHz, CDCh) d ppm 2.60 (s, 3H), 3.88 (s, 3H), 8.16 (d, J=1.5 Hz, 1H), 8.67-8.72 (m, 2H). 2) l-[3-Chloro-5-(tris-decyl)pyridine-pyridin-2-yl]-3-methyl-lH-e than saliva- 4-曱.Awake at 0°C' Diisobutylaluminum hydride (1.5 M solution in toluene, 58.4 mL) was added dropwise to the above-prepared 1-[3-chloro-5-(trifluoromethyl)β-buty-2-yl]-3-indole A solution of decyl-pyrazole-4-carboxylic acid decyl ester (7.0 g) in tetrahydrofuran

0 (150 mL). After stirring for 30 minutes, the reaction mixture was poured into 2N hydrochloric acid &lt;RTIgt; The extract was dried over magnesium sulfate and the solvent was evaporated. The residue was treated in the same manner as in Example 1 (5) to give the title compound (1.7 g, 27%). !H NMR (300 MHz, CDCh) δ ppm 2.63 (s, 3H), 8.19 (s, 1H), 8.70-8.73 (m, 2H), 10.07 (s, 1H). (3) {l-[3- Chloro-5-(trifluoromethyl)"pyridin-2-yl]-3-indolyl-1?-»biazole~4-yl}(cyclohexyl)methanol oxime in the same manner as in Example 1 (6) The above-prepared 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-indolyl-1H-pyrazole-4-furaldehyde (1.7 g) was obtained to give The title compound of the title compound (1.5 g, 66%). !H NMR (300 MHz, CDCh) 5 ppm 0. 94-2. 02 (m, 11H), 2.39 (s, 3H), 4.47 (d, J=7. 2 Hz, 1H), 8.05-8.14 (m , 1H), 8.18 (s, 1H), 8.66 (s, 2H). U) 3-{[(4-{[{l-[3-chloro-5-(trifluoromethyl)acridin-2- ]]-3-mercapto-1H-pyrazol-4-yl}(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino}propionic acid 191 321426 201029996 by the same method as in Example 1 (7) Using the above synthesized {1-[3- gas-5-(trifluoromethyl)pyridin-2-yl]-3-indolyl-1H-pyrazol-4-ylindole (cyclohexyl)methanol (0 74 g) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0. 57 g) synthesized in Example 1 (2), obtained as an amorphous pale yellow solid. Title target compound (0.11 g, 10%). 4 Li R (300 MHz, CDC13) 6 ppm0.91-1.98 (m, 11H), 2. 37 (s, 3H), 2.50-2.72 (ra, 2H), 3.44-3.75 (m, 2H), 4.24 ( d, J=6.2 Hz, 1H), 6.51 (d, J=8. 1 Hz, 2H), 6.66 (br. ϋ v s. , 1H), 6.89 (br. s. , 1H), 7.52 (d, J=8. 1 Hz, 2H), 7.98-8.20 (m, 2H), 8.60 (s, 1H). Example 3 2 3-{[(4-{[{l-[3-气-5-( Third, thiol) hydrazin-2-yl]-3-mercapto-1H-indazol-4-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino} Propionic acid.

Using the same procedure as in Example 1 (7), the compound {1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-1H synthesized in Example 31 (3) was used. -pyrazol-4-yl}(cyclohexyl)methanol (〇. 74 g) and 3-{[(4-aminophenyl)carbonyl](indenyl)amine oxime synthesized in Example 2(2) The title compound (54.4 mg, 5%) was obtained as a pale yellow solid. ]H NMR (300 MHz, CDCL·) δ ppm 0. 94-1. 98 (m, 11H), 2.36 192 321426 201029996 (s, 3H), 2.58-2.74 (m, 2H), 3.04 (s, 3H) , 3.59-3.82 (m, 2H), 4.23 (d, J=6. 0 Hz, 1H), 6.55 (d, J=8.5 Hz, 2H), 7.01 (br. s. , 1H), 7.21 (d, J=8. 5 Hz, 2H), 8.08 (s, 1H), 8.13 (s, 1H), 8.63 (s, 1H). Example 3 3 3 - [({4-[(cyclohexyl){3-(曱 曱 )))-i-[4-(trifluoromethoxy)phenyl]-lH-η-pyrazol-4-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3-(decyloxymethyl)-1-[4-(trifluorodecyloxy)phenyl]-in-»pyrazole-4-carboxylic acid oxime ester is the same as in Example 15 (1) Method using 4-methoxyethyl hydrazide acetate (3.2 g), dimethyl decyl dimethyl acetal (2.9 mL) and 4~ trifluoromethoxyphenyl hydrazine hydrochloride (5.0 g) gave the title compound (3.4 g, 47%). NMR NMR (300 MHz, CDCh) δ ppm 3.46 (s, 3H), 3.89 (s&gt; 3H), 4.70 (s, 2H), 7.37 (d, J=9. 0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 8.08 (s, 1H). (2) 3-(decyloxy)-l-[4-(trifluoromethoxy)phenyl]-1H-oxime _4- The formic acid was treated in the same manner as in Example 1 (5) to give the above-mentioned 3-(methyl 321426 193 201029996-methyl)-1-[4-(trifluoromethoxy)phenyl]-1 fluorene-pyrazole. Methyl 4-carboxylate (3.4 g) gave the title compound ( 2.9 g, 93%, NMR (300 MHz, CDCh) δ ppm 3. 41 (s, 3H), 4. 70 (s, 2H), 7.37-8.08 (m, 5H)' 10.00 (s, 1H). (3) Cyclohexyl {3-(decyloxymethyl)-i_[4_(trifluoromethoxy)phenyl -1H-pyrazol-4-yl}nonanol The 3-(decyloxyindenyl)-1-[4-(trifluorodecyloxy) synthesized as described above was treated in the same manner as in Example 1 (6). Phenyl]_ih-0 is the title compound (2.8 g, 77%) as the title compound (2.8 g, 77%) as a pale yellow solid. 'H NMR (300 MHz, CDCh) 5 ppm 0. 73-2. 28 (m, 11H), 3.41 (s, 3H), 4.30-4.53 (m, 3H), 7.33 (d, J=8.5 Hz, 2H), 7.55-7.75 (m, 3H). (4 ) 3-[({4-[(cyclohexyl) {3- (methoxymethyl) - BU [4- (trifluoromethoxy) phenyl] -1H- roar-4-yl} methyl) amino] phenyl} carbonyl) amino] propionate

In the same manner as in Example 1 (7), the above-prepared cyclohexyl {3-(methoxymethyl)-1-[4-(trifluoromethoxy)phenyl]_1H_0-biazole-4 was used. Methyl methoxide (0.75 g) and 3-{[(4-aminophenyl)methyl]amino}propionic acid ethyl ester (〇. 55 g) synthesized in Example 1 (2), obtained The title compound (〇 43 g, 39%). ]H NMR (300 MHz, DMSO-de) δ ppm 0.90-2.08 (in, 11H), 2.43 (t, J=7.1 Hz, 2H), 3.25-3.49 (m, 5H), 4.29-4.31 (m , 1H), 4.39-4.59 (m, 2H), 6.43 (d, J=8.5 Hz, 1H), 194 321426 201029996 6.63 (d, J-8. 9 Hz, 2H), 7.45-7.58 (m, 4H) , 7.63-7.77 (m, 3H), 7. 94-8. 09 (m, 1H). Example 34 3-[({4-[(cyclohexyl){3-(methoxyindolyl)-l- [4-(Trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}indenyl)amino]phenyl}carbonyl)(indenyl)amino]propionic acid

According to the same method as in Example 1 (7), the cyclohexyl {3-(decyloxyindenyl)-1-[4-(trifluorodecyloxy)phenyl]_1H_ synthesized using Example 33 (3) was used. ° 5-oxazol-4-yl}methanol (0.75 g) and 3-{[(4-aminophenyl)carbonyl](methyl)aminopropionate ethyl ester (合成) synthesized in Example 2 (2) The title compound was obtained as a colorless solid (0.42 g, 39%). NMR (300 MHz, DMSO-de), 5 ppm 0.87-2.12 (m, 11H), 2-40-2.50 (m, 2H) , 2.90 (s, 3H), 3.31 (s, 3H), 3.52 (t, J-7.2 Hz, 2H), 4. 21-4. 36 (m, 1H), 4.36-4.59 (m, 2H)&gt; 6.32 (d, J=8. 7 Hz, 1H), 6.62 (d, J=8. 7 Hz, 2H), 09 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H ), 7· 64-7. 79 (m, 3H). 'Example 35 3~(U4-({cyclohexyl[3-(methoxy)-)-(4-methoxyphenyl) 321426 195 201029996

-lH-t-4-yl]methyl}amino)phenyl]alkyl}amino)propionic acid (1) 3-(methoxymethyl)-1-(4-methoxyphenyl _ιΗ_Pyrazole-4-carboxylic acid methyl ester ❹ In the same manner as in Example 15 (1), 4-methoxymethoxyacetic acid decyl ester (5·8 g), dimethyl decylamine dioxime was used. The title acetal (5. 5 g, 50%) was obtained as a white solid. 'H NMR (300 MHz, CDCh) δ ppm 3.42 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.64 (s, 2H), 7.00 (d, J=9.0 Hz, 2H) , 7.53 (d, J=9.0 Hz, 2H), 8.05 (s, 1H). (2) 3-(decyloxymethyl)-1-(4-methoxyphenylpyrazole_4-furfural处理 The above-prepared 3_(methoxyindolyl)-1-(4-decyloxyphenyl)-ih-indazole-4-carboxylic acid was prepared in the same manner as in Example 1 (5). (2 § g) 'The title compound (2.0 g, 83%) was obtained as a pale yellow solid. NMR (300 MHz, CDCh) δ ppm 3.42 (s, 3H), 3.87 (s 3H), 4.64 (s, 2H ), 7.00-8.05 (m, 5H), 10. 〇〇(Sj JH) (3) Cyclohexyl[3-(methoxymethyl)-indenyl-monomethoxyphenyl)_1H_ than saliva- 4-yl]methanol was treated in the same manner as in Example 1 (6) to give the above-mentioned synthesized 3-(methoxy 321426 196 201029996 fluorenyl)-1-(4-methoxyphenyl to sal-4~·carboxylic acid ( 2 〇g), the title compound (2. 1 g, 77%) was obtained as a white solid. NMR (300 MHz, CDCh) δ ppm 0. 73-2. 28 (m, hh) 3 36 (s, 3H ),3· 86 (s,3H), 4. 30-4. 53 (m,3H),6 97 (d J=8. 9 Hz' 2H), 7.44 (d, J=8.9 Hz, 2H), 7_59 (s,1H) (4) 3-({[4-({cyclohexyl[3-(decyloxymethyl)-bu(4-methoxyphenyl)-IP than 嗤-4-yl]- The same procedure as in Example K7), using the cyclohexyl[3-(decyloxymethyl)-1-(4-methoxy) synthesized as described above. Ethylphenyl to salidyl-4-methanol] (75 g) and 3_{[(4-aminophenyl)carbonyl]amino}propionic acid ethyl ester (0.54 g) synthesized in Example 1 (2) The title compound (0.39 g, 33%) was obtained as a white solid. H NMR (300 MHz, DMSO-de) δ ppm 0.89-2.11 (m, 11H), 2. 44 (t, J = 7. 2 Hz, 2H), 3. 32 - 3. 46 (m, 2H), 3. 80 (s, 3H), 4.22-4.56 (m, 3H), 6.40 (d, J=8. 7 Hz, 1H), 6.62 ❹(d, J=8.9Hz, 2H), 7.04(d, J=9. 0 Hz, 2H), 7. 36-7. 55 (m, 4H), 7.57 (s, 1H), 8. 01 (s, 1H)· Example 3 6 3-[{[4-({cyclohexyl[3-(methoxyindolyl)-p-methoxyphenyl)-yl]methylammonium Phenylfluorenyl}(methyl)amino]propionic acid 197 321426 201029996

Using the same procedure as in Example 1 (7), the cyclohexyl[3-(methoxymethyl)-bu(1)-methoxyphenyl)_1H-pyrazole oxime synthesized in Example 35 (3) was used.

-4-yl]methanol (0.75 g) and 3-{[(4-aminophenyl)carbonyl](indolyl)amino}propionic acid ethyl ester (〇57g) synthesized in Example 2(2), The title compound was obtained as a white solid (0.44 g, 36%). NMR (300 MHz, DMSO-de) ^ ρριη 0.90-2.12 (m, llH) 2.42-2.50 (m, 2H), 2.91 (s, 3H), 3·26 (s, 3H), 3 52 (t, J =7.4 Hz, 2H), 3.80 (s, 3H), 4. 14-4.54 (m, 3h) 6.29 (d, J=8. 5 Hz, 1H), 6.62 (d, J=8. 7 Hz, 2H ), β. 97I 7.19 (m, 4H), 7.44 (d, J = 8.9 Hz, 2H), 7.58 (Sj lH) Example 37 ' 3-({[4-(·{cyclohexyl]3- (曱乳 methyl)-i-phenyl-lH-e than salivation, hydrazinyl}amino)phenyl]carbonyl}amino)propionic acid &amp;

(1) 3-(decyloxyindenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid methyl ester 321426 198 201029996 In the same manner as in Example 15 (1), 4-methoxy B was used.曱 醯 醯 ( ( 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7.9 7. 3 g, 55%). H NMR (300 MHz, CDCh) d ppm 3. 44 Cs, 3H), 3. 89 (s 3H), 4.68 (s, 2H), 7.30-7.70 (m, 5H), 8.08 (s, 1H). 2) 3-(decyloxymethyl)-1-phenyl is treated with saliva-4-decanoic acid in the same manner as in Example 1 (5). The above-mentioned 3 gas methoxymethylmethyl)-benzene was synthesized. Methyl-1H-pyrazole-4-carboxylate (3.5 g) gave the title compound (2. 5 g, 82%). !H NMR (300 MHz, CDCh) δ ppm 3. 45 (s, 3H), 4. 67 (s 2H), 7.40-8.20 (m 6H), 10.08 (s, 1H). (3) -(decyloxymethyl)-1-phenylin-4-yl]methanol The above-prepared 3-(methoxymethyl)-1_phenyl group was treated in the same manner as in Example 1 (6). The title compound (3.1 g, 75%) was obtained as a white solid. ]H NMR (300 MHz, CDCls) δ ppm 0. 73-2. 40 (m, 11H), 3.33 (s, 3H), 4·40 (s, 2H), 4.42-4.55 (m, 1H), 7 . 27-7.7〇(m, 6H). (4) 3-({[4-({cyclohexyl[3-(methoxycarbonyl)-l-phenyl-1H-indole is 0--4- The same procedure as in Example 1 (7), using the cyclohexyl[3-(methoxyindolyl)-1-benzene synthesized as described above --lH-η-pyrazol-4-yl]methanol (〇. 5〇g) and 3-{[(4-aminophenyl)carbonyl]aminopyridinium 321426 199 synthesized in Example 1 (2) The title compound (〇37 g, 46%) was obtained as a white solid. !Η NMR (300 MHz, CDCh) δ ppm 0. 97-2. 17 (m, 11H), 2.58 -2.78 (m, 2H), 3.34 (s, 3H), 3.58-3.76 (m, 2H), 4.21 -4.51 (m, 3H), 6.51-6.71 (m, 3H), 7.36-7.74 (m, 8H). Example 38 3-[{[4-({cyclohexyl[3-(methoxymethyl)) -1_phenyl_111_carbazole_4_yl]methyl}amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid

According to the same procedure as in Example 1 (7), the cyclohexyl[3-(methoxyindolyl)-;i-phenyl-1 Η_σ-biazole-4-yl]methanol oxime 50 synthesized in Example 37 (3) was used. S) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.42 g) synthesized in Example 2 (2). Show compound (0.33 g, 39%). H NMR (300 MHz, CDCls) δ ppm 0. 98-2. 11 (m, 11H), 2.61 '2.79 (m, 2H), 3.07 (s, 3H), 3.34 (s, 3H), 3.72 (t, J=6.5 Hz, 2H), 4.25-4.46 (m, 3H), 6.57 (d, J=8. 5 Hz, 2H), 7. 35-7. 61 (m, 8H). Example 39 3~[ ({4-[(cyclohexyl{3_ethyl-(trifluoromethyl)phenyl)] 321426 200

201029996 F

Zin-4-yl}methyl)amino]phenyl}alkyl)amino]propionic acid

OH (1) decyl 3-ethyl-IH-0 was obtained in the same manner as in Example 1 (3) by using the 3-side oxovalerate (6.5 g). Oil target title compound (7 〇g 91%

〇&gt;H NMR (300 MHz, CDCh), 5 ppml.32 (t, J=7.6 Hz, 3HX 3.02 (q, J=7.6 Hz, 2H), 3.84 (s, 3H), 7.96 ( s, 1H), 11. 28 (br. s., 1H). ' (2) 3-ethyl-H4-(trifluoromethyl)phenyl] ruthenium _4 vinegar vinegar according to the same example π (1) The title compound (6. 0 g, 67%) was obtained as a white solid. mp. (3GG MHz, CDC13) 6 _ 133 (t, J=7 4 Hz, 3h), 2.99 (q, J=7.5Hz, 2H), 3.87 (s, 3H), 7.71_7.74 (m> 2H), 7.82-7.85 (m, 2H), 8,41 (s, 1H) (3) 3-ethyl+[4-(trifluoromethyl)phenyl]_ as in the case of saliva + formaldehyde according to Example Κ 5) The title compound (42 g, 78%) was obtained as a white solid. OMR (300 MHz, CDC13) 5 ppm 137 (t, 4 continents) S.OOCq,&gt;7·4Ηζ, 2H), 7.74_7.77(m,' 2Η),·τ.84_7·π 321426 201 201029996 (m, 2H), 8.42 (s, 1H), 10.03 (s, 1H). (4) Cyclohexyl {3-ethyltrifluoromethyl)phenyl]_1}1_pyrazole_4_yl} sterol According to the same method as in Example 1 (6), the above-mentioned synthesized 3-ethyl 1 [4-(difluoroindenyl)benzyl]-indenyl-σ-pyridin-4-carboxylic acid (Ug) was obtained. The title compound (1.9 g, 91%) was obtained as a white solid. ]H NMR (300 MHz, CDCh) 5 ppm 0.86-1. 43 (m, 8H), 1.52-1.90 (in, 5H), 2.05 (br. s, 1H), 2. 72 (q, J=7. 5 Hz, 2H), ❸ 4·46 (dd, J=7.2, 3.0 Hz, 1H), 7.60-7. 71 (m, 2H), ?. 71-7.82 (m, 2H), 7.86 (s, 1H (5) 3-({4-[(cyclohexyl{3-ethyl-l-[4-(trifluoromethyl)phenyl]-iH-pyrazol-4-yl}fluorenyl)) Phenylhydrazinyl}amino)propanoic acid The same procedure as in Example 1 (7) was used, using the cyclohexyl{3-ethyl-1-[4-(trifluoromethyl)phenyl]- lH-n is more than 嗤-4-yl} decyl alcohol (0.90 g) and 3-{[(4-aminophenyl)carbonyl] synthesized in Example 1 (2) ◎ Amino}ethyl propionate (〇·75 g) 'The title compound (82 mg, 6%) was obtained as white solid. JH NMR (300 MHz, CDCh) δ ppm 0. 09-1. 32 (m, 8H), 1.45-1.83 (m, 5H), 1.93-2.11 (m, 1H), 2.37 (t, J=7.0 Hz, 2H), 2.68 (qd, J=7. 5, 4.0 Hz, 2H), 3.35 (q, J=5. 7 Hz, 2H), 4.23 (t, J-7. 8 Hz, 1H), 6.33 (d , J=7. 9 Hz, 1H), 6.60 (d, J=8. 7 Hz, 2H), 7.52 (d, J=8. 9 Hz, 2H), 7.81 (d, J=8.7Hz, 2H) , 7.87-7.98 (m, 2H), 7.98-8.12 (ra, 1H), 8.43 (s, 1H). 321426 202 201029996 Example 40 3-[({4-[(cyclohexyl){3-ethyl-l -[4-(Trifluoromethyl)phenyl]-1H-0-p--4-yl}indolyl)amino]phenyl}yl)(indenyl)amino]propionic acid

According to the same procedure as in Example 1 (7), the cyclohexylethyltrifluoromethyl)phenyl]-1{]-indolepyrimidin-4-yl} sterol synthesized according to Example 39 (4) was used. 0. 90 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}ethyl propionate as synthesized in Example 2 (2). 85 mg, 6%). 'H NMR (300 MHz, CDCls) δ ppm 0. 88-1. 24 (m, 8H), 1.46-1.80 (m, 5H), 1.92-2.09 (m, 1H), 2.46 (t, J=7.5 Hz , 2H), 2. 68 (qd, J=7.5, 3. 3 Hz, 2H), 2. 98 (s, 3H), 3.50 (t, 1=7.2 Hz, 2H), 4.20 (t, 1=1.4 Hz, 1H), 6.22 (d, ❹ J=7. 7 Hz, 1H), 6. 60 (d, J=8. 5 Hz, 2H), 7. 10 (Mountain J=8. 7

Hz, 2H), 7.81 (d, J=8. 7 Hz, 2H), 7.86-8. 05 (m, 2H), 8.43 (s, 1H). Example 41 3-{[(4-{[( L-Benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino}propionic acid 321426 203 201029996

(1) 1-Benzenyl-3-methyl-1H-pyrazole-4-carboxylic acid oxime ester The 3-methyl-1H-pyrazole-4-carboxylic acid oxime synthesized in Example 1 (3) ester

(5.3 g) and phenylhydrazine bromide (4.6 mL), and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjj % ) ° H NMR (300 MHz, CDCh) δ ppm 2. 48 (s, 3H), 3. 78 (s, ❷ 3H), 5.22 (s, 2H)' 6.96-7.45 (m, 5H), 7.77 ( s, 1H). (2) 1-Benzenyl-3-methyl-1Η-»比ο坐-4-曱酸· In the same manner as in Example 1 (5), the above-mentioned synthesized 1-benzene was used. Methyl decyl-3-methyl-1H-pyrazole-4-carboxylate (5·9 g) gave the title compound (5. Η Leg R (300 MHz, CDC13) in ppm 2. 50 (s, 3H), 5. 25 (s, 2H), 6.96-7.45 (m, 5H), 7. 76 (s, 1H), 9.85 (s , 1H). (3) (1-Benzyl-3-indolylpyrazole-4-yl)(cyclohexyl)methanol The same method as in Example 1 (6) was used, and the above-mentioned synthesized benzal was used. 204 321426 201029996 benzyl-3-mercapto-1H-pyrazole-4-furaldehyde (5.0 g). H NMR (300 MHz, CDCh) S ppm 0. 75-1. 97 (m, 11H) 2 25 (s, 3H), 4.34 (d, J=7.4, 3.3 Hz, 1H), 5.20 (s, 2H) 7. 00-7. 50 (m, 6H). (4) 3 {[(4-{[(l-Benzyl-3-methyl-pyran-4-yl)(cyclohexyl)decyl]amine (phenyl)carbonyl]amino}propionic acid The same procedure as in Example (7) was carried out using the above-mentioned (1-benzoin-3-yl-1H-pyrazol-4-yl) ( Cyclohexyl) decyl alcohol (1 〇g) and ethyl 3-{[(4-aminophenyl)carbonyl]amino phthalic acid ethyl ester (0.62 g) synthesized in Example 1 (2) afforded white solid The title target compound (28. 6 4%). ' JH NMR (300 MHz, DMSO-de) (5 ppm 0.77-2.01 (m, 11H)j 2.12 (s, 3H), 2.38-2.46 (m, 2H), 3.35-3.44 (m, 2H) 3.99-4.21 (m, 1H), 5.11-5.19 (in, 2H), 6.25 (d, J=9. 〇❹ Hz, 1H), 6.52 (d, J=8. 7 Hz, 2H), 7.〇4(dd , J=7. 5,19

Hz, 2H), 7.25-7.60 (m, 6H), 7.99 (s, 1H). Example 42 3 {[(4-{[(1- 曱 曱 一 3 _ _ _ _ _ _ (cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)aminopropionic acid 321426 205 201029996

(1-Benzenyl-3-methyl-1H-indazol-4-yl)(cyclohexyl)methanol (〇··················· 65 〇S) and 3-{[(4-Aminophenyl)carbonyl](methyl)amino}propanoic acid ethyl acetate (0.65 g) synthesized in Example 2 (2), obtained as a white solid. Title target compound (18.2 mg, 2%). NMR (300 MHz, DMSO-de) δ ppm 1. 14-2. 〇〇(br s nfj) 2.13 (s, 3H), 2.38-2.46 (m, 2H), 2.90 (s, 3H) 3 42- 3 60 (m, 2H), 4. 00-4. 17 (m, 1H), 5. 16 (s, 2H), 6 17 (d, J=6.0 Hz, 1H), 6.52 (d, J=8 5 Hz, 2H), 6.95-7.36 (m, 7H), 7.52 (s, 1H). ® Example 43 3-({[4_({cyclohexyl[id, 丨-dimercaptopropyl)_3_ Methyl-1H-indazol-4-yl]fluorenyl}amino)phenyl]sodium}amino)propionic acid

206 1 1 (1,1 monomethylpropyl)_3_methyl_ιη_π than salivary-4_ oleic acid methyl vinegar 2 321426 201029996 The 3-mercapto-1H-pyrazole synthesized in Example 1 (3) -4-acidic acid (10.8 g) was dissolved in acetonitrile (1 〇〇 inL), 2-mercapto-2-butyral (16 3 mL) and p-toluenesulfonic acid monohydrate (4.4 g) were added. The mixture was stirred at 120 ° C for 4 hours in a sealed officer. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract is concentrated under reduced pressure, and the residue is purified by EtOAc (EtOAc) %). H NMR (300 MHz, CDCh) δ ppm 0. 68 (t, J=7. 5 Hz, 3H), ❾ 1.53 (s, 6H), 1.88 (q, j=7. 5 Hz, 2H), 2· 46 (s, 3H), 3.80 (s, 3H), 7.90 (s, ih). (2) 1-(1,1-dimethylpropyl)_3-methyl-1H-pyrazolecarboxaldehyde In the same manner as in Example 1 (5), the above-mentioned synthesized (1' 1-dimercaptopropyl)-3-methyl-1H-pyrazole-tetracarboxylic acid methyl ester (46 g) was obtained. The title compound (3. 〇g, 73%). Η 臓 (3GG MHz, CDC13) 6 〇 68 (t, 5 Hz, 3H), ❹ 1.53 (s, 6H), 1.88 (q, j = 7.5 Hz, 2H), 2 46 (s, 3H), 7 90 (s, 1H), 9.85 (s, 1H). (3) Cyclohexyl [i (1, bis-dimercaptopropyl) _3 monomethyl _lHn4 yl] methanol according to Example 1 (6) In the same manner, the title compound (1.4 g, 32%) was obtained as a white solid, using (1,1-dimethylpropyl)~3-methyl-1HH4-carboxylic acid (3 g). . Surface (10) MHz, CDCl3) d ppm().67(t, M.4Hz, 3H), 0.88-2.GG (m, 13H), 1.52 (s, 6H), 2 24 (s, 3fl), 3 61 207 321426 201029996 (br. s., 1H), 4.34 (dd, J=7. 6, 2.0 Hz, 1H), 7.34 (s, 1H). (4) 3-({[4-({cyclohexyl][ 1-(1,1-Dimethylpropyl 3-methyl- 1H_.pyridin-4-yl]indenyl}amino)phenyl]carbonyl}amino)propionic acid The same as in Example 1 (7) The method of using the above-mentioned cyclohexyl[1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl]methanol (1. 〇g) and Example 1 ( 2) Synthesis of ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.67 g), m. NMR (300 MHz, CDCh) δ ppm 0. 56 (t, J=7. 6 Hz, 3H), 0.88-1.35 (m, 5H), 1.48 (s, 6H), 1.55-1.98 (m, 8H), 2.26 (s, 3H), 2.67 (t, J=5. 9 Hz, 2H), 3.68 (q, J=5.8 Hz, 2H), 4.12 (d, J=6. 1 Hz, 1H), 6.46 (d , J=8.7 Hz, 2H), 6.66 (t, J=6.2 Hz, 1H), 7.19 (s, 1H), 7.53 (d, J=9. 1 Hz, 2H). q Example 44 3-({ [4-({1-[3-cyclopropyl-1-(4-methoxyphenyl)_1}1_11-pyrazole_4_yl]

(1) 3-Cyclopropyl-1-(4-decyloxyphenyl)-ιh-indole-4-indolyl ester according to the same procedure as in Example 15 (1), using 3-cyclopropyl- 3_ sideoxy 321426 208 201029996 methyl propionate (3.7 g), dimethylformamide dimethyl acetal (3.6 mL) and p-methoxyphenyl hydrazine monohydrate (4 7 , obtained The title compound (5.9 g, 84%) is obtained as an oil. HNMR (300 MHz, CDCh) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3.87 (s, 3H), 6.98 (d, J=8. 9 Hz, 2H), 7.41 (d, J=9.〇Hz, 2H), 7. 98 (s, 1H). (2) 3-ring Propyl-1-(4-decyloxyphenyl) 1H-B-pyrazole_4-formaldehyde was synthesized in the same manner as in Example 1 (5) using 3-cyclopropyl-1-(4-oxo) synthesized as described above. Phenyl)-ih-pyrazole-4-carboxylic acid decyl ester (5.9 g) gave the title compound (3.6 g, 68%) as an oil. NMR (300 MHz, CDCh) d ppm 3-1. 73-1. 10 (m, 4H), 1. 87-2.07 (m, 1H), 3.88 (s, 3H), 7.01 (d, J=8. 9 Hz, 2H), 7.44 (d, J =8. 9 Hz, 2H), 8.03 (s, 1H), 10.03 (s, 1H). (3) l-[3-Cyclopropyl-1-(4-methoxyphenyl)_1H_pyrazole _4_ base; I-3_methylbutan-1-ol The above-mentioned 3-cyclopropyl-1-(4-methoxyphenyl)-1Η-pyrazani-4-decanoic acid (1.8 g) was dissolved in tetrahydrofuran (10), and bromine was added dropwise (TC). Isobutylmagnesium (1M in tetrahydrofuran, 12 mL) mp. mp. Ppm 0.36-0.91 (m, 5H), 0.99 (d, J=6.4Hz, 6H), 1.48-1.97 (m, 3H), 3.86 (s, 3H), 4.89-5.05 (ra, 1H), 6.96 (d , J=9. 0 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 7.60 (s, 1H). 209 321426 201029996 (4) 3-({[4-({l-[3- Cyclopropyl-1-(4-methoxyphenyl)_ih-&quot;bisazol-4-yl]-3-mercaptobutyl}amino)phenyl]carbonylguanidino)propionic acid In the same manner as in 1 (7), the above-mentioned synthesized Κ3-cyclopropyl-1-(4-decyloxyphenyl)-1Η-pyrazol-4-yl]_3_mercaptobutanol (0.5) was used. g) and 3-{[(4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.31 g), mp. 3%). 'H NMR (300 MHz, CDCh) δ ppm 0. 42-0. 84 (m, 4H), 0. 99 ® (dd, J = 13.8, 5.7 Hz, 6H), l_60-1.80 (m, 4H), 2.60_ 2.65 (m., 2H), 3.64-3.66 (m. , 2H), 3.84 (s, 3H), 4.69 (s, 1H), 6.55 (d, J=8.5 Hz, 2H), 6.70 (br. s. , 1H), 6.94 (d, J=8.8Hz, 2H), 7.39 (d, J=8. 8 Hz, 2H), 7.50 (s, 1H), 7. 58 (d, J=8.5 Hz, 2H). Example 45 3-[ {[4-({l-[3-cyclopropyl-1-(4-decyloxyphenyl)-iH-« is more than "sitting-4-^yl]-3 -mercaptobutyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid

〇 Q

Using the same procedure as in Example 1 (7), 1-[3-cyclopropyl-1-(4-decyloxyphenyl)-1H-pyrazol-4-yl synthesized using Example 44 (3) 3-methylbutan-1-ol (0.5 g) and 3-{[(4-aminophenyl)carbonyl](indenyl)amino}ethyl propionate synthesized in Example 2 (2) (0.33 g), the title compound (80 mg, 9%) was obtained as white solid. 4 丽1? (300 MHz, CDC13) 6 ppm 0.34-0.90 (m, 4H), 0.99 (dd, J=14.0, 4. 8 Hz, 6H), 1.70-2.00 (m, 4H), 2.71 ( Br. s. , 2H), 3. 10(s, 3H), 3. 74 (s, 2H), 3.85 (s, 3H), 4.68 (br. s. , 1H), 6.55 (d, J=8 7 Hz, 2H), 6. 95 (dd, J=8. 7, 1.3 Hz, 2H), 7.31-7.40 (m, 4H), 7.50 (s, 1H). Example 46 3-({[4 -({cyclohexyl[3-cyclopropyl-1-(4-methoxyphenylpyrazole®-4-yl)indolyl)amino)phenyl]dyl}amino)propionic acid

(1) Cyclohexyl[3-cyclopropyl-1-(4-decyloxyphenyl)-ih-pyrazol-4-yl]nonanol In the same manner as in Example 1 (6), Example 44 was used. (2) 3-Cyclopropyl-1-(4-methoxyphenyl)-ih-pyrazole- 4-carbaldehyde (1.8 g) was obtained as the title compound (2. 1 mg, 85%). ]H NMR (300 MHz, CDCh) δ ppm 0. 29-2. 27 (m, 16H), 3 86 (s, 3H), 4. 57 (dd, J=8. 1, 4.0 Hz, 1H), 6.96 (d, J=9. 〇Hz, 2H), 7.42 (d, J=8. 9 Hz, 2H), 7.59 (s, iH) (2) 3-({[4-({cyclohexyl][3 -cyclopropylmethoxy phenyl) - π - fluorene. -4-yl]methyl}amino)phenyl] benzylamino) propyl hydride in the same manner as in Example 1 (7), used The above-mentioned synthesized cyclohexene 321426 211 201029996 [3-cyclopropyl-1 -(4-decyloxyphenyl)-1 Η-indol-4-yl] decyl alcohol (0.5 g) and examples 1-([4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (0.36 g), m. NMR (300 MHz, CDCh) δ ppm 0. 30-2. 20 (m. , 16H), 2.65 (br. s., 2H), 3.66 (br. s. , 2H), 3.85 (s, 3H), 4.45 (d, J=7. 2 Hz, 1H), 6.55 (d, J=8. 9 Hz, 2H), 6.60-6.69 (m, 1H), 6.94 (d, J=9. 0 Hz, 2H) , 7.38 (d, J = 9.0 Hz, ® 2H), 7.47 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H). Example 47 3-[{[4-({cyclohexyl][ 3-cyclopropyl-1-(4-decyloxyphenyl)pyrazol-4-yl]fluorenyl}amino)phenyl]yl}}(methyl) Yl] propionic acid

According to the same procedure as in Example 1 (7), the cyclohexyl [3-cyclopropyl-1-(4-decyloxyphenyl)-ih-pyrazole-4- synthesized by the example &lt;(I) was used. Methyl alcohol (0.5 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}ethyl propionate (0.38 g) synthesized in Example 2 (2) The title compound of the title compound (0.11 g, 14%). H NMR (300 MHz, CDCL·) &lt;5 ppm 〇. 31-2. 00 (m, 16H) 2 70 -2.74 (m, 2H), 3.10 (s, 3H), 3.74 (t, J=6.5 Hz , 2H), 321426 212 201029996 3.85 (s, 3H), 4.45 (d, J=6. 8 Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6.95 (d, J=9. 0 Hz, 2H), 7.30-7.42 (m, 4H), 7.47 (s, 1H). Example 48 3-({[4-({l-[3-ethyl-1-(4-methoxy) Phenyl)-ιη-π-pyrazol-4-yl]-3-fluorenylbutyl}amino)phenyl]alkyl}amino)propionic acid

(1) 3-Ethyl-1-(4-decyloxyphenyl group) is the same as in Example 15 (1), using 3-methoxy valerate (3) 3 g), dimethyl decylamine dimethyl acetal (3·6 mL) and p-methoxyphenyl hydrazine monohydrate (4.7 g), the title target compound is obtained as an oil. (6. 0 g, 84%) 2. 92 (q, J=7. 3 Hz, 2 Η), 3. 86 (s, 3 Η), 3. 87 (s, 3 Η), 7.00 ( d, J=9.0Hz, 2 Η), 7.31 (d, J=9. 0 Hz, 2 H), 7 99 (s, 1 H). (2) 3-Ethyl-1-(4-methoxy Base phenyl)_1h_d than azole_4_formaldehyde method 'Use the above-prepared 3-ethyl-4-trespetide ester (6. 〇g) to obtain &amp; (4. 0 g, 76%). The same procedure as in Example 1 (5) - 1-U-methoxyphenyl)-1H-pyrazole- 4_; title title compound 321426 213 201029996 H NMR (3〇0 MHz, CDC13) 5 ppm ! 18 (t, J=7. 5 Hz, 3H), 2.92 (q, J=7.5 Hz, 2H), 3.88 (s, 3H), 6. 91-7.08 (m, 2H)' 7. 12 -7.22 (m, 2H), 7.33 (d, J = 9.0 Hz, 2H), 8 03 (s, 1H), 9.97 (s, 1H). (3) l-[3-ethyl-1-(4 -nonyloxyphenyl)_1Η_σ-pyrazole_4_yl]_3-methyl 1-Alcohol The same as in the method of Example 1 (6), using the above-prepared 3-ethylethyl (4-methoxyphenyl oxime (2. ig) to give the title compound as a white solid. (1.2 g 47%) Η 臓 (3GG MHz, CDC13) d ppm 〇98 (6H, d,1=6.4 Hz), 1.06(3H, t, J=7. 6 Hz), 1.50 (1H, d, J=4. 3 Hz), I.59-1.96 (3H,m)' 2. 70 (2H,q, j=7.5 Hz), 3 86 (3H,s), 4. 77(1H, dt, J =8. 1, 5.1Hz), 6.97 (2H, d, J=8. 9 Hz), 7.31 (2H, d, J=8.9 Hz), 7. β〇(m, s). (4) 3- ({[4-({1-[3-ethyl-1-(4_decyloxyphenyl)_111_11 is more than sal-4_indolyl]_3_mercaptobutylamino)phenyl]carbonyl}amine Propionate using the same procedure as in Example 1 (7), using the above synthesized ethyl-1-(4-methoxyphenylpyrazol-4-yl)-3-methylbutan-1-ol (0. 5g) and 3_{[(4-aminophenyl)carbonyl]amino}propionic acid ethyl acetate (0.41 g) synthesized in Example 1 (2) to obtain the title target as a white solid Compound (0.2 g, 25%). H NMR (300 MHz, CDCh) δ ppm 0.93-1. 20 (m, 9H), 1.70-1.90 (m, 3H), 2.63 (d, J=6. Hz, 4H), 3.67 (d, J= 5. 5 Hz, 2H), 3.84 (s, 3H), 4.48 (t, J=6. 8 Hz, 1H), 6.58 321426 214 201029996 (d, J=8. 1 Hz, 2H), 6.65-6.80 ( m, 1H), 6.95 (d, J = 8.9 Hz, 2H), 7.25-7.79 (m, 5H). Example 49 3-[{[4-({l-[3-ethyl-i-(4 -Methoxyphenylpyrazole-4-yl]-3-methylbutyl}amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid

Ch3 Ο

In the same manner as in Example 1 (7), 1 was synthesized in Example 48 (3) [3 ethyl-1-(4-methoxyphenyl)-pyridin-4-yl]-3-oxime Butyl-1-ol (0.5 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester (0.44 g) synthesized in Example 2 (2), The title compound (0.1 g, 12%) was obtained as a white solid. H NMR (300 MHz, CDCh) δ ppm 0.90-1.09 (m, 9H) 1.70-1.80 Cm, 3H), 2.59-2.81 (m, 4H ), 3.11 (s, 3JJ) 3.74 (t, J=6. 5 Hz, 2H), 3.86 (s, 3H), 4.41-4.57 (m 1H), 6.55 (d, J=8. 7 Hz, 2H) , 6.97 (d, J=8. 9 Hz, 2H), 7.25-7.36 (m, 4H), 7.53 (s, 1H). Example 50 3-({[4-({cyclohexyl][3-ethyl -1-(4-decyloxyphenyl)-1{1-indenyl-4-yl]methyl}amino)phenyl]aminoindolyl)propionic acid 321426 215 201029996

Ch3 (1) cyclohexyl[3-ethyl-1-(4-methoxyphenyl)_1Η_σ-biazole-4-yl]nonanol was used in the same manner as in Example 1 (6), using Example 48 ( 2) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . HNMR (300 MHz, CDCls) δ ppm 0. 82-2. 18 (m., 12H), 2.66 (q, J=7. 6 Hz, 2H), 3.86 (s, 3H), 4.34 (dd, J= 8. 2, 3.7

Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.57 (s, 1H). (2) 3-({[4-({cyclohexyl) [3-ethyl(4-methoxyphenyl)_1H-pyridin-4-yl]fluorenyl}amino)phenyl] anthranilyl) ruthenium propionate In the same manner as in Example 1 (7), Using the above synthesized cyclohexyl[3-ethyl-1-(4-methoxyphenyl)_1H-pyrazole-4-yl]methanol (〇5 magic and 3-{ synthesized in Example 1 (2) [(4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (0.38 g), ield (m. ) (5 ppm 0.93 (t, J=?.5 Hz, 3H), 1.02-2.07 (m, 11H), 2.64 (t, J=7.3 Hz, 4H), 3.58-3.74

(m, 2H), 3.84 (s, 3H), 4.20 (d, J = 7.0 Hz. m R 321426 216 201029996 (d, J=8. 7 Hz, 2H), 6.61-6.72 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 7.25-7.55 (m, 5H). Example 51

3-[{[4-({cyclohexyl[3-ethyl-l-(4-methoxyphenyl)_1H-indole is more than 〇-4-yl]methyl}amino)phenyl]carbonyl} Methyl)amino]propionic acid

Using the same procedure as in Example 1 (7), the cyclohexyl[3-ethyl-1-(4-decyloxyphenyl)-ih-pyrazol-4-yl group synthesized in Example 50 (1) was used. Methanol (0.5 g) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester (0.40 g) synthesized in Example 2 (2) to afford white The title compound of the title compound (0.15 mg, 18%). H NMR (300 MHz, CDCh) δ ppm 0.94 (t, J=7.5 Hz, 3H), ® ^01-2.11 (m&gt; i2H), 2.56-2.83 (m, 4H), 3.09 (s, 3H) , 3·73 Ct, J=6.4Hz, 2H), 3.85 (s, 3H), 4.19 (d, J=6. 8 Hz&gt; !Η), 6.54 (d, J=8.7 Hz, 2H), 6.96 ( d, J=8. 9 Hz, 2H), 7.27-7.37 (m, 4H), 7.48 (s, 1H). Example 5 2 cyclohexyloxyphenyl)- 3-(1-methylethyl ) _1H~n than saliva~4-yl]methyl}amino)phenyl]alkyl}amino)propionic acid 217 321426 201029996

(1) 1-(4-Methoxyphenyl)-3-(1-methylethyl)-indole-indole. Sit-4-Restoric acid oxime ester Ο

In the same manner as in Example 15 (1), 4-methyl-3-oxo-methoxypentanoate (3.6 g), dimethylformamide-didecyl acetal (3.5 mL) and p-Methoxyphenyl sulfonium monosulfate (4.5 g) gave the title compound (3.5 g, 51%). H NMR (300 MHz, CDCh) δ ppm I.37 (d, J=6. Hz, 6H), 3.20-3.40 (m, 1H), 3.86 (s, 3H), 3.90 (s, 3H), 6.98 (d, J=9.0 Hz, 2H), 7.27 (d, J=9.0 Hz, 2H), 7.29 (s, 1H), 7.99 (s, 1H). (2) 1-(4-decyloxyphenyl) One 曱 乙基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 The title compound (2U4%) was obtained as a sub-coloring solid. H NMR (300 MHz, CDCh) δ ppm 1. 37 (dj J=7 〇^ 6H)5 3-12-3.25 Cm, 1H), 3.88 (s, 3H), 7.01 (d, J=9. 0 Hz , HX 7.29 (d, J = 9.〇Hz, 2H), 8.05 (s, lH), 10.06 (s, methoxyphenyl)-3-(1-methylethyl)_1H - mouth 321426 218 201029996 -4-yl]nonanol was synthesized in the same manner as in Example 1 (6) using the above synthesized (4_methoxyphenyl)-3~(ι-methylethyl)_m4 · 3 g), to obtain the title compound (1.4 g, _. ιΗ 臓(10) 〇, CDCl3) 5ppmG.81_2.2i(m,i8H), 3 〇8 (quint, &gt;7.2 Hz, 1H), 3.86 (s, 3H), 4.52 (dd, J=8. 7, 3·8 HZ, 1H), 6.96 (d, J=9.0 Hz, 2H), 7.27 (d, J=9.0 Hz , 2H), 7. 59 (s, 1H). ❹(4)3-({[4-({cyclohexyl[b(4_foxyphenyl)_3_(b-methylethyl)-1H-indol-4-yl]) Amino]phenyl]ethyl}amino)propanoic acid The same procedure as in Example 1 (7) was used, using the above-mentioned cyclohexyl[1-(4-methoxyphenyl)-3-(1) -methylethyl)-1H-pyrazole-4-yl]methanol (〇·70 g) and 3_{[(4-aminophenyl)carbonyl]amino}propionic acid synthesized in Example Κ2) Ester (0.52 g), to obtain the title compound as a white solid of the target (0. 34 g, 30%). ❹ H NMR (300 MHz, CDC13) &lt;5 ppm 1. 10 (d, J=7.2 Hz, 3H), 1.18 (d, J=7.2 Hz, 3H), 1.20-2.06 (m, 12H) ), 2.64 (t, j=5.5 Hz, 2H), 3.10 (quint, J=7.3 Hz, 1H), 3.66 (q, J=5. 8 Hz, 2H), 3.85 (s, 3H), 4.37 (d , J=7. 2 Hz, 1H), 6.57 (d, J=8. 7 Hz, 2H), 6.61-6.74 (in, 1H), 6.94 (d, J=8. 7 Hz, 2H), 7.20- 7.58 (m, 5H). Example 53 3-{[4-({cyclohexylmethoxyphenyl)_3_(1-methylethyl)-IHH4-yl]methyl}amino)phenyl] }}(mercapto)amino]propionic acid 321426 219 201029996

The cyclohexyloxyphenyl)_3_(1-methylethyl)__1H-pyrazol-4-yl]methanol (〇 synthesized in Example 52(3) was used in the same manner as in Example 1 (7). .7〇g) and 3_u(4-aminophenyl)phenyl](indenyl)amino}ethyl propionate (〇·55 g) synthesized in Example 2(2) to obtain white The title compound of the title compound (0.28 g, 24%). H NMR (300 MHz, CDCh) δ ppm 1. Π (d, J=6. 8 Hz, 3H)

Ll9 (d, J = 7.2 Hz, 3H), 1.20-2· 13 (m, 11H), 2.72 (t J = 6.1 Hz, 2H), 3.03-3.23 (m, 4H), 3.73 (t, J = 6 6 2H), 3.85 (s, 3H), 4.36 (d, J = 7.2 Hz, 1H), 6.55 (廿J = 8.3 Hz, 2H), 6.95 (d, J = 9. 1 Hz, 2H), 7.21 -7.35 (m 4H), 7.50 (s, 1H). '® Example 54 ^U[4-({l-[l-(4-methoxyphenyl)-3-(1-methylethyl) )_1H-pyridin-4-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propionic acid

321426 201029996 (1) Bu [1-(4-methoxyphenyl)_3_(1 -methylethyl) 1H-carbazole _4_ yl]_3_methylbut-1-ol as Example 1 ( In the same manner as in 6), 1-(4-decyloxyphenyl)-3-0-methylethyl)- 1H-pyrazole-4-furfural (1.3) synthesized in Example 52 (2) was used. g) 'To obtain the title compound (1.6 g, 98%) as a white solid. NMR NMR (300 MHz, CDCh) ^ ppm 0&gt; 99 (d&gt; J=5. 7 Hz, 6H), !·28 (dd»J=17. 0, 7.2 Hz, 6H), 1.75-1.98 (m, 2H), 2. 99-3. 19 (m, 1H), 3.86 (s, 3H), 4.96 (dd, J=8. 4, 4.4

Hz, 1H), 6. 97 (d, J=8. 9 Hz, 2H), 7.26 (d, J=9.0 Hz, 2H), 7.62 (s, 1H). (2) 3-({[4- ({l-[l-(4-methoxyphenyl)_3_(1-fluorenylethyl)-1H-pyrazol-4-yl]-3-methylbutyl}amino)phenyl]carbonyl Amidino)propionic acid was synthesized in the same manner as in Example 1 (7) using the above-mentioned synthesis of -(4-methoxyphenyl)-3-(1-methylethyl)-indole-β ratio. Zin-4-yl]-3-methylindole-I-ol (〇.57g) and 3-{[(4-aminophenyl)carbonyl]amino}propyl synthesized in Example 1(2) The title compound (28.0 mg, 3%) was obtained as a white solid. NMR (300 MHz, CDCI3) 5 ppm 0.97 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 1.11-1.98 (in, 9H), 2.67 (t, J = 5.7 Hz 2, 2, 2, 3, 3. ), 6.51-6.77 (m, 3H), 6.95 (d, J=8. 9 Hz, 2H), 7.26-7.59 (m, 5H). Example 55 321426 221 201029996 3-[{[4-({l -[ 1-(4-methoxyphenyl)_3_(1-indenylethyl)_11](_0-pyrazol-4-yl]-3-methylbutyl}amino)phenyl]carbonylindole ( Mercapto)

03⁄4 In the same manner as in Example 1 (7), the compound of Example 54 (1) was used to form [1-(4-methoxyphenyl)-3-(1-methylethyl)- 1Η-pyrazole-4-yl]-3-methylbutan-1-ol (〇·57 g) and 3-U(4-aminophenyl)carbonyl] synthesized in Example 2(2) The title compound (8. ,, 1%) of the title compound was obtained as a white solid. ^ NMR (300 MHz, CDCh) &lt;5 ppm 0.97 (d, J = 6. 6 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H), 1.11-2.01 (m, 9H), 2.72 (br s., J=6.0 Hz, 2H), 2.96-3.24 (m, 4H), 3.74 (br. s., J=6.〇Hz, 2H), 3.86 (s, 3H), 4.63 (d, J =6. 0 Hz, 1H), ® 6.50-6.70 (m, 2H), 6.96 (d, J=8. 9 Hz, 2H), 7.21-7.38 (m, 4H), 7.59 (br. s., 1H Example 56 3~[(U-[(cyclohexyl{i-ethyl-3-trifluorodecyl)phenyl; salam-5-yl}fluorenyl)amino]phenylindenyl)amino ]propionic acid 222 321426 201029996

(1) Ethyl-3-(4-[4-indenyl)phenyl]-1-[4-(trifluoromethyl)phenyl]ethanone (12.0 g) It is dissolved in ethanol (1 mL) and sodium hydride is added carefully under ice cooling, oily, 2.8 ❻S. After stirring for 5 minutes, diethyl oxalate (8.7 mL) was added, and the mixture was stirred at room temperature overnight. The precipitate was collected (18.6 g), and ethanol (16 mL), 6N hydrochloric acid (4.3 mL) and acetonitrile (1.6 g) were added to the precipitate of 7.3 g, and the mixture was stirred at room temperature. Overnight. The solvent was evaporated under reduced pressure and the residue was purified ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced room. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc !H NMR (300 MHz, CDCh) 1. 50 (t, J=7.2 Hz, 3H), (5 ppm 1.42 (t, J=7.2 Hz, 3H), 4. 39 (q, J= l. 2 Hz, 2H), 4. 66 (q, J=7.2 Hz, 2H), 7.17 (s, 1H), 7.65 (d, J=8. 1 Hz, 2H), 7. 92 (d, J =8. 1 Hz, 2H). (2) 1-Ethyl-3-[4~(trifluoromethyl)phenyl]_1H-pyrazole_5_formaldehyde to only use Example 1 (5) Method using the above synthesized hydrazine _ethyl-3-[4-(trimethylmethyl) phenylpyrazine-pyrazole-5-carboxylic acid ethyl ester (5 7 illusion ' to obtain the title target as a white solid Compound (3 2g, 68%) 223 321426 201029996 】 OMR (_MHZ, CDCl3hppml48 (t, j = 72Hz 3H), 4.25 (q, J-7. 2 Hz, 2H), 6.85 (s, 1H), 7. 54 (d, J=8.0

Hz, 2H), 7.77 (d, J=8. 〇Hz&gt; 2H), 10.01 (s, 1H). (3) % hexyl{1-ethyl-3-[4~(trisyl)phenyl ]_1H_nbiazole_5_yl} sterol The same procedure as in Example 1 (8) was used, and the above synthesized 1-ethyl-3-[4-(trimercapto)phenyl phenyl 1 Η 唾 + + 甲 骏 (2 28 g) to give the title compound (12 g, 41%). 1OMR_MHz, CDCl3) (5ppm〇92_2〇〇(m,11H), i39 (t, J=7.2Hz, 3H), 2.27 (d, J=4.7 Hz, 1H), 4.00-4.25 (m, 2H), 4.53 (dd, J=6. 4, 4. 7 Hz, 1H), 6.23 (s, 1H), 7.53 (d, J=7.9 Hz, 2H), 7.72 (d, J=7.9 Hz, 2H). ( 4) 3-[({4-[(cyclohexyl)U_ethyl_3-[4-(trifluoromethyl)phenyl]-lH-t-s--5-yl}methyl)amino]phenyl} Alkyl]amino]propanoic acid The same procedure as in Example 1 (7) was carried out using the above-mentioned cyclohexyl fluorene U-ethyl 3-[4-(trifluoromethyl)phenyl b 1H-pyrazole-5-yl group. Methanol 6 g) and 3_{[(4-aminophenyl)carbonyl]amino}propionic acid ethyl acetate (0.42 g) synthesized in Example 1 (2) to give the title compound (0. 18 g, 20%). ° NMR (300 MHz, CDCh) δ ppm 0.97-1.27 (m, 11H), i 33 (t, &gt;7.3 Hz, 3H), 2.68 (t, J=5. 5 Hz, 2H), 3. 59-3'8〇(m, 2H), 4.11 (q, j=7.2 Hz, 2H), 4.39 (d, J=6.8 Hz 1H), 6.16 (s, 1H), 6.64 (d, J=8. 7 Hz, 2H), 6.70-6.83 (m, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.58 (d, J=8. 7 Hz 321426 224 201029996 2H), 7.69 (d, J=8 1 Hz, 2H). Example 57 3-[U4-[(cyclohexyl{1-ethyl-3_[4-mono(trifluoromethyl)phenyl) 1Η_πΛ 嗤-5-yl}methyl)amino group ;I phenyl oxime)(fluorenyl)amino]propionic acid r\

Using the same procedure as in Example 1 (7), the cyclohexyl{1-ethyl-3-[4-(trifluoromethyl)phenyl]_1H-pyrazole synthesized in Example 56 (3) was used. 5-amino}methanol (0.6 g) and 3_丨[(4-aminophenyl)carbonyl](indenyl)amino}ethyl propionate (〇·48 g) synthesized in Example 2 (2) The title compound (〇 19 g, 19%) was obtained as a white solid. H NMR (300 MHz, CDCla) δ ppm 0. 92-2. 00 (m, 11H), 1.35 Q Ct, J=7.2 Hz, 3H), 2.62-2.78 (m, 2H), 3.09 (s, 3H) , 3-75 (t, J=6. 6 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 4.39 (d, J=6.6 Hz, 1H), 6.18 (s, 1H), 6.61 (d, J=8.7 Hz, 2H), 7.25 (d, J=8. 7 Hz, 2H), 7.50 (d, J=8. 1 Hz, 2H), 7·70 (d, J=8.1 Hz , 2H). Example 58 3-U{4-[(cyclohexyl{i-ethyltrifluoromethoxy)phenyl]_1H_ ° than sal-5-yl}methyl)amino]phenyl}carbonyl )(mercapto)amino]propionic acid 321426 225 201029996 Ο 〇

(1) 1-Ethyl-3-[4~(trifluorodecyloxy)phenyl]_1Η-pyrazole-5-carboxylic acid ethyl acetonate In the same manner as in Example 56 (1), 1-[ 4-(trifluoromethoxyindolyl)phenyl]ethanone (13. 〇g), sodium hydride (6 〇%, oily, 28, oxalic acid diethyl acetoacetate (8.7 mL) and acetamidine (42 g) To obtain the title compound (19.4 g, 92%) as an oil. 1 〇MR (3〇〇MHz^ C^l3)(5ppraL34-l.53 (,, 6H), 4.24 (d, 1= 1.2 Hz, 2H), 4.23 (q, j=7,2 Hz&gt; 2H), 4.43 (q, J-7. 2 Hz, 2H), 4.45 (d, 1=7.2 Hz, 2H), 6.82 (s, 1H), 7.33 (d, J=9.0 Hz' 2H), 7.44 (d, J=9.0 Hz, 2H)· (2) Diethyl_3-[4-(trifluorodecyloxy)phenyl]_1H-pyridyl The azole-5-furfural was synthesized in the same manner as in Example 1 (5) using the above-mentioned ethyl ethyl [4 (difluorodecyloxy)phenyl]-1H-pyrazole monocarboxylic acid ethyl ester g). The title compound was obtained as a white solid (4.9 liters, then J = 7.3 Hz, 2H), 6.8 〇 (s, 1H), 7 3 〇 _7 58 (m, 4H), 10.00 (s, ih) . =) cyclohexyl u-ethyl trimethoxymethoxy decyl diol 321426 226 201029996 in the same way as in Example 1 (6), used Synthesis of 3-ethyl-Bu [4 (difluoromethoxy) phenyl] Yue acid (2 5g), to obtain the objective of the title compound as a white solid (17g, 54%). Η 臓 (300 MHz, CDC13) (5 qing! 26-2. 00 (m, 11H), 1. 39 (t, J=7. 2 Hz, 3H), 4.12 (d, J=7.2 Hz, 2H) , 4.52 (d, J-6.4Hz, 1H), 6.18 (s, 1H), 7.30 (d, J=8. 7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H). (4) 3 —[(U-[(cyclohexyl U-ethyl(trifluoromethoxy)phenyl]-indole-t-s--5-yl}indenyl)amino]phenyl}alkyl)(indenyl)amine Propionate was used in the same manner as in Example 1 (7), using the above synthesized cyclohexyl {1 ethyl 3 [4 (di-f-methoxy)phenyl]_ιη-π 〇 _5_ 丨Hydroxide (0.39 g) and 3-{[(4-aminophenyl)carbonyl](indenyl)amino}propionic acid ethyl ester (0.32 g) synthesized in Example 2 (2) to give white Title title compound of solid (0. 06 g, 11%). !H NMR (300 MHz, CDCls) δ ppm 0. 99-2. 00 (m, 11H), 1.36 ❹(t,J=7.2 Hz, 3H ), 2·74 (t, J=6.2 Hz, 2H), 3. l〇(s, 3H), 3.74 (t, J=6. 2 Hz, 2H), 4.12 (q, J=7. 2 Hz) , (H, 6H), 6.37 ({4-[(l-{l-ethyl-3-[4-(tris)methoxy)phenyl] is 嗤5-ylindole-3-indolyl) ) Amino] phenyl} few-yl) (Yue-yl) amino] propanoic acid 321 426 227 201 029 996

Ch3 (1) U-ethyl-3-[4-(trifluorodecyloxy)phenyl]_1Hn5j}-3-mercaptobutan-1-ol The same procedure as in Example 1 (6) was used. 1(1), the monoethyl- 3~[4-(trifluorodecyloxy)phenyl]_1H-pyrazole-5-furfural (2.5 g) is dissolved in tetrahydrofuran (2 mL) In, and in Yu. A solution of 1 M bromine isobutylmagnesium tetrahydrofuran (12 mL) was added dropwise to give the title compound (0·9 g, 31%) as an oil. H NMR (3GG MHz' CDC13) 5 〇 98 (d, J = 6 4 Hz, 6H), 1.39 (t, J = 7.2 Hz, 3H), 1.56-1.98 (m, 3H), 2.21 (d, J =4. 3 Hz, 1H), 4.10-4.30 (q, J=7. 2 Hz, 2H), 4. 86 (ddd, J=8.9, 4.7, 4. 3 Hz, 1H), 6.22 (s, 1H ), 7.32-7.50 (m, ❹ 4H). (2) 3-[({4-[(l-{l-ethyl-3_[4_(trifluoromethoxy)phenyl) 1H_carbazole-5 -yl}-3-methylbutyl)amino]phenyl phenylcarbonyl)(fluorenyl)amino]propionic acid The same procedure as in Example 1 (7) was used, using the above-mentioned cyclohexyl 1-{1 Ethyl 3 [4 (disorder methoxy)phenyl] is compared with sal-5-yl 3 -methylbutan-1-ol (〇.39 g) and the synthesis of 3 in the example 2 (2) [ (4-Aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester (0.28 g), m. 'H NMR (300 MHz, CDCh) &lt;5 ppm 0.97 (dd, J=19. 1, 6.2 Hz, 6H), 1.34 (t, J = 7.2 Hz, 3H), 1.55-1.97 (m, 3H), 2. 70 (br. s. , 2H), 3.07 (s, 3H), 3. 73 (br. s., 2H), 4.10 (q, J=7.2 Hz, 2H), 4.61 (t, J=6 8 Hz, 1H), 6.17 (s, 1H), 6.67 (d, J=8.0 Hz, 2H), 7.34-7.49 (m, 6H). Example 60

U(4-{[{3-(benzomethoxy)-i-[4-(trifluoromethoxy)phenyl]_1H_ F

(1) 3-(Benzyloxy)-1-[4-(trifluoromethoxy)phenyl]_1H_indoleazole_4_formaldehyde was used in the same manner as in Example 1 (5), using Epi394154 The title compound (2. 1 g) of the title compound (2. 1 g) was synthesized as a white solid. , 75%).臓(10) MHZ, CDC1〇(5_5.5〇(s,2h),7.27_7.7〇(in' 9H),8.24 (s,1H),10.〇〇(s,1H) ❺ Ο (2){31 Methyl lactyl) 'Bu [4' (trifluoromethoxy)phenyl] ruthen-4-yl} (cyclohexyl) decyl alcohol 321426 229 201029996 - in the same manner as in the case of Example 1 (6) The title compound (19 g, obtained as a white solid) was obtained from the title compound (3 g, EtOAc, m. 76%). Η 臓 (3GG MHz, CDC13) (5 ppm 〇. 92_2· oo (m, 12h), 4. 44 (dd, J=6.8, 5.3 Hz, 1H), 5.36 (s, 2H), 7.26-7.51 (m , 9H), 7.66 (s, 1H). (3) 3-{[(4-{[{3-(Phenyloxy))b!^(trifluorodecyloxy)phenyl]-IP ratio嗤-4-yl}(cyclohexyl)methyl]amino}phenyl)benzyl]amino}propanoic acid The same procedure as in Example 1 (7) was used, using the above synthesized hydrazine 3_(benzyloxy) 1-[4-(trifluorodecyloxy)phenyl]_1H-pyrazole-4-yl}(cyclohexyl)nonanol (0.50 g) and the synthesized 3_ in Example i(2) (4-Aminophenyl) carbonyl]amino}ethyl propionate (0.26 g), m. CDCls) δ ppm 0.78-2.00 (m, 11H), ❹ 2. ^-2. 42 (m, 2H), 3. 30-3· 57 (m, 2H), 4. 14 (d, J=7· 0

Hz, 1H), 5.31 (s, 2H), 6.41 (d, J=8. 5 Hz, 2H), 6.77 (br. s. , 1H), 7.12 (d, J=9. 0 Hz, 2H), 7.29-7.67 (m, l〇H). Example 61 3-{[(4-{[{3-(Phenyloxy))-[4-(trifluoromethoxy)phenyl]-111- 11-pyrazol-4-yl}(cyclohexyl)indenyl]amino}phenyl)carbonyl](methyl)aminopropionic acid 321426 230 201029996

Using the same procedure as in Example 1 (7), the {3-(benzyloxy)-1 -[4_(trifluoromethoxy)phenyl]_1H-oxazole synthesized in Example 60(2) was used. -4-yl}(cyclohexyl)methanol (〇·5〇) and 3_{[(4-aminophenyl)carbonyl](methyl)amino}propanoate B synthesized in Example 2(2) The ester (〇 28 g) was obtained as the title compound ( s, 37 g, 52%). H NMR (300 MHz, CDCh) δ ppm 0. 87-2. 05 (m, 11H), 2.52 (t, J=6.0 Hz, 2H), 2.96 (s, 3H), 3.50-3.78 (m, 2H) , 4.20 (d, J = 6.8 Hz, 1H), 5.25-5.46 (m, 2H), 6.47 (d, J-8. 7 Hz, 2H), 7.12-7.62 (m, 12H). Example 62

3-[({4-[(cyclohexyl{3-methoxyfluorofoxy)phenyl]-lH-snack+yl}methyl)amino]phenyl}indolyl)amino]propionic acid

(1) 3:oxy 1 [4~(trifluoromethoxy)phenyl]-1 Η-° than saliva-4-carboxylic acid in the same manner as in the example "5), as described in W02G07/89031 321426 231 201029996 The method of synthesizing 3-methoxy-1H, sit-4-ethyl carboxylate (4 8 )-methoxyl) base] a, a., * . g), to give the title of a white solid Mesh NMR (300 MHz, CDCh) λ η , 1η τ η , 5 PPm 4. 10 (s, 3Η), 7. 33 (d, J=9.11) Hz, 2H), 7. 69 (d, T~oi „ ΟΪΤ, 9.87 (s, 1H). Μ·1Ηζ, 2H), 8.23(s,1H), =hexyl {3-methoxy (three gas) Methoxy)-4-ylindole methanol

2. The same method as in m(8) was carried out, using the above-mentioned synthesized 3_methoxy = difluoromethoxy)phenyl]valrysin-4-methyl (l.〇g), with k being a white solid title target Compound (15 ^ (br. s., 1H), 4. 〇〇 (s qd\ . , n ^ ^s, 3H), 4.40 (dd, J=7. 0, 4.7 Hz, 1H), 7.24-7.62 (m, 4H), 7.64 (s, 1H). (3) 3-decyloxyl-[4-(difluoromethoxy)phenyl-palladium-sodium pyridostrate is the same as in Example 1 (7) The method of using the above synthesized cyclohexyl {3 methoxy 1 [4 (difluoromethoxy) phenyl] _1 { ^ a. than the ternary base methanol) (〇 · 75 £) and real 丨 丨 (2) _3_丨[(4_Aminophenyl)-reactive]amino}propionic acid B (G. 47 g) to obtain the target compound (0. 10 g, 9%) . HNMR (300 MHz, CDCh) (5 ppm 0. 88-2. 〇〇(m, hh), 2.58 (t., J=6.0 Hz, 2H), 3.54-3.68 (m, 2H), 4.00 (s, 3H), 4.20 (d, &gt;6.6 Hz, 1H), 6.52 (d, J=8. 7 Hz, 2H), 321426 232 201029996 6.56-6.68 (m, 1H), 7.20 (d, J=8. 3 Hz, 2H), 7.48-7.59 (m, 5H). Example 6 3 ] 3_[({4-[(cyclohexyl{3-methoxytrifluoromethoxy)phenyl 1H-~wow_4- (amino)phenyl] adenine) (methyl)amino]propionic acid

/ h丨Ά

VIII. Using the same procedure as in Example 1 (7), the cyclohexyl {3-methoxy-1-[4-(trifluoromethoxy)phenyl]- synthesized in Example 62 (2) was used. Ih_pyrazol-4-yl} decyl alcohol (0.75 g) and 3-{[(4-aminophenyl)carbonyl](indenyl)amino}ethyl propionate synthesized in Example 2 (2) (〇.5〇g) 'To obtain the title compound (0.13 g, 12%) as a white solid. !H NMR (300 MHz, CDCh) δ ppm 0. 90-2. 02 (m, 11H), 2.68 (t, J=6.2 Hz, 2H), 3.05 (s, 3H), 3.71 (t, J=6.4 Hz, 2H), 4.01 (s, 3H), 4.19 (d, J=6.6 Hz, 1H), 6.53 (d, J=8. 7 Hz, 2H), 7.17-7.28 (m, 4H), 7.47-7.61 (m, 3H). Example 64 3-[({4-[(cyclohexyl){3-(1-methylethoxy)-l-[4-(trifluoromethoxy)phenyl]-1H- Oxazol-4-yl}mercapto)amino]phenyl}carbonyl)amino]propionic acid 233 321426 201029996 ο ο

α) 3-(ι-fluorenylethoxy)-bu [4__(trifluoromethoxy)phenyl]_1Η-吼β sit-4-carboxylic acid was used in the same manner as in Example 1 (5), 3-(1-methylethoxy)-[4-(trifluoromethoxy)phenyl]-1H-pyrazole synthesized by the method described in w〇2〇〇7/89〇31❹ Ethyl 4-carboxylate (13 g) was obtained as the title compound (m. H NMR (300 MHz, CDCh) δ ppm 1.33 (d, J=6.2 Hz, 6H), 5.20 (quint, J=6.2 Hz, 1H), 7.03-7.76 (m, 4H), 7.98 Cs, 1H) , 9.78 (s, 1H). (2) Cyclohexyl {3-(1-methylethoxy (Tritonyloxy)phenyl] -1 Η-° than sal-4-yl}methanol oxime. The same procedure as in 1 (6), using the above synthesized 3-(1-methylethoxy)-l-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-4-furaldehyde (0.43) g) to obtain the title compound (〇4〇g, 74%) as an oil. H NMR (300 MHz, CDCh) δ ppm 1. 47-2. 20 (m, 17H), 3.61 (br, s. 1H), 4. 20-4. 40 (m, 2H), 7. 28 (d, J=8. 7 Hz, 2H), 7-57 (s, 1H), 7.74 (d, J=8 7 Hz, 2H). (j) 3_[({4-[(cyclohexyl{3-(1-methylethoxy)-i-[4-(trifluoromethyl)phenyl]pyrazole -4_ylmercapto)amino]phenyl}carbonyl)amino] 234 321426 201029996 Propionic acid The same procedure as in Example 1 (7) was used, using the above synthesized cyclohexyl {3-(ι-methyl) Ethoxy)+[4_(trimyl)phenyl]pyrene-yl-yl}methanol (0.20 g) and the 3-{[(4-aminophenyl)-synthesis synthesized in Example 1(2) Base] 丨 丨 propionic acid B s (Q · 12g), Obtained as a white solid: title object compound (0.11 g, 36%).

, H NMR (3〇° MHz^ CDCl3) 5 ppm 1.00-2.08 (m, 11H) Ml-1.18 (m, 6H), 2.50-2.66 (m, 2H), 3.54-3^70 (m! 2H), 1-4.30 (m, 2.8 Hz, 2H), 6. (s, 1H), 7· 57 (d, J = 8.7 Hz, 2H). Example 65 ^[({4-[(cyclohexyldecylethoxy)+[4_(trifluoromethoxy))

Phenyl]-1Η-»bisazol-4-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propionic acid

The cyclohexyl {3-(1-mercaptoethoxy)-bu [4_(trimethylmethoxy)phenyl] synthesized in Example 64 (2) was used in the same manner as in Example 1 (7).峻 _ _ _ _ _ 曱 曱 〇 〇 〇 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 3 3 和 3 3 3 3 3 3 3 3 13 g) 235 321426 201029996 The title compound (0.11 g, 36%) was obtained as a white solid. NMR (300 MHz, CDCh) 5 ppm 0.97-2.00 (m, 11H) 1.12-1.19 (m, 6H ), 2.53-2.70 (m, 2H), 3.05 (S} 3H) 3.63-3.78 (m, 2H), 4.13-4.29 (m, 2H), 6.57 (d, j=8[

Hz, 2H), 7. 27-7.32 (m, 4H), 7.46 (s, 1H), 7. 72 (d J=8. 9 Hz, 2H). 'Example 66 〇❹ 3-({[4 -({[3-(phenyloxyphenylphenyl)-pyrazole-4-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}amino)propionic acid

(1) 3-(stupylmethoxy)-oxime-phenyl is synthesized in the same manner as in Example 1 (5) by the same method as in Example 1 (5), using 3-methyzine synthesized by the method described in Epl394154. Base) + phenyl-1HH4 - sulphuric acid acetamidine (1.8 g) 'To obtain the title compound 90% as an oil. HNMR (3GQMHZ, _Wppm5.5()(s, 2H), 7.29_7.78 (m, 10H), 8.26 (s, 1H), 9 98 (s, 1H) (2) [, 3 - (benzoquinone) The same method as in the oxybuphenyl](cyclohexyl)methanol for gas two)) ft! (6) 'Use the above synthesized 3-(benzyl)-Buben Christ (4) + formazan 4 g The title compound (1.6 g, 91%) was obtained in the title of 321426 236 201029996. ]H NMR (300 MHz, CDCh) δ ppm 1. 58-2. 20 (m, 12H), 4.44 (dd, J=7.2, 5.3 Hz, 1H), 5.37 (s, 2H), 7.10-7.62 (m, 10H), 7.69 (s, 1H). (3) 3-({[4-({[3-(Benzyloxy)-i-phenyl-iH-indazol-4-yl]) Cyclohexyl)hydrazino}amino)phenyl]carbonylguanidino)propionic acid The same procedure as in Example 1 (7) was used, using the above synthesized [3_(benzene)

曱oxy)-1-phenyl-1Η-»bisoxazol-4-yl](cyclohexyl)methanol (〇. 79 g) and 3-{[(4-amino) synthesized in Example 1 (2) Ethyl phenyl)carbonyl]amino-propionic acid ethyl ester (0.51 g) was obtained to give the title compound (yield: 51 g, 43%) as a white solid. H NMR (300 MHz, CDCh) S ppm 0.84-1.97 (m, 11H), 2.30-2.48 (m, 2H), 3.37-3.58 (m, 2H), 4.18 (d, J=6. 6 Hz, 1H ), 5.24-5.42 (m, 2H), 6.44 (d, J = 8.7 Hz, 2H), 6.66 (br. s., 1H), 7.02-7.63 (m, 13H). Example 67 Methyl}amine^ (yl)}(methyl)amino]propionic acid

OH [3-(benzomethoxy)-1-phenyl-1 Η-pyrazole-4~yl] was used in the same manner as in the example 1 (7), using 321426 237 201029996 in Example 66 (2). (cyclohexyl) decyl alcohol (0.79 g) and 3-{[(4-aminophenyl)carbonyl](indolyl)amino}propionic acid ethyl ester synthesized in Example 2 (2) to obtain white The title compound of the title compound (0. 68 g, 55%). R (300 MHz, CDCla) &lt;5 ppm0.91-2.〇l (m,iiH) 2 71 (d, J=6. 0 Hz, 1H), 3.06 (s, 3H), 3.71 (t, J=6.4 Hz, 2H), 4.23 (d, J=6.6 Hz, 1H), 5.28-5.47 (m, 2H), 6.50

Cd, J=8.7 Hz, 2H), 7.10-7.64 (m, 13H) ❹ consistent application 6 8 3_(U4-(丨-cyclohexyl[1-(4-methoxyphenyl)-3-(morpholine) 4-41-methyl)-1H-indazol-4-yl]methyl}amino)phenyl]perylguanidino)propionic acid

(1) 4-(Morpholin-4-yl)-3-oxobutyrate decanoate in tetrahydrofuran solution of methyl 4-chloro-3-oxobutanoate (27. 1 g) under ice cooling Morpholine (34.5 g) was added to (3 mL). The ice bath was removed and the reaction mixture was shaken to '/jm. for 2 hours. The solvent was evaporated, 1N hydrochloric acid (1 mL) was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc 321426 238 201029996 JH NMR (300 MHz, CDCh) δ ppm 2. 37-2. 55 (m, 4H), 3. 26 (s, 2H), 3. 52 (s, 2H), 3. 70-3. 76 (m, 4H), 3. 74 (s, 3H). (2) 1-(4-decyloxyphenyl)-3-(morpholin-4-ylindenyl)-lH-pyrazole-4 - carboxylic acid oxime ester Addition of dimethyl decylamine-difluorenyl group to 4-(morphin-4-yl)-3-oxobutyric acid hydrazide (7.0 g) as described in (1) Acetal (4.9 mL), and the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was allowed to cool to room temperature, and ethanol (200 mL) and 4-decyloxyphenylhydrazine hydrochloride (6 3 ) were added, and the mixture was stirred at 10 0 C for 3 hours. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified EtOAcjjjjjjjjjjj !H NMR (300 MHz, CDCh) δ ppm 2.44-2.50 (m s) 3.60-3.65 (m, 4H), 3.75 (s, 2H), 3.86 (s, 3H), 3.87 ❹(s,3H), 6 · 97 (d, J=9. 1 Hz, 2H), 7. 68 (d, J=9 1 jjz 2H), 8.03 (s, 1H). ' (3) 1-(4-decyloxyphenyl) -3-(morpholin-4-ylmethyl)__1H_n is more than 〇4_ furfural added to the above (2) in an ice-cooled hydrogenated solution (1.4 g) in tetrahydrofuran (8{) mL) Synthetic 1-(4-methoxyphenyl)_3_(Merline-4-ylhydrazino)-1H-indole-4-weilic acid vinegar (11.3 g) in tetrahydrobite (20 mL). The ice bath was removed and the reaction mixture was stirred at rt. The mixture was further ice-cooled, and water (3.7 mL), a gas oxidized 321426 239 201029996 aqueous solution (18.5 mL) and water (3.7 mL) were added dropwise to terminate the reaction. The residue was filtered through celite, and the filtrate was evaporated to dryness crystals crystals crystals The crude product of pyrazole-4-nonanol (8.5 g). This product was dissolved in toluene (15 mL), manganese dioxide (15 g) was added, and the mixture was heated with a Dean-Stark trap for 30 minutes. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The title compound (7.2 g, 70%) was obtained. H NMR (300 MHz, CDCh) δ ppm 2.44-2. 50 (m, 4H), 3.60-3.65 Cm, 4H), 3.72 (s, 2H), 3.88 (s, 3H), 6.99 (d, J=9 . 1 Hz, 2H), 7.60 (d, J=9. 1 Hz, 2H), 8.08 (s, 1H), 10. 10 (s, 1H). (4) Cyclohexyl [1-(4-methoxy) Phenylphenyl)_3_(? _4_ylmethyl)-indolyl-4-yl]methanol methoxyphenyl) synthesized in the above (3) under ice cooling. ❹-3_(morpholin-4- A solution of cyclohexyl bromide (1 mL, 1 M tetrahydrofuran solution) was added dropwise to a solution of tetramethylfuran (15 mL) in methylene)-iH-pyrazole-4-carbaldehyde (2. g). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1, volume ratio) to give the title compound ( 1. 3 g, 51%). H NMR (300 MHz, CDCh) δ ppm 0.92-2.20 (m, ng) 2.24-2.50 C, 4H), 3. 47 (d, J=12.0Hz, 1H), 3.58-3.73 321426 240 201029996 (m,5H ), 3.87 (s, 3H), 4.43 (d, J = 6.6 Hz, 1H), 6. 10 (s, 1H), 6.98 (d, j = 8.9 Hz, 2H), 7.26 (d, J=8. 9 Hz, 2H), 7.49 (s, 1H). (5) 3-({[4-(4-Methoxyphenyl)-3-(morpholin-4-yl) Cyclohexyl]-1Η-pyrazole-4~yl]fluorenyl}amino)phenyl]carbonyl}amino)propionic acid Cyclohexyl group synthesized in the above (4) at room temperature [1-(4-A) Add sulfoxide chloride to a solution of oxyphenyl)-3-(morpholin-4-ylmethyl)-iH-pyrazol-4-yl]nonanol (〇. 65 g) in tetrahydrofuran (15 mL) 0.37 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with EtOAc EtOAc. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was dissolved in dimercaptoacetamide (15 mL), sodium iodide (〇·37 g), sodium carbonate (0·27 g) and 3-{[ synthesized in Example 1 (2) were added. (4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (0.39 g)' and the mixture was stirred at 70 ° C for 12 hours. After cooling Q, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to afford 3-({[4] -({Cyclohexyl[1-(4-methoxyphenyl)-3-(morpholine-ylmethyl)-1Η-oxazol-4-yl]methyl}amino)phenyl]carbonyl}amine Base) propionic acid B g (0. 35 g). This product was dissolved in ethanol (2 mL) and a 1N aqueous solution of sodium hydroxide (1.5 mL) was added at room temperature, and the mixture was allowed to stand at room temperature for one hour. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (15 mL) was added to the residue. The substrate was washed with water to obtain the title compound 321426 241 201029996 (0. 22 g, 22%) as a colorless solid. ]H NMR (300 MHz, CDCh) (5 ppm 0.92-2.00 (m, 11H), 2.24-2.50 (m, 4H), 2.66 (br s. , 2H), 3.44 (s, 2H), 3.58-3.73 ( m, 6H), 3.85 (s, 3H), 4.47 (d, J=7.2 Hz, 1H), 6.47-6.79 (m, 3H), 6.94 (d, J=8.7 Hz, 2H), 7.26-7.30 (m, 2H), 7.50-7.60 (m, 3H). Example 69 3-[{[4-(4-decyloxyphenyl)-3-(morpholin-4- Methyl) ® -1H-oxazol-4-yl]fluorenyl}amino)phenyl]yl}}(fluorenyl)amino]propionic acid

Cyclohexyl[1-(4-decyloxyphenyl)-3-([#-4-ylindenyl)-1Η-吼 -4--4- synthesized in Example 68(4) at room temperature Add sulfoxide (〇. 37 inL) to a solution of decyl alcohol (0.65 g) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and a saturated aqueous sodium hydrogen carbonate (15 mL) was poured. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was dissolved in dimercaptoacetamide (15 mL), sodium iodide (〇. 37 g), sodium carbonate (〇. 27 g) and 3-{[ synthesized in Example 2 (2) were added. (4-Aminophenyl)carbonyl](methyl)amino}ethyl propionate (0.42 g), and the mixture was stirred at 7 (TC for 12 hours. After cooling at 242 321 426 201029996), water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate, hexane = 1 : 1 'volume ratio) to obtain a pale yellow oil. 3-[{[4-({cyclohexyl[1-(4-methoxyphenyl)_3_(morpholin-4-ylmethyl)-1Η-β-pyrazol-4-yl]fluorenyl) Ethyl)phenyl]peryl}(methyl)amino]propionic acid ethyl ester (0 38 g). This product was dissolved in ethanol (2 mL) and 1N aqueous sodium hydroxide solution was added at room temperature (1) 〇mL), and at room temperature 0. 5 hours, the ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1·〇mL) was added to the residue. The precipitate was washed with water to obtain a colorless solid. Title target compound (0. 12 g, 12%). !H NMR (300 MH z, CDCh) δ ppm 0.89-2.10 (m, 11H), 2.50-2.75 (m, 6H), 3.07 (s, 3H), 3.50-3.85 (m, 6H), 3.88 (s, 3H), 4.17-4.25 (m, 2H), 4.70-4.78 (m, 1H), 6.83 (d, J=8.7 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 7.19-7.35 (m, 4H), 7.77 ( s, 1H). 0 Example 70

3-[{[4-({-cyclomethoxyphenyl)_3_methyl-1H-n than wow-4-yl]methyl}amino)phenyl]carbonyl}( Methyl)amino]propionic acid

(1) 1-(3-Methoxyphenyl)-3-methyl-pyrene-4-pyruvylacetate is dissolved in hydrazine, hydrazine-dimercaptoacetamide (50 mL) Example 1 (3) Zhonghe 243 321426 201029996 into 3-methyl-1H-pyrazole-4-carboxylic acid decyl ester (4.6 g), adding 3-methoxyphenyl boronic acid (1. 0 g), acetic acid Copper (1. 0 g) and a pyridine bit (1 〇. 6 mL) were stirred at room temperature overnight. The mixture was passed through a mixture of diatomaceous earth, 1N hydrochloric acid (1 〇〇 mL) was added to the filtrate, and the mixture was extracted by an assay. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The title compound (3.9 g, 48%) was obtained. ❹ 4 NMR (300 MHz, CDC13) 5 ppm 2· 56 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 6.80-8.33 (m, 5H). (2) 1- (3-methoxyphenyl)-3-indolyl-1H-pyrazole-4-methyl is added to the ice-cooled lithium aluminum hydride (0.6 g) in tetrahydrofuran (8 () mL) (1) A solution of methyl 1-(3-methoxyphenyl)~3-methyl-in-o-pyrazole-4-carboxylate (3.9 g) in tetrahydrofuran (2 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The mixture was again ice-cooled, and water (1.6 mL), 1N aqueous sodium hydroxide (7.8 mL) and water (1.6 mL) were added dropwise to terminate the reaction. The residue was transferred through Shixiazao soil, and the filtrate was concentrated under reduced pressure to obtain 1-(3-methoxyphenyl)-3-methyl-1Η-β than saliva-4 as a pale yellow oil. - crude product of methanol (1.9 g). This product was dissolved in toluene (30 mL), manganese dioxide (3.0 g) was added, and the mixture was heated with a Dean-Stark separator for 30 minutes. The reaction mixture was cooled to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to dryness crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssss -7.40 (m, 4H), 8.32 (s, 1H), 10.00 (s, iH). (3) Cyclohexyl [1-(3-decyloxyphenyl)-3-methyl-1-H-pyrazole _ a 4-tetrahydrofuran solution of 1-(3-decyloxyphenyl)-3-yl-yl-1H-pyrazole-4-furfural (0.62 g) synthesized in the above (2) under ice cooling. 15 mL) dropwise addition of cyclohexylmagnesium bromide (4.3 mL, 1 M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and The mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate, hexane = 1:1, volume ratio) to obtain a pale yellow oil. Title title compound (〇.6〇g, 70%) H NMR (300 MHz, CDCh) δ ppm 0. 90-2. 10 (m, 12H), 2 34 (s, 3H), 3.87 (s , 3H), 4.43 (d, 5=1.2 Hz, 1H), 6.70-7.40 (m, 4H), 7.78 (s, 1 H). (4) 3-[{[4-({cyclohexyl[1-(3-decyloxyphenyl)-3-methyl__1 ugly-1»bicarbazol-4-yl]fluorenyl) }Amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid Cyclohexyl[1-(3-decyloxyphenyl)-3-indolyl-1H synthesized in the above (3) at room temperature a solution of pyrazol-4-yl]methanol (〇·30 g) in tetrahydrofuran (3 mL) was added sulphur chloride (0.11 mL). The mixture was stirred at room temperature for 30 min and cooled with ice and carefully The mixture was stirred with aq. Soluble in dimethylacetamide (5 mL) 'Addition of sodium hydride (0. 23 g), sodium carbonate (0.16 g) and 3 245 321426 201029996 U (4) synthesized in Example 2 (2) -Aminophenyl)carbonyl](indenyl)aminopyridinium propionate (〇25 g), and the mixture was stirred at 70 C for 12 hours. After cooling, water was added to the reaction mixture, and ethyl acetate was added. The mixture is extracted. The extract is concentrated under reduced pressure and passed through a silicone tube. The residue was purified by chromatography (ethyl acetate:hexane = 1:1, vol.) to afford 3 </ s. Ethyl 3-methyl-1H-indole-4-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester (〇·38 g). The product was dissolved in ethanol (3 mL), added 1N aqueous sodium hydroxide (15 mL) at room temperature, and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue. The title compound (0.17 g, 34%) was obtained. H NMR (300 MHz, CDCls) δ ppm 0. 96-2. 03 (m, 11H), 2.35 (s, 3H), 2.70 (t, J=6.2 Hz, 2H), 3.06 (s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.85 (s, 3H), 4.19 (d, J=6. 1 Hz, 1H), 6. 50 (d, J=8. 0 Hz, 2H), 6. 76 (dd, J=7. 8, 2.1 Hz, ❹ 1H), 7.09-7.37 (m, 5H), 7.67 (br. s·, 1H). Example 71 3-[{[4-({[1 -(3-chlorophenyl)-3-methyl-indole-πϋ嗤-4-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid

246 321426 201029996 (1) 1-(3-Chlorophenyl)-3-mercapto-1H~d is more than the salivation of 4-methyl-1H_ synthesized in Example 1(3) Methyl pyrazole-4-carboxylic acid (1.6 g) was dissolved in N,N-dimercaptoacetamide (3 〇mL), and 3-chlorophenylboric acid (3·58 g) and copper acetate (5) were added. 0 g) and pyridine (4. 〇 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjjj NMR (300 MHz, CDCla) δ ppm 2.55 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 6.70-8.35 (m, 5H). (2) 1-(3-chlorophenyl) )_3-曱-lH-n is compared to 〇4_ decanoic acid. The ice-cooled hydrogenation is added to the tetrahydrogenate solution (8 〇mL) of aluminum (0·29 g) in the above (1). A solution of 1-(3-phenylphenyl)-3-indolyl-1H-indazole-4-carboxylate (1.9 g) in THF (20 mL). The ice bath was removed, Q and the reaction mixture was stirred at room temperature for 1 hour. The mixture was ice-cooled, and water (0. 80 mL), 1N aqueous sodium hydroxide (4.0 mL) and water (0.80 mL) were added dropwise to terminate the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give 1-(3-chlorophenyl)-3-indolyl-1? The crude product (0. 65 g). This product was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated with a Dean-Stark separator for 30 minutes. The reaction mixture was cooled to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (m. 247 321426 201029996 H NMR (300 MHz, CDC13) 6 ppm 2 59 (s, 3H), 3 88 (s, 3H), 7.20-7.80 (m, 4H), 8.34 (s, ih), lo.oo (s , ih). (3) Cyclohexyl [1-(3-chlorophenyl)-3-indolyl-1H-pyrazole-4-yl]methanol was synthesized in the above (2) under ice cooling (3) To a solution of _chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.35 g) in tetrahydrofuran (5) was added dropwise cyclohexane magnesium bromide (2.4 mL, 1M in tetrahydrofuran). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjd , 51%). !H NMR (300 MHz, CDCL·) δ ppm 0. 91-1. 97 (m, 12H), 2.33 (s, 3H), 4.44 (d, J=7.2 Hz, 1H), 7.20-7.78 (m, 5H). (4) 3-[{[4-({cyclohexyl[1 -(3_phenylphenyl)-3-indenyl) is a 4-alkyl] fluorenyl}amino)phenyl]carbonyl} (fluorenyl)amino] cesium propionate Cyclohexyl[1-(3-phenylphenyl)-3-indolyl-1H-pyrazol-4-yl]methanol synthesized in the above (3) at room temperature ( Add sulfoxide (〇·10 mL) to a solution of 0.25 g) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with EtOAc EtOAc. The reaction mixture was stirred for 10 minutes' and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine to dryness with sulfuric acid and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 mL) to add 'dissolved sodium (〇. 19 g), sodium carbonate (〇. 13 g) and 3-U synthesized in Example 2 (2) 4-aminophenyl)carbonyl](fluorenyl)amine-propionic acid ethyl acetate (0.20 S) ' and 248 321426 201029996 and the mixture was stirred at 7 (TC for 12 hours. After cooling, water was added to the reaction mixture, And the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain a pale yellow oil. 3-[{[4-({cyclohexyl[1-(3-phenylphenyl)-3-methyl-iH-n ratio n--4-yl]methyl}amino)phenyl]carbonyl }(Methyl)amino]ethyl propionate (〇35g). Dissolve this product in ethanol (3 inL), add 1N aqueous sodium hydroxide solution (5 mL) at room temperature, and stir at room temperature. Mixture 〇. 5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue. The title compound (0.24 g, 58%) was obtained as a colorless solid. 'H NMR (300 MHz, CDCh) δ ppm 0. 91-2. 07 (m, 11H), 2.36 (s, 3H), 2.71 (t, J=6.4 Hz, 2H), 3.07 (s, 3H), 3.72 (t, J=6.4 Hz, 2H), 4.19 (d, J=6.1 Hz, 1H), 6.48 (d, J=8. 7 Hz, 2H), 7. 12-7. 73 (m, 7H). Example 72 〇3-[{[4-({[1-(2-methoxyphenyl)-3-indolyl-1H-pyrazol-4-yl](cyclohexyl)methyl}} Amino)phenyl]mine-based}(indenyl)amino]propionic acid

(1) 1-(2-methoxyphenyl)-3-indolyl-iH-n-pyrazole-4-carboxylic acid methyl ester The 3-mercapto-1Η-πΛα synthesized in Example 1 (3) was taken. -4- 酸酸曱 249 321426 201029996 (7.3g) dissolved in N,N-dimethylacetamide (15 (Ul), adding 2_methoxyphenylboronic acid 05.9 g), copper acetate (18.2 g) and pyridine (Μ mL), and the mixture of lions at room temperature overnight. 1N Hydrochloric acid (10) (6) was added to the mash by a % red mail reaction mixture, and the mixture was extracted with a puzzle. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

H NMR (300 MHz, CDCiU) in ppm 2. 55 (s, 3H) 3 85 (s 3H), 6. 80-8. 50 (m, 5H). (2) 1_(2-methoxybenyl) -3-mercapto-1H-sit-4_carboxylic acid _ In the ice-cooled hydrogenated Zhongming (1.6 g) tetrafurfuran solution (35〇'), add 1-(1) synthesized in (1) above 2-Methoxyphenyl)_3_methyl-1Η-β-pyrazole-4-carboxylic acid methyl ester (10.3 g) in tetrahydrofuran (5 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was mixed with ice, and water (4.2 mL), 1N aqueous solution of hydrogen hydroxide (21. 〇 mL) and water (4.2 mL) were added dropwise to terminate the reaction. The filtrate was concentrated under reduced pressure by a residue of celite to give a pale yellow oil of 1-(2-decyloxyphenyl)-3-methyl-1H-pyrazole-4-methanol. The crude product (2.5 g). This product was dissolved in toluene (50 mL), manganese dioxide 〇 g) was added, and the mixture was heated with a Dean-Stark separator under reflux for a few hours. The reaction mixture was allowed to cool to room temperature&apos; and the dioxane was collected by filtration. The title compound (2.2 g, 87%) was obtained. NMR (300 MHz, CDCU) ά ppm 2.58 (s, 3H), 3.92 (s, 321426 250 201029996 3H), 7.00-7.80 4H), 8.50 (s, 1H), 9. 99 (Sj 1H). (3)裱hexyl [1-(2-methoxyphenyl)_3_methyl-1]{{〇 唾 一 4 4 4 ? 醇 于 于 于 于 于 于 于 于 于 于 于 于 于 21 21 ( ( ( ) 3-methyl-1HL4-Jinjun (1.5 g) tetrahydrogen bite D South solution (15... drops into desertified cyclohexylmagnesium (11.0 mL '1M tetrahydrofuran solution). After completion of the instillation The ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of chlorinated solution was added to the reaction hydrazine mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and passed through a septum column. The residue was purified by ethyl acetate (hexane: hexanes: ield: ield: ield) to give the title compound d. 1 g, phantom, HNMR (300 MHz, CDCla) &lt;;5 ppm〇.90-2.1〇(m,12H), 2.34 (s, 3H),3· 87 (s,3H),4.43 (dd,J=7. 6,3.0 Hz,1H), 7.00 -7.75 (m, 4H), 7.92 (s, 1H). (4) 3-[{[4-({cyclohexyl[1-(2-methoxyphenyl)- 3-indolyl}}1_0 Than ◎ sani-4-yl] 曱a cyclohexyl[i-(2-decyloxyphenyl)-3-indenyl group synthesized in the above (3) at room temperature by an amino)phenyl]phenyl](methyl)amino]propionic acid Add sulfoxide (15 mL) to a solution of -1H-pyrazol-4-yl]nonanol (40 g) in tetrahydrofuran (5 mL). Stir the reaction mixture for 3 min at room temperature and ice cold To the residue, the mixture was stirred for 1 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. Concentration. Dissolve the residue in dimercaptoacetamide (5. 〇mL), add sodium iodide (0.30 g), sodium carbonate (0.21 g) and synthesize 251 321426 201029996 in Example 2 (2) 3-{[(4-Aminophenyl)carbonyl](indenyl)aminopyridinium propionate (〇.33 g), and the mixture was stirred at 70 ° C for 12 hours. After cooling, it was added to the reaction mixture. Water 'and extract the mixture with ethyl acetate. The extract was concentrated under reduced pressure' and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) 3-[ { Μαcyclohexyl[1-(2-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]methyl}amino)phenyl ]carbonyl](indenyl)amino]propionic acid ethyl ester (〇. 1() g). This product was dissolved in ethanol (1. 〇 mL). A 1N aqueous sodium hydroxide solution (1. 0 mL) was added at room temperature and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title compound as a colorless solid ( 〇〇 4g, . . . H NMR (300 MHz, CDCh) δ ppm 0. 83-1. 97 (m, 11H), 2.26 (s, 3H ), 2.69 (br. s. , 2H), 3.03 (s, 3H), 3.62-3.78 (m, 2H), 3.82 (s, 3H), 4.20 (d, J=6. 6 Hz, 1H), 6 93-7. 70 (m, 9H). Q Example 73 3[{[4-({[1-(2-Phenylphenyl)-3-methyl-111_|1 is more than 〇-4-yl) (cyclohexyl) fluorenyl}amino)phenyl]phenyl hydrazine (methyl)amino]propionic acid

(1) Methyl 1-(2-chlorophenyl)-3-indolyl-1H-pyrazole-4-carboxylate 321426 252 201029996 The 3_mercaptopyrene-4 synthesized in Example 1 (3) - Resorcinic acid vinegar (4.5 g) is dissolved in ν, Ν-dimercaptoacetamide (1 〇〇) in the 'addition of 2-chlorophenylboronic acid (1〇· 〇g), copper acetate (11 7 g) and pyridine (10.4 mL) 'and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated. The title compound (2.0 g, 25%) was obtained from EtOAc EtOAc (EtOAc: EtOAc: (300 MHz, CDCh) ^ ppm 2.55 (s, 3H), 3.85 (s, 3H), 6.79-7.40 (m, 5H). (2) 1 -(2-Phenylphenyl)-3-methyl-111 - 〇 〇 -4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A solution of -3-methyl-iH-n in tetrahydrofuran (2 mL) of salicyl- 4-carboxylate (2.0 g). The chills were removed, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was ice-cooled, and water (0.80 mL), 1N aqueous sodium hydroxide (4.0) and water (0.80 mL) were added dropwise to terminate the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to afford crude product of 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-methanol as pale yellow oil. (〇36g). This product was dissolved in toluene (10 mL) and manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark separator for 1 hour. The reaction mixture was cooled to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (yield: 27 g 15%) as a colorless solid. 321426 253 201029996 OMR(3GGMHz, CDC13) 3 _2.59 (s,3H),7 Q〇_7. 7〇(m,4H),8.32 (s,1H),10.02 (s,1H). (3)锿-[1-(2-chlorophenyl)_3_indolyl q-p-salt-4-yl]methanol was synthesized in the above (2) under ice cooling (2_chlorophenyl)_3_indolyl-1H-吼 Wow + cap (G.27g) in tetrahydrogen solution (5mL) was added to the evolution of cyclohexan (2.0 mL, 1M tetrahydrogenate solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjj , 79%). H NMR (300 MHz, CDCla) δ ppm 0. 90-2. 20 (m, 12H), 2.35 (s, 3H), 4.45 (d, J=7.2 Hz, 1H), 7.20-7.60 (m, 4H) , 7.76 (s, 1H). (4) 3-[{[4-({Cyclohexyl][1-(2-phenylphenyl)-3-methyl_1H_0biazole_4_indenyl]methyl}amine Benzyl]phenyl](yl)}(methyl)amino]propionic acid Cyclohexyl chlorophenyl)_3_methyl-1H-indazol-4-yl]methanol (0.29) synthesized in the above (3) at room temperature g) Thionyl chloride (0.11 mL) was added to the tetrahydrofuran solution (5 mL). The reaction mixture was stirred at room temperature for 3 hrs and cooled with ice and then poured sat. The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimethyl acetamide (5.0 mL), and sodium iodide (0.11 g), sodium carbonate (0.15 g) and 321426 254 201029996 in Example 2 (2) were added. 3 {[(4-Aminophenyl)carbonyl](methyl)amino}propionic acid ethyl ester (〇24 g)' and the cake mixture was stirred at 7 °C for 12 hours. After cooling, water was added to the reaction, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = ι: ι, volume ratio) to obtain a pale yellow oil of 3 _[丨[4_ ( {衣己基[1 (2chlorobenyl)-3-methyl_1||-〇 〇 一 a 4-yl] fluorenyl}amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid Ethyl ester (〇·24 g). This product was dissolved in ethanol (2. 〇raL), and aqueous sodium hydroxide (1 〇 fflL) was added at room temperature, and the mixture was stirred for 5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1 mL) was added to the residue. The precipitate was washed with water to give the title compound ( s. 18 g, 37%) as a colorless solid. H NMR (300 MHz, CDCh) δ ppm 0. 94-2. 08 (m, 11H), 2.34 (s, 3H), 2.65-2.80 (ra, 2H), 3.08 (s, 3H), 3.73 (br. s·, 2H), 4.23 (d, J=6.1 Hz, 1H), 6.54 (br. s., 2H), 7.29-7.79 (m, 7H). Q Example 74 3-[{[4-({ Cyclohexyl[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl]methyl}amino)phenyl]carbonyl Kmethyl)amino]propionic acid

(1) 1-(4-Methoxyphenyl)-4-methyl-1Η-0 ratio 0 sitting-3-o-acid vinegar 321426 255 201029996 4-mercapto-1H-pyrazole-3-carboxylate Ethyl acetate (2.58 g) was dissolved in N,N-dimethylacetamide (50 mL), 4-methoxyphenyl boronic acid (5.0 g), copper acetate (6.0 g) and pyridine ( 5. 3 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The extract was washed with brine, dried over magnesium sulfate and evaporated. The title compound (2.7 g, 66%). ® ]H NMR (300 MHz, CDCh) (5 ppm 1.21 (t, J=7. 2 Hz, 3H), 2.33 (s, 3H), 3.85 (s, 3H), 4.22 (q, J = 7.2 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 7. 50 (s, 1H). (2) 1-(4-methoxyphenyl) -4-mercapto-1H-carbazole-3-furaldehyde The 1-(4-oxime synthesized in the above (1) was added to a solution of ice-cooled lithium aluminum hydride (0.40 g) in tetrahydrofuran (20 mL). Oxyphenyl)-4-mercapto-1Η-« than q ° sit-3-oleic acid ethyl ester (2.7 g) in tetrahydrofuran solution (10 mL). Remove the ice bath, and The reaction mixture was stirred at room temperature for 1 hour, and the mixture was cooled with ice, and water (1. 0 mL), 1N aqueous sodium hydroxide (5.0 mL) and water (1. The residue was passed through Shixiazao soil, and the filtrate was concentrated under reduced pressure to give 1-(4-decyloxyphenyl)-4-indolyl-1Η-σ ratio as a pale yellow oil. The crude product of -3-曱Sf· (1. 38 g). This product was dissolved in toluene (30 mL), and then, then, and then, Hours. Allow the reaction mixture to cool to The manganese dioxide was collected by filtration, and the title compound was obtained (yield: s. 96 g, 43%) as a yellow solid. MH NMR (300 MHz, CDCh) δ ppm 2 41 (s 3H) 3 87 (s, 3H), 7.01 (d, J=8.7Hz, 2H), 7.38 (d, J=8. 7 Hz, 2H), 7.55 (s, 1H), 9.88 (s , 1H). (3) Cyclohexyl [1-(4-methoxyphenyl)-4-mercapto-1h_d-pyrazole-3-yl]methanol was synthesized in the above (2) under ice cooling (1) 4 methoxyphenyl)_4_ fluorenyl_111_pyrazole furfural (0.96 g) in tetrahydrofuran (10 mL) was added dropwise cyclohexylmagnesium bromide (6.0 mL 'IM tetrahydrofuran solution). After that, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and chromatograph The title compound (0.70 g, 53%). 'H NMR (300 MHz, CDCh) δ ppm 0. 61-1. 87 (m, 12H), 2.19 ❹(s, 3H), 3·86 (s, 3H), 4.34 (dd, J=9. 7 , 4.4 Hz, 1H), 6.95 (d, J=9. 0 Hz, 2H), 7.32 (d, J=9. 0 Hz, 2H), 7.41 (s, 1H). (4) 3-[{[ 4-({cyclohexyl[1-(4-methoxyphenyl)-4-mercapto-1H-indazol-3-yl]indolyl}amino)phenyl]carbonyl}(methyl)amino group ]] Cyclohexyl [1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl]methanol (〇. 40 g) synthesized by propionic acid in the above (3) at room temperature. Thionium chloride (〇·15 mL) was added to the tetrahydrofuran solution (5 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and EtOAc EtOAc EtOAc. The reaction mixture was stirred for 10 minutes&apos; and the mixture was extracted with ethyl acetate. Wash with saturated brine: the extract was dried over sulphuric acid and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (1 mL), sodium iodide (0.30 g), sodium carbonate (0.11 g) and 3-{3) synthesized in Example 2 (2). [(4-Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (0.34 g), and the mixture was stirred at 70 ° C for 12 hr. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated in a reduced pressure under reduced pressure and the residue was purified via EtOAc (EtOAc: hexanes =j: 1 vol.) to afford a pale yellow oil ({cyclohexyl) [1-(4-Methoxyphenyl)-4-methyl-1H-pyrazol-3-yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester ( 〇. 〇6 g). The product was dissolved in ethanol (1.0 niL), and aqueous sodium hydroxide solution (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 5 hours. Ethanol was distilled off under reduced pressure, and 1N HCl (? mL) was added to the residue. The precipitate was washed with water to give the title compound ( 〇〇 4 g, ❹ 6%) as a pale yellow solid. ]H NMR (300 MHz, CDCh) δ ppm 0. 84-2. 07 (m, 11H), 2.18 (s, 3H), 2.71 (br. s. , 2H), 3.08 (s, 3H), 3.72 ( t, J=6.4 Hz, 2H), 3.88 (s, 3H), 4.24 (d, J=9. 1 Hz, 1H), 6.30 (d, J=8.7Hz, 2H), 6.94 (d, J=8 7 Hz, 2H), 7.10- 7.26 (m, 4H), 7.37 (s, 1H). Example 75 3-[{[4-({cyclohexyl[i-(3_methoxyphenyl))) _曱基_1H_obiazole_3_yl]methyl}amino)phenyl]alkyl}(indenyl)amino]propionic acid 258 321426 201029996

ο ο

Ν Ν CH, , CH' (1) 1-(3-methoxyphenyl)-4-methyl-1 Η-pyrazole-3-carboxylic acid ethyl ester 4-methyl-1 Η-pyrazole-3 - Ethyl carboxylate (2.58 g) was dissolved in hydrazine, hydrazine-dimethylacetamide (50 mL), 3-methoxyphenyl boronic acid (5.0 g), ^ copper acetate (6.0 g) And pyridine (5.3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) NMR (300 MHz, CDCh) &lt;5 ppm 1.43 (t, 1 = 1.2 Hz, 3H), φ 2.37 (s, 3H), 3.87 (s, 3H), 4.43 (q, J=7. 2 Hz, 2H ), 6. 94 -7. 50 (m, 5H). (2) 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-furaldehyde in ice-cooled lithium hydride Ethyl 1-(3-decyloxyphenyl)-4-mercapto-1H-pyrazole-3-carboxylate synthesized in the above (1) was added to a solution of aluminum (0.29 g) in tetrahydrofuran (20 mL) (1) 9 g) in tetrahydrofuran (5 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The mixture was ice-cooled, and water (0.76 mL), 1N aqueous sodium hydroxide (3.8 mL) and water (. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure of 259 321 426 s s s s s s s s s s s s s s - crude product of methanol (〇 99 g). This product was dissolved in toluene (15 mL), manganese dioxide (〇.32 magic) was added, and the mixture was heated with a Dean-Stark separator under reflux for a few hours. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The filtrate was concentrated under reduced pressure to give the title compound (yield: 84g, 54%) as a yellow solid. H NMR (300 MHz, CDCla) d ppm 2.39 (s, 3H), 3.89 (s, 3H), 6.80-7.45 (m, 4H), 7.74 (s, 1H), 10.13 (s, 1H). (3) Cyclohexyl [1-(3-decyloxyphenyl)_4_methyl_1H-pyrazole _ a solution of 3-hydroxy]nonanol in tetrahydrofuran (1,4-methoxyphenyl)_4_methyl-1H-pyrazole-3-furaldehyde (0.84 g) synthesized in the above (2) under ice cooling (1) 〇mL) was added dropwise cyclohexylmagnesium bromide (7.0 mL, 1 M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjj , 52 «. !H NMR (300 MHz, CDCls) δ ppm 0. 99-2. 00 (m, 12H) 2 12 (s, 3H), 3.86 (s, 3H), 4.52 (t, J = 6.6 Hz , lH), 6.75- 7.32 (m, 4H), 7.64 (s, 1H). (4) 3-[{[4-({cyclohexyl[1-(3-decyloxyphenyl)-4)) A cyclohexyl group synthesized in the above (3) at room temperature by a radical of 1 - 3 - methyl}amino)phenyl] benzyl}(fluorenyl)amino]propionic acid (3-Methoxyphenyl) 321426 260 201029996 -4-methyl-1H-pyrazol-3-yl]nonanol (〇. 52 g) in tetrahydrofuran (5 mL) was added with sulphur chloride (0 19 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and then poured th The extract was washed with brine, dried over magnesium sulfate and evaporated. Add sodium hydride (0.39 g), sodium carbonate (0.28 g) and ethyl 3-{[(4-aminophenyl)carbonyl](indenyl)amino}propionate synthesized in Example 2 (2) (〇.38 〇g), and the mixture was stirred at 70 ° C for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and passed through a column. The residue was purified by chromatography (ethyl acetate: hexane = 1:1 vol.) to afford (yield. Methyl-1H-pyrazol-3-yl]fluorenyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (0.16 g) e This product was dissolved in ethanol (2.0 mL) The mixture was stirred at room temperature for 1 hr. To give the title compound as a pale yellow solid ( 〇〇 9 g, 110 / 〇. H NMR (300 MHz, CDCh) δ ppm 0. 97-2. 06 (m, 11H), 2.09 (s, 3H) , 2.73 (t, J = 6. 2 Hz, 2H), 3.08 (s, 3 H), 3.72 (t, J=6.2 Hz, 2H), 3.87 (s, 3H), 4.40 (d, J=7.2 Hz, 1H), 6.62 (d, J=8. 7 Hz, 2H), 6.78 ( Dd, J=7. 8, 2.1 Hz, 1H), 7·10-7·50 (m, 5H), 7.57 (s, 1H) 321426 261 201029996 Example 76 3_[{[4-({cyclohexyl][ 1_(3_曱-oxyphenyl)-4-indenyl-sodium_3_yl]indenyl}amino)phenyl]carbonyl Kmethyl)amino]propionic acid

(1) 3-(methoxyindolyl)-1-(3-methoxyphenylpyrazole-4-carboxylic acid methyl ester) 3-(methoxycarbonyl) synthesized in Example 37(1) Addition of 3-nonyloxyphenylboronic acid to a solution of n-phenyl-1H-pyrazole-4-carboxylic acid decyl ester (2.8 g) in N,N-dimercaptoacetamide (50 mL) (5. 0 g), copper acetate (6.0 g) and pyridine (5.3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and 1N hydrochloric acid (50 mL) was added to the filtrate. The mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane = 1: 2, volume ratio) The title compound (1. 1 g, 23°/〇) was obtained as a pale yellow oil.]H NMR (300 MHz, CDCh) (5 ppm 3.51 (s, 3H), 3.87 (s, 3H) , 3.92 (s, 3H), 4.80 (s, 2H), 7.29-7.93 (m, 4H), 8.37 (s, 1H). (2) 3-(decyloxymethyl)-1-(3-曱Addition of the above (1) in the ice-cooled lithium aluminum hydride (0.25 g) in tetrahydrofuran (10 mL) 262 321426 201029996 A solution of 3-(decyloxymethyl)-1-(3-methoxyphenyl)-1H-d in a ratio of 0 to 4-carboxylic acid (1.1 g) in tetrahydrofurfuryl (5 mL). The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled with ice and water (0. 38 mL), 1N aqueous sodium hydroxide (1.9 mL) and water (0.38 mL) to terminate the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give 3-(s. Crude product of phenyl)-indole-indazole-4-indole (0. 68 g). This product was dissolved in toluene (15 mL). The mixture was heated with a a Dean-Stark separator for 1 hour under reflux. The reaction mixture was cooled to room temperature, and then filtered, and then filtered, and evaporated. 30 g, 32%). H NMR (300 MHz, CDCls) δ ppm 3.50 (s, 3H), 3.88 (s, 3H), 4.80 (s, 2H), 6.91 (dd, J=8. 3, 1.5 Hz, 1H), 7.16-7.49 (m, 3H), 8.40 (s, 1H), 10.07 (s, 1H). q (3) Cyclohexyl [3-(methoxy) 3-(methoxyindolyl)-1-one synthesized by the above (2) under ice cooling with decyl)-1-(3-methoxyphenyl)-lH-indazol-4-yl]nonanol (3-methoxyphenyl)-1Η-pyrazole-4-furaldehyde (0.30 g) in tetrafurfuran solution (5 mL) was added dropwise to cyclohexane magnesium (2.0 mL, 1Μ4 Argon 吱 σ South solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with acetic acid. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain the title target of pale yellow 263 321426 201029996 color oil. Compound (0.40 g, quantitative). NMR NMR (300 MHz, CDCh) 5 ppm 0. 89-2. 21 (m, 11H), 3.04 (br. s, 1H), 3.44 (s, 3H), 3.87 (s, 3H), 4.41 (d, J=7. 7 Hz, 1H), 4. 61 (d, J=3. 6 Hz, 2H), 6. 82 (ddd, J=8. 1, 2. 5, 0.8 Hz, 1H), 7.14- 7.40 (m, 3H), 7.77 (s, 1H). (4) 3 - [{[4-({cyclohexyl[1-(3-decyloxyphenyl)-4-fluorenyl-lH-° ratio Benzyl-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid Cyclohexyl [3-(methoxymethyl)-] synthesized in the above (3) at room temperature Thionyl chloride (〇·14 mL) was added to a solution of 1_(3-decyloxyphenyl)-1Η-«bi-6-yl]methanol (0.40 g) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with EtOAc. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (5.0 mL). Addition of sodium (0.23 g), sodium carbonate (0.18 g), and 3-{[(4-amine) synthesized in Example 2 (2) Ethylphenyl)carbonyl](indenyl)amino}ethyl propionate (0.25 g), and the mixture was stirred at 7 (TC) for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to afford 3-[{[[4] -({cyclohexyl^-(3-methoxyphenyl)_4-methyl-carbazole-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid The ester was dissolved in ethanol (3. 〇mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 5 hours under reduced pressure 321426 264 201029996 The ethanol was evaporated, and 1N-hydrochloric acid (1. 〇mL) was added to the residue. The title compound (yield: 〇7 g, 10%) was obtained as a colorless solid. , CDCla) δ ppm 0. 94-2. 12 (m, 11H), 2.73 (t, J=6.5 Hz, 2H), 3.07 (s, 3H), 3.41 (s, 3H), 3.72 (t, J=6.5 Hz, 2H), 3.85 (s, 3H) , 4.34 (d, J=7.2 Hz, 1H), 4.57 (s, 2H), 6.57 (d, J=8. 7 Hz, 2H), 6.79 (dt, J=8.2, 1.3 Hz, 1H), 7.11- 7.38 (m, 5H), 7.72 (s, 1H). Example 77

3-[{[4-({cyclohexyl[1-(2-methoxyphenyl))-4-yl)- 1H-pyrazole-3-yl]methyl}amino)phenyl]yl}} Amino acid] propionic acid

(1) 1-(2-Methoxyphenyl)-4-mercapto-1H-pyrazole-3-carboxylic acid ethyl acetate 4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (4 〇g) dissolved in N,N-dimercaptoacetamide (30 mL), adding 2-decyloxyphenylboronic acid (7.9 g), copper acetate (9.5 g) and pyridine (8.4) (mL) and stir the mixture at room temperature to isolate the mixture by ♦ soil filtration reaction / tt (compound, add 1 N hydrochloric acid (5 〇 mL) in mash) and extract the mixture with diethyl ether. Wash with extract brine, 1 Drying over magnesium sulfate and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1, volume ratio) to obtain the title of 321426 265 201029996 as pale yellow oil. Target compound (1.6 g, 25%). 4 R (300 MHz, CDC13) (5 ppm 1.41 (t, J = 7. 2 Hz, 3H), 2.37 (s, 3H), 3.87 (s, 3H), 4.43 (q, 1=1.2 Hz, 2H), 7. 00-7.45 (m, 4H), 7. 78 (s, 1H). (2) 1-(2-methoxyphenyl)-4-methyl Adding 1-(2) to the 1-(H)-pyrazole-3-furaldehyde in the ice-cooled sulphuric acid (0. 50 g) tetrahydro D-propanol solution (10 mL) -decyloxyphenyl)-4-mercapto-1H -pyrazole-3-carboxylic acid ethyl ester (1.6 g) in tetrahydrofuran (5 mL). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour, then cooled with ice and then added dropwise. Water (1.3 mL), 1N aqueous sodium hydroxide solution (6.5 mL), and water (1.3 mL) were used to terminate the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure. A crude yellow product of 1-(2-decyloxyphenyl)-4-mercapto-1H-pyrazole-3-nonanol (0. 79 g). The product was dissolved in toluene (20 mL) Manganese dioxide (2.0 g) was added, and the mixture was heated with a Dean-Stark separator for 1 hour under reflux. The reaction mixture was cooled to room temperature, and manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure. The title compound (0.97 g, 70%) was obtained as a yellow solid. JH NMR (300 MHz, CDCh) 5 ppm 2.39 (s, 3H), 3.90 (s, 3H), 7.00-7.45 (m, 3H), 7.64-7.84 (m, 2H), 10.13 (s, 1H). (3) Cyclohexyl [1-(2-methoxyphenyl)-4-mercapto-1H-indazol-3-yl]methanol Synthesis of 1-(2-decyloxyphenyl)-4-mercapto-1Η-σ ratio 0--3-indole in the above (2) under ice cooling (0.97 g) in tetrahydrofuran solution (10 mL) dropwise 266 321426 201029996 Cyclohexylmagnesium bromide (5.0 mL, 1 M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled EtOAc EtOAc EtOAc , 40%). !H NMR (300 MHz, CDCh) δ ppm 0. 99-2. 〇〇(m, 12H), 2.12 (s, 3H), 3.86 (s, 3H), 4.52 (t, J=6. 6 Hz, 1H), 6.75-7. 32 (m, 4H), 7. 64 (s, 1H). (4) 3-[{[4-(丨-cyclohexyl[i-(3-methoxyphenyl))4 _Methyl-1H-indenyl-3-yl]methyl)amino)phenyl]indolyl}(fluorenyl)amino]propionic acid Cyclohexyl group synthesized in the above (3) at room temperature [1- (2-Methoxyphenyl)-4-mercapto-1H-carbazole-3-yl]methanol (5. 45 phantom tetrahydrofuran solution (5 mL) was added with sulfinium chloride (〇. 17 mL). The reaction mixture was stirred at rt for 30 min. </RTI> was cooled with EtOAc. EtOAc (EtOAc) The mixture was dried over magnesium sulfate and condensed under reduced pressure. The residue was dissolved in dimercaptoacetamide (1.OmL), and sodium iodide (0.33 g) synthesized in Example 2 (2) was added. Sodium carbonate (0.24 g) and ethyl 3-{[(4-aminophenyl)carbonyl](indenyl)amino}propanoate (0.38 g), and the mixture was stirred at 70 C for 12 hours. , The reaction mixture was added with water' and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio). 3-[{[4-(丨环267 321426 201029996 hexyl[H2-methoxyphenyl)-4~methyl_1η___3_yl]methyl}amino)phenyl] Base ((methyl)amino] propionic acid ethyl vinegar (〇. 〇 9 g). The product was dissolved in ethanol a 〇 in L) </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Ethyl alcohol was given to the tomb under reduced pressure and QmL of (4) was added to the residue. The title compound (〇.〇6 g, 8%) was obtained as a pale yellow solid. !H NMR (300 MHz, CDCh) δ ppm 0. 98-2. 07 (m, 11H), 2.10 (s, 3H), 2.73 (t, J=6.2 Hz, 2H), 3.09 (s, 3H), 3.72 (t, J=6.2 Hz, 2H), 3.86 (s, 3H), 4.41 (d, J=7.2 Hz, 1H), 6.62 (d, J=8. 3 Hz, 2H), 6.96-7.37 (m , 5H), 7.63 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H). Example 78 3-[{[4-({cyclohexyl[3-ethyl-1-(3_methoxy) Phenylphenyl)_1 ugly-17 than 嗤_4_yl]methyl}amino)phenyl]alkyl}(methyl)amine; Ipropionic acid

(1) 3-Ethyl-1-(3-methoxyphenyl)-methylpyran-4-carboxylic acid methyl ester 3-ethyl-1H-pyrazole-4-synthesis synthesized in Example 39(1) Acid 曱S (2.5 g) was dissolved in ν, Ν-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5. 〇g), copper acetate (6.00) was added. g) and pyridine (5.3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered over Celite, and 1N hydrochloric acid (50 mL) was added to the filtrate, and 268 321 426. The extract was washed, dried over magnesium sulfate, and reduced in compression. The residue was purified by EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) Target compound (2 3 g, 54%) NMR (300 MHz, CDC13) 6 ppm L32 (t,J=7 5 Hz, 3H) 2. 98 (q,J=7. 5 Hz, 2H)' 3.86 ( s, 3H), 3 87 (s 3H) 6.86 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 7. 16-7. 46 (m 3H), 8.32 (s, 1H). ' ' ® (2) 3-Ethylmethoxyphenylpyrazole_4-Ajun in the tetrahydrogen solution (i5mL) of ice-cooled hydrogenated bribe (().34§) is added to the above synthesis (1) - B Base-1-(3-methoxyphenyl)_lH-indole-4-pyreoate A (2.3 g) tetrahydrogen solution (5 (6). Remove the ice bath and give the reaction mixture at room temperature After 丨 hours, it was cooled with ice, and water (0.88 mL), 1N aqueous sodium hydroxide solution (4 4 mL) and water (0.88 inL) were added dropwise to terminate the reaction. The residue was filtered through diatomaceous earth and reduced. The filtrate was concentrated under a pressure of 10 to give 3-ethyl-1-(3-methoxyphenyl to sal. To a solution of toluene (50 mL), sulphur dioxide (4.0 g) was added, and the mixture was heated with a Dean-Stark separator mixture for 1 hour under reflux. The reaction mixture was cooled to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssss q, J=7. 6 Hz, 2H), 3.88 (s, 3H), 6.89 (dd, J=8.3, 1.5 Hz, 1H), 7.11-7.50 (m, 3H), 8.33 (s, 1H) , 10. 〇〇269 321426 201029996 (s, 1H). (3) Cyclohexyl [3-ethyl-1-(3-decyloxyphenyl)- Synthesis of 3-ethyl-1-(3-decyloxyphenyl)-1Η-π-pyrazole-4-carbaldehyde (1.9) in the above (2) under ice cooling with 1Η-pyrazol-4-yl]nonanol g) A solution of cyclohexyl bromide (12.0 mL, 1 M tetrahydrofuran solution) was added dropwise to a tetrahydrogenate solution (20 mL). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous vaporized ammonium solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the title compound ( 2.6 g, quantitative). ] NMR (300 MHz, CDCh) ά ppm 0. 86-1. 98 (m, 14H), 2.71 (q, J=7. 5 Hz, 2H), 3. 60 (br, s., 1H), 3. 87 (s, 3H), 4.44 (d, J=7. 3 Hz, 1H), 6.78 (ddd, J=8. 1, 2.4, 0.9 Hz, 1H), 7. 14-7.38 (m, 3H ), 7. 78 (s, 1H). (4) 3-[{[4-({cyclohexyl[3-ethyl-1-(3-methoxyphenyl)-lH- ratio q azole-4) Synthesis of cyclohexyl[3-ethyl-1-(3-decyloxybenzene) in the above (3) at room temperature at room temperature}amino)phenyl]carbonyl}(methyl)amino]propionic acid Hexylsulfide gas (0.13 mL) was added to a tetrahydrofuran solution (5 mL) of a thiol (0.31 g). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimethylacetamide (10.0 mL), sodium iodide (0.23 g), sodium carbonate (0.15 g) and 3-270 321426 synthesized in Example 2 (2) 201029996 {[(4-Aminophenyl)carbonyl](methyl)amino}ethyl propionate (〇25 g), and the mixture was stirred at 7 (TC) for 12 hours. After cooling, water was added to the reaction mixture. And the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain a pale yellow oil. 3_[{[4-({cyclohexyl[3-ethyl-1-(3-decyloxyphenylpyrazole-4-yl)indolyl)amino)phenyl]carbonyl}(fluorenyl) Amino]ethyl propionate (〇. 16g). This product was dissolved in 0 ethanol (3.0 mL), then aqueous sodium hydroxide (1. 〇mL) was added at room temperature and the mixture was stirred at room temperature 0.5 The title compound (〇12 g, 23%) was obtained as a pale yellow solid (yield: 12 g). H NMR (300 MHz, CDCh) 5 ppm 0. 98-2. 07 (m, 1 4H), 2.62-2·81 (m, 4H), 3.07 (s, 3H), 3.72 (t, J=6.0 Hz, 2H), 3-85 (s, 3H), 4.22 (d, J=5.8 Hz , 1H), 6.51 (d, J=8. 5 Hz, 2H), 6.76 (dt, J=8. 2, 1.2 Hz, 1H), 7. 10-7. 37 (m, ❹ 5H), 7.65 ( s, 1H). Example 79 3-[{[4-({cyclohexyl[i-(3-)oxyphenyl)_3_(1-methylethyl)-1H-pyr-4-yl] Mercapto}amino)phenyl]carbonylindole (fluorenyl)amino]propionic acid

271 321426 201029996 Ο) 1_(3-decyloxybenyl)-3-(propan-2-yl)-1Η-σ ratio 0 -4- -4- ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ (1-methylethyl)-1 Η-pyrazole-4-carboxylic acid decyl ester (2.8 g) was dissolved in ν, Ν-dimethylacetamide (50 mL), 3-methoxyphenyl group was added Butyric acid (5. Og), copper acetate (6.0 gram) and bismuth. (5. 3 mL) ' and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and 1N hydrochloric acid (50 mL) was added to the filtrate and the mixture was extracted with EtOAc. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc JH NMR (300 MHz, CDCla) δ ppm 1.36 (d, J=7. 〇Hz, 6H) 3.56-3.59 (m, 1H), 3.85 (s, 3H), 3.87 (s, 3H), 6.85 (ddd, J-8. 1, 2. 5, 1. 0 Hz, 1H), 7. 18-7. 45 (m, 3H), 8 31 (s, 1H). '

(2) 1-(3-Methoxyphenyl)-3-(propan-2-ylpyrazole-4-furanal was added in ice-cooled lithium aluminum hydride (0.48 g) in tetrahydrofuran (35 mL) A solution of 1-(3-decyloxyphenyl)_3_(propan-2-yl)-1H-pyrazole-4-carboxylic acid methyl ketone (3.4 g) in tetrahydrofuran (15) synthesized in the above (1). The ice bath was removed, and the reaction mixture was stirred at room temperature for a few hours, and water (u.25 mL), 1N aqueous solution, and water (1.25 mL) were sequentially applied to terminate the reaction. The residue was purified by celite, and the filtrate was concentrated under reduced pressure to give y-(3-methoxyphenyl)-3-(propan-2-yl)H as a pale yellow oil. Crude product of 4_sterol (27 321426 272 201029996 g). The product was dissolved in toluene (50 mL), manganese dioxide (3. g) was added, and the mixture was heated with a Dean-Stark separator for one hour under reflux. The reaction mixture was allowed to cool to room temperature&apos; The solvent was evaporated under reduced pressure to give the title compound (26 g, 84%). , !Η NMR (300 MHz, CDCla) δ ppm 1.39 (d, J=6. 8 Hz 6H) 3.48-3.52 (m, 1H), 3.88 (s, 3H), 6.88 (dd, J=7. 2.1 Ο

Hz, 1H), 7.09-7.45 (m, 3H), 8.33 (s, 1H), l〇.〇2 (s 1H). 5 (3)cyclohexyloxyphenyl)-1-3 (prop-2- _基)_1H-pyrazole_4_yl]methanol was synthesized in the above (2) under ice cooling. (3-methoxymethanthine v (propan-2-yl)-s--4-carboxylic acid (2.6 g) To the tetrahydrogen cough solution, cyclohexylmagnesium bromide (15.0 mL, 1 M tetrahydrofuran solution) was added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. The aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. EtOAc (EtOAc m. (300 MHz, CDCla) δ ppm 0.90-2.15 (m, 17H), 3.00-3.20 (m, 1H), 3.86 (s, 3H), 4.46 (d, J=7.6 Hz, 1H), 6.63-7.48 Cm, 4H), 7.77 (s, 1H). (4) 3-[{[4-({3-Hydroxyphenyl)-((diphenyl)ethyl) 1H ° ratio -4- a cyclohexyl group [1 _(3-methoxyphenyl) 321426 273 synthesized in the above (3) at room temperature by a methyl hydrazinyl) phenyl] benzyl hydrazide (methyl) amide] propionic acid 201029996 -3-(prop-2- ) -1Η-0-pyrazol-4-yl] Yue-ol (0. 45 g) of tetrahydro-thiopyran squeak solution (5 mL) was added thionyl acyl chloride (square. 18 mL). The reaction mixture was stirred at room temperature for 30 min, cooled with EtOAc EtOAc EtOAc. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (10. 〇mL), sodium molybdenum (0. 30 g), sodium carbonate (0.11 g) and 3-3 synthesized in Example 2 (2) were added. {[(4-Aminophenyl)benzyl](indenyl)amino}ethyl propionate (〇. 34 ® g), and the mixture was stirred at 70 ° C for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by methylene chloride column chromatography (ethyl acetate: hexane = 1 : 1, volume ratio) to obtain 3-[{[4] -({cyclohexyl[1-(3-decyloxyphenyl)_3_g_indolylethyl) 1H pyrazol-4-yl]fluorenyl}amino)phenyl]carbonyl}(methyl)amino] Ethyl propionate (0.37 g). The product was dissolved in ethanol (5 mL), and a 1N aqueous solution of sodium hydroxide (1. 〇mL) was added at room temperature, and the mixture was stirred at room temperature for 5 hours to evaporate ethanol under reduced pressure. (丨.〇此). The title compound (0·28 g, 38%) was obtained as a pale yellow solid. (10) MHz, CDC1 心卿 G备127(m,nH) i.3〇-1.40 (m, 6H), 2.73 (d, J=6. 0 Hz, 2H), 2.94-3.17 (in, 4H)S 3.73 (d, 1=6.0 Hz, 2H), 3.85 (s, 3H), 4.26 (d, J-6.0Hz, 1H), 6.52 (d, J=8. 7 Hz, 2H), 6.75 (ddd, J= 8. 2, 2.5, 0.9 Hz, 1H), 7.10-7.32 (m, 5H), 7.62 (s, 1H). 321426 274 201029996 Example 80 3-[({4-[{cyclohexyl[3-ethyl] -1-(3-decyloxyphenyl)-1 Η-σ-pyran-4-yl]fluorenyl}(fluorenyl)amino]phenyl}carbonyl)(fluorenyl)amino]propionic acid

3- 3-[{[4-({cyclohexyl[3-ethyl-1-(3-decyloxyphenyl)-fluorene-)--wow---- 4-yl] fluorenyl}amino) benzyl] benzyl} (mercapto)amino] propionic acid ethyl vinegar (1·1 g), hydrazine-dimethylacetamide (5 mL) solution Sodium hydride (〇 16 g) was added, and mothane (0·37 mL) was added after 3 minutes of mixing. The ice bath was removed, and the reaction mixture was stirred at room temperature overnight. A saturated aqueous solution was added and the mixture was extracted with a slat. Wash with brine extract to obtain 3_[(丨4_[{ field hexyl[3-ethyloxyphenyl]pyran-4-yl]methyl}(methyl)amine group as a pale yellow oil ]Phenyl}alkyl)(methyl)amino]propionic acid ethyl vinegar (0.23 g 75%). The product was dissolved in EtOAc (3 mL). Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexanes </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> to give the title compound (0. 10 g, 10%) as a pale yellow solid. 321426 275 201029996 !H NMR (300 MHz, CDCh) δ ppm 0. 94-1. 99 (m, 14H), 2. 17 (s, 3H), 2.72 (q, J=7.4 Hz, 2H), 2.76- 2.90 (m, 2H), 3.07 (s, 3H), 3.75-3.85 (m, 5H), 4.22 (d, J=5. 3 Hz, 1H), 6.50 (d, J=8. 7 Hz, 2H) , 6.76 (d, J=8. 3 Hz, 1H), 7.07-7.43 (m, 5H), 7.65 (s, 1H). Example 81 ❹ 3-[{[4-({cyclohexylΠ-(3 , 5-dimethoxyphenyl)-3-indolyl-1H-indazol-4-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid

(1) 1-(3,5-Dimethoxyphenyl)-3-indolyl-1H-indazole-4-carboxylic acid methyl vinegar 3-ylidene-1H synthesized in Example 1 (3) -0 ~° -4- 几 几 曱 ❹ ❹ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 〇 g), copper acetate (10.0 g) and hydrazine (89 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and 1N hydrochloric acid (50 mL) was added to the mixture, and the mixture was extracted by the mixture. The extract was washed with brine, dried over sulphuric acid and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCh) δ ppm 2.55 (s, 3H), 3.85 (s, 321426 276 201029996 6H), 6.41 (t, J=2. 3 Hz, 1H), 6.83 (d, J=2.3 Hz, 2H), 8.30 (s, 1H). (2) 1_(3,5-Dimethoxyphenyl)_3_methyl_111-11 than 〇 曱 曱 曱 acid · Lithium aluminum hydride in ice cooling (0. 42 g) in tetrahydrofuran solution (35 mL), the 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate synthesized in the above (1) was added. A solution of methyl ester (3.0 g) in tetrahydrofuran (15 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled with ice, and water (1.1 mL), 1N aqueous sodium hydroxide (5. 5 mL) and water (1·1) (mL) to terminate the reaction. The filtrate was filtered through celite, and the filtrate was concentrated under reduced pressure to give a pale yellow oil of 1-(3,dimethoxyphenyl)-3-methyl-1H-pyrazole- The crude product of 4-nonanol (2.7 g). This product was dissolved in toluene (30 mL), manganese dioxide (2· 〇 g) was added, and the mixture was heated with a Dean-Stark separator under reflux for a few hours. The reaction mixture was cooled to rt. ❹ H (30〇MHz' CDCl3) 6 ppm 2. 55 (s, 3H), 3. 85 (s, 6H), 6.44 (s, 1H), 6.82-6.84 (m, 2H), 8.30 (s, 1H ), 9.98 (s, 1H). (3) Cyclohexyl [1-(3'5-dimethoxyphenyl)_3_indolyl_111_carbazole-4-yl]nonanol under ice cooling in the above (2) In the synthesis of Bu (3,5-di-oxyphenyl) _3_methyllu ° than 嗤 + A Jun (2.0 g) of tetrahydrogenate solution (10 mL) dripping into the desertification ring (4) 5.QmL, lM tetrahydro (tetra) solution). The ice bath was removed after completion of the instillation and the mixture was allowed to stand at room temperature for 15 minutes. In the anti-321426 277 201029996 aqueous solution of ammonium chloride, and extracting the mixture of Ethyl acetate in ethyl acetate and purifying the residue 1 by column chromatography (acetic acid acetate hexane m 2, volume ratio) Target compound (2.6 g, 4%). , 兴色油1〇MR(3GGMHz, CDCh) 6 PpmO.89-2. 〇Q(m,12{〇, 2 sin (s,3H), 3.84 (s,6H), 4.40-4.45 (m, 1H), 6 34 (t, J=2.1 Hz' 1H), 6.81 (d, J=2.3Hz, 2H), 7·76 (s, 1H)'

(4) 3-[ {[4-({cyclohexyl[1 -(3,5-dimethoxyphenyl)_3-methyl-1HH4-yl]methyl}amino)phenyl]yl} Synthesis of cyclohexyl[i~(3,5-dimethoxyphenyl)-3-indolyl-1H-indole-4- in (3) at room temperature in (methyl)amino]propionic acid Thionite-brewed chlorine (0.40 mL) was added to a solution of decyl alcohol (1. 〇g) in tetrahydrofuran (20 niL). The reaction mixture was allowed to stand at room temperature for 30 minutes to cool with ice and carefully added saturated hydrogen carbonate steel &gt; trough solution (15 inL). The reaction mixture was scrambled for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (15.0 mL), sodium iodide (0.67 g), sodium carbonate (〇.45 g) and 3-{[() synthesized in Example 2(2) were added. 4-(Aminophenyl)carbonyl](fluorenyl)amino}ethyl propionate (0.75 g), and the mixture was stirred at 70 ° C for 12 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1, volume ratio) to obtain 3-[{[ 4-([cyclohexyl[1-(3,5-dimethoxyphenyl)-3-indenyl)-0-yl]methyl}amino)phenyl]carbonylindole (methyl)amine Base] ethyl propionate (0.74 g). 278 321426 201029996 This product was dissolved in ethanol (5.0 mL), ^ τ τ, ^ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. Ethanol was formed under reduced pressure and 1N hydrochloric acid (3 mL) was added to the residue. The title compound (〇 29%) was obtained as a colorless solid. H NMR (300 MHz, CDCh) δ ppm 〇, gi-2. 〇2 (m, 11H), 2. 35 (s, 3H), 2.70 (br. s., 2H), 3. 06 (s, 3H), 3.71 (t, 1=6.4 Hz, 2H), 3.82 (s, 6H), 4. 18 (d, J=5. 8 Hz, 1H)! 6.32 (t, J=2.2 Hz, 1H), 6.49 (d, J=8.7 Hz, 2H), 6.77 (s, 2H), 7.26 (d, 2H), 7.64 (s, 1H). 'Example 8 2 3-({[4-({cyclohexyl) [ 1-(3,5-Dimethoxyphenyl)_3_methyl_1Η_〇Λ sial-4-yl] fluorenyl}amino)phenyl]alkyl}amino)propionic acid

Cyclohexyl[1-(3,5-diindolylphenyl)-3-methyl-1 fluorene-π ratio σ-spin-4-yl]methanol synthesized in Example 81 (3) at room temperature ( 1.0 g) of tetrazolium solution (20 mL) was added with sulfoxide (0.40 inL). The reaction mixture was stirred at room temperature for 30 min and cooled with EtOAc EtOAc. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried MgSO.sub. The residue was dissolved in dimethylacetamide (15. 〇mL), sodium iodide (〇·67 g), sodium carbonate (0·45 g) and 3-{3 synthesized in Example j (2) were added. [(4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (〇. 70 g) and the mixture was taken at 7 ° C for 12 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain a pale yellow oil. ^"Cyclohexyl D-(3,5-dimethoxyphenyl)-3-methyl-1H-indazol-4-yl]methylnonylamino)phenyl]alkyl}amino)propionic acid Ethyl vinegar (1.3 g). Dissolve this product in ethanol (5.0 mL). Add in sodium hydroxide solution (3.0 inL) at room temperature and smash the mixture to a temperature of 5 hours. The evaporation of ethanol was carried out and hydrochloric acid (3. 〇mL) was added to the residue. The precipitate was washed with water to give the title compound ( 〇. 65 g, 42%) as a colorless solid.]H NMR (300 MHz, CDCh) δ ppm 0. 96-1. 98 (m, 11H), 2.35 (s, 3H), 2.65 (t, J=6. Hz, 2H), 3.66 (d, J=6. 0 Hz , q 2H), 3.80 (Sj 6H), 4.20 (d, J=6. 0 Hz, 1H), 6.31 (t, J=2. 2 Hz, 1H), 6.49 (d, J=8. 7 Hz, 2H), 6. 60 (d, J=6. OHz, 1H), 6.75 (s, 2H), 7.53 (d, J=8. 9 Hz, 2H), 7.62 (s, 1H). Example 83 3 -[{[4-({cyclohexyl[1-(3-ethoxyphenyl)-3_ethyl_1H-carbazole_4_yl]hydrazino}amino)phenyl Carbonyl}(mercapto)amino]propionic acid 280 321426 201029996

(1) Bu (3-ethoxyphenyl)_3-ethyl-1H_° ratio ° sit--4 province &amp; formazan will be synthesized in Example 39 (1) 3_ethyl-^ ratio bite + Methylated acid methyl ester (6.9 g) was dissolved in N,N-dimethylacetamide (150 mL) with oxyphenylboronic acid (15.0 g), copper acetate (16.4 and pyridine (14.05 mL) And the mixture was stirred overnight at room temperature. The reaction milk was filtered through diatomaceous earth.

To the filtrate, 1N hydrochloric acid (7) mL) was added to the filtrate, and the mixture was extracted with ethyl ether. The extract was washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: !H NMR (300 MHz, CDCh) δ ppm 1.32 (t, J=7. 5 Hz, 3H), ❹ 1.44 (t, J=7.0 Hz, 3H), 2.98 (q, J=7. 5 Hz, 2H ), 3. 85 (s, 3H), 4. 10 (q, J=7. 0 Hz, 2H), 6.84 (dd, J=8. 2, 1.6 Hz, 1H), 7. 14-7.43 (m , 3H), 8.31 (s, 1H). (2) 1-(3-Ethoxyphenyl)-3-ethyl_ij|-pyrazole-4-A lithium hydride lithium hydride in the cold part · 61 g) of tetrahydrofuran solution (35 mL) was added to the above-mentioned (1)-diethyl (3-ethoxyphenyl)-3-ethyl-1H-indole. Take 4-hydrogenated methyl vinegar (4.4 g) in tetrahydrogenate solution (15). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour, then 321426 281 201029996 was mixed with ice and water (1.6 mL), 1 N aqueous sodium hydroxide (8.0 mL) was added dropwise. And water (1.6 raL) to stop the reaction. The residue was filtered through celite, and the sluice was concentrated under reduced pressure to afford 1 __(ethoxyphenyl)-3-ethyl-1H-pyrazole-4-methanol as a pale yellow oil. Crude product (3.5 g). The product was dissolved in toluene (100 mL), oxidized (4· 〇 g) was added, and the mixture was heated under reflux with a Dean-Stark separator for 1 hour. The reaction mixture was cooled to room temperature, and then filtered, and then filtered, and then evaporated to give the title compound ( 3.4 g, 87 «. ® H NMR (300 MHz, CDCI3) (5 ppm 1. 29-1. 50 (m,6H), 2.99 (q, J=7.5Hz, 2H), 4.11 (q, J=7. 0 Hz, 2H), 6.88 (ddd, J=8.2, 2.4 , 0.8 Hz, 1H), 7.15-7.45 (m, 3H), 8.32 (s, 1H), 10.00 (s, 1H). (3) Cyclohexyl [1-(3-ethoxyphenyl)_3-B Base-1 h*~d than sit-4-yl] sterol. 1-(3-ethoxyphenyl)_3-indenyl-1Ιί-pyrazole synthesized in the above (2) under ice cooling -4-carbaldehyde (1.7 g) in tetrahydrofuran solution (2 mL) was added dropwise cyclohexylmagnesium bromide (12.0 roL, 1 M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed and at room temperature. The mixture was stirred for 15 minutes. An aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was taken up under reduced pressure and chromatographed on silica gel column (ethyl acetate. : 2, by volume) Purify residue to give the title compound (2.2 g, 96%) !H NMR (300 MHz, CDCh) d ppm 0.79-1. 97 (m, 18H), 2.71 (q, J=7. 5 Hz, 2H), 4. 07-4. 21 (m, 2H) , 4. 44 (dd, J=7. 3, 321426 282 201029996 2. 6 Hz, 1H), 6.77 (dd, J=7. 9, 2.1Hz, 1H), 7.13-7.37 (m, 3H), 7.78 (s, 1H). (4) 3-[{[4-({cyclohexyl[b(3-ethoxyphenyl)-3-ethyl-1H-吼β)-4-yl]fluorenyl} Amino)phenyl][indenyl}(methyl)amino]propionic acid Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H synthesized in the above (3) at room temperature -pyrazole-4-yl]methanol (0. 60 g) in tetrahydrofuran (10 mL) was added sulphur chloride (0. 24 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice and carefully The mixture was stirred for 10 min. In the dimercaptoacetamide (10.0 mL), sodium iodide (0.27 g), sodium carbonate (0.19 g) and 3-{[4 in the synthesis of Example 2 (2) were added. -aminophenyl)carbonyl](fluorenyl)amino}ethyl propionate (0. 45 g), and the mixture was stirred at 70 ° C for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure Q, and residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain 3-[{[ 4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-indazol-4-yl]indolyl}amino)phenyl]carbonyl}(indenyl)amino group ]ethyl propionate (0.7 g). The product was dissolved in EtOAc (3 mL). Ethyl alcohol was evaporated under reduced pressure, and 1N hydrochloric acid (3.0 mL) was added to the residue. The precipitate was washed with water to give the title compound (0.66 g, 69%). 4 丽R (300 MHz, CDC13) d ppm 0. 90-2. 30 (m, 17H), 2. 60- 283 321426 201029996 2.75 (m, 4H), 3.06 (s, 3H), 3.72 (t, J =6.4 Hz, 1H), 4.08 (q, J=6.9 Hz, 2H), 4.22 (d, J=5. 7 Hz, 1H), 6.50 (d, J=8.7Hz, 2H), 6.74 (dd, J =8. 7, 1.9 Hz, 1H), 7.09-7. 34 Cm, 5H), 7. 64 (s, 1H). Example 84 3-({[4-({cyclohexyl][1-(3- Ethoxyphenyl)-3-ethyl-1H-indazol-4-yl]fluorenyl}amino)phenyl]carbonyl}amino)propionic acid

Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1-indole-pyrazol-4-yl]nonanol (0. 60 g) synthesized in Example 83 (3) at room temperature To the tetrahydrogenate solution (10 mL) was added sulfoxide chloride (0.24 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with EtOAc EtOAc. The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (10.0 mL), sodium iodide (0.27 g), sodium carbonate (0.29 g) and 3-{[(4-amine) synthesized in Example 1 (2) Ethylphenyl)carbonyl]amino}propionic acid ethyl ester (0.43 g), and the mixture was stirred at 70 ° C for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane 284 321426 Hexyl [1-(3-ethyllacylphenyl)-3-ethyl-1H_〇tbβ-supplement-4-yl]methyl]}amino)phenyl]carbonyl}amino)propionic acid ethyl ester (0.6 g). The product was dissolved in EtOAc (3 mL). Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (3 mL) was added to the residue. The precipitate was washed with water to give the title compound (0.59 g, 63%). ❹ 4_1^(300 1^^,0)(:13)6卩? 111〇.97-2.00 (111,1711),2.56- 2.81 (m, 4H), 3.64 (q, J=5. 8 Hz, 2H), 4.06 (q, J=7. 0

Hz, 2H), 4.24 (d, J=6.0 Hz, 1H), 6.50 (d, J=8. 7 Hz, 2H), 6.54-6.62 (m, 1H), 6.73 (dd, J=7. 2.1 Hz, 1H), 7.07-7.32 (m, 3H), 7.53 (d, J=8. 9 Hz, 2H), 7.63 (s, 1H). Example 85 3-[{[4-({l- [l-(3-Ethoxyphenyl)-3-ethyl-1H-indazol-4-yl] ❹-3-mercaptobutyl}amino)phenyl]carbonylindole (indenyl)amino group Propionic acid

Ch3 Π) l-[l-(3-ethoxyphenyl)-3-ethyl_1Η-η-pyrazol-4-yl]-3-methylbutan-1-ol under ice cooling in the examples a solution of 1-(3-ethoxybenzene 285 321426 201029996)-3-ethyl-1H-pyrazole-4-furaldehyde (1.7 g) in tetrahydrofuran (2 mL) synthesized in 83(2) Drop in &gt; stinky isobutyl (12. 0 mL, 1M four gas urethane solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of chlorinated money was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified eluting eluting eluting elut elut , 67%). !H NMR (300 MHz, CDCh) δ ppm 0. 98 (dd, J=6. 4, 2. 4 Hz, ❹ 6H), 1.18-1.90 (m, 9H), 2.75 (q, J=7. 6 Hz, 2H), 4.09 (q, J=7. 0 Hz, 2H), 4.81 (d, J=3. 6 Hz, 1H), 6.77 (ddd, J=8. 1, 2.4, 0.9 Hz, 1H) , 7.11-7.38 (m, 3H)S 7.79 (s, 1H). (2) 3-[{[4-({l-[ 1-(3-ethoxyphenyl)-3-ethyl-1H -oxazol-4-yl]-3-mercaptobutyl}amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid 1-[1- synthesized in the above (1) at room temperature (3-ethoxyphenyl) indole-3-ethyl-1H-pyrazol-4-yl]-3-mercaptobutan-1-ol (〇. 71 g) tetrahydrogen bite solution (10 Thionium chloride (0.39 mL) was added to mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice and a saturated aqueous sodium hydrogen carbonate (15 mL). The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimercaptoamine (15.0 mL) to add moth (n. 53 g), sodium carbonate (0.35 g), and 3- of the synthesis in Example 2 (2). {[(4-Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (0.59 g) 'and the mixture was stirred at 7 (TC for 12 hours. After cooling at 286 321 426 201029996, in the reaction mixture Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1 : volume ratio). 3-[{[4-({1-[1-(3-ethoxyphenyl)_3_ethyl_1H_pyrazol-4-yl]-3-methylbutyl)amine as a yellow oil Ethyl phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (0.55 g). The product was dissolved in ethanol (3. 〇mL), and 1N aqueous sodium aroxide solution (3·〇mL) was added at room temperature. And the mixture was stirred at room temperature for 0.5 hours. Ethanol was evaporated under reduced pressure, and 1N guanidine hydrochloride (3. 〇mL) was added to the residue. The precipitate was washed with water to give a colorless solid title. Target compound (0.46 g, 39%). HNMR (300 MHz, CDCh) δ ppm. 89-2. 00 (m, 15H), 2.56-2.82 (m, 4H), 3.06 (s, 3H), 3.72 (t, J=6.2 Hz, 2H), 4.08 (q, J=6.8 Hz, 2H) , 4.46 (t, J=6. 8 Hz, 1H), 6.55 (d, J=7.2 Hz, 2H), 6. 75 (dd, J=8. 0, 1.5 Hz, 1H), 7.05-7.38 (m, 5H), 7.72 (br. s., 1H).

Example 86 3 -({[4-({l-[l-(3-ethoxyphenyl)_3_ethyl-anthracene-t» than η--4-yl]-3-methylbutyl} Amino)phenyl]carbonyl}amino)propionic acid

1-[1-(3-Ethoxyphenyl) 287 321426 201029996 -3-ethyl-1 Η-«比唾-4-yl]-3- synthesized in Example 85(1) at room temperature Thionyl chloride (0.39 mL) was added to a solution of methylbutan-1-ol (〇. 71 g) in tetrahydrofuran (10 mL). The reaction mixture was quenched at room temperature for 30 min and cooled with ice and a saturated aqueous solution of sodium bicarbonate (15 ffl) was carefully added. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in bis-glycidylamine (15.0 niL), sodium iodide (〇. 53 g), sodium carbonate (〇·35 g), and 3-{3 synthesized in Example 1 (2) were added. [(4-Aminophenyl)carbonyl]aminoethyl phthalate (〇·55 g), and the mixture was stirred at 7 (TC for 12 hours. After cooling) water was added to the reaction mixture, and acetic acid was added. The extract was concentrated under reduced pressure, and the residue was purified by chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain a pale yellow oil. 3-({[4-({l-[l-(3-ethoxyphenyl)-3-Iethyl-1H-biwa-4-yl]_3-methylbutyl}amino)benzene (carbonyl) carbonylamino)propionic acid B (0.56 g). This product was dissolved in ethanol (3.0), and 1N aqueous sodium hydroxide solution (3.0 mL) was added at room temperature and The mixture was stirred for 5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (3 mL) was added to the residue. The precipitate was washed with water to give a colorless solid. , 47%). ° ]H NMR (300 MHz, CDCh) δ ppm 0.84-1. l〇(m, 6H), i ^ (t, J = 7.6 Hz, 3H), 1.41 (t, J = 7.0 Hz ' 3H), 1.574 87 (ra, 3H), 2.58-2.80 (m, 4H), 3.67 (q, J = 5. 9 HZ , 2H) 4. 07(q, J=6.8Hz, 2H), 4.48(t, J=6.6Hz, 1H), 4·75 (br. s. , 1H), 6.53 (d, J=8.7 Hz, 2H), 6.66 (t, j=5 321426 288 201029996

Hz, 1H), 6.74 (dd, J=8.1, 1.7 Hz, 1H), 7.07-7. 33 (m, 3H), 7.57 (d, J=8. 7 Hz, 2H), 7.68 (s, 1H) Example 87 3-[ {[4-({cyclohexyl[i-(3,5-bis-phenyl)-3-ethyl)] fluorenyl}amino)phenyl]carbonyl}(methyl) Amino]propionic acid

0) 1-(3,5-monophenyl)-3-mercapto-1H-D is more than 〇 -4- 酸 酸 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲And dimethyl ketoamine- fluorenyl-acid ('5.6 mL) overnight and the mixture was allowed to cool to room temperature. Ethanol (100 mL) and 3,5-difluorophenylhydrazine hydrochloride (7.9 g) were added to the reaction mixture and the mixture was further stirred for 15 hr. After cooling, ethanol was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sulfuric acid and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) &lt;5 ppm 1.21 (t, J=7. 4 Hz, 3H), 3.03 (q, J=7.4 Hz, 2H), 3.87 (s, 3H), 6.87-7.11 ( m, 3H), 8.02 (s, 1H). (2) 1_(3, 5-Difluorophenyl)-3-methyl-IH-0 is 0 -4- 3-4 321426 289 201029996 in ice cooling To a solution of lithium aluminum hydride (0.94 g) in tetrahydrofuran (65 mL), 1-(3,5-fluorophenyl)-3-methyl-1Η-»bazole-4-carboxylate synthesized in the above (1) A solution of the decanoate (6.5 g) in tetrahydrofuran (35 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The mixture was further cooled with ice and water (2.5 mL), 1N aqueous sodium hydroxide (12.5 mL) and water (2.5 mL) were added dropwise to terminate the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give 1-(3,5-di-fluorophenyl)-3-indolyl-1H-pyrazole-4 as pale yellow oil. - crude product of sterol (3.3 g). This product was dissolved in toluene (100 mL). A pentoxide (6. 0 g) was added and the mixture was heated under reflux with a Dean-Stark separator for 1 hour. The reaction mixture was cooled to rt. H NMR (300 MHz, CDCh) (5 ppm 1.25 (t, J = 7. 6 Hz, 3H), 3.03 (q, J = 7. 6 Hz, 2H), 6.85-7.11 (m, 3H)&gt; 8 07 (s, 1H), 9.99 (s, 1H). 〇(3)cyclohexyl[1-(3,5-difluorophenyl)_3-indenyl-ijj-t» than salivation 4-yl] A solution of 1-(3,5-difluorophenyl)_3_methyl-1H-indole-4-carboxylic acid (1.5 g) in tetrahydrofuran (1 g) synthesized in the above (2) under ice-cooling The brominated cyclohexanol (12.0 mL, 1 Μ 虱.) was added dropwise. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. Ammonium chloride was added to the reaction mixture. The aqueous solution was extracted, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1 : 2 vol. Yellow oil 321426 290 201029996 title title compound (1. 9 g, quantitative). ]H NMR (300 MHz, CDCh) 5 ppm 1.26 (t, J=7.2 Hz, 3H), 1.32-2.14 (m , 12H), 2.78 (q, J=7. 2 Hz, 2H), 4.35 (dd, J=8.2, 2.9 Hz, 1H), 6.80-7.12 (m, 3H), 7.62 (s, 1H). (4 ) 3-[{[4-({cyclohexyl[1-( 3, 5-Difluorophenyl)-3-ethyl~1Η_ο oxazol-4-yl]methyl}amino)phenyl]alkyl}(methyl)amino]propionic acid

Cyclohexyl[1-(3,5-difluorophenyl)-3-indolyl-1H-pyrazol-4-yl]methanol (〇. 96 g) synthesized in the above (3) at room temperature Add sulfoxide (〇. 40 mL) to tetrahydrofuran solution d5 mL). The reaction mixture was stirred at room temperature for 3 min and cooled with ice and a saturated aqueous sodium bicarbonate (10 mL) was carefully added. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (15.0 fflL), and sodium hydride (0.68 g), carbonic acid steel (0.48 g) and the example of 3-{[(4-aminophenyl) were added. ) money] (methyl) aminyl acetoacetate ethyl acetate (〇7Q5 g) 'and a mixture at 7G ° C for 12 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with acetic acid. The extract was concentrated under reduced pressure, and the residue was purified by (4) hexane column chromatography (yield = 1:1, volume ratio) to obtain a pale yellow oil; 5-difluorophenyl)-3-ethyl,pyrazolamino)pyridyl]silk methyl)amine fine acid B (tetra)(tetra)g) e is dissolved in ethanol (3.0 mL) and added at room temperature ( 3.0 mL), and ethanol was added to a fresh mixture of Q^ aqueous solution at room temperature and 1N salt hydrazine was added to the residue (hour. C3. 〇mL was evaporated under reduced pressure). The precipitate was washed with water 321426 291 201029996 to give the title compound (0.70 g, 44%) as a colorless solid. H NMR (300 MHz, CDCh) &lt;5 ppm 0. 94^2· 08 14H), 2.59- 2.89 (ra, 4H), 3.08 (s, 3H), 3.73 (t, J=6· 5 Hz, 2H)' 4.19 (d, J = 6.8 Hz, lH), 6.53 (d, J = 8.5 Hz, 2H), 6.77_ 7.30 (m, 5H), 7.52 (s, 1H). Example 88 3-({ [4-({cyclohexyl[1-(3,5-difluorophenyl)-3_ethyl-111_〇) 11 sits a 4-methyl]methyl}amino)phenyl]carbonyl}amino) Meat &amp;

F ch3 cyclohexyl[1-(3,5-diphenyl)-3-methyl-1H-pyrazol-4-yl]carboxamidine (〇·) synthesized in Example 87 (3) at room temperature Thionyl chloride (〇. 40 ® L) was added to 96 g) of tetrahydrofuran solution (15 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and a saturated aqueous sodium hydrogen carbonate (10 mL). The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimethylacetamide (15.0 mL), sodium iodide (〇.68 g), sodium carbonate (0.48 g), and 3-([4-(4-) Aminophenyl)carbonyl]amino-propionic acid ethyl acetate (0.72 2), and the mixture was stirred at 70 ° C for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue was rolled down under reduced pressure 321 426 292 201029996, and the residue was purified by column chromatography (acetic acid ethyl acetate: hexane = 1:1, volume ratio) to obtain a pale yellow oil. 3_({[4-({cyclohexyl][b(10)-difluorophenyroline+ethylhino(tetra)^methyl}amino)phenyl]amino}amino)propionic acid ethyl vinegar (〇8〇g). This product was dissolved in ethanol (3.0 mL), a 1N aqueous solution of sodium hydroxide (3. 〇 mL) was added at room temperature and mixture was stirred at room temperature for 5 hours. Ethyl alcohol was evaporated under reduced pressure and 1N hydrochloric acid (3. 〇 fflL) was added to the residue. The Sushen Temple was washed with water to obtain the title compound (〇.5〇 g, 33%) as a colorless solid. H NMR (300 MHz, CDCh) δ ppm 1.02 (t, J = 7. 5 Hz, 3H), 1.06-2.08 (m, 11H), 2.65 (t, J = 5. 7 Hz, 2H), 2.78 (q , J=7. 5 Hz, 2H), 3.67 (q, J=7. 0 Hz, 2H), 4.20 (d, J=6. 8 ^ 1H), 6.52 (d, J=8. 7 Hz, 2H ), 6.57-6.68 (m, 1H), 6· 77-7. 10 (m, 3H), 7.51 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H). Example 89 O 3-[ (U-[(cyclohexyl{3-(decyloxymethyl)-l-[4-(trifluoromethyl)pyridine~2~yl]-1H-pyrazol-4-yl}fluorenyl)) Phenyl}carbonyl)(methyl)amino group]

(1) 3-(decyloxy)-[4-(trifluoromethyl)acridin-2-yl]-1Η-° ratio 293 321426 201029996 oxazol-4-carboxylate ester in Example 37 (1) A solution of 3-(methoxymethyl)_1Η_π-pyrazole-4-carboxylic acid methyl ester (1.8 g) synthesized in the middle, and a solution of 2-indole-dimethylformamide (2%) Gas-4-trifluoromethylpyridine (2. g) and potassium carbonate (23 g), and the mixture was stirred at 100 C overnight. The reaction mixture was cooled to room temperature and filtered through celite, water was added to filtrate, and mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: H NMR (300 MHz, CDCh) δ ppm 3. 54 (s, 3H), 3. 89 (s, 3H), 4. 83 (s, 2H), 7. 47 (dd, J=5. 1, 0 . 9 Hz, 1H), 8.31 (s, 1H), 8.61 (d, J=5. 1 Hz, 1H), 9.04 (s, 1H). (2) 3-(methoxymethyl)-1- [4-(Trifluoromethyl)B is more than η 一 基 基 一 η -4- ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ ❹ 1) 3-(Methoxyindenyl)-(4-trifluoromethyl) D synthesized in the middle of butyl-2-yl]-1H-pyrazole-4-carboxylic acid oxime ester (〇. 62 g) Tetrafuran solution (2 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The mixture was ice-cooled, and water (〇. 2 mL), 1N aqueous sodium hydroxide (1.0 mL) and water (0.2 mL) were added dropwise to terminate the reaction. The filtrate was concentrated under reduced pressure by celite to give 3-(methoxymethyl)--i-[4-(trifluoromethyl)pyridine-2 as a pale yellow oil. The crude product of ]]- 1H-pyrazole-4-nonanol (〇. 53 g). The product was dissolved in toluene (3 〇 mL), 294 321426 201029996 was added to oxidize (2·0 g)' and the mixture was heated with a Dean-Stark separator under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (0.59 g, quantitative). ]H NMR (300 MHz, CDCh) δ ppm 3.53 (s, 3H), 4.83 (s, 2H), 7.50 (d, J-4.9 Hz, 1H), 8.31 (s, 1H), 8.63 (d, J= 5.1 Hz, 1H), 9.09 (s, 1H), 10.10 (s, 1H). (3) Cyclohexyl {3-(methoxyindolyl)-bu [4_(trifluoromethyl)pyridine-2-yl 3-(Methoxyindenyl)-i[4-(trifluoromethyl)pyridine-2 synthesized in the above (2) with ❹-1Η-η-Bizozol-4-yl}nonanol under ice cooling To a solution of -in-pyrazole- 4-formaldehyde (〇·59 g) in tetrahydrofuran (10 mL) was added dropwise cyclohexylmagnesium bromide (4. 〇mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. An aqueous vaporized ammonium solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified to mjjjjjjjjjjjj 23 g, 3〇%). NMR (300 MHz, CDCh) c5 ppm 0.94-1. 96 (m, 12 H), 3 45 C^H), ,43 (d, J=,7Hz5lH), ,5Β-,Β5(Λη), ^• 38 (d, J=〇.9 Hz, 1 H), 8.15-8.60 (m, 3 H). (4) 3-[({4-[(cyclohexyl){3-(methoxymethyl))卜 [4_(三吼 bit-2-yl) 吼 吼 + 基 基 基 基 甲基 甲基 曱 曱 曱 曱 曱 环 环 环 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 3_(methoxymethyl) 321426 295 201029996 -l-[4-(trifluoromethyl)pyrene-But-2-yl]-1H-0 than -4--4-yl} sterol (〇· 23 g) Thionine chloride (〇·1 mL) was added to a solution of tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and saturated aqueous sodium hydrogen carbonate (5 mL) was carefully added. The reaction mixture was stirred for 1 hr and the mixture was extracted with EtOAc. EtOAc EtOAc. In addition, moth (n. 14 g), sodium carbonate (〇. 1〇g), and 3-{[(4-aminophenyl)carbonyl] synthesized in Example 2 (2) were added. Amine oxime propionate ethyl ester _ Π g), and at 7 (TC stirred the mixture for 12 hours. After cooling, water was added to the reaction mixture' and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and passed through a column chromatography. (ethyl acetate: hexane = 1 : 1, volume ratio), the residue was purified to give 3-[({4-[(cyclohexyl){3-(methoxymethyl)) as a pale yellow oil. ^^-(trifluoromethyl) ° ratio 0 to -2-yl]-1 Η-° ratio. sit-4-yl}methyl)amino]phenyl} carbonyl)(methyl)amino]propionic acid Ethyl ester (〇·1〇g). This product was dissolved in EtOAc (1 mL). A 1N aqueous sodium hydroxide solution (1 〇mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. The ethanol was evaporated, and 1N-hydrochloric acid (1. 0 mL) was added to the residue. The title compound (yield: 4 g, 1%) was obtained as a pale yellow solid. NMR (300 MHz, CDCh) δ ppm 0. 95-2. 18 (m, 11H), 2.70 (t, J = 6.3 Hz ' 2H), 3.06 (s, 3H), 3.42 (s, 3H), 3.71 ( t, J=6.3 Hz, 2H), 4.36 (d, 1=1.2 Hz, 1H), 4.57 (d, J=2.1 Hz, 2H), 6.56 (d, J=8. 7 Hz, 2H), 7.24 (d, J=8. 7 Hz, 2H), 7.37 (d, J=5.3 Hz, 1H), 8.16 (s, 1H), 8.36 321426 296 201029996 (s, 1H), 8.53 (d, J = 5. 3 Hz, 1H). Example 90-2-yl]-lH-η-pyrazol-4-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]

O (1) 3-(nonyloxyindenyl)-1_[6-(trifluoroindolyl) η ratio bite_2_yl]-1H-d ratio π sit-4-reoxypyruvate is intended to be an example Addition of methyl 3-(decyloxymethyl)-ih-pyrazole-4-carboxylate (5.1 g) synthesized in 37(1), hydrazine-dimercaptocaramine (70 mL) 2-Chloro-6-trifluoromethyl η was bitten (5.0 g) and dehydrated (6.2 g), and 0 and the mixture was mixed overnight at 10 °C. The reaction mixture was allowed to cool to room temperature, and filtered through celite, water was added to filtrate, and mixture was extracted with acetonitrile. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1 : 4, vol.) to give the title compound (65 g, 69 «.H NMR (300 MHz, CDCla) δ ppm 3.54 (s, 3H), 3.89 (s 3H), 4.83 (s, 2H), 7.62 (d, J=7.2 Hz, 1H), 8.00-8.02 (m, 1H), 8. 25 -8.30 (m, 1H), 9.06 (s, 1H). 321426 297 201029996 (2) 3-(methoxymethyl)-i_[6-(trifluoromethyl)bite_2-based] ratio σ Add 3-(methoxyfluorenyl)-bu [6_() synthesized in the above (1) to a solution of ice-cooled lithium aluminum hydride (〇·79 g) in tetrahydrofuran (25 mL). A solution of methyl trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate (6.5 g) in tetrahydrofuran (10 mL). The ice bath was removed and the mixture was stirred at room temperature. The mixture was ice-cooled, and water (2·〇mL), 1N aqueous sodium hydroxide solution (10 μmL), and water (2.0 mL) were added dropwise to terminate the reaction. The residue was filtered through celite. The filtrate was concentrated under reduced pressure to give 3-(methoxymethyl)-[6-(trifluoromethyl)pyridin-2-yl-]-lH as a pale yellow oil. The crude product of pyrazole-4-methanol (6·〇g). This product was dissolved in toluene (1 mL), manganese dioxide (3. 〇g) was added, and the mixture was heated with a Dean_Strk separator under reflux. The reaction mixture was cooled to room temperature, and MgSO4 was evaporated. , CDC13) 5 ppm 3. 53 (s, 3H), 4. 83 (s 2H), 7.66 (d, J=7.5 Hz, 1H), 8.05-8.08 (m, 1H), 8.27 (d, J=8.3 Hz, 1H), 9.13 (s, 1H), 1〇1〇(s,1H)· (3)Cyclohexyl {3-(nonyloxyindenyl (trifluoromethyl) _2_2-yl] - 3-(methoxymethyl)-[6-(trifluoromethyl)pyridin-2-yl]-1Η synthesized by the above-mentioned (2) under ice cooling with 1Η-πϋβ?-4-ylindole methanol - a solution of pyrazole- 4 formaldehyde (5 3 g) in tetrahydrofuran (100 mL) was added dropwise to cyclohexyl bromide (25 Torr, 1 M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed and Stir the mixture at room temperature for 321426 298 201029996 for 15 minutes. An aqueous vaporized ammonium solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced-purification, and the residue was purified by EtOAc EtOAc (EtOAc (EtOAc) g, 67%). ]H NMR (300 MHz, CDCh) δ ppm 〇. 94-2. 22 (m, 11H), 2. 95 (d, J=6.0Hz, 1H), 3.45 (s, 3H), 4.44 (dd, J =7. 7, 6.0 Hz, 1H), 4.50-4.65 (m, 2H), 7.53 (d, J=7.0 Hz, 1H), 7.93-8.00 (m, 1H), 8.14 (d, J: 8.3 Hz, 1H), 8.45 (s, 〇1H). (4) 3-[(丨4-[(cyclohexyl{3-(decyloxy)-l-[6-(trifluoromethyl) fluorene ratio 0 Ding-2-yl]-1Η-η ratio η-4-yl}methyl)amino]phenyl}propenyl)(fluorenyl)amino]propionic acid at room temperature in the ring of the above (3) synthesis Hexyl{3-(methoxymethyl)-bu [6-(trifluoromethyl)pyridin-2-yl]_1Η-pyrazole-4-yl}methanol (〇. 5〇g) tetrahydrogen Add ruthenium chloride (0.15 mL) to the solution (5 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice EtOAc & &lt The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (5.0 mL), sodium iodide (0.33 g), sodium carbonate (0.26 g), and 3-3 synthesized in Example 2 (2) {[(4-Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (0.33 g), and the mixture was stirred at 70 ° C for 12 hr. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified via silica gel column chromatography 299 321426 201029996 (ethyl acetate:hexane = 1 : 1 'volume ratio) to afford 3-[ ({4-[(cyclohexyl{3-(methoxymethyl)-:1-[6-(trifluoromethyl))pyridin-2-yl]-1Η-° than sal-4-yl} Methyl)amino]phenyl}alkyl)(indenyl)amino]propionic acid ethyl ester (〇. 08 g). This product was dissolved in ethanol (3. 〇 mL). An aqueous solution of IN sodium hydroxide (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hours. Ethanol was evaporated under reduced conditions, and 1N hydrochloric acid (1. 〇 mL) was added to the residue. The precipitate was washed with water to give the title compound ( 〇. 〇 6 g, 7%) as a colorless solid. JH NMR (300 MHz, CDCh) δ ppm 0. 92-2. 19 (m, 11H), 2.73 (br. s., 2H), 3.08 (s, 3H), 3.41 (s, 3H), 3.72 (t , J=6-2Hz, 2H), 4.36 (d, J=8. 0 Hz, 1H), 4.57 (d, J=2.1 Hz, 2H), 6.58 (d, J=8. 7Hz, 2H) , 7.20-7.30 (m, 2H), 7- 51- 8. 12 (m, 3H), 8. 40 (s, 1H). Example 91

3_[U4-[(cyclohexyl{3-(decyloxymethyl M_[6-(trifluoromethyl)indolyl-2-yl]-1H-pyrazol-4-yl}methyl)amino] Phenyl}carbonyl)amino]propionic acid

Cyclohexyl {3-(methoxymethyl)~1-[6-(trifluoromethyl)pyrene-But-2-yl]-1H-0 ratio synthesized in Example 90(3) at room temperature啥-4-Mercaptool 321426 300 201029996 (0. 50 g) in tetrahydrofuran solution τ, 丄 )) added sulfoxide (〇 15 mL). The reaction mixture was stirred at room temperature for ^ ^ min and cooled with ice, and

Saturated sodium bicarbonate k A ν, Λ . α ^ coil (5 mL) was carefully added. The reaction mixture was stirred for 10 min and concentrated with EtOAc EtOAc EtOAc. Dissolve the residue in the solution, add sodium iodide (〇 37 g), sodium carbonate (0.26 g) and a g g ^ in Example 1 (2), 3-{[(4-aminobenzene) Ethyl) carbonyl] Ο 胺 amino} ethyl propionate (0.32 g), and recognized. and the mixture was stirred at 7 CTC for 12 hours. After cooling, water was added to the reaction mixture φ, , * 1 tr, and acetic acid B The mixture is extracted with an ester. The extract is extracted under reduced pressure and the residue is purified by a silica gel column chromatography (ethyl acetate:hexane = 1 ··1, volume of uL, u volume ratio). 3-[({4-[(cyclohexyl){3(methoxymethyl)+[6-(Sandonyl))-)], ^4_yl} fluorenyl) Amino]phenyl} benzyl)amino]propionic acid B. 〇 7g). This product was dissolved in ethanol (3 〇 mL), and an aqueous solution of IN sodium hydroxide (1 〇 mL) was added at room temperature, and The mixture was stirred at room temperature for 0.5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1 · 〇jqL) was added to the residue. The sputum, dt swim, I ►; The title compound (〇.〇6 g, 8%). 1〇MR(3_Z,GDGl3)5 PP (4) Ι2.Π0Π, battle 2.67 (t, J-5.7 Hz, 2H), 3.41 (Sj 3H), 3.56-3.77 (m, 2H), 4.38(d,&gt;7 ·6Ηζ,1H), 4.56 (d, j=2.3 Hz, 2H), 6 471 6.71 (m, 3H)' 7.46-8.H (m, 5H), 8 4 〇 (s, 1H) · Example 92 3-({[4-({cyclohexyl][b(3_ethoxyphenyl)_3_ethyl_ih-ratio-salt-321426 301 201029996]]]]yl}amino)phenyl]yl} Amino) 2 - mercaptopropionic acid

Ch3 (1) 4-(·{cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-111-fluorenylpyran-4-yl]decyl}amino)benzoic acid decyl ester @cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]nonanol (0. 64 g) synthesized in Example 83 (3) at room temperature Thionyl chloride (0.22 mL) was added to the tetrahydrofuran solution (5 mL). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and sat. The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (10.0 mL), sodium iodide (0.44 g), sodium carbonate (0.30 g) and 4-aminobenzoic acid decyl ester (0. 35 g), and the mixture was stirred at 70 ° C overnight. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjj , 38%). ^R(300 MHz, CDCl3) 6ppm 0.76-1.85 (m, 17H), 2.63-2.82 (m, 2H), 3.82 (s, 3H), 4.02-4.11 (m, 2H), 4.27 (br. s. , 1H), 6.51 (d, J=8. 9 Hz, 2H), 6.75 (dd, J=2. 4, 302 321426 201029996 〇. 9 Hz, 1H), 7. 09-7. 26 (m, 3H) , 7. 64 (s, 1H), 7. 80 (d, J=8.9 Hz, 2H). (2) 4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl嗤_4_基基曱基}amino)benzoic acid 4-({cyclohexylethoxyphenyl)_3_ethyl-1H-pyrazol-4-yl]fluorenyl] synthesized in the above (1) A 1 N aqueous solution of sodium hydroxide (6. 〇 mL) was added to a solution of the dimethyl benzoate ( s. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (8.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. !H NMR (300 MHz, CDCh) δ ppm 0. 92-2. 00 (m, 17H), 2.72 (q, J=7. 5 Hz, 2H), 3.99-4.11 (m, 2H), 4.28 (d , J=5.8 Hz, 1H), 6. 52 (d, J=8. 9 Hz, 2H), 6. 74 (ddd, J=8. 1, 2.5, ❹ 〇. 8 Hz, 1H), 7. 10-7. 25 (m,3H), 7. 65 (s' 1H), 7. 84 (d, J=8. 9 Hz, 2H). (3) 3-({ [4-({cyclohexyl) [1-(3-ethoxyphenyl)-3-ethyl-ijj-t»pyrazol-4-yl]fluorenyl}amino)phenyl]carbonyl}amino)-2-methylpropionic acid 4-({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]indolyl)amino)benzoic acid synthesized in the above (2) (〇. 18 g) was dissolved in N,N-didecylguanamine (3 mL), and added ethyl ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at room temperature. (〇·11 g), l-hydroxybenzotriazole • monohydrate (〇. 09 g) and methyl 3-amino-2-mercaptopropionate (〇. 〇7 321426 303 201029996 g) 'and Mix the mixture overnight. Water was added to the reaction mixture, and the mixture was extracted by an assay. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1 : hexane, volume ratio) to afford 3-({[4- ({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]fluorenyl}amino)phenyl]carbonylguanidino)_2_methylpropionic acid Methyl ester (〇. 03 g). This product was dissolved in ethanol (2· 〇 raL), 1N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hour. Ethanol was evaporated under reduced pressure, and hydrazine 1N hydrochloric acid (5 mL) was added to the residue. The precipitate was washed with water to give the title compound (0.02 g, 9%). 'H NMR (300 MHz, CDCh) δ ppm 0. 96-2. 00 (m, 20H), 2.62-2.91 (in, 3H), 3.59-3.75 (m, 2H), 4.07 (q, J=6.8 Hz , 2H), 4.24 (d, J=6. 0 Hz, 1H), 6.43-6.59 (m, 3H), 6.74 (dd, J=8. 1, 2.4 Hz, 1H), 7.08-7.66 (m, 6H) Example 93 ❹ [({[4_({cyclohexyl[l-(3_ethoxyphenyl)-3-ethyl-1H-indol-4-yl]fluorenyl}amine)) Carbonyl}amino)mercapto]-2-ethylbutyric acid

Ch3 will be synthesized in Example 92 (2) 4-({ hexylhexyl [1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino Phenyl phthalic acid (〇· 18 g) dissolved 321426 304 201029996 Adding ethylidene-3-tris(3-dimethylaminopropyl)carbon at room temperature in N,N-dimethylformamide (3 mL) Diimine hydrochloride (0.11 g), hydrazine-p-benzotriazole monohydrate (0.09 g) and 2-(aminomethyl)_2-ethylbutyrate (0. 12 g) and triethylamine (0.09 mL), and the mixture was mixed overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by chromatography (ethyl acetate:hexane = 1:1, volume ratio) to afford 2-[({[ 4-({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-indole®oxazol-4-yl]indolyl}amino)phenyl]alkyl}amino) A Base]_2_ethylbutyric acid B Sb (0.18 g). This product was dissolved in ethanol (2·〇 mL), and a 1N aqueous solution of sodium sulphate (2. GmL) was added at room temperature, and the mixture was partitioned. Ethanol was released under reduced pressure, and 1N hydrochloric acid (2. 〇 raL) was added to the residue. The precipitate was washed with water to obtain the title compound (0·17 g, 74%) as a colorless solid. !H NMR (300 MHz, CDCh) d ppm 0.91 (t, J=7. 4 Hz, 6H), ❿ 1.00-1.99 (m, 21H), 2.72 (q, J=7. 5 Hz, 2H), 3.62 (d, J=6. 2 Hz' 2H), 4. 07 (q, J=7. 〇Hz, 2H), 4. 24 (d, J=6. 0

Hz, 1H), 6. 38-6.47 (m, 1H), 6.51 (d, J=8.9 Hz, 2H), 6.73 (ddd, J=1A, 1.5, 1.2 Hz, 1H), 7.09-7.24 (m, 3H), 7.54 (d, J = 8.9 Hz, 2H), 7.63 (s, 1H). Example A1 3-{[(4-{[l-benzothiophen-3-yl)(cyclohexyl)methyl Amino phenyl)carbonyl]amino}propionic acid 321426 305 201029996

(1) 1-Benzothiophen-3-yl (cyclohexyl)methanol was added dropwise to a 1.0 M bromination ring in 1-benzothiophene-3-carbaldehyde (2.25 g) in tetrahydrofuran (40 mL) at 0 °C. 5小时。 The mixture was stirred for 1.5 hours. IN hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) 5 ppm 1. 00-1. 31 (m, 5H), 1.43-1.52 (m, 1H), 1.60-1.73 (m, 2H), 1.74-1.83 (m, 1H) , 1.83-1.96 (m, 2H), 1.97-2.05 (m, 1H), 4.83 (dd, J=6. 8, 3.2 Hz, 1H), 7.30-7.40 (m, 3H), 7.82-7.93 (m, 2H). ❹ (2) 3-[Chloro(cyclohexyl)decyl]-:l-benzothiophene 1-benzothiophen-3-yl (cyclohexyl)methanol (2. 32 g) synthesized above To a solution of toluene (25 mL), ruthenium chloride (824 μ! 滴) was added dropwise, and the mixture was stirred at room temperature for 4 hours. An ice-cooled saturated aqueous solution of sodium hydrogencarbonate was poured over the mixture and extracted with ethyl acetate. The mixture was washed with EtOAc EtOAc (EtOAc m. (5 ppmO. 95-1.34 (m,5H), 1.46- 306 321426 201029996 1.56 Cm, 1H), 1.60-1.72 (m, 2H), 1.76-1.86 (m, 1H), 2.10-2.28 (m, 2H) , 5.03 (d, J=8. 1 Hz, 1H), 7.32-7.43 (m, 3H), 7.82-7.93 (m, 2H).

(3) 4-{[1-Benzophenant-3-yl(cyclohexyl)methyl]amino}benzoic acid 3-(milk (3⁄4 hexyl) fluorenyl)-1- Benzo-n-decene (2.42 g), 4-aminobenzoic acid decyl ester (2.77 g), sodium iodide (2.77 g) and hydrazine, hydrazine-dimethylacetamide (50 Sodium carbonate (1. 94 g) was added to the mixture of mL) and the mixture was mixed overnight with a mixture of rat gas and 100 C. 1N hydrochloric acid was added to terminate the reaction' and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc A mixture of the obtained oil, tetrahydrofuran (2 mL) and ethanol (20 mL) was added 1 N aqueous sodium hydroxide (2 mL), and the mixture was stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (40 mL). The title compound (1. 80 g, 54%) was obtained as a white solid. &lt;&gt;H NMR (300 MHz, CDCh) δ ppm 1.02. -1. 35 (m, 5H), 1.60- 2.03 (m, 6H), 4.69 (d, J=5. 7 Hz, 1H), 6.43-6.53 (m, 2H), 7.22 (s, 1H), 7.32 -7.47 (m, 2H), 7.73-7.91 (m, 4H). (4) 3-{[(4-{[l-benzothiophen-3-yl (cyclohexyl)methyl)amino}phenyl ^)]amino}propionic acid 307 321426 201029996 4-{[1-benzoindole-3-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized in the above, 々- Alanine ethyl ester hydrochloride (126 mg), dipyridylbenzotris monohydrate (126 mg), triethylamine (114/zL) and Ν'N-methylcarboxamide (1 〇mL) To the mixture was added ethyl ethyl 3-(3-methylaminopropyl) 1⁄4-imine hydrochloride (157 mg), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added to terminate the reaction, and ethyl acetate was added. The extract was extracted. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl ester: hexane 〇 = 1: 1, volume ratio) Purified residue to give a pale yellow oil. 1N hydrogen was added to a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) Aqueous sodium oxide solution (1 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and residue was dissolved in water (1 mL) and &lt;1&gt; The title compound (2 〇 1 mg, 67%) was obtained as a white solid. </ RTI> < NMR (300 MHz, CDCh) &lt;5 ppm 1. 00-1. 32 (m, 5H), 1.57- ❹ 1.81 (m, 4H), 1.81-1.99 (m, 2H), 2.57 (t, J=5.7 Hz, 2H), 3. 53-3. 63 (id, 2H) , 4. 63 (d, J=5. 7 Hz, 1H), 6 42 (d, J=8.7 Hz, 2H), 6.62 (t, J=6.1 Hz, 1H), 7.18 (s, 1H) , 7.31-7.46 (m, 4H), 7.80-7.89 (m, 2H). Example A2 [(4-{[1-benzothiophen-3-yl(cyclohexyl)indenyl]amino}phenyl) Carbonyl](methyl)amino}propionic acid 321426 308 201029996

4-{[1-benzothiophene-3-yl(cyclohexyl)methyl]aminobenzinobenzoic acid (250) synthesized in Example A1(3) was used in the same manner as in the example Al(4). The title compound (22 mg, η%) was obtained as a white solid. HI HIOTKSOOMHz, CDC13) δ Qing! Oh 34(m,5H),16b1.83 (m, 4H), 1.83-2.00 (m) 2H), 2.67 (t, J=6.4 Hz, 2H), 3.02 (s, 3H), 3.69 (t, J =6.4 Hz, 2H), 4.64 (d, J=5. 7 Hz, 1H), 6.45 (d, J=8. 7 Hz, 2H), 7. 19(d, J=8. 7

Hz, 2H), 7.21 (s, 1H), 7.33-7.45 (m, 2H), 7.82-7 91 (m, 2H). * Example A3 3-U(4-{[cyclohexyl (1-methyl) -1H_benzimidazol-2-yl)methyl]amino}} phenyl)alkyl]amino}propionic acid

(1) Cyclohexyl (1-methyl-1H-benzoimidazolyl-2-yl) decyl alcohol was obtained in the same manner as in Example AK1) using benzyl-1H benzophenan-2-methyl 15a 〇3gwx The title compound (0·58 g, 37%) was obtained as a brown oil. Ding 321426 309 201029996 NMR (300 MHz, CDC13) 5 ppm 1. 05η 3〇(m,5H),i %1.46 (m,1H)' 1.58-2.03 (m,5H),3 77 (s,3H) , 4 65 (d, J=7.2 Hz, 1H), 7.20-7.30 (m, 3H)} 7.65-7 73 rm 1H). · (2) 2-[Chloro(cyclohexyl)methyl]-i- The base ~iH-benzimidazole was used in the same manner as in the example Al (2), and the above-prepared base U-mercapto-1H-benzo-yt-2-yl) decyl alcohol (〇58g) was used to obtain The title compound (6〇5 1^, 97%). ◎^NMRGOOMHz'CDCl^ppmO.gi-uCmJIO'iso- 1.60 (m, 1H), 1.62-1.75 (m, 2H), 1.81-1.92 (m, iH), 2.33-2.49 (m, 2H), 3.87 ( s, 3H), 4.88 (d, J=9. 9 Hz! 1H), 7.24-7.38 (m, 3H), 7.74-7.79 (m, 1H). (3) 4-{[cyclohexyl (i_A) Benzobenzimidazole-2-yl)indenyl]amino}benzoic acid In the same manner as in Example A1 (3), 2-[Chlorohexyl)indenyl]-1-methyl-1H synthesized above was used. -benzimidazole (605 mg) to give the title compound (87. 〇mg, 10%) as a white solid. JH NMR (300 MHz, CDCh) δ ppm 1.04-1. 32 (m, 5H), 1.39-1.51 (m, 1H), 1.60-1.84 (m, 3H), 2.03-2.20 (m, 2H), 3.90 ( s, 3H), 4.63-4.72 (in, IH), 5.90-6.04 (m, 1H), 6.69 (d, J=8.7Hz, 2H), 7.25-7.39 (m, 3H), 7.73-7.81 (m, 1H), 7·88 (d, J=8.7 Hz, 2H). (4) 3-{[(4-{[cyclohexylu-fluorenyl-1H_benzimidazol-2-yl)indenyl]amine Base phenyl)carbonyl]amino}propionic acid 310 321426 201029996 Using the same procedure as in Example A1 (4), using the above synthesized 4~{[cyclohexyl(1-mercapto-1H-benzimidazole_2 _ base) fluorenyl]amino benzoic acid (78.3 mg)' to obtain the title compound (39.5,

H NMR (300 MHz, CDCh) δ ppm 0.98-1.40 (m, 6H), 1.59-1.71 (m, 2H), 1.71-1.84 (m, 1H), 1.92-2.08 (m, 1H), 2.13-2.26 ( m, 1H), 2.71 (t, J=5.3 Hz, 2H), 3.71-3.83 (m, 2H), 3.93 (s, 3H), 4.59-4.71 (m, 1H), 6.74 (d, 7.20-7.40 ( m, 4H), 7.59-7.70 (m, 3H). Example A4 3-{[(4-{[l-benzofuran-2-yl(cyclohexyl)methyl]amino}phenyl)carbonyl] (methyl)amino}propionic acid

(1) 1-Benzobenzopyran-2-yl(cyclohexyl)methanol The same procedure as in Example Al (1) was used, using benzfurfuran-2-furfural (2.52 g) to obtain a yellow oil. The title compound of the title (2·38 g, 60%). NMR (300 MHz, CDCh) d ppm 1. 〇〇-ΐ. 36 (m, 5H), 1.49- 1.59 (m, 1H), 1.61-2.03 (m, 6H), 4.50-4.57 (m, 1H), 6.60 (s, 1H), 7.16-7.29 (m, 2H), 7.43-7.47 (m, 1H), 7.50-7.55 (m, 1H). 321426 311 201029996 (2) 2-[gas (cyclohexyl) fluorenyl 1-Benzene acetophenone The same procedure as in Example Al (2) was used, and the above-obtained benzofuran-2-yl(cyclohexyl)nonanol (1.2 〇g) was used to obtain a yellow oil. The title compound (1.17 g, 9〇%). 4 I^MR (300 MHz, CDCl3) 6 ppm 98.98-i.38 (m, 5H), 1.50- 1.86 (m, 4H), 2.08-2.23 (m, 2H), 4.78 (d, J=8. 1 Hz, 1H), 6.66 (s, 1H), 7.12-7.32 (m, 2H), 7.45-7.56 (m, 2H). 0 (3) 4-{[l-benzofuran-2-yl (cyclic The same method as in the case of Al(3), using the above synthesized 2-[gas(cyclohexyl)indenyl]-1-benzofuran (1.17 g), The title compound (523 mg, 32%) was obtained as a pale brown solid. ]H NMR (300 MHz, CDCh) &lt;5 ppm 1. 05-1. 38 (m, 5H), 1.57- 1.86 (m, 4H), 1.88-2.03 (m, 2H), 4.41-4.50 (m, 1H), 4.52-4.62 (m, 1H), 6.53 (s, 1H), 6.60 (d, J=8.9 Hz, ❹ 2H), 7. 14-7. 25 (m, 2H), 7. 4 b 7 50 (m, 2H), 7. 85 (d, J=8. 9 Hz, 2H). (4) 3-{[(4-{[1-benzofuran-2-yl(cyclohexyl)fluorene) Amino phenyl phenyl) carbonyl] (methyl) amino} propionic acid The same procedure as in Example A1 (4) was used, using 4-{[1-benzofuran-2-yl (cyclo) synthesized above. Hexyl) fluorenyl]amino}benzoic acid (250 mg) and ethyl 3-(decylamino)propanoate (113 mg) to give the title compound (226 mg, 73%) . H NMR (300 MHz, DMSO-de) δ ppm 0.98-1.29 (m, 5H), 312 321426 201029996 1.39-1.50 (m,1H), 1.55-1.78 (m,3H),1.83-2. 03 (m, 2H), 2.43-2.54 (m, 2H), 2. 89 (s, 3H), 3. 51 (t, J=7. 3Hz, 2H), 4.38-4.49 (m, 1H), 6.46 (d, J =8. 1 Hz, 1H), 6.67 (d, J=8.7 Hz, 2H), 6.75 (s, 1H), 7.11 (d, J=8.7 Hz, 2H), 7.14-7.26 (m, 2H), 7.47 -7.57 (m, 2H). Example A5 3-{[(4-{[l-benzothiophen-2-yl(cyclohexyl)decyl]amino phenyl)carbonyl](methyl)amino }propionic acid

2 benzothiophene-2-carbaldehyde (2.00 g) was used to give the title compound (1.93 ❹ g' 64%) as a yellow solid. H NMR (300 MHz, CDCh) δ ppm 0. 96-1. 35 (in 5H) 1 50-1.84(, 5H), 1.99-,.0 (ra, 2H)&gt;

Hz, 1H), 7. 15(s, 1H), 7.24-7.36 (m, 2H), 7.67-7.73 (m, 1H), 7.77-7.83 (m, 1H). (2) 2-[Chlorine (ring) Hexyl)methyl]-benzothiophene The above synthesized benzothiophen-2-yl (cyclohexyl) decyl alcohol (1.93 g) was used in the same manner as in the Example A (2) to give a brown solid. The title compound (1.94 g, 94%). 321426 313 201029996 ]H NMR (300 MHz, CDCh) δ ppm 0. 98-1. 38 (m, 5H), 1.50-2.01 (m, 5H), 2.15-2.25 (m, 1H), 4.97 (d, J =7.8 Hz, 1H), 7.21 (s, 1H), 7.26-7.37 (m, 2H), 7.66-7.73 (in, 1H), 7.74-7.82 (m, 1H). (3) 4-{[l- Benzothiophen-2-yl(cyclohexyl)indenyl]aminoindanic acid was synthesized in the same manner as in Example Al (3) using 2-[chloro(cyclohexyl)methyl]-1-benzene synthesized above. The title compound (719 mg, 27%) was obtained as a white solid. ® JH NMR (300 MHz, CDCh) δ ppm 1. 06-1. 37 (m, 5H), 1.61-1.90 (m, 5H), 1.91-2.04 (m, 1H), 4.51-4.67 (m, 1H) , 6.61 (d, J=8.8 Hz, 2H), 7.16 (s, 1H), 7.21-7.36 (m, 2H), 7.67 (d, J=7. 0 Hz, 1H), 7.74 (d, J=7 9 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H). (4) 3-{[(4-{[l-benzothiophen-2-yl(cyclohexyl)methyl]amino} Phenyl) carbonyl](methyl)amino} cesium propionate In the same manner as in Example A1 (4), 4-{[1-benzothiophen-2-yl(cyclohexyl)methyl group synthesized above was used. Amino}benzoic acid (250 mg) and ethyl 3-(decylamino)propanoate (1 </ RTI> 8 mg) gave the title compound (277 mg, 90%). !H NMR (300 MHz, DMSO-de) ^ ppm 1.06-1.36 (m, 5H), 1.62-1.87 (m, 5H), 1.91-2.01 (m, 1H), 2.65 (t, J=6.4 Hz, 2H ), 3.01 (s, 3H), 3.69 (t, J=6.4 Hz, 2H), 4.49 (d, J=6.2 Hz, 1H), 6.58 (d, J=8.7 Hz, 2H), 7.15 (s, 1H) ), 7.18-7.35 (m, 4H), 7.64-7.70 (m, 1H), 7.71-7.76 314 321426 201029996 (m, 1Η). Example A6 3-{[(4-{[l-benzothiophene~ 2-yl(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propionic acid

4- 4-{[1-benzothiophen-2-yl(cyclohexyl)methyl]amino}benzoic acid synthesized in Example A5(3) was used in the same manner as in Example A (4). 250 rag) to give the title compound (275 mg, 92%). H NMR (300 MHz, CDCh) d ppm 1. 06-1. 35 (m, 5H), 1.61- 1.87 (m, 5H), 1.89-2.01 (m, ih), 2.60 (t, J=5· 7 Hz, 2H), 3. 55-3. 67 (m, 2H), 4.50 (d, J=6. 2 Hz, 1H), 6.53-

6.64 (m, 3H), 7.14 (s, 1H), 7.19-7.34 (in, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.66 (d, J=7.3 Hz, 1H), 7.72 (d , J=7. 9 Hz, 1H). Example A7 3-{[(4-{[cyclohexyl(l-methyl-lH-indazole-3-yl)methyl]amino)phenyl)carbonyl ](mercapto)amino}propionic acid 321426 315 201029996

N*x^N^C〇2H α) cyclohexyl (ι_mercapto-1H-azole-3~-yl)methanol The same procedure as in Example Al(l) was used, using 3-methyl (1.0 Gg) ) to obtain the standard of light yellow oil (799 mg, 52 «. % 曰 化 ❹ 4 legs (10) MHZ, CDCl3) (5ppml 〇3_137(m, 1.54(,, 1H), 1.60-1.82 ( ,, 3H), 1. 84-2. 03 (ro 2 ' 2.37-2.43 0Π, ΠΟ, 4.02(s, 3H), 4|4 89 (m,, 7.09-7.16(,, 1H), 7.31-7.41 (m, 2H), 7. 8〇

Hz, 1H). , 1 (2) 3-[Chloro(cyclohexyl)indenyl]~-methyl-methyl-bronze was taken in the same manner as in the example Al (2), using the above synthesized cyclohexyl group (1-A) Base-1H-indazol-3-yl)methanol (799 mg) (m. ' JH NMR (300 MHz, CDC13) δ ppm 0.92-1. 38 (m, 5H), \ 40_ 1.50 (m' 1H), 1.59-L 70 (m, 2H), 1.77-1.87 (m, 1H) 2.18 -2.40 (m, 2H), 4.03 (s, 3H), 5.06 (d, J = 8.7 Hz 1H), 7. 12-7.19 (m, 1H), 7.32 - 7.42 (m, 2H), 7.87 ( d J=8. 1 Hz, 1H). (3) 3-{ [(4-·([cyclohexyl(i-fluorenyl-iH-indazol-3-yl)methyliamine] i phenyl) Carbonyl](methyl)amino}propionic acid 321426 316 201029996 3-[Chloro(cyclohexyl)indenyl]-1-methyl-1H-indazole (465 mg) synthesized above, Example 2 (2 3-{[(4-Aminophenyl)carbonyl](fluorenyl)amino}propionic acid ethyl s-propane (531 mg), moth (531 mg) and N,N-didecyl Sodium carbonate (375 mg) was added to a mixture of the amine acetate (10 mL), and the mixture was stirred overnight under argon and 100 ° C. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed, dried over magnesium sulfate, and evaporated, evaporated, evaporated, evaporated. A 1N aqueous solution of ruthenium oxide (2.00 mL) was added to a mixture of solid, tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to dissolve residue. 1N Hydrochloric acid (2.0 mL) was added to water (10 mL), and the title compound (356 mg, 45%) was obtained as a white solid. (300 MHz, CDCh) 5 ppm 0. 97-1. 34 (m, 5H), 1.47-q 1.82 (m, 4H), 1.89-2.10 (m, 2H), 2.66 (t, J=6.5 Hz, 2H ), 3.03 (s, 3H), 3.69 (t, J=6. 5 Hz, 2H), 4.01 (s, 3H), 4.70 (d, J=7.0Hz, 1H), 6.60 (d, J=8.6Hz , 2H), 7.06-7.14 (m, 1H), 7.20 (d, J=8. 6 Hz, 2H), 7. 29-7.40 (m, 2H), 7. 74 (d, J=8. 1 Hz , 1H). Example A8 3-{[(4-{[cyclohexyl(2-indolyl-1-benzothiophen-3-yl)indolyl]amino}phenyl)carbonyl]amino}propionic acid 317 321426 201029996 ο

n,^C〇2h Η (1) 3 - Desert-2-mercapto-1-benzo D thiophene at 0 ° C in 2-methyl-1-benzothiophene (5.00 g) in acetic acid solution (50 Bromine (1.90 mL) was added dropwise to EtOAc and mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: R (300 MHz, CDC13) &lt;5 ppm 2. 56 (s, 3H), 7. 28-7. 36 (m, 1H), 7.36-7.44 (m, 1H), 7.67-7.75 (m, 2H (2) Cyclohexyl (2-methyl-1-benzothiophen-3-yl)methanol^ The above-prepared 3-bromo-2-indolyl-1-benzo[beta] phenanthrene was synthesized at -78 °C. (2.00 ❿ g) was dissolved in tetrahydrofuran (40 mL), and 1. 6 Μ n-butyllithium hexane solution (6. 63 mL) was added dropwise. The mixture was stirred under nitrogen for 10 minutes, cyclohexane furfural (2.50 mL) was added, and the mixture was stirred at -78 °C for 30 minutes, and then the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of chlorinated water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 318 321426 201029996 H NMR (300 MHz, CDCh) δ ppm 0.95-1.42 (m, 5jj^ 1.70 (m, 2H), 1.7 1.92 (m, 3H), 197_213 &amp; * 5 b 2.24 - 2.35 (m, 1H ), 2.54 (s, 3H), 4.74 (dd, Jg/j ^

Hz, 1H), 7.21-7.35 (m, 2H), 7.71-7.77 (m, 13⁄4) 7 2, 2 8.05 (m, 1H). 9 *97~ (3) 3-[Chloro(cyclohexyl)methyl ]-2-methylbenzothiophene was used in the same manner as in the Example Μ(2), using the above-mentioned (2-methyl-1-benzoindole-3-yl)methanol (195 gW obtained hexane oil) Title target compound (1. 98 g 95%). Brown HNMR (300 MHz, CDCh) δ ppm 0.70-0. 85 (m, 1H)S 〇9β_ 1· 40 (m, 4H), 1.49-1.91 (m , 4H), 2 24_2 32 (m 2.46-2.58 (m, 4H), 4.94 (d, J=l〇.5Hz, 1H), 7. 23-7. 36 (m, 2H), 7.70-7.75 (m , 1H), 7.99 (d, j = 7.5 Hz, (8) (4) 4-{[cyclohexyl(2-indolyl-benzobenzoin-3-yl)methyl]amino}benzoate ❹π as Example Al (3) In the same manner as in (3), the title compound (1 69 g, mp. (%) , 1.93-2.08 (m, 1H), 2.09-2.20 (m, 1H), 2.58 (s, 3H), 4.56 (d, J=8. 5 Hz, 1H), 6.46 (d, J=9. 0 Hz , 2H), 7.2 1-7.36 (m, 2H), 7.69-7.84 (m&gt; 4H). (5) 3-{[(4-·([cyclohexyl(2__methyl_丨_benzothiophene-3-yl)) Amine 319 321426 201029996 yl}phenyl)carbonyl]amino}propionic acid The same procedure as in Example Al (4) was used, using the above synthesized 4-{[cyclohexyl(2-mercapto-1-benzothiophene) -3_yl) fluorenyl]amino}benzoic acid (300 mg) to give the title compound (323 mg, 91%) as a white solid. H NMR (300 MHz, CDCh) δ ppm 0.94-1. (m, 5H), 1.40-1.51 (m, 1H), 1.61-1.72 (m, 2H), 1.78-1.88 (m, 1H), 1.92-2.07 (m, 1H), 2.09-2.20 (m, 1H) , 2.53-2.65 (m, 5H), 3.54-3.65 (m, 2H), 4. 52 (d, J=8. 7 Hz, 1H), 6.39-6.55 (m, 3H), 7.20-7.34 (m, 2H), 7.39-7.48 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H). Example A9 3-{[(4-{[cyclohexyl) (2-methyl-i-benzothiophene-3-yl) fluorenyl]amino}benzyl]carbyl](indenyl)aminopropionic acid

4-{[cyclohexyl(2-indolyl+benzothiophen-3-yl)methyl]amino}benzoquinone synthesized in Example A8(4) was used in the same manner as in Example A1 (4). Acid (300 mg) and ethyl 3-(decylamino)propanoate (124%) to give the title compound (312 mg, 85%). NMR NMR (300 MHz, CDCh) 5 ppm 0.95-1. 35 (m, 5H), 1.39-1.50 (m, 1H), 1.61-1.73 (m, 2H), 1.78-1.88 (m, 1H), 320 321426 201029996 1.91-2.06 (ra, 1H), 2.09-2.20 (ra, 1H), 2.57 (s, 3H), 2.58-2.67 (m, 2H), 2.99 (s, 3H), 3.67 (t, J=6.4 Hz , 1H), 4.50 (d, J=8.7 Hz, 1H), 6. 44 (d, J=8. 5 Hz, 2H)! 7.17 (d, J=8.5 Hz, 1H), 7.21-7.35 (m, 2H), 7.73 (d &gt; 7.2 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H). Example A10 3-{[(4-{[%, hexyl (3-methyl-b) Benzophenan-2-yl)methyl]amino} benzyl] benzyl]amino}propionic acid

(1) Cyclohexyl (3-methyl-1-benzoindole-2-yl)methanol The same procedure as in Example Al (1) was used, using 3-methyl-hydrazine- benzothiophene-2-carbaldehyde (2. 00 g) to give the title compound (1· 65 g, 56%) as a yellow oil. . H NMR (300 MHz, CDCh) δ ppm 0. 85-1. 36 (m, 5H) ] 4j_ 1.52 (m, 1H), 1.60-1.86 (m, 4H), 2.01 (d, J.3.3 Hz 1H) , 2. 14-2. 24 (m, 1H), 2. 37 (s, 3H), 4. 83 (dd J=8 j 3.3HZ, W, 7.27-7.39 (m, 2H), 7 62_7 67 ( Mh ' 7.77-7.82 (m, 1H). 5 Λ ❹ (2) 2-[Chloro(cyclohexyl)methyl]U group, j-stupyl n-cephene The same method as in Example Ai (2), using the above group (3-Methyl-1-benzoxepeno-2-yl)methanol (g), mp. 321426 321. δ ppm 0. 84-0. 99 (m, 1H), l.〇4_ 1.39 (m, 4H), 1.56-1.71 (m, 3H), 1.77-1.88 (m, ih)5 1.88-2.03 (m, 1H), 2.32-2.45 (m, 4H), 5.09 (d, J=9. 6

Hz, 1H), 7.29-7.39 (m, 2H), 7. 62-7. 67 (m, 1H), 775, 7.80 (ra, 1H). · (3) 4-{[裱己基(3-曱Benzyl benzothiophene-2-yl) fluorenyl hydrazinic acid The same procedure as in Example A1 (3) was used in the same manner as in the above-mentioned 2-[[(hexylhexyl)methyl]-3-methyl Base + benzo porphin (168 §) to give the title compound (1.63 g, γι%) as a yellow solid. Η 臓 (3GG MHz, CDCh) 5 Qing Q (M 34 (m, 5H), i 53_ 1.87 (m, 5H), 2.03-2.16 (m, 1H), 2.44 (s, 3H), 4 54-4.63 On, 1H), 6.46 (d, J=8 6Hz, 2H), [mg (team 1H), 7.30-7.38 (m, 1H), 7.63 (d&gt; J=7. 9 Hz, 1H), 7.69 ❹ ( d, J = 7.7 Hz, 1H), 7_75 (d, J = 8 6 Hz, 2H). (4) 3 {[(4-{[% hexyl (3-methyl + benzoxephen-2-yl) fluorenyl) Amino}phenyl)carbonyl]amino}propionic acid The same procedure as in the above Example (4) was carried out, using the above-mentioned 4-based thiophene-2-yl)methyl]amino}benzoic acid (3 〇〇 mg) ) to obtain the title compound (10) as a white solid 'H NMR (300 MHz, CDCh) d 1. 85 Cm, 5H), 2. 03-2. 14 ppml.〇l-1.34(m,5H) , 1.53-(m,m), 2.44 (s,3H),2.53 321426 322 201029996 (t, J=5. 6 Hz, 2H), 3.50-3. 61 (m, 2H), 4.54 (d, J= 7. 7Hz, 1H), 6.48 (d, J=8. 8 Hz, 2H), 6.58 (t, J=5.9 Hz, 1H), 7.20-7.27 (m, 1H), 7.29-7.37 (m, 1H), 7.46 (d, 1=8.8

Hz, 2H), 7.62 (d, J=7. 5 Hz, 1H), 7.67 (d, 1=7.5 Hz, 1H). Example All 3-({[4-({cyclohexyl[5-(three) Fluoromethyl)-1-benzothiophene-2-yl]hydrazino}amino)phenyl]carbonyl}amino)propionic acid

(1) 3-Methyl-5-(trifluoromethyl)-i-benzothiophene-2-furfural in Ot: in 3-methyl-5-(trifluoromethyl)-;[1-benzo To a solution of thiophene-2-carboxylic acid methyl ester (2.0 S) in tetrahydrofuran (40 mL) was added lithium aluminum hydride (292 mg) and the mixture was stirred for one hour. Add water (3 〇〇 〇〇 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 终止 1 1 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授The filtrate was reduced to obtain a white solid. Active manganese dioxide (9.00 g) was added to a solution of the obtained solid in tetrahydrofuran (4 mL), and the mixture was stirred overnight at room temperature, and manganese dioxide was filtered off. The filtrate was concentrated under reduced pressure to dryness crystals crystals crystalssssssssssssssssssssssssssssssssssss 323 201029996 8.06 (m, 1H), 8.11 (s, lH), 8.21-8.25 (m, 1H), 10.14 (s, 1H). (2) Cyclohexyl [3 - fluorenyl-5-(trifluoromethyl)- 1-benzothiophen-2-yl]methanol The same procedure as in the case of Al (l), using the above synthesized 3-methyl-5-(dimethylmethyl)-1-benzophenophen-2 Formic acid (1. 15 g) to give the title compound (86 mg, 55%) as a pale yellow solid. H NMR (300 MHz, CDCh) δ ppm 0.98-1.35 (m, 5H), 1.50-1.59 ( m, 1H), 1.62-1.85 (m, 4H), 1.95-2.06 (in, 1H), 2.12-2 .18 (m, 1H), 4.75 (d, J=7.2 Hz, 1H), 7.22 (s, 1H), 7.48-7.53 (m, 1H), 7.87-7.92 (m, 1H), 7.97 (s, 1H) (3) 2-[Gas (cyclohexyl)methyl]-3-methyl-7-(trifluoromethyl)-benzothiophene in the above synthesis of cyclohexyl [3-indolyl-5-(three Add sulfoxide (239#L) to a solution of fluorenyl)-1-benzoindole phen-2-yl]nonanol (860 mg) in benzene (20 mL) and at l〇〇°c The mixture was stirred for 1 hour. The reaction mixture was poured with EtOAc EtOAc EtOAc. The title compound (806 mg, 89%) was obtained as a pale brown oil..H NMR (300 MHz, CDCh) 5 ppm 0. 99-1. 37 (m, 5H), 1.58-2.01 (m, 5H ), 2.13-2.23 (m, 1H), 4.97 (d, J=7. 8 Hz, 1H), 7.29 (s, 1H), 7.51-7.56 (ra, 1H), 7.86-7.91 (m, 324 321426 201029996 Πί), 7. 96-7. 99 (m,ijj) (4) 4-({cyclohexyl[3-indolyl-5-(trifluoromethyl)-benzoyl- 2]yl]methylhydrazine Amino)benzoic acid with the interphase between the examples A1 (3) , the method of sulphate 仴U, using the above synthesis of 2_[chloro(3⁄4hexyl)methyl]-3-methylonda, rape, .C-fluoromethyl)-1-benzophenophene (8〇 6 mg) to give the title compound (68 7 7%) as a pale yellow oil. OMR (300 MHz, CDC13) (5 ppm 丨.oh 37 (m,5H),} 62_ 1.89 (m,5H), 1.90-2.00 (m,1H),4 58 (d,J=6 3 Hz, 1H ), 6.59 (d, J=8.7Hz, 2H), 7.25 (s, 1H), 7.45-7.50 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.84 (d, J=8. 7 Hz, 2H), 7. 93-7. 96 (m, 1H). (5) 3-({[4-({cyclohexyl)[5-(trifluoromethyl)- benzothiophene_2_ Methyl]amino)amino)phenyl]carbonyl}amino)propanoic acid The same procedure as in Example A1 (4) was used, using the above synthesized 4-indole (indole cyclohexyl [3-indolyl-5-( Trifluoroindolyl)-p-benzothiophene-2-yl]hydrazino} Amino)benzoic acid (68. 7 mg) </ RTI> The title compound (57. 8 mg, 73%). !H NMR (300 MHz, CDCh) δ ppm 1.02-1.36 (m, 5H), 1.59-1. 87 (m, 5H), 1.88-1.99 (m, 1H), 2.58 (t, J=5. 3 Hz , 2H), 3.54-3.66 (m, 2H), 4.51 (d, J=6.4 Hz, 1H), 6.56 (d, J=8.3 Hz, 2H), 6.63 (t, J=5. 7 Hz, 1H) , 7.22 (s, 1H), 7.43-7.49 (in, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.80 (d, 1=8.7 Hz, 1H), 7.93 (s, 1H). 325 321426 201029996 Example A12 3-({[4-({-Trifluoromethyl)-1-benzothiophen-2-yl]] Yl} amino) phenyl] several yl} amino) propanoic acid

(1) 3-Methyl-6-(dimethylmethyl)-j-benzo[beta]-sept-2-yl-in the same manner as in the example All (1), using 3-mercapto-6-( Methyl trifluoromethyl)-1-benzothiophene-2-carboxylate (2.07 g) gave the title compound (1·38 g, 75%). JH NMR (300 MHz, CDCls) 5 ppin 7.63-7.69 (m, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 8. 18-8.22 (m, 1H), 10.15 (s, 1H). (2) Cyclohexyl[3-indolyl-6-(trifluoromethylbenzilthiophen-2-yl)nonanol was used in the same manner as in Example Al(l). The above-prepared 3_mercapto-6-(difluoromethyl)-1-benzothiophene-2-formaldehyde (138 g) was obtained to give the title compound (668 mg, 35%) as a yellow solid. 300 MHz, CDC13) (5 ppm 〇35 (m, 5H),! 5〇_ 1.60 (m, 1H), 1.62-1.84 (m, 4H)&gt; L94_2. 〇4 (m, 1H), 2.15-2.20 (m, 1H), 4. 76 (dd, j=6&gt;9&gt; 3. 6 Hz, 1H), 7.21 (s, 1H)' 7. 52-7. 58 (m, 1H), 7.79 (d, J=8. i Hz,1H), 321426 326 201029996 8.06-8.10 (m, 1H). -6-(Trifluoromethyl)- benzo-(3) 2-[chloro(cyclohexyl)indenyl]_3 _Methylthiophene was used in the same manner as in Example All (3m), using the above-synthesis of methyl-6-(trifluoromethylbenzophenan-1-yl)methanol (10) (4) to give the title of brown oil. Target compound (93%).

NMR (300 MHz, CDCh) 5 ppml.〇〇-L37 (m, 5H), L 58_ 1.86 (m, 4H), 1.88-2.01 (m, iH)j 2. 12-2. 22 (in, 1H) 4.97 (d, &gt; 7.8 Hz, 1H), 7.28 (s, 1H), 7.53-7.58 (m! 1H), 7.80 (d, J=8.4 Hz, 1H), 8.05-8.08 (m, 1H). (4)4 -Ucyclohexyl[3-methyl+(trifluoromethyl)-benzobenzophen-2-yl]hydrazino}amino)benzoic acid was synthesized in the same manner as in Example A1 (3) using the above synthesis 2_ [Gas (cyclohexyl) fluorenyl]-3-methyl-6-(trifluoromethyl)-benzophenone (10) mg) to give the title compound (82 5 mg, 10%) ). !11 NMR (300 MHz, CDCh) δ PPm 1. 02-1. 37 (m 5H) 1 62- 1.88 (m, 5H), 1.90-1.99 (m, 1H), 4.58 (dj=6 3 Hz 1H) , 6.59 (d, J: 8 · 7 Hz, 2H), 7.23 (s, 1H), 7. 50-7.55 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.84 (dj=8 7 Hz 2H),7·99- 8. 02 (m,1H). (5) 3-({[4-({cyclohexyl[6-(trifluoromethyl)))) (])}amino}phenyl]carbonyl}amino)propionic acid 321426 327 201029996 In the same manner as in Example AK4), the above synthesis was used - ({cyclohexyl[3-mercapto-6-(three) Fluoromethyl)-benzophenan-2-yl]methyl}amino)benzoic acid (8). 5 mg)yield titled Compound (54.0 mg, 56%) 4 earn (10) leg, CDCl3) d (four) 35 (m, 5Η), 1 58-1.87 (in, 5H), 1.88-1.99 (m, 1H)&gt; 2.53-2.63 (m, 2H), 3. 54-3.66 (m, 2H)' 4.52 (d, j=6 l Hz, 1H), 6 56 (d, J-8. 7 Hz, 2H), 6.58-6.66 (m, iH)? 7.2〇(s, 1H) , 7.46- 7.55 (m, 3H), 7.73 (d, J=8. 3 Hz, 1H), 7.98 (s, 1H). Example A13 {[(4-{[cyclohexyl (3-methyl-i) - stupid and thiophene-2-yl) fluorenyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

4-{[cyclohexyl(3-methyl-indole_benzothiophen-2-yl)indenyl]amine synthesized in Example A1〇(;3) was used in the same manner as in Example Al (4). Phenyl phthalic acid (300 mg) and ethyl 3-(methylamino)propanoate (124 mg) afforded the title compound (269 mg, 73%). ]H NMR (300 MHz, CDCh) (5 ppm 1. 02-1. 34 (m, 5H), 1.53-1.87 (m, 5H), 2.05-2.16 (m, 1H), 2.45 (s, 3H), 2.59 (t, J=6.4 Hz, 2H), 2.97 (s, 3H), 3.65 (t, J=6.4 Hz, 328 321426 201029996 2H), 4.53 (d, J=7.5Hz, 1H), 6.50 (d, J=8. 7 Hz, 2H), 7. 18 (d, J=8.7 Hz, 2H), 7.22-7.29 (m, 1H), 7.30-7.38 (m, 1H), 7.63 (d, J=7. 5 Hz, 1H), 7.70 (d, J=7. 7 Hz, 1H). Example A14 3-{[(4-{[cyclohexyl(1-phenyl-iH-carbazol-3-yl)) Amino}phenyl)carbonyl]amino}propionic acid

(1) 1-Phenyl-1H-D, oxazolidine methyl ester in 1H-carbazole-3-carboxylic acid decyl ester (3.44 g), phenylboronic acid (4. 76 g), Add a solution of copper (11) (5. 32 g) to a mixture of pyridine (2.84 mL) and N,N-dimercaptocaramine (70 mL), and stir the mixture overnight at 3 (TC). The insoluble material was added to the residue and the aqueous solution of chloroacetate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound (1.58 g, 32%) was obtained eluted eluted elut elut elut elut elut elut elut elut elut 4.07 (s, 3H), 7.35-7.60 (m, 5H), 7.70-7. 77 (m, 3H), 8.30-8. 35 (m, ih). (2) 1-phenyl-1Η-σβίβ sit _3-Mex 321426 329 201029996 In a solution of the above synthesized 1-phenyl-1H-carbazole-3-carboxylic acid methyl ester (2.25 g) in tetrahydrofuran (40 mL) was added dropwise at 0 °C. 5M diisobutylaluminum hydride benzene solution (26.7 mL), and the mixture was stirred for 1 hour. 1N hydrochloric acid was added to complete The reaction was quenched, and the mixture was extracted with ethyl acetate. EtOAc was evaporated, evaporated, evaporated. Active manganese dioxide (8.00 g) was added to the solution of flurane (40 mL), and the mixture was stirred at 50 ° C for 5 hours. Additional active manganese dioxide (1.00 g) was added, and the mixture was stirred at 50 ° C for 1 hour. The manganese dioxide was filtered off, and the mash was concentrated under reduced pressure. The residue was purified by Shi Xisheng column chromatography (acetic acid ethyl acetate: hexane = 3: 17, volume ratio) to obtain a pale yellow oil. Title target compound (926 mg, 47%). NMR (300 MHz, CDCh) (5 ppm 7. 39-7. 47 (m, 1H), 7.47-7. 55 (m, 2H), 7 57-7.64 (m, 2H), 7.72-7.80 (m, 3H), 8.37-8.42 (m, 1H), 10.34 (s, 1H). q (3) cyclohexyl (1-phenyl-1H-indole) Zyridin-3-yl)methanol The same procedure as in Example Al (1) was used, and 1-phenyl-1H-carbazole-3-carbaldehyde (926 mg) synthesized above was used to obtain a pale yellow oil. Title target compound (716 mg, 56%). fiMR (300 MHz, CDCl3) (5 ppml.: n-1.31 (m, 5H), 1.51-1.84 (m, 4H), 1.94-2.08 (m, 2H), 2.52 (d, J = 4.5 Hz, 1H), 4.93-5.00 (m, 1H), 7.18-7.25 (m, 1H), 7.31-7.38 (m, 1H), 7.39-7.45 (m, 1H), 7.49-7.56 (m, 2H), 7.68-7.74 (m , 3H), 7.87-7.92 (m, 1H). 330 321426 201029996 (4) 3-[Chloro(cyclohexyl)methyl]-i-phenyl- iff-. Introduced in the above synthesized cyclohexyl group (1_ Add ruthenium chloride (256 μΙ〇) to a mixture of phenyl_1H-.sodium-3-yl)methanol (716 mg), pyridine (284 μΙ〇 and toluene (20 inL), and stir the mixture at room temperature 2 The mixture was quenched with a saturated aqueous solution of sodium hydrogen sulfate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. Title target compound (767 mg, quantitative) ❹ HNMR (300 MHz, CDCl3) (5 ppm 0.99-1.38 (m, 5H), 1.46-1.55 (m, 1H), 1.60-1.72 (m, 2H), 1.80-1.90 (m, 1H), 2.24-2.44 (in, 2H), 5.15 (d, J=9. 0 Hz, 1H), 7.21-7.27 (m, 1H), 7.32-7.39 (m, 1H), 7.40-7.46 (m, 1H), 7.49- 7.56 (m, 2H), 7.67-7.74 (m, 3H), 7. 96-8. 00 (m, 1H). (5) 3-{[(4-{[ring Hexyl-phenyl_1H-carbazole _3_yl) fluorenyl]amino} benzyl] benzyl]amino} propionate ❿ In the same manner as in Example A7 (3), the above synthesized 3_ [Chloro(cyclohexyl)methyl]-1-phenyl_1H-indazole (37 mg) and the 3-{[(4-aminophenyl)carbonyl]amino group synthesized in Example j(2) The title compound (791 mg, 14%) was obtained as a pale yellow solid. HNMR (300 MHz, CDCh) 5 ppm 1. 01-1. 36 (m, 5H), 1.54-1.84 (m, 4H), 1.98-2.13 (m, 2H), 2.52-2.64 (m, 2H), 3.53-3.66 (m, 2H), 4.81 (d, J=6. 8 Hz, 1H), 6.52-6.71 (m' 3H)' 7.16 (t, J = 7.6 Hz, 1H), 7.29-7.42 (m, 2H), 7. 45- 7. 56 (m, 4H), 7. 62-7. 71 (m, 3H), 7. 81 (d, J = 8.3 331 321426 201029996

Hz, 1H). Example A15 Carbonyl](methyl)amino}propionic acid

(amino) phenyl) 'Growth 丞-in-05iazole mg) and 3~{[(4-aminophenyl) benzyl](methyl)amine synthesized in Example 2(2) Base ethyl propionate (10) 5 mg) to give the title compound (76. 9 mg, 12%) as pale yellow (4). ❹ HNMR (300 MHz, CDCh) 5 ppm 1. 04-1. 35 (m, 5H), 1.54- 1.84 (m' 4H)' 1.98-2.13 (m, 2H), 2. 56-2.67 (m, 2H ), 2.99 (s, 3H), 3.67 (t, j = 61 Hz, 2H), 4 8 〇 (d, J = 6 4

Hz, 1H), 6.66 (d, J=8.7Hz, 2H), 7.13-7.18 (m, 1H), 7.21 (d, J=8.7 Hz, 2H), 7.30-7.42 (m, 2H), 7.52 (t , J=7. 8 Hz, 2H), 7.64-7.72 (m, 2H), 7.82 (d, J=8. 3 Hz, 1H). Example A16 3-UU-U cyclohexyl (3-mercapto+ Benzo[2]yl)methyl]amino} 321426 332 201029996 Phenyl)carbonyl](fluorenyl)amino}propionic acid

(1) 3-Mercapto-1-benzofuran-2-furaldehyde in a solution of 3-indolyl-1-benzopyran-2 -reoxyacetate (2.00 g) in tetrahydrofuran (40 mL) A solution of 1. 5 M diisobutylaluminum hydride hydrazine hydrazine (19. 6 mL) was added dropwise, and the mixture was stirred for 2 hr. 1N hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated Dess-Martin periodinane (4.96 g) was added to the obtained solid solution of dichloromethane (40 mL), and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium sulfite was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution Q and saturated brine, dried over sulphuric acid and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ]H NMR (300 MHz, CDCla) (5 ppm 2.63 (s, 3H), 7.30-7.37 (m, 1H), 7.48-7.58 (m, 2H), 7.67-7.71 (m, 1H), 10.03 (s, 1H). (2) Cyclohexyl (3-mercapto-1-benzofuran-2-yl) decyl alcohol The same method as in the example Al (l) was used, using the above synthesized 3_曱333 321426 201029996 base_ 1_Benzo-benzofuran-2-carboxylic acid (753 mg) ' to give the title compound (843 mg, 73%) as pale yellow oil.]11 NMR (300 MHz, CDCh) δ ppm 0. 85-1 〇3 (m, 1H), 1.03-1.34 (m, 4H), 1.34-1.44 (m, 1H), 1.60-1.71 (m, 2H), 1.75-1.99 (m, 3H), 2.10-2.20 (ra , 1H), 2.23 (s, 3H), 4.49-4.56 (m, 1H), 7.18-7.29 (m, 2H), 7.39-7.49 (m, 2H). (3) 2-[Gas (cyclohexyl) hydrazine 3-methyl-1-benzopyranopurine cyclohexyl (3-mercapto-1-benzopyran-2-yl) decyl alcohol (843 mg) and toluene (20 mL) synthesized above Add sulfite gas (256 μ〇' to the mixture and stir the mixture for 2.5 hours at room temperature and 1.5 hours at 5 ° C. Add saturated aqueous sodium bicarbonate solution to terminate the reaction, and Extract the mixture and wash the extract with saturated brine to The title compound (862 mg, 95%) was obtained as a yellow oil. m.H NMR (300 MHz, CDCla) δ ppm 0. 84-0. (m, 1H), 1.00- 1.37 (m, 4H), 1.42-1.53 (m, 1H), 1.57-1.77 (m, 2H), 1.77-1.88 (in, 1H), 2.12-2.28 (m, 4H) , 2.08-2.38 (m, 1H), 4.82 (d, J=9. 6 Hz, 1H), 7.14-7.33 (m, 2H), 7. 43-7.50 (m, 2H). (4) 3-{ [(4-.([Cyclohexyl(3-indolyl-i-benzofuran-2-yl)indolyl]amino fluorenylphenyl)carbonyl](methyl)amino}propionic acid as Example A7 ( The same procedure as in 3), using the above synthesized 2_[qi (3⁄4 hexyl)methyl]-3-methyl-1-benzofuran (429 mg) and the synthesis of 3 in Example 2 (2) 321426 334 201029996 -{[(4-Aminophenyl)carbonyl](methyl)amino-propionic acid ethyl ester (408 mg) - ield. H NMR (300 MHz, CDCls) δ ppm 0. 94-1. 37 (m, 5H), 1.47-1.58 (m, 1H), 1.60-1.73 (in, 2H), 1.73-1.83 (m, 1H), 1.84-1.98 (m, 1H), 2.03-2.15 (m, 1H), 2.25 (s, 3H), 2.59-2.69 (m, 2H), 3.01 (s, 2H), 3.68 Ct, J=6.5 Hz, 2H ), 4.38 (d, J=7.9 Hz, 1H), 6.56 (d, J=8. 7 Hz, 2H), 7.16-7.27 (m, 4H), 7.35-7.40 (m, 1H), 7.41- 7.45 (m, 1H). , Example A17 3-{[(4-{[cyclohexyl(3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amine Propionate

2-[Chloro(cyclohexyl)indolyl]-3-methyl-1-benzofuran (433 mg) synthesized in Example A16 (3) was used and carried out in the same manner as in Example A7 (3). 3-{[(4-Aminophenyl)carbonyl]amino}propanoic acid ethyl ester (390 mg), mp. . HNMR (300 MHz, CDCl3) 0'ppui〇.93-1.37 (in5H)146-1.59 (m,1H), 1.59-1.74 (m,2H),1.74-1.84 (m,1H), 321426 335 201029996 1.84- 1.99 (m, 1H), 2.02-2.13 (m, 1H), 2.25 (s, 3H), 2.55-2.66 (m, 2H), 3.57-3.68 (m, 2H), 4.40 (d, J=8.11) Hz, 1H), 6.51-6.65 (m, 3H), 7.14-7.25 (m, 2H), 7.34-7.39 (m, 1H), 7.39-7.45 (m, 1H), 7.52 (d, J=8. 9 Hz, 2H)· Example A18 3-{[(4-{[cyclohexyl(l-cyclohexyl-1H-indazol-3-yl)methyl]amino)phenyl)carbonyl](indenyl)amine Propionate

(1) Cyclohexyl-1H-indazole-3-carboxylic acid decyl ester in 1H-indazole-3-carboxylic acid decyl ester (5.0 g), cyclohexanol (9.0 mL), decyltriphenyl A mixture of phosphine (14-9 g) and tetrahydrofuran (100 mL) was added 40% diethyl azodicarboxylate benzene solution (25·6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added to the residue and evaporated. (: The mixture was stirred, the precipitate was filtered off, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1 : 9, volume ratio). The title compound (6. 84 g, 93%) was obtained as a pale red oil. H NMR (300 MHz, CDCh) ά ppm 1. 25-1. 43 (m, 1H), I.45- 1.62 (m , 2H), 1.72-1.82 (m, 1H), 1.90-2.00 (m, 2H), 321426 336 201029996 2.01-2.16 (m, 4H), 4.03 (s, 3H), 5, 50-5.62 (m, 1H ), 7.24-7.37 (m, 2H), 7.78-7.83 (id, 1H), 7.99-8.04 (m, 1H). (2) Cyclohexyl-1H-carbazole-3-carbaldehyde as Example A14 (2) The same procedure as above, using the above synthesized 1, decyl-1H-indazole-3-carboxylic acid decyl ester (3.08 g) to give the title compound (1.98 g, 73) as pale yellow oil. %).H NMR (300 MHz, CDCh) δ ppm 1. 31Ί. 43 (m, 1H), 1.45^ ® 1.63 (m, 2H), 1.74-1.84 (m, 1H), 1.92-2.02 (m, 2H), 2.06-2.18 (m, 4H), 5.24-5.36 (m, 1H), 7.33-7.43 (m, 2H), 7.83-7.90 (m, 1H), 7.98-8.05 (m, 1H), 10.32 ( s, 1H). * (3) Cyclohexyl (1-cyclohexyl-lH-°-bung-3-yl) decyl alcohol The same procedure as in the above Example (1) was carried out using the above-prepared product - hexyl-1H-carbazole-3-carbaldehyde (980 mg) to give the title compound as a white solid ( s. JH NMR (300 MHz, CDCh) δ ppm 0. 82-1. 00 (m, ih), \ 〇5 2.07 (m, 17H), 2.07-2.33 (m, 4H), 4.48-4.62 (ra, iH )^ 4.93 (dd, J=8.9, 3.6 Hz, 1H), 6.99-7.07 (m, 1H) '7. Claw 7.28 (m, 1H), 7.65-7.73 (m, 2H). (4) 3- [Chloro(cyclohexyl)methyl]-i-cyclohexyl oxime. The same procedure as in Example A14 (4) was used, using the above-mentioned cyclic ring-based U-cyclohexyl-lH-t-s--3-yl decyl alcohol. (934 mg) to give the title compound (1.05 g, quantitative). , 321426 337 201029996 ]H NMR (300 MHz, CDCh) δ ppm 0. 75-0. 89 (in, 1H), 1.06-2.08 (m, 16H), 2.09-2.38 (m, 3H), 2.45-2.56 ( m, 1H), 4.41-4.54 (m, 1H), 5.09 (d, J=10.5Hz, 1H), 7. 04-7. 11 (in, 1H), 7.21-7.29 (m, 1H), 7.66- 7.72 (m, 2H). (5) 3-{[(4-{[cyclohexylcyclohexyl_1H-carbazole-3-yl)indenyl]amino}phenyl)carbonyl](methyl)amino }propionic acid The same procedure as in Example A7 (3) was used, using 3-[chloro(cyclohexyl)methyl]-1-cyclohexyl-1H-indazole (4 mg) synthesized above and Example 2 (2) 3-{{(4-Aminophenyl)carbonyl](indolyl)amino}propionic acid ethyl ester (303 mg) 72%). NMR NMR (300 MHz, CDCh) (5 ppm 0.92-1. 50 (m, 9H), 1.61-2.04 (m, 9H), 2.06-2.29 (in, 3H), 2.57-2.69 (m, 2H), 2.99 (s, 3H), 3.67 (t, J = 6.2 Hz, 2H), 4.43-4. 57 (m, 1H), 4.72 (d, J = 8.3 Hz, 1H), 6.47 (d, J=8. 7 Hz, 2H), ❹ 6.99-7. 06 (m, 1H), 7. 17 (d, J=8.7 Hz, 2H), 7. 20- 7. 29 (m, 1H), 7. 65-7. 73 (m, 4H). Example A19 3-{[(4-{[cyclohexyl(l-cyclohexyl_iH-indazol-3-yl)indolyl]amino}phenyl)carbonyl]amino} Propionic acid 338 321426 201029996

N^^\^C02H was synthesized in the same manner as in Example A7 (3) using 3-[chloro(cyclohexyl)fluorenyl; μ-cyclohexyl-1H-carbazole synthesized in Example 18(4). (4 〇〇 mg) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (286 mg) synthesized in Example 1 (2) to obtain the title target as a white solid. Compound (441 mg, 72%). ]H NMR (300 MHz, CDCh) δ ppm 0.93-1. 48 (m, 9H), 1.61-2. 04 (m, 9H), 2. 03-2. 29 (m, 3H), 2. 61 ( t, J=5. 7 Hz, 2H), 3.54-3.69 (m, 2H), 4.43-4.55 (ra, 1H), 4.74 (d, J=8.3Hz, 1H), 6.46 (d, J=8. 7 Hz, 2H), 6.67 (t, J=5. 8 Hz, 1H), 6.97-7.06 (m, 1H), 7.18-7.29 (m, 1H), 7.46 ❹(d, J=8.7 Hz, 2H) , 7. 68 (d, J = 9.4 Hz, 2H). Example A20 3-{[(4-{[cyclohexyl(7-methoxy-i-benzofuran-2-yl)indenyl]amine Base} base]|carbon-based]amino}propionic acid

(1) 7-methoxy-1-benzoquinone-p-butan-2-carboxyl 321426 339 201029996 In the same manner as in Example A14 (2), 7-methoxy-indole-benzofuran-2- The title compound (950 mg, 59%) was obtained as a brown oil. H NMR (300 MHz, CDCI3) (5 ppm 4. 〇4 (s 3H) 6 96-7. 00 (m, 1H), 7. 22-7. 34 (m, 2H), 7_54 (s, 1H) , 9.90 (s, 1H). (2) Cyclohexyl (7-decyloxy-1-benzofuran-2-yl)f alcohol. In the same manner as in the example Al (l), the above synthesized 7_ The title compound (790 mg, 56%) was obtained as a yellow oil. H NMR (300 MHz, CDCh) δ ppm 1. 〇2-l. 34 (raj 5H), 1.49-1.60 (m, 1H), 1.60-1.83 (m, 3H), 1.84-2.02 (ra, 3H), 4.00 (s, 3H), 4.53-4.59 (m , 1H), 6.60 (s, 1H), 6.74- 6.81 (m, 1H), 7.09-7.17 (m, 2H) (3) 2-[Chloro(cyclohexyl)fyl]-7-methoxy_丨_benzofuran The same procedure as in the example Al (2) was used, using the cyclohexyl (7-methoxy-1 benzofuran-2-yl)methanol (790 mg) synthesized above to obtain Title title compound (823 mg, 97%) in yellow oil. !H NMR (300 MHz, CDCh) δ ppm 1. 02-1. 37 (m, 5H), 1.55-1.84 (m, 4H), 2.06 -2.25 (m, 2H), 4.01 (s, 3H), 4.81 (d, J=7· 8 Hz' 1H), 6.67 (s, 1H), 6. 75-6.83 (m, 1H), 7. 10 -7. 18 ( m,2H). (4) 3-{[(4-·[[cyclohexyl(7-decyloxy);[_benzofuran-2-yl)indolyl]amino}phenyl]carbonyl]amine Propionate in the same manner as in Example A7 (3), using the above synthesized 2__[chloro340 321426 201029996 (cyclohexyl)methyl]-7-methoxy-i-benzofuran (422 mg) and carried out 3-{[(4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (357 mg), mp. , 9%).H NMR (300 MHz, CDCh) &lt;5 ppm 1. 02-1. 34 (m, 5H), 1.54-1.82 (m, 4H), 1.87-2.07 (m, 2H), 2.64 (t, J=5.6 Hz, 2H), 3.59-3.69 (m, 2H), 4.00 (s, 3H), 4.43 (d, J=6.4

Hz, 1H), 6.50 (s, 1H), 6.53-6.61 (m, 3H), 6.75 (dd, J=7. 5, 1.3 Hz, 1H), 7.02-7.13(m, 2H), 7.53 (d, J=8. 7 Hz, 2H). Example A21 3-{[(4-{[cyclohexyl(7-decyloxy-i-benzofuran-2-yl)methyl]amino}} (methyl)amino}propionic acid

2-[Chloro(cyclohexyl)methyl]-7-methoxy-j-benzopyran (4〇) synthesized in Example A2(3) was used in the same manner as in Example A7 (3). M()) and 3-{[(4-aminophenyl)carbonyl](indenyl)-mercapto}propane S (360 mg) 'synthesized in Example 2 (2) to obtain a white solid Title target compound (48. 7 mg, 7%). NMR (300 MHz, CDC13) (5 ppm 1.03-1· 34 (m, 5H), 1.54-321426 341 201029996 1·82 (m, 4H), 1.88-2.08 (m, 2H), 2. 68 (t, J=6 4 Hz 2H), 3.04 (s, 3H), 3.71 (t, J=6.4 Hz, 2H), 4 〇1 (s' 3H), 4.42 (d, J=6.6 Hz, 1H), 6. 51 (s, 1H), 6.57 (/ J=8.7Hz, 2H), 6.76 (dd, &gt;7.3, 1.5 Hz, 1H), 7.04-7.15 (m, 2H), 7. 24 (d, J=8 7 Hz, 2H). Example A22 3-{[(4-U-cyclohexyl(5-methoxy-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino }propionic acid

(1) 5-methoxy-1-benzopyrene-2-carboxylic acid Ethyl 5-methoxy-indole-benzofuran-2-carboxylate was used in the same manner as in Example A14 (2) (2.00 g) 'To obtain the title compound (914 mg, 57%) as a brown solid. 'H NMR (300 MHz, CDCh) δ ρριη 3.86 (s, 3Η), 7.10-7.16 (m, 2Η), 7.46-7.52 (m, 2H), 9.82 (s, 1H). (2) Cyclohexyl (5) -Methoxy-l-benzofuran-2-yl)methanol The same procedure as in the case of Al(l) was used, using 5-methoxy-1-benzofuran-2-furaldehyde as synthesized above ( The title compound (702 1^, 52%;) was obtained as a brown oil. Η R (300 MHz, CDC13) 5 ppra〇.35(m,5jj), 1.47- 342 321426 201029996 1.58 (m, 1H), 1.60-2.02 (m, 6H), 3.83 (s, 3H), 4 4 ?_ 4.53 (m, 1H), 6.54 (s, 1H), 6.85 (dd, J=8. 7, 2 7 Hz 1H), 6.99 (d, J=2.7Hz, 1H), 7.33 (d, J= 8.7 Hz, (3) 2-[Chloro(cyclohexyl)methyl]-5-methoxy_i_benzopyrene The same procedure as in Example (1 (2) was used, using the cyclohexyl group synthesized above (5) - methoxy-1-benzofuran-2-yl)methanol (7 〇 2 mg) to give the title compound (722 mg, 96%) as a brown oil. H NMR (300 MHz, CDCls δ ppm 0. 98-1. 38 (m, 5H), i 5^ 1.86 (m, 4H), 2.06-2.21 (m, 2H), 3.83 (s, 3H), 4.75 (d, J=8. 1 Hz, 1H), 6.59-6.61 (m, 1H), 6. 88 (dd, J=8 9 2. 4 Hz, 1H), 6.97 (d, J=2. 4 Hz, 1H), 7.33-7.38 (m, 1H) (4) 3 {[(4 {[cyclohexyl(5-methoxyl-1,4-benzoindole]-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid 2-[Chloro(cyclohexyl)methyl]-5-methoxy-indole-benzofuran (360 mg) synthesized above, 3_{[(4-aminophenyl) synthesized in Example 1 (2) Ethyl carbonyl]amino propyl propionate (305 Mg) Add sodium carbonate (2〇6 mg) to a mixture of sodium iodide (291 mg) and N,N-dimethylacetamide (10 mL) at 80 (: mix the mixture overnight. Add The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. 9. The volume fraction was purified to obtain a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (2.5 mL) and ethanol (2.5 mL) was added 1 N aqueous sodium hydroxide (1 mL) and The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 343 321 426 &lt;RTI ID=0.0&gt;&gt; The title compound (96 mg, 17%) was obtained as a yellow solid. NMR (300 MHz, CDCh) 5 ppm 1. 02-1. 35 (m, 5H), 1.54-1.84 (m, 4H), 1.85-2.01 (m, 2H), 2.60-2.69 (m, 2H), 3.59 -3.70 (m, 2H), 3.80 (s, 3H), 4.38 (d, J=6.4 Hz 1H), 6.44(s, 1H), 6. 53-6. 62 (m, 3H), 6.82 (dd, J=9. l! 2. 7 Hz, 1H), 6.92 (d, J=2.7 Hz, 1H), 7_3〇 (Mountain j=9.i Ό Hz, 1H), 7.54 (d, J=8. 7 Hz, 2H). Example A23 3-{[(4-{[3-indolyl-i-(3-mercaptobenzofuran-2-yl)butyl]amino}phenyl)carbonyl]amino }propionic acid

(1) N-methoxy-N,3-dimethyl-1-benzox-sigma-sigma-2-carboxamide in 3-mercapto-benzofuran-2-indoleic acid (15 〇g ), Ν 〇 dimethyl hydroxylamine hydrochloride (9. 95 g), 1-hydroxybenzotriazole • monohydrate (15.6 g), triethylamine (14.2 mL), and hydrazine, hydrazine-II 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.6 g) was added to a mixture of methylformamide (150 mL) and stirred at room temperature The mixture was overnight. Further, N,0-dimethylhydroxylamine hydrochloride (4. 16 g), 1-hydroxybenzotriazole monohydrate (6·52 g), triethylamine (5. 94 inL), and 1 were added. -ethyl-3-(3-dioxin 344 321426 201029996 amidopropyl) carbodiimide hydrochloride (8. ng), and the mixture was stirred at room temperature for 4 hr. 1N hydrochloric acid was added to terminate the reaction, and the mixture was taken with ethyl acetate =. The extract was washed with aq. The residue was purified by silica gel column chromatography (ethyl acetate: (4), dec., s.), to give the title compound (16 2 g § j. ]H NMR (300 MHz ,CDC13) d _ 2.51'(s °3in h Ο ^ 3.37 (s, 3H), , 25-, 32 (m, 1H); , ^;::;:; 2H), 7.58-7.63 (m, 1H (2) 3-Methyl-1-(3-methyl-i-benzofuran-2-yl)butanone synthesized at 0 ° C above N-decyloxy _n, 3-dimethyl Base

Into the tetrahydrocarbamate aGG g) tetrahydrogenate solution (2) mL), 1 〇M desertified isobutylate tetrahydron liquid (6.84 mL) was added dropwise, and the mixture was stirred for 1 hour. Town tetrazide solution (6 84 mL) 'and mix the mixture at TC for 2 hours, then drop at room temperature for 2 hours. Add saturated aqueous ammonium chloride solution, and extract the mixture with ethyl acetate. The residue was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by gel column chromatography (ethyl acetate: hexanes: 9 vol.) to obtain a colorless oil. Title target compound (873 mg, 89%) i〇MR (10) MHz, CDChW ppml.〇2 (d, J=6 9Hz, 6H), 2.26-2.41 (m, 1H), 2.61 (s, 3H) , 2.87 (d, J=6. 9 Hz, 2H), 7.26-7.33 (m, 1H), 7.42-7.53 (m, 2H), 7.62-7.67 (m, 1H). 321426 345 201029996 (3) 4- {[3-Methyl-1-(3-methyl-1-benzofuran-2-yl)butyl]amino} benzoyl methacrylate 3-oxo-1 synthesized above at 0 °C -(3-Methyl-1-benzopyran-2-yl)butan-1-one (200 mg), 4-aminobenzoic acid methylg (140 mg), Sanyiyue female (1 · Titanium chloride (IVK122 μΙ〇' was added to the mixture of 0 3 niL ) and the gas hyacic acid (5 inL) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and acetonitrile was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure to give a dark brown solid to obtain solid, acetic acid (1 mL), simmer (5 niL) and Sodium cyanoborohydride (175 mg) was added in a small amount in a mixture of EtOAc (5 mM), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and ethyl acetate was added. The mixture was extracted with EtOAc (EtOAc m. Obtained the title target compound (254 mg, 78%) as a pale yellow solid.] H NMR (300 MHz, CDCls) &lt;5 ppm 〇. 92 (d, J=6. 6 Hz, 3H) 1.01 (d , J=6.6Hz, 3H), 1.49-1.64 (m, 1H), 1.79-1 96 (m, 2H) , 2.29 (s, 3H), 3.81 (s, 3H), 4.48 (d, J = 7, 8

Hz, 1H), 4.70-4.80 (m, 1H), 6.58 (d, J=8.9 Hz, 2H), 7.16-7.26 (m, 2H), 7.34-7.39 (m, 1H), 7.41-7.45 (m 1H ), 7.80 (d, J=8.9 Hz, 2H). '(4) 4-{[3-Methyl-1-(3-methyl-1-benzofuran-2-yl)butyl]amino group } Benzoic acid 321426 346 201029996 4-{[3-methyl+(3-methyl+benzoxanthyl)butyl]amino}benzoic acid methyl (1.38g), tetrahydrogen synthesized above A 1 N aqueous solution of sodium hydroxide (10 mL) was added to a mixture of ss. (2 s) and ethanol (20 mL), and was heated under reflux and the mixture was stirred overnight. Further, 1N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was heated under reflux and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure. EtOAc. The extract was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether to give the title compound (1.06 g, 80 W. H NMR (300 MHz, CDCI3) (5 ppm 〇· 92 (d, J=6. 6 Hz, 3H) 1.01 (d, J=6. 6 Hz, 3H), 1.49-1.64 (m, 1H), 1.79-1. 97 (ra, 2H), 2.30 (s, 3H), 4.77 (t, J=7.5 Hz, 1H), 6.59 (d, J=9.0 Hz, 2H), 7.16-7.28 (m, 2H), 7.35-7.40 (m, 1H), 7.42-7.47 (m, 1H)} 7.86 (d, J= 9. 0 Hz, 2H). Q (5) 3_{[(4-{[3-Mercapto-1-(3-methyl-benzofuran-2-yl)butyl]amino}phenyl Carbonyl]amino}propionic acid In the same manner as in the example Al (4), 4_{[3-methyl-1-(3-methyl-1-benzofuran-2-yl) synthesized above was used. Butyl]amino benzoic acid (300 mg) to give the title compound (289 mg, 80%) as a white solid. &lt;&gt;H NMR (300 MHz, CDCh) δ ppm 〇. 91 (d, J=6 6 Hz, 3H), 1.00 (d, J=6.6Hz, 3H), 1.48-1.64 (m, 1H), 1. 78-1.94 (m, 2H), 2.28 (s, 3H), 2.64 (t, J=5. 5 Hz, 2H), 3.60-347 321426 201029996 3.69 (m, 2H), 4.73 (t, J=7.5 Hz, 1H), 6.54-6.65 (m, 3H), 7.15-7.26 (in, 2H ), 7.34-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.54 (d, J=8. 7 Hz, 2H). Example A24 3-{mercapto[[4-{[3-indolyl-l-(3~methyl-i-benzofuran-2-yl)butyl] Amino}phenyl)carbonyl]amino}propionic acid

I 4-(3-mercapto-1-(3-methyl-1-benzofuran-2-yl) synthesized in Example A23(4) was used in the same manner as in the Example A (4). Butyl]amino}benzoic acid (300 mg) and ethyl 3-(methylamino)propanoate (HO mg) afforded the title compound (221 mg, 59%). !H NMR (300 MHz, CDCh) δ ppm 0.91 (d, J=6. 6 Hz, 3H), © 1.00 (d, J=6.6Hz, 3H), 1.48-1.64 (m, 1H), 1.81-1.92 (m, 2H), 2. 29 (s, 3H), 2. 61-2. 71 (m, 2H), 3. 03 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 4.71 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 8.5 Hz, 2H), 7.16-7.29 (m, 6H), 7.35-7.40 (m, 1H), 7.41-7.46 (m, 1H). Example A25 3-U(4-·([cyclohexyl(5-methoxy-1-benzofuran-2-yl)indolyl]amino}phenyl)carbonyl](indenyl)amino}propyl Acid 321426 348 201029996

n^\zc〇2h Using the same procedure as in Example A22 (4), 2-[chloro(cyclohexyl)indenyl]-5-decyloxy-1-benzene synthesized in Example a22(3) was used. Furan (361 mg) and 3 - UU-aminophenyl)carbonyl](indenyl) hydrazino}ethyl propionate (325 ms) synthesized in Example 2 (2) to give a white solid title The target compound (87. 0 mg, 14%). ^ NMR (300 MHz, CDCh) δ ppm 1.02-1. 36 (m, 5H), 1.55-1.84 (m, 4H), 1.86-2.01 (m, 2H), 2.61-2.74 (m, 2H), 3.04 ( s, 3H), 3.71 (t, J=6.2 Hz, 2H), 3.81 (s, 3H), 4.36 (d, J=6. 1 Hz, 1H), 6.45 (s, 1H), 6.57 (d, J =8. 7

Hz, 2H), 6.83 (dd, J=8. 9, 2. 5 Hz, 1H), 6.94 (d, J=2.5

Hz, 1H), 7.21-7.29 (m, 2H), 7.31 (d, J=8.9 Hz, 1H). ®Example A26 * 3~{[(4-{[cyclohexyl (2-ethyl-i-) Benzofuran-3-yl)methyl]amino} Benzo)alkyl](methyl)amino}propionic acid

(1) 裱-hexyl (2-ethyl-1-benzofuran__3_yl)methanol The same procedure as in the example Al (l), using 2-ethyl-b-benzophenone 321426 349 201029996 - Formaldehyde (1.20 g) 'A title compound (1.76 g, 99%). τ mouth NMR (300 MHz, CDCla) d ppm 〇. 79-〇. 94 (ffl5 1H) } 〇1_ 1.19 (m,3H), 1.20-1.34 (m,4H),i.37_146 (m,(8) 1.57- 1.70 (m,2H)' 1.77-2.02 (m,3H), 2.17-2.27 (m, 1H), 2. 70-2. 85 (m, 2H), 4. 54 (dd, J=8. 2. 7 Hz 1H) 7. 14-7.24 (m, 2H), 7.37-7.41 (m, in), 7.60-7 65 (m 1H).

(2) 3-[Chloro(cyclohexyl)methyl]-2-ethyl-b-benzopyrene The same procedure as in Example Al (2) was used, using the above-mentioned cyclohexyl (2-ethyl-1) - benzofuran-3-yl)methanol (763 mg), m. H NMR (300 MHz, CDCh) &lt;5 ppm 〇. 75-0. 89 (m, 1H) 1 〇〇-1.39 (m, 7H), 1.43-1.53 (m, 1H), 1.58-1.69 (m, 2H), 1.78-1.89 (m, 1H), 2.12-2.26 (m, 1H), 2.35-2.46 (m, 1H), 2. 70-2. 85 (m, 2H), 4.78 (d, J=9 9 Hz, 1H), 7.14-7.28 (m, 2H), 7.37-7.42 (m, 1H), 7.67-7.72 (m, 1H). (3) 3-{ [(4-{[cyclohexyl (2) -ethyl-i-benzofuran_3_yl)methyl]amino}phenyl)carbonyl](fluorenyl)amino}propionic acid The same procedure as in Example A22 (4) was used, using the above synthesis 3-[Chloro(3⁄4-hexyl)decyl]-2-ethyl-1-benzofuran (3〇〇mg) and 3-{[(4-aminophenyl) synthesized in Example 2(2) The title compound (287 mg, 57%) was obtained as a white solid. 321426 350 201029996 】H NMR (300 MHz, CDC13) (5 ppm 0.87-1.23 (m, 5H), 1.28 (t, J=7.5 Hz, 3H), 1.55-1.75 (ra, 3H), 1.75-1.98 (m , 2H), 2.04-2.15 (m, 1H), 2.61-2.71 (m, 2H), 2.75-2.90 (m, 2H), 3.02 (s, 3H), 3.69 (t, J=6.4 Hz, 2H), 4.30 (d, J=7.9Hz, 1H), 6.49 (d, J=8.7 Hz, 2H), 7.12-7.24 (m, 4H), 7.35-7.41 (m, 1H), 7.53-7.59 (m, 1H) Example A27

3-{[(4-{[cyclohexyl(5-decyloxy-3-methyl-1-benzofuran-2-yl)methyl]amino)phenyl)carbonyl](fluorenyl)amine Propionic acid

(1) 5-decyloxy-3-mercapto-1-benzophenone d-nan-1-rebel acid vinegar hydrazine in 1-(2-hydroxy-5-nonyloxyphenyl)ethanone (5. a mixture of potassium carbonate (12.5 g), a mixture of methyl bromoacetate (3.13 mL) and N,N-dimercaptocaramine (50 mL), and the mixture was stirred at room temperature. Overnight. Water was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. Sodium decoxide (1·3 g) was added to a methanol solution (5 〇 mL) of the obtained oil, and the mixture was stirred under reflux for 3 hr. 1N hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO.sub. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc , HNMR (3〇〇MH^ CDCIO, ppm2.57 (Sj 3Ηχ 3&gt;87 (s&gt; 3H), 3.97 (s, 3H), 6.99 (d, J=2. 6 Hz, 1H), 7.06 (dd, J=9. 0, 2.6 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H). (2) 5-methoxy-3-indolyl_;[_benzofuran-2-formaldehyde 0 0 C is added lithium aluminum hydride (862 mg) in a solution of 5 methoxy-3-methyl-ι-benzo-benzopyrene (5.00 g) in tetrahydrofuran (1 mL), and The mixture was stirred for 1.5 hours. Water (86 〇 / zL) was added to terminate the reaction, 1 N aqueous sodium hydroxide solution L) was added, and the mixture was stirred at room temperature for 1 hour. The insoluble matter produced was filtered off and decompressed. The filtrate was concentrated to give a pale-yellow solid. Toluene (21.2 g) was added to a solution of the obtained solid in tetrahydrofuran (8 〇mL), and the mixture was stirred overnight at 5 TC. Manganese dioxide was filtered off and The filtrate was concentrated under reduced pressure to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssss (d, J=2. 5 Hz, 1H), 7. 14 (dd, J=9. 〇, 2.5 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 10.00 (s, 1H). (3) Lycium hexyl (5-decyloxy-3-mercapto-1-benzophenan-2-yl) decyl alcohol using the above-exemplified Example Al(l) 5-曱Oxy-3-indolyl-1-benzofuran-2-carbaldehyde (1. 50 g) </ RTI> </ RTI> <RTI ID=0.0> , CDCh) 5 ppm 0. 84-0. 99 (m, 1H), 1. 〇〇- 352 321426 201029996 1.33 (m,4H),1.33-1.44 (m,1Η),1·6〇~ι·7 〇(m,2H), 1.74-1.99 (m, 3H), 2.09-2.22 (m, 4H), 3 〇5 Cs 3H) -H, 1H), ,86(dd, ,88 7;2:6Η; ; 1H), 6.91 (d, J=2. 6 Hz, 1H), 7.30 (d, J=8. 7 Hz, 1H). (4) 2-[Gas (cyclohexyl)indenyl]methoxy_ 3~Methyl y-benzofuran The above synthesized cyclohexyl group (5-decyloxy-3-indolyl-1-benzofuran-2-yl) was used in the same manner as in the shell example A1 (2). Methanol (754 mg) was obtained as a target compound (795 mg, 99%). ]H NMR (300 MHz, CDCh) ^ ppm 0. 83-0. 97 (m, 1H), 1.00- 1.40 (m, 4H), 1.42-1.52 (m,in), 1.60-1.70 (m,2H) , 1.77-1.87 (m, 1H), 2.10-2.38 (m, 5H), 3.85 (s, 3H), 4.80 (d, J-9. 6 Hz, 1H), 6.86-6.91 (m, 2H), 7 31-7 36 (m, 1H). (5) 3-{[(4-{[cyclohexyl(5-methoxy-3-indolyl-benzofuran-2-yl)indolyl]amino} Phenyl) benzyl](methyl)amino} cesium propionate The same procedure as in Example A22 (4) was used to use the above-synthesized 2-[qi(cyclohexyl)methyl]-5-decyloxy- 3-mercapto-1-benzofuran (395 mg) and 3-{[(4-aminophenyl)carbonyl](methyl)aminopropionate ethyl ester synthesized in Example 2 (2) 338 mg) to give the title compound (305 mg, 47%). ]H NMR (300 MHz, CDCh) δ ppm 0. 93-1. 37 (m, 5H), 1.47-1.57 (m, 1H), 1.60-1.96 (m, 4H), 2.03-2.13 (m, 1H) , 2.23 (s, 3H), 2.65 (t, J=6.4 Hz, 2H), 3.02 (s, 3H), 3. 69 (t, J=6.4 Hz, 2H), 3.83 (s, 3H), 4. 36 (d, J=8. 0 353 321426 201029996

Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6.82 (dd, J-8. 9, 2.4 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 7.19-7.29 (m, 3H). Example A28 3-丨[(4-{[cyclohexyl(6-decyloxy-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](曱Amino}propionic acid

(1) 6-decyloxy-1-benzofuran-2-indolecarbonitrile in 2-hydroxy-4-decyloxybenzaldehyde (10.0 g), bromoacetonitrile (5.04 mL) and acetone ( Potassium carbonate (18.1 g) was added to a mixture of 100 mL), and the mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a pale brown solid. Add 1,8-diazabicyclo[5.4.0]undec-7-ene (9.83 mL) to the obtained solid N,N-dioxylcarbamide solution (100 mL), and The mixture was stirred at 140 ° C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (5. 32 g, 47%) was obtained. R (300 MHz, CDC13) (5 ppm3.88 (s, 3H), 6. 96-7. 04 354 321426 201029996

Cm, 2H), 7.39 (d, J = 0.9 Hz, 1H), 7.52 (d, 1 = 8.5 Hz, 1H). (2) Cyclohexyl (6-decyloxy-i-benzofuran-2 To a solution of 6-methoxy-1-benzofuran-2-indanonitrile (1 〇〇g) in tetrahydrofuran (20 niL), a solution of L0M cyclohexylmagnesium tetrahydrofuran (11.5) was added. (5 mL), and the mixture was stirred overnight at TC and stirred under reflux for 1 hour. A saturated aqueous solution of ammonium sulphate was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. The magnesium was dried and concentrated under reduced pressure. EtOAc (EtOAc:EtOAc: %) H NMR (300 MHz, CDCh) δ ppm 1. 20-1. 64 (m, 5H), 1.69-1.79 (m, 1H), 1.81-1.98 (m, 4H), 3.09-3.21 (m, (H, 1H) 8.4 Hz, 1H). ❹(3) [Cyclohexyl (6-methoxy-1-benzofuran-2-yl)methyl]aminoj-benzoic acid methyl ester as Example A23 In the same manner as in (3), the above synthesized cyclohexyl (6-methoxy-1-benzonofol-2-yl)carboxamidine (584 mg) was used to obtain the title target as a brown oil. Compound (682 mg, 77%).]H NMR (300 MHz, CDCh) δ ppm 1. 03-1. 36 (m, 5H), 1.56-1.84 (m, 4H), 1.86-2.00 (m, 2H) , 3.81 (s, 3H), 3.83 (s, 3H), 4.35-4.57 (m, 2H), 6.44 (s, 1H), 6.58 (d, J=8.9Hz, 1H), 6. 81 (dd, J =8. 6, 2. 3 Hz, 1H), 6.97 (d, 321426 355 201029996 J=r8. 6 Hz, 1H), 7. 80 Cd, J=8. 9 J=2. 3 Hz, 1H), 7. 31 (d, Hz, 2H). methoxy-1-benzofuran-2-yl)methyl]amino} (4) 4-{[cyclohexyl (6-methoxy; benzoic acid In the embodiment A23 (4), the phase is printed aa ', 丄 _

Mg, 96%) °

1. 86 (m, 4H), 1· 86-2. 01 (m, PPm 1. 02-1. 37 (m, 5H), 1. 56-2H), 3.83 (s, 3H), 4.36- 4.46 (m, 1H), 4.48-4.65 (m, iH), 6.45 (s, 1H), 6.60 (d, J=8. 9 Hz, 2H), 6.82 (dd, J=8. 6, 2. 3 Hz , 1H), 6.98 (d, J=2.3 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.86 (d, J=8. 9 Hz, 2H). (5) 3 {[(4 -{[cyclohexyl(6-decyloxy-i-benzoxan-2-yl-2-yl)methyl]nonylamino}phenyl)carbonyl](methyl)amino}propionic acid as Example Al ( 4) In the same manner, using the above synthesized 4_{[cyclohexyl(6-methoxy-1-benzofuran-2-yl)indolyl]aminoindanic acid (300 mg) and 3-( Methylamino)ethyl propionate (125 mg) was obtained as the title compound (201 mg, 55%). H NMR (300 MHz, CDCla) δ ppm 1. 03-1. 36 (m, 5H), 1.55- 1.84 (m, 4H), 1.85-2.00 (m, 2H), 2.67 (t, J=6. 5 Hz, 2H), 3.03 (s, 3H), 3.70 (t, J=6.5 Hz, 2H), 3.83 (s, 3H), 4.35 (d, J=6. 6 Hz, 1H), 6.44 (s, 1H) ), 6.57 (d, 321426 356 201029996 J=8. 7 Hz, 2H), 6.82 (dd, J=8.5, 2. 2 Hz, 1H), 6.98 (d, J=2. 2 Hz, 1H), 7.22 -7.28 (m, 2H), 7.32 (d, J = 8.5 Hz, 1H). Example A29 3-{[(4-·([cyclohexyl(2-ethyl-1-benzofuran]3 _ base) fluorenyl]amino}phenyl)carbonyl]amino}propionic acid

In the same manner as in Example A22 (4), 3-[gas(cyclohexyl)indenyl]-2-ethyl-i-benzopyrene synthesized in Example A26(2) was used (3〇〇mg). And 3-{[(4-aminophenyl)carbonyl]amino}propionic acid ethyl acetate (255 mg), which was synthesized in Example 1 (2) to give the title compound as a light brown solid (374 mg) , 77%). 〇H NMR (300 MHz, CDCh) δ PPm 0. 92-1. 23 (m 5H) 1 ?7 (t, 1 = 7.5 Hz, 3H), 1.55-1.74 (m, 3H), i.76-1.97 (m, 2H), 2.04-2.15 (m, 1H), 2.56-2.66 (m, 2H), 2.71-2.92 (m, 2H), 3.56-3.66 (m, 2H), 4.31 (d, J=7.9 Hz , 1H) 6.48 (d, &gt;8. 7 Hz, 2H), 6.52-6.62 (m, lH), 7 n_7 22 On, 2H), 7.34-7.40 (m,1H), 7.47 (d, J=8 7 7.52-7.57 (m, 1H). Example A30 1-benzofuran-2-yl)methyl 3-{[ (4-·([cyclohexyl (5-methoxy-3-methyl 321426 357 201029996 Amino}phenyl]weiki]amino}propionic acid

2-[Chloro(cyclohexyl)methyl]-5-methoxy-3-methyl-1-benzene synthesized in the oxime of Example A27(4) was used in the same manner as in Example A22 (4). Furan (395 mg) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (319 mg) synthesized in Example 1 (2) to give the title compound (413 mg, 66%). ^ NMR (300 MHz, CDCh) δ ppm 0. 92-1. 36 (m, 5H), 1.46- 1.58 (m, 1H), 1.60-1.97 (m, 4H), 2. 01-2.13 (m, 1H) ), 2.22 (s, 3H), 2.61 (t, J=5. 9 Hz, 2H), 3.57-3.67 (m, 2H), 3.82 (s, 3H), 4.37 (d, J=8.0 Hz, 1H) , 6.55 (d, ® J=8. 7 Hz, 2H), 6. 61 (t, J=6. 1 Hz, 1H), 6. 81 (dd, J=9. 1, 2. 7 Hz, 1H ), 6. 87 (d, J=2. 3 Hz, 1H), 7. 21-7. 28 (m, 1H), 7.52 (d, J=8.7 Hz, 2H). Example A31 3-{[ (4-{[ 1-(3-ethyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl](methyl)amino}propionic acid 321426 358 201029996

(1) Methyl 3-ethyl-1-benzofuran-2-carboxylate in 1-(2-pyridylphenyl)propan-1-one (1〇.〇g), desert acetic acid vinegar (5.111111 Potassium carbonate (18.4 ❹ g) was added to a mixture of hydrazine and propylene (10 〇 1111 )) and stirred at room temperature overnight. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. (Ethyl acetate: hexane = 1 : 4, by volume) Purify residue to give a colorless oil. Add 1 in the N,N-dimethylformamide solution (150 niL) of the obtained oil. , 8_diazabicyclo[5.4.0]undec-7-ene (8.12 mL), and the mixture was stirred at 120 ° C for 2 hours. The reaction was quenched with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO.sub.subsubsubsubsubsubsubsubsubsubsubsubsubsub The title compound (7. 14 g, 52%) was obtained as a white solid. NMR (300 MHz, CDCh) δ ppm. 31 (t, J=7. 5 Hz, 4H), 3.12 (q, J=7.5 Hz, 2H), 3.99 (s, 3H), 7.27-7.34 (m, 1H), 7.41-7.49 (ra, iH) , 7.53-7.58 (m, 1H), 7.65-7.70 (m, 1H). (2) 3-ethyl-1-benz and π. South__2-decanoic acid 321426 359 201029996 by Example A27(2) In the same manner, the title compound (2.27 g, 90%) was obtained from the title compound (2. NMR (300 MHz, CDC13) (5 ppm 1.40 (t, J = 7. 6 Hz, 3H), 3.12 (q, J = 7. 6 Hz, 2H), 7.30-7.37 (m, 1H), 7.48-7.60 (m, 2H), 7.71-7.76 (m, 1H), 10.04 (s, 1H). (3) 1-(3-Ethyl-1-benzofuran-2-yl)_3_mercaptodine_1 _ alcohol 0 in 〇C in the above-prepared 3-ethyl-1-benzofuran-2-furfural (2.27 g) in tetrahydrofuran solution (5 〇mL) was added dropwise i 〇M brominated isobutylmagnesium Tetrahydrofuran solution (19.5 mL), and the mixture was stirred for 1 hour. A saturated aqueous solution of ammonium sulfate was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The title compound (1.55 g, 51%) was obtained. ❿ H NMR (30G MHz, CDC13) (5 〇. 94 (d, J=6·6 Hz, 3H) 0.96 (d, J-6.6HZ, 3H), 1.28 (t, J=7. 5 Hz, 3H)/l.56- 1.73 (m, 1H), 1.74-1.86 (m, 2H), 1.88-1.99 (m, 1H), 2.74 (q, J=7. 5 Hz, 2H), 4.91-4.99 ( m, 1H), 7.18-7.31 (m, 2H), 7·41-7·47 Cm, 1H), 7.50-7.56 (m, 1H). (4) 2-U-Chloro-3-methylbutylethyl The benzophenone bite was carried out in the same manner as in the example AK2), using the above synthetic (3) ethyl bromide-2-yl)j methylbutanol (1 〇〇g) to obtain The title compound (1 〇 3 g, 96%) of yellow oil. 321426 360 201029996 NMR (300 MHz, CDCh) δ ppm 0. 92-0. 97 (m, 6H), 1· 29 (t, J=7.5 Hz, 3H), 1.60-1.75 (m, 1H), 2.14- 2.21 (m, 2H), 2.73 (q, J=7. 5 Hz, 2H), 5.22 (t, J=8. 0 Hz, 1H), 7.19-7.33 (m, 2H), 7.41-7.48 (m, 1H), 7.51-7.55 (m, 1H). (5) 3_{[(4_{[1_(3-ethyl-1-benzo-Bis π-N- 2-yl)-3-methylbutyl]amine }}Phenyl)carbonyl](methyl)amino} cesium propionate In the same manner as in Example A22 (4), 2-(1-carb-3-methylbutyl)-3- Ethyl-1-benzofuran (3 〇〇 mg) and 3-{[(4-aminophenyl)carbonyl](methyl)amino}propionic acid ethyl acetate synthesized in Example 2 (2) 300 mg) to give the title compound (97·4 mg, 19%) as a yellow solid. !H NMR (300 MHz, CDCh) δ ppm 0. 92 (d, j=g β Hz 3H) 1.00 (d, J=6.4Hz, 3H), 1.27 (t, J=7. 6 Hz, 3H), 1 51- 1.69 (m,1H), 1.82-1.89 (ra, 2H), 2.60-2.70 (m, 2H) ❿ 2.77 (q, J=7.6 Hz, 2H), 3·02 (s, 3H), 3.69 (t, J=6 4

Hz, 2H)' 4.72 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 8.7 Hz, 2H), 7. 15-7. 28 (m, 4H), 7.36-7.42 (m, 1H), 7. 47_7 52 (m, 1H). Example A32 3-·[Methyl[(4-{[3_曱基_1-(3-mercapto-1-benzon-septene-2) Monokily)butyl]amino}phenyl]carbonyl]amino}propionic acid 321426 361 201029996 ο

ο , 'ΟΗ

(1) 3-mercapto-1-(3-mercapto-1-benzoin-2-yl)butan-1-one at 0 ° C in 3-mercapto-1-benzothiophene (5. 00 g), a mixture of isoprene chloride (4.22 mL) and nitro-methyl (50 mL) was added with aluminum chloride (I π ) ❹ (8·98 g) ' and the mixture was stirred at 〇 ° C 30 After a minute, it was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cooled water, and the mixture was taken in ethyl acetate. The extract was washed with 1N HCl and brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc NMR (300 MHz, CDCls) δ ppm 1.03 (d, J=6. 8 Hz, 6H), 2.28-2.43 (m, 1H), 2.77 (s, 3H), 2.80 (d, J=7. 0Hz, 2H ), 7.39-7.53 (m, 2H), 7.81-7.90 (m, 2H). (2) 4-{[3-mercapto-1-(3-methyl-1-benzothiophen-2-yl) Butyl]amino}methyl benzoate was synthesized in the same manner as in Example A23 (3) using 3-methyl-1-(3-methyl-1-benzothiophen-2-yl) The title compound (923 mg, 58%) was obtained as a pale brown solid. H NMR (300 MHz, CDCh) δ ppm 〇. 98 (d, J=6. Hz, 3H), 1.02 (d, J=6. Hz, 3H), 1.68-1.81 (m, 2H), 1.81-1.95 321426 362 201029996 (m,1H), 2.47(s, 3H), 3.80(s,3H), 4. 40-4. 47 (m,1H), 4. 86-4. 95 (m,1H ) 6.54 (d, J=: 8.1 Hz, 2H), 7 23- 7 30 (m, 1H), 7.32-7.39 (m, 1H), 7.62-7.67 ^ 2H) 7 69-7.74 (m, 1H) , 7.79 (d, J=8. 1 Hz, 2H) ' (3) 4-{[3-methyl+(3-methyl+benzoindole-2-yl)butyl]amino}benzoic acid In the same manner as in Example A23 (4), the above synthesized 4-({[3-indolyl-b-(3-indolyl)-benzophenan-2-yl)butyl]amino}benzoic acid methyl ester was used. (923 mg) to give the title compound (817 mg, 92%). NMR NMR (300 MHz, CDCh) (5 ppm 0.98 (d, J = 6.2 Hz, 3H) 1.02 (d, J = 6.2 Hz, 3H), 1.67-1.96 (m, 3H), 2.47 (s 3H), 4 88-4. 96 (m, 1H), 6. 55 (d, J=8. 9 Hz, 2H), 7.23-7.30 (m, 1H), 7.32-7.39 (m, 1H), 7.62-7.68 ( m, 1H), 7.69-7.74 (ra, 1H), 7.84 (d, J=8.9 Hz, 2H). ❹ (4) 3-{曱基[(4-{ [3-曱--1-(3) - mercapto-1-phenylindole-2-yl)butyl]amino}phenyl)carbonyl]amino}propionic acid The same procedure as in Example A1 (4) was used, using 4-{ [3-Mercapto-1-(3-indolyl-1-benzoindole-2-yl)butyl]amino}benzoic acid (300 mg) and ethyl 3-(decylamino)propionate (134 mg) to give the title compound (218 mg, 59%) as a white solid. NMR (300 MHz, CDCls) δ ppm 0. 98 (d, J = 6. 2 Hz, 3H), 1.02 (d, J=6.2 Hz, 3H), 1.66-1.94 (m, 3H), 2.46 (s, 3H), 2.62-2.72 (m, 2H), 3.02 (s, 3H), 3.70 (t, J=6.4 321426 363 201029996

Hz, 2H), 4.82-4.89 (m, 1H), 7.20-7.31 (m, 3H), 7. 32-7. 39 Hz, 1H), 7. 72 (d, J=7.3 Hz, example A33 6· 54 (d, J=8. 7 Hz, 2H), (m,1H), 7.65 (d, J=7.9 1H). 3-{[(4-{[3-methyl-:l- (3-methyl-j-yl}phenyl)carbonyl]amino}propionic acid

Benzothiophen-2-yl)butyl]amine was synthesized in the same manner as in Example A1 (4), using the same procedure as in Example A1 (4), using 4-{[3-indolyl-1 synthesized in Example (32(3). -(3-methyl-1, τ丞1~open thiophene-2-yl)butyl]amino}benzoic acid (300 mg) to give 5 ώ m _ t to the title of white solid Target compound (316 mg, 88%) 0 H MR (300 MHz, CDCI3) δ ppm 〇97 (d, J=6. 0 Hz 3H) Φ 1.01 (d, J=6.2 Hz, 3H), 1.66-1.94 ( m, 3H), 2.46 (s, 3H), 2.61 (t, J=5.7Hz, 2H), 3.57-3.67 (m, 2H), 4.83-4.91 (m, 1H), 6.50-6.62 (m, 3H) , 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.51 (d, J=8. 7 Hz, 2H), 7.64 (d, J=7.5 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H). Example A34 3-{[(4-{[1-(3-Ethyl-1-benzoheptan-2-yl)-3-indolylbutyl]amino}benzene Alkylamino}propionic acid 364 321426 201029996

2-(1-Ga-3-mercaptobutyl)-3-ethylbenzofuran (3 〇〇 mg) synthesized in Example A3K4) was used in the same manner as in Example A22 (4) and examples 3-{[(4-Aminophenyl)carbonyl]amino}-propanoic acid ethyl ester (283 mg), mp. ). 4 NMR (300 MHz, CDC13) 5 ppm 〇. 91 (d, J=6. 6 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H), 1.27 (t, J = 7.5 Hz, 3H), 1.51-1.68 (m,1H), 1.81-1.90 (m,2H), 2.58-2. 68 (m,2H), 2.76 (q,J=7. 5 Hz, 2H), 3.58-3.68 (m, 2H) ), 4.73 (t, J=7.5 Hz, 1H), 6.54-6.63 (m, 3H), 7.14-7.26 (m, 2H), 7.35-7.40 (m, 1H), 7.46-7.51 (m, 1H) ), 7.54 (d, J = 8.7 Hz Hz, 2H). Example A35 3-{[(4-{[cyclohexyl(6-decyloxy-4-benzofuran-2-yl)indenyl]amino group Amino]propanoid

321426 365 201029996 Using the same method as in the practice of (4) A1 (4), the 4-{[diacarbenyl(6-decyloxy-bromo-bromo-2-yl)methyl]amine group synthesized in Example A28(4) was used} Benzoic acid (1G2 mg) gave the title compound (40.0 mg, 33%). HNMR (300 MHz, CDCl3) (5 ppm, 〇〇~i35 (m, 5H), 1.54-1.84 (m, 4H), 1.84-1.99 (m, 2H), 2. 55-2.68 (m, 2H), 3.56 -3.69 (m, 2H), 3.82 (s, 3H), 4.36 (d, J=6.4 Hz, 1H), 6.42(s, 1H), 6.51-6.66 (m, 3H), 6. 81(dd, J =8. 5, 2.1 Hz, 1H), 6.97 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H). Example A36 3-{[(6-{[3-Mercapto-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}°~pyridin-3-yl)carbonyl] Amino}propionic acid

U) [3-Mercapto-1-(3-indolyl-1-benzothiophen-2-yl)butyl]amino} D-pyridyl~3-carboxylate at 0 ° C in Example A32 (l) 3-methyl-1-(3-methyl~1-benzothiophen-2-yl)butan-1-one (1.00 g), 6-aminopyridine-3-carboxy Titanium (IV) chloride (566 / zL) was added to a mixture of methyl ester (654 mg), triethylamine (4.89 mL) and dichloromethane (20 mL), and the mixture was stirred at room temperature 366 321426 201029996 overnight . A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate sulfate Sodium cyanoborohydride (540 mg) was added to a mixture of the obtained solid, acetic acid (2 mL) and tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1 : 4, volume ratio) to afford a pale brown solid. Sodium cyanoborohydride (251 mg) was added to a mixture of solid, trifluoroacetic acid (1.00 mL) and ethanol (10 mL), and the mixture was stirred at room temperature for 1 hour. Further, sodium cyanide hydride (251 mg) was added, and the mixture was stirred at room temperature for 30 minutes, followed by stirring at 50 ° C for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc EtOAc EtOAc. ]H NMR (300 MHz, CDCh) (5 ppm 0. 98 (d, J=6. 3 Hz, 3H), 1.01 (d, J=6.3 Hz, 3H), 1.64-1.96 (m, 3H), 2.48 (s, 3H), 3.83 (s, 3H), 5.25-5.40 (m, 2H), 6.28 (d, J=8. 7 Hz, 1H), 7.24-7.39 (m, 2H), 7.61-7.66 (m , 1H), 7.71-7.76 (in, 1H), 7.91 (dd, J=8.7, 2.0 Hz, 1H), 8.73 (d, J=2. 0 Hz, 1H). (2) 6-{ [3- Mercapto-1-(3-indolyl-1-benzoin-2-yl)butyl]amino} acridine-3-carboxylic acid 367 321426 201029996 The same procedure as in Example A23 (4) was used, using the above synthesis 6-{[3 - fluorenyl + (3-mercapto-1-benzoindoleyl) butyl] amide ibby -3- oleic acid methyl vinegar (743 mg) to obtain a white solid Title target compound (236 mg, 33%) H NMR (300 MHz, CDCh) c5 ppm 〇. 9〇-〇. 99 (m? 6H)? L 58, 1.78 (m, 2H), 1.81-1.95 ( m, 1H), 2 44 (s, 3H), 5. 5 b 5.64 (m, 1H), 6.53 (d, J = 8.7 Hz, 1H), 7.24-7. 38 (m, 2H), 7.67 (d , J=8.1Hz, 1H), 7. 73-7. 92 (ra, 3H), 8.50 ^ (d, J=2.4 Hz, 1H), 12.29 (br s, 1H) (3) 3-{[( 6-{[3-methyl+(3-methyl+benzobenzophen-2-yl)butyl]amino}pyridin-3-yl)carbonyl]amino}propyl The above synthesized 6_{[3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]aminopurinium pyridine was used in the same manner as in the example Al (4). 3-carboxylic acid (115 mg) to give the title compound (112 mg, 81%) as a white solid. ❹]H NMR (300 MHz, CDCh) 6 ppm 〇. 98 (Mountain j=6. 〇Hz, 3H), 1.03 (d, J-6. 2 Hz, 3H), 1. 71-1.85 (m, 2H), 1 95-2 11 (m, 1H), 2.49 (s, 3H), 2.57-2.67 ( m, 2H), 3 67-3 79 (in, 2H), 4.86-4. 98 (m, 1H), 6.48 (d, J=9. 2 Hz 1H), 7.24-7.33 Cm, 1H), 7.33- 7.41 (m, 1H), 7.61-7.75 (m, 3H), 8.10-8.20 (m, 2H), 8.87-8.97 (m, 1H). Example A37 3-{[(4-·([cyclohexyl ( 5-fluoro-3-methyl-1-benzofuranylmethyl]amino}phenyl)carbonyl](methyl)amino}propionic acid 321426 368 201029996 Ο ο

7 ΟΗ

F(1) 5-Fluoro-indenyloxy-indole, 3-dimethyl-1-benzofuran-2-indanamide in 1-(5-fluoro-2-hydroxyphenyl)ethanone Ig〇〇g), 2_chloro-b- oxime-N-methylacetamide (9. 82 g), sodium iodide (19 5 g) and N,N-di-methyl acetamide ( Potassium carbonate (18. g) was added to a mixture of 200 mL), and the mixture was stirred at 80 C overnight. 1N hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, Add 1,8-diazabicyclo[5·4·0]H 7-ene (9. 71 mL) to the obtained solid N,N-dimethylformamide solution (2 mL) And the mixture was stirred at 4 hours. The mixture was stirred for 4 hours. The reaction was quenched with ethyl acetate. The mixture was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Chromatography (ethyl acetate: hexanes = 1 : 3 vol.) was purified to afford the title compound (4. 37 g, 28%) as a brown oil. NMR (300 MHz, CDCh) (5 ppm 2.47 (s, 3H), 3.38 (s, 3H), 3.86 (s, 3H), 6.98-7.16 (m, 1H), 7.21-7.27 (m, 1H), 7.37-7.43 (m, 1H) (2) Cyclohexyl (5-fluoro-3-mercapto-1-benzofuran-2-yl)methanol 5-F-N-methoxy-N,3-di synthesized above at 0 °C Methyl 321426 369 201029996 benzofuran-2-carboxamide (4.37 g) in tetrahydrofuran solution (8 〇mL) was added dropwise 1.5 M diisobutylaluminum hydride in toluene solution (24.5 mL), And the mixture was stirred for 1 hour. 1N hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over MgSO.sub.sub.sub.sub.sub. To the obtained solid tetrahydrofuran solution (5 mL), a solution of tetrahydrofuran bromide tetrahydrofuran (21. 8 mL) was added dropwise, and the mixture was stirred for one hour. A saturated aqueous solution of ammonium chloride was added thereto. The reaction was quenched, and the mixture was extracted with EtOAc. EtOAc (EtOAc m. The title compound (1. 32 g, 27%) was obtained as a pale yellow oil. H NMR (300 MHz, CDCh) d ppm 0. 85-1. 43 (m, 6H) , 1.61-1.71 (m, 2H), 1.75-1.98 (m, 3H), 2.09-2.21 (m, 4H), ❹ 4.51 (dd, J=8.4, 6.0 Hz, 1H), 6. 92-7. G0 (m,1H), 7 〇g_ 7. 13 (m, 1H), 7.30-7.36 (m, lH). ' (3) 2-[Chloro(cyclohexyl)methyl]-5-fluoromethyl- Benzofuran is treated in the same manner as in Example A11 (3m) Using the above-prepared cyclohexyl (5-fluoro-3-methyl+benzofuran-2-yl)methanol (1 lg) to give the title compound (9 〇〇mg 83%) as pale yellow oil ). 4 swollen (3) OMHz, CDCh) 5 ppmUuG'a, 5H), i for 1.50 (m, 1H), 1.60-1.72 (m, 2H), 1.77-1.88 (m, ]H) 2.10-2.25 (m, 4H), 2.28-2.38 (m, iH), 4. 79 (d, J, 9. 6 321426 370 201029996

Hz, 1H), 6.96-7.04 (m, 1H), 7.09-7.14 (m, 1H), 7.34-7.39 (m, 1H). (4) 3-{[(4-{[cyclohexyl (5-fluoro) _3_ fluorenyl-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](fluorenyl)amino}propionic acid was synthesized in the same manner as in Example A22 (4). 2-[Chloro(cyclohexyl)methyl]-5-fluoro-3-methyl+benzophenone (mg) and 3-{[(4-aminobenzene) synthesized in Example 2(2) The title compound (303 mg, 46%) was obtained as a pale yellow solid. H NMR (300 MHz, CDCla) δ ppm 0. 92-1. 37 (m, 5H), 1.45-1.56 (m, 1H), 1. 60-1. 97 (m, 2. 03-2. 14 ( m, 1H), 2. 22 (s,3H), 2.64 (t, J=6.5 Hz, 2h), 3.02 (s, 3H), 3. 69 (t, J-6. 5 Hz, 2H), 4 36 (d, J=7 9 Hz 1H) 6 55 (d, J=8.7Hz, 2H), 6.88-6.97 (,, 1H), 7. 〇7 (dd, 5, 2. 6 Hz, 1H) , 7. 23(d, J=8. 7 Hz, 2H), 7. 25-7. 31 (m, 1H). ❹Example A38 3-{Methyl[(6-{[3-methyl- 1-(3-methyl-p-benzothiophene-2-yl)butyl]aminodipyridyl-3-yl)alkyl]amino}propionic acid

6-{[3-methyl-1-(3-methyl-indole_benzothiophene_2_) synthesized in the same manner as in Example Al (4) using 321426 371 201029996 in Example A36(2) Benzyl]aminopyridinium-3-carboxylic acid (121 mg) and ethyl 3-(decylamino)propionate (67.2 mg) to give the title compound as a white solid 〇 15 mg, 77% ). H NMR (300 MHz, CDCh) δ ppm 97 j=6. 2 Hz, 3Η), 1.01 (d, J=6.4Hz, 3H), 1.67-1.86 (m, 2H), 1.93-2.08 (m, 1H) , 2.47(s, 3H), 2.62-2.71 (m, 2H), 3. 08 (s, 3H), 3.67-3.84 (m, 2H), 4.84-4.95 (m, 1H), 6.35 (d, J= 8. 9 Hz, 1H), 7.24-7.31 (m, 1H), 7.32-7.39 (m, 1H), 7.51-7.59 (m, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.73 (d , J=7. 7

Hz, 1H), 8. 05-8. 17 (m, 1H). Example A39 3-{[ (4-{[cyclohexyl (5-gas-3-methyl-! _benzo-^) _2_yl)methyl]amino}phenyl)carbonyl]amino}propionic acid

2-[Chloro(cyclohexyl)indenyl]-5-fluoroindolyl-indole-benzofuran (400 mg) synthesized in Example New Zealand (3) was used in the same manner as in Example A22 (4), and Example 1 (2) 3M[(4-aminophenyl)carbonyl]amino}propionic acid ethyl ester (336 rag) was synthesized to give the title compound (321 mg, 50%) as pale brown solid. 321426 372 201029996 'H NMR (300 MHz, CDCh) δ ppm 0. 91-1. 36 (m, 5H) 1 43. 1.56 (m, 1H), 1.59-1.95 (in, 4H), 2.00-2.12 (m , 1H) 2.20 Cs, 3H), 2.59 (t, J=5. 7 Hz, 2H), 3.55-3.67 (m, 2H), 4. 37 (d, J=8. 1 Hz, 1H), 6. 54 (d, J=8. 8 Hz 2H) 6.71 (t, J=6.0 Hz, 1H), 6.87-6.95 (m, 1H), 7.05 (dd J=8. 5, 2. 4 Hz, 1H), 7. 21-7. 30 (m, 1H), 7. 52 (d, J=8 g Hz, 2H). *

Example A40 3-[{[4-({cyclohexyl[6-(trifluoromethyl)imidazo[i, 2-3]pyridylmethyl}amino)phenyl]carbonyl}(methyl) Amino]propionic acid 0 Q 〇

-2-base]

(1) 6 (Difluoromethyl)-flavored β-sit and [i,2-a]n is more than a bite at 2 甲 at room temperature in 5-(trifluoromethyl)~biter_2_amine (12 · 9 仏 于 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲 二甲5GmL), and the mixture was heated under reflux for 3 hours. After cooling to warm, the solvent was evaporated under the pressure, and a saturated aqueous solution of canona sulphuric acid was added to (4) and ethyl acetate to tetrahydrofuran was used. : i, volume ratio) extraction mixture. Read and brine wash / feed, dry with magnesium sulfate, dragon 321426 373 201029996 and square; under reduced pressure / deflation. Via Shixi rubber column chromatography (ethyl acetate: The residue was purified by flash = 1 : 2 by volume to give 2 -(dichloroindenyl)-6-(trifluoromethyl)imidazopyridine (1 〇 3 g) as a white solid. The mixture was suspended in a mixed solvent of water (100 mL) and tetrahydrofuran (20 mL;), and calcium carbonate (80 g) was added to the mixture at room temperature, and the mixture was stirred at 1001 &gt; C for 1 hour. The residue was filtered off with ethyl acetate. Title title compound (7.3 g, 43%). H NMR (300 MHz, CDCh) δ ppm 7.43 (d, J = 9. 8 Hz, 1H) 7.82 (d, J = 9.8 Hz, 1H), 8.26 ( s, 1H), 8.58 (s, 1H), 10. 19 (s, 1H). ' (2) Cyclohexyl [6-(trifluoromethyl) imidazo[1,2-a&gt;曱 曱 于 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在Cyclohexylmagnesium bromide (1M in tetrahydrofuran, 15 mL) was added, and the mixture was stirred at 0 ° C for 1 hour, and aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The title compound (0.9 g, 30%) was obtained as a colorless solid. JH NMR (300 MHz, CDCh) 5 ppm 1. 01-1. 96 (m, 11H), 2 43 (d, J=6. 1 Hz' 1H), 4.66 (t, J=5.9 Hz, 1H), 7. 3! (d J=9.8 Hz, 1H), 7.59 (s , 1H), 7.66 (d, J=g. 8 Ηζ? 1H) 8.46 (s, 1H). ' (3) 3-[ {[4-({cyclohexyl[6-(trifluoromethyl) σ m 0 sits and [i, 2-a]ntilI^ 321426 374 201029996-2-yl]methyl}amino)phenyl]]yl}(indenyl)amino]propionic acid The same method as in Example 4, Using the above synthesized cyclohexyl [6_(difluoroindolyl) 0 mO sit and [1,2~a]n than biti-2-yl]sterol (1.1 g) and in Example 2 (2) Synthesis of 3-{[(4-Aminophenyl)carbonyl](indenyl)amino}propanoic acid ethyl ester (0·94 g) to give the title compound (3. 2%). H NMR (300 MHz, CDCls) δ ppm 0. 98-2. 16 (in, 11H), 2.50-2. 75(m, 2H), 3. 06 (s, 3H), 3. 10-3. 25 (br s, 1H), 3.61-3.82 (m, 2H), 4.43 (d, J=6. 0 Hz, 1H), 6.54 (d, J=9. 0 Hz, 2H), 7.16 (d, J= 9.0 Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 8. 53 (s, 1H). , Example A41 3-U(4-{[cyclohexyl(3-methyl-i-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid

High performance liquid chromatography (column: CHIRALPAK AD (50 mm inner diameter (ID) x 500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (500/500) 'flow rate: 60 mL/ Minutes, column temperature: room temperature) fractionated 3-{[(4-{[cyclohexyl(3- 321426 375 201029996 methyl-1-benzofuran-2-yl)indenyl]amine synthesized in Example A16 Ethyl phenyl)carbonyl](methyl)amino}ethyl propionate (9. 85 g). Concentrated fractions containing optically active forms having a shorter residence time under the conditions of the above high performance liquid chromatography, To obtain an amorphous form (4.85 g, 99.9% ee). Add a solution of lithium indium hydroxide (22 mL) in a mixture of amorphous, ethanol (2 〇 mL) and tetrahydrofuran (2 〇 mL) obtained. The mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (2 mL) was added to the mixture. The title compound (4. 41 g, 97%, 99.9% ee) was obtained as a white solid. White solid (50 mg) obtained from ethanol/water crystals to give Crystallization of ethanol (41 mg). Crystals of ethanol (35 mg) were recrystallized from diethyl ether to give solvent-free colorless crystals (18 mg).]H NMR (300 MHz, DMSO-de) 5 ppm 0.97-1.28 ( Ra, 5H) 1.30-1.39 (m,1H) 1.52-1.81 (m,3H) 1.81-2. 00 (m,1H) 2. 03-2. 18 (m, 1H) 2. 26 (s, 3H) 2. 40-2. 49 (m, 2H) 2. 88 ❹(s,3H) 3.50 (t, J=7.38 Hz, 2H) 4·41 (t, J=8.33 Hz, 1H) 6.48 (d, J =7. 95 Hz,1H) 6. 60 (d, J=8. 71 Hz, 2H) 7.09 (d, J=8.33 Hz, 2H) 7.14-7. 29 (m, 2H) 7.36-7.55 (m, 2H) 12.27 (brs, 1H). Example A42 3-{[(4-((cyclohexyl(3-methyl-1-benzofuran-2-yl)indolyl]amino}phenyl)carbonyl) ](mercapto)amino}propionic acid 1 321426 376 201029996

,CO.H Ο

High performance liquid chromatography (column: CHIRALPAK AD (50 _ IDx500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (500/500), flow rate: 60 mL/min, column temperature : room temperature) fractionated 3-{[(4-·([cyclohexyl(3-indolyl-1-benzofuran-2-yl)indolyl]amino}phenyl)carbonyl] synthesized in Example A16] (mercapto)amino}ethyl propionate (9. 85 g). Concentrate a fraction containing an optically active form having a longer residence time under the conditions of the above high performance liquid chromatography to obtain an amorphous form (4) 81 g, 99. 9% ee). Add a mixture of amorphous, ethanol (20 mL) and tetrahydrofuran (20 mL) to an aqueous solution of ION (22 mL) and stir the mixture at room temperature 1 The residue was dissolved in water (20 mL), and 1N hydrochloric acid (20 mL) was added to the mixture. The resulting precipitate was collected by filtration to give a white solid title. Target compound (4.43 g, 98%, 99.9% ee). H NMR (300 MHz, DMSO-de) δ ppm 0. 97-1. 28 (m, 5H) 1. 30-1.39 (m, 1H) 1 52-1. 81 (m, 3H) 1. 81-2. 00 (m, 1H) 2. 03-2.18 (m, 1H) 2.26 (s, 3H) 2.40-2.49 (m, 2H) 2.88 (s, 3H) 3.50 (t, J=7. 38 Hz, 2H) 4.41 (t, J =8. 33 Hz, 1H) 6.48 (d, J=7.95 Hz, 1H) 6.60 (d, J-8. 71 Hz, 2H) 7.09 (d, J=8. 33 Hz, 2H) 7. 14-7 . 29 (m, 2H) 7. 36-7. 55 (m, 2H) 377 321426 201029996 12. 27 (brs, 1H). Example A43 3-{[(4-{[cyclohexyl (5-methoxy) 3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)aminopropionic acid

❹ h3c_o (1) 4-((cyclohexyl(5-methoxy-3-methyl-1- benzofuran-2-yl)methyl]amino}benzoic acid in Example A27(4) Synthesis of 2-[Chloro(cyclohexyl)indenyl]-5-methoxy-3-methyl-1-benzopyrene (748 mg), 4-aminobenzoic acid methyl vinegar (385 mg), Aihua Sodium carbonate (541 mg) was added to a mixture of sodium (764 mg) and N,N-dicarbhydrylamine (15), and the mixture was stirred overnight at 8 (Tc was added to the mixture. 1 N hydrochloric acid was added to terminate the reaction, and The mixture was extracted with EtOAc. EtOAc EtOAc m. In a mixture of the obtained oil, tetrahydrofuran (20 mL) and ethanol (20 mL), EtOAc (20 mL). The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20 mL) was then weighed, and the resulting precipitate was collected by filtration to give the title compound as a pale brown solid. (745 mg, 74%). 378 321426 201029996 ]H NMR (300 MHz, CDCh) δ ppm 0. 92-1. 37 (m, 5H), 1.47-1.58 (m, 1H), 1.61-1.98 (m, 4H), 2.02-2.12 (m, 1H), 2.24 (s, 3H), 3.83 (s, 3H), 4.42 (d, J=7. 9 Hz, 1H), 6.57 (d, J=8. 9 Hz , 2H), 6.83 (dd, J=8. 8, 2. 5 Hz, 1H), 6.88 (d, J=2.5 Hz, 1H), 7.26 (d, J=8. 8 Hz, 1H), 7.85 (d, J=8. 9 Hz, 2H). (2) 3-{[(4-U-cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)-) Ethyl]amino}phenyl)carbonyl](methyl)amino}ethyl propionate 4-{[cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2) synthesized above -yl)methyl]amino}benzoic acid (745 mg), ethyl 3-(methylamino)propionate (298 mg), 1-hydroxybenzotriazole monohydrate (348 mg), triethyl Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to a mixture of amine (633 μιη) and N,N-didecylguanamine (1 mL) (435 mg), and the mixture was stirred at room temperature overnight, then stirred at 5 ° C for 3 h. 1N hydrochloric acid was added to terminate the reaction' and the mixed φ was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) Η NMR (300 MHz, CDCla) δ ppm 0.93-1.35 (m, 8H), 1.47-1.60 (m, 1H), 1.60-1.97 (m, 4H), 2.02-2.14 (m, 1H), 2.22 (s , 3H), 2.61 (t, J=7. 0 Hz, 2H), 3.01 (s, 3H), 3.70 (t, J=7.0 Hz, 2H), 3.84 (s, 3H), 4.07-4.17 (m, 2H), 4.30-4.40 (m, 2H), 6.56 (d, J=8. 7 Hz, 2H), 6.82 321426 379 201029996 (dd, J=8. 9, 2. 6 Hz, 1H), 6. 88 (d, J=2. 6 Hz, 1H), 7.18-7.30 (in, 3H). (3) 3-{[(4-{[cyclohexyl (5-methoxy-3-methyl-1-) Benzofuran-2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid by high performance liquid chromatography (column: CHIRALPAKAD (50 mm IDx500 mraL ' Daicel Chemical Industries, Manufactured by Ltd., mobile phase: hexane/ethanol (400/600) 'flow rate: 60 mL/min, column temperature: 3 ° C) fractionation of the above synthesized 3-{[(4-{[cyclohexyl ( 5-methoxy-3-indolyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate (795 mg). An optically active form having a shorter residence time under the conditions of the above high performance liquid chromatography to obtain an amorphous form (413 mg, 99.9% ee) Add a solution of sodium hydroxide in water (2. 00 mL) in a mixture of amorphous, ethanol (5 mL) and tetrahydrofuran (5 mL). The mixture was poured at room temperature for 2 hours and concentrated under reduced pressure. Dissolve the residue in water (10 mL) and dry in EtOAc (EtOAc: EtOAc (EtOAc) 47%, 99.9% ee) NMR (300 MHz, CDCh) δ PPm 0. 93-1. 37 (m, 5H) l 47_ 1.57 (m, 1H), 1.60-1.96 (in, 4H), 2.03 -2.13 (m, 1H), 2.23 (s' 3H), 2·65 (t, J=6.4 Hz, 2H), 3. 02 (s, 3H) 3.69 (t, J=6.4 Hz, 2H), 3.83 (s, 3H), 4.36 (d, J=8 0 Hz, 1H), 6.55 (d, J=8.7Hz, 2H), 6. 82 (dd, J=8. 9, 2. 4 Hz, 1H) , 6.88 (d, J = 2.4 Hz, 1H), 7.19-7.29 (m, 3H) Example A44 321426 380 201029996 3-{[(4-{[cyclohexyl (5-decyloxy-3-methyl-) 1-benzofuran-2-yl)indolyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

高效High performance liquid chromatography (column: CHIRALPAKAD (50 mm IDx500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (400/600), flow rate: 60 mL/min, column temperature) :30 ° C) fractionation of 3-{[(4-{[cyclohexyl (5-methoxy-3-pyridyl-I-benzo-fol-2-yl)) synthesized in Example A43 (2) Ethyl]amino}phenyl) benzyl](methyl)amino}ethyl propionate (795 mg) concentrated in an optically active form having a longer residence time under the conditions described above for high performance liquid chromatography Distillate to obtain a non-crystalline (418 mg, 99.9% ee). Add 1N aqueous sodium hydroxide solution (2. 00) to a mixture of amorphous, ethanol (5 mL) and tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 1.5 hours, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2. The precipitate was obtained to give the title compound (354 mg, 47%, 99.9% ee) as a white solid.]H^R (300 MHz, CDCl3) 6 ppm 0.93-1.37 (m, 5H), 1.47-1.57 ( m, 1H), 1.60-1.96 (m, 4H), 2.03- 2.13 (ra, 1H), 2.23 (s, 3H), 2.65 (t, J-6.4 Hz, 2H), 3.02 (s, 3H), 381 321426 201029996 3.69 (t, J=6.4 Hz, 2H), 3.83 ( s, 3H), 4.36 (d, J=8. 0 Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6.82 (dd, J=8. 9, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 7.19-7.29 (m, 3H). Example A45 3_{[(4-·([cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-) 2-yl) fluorenyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid

(1) 4-{[Cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)indenyl]amino}benzoic acid 2-in the synthesis of Example A37 (3) [Gas (cyclohexyl) fluorenyl]-5-fluoro-3-indolyl-1-benzofuran (1.43 g), 4-aminobenzoic acid decyl ester (776 mg), sodium iodide (1. Sodium carbonate (1.09 g) was added to a mixture of 54 g) and N,N-dimercaptocarbamide (30 mL), and the mixture was stirred overnight. 1N hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified via EtOAc EtOAc (EtOAc:EtOAc) Add a solution of sodium hydroxide in water (2 mL) in a mixture of the obtained solid, tetrahydrofuran (2 mL) and ethanol (20 mL) and warmed under reflux and stirred mixture overnight and concentrated under reduced pressure 321 426 382 201029996 Shrink. The residue was dissolved in water (40 mL) and 1N hydrochloric acid (20 mL) was then weighed. The resulting precipitate was collected by filtration to afford title compound (1.06 g, 54%). ]H NMR (300 MHz, CDCls) δ ppm 0. 92-1. 37 (m, 5H), 1.46- 1.58 (m, 1H), 1.60-1.99 (m, 4H), 2.02-2.13 (m, 1H) , 2.23 (s, 3H), 4.43 (d, J=8. 0 Hz, 1H), 4.51-4.73 (m, 1H), 6.57 (d, J-8.7Hz, 2H), 6.87-6.98 (ra, 1H ), 7.04- 7.11 (m, 1H), 7.24-7.32 (in, 1H), 7.85 (d, 3=8.7 Hz, ^ 2H). (2) 3-{[(4-{[cyclohexyl (5- Fluoro-3-indolyl-1-benzoxan-2-yl)indenyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate 4-{[cyclohexyl) synthesized above (5-Fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (106 g), 3-(decylamino)propionic acid ethyl acetate (438 mg), 1 -Hydroxybenzotriazole monohydrate (512 °), triethylamine (930 /zL) and a mixture of hydrazine, hydrazine-dimercaptocaramine (2 〇mL) were added to the ethyl-3-(3- 5小时。 The dimethylaminopropyl carbodiimide hydrochloride (64 〇 mg) 1 n Hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The title compound (564 mg, 41%) was obtained eluted eluted elute NMR NMR (300 MHz, CDCh) ^ ppm 0. 93-1. 37 (m, 8H), 1.46-1.56 (m, 1H), 1.61-1.98 Cm, 4H), 2.03-2.14 (m, 1H), 2.22 (s, 3H), 2.61 (t, J=7. 0 Hz, 2H), 3.01 (s, 3H), 383 321426 201029996 3. 70 (t, J=7. OHz, 2H), 4. 06-4 17(m,2H), 4.28-4 41 (m, 2H), 6.56 (d, J=8_7Hz, 2H), 6.88-6.97 (m,1H) 7. 04-7.09 (m,1H), 7. 22 (d, J=8.7 Hz, 2H), 7. 25-7 31 (m, 1H). ' (3) 3-{[(4-{[cyclohexyl (5-fluoro-3-methyl-1) -Benzylpyrano-2-yl)methyl]amino}phenyl)carbonyl](indenyl)aminopropionic acid by high performance liquid chromatography (column: CHIRALPAK AD (50 mm丨Dx5 〇〇 Manufactured by L' Daicel Chemical Industries, Ltd., mobile phase. hexane/ethanol (400/600) 'flow rate: 60 niL/min, column temperature. 3〇C). 4-{[cyclohexyl (5-fluoro-3-methyl-;[monobenzofuran-2-yl)indolyl]amino}phenyl)carbonyl](methyl)aminopropionic acid ethyl ester ( 564 mg). Concentrate an optically active form fraction having a shorter residence time under the conditions of the above high performance liquid chromatography to obtain an amorphous form (274 mg) 99.9% ee). Add 1N aqueous sodium hydroxide solution (1. 〇〇niL) to a mixture of amorphous, ethanol (5 mL) and tetrahydrofuran (5 mL), and give a mixture at room temperature. 1. 5 hours, and concentrated under reduced pressure. The residue was dissolved in water (10 inL), and 1N hydrochloric acid (1. 〇〇mL) was added to 〇°c. The resulting precipitate was collected by filtration to obtain The title compound (249 mg, 47%, 99.9% ee) as a white solid. NMR (300 MHz, CDCh) δ ppm 0. 92-1. 37 (m, 5H), 1.45-1.56 (m, 1H), 1.60-1.97 (m, 4H), 2.03-2.14 (m, 1H), 2.22 (s, 3H), 2.64 (t, J=6. 5 Hz, 2H), 3.02 (s, 3H), 3.69 (t, J=6. 5 Hz, 2H), 4.36 (d, J=7.9 Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6. 88-6. 97 (m , 1H), 7. 07 (dd, J=8. 5, 321426 384 201029996 2. 6 Hz, 1H), 7. 23 (d, J=8. 7 Hz, 2H), 7· 25-7. 31 (m, 1H). Example A46 3-{[(4-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl (mercapto)amino}propionic acid

^^co2h N CH3 by high performance liquid chromatography (column: CHIRALPAKAD (50 mm ID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd.) Mobile phase: hexane/ethanol (400/600), flow rate: 60 mL/min , column temperature: 30 ° C) fractionation of 3-{[(4-{[cyclohexyl (5-fluoro-3-indolyl-1-benzofuran-2-yl)) synthesized in Example A45 (2) Ethyl]amino phenyl)carbonyl](fluorenyl)amino}ethyl propionate (564 mg). Concentration of optically active forms containing longer residence times under the conditions described above for high performance liquid chromatography To obtain a non-crystalline (273 mg, 99.9% ee). Add 1N aqueous sodium hydroxide solution (1. 00) to a mixture of amorphous, ethanol, and tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1. The resulting precipitate was collected by filtration to give the title compound (248 mg, 99 y ee) as white solid. Η R (300 MHz, CDC13) (5 Ppm〇, 92-1 37 (m, 5Η), 〗 〖45-321426 385 201029996 1.56 (m, 1H), 1.60-1.97 (m, 4H), 2. 03 -2. 14 (m,1H) 2. 22 (s,3H), 2.64 (t, J=6.5 Hz, 2H), 3.02 (s, 3h)' 3. 69 (t, J=6. 5 Hz, 2H), 4.36 (d, J=7.9 Hz, 1H), 6 5'5 (d, J=8. 7 Hz, 2H), 6.88-6. 97 (m, 1H), 7.07 (dd , j=8 5 2. 6 Hz, 1H), 7.23 (d, J = 8.7 Hz, 2H), 7.25-7. 31 (m, 1H), Example A47

3-({[4-({cyclohexyl][5-dun-3-(decyloxymethyl)-1-phenyl), 2~yl]hydrazino}amino)phenyl]phenyl]amine Propionate

(1) Methyl 5-fluoro-3-indol-1-benzofuran-2-carboxylate in 1-(5-fluoro-2-hydroxyphenyl)ethanone (1〇〇g), bismuth bromoacetate Potassium carbonate (135 g) was added to a mixture of ester oxime (67. 6 mL) and N,N-dimethylformamide (5 〇〇mL), and the mixture was stirred at 5 rc for 2 hours. Add 1,8-diazabicyclo[5·4.0]undec-7-ene (97.1 mL)' and mix the mixture for 30 minutes at 120 c. Add 1N hydrochloric acid to the reaction mixture and collect by filtration. Precipitate 'to obtain the title compound of the title compound (77. 9 g, 58%). H NMR (300 MHz, CDCh) δ ppm 2.56 (s, 3H), 3.99 (s, 3H), 7.14-7.22 (m, 1H), 7.24-7.30 (m, 1H), 7.45-7.51 386 321426 201029996 (m, 1H). (2) 3-(Moss)-5_Fluoro-1-Benzofu» </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> N-bromosuccinimide (18.9) and 2,2'-azobis(isobutyronitrile) (1.21 &amp;), and at 50. (: and argon stirred for 2.5 days. Depressed The mixture was purified, and the residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Compound (15.1 g, 71%) H NMR (300 MHz, CDCh) δ ppm 4. 02 (s, 3H), 4. 96 (s, 2H), 7.18-7.27 (m, 1H), 7.41- 7.47 (m, 1H), 7.49-7.55 (m, 1H). (3) 5-Fluoro-3-(decyloxyindenyl)-i-benzobenzoin-2. A methanol solution (8.33 mL) of 28% sodium methoxide was added to a solution of methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate (5.87 g) in methanol (50 mL). The mixture was stirred and heated under reflux for 3 hours. 1N hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc) elute ,3H),3.99 (s, 3H), 4.99 (s, 2H), 7 . 18 (td, J=9. 1, 2. 7 Hz, 1H), 7.46-7.52 (m, 1H), 7.53-7.58 Cm, 1H). (4) 5-Fluoro-3-(methoxymethyl) — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Add sodium borohydride (3.18 g) to a mixture of calcium chloride (4.66 g), ethanol (50 mL), and tetrahydrofuran (5 〇mL), and mix the mixture with /JBL hour. The residual aqueous solution of ammonium chloride was added to terminate the reaction. The organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate and concentrated under reduced pressure to give a colourless oil. Add tetrapropylammonium perruthenate (738 mg) in a mixture of the obtained oil, 4-mercaptomorpholine N-oxide (3.69 g) and acetonitrile (50 mL) at 0 ° C. Stirring The mixture was 1.5 h' and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) δ ppm 3.49 (s, 3H), 4.94 (s, 2H), 7.21-7.29 (m, 1H), 7.47-7.54 (m, 2H), 10.08 (s, 1H). 〇(5)cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methanone 5-fluoro-3-(methoxy) synthesized above at 0 °C Add a solution of 〇M Cyclohexylmagnesium bromide in tetrahydrofuran (7. 71 inL), and stir the mixture, in a solution of benzyl benzofuran-2-carbaldehyde (1.07 g) in tetrahydrofuran (20 mL). 1 hour. A saturated aqueous solution of chlorinated acid was added to terminate the reaction, and tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified via EtOAc EtOAc (EtOAc:EtOAc) Tetrapropyl perrhenic acid (126 mg) was added to a mixture of the obtained oil, 4-methylmorpholine N-oxide (841 mg) and acetonitrile (20 mL), and the mixture was stirred at room temperature 1.5 Hour, travel and concentrate under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) 4 NMR (300 MHz, CDC13) 5 ppm 1. 15-1. 55 (m, 5H), 1. 69_ 1· 80 (m, 1H), 1.80-2.02 (m, 4H), 3.25-3.39 (m, Η), 3.44 (s, 3H), 5. 00 (s, 2H), 7. 15-7. 23 (m, 1H), 7·43_ ❾ 7.49 (m, 1H), 7.57-7.62 (m, 1H (6) 4-({cyclohexyl[5-fluoro-3-(decyloxymethyl)_1-benzofuranyl]methyl}amino)benzoate oxime ester in the above synthesized cyclohexyl group [ 5-Fluoro-3-(methoxyindolyl)-1~ benzofuran-2-yl]anthone (857 mg), 4-aminobenzoic acid decyl ester (491 mg), triethylamine (3.29) Gasified titanium (IV) (388 #L) was added to a mixture of mL) and dichloromethane (1 mL), and the mixture was stirred at room temperature under argon overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to dissolve the chloroform in a solvent, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. Acetic acid (847#L) and sodium cyanoborohydride (371 mg) were added to a tetrahydro 11-propanol solution (20 mL) of the obtained oil, and mixture was allowed to stand at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) *11 NMR (300 MHz, CDCla) δ ppm 0. 97-1. 36 (m, 5H), 1.43- 1.54 (m, 1H), 1.60-1.99 (m, 4H), 2.00-2.11 (m, 1H) , 3.37 (s, 3H), 3.81 (s, 3H), 4.48-4. 64 (m, 4H), 6. 60 (d, J=8.8 Hz, 2H), 6.90-6.99 (m, 1H), 7.17 -7.23 (m, 1H), 7.28-7.34 (m, 1H), 7.79 (d, J=8.8 Hz, 2H). (7) 4-({cyclohexyl[5-fluoro-3-(methoxymethyl) ))-i-benzo D-propan-2-yl] fluorenyl}amino) benzoic acid hydrazide 4-({cyclohexyl[5-fluoro-3-(methoxymethyl))- Adding in sodium hydroxide to a mixture of diben-2-yl]methyl}•amino)benzoic acid methyl vinegar (454 mg), tetrahydrofuran (10 mL) and ethanol (10 mL) Aqueous solution (10.OmL) &lt;&gt; and the mixture was stirred and stirred under reflux overnight and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1N hydrochloric acid (10. The resulting precipitate was collected by filtration to give the title compound (423 mg, 96%) as white solid. ❹^R(300 MHz, CDCl3)5ppm0_96-1.36 (m,5H), 1.40- 1.55 (m, 1H), 1.60-1.99 (m, 4H), 1.99-2.13 (m, 1H), 3.38 (s, 3H ), 4.49-4.77 (m, 4H), 6.61 (d, J=8.8 Hz, 2H), 6.90-6.99 (m, 1H), 7.17-7.23 (m, 1H), 7.28-7.35 (in, 1H), 7.84 (d, J=8.8 Hz, 2H). (8) 3-({[4-({cyclohexyl[5-fluoro-3-(methoxymethyl))-1-benzofuran-2-yl) Methyl}amino)phenyl]carbonyl}amino)propionic acid ethyl ester 4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran) synthesized above 2-yl]hydrazino}amino)benzoic acid (200 mg), hydrazine-alanine ethyl 390 321426 201029996 ester hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (112 mg), two Add ethyl 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride to ethylamine (203 μί〇 and N,N-dimethyldecylamine (1 mL) 14 〇 mg), and the mixture was stirred overnight. The saturated aqueous solution of chlorinated acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. Dry and concentrate under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) CDCls) &lt;5 ppm 0. 95-1. 36 (in, 8H), 1.42-1-54 (m, 1H), 1.60-1.97 (ra, 4H), 2.01-2.13 (m, 1H), 2.58 ( t, J=5.8 Hz, 2H), 3.37 (s, 3H), 3.61-3.70 (m, 2H), 4.13 (q, J=7. 1 Hz, 2H), 4.46-4.62 (m, 4H), 6.56 -6.65 (m, 3H), 6.90-6.99 (m, 1H), 7.17-7.23 (m, 1H), 7.27-7.33 (m, 1H), 7.54 (d, J=8.8 Hz, 2H). ❹3-( {[4-({cyclohexyl[5-fluoro-3-(methoxyindolyl)-i-benzofuran-2-yl]indolyl)amino)phenyl]aminoindenyl)propionic acid 3-({[4-({cyclohexyl[5-fluoro-3-(decyloxyindolyl)-1-benzofuran-2-yl)methylindenyl)phenyl]carbonyl group synthesized above Add a 1N aqueous solution of sodium hydroxide (00 mL) to a mixture of ethyl acetate (207 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), stir the mixture at room temperature for 5 hours, and reduce Concentrate under pressure. The residue was dissolved in water (1 () mL), and 1N hydrochloric acid (1. 〇〇 mL) was added to 〇 C. The resulting precipitate was collected by filtration to give the title compound (186 mg, 95%). 391 321426 201029996 !H NMR (300 MHz, CDCh) δ ppm 0.95-1. 35 (m, 5H), 1.41- 1.53 (m, 1H), 1.60-1.97 (m, 4H), 2. 00-2.11 (m , ih), 2. 63 (t, J-5. 7 Hz, 2H), 3. 37 (s, 3H), 3. 59-3. 68 (m, 2H), 4.50 (d, J=8. 1 Hz, 1H), 4.54 (d, J=12.2Hz, 1H), 4. 59 (d, J=12. 2 Hz, 1H), 6. 55-6. 66 (m, 3H), 6. 90 -6 99 (m, 1H), 7. 16-7. 23 (m, 1H), 7. 27-7. 34 (m, 1H), 7. 53 (d, J = 8.9 Hz, 2H). Example A48 ® 3-[{[4-({cyclohexyl[5-fluoro-3-(decyloxyindolyl)-i-benzofuran-2-yl]indolyl}amino)phenyl]carbonyl} Methyl)amino]propionic acid

(1) 3-[{[4-({cyclohexyl[5-fluoro-3-(decyloxyindolyl)-1 benzofuran-2-yl]indolyl)amino)phenyl] 4-({cyclohexyl[5-fluoro-3-(methoxyindolyl)-1-benzofuran-) synthesized in Example A47 (7) by ethyl (methyl)amino]propionic acid 2-yl]methyl}amino)benzoic acid (2〇〇mg), 3-(decylamino)propionic acid ethyl ester (95. 6 rag), 1-p-benzobenzotriazine monohydrate ( Add 1-ethyl-3-(3-didecylaminopropyl) carbon two to a mixture of 112 rag), triethylamine (203 pL) and N,N-dimethyl decylamine (10 mL) The imine hydrochloride (140 mg) was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate to 392 321426. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) 5Η NMR (300 MHz, CDCh) &lt;5 ppm 0. 96-1. 36 (m, 8H), 1.42- 1.53 (m, 1H), 1.59-1.97 (m, 4H), 2.02-2.13 (m, 1H ), 2.61 (t, J=7. 0 Hz, 2H), 3.00 (s, 3H), 3.36 (s, 3H), 3.70 (t, J=7. 0 Hz, 2H), 4. ll(q, J=7. 1 Hz, 2H), 4.35- ® 4. 51(m, 2H), 4. 54 (d, J=12.3Hz, 1H), 4.59 (d, J=12.3

Hz, 1H), 6.59 (d, J=8.5Hz, 2H), 6.90-6.99 (m, 1H), 7.17-7.24 (m, 3H), 7.28-7.34 (in, 1H). (2) 3-[ {[4-({cyclohexyl[5-fluoro-3-(decyloxyindenyl)-1-benzofuran-2-yl]indolyl}amino)phenyl]alkyl}(methyl)amine 3-[{[4-({cyclohexyl[5-fluoro-3-(methoxymethyl))-1-benzofuran-2-yl]methylguanidino) synthesized by propionic acid a mixture of phenyl]carbonyl}(methyl)amino]ethyl decanoate (097 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide (1. Q〇mL), and The mixture was stirred at room temperature for 7 hours and concentrated under reduced pressure. The residue was dissolved in water (1()^B) and 1N hydrochloric acid (1.00 mL) was added to EtOAc. The collected material was collected by filtration to give the title compound (161 mg, 87%) as a pale yellow solid. 〇H NMR (300 MHz, CDCh) (5 ppm 0.95-1. 36 (in, 5H), 1.41-!-53 (m, 1H), 1.59-1.97 (m, 4H), 2.01-2.13 (m, 1H), 2.54-2.70 (m, 2H), 3.01 (s, 3H), 3.37 (s, 3H ), 3.68 393 321426 201029996 (t, J=6. 6 Hz, 2H), 4.47 (d, J-7. 9 Hz, 1H), 4.55 (d, J=12.2Hz, 1H), 4. 60(d , J=12. 2 Hz, 1H), 6. 59 (d, J=8. 5 Hz, 2H), 6.89-7.00 (m, 1H), 7.17-7.25 (m, 3H), 7.28-7.35 (m , 1H). Example A49 3-[{[4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]hydrazino}amino) Phenyl]carbonyl}(indenyl)amino]propionic acid

High performance liquid chromatography (column: CHIRALPAK AD (manufactured by 50 mm IDx500 mmL 5 Dai cel Chemical Industries, Ltd., mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min, column) Temperature: 30 ° C) fractionation of 3-[{[4-({cyclohexyl[5-fluoroO-3-(methoxymethyl))-1-benzofuran-2) synthesized in Example A48 (1) -yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (1.20 g). Concentration with shorter residence time under the conditions of the above high performance liquid chromatography A fraction of the optically active form to obtain an amorphous form (470 mg, 99.9% ee). Add 1N hydroxide to a mixture of amorphous, ethanol (5 mL) and tetrahydro D-propan (5 mL) obtained. The mixture was stirred at room temperature for 1 hr. EtOAc (EtOAc m. The resulting precipitate was collected to give the title compound (433 mg, 38%, 99.9% ee) of 394 321426 201029996 white solid. NMR (300 MHz, CDCh) 5 ppm 0. 95-1.36 (m, 5H) , 1.4i-1.53 (m, 1H), 1.59- 1.97 (in, 4H), 2.01-2.13 (m, 1H), 2.54-2.70 (m, 2H), 3.01 (s, 3H), 3.37 (s, 3H), 3. 68 (t, J=6.6 Hz, 2H), 4.47 (d, J=7.9 Hz, 1H), 4.55 (d, J=12.2Hz, 1H), 4.60 (d, J=12.2Hz, 1H), 6. 59 (d, J=8 5 Hz, 2H), 6.89-7.00 (m, 1H), 7.17-7.25 (m, 3H), 7.28-7.35 (m, 1H). ®Example A50 3-[{[4-({cyclohexyl) [5-fluoro-3-(methoxymethyl)-1-benzofuran-l-yl]hydrazino}amino)phenyl]carbonyl}(methyl)amino]propionic acid

High performance liquid chromatography (column: chiralpakad (5〇mm IDx5〇〇mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min' tube) Column temperature: 3 〇 ° C) fractionation of the synthesis of 3_[丨[4_({cyclohexyl[5-fluoro-3-(methoxymethyl)- benzophenone 0 South-2) in Example A48(1) _yl]methyl}amino)phenyl]benzyl K methyl)amino]propionic acid B g (12 () g). Concentration of the optically active form having a longer retention of 0 (d) under the conditions of the above high performance liquid chromatography was carried out to obtain an amorphous form (465 mg, 99.9% ee). An aqueous solution of IN sodium hydroxide (2. 〇〇mL) was added to a mixture of the obtained amorphous 321426 395 201029996, ethanol (5 mL) and tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hours and reduced. Concentrate under pressure. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to give the title compound ( 415n] g, 37%, 99.9% ee) as white solid. 'H NMR (300 MHz, CDCh) δ ppm 0. 95-1. 36 (in, 5H), 1.41- 1-53 (m, 1H), 1.59-1.97 (m, 4H), 2.01-2.13 (m, 1H), 2.54-2.70 (m, 2H), 3.01 (s, 3H), 3.37 (s, 3H), 3.68 (t, J=6.6 Hz, 2H), 4.47 (d, J=7.9 Hz, 1H ), 4.55 (d, J=12. 2 Hz, 1H), 4. 60 (d, J=12. 2 Hz, 1H), 6. 59 (d, J=8. 5

Hz, 2H), 6.89-7.00 (m, ih), 7.17-7.25 (m, 3H), 7.28-7·35 (m, 1H). Example A51 3-U(6-·([cyclohexyl (5) Monofluoro-3_mercaptobenzofuran-2-yl)methyl]aminodipyridin-3-yl)carbonyl]amino}propionic acid

(1) 2-Bromo-1-cyclohexyl Ethyl ketone was added to a solution of 1-cyclohexyl ketone (25.0 g) in decyl alcohol (π rainbow) at 0 ° C (10. 1 mL) at room temperature. The mixture was stirred for 3 minutes. A saturated aqueous solution of sodium sulfite was added to terminate the reaction, and 321426 396 201029996 mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCh) δ ppm 1. 10-1. 50 (m, 5H), 1.62- 1.73 (m, 1H), 1.75-1.94 (m, 4H), 2.64-2.79 (m, 1H), 3-97 (s, 2H). (2) Cyclohexyl (5-fluoro-3-indolyl-l-benzofuran-2-yl)methanone oxime 5'-fluoro-2,-hydroxy group synthesized above Add potassium carbonate (13.4 g) to a mixture of acetophenone (5. 〇〇g), 2-bromo-1-cyclohexylethanone (7.98 g) and N,N-dimethylformamide (5 〇mL) ) and the mixture was stirred at room temperature. 1N hydrochloric acid was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) δ ppm 1. 19-1. 57 (m, 5H), 1.7〇-2.01 (m, 5H), 2.56 (s, 3H), 3.25-3.36 (m, 1H), 7.15-7.23 (m, 1H) , 7.24-7.30 (m5 1H), 7.42-7.48 (m, 1H). (3) 6 {[cyclohexyl(5-fluoro-3-mercaptobenzon-n-propyl)methyl]aminopurinium pyridine- Methyl 3-carboxylate Cyclohexyl (5-fluoro-3-indolyl-indole-benzofuran-2-yl)methanone (3. 〇〇g), 6-amino group synthesized above at 〇 °C 321426 397 201029996 1.0M titanium chloride (IV) was added to a mixture of pyridine-3-carboxylic acid methyl ester (1.93 g), triethylamine (12. 8 mL) and dichlorodecane (4 〇mL). Dichloromethane solution (13.8 mL), and stirred at room temperature under argon: Mix the mixture for 1.5 days. Add saturated aqueous sodium hydrogencarbonate solution to terminate the reaction, remove the dichloromethane with a vapor, and use acetic acid. The residue was extracted with ethyl acetate. Acetic acid (3.99 mL) and sodium cyanoborohydride (3.61 g) were added to a mixture of the obtained oil, ethanol (40 mL) and tetrahydrofuran (20 mL), and the mixture was stirred at room temperature. The mixture was stirred for 3 hours. The title compound (547 mg, 12%) was obtained eluted eluted eluted eluted elut elut elut elut elut 5 ppm 0. 82-1. 35 (in, 5H), 1.44-1.55 (in, 1H), 1.56-1.86 (m, 3H), 1.85-2. 10 (m, 2H), 2.24 (s, 3H ), 3.83 (s, 3H), 5.02-5.14 (m, 1H), 5.42 ^ (d, J=8. 2 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 6.88-6.97 (m , 1H), 7.04-7.10 (m, 1H), 7.26-7.32 (m, 1H), 7.90 (dd, J=8.8, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H). (4 6-·([cyclohexyl(5-fluoro-3-indolyl-1-benzopyrene~-2-yl)methyl]amino}pyridine-3-carboxylic acid in the above synthesis 6-·[ [cyclohexyl (5-|L-3-A) Addition of a mixture of -1-benzocypano-2-yl)indolyl]aminopurine-3-carboxylic acid oxime ester (547 mg), ethanol (10 mL) and tetrahydrofuran (10 mL) Aqueous sodium hydroxide (10 mL) was added and the mixture was stirred and evaporated under reflux. Further, 398 321426 201029996 IN aqueous sodium hydroxide solution (5. 〇〇 mL) was added, and the mixture was heated under reflux for 5 hours, and concentrated under reduced pressure. The residue was dissolved in water, and 1N aqueous hydrochloric acid (15 mL) was then evaporated. The resulting precipitate was collected by filtration, and the obtained pale brown solid was dissolved in ethyl acetate. The solution was washed with EtOAc (EtOAc m. HNMR (300 MHz, CDCh) δ ppm 0.98-1. 41 (m, 5H), 1.48-1.84 Cm, 4H), 2.01-2.18 (m, 2H), 2.23 (s, 3E), 4.47-4.65 (m, 1H), 6.34 (d, J=8.8 Hz, 1H), 6.87-6.97 (m, 1H), 7.03-7.10 (m, 1H), 7.26-7.33 (m, 1H), 8.08 (d, J=8. 8 Hz, 1H), 8. 70-8. 74 (m, 1H). (5) 3-{[(6-{[cyclohexyl (5-fluoro-3-methylη-benzofuran_2_) ))methyl]amino}π} 咬-3-yl) benzyl]amino} propionate acetamidine is intended to synthesize 6-{[cyclohexyl (5-fluoro-3-indolyl-1-benzo) Wolffyl-2-yl)hydrazino]amino}pyridine-3-carboxycarboxylic acid (300 mg), ethyl alanine hydrochloride (181 mg), 1-p-benzotriazine monohydrate ( Addition of 1-ethyl-3-(3-didecylaminopropyl)carbodiimide to Mi mg), triethylamine (328 pL) and N,N-dimethylformamide (1 〇) The amine hydrochloride (226 mg) was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction' and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) 321426 399 201029996 】11臓(30〇]^,0)(:13)占_〇.93-1.36 (11],811)]43- 1· 55 (m,1H),1.57-1.85 (m,3H ), 1.85-2.08 (m 2H) 2.24 Cs, 3H), 2.60 (t, J=5.9 Hz, 2H), 3.62-3.72 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 5.01-5.12 (m, 1H), 5. (d, J = 8.8 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), β 65 (t J = 6.0 Hz, 1H), 6. 88 -6. 97 (m, 1H), 7. 〇3-7 l〇(m 1H), 7.23-7.31 (ffl, 1H), 7.75 (dd, J=8. 8, 2. 5 Hz, 1H)! 8 48 (d, J=2.5 Hz, 1H). ®(6)3-{[(6-{[cyclohexyl(5ϋmethyl-1-benzo-pyranyl, 2-yl)methyl]amino}pyridine-3 -{)carbonyl]amino}propionic acid 3-{[(6-{[cyclohexyl(5-fluoro_3_methyl-p-benzofuran-2-yl)methyl]amino) synthesized above A mixture of pyridine-3-yl)carbonyl]amino phthalic acid ethyl ester (366 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was added to a 1N aqueous sodium hydroxide solution (1. 〇〇mL). The mixture was stirred overnight and concentrated under reduced pressure. The residue was dissolved in water (1 mL), and 1N hydrochloric acid (1. 〇〇 mL) was added to 〇t: ❿. The resulting precipitate was collected by filtration to give the title compound (287 mg, 83%) as white solid. ]H NMR (300 MHz, CDCh) &lt;5 ppm 0.84-1. 41 (ra, 5H), 1.44-1.55 (m, 1H), 1.59-1.84 (m, 3H), 1.97-2.15 (m, 2H) , 2.23 (s, 3H), 2.55-2.69 (m, 2H), 3.65-3.78 (m, 2H), 4.46 (t, J=7. 8 Hz, 1H), 6.48 (d, J=9. 1 Hz , 1H), 6.89- 6.99 (m, 1H), 7.04-7.11 (m, 1H), 7.27-7.35 (in, 1H), ^•51-7.61 (m, 1H), 8.13 (dd, J=9. 1, 2.1 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.25-8.41 (m, 1H). 400 321426 201029996 Example A52 3-{[(6-{[cyclohexyl (5 _Fluoryl_3_indenyl-benzofuran-2-yl)methyl]amino}°-pyridin-3-yl)carbonyl](methyl)amino}propionic acid

F ® (1) 3—{[ (6-{[cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino) h-pyridin-3-yl)carbonyl [(cyclohexyl)amino}ethyl propionate 6-{[cyclohexyl(5-fluoro-3-methyl-p-benzofuran-2-yl)methyl] synthesized in Example A51 (4) Amino}pyridine-3-carboxylic acid (294 mg), ethyl 3-methyl(methylamino)propionate (151 mg), 1-phenylbenzotriazole monohydrate (176 mg), triethylamine ( Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrazone hydrochloride to a mixture of 322 / / L) and N, N-dimethyl decylamine mL) (mg), and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)

]H NMR (300 MHz, CDCh) δ ppm 0. 94-1. 34 (mj ^ 45_ 1.57 Cm, 1H), 1.58-1.83 (πι, 3H), 1.84-2.09 Cm 2H) 2.23 Cs, 3H), 2.63 (t, J=7. 0 Hz, 2H), 3.05 (s! 3HX 321426 401 201029996 3· 72 (t, J=7. 0 Hz, 2H), 4.03-4. 17 (m, 2H), 4.97- 5.07 (m, 1H), 5.08-5.18 (m, 1H), 6.34 (d, J=8.6 Hz, 1H) 6-88-6.97 (m, 1H), 7.04-7.10 (m, 1H), 7.23-7.31 (ni! 1H), 7.46 (dd, J=8.6' 2.1 Hz, 1H), 8.18 (d, J=2 1 Hz' 1H). ' (2) 3-{[(6-{[cyclohexyl (5 -Fluoro-3 monomethyl-][-benzo-b-butan-yl)-ylamino]aminopyridin-3-yl)-yl](methyl)amino}propionic acid hydrazine -{[(6-{[cyclohexyl(5-fluoro-3-methyl-1-benzo-Df-am-2-yl)indolyl]amino}n} bite _3_yl) 1N aqueous solution of sodium hydroxide (i.oo mL) was added to a mixture of methyl)amino}propionate (236 rag), tetrahydrofuran (5 mL) and ethanol (5 mL) and the mixture was stirred at room temperature for 5 hours. And concentrated under reduced pressure. The residue was dissolved in water (1 mL). The extract was washed with brine, dried over MgSO. 64%).H NMR (300 MHz, CDCh) 5 ppm 0. 84-1. 37 (m, 5H), 1.38-1.53 (m, 1H), 1.55-1.82 (m, 3H), 1.87-2.12 ( m, 2H), 2. 20(s, 3H), 2.48-2.68 (m, 2H), 2.99 (br s, 3H), 3.59-3.79 (m, 2H), 4.54-4.76 (m, 1H), 6.34 (d, J=8.8 Hz, 1H), 6.86-6.97 (m, 1H), 7.01-7.09 (ra, 1H), 7.23-7.34 (m, 1H), 7.51 (d, J=8. 8 Hz, 1H ), 8.11 (br s, 1H). Example A53 402 321426 201029996 3-{[(6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl] Amino}pyridin-3-yl)carbonyl](methyl)amino}propionic acid

F

High performance liquid chromatography (column: CHIRALPAK AD (50 mm ID x 500 mm L', manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/2-propanol (700/300-200/800), flow rate: Fractionation of 3-{[(6-{[cyclohexyl)(5-fluoro-3-indolyl-1-) synthesized in Example A52(l) from 60 mL/min to 50 mL/min, column temperature: room temperature) Benzofuran-2-yl)indenyl]amino}pyridin-3-yl)carbonyl](methyl)amino}ethyl propionate (4.06 g). Concentration of the conditions contained in the above high performance liquid chromatography The fraction of the optically active form having a shorter residence time is obtained to obtain an amorphous form (1.94 g, 99.9% ee). In the obtained amorphous form, ethanol (10 mL) and tetrahydronethane (i〇mL) 1N aqueous lithium hydroxide solution (8 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid was added at 0. The title compound (181 g, 95%, 99 9% Ή NMR (300 MHz, DMSO-de) d ppm 〇. 89-1. 28 (m, 5H) 1 34 (d, J-12. 12 Hz, 1H) 1.49-1.80 (m, 3H) 1.80-2.08 (m, 2H) 2. 23 (s, 3H) 2. 50-2. 54 (m, 2H) 2. 92 (s, 3H) 3. 53 321426 403 201029996 (t, J=7. 38 Hz, 2H) 5.15 (t, J=8. 90 Hz, 1H) 6.56 (d, J-8. 71 Hz, 1H) 7. 05 (td, J=9. 28, 2. 65 Hz, 1H) 7. 31 (dd, J=8. 71, 2. 65 Hz, 1H) 7· 36-7. 56 (m, 2H) 8. 04 (d, J=2. 27 Hz, 1H) 12.22 (brs, 1H). Example A54 3-{[(6-·([cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)methyl]] Amino}pyridin-3-yl)carbonyl](indenyl)amino}propionic acid

High performance liquid chromatography (column: CHIRALPAK AD (50 mm ID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 mL/min, tube, column temperature: room temperature) fractionated 3-{[(6-{[cyclohexyl) (5-dun-3-mercapto-1-benzo-pyranyl) synthesized in Example A52(l) 2-yl) fluorenyl]amino}11-indol-3-yl)carbonyl](methyl)amino}propionic acid ethyl ester (4. 06 g). Concentration of the conditions contained in the above high performance liquid chromatography An optically active form of the fraction having a longer residence time to obtain an amorphous form (1. 96 g, 99.9% ee). Obtained in amorphous form, ethanol (10 mL) and tetrahydro-pyrene (10) 1N aqueous lithium hydroxide solution (8 mL) was added, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1N was added at 0 °C The title compound (1.80 g, 99%, 99.9% ee) was obtained as a white solid 404 321426 201029996 solid. NMR (300 MHz, DMSO-de) δ Ppm 0. 89-1. 28 (m, 5H) 1. 34 (d, J=12. 12 Hz, 1H) 1.49-1.80 (m, 3H) 1.80-2.08 (m, 2H) 2.23 (s, 3H) 2.50-2.54 (m, 2H) 2.92 (s, 3H) 3.53 (t, J=7. 38 Hz, 2H) 5.15 (t, J=8. 90 Hz, 1H) 6.56 (d, J=8. 71 Hz, 1H) 7. 05 (td, J=9. 28, 2. 65 Hz, 1H) 7 31 (dd, J=8. 71, 2. 65 Hz, 111) 7.36-7. 56 (m, 2H) 8.04 (d, J=2. 27 Hz, 1H) 12.22 (brs, 1H). ❹Implementation Example A55 3_{[(5-{[cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)indolyl]amino}pyridin-2-yl)carbonyl]amino}propyl acid

(1) 5 {[%_Hexyl(5-a-3-methyl_1~~benzoquino-f-yl-2-yl)methyl]hydanol}pyridine-2-carboxylic acid methyl ester in the examples Adding sulfite to a solution of cyclohexyl (5-fluoro-3-methyl-1-benzofuran-2-yl) decyl alcohol (1.50 g) synthesized in A37(2) (15 inL) 6 2 5/i L )' and the mixture was shaken at room temperature for 3 hours. The anti-deer mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated In the obtained oily form 321426 405 201029996, methyl 5-aminopyridine-2-carboxylate (957 mg), sodium iodide (171 g) and Ν'N-dimethylformamide (〗 5 mL Sodium carbonate (1. 21 g) was added to the mixture and the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCls) δ ppm 0. 94-1. 37 (m, 5H), 1.46-1.57 (m, 1H), 1.60-2.00 (m, 4H), 2. 02-2.14 (m, 1H ), 2.23 (s, 3H), 3.90 (s, 3H), 4.39 (t, J=8.2 Hz, 1H), 4.70 Cd, J=8. 2 Hz, 1H), 6.84 (dd, J=8. 6 , 3.0 Hz, 1H), 6.89-6.97 (m, 1H), 7.04-7.10 (m, 1H), 7.22-7.30 (m, 1H), 7.88 (d, J=8. 6 Hz, 1H), 8.08 ( d, J=3. 0 Hz, 1H). (2) 5-·[[cyclohexyl(5-fluoro_3_indolyl-1_benzofuran-2-yl)methyl]amino}pyridine- 2-carboxylic acid hydrazine 5-((cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)methyl)amine) An aqueous solution of 1N aqueous sodium hydroxide (20 mL) was added, and the mixture was stirred under reflux for 5 hr, and concentrated under reduced pressure. 1N Hydrochloric acid (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound (751 mg, 86%) was obtained as a brown solid. NMR (300 MHz, CD Ch) ^ ppm 〇. 94-1.39 (m, 5H), 1.46- 321426 406 201029996 1.60 Cm, 1H), 1.62-2.02 (m, 4H), 2.02-2.15 (m, 1H), 2.25 (s, 3H) , 4.41 (t, J=7. 9 Hz, 1H), 4.72-4.83 (m, 1H), 6. 90-7. 00 (m, 2H), 7. 07-7. 13 (m, 1H), 7 24-7 33 (m, 1H), 7. 91-7. 98 (m, 2H). (3) 3-{[(5-{[cyclohexyl (5-fluoro-3-methyl-l_) Benzofuran-2-yl)methyl]amino}°°-decyl-2-yl)alkyl]amino}propionic acid ethyl ester 5-{[cyclohexyl (5-fluoro-3-) Methyl-1_benzobenzopyranyl)methyl]aminopyridinium-2-carboxylic acid (300 mg), ethyl alanine hydrochloride (181 mg), 1-hydroxybenzotriazole monohydrate Add 1-ethyl-3-(3-dimethylaminopropyl) to a mixture of (181?), triethylamine (328//L) and N,N-dimethylformamide (10 mL) Carbodiimide hydrochloride (226 mg), and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium sulfate was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and brine and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCh) δ ppm 0.94-1. 39 (m, 8H), 1.46-2.00 (m, 5H), 2.03-2.14 (m, 1H), 2.24 (s, 3H), 2.60 (t, J=6.2Hz, 2H), 3.64-3.72 (m, 2H), 4.15 (q, J=7. 1 Hz, 2H), 4.34-4.42 (m, 1H), 4.45-4.52 (m, 1H), 6.86 -6.98 (m, 2H), 7.05-7.10 (ra, iH), 7.24-7.30 (m, 1H), 7.87-7.93 (m, 2H), 8.06-8.13 (m, 1H). (4) 3-{ [(5-{[cyclohexyl(5-fluoro-3-indolyl-i-benzofuran-2-yl)phosphonium 321426 407 201029996]]aminobipyridin-2-yl)carbonyl]amino}propyl 3-丨[(5-{[ί辰己基(5-fluoro-3-indolyl-1~benzoindole-2-yl))]aminobibene-2-yl Add a 1N aqueous solution of sodium hydroxide (2. 〇〇mL) to a mixture of ethyl imino}ethyl propionate (361 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), and stir the mixture at room temperature. Hour and concentrate under reduced pressure. The residue was dissolved in water (1 mL), and 1N hydrochloric acid (2. The title compound was collected by filtration to give the title compound as a white solid (324 mg, 95 «. H NMR (300 MHz, CDCh) δ ppm 0. 93-1. 36 (m, 5H), 1.45 -!·56 (m, 1H), 1.61-2.00 (m, 4H), 2.01-2.12 (m, 1H), 2-22 (s, 3H), 2.65 (t, J=6. 1 Hz, 2H) , 3.64-3.75 (m, 2H), 4. 37 (d, J=8.0Hz, 1H), 6. 85-6. 99 (m, 2H), 7.03- 7-l〇(m, 1H), 7.23 -7.30 (m, 1H), 7.86-7.94 (m, 2H), 8· Η (t, J=6. 2 Hz, 1H). 'Example A56 ❹ 3 U(5-{[% 己基(5_ Fluorine_3_methyl-;1_benzofuran-2-yl)indenyl]amino}pyridin-2-yl)carbonyl](methyl)aminopropionic acid

(1) 3-{[(5-([cyclohexyl(p-fluoro_3_methyl- benzophenan-2-yl)methyl]aminobibbit-2-yl) county](methyl)amine Ethyl acetate 321426 408 201029996 5-Ucyclohexyl (5-fluoro-3-methyl-1-benzofluoren-2-yl) fluorenyl]amine synthesized in Example A55(2) Kebbi bite-2-acid acid (3〇〇mg), 3-(decylamino)propionate ethyl ester (155 mg), 1-hydroxybenzotriazole monohydrate (181 rag), triethyl Add 1-ethyl 3-(3-monodecylaminopropyl) carbodiimide salt to a mixture of amine (328//L) and N,N-dimercaptomethylamine (1 mL) Acidate (226 mg) 'and the mixture was stirred at room temperature. A saturated aqueous solution of chlorinated acid was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. Washed with saturated aqueous sodium hydrogencarbonate and saturated brine. The yttrium sulphate was dried and concentrated under reduced pressure. The residue was purified EtOAc EtOAc EtOAc Mg, 82%). 'H NMR (300 MHz, CDCla) δ ppm 0.93-1.38 (m, 8H), 1.46-1.57 (m, 1H) , 1.60-1.99 (m, 4H), 2.03-2.16 (m, 1H), 2.22 (s, 3H), 2.63-2.78 (m, 2H), 3.00-3.21 (m, 3H), 3.69-3.87 (m, 2H), 4.01-4.19 (m, 2H), 4.32-4.40 (m, ❹ 1H), 4. 41-4. 49 (m, 1H), 6. 84-6. 98 (m, 2H), 7. 04-7· ii (in, 1H), 7.24-7.31 (m, 1H), 7.44-7.59 (m, 1H), 7.88-7. 95 (in, 1H). (2) 3-{[(5- {[cyclohexyl(5-fluoro-3-methyl-p-benzofuran-2-yl)indenyl]aminobibbit-2-yl)yl)](methyl)aminopropionic acid above Synthesis of 3-{[(5-{[cyclohexyl(5-fluoro-3-methyl-1-benzopyran-2-yl)methyl]amine) is more than one base] Add 1N aqueous sodium hydroxide solution (2. 〇〇mL) to a mixture of (methyl)amino}ethyl acetate (318 mg), tetrahydrogenethane (5 cc) and ethanol (5 mL) at room temperature The mixture was stirred at 321 426 409 s s s s s s s s s s s s s s s s s s s s s s s s s. The resulting precipitate was collected by filtration to give the title compound (262 mg, 87%) as white solid. ^MR(300 MHz, CDCl3)5ppin 0.93-1.37 (m,5H), 1.46-1.56 (m, 1H), 1.60-1.99 (m, 4H), 2.03-2.13 (m, 1H), 2.23 (s, 3H), 2.68-2.89 (m, 2H), 3.09 (br s, 3H), 3.77 (t, J=6. 8 Hz, 2H), 4.36 (d, J=8. 3 Hz, 1H), 6.87- 6.99 (m, 2H), 7-〇5-7.11 (m, lH), 7.24-7.32 (m, lH), 7.48-7.66 (m, 1H), 7. 90-8.00 (m, 1H). A57 3-{[ (5-{[cyclohexyl(5-fluoro-3-indolyl-i-benzofuran-2-yl)indolyl]amino}n-pyridin-2-yl)carbonyl](A Amino}propionic acid

Inductive liquid chromatography (column: CHIRALPAK AD (50 mm ID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (500/500) 'flow rate: 60 mL/min, column Temperature: room temperature) fractionation of 3-丨[(5-{[cyclohexyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)indenyl]amine synthesized in Example A56(l) Ethyl pyridyl-2-yl)carbonyl](methyl)amino}ethyl propionate (5·83 g). Concentrated optically active form having a shorter residence time under the conditions of the above high performance liquid chromatography Distillation 321426 410 201029996 to obtain amorphous (2.90 g, 99.9% ee). Add 1 to the obtained mixture of amorphous, ethanol (10 mL) and tetrahydropyran (1 mL) The aqueous solution of lithium hydroxide (12 mL) was stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was dissolved in water (30 mL), and then 1N hydrochloric acid (12 mL). The resulting precipitate was collected to give the title compound (2. 67 g, 99%, 99.9% ee) as a white solid.]H NMR (300 MHz, DMSO-de) (5 ppm 0. 98- 1. 29 (m, 5H) 1. 3〇-1.39 (m, 1H) 1.63 (brs, 2H) 1.75 (d, J=11.36 Hz, 1H) ® 1.82-2.00 (m,1H) 2.09 (d,J=ll. 74 Hz' 1H) 2.25 (s, 3H) 2.53-2.66 (m, 2H) 2.88-3.03 (m, 3H) 3.32 (br s, 2H) 4.51 (t, J=8. 33 Hz, 1H) 6.80 (d, J=8. 33 Hz, 1H) 6.96 (dd, J=8. 71, 2. 65 Hz, 1H) 7.05 (td, J=9. 28, 2.65 Hz, 1H) 7.26-7.39 (m, 2H) 7.47 (dd, J =8. 90, 3.98 Hz, 1H) 7.95 (d, J=2. 27 Hz, 1H) 12.26 (br s, 1H). Example A58 ❹ ([Losyl-based (5_U_indol-1-benzo-α) Furan-2-yl)indenyl]aminodipyridin-2-yl)carbonyl](indenyl)amino}propionic acid

High performance liquid chromatography (column: CHIRALPAKAD (50 mm IDx500 _L 'Manufactured by Daicel Chemical Industries, Ltd., mobile phase: 411 321426 201029996 hexane/ethanol (500/500), flow rate · 60 mL/min, Column temperature: room temperature) fractionation of the cyclohexyl (5-fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino}pyridyl)carbonyl group synthesized in Example A56 (1) (indenyl)amino}ethyl propionate (5.83 g). The fraction containing the optically active form having a longer residence time under the conditions of the above high performance liquid chromatography was concentrated to obtain an amorphous form (2.82 g, 99.9% ee). A 1 N aqueous solution of lithium hydroxide (12 mL) was added, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in water (3 mL) and 1N hydrochloric acid (12 mL) was then applied. The resulting precipitate was collected by filtration to give the title compound (2. 64 g, 97%, 99. ee ee) as white solid. H NMR (300 MHz, DMSO-de) ά ppm 0. 98-1. 29 (m, 5H) 1. 3〇-1-39 (m, 1H) 1.63 (brs, 2H) 1.75 (d, J=11.36 Hz, 1H) 1.82-2.00 (m, 1H) 2.09 (d, J=11.74 Hz, 1H) 2.25 (s, 3H) 2.53-2.66 (m, 2H) 2.88-3.03 (m, 3H) 3.32 (br s, ❹ 2H) 4·51 (t, J=8.33 Hz, 1H) 6.80 (d, J=8.33 HZ, 1H) 6.96 (dd, J=8. 71, 2.65 Hz, 1H) 7. 05 (td, J= 9. 28, 2.65 Hz, 1H) 7.26-7.39 (m, 2H) 7.47 (dd, J=8. 90, 3.98 Hz, 1H) 7.95 (d, J=2.27 Hz, 1H) 12.26 (br s, 1H) . ' Azine A59 3-{[(5-{[cyclohexyl(3-indolyl-indole-benzothiophene-2-yl)methyl]amino} ° ° °-2-yl) ](mercapto)amino}propionic acid 321426 412 201029996

(1) 5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)indolyl]aminopyrbidine-2-pyreoylpyrene is intended to be used in Example A10(2) Synthesis of 2-[chloro(cyclohexyl)methyl]-3-mercapto-1-benzophenone (664 mg), 5-amino-based 0-bito-2-carboxylic acid methyl ester (362 mg), Sodium carbonate (505 mg) was added to a mixture of sodium iodide (714 mg) and N,N-dimethylformamide (1 mL), and the mixture was stirred at 80 ° C overnight. A saturated aqueous chloride solution was added to terminate the reaction, and the reaction mixture was taken up in ethyl acetate. The extract was washed with saturated brine, dried over sulfuric acid, and concentrated under reduced dust. The residue was purified by EtOAc EtOAc (EtOAc) Ο !H NMR (300 MHz, CDCh) ^ ppm 1. 03-1. 37 (m, 5H), 1.54-1.88 (in, 5H), 2.07-2.18 (m, 1H), 2.47 (s, 3H), 3.88 (s, 3H), 4.54-4.68 (m, 2H), 6.78 (dd, J=8.6, 2. 7 Hz, 1H), 7.22-7.30 (m, 1H), 7.31-7.38 (m, 1H), 7.63 (d, J=8. 0 Hz, 1H), 7.68 (d, J=8. 0 Hz, 1H), 7.84 (d, J=8. 6 Hz, 1H), 8.05 (d, J=2.7 Hz , 1H). (2) 5-((cyclohexyl(3_fluorenyl~bbenzothiophene-2-yl)methyl]amino}pyridin-2TM-acid 321426 413 201029996 synthesized in the above 5-{[cyclohexyl(3-methylbenzo-3-detyl-2-yl)methyl]aminobibbitidine-2-acidic methyl vinegar (10) mg), ethanol (5), and tetrahydrofurfuryl A 1N aqueous solution of hydrogen (5 〇〇 mL) was added to a mixture (5 mL) and the mixture was warmed overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (1 mL), and the mixture was extracted with EtOAc (5 mL EtOAc), and the mixture was extracted with ethyl acetate. The title compound (452 mg, quantitative) was obtained as a pale brown solid. </ br> H NMR (300 MHz, CDCl3) (5 ppmi. 〇3-i.38 (m, 5H),: L56- 1.90 (m, 5H), 2.08-2.18 (m, 1H), 2.50 (s, 3H), 4.56- 4.64 (in, 1H), 4.68-4.77 (m, 1H), 6.88 (dd, J=8. 7 , 2. 6Hz, 1H), 7. 25-7. 33 (m, 1H), 7.34-7.41 (m, 1H), 7.66 (d, J=7.4Hz, 1H), 7.71 (d, J=7. 7 Hz, 1H), 7.86-7.93 (m, 2H). * (3) 3-{[(5-{[cyclohexyl(3-indolyl-1-benzothiophen-2-yl)methyl]amine 5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)fluorenyl) synthesized by the above-mentioned ethyl ester of mercaptopyridin-2-yl)carbonyl](indenyl)amino}propionate Amino}pyridine-2-ret (200 mg), ethyl 3-(decylamino)propionate (104 mg), 1-hydroxybenzotriazole monohydrate (121 mg), triethylamine (200 yL) and a mixture of N,N-didecylguanamine (1 〇mL) were added with ethyl ethyl-3-(3-didecylamino) Propyl) carbodiimide hydrochloride (151 mg), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the mixture was extracted with ethyl acetate to concentrate saturated sodium bicarbonate. The extract was washed with aq. EtOAc (EtOAc m. The title compound (141 mg, 54%) was obtained as a white solid. NMR (300 MHz, CDCh) δ ppm 1. 03-1. 35 (m, 8H), 1.55- 1.88 (m, 5H), 2.06-2. (m, 1H), 2.46 (s, 3H), 2.61-2.76 (in, 2H), 2.98-3.18 (m, 3H), 3.69-3.87 (m, 2H), 3.98-4.18 (m, 2H), 4.39 (d, J=6. 0 Hz, 1H), 4.51-4.58 Cm, 1H), 6.81 (dd, J=8. 5, 2.7 Hz, 1H), 7.23-7.30 (m, ❹ 1H), 7.31-7.38 (m, 1H), 7.39-7.55 (m, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.84-7.91 (m, 1H). 4) 3-{ [(5-·[[cyclohexyl(3-indolyl-l-benzoindole-2-yl)indolyl]amino}pyridin-2-yl)carbonyl](methyl)amine Based on the above synthesis of propionate 3-{[(5-· ([Cyclohexyl(3-methyl-1-benzo[seceophen-2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amino}ethyl propionate 141 (141 A 1N aqueous solution of sodium hydroxide (1. 〇〇mL) was added to a mixture of EtOAc (EtOAc) (EtOAc) The residue was dissolved in water (1{) mL), and 1N hydrochloric acid (1. The resulting precipitate was collected by filtration to give the title compound (112 mg, 84%). H NMR (300 MHz, CDCh) δ ppm 1. 01-1. 37 (m, 5H), 1.54- 1.89 (m, 5H), 2.06-2.18 (m, 1H), 2.47 (s, 3H), 2.73- 2.90 (m, 2H), 3.08 (br s, 3H), 3.76 (t, J=6. 4 Hz, 2H), 4.55 (d, J=8.0Hz, 1H), 6.83-6.93 (in, 1H), 7.23-7.33 321426 415 201029996 (m, 1H), 7.33-7.41 (m, 1H), 7.47-7.63 (m, 1H), 7.65 (d, J=7.6Hz, 1H), 7.71 (d, J=7.6 Hz , 1H), 7.85-7.94 (m, 1H). Example A60 3-{[(5-·([cyclohexyl(3-methyl-1-benzothiophen-2-yl)indolyl]amino} Pyridin-2-yl)carbonyl](indenyl)amino}propionic acid

High performance liquid chromatography (column: CHIRALPAKAD (50 mm ID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 mL) /minute to 50 mL / min, column temperature: room temperature) fractionated 3-{[(5-{[cyclohexyl (3-methyl-1-benzothiophene-2-) synthesized in Example A59 (3) Ethyl)amino]pyridin-2-yl)carbonyl](indenyl)amino}ethyl propionate (9.31 g). Concentration with shorter residence time under the conditions of high performance liquid chromatography described above a fraction of the optically active form to obtain an amorphous form (4. 67 g, 99.9% ee). In a mixture of amorphous, ethanol (20 mL) and tetrahydroanion (20 mL) obtained. A 1 N aqueous solution of ruthenium oxide (20 mL) was added, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and EtOAc (20 mL). The resulting precipitate was collected by filtration to give the title compound (4.17 g, 99%, 99.9% ee) as a white solid. 416 321426 201029996 Ή NMR (300 MHz, DMSO-de) 5 ppm 1. 00- 1. 32 (m, 5H) 1. 37-1 .51 (m, 1H) 1.52-1.84 (m, 4H) 2.07-2.20 (m, 1H) 2.46 (s, 3H) 2.50-2.57 (m, 2H) 2.87-3.01 (m, 3H) 3.27-3.36 (m , 5H) 3. 43-3. 68 (m, 2H) 4. 63 (t, J=7. 38 Hz, 1H) 6. 87 (d, J=6.82 Hz, 2H) 7.19-7.41 (m, 3H 7.69 (d, J=7. 19 Hz, 1H) 7.79 (d, J=7. 57 Hz, 1H) 7.89 (d, J=2. 65 Hz, 1H) 12. 16 (brs, 1H). Example A61

3_{[(5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)indolyl]amino}pyridin-2-yl)carbonyl](methyl)amino}propionic acid

〇 〜c〇2h ch3

High performance liquid chromatography (column: CHIRALPAKAD (50 cut 1 IDx500 mmL 5 Daicel Chemical Industries, Ltd., mobile phase. Hexane/2-propanol (700/300 to 200/800), flow rate: 60 3-{[(5-{[cyclohexyl(3-mercapto-1-benzothiophene-2) synthesized in Example A59(3) was fractionated from mL/min to 50 mL/min, column temperature: room temperature) -yl)methyl]pyridin-2-yl)carbonyl](indenyl)amino}ethyl propionate (9.11 g). 丨j has a longer retention under the conditions of the above high performance liquid chromatography Time-active form of the fraction to obtain an amorphous form (4.52 g, 99.9% ee;). 1426 of the obtained amorphous form, ethanol (20 mL) and tetrahydrofuran (2〇mL) 417 201029996 Add IN water solution (2 〇 rainbow) to the mixture, pour the mixture at room temperature for 1 hour' and concentrate under reduced ink. Dissolve the residue in water (2 〇) and add in 〇t 1N Hydrochloric acid (2 〇 )). The resulting precipitate was collected by filtration to give the title compound (4. i2 g, 99.9% ee) as a white solid. H NMR (300 MHz, DMS0-d6 ) 5 ppm 1. 〇〇_j. 32 ( m,5H) l 37-1.51 (in, 1H) 1.52-1.84 (m, 4H) 2.07-2.20 (m, 1H) 2.46 (s, 3H) 2. 50-2. 57 (m, 2H) 2. 87 -3. 01 (m, 3H) 3. 27-3. 36 (m, 5H) 3. 43-3. 68 (m, 2H) 4. 63 (t, J=7. 38 Hz, 1H) 6. 87 (d, J=6. 82 Hz, 2H) 7.19-7.41 (m, 3H) 7.69 (d, J=7. 19

Hz, 1H) 7.79 (d, J=7.57 Hz, 1H) 7.89 (d, J=2. 65 Hz, 1H) 12. 16 (brs, 1H). Example A62 3-{[(5-·([ Cyclohexyl (3-methyl-i-benzothiophene-2-yl)methyl]amino} ° pyridine 2 -yl)carbonyl]amino}propionic acid

(1) 3-{[(5-·[[cyclohexyl(3-indolyl-1-benzoindole-2-yl)indolyl]aminobipyridin-2-yl)carbonyl]amino} Ethyl propionate 5-{[cyclohexyl(3-indolyl-benzobenzophen-2-yl)indenyl]amino}pyridine-2-carboxylic acid (247) synthesized in Example A59 (2) Mg), propylamine 321426 418 201029996 acid ethyl ester hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (149 mg), triethylamine (270 /iL) and N,N-dimercaptopurine Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18 6 mg )' to a mixture of decylamine (1 mL) and spoil the mixture overnight at room temperature . A saturated aqueous solution of ammonium chloride was added to terminate the reaction' and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc O1HNMR (300 MHZ, CDCl3) SPpm 1.02-1.35 (m, 8H), 1.54- 1.88 (m, 5H), 2.06-2.18 (m, 1H), 2.47 (s, 3H), 2.58 (t, J=6) 3 Hz, 2H), 3.61-3.71 (m, 2H), 4.13 (q, J=7. 1 Hz, 2H), 4.48-4.60 (m, 2H), 6.80-6.87 (in, 1H), 7.22- 7.30 (m, 1H), 7.31-7.38 (m, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.69 (d, J=8. 0 Hz, 1H), 7.83-7.88 (m, 2H) , 8.07 (t, J=6.3 Hz, 1H). ❹(2) 3-丨[(5-{[cyclohexyl(3-methyl-i-benzothiophene-2-yl)methyl]amine ratio 3-{[(5-{[cyclohexyl(3-indolyl-1-benzothiophen-2-yl)methyl]amino} 咐^ synthesized in the above synthesis of pyridin-2-yl)carbonyl]amino}propionic acid Add a 1N aqueous solution of sodium hydroxide (1· 〇〇mL) to a mixture of 疋-2-yl)methylamino}acetate (gw mg), tetrahydrofuran (5 mL) and ethanol (5 mL). The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. The residue was dissolved in water (1 Torr), and hydrazine hydrochloride (1 00 mL) was added. The resulting precipitate was collected by filtration to give the title compound (235 mg, 91%) as white solid. 321426 419 201029996 H NMR (300 MHz, CDCh) δ ppm 1. 02-1. 36 (m, 5H), 1.54- 1.89 (in, 5H), 2.06-2.18 (m, 1H), 2.47 (s, 3H) , 2.64 (t, J=6. OHz, 2H), 3.61-3.73 (m, 2H), 4.56 (d, J=7.9

Hz, 1H), 6.84 (dd, J=8. 5, 2.4 Hz, 1H), 7.22-7.31 (in, 1H), 7.31-7.40 (m, 1H), 7.64 (d, J=7.99 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.82-7.91 (m, 2H), 8.11 (t, J=6.0

Hz, 1H). Example A63 3-{[(4-{[cyclopentyl(3-methyl-i-benzothiophen-2-yl)methyl]amino} phenyl)carbonyl]amino} Propionic acid

0) cyclopentyl (3-methyl-1-benzo-7-cephen-2-yl)methanone at 0 ° C in 3-methyl-1-benzothiophene (i.oo g), cyclopentane Alkylcarbonyl chloride (903 // L) and nitromethane (a mixture of 10 was added with aluminum chloride (1. 35 g), and the mixture was stirred for 5 hours. Water was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. Target compound (1.54 g, 93%) H NMR (300 MHz, CDCh) δ ppm 1. 60-1. 84 (m, 4H), 1 92- 321426 420 201029996 2.03 (m, 4H), 2.78 (s, 3H), 3.48-3.60 (m, 1H), 7.40- 7.52 (m, 2H), 7.81-7.91 (m, 2H) · (2) 4-((cyclopentyl) (3_methyl_; [1 Benzothiophene-2-yl)methyl]amino hydrazide methyl ester in the above synthesis of cyclopentyl (3-mercapto-1-benzoindole-2-yl)methyl _ (1·54 g Adding vaporized titanium (iv) (829 ❹ VL) to a mixture of methyl 4-aminobenzoate (L05 g), triethylamine (7 〇 2 mL) and dioxane (3 〇 mL) The mixture was stirred for 3 days under argon and room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and dichloromethane was evaporated in an evaporator, and the residue was extracted with ethyl acetate. It is dried with sulphuric acid and concentrated under reduced pressure to give a dark brown oil. EtOAc ( EtOAc / EtOAc / EtOAc ' And the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, the organic solvent was evaporated in an evaporator and the residue was extracted with ethyl acetate. The extract was washed with saturated brine to sulfuric acid. The magnesium was dried and concentrated under reduced pressure. EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCh) δ ppm 1. 30-1. 44 (m, 1H), 1.45-!·82 (m, 6H), 1.90-2.06 (m, 1H), 2.28-2.46 (m, 1H), 2-50 (s, 3H), 3.79 (s, 3H), 4.47-4.56 (m, 1H), 4.62 (d, J=9. 1 Hz, 1H), 6.51 (d, J=9. 1 Hz, 2H), 7.22-7.29 1H), 7.31-7.37 (m, 1H), 7.61-7.66 (m, 1H), 7.67-7· (m, 1H), 7.76 (d, J=9. 1 Hz, 2H) 321426 421 201029996 (3) 4-{[Cyclopentyl (3-methyl-1-benzothiopheny-2-yl)indolyl]aminoindanic acid is synthesized in the above 4-·[[cyclopentyl Addition of a mixture of benzyl (3-methyl-1-benzoindole-2-yl) fluorenyl]amino}benzoate (1.56 g), tetrahydrofuran (2 mL) and ethanol (20 mL) A 1N aqueous sodium hydroxide solution (2 mL. EtOAc) was evaporated. The residue was dissolved in water (40 mL), and (1N hydrochloric acid (20.0 mL) was added to TC. The resulting precipitate was collected by filtration and the obtained pale brown solid was dissolved in ethyl acetate. The solution was washed with EtOAc EtOAc (EtOAc m. 1. 45 (m, 1H), 1.45-1.82 (m, 6H), 1.90-2.05 (m, 1H), 2.27-2.45 (m, 1H), 2. 50 (s, 3H), 4. 63 (d , J=9. 1 Hz, 1H), 6. 52 (d, J=8. 8 Hz, 2H), 7. 22~7. 29 (m, 1H), 7. 31-7. 38 (m, 1H), 7. 61- ❹ 7. 66 (m, 1H), 7· 67-7. 71 (m, 1H), 7· 80 (d, J=8. 8 Hz, 2H). (4) 3 -{[(4-{[Cyclopentyl (3-methyl-1-benzophenan-2-yl)methyl]amino}phenyl) benzyl]amino}propionic acid ethyl acetonate synthesized above 4-{[Cyclopentyl (3-methyl-1-benzothiophene-2-yl) fluorenyl]amino}benzoic acid (300 mg), 10,000-alanine ethyl ester hydrochloride (189 mg) , a mixture of 1-hydroxybenzotriazole monohydrate (188 mg), triethylamine (343 μΙ〇, and hydrazine, Ν-'mercaptocaramine (10 mL) 1-Ethyl-3-tris(3-di-t-aminopropylpropyl)carbodiimide hydrochloride (236 mg) was added, and the mixture was warmed for 5 hours at room 321426 422 201029996. A saturated aqueous solution of ammonium chloride was added. The reaction was quenched and the mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. The title compound (331 mg, 87%) was obtained as a pale brown oil. </ RTI> NMR (300 MHz, CDCh) δ ppm 1.23 (t, J) =7. 1 Hz, 3H), 1.30-1.45 (m, 1H), 1.45-1.81 (m, 6H), 1.90-2.07 (m, ® 1H), 2.27-2.47 (m, 1H), 2.50 (s, 3H), 2.56 (t, J=5.8

Hz, 2H), 3.59-3.68 (m, 2H), 4.12 (q, J=7. 1 Hz, 2H), 4. 42 (d, J=5. 7 Hz, 1H), 4. 60 (dd, J=9.1, 5. 7 Hz, 1H) 6.48-6.60 (m, 3H), 7.21-7.29 (m, 1H), 7.30-7.37 (m, 1H), 7.50 (d, J=8. 8 Hz, 2H ), 7.61-7.65 (m, 1H), 7.66-7.72 (m, 1H). (5) 3-{[(4-{[cyclopentyl (3-methyl-1-benzoindole-2-) Alkyl]amine φ phenyl}phenyl) benzyl]amino}propionic acid 3-{[(4-·([cyclopentyl]3-methyl-1-benzo porphin-) 2-yl)methyl]amino}phenyl)carbonyl]amino}ethyl propionate (331, IV

A 1 N aqueous sodium hydroxide solution (2.00 mL) was added to a mixture of THF (5 mL) and ethyl alcohol (5 mL), and the mixture was stirred at room temperature for 15 hr. The residue was dissolved in water (1 mL), and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to afford title compound (276 mg, 89%) as white solid. NMR NMR (300 MHz, CDCh) δ ppm 1. 28-1. 43 (m, 1H), l 44- 321426 423 201029996 1.80 (m, 6H), 1.89-2. 03 (m, 1H), 2. 25 -2.43 (m,1H) 2.48 (s, 3H), 2.56 (t, J=5.3 Hz, 2H), 3.52-3.63 (m, 2H), 4.58 (d5 J=9. 0 Hz, 1H), 6.45- 6.60 (m, 3H), 7.20-7.28 (m, 1H), 7.29-7.37 (m, 1H), 7.46 (d, J=8. 3 Hz, 2H), 7.62 (d, J=7· 5 Hz, 1H), 7. 68 (d, J=7·9 Hz 1H) Example A64 ' ' 3-{[(4-{[Cyclopentyl (3-mercapto-1-benzothiopheny)) Methyl]amino} benzyl) benzyl](methyl)amino}propionic acid

(1) 3-{[(4-{[Cyclopentyl(3-indolyl-1-benzoindol-2-yl)methyl]amino}} benzyl) benzyl](methyl)amino }Acetylpropionate is intended to be synthesized in Example A63(3) 4-[[cyclopentyl(3-methyl-1-benzoindolethiophen-2-yl)indolyl]amino}benzoic acid (3) 〇〇mg), 3-(methylamino)propionic acid ethyl ester (161 mg), 1-hydroxybenzotriazole monohydrate (188 mg), triethylamine (343 #L), and N,N- Add 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (236 mg) to a mixture of dimercaptocaramine (1 mL) and stir at room temperature The mixture was allowed to stand for 5 hours. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 'H NMR (300 MHz, CDCh) δ ppm 1.21 (t, J=7.2 Hz, 3H), 1.31-1.44 Cm, 1H), 1.45-1.83 (m, 6H), 1.89-2.04 (m, 1H) , 2.28-2.43 (in, 1H), 2.49 (s, 3H), 2.59 (t, J=7. 1 Hz, 2H), 2.98 (s, 3H), 3.68 (t, J=7. 1 Hz, 2H ), 4.09 (q, J=7.2 Hz, 2H), 4.27-4.33 (m, 1H), 4.53-4.61 (m, 1H), 6.51 (d, J=8. 5 Hz, 2H), 7. 17 ( d, J=8. 5 Hz, 2H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.61-7.66 (m, ® 1H), 7.68-7.73 (m, 1H). ( 2) 3-{[(4-{[cyclopentyl(3-indolyl-1-benzoindole-2-yl)methyl]amino}} benzyl) benzyl] fluorenylamino} 3-{[(4-{[cyclopentyl(3-indolyl-1-benzothiophen-2-yl)indolyl]amino}phenyl)carbonyl](indenyl)amine synthesized by propionic acid Aqueous sodium hydroxide solution (2.0 mL) was added to a mixture of ethyl propionate (228 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 3 hr. Concentrate under reduced pressure. The residue was dissolved in water (10 mL) and at 0. (1N HCl (2 mL) was added. 28-1. 44 (m, 1H), 1.44-179 (m, 6H), 1.89-2.04 (m, 1H), 2.26-2.43 (m, 1H), 2- 49 (s, 3H), 2.62 (t , J=6.2 Hz, 2H), 2.98 (s, 3H), 3- 66 (t, J=6.2 Hz, 2H), 4.57 (d, J=9. 0 Hz, 1H), 6.51 Cd, J=8.5 Hz, 2H), 7.20 (d, J=8. 5 Hz, 2H), 7.23-7.30 (m,1H), 7. 31-7. 38 (m, 1H), 7. 64 (d, J=7 5 Hz, 1H), 425 321426 201029996 7. 71 (d, J=7. 5 Hz, 1H). Example A65 3-{[(4-{[cyclopentyl (3-methyl-1-benzene) And thiophen-2-yl)methyl]amino)phenyl)carbonyl](fluorenyl)amino}propionic acid

高效High performance liquid chromatography (column: CHIRALPAKAD (5〇mm IDX500 mmL, manufactured by Daicel Chemical Industries, Ltd.) Mobile phase hexane/ethanol (500/500), flow rate: 60 mL/min, column Temperature: room temperature) fractionated 3-{[(4-{[cyclopentyl(3-indolyl-1-benzothiophen-2-yl)indolyl]amino}benzene synthesized in Example A64(l) Ethyl carbonyl](methyl)amino}ethyl propionate (19.7 g). Concentrate fractions containing optically active forms having a shorter residence time under the conditions of the above high performance liquid chromatography to obtain a non- Crystalline type (8. 75 g, 99.9% ee). Add IN aqueous sodium hydroxide solution to a mixture of amorphous, ethanol (1 〇〇 mL) and tetrahydroanthracene (100 mL) obtained ( The mixture was stirred at room temperature for 5 hr and concentrated under reduced pressure. The residue was dissolved in water (200 mL). The extract was washed with aq. EtOAc (EtOAc m. The solid obtained by the sister to obtain colorless crystals. 321426 426 201029996 】Hl^MR(300 MHz, CDCls) 6ppmi.28-1.44 (m,lH),1.44- 1.79 (m, 6H), 1.89-2.04 ( m, 1H), 2.26-2.43 (m, 1H), 2.49 (s, 3H), 2.62 (t, J=6.2 Hz, 2H), 2.98 (s, 3H), 3.66 (t, J=6.2 Hz, 2H ), 4.57 (d, J=9. 0 Hz, 1H), 6.51 (d, J=8.5 Hz, 2H), 7.20 (d, J=8. 5 Hz, 2H), 7.23-7.30 (m, 1H) , 7.31-7.38 (m, 1H), 7.64 (d, J=7. 5 Hz, 1H), 7.71 Cd, J=7. 5 Hz, 1H). 'Example A66 Ο 3-{[(4-{ [Cyclopentyl (3-methyl-l-benzothiophen-2-yl) fluorenyl]amino} phenyl)carbonyl](methyl)amino}propionic acid

High performance liquid chromatography (column: CHIRALPAKAD (50 mm ID x 500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (500/500), flow rate: 6 〇mL/min, column temperature : room temperature) fractionation of 3-{[(4-{[cyclopentyl(3-methyl-1-benzoindole-2-yl)methyl]amino}benzene synthesized in Example A64(l) a group of (meth)amino}ethyl propionate (19.7 g). Concentration of the optically active form having a longer residence time under the conditions of the above high performance liquid chromatography, Obtained amorphous (8. 95 g, 99.9% ee). Add IN aqueous sodium hydroxide solution to a mixture of amorphous, ethanol (1 〇〇) and tetrahydrofuran (100 mL) obtained 427 321426 201029996 (30 mL), the mixture was stirred at room temperature for 3 hr and concentrated under reduced pressure. The residue was dissolved in water (200 mL). The mixture was washed with EtOAc EtOAc (EtOAc m. H NMR (300 MHz, CDCh) δ ppm 1. 28-1. 44 (in, 1H), ] 44.. 1.79 (m, 6H), 1.89-2.04 (m, 1H), 2.26-2.43 (m, 1H ) 2.49 (s, 3H), 2.62 (t, J=6.2 Hz, 2H), 2.98 (s, 3H) 3.66 (t, J=6.2 Hz, 2H), 4. 57 (d, J=9.0 Hz, 1H ), 6 51 (d, J-8. 5 Hz, 2H), 7.20 (d, J=8. 5 Hz, 2H), 7.23-7 3〇(m, 1H), 7.31-7.38 (m, 1H) , 7.64 (d, J = 7.5 Hz, 1H) 7. 71 (d, J = 7.5 Hz, 1H). Example A67

3-{[(4-{[cyclopentyl(5-fluoro-3-indolyl-1-benzofuranyl)indolyl]amino phenyl)carbonyl](methyl)aminopyridinic acid ester

(1) (2-Ethyl-4-fluorophenoxy)acetic acid was stirred at room temperature with 5'-fluoro-2'-hydroxyacetophenone (25. 〇g), 峋7 / ruthenium acetate (27 2小时。 2 g) and potassium carbonate (33. 6 g) Ν, Ν 二甲 二甲 * * * * 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 Insoluble material was filtered off, and 321426 428 201029996 hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate Tetrahydrofuran (300 mL), ethanol (300 mL), and 1N aqueous sodium hydroxide (300 mL) were added to the obtained oil, and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated under reduced pressure, and 1N hydrochloric acid (300 mL) was added, and the crystals obtained were collected. The crystals were dissolved in EtOAc (EtOAc EtOAc) ® NMR (300 MHz, CDCh) 5 ppm 2.68 (s, 3H), 4.75 (s, 2H), 6.86-7.03 (m, 1H), 7.13-7.30 (m, 1H), 7.43-7.60 (in, 1H) (2) 5-Fluoro-3-indolyl-1-benzofuran The above synthesized (2-ethanesulfonyl-4-fluorophenoxy)acetic acid (22.94 g), sodium acetate was stirred at 110 ° C (44. 38 g) and a mixture of acetic anhydride (200 mL) for 15 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to EtOAc (EtOAc) elute elute R (300 MHz, CDC13) 5 ppm2.20(s,3H), 6.91-7. 03 (m, 1H), 7. 15(dd, J=8. 3, 2. 7 Hz, 1H), 7 35 (dd, J-8. 7, 4.2 Hz, 1H), 7.42 (s, 1H). (3) Cyclopentyl (5-fluoro-3-indolyl-1-benzofuran-2-yl) 5-fluoro-3-indolyl-1 benzo oxafuran (2.0 429 321426 201029996 g), cyclopentane carbonyl gas (1.94 g) of nitrodecane synthesized above at 0 °C (4 () mL) Aluminium chloride (anhydrous) (2.66 g) was added to the solution, and the mixture was stirred for 3 hours. 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 anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was dried to give the title compound (yield: 211 g, 64%). W^JMR (300 MHz, CDC13) &lt;5 ppm 1.67-2.09 (m,8H), 2.57 (s, 3H), 3.64-3.91 (m, 1H), 7.10-7.23 (m, 1H), 7.25 -7.31 (m, 1H), 7.38-7.53 (m, 1H). (4) Cyclopentyl (5-fluoro-3-methyl-1-benzofuran-2-yl)methanol The base (5-fluoro-3-indolyl-1-benzofuran-2-yl)methanone (27·15 g) is dissolved in a mixed solvent of methanol (40 mL)-tetrahydrofuran (240 mL), and Sodium tetrahydroborate (90%, 5.5 g) was added at °C. Yu Yu C gave the reaction mixture for 2 hours. 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 anhydrous magnesium sulfate. After filtration, the filtrate was evaporated to crystalljjjjjjjjjjjj NMR (300 MHz, CDCh) δ ppm 1. 04-1. 20 (in, 1H), 1.42-1.77 (m, 6H), 1.92-2.02 (ra, 2H), 2.21 (s, 3H), 2.42-2.60 (m, 1H), 4.56 (dd, J=9. 3, 5. 9 Hz, 1H), 6.97 (td, J=9. 1, 2. 7 Hz, 1H), 7.11 (dd, J=8. 7, 2. 7 Hz, 1H), 7.33 (dd, J=8. 9, 4. 0 Hz, 1H). (5) 3-{[(4-·[[cyclopentyl (5-fluoro-3) -Methyl-1-benzo-11-pentan-2-yl)-methyl 430 321426 201029996 benzyl]amino}phenyl)carbonyl](methyl)amino}propionic acid ethyl ester obtained at room temperature above To a solution of (5-fluoro-3-methyl-1-benzopyran-2-yl) decyl alcohol (27.31 g) in tetrahydrofuran (200 mL) was added sulphur chloride (10.0 mL). The reaction mixture was stirred at room temperature for 2 hours. An aqueous solution of sodium bismuth carbonate cooled to 0 ° C with ice 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 anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the 3-UU-aminophenyl)carbonyl®](indenyl)amino}ethyl propionate obtained in Example 2 (2) was added to the obtained residue. (28. 90 g), sodium iodide (16.48 g), sodium carbonate (23.3 g) and N,N-dimercaptoacetamide (200 mL), and the mixture was stirred at 80 ° C for 18 hours. 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 anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to EtOAc EtOAc (EtOAc:EtOAc:EtOAc ❹Example A 6 8 3-{[(4-·([cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl] (mercapto)amino}propionic acid

3-{[(4-·([cyclopentyl(5-fluoro-3- 431 321426 201029996 fluorenyl-1-benzofuran-2-yl)indolyl]amine obtained in Example A67 (5) Ethyl phenyl)carbonyl](methyl)amino}ethyl propionate (460 mg) is dissolved in ethanol (1·9 mL) and tetrahydrofuran (19 mL). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. Water (6 mL) was added, and the mixture was neutralized with 1N hydrochloric acid under ice cooling, and stirred for a few hours. The resulting precipitate was collected by filtration, and Dry to give the title compound (352 mg, <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; s,3H), 2.47 (d, J=8.0 Hz, 1H), 2.60-2.70 (m, 2H), 3.01 (s, 3H), 3.69 (t, J=6.6 Hz, 2H), 4.36 (d, J =9. 1 Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6. 86-6. 97 (m, 1H), 7. 07 (dd, J=8. 7, 2. 7 Hz, 1H), 7.18-7.31 (m, 3H). Example A69 3-{ [(4-{[cyclopentyl (5-fluoro-3-indolyl-l-benzofuran-2-yl))曱Q-yl]amino phenyl)carbonyl](methyl)amino}propionic acid

3-{[(4-{[cyclopentyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)indolyl]amino}phenyl) obtained in Example A67 (5) Carbonyl](fluorenyl)amine 321426 432 201029996 】}ethyl propionate (4.18 g) dissolved in hexane-ethanol (1:1, by volume) using CHIRALPAK AD (50 mm IDx500 mmL, Daicel Chemical Industries HPLC, manufactured by hexane-ethanol (1:1, by volume) as a mobile phase and eluted at 30 ° C at a flow rate of 60 mL/min. Concentration produced a fraction containing an optically active form having a shorter residence time to obtain an amorphous form (2.07 g, 99.9% ee). The obtained amorphous form was dissolved in ethanol (9 mL) and tetra-argon-yttrium (9 mL), aqueous sodium hydroxide (8. 6 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, water (15 mL) was evaporated and evaporated The resulting precipitate was collected by filtration and dried to give the title compound (1.81 g, 93.sup.., 99.9% ee). Colorless amorphous (150 mg) obtained from 2-propanol/water crystals to give colorless crystals (140 mg) containing 2-propanol. Further, a colorless amorphous form (773 mg) obtained from the above ethanol/water crystals was obtained to obtain crystals (756 mg) containing ethanol. The Q crystal was recrystallized from the ethyl ether (756 mg) to obtain a solvent-free colorless crystal (553 mg). ]H NMR (300 MHz, CDCh) 5 ppm 1. 15-1. 72 (m, 7H), 1.86-2.09 (m, 1H), 2.24 (s, 3H), 2.40-2.53 (m, 1H), 2.62 (t, J=6.2 Hz, 2H), 3.00 (s, 3H), 3.68 (t, J-6. 6 Hz, 2H), 4.36 (d, J=9.0 Hz, 1H), 6.54 (d, J= 8. 7 Hz, 2H), 6.91 (td, J=8. 9, 2. 6 Hz, 1H), 7.06 (dd, J=8. 7, 2. 6 Hz, 1H), 7. 19-7. 30 (m, 3H). Example A70 433 321426 201029996 3-{[(4-{[cyclopentyl(5-fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino) }phenyl)carbonyl](fluorenyl)amino}propionic acid

β 3-{[(4-{[cyclopentyl(5-fluoro-3-indolyl-1_benzoxanf-11 Nan_2-yl)indolyl]amine obtained in Example A67 (5) Ethyl phenyl) benzyl](methyl)amino}ethyl propionate (4.18 g) was dissolved in hexane-ethanol (1:1 by volume) using CHIRALPAK AD (50 mm IDx500 mmL, HPLC was carried out by Daicel Chemical Industries, Ltd., and hexane-ethanol (1:1 by volume) was used as a mobile phase and eluted at 30 ° C at a flow rate of 60 mL/min. The resulting fraction containing an optically active form having a longer residence time was concentrated to obtain an amorphous form (2.04 g, 99.9% ee). The obtained amorphous form (2. 04 g) was dissolved in ethanol (9 mL) and tetrahydrofuran (9 mL), 1N aqueous sodium hydroxide solution (8.5 mL) was added, and at room temperature The mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure and water (15 mL) was evaporated. The resulting precipitate was collected by filtration and dried to give the title compound (1.88 g, 98%, 99.9% ee). ^R(300 MHz, CDCl3) (5ppml.23-1.75 (m,7H), 1.86-2.03 (m, 1H), 2.25 (s, 3H), 2.39-2.54 (m, 1H), 2.63 434 321426 201029996 ( t, J=6.4 Hz, 2H), 3.01 (s, 3H), 3.69 (t, J=6. 6 Hz, 2H), 4.36 (d, J=9. 1 Hz, 1H), 4.48 (br. s ., 1H), 6.55 (d, J=8. 7 Hz, 2H), 6.92 (td, J=8. 9, 2. 7 Hz, 1H), 7.07 (dd, J=8.5, 2.5 Hz, 1H) , 7.16-7.32 (m, 3H). Example A71 3-{[(4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl) Ethyl}amino}phenyl)carbonyl](methyl)amino}ethyl propionate

(1) 2-Ethyl-1-(5-fluoro-3-methyl-1-benzothiazepin-2-yl)butan-1-one was synthesized in Example A67 (2) at 0 °C. 5-fluoro-3-methyl-1-benzofuran (1. 0 g), 2-ethylbutylphosphonium chloride (9. 58 g) in nitromethane (240 mL) ® solution added with chlorinated 5小时。 Waterless) (12. 94 g), and mix mixture i. 5 small. Water was added to the reaction/tti compound, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to a ruthenium column chromatography (m.p. s.). R R (300 MHz, CDCI3) (5 ppm 0. 91 (ΐ, j=7. 6 Hz 6H) 1.59-1.67 (m, 2H), 1.75-1.91 (m, 2H), 2.58 (s, 3H) , 321426 435 201029996 3.26-3.42 (m, 1H), 7.11-7.35 (m, 2H), 7.40-7.55 (m 1H). ' (2) 2-Ethyl-1-(5-fluoro-3-indenyl) -1- benzofuran-2-yl) butyl hydride; [1] 2-ethyl-i-(5-fluoro_3_indolyl-indole-benzofuran-2-yl)-- The ketone (15.0 g) was dissolved in a mixed solvent of decyl alcohol (5 〇mL)-tetrahydrofuran (25 〇mL), and sodium borohydride (9 〇%, 5. g) was added to 〇. C. The reaction mixture was stirred for 1.5 hours. 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 anhydrous magnesium sulfate. The title compound of the oil (16.17 g, 1%). NMR (300 MHz, CDCh) δ ppm 0.75-0.86 (in, 3H), 〇. 95 (t, J=7. 6 Hz, 3H), 1.10-1.35 (m, 2H), 1.66-1.94 (m, 3H), 2.21 (s, 3H), 4.66-4.81 (m, 1H), 6.90-7.02 (m, 1H), 7.11 (dd, J=8. 7, 2. 7 Hz, 1H), 7.30-7.40 (m, 1H). (3 4-{[2-Ethyl-1 -(5-fluoro-3-indolyl-l-benzofuran-2-yl)butyl]^-amino}benzoic acid decyl ester in the above 2- Add sulphide chloride (32〇aL) to a solution of ethyl-1-(5-fluorenyl-1-benzofluoren ηNan-2-yl)butan-1-ol (1.00 g) in tetrahydrofuranium chloride) 5小时。 The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into an ice-cooled saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over EtOAc EtOAc (EtOAc) The yellow oil (1.11 g), methyl 4-aminobenzoate (638 mg), moth (1.20 g) and sodium carbonate (852 mg) were stirred at 100 ° C. Methyl 321426 436 201029996 Ceramide (10 mL) of gluten solution for 2 hours. Add n p c / small water to terminate the reaction, and extract the compound on a B-day S. The knee extract was washed with a saturated _ ^ solute, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound (790 mg, 52%) was obtained by EtOAc, EtOAc (EtOAc). 4 匪R (300 MHz, CDC13) 5 DDm 〇+ ppm U. 95 (t, J=7. 5 Hz, 6H), L62-L73 〇„, 2H), L84-h94 (m, 2H), 2 23 ❹ 3.81 (S, 3H), 4.46-4.52 (m, 1H), 4 56-* 65 ^, muscle 4. 68-4. 76 (m, 1H), 6. 54-6 6i (m 2H), 6.85 -7.00 (m, 1H), 7. 04-7. 15 (m, 1H), 7 29-7 c person (.d7 (m,1H), 7.80 (d, J=9.0 Hz, 2H). (j 4-{[2-ethyl-H5-gas+fluorenyl+stupidyl-2-yl)butyl]amino}benzoic acid 4-{[2-ethyl-b ( 5 Prepare 3_Methyl _ Benzene bite WWr base 曱 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The mixture was heated under reflux for 14 hours, and then added with sodium hydroxide water & glutamic acid (4.0 mL), and the mixture was further stirred under reflux for 2 hours. 8N aqueous sodium hydroxide solution (2. 〇mL) and ethanol were added to the mixture. (2 mL), and the mixture was further stirred and stirred under reflux for a few hours. The reaction mixture was concentrated under reduced pressure, and aqueous 8N aqueous solution of hydrogen chloride (4 〇mL), ethanol (4 mL), and tetrahydrofuran (4 mL), and The mixture was stirred and heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, 437 321426, 201029996, dried over magnesium sulfate and under reduced pressure Concentration. Purification by column chromatography (hexane-ethyl acetate 100: EtOAc to EtOAc: EtOAc: EtOAc: &gt; H !^MR (300 MHz, CDCl3) (5ppm 0.80-1.02 (ni, 6H),; l32-1.72 (m, 4H), 1.83-1.97 (in, 1H), 2.23 (s, 3H), 4· 5 Bu 4.71 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.87-6.98 (m, 1H), 7.07 (dd, J=8.3, 2. 7 Hz, 1H), 7.27- 7.35 (m, 1H), 7. 86 (d, J=8. 7 Hz, 2H).

A(5) 3-{ [(4-{ [2-ethyl-1-(5-fluoro-3-indolyl-1-benzo-fol-2-yl)butyl]amino}phenyl ) carbonyl](methyl)amino}ethyl propionate was synthesized at room temperature by the above-mentioned 4-{[2-ethyl-1-(5-fluoro-3-methyl-I-benzofuran) -2-yl)butyl]amino}benzoic acid (l〇.77g), 3-(decylamino)propionic acid ethyl s (4. 59 g), 1 _ benzotrisole Monohydrate (5 34 g), triethylamine (3_53 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.69 g) and hydrazine, A mixed q compound of hydrazine-dimercaptocarboxamide (1 Å) was used for 14 hours. A saturated aqueous ammonium chloride solution was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) ]H NMR (300 MHz, CDCh) (5 ppm 0.80-0.88 (m, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.19-1.25 (m, 5H), 1.33-1.54 (m, 2H) , 1.87 (dt, J=7. 3, 4.9 Hz, 1H), 2.22 (s, 3H), 2.61 (t, J=7.0 Hz, 2H), 3.01 (s, 3H), 3.70 (t, J=7.2 Hz, 438 321426 201029996 2H), 4.11 (q, J=6.9Hz, 2H), 4.28 (d, J=8. 7 Hz, 1H), 4.56 (t, J=8.3 Hz, 1H), 6.56 (d, J=8.7 Hz, 2H), 6.92 (td, J=9.0, 2. 6 Hz, 1H), 7. 06 (dd, J=8. 3, 2. 6 Hz, 1H), 7.22 (d, J= 8.7 Hz, 2H), 7.25-7.31 (m, 1H). Example A72 3-{[(4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran)- 2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

CH3 '-'

OH 3-{[(4-{[2-ethyl-1-(5-fluoro-3-indolyl-1-benzofuran-2-yl)butyl]amino) obtained in Example A7K5)丨Phenyl)carbonyl](fluorenyl)amino}ethyl propionate (132 mg) in a mixture of tetrahydrofuran (1 mL) and ethanol (1 mL), EtOAc (0.54 mL) The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound (1〇3 mg, 7〇%) was obtained as a colorless amorphous. 'H NMR (300 MHz, CDCL·) 6 ppm 0. 79-1. 01 (m, 6H), 1.12-1.90 ( m, 6H), 2.21 (s, 3H), 2.58-2.69 (in, 2H), 3.00 (s, 3H), 3.66 (d, 2H), 4.56 (d, J=8.0 Hz, 1H), 6.55 439 321426 201029996 (d, J=8. 3 Hz, 2H), 6. 92 (td, J=8. 9, 2. 7 Hz, 1H), 7 〇g (dd, J=8.3, 2.7 Hz, 1H), 7.19-7.36 (m, 3H). Example A73 3-{[(4-{[2-Ethyl-1-(5-mer-3-yl-1-yl-benzophenan-2-yl)) Butyl]amino}phenyl)carbonyl](methyl)amino}propionic acid o

3-{[(4-{[2-ethyl-1 - (5-methyl-3-methyl-benzofuran-2-yl)butyl]amine) obtained in Example A71 (5) Ethyl phenyl) hydrazide ethyl ester (9. 18g) is dissolved in hexane-ethanol (1: j, by volume),

0H uses CHIRALPAK AD (50 mm IDx500 mmL, Daicel Chemical

HPLC, manufactured by Industries, Ltd., and eluted with hexane-ethanol (1:1, by volume) as a mobile phase and at a flow rate of 60 mL/min at room temperature. The resulting fraction containing the optically active form having a shorter residence time was concentrated to obtain an amorphous form (4 56 g, 99 9% ee). The obtained amorphous form (4.56 g) was dissolved in ethanol (19 mL) and tetrahydrofuran (19 s), and aqueous 1 N aqueous sodium hydroxide (18 6 mL) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under reduced pressure. Water (3 Torr) was added, and the mixture was neutralized with 1N hydrochloric acid (18.6 nL) under ice cooling, and stirred for 2 Torr. The resulting precipitate was collected by filtration and dried to give the title compound (3.63 g, 86%, 99.9% ee) as colorless 321426 440 201029996. A colorless amorphous form (1·〇 g) obtained from 2-propanol/water crystallization to obtain colorless crystals (927 mg). ]H NMR (300 MHz, CDCls) 5 ppm 〇. 85 (t, J=7. 3 Hz, 3H) 0.94 (t, J=7. 5 Hz, 3H), 1.11-1.72 (m, 4H), 1 77-1.92 (m, 1H), 2· 22 (s, 3H), 2· 65 (t, J=6.6 Hz, 2H) 3 02 (s, 3H), 3.69 (t, J=6.8 Hz, 2H ), 4.56 (d, j=7. 9 Hz&gt; 1H), 6.55 (d, J=8.7Hz, 2H), 6.92 (td, J=9. 〇, 2. 6 Hz! 1H), 7.06 (dd, J = 8.5, 2.4 Hz, 1H), 7.18-7.39 (m, Example A74 ' ' 3-{[(4-{[2-ethyl-1-(5-fluoro-3-methyl-l-benzene) And furan-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

3-{[(4-{[2-ethyl-丨-(-fluoro-3-indolyl-1-benzofuran-2-yl)butyl]amine group obtained in Example A71 (5) }Phenyl)carbonyl](methyl)amino}ethyl propionate (9. 18 g) was dissolved in hexane-ethanol (1:j, by volume) using CHIRALPAK AD (50 mm IDx500 mmL, Daicel Chemical)

Manufactured by Industries, Ltd.), hplc was carried out, and hexane-ethanol (1:1 by volume) was used as a mobile phase and eluted at room temperature at a flow rate of 60 mL/min. Concentration produces a score of optical activity 321426 441 201029996 with a longer residence time to obtain a non-S boat j, j c 7 Λ day t (4. 67 g, 99. 9% ee). The obtained hydrazine type (4. 67 g) was dissolved in ethanol (2 〇 cont.) and tetrahydrofuran (10 bp) and 1N hydroxyhydrogen solution (19.4 mL) was added, and the mixture was stirred at room temperature for 2 g. The solvent was evaporated, water (10) was added, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was stirred for 20 minutes. The resulting precipitate (4) was collected and dried to give the title compound (4· Μ light, 96 %, 99. 9% ee).

H NMR (300 MHz, CDCh) δ ppm 0. 80-0. 89 (ra, 3H), 0. 94 (t, J=7.5 Hz, 3H), 1.16-1.71 (m, 4H), 1.74-1.91 ( m, 1H), 2.22 (s, 3H), 2.62 (t, J=6.2 Hz, 2H), 3.01 (s, 3H), 3. 61-3. 76 (m, 2H), 4. 56 (d, J=7. 9 Hz, 1H), 6 55 (d, J=8. 7 Hz, 2H), 6. 92 (td, J=9. 0, 2. 6 Hz, 1H), 7 〇6 (dd , J = 8.5, 2.4 Hz, 1H), 7.16-7.31 (m, 3H). Example A75 3-[{[4-({l-[5-(cyclopropylmethoxy))-3-yl) -1-Benzene biting ❺-2-yl]-2-mercaptopropyl}amino)phenyl] benzyl}(fluorenyl)amino]ethyl propionate

(1) 1-Bromo-3-indolylbutan-2-one 321426 442 201029996 Toluene was added dropwise to a solution of 3-mercapto-2-butanone (43.0 g) in methanol (300 mL) over 20 min. 80 g) and simultaneously cooled in an ice bath. The ice bath was removed and the mixture was stirred at room temperature for 40 minutes. Water (450 mL) was added to the reaction mixture, and the mixture was stirred for 20 min. The reaction mixture was extracted twice with diethyl ether (500 mL). The extract was washed with EtOAc (EtOAc) (EtOAc. 55. 9 g). ❹!H NMR (300 MHz, CDCh) J ppm 1. 17 (d, J=6. 8 Hz, 6H), 2.88-3.05 (m, 1H), 3.98 (s, 2H). (2) Bu [5 -(cyclopropylmethoxy)-3-mercapto-1-benzocehan-2-yl]-2-mercaptopropan-1-one is heated and stirred under reflux with 2',5'-dihydroxybenzene 5小时。 Ethyl ketone (25. 0 g), bromodecylcyclopropane (24.43 g) and potassium carbonate (2. 2 g) acetonitrile (400 mL) solution 2. 5 hours. Bromodecylcyclopropane (4.4 g) was added to the mixture, and q and the mixture was further stirred under reflux for 14 hours. The reaction mixture was cooled to room temperature, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by hydrazine column chromatography (hexane-acetic acid ethyl acetate 100: 0 to 10: 90, v/v) to give a purity of 70. 1-[5-(Cyclopropyldecyloxy)-2-hydroxyphenyl]ethanone (35.5 g) as a yellow oil. The obtained 1-[5-(cyclopropylmethoxy)-2-hydroxyphenyl]ethanone (35.5 g) and the above-obtained 1-bromo-3-indolylbutanone were stirred at room temperature. (35. 5 g) and a solution of potassium carbonate (66.3 g) in N,N-didecylguanamine (350 mL) for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine sat. 443 321426 Add 1,8-diazabicyclo[5.4.0]undec-7-ene (22.5 mL) and N,N-didecylguanamine (300 mL) to the obtained residue, and at 100 The mixture was stirred at ° C for 30 minutes. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (300 mL) The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc ❹ ΑΝΜΚΟΟΟΜΗζ,ΟΟΠΟθρριηΟ^Θ-Ο.δίΚπι,ΕίΟ,Ο.βΙ-0.73 (m, 2H), 1.01-1.46 (in, 7H), 2.57 (s, 3H), 3.44- 3.68 (m, 1H), 3.86 (d, J=7. 2 Hz, 2H), 7.00 (d, J=2. 3

Hz, 1H), 7. ll(dd, J=9. 0, 2. 6 Hz, 1H), 7.39 (d, J=9. 0

Hz, 1H). (3) l-[5-(Cyclopropylmethoxy)-3-indolyl-1-benzofuran-2-yl]-2-mercaptopropan-1-ol ❿ Synthesis of 1-[5-(cyclopropylmethoxyindol-1-benzofuran-2-yl]-2-mercaptopropan-one (19.91 g) in decyl alcohol (40 mL)-tetrahydrogen A mixed solvent of flurane (200 mL) was added, and sodium tetrahydrocyanate (90%, 5.53 g) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction mixture. The mixture was extracted with EtOAc. EtOAc (EtOAc m. Wake up R (300 MHz, CDC13) 5 ppm 0. 32-0· 42 (m, 2H), 0· 60- 444 321426 201029996 0.71 (m, 2H), 0.81 (d, 3H), 1.12 (d, J= 6.4 Hz, 3H) 1.26-1.36 (m, 1H), 1.99 (d, J = 6.0 Hz, 1H), 2 17-2 28 (m, 4H), 3.84 (d, 2H), 4.45 (dd, J= 8.3, 6.4 Hz, 1H), 6.84-6.96 (m, 2H), 7.29 (d, J=8.7 Hz, 1H) ' (4) 3-[{[4-(U-[5-(cyclopropyl) Oxy)-3_methyl- benzobenzoin-2-yl]-2-methylpropyl}amino Phenyl]carbonyl](methyl)amino]propionic acid ethyl ester 1-[5-(cyclopropyldecyloxy)_3-methyl-1-benzofuran-2- obtained above at room temperature 5小时。 The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was stirred at room temperature for 1.5 hours. An ice-cooled aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated to ethyl acetate. To the residue, 3_{[(4-aminophenyl)carbonyl](indolyl)aminopropionic acid ethyl ester (192 g) obtained in Example 2 (2), sodium iodide (21. 9) was added to the residue. g), sodium carbonate (15.4 g) and n,N-dimethylacetamide (2 mL), and the mixture was stirred at 8 ° C for 1.5 hours. Water was added to the reaction mixture, and acetic acid B was added. The mixture was extracted with EtOAc (EtOAc) (EtOAc m.v / v) 'to obtain a yellow amorphous of the title compound (18 34 g, 5〇%). 'H NMR (300 MHz, CDCls) δ ppm 0. 29-0. 40 Cm, 2H), 0.58-0.70 (in, 2H), 0.91 (d, J=6. 8 Hz, 3H), 1.12 (d, J=6. 8 Hz, 3H), 1.19-1.33 (m, 4H), 2.17-2.28 (m, 4H), 2.61 445 321426 201029996 (t, J=6.8 Hz, 2H), 3.01 (s, 3H), 3. 70 (t, J=7.2 Hz, 2H), 3.82 (d, J=7.2 Hz, 2H), 4. 05-4. 16 (m, 2H), 4.27-4.38 (m, 2H ), 6.57 (d, J=9. 0 Hz, 2H), 6.78-6.91 (m, 2H), 7. 17-7. 25 (m, 3H). Example A76 3-[{[4-({ L-[5_(cyclopropyldecyloxy)-3-indolyl-1-benzofuran-2-yl]-2-mercaptopropyl}amino)phenyl]alkyl}(indenyl)amine Propionate

3-[{[4-({1-[5-(cyclopropyldecyloxy)-3-methyl-1-benzofuran-2-yl]-2) obtained in Example A75 (4) -methylpropyl}amino)phenyl] benzyl K benzyl)amino]propionic acid ethyl ester (667 mg) was added to a mixture of tetrahydroanthraquinone (3 mL) and ethanol (3 mL) in Aqueous sodium hydroxide (2.6 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The mixture was stirred at 00 ° C for 30 min, and the resulting precipitate was collected by filtration to give the title compound (5 〇 9 mg, 81%). H NMR (300 MHz, CDCh) δ ppm 0. 28-0. 40 (m, 2H), 0.58-0.71 (m, 2H), 0.91 (d, J = 6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.23-1.34 (m, 1H), 2.17-2.28 (m, 4H), 2.64 (t, J=6.4 Hz, 2H), 3.02 (s, 3H), 3.69 (t, J =6.4 Hz, 321426 446 201029996 2H), 3.82 (d, J=7. 2 Hz, 2H), 4.31 (d, J=8. 0 Hz, 1H), 6.56 (d, J=8.7Hz, 2H), 6.78-6.91 (m, 2H), 7.19-7.25 (m, 3H). Example A77 3-[{[4-({l-[5-(cyclopropylmethoxy)) 3-methyl-i- Benzofuran-2-yl]-2-mercaptopropyl}amino)phenyl]alkyl}(indenyl)amino]propionic acid

3-[{[4-({1-[5-(cyclopropyldecyloxy)-3-indolyl-1-benzofuran-2-yl]-2) obtained in Example A75 (4) - mercaptopropyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (18.23 g) dissolved in hexane-ethanol (1:1 by volume) in 'Use CHIRALPAK AD (50 _ Π)χ500 mmL,

HPLC was performed by Daicel Chemical Industries, Ltd., and hexane-ethanol (1:1 to 1:1 by volume) was used as the mobile phase and was carried out at room temperature at a flow rate of 6 to 50 mL/min. Rushing. Concentration produced a fraction containing an optically active form having a shorter residence time to obtain an amorphous form (9. 08 g, 99.9% ee). The obtained amorphous form (4. g) was dissolved in ethanol (19 mL) and tetrahydrofuran (19 raL), and aqueous sodium hydroxide (18.6 mL) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. Water (40 mL) was added and the mixture was neutralized with hydrochloric acid (18 6 mL) under ice cooling and stirred for 20 min. The resulting precipitate 321426 447 201029996 was collected by filtration and dried to give the title compound (4.27 g, 96%, 99.9% ee). ]H NMR (300 MHz, CDCh) δ ppm 0. 31-0. 38 (m, 2H), 0.58-0.68 (m, 2H), 0.90 (d, J=6. 8 Hz, 3H), 1.12 (d , J=6.4 Hz, 3H), 1· 28 (s, 1H), 2. 17-2. 29 (m, 4H), 2 63 (t J=6.4 Hz, 2H), 3.01 (s, 3H), 3.69 (t, J=6.4 Hz, 2H), 3.82 (d, J=6.8 Hz, 2H), 4.31 (d, J=7.5 Hz, 1H), 6.56 (d, J=8.7 Hz, 2H), 6.78-6.89 (m, 2H), 7.19-7.27 (m, ® 3H). Example A78 3-[{[4-(U_[5-(cyclopropyldecyloxy)-3-methyl 4-benzene And 吱-2-1 yl]-2-methyl propyl}amine phenyl]carbonyl}(methyl)amino]propionic acid

3-[{[4-({1-[5-(cyclopropyldecyloxy)-3-methyl-1-benzofuran-2-yl]-2) obtained in Example A75 (4) -Methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester (18.23 g) dissolved in hexane-ethanol (1:1, by volume) 'using CHIRALPAK AD (50 Mm IDx500 _L, manufactured by Daicel Chemical Industries, Ltd.) ijPLC was carried out, and hexane-ethanol (1:1 to 1:1, volume ratio) was used as the mobile phase and the flow rate was 6 to 50 mL/min. Wen Chong mention. Concentration produces a fraction of the optically active form having a longer reticle, to obtain an amorphous type 321426 448 201029996 ( 岂 ' 99. 9% ee). The obtained amorphous form (4.73 g) was dissolved in ethanol (09 mL) and tetrahydrofuran (19 mL), 1N aqueous sodium hydroxide (18.7 mL) was added, and the mixture was stirred at room temperature for 2 hr. Evaporate / granules under reduced pressure. Water (4 〇 mL) was added, and the mixture was neutralized with in hydrochloric acid (18.7 mL) under ice cooling, and stirred for 3 hr. The resulting precipitate was collected by filtration and dried to give the title compound (4 〇 2 g' 90% ' 98.8% ee) as a colorless amorphous. The obtained colorless amorphous form (5 Å) was dissolved in hydrazine ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a colorless amorphous form. The colorless amorphous form obtained was crystallized from ethyl acetate / hexane to give colorless crystals (401 mg). Further, an amorphous product (60 mg) obtained by dissolving from diethyl ether / hexane crystals to give colorless crystals (45 mg). H NMR (300 MHz, CDCls) δ ppm 0. 27-0. 42 (m, 2H), 〇. 5β-0.66 (m, 2H), 0.91 (d, J=6. 8 Hz, 3H), 1.12 ( d, J=6. 8 Hz, 3H), 1.28 (s, 1H), 2.18-2.28 (m, 4H), 2.66 (t, 〇J=6.4Hz, 2H), 3.03 (s, 3H), 3.70 ( t, J=6. 6 Hz, 2H), 3.82 (d, J=7.2 Hz, 2H), 4.31 (d, J=7. 5 Hz, 1H), 6.56 (d, J=8.7 Hz, 2H ), 6.73-6.89 (m, 2H), 7.19-7.25 (m, 3H). Example A79 3-[{[4-({cyclohexyl[5-(2-decyloxyethoxy)-3-) Mercapto-1-benzofuran-2-yl]fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid 449 321426 201029996

(1) l-[2-Hydroxy-5-(2-decyloxyethoxy)phenyl]ethanone at room temperature in 1-(2,5-dihydroxyphenyl)ethanone (11〇g) To the acetonitrile solution (250 mL) was added 2-methoxyethyl bromide (09.6 mL) and potassium carbonate (12.0 g), and the mixture was heated under reflux for 15 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and filtered. A saturated gasification aqueous solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ❹ 4 NMR (300 MHz, CDC13) 5 ppm 2. 61 (s, 3H), 3. 46 (s' 3H), 3.66-4.21 (m, 4H), 6.92 (d, J=9. 0 Hz, 1H ), 7.15 (d, J=9.0Hz, 1H), 7.22-7.26 (m, 1H), 11.84 (s, 1H). (2) Cyclohexyl [5-(2-methoxyethoxy)~3 Dissolving 1-[2-hydroxy-5-(2-methoxyethoxy)phenyl]ethanone (7.0 g) synthesized in the above (1) In N,N-dimercaptocaramine (14 〇). Potassium carbonate (13.8 g) and 2-bromo-1-cyclohexyl Ethyl ketone (8.9 g) synthesized in Example A51 (1) were added to the reaction mixture at room temperature, and the mixture was stirred for 15 321426 450 201029996 hours. The reaction mixture was filtered through EtOAc, water (200 mL) was added, and the mixture was extracted with acetonitrile (1 〇〇 mL x 2). The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in N,N-dimercaptocaramine solution (100 mL), DBU (5. 3 mL) was added at room temperature, and the mixture was stirred at 10 0 C for 1 hour. The reaction mixture was cooled to room temperature, 1N aqueous hydrochloric acid (1 mL) was then taken and the mixture was extracted with diethyl ether (1 〇〇 mL x 2). The extract was washed with water, a saturated aqueous sodium hydrogen sulfate solution and brine, and evaporated. The title compound (10.3 g, 98%) was obtained. !H NMR (300 MHz, CDCh) &lt;5 ppm 1. 32-2. 00 (m, 11H), 2.56 (s, 3H), 3.30 (d, J=3.4 Hz, 1H), 3.48 (s, 3H ), 3.75-3.85 (m, 2H), 4.15-4.25 (m, 2H), 7.04 (d, J=2.5 Hz, 1H), 7. 13 (dd, J=8. 9, 2. 5 Hz , 1H), 7.40 (d, J=8. 9 Hz, 1H). ❹(3)cyclohexyl[5-(2-decyloxyethoxy)~3_mercaptobenzofuran-2-yl] The sterol is prepared by dissolving the cyclohexyl [5-(2-decyloxyethoxy)-3-methyl-1-benzofuran-2-yl]anthone (10.3 g) synthesized in the above (2). A mixture of tetrahydrofuran (180 mL) and decyl alcohol (20 mL) in a granule. The reaction mixture was ice-cooled, sodium borohydride (90%, 2.7 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, and water (1 mL) and 1N hydrochloric acid (100 mL) was carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc. EtOAc. NMR NMR (300 MHz, CDCh) δ ppm 1. 15-2. 02 (m, 11H), 2.56 (s, 3H), 3.48 (s, 3H), 3.73-3.87 (m, 2H), 4.14-4.26 ( m, 2H), 4.44-4.46 (m, 1H), 7.04 (d, J=2.6 Hz, 1H), 7. 13 (dd, J=9.0, 2.6 Hz, 1H), 7.40 (d, J=9. 0 Hz, 1H). (4) 3-[{[4-({cyclohexyl[5-(2-decyloxyethoxy)-3-methyl-1-benzofuran-2-yl]-) Alkylamino]phenyl]carbonyl}(methyl)amino]propionate is a cyclohexyl[5-(2-methoxyethoxy)-3 which is synthesized in the above (3) at room temperature. Thionyl chloride (4.7 mL) was added to a tetrahydrogenate solution (200 mL) of methyl-1-benzobenzopyran-2-yl]nonanol (10.3 g). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and a saturated aqueous sodium hydrogen carbonate solution (100 mL) was carefully added. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (丨5〇mL), and sodium iodide (8.0 g), sodium carbonate (5.3 g) and sodium synthesized in Example 2 (2) were added. -{[(4-Aminophenyl)carbonyl](methyl)aminopropionic acid ethyl ester (8.9 g) and the mixture was stirred at 80 ° C for 12 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified eluted eluted eluted elut elut elut , 43%). H NMR (300 MHz, CDCh) δ ppm 0. 92-2. 14 (m, 14H), 2.21 Cs, 3H), 2.61 (t, J=6.8 Hz, 2H), 3.01 (s, 3H), 3.46 452 321426 201029996 (s, 3H), 3.60-3.81 (m, 4H), 4.01-4.21 (m, 4H), 4.27-4.46 (m, 2H), 6.56 (d, J=8. 3 Hz, 2H), 6.76 -6.95 (m, 2H), 7.14-7.25 (m, 3H). (5) 3-[ {[4-( {cyclohexyl[5-(2-methoxyethoxy))-3-methylbenzo] Furan-2-yl]methyl}amino)phenyl]carbonylindole (methyl)amino]propionic acid 3-[{[4-({cyclohexyl][5-(2-) synthesized by the above (4) Methoxyethoxy)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonylindole (methyl)amino]propionic acid ethyl ester (5.4 g) Dissolved in ethanol (150 mL), 1N aqueous sodium hydroxide (15 mL) was added at room temperature, and the mixture was stirred at 501: 5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (2 mL) was added to the residue, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjj 59%). !H NMR (300 MHz, CDCls) δ ppm 0. 92-2. 14 (m, 12H), 2.21 (s, 3H), 2.66 (t, J=6. 1 Hz, 2H), 3.03 (s, 3H) ), 3.46 Q Cs, 3H), 3.60-3.81 (m, 4H), 4.01-4.21 (m, 4H), 4.35 (d, J=7. 8 Hz, 2H), 6.55 (d, J=8. 7 Hz, 2H), 6.76-6.95 (m, 2H), 7.14-7.25 (m, 3H). Example A80 3-[{[4-({cyclohexyl[5-(2-decyloxyethoxy)) -3-methyl-1-benzofuran-2-yl]fluorenyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid 453 321426 201029996

3-[{[4-({cyclohexyl[5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl] }}(Methyl)amino]propionic acid by high performance liquid chromatography (column: CHIRALPAK AD (5mm id X ❹ 500 mmL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/2-propanol) /trifluoroacetic acid (500/500/1), flow rate: 60 mL/min, column temperature: 30 ° C) fractionation of 3-[{[4-({cyclohexyl][5] synthesized in Example A79(5) -(2-decyloxyethoxy)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid (3. 〇g). Add triethylamine (10 mL) to the optically active form having a shorter residence time under the conditions described above for high performance liquid chromatography, and concentrate the mixture to obtain the title target compound III Ethylamine salt (3·7 g). 1N Hydrochloric acid (30 mL) was added to the chemical mixture, and the mixture was extracted with EtOAc. The extract was washed with water and saturated brine, dried over sulphuric acid, and under reduced pressure. The title compound (1.49 g, 99.9% ee;) was obtained as a white solid. (300 MHz, CDCh) δ ppm 0. 92-2. 14 (m, 12H), 2.21 (s, 3H), 2.66 (t, J = 6.1 Hz, 2H), 3.03 (s, 3H), 3.46 (s , 3H), 3.60-3.81 (m, 4H), 4.01-4.21 (m, 4H), 4.35 (d, J=7. 8 Hz, 2H), 6. 55 (d, J=8. 7 Hz, 2H ), 6. 76-6. 95 (m, 2H), 7. 14-7.25 (m, 3H). 321426 454 201029996 Example A81 3-[{[4-({cyclohexyl[5-(2-曱) Oxyethoxy)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid

❹ (1) 3-[{[4-({cyclohexyl[5-(2-methoxyethoxy)-3-indolyl-1- benzoate-2-yl]methyl}amino) Phenyl]carbonyl](indenyl)amino]propionic acid by high performance liquid chromatography (column: CHIRALPAK AD (50mm idx 500 mmL 'Manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/2-) Propanol / trifluoroacetic acid (500 / 500 /), flow rate: 6 〇 mL / min 'column temperature: 30. 〇 fractionation of the 3-[{[4-({cyclohexyl) synthesized in Example A79 (5) [5-(2-decyloxyethoxy)-3-methyl-l-benzofuran-2-yl]indolyl}amino)phenyl]alkyl}(indenyl)amino]propionic acid (3〇g) 三 Add triethylamine (3〇raL) to the fraction containing the optically active form having a longer residence time under the conditions of the above high performance liquid chromatography, and concentrate the mixture to obtain the target target Triethylamine salt of the compound (9.2 g), 1N hydrochloric acid (30 mL) was added, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over magnesium sulfate ✓ Chen Shrink to get the title compound of Wang White Solid (1.50 Yun, 99 9% ee) ° H NMR (300 MHz, CDCh) δ ppm 0. 92-2. 14 (in, 12H), 2 21 321426 455 201029996 (s, 3H), 2.66 (t, J=6. 1 Hz , 2H), 3.03 (s, 3H), 3.46 (s, 3H), 3.60-3.81 (m, 4H), 4.01-4.21 (m, 4H), 4.35 (d, J=7. 8 Hz, 2H), 6.55 (d, J=8. 7 Hz, 2H), 6.76-6.95 (m, 2H), 7.14-7.25 (m, 3H). Example A82 3-[{[4-({cyclohexyl]3- 5-(4-hydrodecyloxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propyl

(1) 1-[5-(Phenyloxy)-2-phenylphenyl]ethyl J was dissolved in 1-(2,5-dihydroxyphenyl)ethanone (25.0 g) in acetonitrile at room temperature To the mash (4 〇〇 raL), benzyl bromide (19.6 mL) and potassium carbonate (20.5 g) were added, and the mixture was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature, filtered over Celite, and evaporated. A saturated aqueous solution of ammonium sulfate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated The obtained solid was washed with ethanol-isopropyl ether to give the title compound (31. g, 8%). H NMR (300 MHz, CDCh) d ppm 2. 58 (s, 3H), 5. 〇5 (s 2H), 7. 11-7. 53 (m, 8H), 11.85 (s, 1H). 321426 456 201029996 (2) [5-(Benzyloxy)-3-indolyl-1-benzoxaffran-2-yl](cyclohexyl)methanone was synthesized at room temperature in the above 1-(1) Potassium carbonate (41.4 g) and Example A51 were added to a solution of 5-(benzyloxy)-2-hydroxyphenyl]ethanone (29.5 g) in N,N-dimethylformamide (500 mL). l) 2-Bromo-1-cyclohexylethyl ketone (25.0 g) synthesized, and the mixture was stirred at 601 for 15 hours. The reaction mixture was allowed to cool to room temperature&apos; and filtered through a dreaming soil, β was added water, and mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated The obtained solid was washed with ethyl acetate-diethyl ether to afford titled compound (10.0 g, 43%). H NMR (300 MHz, CDCh) δ ppm 1. 17-2. 10 (m, 10H), 2.56 (s, 3H), 3. 17-3.43 (m, 1H), 5.12 (s, 2H), 7.04- 7.21 (m, 2H), 7. 30-7. 51 (m, 6H). (3) Cyclohexyl (5-hydroxy-3-methyl-1-benzofuran-2-yl) fluorenone oxime (2) [5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methanone (7.3 g) was dissolved in ethanol (15 〇) Palladium carbon-diethylamine complex (1 〇g) was added to tetrahydrofuran (30 mL) at room temperature. The reaction mixture was stirred for 6 hours under TC and hydrogen (1 atm), and then was taken to room temperature, and the catalyst was removed. The filtrate was concentrated under reduced pressure to afford crude title compound as colorless solid. Product (5.2 &amp; quantitation) 臓(10) MHz, CDCl3) 5 卿121_2 ()3(m,(10)),2 54 (s'3H),3.22-3.38 (m,iH),4.78(br.s ., lH), 6.96~7.05 (m, 2H), 7.38 (d, J = 9.5 Hz, 1H). 321426 457 201029996 (4) Cyclohexyl [3-methyl-5-(tetrahydro-2H-派n南- 4-yloxy)-benzofuran-2-yl]methanone The cyclohexyl group (5-hydroxy-3-methyl-1-benzofuran: 2-yl-m-methane (5.2) synthesized above (3) g) dissolved in dimethyl methamine 〇〇〇mL), and added potassium phosphate (7.4 g) and 4-methylbenzenesulfonic acid tetrase synthesized by ep+i36 at room temperature Hydrogen-2H_pyran-4-yl ester (9 〇g), and the mixture was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature, water (150 mL) was added and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjj %). H NMR (300 MHz, CDCh) d ppm 1. 35-2. 10 (m, 14H), 2.56 (s, 3H), 3.24-3.38 (m, 1H), 3. 50-3. 65 (m, 2H ), 3.95-4.07 (m, 2H), 4.50 (tt, J=7. 8, 3. 9 Hz, 1H), 7.04-7.16 (m, 2H), 7.42 (d, J=8. 7 Hz, 1H 〇(5)cyclohexyl[3-indolyl-5_(tetrahydro-2H-piperazin-4-yloxy)-1-benzodropropan-2-yl]nonanol will be as described above (4) Synthesis of cyclohexyl [3_methyl_5_(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl]anthone (7.1 g) in tetrahydrofuran (200 In a solution of mL) and methanol (20 mL), sodium hydride (90%, 1.6 g) was added under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, and water (1 mL) and 1N hydrochloric acid (100 mL) was carefully added and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. ]H NMR (300 MHz, CDCh) δ ppm 0. 82-2. 14 (m, 15H), 2.18 (s, 3H), 3.57 (ddd, J = 11.6, 8.4, 3.4 Hz, 2H), 3.93-4.06 (ra, 2H), 4.36-4.59 (m, 2H), 6.89 (dd, J=8. 7, 2.3 Hz, 1H), 6.97 (d, J=2. 3 Hz, 1H), 7.31 (d, J =8. 7 Hz, 1H). (6) 3-[{[4-({cyclohexyl[3-meryl-5-(tetrahydro-2H-piperidin-4-yloxy) hydrazino-benzo Furan-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]ethyl propionate The cyclohexyl group [3-mercapto-5-(four) synthesized by the above (5) at room temperature Hydrogen-2H-piperazin-4-yloxy)-1-benzofuran-2-yl]nonanol (6.7 g) was dissolved in tetrahydrofuran (120 mL) and sulphur chloride was added. 6 mL). The reaction mixture was stirred at room temperature for 30 min then cooled with ice and a saturated aqueous solution of sodium bicarbonate (1 mL) was carefully added. The mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (100 mL), sodium iodide (5.3 g), sodium carbonate (3. 5 g) and 3-{[(4) synthesized in Example 2(2) -aminophenyl)carbonyl](indenyl)amino}ethyl propionate (4.9 g) and was stirred at 8 (TC for 12 hours. After cooling) water was added to the reaction mixture and acetic acid was added. The mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and purified residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1 : 1 vol.) to give the title title as yellow oil. Compound (6.1 g, 54%) 459 321426 201029996 ^ NMR (300 MHz, CDCla) δ ppm 1. 00-2. 10 (m, 18H), 2 21 (s, 3H), 2.61 (t, J=7 . 0 Hz, 2H), 3. 01 (s, 3H), 3 55 (ddd, 1=11.7, 8.5, 3.2 Hz, 2H), 3. 70 (t, J=7. 〇Hz, 2H), 3.90 -4.05 (in, 2H), 4.27-4.52 (m, 4H), 6.56 (d, J=8. 7 Hz, 2H), 6.77-6.96 (m, 2H), 7.15-7.25 (m, 3H). ( 7) 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2H-piperazin-4-yloxyanthracepin-benzoxanol-2-methyl]methyl) }amino)phenyl]benzyl}(methyl)amino]propionic acid® 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-)- 2Η-π-decyl-4-yloxy)-1-benzophenone π-nan-2-yl]methyl}amino)phenyl] benzyl} (methyl) Yl] propionate (0.6 g) was dissolved in ethanol (2〇 mL), to a temperature at addition of 1N aqueous sodium hydroxide (3 inL), and the mixture was stirred at room temperature for 12 hours scrambling. Ethanol was evaporated under reduced pressure. &lt;RTI ID=0.0&gt;&gt; The extract was washed with saturated brine, dried over sodium sulfate and evaporated. The Q residue was recrystallized from acetone to give the title compound (0.5 g, 77%). NMR (300 MHz, CDC13) (5 ppm 0. 85-2. 14 (m, 15H), 2.21 (s, 3H), 2.67 (t, J=6.2 Hz, 2H), 3.03 (s, 3H), 3.56 (ddd, J=11.6, 8.4, 3.0 Hz, 2H), 3. 69 (t, J=6. 6 Hz, 2H), 3.88-4.08 (m, 2H), 4.27-4.53 (m, 2H), 6.55 (d, J=8. 7 Hz, 2H), 6.78-6.99 (m, 2H), 7.17-7.26 (m, 3H). Example A83 3-[{[4-(丨cyclohexyl[3-methyl] 5-_(tetrahydro-2H-indolyl-4-yloxy)-benzobenzopyran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propyl 460 321426 201029996 acid

ο iL.

OH

°V_^° (1) 3 - [{[4-({%ί己基[3-曱-yl-5_(tetranitro-2H_ brityl-4-yloxy)-1-benzofuran-2- Ethyl]methyl}amino)phenyl]carbonyl}(methyl)amino] φ ethyl propionate by high performance liquid chromatography (column: CHIRALPAK AD (50mm id X 500 mmL, Daicel Chemical Industries, Ltd) Manufacturing, mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min, column temperature: 30 ° C) fractionation of 3-[{[4-({) synthesized in Example A82(6) Cyclohexyl [3-methyl-5-(tetrahydro-2H-°-n-butyl-4-yloxy)-1-benzo-dopy-2-yl]fluorenyl}amino)phenyl]carbonyl} Ethyl)amino]propionic acid ethyl ester (4.0 g). Concentrated fractions containing optically active forms having a shorter residence time under conditions of high performance liquid chromatography to obtain the title target compound (1.8 g) , 99. 9% ee). NMR (300 MHz, CDCh) (5 ppm 1. 00-2. 10 (m, 18H), 2.21 (s, 3H), 2.61 (t, J=7. 0 Hz, 2H), 3.01 (s, 3H), 3.55 (ddd, J=11.7, 8.5, 3. 2 Hz, 2H), 3. 70 (t, J=7. 0 Hz, 2H), 3.90-4.05 (m, 2H), 4.27-4.52 (m, 4H), 6.56 (d, J=8. 7 Hz, 2H), 6.77-6.96 (m, 2H), 7.15-7.25 (m, 3H). (2) 3-[ { [4-( {cyclohexyl[3-indolyl-5-(tetrahydro-2H-piperidin-4-yloxy)-1-benzofuran-2-yl]methyl}amino)phenyl] Carbonyl}(fluorenyl)amino] 461 321426 201029996 3_π[4_πcyclohexyl[3_fluorenyl-5-(tetrahydro-2Η-piperazin-4-yloxy) which will be optically resolved in the above (1) Ethyl)-p-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester (18 g) was dissolved in ethanol (20 mL) and added at room temperature 1N aqueous sodium hydroxide (5 mL) and the mixture was stirred at 5 ° C for 5 hours. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (5 mL) was added to residue and mixture was extracted with ethyl acetate. The extract was extracted with brine, dried over MgSO4, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated MHz, CDCh) (5 ppm 0. 85-2. 14 (m, 15H), 2.21 (s, 3H), 2.67 (t, J=6.2 Hz, 2H), 3.03 (s, 3H), 3.56 (ddd, J=11.6, 8.4, 3.0 Hz, 2H), 3. 69 (t, J=6. 6 Hz, 2H), 3.88-4.08 (m, 2H), 4.27-4.53 (m, 2H), 6.55 (d, J=8. 7 Hz, 2H), 6.78-6.99 (m, 2H), 7.17-7.26 (m, 3H Example A84 ❹ 3-[{[4-({ί承基基[3-曱- 5-(tetrahydro-2H-nivine 0-nan-4-yloxy)-1-benzofuran-2 -yl]methyl}amino)phenyl]alkyl}(indenyl)amino]propionic acid

(1) 3_[{[4-({ 己 基 [ [3_methyl-5_(tetrazo- 2Η-σ bottom 0 nan-4-yloxy 462 321426 201029996 yl)-1-benzopyran-2-基 } } 胺 胺 胺 } } } 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 酉 高效 高效 高效 高效 高效 高效 : : : : : : : : : : : : : : : : : : : : : : : Ltd. Manufactured, mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min, column temperature: 30 ° C) fractionated 3-A (6) synthesized in Example A82 (6) Cyclohexyl[3-methyl-5-(tetrahydro-2H-p-amyl-4-yloxy)-1-benzo[p-amyl~2-yl]methyl}amino)phenyl]carbonyl} Ethyl)amino]propionic acid ethyl ester (4. 〇g). The fraction containing the optically active form having a longer residence time under the above high performance liquid chromatography conditions is concentrated to obtain the title target compound U. 8 g. , 99.9% ee) 〇!H NMR (300 MHz, CDCls) (5 ppm 1. 00-2. 10 (m, 18H), 2.21 Cs, 3H), 2.61 (t, &gt;7.0 Hz, 2H), 3.01 (s, 3H), 3.55 (ddd, J=11.7, 8.5, 3.2 Hz, 2H), 3. 70 (t, J=7. 0 Hz, 2H), 3.90-4.05 (m, 2H), 4.27-4.52 (m, 4H), 6.56 (d, J=8. 7 Q Hz, 2H), 6.77-6.96 (m, 2H), 7. 15-7.25 (m, 3H). (2) 3-[{[4-({cyclohexyl[3-indolyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzene) And furan-2-yl]hydrazino}amino)phenyl]carbonyl}(methyl)amino]propionic acid will be optically resolved in the above (1) 3_[{[4-({cyclohexyl][3 _Mercapto~5-(tetrahydro-2H-piperazin-4-yloxy)-i-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino] Ethyl propionate (18 was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide (5 mL) was added at room temperature and the mixture was stirred at 50 C for 5 hours. Ethanol was evaporated under reduced pressure to give 1N hydrochloric acid (5) 321426 463 201029996 mL), and the residue was extracted with ethyl acetate. The mixture was extracted with EtOAc. 1.5 g, 88%, 99.9% ee). !H NMR (300 MHz, CDCla) δ ppm 0. 85-2. 14 (m, 15H), 2.21 (s, 3H), 2.67 (t, J=6.2 Hz, 2H), 3.03 (s, 3H), 3.56 (ddd, J=11.6, 8.4, 3.0 Hz, 2H), 3. 69 (t, J=6. 6 Hz, 2H), 3.88-4.08 (m, 2H), 4.27-4.53 (m, 2H), 6.55 (d, J=8. 7

Hz, 2H), 6.78-6.99 (m, 2H), 7.17-7.26 (m, 3H). ® Example A85 3-[{[4-({1-[5-(phenylhydroxy)-3-) Mercapto-1-benzo D-propan~2-yl]-2-mercaptopropyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid

(1) 1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-mercaptopropan-1-silk potassium carbonate at room temperature (27· 6 g) and the bromo-3-mercaptobutan-2-one (14.3 g) synthesized in Example A75 (l) was added to 1-[5-(benzoquinone) synthesized in Example A82 (l) A solution of oxy)-2-hydroxyphenyl]ethanone (16.1 g) in hydrazine, hydrazine-dimercaptocaramine (200 mL), and the mixture was stirred for 15 hr. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (100 mL) and 464 321 426. The reaction mixture was stirred at i ° ° for 1 hour. The reaction mixture was cooled to room temperature, then 1N hydrochloric acid (150 mL) was evaporated and evaporated. The extract was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The title compound (n. 7 g, 57%) was obtained. NMR (300 MHz, CDCh) δ ppm 1.23 (d, J=6. 8 Hz, 6H), 2.57 (s, 3H), 3.57 (dt, J=13. 8, 6. 8 Hz, 1H), 5. 12 (s, 2H), 7.11 (d, J=2. 6 Hz, 1H), 7.13-7.21 (m, 1H), 7.30-7. 55 (m, 6H). (2) l-[5-( Phenyloxy)-3-indenyl-i-benzofuran-2-yl]_2-mercaptopropan-1-ol 1-[5-(benzoquinoneoxy) synthesized in the above (1) a 3-methyl-benzofuran-2-yl]-2-mercaptopropan-1-one (11.7 g) dissolved in tetrahydrofuran (150 mL) and methanol (15 mL) and chilled But add the butterfly hydrogenation (9〇%, © 3. 〇S). The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. Water (1 〇 mL) and 1N hydrochloric acid (1 〇〇 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate: hexanes, hexanes, hexanes) to give the title compound (11.3 g, quantitative) as a pale yellow oil. 5H NMR (300 MHz, CDCh) δ ppm 0.82 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.55 (d, J = 2. 6 Hz, 1H), 2.11-2.34 (m, 4H), 4.46 (dd, J=8. 3, 6.0 Hz, 1H), 5.10 (s, 321426 465 201029996 2H), 6.82-7.08 (ra, 2H), 7.28-7.55 (m, 6H). (3) 3-[{[4-({1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl} Amino]phenyl]carbonyl](indenyl)amino]propionic acid ethyl ester 1-[5-(benzomethoxy)-3-indolyl-1-benzopyrene synthesized in the above (2) Silan-2-yl]-2-mercaptopropan-1-ol (10.2 g) was dissolved in tetrahydrotetramine (150 mL) and sulphur sulphite (4.3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min then EtOAc (EtOAc)EtOAc. The reaction mixture was stirred for 10 minutes and the mixture was taken up in ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was dissolved in dimethylacetamide (2 mL), and sodium moth (7.4 g), sodium carbonate (5.0 g) and 3-{[(4-) synthesized in Example 2 (2) were added. Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (8.2 g), and the mixture was stirred at 80 C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was purified under reduced pressure and the residue was purified to purified crystals eluted elut elut elut elut elut elut elut elut ). NMR (300 MHz, CDCh) (5 ppm 0.91 (d, J=6. 8 Hz, 3H), !-12 (d, J=6. 8 Hz, 3H), 1.23 (t, J=7. 2 Hz , 3H), 2.13-2-33 (m, 4H), 2.61 (t, J = 1.2 Hz, 2H), 3.01 (s, 3H), 3.71 (t, J = 7.2 Hz, 2H), 4.12 (q, J=7.2Hz, 2H), 4.25- 4-46 (m, 2H), 5.09 (s, 2H), 6.57 (d, J=8. 7 Hz, 2H), 6*81-7.02 (m, 2H) , 7.15-7.25 (m, 3H), 7.30-7.59 (m 5H). ' (4) 3-[{[4-({1-[5-(Benzyloxy)-3-methyl-l- Benzofuran_2_321426 466 201029996 base]-2-mercaptopropyl}amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid 3-[{[ 4-({1_[5-(Benzyloxy)-3-indolyl-1-benzodropropan-2-yl]-2-methylpropyl}amino)phenyl]-yl} Methyl)amino]propionic acid ethyl ester (0. 38 g) was dissolved in ethanol (5 mL), EtOAc (1 mL) Ethanol was evaporated under reduced pressure, and EtOAc (EtOAc) (EtOAc). Quality to obtain a colorless solid ❹ Target compound (0. 28 g, 79%). H NMR (300 MHz, CDCh) δ ppm 0.91 (d, J = 6.8 Hz, 3H), 1. 12 (d, J = 6. 8 Hz , 3H), 2. 18-2. 30 (in, 4H), 2. 66 (t, J=6. 2 Hz, 2H), 3. 03 (s, 3H), 3. 69 (t, J= 6. 2 Hz, 2H), 4.32 (d, J=7. 5 Hz, 1H), 5.08 (s, 2H), 6.56 (d, J=8. 7 Hz, 2H), 6.83-7.02 (m, 2H) ), 7.17-7.26 (m, 3H), 7.30-7. 53 (m, 5H). ❹ Example A86 3-[ {[4-(U_[5-(phenylhydroxy)-3-methyl- 1-Benzobenzoate-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid

(1) 3- [ {[4-( {1-[5-(Benzenyloxy)-3-methyl-1-benzobenzopyran-2-yl]_2-mercaptopropyl}amino) Phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester 467 321426 201029996 by high performance liquid chromatography (column: CHIRALPAK AD (50mm inner diameter x500 mmL ' Daicel Chemical Industries ' Ltd., mobile phase : hexane/ethanol (200/800) 'flow rate: 60 mL/min, column temperature: 30 ° C) fractionation of the 3-[{[4-({1-[5-()) synthesized in Example A85(3) Alkyloxy)-3-indolyl-1-benzofuran-2-yl]-2-mercaptopropyl}amino)phenyl]alkyl}(methyl)amino]propionic acid (3·〇g). The objective product (1.23 g, 99.9% ee) was obtained by concentrating the optically active form having a longer residence time under the above-mentioned high performance liquid chromatography conditions. ^ NMR (300 MHz, CDCh) δ ppm 0.91 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.23 (t, J = 7. 2 Hz, 3H), 2.13- 2.33 (m, 4H), 2.61 (t, J=7.2 Hz, 2H), 3.01 (s, 3H), 3. 71 (t, J=7.2 Hz, 2H), 4. 12 (q, 2=Hz. -7.25 (m, 3H), 7.30-7.59 (m, 5H). ❹(2) 3-[{[4-({l-[5-(benzyloxy)_3_methylbenzofuran_2_ 1-[{[4-({1-[]] [2-[{[4-({1-[ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ 5-(Benzyloxy^)-3-methyl-1-benzofuran-2-yl]_2-mercaptopropylguanidino)phenyl] benzyl quinolate]amino]propionic acid ethyl vinegar (123 g) was dissolved in ethyl acetate (15 mL), and then added with 1 aqueous sodium hydroxide solution (4 mL) and mixed with 5 (TC stirring = 0.5 hour. Evaporate ethanol under reduced pressure, 1N hydrochloric acid (4 This was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulphate and concentrated under reduced pressure. The residue was washed with ethanol-water to give colorless 321426 468. Target compound (1.22 g, 95%, 99.9% ee). NMR (300 MHz, CDCh) δ ppm 0.91 (d, J=6. 8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 2.18-2.30 (m, 4H), 2.66 (t, J= 6.2 Hz, 2H), 3.03 (s, 3H), 3.69 (t, J=6. 2 Hz, 2H), 4.32 (d, J=7.5 Hz, 1H), 5.08 (s, 2H), 6.56 (d, J=8. 7 Hz, 2H), 6.83-7.02 (m, 2H), 7.17-7.26 (m, 3H), 7.30-7.53 (m, 5H). Example A87 ® 3-[{[4-({ 1-[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl]-2-mercaptopropylguanidino)phenyl]carbonyl}(indenyl)amino] Propionic acid

(1) 3-[{[4-({1-[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl]-2-methylpropyl}amino) Phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester by high performance liquid chromatography (column: CHIRALPAK AD (50 mm inner diameter x 500 mmL 'Manufactured by Daicel Chemical Industries, Ltd., mobile phase: own Alkane/ethanol (200/800), flow rate: 60 mL/min, column temperature: 30 ° C) fractionated 3-[{[4-({1-[5-(benzoquinone) synthesized in Example A85(3)) Oxy))-3-methyl-1-benzo-benzoican-2-yl]-2-methylpropyl}amino)phenyl]alkyl}(indenyl)amino]propionic acid 3.0 g). The fraction containing the optically active form having a shorter residence time under the above high performance liquid chromatography conditions was concentrated to obtain the title compound (1.25 g, 99.9% ee). 321426 469 201029996 j NMR (300 MHz , CDC13) (5 ppm 0.91 (d, J = 6.8 Hz, 3H), 1.12 (d'J = 6.8 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 2.13 - 2.33 (m, 4H) , 2.61 (t, J=7.2 Hz, 2H), 3.01 (s, 3H), 3. 71(t, J-7.2Hz, 2H), 4. 12 (q, J=7. 2 Hz, 2H), 4.25-4.46 (m, 2H), 5.09 (s, 2H), 6.57 (d, J=8. 7 Hz, 2H), 6.81-7.02 (m, 2H), 7.15-7.25 (m , 3H), 7.30-7.59 (m, 5H). (2) 3-[{[4-({l-[5-(Benzomethoxy)-3-indolyl-i-benzopyrene) 2_ ® base] 2-methylpropyl guanidino)phenyl]carbonyl}(methyl)amino]propionic acid 3-[{[4-(U-) in optical resolution in (1) above [5-(Benzomethoxy)_3_indolyl-1-benzofuran-2-yl]-2-mercaptopropyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid The ester (1.25 g) was dissolved in ethanol (15 mL), EtOAc (4 mL) was evaporated. 4 mL) was added to the residue and the mixture was extracted with ethyl acetate. EtOAc (EtOAc m. 1.08 g, 93%, 99. 9% ee). !H NMR (300 MHz, CDCL·) ^ ppm 0.91 (d, J=6. 8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 2.18-2.30 (m, 4H), 2.66 (t , J=6.2Hz, 2H), 3.03 (s, 3H), 3.69 (t, J=6.2 Hz, 2H), 4.32 (d, J-7.5 Hz, 1H), 5.08 (s, 2H), 6.56 (d , J=8. 7 Hz, 2H), 6.83-7.02 (m, 2H), 7.17-7.26 (m, 3H), 7.30-7.53 (m, 5H). Example A88 470 321426 201029996 3-{[(4 -{[(5-Gas-3-methyl-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino}propionic acid

Η Cl (1) 5-Gas-N-decyloxy-N,3-dimercapto-1-benzofuran-2-decylamine 0 Decomposition of carbonic acid (8. 10 g), sodium moth 78 g) and 2-Gas-N-methoxy-N-methylacetamide (4.43 g) were added to 1-(5-chloro-2-hydroxyphenyl)ethanone (5.0 g) A solution of tetrahydrofuran (5 mL) was added and the mixture was stirred and stirred under reflux overnight. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a white solid. Add 1,8-diazabicyclo[5.4.0]undec-7-ene (4.38 mL) to the resulting solid N,N-didecylguanamine solution (50 mL) at 120 C The mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (2. 15 g, 29%) was obtained. H NMR (300 MHz, CDCh) (5 ppm 2.47 (s, 3H), 3.38 (s, 3H), 3.86 (s, 3H), 7.35 (dd, J=8. 9, 1.8 Hz, 1H), 7.40 ( Dd, J=8. 9, 0. 6 Hz, 1H), 7. 57 (dd, J=1.8, 0.6 Hz, 1H). (2) 5-Chloro-3-mercapto-1-benzo η夫喃_2-carboxylic acid: lithium aluminum hydride (322 mg) was added to the above-obtained 5-chloro-N-321426 471 201029996 曱oxy-N,3-dimethyl-1-benzofuran at 0C _2_ guanamine (2.15 g) in tetrahydrofuran (40 mL), and the mixture was stirred for a few hours. Water (32 〇 #1) was added to terminate the reaction 'Add IN aqueous sodium hydroxide solution (32 〇 / zL) and The mixture was stirred at room temperature for 1 hour, and the resulting insoluble material was filtered, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (tetrahydrofuran) to afford a pale yellow solid. The title compound (1.21 g, 73%) was obtained as a pale yellow solid. H (300 MHz, CDCh) d ppm 2.60 (s, 3H), 7.43-7.51 (m, 2H), 7.65-7.67 (m, 1H ), 10.02 (s, 1H). (3) (5-Chloro-3-indolyl-1-benzofuran-2-yl) (cyclohexyl)methanol. 1.0M tetrahydrofuran solution of cyclohexylmagnesium bromide at 0C (4. 62 mL) A tetrahydrofuran solution (1 mL) of the above-prepared 5-chloro-3-indolyl-1-benzofuran-2-furanal (6 〇〇mg) was added, and the mixture was stirred for a few hours. The reaction mixture was quenched with EtOAc (EtOAc m.) The title compound (518 mg, 60%) was obtained as a pale oily oil. H NMR (300 MHz, CDCla) &lt;5 ppm 0. 85-1. 41 (m, 6H), 1.61-1.71 (m, 2H), 1.75-1.98 (m, 3H), 2.09-2.18 (m, 1H), 2.19 (s, 3H), 4.52 (dd, J=8. 4, 6.0 Hz, 1H), 7.20 (dd, J=8. 4, 2.1 Hz, 1H), 7.33 (dd, J=8. 4, 0.6 Hz, 1H), 7.42 (dd, J=2. 1, 0.6 Hz, 1H). (4) 5-Chloro-2-[[ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 5-Chloro-3-indenyl 472 321426 201029996 -1-benzofuran-2-yl)(cyclohexyl)nonanol (518 mg) in benzene (10 mL), and the mixture was stirred at 100 ° C for 1 hour. . The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen sulfate and mixture was evaporated. The extract was washed with EtOAc (EtOAc m. 'HNMROOOMHz' CDClOSppmO.SS-USCm'eHXUO-1.71 (m, 2H), 1.77-1.87 (m, 1H), 2.10-2.24 (m, 4H), 2. 27-2. 37 (m, 1H), 4.78 (d, J-9. 6 Hz, 1H), 7.20-7.26 ❹(m,1H), 7.34-7.38 (m,1H), 7.42-7.44 (m, 1H). (5) 3-{[(4 -{[(5-chloro-3-methyl-1-benzofuran-2-yl)(cyclohexyl)indolyl]amino}phenyl)carbonyl]amino}propionic acid was stirred at 80 ° C Synthesis of 5-chloro-2-[chloro(cyclohexyl)indenyl]-3-mercapto-1-benzoquinone fluoren (270 mg), 3-{[(4) synthesized in Example 1 (2) -aminophenyl)carbonyl]amino}ethyl propionate (215 mg), sodium iodide (204 mg), sodium carbonate (144 mg) and hydrazine, hydrazine-dimercaptocaramine (10 mL) ^ The mixture is overnight. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to afford pale yellow oil. A 1 N aqueous solution of sodium hydroxide (1.0 mL) was added to a mixture of the obtained oil, THF (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (1. The obtained precipitate was collected by filtration to yield title compound (132 mg, 31%). 473 321426 201029996 H NMR (300 MHz, CDCh) &lt;5 ppm 0. 92-1. 35 (m, 5H), 1.44-1.55 (m, 1H), 1.60-1.96 (m, 4H), 2.01-2.12 ( m, 1H), 2.20 (s, 3H), 2.54-2.67 (m, 2H), 3.56-3.68 (m, 2H), 4. 3T(d, J=7.9Hz, 1H), 6.50-6.66 (m, 3H), 7.12-7.18 (m, 1H), 7.23-7.30 (m, 1H), 7.37 (d, J=l. 9 Hz, 1H), 7. 52 (d, J=8. 7 Hz, 2H) Example A89 3-{[(4-{[(5-chloro-3-indolyl-1-benzofuran-2-yl)(cyclohexyl)methyl]® Aminophenyl)carbonyl]] Mercapto)

The 5-chloro-2-[chloro(cyclohexyl)indenyl]-3-methyl-1-benzopyran (283 mg) synthesized in Example A88 (4) was stirred at 80 ° C, Example 2 ( 2) 】 © 3-{[(4-Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (238 mg), sodium for replacement (214 mg), sodium carbonate (152 mg) And a mixture of hydrazine, hydrazine-dimethyl decylamine (10 mL) overnight. 1 Torr hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The residue was purified by EtOAc EtOAc (EtOAc) elute A 1 N aqueous solution of sodium hydroxide (1.00 mL) was added to the obtained oil, mixture of tetrahydrohexane (5mL) and ethanol (5mL) and the mixture was stirred at room temperature 1.5 321 426 474. The residue was dissolved in water (1 mL), and 1N hydrochloric acid (1. The obtained precipitate was collected by filtration to yield title compound (ljj, H NMR (300 MHz, CDCh) ^

Ppm 0. 93-1· 38 (m, 5H), 1.45- 1.56 (m, 1H), 1.61-1.97 (m, 4H), 2. 02-2. 13 (m, 1H), 2.21 (s, 3H) ), 2.60-2.69 (m, 2H), 3.01 (s, 3H), 3. 68 (t, J = 6.2 Hz, 2H), 4.36 (d, J = 7.9 Hz, 1H), 6.54 (d, J= 8.7 Hz, 2H), 7.13-7.19 (m, 1H), 7.20-7.31 (m, 3H), 7. 38 (d, Jl. 9 Hz, 1H). Example A90 3-{[(4-{[ Cyclohexyl (3,5-dimethyl-l-benzofuran-2-yl)indenyl; I-amino}phenyl)carbonyl]amino}propionic acid

〇 h3c (1) N-decyloxy-N,3,5-trimethyl-1~benzoxan-2-amine

Potassium carbonate (9.20 g), sodium iodide (9.98 g) and 2-gas-N-decyloxy-N-methylacetamide (5. 04 g) were added to 1-(2-hydroxy-5-oxime). A solution of phenyl acetophenone (5.00 g) in N,N-dimercaptocaramine (50 mL), and the mixture was stirred at 50 ° C for 5 hours, then stirred overnight at C. To remove the insoluble matter, 1,8-diazabicyclo [5. 4.0] deca-ene (5.00 mL) was added to the filtrate, and the mixture was stirred at 120 ° C for 2 hours. 1N hydrochloric acid was added to terminate the reaction and 321426 475 201029996 was extracted with acetic acid. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (3.78 g, 49%). NMR NMR (300 MHz, CDCh) δ 2.47 (s, 3Η), 2.49 (s, 3H), 3.38 (s, 3H), 3.86 (s, 3H), 7.19-7.24 (m, 1H), 7.32-7.34 ( m, 1H), 7.35-7.39 (m, 1H). (2) 3,5-Dimercapto-1-benzoquinone 11 Fut-N-2-carboxylic acid® Lithium aluminum hydride at -78 ° C (307 mg Addition to the above-prepared N-methoxy-N,3,5-trimercapto-1-benzopyrene. A solution of sodium decylamine (3.78 g) in tetrahydrofuran (50 mL), and the mixture was stirred for 2 hr. Water (350/L) was added to terminate the reaction, 1N aqueous sodium hydroxide (7 〇〇eL) was added and the mixture was stirred at room temperature for 1 hour. The resulting insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with hexane to give title compound (2.08 g' 74%). ❹ 4 NMR (300 MHz, CDC13) (5 ppm 2. 48 (s, 3H), 2. 60 (s, 3H), 7.30-7.35 (m, 1H), 7.40-7.47 (m, 2H), 10.01 ( s, 1H). (3) Cyclohexyl (3, 5-dimethyl-1-benzophenone n-n- 2-yl)methanol. 1.0M tetrahydrofuran solution of cyclohexylmagnesium bromide at 0 ° C (8. 61 mL) To a solution of the above-prepared 3,5-dimercapto-1-benzofuran-2-furfural (1. 〇〇g) in tetrahydrofuran (20 mL) and stir the mixture for 1 hour. The ammonium aqueous solution was gasified to terminate the reaction, and the tetrahydrofuran was evaporated in an evaporator and the residue was taken up in ethyl acetate. The extract was washed with saturated brine, dried with sulfuric acid 321426 476 201029996 and concentrated. (4) (4) The title compound (l l3 g, 76%) was obtained as a pale yellow solid..H NMR (300 MHz, CDCh) ^ ppm 0. 83-0. 99 〇 π, 1Η), 1.00-1-44 (m, 5H), 1.58-1.70(m, 2H), 1.74-1.98 (m, 3H), 2.〇9-2.22(m,4H), 2.45 (s, 3H), 4.51 (dd, J=8.5, 5.9

Hz, 1H), 7.03-7.11 (m, 1H), 7.23-7.33 (m, 2H). (4) 2-[Chloro(cyclohexyl)indenyl]-3,5-diindenyl-benzofuran Pyridine (424 // L) and sulfoxide (382 # L) were added to the above-mentioned synthesized hexyl (3, 5-dimethyl-1-benzofuran-2-yl) methanol (1. 13 g) Toluene solution (20 mL), and the mixture was stirred at room temperature for 5 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc EtOAc m. HNMR (300 MHz, CDCh) δ ppm 0. 82-0. 97 (m, 1H), 1.00-〇L4° 4H), 1.41-1.51 (m, ih), 1.59-1.70 (m, 2H), 1.76- 1.87 (in, 1H), 2.11-2.25 (m, 4H), 2.28-2.38 (m, 1H), 2.44 (s, 3H), 4.80 (d, J=9. 3 Hz, 1H), 7.07-7.12 ( m, 1H), 7.23-7.26 (m, 1H), 7.32 (d, J=8.4 Hz, 1H). (5) 3-{[(4-·[[cyclohexyl(3,5_didecyl) -benzofuran-2-yl)indenyl]amino}phenyl)carbonyl]aminoh-acid The above-prepared 2-[chloro(cyclohexyl)indenyl]-3, 5-12 was stirred at 80 °C. Ethyl-1-benzofuran (4 mg), 3-{[(4-aminophenyl)methyl]aminopropionic acid ethyl ester (343 mg) synthesized in Example 1 (2), A mixture of sodium iodide 477 321426 201029996 (327 mg), sodium carbonate (231 mg) and N,N-dimethylformamide (10 mL) for 5 hours. IN hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (45% ethyl acetate/hexane) to afford a yellow oil. A 1 N aqueous solution of sodium hydroxide (2 mL) was added to a mixture of EtOAc, EtOAc (EtOAc) The residue was dissolved in water (i 〇 mL) and 1N hydrochloric acid (2.0 mL) was added at EtOAc. The resulting precipitate was collected by filtration to afford title compound (436 mg, 67%). H NMR (300 MHz, CDCh) δ ppm 0. 93-1. 36 (m, 5H), 1 47- 1.58 (m, 1H), 1.59-1.97 (m, 4H), 2.02-2.12 (m, 1H) , 2.22 (s, 3H), 2.42 (s, 3H), 2.61-2.69 (m, 2H), 3.60- 3.70 (m, 2H), 4.38 (d, J=8. 0 Hz, 1H), 6.49-6.60 (m, 3H), 7.00-7.06 (m, 1H), 7.19-7.24 (ra, 2H), 7.52 (d, J=7. 6 Hz, 2H). q Example A91 3 {[(4 {[% Hexyl (3,5-dimethyl-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

Benzofuran-2-yl)indole [[cyclohexyl(3,5-didecyl-bu 321426 478 201029996]amino}phenyl)carbonyl](methyl)amino}ethyl propionate at 80° C. 2-[Chloro(cyclohexyl)methyl]-3,5-dimercapto-1-benzofuran (400 mg) synthesized in Example A90 (4), and synthesized in Example 2 (2) 3-{[(4-Aminophenyl)carbonyl](methyl)amino}ethyl propionate (363 mg), sodium iodide (327 mg), sodium carbonate (231 mg) and N,N-di A mixture of methyl decylamine (10 mL) was used for 5 hours. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (471 mg, 66%) yH NMR (300 MHz, CDCla) (5) Ppm 0. 94-1. 36 (m, 8H), 1.48-1.59 (m, 1H), 1.60-1.96 (m, 4H), 2.03-2.13 (m, 1H), 2.22 (s, 3H), 2.42 ( s, 3H), 2.57-2.65 (in, 2H), 3.01 (s, 3H), 3.70 (t, J=7. 1 Hz, 2H), 4.07-4.17 (m, 2H), 4.32-4.40 (m, 2H), 6.56 (d, J=8. 7 Hz, 2H), 7.03 (dd, ❹ J=8.3, 1.3 Hz, 1H), 7. 17-7.24 (m, 4H). (2) 3-{[ (4-{[cyclohexyl(3,5-didecyl-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)aminopropionic acid 1N sodium hydroxide An aqueous solution (2. 〇〇mL) was added to the above-mentioned synthesized 3_ {[(4-{[cyclohexyl(3,5-didecyl-1-benzofuran-2-yl)methyl]amino} benzene) A mixture of ethyl carbonyl](methyl)amino}ethyl propionate (471 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 3 hr and concentrated under reduced pressure. In water (10 mL), 1N hydrochloric acid (2 〇〇mL) was added to 〇ac. The obtained shoal was collected to obtain white Heading target for solids 321426 479 201029996 Compound (407 mg, 92%). HNMR (300 MHz, CDCl3) 5 ppm 0.93-1.37 (m5H) 147- 1.58 (m, 1H), 1.60-1.97 (m, 4H), 2.02 -2.14 (m 1H) 2.23 (s, 3H), 2.42 (s, 3H), 2.62-2. 73 (m 2H) 3 04 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 4.37 (d, J=8 0 Hz, lH), 6.56 (d, J=8.7 Hz, 2H), 7.00-7. 〇6(m,iH)7 19- 7.28 (m, 4H). 'Example A92 ® 3-monodecyloxy-3-methyl-1-benzofuran-2-yl)_3_mercaptobutyl]amino}phenyl)carbonyl]amino}propionic acid

H3c^ h3c-o ❹(1) 1 I(5-decyloxymethyl-1-benzofuran-2-yl)-3-methylbutan-1-ol is 1. GM desertified at 0 °C A tetrahydrofuran solution of isobutylmagnesium (15 〇mL) was added to a solution of 5-nonyloxymethyl-benzofuran-2-carbaldehyde (1.91 g) synthesized in Example A27 (2) in tetrahydrofuran (4 〇). roL), and the mixture was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and tetrahydrofuran was evaporated in an evaporator and the residue was extracted with ethyl acetate. The residue was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) δ ppm 0. 93 (d, J=6. 6 Hz 3H) 0.95 (d, J=6. 6 Hz, 3H), 1.54-1.69 (m, 1H), 1.74- 1.96 (m, 3H), 2. 23 (s, 3H), 3. 85 (s, 3H), 4. 88-4. 97 (m 1H) 6.86 (dd, J=8. 6, 2. 7 Hz , 1H), 6.91 (d, J=2.7 Hz, 1H), 7. 30 (d, J=8. 6 Hz, 1H). (2) 2-(1-Chloro-3-methylbutyl -5-decyloxy-3-methylbenzoindilating acridine (297# L) and sulfinium chloride (268 #L) to the 1-(5-methoxy-- 3-Mercapto-1-benzo-dopyridin-2-yl)-3-mercapto-but-1-propanol (761 mg) in toluene (10 niL) &lt; A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc (EtOAc m. !H NMR (300 MHz, CDCh) &lt;5 ppm 0. 91-0. 96 (m, 3H), 1 12 0 (d, J=6.8 Hz, 3H), 1.58-1.75 (m, 1H), 2.15 (d, J=7. 9

Hz, 2H), 2.24 (s, 3H), 3.86 (s, 3H), 5.20 (t, J=7. g Hz, 1H), 6.86-6.93 (m, 2H), 7.34 (d, J=9.4 Hz , 1H). (3) 3-{[(4-{[l-(5-methoxy-3-indolyl-1-benzoate. Nan-2-yl)-3-methylbutyl]amine 2-(1-chloro-3-methylbutyl)-5~methoxy-3-indenyl group synthesized above by dispersing the above-prepared 2-(1-chloro-3-methylbutyl)-5-methoxy-3-indenyl group at 80 ° C 1-benzofuran (380 mg), 3-{[(4-aminophenyl)carbonyl]amino}propionic acid ethyl ester (350 mg) synthesized in Example 1 (2), sodium hydride ( A mixture of 443 mg), sodium carbonate (314 mg) and N,N-didecylguanamine (1 〇) 321426 481 201029996 for 5 hours. IN hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc) JH NMR (300 MHz, CDCh) (5 ppm 0.91 (d, J=6. 8 Hz, 3H), 1.00 (d, J=6.8Hz, 3H), 1.20-1.30 (m, 3H), 1.49-1.64 ( m, 1H), 1.79-1.91 (m, 2H), 2.26 (s, 3H), 2.59 (t, J=5.9Hz, 2H), 3.62-3.71 (m, 2H), 3.83 (s, 3H), 4.07 -® 4.21 (m, 2H), 4.30-4.44 (m, 1H), 4.70 (t, J=7.4 Hz, 1H), 6.56-6.63 (m, 3H), 6.80-6.85 (m, 1H), 6.88 ( d, J=2. 3 Hz, 1H), 7.25 (d, J=8. 7 Hz, 1H), 7.56 (d, J=8. 7 Hz, 2H). (4) 3-{[(4- {[1-(5-Methoxy-3-indolyl-i-benzofuran-2-yl)-3-indenylbutyl]amino}phenyl)carbonyl]amino}propionic acid

Add 1N aqueous sodium hydroxide solution (2_〇〇mL) to the above-mentioned 3-❹丨[[4_{[1_(5_methoxy-3-methyl-1-benzofuran-2-yl)) a mixture of ethyl 3-mercaptobutyl]amino}phenyl)alkyl]amino}propionate (266 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature £ hours and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to yield title compound ( 216 mg, 86%). R (300 MHz, CDC13) (5 ppm 0.90 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 1.48-1.64 (m, 1H), 1.76-1.93 (m, 2H), 2. 25 (s, 3H), 2. 63 (t, J=5. 7 Hz, 2H), 3. 59- 321426 482 201029996 3.69 (m, 2H), 3.83 (s, 3H), 4.70 (t, J=7.4 Hz, 1H), 6.54-6.65 Cm, 3H), 6.78-6.85 (m, 1H), 6.87 (d, J=2.7 Hz, 1H), 7.20-7.30 (m, 1H) , 7.53 (d5 J=8.7 Hz, 2H). Example A93 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3 -nonylbutyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

(1) 3-{[(4-{[1-(5-Methoxy-3-indol-1-benzofuran-2-yl)-3-indolylbutyl]amino}phenyl) 2-(1-chloro-3-methylbutyl)-5-decyloxy-3 synthesized in Example A92(2) was stirred at 80 ° C at several bases of (indenyl)amino}ethyl acetate. -methyl-1-benzofuran (380 mg), 3-{[(4-aminophenyl)carbonyl](indolyl)amino}propionic acid ethyl ester synthesized in Example 2 (2) 0 ( A mixture of 370 mg), moth (443 mg), sodium carbonate (314 mg) and N,N-didecylguanamine (10 mL) for 5 hours. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (350 mg, 51%) was obtained eluted elute R (300 MHz, CDC13) 5 ppm 0.91 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 1.19-1.30 (m, 3H), 1.49-1.64 483 321426 201029996 ( m, 1H), 1.80-1.89 (m, 2H), 2.26 (s, 3H), 2.61 (t, J-7.0 Hz, 2H), 3.01 (s, 3H)S 3.71 (t, J=7.0 Hz, 2H ), 3.84 (s, 3H), 4.07-4.17 (m, 2H), 4.68 (t, J=7.4 Hz, 1H), 6.58 (d, J=8. 7 Hz, 2H), 6.80-6.86 (m, 1H), 6.88 (d, J=2.3 Hz, 1H), 7.23 (d, J=8. 7 Hz, 2H), 7.26 (d, J=8. 7 Hz, 1H). (2) 3-{[ (4-{[l-(5-decyloxy-3-indolyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl](methyl)amine Addition of 1N aqueous sodium hydroxide solution (2. 〇〇mL) to the above-prepared 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzo) Furan-2-yl)-3-mercaptobutyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate (350 mg), tetrahydrofuran (5 raL) and ethyl acetate (5 mL) The mixture was stirred at room temperature for 5 hours' and concentrated under reduced pressure. The residue was dissolved in water (1 () mL) and at 0. (: 1 N Hydrochloric acid (2.0 mL) was added. The obtained precipitate was collected by filtration to afford title compound (308 mg, 94%) as white solid. ❿ NMR (300 MHz, CDC13) (5 ppm 0·91 (d, J=6.4 Hz, 3H), 1.00 (d, J=6.4Hz, 3H), 1.48-1.65 (m, 1H), 1.81-1.89 (m, 2H), 2.26(s, 3H), 2.65- 2.75 (m, 2H), 3. 05 (s, 3H), 3.71 (t, J=6.4 Hz, 2H), 3.84 (s, 3H), 4.69 (t, J=7.4 Hz, 1H), 6.58 (d , J=8.7 Hz, 2H), 6.80-6.86 (m, 1H), 6.88 (d, J=2.3 Hz, 1H), 7.23-7.30 (ra, 3H). Example A94 3-{[(4-{ [1-(3-Methyl-1-benzo-c-yl-2-yl)-2-phenoxyethyl]amino}phenyl)carbonyl]amino}propionic acid 484 321426 201029996

(1) 1-(3-Methyl-1-benzopyrene sigma-2-yl)-2_benzene-based base B_ Adding carbonic acid clock (655 mg) to 2-bromo-1-(3- a mixture of decyl-1-benzopyrene 〜~2-yl)ethanone (1.00 g), phenol (446 mg) and hydrazine, hydrazine-dimercaptocarboxamide (20 mL) and stirred at room temperature Overnight. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCls) d ppm 2.65 (s, 3H), 5.36 (s, 13 2H), 6.81-6.86 (m, 1H), 6.98-7.06 (m, 2H), 7.20-7.39 (m, 3H), 7.51-7.57 (in, 2H), 7.67-7.73 (m, 1H). (2) 4-{[ 1-(3-methyl-1-benzofuran-2-yl)-2-benzene Ethyloxy]amino}benzoic acid oxime ester Titanium chloride (iv) (344 μL) was added to 1-(3-mercapto-1-benzofuran) synthesized above under argon at 0 °C. a mixture of 2_yl)_2_phenoxyethanone (697 mg), methyl 4-aminobenzoate (399 mg), triethylamine (2.93 mL) and dioxane (10 mL) The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate, and then evaporated and evaporated. The extract was washed with brine, dried over magnesium sulfate and evaporated To the reaction mixture was stirred for 15 minutes at room temperature. The mixture was further stirred for 3 hr. The reaction was quenched with EtOAc EtOAc EtOAc. The title compound (279 mg, μ%) was obtained as a yellow solid. H NMR (300 MHz, CDCh) δ ppm 2.29 (s, 3H), 3.83 (s, 3H) ), 4.32-4.44 (in, 2H), 4.91 (d, J=6. 6 Hz, 1H), 5.08-5.16 (m, 1H), 6.66 (d, J=8. 9 Hz, 1H), 6.81- 6.99 (m, 3H), 7.18-7.31 (m, 4H), 7.38-7.48 (m, 2H), 7.84 (d, J=8. 9 Hz, 2H). (3) 4-{[1-(3 - mercapto-1-benzofuran-2-yl)_2-phenoxyethyl]amine Q-based benzoic acid A solution of IN sodium hydroxide (5. 〇〇mL) was added to the above-mentioned 4- U 1-(3-Mercapto-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoic acid oxime ester (279 mg), four A mixture of furan (5 mL) and EtOAc (5 mL) was evaporated and evaporated. The title compound (220 mg, 82%) was obtained as a white solid. H NMR (300 MHz, CDCh) (5 ppm 2.30 (s, 3H), 4.32-4. 46 486 321426 201029996 (m, 2H), 4.92-5.03 (m, 1H), 5.09-5.20 (m, 1H), 6.69 (d, J=9. 1 Hz, 2H), 6.90 (d, J=7.6 Hz, 2H ), 6.93-7.0] (m, 1H), 7.19-7.34 (m, 4H), 7.38-7.51 (m, 2H), 7.9〇(d, J=8.7 Hz, 2H). (4) 3-{[ (4-{[l-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)alkyl]amino}propionic acid -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74·2 mg) was added to the above-prepared 4-{[1-(3-mercapto-1-) Benzofuran®-2-yl)-2-phenoxyethyl]amino}benzoic acid (1 〇〇 mg), cold-alanine ethyl ester hydrochloride (59.4 mg), 1- Benzotris-tris-monohydrate (59.3 mg), triethylamine (72//L) and N,N-dimercaptocaramine (10 mL) Were combined, and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (63. 0 mg, 50%) was obtained. NMR NMR (300 MHz, CDCh) 5 ppm 1.25 (t, J=7.2 Hz, 3H), 2.29 (s, 3H), 2.59 (t, J=5. 8 Hz, 2H), 3.62-3.72 (m , 2H), 4. 14(q, J=7. 2 Hz, 2H), 4.31-4.44 (m, 2H), 4.78- 4.88 (m, 1H), 5.06-5.15 (m, 1H), 6.60-6.71 (m, 3H), 6.89 (dd, J=8.8, 1.0 Hz, 2H), 6.93-7.00 (m, 1H), 7.18-7.31 (m, 4H), 7.38-7.49 (m, 2H), 7.59 (d , J=8. 9 Hz, 2H). (5) 3-{[(4-{[l-(3-Mercapto-1-benzofuran-2-yl)-2-phenoxyethyl 487 321426 201029996 base]amino}phenyl) benzyl]aminopropionic acid A 1N aqueous solution of sodium hydroxide (1. 〇〇mL) was added to the above-mentioned 3-{[(4-{[1-(3- Methyl-1 -benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)carbonyl]amino}ethyl propionate (63.0 mg), tetrahydrofuran (5 mL) and ethanol ( A mixture of 5 mL) was stirred at rt. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1 〇〇 mL) was then weighed. The resulting precipitate was collected by filtration to give the title compound (55.7 mg, 97%). ® H NMR (300 MHz, CDCh) δ ppm 2. 29 (s, 3H), 2. 68 (t, J=5.9Hz, 2H), 3.63-3.72 (m, 2H), 4.32-4.44 (m, 2H ), 5.10 (t, J=6.1 Hz, 1H), 6.58 (t, J=5. 7 Hz, 1H), 6.67 (d, J-8.7 Hz, 2H), 6.87-6.92 (m, 2H), 6.93 -7.00 (m, 1H), 7.18-7.31 (in, 4H), 7.38-7.43 (m, 1H), 7.44-7.49 (in, 1H), 7.58 (d, J=8. 7 Hz, 2H). Example A95 ❿3-{Methyl[(4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)alkyl]amine Propionate

(1) 3-((indolyl[(4-{[1-(3-indolyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)carbonyl] Amino}ethyl propionate 488 321426 201029996 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (74. 2 mg) was added to Example A94 (3) 4-{[1-(3-Methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoic acid (1 〇〇 mg), 3-( Ethyl mercapto) ethyl propionate (50.8 mg), 1-p-benzotriene. Monohydrate (59.3 mg), triethylamine (54/zL) and N,N-dimethyl A mixture of carbamide (1 〇 mL), and the mixture was stirred at room temperature overnight. The reaction was quenched with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) (300 MHz, CDCh) δ ppm 1.23 (t, J=7.2 Hz, 3H), 2.29 (s, 3H), 2.57-2.67 (m, 2H), 3.02 (s, 3H), 3.72 (t, J =7. 1 Hz, 2H), 4.12 (q, J=7. 2 Hz, 2H), 4.30-4.44 (m, 2H), 5.08 (t, J=6. 0 Hz, 1H), 6.66 (d, J=8. 7 Hz, 2H), 6.90 (dd, J=8. 7, 0. 9 Hz, 2H), 6.93-7.01 (m, 1H), ❹ 7. 19-7. 32 (m, 6H), 7.38-7.50 (m, 2H). (2) 3-{methyl[(4-{ [1-(3-Methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}phenyl)alkyl]amino}propionic acid 1N aqueous sodium hydroxide solution (1 〇〇mL) is added to the above-mentioned 3-{methyl[(4-{[1-(3-mercapto-1-benzofuran-2-yl)-2-phenoxyethyl]amine) A mixture of ethyl phenyl)carbonyl]amino}propionic acid ethyl ester (82.5 mg), tetrahydrofuran (5 idL) and ethanol (5 mL), and the mixture was stirred at room temperature for 5 hr. Dissolve in water (1 〇mL) and add 1 n hydrochloric acid (1. 〇〇mL) at 〇 °c. The resulting precipitate was collected by filtration to afford title title 321426 489 201029996 Compound (54. 8 mg, 70 %). !H NMR (300 MHz, CDCh) δ ppm 2.29 (s, 3H), 2.61-2.72 (m, 2H), 3.04 (s, 3H), 3.71 (t, J=6.6 Hz, 2H), 4.30- 4.42 ( m, 2H), 5.08 (t, J=6. 1 Hz, 1H), 6.66 (d, J=8. 7

Hz, 2H), 6.86-6.92 (m, 2H), 6.92-7.00 (m, 1H), 7.18- 7.31 (m, 6H), 7.38-7.43 (m, 1H), 7.44-7.49 (m, 1H). Example A96 3-{[(4-{[cyclohexyl(6-fluoro-3-indolyl-1-benzocypan-2-yl)methyl]) Amino}phenyl)carbonyl]amino group }propionic acid

(1) 6-Fluoro-N-decyloxy-N, 3-dimercapto-1-benzofuran-2-indole amine 2-chloro-N-methoxy-N-methylacetamidine Amine (4.90 g), sodium iodide (9.71 g) and potassium carbonate (8.96 g) are added to 1_(4-fluoro-2-hydroxyphenyl)

A solution of ketone (5.00 g) in N,N-dimercaptocaramine (5 mL) was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature and the insoluble material was filtered. To a solution of hydrazine, 8-diazabicyclo[5.4.0]undec-7-ene (4.85 mL) was added and the mixture was stirred at 120 ° C for 2 hours. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to afford titled 321426 490 201029996 (3. 65 g, 47%). ]H NMR (300 MHz, CDCh)^ 2.50 (s, 3H), 3.38 (s, 3H), 3.87 (s, 3H), 7. 01-7. 11 (m, 1H)? 7. 18 (dd, J=8. 8, 1.9 Hz, 1H), 7.54 (dd, J=8.8, 5.5 Hz, 1H). (2) 6-Oxo-3-methyl-1-benzopyrene-2-carboxylic acid· 01 Add lithium aluminum hydride (2921^) to the above-mentioned synthesized 6-fluoro-4-methoxy-N,3-dimercapto-1-benzofuran-2-ylidene (3 65 g) σ 喃 ;; trough solution (50 mL), and the mixture was searched for 1 hour. Water was added (3 〇〇 &quot; l) ❹ to terminate the reaction, 1N aqueous sodium hydroxide solution (6 〇〇/zL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound 88 g. !H NMR (300 MHz, CDCls) 5 ppm 2.62 (s, 3H), 7.07-7 15 (m, 1H), 7.22-7.28 (m, 1H), 7.65 (dd, J=8.8, 5.4 Hz, 1H) , 9.99 (s, 1H). 0 (3) Cyclohexyl (6-fluoro-3-methyl-1-benzofuran-2-yl) decyl alcohol at 0 ° C 1.0 M cyclohexane magnesium tetrahydrofuran solution ( 7. 92 mL) To a solution of the above-prepared 6-fluoro-3-methyl-1-benzofuran-2-furanal (94 〇mg) in tetrahydrofuran (2 mL), and the mixture was stirred for hr. A saturated aqueous solution of ammonium sulfate was added to terminate the reaction, and tetrahydroanion was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (931 mg, 67%) was obtained. 321426 491 201029996 ]H NMR (300 MHz, CDC13) 5 ppm 0. 85-1. 00 (m, 1H), l.〇〇-1.44 (m, 5H), 1.60-1.71 (m, 2H), 1.76- 1.99 (m, 3H), 2.10- 2.23 (m, 4H), 4.50 (dd, J=8.3, 6.1Hz, 1H), 6.94-7.02 (m, 1H), 7.10-7.17 (in, 1H), 7.34-7.40 (m, 1H). (4) 2-[Chloro(cyclohexyl)methyl]-6-fluoro-3-methyl-1-benzofuran with thiazinc chloride (311 //L) To the above-prepared cyclohexyl (6-fluoro-3-methyl-1-benzofuran-2-yl)methanol (931 mg) in a solution of benzene (2 〇 mL) and spoiled the mixture at 10 0 C 1 hour. The reaction mixture was poured into a saturated aqueous solution of EtOAc EtOAc. The extract was washed with EtOAc (EtOAc m. ]H NMR (300 MHz, CDCls)^ ppm 0. 82-0. 98 (m, 1H), 0.99-1.52 (m, 5H), 1.60-1.72 (m, 2H), 1.76-1.89 (m, 1H) , 2.11- 2.25 (m, 4H), 2.26-2.39 (m, 1H), 4.79 (d, J=9. 6

Hz, 1H), 6.96-7.04 (m, 1H), 7.15-7.20 (m, 1H), 7.35-^ 7.41 (m, 1H). (5) 4-{[cyclohexyl (6-fluoro-3-) Sodium carbonate (712 mg) was added to the above-prepared 2-[chloro(cyclohexyl)fluorenyl]-6-fluoro-(sodium benzopyran-2-yl) fluorenyl]amino}benzoic acid 3-mercapto-1-benzofuran (945 mg), 4-aminobenzoic acid decyl ester (508 mg), sodium iodide (1. 〇1 g) and N, N-dimethyl amide ( 10 mL) of the mixture' and the mixture was stirred at 80 ° C overnight. IN hydrochloric acid was added to terminate the reaction&apos; and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (2% EtOAc EtOAc EtOAc EtOAc EtOAc A 1N solution of sodium oxychloride in water (10.0 mL) was added to a mixture of the obtained solid, EtOAc (EtOAc) (EtOAc) The residue was dissolved in water (40 mL) and 1N hydrochloric acid (1 〇 〇 mL) was added to 〇t. The resulting precipitate was collected by filtration to give the title compound (722 mg, 56%). ^NMRQOOMHz, CDCI3) 6 ppm〇. 92-i.38(m,5H),146_ 1.57 (m, 1H), 1.61-1.98 (m, 4H), 2.02-2.13 (m, 1H), 2.25 (s, 3H), 4.40 (d, J=7.9 Hz, 1H), 4.51-4.74 (m, 1H), 6.57 (d, J=8. 8 Hz, 2H), 6.91-7.00 (m, 1H), 7.06 - 7.12 (m, 1H), 7.29-7.36 (m, 1H), 7.85 (d, J=8.8 Hz, 2H). * (6) 3-{[(4-{[cyclohexyl (6-fluoro-3) - mercapto-l-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride ❹ (265 mg) was added to the 4-{[cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)indenyl]amine group synthesized above. Benzoic acid (350 mg), stone-alanine ethyl ester hydrochloride (212 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383 gL) and hydrazine, hydrazine a mixture of dimercaptoguanamine (10 mL) and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine. The title compound (403 mg, 91%) was obtained eluted elute 493 321426 201029996 Juli R (300 MHz, CDC13) (5 ppm 0.94-1.39 (m, 8H), i 46_ 1.57 (m, 1H), 1.62-1.97 (m, 4H), 2.03-2.14 (m&gt; 1H) 2.24 (s, 3H), 2.58 (t, J=5.9 Hz, 2H), 3. 61-3.7〇^ 2H), 4. 14(q, J=7. 2 Hz, 2H), 4.32-4.47 (m , 2H), 6&gt; 541 6.63 Cm, 3H), 6.90-7.00 (m, 1H), 7.05-7.12 (m, 1H) 7.28-7.35 (m, 1H), 7.55 (d, J=8.9 Hz, 2H) (7) 3-{[(4-{[Cyclohexyl(6-fluoro-3-methyl-1-benzofuran~2~yl)methyl]amino}phenyl)]amino]amino} Propionic acid 1N aqueous sodium hydroxide solution (2. 〇〇mL) was added to the above synthesized 3_ {[(4-{[cyclohexyl (6-fluoro-3-indolyl-1-benzopyran-2-) a mixture of methyl]amino}amino}benzyl]amino}propionate (g) (4〇3 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), and The mixture was stirred at room temperature for 3 hr and concentrated under reduced pressure. The residue was dissolved in water (1 〇 mL) and applied to hydrazine. (: 1N Hydrochloric acid (2. 〇〇mL) was added. The obtained precipitate was collected by filtration to give the title compound (355 mg, 93%) as a white solid. Η NMR (300 MHz, CDC13) (5 ppm 0.92- 1. 37 (m, 5H), 1.44-1.56 (in, 1H), 1.60-1.96 (m, 4H), 2.00-2.12 (m, 1H), 2.22 (s, 3H), 2.53-2.66 (m, 2H) ), 3.54-3.67 (ra, 2H), 4. 35 (d, J=8.3Hz, 1H), 6.48-6.64 (m, 3H), 6.89-6.99 (m, 1H), 7.03-7.11 (m, 1H) ), 7.27-7.34 (m, 1H), 7.52 (d, J = 8.7 Hz, 2H). Example A97 3-{ [(4-·[[cyclohexyl(6-fluoro-3-indolyl-1-) Benzofuran-2-yl)indenyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid 494 321426 201029996 ο

(1) 3-{[(4-{[cyclohexyl(6-gas-3-methyl-1-benzocypano-2-yl)methyl]amino}phenyl)carbonyl](methyl Amino}ethyl propionate added 1-ethyl-3_(3_&gt;-decylaminopropyl)carbodiimide hydrochloride (265111 §) to the 4-mer synthesized in Example 496(5) {[Cyclohexyl(6-fluoro_3_indolyl-1_benzofuran-2-yl)methyl]amino}benzoic acid (35 〇rag), ethyl 3-(decylamino)propionate a mixture of (181 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383//L) and N,N-dimethyldecylamine (10 raL) The mixture was stirred overnight overnight. The reaction was quenched by the addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: 〇'H NMR (300 MHz, CDC13) (5 ppm 0. 93-1. 37 (m, 8H), 1.46-1.56 (m, 1H), 1.60-1.96 (m, 4H), 2.02-2.14 (m, 1H), 2.23 (s, 3H), 2.61 (t, J=6. 9 Hz, 2H), 3.01 (s, 3H), 3.70 (t, J=6.9 Hz, 2H), 4.07-4.17 (m , 2H), 4.27-4.39 (in, 2H), 6.56 (d, J=8.7 Hz, 2H), 6.91-7.00 (m, 1H), 7.06-7.12 (m, 1H), 7.21 (d, J=8 7 Hz, 2H), 7.28-7.35 (m, 1H). (2) 3-{[(4-{[cyclohexyl(6-say-3-mercapto-l-benzo-butan-2-yl) ) a 495 321426 201029996 benzyl]amino}phenyl)carbonyl](methyl)amino}propionic acid A 1N air-oxidized sodium aqueous solution (2·Q〇mL) was added to the above-mentioned 3-{[(4- {[Cyclohexyl(6-fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino fluorenylphenyl)carbonyl](methyl)amino}ethyl propionate (432 mg) a mixture of tetrahydroanthraquinone (10 mL) and ethanol (1 mL) and the mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and added to 1N hydrochloric acid. The title compound (367 mg, 90%) was obtained as a pale red solid. ???H NMR (300 MHz, CDCla) ppm 0. 93-1. m, 5H), 1.46-1.57 (m, 1H), 1.61-1.96 (m, 4H), 2.03-2.14 (m, 1H), 2.23 (s, 3H), 2.67 (t, J=6.4 Hz, 2H), 3.04 (s, 3H), 3.70 (t, J=6.4Hz, 2H), 4.35 (d, J=8.0 Hz, 1H), 6.56 (d, 1=8.7 Hz, 2H), 6.91-7.00 (in, 1H) , 7.06-7.12 (m, 1H), 7.21-7.28 (m, 2H), 7.29-7.36 (m, 1H). Example A98 ❹3_{[(4-{[(5-Cyano-3-indolyl)- 1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino}propionic acid

(1) Methyl 5-bromo-3-indolyl-1-benzofuran-2-carboxylate Ethyl bromoacetate (4.85 mL) and potassium carbonate (12.9 g) were added to 1-(5-496 321426 201029996 A solution of bromo-2-hydroxyphenyl)ethanone oxime 〇g) in N,N-dimethylformamide (100 mL), and the mixture was stirred at room temperature overnight. The insoluble material was filtered off, and 1,8-diazabicyclo [5. 4·0] Η 7-ene (6.95 mL) was added to the filtrate, and the mixture was stirred at 120 C for 2 hours. The reaction was quenched by the addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (6 〇 6 g, 48%). ® ^ NMR (300 MHz, CDCh) ^ ppm 2.56 (s, 3H), 3.99 (s, 3H), 7.39-7.44 (m, 1H), 7.51-7.56 (m, 1H), 7.76 (d, J=l 9 Hz, 1H). (2) 5-cyano-3-methyl-l-benzofuran-2-carboxylic acid oxime ester 肆(triphenylphosphine)palladium(0) (1.31 g) was added to The above-mentioned synthesized 5-I odor-3-mercapto-1-benzo π σ 南 -2- -2- carboxylate methyl ester (β· 〇 6 g), zinc cyanide (2.64 g) and Ν, Ν-二A mixture of methylformamide (60 mL) was degassed under argon helium at 80 ° C and the mixture was stirred overnight. Water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (4.20 g, 87%). !H NMR (300 MHz, CDCh) &lt;5 ppm 2.61 (s, 3H), 4.01 (s, 3H), 7.61-7.66 (m, 1H), 7.69-7.74 (m, 1H), 8.00 (d, J =0. 9 Hz, 1H). (3) 5-cyano-3-indenyl-l-benzofuran-2-carboxylic acid 虱 虱 oxidized clock monohydrate (1.64 g) was added to the above synthesized 5 -Cyanide 497 321426 201029996 a mixture of decyl-3-mercapto-1-benzofuran-2-carboxylate (4.20 g), tetrahydrofuran (80 mL), water (20 mL) and methanol (20 mL), The mixture was stirred at room temperature overnight and concentrated under reduced pressure. 1N Hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was washed with EtOAc (EtOAc m. !H NMR (300 MHz, DMSO-d6) ppm 2.55 (s, 3H), 7.85-7.89 (m, 1H), 7.91-7.95 (m, 1H), 8.44-8.47 (m, 1H), ® 13.76 (br s, 1H). (4) 2-Mercapto-3-mercapto-1-benzofuran-5-indolecarbonitrile oxalate (1.32 mL) and a few drops of N,N-dimercaptopurine The amine was added to the above-prepared 5-cyano-3-indolyl-1-benzofuran-2-carboxylic acid (2. 58 g) in THF (30 mL). The reaction mixture was concentrated under reduced pressure and the residue was washed with diisopropyl ether to afford a pale brown solid. 1. 1M lithium hydride tris(isobutoxy)aluminum tetrahydrofuran 0 solution (12.0 mL) was added to the resulting solid tetrahydrofuran solution (50 mL) at -78 ° The mixture was stirred for 1.5 hours, then stirred at 0 ° C for 3 hours. The reaction was quenched by the addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. Active manganese dioxide (10.0 g) was added to a solution of the obtained solid in tetrahydrofuran (40 mL), and the mixture was stirred at 50 ° C overnight. Manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc (EtOAc m. R (300 MHz, CDC13) 5 ppm 2.65 (s, 3H), 7. 65 (d, 498 321426 201029996 J=8. 7 Hz, 1H), 7. 77 (dd, J=8. 7, 1.5 Hz , 1H), 8.05-8.08 (m, 1H), 10.08 (s, 1H). (5) 2-[Cyclohexyl(hydroxy)indolyl]-3-mercapto-1-benzofuran-5-carbonitrile A 1.0 M solution of cyclohexylmagnesium bromide in tetrahydrofuran (12.1 mL) was added to the above-prepared 2-mercapto-3-indolyl-1-benzofuran-5-carbonitrile (1.49 g). A solution of tetrahydrofuran (30 mL) was added and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute 43%). !H NMR (300 MHz, CDCh) δ ppm 0. 84-1. 43 (m, 6H), 1.48-1.99 (m, 5H), 2.03-2.19 (m, 1H), 2.24 (s, 3H), 4.56 (dd, J=8.4, 5.4 Hz, 1H), 7.47-7.51 (m, 1H), 7.52-7.57 (ra, 1H), 7.78-7.81 (m, 1H). ❹ (6) 2_[乳(i心Hexyl) fluorenyl]-3-methyl-1-benzopyrene- 5-Achay ruthenium chloride (374 a L) was added to the 2-[cyclohexyl (trans)methyl) synthesized above. Toluene solution (10 mL) of -3-mercapto-1-benzobenzopyran-5-indenecarbonitrile (922 mg) was stirred at 100 ° C for 1 hour. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen sulfate and the mixture was evaporated. The extract was washed with EtOAc (EtOAc m. !H NMR (300 MHz, CDCh) ppm 0.85-1. 55 (in, 6H), 1.62-1.74 (m, 2H), 1.79-1.90 (m, 1H), 2.10-2.22 (m, 1H), 321426 499 201029996 2.26 (s, 3H), 2.28-2.39 (m, 1H), 4.80 (d, J=9. 6 Hz, 1H), 7.51-7.55 (m, 1H), 7.56-7.61 (m, 1H), 7.81 -7.83 (m, 1H). (7) 4-{[(5-Cyano-3-methyl-i-benzofuran-2-yl)(cyclohexyl)indenyl]amino}benzoic acid will Sodium carbonate (638 rag) was added to the above-mentioned 2-[aero(cyclohexyl)indolyl]-3-mercapto-1-benzofuran-5-carbonitrile (868 mg), 4-aminobenzoic acid A mixture of decyl ester (546 mg), sodium iodide (9 〇 2 mg) and n,N-dimethylformamide (1 〇® mL) was mixed overnight at 80 C. 1 n Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (3 (10) ethyl acetate /hexane) to afford a pale brown solid. A 1N aqueous solution of hydrogen chloride (3.38 mL) was added to a mixture of the obtained solid, tetrahydro-pyran (2 mL), water (8 mL) and ethanol (10 mL), and the mixture was stirred under reflux overnight. And concentrated under reduced pressure. The residue was dissolved in water (4 mL) and added to HCl (3·50 mL). The obtained precipitate was collected by filtration to give the title compound (621 mg, 53%). !H NMR (300 MHz, CDCh) δ ppm 0. 90-1. 41 (m, 5H), 1.44- 1.56 (m, 1H), 1.62-2.01 (m, 4H), 2.03-2.14 (m, 1H) , 2.28 (s, 3H), 4.40-4.51 (m, 1H), 4.52-4.67 (m, 1H), 6.56 (d, J=8.8Hz, 2H), 7.41-7.46 (m, 1H), 7.49-7 54 (m, 1H), 7.75-7.77 (m, 1H), 7.85 (d, J=8. 8 Hz, 2H). (8) 3 {[(4-{[(5-Cyano-3-) Methyl-i-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino}ethyl propionate 321426 500 201029996 1-ethyl-3-(3-di Mercaptopropyl propyl) carbodiimide hydrochloride (185 mg) was added to the above-prepared 4-{[(5-cyano-3-indolyl-1-benzofuran-2-yl) ( Cyclohexyl)methyl]aminobenzinobenzoic acid (250 mg), point-alanine ethyl ester hydrochloride (148 mg), 1-hydroxybenzotrione monohydrate (148 mg), triethylamine ( A mixture of 269 //L) and N,N-dimethyldecylamine (1 mL) was stirred at room temperature overnight. 1N hydrochloric acid was added to terminate the reaction and the mixture was extracted with acetic acid. The extract was washed with saturated aqueous sodium hydrogencarbonate and saturated brine. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) &lt;5 ppm 0. 95-1. 38 (m, 8H), 1.45-1.63 (m, 3H), 1.63-1.99 (m, 2H), 2.03-2.15 (m, 1H), 2.27 (s, 3H) ), 2.54-2.61 (in, 2H), 3.61-3.70 (m, 2H), 4. 14 (q, J=7. 2 Hz, 2H), 4.39-4.46 (m, 1H), 6.53-6.64 (m , 3H), 7.41-7.45 (m, 1H), 7.48-7.53 (m, 1H), 7.55 ❹ (d, J=8.7 Hz, 2H), 7.76 (d, J=1.5 Hz, 1H). (9) 3-{[(4-{[(5-Cyano-3-mercapto-1-benzoyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propyl Acid 1N aqueous solution of iodine (800 // L) was added to the above-prepared 3-{[(4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)) a mixture of cyclohexyl)methyl]amino}phenyl) oxyl]amino}propionic acid ethyl acetate (195 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) and stirred at room temperature After 5 hours, it was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (800 # L) was added to 〇°c. Heading 321426 501 201029996 Standard compound (168 mg, 92%). HNMR (300 MHz, CDCl3) (5ppin 0.94-1.37 (m, 5H), 1.43 - 1.54 (in, 1H), 1.62-1.98 (m, 4H ), 2.03-2.14 (m, 1H), 2.26 (s, 3H), 2.57-2.67 (m, 2H), 3.54-3.70 (m, 2H), 4.42 (d, J=8.1 Hz, 1H), 6.51-6.65 (m, 3H), 7.39-7 44 (m, 1H), 7.45-7.56 (m, 3H), 7.74 (d, J=l. ] Hz, 1H). Example A99 3-{ [( 4-{[(5-Cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)fluorenyl]yl]amino}phenyl)benzyl](fluorenyl)amino}propyl acid

(1) 3-{[(4-{[(5-Cyano-3-indolyl-1-benzopyrano-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]( Methyl)amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (185 mg) was added to the compound of Example A98 (7) 4-{[(5-Cyano-3-methyl-1-benzonyridin-2-yl)(cyclohexyl)methyl]aminobenzoic acid (250 mg), 3-(methylamino) a mixture of ethyl propionate (127 mg), 1-hydroxybenzotriazole monohydrate (148 mg), triethylamine (269//L) and hydrazine, hydrazine-dimercaptocaramine (10 mL) 'And the mixture was stirred overnight at room temperature. In hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (193 mg, 60%) was obtained eluted elute *H NMR (300 MHz, CDCh) (5 ppm 0. 95-1. 38 (m, 8H), i.44_ 1.54 (m, 1H), 1.62-1.98 (m, 4H), 2.05-2.15 (m, iH) 2.27 (s, 3H), 2.55-2.66 (m, 2H), 3.00 (s, 3H), 3.7〇 (t, J=7. 1 Hz, 2H), 4.11 (q, J=7. 0 Hz , 2,,,,,, , 2H), 7.40-7.46 (m, 1H), 7. 48-® 7.54 (m, 1H), 7.76 (d, J=l. 5 Hz, IH). (2) 3-{[(4-{ [(5-Cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid

Add 1N aqueous lithium hydroxide solution (770 // L) to the above-mentioned synthesized 3 -{[(4 {[(5-lacyl-3-fyl-1-benzoxufu~2-yl)) a mixture of (cyclohexyl)methyl]aminophosphonium)carbonyl](methyl)amino}propionic acid ethyl ester (193 mg), tetrahydrofuran (5 mL) and ethanol (5 mL). 3 hours, and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (770 yL) was added. The resulting precipitate was collected by filtration to yield title compound (163 mg, 90%). HNMR (300 MHz, CDCh) ^ppm 〇.94-1.37 (m, 5H), 1.44 - 1.54 (m, IH), 1.62-1.98 (m, 4H), 2.04-2.15 (m, IH), 2.27 (s , 3H), 2.61-2.70 (in, 2H), 3.03 (s, 3H), 3.69 (t, J=6.5 Hz, 2H), 4.40 (d, J=7. 9 Hz, IH), 6.55 (d, J=8. 9 Hz, 2H), 7.24 (d, J=8. 9 Hz, 2H), 7.40-7.46 (m, IH), 7.48-7.53 (m, IH), 7.76 (d, J=l. l Hz, IH). 321426 503 201029996 Example A100 3-{[(4-{ [ 1-(5-Ga-3-indolyl-1-benzoheptan-2-yl)-3-indolyl) Amino}phenyl]carbonyl]amino}propionic acid

❺ (1) 1-(5-Chloro-3-methyl-1-benzohexan-2-yl)-3-methylbutan-1-ol 1.0 M brominated isobutylate at 0 ° C Magnesium tetrahydrofuran solution (1 mL. 3 mL) was added to a solution of 5-chloro-3-methyl-1-benzofuran-2-furaldehyde (1.00 g) in tetrahydrofuran synthesized in Example A88 (2) (20 (mL) and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (650 mg, 50%) was obtained. ❹!H NMR (300 MHz, CDCh) 5 ppm 0. 91-0. 98 (m, 6H), 1.53-1.70 (m, 1H), 1.71-1.97 (m, 3H), 2.22 (s, 3H), 4.89-4.98 (m, 1H), 7.19-7.23 (m, 1H), 7.31-7.35 (m, 1H), 7.43 (d, J=2.2 Hz, 1H). (2) 5-Chloro-2-(1) -Chloro-3-methylbutyl)-3-methyl-1-benzofuran Adding sulfurous chlorine (225 μL) to 1-(5-chloro-3-indolyl-1-) synthesized above Toluene solution (10 mL) of benzofuran-2-yl)-3-mercaptobutan-1-ol (650 mg) was stirred at 50 ° C for 2 hr. The reaction mixture 504 321426 201029996 was poured into an ice-cooled saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc EtOAc (EtOAc). Cd, J=2. 5 Hz, 3H), 0.95 (d, J=2.7 Hz, 3H), 1.58-1.74 (m, 1H), 2.06-2.21 (in, 2H), 2.23 (s, 3H), 5.17 (t, J=B. 〇Hz, 1H), 7.22-7.27 (m,1H), 7.34-7.38 (m, 1H), 7.44 (d,J=2·2 Hz' 1H). ® (3 4-{[l-(5-chloro-3-methyl-1-benzofuran-2-yl)_3-methylbutyl]amino}benzoic acid sodium carbonate (521 mg) was added to the above The synthesized 5-gas-2-(1-carb-3-mercaptobutyl)-3-mercapto-1-benzofuran (668 mg), 4-aminobenzoic acid vinegar (410 mg), broken A mixture of sodium (737 mg) and N,N-dimethylguanamine (1 mL) was stirred at 8 (TC) for 8 hours. 1N hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. (10.0 mL) added to A mixture of the obtained oil, tetrahydro-singing (10 mL) and ethanol (10 mL), and the mixture was stirred under reflux for 8 hrs and concentrated under reduced pressure. The residue was dissolved in water (20 mL) (: 1N Hydrochloric acid (10. 0 mL) was added. The obtained precipitate was collected by filtration to give the title compound ( 394 11 s, 43 « . . . H NMR (300 MHz, CDCh) d ppm 0.92 ( d, J=6. 6 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H), 1.47-1.65 (m, 1H), 1.87 (t, 505 321426 201029996 J=7.4 Hz, 2H), 2.27 ( s, 3H), 4.75 (t, J=7. 4 Hz, 1H)S 6. 58 (d, J=8. 7 Hz, 2H), 7.16-7.21 (m, 1H), 7.27-7.31 (in, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H). (4) 3-{[(4-{[l-(5-chloro-3-) Methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl-3-(3-dimethyl Aminopropyl)carboniferous diimine hydrochloride (139 mg) was added to the above-prepared 4-{[1-(5-chloro-3-methyl-1-benzo-furan-2-yl)- 3-methylbutyl]amino}benzoic acid (18 mg), cold-alanine ethyl ester hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (5). The mixture was stirred at room temperature for 2.5 days. The mixture was stirred at room temperature for 2. 5 days. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (196 mg, 86%) was obtained eluted elute !H NMR (300 MHz, CDCh) (5 ppm 0. 91 (d, J=6. 3 Hz, 3H), 1.00 (d, J=6.6Hz, 3H), 1.25 (t, J=7.11 Hz , 3H), 1.48- 1.64 (m, 1H), 1.85 (t, J=7. 3 Hz, 2H), 2.25 (s, 3H), 2.55-2.62 (m, 2H), 3.61-3.69 (m, 2H) ), 4.13 (q, J=7. 1 Hz, 2H), 4.30-4.39 (m, 1H), 4.65-4.76 (in, 1H), 6.53- 6.65 (m, 3H), 7.13-7.19 (m, 1H) ), 7.23-7.29 (in, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H). (5) 3-{[ (4-{[ 1-( 5-Chloro-3-methyl-1-benzo-Binding b-N-2-yl)-3-indole 506 321426 201029996 butyl butyl]amino}benyl)alkyl]amino}propionic acid 1N hydroxide A sodium aqueous solution (1.50 mL) was added to the above-mentioned 3 {[(4-{[1-(5-chloro-3-indolyl-1-benzofuran-2-yl)-3-methyl) a mixture of amino}phenyl)alkyl]amino}propionic acid ethyl acetate (196 mg), tetrahydronethane (5 mL) and ethanol (5 mL) and the mixture was stirred at room temperature for 2 hours and reduced Concentration by pressure. The residue was dissolved in water (10 mL) EtOAc (EtOAc (EtOAc) %). 5H NMR (300 MHz, CDCh) δ ppm 0. 91 (d, J=6. 8 Hz, 3H), 1.00 (d, J=6.4 Hz, 3H), 1.48-1.63 (m, 1H), 1.85 (t, J=7.5 Hz, 2H), 2.24 (s, 3H), 2.64 (t, J=5. 9 Hz, 2H), 3.60-3.69 (m, 2H), 4.70 (t, J=7.5 Hz, 1H), 6.57 (d, J=8. 7 Hz, 2H), 6.62 (t, J=6. 1 Hz, 1H), 7.14-7.19 (m, 1H), 7.24-7.29 (m, 1H), 7.38 (d, J=1.9Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H). q Example A101 3-{[(4-{[l-(5-Ga-3-indolyl-1_benzoxanf-2)') 3-methylbutyl]amino}phenyl)carbonyl](fluorenyl)amino}propionic acid

(1) 3-{[(4-{[1-(5-Chloro-3-methyl-1-benzophenanthrene. South_2_ 某)_3-甲321426 507 201029996 butyl]amino}}phenyl Carbonyl](fluorenyl)amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg) was added to Example A100 ( 3) 4-{[1-(5-Gas-3-methyl-1-benzofuran-2-yl)-3-mercaptobutyl]amino}benzoic acid (180 mg) synthesized, Ethyl 3-(methylamino)propionate (95. 2 mg), 1-phenylbenzotrisole monohydrate (111 mg), triethylamine (202 #L) and N,N-dimethyl 5小时。 The mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The title compound (199 mg, 85%) was obtained. !H NMR (300 MHz, CDCh) δ ppm 0. 91 (d, J=6. 6 Hz, 3H), 1.00 (d, J=6. 6 Hz, 3H), 1.23 (t, J=7.11) Hz, 3H), 1.49-1.64 (m, 1H), 1.84 (t, J=7. 3 Hz, 2H), 2.25 (s, 3H), 2.56-2.67 (m, 2H), 3.01 (s, 3H) , 3.70 (t, J=7.0 Hz, ❹ 2H), 4.06-4. 17 (m, 2H), 4.19-4.29 (m, 1H), 4· 63-4. 73 (m, 1H), 6.56 (d , J=8.5 Hz, 2H), 7.14-7.19 (m, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.25-7.29 (m, 1H), 7.38 (d, J=2. 2 Hz, 1H). (2) 3-{[(4-{[1-(5-Chloro-3-indolyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl Carbonyl](methyl)amino}propionic acid A 1N aqueous solution of sodium hydroxide (1.50 mL) was added to the above-prepared 3-{[(4-{[1-(5-chloro-3-methyl) -1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl) benzyl](methyl)amino}propionic acid 乙g(199 mg), tetrahydro ke 508 321426 A mixture of EtOAc (5 mL) and EtOAc (5 mL). The residue was dissolved in water UO mL) and dried. (: 1N Hydrochloric acid (1.50 mL) was added. The obtained precipitate was collected by filtration to afford the title compound ( 174 rog, 93%) as a white solid. H NMR (300 MHz, CDCh) &lt;5 ppm 0. 92 (d , J=6. 8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 1.48-1.64 (m, 1H), 1.85 (t, J=7.2 Hz, 2H), 2.25 Cs, 3H), 2.67 (t, 1=6.3 Hz, 2H), 3· 〇4 (s, 3H), 3. 71 (t, J=6. 3 Hz, 2H), 4. 69 (t, J=7. 6 Hz , 1H), 6.57 (d, J=8. 7 Hz, 2H), 7. 15-7.20 (m, 1H), 7.22-7.31 (m, 3H), 7.39 (d, J=1.9 Hz, 1H). Example A102 3-{[(4-{[(3-Bromo-5-methoxy-1-benzopyran-2-yl)(cyclohexyl)methyl]amino}phenyl)) Amino}propionic acid

(1) N,5-Dimethoxy-N-methyl-1-benzopyrene-2-carboxamide 2-Chloro-N-decyloxy-N-mercaptoacetamide (12. 1 g), oxidized sodium (24.0 g) and potassium carbonate (22.1 g) added to 2-carbyl-5-methoxybenzoic acid (10.0 g) of N,N-dimethylmethyl The guanamine solution (1 〇〇 mL) was stirred at 50 〇C overnight. The reaction mixture was cooled to room temperature and the insoluble matter was removed. 1,8-Diazabicyclo[5.4.0]undec-7-ene (9.82 mL) was added to 321426 509 201029996 and the mixture was stirred at 12 0 C for 2 hours. 1 n Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (9. 42 g, 61%) was obtained. H NMR (300 MHz, CDCla) δ ppm 3. 42 (s, 3H), 3. 83 (s, 3H), 3.85 (s, 3H), 7.01-7.06 (m, 1H), 7.07-7.09 (m, 1H), 7.43-7.45 (m, 1H), 7.46-7.51 (m, 1H). (2) 3-Bromo-N,5-dimethoxy-N-methyl-i-benzofuran-2- Indoleamine bromine (2.21 roL) was added dropwise to the above-prepared N,5-dimethoxy-N-methyl-1-benzofuran-2-indoleamine (9. 24 g) of acetic acid The solution (100 mL) was stirred overnight at room temperature. The resulting precipitate was collected by EtOAc (EtOAc m. H NMR (300 MHz, CDCh) δ ppm 3.43 (s, 3H), 3.85 (s, ❹ 3H), 3. 95 (s, 3H), 7. 09 (d, J=9. 0 Hz, 1H) , 7. 46-7. 54 (m, 2H). (3) 3-Bromo-5-decyloxy-1-benzon-propan-2-indoleic acid lithium aluminum hydride (241 mg) at 0 ° C Addition to the above-mentioned 3-bromo-N,5-dimethoxy-N-mercapto-1-benzofuran-2-ylamine (4. 〇〇g) in tetrahydrofuran (40 mL) And the mixture was stirred for 1 hour. Hydrogenation (241 mg) was additionally added, and the mixture was stirred for 1 hour. 1N hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (880 mg, 27%) was obtained eluted eluting eluting eluting eluting 'H NMR (300 MHz, CDCh) δ ppm 3.96 (s, 3H), 7.17 (d, J-9. 1 Hz, 1H), 7.48-7.53 (m, 1H), 7.55-7.56 (m, 1H), 9.M (5,5H5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanol at -78 ° C 1. 0M cyclohexane magnesium bromide To a tetrahydrofuran solution (50 mL) of the above-prepared 3-bromo-5-decyloxy-1-benzofuran-2-carbazide (2.26 g), The mixture was stirred at -78 ° C for 30 minutes' and then stirred at QC for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of chloroform, and the residue was evaporated and evaporated to ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (1.82 g, 67%). JH NMR (300 MHz, CDCh) δ ppm 0. 99-1. 37 (m, 5H), 1.49- q 1.60 (in, 1H), 1.62-2.02 (m, 6H), 3.93 (s, 3H), 4.53 (t, J=6.0 Hz, 1H), 6.63 (s, 1H), 6.89 (d, J=8. 8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H). (5) 3-bromo -2-[Chloro(cyclohexyl)methyl]-5-methoxybenzofuran chelate sulfite chloride (469 /z L) was added to the above synthesized (3-di-5-methoxy- 5小时。 The mixture of 1-benzofuran-2-yl) (cyclohexyl) decyl alcohol (1·82 g) in benzene (20 mL) and the mixture was stirred at 100 ° C for 1.5 hours. The reaction mixture was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc EtOAc EtOAc EtOAc. ]H NMR (300 MHz, CDCh) ^ ppm 0. 98-1. 39 (m, 5H), 1.5i_ 1.87 Cm, 4H), 2.03-2.21 (m, 2H), 3.92 (s, 3H), 4.74 ( d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H). (6) 4-{ [(3 -Min-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}benzoic acid

❹ Add sodium carbonate (1.03 g) to the above-prepared 3-bromo-2-[chloro(cyclohexyl)methyl]-5-methoxy-1-benzopyrene (1.73 g), 4 a mixture of methyl aminobenzoate (878 mg), moth (1.45 g) and N,N-dimethylformamide (30 mL) and the mixture was stirred at 80 ° C for 8 hours. The reaction was stopped by the addition of 1 N hydrochloric acid and the mixture was taken up in ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc (EtOAc:EtOAc) A 1N aqueous solution of sodium hydroxide (10.0 mL) was added to a mixture of the obtained oil, tetrahydrofuran (1 mL) and ethanol (10 mL) and the mixture was heated under reflux.

Time and concentrate under reduced pressure. The residue was dissolved in water (10 mL mL) and 1N hydrochloric acid (10.0 mL) was then applied. The obtained precipitate was collected to give the title compound (318 mg &gt;14%;) as pale brown solid.

Ppm 1. 04-1. 37 (m, 5H), 1. 55-(m, 2H), 3.90 (s, 3H), 4.44 (s, 1H), 6. 61 (d, J=8.9 Hz, iH ), 7.29-7.35 (m, 1H), 7.87 NMR (300 MHz, CDCh) 5 1.86 (m, 4H), 1.87-2.02 (d, &gt;6.6 Hz, 1H), 6.56 2H), 6.87 (d, J =9. 0 Hz, (d, J=8.9 Hz, 2H). 321426 512 201029996 (7) 3-{[(4-{[(3-bromo-5-decyloxy-1-benzofuran-2) -yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride Salt (78. 6 mg) was added to the above-prepared 4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg), stone-alanine ethyl ester hydrochloride (63.0 mg), 1-hydroxybenzotriazole monohydrate (62.9 mg), triethylamine (iMeL) and N,N-dimethyl Mixture of guanamine (1 mL) and stir the mixture overnight at room temperature. Add 1N hydrochloric acid to terminate the reaction and extract the mixture with ethyl acetate. Wash the extract with saturated aqueous sodium hydrogencarbonate and saturated brine. Dry and concentrated under reduced pressure. Purified by column chromatography (50% ethyl acetate / hexane) The title compound (134 mg, 88%) was obtained as a pale yellow oil..H NMR (300 MHz, CDCla) 5 ppm 1.03-1. 37 (m, 8H), 1.54-1.85 (m, 4H), 1.87-1.99 (m, 2H), 2.56-2.61 (in, 2H), 3.62-3.70 (m, 2H), 3.90 (s, 3H), 4.14 (q, J=7. 1 Hz, ❾ 2H ), 4.36-4.41 (m, 2H), 6. 53 (d, J=0. 8 Hz, 1H), 6.56- 6.64 (m, 3H), 6. 86 (d, J=8. 8 Hz, 1H ), 7.29 (dd, J=8. 8, 0.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H). (8) 3-{[(4-{[(3-bromo-5-曱) Oxy-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)alkyl]amino}propionic acid To a solution of 1N aqueous sodium hydroxide (1. 〇〇mL) Synthesis of 3-{[(4-{[(3-bromo-5-decyloxy-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino]}phenyl]amino]amine A mixture of ethyl propionate (134 mg), tetrahydrofuran (5 mL) and EtOAc (5 mL). The residue was dissolved in water (10 mL) and EtOAc (1. 00 mL). The resulting precipitate was collected by filtration to afford title compound (116 mg, 91%). H NMR (300 MHz, CDCh) s ppm 1. 02-1. 35 (m, 5H), 1.53-1.84 (m, 4H), 1.84-1.99 (in, 2H), 2.61 (t, J=5. 7 Hz, 2H), 3.59-3.68 (m, 2H), 3.89 (s, 3H), 4.38 (d, J=6.4 Hz, 1H), 6.52-6. 66 Cm, 4H), 6.85 (d, J=8 9 Hz, 1H), 7-30 (dd, J=8.9, 0.8 Hz, 1H), 7. 54 (d, J=8. 7 Hz, 2H). 0 Example A103 3-{[(4- {[(3-Bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid

❹(〇3-{[(4-{[(3-Bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)decyl]amino}phenyl) thiol]( Ethyl)amino}ethyl propionate 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (78. 6 mg) was added to Example A102 (6) 4-{[(3-Bromo-5-decyloxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg), 3-(A) Amino acid) propionate B g (53.8 rag), 1-p-benzobenzotrisole monohydrate (62.9 mg), triethylamine (114//L) and N,N-dimercapto A mixture of decylamine (10 mL) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with EtOAc EtOAc (EtOAc) The title compound (124 mg, 79%) was obtained from EtOAc (EtOAc) MHz, CDCh) &lt;5 ppm 1. 04-1. 36 (m, 8H), 1.55-1.85 (m, 4H), 1.86-2.00 (m, 2H), 2.62 (t, J=7. 0 Hz, 2H), 3.02 (s, 3H), 3. 72 (t, J=7.0 Hz, 2H), 3.91 (s, 3H), 4. 12(q, J=T. 1 Hz, 2H), 4.24-4.41 (m, 2H), 6.54- 6.55 (ra, 1H), 6.58 (d, J=8. 8 Hz, 2H), 6.86 (d, J=8. 8 ❹ Hz, 1H), 7. 24 (d, J=8. 8 Hz, 2H), 7. 30 (dd, J=8.8, 0.8

Hz, 1H). (2) 3-{[(4-{[(3-Bromo-5-methoxy-1_benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl Carbonyl](fluorenyl)amino}propionic acid A 1N aqueous solution of sodium oxide (iQ〇mL) was added to the above-prepared 3-{[(4-{[(3-bromo-5-decyloxy-1) -benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate (124 mg), tetrahydrofuran (5 mL) and A mixture of ethanol (5 inL) and the mixture was stirred at room temperature for 2 hr. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in ethanol (5 <RTI ID=0.0></RTI> </RTI> <RTIgt; The residue was dissolved in water (5 mL) and EtOAc (EtOAc (EtOAc). (300 MHZ, CDC13) 5 pprol.03—uea, 5H), 153_ 321426 515 201029996 1.84 (m, 4H), 1.85-2.00 (m, 2H), 2.62-2.75 (m, 2H), 3.05 (s, 3H ), 3.70 (t, J=6. 2 Hz, 2H), 3.90 (s, 3H), 4.37 (d, J=6.4 Hz, 1H), 6.55 (s, 1H), 6.58 (d, J=8. 7 Hz, 2H), 6.87 (d, J=8.9 Hz, 1H), 7.22-7.35 (m, 3H). Example A104 3-{[(4-{[2-ethyl-1-(5-A) Oxy-3-indolyl-1-benzocylan-2-yl)butyl]amino}phenyl)carbonyl]amino}propionic acid

(1) (2-Ethyl-4-methoxyphenoxy)acetic acid Potassium carbonate (31.1 g) was added to 1-(2-hydroxy-5-methoxyphenyl)ethanone (25. 0 g), a mixture of bromoacetate (15.5 mL) and N,N-dimercaptocaramine (250 mL), and the mixture was stirred at room temperature overnight. The insoluble material was filtered off, 1N hydrochloric acid was added to filtrate, and mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated A 1N aqueous solution of sodium sulphate (300 mL) was added to a mixture of EtOAc, EtOAc (EtOAc). In HCl (3 〇〇 mL) was added to EtOAc (3 mL). H NMR (300 MHz, CDCh) δ ppm 2.67 (s, 3H), 3.83 (s hc-o 321426 516 201029996 3H), 4.72 (s, 2H), 6.92 (d, J=9. 0 Hz, 1H), 7.04-7.09 Cm, 1H), 7. 29 (d, J=3. 0 Hz, 1H). (2) 5-decyloxy-3-methyl-1-benzofuran stirred at 110 ° C A mixture of (2-acetamido-4-nonyloxyphenoxy)acetic acid (10.0 g), acetic acid needle (1. 3 g) and acetic acid (1 mL) was mixed for 5 hours. The mixture was extracted into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over EtOAc and evaporated. The title compound (5.87 g, 81%) was obtained eluted eluted eluted eluted eluted eluted NMR (300 MHz, CDCls) δ ppm 2.21 (d, J=l. 1 Hz, 3H), 3.86 (s, 3H), 6.85-6.91 (m, 1H), 6.95 (d, J=2.7 Hz, 1H) , 7.33 (d, J=8.8 Hz, 1H), 7.35-7.39 (m, 1H). (3) 2-Ethyl-1-(5-decyloxy-3-mercapto-1-benzoate) -2-yl) butyl-1 - oxime added aluminum hydride (3.28 g) to the above-prepared 5-methoxy-3-methyl-2-ylbenzofuran (2 00 g), 2- 5小时。 The mixture of a mixture of butyl sulfonium (1. 85 mL) and nitro decane (30 mL), and the mixture was stirred at room temperature for 1.5 hours. Water was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (3.12 g, 97 «. 'H NMR (300 MHz, CDCls) δ ppm was obtained as a pale yellow oil. 0. 86-0. 95 (m, 6H), 1.52-1.66 (m, 2H), 1.72-1.88 (m, 2H), 2.59 (s, 3H), 3.29-3.41 (m, 1H), 3.88 (s , 3H), 7.00-7.02 (m, 1H), 7.06- 517 321426 201029996 7.11 (m, 1H), 7.37-7.42 (m, 1H). (4) 4-{[2-ethyl-1-(5 -曱oxy_3_fluorenyl-1_benzofuran-2-yl)butyl]amino}benzoic acid methyl ester Titanium (IV) chloride (4〇4//L) was added to the above synthesized 2-Ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl-butanone (8 mg), 4-aminobenzoic acid decyl ester a mixture of (464 mg), triethylamine (3.43 mL) and dichloromethane (10 mL), and the mixture was stirred overnight at room temperature under argon. The residue was extracted with ethyl acetate and the residue was evaporated to ethyl acetate. EtOAc (EtOAc) Cyanide sodium hydride (386 mg) To the resulting oil solution of tetrahydro-thiopyran squeak (2 0 mL) 'at room temperature and the mixture was granted fell 1. 5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (718 mg, 59%) was obtained. !H NMR (300 MHz, CDCh) 5 ppm 0.85 (t, J=7. 4 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H), 1.14-1.74 (m, 4H), 1.81- 1.95 (m, 1H), 2.23 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 4.47-4.53 (m, 1H), 4.59 (t, J=8. 1 Hz, 1H) , 6.56 (d, J=8. 8 Hz, 2H), 6. 81 (dd, J=8. 8, 2. 6 Hz, 1H), 6. 86 (d, J=2. 6 Hz, 1H) , 7. 24 (d, J=8. 8 Hz, 1H), 7. 79 (d, J=8. 8 Hz, 2H). (5) 4-{[2-ethyl-l-(5_曱oxy-3-methyl-1-benzo-n-pentan-2-yl) 321426 518 201029996 butyl]amino}benzoic acid A 1N aqueous solution of sodium hydroxide (5. 〇〇mL) was added to the above Synthesis of 4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoic acid methyl ester (718 mg) A mixture of tetrahydrofuran (5 mL) and EtOAc (5 mL). The residue was dissolved in water (10 mL) and 1N hydrochloric acid (5. The resulting precipitate was collected by filtration to afford title compound (574 mg, 83%). 6 H NMR (300 MHz, CDCls) &lt;5 ppm 0.85 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H), 1.16-1.74 (m, 4H), 1.82- 1.95 (in, 1H), 2.24(s, 3H), 3. 83 (s, 3H), 4. 54-4. 66 (m, 2H), 6.58 (d, J=8. 8 Hz, 2H), 6.83 (dd, J=8. 8, 2. 6 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.8 Hz , 2H). (6) 3-{[(4-{[2-Ethyl-1-(5-decyloxy-3-indolyl-1-benzofuran-2-yl)butyl]amine Ethyl}phenyl)carbonyl]amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg) was added to the above synthesized 4-{[2-ethyl-1-(5-methoxy-3-indolyl-1-benzofuran-2-yl)butyl]amino}benzoic acid (250 mg), y5-propylamine Acid ethyl ester hydrochloride (151 mg), 1-hydroxybenzotriazole monohydrate (151 mg), triethylamine (275/zL) and N,N-dimethylformamide (10 mL) The mixture was stirred at room temperature for 1 day. IN hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (85.0 mg, 27%) was obtained eluted elute NMR (300 MHz, CDC13) 5 ppm 0. 87 (t, J=?.4 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), i .3〇- 1.74 (m, 4H), 1.81-1.93 (in, 1H), 2.23 (s, 3H), 2.54-2.62 (ra, 2H), 3.65 (q, J=6. 1 Hz, 2H), 3.83 (s, 3H), 4. 13 (q, J=7. 1 Hz, 2H), 4.40 (d, J=8. 8 Hz, 1H), 4.52-4.60 (m, 1H), 6.53-6.62 (m , 3H), 6.78-6.84 (m, 1H), 〇6.86 (d, J=2.7 Hz, 1H), 7.22 (s, 1H), 7.54 (d, J=8.8 Hz, 2H). (7) 3- {[(4-{[2-ethyl-1-(5-decyloxy-3-indolyl-l-benzo-n-n-n-2-yl)butyl]amino}phenyl)carbonyl]amine A solution of 1 N sodium hydroxide (1. 〇〇mL) was added to the above-prepared 3-{[(4-{[2-ethyl-1-(5-methoxy-3-indolyl) group). -1-benzofuran-2-yl)butyl]amino}benzyl)amino}propionic acid ethyl ethoxylate (85.0 mg), tetraterpene quinone (5 mL) and ethanol (5 mL) The mixture was stirred at room temperature for 2 hours' and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1. The resulting precipitate was collected by filtration to afford title compound (75. 4 mg, 94%). ]H NMR (300 MHz, CDCh) δ ppm 0.84 (t, J=7.3 Hz, 3H), 0. 94 (t, J=7.3 Hz, 3H), 1. 14-1. 72 (m , 4,,,,, 4.57 (d, J=7. 7 Hz, 1H), 6. 52-6. 62 (m, 3H), 6.81 (dd, J=8. 9, 2. 5 Hz, 1H), 6.86 321426 520 201029996 ( d, J = 2. 5 Ηζ, 1 Η), 7·24 (d, J = 8.9 Hz, 1H), 7. 52 (d, J = 8.9 Hz, 2H). Example A105 3-{[( 4-{[2-ethyl-1-(5-methoxy-3-indolyl-1-benzocyano-2-yl)butyl]amino}phenyl)carbonyl](indenyl)amine Propionate

(1) 3-{[(4-{[2-ethyl-1-(5-methoxy-3-indolyl-1-benzoxantan-2-yl)butyl]amino}benzene Ethyl carbonyl](fluorenyl)amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg) was added to Example A104C5 Synthesis of 4-{[2-ethyl-1-(5-decyloxy-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoic acid (250 mg), 3-(decylamino)propionic acid ethyl ester (129 mg), 1-p-benzotrisamine monohydrate (Ιδί mg), triethylamine (275 μL) and hydrazine, hydrazine-dimethylformamidine A mixture of amines (1 mL) and the mixture was stirred at room temperature for 1 day. In hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (261 mg, 81 ° /.) was obtained eluted eluted elute H NMR (300 MHz, CDCh) (5 ppm 0.85 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7. 4 Hz, 3H), 1.23 (t, J = 7. 1 Hz, 3H ), 1.29- 521 321426 201029996 1.73 (m, 4H), 1.79-1.93 (m, 1H), 2.22 (s, 3H), 2.61 (t, J=7. 1 Hz, 2H), 3.01 (s, 3H) , 3.70 (t, J=7. 1 Hz, 2H), 3.83 (s, 3H), 4.11 (q, J=7. 1 Hz, 2H), 4.28 (d, J=8. 5 Hz, 1H), 4.50-4.58 (m, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6.79-6.83 (in, 1H), 6.86 (d, J=2.5 Hz, 1H), 7.20 (d, J= 8.7 Hz, 2H), 7.24 (d, J=8.8 Hz, 1H). (2) 3-{[(4-{[2-ethyl-1-(5-decyloxy-3-mercapto-1) -benzofuran-2-yl)butyl]amino phenyl)carbonyl](methyl)amino}propionic acid A 1N aqueous sodium hydroxide solution (1. 〇〇mL) was added to the above-mentioned synthesis 3 - {[(4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}phenyl))] a mixture of methyl)amino}propionic acid ethyl ester (261 mg), tetrahydronethane (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Dissolve in water 〇〇mL) and add 1N hydrochloric acid (1. 〇〇mL). The resulting precipitate was collected by filtration to give the title compound (231 mg, 94%). ❹NMR (300 MHz, CDCI3) 5 ppm 0·85 (t, J=7. 3 Hz 3H) 0.94 (t, J=7.4Hz, 3H), 1.15-1.73 (m, 4H), 1.80-1.93 (in, 1H), 2.23 (s, 3H), 2.65 (t, J=6.6 Hz, 2H) 3 03 (s, 3H), 3. 69 (t, J=6. 6 Hz, 2H), 3. 83 (s , 3H) 4.55 (d, ]=1. 7 Hz, 1H), 6. 56 (d, J=8. 9 Hz, 2H), 6. 82 (dd, J-8. 8, 2. 4 Hz, 1H), 6. 87 (d, J=2.4 Hz, 1H), 7 20_7 28 (m, 3H). Example A106 3-[({4-[(1-{5-chloro-1-[ 3-(trifluoromethyl)phenyl]_11][_0丨11丨_2_基} 321426 522 201029996 heptyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 5-Chloro-N-decyloxy-N-mercapto-1H-indole-2-carboxamide hydrazine 1-ethyl-3-(3-didecylaminopropyl) carbon Imino hydrochloride (Π. 6 g) was added to 5-chloro-1H-indole-2-carboxylic acid (15.0 g), N,0-dimercaptohydroxylamine hydrochloride (8. 97 g a mixture of 1-hydroxybenzotriazole monohydrate (14.1 g), triethylamine (25·6 mL) and N,N-dimethylguanamine (200 mL) and stirred at room temperature The mixture was overnight. The reaction was quenched by the addition of 1N EtOAc (EtOAc). © H NMK (300 MHz, CDCh) δ ppm 3.43 (s, 3H), 3.85 (s, 3H), 7. 14-7. 18 (m, 1H), 7.25 (dd, J=8. 7, 1. 9 Hz, 1H), 7-36 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 9.32 (br s,1H). (2) 1-(5-chloro- 1H-indol-2-yl)heptan-l-one was added to a solution of 2. 3M hexyllithium in hexane (5 〇. 〇 mL) to the above-obtained 5-chloro-N-decyloxy group at -78C. A solution of N-mercapto-1H-indole-2-amine (9.14 g) in tetrahydrofuran (100 mL) and mixture was stirred under nitrogen for 15 hr. A 2.3 M hexyllithium hexane solution (38 3 mL) was additionally added, and the mixture was stirred at _78 321426 523 201029996 ° C for 2 hours. IN hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was washed with EtOAc (mjjjjj: NMR NMR (300 MHz, CDCh) δ ppm 0. 86-0. 95 (m, 3H), 1.26-1.48 (in, 6H), 1.71-1.85 (ni, 2H), 2.92 (t, J=7. 7 Hz, 2H), 7.11-7.14 (m, 1H), 7. 29 (dd, J=8. 8, 1.9 Hz, 1H), 7. 36 (d, J=8. 8 Hz, 1H), 7. 66-7. 70 (m, 1H), 9.05-9.19 ® (in, 1H). (3) l-{5-Chloro-l-[3-(trifluoromethyl)phenyl]-1H-indole -2-yl}heptan-1-one 1-(5-chloro-1H-indol-2-yl)heptan-1-one (9.14 g), 3-indoletrifluorobenzene a mixture of (3-iodobenzotrif luoride) (1.77 mL), copper (1) bromide (327 mg), potassium carbonate (2.36 g) and N-methyl-2-pyrrolidone (30 mL), The mixture was stirred under argon at 180 ° C for 1 day. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (0.78 g, 17%). NMR NMR (300 MHz, CDCh) δ ppm 0. 84-0. 92 (m, 3H), 1.22-1.41 (m, 6H), 1.62-1.74 (m, 2H), 2.90-2.97 (m, 2H), 6.95 (d, J=8.8Hz, 1H), 7.25 (dd, J=8. 8, 1.9 Hz, 1H), 7.35 (s, 1H), 7.42-7.47 (m, 1H), 7.49-7.53 (m, 1H), 7.59-7.66 (m, 1H), 7.69-7.74 (m, 2H). 524 321426 201029996 (4) 4-[(l-{5-Gas-l-[3-(Trifluoromethyl)benzene) Methyl]-1H-indol-2-yl}heptyl)amino]benzoic acid methyl ester The titanium (IV) gas (229/iL) is added to the above-mentioned 1-{5-gas-1- [3-(Tri-|indolyl)phenyl]-111-indole-2-yl}heptan-1-one (709 11^), 4-aminobenzoic acid decyl ester (263 mg), three A mixture of ethylamine (1. 94 mL) and dichloromethane (10 mL) was stirred at room temperature under argon overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with aq. 5小时。 The acetic acid (498 / / L) and sodium cyanoborohydride (219 mg) was added to the resulting oil in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1.5 hours. Saturated sodium carbonate aqueous solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (645 mg, 68%) was obtained eluted elute ❹ $ NMR (300 MHz, CDC13) (5 ppm 0. 84 (t, J=6.9 Hz, 3H), 1.12-1.41 (m, 8H), 1.74-1.93 (m, 2H), 3.83 (s, 3H), 4.03-4.15 (m, 1H), 4.41-4.52 (m, 1H), 6.33 (d, J=8.8 Hz, 2H), 6.57 (s, 1H), 6.88 (d, J=8. 8 Hz , 1H), 7.09 (dd, J=8.8, 1.9 Hz, 1H), 7.45-7.52 (m, 1H), 7.54-7.65 Cm, 3H), 7.68-7.79 (m, 3H). (5) 4-[ (l-{5-Gas-l-[3-(Trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoic acid 1N aqueous sodium hydroxide solution (5. 〇 〇mL) is added to the above synthesized 4-525 321426 201029996 [(l-{5-chloro-l-[3-(trifluoromethyl)phenyl]~iH-indole-2-ylheptyl) A mixture of benzyl benzoate (645 mg), tetrahydrofuran (5), and ethanol (5 mL) was evaporated. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (5. The obtained precipitate was collected by filtration to give the title compound (589 mg, 94%). Η NMR (300 MHz, CDCh) δ ppm 0. 80 (t, J=6. 8 Hz, 3H) 1.03-1.34 (m, 6H), 1.63-1.83 (m, 2H), 4.29-4.44 (m, 1H), 6.18 (d, J=8.3 Hz, 2H), 6.49 (s, 1H), 6.82 (d, J=8. 5 Hz, 1H), 7.02 (dd, J=8. 5, 1.9 Hz, 1H ), 7.34-7.56 (m, 4H), 7.60 (d, J=7. 6 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H). (6) 3-[({4-[(l -{5-chloro-l-[3-(trifluoromethyl)phenyl]-in-fluorenyl-2-yl}heptyl)amino]phenyl}alkyl)amino]propionic acid 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride ❹ (136 mg) was added to the above-mentioned 4-[(1-{5-gas-1-[ 3-(Trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoic acid (250 mg), ethyl lysine hydrochloride (1〇9 mg) a mixture of 1-p-benzobenzotrisole monohydrate (109 mg), triethylamine (i98yL) and N,N-dimethylformamide (1 〇 rainbow) and the mixture was stirred at room temperature 3 day. IN hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (272 mg, 92%) was obtained eluted elute 526 321426 201029996 JH NMR (300 MHz, CDCh) δ ppm 0. 83 (t, J=6. 7 Hz, dH), 1. 11-1. 39 (m, 11H), 1. 75-1. 90 ( m, 2H), 2. 60 (tic Hz, 2H), 3.63-3.72 (m, 2H), 3.93-4.04 (m, 1H), 4 ^ (q, &gt;7.1 Hz, 2H), 4.38-4.50 ( m, 1H), 6.35 (d τ 〇, , J^. 5

Hz, 2H), 6.53-6.64 (m, 2H), 6.87 (d, J 8.6 Hz, lH) 7. 08 (dd, J=8.6, 2. 1 Hz, 1H), 7. 45-7.66 (m ,6H) 7 A 7〇(d, J=7. 1 Hz, 1H). (7) 3-[({4-[(l-{5-Chloro-1-[3-(trifluoromethyl)) Phenyl®-2-ylindenyl)amino]phenyl}carbonyl)amino]propionic acid $ 1N aqueous sodium hydroxide solution (5. 〇〇mL) was added to the above synthesized 3 [({4- [(1-{5-Chloro-1-[3-(trifluoromethyl)phenyl]-1H-indole, 2~yl}heptyl)1N-yl]]yl}amino)amino]propyl A mixture of ethyl acetate (273 mg), tetrahydrofuran (5 mL) and EtOAc (5 mL). The residue was dissolved in water (1 mL) and 1N hydrochloric acid (5·00 mL) was added. The obtained precipitate was collected by filtration to give the title compound (253 mg, 97%). JH NMR (300 MHz, CDCh) &lt;5 ppm 0.78 (t, J=6. 8 Hz, 3H), 1.01-1.32 (m, 8H), 1.64-1.78 (m, 2H), 2.30-2.43 (ra, 2H), 3.37-3.53 (m, 2H), 4.29-4.43 (m, 1H), 6.27 (d, J=8.7 Hz, 2H), 6.47 (s, 1H), 6.76-6.89 (m, 2H), 7.00 (dd, J=8. 7, 1.9 Hz, 1H), 7.39-7.59 (in, 6H), 7.63 (d, J=7. 6 Hz, 1H). Example A107 3-[({4-[( L-{5-Chloro-l-[3-(trifluoromethyl)phenyl]-1H_吲哚2-yl} 527 321426 201029996 heptyl)amino]phenyl}carbonyl)(methyl)amine Propionate

❹ (1) 3-[ ({4-[ (1-{5-Gas-1-[3-(tris-methyl)phenyl]-indole- sulphate-2-yl}heptyl)amine Ethyl]phenyl}carbonyl)(indenyl)amino]propionic acid ethyl ester 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (13611^) is added to Example 4-[(1-{5-Chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino) synthesized by human 106(5) Benzoic acid (250 mg), ethyl 3-(decylamino)propionate (93.1 mg), 1-p-benzotris-sodium monohydrate (109 mg), triethylamine (198) A mixture of #L) and N,N-dimercaptocaramine (10 mL) was stirred at room temperature for 3 days. 1N Hydrochloric acid hydrazine was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (254 mg, 84%) was obtained eluted elute NMR (300 MHz, CDCh) δ ppm 0. 83 (t, J=6.9 Hz, 3H), 1.11-1. 37 (m, 11H), 1.76-1.86 (m, 2H), 2. 62 (t , J=7. 3 Hz, 2H), 3.02 (s, 3H), 3.72 (t, J=7. 3 Hz, 2H), 3.88 (d, J=7.7 Hz, 1H), 4.07-4.17 (m, 2H), 4.35-4.46 (m, 1H), 6.34 (d, J=8.5 Hz, 2H), 6.56 (s, 1H), 6.88 (d, 528 321426 201029996 J=8. 8 Hz, 1H), 7.08 ( Dd, J=8. 8, 2.0 Hz, 1H), 7. 17 (d, J=8. 5 Hz, 2H), 7.51 (d, J=7. 7 Hz, 1H), 7.56 (d, J= 2. 0 Hz, 1H), 7.57-7.66 (m, 2H), 7.71 (d, J=7. 7 Hz, 1H). (2) 3-[({4-[(l-{5-chloro-) [3-(Trifluoromethyl)phenyl]-iH-indol-2-yl}heptyl)amino]phenyl phenylcarbonyl)(fluorenyl)amino]propionic acid 1N aqueous sodium hydroxide solution ( 1. Q〇mL) is added to the above-mentioned 3-[({4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H_吲哚_2_) a mixture of ethyl (heptyl)amino]phenylphosphonium carbonyl)(indenyl)amino]propionic acid ethyl ester (254 mg), tetrahydrofuran (5 mL) and ethanol (5 mL). And concentrated under reduced pressure. The residue was dissolved in water (丨 0 mL) and 1N hydrochloric acid (1· 〇〇 mL) was added to 〇〇c. The obtained precipitate was collected by filtration to yield title compound (223 mg, 92%). !H NMR (300 MHz, CDCh) (5 ppm 0.81 (t, J=6. 8 Hz, 3H) 1.06-1.35 (ro, 8H), 1. 70-1.82 (m, 2H), 2.39-2.49 (m , 2H), 2.92 (s, 3H), 3.51-3.72 (m, 2H), 4.38 (t, J=6.8 ❹ Hz, 1H), 6. 32 (d, J=8.5 Hz, 2H), 6. 53 (s, 1H), 6 86 (d, J-8. 7 Hz, 1H), 7. 05 (dd, J=8. 7,1 Hz, ih) 7 14 (d, J=8. 5 Hz, 2H), 7.47-7.55 (m, 2H), 7.55~7.67 (m, 2H), 7.70 (d, J=7.6 Hz, 1H). Example A108 3-{[(4-{[(3- Cyano-5-methoxy-1-benzo-cough-2~yl)(cyclohexyl) fluorenyl]amino}phenyl)carbonyl]amino}propionic acid 321426 529 201029996

J^jj^ 9 c〇2,h h3c-〇(1) (3-bromo-5-decyloxy-1-benzofuran-2-yl)(cyclohexyl)fluorenone at -78 ° C A mixture of fluoroacetic acid needle (1. 63 mL) was added to a mixture of dimercapite (831 mL) and tetrahydrofuran (20 mL), and the mixture was stirred for 30 minutes, and synthesized by the addition of Example A102 (4) (3- A solution of bromo-5-decyloxy-1-benzofuranol-2-yl)(cyclohexyl)methanol (2.03 g) in tetrahydrofuran (20 mL). The reaction mixture was stirred under argon at -78 °C for 1 hour, triethylamine (3.33 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced EtOAc. mjjjjjjjj !H NMR (300 MHz, CDCh) δ ppm 1. 20-1. 63 (m, 5H), 1.70-1. 81 (m, 1H), 1.82-2. 00 (m, 4H), 3. 13- 3. 24 (m, 1H), Lu 3.95 (s, 3H), 7. 12 (d, J=9. 3 Hz, 1H), 7. 46-7. 50 (m, 2H). (2 4-{[(3-)-5-decyloxy-1-benzoa-f-yl-2-yl)(cyclohexyl)indolyl]amino fluorenyl phthalate will be titanium (IV) chloride (593/z L) was added to the above-prepared (3-bromo-5-decyloxy-1-benzofuran-2-yl)(cyclohexyl)methanone (1.52 g), 4-aminophenylhydrazine A mixture of decyl acetate (682 mg), triethylamine (5.03 mL) and dioxane (20 mL) was stirred at room temperature under argon overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate to 530 321426 201029996. The extract was washed with saturated brine. Acetic acid (1. 29 mL) and sodium cyanoborohydride (567 mg) were added to a solution (20 mL) of EtOAc. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and tetrahydro D-propanol was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ❹1H NMR (300 MHz, CDC13) (5 ppm 1. 03-1. 38 (m, 5H), 1 54- 1.85 (ra, 4H), 1.85-2.01 (m, 2H), 3.82 (s, 3H), 3 9〇(s' 3H), 4.36-4.56 (m, 2H), 6.54 (s, 1H), 6 58 (d, J=9.0Hz, 2H), 6.86 (d, J=8· 8 Hz, 1H ), 7.30 (d, J=8 8

Hz, 1H), 7. 81 (d, J=9. 0 Hz, 2H). · (3) 4-{[(3-Cyano-5-decyloxy-1-benzofuran-2-yl) (cyclohexylmethyl)amino}benzoic acid lanthanum 肆 (triphenylphosphine) palladium (0) (357 mg) is added to the above-mentioned tetramethyl) (cyclohexyl); A mixture of this decyl ester (1.46 g), zinc cyanide (362 mg) and ν fm-methylmethylamine (30 mL), and degassed, under argon, 8. One by one 搅拌 搅拌 搅拌 stirring the temperature eight things overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue was purified by column chromatography (4% ethyl acetate / hexanes) eluting with hydrazine: A 1 N aqueous solution of hydrogen chloride (2.88 fflI) was added to a solution of (tetra)hydrofuran (10 mL), and the mixture was stirred and stirred under reflux overnight. 321426 531 201029996 ethanol (10 mL) and water (10 mL) were added to the reaction mixture, and The mixture was stirred and heated under reflux for 3 hr. EtOAc (EtOAc m. 1N Hydrochloric acid (4.35 mL) was added. , 5H), 1.53-1.87 (m, 4H), 1.87-2.01 (in, 2H), 3.94 (s, 3H), 4.42-® 4.60 (m, 2H), 6.58 (d, J=8. 8 Hz, 2H), 6.68 (d, J=0. 8 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 7.53 (dd, J=9. 1, 0.8 Hz, 1H), 7. 87 (d, J=8.8 Hz, 2H). (4) 3-{[(4-{[(3-Cyano-5-fluorenyl-1-benzofuran-2-yl)(cyclohexyl) T-amino]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg) was added to 4- of the above synthesis {[(3-Cyano-5-methoxy-1-benzoxan-2-yl)(cyclohexyl)indenyl]amino}benzoic acid (240 mg), /3-alanine ethyl S Hydrate (137 mg), 1-benzopyranotriene monohydrate (136 mg), triethylamine (248//L) and N,N-dimethylformamide (10 mL) The mixture was stirred at room temperature overnight. The mixture was stirred with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut elut elut , 8H), 1_53- 532 321426 201029996 1.86 (m, 4H), 1.86-2.00 (m, 2H), 2.59 (t, J = 6.3 Hz, 2H), 3.62-3.70 (m, 2H), 3.93 (s, 3H), 4.14 (q, J=7. 1 Hz, 2H), 4.35-4.45 (m, 2H), 6.57 (d, J=8. 8 Hz, 2H), 6.60 (t, J=5.2 Hz, 1H ), 6.65 (d, J = 0.5 Hz, 1H), 6.83 (d, J = 9. 1 Hz, 1H), 7.51-7.60 (m, 3H). (5) 3-{[(4-{ [(3-Cyano-5-decyloxy-1-benzofuran-2-yl) (cyclohexyl)曱 ] 胺 胺 胺 } } } 将 将 将 将 将 将 © © © © © © © © © 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 5-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)benzyl]amino}propionic acid ethyl ester (285 mg), tetrahydrofuran ( A mixture of 5 mL) and EtOAc (5 mL). The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1. The resulting precipitate was filtered to give the title compound (246 mg, 92%). 'H NMR (300 MHz, CDCh) δ ppm 1. 04-1. 37 (m, 5H), 1.50- ❹ 1. 63 (m,1H), 1. 63-1. 85 (m, 3H), 1 85-2· 01 (m, 2H), 2.64 (t, J=5. 7 Hz, 2H), 3.60-3.70 (m, 2H), 3.93 (s, 3H), 4.42 (d, J=6.4 Hz , 1H), 6.58 (d, J=8. 7 Hz, 2H), 6.62-6.70 (m, 2H), 6.83 (d, J=9. 2 Hz, 1H), 7. 5〇_ 7. 59 ( m, 3H). Example A109 3-{[(4-{[(3-Cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)indolyl]amino}benzene Carbonyl)(methyl)amino}propionic acid 321426 533 201029996

N々^C〇2H ch3 (1) 3-{[(4-{[(3-Cyano-5-methoxy-1-benzopyran-2-yl)(cyclohexyl)decyl]amine Ethyl phenyl)carbonyl](methyl)amino}ethyl propionate I-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (171 mg) was added to 4-{[(3-Cyano-5-fluorenyl-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}benzoic acid synthesized in Example A108 (3) 24〇mg), ethyl 3-(decylamino)propionate (117 mg), 1-hydroxybenzotriazole monohydrate (136 mg), triethylamine (248//L) and N,N a mixture of dimethyl ketoamine (1 〇 raL) and the mixture was stirred at room temperature overnight. In hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (253 mg, 82%) was obtained eluted elut elut elut elut elut !H NMR (300 MHz, CDCh) &lt;5 ppm 1. 04-1. 36 (m, 8H), 1.52-1.85 (m, 4H), 1.85-1.99 (m, 2H), 2.62 (t, J= 6. 9 Hz, 2H), 3.02 (s, 3H), 3.71 (t, J=6.9 Hz, 2H), 3.94 (s, 3H), 4.11 (q, J=7. 1 Hz, 2H), 4.27- 4.33 (m, 1H), 4.35- 4.43 (m, 1H), 6.56 (d, J=8. 5 Hz, 2H), 6.66-6.67 (m, 1H), 6.83 (d, J=9.11 Hz, 1H), 7.23 (d, J=8. 5 Hz, 2H), 7. 52 (dd, J-9. 1, 0. 8 Hz, 1H). 534 321426 201029996 (2) 3-{[(4- {[(3-Cyano-5-methoxy-1 -benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl](fluorenyl)aminopyridinic acid 1N An aqueous solution of sodium hydroxide (1 oo mL) was added to the above-prepared 3-{[(4-{[(3-cyano-5-decyloxy-1-benzofuran-2-yl)(cyclohexyl)) a mixture of methyl]amino}phenyl)benzyl](methyl)amino}propionic acid ethyl ester (253 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 3 hours. And concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1.00 mL) was added to Ot. The resulting precipitate was collected by filtration to give the title compound (218 mg, 91%). !H NMR (300 MHz, CDCh) δ ppm 1.04-1. 36 (m, 5H), 1.53-1.63 (m, 1H), 1.63-1.84 (m, 3H), 1.85-2.00 (m, 2H), 2.61 -2.73 (m, 2H), 3.05 (s, 3H), 3.71 (t, J=6.6 Hz, 2H), 3.94 (s, 3H), 4.40 (d, J=6.4 Hz, 1H), 6.57 (d, J=8. 7 Hz, 2H), 6.67 (d, J=0. 8 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 7.26 (d, J=8. 7 Hz, 2H ), 7.55 (dd, J=9. 1, 0.8 0 Hz, 1H). Example A110 3-[{[4-({[5-(Ethylamino)-3-indolyl-1-benzene) And furan-2-yl](cyclohexyl)fluorenyl}amino)phenyl]carbonylindole (fluorenyl)amino]propionic acid

535 321426 201029996 (1) Cyclohexyl (3-mercapto-5-succinyl-1-benzoindole-2-yl) methylate potassium carbonate (7. 63 g) was added to 2'-hydroxy-5,- Nitroacetophenone (5. 〇〇g), 2-bromo-1-cyclohexylethyl hydrazine (6. 79 g) synthesized by the application of Example A51 (l), and hydrazine, hydrazine-methyl ketone A mixture of (50 mL) was added and the mixture was taken at room temperature overnight. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was washed with EtOAc (EtOAc m. !H NMR (300 MHz, CDCh) δ ppm 1. 19-1. 54 (m, 5H), 1 7〇- 1.81 (m, 1H), 1.82-1.92 (m, 2H), 1.92-2.02 (m, 2H), 2.65 (s, 3H), 3.24-3.36 (m, 1H), 7.62 (d, J=9.2 Hz, 1H), 8.37 (dd, J=9. 2, 2. 4 Hz, 1H), 8.59 (d, J=2. 4 Hz, 1H). ' (2) 4-((cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methyl]amine Methyl benzoate ❹ Titanium (IV) chloride (1.37 mL) was added to the cyclohexyl (3-indolyl-5-nitro-1-benzofuran-2-yl) oxime synthesized above. a mixture of ketone (3. 〇〇g), benzyl 4-aminobenzoate (1.57 g), triethylamine (11.6 mL) and dioxane (4 〇 mL) under argon at room temperature The mixture was stirred overnight. Aq. EtOAc EtOAc (EtOAc m. And sodium cyanoborohydride (1. 31 g) was added to a tetrahydrofuran solution (4q mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction. 21426 536 201029996 The reaction mixture was extracted with ethyl acetate. EtOAc (EtOAc m. The title compound of the title compound (2. 66 g, 61%). NMR (300 MHz, CDCh) (5 ppm 0. 96-1. 38 (m, 5H), 1.45-1.59 (m, 1H), 1.62 -2.01 (m, 4H), 2.05-2.15 (m, 1H), 2.32 (s, 3H), 3.81 (s, 3H), 4.41-4.56 (m, 2H), 6.55 ^ (d, J=9.11) Hz, 2H), 7.43 (d, J=8. 9 Hz, 1H), 7.80 (d, J=9. 1Hz, 2H), 8. 16(dd, J=8. 9, 2. 4 Hz, 1H ), 8.36 (d, J=2.4 Hz, 1H). (3) 4-{[Cyclohexyl (3-methyl-5-nitro-indole-benzofuran-2-yl)methyl]amine To a solution of 4-{[cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)anthracene as described above, was added 1 N aqueous sodium hydroxide (2 mL.OmL). A hydrazine mixture of hydrazinyl benzoate (2.66 g), tetrahydrofuran (2 〇 mL) and ethanol (2 mL) was stirred and evaporated. The residue was dissolved in water (40 raL) and added to 1N hydrochloric acid (2 mL). The obtained solid was collected by filtration and the obtained solid was dissolved in ethyl acetate. The title compound (2. 22 g, 86%) was obtained as a pale brown solid titled compound (2. 22 g, 86%). 1. 40 (m, 5H), 1.45-1.58 (m, 1H), 1.63-2.02 (m, 4H), 2.04-2.16 (m, 1H), 2.33 (s, 3H), 4.48 (d, J=8 . 0 Hz, 1H), 6.57 (d, J=9. 1 321426 537 201029996

Hz, 2H), 7.43 (d, J=8. 9 Hz, 1H), 7.86 (d, J=9. 1 Hz, 2H), 8.17 (dd, J=8.9, 2. 4 Hz, 1H), 8.37 (d, J=2. 4 Hz, 1H). (4) 3-{[(4-{[cyclohexyl(3-indolyl-5-nitro-l-benzofuran-2-yl)methyl) Amino}phenyl)carbonyl](methyl)amino}ethyl propionate 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (867 mg) Add to the above-mentioned 4-{[cyclohexyl(3-indolyl-5-nitro-1-benzofuran-2-yl)methyl]amino}benzoic acid u. 54 g), 3- (Hydrazinylamino)ethyl propionate (593 mg), 1-hydroxybenzotriazole monohydrate (692 mg), triethylamine (1.66 mL) and N,N-dimercaptocaramine (15 mL) mixture and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc ❹ WNMROOOMI^CDClOSppmO.ge-UOCin'SID'ljd- 1.56 (m, 1H), 1.58-2.00 (m, 3H), 2.06-2.17 (m, 1H), 2.31 (s, 3H), 2.61 (t, J =7.0 Hz, 2H), 3.01 (s, 3H), 3.70 (t, J=7. 0 Hz, 2H), 4.06-4.16 (m, 2H), 4.28-4.34 (m, 1H), 4.42 (t, J=8. 0 Hz, 1H), 6.55 (d, J=8.7 Hz, 2H), 7.22 (d, J=8. 7 Hz, 2H), 7.43 (d, J=9. 1 Hz, 1H), 8.16 (dd, J=9. 1, 2.5 Hz, 1H), 8.35-8.37 (in, 1H). (5) 3-{[(4-{[(5-Amino-3-methyl-1-) Benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)alkyl](indenyl)amino}propionic acid ethyl 538 321426 201029996 Platinum (IV) oxide (60.G mg Addition to the above-mentioned synthesis of 3_丨[(4_ {[裱己基(3-methyl-5-nitro-1-benzofuran-2-yl)indolyl]amino}phenyl)carbonyl]( A solution of ethyl hydrazide ethyl phthalate (6 〇〇 mg) in ethanol (2 〇^), and the mixture was stirred under a hydrogen atmosphere at room temperature for a few hours. The platinum oxide was filtered off and the filtrate was concentrated to give the title compound (yield 579) as a white solid. 'H NMR (300 MHz, CDCh) δ ppm 0. 93-1. 35 Cm, 8H), 1.49- ❹ 1.60 (m, 1H), 1.60-1.95 (m, 4H), 2.01-2.12 (m, 1H) , 2. 17 (s, 3H), 2. 61 (t, J = 7. 1 Hz, 2H), 3.01 (s, 3H), 3. 56 (br s, 2H), 3. 70 Ct, J= 7. 1 Hz, 2H), 4. 11 (q, j=7. i Hz, 2H), 4.30-4.34 (m, 2H), 6.55 (d, J=8. 7 Hz, 2H) 6.59 (dd, J=8. 5, 2. 5 Hz, 1H), 6. 69 (d, J=2. 5 Hz, 1H), 7.14 (d, 1=8.5 Hz, 1H), 7.20 (d, J=8. 7 Hz, 2H). (6) 3-[{[4-({[5-(Ethylamino)-3-indolyl-i-benzofuran-Nan-2-yl](cyclohexyl)indole Ethyl)amino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester 三 Add triethylamine (204/zL) and acetic anhydride (138# L) to the above-mentioned 3-{[( 4-{[(5-Amino-3-indenyl-1-benzofuran-2-yl)(cyclohexyl)indolyl]amino}phenyl)carbonyl](methyl)amino}propionic acid The ester (48 〇 mg) in tetrahydrofuran (10 dl) was stirred and the mixture was stirred at room temperature for 2.5 days. A saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. Dry over magnesium sulfate and concentrate under reduced pressure. The residue was purified by EtOAc (EtOAc: EtOAc (EtOAc) 5 ppm 0.92-1.38 (m,8H), 1.45-539 321426 201029996 1.57 (m, 1H), 1.60-1.97 (m, 4H), 2.01-2.13 (m, 1H), 2.17 (s, 3H), 2.22 ( s, 3H), 2.61 (t, J=7. 1 Hz, 2H), 3.01 (s, 3H), 3.71 (t, J=7. 1 Hz, 2H), 4.06-4.17 (m, 2H), 4.31 -4.41 (m, 2H), 6.55 (d, J=8. 5 Hz, 2H), 7.09 (dd, J=8.8, 2.1Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.26 ( d, J=8.8Hz, 1H), 7.39-7.50 (m, 1H), 7.71 (d, J=2. 1 Hz, 1H). (7) 3-[{ [4-({[5-( B Mercaptoamino)-3-mercapto-1-benzofuran-2-yl][cyclohexyl]fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid 1N hydroxide An aqueous lithium solution (1. 〇〇mL) was added to the above-mentioned 3_[{[4-({[5-(ethyl)amino)-3-methyl-1-benzofuran-2-yl] ( a mixture of cyclohexyl)fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester (366 mg), tetramethylpyran (5 mL) and ethyl Sj· (5 mL), The mixture was mixed at room temperature for 1 hour. An additional 1 N aqueous lithium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in hydrazine (10 mL) and EtOAc (EtOAc (EtOAc:EtOAc) 300 MHz, CDCIs) 6 ppm 0. 93-1. 37 (m, 5H) 1 1.57 (m, 1H), 1.60-1.99 (m, 4H), 2. 04-2.25 (m 7H) 2.44-2.68 (m , 2H), 2.99 (s, 3H), 3.45-3.73 (m 2H&gt;, 4. 35 (d, J=7. 9 Hz, 1H), 6. 54 (d, J=8· 7 Hz. ' B , ,, 7. 〇 3~ 7. 11 On, 1H), 7.12-7.28 (m, 3H), 7.57-7.68 (m 2H) Example All 1 ' ' 321426 540 201029996 3-[({4-[( Cyclohexyl {3-methyl_5-[(methylsulfonyl)amino]~1 ",furan-2-ylindolemethyl)amino]phenylindolecarbonyl)(fluorenyl)amino]% Sakamoto

Triethylamine (16〇vL) and sulfonium chloride (89. 0 with 1〇 plus $番王贯施{歹1丨A110(5)) 3-{[(4-{[(5- Amino-3-methyl y-benzofur-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl](indenyl)amino oxime ethyl ester (412 mg) of N, N-dimethylacetamide solution (1 mL) acid and the mixture was stirred overnight at room temperature. A saturated aqueous solution of chlorinated acid was added to iron-, ', and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over MgSO.subsubsubsubsubsubsubsubsubsubsubsubsubsub L) To a mixture of the obtained oil, tetrahydromethane (5 mL), ethanol (5 mL) and water (1 mL) and mixture mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The title compound (379 mg, 91%) was obtained as a white solid. <H NMR. (300 MHz, CDCh) δ PPm 0. 92-1. 39 (m, 5H), 1.45 -1.57 (m, 1H), 1.62-1.98 (m, 4H), 2.06-2.15 (m, 1H), 2. 22 (s,3H), 2. 64 (t, J=6.2 Hz, 2H), 2.93 (s, 3H), 3.03 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 4.37 (d, J=8. 0 321426 541 201029996

Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 6. 65-6. 71 (m, 1H), 7.06 (dd, J=8.6, 2. 2 Hz, 1H), 7.23 ( d, J=8. 7 Hz, 2H), 7.31 (d, J=8. 6 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H). Example A112 3-{ [(4-·( [Cyclohexyl (3-mercaptofuro[3,2-b]pyridin-2-yl)indenyl]amino}phenyl)carbonyl]amino}propionic acid

(1) Cyclohexyl (3-methyl-D-fusino[3,2-b]eit^-2-yl)methanone added potassium carbonate (13.2 g) to 1-(3-hydroxypyridin-2-yl) a mixture of 2-bromo-1-cyclohexyl Ethyl ketone (9.82 g) and N,N-dimethyl decylamine (50 mL) synthesized in Example A51 (1), 5小时。 The mixture was stirred at room temperature for 2.5 days. 1N hydrochloric acid was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) NMR (300 MHz, CDCh) (5 ppm 1. 19-1. 59 (m, 5H), 1. 70-1-92 (m, 3H), 1.92-2.03 (m, 2H), 2.69 (s, 3H ), 3.26-3-39 (m, 1H), 7.39 (dd, J=8.3, 4.6 Hz, 1H), 7.82 (dd, J=8.3, 1.4 Hz, 1H), 8.65 (dd, J=4.6 , 1.4 Hz, 1H). (2) 4-((cyclohexyl(3-mercaptofuro[3,2-b]pyridin-2-yl)indolyl]amino}benzoate 542 542 321426 201029996 Adding titanium (IV) gas (584//L) to the above-mentioned cyclohexyl group (3-mercaptopuro[3,2-b]0-bit-2-yl)methanone (1. 8 g), a mixture of benzyl 4-aminobenzoate (738 mg), triethylamine (4.95 mL) and dichloromethane (2 mL), and the mixture was stirred overnight at room temperature under argon. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction mixture and the mixture was crystallised from ethyl acetate. The mixture was washed with EtOAc EtOAc. Sodium hydride (558 mg) was added to the tetrahydroanthracene solution (2 mL) of the obtained oil, and the mixture was stirred for 1 hour at room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction. The residue was extracted with ethyl acetate and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The title compound (789 mg, 47°/.) was obtained as a pale brown solid. </ br> NMR (300 MHz, CDCh) δ ppm 0. 99-1. 38 (m, 5H), 1.42-1.53 (m, 1H), 1.64-2.01 (m, 4H), 2.06-2.16 (m, 1H), ❺ 2. 77 (s' 3H), 3· 81 (s, 3H), 4. 50- 4. 63 (m, 2H), 6· 54 (d, J=9. 1 Hz, 2H), 7.37 (dd, J=8. 2, 5.8 Hz, 1H), 7.81 (d, J=9.11) Hz, 2H), 7.98 (dd, J=8. 2, 1.1 Hz, 1H), 8.49

Cdd, J=5.8, 1. 1 Hz, 1H). (3) 4-((cyclohexyl(3-mercaptofuro[3,2-b]pyridin-2-yl)methyl]amino} A solution of 1N sodium hydroxide (1 〇·〇mL) to the above-prepared 4-{[cyclohexyl(3-mercaptofuro[3,2-b]pyridin-2-yl)methyl] Mix 543 321426 201029996 of amino}benzoic acid methyl vinegar (789 mg), tetrahydrofuran (1 〇mL) and ethanol (10 mL), and the mixture was stirred with stirring under reflux and concentrated under reduced pressure. The title compound (718 mg, 94%) was obtained as a white solid. H NMR (300 MHz). , CDCh) δ ppm 0. 96-1. 39 (m, 5H), 1.47- 1.60 (m, 1H), 1.62-2.02 (m, 4H), 2.03-2.17 (m, 1H), 2.38 (s, 3H ), 4.47-4.72 (m, 2H), 6.58 (d, J=8. 9 Hz, 2H), 7.18 (dd, J=8.3, 4.9 Hz, 1H), 7.65 (dd, J=8.3, 1.2 Hz, 1H), 7.86 (d, J=8. 9 Hz, 2H), 8.51 (dd, J=4. 9, 1. 2 Hz, 1H). ' (4) 3-{ [ (4-([cyclohexyl) (3-methylfuro[3,2-b]pyridine-2-yl)methyl]amino}phenyl)carbonyl]amino}ethyl propionate 1- Base-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (261 mg) was added to the above-mentioned 4_{[cyclohexyl (3-methylfuro[3,2-bM] Bite-2-yl)hydrazino]amino}benzoquinone (3)〇mg), $_propylamine citrate ethyl ester hydrochloride (2〇9 mg), 1-hydroxybenzotriazole monohydrate ( 2〇8 )), a mixture of diethylamine (379//L) and N,N-dimethyl decylamine (1 () mL), and the mixture was stirred overnight at room temperature. The reaction was quenched and the mixture was extracted with ethyl acetate. EtOAc (EtOAc m.j. The title compound (383 mg, 91%) was obtained as a pale brown oil. H NMR (300 MHz, CDCh) δ ppm 〇. 96-1. 38 (m, 8H), 1.47-1.58 (m, 1H) , 1.61-2.00 (m, 4H)j 2.05-2.16 (m, 1H), 321426 544 201029996 2. 35 (s,3H), 2.58 (t, J=5. 8 Hz, 2H), 3.61-3 69 Cm 2H), 4.13 (q, J=7. i Hz, 2H), 4. 42-4. 52 (m, 2H), 6.53 - 6.65 (m, 3H), 7.13 (dd, J=8. 2, 4. 7 Hz, 1H), 7.54 (d J=8.8Hz , 2H), 7.58-7.62 (in, 1H), 8.45-8.49 (m, ^ (5) 3-{ [(4-{[cyclohexyl (3-methylfuro[3, 2_b]pyridine~yl)) Amidino]amino}phenyl)Icarbonyl]amino}propionic acid A 1N aqueous solution of sodium hydroxide (2. 〇〇mL) was added to the above synthesized 3_ {[(4_{[cyclohexyl (3_A) Isofuro[3,2-b]pyridin-2-yl)methyl]amino}benzyl)Ikyl]amino}propionic acid ethyl vinegar (383 mg), tetrahydronaphthyl (5 mL) and A mixture of EtOAc (5 mL) was evaporated. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (2. 〇〇 mL) was then weighed. The obtained precipitate was collected by filtration to give the title compound (315 mg, 88%). NMR (300 MHz, CDCh) δ ppm 0.97-1. 38 (m, 5H), 1.44-1.57 (m, 1H), 1.61-2.00 (m, 4H), 2.05-2.18 (ra, 1H), ❿ 2· 35 (s,3H), 2.64 (t, J=5. 7 Hz, 2H), 3. 56-3. 78 (m, 2H), 4.46 (d, J=8.0 Hz, 1H), 6.55 ( d, J=8. 7 Hz, 2H), 6.72 (t, J=6. 1Hz, 1H), 7. 18 (dd, J=8.3, 4. 9 Hz, 1H), 7.54(d, J =8.7 Hz, 2H), 7.66 (dd, J=8.3, 1.3 Hz, 1H), 8.49 (dd, J=4.9, 1.3 Hz, 1H). Example A113 3-{[ (4-{[ring Hexyl (3-indolyl D-fusin-N-[3,2-b]-indenyl-2-yl)indenyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid 321426 545 201029996

(1) 3-{[(4-{[cyclohexyl(3-mercaptofuro[3,2-b]pyridine-2-yl)indolyl]amino}phenyl)carbonyl](indenyl)amine Ethyl propionate added 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (261 mg) to the 4-{ synthesized in Example A112(3) [Cyclohexyl (3-fluorenylfurfuro[3,2-b]pyridin-2-yl)indolyl]aminoindenic acid (330 mg), ethyl (methylamino)propionate (178 a mixture of 1-)-benzobenzotrisole monohydrate (208 mg), triethylamine (379 //L) and N,N-dimercaptocaramine (10 mL) at room temperature The mixture was stirred overnight. A saturated aqueous solution of ammonium carbonate was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The title compound (292 mg, 67%) was obtained. JH NMR (300 MHz, CDCh) δ PPm 0. 97-1. 38 (m, 8H), 1.47-1.58 (m, 1H), 1.61-2.00 (m, 4H), 2.05-2.16 (m, 1H), 2.35 (s, 3H), 2.60 (t, J=6. 9 Hz, 2H), 3.00 (s, 3H), 3.69 (t, J=6. 9 Hz, 2H)' 4. 10 (q,j= 7 〇Hz, 2H), 4. 35 (d, J=8.3 Hz, 1H), 4.45 (t, J=8.3 Hz, 1H), 6.56 (d, J=8. 5 Hz, 2H), 7. 13 (dd, J=8. 2, 4. 9 Hz, 1H), 7.20 (d, J-8. 5 Hz, 2H), 7. 60 (dd, J=8. 2, 1.4 Hz, 1H), 8 . 47 (dd, J=4.9, 1.4 Hz, 1H). 546 321426 201029996 (2) 3-{[ (4-([cyclohexyl(3-mercaptofuro[3,2-b]pyridine-2-) Methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid A 1N aqueous solution of sodium hydroxide (1. 〇〇mL) was added to the above-mentioned 3-{[(4-{[ Cyclohexyl (3-methylfuro[3,2-b]pyridin-2-yl)indenyl]amino}benzyl)Ikyl](methyl)amino}ethyl propionate (292 mg), a mixture of tetrakis π-propanol (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 5 hrs and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and acidified mixture with acetic acid and Extracted with ethyl acetate. Wash the extract with saturated brine and sulphuric acid The title compound (278 mg, quantitative) was obtained as a yellow solid. NMR C300 MHz, CDCh) 5 ppm 0. 95-1. 39 (m, 5H), 1.47-1.58 (m, 1H) ), 1.61-2.00 (m, 4H), 2.06-2.16 (m, 1H), 2.34 (s, 3H), 2.60-2.73 (m, 2H), 3.03 (s, 3H), 3.70 (t, J=6 8 Hz, 2H), 4.45 (d, J=8.0 Hz, 1H), 6.56 (d, J=8. 5 Hz, 2H), 7. 17 (dd, J=8.2, 4. 8 Hz, 1H), 7.23 (d, ❹ J=8· 5 Hz, 2H), 7. 65 (dd, J=8. 2,1. 3 Hz, 1H), 8· 50 (dd, J=4.8 1.3 Hz, 1H). Example A114 3-{[(4-{[(5-Methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)indolyl]amino} Phenyl)carbonyl](methyl)amino}propionic acid

H3c-o 321426 547 201029996 (1) (5-methoxy-3-indolyl-1-benzofuran-2-yl)(phenyl)fluorenone Addition of vaporized aluminum (3.28 g) to Example A104 (2) a mixture of 5-nonyloxy-3-mercapto-1-benzofuran (2.00 g), benzoquinone chloride (1.68 mL) and nitromethane (20 mL), and at room temperature The mixture was stirred for 2 hours. Water was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. Purification of the residue by silica gel column chromatography (30% ethyl acetate / hexanes) Compound (2.03 g, 62%). ]H MIR (300 MHz, CDC13) 5 ppm 2.62 (s, 3H), 3.89 (s, 3H), 7.05 (d, J=2.5Hz, 1H), 7. 10 (dd, J=9. 1, 2 5 Hz, 1H), 7.42 (d, J=9.1Hz, 1H), 7. 47-7. 63 (m, 3H), 8.04-8. 09 (m, 2H). (2) 4-{ [ (5-methoxy-3-indolyl-1-benzofuran-2-yl)(phenyl)indenyl]amino}benzoate decyl ester Q. Gasification of titanium (IV) (1. 00 mL Addition to (5-methoxy-3-indolyl-1-benzofuran-2-yl)(phenyl)fluorenone (2.03 g) synthesized above, decyl 4-aminobenzoate ( 1.27 g), a mixture of triethylamine (8.50 mL) and dichloromethane (30 mL), and the mixture was stirred overnight at room temperature under argon. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, dichloromethane was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate 5小时。 The acetic acid (2. 18 mL) and sodium cyanosulfonate (955 mg) was added to the resulting oil in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 2.5 hours. Saturated hydrogen carbonate 548 321426 201029996 aqueous sodium solution was added to terminate the reaction, the organic solvent was evaporated in an evaporator and the residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut NMR NMR (300 MHz, CDCh) ppiI1 2. 26 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 4.98 (d, J=6.0 Hz, 1H), 5.82 (d, J= 6. 0 Hz, 1H), 6.60 (d, J=8. 7 Hz, 2H), 6. 84 (dd, J=8. 8, 2. 6 Hz, 1H), 6.90 (d, J=2. 6 Hz, 1H), 7. 23-7. 37 (m, 4H), 7.39-7.44 (m, 2H), 7.82 (d, J=8. 7 Hz, 2H). (3) 4-{[( 5-N-oxy-3-indolyl-1-benzofuran-2-ylphenyl)methyl]amino}benzoic acid A 1N aqueous solution of sodium hydride (2 〇·〇mL) was added to the above synthesis. 4-[{5-methoxy-3-indolyl-1-benzofuran-2-yl)(phenyl)methyl]amino} decyl benzoate (2.36 g), tetrahydrofuran (2 〇 A mixture of mL) and EtOAc (2 mL) was evaporated. The residue was dissolved in water (40 mL) and dried. (1N Hydrochloric acid (2 mL) was added. The obtained precipitate was collected by filtration, and the obtained solid was dissolved in ethyl acetate. Title target compound (1.09 g, cent%) Η Dirty (3GG MHz, CDC13) 5 ppm 2.27 (s, 31〇, 3.84 (s, 3H), 5. 00-5. 11 (m, ih), 5. 84 (br s, 1H), 6. 61 (d, J=8. 8

Hz' 2H), 6.81-6.88 (m, 1H), 6.91 (d, J=2.7Hz, 1H), ^.24-7.38 (m, 4H), 7.39-7.45 (m, 2H), 7.88 (d, J=8. 8 Hz, 2H). 321426 549 201029996 (4) 3-{[(4-{[(5-methoxy-3-indol-1-benzofuran-2-yl))phenyl Ethyl]amino}phenyl)carbonyl](fluorenyl)amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 297 mg) was added to the above-prepared 4-{[(5-decyloxy-3-indolyl-1-benzofuran-2-yl)(phenyl)indenyl]amino}benzoic acid (4 〇) 〇mg), ethyl 3-(decylamino)propionate (203 mg), 1-hydroxybenzotriazole monohydrate (237 mg), triethylamine (431/zL) and N,N-di A mixture of decylguanamine (1 blush) and the mixture was stirred overnight at room temperature. Water was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The residue was purified by EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCh) δ ppm 1. 24 (t, J = 7. 1 Hz, 3H) 2.26 (s, 3H), 2.56-2.67 (m, 2H), 3.02 (s, 3H), 3.71 ( t, J = 7.1 Hz, 2H), 3.84 (s, 3H), 4.12 (q, J = 7.i Hz, ❹ 2H), 4.76 (d, J = 6. 0 Hz, 1H), 5.77 (d, J=6. 0 Hz, 1H), 6.60 (d, J=8.5Hz, 2H), 6.84 (dd, J=8. 9, 2. 6 Hz, 1H), 6.90 (d, J=2.6Hz, 1H ), 7.20-7.37 (m, 6H), 7. 39-7.45 (m, 2H). (5) 3-{[(4-{[(5-decyloxy-3-mercapto-1-benzo) Furan-2-yl)(phenyl)methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid A 1N aqueous solution of sodium hydroxide (2. 〇〇mL) was added to the above synthesized { [(4-{[(5-decyloxy-3-methyl-1-benzofuran-2-yl)(phenyl)methyl]amino}}phenyl)carbonyl](methyl)amino} Ethyl propionate (486 mg), tetraammine. A mixture of EtOAc (5 mL) and EtOAc (5 mL). The residue was dissolved in water (10 mL) and 1N hydrochloric acid (2. The obtained precipitate was collected by filtration to give the title compound (412 mg, 90%). JH NMR (300 MHz, CDCh) 5 ppm 2.26 (s, 3H), 2.68 (t, J = 6.4 Hz, 2H), 3.05 (s, 3H), 3.72 (t, J = 6.4 Hz, 2H), 3.84 ( s, 3H), 5.78 (s, 1H), 6.60 (d, J=8. 7 Hz, 2H), 6. 84 (dd, J=8. 9, 2. 5 Hz, 1H), 6.91 (d, J=2. 5 Hz, 1H), 7.23-7.39 (m, 6H), 7.39-7.47 (in, 2H). Example A115 3-[({4-[(cyclohexyl){5-[(ethylamine) Indenyl)amino]-3-mercapto-1-benzofuran-2-yl}indenyl)amino]phenyl}carbonyl)(indenyl)amino]propionic acid

(1) 3-[({4-[(Cyclohexyl){5-[(ethylaminoindolyl)amino)-3-indolyl-benzofuran-2-yl}methyl)amino] Phenyl}carbonyl)(methyl)amino]propionic acid ethyl ester Triethylamine (95//L) and ethyl isocyanate (54# L) were added to the synthesis of Example 8 110(5) -{[(4-{[(5-Amino-3-indolyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](fluorenyl)amine }Protein 551 321426 201029996 A solution of vinegar (280 mg) in tetrahydrofuran (i 〇 mL), and the mixture was stirred at room temperature for 1 day. Additional triethylamine (95/L) and ethyl isocyanate (54 a L) were added and the mixture was allowed to warm overnight. The reaction mixture was concentrated under reduced pressure and purified titled mjjjjjjjjjjjj %). !H NMR (300 MHz, CDCls) δ ppm 0.93-1.37 (m, 11H), 1-44-1.57 (m, 1H), 1.59-1.96 (m, 4H), 2.04-2.15 (m, 1H), 2.19 (s, 3H), 2.56-2.66 (m, 2H), 3.02 (s, 3H), 3.14-3.28 (m, 2H), 3.71 (t, J=7.0 Hz, 2H), 4.11 (q, J=7 . 1 Hz, 2H), 4.29-4.45 (m, 2H), 6.55 (d, J=8. 8 Hz, 2H), 6.72-6.83 (m, 1H), 7.15-7.23 (m, 3H), 7.43- 7.48 (m, 1H). (2) 3-[({4-[(Cyclohexyl){5-[(ethylaminoindolyl)amino]_3_indol-1-benzofuran-2-yl }Methyl)amino]phenylphosphoniumcarbonyl)(methyl)amino]propionate Propionate A 1N aqueous solution of hydrazine hydroxide (2.0 mL) was added to the above-mentioned 3-[({4-[( Hexyl{5-[(ethylaminoindenyl)amine;|_3_methyl-nonylbenzo-11-pentan-2-yl}methyl)amino]phenyl}carbonyl)(indenyl)amine A mixture of ethyl propionate (304 mg), tetrahydrofuran (5') and ethanol (5 mL), and the mixture was stirred at room temperature for 2 hr. The residue was dissolved in water oomL) and 1N hydrochloric acid (2.0 mL) was added at 0 C. The resulting precipitate was collected by filtration to afford title compound (258 mg, 89%). H NMR (300 MHz, CDCL·) δ ppm 0. 93-1. 39 (m, 8H), 1.45-1.57 (m, 1H), 1.61-1.98 (m, 4H), 2.06-2.20 (in, 4H) , 321426 552 201029996 2.47-2.65 (in, 2H), 2.99 (s, 3H), 3.12-3.25 (m, 2H), 3.52-3.70 (m, 2H), 4.34 (d, J=8. 1 Hz, 1H ), 4.94-5.06 (m, 1H), 6.53 (d, J=8. 7 Hz, 2H), 6.88 (dd, J=8. 7, 2.0 Hz, 1H), 7.14-7.24 (m, 3H), 7.35 (d, J=2.0 Hz, 1H). Example A116 3_{[(4-·{[cyclohexyl(6-decyloxy_1-fluorenyl-1H-benzo-flavor 11 sitting-2- Methyl]amino}phenyl)carbonyl]amino}propionic acid

(1) 5-methoxy-N-mercapto-2-nitroaniline A mixture of citric acid (7.64 g) and acetic anhydride (16.9 g) was stirred at 60 ° C for 2 hours, followed by dropwise addition of 5-oxime A solution of benzyl-2-nitroaniline (9.30 g) in THF (100 mL). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous A 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran (140 mL) was added to a residue in tetrahydrofuran (200 mL) and the mixture was stirred under reflux for 2 hr. Methanol was added to the reaction mixture at 0 ° C and the mixture was stirred at room temperature for 30 minutes. After stirring, 1 N hydrochloric acid was added to adjust to pH = 2. The reaction mixture was stirred with heating under reflux for 1 hr and concentrated under reduced vacuo. The solution was washed with EtOAc (EtOAc m. JH NMR (300 MHz, CDCla)^ ppm 3.01 (d, J=5.1 Hz, 3H) 3. 88 (s, 3H), 6. 12 (d, J = 2.7 Hz, 1H), 6.24 (dd, J=9. 6, 2.4 Hz, 1H), 8. 14 (d, J=9. 6 Hz, 1H), 8. 29 (br, 1H) (2) 6-decyloxy-1-methyl- 1H-benzimidazole 10% / carbon (1.00 g) was added to the above-prepared 5-methoxyindol-2-nitroaniline (6.30 g) in methanol (200 mL) and hydrogen, The mixture was stirred overnight at room temperature. The palladium on carbon was filtered off and the filtrate was concentrated. The residual citric acid solution (150 mL) was heated and stirred under reflux and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCI3) (5 ppm 3. 78 (s, 3H), 3. 87 (s 3H), 6.81 (d, J = 2.4 Hz, 1H), 6.91 (dd, J=8. 2.4 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.75 (s, 1H). ❹(3) N-methoxy-N-methylcyclohexane-burning amine at room temperature stirring ring Hexanecarboxylic acid (610 g), N, fluorenyl-dimercaptohydroxylamine hydrochloride (7. 31 g), 1-ethyl-3-(3-didecylaminopropyl) carbodiimide a mixture of hydrochloride (14.4 g), N,N-diisopropylethylamine (9. 68 g), 4-dimethylaminopyridine (600 mg) and dioxane (150 mL) The reaction was quenched with EtOAc (EtOAc) (EtOAc). , CDC10 5 ppm l 2 Bu 1. 30 (m, 3H), 1. 42-321426 554 201029996 1.50 (m, 2H), 1.64-1.80 (m, 5H), 2.65 (m, 1H), 3.14 (s, 3 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 a lithium hexane solution (30.1 mL) was added to the 6-methoxy-1-oxime synthesized in the above (2) -1H-benzimidazole (4.07 g) in tetrahydrofuran (100 mL) and the mixture was stirred under nitrogen for 30 min. The N-methoxy-N-methylcyclohexane synthesized in the above (3) was added. A solution of the alkalamine 0 (5.15 g) in tetrahydrofuran (5 mL) was stirred and stirred at -78 ° C for 1 hour, and stirred for 2 hours at ambient temperature. A saturated aqueous solution of ammonium chloride was added to terminate the reaction. The reaction mixture was extracted with EtOAc EtOAc (EtOAc)EtOAcEtOAcEtOAc. The title compound (5.80 g, 85%) was obtained as white crystals. H NMR (300 MHz, CDCh) δ ppm 1.23-1. 33 (m, 1H), 1.45-1.52 Cm, 4H), 1.64-1.72 (m, 1H), 1.78-1.86 (m, 2H), ❹ 1. 96*~2. 01 (m, 2H), 3. 82-3. 90 (m, 1H), 3. 91 (s 3H) 4. 09 (s, 3H), 6. 77(d, J=2. 4 Hz, 1H), 7. 〇〇 (dd, J=9. 〇, 2.4 Hz, 1H), 7.76 (dd, J=9. 0 , 2.4 Hz, 1H). (5) 4-{[Cyclohexyl (6-methoxy-1-methyl-1H-benzo-sali-2-yl)methyl]amino}benzoic acid methyl ester Titanium (IV) chloride (482 // L Addition to the above-mentioned cyclohexyl (6-decyloxy-1-methyl-1H-benzimidazol-2-yl)methanone (1. 〇〇g), 4-aminobenzoic acid methyl vinegar (611) Mixture of mg), triethylamine (4.10 mL) and dichloromethane (2 〇 π^) and mix the mixture overnight under argon at room temperature. Saturated carbon 321426 555 201029996 aqueous sodium hydrogen hydride solution was added to terminate the reaction, the dichloromethane was evaporated in an evaporator and the residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate Acetic acid (1 〇 5 mL) and sodium cyanoborohydride (461 mg) were added to a solution of the obtained solid in tetrahydrofuran (2 mL), and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and tetrahydrofuran was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (625 mg, 42%) was obtained from EtOAc (EtOAc) δ ppm 1. 02-1. 34 (m, 5H), 1.46- 1.58 (m, 1H), 1.59-1.84 (m, 4H), 1.95-2.11 (m, 1H), 3.77 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 4.59 (t, J=8.0Hz, 1H), 5.04 (d, J=8. 0 Hz, 1H), 6.63 (d, J=8. 8

Hz, 2H), 6.76 (d, J=2.4Hz, 1H), 6.88 (dd, J=8. 7, 2.4

Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.80 (d, J=8 8 Hz ❹ 2H). , (6) 4-{[cyclohexyl (6-decyloxy-p-methyl-1H) -benzimidazolyl-2-yl)indenyl]amino}benzoic acid A 1N aqueous solution of sodium hydroxide (5. (10) mL) was added to the above-mentioned 4_{[cyclohexyl (6-methoxy-1-methyl) a mixture of 1-1H-benzimidazol-2-yl)methyl]amino} methyl benzoate (625 mg), tetrahydrofuran (10 mL), and ethanol (1 mL) and the mixture was stirred and stirred under reflux overnight. Concentrate under reduced pressure. The residue was dissolved in water (20 mL) and EtOAc (EtOAc EtOAc EtOAc (EtOAc) NMR NMR (300 MHz, CDCh) ^ ppm 1. 01-1. 36 (m, 5H), 1.40-1.53 (m, 1H), 1.56-1.86 (in, 3H), 1.98-2.19 (m, 2H) , 3.83 (s, 3H), 3.87 (s, 3H), 4.59-4.69 (ra, 1H), 5.82- 5.96 (m, 1H), 6.68 (d, J=8. 9 Hz, 2H), 6.78 (d , J=2. 3

Hz, 1H), 6.91 (dd, J=8. 9, 2. 3 Hz, 1H), 7.64 (d, J=8. 9

Hz, 1H), 7.88 (d, J=8. 9 Hz, 2H). (7) 3-{[(4-{[cyclohexyl (6-methoxy-1-indenyl-1H-benzo) Jun-2-yl)indenyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (198 mg) was added to the above-prepared 4_{[cyclohexyl(6-methoxy-1-methyl-1H-benhamido-2-yl)indolyl]amino}benzoic acid (270 Mg), acetamino acid hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (158 mg), triethylamine (287 μL) and N,N-dimercaptocarboxamide (1 〇 mL) mixture and the mixture was stirred at room temperature overnight. The remaining aqueous solution of ammonium sulfate was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. The title compound (151 mg, 45%) was obtained eluted eluted elut elut elut elut elut elut elut ^ NMR (300 MHz, CDCL·) δ ppm 1. 03-1. 35 (m, 8H), 1.45-1.55 (m, 1H), 1.58-1.85 (m, 3H), 1.94-2. ll(m, 2H), 2.58 (t, J=6. 1 Hz, 2H), 3.66 (q, J=6. 1 Hz, 2H), 3.76 (s, 3H), 3.86 (s, 3H), 4.14 (q, J =7. 1 Hz, 2H), 4.56 557 321426 201029996 (t, J=7.8 Hz, 1H), 4.90 (d, J=7.8 Hz, 1H), 6.58-6.67 (m, 3H), 6.75 (d, J =2. 5 Hz, 1H), 6. 88 (dd, J=8. 8, 2.5

Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H). (8) 3-{[(4-{[cyclohexyl (6-methoxy-) Diethyl-1H-benzimidazol-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid A 1N aqueous solution of sodium hydroxide (1·〇〇mL) was added to the above-mentioned 3-( [(4-{[cyclohexyl(6-decyloxy-1-methyl-1H-benzimidazol-2-yl)indolyl]amino}phenyl)alkyl]amino}propionic acid (151 mg), a mixture of tetrahydrofuran (5 mL) and ethanol (5 mL) and the mixture was stirred at room temperature for 2.5 hr and concentrated under reduced pressure. The residue was dissolved in water (10 mL) The title compound (124 mg, 87%) was obtained as a white solid. H NMR (300 MHz, CDCls) δ ppm 0. 96-1. 30 (m, 5H), 1.30-1-40 (m, 1H), 1.60-1.70 (m, 2H), 1.71-1.83 (m, 1H), ❹ 1.90-2.05 (m, 1H), 2. 12- 2.23 (m,1H), 2.71 (t, J=5.4

Hz, 2H), 3.72-3.84 (m, 2H), 3. 86 (s, 3H), 3. 87 (s, 3H), 4. 57-4. 66 (m, 1H), 6. 74 (d , J=8. 9 Hz, 2H), 6. 78 (d, J=2.4Hz, 1H), 6.90 (dd, J=8. 9, 2.4 Hz, 1H), 7.24-7.32 (m, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.9 Hz, 2H). 'Example A117 3 -{[(4-·[[cyclohexyl(6-decyloxy-1) -mercapto-1H-benzimidazole-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid 321426 558 201029996

(1) 3_{[(4-{[cyclohexyl(6-decyloxy-1-methyl-1H-benzimidazolyl-2-yl)indolyl]amino}phenyl)carbonyl](fluorenyl) Amino}ethyl propionate added 1-ethyl-3-(3-didecylaminopropyl) succinimide hydrochloride hydrazine (198 mg) to the compound synthesized in Example All6 (6) -{[cyclohexyl(6-decyloxy-1-indenyl-1H-benzopyridin-2-yl)methyl]amino}benzoic acid (27 〇mg), 3-(methylamino) Ethyl propionate (135 mg), 1-hydroxybenzotriene, monohydrate (158 mg), triethylamine (287/zL) and N,N-dimethylguanamine (1 mL) The mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, aq. The residue was purified by EtOAc (EtOAc) eluting eluting JH NMR (300 MHz, CDCh) δ PPm 1. 02-1. 33 (m, 8H), 1.45-1.55 (m, 1H), 1.59-1.92 (m, 3H), 1.92-2.13 (in, 2H), 2.61 (t, J=7. 0 Hz, 2H), 3.01 (s, 3H), 3. 7〇 (t, J=7 0 Hz, 2H), 3.76 (s, 3H), 3.86 (s, 3h), (η (q, j=7.i Hz, 2H), 4.49-4.57 (m, 1H), 4.75 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 2.4 Hz, 1H), 6.88 321426 559 201029996 (dd, J=8. 8, 2. 4 Hz, 1H), 7.22 (d, J=8. 5 Hz, 2H ), 7.59 (d, J=8.8 Hz, 1H). (2) 3-{[(4-{[cyclohexyl(6-decyloxy-1-indolyl-1H-benzimidazol-2-yl)) Methyl]amino}phenyl)carbonyl](fluorenyl)amino}propionic acid A 1N aqueous solution of sodium hydroxide (1. 〇〇mL) was added to the above-prepared 3-{[(4-{[cyclohexyl) (6-decyloxy-1-methyl-1H-benzoxan-2-yl)indenyl]amino}bentonyl](methyl)amino}ethyl acetate propionate mg), tetrahydrofuran ( Mixture of 5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1. The resulting precipitate was collected by filtration to obtain a pale brown solid. Title target compound (72.1 mg, !H NMR (300 MHz, CDCh) δ PPml.〇〇-i 3〇(mj 131-1.41 (in, 1H), 1.57-1.81 (m, 3H), 1.88-2.03 (m, 1H), 2. 07-2. 19 (m, 1H), 2. 69-2.81 (m, 2H), 3.10 (s, 3H), 3.73-3.82 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.54 ❿ (d, J=8.1 Hz, 1H), 6.59 (d, 5 Hz, 2H), 6.77 (d, J=2.4Hz, 1H), 6.88 (dd , J=8. 9, 2. 4 Hz, 1H), 7.20-7.28 (m, 2H), 7. 54 (d, J=8. 9 Hz, ih). Example A118 3-{[(4- {[1-(5-Methoxy-3-methyl-1_benzofuran-2-yl)heptyl]amino}phenyl)carbonyl]amino}propionic acid 321426 560 201029996

Η h3c-o (1) 1-(5-decyloxy-3-mercapto-1-benzoyridin-2-yl)heptan-1-one Aluminium chloride (3.07 g) was added to Example A104 (2) 5-Alkyloxy-3-mercapto-1-benzo-pyran (1. 87 g), heptane chloride (2.14 mL) and nitrodecane (20 mL) synthesized The mixture was stirred at room temperature overnight. Water was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCh) δ ppm 0. 84-0. 95 (in, 3H), 1.24-1.48 (m, 6H), 1.67-1.82 (m, 2H), 2.57 (s, 3H), 2.96 ® (t, J = 7.4 Hz, 2H), 3.87 (s, 3H), 7. 00 (d, J = 2. 6 Hz, 1H), 7. 07 (dd, J=9. 1, 2. 6 Hz, 1H), 7.38 (d, J=9.1 Hz, 1H). (2) 4-{[1-(5-Methoxy-3-methyl-1-benzofuran-2-yl) Heptyl]amino}benzoic acid methyl ester added titanium (IV) chloride (566//L) to the above-mentioned synthesized i-(5-methoxy-3-indolyl-1-benzopyrene η-N- 2-yl)heptan-1-one (1.18 g), 4-aminobenzoic acid decyl ester (715 mg), triethylamine (4.79 mL) and dioxane (2 〇 mL) 321426 561 201029996 The mixture was stirred under argon at room temperature overnight. A saturated aqueous solution of sodium bismuth carbonate was added to terminate the reaction, dichloromethane was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate Acetic acid (1. 23 mL) and sodium cyanoborohydride (540 mg) were added to a solution of the obtained oil in tetrahydrohydamine (20 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The title compound (1.17 g, 66%) was obtained eluted eluted eluted eluted f^MR(300 MHz, CDCl3) 5ppm 0.82-0.88 (m, 3H), 1.18-1.40 (m, 8H), 1.88-2.03 (m, 2H), 2.24 (s, 3H), 3.81 (s, 3H) , 3.83 (s, 3H), 4.51 (d, J=7. 7 Hz, 1H), 4.58-4.68 (m, 1H), 6.56 (d, J=8. 8 Hz, 2H), 6.82 (dd, J =8. 8, 2.5 Hz, 1H), 6.87 (d, 1=2. b Hz, 1H), 7.25 (d, J=8.8 q Hz, 1H), 7.80 (d, J=8.8 Hz, 2H). (3) 4-{[ 1-(5-Methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}benzoic acid 1N aqueous sodium hydroxide solution (20. 0 Addition of the above-prepared 4-{[1-(5-decyloxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}benzoate oxime ester (1. A mixture of 17 g), THF (20 mL) and EtOAc (EtOAc) The residue was dissolved in water (20 mL) and 1N hydrochloric acid (20.0 mL). The resulting precipitate was collected by filtration to afford titled compound 562 321 426. !H NMR (300 MHz, CDCh) δ ppm 0. 80-0. 92 (m, 3H), 1.16- 1.44 (m, 8H), 1.90-2.03 (in, 2H), 2.25 (s, 3H), 3.84 (s, 3H), 4.65 (t, J=7.3 Hz, 1H), 6.58 (d, J=8.8 Hz, 2H), 6.84 (dd, J=8. 9, 2. 5 Hz, 1H), 6.89 ( d, J=2. 5 Hz, 1H), 7.26 (d, J=8. 9 Hz, 1H), 7.87 (d, J=8. 8 Hz, 2H). (4) 3-{[(4- {[1-(5-Methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (219 mg) was added to the above-prepared 4-{[1-(5-methoxy-3-indolyl-1- Benzopyran-2-yl)heptyl]amino}benzoic acid (300 mg), /3-alanine ethyl ester hydrochloride (175 mg), 1-p-benzotriene monohydrate ( 175 mg), a mixture of triethylamine (318#1〇 and N,N-dimethylformamide (10 mL), and the mixture was stirred overnight at room temperature. A saturated aqueous chloride solution was added to finally react and The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m. The title compound (320 mg, 85%) was obtained as a colorless oil. NMR (300 MHz, CDCh) (5 ppm 0.81-0. 90 (m, 3H), \ .\1~ 1.44 (m, 11H), 1.89-2.00 (m, 2H), 2.24 (s, 3H), 2.58 (t, J=6.0 Hz, 2H), 3.66 (q, J=6.0 Hz, 2H) , 3.83 (s, 3H), 4. 14 (q, J=7. 1 Hz, 2H), 4.37-4.44 (m, 1H), 4.55-4.66 (m, 1H), 6.53-6.64 (m, 3H) , 6.82 (dd, J=8. 8, 2.4 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 563 321426 201029996 1H), 7. 55 (d, J=8.8 Hz, 2H). (5) 3-{[(4-{[1-(5-Methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino} Phenyl)carbonyl]amino}propionic acid A 1N sodium hydroxide aqueous solution (2. 〇〇mL) was added to the above-mentioned 3-{[(4-{ [1-(5-methoxy-3-) Benzyl-1-benzofuran-yl)heptyl]amino}benyl)alkyl]amino}propionic acid ethyl ethane (320 mg), tetrahydro alpha-propanol (5 mL) and ethanol (5 mL) The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and dried. In Add in hydrochloric acid (2 孤 lone mL). The resulting precipitate was collected by filtration to give the title compound (213 mg, 71%). H NMR (300 MHz, CDCI3) δ ppm 0. 85 (t, J=6 8 Hz 3H) 1.16-1.43 (m, 8H), 1.85-2.03 (m, 2H), 2.23 (s 3H) 2. 63 ( t, J=5. 8 Hz, 2H), 3. 59-3. 69 (m, 2H), 3 83 (s 3H), 4. 60 (t, J=7. 3 Hz, 1H), 6. 56 (d, J=8. 9 Hz, 2H) 6.64 (t, J=6. 1 Hz, 1H), 6.82 (dd, J=8. 9, 2. 5 Hz, 1H), ◎ 6. 88 ( d, J=2.5 Hz, 1H), 7. 23-7.27 (m, 1H), 7 53 (d J=8. 9 Hz, 2H). Example A119 3-{[(4-{[1-( 5-methoxy-3-indolyl-1-benzofuran-2-yl)heptyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid 321426 564 201029996

(1) 3-{[(4-{[1-(5-曱-oxy-3-methyl-1 -benzonitrile. Nan-2-yl)heptyl]amino}phenyl)) (Mercapto) Amino} Ethyl Acetate &lt; £| Ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (219 mg) was added to Example A118 (3) Synthesis of 4-{[1-(5-decyloxy-3-indolyl-1-benzoxan-2-yl)heptyl]amino}benzoic acid (300 mg), 3- (Methylamino)propionic acid B g (150 mg), 1-Phenylbenzotrisole monohydrate (175 11^), triethylamine (318#1〇 and ratio!^-dimercaptopurine A mixture of decylamine (1 〇 11 </ RTI> was stirred and the mixture was stirred at room temperature overnight. Aq. saturated aqueous ammonium chloride was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and brine. The title compound (289 mg, 75%) was obtained. !H NMR (300 MHz, CDCh) (5 ppm 0.86 (t, J=6.9 Hz, 3H), 1.17-1.45 (in, 11H), 1.88-2.01 (m, 2H), 2.24 (s, 3H) , 2.61 (t, J=7. 0 Hz, 2H), 3.01 (s, 3H), 3.70 (t, J=7. 0 Hz, 2H), 3.84 (s, 3H), 4.11 (q, J=7. 1 Hz, 2H), 4.23-4.37 (m, 1H), 4.54-4.63 (m, 1H), 6.56 (d, J=8.8 Hz, 2H), 6.82 (dd, J=8. 8, 2. 4 Hz, 1H), 6.88 (d, J=2. 4 Hz, 565 321426 201029996 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 1H) (2) 3-{[(4-{[ 1-(5-decyloxy-3) - mercapto-1-phenyl-furanyl)heptyl]amino}benzyl)-based](methyl)amino}propionic acid 1N aqueous sodium hydroxide solution (2. 〇〇mL) was added to the above synthesis 3_ {[(4-{ [1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]aminopurinylphenyl)carbonyl](fluorenyl)amine A mixture of ethyl propionate (289 mg), tetrahydrogen, a mixture of sodium (5 mL) and ethanol (5 mL) and the mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. mL) and 〇. (: </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; J=6. 6 Hz, 3H), 1.16-1.44 (m, 8H), 1.86-2.02 (m, 2H), 2.24 (s, 3H), 2.64 (t, J=6.6 Hz, 2H), 3.02 (s , 3H), 3.69 (t, J=6. 6 Hz, 2H), 3.84 (s, 3H), 4.59 (t, J=7.3 Hz, 1H), 6.56 (d, J=8. 7 Hz, 2H) , 6. 83 (dd, J=8. 8, 2.5 Hz, 1H), 6.89 0 (d, J=2.5 Hz, 1H), 7.20-7.29 (m, 3H). Example A120 3-{[(4 -{[1-(5-Methoxy-3-indolyl-1-benzofuran-2-yl)-5-(methylthio)pentyl]amino}phenyl)carbonyl]amino} Propionic acid 566 321426 201029996

(1) 5-Gas-1-(5-decyloxy-3-indolyl-1-benzopyran-2-yl)indole-1-indole Aluminized at 0 ° C (2. 47 g) 5-methoxy-3-methyl-1-benzofuran (2.00 g) and 5-chlorovaleryl chloride (1.74) synthesized in the above Example A104 (2) A mixture of mL) and sulphuric acid (40 mL) and the mixture was stirred for 2 hours. Water was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (2·63 g, 76%) was obtained. ® JH NMR (300 MHz, CDCh) δ ppm 1. 83-1. 97 (m, 4H), 2. 58 (s, 3H), 2.98-3.05 (m, 2H), 3.56-3.63 (m, 2H) , 3.87 (s, 3H), 7.00 (d, J=2. 7 Hz, 1H), 7.08 (dd, J=9. 0, 2.7 Hz, 1H), 7. 38 (d, J=9. 0 Hz , 1H). (2) 1-(5-decyloxy-3-methyl-1-benzofuran-2-yl)-5-(indolylthio)indole-1 -indole will be added to 15% Sodium methanethiolate aqueous solution (4.33 mL) was added to the above-mentioned 5-chloro-1-(5-methoxy-3- 567 321426 201029996 methyl-1-benzofuran-2 A mixture of pentyl-I-ketone (1.30 g), methanol (15 mL) and THF (15 mL) was stirred at room temperature for one hour and then at 50 ° C for one hour. Sodium decanethiolate (325 mg) was additionally added, and the mixture was stirred at 50 ° C for 1 hour. Additional sodium methanethiolate (325 mg) was added again, and the mixture was stirred for 5 hours at TC. Water was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (492 mg, 36%) was obtained as a yellow solid. </ br> </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 111,211), 1.79- 1.92 (m, 2H), 2.11 (s, 3H), 2.51-2.62 (m, 5H), 3.00 (t, J=7.3 Hz, 2H), 3.87 (s, 3H), 7 00 (d, J=2.5 Hz, 1H), 7.08 (dd, J=9. 1, 2. 5 Hz, 1H), 7.38 (d, J=9. 1 Hz, 1H). (3) 4- {[ 1-(5-Methoxy-3-indolyl-1_benzofuran-2-yl)-5-(indolylthio)pentyl]amino}benzoate oxime ❹ C. A 1.0 M solution of titanium (IV) chloride in dichloromethane (2.77 mL) was added to the 1-(5-decyloxy-3-mercapto-1-benzofuran-2-) synthesized above. -5-(methylthio)pentan-1-one (658 mg), 4-aminobenzoic acid decyl ester (375 mg), triethylamine (2.50 mL) and dioxane ( 10 mL) of the mixture, and the mixture was given 3. 5 days in the wind and to the temperature. The aqueous solution of sodium hydrogencarbonate was used to terminate the reaction, and the residue was evaporated in vacuo. EtOAc was evaporated. Acetic acid (647# L) and sodium cyanoborohydride (283 rag) were added to a solution of the obtained oil in tetrahydrofuran (1 mL), and the mixture was allowed to stand for 1 hour at room temperature of 568 321426 201029996. The reaction mixture was quenched and the mixture was extracted with ethyl acetate. EtOAc EtOAc m. The title compound (645 mg, 67%) was obtained as a brown oil.]H NMR (300 MHz, CDCh) ά ppm 1. 30-1. 71 (m, 4H), 1.91- 2.08 (m, 5H), 2.25 (s, 3H), 2.46 (t, J=7. 3 Hz, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 4.52 (d, J=8. 0 Hz, 1H ), ❹ 4. 59-4.70 (m,1H), 6.57 (d, J=8. 8 Hz, 2H), 6.83 (dd, J=8.7, 2.5 Hz, 1H), 6.87 (d, &gt;2.5 Hz) , 1H), 7.25 (d, J=8. 7 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H). (4) 4 -{[1-(5-decyloxy-3-indolyl-1-benzofuran-2-yl)-5-(methylthio)pentyl]aminopurine benzoic acid 1N sodium hydroxide An aqueous solution (10. 〇mL) was added to the above-prepared 4_{[1-(5-methoxy-3-indolyl-1-benzofuran-2-yl)-5-(methylthio) A mixture of decylamino]indolyl phthalate (Ul g), tetrahydrofuran (10 rnL) and ethanol (10 mL) was stirred and evaporated. The residue was dissolved in water (20 roL) and 1N guanidine hydrochloride (mL) was added at 〇 °c. The resulting precipitate was collected to give the title compound ( 915 mg, 94%). !H NMR (300 MHz, CDCla) δ ppm 1.29-1.70 (m, 4H), 1.93- 2.09 (m, 5H), 2. 25 (s, 3H), 2.46 (t, J=7.3 Hz, 2H) 3.83 (s, 3H), 4.65 (t, J=7. 3 Hz, 1H), 6.57 (d, J=8. 8

Hz, 2H), 6.83 (dd, J=8. 8, 2.5 Hz, 1H), 6.88 (d, J=2. 5 321426 569 201029996

Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.86 (d, J=8. 8 Hz, 2H). (5) 3-{[(4-{[l-(5-methoxy) 3-methyl-1-benzofuran-2-yl)-5-(fluorenylthio)indolyl]amino}phenyl)propenyl]amino}propionic acid ethyl hydrazide -3-(3-Dimercaptopropylpropyl)carbodiimide hydrochloride (314 mg) was added to the above-prepared 4-{[1-(5-methoxy-3-methyl-1) -benzopyran-2-yl)-5-(fluorenylthio)pentyl]amino}benzoic acid (450 mg), hydrazine-alanine ethyl ester hydrochloride (252 mg), 1- A mixture of hydroxybenzotriazole monohydrate (251 mg), triethylamine (456 L) and N,N-dimethylamine (10 mL) was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and evaporated The title compound (518 mg, 93%) was obtained eluted elute ❹ 4 NMR (300 MHz, CDCh) (5 ppm 1. 25 (t, J=7·1 Hz, 3H), 1.31-1.72 (m, 4H), 1.91-2.10 (m, 5H), 2.25 (s, 3H), 2.42-2.50 (m, 2H), 2.59 (t, J=5. 8 Hz, 2H), 3.61-3.71 (m, 2H), 3.84 (s, 3H), 4.07-4.19 (m, 2H) , 4.38-4.45 (m, 1H), 4.57-4.68 (m, 1H), 6.54-6.66 (m, 3H), 6.83 (dd, J=8. 7, 2. 5 Hz, 1H), 6.88 (d, J=2. 5 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H). (6) 3-{[(4-{[l-(5 -Methoxy-3-mercapto-1-benzofuran-2-yl)-5-(fluorenylthio)pentyl]amino}phenyl)carbonyl]amino}propionic acid 570 321426 201029996 Will IN Aqueous sodium hydroxide (2. mLQ mL) was added to the above-mentioned 3-{{(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)) a mixture of _5_(methylthio)pentyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester (253 mg), tetrahydronethane (5 mL) and ethanol (5 mL) at room temperature The mixture was stirred for 3 hours and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and then 1N hydrochloric acid (2. Target compound (133 mg, 5 6%).H NMR (300 MHz, CDCla) δ ppm 1. 30-1. 69 (m, 4H), 1.90-® 2.04 (m, 2H), 2.05 (s, 3H), 2.24 (s, 3H) ), 2.41-2.50 (in, 2H), 2.63 (t, J=5.8 Hz, 2H), 3.59-3.69 (m, 2H), 3. 83 (s, 3H), 4. 62 (t, J=7 3 Hz, 1H), 6. 57 (d, J=8. 7 Hz, 2H), 6. 65 (t, J=5. 9 Hz, 1H), 6. 83 (dd, J=8. 8 , 2.5 Hz, 1H), 6.88 (d, J=2. 5 Hz, 1H), 7.22-7.28 (m, 1H), 7. 54 (d, J=8.7 Hz, 2H). Example A121 ❹ 3- {[(4-{[1-(5-Methoxy-3-indolyl-1-benzofuran-2-yl)-5-(indolylthio)pentyl]amino}phenyl)carbonyl (mercapto)amino}propionic acid

(1) 3-{[(4-{[1-(5-Methoxy-3-methyl-1-benzofuran-2-yl) 321426 571 201029996 -5-(methylthio)pentyl Amino}phenyl)carbonyl](indenyl)amino}propionic acid

酉I 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (320 mg) was added to the 4-{[1-() synthesized in Example A120(4) 5-decyloxy-3-mercapto-1-benzofuran-2-yl)-5-(methylthio)pentyl]amino}benzoic acid (460 mg), 3-(decylamino) a mixture of ethyl propionate (219 mg), 1-hydroxybenzotriazole monohydrate (256 mg), triethylamine (464 μL) and N,N-dimercaptocaramine (10 mL) The mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over magnesium sulfate. The residue was purified by silica gel column chromatography (30 to 50% ethyl acetate / hexane) to afford the title compound ( 514 mg, 88%). !H NMR (300 MHz, CDCh) ¢5 ppm 1.23 (t, J=7. 1 Hz, 3H), 1.30-1.73 (m, 4H), 1.88-2.10 (m, 5H), 2.24 (s, 3H) , 〇2.41-2.50 (m, 2H), 2.55-2.67 (in, 2H), 3.01 (s, 3H), 3.70 (t, J=7.3 Hz, 2H), 3.84 (s, 3H), 4.11 (q, J=7. 1 Hz, 2H), 4.27-4.35 (m, 1H), 4.54-4.65 (m, 1H), 6.57 (d, J=8.8Hz, 2H), 6.83 (dd, J=8.8, 2.6 Hz , 1H), 6.88 (d, J=2.6 Hz, 1H), 7.18-7.30 (m, 3H). (2) 3-{[(4-{[1-(5-曱-oxy-3_fluorenyl) 1;[_benzofuran-2-yl)-5-(fluorenylthio)pentyl]amino}phenyl)benzyl](fluorenyl)amino}propionic acid 1N aqueous sodium hydroxide solution (1 · 〇〇mL) is added to the above-prepared 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)_5_(methyl 572 321426) 201029996 A mixture of lysyl]amyl]amino}benzyl)Ik-based](methyl)amino}propionic acid (251 mg), tetra-gas pentane (5 mL) and ethanol (5 mL) The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved in water (1 〇 mL) and 1N hydrochloric acid (1.0 mL) was added to EtOAc. The resulting target compound was collected over a pale brown solid to give the title compound (74. 8 mg, 5 〇. !H NMR (300 MHz, CDCla) δ ppm 1. 30-1. 69 (m, 4H ), 1.90-2.05 (m, 2H), 2.06 (s, 3H), 2.24 (s, 3H), 2.46 (t, J=6. 8 Hz, 2H), 2.66 (t, J=6. 6 Hz, 2H), 3.03 (s, 3H), 3.70 (t, J=6. 6 Hz, 2H), 3.84 (s, 3H), 4.60 (t, J=7. 3 Hz, 1H), 6.57 (d, J =8. 9 Hz, 2H), 6. 84 (dd, J=8. 9, 2.5 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 7.21-7.30 (m, 3H). A122 3-{ [(4-{ [ 1-(5-Methoxy-3-indolyl-1-benzoxan-2-yl)-5-(methylsulfonyl)pentyl]amine }phenyl)carbonyl](methyl)amino}propionic acid

(1) 3_{[(4-{[1-(5-Methoxy-3-indol-1-benzofuran-2-yl)-5-(indolylsulfonyl)pentyl]amine }Phenyl)carbonyl](fluorenyl)amino}ethyl propionate m-chloroperbenzoic acid (aqueous, purity 69 to 75%) (344 mg) 573 321426 201029996 added to Example A121 at 0 ° C The 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(indolylthio)pentyl]amine synthesized) Base phenyl) carbonyl] (methyl) amino} ethyl propionate (263 mg) in acetone (mL), and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite was added to terminate the reaction' and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous Purification of the residue by silica gel column chromatography (30 to 70% ethyl acetate / hexanes) (104 mg, 37%). 4 丽R (300 MHz, CDCh) as ppm 1. 24 (t, J=7.1 Hz, 3H), 1.34-1.69 (m, 2H), 1.76-2.14 (m, 4H), 2.24 (s, 3H ), 2.62 (t, J=6. 9 Hz, 2H), 2. 85 (s, 3H), 2.97 (t, J=8. 0 Hz, 2H), 3.02 (s, 3H), 3.71 (t, J=6. 9 Hz, 2H), 3.84 (s, 3H), 4.12 (q, J=7. 1 Hz, 2H), 4.30 (d, J=8. 0 Hz, 1H), 4.57-4.68 (m , 1H), 6.58 (d, J=8. 7 Hz, 2H), 6.85 ❹ (dd, J=8. 7,2 Hz, 1H), 6.89 (d, J=2· 5 Hz, 1H) , 7. 19-7. 31 (m, 3H). (2) 3-{[(4-{[l-(5-Methoxy-3-methyl-1-benzofuran-2-yl)) -5-(Methylsulfonyl)pentyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid A 1N aqueous sodium hydroxide solution (1. 〇〇mL) was added to the above-mentioned synthesis 3 -{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}phenyl A mixture of carbonyl](fluorenyl)amino}ethyl propionate (1 〇 4 mg), tetrahydrofuran (5 mL) and ethanol (5 mL). The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1. 00 mL) was added at 321 426 574. The resulting precipitate was collected by filtration to give the title compound (52.7 &lt 'H NMR (300 MHz, CDCh) δ ppm 1. 34-1. 59 2h), 1.76- 2. 13 (m, 4H), 2.23 (s, 3H), 2.66 (t, j=6 4 Hz, 2H ), 2.85 (s, 3H), 2.96 (t, J = 7.8 Hz, 2H), 3 04 (s, 3H), 3. 70 (t, J = 6.4 Hz, 2H), 3. 84 (s, 3H ), 4 59-4. 66 (m, 1H), 6.58 (d, J=8. 7 Hz, 2H), 6. 85 (dd, j=9 1 2. 5 Hz, 1H), 6.89 ( d, J = 2. 5 Hz, 1H), 7.21-7.30 (m, 3H) ® Example A123 3-{[(4-{[5-methoxy-1-(5-methoxy-3-) Methyl-benzofuran-2-yl)indolyl]amino}phenyl)alkyl]amino}propionic acid

(1) 5-methoxy-1 -(5-decyloxy-3-indolyl-1-benzopyran-2-yl)pentan-1-indole sodium moth (1.54 g) and Sodium methoxide (1.86 g) was added to the 5-chloro-1-(5-methoxy-3-methyl-1-benzo oxazol-2-yl) synthesized in Example A12(1). A solution of pentan-1-one (1.93 g) in decyl alcohol (2 mL) was applied and the mixture was warmed to reflux overnight and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) 1.89 (m, 2H), 2.58 (s, 3H), 3.00 (t, J=7·3 Hz, 2H), 3.33 (s, 3H), 3.43 (t, J=6. 3 Hz, 2H), 3.87 (s, 3H), 7. 00 (d, J=2. 4 Hz, 1H), 7. 07 (dd, J=9. 〇, 2. 4 Hz, 1H), 7. 38 (d, J= 9. 0 Hz, 1H). (2) 4-{[5-Methoxy-i-(5-methoxy-3-methyl-l-benzocypanol-2--2-yl)penta Methyl]amino}benzoic acid methyl g was added to 1.0 M titanium chloride (IV) in dichloromethane (3.46 mL) to the above-mentioned 5-methoxy-1-(5-oxime) 1-methyl-1-benzofuran-2-yl)pentan-1-one (797 mg), 4-aminobenzoic acid oxime ester (479 mg), triethylamine (3.11 mL) and dichloro 5小时。 Mixture of decane (10 inL), and argon gas, the mixture was stirred for 3.5 days. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate and evaporated. Acetic acid (824 / / L) and sodium cyanoborohydride (362 mg) were added to a solution of the obtained oil in THF (10 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (1.07 g, 90%) was obtained. !H NMR (300 MHz, CDCh) &lt;5 ppm 1. 27-1. 67 (in, 4H), 1.91- 576 321426 201029996 2.08 (m, 2H), 2.24 (s, 3H), 3.30 (s, 3H ), 3.31-3.37 (m, 2H), 3. 81 (s, 3H), 3. 83 (s, 3H), 4. 51-4. 56 (m, 1H), 4.60-4.69 (m, 1H) , 6.56 (d, J=8. 8 Hz, 2H), 6.83 (dd, J=8.8, 2.5 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 7.25 (d, &gt;8.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H). (3) 4-{[5-Methoxy-1-(5-decyloxy-3-methyl-1-benzofuran- 2-yl)pentyl]amino}benzoic acid hydrazine A 1 N aqueous sodium hydroxide solution (10. 〇mL) was added to the above-prepared 4-{[5-decyloxy-1-(5-methoxy-) a mixture of 3-methyl-1-benzofuran-2-yl)pentanyl]aminoguanidinium methyl ester (1.07 g), tetrahydrofuran (1 () mL) and ethanol (10 mL) under reflux The mixture was stirred with heating for 1 day and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and dried. (: 1N Hydrochloric acid (10.0 mL) was added. The obtained precipitate was collected by filtration to give the title compound (875 mg, 85%) as a brown solid. H NMR (300 MHz, CDCls) δ ppm 1. 26-1. (m, 4H), 1.90- q 2. 10 (m, 2H), 2.25 (s, 3H), 3. 30 (s, 3H), 3.35 (t, J = 6.5 Hz, 2H), 3.84 (s, 3H), 4.66 (t, J=7. 3 Hz, 1H), 6.58 (d, J=8.8Hz, 2H), 6. 84 (dd, J=8. 9, 2. 5 Hz, 1H), 6 89 (d, J=2. 5 Hz, 1H), 7. 26 (d, J=8. 9 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H). (4) 3-{ [ (4-{[5-methoxymethoxy 3-yl-benzobenzopyran-2-yl)pentyl]amino}phenyl)carbonyl]amino phthalic acid ethyl ester 1-ethyl -3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (291 mg) was added to the above-prepared 4_{[5-methoxy-^(b-methoxy-321426 577 201029996 - 3-mercapto-1-benzofuran-2-yl)pentanyl]amino}benzoic acid (400 mg), stone-alanine ethyl ester hydrochloride (234 mg), 1-hydroxybenzotriazole 5小时。 Mixture of a mixture of monohydrate (233 mg), triethylamine (422# L) and N,N-dimercaptocarboxamide (1 mL) and stirred at room temperature for 2.5 days. A saturated aqueous solution of ammonium carbonate was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated. The title compound (489 mg, ® 97%) °H NMR (300 MHz, EtOAc, EtOAc) CDCh) 5 ppm 1.25 (t, J=7.11 Hz, 3H), 1.30-1.69 (in, 4H), 1.88-2.08 (m, 2H), 2.24 (s, 3H), 2.55-2.62 (m, 2H) ), 3.30 (s, 3H), 3.34 (t, J=6. 7 Hz, 2H), 3.62-3.70 (m, 2H), 3.83 (s, 3H), 4.14 (q, J=7. 1 Hz, 2H), 4.39-4.47 (m, 1H), 4.57-4.68 (m, 1H), 6.54-6.64 (m, 3H), 6.82 (dd, J=8.8, 2.4 Hz, 1H), 6.87 (d, DJ= 2.4Hz, 1H), 7. 24(d, J=8. 8 Hz, 1H), 7.55 (d, J=8. 8 Hz, 2H). (5) 3-{[(4-{[5-曱oxy-1-(5-decyloxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}phenyl)carbonyl]amino}propionic acid

A 1N aqueous solution of sodium hydroxide (2.0 mL) was added to the above-prepared 3-{[(4-{[5-methoxy-1-(5-methoxyl_3-methyl-1-benzene) And a mixture of ketone-2-yl)pentyl]amino}phenyl)alkyl]amino}propionic acid ethyl s (489 mg), four-nose π-nan (5 mL) and ethanol (5 mL) The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and added to 1N 578 321426 201029996 hydrochloric acid (2.0 mL). Passing the smashing road p-, willing to collect the sinking of the sink; the solid and the resulting solid: acetic acid B δθ 卩 saturated brine for n nights, dried with sulfur and reduced pressure is said to be light brown (four) title Target combination 98%). 〇MR(3_z, CDCl3)dppml27_167(m4H)i9i-2.03 (,, 2H), 2.23 (s, 3H), 2.63 (t, J=5. 7 Hz, 2H), 3.30 (s, 3H), 3.35 (td, J=6. 3, 1.2 Hz, 2H), 3.60-3.69 (m, 2H), 3.83 (s, 3H), 4.61 (t, J=7.2 Hz, 1H), 6.56 (d, J=8 8 Hz, 2H), 6.66 (t, J=6. 0 Hz, 1H), 6.82 (dd, J-8. 9, 2. 5 Hz, 1H), 6. 87 (d, J=2.5 Hz, 1H), 7. 22-7. 27 (m, 1H), 7.54 (d, J = 8.8 Hz, 2H). Example A124 3-{[(4-{[5-methoxy-1- (5-methoxy-3-methyl-benzofuran-2-yl)pentyl]amino}phenyl)benzyl](methyl)amino}propionic acid

(1) 3-{[(4-{[5-methoxy-1-(5-decyloxy-3-methyl-1-benzo-dopyridin-2-yl)pentyl]amino}benzene Ethyl]carbonyl](methyl)amino}ethyl propionate 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (291 mg) was added to Example A123 (3) 4-{[5-Methoxy-indole-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}benzoic acid synthesized 579 321426 201029996 ( 400 mg), ethyl 3-(decylamino)propionate (199 mg), 1-p-benzobenzoate monohydrate (233 mg), triethylamine (422//L) and N, 5小时。 Mixture of N-dimercaptoamine (10 mL) and the mixture was stirred at room temperature for 2.5 days. A saturated gasification bath was added to terminate the reaction and the reaction mixture was extracted with acetic acid. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over magnesium sulfate. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) ® 'H NMR (300 MHz, CDCls) δ ppm 1.24 (t, J=7. 1 Hz, 3H), 1.30-1.67 (m, 4H), 1.88-2.06 (m, 2H), 2.24 (s, 3H) , 2.62 (t, J=7. 0 Hz, 2H), 3.02 (s, 3H), 3.30 (s, 3H), 3.35 (t, J=6. 3 Hz, 2H), 3.71 (t, J=7 . 0 Hz, 2H), 3.84 (s, 3H), 4.12 (q, J=7. 1 Hz, 2H), 4.27-4.36 (m, 1H), 4.55-4.66 (m, 1H), 6.57 (d, J=8. 8 Hz, 2H), 6.83 (dd, J=8. 8, 2. 5 Hz, 1H), 6. 88 (d, J=2. 5 Hz, 1H), 7.18-7.28 q (m , 3H). (2) 3-{[(4-{[5-methoxy-1-(5-decyloxy-3-indolyl-1-benzofuran-2-yl)pentyl]amine }}phenyl)carbonyl](fluorenyl)amino}propionic acid A 1N aqueous solution of sodium hydroxide (2.0 mL) was added to the above-prepared 3-{[(4-{[5-decyloxy-1). -(5-decyloxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}benyl)benzyl](methyl)amino}propionic acid A mixture of tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to give the title compound ( 428 mg, 99%). ^NMROOOMI^CDClOSppmUT-l.GTCm'AHXl.SS-2.06 (m, 2H), 2.23 (s, 3H), 2.67 (t, J=6. 6 Hz, 2H), 3.04 (s, 3H), 3.30 ( s, 3H), 3.35 (td, J=6.4, 1.0 Hz, 2H), 3.70 (t, J=6.6 Hz, 2H), 3.84 (s, 3H), 4.61 (t, J=7.2Hz, 1H), 6.56 (d, J=8. 7 Hz, 2H), 6. 83 (dd, J=8. 8, 2.4 Hz, 1H), 6. 88 (d, J=2.4 Hz, 1H), 7. 21-7. 30 (m, 3H). Example A125 ® 3-{ [(4-{ [(5-bromo-3-indolyl cougho[3, 2-b]) (cyclohexyl)methyl]amino phenyl)carbonyl]amino}propionic acid

Br (1) 3-(benzyloxy)-6-bromo η-pyridine-2-carbonitrile (N-bromosuccinimide (π. 8 g) was added to 2-cyano-3- a mixture of hydroxy bite (10.0 g), water (4 〇mL) and acetonitrile (2 〇〇mL), and the mixture was stirred at 0 °C for 2 hrs and stirred at room temperature for 1 hour. The solution was washed with water and saturated brine, dried over magnesium sulfate, and evaporated to dryness to give a white solid. The phenyl bromide (1 I 9 mL) * potassium salt (23·1 g) was added to the obtained solid. Acetone solution (2 〇〇 mL) / and the mixture was stirred and heated under reflux. The mixture was filtered and evaporated to dryness. , 139〇. !H NMR (300 MHz, DMSO-d) δ ppm 5. 36 (s, 2H), 7. 32-7 50 (m, 5H), 7.87 (d, J=9. 1 Hz, 1H ), 7.96 (d, J=9. 1 Hz, 1H). ' (2) l-[3-(benzoxyloxy)-6- desertu than bite_2-yl] ethyl ketone at 0 C will be 1 0M methylmagnesium bromide in tetrahydrofuran solution (27. 6 mL) was added to the above-mentioned 3-(benzyloxy)-β-invasive π-bito-2-carbonitrile (4. The mixture was stirred for 5 hours at room temperature, and a solution of 1.0 M of bismuth magnesium bromide in tetrahydrofuran (13.8 mL) was added, and the mixture was further stirred at room temperature for 1 hour. Then, hydrochloric acid (8 mL) was added. The mixture was stirred at room temperature overnight, and then aq. The title compound (1.45 g, 34%) was obtained. Ppm 2· 65 (s, 3H), 5. 18 (s, 2H), 7.25 (d, J=8.5Hz, 1H), 7.28-7.46 (m, 5H), 7.48 (d, J=8.5 Hz, 1H (3) 1-(6-bromo-3-pyrimidinyl pi-but-2-yl)ethanone added dithiol gasification (1.32 g) to gasification|Lv (3·96 g) A stupid suspension (30 mL)' and the mixture was stirred under argon at room temperature for a few hours. The above-prepared 1-[3-(benzomethoxy)-6-bromoindole_2_yl] Ketone (2 · 81 g) sputum solution (3 〇 mL) was added to the mixture and in the chamber The mixture was stirred for 3 hours granted. The reaction mixture was concentrated under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc NMR (300 MHz, CDCh) (5 ppm 2. 74 (s, 3H), 7.23 (d, J=8.8Hz, 1H), 7.52 (d, J=8. 8 Hz, 1H), H.77 (S} 1H). (4) (5-Bromo-3-methyl-trimethane [3, 2-b]17 ratio. Defen-2-yl) (cyclohexyl) formamidine with potassium carbonate (3 · 15 g) added to the above-mentioned 1-(6-bromo-3-hydroxypyridin-2-yl)ethanone (1. 64 g), 2-bromo-1- synthesized in Example A51 (l) a mixture of cyclohexyl ethyl ketone (2.34 g) and N,N-dimethylformamide (2 〇 mL), and the mixture was stirred overnight to a temperature. The saturated aqueous solution of acetic acid was added to terminate the reaction, and The mixture was extracted with aq. EtOAc. EtOAc (EtOAc). (300 MHz, CDCh) &lt;5 ppm 1.19-1. 54 (m, 5H), 1.7〇-1.81 (m, 1H), 1.81-2.00 (m, 4H), 2.63 (s, 3H), 3.23- 3.35 (m, 1H), 7.52 (d, J=8. 7 Hz, 1H), 7.69 (d, J=8. 7 Hz, 1H). · (5) 4-{ [(5-bromo-3-) Isofuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoic acid oxime ι 〇 ° ° C will be 1. 0M titanium chloride (IV) in dichloromethane (5 44 rainbow) was added to the above synthesized (5-bromo-3-mercaptofuro[3, 2_b]pyridine-2-yl) (cyclohexyl) hydrazine a mixture of ketone (1.46 g), 4-aminobenzoic acid decyl ester (753 mg), three 321426 583 201029996 ethylamine (5.05 mL) and dichlorohydrazine (15 mL) in argon, chamber The mixture was stirred overnight, and the mixture was stirred and evaporated to dryness, and then the mixture was evaporated. Acetic acid (1.30 mL) and sodium cyanoborohydride (569 mg) were added to a solution (20 mL) of EtOAc. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m. m. The title compound (0.86 g, 9%) was obtained as a pale brown solid. H NMR (300 MHz, CDCla) δ ppm 1. 00-1. 35 (m, 5H), 1.45-1.55 (m, 1H), 1.63-2.00 (m, 4H), 2.04-2.14 (m, 1H), 2.33 (s, 3H), 3.82 (s, 3H), 4.43-4.54 (in, 2H), 6.55 (d, J-9. 0 Hz, 2H), 7.29 (d, J=8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 9. 0 Hz, 2H). ❹(6) 4_{[(5-bromo-3-methylfuro[3,2-b] Pyridin-2-yl)(cyclohexyl)methyl]amino}benzoic acid A 2N aqueous lithium hydroxide solution (1 () 2 mL) was added to the above-prepared hydrazine {[(5-bromo-3-methyl) A solution of furo[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino benzoic acid methyl ester 〇·86 g) in tetrahydrofuran (20 mL) and the mixture was stirred and stirred under reflux for 2 hr. . An additional 4 N aqueous lithium hydroxide solution (5.10 mL) was added and the mixture was stirred under reflux for 4 hours. Further, 4N aqueous lithium hydroxide solution (51 mL) and ethanol (2 mL) were added, and the mixture was stirred under reflux for 4 hr. The residue was dissolved in water (4 mL) 321426 584 201029996 and IN hydrochloric acid (61.2 mL) was then weighed. The obtained precipitate was collected by filtration to give the title compound (yield: </ RTI> NMR (300 MHz, CDCh) δ ppm 0.95-1.41 (m, j 54_ 1.81 (m, 3H), 1.87- 2.02 (m, 1H), 2.02-2.15 (m, 1H), 2.27 (s, 3H), 4.52-4.62 (m, 1H), 6.63 (d, ]=sl Hz, 2H), 6.92 (d, J= 8.0 Hz, 1H), 7.43 (d5 J=8. 7 Hz, 1H), 7.61 (d, J=8.7Hz, 2H), 7.90 (d, J=8. 7 Hz, 1H), 12.01 (br s, 1H). o (7) 3-{[(4-{[(5-bromo-3-indenyl) and [3, 2-b] n ratio bit 2-yl) (1⁄4 hexyl)methyl] Amino}phenyl)methylamino]aminopropionic acid ethyl hydrazine is added to 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (196 mg) to the above Synthesis of 4-{[(5-bromo-3-indolylfuro[3,2-b]pyridinium.din-2-yl)(cyclohexyl)indenyl]amino}benzoic acid (3〇〇) Mg), /3-alanine ethyl ester hydrochloride (157 mg), 1-p-benzotris-beta monohydrate (156 mg), triethylamine (283 μL) and hydrazine, hydrazine-dihydrazino a mixture of amidoxime (1 〇 niL) and the mixture was stirred at room temperature for 1.5 days. A saturated aqueous solution of ammonium hydride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and brine and dried over magnesium sulfate. The title compound (343 mg, 93%) was obtained as a pale yellow oil. 泔fiMR (300 MHz, CDCl3) (5 ppm 0.95-1.37 (m, 8H), 1.44-1.55 (m, 1H), 1.61-1.98 ( m, 4H), 2.02-2.13 (m, 1H), 2.31 (s, 3H), 2.58 (t, J=5. 9 Hz, 2H), 3.61-3.70 (m, 585 321426 201029996 2H), 4.13 (q , J=7.1 Hz, 2H), 4.40-4.50 (m, 2H), 6.55 (d, J=8.8 Hz, 2H), 6.63 (t, J=5.9 Hz, 1H), 7.27 (d J=8. 5 Hz, 1H), 7.47 (d, J=8. 5 Hz, 1H), 7. 54 (d, j=:8 8 Hz, 2H). ' (8) 3-{ [ (4-{ [ (5 - Desert -3- 曱 吱 π Nan and [3, 2-b] 〇 ratio. (Based) (cyclohexyl) fluorenyl]amino}phenyl)carbonyl]amino}propionic acid A 1N aqueous solution of lithium hydroxide (1· 〇〇mL) was added to the above-mentioned synthesized 3-{[(4-{ [ (5-Methyl-3-methyl 0 Fu 0 Nan [3, 2-b]n than 0-but-2-yl) (cyclohexyl) ® methyl]amino}phenyl) anthracenyl] A mixture of ethyl propionate (343 mg), tetrahydromethane (5 mL) and ethanol (5 mL). The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1. 00 mL). The resulting precipitate was collected by filtration to afford title compound (3 g, <RTIgt; NMR (300 MHz, DMS0-d6) ¢5 ppm 0.94-1.30 (m, 5H), 1.30-1.42 (in, 1H), 1.53-1.82 (m, 3H), 1.86-2.02 (m, ❹ 1H), 2 · 03-2. 15 (m, 1H), 2. 26 (s, 3H), 2. 41 (t, J=7· 1

Hz, 2H), 3.29-3.41 (m, 2H), 4.56 (t, J=8.2 Hz, 1H), 6.60 (d, J=8.9 Hz, 2H), 6.66 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.9 Hz, 2H), 7.89 (d, J=8. 6 Hz, 1H), 8.01 (t, J=5. 5 Hz, 1H Example A126 3-{[(4-{[(5-Bromo-3-methylfuro[3,2-1)]acridin-2-yl)(cyclohexyl)indenyl]amino} Phenyl)carbonyl](methyl)amino}propionic acid 586 321426 201029996

Human n'~x〇2〇h ch3 (1) 3-{ [(4-{ [(5-Bromo-3-indolylfuro[3,2-b]pyridin-2-yl) (cyclohexyl)) Methyl]amino}phenyl)carbonyl](methyl)amino}ethyl propionate 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride 196 mg) was added to the 4-{[(5-bromo-3-methyl-D-f-[3-, 2-b]11-decyl-2-yl)-cyclohexyl group synthesized in Example A125 (6) )methyl]amino}benzoic acid (300 mg), ethyl 3-(methylamino)propionate (134 mg), 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine ( 5小时。 The mixture was stirred at room temperature for 1.5 days. A saturated aqueous solution of ammonium chloride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over magnesium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCls) &lt;5 ppm 0. 94-1. 38 (m, 8H), 1.44-1.55 (m, 1H), 1.59-2.00 (m, 4H), 2.02-2.14 (m, 1H), 2.32 (s, 3H), 2.56~2. 66 (m, 2H), 3. 00 (s, 3H), 3 69 (t, J=7.0 Hz, 2H), 4.06-4.17 (m, 2H ), 4.27-4.34 (m, 1H), 4.39-4.46 (m, 1H), 6.53 (d, J=8. 7 Hz, 2H), 7.20 (d, J-8. 7 Hz, 2H), 7.28 ( d, J=8.5 Hz, 1H), 7.48 (d, 321426 587 201029996 J=8. 5 Hz, 1H). (2) 3-{ [(4-{[(5-bromo-3-methylfuran) [3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)aminopropionic acid 1N aqueous solution of iodine (1. 〇〇mL) Addition to the above-mentioned 3-{[(4-{[(5-bromo-3-mercaptofuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzene) A mixture of ethyl carbonyl](fluorenyl)amino}ethyl propionate (271 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and in HCl (1. 00 mL). The resulting sediment was collected by filtration to give the title compound (271 mg, 90%) as pale yellow solid. JH NMR (300 MHz, CDCh) 5 ppm 0.95-1. 37 (m, 5H), 1.44-1.55 (m, 1H), 1.60-1.97 (m, 4H), 2.03-2.14 (m, 1H), 2.31 ( s, 3H), 2.64 (t, J=6. 3 Hz, 2H), 3.02 (s, 3H), 3.69 (t, J=6.3 Hz, 2H), 4.43 (d, J=7.9 Hz, 1H ), 6.54 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.29 (d, 0 J=8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H) Example A127 3-{[(4-{[(5-Chloro-3-methylwhen n-[3,2-b] 〇 ° 定 基-2-yl)(cyclohexyl)decyl]amine Alkyl}propanoid

321426 588 201029996 (1) 3-(Benzaooxy)-6-chloro-2·'disc ratio. Sodium carbonate (16.3 g) and hydrazine (1 〇 8 g) were added to an aqueous solution (100 mL) of 2_gas_5-base bite (10.0 g) and mixed at room temperature for 5 days. The reaction mixture was acidified to pH = 5 with 1N hydrochloric acid and mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulfuric acid and concentrated under reduced pressure to give a yellow solid. The resulting solid was recrystallized from methanol to give a brown solid. The desertified phenylhydrazine group (8.02 mL) and potassium carbonate (15 5 g) were added to a solution of the obtained solid in acetone (2 GG mL), and the mixture was stirred and stirred under reflux overnight. Remove the non-bath material and concentrate the filter and liquid under reduced pressure. The residue was purified by silica gel chromatography eluting elut elut elut elut eluting H NMR (300 MHz, CDCh) S ppm 5.17 (s, 2H), 6.97 (d, J=8. 4 Hz, 1H), 7.15 (d, J=8. 4 Hz, 1H), 7.30-7.47 (in , 5H). (2) l-[3-(Phenyloxy)-6-gas than 唆-2-yl]ethanol oxime at -45 ° 〇 1. Grab the solution of isopropylmagnesium bromide in tetrahydrofuran ( 60.2 mL) To a solution of the above-prepared 3-(benzyloxy)-6-chloro-2-iodopyridine (17.4 g) in tetrahydrofuran (100 mL), and the mixture was stirred at the same temperature for 1 hour. Acetaldehyde (10.2 mL) was added to the reaction mixture and the mixture was stirred at -45 °C for 30 min, then stirred at room temperature for 2 hr. A saturated aqueous solution of ammonium chloride was added to terminate the reaction, and tetrahydrofuran was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (6. 82 g, 589 321426, 201029996 52%) was obtained from the title compound. 'H NMR (300 MHz, CDCh) δ ppm 1.46 (d, J=6. 6 Hz, 3H), 3.95 (d, J=7.7 Hz, 1H), 5.06-5.18 (m, 3H), 7.14 (d, J=8.5Hz, 1H), 7. 17(d, J=8.5 Hz, 1H), 7.31-7.44 (m, 5H).

(3) l-[3-(Phenyloxy)-6-chloro-11 to 0-but-2-yl]ethyl I. Ammonium tetrapropylammonium citrate (938 mg) was added to 1- [3-(Phenyloxy)-6-chloro &quot;biti-2-yl]ethanol (7. 04 g), 4-mercapto-N-oxide (6.26 g) and acetonitrile (140 mL) The mixture was stirred at room temperature for 3 hours and concentrated under pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) 5 ppm 2.66 (s, 3H), 5.19 (Sj 2H), 7.27-7.47 (m, 7H). (4) 1-(6-Chloro-3-trans-base σ ratio bite -2-yl)ethanone oxime dimethylammonium chloride (4·75 g) was added to a suspension of ruthenium chloride (14.3 g) in benzene (80 mL) and stirred under argon at room temperature. The mixture is 丨 hour. Adding the above-mentioned 1-[3-(phenylhydroxy)-6-chloropyridin-2-yl]ethanone (8. 66 g) to a solution of benzene (8 〇m L) to the mixture and in the room The mixture was stirred at temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and aqueous saturated aqueous The extract was washed with saturated brine, dried over magnesium sulfate The title compound (4. 89 g, 86%) was obtained. 590 321426 201029996 Ή NMR (300 MHz, CDCh) ά ppm 2.74 (s, 3H), 7.31 (d, J=8.8Hz, 1H), 7.39 (d, J=8. 8 Hz, 1H), 11.77 (s , 1H). (5) (5-Galy-3-mercaptofuro[3,2-b]pyridin-2-yl)(cyclohexyl)fluorenone added potassium carbonate (11.8 g) to the above Synthesis of 1-(6-chloro-3-hydroxyl 11-butoxy-2-yl)ethanone (4.99 g), 2-oxa-1_cyclohexylethyl ketone synthesized in Example A51 (l) (7.01 g) And a mixture of n,N-dimercaptocarbamide (50 mL) and the mixture was stirred overnight at room temperature. A saturated aqueous chloride solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether to afford title compound (5 78 g, 73%). H NMR (300 MHz, CDCh) δ ppm 1. 19-1. 61 (m, 5H), 1.70- 1.80 (m, 1H), 1.81-2.01 (m, 4H), 2.63 (s, 3H), 3.23- 3.35 (m, 1H), 7.39 (d, J=8. 7 Hz, 1H), 7.78 (d, J=8. 7 Hz, 1H). ❹ (6) 4_{[(5-chloro-3-曱Methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)indenyl]amino}benzoic acid methyl ester in 〇〇C will be 1.0 M titanium chloride (IV) in dioxane solution ( 4.32 mL) was added to the above-mentioned (5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)fluorenone (1·00 g), 4-amino group A mixture of methyl benzoate (599 mg), triethylamine (4.11 mL) and dichloromethane (1 mL) was stirred and the mixture was stirred overnight at room temperature under argon. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. To a solution of the obtained oil in tetrahydrofuran (15 raL), EtOAc EtOAc EtOAc (EtOAc) A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc) NMR NMR (300 MHz, CDCh) 5 ppm 0. 96-1. 37 (ra, 5H), 1.45-L56 (in, 1H), 1.63-1.99 (m, 4H), 2.03-2.14 (m, 1H), 2.32 (s, 3H), 3.81 (s, 3H), 4.43-4.56 (ra, 2H), 6.54 (d, J=9. 0 Hz, 2H), 7.14 (d, J=8. 5 Hz, 1H) , 7.56 (d, J=8. 5 Hz, 1H), 7.79 (d, J=9. 0 Hz, 2H). (7) 4-{ [(5-chloro-3-mercaptofuran [3, 2-b]«Byridin-2-yl)(cyclohexyl) fluorenyl]amino}benzoic acid A 1N aqueous solution of hydrazine hydroxide (2 〇 mL) was added to the above-prepared 4-{[(5-chloro) Benzylfuro[,,,,,,,,,,, The mixture was stirred and heated under reflux for 3 hours and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and EtOAc (EtOAc) The resulting precipitate was collected by filtration and the obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (1.21 g, 96 ° / 〇) was obtained as the title compound as a pale yellow solid. H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.42 (m, 6H), 1.54-1.82 (m, 3H), 1.87-2.03 (m, 1H), 2.04-2.16 (m, 592 321426 201029996 1H) , 2.28 (s, 3H), 4.53-4.64 (m, 1H), 6.64 (d, J=8. 9 Hz, 2H), 6.95 (d, J=7.9 Hz, 1H), 7.32 (d, J =8. 6 Hz, 1H), 7.62 (d, J=8. 9 Hz, 2H), 7.99 (d, J=8. 6 Hz, 1H), 12. 02 (br s, 1H). (8) 3-{[(4-{[(5-chloro-3-indolylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl]amino }ethyl propionate added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ❹ (2Π mg) to the above synthesized 4_{[(5_气_ 3-decylfuro[3,2-b;l.pyridin-2-yl)(cyclohexyl)indenyl]amino}benzoic acid (3 〇〇mg), 々-alanine ethyl ester hydrochloride a mixture of salt (Π4 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (315eL) and N,N-didecylguanamine (10 mL) and stirred at room temperature 25 days. A saturated aqueous solution of ammonium chloride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine, and evaporated and evaporated. The title compound (383 mg, quantitative) was obtained from the title compound. H ]^MR(300 MHz, CDCl3)5ppin 0.96-1.37 (in,8H),1.45-1.56 (m, 1H), 1.61-1.99 (m, 4H), 2.02-2.14 (m, 1H), 2.31 (s ,3H),2.54-2.62 (m,2H), 3.60-3.69 (m,2H), 4.13 (q, J=7. 1 Hz, 2H), 4.40-4.50 (m, 2H), 6.55 (d, J =8.8Hz, 2H), 6.62 (t, J=5. 9 Hz, 1H), 7. 14 (d, J=8. 5 Hz, 1H), 7.54 (d, J=8. 8 Hz, 2H) , 7.55 (d, J=8. 5 Hz, 1H). 593 321426 201029996 (9) 3-{[(4-{[(5-chloro-3-methylfuro[3,2-b]acridine) -2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]aminopropionic acid A 1N aqueous solution of sodium hydroxide (2. 〇〇mL) was added to the above-mentioned 3-{[(4 -{[(5-chloro-3-methylfuro[3,2-13]pyridin-2-yl)(cyclohexyl)indolyl]amino}phenyl)carbonyl]amino}ethyl propionate ( A mixture of 383 mg), tetrahydrofuran (5 mL) and EtOAc (5 mL). The residue was dissolved in water mL) and in hydrochloric acid (2.0 mL) was added at EtOAc. The resulting precipitate was collected by filtration to afford title compound ( 328 mg, 93%). H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.30 (m, 5H), 1.30-1.41 (m, 1H), 1.55-1.82 (m, 3H), 1.87-2.01 (m, 1H), 2.04- 2.16 (m, 1H), 2.26 (s, 3H), 2.42 (t, J=7. 2 Hz, 2H), 3.26~3.42 (m, 2H), 4.56 (t, J=8.2 Hz, 1H) 6.60 ( d, J=8. 9 Hz, 2H), 6.68 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.52 (d, J=8. 9 Hz, 2H), 7.93-8.06 φ (m, 2H). Example A128 3-{ [(4-{ [(5-Chloro-3-indolyl][0,2-b]° ratio bit-2-yl) (cyclohexyl)indenyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid

321426 594 201029996 (1) 3-{[(4-{[(5-chloro-3-indolylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)indenyl]amino}benzene Ethyl carbonyl](methyl)amino phthalic acid ethyl ester 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (217 rag) was added to the example Α127 (7) 4-{[(5-Chloro-3-methylindolo[3,2-b]acridin-2-yl)(cyclohexyl)methyl]amino}benzoic acid synthesized ( 300 rag), 3-(methylamino)propionate ethyl ester 〇 48 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (315//L) and N,N- 5小时。 Mixture of dimercaptoamine (1 〇 mL) and the mixture was stirred at room temperature for 2.5 days. A saturated aqueous solution of ammonium chloride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and brine and dried over EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCls) δ ppm 0. 96-1. 38 (m, 8H), 1.44-1.56 (m, 1H), 1.61-1.99 (m, 4H), 2.03-2.15 (m, 1H), ❺ 2.31 (s, 3H), 2. 61 (t, J=6.9 Hz, 2H), 3.00 (s, 3H), 3.69 (t, J=6.9Hz, 2H), 4. 06-4. 17 (m , 2H), 4.29-4.36

Cm, 1H), 4.39-4.47 (m, 1H), 6.54 (d, J=8. 7 Hz, 2H), ^•14 (d, J=8. 5 Hz, 1H), 7.21 (d, J= 8. 7 Hz, 2H), 7.56 (d, J=8.5 Hz, 1H). (2) 3-{[(4-{[(5-Chloro-3-indolylfuro[3, 2-b]] Acridine-2-yl)(cyclohexyl)fluorenyl]amino phenyl)carbonyl](fluorenyl)aminopyridinic acid A 1N aqueous lithium hydroxide solution (3. 〇〇mL) was added to the above synthesized 3_ {[(4-{ [(5-Galy-3-mercaptofuro[3,2-b]pyridin-2-yl)(cyclohexyl) 321426 595 201029996 methyl]amino}phenyl) A mixture of carbonyl](fluorenyl)amino}ethyl propionate (332 mg), THF (5 mL) and EtOAc (5 mL). The residue was dissolved in water (1 mL) and 1N hydrochloric acid (3. The resulting precipitate was collected by filtration to give the title compound (278 mg, 89%). HJ^MR (300 MHz, CDCl3) 6 ppm 0.94-1.38 (m, 5H), 1.44 - 1.56 (m, 1H), 1.61-1.98 (m, 4H), 2.02-2.15 (m, 1H), ❹ 2. 31 (s,3H), 2.62 (t, J=6.3 Hz, 2H), 3.00 (s, 3H), 3.68 (t, J=6.3 Hz, 2H), 4.43 (d, J=8. 0 Hz, 1H) , 6.54 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5 Hz, 1H). Example A129 3-[({4-[(cyclohexyl{3-indolyl-5-[(phenylcarbonyl)amino]-i-benzofuran-2-yl}indolyl)amino]phenyl} Carbonyl)(methyl)amino]propionic acid

Addition of benzamidine chloride (99//L) to 3-U(4-{[(5-amino-3-methyl-1-benzofuran-2-yl) synthesized in Example A110(5) (cyclohexyl)methyl]amino}phenyl) benzyl](fluorenyl)amino}propionic acid ethyl vinegar (280 mg) in hydrazine, hydrazine-dimethylacetamide solution (10 mL) The mixture was stirred at room temperature overnight. A solution of 596 321426 201029996 and aqueous ammonium chloride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (30 to 70% ethyl acetate /hexane) to afford pale oil. A 1N aqueous solution of lithium hydroxide (2.00 mL) was added toEtOAc. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (2. 00 mL) was then weighed. The resulting precipitated product was collected by filtration to give the title compound (303 mg, 94%). ]H NMR (300 MHz, CDCh) δ ppm 0. 93-1. 38 (m, 5H), 1.46-1.58 (m, 1H), 1.60-1.99 (ra, 4H), 2.03-2.16 (m, 1H) , 2.19 (s, 3H), 2.44-2.60 (m, 2H), 2.96 (s, 3H), 3.49-3.64 (m, 2H), 4.36 (d, J=8. 0 Hz, 1H), 6.54 (d , J=8. 7 Hz, 2H), 7.13-7.33 (m, 4H), 7.39-7.56 (m, 3H), 7.80 (s, 1H), 7.85-7.92 (m, 2H), 8.21 (s, 1H Example A130 H 3-[({4-[(cyclohexyl){3-methyl-5-[(phenylsulfonyl)amino)-p-benzofuran-2-yl}fluorenyl) Amino]phenyl}alkyl)(methyl)amino]propionic acid

(1) 3-[({4-[(cyclohexyl){3-indolyl-5-[(phenylsulfonyl)amino]- _ 321426 597 201029996 benzofuran-2-yl}methyl)amine Ethyl]phenyl}carbonyl)(indenyl)amino]propionic acid ethyl ester The gasified benzenesulfonyl (99/2 L) was added to the 3-{[(4-{) synthesized in Example All0(5). [(5-Amino-3-methyl-1-benzopyrene~-2-yl)(cyclohexyl)indenyl]amino}phenyl)benzyl](methyl)amino}propionic acid A solution of vinegar (254 mg) in N,N-dimercaptoacetamide (1 mL) was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (312 mg, 96%) was obtained eluted elute ]H NMR (300 MHz, CDCh) 5 ppm 0. 95-1. 34 (m, 8H), 1.41-1-54 (m, 1H), 1.58-1.95 (m, 4H), 2.04-2.12 (m, 1H), 2.18 (s, 3H), 2.56-2.68 (m, 2H), 3.02 (s, 3H), 3.71 (t, J=6.7Hz, 2H), 4.12 (q, J=7. 1 Hz, 2H ), 4.28-4.39 ❹(m, 2H), 6.51-6.58 (m, 3H), 6.78 (dd, J=8. 8, 2.2 Hz, 1H), 7.14-7.24 (m, 4H), 7.37-7.46 ( m, 2H), 7.48-7.56 (m, 1H), 7. 68-7.74 (m, 2H). (2) 3-[({4-[(cyclohexyl){3-methyl-5-[(benzene Alkylsulfonyl)amino]-1 -benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(fluorenyl)amino]propionic acid 1N aqueous sodium hydroxide solution (2. 〇〇 Add to the above-prepared 3-[({4-[(cyclohexyl){3-indolyl-5-[(phenylsulfonyl)amino]-1-benzofuran-2-yl}) a mixture of ethylamino]phenyl}alkyl)(indenyl)amino]propionic acid ethyl ester (312 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) and stirred at room 598 321426 201029996 Hour and concentrate under reduced pressure. The residue was dissolved in hydrazine (mL) and 1N hydrochloric acid (2. 〇〇 mL) was added at 0 °C. The resulting precipitate was collected by filtration to afford title compound (240 mg, 80%). ]H NMR (300 MHz, CDCh) 5 ppm 0. 89-1. 37 (m, 5H), 1.40- 1.55 (m, 1H), 1.58-1.97 (m, 4H), 2. 02-2.13 (m, 1H), 2. 16 (s, 3H), 2.62 (t, J = 6. 1 Hz, 2H), 3.01 (s, 3H), 3.68 (t, J = 6.1 Hz, 2H), 4.34 (d, J =8.0 Hz,1H),6.53 (d, J=8.7 Hz, 2H), 6.79 (dd, J=8. 7, 2.3 Hz, 1H), ® 6.84-6.98 (m, 1H), 7.11-7.25 (m , 4H), 7.34-7.42 (m, 2H), 7.45-7.53 (m, 1H), 7.67-7.74 (m, 2H). Example A131 3-[{ [4-({[5-(Benzylmethyl) Amino)-3-mercapto-1-benzofuran-2-yl] (1⁄4 hexyl) fluorenyl}amino)phenyl] mercaptopurine (fluorenyl)amino]propionic acid

(1) 3_[{[4-({[5-(phenylhydrazinyl)-3-indolyl-1-benzofuran]-2-yl](%hexyl)methyl}amino) Phenyl] benzyl}(fluorenyl)amino]propionic acid B g is added to acetic acid (56 // L) and sodium cyanide hydride (61. 6 mg) to the synthesis of Example 8 110 (5) -{[(4-{[(5-Amino-3-indolyl-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)carbonyl](indenyl)amino 5小时。 The mixture of a mixture of ethyl acetate (322 mg), a mixture of benzaldehyde (100 / / L) and ethanol (10 mL) and stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc) elute ]H NMR (300 MHz, CDCh) δ ppm 0. 92-1. 37 (m, 8H), 1.47-1.96 (m, 5H), 2.01-2.12 (m, 1H), 2.17 (s, 3H), 2.56 -® 2.67 (m, 2H), 3.02 (s, 3H), 3.66-3.77 (m, 3H), 4.06- 4. 18 (m, 2H), 4. 29-4. 39 (in, 4H), 6 51-6. 64 (m, 4H), 7.14-7.43 (m, 8H). (2) 3-[{[4-({[5-(phenylhydrazino))-3-yl-1 -benzofuran-2-yl](cyclohexyl)fluorenyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid A 1N aqueous solution of sodium hydroxide (2.0 mL) was added to the above synthesis. 3-[{[4-({[5-(benzylamino))-3-methyl-1-benzo[rho]-2-yl](cyclohexyl)fluorenyl}amino)benzene A mixture of ethyl carbonyl (indenyl)amino]propionic acid (354 mg), THF (5 mL) and EtOAc (5 mL). The residue was dissolved in water (1 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to give the title compound (d. NMR NMR (300 MHz, CDCh) &lt;5 ppm 0. 92-1. 34 (m, 5H), 1.47-1.58 (m, 1H), 1.60-1.97 (m, 4H), 2.01-2.12 (m, 1H ), 2.17 (s, 3H), 2.67 (t, J-6.4 Hz, 2H), 3.04 (s, 3H), 3.65-3.73 (m, 2H), 4.30-4.36 (m, 3H), 6.55 (d, J=8. 7 600 321426 201029996

Hz, 2H), 6.59 (dd, J=8. 7, 2. 7 Hz, 1H), 6.63-6.67 (ra, 1H), 7.17 (d, J=8. 7 Hz, 1H), 7.20-7.42 ( m, 7H). Example A132 3-[({4-[(cyclohexyl){5-fluoro-3-[(2-methoxyethoxy)indolyl]-1-benzofuran-2-yl }曱))amino]phenyl}carbonyl)amino]propionic acid

(1) 5-Fluoro-3-[(2-methoxyethoxy)methyl]-i_benzoxanthin-2-reotrophic acid sodium hydride (60%, oil) at 0 ° C The solution was added to a solution of 2-methoxyethanol (2.74 mL) in N,N-dimethylamine (25 mL). After the scramble, the 3-(bromoindolyl)-5-fluoro-1-benzopyrene-N-methyl-methyl acid (5.00 g) synthesized in Example A47 (2) was added at 〇 °C. N,N-dimercaptoamine solution (25 mL). The reaction mixture was stirred at 80 ° C for 5 hr. then a saturated aqueous solution of ammonium sulfate was added and the mixture was extracted with ethyl acetate. The extract was washed with brine and brine to dryness with sulfuric acid and concentrated under reduced pressure. The title compound (1. 54 g, 31%) was obtained. !H NMR (300 MHz, CDCh) δ ppm 3.40 (s, 3H), 3.57-3.62 (m, 2H), 3. 66-3. 72 (m, 2H), 3. 99 (s, 3H), 5 .ll(s, 2H), 7.14-7.22 (m, 1H), 7.45-7.51 (m, 1H), 7.60-7.65 (m, 1H). 601 321426 201029996 (2) {5-fluoro-3-[( 2-methoxyethoxy)methyl]_1_benzofuran__2-yl} sterol sodium borohydride (825 mg) was added to the above-mentioned 5-fluoro-3-[( 2-methoxyethoxy)methyl]-benzoic acid methyl ester 54 g), calcium chloride (1.21 g), ethanol (15 niL) and tetrahydrofuran (15 mL) / The mixture was incubated at the temperature for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc EtOAc (EtOAc m. !H NMR (300 MHz, CDCh) δ ppm 3.38 (s, 3H), 3.55-3.60 (m, 2H), 3.63-3.68 (m, 2H), 4.73 (s, 2H), 4.76 (br s, 2H) , 6. 95-7. 04 (m, 1H), 7.17-7.23 (m, 1H), 7.33-7.40 (m, 1H). (3) 5 both 3-[(2-methoxyethoxy) )methyl]-1-benzoxyf π-nan-2-carboxaldehyde oxime tetrapropylammonium perruthenate (366 mg) was added to the above-mentioned synthesized {5-fluoro~3-[(2-decyloxy) a mixture of ethoxy)indenyl]-benzofuran-2-yl}sterol (2.65 g), 4-methylmorpholine N-oxide (2.44 g) and acetonitrile (50 mL) and stirred The mixture was stirred for 5 hrs. EtOAcjjjjjjjjjj 'H NMR (300 MHz, CDCh) δ ppm 3.41 (s, 3H), 3.58-3.64 2H), 3.72-3.77 (m, 2H), 5.07 (s, 2H), 7.21-7.29 (m,1H), 7.48 -7.57 (m, 2H), 10.09 (s, 1H). 602 321426 201029996 (4) Cyclohexyl {5-fluoro-3-[(2-methoxyethoxy)methyl]_ι_benzofuran- 2-Methyl}anthrone was added to a solution of 1.0 M tetrahydrofuran bromide in tetrahydrofuran (7.91 mL) at 0 ° C to the above-mentioned 5-fluoro-3-[(2-methoxyethoxy)methyl group. A solution of benzofuran-2-furaldehyde (1.33 g) in tetrahydrofuran (2 mL) and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (EtOAc EtOAc) To a mixture of the obtained oil, 4-mercaptomorpholine N-oxide (933 mg) and acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. It was concentrated under reduced pressure. The title compound (881 mg, 50%) was obtained. Η NMR (300 MHz, CDCh) δ ppm 1.17-1. 55 (m, 5H), 1.70- 1.80 (m, 1H), 1.80-2.01 (m, 4H), 3.24-3.37 (m, 1H), ❹ 3.40 (s,3H), 3. 57-3.63 (m, 2H), 3. 66-3.72 (m, 2H), 5.11 (s, 2H), 7.14-7.23 (m, 1H), 7.41-7. 48 (m, 1H), 7.64-7.70 (m, 1H). (5) 4_[(cyclohexyl{5-fluoro-3-[(2-decyloxyethoxy)methyl]-; Furan-2-yl}hydrazino)amino]benzoic acid hydrazine was added to a 1.0 M solution of titanium (IV) in methylene chloride (3.16 mL) to the above-mentioned cyclohexyl group {5-fluoro -3-[(2-decyloxyethoxy)methyl][monobenzofuran-2-yl}fluorenone (881 mg), 4-aminobenzoic acid oxime ester (44 mg), triethyl A mixture of the amine (2.93 mL) and methylene chloride (1 mL) was stirred at room temperature under argon 321426 603 201029 996. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. Acetic acid (301 / L) and sodium cyanoborohydride (331 mg) were added to the obtained solid THF (10 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , CDCh) δ ppm 0.96-1.35 (m, 5H), 1.41-1.51 (m, 1H), 1.58-1.85 (m, 3H), 1.86-2.01 (m, 1H), 2.01-2.13 (m, 1H), 3.43 (s, 3H), 3.53-3.60 (m, 2H), 3.60-3.67 (m, 2H), 3.80 (s, 3H), 4.46-4.72 (m, 3H), 4. 99 (d, J=8 8 Hz, 1H), 6. 60 (d, J=9. 0 Hz, 2H), 6.88-6.98 (m, 1H), 7.13-7.19 (m, 1H), 7.27-7.34 (m, 1H), ❹ 7. 78 (d, J=9. 0 Hz, 2H). (6) 4-[(cyclohexyl{5-fluoro_3_[(2-methoxyethoxy)indolyl]-p-benzoyl Furan-2-yl}methyl)amino]benzoic acid A 1N aqueous solution of sodium hydroxide (5.0 mL) was added to the above-mentioned 4_[(cyclohexyl{5-fluoro-3-[(2-) a mixture of oxyethoxy)indolyl]-benzofuran-2-yl}methyl)amino]benzoic acid oxime ester (482 mg), tetrahydrofuran (5 rainbow) and ethanol (5 mL) and refluxed The mixture was stirred under heating, and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (5. Precipitate to give a reddish solid 321426 604 201029996 title title compound (437 mg, 93%).]H NMR (300 MHz, CDCh) δ ppm 0. 99-1. 35 (m, 5H), 1.4〇- 1.53 (m, 1H), 1.59-1.85 (m, 3H), 1.86-2.14 (m, 2H), 3.44 (s, 3H), 3.52-3.70 (m, 4H), 4.49-4.73 (m, 3H), 6.62 (d, J-8. 9 Hz, 2H), 6.91-7.00 (m, 1H), 7.14-7.20 (m, 1H), 7.29-7.36 (m, 1H), 7.84 (d, J=8. 9 Hz, 2H) (7) 3-[ ({4-[(cyclohexyl){5-fluoro-3-[(2-methoxyethoxy)methyl]-benzofuran-2-yl}- Ethyl]amino}phenyl}carbonyl)amino]propionic acid ethyl ester 1-ethyl-3-(3-didecylaminopropyl) carbodiimide hydrochloride (126 mg) was added to the above Synthesis of 4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-ylindenyl)amino]benzoic acid (200 mg),/5-alanine ethyl ester hydrochloride (1〇1 mg), 1-hydroxybenzotriazole monohydrate (101 mg), triethylamine (184#L) and N,N A mixture of dimethylformamide (10 mL) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (216 mg, 89%) was obtained eluted elute H NMR (300 MHz, CDCI3) δ ppm 1. 00-1. 34 (m, 8H), 1.41-1.52 (m, 1H), 1.60-2.01 (m, 4H), 2.03-2.13 (m, 1H), 2.58 (t, J=5.9 Hz, 2H), 3.43 (s, 3H), 3.54-3.69 (m, 6H), 4.13 (q, J=7. 1 Hz, 2H), 4.45-4.53 (m, 1H) , 4.57 (d, J=12. 1Hz, 1H), 4.65 (d, J=1. 1 Hz, 1H), 4.87 (d, J=8. 5 Hz, 1H), 6.56-6.65 (m, 3H) , 6.88-6.98 (m, 1H), 605 321426 201029996 7.14-7.20 (m, m), 7.28-7.34 (m, 1H), 7.53 (d, J=8.8 Hz, 2H). (8) 3-[( {4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-benzofuran-2-ylindolemethyl)amino]phenyl}carbonyl)amine A solution of 1N sodium hydroxide (1. 〇〇mL) was added to the above-prepared 3-[({4-[(cyclohexyl){5-fluoro-3-[(2-methoxyethoxy) Ethyl)methyl]-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid ethyl ester (216 0 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) of the mixture was stirred at room temperature for 3 hr and concentrated. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1.00 mL) was added to EtOAc. The title compound (69. 6 mg, 34%) was obtained as a pale yellow solid. !11 NMR (300 MHz, CDCls) δ ppm 0. 99-1. 35 (m, 5H), 1.40-1.51 (m, 1H), 1.59-1.85 (m, 3H), 1.84-2.00 (m, 1H) , 2.01-2.12 (m, 1H), 2.63 (t, J=5.7 Hz, 2H), 3.42 (s, 3H), 3.54-3.69 (m, 6H), 4.49 (d, J=8. 3 Hz, 1H ), 4.56 ❿ (Mountain J=12. 1 Hz, 1H), 4. 64 (d, J=1. 1 Hz, 1H)' 6· 53- 6· 67 (m, 3H), 6.88-6.99 (m , 1H), 7.12-7.20 (m, 1H), 7.27-7. 34 (m, 1H), 7. 52 (d, J=8. 7 Hz, 2H). Example A133 3-[({4- [(Cyclohexyl{5-fluoro-3-[(2-decyloxyethoxy)methyl]-benzofuran-2-yl}indolyl)amino]phenyl}yl)(methyl) Amino] propionic acid 321426 606 201029996

(1) 3-[({4-[(cyclohexyl){5-fluoro-3-[(2-decyloxyethoxy)methyl] _1-benzofuran~2-yl}decyl)amino Phenyl}carbonyl)(methyl)amino]propionic acid ethyl ester 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride salt (126 mg) was added to 4-[(Cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-benzofuran-2-yl}methyl)amine synthesized in Example A132(6) Benzoic acid (200 mg), ethyl 3-(methylamino)propionate (86.4 mg), dipyridylbenzotrisole monohydrate (1 〇 1 mg), triethylamine (184# L) and A mixture of N,N-dimercaptocarhamamine (1 mL) and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (175 mg, 70%) was obtained eluted elute H NMR (300 MHz, CDCI3) S ppm 1. 00_1. 37 (m, 8H), 1. 42-1.53 (m' 1H), 1.59-2. 〇〇(m, 4H), 2.03-2. 14 ( m, 1H), 2.61 (t, J=7. 0 Hz, 2H), 3. 01 (s, 3H), 3.42 (s, 3H), 3. 54-3.75 (m, 6H), 4. 11 ( q, j=7.1 Hz, 2H), 4. 42-4. 51 (m, 1H), 4.59 (d, J=12. 1 Hz, 1H), 4.65 (d, J=1. 1 Hz, 1H) , 4·71 (d, J=8.5 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 607 321426 201029996 6.89-6.98 (m, 1H), 7.16-7.23 (m, 3H), 7.28-7.34 (m, 1H). 9 (2) 3-[({4-[(cyclohexyl{5_fluoro_3_[(2-methoxyethoxy)methyl)]) -2-yl}indenyl)amino]phenyl}alkyl)(methyl)amino]propionic acid A 1N aqueous solution of sodium hydroxide 〇〇. 〇〇mL) was added to the above synthesized 3- [({4 -[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)indolyl]_1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl) (methyl) A mixture of amino]ethyl propionate (175 mg), tetrahydrofuran (5 mL) and ethanol (5 mL). The residue was dissolved in water (1 mL), 1N hydrochloric acid (1. The extract was washed with EtOAc (EtOAc m. JH NMR (300 MHz, CDCh) δ PPm 0. 99-1. 35 (m, 5H), 1.40-1.51 (m, 1H), 1.60-2.00 (m, 4H), 2.02-2.15 (m, 1H), 〇 2.64 (t, J=6.4Hz, 2H), 3.02 (s, 3H), 3.42 (s! 3H)! 3.54-3.75 (m, 6H), 4.47 (d, J=8.3 Hz, lH), 4.59 ( d, &gt;12. 3 Hz, 1H), 4.66(d, &gt;12. 3 Hz, iH), 6&gt;6〇(d&gt; J=8 ?

Hz, 2H), 6.89-6.99 (m, 1H), 7.16-7.25 (m, 3H), 7.28-7.35 (m, 1H). Example A134 Ethyl + (3-methyl + stupid n-cephene + Benzyl]amino}phenyl}carbonyl]amino}propionic acid 321426 608 201029996

CH, CH, O

n^^co2h (1) 2-Ethyl-1-(3-methyl-1-benzoxen-2-yl)butan-1-one was added to the gasification (1.35 g) at 0 °C. A mixture of 3-methyl-1-benzophenone (1.00 g), 2-ethylbutylphosphonium chloride (1.02 mL) and trimethoprim (10 mL) and the mixture was stirred for 3 hours. Water was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound ( 丨. 65 g, 99%) was obtained. NMR (300 MHz, CDCh) δ ppm 0.93 (t, J=7.4 Hz, 6H), 1.51-1.67 (m, 2H), 1.75-1.92 (m, 2H), 2.78 (s, 3H), 2.97-3.08 ( m, 1H), 7.40-7.53 (m, 2H), 7.81-7.91 (m, 2H). 9 ® (2) 4-{[2-ethyl-1-(3-indolyl-1-benzothiophene) -2-yl)butyl]amino}benzoic acid methyl hydrazine To a solution of 1.0 M titanium chloride (IV) in dichloromethane (8 〇 4 mL) was added to the above-mentioned 2-ethyl-1- (3-mercapto-1-benzoindole-2-yl)-butan-one (1.65 g), 4-aminobenzoic acid methyl ester (1.15 g), triethylamine (7 47) and A mixture of dichloromethane (15 mL) was mixed with argon at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the mixture was evaporated to dryness and evaporated to ethyl acetate. Washed with saturated brine 321426 609 201029996. Chlorinated (IV) (882#L) was added to the obtained oil, 4-aminobenzoic acid vinegar (506 mg), triethylamine (7.47 mL) and dichloromethane (30 mL) The mixture was stirred under argon at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. Acetic acid (797 / U) and sodium cyanoborohydride (842 呃) were added to a solution of the obtained oil in THF (30 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction. The organic solvent was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound (580 mg, 23%) was obtained eluted eluted elute NMR (3〇〇MHz, CDCls) 5 ppm 0. 84-0. 99 (m, 6H), 1.33-(m, 3H), 1.67-1.84 (m, 2H), 2.46 (s, 3H), 3.79 O (s,3H)'4.45(d,J=6.6Hz,lH),4,81-4.89(m,lH), 6.52 (d, J=9.0 Hz, 2H), 7.22-7.29 (m, 1H), 7.31-7.38 1H), 7.61-7.66 (m, lfl), 7.67-7.71 (m, 1H), 7.77 (d, J=9.0 Hz, 2H). (3) 4-{[2-ethyl-1_( 3~Methyl-i- stupid and n-cephen-2-yl)butyl]amino} Benzoic acid A 1N aqueous solution of sodium hydroxide (1 〇·〇mL) was added to the above-mentioned 4-{[2 -ethyl-i-(3-methyl-1-benzophenphen-2-yl)butyl]amino}benzoic acid methyl ester (580 mg), tetrahydrofuran (10 mL) and ethanol (10 mL) The mixture was mixed with 610 321426 201029996, and the mixture was stirred and evaporated under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL) EtOAc (EtOAc) H NMR (300 MHz, CDCla) δ ppm 0. 87-0. 99 (m, 6H), 1.32-1.56 (m, 3H), 1.67-1.83 (m, 2H), 2.46 (s, 3H), 4.46- 4.54 (m, 1H), 4.82-4.91 (m, 1H), 6.53 (d, J=8.7 Hz, ^ 2H), 7.22-7.30 (m, 1H), 7.32-7.39 (m, 1H), 7.65 (d , J=7.6Hz, 1H), 7.70 (d, &gt;7.6 Hz, 1H), 7.81 (d, &gt;8.7 Hz, 2H). (4) 3-{[(4-{ [2-B Ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 1-ethyl-3-(3-di Mercaptopropyl propyl) carbodiimide hydrochloride (196 mg) was added to the above-prepared 4-{[2-ethyl-1-(3-mercapto-1-benzoindole-2- Butyl]amino}benzoic acid (250 mg), alanine ethyl φ ester hydrochloride (157 mg), 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine (284) /zL) and a mixture of hydrazine, hydrazine-dimethyl methamine (10 mL) and the mixture was stirred at room temperature for 2.5 days. A saturated aqueous solution of chlorinated acid was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (30 to 70% ethyl acetate / hexane) to afford title compound (330 mg, quantitative). ]H NMR (300 MHz, CDCls) δ ppm 0. 86-0. 97 (m, 6H), 1.24 (t, J-7. 1 Hz, 3H), 1.33-1.55 (m, 3H), 1. 67 -1.83 (m, 321426 611 201029996 2H), 2.46 (s, 3H), 2.54-2.60 (m, 2H), 3.60-3.68 (m, 2H), 4.12 (q, J=7. 1 Hz, 2H), 4.35 (d, J=6. 6 Hz, 1H), 4.79-4.86 (m, 1H), 6.50-6.61 (m, 3H), 7.22-7.29 (m, 1H), 7.31-7.37 (m, 1H), 7.52 (d, J=8. 5 Hz, 2H), 7.61-7.66 (m, 1H), 7.66-7.71 (m, 1H). (5) 3-{[(4-{[2-ethyl-1 -(3-methyl-1-benzothiophen-2-yl)butyl]amino}phenyl)carbonyl]amino}propionic acid ◎ 1N aqueous sodium hydroxide solution (2.0 mL) was added to the above Synthesis of 3-{[(4-{[2-ethyl-1-(3-methyl-1-benzoinphen-2-yl)butyl]amino}phenyl)]amino]amino} A mixture of ethyl propionate (330 mg), tetrahydrofuran (5 mL) and ethanol (5 mL). The residue was dissolved in water (10 mL) and dried. The title compound (272 mg, 91%) was obtained as a pale yellow solid. JH NMR (300 MHz, CDCh) δ ppm 0. 86 -0. 97 (m, 6H), 1 32-〇1-56 (m, 3H), 1.66-1.83 (m, 2H), 2.45 (s, 3H), 2.60 (t, J=5. 5 Hz, 2H), 3.57-3.66 (m, 2H), 4.82 (d, J=6 0

Hz, 1H), 6.47-6.58 (m, 3H), 7.22-7.29 (m, 1H), 7.31- 7.38 (in, 1H), 7.50 (d, J=8. 7 Hz, 2H), 7.64 (d, J=7 5

Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H). Example A135 3-{ [(4-{[2-ethyl-1-(3-indolyl-1-benzoindole-2) -yl)butyl]amino}phenyl)carbonyl](fluorenyl)amino}propionic acid 321426 612 201029996 CH, CH. n

ν^^°°2Η ch3 (1) 3-{[(4-{[2-ethyl-1-(3-indolyl-1-benzothiophen-2-yl)butyl]amino}phenyl Ethyl carbonyl](fluorenyl)amino}ethyl propionate ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg) was added to Example A134(3) Synthesis of 4-{[2-ethyl-1-(3-0 fluorenyl 1-benzothiophen-2-yl)butyl]amino}benzoic acid (250 mg), 3-(fluorenyl) Amino)ethyl acetate (134 mg), 1-p-benzoquinone trihydrate monohydrate (156 mg), triethylamine (284//L) and hydrazine, hydrazine-dimethylhydrazine ( 5小时) The mixture was stirred at room temperature for 2.5 days. A saturated aqueous solution of ammonium carbonate was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and aq. The title compound (253 mg, ❹ 77%) was obtained. ]H NMR (300 MHz, CDCh) δ ppm 0. 87-0. 97 (m, 6H), 1.22 (t, J=7. 1 Hz, 3H), 1.32-1.54 (m, 3H), 1.67-1.82 (m, 2H), 2.45 (s, 3H), 2.60 (t, J=7.0 Hz, 2H), 3.00 (s, 3H), 3.69 (t, J=7. 0 Hz, 2H), 4.10 (q, J=7. 1 Hz, 2H), 4.23 (d, J=6.3 Hz, 1H), 4.76-4.83 (in, 1H), 6.51 (d, J=8.8 Hz, 2H), 7.19 (d, J=8 8 Hz, 2H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.61-7.66 (m, 1H), 7.68-7.72 613 321426 201029996 (m, 1H). (2)3 -{[(4-{[2-ethyl-1-(3-1)-l-benzoxen-2-yl)butyl]amino phenyl)carbonyl](methyl)amino }Propanic acid A 1N aqueous solution of sodium hydroxide (2·〇〇mL) was added to the above-prepared 3-{[(4-{[2-ethyl-1-(3-methyl-1-benzothiophene)- a mixture of 2-phenyl)butyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid ethyl ester (253 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) 2 hours and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to afford title compound ( 225 mg, 95%). 'H NMR (300 MHz, CDCh) δ ppm 0. 84-0. 99 (m, 6H), 1.3〇-1.56 (m, 3H), 1.66-1.81 (m, 2H), 2.45 (s, 3H), 2.64 (t, J=6.4 Hz, 2H), 3.01 (s, 3H), 3.68 (t, J=6.4 Hz, 2H), 4.80 (d, J=6.4Hz, 1H), 6.52 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7Hz, 2H), 7.23-7.30 (m, 1H), 7.31-7.38 ^ (in, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.71 ( d, J = 7.5 Hz, 1H). 'Example A136 3-{[(4-·([cyclohexyl(3-mercaptothieno[2,3-c]pyridin-2-yl)methyl]amine) (phenyl)carbonyl](fluorenyl)amino}propionic acid

321426 614 201029996 (1) Ethyl 3-mercaptothieno[2,3-c]pyridine-2-carboxylate A solution of 3.0 M cerium magnesium chloride in tetrahydrofuran (49.8 mL) was added at 0 ° C under nitrogen. To a solution of 3-chloropyridine- 4-carbonitrile (10.3 g) in tetrahydrofuran (120 mL). Water (50 mL) was added to the reaction mixture, then sulfuric acid (1 mL) was added to the mixture and mixture was stirred overnight. Sodium carbonate was added to acidify the solution to pH = 9 and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a colourless oil ( 6.10 g). Sodium hydride (60%, oily, 4. g) was added to the obtained oil (6.00 g), ethyl mercaptoacetate (in mL) and anhydrous N, N- during 5 min. A mixture of dimercaptodecylamine (100 mL) and the mixture was stirred at 5 °C for 20 minutes' then was then allowed to stand overnight at room temperature. A saturated aqueous solution of hydrogencarbonate was added to terminate the reaction and the reaction mixture was poured into water. The precipitated solid was collected by EtOAc (EtOAc) elute Q ]H NMR (300 MHz, CDCh) (5 ppm 1.42 (t, J=7. 2 Hz, 3H), 2.76 (s, 3H), 4.41 (q, J=7. 2 Hz, 2H), 7. 69 (dd, J=5. 7, 0.9 Hz, 1H), 8.57 (d, J=5. 7 Hz, 1H), 9.14 (d, J=〇-6 Hz, 1H). (2) 3-曱Sodium thiophene[2,3-c]pyridine-2-furaldehyde was added to sodium 3-borothi[2,3-c]pyridine-2 as described above at 0 °C with sodium borohydride (1.37 g). a mixture of ethyl carboxylate (2.00 g), calcium carbonate (2.01 g), ethanol (30 mL) and tetrahydroquinone (30 mL) and the mixture was stirred at room temperature for 3 hr. The reaction was quenched and the mixture was extracted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. A solution of the titled compound (1.39 g, 8Y%) was obtained as a pale brown solid. H NMR (300 MHz, CDCh) δ ppm 2. 81 (s, 3H), 7. 75 (dd, J=5.5, 1.1 Hz, 1H), 8.61 (d, J = 5.5 Hz, 1H), 9.20 (d , J=ll Hz, 1H), 10.41 (s, 1H). (3) Cyclohexyl (3-methyl-Shen-[2, 3~c]0-bit-2-yl)methanone at 0 ° C 1.0 M tetrahydrofuran solution (15.7 mL) of cyclohexyl bromide was added to the above-prepared 3-methyl porphin [2, 3_c] ° 咬 曱 曱: (1_ 39 g) of tetrahydrogen The mixture was immersed in a solution (30 mL) and the mixture was stirred for 1.5 hours. The reaction was quenched by the addition of a saturated aqueous chloride solution, and the residue was evaporated in ethyl acetate. The extract was dried over MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. A mixture of the obtained solid, 4-mercaptomorpholine N-oxide (680 mg) and acetonitrile (20 mL), and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The title compound (628 mg, 31%) was obtained. !H NMR (300 MHz, CDCh) δ ppm 1. 22-1. 62 (m, 5H), 1.70-1.81 (m, 1H), 1.82-1.94 (m, 2H), 1.95-2.06 (m, 2H) , 2.73 (s, 3H), 2.97-3.09 (m, 1H), 7.71 (dd, J=5. 5, 1.1 616 321426 201029996 HZ' 1H), 8.58 (d, J=5.5 Hz, 1H), 9.16 ( d, &gt;1·1 Hz, 1H). (4) 4-{[Cyclohexyl (3~-decylfuro[2,3_c]indolepyridin-2-yl)methyl]amino}benzoic acid will Chlorinated (IV) (318//L) was added to the above-mentioned cyclohexyl (3-mercaptothieno[2,3~c]pyridin-2-yl)fluorenone (628 mg), 4-amine A mixture of methyl benzoic acid methyl ketone (402 mg), triethylamine (2.7%) and dioxane (mL) was stirred under nitrogen at room temperature overnight. A saturated aqueous solution of sodium carbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. Extracted with @ and brine, dried in sulphur and decompressed (iv) to obtain a dark brown/yield acetic acid (277 in L) and sodium cyanoborohydride (304 mg) to the tetrahydrofuran The solution (3 mL) was stirred and the mixture was stirred at room temperature for 2 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction, and the organic solvent was evaporated in an evaporator and residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (30 to 70% ethyl acetate /hexane) to afford an orange solid. A 1N aqueous solution of sodium hydroxide (5 〇{) mL) was added to a mixture of the obtained solid, tetrahydrohexane (5 mL) and ethanol (5 mL), and the mixture was stirred under reflux for 4 hours. In hydrochloric acid (5. 〇〇 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulfuric acid and concentrated under reduced pressure. The title compound (2 〇 2 mg, 22%) was obtained eluted eluted eluted elute HNMR (300 MHz, CDCls) 6 ppml.07-1.34 (m, 5H), 1 40-321426 617 201029996 1.93 (m, 5H), 2.01-2.16 (m, 1H), 2.50 (s, 3H), 4.58 -4.69 (m, 2H), 6.51 (d, J=8. 8 Hz, 2H), 7.52 (dd, J=5. 6, 0.9 Hz, 1H), 7.82 Cd, J=8.8 Hz, 2H), 8.49 (d, J = 5.6 Hz, 1H), 8. 95 (d, J = 0.9 Hz, 1H). (5) 3-{[(4-{[cyclohexyl (3-mercaptothiophene [2] , 3_c]pyridine-2-yl) fluorenyl]amino}phenyl)carbonyl](fluorenyl)amino propyl propionate ethyl ester 1-ethyl-3-(3-didecylaminopropyl) The carbodiimide hydrochloride (152 mg) was added to the above-prepared 4-((cyclohexyl(3-mercaptofuran® [2,3_c;h-pyridin-2-yl)indenyl]amine group) Benzoic acid (202 mg), ethyl 3-(methylamino)propionate (104 mg), 1-hydroxybenzotriazole monohydrate (122 mg), triethylamine (222; f/L And a mixture of N,N-dimethyl decylamine (10 mL) and the mixture was dropped for 1 day at room temperature. A saturated aqueous chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a sodium aqueous solution and saturated brine, dried over magnesium sulfate and evaporated. The title compound (151 mg, 58%) was obtained from EtOAc (EtOAc: EtOAc) (300 MHz, CDCL·) (5 ppm 1. 06-1. 36 (m, 8H), 1.53-1.88 (m, 5H), 2.03-2.16 (m, 1H), 2.48 (s, 3H), 2.60 ( t, J=7.0 Hz, 2H), 2.99 (s, 3H), 3.69 (t, J=7.0 Hz, 2H), 4.10 (q, J=7. 1 Hz, 2H), 4.35 (d, J=5 7 Hz, 1H), 4.58 (dd, J=7. 3, 5. 7 Hz, 1H), 6.49 (d, J=8. 7 Hz, 2H), 7. 19(d, J=8.7Hz, 2H), 7. 51 (dd, J=5. 7, 1. 1 Hz, 1H), B. 48 (d, J=5.7 Hz, 1H), 8.95 (d, J = l. 1 Hz, 1H) 618 321426 201029996 (6) 3-{[(4-·([Cyclohexyl(3-methylthieno[2,3-c]pyridine-2-yl)methyl]amino}phenyl)carbonyl] (Mercapto)amino}propionic acid A 1N sodium hydroxide aqueous solution (1. 〇〇mL) was added to the above-mentioned 3-{[(4-((cyclohexyl)-[3-methyl fluorene [2] , 3-c]D-pyridin-2-yl)methyl]amino phenyl)carbonyl](methyl)amino}ethyl propionate (151 mg), tetrahydrofuran (5 mL), and ethanol (5 mL) The mixture was stirred at room temperature for 5 hours' and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1 00 mL) was added. The resulting precipitate was collected by filtration to afford titled compound (8. 2 mg, 56%). H NMR (300 MHz, CDCh) d ppm 1. 04-1. 34 (m, 5H), 1.50-1.62 (m, 1H), 1.63-1.88 (m, 4H), 2.02-2.14 (m, 1H), 2.48 (s, 3H), 2.53-2.68 (m, 2H), 3.00 (s, 3H), 3.58-3.74 (m, 2H), 4.57 (d, J=7. 5 Hz, 1H), 6.47 (d, J=8. 5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 7.55 (d, J=5.7 Hz, 1H), 8.43 (d, J=5. 7 Hz, 1H), 8.94 ( s, 1H). ^ Example A137 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-c]. 1-2 base) methyl]amino}phenyl Carbonyl]amino}propionic acid

(1) 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid Ethyl ester 321426 619 201029996 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (152 mg) was added to the 4-{[ synthesized in Example A136(4) Cyclohexyl (3-mercaptofuro[2,3-c]pyridin-2-yl)indolyl]aminoindolebenzoic acid (201 mg), /5-alanine ethyl ester hydrochloride (122 mg) a mixture of 1-hydroxybenzotriazole monohydrate (121 mg), triethylamine (220//L) and N,N-didecylguanamine (1 mL) and mix the mixture at room temperature Overnight. A saturated aqueous solution of chlorinated water was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (209 mg, 83%) was obtained eluted elute !Η NMR (300 MHz, CDCh) δ ppm 1. 06-1. 37 (m, 8H), 1.53-1.89 (m, 5H), 2.05-2.16 (m, 1H), 2.48 (s, 3H), 2.56 (t, J=5.8Hz, 2H), 3.59-3.68 (m, 2H), 4.12 (q, J=7. 1

Hz, 2H), 4. 50 (d, J=5.8 Hz, 1H), 4. 58-4.64 (m, 1H), ^ 6. 50 (d, J=8.8 Hz, 2H), 6.61 (t, J =5. 9 Hz, 1H), 7.51 (dd, J=5. 5, 1.1 Hz, 1H), 7.52 (d, J=8. 8 Hz, 2H), 8.47 (d, J=5.5 Hz, 1H) , 8.93 (d, J=l. 1 Hz, 1H). (2) 3-{[(4-{[cyclohexyl(3-mercaptothieno[2,3-c]pyridin-2-yl)) Amino]phenyl)carbonyl]amino}propionic acid A 1N aqueous solution of sodium hydroxide (1. 〇〇mL) was added to the 3-U synthesized above (4-{[cyclohexyl (3-mercaptothiophene) And [2,3-c]pyridin-2-yl)indolyl]amino}phenyl)carbonyl]amino}ethyl propionate (2〇9 mg), tetrahydrofuran (5 inL) and ethanol (5 mL) The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure of 620 321426 201029996. The residue was dissolved in water (10 mL) and EtOAc (EtOAc) The obtained precipitate was filtered, and the title compound ( 169 mg, 86%) H NMR (300 MHz, CDCla) δ ppm 1. 04-1. 36 (m, 5H), 1.49-1.89 (m, 5H), 2.02-2.14 (in, 1H), 2.48 (s, 3H), 2.59 ( t, J = 5.7 Hz, 2H), 3.51-3.77 (m, 2H), 4.59 (d, J = 7.2

Hz, 1H), 6.47 (d, ]=8.1 Hz, 2H), 6.85 (t, J=5.8 Hz, 1H), 7.48-7.60 (ra, 3H), 8.42 (d, J=5. 7 Hz, 1H ), 8 88 © (s, 1H). Example A138 3-{[ (4-{[cyclohexyl(3-indolyl benzophenan [3, 2-c] quinone-2-yl) fluorenyl] Amino}phenyl)carbonyl]amino}propionic acid

〇(1) Ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate sulfoxide (100 mL) was added to 4-chloro acid (22.4 g) and The mixture was stirred with heating under reflux for 4 hours and concentrated under reduced pressure. To a residual dioxane solution (300 mL) was added hydrazine, hydrazine-dihydrazinylhydroxylamine hydrochloride (13.8 g) and triethylamine (60 mL), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture and the reaction mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and decompressed. A solution of 3.0 M gasified sulfhydryl scales (54 mL) was added to a residual tetrahydrofuran solution (300 mL) at -78 ° C, and a mixture of 621 321426, 201029996 was stirred at room temperature for 10 hours. The reaction mixture was acidified with aqueous sodium carbonate to pH = 9 and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure to give crystals. Sodium hydride (60%, oily, 7.34 g) was added to the obtained oil, ethyl acetate ethyl acetate (21 mL) and anhydrous N,N-didecylamine in vacuo over 30 min. A mixture of 200 mL) and the mixture was stirred at 5 ° C for 20 minutes and then at room temperature for 18 hours. Water was added to terminate the reaction and the reaction mixture was extracted with acetic acid. The material was extracted with sulfuric acid and concentrated under reduced pressure. The solid was recrystallized from petroleum ether / ethyl acetate to afford title compound (5. 45 g, 17%) as white solid. H NMR (300 MHz, CDCla) (5 ppm ι·43 (士,j=7 2 Hz 3H) 2.85 (s, 3H), 4.42 (q, J=7. 2 Hz, 2H), 7.74 (dd, J =5. 0.9 Hz, 1H), 8.55 (d, J=6. 0 Hz, 1H), 9. 14 (d&gt; J=1 2 Hz, 1H). ' (2) 3-mercaptothiophene [ 3,2-c]pyridine-2-formaldehyde Sodium borohydride (2.33 g) was added at 0 ° C to the above-mentioned synthesized 3 _ _ ❾ ❾ [ [3,2-c] 吼 bit-2, acid A mixture of vinegar (3.4 g), gasification (3 g), ethanol (30 mL) and tetrahydrofuran (30 mL) and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m. A solution of tetrahydrofuran (6 Torr) and the mixture was stirred overnight at 5 ° C. Manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. EtOAc was washed with diisopropyl ether to give the title compound (1.54 g. , 56%). τ mouth 321426 622 201029996 old 臓 (300 MHz, CDC13) 5 ppm 2. 89 (s, 3H), 7· 79 (dd, J-5.5, 0.8 Hz, 1H), 8.58 (d, J=5. 5 Hz, 1H), 9.21 (d, J=0.8 Hz, 1H), 10. 35 (s, 1H). (3) Cyclohexyl (3-mercaptothiophene [3, 2-c]pyridine-2-yl)methanone was added to a solution of 1·0Μ cyclohexylmagnesium bromide in tetrahydrofuran (212 mL) to the above-prepared 3-methylthieno[3,2_c]pyridinium aldehyde. (1.87 g) of a tetrahydrofuran solution (4 mL) and the mixture was stirred for hr., and a solution of 1.0 M of cyclohexane magnesium bromide in tetrahydrofuran (1 mL) was further added, and the mixture was further stirred at 〇〇 °c for 1 hour. The reaction mixture was quenched with aq. The residue was purified to give a pale yellow solid. Ammonium tetrapropyl perruthenate (164 mg) was added to the obtained solid, 4-methyl-M-N-N-oxide (1.24 mg) and acetonitrile (30) Mixture of mL) and the mixture was stirred at room temperature for 4 hours, and concentrated under reduced pressure. The residue was purified by column chromatography (1 〇 to acetonitrile/hexane) to afford a white solid. Title Standard compound (864 mg, 31%). NMR (300 MHz, CDCh) δ ppm 1. 19-1. 61 (m, 5H), 1.69-1.80 (m, 1H), 1.81-1.92 (m, 2H), 1.93-2.04 (m, 2H), 2.82 (s, 3H), 2.93-3.05 (m, 1H), 7.75 (dd, J=5. 7, 1.0 Hz, 1H), 8.55 (d, J=5. 7 Hz, 1H), 9.17 (d, J =l.〇Hz, 1H). (4) 4-·([Cyclohexyl (3-methyl-D-fu and [3, 2-c] ° ratio. -2-yl)methyl]amino} Benzoic acid 623 321426 201029996 Titanium chloride (iv) (439//L) was added to the above-prepared cyclohexyl group (3-methylthieno[3,2-c]pyridin-2-yl) at 〇 °C A mixture of anthranilone (864 mg), dimethyl 4-aminobenzoate (553 mg), triethylamine (3.71 mL) and dichloromethane (2 mL) was stirred overnight at room temperature under argon. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The sodium cyanoborohydride (419 mg) was added to a solution (20 mL) of EtOAc. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m. A mixture of 1 n aqueous sodium hydroxide (5. 00 mL) was added to the obtained solid, tetrahydrofuran (5 mL) and ethanol (5 mL) and the mixture was stirred and stirred under reflux overnight. The mixture was stirred and stirred under reflux for 2.5 hours, and ethylenediamine (1.0 mL) was added to the mixture, and the mixture was stirred with EtOAc (5 mL). The mixture was stirred under reflux for 4 hours and concentrated under reduced pressure. The residue was evaporated to drynessjjjjjjjjjjjjjjjjj The title compound (432 mg, 34%) was obtained from EtOAc EtOAc (EtOAc) 1. 〇4-i. 37 5Η)} L 53_ 1.90(m,5H), 2.03-2.l5(m,iH),2.56(s,3H),4. 55- 4.66 (m, 2H), 6.51 (d, J=8. 7 Hz, 2H), 7,63 (dd, 1=5.5, 321426 624 201029996 1.1 Hz, 1H), 7.84 (d, J=8. 7 Hz, 2H), 8.39 (d, J=5.5

Hz, 1H), 8. 97 (d, J=l. i Hz, 1H). (5) 3-{[(4-{[cyclohexyl(3-fluorenyl)[3,2_c]pyridine-2 Ethyl)amino]phenyl)alkyl]amino phthalic acid ethyl ester 1 ethyl 3 (3-monodecylaminopropyl) carbodiimide hydrochloride (160 mg) plus To the above synthesized 4_丨[cyclohexyl(3fluorenylfuro[3'2-c]pyridin-2-yl)methyl]amino}benzoic acid (211 mg), stone-alanine ethyl ester a mixture of hydrochloride (128 mg), 1-hydroxybenzotriazole monohydrate (eg), triethylamine (233 /iL) and N,N-dimethyldecylamine (10 mL) The mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut elut elut !Η NMR (300 MHz, CDCh) d ppm 1. 05-1. 37 (m, 8H), 1.53-❹ L 91 (team 5H), 2. 04-2. 16 (m, 1H), 2. 50 -2. 63 (m,5H), 3.58-3.70 (m, 2H), 4.12 (q, J=7. 1 Hz, 2H), 4.42 (d, J=5.8Hz, 1H), 4.52-4.62 (m , 1H), 6.51 (d, J=8. 7 Hz, 2H), 6.59 (t, J=5.8Hz, 1H), 7.52 (d, J-8. 7 Hz, 2H), 7.60 (d, J= 5.5 Hz, 1H), 8.37 (d, J=5.5 Hz, 1H), 8.93 (s, 1H). (6) 3-{[(4-{[cyclohexyl (3_methylthieno[3, 2 -c]pyridin-2-yl)nonyl]amino}phenyl)carbonyl]aminopropionic acid A 1N aqueous solution of sodium hydroxide (L 〇〇fflL) was added to the above-mentioned 3-625 321426 201029996 {[ (4-((cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}ethyl propionate (186 mg) A mixture of tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for a few hours and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (1 〇) The title compound (186 mg, 93%) was obtained as a white solid. H NMR (300 MHz, CDCh) δ ppm 1. 05-1. 36 (m, 5H), 1.55-1 .64 (m, 1H), 1.65-1.90 (in, 4H), 2.03-2.15 (m, 1H), ® 2.56 (s, 3H), 2.61 (t, J = 5.1 Hz, 2H), 3.52-3.67 ( m, 1H&gt;, 3.73-3.89 (m, 1H), 4.56 (d, J=7.2 Hz, 1H), 6.48 (d, 1=8.7 Hz, 2H), 6.89-6.99 (m, 1H), 7.58 (d, 1=8.7

Hz, 2H), 7. 69 (d, J=5. 7 Hz, 1H), 8. 31 (d, J=5. 7 Hz 1H), 8.96 (s, 1H). * ’ Example A139

3_{[(4-{[cyclohexyl(3-mercaptothieno[3,2-c]pyridine-2-yl)methyl] φamino}phenyl)carbonyl](methyl)amino}propyl Acid (1) 3-{[(4-·([cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)indolyl]amino}phenyl))] Amino-3-(3-didecylaminopropyl)carbodiimide hydrochloride (158 mg) was added to the compound of Example A 138 (4). 4-{[cyclohexyl (3-mercapto 321426 626 201029996 furo[3,2-c]pyridin-2-yl)methyl]amino}benzoic acid (209 mg), 3-(decylamino) Ethyl propionate (108 mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (229//L) and N,N-dimethylformamide (1 mL) The mixture was stirred overnight at rt. EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (60 to 100% ethyl acetate / hexanes, then 0 to 10% methanol / ethyl acetate) to give a colorless oil. Target compound (180 mg, 66%). !H NMR (300 MHz, CDCls) δ ppm 1. 04-1. 38 (m, 8H), 1.52-1.94 (m, 5H), 2.02-2.16 (m, 1H), 2.55 (s, 3H), 2.60 (t, J=6.9 Hz, 2H), 2.99 (s, 3H), 3.69 (t, J=6.9 Hz, 2H), 4. 10(q, J=6.8 Hz, 2H), 4.27-4.39 (m, 1H), 4.49-4.59 (m, 1H), 6.49 (d, J=8. 5 Hz, 2H), 7.19 (d, J=8. 5

Hz, 2H), 7.62 (d, J=5.5 Hz, 1H), 8.38 (d, J=5.5 Hz, ^ 1H), 8.93 (s5 1H). (2) 3-{[(4-·([ring Hexyl (3-methyl benzophenan [3, 2-c] n ratio bit 2 -yl) fluorenyl]amino}phenyl) benzyl](methyl)amino}propionic acid 1N sodium hydroxide An aqueous solution (丨·mL) was added to the 3-U (4-{[cyclohexyl(3-mercaptothieno[3,2-c]pyridin-2-yl)indenyl]amino} group synthesized above. A mixture of a mixture of hydrazide and acetonitrile (5 mL) and ethanol (5 mL) was stirred at rt. The residue was dissolved in water (1 () mL) and dried. (: 1N Hydrochloric acid (1.00 mL) was added. The obtained precipitate was collected by filtration to afford title compound ( 136 mg, 80%) as a white solid 321426 627 201029 996. H NMR (300 MHz, CDCh) &lt;5 ppm 1 03-1. 32 (m, 5H), 1. 52-1.63 (m, 1H), 1.63-1.89 (m, 4H), 2.03-2.15 (m, 1H), 2.53 (s, 3H), 2.58- 2.74 (m, 2H), 3.03 (s, 3H), 3.62-3.79 (m, 2H), 4.54 (d, J=7. 5 Hz, 1H), 6.48 (d, J=8. 7 Hz, 2H) , 7.22 (d, J=8. 7 Hz, 2H), 7.67 (d, J=5. 5 Hz, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.93 (s, 1H). A140 ® 3-{[(4-{[1-(5-chloro-1-indenyl-111-indol-2-yl)heptyl]amino}phenyl)carbonyl]amino}propionic acid

Co2h (1) 1-(5-Chloro-1-methyl-1H-indol-2-yl)heptan-1-one © Sodium hydride (60%, oil, 182 mg) Example A106 (2) 1-(5-chloro-1H-indol-2-yl)heptan-1-one (1.0 g) of N,N-didecylguanamine solution (10) (mL) and the mixture was stirred under argon for 30 minutes. After stirring, 'iododecane (354//L) was added. The reaction mixture was stirred at room temperature overnight, then aq. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title residue was obtained as a pale brown solid (367 mg, 35%). 628 321426 201029996 *11 NMR (300 MHz, CDCh) δ PPm 〇. 85-〇, 94 (m) 33⁄4) j 24- 1.46 (m, 6H), 1.68-1.81 (m, 2H), 2.90-2.98 (m , 2H), 4.05 (s, 3H), 7.19 (s, 1H), 7.28^7.31 (m, 2H), 7.63-7. 66 (m, 1H). (2) 4-{[1-(5- Chloro-1-methyl-111-.bamboo~2__yl)heptyl]amino}benzoate decyl ester in OC will be 1.0M chlorinated (IV) digassole solution (4.54 mL) Addition to the above-mentioned 1-(5-chloro-1-indolyl-2-yl)glyoxime (1. 05 g), 4-aminobenzoic acid methyl ester (629 mg), three A mixture of ethylamine (4.21 mL) and di-methane (10 mL) was stirred and the mixture was stirred overnight at room temperature under argon. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate Acetic acid (1.08 mL) and sodium cyanoborohydride (475 mg) were added to a solid solution (10 mL) of the obtained solid and the mixture was stirred at room temperature for 1 hour. Saturated sodium carbonate aqueous solution was added to terminate the hydrazine reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) δ ppm 0. 83-0. 91 (m, 3H), 1.21-1.53 (ra, 8H), 1.88-2.08 (m, 2H), 3.68 (s, 3H), 3.83 (s, 3H), 4.25 (d, J=7. 1 Hz, 1H), 4.60-4.70 (m, 1H), 6.37 (s, 1H), 6.55 (d, J=8. 8 Hz, 2H), 7. 13 (dd, J=8. 7, 1.9 Hz, 1H), 7.19 (d, J=8. 7 Hz, 1H), 7.49 (d, J=l. 9 629 321426 201029996

Hz, 1H), 7.83 (d, J=8. 8 Hz, 2H). (3) 4-{[1-(5-Ga-1-methyl-1H-吲哚_2-yl)heptyl] Aminopyristilic acid 1N aqueous sodium hydroxide solution (15 mL) was added to the above-prepared 4-{[1-(5-chloro-1-methyl-1H-indenyl-2-yl)heptyl] A mixture of methyl phthalic acid (1·15 g), tetrahydrofuran (15 mL) and ethanol (15 mL) was evaporated. The residue was dissolved in water (30 mL) and 1N hydrochloric acid (15 mL). The title compound (1. 09 g, 98%) was obtained as a white solid. *H NMR (300 MHz, CDCh) δ ppm 0. 86 (t, J=6. 5 Hz, 3H), 1.11-1.51 (m, 8H), 1.79-2.04 (m, 2H), 3.58 (s, 3H) ), 4.49-4.63 (m, 1H), 6.31 (s, 1H), 6.42 (d, J=8.3 Hz, 2H), 7.05-7.17 (m, 2H), 7.46 (s, 1H), 7.80 (d, J=8.3 Hz, 2H). (4) 3-{[(4-{[1-(5-Chloro-1-indolyl-111-indol-2-yl)heptyl]amino} 0 phenyl Ethyl carbonyl]amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg) was added to the above-prepared 4-{[ 1-(5-Chloro-1-methyl-1H-indol-2-yl)heptyl]amino}benzoic acid (300 mg), yS-alanine ethyl ester hydrochloride (174 mg), A mixture of hydroxybenzotriazole monohydrate (173 mg), triethylamine (158//L) and N,N-dimethyldecylamine (10 mL) was stirred at room temperature overnight. A saturated gasification aqueous solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (349 mg, 93%) was obtained eluted eluted eluted eluted eluted eluted eluted eluted elution *Η NMR (300 MHz, CDCh) δ ppm 0. 88 (t, J=6.9 Hz, 3H), 1.18-1.55 (m, 11H), 1. 87-2. 10 (m, 2H), 2 . 60 (t, J=5. 8

Hz, 2H), 3.61-3.76 (m, 5H), 4.06-4.23 (m, 3H), 4.57- 4.69 (m, 1H), 6.37 (s, 1H), 6.57 (d, J=8.5 Hz, 2H) , 6. 64 (t, J=5. 8 Hz, 1H), 7. 11-7. 16 (m, 1H), 7. 17-7. 23 (m, 1H), 7.50 (d, J=l 6 Hz, 1H), 7.59 (d, J=8. 5 Hz, ® 2H). (5) 3-{[(4-{[1-(5-Ga-1-methyl-1H-吲哚) -2-yl)heptyl]amino}phenyl)carbonyl]amino}propionic acid A 1N aqueous solution of sodium hydroxide (2. 〇〇mL) was added to the above-mentioned 3_ {[(4-{[1- (5-Chloro-; 1-methyl-111-tetrado-2-yl)heptyl]amino}phenyl)carbonyl]amino-propionic acid ethyl ester (349 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) mixture was stirred at room temperature for 3 hr and concentrated. The hydrazine residue was dissolved in water (GO mL) and 1N hydrochloric acid (2 〇〇 mL) was added. The resulting precipitate was collected by filtration to afford title compound (302 mg, 92%). H NMR (300 MHz, CDCh) d ppm 0.86 (t, J = 6. 4 Hz, 3H), 1.17-1.55 (m, 8H), 1.84-2.05 (m, 2H), 2.62 (t, J=5. 7 Hz, 2H), 3.58-3.72 (m, 5H), 4.60 (t, J=6.8 Hz, 1H), 6.33 (s, 1H), 6.52 (d, J=8. 7 Hz, 2H), 6.69 ( t, J=5. 8

Hz, 1H), 7. 12(dd, J=9. 0, 2.1Hz, 1H), 7. 17 (d, J-9. 0

Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.55 (d, J=8.7 Hz, 321426 631 201029996 2H). Example A141 3-{[(4-{[l-(5 -chloro_1-fluorenyl-1H-indol-2-yl)heptyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid

(1) 3-丨[(4-{[Bu(5-Gas-didecyl-1H-indol-2-yl)heptyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid The ester was added to the 4-{[1-(5-) synthesized in Example A140(3) by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg). Chloro-1-indenyl-111-indol-2-yl)heptyl]amino}benzoic acid (30〇11^), ethyl 3-(decylamino)propionate (148 mg), 1- A mixture of hydroxybenzotriazole monohydrate (173 mg), triethylamine (158//L) and N,N-dimethylformamide (1 mL) was stirred and the mixture was stirred overnight. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The residue was purified by EtOAc EtOAc (EtOAc) ]H NMR (300 MHz, CDCh) (5 ppm 0.87 (t, J=6. 6 Hz, 3H), 1.17-1.53 (m, 11H), 1.89-2.06 (m, 2H), 2.63 (t, J= 6. 7 Hz, 2H), 3.04 (s, 3H), 3.65-3.79 (m, 5H), 4.02 (d, 632 321426 201029996 J=7. 1 Hz, 1H), 4.12 (q, J=7. 1 Hz, 2H), 4.54-4.65 (m, 1H), 6.37 (s, 1H), 6.55 (d, J=8.4 Hz, 2H), 7.13 (dd, J=8.8, 1.8 Hz, 1H), 7.20 (d , J=8. 8 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H). (2) 3-{[(4-{[l-( 5-Chloro-1-indenyl-1H-indol-2-yl)heptyl]amino}phenyl]carbonyl](methyl)amino}propionic acid 1N aqueous sodium hydroxide solution (2.0 mL) Addition to the above-prepared 3-{[(4-{[1-(5-chloro-1-methyl-1H-indol-2-yl)heptyl]amino}phenyl) ® benzyl] A mixture of (methyl)amino}ethyl propionate (235 mg), tetrahydro-pyran (5 mL), and ethanol (5 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The title compound (211 mg, 95%) was obtained as a pale yellow solid. NMR (300 MHz). , CDCh) 5 ppm 0.87 (t, J=6. 8 Hz, 3H), 1. 16-1.54 (m, 8H), 1.84-2.05 (m, 2H), 2.63 (t, J=5. 8 0 Hz, 2H), 3.02 (s, 3H), 3.62-3.76 (m, 5H), 4.59 (t, J=6.8Hz, 1H), 6.35 (s, 1H), 6.53 (d, J=8.5 Hz, 2H), 7. 12 (dd, J=8. 7, 1.9 Hz, 1H), 7. 19 (d, J-8. 7 Hz, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.49 (d, J=1.9 Hz, 1H). Example A142 3_{[ (4-{ [ϊ克己基(3-mercapto 0-deseno[2,3-b]0-0-but-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid 321426 633 201029996

M Ο) 3 methyl e-dephene [2,3-b] ° ratio 0 _2 - acid acetate at -78 ° C 3. 0M methyl magnesium chloride solution in tetrahydrofuran (72. 5 mL The mixture was added to 2-gas "tetrahydrofuran solution (3 〇〇 mL) than _3- acetonitrile (15 〇g) and the mixture was stirred at room temperature for 1 hr. Water mL) was added to the 0 reaction mixture followed by 10% sulfuric acid (1 mL) and the mixture was stirred overnight. Sodium carbonate was added to acidify the reaction mixture to pH = 9 and extracted with ethyl acetate. The extract was purified by sulfuric acid and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) The sodium (4), oily, 4.68 g) was added to the obtained oil α〇〇g), lycol acetic acid (13 mL) and anhydrous n, n-dimethyl ketone W (4) over a period of 30 minutes. The mixture was mixed at 5 minutes for 2Q, then at & _ 18 '. Adding a saturated carbon*il#3 aqueous solution a terminates the reaction and © pours the mixture to water. The solid of the whip was filtered, and the title compound (614 g, 29%) was obtained as a white solid. WMRUOOMHz, CDCW &lt;5 ppml 45 (t J = 7 2Hz, 3H), 2.78 (s, 3H), 4.43 (Q, J = 7. 2 Hz, 2H), 7.38-7.40 (m, 1H), 8.11- 8.13 (m, 1H), 8.7〇-8. 72 (m? 1H). (2) 3-methylthieno[2,3-b]pyridine~acid in n: will be saponin α〇6 g) added to the above synthesized 3_mercapto 321426 634 201029996 thieno[2,3_b]pyridine-2-carboxylic acid ethyl ester (3.00 g), calcium chloride (3.02 g), ethanol (50 mL) A mixture of tetrahydrofuran (50 inL) and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulphuric acid and concentrated under vacuo to give a white solid. Active manganese dioxide (12.5 g) was added to the resulting solid solution in tetrahydrofuran (5 mL) and the mixture was stirred overnight. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. Residues with diisopropyl-wash strips to give the title compound (2. 07 g, 86%) ° JH NMR (300 MHz, CDCla) &lt;5 ppm 2. 79 (s, 3H) , 7. 39 (dd, J=8. 2, 4. 5 Hz, 1H), 8. 16 (dd, J=8. 2, 1. 6 Hz, 1H), 8.72 (dd, J=4.5, 1.6 Hz, 1H), 10.36 (s, 1H). (3) Cyclohexyl (3-indolyl benzophenan [2, 3-b]n than butyl-2-yl) fluorenone at 1.0 Torr Tetrahydrofuran solution (π. 6 mL) of cyclohexylmagnesium was added to the tetrahydrogen of 3-methylthieno[2,3-b]pyridine-2-furaldehyde φ (2. g) synthesized above. A solution of π flu (6 〇) and the mixture was scrambled for 1 hour. A saturated aqueous ammonium chloride solution was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (1 EtOAc) To a mixture of the obtained solid, 4-mercaptomorpholine N-oxide (1.81 g) and acetonitrile (40 mL), and the mixture was stirred at room temperature for 3 hr. Concentrate under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) 635 321426 201029996 Ή NMR (300 MHz, CDCh) (5 ppm 1. 18-1. 62 (m, 5H), l.6g^ 1.80 (in, 1H), 1.81-1.91 (m, 2H), 1.95-2.06 (m, 2H) 2.73 (s, 3H), 2.95-3.07 (m, 1H), 7.37 (m, J=8.2, 4.4 Hz, 1H), 8. 13 (dd, J=8.2, 1.6 Hz, 1H) , 8.70 (dd, J=4&gt; 4j 1.6 Hz, 1H). (4) 4-{[Cyclohexyl (3-methylfuro[2,3-b]pyridin-2-yl)methyl]amine }Methyl benzoate chlorinated (IV) (508 jwL) was added to the above-mentioned cyclohexyl (3-methylthieno[2,3-b]pyridin-2-yl) a mixture of ketone (1. 〇〇g), 4-aminobenzoic acid decyl ester (642 mg), triethylamine (4.31 mL) and methylene chloride (2 〇 mL) in argon, chamber The mixture was stirred for 1 hr. The reaction was quenched with EtOAc EtOAc (EtOAc m. (442 &quot; L) and sodium cyanoborohydride (485 mg) were added to the obtained solid tetrahydrofuran solution (20 mL) and mixed with a mixture of hexanes at room temperature for 1.5 hours. Take The reaction mixture was quenched and the mixture was extracted with ethyl acetate. EtOAc (EtOAc m. The title compound (975 mg, 64%) was obtained as a pale brown solid..H NMR (300 MHz, CDCh) δ ppm 1. 00-1. 35 (m, 5H), 1. 48-1.96 (m , 5H), 2.02-2.19 (m, 1H), 2.55 (s, 3H), 3.81 (s, 3H), 4.54-4.70 (m, 2H), 6.51 (d, J=8.8 Hz, 2H), 7.59 ( Dd, J=7. 6, 5. 7 Hz, 1H), 7.78 (d, J=8. 8 Hz, 2H), 636 321426 201029996 8. 22 (d, J-7. 6 Hz, 1H), 8 63 (d, J=5. 7 Hz, 1H). (5) 4-{[cyclohexyl (3-methyl cough nan] [2, 3_b]. Than a 2-yl)methyl]amino}benzoic acid 1N hydrazine oxide aqueous solution (iq mL) was added to the above-mentioned 4-{{cyclohexyl (3-methylfuro[2, 3- a mixture of b]pyridin-2-yl)methyl]amino}benzoic acid methyl ester (975 mg), tetrahydrofuran (10 mL) and ethanol (1 〇) and the mixture was stirred and stirred under reflux overnight and decompressed. concentrate. The residue was dissolved in water mL), 1N hydrochloric acid (10 &lt The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCla) ppm 1. 01-1. 39 (in, 5H), 1.53-1.92 (m, 5H), 2.07-2.20 (m, 1H), 2.46 (s, 3H), 4.60 (d , J=8.0Hz, 1H), 6.53 (d, J=8. 5 Hz, 2H), 7.21-7.31 (m, 1H), 7.82 (d, J=8. 5 Hz, 2H), 7.87 (dd, J=8. 1, 1.3 ❹ Hz, 1H), 8.47 (dd, J=4.4, 1.3 Hz, 1H). (6) 3-{[(4-{[cyclohexyl (3-methylthieno[2] ,3_b]pyridine-2-yl) fluorenyl]amino}phenyl)carbonyl]amino}ethyl propionate 1-ethyl-3-(3-didecylaminopropyl)carbodiimide Hydrochloride (226 mg) was added to the above-prepared 4-{[cyclohexyl(3-methylfuro[2'34]indole-2-yl)methyl]amino}benzoic acid (3 〇〇) ^), ^5_alanine ethyl vine hydrochloride (10) mg), dipyridyl benzotriazine monohydrate (10), diethylamine (329//L) and N,N-dimethylformamide ( A mixture of 1Q mL) and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction at 321426 637 201029996 and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate and brine and dried over magnesium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) δ ppm 1. 02-1. 38 (m, 8H), 1.54-1.90 (m, 5H), 2.08-2.21 (m, 1H), 2.45 (s, 3H), 2.56 (t, J=5.9 Hz, 2H), 3.59-3.69 (m, 2H), 4.12 (q, J=7. 1 Hz, 2H), 4.40 (d, J=6.3Hz, 1H), 4.53-4.61 ( m, 1H), ® 6. 48-6. 64 (m, 3H), 7· 21-7. 30 (m, 1H), 7. 52 (d, J=8. 5

Hz, 2H), 7. 86 (dd, J=8. 1, 1.5 Hz, 1H), 8. 45 (dd, J=4. 5, 1.5 Hz, 1H). (Ό 3-{[(4- {[Cyclohexyl (3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid 1N aqueous sodium hydroxide solution (2. 〇 〇mL) is added to the above-prepared 3-{[(4-{[cyclohexyl(3-mercaptothieno[2,3-b]pyridin-2-yl)indolyl]aminoindenyl}phenyl) A mixture of carbonyl]amino}propionic acid ethyl ester (335 mg), tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. The title compound (281 mg, 89%) was obtained as a white solid. NMR (300 MHz, CDCh). δ ppm 1. 〇〇-1. 34 (m, 5Η), 1.51-1.87 (ra, 5H), 2.06-2.19 (m, 1H), 2.44 (s, 3H), 2.52-2.64 (m, 2H), 3.53-3.68 (m, 2H), 4.55 (d, J=8. 0 Hz, 1H), 6.49 (d, J=8.7 Hz, 2H), 6.71 (t, J=5. 3 Hz, 1H), 321426 638 201029996 7.23-7.31 (m, 1H), 7.49 (d, J=8. 7 Hz, 2H), 7.88 (dd, J=8. 0, 1.1 Hz, 1H), 8.45 (dd, J=4.5 , 1.1 Hz, 1H Example A143 3-{[(4-{[cyclohexyl(3-methylindeno[2,3-b] 吼_2-yl)indolyl]amino}phenyl)carbonyl]( Methyl)aminopropionic acid

(1) 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)indolyl]amino}phenyl)carbonyl](methyl)amine Ethyl propionate ethyl 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (226 mg) was added to the 4- 4- synthesized according to Example A 142 (5) ([Cyclohexyl(3-mercaptofuro[2,3-b]pyridin-2-yl)indenyl]amino}benzoic acid (3〇〇mg), 3-(methylamino)propionic acid a mixture of ethyl ester (155 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (329//L) and N,N-dimercaptocaramine (1 mL) and The mixture was stirred overnight and the mixture was stirred with EtOAc. EtOAc (EtOAc m. The title compound (333 mg, 85%) was obtained from EtOAc (EtOAc, EtOAc) δ ppm 1. 00-1. 37 (m, 8H), 1.52-1.89 (in, 5H), 2.07-2.21 (m, 1H), 2.45 (s, 3H), 2.60 321426 639 201029996 (t, J=6.8 H z, 2H), 2.99 (s, 3H), 3.69 (t, J=6.8 Hz, 2H), 4.02-4.17 (m, 2H), 4. 32 (d, J=5. 8 Hz, 1H), 4.49 -4.58 (m, 1H), 6.52 (d, J=8. 5 Hz, 2H), 7. 19 (d, J=8. 5 Hz, 2H), 7.22-7.31 (m, 1H), 7.86 (dd , J=8.0, 1.1 Hz, 1H), 8.43-8.50 (m, 1H). (2) 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-b]pyridine- 2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid A 1N aqueous solution of sodium hydroxide (2. 〇〇mL) was added to the above-mentioned 3-indole [cyclohexyl ( 3_mercaptothieno[2,3-b]pyridin-2-yl)indenyl]amine

a mixture of (methyl)amino}propionic acid ethyl ester (333 mg), tetrahydronethane (5 mL) and ethanol (5 mL) and the mixture was stirred at room temperature for 4 hr. Concentrate under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to yield title compound ( 275 mg, 88%). *H NMR (300 MHz, CDCls) (5 ppm 1. 02-1. 35 (m, 5H), 1.54- ❹ ^8 (^, 511), 2.07-2.19 (111,110,2.45 (3,311), 2 58- 2.70 (m, 2H), 3.01 (s, 3H), 3.68 (t, J=6.6 η1, 2H), 4.54 (d, J=7.6 Hz, 1H), 6.51 (d, J=8. 7 Hz, 2H ), 7.20 (d, J=8.7Hz, 2H), 7.27 (dd,:=8. 1,4.7 Hz, 1H), 7.88 (dd, J=8.1, 1.6 Hz, 1H), 8.47 (dd, J=4. 7, 1.6 Hz, 1H) Example A144 ' · 3-U(4-{[cyclohexyl(3-methylthieno[3,2_b]pyridine-2-yl)methyl]amino} Phenyl) thiol]amino}propionic acid 321426 640 201029996

(1) 3-methyl-snap-[3,2-b&gt; is added to a 3-chloropyridyl ether solution of 3. 0M methylmagnesium bromide (48. 〇mL). A solution of 2-carbonitrile (10.0 g) in tetrahydrofuran (1 〇 0 fflL) was taken and the mixture was stirred at room temperature for 3 hr. 2N Hydrochloric acid (300 mL) was added to the reaction mixture, and the mixture was evaporated and evaporated. The extract was washed with saturated brine. The residue was purified by column chromatography (30 to 70% ethyl acetate /hexane) to afford pale oil. Potassium carbonate (16.0 g) was added to a mixture of the obtained oil, ethyl mercaptoacetate (4.23 mL) and N,N-dimethylformamide (60 mL) and stirred at 5 ° C. The mixture was overnight. Water was added to terminate the reaction, and the precipitated solid was collected by filtration to afford title compound ( 6.75 g, 〇 79%) as white solid. NMR (400 MHz, CDCh) δ ppm 1.44 (t, J = 7. 2 Hz, 3H), 2.87 (s, 3H), 4.44 (q, J = 7. 2 Hz, 2H), 7.37 (dd, &gt; 8.3, 4. 4 Hz, 1H), 8.17 (dd, J=8. 3, 1. 5 Hz, 1H), 8.78 (dd, J=4.4, 1. 5 Hz, 1H). (2) 3-A Thiophene[3,2-b]pyridine-2-furaldehyde was added to the above-prepared 3-methyl π-phene[3, 2-b]0 at 0 ° C. a mixture of 0-2-pyrexate (3.0 g), chlorinated feed (3. 〇2 g), ethanol (30 mL) and tetrahydroanthracene (30 mL) at room temperature 321426 641 201029996

The mixture was disturbed for 5 hours. A saturated aqueous solution of chlorinated acid was added so that L, ''; this reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. Active 2 (12.2 g) was added to a solution of the obtained solid in tetrahydrofuran (5 mL) at ° (methanol mixture was stirred overnight. Manganese dioxide was filtered off and concentrated under reduced pressure to give a white solid. Title target compound (2.24 g, 93%). 沱 沱 R (300 MHz, CDC13) d ppm 2. 90 (s, 3H), 7 40 (dd J=8.2, 4.6 Hz, 1H), 8.21 (dd, J = 8.2,1·4Ηζ ΐτη . ' 5 8. 79 (dd, J=4.6, 1.4 Hz, 1H), 10.43 (s, 1H). (3) Cyclohexyl (3-methyle-depheno[3] , 2-b]n is more than 0-but-2-yl). A solution of 1.0 M cyclohexylmagnesium bromide in tetrahydrofuran (18 9 is added to the above-mentioned 3-mercaptothiophene [3, 2] -b]pyridin~2_•A (2.24 g) in tetrahydrofuran (50 mL), and the mixture was stirred under argon and hydrazine for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to terminate the reaction and ethyl acetate. The reaction mixture was extracted, the extract was washed with saturated brine, dried over magnesium sulfate and evaporated and evaporated. Oily substance. Add tetrapropyl glutamic acid (238 mg) to the obtained A mixture of oil, 4-methylmorpholine N-oxide (g) and acetonitrile (40 mL) was stirred at room temperature for 2 hrs, and then concentrated under reduced pressure. The title residue was obtained as a colorless oil (yield: 79%). g, 沱 R (300 MHz, CDCI3) (5 ppml.l9-1.65) (m,5H) 1 1.81 (m,1Η),1.82-1.94 (m,2Η), 1.94-2. 08 (m,2η) 321426 642 201029996 2.86 (s, 3H), 3.01-3.15 (m, 1H) , 7.37 (dd, J=8. 2, 4 4 Hz, 1H), 8. 17 (dd, J=8.2, 1.5 Hz, 1H), 8. 78 (dd, J=4 4 1.5 Hz, 1H). ' . ' (4) 4-{[Cyclohexyl (3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}benzoic acid oxime ester &amp; Titanium (IV) (700 / zL) was added to the above-mentioned cyclohexyl (3-mercaptothieno[3,2-b]pyridin-2-yl)fluorenone (1·38 g), 4-amine The mixture was stirred for 3 days under argon at room temperature for a period of 5%. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. Acetic acid (607//L) and a nitrogen sulphate (666 mg) were added to the obtained oily solution in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO. The residue was purified by EtOAc EtOAc (EtOAc) !H NMR (300 MHz, CDCh) (5 ppm 1.07-1. 37 (m, 5H), 1.55-1.90 (m, 5H), 2.03-2.16 (m, 1H), 2.59 (s, 3H), 3.79 ( s, 3H), 4.56 (d, J=5.8 Hz, 1H), 4.63-4.72 (m, 1H), 6.51 (d, J=8. 5 Hz, 2H), 7.16 (dd, J=8.11) 4. 6 Hz, 1H), 7. 77 (d, J=8. 5 Hz, 2H), 7.98 (dd, J=8. 1, 1.2 Hz, 1H), 8. 64 (dd, J=4. 6, 1. 2 Hz, 1H). 643 321426 201029996 (5) 4-{[Cyclohexyl (3-methylthieno[3, 2_b]pyridine-2-yl)methyl]amino}benzoic acid 1N Aqueous sodium hydroxide (1 () mL) was added to the above-mentioned 4-{{cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}benzoic acid Methyl ester (1.31 g), tetrahydrofuran (1 〇 mL), and ethanol (1 〇 mixture) and the mixture was stirred and stirred under reflux overnight. An additional 1N aqueous sodium hydroxide (5 mL) was added, and the mixture was further stirred under reflux for 7 hours. The residue was dissolved in EtOAc (EtOAc) (EtOAc) Brine washing solution, dried with sulfuric acid and concentrated under reduced pressure The title compound (804 mg, 64%) was obtained as a brown solid. H NMR (300 MHz, CDCh) δ ppm 1.07-1. 36 (m, 5H), 1.55-1.91 (m, 5H), 2.02-2.15 (m, 1H), 2.60 (s, 3H), 4.52-4.74 (m, 2H), 6.52 (d, J=8. 7 Hz, 2H), 7. 17 (dd , J=8. 0, ❹ 4.6 Hz, 1H), 7.82 (d, J=8. 7 Hz, 2H), 7.99 (dd, J=8.0, 1.4 Hz, 1H), 8.66 (dd, J=4.6, 1.4 Hz, 1H). (6) 3-{[(4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)indolyl]amino}phenyl)carbonyl Amino}ethyl propionate 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) was added to the 4-{[cyclohexyl] synthesized above. (3-Methylthieno[3,2-13]indole-2-yl)methyl]amino}benzoic acid (3〇〇), in case of ethyl propylamine hydrochloride (181 mg) , 1-hydroxybenzotriazine monohydrate mg), triethylamine (329 //L) and N,N-dimethylguanamine (1〇mL), 321426 644 201029996 Mix the mixture for 1 day. Saturated aqueous ammonium chloride solution was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The residue was purified by EtOAc EtOAc (EtOAc) H NMR (300 MHz, CDCls) δ ppm 1. 07-1. 36 (m, 8H), 1.56-1.90 (m, 5H), 2.02-2.16 (m, 1H), 2.52-2.63 (in, 5H), 3.59-3.68 (in, 2H), 4.12 (q, J=7. 1 Hz, 2H), 4.49 (d, ❻ J=5. 8 Hz, 1H), 4.62-4.69 (m, 1H), 6.52 (d , J=8. 5 Hz, 2H), 6.59 (t, J=5. 8 Hz, 1H), 7. 16 (dd, J=8. 1, 4. 6 Hz, 1H), 7.52 (d, J =8.5Hz, 2H), 7.99 (dd, 1=8.1, 1.4 Hz, 1H), 8.64 (dd, J=4. 6, 1.4 Hz, 1H). (7) 3-{[(4-{[ring Hexyl (3-methyl benzophene 2_b) pyridine 2-yl) methyl]amino}phenyl) benzyl]amino hydrazine propionic acid 1N aqueous sodium hydroxide solution (2·〇〇mL) was added to The above-mentioned synthesized 3 ❹{[(4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]aminopurine A mixture of ethyl propionate (33 mg), tetrahydrofuran (5 mL) and ethanol (5 mL). The residue was dissolved in water (10 mL) and dried. € Add 1N hydrochloric acid (2. 〇〇 虬). The resulting precipitate was collected by filtration to afford title compound (291 mg, 94%).

HiiMR (300 MHz, CDCi3) 6 ppml. 〇7-i.36 (m, 5H), 1.55- 1-89 (m, 5H), 2.03-2.14 (m, 1H), 2.57 (s, 3H), 2.63 ( t, J = 5.7 Hz, 2H), 3.55-3.77 (m, 2H), 4.64 (d, J = 7.2 321426 645 201029996

Hz, 1H), 6.49 (d, J=8. 9 Hz, 2H), 6.78 (t, J=6. 0 Hz, 1H), 7. 19(dd, J=8. 0, 4. 6 Hz, 1H), 7.53 (d, J=8. 9 Hz, 2H), 8.01 (dd, J=8.0, 1.5 Hz, 1H), 8.64 (dd, J=4.6, 1. 5 Hz, 1H). Example A145 3-{[ (4-{[cyclohexyl(3-indolyl σ-seceno[3,2-b]0 σ σ-2-yl)methyl]amino}phenyl)carbonyl](methyl Amino}propionic acid

(1) 3-{[(4-{[cyclohexyl(3-mercaptothieno[3,2-b]acridin-2-yl)indolyl]amino}phenyl)carbonyl](methyl) Amino}ethyl propionate 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (226 mg) was added to the 4-mer synthesized in Example A144 (5) {[Cyclohexyl (3-mercaptothieno[3,2-b]pyridin-2-yl)methyl]amino}benzoic acid (300 mg), ❹ 3-(methylamino)propanoic acid B a mixture of ester (155 mg), 1-p-benzotriazine monohydrate (181 mg), triethylamine (329 //L) and N,N-didecylguanamine (10 mL) in a chamber The mixture was stirred at room temperature for 1 day. A saturated aqueous solution of ammonium hydride was added to terminate the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous The title compound (325 mg, 84%) was obtained eluted elute 646 321426 201029996 H NMR (300 MHz, CDCla) δ ppm 1. 07-1. 36 (m, 8H), 1.54-1.92 (m, 5H), 2.01-2.16 (m, 1H), 2.51-2.68 (m, 5H), 2.99 (s, 3H), 3.69 (t, J=7. 0 Hz, 2H), 4.10 (q, J=6. 9 Hz, 2H), 4.36 (d, J=5.2 Hz, 1H), 4.58-4.67 (m, 1H), 6.51 (d, J=8. 5 Hz, 2H), 7.13-7.23 (m, 3H), 8.00 (d, J=8. 0 Hz, 1H), 8.64 (d, J=4.4 Hz, 1H). (2) 3-{[(4-{[cyclohexyl(3_methylthieno[3,24&gt;bipyridin-2-yl)methyl]amino}phenyl) Carbonyl](methyl)amino} cesium propionate A 1N aqueous solution of sodium hydroxide (2.0 mL) was added to the above-prepared 3-{[(4-{[cyclohexyl (3-mercaptothiophene [3] , 2-1&gt;] acridin-2-yl)methyl]amino phenyl)carbonyl](methyl)amino}ethyl propionate (325 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) The mixture was stirred at room temperature for a few hours and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and 1N hydrochloric acid (2. The resulting precipitate was collected by filtration to give the title compound (277 mg, 90%). ❹ $ delete 1^(300 ”}^,00(:13)5?卩1111.06-1.34 (111,51〇,1.55- 1.88 (m, 5H), 2.03-2.15 (m, 1H), 2.58 (s, 3H), 2.66 (t, J=6.3 Hz, 2H), 3.02 (s, 3H), 3.70 (t, J=6. 3 Hz, 2H), 4. 62 (d, J=7.5 Hz, 1H), 6. 50 (d, J=8. 7 Hz, 2H), 7. 15-7. 25 (m, 3H), 8.01 (dd, J=8. 3, 1.5 Hz, 1H), 8.66 (dd, J =4· 5,1. 5 Hz, 1H). Example A146 3-[{[4-({cyclohexyl[3-indolyl-6-(trifluoromethyl)thiophene[3,2Hb; ht( Indole-2-yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid 321426 647 201029996

(1) ethyl 3-mercapto-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxylate 3.0 M diethyl ether bromide in diethyl ether solution at 0 ° C (16 . 1 mL) added to 3-gas-5-(trifluoromethyl) π-bito-2-indene nitrile (5·00 g) in tetrahydrogen nibble solution (50 mL) 'under argon The mixture was mixed for 3 hours. In hydrochloric acid (300 mL) was added to the reaction mixture to acidify the solution to pH = 3 to 4, 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 silica gel column chromatography (purified to 10% ethyl acetate / hexane) to afford a pale yellow solid. Potassium carbonate (5. 56 g) was added to a mixture of the obtained solid, ethyl acetate (1. 61 mL) and N,N-didecylamine (3 〇mL) and given at 50 C Fell the mixture for 1 hour. Water was added to terminate the reaction and the collection was filtered; the solid of the chamber was obtained to give the title compound (3. 76 g, 54%) as a white solid. !H NMR (300 MHz, CDCh) δ ppm 1.45 (t, J=7. 1 Hz, 3H) 2.88 (s, 3H), 4.45 (q, J=7. 1 Hz, 2H), 8.39-8.45 (m , 1H), 8. 94-9. 02 (m, 1H). (2) 3-Mercapto-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-furaldehyde at 0 Sodium borohydride (1.94 g) was added to the above-prepared ethyl 3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridine-2-carboxylate (3.69 g). Mixture of 321426 648 201029996 of calcium chloride (2.84 g), ethanol (4 〇) and tetrahydrofuran (40 mL) and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulphuric acid and concentrated to give a white solid. Active disulfide (16.3 g) was added to the resulting solid tetrahydrogenate solution (60 mL) and the mixture was stirred at 50 ° C for 5 hours. The manganese dioxide was filtered off and the filtrate was evaporated. ] NMR (300 MHz, CDCh) c5 ppm 2. 93 (s, 3H), 8.47-8.50 ❿(m, 1H), 9.00 (d, J=l. 6 Hz, 1H), 10.46 (s, 1H) (3) Cyclohexyl [3-mercapto-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]anthone at 1.0 ° C 1.0 M cyclohexylmagnesium bromide Tetrahydrofuran solution (8.81 mL) was added to the above-prepared 3-methyl-6-(trifluoromethyl)noneno[3,2-b]pyridin-2-furaldehyde (1.44 g) in tetrahydrofuran (15 mL) and the mixture was stirred under argon for 1 hour. A saturated aqueous ammonium chloride solution was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (1 () to 50% ethyl acetate / hexane) to afford a yellow oil. To a mixture of the obtained oil, 4-methylmorpholine N-oxide (817 mg) and acetonitrile (20 mL), and the mixture was stirred at room temperature for 1 hour. It was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) ]H NMR (300 MHz, CDCh) (5 ppm 1.19-1. 65 (m, 5H), 1.70-1.81 (m, 1H), 1.82-2.07 (m5 4H), 2.86 (s, 3H), 3.01- 649 321426 201029996 3. 15 (m, 1H), 8.42 (s, 1H), 8.98 (s, 1H). (4) 4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thiophene [3,2-b]pyridin-2-yl]fluorenyl}amino)benzoic acid oxime ester Titanium (IV) chloride (323 // L) was added to the above-mentioned cyclohexyl group at 〇 °C [ 3-methyl-6-(trifluoromethyl)"ephedo[3,2-b] ° ratio -2-yl] oxime (805 mg), 4-aminobenzoic acid oxime ester (410 Mixture of mg), triethylamine (2.75 mL) and dichloromethane (10 mL), and the mixture was stirred under argon at room temperature for 1 day. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and extracted with ethyl acetate. The reaction mixture was washed with saturated brine, dried over magnesium sulfate, and evaporated to dryness to give a dark brown oil. EtOAc (282 g) and sodium cyanohydride (309 mg). A solution of tetrahydrofuran (1 mL) was added and the mixture was stirred for 1 hour at room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added to terminate the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO.subsubsubsubsubsubsubsubsubsubsubsubsubsub 775 mg, 68%). H NMR (300 MHz, CDCh) δ ppm 1. 05-1. 36 (m, 5H), 1.53-1.91 (m, 5H), 2.02-2.15 (m, 1H), 2.62 (s, 3H), 3.79 ( s, 3H), 4.58 (d, J=5.5 Hz, 1H), 4.66-4.74 (in, 1H), 6.50 (d, J=8.8 Hz, 2H), 7.77 (d, J=8. 8 Hz, 2H ), 8.23 (d, J = 1.3 Hz, 1H), 8.87 (d, J = 1.3 Hz, 1H). (5) 4-({cyclohexyl[3-decyl-6-(trifluoromethyl)thiophene [3,2-b]Acridine-2-yl]methyl}amino)benzoic acid A 1N aqueous solution of sodium hydroxide (1 mL) was added to the above-prepared 4-650 321426 201029996 ({cyclohexyl[3 - mercapto-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]nonyl}amino)benzoic acid oxime ester (775 mg), tetrahydrofuran (1 〇 mL) and A mixture of ethanol (10 inL) was added and the mixture was stirred and stirred under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and dried. (: In-hydrochloric acid (i 〇 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure toluene column chromatography (30 to 7 % acetic acid The title compound (671 mg, 87%) was obtained as a pale brown solid. mp.: 1.93 (m, 5H), 2.00-2.14 (m, 1H), 2.62 (s, 3H), 4.55 -4.80 (m, 2H), 6.50 (d, J=8. 8 Hz, 2H), 7.82 (d, J=8. 8 Hz, 2H), 8.23 (d, J=1.3 Hz, 1H), 8.88 ( d, J=l. 3 Hz, 1H). (6) 3-[{[4-({cyclohexyl[3-fluorenyl-6-(trifluoromethyl))) [3, 2-b] Acridine-2-yl]hydrazino}amino)phenyl]carbonyl}(fluorenyl)amino]propionic acid ethyl phthalate is intended to be 1-ethyl-3-(3-didecylaminopropyl) carbon The imine hydrochloride (221 mg) was added to the 4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl] synthesized above. Hydrazinylamino)benzoic acid (343 mg), ethyl 3-(decylamino)propionate (151 mg), 1-p-benzotriene monohydrate (176 mg), triethylamine 5小时。 Add a mixture of (321 / L) and N, N-dimethylformamide (10 mL) and stirred at room temperature for 2.5 days. The reaction mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate. EtOAc (EtOAc) The title compound (310 mg, 72%) was obtained as a white solid.</RTI> NMR (300 MHz, CDCh) (5 ppm 1.08-1. 35 (m, 8H), i&gt; 54_ 1.92 (m, 5H), 2.01-2.13 (m, 1H), 2.51-2.68 (m, 5R), 2.99 (s, 3H), 3.69 (t, J=7. 0 Hz, 2H), 4.10 (q , j=? j

Hz, 2H), 4.37-4.46 (ra, 1H), 4.60-4.68 (m, 1H), 6.49 (d, J=8. 7 Hz, 2H), 7.19 (d, J=8. 7 Hz, 2H) , 8.24 (s&gt; 1H), 8.87 (s, 1H). d (7) 3-[{[4-({cyclohexyl[3-indolyl-6-(trifluoromethyl)thiophene [3, 2 -b&gt;bipyridin-2-yl]methyl}amino)phenyl]alkyl}(methyl)amino]propionic acid A 1N aqueous sodium hydroxide solution (2. 〇〇mL) was added to the above synthesized 3-[{[4-( {cyclohexyl[3-indolyl-6-(trifluoromethyl)indeno[3,2-b] ° 〇 -2--2-yl]methyl}amino) A mixture of phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (31 mg), THF (5 mL) andEtOAc (5 mL). Dissolve the residue in water (10 mL) on 〇. (: 1 N Hydrochloric acid (2. 00 mL) was added. The obtained precipitate was collected by filtration to give the title compound (284 mg, 96%) as a white solid. JH NMR (300 MHz, CDCh) δ ppm 1. 35 (m, 5H), 1.53-1.89 (m, 5H), 2.00-2.12 (m, 1H), 2.54-2.69 (m, 5H), 3.00 (s, 3H), 3.68 (t, J=6. 6 Hz, 2H), 4.64 (d, J=7.2

Hz, 1H), 6.49 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 8.25 (s, 1H), 8.88 (s, 1H). Example A147 652 321426 201029996 3-[({4-[(cyclohexyl{3-indolyl-5-[2-(indolylthio)ethoxy)-1-benzofuran-2-yl}indolyl)] Phenyl}carbonyl)(methyl)amino]propionic acid

(1) Cyclohexyl {3-mercapto-5-[2-(indolylsulfonyl)ethoxy]-1dibenzo- 0 bit 11 Nan-2-yl} A_ Example A82(3) The synthesized cyclohexyl (5-hydroxy-3-methyl-1-benzofuran-2-yl)fluorenone (〇. 76 g) was dissolved in tetrahydrofuran (15 mL), and 2-( Methylthio)ethanol (〇26 mL), tributylphosphine (1.5 fflL), and 1,1~(azadiweiyl)di® bottom bit (1.46 g) were added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h. Hexane (15 mL) was added to the mixture and the sediment was removed by chopping algae. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjjjj ). NMR NMR (300 MHz, CDCh) &lt;5 ppm 1. 18-2. 01 (m, 10H), 2.24 (s, 3H), 2.57 (s, 3H), 2.92 (t, J=6.8 Hz, 2H) , 3.25- 3-40 (m, 1H), 4.21 (t, J=6.8 Hz, 2H), 7.03-7.41 (m, 3H). ' (2) Cyclohexyl {3-mercapto-5-[2- (Mercaptothio)ethoxy] benzophenan-2-yl} decyl 321426 653 201029996 The cyclohexyl hydrazone 3_methyl_5_[2_(methyl sulphide) synthesized in the above (1) Ethyl]-1-benzofuran-2-yl fluorenone (0 73 g) was dissolved in tetrahydrofuran (10 mL) and methanol (5 mL) and sodium borohydride (9 于) %, 〇. 18 g) added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature for a little hour. The mixture was again ice-cooled, and water ( 丨 mL) &amp; 1N hydrochloric acid (5 mL) was carefully added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1, vol.) to give the title compound (0. 67 g, 91%). Η 醒 R (300 MHz, CDC13) d ppm〇.86-1.99(m,11H), 2. 19 (s, 3H), 2.23 (s, 3H), 2.91 (t, J=6. 9 Hz, 2H ), 4.20 (t, J=6. 9 Hz, 2H), 4.51 (dd, J=8. 5, 6.0 Hz, 1H), 6.79-6.98 (m, 2H), 7.31 (d, J=9. 0) Hz, 1H). (3) 3-[({4-[(cyclohexyl{3-indolyl-5-[2-(indolylthio)ethoxy)-1-benzofuran-2-yl) }Methyl)amino]phenyl}carbonyl)(indenyl)amino]propanoic acid B is the cyclohexyl {3-methyl-5-[2-(methyl) synthesized in the above (2). Thio)ethoxy]-1-benzocyano-2-yl}methanol (〇. 34 g) is dissolved in tetrahydroanthracene (5 raL) and thiorubic chloride is added at room temperature (0.11) mL) is added to the solution. The reaction mixture was stirred at room temperature for 30 minutes, then cooled with ice, and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 minutes' and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in vanad dimethylacetic acid amine (5 mL), sodium iodide (0.23 g), sodium carbonate (0.15 g) and 3-52 synthesized by 654 321426 201029996 Example 2(2) [(4-Aminophenyl)carbonyl](methyl)aminopropionic acid ethyl ester (0.25 g) was added to the solution, and the mixture was stirred at 8 hr. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified mjjjjlilililililililililililili

Wl^MROOOMHz, CDC13) 6 ppml.〇〇-2. 〇〇(m,15H), 2. 05 (s, 3H), 2.22 (s, 3H), 2.61 (t, J=6.8 Hz, 2H), 2.89 ® (t, J-6.9 Hz, 2H), 3.01 (s, 3H), 3.70 (t, J=6.8 Hz, 2H), 4.00-4.20 (m, 4H), 4.36 (d, J=8. 0 Hz, 1H), 6.56 (d, J=8. 7 Hz, 2H), 6.78-6.94 (m, 2H), 7.14-7.25 (m, 3H). (4) 3-[({4-[(ring) Hexyl {3-methyl-5-[2-(indolylthio)ethoxy]-1-benzofuran-2-yl}indenyl)amino]phenyl}carbonylindenyl)amino]propyl The acid will be 3-(({4-[(cyclohexyl){3-indolyl-5-[2-(indolylthio)ethoxy)-1-benzopyrene) synthesized in the above (3) 2-yl}methyl)amino]phenyl}carbonyl)(fluorenyl,)amino]propionic acid ethyl ester (〇·33 g) dissolved in ethanol (2 mL) '1N aqueous sodium hydroxide solution at room temperature 5小时。 The mixture was stirred at 0 ° C. Ethanol was evaporated under reduced pressure, and hydrochloric acid (1. 5 mL) was added to residue, and the mixture was extracted with ethyl acetate. The residue was washed with saturated saline water and dried over sulfuric acid and concentrated under reduced pressure. The title compound (0.20 g, 63%) was obtained. !H NMR (300 MHz, DMSO-de) δ ppm 0.88-2.11 (m, 12H), 655 321426 201029996 2.15 (s, 3H), 2.23 (s, 3H), 2.40-2.46 (m, 2H), 2.76- 2.96 (m, 5H), 3.50 (t, J=7. 3 Hz, 2H), 4.15 (t, J=6. 7

Hz, 2H), 4.37 (t, J=8.3 Hz, 1H), 6.46 (d, J=8. 1 Hz, 1H), 6.59 (d, J=8. 7 Hz, 2H), 6.80 (dd, J =8. 7, 2. 6 Hz, 1H), 7.03 (d, 3=2. Q Hz, 1H), 7.09 (d, J=8. 7 Hz, 2H), 7. 32 (d, J=8 · 7 Hz, 1H). Example A148 3-[({4-[(cyclohexyl){3-methyl-5-[2-(methylthio)ethoxy]-1-phenyl®) 2-yl}indenyl)amino]phenyl}carbonyl)amino]propionic acid

Dissolving cyclohexyl {3-indolyl-5-[2-(indolyl fluorenyl)ethoxy]-1-benzoaphthyl-2-yl} decyl alcohol synthesized in Example A147(2) Add tetrazolium chloride (5 mL) to the solution and add sulfoxide (〇. 13 mL) to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then cooled with ice, and a saturated aqueous solution of sodium carbonate (10 mL) was carefully added to the mixture. The reaction mixture was scrambled for a few minutes and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was dissolved in N,N-dimercaptoacetamide (5 mL), sodium iodide (0.23 g), sodium carbonate (0.15 g) and Example U2) were synthesized. Aminophenyl)carbonyl]amino}ethyl propionate (〇. 25 g) 'and the mixture was stirred for 12 hours at 8 rc. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc: EtOAc (EtOAc) 38 g' 69%). Dissolve in ethanol (2 mL). Add in sodium hydroxide solution (1.5 mL) to the solution at room temperature, and stir the mixture at 50 ° C for 5 hours. Ethanol was evaporated, 1N hydrochloric acid (15 mL) was added to the residue, and the mixture was applied to ethyl acetate. The mixture was extracted with ethyl acetate. Title target compound (0. 18 g, 49%) H NMR (300 MHz, DMSO-de) S ppm 0.88-2.10 (m, 12H), 2.15 (s, 3H), 2.23 (s, 3H), 2.42 (t, J=7 .2 Hz, 2H), 2.84 (t, J=6.5 Hz, 2H), 3.47-3.55 (m, 2H), 4.15 (t, J=6.6Hz, 2H), 4.41 (t, J=8.4Hz, 1H ), 6.49-6.64 (m, 3H), 6.79 (dd, J=8. 9, 2. 5 Hz, 1H), 7.03 (d, J=2. 4 Hz, 1H), 7.32 (d, J=8 9 Hz, 1H), 7.51 (d, J=8. 7 Hz, 2H), 7.99 (t, J=5.5 Hz, 1H). Q Example A149 3-[{ [4-({cyclohexyl][5 -(2-methoxyethoxy)-3-methyl-i-benzoindolen-n-n-yl]indenyl}amino)phenyl]diyl}amino]propionic acid

Thionyl chloride (0.35 mL) was added to the cyclohexyl [5-(2-decyloxyethoxy)-3-indolyl-1-benzoate synthesized in Example A79 (3) at room temperature. -2- 321426 657 201029996 base] methanol (0.86 g) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 30 min then cooled with EtOAc EtOAc. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in N,N-dimethylacetamide (15 mL), sodium iodide (0.61 g), sodium carbonate (0.41 g) and 3-{[( 4-Aminophenyl)alkyl]amino}propionic acid B g (〇. 64 g) was added to the solution and the mixture was stirred at 80 C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by EtOAc (EtOAc: EtOAc: hexanes: 1:1) to afford 3-[{[4-( {cyclohexyl[5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl]indenyl}amino)phenyl]carbonyl}amino]ethyl propionate (0. 62 g, 43%). This was dissolved in ethanol (5 mL), and a 1N aqueous solution of sodium chloride (3.0 mL) was added to the mixture at room temperature for 0.5 hour. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (3. 〇 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (0.54 g, 91%) was obtained. H NMR (300 MHz, CDCh) δ ppm 0. 93-2. 13 (m, 12H), 2.21 (s, 3H), 2.66 (t, J = 5.7 Hz, 2H), 3.46 (s, 3H), 3.58 - 3-71 (m, 2H), 3.76 (dd, J=5. 6, 4.1Hz, 2H), 4.14 (dd, J 5.7,4.1Hz, 2H), 4.38 (d, J=7.99 Hz, 1H), 6.57-6.65 (m, 3H), 6. 80-6.98 (m, 2H), 7.22-7. 26 (m, 1H) 7 53 (d, J=8.7 Hz, 2H). ' 321426 658 201029996 Example A150 3-[({4-[(cyclohexyl{3-indolyl-5-[3-(indolylthio)propoxy)-1- benzofuran-2-yl}methyl) Amino]phenyl}carbonyl)(fluorenyl)amino]propionic acid

(1) Cyclohexyl {3-indolyl-5-[3-(methylthio)propoxy]-1-benzofuran-2-yl-2-yl}anthone is synthesized in Example A82(3) Cyclohexyl (5-hydroxy-3-indolyl-1-benzocypan-2-yl)indanone (2.4 g) was dissolved in tetrahydrofuran (50 mL) and 2-cooled under ice cooling (Mercaptothio)propanil (1.0 mL), tributylphosphine (4.7 mL) and 1, hydrazine-(azadicarbonyl)dipiperidine (4.7 g) were added to the solution. The ice was removed and the reaction mixture was dropped for 12 hours at room temperature. The calcined (5 〇 mL) was added to the mixture and the precipitate was filtered off through Shixia. Water was added to the mash and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjjjjj . !H NMR (300 MHz, CDCh) δ ppm 1. 18-2. 01 (m, 12H), 2.14 (s, 3H), 2.56 (s, 3H), 2.72 (t, J=7. 2 Hz, 2H ), 3.25-3.40 (m, 1H), 4.08-4.20 (m, 2H), 7.03-7.42 (m, 3H). (2) Cyclohexyl {3-mercapto-5-[3-(mercaptothio) )propoxy]benzophenone °~2-yl}sterol The cyclohexyl {3-mercapto-5-[3-(mercaptosulfur 321426 659 201029996) propoxypropane synthesized in the above (1) Base -1-benzofuran-2-yl}methanone (3.1 g) was dissolved in tetrahydrofuran (50 mL) and methanol (10 mL), and sodium borohydride (90%, 0. 73 g) added to the solution. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour, then cooled with ice, and water (5 mL) and 1N hydrochloric acid (25 mL) was carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (3.0 g, 95%) was obtained. © ]H NMR (300 MHz, CDCh) 5 ppm 1. 18-2. 01 (m, 14H), 2. 13 (s, 3H), 2.19 (s, 3H), 2.72 (t, J=1.2 Hz, 2H), 4.11 (t, J=7.2 Hz, 2H), 4.40-4.55 (m, 1H), 6.80-7.42 (m, 3H). (3) 3_[({4-[(cyclohexyl){3- -5-[3-(indolylthio)propoxy]-1-benzo[indolyl-2-yl}methyl)amino]phenyl})}(methyl)amino]propyl Ethyl ruthenium hydride The cyclohexyl {3-methyl-5-[3-(indolylthio)propoxy]-1-benzodropropan-2-yl}methanol synthesized in the above (2) (1.5 g) was dissolved in tetrazofuran (10 mL) and sulfoxide (〇. 56 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then cooled with ice and a saturated aqueous NaHCI (30 mL). The reaction mixture was scrambled for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate Dissolve the residue in N,N-dimercaptoacetamide (10 mL) 'Sodium iodide (0.95 g), sodium carbonate (〇. 63 g) and the compound of Example 2 (2) -{[(4-Aminophenyl)carbonyl](methyl)amino}propanoic acid B 660 321426 201029996 The ester (1.1 g) was added to the solution and the mixture was stirred at 80 ° C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjjjjjj WNMRCSOOMHz, CDC13) &lt;5 ppml.00-2.00 (m, 17H), 2 12 (s, 3H), 2· 21 (s, 3H), 2. 52-2. 79 (m, 4H), 3. 01 (s, 3H), 3. 70 (t, J=7. 2 Hz, 2H), 4. 00-4. 36 (m, 5H), 6. 56 (d, ❹ J=8. 7 Hz, 2H), 6. 78-6. 94 (m, 2H), 7. 14-7. 25 (m, 3H). (4) 3-[({4-[(cyclohexyl){3-methyl-5 -[3-(Methylthio)propoxy]-1-benzofuran-2-yl}indenyl)amino]phenyl}carbonyl)(indenyl)amino]propionic acid will be as described above (3) 3-[({4-[(cyclohexyl){3-indolyl-5-[3-(methylthio)propoxy]-1-benzofuran-2-yl}decyl)amine synthesized Ethyl]phenyl}carbonyl)(fluorenyl)amino]propionic acid ethyl ester (〇. 37 g) was dissolved in ethanol (5 ❹mL), and 1N aqueous sodium hydroxide solution (2. 〇mL) was added at room temperature to 5小时。 The solution was stirred at 50 ° C for 0.5 hours. Ethanol was evaporated under reduced pressure, and in hydrochloric acid (2.0 mL) was added to residue and mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and evaporated. The title compound (0.28 g, 79%) was obtained. </ RTI> </ RTI> <RTIgt; s, 3H), 3.70 (q, J=6.4Hz, 2H), 4.09 (t, J=6.4 Hz, 2H), 4.36 (d, J=7.9 Hz, 1H), 6.56 (d, J=8. 7 Hz, 2H), 6.77-6.96 661 321426 201029996 (m, 2H), 7.20-7.26 (ra, 3H). Example A151 3-[(H-[(cyclohexyl){3-indenyl-5_[3_(A Thiothio)propoxy-benzo-dozen-2-yl}mercapto)amino]phenylhydrazinecarbonyl)amine;]propionic acid

❹(1) 3-[({4-[(cyclohexyl丨3-indolyl-5-[3-(indolylthio)propoxy)] 1 and biting ^-yl}methyl)amino group Phenyl}amino)amino]propionic acid ethyl carbazide {3-indolyl-5-[3-(methylthio)propoxy]-1- Benzopyran-2-yl} decyl alcohol (1.5 g) was dissolved in tetrahydrofuran (10 mL) and added to the solution at room temperature with thiosyl chloride (0.56 mL). The reaction mixture was stirred at room temperature for 30 min then cooled with EtOAc EtOAc EtOAc. The reaction mixture was stirred for 1 min 13 and extracted with EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in N,N-dimethylacetamide (1 〇, sodium iodide (0.95 g), sodium carbonate (〇. 63 g) and the compound synthesized in Example 1 (2) {[(4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (1. 〇 added to the solution and stirred at 8 (TC for 12 hours). After cooling, water was added to the reaction mixture and ethyl acetate The mixture was extracted, and the residue was purified tolulujjjjjjjjjjjjj NMR (300 MHz, CDCI3) (5 ppm 1.00-2.00 (m, 17H), 2 12 321426 662 201029996 (S, 3H), 2. 21 (S, 3H), 2· 52-2. 79 (m, 4H), 3· 66 (q J=6. 0

Hz, 2H), 4.00-4.60 (m, 5H), 6.56 (d, J=8. 9 Hz, 2H), 6.58 (br. s. 1H), 6.78-6.94 (m, 2H), 7.20-7.60 ( m, 3H). ' (2) 3 -[(丨4-[(cyclohexyl {3-methyl-5-[3-(indolylthio)propoxy]-1-benzofuran-2- 3-[({4-[(cyclohexyl){3-methyl-5-[3-(()))) Methylthio)propoxy]-1-benzofuran-2-ylindolemethyl)amino]phenyl}amino)amino]propionic acid ethyl ester (〇. 25 g) is dissolved in ethanol (5 (mL), 1N aqueous sodium hydroxide solution (2·〇mL) was added to the solution at room temperature and the mixture was stirred for 5 hours at 5 (TC). Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (2. 〇mL) was added. The residue was extracted with ethyl acetate. EtOAc (EtOAc) was evaporated. !H NMR (300 MHz, CDCh) δ ppm 0. 82-2. 16 (m, 14H), 2. 22 Q Cs, 3H), 2.52-2.81 (m, 4H), 3.66 (q, J=6.0 Hz, 2H), 4.08 (t, J=6. 0 Hz, 2H), 4.38 (d, J=7.9 Hz, 1H), 6.43-6.66 (m, 3H), 6 .74-6.96 (m, 2H), 7.20-7.26 (m, 1H), 7. 53 (d, J = 8.9 Hz, 2H). Example A152 3-[({4-[(cyclohexyl){ 3-mercapto-5-[3-(methylsulfonyl)propoxy]-1- benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino] Propionic acid 663 321426 201029996 Ο

OH

(1) 3-[({4-[(cyclohexyl{3-indolyl-5-[3-(methylsulfonyl)propoxy]-1-benzofuran-2-yl}fluorenyl) Amino]phenyl}carbonyl)(methyl)amino]propionic acid B.Sup.3-[({4-[(cyclohexyl){3-methylindole-5) synthesized in Example Α150(3) -[3-(indolylthio)propoxy]-1-benzopyran-2-yl}methyl)amino]]yl}yl)(indenyl)amino]propionic acid ethyl acetonate 0.61 g) Dissolved in methanol (15 mL) and water (2 mL). To the solution was added oxone (2.1 g) at room temperature and the mixture was stirred for 30 minutes. Water was added to the reaction mixture and the mixture was extracted by HPLC. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj !H NMR (300 MHz, CDCls) δ ppm 0. 94-2. 01 (m, 17H), 2.21 Ό Cs, 3H), 2.28-2.42 (m, 2H), 2.61 (t, J=6. 9 Hz , 2H), 2.95 (s, 3H), 3.01 (s, 3H), 3.20-3.36 (m, 2H), 3.70 (t, J=6. 9 Hz, 2H), 4.04-4.19 (in, 2H), 4.26-4.44 (m, 1H), 6.56 (d, J=8. 7 Hz, 2H), 6.74-6.91 (in, 2H), 7.15- 7.25 (m,3H). (2) 3-[({4 -[(cyclohexyl{3-indolyl-5-[3-(methylsulfonyl)propoxy]-l-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)( Methyl)amino]propionic acid 664 321426 201029996 3-[({4-[(cyclohexyl丨3_methyl_5_[3-(methyl sulphate)) propoxy) synthesized in the above (1) ]—1-Benzo^^^^ylylamino)amino]phenyl}carbonyl)(methyl)amino]propionic acid ethyl ester (〇·48 g) dissolved in ethanol (5 mL) 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution at room temperature, and the mixture was allowed to stand at 5 0 C for 5 hours. Ethanol was evaporated under reduced pressure and 1 n hydrochloric acid (1.5 mL) was then evaporated. The extract was washed with brine, dried over magnesium sulfate The residue was washed with ethanol_water to give the title compound ( 〇. 35 g, ❹ 78%) as a colorless solid. ' ^ NMR (300 MHz, CDCh) δ ppm 0. 87-2. 15 (m, 12H), 2 21 (s, 3H), 2.25-2.45 (m, 2H), 2.67 (br. s., 2H) , 2.95 (s, 3H), 3.04 (s, 3H), 3.17-3.36 (m, 2H), 3.69 (t, J=6.5Hz, 2H), 4. 13(t, J=5. 7 Hz, 2H ), 4.36 (d, J=7.9 Hz, 1H), 6.56 (d, J=8.7Hz, 2H), 6.70-6.93 (m, 2H), 7. 16-7. 26 (m, 3H). q Example A153 3-[({4-[(cyclohexyl){3-methyl-5-[3-(methylsulfonyl)propoxy]-benzofuran-2-yl}methyl) Amino]phenyl}carbonyl)amino]propionic acid

(1) 3-[({4-[(cyclohexyl{3-methyl-5-[3-(indolyl)-yl)propoxy]-1-benzofuran-2-yl}fluorenyl) Amino]phenyl}carbonyl)amino]propionic acid ethyl ester 665 321426 201029996 Example A151 (l) synthesized 3-[({4 - [(cyclohexyl){3_methyl-5-[3-( Ethylthio)propoxy]-1-benzopyran-2-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid ethyl ester (0.16 g) dissolved in propylene steel (5 mL) ), m-chloroperbenzoic acid (0.2 g) was added to the solution under ice cooling and the mixture was stirred for 15 minutes. An aqueous solution of sodium sulfite was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjj ). © 4 NMR (300 MHz, CDCls) (5 ppm 0. 89-1. 92 (m 17H) 2 22 (s, 3H), 2.25-2.44 (m, 2H), 2.58 (t, J=5.8 Hz, 2H ), 2.95 (s, 3H), 3.14-3.35 (m, 2H), 3.66 (q, J=6.8 Hz, 2H), 4.13 (q, J=7. 2 Hz, 2H), 4.38 (d, J= 7. 9 Hz, 1H), 6.43-6.64 (m, 3H), 6.73-6.90 (m, 2H), 7.16-7.25 (m, 1H), 7.54 (d, J=8.7 Hz, 2H). (2) 3-[({4-[(cyclohexyl){3-indolyl-5-[3-(methylsulfonyl)propoxy] fluorenylbenzofuran-2-yl}methyl)amino]phenyl }carbonyl]amino group;|propionic acid 3-[({4-[(cyclohexyl{3-indolyl-5-[3-(methylsulfonyl)propoxy)] synthesized in the above (1)] -1-benzofuran-2-ylindolemethyl)amino]phenyl}carbonyl}amino]propionic acid ethyl ester (〇. 11 g) dissolved in ethanol (3 mL), 1N hydr The sodium aqueous solution (ί ο mL) was added to the solution and the mixture was stirred for 0.5 hr at 5 〇t&gt;c. Ethanol was evaporated under reduced pressure, and 1N HCl mL) was added to residue and mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The title compound (〇9 g, 8〇%) was obtained as a colorless solid. 666 321426 201029996 ]H NMR (300 MHz, CDCh) &lt;5 ppm 0. 90-2. 14 (in, 14H), 2.22 (s, 3H), 2.26-2.42 (m, 2H), 2.60-2.72 (m , 2H), 2.95 (s, 3H), 3.17-3.33 (m, 2H), 3.66 (q, J=5. 7 Hz, 2H), 4. 13(t, J=5. 7 Hz, 2H), 4.38 (d, J=7.9 Hz, 1H), 6.47-6.62 (m, 3H), 6.74-6.90 (m, 2H), 7.20-7.26 (m, 1H), 7. 53 (d, J=8 7 Hz, 2H). Example A154 3-Π[4-({[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl](cyclohexyl) fluorenyl) Amino)phenyl]carbonyl}(indenyl)amino]propionic acid

(1) [5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl](cyclohexyl)methanol 1-(5- synthesized in Example A82(2) (Benzyloxy)-2-hydroxyindole phenyl]ethanone (1.5 g) was dissolved in tetrahydrofuran (25 mL) and methanol (5 mL), and sodium borohydride (90%, 〇. 36 g) added to the solution. The reaction mixture was allowed to stand at room temperature for 1 hour, then cooled again with ice, and water (5 mL) and 1N hydrochloric acid (10 mL) was carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The title compound was obtained as a pale yellow oil (yield: 4 g, 95%). 667 321426 201029996 ]H NMR (300 MHz, CDCh) (5 ppm 0. 81-2. 00 (m, 12H), 2.18 (s, 3H), 4.51 (d, J=8.3 Hz, 1H), 5.10 (s , 2H), 6.87- 7.06 (m, 2H), 7.29-7.58 (m, 6H). (2) 3-[{[4-({[5-(Benzyloxy)-3-indolyl-1 -benzofuran-2-yl](cyclohexyl)fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester [5_(benzyloxy) synthesized in the above (1) ))-3-mercapto-1-benzofuran-2-yl](cyclohexyl)methanol (1.5 g) was dissolved in tetrahydrofuran (2 mL) and sulfite chloride (0.57 mL) at room temperature The solution was added to the solution, and the mixture was stirred at room temperature for 30 minutes, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (30 mL) was carefully added to the mixture. The mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (15 mL). 3-([4-Aminophenyl)carbonyl](indenyl)amino}propionic acid ethyl ester (1.1 g) synthesized in the mixture (0.15 g) and Example 2 (2) 80C mixing mixture 12 small After cooling, the hydrazine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio). The title compound (1 8 g 72%) was obtained as a yellow oil. 'H NMR (300 MHz, CDCh) δ ppm 0. 86-2. 00 (m, 15H), 2.21 (s, 3H ), 2.61 (t, J=7. i Hz, 2H), 3.01 (s, 3H), 3.70 (t J=7.1 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 4.27- 4.43 (m'2H), 5.08 (s, 2H), 6.56 (d, J = 8.7 Hz, 2H), 6.79 - 7·01 (m, 2H), 7.13-7.24 (m, 3H), 7.30-7.59 ( m, 5H). 321426 668 201029996 (3) 3-[{[4-({[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl](cyclohexyl)anthracene 3-[{[4-({[5-(()))]]]]]]]] Benzyl-1-benzofuran-2-yl](cyclohexyl)fluorenyl}amino)phenyl]pyridyl fluorenyl (indenyl)amino]propionic acid (g) (0.2 g) dissolved in ethanol (5 mL) Add 1N aqueous sodium hydroxide solution (1.5 mL) to the solution at room temperature and mix the mixture at room temperature for 5 hours.Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (15 mL) was evaporated. The extract was washed with brine, dried over MgSO The residue was washed with ethanol-water to give title compound (yel. 18 g, 94%). H NMR (300 MHz, CDCh) δ ppm 0. 79-2. 14 (m, 12H), 2.21 (s, 3H), 2.63 (t, J=6.2 Hz, 2H), 3.01 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 4.36 (d, J=7.9 Hz, 1H), 5.08 (s, 2H), 6.55 (d, J=8. 7 Hz, 2H), 6.80-7.03 (m, 2H), 7.13-7. 52 (m, 8H).

Example A155 3-[{[4-({cyclohexyl[3-indolyl_5_(acridin-2-ylmethoxy)-p-benzopyran-2-yl]methyl}amino)benzene Carbonyl hydrazide (mercapto) amino] propionic acid

(1) 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl) 321426 669 201029996 fluorenyl]amino phenyl)carbonyl](曱Ethylamino-propionic acid ethyl ester 3-[{[4-({[5-(benzyloxy)-3-methyl-1-benzofuran-2) synthesized in Example A154(2) -yl](cyclohexyl)methyldecylamino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (2.46 g) was dissolved in ethanol (5 〇mL) and oxidized (0.33 g) was added. To the solution. The reaction mixture was stirred overnight at room temperature under hydrogen (1 afm). The reaction mixture was passed through and washed with ethanol. The filtrate was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ). ^ NMR (300 MHz, CDCh) δ ppm 0. 91-1. 91 (in, 15H), 2.18 (s, 3H), 2.61 (t, J=7. 1 Hz, 2H), 3.01 (s, 3H) , 3.71 (t, J=7. 1 Hz, 2H), 4.02-4.18 (m, 2H), 4.28-4.41 (m, 1H), 4. 86 (s, 1H), 6. 55 (d, J= 8. 7 Hz, 2H), 6.66-6.87 (m, 2H), 7.14-7.25 (m, 3H). (2) 3-[ {[4-({cyclohexyl[3-indolyl-5_(0 ratio) Ethyl 2-methoxycarbonyl)-dibenzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester will be synthesized as described in (1) above. 3-{[(4-·[[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](fluorenyl)amine } Ethyl propionate (0.23 g) was dissolved in tetrahydrofuran (5 mL) r and 2-pyridine methanol (62 mg), tributylphosphine (0 21 mL) and li, one (aza-carbonyl) Dipiperidine (0.21 g) was added to the solution. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hr then hexane (15 mL) was applied to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and extracted with ethyl acetate 321426 670 201029996. The extract was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjj 70%). !11 NMR (300 MHz, CDCls) δ ppm 0. 88-1. 95 (m, 15H), 2.21 (s, 3H), 2. 54-2.72 (m, 2H), 3· 01 (s, 3H) , 3.70 (t, J=7. 2 Hz, 2H), 4.01-4.21 (m, 2H), 4.22-4.54 (m, 1H), 5.10 (s, 2H), 6.56 (d, J=8.7 Hz, 2H ), 6.80-7.05 (m, 2H), 7.21 (d, J=8. 7 Hz, 2H), 7.28-7.40 (m, 2H), 7.79 ° (d, J=8.0 Hz, 1H), 8.58 (d , J=4.5 Hz, 1H), 8.70 (s, 1H). (3) 3-[ {[4-({Cyclohexyl[3-methyl-5-indenyl-2-yloxy))- 1-Benzofluoren-2-yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid 3-[{ [4-({ ring) synthesized in the above (2) Hexyl [3-methyl-5-(peptidyl-2-ylmethoxy)-1-benzopyran-2-yl]methyl}amino)phenyl] benzyl}(methyl)amine Ethyl propionate (〇. 19 g) was dissolved in ethanol (5 mL). EtOAc (1 mL EtOAc) Evaporate the ethanol under reduced pressure, and then add 丨n hydrochloric acid (yield) to residue and extract the mixture with ethyl acetate. The extract was washed with saturated brine, dried over sulphuric acid and concentrated under reduced pressure. The title compound (0.11 g, 41%) was obtained as a yellow solid. H NMR (300 MHz, CDCla) δ ppm 0. 92-2. 16 (m5 12H), 2 20 (s, 3H), 2.62 (br s., 2H), 3.02 (s, 3H), 3.65 (br. s. , 2H), 4.34 (d, J=7. 9 Hz, 1H), 5.15 (S) 2H), 6.54 (d, J =8.3 Hz, 2H), 6.75-6.98 (m, 2H), 7.11-7.30 (m 321426 671 201029996 4H), 7.35-7.52 (m, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.50-8.70 (m, 2H). Example A156 3-[{[4-({cyclohexyl[3-indolyl-5-(acridin-3-ylmethoxy)-1-benzofuran-2 -yl]methyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid

(1) 3-[{[4-({cyclohexyl[3-methyl-5-(D-0-but-3-yloxy)-1-benzofuran-2-yl]decyl}amine Ethyl)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester 3-{[(4-{[cyclohexyl(5-hydroxy-3-indolyl-1) synthesized in Example A155(l) -benzofuran-2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate (0.23 g) was dissolved in tetrahydrofuran (5 mL) and 3-pyridinemethanol (62 mg), tributylphosphine (0.21 mL) and li, one (azepinediyl) two brigade bite (〇. 21 g) were added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h then hexanes (5 mL) was then applied to mixture and passed through. Water was added to the mash and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjj %). ]H NMR (300 MHz, CDCh) ^ PPm 0. 85-1. 95 (m, 15H), 2.19 (s, 3H)' 2. 61 (br. s.,2H), 3· 〇i (s, 3h), 3. 7〇(t, 321426 672 201029996 J=7.2Hz, 2H), 4. 12(q, j=7> 2, 2. 8 Hz, 2H), 4.25-4.45 (m, 2H), 5.24 (s, 2H), 6.55 (d, J=8.7 Hz, 2H), 6.84-7.02 (m, 2H), 7.13-7.30 (m, 4H), 7.55 (d, J=7. 9 Hz, 1H) , 7.67-7.82 (m, iH), 8.48-8.71 (m, 1H). (2) 3 [{[4-({cyclohexyl[3-indolyl_5_(pyridine_3_yloxy))_ Benzenefuran-2-yl]fluorenyl}amino)phenyl]carbonylindole (methyl)amino]propionic acid will be synthesized as described above in (1) [3_fluorenyl-5_ (° ratio Pyridin-3-yloxy)phenylbenzofuran-2-yl]fluorenyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid ethyl ester (〇13 g) is dissolved in ethanol (5 (mL), 1N aqueous sodium hydroxide solution (3. 〇mL) was added to the solution and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (3. The extract was washed with brine, dried over magnesium sulfate The title compound (0 08 g, 95%) was obtained eluted eluted eluted elute H NMR (300 MHz, CDCh) δ ppm 0. 83-2. 13 (m, 12H), 2.18 ❿(s, 3H), 2.50-2.75 (br. s., 2H), 3.01 (s, 3H), 3.64 (br. s., 2H), 4. 35 (d, J=7.9 Hz, 1H), 5.44 (s, 2H), 6.55 (d, J=8. 7 Hz, 2H), 6.79-7.09 (m, 2H), 7.12-7.25 (m, 3H), 7.45-8.01 (m, 3H), 8.66 (br. s., 1H). Example A157 3-[{[4-({cyclohexyl][3 -methyl-5-(pyridin-4-ylmethoxy)-1-benzofuran-2-yl]indolyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid 321426 673 201029996

(1) 3-[{ [4-({cyclohexyl[3-methyl-5-(acridin-4-ylmethoxy)-1-benzofuran-2-yl]hydrazino}amino) Phenyl]carbonyl}(methyl)amino]propionic acid 3-{[(4-{[cyclohexyl(5-hydroxyindole-3-methyl-1-benzo) synthesized in Example A155(l) Furan-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}ethyl propionate (0.23 g) dissolved in tetrahydrofuran (5 mL) and 4-pyridine under ice cooling Sterol (62 mg), tributylphosphine (0.21 mL) and 1, hydrazine-(azabicyclo) bismuth (0.21 g) were added to the solution. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h then hexane (5 mL) was then applied to mixture and the siftings were removed. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified (jjjjjjjjjjjjjj 64%). WMRQOOMHz' CDC13) 5 _〇·,97(m,15H),2 2〇(s' 3H)' 2·61 (t,J=7.2 Hz, 2H), 3.01 (s,3H), 3.70 (t, &gt;7.2ΗΖ, 2H), 4.06_4.18(q, J=7 2Hz, 2h), a (d, J=4.0 Hz, 1H) ^11 rc 〇u\ 〇r. 11 people m (s, 2H ), 6. 56 (d, J=8·7 Hz, 2H), 6. 82-6.99 (m 2H) 7 14 7 , zha /.14-7. 31 (m, 3H), 7 38 (mountain J =6-〇Hz, 2H), 8.60-8.69 (m, 2H). (2) 3-Π[4-({cyclohexyl[3_methyl_5 decyl methoxy)+ 321426 674 201029996喃-2-yl] fluorenyl}amino)phenyl]reinyl (methyl)amino]propionic acid 3-[{[4-({cyclohexyl][3-] synthesized in the above (1) Mercapto-5-(Bite-4-yloxy)-1-benzofuran-2-yl]nonylamino)phenyl]carbonyl}(fluorenyl)amino]propionic acid ethyl ester ( 17 g) Dissolved in ethanol (5 mL), a 1 N aqueous solution of sodium hydroxide (3. 〇mL) was added to the solution and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and EtOAc (3 mL) was applied. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (0. 13 g, 77%) was obtained eluting with EtOAc EtOAc. JH NMR (300 MHz, CDCh) δ ppm 0. 81-2. 13 (m, 12H), 2. 19 (s, 3H), 2.50-2.75 (br. s. , 2H), 3.03 (s, 3H) , 3.60-3.75 (m, 2H), 4.34 (d, J=7. 9 Hz, 1H), 5.16 (s, 2H), 6.53 (d, J=8. 5 Hz, 2H), 6. 78-6 . 97 (m, 2H), 7.12-7.31 (m, 3H), 7.44 (d, J=5. 8 Hz, 2H), 8.60 (d, J=5.8 Hz, 2H). 〇Example A158 3-( {[4-({[5-(Benzyloxy)-3-indolyl-1-benzopyrene-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}amino) Propionic acid

(1) 3-({[4-({[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl) ]carbonyl}amino)propionic acid ethyl ester 675 321426 201029996 [5-(Benzyloxy)-3-methyl-i-benzopyran-2-yl] synthesized according to Example A154 (1) Cyclohexyl)methanol (1.0 g) was dissolved in tetrahydrofuran (15 mL) and sulfoximine (〇· 38 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then cooled with ice and a saturated aqueous sodium hydrogen carbonate solution (30 mL) was carefully added to the mixture. The reaction mixture was stirred for 1 (min) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and evaporated. The residue was dissolved in N,N-dimethylethanoamine (2 mL), sodium molybdenum (〇·65 g), sodium carbonate (0.43 g) and the compound synthesized in Example 1 (2) {[(4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (0.68 g) was added to the solution and the mixture was stirred at 8 (TC) for 12 hours. After cooling, water was added to the reaction mixture and ethyl acetate The mixture was extracted, and the residue was purified (jjjjjjjjjjjj , 48%). 'H NMR (300 MHz, CDCh) δ ppm 0. 92-1. 98 (m, 15H), 2.21 ❹(s,3H), 2.58 (t, J=5. 7 Hz, 2H) , 3.48 (q, J=7. 0 Hz, 1H), 3.66 (q, J=5. 7 hz, 2H), 4.11 (q, J=7. 2 Hz, 2H), 4.30-4.54 (in, 2H ), 5.08 (s, 2H), 6.57-6.62 (m, 3H), 6.82-7.02 (m, 2H), 7.18-7.60 (m, 8H). (2) 3-[{[4-({[5 -(benzyloxy)_3 monomethyl q-benzofuran-2-yl](cyclohexyl)nonylamino)phenyl]yl}}(methyl)amino]propionic acid will be as described above (1) Synthesis of 3-({[4-({[5-(phenylhydroxy)-3-indolyl 1-benzofuran-2-yl](cyclohexyl)) Methyl decyl) phenyl]carbonyl hydrazinyl) propionic acid ethyl vinegar (0.78 g) was dissolved in ethanol (5), and 1N hydrogen 676 321426 201029996 sodium hydroxide aqueous solution (3.0 mL) was added to the solution at room temperature. The mixture was stirred at room temperature for 5 hours. Ethyl alcohol was evaporated under reduced pressure, and 1N hydrochloric acid (3·mL) was added to residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. Concentration by pressure. The residue was washed with ethyl acetate-water to afford title compound (yield: 70 g, 94%) as a colorless solid. H NMR (300 MHz, CDCla) δ ppm 0. 81-2. 10 (m, 12H ), 2 17 (s, 3H), 2.50 (br. s., 2H), 3.55 (br. s., 2H), 4.32 (br. s. , 1H), 5.04 (s, 2H), 6.51 (d , J=8. 7 Hz, 2H), ® 6.68 (br.s., lH), 6.8j^6.99 (ra, 2H), 7.23-7.59 (m, 8H). 5 Example A159 3-[{[ 4-({l-[5-(Benzyloxy)-3-methyl-i-benzofuran-2-yl]-3-methylbutyl}amino)phenyl]yl}} Amino acid] propionic acid

(1) 5-(Benzyloxy)-3-methyl-1-benzopyrene-2-acidic ethyl ester at room temperature to remove carbonic acid (13.1 g) and ethyl bromoacetate (7.7 mL) Addition of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (15.3 g) to N,N-dimethylformamide solution (200) obtained in Example A82 (1) (mL) and the mixture was disrupted at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted by an assay. The extract was concentrated under reduced pressure, and the obtained residue was redissolved in N,N-dimethylformamide (100 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene 321426 677 201029996 (12.2 mL) was added to the solution. The reaction mixture was stirred overnight at rt (EtOAc) EtOAc (EtOAc m. Compound (3.3 g, Π%) H NMR (300 MHz, CDCh) δ ppm 1.44 (t, J = 7. 2 Hz, 3H), 2-55 (s, 3H), 4.45 (q, 5 = 1.2 Hz , 2H), 5.12 (s, 2H), ^.01-7.21 (m, 2H), 7.30-7.60 (m, 6H). φ (2) [5-(Benzyloxy)-3-methyl- Addition of lithium hydride (〇. 42 g) to 5-(benzoxyloxy)-3-methyl-1- which is synthesized by the above (丨) under ice cooling with benzopyrene-2-yl]methyl-fermentation Ethyl benzofuran-2-carboxylate (3.3 g) in tetrahydrofuran (5 mL). The ice bath was removed and the mixture was stirred at room temperature for 1 hour, then cooled again with ice. Water (11 mL), 1N aqueous sodium hydroxide (5. 5 mL), and water (1. 1 mL) were used to terminate the reaction. The residue was filtered through celite and filtrate was concentrated under reduced pressure to give a pale yellow solid title. Compound (2.8 g, quantitative) 〇NMR (300 MHz, CDC13) &lt;5 ppm 1. 70-1. 90 (b Rs,1H), 2.22 (s, 3H), 4.73 (d, J=6. 0 Hz, 2H), 5.10 (s, 2H), 6.88-7.06 (m, 2H), 7.28-7.56 (m, 6H) (3) 5-(Phenyloxy)-3-indenyl-i-benzofuran-2-carbaldehyde is added to the [5-(benzoquinone) synthesized in the above (2) by oxidizing (5 g) a solution of oxy)-3-mercapto-1-benzofuran-2-yl]nonanol (2.8 g) in toluene (30 mL) and the mixture was heated with a Dean-Stark separator under reflux for one hour. After cooling to room temperature, the catalyst was filtered with EtOAc (EtOAc) (EtOAcjjjjjjjjj s,3H),5. 12 (s, 2H), 7.06-7.25 (m, 2H), 7.32-7.57 (m, 6H), l〇.〇〇(s, 1H). (4) 3-[{ [4-({l-[5-(Benzyloxy)_3_methyl-p-benzofuran-2-yl]-3-mercaptobutyl}amino)phenyl]carbonylindole (methyl)amine Ethyl propionate ethyl bromide (1M, tetrahydrofuran solution) was added dropwise to the 5-(benzyloxy)-3-methyl-indole-benzene synthesized in the above (3) under ice cooling. And furan oxime-2-furaldehyde (1·2 g) in tetrahydrofuran solution (15 mL). The ice bath was removed, and the reaction mixture was stirred at room temperature for 15 minutes and a chlorinated aqueous solution was added to terminate the reaction. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc:EtOAc:EtOAc Benzyl-3-indolyl-i-benzofuran-2-yl]-3-mercaptobutan-1-ol (0-82 g, 56%). This was dissolved in tetrahydrofuran (15 mL) and sulfinium chloride (0.35 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes', then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 mL) was carefully added to the mixture. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in N,N-dimethylacetamide (15 mL), sodium iodide (0.56 8), sodium carbonate (0.38 8), and 3_{[(4) synthesized in Example 2 (2). -Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (0.63 g) was added to the solution and the mixture was stirred at 80 ° C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was taken with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjjjj %). JH NMR (300 MHz, CDCh) (5 ppm 0. 76-1. 05 (m, 6H), 1.11-1.90 (m, 6H), 2.24 (s, 3H), 2.47-2.69 (m, 2H), 3.01 (s, 3H), 3.56-3.80 (m, 2H), 3.95-4.32 (m, 3H), 4.56-4.78 (in, 1H), 5.09 (s, 2H), 6.57 (d, J=8.7 Hz, 2H ), 6.80-7.02 (m, 2H), 7.12-7.53 (m, 8H). (5) 3-[{[4-(U-[5-(Benzyloxy)-3-indolyl-1- Benzofuran-2-yl]-3-mercaptobutyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid® 3-[{[4- (U-[5-(phenylhydroxy)-3-indolyl-1-benzofuran-2-yl]-3-indenylbutyl}amino)phenyl]carbonyl}(indenyl)amino group 5小时。 After the mixture was stirred at room temperature for 0.5 hours. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid &lt The extract was washed with brine, dried over magnesium sulfate The residue was washed with ethanol-water to give the title compound (0.45 g, quantitative). NMR (300 MHz, CDCh) δ ppm 0. 90 (d, 3H, J=6. 0 Hz), 0.99 (d, 3H, J=6.0 Hz), 1.25-2.00 (m, 4H), 2.24 (s, 3H), 2.67 (br. s., 2H), 3.03 (s, 3H), 3.71 (br. s., 2H), 4.20-4.40 (m, 2H), 5.08 (s, 2H), 6.59-7.05 ( m, 4H), 7. 31-7· 57 (m, 8H). Example A160 3-[{[4-({cyclohexyl[3-indolyl_5_(tetrahydro-2H-thiopyran)- 4-yloxyindole-benzofuran-2-yl]fluorenyl}amino)phenyl]carbonyl}(methyl)amino] 680 321426 201029996 propionic acid

(1) 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2-indole-thiopiperan-4-yloxymethyl-benzofuran-2-yl]methyl} Amino)phenyl]carbonyl}(methyl)amino]ethyl propionate Ο 3 3_{[(4_丨[cyclohexyl)(5-hydroxy-3-indolyl-1) synthesized in Example A155C1) -benzofuran-2-yl)methyl]amino phenyl)carbonyl](methyl)amino}ethyl propionate (0.50 g) dissolved in tetrahydrofuran (1 mL) and chilled under ice Hydrothiopentan-4-ol (142 mg), tributylphosphine (0.45 mL) and 1, hydrazine-(azadicarbonyl)dipiperidine (〇. 45 g) were added to the solution. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hrs, then hexane (1 〇 mL) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with acetic acid. The extract was concentrated under reduced pressure and purified titled mjjjjjjjjjjjjjj . ]H NMR (300 MHz, CDCls) δ 0. 91-2. 14 (m, 18H), 2. 20 (s 3H), 2.46-2.99 (m, 6H), 3.01 (s, 3H), 3.33-3.49 (m, 1H), 3.70 (t, J=7. 1 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 4. 25-4. 40 (m, 1H), 6. 56 (d, J=8. 7 Hz, 2H), 6.78-6.94 (m, 2H), 7.16-7.30 (m, 3H). (2) 3-[{[4-( {cyclohexyl[3-meryl] -5-(tetrahydro-2H-thiopiperan-4-321426 681 201029996 oxy)-1-benzofuran-2-yl]fluorenyl}amino)phenyl]carbonylindole (methyl)amine 3-][{4-( {cyclohexyl[3-methyl-5_(tetrahydro-2H-thiopiperazin-4-yloxy)-1) synthesized by the above (1) -benzofuran-2-yl]fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid ethyl ester (〇. 14 phantom dissolved in ethanol (3 mL), 1N hydrogen at room temperature An aqueous solution of sodium oxide (1· 〇mL) was added to the solution and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1 mL) was applied to residue and mixture was extracted with ethyl acetate. The extract was washed with saturated® brine, dried with sulfuric acid and concentrated under reduced pressure. The chromatographic column chromatography (acetic acid b g. yin = 3: 1 'volume ratio) The title compound (〇. 〇6 g, 46%) was obtained as a colorless solid. H NMR (300 MHz, CDCh) δ ppm 0. 86-2. 15 (m, 16H), 2.21 (s, 3H), 2.41-2.95 (in, 6H), 3.06 (s, 3H), 3.72 (t, J=6.4 Hz, 2H), 4.21-4.46 (m, 2H), 6.56 (d, 1=8.7 Hz, 2H ), 6.76-6.95 (m, 2H), 7.22-7.26 (m, 3H). q Example A161 3-{[(4-·[[cyclohexyl(4-fluoro-3-methyl-i-benzo) Furan-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid

(1) Cyclohexyl (4-fluoro-3-indolyl-1-benzofuran-2-yl)anthone at room temperature with potassium carbonate (6.7 g) and 2-31214 of Example A51 (l) 682 201029996 bromo-1-cyclohexyl Ethyl ketone (4.0 g) was added to 1-(2-fluoro-6-hydroxyphenyl)ethanone (2.5 g) in N,N-dimethylformamide solution ( 50 mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was allowed to cool to room temperature and was passed through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate The resulting residue was redissolved in 1 dimethylformamide (5〇1111), and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution. The mixture was stirred and heated at 110 ° C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with 1N HCI andEtOAc. The extract was concentrated under reduced pressure and the crystals crystals crystals crystals crystals crystals !H NMR (300 MHz, CDCla) (5 ppm 1.20-2. 07 (m, l〇H), 2.73 (s, 3H), 3.20-3.36 (m, 1H), 6.92 (ddd, J=10.0, 7.8 , 0.8 Hz, 1H), 7.27-7.44 (m, 2H). (2) Cyclohexyl (4-fluoro-3-methyl-1-benzofuran-2-yl)methanol φ will be as described in (1) above. The synthesized cyclohexyl (4-fluoro-3-methyl-1-benzonyridin-2-yl)methanone (2.6 g) was dissolved in tetrahydrofuran (4 mL) and methanol (4 mL) and cooled in ice. Sodium borohydride (90%, 0. 83 g) was added to the solution. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour, then cooled again with ice, and water (5 mL) and 1N hydrochloric acid ( 1 〇 mL) Carefully added to the mixture' and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified to give the title compound (2.5 g, quantitative) as pale yellow oil. 683 321426 201029996 NMR (300 MHz, CDCh) ^ ppm 〇. 72-2. 22 (m, 12H) , 2.35 (s, 3H), 4.50 (dd, J=8. 6, 6.1 Hz, 1H), 6.86 (ddd, J=10. 1, 7.6, 1.3 Hz, 1H)5 711-7.24 (m, 2H). (3) 3-{[(4-{[cyclohexyl(4-fluoro-3-methyl-4-benzofuran-2-yl)methyl]amino}phenyl)]amino]amino Propyl-propionic acid The cyclohexyl (4-fluoro-3-methylbenzofuran-2-yl) decyl alcohol (0.52 g) synthesized in the above (2) was dissolved in tetrahydrofuran (10 mL) at room temperature. Thiohydrin chloride (〇. 27 mL) was added to the solution. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium hydrogencarbonate (5 mL) was carefully added to the mixture. The mixture was extracted with EtOAc. EtOAc (EtOAc m.) g), sodium carbonate (0.30 g) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propionate (0.45 g) synthesized in Example 1 (2) were added to the solution and The mixture was stirred at 8 (TC) for 12 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and chromatographic column chromatography (ethyl acetate: hexanes = 1) : 1, volume ratio) purified residue to obtain 3-{[(4-{[cyclohexyl(4-fluoro-3-methylbenzofuran-2-yl)methyl]amino}phenyl)carbonyl]aminopurine as a yellow oil Ethyl acetate (〇 12 g, 13%). The obtained oil was dissolved in ethanol (3 mL;), and 1N sodium hydroxide aqueous solution (1 mL) was added to the solution and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1 mL) was applied to residue. The precipitate was washed with water to give the title compound (0.11 g, 95%). 684 321426 201029996 丽R(300 MHz, CDCls) (5 ppm0.85-2.18(m,12H), 2.37 (s, 3H), 2.54 (t, J=5.6 Hz, 2H), 3.41-3.75 (m , (2, H) =8. 5 Hz, 2H). Example A162 3-{[(4-·([cyclohexyl(4-cyclo-3-indolyl-1-benzoxananl-2-yl)methyl]amine) (phenyl)carbonyl](methyl)amino}propionic acid

The cyclohexyl (4-fluoro-3-indolyl-1-benzoxan-2-yl) decyl alcohol (520 mg) synthesized in Example A161 (2) was dissolved in tetrahydrofuran (10 mL). Thionyl chloride (0.27 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium hydrogen sulfate (10 mL) was carefully added to the mixture. The mixture was stirred for 10 minutes and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in hydrazine, hydrazine-dimercaptoacetamide (10 mL), sodium iodide (0.45 g), sodium carbonate (0.30 g) and 3-{3) synthesized in Example 2 (2) [(4-Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (0.50 g) was added to the solution and the mixture was stirred at 80 ° C for 12 hr. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain 3-{[4-4-[[ Hexyl (4-fluoro-3-methyl-1-benzofuran-2-yl) 685 321426 201029996 methyl]amino}phenyl)carbonyl](methyl)amino}ethyl propionate (〇. 15 g, 15%). The obtained oil was dissolved in ethanol (3 mL), and 1N aqueous sodium hydroxide (1········ Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1. 〇 mL) was added to residue. The title compound (0. 14 g, 95%) was obtained. H NMR (300 MHz, CDCh) δ ppm 0. 88-2. 16 (m, 12H), 2.38 (s, 3H), 2.65 (t, J=6.4 Hz, 2H), 3.03 (s, 3H), 3.69 ® J=6.4 Hz, 2H), 4.35 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.7Hz, 2H), 6.75-6.91 (m, 1H), 7.03-7.18 (m, 2H ), 7.23 (d, J = 8.7 Hz, 2H). Example A163 3-{[(4-{[cyclohexyl(5,7-difluoro-3_methylbenzopyran-2-yl)) Alkyl}propanoid

(1) Cyclohexyl (5,7-difluoro-3-methyl-1-benzoindole-2-yl)methyl mesh was decomposed (6.7 g) at room temperature and synthesized in Example A51 (l) 2-bromo-1-cyclohexylethyl ketone (4. 〇g) was added to N,N-dimethylformamidine (2.8 g) The amine solution (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, 321 426 686. The resulting residue was redissolved in N,N-dimethyldecylamine (5〇'), 1,8-diazabicyclo [5. 4. oxime] eleven-7-ene (2.6 mL) Add to the solution and stir the mixture at 11 ° rc. After cooling to room temperature, the reaction mixture is quenched with (7) hydrochloric acid and the mixture is extracted with diethyl ether. The extract is concentrated under reduced pressure and recrystallized with diisopropyl ether-hexane. The title compound (3.1 g, 7 G%) was obtained as a colorless solid. H NMR (300 MHz, CDCh) &lt;5 ppm 1. 09-2. 09 (m, 10H), 2.56 ® ( s, 3H), 3. 17-3.47 (m, 1H), 6.93-7. 16 (m, 2H). (2) Cyclohexyl (5, 7-difluoro-3-methyl-1-benzoate bite Cyclo-2-yl)methanol The cyclohexyl (5,7-difluoro-3-indolyl-indolefuran-2-yl)anthone (3.1 g) synthesized in the above (1) was dissolved in tetrahydrofuran. (5 〇 mL) and decyl alcohol (5 mL), and sodium borohydride (9 〇%, 〇93 g) was added to the solution under ice cooling. The ice was removed and the reaction mixture was dropped at room temperature. After an hour, then cool again with ice' and carefully add water (5 mL) and 1N hydrochloric acid (10 mL) to the mixture and use acetic acid The mixture was extracted with aq. EtOAc (EtOAc m. Title target compound (3.1 g, quantitative). H NMR (300 MHz, CDCh) 5 ppm 0. 83-2. 00 (m, 12H), 2. 2 〇 (s, 3H), 4.52 ( Dd, J=8.5, 6.8 Hz, 1H), 6.79-6.93 (m, 2H). (3) 3-{[ (4-{[cyclohexyl (5, 7-difluoro-3-methyl-1-) Benzofuran-2~yl)methyl]amino}phenyl)phenyl]amine}propionic acid 687 321426 201029996 The cyclohexyl group (5, 7-difluoro-3-methyl) synthesized in the above (2) Methyl hydrazide (0. 56 g) was dissolved in tetrahydrocarbamate (10 mL), and sulfinium chloride (0.26 mL) was added to the solution at room temperature. The reaction mixture was stirred at rt for 30 min then EtOAc (EtOAc)EtOAc. Drying with magnesium sulfate and concentration under reduced pressure. Dissolving residue in N,N-dimethyl ethane (10 mL), sodium monobromide (0.45 g), sodium carbonate (0.30 g) and the 3-{[(4-nonylaminophenyl)alkyl]amino group synthesized in Example 1 (2) } Acetate (0. 45 g) was added to the solution and the mixture was stirred at 80 ° C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified to silica gel column chromatography (ethyl acetate:hexane = 1:1, vol.) to afford 3-{[(4-{[cyclohexyl] (4-Fluoro-3-indolyl-1-benzofuran-2-yl)indolyl]amino phenyl)carbonyl](fluorenyl)amino}ethyl propionate (〇. 17 g, 17« The obtained oil was dissolved in ethanol (3 mL), EtOAc (1 mL) (1 mL) was then added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 hour. Ethanol was evaporated under reduced pressure and 1N Hydrochloric acid (1·1 mL) was added to the residue. The title compound was obtained (0.11 g, 95%) as a colorless solid. NMR (300 MHz, CDCh) (5 ppm 〇. 87-2. 14 (m, 12H), 2.21 (s, 3H), 2. 61 (t, J=5.7 Hz, 2H), 3.63 (q, J=5.7 Hz, 2H), 4.39 (d, J= 8.3Hz, 1H), 6.45-6.64 (m, 3H), 6.67- 6.81 (m, 1H), 6.87 (dd, J=8. 3,2.3 Hz, 1H), 7. 53 (d, J=8. 7 Hz, 2H). 321426 688 201029996 Example A164

3-{[(4-{[cyclohexyl(5,7-difluoro-3-indolyl-i-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amine Base} Propionic acid The cyclohexyl (5,7-difluoro-3-methylindole-benzofuran-2-yl)methanol (〇.56 g) synthesized in Example A163(2) was dissolved in tetrahydrofuran (10). (mL) and thiophosphorus chloride (〇. 26 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and then brine. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate Dissolve the residue in N,N-dimercaptoacetamide (10 mL). Sodium iodide (0.45 g), sodium carbonate (0.30 g) and 3-U synthesized in Example 2 (2) (4-Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (〇·50 g) © was added to the solution and the mixture was stirred at 80 ° C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1, volume ratio) to obtain 3-{[(4-·([ Cyclohexyl (4-fluoromethyl-benzofuran-2-yl)methyl]amino fluorenylphenyl)carbonyl](methyl)amino phthalic acid ethyl ester (0.17 g, 17 W. The oil was dissolved in ethanol (3 niL), and aqueous sodium hydroxide (1.0 mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N 321426 689 201029996 Hydrochloric acid (1.0 mL) was added to the residue. The residue was washed with water to give the title compound ( s. 15 g, 93%) as a colorless solid. ???H NMR (300 MHz, CDCh) δ ppm 0. 88-2. 16 (m, 12H), 2.21 (s, 3H), 2.67 (t, J=6.4 Hz, 2H), 3.04 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 4.38 (d, J=8. 1 Hz, 1H), 6.56 (d, J=8. 7 Hz, 2H), 6.75-6.88 (m, 2H), 7.23 (d, J=8. 7 Hz, 2H). Example A165 ❹3-I (U-[5-(phenylhydroxy)-3-indolyl-i-benzofuran-2-yl]ethyl}amino)phenyl]carbonyl}amino) Propionic acid

321426 690 201029996 target compound (2·5 g, 34%). ]H NMR (300 MHz, CDCh) δ ppm 2.56 (s, 3H), 2.60 (s, 3H), 5.12 (s, 2H), 7.11 (d, J=2.3 Hz, 1H), 7.17 (dd, J= 8.9, 2.3 Hz, 1H), 7.30-7.55 (m, 6H). (2) l-[5-(N-decyloxy)-3-indolyl-i-benzopyridin-2-yl]ethanol 1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]ethanone (〇. 53 g) synthesized in the above (1) was dissolved in tetrahydrofuran (1 〇). (mL) and decyl alcohol (1 mL)' and sodium borohydride (9%, 0.16 g) was added to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr then cooled with ice and water (1 rnL) and 1N hydrochloric acid (5 mL) was carefully added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc (EtOAc m. NMR (300 MHz, CDCh) &lt;5 ppm 1.62 (d, J=6. 6 Hz, 3H), 1.91 (br. s., 1H), 2.21 (s, 3H), 4.95-5.21 (m, 3H) , 0 6.87-7.07 (m, 2H), 7.28-7.58 (m, 6H). (3) 3-({ [4-({ l-[5-(phenylhydroxy)-3-methyl-1) -Benzo-d-d-drinking _2-yl]ethyl}amino)phenyl]carbonyl}amino)propionic acid 1-[5-(Benzyloxy)-3-indole synthesized in the above (2) Base-1-benzofuran-2-yl]ethanol (0.27 g) was dissolved in tetrahydrofuran (5 mL) and sulphur sulphur chloride (0.13 mL) was added to the solution at room temperature. The reaction mixture was spoiled at room temperature for 30 minutes 'after cooling with ice' and a saturated aqueous solution of sodium bicarbonate (1 mL) was carefully added to the mixture. The reaction mixture was scrambled for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over EtOAc EtOAc EtOAc. The residue was dissolved in N,N-dimethylacetamide (〗 〖mL), sodium iodide (0.21 g), sodium carbonate (〇.Hg) and the synthesis of Example 1 (2) Ethyl [(4-aminophenyl)carbonyl]aminopropionic acid ethyl ester (0.23 g) was added to the solution and the mixture was stirred at 8 ° C for 12 hr. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate, hexane = 1:1) to afford 3-({[4-({1- [5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]ethyl}amino)phenyl]carbonylnonylamino)propionic acid ethyl ester (〇. 15 g, ❹31 %). The obtained oil was dissolved in ethanol (3 mL), EtOAc (EtOAc) Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1. 〇 mL) was added to residue. The title compound (0. 13 g, 88%) was obtained. !H NMR (300 MHz, CDCh) δ ppm 1.62 (d, J=7. 0 Hz, 3H), 2.22 (s, 3H), 2.69 (d, J=5. 7 Hz, 2H), 3.57-3.76 ( m, q 2H), 4.65-4.88 (m, 1H), 5.08 (s, 2H), 6.59-6.75 (m, 3H), 6.82-7.04 (m, 2H), 7.29-7.62 (m, 8H). Example A166 3-[{[4-({l-[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl]ethyl}amino)phenyl]carbonyl} Mercapto)

692 321426 201029996 1-[5-(Benzyloxy)-3-methyl-1-benzo-heptan-2-yl]ethanol (0.27 g) synthesized in Example A165 (2) was dissolved in tetrahydrofuran ( 5 mL) and add sulfoxide (〇·13 mL) to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes </ RTI> then cooled with ice, and a saturated aqueous sodium hydrogen carbonate (5 mL) was carefully added to the mixture. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in N,N-dimercaptoacetamide (1 mL), sodium iodide (0.21 g), sodium carbonate (〇. 14 g) and the compound of Example 2 (2). ❹3-丨[(4-Aminophenyl)carbonyl](methyl)aminopropionic acid ethyl ester (〇.24 g) was added to the solution and the mixture was stirred at 80 ° C for 12 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1 : hexane, volume ratio) to obtain 3 丨[(4_{[cyclohexyl) 4-Fluoro-3-indolyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}ethyl propionate (〇. 1〇g, 20% ). The resulting oil was dissolved in EtOAc (3 mL). EtOAc (EtOAc m. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1.0 mL) was added to residue. The precipitate was washed with water to give the title compound ( 〇. 〇 9 g, 90%) as a colorless solid. JH NMR (300 MHz, CDCh) δ ppm 1.63 (d, J=6. 8 Hz, 3H), 2.21 (s, 3H), 2.69 (t, J=6. 5 Hz, 2H), 3.05 (s, 3H) ), 3. 71 (t, J = 6. 5 Hz, 2H), 4.79 (q, &gt; 6.9 Hz, 1H), 5.09 (s, 2H), 6.60 (d, J = 8.3 Hz, 2H), 6.84 -7. 02 (m, 2H), 7.27-7.51 (m, 8H). 693 321426 201029996 Example A167 3-[({4-[(cyclohexyl){5-[(2-fluoroacridin-4-yl)曱oxy]-3-methyl-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid

(1) 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl) 0 fluorenyl]amino}phenyl)carbonyl]amino}propyl Ethyl acetate. 3-[{[4-({[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]) (cyclohexyl) synthesized in Example A158(l) Ethyl)amino)phenyl]carbonyl}amino}propionic acid ethyl ester (5·6 g) was dissolved in ethanol (1 mL) and platinum oxide (0.50 g) was added to the solution. The reaction mixture was stirred overnight at room temperature under hydrogen (1 atm). The reaction mixture was filtered and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure. EtOAc EtOAc (EtOAc:EtOAc: ). 'H NMR (300 MHz, CDCls) &lt;5 ppm 0.94-1. 94 (m, 14H), 2.16 (s, 3H), 2.59 (t, J = 5.8 Hz, 2H), 3.66 (q, j = 5.8 Hz, 2H), 4.03-4.14 (m, 2H), 4.26-4.56 (m, 2H), 5.57 (br. s., 1H), 6.56 (d, J=8. 7 Hz, 2H), 6.61-6.68 -6.71 (m, 1H), 6.73 (dd, J=8. 7, 2. 3 Hz, 1H), 6.83 (d, J=2. 3 Hz, 1H), 7.19 (d, J=8.7Hz, 1H ), 7.55 (d, J=8. 7 Hz, 2H). (2) 3-[({4-[(cyclohexyl){5-[(2-fluoropyridine-4-yl)methoxy]]_3 曱321426 694 201029996 -1--1-benzofuran-2-yl}methyl)amino]phenyl phenylcarbonyl)amino]propionic acid ethyl ester will be synthesized in the above (1) 3-{[(4-{[ Hexyl (5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propionic acid ethyl vinegar (0-36 g) is dissolved in tetrahydroceptine South (5 mL) and 2 -Fluoro-4-pyridine pyridine methanol (114 mg), tributylphosphine (0.35 mL) and azadicarbonyl)dipiperidine (0.33 g) were added to the solution under ice cooling. . The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hr. then hexane (5 mL) was applied to the mixture and the precipitate was filtered through EtOAc. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj H NMR (300 MHz, CDCla) δ ppm 0. 90-2. 00 (m, 14H), 2.22 (s, 3H), 2.58 (t, J=5.8 Hz, 2H), 3.66 (q, J=5.8 Hz, 2H), 4.15 (q, J=7. 0 Hz, 2H), 4.30-4.54 (m, 2H), 5.13 ❹(s' 2H)' 6. 57-6. 75 (m,3H), 6 · 83-6. 96 (m, 2H), 7. 05 (s, 1H), 7.18-7.32 (m, 2H), 7.55 (d, J=8.9 Hz, 2H), 8. 22 (d, J= 5. 1 Hz, 1H). (3) 3-[({4-[(cyclohexyl){5-[(2-fluoroindole _4_yl)methoxy]_3_methyl-1-benzene And furan-2-yl}hydrazino)amino]phenyl}carbonyl)amino]propionic acid 3-(({4-[(cyclohexyl){5_[(2_fluoro)) synthesized in the above (2) Pyridin-4-yl)nonyloxy]-indolyl-1-benzofuran-2-ylindenyl)amino]phenyl}carbonyl)amino]propionic acid ethyl ester (〇. 24 g) Dissolved in ethanol (3 mL), 1 N hydrogen emulsified aqueous solution (1. 〇mL) was added to the solution and the mixture was stirred at room temperature for 321 426 695. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1 mL) was applied to residue. The precipitate was washed with water to give the title compound (0. 17 g, 75%). Not H NMR (300 MHz, CDCh) δ ppm 0. 83-2. 13 (m, 12H), 2 20 (s, 3H), 2.52-2.77 (m, 2H), 3.52-3.77 (m, 2«^ 4^38 (d, J=8.0 Hz, 1H), 5.14 (s, 2H), 6.38-6.93 (m, 5H), 7. 〇4 (s, 1H), 7.17-7.25 (m, 2H), 7 · 53 (d, J=8.7 Hz, 2H), 8.21 (d, J=5.3 Hz, 1H). ' ® Example A168

(1) 3-[({4-[(cyclohexyl){5-[(2-fluoro 0-buty-4-yl)methoxy]-3-fluorenyl)benzofuran-2-yl}fluorenyl Amino]phenyl}carbonyl)(fluorenyl)amino]propionic acid B is a 3-{[(4-{[cyclohexyl(5-hydroxy-3-indolyl)-) synthesized according to Example A155C1) Ethyl benzofuran-2-yl)methyl]amino}phenyl) benzyl](methyl)amino}ethyl propionate (0.35 g) dissolved in tetrahydrofuran (5 mL) and cooled with ice 2-Fluoro-4-pyridinol (108 mg), tributylphosphine (〇·32 mL) and 1,1 _(azepine) were added. Add (0. 32 g) to the solution. The ice bath was removed, and the reaction mixture was stirred at room temperature for 12 hours, after which hexane (5 mL) was added to the mixture of 3-[({4-[(cyclohexyl){5-[(2-fluoro") Methoxy]_3-methyl-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propionic acid 321426 696 201029996, and the precipitate is removed by diatomaceous earth . Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified mjjjjjlililililililililililililililili H NMR (300 MHz, CDCh) J ppm 〇. 94-1. 99 (m, 14H) 2 21 (s, 3H), 2.61 (br. s. , 2H), 3.01 (s, 3H), 3.70 (t , J=7. 1 Hz, 2H), 4.12 (q, J=7.0Hz, 2H), 4.24-4.49 (m, 2H), 5.14(s, 2H), 6.56 (d, J=8. 5 Hz, 2H), 6.83-6.95 (m, 2H), 7. 06 (s, 1H), 7.21-7.28 (m, 4H), 8.22 (d, J=5. 1 Hz, 1H). (2) 3-[ ({4-[(cyclohexyl{5-[(2-fluoroB-indol-4-yl)methoxy]_3_indolyl-1-benzofuran-2-yl}methyl)amino]benzene 3-[carbonyl]amino]propionic acid 3_[({4-[(cyclohexyl){5_[(2-fluoro 0-pyridin-4-yl) decyloxy)-3-) synthesized in the above (1) Mercapto-l-benzofuran-2-yl}methyl)amino]benyl)(methyl)amino]propionic acid ethyl ester (〇. 27 g) is dissolved in ethanol (3 ❹ mL), 1N aqueous sodium hydroxide solution (1. 〇mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1 - 1 mL) was applied to residue. The precipitate was washed with water to give the title compound (0.21 g, 82%). H NMR (300 MHz, CDCh) δ ppm 0. 86-2. 14 (m, 12H), 2.21 (s, 3H), 2.67 (t, J=6.4 Hz, 2H), 3.04 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 4.36 (d, J=8. 0 Hz, 1H), 5.14 (s, 2H), 6.55 (d, J=8.7 Hz, 2H), 6.79-6.96 (m, 2H), 7.05 (s, 1H), 7.20-7.35 (m, 4H), 8.21 (d, J=5.3 Hz, 1H). 697 321426 201029996 Example A169 3-{[(4-{[{5-[ (6-azetidin-3-yl)methoxy]-3-mercapto-1-benzofluoromethyl-2-yl}(cyclohexyl)methyl]amino}phenyl) benzyl] Amino}propionic acid

(1) 3-{[(4-{[{5-[(6-Chloroacridin-3-yl)methoxy)-3-indol-1-ylbenzofuran-2-yl} (cyclo) Ethyl)indenyl]amino}phenyl)carbonyl]amino}propionic acid ethyl ester 3-{[(4-{[cyclohexyl(5-hydroxy-3-fluorenyl)) synthesized in Example A167(l) 1-Benzene bite-flavor-2-yl)methyl]amino}phenyl)alkyl]amino} Propionic acid B (0.35 g) was dissolved in tetrahydrofuran (5 mL) and cooled in ice 6-Chloro-3-pyridinol (〇. 13 g), tributylphosphine (〇. 33 mL) and 1, Γ-(azepine) group (〇·33 g) were added to Solution. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. hexane (5 mL) was then added to the mixture and the precipitate was filtered through Celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified titled mjjjjjjjj 65%). H NMR (300 MHz, CDCI3) 5 ppm 0. 95-2. 13 (m, 14H), 2 22 (s, 2H), 2.58 (t, J = 5. 9 Hz, 2H), 3.65 (q, J =5.9 Hz, 2H), 4.25 (q, J=7. 0 Hz, 2H), 4.29-4.54 (m, 1H), 4.71 (d, J=5.3 Hz, 1H), 5.07 (s, 2H), 6.48 -6.68 (m, 3H), 321426 698 201029996 6.77-7.03 (m, 2H), 7.25 (s, 1H), 7.24-7.40 (m, 2H), 7.54 (d, J=8. 7 Hz, 2H), 7.68-7.76 (m, 1H), 8.34-8.47 (ra, 1H). (2) 3-{[(4-{[{5-[(6-chloropyridin-3-yl)methoxy]-3 _Methyl-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propionic acid 3-{[(4_{Π5_) synthesized in the above (1) [(6-Chloropyridine-3-yl)methoxy]-3-indolyl-1-benzofuran-2-ylindole (cyclohexyl)methyl]amino} phenyl)carbonyl]amino} Ethyl propionate (0·31 g) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide (1 mL) was added to the solution and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (.. 〇 mL) was added to residue. The precipitate was washed with water to give the title compound (0. 22 g, 74%). !H NMR (300 MHz, CDCh) δ ppm 0. 88-2. 13 (m, 12H), 2.21 (s, 3H), 2.62 (t, J=5. 7 Hz, 2H), 3.45-3.77 (m , 2H), ❹ 4_ 37 (d, J=8. 0 Hz, 1H), 5_ 07 (s, 2H), 6. 43-6. 64 (m, 3H), 6.75-6.99 (m, 2H), 7.23-7.26 (m, 1H), 7.35 (d, J=8.0Hz, 1H), 7. 52(d, J=8. 7 Hz, 2H), 7.76 (dd, J=8. 0, 1.9 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H). Example A170 3-{[(4-{[{5-[(6-chloro)pyridin-3-yl)methoxy]-3- Methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid 321426 699 201029996 Ο

OH (1) 3 {[(4 {[{5-[(6-chlorou)α--3-yl)methoxy]-3-methyl_ι_benzofuran-2-yl} (cyclohexyl) Ethylmethyl]amino}phenyl)carbonyl](methyl)amino}ethyl propionate 3-{[(4_{[cyclohexyl(5-hydroxyindole-3)) synthesized in Example A155(l) - mercapto-1-benzofuran-2-yl)methyl]amino phenyl)carbonyl](methyl)aminoethyl phthalate (0·39 g) was dissolved in tetrahydrofuran (5 mL). Add 6-chloro-3-pyridinemethanol (14 〇 mg), tributylphosphine (3)·35 rainbow) and M'-(azadicarbonyl)dipiperidine (〇.36 g) to the solution under ice cooling. . The ice bath was removed and the reaction mixture was stirred at room temperature for 12 hr then hexane (5 mL) was added to the mixture and the precipitate was filtered through Celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjjjjjj %). H NMR (300 MHz, CDCh) δ ppm 〇. 95-2. 13 (ra, 14H), 2 22 (s, 3H), 2.61 (t, J=5.9 Hz, 2H), 3.01 (s, 3H), 3.7〇(t, J=5.9Hz, 2H), 4.25 (q, J=7. 0 Hz, 2H), 4.29-4.71 (m, 2H), 5.07 (s, 2H), 6.55 (d, J=8 . 7 Hz, 2H), 6.77- 7.03 (m, 2H), 7.10-7.40 (m, 4H), 7.68-7.76 (m, 1H), 8. 34-8. 47 (m, 1H). (2) 3-{[(4-{[{5-[(6-apyridin-3-yl)decyloxy]_3_indolyl_1_ 321426 700 201029996 benzofuran-2-yl}(cyclohexyl)fluorenyl Amino}phenyl)monoyl](methyl)amino}propionic acid 3-{[(4-{[{5-[(6-chloro]) Methoxy]-3-methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)alkyl](methyl)amino}propionic acid 5小时。 The mixture was added to a solution of the mixture was stirred at room temperature for 0.5 hours. Ethanol was evaporated under reduced pressure and 1 n hydrochloric acid (1.0 mL) was added to residue. The precipitate was washed with water to give the title compound (0. 26 g, 85%). !H NMR (300 MHz, CDCh) δ ppm 0. 86-2. 15 (m, 12H), 2 21 (s, 3H), 2.52-2.77 (m, 2H), 3.04 (s, 3H), 3.69 ( t, J-6.4 Hz, 2H), 4. 36 (d, J=8. 0 Hz, 1H), 5. 08 (s, 2H) 6.56 (d, J=8. 7 Hz, 2H), 6.71- 7.00 (m, 2H), 7.14-7.26 (m, 3H), 7.36 (d, J=8. 0 Hz, 1H), 7.77 (dd, J=8. 0, l 9 Hz, 1H), 8.44 (d , J=1.9 Hz, 1H).

Example A171 3-({[4-({l-[ 5-(phenylhydroxy)-3-methyl-1-benzo[rho]-[rho] __2-yl]] _2-mercaptopropyl}amine Phenyl]amino]amino)propionic acid

(1) 3-({[4-({1-[5_(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)benzene Ethyl]carbonyl]amino)propionic acid ethyl ester 321426 701 201029996 1-[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl as synthesized in Example A85(2) ]-2-Methylpropan-1-ol (1·〇g) was dissolved in tetrahydrofuran (15 mL) and sulfinium chloride (〇. 43 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then cooled with ice, and a saturated aqueous solution of sodium hydrogencarbonate (15 mL) was carefully added to the mixture. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in N,N-dimercaptoacetamide (15 mL), sodium iodide (〇. 74 g), sodium carbonate (〇. 50 g) and the compound of Example 1 (2) 3-{[(4-Aminophenyl)carbonyl]amino}propionic acid ethyl ester (〇. 76 g) was added to the solution and the mixture was stirred at 8 (TC for 12 hours. After cooling, water was added to the reaction. The mixture was extracted with EtOAc. EtOAc was evaporated. Compound (〇 43 g, 25%) H NMR (300 MHz, CDCh) δ ppm 0.91 (d, J = 6.4 Hz, 3H), O 1 · 12 (d, J = 7. 0 Hz, 3H ), 1. 25 (t, J=7. 0 Hz, 3H), 2. 16- 2.34 (m, 4H), 2.58 (t, J=6. 0 Hz, 2H), 3.66 (q, J=6 . 0

Hz, 2H), 4.15 (q, J=7. 0 Hz, 2H), 4.25-4.54 (in, 2H), 5.08 (s, 2H), 6.48-6.66 (m, 3H), 6.80-7.04 (m, 2H), 7.20-7.48 (m, 6H), 7. 55 (d, J=9. Hz, 2H). (2) 3-({[4-({l-[5-(Benzyloxy)) )-3-methyl-l-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}amino)propionic acid 3-(S) synthesized as described above {[4-({l-[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl]-2-mercaptopropyl}amino)phenyl]carbonyl}amine 702 321426 201029996 base ethyl propionate (0.43 g) was dissolved in ethanol (1 mL), and a solution of sodium hydroxide (2·G mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (2 mL) was applied to residue. The title compound (0.36 g, 89%) was obtained. H NMR (300 MHz, CDCh) δ ppm 0. 93 (d, J = 6. 4 Hz, 3H) 1.13 (d, J = 6.4 Hz, 3H), 2.10-2.40 (m, 4H), 2.67 (br. s. , 2H), 3.66 (br. s., 2H), 4.35 (br. s., 1H), 5.08 (s. , 2H), 6.44-6.69 (m, 3H), 6.79-7.68 (m, 10H Example A172 3_[{[5-({l-[5-(Benzyloxy)-3-methyl-1-benzocypano-2-yl]-2-methylpropyl} Amino)pyridin-2-yl]yl}}(methyl)amino]propionic acid

❹ (1) 5-({1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridine-2- The carboxylic acid oxime ester is 1-[5-(benzyloxy)-3-indolyl-1-benzotrim-2-yl]-2-methylpropan-I synthesized in Example A58(2) - Alcohol (1. 〇S) was dissolved in tetrachlorofuran (15 mL) and sulfinium chloride (0.43 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then cooled with ice and aq. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, EtOAc EtOAc. Dissolve the residue in N,N-dimethylacetamide (15 mL), sodium iodide (〇. 74 g), sodium carbonate (〇. 5〇5-aminopyridine-2-carboxylate) 0.50 g) was added to the solution and the mixture was stirred at 8 ° C for 12 μm, and after cooling, water was added to the reaction mixture and the mixture was extracted with acetic acid. The extract was concentrated under reduced pressure and the column was The title compound (0.22 g, 15°/.). Ppm 0.93 (d, J=6. 8 Hz, 3H), 1.15 (d, J-6.8 Hz, 3H), 2. 16-2.40 (m, 4H), 3 91 (s 3H), 4. 35 (t , J=8. 1 Hz, 1H), 4. 65 (d, J=8. 7 Hz, 1H), 5.08 (s, 2H), 6.72-7.03 (m, 3H), 7.18-7.53 (m, 6H ), 7.89 (d, J=8.3 Hz, 1H), 8.10 (d, J=2. 6 Hz, 1H). (2) 3-[{[5-({l-[5-(Benzyloxy) )-3-methyl-;[_ benzofuran-2-yl]-2-methylpropyl}amino)pyridin-2-yl]carbonylindole (methyl)amino]propionic acid ethyl hydrazine 5-({1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridyl synthesized by the above (1) Ethyl 2-carboxylate (0 22 g) was dissolved in ethanol (5 mL) and aqueous solution of sodium hydroxide (1 mL) was added to the solution at room temperature. The reaction mixture was stirred at 70 ° C for 30 minutes to cool. Concentrate to room temperature and under reduced pressure. Residue was dissolved in N,N-dimethylformamide (1 mL) and 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (0.17 g), l-p-benzobenzotriazine monohydrate (〇. and ethyl 3-(methylamino)propionate (0.1 g) were added to the solution. The mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and 321 426 704 201029996 was purified by gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) The title compound (〇·15 g, 56%) was obtained as a yellow oil. NMR (300 MHz, CDCh) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> (d, J = 6.4 Hz, 3H), 1.14 (d, J=6.4Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.16-2.36 (m, 4H), 2.60-2.80 (m, 2H), 3.80 (br. s., 2H), 4.12 (q, J=7. 2 Hz, 2H), 4.22-4.48 (m, 2H), 5.09 (s, 2H), 6.79-7.05 (m, 3H), 7.24-7.51 (m, 7H), 7.93 ( Br. s.,1H). ❹(3) 3-[{[5-({l-[5-(Benzyloxy)-3-indolyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridine-2 -yl]carbonyl}(methyl)amino]propionic acid 3-[{[5-({1-[5-(benzyloxy))-3-methyl-1-) synthesized in the above (2) Benzofuran-2-yl]-2-methylpropyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propionic acid ethyl ester (〇. 15 g) dissolved in ethanol ◦ mL) 1N aqueous sodium hydroxide solution (1. 〇mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure and in hydrochloric acid (1 〇 mL) was added to the residue. Washing the precipitate with water to obtain a title stick as a colorless solid

砉· A 9 $ ^ ^ Λ V 1 匕令, initial UJ. 14 g, 篁; ]H NMR (300 MHz, CDCh) 5 ρριη 0.93 (d, J=6. 8 Hz 3H) 1.15 (d, J=6. 8 Hz, 3H), 2.24 (s, 3H), 2.27-2.39 (m 1H ), 2.82 (br. s., 2H), 3.10 (s, 3H), 3.77 (t, j=6^

Hz, 2H), 4.31 (d, J = 7.9 Hz, 1H), 5.09 (s, 2H), ' 6 85- 7. 03 (m, 3H), 7. 29-7. 61 (m, 7H), 8· 04 (br. s 1H) Example A173 μ-l-benzofuran 3-[{ [4-({l-[5-(2-methoxyethoxy)-3- 321426 705 201029996-2-yl]-2-mercaptopropyl}amino)phenyl]-based hydrazine (methyl)amino]propionic acid

^-0 (1) l-[5-(2-decyloxyethoxy)-3-indolyl-1-benzofuran-2-yl] _2-methylpropan-1-yl will be at room temperature Potassium carbonate (1.1 g) and 1-0 bromo-3-indolylbutan-2-one (0.56 g) synthesized in Example A75 (1) were added to 1-[2- synthesized in Example A79C1). A solution of hydroxy-5-(2-decyloxyethoxy)phenyl]ethanone (0.55 g) in N,N-didecylamine (10 mL). The mixture was filtered through a pad of Celite, and water (200 mL) was added and the mixture was extracted with a singe (10 mL x 2). The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in N,N-dimethylformamide (1 mL) and 1,8-diazabicyclo[5.4.0]indole-7-ene (0.41 mL) at room temperature ) added to the solution. The reaction mixture was stirred at 100 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (10 mL) was added and the mixture was extracted (1 〇 mL x 2 ). The extract was washed with water, aq. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc NMR (300 MHz, CDCh) δ ppm 1.23 (d, J=6. 8 Hz, 6H), 2. 57 (s, 3H), 3.48 (s, 3H), 3.56 (quin, J=6. 8 Hz, 1H), 3.74-3.85 (m, 2H), 4.10-4.24 (m, 2H), 7.05 (d J=2. 6 321426 706 201029996

Hz, 1H), 7. 14(dd, J=9. 0, 2. 6 Hz, 1H), 7.39 (d, J=9. 0 Hz, 1H). (2) l-[5-(2-曱oxyethoxy)-3~fluorenyl-i-benzofuran-2-yl]-2-methylpropan-1-ol 1-(5-(2-) synthesized in the above (1) Methoxyethoxy)-3-mercapto-1-benzoyridin-2-yl]-2-mercaptopropan-1-one (〇71 g) was dissolved in tetrahydro 11-propanol (5 mL) And decyl alcohol (0.5 mL), and sodium borohydride (90%, 0. 21 g) was added to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled again with ice, and water (1 mL) and 1N hydrochloric acid (5 mL) was carefully added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. NMR NMR (300 MHz, CDCh) δ ppm 0.82 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.96 (br. s. , 1H), 2.12-2.33 ( m, 4H), 3.47 (s, 3H), 3.70-3.85 (m, 2H), 4.10-4.23 0 (m, 2H), 4.46 (d, J=8.3 Hz, 1H), 6.79-7.01 (m, 2H ), 7. 30 (d, J=8. 7 Hz, 1H). (3) 3-[{[4-({1-(5-(2-methoxyethoxy))-3-yl) 1--1-benzo-f-amyl-2-yl]-2-mercaptopropyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid 1 - [ 5-(2-Methoxyethoxy)-3-methyl-I-benzocypan-2-yl]-2-methylpropan-1-ol (0.77 g) was dissolved in tetrahydrofuran ( 10 mL) and thiophosphonium chloride (0.34 mL) were added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous sodium hydrogen carbonate (5 mL) was carefully added to the mixture. The reaction mixture was stirred at 707 321426, 201029996, 10 hrs, and extracted with ethyl acetate. The extract was washed with saturated brine, dried with sulphuric acid and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (EtOAc)化 (0. 56 g), sodium carbonate (〇·38 g) and the aminophenyl group synthesized in Example 2 (2) (Methyl)amino}ethyl propionate (0.63 g) was added to the solution and the mixture was mixed for 12 hours at 8 ° C. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain 3-[{[4-({ 1-[5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]]}} Ethyl]ethyl propionate (〇. 1〇g, the obtained oil was dissolved in ethanol (3 mL), and 1N aqueous sodium hydroxide (1.0 mL) was added to the solution at room temperature and The mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1 · 〇mL) was added to the residue. The title compound was obtained as a colorless solid. , 52%). !H NMR (300 MHz, CDCh) δ ppm 0.91 (d, J=6. 4 Hz, 3H), ❹ 1.12 (d, J=6.4 Hz, 3H), 2.21 (s, 3H), 2.23-2.36 (m, 1H), 2.67 (t, J=6.4 Hz, 2H), 3.04 (s, 3H), 3.46 (s, 3H), 3.69 (t, J=6.4 Hz, 2H), 3.73-3.84 (m, 2H), 4 .15 (dd, J=5.7, 3. 8 Hz, 2H), 4.32 (d, J-7. 5 Hz, 1H), 6.57 (d, J=8.7 Hz, 2H), 6.76-6.98 (m, 2H) ), 7.15-7.25 (m, 3H). Example A174 3-[{[4-({-cyclohexyl[5-(6-decyloxypyridine-3-yl)_3-methyl-p-benzofuran- 2-yl]hydrazino}amino)phenyl]carbonyl}(methyl)amino]propionic acid 708 321426 201029996

Uh (1) (5-Bromo-3-indolyl-1-benzofuran-2-yl)(cyclohexyl)methanone 1-[5-bromo-2-hydroxyphenyl]ethanone (13.4 g) Dissolved in N,N-didecylguanamine (300 raL). Potassium carbonate (25.8 g) and 2-bromo-1-cyclohexylethyl ketone (19. g) synthesized in Example 51A51(l) were added to the reaction mixture at room temperature and the mixture was stirred for 3 hours. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in N,N-dimercaptocarbamide (150 mL), and y,8-diazabicyclo[5.4.0]-]--7-ene (9. 3 mL) was added to the solution and the mixture was stirred at 1 Torr for 1 hour. The reaction mixture was cooled to room temperature, then added 1 mL EtOAc EtOAc EtOAc The extract was washed with water, aq. The precipitate was washed with diisopropyl ether to give the title compound (15. 4 g, 77%). H NMR (300 MHz, CDCls) δ ppm 1. 16-2. 05 (in, 1〇Η), 2.56 (s, 3H), 3.20-3.36 (ra, 1H), 7.40 (d, J=8. 9 Hz, 1H), 7.55 (dd, J=8.9, 1.5 Hz, 1H), 7.77 (d, J=1.5Hz, 1H). (2) (5-bromo-3-methylbenzofuran_2_yl (cyclohexyl)methanol (5-bromo-3-methyl-1-benzofuran_2_321426 709 201029996) (cyclohexyl)methanone (7.5 g) synthesized in the above (1) was dissolved in tetrahydrofuran (100 mL) and decyl alcohol (15 mL) were added to a solution of sodium hydride (90%, 1.9 g). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled again with ice, and water (1 mL) and 1N hydrochloric acid (50 mL) was carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc. 'H NMR (300 MHz, CDCh) δ ppm 0. 83-2. 11 (m, 11H), 2. 19 ® (s, 3H), 3.62-3.85 (m, 1H), 4.51 (br. s. , 1H), 7.27- 7. 59 (m, 3H). (3) 3-{[(4-{[(5-Bromo-3-indolyl-1-benzofuran-2-yl)(cyclohexyl) Methyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate (5-bromo-3-indolyl-1-benzofuran-2-yl) synthesized in the above (2) (Cyclohexyl)methanol (7.5 g) was dissolved in tetrahydrofuran (150 raL) and sulfinium chloride (3.1 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then cooled with ice and aq. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in dimercaptoacetamide (100 raL), sodium iodide (5.2 §), sodium carbonate (3.5 g) and 3-{[(4-amino) synthesized in Example 2 (2) Phenyl)carbonyl](methyl)amino}ethyl propionate (5.8 g) was added to the solution and the mixture was stirred at 80t: 12h. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted with %). NMR (300 MHz, CDCh) δ ppm 0.88-1. 97 (m, 14H), 2.22 (s, 3H), 2.61 (t, J=7.1 Hz, 2H), 3.01 (s, 3H), 3.70 ( t, J=7. 1 Hz, 2H), 3.99-4.17 (m, 2H), 4.23-4.47 (m, 2H), 6.55 (d, J=8. 7 Hz, 2H), 7.11-7.37 (m, 4H), 7.54 (d, J=1.7 Hz, 1H). (4) 3-[{[4-({cyclohexyl[5-(6-methoxy 0 to 0--3-yl)_3-曱) (-Phenylbenzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid (6-methoxypyridin-3-yl)boronic acid (〇. 14 g), potassium carbonate (0.13 g) and triphenylphosphine palladium (〇. 05 g) were added to the 3-{[(4-{[(5-bromo-3-) synthesized in the above (3) Alkyl-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}yl}yl)(methyl)amino}propionic acid The mercaptoacetamide solution (5 mL) was stirred and the mixture was stirred under nitrogen for 9 hours at TC. The reaction mixture was cooled to room temperature and filtered through celite, and washed with acetonitrile. The filtrate was concentrated to dryness and the organic layer was evaporated. mjjjjjjjj 3-[{[4-({cyclohexyl[5-(6-methoxypyridine-3-yl)-3-Tyl-1-benzofuran-2-yl]methyl}amino)benzene Carbonyl hydrazine (methyl) amino] propionic acid B. (G. 15 g, 58%). The obtained oil was dissolved in EtOAc (1 mL). (1) and the mixture was stirred at room temperature for 0.5 hours. Evaporate the ethanol under (iv) and add 0.0 mL of in hydrochloric acid to the residue. Wash the water with a water to obtain the title compound of the title 〇·12 g, 85%). 321426 711 201029996 iHNMRQOOMHz, CDCI3) (5 ppml.27-2. 19(m,12H), 2.29 (s, 3H), 2.69 (t, J=6.4 Hz, 2H), 3.05 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 3.99 (s, 3H), 4.41 (d, J=7. 9 Hz, 1H), 6.58 (d, J=8.7 Hz, 2H ), 6.83 (d, J=9. 0 Hz, 1H), 7.19-7.26 (m, 2H), 7. 32-7. 53 (m, 3H), 7. 81 (dd, J=8. 5, 2.4 Hz, 1H), 8. 38 (d, J = 2. 3 Hz, 1H). Example A175 3-{ [(4-{ [ 1-(4-fluoro-3-methyl-1-benzo) Ole-2-yl)-2-methylpropanyl]amino}phenyl)carbonyl](indenyl)amino}propionic acid

(1) 1 -(4_Fluoro-3-indolyl-1-benzonyridin-2-yl)-2-methylpropan-1-yl as potassium carbonate (3.5 g) and at room temperature 1-bromo-3-methylbutan-2-one (1.7 g) synthesized in Example A75 (l) was added to N'N of 1-(2-fluoro-6-hydroxyphenyl)ethanone G 0.3 g) a solution of dimethylformamide (25 mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate The obtained residue was redissolved in N,N-methylmethanoamine (15 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 m) was added. The mixture was stirred and heated at 110 ° C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with hydrochloric acid and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the title compound (1. 4 g, 77%). !H NMR (300 MHz, CDCls) 5 ppm 1.24 (d, J=6. 8 Hz, 6H), 2. 74(s, 3H), 3.50-3. 66 (m, 1H), 6. 93 (dd , J = 10.2, 7.9 Hz, 1H), 7.28-7.50 (m, 2H). (2) l-(4 gas-3-methyl-1-benzothiamethane-2-yl)-2_曱1-(4-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.4 g) synthesized from the above (1) Dissolved in tetrahydro-pyran (20 mL) and ® methanol (2 mL), and added sodium borohydride (90%, 0. 53 g) to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled again with ice, and water (2 mL) and 1N hydrochloric acid (5 mL) was carefully added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. NMR (300 MHz, CDCla) δ ppm 0.82 (d, J=6. 8 Hz, 3H), ❿ 1. 13 (d, J=6. 8 Hz, 3H), 1. 99 (d, J=5· 7 Hz, 1H), 2. 22 (dt, J=8. 3, 6. 8 Hz, 1H), 2.36 (s, 3H), 4.46 (dd, J=8. 3, 5.7 Hz, 1H), 6.77 -7.23 (m, 3H). (3) 3-{[(4-{[l-(4-Fluoro-3-indolyl-1- stupid bite t»South_2_yl)_2_ decylpropyl] Amino}phenyl)carbonyl](fluorenyl)amino}propionic acid 1-(4-Fluoro-3-indolyl-1-benzoate. Nan-2-yl) synthesized in the above (2) 2-Mercaptopropan-1-ol (1.4 g) was dissolved in tetrahydroculphon (2 〇 rainbow) and thionite-brewed chlorine (0.84 mL) was added to the solution at ambient temperature. The mixture was incubated at room temperature for 30 minutes, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate 321 426 s. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in dimercaptoacetamide (3 mL), sodium iodide (1.4 g), sodium carbonate (〇·96 g) and 3-{[(4) synthesized in Example 2(2). -Aminophenyl)carbonyl](methyl)amino}ethyl propionate (1.6) was added to the solution and the mixture was stirred at 80 ° C for 12 hours. After cooling, water was added to the reaction mixture and ethyl acetate. The mixture was extracted, and the extract was concentrated under reduced pressure. {[1-(4-Fluoro-3-indolyl-1-benzofuran-2-yl)-2-methylpropyl]amino}phenyl)carbonyl](indenyl;)amino}propionic acid Ethyl ester (0.20 g, 7%). The obtained oil was dissolved in ethanol (2 mL), and then aqueous sodium hydroxide (2. 〇mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 hour. Ethanol was evaporated under reduced pressure and 1N EtOAc (EtOAc) (EtOAc) (EtOAc) (300 MHz, CDCla) δ ppm 0.92 (d, J=6. 4 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H), 2.09-2.32 (m, 1H), 2 39 (s 3H), 2.69 (t, J=6.2 Hz, 2H), 3.05 (s, 3H), 3 71 (t &gt;6.2Hz, 2H), 4.31 (d, J=7.9 Hz, 1H), 6.58 (d, J=8. 7

Hz, 2H), 6.76-7.19 (m, 3H), 7.25 (d, J=8.7 Hz, 2H). Example A176 ' · 3 {[(4 {[J Yijiji (3-曱基-5一笨] Base [monobenzopyrano-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propionic acid 321426 714 201029996 〇〇

OH

Phenylboronic acid (0.12 g), potassium carbonate (0.4 g) and triphenylphenyl palladium (0.10 g) were added to the 3-{[(4-{[) synthesized in Example A174(3). (5-Bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl) benzyl](indenyl)amino}ethyl propionate (0.28 g) N,N-dimercaptoacetamide solution (5 mL) 'and the mixture was stirred under nitrogen at 70 ° C for 12 hours. The reaction mixture was cooled to room temperature and filtered through celite and washed with EtOAc. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to give 3-{[(4-{[cyclohexyl (3-methyl) as a pale yellow oil. -5-Phenyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](indenyl)amino}ethyl propionate (〇. 15 g, 54%). The obtained oil was dissolved in ethanol (1 mL), and 1N aqueous sodium hydrogen sulfate (1· 〇 mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1 mL) was applied to residue. The title compound (0. 09 g, 67%) was obtained as a colorless solid. !H NMR (300 MHz, CDCh) δ ppm 0. 97-2. 16 (in, 11H), 2.29 (s, 3H), 2.69 (t, J=6.2 Hz, 2H), 3.05 (s, 3H), 3.72 (t, J=6.2 Hz, 2H), 4.41 (d, j=7.9 Hz, 1H), 6.58 (d, J=8. 7 Hz, 2H), 7.23-7.66 (m, l〇H). 321426 715 201029996 Example A177 3-[{[4-({cyclohexyl[5-(2-decyloxypyridin-3-yl)-3-indolyl-1-benzofuran-2-yl]fluorenyl} Amino)phenyl]carbonyl}(methyl)amino]propionic acid

(2-Methoxypyridin-3-yl)boronic acid (〇·29 g), potassium carbonate (0.27 g) hydrazine and hydrazine triphenylphosphine palladium (0.05 g) were added to Example A174(3) Synthesis of 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](fluorenyl) Ethyl phthalic acid ethyl ester (0.53 phantom indane decyl acetamide solution (15 mL), and the mixture was stirred under nitrogen at 90 ° C for 12 hours. The reaction mixture was cooled to room temperature and passed through celite. Filtration, and washing the residue with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1, volume ratio). 3-[{[4-({-methoxypyridin-3-yl)-3-indolyl-1-benzofuran-2-yl]methylhydrazine as a yellow oil Amino) phenyl]carbonyl hydrazone (methyl)amino]propionic acid ethyl ester (〇.5〇g, 89%). The obtained oil was dissolved in ethanol (1 mL), 1N hydrogen at room temperature An aqueous solution of sodium oxide (1. 〇mL) was added to the solution and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1. The title compound (0.4?, quantitative) was obtained as a colorless solid. HNMR (3 〇〇 MHz, CDCh) (5 ppm 0. 97-2. 15 (m, 11H), 2.27 (s, 3H), 2.49-2. 65 (m, 2H), 2. 99 (s, 3H), 3, 65 (br 321426 716 201029996 S. , 2H), 3.95 (s, 3H), 4.39 (d , J=7. 9 Hz, 1H), 6.56 (d, J=8.7Hz, 2H), 6.97 (dd, J=7.2, 4. 9 Hz, 1H), 7.23 (d, J=8. 7 Hz, 2H), 7.38-7.66 (m, 4H), 8. 15 (dd, J=5. 1, 2. 1 Hz, ,1H). Example A178 3-[{[4-({cyclohexyl][ 5-(3,5-dimethylisoxazol-4-yl)-3-indolyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(indenyl)amine Base]

(3,5-Dimercaptoisoxazol-4-yl)boronic acid (0.41 g) and 2N aqueous sodium carbonate solution (1.46 mL) were added to the 3-{[(4-) synthesized in Example A174(3). [(5-Bromo-3-indolyl-1-benzofuran-2-yl)(cyclohexyl)indenyl]amino}phenyl)benzyl](methyl)amino}ethyl propionate ( 〇 54 g) of a solution of benzene (15 mL)' and the mixture was stirred under argon at room temperature for 1 Torr. Adding 2_dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.05 g) and ginseng (diphenylmethyleneacetone) to one (〇) (〇. 〇3 g) To the reaction mixture, the mixture was heated under argon and reflux overnight. The reaction mixture was cooled to room temperature and filtered through EtOAc (EtOAc)EtOAc. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain 3-[{[4-({cyclohexyl[5- ( 3,5-Dimercaptoisoxazole-4-yl)-3-indolyl-1-benzoxan-2-yl]methyl}amino) 321426 717 201029996 phenyl group} Amino]ethyl propionate (0·13 g, 23%). The obtained oily substance was dissolved in ethanol (1 mL), and 1N aqueous sodium hydroxide solution was added to the solution at room temperature and the mixture was stirred at room temperature (4) for 5 hours. Ethanol was evaporated under reduced pressure and iN^O.OmL) was added to EtOAc. The target compound (〇12 g, NMR NMR (300 MHz, CDCh) δ ppm 0. 93-2. 19 (m, hh) 2 26 (s, 3H), is obtained as a colorless solid. 2.27 (s, 3H), 2.39 (s, 3H), 2. 71 (t, J=6 2

Hz, 2H), 3.07 (s, 3H), 3.73 (t, J = 6.2 Hz, 2H), 4.41 (d, J-7. 9 Hz, 1H), 6. 58 (d, J=8. 7 Hz , 2H), 7.08 (dd J=8.3, 1.5 Hz, 1H), 7.20-7.26 (m, 3H), 7.42 (d, J=8 3 Hz, 1H). 'Example A179 3-[{[4- ({l-[5-(Benzyloxy)-3-methyl~1~benzofuran-2-yl]propyl}amino)phenyl]carbonyl}(indenyl)amino]propionic acid

(1) 1-[5-(Benzomethoxy)-3-methyl-1-benzopyran-2-yl]propyl-i-_ Potassium carbonate (13.2 g) and 1-bromo at room temperature Butan-2-one (5.0 mL) was added to the hydrazine, Ν-二 of 1-[5-(benzoxy)-2-hydroxyphenyl]ethyl ketone (7.8 g) synthesized in Example 82 (1) The decylamine solution (150 mL) was stirred at room temperature for 3 hours. The reaction mixture was cooled to room temperature and filtered through celite 321426 718. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over sulfuric acid and concentrated under reduced pressure. The resulting residue was redissolved in N,N-didecylguanamine (100 mL), and 1,diazabicyclo[5.4.0]Η 7-ene (4.9 mL) was added to the solution and Ii〇〇c heats the scramble mixture for 1 hour. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid and the mixture was extracted with EtOAc. The extract was concentrated under reduced pressure and the title compound was crystalljjjjjjjjjjj ® NMR (300 MHz, CDCh) δ ppm 1. 22 (t, J=7.2 Hz, 3H), 2.57 (s, 3H), 3.01 (q, J=7. 2 Hz, 2H), 5.12 (s , 2H), 7.04-7.52 (m, 8H). (2) l-[5-(Benzomethoxy)-3-indolyl-1-benzopyran-2-yl]propan-i-ol 1-[5-(Benzomethoxy)-3-methyl-1-benzofuran-2-yl]propan-1-one (〇·88 g) synthesized in the above (1) was dissolved in tetrahydrofuran ( 15 mL) and methylation (1 mL), and sodium borohydride (9%, 0.25 g) was added to the Q solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr then cooled with ice and water (2 mL) and 1N hydrochloric acid (5 mL) was carefully added to mixture&apos; and the mixture was extracted with ethyl acetate. The extract was washed with EtOAc (EtOAc m. !H NMR (300 MHz, CDCh) δ ppm 0.93 (t, J=7. 4 Hz, 3H), 1.92-2.03 (m, 3H), 2.21 (s, 3H), 4.69-4.87 (m, 1H), 5. 11 (s, 2H), 6.89-7.51 (m, 8H). (3) 3-[{[4-({l-[5-(Benzomethoxy)_3_indolyl-benzofuran- 2- 719 321426 201029996 ]]propyl}amino)phenyl]carbonyl fluorenyl (methyl)amino]propionic acid 1_[5-(benzyloxy)-3-indole synthesized in the above (2) Base-1-benzofuran-2-yl]propanol (0.85 g) was dissolved in tetrahydrofuran (15 mL) and sulphur sulphur (40 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then cooled with ice and a saturated aqueous solution of sodium hydrogen sulfate (2 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in dimercaptoacetamide (15 mL), sodium iodide (0.67 g), sodium carbonate (〇. 45 g) and the 3-UU-amine synthesized in Example 2 (2). Ethylphenyl)carbonyl](methyl)aminopropionic acid ethyl ester (0.75 g) was added to the solution, and the mixture was stirred at 80 ° C for 4 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified to silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to obtain 3-[{[4-({1- [5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]propyl}amino)phenyl]carbonyl Kmethyl)amino] q propionic acid ethyl ester (0. 15 g, 9%). The obtained oil was dissolved in ethanol (2 mL), and 1N aqueous sodium hydroxide (1········ Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1.0 mL) was applied to residue. The title compound (0. 10 g, 71%) was obtained. NMR NMR (300 MHz, CDCh) (5 ppm 0.94 (t, J = 7. 3 Hz, 3H), 1.87-2.08 (m, 2H), 2.23 (s, 3H), 2.66 (t, J = 6.2 Hz, 2H), 3.03 (s, 3H), 3.70 (t, J=6. 2 Hz, 2H), 4.52 (dd, J=8.3, 6. 2 Hz, 1H), 5.09 (s, 2H), 6.57 (d, J=8. 7 Hz, 720 321426 201029996 2H), 6.82-7. 02 (m, 2H), 7. 18-7.51 (m, 8H). Example A180 3-(曱基{[4- ({2-mercapto-1-[3-indolyl-5-(tetrahydro-211-pyran-4-yloxy)-1-benzofuran-2-yl]propyl}amino) Phenyl]glycosyl}amino)propionic acid

(1) 1-(5-Hydroxy-3-indolyl-1-benzofuran-2-yl)-2-methylprop-1- - a carbon-ethylenediamine complex (1.1 g at room temperature) Addition to 1-[5-(phenylhydrazino)-3-indolyl-1-benzofuran-2-yl]-2-mercaptopropan-1-one synthesized in Example A85 (1) 11.4 g) of ethanol (2 〇〇 mL) solution. The reaction mixture was stirred at room temperature under hydrogen (1 atm) for 16 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound (d. H NMR (300 MHz, CDCh) δ ppm 1.24 (d, J=6. 8 Hz, 6H), 2·55 (s, 3H), 3.48-3.63 (in, 1H), 6.95-7.40 (m, 3H) (2) 3: (methyl {[4_({2_methyl_143_methyl_5 (tetrahydro-2H_pyran-4-yloxy)_]_benzofuran_2_yl]-propyl Alkylamino)phenyl]carbonyl}amino)propionic acid _ 1-(5-hydroxy-3-indolyl-1-benzofuran-2-yl)~2~ synthesized in the above (1) Methyl propyl ketone (1.1 S) was dissolved in tetrahydrofuran (15 mL) and 321426 721 201029996 sterol (1 mL), and sodium borohydride (90%, 0.33 g) was then Solution. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled with ice, and water (5 mL) and 1N hydrochloric acid (15 mL) was carefully added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with aq. EtOAc (EtOAc m. Alcohol (0.71 g, 65%). The resulting oil was dissolved in tetrahydro wah (15 mL) and sulphur sulphur (0.30 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 3 〇 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulphuric acid and concentrated under reduced pressure. The residue was dissolved in dimethyl ethanoamine (15 mL), and the sodium moth (〇·52 g), sodium carbonate (0·35 g) and the compound of Example 2 (2) were synthesized 3-{[( 4-Aminophenyl)carbonyl](indenyl)amino}propionic acid ethyl ester (0.58 g) was added to the mixture at 7 Torr. (: The mixture was stirred for 4 hours. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The mixture was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: hexane = 1:1) The residue is purified to obtain 3-(indenyl {[4-({2-methyl-U3-indolyl_5_(tetrahydro-2H-pyran-4-yloxy)) as a yellow oil. -1-benzofuran-2-yl]propyl}amino)phenyl]carbonyl}amino)propionic acid ethyl ester (〇·54 g, 46%). The obtained oil was dissolved in ethanol (3) To a solution, a 1N aqueous solution of sodium hydroxide (3 mL) was added to the mixture and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure and hydrochloric acid (3.0 mL) was added to residue. The precipitate was washed with water to give the title compound (0.53 g, 98%) as a colorless solid. 321 426 722 201029996 ]H NMR (300 MHz, CDCh) 5 ppm 0.92 (d, J = 6.8 Hz, 3H), 1.13 (d, J=6.8 Hz, 2H), 1.70-2.09 (m, 4H), 2.21 (s, 3H), 2.22-2.27 (ra, 1H), 2.67 (t, J=6. 2 Hz, 2H) , 3.04 (s, 3H), 3.56 (ddd, J=11.5, 8.5, 3.4 Hz, 2H), 3.70 (t, J=6. 2 Hz, 2H), 3.91-4.08 (m, 2H), 4.32 (d , J=7. 6 Hz, 1H), 4.43 (tt, J=7. 9, 3. 8 Hz, 1H), 6.57 (d, J=8. 7 Hz, 2H), 6.85 (dd, J=8 7, 2. 7 Hz, 1H), 6.93 (d, J=2. 3 Hz, 1H), 7. 19-7. 26 (m, 3H). ❺Example A181 3-[{[4-( {cyclohexyl[3-indolyl_5-(l-fluorenyl-1H-pyrazol-4-yl)-i-benzofuran-2-yl]indolyl}amino)phenyl]carbonyl}(曱Amino acid] propionic acid

ΟMethyl 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Η-pyrazole (0.44 g), potassium carbonate (0.29 g) and hydrazine Triphenylphosphine palladium (0.06 g) was added to the 3-{[(4-{[(5-)-3-methyl-1-benzo-α-pyran-2-yl group synthesized in Example A174(3) (cyclohexyl) fluorenyl]amino}phenyl)carbonyl](methyl)amino}propionic acid ethyl ester (0.59 g) in hydrazine, hydrazine-dimethylacetamide solution (15 mL), The mixture was stirred under argon at 701 for 24 hours. The reaction mixture was cooled to room temperature and filtered through EtOAc (EtOAc)EtOAc. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by Shixi gum column sound 321426 723 201029996 (ethyl acetate: hexane = 1 : 1, volume ratio) to obtain 3-[{[4-({cyclohexyl][ 3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-benzofuran-2-yl]nonylamino)phenyl]carbonyl}(fluorenyl)amine ]ethyl propionate (0.23 g, 39%). The resulting oil was dissolved in EtOAc (1 mL), EtOAc (EtOAc) Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1.0 mL) was added to residue. The precipitate was washed with water to give the title compound ( 〇. 〇 4 g, 16%) as a colorless solid. ❹NMR (300 MHz, CDCls) (5 ppm 0·93-2. 11 (m,11H), 2.27 (s,3H), 2.67 (br. s.,2H), 3.03 (s, 3H), 3.70 (t, J=6. 2 Hz, 2H), 3.94 (s, 3H), 4.38 (d, J=7. 8 Hz, 1H), 6.57 (d, J=8.6Hz, 2H), 7.23 (d, J=8. 6 Hz, 2H), 7.29-7. 39 (m, 2H), 7. 49 (s, 1H), 7. 59 (s, 1H), 7. 75 (s, 1H). A182 3-[{[4-({l-[5-(6-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl]-2-methyl) Propyl}amino)phenyl]alkyl}(methyl)amino;|propionic acid

(1) 1-(5-'/odor-3-methyl-1-benzo-acean-2-yl)-2-mercaptopropan-1-one 1-[5-bromo-2-hydroxybenzene Ethyl ketone (8.4 g) was dissolved in N,N-dimethyl decylamine (50 mL). Potassium carbonate (16.2 g) and 1-bromo-3-indolylbutan-2-one (8.4 g) synthesized in Example A75(l) 724 321426 201029996 were added to the reaction mixture at room temperature, and at 60 The mixture was stirred at ° C for 1 hour. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The title compound (1. 2 g, 77%) was obtained as a pale yellow solid. !H NMR (300 MHz, CDCh) δ ppm 1.25 (d, J=6. 8 Hz, 6H), 2.57 (s, 3H), 3.48-3.70 (m. 1H), 7.39 (d, J=8. 7 Hz, ❹ 1H), 7. 55 (dd, J=8. 7,1.9 Hz, 1H), 7.78 (d, J=1.9Hz, 1H). (2) 3-{[(4-{[ L-(5-bromo-3-methylbenzofuran-2-yl)-2-methylpropyl]aminoindole phenyl)carbonyl](methyl)amino}ethyl propionate will be as described above (1 The 1-(5-bromo-3-methyl-1-benzofuran "Nan-2-yl)-2-mercaptopropan-1-one (6.2 g) synthesized was dissolved in tetrahydrofuran (1 mL) And decyl alcohol (10 mL), and sodium borohydride (90%, 1.8 g) Q was added to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr then cooled with ice and water (10 mL) and 1N hydrochloric acid (50 mL) was carefully added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO.sub. Prop-1-ol (6.1 g, quantitative). The obtained oil was dissolved in tetrahydrofuran (50 mL) and sulphurous chlorobenzene (2.3 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then cooled with EtOAc EtOAc &lt The reaction mixture was stirred for 10 min and the mixture was taken with EtOAc EtOAc EtOAc EtOAc EtOAc. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in dimethylacetamide (100 mL), sodium ruthenium (3.9 g), sodium carbonate (2.7 g) and 3-{[(4-) synthesized in Example 2 (2). Aminophenyl) benzyl](indenyl)amino}ethyl propionate (4.4 g) was added to the solution and the mixture was stirred at 7 ° C for 4 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified mjjjjjlilililililililililililili ® ]H NMR (300 MHz, CDCh) (5 ppm 0.91 (d, J=6. 4 Hz, 3H), 1.13 (d, J=6.4Hz, 3H), 1.18-1.26 (t, J=7.2 Hz, 3H), 2.20-2.35 (m, 4H), 2.61 (t, J=7.0 Hz, 2H), 3.01 (s, 4H), 3.70 (t, J=7. 0 Hz, 2H), 4. 09-4 17 (m, 2H), 4.24-4.41 (m, 2H), 6.56 (d, J=8. 7 Hz, 2H), 7.15-7.36 (m, 4H), 7. 55 (d, J=l. 9 Hz, 1H). (3) 3-[{[4-({l-[5-(6-methoxyacridin-3-yl)-3-indolyl-1-benzoindoloin _2-yl]-2-mercaptopropyl}amino)phenyl]alkyl}(methyl)amino]propionic acid (6-methoxypyridin-3-yl)boronic acid (0.33 g ), potassium carbonate (〇. 29 g) and triphenylphosphine palladium (〇. 12 g) are added to the 3-{[(4-{[1-(5-漠-3-) synthesized in the above (2) N-methyl-1-benzobaffin-2-yl)-2-mercaptopropyl]amino}phenyl)-reactive](methyl)amino}ethyl propionate (0.55 g) of N, N-dimethylacetamide solution (10 mL), and the mixture was stirred under argon, 7 (TC) for 24 hours. The reaction mixture was cooled to room temperature and filtered through celite i and washed with diethyl ether. The filtrate was concentrated under reduced pressure, and the organic layer was concentrated under hexanes 726 321426. Ester: hexane = 1: 1, volume ratio) Purification residue to give 3-Π[4-({1-[5-(6-methoxypyridine-3-yl))3 as a pale yellow oil _Methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonylindole (methyl)amino]propionic acid ethyl ester (0.1 g). The oil was dissolved in ethanol (1 mL), and 1N aqueous sodium hydroxide solution (······················· The title compound (0. 06 g, 10%) was obtained as a colorless solid. ❽ JH NMR (300 MHz, CDCh) 5 ppra 〇. 94 (d, J) =6. 8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H), 2.15-2.37 (m, 1H), 2.29 (s, 3H), 2.66 (t, J=6.2 Hz, 2H), 3.03 (s, 3H), 3.70 (t, J=6.2 Hz, 2H), 3.98 (s, 3H), 4.36 (d, J=7. 5 Hz, 1H), 6.58 (d, J=8. 7 Hz, 2H), 6.82 (d, J=8. 7 Hz, 1H), 7.23 (d, J=8. 7 Hz, 2H), 7.30-7.46 (m, 2H), 7.53 (d, J=1.9

Hz, 1H), 7.79 (dd, J=8. 5, 2. 4 Hz, 1H), 8.38 (d, J=2. 4 ❹ Hz' 1H). Example A183 3-[{[4-({ 1-[5-(2-Methoxypyrimidin-3-yl)-3-methyl-1-benzonyridin-2-yl]-2-mercaptopropyl}amino)phenyl]carbonyl }(mercapto)amino] propionate

IJI 八"^ΌΗ 727 321426 201029996 (2_methoxypyridin-3-yl)boronic acid (〇. 33 g), potassium carbonate (〇. 29 g) and 肆triphenylphosphine palladium (〇·12 g) Addition to the 3-{[(4-{[1-(5-&gt; odor-3 -methyl-1-•benzopyrene 2)-)-A synthesized in Example A182(2) Propyl, hydrazine-dimethylacetamide solution (10 mL), and argon, 70, ethyl propyl phenyl) carbonyl] (fluorenyl) amino phthalic acid ethyl ester (0.55 g) . (The mixture was stirred for 24 hours. The reaction mixture was cooled to room temperature and filtered through celite) and residue was washed with diethyl ether. Water was added to filtrate and the organic layer was concentrated under reduced pressure. : hexane = 1 : 1, volume ratio) Purification residue to obtain 3-[{[4-({l-[5-(2- methoxy oxy-3-yl))) as a pale yellow oil 3-mercapto-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl] benzyl}(fluorenyl)amino]propionic acid ethyl ester (0.11 g). The obtained oil was dissolved in ethanol (1 mL). A 1N aqueous sodium hydroxide solution (1 mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 5 hours. Ethanol was evaporated under reduced pressure. 1N Hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title compound (0.18 g, ❹]H NMR (300 MHz, CDCW (5 ppm 〇· 94 (d, J) =6. 4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 2.12-2.40 (m, 1H) 2 27 (s 3H), 2.67 (t, J=6.2 Hz, 2H), 3. 04 (s,3H) 3 70 (t J=6. 2 Hz, 2H), 3. 96 (s, 3H), 4. 36 (d, J=7 9 Hz 1H) 6. 58 (d, J= 8. 7 Hz, 2H), 6. 97 (dd, J=7. 2, 4 9 Hz, 1H) 7.23 (d, J=8. 7 Hz, 2H), 7.33-7.77 (m, 4H), 8.16 (dd, J=4. 9, 1. 9 Hz, 1H). Example A184 3 -{[(4-{[1-(5-cyclopropyl-3-indolyl-1~benzoxan-2-yl)_2-曱321426 728 201029996 propyl]amino}phenyl)carbonyl (methyl)amino}propionic acid

(1) 1-(5-Cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-indole Cyclopropaneboronic acid (〇·92 g), 2N carbonic acid The sodium aqueous solution (5.3 mL) was added to the 1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-mercaptopropane-1 synthesized in Example A182 (1) a ketone (1. 〇g) in toluene solution (2 〇 mL), and the mixture was turbulently stirred for 1 minute in the air. Adding 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (〇·ΐ8 g) and ginseng (diphenylmethyleneacetone) dipalladium (〇.10 g) to the reaction mixture The mixture was heated overnight under argon and reflux. The reaction mixture was cooled to room temperature and filtered through Celite, and washed with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The title compound (0.80 g, (10)%) was obtained from the title compound (yield: EtOAc). NMR (300 MHz, CDCls) (5 ppm 0.59-1.08 (m, 4H), 1.23 (d, W.8Hz, 6H), L9, 2.u (m, 1H), 2 35 (s, 'ih), 2.58 (s, 3H), 7.07-7.51 (m, 3H). (2) 1-(5-cyclopropyl-3_mercapto-i-benzofuran__2-yl)_2-methylpropan-1 - The alcohol is dissolved in the four gas argon (K5-cyclopropylmethyl hydrazine-benzofuran-2-yl)-2-mercaptopropan- _ (0.80 g) synthesized in the above (1) 1 〇 ) 321426 729 201029996 and decyl alcohol (1 mL), and sodium borohydride (9 〇%, 〇34 g) was added to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at rt EtOAc then EtOAc &lt;RTI ID=0.0&gt;&gt; The extract was washed with EtOAc (EtOAc m. 'H NMR (300 MHz, CDCh) δ ppm 0. 63-0. 75 (m, 2H), 〇80 (d, J=6.8 Hz, 3H), 0.88-1.01 (m, 2H), 1.11 (d, j=6.8 ® Hz, 3H), 1.20- 1.30 (m, lH), 1.93-2.03 (m, lH), 2.12-2. 30 (m, 4H), 4.46 (d, J = 8. 3 Hz, 1H ), 7.01 (dd, J=8.3, 1.9 Hz, 1H), 7.17 (d, J=l. 9 Hz, 1H), 7.29 (d, J=8. 3 Hz, 1H). (3) 3 -{[(4-{[l~(5-cyclopropyl-3-indolyl-1-benzotrim-2-yl)-2-mercaptopropyl]aminopurinylphenyl)carbonyl]( Methyl)amino}propionic acid thiorubic acid chloride (0.22 mL) was added to the 1-(5-cyclopropyl-3-3-mercapto-1-benzopyrene) synthesized in the above (2) at room temperature. A solution of 2-yl)-2-mercaptopropan-1-ol (0.40 g) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 30 min then cooled with EtOAc EtOAc. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 mL). Sodium iodide (0.373 g), sodium carbonate (〇. 25 g) and 3-{[(4-) synthesized in Example 2 (2) Aminophenyl)carbonyl](fluorenyl)aminopyridinic acid B-(0·41 §) was added to the solution and stirred at 7 (TC for 2 hours. After cooling, 'add water to the reaction mixture 730 321426 201029996 The mixture was extracted with EtOAc. EtOAc was evaporated. -{[(4-{[1-(5-cyclopropyl-3-methyl-1) benzofuran-2-yl)-2-methylpropyl]amino}phenyl)carbonyl](罗) Ethyl propyl acetate (0. 25 g). The obtained oil was dissolved in ethanol (2 mL), and 1N aqueous sodium hydroxide solution (1. 〇mL) was added to the solution at room/jm· The mixture was stirred at room temperature for 0.5 hours. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1 mL) was added to residue. The precipitate was washed with water to give the title compound (0. g, 32%) H NMR (300 MHz, CDCh) δ ppm 0. 62-0. 73 (m, 2H), 〇. 82-1.0 0 (m, 5H), 1.12 (d, J=6.8 Hz, 3H), 1.90-2.07 (m, 1H), 2.14-2.32 (m, 4H), 2.67 (t, J=6.2 Hz, 2H), 3.03 (s, 3H), 3.70 (t, J=6.2 Hz, 2H), 4.32 (d, J=7.9 Hz, 1H), 6.56 (d, J=8.7Hz, 2H), 6.98 (dd, J= 8. 7, 1.9 Hz, 1H), 7.13 (d, J=1.9 Hz, 1H), 7.19-7.25 (m, 3H). ^ Example A185 3_{[(6-{[私己基(5, 7- Difluoro-3-indolyl-i-benzo-df e-nan-2-yl)indolyl]amino}°pyridin-3-yl)carbonyl](indenyl)amino}propionic acid

The cyclohexyl (5,7-difluoro_3-methyl-1-benzofuran-2-yl) decyl alcohol (0.52 g) synthesized in Example A163 (2) was dissolved in tetrahydrofuran (5 mL) 731 321426 Add ruthenium chloride (〇. 24 mL) to the solution at room temperature at 201029996. The reaction mixture was stirred at room temperature for 30 minutes </ RTI> then cooled with ice, and a saturated aqueous sodium hydrogen carbonate (3 mL) was carefully added to the mixture. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was dissolved in dimethylacetamide (5 mL), sodium iodide (0.45 g), sodium carbonate (0·30 g), ethyl 6-aminopyridine-3-carboxylate (0) . 45 Ο

g) Add to solution and stir the mixture overnight at 60 °C. It was allowed to cool to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the residue was purified to silica gel column (ethyl acetate:hexane = 1:1) to afford 6-{[cyclohexyl (5,7) Difluoro~3_fluorenyl-benzofuran-2-yl)methyl]amino}pyridine-3-carboxylate (〇1〇g). The obtained oil was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL), and the mixture was allowed to stand for 1 hour in the presence of 1 N aqueous sodium hydroxide (2 mL). Concentrate to room temperature and under reduced pressure. The residue was dissolved in 24 Ν '7 Ψ / ^ (20 mL) ^ ^ (0.24 g), and ethyl 3-(3-didecylaminopropyl) carbon (〇) · 48 g) and hydroxybenzotriazole monohydrate (Chen Gong a *. rectification) was added to the solution and mixed at 70 C for 4 hours. The reaction mixture was stirred and the mixture was extracted with diethyl ether. Washing with drying. Evaporate the solvent under reduced pressure, add ethanol (5 mL 5 in sulphuric acid: liquid (1·〇mL) to the residue and stir the mixture at room temperature:: condensed reaction mixture; 1. In this case, the spear is taken. The extract is evaporated under reduced pressure and the mixture is called vinegar.

The residue was purified by calcination = 1 : 4 vol. to obtain the target compound (0.05 g, 6%) as ethyl acetate ethyl acetate J 321426 732 201029996. !H NMR (300 MHz, CDCb) δ ppm 1. 〇〇-l. 93 (m, 11H), 2. 22 (s, 3H), 2.68-2.75 (m, 2H), 3.09 (s, 3H), 3.70-3.80 (m, 2H), 4.10-4.20 (m, 1H), 6.36 (d, J=8. 7 Hz, 1H), 6.69-6.94 (m, 2H), 7.50-7.58 (m, 1H), 8.15 (d, J = 1.9 Hz, 1H). Example A186 3-[ {[4-({cyclohexyl[3-indolyl-5-(morphin-4-yl)-1-benzopyran)- 2-yl] fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid

o (1) 5-Molyl-3-mercapto-1-benzo-Bindon _2-Resinized methyl vinegar Add potassium carbonate (24.0 g) and methyl bromoacetate (11.5 mL) to the room temperature at room temperature A solution of bromo-2-hydroxyphenyl)ethanone (25.0 g) in N,N-dimercaptocaramine (200 mL) was stirred at room temperature for 15 h. The reaction mixture was filtered. To the filtrate was added 1,8-diazabicyclo[5·4.0] Η-7-7 (23. 2 mL), and the mixture was stirred at 1 ° C for 3 hr. The reaction mixture was allowed to cool to room temperature and ice water was added. The title compound (16. 8 g, 52%) was obtained. ]H NMR (300 MHz, CDCh) 5 ppm 2.56 (s, 3H), 3.99 (s, 3H), 7.36-7.46 (m, 1H), 7.49-7.60 (m, 1H), 7.77 (d, 733 321426 201029996 J=2·3 Hz, 1H). (2) 3-Mercapto-5-(N-Phen-4-yl)-Phenylbenzopyrene-2-monomethyl ester will be drenched (5.2 mL) , cesium carbonate (13. 〇g), ginseng (diphenylarbenium acetonide), two (〇) (〇. 92 g) and 9,9-dimercapto-4, 5-bis((diphenylphosphine) Dibenzopyran (1.1 g) added to the above-mentioned (1) methyl 5-bromo-3-indolyl-1-benzofuran-2-carboxylic acid methyl ester (5.4 g) The solution (1 mL) was heated with argon under reflux for 20 hours. The reaction mixture was cooled to room temperature and filtered through EtOAc (EtOAc). The extract was concentrated, and the residue was purified mjjjjjjjjjjjj !H NMR (300 MHz, CDCls) δ ppm 2. 57 (s, 3H), 3. 06-3. 22 Cm, 4H), 3.83-3.94 (m, 4H), 3.97 (s, 3H), 7.02 (d, J-2. 3 Hz, 1H), 7. 15 (dd, J=9. 0,2. 3 H z,1H), 7.45 (d J=9. 0 Hz, 1H). ❹(3) 3-methyl-5-(morphin-4-yl)-1-benzopyran-2-carboxylic acid A solution of methyl 3-methyl-5-(morpholin-4-yl)-benzofuran-2-carboxylate (0.69 g) in tetrahydrofuran (2 mL) synthesized in the above (2) was added to hydrogenation An ice-cold solution (5 mL) of lithium aluminum (0.25 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then ice-cooled again, and water (〇. 65 mL), 1N aqueous sodium hydroxide (3 2 mL) and water (0.65 mL) were added dropwise. To terminate the reaction. The residue was filtered through diatomaceous earth and decompressed to obtain the [3-methyl_5_(Merlin-4-yl)-1-benzofuran-2-yl] as a pale yellow oil. The crude product of sterol (〇. 48 g). The obtained 321426 734 201029996 oil was dissolved in acetonitrile (5 Torr), and tetrapropylammonium perruthenate (〇〇7 g) and N-mercaptomorpholine N-oxide (〇. 46 g) were added at room temperature. ) was added to the solution and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure and purified titled mjjjjjjjjjjj %). H NMR (300 MHz, CDCh) δ ppm 2. 59 (s, 3H), 3 〇9-3 22 (m, 4H), 3. 79-3. 98 (m, 4H), 7. 05 (d, J=2. 3 Hz, 1H), 7. 23 (dd, J=9. 2, 2. 3 Hz, 1H), 7. 46 (d, J=9. 2 Hz, 1H), ® 10.00 (s , 1H). (4) Cyclohexyl [3-indolyl-5-(morphin-4-yl)-l-benzofuran-2-yl]nonanol is brominated cyclohexylmagnesium under ice cooling ( 2 mL, 1 M tetrahydro-α-n-n solution) was added dropwise to 3-mercapto-5-(morpholin-4-yl)-1-benzofuran-2-carbaldehyde synthesized in the above (3) ( 〇· 24 g) in tetrahydrofuran (5 mL). After the dropwise addition was completed, the ice bath was removed and the mixture was stirred at room temperature for 15 minutes. A solution of ammonium chloride in water n was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted (morpholin-4-yl)-1-benzofuran-2-yl]methanol (0.39 g, quantitative). 4 NMR (300 MHz, CDC13) (5 ppm 1. 07-2. 01 Ο, 12H), 2. 19 (s, 3H), 3.11-3.21 (m, 4H), 3.83-3.95 (m, 4H), 4.50 (d, J=8. THz, 1H), 6.90-7.01 (m, 2H), 7.33 (d, J=9.8 Hz, 1H). (5) 3-[ {[4-({cyclohexyl][3 - mercapto-5-(morphin-4-yl)_1-benzoate bite 735 321426 201029996 -2--2-yl]methyl}amino)phenyl] benzyl K methyl) amide] propisin Thionyl chloride (〇·13 mL) was added to the cyclohexyl[3_fluorenyl-5-(morpholin-4-yl)-1-benzofuran-2-based group synthesized in the above (4) at room temperature. A solution of methanol (0.39 g) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 30 min then cooled with ice and a saturated aqueous NaH.sub. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate The residue was dissolved in dimercaptoacetamide (5 mL), sodium (0.23 g), sodium carbonate (0.15 g) and 3-{[(4) synthesized in Example 2 (2). -Aminophenyl)carbonyl](methyl)amino}ethyl propionate (0.25 g) was added to the solution and the mixture was stirred at 70 ° C for 15 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1, volume ratio) to afford 3-[{[4-({ Hexyl [3-methyl-5-(morpholin-4-yl)-l-benzofuran-2-yl]methyl}amino)phenyl]carbonylindole (methyl)amino]propionic acid Ester (0.25 g). The obtained oily substance was dissolved in ethanol (2 mL), and 1N aqueous sodium hydroxide (1. 〇 mL) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 hour. Ethanol was evaporated under reduced pressure and 1N hydrochloric acid (1. 〇 mL) was added to residue. The precipitate was washed with water to give the title compound (0. 19 g, 33%). !H NMR (300 MHz, CDCh) δ ppm 0. 90-2. 16 (m, 11H), 2 22 (s, 3H), 2.68 (br. s., 2H), 3.04 (s, 3H) , 3.14 (br. s. , 4H), 3.58-3.77 (in, 2H), 3.89 (br. s., 4H), 4.36 (d, J-8.3Hz, 1H), 6.56 (d, J=9. 0 Hz, 2H), 6.84-7.02 321426 736 201029996 (m, 2H), 7. 17-7.27 (m, 3H). Example A187 3-[{[4-(丨cyclohexyl[3-methyl-5] -(thiomorpholin-4-yl)-l-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid

(1) Cyclohexyl [3-indolyl-5-(thio-infrared-4_yl)_1_benzo-d-pentan-2-yl]fluorenone will be thio- merin (0.72 g), carbonic acid ( 2.3 g), ginseng (diphenylarbenium acetonide) dipalladium (〇) (〇. 16 g) and 9,9-dimercapto-4, 5-bis(diphenylphosphino) diphthyl Add (0.2 g) to (5-bromo-3-indolyl-1-benzofuran-2-yl)(cyclohexyl)methanone (〇. 75 g) synthesized in Example A174(l) The benzene solution (15 mL) was heated under argon and reflux for 18 hours. The reaction mixture was cooled to room temperature and filtered through EtOAc (EtOAc)EtOAc. , quantitative). JH NMR (300 MHz, CDCh) δ ppm 1. 37-2. 01 (m, 1〇Η), 2.56 (s, 3H), 2.70-2.88 (m, 4H), 3.25-3.40 (m, 1H), 3.42-3.70 (m, 4fl), 7.00-7.78 (m, 3H). (2) Cyclohexyl [3-indolyl-5-(thiomorpholinyl)-benzofuran-2-yl]methanol 321426 737 201029996 Cyclohexyl[3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl]fluorenone (〇. 83 g) synthesized in the above (1) Dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.2 g) was added to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr then cooled with ice and water (1 mL) and 1N hydrochloric acid (5 mL) was carefully added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1). !H NMR (300 MHz, CDCh) δ ppm 0.81-1.93 (m, 11H), 2.20 (s, 3H), 2.70-2.91 (m, 4H), 3.34-3.53 (m, 4H), 4.50 (d, J =8.3 Hz, 1H), 4.99 (t, J=6.4 Hz, 1H), 6.90-7.40 (m, 3H). (3) 3-[{[4-({cyclohexyl[3-indolyl-5- (thiomorphin-4-yl)-1-benzofuran-2-yl]fluorenyl}amino)phenyl]carbonyl}(methyl)amino]propionic acid q sulfite chloride at room temperature (0.07 mL) was added to the cyclohexyl[3-methyl-5-(thio- phenan-4-yl)-1-benzofuran-2-yl]methanol (0. 18 g) synthesized in the above (2). A solution of tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 30 min then cooled with ice EtOAc. The reaction mixture was stirred for 10 minutes and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was hydrolyzed to a hydrazinylamine (5 mL), and the mononuclear (〇.15 g), sodium carbonate (〇.g) and the 3-{[(4) synthesized in Example 2(2) were obtained. -Aminophenyl)carbonyl](indenyl)amino}ethyl propionate (0.13 g) was added to the solution and the mixture was stirred at 321426 738 201029996 70 ° C for 15 hours. After allowing to cool, water was added to the reaction mixture and the mixture was extracted with acetic acid. The extract was decompressed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1 :;) to afford 3-[{[4- ({Cyclohexyl[3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonylindole (indenyl) Amino ]ethyl propionate (0.08 g). The resulting oil was dissolved in ethanol (2 mL). EtOAc (1Q mL). Ethanol was evaporated under reduced pressure and in hydrochloric acid (1. 0 mL) was added to residue. The precipitate was washed with water to give the title compound ( 〇. 〇 5 g, 18%) as a colorless solid. 'H NMR (300 MHz, CDCls) ^ ppm 0. 88-2. 17 (m, 11H), 2.20 (s, 3H), 2.59 (br. s. , 2H), 2.80-3.20 (m, 7H), 3.50-3.70 (m, 6H), 4.38 (d, J=7.9 Hz, 1H), 6.55 (d, J=8. 7 Hz, 2H), 7.08-7.47 (m, 5H). Example A188 ❹3_ [({4-[(cyclohexyl){5-[(2-decyloxyethyl)(methyl)amino]-3-methyl-1~ benzofuran-2-ylindenyl)) Phenyl}carbonyl)(fluorenyl)amino]

^-N \ (1) 5-[(2-decyloxyethyl)(fluorenyl)amino]_3_mercapto-benzofuran- 2-reoxalate 旨g 739 321426 201029996 Oxy-N-methylethylamine (2.7 g), carbonic acid planing (9.8 g), ginseng (diphenylarbenium acetonide) dipalladium (0) (0.69 g) and 9, 9- Dimethyl-4,5-bis(diphenylphosphino)dibenzopyran (0.87 g) was added to the 5-bromo-3-methyl-1-benzofuran synthesized in Example A186(l) A solution of _2-carboxylic acid oxime ester (2.7 g) in a solution (50 mL), and the mixture was stirred under argon and reflux for 6 hours. The reaction mixture was cooled to room temperature and filtered through Celite, water was added to filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated, and the residue was purified mjjjjjlililililililililililililili H NMR (300. MHz, CDC13) in ppm 2. 55 (s, 3H), 3. 01 (s, 3H), 3.37 (s, 3H), 3.40-3.70 (m, 4H), 3.97 (s, 3H) ), 6· 77-7. 15 (m, 3H). (2) 5-[(2-Methoxyethyl)(indenyl)aminodibu-3-methyl-l-benzofuran-2- Furfural 5-((2-methoxyethyl)(methyl)amino] ❹_3-mercapto-1-indolofuran-2-carboxylic acid oxime ester synthesized in the above (1) (2.7 g A solution of tetrahydrofuran (10 mL) was added to an ice-cooled solution (40 mL) of lithium aluminum hydride (yield: 38 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, then cooled again with ice, and water (1·〇mL), 1N aqueous sodium hydroxide (5.0 mL) and water (1. ) to terminate the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to afford (5-[(2-methyl- propylethyl)(methyl)amino)] and. The crude product of methanol (0. 41 g). The obtained oil was dissolved in acetonitrile (20 mL) to give tetrapropylammonium perruthenate (〇. 〇7 g) and N-mercaptomorpholine N- 740 321426 201029996 oxide (0·46) at room temperature. g) Add to the solution and stir the mixture for 3 minutes. The solvent was evaporated under reduced pressure and purified titled mjjjjjjjjjjjjj %). . H NMR (300 MHz, CDCh) δ ppm 2. 58 (s, 3H) 3 〇2 (s 3H), 3.38 (s, 3H), 3.47-3. 66 (m, 4H), 6.81 (d, J = 2 6

Hz, 1H), 7. 10(dd, J=9. 0, 2. 6 Hz, 1H), 7.40 (d, J=9. 〇Hz, 1H), 9.97 (s, 1H). · ❹(3 Cyclohexyl {5-[(2-methoxyethyl)(methyl)aminodipyridin-3-methylbenzoxadol-2-n-yl}methanol brominated cyclohexyl hydride under ice cooling 2 mL, 1 Μ tetrahydrofuran solution) was added dropwise to 5-[(2-decyloxyethyl)(methyl)amino]-3-mercapto-1-benzofuran-2 synthesized in the above (2) - Formaldehyde (〇.09 g) in tetrahydrofuran (5 mL). After the dropwise addition was completed, the ice bath was removed and the mixture was stirred at room temperature for 15 minutes. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified mjjjjjlilililililililili H NMR (300 MHz, CDCla) δ ppm 0. 99-1. 96 (m, 12H), 2.18 (s, 3H), 2.99(s, 3H), 3. 37 (s, 3H), 3.45-3.72 ( In, 4H), 4-49 (d, J=8.7 Hz, 1H), 6.77-7.30 (m, 3H). (4) 3-[({4-[(cyclohexyl){5-[(2-曱Oxyethyl)(methyl)amino]-3-indolyl-1-benzofuran-2-ylindolemethyl)amino]phenylindolecarbonyl)(methyl)amino]propionic acid 321426 741 201029996 Add sulfinium chloride (0.10 fflL) to the above (3) cyclohexyl{5-[(2-methoxyethyl)(methyl)amino]]_3_methyl one at room temperature = a solution of the benzoic acid 2-yl}methanol (0.11 g) in tetrahydrofuran (10 mL). The reaction mixture was stirred for 30 minutes at room, and then ice-cooled, and saturated aqueous sodium hydrogen carbonate (5 mL) was