TW201206909A - Quinoline derivative - Google Patents

Abstract

The present invention provides a compound having a melanin-concentrating hormone receptor antagonistic action and low toxicity, which is useful as an agent for the prophylaxis or treatment of obesity and the like. The present invention relates to a compound represented by the formula (I): (I) wherein each symbol is as defined in the specification, or a salt thereof.

Description

201206909 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a quinoline derivative having melanin concentration

The receptor antagonism is applied to a prophylactic or therapeutic agent for obesity or the like. [Prior Art] MCH is a hormone derived from the hypothalamus, which is known to have an effect of improving your diet. In addition, it has been reported that MCH knockout mice are normal, but their food intake is significantly reduced and their body weight is lighter than normal mice (Nature, ν〇1·396, p.670, 1998). It is therefore expected that the mCH receptor antagonist may be a superior appetite suppressant or anti-obesity agent. As the compound having MCH receptor antagonism, the following compounds are known. 1) WO 01/21577 (Patent Document 1) discloses a melanin-concentrating hormone antagonist, which comprises a compound represented by the following formula or a salt thereof:

among them,

Ar1 is a cyclic group 'which may optionally have a substituent (group); X is a spacer having 1 to 6 atomic number in the main chain; Y is a bond or the main chain has 1 to 6 atomic number Spacer

Ar is a monocyclic aromatic ring which may be condensed with 4 to 8 membered non-aromatic rings as needed, and further optionally has a substituent (group); 322147 4 201206909 R and R are the same or different and are each a hydrogen atom or It may be desirable to have a substituent (group) group, and R2 may form a nitrogen-containing heterocyclic ring which may have a substituent (group) together with an adjacent nitrogen atom, and R and Ar together form a snail R which may be adjacent to a nitrogen atom and Y. A nitrogen-containing heterocyclic ring having a substituent (group) as needed is formed. 2) W0 01/82925 (Special (4) Document 2) discloses melanin-concentrating hormone inhibitors, which include a compound represented by the following formula or a salt thereof:

Ar - X - Ar - Y - pj. Among them,

Ar1 is a cyclic group having a substituent (group) as desired. To 6 atomic numbers X and Y are the same or different, and each has a spacer of ^ as a main chain;

The second is = a condensed polycyclic aromatic ring having a substituent (group); R and R are the same or different from each other and are each a hydrogen atom or a hydrocarbon group which may optionally have a substituent (group), and R1 and R2 may be Phase, the adjacent nitrogen atoms together form a ring containing a substituent (group) which may optionally have a substituent (group), and R2 may form a nitrogen-containing heterocyclic ring having a substituent (fresh) together with an adjacent nitrogen atom and γ, < R2 may form a nitrogen-containing fused ring which may have a substituent (group) as an adjacent nitrogen atom Y and Ar-s. 3) W0 Guan Cong (Patent Document 3) discloses a melanin-concentrating hormone antagonist comprising a compound represented by the following formula or a salt thereof: 322147 5 201206909

Y — ν wherein R is a hydrogen atom, a halogen atom or a cyclic group which may optionally have a substituent (group); X is a substituent having a bond or a main chain having 1 to 1 atomic number; Y is a spacer having 1 to 6 atomic number in the main chain; A ring is a benzene ring, which may further have a substituent (group) as needed; and a ring B is a 5 to 9 member nitrogen-containing non-aromatic hetero ring, Further having a substituent (group) as needed; R and R2 are the same or different from each other and are each a hydrogen atom, a hydrocarbon group optionally having a substituent (group) or a heterocyclic group having a substituent (group) as desired, R1 and R2 may form a nitrogen-containing heterocyclic ring which may have a substituent (group) together with an adjacent nitrogen atom, or R2 may form a nitrogen-containing hetero atom which may have a substituent (group) as needed with an adjacent nitrogen atom and γ. ring. 4) WO 03/035624 (Patent Document 4) discloses a chemical compound or a salt thereof or a prodrug thereof as shown in the following formula:

among them,

Ar is a cyclic group which may have a substituent (group) as required; 322147 6 201206909 The main chain has a spacer of 1 to 6 atomic number; the generation is different, and each is a hydrogen atom or may have a nitrogen atom The atom __ is required to have a substituent (group) Y3 = a divalent hydrocarbon group having a substituent (group) (excluding ruthenium) as needed; R is a ruthenium atom or a hydrocarbon group optionally having a substituent (group); The earthworm ring and the anthracene ring may have a substituent (group), and when the ring further has a substituent (group), the substituent (group) may bond with R1 to form a ring. 5) W0 2_/072() 18 (Patent Document 5) discloses a compound represented by the following formula or a salt thereof:

〇 Ra1 .I

Ar — c —N—C-R Ra: where,

Ar is a cyclic group which may have a substituent (group) as desired; R is a hydrogen atom, may be a chroma group which needs to be oxidized, a phenyl group which may have a substituent (group) as needed, or may optionally have a substituent (group) Acridine group;

Ra1, Ra2, Ra3 and Ra4 are the same or different, and each is a hydrogen atom, a Ch alkyl group which may be halogenated, a phenyl group which may have a substituent (group), a halogen atom, and optionally a substituent (group) Acridine group, cyano group, Ch alkoxy group which may be functionalized, Ci-6 alkylthio group which may be dentate, amine group, mono- or di-Ch alkylamino group, formazan Base, visible needs to be halogenated 7 322147 201206909 ^ = base i or as needed to be self-developed one of the filaments; to have a (four) base (4) single observation ring; for the need to toothed extension of the base; (1) R and R2 is the same or different, and is divided into 4 R2 objects adjacent to the nitrogen material 院6 yard base, (2) (fresh) nitrogen-containing heterocycle, (3) Ri and γ $ need to have a substituent, optionally having a substituent (group) : Miscellaneous: ^ is calcined, but (d) the conditions are t Rl and r2 (d) ortho atom or Ch nitrogen-containing heterocyclic ring is a ring-shaped group formed by the mother-in-law or when R4Ci_4 is burned.曷 has a substituent (group) 〇 W〇2_/11832() (Special (4) Document 6) reveals a compound or a salt thereof:

Ar is a ring which is required to be substituted; wherein A is a spacer having 1 to 4 atoms in the main chain; B is a bond, Cm. An alkyl group or an oxygen atom; V and R5 are each independently a hydrogen atom or a substituent; R4 is a lysine group or an alkyl group which may be optionally substituted; and C?-1 is substituted with 1 and R2. A hydrogen atom or a substituent, R1 /, R or B bond point 322147 8 201206909 A nitrogen-containing heterocyclic ring which may be substituted may be used, or R1 may be bonded to Ar to form a nitrogen-containing fused heterocyclic ring which may optionally be substituted. 7) JP-A-2008-88120 (Patent Document 7) discloses a compound represented by the following formula or a salt thereof:

I Η 1 R2 R1 _ wherein R1 is a Ch alkoxy group which may be optionally substituted; R2 is a hydrogen atom, a fluorenyl group or a halogen atom; and X is a Cw hydrocarbon group substituted by a hydroxyl group or a pendant oxy group. 8) WO 2009//123194 (Patent Document 8) discloses a compound represented by the following formula or a salt thereof: R2

R1 wherein, the A ring is a 6-membered ring, which may be further substituted as needed; R1 is a hydrogen atom, a halogen atom or a Cl-6 group; R2 is a hydrogen atom or a C!-6 alkyl group; and R3 is represented by the following formula: The group: -Y-SCO^-R43, wherein Y is a bond or NH; ml is an integer of 1 or 2; R4a is a Ch alkyl which may be substituted by 1 to 3 halogen atoms 9 322147 201206909, or as follows a cyclic group of the formula:

S(〇)m3 or

Wherein 1112, 1113, 1114, 111, 112 and 113 are each independently an integer of 1 or 2; R4b is an anthracene-6 alkyl group which may be substituted with 1 to 3 tooth atoms (the ring portion of the cyclic group (moiety) Further substituted according to requirements); R5 is a 5- or 6-membered cyclic group which may be further substituted as needed; X1 is a bond or a C!-6 alkyl group; and · X2 is a bond or C!-6 Alkyl. [Previous Technical Literature] [Patent Literature] Patent Document 1: W0 01/21577 Patent Document 2: W0 01/82925 Patent Document 3: W0 01/87834 Patent Document 4: W0 03/035624 Patent Document 5 : W0 2004/072018 · Patent Document 6: W0 2006/118320 Patent Document 7: JP-A-2008-88120 Patent Document 8: W0 2009/123194 [Summary of the Invention] [Problems to be Solved by the Invention] There is a need to develop a compound having a low toxicity to MCH receptor antagonism, which is suitable for use as a prophylactic or therapeutic agent for obesity or the like. 10 322147 201206909 [Method for Solving the Problem] The inventors of the present invention have intensively studied a kind of MCH receptor antagonism with low toxicity (specifically, cardiotoxicity (for example, human ether-a-go-go related gene (hERG)) A compound which inhibits the activity), the phospholipidosis (PLsis)-inducing potential, etc., which often causes drug development problems, and finds that the compound (I) described below has superior MCH receptor antagonism and its toxicity (for example: Cardiotoxicity (e.g., hERG inhibitory activity), PLsis-evoked potential, etc., is lower than conventional MCH receptor antagonists, thus completing φ the present invention. Accordingly, the present invention relates to: [1] A compound of the formula (I) or a salt thereof (hereinafter sometimes referred to simply as "compound (1)"): R3

Wherein, the ring A is a tetrahydrofuran ring, which may be further substituted as needed; R1 is a hydrogen atom or a halogen atom; R2 is a hydrogen atom, a halogen atom or a Cl-6 alkyl group; R3 is a hydrogen atom or a Ch alkyl group; and R4 and R5 (1) Cw which is independently a hydrogen atom, which may be substituted as needed, and Cw which is required to be replaced by 11 322147 201206909. A cycloalkyl group may optionally be substituted with a 5 or 6 membered heterocyclic group, or (2) may form a substituted 4 to 6 membered nitrogen-containing heterocyclic ring together with an adjacent nitrogen atom, with the proviso that R4 and R5 When one is a hydrogen atom, the other is not a group represented by the following formula, wherein X1 is a bond or a Cm alkyl group; and RA1 is a group represented by the formula: -YS(0)ml-RB1 Wherein Y is a bond or NH; ml is an integer of 1 or 2; and RB1 is a Cw alkyl group which may be substituted with 1 to 3 halogen atoms, or a cyclic group represented by the following formula:

Wherein m2, m3, m4, nl, n2 and n3 are each independently an integer of 1 or 2; and RB2 is a Cw alkyl group which may be substituted with 1 to 3 halogen atoms (the ring portion of the cyclic group may be optionally required) Further substituted), 12 322147 201206909 methyl; [4] a compound according to the above item or a salt thereof, wherein R3 is a hydrogen atom or a methyl group, [5] a compound of the above item [1] or a salt thereof, wherein r4 is (a). a -6 alkyl group which may optionally be substituted with three substituents selected from the group consisting of a hydroxyl group, a 6 and 5 or an oxygen-containing heterocyclic group, 6, a hydroxyl group or (b) a C3-1 <> ring An alkyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy- and hydroxy groups, and a sulphur- 6-salt R is a nitrogen atom; [6] a compound of the above item [1] or a salt thereof , the towel, R4 and R5 together with the nitrogen atom of the phase form a 4 to 6 member nitrogen-containing heteroquinone substituted by a radical (group) and the nitrogen-containing heterocyclic ring may be substituted by an alkyl group (group) as needed; The compound of the above item [丨] or a salt thereof, wherein A ring-ring; ring tetrahydrofuryl R is a hydrogen atom or a fluorine atom; R2 is a fluorine atom or a methyl group; R3 is a hydrogen atom or a fluorenyl group; (a melon 6 alkyl group) may optionally be substituted with i to 3 substituents selected from the group consisting of a thiol group and a 5 or 6 membered oxygen-containing heterocyclic group, 4 groups or 3 groups selected from the group consisting of a fun group and a Ci_6 group ( bX: 3-, cycloalkyl, which may be substituted with a substituent of the group as required; and 322147 13 201206909 R5 is a hydrogen atom; [8] The compound of the above item (1) or a salt thereof, wherein the a ring is a tetrahydrofuran ring ; R is a hydrogen atom or a fluorine atom R is a fluorine atom or a fluorenyl group; R3 is a hydrogen atom or a methyl group; and R and R together with an adjacent nitrogen atom form a 5- or 6-membered nitrogen-containing heterocyclic ring substituted with a hydroxyl group (group), and the nitrogen-containing heterocyclic ring Substituting G 6 alkyl (group) as needed; [9] a compound or a salt thereof, which is n~[8_mercapto[[2S] ru-tetrahydrofuran-2-ylindenyl]amine hydrazine a quinolate- 7-yl]- 4_[(2S)-tetrahydrofuran-2-yl fluorenyloxy]benzoguanamine; [10] a compound or a salt thereof, the compound is N_{8_methyl_3_ [(tetrahydro-2H-piperazin-4-ylamino)methyl]quinolin-7-yl b 4_[(2S)_tetrahydrofuran-2-ylmethoxy]benzamide; [11] a a compound or a salt thereof, which is N_(8-fluorenyl_3_丨[(2-mercaptopropyl)amino]indolyl}quinolin-7-yl)-4-[(2S)-tetrahydrofuran-2 - methoxy]benzamide; Lu [12] a compound or a salt thereof, which is trans-4-hydroxy-4-indolylcyclohexylamino)-yl}-8-fluorenyl Quinoline-7-yl)-4-[(2S)-tetrahydro-Ofol-2-ylmethoxy]benzamide; [13] a compound or a salt thereof, the compound is n-{3 -[(4-hydroxy-4-mercaptopiperidin-1-yl) a compound of the above [1] or a compound thereof, or a compound thereof, or the compound of the above item [1], or the compound of the above [1] a prodrug of a salt; 322147 14 201206909 [15] A medicament comprising the compound of the above item [1] or a salt thereof or a prodrug thereof; [8] The agent according to the above item [15], which is a melanin concentration a hormone receptor antagonist; [Π] The agent according to the above [15], which is an anorexigenic agent; [18] The agent according to the above [i5], which is prevention or treatment of obesity Agent

[19] A method for preventing or treating obesity in a mammal, comprising administering to the mammal an effective amount of the compound of the above item (1) or a salt prodrug thereof; 〃 [20] - a compound of the above item (1) or The use of the salt or its prodrug is used in the manufacture of a prophylactic or therapeutic agent for obesity; The utility of the present invention is to distinguish!! Compound (1) has a height of mch = - compared to the I know MCH reading antagonist. Anti-acting action and low toxicity such as visceral toxicity (for example, hERG inhibition activity (IV) - PLsis-evoked potential, etc. Therefore, the compound (1) is extremely suitable as a safe drug for preventing or treating obesity and the like. [Embodiment] Each symbol in the formula (1) The definitions are detailed below. Sub, in the book 'unless otherwise stated', the original core fluorine atom, gas atom, desert atom or moth atom. In this specification 'unless otherwise stated, otherwise "Cl 6 322147 15 201206909 alkyl" as used herein means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl, isopentyl, Neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-didecylbutyl, 2,2-didecylbutyl, 1,2,2-trimethylpropyl, 3, 3-dimercaptobutyl, 2-ethylbutyl, etc. In the present specification, unless otherwise stated, "C3-1 anthracenyl" used means cyclopropyl, cyclobutyl, cyclopentane. Base, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc. In this specification, unless otherwise stated, 0-6 alkoxy" means a decyloxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, etc. The methoxy group and the isopropoxy group are preferred. The ring A is a tetrahydrofuran ring which may be further substituted as needed. The "tetrahydrofuran ring" of the ring A which may be further substituted with a tetrahydrofuran ring, except for the group - Further, CH2-0- may have 1 to 4 substituents at a substitutable position. When the number of substituents is less than 2, each substituent may be the same or different. Examples of such substituents include (1) C3-i. A cycloalkyl group (for example: cyclopropyl, cyclohexyl); (2) a C6-u aryl group (for example, phenyl, naphthyl), which may optionally have 1 to 3 substituents selected from the group consisting of Substituting: (aWw alkyl, which may optionally be substituted with 1 to 3 halogen atoms, (b) trans group, (cOCw alkoxy, which may optionally be substituted with 1 to 3 halogen atoms, and (d) a halogen atom; 16 322147 201206909 (3) Aromatic heterocyclic group (for example: ° thiophene group, α-fumonyl group, ° ratio σ group, π ratio. Sit-base, σm 11-sitting group, tetra-salt group, oxime-salt group. Plug Sodium, succinyl, alpha-soxadiazole, which may optionally be substituted with one to three substituents selected from the group consisting of: (a) a CH alkyl group which may be substituted with from 1 to 3 halogen atoms as desired. (b) a hydroxy group, (OCw alkoxy, which may optionally be substituted with 1 to 3 tooth atoms, and (d) a halogen atom; (4) a non-aromatic heterocyclic group (eg tetrahydrofuranyl, morpholinyl, sulfur) Morpholine φ group (^11丨〇111〇印11〇1丨1171), 派定定, ° ratio 11 11 base, 哄 base), which may be replaced by 1 to 3 substituents selected from the following : (3) 0-6 alkyl, which may optionally be substituted with 1 to 3 halogen atoms, (b) via, (c) Ch alkoxy, which may optionally be substituted with 1 to 3 halogen atoms, and d) a halogen atom; (5) an amine group which may be mono- or disubstituted by a substituent (group) selected from the group consisting of: ® (a)CH alkyl, which may be substituted by 1 to 3 atoms, as desired. (tOG-e alkyl-carbonyl, which may optionally be substituted with 1 to 3 halogen atoms, and (c) Ch alkoxy-carbonyl, which may optionally be substituted with 1 to 3 halogen atoms; (6) 0-6 Alkyl-carbonyl, which may optionally be taken from 1 to 3 halogen atoms (7) Ch alkoxy-carbonyl, which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: 17 322147 201206909 (a) a halogen atom, and (b) a 烷6 alkoxy group; (8) Ci -e Hyun base (eg, sulfhydryl, ethyl ruthenyl, isopropylsulfonyl) can be optionally substituted with 1 to 3 atoms; (9) Amine thiol, It may be mono- or di-substituted by Cm alkyl group (the Cw-based group (group) may be substituted by 1 to 3 functional atoms as needed; (10) thiocarbamoyl, which may be used as needed Ci-6 thiol (group) mono- or di-substituted, the Ch alkyl group (group) can be substituted by 1 to 3 halogen atoms; (11) Amine sulfonyl group, which can be via Ch alkyl group Monosubstituted or double substituted 'The Cw alkyl group (group) may be substituted with 1 to 3 tooth atoms; (12) carboxyl group; (13) thiol group; (14) 匕-6 alkoxy group, which may be subjected to 1 Up to 3 substituents selected from the group consisting of: (a) a halogen atom, (b) a carboxyl group, (C) a Cl-6 alkoxy group, (d) a Cl-6 alkoxy-carbonyl group, ^ (e) an amine group , which can be selected from the group consisting of Cl-6 base and Ci-e flaming base base The substituent (group) is monosubstituted or disubstituted '(f) Ce-i4 square (e.g., stupid)' (g) C3-!. a cycloalkyl group (for example: cyclopropyl, cyclobutyl)' and (h) an aromatic heterocyclic group (for example, thienyl, furyl); 322147 201206909 (15) C2-e-glycosyloxy (eg, B) a dilute oxy group which may be substituted with 1 to 3 tooth atoms as desired; (16) Ce-u aryloxy (eg phenyloxy, naphthyloxy); (17) Ci-e alkyl - alkoxy group (for example: ethenyloxy, tert-butyloxy); """ (18) Ce-i4 aryl-alkyl (for example: benzamidine), It may optionally be substituted with 1 to 3 substituents selected from the group consisting of: (a) iii atoms, and

(b) a Ci-6 alkyl group which may optionally be n(n., which is substituted by 1 to 3 halogen atoms; (19) a non-fragrant heterocyclic carbonyl group (I^, for example, pyrrolidinylcarbonyl, Morpholinylcarbonyl, 1, dioxide, 150 yg, pt morpholinylcarbonyl), which may be substituted by 1 to 2 Ci-6 groups, read by p atom; Ll, 6 The alkyl group may be subjected to 1 to 3 halo(20) thiol groups; (21) Ci-e alkylthio group (for example, a to be substituted by i to 3 atoms; thiol, B a thiol group, which may be a thiolthio group (for example, a benzylthio group); (23) a C6-m arylthio group (for example: (10) a cyano group; a thio group, a naphthylthio group h ( 25) nitro; (26) halogen atom; (27) Ci-3 alkyl dioxy; (28) aromatic heterocyclic carbonyl (eg, isoxazolylcarbonyl, π-pyridylcarbonyl, ··pyridyl The oxazocarbonyl group, the pyridylcarbonyl group, the sinyl group) can be optionally substituted by 322147 201206909 1 to 3 Cu alkyl groups, which may be substituted by 1 to 3 tooth atoms; a hydroxyimino group which may be substituted by c, -6 alkyl (group) as desired, the Ci-6 The group (group) may optionally be substituted with 1 to 3 C6-h aryl groups (for example: phenyl); (30) Ch alkyl group, which may optionally be substituted with 1 to 3 substituents selected from: (a) Halogen, (b) carboxy, (c) thiol, (cOCm alkoxy-carbonyl, (e) Ci-6 alkoxy, (nonylamino, which may be monosubstituted by Cm alkyl (group) as desired or Disubstituted 'and (g) C3-1() cycloalkyloxy (preferably cyclopropyloxy); (31) indol-6 alkenyl (eg vinyl), which may be 1 to 3 as needed Substituted by a substituent selected from the group consisting of: (a) a halogen atom, (b) a carboxyl group, (c) a hydroxyl group, (d) a Ci-6 alkoxy group, (eKw alkoxy group, (ammonium group) Monosubstituted or doubled by Cw alkyl (group) as desired and (g) C 3-10 cycloalkyl (.. for example: cyclopropyl); 322147 20 201206909 (32) C2-6 alkynyl (eg acetylene) a group), which may optionally be substituted with 1 to 3 C3-1 anthracenecycloalkyl groups (for example: cyclopropyl, cyclobutyl); (33) 0-η aralkyl (for example: benzoinyl), which is visible It is required to be substituted with 1 to 3 substituents selected from the group consisting of: (a) a G-6 alkyl group which may optionally have 1 to 3 halogen atoms And (b) a hydroxyl group, (C) a Cl-6 alkoxy group, and (d) a halogen atom; 0 (34) a pendant oxy group; etc. The A ring is preferably a tetrahydrofuran ring, which may further be subjected to 1 to 3 as needed. Substituents selected from the group consisting of: (1) Cl-6 alkyl; (2) 0-6 alkoxy; (3) pendant oxy; The ® ring is more preferably a tetrahydrofuran ring. R1 is a hydrogen atom or a halogen atom (for example, a fluorine atom). R1 is preferably a halogen atom or a fluorine atom. R2 is a hydrogen atom, a halogen atom (for example, a fluorine atom) or an alkyl group (for example, a fluorenyl group). R2 is preferably a fluorine atom or a fluorenyl group. R3 is a hydrogen atom or a Ch alkyl group (for example, a methyl group). R3 is preferably a hydrogen atom or a methyl group. 21 322147 201206909 R4 and R5 (1) are each independently a hydrogen atom, a C!-6 alkyl group which may be substituted, a C3-1D cycloalkyl group which may be substituted, or a 5 or 6 member which may be substituted as needed. a cyclic group, or (2) may form a substituted 4 to 6 membered nitrogen-containing heterocyclic ring together with an adjacent nitrogen atom, but the restriction is that when one of R4 and R5 is a hydrogen atom, the other is not The group shown: H ' wherein X1 is a bond or C!-6 alkyl; and RA1 is a group of the formula: -YS(0)ml-RB1, wherein Y is a bond or NH; ml is an integer of 1 or 2; and RB1 is a G-6 alkyl group which may be substituted with 1 to 3 halogen atoms, or a cyclic group represented by the following formula:

Wherein m2, m3, m4, nl, n2 and n3 are each independently an integer of 1 or 2; and RB2 is optionally substituted by 1 to 3 halogen atoms (^-6 alkyl group (the ring portion of the cyclic group) Further substituted as needed.) The "Cw alkyl group" of the "C!-6 alkyl group which may be substituted as needed" of R4 or R5 is preferably a mercapto group, an ethyl group, a propyl group, an isopropyl group or an isobutyl group. Second butyl, neopentyl, 1-ethylpropyl, 1,2,2-trimercaptopropyl, etc. More preferably 22 322147 201206909 fluorenyl, isobutyl, etc. R or R5 "visual need The substituted Cw alkyl group, the "Ci 6 alkyl group may optionally have 1 to 5 (preferably 1 to 3) substituents (group) at the substitutable position. Examples of such substituents include these The tetrahydrofuran ring of the tetrahydrofuran which may be further substituted as exemplified in the items (1) to (29) may be similarly desired as the substituent. When the number of substitutions is 2 or more When appropriate, the substituents may be the same or different.

The substituent of the "Ci ealkyl group which may be optionally substituted by R4 or R5" is preferably a functional atom, a hydroxyl group, a Cl_e alkoxy group, a G~cycloalkyl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. More preferably, it is preferably a hydroxy group, a Ci 6 alkoxy group (e.g., methoxy group, isopropoxy group) or a 5- or 6 membered oxygen-containing heterocyclic group (e.g., tetrahydrofurfuryl, tetrahydropyranyl). As a substituent of R4 or R5, which may be substituted by one of the filaments, "5 "6-membered oxygen-containing heterocyclic group, examples include 5 or 6 members containing a cyclic group - which contains in addition to carbon atoms" At least one oxygen atom is used as a ring constituent atom, and may further include 1 to 3 hetero atoms selected from an oxygen atom, a furnace atom and a nitrogen atom as needed. 疋5 or "oxygen heterocyclic group, a clear example package Such as: 2 orders South base, 3 orders South base), sitting base (for example: 2 brother sitting on the base soil, (column 'sitting base, 5_· base), different drinking saliva, halophilic (such as .1 soil f Γ5-yl, 1,3,4, 朴 )), four gas base (for example: 虱吱: Nanji, 3-tetrahydrocampyl), sent shouting (for example: 2 "Chen. South Earth), tetrahydropyranyl (for example · 4_tetrahydropyranyl), N-Nipyl), morpholinyl (for example: 2,5-dihydro-azole: base (Example 2: 322147 23 201206909 Dihydroanthracene-3-yl) ), biting base (for example: 曙β sitting bite - 3- λ 迅), dihydro oxadiazolyl (for example: 4, 5-dihydro-1,2, 4-Pf diazol-3-yl) More preferably, it is tetrahydro-sulphuryl, tetrahydropyranyl, etc. R4 or R5 "may be substituted with a Cl_e alkyl group, preferably [η alkyl group (for example: fluorenyl group, ethyl group) , propyl, isopropyl, butyl, isobutyl, first butyl, second butyl, pentyl, neopentyl, 1-ethylpropyl, 1 2 trimethylpropyl), visible It is required to be substituted with 1 to 3 substituents selected from the group consisting of: '(1) a functional atom (for example, a fluorine atom); (2) a hydroxyl group; (3) (^-6 alkoxy group (for example, alkoxy group, different) (4) C3-h cycloalkyl (eg, cyclopropyl, cyclohexyl), which may optionally be substituted with i to 3 substituents selected from the group consisting of a thiol group and a Ci-e alkyl group; 4 to 6 members of an oxygen-containing heterocyclic group (for example, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl) C!-6 alkyl (group) (for example: methyl) substitution; (6) Amine 'which may be mono- or di-substituted with a substituent (group) selected from: (a) Ci-6 alkyl , which may optionally be substituted with 1 to 3 tooth atoms, (b) Ci-e alkyl-carbonyl (eg methylcarbonyl, ethylcarbonyl), which may be substituted with 1 to 3 halogen atoms as desired, (c) Ci-e alkoxy-carbonyl (eg methoxycarbonyl, ethoxy)] which may optionally be substituted with 1 to 3 tooth atoms, (d) an amine carbenyl group, which may optionally be C, -6 Alkyl (group) monosubstituted or double 24 322147 201206909 C 卜 6 : generation (eg methylamine methyl, ethylamine methyl thiol), the group (group) can be replaced by i to 3 - atom, optionally And (e) a mercapto group; a halogen atom substituted; etc., (7) a Ci-e alkyl-carbonyl group which can be optionally subjected to the same. R4 or R5 "can be replaced by the need to 俨 its an. Tian Gan w-6 play 丞文佳 for Cl_6

: group (eg. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, first butyl, tert-butyl, pentyl, neopentyl, 1-ethylpropyl, i 2 2 = propyl) ' It may optionally take 1 to 3 substituents selected from the group consisting of (1) a halogen atom (for example, a fluorine atom); (2) a hydroxyl group; (3) a Cl-6 alkoxy group ( For example: methoxy, isopropoxy); (4) C3-h) cycloalkyl (for example: cyclopropyl, 5 Q ^ ^ ^ hexyl), which may be selected from 1 to 3 Substituted substituents: (5) 4 to 6 members of an oxygen-containing heterocyclic group (for example, oxetanyl, tetrahydroanthranyl, fluorenyl), which can be used as needed For example: methyl) substitution; R or R can be substituted for the k-ring group, the "C (a). Cycloalkyl group" is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a diamond Alkyl and the like. More preferably, it is a cyclohexyl group or the like. The substituents of "C3, cycloalkyl" which may be substituted by G i. cycloalkyl, include the "tetrahydrofuran ring which can be further replaced by 322147 25 201206909" with the ring A. The tetrahydrofuran ring may have similar substituents as desired. The substituent of the cycloalkyl group is preferably a tooth atom, an interesting group, a Cl-6 alkyl group, a Cl, a 6 alkoxy group, etc. More preferably a trans group, a methyl group or the like. The "Ci-e cycloalkyl group" can be used in The substitutable position has 1 to 5, preferably 1 to 3 'more preferably 1 or 2 substituents. When the number of substituents is two or more, the substituents may be the same or different. The R or R may optionally be substituted by a C3-id cycloalkyl group, preferably a C3-1D cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl) It may optionally be substituted with 1 to 3 substituents selected from the group consisting of: (1) a tooth atom (eg, a fluorine atom); (2) a hydroxyl group; (3) a (^-6 alkoxy group (eg, a decyloxy group, (4) C!-6 alkyl (eg, fluorenyl); (5) an amine group which may be mono- or di-substituted with a substituent (group) selected from: (a) a Ci-6 alkyl group which may optionally be substituted with 1 to 3 halogen atoms, (b) a Ci-e alkyl-carbonyl group (for example, a mercaptocarbonyl group, an ethylcarbonyl group) which may optionally have 1 to 3 halogen atoms. Substituted, (cX!-6 alkoxy-carbonyl (eg methoxycarbonyl, Oxycarbonyl), which may optionally be substituted with from 1 to 3 dentate atoms, (d) an amine fluorenyl group which may be mono- or di-substituted with a Cl-6 alkyl group as desired (eg, mercaptoamine oxime) Base, ethylamine fluorenyl), the Ch alkyl group can be substituted with 1 to 3 halogen atoms, and (e) fluorenyl; 26 322147 201206909 (6) pendant oxy; et al. R4 or R5 "may be substituted with a cycloalkyl group, more preferably a Cho cycloalkyl group (for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl)" Up to 3 substituents selected from the group consisting of: (1) hydroxy; & '(2) Cl-6 alkyl (eg methyl); etc., etc. R4 or R5 "may be substituted 5 or 6 a heterocyclic group, or a 6-membered heterocyclic group" is a 5- or 6-membered aromatic heterocyclic group, a 5- or 6-membered non-fragrant heterocyclic group, etc. "5 or 6 membered aromatic heterocyclic group, Examples include a 5- or 6-membered aromatic heterocyclic group which contains, in addition to a carbon atom, 1 to 4 kinds of impurities selected from an oxygen atom, a sulfur atom (oxidation), and a nitrogen material as particles into atoms;

Specific examples of the 5- or 6-membered aromatic heterocyclic group include a screaming group (for example, 2-furanyl, 3,thenyl), a succinyl group (for example, 2-thinyl, 3-nonyl), A bite base (for example: 2 a bite base, 3 kiss base, 4_σ ratio bite base) "mididine group (for example: 2 odd base, 4 tone base, 5 + fixative), tamarind (for example, 3-3 Pentyl, 4-cyanoyl), pyridinyl (for example: 2_pyrroxy), pyridyl (for example: bupoliki, 2-base, 3 kiss), sputum ( For example, bume sulphate, 2-midenyl, 4-sodium sulphate, 5-s-salt group, π-wow group (for example, babi-salt, 3_π-wowyl, 4_n-saltyl) Base (eg, stagnation, 4-indolyl, 5-saltyl), isoindolyl (eg, 4_iso 322147 27 201206909 (eg, s, "B, 5, oxazolyl", A heterosexuality is 0, such as 基, 卩, etc. (example ί,, 5, base, m =: 12 _ base, beauty (gast like A 3 'three saliva - 2 - base, h 2, 3 ~ three saliva, 4-base), tetrazole*tetraki-one-based, tetra-anthracepin-5-yl), triterpene (for example: 1,2,4-well-'buji, 1,2, triterpene l 3,5-trisyl]-yl), or 6 beifang, a heterocyclic group, and examples of which include an aromatic heterocyclic group, which in addition to a carbon atom, also includes a sulfur atom (which A hetero atom which may be oxidized and a nitrogen atom is used as a ring constituent atom; etc. Specific examples of the 5- or 6-membered non-aromatic heterocyclic group include a tetrahydrofuranyl group (for example, .2-tetrahydrofuranyl group), a dihydropyrrolyl group (for example, 2) , 3-dihydro-1H-pyridyl, pyrrolidinyl (for example: 1-pyrrolidinyl), 1, dioxin _ tetrahydro phenyl (for example, · · i, dioxin_tetrahydro _ 3 嗟 基 )), 唆 唆 (for example, N-piperidinyl), morpholinyl (for example: N _ morpholinyl), thiomorpholinyl (for example, N-thiomorpholinyl), hydrazine, Dioxalate-thiomorpholinyl (for example: 1, dioxo-N-thiomorpholinyl), piperidinyl (for example: piperidinyl), hexamethyleneiminyi (for example: Hexamethyleneimine-diyl), oxazoline group (eg, 2,5-dihydrocarbazole-3-yl, 3,4-dihydrocarbazol-3-yl), thiazolinyl (eg : 2, 5_dihydrothiazole _3_yl, 3, 4-dihydrothiazol-3-yl , imidazolinyl (for example: 2-imidazolyl-3-yl), oxazolidinyl (for example: oxazolidin-3-yl), thiazolidinyl (for example: thiazolidine-3-yl), imidazolidinyl Base (for example: imidazolidinyl-3-yl), dioxolyl (for example: 322147 28 201206909 1, 1, 3-dioxole-4), dioxocyclopentyl (eg:丨, 3_dioxocyclopent-4-yl), dihydrooxadiazolyl (for example: 4,5-dihydrogen as -oxadiazol-3-yl), thioketooxazolidinyl (thi 〇x〇〇xaz〇Hdinyi) (example: 2_

Thiol-yl-1,3-line-5-yl), tetrahydro(tetra)yl (eg 4-tetrachloropyranyl), tetrahydr〇thi〇pyranyi (eg: one or four) Hydrogen-sulfur bridging base, 1, di-oxidized-tetrahydrosulfanyl π-nanyl (for example: hydrazine, dihydrogen-tetrahydrothiopyran-4-yl), pyrazolinyl (eg pyrazoline _ 3_ base)., Pixian (for example, 4 money + base), pendant oxytetrahydropin (for example, .3-sideoxy-2,3,4,5-tetrahydroindole 4-yl) and the like. The R or R may be substituted with a 5 or 6 membered heterocyclic group, and the "5 or 6^ heterocyclic group, preferably a tetrahydrocarbyl group, a tetrahydrogen group, etc. Substituents for substituted 5 or 6 membered heterocyclic groups, % or 6 membered heterocyclic groups include "tetrahydrofuran ring which can be optionally substituted with A ring" & The sigma- orthocyclic ring may be similar to those having a 2-substituent. The "5 or 6-membered heterocyclic group" preferably has a substituent of a tooth atom, a meridine group, a k-yard group, an α-hydroxy group, and the like. Better, methyl, etc. ▲ 5 or 6 membered heterocyclic group may have 丨 to 5 (preferably 1 or 2) substituents at a substitutable position. When the number of substituents is two or more, 'each substituent may be the same Or a different R. 5 or a 6 member 6 heterocyclic group, preferably a 5 or 6 membered heterocyclic group (for example, a tetrahydroanthine group, a tetrahydronephrine group), It may be substituted with 1 to 3 substituents selected from the following: , (1) a halogen atom; 322147 29 201206909 (2) a hydroxyl group; (3) a Cl-6 alkyl group (for example, a fluorenyl group); (4) (^ -6 alkoxy; etc., etc. The "5 or 6 membered heterocyclic group which may be optionally substituted" of R4 or R5 is more preferably a 5- or 6-membered heterocyclic group (for example: tetrahydrogenated D-substrate, tetrahydrogen) σ 南 基 ) ) 。 。 。 R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R A 4- to 6-membered nitrogen-containing heterocyclic ring containing at least one nitrogen atom as a ring constituent atom and optionally further containing 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Clear instance package Pyrrolidine, imidazoline, σ米嗤 bite, α than β sitbit, υ 唾 唾 、 α, α bottom β 定, travel, three β sit 琳, υ than mouth each, ° ratio. Sitting, taste ° sit, three Salivary, nitrogen, dihydrogen 11 pir, dihydro π ratio β sitting, dihydroimidazole, dihydrothiazole, tetrahydropyridine, etc. Preferably, pyrrolidine, piperidine, piperene, etc. R4 and R5 and adjacent Examples of the substituent of the "4 to 6 member nitrogen-containing heterocyclic ring" of the "substituted 4- to 6-membered nitrogen-containing heterocyclic ring" formed by the nitrogen atom together include the "tetrahydrofuran ring which may be further substituted as needed" with the anthracene ring. The "tetrahydrofuran ring" may optionally have a substituent. The substituent of the "4 to 6 member nitrogen-containing heterocyclic ring" is preferably a halogen atom, a hydroxyl group, a Cw alkyl group, a Cm alkoxy group, etc. More preferably, it is a hydroxyl group.曱基等, etc. "4 to 6 member nitrogen-containing heterocyclic ring" may have 1 to 5 (preferably 1 or 2) substituents at a substitutable position. When the number of substituents is two or 30 322147 201206909 When plural, the substituents may be the same or different. The "substituted 4- to 6-membered nitrogen-containing heterocyclic ring" formed by R and R and the adjacent nitrogen atom is preferably 4 to 6 members of nitrogen. Rings (eg, piroxime, morphine) can be optionally substituted with i to 3 substituents selected from the group consisting of: (1) halogen atoms; (2) hydroxyl groups; (3) a group (for example, methyl); (4) a Cl-6 alkoxy group; a #(5)amino group which may be mono- or disubstituted with a substituent (group) selected from the group consisting of: (a) a CM alkyl group, It may optionally be substituted with three self-atoms, (b) Ci-e alkyl-based (eg methyl | ε, ethyl), which may be substituted with 1 to 3 halogen atoms as desired. (c) Cm alkoxy-carbonyl (for example: methoxycarbonyl, ethoxycarbonyl), which may optionally be substituted with 1 to 3 halogen atoms, (d) an amine formazan group, which may optionally be subjected to alkane The group (group) is mono- or di-substituted (for example: methylamine sulfhydryl, ethylamine sulfhydryl), and the 匕6 alkyl group (group) may be substituted with 1 to 3 halogen atoms as needed, & (e ) a thiol group; (6) a pendant oxy group; etc., etc. R4 and R5 together with an adjacent nitrogen atom form a "substituted 4- to 6-membered nitrogen-containing heterocyclic ring" more preferably a 4- to 6-membered nitrogen-containing heterocyclic ring substituted by a hydroxyl group (preferably via a hydroxyl group) Substituting a 5- or 6-membered nitrogen-containing heterocyclic ring (e.g., piperidine), 322147 31 201206909 may be substituted with a Ci-6 alkyl group (e.g., fluorenyl) or the like as needed. Preferably, 1) R4 and R5 are independently (1) a hydrogen atom, and (2) a G-6 alkyl group (e.g., anthracenyl, ethyl, propyl, isopropyl, butyl, isobutyl, Dibutyl, tert-butyl, pentyl 'neopentyl, 1-ethylpropyl, 1,2,2-trimercaptopropyl), which may optionally have 1 to 3 substituents selected from the group consisting of Substitution: (a) a halogen atom (for example, a fluorine atom)' (b) a light group, (cOCw alkoxy group (for example, methoxy group, isopropoxy group), (d) a C3-ie cycloalkyl group (for example: Cyclopropyl, cyclohexyl), which may optionally be substituted with 1 to 3 substituents selected from hydroxy and Cm alkyl groups, (e) 4 to 6 membered oxygen-containing heterocyclic groups (eg, oxetanyl, tetra Argon ti-bromo, tetrahydropyranyl), which may optionally be substituted by Cw alkyl (group) (for example: methyl), (1) amine 'which may optionally be substituted by a substituent (group) selected from the following Or double-substituted: (i) C-Bu 6-alkyl group which can be replaced by 1 5 kings and 3 atoms _ atoms (ii) Ci-6 alkyl-carbonyl groups (eg, A-Ar-based, ethyl-based), It may optionally be substituted by 1 to 3 South atoms (iii) C a 6 alkoxy-carbonyl (eg : , # , ^ ^oxycarbonyl, ethoxylated) ' can be optionally substituted with 1 to 3 _, (iv) amine carbaryl, which can optionally be 蟑Γ & Cl-6 alkyl ( Group) monosubstituted 322147 32 201206909 or double substituted (eg methylamine methyl, ethylamine), the Cm alkyl group (group) can be replaced by j3 tooth atoms, and (v) formazan And (g) Ci-e alkyl-carbonyl 'is visible cloud i (3) "cyclosyl (for example: ring internal, ^ to 3 tooth atom substitution, adamantyl), which may optionally be cyclopentane a group, a cyclohexyl group, (4) a halogen atom: a gas atom) substituted with a substituent selected from the group consisting of: (b) a hydroxyl group, (C) a Ci-e alkoxy group (for example: a methylidene t-milk, a isopropyl group) (d) a Ci-e alkyl group (for example, a fluorenyl group), (e) an amine group which may optionally be substituted by a substituent (group) selected from or substituted by a double group: (i) Depending on the need, (ii) CH alkyl-carbonyl (for example: methylamino = one tooth atom substitution, which may optionally be 1 to 3 atoms = base, ethyl carbonyl), (iii) CH alkoxy group (eg: 曱, ,, carbonyl), which can be viewed as needed q Soil carbon-based, ethoxy (five) amine A with a base, which may be required to be two, atomically substituted, " several through CN6 pi, or double substitution (for example: methylamine carbaryl (group) monosubstituted 啰丞,乙其ΒΑ The C 卜6 alkyl group (group) can be used to relax the carbaryl group, and,,, to three tooth atom substitutions, (ν) formazan, and (f) pendant oxy group, 322147 33 201206909 (4) A 5- or 6-membered heterocyclic group (for example, tetrahydrofuranyl, tetrahydropyranyl), which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) halogen Atom, (b) hydroxy, (C%-6 alkyl (eg, fluorenyl), and ((DCh alkoxy, etc., or 2) R4 and R5 with adjacent nitrogen atoms ~ form 4 to 6 members Nitrogen-containing heterocycle (for example: ° ratio (four),. (4), Tourism), which may be substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atom, (2) hydroxyl group, (3) (^-6 alkyl group (eg thiol group), ( 4) Cl-6, an amine group, (5) an amine group which may be mono- or disubstituted by a substituent (group) selected from the group consisting of: (a) ^-6 alkyl group, which may be subjected to hydrazine to 3 as needed Substituted by a halogen atom, (b) C!-6 alkyl-carbonyl (eg methylcarbonyl, ethylcarbonyl) which may optionally be substituted with 1 to 3 halogen atoms, (c) C!-6 alkoxy a carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) which may optionally be substituted with 1 to 3 South atoms, (d) an amine sulfhydryl group which may be monosubstituted by a Ci 6 building group (group) as needed Disubstituted (for example: methylamine carbaryl, ethylamino fluorenyl), the Cl-6 leuko group (group) may be substituted with 1 to 3 halogen atoms, and 322147 34 201206909 (e) fluorenyl And (6) a pendant oxy group, etc. More preferably, 1) R4 and R5 are independently (1) a hydrogen atom, and (2) a Ch alkyl group (e.g., anthracenyl, ethyl, propyl, isopropyl , butyl, isobutyl, t-butyl, tert-butyl, pentyl Neopentyl, ethylidene, decyl 1,2,2-trimercaptopropyl), which may optionally be substituted with from i to 3 substituents selected from the group consisting of: (a) a halogen atom (eg, a fluorine atom), b) thiol, (cOC!-6 alkoxy (eg methoxy, isopropoxy), (d) C3, cycloalkyl (eg cyclopropyl, cyclohexyl), as needed to 3 Substituted for substituents selected from the group consisting of a base and a Ci base, and

(e) 4 to 6 members containing gas ^ ', clothing (eg oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), optionally via Cl-β (group) (eg T group) Substituted, (3) C3-l〇 cycloalkyl (for example: di-glycolylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, orthoke), which can be visualized by one or three Substituted from the following substituents: (a) hydroxyl and (b) Ci-e base (eg, methyl), (4) 5 or 6 membered heterocyclic (example '.β, a, 』, eg, 虱It is optionally substituted by the following substituents from 1 to 3 courses: 35 322147 201206909 (i) Hydroxy, and (iOCw alkyl (eg:曱基), etc., or 2) R4 and R5 together with an adjacent nitrogen atom form a 4 to 6 member nitrogen-containing heterocyclic ring substituted by a hydroxy group (preferably substituted by a hydroxyl group (group) 5 or 6 members A nitrogen-containing heterocycle (e.g., pyridine) can be optionally substituted with Ci-6 alkyl (group) (e.g., methyl), and the like. Still preferably, φ R4 is (1) Ci-6 alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, first butyl, second butyl, pentyl) The group, neopentyl, 1-ethylpropyl, 1,2,2-trimethylpropyl)' may be optionally substituted with 1 to 3 substituents selected from the group consisting of: (i) a halogen atom (eg, • fluorine atom), (ii) trans group, (iii) Ci-e alkoxy (eg methoxy, isopropoxy), _ (iv) C3-u> cycloalkyl (eg cyclopropyl) , cyclohexyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of a thiol and a hexyl group, and (v) 4 to 6 members of an oxygen-containing heterocyclic group (for example, oxetanyl, Tetrahydrocarbyl, tetrahydropyranyl), which may optionally be substituted by Cm alkyl (group) (eg methyl), (2) C3-1D cycloalkyl (eg · cyclopropyl, cyclobutane) A group, a cyclopentyl group, a cyclohexyl group, an adamantyl group) can be optionally substituted with 1 to 3 substituents selected from the group consisting of: 322147 36 201206909 (i) a carboxyl group, and (ii) a Ci-6 alkyl group (eg: Sulfhydryl), or (3) 5 or 6 beta heterocyclyl (eg tetrahydrofuranyl, tetrahydropyranyl) And it may be substituted with 1 to 3 substituents selected from the group consisting of: (i) a thiol group, and (ii) a Ci-e phenyl group (e.g., a methyl group); and R5 is a hydrogen atom. Particularly preferably, • R4 is (DCh alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, neopentyl) , ethyl ethyl propyl 1 '2, 2-trimethyl propyl), which may optionally be substituted with up to 3 substituents selected from the group consisting of: (a) hydroxy, (b) Cl_6 alkoxy (eg, a Oxyl, isopropoxy), and (c) 5 or 6 membered oxygen-containing heterocyclic groups (eg, tetrahydrofuranyl, tetrahydropyranyl), or (2) C3-1Q cycloalkyl (eg, ring) a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) a thiol group, and (b) a Ci-6 alkyl group. (e.g., methyl); and R5 is a chlorine atom. 4 Further, in another preferred embodiment of R and R5, R and R form an alkyl group (group) with an adjacent nitrogen atom. Substituted 4 to 6 322147 37 201206909 A nitrogen-containing heterocycle (preferably a 5- or 6-membered nitrogen-containing heterocycle (eg, piperidine) substituted with a hydroxy group (group)), which may optionally be Cw alkyl (group) (eg: thiol) substituted. About compound (I The following compounds are preferred. [Compound A1] The compound (I) wherein the ring A is a tetrahydrofuran ring, which may be further substituted with 1 to 3 substituents selected from the group consisting of: (i) α6 alkyl, ( 2) 〇6 alkoxy group, and (3) pendant oxy group; R1 is a hydrogen atom or a halogen atom; R2 is a hydrogen atom, a halogen atom or a Cw alkyl group; R3 is a hydrogen atom or a Cl-6 alkyl group; and R4 is R5 is 1) independently of (1) a hydrogen atom, and (2) an anthracene-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, Tributyl, pentyl, neopentyl, 1-ethylpropyl, 1,2,2-trimercaptopropyl), which may optionally be substituted with from 1 to 3 substituents selected from: (a) a halogen atom (for example, a fluorine atom), (b) a hydroxyl group, (cOC^alkoxy group (e.g., decyloxy group, isopropoxy group), 38 322147 201206909 (d) C3-i. A cycloalkyl group (for example, a ring) a propyl group, a cyclohexyl group, which may optionally be substituted with 1 to 3 substituents selected from a hydroxyl group and a Ci-6 alkyl group, (e) 4 to 6 moles per gram of per group (for example: oxetanyl, Tetrahydro-sulphur-based, tetrahydro-snap, and its visual needs Substituting a 'C-alkyl group (eg, methyl group) for the '(f) amine group, which may be mono- or di-substituted by a substituent (group) selected from the group below (DCw alkyl, which may be subjected to 1 Up to 3 dentate substitutions, • (ϋ)〇6 alkyl-carbonyl (eg methylcarbonyl, ethylcarbonyl), which may optionally be substituted with 1 to 3 halogen atoms, (iii) Ci-6 alkoxy - a carbonyl group (e.g., decyloxycarbonyl, ethoxycarbonyl) which may optionally be substituted with 1 to 3 halogen atoms, (iv) an amine carbenyl group which may optionally be substituted by a G-6 alkyl group Or disubstituted (for example: mercaptocarbamyl, ethylamine sulfhydryl), the Ci-e pit group (group) may be substituted with 1 to 3 halogen atoms, and • (V) fluorenyl group, And (g) Ci-e alkyl-carbonyl 'which may optionally be substituted with 1 to 3 halogen atoms, (3) C3-!. A cycloalkyl group (for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl) which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom (for example: Fluorine atom), (b) trans group, (dCw alkoxy (eg methoxy, isopropoxy), (d) Ci-e alkyl (eg methyl), 39 322147 201206909 (e) amine a group which may be mono- or disubstituted by a substituent (group) selected from the group consisting of: (i) Ci-6 leuko, which may be substituted by 1 to 3 halogen atoms as desired (iUCualkyl-carbonyl (for example) : mercaptocarbonyl, ethylcarbonyl)' may be substituted by 1 to 3 tooth atoms as needed (iii) Ci-e alkoxy group (eg, methoxycarbonyl, ethoxycarbonyl), It may optionally be substituted with 1 to 3 i atoms, (iv) an amine sulfhydryl group which may be mono- or di-substituted with a 匕-6 alkyl group as desired (eg, mercaptoamine, ethylamine, ethylamine) The fluorenyl group, the Cl-6 alkyl group (group) may be optionally substituted with 1 to 3 halogen atoms, and (V) anthracenyl group and (fluorenyloxy group, or (4) 5 or 6 membered heterocyclic ring. Base (eg tetrahydrofuranyl, tetrahydrogen)喃 )), which may be substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom, (b) a mesogenic group, (C) a C1-6 alkyl group (eg, a methyl group) and (OCh alkoxy, or 2) R4 and R5 together with an adjacent nitrogen atom form a 4 to 6 member nitrogen-containing heterocycle (eg, pyrrolidine, piperidine, piperene), which is selected from 1 to 3 Substituted by the following substituents: (1) a functional atom; (2) a hydroxyl group; 322147 40 201206909 (3) 0-6 alkyl (eg methyl); (4) Cl-6 alkoxy, (5) an amine group It may optionally be mono- or di-substituted with a substituent (group) selected from the group consisting of: (aWH alkyl, which may optionally be substituted with 1 to 3 halogen atoms, (tOC^alkyl-carbonyl (eg, mercaptocarbonyl) , ethylcarbonyl), which may optionally be substituted with 1 to 3 halogen atoms, (C) Cl-6-oxyl-yl (eg, decyloxy, ethoxy), • as needed Substituted with 1 to 3 halogen atoms, (d) an amine carbenyl group which may be mono- or di-substituted with a G-6 alkyl group as desired (for example: methylamine thiol, ethylamine carbaryl) ), the Ch alkyl group can be visually 1 to 3 a halogen atom substituted, and (e) a decyl group, and (6) a pendant oxy group. [Compound A2] Compound (I) wherein the Ring A ring is a tetrahydro sigma ring; R1 is a ruthenium atom or a functional atom; R2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group; R3 is a hydrogen atom or a Cw alkyl group; and _R4 and R5 are each 1) independently a (1) hydrogen atom, and (2) a Cl-6 alkyl group (for example) : mercapto, ethyl, propyl, isopropyl, butyl, iso 41 322147 201206909 butyl, first butyl-butyl, pentyl, neopentyl, ethylidene, 1,2' 2- The bis-f-propyl)' can be optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom (for example, a fluorine atom), (b) a hydroxyl group (cOCw-glycation oxy group (for example, oxime) Base, isopropoxy), (d) 〇i. Alkyl (for example: cyclopropyl, cyclohexyl) which may optionally be substituted with from i to 3 substituents selected from the group consisting of It and Gi 6 (p. to heterocyclyl (eg oxetanyl) , tetrahydrofuranyl '(iv) _' can be optionally substituted by a G group (group) (for example: methyl), (1) an amine group which may be monosubstituted or doubled by a substituent (group) selected from the following Substituting: (1) 匕-6 炫基' can be replaced by i to 3 _ atoms, calcinyl-slow base (eg methyl silk, ethyl county), which may wish to be replaced by 1 to 3 _ atoms , (iii) CH alkoxy-county (eg, f-oxygen, ethane-based), which may optionally be substituted with 1 to 3 tooth atoms, (iv) amine carbaryl, which may optionally be Cw-alkane a group (group) mono- or di-substituted (eg, mercaptoamine thiol, ethyl amide thiol), the Cw group (group) may optionally be substituted with 1 to 3 halogen atoms, and (v) Thiol' and (g) Ci-e-based analyzyl' can be optionally substituted with 1 to 3 _ atoms, 322147 42 201206909 (3) C3-i〇cycloalkyl (eg cyclopropyl, cyclobutane) Base, cyclopentyl, cyclohexyl, Adamantyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom (eg, an atom), (b) a hydroxyl group, (cOCh alkoxy group (eg, methoxy, Isopropoxy), ((DCh alkyl (eg fluorenyl), (e) an amine group, which may be mono- or di-substituted with a substituent (group) selected from the following: • (i) CH alkyl , which may optionally be substituted with 1 to 3 halogen atoms, (ii) Ci-6 alkyl-based (eg, fluorenyl, ethyl), which may optionally be substituted with 1 to 3 halogen atoms, (iii) Ci-6 alkoxy-carbonyl (for example: decyloxycarbonyl, ethoxycarbonyl) which may optionally be substituted with 1 to 3 halogen atoms, (iv) amine fluorenyl, which may optionally be Cm Alkyl (group) mono- or di-substituted (for example: mercaptoamine-methyl, ethylamine sulfhydryl), the Ch alkyl group can be substituted by 1 to 3 halogen atoms, and (v a thiol group, and (f) a pendant oxy group, or (4) a 5 or 6 membered heterocyclic group (eg, tetrahydrofuranyl, tetrahydro bromo), which may optionally be selected from 1 to 3 Substituted from the following substituents: (a a halogen atom, (b) a hydroxyl group, (cOCh alkyl group (for example, fluorenyl group), and 43 322147 201206909 (cOCh alkoxy group, or 2) R4 and R5 together with an adjacent nitrogen atom form 1 to 3 4- to 6-membered nitrogen-containing heterocycles substituted with the following substituents (eg, pyrrolidine, piperidine, piperene): (1) a halogen atom; (2) a hydroxyl group; (3) (^-6 alkyl group (for example) (methyl); (4) Cl-6 alkoxy; (5) an amine group which may be mono- or di-substituted with a substituent (group) selected from the group consisting of: (aWw alkyl, which may be subjected to 1 Substituted to 3 halogen atoms, (WCm alkyl-carbonyl (eg, fluorenylcarbonyl, ethylcarbonyl), which may be substituted with 1 to 3 ii atoms, (C)Cl-6 alkoxy-rebel ( For example: an oxiranyl group, an ethoxylated group)' may optionally be substituted with 1 to 3 halogen atoms, (d) an amine fluorenyl group which may be monosubstituted by 匕-6 alkyl (group) as desired or Double substituted (for example: methylaminoindenyl, ethylamine fluorenyl), the 0-6 alkyl group (group) may be substituted by 1 to 3 ii atoms, and (e) fluorenyl, and 6) Side oxy group. [Compound A3] Compound (I) wherein ring A is a tetrahydroanion ring; R1 is a hydrogen atom or a halogen atom; 44 322147 201206909 R2 is a hydrogen atom, a halogen atom or a C!-6 alkyl group; R is a gas atom or Cl-6 alkyl; and R4 and R5 are 1) independently (1) a hydrogen atom, and (2) a Ci-s alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, iso) Butyl, t-butyl, tert-butyl, pentyl, neopentyl, 丨-ethylpropyl, 1' 2, 2-trimercaptopropyl), which may optionally be cleaved to 3 selected from 3 The following substituents are substituted: (a) a halogen atom (for example, a fluorine atom), (b) a hydroxyl group, (C) a Ci-6 alkoxy group (for example, a methoxy group, an isopropoxy group), (d) C3...cycloalkyl (for example: cyclopropyl, cyclohexyl), which may optionally be substituted with 1 to 3 substituents selected from woven and L-filaments, and (e) 4 to 6 membered oxygen-containing heterocyclic groups (for example) : Oxygen heterocyclic T group, tetrahydroanthracene

Substituted, tetrahydropyranyl) ' can be replaced by c 6 groups (for example: methyl), (3) C3_10 cyclos (for example: net and its y. propyl, butyl a group, a cyclopentyl group, a cyclohexyl-hydroxyalkyl group), which may optionally have a silky chain I, and, for example, 1 to 3 substituents selected from the group consisting of f (a) a hydroxyl group, and (b) a Ci-6 alkyl group ( For example: methyl), or (4) 5 or 6 membered heterocyclic groups (such as · 2, and R5 with an adjacent nitrogen atom tetrahydro (tetra)), or 6 members of the nitrogen-containing frequency pulse _) 2 The 4th to the acyl group) can be replaced by a Cl_6 alkyl group (such as 322147 45 201206909 such as methyl) as needed. [Compound B1] The compound (I) wherein the ring A is a tetrahydrofuran ring; R is a hydrogen atom or a fluorine atom; R is a fluorine atom or a fluorenyl group; R is a hydrogen atom or a methyl group; and R4 is a (1) C»-6 alkane. Base (for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, neopentyl, ethylidene: U'2' Methyl propyl) ' can be optionally substituted with 1 to 3 substituents selected from the group consisting of: (i) a halogen atom (for example: a fluorine atom), a (hydroxy) hydroxyl group, (liDG-6 alkoxy group (for example: A Oxyl, isopropoxy),

(iv) a C3-ltl cycloalkyl group (e.g., cyclopropyl, cyclohexyl), which may optionally be substituted with 1 to 3 substituents selected from the group consisting of a trans group and an L group, and (v) 4 to 6 members. Oxyheterocyclyl (eg, oxetanyl, tetrahydronyl, tetrahydropyranyl), which may optionally be substituted by Ci ealkyl (group) (eg, thiol), (2) (: a cycloalkyl group (for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexademantyl)] which may optionally be subjected to 3 (i) hydroxyl groups, and 3 substituents selected from the group consisting of: (ii) Ci-e alkyl (eg methyl), or 322147 46 201206909 (3) 5- or 6-membered heterocyclyl (eg tetrahydrofuranyl, tetrahydropyranyl), which may optionally be 1 to 3 Substituted by a substituent selected from the group consisting of: (i) a thiol group, and (ii) a Ci-e alkyl group (for example, a methyl group); and R5 is a hydrogen atom. [Compound C1] Compound (I) wherein A ring is Tetrahydrofuran ring; Φ R is a hydrogen atom or a fluorine atom; R is a fluorine atom or a methyl group; R is a hydrogen atom or a methyl group; R4 is

Substituted: (i) thiol, (ii) Ci-6 alkoxy (eg ethyl, propyl, isopropyl, butyl, iso-, pentyl, neopentyl, 1-ethylpropenyl) a group of 1 to 3 selected from the group consisting of the following: oximeoxy, isopropoxy), and (11. 5 or 6 members of an oxygen-containing heterocyclic group (for example, tetrahydrofuranyl, tetrahydropyran 11 ortho), or

(i) a hydroxyl group, and a methyl group; and (ii) a Ci-e alkyl group (for example, 47 322147 201206909 R5 is a hydrogen atom. [Compound C2] Compound (I) wherein the ring A is a tetrahydroanion ring; Is a hydrogen atom or a fluorine atom; R23 is a deficient atom or a methyl group (preferably a fluorenyl group); ^ is a quinone 5 atom or a methyl group (preferably a hydrogen atom); and is formed with an adjacent nitrogen atom. Substituent (group) substitution of 5 or 6 members of 3 aza (eg, Niang bite), which may be substituted by 6 alkyl groups (eg, methyl groups) as needed. [Compound D] [(3-{[ (2-hydroxy-2-mercaptopropyl)amino]indenyl}_8_decylquinoline__7_yl)-4-(tetrahydrofurazan-3-yloxy)benzamide or Salt. N {8-mercapto-3-[(tetrahydro-2H-0- bottom 0-alkyl-4-ylamino)indolyl]phosphonium-7-yl} _4-(tetrahydrofuran-3-yloxy) Phenylamine or a salt thereof. (3-{[(trans-4-hydroxycyclohexyl))amino]indolyl}-8-mercaptoquinolin-7-yl)-4-(tetrahydrofuran-3- Benzyloxy)benzamide or a salt thereof. Lu N^3-[(cyclopentylamino)methyl]-8-methylquinolin-7-yl}-4_(tetrahydrofuran-3-ylindole Oxy)benzamide or a salt thereof. Ν_[8- 3-({[(2R)-tetrahydrofuran-2-ylmethyl]amino}methyl)quinolin-7-yl]-4-[(2R)-tetrahydrofuran-2-ylmethoxy]benzene Guanamine or its rr/te

Bp Ο Ν_{3-[(cyclopentylamino)indolyl]-8-methylquinolin-7-ylbu 4-[(2R)_tetrahydrofuran-2-yloxy]benzamide or Its salt. 48 322147 201206909 卜(3-{[(2, 2-Dimethylpropyl)amino]methyl b-8-methylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-yl Methoxy]benzamide or a salt thereof. N-[8-Methyl-3-({[(2R)-tetrahydrofuran-2-ylindenyl]amino}indolyl)quinolin-7-yl]-4-[(2S)-tetrahydrofuran-2- Alkyloxy]phenylguanamine or a salt thereof. N-(3-{[(2-hydroxy-2-methylpropyl)amino]methyl b-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-yl Oxy]benzamide or a salt thereof. N-[8-fluorenyl-3-({[(2S)-tetrahydrofuran-2-ylindolyl]amino hydrazinylmethyl) quinal _7-yl]-4-[(2S)-tetrahydrobitate Ory-2-yloxylphenylamine or a salt thereof. N-(3-{[(2-曱oxy-2-methylpropyl)amino]indolyl}_8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2- Methoxy] carbamide or a salt thereof. N-{8-mercapto-3-[(tetrahydro-2H-piperidin-4-ylamino)indolyl]quinoline-7-yl}-4-[(2S)-tetrahydrofuran-2 - hydrazinyl] benzoguanamine or a salt thereof. N-(8-Mercapto-3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]indolylquinolin-7-yl)-4-[(2S)-tetrahydrofuran- 2-Based oxime] benzoate or its stomach sputum.

JWU N-(8-fluorenyl-3-{[(tetrahydro-2H-piperazin-4-ylindenyl)amino]indolylquinolin-7-yl)-4-[(2R)-tetra Hydrogen oxime-2-ylmethoxy]benzamide or its salt 0 N-[8-fluorenyl-3-({[(3-indolyl oxetan-3-yl)methyl]amine)丨曱 )) 啥 -7-7-yl]-4-[(2S)-tetrahydro-2-ylmethoxy]benzoquinone or a salt thereof. N-{3-[(ethylamino)indolyl]_8-fluorenylquinoline-7-yl}_4_[(2S)-four 322147 49 201206909 Hydrofuran-2-yl decyloxy] alum Or its salt. N-{3-[(cyclopentylamino)indolyl]-8-fluorenylquinolin-7-yl}_4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide or its salt. N-(3-{[(cyclopropylindenyl)amino]indolyl}-8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-yldecyloxy]benzene Indoleamine or a salt thereof. N-(8-Mercapto-3-{[(2-mercaptopropyl)amino]indolylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy] Phenylamine or a salt thereof. ^(3-{[(2,2-Dimercaptopropyl)amino]indolyl}-8-decylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylindole Benzoylamine or a salt thereof. · N-(3-{[(trans-4-hydroxycyclohexyl)amino]methyl b 8-methylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-ylmethoxy Benzobenzamide or a salt thereof. N_[3_({[(1-hydroxycyclohexyl)decyl)amino)methyl)_8-decylquinolin-7-yl]-4-[(2S)-tetrahydrofuran-2-ylmethoxy] Phenylamine or a salt thereof. N-(3-{[(5-Hydroxytricyclo[3.3.1.13'7]癸_2_yl)amino]indenyl}_8_methylquinolin-7-yl)-4-(tetrahydrofuran-2- Alkyloxy)phenylguanamine or a salt thereof. Ν'-Methyl I({[2_(b-methylethoxy)ethyl)amino}methyl) 啥 ···············~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Or its salt. Bu(3~{[(3~hydroxytricyclo[3·3. 1.13'7]癸-1-yl)amino]methyl}-8-methyl hydrazine '7-yl) '4-(tetrahydrogen) Ory-2-yloxy)benzamide or j: salt. /, ^ {Methyl-3-[(propylamino)methyl]quinoxa-7-yl}-4-[(28)-tetrahydrofuranylmethoxy]benzamide or a salt thereof. tUKU(lR,2R)-2-hydroxycyclohexyl]aminopurine methyl)-octamethylquinoline 322147 50 201206909 -7-yl]-4-[(2S)-tetrahydrofuran-2-ylmethoxy Benzoguanamine or a salt thereof. -U[(1S,2S)-2-hydroxycyclohexyl]aminoindenyl)-8-mercaptoquinolin-7-yl]-4-[(2S)-tetrahydrofuran-2-ylmethoxy] Benzylamine or a salt thereof. N-(3-{[(trans-4-hydroxycyclohexyl))amino]indolyl 8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-yloxyl Benzoguanamine or a salt thereof. N-[8-Mercapto-3-({[2-(1-methylethoxy)ethyl]aminoindolyl)quinolin-7-yl]-4-[(2S)-tetrahydrofuran- 2-Ginyloxy]benzamide or a salt thereof.卜(3-{[(trans-4-hydroxy-4-methylcyclohexyl)amino]] yl}-8-fluorenyl ruthenium-7-yl)-4-[(2S)-tetrahydrofuran- 2-Ginyloxy]benzamide or a salt thereof. N-(3-{[(trans-4-hydroxy-4-fluorenylcyclohexyl)amino]methylindole-8-indolyl-7-yl)-4-[(2R)-tetrahydrofuran- 2-Ginyloxy]benzamide or a salt thereof. N-(3-{[(cis-4-hydroxy-4-fluorenylcyclohexyl)amino]methyl b-8-fluorenyl-7-yl)-4-[(2S)-tetrahydrofuran-2 - methoxyl]benzamide or a salt thereof. N (3 {[(1-ethylpropyl)amino]methyl hydrazine_8-methyl hydrazino) -4-[(2S)-tetrahydrofuran-2-yl decyloxy]phenyl hydrazine or Its salt. N-[8-Methyl^-({[(ir)-!-mercaptopropyl]aminoindenyl)quinoline-7-yl]-4-[(2S)-tetrahydrofuran-2-ylmethoxy Benzoylamine or a salt thereof. N-[8-Methylmethylpropyl]amino}methyl)quinoline-7-yl]-4-[(2S)~tetrahydrofuran-2-yloxy]phenylguanamine or a salt thereof. N-{3-[(cyclobutylamino)methyl]_8-methylquinoline-7-yl}_4-[(2S)-tetrahydroindole. Nan-2-ylmethoxy]benzamide or a salt thereof. 51 322147 201206909 N-[8-mercapto-3~({[(11〇-1,2,2-trimercaptopropyl)amino}indolyl)quina-7-yl]-4-[( 2S)-Tetrahydrofuran-2-ylmethoxyoxy]phenylguanamine or a salt thereof. N-(8-Mercapto-3-{[(2-mercaptopropyl)amino]indenyl}quinoline-7 -yl)-4-(tetrazonitrile-3-ylmethoxy)phenylamine or a salt thereof. 2-Dimercaptopropyl)amino]methyl b-8-methylquinoline _7- Base) -4-(tetrahydrocarbamate_3_yloxy)benzamide or a salt thereof. N-(8-fluorenyl-3~{[(tetrahydro-2H-piperazin-4-ylindenyl)amino]indolyl}quinol-7-yl)-4-(tetrahydrofuran_3_ylindole) Oxyphenyl)benzamide or a salt thereof. · N-(3-{[(trans_4-hydroxy-4-indolylcyclohexyl)amino]methyl b-8-mercapto-7-yl)-4-(tetrahydrofuran_3_yloxy) Benzoamine or a salt thereof. N -(3-{[(2-methoxy-2-indolyl)amino]indenyl}_8-decylquinoline-7-yl)-4-(tetrahydrofuran-3-yloxy) Benzoylamine or a salt thereof. N-{3-[(4-Hydroxy-4-cyclopiperidin-1-yl)indenyl]_8-decylquinoline-7-yl}-4-(tetrahydrofuran_3_ylmethoxy)phenylhydrazine Indoleamine or a salt thereof. 2-^-Ν-(3-{[(2-hydroxy-2-methylpropyl)amino]methyl b-8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran- 2-ylmethoxy]benzamide or its ruthenium 0 N (3~{[(2, 2-dimethylpropyl)amino]methyl b8-mercaptoquinoline-7-yl) 2-Fluoro-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide or a salt thereof. 2-fluoro-N-(3-{[(trans-4-hydroxy-4-methylcyclohexyl)amino]methyl}-8-mercaptoquinolin-7-yl)-4-[(2S )-tetrahydrofuran-2-ylmethoxy]benzamide or a salt thereof. 2fluoroindole-(8-methyl-3-{[(2~methylpropyl)amino]methyl}quinoline-7-yl) 322147 52 201206909 -4-[(2S)-tetrahydrofuran-2] Methoxy]benzamide or a salt thereof. 2-Fluoro-N-{8-methyl-3-[(propylamino)methyl]quinoline-7-yl b-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzimidazole An amine or a salt thereof. N-{3-[(4-Hydroxy-4-methylpiperidin-bu)methyl]_8-methylquinolin-7-yl}-4-[(23)-tetrahydrofuran-2-ylmethoxy Benzoguanamine or a salt thereof. [Compound E] N_[8-methyl-3-({[(2S)-tetrahydrofuran-2-ylmethyl]aminoindolemethyl)quinolin-7-yl]-4-[(2S)-tetrahydrofuran 2-Benzyloxy]benzamide or its φ salt. N-{8-methyl-3-[(tetrahydro-2H-piperidin-4-ylamino)indolyl]quinoline-7-yl}-4-[(25)-tetrahydrofuranylmethoxy]benzene Formamide or a salt thereof. 1^-(8-Methyl-3-{[(2-methylpropyl)amino]indolyl quinolinyl-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy Benzoguanamine or a salt thereof. N-(3-{[(trans-4-yl)-4-methylcyclohexyl)amino]methyl}_8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydrofuran- 2-yl decyloxy] benzoic acidamine or a salt thereof. _ N-{3-[(4-Pyano-4-methyl)-yl)methyl]_8-methylindole-7_*}-4-[(2S)-tetrahydrofuran-2-yloxyloxy Benzoguanamine or a salt thereof. When the compound (I) is in the form of a salt, specific examples thereof include a salt formed with an inorganic test, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, and A salt or the like formed by an acidic or acidic amino acid. Preferred examples of the salt formed with the inorganic base include alkali metal salts such as sodium salts, potassium salts, etc.; soil test metal salts such as salt, town salt, 322147 53 201206909 salt, aluminum salt, etc. . Preferable examples of the salt formed with an organic base include tridecylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, Ν'-diphenyl a salt formed by an ethylenediamine or the like. Preferable examples of the salt formed with the inorganic acid include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like. Preferred examples of the salt formed with an organic acid include with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, sulfonic acid, benzenesulfonic acid, a salt formed of benzenesulfonic acid or the like. Preferable examples of the salt formed with the basic amino acid include salts formed with arginine, lysine, ornithine, and the like. Preferable examples of the salt formed with the acidic amino acid include salts formed with aspartic acid, glutamic acid and the like. Among them, pharmaceutically acceptable salts are preferred. The compound (I) may be either an acid anhydride (non-hydrate) or a hydrate. Further, the compound (I) may be either an unsolvated compound or a solvate. Further, the compound (I) can be labeled with an isotope (for example, 3H, 14C, 35S, 1251, etc.). Further, an anthracene exchange compound which converts 1 Torr to 2H (D) is also included in the compound (I). Compound (I) may be a pharmaceutically acceptable cocrystal or co-crystal salt. Here, the co-crystal or co-crystal salt means two or more kinds having different physical properties (for example, structure, melting point, heat of fusion, n-solution, stability, etc.) at room temperature of 54 322147 201206909, respectively. Specific solids are grouped with various substances. The co-crystallized and co-crystallized salt can be made according to what is known per se: sputum. , ', , ° day method of preparation When the compound (I) contains optical isomers, stereoisomers, sites or rotamers, these isomers are also included in the compound (heterogeneous can be based on itself Knowing the synthesis method and the separation method, the optical isomer of the compound _ is also included in the compound (1). When the compound (1) has an optical isomer, the optical isomer can be known per se. Method of manufacture (eg, segmental recrystallization, palm column method, non-image isomer method) σ 1) Fractional recrystallization method This method is first with optically active compounds (eg: (+)-mandelic acid , (-)-mandelic acid, (+)-tartaric acid, (_)_tartaric acid, (+)-p-phenethylamine, (-)-1-benethylamine, cinch〇nine, (_)_cinch〇nidine, brucine, which forms the salt of the racemate, and then is separated by fractional recrystallization. If necessary, the neutralization step can be used to obtain free Optical isomers. 2) Palm column method This method applies a racemate or a salt thereof to a separation column (a palm column) of an optical isomer for separation. For liquid chromatography, for example, a mixture of optical isomers is applied to a palm column, such as: ENANTIO-OVMC Tosoh, Inc., CHIRAL series (Daicel)

Chemical Industries, Ltd., etc., and used alone or in a variety of buffers (eg, discate buffer) and organic solvents (eg, 6 alcohol, methanol, isopropanol, acetonitrile, three) When fluoroacetic acid or diethylamine is developed to separate optical isomers, gas chromatography is carried out by, for example, CP~chirasil-DeXCB (manufactured by GLS Science Inc.). 3) Non-image isomer method s X method, by 岐 肖 肖 混合物 mixture and optically active reagents for chemical reaction ^ 4 compound prepared as a mixture of non-image isomers, and

The optically active reagent portion is obtained by separating the optically active reagent portion by a knife-by-method method (for example, a stepwise recrystallization method or a method), and then performing a chemical treatment (for example, hydrolysis, etc.) to obtain an optical isomerism. Things. For example, when the chemical substance (1) contains a trans- or a- or a secondary amine group in a knife, the compound can be reacted with an optically active organic acid (for example, ΜΤΡΑ[α-methoxy-α-(three) The gas methyl)phenylacetic acid], (i)-nonyloxyacetic acid, and the like are subjected to a condensation reaction to separate into a non-image isomer in the form of an ester or in the form of a guanamine. When the compound (I) has a decanoic acid, the compound can be subjected to a condensation reaction with an optically active amine or an optically active alcohol to obtain a non-image isomer in the form of a decylamine or an ester, respectively. The isolated non-image isomer is converted to the optical isomer of the original compound by acid hydrolysis or alkaline hydrolysis. The compound (I) is a compound which can be converted into a compound (I) by an enzyme, a gastric acid or the like under physiological conditions in vivo, that is, can be converted into a compound by oxidation, reduction, hydrolysis, or the like of an enzyme. a compound; or a compound converted to the compound (I) by hydrolysis of gastric acid or the like. The compound (D prodrug may be a compound obtained by subjecting an amine group in the compound (I) to a thiol group 322147 56 201206909, calcination or scalification (for example, making the amine group in the compound (i) Carbonization, propylamine oximation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-1,3-dioxol-4-yl)methoxycarbonylation a compound obtained by tetrahydrofuranylation, pyrrolidinylmethylation, pentylmethyloxymethylation or tert-butylation; or a base group in the compound (I) a compound obtained by acidification, acidification or boring (for example, by subjecting a base group in the compound (I) to acetylation, thiolation, propylation, pivalidylation, a compound prepared by succinylation, fumarylation, propylamine enrichment or dimethylaminomethylmethylation; esterification of a slow group in compound (I) Or a compound obtained by hydrazylation (for example, esterification of a carboxyl group in the compound (I), phenyl esterification, esterification of a carboxyl group, methylation of a dimercaptoamine group) Ethyl pentamethoxy oxime esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxole -4-yl) oxime esterification, cyclohexyloxycarbonylethylation or hydrazinoylation of the compound), etc. ® Any of these compounds can be prepared from the compound (I) according to a method known per se. The prodrug of the compound (I) may also be a compound which is converted into the compound (I) under physiological conditions, for example, as described in "IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7 (Molecular Design ( Design of Molecules)), p. 163-198 (1990), published by HIROKAWA SHOTEN. 57 322147 201206909 Compound (I) can be used according to [Method 1-1] to [Method 3-1] as detailed below or The compound which is a starting compound can be used in the form of a salt, and the salt can be exemplified by the above-mentioned compound (I), etc. ] to [Process 3~1], when alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction When the hydrazide reaction, the esterification reaction, the etherification reaction, the oxidation reaction, the reduction reaction, etc., the reactions are carried out according to a method known per se, for example, they are described in "Organic Functional Group Preparations". , 2nd Edition, Academic Press Inc., 1989; Comprehensive Organic Transformations, VCH Publishing Company, 1989"; In the following preparation method, "room temperature" is 15 to 30 °C. The solvent used in each reaction is explained below. Examples of the "alcohol solvent" include methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, tert-butanol, and the like. Examples of the "ester solvent" include decyl acetate, ethyl acetate, n-butyl acetate, t-butyl acetate, and the like. Examples of the "ether solvent" include diethyl ether, diisopropyl ether, tert-butyl decyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and the like. Examples of the "halogenated hydrocarbon solvent" include dichloromethane, gas-form, 1,2-dichloroethane, tetra-carbonized carbon, and the like. Examples of the "aromatic solvent" include benzene, toluene, xylene, and pyridine 58 322147 201206909 and the like. Examples of the nitrile solvent include acetonitrile, propionitrile, and the like. Examples of the "guanamine solvent" include n,n-dimethylformamide (10)F), N,N-dimethylacetamide (dma), diterpenyl-2-pyrrolidone (匪p) and the like. Examples of the "ketone solvent" include acetone, mercaptoethyl ketone, and the like. Examples of the "arylene solvent" include dimethyl sulfoxide (DMS0) and the like. Examples of the organic acid solvent include formic acid, acetic acid, and the like. [Production Process 1-1] The compound (I) can be subjected to reductive amination reaction of the compound (II) and the compound (III), for example, according to the following reaction scheme. Preparation (Reaction Figure 1)

# where, each symbol is as defined above. In other words, the compound (11) and the compound (III) in an amount of from 1 to 50 equivalents (preferably 1.2 to 5 equivalents) relative to the compound (II) can be reacted with a reducing agent in an inert solvent. The compound (I) was obtained. Examples of the inert solvent include an alcohol solvent, an ether solvent, a halogenated hydrocarbon solvent, an aromatic solvent, a nitrile solvent, a guanamine solvent, an organic acid solvent, and the like. A mixture of two or more of them may be used in an appropriate ratio. Among them, methanol, ethanol, DMF, hydrazine, NMP, acetic acid and the like are preferred. 59 322147 201206909 For the reducing agent, sodium borohydride, sodium triethoxy borohydride, sodium cyanoborohydride or the like is used. The reducing agent is used in an amount of usually 1 to 20 equivalents, preferably 1 to 5 equivalents based on the compound (II). The reaction temperature is usually -20 ° C to 150 ° C, preferably 0 ° C to 60 ° C. The reaction time is usually from 5 minutes to 40 hours, preferably from 1 hour to 24 hours. Further, the reaction can also be carried out in the presence of an acid. Examples of the acid to be used include organic acids such as acetic acid, hydrazine sulfonic acid, etc.; inorganic acids such as hydrochloric acid, sulfuric acid, etc.; and Lewis acid such as titanium tetrachloride, titanium isopropoxide, etc. . The acid is used in an amount of from 0.01 to 100 equivalents of the organic acid or the Lewis acid, and from 0.1 to 10 equivalents, based on the compound (II). When an organic acid is used, an excess of an organic acid can be used as a reaction solvent. The compound (III) can be produced according to a method known per se. The compound (11) can be produced according to the following [Production Method 2-1] or the like, or can be produced from the following compound (II a) according to an oxidation reaction known per se. [Production Process 1-2] The compound (I) can also be produced, for example, by subjecting the compound (IV) to the amination reaction of the compound (III), as shown in the following reaction scheme 2. (Reaction Figure 2) 60 322147 201206909

Αν) (ΐ) where L is the leaving group and the other symbols are as defined above. Examples of the "leaving group" of L include a halogen atom (for example, chlorine, bromine, iodine), and a halogenated Cl-6-based aryloxy group (for example, vermiculite-based oxygen group, B, A sulfonyloxy group, a trifluorosulfonyloxy group, a Cho arylsulfonyloxy group having a substituent (group), a hydroxyl group, and the like. The "leaving group" is preferably a halogen atom (e.g., chlorine, bromine, iodine), anthracene sulfhydryloxy group, trifluorosulfonyloxy group, p-toluenesulfonyloxy group or the like. This reaction is usually carried out in an inert solvent. Examples of the "inert solvent" include an alcohol solvent, a mystery solvent, a halogenated hydrocarbon solvent, an aromatic solvent, a nitrile solvent, a guanamine solvent, a ketone solvent, a solvent solvent, water, and the like. A mixed solution in which two or more solvents are formed in an appropriate ratio can be used. Among them, acetonitrile, DMF, DMA, NMP, acetone, ethanol, pyridine and the like are preferred. The compound (III) is used in an amount of usually 1 to 100 equivalents based on the compound (IV). Further, an excess amount of the compound (III) can be used as a reaction solvent. The reaction temperature is usually from about -20 ° C to 200 ° C, preferably from room temperature to 100 ° C. The reaction time is, for example, about 0.5 hours to 1 day. This reaction can be carried out in the presence of a base as needed. 61 322147 201206909 Examples of "alkali" include: 1) Strong tests, such as metal or soil metal hydrides (eg hydrogenation clocks, sodium hydride, hydrogenated oblique, gasified cranes), metal or soil metallization (eg lithium aluminide, sodium amination, lithium diisopropylamide, lithium dicyclohexylamine, lithium hexamethyldisilazide, hexamethyldimonamide, hexamethylene Base bismuth ammonia potassium), metal or soil test metal Cl-6 alkoxide (eg sodium decoxide, sodium ethoxide, potassium butoxide); 2) inorganic tests, such as metal or soil test Oxide oxides (eg sodium hydroxide, strontium hydroxide, hydrazine hydroxide, barium hydroxide), metal or soil-spectrum genus carbonate (eg sodium carbonate, potassium carbonate, carbonic acid planing), alkali metal hydrogencarbonate Salt (eg sodium bicarbonate, hydrogencarbonate clock, etc.); 3) organic bases such as amines (eg triethylamine, N,N-diisopropylethylamine, N-mercaptomorpholine, 4 - Dimercapto-aminopyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4. 3. 0] 壬 -5-dilute)), a test heterocyclic compound (for example: ° bite, taste ° sit, 2, 6-dimethyl 0-pyridine); Among the above bases, triethylamine, N,N-diisopropylethylamine, pyridine or the like is preferred. The base is used in an amount of usually 0.1 to 100 equivalents, preferably 1 to 10 equivalents based on the compound (IV). The compound (IV) can be produced according to the following [Production Method 2-2] or [Process 2-3] or the like. [Production Method 2-1] 62 322147 201206909 The compound (I la) is a compound of the compound (II) wherein R3 is hydrogen, which can be produced according to, for example, the method shown in the following reaction scheme. (Reaction Figure 3)

Wherein, X- is a counter anion, such as a tetrahydrofluoride acid anion, and the other symbols are as defined above. The compound (Via) is converted into the compound (Va) which is a carboxylic acid halide by reacting the compound (V) with, for example, a halogenating agent (e.g., grass φ helium, sulfoxide, etc.), and then It is obtained by reacting the compound (VI) in the presence of a base such as triethylamine or the like. Further, the compound (Via) can also be obtained by using the compound (V) and the compound (VI) in a condensing agent (e.g., a carbodiimide derivative or the like, for example, 1-ethyl-3-(3-didecyl). Aminopropyl)carbodiimide hydrochloride) and an additive (for example, 1-hydroxybenzotriazole, 4-didecylamine "bipyridine", etc.) are directly reacted. The nitro group of the compound (VI a) is reduced by catalytic hydrogenation or by reduction 63 322147 201206909 (e.g., iron, tin chloride, etc.) to give the compound (VIb). Subsequently, the compound (Ila) can be produced, for example, by reacting the compound (VIb) with the compound (VII) in the presence of morpholine in bubutanol at 80 ° C overnight. The compound (V) can be produced according to a method known per se or [Method 3-1] described below. The compound (VI) can be produced according to a method known per se. The compound (VII) can be produced according to a method known per se, for example, Synthesis, 64, 645 (1988), and the like. [Production Process 2-2] The compound (IVa) is a compound of the compound (IV) wherein R3 is a hydrogen atom, which can be produced, for example, according to the method shown in the following reaction scheme. (Reaction Figure 4)

Wherein, each symbol is as defined above. The compound (V111) is obtained by reacting the compound (11a) with, for example, a reducing agent (e.g., hydrogen hydride, hydrogenated rixi, etc.). Then, the compound (IVa) is obtained by reacting the compound (VIII) with, for example, a halogenated 64 322147 201206909 agent, a sulfonating agent or the like. In this case, a compound in which L is a halogen atom in the compound (I Va) is obtained by reacting the compound (V111) with, for example, a halogenating agent (e.g., sulfinium chloride, tribromophosphine, etc.). Further, in the compound (IVa), L is a sulfonyloxy group (for example, a G-6 alkylsulfonyloxy group which may be required to be functionalized, and optionally has a substituent (group). Arylsulfonyloxy The compound of the formula (V111) can be obtained by reacting the compound (V111) with, for example, a scutellarin (e.g., sulphuric acid, p-sulfonium sulfonium, etc.) in the presence of a base (e.g., triethylamine, etc.). . [Production Process 2-3] The compound (IVb) is a compound in which the R3 is a Ci-6 alkyl group in the compound (IV), which can be produced, for example, according to the method shown in the following Reaction Scheme 5. (Reaction Figure 5)

Wherein, Ra is a Cl-6 alkyl group, and other symbols are as defined above. The compound (V111 a) is obtained by reacting the compound (11 a) with, for example, a Grignard reagent (e.g., granified methyl bromide or the like) or a burning agent (e.g., an alkyllithium or the like). Then, the compound (I Vb) is obtained by reacting the compound (V111 a) with, for example, a halogenating agent, a sulfonating agent or the like. In this case, the compound of the compound (IVb) wherein L is 65 322147 201206909 halogen atom is obtained by reacting the compound (VIIla) with, for example, a halogenating agent (e.g., sulfinium gas, tribromophosphine, etc.). Further, in the compound (I Vb), L is a sulfonyloxy group (for example, a C6-1 alkylsulfonyloxy group which may optionally be halogenated, and a C6-1D arylsulfonyloxy group which may have a substituent (group) as needed. The compound of the group can be prepared by reacting the compound (VI Ila) with, for example, a retanning agent (e.g., sulfonium sulfonium, p-toluene sulfonium chloride, etc.) in the presence of a base (e.g., triethylamine). Got it. [Method 3-1]

Compound (V) can be produced according to, for example, the method shown in the following reaction scheme. (Reaction Figure 6)

(IXb) (IX)

(Vb) (IXa)

(V)

Wherein, Rb and Re are respectively Ch alkyl groups, and other symbols are as defined above. The compound (IXb) is produced by converting the compound (IX) into a compound (IXa) by a conventional esterification reaction, and then reacting with, for example, a reducing agent (e.g., hydrogen side sodium, lithium aluminum hydride, etc.). Further, the compound (IXb) can also be produced by directly reacting the compound (IX) with, for example, a reducing agent (e.g., lithium aluminum hydride). 66 322147 201206909 Next, the compound (IXb) and the compound (X) are used as a starting material, and an etherification reaction (for example, a Mitsunobu reaction) is carried out using diethyl azobis(dicarboxylate) and triphenylphosphine. Compound (Vb). The ester compound (Vb) is subjected to a conventional hydrolysis reaction to obtain a compound (V). The compound (IX) and the compound (X) can be produced according to a method known per se. In the compound (I) thus obtained, a functional group in the molecule can also be converted into a target functional group by a chemical reaction known per se in the composition. Examples of such chemical anti-φ can be mentioned as oxidation reaction, reduction reaction, alkylation reaction, hydrolysis reaction, amination reaction, hydrazine reaction, esterification reaction, aryl-coupling reaction, deprotection reaction and the like. In the above process, when the starting compound has an amine group, a carboxyl group, a trans group, a carbonyl group or a thiol group as a substituent, a protecting group commonly used in peptide chemistry or the like can be introduced into such groups. The protecting group can be removed after the reaction if necessary to obtain the target compound. Examples of the amine-protecting group include a mercapto group; a Cl-6 alkyl-carbonyl group (e.g., an ethyl fluorenyl group, a propyl fluorenyl group), a Ci-e oxyoxy group-carbonyl group (e.g., an oxiranyloxycarbonyl group, an ethoxy group). Carbonyl, tert-butoxycarbonyl), benzoinyl, C7_ig aralkyl-prison (eg, alkoxycarbonyl), 〇-η aralkyloxy-carbonyl (eg, benzyloxycarbonyl) , 9-p-methoxycarbonyl), triphenylsulfonyl, anthracenyl, N,N-dimethylaminomethylene, substituted alkylene (eg, trimethylsulfonyl, diethyl A thiol group, a dimethylphenyl sulfonyl group, a tert-butyldicylidene decyl group, a tert-butyldiethyl decyl group, and a C2_6 alkenyl group (for example, a propyl group). These groups may be substituted with 1 to 3 substituents selected from the group consisting of 322147 67 201206909: a tooth atom, a Cl-6 alkoxy group and a nitro group. Examples of the carboxy-protecting group include a Ch alkyl group, Cn. Aralkyl (for example: benzyl), phenyl, trityl, substituted decyl (eg trimethyl decyl, triethyl decyl, dimethyl phenyl decyl, third butyl) A dimethyl decyl group, a tert-butyldiethyl decyl group, a C2-6 alkenyl group (for example, 1-allyl), and the like. These groups may be optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a Cm alkoxy group and a nitro group. Examples of the hydroxy-protecting group include a C]-6 alkyl group, a phenyl group, a trityl group, a C7-1D aryl group (for example, a benzoinyl group), a fluorenyl group, a Ci-6 alkyl group-carbonyl group, and a benzene group. Mercapto, C7-1D aralkyl-carbonyl (eg benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted decyl (eg trimethyl sulfonyl, triethyl) An alkyl group, a dimethyl benzyl decyl group, a tert-butyl dimethyl decyl group, a tert-butyldiethyl decyl group, a C 2-6 alkenyl group (for example, 1-allyl), and the like. These groups may be substituted with from 1 to 3 substituents selected from the group consisting of a tooth atom, a Cl.6 yard group, a Cl-6 alkoxy group, and a nitro group. Examples of the carbonyl-protecting group include a cyclic acetal (e.g., 1,3-di-anthracene), an acyclic acetal (e.g., a di-Cw alkyl acetal), and the like. Examples of the thiol-protecting group include a Cu alkyl group, a phenyl group, a triphenyl fluorenyl group,

Cho aryl group (for example: benzoinyl), Cl_e alkyl-carbonyl, benzhydryl,

Cvi° aralkyl-carbonyl (eg phenylhydrinylcarbonyl), Ch alkoxy-carbonyl,

Ce_14 aryloxy ~ carbonyl (for example: phenyloxycarbonyl), C7-H aralkyloxy-alkyl (for example: benzoyloxycarbonyl, 9-yloxycarbonyl), 2_four Hydroperfluoromethyl, Ch alkylamino-carbonyl (for example: mercaptoaminocarbonyl, ethylaminocarbonyl) and the like. These groups may be optionally substituted with from 1 to 3 substituents selected from the group consisting of: a halogen atom, a Cw alkyl group, a Ch alkoxy group and a nitro group. The compound (I) can be isolated and purified according to a method known per se, such as a solvent extraction method, a liquid property change method, a transdissolution method, a crystallization method, a recrystallization method, a chromatography method and the like. The starting compound of the compound (I) or a salt thereof may be isolated and purified by the same method as above, but the starting compound of the compound (I) or a salt thereof may also be used as a reaction mixture in the form of a reaction mixture without isolation. The starting material for the step. Since the compound (I) and its prodrug (hereinafter simply referred to as "the compound of the present invention" (also referred to as "the compound of the present invention") have superior MCH receptor antagonism, it is suitably caused by MCH. A preventive or therapeutic agent for the disease. In addition, the compounds of the present invention also exhibit low toxicity (eg, cardiotoxicity (eg, hERG inhibitory activity), PLsis-inducing potential, acute toxicity, chronic toxicity, genotoxicity, lean toxicity, drug interaction, carcinogenicity, phototoxicity) . Furthermore, the compounds of the invention have superior oral absorbability. In addition, the compounds of the present invention have superior brain transfer function. Thus, the compounds of the present invention can be safely administered to mammals (e.g., rats, mice, guinea pigs, rabbits, sheep, horses). , pig, cow, monkey, human), as a preventive or therapeutic agent for diseases caused by MCH. Diseases caused by MCH include, for example, obesity [eg, malignant mastocytosis, exogenous obesity, hypersensitivity of islet hyperplasia, protozoal proliferative obesity, pituitary obesity, hypogenic obesity, 69 322147 201206909 Hypogonad dysfunction obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal infertility obesity, systemic hypertrophy Cell hyperplasia, simple obesity, central obesity, etc.], overeating, mood disorders, sexual dysfunction, depression, anxiety, etc. The compound of the present invention is also suitable for use as a prophylactic or therapeutic drug for lifestyle-related diseases such as diabetes (for example, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity, diabetes, etc.) B〇nieriine diabetes, impaired glucose tolerance (IGT), complications of diabetes (eg, retinopathy of diabetes, diabetic neuropathy, diabetic nephropathy), hyperlipidemia (eg: succinic acid) Glycerolemia, hypercholesterolemia, hypercholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia, arteriosclerosis, knee arthritis, metabolic syndrome, and the like. Furthermore, the compounds of the invention are also suitable for use as a palsy. The compounds of the invention may also be combined with dietary therapies (e.g., dietary therapy for diabetes) or exercise therapy. Further, the compound of the present invention is also suitable for use as a prophylactic or therapeutic drug for nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (nafld). The compounds of the present invention are useful for the prevention or treatment of pigmentation disorders caused by abnormalities in melanin or melanocytes. Here, the pigmentation diseases described above are pigment hyperplasia, hypopigmentation, and the like. Pigment hyperplasia and drug pigmentation caused by anti-tumor agents; and diseases (eg, endocrine and metabolic diseases 70 322147 201206909: (1) such as < Addis〇n's disease' genetic disease chronic liver disease, renal failure In the sputum, there are diseases, pigmentation and hypopigmentation! t disease, systemic scleroderma, etc.) related sexual or local white ^ can talk about aquarium, general white leukoplakia; ^ body: ^ hardening Disease-related leukoplakia or depigmentation associated with scleroderma. Compounds such as plaques can be used to prevent or treat 40% of depigmentation caused by liver spots, freckles and sunburn; and can be hyperplasia or hypopigmentation. ^ Purpose for the color method [The compound of the invention may be used by itself or may be used according to a method known per se (for example, the method of blood stasis of the drug) and the prescription described by the two Panese Pharmacopoe ia). Examples of carriers in which the carrier of the fork is formulated into a preparation and are in the form of a pharmaceutical composition include various organic or inorganic carriers which are conventionally used as preparation materials. λ. ^, λ. X For example, for a solid preparation Forming agent, =, fine nder) and disintegrant; using Nasuke / gluten, suspending agent, isotonic agent, antioxidant, inter-additive additives, such as anti-corrosion excipients, Adsorbent, wetting agent, etc. Corn starch, crystalline fiber candy, d~mannitol, house powder, and light anhydrous citric acid. #石广: 1 agent: including magnesium stearate, calcium stearate, talc and colloidal colloidal silica. Binding agent = examples include crystalline cellulose, sucrose, d_, dextrin, propyl cellulose, propyl methyl cellulose, polyethylene bite 322147 71 201206909 ketone, starch, sucrose, gelatin, methyl cellulose And sodium carboxymethyl cellulose. Examples of the disintegrant include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose (L-HPC). Examples of the solvent include water for injection, alcohols, propylene glycol, macrogol, sesame oil, and corn oil. Examples of the co-solvent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, quinone decane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Examples of suspending agents include surfactants such as: stearyl triethanolamine, sodium lauryl sulfate, lauryl alanine, lecithin, benzalkonium chloride, benzethonium chloride Chloride), glyceryl monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, sulfhydryl cellulose, fluorenyl cellulose, hydroxyethyl Cellulose, hydroxypropyl cellulose, and the like. Examples of the isotonic agent include glucose, D-sorbitol, sodium carbonate, glycerin, and D-mannitol. Examples of the buffer include, for example, a phytate buffer, an acetate buffer, a carbonate buffer, a citrate buffer, and the like. Examples of the soothing agent include benzoquinone and the like. Examples of preservatives include p-hydroxybenzoate, chlorobutanol, benzoquinone, phenylethyl alcohol, dehydroacetic acid, and sorbic acid. Examples of antioxidants include sulfites and ascorbates. Examples of the coloring agent include water-soluble edible tar pigments (for example, food color 72 322147 201206909 No. 2 and No. 3, food eater yellow No. 4 and such as: the above-mentioned watery human color No. 1 and No. 2, etc.), water insoluble Color hall pigments (example & tar pigments) and natural pigments (for example: jujube, chlorophyll, red iron oxide). Examples of sweeteners include sugar _, licorice H (10) sweet and stevia

Examples of the adsorption enthalpy include porous temple powder, Shi Xi Lai (product name: F1〇riteRE), magnesium aluminum bismuthate (product name: NeUSilin) _ helmet hydrazine acid (product name: Sylysia). Examples of the humectant include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate g|, and polyoxyethylene ethyl laurel.

Examples of the pharmaceutical composition of the above-mentioned pharmaceutical composition include a tablet (including a sugar-coated key, a film-coated tablet, a sublingual spine, a disintegrating tablet in the mouth, a buccal ingot, etc.), a pellet (9) (1), a powder, a granule, a capsule (including a soft knee pocket, Microcapsules), mouth-containing bonds (centering), syrups, liquids, emulsions, suspensions, controlled release preparations (eg, immediate release formulations, sustained release formulations, sustained release microcapsules), sprays, films (eg: Intraoral disintegrating film, oral mucosa patch film), injection (for example: subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), drip infusion, wearing type absorption preparation, oil f, Lotion, adhesive preparation, suppository (eg rectal suppository, vaginal suppository), pellet, nasal, pulmonary (inhalation), eye dr〇p Etc., and such dosage forms can be administered by oral or parenteral administration (eg, intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, intraocular instillation, intracerebral, rectal, vaginal, peritoneal Internal and swollen Within the administration, 73 322 147

S 201206909 is administered to the vicinity of the tumor, etc., and directly to the lesion, and is safely administered. The content of the compound of the present invention in the pharmaceutical composition is, for example, about 0.1 to 100% by weight based on the total amount of the pharmaceutical composition. The dose of the compound of the present invention is appropriately determined depending on the administration target, the administration route, the disease, and the like. For example, an adult patient suffering from obesity (body weight about 60 kg) orally administered a compound of the invention at a daily dose of from about 0::! to about 500 mg, preferably from about 1 to about 100 mg, more preferably about 5 to about 100 mg. This amount can be administered once a day or in divided doses (for example: 1 to 3 times). If it is desired to enhance the effects of the compound of the present invention (the therapeutic effects of obesity, diabetes, depression, anxiety, etc.) and to reduce the amount of the compound of the present invention, and the like, and to prevent or treat complications and improve the prognosis, for example, The compounds of the invention are used in combination with a co-administrative drug that does not adversely affect the compounds of the invention. Examples of such concomitant drugs include therapeutic drugs for diabetes, "therapeutic drugs for diabetic complications", "anti-obesity agents", "therapeutic drugs for hypertension," "therapeutic drugs for hyperlipidemia", and "anti-atherosclerosis" Drugs,, "anti-thrombotic agents,", "diuretics", "therapeutic drugs for arthritis,", "anxiolytic drugs", "anti-depressants", "psychotic drugs", "induced sleep" (sieep_ inducing) drugs, etc. These concomitant drugs may be low molecular weight compounds or molecular weight proteins, polypeptides, antibodies, vaccines and the like. Further, two or more of these concomitant drugs may be used in combination in an appropriate ratio. The above "therapeutic agent for diabetes," examples include insulin preparations (Example 74 322147 201206909 eg animal insulin preparations extracted from bovine and porcine pancreas; using E. coli (£"sc/?eric/n'a i) or Genetically engineered human insulin preparation; zinc insulin; protamine zinc insulin; insulin fragment or derivative (eg INS-1), oral insulin preparation), insulin sensitizer (eg dermatone) (pioglitazone) or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Metaglidasen, AMG-131, paglitazone ( Balaglitazone), MBX-2044, Rivoglitazone, φ Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT -505, THR-092, described in WO 2007/013694, WO 2007/018314, WO 2008/093639 or WO 2008/099794), alpha-glucosidase inhibitors (eg, voglibose (voglibose) , acarbose (acarbose), MiG Miglitol, emiglitate, biguanide (eg, Metformin, buformin or a salt thereof (eg hydrochloride, fumarate, barium succinate) )), insulin secretagogues (for example: sulfonyl urea (for example: tolbutamide, giibenclamide, gliclazide, chi-rpropamide) Tolazamide, acet〇hexamide, glyclopyramide, gi imepiride, glipizide, glytin. sit (giybuz 〇ie)), repaglinide, nategUnide, mitiglinide or its calcium salt hydrate, dipeptidyl peptidase IV inhibitor 75 322147 201206909 (eg: Alogliptin or its salt (preferably benzoate), vildagliptin, sitagliptin, sagagliptin, BI1356, GRC8200, MP- 513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-02, KRP-104 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-indolyl-2, 4-di-oxy-1(2H)-pyrimidine (Alkyl)-4-fluorobenzoquinone or its salt), agonist (for example: N-5984), GPR40 agonist (for example: described in WO 2004/041266, W0 2004/106276, W0 2005/ 063729 > W0 2005/063725 'W0 2005/087710 > W0 2005/ 095338, W0 2007/013689 or WO 2008/001931 compounds), GLP-1 receptor agonist (eg GLP-1, GLP-1MR) Agent, liraglutide, Exenatide, AVE-0010, BIM-51077, Aib (8, 35) hGLP-l (7, 37) NH2, CJC-1131, Abundai ( Albiglutide)), amyloid agonist (eg, pramlintide), phosphotyxin osine phosphatase inhibitor (eg sodium sulphate), inhibitor of glucose production (eg: hepatic cansinase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg: Di

Depagliflozin, AVE2268, TS-033, YM543, TA-7284, Reg〇giifi〇zin, ASP1941), sgltI inhibitor, ΐβ-hydroxysteroid dehydrogenase inhibitor (eg: BVT_3498, INCB-13739), adiponectin or its agonist, IKK inhibitor (eg. AS-2868), a drug that improves resistance to ieptin, body 76 322147 201206909 Somatostat iη) receptor agonist, glucokinase activator (eg: Piragliatin 'AZD1656, AZD6370, ΤΤΡ-355, illustrated on W0 2006/112549, W0 2007/028135, W0 2008/ 047821, WO 2008/05082, WO 2008/136428 or a compound of WO 2008/156757), GIP (glucose-dependent insulinotropic peptide), GPR119 agonist (for example: PSN821), FGF21, FGF analog and the like. Examples of the above "therapeutic drugs for diabetic complications" include aldose reductase inhibitors (for example: tolrestat, epalrestat, zopolrestat, fidarestat) ), CT-112, ranirestat (AS-3201), lidorestat, neurotrophic factor and its promoting drugs (eg NGF, NT-3, BDNF and described in W001/14372) Neurotrophin production/secretion promoter (for example: 4-(4-chlorophenyl)-2-(2-mercapto-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl ]carbazole), a compound described in WO 2004/039365, a PKC inhibitor (eg, ruboxistaurin mesylate), an AGE inhibitor (eg, ALT946, N-benzimidylthiazole) Iron bromide (ALT766), EX0-226, Pyridorin, Pyridoxamine, GABA receptor agonist (eg gabapentin, pregabalin) , serotonin-norepinephrine reuptake inhibitors (eg: duloxetine), sodium channel inhibitors (eg: Leke (lacosamide), active oxygen scavengers (eg, lipoic acid), cerebral vasodilators (eg, tiapride, mexiletine), somatostatin agonists (eg, BIM23190) ), apoptosis signal regulation 322147 77 201206909 kinase-1 (ASK-1) inhibitor and the like. Examples of the above "anti-obesity agents" include monoamine absorption inhibitors (for example, phentermine, sibutramine, mazindol, fluoxetine, fisoxetine, tesofin) Tesofensine, serotonin 2C receptor agonist (eg, lorcaserin), serotonin 6 receptor antagonist, histamine H3 receptor, GABA-regulator (eg, tropine). Specific ester (bp 丨ramate), neuropeptide gamma antagonist (eg · veneperit), cannabinoid receptor antagonist (eg: rimonabant, tayronaban) (taranabant)), ghrelin antagonist, ghrelin receptor antagonist, ghrelin oxidase inhibitor, opioid receptor antagonist (eg: GSK-1521498), orexin receptor antagonist, melanin Cortinin 4 receptor agonist, 11β-base steroid dehydrogenase inhibitor (eg Azd-4017), pancreatic lipase inhibitor (eg: 〇rlistat, cetirizide (cetilistat) )), /5 3 agonist (eg n-5984), dimercaptoglycerol thiol transferase 1 (DGAT1) inhibitor, acetyl group c〇a Carboxylase (ACC) inhibitors, stearyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (eg, r-256918), Na-glucose cotransporter vector inhibitors (eg : JNJ—28431754, remogliflozin, NF/c inhibitors (eg HE-3286), PPAR agonists (eg GFT-505, DRF-11605), phosphotyrosine phosphatase inhibition Agents (eg sodium sulphate, Tr〇dusquemin), GPR119 agonists (eg PSN-821), glucokinase activators (eg AZD-1656), leptin, alizarin derivatives (eg : koji leptin 78 322147 201206909 (metreleptin)), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonist, glucagon peptide-l (GLP-l Formulations (eg, animal GLpq preparations extracted from the pancreas of cattle and pigs, human GLP-1 preparations genetically synthesized using Escherichia coli, yeast, fragments or derivatives of GLP~1 (eg: Essex) Peptide (exenatide, liraglutide), amyloid preparation ( Such as: pramlintide, AC-2307), neuropeptide Y agonist (for example: PYY3-36, derivatives of ργγ3-36, obinePitide, TM-30339, TM-30335 , oxyntomodulin preparation: FGF21 preparation (for example: animal FGF21 preparation extracted from the pancreas of bovine and pig; human FGF21 preparation synthesized by genetic engineering using Escherichia coli, yeast; fragment or derivative of FGF21) ), an appetite reducing agent (for example: P-57). The above "drug therapeutic drugs, examples include angiotensin-converting enzyme inhibitors (for example: captopril, enalapril, deriprii), angiotensin II antagonist Lu (eg, candesartan ci lexeti 1 , candesartan, losartan, losartan potassium, eprosartan, valsartan ( Valsartan), telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, Azsarartan medoxomil, #5 antagonist (eg, manidipine, nifedipine, mödöping 79 322147 201206909 (amlodipine), efonidipine, nick Nicardipine, cilnidipine, beta blockers (eg metoprolol, atenolol, propranolol, carvedilol) ), heart (pin) Dolol)), clonidine, etc. Examples of the above "therapeutic drugs for hyperlipidemia" include HMG-CoA reductase inhibitors (for example: pravastatin, pravastatin, simvastatin) , lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (eg sodium salt, calcium salt) )), squalene synthetase inhibits Qi Ij (for example, a compound described in W097/10224, for example: ^[[(31^,55)-1-(3-acetoxy-2,2-dimethyl) Propyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3' 5-tetrahydro-4,1-benzoxazepine Cycloheptan-3-yl]ethinyl]pipetazone 4, Fibrate compounds (eg, bezafibrate, clofibrate, bisf) Ibrate), cl inof ibrate, anion exchange tree. lipids (eg colestyraraine), probucoi, nicotinic acid drugs (eg nick〇m〇 1), Nisitello (niceritrol), Niacin sustained-release tablets (niaspan), ethyl iC0sapentate, phytosterols (eg, soy sterol, r-oryzanol), cholesterol absorption inhibitors (eg: Seda ( z纣丨^), CETP inhibitors (eg, daleetrapib, anacetrapib), omega-3 fatty acid preparations (eg, ethyl omega acid 9〇) 322147 80 201206909

Examples of the above "anti-atherosclerosis drug" include a sputum enzyme A cholesterol thiol transferase (ACAT) inhibitor (for example, K-604), an LpPLA2 inhibitor (for example, darapladib, rilapa). (rilapladib), FLAP inhibitors (eg AM103, AM803, etc.), 5L0 inhibitors (eg · via-2291), sPLA2 inhibitors (eg A-002), apoAI peptidomimetic (eg : D4F), HDL preparation (for example: CSL-111), and the like. # Examples of the above "antithrombotic agents" include heparin (for example: heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), acetone farin (warfarin) (for example: acetone) Benzyl hydroxycoumarin potassium), antithrombin drugs (eg: aragatroban, dabigatran), FXa inhibitors (eg rivaroxaban, Abigail) Class (apixaban), edoxaban, YM150, compounds described in w〇02/06234, WO 2004/048363, ^w〇2005/030740, W0 2005/058823 or W0 2005/113504), thrombolytic Agents (eg, urinkinase, tisokinase, alteplase, nateplase, monteplase, pampiteplase) Platelet aggregation inhibitors (eg, ticlopidine hydrochloride, ci〇pid〇grel, prasugrel, E5555, SHC530348, cilostazol, One stone anti-pentaic acid ethyl vinegar, burbprost sodium, sand Grid (sarpogrelate) hydrochloride) and the like. 81 322147 201206909

Examples of the above "diuretic" include xanthine derivatives (for example: theobromine sodium salicylate, cocoa salicylic acid i bow), and beta thiazide preparations (e.g.塞哄 (1±1&21(16), cyclopentazone 〇(〇7(:1〇卩€111:1^321(16), trichloromethazide, hydrochloroquinone) Hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutiazide, polythiazide, methyclothiazide, anti-make Solid preparations (eg, spironolactone, triamterene), acid chymase inhibitors (eg, acetazolamide), chlorophenyl salicylamine preparations (eg, chloride towers) Chlortalidone, mefruside, indapamide, azosemide, isosorbide, ethacrynic acid, pitartanide, Budtanide, 弗色

Amine (furosemide) and the like. Examples of the above "therapeutic drug for arthritis" include ibuprofen and the like. Examples of the above "anti-anxiety drugs" include alprazolam, etizolam, oxazolam, tandospirone, cloxazolam, and thiazolidine. Nitrogen (clotiazepam), clorazepate diterpenes, diazonium oxychloride 322147 82 201206909 (chlordiazepoxide), diazepam, fludiazepam, flutazolam ), flutoprazepam, prazepam, bromazepam, prazepam, bromazepam, mexazolam, Medaxi Med (medazepam), ethyl loflazepate, lorazepam, and the like.

Examples of the above "anti-depressants" include tricyclic antidepressants (for example: imipramine, trimipramine, clomipramine, amitriptyline, deuterium) Nortriptyline, amoxapine, lofepramine, dosulepin, desipramine, tetracyclic antidepressants (eg, cytosine) (maproti 1 ine), mianserin, Japanese parsley purine, selective serotonin absorption inhibitors (eg fluoxetine, fluvoxamine) , paroxetine, sertraline, escitalopram, serotonin-norepinephrine absorption inhibitors (eg, milnacipran, duloxetine) , venlafaxine), trazodone, mirtazapine, moclobemide, and the like. Examples of the above "psychotic agent" include conventional antipsychotic agents (for example: clocapramine, chlorpromazine, phenobarbital, sulpiride 322147 83 201206909 ( Sultopride), tiapride, thioridazine, floropipamide, mosapramine, molerone, glucoside Oxypertine), carpipramine, spiperone, sulpiride, zotepine, timiperone, nemonapride, fluoride Haloperidol, pimozide, prochlorperazine 'propericiazine, bromperidol, perphenazine, fluphenazine ( Fluphenazine) maleate, mizoribine, levomepromazine, atypical antipsychotic agents (eg perospirone, olanzapine, quetiapine) Quetiapine), lixirocyclone (r Isperidone), clozapine, aripiprazole, ziprasidone, blonanserin, lurasidone, and the like. Examples of the above "inducing sleep drugs" include Rameteon, GABAergic hypnotics (e.g., bortizolam, estazolam, flurazepam). , nitrazepam, triazolam, flunitrazepam, lormetazepam, hlmazafone, quazepam, zopiclone, Ezopiclone, zolpidem, zaleplon, 84 322147 201206909 Indiplon 'gabaxadol'; non-GABA-induced sleeping pills (eg: Elimin (epHvanserin), pruvanserin, diphenhydramine, trazodone, doxepin, and the like. The administration time of the above-mentioned concomitant drug is not limited, and the compound of the present invention and the concomitant drug can be administered simultaneously or in a staggered manner to the administration object. The dose of the combined drug can be determined according to the dose used in clinical practice, and can be appropriately selected depending on the administration target, the drug-administering route, the disease, the combination, and the like.

The mode of administration of the drug to be used is not particularly limited, and the compound of the present invention and the concomitant drug need only be combined at the time of administration. Examples of such reliance include the following: (1) administering a single-formulation of the compound of the present invention and a concomitant drug simultaneously (2) to separately produce the compound of the present invention and the two preparations of the drug, and simultaneously administering the drug via the (iv) administration route, and (3) separately manufacturing the present month. The phlegm 5 and the two preparations of the drug are administered by the same administration route, in a staggered manner, the drug ('4) is used to produce the compound of the present invention and the two drugs of the concomitant drug are administered by different drugs (4), and (5) to separately manufacture the compound of the present invention. t and the two preparations of the drug are administered in a staggered manner via different administration routes (for example, sequentially administering the combined drug of the present invention or administering in the reverse order), etc. - the seventh sigma and the concurrent drug The mixing ratio can be appropriately selected depending on the subject to be administered, the administration of the drug, the disease, and the like. EXAMPLES The present invention is explained in detail by the following Reference Examples, Examples, and Experimental Examples 85 322147 201206909. The embodiments are not intended to limit the invention, and modifications may be made without departing from the scope of the invention. The term "room temperature" in the following Reference Examples and Examples means a temperature of from 15 ° C to 30 ° C. The dehydration of the organic layer is carried out using anhydrous magnesium sulfate or anhydrous sodium sulfate. Unless otherwise stated herein, "%" is % by weight. The following reference examples and the 2-didecylamino fluorenyl-1,3-bis(dimethy 1 immonio)-propyl bis-tetrafluoro-folate used in the examples are based on F. Method preparation by Wudi et al. (Synthesis 1988, 641-644). The definitions of abbreviations used in this specification are as follows:

Ac.

Me : thiol s : single peak cT · doublet t : triplet q : four peaks dd : doublet dt : double triplet m : multimodal br : broad peak J : coupling constant

Hz: Hertz CDC13: Deuterated chloroform DMA: dimethylacetamide 86 322147 201206909 THF: tetrahydro D-propanol NMP: diterpenyl-2-pyrrolidone DMF: N,N-didecylguanamine DMS0: two Methane sulfoxide &quot;H-NMR: Proton nuclear magnetic resonance FABMS (pos): Mass spectrometry measured by the (+) method on a fast atomic impact mass spectrometer Reference Example 1 • 4-(tetrahydrofuran-2-yloxy)phenylhydrazine The acid was slowly added dropwise at 0 ° C in a solution containing tetrahydrofurfuryl alcohol (25 g), decyl 4-hydroxybenzoate (38 g) and triphenylphosphine (72 g) in tetrahydrofuran (300 mL). A solution of diethyl benzene dicarboxylate (136 mL, 40% in benzene solution) was stirred at room temperature for 2 hours. The reaction solution was concentrated to precipitate triphenylphosphine oxide from ethyl acetate-hexane. The triphenylphosphine oxide was removed by filtration through a glass filter, and the mother liquor was concentrated. The residue was purified by &gt;5 celestial column chromatography [developing solvent; hexane: acetic acid ethyl acetate = 100:0 (volume ratio: hexane: ethyl acetate = 70:10 (volume ratio)], resulting in The obtained colorless oil was dissolved in THF (200 mL) and EtOAc (100 mL). The reaction solution was concentrated, cooled to 0 ° C, EtOAc EtOAc (EtOAc) Colorless crystals of 31%) 4 NMR (300 MHz, DMS0-d6) (5: 1.6 hl. 72 (lH, m), 1.76-1.87 (2H, m), 1.89-2. 06 (1H, m), 3. 69(1H,q,J=6.9Hz), 87 322147 201206909 3.79C1H, q, J=6. 9Hz), 3. 82-4. 06(2H, m), 4. 12-4. 20( 1H, m), 6.99-7. 〇4 (2H, m), 7.85-7.90 (2Η, m), 12.61 (1H, s). Reference Example 2 N_(3_曱醯基~8~methyl Quinoline-7-yl)-4-(tetrahydrofuran-2-yloxy)p-methylcarboxamide was taken as 4-(tetrahydrofuran-2-ylmethoxy)benzoic acid (1. 0 g) (from Reference example 1), Oxalyl dichloride (1. 0 g) and n, n-dimercaptomethyl guanidine (2 drops) were mixed in four atmospheres (250 mL), and the mixture was stirred at room temperature for 2 hours. Narrow the reaction mixture, add n, dimercaptoamine (50 mL), add 2_mercapto-3-stone sulfanilide (10.3 g) and triethylamine (13.9 mL) to the mixture under ice cooling. A solution of N,N-dimethylacetamide (50 mL) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Dehydration, and evaporating the solvent under reduced pressure to give crystals. The obtained crystal, reduced iron (19.5 g) and chlorinated dance (3.9 g) in a mixed solvent of ethanol (500 mL) and water (70 mL) The mixture was heated and stirred for 4 hr. The reaction mixture was filtered and evaporated <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Add morpholine (26 2mL), 2-dimethylaminomethylene-1,3-bis(dimethylimido)propane double Fluoroboric acid (35.7 g) and Bu Ding alcohol (300 here), the mixture was 9〇 £ &gt; c stirred for 24 hours. Acetic acid (5 () mL) and water (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The precipitated crystals were collected, washed with acetic acid and 322147 88 201206909, and dried to give the title compound (7. g, yield 23%) as brown crystal. ^ NMR (300 MHz, DMSO-de) ά : 1. 66-1. 75(1H, m), 1.82-1.94(2Η, m), 1. 98-2. 06(1H, m), 2. 69 (3H, s), 3. 69 (1H, q, J=6.0Hz), 3. 78(1H, q, J=6. 0Hz), 3. 99-4. 11 (2H, m), 4. 16-4. 21(1H, m), 7. 10(2H, d, J=8. 7Hz), 7. 81(1H, d, J=8.7Hz), 8. 01-8. 07(3H, m), 8. 92 (1H, d, J = 2. 1 Hz), 9.30 (1H, d, J = 2.1 Hz), 1 〇 · 18 (1 Η, s), 10.25 (1H, s). • Reference Example 3 4-(tetrahydrofuran-3-ylindoleoxy)benzoic acid in 〇 ° C ' in tetrahydrofuran-3-ylmethanol (21. 89 g), 4-hydroxybenzolic acid vinegar (33. 5 g) tetrahydrogen with triphenylphosphine (64. 5g). A solution of diethyl azodicarboxylate in benzene (12 〇 mL, 4% by weight in toluene) was slowly added dropwise to a solution of π nan (4 〇〇 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and triphenylphosphine oxide was precipitated from ethyl acetate-hexane and filtered using a glass φ filter, and the mother liquid was concentrated. The residue was purified by hydrazine column chromatography [developing solvent; hexane: ethyl acetate = 90: 1 〇 (volume ratio) - hexane: ethyl acetate = 40: 10 (volume ratio)] to give a colorless oil Things. The obtained colorless oil was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL), and 8N sodium hydroxide aqueous solution (1 mL) was added, and the mixture was stirred and stirred at 8 ° C for 2 hours. The reaction solution was concentrated, cooled to EtOAc: EtOAc (EtOAc) The organic layer was washed with EtOAcq. NMRC300 MHz, DMSO-de) ^ : 1. 61-1. 71 (1H, m), 1 97- 322147 89 201206909 2. 08C1H, in), 2. 60-2. 73(1H, m), 3.48- 3. 56(1H, in), 3. 62-3. 69(1H, m), 3. 73-3. 82(2H, m), 3. 88-4. 04(2H, m), 7.02C2H , d, J = 9.3 Hz), 7.88 (2H, d, J = 9.3 Hz), 12.59 (1H, br). Reference Example 4 N-(3-Methylcarbonyl-8-fluorenyl-7-yl)-4-(tetrahydro D-furan-3-yloxy)benzamide was taken as 4-(tetrahydrofuran- 3-methylmethoxy)benzoic acid (22.2 g) (from Reference Example 3), grass oxime (10.2 mL) and N,N-dimethylformamide (2 drops) in tetrahydrofuran (250 mL) After mixing, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and tetrahydrofuran (200 mL) was then evaporated. A solution containing 2-mercapto-3-nitroaniline (14.1 g) and triethylamine (16.7 mL) in tetrahydrofuran (100 mL) was added to the mixture, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate A solution of the obtained crystal, reduced iron (26.0 g) and calcium chloride (5.6 g) in a mixed solvent of ethanol (500 mL) and water (50 mL) was stirred and stirred at 90 ° C for 16 hours. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate To the residue, morphine (26. 2 mL), 2-dimethylaminomethylene-1,3-bis(dimethylimido)propane ditetrafluoroborate (35.7 g) and 1-butanol (300 mL), and the mixture was stirred at 90 ° C for 24 hours. Acetic acid (50 mL) and water (50 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 90 s. The precipitated crystals were washed with EtOAc (EtOAc)EtOAc. FABMS(pos): 391 [MH]+ Reference Example 5 4-[(2R)-tetram-oxa-2-ylmethoxy]benzoic acid containing (2R)-tetrahydrofuran-2-carboxylic acid (23.2 g The solution of benzene (240 mL) and decyl alcohol (80 mL) was cooled to 0 ° C, and triazomethane (100 mL, 2.0 Μ hexane solution) was slowly added dropwise. After the dropwise addition was completed, the mixed φ was stirred at 0 ° C for 30 minutes. The reaction solution was concentrated, and tetrahydrofuran (500 mL) was added to residue. The reaction solution was cooled to 0 ° C, and the hydrogenation chain was slowly added dropwise (100 mL, 2.0 Μ tetrahydrofuran solution). After the dropwise addition was completed, the mixture was stirred at 0 ° C for 2 hours. Sodium sulfate decahydrate was slowly and carefully added to the reaction solution at 0 ° C until the foaming was stopped, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite (ce 1 i te) to remove insoluble material, and the solvent was evaporated under reduced pressure to give a colorless liquid (10.0 g). Slowly at 0 ° C in a solution containing the resulting colorless liquid (18.0 g), 4-hydroxybenzoic acid decyl ester (27. 4 g) and triphenyl phosphine (53.2 g) in tetrahydrofuran (400 mL) A solution of toluene (40 ° / benzene solution) (99 mL) containing diethyl azodicarboxylate was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and triphenylphosphine oxide was precipitated from ethyl acetate-hexane and filtered using a glass filter, and the mother liquid was concentrated. The residue was purified by NH-Shih-Hybrid column chromatography [developing solvent; hexanes: ethyl acetate = 100: 0 (volume ratio) - hexane: ethyl acetate = 90: 10 (volume ratio)], yielding colorless Oily. The obtained colorless oil was dissolved in tetrahydrofuran (200 mL) and methanol (200 mL), and the mixture was stirred and stirred at 80 ° C for 2 hr. The reaction solution was concentrated, cooled to EtOAc (EtOAc),EtOAc. The organic layer was washed with EtOAc EtOAc EtOAc. 4 ^R(300 MHz, DMSO-d6) 6: 1.61-1.72 (lH, m), 1.75- 1.92C2H, m), 1. 94-2. 06(1H, m), 3. 67(1H, q , J=6. 3Hz), 3. 77(1H, q, J=6. 3Hz), 3. 81-4. 06(2H, m), 4. 12-4. 20(1H, m), 7.01 (2H, d, J = 9. OHz), 7.87 (2H, d, J = 8.4 Hz), 12. 60 (1H, s). _ Reference Example 6 N-(3-Methylcarbonyl-8-methylindol-7-yl)-4-[(2R)-tetrahydropyran-2-ylmethoxy]benzimidamide 4 -[(2R)-tetrahydrofuran-2-yloxy]phenyl decanoic acid (38.3 g) (from Reference Example 5), grass 醯 gas (17.5 mL) and N,N-dimethyl decylamine (3 drops) were mixed in tetrahydrofuran (250 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and tetrahydro-p-pyran (300 mL) was added to the residue. Add a solution of 2-mercapto-3- nitrosoaniline (25 g) and triethylamine (28.7 mL) in tetrahydrofuran (1 mL) at room temperature under ice cooling. The mixture was disturbed for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate Palladium on carbon (1.5 g) was added to a solution of the obtained crystals of methanol (500 mL) and tetrahydrofuran (200 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. Add 322147 92 201206909 to the residue obtained, add morpholine (78 mL), 2-dimethylaminomethylene-^-bis(dimethylammonium)propane ditetrafluoroborate (丨07幻和丨_ Butanol (5 〇〇 mL), the mixture was stirred at 80 C for 14 hours. To the reaction mixture was added EtOAc (EtOAc) and water (EtOAc) The reaction mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. NMR NMR (300 MHz, DMSO-de) 5 : 1. 66-1. 75C1H, m), 1.81-1.94 (2H, m), 1. 98-2. 04(1H, in), 2. 69(3H , s), 3.68 (1H, • q, &gt; 6.3 Hz), 3.78 (1H, q, J=6. 3Hz), 3. 99-4. 10(2H, ffl), 4.17-4.2K1H, m) , 7.08-7.12(2H, m), 7.81(1H, d, 8.7Hz), 8.01-8.06C3H, m), 8.91(1H, d, J=2.4Hz), 9.30 (1H,d,&gt;2.4Hz ), 10.17 (1H, s), 10.24 〇Η, s). Reference Example 7 (2S)-tetrahydrofurfuryl alcohol Take (2S)-tetrahydro Ml (46.4 g) toluene (10) This) and methanol (16 〇mL) solution was cooled to rc, slowly added (three Basestone Xizhuo base) Diazo A burn (200 mL ' 2. G Μ 院 院 solution). After the dropwise addition was completed, the mixture was stirred at 〇 ° C for 30 minutes. Concentrate the reaction solution and add four nitrogen bites to the south (10) rainbow) to the residue (four) +. The reaction was cold and light, and the hydrogenation was slowly carried out (2 〇〇 mL, 2.0 M tetrahydrogen solution). After the dropwise addition was completed, the mixture was stirred for 2 hours. At 〇t, the sulfuric acid and the decahydrate were slowly added carefully to the reaction solution until the foaming was stopped, and the mixture was stirred at room temperature for 2 hours. The reaction solution was passed through a celite to remove the insoluble material, and the solvent was evaporated under reduced pressure to give the title compound (28.7 g, yield as a colorless oil. 322147 93 201206909 NMR (300 MHz, CDCh) d : 1 62-1. 70(1H, m), 1.85-1.99C3H, m), 2. 56-2. 62(1H, m), 3. 46-3. 54(1H, in), 3.63 -3.70 ( 1H, m), 3.74-3.90 (2H, m), 3. 97-4.05 (1Η, m). Reference Example 8 4-[(2S)-Tetrahydrofuran-2-ylmethoxy]benzoic acid at 0 ° C, containing (2S)-tetrahydrofurfuryl alcohol (28.7 g) (from Reference Example 7), 4 - Benzyl hydroxybenzoate (44g) and triphenylphosphine (85 g) in tetrahydrofuran (400 mL) were slowly added dropwise with diethyl azodicarboxylate (40 ° / benzene) The solution (99 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated, and triphenylphosphine oxide was precipitated from ethyl acetate-hexane and filtered using a glass filter, and the mother liquid was concentrated. The residue was purified by NH-purchhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh The obtained colorless oil was dissolved in tetrahydrofuran (400 mL) and methanol (200 mL), and 8N aqueous sodium hydroxide (120 mL) was added, and the mixture was stirred and heated at 80 ° C for 2 hours. The reaction solution was concentrated and cooled to 0. The mixture was stirred with EtOAc EtOAc EtOAc. ^R(300 MHz, DMSO-d6) 5: 1.64_1.72 (lH, m), 1.82-1.92 C2H, m), 1. 95-2. 04(1H, m), 3.68(1H, q, J =7. 2Hz), 3. 78(1H, q, J=7. 2Hz), 3. 95-4. 06(2H, m), 4. 14-4. 19(1H, m), 7. 02 (2H, d, J=8. 7Hz), 7. 88(2H, d, J=8. 4Hz), 12.62 (1H, s). 94 322147 201206909 Reference Example 9 N-(3-Methylamino-8-indenylhydrazone #-7-yl)-4-[(2S)-tetrahydrofuran-2-yloxyl] 4-[(2S)-Tetrahydro-pyranosyl-methoxy]benzoic acid (45 g) (from Reference 8), grass chloroform (19.5 mL) and N,N-dimethylmethyl The guanamine (〇 5 mL) was mixed in tetrahydrofuran (280 raL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and tetrahydrofurane (3 〇〇 EtOAc) was then evaporated. A solution of 2-methyl-3-nitroanilide (29.5 g) and triethylamine (32 mL) in tetrahydrofuran (100) was added to the mixture, and the mixture was stirred at room temperature for 24 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate Palladium carbon (3.0 g) was added to a solution of the obtained crystals in methanol (600 mL), and the mixture was stirred at room temperature for 4 hr. After the reaction was completed, the solvent was evaporated under reduced pressure. To the residue was added morpholine (102 mL), 2-didecylamino fluorenyl-1,3-φ bis(dimethylimido)propane ditetrafluoroborate (139 g) and 1- Butanol (500 mL) 'The mixture was stirred at 80 ° C for 14 hours. Acetic acid (70 mL) and water (80 mL) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with ethyl acetate. The organic layer was purified by EtOAcjjjjjjjjjjj H NMRC 300 MHz, DMSO-de) 5 : 1. 69-1. 75(1H, m), 1.84-^94(211, m), 1. 98-2. 07(1H, m), 2. 69( 3H, s), 3.69 (1H, J=6.6Hz), 3.79(1H, q, J=6. 6Hz), 3. 99-4. 10(2H, m), 322147 95 201206909 4. 15-4. 22(1H, m), 7. l〇(2H, d, J=8. 7Hz), 7.82(1H, d, J=8.7Hz), 8.02-8.05(3H, m), 8.89(1H, d, J = 2. 1 Hz), 9.29 (1H' d, J = 2.4 Hz), 10. 17 (1H, s), 10.24C1H, s). Reference Example 10 Methyl 2-fluoro-4-hydroxybenzoate A solution of 2-fluoro-4-hydroxybenzoic acid (50. 〇g) and concentrated sulfuric acid (1 〇) in decyl alcohol (700 mL) at 9 Hey. (The mixture was heated and stirred for 16 hours. The obtained colorless crystals crystals crystals crystals crystals crystals crystals crystalssssssssssssssssssssssss (3H, s), 6. 61-6. 72(2H, m), 7.73-7.79C1H, m), 10.80(1H, br). Reference Example 11 2-Fluoro-4-[(2S)-tetrahydrofuran-2-ylindoleoxy] oxalic acid at 0 ° C ' in (2S)-tetrahydrofurfuryl alcohol (30. 0 g) (from reference Example 7), 2-fluoro-4-hydroxybenzoic acid decyl ester (50.0 g) (from Reference Example 1) and triphenylphosphine (88.9 g) in tetrahydrofuran (350 mL) solution slowly A solution of azo-mono-acid-acetic acid (40% benzene solution) (166 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the triphenylphosphine oxide was precipitated from ethyl acetate-hexanes and removed using a glass filter. The mother liquor was concentrated. The residue was purified by NH-purchhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh Colorless crystals. The obtained colorless crystals were dissolved in tetrahydrofuran (500 mL). </ RTI> </ RTI> </ RTI> </ RTI> 8N aqueous sodium hydroxide solution (1 liter) was added, and the mixture was heated at (10) for 3 hours. The reaction solution was concentrated, cooled to EtOAc (EtOAc)EtOAc. The organic layer was washed with EtOAc EtOAc. NMR NMRC300 MHz, DMSO-de) &lt;5 : 1. 60-1. 71 (1H, m), 1.75-1.92C2H, m), 1. 94-2. 06(1H, m), 3.69(1H, q, J=6. 9Hz), 3. 77(1H, q, J=6. 9Hz), 3. 96-4. 09(2H, m), 4. 12-4. 20(1H, m), 6. 84-6. 92(2H, m), 7. 78-7. 84(1H, m), 12.85(1H, br) ° • Reference Example 12 2 - Fluorine-N-(3 - 曱-based - 8-fluoro-4-[(2S)-tetrahydrofuran, 4-[(2S)-tetrazo-α-Fruccinan-2-yloxy]benzamide -2-yl decyloxy]benzoic acid (11.0 g) (from Reference Example 11), chlorophyll chloride (4.77 mL) and N,N-dimethylformamide (0.55 mL) It was mixed with tetrahydro D-propan (200 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and EtOAc (EtOAc) A solution of 2-w-mercapto-3-nitroaniline (6.85 g) and triethylamine (8.36 mL) in tetrahydrofuran (100 mL) was added to the mixture and the mixture was stirred at room temperature for 24 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated. Palladium carbon (1.0 g) was added to a solution of the obtained sterol (750 mL), and the mixture was stirred at room temperature for 4 hr. After the reaction was completed, the solvent was evaporated under reduced pressure. To the residue was added morpholine (23 mL), 2-didecylamino fluorenyl-1,3-bis(dimethylimido)propane ditetrafluoroborate (30.0 g) and 97 322147 201206909 1-butanol (300 mL), the mixture was stirred at 8 (TC) for 14 hours. Acetic acid (20 mL) and water (20 mL) were added to the mixture and the mixture was stirred at room temperature for 2 hr. The organic layer was washed with EtOAc EtOAc (EtOAc m. 5 : 1.64-1.73(1H, m), 1.83-1.93(2H, m), 1. 97-2. 05(1H, m), 2. 72(3H, s), 3. 71(1H, q, J=6. 3Hz), 3. 79(1H, q, J=6. 3Hz), 4. 00-4. 09(2H, m), 4. 11-4.20C1H, m), 6.93-7. 04 (2H, m), 7.77 (1H, d, J = 8.7 Hz), 7. 97-8.08 (2H, m), 8.91 (1H, s), 9.29 (1H, s), 10.03 (1H, s), 10.24 (lH, s). Reference Example 13 (cis-4-hydroxy-4-mercaptocyclohexyl)amine benzoate (trans-4-hydroxy-4-mercaptocyclohexyl)amine benzoate benzoate under nitrogen atmosphere, Phenyl benzoate (4-oxocyclohexyl)amine phthalate (2 〇 1 mg) was dissolved in THF (15 mL) and the mixture was cooled to -78. A THF solution (1.5 M, 1.63 mL) containing methyllithium-lithium bromide complex was added dropwise at the same temperature, and the mixture was stirred for 3.5 hours. A saturated aqueous solution of ammonium chloride was added, and the mixture was heated to room temperature and partitioned and extracted with ethyl acetate. The organic layer was washed with water and brine, and evaporated. The residue was purified by silica gel column chromatography [developing solvent, calcined. acetic acid B: 8: 2 (volume ratio) &gt; hexane: ethyl acetate = 7 : 13 (volume ratio)] The title compound (trans type 33.9 mg, yield 16%) was obtained as a colorless oil. 322147 98 201206909 cis type ^HNMRCSOOMHz, CDC13)&lt;5:1·〇9(1Η,br. s.),1.23 (3H, s), 1.41-1. 71(6H, m), 1. 74- 1. 88(2H, m), 3. 48(1H, br. s. ), 4. 65(1H, br. s. ), 5. 09(2H, s), 7. 28-7. 39( 5H, m) ° Trans type: ^ NMR (300 MHz, CDC13) c5 : 1.19_1.30(4H, m), 1. 31-1.47C2H, m), 1.47-1. 70(4H, m), 1. 88-2. 03(2H, m), 3. 57-3.72(1H, m), 4.69(1H, br. s. ), 5. 09(2H, s), 7. 29-7. 40 (5H, m). φ Reference Example 14 cis-4-amino-1-indolylcyclohexanol (cis-4-hydroxy-4-methylcyclohexyl)amine benzoate (28, 76 g) (obtained from Reference Example 13) was mixed with palladium hydroxide (P(i: 20%, 2.876 g) in THF (100 mL) and decyl hydrazine) in a mixed solvent of activated carbon, and the mixture was mixed at 1 atm. Atm) was stirred under hydrogen for 15 hours. The reaction solution was filtered through celite, and the filtrate was evaporated. The residue was suspended in ethyl acetate. EtOAc (EtOAc m. HIVMR (300 MHz, DMS0-d6) 3: i. 〇 6 (3H, s), 1.17-1.57 (8 Η, m), 2.42-2.47 (1 Η, m). Reference Example 15 Trans-4-Amino-1-methylcyclohexanol Benzyl (trans-4-hydroxy-4-methylcyclohexyl)aminecarboxylate (1 〇〇g) (from Reference Example) 13) Mix with the carbon (Pd: 5%, 1 () §) in decyl alcohol (1 L) and mix for 18 hours under hydrogen atmosphere. Remove the insoluble material, minus 99 322147 201206909 Concentrate the filtrate to give the title compound (49 q „ solid. Colorless 'H NMRC 300 MHz, CDCh) (5: 1 ίο , 〇p, · chuan hunger m), 2.76- Reference Example 16 4-Phenyl-4-indenyl-e-deconazole-based benzalkonium chloride was taken in ruthenium chloride (9.33 mL, 3. 〇M Α hydrazine (45.5 mL). Take 4-sided oxy-, =% solution) to add four g) dissolved in tetrahydrogen (8.8 mL)' and add dropwise to ice-cooled gasification (5 A = tetrahydrogen (tetra) solution The mixture was incubated at room temperature for a few hours. The mixture was ice-cooled, and the vaporized ammonium cut solution was added dropwise (chlorinated § §, 15(6)' was dissolved in acetic acid and the mixture was extracted. The aqueous layer was subjected to ethyl acetate. Stretching, the combined organic layer was dehydrated by magnesium sulfate. (4) Purification by column chromatography [developing solvent; hexane: ethyl acetate: 2 〇 (volume ratio 40 (volume ratio)]. The more the knees were washed, and dried under reduced pressure to give the title compound (4.20 g, yield: 79%) as one color solid, HNMRCSOO MHz, DMS0-d〇, :., 12 (3H, 3),, 31-1.52 (^ ^ 3.20(2H, br. S), 3. 63(2H, dt, J=i3.〇, 3. 9Hz), 4.35 OH , s), 5.06 (2H, s), 7.26-7.54 (5H, m) Reference Example 17 4-methylpiperidin-4-ol monohydrochloride. 4-hydroxy~4~methylpiperidine-1 - Carboxylic acid benzyl ester (6 28g) is dissolved in A, (丨 25 ml), 1% palladium on carbon (9 〇〇) is added, and the mixture is mixed with hydrogen at room temperature for 14 hours at room temperature. The residue was diluted with MeOH (25 mL). EtOAc (EtOAc) 3.57 g, 93%) of a colorless solid. 沱fiMR (300 MHz, DMSO-de) 5 : 1.16 (3H, s), 1.54-1 · 74 (4H, m), 2. 95-3. 08 (4H, m), 4. 70(1H, s), 8. 90(1H, s), 9.00 (1H, s). Example 1 1^-(3-{[(2-hydroxy-2-methylpropyl) Amino]mercapto}-8-mercaptoquinoline-7-•yl)-4-(tetrahydrofuran-2-ylindoleoxy)benzamide

Take N-(3-methylindenyl-8-methylindol-7-yl)-4-(tetrahydromethane-2-yloxy)benzamide (1.0 g) (from reference example) 2) Suspended with 1-amino-2-methylpropan-2-ol (321 mg) in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7.0 mL), stirred at room temperature The mixture was 3 hours. Sodium triethyl sulfoxyborohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous solution of sodium oxide and the mixture was assayed. The mixture was partitioned and extracted with ethyl acetate. The organic layer was added to a solution of citric acid (4.0 g) in water (4 〇 raL)-dimethylsulfoxide (2 〇mL), and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (280 mg, ^NMROOOMHz, DMSO-de) 5 : 1. 12(6H, s) , 1.66-1.75(1Η, m), 1. 83-1. 92(2H, m), 1. 94-2. 05(1H, m), 2.42(2H, s), 2.64(3H, s), 3. 33C1H, br), 3.66-3.73(1H, m), 3.77- 3.84(1H, m), 3. 94(2H, s) , 3. 98-4. 10(2H, m), 4.15- 4.22(2H, m), 7. 08(2H, d, J=9.0Hz), 7.58(1H, d, J= 8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 02(2H, d, J=9. 0Hz), 8. 19(1H, s), 8.90C1H, s),10.05(1H, s ).

Melting point: 138 ° C Elemental analysis (C27H33N3 〇 4. 0.25H2 〇) Calculated: C, 69.28; H, 7.21; N, 8.98 Found: C, 69.26; H, 7.13; N, 8.68 Example 2 N_( 3-{[(trans-4-hydroxycyclohexyl)amino]indolyl 8_mercaptoquinoline-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)phenylamine

Take N-(3-mercapto-8-methylindole +yl)_4_(tetrahydrocarbamate-2-yloxy)benzamide (1.0 g) (from Reference Example 2) and trans _4_Amino-p-hexanol (415 mg) is written in lm. Mix the mixture (2Q mL) with acetic acid (7.0 mL) for 3 hours at room temperature (iv). Triethyl ethoxylated 322147 102 201206909 Sodium borohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding an aqueous solution of hydrogen in hydrogen and the mixture was assayed. The mixture was partitioned with ethyl acetate and the mixture was evaporated. EtOAc EtOAcjjjjjj A 1 N aqueous solution of sodium hydroxide was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether afforded the title compound (130 mg, yield 10%). • !H NMR (300 MHz, DMSO-de) (5: 1. 01-1. 14(4H, ra), 1.72-2.01 (9H, m), 2. 10-2.37 (2H, m), 2. 63(3H, s), 3.68-3.7K1H, m), 3. 79-3. 81(1H, m), 3.91(2H, s), 4.00-4.10 (2H, m), 4. 17-4. (1H, d, J) =8. 7Hz), 8.01(2H, d, J=8.4Hz), 8. 19(1H, s), 8.88(1H, s), 10. 04(1H, s). Melting point: 155 ° C Example 3 N-[3-({[(lS,2S)-2-hydroxycyclohexyl]amino}indolyl)-8-mercaptoquinolin-7-yl]-4-( Tetrahydrofuran-2-yl decyloxy) benzoguanamine

103 322147 201206909 Take N-(3-methylindenyl-8-methylquinolin-7-yl)_4_(tetrahydrofuran-2-ylmethoxy)benzamide (1. 〇g) (from Reference Example 2) And trans-aminocyclohexanol (546 mg) was suspended in 1-methyl-2-pyrrolidinone (2 mL) and acetic acid (7.05 LL), and the mixture was stirred at room temperature for 3 hours. Sodium triethoxy hydride sodium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous solution of sodium hydroxide and the mixture was assayed. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to water (br. br.) (4 g of dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. The aqueous layer was partitioned between EtOAc and EtOAc (EtOAc m. Compound (395 mg 'yield 32%) as a colorless solid. </RTI> NMR (300 MHz, DMSO-de) 5 : 0. 98-1. 23 (4H, m), 1.59-2.08 C9H, m), 2. 22-2. 29(1H, m), 2. 64(3H, s), 3.17-3.19 (1H, ra), 3.66-3.9K3H, m), 3. 98-4. 10(3H, m), 4.15-4. 23(1H, m), 4. 64(1H, d, J=4. 8Hz), 7. 08(2H, d, J=9. 0 Hz), 7. 57(1H, d, J=9. 0Hz), 7. 77(1H, d, J=9. 0Hz), 8.01 (2H, d, J=9.0Hz), 8. 21(1H, s), 8. 89(1H, s ), 10.04 (1H,

s). Melting point: 197 ° C Elemental analysis (C29H35N3 〇4 · 0. 2H2 〇) Calculated: C, 70.62; H, 7.23; N, 8. 52 Found: C, 70. 81; H, 7.28; N, 8 31 Example 4 104 322147 201206909 N_[3-({[(1S,2S)-2-hydroxycyclopentyl]amino fluorenylmethyl)-8-fluorenylquinolin-7-yl]-4-(tetrahydrofuran -2-ylmethoxy)benzamide

N-(3-Mercapto-8-fluorenylquinolin-7-yl)-4-(tetrahydrofuran-2_ rumyloxy)benzamide (1.3 g) (from Reference Example 2) And (is, 2S)-2_Aminocyclopentanol (633 mg) was suspended in 1-methyl-2-π ratio α each ketone (2 〇) and acetic acid (7.0 mL), stirred at room temperature The mixture was 3 hours. Sodium triacetate sodium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1N aqueous sodium hydroxide and the mixture was basified, partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography [developing solvent, decyl alcohol: ethyl acetate = 0: 100 (volume ratio) - decyl alcohol: ethyl acetate = 20: 80 (volume ratio)] to give the title compound (59.2, yield 4%) of a colorless solid. H NMR (300 MHz, DMSO-de) &lt;5: 1. 29-1.46 (3H, m), 1 53-1.63 (2H, m), 1.66-1.76 (1H, m), 1.77-1.94 (3H, m), 1. 98-2. 06(1H, m), 2.23(1H, br), 2.63(3H, s), 2. 78-2. 8K1H, m), 3. 66-3. 73(1H , m), 3. 77-3. 84(2H, m), 3. 92(2H, s), 3. 98-4. 10(2H, m), 4. 15-4. 21 (1H, m ), 4. 51(1H, d, J=4. 2 Hz), 7. 〇8(2H, d, J=8. 7Hz), 7. 57(1H, 322147 105 201206909 d, J=8.4Hz) , 7.77C1H, d, J=8.4Hz), 8. 01(2H, d, J=8.7Hz), 8.20(1H, s), 8.89(1H, s), 10.03C1H, s). Elemental analysis (C28H33N3O4) Calculated: C, 70. 71; H, 6.99; N, 8. 84 Found: C, 70.48; H, 7. 02; N, 8. 68 Example 5 N-( 3-{[(2-methoxy-2-mercaptopropyl)amino]indenyl}-8-decylquinolin-7-yl)-4-(tetrahydrofuran-2-ylindoleoxy)benzene Indoleamine monohydrochloride

Taking N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (1.0 g) (from Reference Example 2) 2-oxo-2-methylpropan-1-amine 0.5 oxalate (600 mg) was suspended in hydrazin-2-pyrrolidone (10 mL) and acetic acid (5.0 mL) and stirred at room temperature The mixture was 3 hours. Sodium triethoxysulfonium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned with EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained amorphous product was dissolved in ethyl acetate, and a 4N hydrochloric acid-ethyl acetate solution (0.15 mL) was added. The obtained solid was recrystallized from EtOAc EtOAc (EtOAc:EtOAc)沱 R (300 MHz, DMSO-ώ) 6 : 1. 20 (6H, s), 1. 68-1. 72 (1H, m), 1.87-1.90C2H, m), 1. 96-2.00 (2H , m), 2.68(3H, s), 2. 97-3. 00(1H, m), 3. 11(3H, s), 3. 68-3. 81 (2H, m), 4. 02- 4. 06(2H, m), 4. 16-4. 20(1H, m), 4. 42(2H, s), 7.09 (2H, d, J=8. 7Hz), 7. 75C1H, d, J=8.7Hz), 7. 90(1H, d, J=8. 7 Hz), 8.04C2H, d, J=8. 7Hz), 8.72(1H, s), 9. 20(1H, • s) , 9.27 (2H, br), 10.25 (1H, s). Example 6 N-(3-{ [(2-Hydroxy-2-methylpropyl)amino]indolyl}-8-fluorenylquinolin-7-yl)-4-(tetrahydroanthracene- 3-ylmethoxy)phenylamine

φ N&quot;*(3_fluorenyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-3-yloxy)benzamide (1.1 g) (from Reference Example 4) And 1-amino-2-methylpropan-2-ol (351 mg) was suspended in 1-mercapto-2-pyrrolidone (2 〇) with acetic acid (7.0 mL), and the mixture was stirred at room temperature 3 hours. Triethylphosphonium hydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a 1N aqueous solution of sodium hydroxide and mixture mixture was partitioned, ethyl acetate was partitioned and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography 322147 107 201206909 [developing solvent; decyl alcohol: ethyl acetate = 0: 100 (volume ratio) - decyl alcohol: ethyl acetate = 20: 80 (volume ratio)] Compound (58 mg, yield 4 ° / mp) as a colorless solid. !H NMR (300 MHz, DMSO-de) d : 1.11 (6H, s), 1. 66-1. 72 (1H, m), 1.99-2.08 (lH, m), 2.31 (1H, br), 2.48 (2H, s), 2.64 (3H, s), 2.69-2. 72(1H, m), 3.54-3.58(1H, m), 3.63-3. 71(1H, m), 3. 75-3. 84(2H, m), 3. 94(2H, s), 3.99-4.08 (2H, m), 4.21(1H, s), 7.09(2H, d, J=8.4Hz), 7.57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 02(2H, d, J=8. 4

Hz), 8.20 (1H, s), 8.91 (1H, s), 10.05 C1H, s). Elemental analysis (C27H33N3 〇 4. 0.75H2 〇) calcd.: C, 67.97; H, 7.29; N, 8.81 Found: C, 67.85; H, 6.90; N, 8. 43 Example 7 N -(8-Methyl-3-{[(l-decylethyl)amino]indolylquinoline-7-yl)_4_(tetrahydrofuran-3-yloxy)benzamide

Taking N-(3-methylindenyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-3-ylindoleoxy)benzamide (1.1 g) (from Reference Example 4) Isopropylamine (233 mg) was suspended in 丨-methyl-2-pyrrolidinone (2 )) and acetic acid (7. 〇) to stir the mixture for 3 hours. Add sodium triethoxy borohydride

10S 322147 201206909 (2. 35 g), the mixture was stirred at room temperature for 3 hours. A 1 N aqueous sodium hydroxide solution was added to terminate the reaction and alkalinize the mixture. The mixture was partitioned with ethyl acetate and the mixture was extracted. EtOAc (EtOAc) A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (yield: 1.71(1H, in), 2. 03-2. 07(1H, m), 2. 50-2. 54(2H, m), 2.63 (3H, s), 2.69-2.77C2H, m), 3.54- 3.58(1H, m), 3.66-3. 71(1H, m), 3.79-3.84C2H, m), 3. 89-4. 04(3H, m), 7. 〇8 (2H, d, J= 8.4Hz), 7.57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8.7Hz), 8. 02(2H, d, J=8.4Hz), 8. 20(1H , s), 8.89 (1H, s), 10. 04 (1H, s).

Melting point: 106°C Elemental analysis value (C26H31N3O3. 3.OH2O) Calculated: C, 64· 05 ; H, 7· 65 ; N, 8. 62 Found: C, 64. 03 ; H, 7. 38 N, 8. 31 Example 8 N-丨8-mercapto~3-[(tetrahydro-2H-piperidin-4-ylamino)indolyl]quinolin-7-yl} 4—(tetraindole) 0f-amyl-3-yloxy)benzamide 109 322147 201206909

J N-. -Methylmercapto-methylsulfonyl)- 4_(tetra-argon-methyl-3-yloxy) 4-SiSiamine (1.5 g) (from Reference Example 4) and tetrahydropentan-4 -Amine hydrochloride (10 mg) was suspended in a mixture of the mixture of the mixture and the mixture. Triethyl ethoxylated sodium (2.35 g) was added at room temperature _ mixture 3 ^. The reaction was quenched by the addition of 1 N sodium hydroxide and the mixture was assayed, dissolved in ethyl acetate and the mixture was extracted. The organic layer, _ and brine, were dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc Rate of colorless solid. °H NMR (300 MHz, DMSO-d6) (5: 1.24- 1.37 (2H, in) i65- 1.74 (1H, m), 1.80-1. 84 (2H, m), 1.99-2. 10(1H,m),2 58 (2H, s), 2.61-2.73C1H, m), 2. 63(3H, s), 3. 22~3. 39(4H, in), 3. 54-3 63(1H, m), 3. 66-3. 75(1H, m), 3.77-3.85(3H in), 3.94(1H, s), 3. 98-4.08(2H, m), 7. 〇 8(2H, d, J=8.7 Hz), 7. 57(1H, d, J=8.7Hz), 7.77(1H, d, J=8. 7Hz) B.〇2(2H, d, J=8 .7Hz), 8.20(1H, s), 8. 9〇(iH, s)' 10. 05(1H,s). 'Elemental analysis value (—Ν3〇4 · 1. 6H2〇) 322147 110 201206909 Calculated value : C, 66. 67 ; H, 7. 23 ; N, 8. 33 Found: C, 66.50 ; Η, 7.06 ; N, 8. 03 Example 9 N-(3-{[(trans-4-) Hydroxycyclohexyl)amino]methyl b-8-methylquinoline-7-yl)-4-(tetrahydrofuran-3-ylmethoxy)benzamide

Take N-(3-mercapto-8-fluorenylquinolin-7-yl)_4_(tetrahydrofuran_3_ylmethoxy)phenylguanamine (1.5 g) (from Reference Example 4) and The _4-aminocyclohexanol (622 mg) was suspended in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxy hydride sodium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was stopped and the mixture was assayed by adding 1 N hydrogen peroxide to water. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to a solution of citric acid (4 〇 g) in water (4 〇mL) _ 曱 曱 。 (20 mL) and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained solid was recrystallized from ethyl acetate-diisopropyl ether afforded the title compound (yield: H NMR (300 MHz, DMSO-ds) 5 : 1. 02-1. 14(4H, m), 1.63-1.74 (2H, m), 1. 78-1. 91(4H, m), 1. 99-2. 10(1H, m), 2. 36-2. 38(1H, m), 2. 63(3H, s), 2. 64-2. 71 (1H, m), 322147 111 201206909 3 32-3. 34(1H, m), 3. 53-3. 58(1H, m), 3. 63-3. 70(1H, m), 3. 75-3.84(2H, m), 3 91(2H, s), 3. 95-4. 08(2H, in), 4. 44(1H, d, J=3. 9Hz), 7. 09(2H, d, J=8. 7Hz) , 7. 57(1H, d, J=8.7 Hz), 7.77(1H, d, J=8.7Hz), 8.02(2H, d, J=8. 7Hz), 8. 18(1H,s),8.88 (1H, s), 10.03 (1H, s). Elemental analysis (C29H35N3 〇4 · 0.4M)) Calculated: C, 70.11; H, 7.26; N, 8. 46 Found: C, 70. 41; H, 7.25; N,8 49 Example N N-(8-Mercapto-3-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}quinolin-7-yl)-4-(tetrahydrofuran-2-yloxime Benzomamide

Taking N-(3-mercapto-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (2.5 g) (from Reference Example 2) Tetrahydrofurfurylamine U. 01 g) was suspended in 1-mercapto-2-n ratio p π ketal (2 〇 mL) and acetic acid (7. 〇 mL) in a mixture of /jm for 3 hours. Sodium triethoxy hydride sodium hydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was stopped by adding 1 N aqueous sodium hydroxide solution and the mixture was alkalized. The mixture was partitioned with ethyl acetate and the mixture was extracted, and the organic layer was applied to water (4 〇g) of water (4 〇 </ RTI> </ RTI> </ RTI> dimethyl sulfoxide (2 〇 raL) and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with EtOAc EtOAc EtOAc EtOAc. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (1.93 g, yield: NMR NMR (300 MHz, DMSO-de) (5: 1. 50-1. 58(1H, m), 1.66-2.08C6H, m), 2. 57-2. 59(2H, in), 2. 63 (3H, s), 3.27-3.32 (2H, m), 3.56-3.66(1H, m), 3.68-3.84(3H, m), 3.86-3.93C4H, m), 3. 98-4. 10(2H , m), 4. 15-4. 23(1H, m), 7.08 (2H, d, J=8.7Hz), 7. 57(1H, d, J=8.7Hz), 7. 77(1H, d , • J=8.7Hz), 8. 02(2H, d, J=8. 7Hz), 8. 19(1H, s), 8.89(1H, s), 10. 05(1H, s). Elemental analysis (C28H33N3 〇4. 2.5H2 〇) Calculated: C, 64. 60 ; H, 7. 36 ; N, 8. 07 Found: C, 64. 47 ; H, 7. 20 ; N, 8 08 Example 11 N-(3-{[(2, 2-Dimethylpropyl)amino]indolyl}-8-methylquinolinyl-7-yl) ▲ -4-(tetrahydrofuran -2-yloxy)phenylamine

B^I&lt; Take N-(3-methyldecyl-8-fluorenylquinolin-7-yl)-4-(tetrahydrofuran-2-yloxy)benzamide (2.5 g) (from phase 2) And the neopentylamine «72 1^) was suspended in the oxime-based 2_ 吼 辋 辋 辋 (2〇乩) and acetic acid 〇乩 〇乩 中The mixture was stirred at room temperature for 3 hours by adding triethyl ethoxylation to sodium 322147 113 201206909 (3. 5 g). The reaction was stopped by adding 1 N aqueous sodium hydroxide solution and the mixture was alkalized. The mixture was partitioned with EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from ethyl acetate-diisopropyl acetate to give the title compound (1. 79 g, yield 61%) as a colourless solid. !H NMR (300 MHz, DMSO-de) (5: 0.88 (9H, s), 1. 66-1. 75 (1H, m), 1. 84-1. 94(2H, m), 1. 98 -2. 06(1H, m), 2. 15(1H, br), 2.27(2H, s), 2.64(3H, s), 3. 69(1H, q, J=8. 1Hz), 3.79 ( 1H, q, J=8. 1Hz), 3.92(2H, s), 3.98-4. 10(2H, m), 4. 17-4. 21(1H, m), 7. 08(2H, d, 0=9. 0Hz), 7. 57(1H, d, J=9.0Hz), 7.77(1H, d, J=9. 0Hz), 8.0K2H, d, J=9. 0Hz), 8. 18( 1H, s), 8. 90 (1H, s), 10. 04 (1H, s). Elemental analysis (C28H35N3 〇3. 0·4Η2〇) Calculated: C, 71.74; H, 7.70; N, 8. 96 Found: C, 71. 98 ; H, 7. 47 ; N, 8. 75 Example 12 N-{3-[(cyclopropylamino)indenyl]-8-fluorenylquinoline-7-yl}-4-(tetrahydrofuran-2-ylindoleoxy)phenyl hydrazine 114 322147 201206909

Taking N-(3-methylindenyl-8-fluorenylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)phenylguanamine (2.5 g) (from Reference Example 2) and ring The propylamine (571 mg) was suspended in hydrazino-2-pyrrolidine _(2 〇mL) and acetic acid (7·mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxy borohydride Φ (3.5 S) was added, and the mixture was stirred at room temperature for 3 hr. The in-aqueous sodium hydroxide solution was added to stop the reaction and alkalinize the mixture. The mixture was partitioned with EtOAc and EtOAc (EtOAc)EtOAc A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield the title compound (186 g, yield: 67%). ® ^ NMR (300 MHz, DMSO-de) δ : 0. 25-0. 29(2H, m) 〇. 32-0. 40(2Η, m), 1. 66-1. 75(1Η, m) , 1. 82-1. 97(2Η, m), 2. 00-2. 11 (2Η, m), 2. 64(3H, s), 2. 88(1H, br), 3.7〇 (lH, q, J=7. 2Hz), 3.80C1H, q, J=7. 2Hz), 3. 84(2H, s), 3.93-4. 10(2H, m), 4. 17-4. 21( 1H, m), 7. 08(2H, d, J=9. 0Hz), 7. 57(IH, d, J=8.4Hz), 7. 77(1H, d, J=8.4Hz), 8.01( 2H, d, J = 9.0 Hz), 8. 18 (1H, s), 8.88C1H, s), 10.03 (1H, s). Elemental analysis (C26H29N3〇3·1.5H2〇) 115 322147 201206909 N, 9.16 N, 9.12 Calculated: C, 68. l〇; h, 7. 03 ; Found: C, 68. 16 ; H, 6. 91 ; Example 13 N-(8-methyl-3-{[(i-methylethyl)amino]indolyl}quinoline-7-yl)- 4-(tetrahydro-butan-2-ylmethoxy) Benzoylamine

Take N-(3-methylindenyl-8-fluorenylquinoline-7-yl)_4_(tetrahydrofuran-2-yloxy)benzamide (2.5 g) (from Reference Example 2) and isopropyl The amine (591 mg) was suspended in a mixture of m-methyl-2-pyrrolidone (2 Å) and acetic acid (7 〇) in a room temperature county for 3 hours. Triethyl ethoxylated sodium hydride (3.5 g) was added to the mixture for 3 hours. The reaction recording mixture was stopped by adding a solution of sodium hydroxide in water. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to a solution of citric acid (4 〇 g) in water (4 〇乩) - dimethyl hydrazine (2 〇 raL), and the mixture was washed with ethyl acetate. Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned with acetic acid and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from acetic acid ethyl acetate (yield: 43%) to give the title compound (m. · ]HNMR (300 MHz, DMSO-de) 5 : 1. 〇4(6H, d, J=6. 3Hz) ! 63_ 1.77(1H, m), 1.80-1.94C2H, m), 1. 97-2 . 08(1H, m) 2 21 (1H, br), 2.64(3H, s), 2. 69-2.80(1H, m), 3.69(iH, q, 322147 116 201206909 J=7.2Hz), 3. 81(1H, q, J=7. 2Hz), 3. 90(2H, s), 3.98-4. 10(2H, m), 4. 15-4. 23(1H, m), 7. 09( 2H, d, J=9. 0Hz), 7. 57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 01(2H, d, J = 9.0 Hz), 8.20 (1H, s), 8.89 (1H, s), 1 〇. 〇 4 (ih, s). Elemental analysis (C26H31N3O3· 1.5H2 〇) calcd.: C, 67.80; H, 7.44; N, 9.12 Found: C, 68. 00; H, 7.37; N, 9.18 Example 14

N-{8-Mercapto-3-[(tetrahydro-2H-indolyl-4-ylamino)methyl]indole-7-yl}-4-(tetrahydrofuran-2-ylindoleoxy) Benzylamine

Take N-(3-methylindenyl-8-fluorenylquinolin-7-yl)_4_(tetrahydrofuran-2-yloxy) oxamoylamine (2.5 g) (from Reference Example 2) and tetrahydro- 2H-Bhol-4-amine hydrochloride (1·37 g) was suspended in hydrazin-2-pyrrolidone (2 〇) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hours. Sodium triethyl sulfoxyborohydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (300 mg, yield: 1%). 4 wake up 1^(300 1112,1^0-(16)(5:1.26-1.37(211,111),1.66- 1.75(1H, in), 1. 80-1. 94(4H, m), 1 97-2. 06(1H, m), 2.42 (1H, br), 2.59-2.69(lH, m), 2. 64(3H, s), 3. 23-3. 39(2H, m), 3.69C1H, q, J=8. 1Hz), 3. 76-3. 85(3H, m), 3. 94(2H, s), 3. 98-4. l〇(2H, m), 4. 17-4. 21 (1H, m), 7. 08(2H, d, J=8. 7Hz), 7. 57(1H, d, J=8. 7Hz), 7. 77(1H, d, J =8. 7Hz), 8.0K2H, d, J=8.7Hz), 8.21(1H, s), 8. 90(1H, s), _ 10.04(1Ή, s). Elemental analysis (C28H33N3 〇4·1.0H2 〇) Calculated: C, 68.13; H, 7.15; N, 8. 51 Found: C, 68. 00; H, 6.97; N,8 39 N-(3-{[(cyclopropylmethyl)amino]methyl b-8-fluorenylquinoline-7-yl)_4_(tetrahydrofuran-2-yldecyloxy)phenylhydrazine amine

Taking N-(3-methylindenyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)bendramine (2.5 g) (from Reference Example 2) The cyclopropyl decylamine (711 mg) was suspended in 1-mercapto-2-pyrrolidone (2 mL) and acetic acid (7. 〇 mL) and the mixture was stirred at room temperature for 3 hours. Adding triethyl oxy hydride hydrogenation

322147 118 201206909 Sodium (3.5 g), the mixture was stirred at room temperature for 3 hours. The reaction was stopped by adding an aqueous solution of sodium hydroxide and the mixture was assayed. The mixture was partitioned with ethyl acetate and the mixture was extracted. EtOAc (EtOAc) (EtOAc) A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield the title compound (1.6 g, yield: 56%). • lH^R(3〇〇MHz, DMSO-d6)5: 0.08-0.13(2H,m), 〇.38- 〇.44(2H, m), 0.91-0.95C1H, m), 1.66-1. 75(1H, m), 1-81-1.9K2H; m), 1. 94-2. 06(1H, m), 2.31(1H, br), 2.42(2H, d, J=6.6Hz), 2 64(3H, s), 3.69(1H, q, J=8.1 Hz), 3.80(1H, q, J=8.1Hz), 3. 92(2H, s), 3. 98-4. 10 (2H, 4. 16-4.22(1H, m), 7. 08(2H, d, J=9. 0Hz), 7. 57(1H, J=9.0Hz), 7.77(1H, d, J=9.0 Hz), 8.01(2H, d, J=9. 0 φ Hz), 8.20(1H, s), 8.89(1H, s), 10.04(1H, s) Elemental analysis value (C27H31N3〇3 . 0. 2H2 〇) Calculated: C, 72.20; H, 7. 05; N, 9. 36 Found: C, 72. 28; H, 7. 06; N, 9. 29. Example 16 Cyclopentylamine Base) fluorenyl]-8-mercaptoquinolin-7-yl}-4-(tetrahydrofuran-3-yloxy)benzamide 119 322147 X) 201206909

Take N-(3-mercapto-8-fluorenylquinoline-7-yl)-4-(tetrahydrofuran_3_ylmethoxy)benzamide (1.5 g) (from Reference Example 4) and cyclopentane The amine (511 mg) was suspended in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7 Torr, and the mixture was stirred at room temperature for 3 hours. Add sodium triethoxy borohydride (2. 35 g), the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of 1N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to citric acid (4.0 g) water (40 mL) - dimethyl hydrazine (20 mL), the mixture was washed with ethyl acetate. A 1N aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned with ethyl acetate and the mixture was extracted. The title compound (582 mg, yield 33%) was obtained as a colorless solid. <H NMR (300 MHz, DMS0-d6). (5: 1. 38-1. 49(4H, m), 1.63-1.76(5H, in), 2. 01-2. 08C1H, m), 2. 63(3H, s), 2.65- 2. 71 (1H, m), 3. 03-3. 07C1H, m), 3.29-3. 35(1H, m),

3. 54-3.58(lH, m), 3. 66-3. 71 (1H, m), 3. 75-3. 84(2H, ra), 3.90(2H, s), 3. 95-4. 04(2H, d, J=8. 7Hz), 7. 57(1H, d, J=8.7Hz), 7. 77(1H, d, J=8. 7Hz) , 8. 02 (2H, d, J = 8.7 Hz), 8.2 K1H, s), 8.89 (1 Η, s), 10.04 (1H, s). Melting point: 148 to 149 ° C 120 322147 201206909 Elemental analysis value (C28H33N3O3 · 0. 5H2O) Calculated: C, 71. 77 ; H, 7. 31 ; N, 8. 97 Found: C, 71.47 ; Η, 7 . 23 ; N, 8. 83 Example 17 N-[8-Methyl-3-({[(2R)-tetrahydrofuran-2-ylindenyl]amino}indolyl)quinolin-7-yl]- 4-[(2R)-tetrahydrofuran-2-yloxy]benzamide

Take N-(3-methylindenyl-8-fluorenylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-ylmethoxy]phenylamine (3 〇g) (from Reference Example 6) and (1 〇_tetrahydrofurfurylamine (1.1 g) were suspended in didecyl-2-pyrrolidinone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hours. Sodium acetoxyborohydride (4.0 g), the mixture was stirred at room temperature for 3 hours. The reaction was quenched with 1N aqueous sodium hydroxide and the mixture was basified. A solution of citric acid (4.0 g) in water (4 mL) - dimethyl hydrazine (20 mL), and the mixture was washed with ethyl acetate. Aq. The organic layer was washed with EtOAc EtOAc EtOAc. Colorless solid. !H NMR (300 MHz, DMSO-de) 5 : 1. 47-1. 63 (1H, m), 1.66-1.9K6H, m), 1.93-2.08C1H, m), 2.29 (1H, br ), 2.56- 322147 121 201206909 2.59C2H, m), 2. 64(3H, s), 3. 56-3. 81 (5H, in), 3.83-4.00 (2H, m), 4. 01-4. 10(2H, in), 4. 15-4. 23(1H, m) , 7. 08(2H, d, J=8. 7Hz), 7.57C1H, d, J=8.7Hz), 7.77(1H, d, J=8 ; 7Hz), 8. 01(2H, d, J= 8. 7Hz), 8. 19(1H, s), 8.88(1H, s), 10. 03(1H, s). Elemental analysis (C28H33N3O4 · 2.OH2O) Calculated: C, 65. 73; H, 7.29; N, 8.21. Found: C, 66. 02; Η, 7. 19 ; N, 8. 32 Example 18 N-(3-{[(2-Methoxy-2-mercaptopropyl)amino]indolyl 8-decylquinolin-7-yl)-4-[(2R)-tetra ° ° ° ° Nan-2-yl decyloxy] benzoguanamine dihydrochloride

喃-2-ylmethoxy]phenylguanamine (3.0 g) (from Reference Example 6) and 2-methoxy-2-methylpropanolamine. 5-oxalate (1. 0 g) The mixture was stirred at room temperature for 3 hours in 1 -methyl 2 -pyrrolidone (20 raL) and acetic acid (7.0 mL). Sodium triethyloxyborohydride (3.5 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was basified. Dissolve in ethyl acetate and extract the mixture. The organic layer was added to a solution of citric acid (4. 〇 g) in water (40 niL)-dimethyl sulfoxide (20 niL). The mixture was subjected to ethyl acetate 322147 122 201206909

Washing. IN aqueous sodium hydroxide solution was added to the aqueous layer, the mixture was partitioned with ethyl acetate and mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained amorphous product was dissolved in ethyl acetate, and a 4N salt k-ethyl acetate solution (. 40 mL) was added. The obtained solid was recrystallized from ethyl acetate-methanol to yield titled compound (388 mg, yield: 14%). !H NMR (300 MHz, DMSO-de) 5 : 1. 20(6H, s) , 1. 66-1. 75(1H, m), 1. 84-1. 94(2H, m), 1. 98-2. 06(2H, ra), 2. 69(3H, s), 2. 96-3. 00(1H, m), 3. 11(3H, s), 3. 70(1H, q, J=7. 5Hz), 3.80C1H, q, J=7. 5Hz), 3. 99-4. 11 (2H, m), 4. 15-4. 21 (1H, m), 4. 44(2H , s), 4. 69(1H, br), 7. 09(2H, d, J=8 . 7Hz), 78(1H, d, J=9.0Hz), 7. 93(1H, d, J= 9. 0Hz), 8. 05(2H, d, J=8.7Hz), 8. 78(1H, s), 9. 23(1H, s), 9.30(2H, br), 10.29(1H, s) . Elemental analysis value (C28H37N3O4CI2. i.5h2〇) a ten nose value. C, 58.23, Η, 6.98; n 7 28 Found: C, 57.97; H, 6.88; N, 7. 68 Example 19 N-[8 -mercapto-3-({[(2S)-tetrahydrofuran-2-ylmethyl]aminoindolyl)quinolin-7-yl]-4-[(2R)-tetrahydrofuran-2-yloxy) Benzene

The indoleamine is N-(3-mercapto-8-mercaptoquinolyl)_4_[(2R)-tetrahydrofuran 123 322147 201206909 -2--2-yl decyloxy] benzoguanamine (3.0 g) ( From Reference Example 6) and (s)-tetrahydrofurfurylamine (1.1 g) were suspended in indole-2-pyrrolidone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxyphosphonium borohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl acetate to afford titled compound (2.2 g, yield 60%). NMR NMR (300 MHz, DMSO-de) (5: 1.47-1.58 (1H, in), 1.63-1.9Κ6Η, m), 1.93-2.08 (1H, m), 2.3K1H, br), 2.56-2.58C2H, m), 2. 64(3H, s), 3. 41-3. 81 (5H, m), 3. 90(2H, s), 3.93-4.09(2H, m), 4. 15-4.23(1H , m), 7. 08(2H, d, J=8.7Hz), 7. 57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8.0K2H , d, J=8.7Hz), 8. 19(1H, s), 8.88(1H, s), 10.04 (1H, s). Elemental analysis (C28H33N3O4· 1.75H2 〇) calcd. C, 66.32; H, 7.25; N, 8.29 Found: C, 66.22; H, 7.28; N, 8.33 Example 20 N-{ 8-Methyl-3-[(tetrahydro-2H-piperidin-4-ylamino)methyl]quinolin-7-yl}-4-[(21〇-tetrahydrofuran-2-ylmethoxy)] Benzylamine 124 322147 201206909

Taking N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-[(2R)-tetrahydroolfufen-2-ylmethoxy]benzamide (3.5 g) (from Reference Example 6) and tetramethyl-2H-piperidin-4-amine hydrochloride (3.57 g) suspended in 1-methyl-2-pyridinine (20 mL) and acetic acid (7. In 0 mL), the mixture was stirred at room temperature for 3 hours. The mixture of sodium hydride and sodium hydride (4.0 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (583 mg, yield: 14%). H NMR (300 MHz, DMSO-de) &lt;5: 1. 28-1. 33 (2H, m), 1.69-m), 1.78-1. 86 (4H, m), 1.98-2. 03 ( 1H,m),2.53 ~2-58(2H, m), 2.64(3H, s), 3. 23-3.30(2H, m), 3.66-3-83(4H, m), 3.94(2H, s ), 4. 01-4. 06(2H, m), 4.16-4·20(1Η, m), 7.08(2H, d, J=8.4Hz), 7. 57(1H, d, J=8.4 Hz ), 7.77 (1H, d, J = 8.4 Hz), 8.01 (2H, d, J = 8.4 Hz), 8.20 (1H, s), 8.90 (1H, s), 10. 〇 4 (lH, s ). Elemental analysis (C28H33N3O4·0.75H2 〇) 125 322147 201206909 Calculated: C, 68.76; H, 7.11; N, 8. 59 Found: C, 68.77; Η, 7·09; N, 8. 68 Example 21 Ν_(3-{ [(2-Phenyl-2-methylpropyl)amino]] fluorenyl hydrazino _7_yl)-4-[(2R)-tetrahydrofuran-2 -ylmethoxy]benzoquinone

Taking N-(3-methylindenyl-8-methylquinolin-7-yl)-4-[(2R)_tetrahydroylan-2-ylmethoxy]benzamide (2.0 g) ( From Reference Example 6) with amidino-2-mercaptopropan-2-ol (1.78 g) suspended in a mixture of methyl 2-pyrrolidinium (2 mL) and acetic acid (7.0 inL) Stir at room temperature for 3 hours. Triethyloxy sodium borohydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hours. Add 1N nitrogen oxide to the water; r solution stops the reaction and tests the mixture. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was applied to a solution of citric acid (4.0 g) in water (4 〇mL) - hexane (20 mL) and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield the title compound (m. NMR NMR (300 MHz, DMSO-de) 5 · 1. 11(6H, s), 1. 66-1. 75(1H, m), 1.84-1.90C4H, m), 1. 97-2. 03C1H, m), 2. 18(1H, s), 2.64C3H, s), 3.68-3.73(1H, m), 3.77-3.83(1H, m), 322147 126 201206909 3.95C2H, s), 4. 02-4 06(2H, m), 4. 21(2H, s), 7. 08(2H, d, J=8.4Hz), 7. 58(1H, d, J=8. 7Hz), 7. 77( 1H, d, J=8. 7Hz), 8.02C2H, d, J=8. 4Hz), 8. 19(1H, s), 8.9K1H, s), 10. 04(1H, s). Elemental analysis (C27H33N3O4·O.2H2O) Calculated: C, 69.42; Η, 7. 21 ; N, 8. 99 Found: C, 69. 54 ; H, 7. 17 ; N, 8. 98 Example 22 • N-[8-Mercapto-3-({[(3-methyloxetan-3-yl)methyl]amino}methyl)quinolin-7-yl]-4- [(2R)-tetrahydrofuran-2-yl decyloxy]benzamide

-(3-Methylmethyl-8-fluorenylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-ylmethoxy]phenylamine (2.15 g) (from reference example) 6) Suspension with 1-(3-r-decyloxycyclobutan-3-yl)guanamine (500 mg) in 1-methyl-2-npyridone (20 mL) and acetic acid (7.0 mL) The mixture was stirred at room temperature for 3 hours. Diethoxydecane hydride (2.33 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was stopped by adding an aqueous solution of sodium hydroxide and the mixture was alkalized. The mixture was partitioned with ethyl acetate and the mixture was evaporated. EtOAc EtOAcjjjjjj A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to afford titled compound (780 mg, yield: 'HNMROOOMHz, DMSO-de) 5 : 1. 26(3H, s) , 1. 69-1. 74(1H, m), 1.86-1.93(4H, m), 1. 99-2. 01 (1H, m), 2. 65(3H, s), 2. 68(2H, s), 3. 68-3. 72(1H, m), 3. 79-3. 81 (1H, m), 3.94 (2H , s), 4. 01-4. 06(2H, m), 4. 16-4. 18(2H, in), 4. 35(2H, d, J=4. 8Hz), 7. 07(2H , d, J=8. 4Hz), 7. 57(1H, d, J=8.4Hz), 7. 77(1H, d, J=8.4Hz), 8. 01(2H, d, J=8.4

Hz), 8.20 (1H, s), 8.92 (1H, s), 10.04 UH, s). Elemental analysis (C28H33N3O4. 1.7H2 〇) Calculated: C, 66.44; H, 7.25; N, 8.30 Found: C, 66.64; H, 7. 05; N, 8. 00 Example 23 N -(8-fluorenyl-3-{[(3,3,3-trifluoropropyl)amino]methyl}quinoline-7-yl)-4-[(2R)-tetrahydrofuran-2-ylindole Oxyphenyl]benzamide

Take N-(3-methyl-branched-8-fluorenylquinolin-7-yl)-4-[(2R)-tetrahydrofuranol-2-yloxyl]benylamine (3.0 g) (Reference Example 6) Disc 3 3 3_ Tri II propan-1-amine hydrochloride (1.0 g) was suspended in 1-methyl-2-pyrrole (20 mL) and acetic acid (7.0 mL). The mixture was stirred at room temperature for 3 hours. Sodium triethoxy borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hours. 322147 128 201206909 The IN aqueous sodium hydroxide solution was added to quench the reaction and alkalinize the mixture. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to EtOAc (4··········· The sodium hydroxide aqueous solution was added to the aqueous layer, and the mixture was evaporated to ethyl acetate. The title compound (462 mg, yield 14%) was obtained as a colourless solid. *H NMR (300 MHz, DMSO-de) (5: 1. 67-1. 72 (1H, m), 1.87-• 1.92 (4H, m), 1.97-2.01C1H, m), 2.54(1H, br), 2. 64(3H, s), 2. 69-2. 79(2H, m), 3. 68-3. 73(1H, In), 3. 76-3. 81 (1H, m), 3. 93(2H, s), 3. 98-4. 06(2H, m), 4. 17-4. 18(1H, m) , 7. 08(2H, d, J=8. 4Hz), 7. 58(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8.0K2H, d , J=8.4Hz), 8.20(1H, s), 8.89 (1H, s), 10. 05(1H, s). Elemental analysis (C26H28N3 〇3F3 · 3. 5H2 〇) Calculated: C, 56.72; H, 6.41; N, 7. 63 Stomach value: C, 56.54; H, 6.18; N,7 79 EXAMPLE N N-{3-[(Cyclopentylamino)methyl]-8-mercaptoquinolin-7-yl}-4-[(21〇-tetrahydrofuran-2-ylmethoxy) Benzoylamine

129 129 322147 201206909 Take N-(3-mercapto-8-methylquinolinyl)_4_[(2R)_tetrahydrofuran-2-yloxyl]bendramine (2. 〇g) (from reference Example 6) Suspension of the mixture with 1-methyl-2-pyrrolidinone (2 hydrazine) and acetic acid (7 〇mL) with cyclopentylamine (851 mg), and the mixture was stirred at room temperature for 3 hours. Sodium triethoxysulfonium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned with EtOAc and EtOAc (EtOAc) (EtOAc) A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (1. NMR (300 MHz, DMSO-de) ^ : 1. 34-1.49 C4H, m), L 62- 1.75 (5H, m), 1.79-1.94 (2H, m), 1.97-2. 〇1 (ih, m ), 2·41(1Η, br), 2.64(3H, s), 2. 99-3. 07(1H, m), 3.69C1H, ^ J=6. 0Hz), 3.80(1H, q, J= (6H, m) Hz)&gt; 7. 57(1H, d, J=8.7Hz), 7. 76(1H, d, J=8. 7Hz), 8.01 (2H, d, J=8.7Hz), 8. 19(1H , s), 8.88(1H, s), 1〇.〇3(ih, s). Elemental analysis (C28H33N3 〇3. 1. oh2 〇) Calculated: C, 70.42; H, 7. 39; N, 8. 80 Found: C, 70.65; H, 7.23; N, 8. 90 Example 25 322147 130 201206909 N (3 {[(2,2-Dimethylpropyl)amino]indolylmethylquininyl-7-yl) _4-[(2R)~tetrahydrofuran-2-ylmethoxy]benzamide Guanamine

Take N-(3-carbamimid-8-fluorenylquinolin-7-yl)_4-[(2R)-tetrahydrofuran 2-ylmethoxy]benzamide (2.0 g) (from Reference Example 6) was suspended in a mixture of p-methyl-2-pyrrolidone (2 〇) and acetic acid (7 〇mL) with neopentylamine (1.74 g) for 3 hours. Triethyloxonium hydride sodium hydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned with EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The resulting solid was recrystallized from ethyl acetate-diisopropyl ether afforded the title compound (1·79 g, yield 61%). Legs R (300 MHz, DMSO-d6) (5: 〇.88 (9H, s), 1.66-1.75C1H, m), 1. 82-1. 91(2H, m), 1. 98-2. 06(1H, m), 2. 13 [)H, br), 2. 27(2H, s), 2. 64(3H, s), 3. 69(1H, q, J=8. 1Hz), 3.80 (1H, q, J=8. 1Hz), 3. 92(2H, s), 3. 98-4. l〇(2H, m), 4. 17-4. 21(1H, in), 7 09(2H, d, J=8. 7Hz), 7. 58(1H, d, 1=8.7 Hz), 7.76(1H, d, J=8. 7Hz), 8.01(2H, d, J=8 7Hz), 322147 131 201206909 8. 18(1H, s), 8.90 (1H, s), 10.04 (1H, s). Melting point: 110 to 111 ° C Elemental analysis value (C28H35N3 〇 3 · 1.5H2 〇) Calculated value: C, 68. 83 ; H, 7. 84 ; N, 8. 60 Measured value · · C, 68. 55 ; , 7. 81 ; N, 8. 66 Example 26 N-(3-{[(cyclopropylindenyl)amino]methyl b 8-methylporphyrin-7-yl)_4_ [(2R)- Tetrahydrofuran-2-ylmethoxy]benzamide

Taking N-(3-methylindenyl-8-methylquinolin-7-yl)_4_[(2R)_tetrahydrofurfu-2-yloximeoxy]bendramine (2.〇g) ( From Reference Example β) and cyclopropylmethylamine (1.44 g) were suspended in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature 3 hour. Sodium triethoxy hydride sodium borohydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous solution of hydrogen peroxide and the mixture was assayed. The mixture was partitioned with EtOAc (EtOAc) (EtOAc m. A 1 N aqueous solution of sodium hydroxide was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether toield 132 322147 201206909 !H NMRC300 MHz, DMSO-de) 5 : 0. 11-0. 12(2H, m), 0.38-0.44C2H, m), 0. 90-0. 96( 1H, m), 1. 66-1. 75(1H, m), 1.86-1.9K2H, m), 1. 98-2. 06(1H, m), 2. 44(2H, d, J=6. 6 Hz), 2.63( 3H, s), 3.32(1H, br), 3. 69(1H, q, J=6. 9Hz), 3.80C1H, q, J=6.9Hz), 3. 94(2H, s), 3. 98 -4. 10(2H, m), 4. 17-4. 21(1H, m), 7. 08(2H, d, J=9. 0Hz), 7. 57(1H, d, J=8. 7 Hz), 7. 77(1H, d, J=8. 7Hz), 8. 01(2H, d, J=9. 0Hz), 8.21(1H,s),8.89C1H,s), 10.04(1H , s). The value of the elemental analysis (C27H31N3O3 · 1 · 8H2O) calculated: C, 67.85 ; Η, 7· 30 ; N, 8. 79 Found: C, 66. 91 ; H, 7 · 38 ; N, 8. 65 Example 27 N-[8-Mercapto-3-({[(2R)-tetrahydrofuran-2-ylindenyl]aminoindenyl)quinolin-7-yl]-4-[(2S)- Tetrahydrofuran-2-yl decyloxy]benzamide

Take N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]phenylamine (2.5 g) From Reference Example 9) and (R)-tetrahydrofurfurylamine (1.1 g) were suspended in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature 3 hour. Sodium triethoxyphosphonium borohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned between EtOAc and EtOAc (EtOAc) (EtOAc). A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from ethyl acetate-di-hexane to yield title compound (1. 4 g, yield 46%). lH NMR (300 MHz, DMSO-de) (5: 1. 52-1. 56 (2H, in), 1.69-1.93 (6H, m), 2.59 (2H, d, J = 5. 7 Hz), 2. 64(3H, s), 3.32 (1H, br), 3. 59-3. 89(4H, m), 3. 91-3. 98(3H, m), 4.01-4. 10(2H, m) , 4. 17-4. 21(1H, m), 7. 08(2H, d, J=8. 7Hz), 7. 57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 01(2H, d' J=8.7Hz), 8. 19(1H, s), 8.89C1H, s), 10·04(1Η, s).

Melting point: 92 to 94 ° C Elemental analysis value (C28H33N3 〇 4 · 0. 5H2 〇) Calculated: C, 69 · 40 ; H, 7 · 07 ; N, 8. 67 Found: C, 69 · 35 ; , 6.98; N, 8.62 Example 28 ^(3-{[(2-hydroxy-2-methylpropyl)amino]indolyl}-8-methylquinolin-7-yl)- 4-[(2S)-tetrahydrofuran-2-ylindoleoxy]benzamide

Take N-(3-mercapto-8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydrofuran 134 322147 201206909 m--2-ylmethoxy]benzamide (3 · 〇g) (from Reference Example 9) and amidino-2-methylpropan-2-ol (1.78g) suspended in a mixture of benzyl such as bis(4) (2〇mL) and acetic acid (7.0 mL) Stir at room temperature for 3 hours. Sodium triethyl sulfoxyborohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned with ethyl acetate and the mixture was extracted. EtOAc EtOAc EtOAc EtOAc A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned with ethyl acetate and extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The resulting solid was recrystallized from ethyl acetate-diisopropyl ether to afford titled compound (1. NMR NMR (300 MHz, DMSO-de) 5 : 0. 11 (6H, s), 1.66-1.75 (lH, m), 1. 82-1. 91 (2H, m), 1.90C1H, br), 1 97-2. 06(1H, m), 2.42(2H, s), 2. 64(3H, s), 3. 69(1H, q, J=6. 3Hz), 3.77(1H, q, J =6.3Hz), 3. 94(2H, s), 3. 98-4. 10(2H, m), ^ 4. 20(2H, s), 7. 08(2H, d, J=8. 7Hz ), 7. 57(1H, d, J=8. 7

Hz), 7. 77(1H, d, J=8. 7Hz), 8.01(2H, d, J=8. 7Hz), 8. 19(1H,s), 8.90(1H,s),10.04(1H , s). Elemental analysis (C27H33N3 〇 4 . 0. 2H2 〇) Calculated: C, 69.42; H, 7.21; N, 8. 99 Found: C, 69.35; H, 7.11; N, 8.90 Example 29 N-[8-Methyl-3_({[(2S)-tetrahydrofuran-2-ylmethyl]amino}methyl)quinolin-7-yl]-4-[(2S)-tetrahydrofuran-2 -ylmethoxy]benzamide 135 322147 201206909

Take N-(3-methylmercapto-8-methyl money _7_yl)_4_[(2s)~four gas biting-2-ylmethoxy]benzyl_(3·Q g) The reference phase 9) and (8)-tetrahydrofurfurylamine (1.1 g) were suspended in a methyl group such as _(2() rainbow) and acetic acid (7.0 mL), and the mixture was allowed to stand at room temperature for 3 hours. Sodium triethyl borohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was stopped by adding an aqueous solution of sodium hydroxide and the mixture was alkalized. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from EtOAc (EtOAc:EtOAc) 'H NMR (300 MHz, DMSO-ώ) ^ : 1. 50-1. 58(1H, m), 1.66-1.97(6H, m), 2. 00-2. 05(1H, m), 2.25( 1H, br), 2. 58(2H, d, J=6.0Hz), 2.64(3H, s), 3.56-3. 90(5H, m), 3. 93(2H, s), 3. 98- 4. 10(2H, m), 4. 15-4. 21 (1H, m), 7. 08(2H, d, J=8.7Hz), 7.57(1H, d, J=8. 7Hz), 7.76 (1H, d, J=8. 7Hz), 8.0K2H, d, J=8.7Hz), 8. 18(1H, s), 8.88(1H, s), 10.03 (1H, s).

Melting point: 93 to 94 ° C 322147 136 201206909 Elemental analysis value (C28H33N3O4 · 1.8H2O) Calculated: C, 66.20; H, 7.26; N, 8.27 Found: C, 65.86; H, 6.84; N, 8.29 Example 30 N-(3-{[(2-Methoxy-2-methylpropyl)amino]indolyl}-8-mercaptopurine-7-yl)-4-[(2S)-tetrahydrofuran -2-yl methoxy]phenyl hydrazine dihydrochloride

Take N-(3-methylindenyl-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (2.15 g) From Reference Example 9) and 2-methoxy-2-methylpropan-1-amine oxime.5 oxalate (1. 〇g) suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL), the mixture was stirred at room temperature for 3 hours. Diethoxydecane hydride (4·〇g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was stopped by adding an aqueous solution of sodium hydroxide and the mixture was alkalized. The mixture was partitioned with ethyl acetate and the mixture was extracted, and the organic layer was applied to water (4 〇g), dimethyl sulfoxide (2 〇mL), and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained amorphous product was dissolved in ethyl acetate, and a 4N hydrochloric acid-ethyl acetate solution (??? The obtained solid was recrystallized from ethyl acetate-methanol to yield titled compound (499 mg, yield 17%) of 322147 137 201206909 color solid. !Η NMR (300 MHz, DMS0-d6) (5: 1.21 (6H, s), 1.66-1. 75 (1H, m), 1.73-1.94 (2H, m), 1.98-2. 06(1H, m ), 2. 71(3H, s), 3.0K2H, s), 3. 12(3H, s), 3.69(1H, q, J=7.8Hz), 3.78 (1H, q, J=7. 8Hz) , 3. 99-4. 11 (2H, m), 4. 17-4. 21 (1H, m), 4.48(2H, s), 7.09(2H, d, J=9.0Hz), 7.86(1H, d, J=8. 7 Hz), 7.99 (1H, d, J=8.7Hz), 8.07(2H, d, J=9. OHz), 8.98(1H, s), 9.34(1H, s), 9.43 (3H, br), 10.42 (1H, s).

Melting point: 235 to 237 ° C Elemental analysis value (C28H37N3O4CI2 · 0. 5H2 〇) Calculated: C, 60.11; Η, 6. 85 ; N, 7. 51 Found: C, 59. 94 ; Η, 6 72; N, 7. 52 Example 31 N-{8-Mercapto-3-[(tetrahydro-2H-piperidin-4-ylamino)indolyl]quinoline-7-ylindole-4-[ (2S)-tetrahydrofuran-2-ylmethoxy]benzamide

Take sulfhydryl group I methyl sulfonate) _4_[Tetrahydrofuran-2-ylmethoxy]benzamide (3. 〇 g) (from Reference Example 9) and Siqilu

The sulphate 4-amine hydrochloride (3.0 g) was suspended in a solution of bismuth pyrrolidine _ (20 mL) / hexane (7.0 mL), and the mixture was stirred at room temperature for 3 hours. Triethyl 322147 138 201206909 Sodium oxyborohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1N aqueous solution of ruthenium oxide and the mixture was assayed. The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield title compound ( 576 mg, yield: 16%). • H NMR (300 MHz, DMSO-de) &lt;5: 1.25-1. 38(2H, m), ^ 66-1.75(^, m), 1. 80-1. 94(4H, m), 1 97-2. 05(1H, m), 2·35(1Η, br), 2. 63(3H, s), 3.23-3.27(2H, m), 3.66-3·73(1Η, in), 3. 76-3. 85(4H, m), 3. 94(2H, s), 3.98-4.10 m), 4. 17-4.21(1H, m), 7. 08(2H, d, J=9 0Hz), 7*5^(1H, d, J=9.0Hz), 7. 77(1H, d, J=9. 0Hz), 8.0K2H, d, J=9.0Hz), 8.2K1H, s) , 8.89 (1H, s), 10·03 (1Η, s). Lu melting point: 158 to 159 ° C Elemental analysis value (c28h33n3 〇 4) Calculated value: C, 70.71; H, 6.99; N, 8.84 Found: C, 70.44; H, 6.84; N, 8.86 Example 32 N~ (8-Methyl-3_{[(tetrahydro-2H-piperazin-4-ylindenyl)amino]indolyl}quininyl)-4-[(2S)-tetrahydro-schemanol-2- Alkyloxy]benzamine 139 322147 V: 201206909

Take N-(3-mercapto-8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (3.Og) (from Reference Example 9) and 1-(tetrahydro-2H-piperidin-4-yl)methanamine (1.32 g) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) The mixture was stirred at room temperature for 3 hours. Sodium triethoxysilane borohydride (4.0 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned with ethyl acetate and the mixture was evaporated. EtOAcjjjjjjjjjj A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained solid was recrystallized from ethyl acetate-di-diethyl ether to afford the title compound (1.62 g, yield 43%). NMR (300 MHz, DMSO-de) &lt;5: 1. 10-1. 21 (2H, m), 1.63-1.75 (4H, m), 1. 82-1. 94 (2H, m), 1. 97-2. 06(1H, m), 2.45 (2H, d, J=6.3Hz), 2.64C3H, s), 3.23-3.32(2H, m), 3. 66-3. 73(1H, m) , 3. 76-3.85(3H, m), 3. 93(2H, s), 3. 98-4. 10(2H, m), 4. 15-4. 21 (1H, ra), 7. 08C2H , d, J=8.7Hz), 7.57C1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8.0K2H, d, J=8. 7Hz), 8.20( 1H, s), 8.89 (1H, s), 10. 04 (1H, s). 140 322147 201206909

Melting point: 92 to 94 ° C Elemental analysis value (C29H35N3 〇 4 · 1.5H2 〇) Calculated: C, 67.42; H, 7.41; Ν, 8· 13 Found: C, 67. 53; Η, 7.27; Ν,8.17 Example 33 Ν-(8-fluorenyl-3-{[(tetrahydro-2Η-0 喃 -4-ylmethyl)amino] fluorenyl} 啥 -7-yl)- 4-[(2R)-tetrahydrofuran-2-ylmethoxy]phenylguanamine

Take N-(3-methylindenyl-8-methylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-yloximeoxy]benzamide (3.0 g) (from reference Example 6) Suspension with monomethyl(tetrahydro-2H-piperidin-4-yl)methanamine (1.32 g) in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) The mixture was stirred at room temperature for 3 hours. Diethyl oxime shed rat (N. 〇 g ) was added, and the mixture was stirred at room temperature for 3 φ. The aqueous sodium hydroxide solution was added to quench the reaction and alkalinize the mixture. The mixture was partitioned with ethyl acetate and the mixture was evaporated. EtOAcjjjjjjjjjj A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield 4 (yield: H NMR (300 MHz, DMSO-d6) (5: 1.09-1. 17(2H,m),1.63- 322147 141 201206909 1.66C4H, m), 1.86-1. 90(2H, m), 1. 95 -2. 02(1H, m), 2.38 (1H, br), 2.4K2H, d, J=6.3Hz), 2.64(3H, s), 3.23-3. 33(2H, m), 3. 68- 3. 72(1H, m), 3. 77-3. 83(3H, m), 3.90 (2H, s), 3. 98-4. 06(2H, m), 4. 16-4. 20( 1H, m), 7. 08(2H, d, J=8.7Hz), 7.57(1H, d, J=8.7Hz), 7.77(1H, d, J=8. 7 Hz), 8.0K2H, d, J = 8. 7 Hz), 8. 18 (1H, s), 8.89 (1H, s), 10. 03 (1H, s). Elemental analysis (C29H35N3 〇4 · 1. 0H2 〇) Calculated: C, 68· 62 ; H, 7. 35 ; N, 8. 28 Found: C, 68.41; H, 7.28; N, 8. 39 Example 34 N-[8-Mercapto-3-({[(3-mercapto-oxetan-3-yl)methyl]aminoindolyl)quinoline-7-yl]-4-[( 2S)-tetrahydrofuran-2-yloxylphenylamine

Take N-(3-methylindenyl-8-fluorenylquinoline-7-yl)_4-[(2S)_tetrahydrofuran-2-ylmethoxy]phenylamine (2.15 g) (from reference example) 9) Mix with Bu (3-methyloxetan-3-yl)guanamine (500 mg) in a mixture of indole-pyridone (with ag mL in acetic acid) at room temperature for 3 hours. Triethyloxyborohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hours. The 1N oxyhydroxide water was added to stop the reaction assay mixture. The mixture was dissolved in ethyl acetate and the mixture was extracted. The organic layer was added to a solution of citric acid (4 〇 322147 142 201206909 g) in water (40 mL) - methionite (2 〇mL). Ester washing. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield the title compound (960 mg, yield: 41%). LH plane R (300 MHz, DMS0-d6) 5 : 1.25 (3H, s), 1.66-1.75C1H, m), 1. 86-1. 89(4H, m), 1. 97-2. 04(1H , m), 2. 64(3H, s), 2. 67(2H, s), 3.69(1H, q, J=6. 9Hz), 3. 80(1H, q, J=6. 9 _ Hz ), 3. 94(2H, s), 3. 98-4. 10(2H, m), 4. 17(2H, d, J=5. 4 Hz), 4. 35(2H, d, J= 5.4Hz), 7. 08(2H, d, J=8. 7Hz), 7.58 OH, d, J=8.7Hz), 7. 77(1H, d, J=8. 1Hz), 8. 01(2H , d, J = 8.7 Hz), 8.20 (1H, s), 8.91 (1H, s), 10.03 (1H, s). Melting point: 117 to 119t Elemental analysis value (C28H33N3 〇4·1·9Η2〇) Calculated: C, 65.97; H, 7.28; N, 8.24 Found: C, 66_ 05; H, 7. 03; N,8· 25 Example 35 N-{3-[(Ethylamino)methyl]_8-methylquinolin-7-yl}-4-[(25)-tetrahydrofuran-2-ylmethoxy]benzimidazole Amine

Ν' Ν Ν -(3-Methyl decyl-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran 143 322147 201206909 -2--2-ylmethoxy]phenylhydrazine Amine (1.0 g) (from Reference 9) and ethylamine (4 mL, 2.0 M in tetrahydrofuran) were suspended in 1-mercapto-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) The mixture was stirred at room temperature for 3 hours. Triethyleneoxy hydride sodium hydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned with ethyl acetate and the mixture was evaporated. EtOAc mjjjjjj A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (392 mg, yield 37%) as a colourless solid. NMR NMR (300 MHz, DMSO-de) (5: 1.06 (3H, t, J = 7.2 Hz), 1. 64-1. 75 (1H, ra), 1. 77-1. 92 (2H, in) , 1. 94-2. 08(1H, m), 2.42(1H, br), 2. 57(2H, q, J=7. 2Hz), 2. 64(3H, s), 3.69(IH, q , J=6. 3Hz), 3.80(1H, q, J=6. 3Hz), 3.89(2H, s), 3. 98-4. 10(2H, m), 4. 15-4. 23(1H , m), 7. 08(2H, d, J=8.7Hz), 7. 57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8.0K2H , d, J=8. 7Hz), 8. 18(1H, s), 8. 88(1H, s), 10. 03(1H, s). Melting point: 149 to 151 ° C Elemental analysis value (C25H29N3O3 · I.9H2O) Calculated: C, 66. 18 ; Η, 7· 29 ; N, 9.26 Found: C, 66. 23 ; H, 7. 09 ; N, 9. 20 Example 36 144 322147 201206909 N_{3-[(cyclopentylamino)indolyl]-8-methylquinolin-7-*}-4-[(2S)-tetrahydrofuran- 2-yl methoxy]benzamide

喃-2-yl decyloxy] benzoguanamine (1. 〇g) (from Reference Example 9) and cyclopentyl φ amine (851 mg) suspended in 1-methyl-2-pyrrolidone (20 The mixture was scrambled at room temperature for 3 hours with acetic acid (7.05 LL). Triethyloxonium hydride (3.5 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned with EtOAc and EtOAc (EtOAc) (EtOAc) A 1 N aqueous solution of sodium argonoxide was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (375 mg, yield: NMR (300 MHz, DMSO-de) ^ : 1. 37-1.49 (4H, m), 1.62-1.75 (5H, m), 1. 82-1. 94 (2H, m), 1. 98-2. 05(1H, m), 2.29 (1H, br), 2.63(3H, s), 3. 03(1H, t, J=6. 0Hz), 3.70(1H, q' J=6.1Hz), 3.80( 1H, q, J=6. 1Hz), 3. 88(2H, s), 3. 98-4. 10(2H, m), 4. 15-4.21 (1H, m), 7. 08(2H, d, J=8.7Hz), 7. 57(IH, d, J-8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 145 322147 201206909 8.01(2H, d, J=8.7 Hz), 8.20(1H, s), 8.88(1H, s), 10. 03(1H, s). Melting point: 152 to 153 ° C Elemental analysis (C28H33N3O3) Calculated. C, 73. 18, H, 7.24; N, 9. 14 Found: C, 72.92; H, 7.25; N, 9.08 Example 37 N-(3-{[(cyclopropylindolyl)amino]indolyl 8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylindoleoxy]phenylhydrazine Guanamine

Taking N-(3-methyl-bromo-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-yloxy]benzamide (丨_ 〇g) (from Reference Example 9) and cyclopropylmethylamine (711 mg) were suspended in hydrazino- 2-pyrrolidone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxy hydride sodium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The 1 N sodium hydroxide aqueous solution was added to terminate the reaction and alkalinize the mixture. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was applied to EtOAc (4 〇g) water (4 〇 mL Aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic literacy county is washed, and the solvent is evaporated under reduced pressure through anhydrous water. The resulting solid was recrystallized from acetic acid to give the title compound (298 mg, yield: 26%) as a colorless solid. NMR NMR (300 MHz, DMSO-de) &lt;5: 0. 10-0. 15 (2H, m), 0.39-〇.45 (2H, m), 0. 92-0.95 (1H, m), 1 66-1. 75(1H, m), 1. 83-1. 90(2H, m), 1. 98-2. 05(1H, m), 2.46(2H, d, J=6. 6 Hz ), 2.64C3H, s), 3.49C1H, br), 3. 69(1H, q, J=7. 2Hz), 3.80C1H, q, J=6.9Hz), 3. 96(2H, s), 3 98-4. 10(2H, m), 4. 15-4. 21(1H, in), 7. 08(2H, d, J=8. 7Hz), 7. 58(1H, d, J= 8. 7 Hz), 7. 77 (1H, d, J=8. 7Hz), 8.0K2H, d, J=8. 7Hz), • 8.22(1H,s),8.89(1H,s), 10.05( 1H, s). Melting point: 156 to 158 ° C Elemental analysis value (C27H31N3 〇 3 · 1.5H2 〇) Calculated: C, 68.62; Η, 7.25; N, 8.89 Found: C, 68. 53 ; Η, 6. 89 ; 8. 81 Example 38

Cr extraction of N-(3-methylindenyl-8-fluorenylquinoline-7-yl)_4_[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (1.6 g) (from reference Example 9) The isobutylamine (730 mg) was suspended in a mixture of p-methyl-2-pyrrolidone (2 〇) and acetic acid (7 〇 mL) for 3 hours. Adding triethyl ethoxylated hydride hydrazine-(8-fluorenyl-3-{[(2-mercaptopropyl)amino]indolyl quinolinol-7-yl)_4_^ [(2S)_tetrahydrofuran- 2-Benzyloxy]benzamide 322147 147 201206909 Sodium (3.0 g), the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and dehydrated with anhydrous sulfuric acid to reduce the solvent. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to afford titled compound (yield: 704 mg, yield 38%). !H NMRC300 MHz, DMSO-de) 5 : 0. 88 (6H, d, J=6. 6Hz), 1.66-1.75C2H, m), 1. 84-1. 94(2H, m), 1. 98 -2. 06(1H, m), 2.25 (1H, br), 2.34(2H, d, J=6. 6Hz), 2. 63(3H, s), 3. 72(1H, q, J=6.3 Hz), 3.81 (lH, q, J = 6.3 Hz), 3.89 (2H, s), 3.98-4. 09(2H, m), 4. 17-4. 21 (1H, m), 7. 08 ( 2H, d, J=9. 0Hz), 7. 57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 01(2H, d, J =9. 0Hz), 8.19C1H, s), 8.89 (1H, s), 10.04C1H, s). Melting point: 142 to 143 ° C Elemental analysis (C27H33N3O3 · I.OH2O) Calculated: C, 69. 65 ; Η, 7. 58 ; N, 9. 03 Found: C, 69.77; Η, 7.50 ; 9.04 Example 39 N-(3_{[(2, 2-Dimercaptopropyl)amino]indolyl 8-decylquinolin-7-yl)-4-[(2S)-tetrahydrofuran- 2-ylmethoxy]benzamide 148 322147 201206909

Methyl-2-ylmethoxy]benzamide (3.0 g) (from Reference 9) and neopentylamine (2.5 g) were suspended in 1-methyl-2-pyrrolidone (2 mL) The mixture was stirred at room temperature for 3 hours with acetic acid (7 mL). Sodium triethoxysulfonium borohydride (6. 35 S) was added, and the mixture was stirred at room temperature for 3 hr. Add 1N sodium hydroxide water> trough solution to stop the reaction and test the mixture. The organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethylsulfoxide (2 mL) and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine to remove the solvent by anhydrous sulfuric acid. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield the title compound (1. 18 g, yield 33%). φ 4 丽 R (300 MHz, DMS0-d6) 5 : 0. 88(9H, s), 1. 66-1. 75(1H, m), 1.86-1.89(4H, m), 1. 97-2 05(1H, m), 2. 14(1H, br), 2.27(2H, s), 2.64(3H, s), 3. 71(1H, q, J=6.3Hz), 3.82 OH, q, J=6.3Hz), 3. 92(2H, s), 3. 98-4. l〇(2H, in), 4. 17-4. 21(1H, in), 7. 08(2H, d, 0=9. 0Hz), 7. 57(1H, d, J=9. 0Hz), 7. 77(1H, d, J=9. 0Hz), 8. 02(2H, d, J=9. 0Hz ), 8. 19(1H, s), 8. 91(1H, s), 10. 05(1H, s).

Melting point: 114 to 116 ° C 149 322147 201206909 Elemental analysis value (C28H35N3 〇 3. 1 · 5 Η 2 〇) Calculated value: C, 68.83; Η, 7.84; Ν, 8.60 Found: C, 68.58; Η, 7.68; Ν, 8. 61 Example 40 Ν·~(3-{[(trans-4-hydroxycyclohexyl)amino]indolyl 8_mercaptoquinoline_7_yl)-4-[(2R)- Tetrahydrofuran-2-yl decyloxy]benzamide

Take N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide (1.6 g) (from reference Example 6) and trans 4-aminocyclohexanol (944 rag) were suspended in 1-methyl-2-n than ketone (2 〇 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature 3 hour. Sodium triethyl sulfoxyborohydride (4.2 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield the title compound (400 mg, yield 20%). !H NMR (300 MHz, DMSO-do) 5 : 1. 02-1. 12(4H, m), 1.66-1.73C1H, m), 1.75-2.07 (7H, m), 2.38 (1H, br), 2. 63(3H, 322147 150 201206909

s), 3.33 - 3.39 (2H, m), 3.69C1H, q, J = 6.3 Hz), 3. 79 (1H

q, J=6.3Hz), 3.93(2H, s), 3.98-4. 10(2H,m), 4 15 , 4. 21(1H, m), 4.45(1H, d, J=4.5Hz), 7.08(2H, d, Jg 〇Hz), 7. 57(1H, d, J=9. 0Hz), 7. 77C1H, d, J=9. OHz), g. 〇1 (2H, d, J= 9. OHz), 8. 19(1H, s), 8.88(1H, s), 10.〇4(1H s) ° Melting point: 182 to 183°C Elemental analysis value (C29H35N3〇4 · 0. 3H2〇) • Calculated: C, 70.36; H, 7.25; N, 8.49 Found: C, 70.47; H, 7. 22; N, 8.52 Example 41 N-[3-({[(l-hydroxycyclohexyl)) Amino]methyl}methyl)-8-methyl-7-yl]-4-[(2S)-tetrahydrofuro-2-ylmethoxy]benzamide amine salt

OH

Take N-(3-methylindenyl-8-methylquinolin-7-yl)-4-[(2S)-tetraqi0f-am-2-yloxy]benzamide (1.6 g) (Reference Example 9) and ^(Aminomethyl)cyclohexanol hydrochloride (1·36 g) were suspended in 1-methyl (20 mL) and acetic acid (7.0 mL). Stir for 3 hours. Add triethyl decyloxy hydride sodium (4.2 g) and the mixture was allowed to pass at room temperature 2]. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned with ethyl 322147 151 201206909 ethyl acetate and the mixture was extracted. The organic layer was applied to EtOAc (EtOAc) 1N aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned with ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. - Ethyl acetate solution (0.40 mL). EtOAc (EtOAc: EtOAc) 5 : 1. 15-1. 23(1H, in), 1.41-1.57(9H, m), 1.64-1. 72(1H, m), 1. 73-1.94(2H, m), 1.98-2.08( 1H, in), 2.7K3H, s), 2. 91-2.94(2H, m), 3.69C1H, q, J=6.3Hz), 3.80(1H, q, J=6.3Hz), 3.99-4. 11 (2H, m), 4. 15-4. 23(1H, m), 4. 47(2H, s), 6. 38(2H, br), 7. l〇(2H, d, J=9. 0Hz), 7. 85(1H, d, J=8. 7Hz), 7.99 (1H, d, J=8.7Hz), 8. 06(2H, d, J=9. 0Hz), 8. 94(1H , s), 9.30 (1H, s), 9.41 (2H, br), 10.39C1H, s).

Melting point: 242 to 244 ° C Elemental analysis (C3 〇H39N3 〇 4Cl2. 0. 5H2 〇) Calculated: C, 61.53; H, 6.89; N, 7. 18. Found: C, 61.48; H, 6. 82 N, 7.25 Example 42 N-(3-{[(5-Hydroxytricyclo[3.3.1. I3'7]indol-2-yl)amino]indenyl}-8-methyl啥琳-7-yl)-4-(tetrahydro-bit π-nan-2-ylmethoxy)benzoquinone 152 322147 201206909

OH

Take N-(3-methyl-branched hydrazinyl-7-yl)_4_(tetrahydron-pentan-2-yloxy)benzamide (3.2 g) (from Reference Example 2) Suspension in 4-methyl-2-pyrrolidone (a mL) with acetic acid (7.0 mL) at room temperature with 4-amine hydroxybutanol hydrochloride (3. 46 g) at room temperature The mixture was stirred for 3 hours. Sodium triethyl sulfoxyborohydride (6.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was dissolved in ethyl acetate and the mixture was extracted. EtOAc (EtOAc) A 1 N aqueous sodium hydroxide solution was added to the aqueous layer to dissolve in ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained solid was recrystallized from EtOAc (EtOAc) (EtOAc) NMR NMR (300 MHz, DMSO-de) (5: 1. 07-1. 11 (1H, m), 1.17-1.30 (2H, m), 1.58C3H, s), 1. 66-1.80 (1H, m ), 1.85-2.05(6H, m), 2. 15-2. 20(2H, m), 2.37(1H, br), 2. 64(3H, s), 2.69C2H, s), 3.27-3.39( lH, m), 3. 69 (1H, q, J=6.3Hz), 3.80(1H, q, J=6.3Hz), 3.89(2H, s), 3.98-4. 10(2H, m), 4 15-4. 21(1H, m), 4. 30(1H, s), 7. 08(2H, 153 322147 201206909 d, J=9.0Hz), 7.57(1H, d, J=9. OHz) , 7.77(1H, d, J=9. OHz), 8. 02(2H, d, J=9. OHz), 8.20(1H, s), 8.9K1H, s), 10. 04(1H, s) . Example 43 N-[ 8-Mercapto-3-({[2-(1-mercaptoethoxy)ethyl]amino]indolyl)quinolin-7-yl}-4-(tetrahydrofuran-2 -yloxy)phenylamine

Take N-(3-mercapto-8-methylindole-7-yl)-4-(tetrahydroanthracene-2-yloxy)benzamide (3.2 g) (obtained from Reference Example 2) and 2-(1-mercaptoethoxy)ethylamine (1.73 g) were suspended in 1-mercapto-2-pyrrolidone (2 mL) and acetic acid (7.0 mL). The mixture was stirred at room temperature for 3 hours. Sodium triethyl sulfoxyborohydride (6.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was dissolved in ethyl acetate and the mixture was extracted. EtOAc (EtOAc) An aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (980 mg, yield: 25%). H NMR (300 MHz, DMSO-de) d : 1.08 (6H, d, J = 6.0 Hz) 1. 66-1. 75(1H, m), 1.84-1. 97(2H, m), 2. 00 -2. 〇5(2H, m), 322147 154 201206909 2.64C3H, s), 2. 66-2. 70(2H, m), 3. 33(1H, br), 3.44-3.48C2H, m), 3. 51-3. 57(1H, m), 3. 69(1H, q, J = 6. 3Hz), 3.80C1H, q, J=6.3Hz), 3. 94(2H, s), 3. 98-4. 10(2H, m), 4. 17-4.2K1H, m), 7. 08(2H, d, J=9.0Hz), 7.58(1H, d, J=9.0Hz), 7. 77 (1H, d, J=9. OHz), 8. 02(2H, d, J=9. OHz), 8.20(1H,s),8.88(1H,s), 1〇.〇5(ih, s ). Elemental analysis (C28H35N3O4·L8H2O) Calculated: C, 65. 94 ; Η, 7. 63 ; N, 8. 24 φ Found: C, 65. 73 ; Η, 7· 23 ; Ν, 8. 24 Implementation Example 44 Ν-(3-{[(3-Hydroxytricyclo[3.3.1. I3'7]癸-yl)amino]indolyl 8-methylindene-7-yl)-4- (tetrahydro-fusin 0^-2-ylmethoxy)benzamide

Take Ν-(3-methylindenyl-8-fluorenylquinolin-7-yl)-4-(tetrahydropyrene-2-ylmethoxy)phenylhydrazine (1.5 g) (from reference Example 2) was suspended in 1-mercapto-2- with 3__amine fund just-battery hydrochloride (1·29 g). The mixture was stirred at room temperature for 3 hours in the ketone (2 〇 mL) and acetic acid (7.0.mL). Sodium triethyl sulfoxyborohydride (2.35 g) was added to stir the mixture at room temperature for 3 hours. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to a solution of citric acid (4 〇g) (4 〇 322 147 155 201206909 mL) in dimethyl sulfoxide (2 〇mL), and the mixture was washed with ethyl acetate. . A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield title compound ( 172 mg, yield 8%). 'H NMRC300 MHz, DMSO-de) ^ : 1. 15(2H, br), 1. 53-1. 56(9H, in), 1. 66-1. 75(1H, in), 1. 72- 1. 91 (2H, in), 1. 94-2. 05(1H, m), 2. 15(2H, br), 2. 63(3H, s), 3. 33-3. 39(2H, m), 3.69 (1H, q, J=7.2Hz), 3.79(1H, q, J=7.2Hz), 3. 90(2H, s), 3. 98-4. 09(2H, m), 4 17-4. 21 (1H, m), 4.41(1H, s), 7.08 (2H, d, J=8.7Hz), 7.56(1H, d, J=8.7Hz), 7.77(1H, d, J = 8.7 Hz), 8.0 K2H, d, J = 8. 7 Hz), 8.20 (1H, s), 8.88 (1H, s), 10.03 (1H, s). Elemental analysis value (C-304 · 0. 5H2 〇) Calculated value · · C, 71.97 ; H, 7. 32 ; N, 7. 63 Found: C, 72.21 ; H, 7.20 ; N, 7.57 Example 45 N -{8-mercapto-3-[(propylamino)indolyl]quinoline-7-*}-4-[(2S)-tetrahydro-1nan-2-yloxy]phenylamine

Take N-(3-mercapto-8-mercaptoquinolin-7-yl)-4-[(2S)_tetrahydrofuran 156 322147 201206909 -2--2-yl fluorenyloxy] benzoguanamine (1 〇g) (from Reference Example 9) and n-propylamine (414 mg) were suspended in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7 mL), and the mixture was stirred at room temperature. 3 hours. Sodium triethoxysulfonium borohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A aqueous solution of sodium hydroxide was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether toield !H NMR (300 MHz, DMSO-de) ά : 0. 88 (3Η, t, J=7. 2Hz), 1.40-1.52 (2Η, m), 1. 66-1. 75(1Η, m), 1.82-1. 98(4Η, m), 2. 00-2. 06(1Η, m), 2.51(2Η, t, J=7. 2Hz), 2. 64(3Η, s), 3.31(1Η, Br), 3. 69 (1Η, q, J=6. 6Hz), 3.78(1Η, q, J=6.6Hz), 3.89(2Η, s), 3.98-4. 10(2H, m), 4.15- 4.21 (1H, m), 7. 08C2H, d, J=8. 7Hz), 7.57(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 02(2H, d, J=8. 7Hz), 8. 19(1H, s), 8.89(1H, s), 10.04(1H, s). Melting point: 121 to 122 ° C Elemental analysis value (C26H31N3O3 · I.6H2O) Calculated: C, 67. 54; H, 7.46; N, 9. 09 Found: C, 67. 27; H, 7. 20; N, 8.86 Example 46 157 322147 201206909 N-[3-({[(1R,2R)-2-hydroxycyclohexyl]aminoindolyl)-8-methylquinolin-7-yl ]-4-[(2S)-tetrahydrofuran-2-yl decyloxy]benzamide

Take N-(3-methylindenyl-8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (jo g) (from reference Example 9) and (lR, 2R)-2-aminocyclohexanol hydrochloride (1.52 g) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL). The mixture was stirred at room temperature for 3 hours. Diethyloxyborohydride (2.33 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction was stopped by adding an aqueous solution of sodium hydroxide and the mixture was alkalized. The mixture was partitioned with ethyl acetate and the mixture was evaporated. EtOAc EtOAcjjjjjj A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether afforded the title compound (78 mg, yield 6%). NMR NMR (300 MHz, DMSO-de) (5: 0. 98-1. 17 (6H, m), 1.59-2. 00 (8H, m), 2.26 (1H, br), 2. 64 (3H, s), 3. 16-3. 19(1H, m), 3. 68-3.73C1H, m), 3. 77-3. 91(2H, m), 4. 00-4. 05(2H, m ) » 4. 17-4. 19(1H, in), 4. 64-4. 67(1H, m), 7. 08(2H, d, J=8.7Hz), 7.57(1H, d, J= 8. 7Hz), 7.78(1H, d, J=8. 7Hz), 8.0K2H, d, J=8.7Hz), 8.21(1H, s), 8.90(1H, s), 322147 158 201206909 10. 05( 1H, s). Melting point: 142 to 143 ° C Elemental analysis (C29H35N3 〇4 · 0. 6H2 〇) Calculated: C, 69.60; H, 7.29; N, 8.40 Found: C, 69.30; H, 7. 09; , 8. 16 Example 47 N-[3-({[(lS,2S)-2-hydroxycyclohexyl]amino}indenyl)-8-decylquinolin-7-yl]-4-[( 2S)-tetrahydrofuran-2-yloxylphenylamine

Take N-(3-mercapto-8-fluorenyl-7-yl)-4-[(2S)-tetrahydropyran-2-ylmethoxy]phenyl hydrazine (1. 〇g (from Reference Example 9) and (ls, 2S)-2-aminocyclohexanol (1.15 g) suspended in 1-mercapto-2-pyrrolidone (2 mL) and acetic acid (7.0 mL) The mixture was stirred at room temperature for 3 hours. Sodium triethyl sulfoxyborohydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous solution of oxidized sodium and the mixture was basified. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to yield title compound (443 mg, yield: 35%). 322147 159 201206909 ]H NMR (300 MHz, DMSO-de) (5:0. 98-1. 19(6H, m), 1.59-2.05(8H, in), 2. 23-2. 30(1H, m ), 2. 64(3H, s), 3.18-3.20 (1H, m), 3.69C1H, q, J=7.2Hz), 3.80(1H, q, J=7.2Hz), 3. 98-4. 10 (2H, m), 4. 15-4. 21(1H, m), 4. 65(1H, d, J=4. 8 Hz), 7.08(2H, d, J=9.0Hz), 7.58(1H , d, J=9. OHz), 7. 77(1H, d, J=9.0Hz), 8.01(2H, d, J=9. OHz), 8. 22(1H, s), 8. 90( 1H, s), 10. 04 (1H, s). Melting point: 157 to 158 ° C Elemental analysis value (C-304 · 0.4H2 〇) Calculated value·· C, 70. 11 ; Η, 7. 26 ; N, 8. 46 Found: C, 70.35 ; Η, 7 14; N, 8.40 Example 48 1(3-{[(trans-4-hydroxycyclohexyl)amino]] yl}-8-mercaptoquinolin-7-yl)~4-[(2S) -tetrahydrofuran-2-yl decyloxy]benzamide

Cr,,. Take N-(3-mercapto-8-mercaptoquinolin-7-yl)-4-[(2s)_tetrahydrofuran-2-ylmethoxy]phenylamine (ΐ·〇g) From Reference Example 9) and trans-4-aminocyclohexanol (1.15 g) were suspended in m-methyl-2-pyrrolidine _ (di) and acetic acid (7.0 dl), and the mixture was stirred at room temperature for 3 hr. Sodium dimethoxyborohydride (2.33 g) was added to stir the mixture at room temperature for 3 hours. = The reaction was quenched with 1 N aqueous sodium hydroxide and the mixture was basified. The mixture was partitioned with ethyl acetate 322147 160 201206909 and the mixture was extracted. The organic layer was applied to water (4 〇g) of citric acid (4 〇g) - dimethyl broth (20 mL) and the mixture was washed with ethyl acetate. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether afforded the title compound (573 mg. ]H NMRC300 MHz, DMSO-de) ά : 1. 07-1. 12(4Η, m) , 1.66-2.06C8H, m), 2.20-2.37C2H, m), 2. 64(3Η, s), 3.34 (1Η, 镰br), 3. 72(1H, q, J=6. 9Hz), 3.82(1H, q, J=6. 9Hz), 3.92 (2H's), 3.98-4.10(2H,m), 4.17 -4.21(lH,m), 4.44-4*48(1H, m), 7.08C2H, d, J=8. 7Hz), 7. 57(1H, d, J=8. 7 Hz)' 7·76 (ΙΗ, d, J=8.7Hz), 8. 01(2H, d, J=8. 7Hz), 8· UCIH, s), 8·89(1Η, s), 1〇·〇4(1Η, s). Hall 1 point: 183 to 184.匚 分析 分析 calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc calc Example 49 Ν [8-Methyl_3-({[2-(1-decylethoxy)ethyl]amino) hydrazinylmethyl) 啥 ' 'yl]-4-[(2S)-tetrahydrofuran-2 -ylmethoxy]benzamide

161 322147 201206909 Take N-(3-methylindenyl-8-fluorenyl-7-yl)-4-[(2S)-tetracycline-2-ylmethoxy]benzamide (1 0 g) (from Reference Example 9) and Bumen-methylethoxy)ethylamine (1.03 g) suspended in 1-methyl-2-pyrrolidone (2〇inL) and acetic acid (7.0 mL) The mixture was stirred at room temperature for 3 hours. Sodium triethoxy borohydride (2.33 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium aroxide solution and the mixture was basified. The mixture was partitioned with ethyl acetate and the mixture was combined. EtOAc EtOAc m. A 1 N aqueous solution of sodium oxide was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to afford the title compound (280 mg, yield: 23%). !H NMRC300 MHz, DMSO-de) &lt;5 : 1. 08(6H, d, J=6.0Hz), 1. 66-1. 75C1H, m), 1. 82-1. 94(2H, m) , 1. 97-2. 05(1H, m), 2.26(1H, br), 2. 64(3H, s), 2. 65-2. 69(2H, m), 3.45(2H, t, J =5.7Hz), 3.49-3. 57(1H, m), 3.70(1H, q, J=6. 3Hz), 3.80(1H, q, J=6.3Hz), 3. 93(2H, s), 3. 98-4. 10(2H, m), 4. 15-4. 21(1H, in), 7. 08(2H, d, J=8. 7Hz), 7. 58(1H, d, J =7. 7Hz), 7.77C1H, d, J=8. 7Hz), 8.0K2H, d, J=8.7Hz), 8.20(1H, s), 8.88(1H, s), 10.04(1H, s). Melting point: 111 to 113 ° C Elemental analysis (C28H35N3 〇4 · 2. OH2O) Calculated: C, 65.48; H, 7.65; N, 8. 18. Found: C, 65.49; H, 7.48; N, 8. 04 162 322147 201206909 Example 50 N-(3-{[(trans-4-hydroxy-4-mercaptocyclohexyl)amino]methyl}-8-methylquinolin-7-yl)-4- [(2S)-tetrahydrofuran-2-ylmethoxy]phenylguanamine

Me OH /o

NH o

Take N-(3-mercapto-8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydroanthracene-2-ylmethoxy]benzamide (1. 00) g) (from Reference Example 9) and trans-4-amino-1-methylcyclohexanol (397 mg) (from Reference 15) were added to hydrazine, hydrazine-dimercaptoacetamide (10) The mixture was stirred at room temperature for 2 hours in mL). The mixture was cooled to 5 ° C, and acetic acid (0.440 mL) was added dropwise. &lt;&apos;&gt;&gt; The reaction mixture was ice-cooled, EtOAc (EtOAc) The precipitated crystals were collected by filtration, washed with ethyl acetate and dried. The crystals obtained were recrystallized from EtOAc (EtOAc:EtOAc:MeOH: WNMRQOOMHz, DMS0_d〇(5: ll〇(3H, s), 1.18-1. 37(4H, m), 1.48-2. 21(9H, m), 2. 43-2. 49(1H, m), 2. 64(3H, s), 3. 65-3.85(2H, m), 3.9K2H, s), 3. 97-4. 14(3H, m), 4. 15-4. 25(1H, m ), 7. 09(2H, d, J=8.7Hz), 7.58(1H, d, J=8. 7Hz), 7. 77(1H, d, J=8. 7Hz), 8. 02(2H, d, J=8. 7Hz) 322147 163 201206909 8.20(1H, d, J=1.9Hz), 8.90(1H, d, J=2.3Hz), 10.06 (lH, s).

Melting point: 169 ° C Elemental analysis value (C3 〇 H37N3 〇 4 · 1.4H2 〇) Calculated value. C, 68. 13 ; H, 7. 59 ; N, 7. 95 Found: C, 68. 07 ; , 7.46; N, 7.81 Example 50-1 N-(3-{[(trans-4-hydroxy-4-methylcyclohexyl)amino]indolyl 8-methylquinolin-7-yl) -4-[(2S)-Tetrahydrofuran-2-ylmethoxy]phenylamine is N-(3-indolyl-8-fluorenylquinolin-7-yl)-4-[(2S)- Tetrahydrofuran-2-ylindoleoxy]benzamide (6.3 kg) (from Reference Example 9) was suspended in hydrazine, hydrazine-mercaptoacetamide (38 L), and trans-4-amine was added. Base_ι_曱-cyclohexanol (2.5 竑) (from Reference Example 15). It was added dropwise with acetic acid (6.3 L) at 2 to 3 Torr, and the mixture was stirred at 20 to 3 (TC) for 1 hour. Sodium diethyl hydride hydride (5. 13 kg) was added under a nitrogen stream. The mixture was stirred at 3 ° C for 3 hours and 1 minute, heated to 4 (rc, 4 〇 to 55 ΐ: 4 Ν aqueous sodium hydroxide solution (38 L) was added dropwise over 2 Torr. Stirring at 45 to 55 ° C 30 After a minute, the mixture was cooled to 3 Torr over 35 minutes. After stirring for 1 hour at 2 to 30 C, the reaction solution was filtered and washed with clean water (63 L). Kg). Take 7 76 kg of suspension from it in ethanol (54 L) and heat to 62. (: Dissolve the suspension. The solution is dedusted and filtered, and the filtered material is passed through ethanol. L) Washing. The collected filtrate was heated again to 62. (:, the resulting precipitate was dissolved. Pure water (31 L) was added dropwise at 6 to 65 C, and the mixture was cooled at 50 ° C for 35 minutes. at 322147 164 201206909 45 After stirring for 1 hour at 50 ° C, the mixture was cooled at 3 ° C for 35 minutes ' stirred at 20 to 30 ° C for 1 hour. The mixture was further cooled at i ° ° C for 30 minutes '0 to 1 (TC) was stirred for 2 hours. The crystals precipitated were collected by filtration, washed with purified water (16 L), and dried under reduced pressure to give the title compound (6.96 kg, yield: 83°/〇. Elemental analysis value (C3〇H37N3) 〇4· 1.3H2〇)

Calculated: C, 68.37; H, 7.57; N, 7.97 Found: C, 68.28; H, 7.63; N, 7. 95 Example 50-2 N-(3-{[(Reverse 4-Hydroxy-4-hydrazinocyclohexyl)amino]methyl b-8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-yloxy]phenylhydrazine The amine is N-(3-{[(trans-1,4-hydroxy-4-indolylcyclohexyl)amino]indenyl}-8-fluorenylquinolin-7-yl)_4_[(2S)_tetrahydrofuran_ 2_Glyoxime]benzamide (16.0 g) (from Reference Example 5) was dissolved in ethanol (25 mL), and the insoluble material was filtered off. Ethyl acetate (1_mL) was added to the ship, and the mixture was purified by Shih Hose column chromatography [developing solvent; ethyl acetate:methanol = 7:3 (volume ratio)]. From the obtained crude product (12·8 g), 12 〇 g was dissolved in 55 t of methanol (120 mL) and diluted with isopropyl ether (24 〇乩) at the same temperature. A seed crystal is added and the mixture is allowed to cool to 5 it. The crystals of the slab were collected by filtration, washed with a mixture of methanol (10 mL) and isopropyl (4) 4Q, and dried to give the title compound (6 64 g). HNMR (300 MHz, DMSO-de) d : 1. l〇(3H, s), 1.18-1 36(4H 1.47-2.09C8H, m), 2.15〇h&gt; δχ 2.43_2 50(1H) m); 2.63 C3H, s), 3.65-3.85C2H, ra), 3.91(2H, s), 3.98-4.11 322147 165 201206909 (2H, m), 4. 1K1H, s), 4. 15-4.24(1H, m), 7. 09(2H, d, J=8. 7Hz), 7. 57(1H, d, J=8. 7Hz), 7. 78(1H, d, J=8. 7Hz), 8. 02C2H, d , J = 9. 1 Hz), 8.20 (1H, d, J = 1.9 Hz), 8. 90 (1H, d, J = 2.3 Hz), 10.05 (1H, s). Melting point: 165 ° C Elemental analysis (C3 〇H37N3 〇4) Calculated: C, 71.54; H, 7.40; N, 8. 34 Found: C, 71.45; H, 7.35; N, 8.40 Example 51 N- (3-{[(trans-4-hydroxy-4-methylcyclohexyl)amino]methyl b-8-methylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-yl Methoxy]benzamide

Take N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide (500 mg) (from reference Example 6), trans-4-amino-1-methylcyclohexanol (331 mg) (from Reference 15) and acetic acid (2.57 mL) were added to N,N-dimethylacetamide (8 mL) The mixture was stirred at room temperature for 1 hour. Sodium triethoxysilane borohydride (543 mg) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, and aq. The aqueous layer was extracted with acetic acid, and the combined organic layers were washed with brine and purified by Shixia knee column chromatography [developing solvent; acetic acid ethyl acetate-acetic acid methyl acetate: 166 322147 201206909 sterol = 3: 2 (volume ratio)], and then purified by NH-purine column chromatography [developing solvent; ethyl acetate-&gt; ethyl acetate: methanol = 9:1 (volume ratio)]. The obtained solid was washed with EtOAc EtOAcjjjjjjj 4 丽R (300 MHz, DMS0-d6) (5: 1. 10(3H, s), 1. 21-1. 37(4H, m), 1.48-2. 10(9H, m), 2. 44 -2. 53(1H, m), 2. 64(3H, s), 3.65-3. 85(2H, m), 3.91(2H, s), 3. 98-4. 09(2H, m), 4.10 (1H, s), 4. 15-4. 24(1H, m), 7. 09(2H, d, J=9. 0Hz), 7.58 • OH, d, J=9.0Hz), 7. 77 (1H, d, J=8. 7Hz), 8. 02C2H, d, J=8. 7Hz), 8. 20(1H, d, J=1.9Hz), 8.90(1H, d, J=2. 3Hz ), 10·04 (1H, s). Melting point: 167 ° C Example 52 N-(3-{[(cis-4-hydroxy-4-fluorenylcyclohexyl)amino]indolyl 8-methylindene-7-yl)-4- [(2S)-tetrahydrofuran-2-ylmethoxy]benzoquinone

Η Take Ν-(3-mercapto-8-fluorenylquinolin-7-yl)-4-[(2s)-tetrahydrofuran. South 2 base rolling base] decylamine (39 〇 mg) (from Reference Example 9) and cis-4-amino-1-methylcyclohexanol (262 mg) (from Reference Example 14) To the methyl 2-pyrrolidone (3. 〇ra L), acetic acid (1 mL) was added, and the mixture was stirred at room temperature for 8 hr. Add sodium triethoxysulfonate hydride (424, stir the mixture for 15 hours at room 322147 167 201206909. The mixture was diluted by gis, and 2N aqueous sodium hydroxide solution (2 〇mL) was added dropwise at room temperature. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and evaporated, evaporated, evaporated, evaporated. Ethyl acetate: methanol = 85: 15 (volume ratio), the obtained solid was recrystallized from ethyl acetate to give the title compound (2 </RTI> <RTIgt; ) ^ : 1.23(3H, s), 1. 34-1. 52(4H, m), 1.69(2H, d, J=11.7Hz), 1. 75-1. 89(3H, m), 1.92- 2.05(2H, m), 2. 05-2. 19(1H, m), 2. 46-2. 58(1H, m), 2. 8i (3H, s), 3.81-3. 91(1H, m), 3. 92-4. 01 (1H, m), 4. 04(2H, s), 4. 06(2H, d, J=5.3Hz), 4. 26-4. 39(1H, m ), 7. 05(2H, d, J=8. 7Hz), 7. 70(1H, d, J=9.0Hz), 7.89(1H, s), 7.92 (2H, d, J=8.7Hz), 8.06 (1H, d, J = 2.3 Hz), 8.25 (1H, d, J = 9.0 Hz), 8.89 (1H, d, J = 1.9 Hz). Melting point: 159 to 161 ° C Analytical value (C3qH37N3 〇4 · 0.2H2 〇) Calculated: C, 71.04; H, 7.43; N, 8. 28. Found: C, 71. 10; H, 7.45; N, 8. 11 Example 5 3 N -(3-{[(cis-4-hydroxy-4-mercaptocyclohexyl)amino]indolyl 8_methylquinolin-7-yl)-4-[(2R)-tetrahydrofuran-2- Methoxy]benzamide 168 322147 201206909

Take N-(3-methyl-branched I methyl phthalocyanine-7-yl) + [(2r)-tetrapyran-2-yl fluorenyloxy] cumamine (390 mg) (from Reference Example 6) And cis-4-amino-1-indolylcyclohexanol (262 mg) (from Reference Example 14) dissolved in 'b; 鲁基-2-pyrrolidone (3.0 mL) 'added acetic acid (1 〇乩) The mixture was stirred at room temperature for 8 hours. Sodium triethoxysulfonate (424 mg) was added, and the mixture was stirred at room temperature for 15 hours. The mixture was diluted with ethyl acetate and aq. The mixture was poured into water, and the mixture was evaporated. The residue was purified by NH-purified hexane column chromatography [solvent: ethyl acetate:methanol = 100 : hexane (volume ratio ethyl acetate:methanol=85:15 (volume ratio)] Recrystallization, the title compound (238 mg, yield 47%) was obtained as pale yellow solid. H NMR (300 MHz, CDC13) (5: 1.22 (3H, s), 1.34-1.51 (4H, m), 1 64-1. 75(2H, ra), 1. 75-1. 88(3H, m), 1. 91-2. 04(2H, m), 2. 05-2·19(1Η,m) , 2.45-2·58(1Η,m), 2.81(3H, s), 3. 81-3.91(1H,ra), 3. 92-4. 01(lH,ra),4.04(2H,s ), 4.06 (2H, d, J=5. 3Hz), 4. 26-4. 38(1H, m), 7. 05C2H, d, J=9. 〇Hz), 7. 70(1H, d, J=8.7Hz), 7. 89(1H, br. s. ), 7. 92(2H, d, J=8.7Hz), 8.06(1H, d, J=1.9Hz), 8.25(1H, d, J=8. 7 169 322147 201206909

Hz), 8.89 (1H, d, J = 2.3 Hz). Melting point: 163 to 164 ° C Elemental analysis value (C3 〇 H37N3 〇 4) Calculated: C, 71.54; Η, 7.40; N, 8.34 Found: C, 71. 24; Η, 7.24; Ν, 8. 13 Example 54 Ν_( 3-{[(1-ethylpropyl)amino]indolyl}-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethyl Oxy]benzamide

Taking Ν-(3-mercapto-8-methylquinolinyl)_4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (1. g) (from Reference Example 9) And pentylamine (872 mg) was suspended in 1-methyl-2-pyrrolidone (2 mL) and acetic acid (7. 〇mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxy borohydride (2.33 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1 N aqueous sodium hydroxide solution and the mixture was basified. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was applied to water (4············ The aqueous layer was partitioned between EtOAc and EtOAc (EtOAc m. 362 mg 'yield 31% of a colorless solid. 322147 170 201206909 !H NMRC300 MHz, DMSO-de) 5 : 0.85 (6H, d, J=7. 5Hz), 1. 37-1. 46(4H, m ), 1. 66-1. 75(1H, m), 1. 84-1. 94(2H, m), 1. 98-2. 06(1H, m), 2. 34-2. 38(2H , m), 2. 64(3H, s), 3.69 C1H, q, J=6.9Hz), 3.80(1H, q, J=6. 9Hz), 3.90(2H, s), 3. 98-4. 10(2H, m), 4. 17-4. 21 (1H, m), 7. 08(2H, d, j=8.7Hz), 7. 56(1H, d, J=8. 7Hz), 7 77(1H, d, J=8. 7Hz), 8-〇l(2H, d, J=8. 7Hz), 8. 20(1H, s), 8. 91(1H, s), 10.04 ( 1H, s).辕 point: 113 to 115 ° C Elemental analysis value (C28H35N3 〇 3 · 0. 2H2 〇) 言 十算值: C, 72. 29 ; H, 7. 67 ; N, 9. 03 Real value: C, 72.44 H, 7.55; N, 9.06 Example 55 ^[8-indolyl-3-({[(lR)-l-mercaptopropyl]aminoindolyl)quinolin-7-yl] 1~[ (2S)-tetrahydrofuran-2-yloximeoxy]benzamide

Take N-(3-mercapto-8-mercaptoquinolin-7-yl)-4-[(2S)-tetrahydrofuran, 2-ylmethoxy]benzamide (Ig) (from Reference Example 9) and (2R)-butan, 2-amine (500 mg) were suspended in dimercapto-2-pyrrolidone (2 mL) and acetamidine (7.0 mL), and the mixture was stirred at room temperature. 3 hours. Triethyl oxime 322147 171 201206909, sodium hydride (2.35 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was stopped and the mixture was assayed by the addition of an aqueous solution of sodium nitrite. The mixture was partitioned with ethyl acetate and the mixture was extracted. The organic layer was added to water (4 〇g) of water (4 〇^ in a solution of bismuth (20 mL). The mixture was washed with ethyl acetate. The aqueous solution was added to aq. EtOAc (EtOAc m. The title compound (362 mg, yield 34%) was obtained as a colourless solid. HNMR (300 MHz, DMSO-de) 5 : 0. 86 (3H, t, J = 7. 5 Hz), l. 〇3 (3H, d, J=6.0Hz), 1.29-1.36(1H, m), 1. 46-1. 53(1H, m), 1. 66-1. 73(1H, m), 1. 75-1. 92(2H , in), 1. 94-2. 06(1H, m), 2.49-2.58(2H, m), 2. 64(3H, s), 3„69(1H, q, J=6. 9Hz), 3.80 (1H, q, J=6.9Hz), 3. 92(2H, d, J=7.8Hz), 3.98-4.10 (2H, m), 4. 17-4.21(1H, m), 7. 08( 2H, d, J=9. 0Hz), 7. 57(1H, d, J=9. 0Hz), 7. 77(1H, d, J=9. 0Hz), 8.01(2H, d, J=9.0 Hz), 8·20(1Η, s), 8·90(1Η, s), 10·04(1Η, s) Melting point: 118 to 119°C Elemental analysis value (C27H33N3〇3 · 1. 6H2〇) Calculated value: C, 68.07 ; H , 7.66; N, 8. 82 Found: C, 68. 79; H, 7.33; N, 8. 69 Example 56 N-[8-methyl-3-({[(lS)-l- Methylpropyl]amino hydrazinylmethyl)quinoline-7-yl]-4-[(2S)-tetrahydro0fu0an-2-ylmethoxy]benzamide 172 322147 201206909 ο

Η Ν-(3-Methoxymethyl-8-methylquinoline + yl)_4_[p. tetrahydrofuran-2-ylmethoxy]benzamide [.ο g) (from Reference Example 9) and 2s) - Butan-2-amine (1.0 g) was suspended in hydrazino-2 (b) (10) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hr. Add triethyl methoxy hydride • sodium borohydride (4. 67 phantom, stir the mixture for 3 hours at room temperature. Add 1N sodium hydroxide solution to stop the reaction and test the mixture. Dissolve with ethyl acetate and extract the mixture, organic The layer was added to a solution of citric acid (4. 〇g) in water (4 〇 ) _ 曱 sulfoxide (20 mL), and the mixture was washed with ethyl acetate. A 1N aqueous sodium hydroxide solution was added to the aqueous layer to ethyl acetate The ester was partitioned and the mixture was evaporated. EtOAcjjjjjjjjjjjj %) of a colorless solid. ® *H NMR (300 MHz, DMSO-de) 5 : 〇. 86 (3H, t, J = 7. 5 Hz), 1.03 (3H, d, J = 6. 3 Hz), 1. 28-1. 35(1H, m), 1. 44-1. 53(1H, m), 1.66-1.75C1H, m), 1. 82-1. 92(2H, m), 1. 97-2 .05(2H, m), 2. 53-2.56C1H, m), 2. 64(3H, s), 3. 69(1H, q, J=6. 3 Hz), 3.80(1H, q, J =6. 3Hz), 3. 90(2H, d, J=7. 5Hz), 3. 97-4. 09C2H, m), 4. 17-4.21(1H, m), 7. 08(2H, d , J=8. 7Hz), 7. 56(1H, d, J=8. 7Hz), 7.76(1H, d, J=8. 7Hz), 8. 01(2H, d, J=8. 7Hz), 8. 19(1H, s), 8. 89(1H, s), 10.02 173 322147 201206909 (1H, s). Melting point: 122 to 123 ° C Elemental analysis (C27H33N3 〇3· 0.4H2 〇) Calculated: C, 71.31; H, 7.49; N, 9.24 Found: C, 71.53; H, 7.46; 9. 09 Example 57 1{3_[(cyclobutylamino)methyl]-8-mercapto-inden-7-yl}_4_[(2§)_ tetrahydro-0-[0] Alkyl benzoate

Take N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]phenylamine (Ig) From Reference Example 9), cyclobutaneamine (800 mg) was suspended in 1-mercapto-2-pyrrolidone (2%) and acetic acid (7 mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxy borohydride (2.33 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of 1 N aqueous sodium hydroxide solution and the mixture was assayed. The mixture was partitioned with ethyl acetate and the mixture was combined, and then organic layer was applied to water (4 〇g) of water (4 〇mL) dimethyl sulfoxide (20 A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, which was partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine and evaporated The resulting solid was recrystallized from EtOAc (m.) (yield: 26%). 322147 174 201206909 Ή NMRC300 MHz, DMSO-de) (5: 1. 52-1. 75(5H, m), 1.82-1.94(2H, m), 1. 98-2. 12(3H, m), 2 49-2. 50( 1H, in), 2.63 (3H, s), 3. 17-3.22(1H, m), 3. 69(1H, q, J=6. 3Hz), 3. 77-3 8K3H, m) , 4. 00-4. 10(2H, m), 4. 17-4. 21 (1H, m), 7. 08(2H, d, J=8.7Hz), 7. 57( 1H, d, J=8. 7Hz), 7. 77(1H, d, J=8.7Hz), 8. 01(2H, d, J=8. 7Hz), 8. 18(1H, s), 8.86 (1H, s), 10. 04 (1H, s). Melting point: 142 to 144 ° C. Elemental analysis value (C27H3iN3 〇3 · 0. 2H2 〇) Calculated: C, 72.20; H, 7. 05; N, 9. 36 Found: C, 72.26; 7. 07 ; N, 9. 37 Example 58 N-[8-Mercapto-3-({[(lR)-l,2,2-trimercaptopropyl]aminoindolyl)-quinoline- 7-yl]-4-[(2S)-tetrahydrofuran-2-yloximeoxy]benzamide

Take N-(3-mercapto-8-fluorenylquinoline-7-yl)_4_[(2S)_tetrahydrofuran-2-ylindoleoxy]benzamine (2.〇g) (from reference Example 9) and (^_(-)-3'3-dimethyl-2-butylamine ((10)) suspended in the methyl group 2 kiss each bite (2〇虬) with acetic acid (7. 〇mL) The mixture was stirred at room temperature for 3 hours. Sodium triethoxysulfonylborohydride (4.7 g) was added, and the mixture was stirred at room temperature 3. The reaction was quenched by adding 1N aqueous sodium hydroxide and the mixture was tested. The organic layer was added to a solution of citric acid (4 mL) in water (40 mL) - dimethylsulfoxide (20 mL), and the mixture was washed with ethyl acetate. The aqueous solution of sodium was added to the aqueous layer, and the mixture was partitioned with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The title compound (520 mg, yield 21%) was obtained as a colorless solid. 4 NMR (300 MHz, DMSO-d6) (5: 0.85 (9H, s), 0.98 (3H, d, J = 6. 6 Hz), 1.66-1.9K4H, m), 1.98-2.06(1H, m), 2.17 -2. 19(1H, m), 2. 49-2. 50(1H, m), 2. 64(3H, s), 3.69C1H, q, J=6.3Hz), 3.77-3.83(3H, m ), 3. 99-4. 08(2H, m), 4. 15-4. 19(1H, m), 7. 08(2H, d, J=8. 7Hz), 7. 57(1H, d , J=8.7Hz), 7.77C1H, d, J=8. 7Hz), 8. 01(2H, d, J=8. 7Hz), 8.19C1H, s), 8.92(1H, s), 10.03C1H, s). Melting point: 140 to 141 ° C Elemental analysis (C29H37N3 〇3) Calculated: C, 73.23; H, 7.84; N, 8.83 Found: C, 73. 09; H, 7.68; N, 8. 66 Example 59 N-(8-Mercapto-3-{[(2-methylpropyl)amino]indolyl}quinolin-7-yl)-4-(tetrahydrofuran-3-ylindoleoxy)phenylhydrazine Guanamine

Rr 176 322147 201206909 Take N-(3-methylamido-8-methylquinolin-7-yl)_4-(tetrahydro-n-yl-3-ylmethoxy)phenylamine (1.776 g) From Reference Example 4) to 2-methylpropan-1-amine (435 mg) was added to a mixed solvent containing chloromethyl-2-pyrrolidone (1 〇mL) and acetic acid (3.0 inL) Give the mixture for 3 hours. Sodium triethoxy borohydride (1.682 g) was added, and the mixture was stirred at room temperature for 89 hr. The mixture was diluted with ethyl acetate to give a 4N aqueous solution of sodium chloride (40 mL). The organic layer was washed with water twice and then washed with saturated brine, The residue was suspended in EtOAc (EtOAc)EtOAc. 1. Β8(2Η, m), 2.08-2.24C1H, m), 2.49(2H, d, J=6. 8Hz), 2. 72-2.88(4H, in), 3. 70-3. 86(2H , m), 3. 86-4. 07(6H, m), 7. 0K2H, d, J=8.9Hz), 7.7K1H, d, J=8. 7Hz), 7.85-7.98 (3H, m), 8.06(1H, d, J=2. 1Hz), 8.25(1H, d, J=8. 9Hz), 8. 90(1H, d, J=2.3Hz).

Melting point: 132 ° C Elemental analysis (C27H33N3 〇3. 0. 7H2 〇) Calculated: C, 70.47; H, 7· 53 ; N, 9. 13 Found: C, 70. 51 ; H, 7. 35 N, 9. 07 Example 60 and Example 61 N-(8-Methyl-3-{[(2-mercaptopropyl)amino]indolyl}quinoline-7-yl)-4-( Tetrahydrofuran-3-ylmethoxy)benzoin 177 322147 201206909

Taking N-(8-fluorenyl-3-{[(2-mercaptopropyl)amino]methyl}porphyrin-7-yl)-4-(tetrahydrofuran-3-yloxy)benzamide Amine (695 mg) (from Example 59) by HPLC [column: CHIRALCEL 0J 4. 6 mm ID x 250 mmL, mobile phase: hexane·ethanol: diethylamine = 700:300:1 (volume ratio)] Perform optical analysis and recrystallize from ethyl acetate/diisopropyl ether to produce a short residence time component (Example 60, 253 mg (99. 4% ee)) of a colorless solid and a long residence time component. Example 61, 210 mg (98.3% ee) of a colorless solid. Component of short residence time: 'H NMR (300 MHz, CDCh) J : 0. 94(6H, d), 1. 69-1. 87(2H, m), 2. 08-2. 23(1H, m ), 2.49C2H, d, J=6.4Hz), 2.71-2.87 (4H, m), 3. 70-3.86C2H, m), 3. 88-4. 06(6H, m), 7. 01(2H , d, J=9. 1Hz), 7.71(1H, d, J=8. 7Hz), 7.89(1H, s), 7.92(2H, d, J=8. 7Hz), 8.05(1H, d, J =2. 3 Hz), 8.25 (1H, d, J = 8.7 Hz), 8.90 (1H, d, J = 2.3 Hz). Melting point: 133 to 134 ° C Composition of long residence time: NMR (300 MHz, CDCb) 5 : 0. 94 (6H, d), 1. 70-1. 89(2H, m), 2. 06-2. 23(1H, m), 2. 49(2H, d, J=6. 8Hz), 2.70-2.88 (4H, m), 3. 70-3. 86(2H, m), 3. 88-4. 07(6H, m), 7. 01(2H, d, J=8. 7Hz), 7. 71(1H, d, J=9. 1Hz), 7.89(1H, s), 7.92 178 322147 201206909 (2H , d, J=8.7Hz), 8. 05(1H, d, J=l. 9Hz), 8. 25(1H, d, J=8. 7Hz), 8.90(1H, d, J=2.3Hz) . Melting point: 130 to 131 ° C Elemental analysis value (C27H33N3 〇 3. 0.2H2 〇) Calculated: C, 71.88; H, 7.46; N, 9.31 Found: C, 72.08; H, 7.48; N, 9. 25 Example 62 N_(3_{[(2, 2-Dimercaptopropyl)amino]indolyl}-8-methylfluorene-based) • _4-(tetrahydrofuran-3-ylindoleoxy)benzene Formamide

N-(3-Mercapto-8-methylquinolin-7-yl)-4-(tetrahydrofuran-3-ylindoleyl)benzamide (1.776 g) (from Reference Example 4) And 2,2-dimercaptopropan-1-amine (519 mg) was added to a mixed solvent of 1-methyl-2-pyrrolidone (10 mL) and acetic acid (3.0 mL) at room temperature The mixture was stirred for 3 hours. Sodium triethoxysulfonium borohydride (1.682 g) was added, and the mixture was stirred at room temperature for 89 hours. The mixture was diluted with ethyl acetate and aq. 4N sodium hydroxide (4 mL) was then evaporated. The organic layer was washed twice with water, brine, evaporated The residue was purified by hydrazine column chromatography [solvent solvent; ethyl acetate··methanol=97:3 (volume ratio)-ethyl acetate:methanol=9 〇: 10 (volume ratio)], and the obtained solid was suspended in ice-cold However, it is mixed with ethyl acetate_diisopropyl ether. The precipitate was collected by EtOAc (EtOAc) elute JH NMR (300 MHz, CDC13) (5: 0. 93 (9H, s), 1. 70-1. 85 (1H, in), 2.08-2.23 (1H, m), 2.40 (2H, s), 2 71-2.87(4H, m), 3. 71-3. 86(2H, m), 3. 88-4. 07(6H, m), 7. 01(2H, d, J=:8. 9 Hz), 7. 71(1H, d, J=8. 9Hz), 7. 86-7. 97(3H, m), 8.05(1H, d, J=2.3Hz), 8.24(1H, d, J =8. 9 Hz), 8.92 (1H, d, J = 2.3 Hz).

Melting point: 129 ° C Elemental analysis (C28H35N3 〇3 · 0. 1 Η 2 〇) Calculated: C, 72. 57; H, 7.66; N, 9.07 Found: C, 72. 41; H, 7.56; N, 9 01 EXAMPLE N-(8-Mercapto-3-{[(tetrahydro-2H-pyran-4-ylindenyl)amino]indenyl}quinoline-7-yl)-4-(tetrahydrofuran -3-yl decyloxy) benzoguanamine

N-(3-Methylmethyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-3-ylmethoxy)benzamide (1.776 g) (from Reference Example 4) And 丨_(tetrahydro-2H-piperidin-4-yl) decylamine (686 mg) was added to a mixed solvent containing p-methyl-2-pyrrolidinone (10 mL) and acetic acid (3.0 mL). The mixture was stirred at room temperature for 3 hours. Sodium triethoxysulfonate (1.682 g) was added and the mixture was stirred at room temperature for 89 hours. The mixture was diluted with ethyl acetate and aq. EtOAc EtOAc EtOAc (EtOAc) The organic layer was washed with water twice and then washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography [developing solvent; ethyl acetate: decyl alcohol = 9 〇: ι 〇 (volume ratio 彡 - ethyl acetate · methanol = 20: 80 (volume ratio)], solid obtained The title compound (1 · 415 g, yield 73%) was obtained as a pale brown solid. HNMR (300 MHz, CDC13) (5: 1.32 (2H, qd, J=l2. 〇, 3.9 Hz), # 1. 63-1.85C4H, m), 2. 08-2.23 (1H, m), 2. 57(2H, s), 2. 72-2.86(4H, m), 3.39(2H, td, J=11.8, 2.1Hz), 3.70- 3.86(2H, m), 3. 88-4. 〇6( 8H, m), 7. 01(2H, d, J=8. 9Hz), ^•71(1H, d, J-8.9Hz), 7.86-7.96(3H, m), 8. 06(1H, d , &gt;2.1 Hz), 8.26C1H, d, J=8.9Hz), 8.90 (lH/d! J=2·3Hz). Melting point: 122 to 123 ° C Elemental analysis (C29H35N3O4 · 10) Φ Calculated: C, 68.62; H, 7.35; N, 8 28 Found: C, 68.76; H, 7.07; N, 8 27 Example 64 N_ (3-{[(trans-4-hydroxy+methylcyclohexyl))amino]indolyl 8-methylindole-7-yl)-4-(tetrahydroanthracene-3-ylmethoxy) ) phenyl hydrazine _ &quot; 322147 181 201206909

Η Ν-(3-Mercapto-8-decylquinolin-7-yl)-4-(tetrahydrofuran-3-ylmethoxy)benzamide (390 mg) (from Reference Example 4) And trans-4-amino-1-decylcyclohexanol (129 mg) (from Reference Example 15) was dissolved in indolin-2-pyrrolidone (3.0 mL), and acetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 3 hours. Sodium triethoxysulfonium borohydride (424 mg) was added, and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with ethyl acetate, and a 2N aqueous solution of sodium hydroxide (16 mL) was added dropwise. The mixture was poured into water, and brine was evaporated. The residue was purified by hydrazine column chromatography [developing solvent; ethyl acetate:methanol=90:10 (volume ratio) ethyl acetate: decyl alcohol = 40: 60 (volume ratio)] It was recrystallized and dried under reduced pressure to give the title compound ( 246 g, 'H NMR (300 MHz, CDCh) 5 : 1.28 (3H, s), 1. 33-1. 52(5H, m), 1. 69-1. 83(3H, m), 1. 86-1. 99(2H, m), 2. 08-2. 23(1H, m), 2. 64-2. 87(5H, m), 3. 70-4. 08(9H, m), 7. 01( 2H, d, J=8.7Hz), 7.7K1H, d, J=9. 1Hz), 7.85-7.96(3H, m), 8.05C1H, d, J=2.3Hz), 8.26(1H, d, J= 8.7 Hz), 8.90 (1H, d, J = 2.3 Hz). Melting point: 98 to 101 ° C Elemental analysis (C30H37N3O4. 1. 6H2O) 182 322147 201206909 Calculated: C, 67. 67 ; H, 7. 61 ; N, 7. 89 Found: C, 67. 68 ; , 7.43; N, 7. 69 Example 65 -{[(2-Methoxy-2-methylpropyl)amino]indolyl 8 monomethylquinolin-7-yl)-4- (tetrahydrofuran-3-ylmethoxy)benzamide

• N-(3_Mercapto-8-methylquinolin-7-yl)-4-(tetrahydrofuran-3-yloxy)benzamide (1.420 g) (from Reference Example 4) With 2-nonoxy-2-methylpropan-1-amine oxalate 0 5 hydrate (921 dissolved in dimercapto-2-pyrrolidone (10 mL), added triethylamine (〇. 61 mL) The mixture was stirred at room temperature for 1.5 hours. Acetic acid (3. 〇mL) was added. The mixture was stirred at room temperature for 4 hours. Sodium triethoxy borohydride (1. 541 g) was added, and the mixture was stirred at room temperature. The mixture was diluted with EtOAc. EtOAc (EtOAc m. Purification by silica gel column chromatography [developing solvent; ethyl acetate: methanol = 9 〇: 1 〇 (volume ratio) ~ &gt; ethyl acetate· sterol = 75:25 (volume ratio)], N muscara gel Purification by column chromatography [developing solvent; ethyl acetate: decyl alcohol = 100:0 (volume ratio) - ethyl acetate: methanol = 96: 4 (volume ratio)]. The obtained solid was recrystallized from ethyl acetate. Produce the title compound (1·119 g, yield 64%) of a pale yellow solid.

H NMR (300 MHz, CDC13) ^ : 1.20 (6H, s), 1.70-1.84 (1H 322147 183 201206909 m), 2. 07-2. 23(1H, m), 2.61(2H, s), 2. 72-2. 87(4H, in), 3. 18(3H, s), 3.70-3.87(2H, m), 3.87-4.08(6H, m), 7. 01(2H, d, J=8. 7Hz), 7. 71(1H, d, J=9. 1Hz), 7.85-7.97 (3H, m), 8. 06(1H, d, J=2.3Hz), 8.25C1H, d, J=9. 1 Hz), 8.92 (1H, d, J = 2.3 Hz). Melting point: 137 ° C Elemental analysis (C28H35N3O4) Calculated: C, 70.42; H, 7.39; N, 8. 80 Found: C, 69.15; H, 7. 36 ; N, 8. 70 Example 66 1{3-[(4-Hydroxy-4-methylpiperidin-1-yl)methyl]-8-methylquinolin-7-yl}-4-(tetrahydrofuran-3-ylmethoxy Phenylguanamine

Taking N-(3-mercapto-8-fluorenylquinolin-7-yl)-4-(tetrahydrofuran-3-yloxy)benzamide (1.420 g) (from Reference Example 4) and 4 _Methylpiperidin-4-ol monohydrochloride (661 mg) (from Reference 17) was dissolved in methyl-2-pyrrolidone (10 mL), and triethylamine (0.61 mL) was added to the chamber. The mixture was stirred at room temperature for 1.5 hours. Acetic acid (3. 〇 mL) was added, and the mixture was stirred at room temperature for 4.5 hr. Sodium triethoxyhydride borohydride (1541 g) was added and the mixture was stirred for 63 hours. Dilute the mixture with ethyl acetate. t drop of bismuth oxide steel solution (30 mL). The mixture is poured into the skin 』 王 王 王 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. The resulting solid was recrystallized from EtOAc (EtOAc) elute H NMR (300 MHz, CDCl 〇 5 : 1.17 (1H, s), 1.25 (3H, s), 1.58-1.85 C5H, m), 2.08-2.23 (1H, m), 2.45 (2H, td, J=l 〇.8, 3.0Hz), 2. 55-2. 66(2H, m), 2. 73-2. 86(4H, m),

3.68-3.86(4H, m), 3. 88-4. 07(4H, ra), 7. 01(2H, d, J=8. 7

Hz), 7. 70(1H, d, J=9. 1Hz), 7. 86-7. 97(3H, m), 8. 03(ih,

J = 1.9 Hz), 8.26 (1H, d, J = 9. 1 Hz), 8.90 (1H, d, J = 2. 3 Hz). Image point: 160 to 162 ° C Elemental analysis value (C29H35N3O4. O.3H2O) ° Ten values: C, 70.36; Η, 7.25; N, 8.49 Found: C, 70.42; Η, 7.07 ; N, 8.43 Example 67 Fluoro-N-(3-{[(2-hydroxy-2-methylpropyl)amino]methyl b-8-methylquino]7-yl)-4-[(2S)-tetrahydro Bite-2-ylmethoxy]benzamide

2-Fluoro-N-(3-indolyl-8-methylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (1.5 g) (from Reference Example 12) and 322147 185 201206909 1-amino~2-mercaptopropan-2-ol (982 mg) was suspended in 1-mercapto-2-beta-pyrrol. The mixture was stirred at room temperature for 3 hours with the same time (20 mL) and acetic acid (7.0 mL). Sodium diethyl hydride hydride (3. 〇 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a 1N aqueous sodium hydroxide solution and the mixture was partitioned, and the mixture was partitioned with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by hydrazine column chromatography [developing solvent; decyl alcohol: ethyl acetate = hydrazine: 1 〇〇 (volume ratio) - methanol: ethyl acetate = 20: 80 (volume ratio)] to give the title compound ( 900 mg, yield 51%) of a colorless solid. ^ NMR (300 MHz, DMSO-de) ά : 1.11(6H, s) , 1.64-1.73(1H, m), 1.83-1.93C2H, m), 1. 97-2. 05(1H, m), 2 16(1H, br), 2.41(2H, s), 2. 67(3H, s), 3. 69(1H, q, J=6. 9Hz), 3.79 OH, q, J=6.9Hz), 3.94(2H, s), 3. 99-4. 11 (2H, m), 4. 14-4. 20(2H, m), 6. 91-7. 02(2H, m), 7. 70- 7. 79(3H, ra), 8. 18(1H, d, J=1.8Hz), 8. 90(1H, d, J=2.4Hz), 9.89(1H, d, J=2. 4Hz). Melting point: 167 to 168 ° C Elemental analysis value (C27H32N3O4F) Calculated: C:, 67.34; Η, 6.70; N, 8.73 Measured value · · C, 67.17; H, 6.71; N, 8. 70 Example 68 N-(3-{[(2,2-Dimercaptopropyl)amino]indolyl 8-decylquinolin-7-yl)-2-fluoro-4-[(2S)-tetrahydrofuran-2 -ylmethoxy]benzamide 186 322147 201206909

Take 2-fluoro-N-(3-methylindenyl-8-fluorenyl quinolate-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]phenyl hydrazine (1. 〇g) (from Reference Example 12) and neopentylamine (1.0 g) were suspended in hydrazino-2-pyrrolidone (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hr. Triethyl hydrazine was added. Sodium borohydride (3.0 g), and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1N aqueous sodium hydroxide solution and the mixture was basified, partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc 42%) colorless solid. !H NMR (300 MHz, DMSO-de) &lt;5: 0. 88 (9H, s), 1. 64-1. 73 (1H, φ m), 1. 83- 1. 93(2H, m), 1. 97-2. 05(1H, m), 2. 15(1H, br), 2.26(2H, s), 2.67(3H, s), 3.69(1H, q , J=6.3Hz), 3.79 (1H, q, J=6.3Hz), 3.92(2H, s), 3.99-4. 11(2H, m), 4. 14-4. 20(1H, in), 6. 91-7. 02(2H, in), 7. 70-7. 78(3H, m), 8. 17(1H, d, J=1.5Hz), 8.90(1H, d, J=2.4Hz , 9.89 (1H, d, J = 2. 4 Hz) Melting point: 134 to 135 ° C Elemental analysis value (C28H34N3O3F) 187 322147 201206909 Calculated value: C, 70. 12; H, 7.15; N, 8. 76 Found: C, 69·96; H, 7.13; N, 8. 70 Example 69 2-fluoro-N-(3-{[(trans-4-hydroxy-4-methylcyclohexyl) Amino]methyl}-8-mercaptoquinolin-7-yl)-4-[(2S)_tetrahydrofuran-2-yloximeoxy]benzoquinone amine ί^/·ΟΗ

2-Fluoro-indolyl-(3-indolyl-8-fluorenylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]phenylamine (1.5 g) (from Reference Example 12) and trans-4-amino-1-decylcyclohexanol (600 mg) (from Reference Example 15) suspended in 1-mercapto-2-pyrrolidone (20 mL) The mixture was stirred at room temperature for 3 hours with acetic acid (7.0 mL). Sodium triethoxy borohydride (3. 〇 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of a 1N aqueous sodium hydroxide solution and the mixture was basified, partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) Mg, yield 37%) of a colorless solid. 'HNMR (300 MHz, DMSO-de) ^ : 1. l〇(3H, s), 1. 23-1. 35(4H, ra), 1. 56-1. 59(2H, m), 1. 64-1. 73(1H, m), 1. 82-1. 90(4H, m), 1. 97-2. 07(1H, m), 2. 20(1H, br), 2. 67( 3H, s), 3.33 322147 188 201206909 (1H, br), 3. 69(1H, q, J=7. 5Hz), 3. 79(1H, q, J=7. 5Hz), 3.90(2H, s ), 3.99-4. 10(3H, m), 4. 16-4. 19(1H, m), 6. 92-7. 02(2H, m), 7. 69-7.79(3H, m), 8. 19(1H, s), 8. 88(1H, s), 9. 89(1H, s). Melting point: 171 to 172 ° C Elemental analysis (C3 〇 H36N3 〇 4F) Calculated: C, 69.08; H, 6.96; N, 8. 06 Found: C, 68.86; H, 6. 98; N, 7.99 Φ Example 70 2-Fluoro-N-(8-methyl-3-{[(2-methylpropyl)amino]indolyl}quinolin-7-yl)-4 -[(2S)-tetrahydrofuran-2-yl decyloxy]benzamide

Taking 2-fluoro-N-(3-methylindenyl-8-fluorenylquinolin-7-yl)-4-[(2S)-tetraphthylhydrofuran-2-ylmethoxy]benzamide ( 1.0 g) (from Reference Example 12) and isobutylamine (1.0 g) were suspended in dichloromethane (2 mL) and acetic acid (7.0 mL), and the mixture was stirred at room temperature for 3 hr. Sodium triethoxyphosphonium borohydride (3.0 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of aqueous sodium hydroxide and the mixture was basified, partitioned with ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by Shixi rubber column chromatography [developing solvent; decyl alcohol: acetic acid ethyl acetate = 0: 1 〇〇 (volume ratio) - methanol: acetic acid acetonitrile 322147 189 201206909 = 20: 80 (volume ratio)] The title compound (700 mg, yield 61%) was obtained as a colourless solid. !H NMRC300 MHz, DMSO-de) (5: 0.88 (6H, d, J=: 6 6Hz) 1. 64-1. 74(2H, m), 1.82-1. 93(2H,m), 1.97- 2.〇5(ih m) 2.34(2H,d,J=6.6Hz), 2.67(3H,s), 3.69(1H,q,j=6 6

Hz), 3. 79 (1H, q, J=6. 6Hz), 3. 89(2H, s), 3.99-4 11(3H m), 4. 14~4. 20(1H, m), 6 91-7. 02(2H, m), 7.69-7 79(3H m), 8. 18(1H, d, J=1.8Hz), 8.89(1H, d, j=:2 1Hz) 9·89 (1Η, d, J=2. 7Hz). ' Melting point: 133 to 134 ° C Elemental analysis value (C27H32N3 〇3F) Calculated: C, 69.66; H, 6.93; N, 9. 03 Found: C, 69.53; H, 6.89; N, 8.97 Examples 71 2-Fluoro-N-{8-mercapto-3-[(propylamino)methyl]quinolinylbu-4_[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

Η

Take 2-fluoro-indolyl-(3-indolyl-8-methylquinolin-7-yl)-hydrofuran-2-yloxylphenylamine (1.〇g) (from reference Example 12) Suspension of the mixture with n-propylamine (1.0 g) in 1-mercapto-2-pyrrolidone (2 mL) and acetic acid (7.0 mL). Triethyl oxime 322147 190 201206909 Sodium borohydride (3.0 g) was added and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by the addition of an aqueous sodium hydroxide solution and the mixture was alkalized, dissolved in ethyl acetate and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (solvent: methanol: ethyl acetate = hexane: 100 (volume ratio) - decyl alcohol: 'ethyl acetate = 20: 80 (volume ratio)) to give the title compound (68) 〇mg, yield 61%) of a colorless solid. !H NMRC300 MHz, DMSO-de) 5 : 0. 88 (3H, t, J=7. 5Hz) Call 1, 40-1. 52(2H, m), 1. 64-1. 73(1H, m ), 1. 79-1. 90(2H, m), 1. 93-2.07(1H, m), 2.39(1H, br), 2.47-2. 52(2H, m), 2. 67(3H, s), 3. 69(1H, q, J=6. 6Hz), 3. 79(1H, q, J=6. 6 Hz), 3. 89(2H, s), 3. 99-4. 11 (2H, m), 4. 14-4. 20(1H, m), 6. 91-7.02(2H, ra), 7. 69-7. 79(3H, m), 8. 18(1H, s ), 8.88 (1H, d, J = 1.8 Hz), 9.89 (1H, d, J = 2.4 Hz). Melting point: 120 to 121t:

Elemental analysis (C26H3DN3O3F) Calculated: C, 69.16; H, 6.70; N, 9. 31 Found: C, 68. 94; H, 6.71; N, 9. 20 Example 7 2 N-{3-[(4-Hydroxy-4-indolylpiperidin-1-yl)indenyl]-8-methylquinolin-7~yl}-4-[(23)-tetrahydrofuran-2-yl Methoxy]benzamide

191 322147 201206909 N_(3-mercapto~8-decylquinolin-7-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (515 mg) From Reference Example 9), 4-mercaptopiperidin-4-ol monohydrochloride (300 mg) (from Reference 17), acetic acid (2.64 mL) and sodium diethyl hydride hydride (559 mg) The mixture was added to N N-dimercaptoacetamide ( 7.92 mL), and the mixture was stirred at room temperature for 15 hr. The reaction solution was ice-cooled, and aqueous 8N sodium hydroxide (6 59 mL) was added, and the mixture was partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and then the organic layer was combined and purified by EtOAc EtOAc (EtOAc: EtOAc EtOAc EtOAc The obtained solid was subjected to a solvent mixture of ethyl acetate and ethyl acetate. 'H NMRC300 MHz, DMSO-de) &lt;5 : l. i〇(3H, s), 1.48(4H, t, J=5.4Hz), 1. 63-2. 09(4H, m), 2.44( 4H, d, J=5. 5Hz), 2.64C3H, s), 3. 65-3. 85(4H, m), 3. 98-4. 10(1H, m), 4.10 (2H, s), 4. 15-4. 24(1H, 7.99(211, d, J=9. 0Hz), 7.59 (1H, d, J=8.7Hz), 7.80(ih, dj j=8.7Hz), 8.02(2H, d, J = 8.9 Hz), 8. 17 (1H, d, J = 2. 1 Hz), 8. 85 (1H, d, J = 2. 1 Hz), 10. 06 (1H, s).

Melting point: 169 to 174 ° C Elemental analysis value (C29H35N3O4 · Nose value. C, 69.60; Η, 7.29; N, 8.40 Found: C, 69.35; Η, 7.2 〇; Ν, 8 37 Preparation example 1 ( 1) Compound (from Example 1) rn 322147 192 201206909 (2) Lactose 34 mg (3) Corn starch 10. 6 mg (4) Corn starch (paste) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 rag Total 120 mg The above items (1) to (6) are mixed according to a conventional method, and the mixture is compressed into a tablet by a tablet press to produce a tablet. • Experimental Example 1 Using a combination analysis method Binding assay for human and rat MCH1 receptor binding activity assays (1) Preparation of membrance fraction using CH0 cell line expressing human MCH1 receptor (SLC-1) and expressing MCH1 receptor in rat The CH0 cell line of the body (SLC-1) (described in w〇01/82925) was prepared by the following method to prepare the membrane fraction I of the CHCH cell expressing the MCH1 receptor. 100 ml of homogenization buffer (1 mM NaHC〇3) was taken. (pH 7. 4), ImM £0 butyl, 2 complete protease inhibitors ({^〇(:) tablets) added to 3乂109 CH0 representing MCH1 receptor In the cells, the cells were disrupted by a Polygon homogenizer (20 000 rpm, 30 seconds, 3 times). The disintegrated cell fluid was centrifuged at 1,000 g for 15 minutes. The supernatant was then taken at 14 〇, g ultracentrifugation ( Beckman 45Ti rotor) 6 min, a precipitate of the membrane fraction of the CH0 cells expressing the receptor was obtained and collected. The membrane was partially suspended in 30 ral suspension buffer (20 mM Tris-HC1 (pH 7.4) ' 5 mM EDTA, 0.6 capsules of complete protease inhibitors), after storage, stored in _8 〇 (t, 322147 193 201206909, each time after decompression is used. (2) Combining analysis method using membrane buffer using analysis buffer (25 mM Tris-HCl, 1 mM EDTA, 0.1% BSA '0. 5 mM PMSF (phenyl sulfonyl sulfonium fluoride), 1 # g/mi aprotinin A (pepstatin A), l〇eg/ Ml phosphoamidon and 2〇vg/ml leupeptine (pH 7.5) diluted to a membrane fraction at a concentration of g/rol, then each 175 yl aliquot was dispensed into polypropylene 96 wells Intraday (Corning 3363). Human MCH (4-19) and human MCH (1-19) were purchased from the Peptide Institute. Human · MCH (4-19) has labeled 1251 using the Bolton-Hunter method. The combined value (X) of the total binding value (TB), the non-specific binding value (NSB), and the portion treated with the test compound was determined according to the following procedure. Total binding value (TB) assay: To determine the total binding value (TB), add 2# 1 of DMS0 and 25/z 1 of 3. 2 nM 125I-human MCH (4-19) to the membrane fraction suspension . After the mixture was reacted at 25 ° C for 60 minutes, the reaction mixture was suction-filtered using a polyethyleneimine-treated GF/C ® filter plate (PerkinElmer), and washed with a buffer buffer (50 mM Tri-HCl, pH 7.5). ) Wash 3 times. After the filter plate was dried, the radioactivity remaining on the filter plate was measured using a TopCount (PerkinElmer) as the total binding value (TB). Non-specific combined numerical (NSB) assay:

2nM 194 322147 201206909 125I - Human MCH (4-19) is added to the membrane partial suspension. After the mixture was reacted at 25 ° C for 60 minutes, the reaction mixture was filtered with a polyethyleneimine-treated GF/C filter, plate (PerkinElmer), and washed with a buffer (50 1^1'1^-this 1,卩117.5) Wash 3 times. After the raft was dried, the radioactivity remaining on the filter plate was measured using a TopCount (PerkinElmer) as a non-specific binding value (NSB). Binding value (X) assay of the fraction treated with the test compound: To investigate the binding value of the fraction treated with the test compound (X), the test compound of 2/i 1 (dissolved in MS0 with various concentrations) And 25/z 1 of 3. 2 nM 125I-human MCH (4-19) was added to the suspension of the membrane fraction. After the mixture was reacted at 25 ° C for 60 minutes, it was suction-filtered with a GF/C percolate plate (PerkinElmer) treated with polyethionimide, and the reaction mixture was washed with a buffer buffer (50 mM Tri-HC1, pH 7. 5) Wash 3 times. After the filter plate was dried, the radioactivity remaining on the filter plate was measured by TopCount (Perk in Elmer) as the binding value (X) of the portion φ treated with the test compound. The value obtained by subtracting the non-specific binding value (Nsb) from the total combined value (TB) is the estimated specific binding value. The value obtained by subtracting the non-specific binding value (NSB) from the binding value (X) of the fraction treated by the test compound is the binding value of 125I-human MCH (4-19) which is inhibited by the test compound. The binding inhibitory activity (% inhibition of binding) of the test compound to the MCH 1 receptor was calculated by the following equation. Binding inhibition rate % = 1〇〇x[1-(X-NSB)/(TB-NSB)] By comparing the binding inhibition rates of various concentrations of test compounds, 195 322147 201206909 was selected to show lower concentrations at lower concentrations. A compound having high binding inhibitory activity as a compound having high ability to bind to the MCH 1 receptor. The IC5 enthalpy of the test compound was calculated from the binding inhibition rate (%) using GraphPad Prism (GraphPad software). The results are shown in Table 1-1 and Table 1-2.

196 322147 201206909 [Table 1-1 ] Compound number Inhibitory activity (ic5. Value: nM) Human SLC-1 rat SLC -1

Embodiment 16 Embodiment 25 Embodiment 27 Embodiment 29 Embodiment 30 Embodiment 31 Embodiment 32 Embodiment 34 Embodiment 35 Embodiment 36 Embodiment 37 Embodiment 38 Example 39 Example 39 Example 41 Example 45 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Example 54 Example 55 Example 56 Example 57 Example 58 Example 62

twenty two

197 322147 201206909 [Table 1-2] Compound number inhibitory activity (ICso value: nM) Human SLC-1 Rat SLC-1 Example 63 3. 7 4. 5 Example 67 7. 8 11 Example 68 3. 1 2. 8 Example 69 6. 1 7. 1 Example 70 2. 7 3. 2 Example 71 5. 0 8. 0 Example 72 4. 5 4. 3 Can be seen from Table 1-1 and Table 1-2 The compounds of the invention have superior MCH receptor antagonistic activity. Experimental Example 2 Male F344/Jci rats fed a high-fat diet were evaluated for appetite loss. Male F344/Jcl rats (42 weeks old) were administered, and high-fat feed (study feed: D12451) was supplied from 5 weeks of age. Two weeks before the start of the experiment, rats were independently fed to provide a high-fat feed powder (research feed: D12451M), and tap water (0.5 mL) was administered to adapt the rats to the environment. The food intake from 14:00 to 9:00 the day before the start of the experiment was determined, based on the food intake and body weight of the rats on the previous day. On the day of the experiment and the next day, at 16:00, according to 2 mL/kg, 0.5% methylcellulose solution was administered to the control group via the gastric tube, and the compound was administered via the gastric tube. 5%曱The cellulosic suspension (10 mg / kg) was administered to the compound administration group (6 in each group of the control group and the compound administration group). The amount of food intake 198 322147 201206909 was measured within 48 hours from the start of administration. The food intake inhibition rate of each compound administration group and the control group was calculated. The results are shown in Table 2. Table 2 Compound No. Food intake inhibition rate (%) Example 31 - 24. 8 Mumumu Example 50 30, 3 Mumu*«p&lt;0.001 (Dunnett compared to the control group) , s type multiple comparison)) ® As seen from Table 2, the compounds of the present invention showed superior appetite loss effects in a rat model of obesity. In Experimental Example 3 and Experimental Example 4 below, the 4-(cyclopropyldecyloxy)-N-[3-[[(trans-4-hydroxy) ring of Example 5 described in jpu〇〇8-088120 was used. Hexyl)amino]indenyl]-8-methylquinolin-7-yl]benzamide (hereinafter referred to as "Comparative Example") and 4-(cyclopropyldecyloxy)_N_ of Example 9. 3-[[(trans-4-hydroxy-4-mercaptocyclohexyl)amino]methyl]- 8-methylquinoxaline-7-yl]benzamide (hereinafter referred to as "Comparative Example" 2") as a comparative standard of the compound of the present invention. Comparative Example 1 and Comparative Example 2 were prepared in accordance with the description of JP-A-2008-088120. Experimental Example 3 Evaluation of HERG inhibitory activity medium, mm non-essential amino acid solution, acetone Sodium solution and G418 sulfate solution (Geneticin) were purchased from Invitrogen 199 322147 201206909

Corporation (Carlsbad, CA). Bovine serum albumin (BSA, which does not contain fatty acids) is a product of Wako Pure Chemical Industries, Ltd. (Japan's Osaka). Fetal bovine serum (FCS) is a product of Trau Scientific Ltd. (Melbourne, Australia). The HERG expression cell, HERG. T. HEK, was obtained from the Wisconsin ALUMNI Research Foundation. HERG. T. HEK is used at 37 ° C in the presence of 5% C 〇 2 with 10% FCS, 1 mM MEM non-essential amino acid, 1 mM propyl S with sodium sulphate and 500 yg / ml Preservation and subculture of the MEM medium of Geneticin. φ Collection of 80 to 90% confluent cells by TGase treatment was placed on an IVF culture dish (Falcon, Franklin Lakes, NJ). After 2 to 3 hours, a cell cit amp amplifier (Ax0 instruments, Foster City, CA) was used to perfuse the extracellular fluid (137 NaCl, 4 raM KC1, 1 mM MgCl2, 1. 8 mM CaCl2, 10 mM HEPES, 11 mM dextrose: pH 7. 4), allowing cells to adhere to the internal fluid of the filled electrode (7 mM Na (n, 130 mM ΚΠ, 1 mM MgCl2, 5 mM) HEPES, Lu 5 mM EGTA, 5 mM ATP-Na: pH 7. 2) glass electrode (resistance 2 to 3 Μ Ω ) 'by forming a whole cell (wh〇1 e-ce 11) configuration with voltage Stimulation method stimulation (maintenance potential -75 mV, primary voltage 10 mV. 0. 5 seconds 'secondary voltage - 40 mV: 0.5 seconds, stimulation frequency 5 seconds (Example 3i and implementation) Example 5〇) or ι〇sec (Comparative Example 1 and Comparative Example 2)). Pre-stimulation is performed first, and then the HERG current value (peak tai 1 200 322147 201206909 current) is measured after the current waveform is stabilized 〇 When the HERG current is measured under the addition of the test compound, the cells are first perfused with extracellular fluid, and when the waveform is stable The cells are perfused with an extracellular fluid containing 1 〇 test compound. When the current waveform under each perfusion condition is stable, the HERG current is measured. The HERG current value is used as the test compound to calculate the HERG current inhibition of the test compound. The rate (%). The results are shown in Table 3. Table 3 HERG current inhibition rate (%) of Compound No. 10 indole compound Example 31 Example 50 Comparative Example 1 Comparative Example 2 ^θΓδ 2. 1 58 44. 9 3 It can be seen that the compound of the present invention exhibits low HERG inhibitory activity and is confirmed to be low in toxicity. Experimental Example 4 Evaluation of PLsis DMEM medium, L-lactam, penicillin-streptomycin, pyruvic acid and pyruvic acid N-(7-nitrophenyl-2-oxa-1,3-diwasyl-4-yl)-1,2-hexadecanyl-sn-glyceroglyceryl-3-hydric acid ethanolamine ( Phosphoethanolamine) Triethyl Salt (NBD-PE) was purchased from Invitrogen Corporation. Bovine serum albumin (BSA) product from Thermo Trace Ltd. (Melbourne, Australia) and amine ketone from ICN (Costa Mesa, CA) were used. (Amiodarone) products. The test compound was used in the form of a 201 322147 201206909 10 mM DMS0 solution. Add FBS to DMEM medium supplemented with l-glutamine, pyruvic acid and arsenic, the final concentration is 5 v〇1%, and the solid chain mold uses 5% carbon dioxide gas _95% air as the gas phase,殓-b Q7°r&gt; ^ In the incubator, culture in wc. HePG2 cells were suspended in culture medium, cells/mL, placed in a 96-well plate, 50# L/well, and pre-cultured 24 1 fine cultures, then 'removed medium, including 6〇#m NBD~Ρβ top 50 // L/well' is then added with sputum, or 20/ζΜ test: 5 〇eL/well to HepG2 cells in culture medium, and cultured cells 24] t. The final wave of rp is 10 // Aminea moth _ (Amiodarone) as a yang, Bu 4 blade 丨 king control group. After the test compound was treated for 24 hours, the fluorescence intensity (excitation light (εχ.) “5 nm, emission light (heart) 538 nm) of the cells after absorption of NBD-PE was measured by a fluorometer. The addition of 〇# μ test compound solution was subtracted. The blank measurement value was calculated relative to the measured value when adding the m#mamine mothone (Amiodarone), and the maximum value obtained per unit test compound concentration was used as the phospholipidation (PLsis) evoking potential. 4. [Table 4] Compound No. Example 31 Example 50 Comparative Example 1 Comparative Example 2 PLsis-inducing potential 1.7 1.4 23. 5 27.8 It can be seen from Table 4 that the compound of the present invention exhibits a low PLs is induced potential '202 322147 201206909 and confirmed It is a low-toxicity. The industrially-available compound (I) has a melanin-concentrating hormone (MCH) receptor antagonistic action and is low in toxicity. Therefore, the compound is extremely suitable as a prophylactic or therapeutic agent for obesity and the like. No. [Description of main component symbols] ❿ None.

203 322147

Claims (1)

(I) (I) 201206909 7. Scope of application: 1. A compound of the formula (I) or a salt thereof: Wherein ring A is a tetrahydrofuran ring, which may be further substituted as needed; R1 is a hydrogen atom or an il atom; R2 is a hydrogen atom, a halogen atom or a fluorenium-6 alkyl group; R3 is a hydrogen atom or a Ch alkyl group; and R4 and R5 ( 1) independently a hydrogen atom, optionally substituted C!-6 alkyl, optionally substituted C3-1Q cycloalkyl, or optionally substituted 5 or 6 membered heterocyclic group, or (2) A substituted 4 to 6 member nitrogen-containing heterocyclic ring may be formed together with an adjacent nitrogen atom, with the proviso that when one of R4 and R5 is a hydrogen atom, the other is not a group represented by the following formula: Wherein, X1 is a bond or a Ci-6 alkyl group; and RA1 is a group represented by the formula: -YS(0)ml-RB1, 204 322147 201206909 wherein 'Y is a bond or NH; ml is 1 or An integer of 2; and Rb, a C,-6 alkyl group optionally substituted with 1 to 3 tooth atoms, or a cyclic group represented by the formula: Where m2, m3, m4, ru, n2, and n3 are each independently 1 or 2 And RB2 are Ci e alkyl groups which may be substituted by 1 to 3 functional atoms (the ring portion of the cyclic group may be further substituted as needed). 2. The compound of claim 1, or a salt thereof, wherein R1 is a hydrogen atom or a fluorine atom. 3. The compound of claim 1, or a salt thereof, wherein R2 is a fluorine atom or a methyl group. 4. The compound of claim 1, or a salt thereof, wherein R3 is a hydrogen atom or a fluorenyl group. The compound of claim 1 or a salt thereof, wherein R 4 (a) Ch alkyl, which may optionally be substituted with i to 3 substituents selected from the group consisting of hydroxyl, C alkoxy and 5 Or 6 members of an oxygen-containing heterocyclic group, or (b) a C3-1Q cycloalkyl group which may be optionally substituted with 3 substituents selected from the group consisting of a hydroxyl group and a Ch alkyl group; and R is a chlorine atom. The compound according to claim 1 or a salt thereof, wherein R4 322147 205 201206909 and R5 together with an adjacent nitrogen atom form a 4 to 6 member nitrogen-containing heterocyclic ring substituted with a hydroxyl group (group), and The nitrogen-containing heterocycle may optionally be substituted with a Ch alkyl group. 7. The compound of claim 1, or a salt thereof, wherein the ring A is a tetraar-argon ring; R1 is a hydrogen atom or a fluorine atom; R2 is a fluorine atom or a fluorenyl group; and R3 is a hydrogen atom or Alkyl; R4 is (a) a G-6 alkyl group which may optionally be substituted with 1 to 3 substituents selected from the group consisting of a thiol group, a Ci-6 alkoxy group and a 5 or 6 membered oxygen-containing heterocyclic group. Or (b) a C3-1()cycloalkyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a C1-6 alkyl group; and R5 is a hydrogen atom. 8. The compound of claim 1, or a salt thereof, wherein the ring A is a tetrahydrogenated alpha ring; R1 is a hydrogen atom or a fluorine atom; R2 is a fluorine atom or a methyl group; and R3 is a hydrogen atom or a hydrazine. And R4 and R5 together with an adjacent nitrogen atom form a 5- or 6-membered nitrogen-containing heterocyclic ring substituted with a hydroxy group, and the nitrogen-containing heterocyclic ring may be optionally substituted by a Cw alkyl group. A compound or a salt thereof, which is N-[8-fluorenyl-3-({[(2S)-tetrahydrofuran-2-ylindenyl]amino}indolyl)quinolin-7-yl]- 4-206 322147 201206909 [(2S)-Tetrahydrofuran-2-ylmethoxy]benzamide. 10. A compound or a salt thereof, which is N-{8-methyl-3-[(tetrahydro-2H-piperidin-4-ylamino)methyl]quinolin-7-yl}-4 -[(28)-Tetrahydro Df-am-2-yloxy)benzamide. A compound or a salt thereof, which is N-(8-methyl-3-{[(2-mercaptopropyl)amino]methyl}〇查琳-7-yl)-4-[( 2S) - Tetra Argon η 味 -2 - 曱 曱 oxy] phenyl hydrazine. 12. A compound or a salt thereof, which is trans-4-hydroxy-4-methylcyclohexyl)amino]indolyl 8-mercaptoquinoline-7-yl)_4_[(2S)-tetrahydrofuran -2-yl decyloxy] benzoic acidamine or a salt thereof. 13. A compound or a salt thereof, which is ν_{3_[(4_hydroxy_4_methylbendyl-1-yl)methyl]-8-methyl喧line-7-yl}-4- [(28)-Tetrahydro-pentan-2-yloxy]benzamide. 14. A prodrug of a compound or a salt thereof according to the scope of the patent application. 15. An agent comprising a compound or a salt thereof or a prodrug thereof as claimed in the scope of claim. 16. The agent of claim 15 which is a melanin-concentrating hormone receptor antagonist. An agent according to claim 15 which is an appetite reducing agent. 18. The agent of claim 15, which is an anti-obesity or therapeutic agent. A method for preventing or treating obesity in a mammal comprising administering to the mammal an effective amount of the compound or a salt thereof or a prodrug thereof. 322147 207 201206909 20. The use of the compound of claim 1 or a salt thereof or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for obesity. 208 322147 201206909 IV. Designated representative map: There is no schema in this case. (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: 3 322147