TW200815324A - Straight chain amine compound - Google Patents

Abstract

The present invention provides an excellent therapeutic agent for hypertension. The medicine of the present invention comprises a compound of the following formula (I) [wherein, R1: H, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted cyclic hydrocarbon, optionally substituted heterocyclic group etc.; R2: H, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted cycloalkyl group etc.; R3, R4: H, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted cycloalkyl group etc.; R5, R6: H, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkoxy group etc.; R7: H, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkoxy group etc. Y: single bond, optionally substituted alkylene group, optionally substituted alkenylene group, -(CH2)a-X1-(CH2)b- (X1: -NH-, -O- etc.; a, b: 0-5) etc.; R8: optionally substituted cyclic hydrocarbon, optionally substituted heterocyclic group etc.].

Description

200815324 IX. Description of the Invention: [Technical Field] The present invention relates to a novel chain amine compound useful as a medicine (especially for the treatment or prevention of hypertension (suitable for treatment) having excellent renin inhibitory activity] Or a pharmacologically acceptable salt thereof; a renin inhibitor containing a chain amine compound or a pharmacologically acceptable salt thereof; a pharmaceutical composition containing a chain amine compound or a pharmacologically acceptable salt thereof as an active ingredient, a medicine suitable for treating or preventing hypertension a composition for the manufacture of a pharmaceutical composition, which is preferably a chain amine compound or a pharmacologically acceptable salt thereof for use in the treatment or prevention of the above-mentioned diseases; or a pharmacologically effective amount of a chain amine compound or a pharmacologically acceptable salt thereof A blood animal (especially a human) to treat or prevent a disease, a method suitable for the above diseases; and a method for producing a chain amine compound or a pharmacologically acceptable salt thereof. [Prior Art] According to the WHO/ISH guidelines, hypertension is characterized by a maximum blood pressure of 140 mmHg or more, or a minimum blood pressure of 90 mmHg or more. Hypertensive patients now have about 40 million people in Japan and about 1 billion people in the world. Report (Dicision Resources, Inc.). In the state of persistent hypertension, it causes cerebral hemorrhage, cerebral infarction, aortic aneurysm, nephrosclerosis, myocardial infarction, or heart failure, and finally death. Inhibition of these diseases by the administration of therapeutic drugs for hypertension is listed in large-scale clinical trials. Now, we are striving to reduce blood pressure by actively investing in the treatment of hypertension, exercise, and eating, but still hopefully Blood pressure control.

One of the main mechanisms of hypertension is the activation of the renin-angiotensin system (hereinafter referred to as R-A 200815324). R-A is a representative pressurization system for living organisms that retains sodium (salt) in the body to increase circulating blood volume, or shrinks vascular smooth muscle, and raises blood pressure. In the R-A system, angiotensinogen is converted to angiotensin I by renin, and angiotensin-converting enzyme (hereinafter referred to as ACE) converts angiotensin I into angiotensin II. Angiotensin II acts on the angiotensin type 1 receptor (hereinafter referred to as AT1), causing vasoconstriction, cell proliferation, or production of collagen, hypertension, and subsequent spasm. An ACE inhibitor (hereinafter referred to as ACEI) which inhibits the production of angiotensin II, and an angiotensin receptor antagonist (hereinafter referred to as ARB) which inhibits stimulation of AT1 are currently used as therapeutic agents for hypertension, and these agents are known. It has a significant blood pressure lowering effect and a protective effect of the device. Renin is an aspartic acid protease that converts angiotensinogen to angiotensin I, and is regarded as a rhythm enzyme of the R-A system. Therefore, renin inhibitors effectively inhibit the R-A line, and are expected to have the same blood pressure lowering effects as ACEI and ARB (Circulation, 2005, Vol. 112, p. 1012-18). Several 5-amino-r-hydroxy-ω-alkaneamine compounds having renin inhibitory activity are known (see, for example, Patent Document 1 or 2). Further, in the 5-amino-r-hydroxy-ω-alkyl alkanoguanamine compound, a compound in which a carbon atom at the 2-position (α position) is substituted with a nitrogen atom (see, for example, Patent Document 3 or 4), or 8-position A compound in which a carbon atom is substituted with a nitrogen atom (see, for example, Patent Document 5). However, in the 5-amino-7-hydroxy-ω-alkyl decylamine compound, the compound in which the carbon atom at the 7-position is substituted by a nitrogen atom is still unknown. The compound of the present invention is greatly different from the above-mentioned known compound structure because the carbon atom at the 7-position is substituted by a nitrogen atom. [Patent Document 1] U.S. Patent No. 5,559,1,1,1,1,1,1,1,2,2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, In the case of the inventors of the present invention, the inventors of the present invention have developed a novel chain amine compound for developing an excellent therapeutic drug for hypertension. A chain amine compound having a specific structure or a pharmacologically acceptable salt thereof is found to have renin inhibitory activity, solubility, oral absorption, blood concentration, metabolic stability, tissue migration, bioavailability (hereinafter also referred to as BA), in vitro activity, in vivo activity, rapid discovery of drug efficacy, persistence of pharmacodynamics, physical stability, drug interaction, toxicity, etc. have excellent properties as medicines (especially treatment or prevention of hypertension) Treatment) medicine] useful. The present invention has been completed based on the above findings. Means for Solving the Problems The present invention provides a novel chain amine compound or a pharmacologically acceptable salt thereof which is useful as a medicine (especially a medicine for treating or preventing (suitable for treating) blood pressure syndrome), which has excellent renin inhibitory activity; An amine compound or a pharmacologically acceptable salt renin inhibitor; a pharmaceutical composition comprising a chain amine compound or a pharmacologically acceptable salt thereof as an active ingredient; a pharmaceutical composition suitable for treating or preventing hypertension; for producing a pharmaceutical composition, The use of a chain amine compound or a pharmacologically acceptable salt thereof for a pharmaceutical composition for the treatment or prevention of the above diseases; administration of a pharmacologically effective amount of a chain amine compound or a pharmacologically acceptable salt thereof to a warm blood 200815324 animal (especially a human) for treatment Or a disease prevention method, a method suitable for the above diseases; and a method for producing a chain amine compound or a pharmacologically acceptable salt thereof. The present invention provides (1) a compound of the following formula (I), or a pharmacologically acceptable salt thereof;

[wherein R1 is a hydrogen atom, a ChC8 alkyl group, a substituted Ci-Cs group, a c2-c6 alkenyl group, a substituted c2-c6 alkenyl group, a c2-c6 alkynyl group, a substituted c2-C6 alkynyl group, a trans group, a Ci- C6, oxy, substituted Ci-C6, oxy, Ci-C6, thio, substituted, Ci-C6 alkylthio, amine, Ci-Ce alkylamine, substituted Ci-C6, amine, di(Ci- C6 hospital base) amine group (the base can be asked or different), substituted two ((^-(^6 yard)) amine group (the hospital base can be the same or different), formazan, (Cl- C6丨)), substituted (Ci-Ce alkyl)carbonyl, (ChCe alkoxy)carbonyl, substituted (Ci-C6 alkoxy)carbonyl, C3 - C1. cyclic hydrocarbon group, substituted c 3 - ci a cyclic hydrocarbon group, a 3 to 10 membered heterocyclic group, or a substituted 3 to 10 membered heterocyclic group, and a substituent of each of the cyclic hydrocarbon group and the heterocyclic group in R1 is the same selected from the substituent group α or f Or 1 to 3 of a different base, 2 of which may form a C!-C 5 alkylene group, the substituent of the cyclic hydrocarbon group and the heterocyclic group in R1 is the same as that selected by the substituent group α or 1 to 3 different bases; R2 is a hydrogen atom, a Cl-C6 yard, a substituted Cl-C6 yard, a C2-C6 susceptibility, The substituent of each of the C2-C6 alkenyl group, the C2-C6 alkynyl group, the substituted C2-C6 alkynyl group, the C3-C8 cycloalkyl group, or the substituted C3-C8 cycloalkyl group R2 is represented by the substituent 200815324 group α or 1 select the same or different 1 to 3 groups, ... and ^ can form 3 to 1 一起 together with these combined nitrogen atoms. Nitrogen-containing heterocyclic group or substituted 3 to 10 member nitrogen-containing heterocyclic group The substituent of the nitrogen-containing heterocyclic group is the same or different one or three groups selected from the substituent group α; R3 is a hydrogen atom, C丨-C6 alkyl group, substituted Ci_c6 alkyl group, C2-C6 Alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2_C6 alkynyl, C"C8 cycloalkyl, substituted C3_C8 cycloalkyl, hydroxy, c丨-C6 alkoxy, substituted Ci_C6 alkoxy, a Cl-C6 alkylthio group or a substituted C1-C6 alkylthio group, and the substituent of each group in r3 is the same or different one or three groups selected from the substituent group α; R4 is a hydrogen atom, Ci-C6 alkane a substituted, a Ci-C6 alkyl group, a C2-C6 alkenyl group, a substituted C2-C6 stilbene group, a C2-C6 alkynyl group, a substituted C2-C6 alkynyl group, a C3-C8 ring-based group, a substituted C3-C8 cycloalkyl group, Hydroxy, Cl_C6 alkoxy, substituted Cl_C6 alkoxy, Ci-Ce alkylthio, or substituted Cl- a C6 alkylthio group, the substituent of each group in R4 is the same or different one or three groups selected from the substituent group 'R3 and R4 may together form a C1-C5 alkylene group or a substituted Ci-Cs extension. The substituent of the alkyl group is one or three of the same or the same phase selected by the substituent group α; R is a hydrogen atom, a Cl-C6 group, a substituted Cl-C6 group, C3- C8 ring-based, substituted C3-C8 cycloalkyl, hydroxy, Ci-C6 alkoxy, substituted Cl-C6 alkoxy, amine, Cl-C6 alkylamino, substituted Ci-C6 alkylamino, di Cl_Ce alkyl)amino groups (the alkyl groups may be the same or different), or substituted bis (C1-C6-based) amine groups (this; thiol groups may be the same or different), the substituents of each group in R are The same or different 1 to 3 groups selected by the substituent group α; -10- 200815324 R6 is a hydrogen atom, a Ci-C6 alkyl group, a substituted Ci-(:6 alkyl group, a C3_C8 cycloalkyl group, a substitution c : 3-c8 cycloalkyl, hydroxy, (: alkoxy, substituted c decyloxy, amine, Ci-C6 alkylamino, substituted Ci_c6 alkylamino, bis(C1_C6 alkyl) amine (this An alkyl group may be the same or different), or a substituted di((:C6 alkyl)amino group (the alkyl group) The substituents of the respective groups in R6 are the same or different one to three groups selected by the substituent group α; R7 is a hydrogen atom, a Ci-C6 alkyl group, a substituted Ci-C6 alkane , Cs-C8 cycloalkyl, substituted C3-C8 cycloalkyl, hydroxy, —(:6 alkoxy, substituted Ci-C6 alkoxy, amine, Ci-C6 alkylamino, substituted Ci-C6 An alkylamino group, a di(Ci-C6 alkyl)amino group (which may be the same or different), a substituted di(C!-c 6 alkyl)amino group (the alkyl group may be the same or different), A a mercapto group, a (C^Ce alkyl) ore group, a substituted (Cl-C6 alkyl)carbonyl group, a (Cl_C6 alkoxy)carbonyl group, or a substituted (Ci-C6 alkoxy) group, and a substituent of each group in R7 The base is the same or different one to three groups selected by the substituent group α; Υ is a single bond, an alkyl group, a substituted 匕 _ (6 alkyl group, a c2-C6 alkyl group, a substituted ChC6 group) Alkenyl, C2-C6-alkenynyl, substituted c2-C6-alkenyl, or formula-(CHJa-XyCHOb-[wherein X1 is a formula -NH-, -NR9- (wherein R is a Ci-C6 yard) , -〇-, -S-, -SO- or -SO 2 -, each of a and b is an integer from 0 to 5, the sum of a and b is a group of 〇 to 5], and each of γ is Substituent by a substituent group selected r of the same or different groups of 1 to 3; R8 is of formula ([pi]) of [2]

-11· 200815324 [In the formula, A is Cs-Ci. a cyclic hydrocarbon group, a substituted C3-Ci〇 cyclic hydrocarbon group, a 3 to 10 membered heterocyclic group, or a substituted 3 to 1 membered heterocyclic group, and the substituent of each group in A is the same or the phase selected by the substituent group α 1 to 3 groups, X2 is a formula - ΝΗ-, -NR11- (wherein 1^ is (:" 〇alkyl), -〇-, -S-, -SO- or -S〇2 -Based on, R1. is Ci-C6 alkyl, substituted Ci-Ce alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C3-C8 ring An alkyl group, or a substituted Cs-Cs cycloalkyl group, the substituent of each group in R1 being the same or different one or three groups selected from the substituent group 5, or a formula (ΠΙ) or ( IV) [Chemical 3]

[wherein B and D are each a 5- to 6-membered monocyclic cyclic group, and B and D may form a 9 to 10 member nitrogen-containing heterocyclic group together with a fused ring, or a 9 to 10 member nitrogen-containing heterocyclic group; The substituent of the nitrogen-containing heterocyclic group is the same or different one or three groups selected from the substituent group α, and R12 is a group having the same meaning as R1(); the substituent group α is composed of Ci-C6 Alkyl, halogen Ci-C6 alkyl, hydroxy, C丨-C6 alkoxy, halogen Ci-C6 alkoxy, thiol, C!-C6 alkylthio, CVC6 sulfinyl, C 1 - C 6 sulfonyl, amine, C 1 - C 6 amine, bis(C 1 · c6 alkyl) amine (the alkyl may be the same or different), formamidine, (Cl-C6 Alkyl)carbonylamino, carbenyl, (C^c6 alkyl)carbonyl, carboxy, (ChC6 alkoxy)carbonyl, aminecarboxy, (C^Cealkylamino)carbonyl, bis(indenyl 6 alkyl) ) -12- 200815324 Amine carbonyl (the alkyl group may be the same or different), an amine sulfonyl group, a (Ci-G alkylamino) sulfonyl group, and a di(Ci-Ca alkyl) amine sulfonyl group (this a group of alkyl groups which may be the same or different), a cyano group, a nitro group, a halogen group, and an oxy group; a substituent group of 3 is substituted by a C3-C8 cycloalkyl group. 3-(:8-cycloalkyl, C6-nonylaryl, substituted C6-Cμ aryl, 3 to 10 membered heterocyclic, and substituted 3 to 10 membered heterocyclic group; group of substituents The substituent of each group is the same or different one to three groups selected by the substituent group α; the substituent group r is a Ci-Cs alkyl group, a hydroxyl group, a halogen group, an oxy group, a hydroxyimino group, and a group of (C^-Ce alkoxy)imino groups; a substituent group (5 is a hydroxyl group, a C^-Ce alkoxy group, a thiol group, a Ci-Ce alkylthio group, a ChO alkyl sulfinium sulfonate) , C—C6 alkanesulfonyl, amine, C—C6 alkylamino, bis(Ci-Caalkyl)amine (the alkyl may be the same or different), (Ci-Ce alkyl)carbonylamine , (ChCe alkyl) sulfonamide, amine carbonyl amine, (Ci-G alkylamino)carbonylamino, bis(d-c6 alkyl)amine carbonylamino (the alkyl groups may be the same or different) ), an amine sulfonamide group, a (Ci-Cs alkylamino) sulfonamide group, and a bis(Ci-Cs alkyl) amine sulfonamide group (the alkyl groups may be the same or different) A suitable compound of the compound of the formula (I) is (2) a compound as described in (1), and R1 is a CCs alkyl group, a substituted ChCs alkyl group, a C2-C6 alkene. , a C2-C6 alkenyl group, a C2_C6 alkynyl group, a substituted C2-C6 alkynyl group, a C-Ci group, a cyclic hydrocarbon group, a substituted C3-C1Q cyclic hydrocarbon group, a 3 to 10 membered heterocyclic group, or a substituted 3 to 10 member hetero The substituent of each group other than the cyclic hydrocarbon group and the heterocyclic group in R1 is the same or different one to three groups selected from the substituent group αΐ or /31, and the cyclic hydrocarbon group and heterocyclic ring in R1 The substituent of the substituent is the same or different one to three groups selected from the group of substituents, -13-200815324, the substituent group α 1 is composed of a Ci-C6 alkyl group, a halogen Ci-C6 alkyl group, a hydroxyl group, C !-C6 alkoxy, halogen Ci-C6 alkoxy, thiol, Ci-Ce alkylthio, C1-C6 alkylsulfinyl, Ci-Ce alkanesulfonyl, amine, Ci-Ce Amino, bis(Ch C6 ortho)amino (the same or different), amine indenyl, (C1-C6 amidino)carbonyl, di(Ci-C6 alkyl)aminecarbonyl (this The alkyl groups may be the same or different, and the halogen group, and the substituent group θ 1 is a C3-C8 cycloalkyl group or a ChCi. An aryl group and a group of 3 to 10 membered heterocyclic groups. (3) The compound according to (1), wherein 1 is an alkyl group or a substituted alkyl group (the substituent is the same or different one or three groups selected from the substituent group α2 or /32), C3- a C8 cyclic hydrocarbon group or a substituted C3-C8 cyclic hydrocarbon group (the substituent is the same or a different one or three groups selected from the substituent group α2), and the substituent group α 2 is a Ci-C6 alkyl group. a group of a hydroxyl group, an alkoxy group, an aminomethyl group, a (G-C6 alkylamino)carbonyl group, and a di(C!-C6 alkyl)amine carbonyl group (the alkyl groups may be the same or different), substituted The group /3 2 is composed of a C3-C8 cycloalkyl group and Ce-Ci. (4) A compound of the formula (1), wherein R1 is a C2-C7 alkyl group or a substituted C2-C7 alkyl group (the substituent is the same or different from the substituent group α3) To a group of three or a C4-C7 cycloalkyl group, the substituent group α3 is a group of a hydroxyl group and an amine carbenyl group. (5) The compound according to any one of (1) to (4), wherein R2 is a hydrogen atom, an alkyl group, or a C3-C8 cycloalkyl group, and R1 and R2 may be bonded to the nitrogen atom of the group -14-200815324 It forms 3 to 10 members of a nitrogen-containing heterocyclic group. (6) The compound according to any one of (1) to (4), wherein R2 is a hydrogen atom. (7) The compound according to any one of (1) to (6), wherein R3 is a Cl-C6 group, a C3-C8 ring, or a Cl-C6 alkoxy group, R4 is a hydrogen atom, Ci-Cs An alkyl group, or a C3-C8 cycloalkyl group, R3 and R4 may together form a C-C5 alkylene group. (8) The compound according to any one of (1) to (6), wherein 113 is a Ci-Cs alkyl group, and R4 is a hydrogen atom. (9) The compound according to any one of (1) to (8), wherein R5 is a hydrogen atom, a Cl-C6 alkyl group, or a C3-C8 cycloalkyl group, and R6 is a hydrogen atom, a Cl-C6 alkyl group, or C3-C8 cycloalkyl. (10) The compound according to any one of (1) to (8), wherein R5 and R6 are a hydrogen atom, (11), the compound of any one of (1) to (10), and the ruler 7 is 匕- (6) A compound of any one of (1) to (10), wherein is a Cl_C6 alkyl group. (13) as in (1) to (12) The compound according to any one of (12), wherein γ is a single bond, a fluorene-alkylene group, or a substituted Ci-Ce alkylene group (the substituent is the same or different from the substituent group r to 1) (1) The compound according to any one of (1) to (1), wherein γ is c 1 - C 2 alkyl hydrazine (15) as in (1) to (14) Any of the compounds described, r8 is a formula (IIa)

[Chemical 4] -15- 200815324 [Eight in the formula] is C3-Cl. Circle _, replaced. Cycloalkyl, c6-c1()aryl, or substituted. An aryl group, a 5 to 1 member aromatic heterocyclic group, or a substituted 5 to 10 membered aromatic heterocyclic group, and the substituent of each group in Aa is the same or different from 1 to 3 selected from the substituent group αΐ The group, X2a is a group of the formula - ΝΗ-, -0 - or ·; 5 -, R1()a is a Ci-G alkyl group, a substituted Cl_c6 alkyl group, a C2-C6 alkenyl group, a substituted C2-C6 alkenyl group a C2-C6 alkynyl group, or a substituted c2_C6 alkynyl group, the substituent of each of R1〇a* is a group of the same or different 1 to 3 groups selected by the substituent group 51, or a formula (Ilia) ) or (IVa)

[In the formula, each of Ba and Da is a 5- to 6-membered monocyclic cyclic group, and Ba and Da may together form a 9 to 10 member nitrogen-containing heterocyclic group or a 9 to 10 member nitrogen-containing heterocyclic group. The substituent of the nitrogen-containing heterocyclic group is the same or different one or three groups selected from the substituent group αΐ, R12a is a group having the same meaning, and the substituent group 51 is a hydroxyl group, C. ^-Ce alkoxy, C^-Ce alkylthio, Ci-C6 alkylsulfinyl, Ci-C6 alkanesulfonyl, alkylamino, and bis(ChG alkyl)amine (the alkyl group (16) A compound according to any one of (1) to (14), wherein R8 is a formula (lib).

R10b (lib) -16- 200815324

[In the formula, the A to 6-membered aromatic heterocyclic ring is a substituted C 6 · C 1 0 aryl group, or a substituent. The substituent of each group in the oxime is the same or different from the substituent group "丨". X2b is a group of a formula, which is a C 1 -C6 or a substituted alkyl group, a substituted c2-C6 alkenyl group, or a substituted c2-c6 alkynyl group, wherein the substituent of each group is a group of substituents δ 2 select the same or different 丨 to the base of 3, or formula (Illb)

[In the formula, and Db each is a 5- to 6-membered monocyclic cyclic group, and ^ and 01) may form a 9 to 10 membered nitrogen-containing heterocyclic group together with a fused ring, and R12b is a group having the same meaning as R1". Substituent group 6 2 is composed of a thiol group, a Cl-C6 alkoxy group, a Cl-C6 thiol group, a Ci-Ce g yue*, a & Z: ((Μ6 € $ ) 月安* (3⁄4 € πτ丰(1) A compound of any one of (1) to (14), and R8 is a formula (iIc).

/R10c (lie) [wherein Α ε is a substituted phenyl group (the substituent is the same or different one or three groups selected by the substituent group α 4 ), and Χ 2 ε is a group of the formula -0, R 1 . . To replace the C!-C6 alkyl group (which is a group of 1 to 3 identical or different from -17 to 200815324 selected by the substituent group <53), the substituent group α 4 is C !-C6 alkyl, halogen Ci-G alkyl 'C a C6 alkoxy, halogen Ci-C6 alkoxy, amine, Ci-C6 alkylamino, bis(Ci_C6 alkyl) amine (the alkyl a group of substituents which may be the same or different, and a halogen group (5 3 is a group consisting of a hydroxyl group, a fluorenyl-decyloxy group, and an alkylthio group. The above (2) to (4) are selected. R1, R2 selected by (5) or (6), R3 and R4 selected by (7) or (8), R5 and R6 selected by (9) or (10), (11) or (12) Any combination of R7 selected, Y selected by (13) or (14), and R8 selected by (15) to (17) is preferred, for example, the following combination is preferred. (18) R1: (2); R2 : (5) ; R3, R4 : (7) ; R5, R6 : (9) ; R7 : (11) ; Y ·· (13) ; R8 : (15); (19) R1 : (3) ; R2 : (6) ; R3 , R4 : (8) ; R5 , R6 : (10) ; R7 : (12) ; Y : (14) ; R8 : (16); or (20) R1 : (4) ; R2 : (6) ; R3, R4 : (8) ; R5, R6 ·· (10) ; R7 ·_ (12) ; Y : (14) ; R8 : (17) The invention provides: (21) A pharmaceutical composition comprising the compound according to any one of (1) to (20) or a pharmacologically acceptable salt thereof as an active ingredient, (22) a disease inhibiting or treating renin The pharmaceutical composition described in (21) for treatment or prevention, (23) the pharmaceutical composition described in (21) for treating or preventing hypertension, (24) the manufacture of medicines for treating or preventing diseases (1) to (20) Use of any of the compounds described in any one of them, or a pharmacologically acceptable salt thereof, -18-200815324 (25) Use of the disease as described in (23) of the disease, (26) Order (1) to (20) A method for treating or preventing a disease in a warm-blooded animal, or a method described in (26), wherein the disease is a disease which can be treated or prevented by inhibiting renin, (28) The method according to any one of (26) to (28), wherein the disease is a method of (26), or (29) the method of any one of (26) to (28) The "C^-Cs alkyl group" is a linear or branched alkyl group having 1 to 8 carbon atoms, and may be, for example, a methyl group or an ethyl group. _propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3 -pentyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl 1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 3-methyl-2-pentyl, 2 Ethyl-1-butyl, 2,2-dimethyl-1-butyl, 2,3-monomethyl-1-butyl, bheptyl, or heptyl, or octyl, preferably C 2 · c 7 alkyl, especially preferably C3-C6 alkyl, more preferably 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-methyl-1-butyl, 2 , 2-dimethyl-1-propyl, or 3-methyl-2-pentenyl. The 'C2_C6 alkenyl group' in the formula (I) is a linear or branched alkenyl group having 2 to 6 carbon atoms, and may have one or more carbon-carbon double bonds, such as a vinyl group, 2- Propyl (allyl), 2-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 2-hexenyl, or 3-methyl-2-pentenyl. The rC2-C6 alkenyl group in R1 is preferably a C3-C6 candid group, particularly preferably a C4-C6 group. The "〇2_C6 stimulating group" in R2, R3, and R4 is preferably a C2-C4 alkyl group, and particularly preferably a C2-C3 stimulating group. R1. And "12-200815324 C2-C6 alkenyl" in R12 is preferably a C2-C4 alkenyl group, particularly preferably a C3-C4 alkenyl group. In the formula (I), the "C2-C6 alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, and may have one or more carbon-carbon triple bonds, such as an ethynyl group, a propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, or 1-hexynyl group. The "C 2 -C 6 alkynyl group" in R 1 is preferably a C 3 -C 6 alkynyl group, particularly preferably a C4-C6 alkynyl group. The "C2-C6 alkynyl group" in R2, R3, and R4 is preferably a C2-C4 alkynyl group, particularly preferably a C2-C3 alkynyl group. The "C2-C6 alkynyl group" in R1Q and R12 is preferably a C2_C4 alkynyl group, particularly preferably a C3-C4 alkynyl group. In the formula (I), the "Ci-G alkoxy group" is a hydroxyl group substituted with one of the following alkyl groups, for example, a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, or a 1- Butoxy, 2-butoxy, 2-methyl-1-propoxy, 2-methyl-2.propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentyloxy , 3·methyl-1-pentyloxy, 2·ethyl-1-butoxy, 2,2-dimethyl-1-butoxy, or 2,3-dimethyl-1-butoxy base. In 111, "〇1-(:6 alkoxy) is preferably a C3-C6 alkoxy group, particularly preferably a C4-C6 alkoxy group. The "Ci-Ce alkoxy group" in R3, R4 and R7 is preferably a C2-C4 alkoxy group. The group is particularly preferably a C2-C3 alkoxy group. The "Ci-G alkoxy group" in the R5, R6 and the substituent group α is preferably a ChC* alkoxy group, particularly preferably a Ci-C2 alkoxy group. The rCi in the substituent group 5 -C6 alkoxy" is preferably a C^C4 alkoxy group, particularly preferably a C1-C2 alkoxy group, preferably a methoxy group. In the formula (I), "Ci-C6i thiol group" is one of the following Ci -C6-based substituted thiol group, such as methylthio, ethylthio, 1-propylthio, 2-propylthio, 1-butylthio, 2-butylthio, 2-methyl-1- Propylthio, 2-methyl-2-propylthio, 1-pentylthio, 2-pentylthio, 3-pentylthio, 2-methyl-2-butylthio, 3--20- 200815324 Methyl-2-butylthio, 1-hexylthio, 2-hexylthio, 3-hexylthio, 2-methyl-1-pentylthio, 3-methyl-1-pentylthio, 2 -Ethyl-1-butylthio, 2,2.dimethyl-1-butylthio, or 2,3-dimethyl-1-butylthio. 111" (: 1-(: 6) Sulfur-based C3-C6 Institute thio-'C-C6 Institute thiol. R3 and R4 ". 丨·C6 Institute thiol" should be C2-C4 Institute thiol, especially C2-C3 Institute thiol. Replace "C丨-C6 alkylthio group" in group α is preferably Ci-C4 alkylthio group, especially Ci-C2 alkylthio group. Substituent group (5 "Ci-C6 Institute sulfur group" should be C1-C4 hospital sulfur group In the formula (I), the "Ci-C6 alkylamino group" is an amine group substituted with one of the following c丨-C6 alkyl groups, for example, methylamine. Base, ethylamino, 1-propylamino, 2-propylamino, butylamino, 2-butylamino, 2-methyl-1-propylamino, 2-methyl-2-propylamino, 1-pentylamine a group, a 2-pentylamino group, a 3-pentylamino group, a 1-hexylamino group, a 2-hexylamino group, or a 3-hexylamino group. The "Cl_C6 compound amine group" in R1 is preferably a C3-C6 compound amine group, especially It is suitable for C4-C6 compound amine group. R5, R6, and substituent group α in "Ci-C6 compound amine group" should be Ci_C4 compound amine base, especially Ci-C2 compound amine base. R7 "Ci-C6 compound amine base" It is preferably a C2-C4 alkylamino group, particularly preferably a C2-C3 alkylamino group. The r C丨-C6 alkylamino group in the substituent group 5 is preferably a Cl. an alkylamine group, particularly preferably a Ci-C2 alkylamine group. In (I), the "di(C-C6 alkyl)amino group" is an amine group substituted with the same or different two of the following CMC6 alkyl groups, such as dimethylamino, methylethylamino, A Alkylamino group [e.g., N-methyl--diyl) amine group Etc.], methylbutylamino [e.g., N-(l-butyl)-N-methylamino, etc.], methylpentylamino, methylhexylamino, diethylamino, ethylpropylamine [e.g. N-ethyl-N-(1-propyl)amino group, etc.], ethylbutylamino group, dipropylamine group, propylbutylamino group, dibutylamino group, diamylamine group, or dihexylamine group. The "di(ChCa alkyl)amino group" in R1 is preferably a 2-C21-200815324 (C3-C6-based) amine group, particularly preferably a di(c4-C6 alkyl)amino group. In the R5, R6 and the substituent group α, "di(Ci-C6 alkyl)amino group" is preferably a di(Cl-C4 alkyl)amino group, and particularly preferably a di(C1-C2 group) amine group. In R7, "di(Ci-Ce)-based amine group" is preferably a di-(C2-C4 alkyl)amino group, particularly preferably a di(c2_C3 alkyl)amino group. The substituent group constitutes a "di(Ci-C6 alkyl)amino group" di(Ci-C*alkyl)amino group, particularly preferably a di(Ci-Caalkyl)amino group. In the formula (I) of the present invention, the "(ChC^alkyl)carbonyl group" is a carbonyl group substituted with one of the following Ci-C6 alkyl groups, such as methylcarbonyl, ethylcarbonyl, hydrazine-propylcarbonyl, octacarbonylcarbonyl, 1 -Butylcarbonyl, 2-butylcarbonyl, 2-methyl-1-propenylcarbonyl, 2-methyl-2-propancarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 2-methyl-2 - butyl ore, 3-methyl-2-butenyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentylcarbonyl, 3-methyl-1-pentylcarbonyl, 2-Ethyl-1-butanecarbonyl, 2,2-dimethyl-1-butanecarbonyl, or 2,3-dimethyl-1.butylcarbonyl. The "alkyl"carbonyl group in R1 is preferably a (C3-C6 alkyl)carbonyl group, particularly preferably a (c4_C6 alkyl)carbonyl group. The "(Ct-Caalkyl)carbonyl group" in the substituent group α is preferably a (Ci-C* alkyl)carbonyl group, particularly preferably a (C^Cz alkyl)carbonyl group. The "(G-C6 alkyl)carbonyl group" in R7 is preferably a (C2-C4 alkyl)carbonyl group, particularly preferably a (c2-C3 alkyl)carbonyl group. In the formula (I), the "(Ci-C6 alkoxy) group" is a carbonyl group substituted with one of the above-mentioned Ci-C6-oxides, such as methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2- Propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, 2-methyl-propoxycarbonyl, 2-methyl-2-propoxycarbonyl> 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyl ore, 2, methyl-2-butoxylate, 3-methyl-2-butoxylate, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl, 3-hexyloxycarbonyl, 2 -methyl-1-pentyloxycarbonyl, 3-methyl-1-pentyloxycarbonyl, 2-ethyl-1-butoxycarbonyl, 2,2-dimethyl-1-butane-22- 200815324 Oxygen-based Or 2,3-dimethyl-1-butoxylate. In R1, "(Ci-C6 "兀学基基)carbonyl" is preferably a (C3-C6 alkoxy)carbonyl group, particularly preferably a (C4_C6 alkoxy)carbonyl group. The "(Ci-C6 alkoxy)carbonyl group" is preferably a (Ci-C% alkoxy)carbonyl group, particularly preferably a (Ci-G alkoxy)carbonyl group. The "(Κ6 alkoxy)carbonyl group" in R7 is preferably a (C2-C4 alkoxy) group, particularly preferably a (C2-C3 alkoxy) ore group. In the formula (I), "C3-C!. cyclic hydrocarbon group" is a monocyclic or bicyclic cyclic hydrocarbon group having 3 to 10 carbon atoms, and a C3-C"saturated cyclic hydrocarbon group (C3-Ci〇) a cycloalkyl group, a Cs-Ck partially unsaturated cyclic hydrocarbon group, and a C6-C1 () aromatic hydrocarbon group (C6-CM aryl group). C3-Ci. The saturated cyclic hydrocarbon group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, bicyclo[2,2,1]heptyl (halogen Bis), bicyclo[4,2,0]octyl, bicyclo[3,2,1]octyl, bicyclo[4,3,0]decyl, bicyclo[4,2,1]decyl, bicyclo[3 , 3,1]fluorenyl (adamantyl), bicyclo[5,3,0]octyl, or bicyclo[4,4,0]octyl (perhydronaphthyl). The Cs-Cm partially unsaturated cyclic hydrocarbon group is a partially oxidized group of the above G-Cm saturated cyclic hydrocarbon group, such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group. , cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, cyclooctetylene, cyclodecenyl, cyclodecenyl, hydroquinone, or茚基. The C6_Cl° aromatic hydrocarbon group is, for example, a phenyl group or a naphthyl group. R 1 "C 3 - C 1 . cyclic hydrocarbon group" is preferably a C 3 - C 8 cyclic hydrocarbon group, particularly preferably a C3-C8 cycloalkyl group, or a phenyl group, more preferably a C4-C? cycloalkyl group, preferably C5- C6 cycloalkyl. "C3-C!. cyclic hydrocarbon group" in A is preferably C3_ClQ cycloalkyl or C6-C:. An aryl group, particularly preferably a C6-C1Q aryl group, is preferably a phenyl group. In the formula (I), the "3 to 10 membered heterocyclic group" is a monocyclic or bicyclic -23-200815324 having 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The 3 to 10 membered heterocyclic group, the 3 to 10 membered saturated heterocyclic group, the 3 to 10 membered partially unsaturated heterocyclic group, and the 5 to 10 membered aromatic heterocyclic group. The 3- to 1-membered saturated heterocyclic group is, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperidinyl, and hexa Hydropyrimidinyl, morpholinyl, thiomorpholinyl, perhydroazepine, homopipedyl, homomorpholinyl, or decahydroquinolinyl. The 3- to 10-membered partially unsaturated heterocyclic group is a group in which the above 3- to 10-membered saturated heterocyclic group is oxidized, or a 5- to 10-membered aromatic heterocyclic group is reduced, for example, a pyrrolidinyl group, Imidazolinyl, pyrazolinyl, oxazoline, thiazolinyl, dihydropyridyl, tetrahydropyridyl, indanyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrogen Benzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydroquinolyl, tetrahydroquinolyl, dihydroquinazolinyl, or tetrahydroquinazolinyl. The 5- to 10-membered aromatic heterocyclic group is, for example, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, fluorene Azyl, thiadiazolyl, pyranyl, pyridyl, indolyl, pyrimidinyl, pyridinyl, azepine, anthracycline, anthracenyl, fluorenyl, benzofuranyl, Benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolinyl, quinoxalinyl, or quin Oxazolinyl. The "3 to 10 membered heterocyclic group" in the substituent group is preferably a 3 to 8 membered heterocyclic group, particularly preferably a 3 to 8 membered saturated heterocyclic group or a 5 to 6 membered aromatic heterocyclic group, and more preferably 4 to 7 member saturated heterocyclic groups. The "3 to 10 membered heterocyclic group" in A is preferably a 3 to 10 membered saturated heterocyclic group or a 5 to 10 membered aromatic heterocyclic group, particularly preferably a 5 to 10 membered aromatic heterocyclic group, more preferably 5 to 6 Aromatic heterocyclic-24- 200815324. In the formula (I), the "Ci-C6 alkyl group" and the "ChCe alkyl group" of each substituent are a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, and 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3 -pentyl, 2·methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1·pentyl, 3-methyl 1- or 5-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl, or 2,3-dimethyl-1-butyl. R2, R5, R6, R9, R11, the substituent group α, and the "C^Cs alkyl group" in the substituent group r are preferably an alkyl group, particularly preferably a C1-C2 alkyl group. The "Ci-C6 alkyl group" in R3, R4, and R7 is preferably a C丨-C4 alkyl group, particularly preferably a C2-C3 alkyl group, preferably a 2-propyl group. The "Ci-C6 alkyl group" in R1G and R12 is preferably a C2-C6 alkyl group, particularly preferably a C2-C4 alkyl group, more preferably a C3-C4 alkyl group, and most preferably a 1-propyl group. In the formula (I), "〇3-(:8-cycloalkyl group) is a cyclic alkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group. Or a cyclooctyl group, preferably a C3-C6 cycloalkyl group, particularly preferably a C3-C4 cycloalkyl group. In the formula (I), the "3 to 10 member nitrogen-containing heterocyclic group" is the above 3 to 10 membered heterocyclic group. a group containing at least one nitrogen atom, preferably 3 to 10 members of a nitrogen-containing saturated heterocyclic group, or 5 to 10 members of a nitrogen-containing aromatic heterocyclic group, particularly preferably a 5 to 6 membered nitrogen-containing saturated heterocyclic group. In the above, "Ci-Cs alkylene" is a straight or branched chain alkyl group having from ! to 5 carbon atoms, such as methylene, ethylidene [-(CH2)2-], and a formazan Base [-CH(Me)-], trimethylene [-(CH2)3-], methyl extended ethyl [-CH(Me)CH2- or CH2CH(Me)-], tetramethylene [_( (:Η2)4-], methyltri-25-200815324 methylene [-CH(Me)CH2CH2-, -CH2CH(Me)CH2- or CH2CH2CH(Me)-], or pentamethylene[-( CH〇5-], preferably C2-C4 alkylene, especially C3-C4 alkyl. In the formula (I), "Ci-Cs alkyl" is a linear or branched having 1 to 6 carbon atoms. Branches of alkyl groups, such as methylene, ethyl ([(C Η 2)2-], 甲亚Methyl [-CH(Me)-], trimethylene [-(CH2)3-], methyl extended ethyl [-CH(Me)CH2- or CH2CH(Me)-], tetramethylene [- (CH2)4-], methyltrimethylene [-CH(Me)CH2CH, -CH2CH(Me)CH2- or CH2C H2CH(Me)-], pentamethylene[-(CH2)5-], Or hexamethylene [-(CH2)6-], preferably ChC4 alkyl, especially alkyl, preferably methylene. In formula (I), "C2-C6 extended alkenyl" has 2 to 6 a straight or branched chain of carbon atoms, an alkenyl group, or one or more carbon-carbon double bonds, such as a vinyl group [-CH = CH-], a propenyl group (extended allyl group) )[-CH=CH-(CH2)- or (CH2)-CH=CH-], 1-methyl-vinyl group, 2-methyl-vinyl group, butenyl group, 1-methyl-1- Extending propylene, 2-methyl-1-exetylene, 3-methyl-1-propenyl, pentenyl, or hexenyl, preferably C2-C4, alkenyl, especially C2-C3 In the formula (I), the "C2-C6 alkynyl group" is a linear or branched chain alkynyl group having 2 to 6 carbon atoms, and may have one or more carbon-carbon groups. a triple bond such as an ethynyl group [-C tri C-], a propynyl group [-C tri C-(CH 2 )- or (CH 2 )-C tri C-], a butynyl group, a 3-methyl group Propynyl, pentynyl stretched, or stretched hexynyl, should C2-C4 alkynyl group extends, in particular, may extend C2-C3 alkynyl group. In the formula (I), the "9 to 10 member nitrogen-containing heterocyclic group" is a 9 to 10 member group having at least one nitrogen atom in the above 3- to 10-membered heterocyclic group. "9 to 10 members -26- 200815324 nitrogen-containing heterocyclic group" is preferably a 9 to 10 membered partially unsaturated heterocyclic group, and a 9 to 10 membered aromatic heterocyclic group, particularly preferably a 9 to 10 membered partially unsaturated heterocyclic group. More preferably, it is a 2,3-dihydroindenyl group or a 1,2,3,4-tetrahydroquinolyl group. In the formula (I), the "halogen Ci-Ce alkyl group" is the above alkyl group substituted with 1 to 7 of the following halogens, such as fluoromethyl, difluoromethyl, dichloromethyl, dibromomethyl, and tri Fluoromethyl, trichloromethyl, 2-fluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoro Ethyl, trichloroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 5-fluoropentyl, or 6-fluorohexyl, preferably haloalkyl, especially Halogen-(: 2 alkyl (the halogen is a group of 1 to 5 selected from the group consisting of fluorine and chlorine). In the formula (1), the "haloalkoxy" group has 1 to 7 Halogen substituted above alkoxy, for example fluoromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy , 2-bromoethoxy, 2-chloroethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, trichloroethoxy, Pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, or 6-fluorohexyloxy, halo (ChC* alkoxy) Base, especially halogen (ChG alkoxy) group (this The halogen is preferably 1 to 5 groups selected from the group consisting of fluorine and chlorine, and more preferably difluoromethoxy or trifluoromethoxy. In the formula (I) of the present invention, the "(Ch-C% alkyl)carbonylamino group" is an amine group substituted with one of the above (Ci-Ce alkyl)carbonyl groups, for example, a methylcarbonylamino group or an ethyl carbonylamino group. , 1-propenylamino, 2-propenylamino, 1-butoxyamino, 2-butoxyamino, 2-methyl-1-propenylamino, 2-methyl-2-propanol Amino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, 2-methyl-2-butanylamino, 3-methyl-2-butanamine-27-200815324 , 1-hexylcarbonylamino, 2-hexylcarbonylamino, 3-hexylcarbonylamino, 2-methyl-1-pentylcarbonylamino, 3-methyl-1-pentylcarbonylamino, 2-B Alkyl-1-butyronamine, 2,2-dimethyl-1-butancarbonylamine, or 2,3-dimethyl-1-butancarbonylamine, preferably (C!-C4 alkyl)carbonyl Amine group, particularly preferably (Ci-C2 alkyl)carbonylamino group. In the formula (1), the "(Ci-Cs alkylamino)carbonyl group" is a carbonyl group having one of the above hydrazone-substituted groups, for example, a methylaminocarbonyl group, an ethylaminecarbonyl group, a 1-propylaminecarbonyl group or a 2-propylaminecarbonyl group. , 1-butylaminecarbonyl, 2-butylaminecarbonyl, 2-methyl-1-propylaminecarbonyl, 2-methyl-2-propylaminecarbonyl, 1-pentylaminecarbonyl, 2-pentylaminecarbonyl, 3-pentylaminecarbonyl , 1-hexylaminecarbonyl, 2-hexylaminecarbonyl, or 3-hexylaminecarbonyl, preferably (ChG alkylamino)carbonyl, especially preferably (Ci-G alkylamino)carbonyl. In the formula (I), "two ( The C!-(alkyl)aminecarbonyl group is a carbonyl group substituted with one of the above-mentioned di(C-C6 alkyl)amino groups, such as dimethylaminecarbonyl, methylethylaminecarbonyl, methylpropylaminecarbonyl [for example, N-A -N-(l-propyl)aminecarbonyl, etc.], methylbutylaminecarbonyl [e.g., N-(l-butyl)-N-methylaminecarbonyl, etc.], methylpentylaminecarbonyl, methylhexylaminecarbonyl , diethylamine carbonyl, ethyl propylamine carbonyl [eg N-ethyl-N-(l-propyl)amine carbonyl, etc.], ethyl butylamine carbonyl, dipropylamine carbonyl, propyl butylamine carbonyl, dibutylamine carbonyl , dipentylamine carbonyl, or dihexylamine carbonyl, preferably di(C^-CN alkyl)amine carbonyl, especially suitable for Ci (Ci -Cz alkyl)amine carbonyl. In the formula (I), "(匕_(:6 alkylamino)sulfonyl) is a sulfonyl group (-S〇2-) substituted with one of the above ChC6 alkylamino groups. For example, (methylamino)sulfonyl, (ethylamino)sulfonyl, (1-propylamino)sulfonyl, (2-propylamino)sulfonyl, (1-butylamino)sulfonyl (2-butylamino)sulfonyl, (2-methyl-1-propylamino)sulfonyl, (2-methyl-2-propylamino)sulfonyl, (1-pentylamino)sulfonate Sulfhydryl, (2-pentylamino)sulfonyl, (3-pentylamino)sulfonyl, (1-hexylamino)sulfonyl, (2--28-200815324 hexylamino)sulfonyl Or (3-hexylamino)sulfonyl, preferably (C^-C% alkylamino)sulfonyl, especially preferably alkylamino)sulfonyl. In the formula (I), "two (C^- Cealkyl)aminesulfonyl" is a sulfur atom having one of the above two ((:6 alkyl)amino substituted sulfonyl (-S02-), such as (dimethylamino) sulfonyl) , (methylethylamino)sulfonyl, (methylpropylamino)sulfonyl [eg [N-methylpropyl)amino]sulfonyl, etc.], (methylbutylamino)sulfonyl [eg [N-(l-butyl)- N-methylamino]sulfonyl, etc.], (methylpentylamino)sulfonyl, (methylhexylamino)sulfonyl, (diethylamino)sulfonyl, (ethylpropylamino) Enlarged base [eg [N-ethyl-N-(l-propyl)-female]fe-based temple], (ethylbutylamino)sulfonyl, (dipropylamino)sulfonyl, (c) Butyryl)sulfonyl, (dibutylamino)sulfonyl, (dipentylamino)sulfonyl, or (dihexylamino)sulfonyl, preferably di(c^c% alkyl) Aminesulfonyl, especially bis(匕-(:2 alkyl)aminesulfonyl. In the formula (I), "halogen" is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, or bromine, especially Fluorine or chlorine. In the formula (I), the "C6-C1Q aryl group" is an aromatic hydrocarbon group of 6 to 10 members, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group. In the formula (I), the "alkoxy"imine group is a hydroxyimino group (=N-〇H) having one of the above-mentioned G-C6 alkyl groups substituted with an oxygen atom, such as methoxyimino group or ethoxy group. Imino, 1-propoxyiminyl, 2-propoxyimido, 1-butoxyiminyl, pentyloxyimido, or 1-hexyloxyimine, preferably (Ci-C4 alkane) Alkoxy)imino, especially (C1-C2 alkoxy)imino. In the formula (I), "Ci-C% alkylsulfinyl" is a sulfinyl group (-SO-) substituted with one of the above C^C6 alkyl groups, such as sulfinyl group and sulfinamide. Base, -29- 200815324 1-propoxysulfinyl, 2-propoxysulfonyl, 1-butylsulfinyl, 2-butylsulfinyl, 2-methylpropanesulfonyl, 2_ Methyl-2-propensulfonyl, 1-pentylsulfenyl, 2-pentylsulfinyl, 3-pentylsulfinyl, 2-methyl-2-butyrenesulfonyl, 3- Methyl-2-butsulfinyl, 1-hexylsulfinyl, 2-hexylsulfinyl, 3-hexylsulfinyl, 2-methyl-1-pentylenesulfonyl, 3- Methyl-1·pentylsulfinyl, 2-ethyl-1-butsulfinyl, 2,2-dimethyl-1-butsulfinyl, or 2,3-dimethyl-1 - butyl sulfinyl group, preferably Ci-C% alkyl sulfinyl group, especially Ci-G alkyl sulfinyl group. In the formula (I), the "C^-C6 alkanesulfonyl group" is a sulfonyl group (-S02-) substituted with one of the above alkyl groups, for example, a methylsulfonyl group, an ethylsulfonyl group, or a 1-propanesulfonium group. Base, 2-propanesulfonyl, 1-butsulfonyl, 2-butanesulfonyl, 2-methyl-1-propanesulfonyl, 2-methyl-2-propanesulfonyl, 1-pentyl Sulfonyl, 2-pentylsulfonyl, 3-pentylsulfonyl, 2-methyl-2-butsulfonyl, 3-methyl-2-butsulfonyl, 1-hexylsulfonyl, 2 -hexylsulfonyl, 3-hexylsulfonyl, 2-methyl-1-pentylsulfonyl, 3-methyl-1-pentylsulfonyl, 2-ethyl-1-butsulfonyl, 2 , 2-dimethyl-1-butoxysulfonyl, or 2,3-dimethyl-1-butsulfonyl, preferably alkanesulfonyl, especially alkanesulfonyl. In the formula (I), the "(Ci-C6 alkyl)sulfonylamino group" is an amine group substituted with one of the above C^-Cs alkanesulfonyl groups, for example, a methylsulfonylamino group, an ethylsulfonylamino group. , 1-propanesulfonylamino, 2-propanesulfonylamino, 1-butylsulfonylamino, 2-butylsulfonylamino, 2-methyl-1-propanesulfonylamino, 2-methyl 2-propanesulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, 2-methyl-2-butanesulfonylamino, 3-methyl 2-butoxysulfonylamino, 1-hexylsulfonylamino, 2-hexylsulfonylamino, 3-hexylsulfonylamino, 2-methyl-1-pentanesulfonylamino, 3-methyl -1-pentanesulfon-30- 200815324 Amidino, 2-ethyl-1-butoxysulfonylamino, 2,2-dimethyl-1-butylsulfonylamino, or 2,3-dimethyl Butasulfonylamino, preferably (C^-C* alkyl)sulfonylamino, especially (Ci-G alkyl)sulfonylamino. In the formula (I), the "(Ci-C6 alkylamino)carbonylamino group" is an amine group substituted with one of the above (C丨-C6 alkylamino)carbonyl groups, for example, (methylamino)carbonylamino group, ( Ethylamino)carbonylamino, (1-propylamino)carbonylamino, (2-propylamino)carbonylamino, (1-butylamino)carbonylamino, (2-butylamino)carbonylamino, (2-methyl-1-propylamino)carbonylamino, (2-methyl-2-propylamino)carbonylamino, (1-pentylamino)carbonylamino, (2-pentylamino)carbonylamine , (3-pentylamino)carbonylamino, (1-hexylamino)carbonylamino, (2-hexylamino)carbonylamino, or (3-hexylamino)carbonylamine, preferably (Ci a -C4 alkylamino)carbonylamino group, particularly preferably an alkylamino)carbonylamine group. In the formula (I), the "di(Ci-C6 alkyl)aminocarbonylamino group" is an amine group substituted with one of the above-mentioned di(Ci-C6 alkyl)amine carbonyl groups, for example, (dimethylamino)carbonylamino group. , (methylethylamino)carbonylamino, (methylpropylamino)carbonylamino [for example, [N-methyl-N-(1-propyl)amino]carbonylamino], etc., (methyl butyl) Amino)carbonylamino group [e.g. [N-(l-butyl)-N-methylamino]carbonylamino], etc., (methylpentylamino)carbonylamino, (methylhexylamino)carbonylamine , (diethylamino)carbonylamino, (ethylpropylamino)carbonylamino [for example, [N-ethyl-N-(l-propyl)amino]carbonylamine, etc.], (ethyl butyl) Amino)carbonylamino, (dipropylamino)carbonylamino, (propylbutylamino)carbonylamino, (dibutylamino)carbonylamino, (dipentylamino)carbonylamino, or (two) Hexylamino)carbonylamino, preferably di(Ci-C% alkyl)aminecarbonylamino, especially dialkyl)aminecarbonylamino. In the formula (I), the "(C-C6 alkylamino)sulfonylamino group" is a sulfonylamino group (-S02NH-) having one of the above-mentioned Ci-C6 alkylamino groups as a sulfur atom, for example, (methylamino group) Sulfonamide, (ethylamino)sulfonylamino, (propylamino)sulfonylamino, (2--31-200815324 propylamino)sulfonylamino, (1-butyryl)sulfonate Amino, (2-butylamino)sulfonylamino, (2-methyl-1-propylamino)sulfonylamino, (2-methyl-2-propylamino)sulfonylamino, (1- Pentylamino)sulfonylamino, (2-pentylamino)sulfonylamino, (3-pentylamino)sulfonylamino, (1-hexylamino)sulfonylamino, (2-hexylamine) Sulfhydrylamine or (3-hexylamino)sulfonylamino, preferably (Ci-C4 alkylamino)sulfonylamino, especially (C^-Cz alkylamino)sulfonylamino. In the formula (I), the "di(Ci-C6 alkyl)aminesulfonylamino group" is a sulfonylamino group (-S〇2NH) having one of the above-mentioned di(C!-C6 alkyl)amino groups as a sulfur atom. -), for example, (dimethylamino)sulfonylamino, (methylethylamino)sulfonylamino, (methylpropylamino)sulfonylamino [eg [N-methyl-N-(l-) A propyl)amino]sulfonylamino group, etc., a (methylbutylamino)sulfonylamino group [e.g., [N-(l-butyl)-N-methylamino]sulfonylamino group, etc.], Methyl pentaamino)sulfonylamino, (methylhexylamino)sulfonylamino, (diethylamino)sulfonylamino, (ethylpropylamino)sulfonylamino [eg [N-B -N-(l-propyl)amino]sulfonylamino and the like], (ethylbutylamino)sulfonylamino, (dipropylamino)sulfonylamino, (propylbutylamino)sulfonate Amidino, (dibutylamino)sulfonylamino, (dipentylamino)sulfonylamino, or (dihexylamino)sulfonylamino, bis(ChOalkyl)aminesulfonamide , especially dialkyl) amine sulfonamide. In the formula (I), a and b are each preferably an integer of 0 to 3, particularly preferably an integer of 2, preferably 0 or 1. The compounds of the formula (I) of the present invention form acid addition salts, and these acid addition salts are included in the present invention. These acid addition salts are, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, oxalate, malonate, fumarate, maleate, L-apple Acid, D-malic acid, L-tartaric acid, D--32- 200815324 tartaric acid, decanoate, trifluoroacetate, methanesulfonate, besylate, p-toluenesulfonate, 2,4-dimethyl Benzobenzenesulfonate, 2,4,6-trimethylbenzenesulfonate, 4-ethylbenzenesulfonate, or naphthalenesulfonate. The compound of the formula (1) of the present invention may form an acid addition salt with an acid of any ratio, and each acid addition salt (e.g., citrate, 2 acid salt, 1 / 2 acid salt), or a mixture thereof, is included in the present invention. The compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each of them or a mixture thereof is included in the present invention. The compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof may have an optical isomer (including an antipode and if it has at least one asymmetric center, axis asymmetry, carbon-carbon double bond, formyl group, etc.) The diastereomers, geometric isomers, tautomers, and rotamers are present, and these isomers and mixtures thereof are described by a single formula such as formula (1). The present invention encompasses these individual isomers and their mixtures (including racemates) in any ratio. In the present invention, hypertension includes a common form of hypertension such as essential hypertension; and renal hypertension such as renal hypertension, endocrine hypertension, and neuropathy . The compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof is inhibited by renin, solubility, cell membrane permeability, oral absorption, blood concentration, metabolic stability, tissue migration, bioavailability, in vitro activity , in vivo activity, rapid discovery of drug efficacy, persistence of pharmacodynamics, physical stability, drug interaction, toxicity, etc., have excellent properties, and are useful as medicines (especially for the treatment or prevention of hypertension (suitable for treatment)] . Suitable compounds among the compounds of formula (I) are those as shown in Table 1 or 2 below. However, the compounds of the invention are not limited to these compounds. -33- 200815324 In the following Table 1 or 2, the following abbreviation is used; (S) Bu-Me: (S)-2-methyl-1-butyl(S)Bu-OH: (S)-l-hydroxyl -3-methyl-2-butyl cHx : cyclohexyl cPn : cyclopentyl cPr : cyclopropyl

Et : ethyl iBu: 2 -methyl-1-propyl iPr : 2-propyl

Me : methyl

Mor : morpholinyl nBu : 1 -butyl nPr : 1-propyl

Ph :phenyl(S)Pn-OH: (S)-l-hydroxy-3-methyl-2-pentyl (S)Pr-OH: (S)-l-hydroxy-2-propyl (S) Pr-〇Me: (S)-l-hydroxy-3-methyl-2-pentyl Thp: tetrahydroanthracene. -34- 200815324 [Table 1] [Chemical 9]

R7 rL /R8 Y (Μ) 【化1 0】

NH 2

An exemplified compound R1 R7 Y R8 R12 R13 5 1-1 Me iPr gh2 R8a 3-0(CH2)30Me 4-Cl 1-2 Et iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-3 nPr iPr ch2 R8a 3-0(CH2)30Me 4-Cl 1 -4 iPr iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-5 nBu iPr ch2 R8a 3-0(CH2)20Me 4-OMe 1-6 nBu iPr ch2 R8a 3-0(CH2)20Me 4-CI 1-7 nBu iPr ch2 R8a 3-0(CH2)30Me 4-Me 1 -8 nBu iPr ch2 R8a 3_0(CH2)30Me 4 - CF3 1-9 nBu iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-10 nBu iPr ch2 R8a 3-0(CH2)30Me 4-OEt -35- 200815324 1-11 nBu iPr ch2 RSa 3-0(CH2)30Me 4- 0CHF2 1-12 nBu iPr ch2 R8a 3-0(CH2)30Me 4-0CF3 1 -13 nBu iPr ch2 R8a 3-0(CH2)30Me 4-F 1-14 nBu iPr ch2 R8a 3-0(CH2)30Me 4 -CI 1-15 nBu iPr ch2 R8a 3-0(CH2)40Me 4-OMe 1-16 nBu iPr ch2 R8a 3-0(CH2)40Me 4-CI 1-17 nBu iPr ch2 R8a 3-0(CH2)3SMe 4-OMe 1-18 nBu iPr ch2 R8a 3-0(CH2)3SMe 4-CI 1-19 nBu iPr ch2 R8a 3-0(CH2)3S02Me 4-OMe 1-20 nBu iPr ch2 RSa 3-0(CH2) 3S02Me 4-CI 1-21 nBu iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OMe 1-22 nBu iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OEt 1-23 nBu iPr ch2 R8a 3-0(CH2 )2NHC0Me 4-0CHF2 1-24 nBu iPr ch2 R8a 3-0(CH2)2NHC0Me 4-F 1-25 nBu iPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI 1-26 nBu iPr ch2 R8a 3-0(CH2)2NHS02Me 4- OMe 1-27 nBu iPr ch2 R8a 3-0(CH2)2NHS02Me 4-OEt 1-28 nBu iPr ch2 R8a 3-0(CH2)2NHS02Me 4-0CHF2 1-29 nBu iPr ch2 R8a 3-0(CH2)2NHS02Me 4 -F 1-30 nBu iPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-31 nBu iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-OMe 1-32 nBu iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-Cl 1-33 nBu iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-OMe 1-34 nBu iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-CI 1-35 nBu iPr ch2 R8a 3-S(CH2) 30Me 4-OMe 1-36 nBu iPr ch2 R8a 3-S(CH2)30Me 4-CI 1-37 nBu iPr ch2 R8a 3-NH(CH2)30Me 4 - ONI e 1-38 nBu iPr ch2 R8a 3-NH( CH2)30Me 4-CI 1-39 nBu iPr ch2 R8b (CH2)30Me - 1-40 nBu iPr ch2 R8b (CH2)30Me 3-Me 1-41 nBu iPr ch2 R8b (CH2)30Me 3-OMe 1-42 nBu iPr ch2 R8b (CH2)3〇Me 3-F 1-43 nBu iPr ch2 R8b (CH2)3〇Me 3-Cl 1-44 nBu iPr ch2 R8c (CH2)30Me - 1-45 nBu iPr ch2 r8c (CH2) 30Me 5 - Me 1-46 nBu iPr ch2 r8c (CH2)30Me 5~0Me 1-47 nBu iPr ch2 r8c (GH2)30Me 5-F 1-48 nBu iPr ch2 r8c (CH2)3〇Me 5-CI 1-49 nBu iPr ch2 R8d (CH2)3〇Me 一 -36- 200815324

1-50 nBu iPr ch2 R8d (CH2)3〇Me 5-Me 1-51 nBu iPr ch2 Rsd (CH2)3〇Me 5-0Me 1-52 nBu iPr ch2 R8d (CH2)30Me 5-F 1 - 53 nBu iPr ch2 R8d (CH2)30Me 5-Cl 1-54 nBu iPr ch2 R8d (CH2)2NHC0Me - 1-55 nBu iPr ch2 R8d (CH2)2NHC0Me 5 - Me 1-56 nBu iPr ch2 R8d (CH2)2NHC0Me 5-0Me 1 - 57 nBu iPr ch2 R8d (CH2)2NHC0Me 5-F 1-58 nBu iPr ch2 R8d (CH2)2NHC0Me 5-Cl 1-59 nBu iPr ch2 R8d (CH2)2NHS02Me - 1-60 nBu iPr ch2 R8d (CH2) 2NHS02Me 5-Me 1-61 nBu iPr ch2 R8d (CH2)2NHS02Me 5 - OMe 1-62 nBu iPr ch2 R8d (CH2)2NHS02Me 5-F 1-63 nBu iPr ch2 R8d (CH2)2NHS02Me 5-CI 1 - 64 nBu iPr ch2 R8e (CH2)30Me - 1-65 nBu iPr ch2 R8e (CH2)30Me 5-Me 1-66 nBu iPr ch2 RSe (CH2)30Me 5 - OMe 1-67 nBu iPr ch2 R8e (CH2)30Me 5-F 1-68 nBu iPr ch2 R8e (CH2)30Me 5-CI 1-69 nBu iPr ch2 R8e (CH2)2NHC0Me 1-70 nBu iPr ch2 R8e (CH2)2NHC0Me 5-Me 1-71 nBu iPr ch2 R8e (CH2) 2NHC0Me 5-OMe 1 - 72 nBu iPr ch2 R8e (CH2)2NHC0Me 5-F 1-73 nBu iPr ch2 R8e (CH2)2NHC0Me 5-CI 1-74 nBu iPr ch2 R8e (CH2)2NHS02Me - 1-75 nBu iPr ch2 R8e (CH2)2NHS02Me 5-Me 1-76 nBu iPr ch2 R8e (CH2)2NHS02Me 5-OMe 1-77 nBu iPr ch2 R8e (CH2)2NHS02Me 5-F 1-78 nBu iPr ch2 R8e (CH2)2NHS02Me 5-CI 1-79 nBu iPr ch2 R8f (CH2)3〇Me - 1 - 80 nBu iPr ch2 R8f (CH2)3〇Me 5-Me 1-81 nBu iPr ch2 R8f (CH2)30Me 5-OMe 1-82 nBu iPr ch2 R8f (CH2)30Me 5-F 1-83 nBu iPr ch2 R8f (GH2)30Me 5-CI 1-84 nBu iPr ch2 R8f (CH2)2NHC0Me - 1-85 nBu iPr ch2 RSf (GH2)2NHC0Me 5-Me 1- 86 nBu iPr ch2 R8f (CH2)2NHC0Me 5-OMe 1-87 nBu iPr ch2 R8f (CH2)2NHC0Me 5-F 1-88 nBu iPr ch2 R8f (CH2)2NHC0Me 5-GI -37- 200815324 1-89 nBu iPr ch2 R8f (CH2)2NHS02Me -1 - 90 nBu iPr ch2 R8f (CH2)2NHS02Me 5-Me 1-91 nBu iPr ch2 R8f (CH2)2NHS02Me 5-0Me 1-92 nBu iPr ch2 R8f (CH2)2NHS02Me 5-F 1- 93 nBu iPr ch2 R8f (CH2)2NHS02Me 5-CI 1-94 nBu iPr ch2 R8g (CH2)30Me 1-95 nBu iPr ch2 R8h (CH2)30Me 1-96 nBu iPr ch2 R8i (CH2)30Me 1- 97 nBu cPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-98 nBu cPr ch2 R8a 3-0(CH2)30Me 4-CI 1-99 nBu cPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI 1 -100 nBu cPr c H2 R8a 3-0(CH2)2NHS02Me 4-Cl 1-101 nBu cPr ch2 R8d (CH2)30Me - 1-102 nBu cPr ch2 R8e (CH2)30Me - 1-103 nBu cPr ch2 R8f (CH2)30Me - 1- 104 iBu iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-105 iBu iPr ch2 R8a 3-0(CH2)30Me 4-OEt 1-106 iBu iPr ch2 R8a 3-0(CH2)30Me 4-0CHF2 1 -107 iBu iPr ch2 R8a 3-0(CH2)30Me 4-F 1-108 iBu iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-109 iBu iPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI 1-110 iBu iPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-111 iBu iPr ch2 R8d (CH2)30Me a 1-121 iBu iPr ch2 R8e (CH2)30Me a 1-113 iBu iPr ch2 R8f (CH2 30Me-1-14 nPn iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-115 (5) Bu-Me iPr ch2 R8a 3-0(CH2)20Me 4-OMe 1-116 (S)Bu-Me iPr ch2 R8a 3-0(CH2)20Me 4-CI 1-117 (S)Bu-Me iPr ch2 R8a 3-0(CH2)30Me 4-Me 1-118 (S)Bu-Me iPr ch2 R8a 3-0(CH2 30Me 4-CF3 1 -119 (S)Bu-Me iPr ch2 RSa 3-0(CH2)30Me 4-OMe 1-120 (S)Bu-Me iPr ch2 R8a 3-0(CH2)30Me 4-OEt 1 -121 (S)Bu-Me iPr ch2 R8a 3-0(CH2)30Me 4-OCHF; 1-122 (S)Bu-Me iPr ch2 RSa 3-0(CH2)30Me 4-0CF3 1 -123 (5)Bu-Me iPr ch2 R8a 3-0 (CH2 30Me 4-F 1-124 (S)Bu-Me iPr ch2 R8a 3-0(GH2)30Me 4-CI 1-125 (S)Bu-Me iPr ch2 R8a 3-0(CH2)40Me 4-OMe 1 -126 (S)Bu-Me iPr ch2 R8a 3-0(CH2)40Me 4-Cl 1-127 (S) Bu-Me iPr ch2 R8a 3-0(CH2)3SMe 4-OMe -38- 200815324 1-128 (S) Bu-Me iPr ch2 R8a 3-0(CH2)3SMe 4-Cl 1-129 (5) Bu-Me iPr ch2 R8a 3-0(CH2)3S02Me 4 - OMe 1-130 (S)Bu - Me iPr ch2 R8a 3-0(CH2)3S02Me 4-Cl 1-131 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OMe 1-132 (S)Bu-Me iPr ch2 R8a 3-0(CH2) 2NHC0Me 4-OEt 1-133 (S) Bu-Me iPr ch2 R8a 3-0(CH2)2NHC0Me 4-0CHF2 1-134 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHC0Me 4-F 1- 135 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI 1-136 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHS02Me 4-OMe 1-137 (S)Bu- Me iPr ch2 R8a 3-0(CH2)2NHS02Me 4-OEt 1-138 (S)Bu-Me iPr ch2 RSa 3-0(CH2)2NHS02Me 4 - OCHF2 1-139 (S)Bu-Me iPr ch2 R8a 3- 0(CH2)2NHS02Me 4-F 1-140 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-141 (S)Bu-Μθ iPr ch2 R8a 3-0(CH2)2NHC0NH2 4 -OMe 1-142 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-CI 1-143 (S)Bu-Me iPr ch2 R8a 3-0(C H2)2NHS02NH2 4~0Me 1-144 (S)Bu-Me iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-CI 1-145 (S)Bu-Me iPr ch2 R8a 3-S(CH2)30Me 4-OMe 1-146 (5) Bu-Me iPr ch2 R8a 3-S(CH2)30Me 4-CI 1-147 (S)Bu-Me iPr ch2 R8a 3-NH(CH2)30Me 4~0Me 1-148 (5)Bu-Me iPr ch2 R8a 3-NH(CH2)3〇Me 4-CI 1-149 (S)Bu-Me iPr gh2 R8b (CH2)30Me - 1-150 (S)Bu-Me iPr ch2 R8b (CH2)30Me 3-Me 1- 151 (S)Bu-Me iPr ch2 R8b (CH2)3〇Me 3 - OMe 1-152 (S)Bu-Me iPr ch2 R8b (CH2)30Me 3-F 1-153 (S)Bu-Me iPr ch2 R8b (CH2)30Me 3-Cl 1-154 (S)Bu-Me iPr ch2 r8c (CH2)3〇Me - 1-155 (S)Bu-Me iPr ch2 r8c (GH2)30Me 5-Me 1-156 (5)Bu- Me iPr ch2 r8c (CH2)30Me 5-OMe 1-157 (S) Βιι~Μθ iPr ch2 r8c (CH2)30Me 5-F 1-158 (5)Bu-Me iPr ch2 r8c (CH2)30Me 5-CI 1-159 ( S)Bu-Me iPr ch2 R8d (CH2)30Me 1-160 (S)Bu-Me iPr ch2 R8d (CH2)30Me 5-Me 1-161 (S)Bu-Me iPr ch2 R8d (CH2)30Me 5- OMe 1-162 (S)Bu-Me iPr ch2 R8d (CH2)30Me 5-F 1-163 (S)Bu-Me iPr ch2 R8d (GH2)30Me 5-CI 1-164 (S)Bu-Me iPr gh2 R8d (CH2)2NHC0Me 1-165 (5)Bu-Me iPr ch2 R8d (CH2)2NHC0Me 5-M e 1-166 (S)Bu-Me iPr ch2 R8d (CH2)2NHC0Me 5-OMe -39- 200815324 1-167 (5)Bu-Me iPr ch2 R8d (CH2)2NHC0Me 5-F 1-168 (3)Bu-Me iPr ch2 R8d ( CH2)2NHC0Me 5-Cl 1-169 (5) Bu-Me iPr ch2 RSd (CH2)2NHS02Me 1-170 (S) Bu-Me iPr ch2 R8d (CH2)2NHS02Me 5-Me 1-171 (S) Bu-Me iPr ch2 R8d (CH2)2NHS02Me 5-0Me 1-172 (5) Bu-Me iPr ch2 R8d (CH2)2NHS02Me 5-F 1-173 (5)Bu-Me iPr ch2 R8d (CH2)2NHS02Me 5-Cl 1-174 (S) Bu-Me iPr Ch2 R8e (CH2)30Me - 1-175 (5) Bu-Me iPr ch2 R8e (GH2)30Me 5 - Me 1-176 (S)Bu-Me iPr ch2 R8e (CH2)30Me 5-0Me 1-177 (S) Bu- Me iPr ch2 R8e (CH2)30Me 5-F 1-178 (S)Bu-Me iPr ch2 RSe (CH2)30Me 5-CI 1-179 (S)Bu-Me iPr ch2 R8e (CH2)2NHC0Me - 1-180 (S) Bu-Me iPr ch2 R8e (CH2)2NHC0Me 5-Me 1-181 (S)Bu-Me iPr ch2 R8e (CH2)2NHC0Me 5-0Me 1-182 (S)Bu-Me iPr ch2 R8e (CH2) 2NHC0Me 5-F 1-183 (S)Bu-Me iPr ch2 R8e (CH2)2NHC0Me 5-Cl 1-184 (S) Bu-Me iPr ch2 R8e (CH2)2NHS02Me — 1-185 (S) Bu-Me iPr Ch2 R8e (CH2)2NHS02Me 5-Me 1-186 (S)Bu-Me iPr ch2 R8e (CH2)2NHS02Me 5 - OMe 1-187 (S) Bu-Me iPr Ch2 R8e (CH2)2NHS02Me 5-F 1-188 (S)Bu-Me iPr ch2 R8e (CH2)2NHS02Me 5-Cl 1-189 (S)Bu-Me iPr ch2 R8f (CH2)3〇Me - 1-190 (S)Bu-Me iPr ch2 R8f (CH2)30Me 5-Me 1-191 (S)Bu-Me iPr ch2 R8f (CH2)30Me 5-OMe 1-192 (S)Bu-Me iPr ch2 R8f (CH2) 30Me 5-F 1-193 (5) Bu-Me iPr ch2 R8f (CH2)3〇Me 5-Cl 1-194 (S) Bu-Me iPr ch2 R8f (CH2)2NHC0Me - 1-195 (S)Bu-Me iPr ch2 R8f (GH2)2NHC0Me 5_Μθ 1-196 (S)Bu-Me iPr ch2 R8f (CH2)2NHC0Me 5-OMe 1-197 (S)Bu-Me iPr ch2 R8f (CH2)2NHC0Me 5-F 1-198 (S) Bu-Me iPr ch2 R8f (CH2)2NHC0Me 5-Cl 1-199 (S) Bu-Me iPr ch2 R8f (CH2)2NHS02Me - 1-200 (S) Bu-Me iPr ch2 R8f (CH2)2NHS02Me 5-Me 1 -201 (S)Bu-Me iPr ch2 R8f (CH2)2NHS02Me 5-OMe 1-202 (S)Bu-Me iPr ch2 R8f (CH2)2NHS02Me 5-F 1-203 (S) Bu-Me iPr ch2 R8f ( CH2)2NHS02Me 5-CI 1-204 (S)Bu-Me iPr ch2 R8g (CH2)3〇Me - 1-205 (S) Bu-Me iPr ch2 R8h (CH2)30Me One-40- 200815324

1-206 (S)Bu-Me iPr ch2 R8i (CH2)30Me 1-210 (5) Bu-Me cPr ch2 R8a 3-0(CH2)30Me 4~0Me 1-208 (S)Bu-Me cPr gh2 R8a 3 -0(CH2)30Me 4-Cl 1-209 (S)Bu-Me cPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI 1-210 (S)Bu-Me cPr ch2 R8a 3-0(CH2)2NHS02Me 4-Cl 1-211 (S)Bu-Me cPr ch2 R8d (CH2)30Me - 1-212 (5) Bu-Me cPr ch2 R8e (CH2)30Me -1-213 (S)Bu-Me cPr ch2 R8f (CH2)30Me - 1-214 (CH2)20H iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-215 (ch2)3oh iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-216 (S)Pr-OH iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-217 (S)Bu-OH iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-218 (S)Pn-OH iPr ch2 R8a 3-0 (CH2)30Me 4-CI 1-219 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)20Me 4 - OMe 1-220 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)20Me 4-CI 1 -221 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)30Me 4-Me 1 - 222 CH2C(Me)2CH2OH iPr ch2 R8a 3-0(CH2)30Me 4 - CF3 1-223 CH2C(Me)2CH20H iPr Ch2 R8a 3-0(CH2)30Me 4 - OMe 1-224 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)30Me 4-OEt 1-225 CH2C(Me)2CH20H iPr ch2 R8a 3-0(GH2) 30Me 4-OCHF2 1-226 CH2C(Me)2CH20H iPr ch2 R8a 3 -0(CH2)30Me 4-0CF3 1-227 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)30Me 4-F 1-228 CH2C(Me) 2CH20H iPr ch2 R8a 3-0(CH2)30Me 4- CI 1-229 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)40Me 4-OMe 1-230 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)40Me 4-CI 1-231 CH2G(Me) 2CH20H iPr ch2 R8a 3-0(CH2)3SMe 4-OMe 1-232 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)3SMe 4-CI 1-233 CH2C(Me)2CH2OH iPr ch2 R8a 3-0( CH2)3S02Me 4 - OMe 1-234 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)3S02Me 4-CI 1-235 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OMe 1- 236 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OEt 1-237 CH2C(Me)2CH2OH iPr ch2 R8a 3-0(CH2)2NHC0Me 4-0CHF2 1-238 CH2C(Me)2CH20H iPr ch2 R8a 3-0(GH2)2NHC0Me 4-F 1-239 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI Bu 240 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHS02Me 4 -OMe 1-241 CH2C(Me)2CH2OH iPr ch2 R8a 3-0(CH2)2NHS02Me 4-OEt 1-242 CH2C(Me)2CH2OH iPr ch2 R8a 3-0(CH2)2NHS02Me 4-0CHF2 1-243 CH2C(Me ) 2CH20H iPr ch2 R8a 3-0(CH2)2NHS02Me 4-F 1-244 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHS02 Me 4-CI 41- 200815324 1-245 CH2C(Me)2CH2OH iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-OMe 1-246 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-Cl 1 -247 CH2C(Me)2CH20H iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-OMe 1-248 CH2C(Me)2CH2OH iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-CI 1-249 CH2C(Me)2CH20H iPr Ch2 R8a 3-S(CH2)3〇Me 4 - OMe 1-250 CH2C(Me)2GH2OH iPr ch2 RSa 3-S(CH2)30Me 4-GI 1-251 CH2C(Me)2CH20H iPr ch2 R8a 3 - NH( CH2)30Me 4-OMe 1-252 CH2C(Me)2CH2OH iPr ch2 R8a 3 -NH(CH2)30Me 4-Cl 1-253 CH2C(Me)2CH2OH iPr ch2 R8b (CH2)30Me 1-1-254 CH2C(Me) 2CH20H iPr ch2 R8b (CH2)30Me 3-Me 1-255 CH2C(Me)2CH20H iPr ch2 R8b (CH2)30Me 3-OMe 1-256 CH2C(Me)2CH2OH iPr ch2 R8b (CH2)30Me 3-F 1-257 CH2C(Me)2GH2OH iPr ch2 R8b (CH2)3〇Me 3-CI 1-258 CH2C(Me)2GH2OH iPr ch2 r8c (CH2)30Me I1-259 CH2C(Me)2CH2OH iPr ch2 R8c (CH2)3〇Me 5 - Me 1-260 CH2C(Me)2CH2OH iPr ch2 r8c (CH2)30Me 5-OMe 1 - 261 CH2C(Me)2CH2OH iPr ch2 r8c (GH2)30Me 5-F 1-262 CH2C(Me)2CH20H iPr ch2 r8c (CH2)30Me 5-CI 1-263 CH2C(Me)2CH20H iPr ch2 R8d ( CH2)30Me - 1-264 CH2C(Me)2CH2OH iPr ch2 R8d (CH2)30Me 5-Me 1-265 CH2C(Me)2CH2OH iPr ch2 R8d (CH2)30Me 5-OMe 1-266 CH2C(Me)2CH2OH iPr ch2 R8d (CH2)30Me 5-F 1-267 CH2C(Me)2CH2OH iPr ch2 R8d (CH2)30Me 5-CI 1-268 CH2C(Me)2CH2OH iPr ch2 R8d (CH2)2NHC0Me I1-269 CH2C(Me)2G_ iPr ch2 R8d (CH2)2NHC0Me 5-Me 1-270 CH2C(Me)2CH20H iPr ch2 R8d (CH2)2NHC0Me 5-OMe 1-271 CH2C(Me)2CH2OH iPr ch2 R8d (CH2)2NHC0Me 5-F 1-272 CH2G (Me)2CH20H iPr ch2 R8d (CH2)2NHC0Me 5-CI 1-273 CH2C(Me)2CH20H iPr ch2 R8d (CH2)2NHS02Me - 1-274 CH2C(Me)2CH20H iPr ch2 R8d (CH2)2NHS02Me 5-Me 1- 275 CH2C(Me)2CH20H iPr ch2 R8d (CH2)2NHS02Me 5-OMe 1-276 CH2C(Me)2CH20H iPr ch2 R8d (CH2)2NHS02Me 5-F 1-277 CH2C(Me)2CH20H iPr ch2 R8d (CH2)2NHS02Me 5 -CI 1-278 CH2C(Me)2CH20H iPr ch2 R8e (CH2)30Me - 1-279 CH2C(Me)2CH20H iPr ch2 R8e (CH2)3〇Me 5-Me 1-280 CH2C(Me)2CH20H iPr ch2 R8e ( CH2)30Me 5-OMe 1-281 CH2C(Me)2CH2OH iPr ch2 R8e (CH2)30Me 5-F 1-282 CH2C(Me)2CH20H iPr ch2 R8e (CH2)30Me 5-CI 1-283 CH2G(Me)2CH20H iPr ch2 R 8e (CH2)2NHC0Me 1-42- 200815324 1-284 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHC0Me 5~Me 1-285 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHCOMe 5-OMe 1-286 CH2C (Me)2CH20H iPr ch2 R8e (CH2)2NHC0Me 5-F 1-287 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHC0Me 5-CI 1-288 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHS02Me 1- 289 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHS02Me 5 - Me 1-290 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHS02Me 5-OMe 1-291 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHS02Me 5 -F 1-292 CH2C(Me)2CH20H iPr ch2 R8e (CH2)2NHS02Me 5-CI 1-293 CH2C(Me)2CH20H iPr ch2 R8f (CH2)3OMe - 1-294 CH2C(Me)2CH20H iPr ch2 R8f (CH2) 3OMe 5-Me 1-295 GH2C(Me)2CH2OH iPr ch2 R8f (CH2)3OMe 5-OMe 1-296 CH2C(Me)2CH20H iPr ch2 R8f (GH2)30Me 5-F 1-297 CH2C(Me)2CH20H iPr ch2 R8f (CH2)30Me 5-CI 1-298 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHC0Me I1-299 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHC0Me 5-Me 1-300 CH2C(Me)2CH20H iPr gh2 RSf (CH2)2NHCOMe 5~0Me 1-301 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHC0Me 5-F 1-302 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHC OMe 5-Cl 1-303 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHS02Me - 1-304 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHS02Me 5-Me 1-305 CH2G(Me)2CH20H iPr ch2 R8f ( CH2)2NHS02Me 5 - ΟΜθ 1-306 CH2C(Me)2CH20H iPr ch2 R8f (CH2)2NHS02Me 5-F 1-307 CH2C(Me)2CH2OH iPr ch2 R8f (CH2)2NHS02Me 5-CI 1-308 GH2C(Me)2CH20H iPr ch2 R8g (CH2)3OMe-1-309 CH2C(Me)2CH20H iPr ch2 R8h (CH2)3〇Me - 1-310 CH2C(Me)2CH20H iPr ch2 R8i (CH2)30Me - 1-311 CH2C(Me)2CH20H cPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-312 CH2C(Me)2CH20H cPr ch2 R8a 3-0(CH2)30Me 4-Cl 1-313 CH2C(Me)2CH20H cPr ch2 R8a 3-0(CH2 2NHC0Me 4-CI 1-314 CH2C(Me)2CH20H cPr ch2 RSa 3-0(CH2)2NHS02Me 4-Gl 1-315 CH2C(Me)2CH20H cPr ch2 R8d (CH2)30Me 1-1-316 CH2C(Me)2CH2OH cPr ch2 R8e (CH2)30Me 1-1-317 CH2C(Me)2CH20H cPr ch2 R8f (CH2)3〇Me 1-1-318 CH2(1-C_-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-319 CH2(1-CH20H-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-320 GH2(1-C_-cPr) iPr ch2 R8d (CH2)3OMe 1-321 (S)Pr -OMe iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-322 CH2C(Me)2CH2O Me iPr ch2 R8a 3-0(CH2)30Me 4-OMe -43- 200815324 1-323 CH2G(Me)2CH20Me iPr ch2 R8a 3-0(CH2)30Me 4-0Et 1-324 CH2C(Me)2CH20Me iPr ch2 R8a 3-0(CH2)30Me 4-0CHF2 1-325 CH2C(Me)2CH20Me iPr ch2 R8a 3-0(CH2)30Me 4-F 1-326 CH2G(Me)2C_e iPr ch2 R8a 3-0(CH2)30Me 4 -CI 1-327 CH2C(Me)2CH20Me iPr ch2 R8a 3-0(CH2)2NHC0Me 4-CI 1-328 CH2C(Me)2CH20Me iPr ch2 R8a 3-0(CH2)2NHS02Me 4-GI 1-329 CH2C(Me 2CH20Me iPr ch2 R8d (CH2)30Me — 1-330 CH2C(Me)2CH20Me iPr ch2 R8e (CH2)3〇Me 一1-331 CH2C(Me)2CH20Me iPr ch2 R8f (CH2)30Me 1-332 CH2C(Me 2S0Me iPr ch2 R8a 3-0(CH2)30Me 4 - OMe 1-333 CH2C(Me)2S0Me iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-334 CH2G(Me)2S0Me iPr ch2 R8d (CH2) 3OMe-1335 CH2(1-S0Me-cPr) iPr ch2 R8a 3~0(CH2)30Me 4 - OMe 1-336 CH2(1-SOMe-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-337 CH2(1-S0Me-cPr) iPr ch2 R8d (CH2)3OMe - 1-338 CH2C(Me)2S02Me iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-339 CH2C(Me)2S02Me iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-340 CH2C(Me)2S02Me iPr ch2 R8d (CH2)30Me - 1-341 CH2(1-S02Me- cPr) iPr ch2 RSa 3-0(CH2)30Me 4-OMe 1-342 CH2(1-S02Me-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-Cl 1-343 CH2(1-S02Me-cPr) iPr ch2 R8d (CH2)3OMe - 1-344 CH2C(Me)2C02Me iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-345 CH2C(Me)2C02Me iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-346 CH2C(Me)2C02Me iPr ch2 R8d (CH2)30Me - 1-347 CH2(1-C02Me-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-348 CH2(1-C02Me - cPr iPr ch2 R8a 3-0(CH2)30Me 4-Cl 1-349 CH2(1 - C02Me - cPr) iPr ch2 R8d (CH2)30Me 1-350 CH2C(Me)2C0NHMe iPr ch2 R8a 3-0(CH2) 30Me 4-OMe 1-351 CH2C(Me)2G0NHMe iPr ch2 RSa 3-0(CH2)30Me 4-CI 1-352 CH2C(Me)2C0NHMe iPr ch2 R8d (CH2)30Me - 1-353 CH2(1-C0NHMe- cPr) iPr CH2 R8a 3-0(CH2)30Me 4-OMe 1-354 CH2(1-CONHMe-cPr) iPr CH2 R8a 3-0(CH2)30Me 4-CI 1-355 CH2(1-CONHMe-cPr) iPr CH2 R8d (CH2)3OMe - 1-356 CH2G(Me)2C0NH2 iPr ch2 R8a 3_0(CH2)20Me 4-OMe 1-357 CH2G(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)20Me 4-CI 1- 358 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)30Me 4 - Me 1-359 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)30Me 4-CF3 1-360 CH2C(Me)2C0 NH2 iPr ch2 R8a 3-0(CH2)30Me 4 - OMe 1-361 CH2C(Me)2C0NH2 iPr gh2 R8a 3-0(CH2)30Me 4-OEt -44- 200815324 1-362 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)30Me 4-0GHF2 1-363 CH2G(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)30Me 4 - 0GF3 1-364 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)30Me 4 -F 1-365 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-366 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)40Me 4-OMe 1-367 CH2C(Me 2C0NH2 iPr ch2 R8a 3-0(CH2)40Me 4-CI 1-368 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)3SMe 4-OMe 1-369 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0 (CH2)3SMe 4-CI 1-370 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)3S02Me 4-OMe 1-371 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)3S02Me 4-CI 1 -372 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OMe 1-373 CH2C(Me)2C0NH2 iPr gh2 R8a 3-0(GH2)2NHC0Me 4-OEt 1-374 CH2C(Me)2C0NH2 iPr Ch2 RSa 3-0(GH2)2NHC0Me 4_0CHF2 1-375 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHC0Me 4-F 1-376 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHC0Me 4 -CI 1-377 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHS02Me 4-OMe 1-378 CH2C(Me)2C0NH2 iPr c H2 R8a 3-0(CH2)2NHS02Me 4-OEt 1-379 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHS02Me 4-0CHF2 1-380 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2) 2NHS02Me 4-F 1-381 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-382 CH2C(Me)2G0NH2 iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-OMe 1-383 CH2C (Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-Cl 1-384 CH2C(Me)2C0NH2 iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-OMe 1-385 CH2C(Me)2C0NH2 iPr ch2 R8a 3 -0(CH2)2NHS02NH2 4-CI 1-386 CH2C(Me)2C0NH2 iPr ch2 R8a 3-S(CH2)30Me 4-OMe 1-387 CH2C(Me)2C0NH2 iPr gh2 R8a 3-S(CH2)30Me 4- CI 1-388 CH2C(Me)2C0NH2 iPr ch2 R8a 3 - NH(CH2)30Me 4-OMe 1-389 CH2C(Me)2C0NH2 iPr ch2 R8a 3 - NH(CH2)30Me 4-Cl 1-390 CH2C(Me) 2C0NH2 iPr ch2 R8b (CH2)30Me — 1-391 CH2C(Me)2C0NH2 iPr ch2 R8b (GH2)30Me 3-Me 1-392 CH2C(Me)2CONH2 iPr ch2 R8b (CH2)30Me 3-OMe 1-393 CH2C( Me)2C0NH2 iPr ch2 R8b (CH2)3〇Me 3-F 1-394 CH2C(Me)2C0NH2 iPr ch2 R8b (CH2)3〇Me 3-CI 1-395 CH2C(Me)2C0NH2 iPr ch2 r8c (CH2)30Me 1-136 CH2C(Me)2CONH2 iPr ch2 R8. (CH2)3〇Me 5-Me 1-397 CH2C(Me)2C0NH2 iPr ch2 r8c (CH2)30Me 5-0Me 1-398 CH2C(Me)2C0NH2 iPr ch2 r8c (GH2)30Me 5-F 1-399 CH2C( Me)2C0NH2 iPr ch2 r8c (CH2)30Me 5-CI 1-400 CH2C(Me)2CONH2 iPr ch2 R8d (CH2)20Me 1-45- 200815324

1-401 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)30Me - 1-402 CH2C(Me)2CONH2 iPr ch2 R8d (CH2)30Me 5 - Me 1-403 CH2C(Me)2G0NH2 iPr ch2 R8d (CH2)30Me 5 - OMe 1-404 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)3〇Me 5-F 1-405 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)30Me 5-CI 1-406 CH2C(Me)2C0NH2 iPr ch2 RSd (CH2)2NHC0Me - 1-407 CH2C(Me)2G0NH2 iPr ch2 R8d (CH2)2NHC0Me 5 - Me 1-408 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHC0Me 5 - OMe 1-409 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHC0Me 5-F 1-410 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHC0Me 5-CI 1-411 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHS02Me — 1-412 CH2C(Me 2C0NH2 iPr ch2 R8d (CH2)2NHS02Me 5-Me 1-413 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHS02Me 5-OMe 1-414 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHS02Me 5-F 1- 415 CH2C(Me)2C0NH2 iPr ch2 R8d (CH2)2NHS02Me 5-CI 1-416 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)3〇Me 一1-417 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)30Me 5 - Me 1-418 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)30Me 5-OMe 1-419 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)3〇Me 5-F 1-420 CH2C(Me)2C0NH2 iPr c H2 R8e (CH2)3〇Me 5-CI 1-421 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHC0Me - 1-422 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHC0Me 5 - Me 1-423 CH2C( Me)2C0NH2 iPr ch2 R8e (CH2)2NHC0Me 5-OMe 1-424 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHC0Me 5-F 1-425 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHC0Me 5-Cl 1 -426 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHS02Me I1-427 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHS02Me 5 - Me 1-428 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHS02Me 5- OMe 1-429 CH2C(Me)2C0NH2 iPr ch2 R8e (CH2)2NHS02Me 5-F 1-430 CH2C(Me)2C0NH2 iPr ch2 RSe (CH2)2NHS02Me 5-CI 1-431 CH2C(Me)2C0NH2 iPr ch2 R8f (GH2 30Me - 1-432 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)30Me 5-Me 1-433 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)30Me 5-OMe 1-434 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)3〇Me 5-F 1-435 CH2C(Me)2C0NH2 iPr gh2 R8f (CH2)30Me 5-CI 1-436 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)2NHC0Me - 1-437 CH2C(Me) 2C0NH2 iPr ch2 R8f (CH2)2NHC0Me 5-Μθ 1-438 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)2NHC0Me 5-OMe 1-439 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)2NHC0Me 5-F -46- 200815324 1-440 CH2C(Me)2C0NH2 iPr ch2 Rsf (CH2)2NHC0Me 5-Cl 1-441 CH2G(Me)2C0NH2 iPr ch2 R8f (CH2)2NHS02Me 1-4242 CH2C(Me)2C0NH2 iPr ch2 R8f ( CH2)2NHS02Me 5-Me 1-443 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)2NHS02Me 5 - OMe 1-444 CH2C(Me)2C0NH2 iPr ch2 R8f (CH2)2NHS02Me 5-F 1-445 CH2C(Me)2CONH2 iPr ch2 R8f (CH2)2NHS02Me 5-CI 1-446 CH2C(Me)2C0NH2 iPr ch2 R8g (CH2)30Me - 1-447 CH2C(Me)2C0NH2 iPr ch2 R8h (CH2)30Me - 1-448 CH2C(Me)2C0NH2 iPr ch2 R8'1 (CH2)30Me 1-4449 CH2C(Me)2C0NH2 iPr CH2C(=_e) R8c (CH2)30Me 1-450 CH2C(Me)2C0NH2 cPr ch2 R8a 3-0(CH2)30Me 4 - OMe 1-451 CH2C(Me)2CONH2 cPr ch2 R8a 3-0(CH2)30Me 4-CI 1 - 452 CH2C(Me)2CONH2 cPr ch2 R8a 3-0(CH2)2NHC0Me 4-Cl 1-453 CH2C(Me) 2C0NH2 cPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-454 CH2C(Me)2G0NH2 cPr ch2 R8d (CH2)30Me - 1-455 CH2C(Me)2CONH2 cPr ch2 R8e (CH2)30Me - 1-456 CH2C (Me)2C0NH2 cPr ch2 R8f (CH2)30Me 1-457 CH2(1-C0NH2-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-458 CH2(1-G0NH2-cPr) iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-4 59 CH2(1-C0NH2-cPr) iPr ch2 R8d (CH2)30Me - 1-460 CH2C(Me)2S02NH2 iPr ch2 RSa 3-0(CH2)30Me 4-ΟΜθ 1-461 CH2C(Me)2S02NH2 iPr ch2 R8a 3 -0(CH2)30Me 4-CI 1-462 CH2C(Me)2S02NH2 iPr ch2 R8d (CH2)3〇Me - 1-463 CH2(1-S02NH2~cPr) iPr ch2 R8a 3-0(CH2)30Me 4- OMe 1-464 GH2(1 - S02NH2—cPr) iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-465 GH2(1-S02NHrcPr) iPr ch2 R8d (CH2)30Me - 1-466 CH2C(Me)2S02NHMe iPr ch2 R8a 3-0(CH2)30Me 4 - OMe 1-467 CH2C(Me)2S02NHMe iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-468 CH2C(Me)2S02NHMe iPr ch2 R8d (CH2)30Me - 1-469 CH2(1-S02NHMe-cPr) iPr CH2 R8a 3-0(CH2)30Me 4-OMe 1-470 CH2(1-S02NHMe-cPr) iPr CH2 R8a 3-0(CH2)30Me 4-CI 1- 471 CH2(1 - S02NHMe-cPr) iPr CH2 R8d (CH2)30Me 1-42472 CH2CF3 iPr ch2 R8a 3-0(GH2)30Me 4-OMe 1-473 ch2cf3 iPr ch2 R8a 3-0(CH2)30Me 4- Cl 1-474 ch2cf3 iPr ch2 R8d (CH2)30Me - 1-475 (CH2)2CF3 iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-476 (CH2)2CF3 iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-477 (CH2)2CF3 iPr ch2 R8d (CH2)30Me - 1-478 ch2cf2ch3 iPr ch2 R8a 3-0(CH2)30Me 4 ~0Me -47- 200815324 1-479 CH2CF2CH3 iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-480 ch2cf2ch3 iPr ch2 R8d (CH2)30Me - 1-481 (CH2)3CF3 iPr ch2 R8a 3-0 (GH2 30Me 4-OMe 1-482 (CH2)3CF3 iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-483 (CH2)3CF3 iPr ch2 R8d (CH2)30Me 1-44 (CH2)2CF2CH3 iPr ch2 R8a 3-0(CH2)30Me 4-0Me 1-485 (CH2)2CF2CH3 iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-486 (CH2)2CF2CH3 iPr ch2 R8d (CH2)30Me - 1-487 CH2( CF2)2CH3 iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-488 CH2(CF2)2CH3 iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-489 CH2(CF2)2CH3 iPr ch2 R8d (CH2 30Me - 1-490 CH2Ph iPr ch2 R8a 3-0(CH2)30Me 4-CI 1-491 (CH2)2Ph iPr ch2 R8a 3-0 (CH2) 30Me 4-CI 1-492 (CH2)2(4- Mor) iPr ch2 R8a 3-0 (CH2) 3〇Me 4-CI 1-493 cPr iPr gh2 R8a 3-0(CH2)30Me 4-Cl 1-494 cPn iPr ch2 R8a 3-0(CH2)20Me 4- OMe 1-495 cPn iPr ch2 R8a 3-0(CH2)20Me 4-CI 1-496 cPn iPr ch2 R8a 3-0(CH2)30Me 4-Me 1-497 cPn iPr ch2 R8a 3-0(CH2)30Me 4 -CF3 1-498 cPn iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-499 cPn iPr ch2 R8a 3-0(CH2)30Me 4-OEt 1-500 cPn iPr ch2 R8a 3-0(C H2) 30Me 4-0CHF2 1-501 cPn iPr ch2 R8a 3-0(CH2)30Me 4-0CF3 1-502 cPn iPr ch2 R8a 3-0(CH2)30Me 4-F 1-503 cPn iPr ch2 R8a 3-0 (CH2)30Me 4-CI 1-504 cPn iPr ch2 R8a 3-0(CH2)40Me 4-OMe 1-505 cPn iPr ch2 R8a 3-0(CH2)40Me 4-CI 1-506 cPn iPr ch2 R8a 3- 0(CH2)3SMe 4-OMe 1-507 cPn iPr ch2 R8a 3-0(CH2)3SMe 4-CI 1-508 cPn iPr ch2 R8a 3-0(CH2)3S02Me 4-OMe 1-509 cPn iPr ch2 R8a 3 -0(CH2)3S02Me 4-CI 1-510 cPn iPr ch2 R8a 3-0(CH2)2NHC0Me 4-OMe 1-511 cPn iPr ch2 R8a 3-0(GH2)2NHG0Me 4-OEt 1-512 cPn iPr ch2 R8a 3-0(CH2)2NHC0Me 4-0CHF2 1-513 cPn iPr ch2 R8a 3-0(CH2)2NHC0Me 4-F 1-514 cPn iPr ch2 R8a 3-0 (CH2) 2NHC0Me 4-CI 1-515 cPn iPr ch2 R8a 3-0(GH2)2NHS02Me 4 - OMe 1-516 cPn iPr gh2 R8a 3-0 (CH2) 2NHS02Me 4-OEt 1-517 cPn iPr ch2 R8a 3_0(CH2)2NHS02Me 4-0CHF2 -48- 200815324

1-518 cPn iPr ch2 R8a 3-0(CH2)2NHS02Me 4-F 1-519 cPn iPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-520 cPn iPr ch2 R8a 3-0(CH2)2NHC0NH2 4 - OMe 1-521 cPn iPr ch2 R8a 3-0(CH2)2NHC0NH2 4-CI 1-522 cPn iPr ch2 R8a 3-0(CH2)2NHS02NH2 4-OMe 1-523 cPn iPr ch2 R8a 3-0(CH2)2NHS02NH2 4 -CI 1-524 cPn iPr ch2 R8a 3-S(CH2)30Me 4-OMe 1-525 cPn iPr ch2 R8a 3-S(CH2)30Me 4-CI 1-526 cPn iPr ch2 R8a 3-NH(CH2)30Me 4-OMe 1-527 cPn iPr ch2 R8a 3-NH(CH2)30Me 4-CI 1-528 cPn iPr ch2 R8b (CH2)30Me 1-527 cPn iPr ch2 R8b (CH2)30Me 3-Me 1-530 cPn iPr ch2 R8b (CH2)30Me 3-OMe 1-531 cPn iPr ch2 R8b (CH2)30Me 3-F 1-532 cPn iPr ch2 R8b (CH2)30Me 3-Cl 1-533 cPn iPr ch2 r8c (CH2)30Me - 1-534 cPn iPr ch2 r8c (CH2)30Me 5-Me 1-535 cPn iPr ch2 R8c (CH2)30Me 5-OMe 1-536 cPn iPr ch2 R8c (CH2)3〇Me 5-F 1-537 cPn iPr ch2 R8c (CH2)30Me 5-CI 1-538 cPn iPr ch2 R8d (CH2)3〇Me 一1-539 cPn iPr ch2 R8d (CH2)30Me 5-Me 1-540 cPn iPr ch2 R8d (CH2)30Me 5-OMe 1-541 cPn iPr ch2 R8d (CH2)30Me 5-F 1-542 cPn iPr ch2 R8d (CH2 30Me 5-Gl 1-543 cPn iPr ch2 R8d (CH2)2NHC0Me - 1-544 cPn iPr ch2 R8d (CH2)2NHC0Me 5 - Me 1-545 cPn iPr ch2 R8d (CH2)2NHC0Me 5-OMe 1-546 cPn iPr Gh2 R8d (CH2)2NHC0Me 5-F 1-547 cPn iPr ch2 R8d (CH2)2NHC0Me 5-CI 1-548 cPn iPr ch2 R8d (CH2)2NHS02Me - 1-549 cPn iPr ch2 R8d (CH2)2NHS02Me 5-Me 1 -550 cPn iPr ch2 R8d (CH2)2NHS02Me 5-OMe 1-551 cPn iPr ch2 R8d (CH2)2NHS02Me 5-F 1-552 cPn iPr ch2 R8d (CH2)2NHS02Me 5-CI 1-553 cPn iPr ch2 R8e (GH2 30Me-1554 cPn iPr ch2 R8e (CH2)3〇Me 5-Me 1-555 cPn iPr ch2 R8e (CH2)30Me 5-OMe 1-556 cPn iPr ch2 R8e (CH2)30Me 5-F -49- 200815324 1-557 cPn iPr ch2 R8e (CH2)3〇Me 5-CI 1-558 cPn iPr ch2 R8e (CH2)2NHC0Me 1-5559 cPn iPr ch2 R8e (CH2)2NHC0Me 5-Me 1-560 cPn iPr ch2 R8e (CH2)2NHC0Me 5-0Me 1-561 cPn iPr ch2 R8e (CH2)2NHC0Me 5-F Bu 562 cPn iPr ch2 R8e (CH2)2NHC0Me 5-CI 1-563 cPn iPr ch2 R8e (CH2)2NHS02Me 1-554 cPn iPr ch2 R8e (CH2)2NHS02Me 5-Me 565 cPn iPr ch2 R8e (CH2)2NHS02Me 5 - OMe 1-566 cPn iPr ch2 R8e (CH2)2NHS02Me 5-F 1-567 cPn iPr ch2 R8e (CH2)2NHS02Me 5-CI 1-568 cPn iPr ch2 R8f (CH2)30Me -1-569 cPn iPr ch2 R8f (GH2)30Me 5-Me 1-570 cPn iPr ch2 R8f (CH2)3〇Me 5-OMe 1-571 cPn iPr ch2 R8f (CH2)30Me 5-F 1-572 cPn iPr ch2 R8f (CH2)30Me 5-CI 1-573 cPn iPr ch2 R8f (CH2)2NHC0Me-1 -574 cPn iPr ch2 R8f (CH2)2NHC0Me 5-Me 1-575 cPn iPr ch2 R8f (CH2)2NHC0Me 5-OMe 1-576 cPn iPr ch2 R8f (CH2)2NHC0Me 5-F 1-577 cPn iPr ch2 R8f (CH2 2NHC0Me 5-CI 1-578 cPn iPr ch2 R8f (CH2)2NHS02Me 1-5779 cPn iPr ch2 R8f (CH2)2NHS02Me 5 - Me 1-580 cPn iPr ch2 RSf (CH2)2NHS02Me 5-OMe 1-581 cPn iPr Ch2 R8f (CH2)2NHS02Me 5-F 1-582 cPn iPr ch2 R8f (CH2)2NHS02Me 5-CI 1-583 cPn iPr ch2 R8g (CH2)30Me - 1-584 cPn iPr ch2 R8h (GH2)3〇Me - 1 -585 cPn iPr ch2 R8i (CH2)30Me -1-586 cPn cPr ch2 R8a 3-0(CH2)30Me 4 - OMe 1-587 cPn cPr ch2 R8a 3-0(CH2)30Me 4-Cl 588 cPn cPr ch2 R8a 3-0(CH2)2NHC0Me 4-Gl 1-589 cPn cPr ch2 R8a 3-0(CH2)2NHS02Me 4-CI 1-590 cPn cPr ch2 R8d (CH2)30Me 1-5791 cPn cPr ch2 RSe (CH2 ) 30Me 1-592 cPn cPr ch2 R8f (CH2)3〇Me 1-593 cHx iPr ch2 R8a 3-0(CH2)30Me 4-OMe 1-594 cHx iPr ch2 R8a 3-0(CH2)30Me 4 - OEt 1-595 cHx iPr ch2 R8a 3-0(CH2)30Me 4-OGHF; -50 200815324 1-596 cHx 1-597 cHx 1-598 cHx 1-599 cHx 1-600 cHx 1-601 cHx 1-602 cHx 1-603 4-Thp 1-604 4 - Thp 1-605 4-Thp 1-606 4-Thp 1-607 4-Thp 1-608 4-Thp 1-609 4-Thp 1-610 4-Thp 1- 611 4-Thp 1-612 4-Thp 1-613 CH〇C(Me) 2CONH2 [Table 2] [Chemical 1 1 R8a 3-0(CH2)30Me 4-F 2 ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2ch2 ΓΓΓΓΓΓΓΓΓΓΓΓΓΓΓΓΓΓ ppppppppppppppplplpp R8a 3-0(CH2) 30Me 4-CI R8a 3-0(CH2)2NHC0Me 4-Cl R8a 3-0(CH2)2NHS02Me 4-CI R8d (CH2)30Me - R8e (CH2)30Me - R8f (CH2)30Me-R8a 3-0(CH2 30Me 4 - OMe R8a 3-0(CH2)30Me 4-OEt R8a 3-0(CH2)30Me 4-OGHF; R8a 3-0(CH2)30Me 4-F R8a 3-0(CH2)30Me 4-CI R8a 3-(CH2)2NHC0Me 4-Cl R8a 3-(CH2)2NHS02Me 4-CI R8d (CH2)30Me - R8e (CH2)3〇Me - R8f (CH2)30Me-R8c (CH2)30Me

[1 2]

-51- 200815324

Illustrative compound R1 Item number R3 R4 R8 R12 R13 2-1 nBu Et H R8a 3-0(CH2)30Me 4-OMe 2-2 nBu Et H RSa 3-0(CH2)30Me 4-OEt 2-3 nBu Et H R8a 3-0(CH2)30Me 4-0CHF2 2-4 nBu Et H R8a 3-0(CH2)30Me 4-F 2-5 nBu Et H R8a 3-0(CH2)30Me 4-CI 2-6 nBu Et H RSa 3-0(CH2)2NHC0Me 4-CI 2-7 nBu Et H R8a 0(CH2)2NHS02Me 4-CI 2-8 nBu Et H R8d (CH2)30Me - 2-9 nBu Et H R8e (CH2)30Me - 2-10 nBu Et H R8f (CH2)30Me - 2-11 nBu CMe2(0H) H R8a 3-0(CH2)30Me 4 - OMe 2-12 nBu CMe2(0H) H R8a 3-0(CH2)30Me 4-0Et 2-13 nBu CMe2(0H) H R8a 3-0(CH2)30Me 4-0CHF2 2-14 nBu CMe2(0H) H R8a 3-0(CH2)30Me 4-F 2-15 nBu CMe2(0H H R8a 3-0(CH2)30Me 4-CI 2-16 nBu CMe2(0H) H . R8a 3-0(CH2)2NHC0Me 4-Cl 2-17 nBu CMe2(0H) H R8a 0(CH2)2NHS02Me 4 -CI 2-18 nBu CMe2(0H) H R8d (CH2)3〇Me 2-19 nBu CMe2(0H) H R8e (CH2)30Me - 2-20 nBu CMe2(0H) H R8f (CH2)30Me - 2 -21 nBu cPr H R8a 3-0(CH2)30Me 4-0Me 2-22 nBu cPr H R8a 3-0(CH2)30Me 4-OEt 2-23 nBu cPr H R8a 3-0(CH2)30Me 4-0CHF2 2-24 nBu cPr H R8a 3-0(CH2)30Me 4-F 2-25 nBu cPr H R8a 3-0(CH2)30Me 4-CI 2-26 nBu cPr H R8a 3-0(CH2)2NHC0Me 4-CI 2-27 nBu cPr H R8a 0(CH2)2NHS02Me 4-CI 2-28 nBu cPr H R8d ( CH2)30Me - 2-29 nBu cPr H R8e (CH2)30Me - 2-30 nBu cPr H RSf (CH2)30Me -2-31 nBu Me Me R8a 3-0(CH2)30Me 4-OMe 2-32 nBu Me Me R8a 3-0(CH2)30Me 4-OEt 2-33 nBu Me Me R8a 3-0(CH2)30Me 4-0CHF2 2-34 nBu Me Me R8a 3-0(CH2)30Me 4-F -52- 200815324 2 - 35 nBu Me Me R8a 3-0(CH2)30Me 4-CI 2-36 nBu Me Me R8a 3-0(CH2)2NHC0Me 4-Cl 2-37 nBu Me Me R8a 0(CH2)2NHS02Me 4-CI 2 -38 nBu Me Me R8d (CH2)30Me A 2-39 nBu Me Me R8e (CH2)30Me A 2-40 nBu Me Me R8f (CH2)30Me A 2-41 (S)Bu-Me Et H R8a 3-0 (CH2)30Me 4-0Me 2-42 (5) Bu-Me Et H R8a 3-0(CH2)30Me 4-OEt 2-43 (S)Bu-Me Et H R8a 3-0(CH2)30Me 4-0GHF2 2- 44 (5) Bu-Me Et H R8a 3-0(CH2)30Me 4-F 2-45 (S)Bu-Me Et H R8a 3-0(CH2)30Me 4-CI 2-46 (S)Bu - Me Et H R8a 3-0(CH2)2NHC0Me 4-CI 2-47 (S)Bu-Me Et H R8a 0(CH2)2NHS02Me 4-CI 2-48 (S)Bu-Me Et H R8d (CH2)30Me 2- 49 (5) Bu-Me Et H R8e (CH2) 30Me - 2-50 (S) Bu-Me Et H R8f (CH2 30Me 2-51 (S)Bu-Me CMe2(0H) H R8a 3-0(CH2)30Me 4-OMe 2-52 (5) Bu-Me CMe2(0H) H R8a 3-0(CH2)30Me 4-OEt 2-53 (S)Bu-Me CMe2(0H) H R8a 3-0(CH2)30Me 4-0CHF2 2-54 (S)Bu-Me CMe2(0H) H R8a 3-0(CH2)30Me 4-F 2-55 (S)Bu-Me CMe2(0H) H R8a 3-0(CH2)30Me 4-CI 2-56 (S)Bu-Me CMe2_ H R8a 3-0(CH2)2NHG0Me 4-CI 2-57 (S) Bu-Me CMe2(0H) H R8a 0(CH2)2NHS02Me 4-CI 2-58 (S)Bu-Me CMe2(0H) H R8d (CH2)3〇Me - 2-59 (S)Bu- Me CMe2(0H) H R8e (CH2)30Me - 2 - 60 (5) Bu-Me CMe2(0H) H R8f (GH2)30Me - 2-61 (S)Bu-Me cPr H R8a 3-0(CH2)30Me 4- OMe 2-62 (S)Bu-Me cPr H R8a 3-0(CH2)30Me 4-OEt 2-63 (S)Bu-Me cPr H R8a 3-0(CH2)30Me 4-0CHF2 2-64 (S ) Bu-Me cPr H R8a 3-0(CH2)30Me 4-F 2-65 (S)Bu-Me cPr H R8a 3-0(CH2)30Me 4-CI 2-66 (S) Bu-Me cPr H R8a 3-0(CH2)2NHC0Me 4-CI 2-67 (S) Bu-Me cPr H R8a 0(CH2)2NHS02Me 4-CI 2-68 (S) Bu-Me cPr H R8d (CH2)30Me 2- 69 (S) Bu-Me cPr H R8e (CH2)30Me - 2 - 70 (S) Bu-Me cPr H R8f (CH2)30Me 1-71 (S) Bu-Me Me Me R8a 3-0(CH2) 30Me 4-OMe 2-72 (S) Bu-Me Me Me R8a 3-0(CH2)30Me 4- OEt 2-73 (S) Bu-Me Me Me R8a 3-0(CH2)3〇Me 4-0CHF2 -53- 200815324 2-74 (S)Bu-Me Me Me R8a 3-0(CH2)30Me 2 - 75 (S) Bu-Me Me Me R8a 3-0(CH2)30Me 2 - 76 (S)Bu-Me Me Me R8a 3-0(CH2)2NHC0Me 2-77 (S)Bu-Me Me Me R8a 0( CH2)2NHS02Me 2-78 (5) Bu-Me Me Me R8d (CH2)3OMe 2-79 (S)Bu-Me Me Me R8e (CH2)3OMe 2-80 (S)Bu-Me Me Me R8f (CH2)3OMe 2 -81 CH2C(Me)2CH2OH Et H R8a 3-0(CH2)30Me 2-82 CH2C(Me)2CH2OH Et H R8a 3-0(CH2)30Me 2-83 CH2C(Me)2CH2OH Et H R8a 3-0( CH2)30Me 2-84 CH2C(Me)2CH2OH Et H R8a 3-0(CH2)30Me 2-85 CH2C(Me)2CH2OH Et H R8a 3-0(CH2)30Me 2 - 86 CH2C(Me)2CH2OH Et H R8a 3-0(CH2)2NHC0Me 2-87 CH2C(Me)2CH20H Et H R8a 0(CH2)2NHS02Me 2-88 CH2C(Me)2CH2OH Et H R8d (CH2)30Me 2-89 CH2C(Me)2CH20H Et H R8e ( CH2)3OMe 2-90 CH2C(Me)2CH2OH Et H R8f (CH2)3OMe 2-91 CH2G(Me)2CH2OH CMe2(0H)H R8a 3-0(CH2)30Me 2-92 CH2C(Me)2CH2OH CMe2(0H H R8a 3-0(CH2)30Me 2-93 CH2C(Me)2CH2OH CMe2(0H)H R8a 3-0(CH2)30Me 2-94 CH2C(Me)2CH2OH CMe2(OH) H R8a 3-0(CH2 ) 30Me 2-95 CH2C(Me)2CH2OH CMe2(0H) H R8a 3-0(CH 2) 30Me 2-96 CH2C(Me)2CH2OH CMe2(OH)H R8a 3-0(CH2)2NHC0Me 2-97 CH2C(Me)2CH2OH CMe2(OH) H R8a 0(CH2)2NHS02Me 2-98 CH2C(Me) 2CH2OH CMe2(OH)H R8d (CH2)30Me 2-99 CH2C(Me)2CH2OH CMe2(0H)H R8e (CH2)30Me 2-100 CH2C(Me)2CH2OH CMe2(0H) H R8f (CH2)30Me 2-101 CH2C(Me)2CH20H cPr H R8a 3-0(CH2)30Me 2-102 CH2C(Me)2CH2OH cPr H R8a 3-0(CH2)30Me 2-103 CH2C(Me)2CH2OH cPr H R8a 3-0(CH2) 30Me 2-104 CH2C(Me)2CH2OH cPr H R8a 3-0(CH2)30Me 2-105 CH2C(Me)2CH2OH cPr H R8a 3-0(CH2)30Me 2-106 CH2C(Me)2CH20H cPr H R8a 3- 0(CH2)2NHC0Me 2-107 CH2C(Me)2CH20H cPr H R8a 0(CH2)2NHS02Me 2-108 CH2C(Me)2CH20H cPr H R8d (CH2)3〇Me 2-109 CH2C(Me)2CH20H cPr H R8e ( CH2)3OMe 2-110 CH2C(Me)2CH2OH cPr H R8f (GH2)3OMe 2-111 CH2C(Me)2CH20H Me Me R8a 3-0(CH2)30Me 2-112 GH2G(Me)2CH2OH Me Me R8a 3-0 (CH2)30Me 4-F 4-CI 4-CI 4-Cl 4-OMe 4-OEt

4-OMe 4-OEt 4-0CHF2 4-F 4-CI 4-CI 4-CI 4-OMe 4 - OEt 4-0CHF2

4-F

4-CI 4-Cl 4-CI 4-OMe 4-OEt 4-0CHF2

4-F

4-CI 4-Cl 4 -Cl 54- 200815324 2-113 CH2C(Me)2CH20H Me , Me R8a 3-0(CH2)30Me 4-0CHF2 2-114 CH2C(Me)2CH20H Me Me R8a 3-0(CH2 30Me 4-F 2-115 CH2C(Me)2CH20H Me Me R8a 3-0(GH2)30Me 4-CI 2-116 CH2C(Me)2CH20H Me Me R8a 3-0(CH2)2NHC0Me 4-Cl 2-117 CH2C(Me)2GH20H Me Me R8a 0(CH2)2NHS02Me 4-CI 2-118 CH2C(Me)2CH20H Me Me R8d (CH2)3〇Me A 2-119 CH2C(Me)2CH20H Me Me R8e (CH2)30Me 2-120 CH2C(Me)2CH20H Me Me R8f (GH2)30Me - 2-121 CH2C(Me)2C0NH2 Et H R8a 3-0(CH2)30Me 4_0Μθ 2-122 CH2C(Me)2C0NH2 Et H R8a 3-0( CH2)30Me 4-OEt 2-123 CH2C(Me)2C0NH2 Et H R8a 3-0(GH2)30Me 4-0CHF2 2-124 CH2C(Me)2C0NH2 Et H RSa 3-0(CH2)30Me 4-F 2- 125 CH2C(Me)2C0NH2 Et H R8a 3-0(CH2)30Me 4-Cl 2-126 CH2C(Me)2C0NH2 Et H R8a 3-0(CH2)2NHC0Me 4-CI 2-127 CH2C(Me)2C0NH2 Et H R8a 0(CH2)2NHS02Me 4-CI 2-128 CH2C(Me)2C0NH2 Et H R8d (GH2)30Me 2-129 CH2C(Me) 2C0NH2 Et H R8e (CH2)30Me - 2-130 CH2C(Me)2C0NH2 Et H R8f (CH2)30Me - 2-131 CH2C(Me)2C0NH2 CMe2(0H) H RSa 3-0(CH2)30Me 4 - ΟΜθ 2-132 CH2C(Me)2C0NH2 CMe2(0H)H R8a 3-0(CH2)30Me 4-OEt 2-133 CH2C(Me)2C0NH2 CMe2(0H)H R8a 3-0(CH2)30Me 4-0CHF2 2-134 CH2C(Me) 2C0NH2 CMe2( 0H) H R8a 3-0(CH2)30Me 4-F 2-135 CH2C(Me)2C0NH2 CMe2(0H) H R8a 3-0(CH2)30Me 4-CI 2-136 CH2C(Me)2C0NH2 CMe2(0H) H R8a 3-0(CH2)2NHC0Me 4-CI 2-137 CH2C(Me)2C0NH2 CMe2(0H) H R8a 0(CH2)2NHS02Me 4-Cl 2-138 CH2C(Me)2C0NH2 CMe2(0H) H R8d (CH2 30Me - 2-139 CH2C(Me)2C0NH2 CMe2(0H) H R8e (CH2)30Me - 2-140 CH2C(Me)2C0NH2 CMe2(0H) H R8f (CH2)30Me - 2-141 CH2C(Me)2C0NH2 cPr H R8a 3-0(CH2)30Me 4 - OMe 2-142 CH2C(Me) 2C0NH2 cPr H R8a 3-0(CH2)30Me 4-OEt 2-143 CH2C(Me)2C0NH2 cPr H R8a 3-0(CH2) 30Me 4 - OCHF: 2-144 CH2C(Me) 2C0NH2 cPr H R8a 3-0(CH2)30Me 4-F 2-145 CH2C(Me) 2C0NH2 cPr H R8a 3-0(CH2)30Me 4-CI 2-146 CH2C(Me)2C0NH2 cPr H R8a 3-0(CH2)2NHC0Me 4-Cl 2-147 CH2C(Me)2C0NH2 cPr H R8a 0(CH2)2NHS02Me 4-CI 2-148 CH2C(Me) 2C0NH2 cPr H R8d (CH2 30Me - 2-149 CH2C(Me) 2C0NH2 cPr H R8e (CH2)30Me 2-150 CH2C(Me)2C0NH2 cPr H R8f (CH2)30Me - 2H51 CH2C(Me)2C0NH2 Me Me RSa 3-0 (CH2)30Me 4 - OMe -55- 200815324 2-152 CH2C(Me)2C0NH2 Me Me R8a 3-0(CH2)30Me 4-OEt 2-153 CH2C(Me)2C0NH2 Me Me R8a 3-0(CH2)30Me 4-0CHF2 2-154 CH2C(Me)2C0NH2 Me Me R8a 3-0(CH2)30Me 4-F 2-155 CH2C(Me)2C0NH2 Me Me R8a 3-0(CH2)30Me 4-Cl 2-156 CH2C( Me)2C0NH2 Me Me RSa 3-0(CH2)2NHC0Me 4-CI 2-157 GH2C(Me)2C0NH2 Me Me RSa 0(CH2)2NHS02Me 4-Cl 2-158 CH2C(Me)2C0NH2 Me Me R8d (CH2)30Me - 2-159 CH2C(Me)2C0NH2 Me Me R8e (CH2)30Me 1-2-160 CH2C(Me)2C0NH2 Me Me Rsf (CH2)30Me - 2-161 cPn Et H R8a 3-0(CH2)30Me 4-OMe 2-162 cPn Et H R8a 3-0(CH2)30Me 4-OEt 2-163 cPn Et H R8a 3-0(CH2)30Me 4-0CHF2 2-164 cPn Et H R8a 3-0(CH2)30Me 4- F 2-165 cPn Et H R8a 3_0(CH2)30Me 4-CI 2-166 cPn Et H R8a 3-0(CH2)2NHC0Me 4-CI 2-167 cPn Et H R8a 0(CH2)2NHS02Me 4-CI 2- 168 cPn Et H R8d (CH2)30Me 2-169 cPn Et H R8e (CH2)30Me a 2-170 cPn Et H R8f (CH2)30Me - 2-171 cPn CMe2(0H) H R8a 3-0(CH2) 30Me 4-OMe 2-172 cPn CMe2(0H) H R8a 3-0(CH2)30Me 4-OEt 2-173 cPn CMe2(0H) H R8a 3-0(CH2)30Me 4-0CHF2 2-174 cPn CMe 2(0H)H R8a 3-0(CH2)30Me 4-F 2-175 cPn CMe2(0H) H R8a 3-0(CH2)3〇Me 4-CI 2-176 cPn CMe2(0H) H R8a 3- 0(CH2)2NHC0Me 4-CI 2-177 cPn CMe2(0H) H R8a 0(CH2)2NHS02Me 4-CI 2-178 cPn GMe2(0H) H R8d (CH2)30Me - 2-179 cPn CMe2(0H) H R8e (CH2)30Me 2-180 cPn CMe2(0H) H R8f (CH2)30Me - 2-181 cPn cPr H R8a 3-0 (CH2)30Me 4-OMe 2-182 cPn cPr H R8a 3-0(CH2 30Me 4-OEt 2-183 cPn cPr H RSa 3-0(CH2)30Me 4-0CHF2 2-184 cPn cPr H R8a 3-0(CH2)30Me 4-F 2-185 cPn cPr H R8a 3-0( CH2)30Me 4-GI 2-186 cPn cPr H R8a 3-0(CH2)2NHC0Me 4-GI 2-187 cPn cPr H R8a 0(CH2)2NHS02Me 4-CI 2-188 cPn cPr H R8d (CH2)30Me - 2-189 cPn cPr H R8e (CH2)3〇Me - 2-190 cPn cPr H R8f (CH2)30Me I 200815324 2-191 cPn Me Me R8a 3-0(CH2)30Me 4_0Me 2-192 cPn Me Me R8a 3 -0(CH2)30Me 4-OEt 2-193 cPn Me Me R8a 3-0(CH2)30Me 4-OCHF: 2-194 cPn Me Me R8a 3-0(GH2)30Me 4-F 2-195 cPn Me Me R8a 3-0(CH2)30Me 4-Cl 2-196 cPn Me Me R8a 3-0(GH2)2NHG0Me 4-Cl 2-197 cPn Me Me R8a 0(CH2)2NHS02Me 4-Cl 2-198 cPn Me Me R8d (CH2)30Me - 2-199 cPn Me Me R8e (CH2)30Me - 2-200 cPn Me Me R8f (CH2)30Me 1-57- 200815324 Suitable compounds in the compounds shown in Table 1 or 2 above are exemplified as compound numbers 1-14, 1-108, 1- 124, 1-215, 1-216, 1-218, 1-228, 1-360, 1-361, 1-362, 1-365, 1-390, 1-401, 1-446, 1-447, Compounds of 1-449, 1-450, or 1-503, and more suitable compounds are exemplified by the compound number 1-108: (23,43,53)-5-amino-6-{[4-chloro-3-( 3-methoxypropoxy)benzyl]isopropylamine oxime 4-hydroxy-2-isopropylhexanoic acid isobutyl decylamine, exemplified compound No. 1-124: (2S, 4S, 5S)-5- Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylaminobutylide 4-hydroxy-2-isopropylhexanoic acid [(S)-2-methyl Butyl]guanamine, exemplified compound number 1-218: (2S,4S,5S)-5-amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl] Alanyl}-4-hydroxy-2-isopropylhexanoic acid [(S)-1-hydroxymethyl-2-methylbutyl]decylamine, exemplified compound No. 1 -228: (23,43,53) 5-5-amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy-2-isopropylhexanoic acid (3-hydroxy- 2,2 - dimethylpropyl) decylamine, exemplified compound No. 1 -360 : (2S,4S,5S)-5-amino-6-{isopropyl-[4-methoxy-3-(3-methyl) Oxypropoxy)benzyl]amino-4-hydroxy-2-isopropylhexanoic acid (2-aminomethylindol-2-methylpropyl) decylamine, exemplified compound No. 1-361: (2S ,4S,5S)-5-Amino-6-{[4-ethoxy-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy-2-isopropyl Caproic acid (2-Aminomethyl-2-methylpropyl) decylamine, exemplified compound No. 1 - 362: (23,43,53)-5-amino-6-{[4-difluoromethoxy -58- 200815324 -3-(3-methoxypropoxy)benzyl]isopropylaminobutylide 4-hydroxy-2-isopropylhexanoic acid (2-aminoformamido-2-methylpropyl) Indoleamine, exemplified compound No. 1 -365 : (2S,4S,5S)-5-amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino 4-Hydroxy-2-isopropylhexanoic acid (2-aminomethylindol-2-methylpropyl) decylamine, exemplified compound No. 1-401: (2S, 4S, 5S)-5-amino group- 4-hydroxy-2-isopropyl-6-{isopropyl-[1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-ylmethyl]amine Hexanoic acid (2-aminoformamido-2-methylpropyl) Amine, or an exemplary compound No. 1 - 503 : (2S, 4S, 5S)-5-amino-6-{[4-chloro-3-(3-methoxypropoxy)] isopropyl]}- A compound of 4-cyclo-2-isopropylhexanoic acid cyclopentylguanamine. The compound of the formula (I) of the present invention can be produced by the following methods A to C. [化1 3] -59- 200815324 A method - 1 OH (1) A-1 project R3CHC〇Xa (2) 〇^R3 (3) A-2 project (4)

R3 A-4 Project -> A _ 6 Project A-8 Project ->

[化1 4] -60 200815324 A law one 2

N_Ns

NHNs R7 Nk .R8 A-10 Project -►

NHBoc

R7 rL /R8 Y R7 A-11 project

丫

Method [B

-61 200815324

In the structural formulas of the compounds of the above-mentioned methods A to C, R1, R2, R3, R7, & 8, scales 1°, 1112, 3, 0, and 丫 are in the same meaning as in the formula (1), and 八3 is VIII, C6-Ci aryl, substituted Ca-Cw aryl, 5 to 10 membered aromatic heterocyclic group, or substituted 5 to 10 membered aromatic heterocyclic group, Xa is chlorine, bromine or iodine, Xb is The combined hydrogen atoms form an acid such as hydrochloric acid or hydrobromic acid, X. X2 is a group of the formula -NH-, -NR11-, -0- or -S-, Xd is chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonate The base is detached from the group, Bn is a benzyl group, Boc is a third butoxycarbonyl group, and Ns is an o-nitrophenylsulfonyl group. In the reaction of each of the following A to C methods, when the compound to be a reaction substrate has a group which inhibits the purpose of the reaction such as an amine group, a hydroxyl group or a carboxyl group, it may be suitably subjected to the introduction of a protecting group and removal thereof as necessary. The introduced protecting group. Such a protecting group is not limited as long as it is a commonly used protecting group, and can be protected, for example, by TW Greene, PG Wuts, Protective Groups in Organic Synthesis. Third Edition, 1 999, John Wiley & Sons, Inc. base. The reaction of introduction and removal of the protecting groups can be carried out according to the methods described in the above documents. -62- 200815324 The solvent used in the reaction of each of the following methods A to C is not limited as long as it does not inhibit the reaction, and is preferably selected from the following solvent groups. The solvent group is an aliphatic hydrocarbon such as hexane, pentane, petroleum ether or cyclohexane; an aromatic hydrocarbon such as benzene, toluene or xylene; dichloromethane, chloroform, carbon tetrachloride, dichloroethane or chlorine. Halogenated hydrocarbons such as benzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl Ketones such as pentanone and cyclohexanone; esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; carboxylic acids such as acetic acid and propionic acid; Alcohols such as ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, two Anthracene such as methylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphonium triamine; dimethylidene, sulfonium and the like; ; and these mixtures. The acid used in the reaction of each of the following A to C methods is not limited as long as it does not inhibit the reaction, and is selected from the group of acids described below. The acid group is an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid or nitric acid, an organic acid such as acetic acid, propionic acid, trifluoroacetic acid or pentafluoropropionic acid, and methanesulfonic acid or trifluoromethanesulfonic acid. An organic sulfonic acid such as p-toluenesulfonic acid or sulfonic acid. The base used in the respective engineering reactions of the following A to C methods is not limited as long as it does not inhibit the reaction, and is selected from the following group of bases. The alkali group is an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or carbonic acid; an alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; lithium hydroxide, sodium hydroxide or potassium hydroxide; Alkali metal hydroxide; alkaline earth metal hydroxide such as calcium hydroxide or palladium hydroxide; alkali metal hydrogenation such as lithium hydride, sodium hydride or potassium hydride - 63-200815324; lithium decylamine, sodium decylamine, potassium hydrazine An alkali metal amine such as an amine; lithium metal methoxide, sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide, etc.; metal alkyl oxide such as lithium diisopropylamine; lithium bis-trimethyl decylamine; a decylamine such as sodium bis-methyl decylamine; an alkyl lithium such as n-butyl lithium, a second butyl lithium or a third butyl lithium; methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, Ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, isobutyl magnesium chloride, etc.; and triethylamine, tributylamine, diisopropyl Ethylethylamine, N-methylpiperidine, N-methylmorpholine, N-ethylmorpholine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, 4- Pyrrolylpyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-dioxinbicyclo [4,3,0]壬-5·ene (DBN), 1,4-dioxinbicyclo[2,2,2] 辛院(〇人8(1!〇), 1,8-一11丫 double ring [5,4,0] organic carbon such as eleven carbon-7-dilute (DBU). In the following reactions from the A method to the C method, the reaction temperature varies depending on the solvent, starting materials, reagents, etc. The reaction time varies depending on the solvent, starting materials, reagents, reaction temperature, etc. In the reaction of each of the following A to C methods, after the reaction is completed, the target compound of each project can be separated from the reaction mixture by a usual method. The objective compound may, for example, (i) filter out insoluble matter such as a catalyst as necessary, and (ii) extract the target compound by adding water and a solvent (for example, dichloromethane, diethyl ether, ethyl acetate, etc.) which is not mixed with water. (iii) immersing the organic layer in water, drying it with a drying agent such as anhydrous magnesium sulfate, and (iv) distilling off the solvent. The desired compound is obtained, if necessary, by recrystallization, reprecipitation, or by a gel column. Analysis It is more refined. The compound of each project can be used for the next reaction without purification. -64-200815324. In each project, the optically active amines such as dehydroabietylamine can be recrystallized separately or separated by optically active columns. The optical isomers are separated. The reaction of each of the methods A to C is described below. (Method A) The method A is formed by the method A-1 and the method A-2, and is produced in the formula (I). La) Method of compound (A-1 project) A-1 project is a process for reacting compound (1) with compound (2) in the presence of a base. Compound (1) can be based on Tetrahedron Lett., 1989, Manufactured in the method described in Volume 28, p. 6497. The compound (2) is known or easily obtained from a known compound. Alkali metal alkali hydrogencarbonate, alkali metal hydroxide, alkali metal hydride, alkali metal amine, alkali metal alkoxide, lithium alkylamine, decylamine, alkyl lithium, alkyl magnesium halide, or organic amine Particularly preferred is an alkyl magnesium halide or an organic amine, preferably ethylmagnesium bromide, triethylamine, 4-(N,N-dimethylamino)pyridine, or a combination thereof. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether or an ester, particularly preferably an ether or a halogenated hydrocarbon, preferably tetrahydrofuran or dichloromethane. The reaction temperature is preferably -78 to 150 ° C, particularly preferably -30 to 40 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 48 hours. (A-2 Project) The A-2 project is a project in which the compound (3) obtained in the A-1 project is treated with a chopped alkylation reagent and a -65-200815324 alkali. The ruthenium alkylation reagent used is, for example, chlorotrimethyl decane, chlorotriethyl sulfonium, dibutyl dimethyl ketone or the like, or a trichloromethane trifluoroacetate, or three Trimethyl phthalate such as triethyl decyl fluoroacetate or tributyl dimethyl decyl trifluoroacetate is preferably a chlorodecane, preferably chlorotrimethyl decane. The base used is preferably lithium alkylamine, decylamine or alkyl lithium, particularly preferably lithium alkylamine, preferably lithium diisopropylamide. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether, particularly preferably an ether, preferably tetrahydrofuran. The reaction temperature is preferably -78 to 100 ° C, particularly preferably -78 to 40 ° C. The reaction time is preferably from 30 minutes to 96 hours, particularly preferably from 1 to 24 hours. (A-3 Project) A-3 Project (A-3a Project): Project for reacting compound (4) obtained from A_2 project with halogenated reagent; and (A-3b Project): Compound obtained from Project A-3a It is engineered to react with dimethylamine in the presence of a base. (A-3a project) The halogenating agent used is, for example, sulfinium chloride; phosphorus trichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus halide such as phosphorus pentabromide; Or a combination of carbon tetrachloride, four desertified carbon, six gas acetyl, N-gas butyl sulphide S and N-bromosuccinic acid, and a combination of triphenylphosphine, Yiya Sulfonium chloride or grasshopper chlorine, preferably grassy chlorine. The combination of the above halogenated reagent and N,N-dimethylformamidine-66-200815324 amine is preferred. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester or a nitrile, particularly preferably an aromatic hydrocarbon or a halogenated hydrocarbon, preferably methylene chloride. This project can also be carried out in the absence of solvents. The reaction temperature is preferably -78 to 150 ° C, particularly preferably 0 to 80 ° C. The reaction time is preferably from 30 minutes to 96 hours, particularly preferably from 60 minutes to 6 hours. (A-3b engineering) Alkali metal alkali hydrogencarbonate, alkali metal hydroxide, alkali metal hydride, alkali metal amine, alkali metal alkoxide, lithium alkylamine, decylamine, alkyl lithium, or organic amine Especially suitable for organic amines, preferably dimethylamine. In this project, it is preferable to use an alcohol solution or an aqueous solution of dimethylamine, and an aqueous solution of dimethylamine is particularly suitable. The solvent used is the same as that of the A-3a process, and the reaction temperature is preferably -78 to 150 ° C, particularly preferably -30 to 40 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 5 minutes to 24 hours. In the A-3 process, the compound (4) can also be reacted with dimethylamine in the presence of a condensing agent. The condensing agent to be used is not particularly limited as long as it is used for the guanidation reaction, and may be a condensing agent described in R. C. Larock, Comprehensive Organic Transformations. Second Edition, 1999, John Wiley & Sons, Inc. The condensing agent used is, for example, a combination of (i) a phosphate such as diethylphosphonium cyanide and the following base; (ii) 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbamate a carbodiimide such as an imine or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC); a combination of the above carbodiimide and the above base; the above-mentioned carbonized secondary a combination of an amine-67-200815324 type with an N-hydroxy compound such as N-hydroxybutanediamine; or (iii) an imidazole such as N,N'-carbonyldiimidazole (CDI). (A-4 Project) The A-4 project is a project in which the compound (5) obtained in the A-3 project is treated with a halogenated reagent. The halogenated reagent may be a halogen such as chlorine, bromine or iodine; N-chlorobutanediamine, N-bromosuccinimide, N-iodobutylimine, 1,3-dibromo-5, N-halothenamines such as 5-dimethyl allantoin; haloketones such as cycloisopropylidene ester of 5,5-dibromomalonate, hydrazine-haloxime, preferably bismuth-bromobutane Yttrium. In this project, the halogenated test drug should be brominated. In this project, additives may be suitably used as necessary. The additive used is preferably acetic acid or sodium dihydrogen phosphate, preferably acetic acid. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile, a guanamine, water, or a mixture thereof, and particularly preferably a mixture of an ether and water, preferably tetrahydrofuran and water. a mixture. The reaction temperature is preferably -78 to 150 ° C, particularly preferably -30 to 40 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 30 minutes to 24 hours. (A-5 Project) The A-5 project is a project in which the compound (6) obtained in the A-4 project is treated with an azide-based reagent. The azidation reagent used is a metal azide such as lithium azide or sodium azide; ammonium azide such as tetra-n-butylammonium azide; or trimethylsulfonyl azide% sand Sulfhydryl and nitrogen-based, suitable for gasification of metals, the best brine. In this project, the azide-based reagents and additives may be used in combination as necessary. The additives used are preferably inter-phase mobile touches such as tetra-n-butylammonium bromide, benzyltriethyl-68-200815324 ammonium chloride, Aliquat 336 (registered trademark), 15-crown-5-ether, 18-crown-6-ether, etc. Media. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile, a guanamine, an anthraquinone, water, or a mixture thereof, and particularly preferably an anthraquinone or an anthraquinone. Or a mixture of an aromatic hydrocarbon and water, preferably N,N'-dimethyl-propyl propyl urea. The reaction temperature is preferably from 0 to 150 ° C, particularly preferably from 20 to 100 ° C, preferably from 40 to 60 ° C. The reaction time is preferably from 5 minutes to 7 days, particularly preferably from 30 minutes to 96 hours. (A-6 Project) The A-6 project is a project to restore the compound (7) obtained from the A-5 project. This project should be carried out by contact reduction method. The catalyst used in the contact reduction method is, for example, palladium such as palladium-carbon, palladium rhodium, palladium hydroxide or palladium-palladium sulfate; platinum such as platinum oxide or platinum ruthenium; rhodium-alumina, triphenylphosphine-ruthenium chloride, etc. Class; or nickel such as nickel, preferably palladium, preferably palladium-carbon. The hydrogen pressure in the contact reduction method is preferably 1 to 10 atmospheres, particularly preferably 1 atmosphere. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile, an alcohol, a guanamine, water, or a mixture thereof, particularly preferably an ether or an alcohol, preferably ethanol. . In this project, acid may be used as appropriate. The acid used is, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid, preferably hydrochloric acid. The reaction temperature is preferably from -20 to 20 CTC, particularly preferably from 0 to 10 °C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 24 hours. (A-7 Project) • 69- 200815324 The A-7 project is a project in which the compound (8) obtained in the A-6 project is reacted with o-nitrophenylsulfonium chloride in the presence of a base. The base to be used is preferably an alkali metal hydrogencarbonate, an alkali metal hydroxide, a metal alkoxide or an organic amine, particularly preferably an organic amine, preferably triethylamine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile, an alcohol, a guanamine, water, or a mixture thereof, and particularly preferably a mixture of an ether and water, preferably A mixture of tetrahydrofuran and water. The reaction temperature is preferably -78 to 150 ° C, particularly preferably -30 to 40 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 5 minutes to 24 hours. (A-8 Project) The A-8 project is a project in which the compound (9) obtained in the A-7 project is treated with a dehydrating condensing agent. The dehydrating condensing agent used is preferably azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, dimethylformamide of azodicarboxylate or dipiperidinium azodicarboxylate. The acid compound, in combination with a phosphine such as triphenylphosphine or a diphenylphosphine polystyrene carrier, is preferably a combination of diethyl azodicarboxylate and triphenylphosphine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a nitrile or a decylamine, and particularly preferably an aromatic hydrocarbon or an ether, preferably tetrahydrofuran. The reaction temperature is preferably -78 to 150 ° C, particularly preferably 0 to 60 ° C. The reaction time is preferably from 1 minute to 24 hours, particularly preferably from 1 minute to 1 hour. (A-9 Project) The A-9 project is a project to react the compound (1〇) obtained from the A-8 project with the compound (Π). The compound (11) is known or readily available from known compounds, or -70-200815324 is obtained by the B method or the C method. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an acid, an ester, a nitrile or a decylamine, particularly preferably an aromatic hydrocarbon or an acid, preferably toluene. The reaction temperature is preferably from 0 to 200 ° C, particularly preferably from 20 to 15 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 24 hours. (A-10 Project) A_10 works for (A-10a project): the compound obtained by the A-9 project (1 2) in the presence of alkali, treated with deprotection reagent; and (A-10b project) : The compound obtained by the A-10a process is reacted with dibutyl succinate in the presence of a base. (Α-lOa engineering) Deprotection reagents used are, for example, methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, n-butylamine, pyrrole, piperidine, morpholine, pipe trap, N-methylpiperidone. Primary or secondary amines such as trap, hydrazine, N,N-dimethylhydrazine; or sulfur such as methyl mercaptan, ethanethiol, n-propyl mercaptan, n-butyl mercaptan, thiophenol, thioglycolic acid Alcohols, preferably thiols, preferably thiophenol. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile, a decylamine, or a mixture thereof, particularly preferably a nitrile or a guanamine, preferably N,N-dimethyl Guanamine. In this project, organic amines can also be used as solvents. The base used is alkali metal carbonate, alkali metal hydrogencarbonate, alkali metal hydride, alkali metal amine, alkali metal alkoxide, lithium alkylamine, decylamine, alkyl-71-200815324 lithium, or organic amine, particularly suitable Alkali metal carbonate, preferably carbonic acid planing. The reaction temperature is preferably -78 to 200 ° C, particularly preferably 100 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 24 hours. (Α-lOb engineering) The alkali base metal carbonate, alkali metal hydrogencarbonate, alkali metal hydride, metal alkoxide, or organic amine, especially organic amine 'the best solvent for triethylamine hydrazine is suitable for aliphatic Hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, nitriles, guanamines, water; these mixtures, particularly halogenated hydrocarbons, preferably dichloromethane. In this project, organic amines can also be used as solvents. The reaction temperature is preferably -78 to 150 ° C, particularly preferably 0 to 100 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 30 minutes to 48 hours. In this project, the protecting group of the amine group can be protected by a protecting group generally known in the field of organic synthetic chemistry (for example, TW Greene, PG Wuts, Protective Groups in Organic Synthesis, Third Edition, 1 999, John Wiley & Sons, Inc.). Suitable protecting groups are, for example, mercapto, ethenyl, chloroethyl, pentylene, benzinyl, and the like; methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. a carbonyl group; a substituted alkyl group such as methoxymethyl, 2-(trimethyldecyl)ethoxymethyl, benzyloxymethyl, allyl, benzyl; methylsulfonyl, phenylsulfonyl, A sulfonyl group such as toluenesulfonyl, o-nitrophenylsulfonyl, o-, p-dinitrobenzenesulfonyl, and preferably a third butoxycarbonyl group. (Al 1 works) The A-11 project is a project in which the compound (13) obtained from the A-10 project (A) is reacted with the compound of the formula Wnh in the presence of the reagent -72-200815324; and (Al Lb project): The third butoxycarbonyl compound of the compound obtained from Al la engineering is processed based on the removal of acid. The formula ί^ί12 ΝΗ compound is known or readily available from known compounds. The A-1 la engineering can also be carried out according to methods well known in the art of general organic synthetic chemistry (e.g., Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc., ρ.1 973-1 976). (Al la project) The reagents used are, for example, cyano compounds such as sodium cyanide, potassium cyanide or tetra-n-butylammonium cyanide; organoaluminum compounds such as trimethylaluminum; methylmagnesium bromide and methyl iodide A halogenated organomagnesium compound such as magnesium, ethylmagnesium bromide or isopropylmagnesium chloride; an organic acid such as acetic acid; or an organic amphoteric compound such as 2-hydroxypyridine, preferably an organic amphoteric compound, preferably 2-hydroxypyridine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a guanamine or a mixture thereof. The solvent used in this project is particularly suitable for organic amines, preferably triethylamine. This project can also be carried out in the presence of a solvent in the presence of a solvent (13). The reaction temperature is preferably -78 to 200 ° C, particularly preferably 0 to 150 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 30 minutes to 24 hours. (Al lb project) The acid used is hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid, especially hydrochloric acid (especially hydrochloric acid -1,4-dioxane) or Trifluoroacetic acid, preferably trifluoroacetic acid. The solvent to be used is preferably an aliphatic hydrocarbon, a halogenated hydrocarbon, an ester, an alcohol, or an amine, and a halogenated hydrocarbon is the best dichlorocarbyl. The reaction temperature is preferably -78 to 150 ° C, particularly preferably -30 to 80 ° C, more preferably 0 to 50 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 5 minutes to 12 hours. In the A-10b project, when the protecting group of the amine group is protected by a third butoxycarbonyl group, the removal of the protecting groups in the A-lib engineering can generally be carried out according to a method known in the art of organic synthetic chemistry ( For example, TW Greene, P. G. Wuts, δ 蒦 · · 有机 有机 , , 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 The compound (la) of the racemate can be produced. Compound (2) Using the compound of the formula R3R4CCOXa, a compound (I) having R3 and R4 can be produced. The introduction of R5 and R6 into the amine group can generally be carried out according to methods well known in the art of organic synthetic chemistry (e.g., Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc.,). (Method B) The method B is a method for producing a compound (20) containing the compound (11) used in the A_9 project. (B-1 Project) The B-1 project is a project in which the compound (14) is reacted with the compound (15) in the presence of a base. The compounds (丨4) and (15) are known or are readily available from known compounds. The base used is alkali metal carbonate, alkali metal hydrogencarbonate, alkali metal hydride, metal amine, alkali metal alkoxide, lithium alkylamine, decylamine, alkyl-74-200815324 lithium, or organic amine, particularly suitable An alkali metal carbonate, preferably potassium carbonate. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a ketone, an ester, a nitrile or a guanamine, particularly preferably a nitrile or a guanamine, preferably acetonitrile or hydrazine, hydrazine-dimethyl Kealamine. The reaction temperature is preferably -78 to 200 ° C, particularly preferably 0 to 150 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 24 hours. (B-2 Project) The B-2 project is a project in which the compound (16) obtained in the B-1 project is treated with a halogenated reagent. The halogenated reagent used is, for example, a chlorinated reagent or a brominating reagent described in Comprehensive Organic Transformations, Second Edition, 1999, John Wiley & Sons, Inc., p616, preferably N-chlorobutaneimine or N- Bromobutylimine. In this project, a radical initiator may be suitably used as necessary. The free radical starting agent is preferably azobisisobutyronitrile (AIBN) or benzammonium peroxide, preferably azobisisobutyronitrile. The solvent to be used is preferably an aliphatic hydrocarbon, a halogenated hydrocarbon, an ester, or a decylamine, and particularly preferably a halogenated hydrocarbon, preferably carbon tetrachloride. The reaction temperature is preferably from 0 to 150 ° C, particularly preferably from 0 to 100 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 12 hours. (B-3 Project) The B-3 project is a process in which the compound (17) obtained in the B-2 project is treated with an oxidizing agent: This work can also generally be carried out according to methods well known in the art of organic synthetic chemistry (e.g., Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, Inc., ρρ. 1222-1224). -75- 200815324 The oxidizing agent used is preferably a combination of dimethyl hydrazine and the following base. The base to be used is an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydride, an alkali metal alkoxide, or an organic amine, particularly preferably an alkali metal hydrogencarbonate, preferably sodium hydrogencarbonate. The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a ketone, an ester, a nitrile, a guanamine, a flavonoid, water, or a mixture thereof, particularly preferably an anthraquinone, preferably a dimethyl hydrazine. . The reaction temperature is preferably from 0 to 200 ° C, particularly preferably from 20 to 150 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 5 minutes to 24 hours. (B-4 Project) The B-4 project is a project in which the compound (18) obtained in the B-3 project is reacted with the compound (19) in the presence of a reducing agent. This work can also generally be carried out according to methods well known in the art of organic synthetic chemistry (e.g., Comprehensive Organic Transformations, Second Edition, 1 999, John Wiley & Sons, Inc., pp. 835-846). The reducing agent used is, for example, a borane-tetrahydrofuran complex, a borane-dimethyl hydrazine complex, a borane-dimethylamine complex, a borane-pyridine complex, sodium borohydride, and cyanoborohydride. a boron hydride compound such as sodium, cyanoborohydride tetra-n-butylammonium or sodium triethoxy borohydride; an aluminum hydride compound such as lithium aluminum hydride, aluminum hydride or diisobutylaluminum hydride; or hydrogen, preferably boron hydride A compound, preferably sodium cyanoborohydride or sodium triethoxysulfonate. In this project, acid such as hydrochloric acid, formic acid, acetic acid or trifluoroacetic acid (preferably acetic acid) should be used in combination with the above reducing agent. The solvent used is preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, nitriles, alcohols, guanamines, or water, especially halogenated hydrocarbons or alcohols -76-200815324, most Good dichloromethane or methanol. The reaction temperature is preferably -78 to 150 ° C, particularly preferably to 10 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 24 hours. (Method C) The method C is a method for producing a compound (25) which is a compound (11) used in the A-9 project. (C-1 Project) The C-1 project is a project in which the compound (21) is reacted with the compound (22) in the presence of a base. The compounds (21) and (22) are known or readily available from known compounds. The base used is alkali metal carbonate, alkali metal hydrogencarbonate, alkali metal hydride, alkali metal amine, alkali metal alkoxide, lithium alkylamine, decylamine, alkyl lithium, or organic amine, especially alkali metal carbonate Or an alkali metal hydride 'preferably potassium carbonate or sodium hydride. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a ketone, an ester, a nitrile or a guanamine, and particularly preferably an amide amine, preferably N,N-dimethylformamide. The reaction temperature is preferably -78 to 200 ° C, particularly preferably 0 to 150 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 15 minutes to 24 hours. (C-2 Project) The C-2 project is a project in which the compound (23) obtained in the C-2 project is treated with an oxidizing agent in the presence of a base. This project can also be carried out in accordance with conventional methods in the field of organic synthetic chemistry (eg Comprehensive Organic)

Transformations, Second Edition, 1 999, John Wiley & Sons, Inc., -77-200815324 p.1234-1249). The oxidizing agent used is preferably a combination of dimethyl hydrazine and the following reagents. The reagents used are acetic anhydride, trifluoroacetic anhydride and the like; acid halides such as grass chloro, benzene sulfonium chloride and p-toluene sulfonium chloride; sulfur trioxide-pyridine complex; phosphorus pentoxide; A carbodiimide such as propylcarbodiimide or dicyclohexylcarbodiimide, particularly preferably sulfur trioxide-pyridine complex or phosphorus pentoxide, preferably sulfur trioxide-pyridinium complex. The base to be used is preferably an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal hydride, an alkali metal alkoxide or an organic amine, particularly preferably an organic amine, preferably triethylamine. The solvent to be used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, a ketone, an ester, a nitrile, a guanamine, a sulphite, or a mixture thereof, especially a sulphate, preferably dimethyl hydrazine. . The reaction temperature is preferably -78 to 150 ° C, particularly preferably -78 to 60 ° C. The reaction time is preferably from 5 minutes to 96 hours, particularly preferably from 5 minutes to 24 hours. (C-3 Project) The C-3 project is a project in which the compound (24) obtained in the C-2 project is reacted with the compound (19) in the presence of a reducing agent. The C-3 project can be implemented in the same way as the B-4 project. When the compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a medicine, it may be administered as it is, or may be mixed with a suitable pharmacologically acceptable excipient, diluent or the like to prepare a tablet or a capsule. A preparation such as a granule, a granule, a powder or a syrup may be administered orally or as a preparation such as an injection or a sitting agent, and not administered orally (suitable for oral administration). -78- 200815324 These preparations can be produced by a known method using an excipient, a binder, a breaker, a slip agent, an emulsifier, a stabilizer, a flavoring agent, a diluent, a solvent for an injection, and the like. The excipient is, for example, an organic excipient or an inorganic excipient. The organic excipient is a sugar derivative such as lactose, white sugar, glucose, mannitol or sorbitol; a starch derivative such as corn starch, potato starch, α-starch, dextrin or carboxymethyl starch; crystalline cellulose , low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, internal croscarmellose sodium and other cellulose derivatives; gum arabic; Glucose; or polytriglucose. The inorganic excipient is, for example, a phthalic acid derivative such as light phthalic anhydride, synthetic aluminum ruthenate, calcium citrate or magnesium metasilicate aluminate: a phosphate such as calcium phosphate; a carbonate such as calcium carbonate; or calcium sulfate. Sulfate and the like. The binding agent is, for example, the above excipient; gelatin; polyvinylpyrrolidone; or polyethylene glycol or the like. The breaker is, for example, the above-mentioned excipient; chemically modified starch or cellulose derivative such as crotonin sodium or sodium carboxymethyl starch; or crosslinked polyvinylpyrrolidone. The slip agent is, for example, talc; stearic acid; metal stearate such as calcium stearate or magnesium stearate; colloidal vermiculite; anthraquinones such as bee stings and cetyls; boric acid; ethylene glycol; D, L - leucine; carboxylic acid such as fumaric acid or adipic acid; sodium carboxylate such as sodium benzoate; sulfate such as sodium sulfate; dodecyl sulfate such as sodium dodecyl sulfate or dodecyl magnesium sulfate; And tannic acid such as citric acid hydrate; or a starch derivative or the like in the above-mentioned excipient. -79- 200815324 Emulsifiers are colloidal clays such as bentonite, magnesium aluminum silicate, etc.; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium dodecyl sulfate and stearic acid; A cationic surfactant such as bismuth gas; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester. The tranquilizer is, for example, a paraben such as methylparaben or propylparaben; an alcohol such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; an alkyl chloride chloride; a benzene, a discretion, etc. Variety; thiourea; dehydroacetic acid; or sorbic acid. The flavoring agent is, for example, a sweetener, a sour, or a scent commonly used. The diluent is, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid ester or the like. The solvent for the injection is, for example, water, ethanol, or glycerin or the like. The administration amount of the compound of the formula (I) or the pharmacologically acceptable salt thereof as an active ingredient of the present invention varies depending on the symptoms, age, and the like of the patient, and when administered orally, the lower limit of each dose is 0.02 mg/kg (preferably 0.1 mg/kg). , the upper limit l 〇〇 mg / kg (preferably l 〇 mg / kg), non-oral injection, the lower limit of each 0.002mg / kg (Yi 〇. 〇 img / kg), the upper limit of 10mg / kg (preferably lmg / kg The effect of the invention can be applied to the adult 1 to 6 times a day according to the symptoms. The compound of the formula (I) of the present invention or the pharmacologically acceptable salt thereof is inhibited by renin, solubility, cell membrane permeability, oral absorption, Blood concentration, metabolic stability, tissue migration, bioavailability, in vitro activity, in vivo activity, rapid discovery of drug efficacy, persistence of pharmacodynamics, physical stability, drug phase-80-200815324 interaction, toxicity, etc. The point has excellent properties and is useful as a medicine [especially for the treatment or prevention of hypertension (suitable for treatment)]. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below with reference to examples, test examples and preparation examples, but the scope of the invention is not limited thereto. The compound numbers exemplified in the examples show the structures corresponding to the free bodies. For example, the corresponding free form in Example 1 is a compound of the compound number: 1-365, and the compound produced in Example 1 is a fumarate of the compound of the compound number: 1-365. EXAMPLES (Example 1) (2S,4S,5S)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy 2-Isopropylhexanoic acid (2-aminocarbamimido-2-methylpropyl) decylamine fumarate (exemplified compound number: 1-365) (la) (1R)-1-[(benzyl Oxy)methyl]prop-2-en-1yl 3-methylbutyrate (2R)-l-(benzyloxy)but-3-en-2-ol obtained from Reference Example (Id) 24.29 a solution of g (136 mmol), 28.5 ml of triethylamine (205 mmol) and 1.65 g (13.6 mmol) of N,N-dimethylaminopyridine in dichloromethane (250 ml) with isobutylphosphonium chloride 19.9 under ice cooling. A solution of ml (163 mmol) in dichloromethane (20 mL). The reaction mixture was added with hydrazine. 75 ml (42 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) After filtration, the solvent was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssss %). Yellow liquid. 4 NMR spectrum (CDC13, 400MHz), 5 ·· 7.36-7.27 (m, 5H), 5.84 (ddd, 1H, J = 17.2 Hz, 10.6 Hz, 5.9 Hz), 5.54-5.49 ( 1 H, m), 5.33 (dt, 1H, J = 17.2 Hz, 1.2 Hz), 5.24 (dt, 1H, J = 10.6

Hz, 1.2 Hz), 4.58 (d, 1H, J = 12.5 Hz), 4.54 (d, 1H, J = 12.5 Hz), 3.58 (dd, 1H, J = 11.0 Hz, 5.9 Hz), 3.56 (dd, 1H) , J = 11.0 Hz, 4.7 Hz), 2.23 (d, 2H, J = 6.6 Hz), 2.17-2.07 (m, 1H), 0.96 (d, 6H, J = 6.6 Hz). Mass spectrum (FAB + ), m/z: 263 ( (M + H) + ). (lb) (2S,4E)-6-(Benzyloxy)·2_isopropylhex-4-enoic acid A solution of diisopropylamine (23 ml, 163 mmol) in THF (265 mL) 94 ml (148 mmol) of n-hexane (1.57 mol/l) solution of n-butyllithium was added in 45 minutes, and the mixture was stirred at the same temperature for 20 minutes to prepare a tetrahydrofuran solution of lithium diisopropylamide. (1R)-Μ(benzyloxy)methyl]prop-2-en-1-yl 3-methylbutyrate 34.95 obtained by adding 40 ml of the solution (la) in a dry ice-acetone bath. A solution of g (133 mmol) in tetrahydrofuran (70 ml) was stirred 20 min. Next to the reaction mixture, 3 9 ml (3 07 mmol) of trimethylsulfonyl chloride was added in 20 portions, and the mixture was stirred at room temperature for 20 minutes, and then stirred at room temperature for 3 hours. After cooling in an ice bath, 27 ml (667 mmol) of methanol was added to the reaction mixture so that the internal temperature did not exceed 20 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc EtOAc EtOAc EtOAc. The whole aqueous layer was combined with a solution of 78 ml of 6M hydrochloric acid, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the crude title compound 1 9.0 3 g. The obtained (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid is converted into the corresponding methyl ester body by treatment with trimethyldecyl diazomethane in methanol. The optical purity was determined by an optically active HPLC column [ChiralCel® DH (0.46 cm x 25 cm), dissolution solvent: n-hexane/2-propanol = 90/10, flow rate: 0.5 ml/min]. The retention time of the target 2S body was 14.7 minutes, the retention time of the corresponding isomer 2R body was 16.2 minutes, and the optical purity was 9 1 % e e 〇 yellow liquid. Optical rotation, [a ] D = - 9.9 ° (c = 1.07, CHCh). 4 NMR spectrum (〇〇<: 13,400 to !^), (5:7.3 8-7.27 (111,511), 5.72- 5.62 (m, 2H), 4.47 (s, 2H), 3.99-3.91 (m, 2H), 2.40-2.20 (m, 3H), 1.96-1.8 8 (m, 1H), 0.98 (d, 3H, J = 6.6 Hz), 0.97 (d, 3H, J = 6_6 Hz). (lc) ( 2S,4E)-6-(Benzyloxy)-2-isopropylhex-4-enoic acid dimethyl decylamine (2S,4E)-6-(benzyloxy)- a solution of 19.02 g (72.5 mmol) of 2-isopropylhex-4-enoic acid in dichloromethane (180 ml), adding 7.75 ml (87 mmol) and N,N-dimethylformamide 0.11 at room temperature. Ml (1.4 mmol), stirred at the same temperature for 1 hour to prepare a solution of (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enyl chloride in dichloromethane. 50% A solution of 7 6 ml of a solution of methylamine (7 25 mmol) in tetrahydrofuran (180 ml) and a solvent mixture of tert-butanol-83-200815324, and the solution of the above-mentioned chlorohydrin in dichloromethane was stirred for 1 hour under ice cooling for 20 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure and diluted with water (15 ml) to about 1/5. After extraction with ethyl acetate, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssss 5.86-5.60 (m, 2H), 4.47 (s, 2H), 3.97-3.91 (m, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.51-2.47 (m, 1H), 2.43- 2.3 8 (m, 1H), 2.29-2.25 (m, 1H), 1.94- 1.87 (m, 1H), 0.95 (d, 3H, J = 6.9 Hz), 0.90 (d, 3H, J = 6.9 Hz). (Id) (3S,5S)-5-[(lR)-2-benzyloxy-1-bromoethyl]-3-isopropyldihydrofuran-2-one obtained from Example (lc) (2S , 4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid dimethyl decylamine 21.20 g (72.5 mmol) and acetic acid 8.3 ml (145 mmol) in tetrahydrofuran (290 ml) and water (145 ml) The mixed solvent solution was added with 25.81 g (145 mmol) of N-bromosuccinimide under ice cooling, and stirred at the same temperature for 3 hours. 100 ml of saturated sodium hydrogencarbonate water and 100 ml of a 1.5 M aqueous sodium sulfite solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to dryness. After filtration, the solvent was evaporated under reduced pressure. EtOAcjjjjjjjjjjjj ). Colorless liquid. -84- 200815324 4 NMR spectrum (CDCh, 500 MHz), <5: 7.38-7.30 (m, 5H), 4·75_ 4.71 (m, 1H), 4.61 (d, 1H, J = 12.2 Hz), 4.56 ( d, 1H, J = 12.2 Hz), 4.22 (q, 1H, J = 5.9 Hz), 3.84 (dd, 1H, J =: l〇.7

Hz, 5.4 Hz), 3.78 (dd, 1H, J = 10.7 Hz, 6.4 Hz), 2.67-2.63 (m, 1H), 2.27-2.22 (m, 1H), 2.20-2.11 (m, 2H), 1.02 (d, 3H, J two 6.8 Hz), 0.94 (d, 3H, J = 6.8 Hz). (16) (33,53)-5-[(3)-1-azido-2-benzyloxyethyl]-3-isopropyldihydrofuran-2-one obtained in Example (Id) 3S,5S)-5-[(lR)-2-benzyloxy-1-bromoethyl]-3-isopropyldihydrofuran-2-one 22.3 3g (65.4mmol) A solution of propyl urea (130 ml) was added, and 5.10 g (78.5 mm 〇l) of sodium azide was added at room temperature, and stirred at 40 ° C for 3 days. After the reaction mixture was cooled, it was poured into ice water and extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless liquid.卞 NMR spectrum (CDC13, 500MHz), 5 ·· 7.38-7.29 (m, 5H), 4.6 b 4.53 (m, 3H), 3.79-3.73 (m, 2H), 3.66-3.63 (m, 1H), 2.75- 2.70 (m, 1H), 2.20-2.10 (m, 3H), 1.02 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 6.8 Hz). (If) N-{(S)-2-hydroxy- l-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl b-nitrobenzenesulfonamide Example (le) obtained (33,53)-54(3)-1-azido-2-benzyloxyethyl]-3-85-200815324 isopropyldihydrofuran-2-one 10.12 g ( 33.5 mmol), 4N hydrochloric acid-dioxane solution 16.7 ml (66.8 mmol) and 10% palladium on carbon (50% aqueous) 3.5 7 g of ethanol (170 ml) suspension, stirred under a hydrogen atmosphere at room temperature for 6 hours . After the hydrogen in the reaction vessel was replaced with nitrogen, the reaction mixture was diluted with 170 ml of ethanol, and the palladium carbon was filtered and washed with ethanol. The solvent was distilled off under reduced pressure to give (3S,5S)-5-[(S)-l-amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2-one hydrochloride Salt 8.50g. (3S,5S)-5-[(S)-l-Amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2-one hydrochloride 8.50 g (33.5 mmol) A mixed solvent solution of tetrahydrofuran (170 ml) and water (17 ml) was added to a mixture of 13 ml (101 mmol) of triethylamine and 11.12 g (50.1 mmol) of 0-nitrobenzenesulfonyl chloride at room temperature, and stirred at the same temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified eluting eluted eluted eluted eluted eluted eluted eluted eluted eluted g (2 works total yield: 70%). The obtained N-{(S)-2.hydroxy-l-[(2S,4S)-4.isopropyl-5-oxytetrahydrofuran-2-yl]ethyl b-2-nitrobenzenesulfonamide was used for analysis. Optically active η PLC column [Chiralpak AD-H (0.46 cm x 25 cm), manufactured by Daisy, solvent: n-hexane/ethanol = 30/70, flow rate: i. 〇mi/min]] determines the optical purity. The retention time of the [[3), (2 3, 43)] body is 5.7, and the retention time of the [(R), (2R, 4R)] body of the corresponding isomer is 9.0, and the optical purity is 90% ee -86- 200815324 Colorless solid. Optical rotation, [a ] D = + 26.9 ° (c = 1.00, Me 〇 H).屮 NMR spectrum (匚〇 (: 13, 50 (^), 5: 8.15-8.11 (111, 111), 7.92-7.88 (m, 1H), 7.77-7.74 (m, 2H), 5.85 (br d, 1H, J = 8.3 Hz), 4.64-4.61 (m, 1H), 3.71-3.62 (m, 3H), 2.69 (ddd, 1H, J = 10.3 Hz, 6.8 Hz, 5.4 Hz), 2.41 (ddd, 1H, J = 13.7 Hz, 10.7 Hz, 5.4 Hz), 2.20-2.10 (m, 2H), 1.99 (t, 1H, J = 5.4 Hz), 1.00 (d, 3H, J = 6.8 Hz), 0.93 (d, 3H) , J = 6.8 Hz) Mass Spectrum (FAB + ), m/z: 37 3 ((M + H) + ) (lg) (3S,5S)-3-isopropyl-5-[(S)- L-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2-one The N-{(S)-2-hydroxy-l-[(2S) obtained in Example (If) 4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl 2-nitrobenzenesulfonamide 4.00 g (10. 7 mmol) and triphenylphosphine 3.38 g (12.9 mmol) of tetrahydrofuran (l 〇〇ml) solution, 5.9 ml (12.9 mmol) of a solution of diethyl azodicarboxylate in toluene (40%) was added in 10 portions under ice cooling, and the mixture was stirred at room temperature for 10 minutes. It was purified by silica gel column chromatography (solvent solvent, toluene/acetone = 5/1) to give the title compound 3.40 g (yield: 89%). Colorless liquid. NMR spectrum (CDC13, 400 MHz ), 5 : 8.14 (dd, 1H, J two 7.4 Hz,

1.5 Hz), 7.8 3-7.73 (m, 3H), 4.74-4.70 (m, 1H), 3.26-3.23 (m, 1H), 2.83 (d, 1H, J = 7.0 Hz), 2.78 (dt, 1H, J = 9.8 Hz, 4.7 Hz), 2.65 (d, 1H, J =: 4.7 Hz), 2.41-2.35 (m, 1H), 2.29 (dt, 1H, J = 12.9 Hz, 9.4 Hz), 2.18-2.10 ( m, 1H), 1.00 (d, 3H, J -87- 200815324 = 6.6 Hz), 0.90 (d, 3H, J = 7.0 Hz). Mass spectrum (FAB + ), m/z: 3 5 5 ((M + H) + ). (lh) 1-Chloro-2-(3-methoxypropoxy)-4-methylbenzene in 1-chloro-2-hydroxy-4-methylbenzene 6.10g (43mmol) Ν, Ν-二To a solution of methylformamide (50 ml), 6.0 g (39.2 mmol) of 3-methoxypropyl bromide and 17 g (120 mmol) of potassium carbonate were added, and the mixture was stirred at 60 ° C for 2 hours. After the reaction mixture was cooled, water was added and extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals crystals Colorless liquid. 4 NMR spectra (CDCh, 400 MHz), 5: 7.20 (d, 1H, J = 7.8 Hz), 6.75 (d, 1H, J = 1.5 Hz), 6.69 (br d, 1H, J = 7.8 Hz), 4.10 ( t, 2H, J = 6.3 Hz), 3.60 (t, 2H, J = 6.3 Hz), 3.36 (s, 3H), 2.31 (s, 3H), 2.12-2.06 (m, 2H). (li) 4-Bromomethyl-1·chloro-2-(3-methoxypropoxy)benzene obtained in Example (1h) 1-chloro-2-(3-methoxypropoxy)- 4-methylbenzene 10_19 (47.5 mmol) in a solution of carbon tetrachloride (100 ml), force □ N-bromosuccinimide 10.13 g (57.0 mmol) and azobis(isobutyronitrile) 〇.74 g (4.74 Methyl), stirred at 80 ° C for 20 minutes. After the reaction mixture was allowed to cool, the solid was filtered, and the filtrate was evaporated to dryness crystals crystals crystals crystals 75%). Colorless liquid.沱 NMR spectrum (CDCh, 400 MHz), (5: 7.31 (d, 1H, J = 8.2 Hz), -88-200815324 6.97 (d, 1H, J = 2.0 Hz), 6.91 (dd, 1H, J = 8.2 Hz , 2.0 Hz), 4.41 (s, 2H), 4.14 (t, 2H, J = 6.3 Hz), 3.60 (t, 2H, J = 6.3 Hz), 3_37 (s, 3H), 2.14-2.07 (m, 2H (lj) 4-Chloro-3-(3-methoxypropoxy)benzaldehyde 4-bromomethyl-1-chloro-2-(3-methoxypropoxyl) obtained in Example (li) a solution of 10.39 g (35.4 mmol) of dimethyl hydrazine (175 ml) of benzene, adding 29.7 2 g (3 5 4 mm 〇l) of sodium hydrogencarbonate, and stirring for 20 minutes at 100 Torr. After cooling the reaction mixture, add cold water to diethyl ether. After the extraction, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane/ethyl acetate = 5/1) The title compound was obtained (yield: 56%) (yield: 56%). colourless solid. 4 NMR spectrum (CDC13, 400 MHz), 5: 9.94 (s, 1H), 7.54 (d, 1H, J = 7.8 Hz), 7.45 ( d, 1H, J = 2.0 Hz), 7.40 (dd, 1H, J = 7.8 Hz, 2.0 Hz), 4.21 (t, 2H, J = 6.3 Hz), 3.61 (t, 2H, J = 6.3 Hz), 3.37 (s, 3H), 2.16-2.10 (m, 2 H) (lk) [4-Chloro-3-(3-methoxypropoxy)-benzyl] isopropylamine 4-chloro-3-(3-methoxypropoxyl) obtained in Example (1j) a solution of 0.51 g (2.2 mmol) of benzaldehyde, 0.57 ml (6.7 mmol) of isopropylamine and 0.13 ml (2.2 mmol) of acetic acid in dichloromethane (22 ml), and added sodium triethoxysulfonate hydride 0.94 g (4.4 mm) ο 1), stirring at room temperature for 3 hours. The reaction mixture was added with saturated aqueous sodium hydrogen sulfate and extracted with ethyl acetate. [Dissolved solvent: (i) n-hexane / ethyl acetate / triethylamine = 1 / 1 / 0 ~ 〇 / 1 〇〇 / 1 ; (Π) bis-89 - 200815324 methyl chloride / methanol / triethylamine = 100 /10/1] Purified to give the title compound 〇.29 g (yield: 49%). 4 NMR spectrum (CDCh, 400 MHz), 5: 7.28 (d, 1H, J = 8.2 Hz), 6.94 (d, 1H, J = 2.0 Hz), 6.83 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 4.14 (t, 2H, J 2 6.3 Hz), 3.74 (s, 2H), 3.60 (t, 2H, J 2 6.3 Hz), 3.36 (s, 3H), 2.89-2.79 (m, 1H), 2.14-2.05 (m, 2H), 1.09 (d, 6H, J = 6_3 Hz). (11) 1{(3)-2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}_ l-[(2S,4S)-4-isopropyl (5S,5S)-3-isopropyl-5-[(S)-l obtained by the example (gg), 5--5-hydroxytetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide -(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2-one 223 mg (0.63 mmol) and the compound (lk) obtained [4-chloro-3-(3-methyl) A solution of oxypropoxy)benzyl]isopropylamine 23 911^ (0.88111111〇1) in toluene (6.51111) was stirred at 110 ° C for 1 hour. After the reaction mixture was cooled, the residue was evaporated. mjjjjlililililililililililililililili 4 NMR spectrum (CDCh, 400 MHz), 5: 7.97-7.94 (m, 1H), 7.88- 7.85 (m, 1H), 7.78-7.71 (m, 2H), 7.27 (d, 1H, J = 8.2 Hz), 6.87 (d, 1H, J = 1.5 Hz), 6.74 (dd, 1H, J = 8.2 Hz, 1.5 Hz), 5.40 (br d, 1H, J = 7.8 Hz), 4.77-4.73 (m, 1H), 4.17 -4.08 (m, 2H), 3.61 (t, 2H, J = 5.9 Hz), 3.54 (d, 1H, J = 14.1 Hz), -90- 200815324 3.36 (s, 3H), 3.32 (d, 1H, J = 14.1 Hz), 2.85 -2.79 (m, 1H), 2.72 (dd, 1H, J = 13.7 Hz, 9.8 Hz), 2.53-2.47 (m, 1H), 2.26 (dd, 1H, J = 13.7 Hz, 5.9 Hz), 2.14-1.89 (m, 6H), 0.96-0.88 (m, 12H). (lm) (2S,4S,5S)-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy-2-isopropyl- 5 -(2-Nitrophenylsulfonylamino)hexanoic acid (2-aminoformamido-2-methylpropyl)guanamine obtained in Example (11) ^(3)-2-{[4- Chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-l-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl b 2 - nitrobenzenesulfonamide 371 mg (0.59 mmol) of a solution of triethylamine (6 ml), and the obtained 2-amino-2,2-di(methyl)propanamide 206 mg (1 - 78 mmol) and 2 - After stirring 56 mg (0.59 mmol), the mixture was stirred at 85 ° C for 30 minutes. After the reaction mixture was cooled, it was concentrated under reduced pressure and stirred at &lt After the reaction mixture was cooled, the title compound was obtained (yield: 3%) (yield: 3%). Yellow liquid. ^ NMR spectrum (CDC13, 400MHz), δ: 7.95 -7.93 (m, 1H), 7.81-7.79 (m, 1H), 7.75 - 7.67 (m, 2H), 7.29 (d, 1H, J = 8.2 Hz), 6.90 (d, 1H, J = 1.5 Hz), 6.80 (dd, 1H, J = 8.2 Hz, 1.5 Hz), 6.48 (br t, 1H, J = 5.9 Hz), 6.07 (br s, 2H), 5.56 ( Br s, 1H), 4.88 (br s, 1H), 4.20-4.11 (m, 2H), 3.78 (br d, 1H, J = 11.0 Hz), 3.71 (d, 1H, J = 13.7 Hz), 3.65- 3.60 (m, 2H), 3.45 (d, 1H, J = 14.1 Hz), 3.40-3.31 (m, 4H), 3.25 (dd, 1H, J = 13.7 -91 - 200815324

Hz, 5.9 Hz), 3.11-3.08 (m, 1H), 3.01-2.91 (m, 1H), 2.83 (dd, 1H, J = 13.7 Hz, 7.8 Hz), 2.56 (dd, 1H, J = 13.7 Hz, 4.3 Hz), 2.14-2.08 (m, 2H), 1.94- 1.89 (m, 1H), 1.65- 1.56 (m, 1H), 1.29- 1.22 (m, 1H), 1.19 (s, 6H), 1.06-0.97 (m, 7H), 0·76 (d, 3H, J = 6.7 Hz), 0.63 (d, 3H, J = 6.7 Hz). (In) (2S,4S,5S)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamine-4-hydroxy-2-iso Propylhexanoic acid (2-aminoformamido-2-methylpropyl) decylamine fumarate (2S, 4S, 5S)-6-{[4-chloro-3- (3-methoxypropoxy)benzyl]isopropylamine-4-hydroxy-2-isopropyl-5-(2-nitrophenylsulfonylamino)hexanoic acid (2-aminocarbazinyl- Mixture of 364 mg (0.49 mmol) of 2-methylpropyl)guanamine and 192 mg (0.59 mmol) of N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature plus thiophenol 0.1 0 ml (0.98 mmol), stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform / isopropyl alcohol (V/V: 3/1), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent, methylene chloride/methanol/triethylamine = 20/1/0 to 10/1/0 to 100/10/1). (23,43,53)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy-2-isopropyl A solution of 225 mg (0.40 mmol) of hexanoic acid (2-aminoformamido-2-methylpropyl) decylamine in methanol (4 ml) was added to a solution of 47 mg (0.40 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), 5: 7.32 (d, 1H, J = 8.2 Hz), -92- 200815324 7.04 (d, 1H, J = 1.5 Hz), 6.95 (dd, 1H, J = 8.2 Hz, 1.5 Hz), 6.68 (s, 2H), 4.15 (t, 2H, J = 6.3 Hz), 3.65 (br s, 2H), 3.62 (t, 2H, J = 6.3 Hz), 3.42-3.29 (m , 6H), 3.03 - 2.95 (m, 1H), 2.71-2.57 (m, 3H), 2.29-2.23 (m, 1H), 2.09-2.03 (m, 2H), 1.80 (dd, 1H, J = 13.7 Hz , 7.0 Hz), 1.72- 1.65 (m, 1H), 1.54-1.47 (m, 1H), 1.20 (s, 3H), 1.18 (s, 3H), 1.12 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J = 6.7 Hz), 0.95 (d, 3H, J - 6.7 Hz), 0.94 (d, 3H, J = 6.7 Hz) o Mass spectrum (FAB + ), m/z: 556 ((M + H) + ). (Example 2) (2 3,43,53)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy- 2-(Isopropylhexanoic acid) decyl fumarate (exemplified compound number: 1-124) (2 a) {(S)-2-{[4-chloro 3-(3-methoxypropoxy)benzyl]isopropylamino}-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethylindolecarboxylic acid The third butyl ester obtained the 1{(3)-2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-l-[(2S) obtained in Example (11) , 4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide 5.1 0g (8.1 4mmol) and carbonic acid planing 3.20g (9.7 mmol) of N,N A mixture of dimethylformamide (20 ml) was added with thiophenol 2.5 ml (24 mmol) at room temperature under nitrogen atmosphere and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted elution (3S,5S)-[(S)-1-Amino-2-{[4-chloro-3-(3-methoxy-93-200815324-propoxy)benzyl]isopropylamine a solution of 1, 3-isopropyldihydrofuran-2-one in 1,2-dichloroethane (20 ml), adding 2.2 ml (16.2 mmol) of triethylamine and 2.6 g of dibutyl butyl dicarbonate ( 12.2 mmol), stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj屮 NMR spectrum (CDCls, 400 MHz), 5 ·· 7.26 (d, 1H, J = 8.2 Hz), 6.89 (br s, 1H), 6.84 (dd, 1H, J = 8.2 Hz, 1.5 Hz), 4.72 (br t, 1H, J = 7.4 Hz), 4.41 (br d, 1H, J = 9.4 Hz), 4.11 (t, 2H, J = 6.3 Hz), 3.7 5- 3.6 8 (m, 1H), 3.65-3.59 ( m, 3H), 3.53 (br d, 1H, J = 14.5 Hz), 3.36 (s, 3H), 2.93-2.8 3 (m, 1H), 2.64-2.45 (m, 3H), 2.21-2.06 (m, 4H), 2.02- 1.95 (m, 1H), 1.43 (s, 9H), 1.00-0.99 (m, 9H), 0.92 (d, 3H, J = 6.7 Hz). (2b) {(13,23,43)-1-(丨[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylaminomethyl)-2-hydroxy-5- Tert-butyl methyl-4-[(S)-2-methylbutylaminemethanyl]hexyl hydrazide carboxylic acid obtained in Example (2a) {(S)-2-{[4-chloro-3- (3-methoxypropoxy)benzyl]isopropylamino}-1-[(23,43)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carboxylic acid tertidine A solution of 220 mg (0.41 mmol) of triethylamine (2 ml), (3)-2-methylbutylamine 0.141111 (1.2111111〇1) and 2-hydroxypyridine 391112 (0.41 mmol) on an oil bath, 80° C is stirred for 15 minutes. After the reaction mixture was cooled, it was concentrated under reduced pressure and stirred at &lt After the reaction mixture was cooled, 0.48 ml (4.1 mmol) of (S)-2-methylbutylamine was added, and the mixture was further stirred at 80 ° C for 4 hours -94 - 200815324. After the reaction mixture was cooled, the title compound was obtained (yield: 7 8%). Yellow solid. 4 NMR spectrum (CDC13, 400MHz), (5: 7.27 (d, 1H, J = 8.2 Hz), 6.87 (d, 1H, J = 2.0 Hz), 6.82 (dd, 1H, J = 8.2 Hz, 2.0 Hz) , 5.75 (br t,1H,J = 5·9 Hz), 4.92 (br s,1H), 4.12 (t,2H,J = 6.3 Hz), 3.73-3.69 (m, 1H), 3.62 (t, 2H , J = 6.3 Hz), 3.54 (br s, 2H), 3.51 (br s, 1H), 3.37 (s, 3H), 3.20-3.14 (m, 1H), 3.08-3.02 (m, 1H), 2.96- 2.90 (m, 1H), 2.68 (dd, 1H, J = 13.3 Hz, 6.3 Hz), 2.56 (dd, 1H, J = 13.3 Hz, 5.1 Hz), 2.13-2.07 (m, 2H), 2.04- 1.99 ( m, 1H), 1.89- 1.80 (m, 1H), 1.64-1.50 (m, 2H), 1.43 (s, 9H), 1.41-1.34 (m, 1H), 1.20- 1.09 (m, 1H), 1.01 ( d, 3H, J = 6.3Hz), 1.00 (d, 3H, J = 6.3Hz), 0.92-0.88 (m, 12H). (2 c) (2S,4S,5S)-5-Amino- 6- {[4-Chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy-2-isopropylhexanoic acid [(S)-2-methylbutyl]phosphonium Amine 1/2 fumarate {{13,23,43)-1-({[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamine obtained in Example (213) Tertylmethyl)-2-hydroxy-5-methyl-4-[(S)-2-methylbutylamine-mercapto]hexyl}carboxylic acid tert-butyl ester 200 mg (0.3 2 mmol), After adding a solution of 4N hydrochloric acid-dioxane (10 ml) (40 mL), EtOAc. After filtration, the solvent was evaporated under reduced pressure, and residue residue -95-200815324 was chromatographed on a silica gel column (solvent solvent: dichloromethane/methanol/triethylamine = 19/1/0 to 95/5/1 to 90/10/) 1) Refining. Obtained (2S,4S,5S)-5-amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy- a solution of 136 mg (0.26 mmol) of 2-isopropylhexanoic acid [(S)-2-methylbutyl] decylamine in methanol (4 ml), with fusic acid (14.9 mg (0.13 mmol)) . The reaction mixture was concentrated under reduced pressure. hexane was evaporated. Colorless solid. 4 NMR spectrum (CD3〇D, 400ΜΗζ), ά: 7.98 ( br s,1H), 7.32 (d, 1H, J = 8.2 Hz), 7.04 (d, 1H, J = 2.0 Hz), 6.95 (dd, 1H , J = 8.2 Hz, 2.0 Hz), 6.66 (s, 1H), 4.15 (t, 2H, J = 6.3 Hz), 3.64 (br s, 2H), 3.62 (t, 2H, J = 6.3 Hz), 3.43 -3.3 8 (m, 1H), 3.35 (s, 3H), 3.13-3.07 (m, 1H), 3.02-2.95 (m, 2H), 2.73-2.57 (m, 3H), 2.29-2.24 (m, 1H ), 2.09-2.03 (m, 2H), 1.83- 1.67 (m, 2H), 1.60-1.3 8 (m, 3H), 1.19-1.06 (m, 7H), 0.96-0.89 (m, 12H). Mass spectrum (FAB + ), m/z: 528 ((M + H) + ). (Example 3) (23,43,53)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy- 2-isopropylhexanoic acid cyclopentylguanamine fumarate (exemplified compound number: 1-503) (3 a) [(lS, 2S, 4S)-l-({[4-chloro-3-() 3-methoxypropoxy)benzyl]isopropylamino}methyl)-4-cyclopentylaminemethylhydrazine-2-hydroxy-5-methylhexyl]carboxylic acid tert-butyl ester-96- 200815324 {(S)-2-{[4-Chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-l-[(2S,4S)-4- obtained in Example (2a) Isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carboxylic acid tert-butyl ester 136 mg (0.25 mmol), cyclopentylamine oxime. 5 ml (5.1 mmol) and 2-meridylpyrene ratio B 24 mg ( 0.25 mmol), stirred on an oil bath at 80 ° C for 16 hours. After the reaction mixture was cooled, the residue was evaporated. mjjjjlilililililililililililililililililililili Orange solid.沱 NMR spectrum (CDCl3, 400MHz), (5: 7.27 (d, 1H, J = 7.8 Hz), 6.87 (br s, 1H), 6.82 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 5.68 (br d, 1H, J = 7.3 Hz), 4.92 (br s, 1H), 4.23-4.16 (m, 1H), 4.12 (t, 2H, J = 6.4 Hz), 3.77-3.74 (m, 1H), 3.63- 3.52 (m, 5H), 3.37 (s, 3H), 2.94-2.89 (m, 1H), 2.67 (dd, 1H, J = 13.2 Hz, 6.4 Hz), 2.56 (dd, 1H, J = 13.2 Hz, 4.9 Hz), 2.12-2.07 (m, 2H), 2.00- 1.92 (m, 3H), 1.87- 1.80 (m, 1H), 1.67- 1.54 (m, 5H), 1.43 (s, 9H), 1.42- 1.30 ( m, 2H), 1.01 (d, 6H, J = 6.8 Hz), 0.91 (d, 6H, J = 6.8 Hz). (31〇(23,4 3,5 3)-5-Amino-6-{ [4-Chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy-2-isopropylhexanoate cyclopentylguanamine fumarate Example (3&amp ;)[[13,23,43)-1-({[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylaminomethyl) 4-cyclopentylamine formazan 142 mg (0.23 mmol) of tert-butyl 2-hydroxy-5-methylhexyl]carboxylic acid, and added 5 ml of a 4N hydrochloric acid-dioxane solution (20 mm 〇l) at room temperature, and stirred at the same temperature for 10 minutes. After concentration by pressure, add saturated sodium bicarbonate water to the reaction mixture to dichloride After methane extraction, it was dried over anhydrous sodium sulfate -97-200815324. After filtration, the solvent was evaporated under reduced pressure to elute the residue on silica gel (solvent solvent: dichloromethane/methanol/trimamine=97/3/0~19) /5/0~93/7/0 ~93/7/1) refined. Obtained (2S,4S,5S)-5-amino-6-{[4-chloro-3-(3-decyloxy) A solution of 115 mg (0.22 mmol) of methanol (4 ml) of propoxy)benzyl]isopropenyl bromide 4-hydroxy-2-isopropylhexanoic acid cyclopentyl decylamine, 25 mg (0.22 mmol) of fumaric acid, The mixture was stirred at room temperature for 5 min. 4 NMR spectrum (CD3〇D, 400MHz), 5: 7.91 ( br s, 1H), 7.32 (d, 1H, J 8.2 Hz), 7.04 (d, 1H, J = 1.5 Hz), 6.96 (dd, 1H) , J = 8.2 Hz, 1.5 Hz), 6.69 (s, 2H), 4.16-4.08 (m, 3H), 3.64-3.61 (m, 4H), 3.43-3.39 (m, 1H), 3.35 (s, 3H) , 3.02-2.96 (m, 1H), 2.73-2.57 (m, 3H), 2.23-2.18 (m, 1H), 2.09-2.03 (m, 2H), 1.95- 1.84 (m, 2H), 1.80- 1.66 ( m, 4H), 1.64-1.41 (m, 4H), 1.11 (d, 3H, J = 6.6 Hz), 1.08 (d, 3H, J = 6.6 Hz), 0.95-0.92 (m, 6H). Mass spectrum (FAB + ), m/z: 526 ((M + H) + ). (Example 4) (2 3,43,53)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy- 2-isopropylhexanoic acid (3-hydroxy-2,2-dimethylpropyl)decylamine 1/2 fumarate (exemplified compound number: 1-228) Example (3 a) to (3b , {(S)-2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-l-[(2S,4S) obtained by the use of Example (2a) 4-isopropyl-5-oxo-tetra-98- 200815324 hydrobutan-2-yl]ethyl hydrazinecarboxylic acid tert-butyl ester and 3-amino-2,2-dimethylpropan-1-ol, The title compound was obtained (yield: 68%). Colorless solid. 4 NMR spectrum (CD3〇D, 40〇MHz), 5: 8.01 (brs, 1H), 7.32 (d, 1H, J = 8.3 Hz), 7.05 (s, 1H), 6.97 (dd, 1 H, J = 8.3 Hz, 2.0 Hz), 6.72 (s, 1H), 4.16 (t, 2H, J = 5.9 Hz), 3.66 (s, 2H), 3.63 (t, 2H, J = 6.3 Hz), 3.44-3.3 8 ( m, 1H), 3.36 (s, 3H), 3.24-3.14 (m, 3H), 3.04-2.92 (m, 2H), 2.74-2.5 8 (m, 3H), 2.36-2.29 (m, 1H), 2.10 -2.03 (m, 2 H), 1.81 (septet, 1H, J = 6.3 Hz), 1.76- 1.68 (m,1 H), 1.56- 1.49 (m,1H), 1.12 (s, 3H), 1.09 (s , 3H), 0.97 (d, 6H, J = 6.3 Hz), 0.89 (d, 6H, J = 5.9 Hz). Mass spectrum (FAB + ), m/z: 544 ( (M + H) + ). (Example 5) (23,43,53)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy-2 -isopropyl hexanoic acid [(S)-2-hydroxy-p-methylethyl] decylamine 1/2 fumarate (exemplified compound number: 1-216) analogous examples (3 a) to (3b), {(S)-2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-1-[(2 8,43)-4 obtained in Example (2a) - isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carboxylic acid tert-butyl ester and (2S)-2-aminopropanol, the title compound 123 mg (2 engineering total yield: 68%) ). Colorless solid. 4 NMR spectrum (CD3〇D, 400ΜΗζ), δ: 7.33 (d, 1H, J = 7.8 Hz), 7.05 (br s, 1H), 6.97 (dd, 1H, J = 7.8 Hz, 1.5 Hz), 6.68 ( s, -99- 200815324 1H), 4.16 (t, 2H, J = 6.3 Hz), 3.96 (6 lines, 1H, J = 6.3 Hz), 3.75 - 3.66 (m, 2H), 3.63 (t, 2H, J = 6.3 Hz), 3.54 (dd, 1H, J = 10.7 Hz, 5.9 Hz), 3.46-3.39 (m, 2H), 3.36 (s, 3H), 3.00 (5 lines, 1H, J = 6.8 Hz), 2.74 -2.5 8 (m,3H), 2.26-2.21 (m, 1H), 2.07 (5 lines, 2H, J = 6.3 Hz), 1.83-1.74 (m, 1H), 1.71 (t, 1H, J = 11.7 Hz) ), 1.5 8- 1.50 (m, 1H), 1.16-1.05 (m, 9H), 0.96 (d, 3H, J = 6.3 Hz), 0.95 (d, 3H, J = 6.8 Hz). Mass spectrum (FAB + ), m/z: 516 ((M + H) + ). (Example 6) (2S, 4S, 5S)-5-Alkyl-6-{[4- gas-3-(3-methoxypropoxy)] isopropyl] 4-hydroxy-2 -Isopropylhexanoic acid [(S)-l-hydroxymethyl-2-methylbutyl]guanamine 1/2 fumarate (exemplary compound number: 1-218) Example (3 &) ~ (31)), using {(3)-2-indole[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-1-[(23, 43) 4-Isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carboxylic acid tert-butyl ester and L-isobenzylamine to give the title compound 95 mg (yield: yield: 79%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), 5: 7·66 (d, 1H, J = 8.6 Hz), 7.31 (d, 1H, J = 8.2 Hz), 7·04 (d, 1 H, J 2 i·6 Hz), 6.95 (dd, 1H, J = 8.2 Hz, 1.6 Hz), 6.67 (s, 1H), 4.15 (t, 2H, J = 6.3 Hz), 3.81-3.73 (m, 1H), 3.67 -3.56 (m, 5H), 3.46-3.40 (m, 1H), 3.35 (s, 3H), 3.00 (5 lines, 1H, J = 6.6 Hz), 2.75-2.60 (m, 2H), 2.32 - 2.27 ( m,1H),2.06 (5 lines, 2H, J = 6.3 Hz), 丄·87- 1.61 (m, 3H), 1.56- 1.47 (m, 1H), 1.11 (d, 3H, J = 6.6 Hz), -100- 200815324 1.07 (d, 3H, J 2.6 Hz), 0.88-0.99 (m, 12H). Mass spectrum (FAB + ), m/z: 558 ((M + H) + ). (Example 7) (2S,4S,5S)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy-2 - Isobutylguanidinium fumarate fumarate (exemplary compound number: Bu 108) Example (3 a) to (3b), and {(S)-2-{ obtained by the example (2a) [4-Chloro-3-(3-methoxypropoxy)benzyl]isopropylaminopyridin-1-[(23,43)-4-isopropyl-5-oxotetrahydrofuran-2-yl]B The title compound was 131 mg (2 engineering total yield: 77%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), (5: 7.99 ( br s, 1H), 7.32 (d, 1H, J = 8.2 Hz), 7.04 (d, 1H, J = 2.0 Hz), 6.96 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 6.69 (s, 2H), 4.15 (t, 2H, J = 6.3 Hz), 3.66-3.60 (m, 4H), 3.45 -3.3 8 (m, 1H), 3.35 (s, 3H), 3.16-3.08 (m, 1H), 3.04-2.94 (m, 1H), 2.90-2.83 (m, 1H), 2.74-2.56 (m, 3H), 2.29-2.23 (m, 1H) , 2.10-2.03 (m, 2H), 1.85 - 1.66 (m, 3H), 1.57- 1.48 (m, 1H), 1.11 (d, 3H, J = 6.6 Hz), 1.07 (d, 3H, J = 6.6 Hz ), 0.98-0.89 (m, 12H) Mass Spectrum (FAB + ), m/z: 514 ((M + H) + ) (Example 8) (2S, 4S, 5S)-5-Amino-6 -{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylaminobutylide 4-hydroxy-2-isopropylhexanoic acid [(S)-2-methoxy-1- Methylethyl]decylamine fumarate (exemplified compound number: 1-321) -101- 200815324 imitative examples (3a) to (3b), i(S)-2-{ obtained by the example (2a) [4-Chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-1-[(23,43)-4-isopropyl-5-oxotetrahydrofuran-2-yl]B The base product carboxylic acid tert-butyl ester and (S)-(+)-1-methoxy-2-propylamine gave the title compound 101mg (2 work) Total yield: 57%) ° colorless solid. 4 NMR spectrum (CD3 〇 D, 400 MHz), 5: 7.83 (br s, 1H), 7.32 (d, 1H, J = 7.8 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.96 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 6.69 (s, 2H), 4.17-4.05 (m, 3H), 3.66-3.58 (m, 4H), 3.45 -3.39 ( m, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 3.30-3.24 (m, 2H), 3.04-2.95 (m, 1H), 2.74-2.56 (m, 3H), 2.26-2.19 ( m, 1H), 2.09-2.02 (m, 2H), 1.8 3 - 1.65 (m, 2H), 1.57-1.48 (m, 1H), 1.13-1.05 (m, 9H), 0.98-0.90 (m, 6H) . Mass spectrum (FAB + ), m/z: 530 ((M + H) + ). (Example 9) (23,43,5 3)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy- 2-isopropylhexanoic acid [(S)-1-hydroxymethyl-2-methylpropyl]decylamine fumarate (exemplary compound number: 1-217) Example (3 a) to (3) b), using {(S)-2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-1-[(23,43) obtained in Example (2a) ) 4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl hydrazinecarboxylic acid tert-butyl ester and L-valine alcohol, the title compound was obtained (yield: 4%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), 5: 7.64 ( br s, 1H), 7.32 (d, 1H, J = 8.2 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.96 (dd, 1H , J = -102- 200815324 8.2 Hz, 1.6 Hz), 6.69 (s, 2H), 4.15 (t, 2H, J = 6.3 Hz), 3.75-3.57 (m, 7H), 3.47-3.40 (m, 1H) , 3.35 (s, 3H), 3.04-2.95 (m, 1H), 2.74-2.58 (m, 3H), 2.34-2.27 (m, 1H), 2.09-2.03 (m, 2H), 1.93- 1.70 (m, 3H), 1.55- 1.47 (m, 1H), 1.11 (d, 3H, J =: 6.6 Hz), 1.07 (d, 3H, J 6.6 Hz), 1.00-0.89 (m, 12H). Mass spectrum (FAB + ), m/z: 544 ( (M + H) + ). (Example 10) (2S,4S,5S)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy-2 - Isopropylamine isopropyl fumarate 1/2 fumarate (exemplified compound number: 1-4) imitative examples (3 a) to (3b), obtained by the example (2a) {(S) -2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylaminopyridin-1-[(2 3,4 3)-4-isopropyl-5-oxytetrahydrofuran The title compound was 75 mg (2 engineering total yield: 32%). Colorless solid. 4 NMR spectrum (CD3〇D, 40〇MHz), 5: 7.83 (d, 1H, J = 7.4 Hz), 7.31 (d, 1H, J = 8.2 Hz), 7.03 (d, 1H, J = 1.6 Hz) , 6.95 (dd, 1H, J - 8.2 Hz, 1.6 Hz), 6.67 (s, 1 H), 4.15 (t, 2H, J = 6.3

Hz), 3.99 (6 lines, 1H, J = 5·9 Hz), 3.64 (s, 2 h), 3.62 (t, 2H, J: 6.3 Hz), 3.43-3.37 (m, 1H), 3.35 (s, 3H), 2·99 (5 lines, 1H, J = 6·6 Hz), 2.73-2.5 6 (m, 3H), 2.22-2.15 (m, 1H), 2·06 (5 lines, 2H , J = 6.3 Hz), Una (m, 2H), M (m, 1H), 1.17-1.09 (m, 9H), 1.07 (d, 3H, J = 6.6 Hz), 0.95 (d, 3H, J = 6.3 Hz), 0.93 (d, 3H, J = 6.3 Hz). -103- 200815324 Mass spectrum (FAB + ), m/z: 500 ((M + H) + ). (Example 11) (2 3,43,53)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy- 2-isopropylhexanoic acid (2-hydroxyethyl) decylamine fumarate (exemplified compound number: 1-214) imitative examples (3a) to (3b), obtained by the example (2a) {(S -2-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamine hydrazino-l-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran- The 2-butyl]ethyl hydrazinecarboxylic acid tert-butyl ester and 2-aminoethanol gave the title compound 43 mg (2 engineering total yield: 25%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), (5: 8.00 ( br s, 1H), 7.32 (d, 1H, J = 8.2 Hz), 7.05 (d, 1H, J = 1.6 Hz), 6.96 (dd, 1H, J = 8.2Hz, 1.6Hz), 6.72(s, 2H), 4.15(t, 2H, J = 6.3Hz), 3.66-3.58 (m, 6H), 3.44-3.23 (m, 3H), 3.35 ( s, 3H), 3.05 - 2.95 (m, 1H), 2.73 - 2.56 (m, 3H), 2.28-2.20 (m, 1H), 2.10-2.03 (m, 2H), 1.83- 1.50 (m, 3H), 1.12 (d, 3H, J = 6.6 Hz), 1.08 (d, 3H, J = 6.6 Hz), 0.95 (d, 3H, J = 7.0 Hz), 0.93 (d, 3H, J = 7.0 Hz). FAB + ), m/z: 502 ((M + H) + ). (Example 12) (2S, 4S, 5S)-5-Amino-6-{[4-chloro-3-(3- Oxypropoxy)benzyl]isopropylaminobuprop-4-hydroxy-2-isopropylhexanoic acid (3-hydroxypropyl) decylamine fumarate (exemplified compound number: 1-215) 3a)~(3b), {(S)-2-丨[4-chloro-3-(3--104-200815324 methoxypropoxy)benzyl]isopropylamine oxime obtained by the use of Example (2a) -l_[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carboxylic acid tert-butyl ester and 3-amino-propanol, the title compound 69mg (2 works Total yield: 40%). Colorless solid. 4 NMR spectrum CD3〇D,400ΜΗζ),ό: 8.00 ( br s,1H), 7.32 (d, 1H, J = 8.2 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.95 (dd, 1H, J = 8.2 Hz, 1.6 Hz), 6.69 (s, 2H), 4.15 (t, 2H, J = 6.3 Hz), 3.67-3.55 (m, 6H), 3.43-3.16 (m, 3H), 3.35 (s, 3H), 3.04-2.94 (m, 1H), 2.7 3-2.56 (m, 3H), 2.27-2.19 (m, 1H), 2.10-2.03 (m, 2H), 1.83- 1.64 (m, 4H), 1.57- 1.48 ( m,1H), 1.12 (d,3H,J = 6.6 Hz), 1.08 (d, 3H, J = 6.6 Hz), 0.95 (d, 3H, J = 6.6 Hz), 0.93 (d, 3H, J = 6.6) Hz). Mass spectrum (FAB + ), m/z: 516 ((M + H) + ). (Example 13) (2S,4S,5S)-5-Amino-6-{[4-chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-4-hydroxy- 2-isopropylhexanoic acid butyl decylamine fumarate (exemplified compound number: 1-14) imitative examples (3a) to (3b), and {(S)-2-{ obtained by the example (2a) [4-Chloro-3-(3-methoxypropoxy)benzyl]isopropylamino}-l-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]B The title compound 178 mg (2 engineering total yield: 69%) was obtained. Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), 5: 7.96 ( br s, 1H), 7.32 (d, 1H, J = 8·2 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.95 (dd ,1H,J = -105- 200815324 8.2 Hz, 1.6 Hz), 6.69 (s, 2H), 4.15 (t, 2H, J = 6.3 Hz), 3.66-3.59 (m, 4H), 3.43 -3.37 (m, 1H), 3.35 (s, 3H), 3.30-3.21 (m, 1H), 3.12-2.95 (m, 2H), 2.73 -2.56 (m, 3H), 2.26-2.18 (m, 1H), 2.10-2.02 ( m, 2H), 1.83 - 1.65 (m, 2H), 1.57- 1.44 (m, 3H), 1.40-1.30 (m, 2H), 1.11 (d, 3H, J = 6.6 Hz), 1.07 (d, 3H, J = 6.6 Hz), 0.97-0.8 8 (m, 9 Η) o Mass spectrum (FAB + ), m/z: 514 ((M + H) + ). (Example 14) (23,43,5 3)-5-Amino-6-{isopropyl-[4-decyloxy-3-(3-methoxypropoxy)benzyl]amino group }-4-Hydroxy-2-isopropylhexanoic acid (2-aminomethylmethyl-2-methylpropyl) decyl fumarate (exemplary compound number··1 -360) (14 a) 4- Methoxy-3-(3-methoxypropoxy)benzaldehyde in a solution of 5.03 g (33.1 mmol) of isovanaic acid in acetonitrile (10 ml), 1,3-dibromopropyl 66.25 g (328 mmol) And 6.86 g (49.6 mmol) of potassium carbonate, and stirred at 80 ° C for 5 hours. After the reaction mixture was cooled and filtered, water was added and evaporated to ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane/ethyl acetate = 4/1 to 3/1) to give 3-(3-bromopropyloxy)-4- Methoxybenzylaldehyde 8.41 g. A solution of 8.41 g (30.8 mmol) of methanol (45 ml) of 3-(3-bromopropoxy)-4-methoxybenzylaldehyde obtained in the above reaction, MeOH (yield: 28%) 46.1 mmol), stirred at 65 °C for 3 hours. The reaction mixture was cooled and 0.9 ml (15.8 mmol) of acetic acid was added. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. After the filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless liquid. 4 NMR spectrum (CDCh, 500 MHz), (5: 9.85 (s, 1H), 7.47-7.44 (m, 2H), 6.9 8 (d, 1H, J = 8.3 Hz), 4.18 (t, 2H, J = 6.4 Hz), 3.95 (s, 3H), 3.57 (t, 2H, J = 6.4 Hz), 3.36 (s, 3H), 2.16-2.11 (m, 2H). (14b) Isopropyl-[4-methoxy Example 3-(3-methoxypropoxy)benzyl]amine imitation Example (lk), 4-methoxy-3-(3-methoxypropoxy) obtained from Example (14a) Benzal aldehyde and isopropylamine gave the title compound 0.50 g (yield: 82%). colourless liquid. 4 NMR spectrum (CDC13, 400 MHz), 5: 6.90 (d, 1H, J = 2·0 Hz), 6.84 (dd , 1H, J 8.2 Hz, 2.0 Hz), 6.81 (d, 1H, J = 8.2 Hz), 4.12 (t, 2H, J = 6.3 Hz), 3.85 (s, 3H), 3.70 (s, 2H), 3.57 (t, 2H, J = 6.3 Hz), 3.36 (s, 3H), 2.89-2.80 (m, 1H), 2.14-2.07 (m, 2H), 1.09 (d, 6H, J = 6.3 Hz). 14c) (2 3,43,53)-5-Amino-6-{isopropyl-[4-methoxy-3-(3-methoxypropoxy)benzyl]amino-4- Hydroxy-2-isopropylhexanoic acid (2-aminoformamido-2-methylpropyl) decylamine fumarate analogs (11) to (In), obtained by the use of Example (U) (3S ,5S)-3-isopropyl-5-[(S)-l-(2-nitrobenzenesulfonate Mercapto)aziridine-2-yl]dihydrofuran-2-one, isopropyl-[4-methoxy-3-(3-methoxypropoxy)benzyl obtained from Example (14b) The amine and the 3-amino-2,2-di(methyl)propanamide obtained in Reference Example 2 were obtained as the title compound -107-200815324 184 mg (3 engineering total yield: 54%). Colorless solid. 4 NMR Spectrum (CD3〇D, 400MHz), 5: 7.70 (br s, 1H), 6.95-6.92 (m, 3H), 6.69 (s, 2H), 4.09 (t, 2H, J = 6.3 Hz), 3.82 (s , 3H), 3.66-3.57 (m, 4H), 3.3 8-3.29 (m, 6H), 3.07-3.01 (m, 1H), 2.68-2.54 (m, 3H), 2.28-2.23 (m, 1H), 2.06-2.00 (m, 2H), 1.83- 1.74 (m, 1H), 1.69-1.62 (m, 1H), 1.50- 1.43 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 1.12 (d, 3H, J = 6.7 Hz), 1.09 (d, 3H, J = 6.7 Hz), 0.95-0.93 (m, 6H). Mass spectrum (FAB + ), m/z: 55 3 ( (M + H) + ). (Example 15) (2S,4S,5S)-5-Amino-6-{cyclopropyl-[4-methoxy-3-(3-methoxypropoxy)benzyl]amino group Racemate of 4-hydroxy-2-isopropylhexanoic acid (2-aminomethyl-2-methylpropyl) decyl fumarate (exemplified compound number: racem of 1-450) 15a) Cyclopropyl-[4-methoxy-3-(3-methoxypropoxy)benzyl]amine imitation Example (lk), 4-methoxy-3 obtained from Example (14a) -(3-Methoxypropoxy)benzaldehyde and cyclopropylamine gave the title compound 556 mg (yield: 75%). Colorless liquid. 4 NMR spectrum (CDC13, 400 MHz), 5: 6.88 (d, 1H, J = 2.0 Hz), 6.84 (dd, 1H, J = 8.3 Hz, 2.0 Hz), 6.82 (d, 1H, J = 8.3 Hz), 4.12 (t, 2H, J = 6.4 Hz), 3.85 (s, 3H), 3.76 (s, 2H), 3.58 (t, 2H, J = 6.4 Hz), 3.36 (s, 3H), 2.17-2.08 (m , 3H), 0.46-0.36 (m, 4H). -108- 200815324 (151))(23,43,5 3)-5-Amino-6-{cyclopropyl-[4-methoxy-3-(3-methoxypropoxy)benzyl Aminopyr 4-hydroxy-2-isopropylhexanoic acid (2-aminomethylindol-2-methylpropyl) decylamine fumarate imitation examples (11) to (In), using examples (lg) (3S,5S)-3_isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2-one The cyclopropyl-[4-methoxy-3-(3-methoxypropoxy)benzyl]amine obtained in Example (15a) and the 3-amino-2,2-dimethyl obtained in Reference Example 2. The title compound (82 mg (3 engineering total yield: 32%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), <5 ·· 7.72 (br s,1H), 6.93-6.86 (m, 3H), 6.68 (s, 2H), 4.07 (t, 2H, J = 6.3 Hz ), 3.82 (s, 3H), 3.76 (d, 1H, J = 13_3 Hz), 3.69 (d, 1H, J 23.3 Hz), 3.59 (t, 2H, J = 6.3 Hz), 3.36-3.29 (m , 6H), 3.04-2.99 (m, 1H), 2.76-2.64 (m, 2H), 2.31-2.26 (m, 1H), 2.06-2.00 (m, 2H), 1.90-1.67 (m, 3H), 1.56 - 1.49 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H), 0.96-0.93 (m, 6H), 0.64-0.45 (m, 4H). Mass spectrum (FAB + ), m/z: 551 ((M + H) + ). (Example 16) (23,43,5 3)-5-Amino-6-{[4-difluoromethoxy-3-(3-methoxypropoxy)benzyl]isopropylamine Racemate of 4-hydroxy-2-isopropylhexanoic acid (2-aminoformamido-2-methylpropyl) decylamine fumarate (exemplified compound number: 1 -362 racemate) 16 a) 4-Difluoromethoxy-3-(3-methoxypropoxy)benzaldehyde in 4-difluoromethoxy-3-hydroxybenzaldehyde oxime.47g (2.5mmol) in acetonitrile (5ml -109-200815324 The solution was stirred in a solution of 3-methoxypropyl bromide. 57 g (3.8 mmol) and potassium carbonate (0.69 g (5 mmol). After the reaction mixture was cooled, water was added, and ethyl acetate was evaporated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals Colorless liquid. 'H NMR spectrum (CDC13, 500MHz), 5: 9.94 (s, 1H), 7.52 (d, 1H, J = 2.0 Hz), 7.46 (dd, 1H, J = 8.3 Hz, 2.0 Hz), 7.31 (d, 1H, J 2 8.3 Hz), 6.67 (t, 1H, J = 74·5 Hz), 4·21 (t, 2H, J = 6.4 Hz), 3.57 (t, 2H, J = 6.1 Hz), 3.36 ( s, 3H), 2.14-2.09 (m, 2H). (16b) [4-Difluoromethoxy-3-(3-methoxypropoxy)benzyl]isopropylamine imitation Example ( lk), 4-difluoromethoxy group obtained from Example (16a) -3-(3-Methoxypropoxy)benzaldehyde and isopropylamine gave the title compound 541 mg (yield: ield: 7 1%). Colorless liquid.屯 NMR spectrum (CDC13, 400 MHz), 5 ·· 7.08 (d, 1H, J = 8·2 Hz), 6.98 (d, 1H, J = 1.6 Hz), 6.85 (dd, 1H, J = 8.2 Hz, 1.6 Hz), 6.51 (t, 1H, J = 75.9 Hz), 4.12 (t, 2H, J = 6.1 Hz), 3.47 (s, 2H), 3.57 (t, 2H, J = 6.1 Hz), 3.35 (s, 3H), 2.89-2.80 (m, 1H), 2.10-2.04 (m, 2H), 1.09 (d, 6H, J = 6.3 Hz) o (16b) (2S, 4S, 5 S)-5-Amino- 6-{[4-difluoromethoxy-3-(3-methoxypropoxy)benzyl]isopropylaminobutylide 4-hydroxy-2-isopropylhexanoic acid (2-aminocarbazinyl- 2--110-200815324 Methylpropyl) decylamine fumarate imitation Example (11)~(In), using (3S,5S)-3-isopropyl-5-[ (S)-l-(2-nitrobenzene ortho-based)D-propyl B-but-2-yl]diaminofuran-2-awaken, the compound obtained in Example (16b) [4-difluoromethoxy-3 (3-methoxypropoxy)benzyl]isopropylamine and the 3-amino-2,2·di(methyl)propanamide obtained in Reference Example 2 gave the title compound 147 mg (yield: 59%). Colorless solid. 4 NMR spectrum (CDsOD, 400 ΜΗζ), ά: 7.70 (t, 1H, J = 6·5 Hz), 7.12-7.08 (m, 2H), 6.97 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 6.73 (s, 2H), 6.70 (t, 1H, J = 75.5 Hz), 4.15 (t, 2H, J = 6.3 Hz), 3.70-3.58 (m, 4H), 3.43-3.26 (m, 6H), 3.04- 2.97 (m, 1H), 2.74-2.59 (m, 3H), 2.31-2.25 (m, 1H), 2.09-2.03 (m, 2H), 1.84- 1.75 (m, 1H), 1.72- 1.65 (m, 1H) ), 1.56- 1.49 (m, 1H), 1.20 (s, 3H), 1.18 (s, 3H), 1.12 (d, 3H, J = 6.7 Hz), 1.08 (d, 3H, J = 6.7 Hz), 0.96 -0.93 (m, 6H). Mass spectrum (FAB + ), m/z·· 589 ((M + H) + ). (Example 17) (2S,4S,5S)-5-Amino-6-{[4-ethoxy-3-(3-methoxypropoxy)benzyl]isopropylamine-4-hydroxy 2-Isopropylhexanoic acid (2-aminoformamido-2-methylpropyl) guanamine fumarate racemate (exemplified compound number: 1-361 racemate) (17a) [ 4-Ethoxy-3-(3-methoxypropoxy)benzyl]isopropylamine imitation Examples (16a) and (lk) with 4-ethoxy-3-hydroxybenzaldehyde, 3-methyl The title compound 〇.48 g (2 engineering total yield: -111-200815324 71%) was obtained from oxypropyl bromide and isopropylamine. Colorless liquid. 4 NMR spectrum (CDC13, 400MHz), 5: 6.89 (s, 1H), 6.82 (br s, 2H), 4.11 (t, 2H? J = 6.3 Hz), 4.06 (q, 2H, J = 7.0 Hz), 3.69 (s, 2H), 3.58 (t, 2H, J = 6.3 Hz), 3.35 (s, 3H), 2.89-2.80 (m, 1H), 2.12-2.05 (m, 2H), 1.42 (t, 3H, J = 7.0 Hz), 1.09 (d, 6H, Γ = 6.3 Hz). (171)) (23,43,5 3)-5-Amino-6-{[4-ethoxy-3-(3-methoxypropoxy)benzyl]isopropylamino-4-hydroxy 2-Isopropylhexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate imitation Example (11) ~ (In), obtained by the example (lg) (3S, 5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2-one, obtained in Example (17a) [4-Ethoxy-3-(3-methoxypropoxy)benzyl]isopropylamine and the 3:amino-2,2-dimethylpropanamine obtained in Reference Example 2 gave the title compound 113 mg ( 3 total project yield: 46%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), 5: 7.70 (br s,1H), 6.96-6.88 (m,3H),6·68 (s,2H),4.09 (t,2H,J zz 6.5 Hz) , 4.05 (q, 2H, J = 7.0 Hz), 3.65 -3.5 8 (m, 4H), 3.39-3.29 (m, 6H), 3.07-3.00 (m, 1H), 2.68-2.53 (m, 3H), 2.28-2.23 (m, 1H), 2.06-2.00 (m, 2H), 1.83 - 1.74 (m, 1H), 1.69-1.62 (m, 1H), 1.50-1.44 (m, 1H), 1.30 (t, 3H) , J = 7.0 Hz), 1.19 (s, 3H), 1·18 (s, 3H), 1.12 (d, 3H, J = 6.7 Hz), 1.09 (d, 3H, J = 6.7 Hz), 0.95-0.93 (m, 6H). -112- 200815324 Mass spectrum (FAB + ), m/z·· 567 ((M + H) + ). (Example 18) (2S,4S,5S)-5-Amino-4-exogenic-2-isopropyl-6-{isopropyl-[l-(3-methoxypropyl)-l , 2,3,4-tetrahydroquinolin-7-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decyl fumarate (example compound number: 1 -401) (18a) 1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-ylmethanol. 1,2,3,4-tetrahydrogen obtained in Reference Example 3. Quinoline-7-yl methanol 0.812 (4.9 mmol) in N,N-dimethylformamide (10 ml) solution plus 3-methoxypropyl bromide l.lg (7.4 mmol) and potassium carbonate 1.4 g (9.8 mmol) was stirred at 80 ° C for 15 hours. After the reaction mixture was cooled, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssss Yellow liquid. 4 NMR spectrum (CDC13, 400MHz), 5: 6.92 (d, 1H, J = 7.4 Hz), 6.61 (br s, 1H), 6.54 (d, 1H, J = 7.4 Hz), 4.57 (d, 2H, J = 4.7 Hz), 3.44 (t, 2H, J = 5.9 Hz), 3.39-3.34 (m, 5H), 3.27 (t, 2H, J = 5.9 Hz), 2.74 (t, 2H, J 6.5 Hz), 1.96-1.91 (m, 2H), 1·88-1·82 (m, 2H), 1.57 (br s, 1H). (18b) 1-(3-Methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-carbaldehyde The 1-(3-methoxypropyl)- obtained in Example (18a) 1,2,3,4-tetrahydroquinoline-7. Methanol 0.70 g (3.0 mmol) in dimethyl hydrazine (4 ml), under a nitrogen atmosphere, at room temperature with 10 sulphur trioxide A solution of the complex compound 1 · 4 g (8 · 9 mm ο 1) and di-113-200815324 ethylamine 1.3 ml (8.9 mmol) in dimethyl hydrazine (3 ml) was stirred at room temperature for 30 minutes. After the reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with saturated aqueous ammonium chloride and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals Colorless liquid. 4 NMR spectrum (CDCh, 400MHz), 5: 9.86 (s, 1H), 7.08-7.06 (m, 2H), 7.03 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 3.45-3.42 (m, 4H) , 3.35 (s, 3H), 3.32 (t, 2H, J = 5.9 Hz), 2.81 (t, 2H, J = 6.4 Hz), 1.98- 1.93 (m, 2H), 1.90- 1.85 (m, 2H). (18 c) Isopropyl-[M3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-ylmethyl]amine 1-(3) obtained in Example (18b) -Methoxypropyl)-1,2,3,4-tetraaminophthalene-7. Formaldehyde 0.65g (2.8mmol), isopropylamine 0.72ml (8.4mmol) and acetic acid 0.48ml (8.4mmol) dichloride A solution of methane (30 ml) was added to a solution of 1.8 g (8.4 mm) of sodium triethyl sulfonium hydride, and stirred at room temperature for 2 hours. After the reaction mixture was extracted with saturated aqueous sodium hydrogen sulfate and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was applied to silica gel column chromatography eluting solvent: (i) n-hexane / ethyl acetate / triethylamine = 1/1/0 to 0/100/1; (ii) dichloride Purification with methane / methanol / triethylamine = 1 / / / / / / / / / Yellow liquid. 4 NMR spectrum (CDCh, 400 MHz), 5: 6.88 (d, 1H, J = 7.4 Hz), -114- 200815324 6.54 (br s, 1 Η), 6·50 (br d, 1H, J = 7.4 Hz, 1.6 Hz), 3.70 (s, 2H), 3.44 (t, 2H, J = 6·1 Hz), 3.3 8-3.3 5 (m, 5H), 3.26 (t, 2H, J = 5.4 Hz), 2.92-2.82 (m, 1H), 2.72 (t, 2H, J = 6.3 Hz), 1.95- 1.90 (m, 2H), 1.88-1.82 (m, 2H), 1.09 (d, 6H, J = 6.3 Hz). (18d) N-{(S)-2-{isopropyl-[1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-ylmethyl]amine Base}_l-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl 2-nitrobenzenesulfonamide obtained in Example (lg) (3S, 5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2-one 223 mg (0.63 mmol) and its implementation Example (18 c) isopropyl-[1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-ylmethyl]amine 244 mg (0.88 mmol) of toluene (6.5 ml) solution was stirred at ll ° C for 1 hour. After the reaction mixture was cooled, the residue was evaporated. mjjjjlililililililililililililililililili

NMR spectrum (匚〇(:13,40(^1^), 5:8.03 -8.00 (111,1;^), 7.89-7.87 (m, 1H), 7.7 8-7.77 (m, 2H), 6.86 ( d, 1H, J = 7.4 Hz), 6.48 (br s,1H), 6.36 (br d, 1H, J = 7.4 Hz), 5.38 (br s,1H), 4.88-4.84 (m,1H), 3.45- 3.44 (m, 9H), 3·28 (t, 2H, J = 5.5 Hz), 3.18 (d, 1H, J = 13.7 Hz), 2.86-2.80 (m, 1H), 2.76-2.70 (m, 3H) , 2.60-2.54 (m, 1H), 2.14-2.06 (m, 3H), 1.97-1.90 (m, 3H), 1.87-1.81 (m, 2H), 0.96 (d, 3H, J = 6.7 Hz), 0.93 (d, 3H, J = 6.7 Hz), 0.90 (d, 3H, J 6.7 Hz), 0.85 (d, 3H, J - 115 - 200815324 = 6 · 7 Η z) 〇 (18e) (2S, 4S, 5S)-4-Hydroxy-2-isopropyl-6-{isopropyl-[l-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-yl N-{(S) obtained from the compound (18d) of the amino group of 5-(2-nitrophenylsulfonylamino)hexanoic acid (2-aminomethylsulfonylamino)methyl hexanoate -2-{isopropyl-[l-(3-methoxypropyl)_ 1,2,3,4-tetrahydroquinolin-7-ylmethyl]amino}_i_[(2S,4S) 4-Isopropyl-5-oxotetrahydrofuran-2-yl]ethyl b- 2-nitrobenzenesulfonamide 332^(0.5111111101) in triethylamine (5ml), plus Reference Example 2: 178 mg (1.53 mmol) of 3-amino-2,2·di(methyl)propanamide and 49 mg of 2-hydroxypyridine (〇.51 mm〇1) were obtained by silica gel column chromatography. After stirring at 85 ° C for 3 hrs, the reaction mixture was cooled, concentrated under reduced pressure, and stirred at 8.5 ° C for further 4.5 hours. The reaction mixture was cooled and solvent was evaporated: dichloromethane / methanol = 20/1} fine 231 mg ( Yield: 61%). Yellow liquid. !H NMR spectrum (CDCh, 500 MHz), 5: 8 〇', 8. 〇5 (m, lH), 7.82- 7.81 (m, 1H), 7.73-7.68 (m , 2H), 6 Rr , • δ (d, 1H, J 2 7.8 Hz), 6.48-6.40 (m, 3H), 6.15 (br s, 1H), 5 ^ , δ / (br s, 1H), 5.39 (br s, 1H), 5.01 (br s, 1H), 3.77 (br di tr 5 J = 10.7 Hz), 3.56 (d, 1H, J: 13.2 Hz), 3.49-3.26 (m,]9tj\ 3.21 ( Dd, 1H, J = 13.9 Hz, 6.1 Hz), 3.01-2.95 (m, 1H) 〇~ , (79-2.71 (m, 3H), 2.61 (dd, 1H, J = 13.9 Hz, 4.2 Hz), 2 .〇〇ι Πι (m, 3H), 1.89-1.83 (m, 2H), 1·6 Bu 1.54 (m, 1H), 1·32-1·27 (茁, 1H), 1.18 (s, 6H) , 1.15-1.09 (m, 1Η), 0·99 (d, 3Η, J = “,

Hz), 0.94 (d, 3H, J 6.4 Hz), 0.75 (d, 3H, J = 6.4 Hz), 〇64 ^ ^ (d, 3H, J zz 6.4 Hz) -116- 200815324 (18f) (2S, 4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6·{isopropyl-[l-(3-methoxypropyl)-l,2,3,4-tetrahydro Quinoline-7-ylmethyl]amino decanoic acid (2-aminomethylindol-2-methylpropyl) decylamine fumarate obtained in Example (18e) (2S, 4S, 5S)- 4-hydroxy-2-isopropyl-6-{isopropyl-[1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-ylmethyl]amine 5-B 2-(2-nitrophenylsulfonylamino)hexanoic acid (2-amine-mercapto-2-methylpropyl) decylamine 23 1 mg (0.31 mmol) and carbonic acid planing 1 2 1 mg (0 A mixture of 37 mmol) of N,N-dimethylformamide (3 ml) was added with thiophenol 63//1 (0.62 mmol) at room temperature under nitrogen atmosphere and stirred at room temperature for 4 hours. After the reaction mixture was added with water and extracted with a mixed solvent of chloroform/isopropanol (V/V: 3/1), it was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: methylene chloride / methanol / triethylamine = 20/1 / 0 to 10 / 1 / 0 to 100 / 10). A solution of 149 mg (0.27 mmol) of m. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) Yellow solid. !Η NMR spectrum (CD3〇D, 400MHz), 5: 7.68 (br s,1H), 6.87 (d, 1H, J = 7.4 Hz), 6.58 (br s, 2H), 6.52 (br d, 1H, J = 7.4 Hz), 3.62 (d, 1H, J = 13.3 Hz), 3.55 (d, 1H, J = 13.3 Hz), 3.46 (t, 2H, J = 5.9 Hz), 3.39-3.26 (m, 10H), 3.11-3.05 (m, 1H), 2.72-2.60 (m, 5H), 2.28-2.22 (m, 1H), 1.94-1.8 8 (m, 2H), 1.86- 1.72 (m, 3H), 1.69- 1.63 ( m, 1H), 1.50- 1.43 (m, 1H), 1.20 (s, 3H), 1.18 (s, 3H), 1.14-1.11 (m, 6H), 0.95-0.93 (m, -117- 200815324 6H). Mass spectrum (FAB + ), m/z: 562 ((M + H) + ). (Example 19) (2S,4S,5S)-5-amino-4-transyl-2-isopropyl-6-{isopropyl-[H2-methoxyethyl)-1,2, 3,4-tetrahydropipelin-7-ylmethyl]amino}hexanoic acid (2-aminocarbamimido-2-methylpropyl) decylamine fumarate (exemplary compound number: 丨-400) (19a) Isopropyl-[1-(2-methoxyethyl)-1,2,3,4-tetrahydroquinolin-7-ylmethyl]amine imitation Example (18a)~(1 8c), using the 1,2,3,4-tetrahydroquinolin-7-ylmethanol, 2-methoxyethyl bromide and isopropylamine obtained in Reference Example 3 to give the title compound 〇.22 g (3 engineering total yield :34%). Colorless liquid.屮 NMR spectrum (CDCh, 400 MHz), 5: 6.88 (d, 1H, J = 7·4 Hz), 6.54 (br s, 1H), 6.50 (br d, 1H, J = 7.4 Hz, 1.6 Hz), 3.70 (s, 2H), 3.44 (t, 2H, J = 6.1 Hz), 3.39-3.34 (m, 5H), 3.26 (t, 2H, J = 5.4 Hz), 2.92-2.82 (m, 1H), 2.72 ( t, 2H, J = 6.3 Hz), 1.95- 1.90 (m, 2H), 1.09 (d, 6H, J = 6.3 Hz). (19b) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropylisopropyl-[l-(2-methoxyethyl)-1,2,3,4- Tetrahydroquinolin-7-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate imitation Example (11) ~ (In), with implementation (3S,5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2- Ketone, isopropyl-[1-(2-methoxyethyl)-1,2,3,4-tetrahydropipelin-7-ylmethyl]amine obtained in Example (19a) and obtained in Reference Example 2 3-Amino-2,2-di(methyl)propanamide, -118-200815324 The title compound was obtained (yield: 49%). Yellow solid. 4 NMR spectrum (CD3〇D, 4〇0ΜΗζ), ά: 7·68 (br s,1Η),6·87 (d, 1H, J = 7.4 Hz), 6.58 (br s, 2H), 6.52 (br d, 1H, J = 7.4 Hz), 4.21-4.12 (m, 2H), 3.68-3.47 (m, 6H), 3.39-3.26 (m, 6H), 3.10-2.99 (m, 1H), 2.75-2.60 ( m, 5H), 2.28-2.22 (m, 1H), 1.92- 1.88 (m, 2H), 1.81-1.63 (m, 2H), 1.50- 1.43 (m, 1H)? 1.19 (s, 3H), 1.18 ( s, 3H), 1.14-1.11 (m, 6H), 0.95-0.93 (m, 6H). Mass spectrum (FAB + ), m/z: 548 ((M + H) + ). (Example 20) (2S, 4S, 5S)-5-Amino-4-hydroxy-2.isopropyl-isopropyl-[l-(3-methoxypropyl)-2-oxo-1 , 2,3,4-tetrahydroquinolin-7-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decyl fumarate (exemplary compound number: 1 -447) (20a) 1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxaldehyde 2-ethoxy-1 obtained in Reference Example (3b) , 2,3,4-tetrahydroquinoline-7-carboxylic acid methyl ester 0.72 g (3.5 mmol) in N,N-dimethylformamide (35 ml), under sodium atmosphere, sodium hydrogenation at room temperature (55% content) 0.31 g (7 mmol), stirred at the same temperature for 30 minutes. 0.81 g (5.3 mmol) of 3-methoxypropyl bromide was added to the reaction mixture, and stirred at 50 ° C for 5 hours. After the reaction mixture was cooled, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane/ethyl acetate = 1/1) to give 1-(3-methoxypropyl-119-200815324)-2 - Oxy-1,2,3,4-tetrahydroquinoline-7-carboxylic acid methyl ester 〇. 15 g (yield: 15%). Methyl 1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate 〇.49 g (1.8 mmol) of tetrahydrofuran A mixed solvent solution of 1 8 ml) and decyl alcohol (9 ml) was added with 1 ml of a 1N aqueous solution of sodium hydroxide (2.1 mmol) and stirred at 60 ° C for 1 hour. The reaction mixture was cooled and forced to dryness (yield: 2.1 mL). After the mixture was diluted with water, the mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure to give a crude carboxylic acid. A solution of the carboxylic acid in tetrahydrofuran (18 ml) was added. EtOAc (EtOAc m. The reaction mixture was added with a solution of sodium borohydride (0.27 g) (m. After the reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane/ethyl acetate = 1/1 to 0/1) to give 7-hydroxymethyl-1-(3-methoxy Propyl)-3,4-dihydro-1H-quinolin-2-one oxime. 26 g (yield: 59%). The above reaction resulted in 7-hydroxymethyl-1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-2-one 0.262 (1.〇111111〇1) A solution of hydrazine (2.51111) was added to 0.43 ml (3.1 mmol) of triethylamine and 0.49 g (3.1 mmol) of sulfur trioxide pyridine complex at room temperature under nitrogen atmosphere, and stirred at the same temperature for 1.5 hours. After the reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjj %). Colorless liquid. 4 NMR spectrum (CDCh, 500MHz), 5: 9·98 (s, 1H), 7.63 (d, 1H, J = 1.5 Hz), 7.52 (dd, 1H, J = 7.8 Ηζ, 1.5 Hz), 7.34 (d, 1H, J = 7.8 Hz), 4·10 (t, 2H, J = 6.8 Hz), 3.45 (t, 2H, J 2 5.8 Hz), 3.35 (s, 3H), 3.00-2.97 (m, 2H), 2.69-2.66 (m, 2H), 1.98-1.93 (m, 2H). (20b) 7-(Isopropylaminomethyl)-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one imitation Example (lk), using example (20a) 1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-carbaldehyde and isopropylamine afforded the title compound 220 mg (yield: 93%) ). Colorless liquid. 4 NMR spectrum (CDC13, 400MHz), 5: 7.10 (d, 1H, J 2 7.8 Hz), 7.07 (br s, 1H), 6.96 (br d, 1H, J = 7.8 Hz), 4.04 (t, 2H, J = 7.4 Hz), 3.78 (s, 2H), 3.45 (t, 2H, J = 6.1 Hz), 3.35 (s, 3H), 2.88-2.83 (m, 3H), 2.64-2.61 (m, 2H), 1.97-1.91 (m, 2H), 1·10 (d, 6H, J =: 6·3 Hz). (20c) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-{isopropyl-[l-(3-methoxypropyl)-2-oxo-1 , 2,3,4-tetrahydroquinolin-7-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decyl fumarate imitation example (11) ~(11〇, (33,53)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl obtained by the use of Example (12) Dihydrofuran-2-one, 7-(isopropylaminomethyl)-1_(3-methoxypropyl)-3,4-di-121-200815324 hydrogen-1H-quinine obtained in Example (20b) The oxin-2-one and the 3-amino-2,2-dimethylpropanolamine obtained in Reference Example 2 gave the title compound 1 4 2 mg (3 engineering yield: 5 9 %). Colorless solid. 4 NMR Spectrum (CDsOD, 400MHz), 5: 7.70 (br s, 1H), 7.21 (d, 1H, J = 7.8 Hz), 7.16 (br s, 1H), 7.08 (br d, 1H, J = 7.8 Hz), 6.71 (s, 2H), 4.07 (t, 2H, J = 6.3 Hz), 3.69 (br s, 2H), 3.48-3.28 (m, 9H), 3.06-3.00 (m, 1H), 2.90-2.87 (m , 2,,,,, (s, 3H), 1.18 (s, 3H), 1.13 (d, 3H, J = 6.7 Hz), 1.09 (d, 3 H, J = 6.7 Hz), 0.95-0.93 (m, 6H) Mass Spectrum (FAB + ), m/z: 57 6 ((M + H) + ) (Example 21) (2 3,43,5 3)-5-Amino-4-hydroxy-2-isopropyl-6-{isopropyl-[4-(3-methoxypropyl)-%oxy-3,4-dihydro-2H- Benzo[1,4], oxime-6-ylmethyl]amino}hexanoic acid (2-aminoformamido-2-methylpropyl) decylamine fumarate racemate (exemplified compound) No.: 1-448 racemate) (21a) 6-(Isopropylaminomethyl)-[4-(3-methoxypropyl)-4H-benzo[1,4]噚耕-3- Ketone imitation examples (20a) and (Ik), using 6-methoxycarbonyl-2H-1,4-benzoxanthene-3(4H)-one, 3-methoxypropyl bromide and isopropylamine. The title compound 〇.32g (4 engineering total yield: 28%). Colorless liquid. 4 NMR spectrum (CDCh, 400 ΜΗζ), ά : 7.08 (s, 1H), 6.96-6.91 (m, -122- 200815324 2H), 4.57 (s, 2H), 4.04 (t, 2H, J = 7.0 Hz), 3.75 (s, 2H), 3.45 (t, 2H, J = 6.1 Hz), 3.35 (s, 3H), 2.90-2.80 (m, 1H), 1·99-1·92 (m, 2H), 1.10 ( d, 6H, J = 6.3 Hz). (21b) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-{isopropyl-[4-(3-methoxypropyl)-3-oxo-3 ,4-Dihydro-2H-benzo[1,4],噚哄_6-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decyl fumaric acid Salt (3), (In), (3S, 5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl) was obtained by the example (g). 6-(isopropylaminomethyl)-[4-(3-methoxypropyl)-4?-benzene obtained by the example (21a) And [1,4], hydrazine-3-one and 3-amino-2,2-dimethylpropanamine obtained in Reference Example 2 gave the title compound 17 9 mg (3 engineering total yield: 7 2 % ). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), (5: 7·70 (br s, 1H), 7.17 (d, 1H, J = 2.0 Hz), 7.07 (dd, 1H, J = 8.2 Hz, 2.0 Hz) , 6.98 (d, 1H, J = 8.2 Hz), 6.72 (s, 2H), 4.58 (s, 2H), 4.08 (t, 2H, J = 7.0 Hz), 3.71-3.64 (m, 2H), 3.47 ( t, 2H, J = 5.9 Hz), 3.42-3.28 (m, 6H), 3.05-2.99 (m, 1H), 2.74-2.60 (m, 3H), 2.30-2.25 (m, 1H), 1.94- 1.88 ( m, 2H), 1.83- 1.75 (m, 1H), 1.72-1.65 (m, 1H), 1.5 5 - 1.49 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 1.13 (d , 3H, J = 6.7 Hz), 1.10 (d, 3H, J = 6.7 Hz), 0.94 (d, 6H, J = 6.7 Hz) Mass Spectrum (FAB + ), m/z: 578 ((M + H) +) (Example 22) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-{isopropyl-[l-(3-methoxy-123· 200815324 Isopropyl)-1H-indol-6-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate racemate (exemplified compound number) :1-390 racemate) (22a) 1-(3-methoxypropoxy)-lH-indole-6-carboxaldehyde 1H-indole-6-carboxylic acid methyl ester 2.10 g (12 mmol) a solution of N,N-dimethylformamide (36 ml) under nitrogen atmosphere, sodium hydrogenate at room temperature ( 55% content) 0.7 85 g (18 mm 〇l), stirred at room temperature for 5 minutes. To the reaction mixture was added 3-methoxypropyl bromide 6.0 g (3 9.2 mmol), and stirred at room temperature for 20 minutes. After extracting with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane / ethyl acetate =4/1~19/1) Purified to give 2.02 g of methyl 1-(3-methoxypropyl) 1H-indole-6-carboxylate. 0.38 g (10.1 mmol) of tetrahydrofuran. 44 ml) solution, under a nitrogen atmosphere and under ice cooling, a solution of 1-(3-methoxypropyl) 1H-indole-6-carboxylic acid methyl ester 2.02 g (8.4 mmol) of tetrahydrofuran (30 ml). 40 ml) solution, stirring at the same temperature for 15 minutes. After cooling the reaction mixture in an ice water bath, 10 ml of ethanol was added in 30 portions, and the mixture was stirred at the same temperature for 1 hour. A 10% aqueous solution of sodium potassium tartrate and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was extracted with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane/ethyl acetate = 1/1) to give [1-(3-methoxypropyl)-1? -6-yl]methanol 1.73 g. A solution of 0.65 g (3.0 mmol) of [1-(3-methoxypropyl)-1Η-indol-6-yl]methanol in the above reaction, methylene chloride (13 ml), - 200815324 0.96 g (6.7 mmol) of pyridinium chromite, stirred at room temperature for 2 hours. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystalssssssssssssssssssssssssssss Yellow liquid. 4 NMR spectrum (CDCh, 400MHz), 5: 10.06 (s, 1H), 7.94 (s, 1H), 7.71 (d, 1H, J = 8.2 Hz), 7.63 (d, 1H, J 8.2 Hz), 7.33 (br s,1H), 6.57 (br s,1H), 4.34 (t,2H,J = 6·7 Hz), 3.33 (s, 3H), 3.27 (t, 2H, J = 5.9 Hz), 2.12 2.06 (m, 2H). (22b) Isopropyl-[l-(3-methoxypropyl)-1 H-indol-6-ylmethyl]amine imitation Example (lk), 1-(1) obtained from Example (22a) 3-methoxypropoxy)indole-6-carboxaldehyde and isopropylamine gave the title compound 426 mg (yield: 73%). Colorless liquid.屮 NMR spectrum (CDCh, 400 MHz), 5: 7.56 (d, 1H, J = 7.8 Hz), 7.32 (s, 1H), 7.07-7.04 (m, 2H), 6.45 (d, 1H, J = 2.9 Hz) , 4.24 (t, 2H, J = 6.8 Hz), 3.90 (s, 2H), 3.33 (s, 3H), 3.29 (t, 2H, J = 5.9 Hz), 2.94-2.87 (m, 1H), 2.09- 2.04 (m, 2H), 1.12 (d, 6H, J = 6.4 Hz). (22c) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-indole-[1-(3-methoxypropyl)-1Η-吲哚-6-ylmethyl]amino}hexanoic acid (2-aminocarbamimido-2-methylpropyl) decylamine fumarate imitation examples (11) to (In), using examples (lg) (3S,5S)-3-Isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2-one, Example (22b) The obtained isopropyl-[1-(3-methoxypropyl)-iH-indol-6-ylmethyl-125-200815324-yl]amine and the 3-amino-2,2 obtained in Reference Example 2 - dimethylpropanamide, the title compound was obtained (yield: 48%). Colorless solid. 4 NMR spectrum (CD3 〇D, 400MHz), (5: 7.66 (br s, 1H), 7·55 (d, 1Η, J = 8.2 Hz), 7.39 (br s, 1H), 7.19 (d, 1H, J = 3.1 Hz), 7.09 (br d,1H,J = 8.2 Hz), 6.69 (s,2H), 6.42 (d,1H, J = 3.1 Hz), 4.27 (t, 2H, J = 6.8 Hz), 3.85 (d, 1H, J = 13.3 Hz), 3.80 (d, 1H, J = 13.3 Hz), 3.37-3.25 (m, 9H), 3.15-3.08 (m, 1H), 2.74 (dd, 1H, J 2 13.3 Hz, 4.3 Hz), 2.65 (dd, 1H, J = 13.3 Hz, 10.6 Hz), 2.52-2.47 (m, 1H), 2.23-2.17 (m, 1H), 2.08-2.02 (m, 2H), 1.79 - 1.70 (m, 1H), 1.64- 1.57 (m, 1H), 1.41-1.34 (m, 1H), 1.18-1.15 (m, 12H), 0.92-0.86 (m, 6H). Mass spectrum (FAB + ), m/z: 546 ((M + H) + ) (Example 23) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-{isopropyl-[ l -(3-Methoxypropyl)-2,3-dihydro-1H-indol-6-ylmethyl]amino decanoic acid (2-aminoformamidine U-methyl-2-methylpropyl) a racemate of guanamine fumarate (exemplified compound number: 1-450 racemate) (2 3 a) isopropyl-[1-(3-methoxypropyl)2,3-di Hydrogen-1H-indol-6-ylmethyl]amine isopropyl-[1-(3-A) obtained in Example (22b) a solution of 176 mg (0.68 mmol) of acetic acid (2 ml), EtOAc (EtOAc) After the mixture was extracted with saturated aqueous sodium chloride and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate - 126 - < The solvent was evaporated to give the title compound (yield: 36%) (yield: 36%). y NMR spectrum (CDCh, 400 MHz), 5: 6.99 (d, 1H, J = 7·4 Hz), 6.57 (d, 1H, J = 7.4 Hz), 6.45 (s, 1H), 3.70 (s, 2H), 3.49 (t, 2H, J = 6.3 Hz), 3.36 (s, 3H) , 3.34 (t, 2H, J 2 8.2 Hz), 3.16 (t, 2H, J = 6.3 Hz), 2.93 (t, 2H, J = 8.2 Hz), 2.89-2.83 (m, 1H), 1.90- 1.84 ( m, 2H), 1.09 (d, 6H, J = 6.3 Hz). (23b) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-{isopropyl-[l-(3-methoxypropyl)-2,3- Dihydro-1H-indol-6-ylmethyl]amino}hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate imitation Example (11) ~ (In) (3S,5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran obtained by the method (g) 2-ketone, the isopropyl-[1-(3-methoxypropyl) 2,3-dihydro-1:«-fluorenyl-6-ylmethyl]amine obtained in Example (23 &) The 3-amino-2,2-dimethylpropanamine obtained in Reference Example 2 gave 146 mg (yield: 60%). Yellow solid. 4 NMR spectrum (CD3〇D, 400ΜΗζ), δ: 7.68 (br s,1H), 7.02 (d, 1H, J = 7.4 Hz), 6.70 (s, 2H), 6.63 (br d, 1H, J = 7.4 Hz), 6.50 (br s, 2H), 3.63 (d, 1H, J = 13.3 Hz), 3.58 (d, 1H, J = 13.3 Hz), 3.52-3.48 (m, 2H), 3.42-3.28 (m, 11H), 3.22-3.15 (m, 2H), 2.97-2.90 (m, 2H), 2.68-2.60 (m, 1H), 2.29-2.20 (m, 1H), 1.89- 1.63 (m, 4H), 1.50- 1.44 (m, 1H), 1.19 (s, 3H), -127- 200815324 1.18 (s, 3H), 1.14-1.10 (m, 6H), 0.95-0.91 (m, 6H). Mass spectrum (FAB + ), m/z: 548 ((M + H) + ). (Example 24) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-(isopropyl-{2-[l-(3-methoxypropyl) -1H-indol-3-yl]ethyl}amino)hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate (example compound number: 1-613) (24 a) [2-(1Η-Indol-3-yl)ethyl]isopropyl carboxylic acid tert-butyl ester in tryptamine 3.00 g (18.7 mmol), acetone 6.9 ml (97 mmol) and acetic acid 1.7 ml (29.6 mmol) A solution of methylene chloride (90 ml) was added 1 1.9 g (56.2 mmol) of sodium triacetoxyborohydride, and stirred at room temperature for 5 hours. After the reaction mixture was extracted with saturated aqueous sodium hydrogen sulfate and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted Base) ethyl] isopropylamine 3.68 g. A solution of 3.68 g (18.2 mmol) of [2-(1Η-indol-3-yl)ethyl]isopropylamine obtained from the above reaction m. m. And 2,3 g of di-tert-butyl dicarbonate (23 · 8 mmol), and stirred at room temperature for 1 hour. After the reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless liquid. 4 NMR spectra (CDC13, 500 MHz), (5: 8.01 (br s, 1H), 7.66 (br d, -128- 200815324 1H, J = 7.6 Hz), 7.37 (br d, 1H, J = 7.6 Hz) , 7.20 (br t, 1H, J = 7.6 Hz), 7.13 (br t, 1H, J = 7.6 Hz), 7.02 (br s, 1H), 4.39 (br s, 1H), 3.33 (br s, 2H) , 3.01-2.98 (m, 2H), 1.52 (s, 9H), 1.15 (d, 6H, J = 6.8 Hz) (24b) isopropyl-{2-[1-(3-methoxypropyl)吲哚-3-yl]ethyl}amine 0.45 g (1.5 mmol) of [2-(1H-indol-3-yl)ethyl]isopropyl carboxylic acid tert-butyl ester obtained in Example (24a) A solution of N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature, sodium hydride (55% content), 0.13 g (3.0 mmol), and stirred at the same temperature for 10 minutes. 0.34 g (2.3 mmol) of oxypropyl bromide, and stirred at room temperature for 30 minutes. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent: n-hexane/ethyl acetate = 3/1) to give isopropyl-{2-[1-(3-methoxy) Propyl-3-indolyl]ethyl} 0.42 g of butyl carboxylic acid ester (yield: 75%). The isopropyl-{2-[1-(3-methoxypropyl)indol-3-yl]ethyl hydrazide obtained by the above reaction A solution of the acid tert-butyl ester 0.42 § (1.1111111 〇 1) in dichloromethane (3.41111), 1.7 ml (23 mm 〇l) of trifluoroacetic acid at room temperature, and stirred at the same temperature for 10 minutes. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtered, the solvent was evaporated, and the residue was purified by silica gel chromatography (solvent solvent: ethyl acetate / triethylamine = 100/1) Compound 0.28 g (yield: 91%). Yellow liquid. 4 NMR spectrum (CDCh, 400 MHz), 5: 7·33 (d, 1H, J = 7·6 Hz), -129- 200815324 7.20 (t, 1H , J = 7.6 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.93 (s, 1H), 4.20 (t, 2H, J = 6·8 Hz), 3.32 (s, 3H), 3.27 (t , 2H, J = 5.8 Hz), 2.97-2.92 (m, 4H), 2.83-2.77 (m, 2H), 2.07-2.01 (m, 2H), 1.04 (d, 6H, J = 6.3 Hz). (24c) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl- 6-(isopropyl-{2-[l-(3-methoxypropyl)-1Η -吲哚·3-yl]ethyl}amino)hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate imitation Example (11) ~ (In), implemented (3S,5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonyl)aziridine-2-yl]dihydrofuran-2- Ketone, isopropyl-{2-[1-(3-methoxypropyl)indol-3-yl]ethyl}amine obtained in Example (24b) and 3-amino-2,2 obtained in Reference Example 2 _Dimethylpropanamide gave the title compound 85 mg (3 engineering total yield: 48%). Colorless solid. 4 NMR spectrum (CD3〇D, 400MHz), (5: 7.75 (br s, 1H), 7.57 (d, 1H, J = 7.6 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.16 (t, 1H, J = 7·6 Hz), 7.09-7.03 (m, 2H), 6.69 (s, 2H), 4.22 (t, 2H, J = 6.7 Hz), 3.42-3.24 (m, 9H), 3.01-2.88 (m, 5 H), 2.7 1 - 2.69 (m, 2H), 2.32-2.27 (m, 1H), 2.06- 1.99 (m, 2H), 1.84- 1.75 (m, 1H), 1.72- 1.56 (m, 2H), 1.19 (s, 3H), 1.17 (s, 3H), 1.12 (d, 3H, J = 6.7 Hz), 1.10 (d, 3H, J = 6.7 Hz), 0.96-0.94 (m, 6H) 〇 Mass Spectrum (FAB + ), m/z: 560 ((M + H) + ) (Example 25) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6- (isopropyl-{2-[(Z)_methoxy-130- 200815324 imino]-2-[1-(3-methoxypropyl)-1 Η-indol-3-yl]B (Aminoguanidino)hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine fumarate (exemplified compound number: 1-449) (2 5 a) 2-isopropylamino-1- [1-(3-Methoxypropyl)-1Η-indol-3-yl]ethanone oxime-methyl oxime [2-(1Η-吲哚-3-yl)B obtained in Example (24a) Tetrabutyl isopropyl acrylate 1.7 〇 2 (5.6111111 〇 1) of tetrahydrofuran (5 〇 1111) and water (5.61111) The solvent mixture was mixed, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 2.4 g (11.2 mm'ol) was added under nitrogen atmosphere and ice-cooled, and the mixture was stirred at the same temperature for 3.5 hours. After the mixture was extracted with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. : n-hexane / ethyl acetate = 2 / 1) purified to give [2-(1Η-indol-3-yl)-2-oxoethyl]isopropyl carboxylic acid tert-butyl ester 1.54 g (yield: 87%" 1.54 g (4.9 mmol) of [2-(1Η-indol-3-yl)-2-oxoethyl]isopropyl carboxylic acid tert-butyl ester obtained by the above reaction, Ν·dimethyl A solution of methotrexate (24 ml) was added to a solution of 1.60 g (9.7 mm 第三l) of potassium butoxide at room temperature under nitrogen atmosphere, and stirred at the same temperature for 10 minutes. To the reaction mixture, 1.50 g (7.3 mmol) of 3-methoxypropyl bromide was added, and stirred at 50 ° C for 4 hours. After the reaction mixture was cooled, it was diluted with water and evaporated with ethyl acetate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent solvent: toluene/acetone = 1 〇 /1) to give isopropyl-{2-[1-(3-methoxypropyl). -lH-D dec-3-yl]-2-oxoethyl} decanoic acid tert-butyl ester 1.49 g (yield: 79%). -131- 200815324 isopropyl-{2-[l-(3-methoxypropyl)-1Η-indole-3-yl]-2-oxoethyl}decanoic acid tert-butyl ester obtained by the above reaction A mixed solvent solution of 388 mg (1.0 mmol) of ethanol (4 ml) and pyridine (4 ml) was added to 167 mg (2.0 mmol) of 0-methylhydroxylamine hydrochloride, and stirred at 85 ° C for 5 hours. After the reaction mixture was cooled, diluted with EtOAc (EtOAc)EtOAc. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (solvent solvent··hexane/ethyl acetate=2/1) to give isopropyl-{2-[(E,Z)-methoxy Imino]-2-[1-(3-methoxypropyl)-1Η-indol-3-yl-2-ethoxyethyl}carboxylic acid tert-butyl ester 184 mg (yield: 44%). The isopropyl-{2-[(E,Z)-methoxyimino]-2-[1-(3-methoxypropyl MH-indol-3-yl]-2- obtained by the above reaction A solution of 183 mg (0.44 mmol) of oxyethyl}carboxylic acid tert-butyl ester in dichloromethane (2 ml) was added with trifluoroacetic acid 1.0 ml (13 mmol) and stirred at room temperature for 30 min. After extracting with ethyl acetate and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column eluting solvent: (i) ethyl acetate / triethylamine = 100/1; Ii) Methylene chloride/methanol/triethylamine = 200/10/1) was purified to give the title compound 117 mg (yield: 84%). Colorless liquid. 4 NMR spectrum (CDCh, 4 〇〇 MHz), 5: 8.30 (d, 0.6H, J = 7·4 Hz), 7.95 (s, 0.4H), 7.77 (d, 0.4H, J = 7.4 Hz), 7.3 9 -7.3 3 (m, 1.6H), 7.26-7.16 (m, 2H), 4.28-4.22 (m, 2H), 4.02 (s, 1.8H), 3.98 (s, 1.2H), 3.90 (s, 0.8H), 3.81 (s, 1.2H), 3.34-3.25 (m, 5H), 2.95 -2.83 (m, 1H), 2.10-2.03 (m, 2H), 1.09- 1.07 (m, 6H). -132- 200815324 (25b) (2S,4S,5S)-5-Amino-4-hydroxy-2-isopropyl-6-(isopropyl-{2-[(Z)-methoxyimino) ]-2-[ 1-(3-methoxypropylindole-indol-3-yl)ethyl}amino)hexanoic acid (2-aminomethylmethyl-2-methylpropyl) decylamine (3S,5S)-3-isopropyl-5-[(S)-l-(2-nitrophenylsulfonate) obtained by the example (1). Base) aziridine-2-yl]dihydrofuran-2-one, 2-isopropylamino-l-[l-(3-methoxypropyl)-1Η-吲哚 obtained in Example (25a) The 3-amino]ethanone 0-methyloxime and the 3-amino-2,2-dimethylpropanamine obtained in Reference Example 2 gave the title compound (yield: 19%). 'H NMR spectrum (CD3〇D, 400MHz), 5: 8.25 (d, 1H, J = 7.8 Hz), 7.71 (s, 1H), 7·75 (d, 1H, J = 7·8 Ηζ), 7 ·25 (t,1H,J = 7.8 Hz), 7.15 (t, 1H, J = 7.8 Hz), 6.71 (s, 2H), 4.31 (t, 2H, J = 6.8 Hz), 4.06 (s, 3H) , 3.88 (d, 1H, J = 12.9 Hz), 3.68 (d, 1H, J = 12.9 Hz), 3.3 8-3.29 (m, 7H), 3.18-3.06 (m, 2H), 2.75-2.61 (m, 2H), 2.31-2.25 (m, 1H), 2.12-2.05 (m, 2H), 1.80- 1.66 (m5 2H), 1.53- 1. 40 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 1.13-1.09 (m, 6H), 0.93-0.91 (m, 6H). Mass Spectrum (FAB + ), m/z: 603 ((M + H) + ) (Reference Example 1) (2R)-l-(Benzyloxy)but-3-en-2-ol (1&){(43,5 3)-5-[( Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-ylindole methanol (+)-2,3-0-isopropylidene-L-threose A solution of 30.92 g (191 mmol) of N,N-dimethylformamide (285 ml) was obtained under a nitrogen atmosphere and ice-cooling, and the hydrogenated-133-200815324 sodium (60% content) 7.71 g (193 mmol) was fractionated back. Add at 45 minutes and stir at the same temperature for 1 hour. To the reaction mixture was added 23.8 ml (200 mmol) of benzyl bromide in 30 portions, and stirred at the same temperature for 3 hours. 2.2 ml (38 mmol) of D-acetic acid in the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc evaporated. After the filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystalsssssssssssssssssssssssssssss Yellow liquid. 4 NMR spectrum (CDC13, 400MHz), 5: 7.38-7.28· (m, 5H), 4.59 (s, 2H), 4.08-4.03 (m, 1H), 3.97-3.93 (m, 1H), 3.77 (dt, 1H, J = 11.7 Hz, 4.3 Hz), 3.71-3.65 (m, 2H)? 3.56 (dd, 1H, J = 9.8 Hz, 5.9 Hz), 2.17 (dd, 1H, J = 8.2 Hz, 4.7 Hz), 1.42 (s, 3H), 1.4 1 (s,3H) o (lb) {(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-l,3-di [(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1, obtained by the reference example (la), decamosin-4-yl}methyl methanesulfonate a solution of 3-dioxane-4-yl}methanol 35.27g (140mmol) and triethylamine (29.2ml (210mmol) in dichloromethane (270ml). A solution of 168 mmol) in dichloromethane (90 ml) was stirred at room temperature for 20 min. 0.76 ml (42 mmol) of water was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. After filtration, the solvent was evaporated. Yellow liquid. Η NMR spectrum (CDC13, 500MHZ), 5: 7.37-7.28 (m, 5H), 4.58 (s, 2H), 4.42 (dd, 1H, J = 11.2 Hz, 3.4 Hz), 4.27 (dd, 1H, J = 11.2 Hz, 5.4 Hz), 4.15-4.11 (m, 1H), 4.07-4.03 (m, 1H), 3.69 (dd, 1H, J = 9.8 Hz, 4.9 Hz), 3.58 (dd, 1H, J = 9.8 Hz, 5.4

Hz), 3.02 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H). (lc) (4S,5S)-4-[(benzyloxy)methyl]-5-(iodomethyl)_2,2-dimethyldioxane The crude obtained in Reference Example (113) {(43) ,53)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-oxanthene-4-yl}methylmethyl formate 46.19g (140mmol) and iodine A solution of 62.87 g (419 mmol) of acetonitrile (420 ml) was evaporated. After the reaction mixture was cooled, the mixture was evaporated, evaporated, evaporated, evaporated. After filtration, the solvent was evaporated. Yellow liquid. NMR spectrum (CDC13, 400MHz), 5: 7.3 8-7.27 (m, 5H), 4.59 (s, 2H), 3.99-3.95 (m, 1H), 3.9-3.84 (m, 1H), 3.67 (dd, 1H , J = 10.2 Hz, 5.1 Hz), 3.64 (dd, 1H, J = 10.2 Hz, 5.1 Hz), 3.35 (dd, 1H, J = 10.6 Hz, 5.1 Hz), 3.28 (dd, 1H, J = 10.6 Hz) , 5.1 Hz), 1.47 (s, 3H), 1.42 (s, 3H). (ld) (2R)-l-(Benzyloxy)but-3-en-2-ol The crude (4S,5S)-4-[(benzyloxy)methyl]- obtained in Reference Example (lc) a mixture of 5-(iodo-135-200815324 methyl)-2,2-dimethyl-1,3-dioxanthine 49.20 g (136 mmol) and zinc sulphonate 26.66 g (408 mm 〇l) in ethanol (420 ml), Stir at 80 ° C for 3 hours. After the reaction mixture was cooled, the unreacted zinc dust was filtered through diatomaceous earth 545 and washed with ethanol. The filtrate was concentrated under reduced pressure. The mixture was diluted with EtOAc (EtOAc)EtOAc. After filtration, the solvent was evaporated to dryness crystals crystals crystals Yellow liquid. lH NMR spectrum (CDCh, 500 MHz), 5: 7.38-7.29 (m, 5H), 5.84 (ddd, 1H, J = 17.1 Hz, 10.3 Hz, 5.4 Hz), 5.37 (dt, 1H, J = 17.1 Hz, 1.5 Hz), 5.20 (dt, 1H, J = 10.3 Hz, 1.5 Hz), 4.58 (s, 2H), 4.3 8-4.3 3 (m, 1H), 3.55 (dd, 1H, J = 9.8 Hz, 3.4 Hz) , 3.38 (dd, 1H, J = 9.8 Hz, 7.8 Hz), 2.41 (d, 1H, J = 3.4 Hz) 0 (Reference Example 2) 3-Amino-2,2-di(methyl)propanamide (2a) a solution of 3-benzyloxycarbonylamino-2,2-di(methyl)propanol in 3-amino-2,2-dimethylpropanol 13.82 (13 4111111〇1) in tetrahydrofuran (140 ml) N-(benzyloxycarbonyloxy)butaneimine 50.0 g (200 mmol) was added, and stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure. After the filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -136- 200815324 Colorless liquid. 4 NMR spectrum (CDC13, 400MHz), 5: 7.39-7.31 (m, 5H), 5.16 (br s, 1H), 5.11 (s, 2H), 3·42 (t, 1H, J 27.0 Hz), 3.22 (d, 2H, J = 7.0 Hz), 3.04 (d, 2H, J two 7.0 Hz), 0.86 (s, 6H). (2b) 3-Benzyloxycarbonylamino-2,2-di(methyl)propanolamine 3-benzyloxycarbonylamino-2,2-di(methyl)propanol 4.6 obtained in Reference Example (2a) g ( 19.4 mm 〇 1) of a mixture of carbon tetrachloride (40 ml), acetonitrile and water (40 ml), sodium periodate 1 1.6 g (54.2 mmol) and ruthenium trichloride 0.2 g (0.9 6 mmol) Stir at room temperature for 16 hours. To the reaction mixture, 11.6 g (54.2 mmol) of sodium periodate and 0.2 g (0.96 mmol) of ruthenium trichloride were added, and the mixture was further stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. After filtration, 300 ml of a saturated aqueous solution of potassium carbonate was added and washed with ethyl acetate. The aqueous layer was treated with concentrated hydrochloric acid (pH 1) and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give purified crystals of 3-benzyloxycarbonylamino-2,2-di(methyl)propanoic acid. The resulting crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid 3.12 (123111111〇1) in tetrahydrofuran (20 ml) i glutamate 'Likou 1,1 · ore-based bis-1H· The extract was placed at 3.0 g (18.5 mmol) and stirred at room temperature for 1 hour. 20 ml (914 mmol) of a 20% aqueous ammonia solution was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with water and diluted with ethyl acetate. The organic layer was washed with aqueous 1H hydrochloric acid and brine. After filtration, the residue was washed with saturated aqueous potassium carbonate (300 ml) and washed with ethyl acetate. The aqueous layer was extracted with aq. EtOAc EtOAc (EtOAc). After filtration, the residue was evaporated to give the title compound (yield: 54%) (yield: 54%). liquid. 4 NMR spectrum (CDCl3, 400MHz), (5: 7·36·7·28 (m, 5H), 5.82 (br s, 1H), 5.71 (br s, 1H), 5.48 (br s, 1H) , 5.09 (s, 2H), 3.31 (d, 2H, J = 6.7 Hz), 1.21 (s, 6H) 0 (2c) 3-amino-2,2-di(methyl)propanamide (2b) 3-benzyloxycarbonylamino-2,2-di(methyl)propanamide 2.5 £ (1〇111111〇1) and 7.5% palladium carbon (50% aqueous) 1.22 ethanol (5〇1111) The suspension was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the hydrogen in the reaction vessel was replaced with nitrogen, the palladium carbon was filtered and washed with ethanol. The solvent was distilled off under reduced pressure. After drying, the residue was evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssssssss (5: 7·73 (br s, 1H), 5.68 (br s, 1H), 2.78 (s, 2H), 1.16 (s, 6H) (Reference Example 3) 1,2,3,4-tetrahydrogen Quinoline-7-ylmethanol (3 a) methyl 4-(3-methoxy-3-oxoprop-1-en-1-yl)-3-nitrobenzoate in 4-methylindolyl-3 Methyl 1-nitrobenzoate 1.40 g (6.7 mmol) of tetrahydrofuran (13 ml) solution, adding 2.24 g (6.7 mmol) of triphenylphosphinylacetate methyl ester, and stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate - 138-200815324. After the filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4 NMR spectrum (CDCh, 400 MHz), 5: 8.80 (d, 0.15H, J = 2.0 Hz), 8.67 (d, 0.85H, J = 2.0 Hz), 8.28 (dd, 0.85H, J = 8.2 Hz, 2.0 Hz), 8.25 (dd, 0.15H, J = 8.2 Hz, 2.0 Hz), 8.11 (d, 0.85H, J = 16.0 Hz), 7.71 (d, 0.85H, J 8.2 Hz), 7.48 (d, 0.15) H, J = 8.2 Hz), 7.43 (d, 0.15H, J = 11.7 Hz), 6.43 (d, 0.85H, J = 16.0 Hz), 6.16 (d, 0.15H, J = 11.7 Hz), 3.99 (s , 2.55H), 3.98 (s, 0.45H), 3.85 (s, 2.55H), 3_60 (s, 0.45H). (3b) Methyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate 4-(3-methoxy-3-oxoprop-1-ene obtained in Reference Example (3a) a suspension of 1.- -1-yl-3-methylbenzoic acid methyl ester 1.69 g (6.4 mmol) and 10% palladium on carbon (50% aqueous) 0.96 g of acetic acid (128 ml), stirred under a hydrogen atmosphere at 70 ° C. hour. After the reaction mixture was cooled, the hydrogen in the reaction vessel was replaced with nitrogen. The palladium carbon was filtered, and the filtrate was washed with ethyl acetate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent solvent, n-hexane/ethyl acetate = 1 /1) to give the title compound 0.93 g (yield: 71%). Yellow solid. 4 NMR spectrum (CDCh, 400 MHz), 5: 8.13 (br s, 1H), 7.68 (dd, 1H, J = 7.8 Hz, 1.6 Hz), 7.44 (d, 1H, J = 1.6 Hz), 7.24 (d, 1H, J = 7.8 Hz), 3.92 (s, 3H), 3.03 (t, 2H, J = 7.8 Hz), 2.67 (t, 2H, J = 7.8 Hz). -139-200815324 (3c) 1,2,3,4-tetrahydroquinolin-7-ylmethanol A solution of 1.20 g (31.7 mmol) of lithium hydride in tetrahydrofuran (97 ml) under nitrogen atmosphere and ice-cooled to 30 A solution of 2.60 g (12.7 mmol) of tetrahydrofuran (30 ml) of methyl 2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxylate obtained in Reference Example (3b) was added, and stirred at room temperature 30 The mixture was stirred at room temperature for 30 minutes and further stirred at 50 ° C for 2 hours. After cooling the reaction mixture in an ice water bath, 20 ml of ethanol was added in 30 portions, and the mixture was stirred at the same temperature for 1 hour. A 10% aqueous solution of potassium tartrate and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yellow solid. 4 NMR spectrum (CDCh, 400 MHz), 5 ·· 6.93 (d, 1H, J = 7.8 Hz), 6.58 (dd, 1H? J = 7.8 Hz, 1.6 Hz), 6.49 (d, 1H, J = 1.6 Hz) , 4.54 (s, 2H), 3.03 (t, 2H, J = 5.9 Hz), 2.75 (t, 2H, J = 6.7 Hz), 1.96- 1.90 (m, 2H). (Test Example 1) Renin inhibitory activity test (1) Method 1 Renin activity was measured by adding a renin and a synthetic renin matrix to the ratio of angiotensin I production after the reaction at 37 °C. Renin is transiently expressed in 293T cells, and its culture supernatant is used as an enzyme source. After the prepared culture supernatant is trypsinized to activate human renin, the test compound is dissolved in a solvent (for example, DMSO, etc.) -140-200815324, or 2/z 1 of the solvent is added to make the final concentration 1% by volume' added buffer containing synthetic renin matrix (NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Glu-C〇OH) The solution (1 mM EDTA, 100 mM Tris-HCl, pH 7.4) was incubated at 37 ° C for 1 hour. The concentration of angiotensin I produced was measured by radioimmunoassay [Renin, Peizhu (registered trademark), Yamasa Soy Sauce Company] according to the attached document. The renin inhibitory activity is IC5 at a concentration of each test compound which inhibits the production of angiotensin I by 50%. I will evaluate it. (2) Method 2 Renin activity is a renin-containing and fluorescent marker to synthesize a renin matrix, and the ratio of angiotensin I produced after the reaction at 37 ° C is measured by a fluorescence method. Renin is transiently expressed in 293T cells, and its culture supernatant is used as an enzyme source. After the prepared culture supernatant is trypsinized to activate human renin, the test compound is dissolved in a solvent (for example, DMSO or the like), or the solvent is added to a final concentration of 1% by volume, and a fluorescent-labeled synthetic kidney is further added. Buffer (ArgMu(EDANS)-Ile-His-Pro-Phe-His-Leu_Val-Ile-His-Thr-Lys(dabcyl)-Arg] (ImM EDTA, 100 mM Tris-HCl, ρΗ7 · 4), keep at 90 ° C for 90 minutes. After the end of the incubation, the angiotensin I concentration generated by fluorescence (Ex: 340 nm, Em: 492 nm) was measured. The renin inhibitory activity is IC5 at a concentration of each test compound which inhibits the production of angiotensin I by 5%. I will evaluate it. The compounds of Examples 1 to 25 were 1 C5 〇〇 below 1 〇〇 nM in the test according to Method 2. The compound of the present invention exhibits excellent renin inhibitory activity and is useful as a medicine for the treatment or prevention of hypertension. -141- 200815324 (Test Example 2) Plasma renin activity (PRA) test Plasma renin activity keeps plasma at 37 ° C as a blood vessel tension per unit time from endogenous angiotensinogen and endogenous renin The amount of production of the prime I was measured. In the mixed cynomolgus monkey plasma, add test compound or solvent (such as DMSO, etc.), add the buffer, and incubate for 1 hour at 37t. The concentration of angiotensin I produced per unit time was measured by radioimmunoassay (refer to Test Example 1). The plasma renin inhibitory activity was 1 C5 at a concentration of each test compound which inhibited PRA by 50%. I will evaluate it. The compound of the present invention exhibits excellent plasma renin inhibitory activity and is useful as a medicine for the treatment or prevention of hypertensive disease. (Test Example 3) In vitro test The renin-angiotensin system was induced by normal animals, or low sodium intake (1 week) and intramuscular injection of furosemide (3 or 10 mg/kg). A marmoset or cynomolgus monkey was sampled before the administration of the test compound, 1, 2, 4, 8, and 24 hours after administration. The test compound was suspended in 1% methylcellulose and forcedly administered orally. The obtained plasma was incubated at 4t: or 37 ° C, and the concentration of angiotensin present in each reaction solution was measured by radioimmunoassay (refer to Test Example 1). The PRA was calculated from the angiotensin I concentration in the reaction solution maintained at 37 ° C minus the angiotensin I concentration in the reaction solution kept at 4 ° C, and was calculated as the angiotensin I concentration per unit time. The PRA inhibitory activity of the test compound was evaluated by the PRA inhibition rate after each administration time relative to the PRA before administration of the test compound. -142- 200815324 The compound of the present invention has excellent PRA inhibitory activity and a low concentration of angiotensin I in plasma, and is useful as a medicine for treating or preventing hypertension. (Test Example 4) Blood pressure lowering test The human renin-derived mouse was introduced into the mouse and the human angiotensinogen gene was introduced into the mouse to obtain a renin-dependent hypertensive mouse (Tsuba high blood pressure mouse). , 1994, Vol. 169, No. 5, p. 422). Blood pressure was measured non-observed under awakening before, after 1, 2, 4, 8, and 24 hours of administration of the test compound. The test compound was suspended in 1% methylcellulose and forcedly administered orally. The compound of the present invention has an excellent blood pressure lowering action and is useful as a medicine for the treatment or prevention of hypertension. (Test Example 5) Solubility test (1) Stock solution The test compound was dissolved in dimethyl hydrazine (DMSO) to a concentration of 10 mM. The resulting solution was used as a stock solution (10 mM). (2) Standard solution The stock solution (10 mM) 25 "1 was added to the HPLC sample bottle (glass, capacity 1.5 ml). Add acetonitrile 475 // 1 to the HPLC sample bottle, and mix the solution well, add distilled water 500 // 1 and densely plugged, the resulting solution is thoroughly mixed. The obtained solution is used as a standard solution (St, 250 // 1). (3) The test solution is the first liquid (JP1) or the second liquid (JP2) of the Japanese Pharmacopoeia, and sodium acetate. Buffer (pH 4.0) or phosphate buffered saline (pBs, pH 7.4) was used as the test solution of -143- 200815324. (4) Test compound solution was dispensed into the microtube dispensing test solution 990 /z 1, and the stock solution was added ( 1 〇 mM) 1 M 1. The resulting solution was stirred for 10 minutes in a mixer (1000 rpm), and the solution was equilibrated by shaking for 10 minutes in a constant temperature water bath at 25 ° C. Using a filter mounted in a syringe ( The solution obtained above was filtered by Ekicrodisc CR3 (pore diameter: 45 mm), and the obtained filtrate was added to an HPLC sample bottle (made of glass, capacity: 1.5 ml), and acetonitrile 500/1 was added thereto to bind the solution, and the resulting solution was thoroughly mixed. Test compound solution. (5) Quantification of test compound The test compound solution obtained in (4) is quantitatively analyzed by high-speed liquid chromatography using a calibration curve prepared from a standard solution, and the concentration of the test compound in the test compound solution is determined. The solubility of the test compound is evaluated by the measured test compound concentration. The compound of the present invention has excellent solubility and is useful as a medicine (especially a medicine for treating or preventing hypertension). (Test Example 6) Drug dynamic test The drug dynamic test can be carried out according to a method known in the field of pharmacokinetics. The test compound is dissolved in a 1% methylcellulose aqueous solution, and the obtained solution is used in an animal (for example, a mouse, a mouse, a marmoset, a cynomolgus monkey, etc.) for a general drug dynamic test in an appropriate range (for example, 3 mg/kg~ 100 mg/kg) was administered by □. The test compound was dissolved in physiological saline, and the obtained solution was used in an appropriate range for the animals used in the general drug dynamic test (for example, mice, mice, marmosets, cynomolgus monkeys, etc.). (eg 1 mg/kg~10 mg/kg) intravenous (-144-200815324 such as tail vein, temporal cutaneous vein, vault vein, etc.) And after a certain period of time (for example, 0.08, 0_25, 0·5, 1, 2, 4, 6, 8, or 24 hours), the appropriate blood collection site (such as jugular vein, orbital venous plexus, temporal cutaneous vein, etc.) The blood is collected, and the obtained blood is centrifuged to prepare a plasma sample, and the concentration of the test compound contained in the plasma sample is determined by quantitative analysis using a liquid chromatography mass spectrometer (LC/MS/MS). The concentration of the test compound (Cmax) in plasma, the area under test compound concentration-time curve (AUC) in plasma, and absolute bioavailability were evaluated. Cmax is the highest concentration of the test compound in the plasma measured after oral administration. The AUC is calculated from the time point from the time when the test compound is administered to the time when the blood is finally collected. The absolute bioavailability is calculated by the following formula: (AUC/administration amount after oral administration) / (AUC/administration amount after intravenous administration) The compound of the present invention exhibits excellent drug dynamics (Cmax, AUC) Or absolute bioavailability) is useful as a medicine (especially for the treatment or prevention of hypertension). (Formulation Example 1) A tablet compound (10 mg), colloidal cerium oxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg), and lactose (Example). 98.8 mg), a tablet was prepared according to the usual method. The resulting lozenge can be coated as necessary. (Formulation Example 2) a hard gelatin compound in a standard two-part hard gelatin-filled powder of the compound of the example -145-200815324 (l〇mg), lactose (150 mg), cellulose (50 mg), and stearic acid Magnesium (6mg), to make hard plastic bottles, washed, and dried. (Formulation Example 3) Soft gelatin The mixture of the digestible oil such as soybean oil or olive oil and the compound of the example contains 10 mg of the active ingredient, and is poured into gelatin to prepare a soft capsule, which is washed and dried. (Formulation Example 4) 5 ml of a suspension suspending agent containing a micronized compound (1 mg), sodium carboxymethylcellulose (100 mg), sodium benzoate (5 mg), sorbitol solution (Japanese Pharmacopoeia, l .Og), and vanillin (0.025 ml) to make a suspending agent. (Formulation Example 5) Creams in Shiraishi Rouge (40% by weight), microcrystalline 蠘 (3% by weight), lanolin (10% by weight), sorbitan monododecanoate (5% by weight), 0.3 % polyoxyethylene (20) sorbitan monododecanoate (〇3 wt%) and water (41.7 wt%) were mixed into a 5 g cream to prepare a micronized compound (10 mg). Cream. # [Industrial Applicability] The compound of the formula (I) of the present invention or a pharmacologically acceptable salt thereof is inhibited by renin, solubility, cell membrane permeability, oral absorption, blood concentration, metabolic stability, tissue migration Sex, bioavailability, in vitro activity, in vivo activity, rapid discovery of drug efficacy, persistence of pharmacodynamics, physical stability, drug interaction, toxicity, etc. have excellent properties as medicines (especially treatment of hypertension or Prevention (suitable for treatment) medicine] useful. [Simple description of the diagram] None -146-

Claims (1)

200815324 X. Patent application scope: 1 ·~ A compound of the following formula (I) or its pharmacologically acceptable salt Wherein R1 is a hydrogen atom, a Ci-C8 alkyl group, a substituted Ci_C8 alkyl group, a C2-alkenyl group, a substituted c2-C6 alkenyl group, a C2-C6 alkynyl group, a substituted c2-c6 alkyl group, a hydroxyl group, a Ci-C6 alkane. Oxy, substituted c丨_C6 alkoxy, C丨-〇6 thiol, substituted Ci-C6 alkylthio, amine, Cl-C6 alkylamino, substituted Ci-C6 alkylamino, di (Ci -C6 alkyl)amino groups (the alkyl groups may be the same or different), substituted bis(CMC6 alkyl)amino groups (the alkyl groups may be the same or different), indolyl, (Cl-C6 alkyl)carbonyl And substituting (Cl-C6 alkyl)carbonyl, (Ci-C6-homoyloxy)carbonyl, substituted (Ci-C6-homoyl)-based, c3-c1() cyclic hydrocarbon, substituted C3-Ci. a cyclic hydrocarbon group, a 3 to 10 membered heterocyclic group or a substituted 3 to 10 membered heterocyclic group, and a substituent of each of the cyclic hydrocarbon group and the heterocyclic group in R1 is the same selected from the substituent group α or /3 Or one or three different bases, two of which may together form a Ci-C5 alkylene group, and the substituents of the cyclic hydrocarbon group and the heterocyclic group in R1 are the same or different selected by the substituent group α 1 to 3 groups; R2 is a hydrogen atom, a Cl-C6 group, a substituted Ci-C6 group, a C2-C6 group, a substituted C2-C6 alkenyl group, a C2-C6 alkynyl group, a substituted C2-C6 alkyne a group, a C3-C8 cycloalkyl group, or a substituted C3-C8 cycloalkyl group, wherein the substituent of each group in R2 is the same or a different one or three groups selected from the substituent group α or /3, R1 and R2 is a substituent which may form a 3- to-147-200815324 10 member nitrogen-containing heterocyclic group or a 3- to 10-membered nitrogen-containing heterocyclic group together with these bonded nitrogen atoms, and the substituent of the nitrogen-containing heterocyclic group is a substituent group ^Select the same or different 1 to 3 groups; R is a hydrogen atom, Ci-C6, substituted Ci-C6, C2-C6, substituted C2-C6 alkenyl, C2-C6 alkyne , substituted c2-C6 alkynyl, C3-C8 cycloalkyl, substituted C3 - C8 cycloalkyl, hydroxy The substituent of each group in the c丨-C 6 alkoxy group, the substituted Ci-C6 alkoxy group, the Ci-C6 alkylthio group, or the substituted Ci-C6 alkylthio group 'R is the same selected from the substituent group ^ Or a different one to three groups; R4 is a hydrogen atom, a G-C6 alkyl group, a substituted Ci-C6 alkyl group, a C2-C6 alkenyl group, a substituted C2-C6 alkenyl group, a C2-C6 alkynyl group, a substituted C2 group -C6 alkynyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, hydroxy, (^-oximeoxy, substituted CMC6 alkoxy, Ci-C6 alkylthio, or substituted Cl-C6 alkane The substituent of each group in R4 is the same or different one or three groups selected from the substituent group a, and R3 and R4 may together form a C1-C5 alkylene group or a substituted Ci-C5 alkylene group. The substituent of the alkylene group is the same or different one to three groups selected by the substituent group α; R5 is a gas atom, a Ci-C6 yard group, a substituted Ci-C6 yard group, a c3-C8 ring fire Complete, substituted C3-C8 cycloalkyl, hydroxy, ChC6 alkoxy, substituted Ci-C0 alkoxy, amine, C丨-C6 alkylamino, substituted Ci-C6 amine, di(C 1 - a C 6 base) amine group (the same may be the same or different), or a substituted bis (C ^ Ce alkyl) amine group (the alkyl group may be the same or Iso), the substituent of each group in R5 is the same or different oxime selected from the substituent group ^ to 3 groups; -148- 200815324 R6 is a hydrogen atom, an alkyl group, a substituted Ci-G alkyl group, c3_c8 Ring-based, substituted C3-C8 cycloalkyl, hydroxy, C^C6 alkoxy, substituted C 1 -C6 alkoxy, amine, C 1 -C 6 amidino, substituted c 1 -C 6 amine, a (Ci-C6 fluorenyl)amino group (which may be the same or different), or a substituted bis(Ci-C6 alkyl) amine group (the alkyl group may be the same or different), each of the groups in R6 The substituent is the same or different one to three groups selected by the substituent group α; R7 is a hydrogen atom, a Cl_C6 yard group, a substituted Cl-C6 yard group, a C3-C8 ring yard group, a substituted C3-Cs ring Alkyl, hydroxy, Ci-C6 alkoxy, substituted C 1 -C6 alkoxy, amine, C 1 -C6 aminyl, substituted c 1 -C 6 amine, bis(C^Ce alkyl)amine (the alkyl groups may be the same or different), substituted bis(Ci-Ce alkyl) amine groups (the alkyl groups may be the same or different), indolyl, (Ci-C6 alkyl)carbonyl, substituted (Ci -C6 alkyl)carbonyl, (Cl_C6 alkoxy)carbonyl, or substituted (Ci-C6 alkoxy)carbonyl The substituent of each group in R7 is the same or different one to three groups selected by the substituent group α; Υ is a single bond, C 1 - C 6 is extended, and C 1 - C 6 is substituted a C 2 -C 6 stretching group, a substituted C2-C6 alkenyl group, a C2-C6 alkynyl group, a substituted C2-C6 alkynyl group, or a formula -(Cl^aX^CI^b-[wherein X1 Is a group of the formula -ΝΗ-, -NR9- (wherein R9 is a CCs alkyl group), -〇-, -S-, 4〇- or -S〇2_, each of a and b is an integer from 〇 to 5 , the sum of a and b is a group of 0 to 5], and the substituent of each group in Y is the same or different one or three groups selected by the substituent group y; R8 is a formula (II) -149- 200815324 (丨丨) [where A is C3 - C ^. Cyclic hydrocarbon group, substituted c 3 - C!. a cyclic hydrocarbon group, a 3 to 10 ring heterocyclic group, or a substituted 3 to oxime heterocyclic group, wherein the substituent of each group in a is the same or different one or three groups selected from the substituent group. X2 is a group of the formula -ΝΗ-, -NR11- (wherein R11 is an alkyl group), -〇-, .S-, -SO- or -S〇2-, R1. Is Ci-Ce alkyl, substituted Ci-C6 alkyl, ChC6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted c2-C6 alkynyl, C3-C8 ring-based, or substituted C3-C8 a cycloalkyl group, the group of R1 (the substituent of each group of 3 is the same or different one or three groups selected from the substituent group 5), or the formula (III) or (IV) A fused ring forms 9 to 10 membered nitrogen-containing heterocyclic groups, or a substituted 9 to 10 membered nitrogen-containing heterocyclic group, and the substituent of the nitrogen-containing heterocyclic group is the same or different from the substituent group α to 1 a group of three, R12 is the same as rk; a substituent group α is composed of a Ci-C6 alkyl group, a halogen C丨-C6 alkyl group, a hydroxyl group, a Ci-C6 alkoxy group, a halogen Ci-C6 alkoxy group. Base, thiol group, Ci-C6 alkylthio group, Ci-C6 alkylsulfinyl group, C丨<6 alkanesulfonyl group, amine group, fluorene-decylamine group, bis(C^C:6 Alkyl)amino group (the alkyl group may be the same or different), methyl-150-200815324 decylamino, (C^Caalkyl)carbonylamino, carbenyl, (ChC6 alkyl)carbonyl, carboxyl, ( Cl-c6 alkoxy)carbonyl, aminemethanyl, (Cl-C6 alkylamino)carbonyl, bis(Ci-C^alkyl)aminecarbonyl (the alkyl group may be the same or different), amine sulfonyl a group of (Ci-Ce alkylamino)sulfonyl, di(CMC6 alkyl)amine sulfonyl (which may be the same or different), cyano, nitro, halogen, and oxy; The substituent group /3 is a C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group, C6-C!. a group in which an aryl group, a substituted C6-C1Q aryl group, a 3 to 1 membered heterocyclic group, and a substituted 3 to 10 membered heterocyclic group, and a substituent of each group in the substituent group /3 are represented by a substituent group α Selecting the same or different 1 to 3 groups; the substituent group r is composed of a Ci-c6 alkyl group, a hydroxyl group, a halogen group, an oxy group, a hydroxyimino group, and a (Ci_C6 alkoxy) imide group. a group of substituents (5 is a hydroxyl group, an alkoxy group, a thiol group, a Cl-C6 alkylthio group, an alkylsulfinyl group, a ChCe alkanesulfonyl group, an amine group, a Cl-C6 alkylamino group, two (C^-Ce alkyl)amino group (the alkyl group may be the same or different), (Cl-C6 alkyl)carbonylamino group, (Cl-C6 alkyl)sulfonylamino group, amine carbonylamino group, ( ChCe alkylamino)carbonylamino, bis(C^Cealkyl)aminecarbonylamino (the alkyl group may be the same or different), amine sulfonamide, (Ci-C6 alkylamino) sulfonamide And a group of di(Ci-C6 alkyl)amine sulfonamide groups (the alkyl groups may be the same or different). 2. The compound of claim 1, or a pharmacologically acceptable salt thereof, wherein R1 is Ci-C8 alkyl, substituted C^c8 alkyl, C2-C6 alkenyl, substituted c2-c6 alkenyl, c2-c6 Alkynyl, substituted c2-c6 alkynyl, C3_Cl. -151- 200815324 cyclic hydrocarbon group, substituted C3-Ci. cyclic hydrocarbon group, 3 to 10 membered heterocyclic group, or substituted 3 to 1 member heterocyclic group, R1 The substituent of each of the cyclic hydrocarbon group and the heterocyclic group is the same or different one or three groups selected from the substituent group αΐ or /31, and the substituent of the cyclic hydrocarbon group and the heterocyclic group in R1 is The same or different one to three groups selected from the substituent group α 1 , which is composed of a Ci-C6 alkyl group, a halogen Ci-C6 alkyl group, a hydroxyl group, a Ci-Ca alkoxy group, and a halogen group. Ci-C6 alkoxy, thiol, Ci-C6 alkylthio, hexane-sulfinyl, CVC6 alkanesulfonyl, amine, Ci-Ce alkylamine, bis(C^-Ce) a group of amino groups (the alkyl groups may be the same or different), an amine carbenyl group, an alkylamino)carbonyl group, a dialkyl)amine carbonyl group (the alkyl groups may be the same or different), and a halogen group. The substituent group /31 is a group of a C3-Cs ring-based group, a C6-Ci-fluorene group, and a 3- to 10-membered heterocyclic group. 3 The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the alkyl group or the substituent (^-(6 alkyl group) (the substituent is the same or different from the substituent group α2 or 02) To three groups), a C3-C8 cyclic hydrocarbon group, or a substituted (: 3-(:8 cyclic hydrocarbon group (the substituent is the same or different one or three groups selected by the substituent group α2) , the substituent group α2 is composed of a Ci-C6 alkyl group, a hydroxyl group, a Ci-Ce alkoxy group, an amine carbenyl group, a (Ci-C6 alkylamino)carbonyl group, and a di(Ci-C6 alkyl) amine carbonyl group (this a group of alkyl groups which may be the same or different, and a substituent group of /32 is a group of -Cd-C8 (cycloalkyl) and a C6-C1() aryl group - 152 - 200815324. The compound of Item 1, or a pharmacologically acceptable salt thereof, wherein R1 is a c2-c7 alkyl group or a substituted c2-c7 alkyl group (the substituent is the same or different one or three groups selected from the substituent group α3) Or a c4-C? cycloalkyl group, the substituent group α3 is a group of a hydroxyl group and an amine carbenyl group. 5 - A compound according to any one of claims 1 to 4, or a pharmacological thereof thereof Allow salt, of which R2 is a hydrogen atom, a Ci-c6 alkyl group, or a c3-c8 cycloalkyl group 'R1 and R2 may form a 3 to 10 member nitrogen-containing heterocyclic group together with these bonded nitrogen atoms. Or a pharmacologically acceptable salt thereof, wherein R2 is a hydrogen atom. The compound of any one of claims 1 to 6, or a pharmacologically acceptable salt thereof, wherein the ruler 3 is Ci -Ce alkyl, C3-C8 cycloalkyl, or Ci-G alkoxy 'R4 is a hydrogen atom, a Ci-c6 alkyl group, or a ChC8 cycloalkyl group, and R3 and R4 may together form a C^-Cs alkylene group. 8. A compound according to any one of claims 1 to 6, wherein R3 is a Ci-C6 alkyl group, and R4 is a hydrogen atom, as in any one of claims 1 to 6, wherein the scope of claims 1 to 8 A compound according to any one of the compounds, or a drug thereof, wherein R5 is a hydrogen atom, a Ci-CU or a C3-Cs ring, and R6 is a hydrogen atom, a C^-Cs alkyl group, or a compound thereof. Or a compound or a pharmacologically acceptable salt thereof, wherein R5 and R6 are a hydrogen atom. 11. Patent Application No. 1 to A compound according to any one of the items 1 to 10, or a pharmacologically acceptable salt thereof, wherein 117 is a C^-Cs alkyl group or a C3-C8 cycloalkyl group. 12. A compound according to any one of claims 1 to 10 Or a pharmacologically acceptable salt thereof, wherein R7 is a hexanyl group. The compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof, wherein Y is a single bond, Ci-Ce An alkyl group, or a substituted fluorene-terminated alkyl group (the substituent is the same or a different one or three of the groups selected by the substituent group r). 14. The compound of any one of claims 1 to 12, or a pharmacologically acceptable salt thereof, wherein Y is a Ci-Cz alkylene group. The compound of any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, wherein R8 is a formula (Ila) -154- 200815324 [Equation 8 & C3-C1. Ring yard base, replacing C3-Cl. Ring-based, C6-Cic aryl, or substituted C6-Ci. An aryl group, a 5 to 10 membered aromatic heterocyclic group, or a substituted 5 to 10 membered aromatic heterocyclic group, and the substituent of each group in Aa is the same or different from the substituent group αΐ, 1 to 3 The group X2a is a group of the formula -ΝΗ-, ·0- or -S-, wherein C3 is a Ci-G alkyl group, a substituted C-C6 alkyl group, a C2-C6 alkenyl group, a substituted C2-C6 alkenyl group, and a C2 group. a -C6 alkynyl group, or a substituted C2-C6 alkynyl group, the substituent of each group in R1Qa being the same or a different one or three groups selected from the substituent group 51, or in the formula (Ilia) or (IVa) [In the formula, each of Ba and Da is a 5- to 6-membered monocyclic cyclic group, and Ba and Da may together form a 9 to 10 member nitrogen-containing heterocyclic group or a 9 to 10 member nitrogen-containing heterocyclic group. The substituent of the nitrogen-containing heterocyclic group is the same or different one or three groups selected from the substituent group αΐ, and <12a is a group having the same meaning as R1C)a, and the substituent group (51 is Hydroxy, 0-(:6 alkoxy, Ci-C6 alkylthio, alkylsulfinyl, Ci-C6 alkanesulfonyl, Ci-C6 alkylamino, and di(Ci-G alkyl) amine The compound of any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, wherein R8 is a formula (lib) -155- 200815324 [wherein Ab is a substituted c6-C1() aryl group or a substituted 5- to 6-membered aromatic heterocyclic group, and the substituent of each group in the Ab is the same or different one or three selected from the substituent group α1 Further, X2b is a group of the formula-0-, a d C丨-C6 alkyl group, a substituted C1-C6 alkyl group, a substituted C2-C6 alkenyl group, or a substituted C2-C6 alkynyl group, wherein the substituent of each group is a group of the same or different 1 to 3 groups selected by the substituent group 52, or a formula (Illb) (Tb^Td^) (mb) R12b [wherein Bb and Db are each 5 to 6 members a monocyclic cyclic group, Bb and Db may form a 9 to 10 member nitrogen-containing heterocyclic group together with a fused ring, R12b is a group having the same meaning, and the substituent group δ 2 is a hydroxyl group, a Cl-C6 alkoxy group. a group of Ci-C6 alkylthio, c^c: 6-amine amine, and bis(Cl_C6 alkyl)amine (the alkyl groups may be the same or different). 17. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, wherein R8 is a formula (lie) [Form φ A. Is a substituted phenyl group (the substituent is the same or different one or three groups selected by the substituent group α 4), -156· 200815324 X2 e is a group of the formula -〇-, &1" Substituting (: 1-(:6-alkyl) (the substituent is a group of the same or different 1 to 3 groups selected by the substituent group), and the substituent group α4 is a Ci-C6 alkane a halogen, C丨-C6 alkyl group, a Ci-C6 alkoxy group, a halogen Ci-C6 alkoxy group, an amine group, a Ci-Ce alkylamino group, a di(Ci-Ce alkyl) amine group (the alkyl group can be a group of substituents which are the same or different) and a halogen group (5 3 is a group consisting of a hydroxyl group, a fluorene 6 alkoxy group, and an alkylthio group. 18) a pharmaceutical composition which is patented as claimed The compound of any one of the items 1 to 17, or a pharmacologically acceptable salt thereof, is an active ingredient. 19. The pharmaceutical composition according to claim 18, for treating or preventing a disease which can be treated or prevented by renin inhibition 2Q·If the pharmaceutical composition of claim 18 is used to treat or prevent hypertension. -157- 200815324 VII. Designated representative map: (1) The representative representative of the case is: (B) representing a symbol elements representative diagram of the present briefly described Μ eight billion, when the case if the formula, please disclosed invention features most indicative of the formula: