TW201111364A - Renin inhibitors - Google Patents

Abstract

The present invention relates to pyridine-bearing amino amide-based renin inhibitor compounds, and their use in treating cardiovascular events and renal insufficiency.

Description

201111364 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel renin inhibitors of the general formula (I). The invention also relates to some related aspects, including a method of preparing the compound, a pharmaceutical composition comprising one or more compounds of formula (I), and especially its use as a renin inhibitor in cardiovascular events and renal insufficiency. This application claims the benefit of U.S. Provisional Application Nos. 61, 88, 303 and 61/126, 529, filed on August 7, 2008, and on May 5, 2008. • [Prior Art] In the renin-angiotensin system (RAS), the bioactive vasoconstrictor π (Ang II) is produced by a two-step mechanism. The highly specific enzyme renin cleaves vasopressin into angiotensin I (Ang I), which is then further processed into Ang II by a less specific angiotensin converting enzyme (ACE). Ang II is known to act on at least two receptor subtypes called AT! and AT2. Although Octopus seems to transmit most of the known functions of Ang II, the role of aT2 is still unknown. ® RAS modulation represents a major advance in the treatment of cardiovascular disease. ACE inhibitors and AT! blockers have been accepted to treat hypertension (Waeber B. Dedicated, "Renin-Cytokinin system: role in experiments and human hypertension' at Birkenhager W. H" Reid JL (eds.): Hyperiewsion, Amsterdam, Elsevier Science Publishing Company, 1986, 489-519; Weber MA, Am. J. Z/yperie/w., 1992, 5, 247S). In addition, ACE inhibitors are used. Kidney protection (Rosenberg ME et al., Junimaiiona/, 1994, 45, 403; Breyer J. Α· et al., Yan Ye (4) 2/, 1994, 45, S156) to prevent septic heart failure (Vaughan D Ε· 143482-1 201111364 et al., Qzrd/oviwc. /?α·, 1994, 2S, 159; Fouad-Tarazi F. et al., Am. 乂Med., 1988, private (#龙3A), 83) And myocardial infarction (Pfeffer MA et al, Μ J. Mei/., 1992, 327, 669). The theoretical basis for the development of renin inhibitors is the specificity of renin (1^&1111·D., Cari/wwwc Dmgj·, 1995, 9, 645). The only substrate known to renin is angiotensinogen, which can only be treated with renin (under physiological conditions). In addition to Ang I, ACE can also cause vasopressin cleavage and can be bypassed by chymotrypsin, which is a serine protease (Husain A·, J. //Shazhou Pan Muscle, 1993, 7i , 1155). In patients, inhibition of ACE results in accumulation of vasopressin, coughing (5-20%), and potentially life-threatening vascular edema (0.1-0.2%) (Israili ZH Et al., Chilling, 1992, W7, 234). Chymotrypsin is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Repression of AT\receptors (eg, by losartan) overexpresses other AT-receptor subtypes (eg, AT2) to Ang II at concentrations that are inhibited by AT! receptors Significantly increased. In summary, renin inhibitors are expected to exhibit different pharmacological modalities from ACE inhibitors and AT! blockers in terms of their efficacy in blocking RAS and in terms of safety. Confirmation of a renin inhibitor with non-peptide properties and low molecular weight. Specifically, oral active renin inhibitors are described as having a long duration of action and are active in indications other than blood pressure regulation, wherein the tissue renin-chymotrypsin system can be activated, resulting in pathophysiology Local changes in the way, such as kidney, heart and blood vessel transformation, atherosclerosis 143482-1 201111364 tumor hardening, and possibly restenosis. The compounds described in the present invention represent the species. SUMMARY OF THE INVENTION The novel structure of w is directed to certain compounds, and their effects on the renin enzyme, including the treatment of symptoms known to be associated with the renin system. ' The invention is specifically directed to compounds of formula I: for inhibition

R2 R3

(Ζ)η1Υ

And optically pure mixture of palmo-isomers, palmo isomers, ... racemates, diastereomers, mixtures of diastereomers, :: imager racemates a mixture of diastereomeric racemates in the form of a racemic formula; a salt, a solvate, and a morphological form, wherein the members of the component are referred to herein. DETAILED DESCRIPTION OF THE DISCLOSURE The present invention provides a compound having Formula I: 143482-1

I I201111364

Or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of Ci_C6_homoyl, cycloalkyl, CVC6 alkenyl, CVC: 6 cycloalkenyl and azetidinyl, wherein each of the foregoing Depending on the case, it is substituted by 1-3 halogens and/or Cl _C5 alkoxy groups; R 2 and R 3 are independently selected from the group consisting of hydrogen, ketone, c] _c5 alkyl, c3-c8 cycloalkyl 'c2_c5 a dilute group, a C3_Cyf dilute group, an alkynyl group, an aryl group, a Cl-C: 5 alkoxy group, an aryl group and a heteroaryl group, wherein the heteroaryl group has 1 to 3 hetero atoms, and is independently selected from the group consisting of the following groups : N, Ο and S, wherein each (10) is in the form of an oxide as appropriate and each S is in the form of an oxide, selected from the group consisting of: S (= 〇) and s (= 〇) 2 Wherein the aryl group and the heteroaryl group are optionally substituted by M halogens, wherein the alkyl group, the cycloalkyl group, the alkenyl group, the cycloalkenyl group, the alkynyl group and the alkoxy group are optionally referred to as _3 substituents. Substituting each of them independently selected from the group consisting of _, c丨-C5 alkyl, c2_C5 alkenyl, cyano and Ci_c5 alkoxy, wherein each of the aforementioned alkyl, alkenyl and alkoxy groups is substituted Base system as appropriate Substituted by 1-3 halogens; you are cyclopropyl, unsubstituted or substituted by fluorine mono-, di-, tri-, tetra- or 143482-1 2011Π364 five; X is selected from the group consisting of: OR4 , R4, -(C丨-〇5), -(〇)〇-1 -aryl and -(Ci extended alkyl)_(〇)〇-1 -heteroaryl' wherein R4 is selected from the following Group consisting of: hydrogen, C--C5 alkyl, C3_C8 cycloalkyl, C2-C5 dilute, C3-C8 cycloaliphatic, C2-C5 alkynyl, C1-C5-cyano, -(C, - C5 alkyl)-〇-R5, -(q-c5 alkyl)-N(-R5)-0(=0)-((^-C5 alkyl), -(C!-C5 alkyl) )-C(=〇)-N(-R5 HQ -C5 alkyl), -(C! -C5 alkylene)-N(-R5)-(:(=0)-0-((:]- C5 alkyl), -(C, -C5 alkyl)-0-C(=0)-N(-R5)-(C!-C5 alkyl);-(Ci-C5 extension)-N (-R5)-%-C5 炫基), -(Ci-C5 alkyl)-SA-C5 alkyl), -(C!-C5 alkyl)-5(=0)-((^ C5 alkyl) and -(C! -C5 alkyl) 4(=0)2-((^-(:5 alkyl), wherein R4 'except hydrogen is replaced by i_3 substituents as appropriate, The substituents are independently selected from the group consisting of halogen, C(=〇)〇H, q-C5 alkyl, CyC: 5 alkenyl and C 〖-C: 5 alkoxy, wherein each alkyl, alkenyl and alkoxy substituent is optionally substituted with 1-3 halogens, wherein -(C! -C:5 The alkyl)-(0)〇_t-heteroaryl heteroaryl group contains 1-3 heteroatoms' independently selected from the group consisting of N, hydrazine and s, wherein each N is optionally an oxide In the form of an oxide, each of which is optionally in the form of an oxide selected from the group consisting of s(=0) and s(=〇)2, wherein -(c!-csalkyl)-(〇 〇 _ _ _ aryl and _ (Ci _C5 alkyl) 〇 (〇) 〇 M heteroaryl aryl and heteroaryl are individually substituted by 1-4 halogens, and wherein R 5 is selected from a group consisting of hydrogen, Ci_C6 alkyl, C3 C6% alkyl 'C2-C6 alkenyl, C3_C6 cycloalkenyl and C2-C6 alkynyl, wherein 143482-1 201111364 each of the aforementioned alkyl, ring, silk, (d) The base and silk substituents are optionally substituted by 1-3 halogens; B is (: 1-〇2 alkylene, optionally substituted by μ2 substituents, the substituents are independently selected from the group consisting of: , Ci, alkyl and. Cycloalkyl: wherein the aforementioned substituent and cycloalkyl substituent are optionally substituted by U(tetra); nl is 0 or 1; di(1)5- or 6-membered saturated or unsaturated heterocyclic or carbocyclic ring Cyclic ring, V or (8) penta- or six-membered saturated or unsaturated heterocyclic or = cyclocyclic ring, which is a sulphonic or unsaturated heterocyclic or carbocyclic ring. (,, fused ring "), wherein the hetero ring of (1) or (8) contains 丨_3 independently selected from N, 〇 and 3, each of which is in the form of an oxide, and each s is oxidized as it is. : a form selected from the group consisting of: s(=〇) and s(=〇)2 ' _ _ "the heterocyclic or carbocyclic ring of (1) or (8) is optionally treated as a single _; Two: four-, five- or six-substituted, wherein each substituent is independently selected from the group consisting of: (1) ii, (2) -OH, (3)-NH(R6), (4) keto, ( 5) -C(=〇).r6 , (6) -0-C(=〇).r6 , ()c〗-C5 alkyl, optionally substituted by 13 halogens, (8) Q-C8 cyclodextrin The situation is replaced by a halogen, 143482-] 201111364 (9) C2 -C5 alkenyl' is replaced by ι_3 halogens, (10) C3 -C8 cycloalkenyl 'Substituted by 1_3 halogens, (11) C2-C5 alkynyl, optionally substituted by 1_3 halogens, (12) C]-C5 alkoxy, optionally substituted by 1-3 halogens, (13) Cyano, (14) Cyano' is optionally substituted by 1-3 halogens, (15) -OCF3, (16) -C(R7)3, (17) -(C) -CI5 extended alkyl)-OR8 , as the case may be replaced by ι_3 halogens, (18) -NCR6)-% -Q extended alkyl)-〇R8, optionally substituted by 1_3 halogens, (19) -0-(C丨-C5 stretching base) -OR8, substituted by 1-3 halogens as appropriate, (20) -S-(C! -C5 stretching base)-OR8 'Substituted by 1-3 _ primes, (21) -S(=0 )-(C] -C5 extended alkyl)-OR8, optionally substituted by 1-3 halogens, (22) -S(=0)2-(C丨-C5 extension base)-OR8 'as appropriate 1-3 halogen substitutions, (23) -(C--C5 alkylene)-N(R6)-C(=0)-(Cl _c5 alkyl)-R8, optionally substituted by 1-3 halogens , (24) -(C)alkylene)-N(R0)-C(=〇)-〇R8, optionally substituted by 1-3 halogens, (25) -(C! -C:5-alkylene Base)-N(R6)(R8) 'Replaced by _3 dentitions as appropriate, (26) -CKC〗-C5 alkyl)-C(R6)2-C(=〇)〇r8, as appropriate Being 13 143482-1 20 1111364 halogen substitutions, (27) -(C) -C5 alkylene)-C(R6)2-C(=0)-0R8, optionally substituted by 1-3 halo, (28) -0-( (:! -C5 alkyl)-morpholine, optionally substituted by 1-3 halogens, (29) -0C(=0)-morpholine, (30) -SR8, (31) -S( =0)-R8, (32) -S(=0)2-R8 (33) -N(R6)(R8), (34) -(C] -C5 alkylene)-C(R6)2- (R8), optionally substituted by 1-3 halogens, (35) -(R9)〇-iR10 5 (36) C2-C5 alkenyl-OR8 'Substituted by 1-3 halogens, (37) C2 -C5 alkynyl-OR8, optionally substituted with 1-3 halogens, (38) -(C! -C5alkyl-C5 alkylene)-R8, optionally substituted by 1-3 halo' ) -(C! -Q alkylene)-〇-C(=0)-(C丨-C5 alkyl)-R8, optionally substituted by 1-3 halogens '(40) _(CrC5) Base) -C(=0)-N(R6)(R8), optionally substituted by 1-3 halogens, (41) -(q -C5 alkylene)-0-C(=0)-N( R6)(R8), as the case may be replaced by 1-3 halogens, (42MQ _C5 alkylene group) - Zhang 8 'as replaced by 1-3 i elements as appropriate] 143482-1 •10- 201111364 (43) -( q -C:5 stretching base)-S(=〇)-R8 'Substituted by 1-3 halogens, and (44 -(q -C5alkylene)-S(=〇)2 -R8, optionally substituted by μ3 halogens, wherein R6 is selected from the group consisting of hydrogen, Cl _c6 alkyl, Qc: 8 ring An alkyl group, qc:6 alkenyl group, Q-C8 cycloalkenyl group and 匸2_匚6 alkynyl group, wherein each of the aforementioned alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally taken 1 -3 halogen substitutions,

Wherein R7 is halogen, wherein R8 is selected from the group consisting of hydrogen, q% alkyl, C3-Cs cycloalkyl, (VC6 alkenyl, C3_C8 cycloalkenyl) and C2_C6 alkynyl, wherein each alkane The base, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents are optionally substituted with from 1 to 3 halogens, wherein R9 is selected from the group consisting of: _c(H)(〇H), _c( =〇)_, 0C(-0)_, -C(=0)0_, _〇_, _〇c(=〇)〇, q Q alkyl, C2_C5 alkenyl, -N(R6)- , -s-, -S(=0)_, raise 〇) 2 _, _N(R6)_c(=〇)_, _c(=〇)_ _)-, -0C(=0)_N(R6) ·, _N(R6)c(=〇)〇_, war 6)|_〇)2_, , (〇)2-N(R)-, wherein each of the above-mentioned extended and extended substituents is as appropriate Substituted by 1-3 halogens, and wherein the Shanghai system is defined above, and wherein R10 is a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring, which is singular, two or three depending on the situation. a tetra- or penta-substituted group in which each substituent is independently selected from the group consisting of halogen, -OH, -SR6, N(R)(R), c]-c5 alkyl, CrG cycloalkyl, alkene Base '匸...ring' soil c2-c5 alkynyl, C丨-c5 alkoxy, cyano and C1_C5_cyanide Wherein 143482-1 201111364 the heterocyclic ring contains 1 to 3 heteroatoms independently selected from N, fluorene and 5, wherein each n is optionally in the form of an oxide and each of the 5 systems is optionally an oxide 'Selected from the following group: s (= 〇) or s (= 〇) 2, and % and helper lines are defined above. In a specific embodiment, the present invention provides a compound of the formula, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the monocyclic or copper ring of γ(1) or (9) is individually selected from the following:

'43482-1 -12- 201111364 In another embodiment, the invention provides a compound of formula i or a pharmaceutically acceptable salt thereof or an optical isomer thereof wherein R2 and R3 are independently selected from the group consisting of Groups: H, -〇ch2〇Ch3 and _ch3. The present invention provides a hydrazine compound or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein X is H, -〇H or .OCH3. In another embodiment, the invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein W is cyclopropyl. In another embodiment, the invention provides a compound of formula 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein (Z)nl is -CH2- or a bond. In another embodiment, the invention provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein: R is _c2 alkyl optionally substituted with 1-3 halo, R Independent of the R3 series selected from the group consisting of hydrogen, halogen, q-c5 alkyl C1-c:5 alkoxy and -CKC--c5 alkyl)-〇-(CH2)0 _ 3 -CH3 Wherein alkyl, alkoxy and -CHCi-C5 alkylene)_〇_(CH2)G · 3 _Ch3 are optionally substituted by 1-3 substituents. The substituents are independently selected from the group consisting of: A dentate, optionally substituted with 1-3 halogens, and optionally substituted by μ3 halogens (^-(:5 alkoxy, X is selected from the group consisting of hydrogen, _〇Η) And q _c5 alkoxy, and z is c]-c2 alkyl. In another specific embodiment, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein Γ-ray 143482-1 •13- 201111364 Depending on the case, it is described in the formula 于 in another specific, --, three-, four- or five-substituted. In the pharmaceutical case, the invention provides a compound of formula II or Its salt or its optics Isomer,

II

Group A is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) Ci-C5, (4) q-Cs alkoxy, and (5) -S-(CH2)〇.3-CH3. · Where (3) and (4) are replaced by 1_3 elements as appropriate. 'B is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) CVCs alkyl, (4) CVC5 alkoxy, (5) -OH » ^3482-1 14 201111364 (6)-CF3, (7)-c(:o)-ch3, (8)-oA-c5 alkylene)-oxime-cyclopropyl, (9)-〇-(c 丨-C5 alkylene)-〇-(CH2 ) 0 - 2 -CH3, (10) -(C丨-C5 stretching group)-〇-(ch2)0 - 2 -CH3, (11) -0C(=0)-morpholine, (12) - CKq-C5 alkylene)-morpholine, (13) -0-((:, -c5 alkyl)-c(ch3)2-c(=o)oh, (14) -0-(( :[ -C5 alkylene)-C(CH3)2 -C(=0)0CH3, (15)

(16)

Where (3), (4), (8), (9), (10), (12), (13), (14), (15) and (16) are replaced by 1-3 halogens as appropriate , C is selected from the group consisting of: (1) hydrogen, (2) ci - C: 5 fen, optionally substituted by 13 halogens, and (3) Cl VII 5 oxime 'as replaced by 1-3 halogens The D system is selected from the group consisting of: (1) hydrogen, (2) 13⁄4, 143482-1 -15- 201111364 (3) (: 丨-(:5 alkyl, (4) Ο! -C5 burning oxygen Base, (5) C丨-C5 - chaotic base '(6) C2 -C5 alkenyl-anthracene-(CH2)〇- 2 -CH3, (7)-(q -c5 alkylene)-n(h)-c( =o)-o-(ch2 )〇. 2 -CH3, (8)-(c! -c5 alkyl)-n(h)-c(=o)-(ch2 )0.2 -CH3, (9) -( Ci-C5 alkyl)-0-CHF2, (10) -(Ci-C5 alkyl)-〇-(CH2)〇-2 -CH3 ' (11) -CKq -c5 alkyl)-o- (ch2)〇- 2 -CH3, (12) -((^-(:5 alkyl)-OH, (13) 4-((^-C5 alkyl)-OH, (14) -SCF3 ( 15) - wind 11) - ((: 1-(:5 alkyl)-0-(〇12)()_2-〇13, and (16)

Wherein F, G and H are independently selected from the group consisting of hydrogen, halogen and q-C3, optionally substituted by 1-3 halogens, and wherein R11 is selected from the group consisting of: - CH2 -, -C(H)(OH)- and -C(=0)-, where (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13) and (15) are replaced by 1-3 halogens, and R1, R2, R3, X and (Z)n丨 are as in Formula I Said. In another embodiment, the invention provides a compound of formula I or a medicament thereof, 143482-1 • 16-201111364, a salt which is acceptable or optically isomer thereof, wherein the lanthanide

The three-, four-, five- or six-substituted ' is as described above for the formula I. In another specific embodiment, the present invention provides a compound of the formula in or a pharmaceutically acceptable salt thereof or an optical isomer thereof,

Wherein: A is selected from the group consisting of: (1) hydrogen, (2) _, (3) (4) (5) C! -C5 burnt base 'substituted by μ3 halogens, ci alkoxy' as the case may be a halogen substituted, and a fluorenyl group, and B is selected from the group consisting of: hydrogen and !|, C, selected from the group consisting of: (1) hydrogen, (2) _, (3) -Q alkyl Depending on the case, i_3 halogens are substituted, (4) ci-A alkoxy group is optionally substituted by 1_3 halogens, and 143482-1 -17- 201111364 (3) cyano group, D is selected from the group consisting of: (1) hydrogen , (2) halogen, (3) c! -C5 炫, which is optionally substituted by μ3 halogens, (4) C! -C5 alkoxy' is optionally substituted by μ3 halogens, (3)-(c--c5 alkyl)_a (CH2)〇-2_CH3, optionally substituted by a halogen, and (6) a cyano group, and the E is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) CVq alkyl, (4) Q-Cs alkenyl, (5) C^-Cs alkoxy' (6) cyano, | (7)-(c)-C5 alkyl)-C(CF3)2 (H), (8) -(Q -C5 alkyl)-N ( H)-C(=0)-(CH2)〇· 2 -CH3, (9)-(q -c5 alkyl)-〇-(CH2 )〇-2 -CH3, (10)

143482-1 -18- (12) 201111364

Its 'zhong (3), (4), (5), (7), (8) and (9) are taken by ι_3 halogens as the case may be

And wherein (1〇), (11), (12) and (13) are optionally substituted by 1 to 3 substituents, the substituents being independently selected from the group consisting of halogen, q-C5 alkyl, hydrazine 】-<:5 alkoxy and cyano, wherein R1, R2, R3, X and (Z)n丨 are as described in formula I. In another embodiment, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the gamma is selected from the group consisting of:

Substituted by mono-, di-, tri-, tetra- or penta, as described above in Formula I. 143482-1 19 201111364 In another embodiment, the present invention provides a compound of the formula 1 or a pharmaceutically acceptable salt thereof or an optical isomer thereof:

R R

Wherein A is selected from the group consisting of: (1) hydrogen,

(2) ii, (3) C--C5 alkyl, (4) q-Cs alkoxy, (3) cyano, (6) Ci-cv cyano, (7)-(C)-c5 alkyl)-N(H)-C(= 0)-(CH2)〇- 2 -CH3, (8)-(q-C5 alkylene)-〇-(CH2)〇. 2 -CH3, and 143482-1 •20- 201111364 (9)-NCHHCi -c5 alkylene )-〇_(Ch2 2 _CH3, where (3), (4), (6), (7), (8) and (9) are replaced by μ3 _ primes, and wherein R1, R2, R3, Χ and (Ζ) η 1 is as described in the above formula I. In another specific embodiment, the present invention provides a hydrazine compound or a pharmaceutically acceptable salt thereof or an optical isomer thereof, wherein

It is mono- or di-substituted as appropriate, as described above with respect to Formula. In another embodiment, the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, which is

Wherein: the lanthanide is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C]-C5 alkyl, (4) alkoxy, and (5) - (q -C5 alkyl) -〇_(CH2)〇_ 2 -CH3, wherein (3), (4) and (5) are replaced by 1-3 halogens as appropriate, and true B is selected from the group consisting of: 143482-1 • 21 - 201111364 (1) Hydrogen, (2) dentate, (3) CVC5 alkyl, (4) (^-(:5 alkoxy, (5) -(C丨-C5 alkyl)-0-(CH2)〇 . 2 -CH3, and (6) -NOHMq -C5 alkylene)-0-(CH2 )〇_ 2 -CH3, wherein (3), (4), (5) and (6) are 1-3 teeth depending on the situation. Substituted, and wherein R1, R2, R3, X and (Z)n! are as described above in Formula I. The invention also relates to the crystalline form of Formula I. In particular embodiments, the invention is defined (3S,4R)-N-({3-Molyl-4-indenyl_5_[3-(indolyl)propyl]phenyl}indolyl)-N-cyclopropyl-4-(1 - fluorenyl-2-keto-i,2-dihydro-4-pyridyl)-3-hexahydrop-pyrase as a crystalline form of the chitosan hydrochloride or a pharmaceutically acceptable hydrate thereof. In other specific embodiments, the invention relates to a crystalline form of the formula (example) The form as described above, which is characterized by *13 CSS NMR as having a chemical shift absorption peak, having at least one or more of the following chemical shifts expressed in parts per million: 12〇丄31 2, 17丄43 5, 41 6, 29.4, 58.5, 71.4, 28.7, 42.5, 138.3 and 143.6. Specific embodiments have to. 'One, four, five 'six, seven, eight, nine, ten or eleven The above chemical shifts. Other embodiments have all 12 chemical shifts. In other embodiments, the invention relates to a crystalline form of formula i (such as the form described above) which is characterized by the solid state of Figure 2. 13C-SSNMR CPMAS Nuclear Magnetic Resonance Light 6. In other specific embodiments, the invention relates to a crystalline form of Formula I (such as the form described above), which is characterized by the thermogravimetric analysis curve of Figure 3. In a specific embodiment, the present invention is directed to the crystalline form 143482-1 -22-201111364 of Formula I (such as the form 上文 described above), which is characterized by the differential scanning card gauge curve of FIG. 4 in other specific embodiments. The present invention relates to a crystalline form of Formula I (eg, The form I) 'is characterized by X-ray powder diffraction as having one or more of the following reflections corresponding to d-spacing: 10.59, 7, 04, 4.24, 4.22, 3.88, 3.58' 3.51 , 3.31 and 3.08. Particular embodiments have the above-described reflections of up to, - four, five, six, seven, eight, nine, ten or ten. Other embodiments have all nine reflections. In other specific embodiments, the invention is directed to a crystalline form of Formula I (e.g., Form I as described above) characterized by the X-ray diffraction pattern of Figure 5. The compound of formula I above, and pharmaceutically acceptable salts thereof, are renin inhibitors. 4 mouth can be used to inhibit renin, and to treat symptoms such as high blood pressure. Any reference to a compound of formula (I) shall be understood to also refer to the optically pure palmar isomer of such a compound, a mixture of palmomers, such as racemates, diastereomers, non-pairs a mixture of enantiomers, a diastereomeric racemate, a mixture of diastereomeric racemates, a meso form, and an orphan (especially a pharmaceutically acceptable salt) in combination with a solvent (including hydrates)' and morphological forms, in accordance with the appropriate t and expedient means. The present invention encompasses that the t:W compound is isolated in a manner known per se, such as by column chromatography, town k, g decantation (TLC), high performance liquid chromatography (hplc). Or crystallization 0 too. The compound of the present invention may have a center of the palm, for example, a pair of palm centers (providing two crude isomers, (8) and (3)) or two pairs of palm centers. The invention includes the right (R, R), (S, S), (R, W, R)). The two kilograms have such optical isomers and mixtures thereof. Unless otherwise specified 0, the reference to an isomer is applicable to any possible 143482-1 -23- 201111364 structure. Whenever the isomer composition is not specified 'for example, when the bond system for the palm of the hand is depicted as a straight line, it should be understood that the system indicates that: the carbon (four) (four) states are both 'and therefore two Structures and mixtures thereof In addition, 'compounds having a carbon-carbon double bond may exist in the Z- and E-forms' wherein all isomeric forms of the compound are included in the present invention. 〃 The compounds of the invention also include nitrosated compounds of formula (I) which have been subjected to one or more positions such as oxygen (transcondensation via a base), sulfur (hydrosulfide-based and/or = nitrosated). Nitrifying compounds can be prepared by conventional methods known to those skilled in the art. For example, the known methods for making compounds sub-E are described in U.S. Patent Nos. 5,38,758, 5,7, 3, 7, 73, 994, 294. , 632 432 and 6,218,4Π; W0 reg. 9672; and 〇 人 pre pre pre pp 165-198 (1983). Salts in a particular embodiment are pharmaceutically acceptable compounds of formula (1) Salt. The word "(4) acceptable salt" encompasses salts with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminic acid, citric acid, tartaric acid. , phosphite, arsenic, bar acid, formic acid, acid, oxalic acid, cis-succinic acid, lactic acid, tartaric acid, fumaric acid, benzate, phenylglycolic acid, cinnamic acid, palmitic acid, stearic acid , glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, ethane disulfonic acid, p-toluene Acid, salicylic acid, succinic acid, trifluoroacetic acid, etc., which are not t-sexual to living organisms, or in the case where the compound of formula (I) is acidic in nature, is a salt with an inorganic base, Inorganic bases such as alkali metal or alkaline earth metal bases, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. Other examples of pharmaceutically acceptable 143482-1 -24-201111364 salts can be specifically referred to, test drug colonies Awm. (1986), 33, 201-217. Companion, ·, also includes derivatives of τ compounds that are used as prodrugs. These body music are 'lined in the body after administration to the patient. It is converted into a phantom compound by normal metabolism. This prodrug includes a substance that exhibits enhanced use, tissue specificity, and/or cell transport to improve the absorption of the compound of the formula. The role of drugs can be due to physicalization

The physicochemical properties resulting from changes in the properties such as lipophilicity, molecular weight, charge, and other infiltration properties of the test drug. The general terms used in the previous illusions and the following texts have the following meanings in the present disclosure unless otherwise indicated. In the case of using a plural form for a compound, a salt, a medical composition, a disease, or the like, it also means a single compound, a salt or the like. , unless otherwise indicated, m, alone or in combination with other groups, means saturated, straight-bonded, and branched bond groups having from - to six carbon atoms. It can be represented by Cl·6 alkyl or decyl ". When the intended meaning is this Japanese temple, such as when the number of carbon atoms is in the range of one to four carbon atoms, 'this meaning is similar to 'Ci4 alkyl' or "c]_c4 alkyl " said. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl-n-butyl, isobutyl, second-butyl, tert-butyl, pentyl, hexyl and heptyl. Methyl, ethyl and isopropyl groups are described in this particular embodiment. The structure of the compound can be characterized by "_CH3,,,,,CH3", "_Me",,,Me, or "b," (where ^ is equivalent) to display the terminal methyl group. The terminal ethyl group can be described as "-CH2CH3", "CH2CH3,, ' "_Et", "Et" or " (meaning that these 143482-1 •25·201111364 have considerable significance). The term refers to any divalent linear or branched chain aliphatic hydrocarbon group having a number of carbon atoms within the specified range. Thus, for example, "_Ci<:6 alkylene is any q to C:6 linear or branched alkyl, and „_Ci alkyl”, 2 private q to q linear or branched alkyl base. With regard to the present invention, a particularly interesting type of excipient is 2) 16_, and a particularly interesting subgroup includes -(CH2)h-, _(CH2)1 3_, _(CH2) 2 and _CH2_. Another subgroup of interest to us is an alkylene group selected from the group consisting of: 2 CH(CH3 and -C(CH3)2 -. Some words, such as "C, -c4 alkylene-styl "and the 1-4 π-alkyl π π n, Uj alkyl substituted by phenyl, have the same meaning, and can be used interchangeably. π does not specify the pole * Τ - called % six or six. Two, two or six carbon atoms are unsaturated (meaning having at least one) direct bond and branched chain groups (which can, c2 6 dilute, or, C2 C6 alkenyl) The meaning of Θ 奴 slave is not the case when 'for example, when the number of carbon atoms is one: four carbon atoms', this meaning is represented by a dilute base, or, C2-C4 alkenyl.伸县"—(4) Yu Di valence linear or branched chain (4) Single unconstrained soil, with the number of carbon atoms within the specified range. Unless otherwise specified, 丨 alkyne" _ Μ 。 。咅 phase 1 death, soil 3, early alone or with other groups 4 ^ ^ have two to six carbon atoms of unsaturated (meaning that there is at least _ in two to.: the intended meaning is not this, For example when carbon atoms are drawn - In the case of - four carbon atoms, this meaning is expressed in a similar manner "143482-1 -26- 201111364 Ά·4 fast base" or "c2-c4 block base". Mounting "" word alone or with other The group ☆ and 'refers to the R-〇- group, and is an alkyl group. Examples of the alkoxy group are a decyloxy group, an oxime isopropoxy group, an isobutoxy group, a second _butoxy group and the first Trisylpropionyl, A:yl: Γ-word, alone or in combination with other groups, means fresh base. Examples of bases are, 2, HaCH2CH2CH2- and CH3CH(OH)-. The word system means fluorine, gas, bromine or broken. In a specific embodiment or gas rat, chlorine or desert. In a specific embodiment, the element is gas: 'other! indicate, otherwise, 'ring-burning base' a word, a saturated cyclic hydrocarbon ring system having 3 to 8 carbon atoms, alone or in combination with other groups, such as ruthenium, butyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. : C3 '8% burnt base or "c3_q ring yard base" · expressed. When the intended meaning = this item 'for example, when the number of carbon atoms is in the range of three to six carbon atoms, the machine does not. Point out 'otherwise in this article The use of "carbocycle,, (and its variants; ; family %V'carbocyclyl")_, means cjq monocyclic saturated or oxime and ring. The carbocyclic ring can be attached to any carbon atom to The rest of the molecule, = causing a stable compound. Saturated "family ring is also known as a cycloalkyl ring, such as cyclopropyl, cyclobutyl, etc. As used herein, "monocyclic" (and its variants, such as ' The term "monocyclic" refers to an I-ring which may be substituted by - or a plurality of substituents as described herein 143482-1 -27- 201111364 or may be unsubstituted. "Heterocycle,, (and its variants, such as "heterocyclic" or "heterocyclyl,") is a broad term also known as a female 疋4- to 8-membered saturated or unsaturated monocyclic ring. , which contains - or a hetero atom selected from N, hydrazine and S (for example, to 6 heteroatoms or 1 to 4 heteroatoms), and the remainder being a carbon atom (typically at least one carbon atom); Any one or more of the nitrogen and sulfur heteroatoms are oxidized as appropriate, and any or a nitrogen-fixing hetero atom is optionally quaternized. Unless otherwise indicated, the material is attached to any heteroatom or carbon. On the atom, the condition is that the connection will be: 疋'. The formation of the structure. Unless otherwise indicated 'otherwise when the heterocyclic ring has taken 4, soil' it is understood that the substituent may be attached to any of the original atoms or carbon atoms in the ring, provided that it will result in a stable chemical structure: Used alone or in combination, with respect to phenyl, phenyl or amphoteric. In the embodiment, the "aryl group" is a phenyl group. The abbreviation '.Ph' table is dull and sloppy. The 'individually or in combination, means that there are - to four nitrogen atoms... eight benzo-fused six-membered aromatic ring of one or three nitrogen atoms, containing - Bayer's right (four) nitrogen or a sulfur atom Aromatic ring 3 has an oxygen, a nitrogen or a sulfur atom stupid and fused five-membered aromatic: a shell containing two heteroatoms independently selected from oxygen, nitrogen and sulfur: a fused derivative; a benzopyrene derivative containing three nitrogen atoms; a tetras-silacyclyl ring; a "base ring; a ring and a species; an example of a system is a thiol group, and a thiophene group , base, such as forest base, heterogeneous base, taste sulphate, ^ 1 sulphate, hetero-yl, tahki, wow, w, ke, ke, ke, ke, ke, ke, ke, ke, ke 4 „基.▲ 坐基, 143482-1 -28- 201111364 Specific examples of the compound of formula i and its pharmaceutically acceptable salts include those listed below: trans-N-cyclopropyl-N-[(2 ,3-diphenylphenyl)methyl]-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)-3-hexahydropyridinecarboxamide (Example 1) trans-N-[{5-Chloro-2-[3-(methoxy)propyl]-4-acridinyl}indenyl]-N-cyclopropyl- 4-(1-Methyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 2) trans-N-({2- gas-based- 5-[3-(indolyl)propyl]phenyl}indenyl)_N-cyclopropyl-4-(1-methyl-2-keto-1,2-diar-ar--4-p ratio ))-3-hexahydro said biting slow amide (Example 3) trans-N-({2-chloro-5-[2-(decyloxy)ethyl]phenyl}fluorenyl)·ν_ Cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-ρ ratio β-decyl)-3-hexahydro (7-bit retinoylamine (Example 4) trans- Ν-cyclopropyl-hydrazine-({2,3-dioxa-5-[3-(indolyl)propyl]phenyl}methyl)-4-(1-indol-2-yl-- 1,2-dihydro-4-pyridyl)-3-hexahydropyridylcarboxamide (Example 5) trans-Ν-cyclopropyl-Ν-({2,3-digas-5-[2 -(decyloxy)ethyl]phenyl}indolyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide ( Example 6) trans-Ν-cyclopropyl-fluorene-({2-mercapto-5-[3-(methoxy)propyl]phenyl}indolyl)-4-(1-methyl-2 -keto-1,2-dihydro-4-pyridyl)_3-hexahydropyridine carboxamide (Example 7) trans-Ν-cyclopropyl-Ν-({2-mercapto-5-[2 -(decyloxy)ethyl]phenyl}indolyl-4-(1-mercapto-2-keto-1,2-dihydro-4- Pyridyl)_3_hexahydropyridine carboxamide (Example 8) trans-Ν-cyclopropyl-fluorene-({2,3-diox-5-[3-(decyloxy)propyl]phenyl )曱143482-1 -29- 201111364 base)-4-(1-mercapto-2-keto-1,2-dihydro-4-ρ ratio octyl)-3-hexahydrop than biting decylamine (Example 9) trans-Ν-ί propyl-4-(1-methyl-2-indolyl-1,2-diaza-4-p ratio σ-based)_n_({3_(methoxy) -5-[3-(decyloxy)propyl]phenyl}indolyl)-3-hexahydro-P is a bit of a chiral amine (Example 10) trans-N-cyclopropyl-4-(1- Mercapto-2-keto-1,2-dihydro-4-P ratio bite)_ν_({3·{[2-(decyloxy)-ethyl]oxy}-5-[3-(曱oxy)propyl]phenyl}indenyl)_3•hexazapyridine carboxamide (Example 11) trans-Ν-cyclopropyl-4-(1-ethyl-2-keto-1,2 -dihydro-4-ρ ratio bite)_n_({3_ {[2-(decyloxy)-ethyl]oxy}-5-[3-(methoxy)propyl]phenyl}methyl _3_ hexahydropyridine carboxamide (Example 12) trans-Ν-cyclopropyl-fluorene-({3-{[2-(decyloxy)ethyl)oxy b-[3-(曱) Oxy) propyl] phenyl} fluorenyl)-4-(1,5,6-tridecyl-2-keto-1,2-dihydro-4-ρ ratio. Benzyl)-3-hexahydropyridine carboxamide (Example 13) trans-Ν-cyclopropyl-4-(1-indolyl-5-{[(methoxy)indolyl]oxy]keto- 1,2-dihydro-4-pyridyl)-indole-({3-{[2-(decyloxy)ethyl)oxy}-5-[3-(decyloxy)propyl]benzene }}methyl)-3-hexahydropyridine carboxamide (Example 14) trans-Ν-cyclopropyl-Ν·{[2,3-dioxa-5-(3-cyanopropyl)phenyl ] 曱基卜 4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 15) trans-Ν-{[5 -(3-cyanopropyl)-2,3-difluorophenyl]methyl}-indole-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4 -pyridyl)-3-hexahydropyridine carboxamide (Example 16) trans-indole-cyclopropyl-indole-{[2,3-dichloro-5-(4-hydroxybutyl)phenyl]indole }-4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 17) trans-hydrazine-cyclopropyl- 4-(1-Methyl-2-keto-1,2-dihydro-4-pyridyl)-indole-({3- 143482-1 •30- 201111364 [3-(methoxy)propyl] -1-mercapto}methyl)-3-hexahydropyridine carboxamide (Example 18) trans-(2-{3,4-digas-5-[(cyclopropyl{[4-(1- Methyl-2-keto-1,2-dihydro-4-pyridyl)-3 - hexahydropyridyl]methyl}amino)methyl]phenyl}ethyl)carbamic acid methyl ester (Example 19) trans-N-Lactylpropyl-4-(1-indolyl-2-indole Base-1,2-two wind-4-p ratio °-based)-N-(8-p-quinoline-methyl)-3-hexahydro-p-butanylamine (Example 20) trans-N- Cyclopropyl-N-(8-iso-4-linylmethyl)-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridinecarboxylate Amine (Example 21) trans-N-cyclopropyl-N-(5-isoindolyl fluorenyl)-4-(1-indol-2-yl-1,2-dihydro-4-pyridine Benzyl-3-hexahydropyridine carboxamide (Example 22) trans-N-cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)- N-(5-quinolinylfluorenyl)-3-hexahydropyridine carboxamide (Example 23) trans-N-cyclopropyl-N-(l-isoquinolinylfluorenyl)-4-(1 - mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 24) trans-N-cyclopropyl-4-(1-methyl -2-keto-1,2-dihydro-4-pyridyl)-N-({2-P-(decyloxy)propyl]-4-quinolinyl}methyl)-3-hexahydro Pyridinium Carboxamide (Example 25) trans-N-Cyclopropyl-4-(1-methyl-2-keto-1,2-di-aryl-4-pyridyl)-N-({6-[ 3-(methoxy)propyl]-8-p quinolyl X-yl)-3-hexahydropyridine carboxamide (Example 26) trans-N-[(5-bromo-2,3-dichlorophenyl)indenyl]cyclopropyl_4-(1- Mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine Carboxamide (Example 27) trans-N-({3-气基-5-[3- (decyloxy)propyl]phenyl}methyl)_N-cyclopropyl-4-(1-methyl-2-keto-1,2-diar-aryl-4-pyridyl)-3-hexahydropyridine Carboxylamidine (Example 28) trans-N-cyclopropyl-4-(1-indol-2-oneyl-ι,2-dihydro-4-pyridyl)-indole-({1-[3 -(decyloxy)propylHH-indole-3-ylindolemethyl)_3_hexahydropyridinecarboxamide (Im 143482-1 •31 . 201111364 Example 29) trans-N-cyclopropyl-N -{[2,3-dioxa-5-(2-cyanoethyl)phenyl]methyl}-4-(l-nonyl-2-keto-1,2-dihydro-4-pyridine ))-3-hexahydropyridine carboxamide (Example 30) trans-(2-{3,4-dioxa-5-[(cyclopropyl{[4-(1-mercapto-2-)yl) -1,2-dihydro-4-pyridyl)-3-hexahydropyridyl]amino}amino)indenyl]phenyl}ethyl)amino decanoic acid ethyl ester (Example 31) trans-N -({3-Molyl-5-[3-(methoxy)propyl]phenyl}methyl)_N_cyclopropyl_4_(1-indol-2-yl-1,2-di Hydrogen-4-pyridyl)-3-hexahydropyridinecarboxylate Indoleamine (Example 32) trans-N-cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)-N-({5-[3- (Methoxy)propyl]-3-biphenyl}indenyl)-3-hexahydropyridinecarboxamide (Example 33) trans-N-cyclopropyl-4-(1-indolyl-2- Ketol-1,2-dihydro-4-leaf 1: dimethyl)-N-{[[3-(indolyl)propyl]-5-(3-pyridyl)phenyl]methyl b 3 - hexahydropyridine carboxamide (Example 34) trans-N-cyclopropyl-N-[(2,3-dioxa-5-{[2-(methoxy)ethyl]amino}} ) methyl]-4-(1-methyl-2-keto-1,2-dihydro-4-indole)-3-hexahydrop ratio biting retinoic acid (Example 35) trans-N - cyclopropyl-4-(1-mercapto-2-one-1,2-dihydro-4-p ratio. Stationary)_N-[(3-{[2-(indolyl)ethyl]amino}-l-naphthyl)indolyl]-3-hexahydroindole.醢 醢 ( (Example 36) trans-N-{[6-(2-Cyanoethyl)-8-p-quino-•indolyl]methyl}-N-cyclopropyl-4-(1- Mercapto-2-keto-1,2-dihydro-4-p ratio. Azide)-3-hexahydrop ratio. Detamine (Example 37) trans-N-cyclopropyl-4-(1-methyl-2-keto-1,2-di-argon-4-p ratio. Base)_n_({3_[2 -(Methoxy)ethyl]-1-indenyl}methyl)-3-hexahydrop ratio. Detamine (Example 38) trans-N-({3-[2-(ethylamino)ethyl]-1-teayl} fluorenyl)_N-cyclopropyl phenyl (1_ 143482-1 • 32· 201111364 methyl-2-yl-l,2-dihydro-4-ρ ratio bite base)_3_hexahydro-p ratio to biting guanamine (Example 39) trans-N-[(2-ami Methyl]_N_cyclopropyl-4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 40) -N-cyclopropyl·4-(1-indolyl-2-keto-I,2-dihydro-4-pyridyl(9)-(1)-[2-(methoxy)ethyl]-1Η-丨哚-3-yl}mercapto)-3-hexahydropyridinium carboxamide (Example 41) trans-Ν-cyclopropyl-4-(1-methyl-2-keto-1,2 -Dihydro-4-pyridyl)·Ν-{[1-(2,2,2-trifluoroethyl)-1Η-吲哚_3-yl]indolyl}-3-hexahydropyrryl. Carboxylamidine® (Example 42) trans-Ν-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-Ν-{[1- (4,4,4-Trifluorobutyl)-1Η-indol-3-yl]indolyl}-3-hexahydroport than biting decylamine (Example 43) trans-N-[(l-butyl) Η-1Η-啕哚-3-yl) fluorenyl]-indole-cyclopropyl-4-(1-methyl-2-ketodihydro-4-pyridyl)-3-hexapyridine carboxy guanamine (Example 44) trans-Ν-cyclopropyl-indole-({1-[3-(ethoxy)propyl]_1Η_吲哚}}}}})) Base-1,2-dihydro-4_ρ ratio. Base) each hexahydro ρ ratio. Hydrazine (Example 45) trans-Ν-cyclopropyl-4-(1-indol-2-one-1,2-dihydropyridinyl)-indole-({1-[3, 3,3-Trifluoro-2-(trifluoromethyl)propyl]-1Η-indol-3-yl}indenyl)_3_hexahydropyridine carboxamide (Example 46) trans-Ν-({ Η3-(Ethylamino)propyl]-1Η-吲哚_3-yl}indenyl)_Ν_cyclopropylindol-2-one-1,2-dihydropyridinyl)-3- Hexahydropyridine carboxamide (Example 47) trans-Ν-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl 143482-1 -33· 201111364 [3-(Propylamino)propyl]-oxime-called 丨p-3-yl}fluorenyl)-3-hexahydrop ratio. Detamine (Example 48) trans-Ν-({1-[2-(ethylamino)ethyl]-1Η-indol-3-yl}fluorenyl)·ν_cyclopropyl- 4-(1-Methyl-2-keto-1,2-dihydro-4-ρ ratio. Azide)-3-hexahydroindole. Hydrazine (Example 49) trans-Ν-cyclopropyl-4-(1-mercapto-2-keto-1,2-dihydro-4-ρ ratio)-Ν-({ 1 -[2-(Propylamino)ethyl]-1Η-indol-3-yl}indenyl)-3-hexahydropyridinecarboxamide (Example 50) trans-indole-cyclopropyl-4 -(1-methyl-2-keto-1,2-dihydro-4-pyridinyl)-indole-{[1-(2-propan-1-yl)-1Η-吲嗓-3 -yl]mercapto}-3-hexahydron-rheptin (Example 51) trans-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4 -P ratio bite)-Ν-{[1-(phenylmethylindol-3-yl)indolyl}-3-hexahydrop ratio biting retinoic acid (Example 52) trans-N-cyclopropane 4-(1-mercapto-2-keto-1,2-dihydro-4-P ratio. Stationary)-Ν-{[1-(2-p ratio dimethyl)-1Η-吲Indole-3-yl]methyl}-3-hexahydropyridine carboxamide (Example 53) trans-N-cyclopropyl_4-(1_mercapto-2-keto-1,2-dihydro -4-pyridyl)-N-{ [1-(3-p-Bitylmethyl)-1Η-indol-3-yl]methyl}-3-hexahydropyridine Carboxamide (Example 54) -N-cyclopropyl·4-(ι_methyl_2-keto-i,2-dihydro-4-pyridyl)-indole-{[1-(4-pair 匕°-decylmethyl) -1Η-indol-3-yl]methyl}-3-hexahydropyridinecarboxamide (Example 55) trans-N-cyclopropane __n-({1-[(4-Fluorophenyl)indolyl]-1H-decaol-3-yl}indolyl)-4-(1-indol-2-ylyl-i,2- Dihydro-4-pyridyl) each hexahydropyridine carboxamide (Example 56) trans-N-({i-[(4-Phenylphenyl)methyl]_1Η_Ρ?|哚 丨 丨 methyl)_N Cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide (Example 57) 143482-1 •34· 201111364 Trans -N-cyclopropyl-N_(U-[(3-fluorophenyl)methyl]·1Η丨哚丨哚_3yl}methyl> 4-(1-methyl-2-keto-U- Dihydropyridinyl)_3_hexahydropyridine carboxamide (Example 58) trans-Ν-({1-[(3-chlorophenyl)indolyl]_1H-indole_3D methylcyclopropyl- 4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide (Example 59) trans-Ν-({1-[(3- Cyanophenyl)indenyl]_1H_吲哚_3yl)methyl)ncyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl) Hexahydropyridine carboxamide (Example 60) trans-N-cyclopropyl-4-(1-methyl-2-keto-u-dihydropyridinyl) N_ ({H(3-mercaptobenzene) Methyl HH, ind-3-yl}fluorenyl)_3•hexahydropyridine carboxamide (Example 61) trans-N-cyclopropyl-N-({5- -1-[3-(decyloxy)propyl]_m_decadet-3-yl} fluorenyl-4-(1-methyl-2,yl-1,2-dihydro-4-pyridyl )_3_hexahydropyridine carboxamide (Example 62) trans-N-{[6-bromo-1-(phenylindenyl)-iH-indole_3_yl]indolyl N-cyclopropane 4-(1-mercapto-2-keto-1,2-dihydro-4-tonidyl)-hexahydropyridine carboxamide (Example 63) trans-N-cyclopropyl-N- UH(3-fluorophenyl)methyl]_6_(decyloxy)_1Η·Ρ 哚-3-yl]methyl)-4-(1-mercapto-2-keto-1,2-dihydro _4_pyridyl)_3_hexahydropyridine carboxamide (Example 64) trans-Ν-cyclopropyl-4-(1-indolyl-2-yl), 2_dihydro_4^ ratio π Stationary)_ν_{[4-methyl-1-(phenylindenyl)-1Η-indol-3-yl]methylidene 3-hexahydropyridinecarboxamide (Example 65) 143482-1 •35· 201111364 Trans-N-{[4-cyano-1-(phenylindenyl)_1H_indole)]indolyl N-cyclopropyl_4-α-mercapto-2-one-1, 2-Dihydro-4-pyridyl)_3_hexahydropyridine carboxamide (Example 66) trans-Ν-cyclopropyl-hydrazine-{[4-fluoro-1-(phenylindenyl)-plaw _吲哚_3_yl]methylmethyl-2-mercapto-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide (Example 67) trans-Ν-ring Propyl-indole-({4-fluoro-1-[(3-fluorophenyl)indolyl]_1Η吲哚_3yl]methyl M-(l-methyl-2-yl-1,2 -dihydro-4-pyridyl) hexahydropyridine carboxamide (Example 68) trans-Ν-cyclopropyl-fluorene-({4-fluoro-1-[3-(methoxy)propyl) ]_1Η吲哚_3_yl)methyl)-4-(1-mercapto-2-keto-1,2-dihydropyridinyl) each hexahydropyridine carboxamide (Example 69) trans- Ν-({4-Alkyl-1-[3-(oximeoxy)propyl]_出_吲哚_3yl}methylcyclopropyl-4-(1-methyl-2-keto- 1,2-dihydropyridylpyridyl) winter hexahydropyridine carboxamide (Example 70) trans-N-U4-carbyl-1-(stylmethyl)_1Η_吲哚_3yl]methyl} _Νcyclopropyl phenyl (1-mercapto-2-keto-1,2-dihydropyridinyl)_3_hexahydropyridine carboxamide (example Ή) trans-Ν-{[4-bromo- 1-(phenylindenyl)_this 吲哚3-yl]methyldiphenylcyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)_3 - hexahydropyridine carboxamide (Example 72) trans-Ν-({4-bromo-1-[(3-fluorophenyl)indolyl]ΗΗ_3•yl}methyl)& Propyl-4-(1-methyl-2-keto 4,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide (Example 73) 143482-1 -36· 201111364 trans-N-({>Smellyl-1-[3-(methoxy)propylHH-indol-3-yl}indenyl)-N-cyclopropyl-4-(1 -Methyl-2-keto 4,2-dihydro-t-pyridyl)_3_hexahydropyridine carboxamide (Example 74) trans-N-cyclopropyl-oxime [(4-fluoro-1H) -Indol-3-yl)methyl]-4-(1-methyl-2-yl-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide (Example 75) -Ν-ί辰propyl_N_{[4_Fluoro-small (3_pyridylmethyl)_1H-indole-3-yl] fluorenyl}-4-(1-methyl-2-keto- i,2-Dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 76) ® trans-N-cyclopropyl-N-{[4-fluoro-1-(4-pyridine) Methyl)_ih-W哚-3-yl] fluorenyl}-4-(1-methyl-2-keto-1,2-diin-4-pyridyl)-3-hexahydropyridinecarboxylate Amine (Example 77) trans-N-({3-Ethyl-5-[3-(indolyl)propyl]phenyl}methyl)-N-cyclopropyl-4-(1-A Benz-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 78) trans-N-({1,3-bis[3-(methoxy) Propyl]-2,4-dione-1,2,3,4-tetrahydro-5-pyrimidinyl}methyl)-N-cyclopropyl-4-(1-methyl- 2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 79) trans-N-cyclopropyl-N-({2,3-dimethyl-5-[3-(methoxy)propyl]phenyl}methyl)-4-(1- Mercapto-2-keto-1,2-dihydrobutyric is determined by the ratio of 3-hexahydrop. Detamine (Example 80) trans-N-[(2-carbyl-5-{[2-(indolyl)ethyl]))}phenyl)indolyl]-N-cyclopropyl 4-(1_methyl-2-S-iso-1,2-.murine σ-yl)-3-hexanitro-p ratio. Derivatives (Example 81) trans _ Ν-cyclopropyl-4-(1·methyl ketone_1,2- 虱-4-ρ ratio. 定)-Ν-(2- each 143482- 1 -37- 201111364 hydrazino)-3-hexahydropyridine carboxamide (Example 82) trans-N-cyclopropyl-4-(1-mercapto-2-keto-1,2-dihydro -4-p ratio bite)_n_({3-[(trifluoromethyl)thio]phenylindolemethyl)-3-hexahydropyridine carboxamide (Example 83) trans-N-cyclopropyl 4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl(methoxy)propyl]-2-(indolyl)phenyl]methyl}-3- Hexahydro-p ratio. Detergent amine (Example 84) trans-N-({3-bromo-4-methyl-5-[3-(methoxy)propyl]phenyl}methyl) ring Propyl-4-(1-mercapto-2-keto-1,2-dihydro-4-ρ ratio octyl)-3-hexahydrop ratio biting slowing amine (Example 85) #trans-N -[3,5-bis(3-decyloxypropyl)indenyl]-N-cyclopropyl-4-(1-methyl-2-indoleyldihydro-4-p ratio) 3-hexahydrop to bite giamine (Example 86) trans-N-cyclopropyl-N-[3-(3-methoxypropyl)-5-mercapto]-4-(1- Mercapto-2-keto-1,2-dihydro-4-pyridyl) hexahydropyridine carboxamide (Example 87) trans-N-[2-Molyl-3,5-bis(3- Methoxypropyl)henyl] -N-cyclopropyl_4-(1_mercapto-2-keto-1,2-dihydro-4-p ratio octyl)-3-hexahydroindole retinoic amine (Example 88) trans -N-[2-carbyl-3,5-bis(3-decyloxypropyl)-yl]_N_cyclopropylidene (1_mercapto-2-keto-1,2-dihydro- 4-P ratio bite)_3-hexahydro? than D-denidamine (Example 89) ® trans-N-cyclopropyl_n_[2-methoxy-3,5-bis(3-methoxy Propyl)-4-(1-methyl-2-keto-1,2-dihydropyridinyl)·3-hexahydropyridinecarboxamide (Example 9〇) trans-N- Cyclopropyl-N_[3_(3-methoxypropyl)_5_(trifluoromethyl)]]]4_(1_methyl-2-keto-1,2-dihydro-4-pyridyl)_3 _ hexahydropyridine carboxamide (Example 91) trans-N-cyclopropyl_N_[3_hydroxy_5·(3methoxypropyl)]]4 (1 methyl-2-keto- 1'2-monohydro-4-pyridyl)_3-hexahydropyridine carboxamide (Example 92) trans-indole-(3-benzhydryl-5-bromodecylcyclopropyl-4) Methyl-2-ketone 143482-1 •38- 201111364 yl-1'2-dihydro-H-decyl)-3-hexahydroindole sigmaamine (Example 93) trans-N-{3-bromo group -5-[(1Ε)-3-decyloxypropenyl small group]-based group N•cyclopropyl-4-(1-mercapto-2-keto-1,2-dihydrogen Pyridyl)_3_hexahydropyridinium carboxamide (Example 94) trans-N-{3-bromo-5-[(2-hydroxyethyl)thio]-yl}}-cyclopropyl ice (1_ Mercapto-2-keto-1,2-dihydro-4-Ppyridyl)_3_hexahydropyridylcarboxamide (Example 95) trans-N-cyclopropyl-N-[3-[ 2-(cyclopropyloxy)ethoxy>5-(3-methoxypropyl)-yl]-4-(1-methyl-2-keto-l,2-dihydro-4- Pyridyl) each hexahydropyridine carboxamide (Example 96) trans-N-cyclopropyl-N-{3-(3-methoxypropyl)_5_[2_(4_morpholinyl) ethoxylate ]]}}(1-methyl-2-keto-i,2-dihydro-4-pyridyl)-3-hexahydropyridine decylamine (Example 97) trans-3-[ (cyclopropyl {[4-(1-indolyl-2-keto)dihydro-4-pyridyl)3 hexahydropyridyl]carbonylguanidinyl)methyl]-5-(3-methoxypropane Phenyl 4-morpholine carboxylate (Example 98) trans-N-cyclopropyl-N-[6-(3-methoxypropyl)_2,3-dihydro-1H- though- 1-yl]_4_(1-mercapto-2-keto-1,2-dihydro-4-p than dimethyl)_3_hexahydro? Tough acid amine (Example 99) trans-N-cyclopropyl-N-[7-(3-methoxypropyl)_ι, 2,3,4-tetrahydro-1-chalyl-4 -(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridylcarboxamide (Example 100) trans-N-[3-bromo- 5-(3-Hydroxypropyl)-4-indolebenzyl]-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-? ratio α-based) -3-hexahydrop is more than a chitosamine (Example 1〇).) trans-Ν-[3-bromo-5-(3-ethoxypropyl)-4-indenyl]-oxime- Cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-ρ ratio. Alkyl)-3-hexahydrop-pyridine hydrazide (Example 1〇2) 143482 -1 -39- 201111364 trans-N-{3-bromo-5-[3-(difluorodecyloxy)propyl]_4_indolyl ρΝ_cyclopropyl-4-(1-indenyl) 2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 103) trans-Ν-(3-ylyl-5-methylindenyl)_Ν_ Cyclopropyl ice (1_methyl-2-keto^hydro-4-pyridyl)-3-hexahydrop ratio carboxy carbamide (Example 1〇4) trans-N-[3-Momot -5-(3-fluoroindolyl)_4_曱benzyl]_N_cyclopropyl_4-(l-fluorenyl-2-keto-1,2-dihydro-4-pyridyl)-3- Hexahydropyridine carboxamide (Example 1〇5) trans-N-[3-bromo-5-(3- Fluorobenzoyl)_4-mercapto]_Ν·cyclopropyl winter (1_ decyl-2-keto-1,2-dipho-4-pyr ratio. Stationary)-3-hexahydro? Ratio D to slow amine (Example 1〇6) trans-N-{3-bromo-5-[(3-fluorophenyl)(hydroxy)indenyl]_4_曱benzyl}_N_cyclopropyl 4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide (Example 107) trans-N-[2- gas-based- 5-(2-decyloxyethyl)benzyl]cyclopropyl-4_hydroxy_4_(1-indol-2-one-1,2-dihydro-4-p ratio) - Hexahydrogen? Determining g-amine by ratio π (Example 108) trans-N-[2-carbyl-5-(2-methoxyethyl)]]-n-cyclopropyl_4_decyloxy-4- (1-Methyl-2-keto-1,2-dihydro-4-ρ ratio octyl)-3-hexahydrop to chiral acid amine (Example 109) trans-N-cyclopropyl-4 -hydroxy-N-[3-(2-decyloxyethoxy)_5_(3-methoxypropyl)octyl]-4-(1-methyl-2-keto-1,2-di Hydrogen-4-pyridyl) each hexahydropyridine slow oxime (Example 110) trans-N-cyclopropyl-4-methoxy-N-[3-(2-methoxyethoxy)_5_( 3-methoxypropyl)henyl]-4-(1-indolyl-2-keto-l,2-dihydro-4-? ratio. Stationary)_3_hexahydro-P ratio Example 111) 143482-1 -40- 201111364 The invention also encompasses a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable crystalline form or hydrate thereof. A specific embodiment is a pharmaceutical composition of a compound of formula I which additionally comprises a second agent. List of abbreviations: BINAP 2,2'-bis(diphenylphosphino)-1, hydrazine-hydrazine BOC tert-butoxycarbonyl BSA bovine serum albumin _ COD 1,5-cyclooctadiene DBU 1, 8-Diazabicyclo[5.4.0]unde-7-dilute DCM Dioxane DIBA1-H Diisobutylaluminum hydride DMAP 4-Dimethylaminopyridine DME 1,2-dimethoxy ethane DMF Ν, Ν-dimercaptoamine • DMP Dess-Martin over-fired DMSO 曱 曱 曱 D DPPB 1,4-bis(diphenylphosphino)butane DPPF 1, Γ-bis (diphenyl Phosphyl) Dicyclopentadienyl Iron EDTA Ethylenediaminetetraacetic Acid EIA Enzyme Immunoassay Et20 Ethyl Acetate Ethyl Acetate HATU Hexafluorophosphonium Phosphate-(7-Nitrobenzotriazol-1-yl)-Ν,Ν,Ν ',Ν'-四曱基锞143482-1 -41 - 201111364

Hex hexane IPA isopropanol KHMDS hexamethylene dihydrazine potassium hydride mCPBA m-gas perbenzoic acid MeOH sterol NBS N-bromo amber quinone imine NMO N-methylmorpholine-N-oxide n -PrOH n-propanol PBS sulphate buffered saline PG protecting group PPh3 triphenylphosphine RT room temperature TBAF tetrabutylammonium fluoride TFA trifluoroacetic acid THF tetrahydropuffan TMEDA Ν, Ν, Ν·, Ν' - Tetradecylethylenediamine Tol Benzene MTBE Methyl Third-Butyl Ether COD Cyclooctadiene c. HCl Concentrated HC1 All ranges quoted herein are inclusive unless explicitly stated to the contrary. For example, an alkyl group described as a q-c6 alkyl group means that the alkyl group may contain 1, 2, 3, 4, 5 or 6 carbon atoms. When a specific range contains 〇 (for example, (CH2) 0-3), the 0 system means a direct covalent bond. 143482-1 -42- 201111364 When any variable appears in any composition' or occurs in any chemical formula that describes and describes a compound of the invention, its definition at each occurrence is defined in each of its other places of existence. Nothing. Moreover, combinations of substituents and/or variables are permissible only if such combinations result in a stability compound. The term "replacement of the left" (for example, in the "aryl group substituted by one or more substituents as appropriate") includes the single- and multiple-substituted substitutions of the indicated substituents, Multiple substitutions at the same position are chemically terminated and result in a degree of stability of the compound. The stability of a compound is a compound that can be prepared and isolated, and its structure and properties remain intact or can be kept substantially unchanged, and it is sufficient to allow the use of g-shell compounds at 5 noon. The time of the purpose (eg, administration to a patient for treatment or prevention). In the compound of the present invention having a pyridyl N-oxide moiety, the pyridyl-N-oxide moiety is structurally represented by a conventional representation _ 乂 N - 0 Ο " '0' The meaning. The present invention relates to a method for treating and/or preventing diseases related to hypertension, septic heart failure, pulmonary hypertension, systolic hypertension, renal insufficiency, renal blood loss, renal failure, renal fibrosis, heart Insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, spheroid nephritis, renal colic, complications caused by diabetes, such as kidney disease, vascular disease and neuropathy, glaucoma, high intraocular pressure, Atherosclerosis, restenosis after angioplasty, complications after vascular or cardiac surgery, 143482-1, 43- 201111364 Erectile dysfunction, aldosteronism, pulmonary fibrosis, scleroderma, anxiety, Cognitive disorders, complications treated with immunosuppressive agents, and other diseases known to be associated with the renin-angiotensin system include administering a compound as defined above to a human or animal. In another embodiment, the invention relates to a method of treating and/or preventing a disease, relating to hypertension, septic heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, Renal fibrosis, cardiac dysfunction, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy 'complications due to diabetes, such as kidney disease, vascular disease and neuropathy. In another embodiment, the invention relates to a method of treating and/or preventing a disorder associated with the regulation of dysfunction of the renin-angiotensin system, and a method of treating the above mentioned diseases. / The present invention also relates to the use of a compound of the formula (1) for the preparation of a medicament for the treatment and/or prevention of the diseases mentioned above. The compound of formula 1 or the pharmaceutical composition mentioned above may also be combined with other music active compounds including ACE, formulation, neutral endopeptidase inhibitor, angiotensin 11 receptor antagonist, endothelin receptor antagonist Agent, vasodilator ' @ antagonist, potassium activator' diuretic, antisympathetic agent, adrenergic antagonist, (iv) adrenergic antagonist or other beneficial to prevent or treat the above mentioned diseases drug. 'About the compound of formula I, "injection" - and its variants (for example, administration, compounding means providing a compound or a human body to a subject in need of treatment or prevention. When the compound of the invention Or its prodrug; other active agents (such as a drug, such as blood vessels = 143482-1 201111364 4 d ACE inhibitors or other active agents known to lower blood pressure) and provided, should be clear,, dosing " and its variants each include providing the compound or prodrug and other agents at (iv) or at different times. When the de-grouped agents are administered simultaneously, they may be administered together in a single composition. Can be administered individually. The composition used in this article

^ 3 products of the & components, and any products directly or indirectly due to the specific combination of specific components. It is understood that the pharmaceutically acceptable ingredients mean that the ingredients of the pharmaceutical composition are compatible and not deleterious to the recipient. The term "patient" as used herein refers to an animal, in the case It is a mammal, and in a particular embodiment is a human being, a target for treatment, observation or experimentation. ','' used in this article '·effective amount' or 'medical activity amount, the word sound * the amount of active compound or agent' will lead to the researcher, the organization that the bed is seeking, system' A biologically dry or medicinal response in an animal or human. In one embodiment, there is a symptom of amelioration of the disease or condition being treated, • a therapeutically effective amount, and an effective amount in the second = =1 V is prevented from being prevented Disease or Symptoms: and the dose ". The term also includes herein sufficient to inhibit the monthly element and the wrong to lead to the response sought, w externally effective amount ·> when the active compound (meaning: substance: u, That is, the inhibition system is directed to the free form of the compound (meaning that it is not specifically described in the specific embodiment, this amount includes between daily milligrams and 143482-1 -45-201111364 1000 mg. In other specific sinus 竑 丨ώ 八In the case of body%, this amount includes between i and 500 mg per day.

/, in the body target, this amount includes between 1 mg and 200 mg. I In the method of the invention (meaning to inhibit renin), formula! The compound, as the case may be, is in the form of a salt which can be administered by any means which produces an active agent in contact with the site of action of the agent. Such administration methods as described form a particular embodiment of the invention. The compound can be used in conjunction with the prescription of the medicine: gas administration, individual treatment or combination of therapeutic agents: it can be administered separately, but it is usually based on the selection route and standard (4) practice. The selected pharmaceutical carrier - from the drug. The compounds of the present invention can be administered, for example, orally, mucosally (including sublingual, face-clamped 'rectal, nasal or vaginal administration), parenteral (including subcutaneous injection, bolus injection, intra-arterial, intravenous, intramuscular). , intrathoracic injection, or perfusion medication technology), by inhalation spray, percutaneous, such as by sputum or iontophoresis, or local history, w contains effective 3: compound and conventional non-toxic pharmaceutically acceptable The pharmaceutical composition of the carrier, adjuvant and vehicle is administered in unit dosage form. The above-described administration techniques using the compounds as described herein form an important embodiment of the invention. Examples of dosage forms to be encompassed as part of the present invention include, but are not limited to, tablets, sachets, capsules, such as soft elastic gelatin capsules, cachets, lozenges, lozenges, dispersions, suppositories, ointments. , cataplasm (porridge), paste, blister, dressing 'cream, plaster, solution' patch, aerosol (eg nasal spray or inhalation | §), gel, suitable for oral or mucosal cast Liquid dosage forms for patients, including suspensions (such as aqueous or non-aqueous liquid suspensions, oil-based emulsions or water-based liquid emulsions), solutions and elixirs, suitable for 143482-1 -46- 201111364 Liquid dosage forms for enteral administration, and Helmets, trapped solids (e.g., crystalline or non-steroidal solids), which can be reconstituted to provide a liquid dosage form suitable for parenteral administration. Liquid preparations suitable for oral administration (e.g., suspensions, glycolics, ugly agents, etc.) can be made according to techniques known in the art, and any conventional medium such as water, glycols, oils, alcohols can be employed. Wait. Solid preparations suitable for oral administration (e.g., powders, pills 'capsules and tablets) can be made according to techniques known in the art, and can employ solid excipients such as starch, sugar, kaolin, lubricants, Adhesives, disintegrators, etc. The parenteral compositions can be made according to techniques known in the art, and typically employ sterile water as a vehicle, together with other ingredients such as dissolution aids. The /priming' solution can be made according to methods known in the art, and the carrier is a solution of saline solution, dextrose solution or a mixture of saline and glucose. A method suitable for the preparation of a pharmaceutical composition for use in the present invention, and further description of the ingredients suitable for use in the composition, is provided

Remmgt () N Medical Science, 18th Edition, edited by A.R. Gennaro, Mack, Ltd., 1990. The method of preparing the compounds described herein is also known. In the specific & embodiment, the invention relates to a method for preparing a compound of the formula: R1

Wherein: · U3482-1 -47- 201111364 R1 is a Q-C2 alkyl group optionally substituted by 1-3 halogens, and R2 and R3 are independently selected from the group consisting of hydrogen, halogen, q-C5 alkyl , C]-C5, alkoxy and -0-(C丨-C5 extended alkyl)-0-(CH2)〇-3 -CH3 ' wherein alkyl, alkoxy and-0-((:! -C5 The alkylene group -0-(CH2)〇-3 -CH3 is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halogens, optionally substituted by 1-3 halogens. a C-C5 alkyl group and a C-alkoxy group substituted by 1-3 halogens, X is selected from the group consisting of hydrogen, -OH and C, -C5 alkoxy, (Z) n丨 is C丨-C2 alkylene, and A is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) CVC5 alkyl, (4) CVCs alkoxy, and (5)-S -(CH2 )〇. 3 "CHj > where (3) and (4) are replaced by μ3 halogens as appropriate. ' Β is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) alkyl, ( 4) CVC5 alkoxy, (3)-OH, (6)-CF3, (7) _c(=0)-CH3, 143482-1 201111364 (8) -0-(C丨-C5 alkyl)-0-(CH2 )〇— 2 -CH3, (9) -(C -C5 alkylene)-0-(CH2)0.2 -CH3, (10) -0-(C丨-c5 alkylene)-C(CH3)2 -C(=0)0H, and (11)- O-CCrCs alkyl)-C(CH3)2-C(=0)0CH3, wherein (3), (4), (8), (9) and (11) are optionally substituted by 1-3 halogens, Group C is selected from the group consisting of: (1) hydrogen, (2) qQ alkyl, optionally substituted with 1-3 halogens, and (3) Q-C5 alkoxy, optionally substituted with 1-3 halogens And D is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) (VC5 alkyl, (4) QQ alkoxy, (5) cyano, (6) C2 - C5 Base-0-(CH2)〇. 2 -CH3, (7) -(q -C5 alkylene)_N(H)-C(=0)-0-(CH2 )0 - 2 -CH3, (8) -(C! -C5 alkylene)-N(H)-C(=0)-(CH2)〇- 2 -CH3, (9) -(q -C5 alkylene)-0-CHF2, (10 -(C--C5 alkylene)-O-(CH2)0.2-CH3, (11)-0-(Ci-C5 alkylene)-O-(CH2)0-2-CH3, (12) -((VC5 alkylene)-OH, (13) -SA-Cs alkylene)-OH, 143482-1 -49- 201111364 (14) -SCF3, and (15) -NCHHq -C5 alkylene) -0-(CH2 )〇_ 2 -CH3, where (3), (4), (5), (6), (7), (8), (9), (10) (11), (12), (13) and (15) are optionally substituted by 1 to 3 halogens, which comprise the following steps: (1) Coupling a compound of the formula (8) or a salt thereof in the presence of a solvent to the formula (8) Compound or its salt:

To form a compound of the formula (6) or a salt thereof

(2) The compound (6) is removed from the protection by removing Boc. In a particular embodiment, the solvent is/comprising one or more compounds selected from the group consisting of DMF, gasified grass mash, and /Pr2Net. In a particular embodiment, the removal protection step is carried out with one or more compounds selected from the group consisting of HC1, IPA, and MTBE. In a particular embodiment, the invention is directed to a method of preparing a compound of the formula: 143482-1 -50- 201111364

It comprises the following steps: (1) coupling a compound of formula (8) having a Boc group to formula (b) below, in the presence of DMF, chlorinated mash and zPr2NEt:

To form a compound of formula (c)

Me

(C); with

(2) The formed compound is removed by removal of the Boc group and the protection is removed in the presence of HCL, IPA and MTBE. Synthetic Methods The compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown below and in the description, which form the specific embodiment of the invention 143482-1 201111364. Starting materials and reagents for the preparation of such compounds are generally prepared by commercially available suppliers, such as Aldrich Chemical Company, or by methods known to those skilled in the art, in accordance with the procedures set forth in the references. For example, Fieser and Fieser's reagents for organic synthesis; Wiley & Sons: New York, Vol. 1-21; RC LaRock, Integrated Organic Transformation, 2nd Supplement Wiley-VCH, New York 1999; Integrated Organic Synthesis, B. Trost And I. Fleming (eds.), Volumes 1-9, Pergamon, Oxford, 1991; Integrated Heterocyclic Chemistry, AR Katritzky and CW Rees (eds.) Pergamon, Oxford, 1984, vol. 1-9; Integrated Heterocyclic Chemistry II, AR Katritzky and CW Rees (ed.) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic schemes and examples are merely illustrative of some of the methods by which the compounds of the present invention can be synthesized, and various modifications of such synthetic schemes can be performed, and reference is made to the disclosure contained in the present application. Those who are familiar with this art are born out of heart. The starting materials and intermediates of the synthetic reaction scheme can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional methods, including physical constants and spectral data. Unless otherwise stated, the experimental procedure was carried out under the following conditions. The evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 kPa: 4.5-30 mm Hg) at a bath temperature of 60 ° C. Unless otherwise indicated, the reaction is typically carried out under nitrogen atmosphere at ambient temperature. Anhydrous solvents such as THF, DMF, Et2®, DME and sputum are commercially available. The reagents were commercial grade and used without further purification. Rapid-type chromatography 143482-1 -52- 201111364 is operated on Shishijiao (collar net). The reaction is traced by (tetra) layer chromatography (TLC) or nuclear magnetic resonance (NMR) spectrometry, and the reaction time is merely illustrative. The structure and purity of all final products were determined by TLC, mass spectrometry, and high pressure liquid chromatography (Η·). Chemical symbols have their usual meanings. The following abbreviations have also been used: v (volume), W (weight), bP (boiling point), mP (melting point), L (liter), chaos (ml), g (g), mg (mg) 'mol (mo Ear), Congyi 1 (millimeter), called (equivalent).

All variables mentioned below have the meaning as provided above unless otherwise indicated.

In general, the compounds of the present invention can be prepared via the appropriately substituted pyridone and the appropriately functionalized amine π, followed by the removal of the B〇c_ protecting group from the guanamine m (Figure 1). . Figure 1

Necessary tons. The synthesis of the ketone I can be carried out, for example, as exemplified in Scheme 2. Typically, it is prepared from a dihydroxy borane ester blade of known trifluorosulfonate V (e.g., 1434S2-1.53-201111364)

Ujjarnwalla et al., Bioorg. Med. Chem. Lett.; 15 (18), 2005, pp. 4-23- 4028) Metal-catalyzed Suzuki coupling with halide vn provides a, non-unsaturated ester VIII ^ double The reduction of the bond; the most convenient use of magnesium or hydrazine iodide to achieve the equilibrium of the subsequent base, followed by the acquisition of the saturated ester IX as a single diastereomer. Conversion to the corresponding pyridone x can be carried out in two steps, via ester IX with mCPBA; or an equivalent amount of oxidizing agent, followed by reaction of the formed pyridine N-oxide with TFAA in triethylamine; or equivalent rearrangement This is achieved by the initial treatment of the accelerator. Alternatively, in the case where the v group of the ester oxime is 〇Bn, the simple hydrogenation under typical conditions is the direct obtaining of the pyridone and the case where the V group of the ester IX is OMe, in the presence of moth The reaction of the alkyl halide is obtained as a pyridone oxime. In fact, we can also obtain the edge via the alkylation of pyridone X with an appropriate reagent. The most important saponification of 11 is pyridine ketone to obtain pyridone j. 143482-1 -54· 201111364 F3c- ,s* Figure 2 M^^Me Ίν

Ό O (^V^OEt

.Λ Me N#ΛΛ) V 〇, B'〇0

OEt VII VI R2v.Ns R2^Ns

Ri

OEt

Me N ίίΛΛ) XI

R3 γ 〇 Me^O^O

X R2^N^V U = Br, I V = H,OMe, OBn V = H, OBn

V = OMe Regarding the halide VII used in the preparation of I, wherein v is 0Me or 〇Bn, the synthesis can be achieved extremely easily from its corresponding pyridone XIV. For example, this transformation can be achieved by reacting pyridone XIV with a mercapto or fluorenyl halide in the presence of silver carbonate (Figure 3). For the case where pyridone XIV is neither commercially available nor known in the literature, the essential compound can be passed via hydrazine. Define the intermediary of oxide XIII, made from its corresponding p-bite. Figure 3

R2\^N

U XII 〇一

u XIII R2^n^o

u XIV U = Br, l V = OMe, OBn r2^n.

u

VII In most cases, the route for the preparation of the amines used in the figures 143482-1 • 55· 201111364 has been disclosed in the published patent application w〇2〇〇7/〇〇925〇ai. Non-known persons can be synthesized according to, for example, the method exemplified in Fig. 4. Where appropriate, the aldehyde XV system first desertified in a regioselective manner. The resulting bromide XVI is then subjected to general reductive amination conditions to yield an amine. If necessary, the amine XVI1 can then be protected as its corresponding N.BQC derivative XVIII. Coupling using a typical metal medium, such as Suzuki or Bu-Ten U1, allows the R bond in the amine to be attached to the amine χνπ or amine χνιπ. When necessary, 'simple chemical modification' can be performed, such as hydrogenation, thinning, reduction, deuteration, ozonolysis, oxidation, and other processes to achieve the desired R group in amine II. Finally, with regard to amine χιχ, it is necessary to simply remove the protective step.

R" FT XV

Figure 4

«Another common skeleton seen in the amine π. Under the eight-type reaction conditions, these compounds can be re-introduced by a simple chemical modification, such as hydrogenation thinning, reduction, brewing, ozonolysis, oxidation/ And act to achieve the desired R group in the amine n. Finally, X New Year 143482-1 • 56- 201111364 The feminization of the month is the desired amine. If 啕哚χχι is not commercially available, it can be obtained via a simple formazanization of, for example, 4 xx, which is most conveniently achieved with P〇Cl3 in DMF. ’,

With respect to the compounds of the invention having an alkoxy group at position 4 of the hexahydropyridine ring, which is most conveniently formed via the initial guanamine between the amine oxime and the ketone ester oxime, followed by addition from appropriate protection and appropriate Obtained as a Gignard reagent substituted with hydroxypyridine. If necessary, the functionalization of the alcohol oxime formed is prior to the conversion of the protected hydroxypyridine XXVI to the desired pyridone XXVII using the chemical techniques previously described. Finally, B〇C removal can be achieved under typical conditions (Figure 6).

143482-1 57- 201111364 Figure 6 〇〇

R2^n_opg

OEt + ΗΝ,(Ζ)ηΐΥA R3 Ξ〇 r4〇Aa Me^H L Me^J L Me into the 〇人〇

N'(Z)n1YA

XXVI

The representative cyclopropylamine structural unit of XXVII xxvm is shown in Table 1. Table 1 Compound Structure Amine 1 Άα Amine 2 Η ψ OMe

143482-1 -58- 201111364

Compound structure amine 3 A.

CI

Amine 7 amine 8 amine 9 amine 10 amine 11 amine 12 143482-1

Me

A.

Me

OMe A.

OMe s 〇 A.

Cl

Cl 〇Me OMe OMe H OMe OMe CN Compound Structure Amine 6, 兮°' ^OMe Amine 14 Me〇2C> Amine 15 Ί OMe Amine 16 HN 丫. OMe amine 17 Ά amine 18 amine 19 ΆΝ -59- 201111364

Compound structure amine 20 Άν amine 30 匕CN amine 31 ^^〇Me amine 32 k^N^Me guanamine 33 amine 34 A Nn-, 〇Me amine 35 human XV V-CF3 amine 36 HN^Y\JA Vy^CF3 143482-1 ·60· 201111364

Compound structure amine 28 ^K^nrBr OMe amine 29 HN-OMe amine 39 into Nv^cf3 cf3 amine 40 A ^NH amine 41 Ηϊ^χΡ A ^NH 〇^Et amine 42 Axv HN-f〇Me amine 43 HN^rrO Human HN--f〇Et Amine 44 A Compound Structure Amine 37 ηγτΡ Δ ^s^y^Me Amine 38 A L.Vy-〇Et Amine 47 A Amine 48 \^N Amine 49 ηϊΎΡ A Ns> Amine 50 HrtP Ns> c amine 51 κ ^ F amine 52 λ 4 Cl 143482-1 • 61 - 201111364 Compound structure compound structure amine 45 amine 53 ΗΝ^ττΟ CN amine 46 amine 54 A^q Me amine 55 F AXn^ ^-〇Me amine 63 Cl HN^VV^ ΑχΝζ V〇Me Amine 56 A^o Amine 64 Cl, Amine 57 A nq F Amine 65 BrV\ hn^yv) A^o Amine 58 Mev^\amine 66 BrV\ HN^TV) F Amine 59 NCWx HN^rAJ A^o Amine 67 h〇cP A ^-~〇Me Amine 60 hn^AJ^ Amine 68 A ΙνΓ 143482-1 -62- 201111364

Compound structure amine 61 F amine 62 ΑχΝζ V〇Me amine 71 Me HN 八 YVMe A y amine 72 Cl hn^yS AV 〇-v^OMe amine 73 HpDO amine 74 ΗΓΡ scf3 amine 75 SMe HN ~ AY amine 76 HN^^V3⁄4γBr A γΜβ ^^OMe

143482-1 63- 201111364

Compound Structure Compound Amine 77 〇Me ΗΝ^Τ^Γ ay ^^OMe Amine 86 HN W/ )> ^OMe Amine 78 AY . ^^OMe Amine 87 ΗΝ^τί^νΒΓ A Vmo Amine 79 〇Me Br pay ^ ^OMe Amine 88 HN^T^TBr A ^Me ^^OEt Amine 89 HN^ri^VBr A γΜβ ochf2 Amine 91 TO: l〇rF Amine 90 % Amine 92 TO! °^aF [Embodiment] Amine 1 N- (2,3-Dimethylbenzyl)cyclopropylamine 1 is made according to the procedure described in the published patent application WO 2007/009250 A1. Amine 2 N-{[5-Alkyl-2-(3-decyloxypropyl)-4-pyridyl]methyl}cyclopropylamine 2 is according to the published patent application WO 2007/009250 A1. The program is made. 143482-1 • 64- 201111364 Amine 3 N-({2-carbyl-5-[3-(methoxy)propyl]phenyl}methyl)cyclopropylamine 3 is based on the published patent application w It is made by the procedure described in 〇2〇〇7/〇〇925〇A1. Amine 4 N-({2-carbyl-5-[2-(decyloxy))ethyl]phenyl}methyl)cyclopropylamine 4 is according to the published patent application w〇2007/009250 A1 The program is made. ®amine 5 N-({2,3-dioxa-5-[3-(methoxypropyl)propyl)phenyl)indolyl)cyclopropylamine Step 1: 5-bromo-2,3-di Gasbenzaldehyde was added to a solution of 2,3-dioxabenzaldehyde (1 equivalent) in TFA (0.38 M) with sulfuric acid (5 eq.). Over a period of 3 hours, the bromo amber imine (1.5 equivalents) was added in portions at room temperature to finally obtain a yellow orange solution. After % hours, the crude reaction mixture was diluted with 9:1 (v/v) hexane: hydrazine and washed successively with water, in NaOH φ aqueous solution, water and brine. The organic extract was dried with EtOAc (EtOAc m. Step 2: N-[(5-Bromo-2,3-dioxa)indolyl]cyclopropylamine will be obtained from the previous step of 5-bromo-2,3-dibenzoquinone (1 equivalent) Combined with cyclopropylamine (2 equivalents) in CH2C12 (0.1 M). Then add it to it

(1 eq.) and the resulting suspension was stirred at room temperature for 18 h. Next, the insolubles were removed via filtration through a diatomaceous earth pad and the effluent was concentrated in vacuo. The crude imine thus obtained was then redissolved in a 2.1 (v/v) mixture (0.17 M) of THF : MeOH 143482-1 - 65 · 201111364. Here, sodium borohydride (10 equivalents) was added in portions to the solution, and the resulting mixture was stirred at room temperature for 48 hours. The reaction was quenched with aq. The combined organic extracts were then washed with water and brine, dried over NasSO4, filtered, and concentrated. The crude product thus obtained was purified by flash chromatography eluting elut elut elut Step 3: N-({2,3-digas-5-[(1E)-3_(methoxy H•propene·Η]phenyl}methyl)cyclopropylamine will be obtained from the previous step-[( 5-Mosyl·2,3_di-phenyl)methyl]cyclopropylamine (1 eq.) and 4,4,5,5-tetramethyl-2-[[1](曱 Η Η) ] Oxygen side garden α.5 equivalent) was combined in DMF: n_Pr〇H in a 5:1 (v/v) mixture (0.17M). Then, in this solution, trans bis (triphenyl sulfonate) was added. Palladium amount), and the vessel was repeatedly evacuated and backfilled with nitrogen. Finally, 2NNa2C〇3 water (2 equivalents) was added, and the (IV) two-phase suspension was heated at 9 (TC for 8 hours). The black suspension is cooled to room temperature and diluted with water and taken in the test. Then, the combined organic extracts are further swept in a Na〇H aqueous solution, water and brine. It is dehydrated and dried with Na2S04; it is considered; the solution is concentrated in a vacuum to obtain a viscous red oil. The crude product thus obtained is purified by flash chromatography (Si〇2, 炫炫-3:7 (v /v) Hexane: EtOAc) to give the title compound as a yellow oil. Step 4: Amine 5 (丨2,3-, 1 -muscle·J-LUt)-3-(methoxy)-1-propanyl]benyl}mercapto)-cyclopropylamine (1 告吾>1Λ^ U田置) with 10% w/w palladium on charcoal (0.1 eq. 143482-1 -66 - 201111364 floated in EtOAc (0.03M). Then 'pump the container and let the gas h2. In the gas cylinder filled with H2 atmosphere The reaction suspension was stirred at room temperature for 2 hours, then 'quenched with CI^Cl2' through a bed of diatomaceous earth, and the filtrate was concentrated in vacuo. The crude product thus obtained was subjected to a flash. Purification by chromatography (Si 2 2 hexanes - 1:1 (v/v) hexanes:EtOAc) [2-(decyloxy)ethyl]phenyl}methyl)cyclopropylamine* Step 1: [(5-Mothyl-2,3-dichlorophenyl)methyl]cyclopropylaminocarboxylic acid u_ Dimethylethyl ester will be obtained from N-[(5-glycosyl-2,3-dichlorophenyl)methyl]cyclopropylamine (1 'in) of amine 5 step 2 and di-third to di-dicarbonate The ester q J equivalent) was combined in CH 2 Cl 2 (〇 '17M). Then, to this solution, Hunig's test (1.2 equivalents) was added, and the resulting yellow solution was stirred at room temperature for 3 hours. Next, the reaction mixture was diluted with ether and washed successively with water and brine. Then, the organic layer was dried over Na 2 S 〇 4, filtered, and the filtrate was concentrated in vacuo to give a color oil. The product was purified by flash chromatography eluting elut elut elut elut v, step 2. %, propyl [ο divinylvinylphenyl) fluorenyl] guanidinium ruthenate, 丨 曱 曱 乙 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 ( ( ( ( ( ( ( ( ( ( ( ( ( Dichlorophenyl)methyl]cyclopropylcarbamic acid U-didecylethyl ester (1 equivalent) and 2-vinyl-4,4,5,5-tetradecyl 1,3,2-oxygen Boronum (1 equivalent) is combined in: n_pr〇H of 2:1 (v/v) mixed 143482-1 -67- 201111364 (0.1M). Then, in this solution, acetic acid Ib (π) (〇 5 equivalents) and triphenylphosphine (〇 15 equivalents) were added, and then the vessel was repeatedly evacuated and counter-filled with nitrogen. Finally, 2 Ν aqueous NafO 3 (2 equivalents) was added, and the resulting two-phase suspension was heated at 90 ° C for 18 hours. The current black suspension was allowed to cool to room temperature, diluted with water and extracted with 1:1 (v/v) hexanes: ether. The combined organic extracts were then further washed with aqueous IN NaOH, water and brine. Then, it was dehydrated and dried with Na2S〇4, and the filtrate was concentrated in vacuo to give a pale yellow oil. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc (EtOAc) Step 3: Cyclopropyl {[2,3-dichloro-5-(2-hydroxyethyl)phenyl]methylindolyl decanoic acid u_ fluorenyl B. The cyclopropyl group obtained from the previous step [(2,3_divinylvinylphenyl)indenyl] 1,1-dimethylethyl carbamic acid (1 equivalent), [Ir(c〇D)cl]2 (〇〇25 equivalent) and DPPB (〇.〇5 equivalent) was combined in THF (〇nM). Then, in this solution, 4,4,5,5-tetradecyl-l,3,2-dioxaborin (1.3 eq.) is added, and the formed, 'work color> gluten solution is Stir at room temperature for 12 hours. Finally, sodium perborate (0.1 M aqueous solution, 1 equivalent) was added, and the current black two-phase solution was vigorously stirred at room temperature for further 12 hours. The aqueous layer was separated and back extracted with ether. The combined organic extracts were then further washed with aqueous 1 N NaOH, water and brine. Then, it was dried over NasSO4, filtered, and the filtrate was concentrated in vacuo to give a pale yellow oil. The crude product thus obtained was purified by flash chromatography (Si </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Colorless oil. 143482-1 •68- 201111364 Step 4: Cyclopropanol (72 3 gcm ^ (helium·5_[2-(methoxy)ethyl]phenyl)methyl)carbamic acid 1,1-dimethyl The ethyl ester was dissolved in THF (〇3M) tj7 with % propyl {[2,3-dichloro! (2-hydroxyethyl)phenyl]methyl}aminocarbamic acid u-dimethyl ethane. Then, in this solution, sodium hydride ((9)% w/w dispersion in oil, i equivalent) was added, and the resulting stock solution was stirred for 5 minutes under / phoenix. Finally, moths were added. (1〇当罝)' and the current light yellow solution was stirred in the dark at room temperature for 10 φ hours. Then, the volatile matter was removed in vacuo, and the residue formed was tested in 1NHC1 aqueous solution. The liquid layer was separated and the aqueous layer was separated and subjected to reverse extraction with ether. Then, the combined organic extracts were washed with an aqueous solution of water, water and brine, followed by dehydration with Na2S 4 and filtration. And the filtrate is concentrated in vacuo to give the title compound (oil-contaminated) as a pale yellow oil. Step 5: Amine 6 to give the cyclopropyl group from the previous step ({2,3_二气_5_[2_( Methoxy Ethyl]ethylidene}methyl)carbamic acid U-didecylethyl ester (1 equivalent) is dissolved in CH2C12 (0.1M). Then, in this solution, HC1 (40m, in dioxane, 30 eq.), and the resulting solution was stirred at room temperature for 2 hours. Then, the reaction was quenched with aqueous 1N NaOH and extracted with ether. Then, the organic extract was washed with water and brine. Drying with Na2S〇4, filtration, and concentrating the filtrate in vacuo. The crude product thus obtained was purified by flash chromatography (SiO2, 9:1 (v/v) hexane: Et 〇Ac- Et 〇Ac ), the title compound was obtained as a colorless oil. Amine 7 143482-1 -69- 201111364 N-(2-indolyl-5-[3-(indolyl)propyl]phenyl}indolyl) propylamine Step 1 : 5-A-N-cyclopropyl-2-methylbenzamide at 0 C in a solution of 5-oxo-2-indenylbenzoic acid (1 eq.) and DMF (12 eq.) In 1M), the gasified grasshopper (I2 equivalent) was added dropwise, and the solution was mixed for 2 hours under 〇t, and then the volatile matter was removed in a vacuum to form a residue. Soluble In a gas methane (10), cooled to o ° C, and successively added cyclopropylamine (15 equivalents) and Hunig's base (2 equivalents) dropwise. The resulting suspension was stirred at room temperature for 18 hours. The reaction was quenched with aqueous HCl and extracted with dichloromethane. The combined organic extracts were dried with &lt;RTI ID=0.0&gt; In the suspension, an equal volume of hexane was added and the title compound was isolated by vacuum filtration. Step 2: N-[(5-Alkyl-2-mercaptophenyl)methyl]cyclopropylamine at 〇 ° C, 5_chloro_N_cyclopropyl-2-methyl obtained from the previous step To a suspension of benzamide (1 eq.) in THF (0.4 M) was added borane (1 〇M in THF, 3 eq.). The resulting suspension was allowed to warm to room temperature over a period of time and then heated under reflux for 1 hour. The current pale yellow solution was re-cooled to 〇 C and the reaction was carefully quenched with aqueous EtOAc. The resulting mixture was heated under reflux for 1 hour to ensure complete decomposition of the amine-sane complex. After careful neutralization with aqueous 1 N NaOH solution, the aqueous layer was separated and purified with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub. The filtrate was concentrated in vacuo, and the crude material obtained was purified further purified eluting eluting eluting eluting eluting Colorless oil. 143482-1 ► 70- 201111364 Step 3: [(5-Alkyl-2-methylphenyl)indenyl]cyclopropylamino decanoic acid ι, ΐ-dimethylethyl ester at -78 ° C, To a solution of N_[(5-carbyl-2-methylphenyl)methyl]cyclopropylamine (1 equivalent) in THF (0.3 M) from the previous step, hexamethyldifluoride (0.5 g) was added. M 'in toluene, 1.2 equivalents). After stirring at -78 ° C for 1 hour, a slave was added, and the resulting mixture was slowly warmed to room temperature for 2 hours. The reaction was quenched with saturated aqueous NH.sub.4Cl. The combined organic extracts were washed with brine, dried with EtOAc EtOAc EtOAc. Further purification (Si 2 , hexane - 4:1 (v/v) hexane: EtOAc) was obtained by flash chromatography to afford the title compound as pale yellow oil. Step 4: Cyclopropyl ({2-mercapto-5-[(1Ε)-3-(methoxy)-1-propen-1-yl]phenyl}methyl)carbamic acid 1,1-di Thioglycol ethyl ester will be obtained from [(5-carbyl-2-mercaptophenyl)methyl]cyclopropylamino. decanoic acid 1,1-didecylethyl ester (1 equivalent) and 4 , 4 5,5_tetradecyl 2 [(1e) 3 (曱 oxygen • yl) propylene-1·ylindole, 3,2·dioxaboron (1 eq.) combined with n-BuOH ( 0.48M). Then, in this solution, a ginseng (diphenylarbenium acetonide) dipalladium (yttrium) gas imitation adduct (0.02 equivalent), [2,6,-bis(decyloxy)-2-biphenyl was added. (dicyclohexyl) discane (〇.〇8 equivalent) and powdered potassium phosphate (2 equivalents). The vessel was repeatedly evacuated and counter-filled with nitrogen, and then the resulting suspension was placed at 1 Torr. Heat under 16 for 16 hours. The current black suspension was allowed to cool to room temperature, diluted with Et〇Ac, and transitioned through a Si〇2 batter. Then, the filtrate was concentrated in vacuo, and the crude product thus obtained was directly subjected to purification by flash chromatography (Si 〇 2, hexane - 3:7 (v/v) hexane: Et EtOAc). The title compound was isolated from 143482-1 -71 - 201111364 as a pale yellow oil. Step 5. Indole propyl ({2-methyl·5_[3_(decyloxy)propyl)phenyl}indolyl) decanoic acid 1,1_·indolyl hydrazine Propyl ({2 methyl_5 [(1Ε)_3 (decyloxy H-propenyl)phenyl}indolyl) decanoic acid 1,1-didecylethyl ester (1 equivalent) and 10% w/w palladium/carbon (0.1 eq.) was suspended in Et〇Ac (〇〇8M). Then, the vessel was evacuated and scrubbed with H2. The reaction suspension was placed under a cylinder filled with % atmosphere. After stirring at room temperature for 2 hours, the reaction was quenched with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. - 1:1 (v/v) hexanes: EtOAc (m.) EtOAc: EtOAc: EtOAc Propyl]phenyl}decyl)amino decanoic acid 1,1-didecylethyl ester (1 equivalent) is dissolved in CH2Cl2 (〇1M). Then, in this solution, HC1 (4 〇M, In a dioxane field, 30 equivalents), and the resulting solution was stirred at room temperature for 2 hours. The reaction was quenched with aqueous EtOAc (aq. EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Purification by flash chromatography (Si </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> -(Methoxy)ethyl] phenyl}methyl)cyclopropylamine 8 is prepared according to the procedure described for amine 6, but alternatively using step 3 from amine 143482-1 -72-201111364 7 [ (5-Alkyl-2-indenyl)methyl]cyclopropylamino decanoic acid with -didecylethyl ester as the acceptor, n-BuOH as the solvent, ginseng (diphenylarbenium acetonide) Palladium (9) gas imitation adduct as palladium source, [2,6,-bis(methoxy)_2-biphenyl](dicyclohexyl)yl alkane as a ligand, and powdered potassium phosphate as a base, For Suzuki coupling (step 2). Amine 9 N-({2,3-difluoro-5-[3-(methoxy)propyl]phenylindolyl)cyclopropylamine 9 based on amine 5 Made in the procedure described, but alternatively used 2,3_two Benzofurfural is used as a starting material. Amine 10 N-({3-(decyloxy)-5-[3-(methoxy)propyl]phenyl) propylamine Step 1 : 3-bromo group -5-Hydroxybenzaldehyde Addition of n-butylmagnesium hydride in a toluene solution (1.6 M) of n-butyllithium (2.5 M in hexane, 2.1 eq.) at -10 C. 〇M 'in THF, 〇6 when i). The reaction mixture was stirred at -10 ° C for 3 minutes, then 3,5-dibromophenol (1 equivalent) in benzene (0.7 M) was added dropwise over a period of 35 min. After stirring at -10 C for an additional 30 minutes, the reaction mixture was cooled to _4 〇 C then DMF (20 eq.) was added dropwise over 2 s. It was stirred at room temperature for 1 hour. The reaction was carefully quenched with 1 ΝΗ aqueous solution at 〇 ° C and taken with ether. The combined organic extracts were washed with water and brine, dried over MgSO 4 and filtered. The liquid was concentrated in vacuo to give a yellow solid. The recrystallization of the crude product thus obtained was carried out to give the title compound as a beige powder. 143482-1 -73- 201111364 Step 2: 3-Pentyl-5-[(1Ε)-3-(decyloxy)-1-propanyl]benzoic acid will be obtained from the previous step 3-bromo -5-Hydroxybenzaldehyde (1 equivalent) combined with 3-decyloxyprop-1-en-1-yl]-4,4,5,5-tetradecyl-dioxaboron (1 equivalent) In DMF (0.05M). Then, to this solution, palladium acetate (indole), two scales (0.2 as straight), and 2 M aqueous sodium carbonate (4 equivalents) were added. The resulting suspension was heated at 80 ° C for 16 hours. The reaction mixture was quenched with a 1N aqueous solution of EtOAc and extracted with ether. The combined organic extracts were washed with water, aq. NaH.sub.3, and brine. The mixture was dehydrated and dried with MgS(R), and the filtrate was concentrated in vacuo to give a crude product as a brown tar. The title compound was obtained as a yellow oil. m. m. Step 3: 3-(Methoxy)-5-[(1Ε)-3-(methoxy)-1-propanthene]ylbenzene disc will be obtained from the previous step 3-hydroxy-5-[ (1 Ε)-3-(methoxy)+propenyl]benzaldehyde (1 eq.) and iododecane (2-2 eq.) were combined in acetone (〇〇7M). Then, potassium carbonate (2 equivalents) was added to the solution, and the reaction suspension was heated under reflux for 16 hours. The resulting reaction mixture was concentrated in vacuo and the residue was partitioned between water and ether. The aqueous wash was separated and extracted by mystery. The combined organic extracts were further washed with brine, dried over MgSO 4 , filtered, and evaporated. The crude product thus obtained was further purified by flash chromatography ( </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Yellow oil. Step 4: N-({3-(Methoxy)_5_[(1e)-3-(decyloxy)propenyl)]phenyl}indolyl)-cyclopropylamine 143482-1 • 74· 201111364 3_(Methoxy)_5 [(10)_3 (methoxy W prop-1-ene-1-yl)benzaldehyde (1 equivalent) in dichloromethane (〇5M) In the solution, % propylamine (2 eq.) and magnesium sulfate (15 eq.) were added. The resulting suspension was stirred at room temperature for 12 hours. Insolubles were removed by filtration. The filtrate was concentrated in vacuo to give crude. The imine is a yellow oil. Then, it is dissolved in methanol (0.3M), and then sodium borohydride (15 eq.) is added in portions over 5 minutes. The reaction mixture is slowly warmed. The mixture was stirred for 2 hours at room temperature and then stirred at room temperature for 2 hours. After carefully quenching the reaction with a saturated aqueous solution of NaHCO3, the mixture was extracted with a mixture. The combined organic extracts were washed with water and brine. Dehydrated with MgS 4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow oil. Step 5: Amine 10 from the previous one N-({3-(Methoxy)-5-[(ie)-3-(methoxy)-1-propen-1-yl]phenyl)indolyl)cyclopropylamine (1 eq.) In the solution of Et0Ac (〇〇4M), palladium (10% w/w, on activated carbon, αι equivalent) was added, the vessel was evacuated, and φ was backfilled with argon. Then, the reaction suspension was placed in a hydrogen cylinder atmosphere. After stirring for 5 hours, the reaction was quenched with EtOAc (EtOAc m.) N-({3-{[2-(Methoxy)ethyl]oxy)5-[3-(indolyl)propyl]phenylhydrazinemethyl)cyclopropylamine 11 is as described in amine 10 The procedure is followed, but in step 3, 2-bromoethylindenyl hydrazine is alternatively used as the alkylating agent, and carbonic acid is used as a solvent, 143482-1 -75- 201111364 and DMF as a solvent. Amine 12 4-{ 3,4-Dichloro·5_[(cyclopropylamino)methyl]phenylindolonitrile 乂1 1 cyclopropyl {[2,3-dichloro-5-(2-ketoethyl)phenyl] 1,1-Dimethylethyl hydrazide for the cyclopropyl group of the amine 6 step 3 ([2,3_digas_5(2-hydroxyethyl) Phenyl] methyl} carbamic acid methyl ethyl ester U- station (1 eq) and sodium bicarbonate square equiv) was suspended in times called iv) Order. At (TC), DMP (1 eq.) was added, and the resulting mixture was stirred at EtOAc for 15 min and then quenched at room temperature. The reaction was quenched with aqueous NaOH and extracted with ether. The combined organic extracts were washed with water and brine, dried with EtOAc EtOAc (EtOAc m. {2,3_Digas·5_[(2E) each cyanobutyryl small group] phenyl}methyl)amino decanoic acid 1,1-dimethylethyl ester in anhydrous lithium carbonate (1.2 equivalents) In a suspension of THF (0.1 M), diethyl (cyanoguanidino)phosphonate (1.2 equivalents) and 1) 611 (1 equivalent) were successively added. The formed suspension was stirred at room temperature for 15 minutes, and then the cyclopropyl group [[2,3_digas_5_(2-ketone) obtained from the previous step was added dropwise with a THF (〇im) solution. U-diphenylacetic acid (1 equivalent) of ethyl ethyl)phenyl]methyl}aminocarbamate. The resulting pink suspension was stirred at room temperature for 12 hours, then the α1ΝΗα aqueous solution was carefully quenched and then extracted with ether. The combined organic extracts were further washed with water and brine and dried over N?SO? Filter, and concentrate the filtrate in vacuo. The crude product thus obtained was purified by flash chromatography, 1434S2-1 -76 - 201111364 (Si2, hexanes &gt; 3:7 (v/v)hexane: EtOAc) to give the title compound as colorless oil . Step 3: cyclopropyl {[2,3-dichloro-5-(3-cyanopropyl)phenyl]-indenyl carbamic acid U-didecylethyl ester in Cyclohexane from the previous step 1,2,3-Dichloro-5-[(2E)-3-cyano-2-propan-1-yl]phenyl}indolyl) decanoic acid 1,1-dimethylethyl hydrazine A solution of (1 eq.) in EtOAc (0.04 M) was added (10% w/w over EtOAc). The container is evacuated and backfilled with hydrogen. Then, the reaction suspension was stirred under a hydrogen atmosphere for 1.5 hours. The reaction was quenched with dioxane and filtered through a pad of Celite. The insoluble material was further washed with EtOAc. The filtrate was concentrated in vacuo to give the title compound. Step 4: Amine 12 is obtained from the previous step of cyclopropyl {[2,3-dioxa-5-(3-cyanopropyl)phenyl]decyl}carbamic acid U-dimethylethyl ester ( 1 equivalent) In a solution of CH2Cl2 (〇〇6M), zinc bromide (11) (10 equivalents) was added, and the resulting suspension was sonicated for φ 15 minutes' and then it was stirred at room temperature for 18 hours. The reaction was quenched with 1N aqueous EtOAc then EtOAc. The combined organic extracts were further washed with water and brine, dried over NaHSOs, filtered, and evaporated. The crude product thus obtained was purified by flash chromatography (SiO 2 , 9:1 (V/V) hexane: Et0Ac-3:7 (v/v) hexane: Et EtOAc) Colorless oil. Amine 13 M3-[(cyclopropylamino)indolyl]_4,5-difluoro-p-phenyl}-d-butylamine U is synthesized according to the procedure described in amine 12, but is used instead of class 143482-] •77· 201111364 a cyclopropyl {[2,3-difluoro-5-(2-ethyl)phenyl]decyl}amino phthalic acid U-dimethylethyl ester from 2,3-difluorobenzaldehyde . Amine 14 4-{3,4-Dichloro-5-[(cyclopropylamino)indolyl]phenyl}butanoic acid decylamine 14 was prepared according to the procedure described for amine 12, but in Wittig thinning In the step (step 2), the anhydrous gasification of diethyl (cyanoguanidino)phosphonate and DBU are replaced by (triphenyl-into-5-phosphinoalkyl)methyl acetate. Amine 15 N-({3-[3-(indolyl)propyl]-1-teayl}methyl)cyclopropylamine Step 1: 3-[(1Ε)-3-(decyloxy)-1- Propylene small base] small tea carboxylic acid vinegar vinegar 3-bromo-1-benzenecarboxylic acid oxime ester (1 equivalent) and 4 4 5 5 -tetramethyl 2 耵 各 各 (曱 ))-1-propene 1-yl]-1'3,2-dioxaboron (15 equivalents) was combined in a 5:1 (v/v) mixture (0.2 M) of DMF: n-PrOH. Then, in this solution, trans-bis(triphenylphosphine) evolved palladium (IIX 0.05 equivalent) was added, and the vessel was repeatedly evacuated and counter-filled with nitrogen. Finally, a 2NNa2C〇3 aqueous solution (2 eq.) was added and the resulting two-phase suspension was heated at 9 (TC for 8 hours. The current black suspension was cooled to room temperature, diluted with water and taken at 1:1 ( v/v) Hexane: Ether extraction. Then 'the combined organic extracts were further washed with 1N Na〇H aqueous solution, m Ηα aqueous solution, water and brine. Then 'dehydrated with ~〇4, filtered, and made The filtrate is concentrated in vacuo to give the title compound as a red oil. Step 2: 3-[3-(decyloxy)propyl]-i- _ _ _ _ _ _ _ _ _ _ _ )-3-(decyloxy)4-propenylhydrazone H荇carboxylate (1 equivalent) and 10% w/w palladium/carbon (αΐ equivalent) suspended in Me〇H (〇〇8M) 143482-1 -78- 201111364 = ° Then, the vessel was evacuated and gas was purged with h2. The reaction suspension was stirred at room temperature for 2 hours under a bottle filled with an atmosphere. Then, the reaction was quenched with CH2Cl2. The filtrate was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (Si.sub.2, hexanes (v/v) hexane: EtOAc). The title compound is a colorless oil. Step 3: 3-[3-(Methoxy)propyl]+naphthoic acid is obtained from the previous step of 3-[M. 1 When _I) is dissolved in Me0H: 2:1 (v/v) mixture (0.08 M). Then, LiOH (2.0 M aqueous solution, 3 equivalents) was added to the solution, and the resulting turbid suspension was vigorously stirred at /JEL for 24 hours. Next, the volatile material was removed in vacuo, and the pH of the residue was carefully adjusted to &lt;~&apos;&apos;&apos; The combined organic extracts were further washed with water and brine, dried over Na 2 SO 4 and filtered. The title compound was obtained as a white solid (yield). Step 4: N-cyclopropyl-3-[3-(indolyl)propyl]-1-indolecarboxamide • at 0 ° C 'from the previous step 3_[3_(decyloxy) In a CH2C12 solution (0.1 M) of propyl H-decanoic acid (1 equivalent), gasified grass mash (1 - 2 equivalents) was added followed by a few drops of DMF. The resulting solution was stirred at room temperature for 2 hours and then the volatiles were removed in vacuo. The resulting residue was dissolved in dioxon (0.1 M), cooled to 〇〇c, and Hunig base (1.2 eq.) and cyclopropylamine (U equivalent) were added dropwise. The resulting suspension was stirred at room temperature for 18 hours. The reaction was quenched with aqueous <RTI ID=0.0>IN </RTI> </RTI> <RTIgt; The combined organic extracts were further washed with aq. aq. NaOH, water and brine, dried over Na? The filtrate was concentrated in vacuo to give title titled <RTIgt; Step 5: Amine 15 in a THF solution of N-cyclopropyl-3-[3 (decyloxy)propyl]-1-calylamide (1 equivalent) from the previous step under reflux. In addition, a borane-sulfurized decane complex (6.6 equivalents) was added. A short path distillation unit was attached to the reaction vessel and most of the volatiles were slowly distilled over a period of 15 hours. The current yellow solution was again cooled to 〇 ° C and the reaction was carefully quenched with 1N aqueous HCl. The resulting mixture was heated under reflux for a few hours to ensure complete decomposition of the amine-paraffin complex. After careful neutralization with a 1 N aqueous NaOH solution, the water layer was separated and extracted with EtO Ac. The combined organic extracts were washed with brine, dried over Nad.sub.4, and filtered. The filtrate was concentrated in vacuo <RTI ID=0.0></RTI> and the crude material thus obtained was further purified by flash chromatography (SiO 2 &lt;RTI ID=0.0&gt;&gt; To display the title compound as a colorless oil. Amine 16 (2-{3,4-Dichloro-5-[(cyclopropylamino)methyl]phenyl}ethyl)amino decanoic acid hydrazine Step 1: Ring propyl [(2, 3-) Gas-5-nonylphenyl)indenyl]amino acid ι,μ dimethylethyl ester in cyclopropyl [2,3-dioxa-5-vinylphenyl] from step 6 of amine 6 A solution of U-dimercaptoethyl urethane (1 eq.) in dioxane methane (0.03 M) was bubbled with freshly generated ozone at -78 °C until a persistent blue color was observed. Then, triphenylphosphine (1.2 equivalents) was added thereto in a quick portion, and the resulting mixture was slowly warmed to room temperature over 3 hours. Volatile materials were removed in vacuo and the remaining residue was triturated with 2: 1 (v/v) hexanes: Et20. 143482-1 •80· 201111364 The insolubles were removed via hydrazine and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography eluting elut elut elut Step 2 · propyl {[2,3~di-5-(methyl)phenyl]methyl}aminocarbamic acid 1,1-dimethylethyl ester at 0 C, obtained from the previous step Sodium borohydride (U equivalent) was added to a solution of cyclopropyl [(2,3 dioxo-5 methionylphenyl) fluorenyl] methic acid dimethyl acetate in methanol (016M). The resulting solution was stirred under 〇c&gt;c for 2 hours and then the volatiles were removed in vacuo. Next, the resulting residue was subjected to liquid separation between ether and aqueous solution of IN HCl. The aqueous layer was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered, and evaporated. The crude product thus obtained was purified by EtOAc EtOAc (EtOAc) Step 3: decanesulfonic acid {3,4-dichloro-5-[(cyclopropyldimethylethyl)oxy]carbonyl}amino)methyl]phenyl}methyl ester at 〇 ° C, From the previous step, cyclopropyl {[2,3 dioxo-phenyl]indolyl} guanidinoic acid U-dimethyl oxime (1 equivalent) in a solution of dimethyl gas (〇1M) Hunig's base (3 equivalents) and gasified decanesulfonium (U equivalent) were successively added. The resulting solution was stirred at (TC for 30 minutes and then at room temperature for 15 minutes. Then, the reaction mixture was diluted with ether and the mixture was carefully quenched with aqueous EtOAc. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. Cyclopropyl {[2,3-dioxa-5-(|L-indenyl)phenyl]decyl}carbamic acid U-didecylethyl ester in the decanesulfonic acid {3, obtained from the previous step 4-Dimethyl-5-[(cyclopropyl{[(u-didecylethyl)oxy]methyl}}amino)indolyl]phenyl decyl ester (1 equivalent) in DMS 〇 (0.48M In the bath, add a chaotic clock (1·3 equivalent) and a packed sodium (〇1 equivalent). The resulting solution was stirred at room temperature for 3 hours, then diluted with ether and taken in IN. The reaction was quenched with aqueous NaOH solution, and the aqueous layer was separated and extracted with ether. The combined organic extracts were further washed with water and brine, dried with NaJO4, filtered, and filtered. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc (EtOAc) Oil. Step 5: {[5-(2-Aminoethyl)-2,3-dioxaphenyl] fluorenyl}cyclopropylamino decanoic acid U-didecylethyl ester at 〇 ° C, Cyclopropyl {[2,3_diox_5(cyanomethyl)phenyl]decyl}amino decanoic acid 1,1-didecylethyl ester (1 equivalent) and gas obtained from the previous step Cobalt (light) hexahydrate (2 equivalents) in a solution of decyl alcohol (0.07 M), sodium borohydride (10 eq.) was added portionwise. The resulting mixture was stirred for 1 hr. The next 2 hours. The current brown suspension was quenched with aqueous NaOH solution and then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Naz. The crude title compound was obtained as a pale brown amorphous solid. Step 6: cyclopropyl {[2,3-diox-5-(2-{[(decyloxy))). Aminomethyl)phenyl] 143482-1 •82- 201111 364 曱 } 胺 1 胺 胺 胺 胺 胺 胺 胺 胺 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ {[5-(2-aminoethyl)-2,3-diphenyl To a solution of 1,1-dimethylethylcyclopropylamino decanoate (1 eq.) in dichlorohydrazine (0.07 M), Hunig's base (1.2 eq.) and gas were added sequentially. Methyl formate. Then, the resulting solution was slowly warmed to room temperature for 3 hours. Then, the crude reaction mixture was diluted with ether and successively taken in 1N NaHH aqueous solution, aqueous solution of IN HCl, water and brine. washing. Then, the ether extract was dehydrated and dried with Na S04, filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut Step 7: Amine 16 is obtained from the previous step of cyclopropyl {[2,3-dioxa-5-(2-{[(indolyl))]amino}ethyl)phenyl] fluorenyl} To a solution of 1,1 -didecylamine amide (1 eq.) in CH.sub.2Cl.sub.2 (.sup..sup.6M) was added HCl (4.0M in EtOAc, 30 eq.). The resulting solution was stirred at room temperature for 3 hours. Then, the reaction was quenched with _IN aqueous NaOH solution and extracted with a scale. Next, the human organic extract was further washed with water and brine, dried over MgSO.sub.4, filtered, and concentrated. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc (EtOAc) Amine 17 N-(8-4: arylmethyl)cyclopropylamine in a solution of 8-quinolinecarboxaldehyde (1 eq.) in dioxane (〇 13M), added magnesium sulfate (1 eq.) and cyclopropyl Amine (2 equivalents). The resulting suspension was thrown at room temperature for 14 hours at 143482-1 -83-201111364. After passing through the cold, and flushing with nitroxamidine, then the combined filtrate was placed in a vacuum, koji, 蝻. The crude imine thus obtained was dissolved in decyl alcohol (0.13 M), followed by VIII, knife-under-added rotten fish steel q 5 )). The reaction mixture was stirred at room temperature and the solution was quenched to quench the reaction. Then, with 1N N", then, then the HC1 water is adjusted to ~1G ' and then it is extracted with ether to remove the pH of the solution into the salt water step by step - dehydrated with Na2S04: and the organic extract is water and Concentrate in vacuo to give the crude title compound: <RTI ID=0.0>

N-(8-isoindolyl fluorenyl)cyclopropylamine 18 is based on the order described in amine 17 towards quinolinecarboxaldehyde as the starting material. Alternatively, but 8-isoamine 19 N-(5-isoquinoline 17-linylmethyl)cyclopropylamine 19 is used as the starting material according to the quinoline carboxaldehyde as described in the amine 17. Amine 20 is made, but instead uses 5-iso

N-(5-carbolinylmethyl)cyclopropylamine 20 is prepared according to the procedure described for the carboxaldehyde in the amine 17 as the starting material, amine 21, but alternatively 5-quino-N-(l-isosaki: #基基)Cyclopropylamine 21 is based on the life described in amine 17. q Quinoline carboxaldehyde as a starting material. Gas-forming but using 1-iso 143482-1 -84 instead. 201111364 Amine 22 N-({2-[3-(decyloxy)propyl]-4-4 phenyl)methyl)cyclopropylamine 22 It is made according to the procedure described in the published patent application WO 2007/009250 A1. Amine 23 N-({6-[3-(Methoxy)propyl]-8-4 lysyl} decyl) cyclopropylamine Step 1: 6-({[(1,1-didecylethyl)) (Dimethyl) oxalate]oxy}methyl)_8_quinolinecarboxyformaldehyde at 8-78 ° C, at 8-bromo-6-({[(l,l-didecyl) n-Butyllithium (2.5 M 'in hexanes) 2.1 equivalents), over a period of 1 minute. The resulting yellow solution was stirred at -78 °C for 15 minutes and then DMF (2 eq.) was added dropwise over a period of 1 s. The current red solution was stirred at _78 ° C for an additional 2 hours, then the reaction mixture was quenched by the addition of saturated aqueous nh 4 C1. The aqueous layer was separated&apos; and back extracted with ether. Then, the combined φ machine extracts were washed with brine, dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (EtOAc EtOAc (EtOAc) Cured. Step 2: Ν-{[6-({[(1,1-dimethylethyl)(didecyl)decyl]oxy}methyl)methylquinolinyl]hydrazino}cyclopropylamine from the former a step of 6-({[(1,1-didecylethyl)(didecyl)decyl]oxy}indolyl)-8-quinolinecarboxaldehyde (1 equivalent) of di-methane (〇 12M) Adding magnesium sulfate (1 eq.) and cyclopropylamine (2 eq.) in solution. The resulting 143482-1 -85 - 201111364 suspension was stirred at room temperature for 16 hours. The insolubles were removed via filtration and rinsed with di-methane m~ then the combined filtrate was concentrated in vacuo. The crude imine thus obtained was dissolved in decyl alcohol (0.12 Torr), and then sodium borohydride (1.5 eq.) was added portionwise. The reaction mixture was stirred at room temperature for 2 hours. Next, remove the volatiles in a vacuum and allow the residue to form in ether and claws.

A liquid separation treatment was carried out between the aqueous NaOH solutions. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed with EtOAc (EtOAc m. Step 3: cyclopropyl-[(U•didecylethyl)(dimethyl) oxalate]oxy} fluorenyl)-8-quinolinyl]fluorenyl}aminocarboxylic acid u-dimethyl The ethyl ester is obtained from the previous step -{[6-({[(1,1-didecylethyl)(dimethyl)decyl]oxy}methyl)-8-carbolinyl] Methyl anthracycline (1 eq.) in a solution of di-methane (0.12 M), successively adding a solution of strontium (丨2 equivalent) and bis(1,1-dimethylethyl) dicarbonate Vinegar (11 equivalents). The resulting solution was stirred at room temperature for 8 hours. Then, the volatiles were removed in vacuo. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut Step 4: Cyclopropyl {[6-(hydroxymethyl)- each, oxalinyl]methyl}aminocarbamic acid u• dimethylethoxime for the cyclopropyldidecylethyl group obtained from the previous step) Add TBAF to a solution of dimethylidene ethyl methacrylate (1 §) in THF (0.12 M) (10 M, placed in hexane 1.6). The resulting solution was stirred at room temperature for 2 hours, then 143482-1 201111364 was removed in vacuo to remove volatiles. The resulting residue is subjected to liquid separation between ether and water. The aqueous layer was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered, and evaporated. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc (EtOAc:EtOAc) oil. Step 5: Cyclopropyl [(6-fluorenyl porphyrinyl)methyl]carbamic acid u-decylethyl ester at 0 C in cyclopropyl{[6_(hydroxymethyl) from the previous step ) _8_ porphyrinyl] fluorenyl} 1,1-didecyl ethyl carbazate (1 equivalent) and sodium hydrogencarbonate J equivalent) In a suspension of dioxane (0.1 M), DMp was added. (u equivalent). The resulting mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous NaH.sub.3, and then extracted with EtOAc. Combine the organic extracts in

The NaOH aqueous solution, water and brine were further washed, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo to give crystallite crystallite Step 6: 3-{8-[(cyclopropyl{[(U-dimethylethyl)oxy)carbonyl}amino)methyl]-6-quinolinyl}-2-propenoic acid methyl ester in hydrazine 1,1-dimethylethyl ester (1 equivalent) in dioxane (1) obtained from the previous step in cyclopropyl [(6-methylindenyl-8 oxalinyl) hydrazinyl] (Diphenylphosphoranylidene) decyl acetate (11 equivalents) was added to the solution in 〇6M). The resulting solution was then slowly warmed to room temperature over 4 hours. Next, the volatiles are removed in a vacuum. The crude product thus obtained is purified by flash chromatography (Si〇2, 9:1 (v/v) hexane: Et0Ac_ 3:7 (v/v) hexane: Et 〇Ac), 143482-1 •87 · 201111364 The title compound is obtained as a white solid. Step 7: 3-{8-[(cyclopropyl{[(1 l 甲甲 | 土mi'i-methylethyl)oxy] benzylamino) Mercapto]-6-P-quinein}methyl-propionate is the 3-sided cyclopropyl{[(U-dimethylethyl)oxyl)amino)methyl]-6 from the previous step. -4 啉 基 _2 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Pump down and repeat the filling with hydrogen. Finally, the reaction suspension was stirred for 3 hours under a hydrogen-filled gas cylinder atmosphere. The reaction was quenched by the addition of methylene chloride and filtered through a pad of Celite. Then, the filtrate was concentrated in a vacuum. The crude product thus obtained was purified by flash chromatography (yield: </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Step 8: cyclopropyl {[6-(3-hydroxypropyl)_8-quinolinyl]methyl}carbamic acid la dimethyl ethyl ester from the previous step 3·{8_[(cyclopropyl) ([(1)^Dimercaptoethyl)oxy]carbonyl}amino)indenyl]-6-4 phenyl}}-propionic acid propionate q equivalent) in a solution of THF (〇〇8Μ), added hydrogenation Lithium (5 equivalents). The resulting mixture was stirred at room temperature for 14 hours' then diluted with ether and quenched with 1N aqueous NaH. The aqueous layer was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na.sub.2, and filtered. The broth was concentrated in vacuo to give the crude title compound. Step 9: Cyclopropyl ({6-[3-(decyloxy)propyl]-8-4 phenyl}} yl} carbamic acid 1,1-dimercaptoacetate for the ring from the previous step Propyl {[6_(3-hydroxypropyl)-8-quinolinyl]methyl} 143482-1 -88- 201111364 Amino acid ι,ι-dimethylethyl ester U equivalent) in THF (0 3M) Adding hydrogenation (60% (w/w) dispersion in paraffin oil, L2 equivalent) in the solution. The resulting suspension was stirred at room temperature for 15 minutes and then added with decane (14 equivalents) ). The current yellow solution was stirred at room temperature for 12 hours then quenched by aqueous EtOAc. The aqueous layer was separated and extracted by hiccup. The combined organic extracts were further washed with water and brine, and dried with Na2 dehydration, and the mixture was allowed to react in a vacuum. The crude product thus obtained was purified by flash chromatography (EtOAc EtOAc (EtOAc) Step 10: Amine 23 is obtained from the previous step of 1,1-didecylethyl ({6-[3-(methoxy)propyl]indolyl)methyl}carbamic acid (1). Equivalent) In a solution of CH2Cl2 (〇〇6M), add HCl (4.0M in 3D equivalents in dioxane). Mix the formed solution for 6 hours at room temperature. Then, in NaOH The aqueous solution was quenched with EtOAc (EtOAc)EtOAc. Amine 24 N-({3-carbyl-5-[3-(indolyl)propyl]phenylindenyl)cyclopropylamine Step 1: N-[(3-Molyl-5-phenyl)曱 ]] cyclopropylamine in 3-bromo-5-gasbenzaldehyde (1 equivalent) and cyclopropylamine (u equivalent) in 4:1 (v/v) MeOH: THF solution (0.06 M) Subsequent addition of sodium cyanoborohydride (丄5 eq.) was followed by pure acetic acid (3 eq.). The resulting mixture was stirred at room temperature for 20 hr. then the volatile material was removed in vacuo. -1 -89- 201111364 The residue is dissolved The aqueous layer was separated with EtOAc (EtOAc)EtOAc. , as a yellow oil. Step 2: N-({3-carbyl-5-[(1E)-3-(methoxy)4-propenyl]phenyl}methyl)cyclopropylamine from the previous step N-[(3-Molyl-5-phenylphenyl)indolyl]cyclopropylamine (1 equivalent) and 4,4,5,5-tetradecyl-2-[(1Ε)-3-(oxime Base) + propylene small group h, 3 2 dioxonium (2 equivalents) of 4:1 (v/v) DMF: n-propanol solution (〇15M), add trans-di-di-diyl double ( Triphenylphosphine (11) (0.05 equivalents) followed by sodium carbonate (2M in water, 3 eq.). The reaction vessel was evacuated and purged with nitrogen five times and then heated at 100 ° C for 2 hours. The cooled reaction mixture was poured into a saturated aqueous solution of NH.sub.4Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Crude product Purification (Si02 '3.7 (v/v) hexanes: EtOAc-EtOAc) EtOAc. 5-[(1Ε)-3-(decyloxy)+propen-1-yl]benyl}mercapto)cyclopropylamine (1 eq.) in EtOAc (0.2M). w/w) 'On carbon, 〇. 4 equivalents). The reaction vessel was evacuated and hydrogenated twice with hydrogen, then stirred at room temperature for 14 hours. Next, the reaction suspension was filtered through a silicone pad and the insoluble material was rinsed with Et〇Ac. The filtrate was concentrated in vacuo to give the title compound as a pale green oil. 143482-1 -90- 201111364 Amine 25 Ν-{[1-(3-Methoxypropyl hydrazin-3-yl)indolyl}cyclopropylamine Step 1: 1-(3-methoxypropyl)_ih-啕嗓_3_ Rebel is placed in a dmf (0.1M) solution of indole-3-carboxyfurfural (1 equivalent) at 0 C, adding sodium hydride (60% (w/w) in oil) The dispersion, 丨丨 equivalent), followed by 1-bromo-3-indolylpropane (m·5 eq. p. The reaction mixture was stirred at 5 〇 &lt;&gt;c for 4 hours. Then, the mixture was diluted with ether Washed with water and brine, dehydrated with MgS〇4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (Si〇2, 1:1 (v/v) Hexane: a 〇Ac-EtO Ac), the title compound was obtained as a colorless oil. Step 2: Amine 25 at 0 C in 1-(3-methoxypropyl-Bu-Zhu-3-Jiejia Road (1) Equivalent) 3:1 (Wv): MeOH solution (0.1 M) was added with cyclopropylamine (2 eq.) &apos; acetic acid (2.5 eq.), followed by sodium trioxy borohydride (15 eq.). The reaction was slowly warmed to room temperature and stirred at room temperature for 3 hours. Then, saturated aqueous solution of NaHC? It should be quenched, extracted with di-methane, dehydrated with MgSO 4 , filtered, and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (Si 〇 2, 96:4 (v/) v) CH2Cl2: 2.0M NH3 in · 〇Η 'The title compound is obtained as a colorless oil. Amine 26 3-{3,4-dis-5-[(cyclopropylamino)indolyl]phenyl propyl Nitrile Step 1: (5-Bromo-2,3-dioxaphenyl) decyl alcohol at 〇 ° C, obtained from the amine S step 基 _2 2, 3 _ 2 gas aldehyde (1 equivalent) 5 :1(Wv)Me0H: In a THF solution (0.38 M), sodium borohydride 143482-1 -91 - 201111364 (U equivalent) was added in portions over 45 minutes. The reaction solution was stirred at 〇t: for 2 hours. The volatiles are then removed in a vacuum. The resulting residue is then subjected to a liquid separation between the aqueous solution and the aqueous solution. The aqueous layer is separated and stripped with ether. The combined organic extract is 1N. The aqueous solution of Na〇H, water and brine are further washed with dehydrated Na2SO4, dried, and concentrated in vacuo. The crude product thus obtained is purified by flash chromatography (10), 9:1 ( v/v) burned: Et0Ac 3:7 (v/v) hexanes: EtOAc (EtOAc: EtOAc) Adding (u dimethylethyl) dimethyl decane to a solution of (5·bromo-2-,3-diphenyl) sterol (1 eq.) in DMF (0.34 M) from the previous step Base (11-decylethyl) dimethyl decane (U equivalent) with imidazole (1,5 equivalents). The resulting yellow solution was stirred at room temperature for 16 hours. Then, the reaction mixture was diluted with ether and washed successively with a 10% aqueous HCl solution of water and brine. The ether extract was dehydrated to dryness with Na.sub.2.sub.4, and the title compound was obtained as a colorless oil. Step 3: {[(2,3-Dichloro-5-vinylphenyl)indolyl]oxy}(11-didecylethyl)dimethyloxane will be obtained from the previous step {[(5_bromo) Base 2,3_di-phenylphenyl)indolyl]oxy}(u-monomethylethyl)didecyldecane (1 equivalent) with 2 vinyl _445,5 tetramethyl-1,3,2 - Monooxonil (1 equivalent) was combined in a 2:1 (v/v) mixture of DMF: n_pr〇H (0.11 M). Then, to this solution, palladium acetate (9) (5 eq.) and triphenylphosphine (0.15 equivalent) were added, and then the vessel was repeatedly evacuated and counter-filled with nitrogen. 143482-1 -92· 201111364 Finally, an aqueous solution of INNa^O3 (2 equivalents) was added, and the resulting two-phase suspension was heated at 90 ° C for 8 hours. The current black suspension was allowed to cool to room temperature, diluted with water and extracted with 1:1 (v/v) hexanes: ether. The combined organic extracts were then further washed with aqueous IN NaOH 'water and brine. Then, the title compound was obtained as a black oil. Step 4: 2-[3,4-Dioxa-5-({[l,l-dimethylethyl)(dimethyl)decyl]oxy}methyl)phenyl]ethanol will be obtained from the former {[(2,3·二气_5_vinylphenyl)indenyl]oxyku-dimethylethyl)didecyldecane (1 equivalent) '[Ir(COD)a]2 (0025 eq.) and DPPB (0.05 eq.) were combined in THF (0·11 Μ). Then, 4,4,5,5-tetradecyl-indole, 3,2-dioxaboron (1.3 eq.) was added to the solution, and the resulting red solution was stirred at room temperature for 16 hours. . Finally, sodium perborate (〇'1Μ aqueous solution' 1 equivalent was added and the current black two-phase solution was vigorously searched for 8 hours at room temperature. The aqueous layer was separated and stripped with ether. Then, the combined organic extracts were combined. It was further washed with aq. NaOH, water and brine, then dried over Na2SO4, filtered, and concentrated to give a black oil in vacuo. The crude product thus obtained was purified by flash chromatography. SiO 2 '9:1 (v/v) hexanes: EtOAc (EtOAc): _Dichloro_5_({[(u_didecylethyl)(diindenyl) fluorenyl]oxy}methyl)phenyl]ethyl ester at o °c 'from the previous step _ 2_ [3 4_二气_5_(丨[(11-dimethylethyl)(didecyl)decyl]oxyindenyl)phenyl]ethanol (1 equivalent) of dioxane 143482-1 - 93· 201111364 Add a Humg test (15 equivalents) and a gasified formazan (1) equivalent in a solution of the burnt (〇.11Μ) solution. The suspension formed is given at (TC) sub-H (four) temperature 15 Minutes. Then 'put the reaction to Dilute and quench the reaction with 1N aqueous HCl solution. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with IN Na0H aqueous solution, water and brine, and dried under reduced pressure. And the filtrate is concentrated in vacuo to give the title compound as a brown oil. Step 6. 3-[3'4-di-gas_5_({[(u-dimethylethyl))) Alkyl]oxy} decyl)phenyl]propionitrile in the previous step of methanesulfonic acid 2_[3,4_digas_5_({[(11-didecylethyl))) Addition of potassium cyanide (13 equivalents) to a solution of DMSO (0.4 M) in DMSO (0.4 eq.). The resulting solution was stirred at 8 ° C. Then, the reaction was diluted with ether and the reaction was quenched with water. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with water and brine, dried over N?SO? And the filtrate is concentrated in vacuo to give the title compound as a pink oil. Step 7: 3-[3,4-dis-5-(methyl)phenyl]propanenitrile from the previous step 3-[3,4-digas-5-({[(l, Add TBAF (1.0 Μ THF solution) to a solution of l-dimercaptoethyl)(dimethyl)oxalyl]oxy}mercapto)phenyl]propanenitrile (1 eq.) in THF (0·1 Μ) 1.2 equivalents.) The resulting solution was stirred at room temperature for 3 hours. Then, the reaction was diluted with ether and quenched with water. The aqueous layer was separated and extracted with ether. The extract was further washed with water and brine, dried over Na2SO4, filtered, and then evaporated. The crude product thus obtained was purified by flash chromatography 143482·] -94- 201111364 (Si 〇 2 ' 9:1 (v/v) hexane: EtOAc-^ 3:7 (v/v) hexane: EtOAc The title compound was obtained as a colorless oil. Step 8: 3-(3,4-Dichloro-5-methylphenyl)propionitrile at 0 ° C in 3-[3,4-digas-5-(hydroxyl) obtained from the previous step Add a DMP (1.1 eq.) to a suspension of phenyl]propionitrile (1 eq.) and sodium bicarbonate (1.1 eq.) in dioxane (0.1 M). The mixture was stirred for 2 hours, then the reaction was quenched with saturated aqueous NaHS03, then

Et2〇 extraction. The combined organic extracts were further washed with aqueous 1N NaOH, water and brine. The filtrate was concentrated in vacuo to give crystallite crystallite Step 9: Amine 26

Add magnesium sulfate (1 equivalent) and cyclopropane to a solution of 3_(3,4_diqi_5-nonylphenyl)propanenitrile (1 eq.) in dioxane (0.11 M) from the previous step. Amine (1.2 inside). The resulting suspension was stirred at room temperature for 16 hours. By filtration: In addition to insoluble matter, and rinsed with two gas, then the combined mash: true 辰 / 缩. The crude imine thus obtained was dissolved in methanol (011 M), followed by sodium borohydride (3 eq.). The reaction mixture was stirred at room temperature for 16 hours. Then, the volatile matter was removed in a vacuum, and the resulting residue was subjected to liquid separation between (iv) 1N Na〇H aqueous solution. The aqueous layer was separated and extracted by (iv). The combined organic extracts were further washed with water and brine to dryness, filtered, and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (10) 2, 9: y (yield: EtOAc: EtOAc (EtOAc) Amine 27 143482-1 -95- 201111364 N-(2-{3,4-dioxa-5-[(cyclopropylamino)indolyl]phenyl}ethyl)propanamide Step 1: ({[5- (2-Azidoethyl)_2,3-dioxaphenyl]indolyl}oxy)(u-didecylethyl)dimethyl decane at room temperature in step 5 of amine 26 2,[3,4_diox_5_({[(l'l-dimethylethyl)(didecyl)decyl]oxy}indolyl)phenyl]ethyl sulfonate (1 Add sodium azide (5 equivalents) to a solution of DMF (0.4 M) in 罝). The resulting solution was stirred at room temperature for 2 hours and then at 8 ° C for 3 hours. Next, the reaction mixture was diluted with ether and washed with water. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with EtOAc EtOAc EtOAc. Step 2: 2-[3,4-Digas-5-({[(u_:methylethyl)(dimethyl)))]oxy)methyl)phenyl]ethylamine from the previous Step ({ [5-(2_azidoethyl)_2,3 dioxaphenyl]methyl}oxy)(1'1 monomethylethyl)didecyldecane oxime equivalent) with triphenyl Phosphine (1 2 when, add water (3 equivalents). The solution formed

In THF (0.1 M) solution, the mixture was stirred at 50 ° C for 18 hours. then,

Oxy}methyl)phenyl]-ethyl}propanamide

, Hunig's base (3 equivalents) 143482-1 • 96· 201111364 and propionic acid (1.1 equivalents) in DMF (0.2M) solution, adding hexafluorophosphate 0-(7-nitrobenzotriazole-1-) Base) - N, N, N', N, - tetradecyl hydrazine (1⁄2 eq.). The resulting reaction solution was stirred at room temperature for 48 hours. The current reddish solution was diluted with ether and washed successively with 1N aqueous NaOH, water and brine. Then, the organic extract was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give brown oil. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc (EtOAc) _ Step 4 ·· N-{2-[3,4-Dichloro-5-(methyl)phenyl]ethyl}propanamine in N-{2-[3,4- from the previous step Dichloro-5-({[(1,1-dimethylethyl)(dimethyl)) oxo]oxy}methyl)phenyl]ethyl hydrazinamine q equivalent) of THF ( Add TBAF (1·〇Μ THF solution, i乂 equivalent) in 0.12 M) solution. The resulting solution was stirred at room temperature for 2 hours. The current orange solution was diluted with ether and quenched with aqueous 1N NaOH. The aqueous layer was separated and extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 s 〇 4 _, and filtered. The filtrate was concentrated in vacuo to give crude title compound <RTI ID=0.0> Step 5: N-[2-(3,4-dioxa_5-methylnonylphenyl)ethyl]propanamide at 〇°C, n_{2_[3,4_ from the previous step Dioxo_5_(hydroxymethyl)phenyl]ethyl 1 propylamine (1 eq.) and sodium argon carbonate (U eq.) in a suspension of dioxane (0.1 M), MDMP equivalent). The resulting mixture was stirred at ambient temperature for 2 hours, then quenched with saturated aqueous NaH.sub.3, and then extracted with EtOAc. The combined organic extracts were further washed with aq. 1N NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The crude product thus obtained was passed through a flash layer (Si 〇 2 ' 19.1 (v/v) hexane: Et 〇Ac-3:7 (v/v) hexane: Et 〇Ac). Step 6: Amine 27 is added to a solution of di-methane (〇11M) obtained from the pre-step (3,4_dioxa-5-nonylphenyl)ethyl] arylamine (1 equivalent). Magnesium sulfate U equivalent) with cyclopropylamine (1.2 equivalents). The resulting suspension was allowed to stand at room temperature for an hour. The insolubles were removed via filtration and washed with dichloromethane, then the combined filtrate was concentrated in vacuo. The crude imine thus obtained was dissolved in decyl alcohol (0.11 M), followed by sodium borohydride (15 eq.). The reaction mixture was stirred at room temperature for 8 hours. Then, the volatile matter was removed in a vacuum, and the resulting residue was subjected to liquid separation between Et0Ac and 1N Na〇H aqueous solution. The aqueous layer was separated and back-extracted with Et 〇Ac. The combined organic extracts were further washed with water and brine, dried over Na.sub.2.sub.4, filtered, and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc: EtOAc Amine 28 N-[3-Bromo-5-(3-decyloxypropyl)decyl]cyclopropylamine Step 1: 3-Bromo-5-(3-methoxypropyl)benzaldehyde at room temperature Next, a borax-sulfurized decane complex (1·〇 equivalent) was added to a solution of allylic methyl ether (3 J equivalent) in THF (〇3M). This solution was stirred at room temperature for 30 minutes. Then, in this solution, 3 5 dibromobenzaldehyde (1.0 equivalent), Pd (dppf) Cl 2 (0 25 equivalent), and solid sodium decoxide (1 5 when 143482-1 - 98 - 201111364) were successively added. The resulting mixture was heated to reflux and allowed to stand for 5 hours. The cooled reaction mixture was diluted with water and extracted with ether. The combined organic extracts were dried over MgSO.sub.4, filtered and evaporated. The crude product thus obtained is purified by flash chromatography (Si〇2, 5.95)

EtOAc: hexane - 7:3 (v/v). Step 2: Amine 28 _ 3-bromo-5-(3-methoxypropyl)benzaldehyde (1 mM) from the previous step was combined with cyclopropylamine (2 eq.) in CH2 (3⁄4 ( Then, MgS〇4 (1 equivalent) was added thereto, and the resulting suspension was stirred at room temperature for 23 hours. Then, through filtration, the insoluble matter was removed through a diatomaceous earth pad, and The filtrate was concentrated in vacuo. The crude imine thus obtained was redissolved in MeOH (0.19 M). To this solution, sodium borohydride (1.5 eq.) was added portionwise and the mixture formed was : stirring for 3 minutes, then at room temperature for 16 hours. The reaction was quenched by stirring with 2N HCl aqueous solution for 3 Torr. Next, the resulting mixture was basified with IN NaOH aqueous solution and vacuum The volatiles are removed. The residue is taken from water, EtOAc (EtOAc m. )methyl]-N-[2-(methoxy)ethyl]_2-theanine Step 1: 3-{[2-(Methoxy)ethyl]amino} oxime carboxy Acid methyl ester The freshly purified cesium carbonate (1.4 eq.), palladium acetate (9) (〇〇2 eq.) and racemic-BINAP (0.03 eq.) were combined in anhydrous toluene (〇25M). The container weighed 143482-1. 99- 201111364 Re-extraction' and filling with nitrogen. Finally, methyl 3-bromo-naphthalenecarboxylate (1 equivalent) and 2-methoxyethylamine (1.2 equivalents) are added, and the resulting mixture is Heat at 20 ° C for 20 hours. Allow the current black suspension to cool to room temperature, dilute with ether and filter through a pad of diatomaceous earth. Concentrate the filtrate in vacuo to give a brown oil. Further purification of (5) 〇2, 19:1 (v/v) hexanes: EtOAc - 1:1 (v/v) hexane: EtOAc (EtOAc) Step 2: 3-{[2-(decyloxy)ethyl]amino}calic acid formic acid 3_{[2_(methoxy)ethyl]amine hydrazide carboxylic acid from the previous step The hydrazine (1 equivalent) was dissolved in a 2:1 (v/v) mixture of MeOH: THF (〇. 〇 8M). Then, LiOH (1 Torr aqueous solution, 3.4 equivalent) was added to the solution, and the resulting turbid solution was vigorously stirred at room temperature for 16 hours. Next, the volatile matter was removed in vacuo, and the pH of the residue was carefully adjusted to &lt;~&gt; The combined organic extracts were further washed with water and brine, dried over NasSO4 and filtered. The filtrate was concentrated in EtOAc to give the title compound as a yellow solid. Step 3: N-cyclopropyl·3·{[2_(methoxy)ethyl]amino H tea carboxamide · 3-[2-(decyloxy)ethyl] from the previous step Addition of bismuth hexafluorophosphate (7-nitrobenzene) in a solution of aminic decanoic acid (1 equivalent), Hunig's base (3 equivalents) and cyclopropylamine (15 equivalents) in dmf (〇im) And triazole small group) n, n, n,, N, _ tetramethyl hydrazine (1.2 equivalents). The resulting reaction solution was stirred at room temperature for 48 hours. The current reddish solution was diluted with Et0Ac and washed sequentially with 1N Na〇H aqueous solution, water and brine. Then, the organic extract wNa2s 〇4 was dehydrated, filtered, and the filtrate was concentrated in vacuo to give a brown oil. Thus 143482-1 • 100· 201111364 The title compound was obtained as a white solid. Step 4: A solution of the N-cyclopropyl_3_{[2_(decyloxy)ethyl]amine H-carboylguanamine (1 eq.) in THF from the previous step. In M), a borane-sulfurized decane complex (6.2 equivalents) is added. Then, a short path distillation apparatus is connected to the reaction vessel' and slowly vaporizes most of the volatile matter over a period of 1 ^ hour. . The current brown solution was again cooled to Ot: and the reaction was carefully quenched with aqueous <RTI ID=0.0># </RTI> The resulting mixture was heated under reflux for 1 hour to ensure complete decomposition of the amine-blow-burning complex. After careful neutralization with aqueous IN NaOH, the aqueous layer was separated and extracted with Et0Ac. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4 and dried. The filtrate was concentrated in vacuo and EtOAc (EtOAc m. It quickly deepens when it is still standing. • Amine 30 3-{8-[(cyclopropylamino)indolyl]-6-4 phenyl hydrazinonitrile Step 1: {[6-(2-Cyanoethylene)-8-Jun] Methyl}cyclopropylamino decanoic acid 1,1-didecylethyl ester in freshly dried lithium (1.2 equivalents) and (cyanomethyl)phosphonic acid (1 2 equivalents) of THF ( In a suspension of 0.13 M), DBU (1.2 equivalents) was added. The reaction suspension was stirred at room temperature for 30 minutes, and finally, 1,1-didecylethyl cyclopropyl [(6-methylindolyl quinolyl) fluorenyl] decanoate (1 equivalent, Amine 23 Step 5). Then, the resulting solution was stirred at room temperature for 16 hours. 143482-1 201111364 10% aqueous HC1 solution The crude reaction mixture thus obtained was quenched and extracted with ether. The combined organic extracts were washed with aq. 1N NaOH, water and brine &lt;&apos;&gt; The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc (EtOAc:EtOAc) solid. Step 2: {[6-(2-Cyanoethyl)-8-quinolinyl]methyl}cyclopropylamino decanoic acid ι,ι_didecylethyl ester in the previous step {[6- (2-Cyanovinyl)-8-quinolinyl]fluorenyl}cyclopropylamino decanoic acid 1,1-didecylethyl ester (1 equivalent) in EtEAc (〇1M) solution 'Add palladium (10% (w/w) on carbon, 0 2 equivalents). The resulting suspension was evacuated and repeatedly filled with hydrogen. Finally, the reaction suspension was stirred under a hydrogen-filled gas cylinder atmosphere for 4 hours. The reaction was quenched by the addition of dichlorohydrazine and filtered through a bed of diatomaceous earth. Then, the filtrate was concentrated in a vacuum. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut oil. Step 3: Amine 30 is obtained from the previous step of {[6-(2-cyanoethyl)-8-carbinyl]hydrazinylcyclopropylcarbamic acid U-dimethylacetic acid (1 equivalent) CW liquid (in _, add zinc bromide (11) (10 equivalents). The resulting suspension was sonicated for 15 minutes, 'stirred under the coffee. By adding Et〇Ac and 1N Na〇 The aqueous solution of H is quenched and then sonicated for 15 minutes. The aqueous phase is separated and subjected to reverse extraction with Et〇Ac. The combined organic extracts are fed with water and brine to a volume of 〇4 143482-1 -102- 201111364 Dehydrated and dried, and filtered. The title compound was obtained as a yellow oil from EtOAc (EtOAc: EtOAc) Cyclopropylamine Step 1: 3-Ethyl-1-butylic acid methyl vinegar 3-Methyl-1-carboxylic acid A (1 equivalent) and 2_Ethyl 々Μ-tetramethyl-1,3 , 2-dioxane shed (1 equivalent) is combined in DMF: n_pr〇H 2: ι mixture (〇·1Μ). In this solution, first add Pd(PPh3)2Br2 (0.05 eq.), followed by ZNNa2CCVJc solution (2 equivalents). The two-phase suspension is evacuated and filled three times with an atmosphere. It was then heated under thieves for 8 hours. The current black suspension was cooled to room temperature, diluted with water and extracted with 1:1 (v/v) hexanes: ether. Next, the combined organic extracts were taken at 1N. The aqueous solution of Na〇H, 1% aqueous solution of Ηα, water and brine were further washed. Then, it was dried over Na 2 SO 4 and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give crude title compound. Oil φ Step 2: 3-(2·Hydroxyethyl)-1_indole carboxylic acid oxime ester The 3' vinyl carboxylic acid oxime ester (1 equivalent), [Ir(COD)Cl] from the previous step 2 (0.025 eq.) and DPPB (〇.〇5 eq.) were combined in THF (0.12 M). Then, 4,4,5,5-tetradecyl^dioxadifluoride was added to the solution. (1.2 eq.)' and the resulting red solution was stirred at room temperature for 16 hours. Finally, sodium sulphate (0.1 M in water, 2 eq.) was added and the current black phase/cold solution was applied to the temperature. The mixture was vigorously stirred for 2 hours. The aqueous layer was separated and back-extracted with ether. Then the combined organic extracts were further washed with 1N NaH aqueous solution, water and brine. After the 'dehydration and drying with Na2S04, filtration, 143482-1 • 103- 201111364 and the solution; the liquid is in the true two", and the pale yellow oil is obtained. The crude product thus obtained is purified by flash chromatography ( Si〇2,9:1 (v/v) Hexane: Et〇Ac—1:1

The title compound was obtained as a pale yellow oil. Step 3: Methyl 3-(2-(decyloxy)ethyl]-1-carboxylate, 3-(2-hydroxyethyl)_1-indolecarboxylate (1 equivalent) and iodine from the previous step The decane (19 equivalents) was dissolved in THF (0.33). Then, to this solution, sodium hydride (60% w/w dispersion in oil, 1 equivalent) was added, and the resulting suspension was stirred at room temperature for 18 hours in the dark. Next, the volatile matter was removed in a vacuum and the resulting residue was subjected to liquid separation between ether and 1N water/cold. The aqueous layer was separated and back extracted with ether. The combined organic extracts were then further washed with 1N aqueous NaOH, water and brine. Then, it was dehydrated and dried with NaaSO4, filtered, and the filtrate was subjected to a second oil to give a yellow oil. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc (EtOAc) Yellow oil. Step 4: {3-[2-(Methoxy)ethyl]小茶基} sterol

The 3-(2-(decyloxy)ethyl] tea carboxylic acid oxime ester (1) was dissolved in toluene (0.1 M) from the previous step. Then, in this solution, DIBA1_H 〇 5M toluene solution (2.4 eq.) was added and the resulting solution was vigorously stirred at room temperature for 4 hours. The reaction mixture thus obtained was quenched with an aqueous solution of 1 Η Ηα, and extracted by shouting. The combined organic extracts were further washed with water and brine, dried &lt;RTI ID=0.0&gt; The filtrate was in a vacuum to give the title compound as a colorless oil. Step 5: 3·[2-(Methoxy)ethyl]-1-indolecarboxyfurfural 143482-1 201111364 At 〇°C, in the previous step {3_[2·(methoxy)B DMP (1.1 eq.) was added to a suspension of decyl alcohol (1 eq.) with sodium bicarbonate (1.1 eq.) in dichloromethane (1M). The resulting mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous NaH.sub.3 solution. The combined organic extracts were further washed with aq. EtOAc EtOAc EtOAc. The crude product thus obtained was purified by flash chromatography (Si2, 19:1 (v/v) hexane: EtOAc (EtOAc/EtOAc) It is a colorless oil. Step 6: Amine 31 is added to a solution of 3-[2-(methoxy)ethyl]indolecarboxaldehyde (1 eq.) in one of the previous steps in methane (0.15 M). Propylamine (1.2 when placed). The resulting suspension was stirred at room temperature for 2 hours. The insoluble material was removed by filtration and washed with dichloromethane. then the combined filtrate was concentrated in vacuo. The crude imine thus obtained was dissolved in methanol (〇15M), followed by sodium borohydride (1.5 eq.). The reaction mixture was stirred at room temperature for 8 j. Then, the volatile matter was removed in a vacuum, and the resulting residue was subjected to liquid separation between Et?Ac and 1NN a0H aqueous solution. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, and filtered. The filtrate was reduced in vacuo to give the title compound as a colourless oil. Amine 32 [(cyclopropylamino)methyl]_2-naphthyl}ethyl)acetamidine Step 1 ··3-0[(Methanesulfonyl)oxy]ethylhydrazine tea carboxylic acid methyl ester 143482- 1-105-201111364 2-(2-hydroxyethyl)-1-carboxylic acid carboxylic acid ester (1 equivalent) and Hunig's base (1.5 equivalents) obtained from step 2 of amine 31 at 0 °C To the gas decane (0 〇 3 M) solution, decanesulfonium chloride (1.3 eq.) was added. The resulting solution was stirred under reflux for 3 Torr and then at room temperature for 15 minutes. The reaction mixture was then quenched with a 1% aqueous solution of Ηα. The aqueous wash was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 s 4 and filtered. The filtrate was concentrated in vacuo to give the crude title compound. Step 2: 3-(2-azidoethyl H-indolecarboxylate) is obtained from methyl 3-{2-[(methylsulfonyl)oxy]ethyl} hydrazide carboxylate from the previous step (1 equivalent) of DMFC 0.25 M) solution was added sodium azide (5 equivalents). The resulting solution was at 55. (: stirring for 12 hours, then at 80t for an additional 3 hours. Next, the reaction mixture is diluted with hydrazine and washed with water. The aqueous layer is separated and stripped with ether. The combined organic extracts are further water and brine. The mixture was washed with EtOAc (EtOAc m. Vinegar % is added to a solution of 3-(2-azidoethyl H-indolecarboxylic acid) from the previous step (1 eq.) and triphenylphosphine (1.2 eq.) in THF (0.1 M). Equivalent j. The resulting solution was stirred at 50 ° C for 5 hours. Then, the volatile material was removed in vacuo, and the crude product thus obtained was purified by flash chromatography (Si 〇 2 ' 96:4 ( v/v) (3⁄43⁄4: 2·〇Μ NH3 in MeOH), the title compound is obtained as colorless oil. Step 4, 3-[2-(ethylamino)ethyl]-tea 143482-1 -106- 201111364 3-(2-Aminoethyl)-1-baramic acid vinegar (1 eq.), Hunig's base (3 eq.) and acetic acid (1.1 eq.) from the previous step DMF (0.2M In the solution, 0-(7-azabenzotriazole_ι_yl)_N,N,N,,N,·tetradecylphosphonium hexafluorophosphate (1.1 equivalent) was added in portions. The resulting reaction solution was added. Stir at room temperature for 48 hours. Dilute the current reddish solution with ether and wash successively with 1 N aqueous NaOH solution, water and brine. Then, the organic extract is dehydrated and dried with N^SO4, and the filtrate is placed in vacuo. Concentrated to give a pale yellow oil. The crude material thus obtained was purified by flash chromatography (Si 〇 2, 7:3 (Wv) hexane: Et 〇Ac~&gt; EtOAc - 95:5 (v/ v) CH2C12: 2.0M NH3 in MeOH afforded the title compound as colourless oil. Step 5: N-{2-[4-(sulfenyl)-2-mercapto]ethyl}ethylamine 3-[2-(ethylamino)ethyl hydrazide carboxylic acid oxime ester (1 eq.) was dissolved in THF (0-18 M) from the previous step. Then, lithium borohydride (12 eq.) was added to this solution. The resulting solution was stirred vigorously for 5 hours at 5 Torr: The reaction mixture thus obtained was further diluted with ether and the reaction was quenched carefully with 1N aqueous EtOAc. The combined organic extracts were washed with EtOAc EtOAc EtOAc EtOAc. -(4-indolyl-2-yl-naphthyl)ethyl]acetamidine at 〇C, from the previous step {·{2-[4-(hydroxyindenyl)_2-naphthyl]ethyl } Ethylamine (1) is added to a suspension of sodium bicarbonate (1.2 equivalents) in dichloromethane (0.09 Torr) with DMPai equivalent). The resulting mixture was quenched at room temperature (IV) for 18 hours (4) with saturated aqueous NaHSC &gt; 3, 143482-1 • 107·201111364 followed by extraction with EhO. The combined organic extracts were further washed with aq. 10% aqueous HCI, water and brine. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc (EtOAc) Step 6: Amine 32 in a solution of N-[2-(4-mercapto-2-indolyl)-ethyl]acetamide (1 eq.) in dichloromethane (0.12M) from the previous step Add magnesium sulfate (丨 equivalent) and cyclopropylamine (2 equivalents). The resulting suspension was stirred at room temperature for 48 hours. The insolubles were removed via filtration and rinsed with di-methane, then the combined mixture was concentrated in vacuo. The crude imine thus obtained was dissolved in decyl alcohol (0.12 M), followed by sodium hydride (5 eq.). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were then removed in vacuo and the residue formed was partitioned between EtOAc and aqueous EtOAc. The aqueous layer was separated and back-extracted with Et0Ac. The combined organic extracts were further washed with water and brine, dried over N?SO?, and filtered. The title compound was obtained as a colorless oil. Amine 33 N-[(2-Bromophenyl)indolyl]cyclopropylamine To a solution of 2-bromodecyl alcohol (1 eq. The reaction mixture was allowed to cool to dryness, and then vaporized decanesulfonium (1.3 eq.) was added dropwise. Next, the formed solution was slowly warmed to room temperature. Cyclopropylamine (5 equivalents) was added to the current turbid suspension after 1.5 hours. After another 18 hours, the reaction mixture was diluted and tested with claws 143482-1 -108- 201111364

The reaction was quenched with aqueous NaOH. The organic extract was separated, washed with brine, dried over Na 2 SO. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc:EtOAc:EtOAc . Amine 34 N-{ [1-(2-decyloxyethyl)_1H_indenyl]methyl}cyclopropylamine Step 1: 1-(2-methoxyethyl hydrazine _3_carboxaldehyde Benzyl-3-carboxaldehyde (1 eq.) was dissolved in dmf (0.46 M). Sodium hydride (1.3 eq.) was added and the resulting solution was stirred at room temperature for 20 min. Then, potassium iodide (1 eq.) was added. The reaction mixture was quenched with brine and extracted with EtOAc over EtOAc (EtOAc). The MgS〇4 was dehydrated and dried. Filtration, 'and the filtrate was concentrated in vacuo to give a yellow oil. The crude product thus obtained was purified by flash chromatography (Si02, 9·1 (v/v) hexane: EtOAc^ EtOAc) to give the title compound as an orange oil. Step 2: Amine 34 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; In CH2Cl2 (〇15M). Then, strontium magnesium (1 in summer) and formic acid (〇1 equivalent) were added, and the resulting suspension was stirred at room/m for 8 hours. Insoluble matter was removed by filtration. And the filtrate was allowed to dry in vacuo. The residue was dissolved in MeOH (0.15M) and sodium borohydride (1.5%) was added portionwise. The resulting suspension was stirred at room temperature for 16 hours. : Remove volatiles from the work. Then, dissolve the residue in 143482·1 -109- 201111364 ether, carefully quench the reaction with 1NHC1 aqueous solution, and then neutralize with ινν &amp; The aqueous washings were separated and extracted with ether. The combined organic extracts were further washed with water and brine, dried over NaHSO4, filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was subjected to flash chromatography Purification (Si 2 , EtOAc - 7:3 (EtOAc):EtOAc) lH-Indol-3-yl]fluorenyl}cyclopropylamine 35 is prepared according to the procedure described in amine 34, but in the step, 1-iodo-2,2,2-trifluoroethane is used instead. As an alkylation reagent. Amine 36 Ν-{[1-(4,4,4-trimethylbutyl)-1Η-called 丨哚-3-yl]nonyl fluorenyl propylamine 36 is based on amine 34 Said program However, in step 1, 1-iodo-4,4,4-trifluorobutane is alternatively used as the alkylating agent. Amine 37 N-[(l-butyl-1H-4嗓-3) -Based] fluorenyl] Cyclopropylamine 37 is prepared according to the procedure described for amine 34, but in step i, 1-iodobutane is alternatively used as the alkylating agent. Amine 38 Ν-({ 1-[3-(Ethoxy)propylHH-indol-3-yl}methyl)cyclopropylamine 38 is prepared according to the procedure described for amine 34, but in step 1, alternatively 1 is used. -Bromo-3-ethoxypropane as an alkylating agent. Amine 39 N-({ 1-[3,3,3-difluoro-2-(difluoroindolyl)propyl]_1H吲哚_3yl fluorenylmethyl)cyclopropylamine 143482-1 -]]0· 201111364 Amine 39 is prepared according to the procedure described for amine 34, but in step 1, 1,1,1,3,3,3-hexafluoro-2-(iodomethyl)propane is optionally used as the alkyl group. Chemical reagent. N-(3-{3-[(cyclopropylamino)indolyl]-m•indolyl}propyl)acetamide Step 1: [3-(3-methylindolyl-1Η-哚哚小基) The propyl] carbamic acid tert-butyl ester was dissolved in DMF (〇15M). Add sodium hydride φ (1.3 when set) and stir the resulting solution at room temperature for 20 minutes, then add 'tetrabutylammonium iodide (1 equivalent) and 3 -bromopropylamino decanoic acid Butyl ester (2 equivalents), and the reaction solution was stirred at room temperature for 18 hours. Next, the reaction mixture was quenched with a saturated aqueous solution of EtOAc and extracted with EtOAc. The combined organic extracts were dehydrated and dried with MgS A. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. The crude product thus obtained was purified by flash chromatography (EtOAc EtOAc (EtOAc) • Step 2: N-[3_(3-methylindolyl-m-indol-1-yl)propyl]acetamide is obtained from the previous step [3_(3_曱醯基·m_吲哚小小The propyl]amino]carbamic acid tert-butyl ester was added to a stirred two-gas methane (〇〇9M) solution (4N solution in dioxin, 45 equivalents). The resulting solution was stirred at room temperature for 1 hour and then the volatiles were removed under vacuum. Next, the second gas chamber was added to the red residue, and the volatile matter was again removed in a vacuum to obtain a red gum. Then, in the crude amine thus obtained, a second gas is added (0._ with triethylamine (22 equivalents). # When the reaction solution becomes homogeneous, chlorinated ethylene (1〇5 equivalent) is added, and The resulting mixture was stirred for an additional 2 hours at 143482-1 201111364 to / melon. Finally, the reaction was quenched with 1N aqueous NaOH solution and extracted with MeOH. The combined organic extracts were dried with &lt;RTIgt; And the filtrate is concentrated in vacuo to give the crude title compound as a yellow solid. Step 3: Amine 40 </ RTI> </ RTI> N-[3-(3-indolyl-1H- 吲 -1- -1- yl) The arylamine (equivalent) and cyclopropylamine (2 equivalents) were dissolved in CH2Cl2 (〇1M). Then, magnesium sulfate (2 equivalents) and formic acid (〇2 equivalent) were added, and the resulting suspension was stirred at room temperature for 20 hours. The insolubles were removed via filtration and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH (0.1M) and sodium borohydride (1 eq.). The resulting suspension was stirred at room temperature for a period of time. Remove volatiles in a vacuum. Then, the formed residue/valley was subjected to an examination, and the reaction was carefully quenched with an aqueous solution of IN HCl, followed by neutralization with an aqueous solution of IN NaOH. The aqueous wash solution was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 S 〇 4, and allowed to concentrate in vacuo. The crude product thus obtained was purified by flash chromatography (SiO2, 1:9 (v/v) MeOH: EtOAc-&gt; 1:1 EtOAc:

The title compound was obtained as a white solid. Amine 41 N-(3-{3-[(cyclopropylamino)indolyl]-exidine-mercaptopropyl)propanamide 41 is prepared according to the procedure described in amine 40, but in the step In 2, propionyl chloride is used instead as an alkylating agent. Amine 42 N-(2-{3-[(cyclopropylamino)indolyl]_1H-吲哚4_yl}ethyl)ethylamine 143482-1 201111364 Amine 42 is based on the oxime 4 described in the amine 40 The core is prepared, but in step 1, 2-bromoethylaminocarbamidine-T® second-butyl ester is alternatively used as the alkylation reagent. The amine 43 is called {3_[(cyclopropylamino)methylHH♦dol +yl}ethyl)propanolamine 42 is prepared according to the procedure described in the amine 4G, but in step η, instead of 2-di Triethyl butyl citrate as the alkylation test

It is known that in step 2, gasification is used as a hospitalization reagent. Amine 44 Ν-{[1-(2· propylene small group)-ΐΗ_吲哚_3_yl]methyl}cyclopropylamine Step 1: 1-Dilyl-1Η-called 卜果-3-慢甲Let 丨^ each of the formic acid α equivalent) dissolved in DMF (ο··). Sodium hydride (2.5 as straight) was added and the resulting solution was stirred at room temperature for a minute. Then, 3-bromopropene (1 equivalent) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was then quenched with brine and extracted with EtOAc. The combined organic extracts were dehydrated and dried with MSS®4. Filtration and concentration of the filtrate in vacuo afforded a coloured oil. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc: EtOAc (EtOAc) Yellow oil. Step 2: Amine 44 was dissolved in MeOH (0.05 M) from the previous step of 1- allyl-1H-indole-3-carbaldehyde (e.e. equivalent) and cyclopropylamine (2 eq.). Then, sodium cyanoside (2 equivalents) and acetic acid (4 equivalents) were added, and the resulting suspension was stirred at room temperature for 18 hours. Next, the volatiles are removed in a vacuum. Office 143482^1 -113- 201111364 The residue formed was dissolved in the mystery and the reaction was carefully quenched with aqueous 1N NaOH. The aqueous wash was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered and evaporated. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut Amine 45 Ν-{[1-(phenylmethyl)-1H-indol-3-yl]indolyl}cyclopropylamine 45 is made according to the procedure described in amine 44, but in step 1, instead Barium bromide is used as an alkylation reagent. Amine 46 Team {[1-(2-Acridinesulfinyl)HH_indolyl]hydrazino}cyclopropylamine 46 was prepared according to the procedure described for amine 44, but in step i, alternatively used Tetrabutylammonium iodide (1 equivalent) and 2-methylpyridine hydrochloride (1.5 equivalents) were used as the alkylation mixture. Amine 47 N-{[1-(3-pyridylmethylΗΗ·吲)哚_3_yl]methyl}cyclopropylamine 47 is prepared according to the procedure described in amine 44, but in step κ, instead using tetrabutylammonium iodide (1 equivalent), J-, gasification 3-methyl hydrazine hydrochloride (1.5 eq.) as a mixture of alkylation. Cycloamine 48 N-UH4 jinding I methyl HH ♦ _3_ yl] methyl} cyclopropylamine 48 based on amine The procedure described above is used as a substitute for the bite gas salt (1 equivalent) as: base 2: 143482-1 -114. 201111364 reagent. amine 49 Ν-({1-[(4-fluorophenyl)) Indolyl]-1Η-indolyl-3-yl}hydrazino)cyclopropaminan 49 is prepared according to the procedure described in amine 44, but in the step, instead of 1-(bromomethyl)- 4-fluorobenzene (1.5 equivalents) as an alkylating agent. Amine 50 Ν-({1-[(4-chlorophenyl)methyl]-lH-indol-3-yl}曱Cyclopropaminan 50 is prepared according to the procedure described for amine 44, but in step i, 1-(bromomercapto)-4- benzene (1.5 equivalents) is alternatively used as the alkylation. Reagents: Amine 51 Ν-({1-[(3-fluorophenyl)methyl]-1H-indol-3-yl} yl)cyclopropaminan 51 is prepared according to the procedure described for amine 44 However, in the step 1, 1-(bromodecyl)-3-fluorobenzene (1.5 equivalents) was used instead as the alkylation reagent. Amine 52 Ν-({1-[(3) -Phenylphenyl)indenyl]_1Η-indol-3-yl}indenyl)cyclopropylamine 52 is prepared according to the procedure described in amine 44, but in step 1, alternatively 1-(bromo)曱3) Benzene (1.5 eq.) as an alkylation reagent. Amine 53 3-({3-[(cyclopropylamino)indolyl hydrazide} methyl) cumin nitrileamine 53 based on amine Prepared by the procedure described in 44, but in step 1, instead of 1-? 143482-1 • 115· 201111364 methyl)-3-cyanobenzene (1·5 equivalent) as the alkylation reagent Amine 54 Ν-({ Η(3-methylphenyl)methyl]_1 Η 啕哚 啕哚 丨 丨 methyl) Cyclopropylamine 54 is based on the procedure described in amine 44 , But using Η desert-ylmethyl alternative in the step ι) -3_ toluene (L5 eq) of the base functions as a burning reagent. Amine 55 N-({5-fluoro-1-[3-(indolyl)propyl;|-1H_啕哚_3yl}decyl)cyclopropylamine SS based on the procedure described for amine 44 Manufactured, but in the step, using tetrabutylene (1 equivalent) _ odoryl _3 methoxy propylene (21 equivalents) as the alkylation mixture, and 5-fluoro group _m吲哚_3 Carboxaldehyde (ι equivalent) was used as the starting p?丨嗓. N-{[6-Molyl-1-(phenylmethyl)·1Η_吲哚; yl] fluorenyl} cyclopropylamine Step 1: 6-Alkyl-1Η-Μ丨11-3-hydroxycarboxylic acid·

Gasified phosphonium (1.2 equivalents) was added to a solution of 6-bromo-1 Η-♦ (1 equivalent) in DMF at 〇 °C. The resulting solution was allowed to warm to room temperature and stirred at room temperature for 16 hours. The resulting solution was re-cooled to 〇 &lt;t, then Na 〇H (2M aqueous solution, 2.8 eq.) was carefully added. After stirring for an additional 2 hours at room temperature, the crude reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous MgS 4 . Filtration and concentration of the filtrate in vacuo afforded a yellow oil. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc-EtOAc)

143482-1 •116- 201111364 Step 2: 1-Mercapto-6-bromo _ih, hydrazine-3-carboxyfurfural so that the 6-bromo hydrazine carboxaldehyde (1 eq.) from the previous step is dissolved in DMF (0.19Μ). Sodium hydride (15 eq.) was added and the resulting solution was sanded at room temperature for 20 min. Then, benzyl bromide (1 equivalent) was added, and the reaction solution was stirred at room temperature for 24 hours. The reaction mixture was then quenched with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc (EtOAc) solid. Step 3: Amine 56 is obtained by dissolving 1 -benzyl-6-bromo-1H_^ each carboxaldehyde (1 equivalent) and cyclopropylamine (2 equivalents) in the previous step in Me〇H (〇〇5M). Then, sodium cyanoborohydride (2 eq.) and acetic acid (4 eq.) were added, and the resulting suspension was stirred at room temperature for 16 hr. Next, the volatiles are removed in a vacuum. Then, the resulting residue was dissolved in ether, and the reaction was quenched with a 1 N NaH aqueous solution. The aqueous wash was separated and back extracted with ether. The combined organic strokes were further washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc (EtOAc) Amine S7 n_UH(3-fluorophenyl)methyl]-6-(methoxy)_1H•indenyl]methyl}cyclopropylamine 57 is prepared according to the procedure described in amine 44, but in the step In 2, 1-(bromoindenyl)-3-fluorobenzene (1.5 equivalents) is used instead as the alkylation test 143482-1 201111364, and in step 1, 6_methoxy_1H is used. _吲哚_3绫formaldehyde (1 equivalent) as the starting point. Amine 58 N-{[4-indolyl small (phenylmethyl)_1H_吲哚_3_yl]indolyl}cyclopropylamine 58 is made according to the procedure described in amine 56, but in step i Alternatively, 4-methyl-1 hydrazine (1 equivalent) was used as the starting hydrazine, and in step 2, cesium bromide (1 equivalent) was used as the alkylating agent. The amine 59 3_[(cyclopropylamino:)methyl]-1-(phenylmethyl bromide 4 carbonitrile amine 59 is prepared according to the procedure described in the amine 56, but is used alternatively in the step ι Budo-4-carbonitrile (1 equivalent) is used as a starting point, and in step 2, cesium bromide (1 equivalent) is used as an alkylating agent. Amine 60 N-U4-fluoro-H-phenyl ))-1H_吲哚冬基]曱基}Cyclopropylamine 60 is made according to the shoe last's spearman's order described in amine 56, but in step 1, instead using 4·gas base "(1 equivalent) as the starting (four), and in step 2, using the evolutionary master (1.5 equivalents) as the saponification reagent. · Amine 61 N. aryl-indole (3. fluorophenyl) methyl HH_ ah _ 3 yl} methyl) cyclopropylamine 6: L is prepared according to the procedure described in amine 56, but in step ^ Instead of using 4-fluoro-1H-»?丨哚 (1 equivalent) as the main I) as the starting ten, and in Step 2, 'using 1-(bromomethyl)-3-fluoro Stupid (15 to Dantian) as an alkylation reagent. Amine 62 143482-1 •118- 201111364 N-({4-Fluoro-i_[3_(decyloxy)propyl]_1H_吲哚}}methyl propylamine 62 is based on the amine 56 The procedure was made, but in the step, 4-fluoroyl-1Ηβ丨哚 (1 equivalent) was used instead as the starting oxime. Furthermore, odoryl-3-methoxypropane (2 equivalents) and Aihua Tetrabutyl (1 equivalent) is used as an alkylation mixture in Step 2. Amine 63 ΜΗ-Chloro-H3-(methoxy)propyl ΗΗ·4哚彳 丨 methyl) Cyclopropylamine The amine 63 was prepared according to the material described for the amine 56 towel, but 4-chloro-based oxime (1 equivalent) was used as the starting powder. Further, (iv)yl-3-methoxypropene (2 equivalents) and moth tetrabutyl-equivalent are used as the alkylation mixture in the step 2. Amine 64 Ν-([4-Chloro-small (phenylmethyl) Η 啊 _ _ 3 yl] methyl propylamine amide 64 is made according to the procedure described in amine 56, but in the step, alternatively Use a 4-gas base, ♦ (1 equivalent) as the starting ♦, and in step 2 'Use desertification xin (1.5 equivalents) as the pheno-acting amine 65 called Moji-small (phenylmethyl)_1Η ♦ Tobacco methyl} cyclopropylamine / guanidine is made according to the procedure described in % of amine 'but in the step, instead of 4-bromo-1Η-卩 卩 ( (1 Chundan from | wood ( 1 (Tianli) as the starting β哚, and in step 2, using cesium bromide (1.5 equivalents) as the alkylation reagent. Amine 66 Ν-[(4-Moji-H (3_a stupid) Methylamine (10) root two; methyl group propylamine 4, but in the step, for the 201111364 start whistle, and in step 2) as the alkylation test using 4-bromo-1H 蚓哚(1 equivalent) As a starting point, use ί-(bromomethyl)-3-dylbenzene (15 equivalents of 0 amine 67 Ν-({4-Mosyl small [3-(methoxy))propyl]) _ 吲哚 J J violent } methyl) cyclopropylamine 67 is made according to the procedure described in amine 56, but in step η Alternatively, 4-diyl amide (1 equivalent) is used as the starting (4). Further, 卜-methoxy-3-methoxypropane (2 equivalents) and moth tetrabutyl equivalent) are used in step 2 as The alkylation mixture is used. Amine 68 Ν-[(4-Fluoro-1Η-indol-3-yl)methyl)cyclopropylamine 68 is prepared according to the procedure described in amine 56, but in step i Instead of using 4-fluoro-1H ♦ (1 equivalent) as the starting ♦. Furthermore, step 2 is not necessary. 1-{H(Cyclopropylamino)methyl]-5-[3-(methoxy)propyl]phenyl acetophenone amine 69 is according to the procedure described in the published patent application 2 (10) 7/(10) 925 已production. Amine 70 5-[(cyclopropylamino)methyl]-1,3-bis[3-(methoxy)propyl]_2,4(1H,3H)-pyrimidinedione Step 1: 1,3-double (3-methoxypropyl)-2,4-dione-l,2,3,4-tetrahydropyrimidinium formaldehyde at 〇 ° C in 5-methylmercaptouracil (1 equivalent) In the DMF (0.35 M) solution, 1-bromo-3-methoxypropane (2.2 equivalents) and DBU (2.2 when 143482-1 -120-201111364 amount) were successively added. The resulting solution was stirred at room temperature for 72 hours. The volatiles are then removed in a vacuum. The crude product mixture thus obtained was directly purified by column chromatography to give the title compound (yield: EtOAc). Step 2: Amine 70 is obtained from the previous step of 1,3-bis(3-decyloxypropyl)_2,4•dioneyl_u,3,4_tetrahydrozeridin-5-carboxaldehyde α equivalent) In the di-methane (01M) solution, # sulfuric acid (1 equivalent) and cyclopropylamine (2 equivalents) were added. The resulting suspension was stirred at room temperature for 16 hours. The insoluble material was removed by filtration and washed with dioxane, and then the combined filtrate was concentrated in vacuo to give the crude imine thus obtained dissolved in methanol. In the case of 0·1Μ), the butterfly hydrogenation (15 equivalents) was added in portions. The reaction mixture was stirred at room temperature for 16 h then EtOAc EtOAc m. The combined organic extracts were further washed with water and brine, dried over NasSO4, filtered, and concentrated. The crude product thus obtained was purified by column chromatography eluting elut elut elut elut elut elut elut elut Amine 71 N-[5-(3-methoxypropyl)-2,3-dimercaptobenzyl]cyclopropylamine Step 1: 5-Bromo-2,3-dimethylbenzoic acid at 2,3 Nitric acid (12 equivalents), water (25 equivalents) and bromine (U equivalent) were successively added to a stirred acetic acid solution (1) 2M) of dimethylbenzoic acid (1 eq.). Finally, silver nitrate (1 M aqueous solution '1.3 equivalents) was added dropwise over a period of 30 minutes. After stirring for an additional hour at room temperature, the crude reaction mixture was diluted with water, 143482-] • 121 - 201111364 and extracted with EtOAc. The combined organic extracts are then washed with brine to

Na2S04 was dehydrated, filtered, and the mash was concentrated in vacuo. The crude product thus obtained was triturated in hexane to give the title compound as a yellow solid. Step 2: 5-Bromo-N-cyclopropyl-2,3-dimercaptobenzamide in 5-bromo-2,3-dimercaptobenzoic acid (1 equivalent) from the previous step The reaction mixture formed by adding HATU (U equivalent), cyclopropylamine (12 equivalents) and Hunig's test (3 when 胄.) was stirred in a DMF (0.2 M) solution for 18 hours at room temperature. The reaction was then quenched with saturated aqueous ammonium sulphate and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried and evaporated, and evaporated and evaporated. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc N-cyclopropyl_5_[(10) methoxy+propyl small base] 2,3 dimethyl benzamide will be obtained from the previous step of 5-bromo-indole_cyclopropyl-2,3 dif Benzobenzamide (1 eq) with 4,4,5,5-tetramethyl![(1e)_3_(methoxy)propenyl η,3,2·dioxaboron (1.5 equivalents) ) is combined in a 5:1 (v/v) mixture (0.1 Μ) of DMF ·· n_pr〇H. Then, in this solution, add Trans bis(triphenylphosphine) desertified palladium (11) (0.05 ton) and the gas was repeatedly pumped and reverse packed with nitrogen. Finally, 2 Μ aqueous Na2C03 (3 equivalents) was added and formed The two-phase suspension was heated at 18 ° C. The current black suspension was cooled to room temperature and diluted with water and extracted with (10). The combined organic extracts were washed with water and brine and dried over NaaSO. Filtration, and the filtrate was concentrated in a vacuum 143482-1 •122· 201111364. The crude product was purified by flash chromatography (Si〇2,9:i(v/v): Ε·-EtO Ac), The title compound is obtained as a white solid. Step 4: &amp; cyclopropyl- hydrazino-methoxypropyl)-2,3-dimethylbenzamide as the N-cyclopropyl _5. (1Ε)·3_曱oxy propylene small base]_ 2'3 monomethylbenzamide (1 when illusion and Pengji / charcoal (〇〇 5 equivalent) suspended in EtOAc ((Χ2Μ) Then, the vessel was evacuated and purged with a strip of gas. The reaction suspension was stirred at room temperature for 6 hours under a filled &amp; atmospheric cylinder. Next, the reaction suspension was passed through a bed of diatomaceous earth. Filtration and concentrating the filtrate in vacuo to give the title compound as a white solid. Step 5:amine 71 </RTI> </RTI> <RTIgt; The borane-dioxane-sulphide complex (6 equivalents) was added dropwise in a short-path distillation apparatus in a refluxing solution of dimercaptobenzamine (1 equivalent) in THF (0.1 M). The solution was concentrated to 0.3 M over 30 minutes and HCl (2N aqueous solution &lt The mixture was stirred at 80 &lt;0&gt;C for 1 h, cooled to rt and EtOAc (EtOAc)EtOAc. Then, the combined organic extracts were washed with brine, dried over NazSO4, filtered, and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut Amine 72 N-[2-Alkyl-5-(2-decyloxyethoxy)indolyl]cyclopropylamine Step 1: 1-Alkyl-4-(2-methoxyethoxy)·2- Toluene was added to &lt;CO3 (1.2 eq.) in a stirred solution of 4-chloro-3-methyl-(1 eq.) in DMF (0.7 EtOAc). The mixture was stirred at 50 ° C for 5 minutes, 143482-1 • 123 201111364 and then 1-bromo-2-methoxyethene (1.5 equivalents) was added. After 2 hours at 7 ° C, the reaction mixture was cooled to room temperature then diluted with water and ether. The organic phase was separated and washed successively with 2N aqueous NaOH, water and brine. The organic extract was dried over Na.sub.2.sub.4, filtered, and then evaporated to dryness to give the title compound as a yellow oil. Step 2: 2-(Bromoindenyl)-μ-carbyl-4-(2-decyloxyethoxy)benzene is added to 1-chloro-4-(2-methoxy-4-) from another step A mixture of oxy) 2 - fluorene (1 hydrazine), NBS (1.1 eq.) and diphenylguanidinium peroxide (5 eq.) in (0.2 M) was refluxed for 2 hours. Then, the volatile matter was removed in a vacuum, and the residue which was opened was suspended in the burned. The insoluble material was removed via filtration and further washed with hexane. The filtrate was concentrated in vacuo to give the title compound. Step 3: 2-Alkyl-5-(2-decyloxyethoxy)benzofural will be obtained from the previous step 2-(bromomethyl H• gas-based _4_(2-methoxyethoxy) Benzene (1 eq.) and NM0 (3 eq.) were mixed in dioxane (〇3M) for 6 hours at 9 〇t. 'Then' then quenched with a saturated aqueous solution of sodium bicarbonate, and The combined organic extracts were further washed with water and brine, dried over NaiSO4, filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (Si〇2,9 : ι (v/v) hexanes: EtOAc (EtOAc) ieldielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel Propylamine (2 equivalents) was combined in CH2C12 (〇2M). Then, MgS04 (1.5 equivalents) was added thereto, and the resulting suspension was stirred at room temperature for 143482-1 • 124 - 201111364 for 18 hours. Next, the insoluble matter was removed through a diatomaceous earth pad through filtration, and the filtrate was concentrated in vacuo. Then, the crude imine thus obtained was redissolved in a 2:1 (v/v) mixture (0.2 M) of THF : Me〇H. To this solution, sodium hydrogen halide (5 eq.) was added in portions, and the resulting mixture was poured at room temperature for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Next, the combined organic extracts were washed with brine, dried over Celite, filtered, and concentrated. The crude product was purified by flash chromatography eluting elut elut elut elut The amine 73 N-(2-naphthylmethyl)cyclopropylamine amine 73 was prepared according to the procedure described for the amine π, but instead using phthalamic acid as the starting material. Amine 74 N-({3-[U-fluoroindenyl)thio]]yl}indenyl)cyclopropylamine 74 is prepared according to the procedure described for amine 17, but alternatively using succinyl) Thio]benzoquinone is used as a starting material. Amine 75 N-{[5-[3-(indolyl)propyl]_2-(methylthio)phenyl]methyl}cyclopropylamine Step 1: 5-bromo-2-(methylthio)benzoic acid The oxime ester was added to the DMp (0.2 M) suspension of cesium carbonate (3 eq.) and 5-bromo-2-indolebenzoic acid (1 eq.) in EtOAc (5 eq.). Then, the formed suspension was stirred at room temperature for 1 hour. The volatiles were removed, followed by EtOAc and saturated aqueous. The organic phase was separated, dried over Na 2 EtOAc EtOAc (EtOAc) It was again dissolved in DMF (0.2 M), and sodium hydride (3 eq.) and methane (5 eq.) were successively added. Next, the reaction vessel was sealed and heated to 7 ° C for 16 hours. After cooling to room temperature, Et 〇Ac and a saturated aqueous solution of Nh 4 C 1 were added to the crude reaction mixture. The organic phase was separated, dried with EtOAc (EtOAc)EtOAc. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut Step 2: Methyl 5-[3-(decyloxy)propyl]_2-(methylthio)benzoate is added dropwise to a solution of 9-BBN (2 equivalents) in THF (〇.29M) Propylmethylhydrazine (2.1 equivalents)' and the resulting solution was stirred at room temperature until no more gas evolution was observed. The reaction mixture was then heated to 50c»c for 1 hour. Next, in this solution, methyl 5-bromo-2-(indolyl)benzoate (1 equivalent), potassium phosphate (2.5 equivalent) and [1,1,-bis(diphenyl) were added from the previous step. A solution of phosphinyl)-dicyclopentadienyl iron] dipalladium (π) digas methane complex (labile equivalent) in DMF (0.34 M). The resulting red suspension was heated at 8 ° C for 16 hours. After cooling to room temperature, the reaction was diluted with ether and water. The organic layer was separated and washed further with water and brine, dried with &lt;RTI ID=0.0&gt;&gt; The crude product thus obtained was purified by flash chromatography (Si 〇 2 ' 9:1 (v/v) hexane: EtOAc - 7:3 (v/v) hexane: EtO Ac) Colorless oil. Step 3: 5-[3-(indolyl)propyl]_2_(indolyl)-alcohol allows 5_[3_(decyloxy)propyl]·2_(methylthio)benzoic acid from the previous step Methyl vinegar (1 eq.) was dissolved in THF (0.1 Torr) and then lithium aluminum hydride (1 eq.) was added. 143482-1 -126- 201111364 The reaction mixture thus obtained was stirred at room temperature for 16 hours. The reaction was then quenched with aqueous <RTI ID=0.0> IN </RTI> </RTI> <RTIgt; The combined organic extracts were further washed with water and brine, dried over NkSO4 and filtered. The filtrate was concentrated in vacuo to give crystallite crystallite Step 4: 5-[3-(Methoxy)propyl]-2-(methylthio)benzoquinone is obtained from 5-[3-(methoxy)propyl]_2•(曱) obtained from the previous step. To a solution of thio)hanol (1 equivalent) in dioxane, sodium hydrogencarbonate (5 equivalents) and DMp (11 equivalents) were added. The resulting reaction suspension was stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous Na.sub.3 solution and then extracted with dichloromethane. The combined organic extracts were further washed with aqueous INNaOH, water and brine to

The MgS〇4 was dehydrated and dried, and filtered. The filtrate was concentrated in vacuo to give the crude title compound. Step 5: Amine 75 Combine 5-[3-(methoxy)propyl]_2-(indolyl)benzaldehyde (1 eq.) from the previous step with cyclopropylamine (2 eq.) in CH2C12 (〇 1m). Then, MgS〇4 (2 equivalents) and citric acid (αΐ equivalent) were added thereto, and the resulting suspension was stirred at room temperature for 20 hours. Then, via infiltration, the insoluble matter was removed through the diatomaceous earth and the filtrate was concentrated in vacuo. Next, the crude imine thus obtained was redissolved in MeOH (0.1 Torr). To the solution, sodium borohydride (5 eq.) was added portionwise, and the resulting mixture was stirred at room temperature for 16 hr. The reaction was quenched with 1N aq. Then, the combined organic extracts were further washed with water and brine, dried over MgSO 4 , filtered, and concentrated in vacuo. Purification of the crude product by flash chromatography (Si 〇 2, 3:2 (v/v) hexanes: Et sAc) 43482-1 -127 - 201111364 -1:4 (v/v) hexane: EtOAc) 'The title compound was obtained as a colorless oil. Amine 76 N-[3-Bromo-5-(3-methoxypropyl)-m-methylbenzyl]cyclopropylamine Step 1: 3,5-Dibromo-N-cyclopropyl: 4-methylbenzene Addition of HATU (1.3 eq.), cyclopropylamine (丨丨) to a stirred bath of 3,5-dibromo-4-indolylbenzoic acid (q equivalent) in DMF (〇4M) Equivalent) and Hunig's test (3 equivalents). The resulting yellow mixture was stirred at room temperature for π hours. Then, the reaction was quenched with a saturated aqueous solution of ammonium sulfate and extracted with ethyl acetate. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered, and evaporated. The crude product thus obtained was triturated in a mixture of ether and hexane to give the title compound as pale white solid. Step 2: 3-Bromo-N-cyclopropyl-5-[(1Ε)-3-methoxypropane d- ene small base] mercaptobenzamide is obtained from the previous step 3,5-two Bromo-N-cyclopropyl-4-methyl carbamide (1 eq.) and 4,4,5,5-tetradecyl-2-[(1Ε)-3-(decyloxy)_! Propylene small base]_13,2_dioxite Pengwuyuan (1.1 equivalent) in a solution of DMF (0.1M), add trans-bis (triphenylphosphine palladium (IIX 0.05 equivalent). Repeat the pump Gas, and reversed with nitrogen. Finally, 2M NaaCO3 aqueous solution (3 eq.) was added, and the resulting mixture was heated at 1 ° C for 1 hour. The current black suspension was cooled to a temperature 'diluted with water' And extracted with ethyl acetate. The combined organic extracts were further washed with water and brine, dried over NadO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (Si? 9:1 (v/v) Hexane: EtOAc - EtOAc (m.) EtOAc EtOAc EtOAc EtOAc -Methoxypropyl)-4-methylbenzamide in 3-bromo-N-cyclopropyl-5-[(s) from the previous step 1-Ε)-3-decyloxyprop-1-en-1-yl]-4-mercaptophenylguanamine (1 equivalent) in a solution of refluxing toluene (〇·ΐΜ) The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered, and filtered and evaporated in vacuo. The crude product was purified by flash chromatography (Si 〇 2 ' 9:1 (v/v) Hexane: EtOAc - EtOAc (EtOAc) The sodium borohydride (4 equivalents) and the BF3_THf complex (45 equivalents) were successively added to the stirred solution of decyl benzoguanamine (1 equivalent) in THF (0.2 M). The solution was heated at 40 ° C for 5 hours and cooled to 0. (:, then slowly poured into a 6 N aqueous HCl solution (4.5 eq.). After heating for 1 hour, cooling to room temperature, basifying with 1 〇N Na〇H aqueous solution, and finally extracting with ether. Then, the combined organic extracts were further washed with water and brine, dried over NazSO4, filtered, and The filtrate was concentrated in vacuo to give the title compound as a colourless oil. s s s s s s s s s s s s s s s s s s s s s s s s Salt 143482-1 •129· 201111364

D. PdCI2(PPh3)2. OH THF

Step 1: 3-Bromo-5-iodo-4-methyl-benzoic acid in 3-bromo-4-indolylbenzoic acid in 96% sulfuric acid, stirred solution (~0.58M reaction concentration) N-iodoylsuccinimide (1.1 equivalents) was added, and the temperature was maintained between 10 and 30 ° C over 1 hour. The reaction mixture was allowed to mature for 10 minutes and then quenched in water. The syrup was filtered and washed with water, sodium bisulfite, and then water, and the title compound was obtained as an off white solid. 1 H NMR (400 MHz, dmso-d6): (5 13.4 (br s, 1H); 8.30 (s, 1H); 8.00 (s, 1H); 2.64 (s, 3H). HRMS (ES, M-Η) Calculated value 338.8518. Found 338.8516. Step 2: 3-Bromo-5-(3-decyloxy-prop-1-ynyl)-4-mercapto-benzoic acid on 3-bromo-5- To a stirred solution of iodo-4-indolyl-benzoic acid in THF (0.98 M), triethylamine (7.5 eq.) and copper iodide (0.01 eq.), followed by PdCl2 (PPh3)2 (0.005) Then, add propargyl decyl ether (1.5 eq.), and heat the mixture to ~65 ° C for ~24 hours. Allow the mixture to cool to 20 ° C, then dilute with MTBE and water. The organic material was washed with additional water. The combined aqueous layers were mixed with additional MTBE and 5N HCl. The organic layer was 1 M HCl, 3% w/v sodium bisulfite (twice), and 143482 -1 -130- 201111364 Finally, it was washed with water. The resulting solution was concentrated to ~ 〇 38M, and used in THF in the next step. iH NMR (4 〇〇 MHz, acetone _d6): 8% 13 (s,1Η) ; 8.00 (s,1Η) ; 4.40 (s,2Η) ; 3·41 (s,3Η) ; 2.59 (s 3 Η). HRMS (ES, MH) calc. 280.9813. Found: 280.9820. Step 3: 3-bromo-N-cyclopropyl-5-(3-methoxy-propi-propynyl)_4-fluorenyl-benzene Addition of N,N-diisopropyl to metoamine in 3-/odoryl-5-(3-methoxy-propynyl)-4-methyl-benzoic acid (0.38 M solution in THF) Ethylethylamine (18 equivalents) and cyclopropyl φ amine (1.35 equivalents), keeping the internal temperature below 25 ° C. The mixture was cooled to 5 ° C and 2-propane phosphoric anhydride (50% by weight, at Et) 〇Ac, 15 equivalents) while maintaining the internal temperature below 25 t. The reaction mixture was aged at ~2 〇t: for 1 hour, then cooled to 2 ° C, and 1 〇 wt% NH4C1 aqueous solution was added to maintain the internal temperature &lt; 3 (TC. Add isopropyl acetate and settling the liquid layer. Remove the lower aqueous layer. Then, the organic material is washed with 1 Μ Η α, followed by solution, and finally with 10% Naa solution. The organic layer is concentrated to ~1M, then add toluene. Then, the batch was re-concentrated to ~2M, and the formed liquid was immersed for 18 hours. Then, heptane was added, and the solid was filtered. U toluene / g Alkane The mixture was washed and dried to give the title compound m. 1 H NMR (500 MHz 'acetone·d6): 8 〇 1 (s, m), 7% (» 1H), 7.86 (s, 1H), 4.37 (s, 2H), 3.39 (s, 3H), 2.95-2.89 (m, 1H), 2.53 (s, H), 0.76 0.67 (m, 2H), 0.68-0.60 (m, 2H). HRMS (ES, M+H) calculated 322 Ό 443. Found 322.0457. Step 4: 3-Di-N-cyclopropyl-5-(3-methoxy-propyl)-glacial methyl-benzamide in 3 bromo-N-% propyl _5·(3-methoxy _propynyl), fluorenyl-benzamide and oxidized ruthenium (_equivalent) in toluene (sand) in a mixed solution, add 143482 · 1 -131 - 201111364 plus triethylamine (〇·2 equivalent). The resulting solution was hydrogenated at 丨8 for 3 hours and then filtered to remove the catalyst. The solution was concentrated to ~4 parts by volume followed by heptane (8 parts by volume). The resulting slurry was filtered to give the product as an off white solid. 1 H NMR (500 MHz, Acetone-4): 5 7.87 (m, 2H), 7.65 (s, 1H), 3.35 (t, J = 6.12 Hz, 2H), 3.27 (s, 3H), 2.93-2.86 ( m, 1H), 2.75 (t, J = 7.91 Hz, 2H); 2.39 (s, 3H), 1.80-1.72 (m, 2H), 0.75-0.67 (m, 2H), 0.61-0.56 (m, 2H) . HRMS (ES, M+H) calcd. 326.0767. Found. Step 5: Amine 76 ❿ In a stirred solution of sodium borohydride (2.0 eq.) in Thf (8 vol.), boron trifluoride THF complex (2.5 eq.) was added, maintaining the temperature &lt;3 〇t. Then, a solution of 3-bromo-N-cyclopropyl-5-(3-decyloxy-propyl) halocyl-benzoguanamine in THF (3 parts by volume) was added, and the solution was allowed to be 35. Cooked for 18 hours. The reaction mixture was quenched by addition to a 5M aqueous solution of hydrochloric acid, then the mixture was warmed to 50 &lt After cooling to 2 Torr, heptane (3 parts by volume) and methyl third-butyl ether (3 parts by volume) were added. The liquid layer is allowed to settle and the lower layer is cut. The upper organic material was washed with 5 M HCl and the lower aqueous solution was combined with the first aqueous layer. The combined aqueous layers were allowed to cool to and then 48% NaOH was added to adjust the yang to 14. Methyl tertiary butyl ether (68 parts by volume) was added, and the liquid layer was separated. The aqueous layer was back extracted with MTBE. The combined organic material was concentrated to ~4 parts by volume followed by THF (3 parts by volume). The solution was allowed to warm to 40 ° C and decanesulfonic acid (〇_95 equivalent) was added. The resulting slurry was allowed to cool to ambient temperature then filtered and the solid was washed with &lt 1H NMR (5〇〇MHz, DMS〇d6) 5 8 87 143482-1 -132- 201111364 (s, 2H), 7.61 (s, 1H), 7.30 (s, 1H), 4.17 (s, 2H), 3.35 (m, J = 6.23 Hz, 2H), 3.24 (s, 3H), 2.71-2.64 (m, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.77-1.69 (m, 2H), 0.82-0.77 (m' 2H), 0.77-0.70 (m, 2H). HRMS (ES, M+H) calculated 312.0963. Found 312.0978. Amine 77 N-({3,5-bis[3-(methoxy)propyl]phenylindenyl)cyclopropylamine Step 1: N-[(3,5-Dibromophenyl)methyl] ring The propylamine was stirred for 3 hours in dichloromethane (0.1 M) in 3,5-dibromobenzaldehyde (1 eq.), cyclopropylamine (2 eq.) and magnesium sulfate (1). The insolubles were then removed via filtration through a pad of diatomaceous earth and further washed with dichloromethane. The filtrate was concentrated in vacuo to give crude imamine, which was then taken again in MeOH (0.1M). To the solution, sodium borohydride (5 eq.) was added portionwise, and the resulting mixture was stirred at room temperature for 4 hr. The reaction was quenched with aqueous 1 Η Ηα, neutralized with aqueous 1 N NaOH and extracted with ether. Then, the combined organic strokes were further washed with water and saline, dehydrated with MgS 4 and filtered. The filtrate was concentrated in vacuo to give the title compound. Step 2: Cyclopropyl (3,4-dibromobenzyl)amine decanoic acid tert-butyl ester from the previous step of the team [(3,5-dibromophenyl)indolyl]cyclopropylamine (1 Equivalent) is dissolved in dioxane (〇 12M) with mono-tri-butyl acrylate (1 equivalent). Then, Hunig's base (1.3 equivalents) was added thereto, and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue formed was dissolved in a 1:1 (v/v) mixture of hexanes and ether. Next, the suspension was washed with water and brine of ιο% Ηα, dehydrated with Na2S〇4, 143482-1 • 133·201111364, and the mixture was hanked in a vacuum. The crude product thus obtained was purified by EtOAc EtOAcjjjjjjj Step 3: {3,5-bis[(1E&gt;3_methoxypropenyl small group] benzylidene Cyclopropylaminocarbamic acid tert-butyl ester in the cyclopropyl group from the previous step (3,4 Di-tert-butyl ester (1 equivalent) and 4,4,5,5-tetramethyl-2-[(1E)_3-(decyloxy)·μpropene + base -1'3,2-dioxaboron (2.2 equivalents) in a solution of DMF (0.14 Torr), adding trans-bis(triphenylphosphine), palladium (11) (〇1 equivalent) ρ The vessel was repeatedly evacuated and flushed with nitrogen. Finally, 2M Na2c〇3 aqueous solution (6 equivalents) was added, and the resulting mixture was heated at 90 ° C for 6 hours. The current black suspension was cooled to room. The mixture was diluted with water and extracted with ether. The combined organic extracts were further washed with 10% aqueous HCl solution &lt;RTI ID=0.0&gt; Purification by flash chromatography (Si〇2, hexane-&gt; 1:i (v/v) hexane:

The title compound was obtained as a pale yellow oil. Step 4: [3,5-bis(3-methoxypropyl); yl]cyclopropylamino decanoic acid tributyl hydrazine is made from the previous step of {3,5-bis[(1Ε)-3-曱oxy-1-propenyl-μ; aryl cyclopropylaminocarbamic acid tert-butyl ester (1 equivalent) and 10% w/w palladium on charcoal (〇1 equivalent) suspended in EtOAc (0.05 M) . Then, pump the container and call it a gas. The reaction suspension was stirred at room temperature for 3 hours under a cylinder filled with % atmosphere. The reaction suspension was then quenched with dichloromethane and filtered through a bed of celite. The filtrate was concentrated in vacuo to give the title compound. 143482-1 -134- 201111364 Step 5: Amine 77 from [3,5-bis(3-decyloxypropyl)hanyl]cyclopropyl-aminopyruic acid second-butyl ester (1 eq.) In a solution of CH2C12 (0.1 M), HCl (4 ΌΜ 'in-oxan, 3 〇 equivalent) was added. The resulting solution was stirred under the chamber for 2 hours. Next, the reaction was quenched with m Ν &amp; aqueous solution and extracted with ether. The combined organic extracts were then further washed with water and brine, dried over Na.sub.2.sub.4 water, and then filtered and concentrated. The crude product was purified by flash chromatography (EtOAc: EtOAc:EtOAc: Amine 78 N-[3-(3-methoxypropyl)_5-methylindenyl]cyclopropylamine Step 1. (3-Sodium _5-methylbenzylidene benzyl) cyclopropyl carbamic acid tert-butyl Add the n-butylmagnesium bromide (2.0 M in THF) to a solution of n-butyllithium (2 5 M in hexanes, 12 eq.) in toluene (1 M). , 0.4 when 罝). The resulting suspension was stirred at _1 (rc) for 2 min, then added • % propyl (3,4-dibromobenzyl)amine decanoic acid tert-butyl ester (1 equivalent, amine 77 steps) 2), the current yellow-red suspension was stirred under 〇β (: 3 〇, then pure DMF (30 eq.) was added dropwise at _78 C. The reaction mixture was slowly warmed to room temperature over 3 Hour. The current black suspension was quenched with aqueous solution of HCl and then extracted with ether. The combined organic extracts were further washed with water and brine, dried over NadO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc EtOAc (EtOAc) Mercapto-5-[(1Ε)-3-decyloxy-1-propenyl]-yl} 143482-1 -135- 201111364 Aminobutyric acid tert-butyl ester obtained from the previous step (3- Bromo-5-indenyl)cyclopropylaminocarbamic acid tert-butyl vinegar (1 equivalent) and 4,4,5,5-tetramethyl-2_[(1E) each (methoxy) Small propylene-1-yl]-1,3,2-dioxaboron (1 equivalent) in DMF ( In the solution in 〇2M), the trans-bis(triphenylphosphine) desertified palladium (ΙΙ) (α〇5 equivalent) was added to repeatedly evacuate the vessel, and the nitrogen was reversely packed. Finally, 2Μ NaaCO3 aqueous solution was added (3) Equivalent), and the resulting mixture was heated at 90 ° (.: 6 hours. The current black suspension was cooled to room temperature, diluted with water and extracted with ether. The combined organic extracts were taken in 10% aqueous HCl. 1N aqueous solution of Na0H, water and brine were further washed, dried over NasSO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (Si 2 , hexane - 3:7 (v/v) Ethyl alcohol: EtOAc) 'Yield of the title compound as a pale yellow oil. Step 3: </RTI> </RTI> <RTIgt; </RTI> </RTI> </RTI> <RTIgt; One step of cyclopropyl hydrazino 3-mercapto-5-[(lE)-3-decyloxy_ι-propen-1-yl]-yl}amino decanoic acid tert-butyl ester (1 equivalent) Suspended in 10% w/w palladium on charcoal (〇.1 eq.) in EtOAc (0.1 M). Then, the vessel was evacuated and ventilated in %. The reaction was suspended in a gas cylinder filled with H2 atmosphere. Stirring at room temperature After 3 hours, the reaction suspension was quenched with dioxane and filtered over a pad of celite. The filtrate was concentrated in vacuo to give the title compound as yellow oil. Step 5:amine 78 in CH2C12 (0.1M环α (4 〇M, in the cyclopropyl [3(3 methoxypropyl)-5-methyl-yl] carbamic acid tri-butyl vinegar (1 eq.) obtained from the previous step In the dioxane, 30 equivalents). The resulting solution was stirred at room temperature for 2 143482-1 -136·201111364 hours. Next, the reaction was quenched with a 1 N aqueous solution of NaOH and extracted with a mixture. The combined organic extracts were then further washed with water and brine, dried with dehydration, and filtered. The filtrate was concentrated in vacuo to give the title compound. Amine 79 N-[2-bromo-3,5-bis(3-methoxypropyl)benzyl]cyclopropylamine Step 1. 3,5-Dibromo-N-cyclopropylbenzoic acid amine in 3 To a stirred solution of 5-dibromobenzoic acid (1 eq.) in DMF (0.15 M), HATU (1.3 eq.), cyclopropylamine (u eq.) &amp;Hunig's base (3 eq.). The resulting yellow mixture was stirred at room temperature for 18 hours. Then, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were further washed with water and brine, dried and dried with N &amp; The crude product thus obtained was triturated in a mixture of ether and hexane to give the title compound as white solid. _ Step 2: N-cyclopropyl-3,5-bis[(1Ε)-3-decyloxyprop-1-en-yl]benzamide in 3,5-dibromo obtained from the previous step - Ν-cyclopropyl benzoguanamine (1 equivalent) and 4,4,5,5-tetradecyl-2-[(1Ε)-3-(methyl-rollyl)-1-propanyl]- 3,2-dioxaboron (2.3 eq.) In a solution of DMF (0.13 Torr), trans-bis(triphenylphosphine)palladium bromide (πχο.ι equivalent) was added. The vessel was repeatedly evacuated and counter-filled with nitrogen. Finally, 2 Μ aqueous NasCO 3 (6 equivalents) was added, and the resulting mixture was heated at 90 ° C for 16 hours. The current black suspension was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with IN NaOH aqueous solution, 10% aqueous HCl solution, water and brine, dried over Na 2 s 〇 4 143482-1 -137- 201111364, and filtered as 'black oil filtrate in vacuum Concentration in the middle to obtain the crude title step 3: N-cyclopropyl_3,5-bis(3-methoxypropyl)benzamide from the previous step of N-cyclopropyl_3 5_double [ (10) Each of the thioglycolate (1 eq.) EtOAc (0.15 M) solution was passed through a H-Cube hydrogenation apparatus equipped with a 1% palladium/carbon cartridge. The solution was eluted with EtOAc as a dissolving agent at a rate of cc/min. The hydrogenation was carried out at room temperature using a hydrogenation setting. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut Step 4: 2-Bromo-indole-cyclopropyl-3,5-bis(3-decyloxypropyl)benzamide at -78 ° C in the previous step from Ν_cyclopropyl_ 3 5_bis(3methoxypropyl)phenyl hydrazide (1 eq.) with a freshly distilled TMEDA (1 eq.) in THF (0.1 Μ) solution, 'DTH-butyllithium was added dropwise (17 Μ, at In pentane, 1 equivalent), after 10 minutes. The resulting reaction mixture was then slowly warmed to 〇 °c over 1 hour and stirred at 〇t for 1 hour. Here, the current orange reaction solution was again cooled to -78 ° C ', and the i,2-dibromotetrafluoro phenyl group was added dropwise without solvent for 10 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 h. The reaction was then quenched with aqueous EtOAc (EtOAc)EtOAc. The combined organic extracts were further washed with a 10% aqueous HCl solution, water and brine, dried over Naz S04, filtered and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc (EtOAc): EtOAc (EtOAc) Amine 79 was stirred from the previous step in 2-bromo-N-cyclopropyl-3,5-bis(3-methoxypropyl)benzamide (1 eq.) in THF (0.16M) Sodium borohydride (4 equivalents) and bf^thf complex (45 equivalents) were successively added to the solution. The reaction solution thus obtained was heated at 40 ° C for 5 hours and cooled to hydrazine. (:, then slowly pour into a 6N HCl solution (4.5 eq.) and pour the resulting mixture at 5 Torr. (: further heat for 1 hour, cool to room temperature, basify with 10 N aqueous NaOH, and finally Ether extraction. Then the combined organic extracts were washed with water and brine, dried over NaeO4, filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (Si. 2,4:1 (v/v) hexanes: Et.Ac-&gt; EtOAc. Propyl) mercapto-pyridylamine step 1: 2-chloro-indole-cyclopropyl-3,5-bis(3-decyloxypropyl) azelaamine in 2-bromo-indole-cyclopropyl -3,5-bis(3-methoxypropyl)benzamide Q equivalent, amine φ 79 Step 4) in DMF (〇.13Μ) solution, adding vaporized copper φ (2 equivalents). The suspension was sealed and heated in a microwave at BOt for 1 Torr. Then, the reaction was quenched with 10% aqueous HCl solution and extracted with Et.sub.Ac. The combined organic extracts were taken from aqueous solution of IN NaOH, water and brine. Further washing, taking NaaSO4 off The title compound was obtained by EtOAc (EtOAc) elute It is a light yellow oil. Step 2: Amine 80 is obtained from the previous step of 2-gas-N-cyclopropyl-3,5-bis(3-methoxypropyl) stupid 143482·1 -139- 201111364 formazan A solution of the amine (1 equivalent) in THF (0.06 M) in a stirred solution, sodium borohydride (4.2 eq.) and BFg-THF complex (45 eq.) were added sequentially. The reaction solution thus obtained was heated at 40 C. After 5 hours, cool to 〇 ° C, then slowly pour into a 6 N aqueous HCl solution (4.5 eq.). The resulting mixture was heated at 5 ° C for an additional 1 hour 'cooling to room temperature' at 1 〇N Na〇 The H aqueous solution is basified and finally extracted with ether. The combined organic extracts are further washed with water and brine, dried over NasSO4, filtered, and the filtrate is concentrated in vacuo. Purification by chromatography (Si2, 4:1 (v/v) hexanes:EtOAcEtOAcEtOAc 81 N-[2-decyloxy-3,5-bis(3-decyloxypropyl) aryl]cyclopropylamine Step 1: 2-methoxy-3,5-bis[(lE)-3-曱oxypropene small base] benzaldehyde to 3,5-dibromo-2-indolylbenzaldehyde (1 equivalent) and 4,4,5,5 tetradecyl-2-[(1Ε)- 3-(decyloxy)-1-propen-1-yl]_13 2_dioxaboron 2 equivalents) in a solution in DMF (0.1M), adding trans-bis(triphenylphosphine) desertification Palladium (9) (〇) when). The trough was repeatedly evacuated and counter-filled with nitrogen. Finally, 2 M c 3 aqueous solution (6.5 eq.) was added, and the resulting mixture was heated at 9 Torr: for 16 hours. The desired black suspension was cooled to room temperature, diluted with water and extracted with ether. The combined organic extracts were further washed with aqueous 1 N NaOH, 1% aqueous HCl solution, water and brine, dried over N?SO? The filtrate was concentrated in vacuo to give crude title compound <RTI ID=0.0> Step 2: 2-Methoxy-3,5-bis(3-methoxypropyl)benzene is added to the 2-methoxy group of 3,5-bis[(1Ey3_methoxy) Propylene small base] benzoate (1 when 1) and ίο% w/w I bar / charcoal (〇a equivalent) suspended in Et〇Ac 143482-1 • 140- 201111364 and scrubbed with H2. Filling % The mixture was stirred for 4 hours at room temperature. Then, (0.1M). Then, the vessel was evacuated, and the reaction suspension was quenched with a second gas to make the reaction suspension quenched under the atmosphere of a gas cylinder. The rare soil bed was depleted. The crude product was obtained as a coloured oil (yield: EtOAc). Step 3: Amine 81 Combine 2-methoxy-3,5-bis(3-methoxypropyl)benzaldehyde (1 equivalent) from the previous step with cyclopropylamine (2 equivalents) in 〇^ 〇2 (〇1_. Then, MgS〇4 (1.2 eq.) was added thereto, and the resulting suspension was stirred at room temperature for 20 hours. Then, through filtration, the insoluble matter was removed through a diatomaceous earth pad. And let the liquid shrink in a vacuum. Then, make The crude imine thus obtained was redissolved in MeOH (0.1 M). To this was added sodium borohydride (2 eq.), and the mixture was stirred at room temperature for 25 hr. The aqueous solution quenched the reaction and was neutralized with aq. NaOH aqueous solution and extracted with ether. The combined organic extracts were further washed with water and brine, dried and dried with &lt;RTI ID=0.0&gt; The title compound is obtained as a light yellow oil.amine 82 N-[3-(3-decyloxypropyl)-5-(trifluoromethyl)indolyl]cyclopropylamine Step 1 : 3-Amino-5-( Tri-Imethyl)benzoic acid at -15 ° C in a stirred solution of n-butyllithium (2.5 M in hexanes '8 eq.) in toluene (0.2 M) Add n-butylmagnesium chloride (2.0 M, '0.4 equivalents in THF). After 20 minutes, add 1,3-di-mial-5-(three 143482-1 -141 - 201111364 fluoroindolyl)benzene (1 Equivalent) solution in toluene was carried out for 1 minute. The reaction mixture thus obtained was stirred at -15 C for 2 hours then DMF (3 eq.) was added. The reaction was allowed to warm to 〇 ° C. After the addition, a saturated aqueous solution of ammonium sulphate was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with N?SO?, filtered, and concentrated. Purification by flash chromatography (Si 2 , hexanes 1:1 (v/v) hexanes:EtOAc) Olefinyl]_5_(trifluoromethyl)benzofural in 3-bromo-5-(trifluoromethyl)benzaldehyde (1 equivalent) and 4,4,5,5- Tetramethyl-2-[(1Ε)-3-(methoxypropenyl H,3,2 dioxaboron (1.5 eq.) in DMF (0.2 M) solution, add trans bis ( Triphenyl scales are desertified palladium (11) (0.05 equivalents). The vessel was repeatedly evacuated and counter-filled with nitrogen. Finally, 2 M aqueous Na^O3 (3 eq.) was added, and the resulting mixture was stirred at 1 ° C for 2 hours. The current black suspension was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried with Na2SO4, and then evaporated and evaporated. The crude product was purified by flash chromatography eluting elut elut elut elut elut Step 3. Ν-[3-[(1Ε)-3-methoxypropan-4-ene small group]_5 (tris-decyl) yl) propylamine will be obtained from the previous step of 3_[(1E) each Addition of MgS04 (1.5 equivalents) to oxypropione small group]·5 (trifluoromethyl)benzaldehyde (1 when S) and cyclopropylamine (2 equivalents) in CH2Cl2 (〇2Μ) The resulting suspension was stirred at room temperature for 18 hours. Then, through filtration, the insoluble matter was removed by diatomaceous earth pad 143482-] • 142·201111364, and the filtrate was concentrated in a vacuum. The crude imine thus obtained was then redissolved in a 2:1 (Wv) mixture of THF:MeOH (〇 2M). To the bath, sodium borohydride equivalent was added in portions, and the resulting mixture was stirred at room temperature for 18 hr. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Then, the combined organic extracts were washed with brine, dried over Naj.sub.4, filtered, and concentrated. The crude product was purified by flash chromatography eluting elut elut elut elut elut ® Step 5: Amine 82 is obtained from the previous step - [3-[(1Ε)-3-methoxyprop-1-1-ene small group] „5_(trifluoromethyl) yl]cyclopropylamine (1 equivalent And suspending / charcoal (〇1 equivalent) in EtOAc (0.03 M) with 1% w/w. Then, the vessel was evacuated and scrubbed with a gas. The reaction was carried out under a gas cylinder filled with H2 atmosphere. The suspension was stirred overnight at room temperature. The reaction was then filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (Si2, hexane-hexane 9 hexane : φ EtOAcO, the title compound is obtained as a colorless oil. Amine 83 3-[(cyclopropylamino)indolyl]_5_(3-methoxypropyl)phenolamine 83 is based on the published patent application w〇2〇 Prepared by the procedure described in 〇7/(10)%邠. Amine 84 N-(3-Bromo-5-iodohydrazinyl)cyclopropylamine Step 1: (3-Bromophenylphenyl)methanol to μ , in the solution of 3->Smelly _5_iodobenzoic acid Q 〇 equivalent) in THF (〇2M) 143482-1 • 143 - 201111364 'Adding a simmer-sulfurized broth compound (1.5 eq.). After stirring at room temperature for 3 days, 'carefully use 2N HCl solution The reaction mixture was quenched and extracted with EtOAc EtOAc (EtOAc m. Colorless oil. Step 2: 3-Bromo-5-E-benzaldehyde will be obtained from the previous step (3-bromo-5-iodophenyl)nonanol (I··e equivalent) and Dess-Martin peremoline A mixture of (1.18 eq.) was stirred at room temperature for 45 minutes in dioxane (0.1 M). The reaction mixture was diluted with ether, filtered over a pad of EtOAc, and EtOAc: 3:1 (v/v) mixture was washed. The solution was concentrated in vacuo, and the column was again filled with Si〇2, and hexanes: 3:1 (v/v) mixture of EtOAc was dissolved. The title compound is obtained as a pale yellow solid. Step 3:amine 84 3-bromo-5-iodobenzaldehyde (1 eq.) from the previous step and cyclopropylamine (2) combined with CH2 (3⁄4) (0.1 M). Then, MgS〇4 (j equivalent) was added thereto, and the resulting suspension was stirred at room temperature for 2 hours. Then, through filtration, passed through The algae pad removes the insoluble matter, and the filtrate is vacuumed/shrinked. Then, the crude imine thus obtained is redissolved in hydrazine &amp; 〇Η (〇5M) in this solution, and hydroboration is added in portions. Sodium (15 equivalents), and the resulting mixture was stirred at 0 C for 30 minutes and then at room temperature for 2 hours. The reaction was quenched by stirring with 2N HCl water and stirring for 25 minutes. 〇H water / gluten liquid was tested and concentrated in vacuum. The residue was extracted with water from EtOAc (EtOAc)EtOAc. Amine 85 N-cyclopropyl-6-(3-methoxypropyl)hydroquinone small amine Step 1: 6-[(1E)-3-methoxyprop-1--1-yl-1-hydroquinone 1- Ketone in 6-Moalhydroquinone ketone (1 equivalent) and 4,4,5,5-tetradecyl_2_[(1e)_3 (methoxy)-1-propan-1-yl ]-1,3,2-Dioxaboron (1.3 eq.) in a solution in DMF (0.1 M) was added 'trans-bis(triphenylphosphine) desertified palladium (9) (〇〇5 equivalent). The vessel was repeatedly evacuated and counter-filled with nitrogen. Finally, 2 M Na 2 C 〇 3 aqueous solution equivalent) was added, and the resulting mixture was stirred at 1 〇 crc for 丨 hr. The current black suspension was allowed to cool to room temperature&apos; diluted with water and extracted with ethyl acetate. The combined organic strokes were washed with water and brine, dried over Na s s 4, filtered, and concentrated. The crude product was purified by EtOAc EtOAcjjjj: Step 2 · N-cyclopropyl each [(1E) decyloxypropenyl small group] hydroquinone small amine in the previous step 6-[(1E) each methoxypropenyl small group] In a solution of hydroquinone ketone (1 s) in MeOH (2M), &lt;RTI ID=0.0&gt;&gt; This solution was stirred at room temperature for 1 hour, then sodium hydride (1 eq.) was added at EtOAc. Water was added after 3 minutes and the mixture was extracted with ethyl acetate. Next, the combined organic extracts were washed with water and brine, dehydrated and dried, and the filtrate was concentrated in the air. The crude product was purified by EtOAc (EtOAc) Step 3: Amine 85 143482-1 -145· 201111364 N-cyclopropyl-6-[(1E)-3-methoxypropenyl]hydroquinone-1-amine (1 equivalent) from the previous step It was suspended in Et 〇Ac (0.2 M) with 10% w/w palladium on charcoal (〇.1 eq.). The container is then evacuated and scrubbed in %. The reaction suspension was stirred at room temperature for 3 hours under a gas cylinder filled with helium. Next, the reaction was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give the title compound. Amine 86 Ν-cyclopropyl-7-(3-decyloxypropyl)-1,2,3,4-tetrahydrocha-1-amineamine 86 was prepared according to the procedure described for amine 85, but Instead of 7-glycine-3,4-dihydroindole·1(2Η)-one, a starting material is used. Amine 87 3-{3·bromo-5-[(cyclopropylamino)indolyl]-2-methylindolyl i-propanol is added to a solution of amine 76 (1 eq.) in chloroform (0.1 Μ) Iodo-trimethyl sulphate (6 equivalents). The resulting red solution was allowed to stand in the dark for 18 hours at room temperature. The reaction was quenched with methanol and the volatiles were removed in vacuo. Next, the resulting residue was subjected to liquid separation between ether and a 10% aqueous HCl solution. The aqueous layer was separated and aq. The combined EtOAc extracts were further washed with water and brine, dried over Na.sub.4, and then evaporated and evaporated. Purification of the crude product by flash chromatography (5) 〇2,97:3 (v/v) CH2 α2 :

The title compound was obtained as a colorless oil (yield: 2.0M NH3 - 94: 6 (Wv) CH2C12: Amine 88 N-[3-,; odoryl-5-(3-ethoxypropyl)-4-hydrazinobenzyl]cyclopropylamine 143482-1 -146- 201111364 Step 1' 3-Bromooxy+propene Methyl]_4_f-based benzoic acid methyl ester in methyl 3'5------- 4-methylbenzoate (1 equivalent) and 4,4,5,5-tetramethyl 2 [(1Ε) 3_(Τ? Addition of trans-bis(triphenylphosphine) desertified palladium in a solution of DMF (0.1 M) in a solution of -1 -propen-1-yl]-1,3,2-dioxaborin (1.1 eq.) (9) (〇〇2 when 罝). The vessel was repeatedly evacuated&apos; and backfilled with nitrogen. Finally, 2M Na2c〇3 aqueous solution (3 equivalents) was added and the resulting mixture was heated at 1 Torr &lt;t&gt; for 2 hours. The current black suspension was allowed to cool to chamber s, released with water and extracted with ether. The combined organic extracts were further washed with water and brine, dried over Celite, and concentrated. The title compound was obtained as a colorless oil. EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) . Step 2 · 3-Bromo-5-(3-methoxypropylmethylbenzoic acid methyl ester in 3-bromo-5-[(ιΕ)_3·methoxy propylene 丨 得 from the previous step Base]_4_methylbenzoic acid methyl s (1 equivalent) in dichlorohydrazine (α2Μ) solution, added

Crabtree's catalyst (〇.〇丨 equivalent). The resulting orange-red solution was bubbled with hydrogen for a few minutes to activate the catalyst and then allowed to mix for 3 hours at room temperature under a static hydrogen cylinder. Finally, the volatile material was removed in vacuo to give the crude title compound as a yellow oil. Step 3: Methyl 3-bromo-5-(3-Ethylpropyl) 4-mercaptobenzoate in 3-bromo-5-(3-methoxypropyl) from the previous step In the gas-like (cum) solution of the cockroach base, the iodine trimethyl oxalate (methane equivalent) is added. The resulting red solution was stirred at room temperature for one hour in the dark. The reaction was quenched with methanol and the volatiles were removed in vacuo. Next, the formed residue is dissolved in ether to a 1%% Ηα aqueous solution, 'w 143482-1 -147· 201111364

The NaOH water-cooled liquid, water and brine were successively washed and dried by dehydration, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc) Step 4. 3-Bromo-5-(3.ethoxypropyl)ethylidene benzoate in 3-bromo-5-(3-iodopropyl)-4-yl from the previous step To a solution of decyl phthalate (1 equivalent) in ethanol (0.1 Torr), freshly prepared sodium ethoxide (3 畺) was added. The resulting solution was heated under reflux for 18 hours. After cooling to room temperature, the volatiles were removed in vacuo. Then, the resulting residue was dissolved in ether and further washed with a 10% aqueous HCl solution, aqueous solution of &lt;RTI ID=0.0&gt;&gt; The crude product was purified by flash chromatography eluting elut elut elut elut Step 5: 3-Bromo-5-(3-ethoxypropyl)-4-mercaptobenzaldehyde in 3-bromo-5-(3-ethoxypropyl)_4_ from the previous step To a solution of ethyl methyl benzoate (1 eq.) in dioxane methane (0.07 M), DIBAL-H (1.5 M solution in toluene &lt; The resulting solution was stirred at room temperature for 1.5 hours. Then the reaction was carefully quenched with a 1% aqueous solution of HCI. The aqueous layer was separated&apos; and back extracted with ether. The combined organic extracts were further washed with brine, dried over Na Na. The crude alcohol thus obtained was once again dissolved in dioxane (0.07 M), followed by addition of Dess-Martin periodinane (1. dec.) and sodium hydrogencarbonate (1.2 eq.). After stirring at room temperature for 40 minutes, the reaction mixture was diluted with ether and washed sequentially with saturated aqueous NaH.sub.3, aqueous EtOAc, water and brine. The organic extract 143402-1 -148- 201111364 was dried over Na2S〇4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography eluting elut elut elut elut Step 6: Amine 88 combines 3-bromo-5-(3-ethoxypropyl)-4-mercaptobenzoic acid (1 eq.) from the previous step with cyclopropylamine (2 eq.) CH2C12 (0.1M). Then, MgS〇4 (1 equivalent) was added thereto, and the resulting suspension was allowed to stand at room temperature.

Stir for 20 hours. The insolubles were then removed via filtration through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The crude imine thus obtained was then redissolved in MeOH (0.5 M). To the solution, sodium borohydride (15 eq.) was added portionwise, and the resulting mixture was stirred under stirring for 3 hrs and then at room temperature for 2 hr. The reaction was quenched by stirring with a 2N aqueous solution of EtOAc for 25 minutes, basified with aqueous NaOH solution and concentrated in vacuo. The residue was extracted with water from EtOAc (EtOAc m. Amine 89 N-{3-/Smelly-5-[3-(difluorodecyloxy)propyl]_4•indolebenzyl anthracycline Step 1: 3-Bromo-5-(3-hydroxypropyl _4_Methyl benzoate is methyl 3-bromo-5-(3-methoxypropyl)-4-nonylbenzoate. Equivalent, amine, step 2) in chloroform (0.1M) solution with 1 iodotrimethyl; alkane. When). The resulting red solution was allowed to stand at room temperature for -18 hours in the dark. The reaction was quenched with methanol and then the volatiles were removed in vacuo. Then, the formed residue is dissolved in the bond, and the aqueous solution of m is skipped, then the aqueous solution of (iv), water and brine are successively washed. Dehydrated by ~4, filtered, 143482-1 • 149-201111364 and the filtrate is placed in a vacuum. concentrate. The crude product was purified by flash chromatography eluting elut elut elut ' Step 2 . 3_ / 臭基 '5_[3 仁 曱 曱 oxy) propyl M- fluorenyl formic acid methyl vinegar at 5 ° C, in the previous step 3-bromo-5-(3 -Hydroxypropyl)_4_mercaptobenzoic acid vinegar (1 eq.) and sodium sulphate (〇2 #) of acetonitrile (in the suspension of the guanidine, dropwise addition of difluoro(fluorosulfonyl)acetic acid ( 1 eq.), over a period of 10 minutes. After the addition is complete, the reaction suspension is heated at 5 Torr (reheated to room temperature. Then, the reaction mixture is allowed to cool to room temperature, poured into water and extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na2ssssssssssssssssssssssssssssssssssssssssssss </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> An aldehyde in a dioxane (0.07 M) solution of 3-bromo-5-[3-(difluoromethoxy)propyl]-4-indolyl benzoate (1 equivalent) from the previous step. Add DIBAL-H (1.5M solution in toluene, 2.2 when) The resulting solution was stirred at room temperature for 1.5 hours, then the reaction was quenched carefully with a 10% aqueous HCl solution. The aqueous layer was separated and extracted with ether. The combined organic extracts were further washed with brine. The Na2S04 was dried over Celite, filtered, and the filtrate was concentrated in vacuo. The crude alcohol thus obtained was again dissolved in dioxane (0.07M), followed by Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.) After stirring at room temperature for 40 minutes, the reaction mixture was diluted with ether and washed successively with saturated aqueous NaH.sub.3 O.sub.3, aqueous NaOH, water and brine. </ RTI> 143482-1 • 150· 201111364 organic extract with NaaSO4 Dehydration and drying, filtration, and concentrating the filtrate in vacuo. EtOAc (EtOAc) Step 6: Amine 89 will be obtained from the previous step of 3-bromo-5-[3_(difluoromethoxy)propyl]-4-methylbenzaldehyde (1 equivalent) and cyclopropylamine (2 equivalents) ) is merged into Ch2 (〇1M). Then, add MgS〇4 (1) Equivalent), and the resulting suspension was stirred at room temperature for 20 hours. Then, the insoluble matter was removed by filtration through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. Then, the crude imine thus obtained was obtained. Re-dissolved in MeOH (0.5 M). To this solution was added sodium borohydride (1.5 as 1) in portions, and the resulting mixture was stirred under stirring for 3 hrs and then at room temperature for 2 hr. The reaction was quenched by stirring with a 2N aqueous HCl solution for 25 min, basified with aqueous <RTI ID=0.0># </RTI> NaOH and concentrated in vacuo. The residue was extracted with EtOAc (EtOAc)EtOAc. Amine 90 Ν-(3-benzyl-5-methylbenzyl)cyclopropylamine Step 1: 3-Benzyl-5-mercaptobenzaldehyde to (3-methylindolyl-5-methylphenyl)dihydroxyboron A fluorinated planer (3 equivalents), hydrazine (triphenylphosphine) (〇1 equivalent) and cesium bromide (1.2 equivalent) were added to a solution of alkane (1 equivalent) in DME (0.1 M). The mixture was refluxed for 3 hours, cooled to room temperature and then quenched with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na~s~~~~~~~~~~~~ The crude product was purified by EtOAc EtOAcjjjjj: Step 2: Amine 90 3-Mercapto-5-mercaptobenzaldehyde (1 eq.) obtained from the previous step was combined with cyclopropylamine (2 eq.). Then, MgS〇4 (1.5 eq.) was added thereto, and the resulting suspension was stirred at room temperature for 18 hr. Then, through filtration, the insoluble matter was removed through a diatomaceous earth pad, and the filtrate was concentrated in the sky. The crude imine thus obtained was then redissolved in a 2:1 (v/v) mixture of HF:Me〇H (〇·2Μ). To the solution, sodium borohydride (yield) was added in portions, and the resulting mixture was stirred at room temperature for 18 hr. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried with EtOAc EtOAc EtOAc. The crude product was purified by flash chromatography (EtOAc:EtOAc:EtOAc: Amine 91 N-[3-Bromo-5-(3-fluoroindolyl)-4(indolyl)cyclopropylamine Step 1: 3-bromo-5-indolyl hydrazinyl benzoate decyl ester in 3 - Dimethyl methane (〇16M) of methyl bromide-5-[(lE)-3-methoxy-1-propenyl+yl]-4-methylbenzoate (1 equivalent, amine 88, step 1) In the solution, under _78 &lt; ^, the ozone just generated is foamed until a persistent blue color is found. Then, the reaction reactor was sufficiently purged with nitrogen, followed by the addition of triphenylphosphine (ι eq). The resulting mixture was allowed to slowly warm to room temperature over 6 hours. The volatiles were then removed in the air and the resulting residue was suspended in a 1:1 (Wv) mixture of burned and scaly. After passing through the (4) gasket, the insoluble 143482-1 -152- 201111364 was removed. The sputum thus obtained was in a vacuum and traced to a white solid. The title compound was obtained as a white solid. m.jjjjjjjjjjjjjjjjjjjjjjjjjjj - bromo-5-(hydroxyindolemethyl benzoic acid decyl ester) in the previous step from 3-meryl-5-methyl-branched 4-methylbenzoic acid methyl vinegar (丄 equivalent) of the f-alcohol ( In the am) solution, the degassing sodium (4 equivalents) was added in portions. The resulting mixture was mixed at room temperature for 3 hours. Then, with cold m

The aqueous solution quenched the reaction&apos; and (4) after extraction 1, the combined organic extracts were washed with water and brine, dried over Na 2 s 4 and dried. The mixture was concentrated in vacuo to give the title compound. Step 3: Methyl 3-bromo-5-(e-ylindenyl)-4-mercaptobenzoate is added to triphenylphosphine (U equivalent) in a three-gas calcined solution (11 罝) ). The resulting orange suspension was stirred at room temperature for 3 minutes, then added with imidazole (1.2 equivalents) and finally obtained from the previous step of 3-bromo; (hydroxyindole M-mercaptobenzoic acid) 1 equivalent). The current pale yellow solution was stirred at room temperature for a further 30 minutes. The volatiles were removed in vacuo and the residue was triturated with a 1:1 (Wv) mixture of hexanes and ether. The insoluble material was removed through a silica gel pad. The filtrate was concentrated in vacuo to give the title compound as a white solid. Step 4: 3-bromo-5-(3-fluorobenzyl)-4-methylbenzoate The ester was added to a suspension of CuCN (2 equivalents) in THF (0.1 M) at -78 ° C, and then added 3-fluorophenylmagnesium bromide (5 Μ solution in THF, 4 equivalents) over 5 minutes. The resulting mixture was stirred at -78 t for 2 min and then at 〇 ° C for an additional 20 min. The current yellow suspension was allowed to cool again, followed by 143482·1 •153·201111364 added from the previous step 3 - bromo-5-(mothylmethyl)-4-mercaptobenzoic acid decyl ester (1 equivalent). The resulting mixture was stirred at -781 for 20 min. The crude reaction mixture was quenched with a saturated aqueous solution of N.sub.2C.sub.1: EtOAc (aq.). The combined organic extracts were further washed with water and brine, dried over Na NaSO 4, filtered, and the filtrate was concentrated in vacuo. The crude product was further purified by flash chromatography (Si〇2, hexane-u (v/) v) Hexane:

The title compound was obtained as a colorless oil. Step 5: 3-Bromo-5-(3-fluorobenzyl)-4-mercaptobenzoic acid was triturated from 3-bromo-5-(3-fluorobenzyl)-4-methyl from the previous step To a solution of methyl benzoate (1 eq.) in a gas smoldering (0.1 M) solution, DIBAL-H (1.5 M drop in toluene '2.2 eq.) was added. The resulting solution was stirred at room temperature for 5 hours' and then the reaction was carefully quenched with a 10% aqueous HCl solution. The aqueous layer was separated and back extracted with ether. The combined organic extracts were further washed with brine, dried <RTI ID=0.0>Aq. The crude alcohol thus obtained was again dissolved in dichloromethane (〇1M), then Dess-Martin periodinane (1. 〇 equivalent) and sodium hydrogencarbonate (12 eq.) were added. After stirring at room temperature for 40 minutes, the reaction mixture was diluted with ether and washed successively with saturated aqueous NaHCI3, aqueous EtOAc, water and brine. The organic extract was dried over NadO4, filtered, and the filtrate was concentrated in vacuo. Purification of the crude product by flash chromatography (SiO 2 , hexane - 1:1 (v/v) hexane:

EtO Ac) 'The title compound was obtained as a colorless oil. Step 6: Amine 91 will be obtained from the previous step of 3-bromo-5-(3-fluoroindolyl)-4-mercaptobenzaldehyde (1 when 143482-1 • 154-201111364) and cyclopropylamine ( 2 equivalents) were combined in CH2Cl2 (〇1M). Then, MgS〇4 (1 equivalent) was added thereto, and the resulting suspension was subjected to a drop at room temperature. The insoluble matter was removed from the mash, and the filtrate was concentrated in vacuo. Then, the crude imine thus obtained was redissolved in Me〇H (〇.1M). To this solution, sodium borohydride (15 equivalents) was added portionwise, and the resulting mixture was stirred at 0 ° C for 30 minutes, then at room temperature for 2 hours. The reaction was quenched by stirring with a 2N aqueous HCl solution for 25 min, basified with 1N aqueous NaHH and concentrated in vacuo. The residue was extracted with EtOAc (EtOAc)EtOAc. Amine 92 {3-Bromo-5-[(cyclopropylamino)indolyl]-2-methylindolyl K3_fluorobenzyl)fluorenone Step 1 ·· 3-Bromo-5-[(1Ε)- 3-methoxy-1-propenyl small group]_4_methylbenzaldehyde in 3-bromo-5-[(1Ε)-3-decyloxy-1-propen-1-yl]_4-mercaptobenzene To a solution of methyl formate (1 equivalent of 'amine 88 step 1) in dioxane (0.1 Torr), DIBAL-H ru (1. 5 Μ solution in the sputum '2.2 eq.) was added. The resulting solution was stirred at room temperature for 1.5 hours and then quenched carefully with 10% aqueous EtOAc. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed with brine and dried over Na.sub.2SO.sub. The crude alcohol thus obtained was again dissolved in dioxane (0.1 M), followed by addition of Dess-Martin over-crushing (1.0 eq.) and argon carbonate (1.2 eq.). After stirring at room temperature for 40 minutes, the reaction mixture was diluted with ether and washed successively with saturated aqueous NaH.sub.3, aqueous NaOH, water and brine. The organic extract was dehydrated and dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo. 143482-1 -155- 201111364 Purification of crude product by flash chromatography (Si 〇 2, hexane - ι: ι hexane:

The title compound was obtained as a colorless oil, which was solidified upon standing. Step 2: N-{3-Mojiki E)_3_methoxy propylene small base]_4 甲幻幻环丙胺2 2 from the previous step 3 · bromo _5 · [(1ε) 3 methoxy Small propylene small base] Benzene benzoate (1) and cyclopropylamine (2 equivalents) are combined in C% C12 (〇1Μ), and then 'Mgso4 (1 equivalent) is added thereto, and The formed county float was stirred at room temperature for 20 hours. Next, through the transition, the insoluble matter was removed through the diarrhea, and the liquid was concentrated in a vacuum. The crude imine thus obtained was then redissolved in MeOH (0.11 Torr). To this solution, sodium hydride (1.5 equivalents) was added in portions and the resulting mixture was searched for a period of four (4) minutes and then at room temperature for 2 hours. The reaction was quenched by searching for a minute with the addition of the aqueous solution of the fertilizer. The phantom NNaQH was hydrolyzed (four) and concentrated in a vacuum. The residue is extracted from water with hydrazine, and the title compound is obtained as a colorless oil. Step 3: {3-基基-5__.methoxy-acrylic-acrylic]Icyl yl propyl propylaminocarbamic acid tri-butyl ester makes the self-step-like N__base _5•[3 _Methoxy](tetra)小基]· 4-Merylcyclopropylamine (1 eq.) and diacetate diacetate (u eq.) ^ in dioxane (α_. Then, add Humg to it) Test (4)) and the resulting mixture was stirred at room temperature for 3 hours. The volatile matter is removed from Yuzhen*, and the residue formed by the money is dissolved in the mixture of (4) and (v/v). Then, the suspension was dehydrated and dried with a 1% aqueous solution of fertilizer, water and brine, and the mash was concentrated in a vacuum 143482·] -156- 201111364. The crude product thus obtained was purified by column chromatography (EtOAc EtOAc (EtOAc) Step 4: (3-Bromo-5-mercapto-4-methylindenyl)cyclopropylamino decanoic acid tert-butyl ester from {3-bromo-5-[(1Ε) obtained from the previous step a solution of 3-methoxy-1-enediyl small group]_4_methylamino}cyclopropylaminocarbamic acid tert-butyl ester (1 equivalent) in dichlorodecane (0.08 M) at -78 At °c, the ozone just generated is foamed until a long-lasting blue color is found. Then, the reaction vessel was sufficiently purged with nitrogen, followed by the addition of triphenylphosphine (1 equivalent). The resulting mixture was allowed to slowly warm to room temperature for 16 hours. The volatiles were then removed in vacuo and the resulting residue was suspended in a 1:1 (v/v) mixture of hexanes and ether. The insoluble matter was removed through the zebra capsules. The thus obtained liquid was concentrated in a vacuum to obtain a colorless oil. The crude product was further purified by flash chromatography (Si </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 5: {3-Molyl-5-[(3-fluorophenyl)(trans)indolyl]-4-indolylcyclopropylamino decanoic acid tert-butyl ester at 〇°C , in a solution of (3_bromo-5-fluorenyl-4-benzyl)cyclopropylamino decanoic acid tert-butyl ester (1 equivalent) in THF (〇13M) from the previous step, 3-Fluorophenylmagnesium bromide (0.5 Torr in THF, u equivalent) was added. The resulting solution was slowly warmed to room temperature over 2 hours and then quenched with saturated aqueous NH4CI. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with water and brine, dried over N?SO?, filtered, and concentrated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) Step 6: [3-Bromo-5-(3-fluorobenzyl)-4-indolyl]cyclopropylamino decanoic acid tert-butyl ester from the 3-bromo group obtained from the previous step - 5-[(3-Fluorophenyl)(hydroxy)indolyl]-4-hydrazino}}cyclopropylaminocarbamic acid tert-butyl ester (1 equivalent) in dioxane (〇1M) in solution Add Dess-Martin periodinane (lo equivalent) with sodium bicarbonate (丨2 when 1). After the mixture was allowed to stand at room temperature for 1 hour, the reaction mixture was diluted with ether and washed successively with a saturated aqueous solution of Na.sub.2.sub.3, in aqueous NaOH, water and brine. The organic extract was dried with EtOAc (EtOAc)EtOAc. Step 7: Amine 92 in cH2C12 (o.im) from [3_bromo- 5-(3-fluorophenylindenyl)-4-hydrazinobenzyl]cyclopropylamino decanoic acid Within the tri-butyl ester (1 equivalent), Ηα (4.0 M in dioxane, 2 〇 equivalent) was added. The resulting solution was stirred at room temperature for 2 hours. Then, the reaction was quenched with a 1N aqueous NaH solution and extracted with ether. Next, the combined organic extracts were further washed with water and brine, dried over NazSO4, and filtered. The filtrate was concentrated in vacuo to give the title compound <RTI ID=0.0> The aromatic ring structural units in Table 2 were synthesized as follows. Table 2 Compound structure Compound structure Arrocyclic ring 1 Br Aromatic ring 3 1 143482-1 -158- 201111364 Compound structure aromatic ring 2 Me^N^OBn MeV Br Compound structure aromatic ring 4 Ν^ΟΒη (J Τ Br aromatic ring 1 4- Bromo-2-(decyloxy)pyridine aromatic ring 1 is based on Fraley, Μ· E. et al. C/zem/jtry

The procedure described in Leiiers 2002, 〗 2, 3537-3542. Aromatic Ring 2 ® 4-Bromo-2,3-dimethyl-6-[(phenylindenyl)oxyacridine is based on by McElroy, W. Τ; DeShong, R Ogam'c Leiiers 2003, 5, The 4-bromo-5,6-dimercapto-2(1H)-pyridone (1 eq.) prepared as described in 4779-4782 was suspended in benzene (0.13 M). Then, silver carbonate (0.6 equivalents) and benzyl bromide (1.2 equivalents) were added thereto, and the suspension was heated at 45 ° C for 3 days in the dark. The reaction suspension was cooled to room temperature, diluted with benzene and filtered over a pad of Celite. The filtrate was washed with aq. aq. EtOAc (aq.). The title compound was obtained as a colorless oil. Aromatic ring 3 4-iodo-3-{[(methoxy)methyl]oxy}pyridine Step 1: 2-{[(indolyl)indenyl]oxy}pyridine gives 3-pyridinol (1 Equivalent) is dissolved in a 2:1 (v/v) mixture of DMF:THF (0.9 M). Then, potassium tributoxide (1.1 equivalent) was added thereto at -15 ° C, and the resulting suspension was stirred at -15 ° C for 25 minutes, followed by dropwise addition of 143482-1 -159- 201111364 Gas-based methyl methyl ether (u equivalent) over 15 minutes. Then, the mixture was allowed to warm to room temperature over 1 hour, and it was stirred at room temperature for further 2 hours. Next, the reaction mixture was concentrated in vacuo to give a crystallite crystal crystal crystal crystal crystals The aqueous layer was separated and taken up in reverse. The combined organic extracts were washed with water and brine, dried over Na2ssssssssssssssssssssssssss Step 2: The aromatic ring 3 is at -78 ° C in a solution of 2_丨[(decyloxy)indolyl]oxy}pyridine (1 equivalent) in the previous step in ether (0.16 M). Ternary butyllithium (1.7 M in pentane, U equivalent) was added dropwise over a period of 3 min. It was stirred at % ° C for 15 minutes, then iodine (〇 5M in ether, i 2 ) was added dropwise over a period of 30 minutes. Next, the reaction mixture was at -78. The mixture was stirred for 1 hour, and then quenched with water. The aqueous layer was separated and back extracted with ether. The combined organic extracts were washed successively with 10% aq. NaH.sub.3, water and brine, dried over NasSO4 and filtered. The filtrate was concentrated in vacuo to give a beige powder. The crude product thus obtained was purified by EtOAc EtOAcjjjjjjjj Aromatic ring 4 2-(benzyloxy)-4-bromopyridine in 4-bromo-2-fluoropyridine (1 equivalent), decyl alcohol (12 equivalents) and dibenzo- 18_ crown-6 ether (〇 〇5 equivalents) Potassium hydroxide (2 equivalents) was added to a solution of toluene (〇·4Μ). Then, the Dean_Stark apparatus was connected, and the reaction suspension was heated under reflux for 14 hours at 143482-1 • 160-201111364. After cooling to room temperature, the reaction mixture was diluted with hexanes and filtered thru a pad. The filtrate was concentrated in vacuo to give a yellow oil. The crude product thus obtained was purified by column chromatography ( &amp; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Carboxylic acid 1 tickic acid structural unit (carboxylic acid i; (3S, 4S)-r-mercapto-2·-keto_3,4,5,6,Γ,2,-hexahydro-2Η-[4, 4']bipyridyl-indole, 3-dicarboxylic acid μ-t-butyl ester) was synthesized as follows.

TFA Step 1: 4-Bromo-2-methoxy ρ ratio bite 4-sodium-2-carboindole D, sodium methoxide (16 equivalents) and toluene (j part volume) heated to 95 C, after 40 hour. Toluene (61 parts by volume) and water (3 parts by volume) were added and the lower aqueous phase was removed. The organic material was washed with water (1·5 parts by volume), and then the volatile material was evaporated to give the title compound as an oil. Hrms (ES, M+H) calculated 187·9711 measured value ΐ87 97ΐι.骤2. 2 -Methoxy_5,6-dihydro-2η [4 4,]bipyridyl-indole dicarboxylic acid 3 ethyl ester trifluorodecyl ester 143482-1 -161 - 201111364 Potassium acetate (2.0 equivalents), bis(quinolyl)diboron (1〇5 equivalent) and commercially available Pd(Cl)2dppf. digas methane complex (0.02 equivalents) in 2_mercapto THF (6.5 parts) The volume is mixed with N,N-dimercaptoacetamide (1 part by volume). 4-Bromo-2-indolylpyridine in 2_ mercapto THF (3.4 parts by volume) was added, and the mixture was heated to 85 ° C for 4 hours and then cooled to 25t. Add potassium bicarbonate (3. 〇 equivalent) dissolved in water (4.9 parts by volume), followed by 3-(ethoxycarbonyl)-1-(2'2,2-trifluoroethyl trifluoromethanesulfonate醯,), 2,5,6-tetrahydropyridine _4_yl ester (1 〇 2 equivalent). 3-(ethoxycarbonyl)succinyl (2,2,2-trifluoroethyl)tetrahydropyridin-4-yl difluoromethanesulfonate can be used to obtain trifluoroacetamidine which is present on nitrogen A known method in which a group is a similar compound of a Boc group is obtained using a commercially available /3 ketoester (bottom 1).

rNcc

ο 0B Additional Pd(Cl) 2dPPf. digas methane complex (〇 5 equivalents) was added and the batch was heated to 85 t for 2 hours' then cooled to 20 t and allowed to settle. The lower aqueous phase is cut off and the organic material is washed with water, followed by filling the column with sand. The organic solution was concentrated to ~116 parts by volume, and then commercially available HBF4.〇Et2 (1.1 equivalent) was added. The batch was allowed to cool to 2 (rc, cooked for an hour, then an additional 4 parts by volume of solvent was removed by distillation and the slurry was taken to 1 C. The resulting slurry was filtered and the solid was isopropyl acetate. The compound is known as an off-white solid. 1 H NMR (4 〇〇 MHz, fine (4) 6) 5 12·2 (br S, 1H), 817 (cU = 5.2 Hz, 1H), 6.90 (d, J = 4.8) Hi H), 6.81-6.79 (m, 1H), 4.43-4.35 (m, 2H), 3.97-3.83 (m, 5H), 3.82-3.75 143482-1 •162- 201111364 (m,2H), 2.62-2.55 (m, 2H), 0.92-0.83 (m, 3H). HRMS (ES, M+H) calc. 359.1212. Found 359.1237. Step 3: (3R,4S)-2,-methoxy-3,4 ,5,6-tetrahydro-2H-[4,4,]bipyridyl-1,3-di-acid 3-ethyl 1-trifluorodecyl ester 2'-decyloxy-5,6- Dihydro-2H-[4,4']bipyridyl-l,3-dicarboxylic acid 3-ethyl ester 1-trifluorodecyl ester in 2-mercapto THF (6.4 parts by volume) with dioxane ( 1.5 parts by volume) is formulated into a slurry' and HBF4.OEt2 (〇_1 equivalent) is added. The catalyst solution is commercially available bis(2-decylallyl) (COD) Ru(II) (0.01 equivalent) and commercially available (R)-1-[(S)-di-2-furan Phosphino] dicyclopentadienyl iron-yl] -ethyl two - third - butylphosphine (0.0125 eq.) Was dissolved in dioxane gas Yue (0J2 parts by volume) prepared as in 'and added to the slurry. The slurry was then heated to 5 crc and pressurized to 8 bar with hydrogen. After 2 hours of ripening, the batch was cooled to 2 °C. An aqueous solution of NaHCOs (1.5 eq.) was added and the layers were allowed to settle. Flow out of the lower aqueous phase' and discard. The organic layer was washed with a 10% by weight NaCl solution, and the lower aqueous phase was excised and discarded. With respect to the product, the solution was distilled in a vacuum of # to ~2 parts by volume. Then DMF (2 parts by volume) was added, and the resulting solution was used in the next step. HRMS (ES, M+H) calculated 361.1375. Found 361.1367. Step 4. (3R'4S)-r-Methyl-2'-keto-3,4,5,6/,2: hexahydro-2H-[4,4,]bipyridyl-1,3- (3R,4S)4,_methyl-2,keto-3,4,5,6,1' as a solution of 3-ethyl ester of dicarboxylic acid 1-trifluoromethyl ester in DMF/2-MeTHF , 2'-hexahydro-2«:-[4'4']bipyridyl-1,3-dicarboxylic acid 3-ethyl acetate 1-trifluoromethyl ester in a stirred solution, adding triazine iodide Pyrithione (15 equivalents), magnesium hydroxide (1.5 equivalents) and water (1. 〇 equivalent). The slurry was heated to l〇〇t and passed through Ϊ 43482-1 -163- 201111364 for 5 hours and then cooled to ambient temperature. Dioxane (3 parts by volume) and isopropyl acetate (5 parts by volume) were added followed by 4M HCl (2.5 equivalents). Then, the liquid phase was separated and the lower aqueous solution was extracted with dioxane (1·89 parts by volume), and the organic substances were combined. The organic material was washed with a 25% by weight LiCl solution. With respect to the product 'the organic layer was distilled in vacuo to ~5 parts by volume and the product was crystallized. With respect to the product, the distillation was continued to ~2.5 parts by volume, then methyl-tert-butyl ether (1 part by volume) was added, and the slurry was cooled to _3t:, matured for 2 hours, and then filtered. The solid was washed with decyl-tert-butyl ether to give the product as 6.13 (m, 2H), 4.59-4.55 ((m, 0.6H), 4.47-4.40 (m, 0.4H), 4.08-3.95 ( m, 1H), 3.92-3.82 (m, 2H), 3.69-3.53 (m, 0.4H), 3.45-3.25 (m, 4.6H), 3.12-2.95 (m, 1H), 2.34-2.18 (m, 1H ), 1.85-1.75 (m, 1H), 1.03-0.96 (m, 3H). HRMS (ES, M+H) calculated 361.1375. Found 361.1392. Step 5: (3S,4S)-1·-Methyl -2'-keto-3,4,5,6,anthracene,2,-hexahydro-2H-[4,4]bipyridyl-1,3-dicarboxylic acid 1-tris-butyl ester 3R,4S)-1'-mercapto-2'-keto-3,4,5,6,1_,2,-hexahydro-2H-[4,4]bipyridyl-1,3-? Acid 3-ethyl ester 1-trifluorodecyl ester In ethanol (4.1 parts by volume), sodium ethoxide (1.20 equivalents) was added via a sandalwood solution. The mixture was aged for 3 minutes, then water (1.20 equivalents) was added. After 1 hour of aging, b〇c anhydride (1.20 equivalents) was added and the solution was allowed to mature for 1 hour. Sodium hydroxide (2M, 5.00 equivalents) was added and the solution was heated to 70 ° C for 1 hour to cool the mixture. Up to 3 ° C, and concentrate the solution to the volume so that most of the ethanol The solution was washed with MTBE (2.5 parts by volume). The aqueous layer was separated and then acidified with concentrated HCl to give a slurry. Next, 2-mercaptotetrahydrofuran (6 parts by volume) was added, and 143482-1 - 164- 201111364 : - Do not pick up the mixture and then separate the liquid layer. Remove the water layer and collect the material Wu. Then, refill the water layer to the extractor and use MeTHF (2 wound volume) Reverse extraction. The organic fraction was then refilled into an extractor and washed with 50% sodium sulphate/spike. The organic layer was collected and concentrated in vacuo to give a pale yellow solid. The mixture was slurried and stirred at room temperature for 18 hours. The slurry was filtered and washed with EtOAc to give the title compound as an off-white solid. H NMR (5 〇〇MHz, CHa3) : δ 7.30-7.26 (m, 1H), 6.74 (s, 1H), 6.25 (dd, J = 6.96, 2.00 Hz, 1H), 4.44 (s, 1H), 4.30 (s, 1H), 3.52 (s, 3H), 3.09-2.73 (m, 3H), 2.59 (s, 1H), 1.77 (d, J = 13.10 Hz, 1H), 1.61 (d, J = 12.58 Hz, 1H), 1.48 (s, 9H). HRMS (ES, M+H) calc. 337· 1763. Found 337.1768. Example 1 trans-N-cyclopropyl-N-[(2,3-diphenyl)indenyl]-4-(1-methyl-2-keto-1,2-dihydro-4- p is more than decyl)-3-hexahydrop. Fixed amine

Me

Step 1: 4-(4,4,5,5-tetradecyl-1,3,2-oxo-indole-2-yl)-5,6-diaza-1,3 (2ΗΗ: σ定2,1,1-dimercaptoethyl)3-ethyl ester in 4-{[(trifluoromethyl)methyl]oxybu 5,6-dihydro-1,3(2H)- 1-(1,1-dimethylethyl) 3 -ethyl pyridine (1 equivalent) and 7 4,4',4,5,5,^--octamethyl-2,2, - Addition of potassium acetate (3 equivalents) in a solution of bis-1,3,2-dioxane (1.1 equivalents) in dioxane. The suspension was evacuated' and backfilled with A. Finally, add [丨,1'-bis(diphenylphosphino)dicyclopentadienyl]dichloride 143482-1 -165- 201111364 palladium(II) (0.03 equivalent)' in a quick portion and react The suspension was heated at 8 ° C for 14 hours. The reaction was then quenched by the addition of diethyl ether and saturated aqueous NH4CI. The aqueous layer was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered, and evaporated. The crude product thus obtained was purified by column chromatography (Si.sub.2, 95:5-8:2 (v/v) benzene: EtOAc (EtOAc)). Step 2. 2 (Methoxy)_5,6-dioxin-4,4'-linked p ratio σ定_ι,3(2Η)-ditrologous acid 1_(1,1-dimethylethyl)3 - 酉 酉 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 2H)-Pyridinedicarboxylic acid (dimercaptoethyl)3 ethyl ester equivalent) and an aromatic ring 1 (1 equivalent) of n-Pr0H solution (015_, added sodium carbonate (2M aqueous solution, 3 equivalents). The suspension is evacuated and filled with reversed. Finally, a portion of [Iridium bis(diphenylphosphino)dicyclopentadienyl]di-palladium(II) (0.03 equivalent) is added in a quick portion and The reaction suspension was heated to "hours" at 8 Torr. The reaction was then quenched by the addition of diethyl ether and a saturated aqueous solution of EtOAc. The aqueous layer was separated and extracted with ether. The combined organic extracts were taken with water and brine. - Step Washing, dehydrated and dried with Na2S〇4; and, and the liquid solution is concentrated in vacuo. The crude product thus obtained is purified by column chromatography (si〇2, 95:5 (v/v) The title compound was obtained as a white solid. Step 3 ··············· Base R3j Nitrogen-densine di-acid 1-(1,1-mono-T-ethyl)3-ethylidene is derived from the pre-step 2: (methoxy)_5,6-dihydro·44Ι• Acid l-(u-dimethylethyl) 3-ethyl vinegar (1 equivalent) in Me〇H solution (〇iM) 'Adding swarf (3.3 eq.) 1 This suspension is pumped and refilled with Ν2 143482-1 -166- 201111364 Fill in. Finally 'The reaction mixture was sonicated at room temperature for 3.5 hours, during which time the magnesium swarf disappeared. Then, the reaction was quenched by adding an ethyl bond with saturated aqueous NH4Cl. The aqueous layer was separated and extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na Na. Purification (Si02 '90:10 (v/v) hexanes: EtOAc - EtOAc) </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 1-(1,1-Dimercaptoethyl) 3 -ethyl 1,3-hexahydropyridine dicarboxylate in cis-4-[2-(methoxy)-4-pyridine obtained from the previous step Base]_],3_hexahydrop-pyridyldicarboxylic acid 1-(1,1-didecyl A solution of 3-ethyl ester (1 equivalent) in ethanol (〇, 1 Μ) was added with freshly prepared sodium ethoxide (1.1 eq.). The resulting yellow orange solution was heated at 55 ° C for 12 hours. The volatiles were removed in vacuo and the residue was partitioned between diethyl ether and saturated aqueous NH.sub.4Cl. The combined organic extracts were further washed with water and brine, dried over Na.sub.SO*, filtered, and concentrated. The crude product thus obtained was purified by column chromatography (EtOAc EtOAc (EtOAc:EtOAc) -Methyl-2-keto-1,2-dihydro-4-pyridyl)-1,3-hexahydropyridinedicarboxylic acid HU-dimercaptoethyl)3-ethyl ester obtained from the previous step Trans-4-[2-(methoxy)-4-pyridyl]-1,3-hexahydroazepine------ 1-(1,1-monomethylethyl) 3-ethylacetate Pure iodomethane (3 equivalents) was added to a suspension of acetonitrile (0.1 M) with sodium hydride (3 eq.). Then, 143482-1 167. 201111364 The reaction vessel was sealed and heated at 45 ° C for 3 days. Next, the volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated aqueous NH4CI. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were further washed with aqueous 1 N NaOH, water and brine, dried &lt;RTI ID=0.0&gt;&gt; The crude product thus obtained was purified by column chromatography (Si〇2, 80:20 (v/v) hexane: Et0Ac-

EtOAc-95:5 (v/v) EtOAc (EtOAc) Step 6: trans-1-{[((, ΐ-didecylethyl)oxy)carbonyl} 4 (1 methyl-2-keto-1,2-dihydro-4-p ratio) -3-hexahydrop ratio. The acid is neutralized in the trans step (1-mercapto-2-keto-u-dihydropyridinyl)-1,3-hexahydropyridinedicarboxylic acid L-dimethylethyl) from the previous step. Ethyl acetate (1 eq.) 3:2 (Wv) THF: MeOH solution (.07M), lithium hydroxide (1M aqueous solution, 3.1 eq.). The resulting cloudy solution was vigorously stirred at room temperature for 18 hours. The volatiles were then removed in vacuo and the residue was partitioned between Et EtOAc and 10% EtOAc. The aqueous layer was separated and back-extracted with Et 〇Ac. The combined organic extracts were further washed with water and brine, dried over Naz.sub.4, and filtered. The filtrate was concentrated in vacuo to give title compound as a white solid. Step 7. trans-3-({cyclopropyl[(2 3 ·diphenyl)indolyl]amino}carbonyl)4 (1 - decyl-2-keto-1,2-dihydro-4 _Pyridinyl) small hexahydropyridinecarboxylic acid with -didecylethyl ester in trans-dimethylethyl)oxy]carbonyl}-4-(1-mercapto-2-oneyl) Hydrogen pyridine pyridyl) 3_hexahydropyridinecarboxylic acid (1 equivalent), Humm's test (3 equivalents) and amine 1 (1 equivalent) in DMF (〇lM) solution, fraction 143482-1 201111364 Add hexafluorophosphate 〇_(7-nitrobenzotriazole small group)_n,n,N',N'_tetramethylguanidine (1.2 equivalent). The resulting reaction solution was stirred at room temperature for 48 hours. The current reddish solution was diluted with EtOAc and washed successively with 1% aqueous HCl solution, 1N aqueous NaOH solution and brine. Then, the organic extract was dehydrated to dryness &lt;RTI ID=0.0&gt;&gt; The crude product thus obtained was purified by flash chromatography (si 〇 2, 7:3 (v/v) hexane:

EtOAc - EtOAc - 95:5 (V/V) Step 8: trans-N-cyclopropyl-N-[(2,3-diphenyl)methyl]-4-(1-indol-2-yl-1,2-dihydro-4 -p ratio -3-hexahydrop to π cis hydrazide in trans-3-({cyclopropyl[(2,3-dichlorophenyl)methyl]amino) from the previous step Chen Ji) 1,1-Didecylethyl 4-(1-nonyl-2-keto-l,2-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylate (1 equivalent) In the CH2C12 solution (0.05 M), HCl (4.0 M - oxygen guanidine solution '30 equivalents) was added. The resulting solution was stirred at room temperature for 3 hours. After removing the volatiles in a vacuum, the resulting residue was directly loaded onto a 94:6 (v/v) CH^Cl2: 2.0 M NH3 filled Si 〇 2 column in MeOH. . The title compound was obtained as a white foam by dissolving in the same solvent system. MS (ESI+, M+H): 434. Example 2 trans-N-[{5-Gasyl-2-[3-(methoxy)propyl]_4_pyridyl}indenyl]-N•cyclopropyl-4-(1-methyl-2 -keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide 143482-1 -169- 201111364

It was made according to the procedure described in Example 1, but instead of using amine 2 as the starting material, the title compound was obtained as a white foam. MS (ESI+, M+H): 473. Example 3 trans-N-({2-carbyl·5_[3_(decyloxy)propyl]phenyl}indenyl)_N_cyclopropyl ice (1- _methyl-2-keto-1 , 2-dihydro-4-pyridyl) each hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 3 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 472 ° Example 4 trans-N-({2-carbyl-5-[2-(decyloxy)ethyl]phenyl}methyl)-N-cyclopropyl -4-(ι_ decyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead of using amine 4 as the starting material of ?170·143482-1 201111364. The title compound was obtained as a white foam. MS (ESI+, M+H): 458. Example 5 trans-N-cyclopropyl-N-({2,3-dioxa-5-[3-(methoxy)propyl]phenyl}indolyl)-4-(1-indenyl- 2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

Me

It was made according to the procedure described in Example 1, but instead of using amine 5 as the starting material. The title compound was obtained as a white foam. </ RTI> <RTIgt; 2.49-2.63 (m, 3H), 2.76-2.90 (m, 2H), 2.95-3.04 (m, 1H), 3.19-3.24 (m, 1H), 3.27-3.38 (m, 6H), 3.48-3.55 (m , 4H), 4.49 (d, J = 15.6 Hz, 1H), 4.56 (d, J = 15.6 Hz, 1H), 6.05-6.09 (m, 1H), 6.46 (s, 1H), 6.70 (s' 1H) , 7'13 (d, J = 6.9 Hz, 1H), 7.19 (s, 1H). Human renin IC50 (buffer): 0.3 nM. Human renin ic50 (blood aggregation): 1.3 nM. Example 6 trans-N-cyclopropyl_N_({2,3-dioxa-5-[2-(methoxy)ethyl]phenyl}indolyl)-4-(1-methyl-2- -keto-l,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead of using amine 6 as the starting material from 143482-1 -171 - 201111364. The title compound was obtained as a colorless oil. MS (ESI+, M+H): 492. Example 7 trans-N-cyclopropyl_N_(丨2_methyl·5_[3(decyloxy)propyl]phenyl}indolyl-2-yl-yl-indole, 2-dihydro_ 4_pyridyl) winter hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead of using amine 7 as the starting material. The title compound was obtained as a white foam. MS (ESI+, Μ+Η): 452. Example 8 trans-Ν-cyclopropyl_Ν_({2_methyl_5-[2-(methoxy)ethyl;|phenyl}methyl)methyl-2-keto-l,2 -dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 8 as the starting material. The title compound was obtained as a white foam. MS (ESI+, Μ+Η): 438. Example 9 trans-N-cyclopropyl-N-({2,3-difluoro-5-[3-(methoxy)propyl]phenyl}methyl)_ 4_(1-indolyl-2 -keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide 143482-1 • 172- 201111364

It was prepared according to the procedure described in Example 1, but instead using amine 9 as the starting material, the compound was white foam. MS (ESI+, M+H): 474. Example 10

trans-N-cyclopropyl_4-(1-methyl-2-keto-l,2-dihydro-4-pyridyl)-N-({3-(decyloxy)-5-[ 3-(methoxy)propyl]phenylindolemethyl)hexahydropyridine carboxamide

Me

It was prepared according to the procedure described in Example 1, but using amine 10 as a starting material instead. The title compound was obtained as a white foam. MS (ESI+, M+H): 468. Example 11 trans-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-N-({3-{[2-(methoxy) Ethyl]oxy}-5-[3-(decyloxy)propyl]phenyl)methyl)-3-hexahydropyridine carboxamide V8

143482-1 -173 201111364 was prepared according to the procedure described in Example 1, but using amine 11 as the starting material instead. The title compound was obtained as a white foam. MS (ESI+, M+H): 512. Example 12 trans-N-cyclopropyl-4-(1-ethyl-2-keto 4,2-dihydro-4-pyridyl)-N-({3-{[2-(oximeoxy) Ethyl]oxy}-5-[3-(methoxy)propyl]phenyl}methyl)-3-hexahydrop-pyridinium carboxamide

Step 1: 5,6-Dihydro-4,4,-bipyridine-1,3(2H)-dicarboxylic acid 1-(1,1-dimethylethyl)3_ethyl ester in 4 {[(1 Fluoromethyl) 3⁄4 aryl]oxy}-5,6-dihydro-l,3(2H)-p ratio. The acid is 1 - (1' 丨 - monomethyl ethyl) 3-ethyl vinegar (1 equivalent) and the ratio of 4-ρ. Sodium carbonate (2 水溶液 aqueous solution, 2.6 eq.) was added to a solution of 1:1 (ν/ν) ethanol: benzene solution (018 M) in a base stone base (1 1 eq.). The suspension was evacuated and backfilled with Ν. Finally, ruthenium (triphenylphosphine)palladium (9) (〇4 equivalent) was added in a quick portion, and the reaction suspension was heated at 8 (TC for 18 hours. Then, a saturated Nh4C1 aqueous solution was used.

80:20 (v/v) hexane: EtOAc - EtOAc. 143482-1 -174- 201111364 Step 2 '· cis-4-(4-卩 ratio η 定3 _x_ g , , 吞 J, 乂, 虱 pyridine dicarboxylic acid 1-(1,1-didecyl B 3-ethyl ester in 5,6-dihydro-4,4'-bipyridine-i,3 (2H&gt; dicarboxylic acid from the previous step

An antimony crumb (3 equivalents) was added to the Me〇H solution 1_ of HU monomethylethyl) 3 · ethyl (1 equivalent). The suspension was evacuated and backfilled with N2. Finally, the reaction mixture was sonicated at room temperature for 2 hours during which time the iron filings disappeared. The reaction was then quenched by the addition of Et0Ac and 1NN aq. Separate the water layer ' JiiXEtOAe back extraction. The combined organic extracts were washed with water and brine, and the title compound was obtained from EtOAc. Step 3: trans-bucket (4-pyridyl H,3-hexahydropyridine bis-didecylethyl) 3-ethyl ester in cis-4-(4-pyridyl H,3 from the previous step Add sodium ethoxide (u equivalent) freshly prepared to a solution of hexahydropyridine dicarboxylic acid ι-(ι,ι-dimethylethyl) 3 · vinegar (1 eq.) in ethanol (〇4m). The resulting yellow-orange solution was heated at 6 Torr for 12 hours. Then the volatiles were removed in vacuo and the residue was partitioned between EtOAc and sat. The combined organic extracts are further washed with water and brine, dried over NazSO4, treated with activated carbon, filtered, and concentrated in vacuo. The crude product thus obtained is purified by column chromatography (Si〇2) , 80:20 (v/v) hexane: Et0Ac_&gt; Et0Ac) to give the title compound as pale yellow oil. Step 4: trans-4-(1-oxo-4-pyridyl)-1,3-hexa Hydropyridine _, ~ hydrazine-carboxylic acid-dimethylethyl) 3-ethyl ester 143482 ·] -175- 201111364

Trans-4-(4-p ratio)-1,3-hexa-p-p-rhenidine--------------------------- In the dioxane solution (0.1 M), 3-oxoperoxybenzoic acid (1 equivalent) was added. The resulting colorless solution was stirred at room temperature for 13 hours. The reaction was then quenched with saturated aqueous NaHS03 and 1N aqueous NaH. The aqueous layer was separated and back-extracted with EtO Ac. The combined organic extracts were further washed with water and brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a white solid. Step 5: trans-4-(1-ethyl-2-keto-1,2-dihydro-4-pyridyl)_ι,3_hexahydro? 1-(1,1-dimethylethyl)3-ethyl ester of dicarboxylic acid in trans--4-(1-piperidinylpyridinyl hexahydroindole dicarboxylic acid 1 obtained from the previous step To a solution of -(1,1-dimethylethyl)3-ethyl ester (1 equivalent) in benzene (〇〇6m), triethylamine (3 equivalents) was added, and the reaction vessel was immersed in an ice water bath. Pure trifluoroacetic anhydride (3 eq.) was added dropwise over a period of 5 min. The resulting yellow solution was slowly warmed to room temperature and then stirred at room temperature for 18 h. by Et0Ac and sat. The aqueous solution was quenched with aqueous NH4C1. The aqueous layer was separated and extracted with Et0Ac. The combined organic extracts were further washed with water and brine, dried over NhSO4, filtered, and concentrated in vacuo. The sticky orange oil was immediately dissolved in ethanol (〇im), and then, sodium argon (2M aqueous solution, 3 equivalents) and diethyl sulfate (4 equivalents) were added at 〇 ° C. The orange solution was slowly warmed to chamber S'. Then, it was stirred at room temperature for 42 hours. The volatiles were removed in vacuo and the residue was left. Separate between water and water. Separate the water layer' and carry out reverse extraction with the job. The combined organic extracts are further washed with water 143482-1 -176- 201111364 with brine, dehydrated with Na2S〇4, filtered And the filtrate is concentrated in vacuo. The crude product obtained is purified by column chromatography (SiO2, 95:5 (v/v) CH2Cl2. Light yellow vesicles. Step 6: trans-H[(U•dif-ethyl)oxy]carbonyl} 4 (1 ethyl-2-keto-1,2-dihydro-4-pyridyl) -3- Hexahydropyridinecarboxylic acid in the counter-step (1_ethylbutanyldihydro-4-pyridyl)1,3-octahydro! from the previous step!: than biting two oxic acid ^ (丨丨3:2 (V/V) of dimethylethyl)3 ethyl ester (1 equivalent) in THF: MeOH solution (0·07 Torr), lithium hydroxide (1 M aqueous solution, 3.1 eq.) was added. The solution was stirred vigorously for 18 hours at room temperature. Then, the volatiles were removed in vacuo, and the residue was partitioned between Et 〇Ac and 1 〇% HCl. The aqueous layer was separated and Segmental reversal extraction. Combined organic extracts It is further washed with water and brine, dried over water, and filtered, and filtered. The filtrate is concentrated in vacuo to give the title compound as a white solid. Step 7: trans-3-{[cyclopropyl({3][2_(曱Oxy)ethyl]oxybu 5_丨&gt;(decyloxy)propyl]phenyl}methyl)amino]]yl}·4_(1_ethyl_2-keto-u dihydrogen U-dimercaptoethyl ester of winter pyridyl)-1-hexahydropyridinecarboxylate in the trans-_H[(U-dimethylethyl)oxy]carbonyl}_ 4-(1- obtained from the previous step Addition of hexafluorophosphate to the DMF solution of ethyl-2-ketodihydropyridinyl) winter hexahydropyridinecarboxylic acid (1 equivalent), Humg's base (3 equivalents) and amine U (1 equivalent) -(7-aza-benzotriazole small group)_N,N,N,,N,_tetramethylguanidine 2 equivalents). The resulting reaction solution was stirred at room temperature for 48 hours. The current reddish solution was diluted with EtOAc and washed successively with 1% aqueous solution of Ηα, m Na〇H water soluble 143482-1 -177- 201111364 and brine. Then, the organic extract was dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo to give a yellow oil. The crude product thus obtained is purified by flash chromatography (Si〇2, 7:3 (v/v) hexane: Et 〇Ac_

EtOAc-95:5 (v/v) <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; Step 8: trans-N-cyclopropyl-4-(1-ethylketo-i,2-dihydro-4-pyridyl)_N-({3-{[2-(曱)) Ethyl]oxy}-5-[3-(decyloxy)propyl]phenylindenyl)_3·hexahydroindole. Cyclohexylamine in trans-3-{[cyclopropyl({3-{[2-(decyloxy)ethyl)oxy)}-5-[3-(methoxy) from the previous step )propyl]phenyl}indolyl)aminoindolyl 4_(1-ethyl-2-keto-1,2-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylate; To the solution of dimercaptoethyl ester (1 eq.) (3⁄4⁄4⁄4 solution (0.07M), add HCl (4.00 dioxin solution, 30 equivalents). The resulting solution was stirred at room temperature for 3 hours. After removing the volatiles, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2C12: 2.0 Μ3 in MeOH. Dissolution from the same solvent system' The title compound was obtained as a white foam. MS (ESI+, M+H): 526. Human renin IQ buffer: 200 nM. Human® Renin IC50 (plasma): 460 nM. Example 13 trans-N-cyclopropyl-N-({3-{[2-(methoxy)ethyl]oxybu 5-[3-(decyloxy)propyl]phenyl}fluorenyl )-4-(1,5,6-tridecyl-2-keto-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide 143482-1 -178- 201111364

Step 1: 2',3'-Dimercapto-6,_[(phenylmethyl)oxy]_5,6-dihydro-4,4,bipyridin-1,3(2H)-dibasic acid 1-(1,1-Dimercaptoethyl)3·ethyl ester in 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)_5 ,6 dihydrogen·j, imprinting _ pyridine dicarboxylic acid 1-U,1-didecylethyl) 3 -ethyl vinegar (1 equivalent, example wei step) • 3 with aromatic ring 2 (1 equivalent) : 1 (v/v) Toluene: Ethanol solution (〇·〇85Μ)*, sodium carbonate (2 Μ aqueous solution, 3 equivalents) was added. The suspension was evacuated and refilled. Finally, a group of bis(diphenylphosphino)dicyclopentadienyl]digas palladium (II) (0.06 equivalents) was added in a quick portion, and the reaction suspension was heated at 8 Torr &lt;t 18 hour. Then, the reaction was quenched by the addition of diethyl ether and a saturated aqueous solution of EtOAc. The aqueous layer was separated and back extracted with ether. The combined organic extracts were further washed with water and brine, dried over Naz. The crude product thus obtained was purified by column chromatography eluting elut elut elut elut elut eluting Step 2 ·· cis-4-〖2,3-dimercapto_6-[(phenylindenyl)oxy]_4_pyridyl}_13_ hexahydrop than biting dicarboxylic acid 1-(1,1 -Dimethylethyl)3_ethyl ester from 2,3,-dimethyl-6,-[(phenylindenyl)oxy]_5,6-dihydro-4,4 from the previous step Adding magnesium to hydrazine solution (峨·〇9Μ) in a solution of hydrazine-1,3(2H)-bismuth bismuthate-(I, dimethyl-dimethyl 3-ethyl 3-ethyl ester (1 eq.) Hammer (3.3 equivalents). The suspension was evacuated&apos; and backfilled with N2. Finally, the reaction mixture was allowed to vibrate for 3 hours at room temperature 143482-1 •179-201111364. During this period, the magnesium swarf disappeared. The reaction was then quenched by the addition of diethyl ether and saturated aqueous NH4CI. The aqueous layer was separated and extracted with ether. The combined organic extracts were further washed with water and brine, dried over Na. The crude product thus obtained was purified by column chromatography (EtOAc: EtOAc: EtOAc: 1:1 (v/v) Yellow oil. Step 3: trans-4-(2,3-dimercapto-6-[(phenylmethyl)oxy]-4-indolyl}-1,3-hexahydropyridinedicarboxylic acid 1-( 1,1-Dimethylethyl)3_ethyl ester in cis-4-(2,3-dimercapto-6-[(phenylindenyl)oxy]-4-p from the previous step Adding freshly prepared sodium ethoxide (1.2 equivalents) to an ethanol solution (0.1 Å) of a fixed amount of 1-1,3-hexahydroacridine dicarboxylic acid dimethylethyl) 3 - ethyl ester (1 equivalent) The resulting yellow-orange solution was heated at 55 ° C for 16 hours. Then, the volatiles were removed in vacuo and the residue was partitioned between Et0Ac and saturated aqueous nh 4 C1. And the combined organic extracts were further washed with water and brine, dried over Na 2 s 〇 4, and then allowed to pass, and the filtrate was concentrated in vacuo. The crude product thus obtained was subjected to column chromatography. Purification (Si 〇 2, 90:10 (v/v) hexanes: EtOAc - 1:1 (Wv) hexanes: EtOAc. 1-hydroxy-1,3-dimercapto-4-pyridyl)-1,3-hexahydropyridinedicarboxylic acid 1-(1,1-dimercaptoethyl) 3 -ethyl ester Trans-ice {2,3-dimercapto-6-[(phenylindenyl)oxy]- 4-p-bityl}-1,3-hexahydropyridinedicarboxylic acid dimethyl from the previous step Palladium (1〇% w/w, on carbon, 〇3 as 篁) was added to an ethanol solution (〇·07Μ) of ethyl)3•ethyl ester (1 eq.). The resulting suspension was evacuated and purged with hydrogen. The reaction mixture was stirred at room temperature for 2 hours under a gas cylinder filled with hydrogen 143482-1 -180 - 201111364. Then, the reaction is quenched with CH2C12, filtered through a bed of diatomaceous earth, and the insoluble matter is

Rinse with EtOAc. The filtrate was concentrated in vacuo to give the title compound as white crystal. Step 5: trans-4-(l,5,6-trimethyl-2-keto-dihydropyridylpyridyl H,3-hexahydropyridinedicarboxylic acid HU-dimercaptoethyl) 3_ethyl vinegar In the first step of the counter-type (6-hydroxy-2,3-dihydropyridylpyridyl)_U-hexahydropyridinedicarboxylic acid 1-(U-dimethylethyl) 3 ethyl ester ( Methyl iodide (1.5 equivalents) was added to a DMF suspension (〇liM) of sodium hydride (60% dispersion in oil, 2 eq.). Then, the resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of EtOAc and saturated aqueous NH4CI. The aqueous phase was separated and extracted with EtOAc. The combined organic extracts were washed successively with water and brine, dried over N?SO?, filtered, and concentrated. The crude product thus obtained was purified by column chromatography eluting elut elut elut elut elut elut elut elut Step 6: trans-H[(U-didecylethyl)oxy]refenyl} 4 (15,6-trimethyl-2-keto-1,2-dihydro-4-P ratio) -3- hexahydro it ratio. The slow acid is obtained from the previous step of trans-4-(l,5,6-trimethyl-2-keto 4,2-dihydro-4-port thiol)-1,3-hexahydro Ντ ratio. Add lithium hydroxide to a solution of 1-(1,1-dimercaptoethyl)3_e (([equivalent) 3:2 (v/v) THF: MeOH (0.07M) 1M aqueous solution, 11 equivalents) The vigorously formed turbid solution was stirred vigorously at room temperature for 18 hours. Then, the volatiles were removed in vacuo and the residue was partitioned between EtOAc and 10% EtOAc. The aqueous layer was separated, and 143482-1 -181 - 201111364 was reversed with EtOAc. The combined organic extracts were further washed with water and brine, dried over NasSCXj and filtered. The filtrate was concentrated in vacuo to give title titled Step 7. trans-3-{[cyclopropyl({3-{[2-(methoxy)ethyl)oxy)5_[3.(decyloxy)propyl]phenyl}methyl) Amino]behide 4_(15,6-tridecyl-2-keto-yl-12-di-aryl-4-pyridyl)-1-hexahydropyridinecarboxylic acid u-didecylethyl ester obtained from the previous step Trans-dimethylethyl)oxy]pyridyl 4-(1,5,6-dimercapto-2-one-l,2-dihydro-4-P ratio. Stationary)_3_6 hydrogen? Add hexafluoro-J sulphate-(7-nitrobenzotriazole) in portions of dmf (0.1 M) solution of dilute acid (1 eq.), Hunig's test (3 eq.), and amine 11 (1 eq.). Sit on the small base) _ν, ν, Ν ', Ν '- four 曱 锞 (1.2 equivalents). The resulting reaction solution was stirred at room temperature for 48 hours. The current reddish solution was diluted with EtOAc and washed successively with 1% aqueous HCl solution, aqueous NaOH solution and brine. Then, the organic extract was dehydrated to dryness &lt;RTI ID=0.0&gt;&gt; The crude product thus obtained was purified by flash chromatography (Si 〇 2, 7:3 (v/v) hexanes: EtOAc - EtOAc - 95:5 (v/v) CH2C12: 2.0M NH3 in MeOH) , the title compound was obtained as a white solid. Step 8: trans-N-cyclopropyl-N-({3-{[2-(decyloxy)ethyl)oxy(decyloxy)propyl]phenyl}indolyl)-4-( 1,5,6-tridecyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydroguanidine amide in trans -3- from the previous step [Cyclopropyl ({3-{[2-(decyloxy)ethyl]oxy}-5-[3-(methoxy)propyl]phenyl}indolyl)amino]] 1,1-dimethylethyl 4-(1,5,6-trimethyl-2-keto-1,2-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylate (1 equivalent In the CH2C12 solution (0.06 M), HCl (4.0 M dioxane solution, 143482-1 -182 - 201111364 30 equivalents) was added. The resulting solution was stirred at room temperature for 4 hours. After removing the volatiles in vacuo, the residue formed was directly loaded to 94:6 (v/v) CH2C12: 2.0 in MeOH. ΝΗ3 Filled on the Si02 column. The title compound was obtained as a white foam. MS (ESI+, M+H): 540. Human renin IC5 〇 (buffer): 25 nM. Human renin IC5 〇 (plasma): 80 nM. Example 14

trans-N-cyclopropyl-4-(1-methyl-5-{[(indolyl)indolyloxy)-2-keto]ndihydro-4-pyridyl)_N-({3 -{[2-(decyloxy)ethyl]oxy}decyloxy)propyl]phenyl}methyl)-3-hexahydrop ratio

Step 1: 3'-{[(曱oxy)indolyl]oxy}_5,6-dihydro-4,4,bipyridyl {Bodio-carboxylic acid HU-dimethylethyl) 3-ethyl ester 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)_5,6-dihydro-U(2H)_叶匕°疋缓1-(1,1-Methylethyl) 3 -ethyl acid (equivalent, example i step) and aromatic ring 3 (1 equivalent) of 3:1 (v/v) toluene: ethanol solution (〇 In 1M), sodium carbonate (2M aqueous solution, 3 equivalents) was added. The suspension was evacuated and backfilled with A. Finally, [1 JL of bis(diphenylphosphino)bicyclononanediene]digaspalladium(II) (0.06 equivalent) was added in a quick portion, and the reaction suspension was heated at 8 °t for 16 hours. The reaction was then quenched by the addition of Et0Ac and water. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with aq. 1N NaH aqueous solution, &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& The crude product thus obtained was purified by column chromatography (EtOAc: EtOAc: EtOAc: EtOAc (EtOAc) {[(Methoxy)methyl]oxy}_4•pyridyl)13•hexahydropyridinedicarboxylic acid HU-dimethylethyl)3-ethyl ester obtained from the previous step 3, -{[( Methoxy)methyl]oxybu 56_dihydro-44, bipyridyl-1,3(2H)-dicarboxylic acid 1-(1,1-dimethylethyl) 3 ethyl ester (1 equivalent Magium swarf (3.3 eq.) was added to Me〇H Lok (0.09 M). The suspension was evacuated and filled in %. Finally, the reaction mixture was sonicated at room temperature for 15 hours during which time the magnesium swarf disappeared. Then, the reaction was quenched by the addition of Et 〇Ac and 1N Na〇H aqueous solution. The aqueous layer was separated and back-extracted with Et 〇Ac. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, and filtered. The filtrate was concentrated in vacuo to give the title compound as pale yellow oil. Step 3: trans-4_(3_U(decyloxy)methyl]oxy}piperidinyl)13•hexahydropyridyldicarboxylic acid 1-(1,1-dimercaptoethyl)3_ethyl ester Cis- 4-(3-{[(indolyl)methyl]oxyb 4_p-pyridyl)-1'3-hexahydropyridinedicarboxylic acid dimercaptoethyl)3 from the previous step To the ethanol solution (0.1 M) of ethyl ester (1 equivalent), freshly prepared sodium ethoxide (1.2 equivalents) was added. The resulting yellow orange solution was heated at 55 ° C for 16 hours. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and sat. The aqueous layer was separated and back-extracted with Et. The combined organic extracts were further washed with water and brine, dehydrated to dryness, transition, 143482*1 • 184 · 201111364 and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc . Step 4: trans-4-(3-{[(methoxy)methyl]oxypyrrole_oxidation_4_pyridyl)_13 Hexahydropyridinedicarboxylic acid 1-(1,1-dimethylethyl Base 3_ethyl ester in trans-4-(3-{[(methoxy)methyl]oxy}piperidinyl)-1,3-hexahydropyridine dicarboxylic acid dimethyl obtained from the previous step 3-Chloroperoxybenzoic acid (1 equivalent) was added to a solution of chlorodecane (0.1 Torr) in one of ethyl ethyl) 3-ethyl ester (1 eq.). The resulting colorless solution was stirred at room temperature for 13 hours. Then, the reaction was quenched with saturated aqueous NaHS 3 aqueous solution. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried over Na.sub.2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound as white crystal. Step 5: trans-4-(1-methyl-5-{[(indolyl)methyl]oxy}_2-one dihydropyridinyl)-1,3-hexahydropyridinedicarboxylic acid • Dimercaptoethyl) 3_ethyl ester in the counter-step (3_{[(曱oxy)methyl]oxy H oxidized pyridyl)-1,3-hexahydropyridine dicarboxylate from the previous step Triethylamine (3 equivalents) was added to a toluene solution (0.06 M) of EtOAc. Among them, the reaction barr &gt; and &gt; was again added dropwise in a ice water bath to pure trifluoroacetic anhydride (3 equivalents) over a period of 2 minutes. The resulting yellow solution was slowly warmed to room temperature and then stirred at room temperature for 18 hours. The reaction was quenched by the addition of hydrazine and saturated water/liquid. The aqueous layer was separated and back-extracted with Et 〇Ac. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered, and evaporated. The thus obtained adhesive orange oil 143482-1 -185. 201111364 Immediately dissolved in methanol __. Then, in its A, in the hustle and bustle. Mouth, adding sodium (10) aqueous solution of nitrogen oxide, 3 equivalents) and diterpene sulfate equivalent). The resulting orange solution was slowly warmed to room temperature and then it was stirred at room temperature. The volatile matter f was removed from the vacuum towel, and the residue of the residue was subjected to liquid separation between her c and a saturated aqueous NH4Cl solution. The aqueous layer was separated and back-extracted with Et0Ac. The combined organic extracts were washed with water and brine, dried over Na.sub.2.sub.4, and then evaporated and evaporated. The crude product thus obtained was purified by column chromatography (Si〇2, 95:5 (v/v) cH2ci2: at

2. The title compound was obtained as a lavender soak in MeOH. Step 6: trans-W[(U_: f-ethyl)oxyindenyl}-o--------------------- Fixation of 3 hexamethylene argon to the di-ortho-indolyl_5_{[(decyloxy)indolyl]oxy}-2-keto-1,2-dihydro-4 - Pyridyl H,3-hexahydropyridinedicarboxylic acid Hu-dimethylethyl) 3-ethyl vinegar (1 equivalent) of 3:2 (v/v) Avoid: Me〇H solution (〇〇娜中, Lithium hydroxide (aqueous solution of hydrazine, 3 eq.) was added. The resulting turbid solution was vigorously quenched (tetra) for 24 hours at room temperature. The volatiles were then removed in vacuo and the residue was taken from EtOAc and EtOAc. The aqueous layer was separated and the title compound was obtained from EtOAc EtOAc. Is a pink solid. Step 7: trans-3-{[cyclopropyl({3_{[2-(methoxy)ethyl]oxy) 5 [3 (methoxy)propyl]benz} Amino]carbonyl] 4-(1-methyl-5-{[(methoxy)methyl]oxy}-2-one-1,2-dihydro-4-P ratio) _ι_ hexahydrop-pyridyl acid, 丨 dimethyl dimethyl ester from the previous step of the anti-dimethylethyl oxy] carbonyl b 4 _ 143482-1 -186· 201111364 (1-Methyl-5-{[(methoxy)indenyl]oxy}_2-keto-dihydro-4-pyridyl)_3_ hexahydropyridinecarboxylic acid (1 Equivalent), Hunig's base (3 equivalents) and amine 11 (1 equivalent) in DMF (0.1M) solution 'sequential addition of hexafluorophosphate 0·(7-azabenzotriazole small group)-Ν, Ν, Ν·,Ν·-four 曱 锞 (1.2 equivalents). The resulting reaction solution was stirred at room temperature for 48 hours. The current reddish solution was diluted with Et〇Ac and washed successively with 1% HCl aqueous solution, 1 N aqueous NaOH solution and brine. Then, the organic extract was dehydrated and dried over Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo to give a purple oil. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc: EtOAc (EtOAc) Step 8: trans-N-cyclopropyl-4-(1-indolyl-5-{[(methoxy)methyl]oxybu 2__yl-1,2-dihydro-4-pyridyl) -N-({3-{[2-(decyloxy)ethyl)oxy}-5-[3-(decyloxy)propyl]phenyl}methyl)-3-hexahydroindole. Derivatization of trans-amine -3-{[cyclopropyl({3-{[2-(methoxy)ethyl)oxy}-5-[3-(decyloxy))) Propyl]phenyl}indolyl)amino]carbonyl-4-(1_methyl_5_丨[(methyllacyl)methyl]oxy}-2-keto-1,2-dihydro-4 -p octyl bromide (1) was added to a CI^Cl2 solution (0.02 M) of U-dimercaptoethyl ester (1 equivalent), and zinc bromide (11) (10 equivalents) was added. The resulting suspension was sonicated for 15 minutes and stirred at room temperature for 13 hours. The reaction was quenched by the addition of EtOAc and aqueous EtOAc EtOAc. The combined organic extracts were further washed with water and brine, dried over Na 2 EtOAc, filtered, and evaporated. The crude product thus obtained was purified by flash chromatography (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ESI+, M+H): 572. 143482-1 -187- 201111364 Example 15 trans-N-cyclopropyl-N-{[2,3-dichloro-5-(3-cyanopropyl)phenyl]methylindole-d-methyl -2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

The procedure described in Example 1 was followed, but instead the amine 12 as the starting material and the zinc bromide-promoted BOC-extraction protection as in Example 8 Step 8 were used. The title compound was obtained as a pale green foam. MS (ESI+, M+H): 502. Example 16 trans-N-{[5-(3-Cyanopropyl)-2,3-difluorophenyl]methyl}-N-cyclopropyl-4-(1-methyl-2-one Base-1,2-dihydro-4-pyridyl)·3-hexahydropyridine carboxamide

The procedure described in Example 1 was followed, but instead the amine 13 as the starting material and the zinc (II) bromide-promoted BOC- removal protection as in Example 8 Step 8. The title compound was obtained as a pale green foam. MS (ESI+, M+H): 469. Example 17 trans-N-cyclopropyl-N-{[2,3-dioxa-5-(4-hydroxybutyl)phenyl]nonylmethyl-2-keto-1,2-dihydro -4-pyridyl)_3_hexahydropyridine carboxamide 143482-1 -188 · 201111364

Me

Step 1: trans-3-{[cyclopropyl({2,3-dichloro-5-[4-(methoxy)-4- ketobutyl]phenyl}methyl)amino) -4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylic acid 1,1-dimethylethyl acetonate in trans-1- {[(1,1-Dimethylethyl)oxy]carbonylmethyl-2-keto) φ-1,2-dihydropyridinyl)-3-hexahydropyridinecarboxylic acid (1 equivalent, Example 1 Step 6),

Hunig's base (3 equivalents) and amine 14 (1 equivalent) in DMF (0.1M) solution, adding hexafluorophosphate 0-(7-azabenzotriazol-1-yl)_ν, Ν, Ν' , Ν '- four 曱 锞 (1.2 equivalent). The resulting reaction solution was stirred at room temperature for 48 hours. The current yellow solution was diluted with EtOAc and washed sequentially with 1% aqueous HCl solution, aqueous 1 N NaOH and brine. Then, the organic extract was dehydrated and dried over Na 2 s 4 , dried, and concentrated to give a red-brown oil. The crude product thus obtained was purified by flash chromatography (Si 〇 2, 7:3 (v/v) hexane: EtOAc EtOAc - EtOAc - 95:5 (v/v) CH2C12: 2.0M NH3 in MeOH ), the title compound was passed as a light yellow bubble. Step 2: trans-3-[(cyclopropyl{[2,3-dichloro-5-(4-hydroxybutyl)phenyl]decyl}amino]]yl}-4-(1-indole) 1,2-dihydro-4-pyridyl) hexahydropyridinium acid 1-diethyl phthalate in trans--3-{[cyclopropyl] from the previous step (2,3-Dichloro-5-[4-(decyloxy)-4- ketobutyl]phenyl}methyl)amino)carbonyl] 4_(1_fluorenyl-2-keto) u dihydro-4-p ratio bite base)-1-hexahydropyridyl &quot; deuterated acid dimercaptoethyl ester (丨 equivalent) of 143482-1 -189- 201111364 solution (0.08M), to a fast department Lithium borohydride (7) equivalents were added in portions. At 3

The filtrate was concentrated in vacuo to give the title compound as white powder.

4-(1-Methyl-2-keto-1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide in trans _3_[(cyclopropyl{[] from the previous step 23_二气_5·(4hydroxybutyl)phenyl]methyl}amino)carbonyl]-4-(1-indolyl-2-keto-1,2-dihydro-4-pyridyl) -1_ _ 1,2-dimethylethyl octahydropyridinecarboxylate (1 equivalent) in a CH2C12 solution (〇〇5Μ) was added with HCl (4.0 Μ dioxane solution, 3 〇 equivalent). The resulting solution was stirred at room temperature for 3 hours. After removal of the volatiles in vacuo, the resulting residue was loaded directly onto a &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The title compound was obtained as a white foam. MS (ESI+, M+H): 508. Example 18 Transcyclopropyl_4-(1-methyl-2-keto--dihydro-4-pyridyl(methoxy)propyl-anthracene-methyl)dihydropyridinecarboxylate amine

It was made according to the procedure described in Example 1, but instead using amine 15 as the starting material. The title compound was obtained as a white foam. MS (ESI+, 143482-1 -190· 201111364 M+Na)· 510 ° NMR (CDC13) δ (ppm); 0.72-0.78 (br m, 1H), 0.82-0.96 (br m, 3H), 1.59-1.66 (m, 1H), 1.74-1.84 (br s, 2H), 1.91-1.97 (m, 2H), 2.22-2.28 (br m, 1H), 2.74-2.87 (m, 4H), 3.03 (dt, J = L〇.4, 5 2 Hz 1H) 3.14-3.21 (m, 2H), 3.36 (s, 3H), 3.37 (s, 3H), 3.42 (t, J = 7.4 Hz, 2H), 3.43-3.47 (m , 1H), 4.83 (d, J = 14 Hz, 1H), 5.02 (d, J = 14 Hz, 1H), 5.94 (d, J = 6.9 Hz, 1H), 6.34 (s, 1H), 6.78 (d , J = 6.9 Hz, 1H), 7.16 (s, 1H), 7.33-7.46 (m, 2H), 7.55 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H). Human renin IC5 缓冲 (buffer): 〇. 4nM. Human renin IC5 (blood): 1.8 nM. Example 19 trans-(2-{3,4-dioxa-5-[(cyclopropyl{[4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)) -3-hexahydropyridyl]-yl}amino) fluorenyl] phenyl} ethyl) amide decyl decanoate

It was made according to the procedure described in Example 1, but instead using amine 16 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 535. Example 20 trans-N-cyclopropylindenyl-2- keto-1,2-dihydro-4-pyridyl)-N-(8-fluorenylmethyl)-3-hexahydropyridinecarboxylate Guanamine 143482-1 • 191- 201111364

It was made according to the procedure described in Example 1, but instead using amine p as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 417 </RTI> </RTI> <RTI ID=0.0>############################################################## 2-dihydro-Otb dimethyl)-3-hexahydrop ratio

Me

It was made according to the procedure described in Example 1, but instead using amine 18 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 417. Example 22 trans-N-cyclopropyl-N-(5-isoindolylmethyl)-4-(1-indolyl-2-keto-l,2-dihydro-4-ρ ratio )-3-hexanitrogen p ratio

It was made according to the procedure described in Example 1, but instead using amine 19 as the starting material. The title compound was obtained as a white foam. MS (ESI+, 143482-1 • 192-201111364 M+H): 417. Example 23 trans-N-cyclopropyl_4·(ι_indolyl-2-keto-1,2-dihydro-4-pyridyl)_n_(5-quinolinylfluorenyl)-3-hexa Hydropyridine carboxamide

Me

It was made according to the procedure described in Example 1 but using amine 20 as a starting material instead. The title compound was obtained as a white foam. MS (ESI+, M+H): 417. Example 24 trans-N-cyclopropyl-N-(1-isoindolyl fluorenyl)-4-(1-methyl-2-keto-i,2-dihydro-4-p ratio )-3-hexahydro? ratio. Detamine

Me

It was made according to the procedure described in Example 1, but instead using amine 21 as the starting material. The title compound was obtained as a white blister. MS (ESI+, M+H): 417. Example 25 trans-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-ρ ratio. Stationary)_n_({2_[3_(decyloxy)propane ]]-4-quinolyl}hydrazino)_3_hexahydropyridine carboxamide 143482-1 -193- 201111364

It was made according to the procedure described in Example 1, but instead using amine 22 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 489. 4 NMR (CD3OD) 5 (ppm): 0.83-0.88 (m, 1H), 0.89-0.97 (m, 1H), 1.00-1.08 (m, 2H), 1.69 ( Qd, J = 12.8, 4.1 Hz, 1H), 1.82 (d, J = 13.3 Hz, 1H), 2.02 (p, J = 7.0 Hz, 2H), 2.67-2.71 (m, 1H), 2.72-2.81 (m , # 2H), 2.93 (m, 2H), 3.04 (dt, J = 12.8, 4.1 Hz, 1H), 3.18 (d, J = 13.0 Hz, 1H), 3.32-3.38 (m, 3H), 3.40-3.47 (m, 5H), 3.72 (m, 2H), 4.78 (d, J = 7.5 Hz, 1H), 5.18 (d, J = 7.5 Hz, 1H), 6.27 (d, J = 6.9 Hz, 1H), 6.42 (s, 1H), 6.99 (s, 1H), 7.39 (d, J = 6.9 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.99 (t, J = 7.3 Hz, 2H). Human renin IC50 (buffer): L4 nM. Human renin IC5 〇 (plasma): 3 〇 nM. Example 26 trans-N-cyclopropyl_4·(1_fluorenyl ketone ketone 12-dihydropyridinyl (methoxy)propyl]-8-quinolinyl}methyl)·3 _ hexahydropyridine carboxamide

Prepared according to the procedure described in Example 1, but instead using amine 23 as the starting material. The title compound was obtained as a white soak. MS (ESI+, M+H): 489. 143482-1 •194- 201111364 Example 27 trans-N-[(5-,; odoryl-2,3-diphenyl)indenyl]_N_cyclopropyl_4_(1_mercapto_2_ Keto-1,2-dihydro-4-Ppyridyl)_3_hexahydropyridine carboxamide

Prepared according to the procedure described in Example 1, but instead using N_[(5-bromo #2,3-dichlorophenyl)indolyl]cyclopropylamine (amine 5 step 2) as the amine starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 512. Example 28 trans-N-({3-carbyl-5-[3-(methoxy)propyl]phenyl)indolyl}_N-cyclopropylmethyl-2-keto-1,2- Dihydro-4-pyridyl)_3_hexahydropyridine Carboxamide Me

It was made according to the procedure described in Example 1, but instead the amine 24 starting material was used. The title compound was obtained as a pale yellow foam. MS (ESI+, M+H): 472. Example 29 trans-N-cyclopropyl-4-(1-indol-2-oneyl-i,2-dihydro-4-pyridyl)-indole-({1-[3-(methoxy) )propylHH-indol-3-yl}indenyl)_3_hexahydropyridine carboxamide 143482-1,195· 201111364

The procedure described in Example 1 was followed, but instead the amine 25 as the starting material and the zinc bromide-promoted B〇c_ removal protection as in Example 8 Step 8 were used. The title compound was obtained as a white foam m. MS (ESI+, M+H): 477. Example 30 trans-N-cyclopropyl-N-{[2,3-dioxa-5-(2-cyanoethyl)phenyl]indolyl}_4_(1_methyl-2-keto- 1,2-dihydro-4-Ppyridyl)-3-hexahydropyridine carboxamide

The procedure described in Example 1 was followed, but instead the amine 26 as the starting material and the zinc bromide (11)-promoted B〇c_ removal protection as in Example 8 Step 8. The title compound was obtained as a white blister. Ms (ESI+, M+H). 487. Human renin 1C5 〇 (buffer): 8.4 nM. Human renin sink 5 血 (blood): 17 nM. Example 31 trans-(2-{3'4-digas_5-[(cyclopropyl{[4-(1-mercapto-2-one)-i,2-dihydro_4-p ratio bite Ethyl)-3-hexahydro'»bitergic]amino}amino)methyl]phenylhydrazineethyl)urethane 143482-1 -196· 201111364

Me

Starting material. The title compound 549 was obtained as a white solid. MS (ESI+, M+H): Example 32 trans-invitrogen 5-[3-(decyloxy)propyl]phenyl}methyl)-N-cyclopropyl-4-mercapto 2 ketone 1 , 2-monohydrogen _4: thiol) winter hexahydrogen bite retinoin

Me

CC Step 1. trans-3-{[[3-Bromo-5-(3-methoxypropyl)ylidene](cyclopropyl)amino]carbonylcarbonyl·4_(1_methyl_2 _keto-_u_dihydroindolyl) small hexahydropyridinecarboxylic acid tert-butyl ester in trans-1-{[(1,1-dimethylethyl)oxy]carbonyl b 4 ( 1 mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridinecarboxylic acid (1 equivalent, Example i Step 6), Hunig's base (3 equivalents) and amine 28 (1) In an equivalent amount of DMF (〇1M) solution, 0-(7-azabenzotriazol-1-yl)-N,N,N,,N,-ra-indole (12 equivalents) of hexafluorophosphate was added in portions. The resulting reaction solution was stirred at room temperature for 48 hours. The current yellow solution was diluted with EtOAc and washed sequentially with 1% aqueous HCl solution, aqueous NaOH solution and brine. Then, the organic extract was dehydrated and dried over Na 2 S 〇 4, filtered, 143482, 1-197-201111364, and the filtrate was concentrated in vacuo to give a red orange oil. The crude product thus obtained was purified by flash chromatography (Si.sub.2, EtOAc (m/vj. ({3-Bromo-5-[3-(methoxy)propyl]phenyl}methyl)-b-cyclopropyl-4-(1-mercapto-2-one-1,2-dihydro 4-pyridyl)_3_hexahydropyridine carboxamide in trans-3-{[[3-bromo-5-(3-methoxypropyl)-yl] (cyclopropyl) from the previous step Amino]amino]-4-(1-methyl-2-keto-i,2-dihydropyridyl) tris-butylpyridine carboxylic acid tri-butyl ester (1 equivalent) (3⁄43⁄4 In the solution (0·05Μ), Lu HC1 (4.0M dioxane solution, 30 equivalents) was added, and the resulting solution was stirred at room temperature for 1.5 hours. After removing volatile substances in a vacuum, it was formed. The residue was directly loaded onto a column of a mixture of the following solvent: MS (ESI+, M+H): 516. Example 33: &lt;RTI ID=0.0&gt;&gt; -N-({5-[3-(methoxy)propane) ] -3-biphenylyl} methyl) -3-piperidine-2carboxamide

Step 1: trans-3-[(cyclopropyl{[5-(3-methoxypropyl)biphenyl-3-yl]indolyl)amino)carbonyl]-4-(1-indenyl- 2-keto-U-dihydropyridin-4-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester 143482-1 •198- 201111364 trans-3-{[[3-bromo-5 -(3-methoxypropyl)indenyl](cyclopropyl)amino]carbonyl}-4-(1-mercapto-2-one-1,2-dihydrop ratio. Base)-1-hexahydrop to bite-acid acid tert-butyl ester (1.0 equivalents 'Example 32 Step 1), phenyl dihydroxyborane (1.2 equivalents) and sodium carbonate (4_0 equivalents) in DMF (0.1M) The solution in the solution was repeatedly evacuated and counter-filled with nitrogen. Then, Pd(dppf)Cl2 (0.13 equivalent) was added, and the flask was evacuated and backfilled again with nitrogen. The reaction mixture was heated to 9 CTC for 16 hours' and at 100-110 C for 30 minutes. The reaction mixture was cooled to rt then EtOAc (EtOAc) The combined organic extracts were dried with Na2SO4, filtered and filtered. The crude product thus obtained was purified by flash chromatography (EtOAc EtOAc EtOAc (EtOAc) β Step 2: trans-Ν-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-&lt;: than bite)-Ν-({5-[ 3-(decyloxy)propyl]-3-biphenyl}indenyl)_3-hexahydro-p-butanyl hydrazide is obtained from the previous step -3-[(cyclopropyl{[5- (3-methoxypropyl)biphenyl-3-yl]fluorenyl}amino)numberyl]-4-(1-methyl-2-keto-1,2-dihydropyridyl_4_ Base) six φ hydrogen? HCl (4.0 M dioxane solution, 30 equivalents) was added to a CKCl2 solution (〇.05Μ) of a bite-1·carboxylic acid tert-butyl ester (1 equivalent). The resulting solution was stirred at room temperature for 45 minutes. After removal of the volatiles in vacuo, the resulting residue was loaded directly onto a &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The title compound was obtained as a white foam. MS (ESI+, M+H): 510 human renin IC5 (buffer): 15 nM. Human renin 1 (: 5 〇 (plasma): 81 nM. Example 34 trans-N-cyclopropyl-4-(1-methyl-2-keto-i,2-dihydro-4-pyridyl (曱143482-1 - 199- 201111364

Oxy)propyl]-5-(3-p ratio dimethyl)phenyl]methyl}-3-hexahydrop ratio. The entamamine was prepared according to the procedure described in Example 33, but in the step i, p was used as the starting material instead of the ? The title compound was obtained as a white solid. MS (ESI+, Μ+Η): 515. Example 35 trans-N-cyclopropyl-N-[(2,3-dichloro-5-{[2-(methoxy)ethyl]aminoindolylphenyl)indolyl]-4-(1) -mercapto-2-keto-1,2-dihydro-4-p ratio thiol)-3-hexahydropurine ruthenium

Step 1: trans-3-({cyclopropyl[(2,3-dichloro-5-{[2-(decyloxy)ethyl)amino}phenyl)indolyl]amino}yl -4-(1-methyl-2-keto-1,2-dihydro-4-p ratio), 1,1-didecylethyl ester of 1-hexahydrohydropyridinecarboxylate will be purified Carbonate planer (1.4 equivalents), palladium acetate (π) (〇.〇2 equivalent) and racemic-BINAP (〇.〇3 equivalent) were combined in anhydrous toluene (〇〇8M). The vessel was repeatedly evacuated&apos; and backfilled with nitrogen. Finally 'adding trans_3_{[[(5_基基_2,3-diphenyl)indolyl](cyclopropyl)amino]carbonyl-4- 4-(indolyl-2-yl) 1,1-didecylethyl ester of -1,2-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylate (丨〇 equivalent, Example 27) and 2-methoxyethylamine (1.2 equivalents) The resulting mixture was heated at 10 ° C for 20 hours. The current black suspension was allowed to cool to room temperature and diluted with Et 〇Ac and saturated 143482-1 -200-201111364 NH4C1 aqueous solution. Then, the organic layer was separated, washed further with water and brine, dried over Na 2 EtOAc, filtered, and concentrated. The crude product thus obtained was purified by column chromatography (EtOAc: EtOAc: EtOAc (EtOAc) --N-[(2,3-dichloro-5-{[2-(methoxy)ethyl]amino}phenyl)methyl]-4-(1-indol-2-yl-- 1,2-Dihydro-4-pyridyl)-3-hexahydropyridine carboxamide in trans-3-({cyclopropyl[(2,3-dichloro-5-{[]) 2-(Methoxy)ethyl]amino}phenyl)methyl]amino}yl)-4-(1-indol-2-ylyl-ι,2-dihydro-4-pyridyl In the CH2 (3⁄4 solution (0.09M) of 1-hexahydropyridinecarboxylate (1 eq.), HCl (4.0 M dioxane solution, 30 eq.) was added. The resulting solution was Stir at room temperature for 4 hours. After removing the volatiles in vacuo, the residue formed was directly loaded into a SiO2 column filled with 95:5 (v/v) CH2C12: 2.0 M NH3 in MeOH. The desired compound was obtained by dissolving in the same solvent system, but was still contaminated with impurities. Further purification by preparative HPLC-MS (C-18 reverse phase column, 15 ml/min, 95:5 (v/) v) H20: CH3CN~^ 5:95 (v/v) H20: CH3CN), ield of the title compound as a white solid. MS (ESI+, M+H): 508 » Example 36 trans-N-cyclopropyl- 4-(1-Mercapto-2-keto-1,2-dihydro-4-pyridyl)-N-[(3-{[2-(decyloxy)ethyl]aminopurine-fluorenyl) )methyl]-3-hexahydropyridine carboxamide 143482-1 -201 · 201111364

〇Me According to the suede path sequence I described in Example 1, but instead of using amine 29 as a starting material. Obtained the title of the person, the second person. The object 'is a white solid. MS (ESI+, m+h): 489. Renin IC5 〇 (buffer): $ U 53 ηΜ. Human renin IC50 (plasma): 2.4

nM trans-N-{[6-(2-cyanoethyl-2-indolyl-1,2-diaza-4-port ratio 37-group)-8-4 phenyl]methyl}_N_ ring Propyl ice (1•曱. 定)-3-hexahydropyridine carboxamide

The procedure described in Example 1 was followed, but instead the amine 30 as the starting material and the zinc (II) bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 470. Example 38 trans-N-cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)-N-({3-[2-(methoxy) Ethyl] hydrazino} decyl)-3-hexahydropyridine carboxamide 143482-1 • 202- 201111364

It was made according to the procedure described in Example 1, but instead using amine 31 as the starting material. The title compound was obtained as a white solid. MS (ESI+, M+H): 474 〇 Example 39 φ trans-N-({3-[2-(ethylamino)ethyl]]-naphthalenyl}methyl)-N-cyclopropyl-4 -(1-Methyl-2-yl-1,2-dihydro-4-p ratio octyl)-3-hexahydrop ratio

It was made according to the procedure described in Example 1, but instead using amine 32 as the starting material. The title compound was obtained as a white solid. MS (ESI+, M+H): 501. Example 40 trans-N-[(2-bromophenyl)indolyl]-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl) )-3-hexahydropyrrole. Carboxylamidine

Prepared according to the procedure described in Example 1, but instead using amine 33 as the starting material for 143482-1 • 203 201111364. The title compound was obtained as a white solid. MS (ESI+, M+H): 444 〇 Example 41 trans <N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-indole- ({1-[2-(decyloxy)ethylHH-indol-3-yl}indolyl)-3-hexahydropyridinecarboxamide

The procedure described in Example 1 was followed, but instead the amine 34 as the starting material and the zinc (II) bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+Na): 485. Example 42 trans-N-cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)-indole-{[1-(2,2,2- Trifluoroethyl)·1Η_丨嗓丨嗓-3_yl]fluorenyl}_3-hexahydropyridylcarboxamide

The procedure described in Example 1 was followed, but instead the amine 35 as the starting material and the zinc bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 487. Example 43 143482-1 -204- 201111364 trans-N-cyclopropyl_4_(ι_methyl-2-mercapto-1,2-dimur-4-p ratio. Stationary (4,4,4- Trifluorobutyl)indole_3_yl;j曱kib 3-hexahydropyridinecarboxamide

The procedure described in Example 1 was followed, but instead the amine 36 as the starting material and the zinc bromide-promoted BOC_ removal protection as in Example 8 Step 8 were used. The title compound was obtained as a white soak. MS (ESI+, M+H): 515. Example 44 trans-N-[(l-butyl-1H-indol-3-yl)indolyl]-N-cyclopropyl-4-(1-indolyl-2-keto-1,2- Dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

Me

The procedure described in Example 1 was followed, but instead the amine 37 as the starting material and the brominated (C)-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 461. Example 45 trans-N-cyclopropyl-indole-({1-[3-(ethoxy)propylHH-(9)indol-3-yl}indenyl)-4-(1-indolyl-2-) Mercapto-1,2-digas-4-p ratio bite base)-3-hexanitrogen p than bite-resistant amine 143482-1 -205- 201111364

Me

The amine 38 as the starting material and the zinc bromide (π)-promoted boc-removal protection as in the step 8 of Example 14 were prepared as follows according to the procedure described in Example 1. The title compound was obtained as a white foam. MS (ESI+, M+H): 491. Example 46 trans-N-cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)-indole-({1-[3,3,3- 2-dis-2-(difluoro(fluorenyl)propyl]indol-3-yl}mercapto)-3-hexahydrop

The procedure described in Example 1 was followed, but instead the amine 39 as the starting material and the zinc (II) bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 569. Example 47 trans-Ν-({1-[3-(ethylamino)propyl)HH-indol-3-yl}methyl)-N-cyclopropyl-4-(1-indolyl-2 -keto-1,2-dihydro-4-p ratio β-fixed)-3-hexahydrogen I: ° 醯 醯 醯 143482-1 -206- 201111364

According to the procedure described in Example 1, 'but the amine 40 as the starting material and the zinc bromide (π)-promoted BOC as in the step 8 of Example 14 were used instead.

Remove protection. The title compound was obtained as a white foam. MS (ESI+, Μ+Ϊ1): 504. Example 48 trans-N-cyclopropyl-4-(ι-methyl_2-ketodihydropyridinyl)N ({1[3_(propyl decylamino)propyl)·1Η-啕哚-3-yl}methyl)hexahydropyridine carboxamide

Me

The procedure described in Example 1 was followed, but instead the amine 41 as the starting material and the bromide (11)-promoted b〇c_ removal protection as in step 8 of Example 14 were used. The title compound was obtained as a white foam. MS (esi+, M+H): 518. Example 49 trans-NAHM acetamino)ethyl]_1H_+poly}methyl)-N-cyclopropyl (1-methyl-2-keto-1,2-dihydropyridinyl) Hexahydropyridine carboxamide 143482-1 •207· 201111364

The procedure described in Example 1 was followed, but instead the amine 42 as the starting material and the zinc bromide-promoted B〇c_ removed in step 8 of Example 14 were used. The title compound was obtained as a white foam. MS (ESI+ M+H): 490. Example 50 trans-N-cyclopropyl-4-(1-indolyl-2-yl-i,2-dihydro_4-P ratio. Stationary)-Ν-({ΐ·[2~ (C Mercaptoamino)ethyl]-1H-indol-3-yl}methyl)_3-hexahydropyridinecarboxylate

The amine was prepared according to the procedure described in Example 1, but instead using amine 43 as the starting material and zinc (II)-promoted boc-removal as in Example 8. The title compound was obtained as a white foam. Ms (ESI+, M+H): 504 〇 Example 51 trans-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-N- { [1-(2-Prop-1-yl)-1Η-&lt;Ί-3-yl]methyl}·3_hexahydro? Than the bite of ruthenium 143482-1 -208- 201111364

The procedure described in Example 1 was followed, but instead the amine 44 as the starting material and the zinc (II) bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam ( MS (ESI+, M+H): 445. Example 52 trans-N-cyclopropyl_4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-indole-{[1-(phenylmethyl 1)- 1H-indol-3-yl]methyl}-3-hexahydropyridine carboxamide

Me

It was made according to the procedure described in Example 1, but instead using the amine 45 as the starting material and the brominated (II)-promoted BOC- removing δ in the step 8 of Example 14. The title compound was obtained as a white soak. Ms (esi+, M+H): 495. Example 53 trans-N-cyclopropyl-4-(1-methyl-2-keto), 2-dihydro-4-pyridyl)_Ν-{[ι_(2_pyridylmethyl)- 1Η-Ί丨哚-3-yl]methyl b 3_hexahydropyridine carboxamide 143482-1 -209- 201111364

The procedure described in Example 1 was followed, but instead the amine 46 as the starting material and the zinc(II) bromide-promoted b〇c_ removal protection as in Example 8 Step 8. The title compound was obtained as a white foam (MS+, M+H): 496. Example 54 trans-N-cyclopropyl-4-(1-indol-2-one-1,2-dihydro-4-pyridyl)-N-{bitenylmethyl)-1Η-吲Indole-3-yl]methyl}-3-hexahydropyridine carboxamide

Me

The procedure described in Example 1 was followed, but instead the amine 47 as the starting material and the zinc (II)-promoted boc-removal protection as in Example 8 Step 8. The title compound was obtained as a white blister. MS (ESI+, M+H): 496. Example 55 trans-N-cyclopropyl-4-(1-indolyl-2-keto-1,2-dihydro-4-pyridyl)-N-{ [1-(4-acridinyl) Base)-1Η-吲哚-3-yl]methyl b 3_hexahydropyridine carboxamide 143482-1 -210- 201111364

The procedure described in Example 1 was followed, but instead the amine 48 as the starting material and the B〇c_ removal protection as promoted by zinc bromide (9) in Step 8 of Example 14 were used. The title compound was obtained as a white foam. Ms (Esi+, M+H): 496.

Example 56 trans-N-cyclopropyl-indole-({Η(4.fluorophenyl)methyl]_m吲哚_3yl}methyl)-4-(1-methyl-2-keto- l,2-Dihydro-4-pyridyl)_3_hexahydropyridine carboxamide

Me

The procedure described in Example 1 was followed, but instead the amine 49 as the starting material and the zinc (II)-promoted BOC_ removal protection as in the step 8 of Example 14 were used. The title compound was obtained as a white blister. MS (ESI+, M+H): 513. Example 57 trans-Ν-({1-[(4-Phenylphenyl)indolyl]-1H-indoleyl}methyl)-N-cyclopropyl-4-(1-methyl-2- Ketopropyl-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide 143482-1 •211- 201111364

Me

Cl was prepared according to the procedure described in Example 1, but instead using amine 50 as the starting material and B〇c_ removal protection as in zinc bromide (π)_promoted in step 8 of Example 14. The title compound was obtained as a white foam. MS (ESI+, M+H): 529. Example 58 trans-N-cyclopropyl-indole-({1-[(3-fluorophenyl)methylHH-indol-3-yl}indolyl)-4-(1-indolyl-2- The ratio of keto-1,2-dihydro-4-1» to α-based)-3-hexahydrop. Detached amine

Me

The procedure described in Example 1 was followed, but instead the amine 51 as the starting material and the zinc bromide (11)-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white bead material &lt;EMI&gt; MS (ESI+, M+H): 513. Example 59 trans-Ν-({1-[(3-chlorophenyl)indolyl]-1Η-indol-3-yl}indenyl)-N-cyclopropyl-4-(1-indenyl) -2-keto-1,2-dihydro_4_acridinyl)_3_hexahydronized carboxylic amine 143482-1 •212- 201111364

The amine 52 as the starting material and the zinc (II) bromide-promoted boc-removal protection as in the step 8 of Example 14 were prepared as follows according to the procedure described in Example 1. The title compound was obtained as a white foam. MS (ESI+, M+H): 529. Example 60 trans-Ν-({1-[(3-cyanophenyl)methyl]-1H-indol-3-yl}methyl)-N-cyclopropyl-4-(1-indenyl) -2-keto-1,2-dihydro-4-p ratio β-fixed)-3-hexafluoropyrene

The procedure described in Example 1 was followed, but instead the amine 53 as the starting material and the zinc bromide-promoted BOC_ removal protection as in Example 8 Step 8 were used. The title compound was obtained as a white foam. MS (ESI+, M+H): 520. Example 61 trans-N-cyclopropyl-4-(ι_indolyl-2-keto-i,2dihydro-4-pyridyl)N ({1[(3-nonylphenyl)indolyl]_1H -吲哚-3-yl}methyl)-3-hexahydropyridine carboxamide 143482-1 •213· 201111364

The procedure described in Example 1 was followed, but instead the amine 54 as the starting material and the zinc bromide (π)-promoted BOC- removal protection as in Example μstep 8 were used. The title compound was obtained as a white foam. MS (ESI+, M+H): 509. Example 62 trans-N-platinyl-N-({5-fluoro-l-[3-(methoxy)propyl]_1Η-啕哚-yl}}yl)-4-(1-A Keto-2-keto-oxime, 2-dihydro-4-pyridyl)_3_hexahydropyridinium carboxamide

Me

Cr: r

OMe was prepared according to the procedure described in Example 1, but instead using amine 55 as the starting material and B〇c_ removal protection as promoted by zinc bromide (11) in Step 8 of Example 14. The title compound was obtained as a white foam. Ms(esi+ m+h): 495 » Example 63 trans-N-{[6-Molyl-H-phenyl-f-based HH_decadetyl]methyl}N-cyclopropyl-4-(1-A Benz-2-keto-1,2-dihydropyridinyl)_3 hexahydropyridine carboxamide 143482-1 •214 ' 201111364

It was prepared according to the procedure described in Example 1, but instead (4) the amine 56 as the starting material and the zinc bromide as in step 8 of Example 14, the age-removal protection. The title compound was obtained as a white foam. (10) Qing+, M+H): 573.

Example 64 trans-N-cyclopropyl-indole-{[1·[(3_-phenylphenyl)indenyl]6(methoxy)_jupo_3_yl]methylindole-α-methyl Phase-based 仏 two gas 'bite base' winter hexahydro hydrazine

The procedure described in Example 1 was followed, but instead the amine 57 as the starting material and the zinc bromide (9) in step 8 of Example 14 were used for the removal protection. The title compound was obtained as a white blister. MS (ESI+, M+H) · 543 〇 Example 65 trans-N•cyclopropyl o-methyl-2-mercapto-U-di-amp; such as bite base) _N. methyl small (phenyl group) Base)-L-polyyl]methyl}_3_hexahydropyridine carboxamide 143482-1 -215· 201111364

The procedure described in Example 1 was followed, but instead the amine 58 as the starting material and the zinc (II) bromide-promoted boc-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 509. Example 66 trans-N-{[4-cyano-1-(phenylmethyl)-1Η-indol-3-yl]indolyl}-N-cyclopropyl-4-(1-indolyl- 2-retinyl-1,2-diaza-4-p ratio thiol)-3-hexanitro-p ratio

The procedure described in Example 1 was followed, but instead the amine 59 as the starting material and the zinc (II) bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 520. Example 67 trans-N-cyclopropyl-N-{[4-fluoro-1-(phenylmethyl)_ih-W哚-3-yl]nonylmethyl-2-keto-U-di Hydrogen-4-pyridyl)-3-hexahydropyridine carboxamide 143482-1 -216- 201111364

The procedure described in Example 1 was followed, but instead the amine 60 as the starting material and the zinc bromide-promoted BOC-removal protection as in Example 8 Step 8 were used. The title compound was obtained as a white foam. MS (ESI+, M+H): 513. Example 68 trans-N-cyclopropyl-N-({4-fluoro-l-[(3-fluorophenyl)indolyl HH-indol-3-yl]indenyl}-4-(1- Mercapto-2-yl-1,2-dihydro-4-? ratio. Alkyl)-3-hexahydrop ratio

The procedure described in Example 1 was followed, but instead the amine 61 as the starting material and the brominated (π)-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H). 531. Human renin 1C5 〇 (buffer): 0.06 nM. Human renin IC5 血 (blood sputum): 0.6 nM. Example 69 trans-N-%, propylfluoromethoxyoxy) propyl hydrazide} fluorenyl-d-methyl-2-keto-l,2-dihydro-4-pyridyl) _3_hexahydropyridine carboxamide 143482-1 -217· 201111364

The procedure described in Example 1 was followed, but instead the amine 62 as the starting material and the zinc bromide (π)-promoted B〇C_ removal protection as in Example 8 Step 8 were used. The title compound was obtained as a white blister. </ RTI> <RTI ID (m, 2H), 2.52 (m, 1H), 2.60-2.71 (m, 2H), 2.88 (td, J = 11.6, 3.9 Hz, 1H), 3.05 (br d, J = 7.0 Hz, 1H), 3.09 -3.19 (m, 3H), 3.23 (s, 3H), 3.27 (s, 3H), 3.43-3.58 (m, 1H), 4.00-4.21 (m, 2H), 4.41 (d, J = 14.8 Hz, 1H ), 4.7 (m, 2H), 6.11-6.22 (m, 1H), 6.30 (d, J = 1.8 Hz, 1H), 6.54-6.67 (m, 1H), 6.74 (s, 1H), 6.93-7.04 ( m, 1H), 7.10 (d, J = 4.0 Hz, 1H)' 7·16 (d, J = 3.6 Hz, 1H). Human renin IC50 (buffer): 0.3 nM ° human renin I (: 5 〇 (Plasma): 〇 9 times. Example 70 trans-Ν-({4-Gayl-ΐ_[3-(oximeoxy)propyl pm, 哚_3_yl}methylcyclopropyl-4- (1-indenyl-2-keto+2-dihydro-4-pyridylhexahydropyridine carboxamide

Prepared according to the procedure described in Example 1, but instead using the amine 63 as the starting material and the zinc(II) bromide as promoted in step 8 of Example 14 B〇C-1434824 •218·201111364 Bao Zun. The title compound was obtained as a white foam. ]Vis (ESI+, M+H): 511. Example 71 trans-N-{[4-Alkyl small (phenylmethyl)_1H-indole-3-yl]indenyl}N-cyclopropyl-4-(1-indol-2-oneyl) 2-dihydropyridinyl)_3_hexahydropyridine carboxamide

The procedure described in Example 1 was followed, but instead the amine 64 as the starting material and the zinc bromide as promoted in step 8 of Example 14 were used to remove the oxime. The title compound was obtained as a white foam. MS (esi+, M+H): 529. Example 72 trans-N-{[4-/ odoryl small (stupylmethyl)_m啕哚_3yl]methyl b-cyclopropyl-4-(1-methyl-2-indolyl-1 ,2-di| _4·pyridyl)_3_hexahydropyridine carboxamide

Me

It was prepared according to the procedure described in Example 1, but instead using the amine 65 as the starting material and the zinc bromide as in Example 14 step 8 to promote the removal of the hydrazine. The title compound was obtained as a color bubble; (10) Qing+, M+H): 575. Example 73 143482-1 • 219- 201111364

trans_N_({4-bromo-H(3-fluorophenyl)methylHH-indol-3-yl}methyl)-N-cyclopropyl-4-(1-methyl-1-keto -1,2·dihydro-4-p-pyridyl)-3_hexanitro-p-pyridylcarboxamide was prepared according to the procedure described in Example 1 but using amine 66 as a starting material instead and as The zinc bromide (Π)-promoted BOC-removal protection in step 8 of Example 14. The title compound was obtained as a white foam. MS (ESI+, M+H): 591.3. 1H NMR (DMSO-d6): 6 (ppm): 0.60-0.66 (m, 1H), 0.89-0.94 (m, 3H), 1.56 (dd, J = 13.3, 10.6 Hz, 1H), 1.67 (d, J = 12.6 Hz, 1H), 2.58 (dt, J = 12.4, 2.2 Hz, 1H), 2.71 (s, 3H), 2.83-2.94 (m, 2H), 3.04 (br d, J = 6.1 Hz, 1H), 3.23 (s, 3H), 3.3 (dd, J = 6.7, 4.0 Hz, 1H), 3.04 (d, J = 12.3 Hz, 1H), 4.87 (q, J = l 〇.l Hz, 2H), 5.35 (d, J = 2.6 Hz, 2H), 6.16-6.23 (m, 1H), 6.79 (s, 1H), 6.88 (d, J = 8.3 Hz, 2H), 6.99 ( t, J = 7.9

Hz, 1H), 7.05-7.12 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.29-7.40 (m, 2H), 7.54 (d, J = 6.9 Hz, lH). Human renin IC5 〇 (buffer): &lt; 〇〇 6 nM. Human renin IC50 (plasma): 〇.5nM. Trans N ({/ odorylmethoxy) propyl] ♦ ♦ each group) methyl) _n _ ring C Instance 74

143482-1 201111364

The procedure described in Example 1 was followed, but instead the amine 67 as the starting material and the zinc bromide-promoted BOC-removal protection as in Example 8 Step 8 were used. The title compound was obtained as a white foam. MS (ESI+, M+H): 557. Example 75 trans-N-cyclopropyl 1[(4-fluoroyl-1Η-indol-3-yl)indolyl]-4-(1-indol-2-ylyl-1,2-dihydro -4-pyridyl)_3_hexahydropyridine carboxamide

Me

Step 1: trans-3-({cyclopropyl[(4-fluoroindol-3-yl)indolyl]aminobucarbonyl)-4-(1-methyl-2-keto-1, 1,1-Dimethylethyl 2-dihydro-4-pyridyl)-1-hexahydropyridylcarboxylate in trans-1-{[(U-didecylethyl)oxy]carbonyl} 4-(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridinecarboxylic acid (1 equivalent, Example 1 Step 6), Hunig's base (3 equivalents) And a solution of amine 68 (1 equivalent) in DMF (0.1 M), adding hexafluorophosphate 0-(7-azabenzotriazol-1-yl)-N,N,N,,N'-four曱 锞 (1.2 equivalents). The resulting reaction solution was stirred at room temperature for 48 hours. The current yellow solution was diluted with EtOAc and washed successively with 10% aqueous HCI, water and brine. Then, the organic extract was dehydrated and dried over Na 2 SO 4 , filtered, and then filtered, and the filtrate was concentrated in vacuo to give a black oil. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut elut Step 2: trans-N-cyclopropyl-N-[(4-fluoro-1H-indol-3-yl)indolyl]-4-(1-indolyl-2-yl-1,2 -Dihydro-4-1» than °) -3-hexafluorop ratio. Derivatization of trans-acetin from the previous step of trans-3-({cyclopropyl[(4-fluoro-1H-indol-3-yl)indolyl]amino}carbonyl)-4-(1- In a solution of 1,2-didecylethyl ester of methyl-2-keto-1,2-di-ar- -4-pyridyl)-1-hexafluoropyridinecarboxylate (1 equivalent) in CH2C12 (0.05 M) Zinc bromide (11) (10 equivalents) was added. The resulting suspension was sonicated for 15 minutes and allowed to mix for 13 hours at room temperature. The reaction was quenched by the addition of EtOAc and aqueous 1N NaOH. The aqueous phase was separated and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried <RTI ID=0.0># </ RTI> <RTI ID=0.0> The crude product thus obtained was purified by flash chromatography (yield: EtOAc, EtOAc: EtOAc: EtOAc: Ms (ESI+,: 423.1H NMR (CD3 OD) (5 (ppm): 〇·79 (m, 1H), 0.87-0.99 (m, 2H), 0.99-1.11 (m, 1H), 1.65-1.75 (m, 1H), 1.78 (m, 1H), 2.53 (m, 1H), 2.72-2.82 (m, 2H), 2.89-3.00 (m, 1H), 3.14-3.26 (m, 2H), 3.34 (s , 3H), 3.51-3.67 (m, 1H), 4.43 (d, J = 14.7 Hz, 1H), 4.96 (d, J = 14.7 Hz, 1H), 6.18 (m, 1H), 6.39 (s, 1H) , 6.66 (m, 1H), 6.88 (s, 1H), 6.99-7.06 (m, 1H), 7.14-7.18 (m, 2H). Human renin IC5 缓冲 (buffer): 12.7 nM. Human renin ic5 〇 (plasma): 8.4 nM 0 Example 76 trans-N-cyclopropyl-N-{[4-fluoro-small (3_pyridinyl fluorenyl)_m啕哚_3yl] A 143482-1 • 222- 201111364 Amidino}-4_(l-methyl-2-copperyl-l,2-dihydro-4-pyridyl)_3_hexahydropyridine

Step 1: trans-3-[(cyclopropyl{[4-fluoroylindole(3)pyridinyl)-ih吲哚_3yl]indenyl}amino)carbonyl]-4-(1-indenyl- 2-keto-___dihydropyridinyl H-hexahydropyridinecarboxylic acid 1,1-dimethylethyl ester

At 0 C, in trans-3-({cyclopropyl[(4-fluoroyl-1Η_吲哚_3_yl)indolyl]amino}carbonyl)-4-(1-methyl-2 -Ketyl-1,2-dihydropyridinyl)+hexahydropyridinecarboxylic acid U-dimethylethyl ester (1 equivalent, in Example 75 step DMF (〇1Μ) solution, sequentially added KHMDS (in toluene) 15% w/v solution, L1 equivalent) and gasified 3-methylpyridine (1.3 equivalents). Then, the formed solution was slowly warmed to room temperature for 16 hours. The mixture was cooled again. The reaction was then quenched with EtOAc EtOAc (EtOAc)EtOAc. Na2 s〇4 is dehydrated and dried, and the filtrate is concentrated in vacuo. The crude product thus obtained is purified by flash chromatography (Si02 'CH2C12-&gt;90:10 (v/v) CH2C12: in MeOH 2.0M NH3), the title compound was obtained as white foam. Step 2: trans-N-cyclopropyl good {[4-fluoro-small (3-pyridinyl)-H-indol-3-yl]曱基}-4-(1-methyl_2.keto-yl) Dihydropyridinyl) winter hexahydropyridine carboxamide in trans-_3-[(cyclopropyl{[4-fluoro-1-(3-pyridyl) 143482-1 •223- obtained from the previous step 201111364 base)-1Η-indol-3-yl]methyl}amino)carbonyl; methyl-2-keto- 12-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylic acid dimercapto Ethyl bromide (0.05 M) was added with bromination (II) (10 equivalents). The resulting suspension was sonicated for 15 minutes and stirred at room temperature for 13 hours. The reaction was quenched by the addition of Et.sub. The aqueous phase was separated and extracted with EtOAc. The combined organic extracts were further washed with water and brine &lt;&quot;&quot;&quot;&quot; The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc (EtOAc) MS (ESI+, Μ+Η): 514. Example 77

trans-N-cyclopropyl-N-{[4-fluoro-1-(4-pyridylfluorenyl)_ih-indol-3-yl]indenyl}-4-(1-indolyl-2 -Kenyl-1,2-dihydro-4-p-pyridyl)-3-hexahydrop is prepared according to the procedure described in Example 76, but in step 1, instead of using gas 4-Mercaptopyridine is used as an alkylation reagent. The title compound was obtained as a white foam. MS (ESI+, M+H): 514. Human renin is 5 〇 (buffer): 0, 2 nM. Human renin IC50 (blood): 〇.5 nM. Example 78 trans-N-({3-Ethyl-5-[3-(indolyl)propyl]phenyl}indolyl)-N-cyclopropyl-4-(1-indolyl-2-one Base-1,2-dihydro-4-pyridyl)-3-hexahydropyridinium 143482-1 -224- 201111364

It was made according to the procedure described in Example 1, but instead using amine 69 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 480. Example 79

Trans-Ν·({1,3-bis[3-(methoxy)propyl]_2,4diketotetrahydro-5-pyrimidinyl}indenyl)-N-cyclopropyl (1_ Methyl ketone _u·dihydropyridinyl)_3•hexahydropyridine carboxamide

It was made according to the procedure described in Example 1 but using an amine as a starting material instead. The title compound was obtained as a white foam. Ms 邸 1+, M+H). 544 human renin 1 (: 5 〇 (buffer) π - % human renin. (plasma): 75 nM. Example 80 trans-N-% propyl·ν_ ({2,3·Dimethyl_5 [3_(methoxy)propyl]phenyl)methyl)_ 4 (1 methyl 2 keto-n-hydro 'c-yl)·3_hexahydroindole Bite a few amines 143482-1 -225- 201111364 starting materials according to the examples. M+H): 466.

The procedure described in 1 was made 'but instead of using amine 71 as the known compound, it was a white foam. MS (ESI+, Example 81 trans-N-[(2-carbyl_5·{[2_(methoxy)ethyl)oxy}phenyl)indolyl]*cyclopropylidene (1-indolyl) -2-keto-I,2-dihydro-4-pyridyl)3 hexafluoropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 72 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 474. Example 82 trans-N-cyclopropyl-4-(1-indolyl-2-keto-1&gt;dihydrotertylpyridyl)-N-(2-hydrazinyl)-3-hexahydropyridinecarboxylate Guanamine

It was made according to the procedure described in Example 1, but instead using amine 73 as the starting material of 143482-1 -226-201111364. The title compound was obtained as a white foam. Ms (ESI+, M+H): 416. Example 83 trans-N-cyclopropyl-4-(1-methyl-2-oxoyl_u diargonyl) N_({3_[(trifluoromethyl)thio]phenyl}anthracene Hexahydropyridine carboxamide

Me

It was made according to the procedure described in Example 1, but instead using amine 74 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 466. Example 84 trans-N-cyclopropyl-4-(1-methyl-2-keto)-dihydro-4-pyridyl)_ν_{[5·[3·(decyloxy)propyl]- 2-(methylthio)phenyl]methyl b 3_hexahydropyridylamine

Me

OMe was prepared according to the procedure described in Example 1, but instead using amine % as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 484 〇 human renin buffer): 47 nM. Human renin 1 (: 5 〇 (plasma): 12.3 nM. Example 85 trans-N-({3-exyl-4-methyl-5-[3-(methoxy)propyl)phenyl} Methyl)_N_cyclopropene 143482-1 -227- 201111364 _4-(l-methyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 76 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 530.1H NMR (CDC13) 6 (ppm): 0.65-0.72 (m, 1H), 0.76-0.82 (m, 1H), 0.89-1.00 (m, 2H), 1.66- 1.90 (m, 5H), 2.33 (s, 3H), 2.41-2.47 (s, φ 1H), 2.69 (t, 2H), 2.78-2.91 (m, 2H), 2.98-3.05 (m, 1H), 3.21 -3.27 (m, 2H), 3.35-3.41 (m, 5H), 3.45-3.54 (m, 4H), 4.20 (d, J = 14.5 Hz, 1H), 4.54 (d, j = 14.5 Hz, 1H), 6.05-6.09 (m, 1H), 6.41 (s, 1H), 6.88 (s, 1H), 7.08 (s, 1H), 7.12 (d'J = 6.9Hz, lH). Human renin lC5 〇 (buffer): 〇 9 nM. Human renin IC5 〇 (blood aggregation): 1.3 nM. trans-N-({3-Molyl-4-methyl-5_[3_(decyloxy)propyl]phenyl}indenyl) n-cyclopropyl

4-(1-indole-keto-U-diazepine-4_, specific B) hexamethylene hydrazone hydrochloride salt 1 in the above compound (1 equivalent) in acetonitrile solution (0.07 M) , added dropwise] (4M dioxane solution, 1 〇 equivalent). The mixture was allowed to stand at room temperature for 4 Torr, during which time the internal crystal system precipitated from the solution. Then, it is diluted with butyl bis = hydrazine until no product is advanced - step (4) is identifiable. Next, the resulting suspension was gently warmed and sonicated, = allowed to mature at room temperature for 18 hours. The title compound thus obtained was filtered to form a white crystalline solid. ,,&&&;143482-1 •228· 201111364 Alternative Procedures:

DMF, gasification grasshopper ch2ci2

(3S,4S)-1'-mercapto-2,-keto-3,4,5,6,Γ,2ΐ-hexahydro-2Η-[4,4·]bipyridyl-1,3- The 1-carboxylic acid di-butyrate (carboxylic acid 1; 1.0 equivalent) was dissolved in dioxane (1 part by volume). DMF (0.2 eq.) was charged and the solution was cooled to _15 °C. Gasified grasshopper (0.95 equivalent) was added over 2.5 hours. N-[3-bromo-5-(3-methoxypropyl)-4-methylbenzyl]cyclopropylamine methane acid salt (amine 76; 〇9 〇 equivalent) was dissolved in two Φ gas smoldering ( In 2 parts by volume, then i-Pr2NEt (3.3 equivalents) was added at ~-15 °C for 1 hour. The reaction was quenched with water (1 part by volume), and the liquid layer was cleaved, and the organic layer was washed with NaHC? The liquid layer was cut and the organic layer was washed with a HCl solution to concentrate the organic layer to ~ 5.7 parts. Add 2-propanol (0.57 parts by volume) followed by concentrated HC1 (6. 〇 equivalent). The reaction mixture was aged at 351 for 75 minutes and then water (57 parts by volume) was added. The liquid layer was cut and the dichlorocarbyl (11.4 parts by volume) was added to the aqueous layer. Sodium hydroxide (67 equivalents) was added and the liquid layer was cut. The organic layer was washed with water (5.7 parts by volume) and concentrated to ~5 parts by volume. 2-propanol (8 parts by volume) was added, and the residual two gas chamber was removed by steaming 143482-1 201111364. Next, concentrated HCl (0.2 equivalents, 37%) in IPA (0.11 parts by volume) was added and the batch was cooked for 3 minutes. An additional concentrated HC1 (0.9 eq, 37%) in IPA (0.5 parts by volume) was added over 1 hour. MTBE (5.4 parts by volume) was added and the batch was cooked for 1 hour. The resulting slurry was filtered, and the solid was washed with MTBE to give (3S,4R)-N-({3-bromopiperidin-5-[3-(decyloxy)propyl]phenyl} Methyl)-N-cyclopropyl-4-(1-methyl-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide hydrochloride, white solid. 1 η NMR (500 MHz, dmso-d6) δ 9.45 (br s, 2H), 7.57 (d, J = 6.9 Hz, 1H), 6.96 (d, J = 0.9

Hz, 1H), 6.79 (d, J = 0.9 Hz, 1H), 6.13 (d, J = 1.7 Hz, 1H), 6.04 (dd, J = 6.9, 1.7, 1H), 4.58 (d, J = 14.9 Hz) , 1H), 4.12 (td, J = 11.5, 3,5, 1H), 4.05 (d, J = 14.9 Hz, 1H), 3.48 (dd, J = 12.2, 3.5 Hz, 1H), 3.34 (s, 1H ), 3.32 (m, 1H), 3.30 (t, J = 6.2 Hz, 1H), 3.24 (s, 1H), 3.07-2.97 (om, 2H), 2.85 (m, 1H), 2.57 (m, 1H) , 2.04 (qd, J = 13.0, 3.8 Hz, 1H), 1.82 (m, 1H), 1.65 (m, 1H), 0_98 (m, 1H), 0.91-0.82 (om, 2H), 0.61 (m, 1H) ). HRMS (ES, M+H) calcd. 530.2018. Found 530.2008. X-ray powder diffraction: X-ray powder diffraction studies are widely used to characterize molecular structure, crystallinity, and polymorphism. The χ-ray powder diffraction pattern was generated on a Philips analysis x, Pert PR0 _ ray diffraction system with a PW3040/60 console. PW3373/00 ceramic Cu LEF X-ray tube κ-α radiation system is used as a source. Figure 5 is a diagram showing the crystalline form I, (3S, 4R)_N_({3 bromo-4 methyl_5 [3_(methoxy)propyl]phenyl}methyl)-N-cyclopropyl·4- A characteristic χ-ray diffraction pattern of (ι·decyl keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide hydrochloride. Form I shows the characteristic inverse corresponding to the d•pitch listed in Table 9 below. 143482-1 230· 201111364 Shooting · Table 9 d-spacing [person] Height [cts] 10.59 945.75 7.04 1736.99 4.24 1588.22 4.22 1312.59 3.88 3855.93 3.58 1166.01 3.51 1569.66 3.31 860.32 3.08 1148.31 Solid state NMR:

In addition to the above X-ray powder diffraction pattern, crystalline Form I was further characterized by its solid carbon-13 nuclear magnetic resonance (NMR) spectroscopy. The carbon-13 spectrum was recorded using a Brnker 4 mm HX CPMAS probe. The carbon-13 spectroscopy uses proton/carbon-13 variable amplitude orthogonal polarization (VACP) to collect with a 5 millisecond contact time and a 10 second pulse delay, while the sample is subjected to magic angle rotation (MAS) at 10 kHz. . Apply a 10 Hz line widening to the carbon-13 spectrum before the Fourier transform. Chemical shifts were reported on the TMS scale using carbonyl carbon (176.03 ppm) of glycine as a secondary reference. Figure 2 illustrates the solid carbon-13 CPMAS NMR spectrum for crystalline Form I. Form I shows the characteristic absorption peaks corresponding to the chemical shifts listed in Table 10 below: 143482-1 -231 - 201111364 Table ί Absorption peak relative (ppm) Intensity 120.1 100 31.2 76 17.1 73 43.5 71 41.6 71 .29.4 68 58.5 67 71.4 66 28.7 64 42.5 64 138.3 60 143.6 58

Differential Scanning Card Method: The DSC data is obtained using the TA Instruments DSC 2910 or equivalent. Retain the sample between 2 and 6 mg in a shallow pan' and cap it. The tray is then distorted and placed in the position of the sample in the card component. Place the empty tray in the reference position. The card meter element is turned off and the flow of nitrogen is passed through this element. The heating procedure was set to heat the sample to a temperature of about 250 C at a heating rate of 1 〇〇c / minute. Start the heating process. When the operation is complete, the data is analyzed using the DSC analysis program included in the system software. The thermal event is integrated between a baseline temperature point above and below the temperature range that covers the discovery of the thermal event. The reported data are the unfolding temperature, the peak temperature, and the differential scanning calorimetry curve for crystalline Form I. Thermogravimetric Analysis·· 143482-1 •232 · 201111364 TG data was acquired using Perkin Elmer TGA7. The experiment was carried out under nitrogen flow and at a heating rate of ιοί /min to a maximum temperature of about 250 °C. After automatically measuring the balance weight, 5 to 2 mg of the sample was added to the platinum tray, the furnace was raised, and the heating procedure was started. The weight/temperature data is automatically collected by the instrument. The analysis of the results is performed by selecting the ΔΥ function in the instrument soft body and selecting the temperature at which the weight loss is to be calculated. The weight loss is reported until the decomposition/evaporation begins. Figure 3 is a graph showing the thermogravimetric analysis curve for crystalline Form I. Purity Purity can be upgraded via slurrying in isopropanol when needed. Substance MW Equivalent Molar HC1 Salt 566.96 1.0 16.74 9.491 kg 178 kg IPA (d = 0.786)

The HCl salt (9491 kg) was slurried in isopropanol (149 kg, 190 liters). The slurry was allowed to warm to 68 ° C for 2 hours, then cooled to 20 ° C and washed with isopropanol (38 L, 29 kg) over 1 hour &apos; The solid was dried under vacuum at <RTI ID=0.0>(4 </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Sulfhydryl]_N_cyclopropyl-4-(1-indolyl-2-keto-1,2-dihydro-4-indole ratio)-3-hexahydroindole ratio η 醯 醯 143 143482- 1 -233 - 201111364

It was made according to the procedure described in Example 1, but instead using amine 77 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 510 〇 Example 87 trans-N-cyclopropyl·Ν_[3_(3_methoxypropyl)_5_indenyl]_4_(1_mercapto-2-one -1,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 78 as the starting material. The title compound was obtained as a white foam. Ms (ESI+, M+H): 452. Example 88 trans-N-[2-Bromo-3,5-bis(3-decyloxypropyl)hanyl]-N-cyclopropyl-4-(1-methyl-2-keto- 1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

Prepared according to the procedure described in Example 1, but instead using amine 79 as the starting material for 143482-1 • 234 201111364. The title compound was obtained as a white foam; M: S (ESI+, M+H): 589. Example 89 trans-N-[2-carbyl-3,5-bis(3-decyloxypropyl)octyl]-N-cyclopropyl ice (1_mercapto-2-steel-yl-1, 2-dihydro-4-p ratio octyl)-3-hexahydrop ratio

Me

It was made according to the procedure described in Example 1, but instead using amine 8 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 544. 4 NMR (CDC13) (5 (ppm): 0.62-0.68 (m, 1H), 0.74-0.79 (m, 1H), 0.82-0.90 (m, 2H), 1.63 -1.93 (m, 8H), 2.46-2.55 (m, 2H), 2.55-2.61 (br m, 1H), 2.72-2.89 (m, 4H), 3.05 (dt, J = l〇.l, 5.5 Hz, 1H), 3.22 (br m, 1H), 3.32-3.37 (m, 9H), 3.38 (t, d = 7.2 Hz, 1H), 3.50-3.58 (m, 4H), 4.23 (d, J = 13.5 Hz, 1H), 4.70 (d, J = 13.5 Hz, 1H), 6.12 (d, J = 7.0 Hz, 1H), 6.47 (s, 1H), 6.52 (s, 1H), 6.92 (s, 1H), 7.18 ( d, J = 7.0 Hz, 1H) Human renin IC50 (buffer): 0.2 nM. Human renin IC50 (plasma): 0.5 nM ° Example 90 trans-N-cyclopropyl-N-[2- Oxy-3,5-bis(3-methoxypropyl)benzyl]-4-(1-methyl-2-yl-1,2-dihydro-4-pyridyl)-3-hexa Hydrogen pyridine carboxamide 143482-1 -235· 201111364

It was made according to the procedure described in Example 1, but instead using amine 81 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 540. Example 91 trans-N-cyclopropyl_N-[3-(3-methoxypropyl)_5_(trifluoromethyl)indenyl]_4_(1_mercapto-2-indenyl-i, 2 -dihydro-4-indole D-based)_3_hexahydro-p ratio

It was made according to the procedure described in Example 1, but instead using amine 82 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 506. Example 92 transcyclopropyl_N_[3_hydroxy_5_(3_methoxypropyl)-based fluorenyl 2·indolyl-1,2-dihydro-4-pyridyl)_3_6 Hydropyridine carboxamide

Me

It was prepared according to the procedure described in Example 1, but instead using amine 83 as the starting material of 143482-1 • 236·201111364. The title compound was obtained as a white material. Ms (four) +, Μ + ίί) : 454. Example 93 trans-p-benzoyl-based ketone-based ketone)-oxime-cyclopropyl-indolyl-2-keto-1,2-dihydro-4-pyridyl)_3_hexahydropyridinecarboxylate Guanamine

Step 1: trans-3-UC3-substrate_5·breaking base)(cyclopropyl)amino]]yl}_4_屮methyl-2-keto-1,2-dihydropyridine_ 4_yl) small hexahydropyridinecarboxylic acid tert-butyl ester in trans-1-{[(1,1-didecylethyl)oxy]carbonyl oxime (1 fluorenyl-2-keto-1 , 2_dihydro-4-pyridyl)·3-hexahydropyridinecarboxylic acid (1 equivalent, Example i, Step 6), Hrniig's base (3 equivalents), and amine 84 (1 equivalent of kDMF (〇1M) solution, Add hexafluorophosphate 0-(7-aza-benzotriazole small base) in fractions. The resulting reaction solution was stirred at room temperature for 48 hours. The current yellow solution was diluted with EtOAc and washed sequentially with a 10% aqueous HCl solution, 1 N NaH aqueous solution and brine. Then, the organic extract was dehydrated and dried with Na2S〇4, and the solution was concentrated in vacuo to give a red-brown oil. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 3-{[(3-Benzenyl-5-bromobenzyl)(cyclopropyl)amino]carbonyl)-4-(1-indol-2-yl-1,2-di Hydropyridine-4-yl)hexahydropyridine small carboxylic acid tert-butyl ester 143482-1 -237- 201111364 at -78 ° C in 1,5-bis (magnesium) pentane (1 〇 equivalent) A solution of CuCN-2LiCl in THF (0.9 M, relative to CuCN) was added from a solution of CuCN (1. 〇 equivalent) and Lid (2.0 eq.) in THF (〇〇5M). The resulting mixture was stirred at -78 C for 30 minutes. Then, the trans-3-{[(3-carbyl-5-iodobenzyl)(cyclopropyl)amine-based sylvestris 4_(1_mercapto-2-one-) derived from the previous step was added. a solution of 1,2-dihydrop-pyridin-4-yl)-i-piperidinecarboxylic acid, a third-butyl ester (1 〇1) in THF (0.2 M) and warming the reaction mixture to room Warm, after 1 hour. Finally, gasified phenylhydrazine (15 equivalents) was added, and the reaction mixture was further stirred for 1 hour. The reaction mixture was quenched by the addition of water then EtOAc. The combined organic extracts were dried over Na2SO4, filtered and filtered and evaporated. The crude product thus obtained was purified by flash chromatography (EtOAc, EtOAc (EtOAc) Step 3: trans-N-(3-Benzylfluorenyl-5-bromoindenyl)_N_cyclopropyl_4 (1_fluorenyl-2-yl-1,2-dihydro-4-pyridine Base)_3_hexahydropyridine carboxamide in trans _3_{[(3_benzylidene-5_bromobenzyl)(cyclopropyl)amino]peptidyl}-4 from the previous step Addition of HC1 to a solution of 1-(1-methyl-2-keto-1,2-dihydropyridinyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (1 equivalent) in CH2C12 (0.1 M) (4.0 M dioxane solution, 30 equivalents). The resulting solution was stirred at room temperature for 45 minutes. After the vacuum is removed to remove volatile substances, it will be formed

The residue was directly loaded onto a 2.0:7 (v/v) CH2C12: 2.0M NH3 filled Si2 column in MeOH. The title compound was obtained by dissolving in the same solvent system. MS (ESI+, M+H): 548. Example 94 143482-1 •238 · 201111364 trans-N-{3-Momot-5-[(1Ε)-3-曱oxy-1-propene_ι_yl]] benzyl N-cyclopropyl- 4-(1-mercapto-2-keto-U-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

Step 1: trans-3-{[{3-bromo-5-[(1Ε)-3-decyloxyprop-1-en-1-yl]-aryl}boruryl)amino] M-(l-fluorenyl-2-keto-l,2-dihydrop-indol-4-yl)hexahydrop-pyridyl-1-carboxylic acid tert-butyl ester will be trans-3-{ [(3-Mosyl-5-iodohydrazino)(cyclopropyl)amino group}·4_(1methyl-2-keto-I,2-dihydroρ than -4-yl) Small hexahydro ρ ratio to biting acid third _butyl ester oxime equivalent 'Example 93 Step 1), 2-[(1Ε)-3-methoxyprop-1-ene-1·yl; 1_4, 4, 5 ,5•Tetramethyl-1,3,2-monooxaboron (1.2 equivalents), sodium carbonate (4.5 equivalents) and Pd(dppf)C12 (〇, 1 equivalent) in dioxere (〇1Μ) The mixture in the mixture was repeatedly evacuated and counter-filled with nitrogen. The mixture was stirred at room temperature for 2 hours in the dark. The current black suspension was diluted with brine and extracted with EtOAc. The combined organic extracts were dried over Na~SO~, filtered, and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut elut elut Step 2: trans-Ν·{3_bromo group_5·[(1Ε) each methoxy propylene small base] 基 }} N_cyclopropyl-4-(1-methyl-2-keto- U_Dihydropyridinyl)3_hexahydropyridine carboxamide in trans-{{3-bromo-5-[(1Ε)-3-methoxyprop-1) from the previous step -diluted-yl group) (cyclopropyl)amino]carboxy)-4-(1-indolyl-2.keto-1,2-dihydropyridyl 143482-1 201111364 pyridine-4-yl To a solution of the hexahydropyridine small carboxylic acid in the third butyl vinegar (1 eq.) in CH 2 Cl 2 (0.1 M), HCl (4.0 M dioxane solution, 30 eq.) was added. The resulting solution was stirred at room temperature for 45 minutes. After removal of the volatiles in vacuo, the resulting residue was loaded directly onto a &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The title compound was obtained by dissolving from the same solvent system. MS (ESI+, M+H): 516. Example 95 trans-N-{3-&gt;Smelly'yl-5-[(2-ethyl)thio]]}N-cyclopropylmethyl-2-copperyl-1,2-di Argon-4-p ratio to hexahydropyrene. Detamine

Step 1: trans-3-{[{3-bromo-5-[(2-ethyl)thio]octyl}(cyclopropyl)amino]]yl}-4-(1-A Keto-2-keto-1,2-dihydroρ than biti-4-yl) hexahydro! τ than biting_ι_slow acid third-butyl ester in trans-3-{ [(3-Mosyl-5-discyl) (cyclopropyl)-amino]|Carbyl 4-( 1-methyl-2-keto-1,2-dihydrop ratio 1 • 1,4-yl)-1-hexahydrop ratio β-determination of taurine third-butyl vinegar (1. 〇 equivalent, example 93 Step 1) Bronze (L1 equivalent) and 2, dithiodiethanol (0.6 equivalents) were added to the solution in DMF (0_3 Torr). The reaction mixture was heated to 110 &lt;0&gt;C over 24 h, cooled and diluted with EtOAc. The resulting suspension was stirred at room temperature for 20 minutes, transitioned through Shixia, and the insoluble material was further rinsed with EtOAc. The filtrate thus obtained was washed successively with a 3:1 (v/v) mixture of concentrated NH4OH: saturated NH4C1 aqueous solution, water and brine to 201111364

The MgS 4 was dehydrated, filtered, and the filtrate was concentrated in vacuo. The crude product thus obtained was purified by flash chromatography eluting elut elut elut elut elut elut elut Step 2: trans-N-{3-bromo-5-[(2-ethyl)sulfanyl]}}Ν·cyclopropyl (1_methyl-2-3⁄4yl-1,2- Dihydro-4-indole ratio -3- hexahydro ρ ratio β 醯 醯 醯 于 于 于 于 于 于 于 于 于 于 于 于 于 -3- -3- -3- -3- -3- -3- -3- { { { { { { { { { { Thio]-yl}(cyclopropyl)amino]]yl}-4-(1-methyl-2-keto-1,2-dihydro-p-biti-4-yl)hexahydropyridine- To a solution of 1-carboxylic acid tert-butyl ester (1 equivalent) in CH2C12 (Ο.ιμ), HCl (4.0 M dioxane solution, 30 equivalents) was added. The resulting solution was stirred at room temperature for 45 minutes. After removal of the volatiles in vacuo, the resulting residue was loaded directly onto a &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The title compound was obtained by dissolving in the same solvent system. MS (ESI+, M+H): 520. Example 96 trans-N-cyclopropyl-N-[3-[2-(cyclopropyloxy)ethoxy]_5-(3-methoxypropyl) φ fluorenyl]-4_(1_ Mercapto-2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

Step 1: trans-3-({cyclopropyl[3_[2-(cyclopropyloxy)ethoxy];_5_(3-methoxypropyl)hanyl]amino}carbonyl)-4 -(1-mercapto-2-keto-1,2-dihydro-4-pyridyl)-1-hexahydrop is more specific than -3- ({cyclopropyl) [3_hydroxy_5_(3_methoxypropyl)benzyl]amino}carbonyl 143482-1 •241- 201111364 base)-4-(1-mercapto-2-keto-i,2-di Hydrogen_4_pyridyl)-1_hexahydropyridinic acid tert-butyl ester (1.0 eq., Example 92) In a solution of DMF (0.1 M), cesium carbonate (2 eq.), sodium iodide ( 005 equivalents) and (2_chloroethoxy)cyclopropane equivalent). The reaction mixture was heated at 100 Torr for 22 hours. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were further washed with water and brine, dried over MgSO 4 , filtered, and evaporated. The crude product thus obtained was purified by flash chromatography (EtOAc: EtOAc: EtOAc (EtOAc) -N-[3-[2-(cyclopropyloxy)ethoxy]_5_(3-methoxypropyl)-yl]-4-(1-methyl-2-keto-1,2 -dihydro-4-pyridyl)-3-hexahydropyridine carboxamide in trans-3-({cyclopropyl[3-[2-(cyclopropyloxy))ethoxy) from the previous step ]-5-(3-methoxypropyl)benzyl]aminoindole carbonyl)_4_(ι_indolyl-2-keto 12-dihydro-4-pyridyl)-1-hexahydropyridinecarboxylic acid Add HCl (4.0 M dioxane solution, 30 equivalents) in a solution of tri-butyl ester (1 equivalent) in CH 2 Cl 2 (0.1 M). The resulting solution was mixed for 4 hours at room temperature. After the volatiles were added, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2: MeOH in MeOH. Dissolution from the same solvent system. The title compound was obtained. MS (ESI+, M+H): 538. </RTI> Example 97 trans-N-cyclopropyl-N-{3-(3-methoxypropyl)-5-[2-(4-? Phenyloxy) decylmethyl-2- Yl-1,2-dihydro-4-pyridinyl) -3-piperidine-2carboxamide 143482-1-242- 201 111 364 according to Example 96 using 4- (2-ethyl gas M + H): 567 billion

Me

Ο )) whallin as an alkylation reagent. MS (ESI+, Example 98 4_N-Phofolinecarboxylic acid trans-[[cyclopropyl{[4-(1-methyl-2-keto-U-dihydropyridinyl]&gt;3·hexahydropyridine Alkyl]carbonyl Iamino)indenyl]-5-(3-methoxypropyl)phenyl Me

It was prepared according to the procedure described in Example 96, but in step 1, alternatively, wortene-4-vaporized dross was used as the alkylating agent, triethylamine was used as the base, and DMAP was used as the catalyst. MS (ESI+, M+H): 567. Example 99 trans-N-cyclopropyl-N-[6-(3-methoxypropyl)-2,3-dihydro-1H-indol-1-yl]-4-(1-methyl- 2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide 143482-1 • 243 - 201111364

A mixture of diastereomers was prepared according to the procedure described in Example 1, but using amine 85 as a starting material instead. MS (ESI+, M+H): 464. Alternatively, the two diastereomers can be separated on preparative reverse phase HPLC and the BOC-protecting group removed. Example 100 trans-N-cyclopropyl_N_[7-(3-methoxypropyl)tetrahydroindenyl]nonyl-2-keto-l,2-dihydro-4-p ratio. Fixed base)-3-hexahydrop ratio

A mixture of diastereomers was prepared according to the procedure described in Example 1, but using amine 86 as the starting material instead. Alternatively, the two diastereomers can be separated on preparative reverse phase HPLC and the B〇c protecting group removed. Diastereomer A: MS (ESI+, M+H): 478. Human renin is busy 5 缓冲 (buffer): 0.3 nM. Human renin % 〆 plasma): UnM. Diastereomer &amp; MS (ESI+, M+H): 478. Human renin IC5 〇 (buffer): 36 nM. Human renin IC50 (plasma): 16.2 nM. Example 101 143482-1 -244- 201111364 trans-N-[3-bromo-5-(3-hydroxypropyl)-4-methylbenzyl], N-cyclopropyl_4·(1_fluorenyl) _2 keto-1,2-one wind-4-ρ ratio bite base)_3_hexahydrogen; 7 than biting slow guanamine

It was made according to the procedure described in Example 1, but instead using amine 87 as the starting material. The title compound was obtained as a white foam. Ms (esi+ φ M+Na): 538. Example 102 trans-N-[3-Acyl-5-(3-ethoxypropyl)-4-indolyl]-indolyl-4-yl-2-yl-2-yl-1 ,2-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 88 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 544 ° Example 103 trans-N-{3-exyl-5-[3-(difluoromethoxy)propyl]_4_曱benzyl}·Ν_cyclopropyl 4-(1-methylketo-iso-dihydro-4-pyridyl)_3_hexahydropyridine carboxamide 143482-1 -245- 201111364

The procedure described in Example 1 was followed, but instead the amine 89 as the starting material and the zinc (II) bromide-promoted BOC-removal protection as in Example 8 Step 8. The title compound was obtained as a white foam. MS (ESI+, M+H): 566. Human renin IC5 (buffer): 〇·3ηΜ. Human renin IC50 (blood group): 1.4 nM 〇 Example 104 trans-N-(3-mercapto-5-methylindolyl)-N-cyclopropyl-4-(1-methyl-2-keto) _1,2_Dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

It was made according to the procedure described in Example 1, but instead using amine 9 as a starting material. The title compound was obtained as a white foam. Ms (ESI+ M+H): . Human renin IC5 缓冲 (buffer): 7.5 nM. Human renin % 血 (blood): 21 nM. Example 105 trans-N-[3-Bromo-5-(3-indolyl)-4-indolyl]-N-cyclopropyl-4 (1indol-2-yl-1,2-di) Hydrogen-4-p ratio octyl)-3-hexahydropyridylcarboxamide 143482-1 -246- 201111364

It was made according to the procedure described in Example 1, but the title compound was obtained as a white foam by using the amine 91 as the starting material. MS (ESI+, M+H): 566. Example 106

trans-N-[3-Bromo-5-(3-fluorophenylindenyl)-4-indenyl]-indole-cyclopropyl-4-(1-indol-2-one-1 ,2-dihydro-4-indolyl)-3-hexahydrop ratio

Me

It was made according to the procedure described in Example 1, but instead using amine 92 as the starting material. The title compound was obtained as a white foam. MS (ESI+, M+H): 582. Example 107 trans-Ν·{3_漠基-5-[(3-fluorophenyl)(hydroxy)indolyl]-4-methylbenzylib N-cyclopropyl-4-(1-indolyl- 2, quinone dihydropyridinyl) each hexahydropyridine carboxamide 143482-1 • 247· 201111364

Me

In trans-N-[3-Molyl-5-(3-fluorobenzhydryl)_4_yl]]N_cyclopropyl_4_(1-indolyl-2-yl-1,2 Sodium borohydride (14 eq.) was added to a solution of MeOH (0.09 M). The resulting solution was stirred at room temperature for 15 hours and then the volatiles were removed in vacuo. To the residue formed, carefully add 1% aqueous solution of Ηα, followed by aqueous IN NaOH, so that the pH of the final solution was 〜10. After extraction with EtOAc, the combined organic extracts were washed with brine, dried over Na NaSOs, filtered, and evaporated. The title compound was obtained as a mixture of diastereomers. </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; MS (ESI+, M+H): 584. Example 108 trans-N-[2-Alkyl-5-(2-methoxyethyl)indenyl]-N•cyclopropyl-4hydroxyl-4 (1-decyl-2-keto-1,2 -dihydro-4-pyridyl)_3-hexahydro?

Me

Step 1. 3-{[[2-Hydroxy-5-(2-methoxyethyl)indolyl κcyclopropyl)amino]carbonyl M-keto-1-hexahydrop-ratio Third-butyl ester 143482-1 -248- 201111364 4-keto-1,3-hexahydropyridinedicarboxylic acid ι_t-butyl 3-ethyl ester (丨 equivalent), amine 4 (1 § 罝And DMAP (0.2 when 1) was heated at 14 ° C for 5 hours. The crude product thus obtained was purified by column chromatography (Si 〇 2, 95:5 - 3:7 (v/v) hexanes: EtOAc) and then in 9:1 (Wv)hexane:EtzO The title compound was obtained as a white solid. Step 2: trans-4-[2-(yloxy)-4-pyridyl]_3_{[[2_carbyl_5_(2-methoxyethyl)phenyl](cyclopropyl)amine ] 几 } -4- -4- -4- -1- -1- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Lithium (2.5 M solution in hexane, 2.1 equivalents). After stirring at _78 ° C for 3 minutes, solid magnesium bromide (2.5 equivalents) was added in a quick portion, and the resulting mixture was stirred at -78 C for 20 minutes. Then, the reaction mixture was slowly warmed to 〇 ° C for 30 minutes, and the 3-{[[2-[2-[2-(2-oxyethyl))) Mercapto](cyclopropyl)amino] benzylidene-4-keto-1-pyropyridinecarboxylic acid tert-butyl vinegar (1 equivalent) followed by stirring the reaction mixture at φ ° C for 1 hour, and After 30 minutes at room temperature, the reaction was then quenched by the addition of a saturated aqueous solution of NH.sub.4Cl. The filtrate was filtered and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (Si.sub.2, 96:4-93:7 (v/v) acetone: toluene) to give the title compound. 3: trans-3_{[[2_chloro-5-(2-methoxyethyl)-yl](cyclopropyl)amino] benzyl}-4-hydroxy-4-(2-keto) -1,2-dihydro-4-pyridyl&gt; 1-hexahydropyridinecarboxylic acid tert-butyl ester 143482-1 -249- 201111364 in the previous step of trans-4-[2-(benzyloxy) Base)_4·pyridyl]_3_{[[2-carbo-5-(2-methoxyethyl)] benzyl](cyclopropyl)amine a solution of a carbonyl group of 4 hydroxy hexahydropyridine carboxylic acid in a butyl (0.08 M) solution, palladium (10% w/w on carbon, 〇. 5 eq.) Acetic acid (11 eq.). The resulting suspension was stirred under a hydrogen atmosphere for 4 hours. The reaction was quenched with di-methane and filtered to remove insolubles from celite pad. 'The title compound was obtained. Step 4: trans-3-{[[2-carbyl-5-(2-decyloxyethyl)ylidene](cyclopropyl)amino]carbonyl H-hydroxy-4- (1-methyl-2-keto-1,2-dihydro-4-pyridyl) 4_hexahydropyridinecarboxylic acid tert-butyl ester at 〇 ° C, obtained from the previous step _ 3_{[[2_气基_5(2methoxyethyl)indolyl](cyclopropyl)amino]carbonyl}-4-hydroxy-4-(2-keto-1,2-dihydro Add NaOH (2N aqueous solution, 3 equivalents) to didecyl succinate (3N) in a solution of 1,4-pyridyl)-i-piperidinecarboxylic acid in a butyl alcohol (1 eq.) in decyl alcohol (〇1M). Equivalent). The resulting mixture was then stirred at room temperature for 12 hours. Then, the volatiles were removed in vacuo and left to dry. The liquid layer was separated from the water and the gas mixture, and the aqueous layer was separated and extracted with dioxane. The combined organic extracts were further washed with brine, dried with MgS〇4, filtered, and filtrated. Concentration in vacuo. The crude product thus obtained was purified by column chromatography (Si </ RTI> <RTIgt; </RTI> <RTIgt; Step 5: Trans-N-[2- gas base! (2-methoxyethyl) aryl]_N_cyclopropyl hydroxy-4-(l-fluorenyl-2-keto-1,2-dihydro-4-pyridyl)_3_hexahydropyridine Carboxylamidine in trans-3-{[[2-carbyl-5-(2-methoxyethyl)indenyl](cyclopropyl)amino]carbonyl-4-hydroxy-from the previous step 4-(1-methyl-2-keto-1,2-dihydrobupyridyl 143482-1 -250. 201111364 pyridine)-1-hexahydropyridinecarboxylic acid tert-butyl ester (1 equivalent) of CH2Cl2 Add HCl (4 ΌΜ dioxygen ore solution, 30 equivalents) to the solution (0.05 M). The resulting solution was stirred at room temperature for 3 hours. After removal of the volatiles in vacuo, the resulting residue was directly loaded onto a column of &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The title compound was obtained by dissolving from the same solvent system. ]VIS (ESI+, M+H): 474. Example 109 trans-N-C2-carbyl-5-(2-methoxyethyl));|_N_cyclopropyl_4_methoxy-4-(1-methyl-2-one Base-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide

Step 1: trans-4-[2-(benzyloxy-4-pyridyl)-3-{[[2-chloro-5-(2-methoxyethyl)-aryl](cyclopropyl) Amino]]yl}-4-methoxy-1-hexahydro? T-butyric acid tert-butyl ester in trans-4-[2-(benzyloxy)-4-pyridyl]-3-{[[2-chloro-5-(2-methoxyethyl) ) (based on the group) (cyclopropyl)amino]]}}-trans-l-hexahydro-p ratio. Sodium hydride (1.2 eq.) and methyl iodide (1.2 eq.) were added to a DMF solution (0.18 M). The reaction mixture was spoiled at room temperature for 30 minutes' and then it was diluted with ether and water. The organic layer was separated and washed with water and brine &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; The crude product thus obtained was purified by EtOAc EtOAc EtOAc (EtOAc: 143482-1 •251 · 201111364 Step 2. Trans-_3-{[[2-carbo-5-(2-methoxyethyl)-yl](cyclopropyl)amino]carbonyl M-oxime 4-(2-keto-1,2-dihydro-4-pyridyl) small hexahydropyridinecarboxylic acid, third-butyric acid, obtained from a one-step trans-4-[2-(yu Oxy-4-pyridyl)-3-{[[2-carboethyl-5-(2-methoxyethyl)](cyclopropyl)amino]carbonyl}_4methoxy^hexahydropyridine Palladium (10% w/w on carbon, 〇. 5 eq.) and acetic acid (1 eq.) were added to a solution of the carboxylic acid tert-butyl ester (1 eq.) in Et EtOAc (1M). The resulting suspension was stirred under a hydrogen atmosphere for 4 hours. The reaction was quenched with dichloromethane and filtered to afford insoluble material. Step 3: trans-3-{[[2-chloro-5-(2-decyloxyethyl)benzyl](cyclopropyl)amino] benzyl}-4-decyloxy-4- (1_mercapto-2-oxo-i,2-di-ar- 4-pyridyl) small hexahydropyridyl acid tert-butyl ester at 〇 ° C, obtained from the previous step _ 3_{[[2_气基_5_(2methoxyethyl) aryl] (cyclopropyl) Amino]carbonyl}-4-methoxy-4-(2-keto-1,2-dihydro-4-indole)-1-hexahydropyridinecarboxylic acid tert-butyl ester (1 equivalent) To a solution of decyl alcohol (0.07 M), Na 〇H (2N aqueous solution, 3 eq.) and dimethyl sulphate (4 eq.) were added. Then, the resulting mixture was stirred at room temperature for 12 hours. The volatiles are removed and the residue is partitioned between water and methylene chloride. The aqueous layer is separated and back-extracted with dioxane. The combined organic extracts are further washed with brine to The title compound 0 143482- was obtained as the title compound (yield: EtOAc, EtOAc). 1 -252· 201111364 Step 5: trans-N-[2-carbyl-5-(2-methoxyethyl)]N-cyclopropyl-4-thiol-4-(1-indenyl) 2-keto-1,2-dihydro-4-pyridyl)-3-hexahydropyridine carboxamide in trans-3-{[[2-chloro-5-(2-) from the previous step曱oxyethyl)]]](cyclopropyl)amino group}-4-methoxy-4-(1-indolyl-2-keto-_u_diaza·4_ 峨 bite Adding HCl (4.0 M dioxane solution, 30 equivalents) to a solution of 1-hexahydroacridinecarboxylic acid in a solution of tri-butyl hydride (1 equivalent) in CH 2 Cl 2 (0.05 M). The mixture was warmed for 3 hours. After removing the volatiles in a vacuum, the resulting residue was directly charged to 94:6 (v/v) CH2C12: 2.0 M NH3 filled Si in MeOH. 〇 2 on the column. The title compound was obtained by dissolving in the same solvent system. MS (ESI+, M+H): 488. iHNMR (Acetone-d6): 5 (ppm) 0.77-1.03 (m, 4H), 2.22-2.36 (m, 2H), 2.52-2.59 (br m, 1H), 2.74-2.85 (br m, 2H), 3.03 (s, 3H), 3.12-3.17 (br m, 2H), 3,28 (s, 3H), 3.32-3.37 (m, 4H), 3.49 (s, 3H), 3.53 (t, d = 7.0 Hz, 1H), 3.91 (br s, 1H), 4.53 (d, J = 13.2 Hz, 1H), 4.75 (d, J = 13.2 Hz, 1H), 6.41 (m, 1H), 6.52 (s, 1H), 7.11 -7.15 (m, 2H), 7.31 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 7.〇Hz, φ 1H). Human renin 1匚5〇 (buffer): 1.3 nM. Human renin 1 (: 5 〇 (plasma) · _ 3.2 nM. Example 110 trans-N-cyclopropyl-4-hydroxy-N-[3-(2-decyloxyethoxy)-5-( 3-methoxypropyl) aryl M-(l-methyl-2-keto-1,2-dihydro-4-p ratio dimethyl)-3-hexahydro-pyramine

143482-1 -253 201111364 Made according to the procedure described in Example 108, but using amine 11 as a starting material instead. MS (ESI+, M+H) ·· 514. Example 111 trans-N-cyclopropyl-4-methoxy-N-[3-(2-methoxyethoxymethoxypropyl)] benzyl]-4-(1-methyl-2 -keto-1,2-dihydro-4^ ratio ° base)_3_hexahydroquinone bite retinodine

Me

Made according to the procedure described in Example 109, but instead using amine 11 as the starting material. MS (ESI+, M+H): 528. Example 112 Confirmation of Detection of Biological Activity The inhibition of human recombinant renin was obtained from human recombinant renin (Proteos) at 50 mM MOPS pH 7.4, 100 mM NaCl, 0.002% Tween 20 at a final concentration of 100 pM. 50 times concentrated DMSO solution and 6 μΜ internal quenching fluorescent peptide: DNP-Lys-His-Pro-Phe-His-Leu-Val-Ile-His-D, L-Amp (sequence identification code: 1) inhibition Agent culture; Paschalidou K. et al., /, 2004, 3S2, 1031). The reaction was carried out in a Costar 384 well black plate (#3573) for 3 hours at 37 °C. Fluorescence was measured at a time of 0 and 3 hours with a SpectraMax Gemini EM reader set at an excitation wavelength of 328 nm and an emission wavelength of 388 nm. The background fluorescence at t = 0 is deducted from the metric at t = 3 hours. The inhibitory activity of the compound is represented by 143482-1 -254-201111364 IC5〇. Inhibition of renin in human plasma Human EDTA-collected plasma was rapidly thawed in warm water and centrifuged at 2900 g for 15 minutes at 4 °C. The supernatant was collected and recombinant renin (Ptoteos) was added at a final concentration of 1 nM. Plasma was transferred to c〇star black 384 well plate (#3573). The renin inhibitor was added from a 17.5-fold concentrated DMS0 solution and pre-incubated at 37 ° C for 10 minutes. The internal quenching fluoropeptide QXL520TM-Lys-His-Pro-Phe-His-Leu-Val-Ile-His-Lys (5-FAM) (Anaspec) was diluted in 3M Tris pH • 7.2, 200 mM EDTA, and Add to the plasma. The final concentrations were: 6 substrate, 342 mM Tris, 23 mM EDTA. The plate was incubated at 37 ° C for 1 hour. The plates were read at a time of 0 and 1 hour in a SpectraMax Gemini EM reader set at an excitation wavelength of 490 nm and an emission wavelength of 520 nm. The background fluorescence at t = 0 is deducted from the measure of t = 1 hour. The inhibitory activity of the compound is represented by IC50. In vivo animal model φ Female double transgenic mouse is purchased from RCC, Fiillingsdorf,

Switzerland. All animals were kept under the same conditions and free access to normal granular rat food and water. First, the rats were treated with enalapril (1 mg/kg/day) during 2 months. Approximately two weeks after the cessation of enalapril treatment, the double transgenic rats became hypertensive and reached an average arterial blood pressure in the range of 160-170 mm Hg. Net delivery device A - use 90 mg / kg Ketamin-HCl (Ketavet, Parke-Davis, Berlin FRG) with 10 mg / kg of benzene" (Rompun, Bayer, 143482-1 - 255 - 201111364

A mixture of LeVerk, FRG) was anesthetized in a peritoneal manner. The force is transmitted to the peritoneal cavity under aseptic conditions, wherein the sensing catheter is placed in the descending aorta below the renal artery, which is directed upstream. The transmitter is sutured to the abdominal muscles and the skin is closed. The remote source U旄-telemetry unit #锃 几 is obtained from Data Sciences (St. Paul, MN)). The implanted sensing system consists of a fluid filling guide, which is connected to the low-conductivity strain gauge pressure sensor, which is connected to the 垃度古立I l ^, 丄 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 ( ( ( ( 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 ;TAllpA_ C40 type) 'The sensor measures the absolute arterial pressure relative to the vacuum, and the RF transmission H;! The top of the word guide is filled with a sticky gel that prevents blood from flowing back, and is coated with an anti-prothrombin film. To suppress the formation of money. Implant (length = 2.5 cm, diameter _] 9 VIII and rainbow - 1.2 s) weight 1 is 9 gram, and has a typical battery life of 6 months 〇 ^ 典 典 典 又 又 又 益 益 ( (RPC- 1 'Data Sciences' is the connection of ''', line U to digitized input', which is sent to a dedicated personal computer (ompaq deskpro). Arterial pressure is calibrated using inputs from ambient pressure reference ^ Data Sciences. Shrinkage, average, and diastolic gray pressure are expressed in millimeters of mercury (mm Hg).立广鸢力彦里--A double-transgenic mouse with an implanted pressure transmitter is administered with a vehicle or a test substance of 1 mg/kg (n-6 per group) by oral feeding, and the average is continuously monitored. Arterial blood pressure. The effect of the test substance was expressed as the maximum decrease in mean arterial pressure (ΜΑρ) in the treatment group relative to the control group. Results According to the activity of the compound of the present invention, IC50 &lt;1 must be I in both renin buffer and plasma. Data on certain compounds are provided throughout the 143482-1 • 256· 201111364 example above. Example 113 Comparison of the test compound trans-Ν·({3-基基-4·methyl·5·[3.(methoxy)propyl]phenylhydrazine in a telephotometric female double-transgenic mouse. Oral and transdermal of fluorenyl)-N. cyclopropyl·4·(1-mercapto-2-keto-1,2·dihydro-4-P-pyridyl)·3·hexahydropyridine carboxamide Injecting animal studies Female double-transgenic mice (human renin and angiotensin-transgenic mice (see, for example, Bohlender et al., J Am Soc Nephrol 11 : 2056 (2000)) were developed. All animals were maintained. Under the same conditions, the normal granular rat food and water can be obtained freely. First, the rats are treated with enalapril (lmg/kg/day), starting at 3 weeks after production and at During the 9-week period, the telemetry transmitter was implanted within 2 to 4 weeks after the treatment of enalaprii was stopped. After about two weeks after the treatment of enalapril, the double-transgenic mouse was used. The system has hypertension and has an average arterial blood pressure in the range of 160-170 mm Hg. #送器礼入- Using isoflurane (via suction) The rats are anesthetized. The pressure transmitter is implanted into the peritoneal cavity under aseptic conditions, wherein the sensing catheter is placed in the descending aorta below the upstream renal artery. The transmitter is sutured to the abdominal muscles, the skin is placed Closed and the rats were individually housed in cages and placed on the telemetry receptor pad to enable blood pressure data to be collected during and after recovery from anesthesia. The rats were kept in the cages' telemetry data. During the recording period, you are named after the Data Sciences International 1 (by Paul MN). The implanted sensor consists of a fluid-filled catheter (. 7 mm diameter, 8 cm long; TA11PA_C4 (4)) connected to a highly stable low-pass 143482-1 - 257 - 201111364 guided strain gauge pressure sensor. Absolute arterial pressure in vacuum, with RF transmitter. The tip of the guide f is filled with a viscous gel that prevents blood from flowing back. The implant (length = 2.5 cm, diameter = 12 cm) weighs 9 grams and has a typical battery life of 6 months. The Receiver Platform (RPC 1 DSI) connects the wireless k5 to the digitized input and is sent to a dedicated personal computer. Arterial pressure was calibrated using input from an ambient pressure reference (APR-1 ' DSI). Contraction, mean and diastolic blood pressure are expressed in millimeters of mercury (mm Hg). Phase crossing (four) knot - digitizes the signal received by the receiver under the 5 〇 ship every 5 minutes for K) seconds. From this signal, mean arterial pressure (MAp), systolic and diastolic blood pressure (SBP and DPB), pulse pressure (pp), heart rate (hr), and akinetic (ACT) were derived. The data-hour moving average is then performed by (10) analysis software. Then the data is output to the coffee template for calculating the group statistics, the area between the curves (ABC), the maximum effect, and the duration of the MAp reduction. ##授#- For oral delivery, a double transgenic mouse with an implanted pressure transmitter is administered with a vehicle (α 5% (10) of this heart 5 ml/kg) or test substance (30 mg/). A single bolus of 5 ml/kg) (n=5 per group). After taking the medicine, return the rats to their cages. Blood pressure data was collected up to 5 days after oral administration. For transdermal delivery, a dual transgenic rat with an implanted pressure transmitter is administered a vehicle (25 μL 〇〇1% DMSO; n=4) or test compound on the shaved skin of rats. (1 〇 mg, in a 25 μl l l% dms ,, 143482-1 -258· 201111364 .3⁄4 ie 33 mg / kg; n = 5) single application. The rats were slightly sedated under anesthesia of 25% isoflurane and the back was shaved to cover an area of 4 square centimeters. Return the animal to its cage to recover from anesthesia. After twenty-four hours, the rats were slightly sedated under 2.5% isophora anesthesia and sterilized 3 times with ethanol in the area of hair. After the ethanol treatment, a volume of 250 μl of only 1% DMS or a compound dissolved in 100% DMSQ solution was applied to the area where the hair was applied using a micropipette. After complete evaporation of the DMSO solution (within 5 cm of coating), the occlusive transparent waterproof film (() pSite) was adhered to the back of the animal 'covering the shaved area' and the jacket was mounted On animals. The isofluranic inhalation was stopped and the animals were individually housed in cages for telemetry data. Blood pressure data were collected and collected on compound 8 〇 solution for up to 5 days. /Examples of the effect of the test substance on hydrazine after POMD transfer are shown in Figure 1 and Table 7 below.

Table 7: TD vs. Ρ〇 Transmission of Test Substance for ABC Maximum MAP Reduction and Reduction ^ Duration of Time Bud Dry Path abc3 6 h Maximum MAP Reduction '- (mm Hg*h) (mm Hg) PO ΙΠ43 \57 TD 514 — _ 30 Duration (days) 2

, drug dynamics φ, drug ^i learning and biomarker site inflammation, after PO transmission, in TG, T6h &amp; T24hT, in the telemetry of the full by tail blood collection or jugular vein, to the active substance f The amount of test substance and bioavailability in the system (as estimated by the area under the curve or AUC 143482-1 -259- 201111364). The blood sample (0.3 ml) was taken from the TD after the TD transmission, and was taken in the dTG of the 'i telemetry by tail blood sampling or jugular vein to determine the 'tongue substance in the system cycle. Test substance content and bioavailability (estimated by the area under the curve or AUC). Blood (tetra) activity (pRA) was also measured at ^ and t4 h. The effect of test substance f on PR A is expressed as a percentage of inhibition at T4 h. The results of the examples are shown in Table 8 below. Table 8. PRA inhibition (%) of TD to PO transport biochemical pathway of test substance after P传输 to TD transmission (%) PO 1.8 na TD 2.9 98 na unusable rate comparison BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1A-B is a graph showing the comparison of TD versus PO transmission for mean arterial blood pressure of a test compound in dTG rats. Figure 2 illustrates solid state C-13 CPMAS NMR spectra for crystalline Form I. Figure 3 is a graph showing the thermogravimetric analysis of crystalline Form I. Figure 4 is a graph showing the differential scanning card method (&quot;DSC&quot;) of crystalline Form I. Figure 5 illustrates an X-ray diffraction pattern of crystalline Form I. 143482-1 -260-

Claims (1)

201111364 VII. Scope of application: 〉Salt, which has the formula 1 a compound of formula I or a pharmaceutically acceptable compound thereof among them: R1 is selected from the group consisting of the following Acvm'w cycloalkyl, C2-C6 alkenyl, c3_c6 cycloalkenyl block groups, wherein each of the foregoing is optionally substituted with 1-3 halogens and/or Ci_C5 alkoxy groups; ^R3 is independently selected from the group consisting of hydrogen, i, Cl-C5, C3&lt;>alkyl, c2&lt;:5 alkenyl, C3_C8if dilute, w block, cyano, q-C5 alkane An oxy group, an aryl group and a heteroaryl group, wherein the heteroaryl group contains 1 to 3 hetero atoms independently selected from the group consisting of N, 〇B, wherein each N is optionally in the form of an oxide. And each S is optionally in the form of an oxide selected from the group consisting of S(=〇) and s(=〇)2, wherein the aryl and heteroaryl are optionally substituted by M halogens, Wherein the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and alkaneyl groups are optionally substituted by L3 substituents, each of which is independently selected from the group consisting of dentate, Cj a -Cs alkyl group, a C2-C5 dilute group, a cyano group and a Cl_C5 alkoxy group, wherein each of the aforementioned alkyl, alkenyl and alkoxy substituents is substituted by 1-3 halogens depending on the case of 143482-2 201111364; Is a cyclopropyl group, Unsubstituted or substituted by fluorine mono-, di-, tri-, tetra- or penta, X is selected from the group consisting of OR4, R4, -(c! -C5 alkyl)-(〇)〇 -1 -Aryl and -(q -C5alkylene)-(0)〇_丨-heteroaryl, wherein R4 is selected from the group consisting of hydrogen, C丨-C5 alkyl, (:3 -(: 8-cycloalkyl, c2-C5 alkenyl' (: 3-(:8 cycloalkenyl, C2-C5 alkynyl, q-cv cyano, -(C-C5 alkyl)-〇- R5, -(C)-C5 alkylene)-N(-R5)-(:(=〇)-(CVQ alkyl), -(qQalkylalkyl), 謇-(qQ alkyl) -N(_R5)_c(=0)_0_(Ci_C5 alkyl), -(Ci_C5 alkyl)-0-C(=0)-N(-R5)-((^-C5 alkyl), -(( q -C5 alkylene)-N(-R5)-(C丨-C5 alkyl), -(C-C5 alkylene)-S·%-C5 alkyl), -(C)-C5 Alkyl)-S(=〇)-(Ci-C5 alkyl) and _(Cl _c5 alkyl)_s(=0)2 _(Ci _c5 alkyl), wherein R4 'except hydrogen, as the case may be Substituted by u substituents' substituents are independently selected from the group consisting of halogen, C(=〇)〇h, qc:5 alkyl, CyC:5 alkenyl and Ci_C5 alkoxy, wherein each alkyl group, Alkenyl and alkoxy The thiol group is optionally substituted by 1 to 3 halogens, wherein -(q -C:5alkylene)-(〇)〇M-heteroaryl heteroaryl has 1-3 heteroatoms independently selected from the following The group consisting of n, 〇 and s, wherein each N is in the form of an oxide, and each s is in the form of an oxide as the case is selected from the group consisting of: s (=0) and s (=0)2, wherein -(qc:5alkylene)-(〇)〇_"aryl and _(Ci_C5alkyl)-(〇)〇-〖-heteroaryl aryl and heteroaryl The base system is individually substituted by 14 _ 素, and 143482-2 -2- 201111364 wherein R5 is selected from the group consisting of hydrogen, Cl _c6 alkyl 'qc: 6 cycloalkyl, c: 2% olefin a c3_C6 cycloalkenyl group and a decyl alkynyl group, wherein each of the above alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally substituted with 1 to 3 halogens; Z is a CrQ alkyl group 'Substituted by μ2 substituents, the substituents are independently selected from the group consisting of il, q-Cs alkyl and C3 cycloalkyl, wherein the alkyl and cycloalkyl substituents are optionally treated as 13 Halogen _ substituted; nl is 0 or 1; γ is (1) five- or six-member And or an unsaturated heterocyclic or carbocyclic monocoat J (monocyclic ring), or (9) a five or six membered saturated or unsaturated heterocyclic or carbocyclic ring, which is fused to five Or a six-membered saturated or unsaturated heterocyclic or carbocyclic ring ("fused ring"), wherein the heterocyclic ring of (1) or (ii) contains 1 to 3 heteroatoms independently selected from ruthenium, osmium and s. Each of the N systems is in the form of an oxide, and each S system is in the form of an oxide selected from the group consisting of: s(=〇) fish S(=〇)2, wherein The heterocyclic or carbocyclic ring of (i) or (ii) is optionally substituted by mono-, mono-, di-, tetra- or hexa-, wherein each substituent is independently selected from the group consisting of Group: , (1) Halogen, (2) -OH » (3)-NH(R6), (4) Keto, 143482-2 201111364 (5) -C(=0)-R6, (6) -0C(= 0)-R6, (7) Q-C5 alkyl group is optionally substituted by 1-3 halogens, (8) C3-C8 cycloalkyl, optionally substituted by 1-3 halogens ' (9) C2-C5 a dilute base, optionally substituted with 1-3 halogens, (10) a C3-C8 cycloalkenyl group, optionally substituted with 1-3 halogens, (11) C2-C5 alkynyl, optionally substituted by 1-3 halogens, (12) Q-C5 alkoxy, optionally substituted with 1-3 halo' (13) cyano, (14) C -C5 -Cyano group 'Substituted by 1-3 halogens' (15) -〇CF3, (16) -C(R7)3, (17) -(q -C5 extended alkyl)-OR8, as appropriate Substituted by 1-3 halogens, (18) -N(R6 MQ -C5 alkylene)-OR8, optionally substituted by 1-3 halogens, (19) -Ο-Α-C5 alkylene)-OR8 , as the case may be replaced by 1-3 halogens, (20) -S-% -C5 stretching base) - 〇R8 'replaced by 1-3 _ primes, (21) -8 (=0)-( (1^-C5 extended alkyl)-OR8, optionally substituted by i_3 halogens, (22) -S(=0)2 -(q -C5alkyl)-OR8, optionally substituted by ι_3 halogens, (23) -(C! -C5 Stretching base)^(1^6)-(^(=0)-((^ -C5 extension base)-R8, -4- 143482-2 201111364 Depending on the situation, 1 -3 halogen substitutions '(24) -((VQalkyl)-N(R6)-C(=0)-0R8 'Substituted by 1-3 halogens' (25) -(C! -C5 Alkyl)-N(R6)(R8), optionally substituted with 1-3 halo, (26) -O-CCi-C5 alkyl)-C(R6)2-C(=0)0R8, 1-3 li Generation '(27) -(A -C5alkylene)-C(R6)2-C(=0)0R8 ' is replaced by 1-3 ® halogens as appropriate, (28) -CKq -C5 - 福福, which is replaced by 1-3 halogens as appropriate, (29) -0C(=0)-?福普林' (30) -SR8, (31) -S(=0)-Rs, (32 ) -S(=0)2-R8 ^ (33) -N(R6)(R8), (34) -(q -C5alkyl)-C(R6)2 -(R8), as appropriate -3 halogen substitutions, (35) -(R9)〇-iR10 ' (36) C2 -C5 alkenyl-OR8, optionally substituted by U halogens, (37) C2-C5 alkynyl-OR8, as appropriate 1-3 halogen substitutions, (38) -(Ci -C5 alkylene)-(:(=0)-((^-C:5 alkyl)-R8, optionally substituted by 1-3 halogens '(39) -(C1-C5 伸院基)-〇_C(=0)-(Ci -C5 伸基基)-R8 ' Subject to 143482-2 201111364 Condition replaced by 1-3 halogens, (40 -(CVQalkylene)-C(=〇)-N(R6)(R8), optionally substituted by 1_3 halogens, (41) -(C--C5 alkylene)-〇-C(= 〇)-N(R6)(R8), as the case may be, replaced by μ3 halogens, (42) -(C! -C:5 extension yard)-SR8 'Substituted by 1-3 fangs, ( 43) -(Q -C:5 alkylene)-S(=〇)-R8, as appropriate by i_3 Halogen substitution, and (44) -(Q -C5alkylene)-S(=〇)2-R8 'Substituted by i_3 halogens, wherein R6 is selected from the group consisting of hydrogen, q-C6 Alkyl, CVC: 8-cycloalkyl, CyC6 alkenyl, anthracene: 3-0:8 cycloalkenyl and c2-C6 alkynyl, wherein each of the aforementioned alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl groups The substituent is optionally substituted by 1-3 halogens, wherein R7 is halogen, wherein R8 is selected from the group consisting of hydrogen, q-C6 alkyl, 匚3-Cg ring, C:2-C a 6-alkenyl group, a C:3-C8 ring-and-lith group, and a c2-C6-radical group, wherein each of the aforementioned alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl substituents is optionally 1 to 3 halogens. Substituted, wherein R9 is selected from the group consisting of: 匚(11)(011)-, -(:(=0)- ' -0C(=0)-, -C(=0)0- ' - 0-, -OC(=〇)〇-, Ci-Cs alkylene group, C2-C5 alkenyl group, -wind 116)-, each, -50=〇)-, -8 (=〇) 2-, _]^(116)-(:(=〇)-, -(:(;=〇;)- N(R6)-, -〇C(=0)-N(R6)-, -N(R6) -C(=〇)〇-, _n(R6)-S(=0)2-, -S(=0)2_N(R6)-, wherein each of the aforementioned alkylene and alkenyl substituents is as defined above. 482-2 -6- 201111364 is replaced by 1-3 halogens, and wherein the uldent 6 is defined above, and "wherein R is a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring, The substituents are mono-, di-, tri-, tetra- or penta-substituted, wherein each substituent is independently selected from the group consisting of halogen, OH, _sr6, ^6) (妁, Cl-C5 alkyl, Indole cycloalkyl, % cation, (iv) ring, eve#, Ci&lt;^oxy, and c. The heterocyclic ring contains (1) heteroatoms independently selected from N and 〇M, each of which is oxidized as appropriate The "f" of each of the formulas N, selected from the lower jaw" and 1 and each of the 8 systems are defined as oxides as defined above. , group: S (= 〇) W (= 〇) 2, and _R8 2. The compound of claim 1 is selected from the following: a single ring or fused ring system of Y(1) or (8) 143482-2 201111364 3. The compound of claim 1, wherein R1 is -ch3 or -CH2CH3. 4. The compound of claim 1, wherein R2 and r3 are independently selected from the group consisting of hydrazine, -〇ch2〇CH3, and -CH3. 5. The compound of claim 1, wherein X is Η '-OH or -〇CH3. 6. The compound of claim 1, wherein (Z)nl is -CH2- or a bond. 7. The compound of claim 2, wherein: R1 is a q-C2 alkyl group optionally substituted with 1-3 halogens, and R2 and R3 are independently selected from the group consisting of hydrogen, halogen, Ci-q alkane Base, q -C:5 alkoxy and -ο-% -C5 alkyl)_〇_(CH2)0 _ 3 -CH3, wherein alkyl, alkoxy and _〇_(CrC5 alkyl) _〇_(CH2)〇-3 _CH3 is optionally substituted with 1-3 substituents. The substituents are independently selected from the group consisting of dentate, optionally substituted with 1-3 halogens, Cl _c5 alkyl. And optionally substituted by 1-3 i-(^-(:5 alkoxy, X is selected from the group consisting of hydrogen, alkoxy, and Z is C)-C. 8. A compound of claim 1, wherein gamma is 143482-2 201111364, as the case requires, by mono-, di-, tri-, tetra- or penta-substituted 9. The compound of claim 7 , which has the formula (II) among them: Group A is selected from the group consisting of: (1) hydrogen, (2) south, (3) Q-C5 alkyl, (4) q-Cs alkoxy, and (5) -S-(CH2)0-3-CH3, Wherein (3) and (4) are replaced by 1-3 halogens, and B is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) G-C5 alkyl, (4) Q-C5 courtyard oxygen Base, (5) -OH, (6)-CF3, (7)-C(=0)-CH3, (8)-〇-(Α-C5 alkyl)-〇·cyclopropyl, (9) -CKq-C5 alkylene Base)-〇_(CH2)〇_ 2 _CH3, 143482-2 201111364 (10) -(Ci -C5 alkyl)-0-(CH2 )〇-2 -CH3, (11) -0C(=0) - 福福淋, (12) -CKCi -C5 stretching base) - 福福,, (13) -CKCi -C5 alkyl)-C(CH3)2 -C(=0)0H, (14) - CKCi -C5 alkyl)-C(CH3 )2 -c(=o)och3, (15) Wherein (3), (4), (8), (9), (10), (12), (13), (14), (15) and (16) are replaced by 1-3 halogens, C It is selected from the group consisting of: (1) hydrogen, (2) G-C5, based on the case, substituted by 1-3 halogens, and (3) C! -C5 alkoxy, optionally substituted by 1_3 halogens And D is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) -C5 alkyl, (4) CVC5 alkoxy, (5) CVC5-cyano, (6) C2 - C5 exo alkenyl-〇_(ch2)〇_ 2 -CH3, 143482-2 -10- 201111364 (7)-(q -c5 alkyl)-n(h)-c(=o)-o-(ch2 ) G. 2 -CH3, (8)-(q -C5 alkylene)-N(H)-C(=0)-(CH2)Q - 2 -CH3, (9)-(Ci-c5 alkylene)-o- Chf2, (10) -(q -c5 alkyl)-o-(ch2)〇· 2 -CH3, (11) -CKCi -c5 alkyl)-o-(ch2 )〇_ 2 -CH3, ( 12) -((VC5 alkyl)-OH, (13) -S-(Ci-C5 alkyl)-OH, (14) -SCF3, (15) -NOIHQ -C5 alkyl)-〇- (CH2)〇_ 2 -CH3, and (16) Wherein F, G and H are independently selected from the group consisting of hydrogen, halogen and C!-C3 alkyl, and wherein R11 is selected from the group consisting of: _CH2_, _c(8)(〇H)_ and -C (=〇)-, and its (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13) and (15) depending on the situation Substituted by 1-3 halogens, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. 1) The compound of claim 1, wherein the compound is selected from the group consisting of 143482-2 201111364 143482-2 •12- 201111364 143482-2 -13- 201111364 143482-2 -14- 201111364 143482-2 -15- 201111364 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 11. The compound of claim 10, which is exemplified by example 103 CH3 Or a pharmaceutically acceptable salt thereof. 12. The compound of claim 10, which is exemplified by example 89 ch3 Or a pharmaceutically acceptable salt thereof. 13. The compound of claim 10, which is exemplified by example 85 ch3 Or a pharmaceutically acceptable salt thereof. 14. The compound of claim 10 which is 143482-2 -16-201111364 instance 80 ch3 Or a pharmaceutically acceptable salt thereof. 15. The compound of claim 10, which is exemplified by example 109 ch3 Ch3 or a pharmaceutically acceptable salt thereof. 16. The compound of claim 10, which is example 5 Or a pharmaceutically acceptable salt thereof. 17. The compound of claim 1, wherein the Y system It is monosubstituted as described in claim 1. Tri-, tetra-, five- or six 143482-2 -17- 201111364 18. The compound of claim 7, which has the formula (ΠΙ): III R1 Wherein: A is selected from the group consisting of: (1) hydrogen, (2) _ 素, ( (3) Q-C5 alkyl, optionally replaced by i_3 i, (4) Q-C5 Optionally, 1-3 halogens are substituted for 'and (5) cyano groups, and B is selected from the group consisting of hydrogen and dentate, and C is selected from the group consisting of: (1) hydrogen, (2) halogen , (3) Q-C5 alkyl group is replaced by i_3 elements, ® (4) ci -C5 alkoxy, optionally substituted by 1-3 halogens and (5) cyano, D is selected from the following composition Groups: (1) hydrogen, (2) halogen, (3) Q-C5 alkyl groups are optionally substituted by 1-3 halogens, (4) Q-Cs alkoxy groups, optionally replaced by 1_3 halogens, 143482- 2 -18- 201111364 (5) (C! -C5 alkyl)-0-(CH2)〇_ 2 -CH3, optionally substituted by 1-3 halogens, and (6) cyano, and E is selected From the following group: (1) hydrogen, (2) halogen, (3) CVq alkyl, (4) CVQ alkenyl, (5) CVC5 alkoxy, (6) cyano, (7) - (CVCs alkyl)-C(CF3)2(H), (8) - (C) -C5 alkyl)-N ( H)-C(=〇HCH2 )〇_ 2 -CH3, (9) -(q -C5 alkyl)-0-(CH2 )〇-2 -CH3, (10) 143482-2 -19- 201111364 where (3), (4), (5), (7), (8) and (9) are replaced by 1-3 halogens as appropriate [and (10), (11), (I2) and (13) are optionally substituted by a substituent which is independently selected from the group consisting of dentate, C-C5 alkyl 'C丨-05 alkoxy and cyano, = " Acceptable 9 or its stereoisomer 143482-2 201111364 Table 5 Example 59 Example 58 Example 74 Example 57 Example 56 Example 71 Example 51 Example 69 Example 70 Example 53 Example 52 Example 62 143482-2 -21 - 201111364 143482-2 22- 201111364 .... . . Table 5 Example 67 〇 Example 72 CH3 实例 Example 55 ch3 0 Example 65 ch3 Vo H3V\ o or Example 77 ch3 Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 20. The compound of claim 19, which is Example 68 ?H3 Or a pharmaceutically acceptable salt thereof. 21. The compound of claim 1 wherein Y is selected from the group consisting of: 143482-2 •23- 201111364 Substituting mono-, di-, tri-, tetra- or penta-substituted as described in claim 1. 22. The compound of claim 7, which is selected from the group consisting of: Wherein A is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) q-C5 alkyl, (4) Ci-C5 alkoxy' (5) cyano, 143482-2 -24- 201111364 (6) q-CV cyano, (7)-(q-c5 alkyl)-n(h)-c(=o)-(ch2)0.2 -ch3, (8)-(q-C5 alkyl)- 〇-(CH2)0 - 2 -CH3, and (9)-NOiMCi -C5 alkylene)-〇-(CH2)〇. 2 -CH3, wherein (3), (4), (6), (7), (8) and (9) Substituted by 1-3 halogens; or a stereoisomer thereof' or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 23. The compound of claim 1 wherein the compound is selected from the group consisting of: 143482-2 -25· 201111364 Example 18 Example 21 H3 Example 26 Example 37 Example 23 Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 24. The compound of claim 23, which is exemplified by example 26 143482-2 -26- 201111364 or a pharmaceutically acceptable salt thereof. 25. The compound of claim 1, wherein the Y system It is mono- or disubstituted as described in claim 1. 26. The compound of claim 7 which is Wherein: A is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) q-C5 alkyl, (4) CVC5 alkoxy, and (5) - (C! - C5 alkylene) Base)-0-(CH2)〇_ 2 -CH3, wherein (3), (4) and (5) are optionally substituted by 1-3 halogens, and B is selected from the group consisting of: (1) hydrogen, (2 Halogen, (3) CVq alkyl, (4) alkoxy, (5) -(C! -C5 alkyl)-0-(CH2)〇_ 2 -CH3, and 143482-2 -27- 201111364 (6)- NOlMq -c5 alkylene)-〇-(ch2)〇_ 2 -CH3, wherein (3), (4), (3) and (6) are optionally substituted by μ3 halogens; or a stereoisomer thereof, or a pharmaceutically acceptable substance thereof A salt acceptable, or a pharmaceutically acceptable salt thereof, of a stereoisomer thereof. 27. The compound of claim 1, wherein the compound is exemplified by example 2 ch3 Example 79 ?h3 Or a pharmaceutically acceptable salt thereof. 28. -(3S,4R)-N-({3-Mosyl_4_fluorenylmethoxy)propyl]phenyl}indenyl)_N-propyl-4-(1-indolyl-2 - Keto group - i, 2, dihydro 4 - pyridyl) each of the hexahydropyridine carboxamide hydrochloride crystal form a pharmaceutically acceptable hydrate thereof. 29. For example, clear the crystal form of item 28! , it is by! 3c ssnmr is characterized by the following chemical shifts expressed in parts per million: 12〇1, 312, 17.1' 43.5, 41.6, 29.4, 58.5, 71.4, 28.7, 42 5, 138 3 and 143 6 . 30. The crystal form of the item 28 is characterized by the solid state of Figure 2, 3c ssnmr CPMAS nuclear magnetic resonance spectrum. 31. As in the crystalline form I of claim 28, 32. as in the crystalline form of claim 28, the curve. It is characterized by the thermogravimetric analysis curve of Figure 3. Characterized by the differential scanning card method of Figure 4, as in the crystalline form I of claim 28, which is characterized by X-ray powder diffraction by 143482-2 -28-201111364 - The following reflections of the spacing: 1〇59, 7〇4, 4 24, 4.22, 3.88, 3.58, 3.51, 3.31 and 3.08. 34. The crystalline form 请求 of claim 28, which is characterized by the re-radiation pattern of Figure 5. 35. A method for preparing a compound of the formula: Wherein: R is a q _c2 alkyl group optionally substituted by 1-3 halogens, and R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, Ci_C5 alkyl, q-C5 alkoxy and _0_( Ci _c5 alkylene) 〇_(CH2 ) 〇 · 3 _Ch3, wherein alkyl, alkoxy and _C5 alkyl) 〇 (CH2 _ 3 _CH3 is optionally substituted by 1-3 substituents The group is independently selected from the group consisting of dentate, a Cl-c5 alkyl group optionally substituted by 1-3 halogens, and an alkoxy group optionally substituted by 1-3 halogens, and X is selected from the following constituents. Group: hydrogen, -OH and q-C5 alkoxy, (Z)n 1 is a -C2 alkyl group, and A is selected from the group consisting of: (1) hydrogen, (2) _, (3) Q-C5 alkane Base, 143482-2 -29- 201111364 (4) (VC5 alkoxy, and (5) -S-(CH2)〇-3 -CH3, where (3) and (4) are 1-3 depending on the situation Substituted by a letter, B is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) C! -C5 alkyl, (4) eves alkoxy, (5) -OH, (6)-CF3, (7) - C(=0)-CH3 &gt; (8)-CMC! -C5 alkylene)-〇-(CH2)〇. 2 -CH3, (9) -(q -C5 alkylene)-〇-(CH2 ) -. 2 -CH3, (10) -O-CCi -C5 alkylene)-C(CH3)2 -C(=0)0H, (11) -CKQ-Qalkylene)-c(ch3)2 -c(=o)och3, wherein (3), (4), (8), (9) and (11) are replaced by 1-3 halogens, and C is selected from the group consisting of: (1) hydrogen, (2) a q-Cs alkyl group, optionally substituted by 1 to 3 halogens, and (3) a q-C5 alkoxy group, optionally substituted by 1 to 3 halogens, and D is selected from the group consisting of the following : (1) hydrogen, (2) halogen, 143482-2 -30- 201111364 (3) Q-C5 alkyl, (4) (VC5 alkoxy, (5) CVQ-cyano, (6) C2 - C5 〇-〇-(CH2 )〇-2 -CH3, (7) -(q -C5 alkyl)-N(H)-C(=0)-0-(CH2 )〇. 2 -CH3, (8 -(q -C5 alkylene)-N(H)-C(=0)-(CH2)〇- 2 -CH3, (9) -(Ci -C5 alkylene)-0-CHF2, (10 ) -(Ci -C5 alkylene)-0-(CH2 )〇-2 -CH3, (11) -CKCi -C5 alkylene)-0-(CH2)〇-2 -ch3, (12) -(A-C5alkylene)-OH, (13) -S-CCVCs alkylene)- OH, (14) -SCF3, and (15) -NCHMCi -C5 alkylene)-0-(CH2)0 2 -CH3, wherein (3), (4), (5), (6), (7 ), (8), (9), (l〇), (11), (12), (13) and (15) are replaced by 1-3 halogens, which include the following steps: (1) The compound of the formula (8) or a salt thereof is coupled to the compound of the formula (b) or a salt thereof in the presence of a solvent: (4) to form a compound of the formula (c) or a salt thereof 143482-2 • 31 201111364 (2) The compound (c) is deprotected by removing Boc. 36. The method of claim 35, wherein the solvent is one or more compounds selected from the group consisting of DMF, gasification, and iPr2Net. 37. The method of claim 35, wherein step (7) is carried out with one or more compounds selected from the group consisting of HC1, IPA, and MTBE. 38. A method for preparing a compound of the formula: The method comprises the steps of: (1) coupling a compound of the formula (8) having a Boc group with the following formula (9) DMF, gasified grasshopper and iPr2NEt: .0 .Br , co2h Α V , Me MsOH ' , 〇Me (8) (b) to form a compound of formula (c) 143482-2 -32- 201111364 (2) The formed compound is removed by the B〇c group, and the protection is removed in the presence of hcl, IPA and MTBE. • 39. 40. 41. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of diseases relating to hypertension, septic heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, Renal fibrosis, Dirty insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, spheroid nephritis, renal colic, complications caused by diabetes, such as kidney disease, vascular disease and neuropathy, glaucoma, high eyeball Stress, atherosclerosis, restenosis after angioplasty, complications after vascular or cardiac surgery, erectile dysfunction, hyperaldase, pulmonary fibrosis, scleroderma, anxiety, cognitive disorders, immunity Complications of inhibitor treatment and other diseases known to be associated with the renin-angiotensin system. A method for treating or preventing a disease, which is related to hypertension, septic heart failure, pulmonary hypertension, renal insufficiency, renal blood loss, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, Myocardial hematopoiesis, cardiomyopathy, spheroid nephritis, renal colic, complications caused by diabetes 143482-2 -33- 201111364 'such as nephropathy, vascular disease and neuropathy, glaucoma, high intraocular pressure, atheroma Sclerotherapy, restenosis after angioplasty, complications after vascular or cardiac surgery, erectile dysfunction, hyperactivity of fecal enzymes, pulmonary fibrosis, scleroderma, anxiety, cognitive disorders, concurrent treatment with immunosuppressive agents And other diseases known to be associated with the renin-angiotensin system. This method comprises administering to a patient a pharmaceutically active amount of a compound of claim 1. 143482-2 -34-