TW201229050A - Dihydropteridinone derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to dihydropteridinone derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel dihydropteridinone derivatives presented by formula (I), the uses for treatment especially for polo-like kinase protein kinase inhibitors, in which each substitute group of general formula (I) is as defined in the specification.

Description

201229050 ir VI. Description of the invention: • Technical field to which the invention pertains The present invention relates to a novel one-off deuterated derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, in particular Use of a Ρ1 k kinase inhibitor. [Prior Art] The cyclin-dependent kinase family (Cdks) has long been recognized as the most important regulator of the cell cycle, but as the research progresses, more and more other protein kinases are found to progress to the cell cycle. Also plays a key role. The Polo-like kinase (plks) family is one of them. PIks are a class of serine/threonine kinases that are important in regulating the cell cycle. According to the literature, Plks is involved in the regulation of many steps in the process of mitosis, including activation of cdc25C and Cdkl/Cyclin B during G2-M phase transformation, centrosome maturation, and spindle formation and assembly. In the later stages of mitosis, Plks is also involved in the separation of sister staining monomers, which promotes the activation of complex components and the regulation of sept in the cytokinesis phase. So far, four subtypes have been found in the Plks family, namely Plkl, Plk2, Plk3 and Plk4. (In which Plkl is particularly important for the regulation of mitosis (see Glover et al., Chem. No. 1998, 12:3777-87; Qian et al., 2〇〇1, 12:1791-9). Plkl expression and activity The level is closely related to the degree of growth of tumor cells (see WO 2004/014899 A1). Excessive expression of Plkl has been shown to be associated with a variety of high-proliferation types of tumors, such as non-small cell lungs 3 95201 201229050 cancer, squamous cell carcinoma, breast Cancer, ovarian or papillary carcinoma, and colorectal cancer (Wolf et al, 1997, 14, 543-549; Knecht et al, 1999, 59, 2794-2797; Wolf et al, corpse 3仏〇7 and es / "rad 2000,196,753-759; Weichert et al., price./2004,90,815-821; Ito et al., and r. 77心77<^厂2004,90,414-418; Takahashi et al. , G/2Ce/* 5W·, 2003, 94, 148-152. The prior art has disclosed a number of dihydrobite derivatives as pikl inhibitors, and the literature reports that such compounds have antiproliferative activity. For example: Patent A dihydroacridone derivative, which is prepared by W0 03/020722, WO 2004/076454 and WO2008050096 Method and use thereof in a pharmaceutical composition for treating a disease associated with the activity of a cell cycle kinase and characterized by excessive or different cell proliferation. Patent WO 〇1 /〇19825 discloses a butterfly alpha ketone derivative as a treatment The use of tumors and viral diseases. Due to the resistance of various types of tumors, there is an urgent need to develop new drugs to overcome tumors. In addition, there are some patents, such as W02004076454, W02006018220, US20040176380, W02007135374, W02006018185, W02006058876, W02006018222, W02006018182 Other compounds are also disclosed as Plkl inhibitors. However, although several Plkl kinase inhibitors have been disclosed, their applications are still limited by pharmacodynamics, pharmacokinetics, etc., and have not been long-lasting. Drugs, there is still a need to develop plkl kinase inhibitors with improved properties such as safety, pharmacokinetics, etc. The present invention aims to provide a 95201 having plkl kinase inhibitory activity.

S 4 201229050 Drugs can be used to treat cell proliferative diseases such as cancer, infection, inflammation and autoimmune diseases. SUMMARY OF THE INVENTION In order to overcome the deficiencies of the prior art, an object of the present invention is to provide a dihydroacridone derivative represented by the formula (I), and tautomers, racemates thereof, Enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts and metabolites or prodrugs:

Wherein: R1 and R2 are each independently selected from a hydrogen atom or an alkyl group; or 'R1 and R2 together with the atom to which they are attached form a 3 to 8 membered ring' wherein the 3 to 8 membered ring contains 〇 to 2 N, 0 or Lu (7) doping atom ' and the 3 to 8 members are further required to be further selected by one or more selected from the group consisting of an alkyl group, an alkoxy group, a dentate group, a hydroxyl group, a cyano group, a nitro group, an aryl group, a heteroaryl group, Substituted by a substituent of -S(〇)〇nr7r8, _c〇NR7R8, -NRY, -S(0)0R9, -C0R9 or _C(0)0R9; R3 is selected from a hydrogen atom, an alkyl group, an alkenyl group Or alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is further protected by one or A plurality of selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, _S(〇)〇nrY, -C_7R8, 7R8, -S(0)0R9, -COR9 or -C( 0) The substituent of 0R9 is substituted by 95201 5 201229050; alternatively, R2 and R3 together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or SCO% a hetero atom, and the 3 to 8 members look around One step is selected from one or more selected from the group consisting of alkyl, alkoxy's, hydroxyl, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)0NR7R8, -C0NR7R8, -NR7R8, ~S (0) Substituted by a substituent of 0R9, -C0R9 or -C(0)0R9; R4 and R5 are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, a cyano group or a nitro group; and L is selected from an alkylene group. Further substituted by one or more substituents selected from halogen, cyano, nitro or alkyl, where necessary, wherein the alkyl group is further substituted by one or more halogens; R6 is selected from alkyl groups, wherein The alkyl group is further substituted by a heterocyclic group; when R6 is selected from an unsubstituted alkyl group, A is selected from a bicycloalkyl group, a biheterocycloalkyl group, a spirocycloalkyl group or a spiroheterocyclic group, wherein the bicyclic ring is exemplified. The base, the biheterocyclyl, the spirulinyl or the spiroheterocyclyl are further substituted by one or more R12; the heterocyclic group, the bridged-Wiki group, the lysyl group, the w-di-hetero group, the bis need to be further Or a plurality of Rlz substituted; when R6 is selected from a heterocyclic group-substituted alkyl group, A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, a bicyclofilament, a biheterocyclic group, a bridge ring, and a miscellaneous Or a spiroheterocyclyl group, wherein the ring, the heterocyclic group, the snail environment or the spiroheterocyclic group, R7 and R8, are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic ring 95201 6 201229050 a group, a group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are optionally substituted into H or more selected from the group consisting of a silk, an alkoxy group, a heterogeneous group, and a group. Substituted by an aryl, heteroaryl, halogen, hydroxy, cyano, -s(〇)〇R9, -COR9, -C(〇)OR9, _s(0)0NRlY1, _c〇NRlY1 or a substituent of state r10r11; Alternatively, R7 and R8 together with the N atom to which they are attached form a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more N, fluorene or S(0)m heteroatoms, and The 3 to 8 membered heterocyclic group is further selected from one or more selected from the group consisting of alkyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)0R9, Substituted by a substituent of -COR9, -C(0)0R9, -SCOWNF^R11, -CONRMR11 or -NFTR11; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or aryl group Further burned by one or more as needed Substituted; R1Q and R11 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; R12 is selected from the group consisting of an alkyl group, an alkoxy group, a cycloalkyl group, a halogen group, a thio group, a cyano group, a nitro group, a carbonyl group, a -S group (0)0NR7R8, -C0NR7R8, -C(0)0R9, -0C(0)R9, -〇(CH2)rC(8)OR9, -〇C(〇)NR7R8, -SCOW, -〇S(0)OR9, -NHC (0) Substituted by a substituent of R9 or -COR9, wherein the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is further further selected from one or more selected from the group consisting of an alkyl group, a cycloalkyl group, a heterocyclic group, Substituted by an aryl or heteroaryl substituent; m is 0 or 1; η is 0, 1 or 2; and r is 1, 2 or 3. Preferred Embodiments of the Invention 'Compounds of the formula (I) are mutually mutated 7 95201 201229050 Constructs, exosomes, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable And a salt thereof, wherein: R1 is selected from a hydrogen atom; R2 is selected from an alkyl group; R3 is selected from an alkyl group or a cycloalkyl group; or R and R3 together with the atom to which they are bonded form a 3- to 8-membered heterocyclic group, wherein The 3 to 8 membered heterocyclic group contains fluorene to 2 N, fluorene or S(0)n heteroatoms, and the 3 to 8 membered heterocyclic group is further selected from one or more selected from the group consisting of alkyl and alkoxy groups. Base, halogen, hydroxy, cyano, nitro, carbonyl, aryl, -S(〇)〇nr7r8, -C〇NR7R8, -NR7R8, -S(0)0r9, -COR9 or -C(0)0R9 Substituted by a substituent; R4 and R5 are each independently selected from a hydrogen atom, a halogen or an alkyl group; R is selected from the group "wherein the alkyl group is further substituted with a heterocyclic group as needed; ; when R6 is selected from unsubstituted alkane A, wherein A is selected from a bicycloalkyl group, a biheterocyclyl group, a spiroalkyl group or a spiroheterocyclyl group, wherein the bicycloalkyl group, the bicyclohetero group, the bridged cycloalkyl group, the bridged heterocyclic group, the spirocycloalkyl group Spiro heterocycle Further substituted with one or more R12 as needed; when R6 is selected from a heterocyclic substituted alkyl group, A is selected from cycloalkyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged cycloalkyl, A bridged heterocyclyl, spiroalkyl or spiroheterocyclyl wherein the cycloalkyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged alkyl, bridged heterocyclyl, spiroalkyl or spiro The heterocyclic group is further substituted by one or more R12 as needed; R7 and R8 are each independently selected from a hydrogen atom, a pyridyl group, a cycloalkyl group, a heterocyclic ring 95201 8 201229050 t = or a heteroaryl group, wherein the radical, Wei The base, heterocyclic group, and aryl group are further selected as needed

C0NR1DRu or -NR10R = ring group, aryl group, heterofilament, _, cyano, cyano group, (d), sincere, -S(0)0R, -COR9, -S(〇)〇NRl〇Rll, one substitution Substituted; μ or R and R together with the N atom to which they are attached form a 3 to 8 member coat wherein the 3 to 8 member % contains one or more N, 〇 or s (〇 > heteroatoms, and the 3 To the 8-membered heterocyclic ring, as needed, one or more selected from the group consisting of alkyl, alkoxy, heterocyclic, aryl 'heteroaryl, dentate, hydroxy, cyano, carboxylic acid, carboxylic acid Substituted by a substituent of an ester, a carbonyl group, _s(〇)〇r9, _c〇r9, -SCCOONRUR11, -CONRMr11 or _NR10R11; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group Or the aryl group is further substituted by one or more alkyl groups as needed; R1D and R11 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; and R is selected from the group consisting of a hospital group, an alkoxy group, a cycloalkyl group, and a dentate element. , thiol, cyano, nitro, carbonyl, -S(0)0NR7R8, -c〇NR7R8, -C(0)0R9,_0C(0)R9, -0(CH〇rC(0)0R9, -0C (0) Substituted by a substituent of NR7R8, -S(0)mR9, -〇S(〇)〇R9, -NHC(0)R9 or -COR9, wherein the alkane Alkoxy, cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; m is 0 or 1 ; η is 0, 1 or 2; and r is 1, 2 or 3. Preferred embodiment of the invention, a compound of the formula (I) or 95201 201229050 tautomeric ship, racemate, Enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts, wherein: R1 and R2 are each independently selected from a hydrogen atom or an alkyl group; R is selected from the group consisting of a gas atom, an alkyl group. Or alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is further desired One or more selected from the group consisting of alkyl, alkoxy, S, hydroxy, fluoro, nitro, aryl, _S(0)0NRY, _C0NR7R8, -NR7R8, -s(〇)〇R9, -COR9 or Substituted by a substituent of -C(0)0R9; or 'R and R3 together with the atom to which they are attached form a 3 to 8 membered ring' wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or 3 ( 0) „1 heteroatoms, and 3 to 8 members are further required to be further selected from one or more selected from the group consisting of alkyl, alkoxy, _, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)0NR7R8, -C0NR7R8 Substituted by a substituent of -NR7R8, -S(0)0R9, -C0R9 or -C(0)0R9; R4 and R5 are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitro group; Further substituted by one or more substituents selected from halogen, cyano, nitro or alkyl, if desired, wherein the alkyl group is further substituted by one or more auxins; R6 is selected From an alkyl group; A is selected from a bicycloalkyl group, a biheterocyclyl group, a spirocycloalkyl group or a spiroheterocyclyl group, wherein the bicycloalkyl group, the biheterocycloalkyl group, the spirocycloalkyl group or the spiroheterocyclyl group are further Substituted by one or more R12; 95201 10 201229050 R7 and R8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, The heterocyclic group, aryl or heteroaryl group is further optionally one or more selected from the group consisting of an alkyl group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen group, a hydroxyl group, and a cyano group. Substituted by a substituent of _s(〇)〇R9, _C0R9, C(0)0R9, —SCCOONITR11, -CONITR11 or -NR10RU; or R7 and R8 together with the N atom to which they are bonded form a 3 to 8 membered heterocyclic group Wherein the 3 to 8 membered heterocyclic group contains one or more N, oxime or SCO% heteroatoms, and the 3 to 8 membered heterocyclic group is further selected from one or more selected from the group consisting of an alkyl group and an alkoxy group. , substituted by heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0) 〇R9, -COR9, C(0)0R9, -S(0)0NRlflRn, -CONRWR11 or -NW1 Substituted; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or the aryl group is further substituted by one or more substituents as needed; R1() and R11 are selected from a hydrogen atom , alkyl, cycloalkyl or aryl; R12 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)0NR7R8, -c〇NR7R8, - C(0)0R9, -〇C(0)R9, -0(CH2)rC(〇)〇R9, -〇c(〇)nry, _s(〇)bR9, -〇s(〇)〇R9, - Substituted by a substituent of NHC(0)R9 or -COR9 wherein the alkyl, alkoxyl, cycloalkyl or heterocyclic group is as desired Further substituted by one or more substituents selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; m is 0 or 1; η is 〇, 1 or 2; and r is 1 ' 2 or 3. 11 95201 201229050 Preferred embodiment of interconversion = a compound of the formula (I) or

Alternatively, R2 and R3 together with the atoms to which they are attached form a 3 to 8 membered ring' wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or 3 (0 夂 heteroatoms, and the 3 to 8 The ringer is further required to be further selected from one or more selected from the group consisting of alkyl, alkoxy, dentate, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)0NR7R8, -C0NR7R8, -NR7R8. Substituted by a substituent of -S(0)0R9, -C0R9 or -C(0)0R9; R4 and R5 are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitro group; Further, optionally substituted by one or more substituents selected from halogen, cyano, nitro or alkyl, wherein the alkyl group is further substituted by one or more halogens; R6 is selected from the group consisting of alkyl groups, Wherein the alkyl group is further substituted by a heterocyclic group; when R6 is selected from a heterocyclic group-substituted alkyl group, A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, a bicycloalkyl group, a biheterocyclic group, a bridged cycloalkyl group. Hybrid bridge cycloalkyl, spiro 12 95201

S 201229050 t-1 alkyl or spiroheterocyclyl, wherein the cycloalkyl, heterocyclyl, bicycloalkyl, bis-heterocyclyl, bridged cycloalkyl, hetero bridged cycloalkyl, spirocycloalkyl or spiro The heterocyclic group is further optionally substituted by one or more R12; R7 and R8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the ring group The alkyl group, heterocyclic group, aryl group or heteroaryl group is further optionally one or more selected from the group consisting of alkyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S (〇) 〇r9, -COR9, C(0)〇R9, -sco^NlTR11, -C〇NRlflRn or a substituent of -NR1QRU; or, R7 and R8 together with the N atom to which they are attached form a 3 to An 8-membered heterocyclic group wherein the 3 to 8 membered heterocyclic group contains one or more n, fluorene or SCO% heteroatoms, and the 3 to 8 membered heterocyclic group is further selected from one or more selected from the group consisting of an alkane Alkyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, thiol, cyano, -S(〇)〇R9, -C〇R9, c(〇)〇r9, -sccoonW1, -CONRWR11 Or substituted with a substituent of -NR1DRn R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or the aryl group is further substituted with one or more alkyl groups as needed; R10 and R11 are selected from a hydrogen atom, an alkyl group, a cycloalkane. Or an aryl group; R is selected from the group consisting of alkyl, alkoxy, cycloalkyl, dentate, hydroxy, cyano, nitro, carbonyl, -S(〇)〇nr7r8, _C0NRY, _c(〇)〇r9, _ 〇c(〇)r9, -〇(CH2)rC(〇)〇R9 x -〇C(〇)NR7R8 ^ -S(0)mR9 ^ -0S(0)0R9 ' -nhc(o)r9 or -C0R9 Substituted by a substituent wherein the alkyl, alkoxy, decyl or heterocyclic group is further protected by one or more substituents selected from the group consisting of alkyl, cycloalkyl, miscellaneous, silk or heterofilament Substituted; 13 95201 201229050 m is 0 or 1; η is 〇, 1 or 2; and r is 1, 2 or 3. Preferred embodiments of the invention, a variant, a racemate, an enantiomer,:: or a mixture thereof, and a pharmaceutically acceptable construct, and a moiety selected from the group consisting of pyridinium Preferably, the ethyl group is a preferred embodiment of the invention, and the first embodiment is an interconversion _, an external _, a __, a = or an or a cyclodyl group, preferably an isoendyl group or a cyclopentyl group. The present invention is selected from the preferred embodiments of the basic invention, and the compound tautomers, racemates, enantiomers, diastereomers, and mixtures thereof of the formula (1) Form, and pharmaceutically acceptable, L is selected from a sub-alkyl group, preferably a methylene group. a salt, wherein ° is a preferred embodiment of the invention, a general formula (1) tautomer, a racemate, an enantiomer, a non-isomer, a mixture thereof, and a pharmaceutical thereof An acceptable salt, r6 and a substituted alkyl group, the oxime is selected from cycloalkyl. , k自杂% Preferred (IV) of the present invention, a compound of the formula (1) or a pot tautomer, a racemate, an enantiomer, a diastereomer, a -= compound form And a pharmaceutically acceptable salt, wherein A is selected from the group consisting of two hetero-formulas (1), which may contain an asymmetric carbon atom, and thus may be a pure diastereomer, a non-antibody mixture, a diastereomer of 95201 14 201229050. The material of the in vitro racemate, the diastereomeric outer matrix is present or exists as a (iv) spiro compound. The invention includes all of these forms. Mixtures of diastereomeric mixtures, diastereomeric racemates or diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography and hydrazine. __ Typical compounds of the invention include, but are not limited to: Compound structure nomenclature 1 6rsV 1 丫0 4-((^-8-cyclopentyl-7-ethyl_5-fluorenyl-6-sideoxy-5 , 6, 7, 8-tetrahydro-acridin-2-ylamino)-3-decyloxy-N-((3疋8aA〇-hexahydro-n ratio p and [2, 1-c] [1,4]-ηoxan-3-ylmethyl)-benzoquinone 2 ----- 4-((N)-8-cyclopentyl-7-ethyl-5-fluorenyl- 6-Sideoxy_5, 6, 7, 8-tetrazino-indole-2-enylamino)-3-indolyl-N-((3a5; 55; 6a«-2-methyl- Octahydro-cyclopentamethylene-5-yl)-benzamide 3 L-- 4-((^〇-8-cyclopentyl-7-ethyl-5-fluorenyl-6-side oxygen) -5, 6, 7, 8-tetrahydro-acridin-2-ylamino)-[ (((3a^ 5iS, 635^-2-mercapto-octahydro-cyclopenta[C7] 〇 ratio咯-5-yl)-methyl)-3-decyloxy-benzoguanamine 15 95201 201229050 4 4_((() -8-cyclopentyl-7-ethyl-5-fluorenyl-6-side Oxy-5, 6, 7, 8-tetrahydro-purine-densation 2-ylamino)-N-(((3a*/?, 55; 68^-5-hydroxy-2-indolyl-eight Hydrogen-cyclopenta[c]0-pyrid-5-yl)-methyl)-3-decyloxy-benzamide 5 4-((friend)-8-cyclopentyl-7-ethyl- 5-mercapto-6-sideoxy-5, 6, 7, 8-four棠口定-2-ylamino)-N-(((3a)P, 57?,63^-5-hydroxy-2-indolyl-octahydro-cyclopenta[]pyr-5-yl) -Methyl)-3-decyloxy-benzamide 6 ώ 4-((-8-cyclopentyl-7-ethyl-5-mercapto-6-sideoxy-5, 6, 7 , 8-tetrahydro-indolizine_2_ylamino)_N-(1_indolyl-bottom-4-yl)-3-(tetrahydro-furan-3-yl-methoxy)- Benzamidine 7 α «ν^° 4-((友)-8-cyclopentyl-7-ethyl-5-methyl-6- pendantoxy_5,6, 7, 8-tetrahydro_嗓〇 -2- 基 -2- -2- - - - 口 口 _ _ 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- ((友)-8-Cyclopentyl_7-ethyl-5-mercapto-6-o-oxy-5,6,7,8-tetrahydro-indole-2-ylamino)-N - 16 95201 s 201229050 ((4&7?,67?,7&5·)-2-mercapto-octahydro-1 and-cyclohexane[c]pyridin-6-yl)-3-decyloxy -phenyl hydrazine 8-2 I 0, 4-(U)-8-cyclopentyl-7-ethyl-5-methyl-6-oxirane_5, 6, 7, 8-tetrahydro-嗓0-di-2-ylamino)-N-((4&5;65;7&>)-2-methyl-octahydro-1 and cyclohexan[C]pyridin-6 -yl)-3-methoxy-benzamide 9 4-(U)-8-cyclopentyl-7-ethyl-5- Keto-6-sideoxy-5,6,8-tetrahydro-°$〇定-2-ylamino)-^ ((3 especially 8aS)_hexanitro-α is 嘻[2, Lc][l,4]oxazin-3-yl)-indolyl)-3-methoxy-benzamide 10 is V domain rH 0' 4-((ΛΟ-δ-cyclopentyl-7-) Ethyl-5-fluorenyl-6-tertiaryoxy-5, 6, 7, 8-tetrahydro-° 0-yl-2-ylamino)-3-methoxy^-((38^,5 ^68^)-2-Mercapto-octahydro-cyclopenta[c]pyrrole-5-yl)-benzimidamide 11-1 \ νή Ρ 0, 4-(U)-8-cyclopentyl- 7-Ethyl-5-mercapto-6-sideoxy_5, 6, 7, 8-tetrahydro-indolyl-2-ylamino)-[ ((43^65 73^-2-曱) Base-octa argon-10,000-cyclopenta[c] °pyridin-6-yl)-3-decyloxy-benzene 17 95201 201229050 formamide 11-2 rH 0' 4-( (·Α〇- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,8-tetrahydro-pteroquinone-2-ylamino)-indole-((4a5; 6疋7ai?)-2-mercapto-octahydro-1 and-cyclopenta[c]0-pyridin-6-yl)-3-methoxy-benzoguanamine 12 4-((None)- 7-Ethyl-8-isopropyl-5-methyl-6-sideoxy_5, 6, 7, 8-tetrahydro-pterin-2-ylamino)·^-((3 friends) ,8aS)_hexahydro-_11 〇[2, lc][l,4]-oxazin-3-ylindenyl)-phenylhydrazine Amine 13 4-((N)-7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro-pterin-2-ylamino) -N-((35",8^51)-hexanitro-pyrolo[2, lc][l,4]-oxazin-3-ylmethyl)-benzoguanamine 14 4-(U )-7-Ethyl-8-isopropyl-5-mercapto-6-sideoxy-5, 6, 7, 8-tetrahydro-indot-2-ylamino)-N-((3) : 8a^〇-hexahydro-° ratios each [2, lc][l,4]-oxazine_3_ylmethyl)_benzoquinone 15 4-((and)-7-ethyl -8-isopropyl-5-methyl-6-oxirane-5, 6, 7, 8-tetrahydro-indole 0-denylamino)-N- 18 95201 201229050 ((351,8a left)-hexahydrogen -° ratio of each [2, lc][l,4]-oxazol-3-ylindenyl)-benzoguanamine 16-1 4-(U)-7-ethyl-8-isopropyl -5-mercapto-6-o-oxy-5,6,8-tetradec-acridin-2-ylamino)-N-((4aT?, 6疋7a5*)_2-fluorenyl- Octanitro-1#-cyclopenta[Bist-6-yl)-3-decyloxy-benzamide-1-2 _NC^ 1 4-(U)-7-ethyl-8-isopropyl 5-(indolyl-6-yloxy-5,6,8-tetrahydro-indole-2-ylamino)-[((435;65;7& magic-2-methyl) - octahydro-1 and -cyclopenta[c]0-pyridin-6-yl)-3-decyloxy-benzoguanamine 17-1 \ H 4 -(〇?)-7-ethyl-8-isopropyl-5-mercapto-6-oxirane-5, 6, 7, 8-tetramethylene-β-bito-2-ylamino)- N-((4a7?, 65",7aiS)_2-Methyl-octa-nitro-1 and-cyclopenta[c] ° ratio σ--6-yl)-3-decyloxy-benzoguanamine 17 -2 ? i 4-(U)-7-ethyl-8-isopropyl-5-mercapto-6-oxo-5, 6, 7, 8-tetrahydroindan-2-ylamino )--((4a5;6y?,7ay?)-2-mercapto-octa-argon_ 1 cyclopenta[c]π-pyridin-6-yl)-3-decyloxy-benzamide 19 95201 201229050 18 α«ν^° i. 4-(U)-7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro-indole-2-ylamino)-oxime -(1-methyl-〇辰咬-4-yl)-3-(tetrahydro-π-pentan-2-yl-decyloxy)-benzoguanamine 19 rr i, H On.sJU 〇· · 〇(00-3-曱oxy-4_(5-fluorenyl-6-oxo-8-nonylbenzene) _6,6a,7,8,9, 10-hexahydro-5 and -吼Qin [2, 1-/7] acridine-2-ylamino)-N-(l-mercaptopiperidin-4-yl)benzamide 20 〇\ (^0-4-(8 -Isopropyl-5-mercapto-6-oxo-6,6a,7,8,9-hexahydro-5 and -° 嗓[2, 1-/?] acridine-2 -ylamino)-3-indolyl-N-(l-methyl-piperidin-4-yl)benzamide 21 a« Vw, 0,H Ln丫N, 0 U)-2-( 2-decyloxy Μα-mercaptopiperidin-4-ylamine fluorenyl)anilino)-indole, fluorene, 5-trimethyl-6-sideoxy-6a, 7, 9, 10-tetrahydro -5 and -0-pyrazine and [2, 1-/7] 〇 -8 -8 (6^0-rebel amine 22 a«V^x 〇\ 0 U)-4-(8-ethyl fluorenyl- 5-methyl-6-tertiary oxy-6,6a,7,8,9-hexahydro-5 and -D ratio 0 dimethyl [2, 1-/?] acridine-2-ylamino )-3-decyloxy-N-(l-mercaptopiperidin-4-yl)benzamide 20 95201 201229050 23

(Anthranil-3-oxo-4-(5-fluorenyl-6-o-oxo_8-phenyl-6,6a,7,8,8-trihydro-5 and-pyridazine) 2,1-Λ]喋β定-2-ylamino)-N-indole-methylpiperidin-4-yl)benzamide or its tautomers, racemates, enantiomers , diastereomers, mixtures thereof, and pharmaceutically acceptable salts. Further, the present invention provides a compound of the formula (IA) which is an intermediate for the preparation of the compound of the formula (I):

(IA) wherein: G is selected from a leaving group, preferably selected from the group consisting of halogen, sulfonyl sulfonyl, p-nonyl fluorenyl, tri-It stellate or alkoxy; R is selected from a hydrogen atom or an alkyl group. R1 is selected from a hydrogen atom or an alkyl group; R2 and R3 together with the atom to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or S(0)n hetero Atom, and the 3 to 8 members are further required to be further selected from one or more selected from the group consisting of alkyl, alkoxy, aryl, halogen, hydroxy, cyano, carbonyl, carboxylic acid, carboxylic acid ester, -S(0)0NR7R8 Substituted by a substituent of -C0NR7R8, -NR7R8, -S(0)0R9 or -C0R9. , 21 95201 201229050 n'F to fi9, as typical compounds of formula (1) 14UA) include compounds

21b

Cl 23k

t stated. 'But not limited to: Named (burning-2-chloro-6-sideoxy-6a, 7, 9, 10-tetrahydro-5 and -° than 嘻[2,1-Λ] bite-8 (6 Throw - tert-butyl carboxylate (Phantom-2-gas-5-methyl-6- pendant oxy-6a, 7, 9, 10-tetrahydro-5^pyrazine and [2, 1-/?] 喋Pyridin-8(6^)-tert-butyl carboxylic acid 0^2-chloro-5-mercapto-8-indolesulfonyl-7, 8, 9, 10-tetrahydro-5 and pyrazine 2, l-/?]^^-6(6a^〇-ketone(皮)-2-chloro-8-isopropyl-5-fluorenyl~7, 8, 9, 10-tetrahydro-511-〇 °β和[2,1-/?]Acridine-6(6a^)-one (Λ0-2-chloro-5-methyl-7,8,9,10-tetrahydro-5-pipyrazin And [2, 1-Λ] acridine-6 (6aZ〇-酉同($)-2-chloro-N, N,5-trimethyl-6-sideoxy-6a,7, 9,10- Tetrahydro-5 and -° ratio 嘻[2,1-h]acridine-8 (6^-carboxylic acid decylamine _(7?)-2- gas-5-methyl-6-sideoxy: ~ -6a, 7, 9, 10-tetrahydro-5 and -° 嗓[2, 1-/?] acridine-8(6^)-carboxylic acid benzyl ester "ΰ〇-2-气- 8-phenyl-7, 8, 9,101 hydrogen-5^pyrazino[2,1-indenyl]acridine-6(6a^〇-酉同(和)- 2-chloromethyl-8-phenyl- 7, 8, 9,10_tetrahydro _5 and -° 嗓[2,1-/?] 嗓 ° -6 (68 milk-ketone 22 95201 201229050 r; further, the present invention provides a general formula ( I) Preparation of the compound , The method comprising:

G

The OR compound of the formula (ΙΑ) is reacted with a compound of the formula (IB) or a salt of a compound of the formula (iβ) to give a compound of the formula (丨). Wherein: R is selected from methyl; G, R to R3 are as defined for the compound of the formula (ία); and A, n, L, R4 to R6 are as defined for the compound of the formula (丨). Another aspect of the invention relates to a compound of the formula (I) according to the invention, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable form The use of a salt in a medicament for preparing a cell proliferative disorder, wherein the cell proliferative disorder is cancer, infection, inflammation, and autoimmune disease, and the cancer is cervical cancer or colon cancer. Another aspect of the invention relates to a method of treating a cell proliferative disorder comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a racemate, an enantiomer thereof a form, a mixture of diastereomers, a mixture thereof, and a pharmaceutically acceptable salt, wherein the cell proliferative disorder is cancer, infection, inflammation, and autoimmune disease, and the cancer is cervical cancer or colon cancer. Another aspect of the invention relates to a compound of the formula (I) according to the invention or its mutual 23 95201 201229050 isomer, racemate, enantiomer, diastereomer, mixture thereof, and pharmacy An acceptable salt is a drug for treating a cell proliferation disease, wherein the cell proliferation disease is cancer, infection, inflammation, and autoimmune disease, and the cancer is cervical cancer or colon cancer. Further, the present invention relates to a compound of the formula (I) of the present invention or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable compound thereof. Use of a salt in the preparation of a Plk kinase inhibitor. Another aspect of the invention relates to a method of inhibiting Plk kinase comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer, racemate, enantiomer thereof, Diastereomers, mixtures thereof, and pharmaceutically acceptable salts. The invention further relates to the compounds of the formula (I) according to the invention, or the tautomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, as A drug that inhibits Plk kinase. Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a tautomer, racemate, enantiomer, diastereomer thereof, and mixtures thereof And pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or excipients therefor. The pharmaceutical composition is used for the preparation of a medicament for treating cancer, infection, inflammation and autoimmune diseases, which is cervical cancer or colon cancer. Use of the pharmaceutical composition in the manufacture of a medicament for a Plk kinase inhibitor. The pharmaceutical composition is a drug for treating cancer, infection, inflammation, and autoimmune diseases, and the cancer is cervical cancer or colon cancer.

24 95201 S 201229050 Another aspect of the invention relates to a method of treating a cell proliferative disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a racemate thereof a pharmaceutical composition of an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, wherein the cell proliferative disorder is cancer, infection, inflammation, and autoimmune disease, The cancer is cervical cancer or colon cancer. The compounds of the present invention and pharmaceutically acceptable salts thereof can be administered orally, dermally or parenterally (e.g., by injection, inhalation, spray, sublingual, rectal or vaginal). "Injectable administration" includes intravenous injection, joint injection, intramuscular injection, subcutaneous injection, parenteral injection, and infusion. Dermal administration includes topical or cross-administration. Oral administration is carried out according to methods well known to those skilled in the art, and one or more auxiliaries such as diluents, sweeteners, flavoring agents, coloring agents and preservatives may also be present in such formulations. The amount of the pharmaceutically active compound in each case should be in the range of from 0.1 to 90% by weight of the total composition, preferably from 0.5 to 50% by weight, in an amount sufficient to achieve the metering range provided below. If necessary, multiple specified doses can be provided daily. In tablets, the active ingredient is mixed with non-toxic, pharmaceutically acceptable excipients. These excipients include: inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulation or disintegrants (such as corn starch, alginic acid) and binders (such as magnesium stearate, Stearic acid, talc). The tablets may be uncoated or they may be coated by a known method to alleviate the decomposition and absorption in the gastrointestinal tract to prolong the efficacy, such as glyceryl stearate or glyceryl distearate. These compounds can also be prepared in a solid, fast release mode. In hard capsules, the active ingredient is mixed with an inert solid diluent such as calcium carbonate, 25 95201 201229050 in acid or clay; in soft capsules, the active ingredient is mixed with water or oil vehicle such as peanut oil, stone or olive oil. In aqueous suspensions, the active ingredient is mixed with excipients which are suitable for pharmaceutical use. These excipients are suspending agents (such as hydroxy strontium cellulose sodium, decyl cellulose, hydroxypropyl-methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum arabic), dispersing agents or wetting agents [including natural a phosphatide (such as lecithin) or a condensate of an alkylene oxide and a fatty acid (such as polyoxyethylene stearate) or a condensate of an alkylene oxide and a long-chain fatty alcohol (such as heptadecyl hexadecyl hexadecanol) Or ethylene oxide and a partially derived condensate derived from a fatty acid and a hexitol (such as polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate, p-hydroxybenzoate); one or more colorants; one or more fragrances and one or more sweeteners. (such as sucrose or saccharin). Dispersible powders or granules suitable for the preparation of aqueous suspensions are prepared by admixing water, active ingredient and dispersing or wetting agents, suspending agents and one or more preservatives. Other excipients such as sweeteners, colorants or fragrances may also be added thereto. The syrup comprising the active ingredient material of the present invention or a composition thereof may additionally include a sweetener such as saccharin, sweetener, glycerin or sugar, and a flavor change agent. For example, sweeteners such as vanilla or orange extracts. In addition, it may also include a suspending aid or a thickening agent (such as sodium carboxymethylcellulose), a wetting agent (such as a condensation product of a fatty alcohol with ethylene oxide) or a preservative (such as p-hydroxybenzoate). ). Injection or infusion solutions are prepared in a conventional manner, for example, by adding an isotonic agent, a preservative (such as p-hydroxybenzoate) or a stabilizer (such as ethylenediaminetetraacetic acid).

26 95201 S 201229050 metal salt), if necessary, use emulsifier and / or dispersant, while using water = dilution (four), you can use organic as a solvent or co-solvent, if necessary, and transfer to injection vial or safety Bottle or bottle. The sigma-detecting agent is, for example, mixed with a cut body (for example, a neutral fat or polyethylene glycol or a derivative thereof) prescribed for this purpose. Suitable excipients can be, for example, water, in pharmaceutically acceptable organic solvents (such as paraffin, for example, petroleum fractions), vegetable derived oils (for example, peanut oil or sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerol). , carrier [such as natural (such as 'casting clay, clay, talcum powder), synthetic mineral powder (for example, highly dispersible ceria and citrate), sugar (for example, crude, lactose and glucose), ritual Chemical agents (for example, lignin, sulfite waste liquid, sulfhydryl cellulose, temple powder and polyethylene strontium _) and lubricants (for example, stearic acid town, talc, stearic acid and lauryl sulfate) sodium). The preparation is administered in a usual manner, preferably by oral or dermal route, preferably orally. In the case of oral administration, the tablet may of course include additives in addition to the above-mentioned carriers (such as sticks, carbonated feed and acid (2) and other additives (such as temple powder) preferably potato starch, gelatin And analogs. It is also possible to use a lubricant to form tablets, such as hard fatty acid money, sodium lauryl sulfate and talc. In the case of water (four) floating liquid, the active substance can be compared with the above-mentioned ingredients. Mixing agent or coloring agent. For the substance solution, a suitable liquid carrier can be used =:: mother hour 1 to _mg, preferably per hour, but it can be deviated from the above dosage as needed, depending on the body weight or administration 95201 27 201229050 Method, the individual's response to the drug, the nature of the formulation used, and the time or interval of administration. Therefore, in some cases it may be sufficient to use a minimum dose less than the above, but in other cases it must exceed the specified Upper limit. When administered in large doses, it is recommended to divide it into a single dose several times a day. Of course, as is well known to those skilled in the art, the dosage of the drug is dose dependent. A variety of factors, including but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion In addition, the optimal treatment modalities such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens. In contrast, the following terms used in the specification and claims have the following meanings: "Alkyl" means a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl, etc. More preferably contains 1 to a lower alkyl group of 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc. The alkyl group may be substituted or unsubstituted, when When substituted, the substituent is preferably one or , independently selected from alkoxy, alkenyl, alkynyl, halogen, hydroxy, amine, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, double hetero Ring group, _S(0)0NR7R8, -C0NR7R8,

28 95201 S 201229050 -NR7R8, -S(0)0R9, -COR9, carboxylic acid or carboxylic acid ester. "Thin base" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, a vinyl group, a propylene group, a 2-propenyl group, a 1-, 2- or 3-butenyl group or the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, alkynyl, i-, hydroxy, amine, nitro , cyano, fluorenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)0NR7R8, -C0NR7R8, -nr7r8, _s(〇)〇 R9, -c〇R9, a carboxylic acid or a carboxylic acid ester. An alkyl group as defined above which consists of an alkynyl group and at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, propynyl, 2-propynyl, 1-'2- or 3-butynyl, and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (f), independently selected from alkyl, alkoxy, alkenyl, halogen, thiol, amine, nitro , nitrogen group, continuation base, % alkyl group, hetero group, aryl group, base group, diweiyl group, diheterocyclic group, -s(o)_V, -C0Nrhr8 "s(8)〇R9, _c〇R9, Lai Or a carboxylic acid ester. "Cycloalkyl," means a non-aromatic monocyclic or polycyclic ring (10) comprising from 3 to 20 carbon atoms, preferably from 3 to 1 carbon atoms, more preferably a cycloalkyl ring. Contains 3 to 8 (four) atoms. A non-limiting example of a single observation package: 3 propyl, butyl butyl, cyclopentyl, cyclopentenyl, oxime, hexanyl, cycloheptyl, cycloheptatriene, etc. . The polycyclic cycloalkyl group includes a ring, a stalk, and a ring of a ring, and non-limiting examples include a naphthalene group, a norbornyl group, a diamond, and the like. The cycloalkyl group may be substituted or unsubstituted 95201 29 201229050, and when substituted, the substituent is preferably a lower group, independently selected from the group consisting of an alkyl group, an alkoxy group, an alkenyl group, a block group, and a dentate group.

Hydroxy, amine, nitro, cyano, carbonyl, cycloalkyl, heterocyclic, aryl I heteroaryl, bicycloalkyl, biheterocyclyl, -s(o)onr7r8, e()NR7R8 ' - NR7R8, -S(0)0R9, -COR9, carboxylic acid or carboxylic acid ester. "Heterocyclyl" means a non-aromatic monocyclic or polycyclic ring comprising from 3 to 20 ring atoms, wherein one or more of the ring atoms is conjugated to < @^ 目 氮, 氧, or S(0)n (where η is an integer 0 to 2) hetero atom, but does not include a ring moiety of n -0-S- or -SS-, and the remaining ring atoms are carbon. Preferably, the heterogeneous product contains 3 to 10 ring atoms, of which 1 to 4 are hetero atoms, and more preferably 3 to 8 ring atoms. Non-limiting twins of monocyclic heterocyclic groups ^Beiwan color examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphinpiperazinyl, etc., polycyclic heterocyclic groups including bicyclic rings Or a heterocyclic ring of a polycyclic ring, a 'directional, a ring, and a ring. The heterocyclic group may be substituted or unsubstituted. When the roll is taken, the substituent is preferably one or more of the following groups independently selected from the group consisting of a ρ group, a oxy group, a dilute group, a fast group, a dentate, a thiol group, an amine group, an exact group, and a nitrogen group. Base, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)0NR7R8, -C0NR7R8, -NR7R8, -S(0)0R9, -C0R9 , citric acid or a carboxylic acid ester. "Bicycloalkyl" refers to a 5- to 14-membered all-carbon fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one of which Multiple rings may contain one or more double bonds 'but none of the rings have a fully conjugated 7-inch electronic system. For example, 30 95201 201229050

It is preferably a 5-member/5 member or a 5-member/6 member bicycloalkyl group. The bicycloalkyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, hydroxyl, hydroxy, amine, nitro, cyano, carbonyl, cycloalkane. Base, heterocyclic, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -NW, -S(0)〇R9, -COR9, decanoic acid or oxalate. "Biheterocyclyl" refers to a 7 to 12 membered fused ring ("fused" ring system means that each ring in the system is co-protonated with a pair of carbon atoms in the other ring of the body") f group Or the plurality of ring atoms selected from nitrogen, oxygen or S(9) η (where η 疋 integer G to 2) heteroatoms' remaining ring atoms are carbon. These may contain: f multiple double bonds 'but no - one ring is fully conjugated; τ electron system. It is preferably 7 to 1 employee. E.g

More preferably 5 members/5. and . Substituted or unsubstituted 5/6 membered heteroheterocyclic groups. The heteroheterocyclic group may be a substituted or unsubstituted, only bicyclic heterocyclic group. a diheterocyclic ring, independently selected from the group: when substituted, the substituent is preferably one or more amino group, nitro group, silly I alkoxy group, dilute group, alkynyl group, #素, hydroxyl group, earth, carbonyl group , cycloalkyl, heterocyclic, aryl, heteroaryl 95201 31 201229050 benzyl, bicycloalkyl, biheterocyclyl, -S(0)0NR7R8, -C0NR7R8, _NRY, -S(0)0R9, -COR9, Carboxylic acid or carboxylic acid ester. "Spirocycloalkyl" refers to a polycyclic group of 5 to 14 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. 7Γ electronic system. It is preferably 7 to 10 members. The spiro ring is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocyclic fluorene (based group and a bispirocycloalkane), depending on the number of common snail atoms between the ring and the ring. Base. For example:

More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. The spirocycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, dentate , hydroxy, amine, exact, cyano, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -s(o)onr7r8, -conr7R8, -nr7r8 ~S(〇)〇R9, -COR9, carboxylic acid or carboxylic acid ester. Spiroheterocyclyl refers to a polycyclic hydrocarbon of 5 to 14 members, sharing a single atom (called a spiro atom) between the monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is Counting to 2) heteroatoms, the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated 7-inch electronic system. It is preferably 7 to the employee. For example 32 95201 201229050 4 ^

Nv S Λ

ο

The NH is classified into a monospiroalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospiroheterocyclic group and a double spiroheterocyclic ring, depending on the number of common spiro atoms between the ring and the ring. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of single spiro heterocyclic groups. The spiroheterocyclyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkoxy group, a dilute group, a fast group, a halogen, Hydroxy, amine, deterministic, cyano, several, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)0NR7R8, -C0NRY, -NR7R8 -S(0)0R9, -COR9, a carboxylic acid or a carboxylic acid ester. "3 to 8 membered heterocyclic group" means that the number of ring atoms constituting the ring is from 3 to 8 members, and the atoms constituting the ring contain one or more N, 0 or S(0) n hetero atoms, and the ring may contain 1 to 2 The double bond is a monocyclic or bicyclic non-aromatic ring group, and when the atom constituting the ring contains a nitrogen atom, a bond may be extended from the nitrogen atom. It is preferably a 4- to 6-membered heterocyclic group, more preferably 5 to 6 members, such as a fluorenyl group, a piperidinyl group or a piperazinyl group. The 3- to 8-membered heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkoxy, alkenyl, alkynyl groups. , halogen, thiol, amine, nitro, cyano, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)0NR7R8, -C0NR7R8 -NR7R8, -S(0)0R9, -COR9, antacid or tacroleate. a bicycloalkyl, bicyclohetero, monospirocycloalkyl or monospiroheterocyclyl group of p/q, meaning bicycloalkane 33 95201 201229050, diheterocyclyl, monospirocycloalkyl or monospiroheterocycle The number of ring atoms of the two rings of the group is p and q, respectively, and p or q is selected from an integer of 3 to 8, preferably an integer of 4 to 7. 'Aryl' refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated 7-inch electron system (ie, with adjacent The ring group for a carbon atom is preferably 6 to 1 member such as a phenyl group, a naphthyl group and an anthracenyl group. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, and Hydroxy, amine, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)0NR7R8, -C0NR7R8, -NR7R8, _S ( 0) 0R9, -C0R9, citric acid or slow acid vinegar. "Heteroaryl" means a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 or 6 members. For example, a thiol group, a thiophene group, a thiol group, a piranthene group, a pyridyl group, a thiol group, a timidyl group, a η-base group, a taste group, a tetradecyl group, and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, and ii. , hydroxy, amine, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -C0R9, ~CONRgRi. , -NR9Ri 竣, tannic acid or rebel vinegar. "Alkoxy" means -〇-(alkyl) and -〇-(unsubstituted cycloalkyl). For example, an oxiranyloxy group, an ethoxy group, a propoxy group, a butoxy group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like. Alkoxy groups may be substituted or not taken 34 95201

S 201229050, when substituted, the substituent is preferably one or more, independently • independently selected from alkyl, alkoxy, alkenyl, alkynyl, hydroxyl, hydroxy, amine, Schiffki, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl: cycloalkyl, biheterocyclyl, -S(〇)〇NR7R8, _C〇Nr7r8, _nr7r8, -S(0)0R9, _C0R9, a carboxylic acid or a carboxylic acid ester. "Aryloxy" means ~-aryl- and heteroaryl, and aryl and heteroaryl are as defined above. For example, a benzene group, a thiol group, a phenanthreneoxy group, a pyrimidineoxy group, a pyrimidineoxy group, a pyrazine gas group, and the like, and derivatives thereof. Soil "Hydroxy" means a ~0H group. Halogen refers to oxygen, chlorine, or broken. "Amine refers to - bribe 2. "Cyano" means ~CN. "Shi Xiaoji" means N〇2. "Carbonyl" means (group) - c(=0)_(group). "Hydroxyalkyl" means ~(alkyl)_0H. "Benzyl" means ~CH2-(phenyl). "Carboxylic acid" means (alkyl) C(=0)0H. ‘Resole vinegar refers to (alkyl) C(=0)0(alkyl). "As needed" or "as needed, means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "a mixture that is replaced by an alkyl group as needed. The cyclic group means that the alkyl group may be, but is not necessarily, present, and the description includes the case of a heterocyclic group substitution and the case where the heterocyclic group is not substituted by an alkyl group. A pharmaceutical composition comprising one or more compounds of the compound or 95201 35 201229050 a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention employs the following technical scheme: The method for producing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:

The compound of the formula (IA) is condensed with a compound of the formula (IB) or a compound of the formula (IB) to give a compound of the formula (I). The above condensation reaction is carried out between an acid and an amine group, under a condensation reagent and basic conditions, and the condensation reagent used is selected from the group consisting of N,N-dicyclohexylcarbodiimide and N,N-diisopropyl carbon. Di-Asian, benzotriazole-N,N,N',N'-tetradecylurea tetrafluoroborate (TBTU), etc., preferably benzotriazole-N,N,Ν',Ν '-tetradecylurea tetrafluoroborate (TBTU); alkaline conditions are provided by organic or inorganic tests, organic tests such as diisopropylethylamine, ° ratio, triethylamine, hexahydropyridine, Ν-mercaptopiperazine, 4-dimethylaminopyridine, etc., preferably diisopropylethylamine; the solvent used is selected from the group consisting of toluene, benzene, dichloromethane, tetrahydrofuran, chloroform or a mixture of the above solvents. Preferably, the reaction temperature is controlled from -80 ° C to 100 ° C, preferably from 0 ° C to 60 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably 15 minutes to 36 95201

S 201229050 24 hours; » ' wherein: R is selected from the group consisting of fluorenyl; G, R1 to R3 are as defined for the compound of the formula (IA); A, η, L, R4 to R6 are as defined for the compound of the formula (I) Said. The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the invention. EXAMPLES The structure of the compounds was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (5) is given in parts per million (ppm). The NMR measurement was carried out using a Bruker AVANCE_4 〇〇 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDCI3), the internal standard was tetramethyl decane (TMS), and the chemical shift was given in units of 10 〇 6 (ppm). The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX). The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4. 6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 < 4.6111111 chromatography column). The average inhibition rate of the kinase and the IC5Q value were determined using a NovoStar plate reader (BMG, Germany). The TLC plate is made of Yantai Yellow Sea HSGF254 or Qingdao GF254 Silicone Sheet. The specifications of the silica gel plate used for thin layer chromatography (TLC) are from 0. 15 mm to 0.2 mm. The specifications for the separation and purification of thin layer chromatography are 37 95201 201229050 0. 4 mm to 〇 · 5 mm 〇 pipe column chromatography generally uses Yantai Huanghai 矽 200~300 mesh 矽 gel as carrier. The starting materials of the present invention are known and commercially available from 'ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company', AccelaChem Bio Inc, Dari Chemicals, etc. The company may alternatively be synthesized or according to methods known in the art. An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus. The hydrogenation reaction is usually evacuated and charged with hydrogen gas, and the operation is repeated three times. The microwave reaction used a CEM Discover-S Model 908860 microwave reactor. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. The room temperature is an optimum reaction temperature of from 20 ° C to 30 ° C. (: The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and decyl alcohol system, B ·············· System 'C: oil shout and acetic acid ethyl acetate system, d: acetone. The volume ratio of the solvent is adjusted according to the polarity of the compound. The system of the eluent for column chromatography includes: A: digastric and decyl alcohol system , B: n-hexane and ethyl acetate system 'C: di-methane and acetone system,

95201 S 201229050 D: n-hexane and acetone system. The volume ratio of the solvent is adjusted depending on the polarity of the compound, and adjustment may be carried out by adding a small amount of ammonia water, acetic acid or the like.

f(U)-8-Cyclopentyl-7-ethyl-5-mercapto-6-sideoxy-5, 6, 7 R 7 > 0~tetrahydro-acridin-2-ylamino) -3-decyloxy-N-((3i?,8a;?)-hexahydro[2, lc][l,4]-oxazol-3-ylindenyl)-benzoguanamine

The first step is 3-methoxy-4-nitro-benzoic acid oxime ester 39 952〇i 201229050 3-曱oxy-4·~石肖其_ , , cn , 巧米酸la(5 g,50 Ment) dissolved in 30 mL of sterol, drop &amp; plus sulfoxide (5. 50 mL, 75 mmol), back to the reaction 3 reaction solution, add saturated sodium bicarbonate solution (50 mL) 'acetic acid B Stuffing extraction (5〇^), combining the organic phase, drying with anhydrous sulphuric acid, and concentrating the surface of the surface of the mixture, and extracting the residue by a gel column chromatography with an eluent system to obtain the title product 3_methoxyl + nitro- Benzoic acid methyl vinegar lb (5.28 g, white solid), yield: 99 6 〇 / 〇. The second step 4-amino-3-methoxy-benzoic acid oxime ester 3-methoxy-4-phenyl-benzoic acid oxime ib (5. 28 g, 25 mmol) was dissolved in 40 mL of sterol In the middle, (600 Å, 1 〇 ° /.) 纪 / carbon, the reaction was stirred for 1 hour under a hydrogen atmosphere. Filtration, and the filtrate was concentrated under reduced pressure. Yellow solid), Yield: 91%. MS m/z (ESI): 182.1 [M+l] The third step (and)-2-amino-butyric acid decyl ester under ice bath '((Λ0-2-amino-butyric acid ld (10 g) 0. 096 mol) was dissolved in 50 mL of methanol, and sulfoxide (13 mL, 0.17 mol) was added dropwise, and the reaction was stirred under reflux for 1 hour, then cooled to room temperature. No)-2-Amino-butyric acid decanoate hydrochloride (colorless oil), directly to the next step. MS m/z (ESI): 118.0 [M+l] 40 95201 s 201229050 β)-2-Cyclopentylamino-butyric acid methyl ester ((«-2-amino-butyric acid methyl ester hydrochloride le(u. 24 g, 〇. 〇96 mol) and % pentanone ( 8. 24 g, 〇. 〇 98 mol) dissolved in 15 〇 mL of di-methane in a stirred reaction for 1.5 hours, adding sodium acetate (8. 〇4 g, 〇. 〇98 m〇1) and - ethoxylated Sodium borohydride (10) · 52 g, G. 14 m (4), chelating reaction for 3 hours. The reaction solution was poured into 15 〇mLi〇% sodium bicarbonate solution, extracted with two gas krypton (lGGmLx3), combined organic phase, saturated Wash with saline (100 mb &lt; 3), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified to purified crystal crystal crystal crystal crystal crystal crystal crystal crystals l] Step 5 U)-2-[(2-Chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-aminobutyric acid decyl ester U)-2-cyclopentylamino group - decyl butyrate if (2.50 g, 13. 5 mmol) and sodium bicarbonate (4. 54 g '54 mmol) were dissolved in loo 乩 cyclohexane, stirred for 30 minutes, and added 2, 4-di-5 -Nitro-pyrimidine (2. 88 g, 14.84 mmol). The reaction was stirred at 60 ° C for 12 h. filtered, filtered cake eluted with dichloromethane (50 mL). 〇mL«Acetylacetate and n-hexane (V: V = 1:4) were mixed with a solvent to recrystallize the residue to give the title product (salt _ 2 _ [(2- gas-5-nitro-pyrimidin-4-yl) )-cyclopentyl-amino]- decanoic acid decyl ester lg (3. 36 g, pale yellow solid), yield: 72. 6%. 41 95201 201229050 MS m/z (ESI): 343.1 [M+l The sixth step (Λ〇-7-ethyl-2-chloro-8-cyclopentyl-7, 8-dihydro-5 and yttrium-6-鲷U)-2-[(2-chloro- 5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butyric acid decyl ester lg (lg, 3 mmol) dissolved in 10 mL Acid, Jia Rulan Nepal Nickel (0. 50 g) 'under a hydrogen atmosphere, the reaction was stirred for 12 hours at 80 ° C. Filtration, the filter cake was washed with dichlorohydrazine (50 mL), the filtrate was concentrated under reduced pressure, and then ethyl acetate (1 mL) was added and washed with water (50 mL×3) and brine (5 〇mL×3). Drying over magnesium sulfate 'filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography using eluent column chromatography. </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> -7-ethyl-2 chloro-8-cyclopentyl- 7重量。 7. 8-dihydro, 5 and to 1 to ketone lh (0. 56 g 'white solid), yield: 66.7%. , 〜6, MS m/z (ESI): 281.2 [M+l] Step 7 U)-7-Ethyl-2-gas-8-cyclopentyl-5-mercapto-7, 8' pyridine -6-ketone will (Λ0-7-ethyl-2-chloro-8-cyclopentyl_7, 8-dione~喋-6-one lh (3. 50 g, 12.5 mmol, according to Patent Publication No. 1 It is prepared by dissolving in pyridine US2004/176380) in 80mL of C-Chip\45, decyl benzoate (3.4 g, 18.7 _〇ι) and potassium carbonate into p-anthraquinone 1 ), refluxing and stirring The reaction was cooled to room temperature, concentrated under pressure for 2 hours, and the title product (Λ-7-ethyl~2- gas-8-cyclopentane) was obtained by the eluent system chromatography. Residual -7,8-dihydro-5#-acridin-6-one lj (3.4 g, white solid base), yield: 95201 42 201229050 93%.

A MS m/z (ESI): 295.4 [M+l] Step 8 (疋)-7-ethyl-8-cyclopentyl-2-(3-decyloxy-benzoic acid oxime ester-4- 4-Amino)-5-methyl-7,8-dihydro~*5#-indole-6-one 4-Ethyl-3-indolyl-benzoic acid decyl lc (305 mg, 1.7 1〇111〇1), (友)-7-ethyl-2-chloro-8-cyclopentyl-5-methyl-7,8-dihydro-5 and-acridin-6-one lj (500 5小时。 The mg ' 1. 7 mmol) and p-benzoic acid (5 〇〇 mg, 25. 5 mmol) dissolved in 20 mL of 4-mercapto-2-pentanol, reflux reaction for 2.5 hours. Reduce the concentrated reaction solution's dropwise to the reaction solution to pH 9 to 1 〇, extract with ethyl acetate (30 mL×3), combine with organic phase, wash with saturated brine (50 mL), dry over anhydrous magnesium sulfate Concentration by pressure, the residue obtained was purified by eluent column chromatography eluting to afford the title product (??)-7-ethyl-8-cyclopentyl-2-(3-decyloxy-phenylhydrazine). Methyl ester~4-yl-amino)-5-mercapto-7, 8-dihydro-5#-acridin-6-one lk (550 mg, white solid), yield: 73%. MS m/z (ESI): 440.2 [M+l] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> -7-ethyl-8-cyclopentyl-2-(3-decyloxy-benzoic acid _4_yl-amine 5-)-5-fluorenyl-7, 8-dihydro-5 and-acridin-6-one U(-7)ethyl-8-cyclopentyl-2-(3-decyloxy-phenylhydrazine) Acid oxime ester-4-yl-amino)-5-mercapto-7, 8-dihydro-5 million-acridine-6-one lk (2 〇〇 beer, 0. 46 mrool) dissolved in 20 mL of methanol 3 mL of a 2 M lithium hydroxide (77 mg, 1.38 mmol) solution was added, and the mixture was stirred for 60 hours under 60 Torr. Reduced concentration 95201 43 201229050 Reduced reaction solution, acetic acid ethyl extraction (5 〇 mLx3), the aqueous phase was diluted with a small amount of water, and then 1 Μ hydrochloric acid was added dropwise until the pH of the reaction solution was 2, and a white solid precipitated. Filtration and drying of the filter cake gave the title product (y?)-7-ethyl-8-cyclopentyl-2-(3-decyloxy-benzoic acid-4-yl-amino)- 5-indenyl group_ 7,8-dihydro-5 and monoacridine-6-one lm (140 mg, white solid), yield: 71%. MS m/z (ESI): 426.3 [M+l] Step 10 2- gas-3-(2-hydroxymethyl-pyrrolidine-i-yl)-propanenitrile under nitrogen gas. 2-Base-nonanol ln (200 mg, 2 ramol) was dissolved in a 5 mL anhydrous gel and 2-chloro-propanenitrile (〇.mL, 2 mmol) was added and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title product, 2-chloro-3-(2-hydroxy-decyl-pyrrolidin-1-yl)-propanonitrile, which was used directly in the next step. MS ra/z (ESI): 189. 1 [M+l] The eleventh step of the six-hydrogen ratio slightly [2,1-c] [ 1,4]- ° oxazine-3-carbonitrile ice bath, will 2-Benzene-3-(2-carbylmethyl-pyrrolidin-1-yl)-propanoid 1〇 (0.38 g, 2 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran, and potassium t-butoxide was added. (0·29 g, 2·6 mmol), the reaction was stirred at room temperature for 1 hour. Filtration, washing the filter cake with 20 mL of decyl alcohol, concentrating the filtrate, concentrating under reduced pressure, and purifying the residue with eluent column chromatography to afford the title product hexahydro-pyrrolo[2, lc][l 4。 - 4]-oxazine-3-carbonitrile lp (〇. 12 g, colorless oil), yield: 37. 8%. MS m/z (ESI): 153.2 [M+1] 44 95201 201229050 The twelfth step [(3 and, 8ae)-3, 4, 6, 7, 8, 8a-hexahydro-1 and -npiro And [2, lc] [ 1,4] ° oxazeto-yl]-nonylamine hexahydro-pyrrolo[2, lc][l,4]-oxazin-3-carbonitrile lp (0.40 g, 2 63 mmol) was dissolved in 20 mL of methanol, and Raney nickel (〇5 g) was added, and the reaction was stirred under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product [(3 especially 8ai?)-3, 4, 6, 7, 8, 8a-hexahydro-1 and _pyrrolo[2, ic][i,4]oxazine 3-yl)-decylamine lq (0.3 g 'colorless oil), yield: 73%, used directly in the next step. MS m/z (ESI): 157.2 [M+l] Step 13 4-(U)-8-cyclopentyl-7-ethyl-5-mercapto-6-sideoxy _5, 6, 7, 8-tetrahydro-嗓π定-2-ylamino)-3-methoxy-N-((3 and ,8aA〇-hexahydro-π ratio p and [2, lc]-[l , 4]-oxazin-3-ylindenyl)-benzoguanamine will [[3/?,8ae)-3, 4, 6, 7, 8, 8a-hexahydro-1 -° ratio [2, 1-c] [1,4]°oxazin-3-yl)-guanamine lq (60 mg, 0.38 mmol), ((Λ〇-7-ethyl-8-cyclopentyl-2-) (3-decyloxy-benzoic acid-4-yl-amino)-5-methyldihydro-5 million-bite-6-one lm (160 mg, 0.38 mmol), stupid and triazole -Ν,Ν,Ν',Ν'-tetradecylurea tetrafluoroborate (243 mg, 0.38 mmol) and diisopropylethylamine (180, 1.4 mmol) dissolved in 12 mL of di-methane The reaction was stirred for 2 hours. Add 20 mL of saturated sodium bicarbonate solution, dichloromethane (50 mL×3), and the organic phase was combined, washed with saturated brine (20 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by eluent system A to give the title product 4-(U)-8-cyclopentyl-7-ethyl-5-methyl-6- Sideoxy-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)_3_decyloxy-N~((3iP, 8a«-hexahydro-pyrrolo[2, lc][ l, 4]-oxazin-3-ylindenyl)-benzoguanamine 1 (100 mg, white solid), yield: 47%. MS m/z (ESI): 564.3 [M+l] NMR ( 400MHz, CDCkppm) δ 8. 58~8.60 (d,1H), 7.72 (s, 1H), 7.63(s, 1H), 7. 49 (s, 1H), 7. 32 (d, 1H), 6.53 ( t, 1H), 4.34 (m, 1H), 4.24-4.27 (m, 1H), 4.06-4.88 (m, 1H), 4. 02(s, 3H), 3. 78~3. 8 (in, 2H ), 3.47-3.48 (m, 2H), 3.39 (s, 3H), 3.11-3.14 (m, 2H), 1.90-2.19 (in, 5H), 1.47-1.92 (m, 12H), 0.90-0.94 (t , 3H) Example 2 4-((^-8-Cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-acridin-2-胺amino)-3-decyloxy-N-((3a5; 55; 6ai?)-2-mercapto-octahydro-cyclopenta[〇]°Pilo_5-yl)-benzoquinone

46 95201 201229050

In the first step, allyl-prop-2-ynyl-amine was dissolved in 2M sodium nitrite solution and bromopropyne was added dropwise in an ice bath (89. 1). mL, i 〇丄.u mol), warmed to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to give the title product ally-prop-2-propynyl-amine 2b, and the crude product was directly used for the next step. MS m/z (ESI): 96. 2 [M+l]. Step 2 - propyl-prop-2-ynyl-amino decanoic acid tert-butyl ester crude propyl-prop-2-yl Amine 2b (90. 05 g, 95. 95 mol), carbonic acid If (130.75 g, 〇. 95 mol) and di-tert-butyl dicarbonate (120 g, 0.55 mol) dissolved in 200 mL of dichloropurine During the burning, the reaction was stirred for 12 hours. Add 20 mL of water, extract with 2 gas (50 mL×3), combine with organic phase, wash with saturated brine (20 mL×3), dry over anhydrous magnesium sulfate, and then filtered. The resulting residue was purified by EtOAc (EtOAc) (EtOAc). The third step is the side oxy-hexahydro-cyclopenta[c]pyrrole-2~carboxylic acid tert-butyl ester under the nitrogen atmosphere, the allyl-prop-2-ynyl-aminocarboxylic acid tert-butyl ester &amp; 16.7g, 〇.86mol) was dissolved in 1〇〇mL ethylene glycol diterpene ether and added to the octadecyl dihedral (29. 4 g, 0.86 _ and 31 mL water, reflux (iv) for 3 hours. Add 10 mL The water was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, 100 mL of water and 50 mL of hydrazine hydrochloride. The mixture was extracted with ethyl acetate (10) mL×3), and the organic phase was combined and washed with saturated brine ((10)mL×3) The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford the title product 5 keto-hexahydro-cyclopenta[c]n ratio 嘻_2 _ tartrate tartrate (7. 69 g), yield: 40%. The fourth step (3a5; 5 charge, 6a skin)-5-hydroxy-hexahydro-cyclopenta[c]t ratio slightly _2-remediate t-butyl ester will be 5-嗣-liufeng- 哀 戊 并 [ (^]»»Bilo-2-retort tartrate 2d (1.8 S'8 mmol, prepared according to the existing literature 0仏49 (23), 5047-54; 1993) dissolved in 30 mL of tetrahydrofuran, Add sodium borohydride (〇·6 g '16 mmol), and stir the reaction for 12 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (50 mL×3), and combine the organic phase and wash with saturated brine (50 mL×3) The title product (3a5; 5 especially 6a milk-5~hydroxyl) was obtained by purifying the residue under reduced pressure and purifying the residue by using an eluent column system B. Hexahydro-cyclopenta[c], pyrrole-2-carboxylic acid tert-butyl ester 2e (1.64 g, yellow liquid), yield: 9 〇%. MS / / (ESI): 228.1 [M+l] Five steps (3a5; 5 especially 6a7?)-5- 酿 酿 - - hexahydro ~ cyclopentapyrrole_2 - tartrate tartrate under ice bath, will (38 ^ 9, 5 billion 6aA) -5- Hydroxy-hexahydro-cyclopenta[c]pyrro-succinic acid tert-butyl S 2e (l. 64 g '7.2 mmol) dissolved in a second gas Add the ochre yellow gas (0.85 raL, u; 〇i) and triethylamine (2 mL ' 14. 4 mmol) to stir the reaction for 2 hours. Add 3 〇乩 saturated carbonic acid nano solution 'with dichloro Extracted by simmering (50 mL×3), combined with organic phase, washed with saturated brine (50 mL×3), dried over anhydrous sulphuric acid, filtered, and dehydrated under reduced pressure. The residue obtained the title product (3a5; 5, 6a, 5, 5, methanesulfonyl), hexahydro-cyclopentaphenoxy-2-tert-butyl tartrate 2f (1.76 g, yellow liquid), yield : 8〇%. MS m/z (ESI): 305.9 [M+l] Step 6 (3&amp;5;55;63-5-azido-hexa-cyclopenta[^pyrrole_2_ Tert-butyl carboxylic acid (3a5; 5 brother 6aA〇-5-曱 醯 --hexahydro-cyclopenta[c]pyrrole_2_carboxylic acid tert-butyl ester 2f (1.76g, 5.76mmol) was dissolved in 2〇 Adding sodium azide (〇.94g, 14.4mmol) to mL N N-dimethyl decylamine, and mixing for 4 hours at 80 ° C. Add 20 mL of water and extract with ethyl acetate (5 〇 mL x 3 ), combined organic phase, saturated brine wash (50mLx3), anhydrous sulfuric acid, dry, 49 95201 20122905 The filtrate was concentrated under reduced pressure. The obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc. Pentylene [c &gt; tert-butyl 2-carboxylic acid tert-butyl ester 2 g (1.5 g, white solid), yield: 79%. MS ra/z (ESI): 253. 〇[M+l] Step 7 (3aiS, 55*, 63^)-5-azido-octahydro-cyclopenta[c]吼p each hydrochloride Dissolve (3a5·,551,6aA)-5-azido-hexahydro-cyclopenta[C]D piroxime-tert-butyl tert-butyl ester 2g (0.62g '2.44mmol) in i〇mL 5小时。 The reaction was stirred for 0. 5 hours. The reaction mixture was concentrated under reduced pressure to give the title product (3a5 &quot;, 55 &quot;, 6a^〇-5-azido-octahydro-cyclopenta[c]n ratio 略 雎 雎 雎 gh (0. 47g 'white solid), Yield: 100% MS m/z (ESI): 153.1 [M+l] (3a5; 55; 6a«-5-azido-2-indolyl-octahydro-cyclopenta[c] In the case of pyrrole = bath, (10) W)-5-azido-octo-penta-pepine hydrochloride 2h (0.45 g ' 2.38 mmol) was dissolved in 1 〇 加入 甲醛 39 ( 39 mL, 4.76 mmol) And triethyl decyloxyborohydride B: medium '(1. 51 g, 7 · 14 _1) 'mixed reaction for 2 hours. Add dropwise, neutralize the solution to pH 1 〇, extract with dichloromethane (5 〇 以 = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 3a5; 5 parent most nitrogen pure 95201 50 201229050 , methyl-octahydro-cyclopenta[c]pyrrole 2j (0.28 g, pale yellow liquid), yield '71%. MS m/z (ESI) :167.1 [M+l] The ninth step (3a5·,551,6a^〇-2-mercapto-octahydro-cyclopenta[c]D ratio p--5-yl-amine will (3aiS&quot;,55 1,6a/?)_5-stacked IL-2-methyl-octahydro-cyclopenta[c] 0 piroxime 2j (150 mg, 0.9 mmol) was dissolved in 20 mL of methanol and added (30 mg, 10%) Palladium/carbon, the reaction was stirred for 2 hours under a hydrogen atmosphere. After filtration, the filter cake was washed with methanol (30mL), and the filtrate was concentrated under reduced pressure to give the title product (SaS, 551, 6af)-2 - mercapto-octane-cyclopentane And [c] 〇 ratio p each 5-amino-amine 2k (〇. 〇 8g, pale yellow liquid), yield: 63%. MS m / z (ESI): 141.4 [M + l] The tenth step. 4-(U)-8-Cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-acridin-2-ylamino)-3 -nonyloxy-N-((3a5; 6a«-2-mercapto-octahydro-cyclopenta[c]pyrrole-5-yl)-benzoguanamine (N)-7-ethyl-8 -cyclopentyl-2-(3-decyloxy-benzoic acid-4-yl-amino)-5-mercapto-7, 8-dihydro-5#-acridin-6-one lm (242 Mg,0. 57 mmol) and (9-benzotriazole-oxime, oxime, Ν', Ν'-tetradecylurea tetrafluoroborate (183 mg, 0.57 mmol) dissolved in 20 mL II In the chloranil, add diisopropylethylamine (0·21 mL, 1.25 mmol) and 10 mL (3a5·,551,6a^〇-2-mercapto-octahydro-cyclopenta[c] 0 to 11 each 5-amino-amine 2k (80 mg '0. 57 mmol) Two gas was methane, and the reaction was stirred for 3 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with methylene chloride (50 mL×3), and the organic phase is combined, saturated with 51 95201 201229050 brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, The residue obtained was purified by column chromatography eluting to afford the title product 4-(U)-8-cyclopentyl-7-ethyl-5-mercapto-6-s-oxy-5, 6, 7 , 8-tetrahydro-indole-2-ylamino)-3-methoxy-N-((SaS,551,6a-less)-2-methyl-octahydro-cyclodecano[c]0 Biloxi)) Benthamide 2 (193 mg, white solid), yield: 62%. MS m/z (ESI): 548. 4 [M+l]^ NMR (400 MHz, CDCkppm) δ 8. 56~8.59 (d, 1H), 7. 72 (s, 1H), 7.62 (s, 1H), 7.47(s,1H), 7.23~7.26(Mountain 1H)' 5.96-5.98 (d, 1H), 4.53-4.66 (m, 2H), 4.24-4.27 (d, 1H), 4.01 (s , 3H), 3.37 (s, 3H), 2.83 (s, 4H), 2.38 (s, 3H), 2.12~2.32 (m, 3H), 1.70~2.12 (m, l3H), 〇. 85~0· 95 (t, 3H) Example 3 4-(U)-8-Cyclopentyl-7-ethyl-5-mercapto-6-oxirane-5, 6, 7, 8-tetrahydro-acridine- 2-Aminoamino)-N-(((3aiP,55; 6a5*)-2-methyl-octa-I-cyclopenta[c&gt;pyr-5-yl)-indenyl)-3-methoxy -benzamide 52 95201 6 201229050

The first step (SaS, 551, 6ae) 5-cyano-hexahydro-cyclopenta[c]° ratio p--2-tert-butyl tert-butyl ester in a dry ice bath, 5-keto-hexahydro-ring Penta[c]pyrrole-2-carboxylic acid tert-butyl ester 2 (1 (1.9 §, 8.4111111〇1) and 2-p-toluenesulfonyl-acetonitrile (1.97 bogey, 10. 1 mmol) dissolved in 20 mL of two gas曱:!: At the end, add 25 mL of t-butanol solution of potassium tert-butoxide (1.88 g, 16.8 mmol), and stir the reaction for 12 hours. Add 10 mL of ice water saturated sodium bicarbonate solution and concentrate under reduced pressure. The mixture was extracted with ethyl acetate (50 mL×3). EtOAc (EtOAc m. The obtained residue obtained the title product (3a5·, 551, 6aA〇-5-cyano-hexahydro-cyclopenta[c]^p-t-butyl 2- decanoate 3a (0.7 g, yellow liquid ), Yield: 35% MS m/z (ESI): 259. 1 [M+23] The second step (3a^ 551, 6ai?)-5-aminomethyl-hexa-argon-cyclopenta- 2-Retensive acid uncle 53 95201 201229050 Butyl ester (3a5; 5 and 6a)?) 5-cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 3a (0. 3 g , 1. 27 mmol Dissolved in 30 mL of methanol, added Raney nickel (0.50 g), and stirred for 6 hours under a hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure gave the title product (3a5; 55; 6a7?)-5-amine Methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 3b (0.2 g, pale yellow liquid), yield: 65%, used directly in the next step. -{ [4-((·/?)-8-cyclodecyl-7-ethyl-5-methyl-6- pendantoxy-5, 6, 7, 8-tetrahydro-acridin-2- Aminoamino)-3-decyloxy-benzoguanamine]-fluorenyl}-(335&quot;,551,6aW)-hexahydro-cyclopenta[c]D is more than π each-2-sodium tartrate The aim is to (3a5; 55; 6aT?)-5-aminoindolyl-hexahydro-cyclopenta[c]pyrrole-2-deoxalate tert-butyl 3# (190 mg, 0.8 mmol), (none)-7 -ethyl-8-cyclopentyl-2-(3-decyloxy-benzoic acid-4-yl-amino)-5-mercapto-7, 8-dihydro-5 and -° -6-keto lm (336 mg, 0.8 mmol), benzotriazin 0-N,N, Ν',Ν'-tetradecylurea tetrafluoro-decanoate (256 mg, 0.8 mmol) and Isopropylethylamine (228 mg, 1.76 mmol) was dissolved in 40 mL of dichlorohydrazine and stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with methylene chloride (50 mL×3), EtOAc (EtOAc) The residue obtained was purified by eluent system A to give the title product 5-{[4-(U)-8-cyclopentyl-7-ethyl-5-methyl-6-s-oxy-5,6 , 7, 8-tetrahydro-azino-2-ylamino)-3-decyloxy-benzoguanamine]-fluorenyl}-(3&amp;5;55; 6ai?)-hexahydro-cyclopentane And [c]pyrrole-2-carboxylic acid tert-butyl ester

54 95201 S 201229050 3c (388 mg, white solid), yield: 75%. MS m/z (ESI): 648.6 [M+l] Step 4 4-«Α〇-8-cyclodecyl-7-ethyl-5-methyl-oxyl_5, 6, 7, 8 Hydrogen-indol-2-ylamino)-N-(((3aA,551, w Λ -- 虱 虱 ϊ ϊ 比 并 并 -5 -5-5-yl)-fluorenyl)-3-carbyl , stupid 5-{[4-(10)-8-cyclopentyl-7-ethyl, 5~ fluorenyl + pendant oxy-5, 6, 7, 8-tetrahydro-4-12-ylamino )-3-methoxy, benzoguanamine]methyl}-(3&amp;5;55;63-hexahydro-cyclopenta-4&gt;pyr~2~sodium tartrate 3c(10)8 mg '0. 46 m〇1) Dissolve in 20 mL of dichloromethane, add 2〇汕6 Μ hydrogen chloride in 1,4- sulphur solution, stir the reaction 〇. 5 hours, concentrate the reaction solution under reduced pressure, add furfural ( 0. 1 mL, 0.92, and two drops of acetic acid. After 0.5 hours of mixing reaction, 'addition of triethylenesulfonyl sulfonate (292, 1.38 mmol) 'scrambled reaction for 2 hours. Add amine water to adjust pH to 9 10' was extracted with methylene chloride (50 mL×3). The organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product 4-((and)-8-cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-indole-2-ylamino) -1(((38^ 551,6aiS)-2-methyl-octahydro-cyclopentapyrol-5-yl)-methyl)-3-methoxy-benzoguanamine 3 (120 mg, White solid), Yield: 46. 5%. MS m/z (ESI): 562.5 [M+l] 4 匪R (400MHz, CDCkppm) δ 8. 54~8.56 (d,1H), 7.68 ( s, 1H), 7.59 (s, 1H), 7.44-7.45 (d, 1H), 7.25-7.27 55 95201 201229050 (m, 1H), 6.17~6.2 (m, 1H), 4. 5~4.54 (m, 1H), 4. 2~4.23 (in, 1H), 3.80(s, 3H), 3. 40-3.43 (t, 2H), 3. 33 (s, 3H), 2.80 (s, 4H), 2.36- 2.42 (m, 4H), 2.26 (s, 2H), 2.13-2.18 (m, 1H), 1.98-2.02 (m, 1H), 1.66-1.89 (m, 10H), 1.50-1.54 (in, 2H), 0.81-0.92 (t, 3H) Example 4 4-((A)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxirane-5, 6, 7, 8-tetrahydrol -嗓σ定-2-ylamino group 55&quot;,6aiS)-5-carbyl-2-indolyl-octahydro-cyclopenta[c]D ratio 11 each-5-yl)-methyl)-3 -decyloxy-benzoguanamine

(3a brother 6a5·)-spiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5, 2'-epoxyethylidene]_2-sodium tartrate Next, under ice bath, 'dissolve tridecyl iodide (293? '丨· 33 56 95201 201229050 • mmol) and sodium hydride (60 mg ' 1.46 mmol) in 2 mL of dimethyl sulphur' _ stir for 1 hour. 2 rL of 5-keto-hexahydro-cyclopenta-pyrrole-2-carboxylic acid tert-butyl ester 2d (0.3 g, 1.33 mmol) in disulfoxide solution, stirring for 10 minutes, stirring at room temperature hour. Add 20 mL of ice water, and extract with ethyl acetate (50 mL×3), and the organic phase is washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified to give the title product (3f, sp.[1,3,3a,4,6,6a-hexahydrocyclopenta[c]nbiha-5, 2'-oxirane] 4-carboxylic acid tert-butyl ester 4a (200 mg, colorless oil), yield: 63%. MS m/z (ESI): 262.3 [M+23] Step 2 (3a7?, 6aiS)-5 -(Amino-indenyl)-5_transcarbyl-hexahydro-cyclopenta[c]. Bis-2-pyreic acid tert-butylate (3a especially 6a5&quot;)-spiral [1,3, 3a,4 , 6, 6a-hexahydrocyclopenta[c]pyrrole-5,2-epoxyethylidene-2-(carboxylic acid tert-butyl ester 4a (; 〇·3 g, 1. 3, 1〇1) dissolved In 30 mL of ethanol, an excess of amine water was added, and the reaction was stirred for 12 hours. The reaction mixture was depressurized under reduced pressure to give the title product (domain (4)_5_(aminomethyl)-5-light-six------- Pyrrole-2-carboxylic acid tert-butyl ester 4b (yellow oil) was used directly in the next step. The third step (3af, 6a5*)-5-{[4~((妁_8_cyclopentyl) _7-ethyl_5_曱_6 pendant oxy-5' 6, 7, 8-tetraqi, acridine-2-yl-amino)_3_decyloxybenzophenone]-methyl b 5-carbyl, hexahydro-cyclo戍和[啦洛_2_缓酸叔丁丁57 95201 201229050

(3a疋6a5&quot;)_5_(Amidino)-5-yl-hexanitro-cycloindolo[c]pyrrole-2-carboxylic acid tert-butyl ester 4b (193 mg, 0.775 ramol), (y ?)-7-Ethyl-8-cyclopentyl-2-(3-decyloxy-benzoic acid-4-yl-amino)-5-fluorenyl-7,8-dihydro-5 and Bite 6-keto lm (320 mg, 0.75 mmol), ί?-benzotriazole-oxime, Ν, Ν', Ν'-tetramethylurea tetrafluoroborate (241 mg, 0.75 Mraol) and diisopropylethylamine (213 mg, 1.65 mmol) were dissolved in 40 mL of dichlorohydrazine and stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution (extracted with dichlorohydrazine (50 mL×3), and the organic phase is combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue obtained was purified by eluent system A to give the title product (3 & left, 6 &amp; ι9)-5-{[4-((_/?)-8-cyclodecyl-7-ethyl-5 -Methyl-6-o-oxy-5,6,8-tetrahydro-acridin-2-yl-amino)-3-indolyl-benzamide-indenyl}-5- Hydroxy-hexahydro-cyclopenta[c]n ratio bis-2-tert-butyl tert-butyl ester 4c (0.42 g, white solid), yield: 84%. MS ra/z (ESI): 664.6 [M+l] Step 4 4-((β)-8-cyclopentyl-7-ethyl-5-indolyl-6- pendant oxy-5, 6, 7, 8-tetrahydro-indot-2-yl-amino)-N-(((3a, especially 6β5·)-5-carbyl-octahydro-cyclopenta[c]pyrrole-5-yl)- Methyl)-3-methoxy-benzamide can be (3a^[4-((皮)-8-cyclopentyl-7-ethyl-5-fluorenyl-6- pendantoxy-5, 6, 7, 8-tetrahydro-acridin-2-yl-amino)-3-methoxy-benzamide>-methyl}-5-hydroxy-hexahydro-cyclopentazone&gt; Slightly -2-butyric acid tert-butyl ester 4c (420 mg, 〇. 63 mol) was dissolved in 20 mL of Erqi Institute, 20 mL of 6 Μ hydrogen chloride in 1,4-dioxane solution was added, and the reaction was stirred for 5 hours. , 95201

S 58 201229050 Adding amine water to the reaction solution at pH 8 to 9, extracting with dichloromethane (50 mL×3), washing the organic phase with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate and filtered Concentrated to give the title product 4_((_8_cyclopentyl-7-ethyl-5-mercapto-6-yloxy_5, 6, 7, 8_tetrahydro-acridin-2-yl)- Amino)-N-(((3aiP,6&amp;5·)-5-hydroxy-octahydro-cyclopenta[c]pyrrole-5-yl)-methyl)-3-indolyloxy- alum Amine 4d (0.32 g, white solid), Yield: 90%. Used directly in the next step. MS m/z (ESI): 564.5 [M+l] Step 5 4-(U)-8- Cyclopentyl-7-ethyl-5-methyl-6-sideoxy_5, 6, 7, 8-tetrahydro-acridin-2-yl-amino)-N-(((3ay?, 55; 6a«-5-hydroxy-2-indolyl-octahydro-cyclopenta[c]pyrrole-5-yl)-methyl)-3-decyloxy-benzamide can be 4-((« -8-cyclopentyl- 7-ethyl_5_fluorenyl_6_sideoxy-5, 6, 7, 8-tetrahydro-acridin-2-yl-amino 6aiS)_5_hydroxy-eight Hydrogen-cyclopentaphene-5-yl)_methyl)_3_decyloxybenzophenone 4d (318 rag, 0.56 mol) was dissolved in 60 mL of dioxane and water (v:v=1: 1) In the mixed solvent, add a Aldehyde (34 mg, 1·13 mmol) and two drops of acetic acid were stirred for 0.5 hour, then sodium triethyloxyborohydride (358 mg, 1.69 ramol) was added and the reaction was stirred for 2 hours. Add 3 mL of saturated sodium hydrogencarbonate solution, extract with dichloromethane (50 mL×3), combine with organic phase, wash with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue obtained was purified by column chromatography eluting to afford the title product 4-((N)-8-cyclopentyl-7-ethyl-5-methyl-6- s-oxy-5, 7, 8-tetrahydroH2-yl-amino)_N_(((3a疋55; 6a5&lt;)_5_ 95201 59 201229050 hydroxy-2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl) -Methyl)_3-methoxy-benzoguanamine 4 (110 mg, white solid), yield: 34%. MS m/z (ESI): 578. 5 [M+l] 'H NMR (400MHz, CDCla, ppm) δ 8.52-8.45 (d, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7. 47 (s, 1H), 7. 33~7. 35 (d, 1H), 6.74 (s, 1H), 4.49-4.57 (m, 1H), 4.20-4.23 (m, 1H), 3.97 (s , 3H), 3.58-3.59 (d, 2H), 3.53 (s, 3H), 2.79-2.84 (m, 4H), 2. 37 (s, 3H), 2. 15~2.19 (m, 3H), 1.96 ~ 2.02 (ra, 3H), 1.66-1.90 (m, 10H), 0.89~0.94 (t, 3H) Example 5 4-((and)-8-cyclopentyl-7-ethyl-5-fluorenyl -6-Sideoxy-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)-N-(((3aA, 5 and, 685)-5-hydroxy-2-indenyl) Octahydro-cyclopenta[c]pyrrole-5-yl)-indolyl)-3-methoxy-benzoguanamine

First Step 4-((i?)-8-Cyclopentyl-7-ethyl-5-mercapto-6-sideoxy-5, 6, 7, 8-tetradecane-11 -Amino)-N-(((3af, 5 685)-5-carbyl-2-methyl·octahydro-cyclopenta[c]pyrrole-5-yl)-methyl)_3 曱Oxybenzophenone 95201 60 201229050 4-(U)-8-Cyclopentyl-7-ethyl-5-mercapto-6-sideoxy-5, 6, 7, 8-tetrahydro- Acridine-2-yl-amino)-N-(((3a&gt;?,6&amp;Λ-5-hydroxy-octahydro-cyclopenta[^:&gt;birol-5-yl)-fluorenyl) -3-decyloxy-benzamide 4d (318 mg' 0. 56 mol) was dissolved in 60 mL of a mixture of di-methane and water (V: V = 1:1) and added to the mixture (34 mg, 1. 13 mmol) and two drops of acetic acid, after 0.5 hour of disruption reaction, 'addition of triethyl ethoxylated side sodium nitrite (358 mg, 1.69 mmol), stir the reaction for 2 hours. Add 30 mL of saturated sodium bicarbonate The solution was extracted with dichlorohydrazine (50 mL×3), and the organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous sulphuric acid, filtered, and concentrated under reduced pressure, using a gel column chromatography to eluent. The resulting residue was purified by System A to give the title product 4-((())-8-cyclopentyl-7-ethyl-5-methyl-6 - sideoxy-5, 6, 7, 8-tetrahydro-indot-2-yl-amino)-N-(((3a疋5 friend, benzyl-2-methyl-octahydro-cyclopentane) And [c]° piroxicam-5-yl)-methyl)-methoxy-benzoguanamine 5 (80 mg, white solid), yield: 25%. MS m/z (ESI): 578. 5 [M+l] NMR (400MHz, CDCh, ppm) δ 8.59-8.62 (d, iH), 7.73 (s, 1H), 7.65 (s, 1H), 7.48-7.49 (s, 1H)S 7.32-7.33 (d, lH), 6.62~6.64 (m, 2H), 4.56~4.58 (m, ijj), 4.25~ 4.28 (m, 1H), 4.02 (s, 3H), 3.71-3.72 (d, 2H), 3.35 (s, lH), 2.96 (s, 2H), 2.75~2.81 (m, 2H), 2.38~2.25 (m, 5H), 2. 19~2. 21 (m, 1H), 2.03~2. 11 ( m, 3h), 1 7i~ 1.93 (m, 11H), 0.89-0.91 (t, 3H) Example 6 4-(U)-8-Cyclopentyl-7-ethyl-5-mercapto-6_ Sideoxy~5, 6, 7, 8-14 95201 61 201229050 Hydrogen-deazed-2-ylamino)-indole-(1-mercapto-π-decyl _4-yl)-3-( Tetrahydro-indol-3-yl-methoxy)-benzamide

The first step is 3-hydroxy-4-nitro-benzoic acid methyl ester. Under a nitrogen atmosphere, 3-hydroxy-4-nitro-benzoic acid 6a (3. 172 g, 17.32 mmol) is dissolved in 40 mL. In anhydrous methanol, sulfoxide (3. 〇9 g, 25.98 mmol) was added dropwise, and the reaction was stirred under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure ethyl acetate (EtOAc (EtOAc) (EtOAcjjjjjjjj The concentrate was obtained to give the titled product, m.p. MS m/z (ESI): 195. 8 [Ml] 95201 s 62 201229050 The second step 4-nitro-3-(tetrahydro-tetra-furan-3-yl-methoxy)-m-benzoic acid methyl ester nitrogen atmosphere Under the dry ice bath, triphenylphosphine (576 mg, 2 2 mm 〇1) was dissolved in 10 mL of anhydrous tetragas. In the mixture, the solution of diethyl azodicarboxylate (382 mg, 2.2 〇1) in tetrahydrofuran was added dropwise, and the reaction was stirred for 3 minutes, and then 5 mL of 3~hydroxy-4-nitro-benzoic acid was added dropwise. A solution of the ester 6b (3 mg, 1.52 mmol) in tetrahydrofuran was stirred for 15 min, and (tetrahydro-furan-3-yl)-nonanol (15 g, 1.46 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc (3〇6mg, white solid), Yield: 74.4%. Step 3 4-Nitro-3-(tetrahydro-furan_3_yl-methoxy)-benzoic acid 4-nitro- Methyl 3-(tetrahydro-furan-3-yl-methoxy)-benzoic acid 6c (240 mg, 0.85 mmol) was dissolved in 5 mL of decyl alcohol, and a solution of 1 〇乩i Μ lithium hydroxide in tetrahydrofuran was added. The reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane (50 mL), EtOAc EtOAc (EtOAc) The mixture was washed with saturated brine (30 mL), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (172 mg, white solid), Yield: 75.4%. MS m/z (ESI): 265.9 [Ml] Step 4 95201 63 201229050 N-(1_曱基-〇瓜咬-4-基) -4-Shishyl-3-(tetrahydro-fluoren-3-yl-methoxy)-benzoguanamine 4-nitrate -3-(tetraar-furfuran-3-yl-decyloxy)-benzoic acid 6d (170 mg, 0.67 mmol), methyl-piperidin-4-yl-amine (77 mg, 0.67 mmol), benzene And triazole-N, hydrazine, Ν', Ν'-tetradecylurea tetrafluoroborate (215 mg '0.67 mmol) and diisopropylethylamine (251 &quot; L, 1.47 mmol) dissolved in 40 The reaction was stirred for 2 hours in dichloromethane, then added with 30 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The organic phase was combined and washed with saturated brine (50 mL×3) The filtrate was concentrated under reduced pressure. The residue obtained was purified eluting with EtOAc EtOAc EtOAc (EtOAc) Tetrahydro-furan-3-yl-decyloxy)-benzoguanamine 6e (0.22 g, pale yellow solid), yield: 94%. MS m/z (ESI): 364.3 [M+l] Step 5 4-Amino-N_(1-indolyl-tupidine-4-yl)-3-(tetrahydro-π-f.South-3-yl-methoxy)-benzamide amide N -(l-methyl-indenyl-4-yl)-4-nitro-3-(tetrahydro-indolyl-3-yl-methoxy)-benzoquinone 6e (220 mg' 0.61 mmol Dissolved in 40 mL of methanol, The reaction was stirred for 12 hours under the addition of (50 mg, 10%) palladium on carbon. Filtration and concentration of the filtrate under reduced pressure afforded the title product 4-amino-N-(l-methyl-piperidin-4-yl)-3-(tetrahydro-furan-3-yl-decyloxy)-phenylhydrazine醯amine (150 mg, white solid), yield: 73.9%. MS m/z (ESI): 334. 3 [M+l] 64 95201 201229050 Step 6 4-((Λ〇-8-cyclopentyl-7-ethyl-5-fluorenyl-6-sideoxy) a 5, 6, 7, 8_tetraki-pterin-2-ylamino)-indole-(1-indolyl-indenyl-4-yl)-3-(tetraindole_biting-3- 4-Amino-benzamide can be 4-amino-N-(l-fluorenyl-pyrylene-4-yl)-3-(tetrahydro-indolyl-3-yl-decyloxy) - benzoguanamine 6f (150 mg, 0.45 mmol), (none) _7-ethyl-2-chloro-8-cyclopentyl-5-mercapto-7, 8-dihydro-5--acridone Lj (132 mg, 〇. 45 mmol) and p-dosylsulfonic acid (137 mg, 〇. 72 mmol) were dissolved in 20 mL of 4-mercapto-2-pentanol, and stirred under reflux for 2 hours. The sodium argon solution was added to the reaction solution to a ratio of 8 to 9 and extracted with dioxane (50 mL×3). The combined organic phase was washed with saturated brine (5 mL mL), dried over anhydrous magnesium sulfate The residue obtained was purified by eluent column chromatography eluting to afford the title product 4-((s) -8-cyclopentyl-7-ethyl-5-methyl-6-s. , 7, 8_tetrahydro-non-2-ylamino)-NU-methyl-pyro-based)_3_(tetrahydro-furanyl-3-yl)-methoxy - benzoyl amine 6 (0.08g 'white solid), yield: 3〇5%. MS m/z (ESI): 592.5 [M+l] NMR (400 MHz, CDCh, ppm) § 8 &lt; 1〇1HX, 50 (s, !H), , 39 (s, 1H)&gt; 5. 98^ 6 (d, 1H), 4.37^4.47(,, iH), 4.19^21 (m&gt;1H)&gt; 3.74-4.13 (in, 7H), 3.33 (s, 3H), 2.91-2.94 (m, 3H) , 2.37 (s, 3H), 2.06^2.29 (m, 7H), 1.68^1.91 ^ 1H), 0.86~0.90 (t, 3H) ' ' Example 7 95201 65 201229050 4-(U)-8-Cyclopentane -7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-acridin-2-ylamino)-indole-(1-indolyl-piperidine- 4-yl)-3-(tetrahydro-furan-2-yl-decyloxy)-benzoguanamine

The first step - 4 - Shi Xiaoji-3-(tetrahydro-indolyl-2-yl-methoxy)-benzoic acid hydrazine vinegar under nitrogen atmosphere 'dry ice bath' will be triphenylphosphine (694 mg, 2. 65 Methyl acetate was dissolved in 20 mL of anhydrous tetrahydrofuran, and 1 mL of diethyl azodicarboxylate (461 mg ' 2. 65 mmol) in tetrahydrofuran and 1 mL mL of 3-pyridyl-4-nitro-benzene were added dropwise.曱 曱酉 6 6b (348 rag, 1.77 mmol) in tetrahydro oxalate, stir the reaction for a minute 'Add 5 mL (tetrahydro-bito-2-yl)-nonanol (198 mg ' 1. 94 mmol The tetrahydrofuran solution was stirred for 30 minutes, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography using eluent system B.

95201 S 201229050 _· Problem product 4_can base_3_(tetrahydrofuran-2-yl-decyloxy)-benzoic acid formazan 7a (317 mg, yellow solid), yield: 64%. MS m/z (ESI): 282.1 [M+l] Step 2 4-nitro-3-(tetrahydro-furan-2-yl-decyloxybenzoic acid 4-nitro-3-(tetrahydro) -furan-2-yl-methoxy)-benzoic acid oxime ester 7a (317 mg ' 1. 1 mm〇l) was dissolved in 3 〇 sterol and added to 20 mL of 1 Μ 氧化 oxidation clock (370 mg, 6.6 (mmol) tetrahydro π-propanol solution, scrambled for 2 hours. Add 1 mL of water, extract with dichloromethane (5 〇 mL), add 1 Μ salt 酉 to the aqueous phase pH 3 to 4, Ethyl acetate extraction (50 mL×3) 'Consolidated organic phase' washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate and dried over EtOAc &lt _Df-am-2-yl-nonyloxy)~benzoic acid 7b (290 mg, pale yellow solid), yield: 99%. Used directly in the next step. Step 3 N-(l-fluorenyl) - piperidine-4-yl)-4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzomethamine 4-nitro~3-(tetra-ar-furan-2 -yl-decyloxy)-benzoic acid 7b (290 mg ' 1. 1 mm〇i), ι_ methyl-anthene-4-yl-amine (125 mg, 1.1 mmo1), benzotriazine Oxazole-oxime, oxime, Ν', ΡΓ-tetramethylurea tetrafluoroborate (353 mg '1·1 _〇ι) and diisopropylethylamine (313 mg, 2.42 mmol) were dissolved in 40 mL of di-methane and stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution. Chlorotrope extraction (5 〇 mL x 3), combined with organic phase 'saturated brine (50 mL×3), dried over anhydrous magnesium sulfate 'filtered, 67 95201 201229050 filtrate concentrated under reduced pressure, using silica gel column chromatography to eluent system B The obtained residue was purified to give the title product N-(l-methyl-piperidin-4-yl)-4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzamide 7c (0.35 g, pale yellow solid), Yield: 87. 5%. MS m/z (ESI): 364.3 [M+l] Step 4 4-Amino-NO-indolyl-piperidine-4- Benzyl-3-(tetrahydro-furan-2-yl-decyloxy)-benzoguanamine will be N-(1-indolyl-indoledi.di-4-yl)-4-nitro-3- (Tetrahydrofuran-2-yl-methoxy)-benzoguanamine 7c (422 mg, 1.16 mmol) dissolved in 40 mL of methanol, added (50 mg '10%) palladium/carbon, hydrogen atmosphere The reaction was stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product 4-amino-N-(l-methyl-piperidin-4-yl)-3-(tetrahydro-furan-2-yl-methoxy)-benzene Indole 7d (307 mg, white solid), yield: 79%. MS ra/z (ESI): 334.3 [M+l] Step 5 4-((A〇-8-cyclopentyl-7-ethyl-5-methyl-6- pendant oxy-5, 6, 7, 8-tetrahydro-indot-2-ylamino)-indole-(1-indolyl-indene-di- 4-yl)-3-(tetrahydro-indol-2-yl-indole 4-Benzyl decylamine 4-amino-N-(l-fluorenyl-piperidin-4-yl)-3-(tetrahydro-furan-2-yl-decyloxy)-benzoguanamine 7d (150 mg, 〇. 45 mmol), ((^0-7-ethyl 2 -chloro-8-cyclopentyl-5-fluorenyl-7, 8-dihydro-5 and -嗓n- 6-_lj (133 mg '0. 45 mmol) and p-indenesulfonic acid (137 mg, 0·72 mmol) were dissolved in 20 mL of 4-mercapto-2-pentanol, and the reaction was stirred under reflux for 3 hours.

95201 S 201229050 , The saturated sodium carbonate solution was added dropwise to the pH of the reaction mixture was 9 to 10 Torr, extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate and filtered. The residue was purified by eluent from EtOAc (EtOAc). - sideoxy_5, 6, 7, 8_tetrahydro-acridine-2-ylaminomethyl-piperidine-4-yl)_3-(tetrahydrofuran-2-yl-methoxy) - Benzamide 5 (0.12 g, white solid), yield: 45%. MS m/z (ESI): 592. 5 [M+l] !H NMR (400MHz, CDCh, ppm) δ 8. 57~8. 59 (d, 1H), 7 70-7. 72 (d, 2H ), 7.46 (s,1H), 7.30 (s,1H),5·94~6 〇3 (d, 1H), 4.41-4.50 (m, 1H), 4.32-4.38 (m, 1H), 4. 18 ~ 4.23 (m, 1H), 4.13-4.16 (m, 2H), 3.94-4.03 (m, 2H), 3.80-3.90 (in, 1H), 3.86 (s, 3H), 2.83-2.93 (d, 2H) , 2.39 (s, 3H), 2.21-2.32 (t, 2H), 1.96-2.18 (m, 7H), 1.65~1.94 (m, 11H), 0.86~0.90 (t, 3H) Example 8 4-(( -8-cyclopentyl-7-ethyl-5-mercapto-6-sideoxy-5,β,7, §-tetrahydro-嗓α-deden-2-ylamino)-N-( (4a friend, 6 especially 7β5·)-2-methyl-octahydro-1 and -cyclohexane and [c]pyridinium _6_yl)-3-decyloxy-clumamine 8-1 4-((and)-8-cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-indole-2-ylamino)- N-((4a5·,6 parent 7a〇-2-mercapto-octahydro-1J7-cyclohexane-[c]pyridin-6-yl)-3-decyloxy-benzoguanamine 8_2 95201 69 201229050

Alkene-1,3,4,6-tetracarboxylic acid

70 S 95201 201229050 In the ice bath of tetradecyl ester, sodium hydroxide (6 4g, 0.16ra〇1) was dissolved in ΐ5ΐ sterol, and 1,3-dihydrofuran dimethyl ketone-acetone (22.6 滴) was added dropwise. , 〇. "mol" 'heated back to the salt to dissolve completely, quickly add glyoxal 8a (12. 85g '0.088 mol), cool to room temperature, stir the reaction for 12 hours, filter, wash with 50 mL of methanol The cake was dissolved in a mixed solvent of 18 pyridine pyridine and water (V: V = 5: 4), and 丨M hydrochloric acid was added dropwise to the reaction solution to pH 6 under an ice bath, and extracted with dichloromethane. (50 inLx3), combined organic phase, saturated brine (50 fflLx3), dried with anhydrous sulphate, and the mixture was evaporated to give the title product (3a5; 6350-2, 5-di- oxy- octahydro __cyclopentadienyl-1,3,4,6-tetracarboxylic acid tetradecyl ester 8b (20 g, white solid), yield: 61%. MS m/z (ESI): 371.3 [M+ l] The second step is cis-tetrahydro- and cyclopentadienyl-2, 5-di-S syndioxin (3a5&quot;, GaS)-2, 5-di-oxy-octahydro-cyclopentadiene-1 , 3, 4, 6-tetracarboxylic acid tetramethyl ester 8b (6. 75 g, 〇. 018 mol) dissolved in 3. 3 mL of acetic acid, plus 30 mL of 1 Μ hydrochloric acid, stirred and refluxed for 3.5 hours, cooled to room temperature, extracted with hexanes (50 mL×3), and the organic phases were combined and concentrated under reduced pressure. Saturated sodium bicarbonate solution until the pH of the reaction mixture was about 7, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 6a5 〇-tetrahydro-cyclopentadiene-2, 5-dione 8c (2 g, white solid), yield: 80% ° third step 71 95201 201229050 (fu (10)-tetrahydrolucyclopenta[c]m_36_two (tetra)w (tetra)(10)-tetrahydrolucyclopenta[small t(four), 6_two嗣 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ' 16.9 coffee D, room temperature _ reaction 24], when adding 20% sodium hydroxide solution to the reaction solution Qiu 1〇 to u, dichloromethane extraction (50 mLx3), combined organic phase, pasta The silk (10), dried over anhydrous sulfur, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent system C to give the title product 4(4aiP,7a«-tetranitro-1 and ring Pentylene [c&gt;bipyridyl-3,6-dione and (435;7&amp;«-tetrahydro-1 and-cyclopenta[^]pyridine-3,6-dione 8 (1 - 2 mixture ( 3 g, white solid), Yield: 1%. MS m/z (ESI): 154.1 [M+l] Step 4 (4ai?, 7ai?)-hexahydrospiro[cyclopenta[c]pyridine-6, 2, -[1,3]dioxol Alkane-3 (4 milk-ketone 8e-l (4a5; 7a5〇-hexahydrospiro[cyclopenta[c]pyridine-6, 2, -[1,3]dioxolane]-3 (4^ )-ketone 8e-2 (4aA,7aA)-tetrahydro-1 and -cyclopenta[c]«» obtained by the above procedure, be compared with -3,6-dione 8d-l and (4ai9, 7a5&quot; a mixture of tetra-argon-1 and -cyclopenta[c]** than bite-3,6-dione 8d-2 (1.2 g' 7. 8 mmol) 'ethylene glycol (1. 34 g) , 21. 5 mmol) and p-toluene acid (24 mg '0·13 mmol) were dissolved in 60 mL of toluene, and the reaction was stirred for 8 hours under reflux. Saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was about 7 Chlorodecane extraction (50 mL) 'aqueous phase 72 95201

S 201229050 - Extraction with methylene chloride (50 mL×3), EtOAc (EtOAc) (EtOAc) The resulting residue was purified to give the titled product (4a, 7a)-hexahydrospiro[cyclopenta[c]pyridine-6,2, -[1,3]dioxolan]-3 (4^- Ketone 8e-1 and GaS,7a5·)-hexahydrospiro[cyclopenta[[]pyridin-6, 2'-[1,3]dioxolane-3-3(4^0-ketone 8e-2 Mixture (1.1 g, white solid), yield: 70%. MS m/z (ESI): 198. 1 [M+l] Step 5 (48疋73- octahydro snail [cyclopenta] »比°定-6,2,-[1,3]dioxane] 8f-l (4aS,7a5·)-octahydrospiro[cyclopenta[e]n than bite_6, 2'-[ ι,3]dioxane] 8f-2

Under an argon atmosphere, lithium aluminum hydride (47 mg, 1.27 mmol) was dissolved in 10 mL of tetrahydrofuran under ice-water bath, and 1 mL of (4a7?,7a-friend)-hexahydrospiro[cyclopenta] obtained in the above step was added. And [c]pyridine-6,2,-[1,3]dioxolane-3 (4iW-ketone 8e-l and (4a5; 7a5·)-hexahydrospiro[cyclopenta[c]pyridine_ 6, 2 -[1,3]-oxopentane]-3 (4^0-ketone 8e-2 mixture (120 mg, 0.6 mmol) in tetrahydrofuran solution' was stirred for 1 hour. Partly added 0.047/zL Water, 0.047 15% gas oxidized nano-solution, extracted with dioxane (50 mLx3) 'combined organic phase, saturated brine wash (5 〇mLx3) 'anhydrous sulphuric acid drying, sputum, fluid decompression and rolling , the title product (4ae, 7aA) - octopus [cyclopenta[c]e than bite-6, 2, -[1,3]dioxane]8f-l and (4a5; 7a5·)- A mixture of octahydrospiro[cyclopenta[0]pyrridine 95201 73 201229050 -6, 2'-[1,3]dioxol]8f-2 (150 mg, oil), yield: 95 %. Directly invest in the next reaction. Step 6 (4a5; 7aW-hexahydrospiro [cyclopenta[c]pyridine-6, 2, -[1,3]dioxan]-2(1^0- Tert-butyl carboxylate gg-i (4a7? ,7a5·)-hexahydrospiro[cyclopenta[c]pyridine_6,2'-[1,3]dioxolan]-2(1 skin)-tert-butyl tert-butyl ester 8g-2 under ice water bath , (4ay?, 7a)?)-octahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolane]8f-l and (4a5; 7a5) obtained by the above steps ·)-A mixture of octahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolane]8f-2 (100 mg, 0.54 mmol) dissolved in 15 mL of two gas To the decane, a solution of diethylamine (109 mg, 1. 〇8 mm〇i) and 5 mL of di-tert-butyl dicarbonate (130 mg, 0.6 mmol) in two portions of methane was added, and the mixture was stirred for 2 hours. The saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was evaporated to dryness (yield: EtOAc, EtOAc (EtOAc) The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product (4a5; 7ai*?)-hexahydrospiro[cyclopenta[c]pyridine_6, 2, _[丨,3] Dioxolane]-2 (1«-carboxylic acid tert-butyl ester and ^^^ with phantom-hexahydrospiro[in] pentacene[c]pyridine-6, 2, -[1,3]dioxolane 2 (1 still mixed with tert-butyl carboxylate 8g_2 Product (100 mg, colorless oil). Yield: 66〇 / square. The seventh step (4a5; 7ai&lt;?)-6-sideoxy-hexahydro-丨pi_cyclopenta[c]pyridine-2 (3 milk-tert-butyl carboxylate 8h-l 74 95201 201229050, (4a5 7aiP)_6-sideoxy, hexahydro-1 hucyclopenta[c]pyridine-2(3^)-carboxylic acid tert-butyl S 8h-2 (4a5;7a)P)- Hexahydrospiro [cyclopenta[c]pyridin-6,2'-[1,3]dicyclopentane]_2 (1 milk-tert-butyl carboxylic acid 88_1 and (4ay?' 7akS)-hexahydro snail [cyclopenta[c]pyridine_6, 2,-[丨,3]dioxobutane 2 (1 milk-diacid tert-butyl ester 8g-2 mixture (620 mg, 2.2 mmol) dissolved in In 50 mL of acetone, add 2 〇虬 曱 benzene sulfonic acid (2 〇〇 mg, ^ 〇 1) of the propyl solution 'reflow and stir the reaction for 2 。 minutes. Add saturated sodium bicarbonate solution to the reaction solution pH 8 to 9. Extract with methylene chloride (50 mL×3), combine the organic phase with saturated brine (50 mL×3), dry the anhydrous sulfuric acid, and dry it under reduced pressure, and elute with Shixi rubber column chromatography. The resulting residue was purified to give the title product, </ br </ </ </ </ </ /> </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4a5; 7a^?)-6-sideoxy _Hexahydro-indole and _cyclopenta[c]pyridine-2 (3 milk-carboxylic acid tert-butyl vinegar 8h-2 mixture (45 〇mg, colorless oil), yield: 85%. !H NMR (400MHz, CDCh, ppm) δ 3.71-3.82 (m, 2H), 3· 25~3· 29 (d, 1H), 2. 9~3· 01 (m, 1H), 2. 32~2. 40 (m,4H), 2.08-2. 18 (m, 2H), 1.69-1.71 (m, 1H), 1.46-1.66 (s, 9H), 1.27~1.37 (m, 1H) Step 8 (4a5; 6疋7a7?)-6-Methanesulfonyl-hexahydro-1 and-cyclopenta[c]pyridine-2 (3^-carboxylic acid tert-butyl ester "one 丨 (4a especially 65; 7a5〇-6-曱Sulfosyl-hexahydro-1 and-cyclopenta[c]pyridine-2 (3 milk-tert-butyl carboxylic acid tert-butyl ester 8j-2 75 95201 i 201229050, (4a5; 7a)P)-6 obtained by the above steps -Sideoxy-hexahydro-1#-cyclopenta[c]pyridine-2 (3 milk-tert-butyl carboxylic acid 8h (22 mg '〇96 Guanlan 1) dissolved in 10 mL tetrahydromanate, Add shed hydrogenation (10 mg, 0.14 to 12 hours of reaction). Concentrate the reaction solution under reduced pressure, use 2 mL of dioxane, dissolve the residue in the solution, add triethylamine (40 μL·, 0.29 mmol) and hydrazine. Helium (2 〇eL, 〇. 14 mmol), and the reaction was stirred for 2 hours. After adding saturated sodium hydrogencarbonate solution, the pH was adjusted to 8 to 9 and extracted with dioxane (5 〇 mL×3). The organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product (4a5; 6 especially 7ay?)-6-methanesulfonyl-hexahydro-indole and cyclopentabipyridine-2 ( 3i7)-tert-butyl carboxylic acid 8j-l and (4aiP,65; 7a5〇-6-nonylsulfonyl-hexahydro-1 and-cyclopenta[c]pyridine-2 (3 milk-carboxylic acid tert-butyl) Mixture of ester 8j-2 (28 rag, colorless oil), yield: 98%. NMR (400MHz, CDCh, ppm) δ 5.12-5.18 (m, 1 Η), 3.61-3.68 (m, 1H), 3.42-3.51 (m, 1H), 3.35-3.48 (m, 1H), 3.1-3.14 (m, 1H), 2.98-3.06 (s, 3H), 2.19-2.26 (m, 2H), 2. 07-2.17 (m, 2H), 1. 79~1.86 (m, 2H), 1.6-1.7 (m, 2H), 1.40~1.50 (s, 9H) Step 9 (4ae, 6-foot 7a5〇-6-azido group -hexahydro-1 and-cyclopenta[c]pyridine-2 (3Z0-carboxylic acid tert-butyl ester 8k-1 (4&amp;5;6-7&amp;skin)-6-azido-hexahydro-If cyclopentane And [c]pyridine-2 (3Z〇-carboxylic acid tert-butyl ester 8k-2) obtained by the above steps (4a5 6, especially 7aiP) -6- Yue sulfo acyl - hexahydro-

76 95201 S 201229050 , -1 and - cyclopenta[c]° ratio bite-2 (3Z〇-telluric acid tert-butyl vinegar 8j-l and. (4a^ 651,7a5〇-6-曱 continued 醯基-六Hydrogen-1 and -cyclopenta[c] 0 ratio. Ding-2 (3i〇-t-butyl tert-butyl ester 8j-2 mixture (32 mg, 0.1 mmol) dissolved in 10 mL of N, Ν'-dimethyl The sodium azide (20 mg, 0.25 mmol) was slowly added, and the reaction was stirred at 70 to 80 ° C for 3.5 hours. Saturated sodium hydrogen carbonate solution was added dropwise until the pH of the reaction solution was from 7 to 8. Extracted with dioxane (50 mL×3), combined with organic phase, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue obtained gave the title product (4 ν?, 6 y 7a5 -6-6-azido-hexahydro-1 and -cyclopenta[c&gt; pyridine-2(3^0-carboxylic acid tert-butyl ester 8k-) a mixture of l and (4a5; 65; 7a7?)-6-azido-hexahydro-1 and-cyclopenta[c]pyridine-2(3)7)-carboxylic acid tert-butyl ester 8k-2 (40 Mg, colorless oil, yield: 100%. !H NMR (400MHz, CDCh, ppm) δ 4. 05~4. 08 (m, 1H), 3.56-3.61 Cm, 1H), 3.39-3.40 ( m, 2H), 3.01-3.10 (m, 1H), 2. 2~2. 29 (m, 2H), 1. 7~1. 83 (m, 5H), 1. 45~1. 51 (s, 9H), 1.20-1.31 (m, 1H) Step 10 (4aA, 6 feet 7a5&quot; )-6-amino-hexahydro-1 and-cyclopenta[c]D ratio bite-2 (3 milk-tert-butyl tert-butyl ester 8m-l (4a5; 65; 7aA)-6-amino-six Hydrogen-1 and -cyclopenta[c]pyridine-2(3^)-carboxylic acid tert-butyl ester 8m-2 (4a7?,6 especially 7350-6-azido-hexahydro-1) obtained in the above step And-cyclopenta[c]pyridine-2 (3^-carboxylic acid tert-butyl ester 8k-l and 77 95201 201229050 (4a5; 65; 7a) i〇-6-azido-hexahydro-1 and-ring A mixture of pentato[c]pyridine-2 (3^-t-butyric acid tert-butyl ester 8k-2 (30 mg, 0.11 mmol) dissolved in 12 mL of decyl alcohol and added (20 mg, 10%) palladium / The reaction was stirred for 2 hours under a carbon and argon atmosphere, filtered, and the filtrate was concentrated under reduced pressure to give the title product (4A?,6,7,7,6,6-amino-hexahydro-1 and -cyclopenta[c]D ratio bite-2 (3Ζ〇-tert-butyl phthalate 8m-l and (4a5; 65; 7a«-6-amino-hexahydro-1 and -cyclopenta[c]pyridine-2 (3^0-carboxylic acid tert-butyl) S A mixture of 8 m-2 (28 mg, light yellow oil), yield: 100%. MS m/z (ESI): 241.2 [M+1] 丨 eleventh step (4a)?, 6 especially 78^-6-(: 4-(((^-8-cyclopentyl-7-ethyl) -5-曱Tom-6-Sideoxy-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)]-hexahydro-10,000-cyclopentanthene]pyridine-2 (3 Edge-carboxylic acid tert-butyl ester 8n-l (4a5; 65; 7a&gt;?)-6-[4-((U)-8-cyclopentyl-7-ethyl-5-mercapto-6-side oxygen Base-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)]-hexahydro-1 and-cyclopenta[c]pyridine-2(3)7)-carboxylic acid tert-butyl ester 8n-2 (4aA, 6 friends, 7a5〇_6_amino-hexanitro-1) and _cyclopenta[c]pyridine-2 (3^0-carboxylic acid tert-butyl ester 8m-l) And (4a5; 65; 7ay?)-6-Amino-hexahydro-1 and -cyclopenta[c]pyridine-2(3^)-carboxylic acid tert-butyl vinegar 8m-2 (28 mg, 0 . 12 mmol), ((Λ〇-7-ethyl_8-cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7, 8- Dihydro-50,000-indole-6-one lm (50 mg, 0.12 mmol), benzotriazide 0-sodium, hydrazine, Ν', Ν'-tetramethylurea tetrafluoroborate (40 mg, 0.12 mmol) and diisopropylethylamine (30 mg, 0.23 mmol) dissolved in 12 mL of two gas A 78 95201

The reaction was stirred for 2 hours in S 201229050 alkane. Add saturated sodium carbonate solution to the reaction solution to 8 to 9, extract with dichloromethane (50 mL×3), combine the organic phase, run and wash with brine (50 mL×3), dry over anhydrous magnesium sulfate, filtered, and smashed and concentrated. The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product (4a, y y y y y y y y y y y y y y y -ethyl-5-mercapto-6-o-oxy-5,6,8-tetrahydrobutan-2-ylamino)]hexahydro-1 and-cyclopenta[c]pyridine- 2 (3 feet)-tert-butyl carboxylic acid 8n-l and (4a5; 65; 73 -6-[4-(((left)-8-cyclopentyl-7-ethyl-5-fluorenyl) 6-Sideoxy-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)]-hexahydro-1#-cyclopenta[c]pyridine-2(3i7)-carboxylic acid Mixture of butyl ester 8n-2 (36 mg, white solid), yield 50%. MS m/z (ESI): 648.6 [M+l] Step 12 4-((N)-8-ring Pentyl-7-ethyl-5-methyl-6-peroxy-5,6,8-tetrahydro-acridin-2-ylamino)-N-((4aiP,6iP,7a«) - octahydro-10,000-cyclopentyridin-6-yl)-3-methoxy-benzoguanamine 8〇-1 4-((and)-8-cyclopentyl-7-ethyl-5- Mercapto-6-sideoxy-5, 6, 7, 8-tetrahydro-indole 11 -2- Amino)-N-((4a5*,651,7ay?)-octahydro-1 and-cyclopentyl[[]pyridin-6-yl)-3-decyloxy-benzamide-8〇-2 Will (4a疋6 especially 7a^S^)-6-[4-((/?)-8-cyclopentyl-7-ethyl^^5^ fluorenyl-6-sideoxy-5,6 ,7,8-tetrahydro-acridin-2-ylamino)]-hexahydro-1 and-cyclopentazone]° than bite-2 (3^-tert-butyl tert-butyl ester 8n-1 and (4aiS) , 651, 7a)?)-6-[4-((())-8-cyclopentyl-7-ethyl-5-methyl-6-sideoxy-5, 6, 7, 8- four Hydrogen-acridin-2-ylamino)]-hexahydro-p-pilycan-cyclopentanyl 79 95201 201229050 [c&gt;bipyridyl-2(3^-carboxylic acid tert-butyl ester 8n-2 mixture (50 mg, 0· 077 mmol) was dissolved in 5 mL of dichloromethane, and 4 mL of a solution of 6 Μ hydrogen chloride in 1,4-dioxane was added dropwise, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title product 4-(( (^-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,8-tetrahydro-acridin-2-ylamino)-N-(( 4ai?,6 especially 7a«-octahydro-1 and-cyclopenta[c]pyridin-6-yl)-3-decyloxy-benzamide 8〇-1 and 4-(((i?) -8-Cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,8-tetrahydro-acridin-2-ylamino)-N-((4a5; 65; 7a^?)-octahydro-1 and-cyclopenta[c] acridine- Mixture of 6-yl)-3-methoxy-benzimidamide 8〇-2 (80 mg, white solid), yield: 100%. Directly invest in the next step. Step 13 4-(U)-8-Cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-acridin-2-ylamine -N-((4a)?,6疋7&amp;5·)-2-mercapto-octahydro-1 and-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzene Formamidine 8-1 4-((iP)-8-cyclopentyl-7-ethyl-5-mercapto-6-oxirane-5, 6, 7, 8-tetrahydro-indole π- 2_ arylamino)-N-((4a5; 65; 7aA〇-2-methyl-octahydro-1 and -cyclopenta[c]n-pyridin-6-yl)-3-methoxy-benzene 4-(((i*?)-8-cyclopentyl-7-ethyl-5-methyl-6- pendantoxy-5, 6, 7, 8 under the amylamine 8-2 ice bath -tetrahydro-acridin-2-ylamino)-N-((4ay?,6 especially 7&amp;5〇-octahydro-1 and-cyclopenta[c]pyridin-6-yl)-3-indole Oxy-benzoic amide amine and 4-(((^0-8-cyclopentyl-7-ethyl-5-mercapto-6- oxo-5, 6, 7, 8-tetrahydro- Acridine-2-ylamino)-N-((4a5; 65; 7ai?)-octahydro-If-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzimidamide 8 Mixture of 〇_2 (80 mg, 0·15 mmol) dissolved in 1 mL of two gas and burned

In a mixture of 95201 S 80 201229050 (V: V = 1:1), 37% furfural solution (0.023 mL, 0.29 mmo 1) and sodium triethoxydecyl hydride (1 〇〇 mg, 0.45 mmo 1) were added. The reaction was stirred at room temperature for 2 hours. The saturated sodium carbonate solution was added dropwise until the pH of the reaction mixture was 8 to 9 and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with brine (50 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product 4-(U)-8-cyclopentyl-7-ethyl-5-methyl-6-s. , 6, 7, 8_tetrahydro-preservation 0-denyl-2-ylamino)-^-((4&amp;疋6友,7&amp;5〇-2-mercapto-octahydro-1 and-cyclopentane And [c]pyridin-6-yl)-3-decyloxy-benzamide 9-1 and 4-((and)-8-cyclopentyl-7-ethyl-5-mercapto-6- Sideoxy-5,6,8-tetrahydro-acridin-2-ylamino)-N-((4a5; 65; 7aiP)-2-methyl-octahydro-1 and-cyclopenta Mixture of [c]e to -6-yl)-3-methoxy-benzoquinone 8-2 (30 mg, white solid), yield: 37%. MS m/z (ESI): 562 . 5 [M+l] *H NMR (400MHz, CDCh, ppm) δ 8.52-8.55 (d, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 ( s, 1H), 6.32-6.34 (d, 1H), 4.59-4.61 (m, 1H), 4.20-4.23 (m, 1H), 3.97 (s, 3H), 3.33 (s, 3H), 2.21-2.82 ( m, 4H), 2. 42~2.68 (m, 4H), 2. 30~2.33 (m, 3H), 2. 02~2.18 (m, 3H), 1.82~2.01 (m, 1H), 1.65~1.78 (m, 11H), 0.85~0.89 (t, 3H) Example 9 4 -((f)-8-cyclopentyl-7-ethyl-5-mercapto-6-oxo-5,6,7-tetrahydro-acridin-2-ylamino)-N -(((3iP,8aS)-hexahydropyrolo[2,K] 81 95201 201229050 [1, 4]oxazin-3-yl)-methyl)-3-decyloxy-benzamide

The first step (35; 8a«-hexahydro-pyrrolo[2, 1-ί:][1,4]oxazine-3-nitrile in an argon atmosphere, ((5〇-° ratio slightly burned-2- The base-methanol 9a (1.99 g, 12.7 mmol) was dissolved in 120 mL of tetrahydrofuran, and 2-gas-acrylonitrile (1.11 g, 12.7 mmol) and tert-butanol were added (2. 14 g). 19.06 mmol), the reaction was allowed to react for 10 minutes. Filtration, the filtrate was concentrated under reduced pressure, and 50 mL of ethyl acetate was added, and then washed with saturated sodium hydrogen carbonate (30 mL) and brine (30 mL) The magnesium was dried, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Oxazin-3-carbonitrile 9b (357 mg, white solid), Yield: 18.5%. MS m/z (ESI): 153.1 [M+l] Step 2 ((35; 8a5·) - hexahydro-pyrrolo[2, lc][l,4]oxazin-3-yl)-decylamine 82 95201 201229050 (35; 8a5·)-hexahydro-pyrrolo[2, lc][l, 4] Oxazine-3-carbonitrile 9b (391 mg, 2.57 mmol) was dissolved in 30 mL of methanol, and then a drop of aqueous ammonia and Resert nickel (0.5 g) were added in sequence, and the reaction was stirred for 18 hours under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure to give the title product ((35; 8a5)_hexahydro-pyrrolo[2,bc][l,4]oxazin-3-yl)-methylamine 9c (200 mg, colorless oil Yield: 50% MS m/z (ESI): 157.2 [M+l] Step 3 4-(U)_8-cyclopentyl-7-ethyl-5-mercapto-6-side Oxy-5, 6, 7, 8-tetrahydro-indot-2-ylamino)-N-(((3) 8aS)-hexahydro-° ratio slightly [2, l_c][l,4 ]oxazol-3-yl)-methyl)-3-decyloxy-benzamide can ((35; SaS)-hexahydro-pyrrolo[2, lc][l,4]oxazin-3 -yl)-methylamine 9c (43 mg '0.28 mmol) was dissolved in 60 mL of di-methane and ((N-)-7-ethyl-8-cyclopentyl-2-(3-methoxy) -benzoic acid-4-yl-amino)-5-mercapto-7, 8-dihydro-5--acridin-6-one lm (117 mg, 0.28 mmol)' benzotriazole -N,N,N,,Ν'-tetradecylurea tetrafluorofolate (88 mg '0.28 romo 1) and monoisopropylethylamine (89 mg, 0.69 ugly 1), scrambled Reaction for 2 hours. Add 30 mL of saturated sodium bicarbonate solution (extracted with dichlorohydrazine (50 mL×3), and the organic phase is combined with saturated brine (5 mL mL), dried over anhydrous magnesium sulfate and filtered. The resulting residue was recrystallized from hexanes and hexanes to afford the title product 4 </ </ </ </ </ </ </ </ Acridine-2-ylamino)-N-(((3疋8aS)-hexahydro-indolo[2, ic][i,4]oxazin-3-yl)-methyl)-3- Methoxy-benzamide 9 (76 mg, white solid), 95201 83 201229050 Yield: 49% MS m/z (ESI): 564. 3 [M+l] !H NMR (400 MHz, CDCh, Pd) δ 8.60-8.62 (d, 1H), 7.73 (s, 1H), 7.66(s, 1H), 7. 36 (s, 1H), 7. 31-7.34 (d, 1H), 6.68-6.77 ( s, 1H), 4.58-4.60 (m, 1H), 4.54-4.56 (in, 1H), 4.14-4.52 (m, 2H), 4.06 (s, 3H), 3.80-4.03 (d, 1H), 3.72 ( m, 2H), 3.37 (s, 3H), 3.17-3.21 (m, 4H), 2.84-2.86 (m, 1H), 2.38 (m, 1H), 1.91-2.19 (m, 5H), 1.76-1.87 ( In, 4H), 1.61-1.74 (m, 4H), 0.92-0.98 (t, 3H) Example 10 4-(U)-8-cyclopentyl-7-ethyl-5-methyl-6- side Oxy-5, 6, 7, 8-tetrahydro-acridin-2-yl Amino)-3-decyloxy-N-((3ay?,5-foot 6a«-2-mercapto-octahydro-cyclopenta[c]pyrrole-5-yl)-benzoguanamine

84 95201 201229050

The first step (3a especially 5 especially 685)-5-benzylamine-hexahydro-cyclopenta[c]^ is compared with each 2-butyric acid tert-butyl ester, 5-keto-hexahydro-ring Pentyl [c]pyrrole-2-carboxylic acid tert-butyl ester 2d (3.37 g, 15 mmol) 'Benzylamine (1.6 g, 15 mmol), acetic acid (0.9 g' 15 mmol) dissolved in 60 The reaction was stirred for 5 hours in dichloromethane (5 mL), and sodium triethyl succinimide (6.4 g, 30 mmol) was added and the mixture was stirred at room temperature for 12 hours. Add 50 mL of saturated sodium bicarbonate solution, dioxane extraction (150 mL), and the organic layer is washed with brine (3 〇mL×3), dried over anhydrous magnesium sulfate, filtered and filtered. The obtained residue was purified with eluent A to give the title product (3a, &lt;&gt;&gt;5&lt;6&gt;&gt; (4. 7 g, white solid), Yield: 100%. MS m/z (ESI): 317.3 [M+l] The second step (3a^,5 especially 6a&gt;iS)-5-amino-six Nitrogen-cyclic oxime is more than each of the -2-sodium tartrate 85 95201 201229050 ester (3ai?, 5 and 6,850-5-benzylamino-hexahydro-cyclopenta[c]pyrrole-2-acid Butyl ester l〇a (4.7 g ' 14. 8 mmol), acetic acid (1 g, 14·8 mmol) dissolved in 100 mL of methanol, added (500 mg, i〇%) palladium / carbon, hydrogen atmosphere The reaction was stirred for 12 hours. After filtration, the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjj , filtration, decompression of the filtrate, and the title product (3a^5疋6a5V5-amine) - hexahydro-cyclopenta[c]° ratio ～2-tert-butyl tert-butyl ester l〇b (1, 7 g, white solid), yield: 51. 5%. Step 3 (a·^, 5尤6a5〇-5-卞oxygreen amino-hexahydro-cyclopenta[π比洛-2-敌酸叔丁酉^^(3a&gt;?,5尤63^)-5-amino group- Hexahydro-cyclopenta[c]pyrrole_2-carboxyl-amp; tert- 1 S-lGb (1.7 g' 7. 5 mmol) was dissolved in (9) mL of dichlorohydrazine, U-benzyloxypurine (1) · 41 g, 8. 26 mmol) and triethylamine 〇 · 52 g, liquid, nml), stirred for 3 hours. Add 5 〇虬 saturated sodium bicarbonate solution mLx3) methyl chloride extraction (1 〇〇 mL), organic The layer was washed with saturated brine (30 mL EtOAc (EtOAc m. 5~Benzyloxycarbonylamino-hexahydro-cyclopenta[C]pyrrole tert-butyl ester 1 〇 (: (1.98 8, colorless viscous liquid), yield: 73.3%. The fourth step (3 from 5 疋6a6V (octahydro-cyclopenta[small-biha-5-yl)-dihydro acid ester 95201

S 86 1 201229050 (3a especially 5i?, 6a5〇-5-benzyloxycarbonylamino-hexahydro-cyclopenta[c] oxime 11 each-2-t-butyl t-butyl ester 10c (1.96 g, 5. 44 mmol) was dissolved in 10 mL of 1,4-dioxane, 10 mL of 2M hydrochloric acid was added, and the reaction was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, and 2M sodium hydroxide solution was added dropwise to the reaction mixture. The pH was 12, and the mixture was extracted with methylene chloride (50 mL). EtOAc (EtOAc) Octahydro-cyclopenta-5-yl)-benzyl decanoate 10d (635 mg, pale yellow oil), yield: 45%. MS m/z (ESI): 261.2 [M+l] The fifth step (3 &amp; no, 5 brother 685 ') - (2-mercapto-octahydro-cyclopentapine |» than 11 each 5-base) - benzyl acid tartrate ice bath, will (3a ^ 5 Left, 6a5〇-(octahydro-cyclopenta[c]D is more than p-5-yl)-benzyl carboxylate l〇d (635 mg, 2.4 mmol) dissolved in 20 mL of acetonitrile and water (V A mixture of :V=9:1), 37% citric acid solution (110 mg, 3. 66 mmol) and triethyl ethoxylated sodium hydride (1.52 g, 7.2 mmol) were added, and the reaction was stirred for 2 hours. Pressure concentrated reaction solution Add 50 mL of saturated sodium bicarbonate solution, dichloromethane extraction (100 mL), and wash the organic layer with saturated brine (30 mL×3), dry over anhydrous magnesium sulfate, and the mixture is concentrated under reduced pressure. The residue obtained was purified by eluent system A to give the title product (33 y, y, y, y, y, y, y, y, y, y, y, y, y Benzene vinegar 10e (559 mg, yellow oil), yield: 85%. Step 6 (3a^?, 5 and, 6aiS〇_2-mercapto-octa-nitro-cyclopenta[c]n ratio p Each 5-amino-amine 87 95201 201229050 (3a7P, 5疋6a«-(2-mercapto-octahydro-cyclopenta[c]pyrrole-5-yl)-carboxylic acid benzyl ester l〇e (550 The title product (3ai?, 5) was dissolved in 20 mL of decyl alcohol, and added (55 mg, 10%), and the mixture was stirred under a hydrogen atmosphere for 1 hour.疋6a5〇-2-meryl-octane-cyclopenta[c&gt; piroxi-5-yl-amine 10f (246 mg, colorless oil), yield: 87.9%. MS m/z ( ESI): 141.2 [M+l] Step 7 4-(((and)_8-cyclopentyl-7-ethyl-5-methyl-6-sideoxy-5, 6, 7, 8-4- Hydrogen-°棠°-2-ylamino)-3-曱oxy-N-((3aA,5-foot 6a5〇-2-methyl-octahydro-cyclopenta- 1»pyr-5-yl)-benzamide will ((A〇-7-ethyl- 8-cyclopentyl-2-(3-methoxy-stanoic acid-4-yl-amino)-5-methyl-7, 8-dihydropenta-6-one lm (i65 mg, 〇 39 mmol) dissolved in 15 mL of dichlorohydrazine and added (3aA*, 5 brother 6a5〇-2-mercapto-octahydro-cyclopenta[c]° piroxicam-5-yl-amine 10f (60 Mg ' 0.42 mmol), benzotriazole-N,N,N,,N,-raf-based urea tetrasoleate (135 mg '0.42 mmol) and diisopropylethylamine (151 mg) , 1. 17 mmol) 'Stirring reaction for 2 hours. Saturated with a saturated gasification solution (30 mL), saturated sodium bicarbonate solution (30 mL), saturated brine (30 roLx3), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified with eluent system A to give the titled product 4-((())-8-cyclopentyl-7-ethyl-5- decyloxyl-5, 6, 7, 8- 4 Hydrogen-acridin-2-ylamino)- 3-indolyloxy_N_((3aiP,5, especially 685)-2-indolyl-octahydro-cyclopenta[c]pyrrole-5-yl)-benzene曱95201

The yield of the phthalamide 10 (47 mg, white solid) was: 22.1%. MS m/z (ESI): 548. 3 [M+l].H NMR (400 MHz, CDCh, ppm) δ 9.52 (s, 1H), 8.52-8.54 (d, 1H), 7.70 (s, 1H), 7.62 (s,1H), 7.57 (s,1H), 7.28-7.29 (d, 1H), 4.65-4.69 (m, 1H), 4.53-4.61 (m, 1H), 4. 22~4.25 (m, 1H) ), 4. 00 (s, 3H), 3. 34 (s, 3H), 2. 84~2. 92 (m, 2H), 2. 73~2. 83 (m, 2H), 2. 47 ( s,3H), 2. 28~2. 3 (m, 2H), 2. 1-2.22 (m, 2H), 1.6-2. 08 (ra, 12H), 0.88~0.91 (t, 3H) 11 4-((Λ〇-8-Cyclopentyl-7-ethyl-5-mercapto-6-sideoxy-5, 6, 7, 8_tetraindole-indole-2-ylamino) -N-((4a5; 6疋7a^?)-2-methyl-octahydro-1 and -cyclopenta[c]0 ratio. D-6-yl)-3-methoxy-stupid Amine 11 - 1 4-((Λ〇-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7-tetrahydro-indole-2-yl) Amino)-N-((4a and,65; 7&amp;5&quot;)-2-mercapto-octahydro-H&quot;cyclopenta[c]pyridin-6-yl)-3-methoxy-benzene Guanamine U-2

89 201229050

H-4+ H- visit six steps m2

H ♦ H-4—^-H

The fifth step 11β-1 11e-2

11f-1 111-2

The first step (4a5&quot;, 7af)_6 -&gt; Amino-Liufeng-1 and - Cyclohexa[c] ° than bite_2-t-tert-butyl ester lla-1 (4ai?,65; 7850- 6-Benzylamino-hexahydro-1 and-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester lla-2 (4a5; 7aiP)-6 obtained in the seventh step of Example 8 under ice bath -Sideoxy-hexahydro-10,000-cyclopentanthene]pyridine-2(3^)-tert-butyl ester 8h-l and (485&quot;,78 especially)_6_sideoxy_hexahydro-1ZM衮 并 和 [^7] ° than bite _2 (3 ^ 〇 - slow 90 95201

S 201229050 . Mixture of acid tert-butyl ester 8h-2 (1.1 g, 4.6 mmol) and benzylamine (492 « mg' 4. 6 mmol) dissolved in 50 mL of dioxane, acetic acid (276) Mg, 4·6 mmol) and sodium triethoxysulfonium borohydride (1. 95 g, 9.2 mmol) were stirred at room temperature for 12 hours. Saturated sodium carbonate solution was added dropwise until the pH of the reaction solution was about 9 'dihydromethane extraction (50 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system A. To give the title product (4a5;6)?,7a)?)-6-benzylamino-hexahydro-10,000-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester lla-Ι and (4af a mixture of 651, 7a5〇-6-benzylamino-hexahydro-1 and-cyclopenta[c]pyrene-batch-2-tert-butyl tert-butyl ester lla-2 (1.25 g, pale yellow oil) , Yield: 83%. MS m/z (ESI): 331.3 [M+l] The second step (4a5*, 6 friends, 7aA〇-6-amino-hexahydro-1 and -cyclopenta[匚]° than 唆-2-teric acid tert-butyl ester llb-1 (4a and, 65*, 785^-6-amino-hexahydro-1 and -cyclopenta[[]° than bit-2-reacid tert-Butyl ester llb-2 (4a5; 6 especially 7a)?)-6-benzylamino-hexahydro-1 and-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester lla- a mixture of Ι and (4a疋65; 7a«-6-benzylamino-hexahydro-If cyclopenta[c]° with tert-butyl pyridine-2-decanoate lla-2 (1.25 g, 3. 78 mmol) dissolved in 2 methanol, added (150 mg, 10%) palladium on carbon, stirred under a hydrogen atmosphere It should be hr. After hydrazine, the solution is concentrated under reduced pressure to give the title product (4a5 &quot;, 6疋7a and amine-hexahydro-1 and _cyclopenta[c]e than β-but-2-decanoic acid tert-butyl vinegar And 91 95201 201229050 (4a and 651, 7a5*)-6-amino-hexahydro-1 and -cyclopenta[c]° ratio. Mixture of tert-butyl decanoate llb-2 (910 mg, light Yellow oil), Yield: 100%. MS m/z (ESI): 241.2 [M+l] The third step (4a5&quot;, 6 especially 7a friend)-6-hydroxylamino group-six Hydrogen-l and-cyclopenta[c]n&amp; pyridine-2-carboxylic acid tert-butyl ester llc-1 (4aA\65&quot;,7aiS)-6-hydroxylaminocarbyl-hexahydro-1 and Cyclopentazone|^]0-pyridyl-2-carboxylic acid tert-butyl ester llc-2 Under ice bath, the above steps were obtained (4&amp;5;6 brother 7&amp;-6-amino-hexahydro-li7- Cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester llb-indole and (4aA, 651, 7a5〇-6-amino-hexahydro-1 and -cyclopenta[e]n ratio bite-2 Uncle

A mixture of butyl sulphate llb-2 (909 mg, 3.78 mmol) was dissolved in 25 mL of monochlorohydrazine. Add 'diethylamine (763 mg '7.56 mmo 1) and chloroformic acid@@(7) 0 7 mg ' 4 · 16 mmo 1) 'Through the reaction for 2 hours. The saturated sodium carbonate solution was added dropwise to a pH of 8 to 9 and extracted with dichloromethane (50 mL×3:), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product ( 435 </ s </ s </ </ </ /> </ </ /> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; /?, 651,785^-6-benzyloxycarbylamino-hexahydro-1 and -cycloindolo[c]pyridine-2-carboxylic acid tert-butyl ester llc-2 mixture (520 mg, colorless oil (form), yield: 37%. The fourth step (4a5&quot;, 6 brothers 7a^〇_octa-nitro-cyclopenta[e] π ratio bite-6-yl-diacid acid festival 92 95201

S 201229050 hydrochloride lld~l (4aiP, 651, 78 phantom ~ octahydro_1 and _cyclopenta[c]pyridine -6-carboxylic acid benzyl ester hydrochloride lld-2 (4a5) ;6^7aiP)-6-benzyloxycarbylamino-hexahydro-1 and-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester llc_ and (4a brother 65; 7a5V6-benzyloxy A mixture of carbamoylamino-hexahydro"cyclopenta[1] (1 pyridine-2-carboxylic acid tert-butyl ester llc_2 (513 呃, 137 丨) was dissolved in 6 mL of dioxane, and 6 was added. 1,4-6 Μ2 dimethyl disulfide solution of hydrogen hydride gas, stirred for 30 minutes, concentrated under reduced pressure to give the title product (4av9, 6 s. 7aA) - octahydro-1 and -cyclopenta[c]^n Benzyl- 6-yl-barbituric acid benzyl ester hydrochloride lid-1 and (4a especially 65; 7a«-octahydro-1^cyclopenta[c]pyridin-6-yl-carboxylic acid benzyl ester hydrochloride ud Mixture of -2 (430 mg, white viscous liquid), yield: 100%, directly to the next step. MS m/z (ESI): 275.2 [M+l] Step 5

GaS,67?,7aA)-2-mercapto-octahydro-1ZM裒penta[c]〇biter _6-yl-benzyl decanoate lle-1 (4a疋65&quot;,785)-2-A Base-octahydro-1 and -cyclopenta[small ratio = _6_yl_ benzyl acid ester-2 lle-2 under ice] (4akS', 6A&gt;, 7aA) obtained from the above steps) - octahydrogen -l) 7-cyclopenta[c]pyridin-6-yl-carboxylic acid benzyl ester hydrochloride ll ¢ il and (4a^ 651,7a5·)-octahydro-1 and-cyclopenta[c]° Than the bite-6-based-slow acid

A mixture of salt it salt lld-2 (425 mg, 1.37 mmol) was dissolved in 2 mL of a mixture of acetonitrile and water (V: V = 1:1), and sodium triethoxysulfonate hydride 95201 93 was added. 201229050 (871 mg, 4.11 mmol), and reacted at room temperature for 12 hours. Add saturated sodium carbonate solution until the pH of the reaction solution is about 9, extract with dichloromethane (50 mL×3), wash with water (50 mL), saturated brine (30 mL×3), dry over anhydrous magnesium sulfate, filter, filtrate Concentration by pressure gave the title product (4aiS, 6 especially 7ae)-2 -mercapto-octa-nitro-1 and-cyclopenta[c]0 to 0-hex-6-yl-t-acid benzyl ester lle-Ι and (4aA , 65; 7a«-2-mercapto-octane-1 and -cyclopenta[c] B a mixture of β--6-yl-treazone benzyl vinegar 1 le-2 (374 mg, light yellow oil Yield: 94%, directly to the next step. MS m/z (ESI): 289.2 [M+l] Step 6 (4ak9,6 especially 7af)-2_methyl-octa-nitro-1 and- Cyclopenta[c]0 is more than -6-aminol llf-1 (4a^6iS,7a5*)-2-mercapto-octa-nitro-1 and-cyclopenta[c]0 is 0--6 -Aminol llf-2 (4a5; 6 especially 7ai〇-2-mercapto-octahydro-1τ7-cyclopenta[c]pyridin-6-yl-carboxylic acid benzyl ester lle-Ι and ( 4af,65; a mixture of 7350-2-methyl-octahydro-1 and-cyclopenta[c]pyridin-6-yl-carboxylic acid benzyl ester lle-2 (374 mg, 1.29 mmol) dissolved in 25 To the mL sterol, (50 mg, 10%) palladium on carbon was added, and the reaction was stirred for 2 hours under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure to give the title product (4a5; 6^7^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ a mixture of 〇-2-methyl-octahydro-1 and-cyclopenta[£7]° 唆-6-aminol llf-2 (198 mg, white solid), yield: 100 ° / ◦, directly Put in the next step. MS m/z (ESI): 155.2 [M+l] 94 95201 s 201229050 Step 7 4-((and)-8-cyclopentyl-7-ethyl-5-methyl-6- Sideoxy-5, 6, 7, 8-tetrahydro-嗓β-denyl-2-ylamino)-N-((4a5I, 6-methylidene-octahydro-1 and -cyclopenta[c]n Than-6-yl)-3-methoxy-codamine 11-1 4-((and)-8-cyclopentyl-7-ethyl-5-fluorenyl-6-sideoxy- 5, 6, 7, 8-tetrahydro-indot-2-ylamino)-N-((4a especially 65; 7a«-2-methyl-octahydro-1 and-cyclopenta[c]pyridine -6-yl)-3-methoxy-benzamide 11-2 (4a5&quot;,6 friends,7a_^)_2_methyl-octa-nitrogen-1 and ~cyclopenta[c a mixture of pyridine-6-aminol llf-indole and (4a brother 65; 7a5 〇-2-methyl-octahydro-1 and -cyclopenta[c]pyridine-6-amine llf-2 (60 mg , 0. 39 mmol) '(U)-7-Ethyl-8-cyclopentyl-2-(3-decyloxy-benzoic acid 4--4-amino-amino)-5-mercapto-7, 8-dihydro-5 and-acridin-6-one lm (182 mg' 0.43 mmol) 'benzotriazole-v, ν, Ν ',N,-tetradecylurea tetrafluoroborate (125 mg, 〇·39 mmol) and diisopropylethylamine (150 mg, 1.17 mmol) dissolved in 20 mL of dichloromethane 'stirring reaction 2 hours. Add saturated sodium carbonate solution until the pH of the reaction solution is about 9, and extract with 2 gas (5 〇mLx3), followed by saturated ammonium chloride solution (3 〇mL), saturated sodium bicarbonate solution (30 mL), and saturated. The residue was washed with brine (3 mL mL), dried over anhydrous magnesium sulfate _7_Ethyl-5-methyl-6- oxo-5,6,7-tetrahydro-acridin-2-ylamino)1-((4a5·,6疋7ai?) 2-mercapto-octahydro-1 and-cyclopenta[c]pyridine_6-95 95201 201229050 benzyl)-3-decyloxy-benzoguanamine 11-1 and 4-(U)-8- Cyclopentyl-7-ethyl-5-methyl-6-o-oxy-5,6,8-tetrahydro-acridin-2-ylamino)-b ((4aV?,65&quot;, 78) a mixture of 5)-2-methyl-octahydro-1 and -cycloindolo[c]n than indol-6-yl)-3-indolyl-benzoguanamine 11-2 (70 mg, White solid, mixture), yield: 32%. MS m/z (ESI): 562. 5 [M+l] Η NMR (400MHz, CDCh, ppm) δ 8.52-8.55 (d, 1H), '7. 67 (s, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 6.32-6.34 (d, 1H), 4.40-4.60 (m, 2H), 4.20-4.23 (m, 1H), 3.95 (s, 3H) , 3.35 (s, 3H), 2.52-2.67 (m, 2H), 2.26~2.4 (m, 6H), 2.11~2.23 (m, 3H), 1.99~2.10 (m, 2H), 1.61-1.9 (m, 11H), 1.45-1.55 (m, 1H), 0.98-1.06 (t, 3H) Example 12 4-((and)-7-ethyl-8-isopropyl-5-mercapto-6-side oxygen Base-5, 6, 7, 8-tetrahydro-indol-2-ylamino)-N-((3 and,8aS)-hexahydrogen ratio p and [2, 1-c] [1,4 ]-oxazin-3-ylindenyl)-benzoguanamine

96 95201 201229050

12a

12 First step ((AO-2-isopropylamino-butyric acid methyl ester) (Phantom-2-amino-butyrate decyl ester hydrochloride le (28.78 g, 0.19 mol) dissolved in 200 mL II In the chloramphenicol, acetone (11.96 g, 0.21 mol) and sodium acetate (30.76 g, 0.38 mol) were added, and the mixture was stirred for 5 minutes, and sodium triacetoxyborohydride (59.61 g, 0.281 mol) was added. Stir the reaction for 12 hours. Add a small amount of 1 Μ hydrochloric acid, add saturated sodium carbonate solution to the reaction solution pH 8 to 9, extract with dichloromethane (50 mL×3), combine the organic phase, wash with saturated brine (30 mL), anhydrous sulfuric acid The magnesium was dried, filtered, filtered, and concentrated under reduced pressure. The residue obtained was purified eluting with EtOAc EtOAc EtOAc 16.4 g, pale oil, yield: 55%. Step 2 (£)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]- Ethyl butyrate was dissolved in 300 mL of cyclohexane with 2,4-dis-5-propion (9. 9 g, 103 mmol) and added (coil-2-isopropylamino-butyric acid) Ester ester 97 95201 201229050 12a (16. 4 g '103 ramol) and sodium arcarbonate (36. 61 g, 412 Methyl), stirred at 80 ° C for 4 hours. Filtration, concentration of the filtrate under reduced pressure, addition of 3 〇 mL of water, dioxane extraction (50 mL x 3), combined organic phase, saturated brine (30 mL) Drying, transition, and concentrating under reduced pressure, and purifying the residue by using eluent system B to obtain the title product (and)-2-[(2-gas-5-shuji-bite bite) -4-yl)-isopropyl-amino]-butyric acid methyl ester 12b (20·5 g 'yellow solid), yield: 62.8%. The third step ((and)-7-ethyl- 2-Chloro-8-isopropyl-7, 8-dihydro-5#-die. Ding-6-ketone will (N)-2-[(2-Ga-5-Shi Xiaoji-Mouth-4-yl) - isopropyl monoamino]-butyl acid methyl ester 12b (7.3 g, 23 mmol) was dissolved in 1 〇〇 醋酸 acetic acid, an excess of Raney nickel was added, and the reaction was stirred under a hydrogen atmosphere at '75 Torr for 2 hours. Filtration, concentration of the filtrate under reduced pressure, addition of 20 mL of ice water, precipitation of solid, over-reduction, drying of the filter cake to give the title product (Λ〇-7-ethyl-2- gas-8-isopropyl-7, 8-Dihydro-5 and - 嗓 ° -6 - steel 12c (1. 1 g, off-white solid), yield: 71.7%. Directly charged to the next reaction. MS m / z (ES I): 255.1 [M+l] The fourth step (none) -7-ethyl-2-gas-8-isopropyl-5-methyl-7, 8-dihydro-5#-bite-6 —3 同对(无)-7-ethyl-2-气-8-isopropyl-7, 8-di-p-indene-6-one 12c (12.1 g, 47.5 mmol) dissolved in 180 mL of propylene g was added to the mixture, and p-toluic acid methyl ester (13.28 g, 71.3 mmol) and carbonic acid unloaded (13.11 g '95 mmol) were stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure, 98 95201 201229050 / Add 30mL of water, dihydromethane extraction (50mLx3), combine the organic phase, wash with saturated brine and brine (3〇mL), dry over anhydrous magnesium sulfate, filter, filtrate concentrate, concentrate The obtained residue was purified by eluent column chromatography using eluent column chromatography to afford the title product (yield) -7-ethyl-2- s -8- isopropyl-5-methyl- s, -7,8- Hydrogen-5)7-acridin-6-one 12d (10.8 g, white solid), yield: 84.7%. , 'The fifth step U)-4-(7-ethyl-8-isopropyl-5-methyl-6-sideoxy_5, 6, 7, 8_tetrazole-die °-2- Aminoamino)-methoxy)-benzoic acid hydrazine is a 4-amino-3-methoxy-4-benzoic acid oxime ester ic (i.7 g, 956 mmol), (W7-ethyl -2-Chloro-8-isopropyl-5-mercapto-7, 8-dihydro-5 and -acridin-6-one 12 (1 (2.4 boge, 9.11111111〇1) and p-toluenesulfonic acid ( 2.8 g, 14. 57 mmol) was dissolved in 50 mL of 4-methyl-2-pentanol, and the reaction was stirred for 2.5 hours under reflux. The reaction mixture was concentrated under reduced pressure, and then filtered and evaporated. The mixture was washed with aq. (y?)-4-(7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro-acridin-2-ylamino) 5%。 曱 ) ) ) 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 MS m/z (ESI): 414. 3 [M-fl] Step 6 (and) -4-(7-ethyl-8-isopropyl-5-methyl-6-s. 6, 7, 8-tetrahydro-azino-2-ylamino)-decyloxy)-benzoic acid 99 95201 201229050

(7?) 4-(7-ethyl-g-isopropyl-5-methyl-β-sideoxy-5,6,7-tetrahydro-acridin-2-ylamino) _ methoxy) benzoic acid oxime ester 2e (l· 7 g ' 4. 15 〇 1) was dissolved in 40 inL of methanol, added 45 mL of 1 Μ lithium hydroxide solution, 8 (TC stirring reaction for 5 hours. The concentrated reaction solution was extracted with ethyl acetate (50 mL×3), and then added with solid potassium hydrogen sulfate until the pH of the reaction mixture was 3 to 4'. The filter cake was washed with water and a small amount of ethanol and dried to give the title product (s). (7-Ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzene Formic acid 12f (2. 24 g 'white solid), yield: 91. (10). Step 7 4-((皮)-7-Ethyl-8-isopropyl-5-fluorenyl-6-oxirane_5, 6, 7, 8-tetrahydro-n-beta-but-2- Amino group)-Ν-((37?,8aS)-hexahydro-ηpiro[2,1-c][1,4]-oxan-3-ylindolyl)-benzoguanamine (3 especially 8aS)-hexahydro-indole [2, dip] [1,4&gt;oxan-3-yl)decylamine (39 mg '0.25 mg, prepared by the known method "CN101392001") Dissolved in 30 mL of di-gas methane and added ((y?)-4-(7-ethyl-8-isopropyl-5-fluorenyl-6-oxirane-5, 6, 7, 8- Tetrahydro-indot-2-ylamino)-methoxy)-formic acid 12f (100 mg, 0.25 mmol), benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethylurea IV The fluoroborate (8 〇 mg, 〇. 25 匪〇 1) and diisopropylethylamine (0.1 mL, 0.63 mmol) were stirred for 1 hour. After adding 30 mL of chlorohydrazine, the mixture was washed with saturated ammonium chloride solution (3 mL), brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. , the title product 4-((iP)-7-ethyl-8-isopropyl-5-methyl-6-oxirane-5, 6, 7, 8-4-95201

S 100 201229050 (· Hydrogen-acridin-2-ylamino)-N-((3^?,8aS)-hexahydro-pyrrolo[2, lc] [1,4]-oxazin-3-yl Benthyl)-benzamide 12 (75 mg, white solid), Yield: 56%. MS m/z (ESI): 538. 3 [M+l]^ NMR (400 MHz, CD Ch, ppm) δ 8. 57 to 8.58 (d, 1H), 7. 63 (s, 1H), 7.46 ( s,1H), 7.34 to 7.36(d,1H),6.86(s, 1H), 4.69 to 4.74 (m,1H), 4.28 to 4.31 (m,1H),4 12 to 4.19 (m, 2H), 3.90 to 3. 98 (m, 4H), 3. 66 to 3. 75 (m, 2H), 3.33 to 3.35 (m, 3H), 3 05 to 3.24 (m, 4H), 2.76 to 2.82 (m, 1H), 1. 89 to 2. 03 (m, 5H), 1. 69 to 1. 77 (m, 1H), 1.37 to 1.45 (m, 3H), 1.30 to 1.36 (m, 3H), 0.87 to 〇. 90 (t, 3H) Example 13 4-(U)-7-ethyl-8-isopropyl-5-fluorenyl- 6-Sideoxy-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)-N-((35; 8a5〇-hexahydropyrho[2, lc][l,4 ]-oxazin-3-ylindenyl)-benzoguanamine

4-((Λ〇-7-ethyl-8-isopropyl-5-fluorenyl-6- pendantoxy-5, 6, 7, 8-tetrazene 101 952012 201229050 Hydrogen-noise-den-2-yl Amine 8a5*)-hexahydrogen ratio η each [2, lc] [1,4]-oxazol-3-ylindenyl)- benzoic acid amine (35; 8a5·)-hexahydro-pyrrole [ 2, lc][i, 4]oxazin-3-yl)methylamine (39 mg, 0. 25 mmol, prepared by the well-known method "CN1 〇 1392001") dissolved in 30 mL of dichloromethane, added ( (yp)_4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7-tetrahydro-acridin-2-ylamino)-oxime Oxy)-benzoic acid 12f (100 mg, 0.25 mmol), benzotriazole-N,N,Ν',Ν'-tetradecylurea tetrafluoroborate (80 mg, 〇. 25 mmol) And diisopropylethylamine (0.1 mL '0. 63 mmol), and the reaction was stirred for 1 hour. Add 30 mL of dioxane, and then wash it with saturated ammonium chloride solution (3 〇mL), saturated brine (30 mL), dry over anhydrous magnesium sulfate, filtered, and the filtrate is decomposed under reduced pressure. To give the title product 4-((^-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,6,4-tetrahydro-acridin-2-yl) Amino)-N-((35;8a«-hexahydropyrolo[2,1-c][1,4]-oxazin-3-ylmethyl)-benzamide 13 (65 mg , white solid), Yield: 44. 8%. MS m/z (ESI): 538.5 [M+l] 4 NMR (400MHz, CDC13, ppm) δ 8·55 to 8.58 (d,1H), 7· 68 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.32 to 7.45 (d, 11〇, 6.51 to 6.54 (111, 11〇, 4.71 to 4.74 (111, 1 illusion, 4.28 to 4.31 (m, 1H), 4. 02 to 4. 06 (m, 1H), 3. 97 (s, 3H), 3.73 to 3.79 (111, 21〇, 3.41 to 3.46 (111, 21〇, 3.33) (3,31〇, 3.11 to 3.14 (m,2H), 2.15 to 2.20 (m,3H), 1.69 to 1.93 (m,6H), 1.40 to 1.45 (m , 3H), 1.36 to 1.37 (m, 3H), 0.85 102 95201 201229050 to 0. 90 (t, 3H) Example 14 4_((·^)_7-ethyl_8_isopropyl -5-5-mercapto-6-sideoxy_5,6,7,8-tetrahydro-acridin-2-ylamino)-indole-((3 brother 8aA)-hexahydro-pyrrolo[2 , 1-c] [1,4]-oxazin-3-ylindenyl)-phenylguanamine

First Step 4-((Left)-7-Ethyl-8-isopropyl-5-mercapto-6-oxirane-5, 6, 7, 8-tetrahydro-嗓β-dec-2-yl Amino)-N-((3 especially 8af)-hexahydro-D-pyrolo[2,1-c][1,4]-oxazol-3-ylindenyl)-benzoguanamine will (( 3 especially 8aA) _ hexahydro-pyrrole [2, lc] [l, 4] oxazin-3-yl) decylamine (39 mg, 〇. 25 mmol, prepared by the known method "CN101392001") dissolved in Add ((y?)-4-(7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro) to 30 mL of dichloromethane. - Bite-2-ylamino methoxy)-benzoic acid 12f (100 mg, 0.25 mmol), benzotriazole is called Chuanzhou, 1^,-tetradecylurea tetrafluoroborate (8 〇1^, 0.25 then 1〇1) and diisopropylethylamine (0.1 mL, 0.63 mmol), stir the reaction for 1 hour. Add 20 mL of dichloromethane, followed by saturated ammonium chloride solution ( 30 mL), washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, evaporated, evaporated. -8-isopropyl-5-methyl-6-oxo-5,6,7-tetrahydro-indole-2-ylamine )-N-((3·/?, 8a no)-hexa-argon ratio slightly [2, [1,4]-β-carbomethoxy)-benzamide 14 (67 mg, white solid), Yield: 50%. MS m/z (ESI): 538.5 [M+l] 4 NMR (400 MHz, CDCh, ppm) δ 8· 55 to 8.58 (d, 1H), 7. 68 (s, 1H), 7.62 ( s, 1H), 7.45 (s, 1H), 7. 30 to 7. 32 (d, 1H), 6. 49 to 6.50 (m, 1H), 4. 69 to 4. 76 (m, 1H), 4.28 To 4.30 (111, 11〇, 4.02 to 4.06 (111, 11〇, 3.97 (3, 31〇, 3.73 to 3.79 (111, 21〇, 3.42 to 3.47 (111, 21〇, 3.33 (3, 31〇, 3) 01 to 3.12 (m, 2H), 2·13 to 2·18 (m, 3H), 1·68 to 1.96 (m, 6Η), 1.43 to 1.45 (m, 3Η), 1.36 to 1.37 (m, 3 Η), 0.85 to 0.90 (t, 3H) Example 15 4-((Λ〇-7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5, 6, 7, 8-tetrahydro-indole-2-ylamino)-N-((35·,8aN)-hexahydropyrazine[2,1-c] [1,4]-Evil Pyrazin-3-ylindenyl)-benzamide

104 95201 201229050 First Step 4-(U)-7-Ethyl-8-isopropyl-5-mercapto-6-sideoxy-5, 6, 7, 8-tetrahydro-bite-2- Amino group)-^1-((35^8aA)-hexahydro-indolo[2,1-c][1,4]-oxazol-3-ylindenyl)-benzoguanamine (3S,8a^?)-hexahydro-pyrrole[2, lc][l,4]oxazin-3-yl)methylamine (39 mg, 〇· 25 mmol, prepared by the well-known method "CN101392001" Dissolved in 30 mL of dichloromethane and added ((^-4-(7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro) - 喋2-ylamino)-decyloxy)-benzoic acid 12f (l 〇〇 mg, 0.25 mmol), benzotriazole-oxime, hydrazine, Ν', Ν'-tetradecylurea Tetrafluoroborate (8 〇 mg, 〇. 25 mmol) and diisopropylethylamine (0.1 mL '0. 63 mmol), stirred for 1 hour. Add 30 mL of dichloromethane, followed by saturation The ammonium chloride solution (3 mL) was washed with saturated brine (30 mL). 7-Ethyl-8-isopropyl-5-mercapto-6-sideoxy-5, 6, 7, 8-tetrahydro-indole咬-2-ylamino)-N-((3S,8a^〇-hexahydrogen ratio p and [2, 1-c] [1,4]-noso-3-ylindenyl)-benzene Indoleamine 15 (62 mg, white solid), Yield: 45. 5%. MS m/z (ESI): 538.5 [M+l] 泔匪R (400 MHz, CDCls, ppm) δ 8. 57 to 8. 59 (d,1H), 7.67 (s,1H), 7.64 (s,1H), 7.47 (s,1H), 7.40 to 7.46 (d, 11〇, 6.96 (3,11〇, 4.68 to 4.75 (111, 11 〇, 4.28 to 4.30 (m, 1H), 4.12 to 4. 22 (m, 2H), 3.94 to 3.98 (m, 4H), 3. 62 to 3. 73 (m, 2H) , 3· 21 to 3. 32 (m, 6H), 3. 01 to 3. 12 (m, 105 95201 201229050 1H), 2. 76 to 2.82 (m, 1H), 1.95 to 2.01 (m, 4H), 1·89 to 1.94 (m, 1H), 1.69 to 1.88 (m, 1H), 1.55 to 1.57 (m, 3H), 1.48 to 1.53 (m, 3H), 0.85 to 0.90 (t, 3H) Example 16 4-(U)-7-Ethyl-8-isopropyl-5-mercapto-6-oxirane-5, 6, 7, 8-tetrahydro-acridine -2-ylamino)-N-((4a7?,67?,7a574a5; 65; 7aiP)-2-mercapto-octahydro-1 and-cyclopenta[c]pyridine-6-yl)-3 -decyloxy-benzoguanamine

16

16-2 First step (43^&gt;, 6^/?, 7&amp;51)_6-azido-octahydro-1 and-cyclopenta[(^]0 than bite hydrochloride 16a-l 106 95201 201229050 (4a5; 651, 7ai?)-6-azido-octahydro-1 and-cyclopenta[c]pyridine hydrochloride 16a_2

(4a^6 foot 7350-6-azido-hexahydro-1 and-cyclopenta[c]pyridine-2 (3^0-carboxylic acid tert-butyl ester 8k-l) obtained in the ninth step of Example 8. And (4ai9, 65, 7a/?)-6-azido-hexahydro-1 and-cyclopenta[c]n ratio bite-2 (3 milk-tert-butyl carboxylate 8k-2 mixture (1 15 g, 4. 32 mmol) dissolved in 5 mL of monochloromethane. Add 1 〇mL of 6 Μhydrogen chloride in 1,4-bis&quot; dysentery solution, stir the reaction for 2 hours. Concentrate the reaction solution under reduced pressure to obtain The title product (48·^, 6 and 7aiS)-6-azido-octahydro-1 and-cyclopenta[c] than the bite hydrochloride 16a-l and ('aiS1,651,7a^〇- a mixture of 6-azido-octahydro-1 and-cyclopenta[c]«&gt;pyridinium hydrochloride 16a-2 (880 mg, colorless oil), yield: 100%. One step. MS m/z (ESI): 167.2 [M+l] The second step (4ae, 6 especially 7a5〇-6-azido-2-indenyl-octane-1 and -cyclopenta[匚] 0 to 0, 16b-l (4a5; 65; 7a^?)-6-azido-2-mercapto-octahydro-1 and -cyclopenta- ace than the 16b-2 ice water bath, the above steps (4a^6疋7a«-6-azido-octahydro-1 and-cyclopenta[c]pyridine hydrochloride 16a-l and (4a5&quot;,651,7aA〇-6_azide _ 八气-1和-J 戍 戍 [〇] π than σ 趟 趟 趟 16a-2 mixture (880 mg ' 4. 32 mmol) dissolved in 2 〇 mL B guess and water (V: V = 1: In the mixture of 1), 37% hydrazine solution (〇71 mL ' 8. 64 mmol) and sodium triethoxy borohydride (2.7 g, 12 96 95201 107 201229050 mmo 1) were added in sequence. After reacting for 2 hours, 10 mL of 1 Μ hydrochloric acid was added, 15 mL of 5% sodium argon oxide solution was added dropwise to the reaction solution at pH 9, stirred for 10 minutes, extracted with dichloromethane (50 mL×3), and the organic phases were combined and washed with saturated brine. (50 mL x 3), dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -2-methyl-octane-1 and -cyclopenta[c]pyridine 16b-1 and (4a5; 65; 7a7?)-6-azido-2-indolyl-octahydro-1 and-ring Mixture of pentylene [c] π to bite 16b-2 (650 mg, colorless oil), yield: 84%. MS ra/z (ESI): 181. 1 [M-fl] Step 3 (4a7 ?6尤7a«-2-mercapto-octahydro-1 and-cyclopenta[c]pyridin-6-yl-amine 16c-l (4&amp;65; 7a^?)-2-methyl- Octahydro-1 -cyclopenta[c]pyridin-6-yl-amine 16c-2 (4a&gt;?, 6 especially 7a«-6-azido-2-methyl-octahydro-1 and-ring obtained in the above step a mixture of pentato[c]pyridine 16b-1 and (4a5; 65; 7af)-6-azido-2-methyl-octa argon-1 pico-cyclopenta[c]0 to 0 lb 16b-2 (650 mg, 3. 6 mmol) was dissolved in 20 mL of methanol, and then added (70 mg, 10%) palladium/carbon, and the mixture was stirred for 2 hours under hydrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure to give the title product (4a 77a«-2-methyl-octahydro-1 and-cyclopenta[c] oxime ratio 0--6-yl-amine 16c-1 and (4akS,6 51,7-2-mercapto-octahydrogen a mixture of -1 Zf-cyclopenta[c][deg.] ratio -6-yl-amine 16c-2 (505 mg, pale yellow oil). Yield: 91%.

108 95201 S 201229050 MS m/z (ESI): 155.2 [M+l] Step 4 4-((Friend)-7-ethyl-8-isopropyl-5-fluorenyl-6-sideoxy- 5, 6, 7, 8-tetrahydro-acridin-2-ylamino)-N-((4aiP,6疋7a5*)-2-indolyl-octahydro-1#-cyclopenta-I» ratio Pyridin-6-yl)-3-decyloxy-benzoguanamine 16-1 4-((Λ〇-7-ethyl-8-isopropyl-5-methyl-6- pendantoxy-5 , 6, 7, 8-tetrahydro-acridin-2-ylamino)-N-((4a5; 65; 7a)P)-2-indolyl-octahydro-1 and-cyclopenta[c] Pyridyl-6-yl)-3-methoxy-benzoguanamine 16-2 (4a7?,67?,7a«-2-mercapto-octahydro-1)7-cyclopentacarb obtained in the above step a mixture of [c]pyridine-6-yl-amine 16c-1 and (4a5; 65; 7aiR-2-methyl-octa argon-1 and -cyclopenta[c]pyridin-6-yl-amine 16c-2 (77 mg, 0.5 mmol), U)-4-(7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro-acridine- 2-Aminoamino)-nonyloxy)-benzoic acid 12f (199.7 mg, 〇. 5 mmol), benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethylurea tetrafluorodecarboxylate (160 mg, 0.5 mmol) and diisopropylethylamine (142 g, 1.1 mmol). Add the amine to the pH of the reaction solution to a pH of 9 to 10, add 50 Torr of water, extract with dioxane (50 mL×3), combine the organic phase, wash with saturated brine (50 mL), dry over anhydrous sodium Concentration under reduced pressure, the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc Oxy-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)-N- ((4ae,6_/?,7&amp;5〇-2-mercapto-octa-nitro-1 and-戍 戍 [c] n than bite-ΘΑ). - 曱 - - benzoguanamine ΐ 6_ι and 4-(U)-7-ethyl-8-isopropyl-5-fluorenyl-6-side oxygen Base-5, 6, 7, 8-tetrahydro-acridin-2-ylamino)-N- 109 95201 201229050 ((4a5*,65&quot;,7aA)-2-mercapto-octahydro-1 and- 3%。 Cyclopenta[c] ° ratio of ~6-yl) -3-decyloxy-benzoguanamine 16-2 mixture (60 mg, white solid), yield: 22.3%. MS m/z (ESI): 536.5 [M+l] NMR (400 MHz, CD Ch, ppm) δ 8. 48 to 8.62 (d, 1H), 7. 58 to 7.71 (d, 2H), 7 36~7. 51 (s,1H),7_ 18~7. 31 (m,1H), 6.12 to 6.28 (mountain 111), 4.68~4.81 (111,11〇,4.55 to 4.65 (m,1H), 4. 21 to 4. 45 (m, 1H), 3.91 to 4. 05 (s, 3H), 3.26 to 3. 41 (s, 3H), 2. 21 to 2. 59 (m, 1H), 2_48 to 2.58 (s, 3H), 2.35 to 2.46 (s, 3H), 2.15 to 2.28 (m, 4H), 1.88 to 2. 02 (m, 2H), 1. 61 to 1 75 (m, 4H), 1_ 43 to 1. 53 (d, 3H), 1.28 to 1.41 (d, 3H), 0.75 to 0.81 (t, 3H) Example 17 4-((^0-7-B) Base-8-isopropyl-5-mercapto-6-o-oxy-5,6,8-tetrahydro-acridin-2-ylamino)-N-((4ai?,65; 7a574a5) ; 6 especially 7a7?)-2-methyl-octahydro-1 and -cyclopenta[c]pyridin-6-yl)-3-decyloxy-benzoguanamine 17-1 4-(U)- 7-Ethyl-8-isopropyl-5-mercapto-6-oxo-5,6,8-tetrahydro-acridin-2-ylamino)-N-((4ai?, 65; 7a574a5; 6 foot 7ai?)-2-methyl-octahydro-1 pico-cyclopenta[c]pyridin-6-yl)-3-decyloxy-benzoguanamine 17-2 110 95201 201229050

The first step is 4-(U)-7-ethyl-8-isopropyl-5-mercapto-6-peroxy_5 虱-acridin-2-ylamino)-N-((4ai? ,66; 7a«-2~methyl-eight% cyclopenta[cM pyridine-6-yl)-3-methoxy-benzoamidamine 17$^ 4-((iP)-7-ethyl- 8-isopropyl-5-methyl-6-sideoxy 6 7 8 Hydrogen-indole-2-ylamino)-Nh((4a»S,6友,7ae)-2-甲其^^ 1 cyclopenta[&lt;^&gt;pyridin-6-yl)-3-methoxy-benzimidamide 17j (4ae, 65; 7a6&quot;)-2- obtained in the sixth step of Example 11 Methyl _ octahydro-1 pico-cyclopenta[〇]° than bite-6-yl-amine 11f-1 and UaS, 6 especially 7a〇-2-methyl-octahydro-1 and -cyclopenta[ c] Mixture of pyridin-6-yl-amine 11f-2 (60 mg, 〇. 39 mmol) '(and)-4-(7-ethyl-8-isopropyl-5-fluorenyl-6-side Oxy-5, 6, 7, 8-tetra-argon-purine-2-ylamino)-decyloxy)-benzoic acid 12f (171. 6 mg '0. 43 mmol) ' &lt;9-benzene And 111 95201 201229050

Diazole-indole, hydrazine, hydrazine, hydrazine-tetramethylurea tetrafluoroborate (125 呃, 〇.39 mmol) and diisopropylethylamine (150 mg, 117 mm 〇1), stirring reaction 2 hour. The saturated sodium carbonate solution was added dropwise to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with brine (5 mL), dried over anhydrous sodium sulfate Concentration, the residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) 5, 6, 7, 8_tetrahydro-acridin-2-ylamino)-N-((4a7?,65; 735)-2-mercapto-octahydro-H cyclopenta[c]pyridine- 6-yl)-3-decyloxy-benzimidamide j74 and 4-(U)-7-ethyl-8-isopropyl-5-mercapto-6-sideoxy-5, 6, 7 , 8-tetrahydro-D-bito-2-ylamino)-N-((4a5; 6 and, 7af)-2-mercapto-octahydro-1 and-cyclopenta[c]pyridine-6- Mixture of benzyloxy-3-benzamide 17_2 (70 mg, white solid), yield: 34%. MS m/z (ESI): 536. 3 [M+l] 4 NMR (400 MHz, CDCI3, ppm) δ 8. 57 to 8. 59 (d, 1H), 7. 76 (s, lH), 7.71 ( s,lH), 7.48(s,lH), 7.29S7.31(m, 11〇, 6.30~6.32 (4 11〇, 4.75 to 4.78 (111,11〇, 4.34 to 4.56(111,11〇,4.32 to 4.34 (111, 11 〇, 4.00 (3, 311), 3.36 (3, 31 〇, 2.52 to 2.58 (111, 21 〇, 2.28 to 2.44 (111, 9 [〇, 1. 92 to 2. 03 (m, 2H), 1·70 to 1.81 (m, 4H), 1.46 to 1.53 (d, 3H), 1.31 to 1.41 (d, 3H), 0.88 to 0.92 (m, 3H) Example 18 4 -((N)-7-ethyl-8-isopropyl-5-fluorenyl-6-oxo-5,6,7-tetrahydro-indole-2-ylamino)- Ν-(1-indolyl-pyrylene-4-yl)-3-(tetrahydro-indole 112 95201 201229050 m--2-yl-methoxy)-crackamine

First step 4-((and)-7-ethyl-8-isopropyl-5-mercapto-6-oxo-5,6,7-tetrahydro-pterin-2-yl Amino)-indole-(1-methyl-π-chenyl-4-yl)-3-(tetrahydro-aceto-2-yl-methoxy)-benzoguanamine 4-amino-N -(l-fluorenyl-〇辰咬4-yl)-3-(tetrahydro-0-pentan-2-yl-methoxy)-benzimidamide 7d (150 mg, 〇. 45 mmol), U)-7-Ethyl-2-chloro-8-isopropyl-5-mercapto-7, 8-dihydro-5 and-acridin-6-one 12d (121 mg, 0.45 mmol) and hydrazine Barium benzenesulfonate 37 mg' 0.72 mmol) was dissolved in 20 mL of 4-methyl-2-pentanol and refluxed for 3 hours. The saturated potassium carbonate solution was added dropwise until the pH of the reaction solution was 9 to 1 Torr, and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated brine (5 〇mL×3), dried over anhydrous magnesium sulfate and filtered. Concentration by pressure, the residue obtained was purified by eluent column chromatography using eluent system A to give the title product 4-((-7-ethyl-8-isopropyl-5-methyl- 6 _ oxy) a 5,6, 7,8_tetradecyl-2-ylamino-methyl-O. chinensis)-3-(tetrahydro-OR-French 113 95201 201229050-an-2-yl-decyloxy) - benzoguanamine 18 (100 mg, white solid), yield: 39%. MS m/z (ESI): 566. 5 [M+l] NMR (400 MHz, CDC13, ppm) δ 8. 45 to 8.65 (d, 1H), 7. 65~7.75 (d, 2H), 7. 40~7.51 (s, 1H), 7. 25~7.38 (m, 11〇, 5.92 to 6.05 (111, 11〇, 4.36~ 4.61 (111, 11〇, 4.33 to 4.46 (m, 1H), 4. 21 to 4. 32 (m, 1H), 4. 06 to 4·18 (m, 21〇, 3.95 to 4.04 (111, 2[〇, 3.80 to 3.92 (111, 11〇, 3.25 to 3.40 (s, 3H), 2. 82 to 2. 96 (d, 2H), 2. 30 to 2. 42 (s, 3H), 2. 15 to 2.28 (m, 2H), 1.95 to 2.06 (m, 6H), 1.63 To 1.75 (m, 4H), 1·42 to 1.53 (d, 3H), 1·30 to 1.41 (d, 3H), 0. 80 to 0.95 (t, 3H) 19((A0-3-decyloxy-4-(5-fluorenyl-6-oxooxy-8-toluenesulfonyl-6,6a,7,8,9-10-hexahydro-5-and- 〇 π π Qin and [2, 1-/?] ° 0 0-2-ylamino)-N-(l-methylpiperidin-4-yl)benzamide

114 95201 201229050

The first step is 3-methoxy-N-(1-methyl-α-bottom-4-yl)-4-nitro-benzoquinone-based 3-methoxy-4-stone-base-benzoic acid la (9. 86 g, 50 mmol) dissolved in 200 mL of di-methane, followed by benzotriazole-N, hydrazine, Ν', Ν'-tetradecylurea tetrafluoroborate (16.1 g , 50 mmol), diisopropylethylamine (18.2 mL '110 mmol) and 1-indolyl-pyrylene-4-yl-amine (5·7 g, 50 mmol) 'Stirring reaction for 2 hours, adding 200 mL The di-methane methane was washed with 1 hydrazine water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title product 3-methoxy-N-(l-methyl-piperidine-4-yl)-4- Shishyl-benzamide 19a (10 g 'yellow solid), yield: 68%. MS m/z (ESI): 294.2 [M+l]. Step 2 4-amino-3-methoxy-N-(l-methyl-piperidine-4-yl)-benzamide -Methoxy-N-(l-fluorenyl-piperidin-4-yl)_4-nitro-benzamide 9a (5g, 17 draws 1〇1) was dissolved in 12 methanol and added (5 〇〇mg, 95201 115 201229050 10°/〇)Palladium/carbon, the reaction was stirred under a hydrogen atmosphere for 1 hour, filtered, and the saponin was washed with 30 mL of decyl alcohol, and the hydrazine was concentrated under reduced pressure to give the title product 4-amine- 3-decyloxy-N-(l-fluorenyl-piperidin-4-yl)-benzamide 9b (4. 36 g, white solid), yield: 97%. MS m/z (ESI): 264. 3 [M+l] The third step ((Λ〇-4-(2-Ga-5-)----4-yl)- 派°秦-1,3 - 1-tert-Butyl 3-oxoate 3-methyl ester (U)-piperazine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 19c (6 g, 24. 6 mmol), 2, 4-Dichloro-5-nitro-° bottom oxime (4.8 g, 24.8 mmol) and sodium bicarbonate (8.3 g, 98.4 mmol) were dissolved in 150 mL of cyclohexane and stirred at 65 °C. The mixture was washed with a saturated aqueous solution of sodium chloride (60 mL×2) and brine (60 mL×2). 4-(2-chloro-5-nitro-pyrimidin-4-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-decyl ester 19d (8.36 g, yellow solid) Yield: 84. 4°/〇 MS m/z (ESI): 402. 2 [M+l] Step 4 U)-2-Chloro-6-sideoxy-6a,7, 9, 10- Tetrahydro-5 and -°biazine[2, 1-/?] acridine-8 (6-milo-tert-butyl ester) ((and)-4-(2-gas-5-nitro-° Bite 4-yl)-11-Bis-1,3-dicarboxylic acid tert-butyl ester 3-decyl ester 19d (8. 36 g, 20.8 mmol) and iron powder (3.5 g, 62.4 mmol) dissolved Stirring reaction at 70 ° C in 350 mL of acetic acid Hour, concentrate the reaction solution under reduced pressure, and add saturated sodium bicarbonate solution to the reaction solution.

116 95201 S 201229050 • · PH is 8 to 9 'dichlorodecane extraction (200 mLx3), washed with saturated brine - (60 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The decane and 50 mL of ethyl acetate were precipitated as a white solid, which was filtered and dried to give the title product (Fanta-6--6-s-oxy-6a, 7, 9, 10-tetrahydro-5 and - pyrazino[2,1-/?] acridine-8 (6-but-carboxylic acid tert-butyl ester 19e (4. 55 g 'white solid), yield: 64.1%. MS m/z (ESI) ): 340.3 [M+l] The fifth step (8)-2-chloro-5-mercapto-6-sideoxy-6a,7,9,10-tetrahydro-5 and-pyridazine[2, 1- Λ] bite -8 (6i5 〇 - tartrate tartrate (A0-2- gas-6-sideoxy-6a, 7, 9, 10-tetrahydro-5 and -pyrazine and [2, Bu /?] Acridine-8 (6Z〇-carboxylic acid tert-butyl ester i9e (5〇〇mg, 147 丽〇1) and potassium carbonate (305 mg, 2.2 mmol) dissolved in 40 mL of dinonyl carbonate, refluxed and stirred The reaction was carried out for 12 hours, 50 mL of dioxane was added, and the mixture was washed with saturated aqueous ammonia (50 mL×2) and brine (5 mL mL). Chromatography The residue obtained was purified by eluent system B to give the title product (n.) </RTI> </RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 乙 嗓 -8 -8 (6^7)-tert-butyl carboxylic acid ester 19f (0. 45 g, white solid), yield: 79. 8% MS m / z (ESI): 354.2 [M+l ] Step 6 U)-2-Gas-5-fluorenyl-8-nonylsulfonyl-7, 8, 9, 1〇_tetrahydro_5)7_σpyrazine[2,1-Λ]嗓(0-2-Ga-5-methyl-6-sideoxy_6a,7,9,1〇_tetrahydro_5 and _ 95201 117 201229050 pyrazino[2,1-Λ]acridine- 8(6i7)-tert-butyl carboxylic acid 19f (415 mg, j mmol) was dissolved in 40 mL of dichloromethane, and hydrogenated gas was added, and the reaction was searched for 2 hours, followed by the addition of triethylamine (0.24 g ' 2.4 Ment) and a pair of suffocating helium (0.33 g, 1.8 mmol), stirring reaction for 2 hours. Washing with sulphur and brine (50 mL×3), anhydrous sulphuric acid, drying, transition, liquid, soil The title product (y?)-2-chloro-5-methyl-8-toluenesulfonyl-7 s 0,' ^ U was obtained by purifying the residue by eluent column chromatography. , 1 〇~ 四风-5 and -〇比嗓[2,1-Λ]0棠 bite-6(6a^〇-g with 19g( 14. 14 g, white solid), yield: 27.7%. MS ra/z (ESI): 408. 2 [M+l] Step 7 ((0-3-T-oxy-4-(5-fluorenyl-6-yloxy-8-methylsulfonyl) a 6,6a' 7, 8, 9, 10-hexahydro-5Fpyrazino[2,lh]acridine-2-aminocarbyl)-N-(l-hydrazinopiperidin-4-yl)benzene Indoleamine 4-amino-3-methoxy-N-(l-fluorenyl-piperidine-4-yl)benzamide 19b (300 mg ' ι 2 mm〇i), (( and )_3_气—1〇_methyl_7_(tolyl 4 continued st base)_6,7,8,8a_tetrahydro_5H,l2,4,qiu 7,1〇_五乱杂-菲-9 -ketone I9g (696 mg, 1.7 mmol) and p-toluenesulfonic acid (L 14 g ' 6 &quot;^οΐ)/combined in 40 mL of 4-mercapto-2-pentanol, stirred for 1 hour under reflux Triethylamine was added dropwise to the pH of the reaction mixture was 8 to 9, and the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by MgSO. One side oxy 118 95201

I 201229050 • -8-Toluenesulfonyl-6, 6a,7, 8, 9, 10-hexahydro-5 and-pyridazine[2, lh] . Acridine-2-ylaminomethylpiperidine 4-yl)benzamide 19 (212 mg, yellow solid), yield: 29.8%. MS m/z (ESI): 635.3 [M+l] 屯丽尺(4〇{^ this, €0(:13,??111)5 8.39 to 8.52 ((1,11〇, 7. 72~7.81 (m, 3H), 7. 56~7.71 (s, 1H), 7. 42~7.55 (s, 1H), 7.34 to 7.41 (m, 2H), 7.21~7.32 (m, 1H), 6.03 to 6. 14 (d,1H), 4.35 to 4.49 (m,1H), 4.16 to 4.28 (m, 11〇, 3.85 to 4.10 (111, 51〇, 3.26 to 3.39 (3, 3[〇, 2.96 to 3. 09 (m, 1H), 2.81 to 2.94 (m, 2H), 2·36 to 2.50 (m, 8H), 2. 26 to 2. 30 (m , 2H), 1.99 to 2.12 (m, 4H), 1.61 to 1.76 (m, 2H) Example 20 U)-4-(8-isopropyl-5-methyl-6 -Sideoxy-6,6a,7,8,8 10-hexa-5 and-pyridazino[2,1-indolyl]acridin-2-ylamino)-3-indolyl-N -(l-decyl-piperidin-4-yl)benzamide

The first step (left)-2-chloro-8-isopropylmethyl-7, 8, 9, 10-tetrahydro-5 and -〇 ratio 0 Qin and 119 95201 201229050 [2,1_Λ]嗓α定_ 6(6a milk-嗣2-chloro-5-mercapto-6-sideoxy-6a,7,9,10-tetrahydro-5 and _pyrazino[2,1-indenyl]acridin-8 (5小时, The reaction solution was concentrated under reduced pressure. 50 mL of methane was added, and triethylamine was added dropwise to pH 8 to 9, and acetone (0.4 g, 7. 1 mmol) was added. The reaction was stirred for 1 hour, and triethyl hydrazine was added. Sodium borohydride (2.5 g, 11.8 mmo 1), and stirred for 12 hours. Add 30 mL of water, dihydromethane extraction (50 mL×3), combine the organic phases, and wash with saturated brine (50 mL×2) The residue was dried over anhydrous magnesium -7, 8, 9, 10-tetrahydro-5 and -pyridazino[2,1-indolyl]acridin-6 (6a- ketone 20a (1. 32 g, white solid), yield: 25.4%. MS m/z (ESI): 296. 1 [M +l] The second step U)-4-(8-isopropyl-5-fluorenyl-6-oxo-6,6a,7,8,8-trihydro-5 and-pyrazine [2,1-Λ]Acridine-2-ylamino)-3-decyloxy-NU-indolyl-piperidin-4-yl)phenylamine 4-amino-3-indolyloxy -N-(l-fluorenyl-Brigade-4-yl)-benzoguanamine 19b (170 mg '0.64 mmol), (y?)-2-chloro-8-isopropyl-5-fluorenyl- 7,8,9,10-tetrahydro-5 pi-11 ratio ° Qin [2,1-/7] 蝶 ° _6 (63 ^ 〇 - Gang 20 &amp; (240 mg, 0.81 mmol) and The p-toluenesulfonic acid (〇. 81 g, 4.3 mmol) was dissolved in 20 mL of 4-mercapto-2-pentanol, and the reaction was stirred under reflux for 2 hours.

120 95201 S 201229050 To room temperature, add 20 mL of saturated sodium bicarbonate solution, extract with two methane (50 mL×3), combine the organic phase, wash the brine with saturated brine, and dry the m. The residue obtained was purified by eluent column chromatography eluting to afford the title product (and) _4_(8- isopropyl-5-methyl-6-s-oxy-6,6a,7,8,9 1〇_hexahydro-5 and monopyrazino[2,1-indolyl-2-ylamino)-3-methoxy-N-(1-methyl-piperidine-4-yl) Indoleamine 20 (61.3 mg, white solid), yield: 18.4%. MS m/z (ESI): 523.4 [M+l] H NMR (400 MHz, CDCI3, ppm) δ 8. 42 to 8. 56 (d, 1H) 7.35-7.61 (d, 2H), 7.52-7.90 (s, 1H), 7.21-7.33 (m, 11〇, 5.99 to 6.12 (〇1,11〇,4.61~4.72((1, 11〇, 4.11 to 4. 22 (d, 1H), 3.92 to 4. 05 (m, 4H), 3. 42 to 3. 58 (d, 11〇, 3.36 to 3.40 (8, 31〇, 2.85) To 2.96 (111, 41 〇, 2.31 to 2.42 (m, 4H), 2. 16 to 2. 28 (m, 2H), 1. 91 to 2. 〇 6 (m, 6H), 1.02 to 1· 15 (m, 3H) 'Example 21 U)-2-(2-methoxy-4-(1-mercaptopiperidine-4-ylamine oxime) -N,N,5-trimethyl-6-sideoxy-6a,7,9,10-tetrahydro-5 and-pyrazino[2, 1-/?] acridine -8 (6^-carboxylic acid decylamine

95201 121 201229050

The third step H

The first step (Λ-2-chloro-5-methyl-7, 8, 9, 10-tetrahydro-5 million-pyrazine and [2, 1-Λ] acridine_6 (6a^〇-one will 2-chloro-5-methyl-6-oxo-6a,7,9-tetrahydro- 50,000-pyrazino[2,1-indenyl]acridine-8 (6 milk-carboxylic acid uncle Butyl ester 19f (2.15 g, 6_ 08 mmol) was dissolved in 50 mL of dichloromethane, hydrogen chloride gas was added, the reaction was stirred for 1 hour, 20 mL of water was added, and the solid of If was added until the pH of the reaction solution was 9 to 10. The mixture was extracted with dichloromethane (50 mL×3). EtOAc (EtOAc)曱7_7,8,9,10-tetrahydro-5 and pyrazino[2, Ι-h]acridin-6(6a^)-one 21a (1.05 g, white solid), yield : 68. 3% MS m/z (ESI): 254.1 [M+l] second step (skin)-2-chloro-N,N,5-trimethyl-6- oxo-6a , 7, 9, 10-tetrahydro-5 and -°biazine and [2, Ι-h] acridine-8(6)7)-carboxylic acid decylamine under ice bath '(A)-2- gas -5-mercapto-7, 8, 9, 10-tetrahydro-5 and -pyridazine[2, Ι-h]嗓. -6 (6a^〇-鲷21a (0. 25 g ' 1 Mmmol) dissolved in 122 95201 s 201229050 15 mL - in the gas hospital Add triethylamine (0.3 mL, 2 mmo 1) and dimethylaminoformamidine chloride (0.1 mL, 1.1 mmol), and stir the reaction for 5 hours. Remove the ice bath and mix at room temperature. After 1 hour, 5 mL of a two-gas methane was added, and the mixture was washed with saturated brine (50 mL &lt; 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product (and)-2-chloro-N,N,5-tridecyl-6-yloxy-6a,7,9, 10-tetrahydro-5 and -pyrazine[ 2, 1-/?? acridine-8 (6-miltal-carboxylic acid decylamine 21b (250 mg, white solid), yield: 78%. MS m/z (ESI): 325.3 [M+l] Step (y?)-2-(2-decyloxy-4-(1-mercaptopiperidin-4-ylaminoindolyl)anilino)-N,N,5-trimethyl-6-side Oxy-6-,7, 9, 10-tetrahydro-5 and -« 比 [ [2, 1-Λ] bite -8 (6 milk - citric acid to make amine 4-amino-3- oxo --N-(l-fluorenyl-n-n-butyl-4-yl)-benzamide 9b (0. 072 g, 0. 27 mmol) '(«-2- gas-N, N, 5-three Methyl-6-oxy-6a,7,9,4-tetrahydro-5 and-pyrazine[2, decylamine 21b (100 mg, 〇·3 mmol) and p-toluenesulfonic acid (〇 g, 0.82 circle 1) was dissolved in 30 mL 4- 2_-methyl pentanol, the return depends on the reaction stirred for 3 hours. Concentrate the reaction solution under reduced pressure, add (10), 4 f % ^ 5% saturated stone 厌 _ _ liquid - (4) water silk (5 〇 mL x 3 anhydrous sulphur dry 'filter, H lang concentrated, when the tube column color residue' Title production (2-methoxy-4-U-methylglycosyl indenyl) aniline quinone, 5-trimethyl fluorene + sideoxy group 7,9,1 (), tetrahydro 1 95201 123 201229050 [ 2, l-Λ] acridine-8 (6 Λ carboxylic acid decylamine 21 (70 mg, white solid), yield: 50%. MS m/z (ESI): 552.4 [M+l] NMR (400 MHz , CDC13, ppm) δ 8. 42 to 8. 45 (d, 1H), 7. 75 (3,11〇, 7.5~7.51 ((1,11〇,7.48(3,11〇,4.55 to 4.58 (m , 1H), 4.1 ~ 4. 15 (m, 2H), 4. 02 to 4. 03 (m, 1H), 4. 01 (5, 3! 〇, 3.73 to 3.76 (111, 11 〇, 3.32 to 3.33) (111,11〇, 3.27 (5,31〇, 3.19 to 3.23 (111,21〇,2.93~2.98(111,21〇,2.9 (3,61〇,2.57(3,31〇,2.62 to 2.65(111) , 21〇, 2.07 to 2. 10 (m, 2H), 1.85 to 1.88 (m, 2H) Example 22 (none)-4-(8-ethyl-bromo-indenyloxy-6,6a, 7 , 8, 9,10-hexahydro-5 and -oxime ratio 0 Qinhe [2, 1-/?] bite 2 -ylamino)-3-decyloxy-N-(l-hydrazinoper Pyridine-4- ) Benzoyl amine

124 95201

S 201229050

First step U)-2-chloro-5-mercapto-6-sideoxy-6a,7,9,10-tetrahydro-5 and-pyrazine[2, 1-/?]® 8 (6 milk - slow acid vinegar ice bath, will (Λ 0-2-chloro-5-mercapto-7, 8, 9, 10-tetrahydro-5 and -pyrazine and [2, Ι-h] Acridine-6 (6a^〇-ketone 21a (1.88 g, 7.8 mmol) was dissolved in 50 mL of dichloromethane, then triethylamine (i. 7 mL, 1 . Benzyl phthalate (1.4 mL, 9.4 mmol), stirred for 0.5 h. Add 20 mL of saturated sodium bicarbonate solution until the pH of the reaction mixture is from 8 to 9, and digested with a gas (40 mL x 2) The mixture was washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. -6-Sideoxy-6a,7,9,10-tetrahydro-5 and-pyrazino[2,l-force]acridine-8 (60,000)-rebel benzyl vinegar 22a (2.25g, White solid), Yield: 74 2%. MS m/z (ESI): 388.3 [M+l] Step 2 95201 125 201229050 U)-2-(2-decyloxy-4-(1-indolyl) Piperidin-4-ylaminoindolyl)anilino)-5-mercapto-6-yloxy-6a,7,9,10-tetrahydro-5 and-pyrazine[ 2, 1-Λ] acridine-8 (6-blade-carboxylic acid benzyl ester 4-amino-3-methoxy-N-(l-fluorenyl-piperidin-4-yl)-benzoguanamine 19b (616 mg, 2.34 mmol) was dissolved in 30 mL of 4-methyl-2-pentanol, and (7?)_2-chloro-5-methyl-6-oxyl_6a,7 was added in sequence. 9, 10-tetrahydro-5 and -π-pyrazine [2, 1-Λ] 嗓 ° -8 (6Z 〇-remediate benzyl ester 22a (999 mg, 2. 58 mmol) and p-benzoic acid (722 mg, 3.75 mmol), refluxing for 3 hours. Concentrate the reaction solution under reduced pressure, add 50 mL of water, add saturated potassium carbonate solution to the reaction solution pH 9 to 10, di-methane extraction (100 The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system A to give the title product. 2-(2-methoxy-4-(1-indolyl)-4-aminoamine oxime) anthranyl)-5-fluorenyl-6-yloxy-6a,7,9, 10% tetrahydro-5·^-° 嗓 [ [2,1-/?] ° 唆-8 (6Z 〇-benzyl phthalate 22b (404 mg, white solid), yield: 14. 2% . MS m/z (ESI): 615. 5 [M+l] Step 3 U)-3-methoxy-4-(5-fluorenyl-6-yloxy-6,6a,7,8 9, 10-hexahydro-5 and-pyrazino[2,1-h]acridin-2-ylamino)-indole-(1-methylpiperidin-4-yl)benzamine will Left)-2-(2-methoxy-4-(l-fluorenyl)-4-ylaminoindolyl)anilino-5-methyl-6-yloxy-6a,7, 9, 10-tetrahydro-5#-pyrazine and [2,1-/?]嗓°-8 (6-blade benzyl benzoate 22b (500 mg, 0.8 mmol)

126 95201 S 201229050 / Solution in a mixed solution of 100 mL of dichloromethane and decyl alcohol (v: v = l: 1), in order - add 5 drops of glacial acetic acid and (100 mg, 1%) G/carbon, 3 The reaction was stirred under a hydrogen atmosphere at atmospheric pressure for 24 hours. Filtration and concentration of the filtrate under reduced pressure afforded the title product (n.) </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; And-pyrazino[2, Ι-h]acridin-2-ylamino)-N-(l-methylpyridin-4-yl)phenylguanamine 22c (277 mg, white solid) Rate: 71%. MS m/z (ESI): 481. 3 [M+l] Step 4 (U)-4-(7-Ethyl-10-indol-9-one-6, 7, 8, 8a, 9 , 10-hexahydro-5 and -2,4,4b,7, 10-pentaza-phenanthren-3-ylamino)-3-methoxy-N-0-mercapto-piperidin-4- - phenylhydrazine in an ice bath 'U)-3-decyloxy-4-(5-methyl-6-oxo-6,6a,7,8,8- 10-hexahydro- 5 and -pyrazino[2, Ι-h] acridine-2-ylamino)-N-(l-methylbend-4-yl)phenylhydrazine 22c (48 mg, 0.1 mmol) Dissolved in 30 mL of dichloromethane, added triethylamine (0.04 mL, 〇. 3 mmol) and B-brewed chlorine (0.08 mL '0. 11 mmol), and the mixture was stirred for 1 hour. After adding 100 mL of water, the organic phase was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. _4_(8_Ethyl _5_methyl-6- oxo-6, 6a,7,8,8- 10-hexahydro-5 and-pyrazine[2, 1-h]喋° Din-2-ylamino)-3-decyloxy-N-(l-fluorenyl-4-yl)benzamide 22 (30 mg 'white solid), yield: 57%. /z (ESI): 523.2 [M+l] 127 95201 201229050 4 is closed to 4001^^,00(:13,??111)3 8.45 to 8.47 ((1,11〇, 7.79~7.83(m,lH)) , 7.42 to 7.5 (m, 2H), 4.58 to 4.65 (m, 3H), 4. 17 to 4. 21 (m, 1H), 4. 01 (s, 3H), 3. 91 to 3. 92 (m , 1H), 3. 31 (s, 3H), 2. 95 to 3. 00 (m, 3H), 2. 41 (s, 3H), 2. 35 (s, 3H), 2. 12 to 2.26 ( m, 4H), 1.97~2. 01 (m, 2H), 1.71 to 1.77 (m, 2H) Example 23 U)-3-methoxy-4-(5-fluorenyl-6-sideoxy- 8-phenyl-6,6a, 7, 8, 9, 10-hexahydro-5 and bisazino[2,bina]acridin-2-ylamino)-N-(l-nonylpiperidine Benzylamine

128 95201 201229050 ·, U)-piperazine-2-carboxylic acid oxime ester (and) - π 唤 -2- carbamic acid 23a (10 g, 0.05 mol) dissolved in 150 mL of methanol, add 30 mL Concentrated sulfuric acid, stirring and refluxing for 8 hours, cooling to room temperature '1 mL of triethylamine was added dropwise to the pH of the reaction mixture was 9 to 1 Torr, and the reaction mixture was concentrated under reduced pressure to give the title product. Methyl carboxylate 23b, directly into the next step. The second step U)-piperazine-1,3-dicarboxylic acid 3-decyl ester 1-benzyl ester under ice bath, (and) - motherazine-2- rebellion Acidic guanidine 23b (7.2 g, 〇·〇5 mol) was dissolved in 200 mL of dichloromethane, and 20 mL of triethylamine and benzyl phthalate (8.5 g, 0.05 mol) were added in sequence. The reaction was stirred for 3 hours. Concentrate the reaction solution under reduced pressure, add 300 mL of ethyl acetate, 300 mL of water, add 1 μ of hydrochloric acid to the pH of the reaction solution 3 to 4 'aqueous layer, add saturated sodium carbonate solution to the reaction solution pH 9, extract with ethyl acetate (100 mL×3), EtOAc (3 mL, EtOAc) Ester 1-ester 23c (6.6 g, yellow oil), yield 47%. MS m/z (ESI): 279.1 [M+l] Step 3 (A〇-piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester 2-methyl ester under ice bath, (Spin-piperazine-1,3-dicarboxylic acid 3-methyl ester 1-benzyl ester 23c (6.6 g, 0.023 mol) and triethylamine (10 mL '0.07 mol) were dissolved in 100 mL of dichloromethane. Add di-tert-butyl dicarbonate (5.4 g, 2.8 mmol), stir the reaction for 2 hours at room temperature, concentrate the reaction solution under reduced pressure, add 200 129 95201 201229050 mL of acetic acid, 100 ml of water, add 1 Μ hydrochloric acid The pH of the reaction mixture was 4 to 5, and the organic phase was washed with brine (50 mL). Acid 4-benzyl ester tert-butyl ester 2-decyl ester 23d (9 g, yellow solid), yield: 100%. MS m/z (ESI): 401.1 [M+23] Step 4 (Λ〇-piperazine-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-decyl ester (and) -0 base 嗓-1,2,4-triotreic acid 4-cabbice 1-tert-butyl 2-pyridyl ester 23d (3 g, 8 mmol) was dissolved in 100 mL of methanol, and then 3 drops of acetic acid and (300 mg, 10%) palladium/carbon were added in sequence, and the reaction was stirred for 12 hours under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure and then filtered. The residue obtained by the purification of the eluent system B gave the title product («-piperazine-1,2-dicarboxylic acid 1-tert-butylpyrazine-2-methylpyrazine 23e (lg, yellow oil). Rate: 52.6%. MS m/z (ESI)··245. 1 [M+1] The fifth step (and)-4-phenyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2 Potassium tert-butoxide (1.45 g, 12.9 mmol), 2-(di-tert-butylphosphine)biphenyl (0.1 g, 0.34 mmol) and tris(dibenzylidene) Base acetone) bis (0.16 g, 0.17 mmol) was dissolved in 40 mL of toluene, and (U)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-nonyl ester 23e was added in sequence. (2. 1 g, 8.6 mmol) and 10 mL of benzene (1.6 g, 10.3 mmol) in benzene solution, stirring at 60 ° C for 2 hours, stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. 1%。 Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 23f (500 mg, yellow solid), yield: 18.1%. MS m/z (ESI): 321.2 [M+l] Step 6 (7?)-4-phenyl-piperazine-2-carboxylic acid oxime ester hydrochloride ((4-phenyl-piperazine) -1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 23f (0.5 g, 1.5 mmol) was dissolved in 20 mL of dichloropyrene, and 5 mL of 6 Μ gasified hydrazine was added. The reaction mixture was stirred for 2 hours, and the reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjj Yield: 100% MS m/z (ESI): 221.2 [M+l] Step 7 (Λ〇-1-(2-Ga-5-石肖基嘴e-4-yl)-4 -phenyl-α-bottom oxime-2-sodium citrate

酉I 23 g of (U)-4-phenyl-piperazine-2-carboxylic acid oxime ester hydrochloride (385. 05 mg, 1.5 mmol) was dissolved in 50 mL of cyclohexane, followed by sodium bicarbonate. Solid (750 mg, 9 mmol) and 2,4-dichloro-5-nitro-dosamine (290 mg, 1. 5 mmol). After cooling to room temperature, add 100 mL of water, 100 mL of ethyl acetate, and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous The filtrate was concentrated under reduced pressure to give the title product (A-l-(2-chloro-5-nitro-pyrimidin-4-yl)-4-phenyl-piperazine-2-carboxylic acid oxime ester 23h (0. 3 g, yellow solid), Yield: 53.5%. 131 95201 201229050 MS m/z (ESI): 378.2 [M+l] Step 8 U)-2-Chloro-8-phenyl-7, 8, 9 , 10-tetrahydro-5 million-pyrazino[2,1-Λ]acridine-6 (6a^〇_ 面同将(友)-1-(2-气-5-nitro-pyrimidine-4 Methyl 4-phenyl-piperazine-2-deconateate 23h (300 mg, 0.8 mmol) was dissolved in 50 mL of glacial acetic acid and iron powder (180 mg, 3. 2 mmol), 70 The reaction was stirred at °C for 3 hours. The reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Concentration under reduced pressure gave the title product (yield-2-chloro-8-phenyl-7, 8, 9, 10-tetrahydro-5 and -pyridazino[2, 1-h] acridine-6 (68 still -ketone 23j (0.1 g, yellow solid) , Yield: 40%. MS m/z (ESI): 316.2 [M+l] </ br> Step 9 U)-2-chloro-5-methyl-8-phenyl-7, 8, 9, 10-4 Hydrogen-5 and -° than the azine and [2,1-/?] butterfly π -6 (6a^〇-嗣 will be U)-2-chloro-8-phenyl-7, 8, 9, 10- four Hydrogen-5 and -pyrazine[2,1-Λ] butterfly bite-6 (6aZ〇-_ 23j (100 mg, 3.1 mmol), potassium carbonate (87 mg, 6.3 mmol) and p-toluene The citric acid vinegar (88 mg, 4.7 mmol) was dissolved in 50 mL of acetone, and the reaction was stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure, and 100 mL of water and 100 mL of dichloromethane were added, and the organic phase was washed with saturated brine ( 50 mL), dried over anhydrous sulphuric acid, filtered, and concentrated under reduced pressure to give the title product U)-2-chloro-5-mercapto-8-phenyl-7, 8, 9, 10-tetrahydro-5 and Comparative 嘻[2, 1-Λ] dian-6 (6a^〇-ketone 23k (80mg, yellow solid 132 95201

S 201229050 体), yield: 78.4%. MS m/z (ESI): 330.1 [M+l] Step 10 (Friend) _3-methoxy-4-(5-fluorenyl-6-yloxy-8-phenyl-6, 6a,7 , 8, 9, 10-hexahydro-5 and -β specific noise [2, 1-Λ] bite-2-ylamino)-N-(l-hydrazinopiperidin-4-yl)phenylhydrazine Indoleamine 4-amino-3-indolyl-N-(l-methyl-nitopic-4-yl)-benzoguanamine 19b (64 mg, 0.25 mmol), ((and)- 3-chloro-10-methyl-7-phenyl-6, 7, 8, 8a-tetrahydro-5Η, 10 and -2, 4, 4b, 7, 10-pentaza-phenanthrene-9-one 23k (80 mg, 0.24 mmol) and p-toluenesulfonic acid (230 mg, 1.2 mmol) were dissolved in 30 mL of 4-mercapto-2-pentanol, and the reaction was stirred under reflux for 3 hours. After adding 100 mL of a saturated solution of potassium carbonate and dichloromethane (100 mL×2), the organic phase was combined, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, The obtained residue was purified to give the titled product (yield) _3-methoxy-4-(5-fluorenyl-6- oxo-8-phenyl-6,6a,7,8,9 , 10-hexahydro-50,000-pyrazino[2,1-indolyl]pyridin-2-ylamino)-indole-(1-methylpiperidin-4-yl)benzamide 23 (30 Mg, white solid , yield: 22.5%. MS m/z (ESI): 557.4 [M+l] 4 NMR (400 MHz, CDC13, ppm) δ 8. 54 to 8.57 (d,1H), 7.77 (s, 1H), 7.46-7.47 (d, 1H), 7.33-7.37 (m, 3H), j 7. 06 to 7.07 (〇1,211), 6.96~7.0(1;,11〇,4.76 to 4.80 (111,:!11〇, 4. 26~4. 33 (ra,2H), 4·13 to 4.19 (m,1H), 4. 01 (s, 3H), 3.75-3.78 (m, 1H ), 3.38 (s, 3H), 3.11-3.20 (m, 3H), 133 95201 201229050 2. 89~2. 95 (m, 2H), 2. 52~2. 57 (m, 5H), 2. 16 To 2.19 (m, 2H), 1.95 to 2. 01 (m, 2H) Test example: Biological evaluation Test Example 1. Inhibition of proliferation of Plk high-performance cells by the compound of the present invention The following in vitro test is used The proliferation inhibitory activity of the compound of the present invention against one human cervical cancer cell line He 1 a of a cell strain exhibiting high P 1 k was determined. The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on tumor cells with high expression of Plk, and the activity can be expressed by the IC5 enthalpy value. The general protocol for such an experiment is as follows: First, Hela cells (purchased in Institute of biochemistry and cell biology) are seeded at a suitable cell concentration (eg 3000 cells/mL medium) on a 96-well culture plate, and then the cells are placed in a carbon dioxide incubator. The culture was carried out, and they were allowed to grow overnight. The medium was changed to a medium containing a series of concentration gradients (generally 7 to 9 concentrations) of the test compound solution, and the plate was returned to the incubator for 72 hours. After 72 hours, the test compound was tested for its ability to inhibit cell proliferation using the CCK8 method. I C5. The value can be calculated from the inhibition values of the test compound for the cells by a series of different concentrations. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was determined by the above test, and IC5 was measured. The values are shown in the table below. 134 95201

S 201229050 Compound number IC5. Value (nM) 1 9 2 0. 8 3 3 4 2 5 14 6 14 8_ 1 and 8 _ 2 mixture 7 9 2 10 0.4 11-1 and 11-2 mixture 0. 6 16-1 and 16-2 Mixture 4 mixture of 17-1 and 17-2 Conclusions: The compounds of the invention all have significant proliferation inhibitory activity against Hela cells. Test Example 2. Inhibition of Proliferation of Plk High-Performance Cells by the Compound of the Present Invention The following in vitro test was conducted to determine the proliferation inhibitory activity of the compound of the present invention against one human colon cancer cell line HCT-116 of a cell line exhibiting high Plk. The in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound on highly-digested digestive tumor cells, and the inhibitory activity of the compound can be expressed by the IC5Q value. The experimental protocol is briefly described as follows: First, HCT-116 cells (purchased from Institute of biochemistry and cell biology) supplemented with 10% FCS (purchased from Gibco) as DMEM in DMEM, at a suitable cell concentration (eg 3000 cells/mL medium) The cells were seeded on a 96-well culture plate, and then cultured overnight in a constant temperature incubator at 37 ° C under 5% C 2 . After the cells are attached, the medium is replaced with fresh medium containing a gradient of the concentration of the test compound 135 95201 201229050 (typically 7 or 9 concentration points). Thereafter, the cell culture plate was continuously cultured for 72 hours under the aforementioned conditions. After 72 hours, the inhibitory activity of the compound against cell proliferation was measured by the method of CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Do j i ndo). The IC5 enthalpy of the compound can be calculated from the inhibition of cell proliferation by the test compound at various concentrations. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was determined by the above test, and IC5 was measured. The values are shown in the table below. Compound No. IC5 〇 Value (nM) 2 3 3 4 4 4 5 10 6 12 8 _ 1 and 8 - 2 mixture 5 Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against HCT-116 cells. Test Example 3: Determination of P1 k 1 kinase inhibitory activity by the compound of the present invention The in vitro Plk1 kinase activity was tested by the following method. The method described below can be used to determine the ability of the compounds of the invention to inhibit Plk1 kinase activity by I C5. The value is expressed. The half of the compound inhibits the concentration IC5. (The concentration of the compound required to inhibit the enzymatic activity to 50%) is determined by mixing a certain amount of the kinase with a specific matrix and different concentrations of the compound to be tested, and then calculating a series of inhibition rates, and then calculating

136 95201 S 201229050 Tool calculated. The Plk1 kinase used in this experiment was a recombinant human protein, and the reaction system was purchased from MBL (Polo-like kinase 1 Assay/Inhibitor Screening Kit, # CY-1163). The Plkl enzyme is reacted with the polypeptide matrix and various concentrations of the test compound in the reaction system (25 ° C, 30 minutes), followed by an anti-Anti-Phospho-Serine/ Threonine Polyclonal Antibody (PPT-07) and a secondary antibody HRP- Conjugated Anti-rabbit IgG Labels the squamized substrate. Final readings at A450 nM quantify Plkl kinase activity. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was measured by the above test, and the IC50 values measured are shown in the following table. Compound No. "ICs. Value (nM) 2 5 3 8 4 25 5 28 6 13 8-1 and a mixture of 8-2 6 9 18 Γό a &quot;1 - 13 Conclusion: The compounds of the present invention all have a Plk-ΐ kinase Significant proliferation inhibition activity. Pharmacokinetic evaluation Test Example 4, pharmacokinetic test of a mixture of compound 2 and examples 8-1 and 8-2 of the present invention 1. Abstract 137 95201 201229050 The test animals were tested for the concentration of the drug in the plasma at different times after intravenous administration of the compound of Example 2, the mixtures of Examples 8-1 and 8-2, respectively, by LC/MS/MS method. Pharmacokinetic behavior in vivo, evaluation of its pharmacokinetic characteristics. 2. Test protocol 2. 1 test drug Example 2 compound, mixture of examples 8-1 and 8-2 2, 2 test animals healthy adult SD large 8 rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016. 2.3 Drug preparation Weigh a certain amount of drug, add DMSO 0.5 mL To dissolve, add 0.1 Μ HC1 1. 5 m L, physiological saline was diluted to the final volume, so that the drug concentration was 2. 5 mg / mL 〇 2.4 administered SD rats, 8 males and females, divided into 2 groups on average, fasted overnight after the tail vein injection, dose Both were 25 mg/kg. 3. Operate 25# L of rat plasma at each time after administration, add 20/L of internal standard solution, 150/L of sterol, vortex for 3 minutes, and centrifuge for 10 minutes ( At 13500 rpm, the plasma samples were taken from the supernatant 5//L for LC-MS/MS analysis. The main pharmacokinetic parameters were calculated using DAS 2.0 software. 4. Pharmacokinetic parameters

138 95201 S 201229050 The pharmacokinetic parameters of the compounds of the invention are as follows: Compound number drug metabolism experiment (25 mg/kg) Curve area half-life retention time clearance rate Apparent distribution volume AUC (&quot;g /mL*h) tl/2 ( h) MRT (h) CL/F (1/h/kg) Vz/F(l/kg) 2 7. 31+1.02 5. 42+5. 87 2. 78±1.32 3. 47 soil 0.47 24. 8 +23.4 Mixture of 8-1 and 8-2 14. 57+1.44 4·12±0·47 5·18±0·46 1.73±0.17 10. 2+1.0 Conclusion: Example 2 compound, Example 8-1 The drug metabolism of the mixture with 8-2 was well absorbed. [Simple description of the diagram] None [Key component symbol description] None 139 95201

Claims (1)

201229050 VII. Patent application scope: 1. A compound represented by the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Pharmaceutically acceptable salts: (I) wherein: R1 and R2 are each independently selected from a hydrogen atom or an alkyl group; or R1 and R2 together with the atom to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains fluorene to 2 N, 0 or S(0)m heteroatoms, and the 3 to 8 members are further required to be further selected from one or more selected from the group consisting of alkyl, alkoxy, dentate, hydroxyl, cyano, nitro, aryl, Substituted by a substituent of a heteroaryl group, a carbonyl group, -S(0)0NRY, _c〇nr7r8, _nr7r8, -S(0)0R, _C〇R9 or -C(〇)〇R9; R3 is selected from a hydrogen atom, an alkane Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is as desired Further by one or more of a self-alkyl group, an alkoxy group, a halogen group, a thiol group, a cyano group, an aryl group, an aryl group, -S(0)0NR7R8, -C0NR7R8, -NR7R8, -S(0)0R9, The substituent of C0R, t -C(0)0R9 is substituted; or R2 and R3 together with the atom to which they are attached form a 3 to 8 membered ring, which is contained in the 3 to 8 member ring! Up to 2 N, 〇 or 95201 1 201229050 S(0)m heteroatoms, and the 3 to 8 members are further required to be further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro Substituted by a substituent of an aryl group, a heteroaryl group, a carbonyl group, -S(〇)〇NR7R8, -C0NR7R8, -NR7R8, -S(0)0R9, -COR9 or -C(〇)〇R9; R4 and R5 Each is independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitro group; and L is selected from an alkylene group as needed further by one or more substituents selected from halogen, cyano, nitro or alkyl. a substitution wherein the alkyl group is further substituted with one or more halogens; R6 is selected from the group consisting of an alkyl group, wherein the alkyl group is further substituted with a heterocyclic group as needed; and when R6 is selected from an unsubstituted alkyl group, A is selected from a bicycloalkyl group, a bi-hetero-based group, a spirocycloalkyl group or a spiroheterocyclyl group, wherein the bicycloalkyl group, the biheterocycloalkyl group, the spiroalkyl group or the spiroheterocyclyl group is further required to be further one or more Substituted by R12; when R6 is selected from a heterocyclic substituted alkyl group, A is selected from the group consisting of cycloalkyl, heteroalkyl, bicycloalkyl, biheterocyclyl, bridged cycloalkyl a heterocyclic cycloalkyl, spiroalkyl or spiroheterocyclyl wherein the cycloalkyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged cycloalkyl, heterobridged alkyl, spirocycloalkyl Or a spiroheterocyclyl group is further substituted by one or more R12 as needed; R7 and R8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a hexyl group or a heteroaryl group, wherein the alkyl group, The cycloalkyl, heterocyclic, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of an alkane, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a hydroxyl group, a hydroxyl group, a cyano group, 2 95201 201229050 -S(0)0R9, -COR9, C(0)0R9, -S(O)ONR10Rn, -CONR10r&quot; or -NR1 (substituted by a substituent of lRn; or N to which R7 and R8 are attached The atoms together form a 3 to 8 membered heterocyclic group wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or S(0)m heteroatoms, and the 3 to 8 membered heterocyclic group is as needed Further one or more selected from the group consisting of an alkyl group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, a cyano group, -S(〇)〇R9, -C0R9, C(0)0R9, -S(0)0NR1DRu, -CONFER11 or -NR1QR&q Substituted by a substituent of uot; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or aryl group is further substituted by one or more alkyl groups as needed; R1Q and R&quot; From a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; R12 is selected from the group consisting of a substituent, an alkoxy group, a cycloalkyl group, a halogen, a thiol group, a cyano group, a nitro group, a carbonyl group, _S(0)0NR7R8, -C〇 NR7R8, -C(0)0R9, -0C(0)R9, -0(CH2)rC(0)0R9, -〇C(〇)NR7R8, -S(0)mR9, -0S(0)0R9,- Substituted by a substituent of NHC(0)R9 or -COR9 wherein the pendant, ortho-, aryl, or heterocyclic group is further optionally selected from one or more selected from the group consisting of alkyl, cycloalkyl, heterocyclyl Substituted by a substituent of an aryl or heteroaryl group; m is 0 or 1; η is 0, 1 or 2; and r is 1, 2 or 3. 2. A compound represented by the formula (1) or a tautomer, a racemate, an enantiomer or a diastereomer thereof as described in the scope of the patent application, 95201 6 3 201229050 And mixtures thereof, and pharmaceutically acceptable salts, wherein: R1 is selected from a hydrogen atom; R2 is selected from an alkyl group; R3 is selected from an alkyl group or a cycloalkyl group; or R2 and R3 together form an atom with the atom to which they are attached a 3- to 8-membered heterocyclic group wherein the 3 to 8 membered heterocyclic group contains 1 to 2 N, 0 or S(0) n heteroatoms, and the 3 to 8 membered heterocyclic group is further required to be one or more A plurality of selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, carbonyl, aryl, -S(〇)〇NR7R8, -C0NR7R8, -NR7R8, -S(0)0R9, _C0R9 or - Substituting for a substituent of C(〇)〇R9; R4 and R5 are each independently selected from a hydrogen atom, a halogen or an alkyl group; R6 is selected from the group consisting of an alkyl group wherein the domain group is further substituted by a heterocyclic group; ^ R When k is from an unsubstituted garden group, A is selected from the group consisting of a bicycloalkyl group, a biheterocyclic group, and a spiro ring stellite, which + the bicyclofilament, the biheterocyclyl group 2, a spirocycloalkyl group or a spiroheterocycle Further optionally, one or more cyclic groups, bicyclofilaments, nrr, A_, and cyclosqualyl groups: a heterocyclic group, a heterocyclic group, a heterocyclic group, a disulfide group, a bridged group, a double (10) 'To each r or more &quot;: R and R are each independently heterocyclic group, silk, shirt, its = material, cycloalkyl, alkyl, cycloalkyl, heterocyclic j 95201 4 201229050 aryl or hetero The aryl group is further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a hydroxyl group, a hydroxyl group, a cyano group, a carboxylic acid, a carboxylic acid, and a -S(0). Substituting a substituent of 0R9, -COR9, -SCOWNR%11, c〇Nr10r11 or -NW1; or 'R7 and R8 together with the N atom to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 member The ring contains one or more n, hydrazine or S(0)m heteroatoms, and the 3 to 8 membered heterocyclic ring is optionally further substituted with one or more selected from the group consisting of alkyl, alkoxy, and heterocyclic groups. , aryl, heteroaryl, halogen, hydroxy, cyano, carboxylic acid, carboxylic acid ester, carbonyl, -S (; QR9, -COR9, -SCO^NITR11, -CONFER11 or -NRl11 substituent substitution; ;' R9 is selected from a hydrogen atom, an alkane a group, a cycloalkyl group or an aryl group; R and R are selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; R12 is selected from the group consisting of an alkyl group, an alkoxy group, a cycloalkyl group, a halogen group, a thiol group, and a nitro group. Base, carbonyl, -S(0)0NR7R8, -C0NR7R8, -0C(0)R9, -0(CH2)rC(0)0R9, -〇C(〇)NR7R8, -S(〇)mR9, -0S Substituting (0) a substituent of -0R9, -NHC(0)R9 or -COR9, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is further selected from one or more selected from the group consisting of alkyl groups, Substituted by a substituent of a cycloalkyl, heterocyclyl, aryl or heteroaryl group; m is 0 or 1; η is 0, 1 or 2; and r is 1, 2 or 3. 3. The compound of the formula (I) as described in the first paragraph of the patent application or S 201229050, its tautomer, exo, ά » # π /w, a polar group, an enantiomer, a non-pair And a pharmaceutically acceptable salt thereof, wherein: r3 is selected from the group consisting of f independently from a hydrogen atom or a burnt group; a# a hydrogen atom, an alkyl group, an alkenyl 'alkynyl group, a cycloalkane a heterocyclic heteroaryl group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or hetero-#, β-hetero are further selected from one or more Alkyl, alkoxy, i 7 broad halogen, hydroxy, cyano, nitro, aryl, S(0)0NR R, Cqnr7r8, -峨8, j(8)(10)9, -(10)9 or -C(0)0R9 Substituted by a substituent; or R2 and R3 together with the atoms to which they are attached form a 3 to 8 member of the jade' wherein the 3 to 8 member ring contains .1 to 2 N, 0 or s(o)m heteroatoms. And the 3 to 8 members are further required to be further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, an i group, a thiol group, a cyano group, an aryl group, an aryl group, a heteroaryl group, a carbonyl group, and a -(S) group. 0NR7R8, -C0NRY, -NR7R8, -S(0)0R 9. Substituted by a substituent of -COR9 or -c(〇)〇R9; R and R5 are each independently selected from a hydrogen atom, an alkyl group, a dentate, a cyano group or an exact group; and L is selected from a sub-alkyl group, as needed Further substituted with one or more substituents selected from halogen, cyano, nitro or alkyl, wherein the alkyl group is further substituted with one or more halogens; R6 is selected from alkyl; a bicycloalkyl, bicyclohetero, spirocycloalkyl or spiroheterocyclyl wherein the bicycloalkyl, biheterocyclyl, spirocycloalkyl or spiroheterocyclyl is further substituted by one or more R12 ; 6 95201 201229050 The ruthenium and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a % group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group; The aryl group is further selected from one or more selected from the group consisting of alkyl, alkoxyheterocyclyl, aryl, heteroaryl, dentate, thiol, cyano, 4(〇)〇κ9, -COR9, C ( 0) Substituted by a substituent of 0R9, -S(0)0NR1qRu, -CONW1 or a secondary iqRu; or 'R7 and R8 together with the N atom to which they are attached form a 3 to 8 membered heterocyclic group Wherein the 3 to 8 membered heterocyclic group contains one or more N, fluorene or S(0)m heteroatoms, and the 3 to 8 membered heterocyclic group is further selected from one or more selected from the group, Oxy, heterocyclic, aryl, heteroaryl, halogen, thiol, cyano, -S(〇)〇R9, -C〇R9, C(0)0R9, -S(0)0NR1Y1, -CONR1 Substituting a substituent of 〇R11 or _NR1〇R11; R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl or aryl group is further substituted with one or more alkyl groups as needed; R1Q and R11 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; R12 is selected from the group consisting of an alkyl group, an alkoxy group, a cycloalkyl group, a dentate element, a thiol group, a cyano group, a schlossyl group, a benzyl group, a -S(0) ) 0NR7R8, -C〇NR7R8, _c(0)0R9, -0C(0)R9, -0(CH2)rC(0)0R9, -〇C(〇)NR7R8, _s(〇)mR9, -0S(0 Substituting a substituent of 0R9, _NHC(0)R9 or -COR9, wherein the alkyl, methoxy, cycloalkyl or heterocyclic group is further optionally selected from one or more selected from the group consisting of alkyl, cycloalkyl, Substituted by a heterocyclic, aryl or heteroaryl substituent; m is hydrazine or 1, 95201 7 201229050 η is 0, 1 or 2; r is 1, 2 or 3. 4. A compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, as described in claim 1 of the patent application. And a pharmaceutically acceptable salt, wherein: R1 and R2 are each independently selected from a hydrogen atom or an alkyl group; R3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group. Or a heteroaryl group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen, and a Substituted by a substituent of a group, a nitrogen group, a aryl group, an aryl group, -S(0)0NR7R8, -CONR7R8, -NRY, -S(0)0R9, -C0R9 or -C(0)0R9; or, R2 and R3 forms a 3 to 8 membered ring together with the atoms to which it is attached, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or S(0) m heteroatoms, and the 3 to 8 members are further viewed as needed One or more selected from the group consisting of alkyl, alkoxy, halogen, thiol, cyano, schiffyl, aryl, heteroaryl, carbonyl, -s(o)onr7r8, -C0NR7R8, -NR7R8, -S(0) a substituent of 0R9, -COR9 or -C(0)0R9 Substituted; R4 and R5 are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitrate group; L is selected from an alkylene group, and further optionally one or more selected from the group consisting of halogen, cyano, and nitro Or substituted with an alkyl substituent, wherein the alkyl group is further substituted by one or more halogens; R6 is selected from an alkyl group, wherein the alkyl group is further taken by a heterocyclic group. 8 95201 ·&gt;201229050; μ田R is selected from the group consisting of a hetero-i-alkyl group-substituted alkyl group, Ait self-cyclyl, hetero-bis-alkyl, diheterocyclyl, bridged-cycloalkyl, hetero-bridged alkyl, alkyl, spiro heterocycle a group wherein the cycloalkyl group, heterocyclic group, bicycloalkanediheytyl group, bridged cycloalkyl group, hetero bridged cycloalkyl group, spirocycloalkyl group or spiroheterocyclyl group are further required to be one or more Substituted by R12; four feet and R are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a 2-cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group, as desired, may be further selected from one or more selected from the group consisting of an alkyl group, a decyl group, a heterocyclic group, an aryl group, a heteroaryl group, a hydroxyl group, a hydroxyl group, a cyano group, -S(0)〇R9 . _c〇R9 N c(〇)〇R9 x _S(〇)〇nri〇rii x _c〇NR»〇Rn or a substituent of -NR1%11; or, R7 and R8 Together with the N atom to which they are attached, a 3 to 8 membered heterocyclic group is formed, wherein the 3 to 8 membered heterocyclic group contains one or more N, fluorene or fluorene (7) fluorene atoms and the 3 to 8 membered heterocyclic ring The base view needs to be further selected from one or more selected from the group consisting of alkyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)0R9, -C0R9, c(〇) 〇R9, -SCO^NR1. Substituted by a substituent of -11, -C0NRlflRn or -NR1QRn; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or the aryl group is further protected by one or more alkyl groups as needed Substituted; R1 (1 and R11 are selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; R12 is selected from the group consisting of an alkyl group, an alkoxy group, a cycloalkyl group, a halogen group, a thio group, a cyano group, a nitro group, a carbonyl group, S(〇)〇NR7R8, -CONRY, -C(0)0R9, 9 95201 201229050 -〇C(0)R9, -〇(CH2)rC(0)OR9, -0C(0)NR7R8, -S(0 Substituting mR9, -〇S(0)〇R9, -NHC(0)R9 or -COR9, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is further protected by one or more Substituents selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are substituted; m is 0 or 1; η is 0, 1 or 2; and r is 1, 2 or 3. a compound represented by the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a mixture thereof, as described in claim 1 a pharmaceutically acceptable salt, wherein ^ is selected from an alkyl group or a cycloalkyl group. a compound represented by the formula (1), or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable salt , wherein the compound comprises: 95201 10 201229050 7. A compound of the formula (A) or a pharmaceutically acceptable salt as an intermediate for the preparation of a compound of the formula (I): Wherein: G is selected from a leaving group; R is selected from a hydrogen atom or an alkyl group; R1 is selected from a hydrogen atom or an alkyl group; 11 95201 S 201229050 R2 and R3 together with the atoms to which they are attached form a 3 to 8 member, ring, Wherein the 3 to 8 member ring contains 1 to 2 N, 0 or S(〇)n heteroatoms' and the 3 to 8 member ring is further required to be further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, and an aryl group. Substituted by a substituent of a dentate, a thiol group, a cyano group, a aryl group, a carboxylic acid, a carboxylic acid ester, -S(0)0NR7R8, -C0NR7R8, -NR7R8, -S(0)0R9 or -COR9; The definition of R7 to R9 is as set forth in claim 1. 8. A compound or pharmaceutically acceptable salt of the formula (ία) according to claim 7 of the scope of the patent application, wherein the compound comprises: (IB) (I) a compound of the formula (ΙΑ) and a compound of the formula (ΙΒ) or a formula of ub) 12 95201 201229050 Salt reaction of the mash "to obtain a compound of the formula (1); wherein: R is selected from the group consisting of fluorenyl; G, R to R3 are as defined in claim 7; n L is set to only 6 as defined The patent application scope is described in item 1 t. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a tautomer thereof, a foreign body, an enantiomer, a non-pair thereof Isomers, mixtures thereof, and pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or excipients. 11. The compound of any one of clauses i to 6 of the invention, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, And the use of a pharmaceutically acceptable salt for the preparation of a medicament for treating a cell proliferative disorder. The use of the pharmaceutical composition according to the first aspect of the invention is for the preparation of a medicament for treating a cell proliferation disease. The use of the πth patent scope, wherein the cell proliferative disorder is cancer, infection, inflammation or autoimmune disease. 14. The use of claim 12, wherein the cancer is selected from the group consisting of non-small cell lung cancer, squamous cell carcinoma, breast cancer, ovarian cancer, cervical cancer, papillary carcinoma or colorectal cancer. The compound according to any one of the preceding claims, or the tautomer, exo-spin, enantiomer, diastereomer, mixture thereof, and pharmaceutically It is acceptable as a drug for treating 95201 13 201229050 cell proliferation diseases, wherein the cell proliferation diseases are cancer, infection, inflammation and autoimmune diseases, and the cancer is cervical cancer or colon cancer. The pharmaceutical composition according to the first aspect of the invention, which is a medicament for treating a cell proliferation disease, wherein the cell proliferation disease is cancer, infection, inflammation and autoimmune disease, and the cancer is cervical cancer. Or colon cancer. The compound of any one of claims 1 to 6 or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, And the use of a pharmaceutically acceptable salt for the preparation of a Plk kinase inhibitor. 18. The use of a pharmaceutical composition according to the first aspect of the invention, which is for use in the preparation of a Plk kinase inhibitor. 19. A method of inhibiting Plk kinase, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1 to 6 or a tautomer, racemate, pair thereof The mixture is in the form of a mixture, and a pharmaceutically acceptable salt. The method of string = two, 'This method includes administering an object that requires treatment. The medical group mentioned in item 1Q of the patent scope of the n. 95201 14 201229050 IV. Designation of the representative figure: There is no drawing in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 2 95201