WO2011113293A1

WO2011113293A1 - Dihydropteridinone derivatives, preparation method and pharmaceutical use thereof

Info

Publication number: WO2011113293A1
Application number: PCT/CN2011/000062
Authority: WO
Inventors: 邓炳初; 张农; 董正; 曾祥全; 舒思杰; 刘伦俊
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2010-03-19
Filing date: 2011-01-14
Publication date: 2011-09-22
Also published as: CN102421779A; CN102421779B; CN102190669A

Abstract

Dihydropteridinone derivatives, preparation method and pharmaceutical use thereof are disclosed. Specifically, disclosed are new dihydropteridinone derivatives represented by general formula (I), their preparation method, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors ,wherein each substituent of the general formula (I) is defined as in the specification

Description

Dihydroacridone derivative, preparation method thereof and application thereof in medicine

The present invention relates to a novel dihydroacridone derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use as a therapeutic agent, particularly as a Plk kinase inhibitor. Background technique

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 be critical to the cell cycle progression. effect. The Polo-like kinase (Plks) family is one of them.

Plks are a class of serine/threonine kinases that are important in regulating the cell cycle. According to the literature, Plks are involved in the regulation of many steps in the process of mitosis, including the 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 are also involved in the separation of sister chromatids, which promote the activation of complex components and the regulation of septiii during cytokinesis.

So far, four subtypes have been found in the Plks family, namely Plkl, Plk2, k3 and Plk4. (In which Plkl is particularly important for the regulation of mitosis (see Glover et al, Dev. 1998, 12:3777-87; Qian et al, Μοϊ Biol Cell., 2001, 12: 1791 -9). Plkl expression and activity levels It is closely related to the degree of growth of tumor cells (see WO 2004/014899 Al). Overexpression of Plk1 has been shown to be associated with a variety of high-proliferation types of tumors, such as non-small cell lung cancer, squamous cell carcinoma, breast cancer, ovarian cancer. Or papillary carcinoma and colorectal cancer (Wolf et al, Oncogene 1997, 14, 543-549; Knecht et al, Cancer Res., 1999, 59, 2794-2797; Wolf et al X, Pathol Res Pract" 2000, 196 , 753-759; Weichert et al, Br: J. Cancer, 2004, 90, 815-821; Ito et al, Br. J. Cancer, 2004, 90, 414-418; Takahashi et al, Cancer Sci" 2003, 94, 148-152).

A number of dihydroacridone derivatives have been disclosed in the prior art as Plkl inhibitors, and such compounds have been reported to have antiproliferative activity. For example: the patents WO 03/020722, WO 2004/076454 and WO2008050096 disclose dihydroacridone derivatives, processes for their preparation and their use in pharmaceutical compositions for the treatment of cell cycle kinase activity and are characterized by excessive or Use of diseases with abnormal cell proliferation. Patent WO 01/019825 discloses the use of pteridin derivatives as therapeutics for 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 a number of other patents, such as WO2004076454, WO2006018220, US20040176380, WO2007135374, WO2006018185, WO2006058876, WO2006018222, WO2006018182, etc., also disclosed as other Plkl inhibitors.

However, although several Plkl kinase inhibitors have been disclosed, their applications are still limited by pharmacodynamics, pharmacokinetics, etc., and there are no long-acting drugs, so there is still a need to develop safety, pharmacokinetics, etc. A Plkl kinase inhibitor with improved properties. An object of the present invention is to provide a medicament having Plk1 kinase inhibitory activity which can be used for the treatment of cell proliferation diseases such as cancer, infection, inflammation and autoimmune diseases. Summary of the invention

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a dihydroacridone derivatives of the formula (I), and their tautomers, racemates, pairs Enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts and metabolites or prodrugs:

(I)

among them:

R ¹ and R ² are each independently selected from a hydrogen atom or an alkyl group;

Or R ¹ and R ² together with the atoms to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 0 to 2 N, 0 or 8 (0) _|71 heteroatoms, and The 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR ⁷ R ^{^{^{8, -CONR 7 R 8, -NR}}} 7 R 8, -S (0) oR 9, - COR 9 , or - C (0) oR ⁹ is substituted with a substituent;

R ^{3 is} selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR ⁷ R ⁸ , - CONR Substituted by a substituent of ⁷ R ⁸ , —NR ⁷ R ⁸ , —S(0)OR ⁹ , —COR ⁹ or —C(0)OR ⁹ ;

Alternatively, R ² and R ³ 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 8 (0) ₁₁₁ heteroatoms, and The 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR ⁷ R ⁸ Substituted with a substituent of -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ or -C(0)OR ⁹ ;

R ⁴ and R ⁵ are each independently selected from a hydrogen atom, a fluorenyl group, a halogen, a cyano group or a nitro group;

L is selected from an alkylene group, optionally further substituted with one or more substituents selected from halogen, cyano, nitro or alkyl, wherein said thiol is optionally further substituted by one or more halogens ;

R ^{6 is} selected from a fluorenyl group, wherein the thiol group is optionally further substituted with a heterocyclic group;

When R ^{6 is} selected from an unsubstituted alkyl group, A is selected from a bicycloalkyl group, a heteroheterocyclyl group, a spirocycloalkyl group or a spiroheterocyclyl group, wherein the bicyclononyl group, the biheterocyclyl group, the spirocycloalkyl group Or a spiroheterocyclyl optionally further substituted with one or more R ¹² ;

When R ^{6 is} selected from heterocyclyl-substituted indenyl, A is selected from cyclodecyl, heterocyclyl, bicyclononyl, biheterocyclyl, bridged cycloalkyl, hetero bridged fluorenyl, spirocycloalkyl or Spiroheterocyclyl, wherein the cycloalkyl, heterocyclyl, Bicyclic fluorenyl, bicyclohetero, bridged fluorenyl, heterobridged fluorenyl, spirocycloalkyl or spiroheterocyclyl optionally substituted with one or more R ¹² ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)OR ⁹ , -COR ⁹ , -C Substituting (0) a substituent of OR ⁹ , -SCOjONR^R ¹¹ , -CONRWR ¹¹ or -NR ^{1 Q} R";

Alternatively, R ⁷ and R ⁸ 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, 0 or S(0) _m hetero An atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of an alkyl group, a decyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, a cyano group, and -S ( 0) 0R ⁹ , -COR ⁹ , -C(0)0R ⁹ , -S(O)ONR ^{10 U} . -CONR ^R ^{1 1} or -NR] ⁰ Substituted by a substituent of R ^N ;

R ^{9 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or aryl group is optionally further substituted with one or more mercapto groups;

R ^1Q and R ^{11 are} selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group;

R ^{12 is} selected from the group consisting of alkyl, alkoxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR ⁷ R ⁸ , -CON ⁷ R ⁸ . -C(0)0R ⁹ , -0C(0)R ⁹ , -0(CH ₂ ) _R C(0)OR ⁹ , - OC(0)NR ⁷ R ⁸ , -S(0) _M R ⁹ , -0S(0)0R ⁹ , Substituted with a substituent of NHC(0)R ⁹ or -COR ⁹ wherein said fluorenyl, decyloxy, cycloalkyl or heterocyclyl is optionally further selected from one or more selected from the group consisting of alkyl, cycloalkane Substituted by a substituent of a heterocyclic group, an aryl group or a heteroaryl group;

m is 0 or 1;

n is 0, 1 or 2; and

r is 1, 2 or 3. Preferred embodiments of the invention, the compounds of the formula (I) are tautomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable Salt: Where:

R ^{1 is} selected from a hydrogen atom;

R ^{2 is} selected from a thiol group;

R ^{3 is} selected from a decyl group or a cycloalkyl group;

Alternatively, R ² and R ³ together with the atoms to which they are bonded form 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 optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, carbonyl, aryl, -S(0)ONR ⁷ Substituted by a substituent of R ⁸ , —CONR ⁷ R ⁸ , —NR ⁷ R ⁸ , —S(0)0R ⁹ , —COR ⁹ or —C(0)0R ⁹ ;

R ⁴ and R ⁵ are each independently selected from a hydrogen atom, a halogen or a fluorenyl group;

When R ^{6 is} selected from unsubstituted indenyl groups, A is selected from a bicycloalkyl group, a biheterocyclyl group, a spirocyclic fluorenyl group or a spiroheterocyclic ring. And wherein said bicycloalkyl, bicyclohetero, bridged fluorenyl, bridged heterocyclyl, spiro fluorenyl or spiroheterocyclyl is optionally substituted with one or more R ¹² ;

When R ^{6 is} selected from heterocyclic substituted alkyl, A is selected from cyclodecyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged fluorenyl, bridged heterocyclyl, spiro fluorenyl or spiro a heterocyclic group, wherein said cyclodecyl, heterocyclyl, bicyclononyl, diheterocyclyl, bridged fluorenyl, bridged heterocyclyl, spirocycloalkyl or spiroheterocyclyl is optionally further substituted by one or Substituted by multiple R ^{1 2} ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, cyano, carboxylic acid, carboxylic acid ester, -S(0)OR ⁹ Substituting -COR ⁹ , -S(0)ONR ^{1 Q} R ^{] 1} , - CONR ^{1 G} R" or - NRWR ^{1 1} ;

Or R ⁷ and R ⁸ together with the N atom to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains one or more N, 0 or S(0) m heteroatoms, and Optionally, the 3 to 8 membered heterocyclic ring is further selected from one or more selected from the group consisting of an anthracenyl group, a decyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, a cyano group, a carboxylic acid, a carboxylic acid ester, Substituted by a substituent of a carbonyl group, -S(0)OR ⁹ , -COR ⁹ , -S^ONR'V^ - CONR' GR ¹¹ or -NRWR ^{1 1} ;

R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or the aryl group is optionally further substituted with one or more alkyl groups;

R ^{1 Q} and R ^{1 1 are} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;

R ^{1 2 is} selected from the group consisting of alkyl, decyloxy, cycloalkyl, hydroxy, cyano, nitro, carbonyl, -S(0)ONR ⁷ R ⁸ , - CONR ⁷ R ⁸ , -C(0)OR ⁹ - - OC(0)R ⁹ , -0(CH ₂ ) _R C(0)OR ⁹ , - OC(0)NR ⁷ R ⁸ , -S(0) _M R ⁹ , -OS(0)OR ⁹ Substituted with a substituent of -NHC(0)R ⁹ or -COR ⁹ wherein the alkyl, decyloxy, cyclodecyl or heterocyclic group is further optionally further selected from one or more selected from the group consisting of fluorenyl and cyclo Substituted by a substituent of an alkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

m is 0 or 1;

n is 0, 1 or 2; and

r is 1, 2 or 3. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt, wherein: R ¹ and R ² are each independently selected from a hydrogen atom or an alkyl group;

R ^{3 is} selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cyclodecyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ Substituted by a substituent of R ⁸ , —NR ⁷ R ⁸ , —S(0)0R ⁹ , —COR ⁹ or —C(0)OR ⁹ ;

Alternatively, R ² and R ³ 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 S(0) _m heteroatoms, and 3~8 yuan ring optional further by one or a plurality of selected thiol groups, decyloxy groups, halogens, light groups, cyano groups, nitro groups, aryl groups, heteroaryl groups, carbonyl groups, -S(0)ONR ⁸ , -CONR ⁷ R ^s , -NR ⁷ R ⁸ , Substituted by a substituent of -S(0)OR ⁹ , - COR ⁹ or -C(0)OR ⁹ ;

R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitro group;

L is selected from the group consisting of an anthracenylene group, optionally further substituted with one or more substituents selected from halogen, cyano, nitro or alkyl, wherein the alkyl group is optionally further substituted by one or more halogens ;

R ^{6 is} selected from a thiol group;

A is selected from a bicyclononyl group, a bicyclic heterocyclic group, a spirocyclic fluorenyl group or a spiroheterocyclyl group, wherein the bicyclic fluorenyl group, the bicyclic heterocyclic group, the spiro fluorenyl group or the spiroheterocyclic group is optionally further substituted by one or Substituted by a plurality of R ¹² ;

R ⁷ and R ^s are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group group optionally further substituted with one or more groups selected from the embankment, embankment group, a heterocyclic group, an aryl group, a heteroaryl group, halogen, hydroxy, ^{cyano, -S (0) 0R 9,} -COR 9, C ( 0) 0R ⁹ , -SiC ONR ¹ °R' ¹ , -CONR ¹ °R' ¹ or - NR ¹ °R ^{! 1} substituted by a substituent;

Alternatively, R ⁷ and R ⁸ 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, 0 or 8 (0), ^^ atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of an alkyl group, a decyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen group, a hydroxyl group, a cyano group, Substituted by a substituent of -S(0)0R ⁹ , -COR ⁹ , C(0)0R ⁹ , -S(0)0NR ^{1 Q} R ^M , -CONI^R ^{1 1} or -NR ¹⁰ R";

R ^{9 is} selected from a hydrogen atom, an alkyl group, a cyclodecyl group or an aryl group, wherein the cycloalkyl or aryl group is optionally further substituted with one or more alkyl groups;

R ^1Q and R ^{11 are} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;

R ^{12 is} selected from the group consisting of alkyl, nonyloxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -C(0)0R ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _r C(0)OR ⁹ , - 0C(0)NR ⁷ R ^s , -S(0) _m R ⁹ , -0S(0)0R ⁹ , Substituted by a substituent of -NHC(0)R ⁹ or -COR ⁹ wherein said alkyl, decyloxy, cyclodecyl or heterocyclyl is optionally further selected from one or more selected from the group consisting of alkyl, cyclo Substituted with a substituent of a heterocyclic group, an aryl group or a heteroaryl group;

m is 0 or 1;

n is 0, 1 or 2; and

R ^{3 is} selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the alkenyl group, the alkynyl group, the cyclodecyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ Substituted by a substituent of R ⁸ , —NR ⁷ R ⁸ , —S(0)0R ⁹ , —COR ⁹ or —C(0)0R ⁹ ; Alternatively, R ² and R ³ 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 ^^, 0 or SC^^ atoms, and the 3~ 8-member ring optionally further substituted with one or more substituents selected from alkyl, alkoxy embankment, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, ^{carbonyl, -S (0) ONR 7 R} 8, - Substituted by a substituent of CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)0R ⁹ , -COR ⁹ or -C(0)0R ⁹ ;

L is selected from an alkylene group, optionally further substituted with one or more substituents selected from halogen, cyano, nitro or fluorenyl, wherein said alkyl group is optionally further substituted by one or more halogens Replace

R ^{6 is} selected from a fluorenyl group, wherein the alkyl group is further substituted with a heterocyclic group;

When R ^{6 is} selected from heterocyclyl-substituted indenyl, A is selected from cycloalkyl, heterocyclyl, bicyclononyl, biheterocyclyl, bridged fluorenyl, hetero bridged fluorenyl, spiro fluorenyl or a spiroheterocyclyl group, wherein the cyclodecyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged cycloalkyl, hetero bridged fluorenyl, spirocycloalkyl or spiroheterocyclyl is optionally substituted Substituted by one or more R ¹² ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)OR ⁹ , -COR ⁹ , C ( 0) 0R ⁹ , -S(O)ONR ^{] 0} R' -CONK ER ^{1 1} or a substituent of -NRWR ¹¹ substituted;

Alternatively, R ⁷ and R ⁸ 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, 0 or 8 (0) „ ₁ a hetero atom, and the 3 to 8 membered heterocyclic group is further optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S (0)0R ⁹ , -COR ⁹ . C(0)0R ⁹ , -S(O)ONR ¹⁰ R ^N . Substituted by a substituent of -CONR^R ^{1 1} or -NR ^R";

R ^{9 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl or aryl group is optionally further substituted with one or more mercapto groups;

R ^1Q and R ^{1 1 are} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;

R ^{12 is} selected from the group consisting of fluorenyl, decyloxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR ⁷ R ⁸ , - CONR ⁷ R ⁸ , -C(0)0R ⁹ -OC(0)R ⁹ , -0(CH ₂ ) _R C(0)OR ⁹ , -OC(0)NR ⁷ R ⁸ , -S(0),"R ⁹ , -0S(0)0R ⁹ , -NHC (0) R ⁹ or -COR ⁹ group substituted with substituents, wherein the embankment group, an alkoxy group, a cycloalkyl group or a heterocyclyl group optionally further substituted with one or more groups selected from alkyl with ring Substituted with a substituent of a fluorenyl, heterocyclyl, aryl or heteroaryl group;

m is 0 or 1;

n is 0, 1 or 2; and

r is 1, 2 or 3. A preferred embodiment of the invention, a compound of the formula (I.) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt, wherein R ^{1 is} selected from a hydrogen atom, R ^{2 is} selected from a thiol group, and R ² is preferably an ethyl group. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt wherein R ^{3 is} selected from decyl or cyclodecyl, preferably isopropyl or cyclopentyl. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt, wherein n is 0 or 1, and L is selected from an alkylene group, preferably a methylene group. Preferred embodiments of the present invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt wherein R ^{6 is} selected from a heterocyclic substituted fluorenyl group and A is selected from cyclodecyl. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt, wherein A is selected from a heterocyclic group. The compound of the formula (I) may contain an asymmetric carbon atom and may therefore exist in the form of an optically pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates. Or exist as a meso 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 HPLC. Typical compounds of the invention include, but are not limited to:

Compound

Structure

Numbering

4-((i?)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine

1 yl)-3-methoxy-N-((3i?,8a?)-hexahydro-pyrrolo[2,1 _-C ][l ,4]-oxazin-3-ylmethyl)-benzene

Formamide

4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine

2 — ΦΊ . ))-3-methoxy-N-((3a5,5S,6a^)-2-A

. , ^Η -- octahydro-cyclopenta[c]pyrrole-5-yl)-benzamide 4-((/)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine

3 base) -N"(((3afan 5 & 6a,S)-2-methyl-octahydro-cyclopenta

Mpyrrole-5-yl)-methyl)-3-methoxy-benzamide

4-( )-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine

4 base) -N-(((3a 5 & 6a )-5-hydroxy-2-A)

- octahydro-cyclopenta Mpyrrole-5-yl)-methyl)-3-methoxy-benzamide

4-((7?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridine-2-ylamine

5 base) -N-(((3ai?,5 6aS)-5-hydroxy-2-A)

^HH decyl-octahydro-cyclopenta ^Mpyrrole -5,yl)-methyl)-3-methoxy-benzamide

, ⁰ 1 4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine

6

-N-(l-methyl-piperidin-4-yl)-3-(tetrahydro-furan-3-yl-methoxy)-benzamide

0 1 4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine

7

-N-(l-methyl-piperidin-4-yl)-3-hydrogen-

^{3⁄4 ώfuran} -2-yl-methoxy:)-benzamide

4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino-1yl ) -N-((4a7?,6i?,7aS -2-methyl-octahydrogen)

-1H-cyclohexanyl [c]pyridine-6-yl)-3-methoxy

-benzamide

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino-2yl ) -N-((4a5,6 & 7ai?)-2-methyl-octahydrogen

- ^η环 cycloheximide M pyridyl-6-yl)-3-methoxy

-benzamide

-N-(l-methylpiperidin-4-yl)benzamide

Or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt. Further, the present invention provides a compound of the formula (IA) which is an intermediate for the preparation of a compound of the formula (I), wherein:

(1A)

among them:

G is selected from a leaving group, preferably selected from the group consisting of halogen, methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl or decyloxy;

R is selected from a hydrogen atom or a sulfhydryl group;

R ^{1 is} selected from a hydrogen atom or a fluorenyl group;

R ² and R ³ together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains! ~ 2 N, 0 or S(0) n heteroatoms, and the 3 to 8 membered ring is optionally further further selected from one or more selected from the group consisting of fluorenyl, decyloxy, aryl, halogen, hydroxy, cyano, Substituted by a substituent of a carbonyl group, a carboxylic acid, a carboxylic acid ester, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ or -COR ⁹ . n, R ^{7 to} R ⁹ are as defined in the general formula (J)

Typical compounds of formula (IA) include, but are not limited to:

Further, the present invention provides a process for the preparation of a compound of the formula (I), which comprises:

】2

(IA) (IB) ( ¹ )

The compound of the formula (IA:) is reacted with a compound of the formula (IB) or a salt of the compound of the formula (IB) to give a compound of the formula (I).

among them:

R is selected from a methyl group;

G, R^R ^{3 is} as defined for the compound of formula (IA);

A, n, L, R ^{4 to} R ⁶ are as defined for the compound of the formula (I). Another aspect of the invention relates to a compound of the formula (I) of the invention or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable The use of the accepted salt for the preparation of a medicament for 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, the method 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 Isomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts, wherein the cell proliferation diseases are cancer, infection, inflammation, and autoimmune diseases, and the cancer is cervical Cancer or colon cancer. Another aspect of the invention relates to a compound of the formula (I) of the invention or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable The accepted 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 the 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 form 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) or the tautomers, racemates, enantiomers thereof, Diastereomers, mixtures thereof, and pharmaceutically acceptable salts are useful as drugs for inhibiting 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 In the form of a mixture, and a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient therefor. The use of the pharmaceutical composition for the preparation of a medicament for the treatment of cancer, infection, inflammation and autoimmune diseases, the cancer being 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 medicament for treating cancer, infection, inflammation, and autoimmune diseases, 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, a pair thereof a pharmaceutical composition of a conjugate, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, wherein the cell proliferative disorder is cancer, infection, inflammation, and autoimmune disease, The cancer described is cervical cancer or colon cancer. The compounds of the invention and their pharmaceutically acceptable salts 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 adjuvants such as diluents, sweeteners, flavoring agents, colorants 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, i.e., 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, rapid release mode.

In a hard capsule, the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or china clay; in a soft capsule, the active ingredient is mixed with water or an oil vehicle such as peanut oil, paraffin or olive oil.

In an aqueous suspension, the active ingredient is mixed with excipients which are suitable for pharmaceutical use. These excipients are suspending agents (such as hydroxymethyl cellulose sodium, methyl cellulose, hydroxypropyl-methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum arabic), dispersing agents or wetting agents [ Including naturally occurring phospholipids (such as egg pity) or condensates of alkylenes and fatty acids (such as polyoxyethylene stearate) or condensates of ethylene and long-chain fatty alcohols (such as heptadecylene oxide ten A condensate of hexaol) or ethylene oxide and a partial ester derived from a fatty acid and a hexitol (such as polyethylene sorbitan monooleate): |. The aqueous suspension may also mean a plurality of preservatives (such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate); one or more colorants; one or more fragrances and one or A variety of 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 flavoring 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 oxime:) or a preservative (such as p-hydroxybenzoic acid). ester;).

Injection or infusion solutions are prepared in a conventional manner, for example, by adding isotonic agents, preservatives (such as parabens) or stabilizers (such as alkali metal salts of ethylenediaminetetraacetic acid), if necessary, using emulsifiers And/or a dispersing agent, when water is used as a diluent, that is, an organic solvent may be used as a dissolving agent or a co-solvent as needed, and transferred to an injection vial or an ampoule or a perfusion bottle.

Suitable suppositories are, for example, admixed with a carrier for this purpose, such as a neutral lipid or polyethylene glycol or a derivative thereof.

Suitable excipients can be, for example, water, in pharmaceutically acceptable organic solvents (such as paraffin, for example, petroleum fractions), vegetable oils (for example, peanut oil or sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerol). , carrier [such as natural mineral powder (for example, kaolin, clay, talc), synthetic mineral powder (for example, highly dispersible silica and silicate)], sugar (for example, raw sugar, lactose and glucose), emulsifier (eg, lignin, sulfite waste, methylcellulose, starch, and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

The formulations may be administered in a conventional manner, preferably by the oral or dermal route, preferably orally. In the case of oral administration, the tablets may of course include additives (e.g., sodium citrate, calcium carbonate, and dicalcium phosphate) in addition to the above-described carriers, and other additives (e.g., starch, preferably potato starch, gelatin, and the like). It is also possible to use a lubricant to form tablets such as magnesium fatty acid, sodium lauryl sulfate and talc. In the case of an aqueous suspension, the active substance may be mixed with various flavoring or coloring agents in addition to the above-mentioned excipients. Suitable liquid carrier materials can be used for the solution of the active substance for parenteral use. The intravenous dose is from 1 to 1000 mg per hour, preferably from 5 to 500 mg per hour.

However, it may be desirable to deviate from the above dosages depending on the weight or method of administration, the individual's response to the drug, the nature of the formulation used, and the time or interval of administration. Therefore, it may be sufficient to use a minimum dose less than the above specified in some cases, but in other cases the specified upper limit must be exceeded. 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 depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's The route, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or pharmaceutically acceptable The type of salt can be verified according to traditional treatment options. ■ Detailed description of the invention

Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Mercapto" refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. A mercapto group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group or a pentyl group or the like is preferable. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of a decyloxy group, an alkenyl group, an alkynyl group, a halogen, a hydroxyl group, an amino group, a nitro group, and a cyano group. , cycloalkyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, diheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ^s , -NR ⁷ R ⁸ , - S( 0) OR ⁹ , -COR ⁹ , carboxylic acid or carboxylic acid ester.

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 2-, 2- or 3-butenyl, and 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 an indenyl group, a decyloxy group, an alkynyl group, a halogen group, a hydroxyl group, an amino group, a nitro group, and a cyano group. , sulfonyl, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, diheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , - COR ⁹ , a carboxylic acid or a carboxylic acid ester.

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-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, independently selected from the group consisting of a decyl group, an alkoxy group, an alkenyl group, a halogen, a hydroxyl group, an amino group, a nitro group, and a cyano group. , sulfonyl, cycloalkyl, heterocyclic, aryl, heteroaryl, bicycloindenyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ^{9. A} carboxylic acid or a carboxylic acid ester.

"Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic cyclic system comprising from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably the cycloalkyl ring contains from 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexane, cyclohexadienyl, cycloheptyl, cycloheptatrienyl Wait. Polycyclic fluorenyl groups include spiro, fused, and bridged cycloalkyl groups, and non-limiting examples include 1-naphthoquinone, norbornyl, adamantyl, and the like. The cycloalkyl 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, decyloxy, alkenyl, alkynyl, halogen, hydroxy, Amino, nitro, cyano, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ , carboxylic acid or carboxylic acid ester.

"Heterocyclyl" means a non-aromatic monocyclic or polycyclic ring system comprising from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)n (where n is An integer of 0 to 2) of a hetero atom, but excluding the ring moiety of -0- 0-, -0-S- or -SS-, the remaining ring atoms being carbon. Preferably, the heterocyclic group contains 3 to 10 ring atoms, of which 1 to 4 are hetero atoms, and more preferably the heterocyclic group contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl And the polycyclic heterocyclic group includes a bicyclic or polycyclic spiro ring, a fused ring, and a bridged heterocyclic group. The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, naphthenic , heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , - CONR ⁷ R ^s , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ , a carboxylic acid or a carboxylic acid ester.

"Bicyclic fluorenyl" means a 5 to 14 membered all-carbon fused ring ("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 one rings with a fully conjugated pi-electron system. E.g

It is preferably a 5-member/5- or 5-membered/6-membered bicycloalkyl group. Bicycloalkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, cyclodecyl, hetero Cyclo, aryl, heteroaryl, bicycloindenyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , COR ⁹ , a carboxylic acid or a carboxylic acid ester.

"Biheterocyclyl" refers to a 12-membered fused ring ("fused" ring system means each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one or more of which The ring atoms are selected from nitrogen, oxygen or a hetero atom of S(0)n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. These can contain one or more double bonds but no π electronic system. It is preferably 7 to 0 yuan. E.g

More preferably, it is a 5-membered/5-membered or 5-membered/6-membered bicyclic heterocyclic group. The bicyclic heterocyclic group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, cycloalkyl, hetero Cyclo, aryl, heteroaryl, bicycloindenyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , COR ⁹ , carboxylic acid or carboxylic acid ester.

"spirocycloalkyl" refers to a polycyclic group of 5 to 14 members, which shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a complete conjugation. π electronic system. It is preferably 7 to 10 yuan. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a double according to the number of common spiro atoms between the ring and the ring. The spirocyclic fluorenyl or polyspiro is preferably a monospiroindole and a bispirocycloalkyl group. E.g:

More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. 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 fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy , amino, nitro, cyano, carbonyl, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ -NR ⁷ R ⁸ , - S(0)OR ⁹ , -COR ⁹ , a carboxylic acid or a carboxylic acid ester.

"spiroheterocyclyl" means a polycyclic hydrocarbon of 5 to 4 members, which shares an atom (called a spiro atom) between the monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (wherein n is an integer 0 to 2) hetero atom, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated π electron system. It is preferably from 7 to 10. E.g

The spirocyclic fluorenyl group is classified into a monospirocycloalkyl group, a bispirocyclic fluorenyl group or a polyspirocycloalkyl group, preferably a monospiroheterocyclic group and a bisspiroheterocyclic group, depending on the number of common snail atoms between the ring and the ring. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiroheterocyclic group. 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 fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy , amino, nitro, cyano, carbonyl, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, diheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ , carboxylic acid or carboxylic acid ester.

"3 to 8 membered heterocyclic group" means that the number of ring atoms is 3 to 8 yuan, 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, and more preferably 5 to 6 members, such as a pyrrolidinyl 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 the group consisting of an indenyl group, a decyloxy group, an alkenyl group, an alkynyl group, Halogen, hydroxy, amino, nitro, cyano, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ , a carboxylic acid or a carboxylic acid ester.

a p-membered/q-membered bicycloalkyl group, a biheterocyclyl group, a monospirocycloalkyl group or a monospiroheterocyclyl group, which refers to a bicyclononyl group, a biheterocyclic group, a monospirocycloalkyl group or a monospiroheterocyclic group. The number of ring atoms of each ring 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" means 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 π-electron system (ie, having adjacent pairs) The ring group of a carbon atom is preferably 6 to 10 members 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, decyloxy, alkenyl, alkynyl, halogen, hydroxy, and independently. Amino, nitro, cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ^s , - NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ , carboxylic acid or carboxylic acid ester.

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 or 6 members. For example, furyl, thienyl, pyridyl, pyrrole, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, 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 fluorenyl, alkoxy, alkenyl, alkynyl, halogen, hydroxy. , amino, nitro, cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -COR ₉ , -CONR ₉ R _{1 Q} , -NR ₉ R _1Q , Carboxylic acid or carboxylic acid ester.

• "Mercaptooxy" means -0-(; fluorenyl) and -0-(unsubstituted cycloalkyl). For example, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy. , amino, nitro, cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicycloalkyl, diheterocyclyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ , carboxylic acid or carboxylic acid ester.

"Aryloxy" means -0-aryl and -0-heteroaryl, and aryl and heteroaryl are as defined above. For example, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy and the like and derivatives thereof. .

"Hydroxy" means an -OH group. .

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -N3⁄4.

"Cyano" means -CN.

"Nitro" means -N0 ₂ .

"Carbonyl" means (group) -C(=0)- (group).

"Hydroxycarbonyl" means -(alkyl)-OH.

"Benzyl" refers to -CH ₂ - (phenyl).

"Carboxylic acid" means (fluorenyl) C(=0)OH.

"Carboxylic ester" means (indenyl) C(=0)0(indenyl).

"Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by a thiol group" means that a fluorenyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by a thiol group. .

"Pharmaceutical composition" means one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof or Mixtures of prodrugs with other chemical components, other components such as physiological/pharmaceutically acceptable carriers and excipients _; the purpose of the pharmaceutical compositions is to facilitate administration of the compounds to the organism. Method for synthesizing the compound of the present invention

In order to complete the present invention, the following technical solutions are adopted:

The method for preparing 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 salt of 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 ruthenium, Ν-dicyclohexylcarbodiimide, ruthenium, osmium-diisopropyl carbon. Di-, 0-benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethyluronium tetrafluoroborate (TBTU), etc., preferably 0-benzotriazole-oxime, ruthenium, osmium ',Ν'-tetramethyluronium tetrafluoroborate (TBTU); basic conditions are provided by an organic base or an inorganic base selected from, for example, diisopropylethylamine, pyridine, triethylamine, hexahydropyridine, N-methylpiperazine, 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 Methylene chloride; the reaction temperature is controlled at -80 ° C to 100 ° C, preferably 0 ° C to 60 ° C; the reaction time is generally controlled from 1 minute to 72 hours, preferably 15 minutes to 24 hours;

among them:

R is selected from a methyl group;

G, Ι^~Ι ^{3 is} as defined for the compound of formula (IA);

A, n, L, R ^{4 to} R ⁶ are as defined for the compound of the formula (I). detailed description

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR was measured by a Bmker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 ₃ ). The internal standard was tetramethylsilyl (TMS), and the chemical shift was given in units of 10 _ ⁰ (ppm).

The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX). HPLC measurements were performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The average inhibition rate of the kinase and the IC ₅ o value were determined using a NovoStar plate reader (BMG, Germany).

Thin layer chromatography silica gel plate using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography

(TLC) The silica gel plate used has a specification of 0.15 mm to 0.2 mm, and the thin layer chromatography separation and purification product has a specification of 0.4 ram-0.5 mm.

Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The starting materials of the present invention are known and commercially available from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemical Companies such as products may be synthesized by 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 uses a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.

There is no particular description in the examples, and the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The optimum temperature for the reaction at room temperature is 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: chloroform and methanol system, B: n-hexane and ethyl acetate system, C: petroleum Ether and ethyl acetate system, D: acetone. The volume ratio of the solvent is adjusted depending on the polarity of the compound.

Column chromatography chromatographic eluent systems include: A: chloroform and methanol systems, B: n-hexyl and ethyl acetate systems, C: dichloromethane and acetone systems, D: n-hexyl and acetone systems. The volume ratio of the solvent is adjusted depending on the polarity of the compound, and it may be adjusted by adding a small amount of ammonia water and acetic acid. Example 1

4-(0?-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3-methoxy -N-((3i?,8ai?)-hexamethyl)-benzamide

First step

3-methoxy-4-nitro-benzoic acid methyl ester

3-methoxy-4-nitro-benzoic acid la (5 g, 50 mmol) was dissolved in 30 mL of methanol, and dichloromethane (5.50 mL, 75 mmol) was added dropwise, and the reaction was refluxed for 3 hours. The reaction mixture was concentrated under reduced EtOAc. EtOAcjjjjjjjjjjjjjjj The resulting residue was purified to afford titled product: 3-methoxy-4-nitro-benzoic acid methyl ester lb (5.28 g, white solid), yield: 99.

Step ~~ ^ step

4-amino-3-methoxy-benzoic acid methyl ester

3-methoxy-4-nitro-benzoic acid methyl ester lb (5.28 g, 25 mmo) was dissolved in 40 mL of methanol, and (600 mg, 10%) palladium/carbon was added thereto, and the reaction was stirred under a hydrogen atmosphere for 1 hour. Filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjj , Yield: 91%.

MS m/z (ESI): 182.1 [M+l]

third step

(i?)-2-amino-butyric acid methyl ester

Under ice bath, ((i?)-2-amino-butyric acid ld (10 g, 0.096 mol) was dissolved in 50 mL of methanol, and thionyl chloride (13 mL, 0.17 mol) was added dropwise, and the reaction was stirred under reflux for 1 hour. , cooled to room temperature, and concentrated the reaction solution under reduced pressure. The title product (7?)-2-amino-butyric acid methyl ester hydrochloride (a colorless oil) was obtained, which was taken directly to the next step. MS m/z (ESI): 118.0 [ +1]

the fourth step

.-2-Cyclopentylamino-butyric acid methyl ester

Dissolve ((i?)-2-amino-butyric acid methyl ester hydrochloride le (1 1.24 g, 0.096 mol) and cyclopentanone (8.24 g, 0.098 mol) in 150 mL of dichloromethane. The reaction was stirred for 1.5 hours, sodium acetate (8.04 g, 0.098 mol) and sodium triacetoxyborohydride (30.52 g, 0.14 mol) were added, and the reaction was stirred for 3 hours. The reaction solution was poured into 150 mL of 10% sodium hydrogencarbonate solution. The mixture was extracted with methylene chloride (100 mL×3), EtOAcjjjjjjjjjjjjjjjjjjjj The title product (7?)-2-cyclopentylamino-butyric acid methyl ester lf (6.04 g, pale yellow oil).

MS m/z (ESl): 186.1 [M+1]

the fifth step

(i -2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butyric acid methyl ester (methyl-2-cyclopentylamino-butyrate) Lf (2.50 g, 13.5 mmol) and sodium bicarbonate (4.54 g, 54 nimol) were dissolved in 00 mL of cyclohexane, stirred for 30 minutes, and 2,4-dichloro-5-nitro-pyrimidine (2.88 g) was added. , 14.84 mmol), the reaction was stirred at 60 ° C for 12 hours. After filtration, the filter cake was washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure with 150 mL of ethyl acetate and hexane (V:V=1) : 4) The solvent was recrystallized to give the title product (ii)- 2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butyric acid methyl ester 1 _g (3.36 g, pale yellow solid), Yield: 72.6 %.

MS m/z (ESI): 343.1 [M+1]

(i?)-7-ethyl-2-chloro-8-cyclopentyl-7,8-dihydro-5H-acridin-6-one (i?)-2-[(2-chloro-5) -Nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butyric acid methyl ester 1 _g (lg, 3 mmol) was dissolved in 10 mL of acetic acid, and Raney nickel (0.50 g) was added under a hydrogen atmosphere. The reaction was stirred at 80 ° C for 12 hours. Filtration, the filter cake was washed with chloroform (50 mL), and the filtrate was evaporated to dryness. EtOAcjjjjjjjjjjjjjj Filtration, the filtrate was concentrated under reduced pressure, and then purified tolulululululululululululululululululululululululululululululululululululululululululu 8-Dihydro-5H-acridin-6-one lh (0.56 g, white solid), Yield: 66.7 %. MS m/z (ESI): 281.2 [M+1]

Seventh step

((7?)-7-ethyl-2-chloro-8-cyclopentyl-5-methyl-7,8-dihydro-5H-acridin-6-one (i?)-7-B Base-2-chloro-8-cyclopentyl-7,8-dihydro-5H-acridin-6-one lh (3.50 g, 12.5 mmol, prepared according to patent publication US2004/176380) dissolved in 80 mL To the acetone, methyl p-toluenesulfonate (3.4 g, 18.7 mmol) and potassium carbonate (3.45 g, 25 mmol) were added, and the mixture was stirred and refluxed for 2 hr, then cooled to room temperature. The residue obtained was purified by column chromatography eluting to afford the title product (i?)-7-ethyl-2-chloro-8-cyclopentyl-5-methyl-7,8-dihydro-5H. - acridine-6-one lj (3.4 g, white solid) Body), Yield: 93%.

MS m/z (ESI): 295.4 [M+l]

Eighth

(7-Ethyl-8-cyclopentyl-2-(3-methoxy-benzoic acid methyl ester-4-yl-amino)-5-methyl-7,8-dihydroacetidine

-6-ketone

4-Amino-3-methoxy-benzoic acid methyl ester lc (305 mg, 1.7 mmol), (i?)-7-ethyl-2-chloro-8-cyclopentyl- 5-methyl- 7,8-Dihydro-5H-acridin-6-one lj (500 mg, 1.7 mmol) and p-toluenesulfonic acid (500 mg, 25.5 mmol) were dissolved in 20 mL of 4-methyl-2-pentanol. The reaction was refluxed for 2.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) (EtOAc) The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut Methyl ester-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridin-6-one lk (550 mg, white solid), yield: 73%.

MS m/z (ESI): 440.2 [M+l]

Ninth

(7?)-7-Ethyl-8-cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7,8-dihydro-5H-indole Pyridyl-6-one will give (i?)-7-ethyl-8-cyclopentyl-2-(3-methoxy-benzoic acid methyl 4- 4-amino-amino)-5-methyl-7, 8-Dihydro-5H-acridin-6-one lk (200 mg, 0.46 mmol) was dissolved in 20 mL of methanol, then added 3 mL of 2 M lithium hydroxide (77 mg, 1.38 mmol) and stirred at 60 ° C Reaction for 12 hours. The reaction mixture was concentrated under reduced pressure and ethyl acetate (50 mL×3). The mixture was diluted with water, and then 1 M hydrochloric acid was added dropwise to pH 2, and a white solid precipitated. Filtered, the filter cake was dried to give the title product (i?) - 7- ethyl-8-cyclopentyl-2- (3-methoxy - benzoic acid 4-yl - amino) - ₅ - methyl _{- 7} , ₈ - Dihydro - 5 / / - acridine - 6 - ketone! .!^^ !^, white solid), yield: 71 % o

MS m/z (ESI): 426.3 [M+l]

Step 10

2-chloro-3-(2-hydroxymethyl-pyrrolidine-1-yl)-propanenitrile

Under a nitrogen atmosphere, pyrrolidin-2-yl-methanol ln (200 mg, 2 mmol) was dissolved in 5 mL of anhydrous diethyl ether, 2-chloro-acrylonitrile (0.16 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-carbylmethyl-pyrrole-1-yl)-propanonitrile, which was directly used for the next reaction.

MS m/z (ESI): 189.1 [M+l]

The eleventh step

Hexahydro-pyrrolo[2,1- _C ][1,4]-oxazin-3-carbonitrile

2-Chloro-3-(2-hydroxymethyl-pyrrole-1-yl)-propanenitrile l _O (0.38 g, 2 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran under ice bath, and tert-butanol was added. Potassium (0.29 g, 2.6 mmol) was stirred at room temperature for 1 hour. Filtration, the filter cake was washed with 20 mL of methanol, and the filtrate was combined, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ]- oxime-3-nitrile lp (0.12 g, colorless oil), yield: 37.8 %. MS m/z (ESl): 153.2 [M+\]

Twelfth

[(37?,8ai?)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1- _ύ ][1,4]oxazin-3-yl) _-methylamine Dissolve hexahydro-pyrrolo[2,1 -c][l ,4]-oxazin-3-carbonitrile lp (0.40 g, 2.63 mmol) in 20 mL of methanol, add Raney nickel (0.5 g), hydrogen The reaction was stirred for 12 hours under an atmosphere. Filtration and concentration of the filtrate under reduced pressure afforded the title product [(3 8a7 -3,4,6,7,8,8a-hexahydro-1 H-pyrrolo[2,lc|[l,4]oxazin-3- -Methylamine lq (0.3 g, colorless oil), Yield: 73%, used directly in the next reaction.

MS m/z (ESI): 157.2 [M+l]

Step 13

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3 -methoxy

-N-((3?,8aii)-hexahydro-pyrrolo[2,1-[1,4]-oxazol-3-ylmethyl)-benzamide [[!K,8ai -3, 4,6,7,8,8a-hexahydro-1H-pyrrolo[2,lc][l,4]oxazin-3-yl)-methylamine lq (60 mg, 0.38 mmol), ((7? )-7-ethyl- 8-cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridine-6 -ketone lm (160 mg, 0.38 mmol), (9-benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea tetrafluoroborate (243 mg, 0.38 mmol) and diisopropyl Ethylethylamine (180 mg, 1.4 mmol) was dissolved in 12 mL of dichloromethane and stirred for 2 hours. Add 20 mL of saturated sodium bicarbonate solution, dichloromethane (50^1^3), combined organic phase The mixture was washed with saturated brine (20 mL×3), dried over anhydrous magnesium sulfate. 8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3-methoxy-N-( (3i?,8a 0-hexahydro-pyrrolo[2,l-c][l,4]-oxazol-3-ylmethyl)-benzamide 1 (100 mg, white solid), yield : 47%.

MS m/z (ESI): 564.3 [M+l]

'H NMR (400MHz, CDC1 _3i ppm) δ 8.58-8.60 (d, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1 H), 7.32 (d, 1H), 6.53 (t, 1H), 4.34 (m, 1H), 4.24-4.27 (m, 1H), 4.06-4.88 (ra, IH), 4.02 (s, 3H), 3.78-3.8 (m, 2H), 3.47-3.48 (m, 2H), 3.39 (s, 3H), 3.1 1-3.14 (m, 2H); 1.90-2.19 (m, 5H), 1.47-1.92 (m, 12H), 0.90-0.94 (t, 3H) Example 2

₄ - _((?) - ₈ - cyclopentyl _ ₇ - ethyl-6-oxo _5- - _5, _6, _7, _8-tetrahydro - pteridine _ ₂ - yl amino) - ₃ - Methoxy-Ν-ί(3 5 & 6 base)-benzamide

First step

Allyl-prop-2-ynyl-amine

Under ice-cooling, acrylamide 2a (225 mL, 3.0 niol) was dissolved in 100 mL of 2 M sodium hydroxide solution, bromopropyne (89.1 mL, 1.0 mol) was added dropwise, and the mixture was warmed to room temperature, and the reaction was stirred for 12 hours. The reaction liquid was concentrated under reduced pressure to give the titled product, propyl-prop-2-ynyl-amine 2b, and the crude product was directly used for the next reaction.

MS m/z (ESI): 96.2 [M+l]

Second step

Allyl-prop-2-ynyl-carbamic acid tert-butyl ester

Dissolve the crude allyl-prop-2-ynyl-amine 2b (90.05 g, 0.95 mol), potassium carbonate (130.75 g, 0.95 mol) and di-tert-butyl dicarbonate (120 g, 0.55 mol) in 200 mL The reaction was stirred for 12 hours in dichloromethane. After adding 20 mL of water and dichloromethane (50 mL > 3), the organic phase was combined, washed with brine (20 mL > < 3), dried over anhydrous magnesium sulfate, filtered, The residue obtained was purified by eluent B to give the titled product, allyl-prop-2-ynyl-carbamic acid tert-butyl ester 2c (76.97 g), yield: 41.7

5-oxo-hexahydro-cyclopenta[c|pyrrole-2-carboxylic acid tert-butyl ester under the nitrogen atmosphere, allyl-prop-2-ynyl-carbamic acid tert-butyl ester 2c (16.7 g, 0.86 Mol) was dissolved in 100 mL of ethylene glycol dimethyl ether, and octacarbonylcobalt (29.4 g, 0.86 mol) and 31 mL of 7_K were added, and the reaction was stirred under reflux for 3 hours. Add 10 mL of water, concentrate the reaction mixture under reduced pressure, and add 100 mL of ethyl acetate, 100 mL of water and 50 mL of 1 M hydrochloric acid to dissolve the residue, which is extracted with ethyl acetate (100 mL×3), and the organic phase is washed with saturated brine. (50 mL x 3), dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, ]pyrrole-2-carboxylic acid tert-butyl ester 2d (7.69 g), Yield: 40%. the fourth step

(3aS,5/?,6ai0-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-furic acid tert-butyl ester 5-keto-hexahydro-cyclopenta[c]pyrrole-2-carboxylate Tert-butyl acid 2d (1.8 g, 8 mmol, prepared according to the existing literature Tetrahedron, 49 (23), 5047-54; 1993) was dissolved in 30 tetrahydrofuran, and sodium borohydride (0.6 g, 16 mmol) was added. The reaction was stirred for 1.2 hours. 30 mL of saturated sodium bicarbonate solution was added, and ethyl acetate (50 mL×3) was added, and the organic phase was combined, washed with brine (50 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by silica gel column chromatography eluting to elute to afford the title product (3aS,5 6 a?)-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-Butyl ester 2e (1.64 g, yellow liquid), yield: 90%.

MS m/z (ESI): 228.1 [M+1]

the fifth step

aS,SR R)-5-methanesulfonyl-hexahydro-cyclopenta Mpyrrole-2-carboxylic acid tert-butyl ester, (3aS, 5 6ai?)-5-hydroxy-hexahydro-cyclopentane And [c]pyrrole-2-carboxylic acid tert-butyl ester 2e (1.64 g, 7.2 mmol) was dissolved in 30 mL of dichloromethane, methanesulfonyl chloride (0.85 mL, 11 mmol) and triethylamine (2 mL, 14.4) Methyl), the reaction was stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution, and extract with methylene chloride (50 mL×3), EtOAc (EtOAc) The resulting eluent B in the residue system, to give the title product (3aS, 5 6ai?) - 5- methanesulfonyl-- hexahydro - cyclopenta _[C] pyrrole-2-carboxylate 2f (1.76 g , yellow liquid), Yield: 80%.

MS m/z (ESI): 305.9 [M+1]

(3a5,5 & 6ai?)-5-azido-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester (3a^5i?,6ai-5-methanesulfonyl-hexahydro) - Cyclopenta[c]pyrrole-2-carboxylate tert-butyl ester 2f(] .76 g, 5.76 mmol) was dissolved in 20 mL of N,N-dimethylformamide and sodium azide (0.94 g, 14.4 mmol), stirring at 80 °C for 4 hours. Add 20 mL of water, extract with ethyl acetate (50 mL×3), EtOAc (EtOAc) The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut Acid tert-butyl ester 2 g (1.15 g, white solid), Yield: 79%.

MS m/z (ESI): 253.0 [M+1]

Seventh step

(3aS,5 & 6ai?)- 5-azido-octahydro-cyclopenta[c]pyrrole hydrochloride (3a5,5 & 6ai?)- 5-azido-hexahydro-cyclopenta [C]pyrrole-2-carboxylic acid tert-butyl ester 2^0.62 g, 2.44 mmol) was dissolved in 10 mL of dichloromethane, and 10 mL of 4 M hydrogen chloride in 1,4-dioxane solution was added and stirred for 0.5. hour. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssss 〗 00%.

MS m/z (ESI): 153.1 [M+1]

Eighth step (3 5 & 6ai?)-5-azido-2-methyl-octahydro-cyclopenta[ _C ]pyrrole in an ice bath, (3a&5&6aT-5-azido-octahydro-cyclopenta[ c] Pyrrole hydrochloride 2h (0.45 g, 2.38 ramol) was dissolved in 10 mL of acetonitrile, adding formaldehyde (0.39 niL, 4.76 mmol) and sodium triacetoxyborohydride (1.5 μg, 7.14 mmol), stirring reaction 2 Hour. Add saturated sodium carbonate solution until the pH of the reaction solution is 10, extract with dichloromethane (50 mL×3), combine the organic phase, wash with saturated brine (50 _m Lx3), dry over anhydrous magnesium sulfate, filter, filtrate Concentration by pressure, the residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut Pyrrole 2j (0.28 g, pale yellow liquid), Yield: 71%.

MS m/z (ESI): 167.1 [M+ l ]

Step 9

(3a5 5 & 6aA)-2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl-amine (3aS,5 & 6ai?)-5-azido-2-methyl-eight Hydrogen-cyclopenta[c]pyrrole 2j (] 50 mg, 0.9 mmol) was dissolved in 20 mL of methanol, and (30 mg, 10%) palladium/carbon was added, and the reaction was stirred for 2 hours under a hydrogen atmosphere. Filtration, the filter cake was washed with methanol (30 mL), and the filtrate was concentrated under reduced pressure to give the title product (3aS, 5 & 6ai -2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl-amine 2k ( 0.08 g, pale yellow liquid), Yield: 63%.

MS m/z (ESI): 141.4 [M+l]

Step 10

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3 -methoxy-N-((3aS,5 & 6ai?)-2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl)-benzamide will be (7?)-7-B -8-cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridin-6-one lm (242 Mg, 0.57 mmol) and (9-benzotriazole-oxime, oxime, Ν', Ν'-tetramethyluronium tetrafluoroborate (183 mg, 0.57 mmol) were dissolved in 20 mL of dichloromethane. Add diisopropylethylamine (0.21 mL, 1.25 mmol) and 10 mL (3aS,5 & 6a?)-2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl-amine 2k (80 Mg, 0.57 mmol) in dichloromethane, stirred for 3 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with dichloromethane (50 mL×3), and the organic phase is washed with saturated brine (50 mL×3) The title compound 4-((??-8-cyclopentyl-7-ethyl-5) was obtained as the titled product. -methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3-methoxy -N-((3aS,5 & 6ai?)-2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl)-benzamide 2 (193 mg, white solid), Yield: 62 %.

MS m/z (ESI): 548.4 [M+ l]

'Η NMR (400MHz, CDCl _3j ppm) δ 8.56-8.59 (d, 1 H), 7.72 (s, 1H), 7.62 (s, 1 H), 7.47 (s, 1 H), 7.23-7.26 (d, 1H), 5.96-5.98 (d, 1 H), 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, 13H), 0.85-0.95 (t, 3H) Example 3

₄ _ ₍₍ ?)- ₈ -Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamine -N-((T3 _a 5S.6a5V2 3-methoxy-benzamide)

First step

(3aS, 55*, 6a/?) 5-cyano-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester in a dry ice bath, 5-keto-hexahydro-cyclopenta[ c]pyrrole-2-carboxylic acid tert-butyl ester 2d (1.9 g, 8.4 mmol) and 2-p-toluenesulfonyl-acetonitrile (1.97 g, 10.1 mmol) were dissolved in 20 mL of dichloromethane, and 25 mL of A solution of potassium butoxide (1.88 g, 16.8 mmol) in tert-butanol was stirred for 12 hours. </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut tert-Butyl ester 3a (0.7 g, yellow liquid), Yield: 35 %.

MS m/z (ESI): 259.1 [M+23]

Second step

(3a5,5 & 6ai?)-5-Aminomethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3aS,5 & 6ai?)-5-cyano-hexahydro -cyclopentazone | c]pyrrole-2-carboxylic acid tert-butyl ester 3a (0.3 g, 1.27 mmol) was dissolved in 30 niL of methanol, lanthanide (0.50 g) was added, and the reaction was stirred under a hydrogen atmosphere for 6 hours. Filtration and concentration of the filtrate under reduced pressure gave the title product (3a & 5 & 6ai?)-5-aminomethyl-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester 3b (0.2 g, pale yellow liquid). Rate: 65 %, used directly in the next reaction.

third step

5-{ [4- )- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3 -methoxy-benzamide]-methyl}-(3 5 & 6ai?)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3a5,5 & 6aW)-5 -aminomethyl-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester 3b (190 mg, 0.8 mmol), (R)-7-ethyl-8-cyclopentyl-2-( 3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridine-6-one] m (336 mg, 0.8 mmol), O-benzo Triazole-indole, hydrazine, hydrazine, Ν'-tetramethylurea tetrafluoroborate (256 rag, 0.8 mmol) and diisopropylethylamine (228 mg, 1.76 mmol) were dissolved in 40 mL of dichloromethane and stirred for 2 hours. After adding 30 mL of saturated sodium hydrogencarbonate solution, the mixture was extracted with methylene chloride (50 mL×3), and the organic phase was combined, washed with brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, The residue obtained was purified by eluent system A to give the title product 5-{[4-((-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7) ,8-tetrahydro-acridin-2-ylamino)-3-methoxy-benzamide]-methyl}-(3a&5 & 6a/?)-hexahydro-cyclopenta Mpyrrole-2-carboxylate tert-Butyl ester 3c (388 mg, white solid), Yield: 75 %.

MS m/z (ESI): 648.6 [M+1]

the fourth step

4-((7 -8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-( ((3ai?,5 & 6 _a S)-2-methyl-octahydro-cyclopenta[ _C ]pyrrole-5-yl)-methyl)-3-methoxy-benzamide will be 5-{ [4-((7?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)- 3-methoxy-benzamide]-methyl}-(3aS,5 & 6ai?)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 3c (388 mg, 0.46 mol) Dissolve in 20 niL of dichloromethane, add 20 mL of 6 M hydrogen chloride in 1,4-dioxane solution, stir the reaction for 0.5 hour, concentrate the reaction solution under reduced pressure, add formaldehyde (0.1 mL, 0.92 mmo) and two drops of acetic acid. After stirring for 0.5 hour, sodium triacetoxyborohydride (292 mg, 1.38 mmol) was added, and the reaction was stirred for 2 hours. The pH was adjusted to 9-10 by adding aqueous ammonia, extracted with dichloromethane (50 mL×3), and organic The mixture was washed with saturated brine (50 mL EtOAc) (EtOAcjjjjjjjj -8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7 ,8-tetrahydro-acridin-2-ylamino)-N-(((3ai?,5 & 6a5)-2-methyl-octahydro-cyclopenta[ _C ]pyrrole-5-yl)-- 3-methoxy-benzamide 3 (120 mg, white solid), Yield: 46.5 %.

MS m/z (ESI): 562.5 [M+1]

'H NMR (400MHz, CDCl _3; ppm) 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 (m, 1H), 6.17-6.2 (m, 1H), 4.5-4.54 (m, 1H), 4.2-4.23 (m, 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 (m, 2H), 0.81-0.92 (t, 3H) Example 4

4-[(7?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((T3ai?,5 & 6a V5- )-methyl)-3-methoxy-benzene

First

(3a7?,6a5 spiro[l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,2'-oxirane]-2-carboxylic acid tert-butyl ester under nitrogen atmosphere , under ice bath, dissolve trimethyl iodide (293 mg, 〗〖33 mmol) and sodium hydride (60 mg, 1.46 mmol) in 2 mL of dimethyl sulfoxide, stir for 1 hour, add 2 mL 5 a solution of ketone-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 2d 0.3 g, 1.33 mmol) in dimethyl sulfoxide, stirred for 10 minutes, and stirred at room temperature for 12 hours. After adding 20 mL of ice water, and extracting with ethyl acetate (50 niLx3), the organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting residue was purified by Detachment System B to give the title product (3a?,6a-spiro[l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,2'-epoxy tert-Butyl 4-carboxylic acid tert-butyl ester 4 _a (200 mg, colorless oil), yield: 63% MS m/z (ESI): 262.3 [M+23]

Second

(3ai?,6aS 5-(amino-methyl)-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester

(3a ?,6a5)-spiro [l,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,2'-oxirane]-2-carboxylic acid tert-butyl ester

4a (0.3 g, 1.3 mmol) was dissolved in 30 mL of ethanol, an excess of aqueous ammonia was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title product (3a?, 6a5 5-(amino-methyl)-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 4b (yellow oil) ), used directly in the next step.

Second step

(3a ?,6aS)-5-{ [4-((i -8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-indole) (pyridine-2-yl-amino)-3-methoxy-benzamide]-methyl}-5-hydroxy-hexahydro-cyclopenta[C]pyrrole-2-carboxylic acid tert-butyl ester (3a 6aS -5-(aminomethyl)-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 4b (193 mg, 0.75 mmol), (i?)-7-ethyl - 8-Cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridin-6-one lm (320 mg , 0.75 mmol), <-benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea tetrafluoroborate (241 mg, 0.75 mmol) and diisopropylethylamine (213 mg, 1.65 mmol) was dissolved in 40 mL of dichloromethane and stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution and extract with dichloromethane. </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; ^ _; 6aS)-5-{[4-((i)-8-cyclopentyl-indole-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridine -2-yl-amino)-3-methoxy-benzamide]-methyl}-5-hydroxy-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester 4c (0.42 g, White solid), Yield: 84%.

MS m/z (ESI): 664.6 [M+l]

the fourth step

₄ - _(W - ₈ - cyclopentyl - 7-ethyl - _5-methyl _ ₆ _ - _ _oxo-5, _6, _7, ₈ - tetrahydro - Noise piperidin _{- 2} - yl - amino) - _N - ( ( ₍ 3ai?, 6aS)-5-Hydroxy-octahydro-cyclopenta[ _C ]pyrrole-5-yl)-methyl)-3-methoxy-benzamide

Will (3ai?,6aS)-5-{[4-((i?)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetra Hydrogen-acridin-2-yl-amino)-3-methoxy-benzamide]-methyl}-5-hydroxy-hexahydro-cyclopenta[C]pyrrole-2-carboxylic acid tert-butyl ester 4c (420 mg, 0.63 mol) was dissolved in 20 mL of dichloromethane, and 20 mL of 6 M hydrogen chloride in 1,4-dioxane solution was added. The reaction was stirred for 0.5 hours, and ammonia water was added dropwise until the pH of the reaction solution was 8-9. The title compound 4-((-8-cyclopentyl) was obtained by the titled product (yield: -8-cyclopentyl). -7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-amino)-indole-(((3 6Β5 5-hydroxy-octahydro) -cyclopenta[c]pyrrole-5-yl)-methyl)-3-methoxy-benzamide 4 (1 (0.32 g, white solid), yield: 90%. .

MS m/z (ESI): 564.5 [M+l]

Fifth

4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-ammonia

-N-(((3ai?,5 & 6a)-5-hydroxy-2-methyl-octahydro-cyclopenta[C]pyrrole-5-yl)-methyl)-3-methoxy - Benzene.

Amide

4-((i?)- 8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-amino) -N-(((3 _a i?,6aS 5-hydroxy-octahydro-cyclopenta[C]pyrrole-5-yl)-methyl)-3-methoxy-benzamide 4d (318 mg, 0.56 mol) dissolved in 60 mL of mixed solvent of dichloromethane and water (V: V = 1 : 1), added with formaldehyde (34 mg, 1.13 mmol) and two drops of acetic acid. After stirring for 0.5 hour, triacetoxy was added. Sodium borohydride (358 mg, 1.69 mmol), and stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with dichloromethane (50 mL×3), and the organic phase is washed with saturated brine (50 mL×3). The residue was dried over anhydrous magnesium sulfate (MgSO4). -5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-amino)-N-(((3a ?,5 & 6aS)-5-hydroxy-2 Methyl-octahydro-cyclopenta[c]pyrrole-5-yl)-methyl)-3-methoxy-benzamide 4 (110 mg, white solid), yield: 34%.

MS m/z (ESI): 578.5 [M+l]

'H NMR (400MHz, CDC1 ₃ , 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 (m, 3H), 1.66-1.90 (m, 10H), 0.89-0.94 (t, 3H) Example 5

_4- _{^) - 8} - cyclopentyl - 7-ethyl - _5-Methyl -6-- _oxo-5, _6, 7, ₈ - tetrahydro - pteridin - _amino-2-yl) -N-ffl3aW, 5 Where 6a6V5-hydroxy-2-methyl-octahydro-cyclopenta Wpyrrole-5-yl)-methyl)-3-methoxy-benzene

First step

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-amino) - N-(((3ai?,5 6a^-5-hydroxy-2-methylhydro-cyclopenta Mpyrrole-5-yl)-methyl)-3-methoxy-benzene

. Formamide

4-((i?)-8-Cyclopentyl-indole-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-amino) -N-(((3ai?,6aS 5-hydroxy-octahydro-cyclopenta[C]pyrrole-5-yl)-methyl)-3-methoxy-benzamide 4d (318 mg, 0.56 mol) Dissolved in 60 mL of a mixed solvent of dichloromethane and water (V: V = 1 : 1), adding formaldehyde (34 mg, 1.13 mmol) and two drops of acetic acid, stirring for 0.5 hour, adding triacetoxy boron Sodium hydride (358 mg, 1.69 mmol), and stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with dichloromethane (50 mL×3), and the organic phase washed with saturated brine (50 mL×3) The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting -methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl-amino)-N-(((3a/?,5 6aS)-5-hydroxy-2-methyl Base-octahydro-cyclopenta[ _C ]pyrrole-5-yl)-methyl)-3-methoxy-benzamide 5 (80 mg, white solid), yield: 25 %.

MS m/z (ESI): 578.5 [M+l]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 8.59-8.62 (d, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.48-7.49 (s, 1H), 7.32-7.33 (d, 1H ), 6.62-6.64 (m, 2H), 4.56~4.58 (m, 1H), 4.25-4.28 (m, 1H), 4.02 (s, 3H), 3.71-3.72 (d, 2H), 3.35 (s, 1H) ), 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), 1.71-1.93 (m , 11H), 0.89-0.91 (t, 3H) Example 6

4-(W)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N- ( 1-methyl-piperidine -4-yl)-3-(tetrahydro-furan-3-yl-methoxy)-benzamide

First

3-light base -4-nitro-benzoic acid methyl ester

3-Hydroxy-4-nitro-benzoic acid 6a (3.172 g, 17.32 mmol) was dissolved in 40 mL of anhydrous methanol under nitrogen atmosphere, and thionyl chloride (3.09 g, 25.98 mmol) was added dropwise and stirred under reflux. 2 hours. The reaction mixture was concentrated under reduced pressure ethyl acetate (EtOAc (EtOAc) (EtOAcjjjjjjj Concentration by pressure gave the title product 3-hydroxy-4-nitro-benzoic acid methyl ester 6b (3.304 g, yellow solid), yield: 96.7%.

MS m/z (ESI): 195.8 [M-l]

Second step

4-Nitro-3-(tetrahydro-furan-3-yl-methoxy)-benzoic acid methyl ester. Dissolve triphenylphosphine (576 mg, 2.2 mmol) in 10 mL under a dry ice bath. In anhydrous tetrahydrofuran, 10 mL of diethyl azodicarboxylate (382 mg, 2.2 mmol) in tetrahydrofuran was added dropwise. After stirring for 30 minutes, 5 mL of 3-hydroxy-4-nitro-benzoic acid methyl ester was added dropwise. 6b (300 mg, 1.52 mmol) in tetrahydrofuran, the reaction was stirred for 1.5 min, then (tetrahydro-furan-3-yl)-methanol (150 mg, 1.46 mmol). The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjli Ester 6c (306 mg, white solid), Yield: 74.4%.

third step 4-nitro-3-(tetrahydro-furan-3-yl-methoxy)-benzoic acid

Dissolve 4-nitro-3-(tetrahydro-furan-3-yl-methoxy)-benzoic acid methyl ester 6e (240 mg, 0.85 mrnol) in 5 mL of methanol, add 0 mL 1 M NaOH A solution of lithium in tetrahydrofuran was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane (50 mL), EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Drying over anhydrous magnesium sulfate, EtOAc (EtOAc m.jjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , Yield: 75.4%.

MS m/z (ESI): 265.9 [M-l ]

the fourth step

N-(l-methyl-(c-pyridin-4-yl)-4-nitro-3-(tetrahydro-furan-3-yl-methoxy)-benzamide 4-nitro-3- (tetrahydro-furan-3-yl-methoxy)-benzoic acid 6d (170 mg, 0.67 mmol), 1-methyl-piperidine-4-yl-amine (77 mg, 0.67 mmol), 0-benzene And triazole-oxime, hydrazine, hydrazine, Ν'-tetramethyluronium tetrafluoroborate (215 mg, 0.67 mmol) and diisopropylethylamine (25 μg, 1.47 mmol) dissolved in 40 mL In dichloromethane, the reaction was stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution, extract with dichloromethane (50 mL×3), and the organic phase was washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure. Hydrogen-furan-3-yl-methoxy)-benzamide 6e (0.22 g, pale yellow solid), yield: 94%.

MS m/z (ES1): 364.3 [M+l]

the fifth step

4-amino-N-(l-methyl-piperidin-4-yl)-3-(tetrahydro-furan-3-yl-methoxy)-benzamide N-(1-methyl-piperidin Pyridin-4-yl)-4-nitro-3-(tetrahydro-furan-3-yl-methoxy)-benzamide 6e (220 mg, 0.61 mmol) was dissolved in 40 mL MeOH. Mg, 10%) palladium on carbon, the reaction was stirred under a hydrogen atmosphere 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-3-yl-methoxy)-benzene Amide 6f (150 mg, white solid), Yield: 73.9%.

MS m/z (ESI): 334.3 [M+l]

Step 6

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N - (1-methyl-piperidine

4-yl)-3-(tetrahydro-furan-3-yl-methoxy)-benzamide 4-amino-N-(1-methyl-piperidin-4-yl)-3-( Tetrahydro-furan-3-yl-methoxy)-benzamide 6f (150 mg, 0.45 mmol), (i?)-7-ethyl-2-chloro- 8-cyclopentyl- 5-methyl -7,8-Dihydro-5H-acridin-6-one lj (132 mg, 0.45 mmol) and p-toluenesulfonic acid (137 mg, 0.72 mmol) were dissolved in 20 mL of 4-methyl-2-pentanol The reaction was stirred under reflux for 2 hours. Add saturated sodium bicarbonate solution to the pH of the reaction solution is 8~9, extract with methylene chloride (50 mL×3), combine the organic phase, wash with saturated brine (50 mL×3), dry over anhydrous magnesium sulfate, filter, filtrate The mixture was concentrated under reduced pressure. -5,6,7,8-tetrahydro-acridin-2-ylamino)-N-(l-methyl-piperidine 4-yl)-3-(tetrahydro-furan-3-yl-methoxy)-benzamide 6 (0.08 g, white solid), yield: 303. MS m/z (ES1): 592.5 [M+l]

NMR NMR (400MHz, CDC) ₃ , ppm) δ 8.10 (d, IH), 7.70 (s, IH), 7.50 (s, IH), 7.39 (s, 1H), 7.25~7.27 (s, IH), 5.98 -6 (d, IH), 4.37-4.47 (m, II- I), 4.19-4.21 (m, IH), 3.74-4.13 (m 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 (m, IH), 0.86-0.90 (t, 3H) Example 7

4-(0 -8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-(l -methyl-piperidine

4-yl)-3-furan-2-yl-methoxy)-benzamide

First step

4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzoic acid methyl ester. Dissolve triphenylphosphine (694 mg, 2.65 mmol) in 20 mL under a dry ice bath. In anhydrous tetrahydrofuran, 10 mL of diethyl azodicarboxylate (461 mg, 2.65 mmol) in tetrahydrofuran and 10 mL of 3-hydroxy-4-nitro-benzoic acid methyl ester 6b (348 mg, 1.77 mmol) were added dropwise. A tetrahydrofuran solution was stirred for 10 minutes, and a solution of 5 mL of (tetrahydro-furan-2-yl)-methanol (198 mg, 1.94 mmol) in tetrahydrofuran was added, and the reaction was stirred for 30 minutes, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified tolulululululululululululululululululululululululululululululu Ester 7a (317 mg, yellow solid), Yield: 64%.

MS m/z (ESI): 282.1 [M+l]

Second step

4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzoic acid Dissolve 4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzoic acid methyl ester 7a (317 mg, 1.1 mmol) in 30 mL of methanol and add 20 mh of M hydrogen A solution of lithium oxide (370 mg, 6.6 mniol) in tetrahydrofuran was stirred for 2 hours. Add 10 mL of water, extract with dichloromethane (50 mL:), add 1 M hydrochloric acid to the aqueous phase pH 3~4, extract with ethyl acetate (50 mL×3), combine with organic phase, wash with saturated brine (50 mL) The organic layer was dried over anhydrous magnesium sulfate, filtered, and then evaporated tolululululululululululululululululululululululululululululululu ), Yield: 99%. Used directly in the next reaction.

third step . .

N-(l-methyl-piperidin-4-yl)-4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzamide 4-nitro-3- ( : tetrahydro-furan-2-yl-methoxy)-benzoic acid 7b 290 m _g , 1.1 mmol), 1-methyl-piperidin-4-yl-amine (125 mg, 1.1 mmol), < -benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea tetrafluoroborate (353 mg, 1.1 13⁄413⁄401) and diisopropylethylamine (313 mg, 2.42 mmol) dissolved in 40 The reaction was stirred for 2 hours in mL dichloromethane. After adding 30 mL of saturated sodium hydrogencarbonate solution, the mixture was extracted with dichloromethane (50 mL×3), and the organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, Chromatography of the residue obtained in eluent B to give the title product N-(]-methyl-piperidin-4-yl)-4-nitro-3-(tetrahydro-furan-2-yl-methyl Oxy)benzamide 7c (0.35 g, pale yellow solid), yield: 87.5

MS m/z (ESI): 364.3 [M+l]

the fourth step

4-amino-N-(1-methyl-piperidin-4-yl)-3-(tetrahydro-furan-2-yl-methoxy)-benzamide N-(1-methyl-piperidin Pyridin-4-yl)- 4-nitro-3-(tetrahydro-furan-2-yl-methoxy)-benzamide 7c (422 mg, 1. ] 6 1^^01) dissolved in 40 0 ^Methanol, (50 ^ 3⁄4, ] 0%) palladium/carbon was added, and the reaction was stirred for 12 hours under a hydrogen atmosphere. 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)-benzamide 7d (307 nig, white solid), Yield: 79%.

MS m/z (ESI): 334.3 [M+l]

the fifth step

W is) - ₈ - cyclopentyl-7-ethyl _--5 _-6-oxo - _5, _6, _7, ₈ - tetrahydro - pteridin-2-ylamino) - _N - ₍₁ - A Base-piperidine

-4-yl)-3-(tetrahydro-furan-2-yl-methoxy)-benzamide 4-amino-N-(1-methyl-piperidin-4-yl)-3-( Tetrahydro-furan-2-yl-methoxy)-benzamide 7d (150 mg, 0.45 mmol), ((i?)-7-ethyl-2-chloro-8-cyclopentyl-5-- Base-7,8-dihydro-5H-acridin-6-one lj (] 33 mg, 0.45 mmol) and p-toluenesulfonic acid (137 mg, 0.72 mmol) dissolved in 20 mL of 4-methyl-2-pentyl In the alcohol, the reaction was stirred for 3 hours under reflux. The saturated sodium carbonate solution was added dropwise until the pH of the reaction mixture was 9 to 10, extracted with dichloromethane (50 mL×3), and the organic phase was combined, washed with saturated brine (50 mL×3), anhydrous sulfuric acid The magnesium was dried, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjj -oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-(methyl-piperidin-4-yl)-3-(tetrahydro-furan-2-yl- Methoxy)-benzamide 7 (0.12 g, white solid), Yield: 45 %. MS m/z (ESI): 592.5 [M+l]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 8.57~8.59 (d, 1H), 7.70-7.72 (d, 2H), 7.46 (s, 1H), 7.30 (s, IH), 5.94-6.03 (d, IH), 4.41-4.50 (m, IH), 4.32-4.38 (m, IH), 4.1 8-4.23 (m, IH), 4.13-4.16 (m, 2H): 3.94-4.03 (m, 2H), 3.80-3.90 (m, IH), 3.86 (s, 3H), 2.83-2.93 (d, 2H), 2.39 (s, 3H), 2.21-2.32 (t, 2B), 1.96-2.18 (m, 7H), 1.65-1.94 (m, 11H), 0.86-0.90 (t, 3H) Example 8

4-(W)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-( T4a ?,6 7 y)-2-methyl-octahydro-1H-cyclohexanyl Wpyridine-6-yl 3-methoxy-benzamide 8-1

4- _{(R) -8} - cyclopentyl - ₇ - _ethyl-6 - oxo - _5, _6, _7, ₈ - tetrahydro - pteridine _ ₂ - ylamino) -N - ((4a, 6 & 7ai?)-2-methyl-octahydro-1H-cyclohexane klpyridine-6-yl)-3-methoxy-benzamide 8-2

First step

(3aS,6a5)-2,5-dione-octahydro-cyclopentadienyl-1,3,4,6-tetracarboxylic acid tetramethyl ester, ice bath, sodium hydroxide (6.4 g, 0.16 Mol) was dissolved in 115 mL of methanol, and dimethyl 1,3-dicarboxylate-acetone (22.6 mL, 0.16 mol) was added dropwise, and the mixture was heated to reflux until the salt was completely dissolved. Ethyl 2a (12.85) was quickly added dropwise at 65 °C. g, 0.088 mol), cooled to room temperature, stirred for 12 hours, filtered, washed with filter cake with 50 mL of methanol, dissolved in 180 mL of mixed solvent of dichloromethane and water (V:V=5:4) , 1 M hydrochloric acid was added dropwise to the reaction solution, and the pH of the reaction solution was 6 and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate Concentration by pressure gave the title product (3aS, 6aS)-2,5- Dioxo-octahydro-cyclopentadienyl-], 3,4,6-tetracarboxylic acid tetramethyl ester 8b (20 g, white solid), Yield: 61 MS m/z (ESI): 371.3 [M+l]

Second step

Cis-tetrahydro-cyclopentadiene -2,5-dione

(3aS,6a5 2,5-dioxo-octahydro-cyclopentadienyl-1,3,4,6-tetracarboxylic acid tetramethyl ester 8b (6.75 g, 0.018 mol) was dissolved in 3.3 mL of acetic acid 30 mL of 1 M hydrochloric acid was added, and the reaction was stirred for 3.5 hours under reflux. The mixture was cooled to room temperature, extracted with dichloromethane (50 mL×3), and the organic phase was combined and evaporated. Saturated sodium hydrogen carbonate 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 (3a & 6a5)-tetrahydro-cyclopentadiene-2,5-dione 8c ( 2 g, white solid), Yield: 80%.

Third

(4a/,7a^)-tetrahydro-1H-cyclopenta[c]pyridine-3,6-dione 8d-l

(4a5,7aS tetrahydro-] H-cyclopenta[c]pyridine-3,6-dione 8d-2, (3a5,6aS)-tetrahydro-cyclopentadiene-2,5 -Dione 8c (1.8 g, 13 mmol) was dissolved in 25 mL of concentrated hydrochloric acid, sodium azide (1.1 g, 16.9 mmol) was added portionwise, and the reaction was stirred at room temperature for 24 hours. 20% sodium hydroxide solution was added dropwise. The pH of the reaction mixture was 10~11, and the mixture was extracted with dichloromethane (50 mL×3), and the organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate and filtered. The residue obtained was purified by eluent system C to give the title product (4 _a 7a -tetrahydrocyclopenta[c]pyridine-3,6-dione 8d-1 and Wa^JaS)-tetrahydro-1H-cyclopentane And [c] a mixture of pyridine-3,6-dione 8d-2 (3 g, white solid), yield: 100%.

MS m/z (ESI): 154.1 [M+l]

the fourth step

(4a?,7ai?)-hexahydrospiro [cyclopenta[c]pyridine-6,2'-[1,3]dioxolane]-3(4H)-one 8c-l

(4a^,7a5 hexahydrospiro [cyclopenta[c]pyridine-6,2'-[1,3]dioxolan]-3(4H)-one 8e-2

(4a?, 7ai?)-tetrahydro-1H-cyclopenta[c]pyridine-3,6-dione 8d-l and (4aS,7aS)-tetrahydro-1H-cyclopentane obtained by the above steps a mixture of [c]pyridine-3,6-dione 8d-2 (1.2 g, 7.8 mmol), ethylene glycol (1.34 g, 21.5 mmol) and p-toluenesulfonic acid (24 mg, 0.13 mmol) dissolved in 60 mL The reaction was stirred under reflux for 8 hours in toluene. Add saturated sodium bicarbonate solution until the pH of the reaction solution is about 7, dichloromethane extract (50 mL), and the aqueous phase is further extracted with dichloromethane (50 mL×3), and the organic phase is combined, washed with saturated brine (50 mL×3), The title compound (4aW, 7ai?)-hexahydrospiro[cyclopenta[c]pyridine- was obtained as the title product (4aW, 7ai?)- 6,2'-[1 ,3]dioxolan]-3(4H)-one 8e-l and (4a5,7aS hexahydrospiro[cyclopenta[c]pyridine-6,2'-[1, 3] Mixture of dioxolane]-3(4H)-one 8e-2 (U g, white solid), Yield: 70%.

MS m/z (ESI): 198.1 [M+l]

the fifth step (4a7?,7ai?)-octahydrospiro[cyclopenta[c]pyridine-6,2'-[l,3]dioxolan]8f-l

(4a&7a-octahydrospiro[cyclopenta[c|pyridine-6,2'-[],3]dioxolane] 8f-2 under an argon atmosphere, lithium aluminum hydride (47 mg, 1.27) Ramoj) is dissolved in 10 mL of tetrahydrofuran, and added to the above step to obtain 0 mL (4a7?,7a/?)-hexahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3] Oxyvalonium] -3(4H)-one 8c-l and (435,7^5)-hexahydrospiro[cyclopenta-jc]pyridine-6,2'-[U]dioxolane]_3(4H A mixture of ketone 8e-2 (020 mg, 0.6 mmol) in tetrahydrofuran was stirred for 1 hour. Add 0.047 L of water, 0.047 15 % sodium hydroxide solution, extract with dichloromethane (50 mL><3), combine with organic phase, wash with saturated brine (50 mL×3), dry over anhydrous magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded the title product (4a^,7ai?)- octahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolan] 8f-l and (4a5,7a5 octahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolan] 8f-2 mixture (] 50 mg, oil), yield: 95 % Directly invest in the next reaction.

, .

J3⁄4 eight steps

(4aS,7ai-hexahydrospiro[cyclopenta Mpyridine-6,2'-[1,3]dioxolane]-2 (1H>tert-butyl carboxylate 8 _g -l (4a/?, 7a Hexahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolane]-2(]H)-carboxylic acid tert-butyl ester 8g-2 in ice water bath, the above steps The resulting (4ai?,7a^)-octahydrospiro[cyclopenta[ _C ]pyridine-6,2'-[1,3]dioxolane 8f-l and (4aS,7aS octahydrospiro[ring A mixture of pentato[c]pyridine-6,2'-[1 ,3]dioxolan] 8f-2 (100 mg, 0.54 mmol) was dissolved in 15 mL of dichloromethane and then triethylamine (109) Mg, 1.08 mmol) and 5 mL of di-tert-butyl dicarbonate (130 mg, 0.6 mmol) in methylene chloride solution, stirring for 2 hours. Add saturated sodium bicarbonate solution until the pH of the reaction solution is 8~9. Dichloromethane extract (50 mL×3), combined with organic phase, washed with brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system C To give the title product (4a^7ai?)-hexahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolan]- 2(1H)-carboxylic acid tert-butyl ester 8g-l and (4a/?,7a5 hexahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolane a mixture of tert-butyl carboxylate 8 _g -2 (100 mg, colorless oil), yield: 66%.

Seventh step

(4aS,7aT-6-oxo-hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8h-l

(4aS,7ai?)-6-oxo-hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8h-2

(4aS,7ai?)-hexahydrospiro[cyclopenta-Wpyridine-6,2'-[1,3]dioxolan]-2(1H)-carboxylic acid tert-butyl ester 8g obtained from the above procedure - a mixture of l and (4a?,7aS hexahydrospiro[cyclopenta[c]pyridine-6,2'-[1,3]dioxolan]-2(1H)-carboxylic acid tert-butyl ester 8g-2 (620 mg, 2.2 mmol) was dissolved in 50 mL of acetone, and 20 mL of p-toluenesulfonic acid (200 mg, 1.1 mmol) in acetone was added, and the reaction was stirred for 20 minutes under reflux. Saturated sodium bicarbonate solution was added dropwise until the pH of the reaction mixture was 8~9, extraction with methylene chloride (50 mL×3), EtOAc (EtOAc) (EtOAc) The resulting residue was purified to give the title product (4a5, 7ai?)-6-oxo-hexahydro-1H-cyclopenta[c]pyridine-2 (3H>carboxylic acid tert-butyl ester 8h-l and (4a5, 7a7?)-6-oxo-hexahydro-] a mixture of H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8h-2 (450 mg, colorless oil), yield : 85 %. NMR NMR (400MHz, CDC1 ₃ , ppra) δ 3.7 3.82 (in, 2H), 3.25 3.29 (d, 1 H), 2.9 3.0] (m, 1H), 2.32-2.40 (m, 4H), 2.08-2.18 ( m, 2H), 1.69-1 .71 (m, 1 H), 1.46-1.66 (s, 9H), 1.27 1.37 (m, 1 H)

Eighth

(4a,67i,7ai?)-6-methanesulfonyl-hexahydro-IH-cyclopenta[c]pyridine-2(3/i)-tert-butyl terephthalate 8j-l

(4ai?,6 & 73^-6-methanesulfonyl-hexahydro-] H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8j-2 (4a5 obtained by the above procedure , 7a/?)-6-oxo-hexahydrocyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8h (22 mg 0.096 mmol) was dissolved in 10 mL of tetrahydrofuran, sodium borohydride was added ( 10 mg 0.14 mmol), the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 20 dichloromethane solution, and triethylamine (40 μί, 0.29 1 ol) and methanesulfonyl chloride (20 \ih, 0.14) The reaction was stirred for 2 hours. The mixture was stirred and dried over anhydrous magnesium sulfate (MgSO4). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified to silica gel elute Pyridine-2(3H)-carboxylic acid tert-butyl ester 8j-1 and (4a 6 & 7aS)-6-methanesulfonyl-hexahydro-] H-cyclopenta Mpyridine-2(3H)-carboxylic acid Mixture of butyl ester 8j-2 (28 mg, colorless oil), Yield: 98

^, H NMR (400MHz, CDC1 ₃ , ppm) δ 5.12-5.18 (m, 1H), 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

(4a 6 7aS 6-azido-hexahydro-1H-cyclopenta[c]pyridine-2 (3H>tert-butyl carboxylate 8k-l

(4aS,6 & 7a^-6-azido-hexahydro-1H-cyclopenta Mpyridine-2(3H)-carboxylic acid tert-butyl ester 8k-2 (4aS 6 ?, 7aW) obtained by the above procedure -6-methanesulfonyl-hexahydro-1H-cyclopenta[c]pyridine-2 (3/-tert-butyl carboxylate 8j-l and (4a/?,6 & 7aS)-6-methanesulfonyl- A mixture of hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8j-2 (32 mg 0.1 mmol) was dissolved in 10 mL of N,N'-dimethylformamide. Slowly add sodium azide (20 mg 0.25 mmol), and stir the reaction at 70 ° C for 3.5 hours. Add saturated sodium bicarbonate solution to the reaction solution at pH 7.8, extract with dichloromethane (50 mL×3), and combine organic The mixture was washed with saturated brine (50 mL EtOAc) (EtOAcjjjjjj -6-azido-hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8k-l and (4a5,6 & 7ai?)-6-azido-six Hydrogen-] a mixture of H-cyclopenta[c]pyridine-2(3/)-carboxylic acid tert-butyl ester 8k-2 (40 mg, colorless oil), yield: 100%

1H NMR (400MHz, CDC1 ₃ , ppm) δ 4.05-4.08 (m, 1 Η), 3.56-3.61 (m, 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

(4ai?,6i?,7aS 6-amino-hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8m-l

(4a5 6S,7a ?)-6-Amino-hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8m-2 (4ai?,6 7a5)-6-azido-hexahydro-]cyclopenta[c]pyridine-2 (3H>tert-butyl carboxylate 8k-l and (4a&6 & 7ai?) obtained by the above procedure a mixture of -6-azido-hexahydro-]H-cyclopenta[ _C ]pyridine-2(3H)-carboxylic acid tert-butyl ester 8k-2 (30 mg, 0.] 1 mmol) dissolved in 2 In a solution of methanol (20 mg, 10%), palladium/carbon was added, and the reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure to give the title product (4a 6 7aS 6 -amino-hexahydrocyclopenta Mpyridine -2(3H)-tert-butyl carboxylic acid 8m-1 and (4a&6 & 7ai?)-6-amino-hexahydro-1H-cyclopenta Mpyridine-2 (3H>tert-butyl carboxylate 8m-2 Mixture (28 mg, light yellow oil), Yield: 100 %

MS m/z (ESI): 242.1 [M+1]

The eleventh step

(4a/?,6i?,7aS 6-[4-((7?)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8- Tetrahydro-acridine-2-ylamino)]-Hexahydrocyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8 _n -l (4aS,6 & 7ai?)-6-[4 - (((;?)- 8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)] - Hexahydro-1H-cyclopenta Mpyridine-2(3//)-carboxylic acid tert-butyl ester 8n-2 (4 _a 6 ?,7a )-6-amino-hexahydro-1H- Cyclopenta[ _C ]pyridine-2(3H)-carboxylic acid tert-butyl ester 8m-1 and (4a5,6S,7ai?)-6-amino-hexahydro-1H-cyclopenta[ _C ]pyridine-2 ( a mixture of 3H)-tert-butyl carboxylic acid 8m-2 (28 mg, 0.12 mmol), ((i?)-7-ethyl-8-cyclopentyl-2-(3-methoxy------- 4-yl-amino)-5-methyl-7,8-dihydro-5H-acridin-6-one lm (50 mg, 0.12 mmol), Obenzotriazole-oxime, oxime, Ν', Ν'- Tetramethylurea tetrafluoroborate (40 mg, 0.12 mmol) and diisopropylethylamine (30 mg, 0.23 mmol) were dissolved in 12 mL of dichloromethane and stirred for 2 hours. Sodium carbonate solution until the pH of the reaction solution is 8~9, extracted with dichloromethane (50 mL×3), combined with organic phase, washed with saturated brine (50 mL×3), anhydrous sulfuric acid Drying, filtration, and concentrating the filtrate under reduced pressure. EtOAc m. Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)]-hexahydrocyclopenta[ _C ]pyridine- 2(3H)-tert-butyl carboxylic acid 8n-l and (4aS 6 & 7ai?)-6-[4-((i?)-8-cyclopentyl-7-ethyl-5-methyl- 6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)]-hexahydrocyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 811-2 Mixture (36 mg, white solid), Yield: 50%.

MS m/z (ESI): 648.6 [M+1]

Step 12

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((4a/?,6van 7a3⁄4-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 8o-l

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((4a5,6 & 7ai?)-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 8o-2 (4&6?,735)- 6-[4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl) Amino)]-hexahydrocyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl quinone 8n-l and (4aS,6S,7aR)-6-[4-(((R)-S- ring Pentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)]-hexahydro-1H-cyclopenta[c] Mixture of pyridine-2(3H)-carboxylic acid tert-butyl ester 8n-2 (50 mg, 0.077 mmol) Dissolve in 5 mL of dichloromethane, add 4 mL of 6 M hydrogen chloride in a solution of 4-dioxane, and stir the reaction for an hour. The reaction solution was concentrated under reduced pressure to give the title product 4-(((-(-)-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridine- 2-ylamino)-N-((4a 6 7a octahydro-1J7-cyclopenta[c]pyridine-6-yl)-3-methoxy-benzamide 80-1 and 4-(((7) ?)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-((4aS, 6 & 7a - a mixture of octahydro-1 cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 8o-2 (80 mg, white solid), yield: 00%. Directly invest in the next step.

Step 13

_{4- (W-8} - cyclopentyl-7-ethyl _--5-- methyl - ₆ - _oxo-5, _6, _7, ₈ - tetrahydro - pteridin-2-ylamino) -N - (( 4ai?,6 7aS 2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 8-1

4-((- 8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2- _ylchloro )- _{Ν-( (} 4;6&7^)- 2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 8-2 Under ice bath, 4-(( ((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N- ( (4a7?,6i?,7aS octahydro-1H-cyclopenta[ _C ]pyridine-6-yl)-3-methoxy-benzamide 8o-l and 4-(((7?)-8 -cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-((4aS,6 & 7ai? a mixture of octahydrocyclopenta[ _C ]pyridin-6-yl)-3-methoxy-benzamide 8o-2 (80 mg, 0.15 mmol) dissolved in 0 mL of dichloromethane and acetonitrile (V) A mixture of :V = 1:1), 37% formaldehyde solution (0.023 mL, 0.29 mmol) and sodium triacetoxyborohydride (100 mg, 0.45 mmol) were added, and the reaction was stirred at room temperature for 2 hours. The sodium carbonate solution was added to the reaction solution at a pH of 8 to 9 and extracted with dichloromethane (50 mL×3). The organic phase was combined, washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate Purification by eluent system A on silica gel column chromatography The residue obtained gave the title product 4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridine- 2-ylamino)-N-((4a^,6i?,7aS-2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 8-1 and 4-((R)-S-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino )-N-((4aS,6 & 7a/?)-2-methyl-octahydro-1H-cyclopenta[ _C ]pyridin-6-yl)-3-methoxy-benzamide 8-2 Mixture (30 mg, white solid), Yield: 37%.

MS m/z (ESI): 562.5 [M+l]

1H NMR (400MHz, CDC1 ₃ , 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, 1 H), 4.20-4.23 (m, 1 H), 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-((?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N- (Y( i?,8aS)-hexahydro-pyrrolo-r2J-c|"l,41oxazin-3-yl)-methyl)-3-methoxy-benzamide

The first step

(3 & 8a )-hexahydro-pyrrolo[2,lc][l,4]oxazine-3-nitrile under argon ((5 pyrrolein-2-yl-methanol 9a (1.29 g, 12.7 mmol) Dissolved in 120 mL of tetrahydrofuran, added 2-chloro-acrylonitrile (1.11 g, 12.7 mmol) and potassium t-butoxide (2.14 g, 19.06 mmol), and stirred for 0 min. The ethyl acetate was washed with a saturated aqueous solution of sodium bicarbonate (30 mL) and brine (30 mL). The obtained residue was purified to purified crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

MS m/z (ESI): 153.1 [M+1]

Second step

((3&8a5)-hexahydro41 pyrrolo[2J- _C ][],4]oxazin-3-yl)-methylamine (3 & 8aS hexahydro-pyrrolo[2,1 - _C ][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 Raney nickel (0.5 g) were added, and the reaction was stirred for 18 hours under a hydrogen atmosphere. Concentration, the title product ((3&8a5)-hexahydro-pyrrolo[2,1- _C ][1,4]oxazin-3-yl)-methylamine 9c (200 mg, colorless oil) : 50%.

MS m/z (ESI): 157.2 [M+1]

third step

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((3 8aS)-hexahydro-pyrrolo[2,1- _C ][1,4]oxazol-3-yl)-methyl)-3-methoxy-benzamide ((3&8a5) )-Hexahydro-pyrrolo[2,lc][l,4]oxazin-3-yl)-methylamine 9c (43 mg, 0.28 mmol) was dissolved in 60 mL of dichloromethane and added ((i? )-7-ethyl-8-cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-amino)- 5-methyl-7,8-dihydro-5H-acridine-6 -ketone lm (117 mg, 0.28 mmol), O-benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea tetrafluoroborate (88 mg, 0.28 nimol) and diisopropyl Ethylamine (89 mg, 0.69 mmol), stirred for 2 hours. Add 30 mL of saturated sodium bicarbonate solution and extract with dichloromethane (50 mL×3) The organic phase was washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallised from methylene chloride and hexane to afford title product 4-(( -8- ring Amyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridine-2-ylamino)-N_((3 8aS)-hexahydro-P比和和[2J -c][l,4]ii ;azin-3-yl)-methyl)-3-methoxy-benzamide 9 (76 mg, white solid), yield: 49%.

S m/z (ESI): 564.3 [M+1]

^] Η ΜΗζ (400ΜΗζ, CDC1 ₃ , ppm) 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, lH), 4.58-4.60 (m, 1H), 4.54-4.56 (m, 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 (m, 4H), 1.61~1.74 (m, 4H) ), 0.92-0.98 (t, 3H) Example 10

4-((-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-3-methoxy Base

The first step.

(3a 5 6a5)-5-benzylamine-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester, 5-keto-hexahydro-cyclopenta[c]pyrrole-2 under ice bath - tert-butyl carboxylate 2d (3.37 g, 15 mmol), benzylamine (1.6 g, 15 mmol), acetic acid (0.9 g, 15 mmol) dissolved in 60 mL of dichloromethane, stirred for 0.5 h, added three Sodium acetoxyborohydride (6.4 g, 30 mmol) was stirred at room temperature for 12 hours. Add 50 mL of saturated sodium bicarbonate solution, dichloromethane (150 mL), and wash the organic layer with saturated brine (30) </ RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI></RTI></RTI></RTI><RTIgt; Hydrogen-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester: 10a (4.7 g, white solid), Yield: 00%.

MSm/z (ESI): 317.3 [ +l]

a trip

(3aW,5 6a5)-5-Amino-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3a 5i?, 6aS 5-benzylamine-hexahydro-cyclopenta[c] Pyrrole-2-carboxylic acid tert-butyl ester 10a (4.7 g, 14.8 mmol), acetic acid (lg, 4.8 mmol) was dissolved in 100 mL of methanol, (500 mg, 10%) palladium/carbon was added, and the reaction was stirred under a hydrogen atmosphere. After filtration, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure to give the title product (3A?, 5 6a, 5-amino-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 10b (1.7 g, white solid), yield: 51.5% .

third step

(3a?,5?,6aS 5-benzyloxycarbonylamino-hexahydro-cyclopenta[C]pyrrole-2-carboxylic acid tert-butyl ester (3ai?,5 6∑uS 5-amino-hexahydro- Cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 10b (1.7 g, 7.5 mmol) was dissolved in 60 mL of dichloromethane, benzyloxy acid chloride (1.41 g, 8.26 mmol) and triethylamine ( 1.52 g, 15 mmol), stirring for 3 hours. Add 50 mL of saturated sodium bicarbonate solution, dichloromethane (5 mL), and the organic layer was washed with brine (30 mL×3) Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography eluting to elute to afford the title product (3ai?,5i?,6aS 5-benzyloxycarbonylamino-hexahydro-cyclopenta-M-pyrrole tert-Butyl 2-carboxylate 10c (1.98 g, colorless viscous liquid), Yield: 73.3%.

the fourth step

(3a 5i?, 6a5 (octahydro-cyclopenta[c]pyrrole-5-yl)-carboxylic acid benzyl ester (3ai?,5 6a5 5-benzyloxycarbonylamino-hexahydro-cyclopenta[c ] Pyrrole-2-carboxylic acid tert-butyl ester 10^1.96 g, 5.44 mmol) was dissolved in 10 mL of 1,4-dioxane, and 2N hydrochloric acid (10 μL) was added, and the reaction was stirred at 50 ° C for 2 hours. The solution was added dropwise with 2% sodium hydroxide solution to a solution of EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAcjjjjjjjj (3a 5 6a5 (octahydro-cyclopenta[ _C ]pyrrole-5-yl)-carboxylic acid benzyl ester 10d (635 mg, pale yellow oil), yield: 45%.

MSm/z (ESI): 261.2 [M+l]

the fifth step

3ai?, 5 of 6aSH2-methyl-octahydro-cyclopenta[ _C ]pyrrole-5-yl)-carboxylic acid benzyl ester under ice bath, (3ai?, 5 6aS)-(octahydro-cyclopenta Mpyrrole-5-yl)-carboxylic acid benzyl ester 10d (635 mg, 2.4 mmol) was dissolved in 20 mL of a mixture of acetonitrile and water (V:V=9:1), and then added to a 37% formaldehyde solution (110 mg, 3.66 mmol) and sodium triacetoxyborohydride (1.52 g, 7.2 mmol) were stirred for 2 h. Concentrate the reaction solution under reduced pressure, add 50 mL of saturated sodium bicarbonate solution, dichloromethane extract (100 mL), and the organic layer is saturated. After washing with brine (30 mL×3), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methyl-octahydro-cyclopenta[c]pyrrole-5-yl)-carboxylic acid benzyl ester 10e (559 mg, yellow oil), Yield: 85 %

1

I3⁄4 eight less

(3a 5 6a5 2-methyl-octahydro-cyclopenta[ _C ]pyrrole-5-yl-amine (3a 5i?,6aS (2-methyl-octahydro-cyclopenta[c|pyrrole-5) -Base) - Benzyl phthalate 10e (550 mg 2.0 mmol) was dissolved in 20 mL of methanol, and then added (55 mg of 10%) palladium/carbon, and the mixture was stirred for 1 hour under hydrogen atmosphere. Product (3a/?,5 6 ]-2-methyl-octahydro-cyclopenta[ _C ]pyrrole-5-yl-amine 10f (246 n]g, colorless oil), Yield: 87.9%

MS m/z (ES1): 141.2 [M+1]

Seventh step

4-(((/?)- 8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)- 3-methoxy-N-((3a 5 6aS 2-methyl-octahydro-cyclopenta[c]pyrrole-5-yl)-benzamide ((i -7-ethyl-8-cyclo) Amyl-2-(3-methoxy-benzoic acid-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridin-6-one lra (165 rag, 0.39 mmol) Dissolved in 15 mL of dichloromethane, and added (3a?, 5 of 6aS 2-methyl-octahydro-cyclopenta[c]P than pyr-5-yl-amine 10f (60 mg 0.42 mmol), < -benzotriazole-oxime, oxime, Ν', Ν'- tetramethylurea tetrafluoroborate (135 mg 0.42 mmol) and diisopropylethylamine (15 mg, 1.17 mmol), stirring reaction 2 Chromatography The residue obtained was purified using eluent system A to give the title product 4-((())-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7 8-tetrahydro-acridin-2-ylamino)-3-methoxy-N-((3afan 57?,6aS 2-methyl-octahydro-cyclopenta[c]pyridyl) 5-yl) - benzamide: 10 (47 mg, white solid), yield: 22.1%

MS m/z (ES1): 548.3 [M+l ]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 9.52 (s, 1H), 8.52 8.54 (d, 1H), 7.70 (s, 1H), 7.62 (s: 1 H), 7.57 (s, IH), 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 (m, 12H), 0.88-0.91 (t, 3H) Example 11

4-(W)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-( (4a,6i?,7a/?V2-methyl-octahydro-1H-cyclopenta Wpyridine-6-yl 3-methoxy-benzamide 11-1

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6 7 8-tetrahydro-acridin-2-ylamino) - Ν-( (4 ? 6<$ 7^-2-methyl-octahydro-1H-cyclopenta[c|pyridin-6-yl)-3-methoxy-benzamide 11-2

First step

(4aS,6i?,7ai?)-6-benzylamino-hexahydro-1H-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester

(4a 6 & 7a5)-6-benzylamino-hexahydro-1H-cyclopenta[ _C ]pyridine-2-carboxylate tert-butyl ester 11a-2

Under the ice bath, the (4a5,7ai? 6-oxo-hexahydro-1H-cyclopenta[c]pyridine-2(3//)-carboxylic acid tert-butyl ester obtained in the seventh step of Example 8 was used. 8h a mixture of -l and (4aS", 7ai?)-6-oxo-hexahydro-1H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8h-2 (1.1 g, 4.6 mniol And benzylamine (492 mg, 4.6 nimol) was dissolved in 50 mL of dichloromethane, and acetic acid (276 mg, 4.6 mmol) and sodium triacetoxyborohydride (1.95 g, 9.2 mmol) were added, and the reaction was stirred at room temperature for 12 hours. Add saturated sodium carbonate solution until the pH of the reaction solution is about 9, dichloromethane extract (50 mL×3), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by eluent system A with silica gel column chromatography. The residue obtained gave the title product (4a,6 7a7?)-6-benzylamino-hexahydro-1H-cyclopenta[ _C ]pyridine-2-carboxylic acid tert-butyl ester ll al and (4aW,6S,7aS) Mixture of -6-benzylamino-hexahydrocyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester lla-2 (1.25 g, pale yellow oil), yield: 83%.

MS m/z (ESI): 331.3 [M+1] Second step

(43^,6 7aA)-6-Amino-hexahydro-]H-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester llb-1 (4a/?,6 & 7a5 6-amino-hexahydro -1H-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester llb-2 (4a5,6 7ai?)-6-benzylamino-hexahydro-1H-cyclopenta[c] obtained by the above reaction Pyridine-tert-butyl carboxylic acid ll.a-1 and (4ai?,6 & 7a5)-6-benzylamino-hexahydro-]H-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl The mixture of ester 11a-2 (1.25 g, 3.78 mmol) was dissolved in 20 mL of methanol, and then added (150 mg, 10%) palladium/carbon, and the reaction was stirred for 12 hours under hydrogen atmosphere. The title product (4a5,6 7a/?)-6-amino-hexahydrocyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester llb-1 and (4ai?,6S,7a 6-amino-hexahydro- Mixture of 1 H-cyclopenta[c]pyridine-2-carboxylate tert-butyl ester llb-2 (910 mg, pale yellow oil), yield: 100%.

MS m/z (ESI): 241.2 [M+l]

Third

(4a5,6i?,7aii)-6-benzyloxycarbylamino-hexahydro-1H-cyclopenta[ _C ]pyridine-2-carboxylic acid tert-butyl ester llc-1 (4 ₃ 6 & 735)-6-benzyl Oxycarbylamino-hexahydro-^-cyclopenta[^]pyridin-2-carboxylic acid tert-butyl ester llc-2 (4aS,6 7ai?)-6-amino group obtained in the above step under ice bath Hexahydro-]H-cyclopenta[c]pyridine-2-carboxylate tert-butyl ester llb-1 and (4a 6 & 7aS)-6-amino-hexahydrocyclopenta[c]pyridine-2-carboxylic acid A mixture of tert-butyl ester llb-2 (909 mg, 3.78 mniol) was dissolved in 25 mL of dichloromethane, and triethylamine (763 mg, 7.56 mmol) and benzyl chloroformate (707 mg, 4.16 mmol) were stirred. Reaction for 2 hours. The saturated sodium carbonate solution was added dropwise until the pH of the reaction mixture was 8-9, 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 (4a5, 6 7a / -6-benzyloxycarbylamino-hexahydro-1H-cyclopenta Mpyridine-2-carboxylic acid tert-butyl ester: llc-1 and (4a? , 6 & 7aS)-6-Benzyloxycarbylamino-hexahydro-1 H-cyclopenta[c]pyridine-2-carboxylic acid tert-butyl ester llc-2 mixture (520 mg, colorless oil) , Yield: 37%.

the fourth step

(4a5,6i?,7ai?)-octahydrocyclopenta[c]pyridine-6-yl-carboxylic acid benzyl ester hydrochloride lld-1

(4a/?,6&7aS octahydro-1H-cyclopenta[c]pyridine-6-yl-carboxylic acid benzyl ester hydrochloride lld-2

(4aS,6i?,7 _a i?)-6-benzyloxycarbylamino-hexahydro-1H-cyclopenta[ _C ]pyridine-2-carboxylic acid tert-butyl ester llc-1 obtained by the above procedure (4a 6 & 7α^-6-Benzyloxycarbylamino-hexahydro-1H-cyclopenta[ _C ]pyridine-2-carboxylic acid tert-butyl ester llc-2 mixture (513 mg, 1.37 mmol) dissolved in 6 mL of dichloromethane was added with 6 mL of 6 M hydrogen chloride in 1,4-dioxane, and the reaction was stirred for 30 minutes. Concentration under reduced pressure gave the title product (4S, 6?, 7a?) -1H-cyclopenta[c]pyridin-6-yl-carboxylic acid benzyl ester hydrochloride lld-1 and (4a?,6 & 7aS octahydro-1H-cyclopenta[c]pyridine-6-yl- Mixture of benzyl carboxylate hydrochloride lld-2 (430 mg, white viscous liquid), Yield: 100%, directly to the next step.

MS m/z (ESI): 275.2 [M+l]

the fifth step

(4aS,6 7a -2-methyl-octahydro-1H-cyclopenta[c]pyridine-6-yl-carboxylic acid benzyl ester lle-1

(4a ?,6 & 7a5 2-methyl-octahydrocyclopenta[c]pyridin-6-yl-carboxylic acid benzyl ester lle-2 (4 _a & 67?, 7 _a 7?)-octahydro-1H-cyclopenta[c]pyridine-6-yl-carboxylic acid benzyl ester lld-1 obtained by the above-mentioned reaction under ice-cooling (4a/?,6 & 7aS octahydrocyclopenta[ _C ]pyridine-6-yl-carboxylic acid benzyl ester hydrochloride lld-2 mixture (425 mg, 1.37 mmol) dissolved in 20 mL of acetonitrile and water (V: V = 1: 1), sodium triacetoxyborohydride (871 mg, 4.1 1 mmol) was added, and the reaction was stirred at room temperature for 12 hours. Saturated sodium carbonate solution was added dropwise until the pH of the reaction solution was about 9. The title product (4aS, 6 凡 7ai) was obtained by extraction with methylene chloride (50 mL×3), washed with water (50 mL), brine (30 mL?? ?)-2-methyl-octahydro-1H-cyclopenta[ _C ]pyridin-6-yl-carboxylic acid benzyl ester lle-1 and (4a?,6 &7a5>2-methyl-octahydro-1H a mixture of cyclopentapyridine-6-yl-carboxylic acid benzyl ester lle-2 (374 mg, light yellow oil), yield: 94%, directly to the next.

MS m/z (ESI): 289.2 [M+l]

Step 6

(4a5,6i?,7aW)- 2-methyl-octahydro-1H-cyclopenta[c]pyridine-6-aminollf-1 ( aR,6S aS)-2-methyl-octahydro-1 H -cyclopenta[c]pyridine-6-aminollf-2 (4aS,6i?,7 _a 7?)-2-methyl-octahydro-1H-cyclopenta[c]pyridine obtained in the above step - 6-yl-carboxylic acid benzyl ester lle-1 and (4ai?,6 & 7aS)-2-methyl-octahydro-1H-cyclopenta[c]pyridine-6-yl-carboxylic acid benzyl ester lle-2 The mixture (374 mg, 1.29^11101) was dissolved in 25 mmol of methanol, and then added (50 mg, 10%) palladium/carbon, and the mixture was stirred for 2 hours under hydrogen atmosphere. Filtration and concentration of the filtrate under reduced pressure afforded the title product (4a,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, a mixture of methyl-octahydro-1H-cyclopenta[c]pyridine-6-aminollf-2 (198 mg, white solid), yield: 100%, directly to the next.

MS m/z (ESI): 155.2 [M+l]

Seventh step

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((4a5,6 7ai?)- 2-methyl-octahydro-] H-cyclopenta[c]pyridine-6-yl)-3-methoxy-benzamide 11-1.

4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N - ((4a 6 & 7a5 2-methyl-octahydrocyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 11-2 (4aS,6i?, 7a/ -2-methyl-octahydrocyclopenta[c]pyridine-6-aminollf-1 and (4a/?,6&7a^-2-methyl-octahydro-1H-cyclopenta[c]pyridine a mixture of -6-aminollf-2 (60 mg, 0.39 mmol), ((i?)-7-ethyl-8-cyclopentyl-2-(3-methoxy-benzoic acid-4-yl-) Amino)- 5-methyl-7,8-dihydro-5H-acridine-6-one lm (182 mg, 0.43 mmol), 0-benzotriazole-oxime, oxime, Ν', Ν'- Tetramethyluronium tetrafluoroborate (125 mg, 0.39 mmol) and diisopropylethylamine (150 mg, 1.17 mmol) were dissolved in 20 mL of dichloromethane and stirred for 2 hours. Saturated sodium carbonate was added dropwise. The pH of the solution to the reaction solution is about 9, and it is extracted with dichloromethane (50 mL×3), washed successively with saturated ammonium chloride solution (30 mL), saturated sodium bicarbonate solution (30 mL), saturated brine (30 mL×3) The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4-((i?)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino:) -N-((4aS,6i?,7ai?)-2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 11-1 and 4-((i?)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetra Hydrogen-acridin-2-ylamino)-N-((4ai?,6 & 7a5 2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy- Benzoamide; a mixture of hydrazine-2 (70 mg, white solid, mixture), yield: 32%.

MS m/z (ESI): 562.5 [M+l]

^I H NMR (400MHz, CDC1 ₃ , 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,]H), 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 (ni, 1H), 0.98-1.06 (t , 3H) Example 12

4-07?)- 7-Ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-( T3 where 8aS six

First step

((i?)-2-Isopropylamino-butyric acid methyl ester

(i?) 2-amino-butyric acid methyl ester hydrochloride le (28.78 g, 0.19 mol) was dissolved in 200 mL of dichloromethane, and acetone (11.96 g, 0.21 mol) and sodium acetate (30.76 g) were added. , 0.38 mol), stirred for 5 minutes, sodium triacetoxyborohydride (59.61 g, 0.281 mol) was added, and the reaction was stirred for 12 hours. A small amount of 1 M hydrochloric acid was added, and a saturated sodium carbonate solution was added dropwise until the pH of the reaction mixture was 8 to 9, and the mixture was extracted with dichloromethane (50 mL×3), and the organic phase was combined and washed with brine (30 mL) Filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjj ), Yield: 55 %.

Second step

(i?)-2-[(2-Chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-butyric acid methyl ester 2,4-dichloro-5-nitro-pyrimidine (19.9 g, 103 mmol) dissolved in 300 mL of cyclohexane and added (7?)-2- Isopropylamino-butyric acid methyl ester 12a (16.4 g, 103 mmol) and sodium hydrogencarbonate (36.61 g, 412 mmol) were stirred at 80 ° C for 4 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) Methyl ester 12b (20.5 g, yellow solid), Yield: 62.8 %.

third step

((i?)-7-ethyl-2-chloro-8-isopropyl-7,8-dihydro-5H-acridin-6-one (i?)-2-[(2-chloro- 5-Nitro-pyrimidin-4-yl)-isopropyl-amino]-butyl acid methyl ester 12b (7.3 g, 23 mmol) was dissolved in 100 mL of acetic acid, and excess Lanney nickel was added, under a hydrogen atmosphere, 75 Ό The reaction was stirred for 2 hours. After filtration, the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) 7,8-Dihydro-5H-acridine-6-one 12c (12.1 g, off-white solid), yield: 71.7%.

MS m/z (ESl): 255.1 [M+1]

the fourth step

0??)-7-ethyl-2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-acridin-6-one (i?)-7-ethyl 2-Chloro-8-isopropyl-7,8-dihydro-5H-acridin-6-one 12c (12.1 g, 47.5 mmol) was dissolved in 180 mL of acetone and methyl p-toluenesulfonate (13.28) g, 71.3 mmol) and potassium carbonate (13.11 g, 95 mmol) were stirred for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Chromatography The residue obtained was purified using eluent B to give the title product (-7-ethyl-2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H- a 6-ketone 12d (10.8 g, white solid), Yield: 84.7 %.

the fifth step

(i?)-4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-A Oxyl) - methyl benzoate

Methyl 4-amino-3-methoxy-4-benzoate lc (1.7 g, 9.56 mmol), ((-7-ethyl-2-chloro- 8-isopropyl-5-methyl) -7,8-Dihydro-5H-acridin-6-one 12d (2.4 g, 9.11 mmol) and p-toluenesulfonic acid (2.8 g, 14.57 mmol) were dissolved in 50 mL of 4-methyl-2-pentanol. The reaction mixture was stirred under reflux for 2.5 hours. The reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The organic layer was concentrated under reduced pressure. ,6,7,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzoic acid methyl ester 12e (1.7 g, white solid), yield: 45.5

MS m/z (ESI): 414.3 [M+1]

Step 6

C/?)-4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-A Oxy)) Formic acid

_W _4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-methoxy) - Methyl benzoate 12e (1.7 g, 4.15 mmol) was dissolved in 40 mL of methanol, 45 mL of 1 M lithium hydroxide solution was added, and the reaction was stirred at 8 CTC for 5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAcjjjjjjjj 4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzene Formic acid 12f (2.24 g, white solid), Yield: 91.8 %.

Seventh step

4-( )-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-(( 3 8aS)-Hexahydro-pyrrolo[2,l-c][l,4]-oxazol-3-ylmethyl)-benzamide

(3i?,8aS)-hexahydro-pyrrole[2,1-c][],4]oxazin-3-yl)methanamine (39 mg, 0.25 mmol, prepared by the known method "CN101392001" Dissolved in 30 mL of dichloromethane and added ((7?)-4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetra Hydrogen-acridin-2-ylamino)-methoxy)-benzoic acid 12f (100 mg, 0.25 mmol), O-benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethylurea IV The fluoroborate (80 mg, 0.25 mmol) and diisopropylethylamine (0.1 mL, 0.63 mmol) were stirred for 1 hour. After adding 30 mL of dichloromethane, the mixture was washed with saturated aqueous ammonium chloride (30 mL) and brine (30 mL). , the title product 4-((/?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl Amino)-N-((3,8aS)-hexahydro-pyrrolo[2,1- _C ][l,4]-oxazol-3-ylmethyl)-benzamide 12 (75 mg, white solid ), Yield: 56%.

MS m/z (ESI): 538.3 [M+l]

1H NMR (400MHz, CDC1 ₃ , ppm) δ 8.57—8.58 (d, 1 H), 7.63 (s, 1H), 7.46 (s, 1H), 7.34~7.36 (d, 1H), 6.86 (s, 1 H ), 4.69~4.74 (m, 1H), 4.28~4.3] (m, 1 H), 4.12—4.19 (m, 2H), 3.90—3.98 (m, 4H), 3.66—3.75 (m, 2H), 3.33 ~3.35 (m, 3H), 3.05—3.24 (m, 4H), 2.76~2.82 (m, 1H), 1.89—2.03 (m, 5H), 1.69~1.77 (m, 1H), 1.37~1.45 (m, 3H) _: L30~1.36 (m, 3H), 0·87~0·90 (t, 3H) Example 13

4-((iQ-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-( i3S,8aS)-hexahydro-pyrrolamide

13

First

4-((i?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((3&8aS')-hexahydro-pyrrolo[2,1- _C ][1 ,4]-oxazin-3-ylmethyl)-benzamide

(3 & 8aS)-hexahydro-pyrrole[2,lc][l,4]oxazin-3-yl)methanamine (39 mg, 0.25 mmol, prepared by the known method "CN10139200") Add ((i?)-4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydrogen) to 30 mL of dichloromethane. -Acridine-2-ylamino)-methoxy)-benzoic acid 12f (100 mg, 0.25 mmol), O-benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethylurea tetrafluoro Borate (80 mg, 0.25 mmol) and diisopropylethylamine (0.1 mL, 0.63 mmol) were stirred for 1 hour. After adding 30 mL of dichloromethane, the mixture was washed with saturated aqueous ammonium chloride (30 mL), brine (30 mL) , the title product 4-((i?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-yl Amino)-N-((3 & 8aS)-hexahydro-pyrrolo[2,lc][l,4]-oxazol-3-ylmethyl)-benzamide 13 (65 mg, white solid) Yield: 44.8 %.

MS m/z (ESI): 538.5 [M+l]

NMR NMR (400MHz, CDC) ₃ , ppm) δ 8.55~8.58 (d, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.32~7.45 (d, 1H) , 6.5 to 6.54 (m, 1H), 4.7 to 4.74 (m, 1H), 4.28 to 4.31 (m, 1H), 4.02 to 4.06 (m, 1H), 3.97 (s, 3H), 3.73 to 3.79 (m, 2H), 3.41—3.46 (m, 2H), 3.33 (s: 3H), 3.1 1~3.14 (m, 2H), 2.15~2.20 (m, 3H), 1.69—1.93 (m, 6H), 1.40~1 .45 (m, 3H) _: 1.36~1.37 (m, 3H), 0.85~0.90 (t, 3H) Example 14

4-((7?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -iOQa ?)- ~2, lc|"l ,4oxazin-3-ylmethyl)-benzamide

First step

4-((i?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((3 8ai?)-hexahydro-pyrrolo[2,l-c][l ,4]-oxazol-3-ylmethyl)-benzamide Preparation of ((3 8ai?)-hexahydro-pyrrole[2,1-c][l,4]oxazin-3-yl)methylamine (39nig, 0.25 mmol, using the known method "CN] 01392001" And dissolved in 30 mL of dichloromethane, added ((i?)-4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8 -tetrahydro-acridin-2-ylamino)-methoxy)-benzoic acid 12fT 100 mg, 0.25 mmol), (9-benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea IV The fluoroborate (80 mg, 0.25 mmol) and diisopropylethylamine (0.1 mL, 0.63 mmol) were stirred for 1 hour. Add 20 mL of dichloromethane and then saturated with saturated ammonium chloride (30 mL). The mixture was washed with brine (30 mL), EtOAcjjjjjjjjjjjjjjj 5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-((3i?,8a/?)-hexahydro-pyrrolo[2, 1- _C ][1,4]-oxazin-3-ylmethyl)-benzamide 14 (67 mg, white solid), yield: 50%.

MSm/z (ESI): 538.5 [M+1]

1H NMR (400MHz, CDC1 ₃ , ppm) δ 8.55~8.58 (d, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.30~7.32 (d, 1H), 6.49~6.50 (m, 1H), 4.69~4.76 (m, 1H), 4.28~4.30 (m, 1H), 4.02—4.06 (m, 1H), 3.97 (s, 3H), 3.73—3.79 (m, 2H) ), 3.42—3.47 (m, 2H), 3.33 (s: 3H), 3.01—3.12 (m, 2H), 2.13~2.18 (m, 3H), 1.68—1.96 (m, 6I-I), 1.43~1.45 (m, 3H) _: 1.36~1.37 (m, 3H), 0.85-0.90 (t, 3H) Example 15

4-(0?)-7-ethyl- 8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N- "3S,8a/?)-Hexahydro-pyrrolo-[2,l-cin,4-oxazin-3-ylmethyl)-benzamide

First

4-((i?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -((3S,8ai?)-hexahydro-pyrrolo[2,1- _C ][1,4]-oxazol-3-ylmethyl)-benzamide will ((3S,8ai?)-six Hydrogen-pyrrole [2, lc] [l, 4]oxazin-3-yl)methylamine (39 mg, 0.25 mmol, prepared by the known method "CN101392001") dissolved in 30 mL of dichloromethane , ((-4-(ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-) Oxy)-benzoic acid 12f (100 mg, 0.25 mmol), O-benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea tetrafluoroborate (80 mg, 0.25 mmol) and Isopropylethylamine (0.1 mL, 0.63 mmol), and the reaction was stirred for 1 hour. Add 30 mL of dichloromethane, and then washed with saturated brine (30 mL), brine (30 mL) , filtering, filtering The liquid was concentrated under reduced pressure, and the residue obtained was purified by HPLC to afford the title product 4-((i?)-7-ethyl- 8- propyl-5-methyl-6-oxo-5,6, 7,8-tetrahydro-acridin-2-ylamino)-N-((3S,8ai?)-hexahydro-pyrrolo[2,1 _-C ]n ,4]-oxazin-3-yl -benzamide 5 (62 mg, white solid), Yield: 45.5 %.

MS m/z (ESI): 538.5 [M+1]

H NMR (400MHz, CDC1 ₃ , ppm) δ 8.57—8.59 (d, 1H), 7.67 (s, l H), 7.64 (s, 1H), 7.47 (s, 1 H), 7.40—7.46 (d, 1H), 6.96 (s, 1H), 4.68~4.75 (m, 1H), 4.28-4.30 (m, 1H), 4.12—4.22 (m, 2H), 3.94—3.98 (m, 4H), 3.62~3.73 ( m, 2H), 3.21 -3.32 (m, 6H), 3.01 - 3.12 (m, 1H), 2.76-2, 82 (m, 1H), 1.95~2.01 (m, 4H),].89~1.94 (m , 1H), 】.69~1.88 (m, 1H), ] .55~1 ·57 (m, 3H), 1.48~1.53 (m, 3H), 0.85~0.90 (t, 3H) Example 16

4-((iT>-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-

N-((4aR,6R aS/4aS,6S aR)-2-methyl-octa-cyclopenta-pyridyl-6-yl)-3-methoxy-benzoyl

First step

(4a^,6?,73^-6-azido-octahydro-1H-cyclopenta[c]pyridine hydrochloride 16a-l (4a5,6 & 7aW)-6-azido-octahydro-1//-cyclopenta[c]pyridine hydrochloride 16a-2

(4a 6 7a5 6-azido-hexahydro-li- /-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8k-l and (4a&6) obtained in the ninth example of Example 8. & 7)-6-Azido-hexahydro-1 H-cyclopenta[c]pyridine-2(3H)-carboxylic acid tert-butyl ester 8k-2 mixture (1.15 g, 4.32 mmol) dissolved in 5 mL To the dichloromethane, 10 mL of a 6 M hydrogen chloride solution of 1, 4-dioxane was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title product (4a7?, 6 7EUS 6-azido-eight a mixture of hydrogen-1H-cyclopenta[c]pyridine hydrochloride 16a-1 and (4aS,6 & 7a/-6-azido-octahydro-1H-cyclopenta Mpyridine hydrochloride 16a-2 (880 mg, colorless oil), yield: 100

%. Go directly to the next step.

MS m/z (ESl): 167.2 [M+l]

Second step

(4a e,6/?,7a5)-6-azido-2-methyl-octahydro-1H-cyclopenta[c]pyridine 16b-l (4a5,6 & 7ai?)-6-azide (4a?,6 7aS)-6-azido-octahydrocyclopentane obtained by the above-mentioned reaction in the presence of benzyl-2-methyl-octahydro-1H-cyclopenta[c]pyridine 16b-2 And a mixture of [ _C ]pyridine hydrochloride 16a-1 and (4a5,6 & 7aW)-6-azido-octahydrocyclopenta[c]pyridine hydrochloride 16a-2 (880 mg, 4.32 mmo) Dissolved in a mixture of 20 mL of acetonitrile and water (V: V = 1:1), followed by 37% formaldehyde solution (0.71 mL, 8.64 mmol) and sodium triacetoxyborohydride (2.7 g, 〗 2.96 mmol) The reaction was stirred for 2 hours, 10 mL of 1 M hydrochloric acid was added, 15 mL of 5 % sodium hydroxide solution was added dropwise to the pH of the reaction solution was 9, stirred for 0 minutes, extracted with dichloromethane (50 mL×3), and the organic phases were combined. The residue was purified by silica gel column chromatography eluting with eluent system A to give the title product (4ai?, 6 7aS 6-). Azido-2-methyl-octahydro-1H-cyclopenta[ _C ]pyridine 16b-l and (4a5',6 & 7ai?)-6-azido-2-methyl-octahydro-1H -cyclopenta[c]pyridine 1 Mixture 6b-2 (650 mg, colorless oil), Yield: 84%.

MS m/z (ESI): 181.1 [M+l]

third step

(4a/?,6i?,7aS 2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl-amine 16c-l ^:

(4aS,6 & 7a ?)-2-methyl-octahydro-1H-cyclopenta Mpyridine-6-yl-amine 16c-2 (4a7?,6 7aS)-6-azide obtained in the above step Benzyl-2-methyl-octahydro-1H-cyclopenta[c]pyridine.16b-1 and (4a,6 & 7a/?)-6-azido-2-methyl-octahydro-1H- A mixture of cyclopenta[c]pyridine 16b-2 (650 mg, 3.6 mmol) was dissolved in 20 mL of methanol, and (70 mg, 10%) palladium/carbon was added. The reaction was stirred for 2 hours under hydrogen atmosphere, filtered, and filtrate was reduced. Concentration by pressure gave the title product (4a?, 6 7a5)-2-methyl-octahydro-1H-cyclopenta[C-]pyridin-6-yl-amine 16c-l and (4aS,6S,7ai?) Mixture of -2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl-amine 16c-2 (505 mg, pale yellow oil), yield: 91%.

MS m/z (ESI): 155.2 [M+l]

the fourth step

4-((i?)- 7-ethyl- 8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino) - Ν-((4α^,6 73^-2-methyl-octahydro-1H-cyclopentanyl[c]pyridin-6-yl)-3-methoxy-benzamide 16-1 4-((-7-Ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N-(( 4aS,6 & 7a7?)-2-methyl-octahydrocyclopentane[c]pyridin-6-yl)-3-methoxy-benzamide 16-2 (4ai?,6 obtained by the above procedure) 7a,S 2-methyl-octahydro-1H-cyclopenta[c]pyridine-6-yl-amine 16c-l and (4a&6 & 7aW)-2-methyl-octahydro-] H-cyclopenta [c] Mixture of pyridin-6-yl-amine 16c-2 (77 mg, 0.5 mraol), (i?) 4-(7-ethyl- 8-isopropyl-5-methyl-6-oxygen Generation-5,6/7,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzoic acid 12f (199.7 rag, 0.5 mmol), <-benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethylurea tetrafluoroborate (160 mg, 0.5 mmol) and diisopropylethylamine (42 mg, 1.1 mmol), stir the reaction for 2 hours. Add ammonia to the pH of the reaction solution. </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut , 7,8-tetrahydro- Pyridin-2-ylamino)-N-((4a 6i?,7a^)-2-methyl-octahydrocyclopentanyl Mpyridine-6-yl)-3-methoxy-benzamide 16-1 And 4-((i?)- 7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)- a mixture of N-((4a5,6&7aW)-2-methyl-octahydro-1H-cyclopentanyl[c]pyridin-6-yl)-3-methoxy-benzamide 16-2 (60 mg, White solid), Yield: 22.3%.

MS m/z (ESI): 536.5 [M+l]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 8.48~8.62 (d, 1H), 7.58~7.71 (d, 2H), 7.36-7.51 (s, 1H), 7.18-7.31 (m, 1H), 6.12—6.28 (d, 1H), 4.68-4.81 (m, 1 H), 4.55~4.65 (m, 1H) 4.21—4.45 (m, IH), 3.91—4.05 (s, 3H), 3.26—3.41 (s, 3H) , 2.21~2.59 (m, 1H), 2.48~2.58 (s, 3H), 2.35~2.46 (s, 3H), 2.15—2.28 (m, 4H), 1.88—2.02 (m, 2H), 1 ·61~ 1 · 75 (m, 4H), 1.43 to 1.53 (d, 3H), 1.28 to 1.41 (d, 3H), 0.75 - 0.81 (t, 3H) Example 17

4-(W)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-indole-( Ϊ437?,6&73^/43^,6fan 7a/D-2-methyl-octahydrocyclopenta-klpyridine-6-yl)-3-methoxy-benzamide 17-1

4-((7?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -(Y4ai?,6S,7aS743⁄4S,6 7ai?)-2-Methyl-octahydro-1H-cyclopenta[c|pyridin-6-yl)-3-methoxy-benzamide 17-2

17-1 17-2

First step

4-((7?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N - ((4a 6 & 7aS)-2-methyl-octahydro-1H-cyclopenta[ _C ]pyridine-6-yl)-3-methoxy-benzamide 17-1

4-(( ?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N- ((4aS,6/?,7ai?)-2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl)-3-methoxy-benzamide 17-2. (4&6 & 7a5)-2-methyl-octahydro-1H-cyclopenta[c]pyridin-6-yl-amine 11f-1 and (4aS,6 7a ?)-2 a mixture of -methyl-octahydro-]H-cyclopenta[6']pyridin-6-yl-amine 11f-2 (60 mg, 0.39 mmol), (W)-4-(7-ethyl-8 -isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzoic acid 12f (171.6 mg, 0.43 mmol) , O-benzotriazole-oxime, oxime, Ν', Ν'-tetramethylurea tetrafluoroborate (125 mg, 0.39 mmol) and diisopropylethylamine (150 mg, 1.17 mmol), The reaction was stirred for 2 hours. The saturated sodium carbonate solution was added dropwise to a pH of 8 to 9, and the mixture was extracted with dichloromethane (50 mL×3). The residue obtained was purified by silica gel column chromatography eluting elut elut ,6,7,8-tetrahydro-acridin-2-ylamino)-N- ((4ε^,6&735 2-methyl-octahydro-1H-cyclopenta[c]pyridine-6-yl:) -3-methoxy-benzamide 17-1 and 4-((; -7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetra Hydrogen-acridin-2-ylamino)-N-((4aS,6W,7ai?)-2-methyl-octahydro-1H-cyclopenta[ _C ]pyridin-6-yl)-3-methoxy Mixture of benzyl-benzamide 17-2 (70 mg, white solid), Yield: 34%.

MS m/z (ESI): 536.3 [M+l]

1H NMR (400MHz, CDC) ₃ , ppm) δ 8.57-8.59 (d, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 7.29—7.31 (m, 1H) , 6.30-6.32 (d, 1H), 4.75~4.78 (m, 1H), 4.34~4.56 (m, 1H), 4.32~4.34 (m, 1H), 4.00 (s, 3H), 3.36 (s, 3H) , 2.52~2.58 (m, 2H), 2.28~2.44 (m _; 9H), 1.92-2.03 (m, 2H), 1.70~1.81 (m, 4H), 1 ·46~1 ·53 (d, 3H), 1.31~1.41 (d, 3H), 0.88-0.92 (m, 3H) Example 18

4-((i?)-7-ethyl- 8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-indole -Π-methyl-piperidine

4-yl)- 3-(tetraoxa-furan-2-yl-methoxy)-benzamide

First step

4-((i?)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-N -(l-methyl-piperidine

^-4 -yl) -3 - (tetrahydro-furan- ² -yl-methoxy)-benzamide 4-amino-N-(1-methyl-piperidin-4-yl)-3- ( Tetrahydro-furan-2-yl-methoxy)-benzamide 7d (150 mg, 0.45 mmol), (i?)-7-ethyl-2-chloro- 8-isopropyl-5-methyl - 7,8-Dihydro-5H-acridin-6-one 12d (121 mg, 0.45 mmol) and p-toluenesulfonic acid (137 mg, 0.72 mmol) dissolved in 20 mL of 4-methyl-2-pentanol The reaction was stirred under reflux for 3 hours. The saturated potassium carbonate solution was added dropwise until the pH of the reaction mixture was 9~0, extracted with dichloromethane (50 mL×3), and the organic phase was combined, washed with brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered The residue was purified by silica gel column chromatography elutd elut elut elut -5,6,7,8-tetrahydro-acridine-2-ylamino)-N-(l-methyl-piperidin-4-yl)-3-(tetrahydro-furan-2-yl-- Oxy)-benzamide 18 (100 mg, white solid), Yield: 39%. MS m/z (ESI): 566.5 [M+l]

'Η NMR (400MHz, CDC1 ₃ , ppm) δ 8.45— 8.65 (d, 1H), 7.65-7.75 (d, 2H), 7.40-7.51 (s, 1H), 7.25-7.38 (m, 1H), 5.92- 6.05 (m, 1H), 4.36-4.61 (m, 1H), 4.33~4.46 (m, 1H), 4.21~4.32 (m, 1H), 4.06~4.18 (m, 2H), 3.95-4.04 (m, 2H) ), 3.80-3.92 (m, 1H), 3.25-3.40 (s, 3H), 2.82~2.96 (d, 2H), 2.30~2.42 (s, 3H), 2.15~2.28 (m, 2H), 1.95- 2.06 (m, 6H), 1.63~ 1.75 (m, 4H), 1.42~1.53 (d, 3H), 1.30~1.41 (d, 3H), 0.80~0.95 (t, 3H) Example 19

0 ?)-3-methoxy-4-(5-methyl-6-oxo-8-toluenesulfonyl-6,6a,7,8,9,10-hexahydro-5H-pyrazine hydrazine 2 J -W acridine-2-ylamino)-N-(l-methylpiperidin-4-yl)benzamide

First step

3-methoxy-N-(l-methyl-piperidin-4-yl)-4-nitro-benzamide 3-methoxy-4-nitro-benzoic acid la (9.86 g, 50 Ment) dissolved in 200 mL of dichloromethane, followed by 0-benzotriazole-oxime, hydrazine, Ν', Ν'-tetramethyluronium tetrafluoroborate (16.1 g, 50 mmol), Isopropylethylamine (18.2 mL, 110 mmol) and 1-methyl-piperidin-4-yl-amine (5.7 g, 50 mmol), stirred for 2 h, added 200 mL dichloromethane, 1 M aqueous ammonia The organic layer was dried (MgSO4) 10 g, yellow solid), Yield: 68%.

MS m/z (ESI): 294.2 [M+l]

Second step

4-Amino-3-methoxy-N-(l-methyl-piperidin-4-yl)-benzamide 3-methoxy-N-(l-methyl-piperidin-4-yl -4-Nitro-benzamide 19a (5 g, 17 mmol) was dissolved in 120 mL of methanol, added (500 mg, 10%) palladium/carbon, stirred for 1 hour under hydrogen atmosphere, filtered, 30 mL The filter cake was washed with methanol, and the filtrate was evaporated to dryness crystals crystals crystalsssssssssssssssssssss , Yield: 97%.

MS m/z (ESI): 264.3 [M+l]

Second

((i?)-4-(2-chloro-5-nitro-pyrimidin-4-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester piperazine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 19c (6 g, 24.6 mmol), 2,4-dichloro-5-nitro - pyridazine (4.8 g, 24.8 nimol) and sodium bicarbonate (8.3 g, 98.4 mmol) dissolved in 150 mL of cyclohexane, stirred at 65 °C for 0.5 h, added 200 mL of ethyl acetate, followed by saturated chlorine The ammonium salt solution (60 mL×2) was washed with saturated brine (60 mL×2), dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated to give the title product ((i?)-4-(2-chloro-5-nitro) -pyrimidin-4-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 19d (8.36 g, yellow solid), Yield: 84.4%.

MS m/z (ESI): 402.2 [M+l]

the fourth step

(7?)-2-Chloro-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1 -/7]acridine-8(6H)-carboxylic acid tert-butyl ester

4-(2-Chloro-5-nitro-pyrimidin-4-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester] 9d (8.36 g, 20.8 mmol) and iron The powder (3.5 g, 62.4 mmol) was dissolved in 350 mL of acetic acid, and the reaction was stirred at 70 ° C for 12 hours. The reaction solution was concentrated under reduced pressure. The saturated sodium hydrogen carbonate solution was added dropwise to pH 8 to 9垸 extraction (200 mL×3), washed with saturated brine (60 mL > < 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then 10 raL of dichloromethane and 50 mL of ethyl acetate. Precipitate, filter, and dry the filter cake to obtain the title product (i?)-2-chloro-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine [2,1-/7]喋Pyridin-8 (6H> tert-butyl carboxylate 19e (4.55 g, white solid), yield: 64.1.

MS m/z (ESI): 340.3 [M+l]

the fifth step .

(i?)-2-Chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine [2J -/7] acridine-8(6H)-carboxylic acid tert-Butyl ester (R)-2-chloro-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1-/2]acridin-8(6H)-carboxylic acid Tert-Butyl ester 19e (500 mg, 1.47 mmol) and potassium carbonate (305 mg, 2.2 mmol) were dissolved in 40 mL of dimethyl carbonate. The reaction was stirred under reflux for 12 hours, 50 mL of dichloromethane was added, followed by saturated chlorination. The amine solution (50 mL×2), EtOAc (EtOAc (EtOAc) ?)-2-Chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1-A]acridine-8(6H)-carboxylic acid Butyl ester 19f (0.45 g, white solid), yield: 79.8 % o

MS ra/z (ESI): 354.2 [M+l]

The sixth step.

(i?)-2-Chloro-5-methyl- 8-toluenesulfonyl-7,8,9,10-tetrahydro-5H-pyrazine[2,1-A]acridine-6(6aH)- Ketone will be (i?) 2-chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine [2,1-acridine-8(6H)-carboxylate Tert-butyl acid ester 19f (415 mg, 1.2 mmol) was dissolved in 40 mL of dichloromethane, hydrogen chloride gas was added, and the reaction was stirred for 2 hours, followed by the addition of triethylamine (0.24 g, 2.4 mmol) and p-toluenesulfonyl chloride (0.34). g, 1.8 mmol), stirred for 2 hours. After washing with saturated brine (50 mL×3), EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 8-(Toluenesulfonyl-7,8,9,10-tetrahydro-5H-pyrazine [2,1-Acridine-6(6aH)-one 1.9 _g (0.14 g, white solid), Yield: 27.7 %.

MS m/z (ESI): 408.2 [M+l]

Seventh step ((X)-3-methoxy-4-(5-methyl-6-oxo-8-toluenesulfonyl-6,6a,7,8,9,10-hexahydro-5^pyridinium [2,1 -h] acridine-2-ylamino)-N-(]-methylpiperidin-4-yl)benzamide 4-amino-3-methoxy-N-(l-A Benzyl-piperidin-4-yl)-benzamide 19b (300 mg, 1.2 mmol), ((7?)-3-chloro-10-methyl-7-(tolyl-4-sulfonyl) -6,7,8,8a-tetrahydro-5H,10H-2,4,4b,7,10-pentaza-phenanthrene-9-one 19g (696 mg, 1.7 mmol) and p-toluenesulfonic acid (1 ] 4 g, 6 mmol) dissolved in 40 mL of 4-methyl-2-pentanol, stirred under reflux for 〖hours. Add triethylamine dropwise to the pH of the reaction solution 8~9, concentrate the reaction solution under reduced pressure, add 20 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3), washed with saturated brine (50 mL×3), dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified to give the title product methoxy-4-(5-methyl-6-oxo-8-toluenesulfonyl-6,6a,7,8,9,10-hexahydro-5H- Pyridino[2,1-h]acridin-2-ylamino)-N-(l-methylpiperidin-4-yl)benzamide 19 (212 mg, yellow solid), yield: 29.8 % .

MS m/z (ESl): 635.3 [M+1]

1H NMR (400MHz, CDC1 ₃ , ppm) δ 8.39~8.52 (d, 1 H), 7.72-7.81 (m, 3H), 7·56~7·71 (s: 1H), 7.42-7.55 (s, 1H ), 7.34—7.41 (m, 2H), 7.21-7.32 (m, 1H), 6.03—6.14 (d, 1H), 4.35~4.49 (m, 1H), 4.16~4.28 (m,]H), 3.85— 4.10 (m, 5H), 3.26—3.39 (s, 3H), 2.96—3.09 (m, 1H), 2.81—2.94 (m, 2H), 2.36~2.50 (m, 8H), 2.26—2.30 (m, 2H) ), ] .99~2.] 2 (m, 4H), 1.6〗 to 1.76 (m, 2H) Example 20

W)— _4- (8-isopropyl-5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyridinium and 2, W acridine-2 - base ammonia

-3-methoxy-Ν-α-methyl-piperidin-4-yl)benzamide

First step

(i?)-2-Chloro- 8-isopropyl-5-methyl-7,8,9,10-tetrahydro-5H-pyrazine [2,1- //]acridine-6 (6aH) -ketone 2-chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[2,1-/0-acridin-8(6H)-carboxylic acid tert-Butyl ester 19f (2.08 g, 5.9 mmol) was dissolved in 50 mL of dichloromethane, trifluoroacetic acid (3.3 g, 29 mmol) was added, and the reaction was stirred for 0.5 hour. The reaction mixture was concentrated under reduced pressure.垸, triethylamine was added dropwise to the pH of the reaction mixture was 8-9, acetone (0.4 g, 7.1 mmol) was added, the reaction was stirred for 1 hour, sodium triacetoxyborohydride (2.5 g, 11.8 mmol) was added, and the reaction was stirred 12 hour. Add 30 mL of water and dilute with dichloromethane (50 mL x 3). The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Isopropyl-5-methyl-7,8,9,10-tetrahydro-5H-pyrazine [2,1-Acridine-6(6aH)-one 20a (1.32 g, white solid), yield: 25.4%.

MS m/z (ESI): 296.1 [M+l]

Second step

_{4 (?)} - _(isopropyl - 5-methyl - 6-oxo _{_{_{_{_ 6, 6a, 7, 8}}}} , 9, 1 0 - hexahydro // - pyrazino [-W pteridine - 2-amino-)-3-methoxy-N-(1-methyl-piperidin-4-yl)benzamide 4-amino-3-methoxy-N-(1-methyl-piperidin Pyridin-4-yl)-benzamide 1.9b (170 mg, 0.64 mmol), (7?)-2-chloro-8-isopropyl-5-methyl-7,8,9,10-tetrahydro -5H-pyrazine [2,1 -2]acridine-6(6aH)-one 20a (240 mg, 0.81 mmol) and p-toluenesulfonic acid (0.81 g, 4.3 mmol) dissolved in 20 mL of 4-methyl- In 2-pentanol, the reaction was stirred under reflux for 2 hours. The mixture was cooled to room temperature, and then added with aq. EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography eluting elut elut elut elut elut elut 9,10-Hexahydro-5.H-pyrazin-2-ylamino)-3-methoxy-N-(l-methyl-piperidin-4-yl)benzamide 20 (61.3 mg , white solid), Yield: 18.4%. MS in/z (ESI): 523.4 [M+l]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 8.42—8.56 (d, 1H), 7.35~7.61 (d, 2H), 7.52-7.90 (s, 1H), 7.21-7.33 (m, 1H), 5.99—6.12 (d, 1H), 4.61~4.72 (d, 1H), 4.1 1~4.22 (d, 1 H), 3.92—4.05 (m, 4H), 3.42—3.58 (d, 1H), 3.36—3.40 (s, 3H), 2.85~2.96 (m, 4H), 2.31~2.42 (m, 4H), 2. ] 6~2.28 (m, 2H), 1.91-2.06 (m, 6H), 1.02~ .15 (m, 3H Example 21

(R)-2-(2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-N,N,5-trimethyl-6-oxo

-6a,7,9,10- -5H-pyrazine and 2, 1 -W acridine-8(6H)-carboxylic acid amide

First step

(i?)-2-Chloro-5-methyl-7,8,9,] 0-tetrahydro-577-pyrazino[2,1-/7]acridine-6(6& /)-one 2-Chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazino[2,l-z]acridine-8(6H)-carboxylic acid tert-butyl ester 19f (2.15 g, 6.08 mmol) was dissolved in 50 mL of dichloromethane, hydrogen chloride gas was added thereto, the reaction was stirred for 1 hour, 20 mL of water was added, and potassium carbonate solid was added until the pH of the reaction solution was 9 to 10, and dichloromethane was extracted ( 50 mL×3), EtOAc (3 mL) 8,9,10-Tetrahydro-5H-pyrazino[2,1-h]acridine-6 (6aHHll 21a (1..05 g, white solid), yield: EtOAc.

MS m/z (ESI): 254.1 [M+1]

Second step

(i?)-2-Chloro-N,N,5-trimethyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1-h]acridine-8 (6H)-carboxylic acid amide under ice bath, (R)-2-chloro-5-methyl-7,8,9, 10-tetrahydro-5H-pyrazino[2,1-h]acridine -6(6aH)-one 21a (0.25 g, 1 mmol) was dissolved in 15 mL dichloromethane, then triethylamine (0.3 mL, 2 mmol) and dimethylcarbamoyl chloride (0.1 mL, 1.1 mmol) The reaction was stirred for 0.5 hours. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour, 50 mL of dichloromethane was added, washed with brine (50 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title product (i?)-2-chloro-N,N,5-trimethyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine [2 , 1-/ | acridine-8(6H)-carboxylic acid amide 21b (250 mg, white solid), yield: 78%.

MS m/z (ESI): 325.3 [M+1]

third step

(7ζ)-2-(2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-N,N,5-trimethyl-6-oxo

-6a,7,9,10-tetrahydro-5H-pyrazino[2,1-/7]acridine-8(6H)-carboxylic acid amide 4-amino-3-methoxy-N-( L-Methyl-piperidin-4-yl)-benzamide 19b (0.072 g, 0.27 mmol), (7?) 2-chloro-N,N,5-trimethyl-6-oxo-6a , 7,9,10-tetrahydro-5H-pyrazine[2,1-/2]acridin-8(6H)-carboxylic acid amide 21b (100 mg, 0.3 mmol) and p-toluenesulfonic acid (0.16 g, 0.82 mmol) was dissolved in 30 mL of 4-methyl-2-pentanol, and the reaction was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The resulting residue was purified by column chromatography using eluent system A to give the title product. (R)-2-(2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-N,N,5-trimethyl-6-oxo- 6a , 7,9,10-Tetrahydro-5H-pyrazino[2J-?] acridine-8(6H)-carboxylic acid amide 21 (70 mg, white solid), yield: 50%.

MS ra/z (ES1): 552.4 [M+l]

^{! H MR (400MHz, CDC1 ppm} 3,) δ 8.42~8.45 (d, 1H), 7.75 (s, 1 H), 7.5~7.51 (d, 1 H), 7.48 (s, 1 H), 4.55~4.58 (m, l H), 4.1-4.1 5 (m, 2H), 4.02-4.03 (m, 1 H), 4.01 (s, 3H), 3.73—3.76 (m, 1H), 3·32~3·33 (m, 1H), 3.27 (s, 3H), 3.19—3.23 (m, 2H), 2.93-2.98 (m, 2H), 2.9 (s, 6H), 2.57 (s, 3H), 2.62—2.65 (m , 2H), 2.07-2.10 (m, 2H), 1.85~1.88 (m, 2H) Example 22

( )- ₄ -(8-acetyl-5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazine and n-W acridine-2-yl ammonia

-3-methoxy-Ν-Π-methylpiperidin-4-yl)benzamide

First step

(i?)-2-chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1-Zz]acridine-8(6H)-carboxylate Benzyl acetate in an ice bath, (i?) 2-chloro-5-methyl-7,8,9, 10-tetrahydro-5H-pyrazino[2,1-h]acridine-6 ( 6aH)-ketone 21a (1.98 g, 7.8 mmol) was dissolved in 50 mL of dichloromethane, and then triethylamine (1.7 mL, 11.7 mmol) and benzyl chloroformate (1. 4 mL, 9.4 mmol) were stirred and stirred. The reaction took 0.5 hours. Add 20 mL of saturated sodium bicarbonate dropwise The solution was stirred to a pH of 8 to 9 and extracted with dichloromethane (40 mL×2), washed with brine (50 mL), dried over anhydrous magnesium sulfate. The resulting residue was purified to give the title product chloro-5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1-/?] acridine-8 (6H)-Carboxylic acid ester 22a (2.25 g, white solid), Yield: 74.2%.

MS m/z (ESI): 388.3 [M+l]

Second step

{R)-2-{2-methoxy-4-(methylpiperidin-4-ylcarbamoyl)phenylamino)-5-methyl-6-oxo-6a,7,9, 10- Tetrahydro-5H-pyrazino[2,1-W-acridin-8(6H)-carboxylic acid benzyl ester 4-amino-3-methoxy-N-0 methyl-piperidin-4-yl) -benzamide 19b (616 mg, 2.34 mmol) was dissolved in 30 mL of 4-methyl-2-pentanol, followed by (i?)-2-chloro-5-methyl-6-oxo-6aJ. 9,10-Tetrahydro-5H-pyrazine [2,1-A]acridine-8(6H)-carboxylic acid benzyl ester 22a (999 mg, 2.58 mmol) and p-toluenesulfonic acid (722 mg, 3.75 mmol) The reaction was stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of water was added, and saturated potassium carbonate solution was added dropwise until the pH of the reaction mixture was 9 to 10, dichloromethane was extracted (100 mL×2), and the organic phase was washed with saturated brine (50 mL). The title compound (i?)-2-(2-methoxy-4-(1-methyl) was purified by silica gel column chromatography. 5-piperidin-4-ylcarbamoyl)phenylamino)- 5-methyl-6-oxo-6a,7,9,10-tetrahydro-5H-pyrazine[2,1 -/0 acridine -8(6H)-Carboxylic acid ester 22b (404 mg, white solid), Yield: 14.2%.

MS m/z (ESl): 615.5 [M+l]

third step

(i?)-3-methoxy-4-(5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazine[2,]-h Acridine-2-ylamino)-N-(l-methylpiperidin-4-yl)benzamide

(i?)-2-(2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-5-methyl-6-oxo-6a,7, 9,10-Tetrahydro-5/J-pyrazino[2,1- /?] acridine-8(6H)-carboxylic acid benzyl ester 22b (500 mg, 0.8 mmol) was dissolved in 100 mL of dichloromethane and Methanol (V: V = ]: 1) In a mixed solution, 5 drops of glacial acetic acid and (100 mg, 10%) of palladium/carbon were sequentially added thereto, and the reaction was stirred under a hydrogen atmosphere for 24 hours under 3 atmospheres. Filtration and concentration of the filtrate under reduced pressure afforded the title product (i?)-3-methoxy-4-(5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro- 5H-Pyrazino[2,1-h]acridin-2-ylamino)-N-(l-methylpiperidin-4-yl)benzamide 22c (277 mg, white solid), yield: 71%. MS m/z (ESI): 481.3 [M+l]

the fourth step

((/?)—4—(7-Acetyl-10-methyl-9-one-6,7,8,8a,9,10-hexahydro-5H-2,4,4b,7,10- Phenanthroline-phenanthrene-3-ylamino)-3-methoxy-N-(l-methyl-piperidin-4-yl)-benzamide under ice bath, (-3-methoxy- 4-(5-Methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[2,1-h] acridine-2-ylamino)-N -(l-Methylpiperidin-4-yl)benzamide 22c (48 mg, 0.1 mmol) was dissolved in dichloromethane (30 mL), triethylamine (0.04 mL, 0.3 mmol) and acetyl chloride (0.008 niL) , 0.11 mmol), stirring for 1 hour. Add 100 mL of water, the organic phase is washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. A purified residue obtained, Title product (i?)-4-(8-acetyl-5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrazine[2,1- h] acridine-2-ylamino)-3-methoxy-N-(l-methylpiperidin-4-yl)benzamide 22 (30 mg, white solid), yield: 57%.

MS m/z (ESI): 523.2 [M+1]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 8.45~8.47 (d, 1H), 7.79-7.83 (m, 1H), 7.42-7.5 (m 2H), 4.58-4.65 (m, 3H), 4.17-4.21 ( m, 1 H), 4.01 (s, 3H), 3.91 -3.92 (m, 1H), 3.31 (s, 3H), 2.95-3.00 (m, 3H), 2.41 (s, 3H), 2.35 (s, 3H) ), 2.12—2.26 (m, 4H), 1.97-2.01 (m, 2H), 1.71-1.77 (m, 2H) Example 23

(70-3-methoxy-4-(5-methyl-6-oxo-8-phenyl-6,6a,7,8,9,10-hexahydro-5H-pyrazine and 2, 1-W acridine-2- -N-(l-methylpiperidin-4-yl)benzamide

First step

(i?)-piperazine-2-carboxylate

(7?)-piperazine-2-carboxylic acid 23a (10 g, 0.05 mol) was dissolved in 150 mL of methanol, 30 mL of concentrated sulfuric acid was added, and the reaction was stirred under reflux for 8 hours, cooled to room temperature, and 100 mL of triethyl ether was added dropwise. The pH of the amine to the reaction mixture was 9 to 10, and the reaction mixture was concentrated under reduced pressure to give the title product (^)-piperazine-2-carboxylic acid methyl ester 23b.

Second (-piperidine-U-dicarboxylic acid 3-methyl ester)-benzyl ester

Under ice bath, (?)-piperazine-2-carboxylic acid methyl ester 23b (7.2 g, 0.05 mol) was dissolved in 200 mL of dichloromethane, and 20 mL of triethylamine and benzyl chloroformate were added in sequence (8.5 g, 0.05 mol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. 300 mL of ethyl acetate, 300 mL of water was added, and then, M hydrochloric acid was added dropwise until the pH of the reaction mixture was 3 to 4, and the aqueous layer was added dropwise with saturated sodium carbonate solution until pH 9 was obtained. (100 mL>G), EtOAc (3 mL), EtOAc (EtOAc) Acid 3-methyl ester 1-benzyl ester 23c (6.6 g, yellow oil), Yield: 47 o

MS m/z (ESI): 279.1 [M+l]

third step

(-Piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester 2-methyl ester, ice bath, (i?)-piperazine-1,3-dicarboxylic acid 3-methyl The 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, and di-tert-butyl dicarbonate (5.4 g, 2.8 mmol) was added at room temperature. The reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (200 mL), EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The residue was dried over MgSO.sub.subsubsubsubsubsubsubsubsubsubsubsubsubsubsub Solid), Yield: 100%.

MS nVz (ESI): 401.1 [M+23]

Fourth

(?)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

Dissolve piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester 2-methyl ester 23d (3 g, 8 mmoi:) in 100 mL of methanol, add 3 drops of acetic acid and (300) Mg, 10%) palladium on carbon, the reaction was stirred under a hydrogen atmosphere for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to eluent to afford the title product (i?)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 23e (lg, yellow oil), Yield: 52.6%.

MS m/z (ESI): 245.1 [M+l]

the fifth step

(i?)-4-phenyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.

Under an argon atmosphere, potassium t-butoxide (1.45 g, 12.9 mmol), 2-(di-tert-butylphosphine)biphenyl (0.1 g, 0.34 mmol) and tris(dibenzylideneacetone) dipalladium (0.16 g, 0.17 mmol) was dissolved in 40 mL of toluene, followed by (OR)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 23e (2.1 g, 8.6 mmol) and 10 mL of bromobenzene (1.6) g, 10.3 mmol) in toluene solution, the reaction was stirred at 60 ° C for 2 hours, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj Pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester 23f (500 mg, yellow solid), Yield: 18.1%.

MS m/z (ES1): 321.2 [M+l]

Sixth (7?)-4-phenyl-piperazine-2-carboxylic acid methyl ester hydrochloride

Dissolve (-4-phenyl-piperazine-), 2-dicarboxylic acid]-tert-butyl ester 2-methyl ester 23f (0.5 g, 1.5 ramol) in 20 mL of dichloromethane, add 5 mL of 6 M The solution of hydrogen chloride in 4,4-dioxane was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title product (i?)-4-phenyl-piperazine-2-carboxylic acid methyl ester hydrochloride. _g (385 mg, yellow solid), Yield: 100%.

MS m/z (ESI): 221.2 [M+l]

Seventh step

(i?)-]-(2-Chloro-5-nitro-pyrimidin-4-yl)-4-phenyl-piperazine-2-carboxylic acid methyl ester 4-phenyl-piperazine-2-carboxylate Acid methyl ester hydrochloride 23 _g (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- Pyrimidine (290 rag, 1.5 mmol) was stirred at reflux for 3 h. After cooling to room temperature, 100 mL of water, 100 mL of EtOAc, EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (mjjjjjjjjjjjjjj , yellow solid), Yield: 53.5 %.

MS m/z (ESI): 378.2 [M+l]

Eighth step

(i?)-2-Chloro-8-phenyl-7,8,9, 10-tetrahydro-5H-pyrazine[2,1-h]acridine-6(6aH)-one (7?) -1 -(2-Chloro-5-nitro-pyrimidin-4-yl)-4-phenyl-piperazine-2-carboxylic acid methyl ester 23h (300 mg, 0.8 mmol) was dissolved in 50 mL EtOAc. Add iron powder (180 mg, 3.2 mmol), stir the reaction at 70 ° C for 3 hours, concentrate the reaction solution under reduced pressure, add 10 mL of water, extract with dichloromethane (50 mL×3), combine the organic phase, wash with saturated brine (50 mL), dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ , 1- h] acridine-6(6aH)-one 23j (0.1 g, yellow solid), yield: 40%.

MS m/z (ES1): 316.2 [M+l]

Step 9

(i?)-2-Chloro-5-methyl-8-phenyl- 7,8,9, 10-tetrahydro-5H-pyrazine [2, 1 -/z] acridine-6(6aH)- Ketone will be (i?)-2-chloro-8-phenyl-7,8,9, 10-tetrahydro-5H-pyrazine[2,1-/2]acridin-6(6aH)-one 23j ( 100 mg, 3.1 mraol), potassium carbonate (87 mg, 6.3 mmol) and p-toluenesulfonic acid formazan (88 mg, 4.7 mmol) were dissolved in 50 mL of acetone and stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. 2-Chloro-5-methyl-8-phenyl-7,8,9,] 0-tetrahydro-5H-pyrazine[2,1 -A]acridine-6(6aH)-one 23k (80 mg , yellow solid), Yield: 78.4%.

MS m/z (ESI): 330.1 [M+l]

Step 10

(i?)-3-methoxy-4-(5-methyl-6-oxo-8-phenyl-6,6a,7,8,9,10-hexahydro-5H-pyrazine) 2, 1-W acridine-2-ylamino)-N-(l-methylpiperidin-4-yl)benzamide

4-Amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide 19b (64 mg, 0.24 mmol), ((/?)- 3-chloro-10-methyl-7-phenyl-6,7,8,8a-tetrahydro-5H,10H-2,4,4b,7,10-pentaza-phenanthrene 9-ketone 23k (80 mg, 0.24 mmol) and p-toluenesulfonic acid (230 mg, 1.2 mmol) were dissolved in 30 mL of 4-methyl-2-pentanol, and the reaction was stirred under reflux for 3 hours. After adding 100 mL of saturated potassium carbonate solution, dichloromethane (100 mL×2), and the organic phase was combined, washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, The obtained residue was purified to give titled product (yield: 3-methoxy-4-(5-methyl-6-oxo-8-phenyl-6,6a,7,8,9, 10-hexahydro-5H-pyrazino[2,l-/z]acridin-2-ylamino)-N-(1-methylpiperidin-4-yl)benzamide 23 (30 mg, white Solid), Yield: 22.5%.

MS m/z (ESI): 557.4 [M+l]

NMR NMR (400MHz, CDC1 ₃ , ppm) δ 8·54~8.57 (d, 1H), 7.77 (s, 1H), 7.46-7.47 (d, 1H), 7.33-7.37 (m, 3H), 7.06—7.07 (d, 2H), 6.96-7.0 (t, 1H), 4.76~4.80 (m, 1H),

4.26-4.33 (m, 2H), 4.13~4J 9 (m, 1H), 4.01 (s, 3H), 3.75-3.78 (m, 〗 H), 3.38 (s, 3H), 3.] ~ 3.20 (m , 3H), 2.89-2.95 (m, 2H), 2.52-2.57 (ni, 5H), 2.]6~2.19 (m, 2H), 1.95~ 2.01 (m, 2H) Test example:

Biological Evaluation Test Example 1. Determination of proliferation inhibition of P]k high expressing cells by the compound of the present invention

The following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the present invention against one human cervical cancer cell line Hda in a cell line highly expressing Plk.

The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on tumor cells that express Plk in high, and the activity can be expressed by the IC _5Q value. The general protocol for such an assay 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 is carried out, and they are allowed to grow overnight. The medium is changed to a medium containing a series of concentration (usually 7 to 9 concentrations) of the test compound solution, and the plate is returned to the incubator for 72 hours. . After 72 hours, the test compound can be tested for its ability to inhibit cell proliferation using the CCK8 method. The IC ₅ o value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.

Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅ o values are shown in the following table.

Mixture of 8-1 and 8-2 7

9 2

10 0.4

11 -1 and mixture of P Π -2 0.6

Mixture of 16-1 and 16-2 4

Mixture of 17-1 and 17-2 4

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against Hela cells. Test Example 2. Inhibition of proliferation of Plk high expressing cells by the compound of the present invention

The following in vitro assay was conducted to determine the proliferation inhibitory activity of the compound of the present invention against human colon cancer cell HCT-116 in a cell line highly expressing Plk.

The in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound on highly proliferating digestive tumor cells, and the inhibitory activity of the compound can be expressed by the IC _5Q value. The experimental protocol is briefly described as follows: First, HCT-116 cells (purchased in 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) The medium was inoculated on a 96-well culture plate, and then cultured overnight in a constant temperature incubator at 37 ° C under 5% CO ₂ . After the cells are attached, the medium is replaced with fresh medium containing a gradient of the test compound (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 on cell proliferation was measured by the method of CCK8 (Cell Counting Kit- 8, Cat. No.: CK04, purchased from Dojindo). The IC _5Q value of the compound can be calculated from the inhibition of cell proliferation by the test compound at various concentrations.

Activity of the compounds of the invention

The biochemical activity of the compound of the present invention was measured by the above test, and the measured IC _5Q value is shown in the following table.

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against HCT-116 cells. Test Example 3: Determination of Plkl kinase inhibitory activity by the compound of the present invention

In vitro Pjkl kinase activity was tested by the following method.

The method described below can be used to assay the compounds of the present invention, and expressed PIk] ability to inhibit kinase activity by ₅₀ value IC. The half-inhibitory concentration of the compound, IC _5Q (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 substrate and a different concentration of the test compound. To a series of inhibition rates, and then use the calculation tool to calculate. The Plk1 kinase used in this experiment was a recombinant human protein, and the reaction system was purchased from Poly-Like kinase 1 Assay/Inhibitor Screening Kit (#CY-]J 63). The Pjk] enzyme reacts with the polypeptide substrate and different 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 The secondary antibody HRP-conjugated Anti-rabbit IgG labels the phosphorylated substrate and finally measures the A450 nM reading to quantify Plkl kinase activity.

Activity of the compounds of the invention

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against P]k-1 kinase. Pharmacokinetic Evaluation Test Example 4. Pharmacokinetic Test of a Mixture of Inventive Example Compound 2 and Examples 8-1 and 8-2

1, abstract

Using rat as the test animal, the concentration of the drug in the plasma at different times after the intravenous administration of the compound of Example 2, the mixture of Examples 8-1 and 8-2, was determined by LC/MS/MS method. The pharmacokinetic behavior of the inventive compounds in rats was evaluated for their pharmacokinetic characteristics.

2. Test plan:

2.1 Test drugs

Example 2 compound, a mixture of Examples 8-1 and 8-2

2.2 Test animals

Healthy adult SD rats, 8 males and females, 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 the drug, dissolve it in DMSO 0.5 mL, add 0.1 M HC1 1.5 mL, dilute to the final volume with normal saline, and make the drug concentration 2.5 mg/mL.

2.4 Administration Eight SD rats, male and female, were divided into two groups. After fasting overnight, they were administered via the tail vein at a dose of 25 mg/kg.

3, operation

Take 25 L of rat plasma at each time after administration, add 20 μί of internal standard solution, 150 L of methanol, vortex for 3 minutes, centrifuge for 10 minutes (13500 rpm), and take 5 μ of supernatant from the plasma sample for LC. - MS/MS analysis. The main pharmacokinetic parameters were calculated using DAS 2.0 software.

4, pharmacokinetic parameters results

The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compound of Example 2, the mixture of Examples 8-1 and 8-2, had good pharmacological absorption.

Claims

Claims: a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof and a pharmaceutically acceptable salt thereof:

in:

Alternatively, R ¹ and R ² together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 0 to 2 N, 0 or S(0) _m heteroatoms, and The 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of decyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR ⁷ R ⁸ Substituted with a substituent of -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ or -C(0)OR ⁹ ;

R ^{3 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 fluorenyl group, the alkenyl group, the alkynyl group, the cyclodecyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ Substituted by a substituent of R ⁸ , —NR ⁷ R ⁸ , —S(0)OR ⁹ , —COR ⁹ or —C(0)OR ⁹ ;

Alternatively, R ² and R ³ together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 〜2 N, 0 or 8 (0), „hetero atom, and The 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR ⁷ Substituted by a substituent of R ⁸ , —CONR ⁷ R ⁸ , —NR ⁷ R ⁸ , —S(0)0R ⁹ , —COR ⁹ or —C(0)0R ⁹ ;

L is selected from an alkylene group, optionally substituted with one or more substituents selected from halogen, cyano, nitro or alkyl, wherein said thiol is optionally further protected by one or more halogens Replace

R ^{6 is} selected from alkyl, wherein said thiol is optionally further substituted with a heterocyclic group;

When R ^{6 is} selected from unsubstituted indenyl groups, A is selected from a bicyclic indenyl group, a bicyclic heterocyclic group, a spirocyclic indenyl group or a spiroheterocyclic group, wherein the bicyclic indenyl group, the diheterocyclic group, the spirocyclic group Or a spiroheterocyclyl optionally further substituted with one or more R ¹² ;

When R ^{6 is} selected from heterocyclyl-substituted indenyl, A is selected from cycloalkyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged cycloalkyl, hetero bridged fluorenyl, spirocycloalkyl or A spiroheterocyclyl group, wherein the cycloalkyl, heterocyclyl, bicycloindenyl, biheterocyclyl, bridged fluorenyl, heterobridged fluorenyl, spiro fluorenyl or spiroheterocyclyl is optionally further Or replaced by multiple R ¹² ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, which The alkyl, cyclodecyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of a decyl group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, Substituted by a substituent of a hydroxy group, a cyano group, -S(0)0R ⁹ , -COR ⁹ , C(0)0R ⁹ , -S^ONR^R ^{1 1} , -CONK ER ^{1 1} or -NR' R ¹¹ ;

Alternatively, R ⁷ and R ⁸ 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, 0 or 8 (0) _{| 11} heteroatoms, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, Substituted by a substituent of S(0)0R ⁹ , -C0R ⁹ , C(0)0R ⁹ , -S(O)ONR ¹⁰ R", -CONK ER ¹¹ or -NR' R ¹¹ ;

R ^{12 is} selected from the group consisting of fluorenyl, decyloxy, cycloalkyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ R ⁸ , -C(0)OR ⁹ -OC(0)R ⁹ , -0(CH ₂ ) _R C(0)OR ⁹ , -OC(0)NR ⁷ R ⁸ , -S(0) _M R ⁹ , -OS(0)OR ⁹ , Substituted by a substituent of -NHC(0)R ⁹ or -COR ⁹ wherein said fluorenyl, alkoxy, cycloalkyl or heterocyclic group is further further selected from one or more selected from the group consisting of fluorenyl and fluorenyl Substituted with a substituent of a heterocyclic group, an aryl group or a heteroaryl group;

■ m is 0 or 1;

n is 0, 1 or 2; and

r is 1, 2 or 3.

2. The compound of the formula (I) according to claim 1, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt, wherein: R ^{1 is} selected from a hydrogen atom;

R ^{2 is} selected from an alkyl group;

R ^{3 is} selected from a decyl group or a cycloalkyl group;

Alternatively, R ² and R ³ together with the atoms to which they are bonded form 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 optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, carbonyl, aryl, -S(0)ON ⁷ Substituted by a substituent of R ⁸ -CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ , -COR ⁹ or -C(0)OR ⁹ ;

When R ^{6 is} selected from unsubstituted indenyl groups, A is selected from a bicycloalkyl group, a heteroheterocyclyl group, a spirocyclic fluorenyl group or a spiroheterocyclic group, wherein the bicyclic fluorenyl group, the heterocyclic group, the bridged ring 垸a cyclyl, bridged heterocyclyl, spirocyclic fluorenyl or spiroheterocyclyl optionally further substituted with one or more R ¹² ;

When R ^{6 is} selected from a heterocyclic-substituted indenyl group, A is selected from cyclodecyl, heterocyclic, bicyclononyl, diheterocyclic a cyclyl group, a bridged fluorenyl group, a bridged heterocyclic group, a spirocyclic fluorenyl group or a spiroheterocyclic group, wherein said cycloalkyl group, heterocyclic group, bicyclononyl group, diheterocyclic group, bridged fluorenyl group, bridged a ring, a spirocycloalkyl or a spiroheterocyclyl optionally substituted with one or more R ¹² ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, carboxylic acid, carboxylic acid ester, -S(0)OR ⁹ Substituted by a substituent of -COR ⁹ , -S(O)ONR ¹⁰ R ^! \ -CONK ER ¹¹ or -NRWR ¹¹ ;

Alternatively, R ⁷ and R' ^s together with the N atom to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains one or more N, 0 or S (C m heteroatoms, and The 3 to 8 membered heterocyclic ring is optionally substituted with one or more selected from the group consisting of a decyl group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen group, a hydroxyl group, a cyano group, a carboxylic acid, a carboxylic acid ester. Substituted by a substituent of a carbonyl group, -S(0)0R ⁹ , -COR ⁹ , -S(O)ONR ^{, 0} R ⁿ , -CONFER ¹¹ or -NR^R";

R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;

R ^{1 Q} and R ^{11 are} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;

R ^{12 is} selected from the group consisting of fluorenyl, decyloxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ON ⁷ R ⁸ , -C0NR ⁷ R ^s , -C(0)OR ⁹ , -0C(0)R ⁹ , -0(CH ₂ ) _r C(0)OR ⁹ , -OC(0)NR ⁷ R ⁸ , -S(0) _m R ⁹ , -0S(0)0R ⁹ , Substituted with a substituent of NHC(0)R ⁹ or -COR ⁹ wherein said fluorenyl, decyloxy, cycloalkyl or heterocyclic group is further further selected from one or more selected from the group consisting of fluorenyl and fluorenyl Substituted with a substituent of a heterocyclic group, an aryl group or a heteroaryl group;

Ni is 0 or 1;

n is 0, 1 or 2; and

r is 1, 2 or 3.

3. The compound of the formula (I) according to claim 1, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt, wherein: R ¹ and R ² are each independently selected from a hydrogen atom or a thiol group;

R ^{3 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 fluorenyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group , aryl or heteroaryl group is optionally further substituted by one or more substituents selected from alkyl, alkoxy, halo, hydroxy, cyano, nitro, ^{aryl, -S (0) ONR 8,} -CONR 7 R 8 Substituting -NR ⁷ R ⁸ , -S(0)0R ⁹ , -COR ⁹ or -C(0)0R ⁹ ;

Or R ² and R ³ together with the atoms to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or 8 (0) ₁₁ , heteroatoms, and The 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR ⁷ R ^{^{^{8, -CONR 7 R 8, -}}} NR 7 R 8, -S (0) 0R 9, - COR 9 or -C (0) 0R ⁹ is substituted with a substituent;

L is selected from an alkylene group, optionally substituted with one or more substituents selected from halogen, cyano, nitro or thiol Substituted, wherein the thiol group is optionally further substituted with one or more halogens;

R ^{6 is} selected from a thiol group;

A is selected from a bicyclic fluorenyl group, a bicyclic heterocyclic group, a spirocycloalkyl group or a spiroheterocyclyl group, wherein the bicyclononyl group, the diheterocyclic group, the spirocycloalkyl group or the spiroheterocyclic group is optionally substituted into one or Substituted by a plurality of R ¹² ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)OR ⁹ , -COR ⁹ , C ( 0) OR ⁹ , -S(O)ONR ¹⁰ R ^{1 J} , substituted with a substituent of -CONK ER ^{1 1} or -NRWR ¹¹ ;

Alternatively, R ⁷ and R ⁸ 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, 0 or 8 (0) ₁₁₁ An atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S ( 0) 0R ⁹ , - C0R ⁹ , C(0)0R ⁹ , -S(O)ONR ¹⁰ R ^N , -C0NR ^{1 ()} R "or -NR ¹⁰ R"substituted;

R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group, wherein the cycloalkyl or aryl group is optionally further substituted with one or more alkyl groups;

R ^IQ and R ^{1 1 are} selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;

R ^{12 is} selected from the group consisting of decyl, decyloxy, cycloalkyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR ⁷ R ⁸ , - CONR ⁷ R ⁸ , - C(0)0R ⁹ , -0C(0)R ⁹ , -0(C3⁄4) _R C(0)0R ⁹ , -OC(0)NR ⁷ R ⁸ , -S(0) _M R ⁹ , -0S(0)0R ⁹ , - Substituted by a substituent of NHC(0)R ⁹ or -COR ⁹ wherein said fluorenyl, alkoxy, cycloalkyl or heterocyclyl is optionally further further selected from one or more selected from the group consisting of fluorenyl and cyclodecyl Substituted with a substituent of a heterocyclic group, an aryl group or a heteroaryl group;

m is 0 or 1;

n is 0, 1 or 2 ; and

r is 1, 2 or 3.

4. The compound of the formula (I) according to claim 1, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and a pharmaceutically acceptable salt, wherein: R ¹ and R ² are each independently selected from a hydrogen atom or a thiol group;

R ^{3 is} selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the alkenyl group, the alkynyl group, the cyclodecyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR ⁷ R ⁸ , -CONR ⁷ Substituted by a substituent of R ⁸ , —NR ⁷ R ^S , —S(0)0R ⁹ , —COR ⁹ or —C(0)0R ⁹ ;

Or R ² and R ³ together with the atoms to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 ^^, 0 or 8 (0) ₁₁₁ heteroatoms, and The 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR ⁷ Substituted by a substituent of R ⁸ , —CONR ⁷ R ⁸ , —NR ⁷ R ^S , —S(0)0R ⁹ , —COR ⁹ or —C(0)0R ⁹ ; R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitro group;

L is selected from an anthracenylene group, optionally substituted with one or more substituents selected from halogen, cyano, nitro or fluorenyl, wherein the thiol is optionally substituted with one or more halogens Replaced

R ^{6 is} selected from a mercapto group, wherein the mercapto group is further substituted by a heterocyclic group;

When R ^{0 is} selected from a heterocyclic-substituted indenyl group, A is selected from cyclodecyl, heterocyclyl, bicyclo indenyl, biheterocyclyl, bridged fluorenyl, hetero bridged fluorenyl, spiro fluorenyl or A spiroheterocyclyl group, wherein the cyclodecyl, heterocyclyl, bicycloindenyl, biheterocyclyl, bridged fluorenyl, heterobridged fluorenyl, spiro fluorenyl or spiroheterocyclyl is optionally further Or replaced by multiple R ¹² ;

1 ⁷ and 1 are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)OR ⁹ , -COR ⁹ , C ( 0) 0R ⁹ , -S(O)ONR ¹⁰ R ^u , substituted with a substituent of -CONR'V or -NR ¹⁽⁾ R";

Alternatively, R ⁷ and R ⁸ 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, 0 or S(0) _m hetero An atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S (0) Substituting a substituent of OR ⁹ , -COR ⁹ , C(0)0R ⁹ , -S^ONR^R ¹¹ , -CONFER ¹¹ or -NI^R'¹;

R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl or aryl group is optionally further substituted with one or more alkyl groups;

R ^{12 is} selected from the group consisting of decyl, alkoxy, cycloalkyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)0NR ⁷ R ^s , -CONR ⁷ R ⁸ , - C(0)OR ⁹ , - 0C(0)R ⁹ , -0(C3⁄4) _r C(0)0R ⁹ , - OC(0)NR ⁷ R ⁸ , -S(0) _m R ⁹ , -0S(0)0R ⁹ , - Substituted by a substituent of NHC(0)R ⁹ or -COR ⁹ wherein said fluorenyl, alkoxy, cyclodecyl or heterocyclic group is further further selected from one or more selected from the group consisting of alkyl, cyclodecyl Substituted with a substituent of a heterocyclic group, an aryl group or a heteroaryl group;

m is 0 or 1;

n is 0, 1 or 2; and

r is 1, 2 or 3.

5. The compound of the formula (I) according to claim 1, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and A pharmaceutically acceptable salt, wherein R ^{3 is} selected from decyl or cyclodecyl.

6. The compound of the formula (I) according to claim 1, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and A pharmaceutically acceptable salt, wherein the compound comprises:

A compound represented by the formula (IA) or a pharmaceutically acceptable salt, which is an intermediate for the preparation of a compound of the formula (I), wherein:

(ΙΑ)

among them:

R is selected from a hydrogen atom or an alkyl group;

R ^{1 is} selected from a hydrogen atom or an alkyl group;

R ² and R ³ together with the atoms to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or S(0) n heteroatoms, and the 3~ The 8-membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, aryl, halogen, hydroxy, cyano, carbonyl, carboxylic acid, carboxylic acid ester, -S(0)ONR ⁷ R ⁸ , Substituted by a substituent of CONR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(0)OR ⁹ or -COR ⁹ ;

R ^{7 to} R ⁹ are as defined in claim 1.

The compound of the formula (IA) or a pharmaceutically acceptable salt according to claim 7, wherein the

9. A process for the preparation of a compound of formula (I), comprising:

The compound of the formula (IA) is reacted with a salt of a compound of the formula (IB) or a compound of the formula (IB) to give a formula (I) Compound

among them:

R is selected from a methyl group;

G, Ri~R ³ are as defined in claim 7;

A, n, L, R ^{4 to} R ⁶ are as defined in claim 1.

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a tautomer, a racemate, an enantiomer thereof, a diastereomer The construct, and mixtures thereof, and pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or excipients.

11. A compound according to any one of claims 6 to 6, or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound Accepted salt, The use of the pharmaceutical composition according to claim 10 for the preparation of a medicament for the treatment of a cell proliferative disorder.

.

The use according to claim 11, wherein the cell proliferative disorder is cancer, infection, inflammation or autoimmune disease.

The use according to 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.

14. A method of treating a cell proliferative disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a tautomer thereof, a racemate thereof, An enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, the pharmaceutical composition according to claim 10, wherein the cell proliferative disorder is cancer, infection, Inflammation and autoimmune diseases, the cancer is cervical cancer or colon cancer.

The compound according to any one of claims 1 to 6, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable compound A salt composition according to claim 10, which is a medicament for treating a cell proliferation disease, wherein the cell proliferation-promoting disease is cancer, infection, inflammation, and autoimmune disease, said cancer For cervical or colon cancer

16. The chemical according to any one of claims 1 to 6 or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and A pharmaceutically acceptable salt, the use of a pharmaceutical composition according to claim 10 for the preparation of a Plk kinase inhibitor.

17. A method of inhibiting Plk kinase, the method comprising administering to a patient in need of treatment a therapeutically effective amount The compound according to any one of claims 1 to 6, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable compound Salt, a pharmaceutical composition according to claim 0.