TW202300149A - Pyridine derivatives and applications in medicine - Google Patents

Pyridine derivatives and applications in medicine Download PDF

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TW202300149A
TW202300149A TW111115534A TW111115534A TW202300149A TW 202300149 A TW202300149 A TW 202300149A TW 111115534 A TW111115534 A TW 111115534A TW 111115534 A TW111115534 A TW 111115534A TW 202300149 A TW202300149 A TW 202300149A
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heterocycloalkyl
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張靖
魏用剛
周錫兵
高成
孫毅
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大陸商成都百裕製藥股份有限公司
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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  • Pyridine Compounds (AREA)

Abstract

The present disclosure is relative to the pyridine derivatives and applications in medicine.

Description

吡啶衍生物及其在醫藥上的應用Pyridine Derivatives and Their Applications in Medicine

本申請涉及吡啶衍生物及其在醫藥上的應用。This application relates to pyridine derivatives and their application in medicine.

PARP(ploy(ADP-ribose)polymerases)是一類聚ADP-核糖聚合酶，催化多種蛋白聚二磷酸腺苷核糖基化(Poly-ADP-ribosylation)，該過程在DNA損傷修復、轉錄調控、染色質重組和重塑等許多細胞過程中發揮重要作用。目前，雖然有多個PARP1/PARP2抑制劑成功上市，但在臨床上無論單獨用藥還是聯用用藥，仍然普遍存在血液、胃腸道等副作用，導致臨床應用受到限制。因此，開發更安全有效的PARP抑制劑依然是臨床亟需解決的問題。一系列研究表明，與PARP1/PARP2抑制劑相比，高選擇性PARP1抑制劑具有更好的療效和更低的毒性，有望減少目前臨床上PARP類藥物的潛在風險，拓寬臨床應用範圍，提高患者的生活品質。PARP (ploy(ADP-ribose) polymerases) is a kind of poly ADP-ribose polymerase, which catalyzes the Poly-ADP-ribosylation of various proteins, which is involved in DNA damage repair, transcription regulation, chromatin Plays an important role in many cellular processes such as recombination and remodeling. At present, although a number of PARP1/PARP2 inhibitors have been successfully marketed, they still commonly have side effects such as blood and gastrointestinal tract in clinical practice, whether they are used alone or in combination, which limits their clinical application. Therefore, the development of safer and more effective PARP inhibitors is still an urgent clinical problem. A series of studies have shown that compared with PARP1/PARP2 inhibitors, highly selective PARP1 inhibitors have better efficacy and lower toxicity, and are expected to reduce the potential risks of current clinical PARP drugs, broaden the scope of clinical application, and improve the quality of life for patients. quality of life.

本申請的目的之一是提供吡啶衍生物或者其藥物可接受的鹽或立體異構物以及包含上述化合物的藥物組合物，以及其在醫藥上的應用。One of the purposes of this application is to provide pyridine derivatives or their pharmaceutically acceptable salts or stereoisomers, pharmaceutical compositions containing the above compounds, and their applications in medicine.

本申請的一個或多個實施方式提供式(I)的化合物或者其藥物可接受的鹽或立體異構物：

Figure 02_image001
(I) 其中： R 1為C 3-8環烷基或C 3-8雜環烷基，所述C 3-8雜環烷基包含1至4個選自N、O和S的雜原子； L為-NH-、-CO-或-(CR L1R L2) n-； R L1、R L2各自獨立地為H或C 1-6烷基，所述C 1-6烷基任選地被1個或者多個選自鹵素、羥基和氰基的取代基取代； A為4至12元雜環，所述4至12元雜環為4至12元單環、5至12元螺環、4至12元並環或4至12元橋環，所述4至12元雜環包含1至4個選自N、O和S的雜原子； R 2為H、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或C 3-8雜環烷基，所述C 3-8雜環烷基包含1至4個選自N、O和S的雜原子；所述C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或C 3-8雜環烷基任選地被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基和C 3-8雜環烷基的取代基取代； n為1或2。 One or more embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
Figure 02_image001
(I) wherein: R is C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O and S ; L is -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 , R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally Substituted by one or more substituents selected from halogen, hydroxyl and cyano; A is a 4 to 12 membered heterocycle, and the 4 to 12 membered heterocycle is a 4 to 12 membered monocyclic ring, a 5 to 12 membered spiro ring , 4 to 12 membered rings or 4 to 12 membered bridged rings, the 4 to 12 membered heterocycles contain 1 to 4 heteroatoms selected from N, O and S; R 2 is H, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl contains 1 to 4 heterocycloalkyl selected from N, O and S atom; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optionally replaced by one or more selected from halogen, hydroxyl, Substituents of cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl; n is 1 or 2.

在一個或多個實施方式中，所述式(I)的化合物被1個或多個(例如1、2、3、4、5、6、7、8、9或10個)氘取代。In one or more embodiments, the compound of formula (I) is substituted with one or more (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuteriums.

在一個或多個實施方式中，所述C 3-8雜環烷基或4至12元雜環包含1、2、3或4個選自N、O和S的雜原子。 In one or more embodiments, the C 3-8 heterocycloalkyl or 4 to 12 membered heterocycle contains 1, 2, 3 or 4 heteroatoms selected from N, O and S.

在一個或多個實施方式中，所述R 1為

Figure 02_image003
或
Figure 02_image005
。 In one or more embodiments, said R 1 is
Figure 02_image003
or
Figure 02_image005
.

在一個或多個實施方式中，L為-CH 2-、-CH(CH 3)-或-CD 2-。 In one or more embodiments, L is -CH 2 -, -CH(CH 3 )- or -CD 2 -.

在一個或多個實施方式中，A為

Figure 02_image007
、
Figure 02_image009
或
Figure 02_image011
。 In one or more embodiments, A is
Figure 02_image007
,
Figure 02_image009
or
Figure 02_image011
.

在一個或多個實施方式中，R 2為氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基；所述氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基任選地被一個或多個選自甲基、甲氧基和羥基的取代基取代。 In one or more embodiments, R 2 is oxolyl, oxanyl, azetidinyl, methyl, ethyl or propyl; , azetidinyl, methyl, ethyl or propyl is optionally substituted with one or more substituents selected from methyl, methoxy and hydroxy.

在一個或多個實施方式中，所述化合物為：

Figure 02_image013
、
Figure 02_image015
、
Figure 02_image017
、
Figure 02_image019
、
Figure 02_image021
、
Figure 02_image023
、
Figure 02_image025
、
Figure 02_image027
、
Figure 02_image029
或
Figure 02_image031
。 In one or more embodiments, the compound is:
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
or
Figure 02_image031
.

在一個或多個實施方式中，上述化合物被1個或者多個(例如1、2、3、4、5、6、7、8、9或10個)氘取代。In one or more embodiments, the above compounds are substituted with one or more (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) deuteriums.

在一個或多個實施方式中，鹵素為F、Cl或Br。In one or more embodiments, the halogen is F, Cl or Br.

本申請的一個或多個實施方式提供藥物組合物，所述藥物組合物包含： (1) 本申請的上述化合物或者其藥物可接受的鹽或立體異構物； (2) 任選的一種或多種其他活性成分；以及 (3) 藥物可接受的載體和/或賦形劑。 One or more embodiments of the present application provide a pharmaceutical composition comprising: (1) The above-mentioned compound of the present application or its pharmaceutically acceptable salt or stereoisomer; (2) Optionally one or more other active ingredients; and (3) Pharmaceutically acceptable carriers and/or excipients.

本申請的一個或多個實施方式提供通式(I’)所示的化合物或者其立體異構物：

Figure 02_image001
(I’) 其中： R 1選自C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子； L選自-NH-、-CO-或者-(CR L1R L2) n-； R L1、R L2各自獨立地選自H或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代； A為4至12元雜環，所述的4至12元雜環選自4至12元單環、5至12元螺環、4至12元並環或者4至12元橋環，所述的4至12元雜環可以包含1至4個選自N、O或S的雜原子； R 2選自H、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子；所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； n為1或者2。 One or more embodiments of the present application provide compounds represented by general formula (I') or stereoisomers thereof:
Figure 02_image001
(I') wherein: R 1 is selected from C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the C 3-8 heterocycloalkyl can contain 1 to 4 members selected from N, O or A heteroatom of S; L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 and R L2 are each independently selected from H or C 1-6 alkyl, and the C 1 -6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano; A is a 4 to 12-membered heterocycle, and the 4 to 12-membered heterocycle is selected from 4 to 12 Monocyclic ring, 5-12-membered spiro ring, 4-12-membered ring or 4-12-membered bridged ring, the 4-12-membered heterocyclic ring may contain 1 to 4 heteroatoms selected from N, O or S ; R 2 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl Can contain 1 to 4 heteroatoms selected from N, O or S; said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane The group is optionally further replaced by 1 or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkane Substituent substituent of group; n is 1 or 2.

本申請的一個或多個實施方式提供通式(I’’)所示的化合物或者其立體異構物：

Figure 02_image001
(I’’) 其中： R 1選自H、鹵素、C 2-6烯基或者C 2-6炔基，所述的C 2-6烯基或者C 2-6炔基任選地進一步被1個或者多個選自鹵素或者C 1-6烷基的取代基取代； L選自-NH-、-CO-或者-(CR L1R L2) n-； R L1、R L2各自獨立地選自H或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代； A為4至12元雜環，所述的4至12元雜環選自4至12元單環、5至12元螺環、4至12元並環或者4至12元橋環，所述的4至12元雜環可以包含1至4個選自N、O或S的雜原子； R 2選自H、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子，所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； n為1或者2。 One or more embodiments of the present application provide compounds represented by general formula (I'') or stereoisomers thereof:
Figure 02_image001
(I'') wherein: R 1 is selected from H, halogen, C 2-6 alkenyl or C 2-6 alkynyl, and said C 2-6 alkenyl or C 2-6 alkynyl is optionally further replaced by One or more substituents selected from halogen or C 1-6 alkyl are substituted; L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 and R L2 are each independently selected from From H or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano; A is a 4 to 12-membered heterocycle , the 4 to 12 membered heterocycle is selected from 4 to 12 membered monocyclic rings, 5 to 12 membered spiro rings, 4 to 12 membered rings or 4 to 12 membered bridged rings, and the 4 to 12 membered heterocycles can be Contains 1 to 4 heteroatoms selected from N, O or S; R is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 hetero Cycloalkyl, the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, Substituents of C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; n is 1 or 2.

本申請的一個或多個實施方式提供通式(I’’’)所示的化合物或者其立體異構物：

Figure 02_image001
(I’’’) 其中： R 1選自C 1-6烷基； L選自-NH-、-CO-或者-(CR L1R L2) n-； R L1、R L2各自獨立地選自H或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代； A為7至12元雜環，所述的7至12元雜環選自7至12元單環、7至12元螺環、7至12元稠環或者7至12元橋環，所述的7至12元雜環可以包含1至4個選自N、O或S的雜原子； R 2選自H、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子，所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； n為1或者2。 One or more embodiments of the present application provide compounds represented by general formula (I''') or stereoisomers thereof:
Figure 02_image001
(I''') wherein: R 1 is selected from C 1-6 alkyl; L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 and R L2 are each independently selected from H or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano; A is a 7- to 12-membered heterocycle, The 7- to 12-membered heterocycle is selected from a 7- to 12-membered monocyclic ring, a 7- to 12-membered spiro ring, a 7- to 12-membered condensed ring or a 7- to 12-membered bridged ring, and the 7 to 12-membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S; R 2 selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycle Alkyl, the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl is optionally further replaced by 1 or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C Substituents of 3-8 cycloalkyl or C 3-8 heterocycloalkyl; n is 1 or 2.

本申請的一個或多個實施方式提供通式(II’)所示的化合物或者其立體異構物：

Figure 02_image034
(II’) 其中： R 1選自C 1-6烷基； L選自-NH-、-CO-或者-(CR L1R L2) n-； R L1、R L2各自獨立地選自H或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代； X 1、X 2各自獨立地選自CR X或者N； R X選自H、羥基、氰基或者C 1-6烷基； 當X 1、X 2均為N時，R a選自羥基、氰基、=O或C 1-6烷基，所述C 1-6烷基任選地進一步被1個或者多個選自羥基、鹵素或者氰基的取代基取代； 當X 1、X 2有一個為CR X時，R a選自H、羥基、氰基、=O或C 1-6烷基，所述C 1-6烷基任選地進一步被1個或者多個選自羥基、鹵素或者氰基的取代基取代； R 2選自H、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子，所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； m為1、2或者3； n為1或者2。 One or more embodiments of the present application provide compounds represented by general formula (II') or stereoisomers thereof:
Figure 02_image034
(II') wherein: R 1 is selected from C 1-6 alkyl; L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 , R L2 are each independently selected from H or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano; X 1 and X 2 are each independently selected from CR X or N; R X is selected from H, hydroxyl, cyano or C 1-6 alkyl; when X 1 and X 2 are both N, R a is selected from hydroxyl, cyano, =O or C 1-6 alkane The C 1-6 alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, halogen or cyano; when one of X 1 and X 2 is CR X , R a is selected from H, hydroxyl, cyano, =0 or C 1-6 alkyl, the C 1-6 alkyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen or cyano; R 2 selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S, the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally is further substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl Substitution; m is 1, 2 or 3; n is 1 or 2.

本申請的一個或多個實施方式提供通式(III’)所示的化合物或者其立體異構物：

Figure 02_image036
(III’) 其中： R 1選自C 1-6烷基； L選自-NH-、-CO-或者-(CR L1R L2) n-； R L1、R L2各自獨立地選自H或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代； R 3選自H、鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基；所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自H、鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； R 2選自C 5-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子；所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； n為1或者2。 m為0、1、2或者3 One or more embodiments of the present application provide compounds represented by general formula (III') or stereoisomers thereof:
Figure 02_image036
(III') wherein: R 1 is selected from C 1-6 alkyl; L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 , R L2 are each independently selected from H or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano; R is selected from H, halogen, hydroxyl, cyano C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; said C 1-6 alkyl, C 1-6 alkoxy Group, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl is optionally further replaced by 1 or more selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 Substituents of alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; R 2 is selected from C 5-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkane or C 3-8 heterocycloalkyl group, said C 3-8 heterocycloalkyl group may contain 1 to 4 heteroatoms selected from N, O or S; said C 1-6 alkyl group, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optionally further replaced by one or more selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C Substituents of 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; n is 1 or 2. m is 0, 1, 2 or 3

本申請的一個或多個實施方式提供通式(III’’)所示的化合物或者其立體異構物：

Figure 02_image038
(III’’) 其中： R 1選自C 1-6烷基； L選自-NH-、-CO-或者-(CR L1R L2) n-； R L1、R L2各自獨立地選自H或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或者多個選自鹵素、羥基或者氰基的取代基取代； R 2選自C 5-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基，所述的C 3-8雜環烷基可以包含1至4個選自N、O或S的雜原子；所述的C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基任選地進一步被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或者C 3-8雜環烷基的取代基取代； n為1或者2。 One or more embodiments of the present application provide compounds represented by general formula (III'') or stereoisomers thereof:
Figure 02_image038
(III'') wherein: R 1 is selected from C 1-6 alkyl; L is selected from -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 and R L2 are each independently selected from H Or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or cyano; R 2 is selected from C 5-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl can contain 1 to 4 selected from N, O or S heteroatom; said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl is optionally further selected from one or more Halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; n is 1 or 2.

本申請的一個或多個實施方式提供本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物在製備抗腫瘤或抗癌藥物中的用途。One or more embodiments of the present application provide the use of the above-mentioned compound of the present application or its pharmaceutically acceptable salt or stereoisomer or the above-mentioned pharmaceutical composition in the preparation of anti-tumor or anti-cancer drugs.

本申請的一個或多個實施方式提供本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物，其用作藥物。One or more embodiments of the present application provide the above-mentioned compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-mentioned pharmaceutical composition, which is used as a medicine.

本申請的一個或多個實施方式提供本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物，其用於治療/預防癌症的方法。One or more embodiments of the present application provide the above-mentioned compound of the present application, or a pharmaceutically acceptable salt or stereoisomer thereof, or the above-mentioned pharmaceutical composition, which is used in a method for treating/preventing cancer.

本申請的一個或多個實施方式提供治療/預防腫瘤或癌症的方法，其包括將本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物用於有此需要的物件。One or more embodiments of the present application provide a method for treating/preventing tumors or cancer, which includes using the above-mentioned compound of the present application or its pharmaceutically acceptable salt or stereoisomer or the above-mentioned pharmaceutical composition for those in need object.

本申請的一個或多個實施方式提供抑制PARP1和/或PARP2的方法，其包括將本申請的上述化合物或者其藥物可接受的鹽或立體異構物或上述藥物組合物用於有此需要的物件。One or more embodiments of the present application provide a method for inhibiting PARP1 and/or PARP2, which includes using the above-mentioned compound of the present application or its pharmaceutically acceptable salt or stereoisomer or the above-mentioned pharmaceutical composition for those in need object.

除非有相反的陳述，在說明書和專利申請範圍中使用的術語具有下述含義。Unless stated otherwise, the terms used in the specification and scope of patent application have the following meanings.

本申請所述基團和化合物中所涉及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況，及本申請所述基團和化合物中所涉及的碳、氫、氧、硫或氮任選進一步被一個或多個它們對應的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氫的同位素包括氕 (H)、氘 (D，又叫重氫)、氚 (T，又叫超重氫)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds described in this application include their isotopes, and the carbon involved in the groups and compounds described in this application , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.

「烷基」是指1至20個碳原子的直鏈或支鏈飽和脂肪族烴基，優選為1至8個(例如1、2、3、4、5、6、7、8個)碳原子的烷基，更優選為1至6個碳原子的烷基，進一步優選為1至4個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構物；當烷基被取代基時，可以任選進一步被1個或者多個取代基所取代。"Alkyl" refers to a straight chain or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms An alkyl group, more preferably an alkyl group of 1 to 6 carbon atoms, and still more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and Its various branched chain isomers; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

「烷氧基」是指烷基中至少1個碳原子被氧原子取代所形成的基團。非限制性實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基。所述的烷基定義與上文所述的「烷基」定義相同。"Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy group and cyclobutoxy group. The definition of the alkyl group is the same as the definition of "alkyl group" mentioned above.

「烯基」是指含有1至10個(例如1、2、3、4、5、6、7、8、9、10個)碳-碳雙鍵，由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基，優選2至12個(例如2、3、4、5、6、7、8、9、10、11、12個)碳原子的烯基，更優選2至8個碳原子的烯基，進一步優選2至6個碳原子的烯基。非限制性實例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任選進一步被1個或者多個取代基所取代。"Alkenyl" means a straight group consisting of 2 to 20 carbon atoms containing 1 to 10 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds. Chain or branched unsaturated aliphatic hydrocarbon group, preferably alkenyl group with 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group having 8 carbon atoms, more preferably an alkenyl group having 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hex En-3-yl, Hepten-2-yl, Hepten-3-yl, Hepten-4-yl, Octen-3-yl, Nonen-3-yl, Decen-4-yl and Undecenyl -3-base. The alkenyl group may be optionally further substituted by one or more substituents.

「炔基」是指含有1至10個(例如1、2、3、4、5、6、7、8、9、或10個)碳-碳三鍵，由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基，優選2至12個(例如2、3、4、5、6、7、8、9、10、11或12個)碳原子的炔基，更優選2至8個碳原子的炔基，進一步優選2至6個碳原子的炔基。非限制性實例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任選進一步被一至多個取代基所取代。"Alkynyl" means a group containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Straight chain or branched unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) alkynyl groups of carbon atoms, more preferably 2 An alkynyl group of 8 to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl , Octyn-3-yl, Nonyn-3-yl, Decyn-4-yl, Undecyn-3-yl, Dodecyn-4-yl. The alkynyl group may be optionally further substituted by one or more substituents.

「芳基」是指是指取代的或未取代的芳香環，其可以是5至8元(例如5、6、7、8元)的單環、5至12元(例如5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，其可以是橋環或者螺環，非限制性實例包括苯基、萘基。所述的芳基可以任選進一步被1個或者多個取代基所取代。"Aryl" refers to a substituted or unsubstituted aromatic ring, which can be 5 to 8 membered (eg 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 5, 6, 7 , 8, 9, 10, 11, 12 membered) bicyclic rings or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, which may be bridged or spiro rings, non-limiting examples Including phenyl, naphthyl. The aryl group may be optionally further substituted by one or more substituents.

「雜芳基」是指取代的或未取代的芳香環，其可以是3至8元(例如3、4、5、6、7、8元)的單環、5至12元(例如5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，且包含1至6個(例如1、2、3、4、5、6個)選自N、O或S的雜原子，優選5至8元雜芳基，雜芳基的環中選擇性取代的1至4個(例如1、2、3、4個)N、S可被氧化成各種氧化態。雜芳基可以連接在雜原子或者碳原子上，雜芳基可以是橋環或者螺環，非限制性實例包括環吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、哌啶基苯並咪唑基、苯並吡啶基、吡咯並吡啶基。雜芳基任選進一步被1個或多個取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be 3 to 8 membered (such as 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (such as 5, 6, 7, 8, 9, 10, 11, 12) bicyclic or 10 to 15 (such as 10, 11, 12, 13, 14, 15) tricyclic system, and contains 1 to 6 (such as 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl, 1 to 4 (eg 1, 2 , 3, 4) N, S can be oxidized into various oxidation states. Heteroaryl groups can be attached to heteroatoms or carbon atoms, heteroaryl groups can be bridged rings or spiro rings, non-limiting examples include cyclopyridyl, furyl, thienyl, pyryl, pyrrolyl, pyrimidyl, pyrimidinyl, Azidinyl, pyridazinyl, imidazolyl, piperidylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl is optionally further substituted with one or more substituents.

「碳環基」或「碳環」是指飽和或者不飽和的芳香環或者非芳香環。當為芳香環時，其定義與上文「芳基」的定義相同；當為非芳香環時，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，可以是橋環或者螺環，非限制性實例包括環丙基、環丁基、環戊基、1-環戊基-1-烯基、1-環戊基-2-烯基、1-環戊基-3-烯基、環己基、1-環己基-2-烯基、1-環己基-3-烯基、環己烯基、環己二烯基、環庚基、環辛基、環壬基、環癸基、環十一烷基、環十二烷基、

Figure 02_image040
、
Figure 02_image042
、
Figure 02_image044
、
Figure 02_image046
。所述的「碳環基」或「碳環」任選進一步被1個或者多個取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl"above; when it is a non-aromatic ring, it can be 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 member) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 member) tricyclic ring system, which may be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2- Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl Cyclooctyl, Cyclononyl, Cyclodecyl, Cycloundecyl, Cyclododecyl,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image044
,
Figure 02_image046
. The "carbocyclyl" or "carbocycle" is optionally further substituted by one or more substituents.

「雜環基」或「雜環」是指飽和或不飽和的芳香性雜環或者非芳香性雜環，當為芳香性雜環時，其定義與上文「雜芳基」定義相同；當為非芳香性雜環時，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，且包含1至4個(例如1、2、3、4個)選自N、O或S的雜原子，優選3至8元雜環基。「雜環基」或「雜環」的環中選擇性取代的1至4個(例如1、2、3、4個)N、S可被氧化成各種氧化態；「雜環基」或「雜環」可以連接在雜原子或者碳原子上；「雜環基」或「雜環」可以為橋環或者螺環。「雜環基」或「雜環」的非限制性實例包括環氧乙基、環氧丙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、硫雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、氧雜環庚基、硫雜環庚基、氧氮雜卓基、二氮雜卓基、硫氮雜卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、哌嗪基、高哌嗪基、咪唑基、嗎啉基、硫代嗎啉基、噻噁烷基、1,3-二噻烷基、二氫呋喃基、二噻戊環基、四氫呋喃基、四氫噻吩基、四氫吡喃基、四氫噻喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、2-吡咯啉基、3-吡咯啉基、二氫吲哚基、2H-吡喃基、4H-吡喃基、二氧雜環己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氫噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氫異喹啉基、3-氮雜雙環[3.1.0]己基、3-氮雜雙環[4.1.0]庚基、氮雜雙環[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代嗎啉基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。所述的「雜環基」或「雜環」可以任選進一步被1個或者多個取代基所取代。"Heterocyclic group" or "heterocyclic ring" refers to a saturated or unsaturated aromatic heterocyclic ring or non-aromatic heterocyclic ring. When it is an aromatic heterocyclic ring, its definition is the same as that of "heteroaryl" above; when When it is a non-aromatic heterocycle, it can be a monocyclic ring with 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 members), a 4 to 12 member (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12) bicyclic or 10 to 15 (such as 10, 11, 12, 13, 14, 15) tricyclic system, and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. "Heterocyclyl" or 1 to 4 (eg 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclic ring" can be oxidized to various oxidation states; "heterocyclyl" or " "Heterocycle" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, epoxypropyl, aziridyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepyl, thiepanyl, oxynitrogen Pyridine, diazepinyl, thiazepinyl, pyridyl, piperidyl, homopiperidyl, furyl, thienyl, pyryl, N-alkylpyrrolyl, pyrimidyl, pyrazine Base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiapentyl Cyclo, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzene Pyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxetane Hexyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithianyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3 ,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolyl Quinazinyl, N-pyridyl urea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclic group" or "heterocycle" may be optionally further substituted by one or more substituents.

「環烷基」是指飽和的環烴基，其環可以為3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多環體系，環碳原子優選3至10個碳原子，進一步優選3至8個碳原子。「環烷基」非限制性實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、1,5-環辛二烯基、1,4-環己二烯基和環庚三烯基等。當環烷基被取代時，可以任選進一步被1個或者多個取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring can be 3 to 10 membered (such as 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (such as 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) more In the ring system, the ring carbon atoms preferably have 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene group, cycloheptenyl group, 1,5-cyclooctadienyl group, 1,4-cyclohexadienyl group and cycloheptatrienyl group etc. When the cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

「雜環烷基」是指取代的或未取代的飽和非芳香環基，其可以是3至8元(例如3、4、5、6、7、8元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，且包含1、2、3或4個選自N、O或S的雜原子，優選3至8元雜環基。「雜環烷基」的環中選擇性取代的1、2或3個N、S可被氧化成各種氧化態；「雜環烷基」可以連接在雜原子或者碳原子上；「雜環烷基」可以為橋環或者螺環。「雜環烷基」非限制性實例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、哌啶基、哌叮基、嗎啉基、硫代嗎啉基、1,3-二噻烷基、四氫呋喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be 3 to 8 membered (such as 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 members) bicyclic rings or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 members) tricyclic ring systems, and comprising 1, 2, 3 or 4 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. The 1, 2 or 3 N, S optionally substituted in the ring of "heterocycloalkyl" can be oxidized into various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; "heterocycloalkane The group "can be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxo Pentyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatri Cyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl.

當上文所述的「烷基」、「烷氧基」、「烯基」、「炔基」、「芳基」、「雜芳基」、「碳環基」、「碳環」、「雜環基」、「雜環」、「環烷基」、「雜環烷基」或者「雜環基」被取代時，可以選進一步被0、1、2、3、4、5、6、7、8、9或者10個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、C 1-6烷基氨基、=O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、=NR q6、-C(=O)OC 1-6烷基、-OC(=O)C 1-6烷基、-C(=O)NR q4R q5、C 3-8環烷基、C 3-8雜環烷基、C 6-10芳基、C 5-10雜芳基、-C(=O)OC 6-10芳基、-OC(=O)C 6-10芳基、-OC(=O)C 5-10雜芳基、-C(=O)OC 5-10雜芳基、-OC(=O)C 3-8雜環烷基、-C(=O)OC 3-8雜環烷基、-OC(=O)C 3-8環烷基、-C(=O)OC 3-8環烷基、-NHC(=O)C 3-8雜環烷基、-NHC(=O)C 6-10芳基、-NHC(=O)C 5-10雜芳基、-NHC(=O)C 3-8環烷基、-NHC(=O)C 3-8雜環烷基、-NHC(=O)C 2-6烯基或者-NHC(=O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8環烷基、C 3-8雜環烷基、C 6-10芳基、C 5-10雜芳基、-NHC(=O)C 6-10芳基、-NHC(=O)C 5-10雜芳基、-NHC(=O)C 3-8雜環烷基或者-NHC(=O)C 3-8環烷基任選進一步被1至3個選自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者=O的取代基所取代；R q1選自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3選自H或者C 1-6烷基；其中，R q4、R q5選自H、C 1-6烷基、-NH(C=NR q1)NR q2R q3、-S(=O) 2NR q2R q3、-C(=O)R q1或者-C(=O)NR q2R q3，其中所述的C 1-6烷基任選進一步被1個或者多個選自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10雜芳基、C 3-8環烷基或者C 3-8雜環烷基的取代基所取代；或者R q4與R q5及N原子形成一個3至8元雜環，所述雜環可以含有1個或者多個選自N、O或者S的雜原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it can be further selected by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, - C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl Aryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, -C( =O)OC 3-8cycloalkyl , -NHC(=O)C 3-8heterocycloalkyl , -NHC(=O)C 6-10aryl , -NHC(=O)C 5-10hetero Aryl, -NHC(=O)C 3-8cycloalkyl , -NHC(=O)C 3-8heterocycloalkyl , -NHC(=O)C 2-6alkenyl or -NHC(=O ) C 2-6 alkynyl substituent, and wherein the substituent C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(=O) C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O)C 3-8 cycloalkyl is optionally further replaced by 1 to 3 selected from OH, F, Substituted by Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =O; R q1 is selected from C 1-6 alkyl, C 1-6 Alkoxy or C 6-10 aryl; R q2 and R q3 are selected from H or C 1-6 alkyl; wherein, R q4 and R q5 are selected from H, C 1-6 alkyl, -NH(C= NR q1 ) NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 alkyl Optionally further selected by 1 or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl Substituent group, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 and R q5 and N atom form a 3 to 8-membered heterocyclic ring, the heterocyclic ring may contain 1 Or a plurality of heteroatoms selected from N, O or S.

鹵素包括F、Cl、Br和I。Halogen includes F, Cl, Br and I.

「藥物可接受的鹽」或者「其藥物可接受的鹽」是指本申請化合物保持游離酸或者游離鹼的生物有效性和特性，且所述的游離酸通過與無毒的無機鹼或者有機鹼，所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。"Pharmaceutical acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present application maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is mixed with a non-toxic inorganic base or organic base, The free base is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.

「藥物組合物」是指一種或多種本申請所述化合物、其藥物可接受的鹽或前藥和其它化學組分形成的混合物，其中，「其它化學組分」是指藥物可接受的載體、賦形劑和/或一種或多種其它治療劑。"Pharmaceutical composition" refers to a mixture of one or more compounds described in this application, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refer to pharmaceutically acceptable carriers, Excipients and/or one or more other therapeutic agents.

「載體」是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。"Carrier" means a material that does not produce significant irritation to an organism and that does not abrogate the biological activity and properties of the administered compound.

「賦形劑」是指加入到藥物組合物中以促進化合物給藥的惰性物質。非限制性實施例包括碳酸鈣、磷酸鈣、糖、澱粉、纖維素衍生物 (包括微晶纖維素)、明膠、植物油、聚乙二醇類、稀釋劑、成粒劑、潤滑劑、粘合劑和崩解劑。"Excipient" means an inert substance added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.

「立體異構物」是指由分子中原子在空間上排列方式不同所產生的異構物，包括順反異構物、對映異構物和構象異構物。"Stereoisomers" refer to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

「任選」或「任選地」或「選擇性的」或「選擇性地」是指隨後所述的事件或狀況可以但未必發生，該描述包括其中發生該事件或狀況的情況及其中未發生的情況。例如，「選擇性地被烷基取代的雜環基」是指該烷基可以但未必存在，該描述包括其中雜環基被烷基取代的情況，及其中雜環基未被烷基取代的情況。"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or circumstance may but not necessarily occur, and that the description includes the circumstances in which the event or circumstance occurs and the circumstances in which it is not what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group, and cases where the heterocyclyl group is not substituted with an alkyl group Condition.

以下實施例詳細說明本申請的技術方案，但本申請的保護範圍包括但是不限於此。The following examples illustrate the technical solutions of the present application in detail, but the protection scope of the present application includes but is not limited thereto.

化合物的結構是通過核磁共振(NMR)或(和)質譜(MS)來確定的。NMR位移(δ)以10 -6(ppm)的單位給出。NMR的測定是用Bruker Avance III 400和Bruker Avance 300核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，內標為四甲基矽烷(TMS)； MS的測定用Agilent 6120B(ESI)和Agilent 6120B(APCI)； 薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法 (TLC)使用的矽膠板採用的規格是0.15 mm - 0.20 mm，薄層層析分離純化產品採用的規格是0.4 mm - 0.5 mm； 柱層析一般使用煙臺黃海矽膠200-300目矽膠為載體。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic instruments, and the determination solvent is deuterated dimethyl sulfide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS); Agilent 6120B (ESI) and Agilent 6120B (APCI) are used for the determination of MS; Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography, and thin-layer chromatography (TLC) The specifications of the silica gel plates used are 0.15 mm - 0.20 mm, and the specifications of thin layer chromatography separation and purification products are 0.4 mm - 0.5 mm; column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

實施例 15-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶醯胺 Example 1 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-methylpyridinamide

化合物 15-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

Figure 02_image048
Figure 02_image050
Compound 1 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
Figure 02_image048
Figure 02_image050

第一步 6-甲醯基-5-硝基煙酸乙酯 1bethyl 6-formyl-5-nitronicotinate 將6-甲基-5-硝基煙酸乙酯 1a(購自江蘇艾康生物醫藥研發有限公司，10 g，45.6 mmol)、二氧化硒(7.6 g，68.4 mmol)溶於二氧六環(100 mL)，在110 ℃下回流4 h，反應完後熱過濾，將濾液減壓濃縮，柱層析得到化合物 1b(黃色固體，9.7 g，產率90%)。 LC-MS m/z (ESI) = 225.10 [M+1]。 The first step 6-formyl-5-nitronicotinate ethyl ester 1b ethyl 6-formyl-5-nitronicotinate 6-methyl-5-nitronicotinic acid ethyl ester 1a (purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., 10 g, 45.6 mmol), selenium dioxide (7.6 g, 68.4 mmol) were dissolved in dioxane (100 mL), refluxed at 110 °C for 4 h, hot filtered after the reaction, and the filtrate was concentrated under reduced pressure , column chromatography to obtain compound 1b (yellow solid, 9.7 g, yield 90%). LC-MS m/z (ESI) = 225.10 [M+1].

第二步 6-(2-溴-3-乙氧基-3-氧丙烷-1-烯-1-基)-5-硝基煙酸乙酯 1cethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate 將2-溴-2-(二乙氧基磷醯)乙酸乙酯(購自上海邁瑞爾化學技術有限公司，20 g，66.6 mmol)溶於四氫呋喃(100 mL)，-78 ℃下緩慢加入氫化鈉(1.6 g，66.6 mmol)，緩慢升溫至40 ℃反應10 min，再降溫到-78 ℃下緩慢滴加 1b(9.7 g，44.4 mmol)的四氫呋喃溶液，反應15 min後加入飽和氯化銨水溶液(100 mL)淬滅，乙酸乙酯(100 mL×3)萃取，合併有機相減壓濃縮，柱層析得到 1c(黃色固體，13 g，產率81%，E/Z=10 : 3)。 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, 1H), 9.23 (d, 0.3H), 8.86 (d, 1H), 8.80 (d, 0.3H), 8.61 (s, 1H), 7.89 (s, 0.3H), 4.46-4.38 (m, 2.6H), 4.34 (q, 2H), 4.16 (q, 0.6H), 1.39-1.34 (m, 3.9H), 1.32 (t, 3H), 1.08 (t, 0.9H)。 LC-MS m/z (ESI) = 373.00 [M+1]。 The second step 6-(2-bromo-3-ethoxy-3-oxypropan-1-en-1-yl)-5-nitronicotinic acid ethyl ester 1c ethyl 6-(2-bromo-3-ethoxy -3-oxoprop-1-en-1-yl)-5-nitronicotinate 2-bromo-2-(diethoxyphosphoryl) ethyl acetate (purchased from Shanghai Merrill Chemical Technology Co., Ltd., 20 g, 66.6 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydride (1.6 g, 66.6 mmol) was slowly added at -78 °C, the temperature was slowly raised to 40 °C for 10 min, and then 1b (9.7 g, 44.4 mmol) in tetrahydrofuran solution, reacted for 15 min, quenched by adding saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL×3), combined organic phases were concentrated under reduced pressure, and column chromatography gave 1c (yellow solid , 13 g, yield 81%, E/Z=10: 3). 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, 1H), 9.23 (d, 0.3H), 8.86 (d, 1H), 8.80 (d, 0.3H), 8.61 (s, 1H), 7.89 ( s, 0.3H), 4.46-4.38 (m, 2.6H), 4.34 (q, 2H), 4.16 (q, 0.6H), 1.39-1.34 (m, 3.9H), 1.32 (t, 3H), 1.08 ( t, 0.9H). LC-MS m/z (ESI) = 373.00 [M+1].

第三步 5-氨基-6-(2-溴-3-乙氧基-3-氧代丙-1-烯-1-基)煙酸乙酯 1dethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate 化合物 1c(13 g，34.8 mmol)溶於醋酸(130 mL)中，加入鐵粉(5.8 g，104.5 mmol)，室溫反應2 h後加入蒸餾水(100 mL)淬滅反應，乙酸乙酯(100 mL×3)萃取，合併有機相減壓濃縮，得到化合物 1d(黃色固體，10 g，產率83 %)。 LC-MS m/z (ESI) = 343.00 [M+1]。 The third step is 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinic acid ethyl ester 1d ethyl 5-amino-6-(2-bromo -3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate Compound 1c (13 g, 34.8 mmol) was dissolved in acetic acid (130 mL), iron powder (5.8 g, 104.5 mmol) was added, and reacted at room temperature After 2 h, distilled water (100 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), and the combined organic phases were concentrated under reduced pressure to obtain compound 1d (yellow solid, 10 g, yield 83%). LC-MS m/z (ESI) = 343.00 [M+1].

第四步 7-溴-6-氧-5,6-二氫-1,5-萘啶-3-羧酸乙酯 1eethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate 將化合物 1d(10 g，29.1 mmol)置於反應瓶中，氮氣保護下加入溴化氫的醋酸溶液(100 mL), 50 ℃下反應4 h後減壓濃縮，飽和碳酸氫鈉水溶液(100 mL)淬滅反應，乙酸乙酯(50 mL×3)萃取，減壓濃縮，柱層析得到化合物 1e(黃色固體，2 g，產率23%)。 1H NMR (400 MHz, DMSO- d 6) δ 12.54 (s, 1H), 8.88 (d, 1H), 8.51 (s, 1H), 8.14 (d, 1H), 4.37 (q, 2H), 1.35 (t, 3H)。 LC-MS m/z (ESI) = 297.00 [M+1]。 The fourth step 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester 1e ethyl 7-bromo-6-oxo-5,6-dihydro-1,5 -naphthyridine-3-carboxylate Put compound 1d (10 g, 29.1 mmol) in a reaction flask, add hydrogen bromide in acetic acid solution (100 mL) under nitrogen protection, react at 50 °C for 4 h, then concentrate under reduced pressure, and saturated carbonic acid The reaction was quenched with sodium hydrogen aqueous solution (100 mL), extracted with ethyl acetate (50 mL×3), concentrated under reduced pressure, and column chromatography gave compound 1e (yellow solid, 2 g, yield 23%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.54 (s, 1H), 8.88 (d, 1H), 8.51 (s, 1H), 8.14 (d, 1H), 4.37 (q, 2H), 1.35 ( t, 3H). LC-MS m/z (ESI) = 297.00 [M+1].

第五步 7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-羧酸乙酯 1fethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate 將化合物 1e(400 mg，1.3 mmol)、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(購自成都叮噹時代醫藥科技有限公司，328 mg，0.40 mmol)、碳酸鉀(745 mg，5.4 mmol)、環丙基硼酸(杭州艾康生物技術有限公司，231 mg，2.7 mmol)溶於二氧六環(4 mL)，110 ℃下回流8 h後加水(5 mL)淬滅，乙酸乙酯(5 mL×3)萃取，減壓濃縮柱層析純化，得到化合物 1f(黃色固體，270 mg，產率77 %)。 1H NMR (400 MHz, DMSO- d 6) δ 12.07 (s, 1H), 8.85 (d, 1H), 8.12 (d, 1H), 7.46 (s, 1H), 4.36 (q, 2H), 2.25-2.12 (m, 1H), 1.34 (t, 3H), 1.02 (dt, 2H), 0.90 (dt, 2H)。 LC-MS m/z (ESI) = 259.10 [M+1]。 The fifth step 1,5-naphthyridine-3-carboxylate Compound 1e (400 mg, 1.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (purchased from Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd., 328 mg, 0.40 mmol), potassium carbonate (745 mg, 5.4 mmol), cyclopropylboronic acid (Hangzhou Aikang Biotechnology Co., Ltd., 231 mg, 2.7 mmol) were dissolved in dioxane (4 mL), refluxed at 110 °C for 8 h, quenched with water (5 mL), extracted with ethyl acetate (5 mL×3), concentrated under reduced pressure and purified by column chromatography to obtain compound 1f (yellow solid, 270 mg, yield rate of 77%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.07 (s, 1H), 8.85 (d, 1H), 8.12 (d, 1H), 7.46 (s, 1H), 4.36 (q, 2H), 2.25- 2.12 (m, 1H), 1.34 (t, 3H), 1.02 (dt, 2H), 0.90 (dt, 2H). LC-MS m/z (ESI) = 259.10 [M+1].

第六步 3-環丙基-7-(羥甲基)-1,5-萘啶-2(1H)-酮 1g3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one 將化合物 1f(270 mg，1 mmol)溶於四氫呋喃(2 mL)，在冰水浴下緩慢滴加四氫鋁鋰的四氫呋喃溶液(購自安耐吉化學，2 mL，2 mmol)，滴加完攪拌10 min，加入乙酸乙酯(1 mL)，減壓濃縮柱層析得到化合物 1g(黃色固體，100 mg，產率44%)。 1H NMR (400 MHz, DMSO- d 6) δ 11.92 (s, 1H), 8.35 (d, 1H), 7.59 (d, 1H), 7.41 (s, 1H), 5.45 (t, 1H), 4.60 (d, 2H), 2.16-2.09 (m, 1H), 0.96 (dt, 2H), 0.82 (dt, 2H)。 LC-MS m/z (ESI) = 217.10 [M+1]。 Step 6 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one 1g 3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H )-one Dissolve compound 1f (270 mg, 1 mmol) in tetrahydrofuran (2 mL), and slowly add tetrahydrofuran solution (purchased from Anaiji Chemicals, 2 mL, 2 mmol) dropwise under ice-water bath, After the dropwise addition, stir for 10 min, add ethyl acetate (1 mL), concentrate under reduced pressure and perform column chromatography to obtain compound 1g (yellow solid, 100 mg, yield 44%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.92 (s, 1H), 8.35 (d, 1H), 7.59 (d, 1H), 7.41 (s, 1H), 5.45 (t, 1H), 4.60 ( d, 2H), 2.16-2.09 (m, 1H), 0.96 (dt, 2H), 0.82 (dt, 2H). LC-MS m/z (ESI) = 217.10 [M+1].

第七步 7-(溴甲基)-3-環丙基-1,5-萘啶-2(1H)-酮 1h7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one 將化合物 1 g(100 mg，0.46 mmol)和三苯基膦(購自上海阿達瑪斯試劑有限公司，242 mg，0.92 mmol)溶於二氯甲烷(1 mL)，在冰水浴下加入四溴化碳(購自安耐吉化學，306 mg，0.92 mmol)的二氯甲烷(0.5 mL)溶液，反應0.5 h，反應液減壓濃縮後經柱層析得到化合物 1h(黃色固體，100 mg，產率78%)。 LC-MS m/z (ESI) = 279.00 [M+1]。 The seventh step 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one 1h 7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H )-one Dissolve compound 1 g (100 mg, 0.46 mmol) and triphenylphosphine (purchased from Shanghai Adamas Reagent Co., Ltd., 242 mg, 0.92 mmol) in dichloromethane (1 mL), and place in an ice-water bath Add carbon tetrabromide (purchased from Anaiji Chemicals, 306 mg, 0.92 mmol) in dichloromethane (0.5 mL) and react for 0.5 h. The reaction solution was concentrated under reduced pressure and then subjected to column chromatography to obtain compound 1h (yellow solid, 100 mg, yield 78%). LC-MS m/z (ESI) = 279.00 [M+1].

第八步 5-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶醯胺 化合物 15-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide 將化合物 1h(100 mg，0.36 mmol)、N-甲基-5-(哌嗪-1-基)吡啶甲醯胺 1i(江蘇藥澤醫藥科技有限公司，86 mg，0.39 mmol)、N,N-二異丙基乙胺(230 mg，1.8 mmol)溶解在乙腈(4 mL)中，80 ℃下反應4 h，反應液減壓濃縮經製備色譜得到 化合物 1(白色固體，40 mg，產率27%)。 1H NMR (400 MHz, DMSO- d 6) δ 11.89 (s, 1H), 8.40 (d, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.38 (dd, 1H), 3.63 (s, 2H), 2.34-3.31 (s, 4H), 2.77 (d, 3H), 2.56-2.53 (d, 4H), 2.19-2.09 (m, 1H), 0.99-0.91 (m, 2H), 0.84-0.76 (m, 2H)。 LC-MS m/z (ESI) = 419.20 [M+1]。 The eighth step 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-Methylpyridinamide Compound 1 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N -methylpicolinamide Compound 1h (100 mg, 0.36 mmol), N-methyl-5-(piperazin-1-yl)picolinamide 1i (Jiangsu Yaoze Pharmaceutical Technology Co., Ltd., 86 mg, 0.39 mmol), N , N-diisopropylethylamine (230 mg, 1.8 mmol) was dissolved in acetonitrile (4 mL), reacted at 80 °C for 4 h, and the reaction solution was concentrated under reduced pressure to obtain Compound 1 (white solid, 40 mg, Yield 27%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.89 (s, 1H), 8.40 (d, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 7.82 (d, 1H), 7.60 ( d, 1H), 7.42 (s, 1H), 7.38 (dd, 1H), 3.63 (s, 2H), 2.34-3.31 (s, 4H), 2.77 (d, 3H), 2.56-2.53 (d, 4H) , 2.19-2.09 (m, 1H), 0.99-0.91 (m, 2H), 0.84-0.76 (m, 2H). LC-MS m/z (ESI) = 419.20 [M+1].

實施例 2( R)-5-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)哌嗪-1-基)- N-(四氫呋喃-3-基)吡啶醯胺 化合物 2( R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(tetrahydrofuran-3-yl)picolinamide

Figure 02_image052
Figure 02_image054
將化合物 2a(22.08 mg，0.08 mmol)和化合物 1h(22.32 mg，0.08 mmol)溶解於乙腈(5 mL)中，加入N,N-二異丙基乙胺(購自上海麥克林生化科技有限公司，51.7 mg，0.4 mmol)，70 °C下反應3 h，旋幹反應液，粗品經柱層析分離(MeOH:DCM=1:60到1:15)，得到 化合物 2(白色固體，26 mg，產率71%)。 1H NMR (400 MHz, DMSO- d 6 ) δ 12.13 (s, 1H), 8.38 (d, 2H), 8.27 (s, 1H), 7.83 (d, 1H), 7.60 (s, 1H), 7.40 (d, 2H), 4.47-4.42 (m, 1H), 3.87-3.79 (m, 2H), 3.73-3.68 (m, 1H), 3.63 (s, 2H), 3.59-3.55 (m, 1H), 3.43-3.37 (m, 4H), 2.56-2.54 (m, 4H), 2.17-2.09 (m, 2H), 1.97-1.91 (m, 1H), 0.99-0.93 (m, 2H), 0.82-0.80(m, 2H)。 LC-MS m/z (ESI) = 475.24 [M+1]。 Example 2 ( R )-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl) -N- (tetrahydrofuran-3-yl)pyridinamide Compound 2 ( R )-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3 -yl)methyl)piperazin-1-yl)- N -(tetrahydrofuran-3-yl)picolinamide
Figure 02_image052
Figure 02_image054
Compound 2a (22.08 mg, 0.08 mmol) and compound 1h (22.32 mg, 0.08 mmol) were dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (purchased from Shanghai Macklin Biochemical Technology Co., Ltd. , 51.7 mg, 0.4 mmol), reacted at 70 °C for 3 h, spin-dried the reaction solution, and the crude product was separated by column chromatography (MeOH:DCM=1:60 to 1:15) to obtain Compound 2 (white solid, 26 mg , yield 71%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.13 (s, 1H), 8.38 (d, 2H), 8.27 (s, 1H), 7.83 (d, 1H), 7.60 (s, 1H), 7.40 ( d, 2H), 4.47-4.42 (m, 1H), 3.87-3.79 (m, 2H), 3.73-3.68 (m, 1H), 3.63 (s, 2H), 3.59-3.55 (m, 1H), 3.43- 3.37 (m, 4H), 2.56-2.54 (m, 4H), 2.17-2.09 (m, 2H), 1.97-1.91 (m, 1H), 0.99-0.93 (m, 2H), 0.82-0.80(m, 2H ). LC-MS m/z (ESI) = 475.24 [M+1].

實施例 35-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)哌嗪-1-基)- N-(2-羥乙基)吡啶醯胺 化合物 35-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(2-hydroxyethyl)picolinamide

Figure 02_image025
Figure 02_image056
參考 化合物 2的合成方法，得到 化合物 3(白色固體，31 mg，產率76%)。 1H NMR (400 MHz, DMSO- d 6 ) δ 11.90 (s, 1H), 8.41-8.33 (m, 2H), 8.28 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.41-7.38 (m, 1H), 4.79 (t, 1H), 3.63 (s, 2H), 3.49 (q, 2H), 3.37-3.35 (m, 2H), 3.34-3.32 (m, 4H), 2.56-2.53 (m, 4H), 2.18-2.12 (m, 1H), 1.01-0.93 (m, 2H), 0.85-0.80 (m, 2H)。 LC-MS m/z (ESI) = 449.22 [M+1]。 Example 3 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N -(2-Hydroxyethyl)pyridinamide Compound 3 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1 -yl)- N -(2-hydroxyethyl)picolinamide
Figure 02_image025
Figure 02_image056
Referring to the synthetic method of compound 2 , compound 3 (white solid, 31 mg, yield 76%) was obtained. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.90 (s, 1H), 8.41-8.33 (m, 2H), 8.28 (d, 1H), 7.83 (d, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.41-7.38 (m, 1H), 4.79 (t, 1H), 3.63 (s, 2H), 3.49 (q, 2H), 3.37-3.35 (m, 2H), 3.34-3.32 ( m, 4H), 2.56-2.53 (m, 4H), 2.18-2.12 (m, 1H), 1.01-0.93 (m, 2H), 0.85-0.80 (m, 2H). LC-MS m/z (ESI) = 449.22 [M+1].

實施例 45-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)哌嗪-1-基)- N-(2-甲氧基乙基)吡啶醯胺 化合物 45-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-(2-methoxyethyl)picolinamide

Figure 02_image058
Figure 02_image060
參考 化合物 2的合成方法，得到 化合物 4(白色固體，28 mg，產率74%)。 1H NMR (400 MHz, DMSO- d 6) δ 11.90 (s, 1H), 8.36 (d, 2H), 8.28 (d, 1H), 7.83 (d, 1H), 7.60 (s, 1H), 7.45-7.37 (m, 2H), 3.63 (s, 2H), 3.46-3.42(m, 4H), 3.39-3.35 (t, 2H), 3.33-3.10 (m, 2H), 3.26 (s, 3H), 2.56-2.53 (m, 4H), 2.18-2.11 (m, 1H), 0.99-0.94 (m, 2H), 0.85-0.79 (m, 2H)。 LC-MS m/z (ESI) = 463.24 [M+1]。 Example 4 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N -(2-Methoxyethyl)pyridinamide Compound 4 5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin -1-yl)- N -(2-methoxyethyl)picolinamide
Figure 02_image058
Figure 02_image060
Referring to the synthetic method of compound 2 , compound 4 (white solid, 28 mg, yield 74%) was obtained. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.90 (s, 1H), 8.36 (d, 2H), 8.28 (d, 1H), 7.83 (d, 1H), 7.60 (s, 1H), 7.45- 7.37 (m, 2H), 3.63 (s, 2H), 3.46-3.42(m, 4H), 3.39-3.35 (t, 2H), 3.33-3.10 (m, 2H), 3.26 (s, 3H), 2.56- 2.53 (m, 4H), 2.18-2.11 (m, 1H), 0.99-0.94 (m, 2H), 0.85-0.79 (m, 2H). LC-MS m/z (ESI) = 463.24 [M+1].

實施例 5( R)-5-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基- N-(四氫呋喃-3-基)吡啶醯胺 化合物 5( R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl- N-(tetrahydrofuran-3-yl)picolinamide

Figure 02_image062
Figure 02_image064
參考 化合物 2的合成方法，得到 化合物 5(白色固體，29 mg，產率76%)。 1H NMR (400 MHz, DMSO- d6) δ 11.89 (s, 1H), 8.41 – 8.34 (m, 2H), 7.80 (d, 1H), 7.60 (s, 1H), 7.48 (d, 1H), 7.42 (s, 1H), 4.50-4.42 (m, 1H), 3.92 – 3.77 (m, 2H), 3.74-3.70 (m, 1H), 3.66 (s, 2H), 3.59 (dd, 1H), 2.96-2.93 (m, 4H), 2.60-2.56 (m, 4H), 2.51 (s, 3H), 2.22 – 2.10 (m, 2H), 1.97-1.89 (m, 1H), 0.99-0.94 (m, 2H), 0.85 – 0.79 (m, 2H)。 LC-MS m/z (ESI) =489.25 [M+1]。 Example 5 ( R )-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl)-6-methyl- N- (tetrahydrofuran-3-yl)pyridinamide compound 5 ( R )-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1, 5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl- N- (tetrahydrofuran-3-yl)picolinamide
Figure 02_image062
Figure 02_image064
Referring to the synthetic method of compound 2 , compound 5 (white solid, 29 mg, yield 76%) was obtained. 1 H NMR (400 MHz, DMSO- d6 ) δ 11.89 (s, 1H), 8.41 – 8.34 (m, 2H), 7.80 (d, 1H), 7.60 (s, 1H), 7.48 (d, 1H), 7.42 (s, 1H), 4.50-4.42 (m, 1H), 3.92 – 3.77 (m, 2H), 3.74-3.70 (m, 1H), 3.66 (s, 2H), 3.59 (dd, 1H), 2.96-2.93 (m, 4H), 2.60-2.56 (m, 4H), 2.51 (s, 3H), 2.22 – 2.10 (m, 2H), 1.97-1.89 (m, 1H), 0.99-0.94 (m, 2H), 0.85 – 0.79 (m, 2H). LC-MS m/z (ESI) = 489.25 [M+1].

實施例 6( R)-5-(4-((7-乙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基- d 2 )哌嗪-1-基)- N-(四氫呋喃-3-基)吡啶醯胺 化合物 6( R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl- d 2 )piperazin-1-yl)- N-(tetrahydrofuran-3-yl)picolinamide

Figure 02_image066
Figure 02_image068
Example 6 ( R )-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl- d 2 )piperazine -1-yl) -N- (tetrahydrofuran-3-yl)pyridinamide Compound 6 ( R )-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin -3-yl)methyl- d 2 )piperazin-1-yl)- N -(tetrahydrofuran-3-yl)picolinamide
Figure 02_image066
Figure 02_image068

第一步 3-環丙基-7-(羥甲基- d 2 )-1,5-萘啶-2(1 H)-酮 6a3-cyclopropyl-7-(hydroxymethyl- d 2 )-1,5-naphthyridin-2(1 H)-one 參考 1g的合成方法，使用四氘鋰鋁代替四氫鋰鋁，得到 6a(白色固體，700 g，產率58%)。 LC-MS m/z (ESI) = 219.1 [M+1]。 The first step 3-cyclopropyl-7-(hydroxymethyl- d 2 )-1,5-naphthyridin-2(1 H )-one 6a 3-cyclopropyl-7-(hydroxymethyl- d 2 )-1, 5-naphthyridin-2(1 H )-one Referring to the synthesis method of 1g , tetradeuterated lithium aluminum was used instead of tetrahydrolithium aluminum to obtain 6a (white solid, 700 g, yield 58%). LC-MS m/z (ESI) = 219.1 [M+1].

第二步 7-(溴甲基- d 2 )-3-環丙基-1,5-萘啶-2(1 H)-酮 6b7-(bromomethyl- d 2 )-3-cyclopropyl-1,5-naphthyridin-2(1 H)-one 參考 1h的合成方法，得到 6b(白色固體，310 mg，產率69%)。 LC-MS m/z (ESI) = 281.1 [M+1]。 The second step 7-(bromomethyl- d 2 )-3-cyclopropyl-1,5-naphthyridin-2(1 H )-one 6b 7-(bromomethyl- d 2 )-3-cyclopropyl-1, 5-naphthyridin-2(1 H )-one Refer to the synthesis method of 1h to obtain 6b (white solid, 310 mg, yield 69%). LC-MS m/z (ESI) = 281.1 [M+1].

第三步 ( R)-5-(4-((7-環丙基-6-氧代-5,6-二氫-1,5-萘啶-3-基)甲基- d 2 )哌嗪-1-基)- N-(四氫呋喃-3-基)吡啶醯胺 化合物 6( R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl- d 2 )piperazin-1-yl)- N-(tetrahydrofuran-3-yl)picolinamide 參考 化合物 2的合成方法，得到 化合物 6(白色固體，26 mg，產率49%)。 1H NMR (400 MHz, DMSO- d 6 ) δ 12.13 (s, 1H), 8.38 (d, 2H), 8.27 (s, 1H), 7.83 (d, 1H), 7.60 (s, 1H), 7.40 (d, 2H), 4.47-4.42 (m, 1H), 3.87-3.79 (m, 2H), 3.73-3.68 (m, 1H), 3.59-3.55 (m, 1H), 3.43-3.37 (m, 4H), 2.56-2.54 (m, 4H), 2.17-2.09 (m, 2H), 1.97-1.91 (m, 1H), 0.99-0.93 (m, 2H), 0.82-0.80(m, 2H)。 LC-MS m/z (ESI) = 477.2 [M+1]。 The third step ( R )-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl- d 2 )piper Oxazin-1-yl) -N- (tetrahydrofuran-3-yl)pyridinamide Compound 6 ( R )-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5- naphthyridin-3-yl)methyl- d 2 )piperazin-1-yl) -N- (tetrahydrofuran-3-yl)picolinamide Refer to the synthetic method of compound 2 to obtain compound 6 (white solid, 26 mg, yield 49%) . 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.13 (s, 1H), 8.38 (d, 2H), 8.27 (s, 1H), 7.83 (d, 1H), 7.60 (s, 1H), 7.40 ( d, 2H), 4.47-4.42 (m, 1H), 3.87-3.79 (m, 2H), 3.73-3.68 (m, 1H), 3.59-3.55 (m, 1H), 3.43-3.37 (m, 4H), 2.56-2.54 (m, 4H), 2.17-2.09 (m, 2H), 1.97-1.91 (m, 1H), 0.99-0.93 (m, 2H), 0.82-0.80 (m, 2H). LC-MS m/z (ESI) = 477.2 [M+1].

生物評價biological evaluation

1. PARP1、PARP2活性抑制試驗1. PARP1, PARP2 activity inhibition test

通過PARP1化學發光分析(Chemiluminescent assay，購買自BPS Bioscience公司，貨號：80551)、PARP2化學發光分析(Chemiluminescent assay，購買自BPS Bioscience公司，貨號：80552)分別檢測化合物對PARP1、PARP2的抑制活性。利用化學發光對結果進行定量，具體實驗方案如下： (1) 使用1×組蛋白混合物(histone mixture，50 μL/孔)對96孔板進行過夜包被； (2) 棄包被液；每孔加入封閉緩衝液3(Blocking buffer 3) (200 μL)，室溫孵育90 min； (3) 棄封閉液，PBST洗2遍；加25 μL主混合物(含2.5 μL 10×PARP buffer、2.5 μL 10×PARP Assay mixture、5 μL活化DNA、15 μL ddH2O)、5 μL抑制劑 (抑制劑初始濃度為10 μM，按1:5倍比稀釋8個濃度)、20 μL酶 (2 ng/µL)；室溫孵育1小時； (4) 棄液體，PBST洗2遍；加入鏈黴親和素(Streptavidin)-HRP封閉緩衝液3(Blocking buffer 3，稀釋50倍) 50 μL；室溫孵育30 min； (5) 棄液體，PBST洗3遍；加入100 μL ELISA ECL Substrate A/B混合(各50 μL)； (6) 酶標儀檢測結果，利用GraphPad Prism 8進行IC 50的計算。 結果表明，本申請化合物對PARP1具有顯著的抑制活性，且相對於PARP2具備良好的選擇性。 The inhibitory activity of the compounds on PARP1 and PARP2 was detected by PARP1 chemiluminescent assay (Chemiluminescent assay, purchased from BPS Bioscience Company, product number: 80551) and PARP2 chemiluminescent assay (Chemiluminescent assay, purchased from BPS Bioscience Company, product number: 80552). The results were quantified by chemiluminescence, and the specific experimental protocol was as follows: (1) Coat the 96-well plate overnight with 1× histone mixture (50 μL/well); (2) Discard the coating solution; Add blocking buffer 3 (200 μL), incubate at room temperature for 90 min; (3) Discard the blocking solution, wash twice with PBST; add 25 μL master mix (containing 2.5 μL 10×PARP buffer, 2.5 μL 10 ×PARP Assay mixture, 5 μL activated DNA, 15 μL ddH2O), 5 μL inhibitor (inhibitor initial concentration is 10 μM, diluted 8 concentrations according to 1:5 ratio), 20 μL enzyme (2 ng/μL); Incubate at room temperature for 1 hour; (4) Discard the liquid and wash twice with PBST; add 50 μL of Streptavidin-HRP blocking buffer 3 (diluted 50 times); incubate at room temperature for 30 min; ( 5) Discard the liquid, wash with PBST 3 times; add 100 μL ELISA ECL Substrate A/B to mix (50 μL each); (6) Calculate the IC 50 using GraphPad Prism 8 for the results of microplate reader detection. The results show that the compound of the present application has significant inhibitory activity on PARP1, and has good selectivity relative to PARP2.

2. PARP1/PARP2捕獲(trapping)試驗：2. PARP1/PARP2 trapping test:

2.1 PARP1捕獲(trapping)試驗： (1) 用緩衝液製備4×PARP1(購買自BPS Bioscience公司，貨號：80501)和Mab anti GST-Tb(購買自cisbio公司，貨號：61GSTTLA)混合液，向384孔板(購買自Greiner公司，貨號：784075)中加入該混合液4 μL/孔； (2) 用緩衝液製備4×DSB DNA probe-1(購買自Generay)，向384孔板中加入4 μL/孔； (3) 向384孔板中加入4 μL/孔抑制(初始濃度為10 μM，按1:5倍比稀釋10個濃度)，室溫孵育1 h； (4) 用緩衝液製備4×NAD(購買自Sigma公司，貨號：10127965001)，向384孔板中加入4 μL/孔，室溫孵育10 min； (5) 結果採用TR-FRET檢測，利用GraphPad 5.0擬合曲線，並進行IC50的計算。 2.1 PARP1 trapping test: (1) Prepare 4×PARP1 (purchased from BPS Bioscience, product number: 80501) and Mab anti GST-Tb (purchased from cisbio company, product number: 61GSTTLA) mixed solution with buffer solution, and transfer to a 384-well plate (purchased from Greiner Company, Product number: 784075), add 4 μL/well of the mixture; (2) Prepare 4×DSB DNA probe-1 (purchased from Generay) with buffer, add 4 μL/well to 384-well plate; (3) Add 4 μL/well inhibitor (initial concentration is 10 μM, diluted 10 concentrations according to 1:5 times ratio) to 384-well plate, incubate at room temperature for 1 h; (4) Prepare 4×NAD (purchased from Sigma, Cat. No.: 10127965001) with buffer solution, add 4 μL/well to a 384-well plate, and incubate at room temperature for 10 min; (5) The results were detected by TR-FRET, the curve was fitted by GraphPad 5.0, and IC50 was calculated.

2.2 PARP2捕獲(trapping)試驗： (1) 用緩衝液製備4×PARP2(購買自BPS Bioscience公司，貨號：80502)和Mab anti GST-Tb(購買自cisbio公司，貨號：61GSTTLA)混合液，向384孔板(購買自Greiner公司，貨號：784075)中加入該混合液4 μL/孔； (2) 用緩衝液製備4×PARP2 probe2(購買自Generay公司)，向384孔板中加入4 μL/孔； (3) 向384孔板中加入4 μL/孔抑制(初始濃度為10 μM，按1:5倍比稀釋10個濃度)，室溫孵育45 min； (4) 用緩衝液製備4×NAD(購買自Sigma公司，貨號：10127965001)，向384孔板中加入4 μL/孔，室溫孵育10 min； (5) 結果採用TR-FRET檢測，利用GraphPad 5.0擬合曲線，並進行IC50的計算。 化合物編號 PARP1捕獲(trapping) IC 50(nM) PARP2捕獲(trapping) IC 50(μM) PARP2/PARP1 對照例 1 1.87 1.16 619 化合物 1 1.08 0.93 861 註： 對照例 1為J. Med. Chem(2021), 64(19) ,14498–14512的化合物25，其按照化合物25的製備方法得到。 結果表明，本申請化合物對PARP1捕獲(trapping)具有顯著抑制活性，且相對於PARP2捕獲(trapping)具有良好的選擇性。 2.2 PARP2 capture (trapping) test: (1) Prepare a mixture of 4×PARP2 (purchased from BPS Bioscience, product number: 80502) and Mab anti GST-Tb (purchased from cisbio company, product number: 61GSTTLA) with buffer solution, and send to 384 Add 4 μL/well of the mixture to the well plate (purchased from Greiner, catalog number: 784075); (2) prepare 4×PARP2 probe2 (purchased from Generay) with buffer, add 4 μL/well to the 384-well plate ; (3) Add 4 μL/well inhibition (initial concentration is 10 μM, diluted 10 concentrations according to 1:5 times ratio) to 384-well plate, incubate at room temperature for 45 min; (4) Prepare 4×NAD with buffer (purchased from Sigma, Cat. No.: 10127965001), add 4 μL/well to a 384-well plate, and incubate at room temperature for 10 min; (5) The results are detected by TR-FRET, the curve is fitted using GraphPad 5.0, and IC50 is calculated . Compound number PARP1 trapping IC 50 (nM) PARP2 trapping IC 50 (μM) PARP2/PARP1 Comparative example 1 1.87 1.16 619 Compound 1 1.08 0.93 861 Note: Comparative example 1 is compound 25 of J. Med. Chem(2021), 64(19), 14498-14512, which was obtained according to the preparation method of compound 25. The results show that the compound of the present application has significant inhibitory activity on PARP1 trapping, and has good selectivity relative to PARP2 trapping.

3. DLD1 BRCA2-/-細胞增殖抑制實驗 用1640 (10% FBS，1% PS)培養基培養DLD-1 BRCA2(-/-)細胞(購買自Horizon Discovery Ltd.公司)，培養條件為37 ℃，5% CO 2。當細胞生長至對數生長期時，重懸細胞，並用1640培養基稀釋至15000個/mL。使用Echo移液器向384孔白板 (PerkinElmer)中每孔加入40 nL待測化合物(終濃度分別為10 μM、2 μM、400 nM、80 nM、16 nM、3.2 nM、0.64 nM、0.128 nM、0.0256 nM、0.00512 nM)；每個濃度梯度做2個重複，設置對照組1(加入0.1% DMSO)和對照組2 (空白培養基)。隨後384孔白板(PerkinElmer)每孔加入40 μL (600個)細胞懸液(對照組2不加細胞)。 將上述384孔板置於CO 2培養箱(37 ℃，5% CO 2)中繼續培養7天，取出384孔板，室溫放置30分鐘。每孔加入20 μL Celltiter Glo檢測液，震板機震盪2分鐘，室溫放置30分鐘。用酶標儀(PerkinElmer；EnVision)測定化學發光值。 用GraphPad Prism 8.0進行曲線擬合併計算IC 50。酶標儀檢測結果，利用GraphPad Prism 8進行IC 50的計算。 化合物編號 DLD1 BRCA2-/-細胞 IC 50(nM) 化合物 1 2.00 結果表明，本申請化合物對DLD1 BRCA2-/-細胞增殖具有明顯抑制作用。 3. DLD1 BRCA2-/- cell proliferation inhibition experiment DLD-1 BRCA2 (-/-) cells (purchased from Horizon Discovery Ltd.) were cultured in 1640 (10% FBS, 1% PS) medium, and the culture condition was 37 ° C. 5% CO 2 . When the cells grow to the logarithmic growth phase, resuspend the cells and dilute to 15000 cells/mL with 1640 medium. Add 40 nL of the compound to be tested to each well of a 384-well white plate (PerkinElmer) using an Echo pipette (final concentrations of 10 μM, 2 μM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.00512 nM); two repetitions were made for each concentration gradient, and control group 1 (with 0.1% DMSO added) and control group 2 (blank medium) were set. Then 40 μL (600 cells) of cell suspension was added to each well of a 384-well white plate (PerkinElmer) (control group 2 did not add cells). The above-mentioned 384-well plate was placed in a CO 2 incubator (37°C, 5% CO 2 ) to continue culturing for 7 days, and the 384-well plate was taken out and left at room temperature for 30 minutes. Add 20 μL Celltiter Glo detection solution to each well, shake the plate machine for 2 minutes, and place at room temperature for 30 minutes. Chemiluminescence values were measured with a microplate reader (PerkinElmer; EnVision). Curve fitting was performed with GraphPad Prism 8.0 and IC50 was calculated. Microplate reader detection results, using GraphPad Prism 8 for IC50 calculation. Compound number DLD1 BRCA2-/- cells IC 50 (nM) Compound 1 2.00 The results show that the compound of the present application has obvious inhibitory effect on the proliferation of DLD1 BRCA2-/- cells.

4. MDA-MB-436細胞增殖抑制實驗 用DMEM培養基(10% FBS，1% PS)培養MDA-MB-436細胞(供應商ATCC)，培養條件為37℃，5% CO 2。當細胞生長至對數生長期時，用DMEM培養基重懸並稀釋細胞至1500個/ml。在384孔板中以每孔40μL加入待測化合物(終濃度分別為10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.00512 nM)；每個濃度梯度做2個重複，設置對照組1 (加入0.1%DMSO)和對照組2 (空白培養基)。隨後向384孔板中加入40 μL細胞懸液 (對照組2不加細胞)。 將上述384孔板置於培養箱(37℃，5% CO 2)中連續培養7天，然後取出384孔板，在室溫放置30min。每孔加入30 µL Celltiter Glo assay kit檢測液，用震板機震盪3min，在室溫放置30min。用酶標儀(PerkinElmer; EnVision)測定化學發光值。 檢測結果用GraphPad Prism 8進行曲線擬合併計算IC 50。 化合物編號 MDA-MB-436細胞 IC50 (nM) 對照例 2 ＞10000 化合物 1 4.96 化合物 4 24.68 註： 對照例 2為專利WO200905337的化合物62，其按照化合物62的製備方法得到。 結果表明，本申請化合物對MDA-MB-436細胞增殖具有明顯抑制作用。 4. MDA-MB-436 cell proliferation inhibition experiment MDA-MB-436 cells (supplier ATCC) were cultured in DMEM medium (10% FBS, 1% PS) at 37°C, 5% CO 2 . When the cells grow to the logarithmic growth phase, resuspend and dilute the cells to 1500 cells/ml with DMEM medium. Add the compound to be tested at 40 μL per well in a 384-well plate (final concentrations are 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.00512 nM); Two repetitions were made for each concentration gradient, and control group 1 (adding 0.1% DMSO) and control group 2 (blank medium) were set. Then 40 μL of cell suspension was added to the 384-well plate (control group 2 did not add cells). The above-mentioned 384-well plate was placed in an incubator (37°C, 5% CO 2 ) for continuous culture for 7 days, and then the 384-well plate was taken out and left at room temperature for 30 minutes. Add 30 µL of Celltiter Glo assay kit detection solution to each well, shake for 3 minutes with a plate shaker, and place at room temperature for 30 minutes. Chemiluminescence values were measured with a microplate reader (PerkinElmer; EnVision). The detection results were curve fitted with GraphPad Prism 8 and IC 50 was calculated. Compound number MDA-MB-436 cell IC50 (nM) Comparative example 2 >10000 Compound 1 4.96 Compound 4 24.68 Note: Comparative example 2 is compound 62 of patent WO200905337, which is obtained according to the preparation method of compound 62. The results show that the compound of the present application has obvious inhibitory effect on the proliferation of MDA-MB-436 cells.

5. 小鼠體內藥代動力學實驗 (1) 試驗動物：ICR雄鼠，5-6周齡，購自成都達碩實驗動物有限公司； (2) 受試物配製：精密稱取適量對照例1和化合物1，配置成0.3 mg/mL透明澄清的溶液，溶媒為5 % DMSO+30 % HP-β-CD； (3) 動物給藥及采血：每只小鼠按照3mg/kg的劑量，分別灌胃給予對照例1和化合物1，每組3只小鼠。按照給藥前(0 h)、給藥後5 min、15 min、0.5 h、1 h、2 h、4 h、6 h、8 h、24 h ，10個採血時間點分別通過眼眶靜脈叢採血0.1 mL，血樣經4℃ 2000g離心10min，收集血漿用於後續檢測； (4) 採用LC-MS/MS法測定血漿內原型藥物濃度，Winnolin 8.2非房室模型計算主要藥動學參數。 化合物編號 C max(ng/mL) AUC all(ng*h/mL) t 1/2(h) 對照例 1 8730 85513 9.27 化合物 1 22667 326458 13.50 註： 對照例 1為J. Med. Chem(2021), 64(19) ,14498–14512的化合物25，其按照化合物25的製備方法得到。 結果表明，本申請化合物在小鼠體內顯示出明顯優於對照例的藥代動力學特徵。 5. In vivo pharmacokinetic experiment in mice (1) Test animals: ICR male mice, 5-6 weeks old, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.; 1 and compound 1, configured into a 0.3 mg/mL transparent and clear solution, and the solvent was 5 % DMSO+30 % HP-β-CD; (3) Animal administration and blood collection: each mouse was dosed at 3 mg/kg, Control Example 1 and Compound 1 were administered by intragastric administration, 3 mice in each group. Blood was collected through the orbital venous plexus at 10 blood collection time points before administration (0 h), 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. 0.1 mL, the blood sample was centrifuged at 2000g at 4°C for 10 minutes, and the plasma was collected for subsequent testing; (4) LC-MS/MS method was used to determine the concentration of the prototype drug in plasma, and Winnolin 8.2 non-compartmental model was used to calculate the main pharmacokinetic parameters. Compound number C max (ng/mL) AUC all (ng*h/mL) t 1/2 (h) Comparative example 1 8730 85513 9.27 Compound 1 22667 326458 13.50 Note: Comparative example 1 is compound 25 of J. Med. Chem(2021), 64(19), 14498-14512, which was obtained according to the preparation method of compound 25. The results showed that the compound of the present application showed better pharmacokinetic characteristics in mice than that of the control example.

本申請說明書對具體實施方案進行了詳細描述，本領域技術人員應認識到，上述實施方案是示例性的，不能理解為對本申請的限制，對於本領域技術人員來說，在不脫離本申請原理的前提下，通過對本申請進行若干改進和修飾，這些改進和修飾獲得技術方案也落在本申請的發明申請專利範圍的保護範圍內。The description of this application has described the specific implementation in detail. Those skilled in the art should recognize that the above-mentioned implementation is exemplary and cannot be understood as a limitation of the application. Under the premise of this application, several improvements and modifications are made to this application, and the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the invention patent scope of this application.

Claims (8)

一種式(I)的化合物或者其藥物可接受的鹽或立體異構物：
Figure 03_image001
(I) 其中： R 1為C 3-8環烷基或C 3-8雜環烷基，所述C 3-8雜環烷基包含1至4個選自N、O和S的雜原子； L為-NH-、-CO-或-(CR L1R L2) n-； R L1、R L2各自獨立地為H或C 1-6烷基，所述C 1-6烷基任選地被1個或者多個選自鹵素、羥基和氰基的取代基取代； A為4至12元雜環，所述4至12元雜環為4至12元單環、5至12元螺環、4至12元稠環或4至12元橋環，所述4至12元雜環包含1至4個選自N、O和S的雜原子； R 2為H、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或C 3-8雜環烷基，所述C 3-8雜環烷基包含1至4個選自N、O和S的雜原子；所述C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或C 3-8雜環烷基任選地被1個或者多個選自鹵素、羥基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基和C 3-8雜環烷基的取代基取代； n為1或2；以及 任選地，所述式(I)的化合物被1個或者多個氘取代。 A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
Figure 03_image001
(I) wherein: R is C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O and S ; L is -NH-, -CO- or -(CR L1 R L2 ) n -; R L1 , R L2 are each independently H or C 1-6 alkyl, and the C 1-6 alkyl is optionally Substituted by one or more substituents selected from halogen, hydroxyl and cyano; A is a 4 to 12 membered heterocycle, and the 4 to 12 membered heterocycle is a 4 to 12 membered monocyclic ring, a 5 to 12 membered spiro ring , 4 to 12 membered condensed rings or 4 to 12 membered bridged rings, the 4 to 12 membered heterocyclic rings contain 1 to 4 heteroatoms selected from N, O and S; R 2 is H, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 3-8 heterocycloalkyl contains 1 to 4 heterocycloalkyl selected from N, O and S atom; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl are optionally replaced by one or more selected from halogen, hydroxyl, Substituted by cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl; n is 1 or 2; and optionally, The compound of formula (I) is substituted with one or more deuteriums. 根據請求項1所述的化合物或者其藥物可接受的鹽或立體異構物，其中所述R 1為
Figure 03_image003
或
Figure 03_image005
。 The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the R is
Figure 03_image003
or
Figure 03_image005
. 根據請求項1所述的化合物或者其藥物可接受的鹽或立體異構物，其中L為-CH 2-、-CH(CH 3)-或-CD 2-。 The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is -CH 2 -, -CH(CH 3 )- or -CD 2 -. 根據請求項1所述的化合物或者其藥物可接受的鹽或立體異構物，其中A為
Figure 03_image007
、
Figure 03_image009
或
Figure 03_image011
。 According to the compound described in Claim 1 or its pharmaceutically acceptable salt or stereoisomer, wherein A is
Figure 03_image007
,
Figure 03_image009
or
Figure 03_image011
. 根據請求項1所述的化合物或者其藥物可接受的鹽或立體異構物，其中R 2為氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基；所述氧雜環戊基、氧雜環己基、氮雜環丁基、甲基、乙基或丙基任選地被一個或多個選自甲基、甲氧基和羥基的取代基取代。 According to the compound described in claim 1 or its pharmaceutically acceptable salt or stereoisomer, wherein R is oxolane, oxanexyl, azetidinyl, methyl, ethyl or propyl ; the oxolane, oxanexyl, azetidinyl, methyl, ethyl or propyl are optionally substituted by one or more substituents selected from methyl, methoxy and hydroxy . 根據請求項1所述的化合物或者其藥物可接受的鹽或立體異構物，所述化合物為：
Figure 03_image013
、
Figure 03_image015
、
Figure 03_image017
、
Figure 03_image019
、
Figure 03_image021
、
Figure 03_image023
、
Figure 03_image025
、
Figure 03_image027
、
Figure 03_image029
或
Figure 03_image031
。 任選地，所述化合物被1個或者多個氘取代。 According to the compound described in Claim 1 or its pharmaceutically acceptable salt or stereoisomer, the compound is:
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
or
Figure 03_image031
. Optionally, the compound is substituted with 1 or more deuteriums. 一種藥物組合物，所述藥物組合物包含： (1) 請求項1至6中任一項所述的化合物或者其藥物可接受的鹽或立體異構物； (2) 任選的一種或多種其他活性成分；以及 (3) 藥物可接受的載體和/或賦形劑。 A pharmaceutical composition comprising: (1) The compound described in any one of Claims 1 to 6 or its pharmaceutically acceptable salt or stereoisomer; (2) Optionally one or more other active ingredients; and (3) Pharmaceutically acceptable carriers and/or excipients. 請求項1至6中任一項所述的化合物或者其藥物可接受的鹽或立體異構物或請求項7所述的藥物組合物在製備抗腫瘤藥物中的用途。Use of the compound described in any one of Claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition described in Claim 7 in the preparation of antitumor drugs.
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