TW202246231A - Quinoline derivative and application thereof in preparation of autoimmune drug - Google Patents

Quinoline derivative and application thereof in preparation of autoimmune drug Download PDF

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Publication number
TW202246231A
TW202246231A TW111109958A TW111109958A TW202246231A TW 202246231 A TW202246231 A TW 202246231A TW 111109958 A TW111109958 A TW 111109958A TW 111109958 A TW111109958 A TW 111109958A TW 202246231 A TW202246231 A TW 202246231A
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azabicyclo
compound
mmol
trifluoromethyl
hexane
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TW111109958A
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Chinese (zh)
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TWI803246B (en
Inventor
袁永海
魏用剛
楚洪柱
李強
卞紅麗
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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Abstract

Provided are a quinoline derivative represented by general formula (I) and an application thereof in the preparation of an autoimmune drug.

Description

喹啉衍生物及其在醫藥上的應用Quinoline derivatives and their applications in medicine

本發明涉及喹啉衍生物或者其立體異構物或藥物可接受的鹽，及其在醫藥上的應用。The present invention relates to quinoline derivatives or their stereoisomers or pharmaceutically acceptable salts, and their application in medicine.

Toll樣受體(Toll-like receptors，TLR)是一類分子模式識別受體，廣泛分佈於不同的組織中，監視識別不同的病原體相關分子模式(PAMP)和損傷相關分子模式(DAMP)，在先天免疫和獲得性免疫中均扮演著重要的角色。Toll-like receptors (Toll-like receptors, TLRs) are a class of molecular pattern recognition receptors that are widely distributed in different tissues and monitor and recognize different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Both immunity and acquired immunity play an important role.

TLR屬於I型跨膜蛋白，到目前為止已發現13個TLR家族成員，其中10個存在於人類中，TLR1、TLR2、TLR4、TLR5、TLR6、TLR10和TLR11位於細胞膜上，可以識別微生物的脂類、脂蛋白等物質；而TLR3、TLR7、TLR8和TLR9位於胞內囊泡結構(如溶酶體、內涵體和內質網等)，識別微生物的核酸。TLR is a type I transmembrane protein. So far, 13 TLR family members have been discovered, 10 of which exist in humans. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are located on the cell membrane and can recognize lipids in microorganisms , lipoproteins and other substances; while TLR3, TLR7, TLR8 and TLR9 are located in intracellular vesicle structures (such as lysosomes, endosomes and endoplasmic reticulum, etc.), and recognize microbial nucleic acids.

TLR7和TLR8在序列和功能上最相似，大量研究表明，TLR7/8的激活可以引發I型干擾素應答及多種炎症反應，在自身免疫性障礙如系統性紅斑狼瘡(SLE)的情況下，TLR7/8的異常持續啟動導致疾病狀態的惡化。因此，開發具有選擇性和強效抑制活性化合物，通過拮抗TLR7/8抑制過度激活的免疫反應有望成為治療自身免疫性疾病的新方法。TLR7 and TLR8 are most similar in sequence and function. A large number of studies have shown that the activation of TLR7/8 can trigger type I interferon responses and various inflammatory responses. In the case of autoimmune disorders such as systemic lupus erythematosus (SLE), TLR7 Aberrant persistent activation of /8 leads to exacerbation of the disease state. Therefore, the development of compounds with selective and potent inhibitory activity to suppress overactivated immune responses by antagonizing TLR7/8 is expected to become a new method for the treatment of autoimmune diseases.

本申請的目的是提供新的喹啉衍生物或者其立體異構物、其藥物組合物或藥物可接受的鹽以及其在製備自身免疫疾病藥物中的應用。The purpose of this application is to provide a new quinoline derivative or its stereoisomer, its pharmaceutical composition or pharmaceutically acceptable salt and its application in the preparation of autoimmune disease medicine.

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、氘代物或藥物可接受的鹽：

Figure 02_image001
(I) 其中： X為C或N； R 1為C 1-6烷基，所述C 1-6烷基任選地進一步被1個或多個鹵素取代； R 2為-CN或C 1-6烷基，所述C 1-6烷基任選地進一步被1個或多個鹵素取代； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-(R a1) m-(R a2) n，所述R a任選地進一步被1個或多個選自D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羥基取代的C 1-6烷基、鹵素取代的C 1-6烷基、C 3-10環烷基、C 3-10雜環烷基和C 1-6烷基-C 3-10環烷基的取代基取代； R a1各自獨立地選自-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10環烷基或者C 3-10雜環烷基，所述C 1-6烷基任選地進一步被1個或多個D取代； R a2為H、D、-OH、鹵素、-NR bR c、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，所述的C 1-6烷基任選地進一步被1個或多個D取代； R b、R c各自獨立地為H或C 1-6烷基； m為1、2或3； n為0、1、2、3或4。 One or more embodiments of the present application provide a compound represented by general formula (I), or its stereoisomer, deuterated product or pharmaceutically acceptable salt:
Figure 02_image001
(I) wherein: X is C or N; R 1 is C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by 1 or more halogens; R 2 is -CN or C 1 -6 alkyl, the C 1-6 alkyl is optionally further substituted by one or more halogens; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -(R a1 ) m -(R a2 ) n , and said R a is optionally further selected from one or more of D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C Substituents of 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl; R a1 are each independently selected from- O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkane The group is optionally further substituted by one or more D; R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl or C 3-8 heterocycloalkyl, said C 1-6 alkyl is optionally further substituted by 1 or more D; R b , R c are each independently H or C 1- 6 alkyl; m is 1, 2 or 3; n is 0, 1, 2, 3 or 4.

在一個或多個實施方式中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-(R a1) m-(R a2) n，所述R a任選地進一步被1個或多個選自D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羥基取代的C 1-6烷基、鹵素取代的C 1-6烷基、C 3-10環烷基、C 3-10雜環烷基和C 1-6烷基-C 3-10環烷基的取代基取代； R a1為-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10環烷基或C 3-10雜環烷基，所述C 1-6烷基任選地進一步被1個或多個D取代； R a2為H、D、-OH、鹵素、-NR bR c、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，所述的C 1-6烷基任選地進一步被1個或多個D取代； R b、R c各自獨立地為H或C 1-6烷基； m為1、2或3； n為0、1、2、3或4。 In one or more embodiments: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , - CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further C substituted by one or more selected from D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxyl Substituents of 1-6 alkyl, C 1-6 alkyl substituted by halogen, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl Substitution; R a1 is -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, so The C 1-6 alkyl is optionally further substituted by one or more D; R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, said C 1-6 alkyl is optionally further substituted by 1 or more D; R b , R c each independently is H or C 1-6 alkyl; m is 1, 2 or 3; n is 0, 1, 2, 3 or 4.

在一個或多個實施方式中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、C 1-6烷基、

Figure 02_image004
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image014
、
Figure 02_image016
、
Figure 02_image018
、
Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image026
、
Figure 02_image028
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image034
、
Figure 02_image036
、
Figure 02_image038
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image044
、
Figure 02_image046
、
Figure 02_image048
、
Figure 02_image050
、
Figure 02_image052
、
Figure 02_image054
、
Figure 02_image056
或
Figure 02_image058
，且R a任選地進一步被1至多個選自D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羥基取代的C 1-6烷基、鹵素取代的C 1-6烷基、C 3-10環烷基、C 3-10雜環烷基和C 1-6烷基-C 3-10環烷基的取代基取代； R b、R c各自獨立地為H或C 1-6烷基。 In one or more embodiments: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , - CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -NH 2 , -OH, piperidinyl, C 1-6 alkyl,
Figure 02_image004
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image014
,
Figure 02_image016
,
Figure 02_image018
,
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image026
,
Figure 02_image028
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image034
,
Figure 02_image036
,
Figure 02_image038
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image044
,
Figure 02_image046
,
Figure 02_image048
,
Figure 02_image050
,
Figure 02_image052
,
Figure 02_image054
,
Figure 02_image056
or
Figure 02_image058
, and R a is optionally further substituted by 1 to more selected from D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted C 1-6 alkane C 1-6 alkyl group, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 Cycloalkyl substituents are substituted; R b and R c are each independently H or C 1-6 alkyl.

在一個或多個實施方式中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、

Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image024
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image052
、
Figure 02_image054
、
Figure 02_image056
、
Figure 02_image058
、
Figure 02_image126
、
Figure 02_image128
或
Figure 02_image130
，且R a任選地進一步被1個或2個C 1-6烷基取代。 In one or more embodiments: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , - CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image024
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image052
,
Figure 02_image054
,
Figure 02_image056
,
Figure 02_image058
,
Figure 02_image126
,
Figure 02_image128
or
Figure 02_image130
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups.

在一個或多個實施方式中： X、R 1、R 2、R定義與上述的定義相同； R a選自-NH 2、-OH、哌啶基、

Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image132
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image135
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
或
Figure 02_image116
，且R a任選地進一步被1個或2個C 1-6烷基取代。 In one or more embodiments: X, R 1 , R 2 , and R are as defined above; R a is selected from -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image132
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image135
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
or
Figure 02_image116
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups.

在一個或多個實施方式中： X、R 1、R 2、R定義與上述的定義相同； R a為-NH 2、-OH、哌啶基、

Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image132
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image135
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image138
、
Figure 02_image124
或者
Figure 02_image052
，且R a任選地進一步被1個或2個C 1-6烷基取代。 In one or more embodiments: the definitions of X, R 1 , R 2 , and R are the same as those defined above; R a is -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image132
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image135
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image138
,
Figure 02_image124
or
Figure 02_image052
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups.

在一個或多個實施方式中： X選自C或N； R 1選自-CF 3或-CH 3； R 2選自-CN或-CF 3； R為-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a選自

Figure 02_image060
、
Figure 02_image062
、
Figure 02_image064
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image072
、
Figure 02_image080
、
Figure 02_image024
、
Figure 02_image094
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image110
、
Figure 02_image114
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image054
或
Figure 02_image130
，且R a任選地進一步被1個或2個C 1-6烷基取代。 In one or more embodiments: X is selected from C or N; R 1 is selected from -CF 3 or -CH 3 ; R 2 is selected from -CN or -CF 3 ; R is -CONHR a , -COOR a , - NHCOR a or -C 1-6 alkyl-R a ; R a is selected from
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image064
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image072
,
Figure 02_image080
,
Figure 02_image024
,
Figure 02_image094
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image110
,
Figure 02_image114
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image054
or
Figure 02_image130
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups.

在一個或多個實施方式中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為

Figure 02_image060
、
Figure 02_image064
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image072
、
Figure 02_image080
、
Figure 02_image024
、
Figure 02_image098
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image110
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image054
或
Figure 02_image130
，且R a任選地進一步被1個或2個C 1-6烷基取代。 In one or more embodiments: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is
Figure 02_image060
,
Figure 02_image064
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image072
,
Figure 02_image080
,
Figure 02_image024
,
Figure 02_image098
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image110
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image054
or
Figure 02_image130
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups.

在一個或多個實施方式中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN； R為-CONHR a、-COOR a或-NHCOR a； R a為

Figure 02_image064
、
Figure 02_image068
、
Figure 02_image072
、
Figure 02_image098
、
Figure 02_image104
、
Figure 02_image106
或
Figure 02_image054
，且R a任選地進一步被1個2個C 1-6烷基取代。 In one or more embodiments: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN; R is -CONHR a , -COOR a or -NHCOR a ; R a is
Figure 02_image064
,
Figure 02_image068
,
Figure 02_image072
,
Figure 02_image098
,
Figure 02_image104
,
Figure 02_image106
or
Figure 02_image054
, and R a is optionally further substituted by 1 2 C 1-6 alkyl groups.

本申請的一個或多個實施方式提供了通式(I’)所示的化合物，或者其立體異構物、氘代物或其藥物可接受的鹽：

Figure 02_image001
(I’) 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、
Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image132
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image144
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image135
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
或
Figure 02_image116
，且R a進一步任選地被1至2個C 1-6烷基取代。 One or more embodiments of the present application provide a compound represented by general formula (I'), or its stereoisomer, deuterated product or pharmaceutically acceptable salt thereof:
Figure 02_image001
(I') wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image132
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image144
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image135
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
or
Figure 02_image116
, and R a is further optionally substituted by 1 to 2 C 1-6 alkyl groups.

本申請的一個或多個實施方式提供了通式(I’’)所示的化合物，或者其立體異構物、氘代物或其藥物可接受的鹽：

Figure 02_image001
(I’’) 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、
Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image132
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image144
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image135
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image138
、
Figure 02_image124
或
Figure 02_image052
，且R a進一步任選地被1至2個C 1-6烷基取代。 One or more embodiments of the present application provide a compound represented by general formula (I''), or its stereoisomer, deuterated product or pharmaceutically acceptable salt thereof:
Figure 02_image001
(I'') wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image132
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image144
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image135
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image138
,
Figure 02_image124
or
Figure 02_image052
, and R a is further optionally substituted by 1 to 2 C 1-6 alkyl groups.

本申請的一個或多個實施方式提供了通式(I’’’)所示的化合物，或者其立體異構物、氘代物或其藥物可接受的鹽：

Figure 02_image001
(I’’’) 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、
Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image132
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image144
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image138
、
Figure 02_image124
、
Figure 02_image052
，
Figure 02_image054
、
Figure 02_image056
、
Figure 02_image058
或
Figure 02_image126
，且R a進一步任選地被1至2個C 1-6烷基取代。 One or more embodiments of the present application provide a compound represented by general formula (I'''), or its stereoisomer, deuterated product or pharmaceutically acceptable salt thereof:
Figure 02_image001
(I''') wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image132
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image144
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image138
,
Figure 02_image124
,
Figure 02_image052
,
Figure 02_image054
,
Figure 02_image056
,
Figure 02_image058
or
Figure 02_image126
, and R a is further optionally substituted by 1 to 2 C 1-6 alkyl groups.

本申請的一個或多個實施方式提供了通式(I’’’’)所示的化合物，或者其立體異構物、氘代物或其藥物可接受的鹽：

Figure 02_image001
(I’’’’) 其中： X為C或N； R 1為C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或多個鹵素取代； R 2為-CN或C 1-6烷基，所述的C 1-6烷基任選地進一步被1個或多個鹵素取代； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-(R a1) m-(R a2) n； R a1各自獨立地為-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10環烷基或C 3-10雜環烷基，所述C 1-6烷基任選地進一步被1個或多個D取代； R a2各自獨立地為H、D、-OH、鹵素、-NR bR c、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 1-6烷基任選地進一步被1個或多個D取代； R b、R c各自獨立地為H或C 1-6烷基； m為1、2或3； n為0、1、2、3或4。 One or more embodiments of the present application provide a compound represented by the general formula (I''''), or its stereoisomer, deuterated product or pharmaceutically acceptable salt thereof:
Figure 02_image001
(I'''') wherein: X is C or N; R 1 is C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more halogens; R 2 is -CN or C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more halogens; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , - COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -(R a1 ) m -(R a2 ) n ; R a1 is each independently -O-, -NH -, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkyl is optionally further Substituted by 1 or more D; R a2 is independently H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 ring Alkyl or C 3-8 heterocycloalkyl, said C 1-6 alkyl is optionally further substituted by 1 or more D; R b , R c are each independently H or C 1-6 alkyl m is 1, 2 or 3; n is 0, 1, 2, 3 or 4.

在本申請的一個或多個實施方式中，R a選自-NH 2、-OH、哌啶基、

Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image144
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image024
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image030
、
Figure 02_image032
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image040
、
Figure 02_image042
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image048
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image052
，
Figure 02_image054
、
Figure 02_image056
、
Figure 02_image058
或
Figure 02_image126
，且R a進一步被1至2個的C 1-6烷基取代。 In one or more embodiments of the present application, R a is selected from -NH 2 , -OH, piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image144
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image024
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image030
,
Figure 02_image032
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image040
,
Figure 02_image042
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image048
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image052
,
Figure 02_image054
,
Figure 02_image056
,
Figure 02_image058
or
Figure 02_image126
, and R a is further substituted by 1 to 2 C 1-6 alkyl groups.

本申請的一個或多個實施方式提供了通式(II)所示的化合物，或者其立體異構物、氘代物或其藥物可接受的鹽：

Figure 02_image214
(II) 其中： R選自-COOH、-NH 2、-CONH 2、-COR a或-COOR a； R a選自-NH 2、哌啶基、
Figure 02_image060
、
Figure 02_image062
、
Figure 02_image006
、
Figure 02_image008
、
Figure 02_image064
、
Figure 02_image132
、
Figure 02_image010
、
Figure 02_image012
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image020
、
Figure 02_image216
、
Figure 02_image086
、
Figure 02_image098
、
Figure 02_image030
或
Figure 02_image032
，且R a任選地進一步被1個或2個C 1-6烷基取代。 One or more embodiments of the present application provide a compound represented by general formula (II), or its stereoisomer, deuterated product or pharmaceutically acceptable salt thereof:
Figure 02_image214
(II) wherein: R is selected from -COOH, -NH 2 , -CONH 2 , -COR a or -COOR a ; R a is selected from -NH 2 , piperidinyl,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image006
,
Figure 02_image008
,
Figure 02_image064
,
Figure 02_image132
,
Figure 02_image010
,
Figure 02_image012
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image020
,
Figure 02_image216
,
Figure 02_image086
,
Figure 02_image098
,
Figure 02_image030
or
Figure 02_image032
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups.

本申請的一個或多個實施方式提供了通式(II’)化合物，或者其立體異構物、氘代物或藥物可接受的鹽：

Figure 02_image214
(II’) R選自-COOH、-NH 2、-CONH 2或-COR a； R a選自-NH 2或哌啶基，且所述哌啶基任選地進一步被1至2個選自C 1-6烷基取代。 One or more embodiments of the present application provide a compound of general formula (II'), or its stereoisomer, deuterated product or pharmaceutically acceptable salt:
Figure 02_image214
(II') R is selected from -COOH, -NH 2 , -CONH 2 or -COR a ; R a is selected from -NH 2 or piperidinyl, and the piperidinyl is optionally further selected from 1 to 2 Substituted from C 1-6 alkyl.

本申請的一個或多個實施方式提供了如下化合物或者其立體異構物、氘代物或藥物可接受的鹽，其中該化合物為：

Figure 02_image218
、
Figure 02_image220
、
Figure 02_image222
、
Figure 02_image224
、
Figure 02_image226
、
Figure 02_image228
、
Figure 02_image230
、
Figure 02_image232
、
Figure 02_image234
、
Figure 02_image236
、
Figure 02_image238
、
Figure 02_image240
、
Figure 02_image242
、
Figure 02_image244
、
Figure 02_image246
、
Figure 02_image248
、
Figure 02_image250
、
Figure 02_image252
、
Figure 02_image254
、
Figure 02_image256
、
Figure 02_image258
、
Figure 02_image260
、
Figure 02_image262
、
Figure 02_image264
、
Figure 02_image266
、
Figure 02_image268
、
Figure 02_image270
、
Figure 02_image272
、
Figure 02_image274
、
Figure 02_image276
、
Figure 02_image278
、
Figure 02_image280
、
Figure 02_image282
、
Figure 02_image284
、
Figure 02_image286
、
Figure 02_image288
、
Figure 02_image290
、
Figure 02_image292
、
Figure 02_image294
、
Figure 02_image296
、
Figure 02_image298
、
Figure 02_image300
、
Figure 02_image302
、
Figure 02_image304
、
Figure 02_image306
、
Figure 02_image308
、
Figure 02_image310
、
Figure 02_image312
、
Figure 02_image314
、
Figure 02_image316
、
Figure 02_image318
、
Figure 02_image320
、
Figure 02_image322
、
Figure 02_image324
、
Figure 02_image326
、
Figure 02_image328
、
Figure 02_image330
、
Figure 02_image332
、
Figure 02_image334
、
Figure 02_image336
、
Figure 02_image338
、
Figure 02_image340
、
Figure 02_image342
、
Figure 02_image344
、
Figure 02_image346
、
Figure 02_image348
或
Figure 02_image350
。 One or more embodiments of the present application provide the following compound or its stereoisomer, deuterated product or pharmaceutically acceptable salt, wherein the compound is:
Figure 02_image218
,
Figure 02_image220
,
Figure 02_image222
,
Figure 02_image224
,
Figure 02_image226
,
Figure 02_image228
,
Figure 02_image230
,
Figure 02_image232
,
Figure 02_image234
,
Figure 02_image236
,
Figure 02_image238
,
Figure 02_image240
,
Figure 02_image242
,
Figure 02_image244
,
Figure 02_image246
,
Figure 02_image248
,
Figure 02_image250
,
Figure 02_image252
,
Figure 02_image254
,
Figure 02_image256
,
Figure 02_image258
,
Figure 02_image260
,
Figure 02_image262
,
Figure 02_image264
,
Figure 02_image266
,
Figure 02_image268
,
Figure 02_image270
,
Figure 02_image272
,
Figure 02_image274
,
Figure 02_image276
,
Figure 02_image278
,
Figure 02_image280
,
Figure 02_image282
,
Figure 02_image284
,
Figure 02_image286
,
Figure 02_image288
,
Figure 02_image290
,
Figure 02_image292
,
Figure 02_image294
,
Figure 02_image296
,
Figure 02_image298
,
Figure 02_image300
,
Figure 02_image302
,
Figure 02_image304
,
Figure 02_image306
,
Figure 02_image308
,
Figure 02_image310
,
Figure 02_image312
,
Figure 02_image314
,
Figure 02_image316
,
Figure 02_image318
,
Figure 02_image320
,
Figure 02_image322
,
Figure 02_image324
,
Figure 02_image326
,
Figure 02_image328
,
Figure 02_image330
,
Figure 02_image332
,
Figure 02_image334
,
Figure 02_image336
,
Figure 02_image338
,
Figure 02_image340
,
Figure 02_image342
,
Figure 02_image344
,
Figure 02_image346
,
Figure 02_image348
or
Figure 02_image350
.

本申請的一個或多個實施方式提供製備本申請化合物的中間體或其立體異構物、氘代物或藥物可接受的鹽，所述中間體為：

Figure 02_image352
、
Figure 02_image354
、
Figure 02_image356
、
Figure 02_image358
、
Figure 02_image360
、
Figure 02_image362
、
Figure 02_image364
、
Figure 02_image366
、
Figure 02_image368
、
Figure 02_image370
、
Figure 02_image372
、
Figure 02_image374
、
Figure 02_image376
、
Figure 02_image378
、
Figure 02_image380
、
Figure 02_image382
、
Figure 02_image384
、
Figure 02_image386
、
Figure 02_image388
、
Figure 02_image390
、
Figure 02_image392
、
Figure 02_image394
、
Figure 02_image396
、
Figure 02_image398
、
Figure 02_image400
、
Figure 02_image402
、
Figure 02_image404
、
Figure 02_image406
、
Figure 02_image408
、
Figure 02_image410
、
Figure 02_image412
、
Figure 02_image414
、
Figure 02_image416
、
Figure 02_image418
、
Figure 02_image420
、
Figure 02_image422
、
Figure 02_image424
、
Figure 02_image426
、
Figure 02_image428
、
Figure 02_image430
、
Figure 02_image432
、
Figure 02_image434
、
Figure 02_image436
、
Figure 02_image438
、
Figure 02_image440
、
Figure 02_image442
、
Figure 02_image444
、
Figure 02_image446
、
Figure 02_image448
、
Figure 02_image450
或
Figure 02_image452
。 One or more embodiments of the present application provide an intermediate for the preparation of the compound of the present application or its stereoisomer, deuterated substance or pharmaceutically acceptable salt, the intermediate being:
Figure 02_image352
,
Figure 02_image354
,
Figure 02_image356
,
Figure 02_image358
,
Figure 02_image360
,
Figure 02_image362
,
Figure 02_image364
,
Figure 02_image366
,
Figure 02_image368
,
Figure 02_image370
,
Figure 02_image372
,
Figure 02_image374
,
Figure 02_image376
,
Figure 02_image378
,
Figure 02_image380
,
Figure 02_image382
,
Figure 02_image384
,
Figure 02_image386
,
Figure 02_image388
,
Figure 02_image390
,
Figure 02_image392
,
Figure 02_image394
,
Figure 02_image396
,
Figure 02_image398
,
Figure 02_image400
,
Figure 02_image402
,
Figure 02_image404
,
Figure 02_image406
,
Figure 02_image408
,
Figure 02_image410
,
Figure 02_image412
,
Figure 02_image414
,
Figure 02_image416
,
Figure 02_image418
,
Figure 02_image420
,
Figure 02_image422
,
Figure 02_image424
,
Figure 02_image426
,
Figure 02_image428
,
Figure 02_image430
,
Figure 02_image432
,
Figure 02_image434
,
Figure 02_image436
,
Figure 02_image438
,
Figure 02_image440
,
Figure 02_image442
,
Figure 02_image444
,
Figure 02_image446
,
Figure 02_image448
,
Figure 02_image450
or
Figure 02_image452
.

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) 本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽； (2) 任選的一種或者多種其他活性成分；以及 (3) 藥學上可接受的載體和/或賦形劑。 One or more embodiments of the present application provide a pharmaceutical composition comprising: (1) The compound of the present application or its stereoisomer, deuterated substance or pharmaceutically acceptable salt; (2) Optional 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本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物製備用於治療自身免疫疾病的藥物中的用途。One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application in the preparation of medicines for the treatment of autoimmune diseases.

本申請的一個或多個實施方式提供本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物在製備用於治療與TLR7、TLR8或TLR9相關的疾病中的用途。One or more embodiments of the present application provide the compound of the present application or its stereoisomer, deuterium or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application in the preparation for the treatment of TLR7, TLR8 or TLR9-related use in disease.

本申請的一個或多個實施方式提供本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物在製備IL-6抑制劑中的用途。One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application in the preparation of an IL-6 inhibitor.

本申請的一個或多個實施方式提供本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物，其用作藥物。One or more embodiments of the present application provide the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application, 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化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物，其用於治療自身免疫疾病的方法。One or more embodiments of the present application provide the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application, which is used for the method of treating autoimmune diseases.

本申請的一個或多個實施方式提供本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物，其用於治療與TLR7、TLR8或TLR9相關的疾病。One or more embodiments of the present application provide the compound of the present application or its stereoisomer, deuterium or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application, which is used for the treatment of TLR7, TLR8 or TLR9-related disease.

本申請的一個或多個實施方式提供本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者本申請的藥物組合物，其用作IL-6抑制劑。One or more embodiments of the present application provide the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application, which is used as an IL-6 inhibitor.

本申請的一個或多個實施方式提供治療自身免疫疾病的方法，其包括將本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽或者本申請的藥物組合物給予有此需要的對象。One or more embodiments of the present application provide a method for treating autoimmune diseases, which includes administering the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt or the pharmaceutical composition of the present application to those in need Object.

本申請的一個或多個實施方式提供治療與TLR7、TLR8或TLR9相關的疾病的方法，其包括將本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽或者本申請的藥物組合物給予有此需要的對象。One or more embodiments of the present application provide a method for treating a disease related to TLR7, TLR8 or TLR9, which comprises the compound of the present application or its stereoisomer, deuterated substance or pharmaceutically acceptable salt or the drug of the present application The compositions are administered to a subject in need thereof.

本申請的一個或多個實施方式提供抑制IL-6的方法，其包括將本申請的化合物或者其立體異構物、氘代物或藥物可接受的鹽或者本申請的藥物組合物給予有此需要的對象。One or more embodiments of the present application provide a method for inhibiting IL-6, which includes administering the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt or the pharmaceutical composition of the present application to those in need Object.

除非有相反的陳述，在說明書和權利要求書中使用的術語具有下述含義。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

本發明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，及本發明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 of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , 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 deuterium), tritium (T, also called super heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen 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體；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-碳參鍵，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 from 1 to 10 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon double 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_image454
、
Figure 02_image456
、
Figure 02_image458
、
Figure 02_image460
。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_image454
,
Figure 02_image456
,
Figure 02_image458
,
Figure 02_image460
. 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、哌啶基、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, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl, 1,3-dithianyl, dihydrofuranyl , dithiapentyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzo Imidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, Dioxanyl, 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 -Indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonane oxatricyclo[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或3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 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. 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.

「藥學上可接受的鹽」或者「其藥學上可接受的鹽」是指本發明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，所述的游離鹼通過与無毒的無機酸或者有機酸反應獲得的鹽。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of free acid or free base, and said free acid is mixed with non-toxic inorganic base or organic Base, the salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.

「藥物組合物」是指一種或多種本發明所述化合物、其藥學上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」是指藥學上可接受的載體、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 of the present invention, 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、黏合劑和崩解劑。"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, and Disintegrant.

「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 (cis-trans isomers)、對映異構物 (enantiomers) 和構象異構物 (conformational isomers)。"Stereoisomers" refers to isomers produced by different arrangements of atoms in molecules in space, including cis-trans isomers, enantiomers and conformational isomers Things (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發明的技術方案，但本發明的保護範圍包括但不限於此。The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

[實施例1] ( 1R,5S)和( 1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 1-A和 化合物 1-B3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

Figure 02_image462
Figure 02_image464
[Example 1] ( 1R,5S ) and ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxylic acid compound 1-A and compound 1-B 3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid
Figure 02_image462
Figure 02_image464

第一步： 1-苄基-4-(三氟甲基)-2,5-二氫-1H-吡咯-3-羧酸乙酯 1cethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate N 2氛圍下，將 1a(10 g，60 mmol) 溶於30 mL二氯甲烷(DCM)中，冰浴下滴加 1b(14.4 g，60 mmol) 的二氯甲烷溶液 (10 mL)，隨後緩慢滴加三氟乙酸 (684 mg，6 mmol) 的二氯甲烷溶液 (10 mL)，室溫攪拌2 h。將反應液加入30 mL水中，DCM萃取三次，有機相用飽和食鹽水30 mL洗，無水硫酸鈉乾燥，旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚 = 1:10)，得到目標產物1-苄基-4-(三氟甲基)-2,5-二氫-1H-吡咯-3-羧酸乙酯 1c(黃色油狀液體，15.5 g， 產率86%)，直接用於下一步反應。 1 H NMR(400 MHz, DMSO- d 6) δ 7.34-7.24 (m, 5H), 4.19 (q, 2H), 3.79-3.78 (m, 4H), 1.20 (t, 3H)。 LC-MSm/z (ESI)= 300.1 [M+1]。 The first step : 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 1c ethyl 1-benzyl-4-(trifluoromethyl)-2,5 -dihydro-1H-pyrrole-3-carboxylate Under N 2 atmosphere, 1a (10 g, 60 mmol) was dissolved in 30 mL of dichloromethane (DCM), and 1b (14.4 g, 60 mmol) was added dropwise under ice cooling Dichloromethane solution (10 mL), then slowly dropwise added trifluoroacetic acid (684 mg, 6 mmol) in dichloromethane solution (10 mL), stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain the target Product 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 1c (yellow oily liquid, 15.5 g, yield 86%), directly used react in the next step. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.34-7.24 (m, 5H), 4.19 (q, 2H), 3.79-3.78 (m, 4H), 1.20 (t, 3H). LC-MS m/z (ESI) = 300.1 [M+1].

第二步：3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 1dethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2氛圍下，將三甲基碘化亞碸 (3.5 g，15.8 mmol) 溶於10 mL二甲亞碸中，冰浴下分批次加入氫化鈉 (633.6 mg，15.8 mmol) 的二甲亞碸溶液 (5 mL)，室溫攪拌30分鐘。隨後滴加 1c(4.3 g，14.4 mmol)的二甲亞碸溶液 (5 mL), 60 ℃反應5 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚 = 1:10)，得到目標產物3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 1d(無色油狀液體，3.5 g, 產率78%)，直接用於下一步反應。 1 H NMR(400 MHz, DMSO- d 6) δ 7.34-7.24 (m, 5 H), 4.11 (q, 2H), 3.66 (s, 2H), 3.08-3.01(m, 2H), 2.86-2.82 (m, 1H), 2.65-2.62 (m, 1H), 1.82-1.79 (m, 2H), 1.15 (t, 3H)。 LC-MSm/z (ESI)= 314.1 [M+1]。 The second step: 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 1d ethyl-3-benzyl-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxylate N 2 atmosphere, trimethyl sulfide iodide (3.5 g, 15.8 mmol) was dissolved in 10 mL dimethyl sulfide, and added in batches under ice bath A solution of sodium hydride (633.6 mg, 15.8 mmol) in dimethyl oxide (5 mL) was stirred at room temperature for 30 minutes. Then a dimethyloxide solution (5 mL) of 1c (4.3 g, 14.4 mmol) was added dropwise, and reacted at 60 °C for 5 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain The target product 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 1d (colorless oily liquid, 3.5 g, yield 78%) , used directly in the next reaction. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.34-7.24 (m, 5 H), 4.11 (q, 2H), 3.66 (s, 2H), 3.08-3.01(m, 2H), 2.86-2.82 ( m, 1H), 2.65-2.62 (m, 1H), 1.82-1.79 (m, 2H), 1.15 (t, 3H). LC-MS m/z (ESI) = 314.1 [M+1].

第三步：5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 1eethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 將 1d(1 g，3.2 mmol) 溶於乙醇50 mL中，隨後加入Pd/C (681 mg，0.64 mmol)，反應體系用1atm H 2置換兩次，升溫至60 ℃反應3 h。矽藻土過濾，旋乾溶劑，得到目標產物5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 1e(無色油狀液體，1 g，產率88%)，直接用於下一步。 1 H NMR(400 MHz, DMSO- d 6) δ 4.11 (q, 2H), 3.20-2.75(m, 5H), 1.75 (d, 1H), 1.48-1.47 (m, 1H), 1.16 (t, 3H)。 LC-MSm/z (ESI)= 224.1 [M+1]。 The third step: 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 1e ethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxylate Dissolve 1d (1 g, 3.2 mmol) in 50 mL of ethanol, then add Pd/C (681 mg, 0.64 mmol), replace the reaction system with 1 atm H 2 twice, heat up to 60 °C for 3 h . Celite was filtered, and the solvent was spin-dried to obtain the target product 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 1e (colorless oily liquid, 1 g, Yield 88%), used directly in the next step. 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.11 (q, 2H), 3.20-2.75 (m, 5H), 1.75 (d, 1H), 1.48-1.47 (m, 1H), 1.16 (t, 3H ). LC-MS m/z (ESI) = 224.1 [M+1].

第四步：(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 1g3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2氛圍下，將5-溴喹啉-8-甲腈 1f(654 mg，2.9 mmol) 溶於1,4-二氧六環30 mL中，隨後加入 1e(804 mg，3.5 mmol)，N 2置換氣三次，依次加入碳酸銫 (4.3 g，13.05 mmol) 和RuPhosPdG3 (486 mg，0.58 mmol), N 2置換氣三次,升溫至90 ℃反應2 h。旋乾溶劑，乙酸乙酯萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，粗產物 1g直接投下一步。 LC-MSm/z (ESI)= 376.1 [M+1], 398.1 [M+23]。 The fourth step: (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 1g 3 -(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2 atmosphere, 5-bromoquinoline-8-carboxylate 1f (654 mg , 2.9 mmol) was dissolved in 1,4-dioxane 30 mL, then 1e (804 mg, 3.5 mmol) was added, N 2 was replaced three times, cesium carbonate (4.3 g, 13.05 mmol) and RuPhosPdG3 (486 mg, 0.58 mmol), N 2 replacement gas three times, heated up to 90 ℃ for 2 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was spin-dried, and 1 g of the crude product was directly used in the next step LC-MS m/z (ESI) = 376.1 [M+1], 398.1 [M+23].

第五步：3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 13-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 將 1g的粗產品 (2.02 g，5.39 mmol) 溶於四氫呋喃溶液10 mL中，將無水氫氧化鋰 (1.29 g，53.9 mmol)的水溶液10 mL滴入反應液中，室溫攪拌過夜。待反應結束，旋乾四氫呋喃，乙酸乙酯萃取，保留水相，用2M鹽酸水溶液將水相PH調至3-4，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水= 47：53)，得到目標產物3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 1(黃色固體，387 mg，21%)。 1 H NMR(400 MHz, DMSO- d 6) δ 13.26 (s, 1H), 9.02-9.00 (m, 1H), 8.64-8.62 (m, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.61 (dd, 1H), 7.25 (d, 1H), 4.05-3.77 (m, 4H), 2.07-1.86 (m, 2H)。 LC-MSm/z (ESI)= 348.1 [M+1], 370.1 [M+23]。 The fifth step: 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Compound 1 3-( 8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 1 g of crude product (2.02 g, 5.39 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 10 mL of an aqueous solution of anhydrous lithium hydroxide (1.29 g, 53.9 mmol) was dropped into the reaction solution, and stirred overnight at room temperature. After the reaction is complete, spin dry THF, extract with ethyl acetate, retain the water phase, adjust the pH of the water phase to 3-4 with 2M hydrochloric acid aqueous solution, extract with ethyl acetate, wash the organic phase with saturated saline, dry over anhydrous sodium sulfate, and remove in vacuo solvent. MPLC separation (acetonitrile: water=47:53), to obtain the target product 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxylic acid Compound 1 (yellow solid, 387 mg, 21%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.26 (s, 1H), 9.02-9.00 (m, 1H), 8.64-8.62 (m, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.61 (dd, 1H), 7.25 (d, 1H), 4.05-3.77 (m, 4H), 2.07-1.86 (m, 2H). LC-MS m/z (ESI) = 348.1 [M+1], 370.1 [M+23].

第六步：3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 1-A和 化合物 1-B3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 通過手性製備高效液相色譜（chiral prep-HPLC）拆分化合物1製備得到化合物1-A和化合物1-B。分析方法：手性柱Ig-3，甲醇作為流動相，流速1 mL/min, 化合物 1-A保留時間為3.619 min， 化合物 1-B保留時間為4.741min。 The sixth step: 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 1-A and Compound 1-B 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid was prepared by chiral prep-HPLC Compound 1 was resolved to prepare compound 1-A and compound 1-B. Analysis method: Chiral column Ig-3, methanol as mobile phase, flow rate 1 mL/min, compound 1-A retention time is 3.619 min, compound 1-B retention time is 4.741 min.

[實施例2] 3-(8-氰基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 2-A和 化合物 2-B3-(8-cyanoquinolin-5-yl)- N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image466
Figure 02_image468
[Example 2] 3-(8- cyanoquinolin -5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 2-A and Compound 2-B 3-(8- cyanoquinolin -5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl) -3-azabicyclo [3.1.0] hexane-1-carboxamide
Figure 02_image466
Figure 02_image468

第一步：3-(8-氰基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 23-(8-cyanoquinolin-5-yl)- N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(40 mg，0.12 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入4-氨基-1-甲基哌啶 2a(26.32 mg，0.24 mmol)，室溫攪拌1 h。原料反應完全，TLC分離 (二氯甲烷:甲醇 = 10:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 2(黃色固體，30 mg，56%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01-9.00 (m, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 8.04 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.02-3.80 (m, 4H), 3.61-3.53 (m, 1H), 2.75-2.66 (m, 2H), 2.15 (s, 3H), 2.00-1.88 (m, 3H), 1.67-1.62 (m, 3H), 1.50-1.40 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -64.85. LC-MSm/z (ESI)= 444.2 [M+1], 466.2 [M+23]。 The first step: 3-(8- cyanoquinolin -5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexane-1-carboxamide Compound 2 3-(8- cyanoquinolin -5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxamide Dissolve compound 1 (40 mg, 0.12 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol ), stirred at room temperature for 10 min, added 4-amino-1-methylpiperidine 2a (26.32 mg, 0.24 mmol), and stirred at room temperature for 1 h. Raw material reaction is complete, TLC separation (dichloromethane:methanol=10:1), obtain target product 3-(8- cyanoquinoline -5-yl)-N-(1-methylpiperidin-4-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 2 (yellow solid, 30 mg, 56%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01-9.00 (m, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 8.04 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.02-3.80 (m, 4H), 3.61-3.53 (m, 1H), 2.75-2.66 (m, 2H), 2.15 (s, 3H), 2.00-1.88 (m, 3H), 1.67-1.62 (m, 3H), 1.50-1.40 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.85. LC-MS m/z (ESI) = 444.2 [M+1], 466.2 [M+23].

第二步：3-(8-氰基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 2-A和 化合物 2-B3-(8-cyanoquinolin-5-yl)- N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 通過手性製備高效液相色譜拆分化合物2製備得到化合物2-A和化合物2-B。分析方法：手性柱Ig-3，流動相為乙醇:乙腈=1:1+0.2%二乙胺，流速1 mL/min， 化合物 2-A保留時間為3.619 min， 化合物 2-B保留時間為4.741 min。 The second step: 3-(8- cyanoquinoline -5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 2-A and Compound 2-B 3-(8- cyanoquinolin -5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 2-A and Compound 2-B were obtained by resolving compound 2 through chiral preparative high-performance liquid chromatography. Analysis method: chiral column Ig-3, the mobile phase is ethanol: acetonitrile=1:1+0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 2-A is 3.619 min, and the retention time of compound 2-B is 4.741 min.

[實施例3] 3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 33-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image470
Figure 02_image472
將 化合物 1(100 mg，0.29 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (166.3 mg，0.44 mmol) 和DIPEA (56.9 mg，0.44 mmol)，室溫攪拌10 min，加入碳酸氫銨 (45.9 mg，0.58 mmol)，室溫攪拌5.5 h。原料反應完全，TLC分離 (二氯甲烷：甲醇 = 10：1)，得到目標產物3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 3(黃色固體，52 mg，52%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01-9.00 (m, 1H), 8.65-8.62 (m, 1H), 8.17 (d, 1H), 7.70 (s, 1H), 7.61 (dd, 1H), 7.44 (s, 1H), 7.22 (d, 1H), 4.01-3.93 (m, 3H), 3.78 (d, 1H), 2.0-1.98 (m, 1H), 1.64-1.62 (m, 1H)。 LC-MSm/z (ESI)= 347.1 [M+1]。 [Example 3] 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 3 3 -(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image470
Figure 02_image472
Compound 1 (100 mg, 0.29 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (166.3 mg, 0.44 mmol) and DIPEA (56.9 mg, 0.44 mmol) were added, and stirred at room temperature for 10 min, add ammonium bicarbonate (45.9 mg, 0.58 mmol), and stir at room temperature for 5.5 h. Raw material reaction is complete, TLC separation (dichloromethane:methanol=10:1), obtain target product 3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-carboxamide Compound 3 (yellow solid, 52 mg, 52%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01-9.00 (m, 1H), 8.65-8.62 (m, 1H), 8.17 (d, 1H), 7.70 (s, 1H), 7.61 (dd, 1H ), 7.44 (s, 1H), 7.22 (d, 1H), 4.01-3.93 (m, 3H), 3.78 (d, 1H), 2.0-1.98 (m, 1H), 1.64-1.62 (m, 1H). LC-MS m/z (ESI) = 347.1 [M+1].

[實施例4] 5-[1-氨基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基]喹啉-8-腈 化合物 45-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile

Figure 02_image474
Figure 02_image476
[Example 4] 5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl]quinoline-8-carbonitrile Compound 4 5-[1- amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile
Figure 02_image474
Figure 02_image476

第一步：叔丁基- N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-基]氨基甲酸叔丁酯 4atert-butyl N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]carbamate 將 化合物 1(60 mg，0.173 mmol) 溶於叔丁醇5 mL中，隨後加入DPPA (71.6 mg，0.26 mmol) 和三乙胺 (70 mg，0.69 mmol)，升溫至95 ℃反應4.5 h，待原料消失，二氯甲烷萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，粗產物 4a直接投下一步反應。 LC-MSm/z (ESI)= 419.1 [M+1], 441.1 [M+23]。 The first step: tert-butyl- N- [3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -yl] tert-butyl carbamate 4a tert-butyl N -[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]carbamate Compound 1 (60 mg, 0.173 mmol) was dissolved in 5 mL of tert-butanol, then DPPA (71.6 mg, 0.26 mmol) and triethylamine (70 mg, 0.69 mmol) were added, and the temperature was raised to 95 °C for 4.5 h until the raw materials disappeared , extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to dry the solvent, and the crude product 4a was directly used for the next reaction. LC-MS m/z (ESI) = 419.1 [M+1], 441.1 [M+23].

第二步：5-[1-氨基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基]喹啉-8-腈 化合物 45-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile 將粗產物 4a溶於氯化氫-二氧六環溶液10 mL中,室溫攪拌4 h，加入三乙胺鹼化，旋乾溶劑，MPLC分離 (乙腈:水= 30:70)，得到5-[1-氨基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基]喹啉-8-腈 化合物 4(黃色固體，30 mg，55%)。 1 H NMR(400 MHz, DMSO- d 6) δ 8.99 (dd, 1H), 8.63 (dd, 1H), 8.12 (d, 1H), 7.59 (dd, 1H), 7.12 (d, 1H), 3.89-3.76 (m, 3H), 3.54 (d, 1H), 2.39-2.32 (m, 2H), 1.48-1.45 (m, 2H)。 LC-MSm/z (ESI)= 319.1 [M+1], 341.1 [M+23]。 The second step: 5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl]quinoline-8-carbonitrile Compound 4 5-[1-amino -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile Dissolve the crude product 4a in 10 mL of hydrogen chloride-dioxane solution, stir at room temperature for 4 h, add Triethylamine was basified, the solvent was spin-dried, and MPLC separated (acetonitrile: water=30:70) to obtain 5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -3-yl]quinoline-8-carbonitrile Compound 4 (yellow solid, 30 mg, 55%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.99 (dd, 1H), 8.63 (dd, 1H), 8.12 (d, 1H), 7.59 (dd, 1H), 7.12 (d, 1H), 3.89- 3.76 (m, 3H), 3.54 (d, 1H), 2.39-2.32 (m, 2H), 1.48-1.45 (m, 2H). LC-MS m/z (ESI) = 319.1 [M+1], 341.1 [M+23].

[實施例5] 3-(4-氰基萘-1-基)- N-(8-甲基-8-氮雜二環[3.2.1]辛-3-基)-5-(三氟甲基)-3-氮雜二環[ 3.1.0]己烷-1-甲醯胺 化合物 5-A 、 5-B 、 5-C 、 5-D3-(4-cyanonaphthalen-1-yl)- N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image478
Figure 02_image480
將 化合物 1(100 mg，0.28 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (165 mg，0.44 mmol) 和DIPEA (56 mg，0.44 mmol)，室溫攪拌10 min，加入3-氨基托烷 5a(81 mg，0.58 mmol)，室溫攪拌3 h。原料反應完全，TLC分離 (二氯甲烷:甲醇 = 5:1)，得到目標產物3-(4-氰基萘-1-基)- N-(8-甲基-8-氮雜二環[3.2.1]辛-3-基)-5-(三氟甲基)-3-氮雜二環[ 3.1.0]己烷-1-甲醯胺 化合物 5(黃色液體，80 mg，61%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.02-9.00 (m, 1H), 8.63 (dd, 1H), 8.19-8.16 (m, 1H), 7.99 (s, 1H), 7.62-7.59 (m, 1H), 7.23 (t, 1H), 3.99– 3.92 (m, 4H), 3.87-3.85 (m, 1H), 2.22 (s, 3H), 1.98-1.91 (m, 3H), 1.64-1.57 (m, 6H), 1.28-1.15 (m, 3H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.57 LC-MSm/z (ESI)= 470.2 [M+1]。 [Example 5] 3-(4- cyanonaphthalene -1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 5-A , 5-B , 5-C , 5-D 3-(4-cyanonaphthalen-1-yl) - N -(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image478
Figure 02_image480
Compound 1 (100 mg, 0.28 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (165 mg, 0.44 mmol) and DIPEA (56 mg, 0.44 mmol) were added, and stirred at room temperature for 10 min, add 3-aminotropane 5a (81 mg, 0.58 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, TLC separation (dichloromethane: methanol=5:1), obtain target product 3-(4- cyanonaphthalene -1-yl)-N-(8-methyl-8-azabicyclo[ 3.2.1] Oct-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 5 (yellow liquid, 80 mg, 61% ). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.02-9.00 (m, 1H), 8.63 (dd, 1H), 8.19-8.16 (m, 1H), 7.99 (s, 1H), 7.62-7.59 (m , 1H), 7.23 (t, 1H), 3.99– 3.92 (m, 4H), 3.87-3.85 (m, 1H), 2.22 (s, 3H), 1.98-1.91 (m, 3H), 1.64-1.57 (m , 6H), 1.28-1.15 (m, 3H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.57 LC-MS m/z (ESI) = 470.2 [M+1].

第二步：3-(4-氰基萘-1-基)- N-(8-甲基-8-氮雜二環[3.2.1]辛-3-基)-5-(三氟甲基)-3-氮雜二環[ 3.1.0]己烷-1-甲醯胺 化合物 5-A 、 5-B 、 5-C 、 5-D3-(4-cyanonaphthalen-1-yl)- N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 通過手性製備高效液相色譜拆分化合物5得到化合物5-A、5-B、5-C和5-D。分析方法：手性柱IG-3，流動相為乙醇+0.2%二乙胺，流速1mL/min，化合物 5-A保留時間為2.997 min，化合物 5-B保留時間為3.376 min, 化合物 5-C保留時間為4.809 min，化合物 5-D保留時間為5.385 min。 The second step: 3-(4- cyanonaphthalene -1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoroform Base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 5-A , 5-B , 5-C , 5-D 3-(4-cyanonaphthalen-1-yl)- N -(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide was resolved by chiral preparative HPLC Compound 5 was divided to obtain compounds 5-A, 5-B, 5-C and 5-D. Analysis method: chiral column IG-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1mL/min, the retention time of compound 5-A is 2.997 min, the retention time of compound 5-B is 3.376 min, compound 5-C The retention time was 4.809 min, and the retention time of compound 5-D was 5.385 min.

[實施例6] 3-(8-氰基喹啉-5-基)- N-[(3 R)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 63-(8-cyanoquinolin-5-yl)- N-[(3 R)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image482
Figure 02_image484
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入(3S)-(9CI)1-甲基-3-吡咯烷胺 6a(29 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，TLC分離 (二氯甲烷:甲醇= 8:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-[(3 R)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 6(黃色固體，55 mg，89%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.64 (d, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.23 (dd, 1H), 4.26 (s, 1H), 4.03-4.00 (m, 1H), 3.98-3.91 (m, 2H), 3.83-3.81 (m, 1H), 2.73-2.69 (m, 2H), 2.32 (s, 3H), 2.13-2.11 (m, 1H), 2.00-1.97 (m, 1H), 1.64-1.63 (m, 2H), 1.30-1.22 (m, 2H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.55, -69.49, -70.74 LC-MSm/z (ESI)= 430.2 [M+23]。 [Example 6] 3-(8-cyanoquinolin-5-yl) -N -[(3 R )-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compound 6 3-(8-cyanoquinolin-5-yl)- N -[(3 R )-1-methylpyrrolidin-3-yl]-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image482
Figure 02_image484
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and stirred at room temperature for 10 min, add (3S)-(9CI)1-methyl-3-pyrrolidinamine 6a (29 mg, 0.29 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, TLC separation (dichloromethane:methanol=8:1), obtain target product 3-(8-cyanoquinoline-5-yl) -N -[( 3R )-1-methylpyrrolidine -3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 6 (yellow solid, 55 mg, 89%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.64 (d, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.23 ( dd, 1H), 4.26 (s, 1H), 4.03-4.00 (m, 1H), 3.98-3.91 (m, 2H), 3.83-3.81 (m, 1H), 2.73-2.69 (m, 2H), 2.32 ( s, 3H), 2.13-2.11 (m, 1H), 2.00-1.97 (m, 1H), 1.64-1.63 (m, 2H), 1.30-1.22 (m, 2H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.55, -69.49, -70.74 LC-MS m/z (ESI) = 430.2 [M+23].

[實施例7] 3-(8-氰基喹啉-5-基)- N-[(3 S)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 73-(8-cyanoquinolin-5-yl)- N-[(3 S)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image486
Figure 02_image488
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入3S-1-甲基-3-吡咯烷胺 7a(29 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，TLC分離 (二氯甲烷:甲醇= 8:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-[(3S)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 7(黃色固體, 42 mg, 68%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.02-9.01 (m, 1H), 8.64 (dd, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.23 (dd, 1H), 4.27-4.23 (m, 1H), 4.01 (t, 1H), 3.96-3.93 (m, 2H), 3.82 (dd, 1H), 2.79-2.68 (m, 2H), 2.33 (s, 3H), 2.13-2.10 (m, 1H), 2.00-1.97 (m, 1H), 1.67-1.63 (m, 2H), 1.28-1.22 (m, 2H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.53, -69.49, -70.74 LC-MSm/z (ESI)= 430.1 [M+1]。 [Example 7] 3-(8- cyanoquinolin -5-yl) -N -[(3S)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compound 7 3-(8-cyanoquinolin-5-yl)- N -[(3 S )-1-methylpyrrolidin-3-yl]-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image486
Figure 02_image488
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and stirred at room temperature for 10 min, add 3S-1-methyl-3-pyrrolidinamine 7a (29 mg, 0.29 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, TLC separation (dichloromethane:methanol=8:1), obtain target product 3-(8-cyanoquinoline-5-yl) -N -[(3S)-1-methylpyrrolidine- 3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 7 (yellow solid, 42 mg, 68%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.02-9.01 (m, 1H), 8.64 (dd, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.23 (dd, 1H), 4.27-4.23 (m, 1H), 4.01 (t, 1H), 3.96-3.93 (m, 2H), 3.82 (dd, 1H), 2.79-2.68 (m, 2H), 2.33 ( s, 3H), 2.13-2.10 (m, 1H), 2.00-1.97 (m, 1H), 1.67-1.63 (m, 2H), 1.28-1.22 (m, 2H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.53, -69.49, -70.74 LC-MS m/z (ESI) = 430.1 [M+1].

[實施例8] 3-(8-氰基喹啉-5-基)- N-(氧雜-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 83-(8-cyanoquinolin-5-yl)- N-(oxepan-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image490
Figure 02_image492
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入4-氨基四氫吡喃 8a(29 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，TLC分離 (二氯甲烷:甲醇= 5:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(氧雜-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 8(黃色固體，50 mg，81%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.01-9.00 (m, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.11 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 4.02 (d, 1H), 3.96-3.94 (m, 2H), 3.87-3.82 (m, 4H), 3.35-3.31 (m, 1H), 2.69 (s, 1H), 2.00 (d, 1H), 1.67-1.60 (m, 3H), 1.48-1.40 (m, 2H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.58 LC-MSm/z (ESI)= 453.1 [M+23]。 [Example 8] 3-(8- cyanoquinolin -5-yl)-N-(oxa-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 8 3-(8-cyanoquinolin-5-yl) -N -(oxepan-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide
Figure 02_image490
Figure 02_image492
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and stirred at room temperature for 10 min, add 4-aminotetrahydropyran 8a (29 mg, 0.29 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, and TLC separates (dichloromethane: methanol=5:1), obtains target product 3-(8- cyanoquinoline -5-yl)-N-(oxa-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 8 (yellow solid, 50 mg, 81%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01-9.00 (m, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.11 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 4.02 (d, 1H), 3.96-3.94 (m, 2H), 3.87-3.82 (m, 4H), 3.35-3.31 (m, 1H), 2.69 (s, 1H), 2.00 ( d, 1H), 1.67-1.60 (m, 3H), 1.48-1.40 (m, 2H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.58 LC-MS m/z (ESI) = 453.1 [M+23].

[實施例9] N-(8-氮雜雙環[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 9 N-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image494
Figure 02_image496
[Example 9] N- (8-azabicyclo[3.2.1]octane-exo-3-yl)-3-(4-cyanonaphthalene-1-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 9 N -(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1- yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image494
Figure 02_image496

第一步： N-叔丁氧羰基-(8-氮雜雙環[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 9b N-Boc-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg, 0.22 mmol) 和DIPEA (27.9 mg, 0.22 mmol)，室溫攪拌10 min，加入 N-Boc-exo-3-氨基托烷 9a(65.6 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，加水淬滅反應，旋乾溶劑，直接投下一步反應。 The first step : N -tert-butoxycarbonyl-(8-azabicyclo[3.2.1]octane-external-3-yl)-3-(4-cyanonaphthalene-1-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide 9b N -Boc-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4 -cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (50 mg, 0.14 mmol) in N,N -dimethylformamide 2 mL, then added HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirred at room temperature for 10 min, added N -Boc-exo-3-aminotropane 9a (65.6 mg, 0.29 mmol), Stir at room temperature for 3 h. The reaction of the raw materials is complete, the reaction is quenched by adding water, the solvent is spin-dried, and the reaction is directly used for the next step.

第二步： N-(8-氮雜雙環[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 9 N-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將上述粗產物 9a溶於氯化氫二氧六環溶液中，室溫攪拌3 h，原料反應完全， MPLC分離 (乙腈:水= 43:57)，得到目標產物 N-(8-氮雜雙環[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 9(黃色固體，58 mg，91%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.01-9.00 (m, 1H), 8.63 (dd, 1H), 8.36-8.34 (m, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.22 (d, 1H), 3.97-3.79 (m, 5H), 2.01-1.90 (m, 3H), 1.86-1.81 (m, 2H), 1.77-1.72 (m, 5H), 1.34-0.97 (m, 3H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.61 LC-MSm/z (ESI)= 456.2 [M+1], 478.2[M+23]。 The second step: N -(8-azabicyclo[3.2.1]octane-external-3-yl)-3-(4-cyanonaphthalene-1-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 9 N -(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide The above crude product 9a was dissolved in hydrogen chloride-dioxane solution, stirred at room temperature for 3 h, the raw materials were completely reacted, separated by MPLC (acetonitrile : water=43:57), obtain target product N- (8-azabicyclo[3.2.1]octane-external-3-yl)-3-(4-cyanonaphthalene-1-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 9 (yellow solid, 58 mg, 91%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01-9.00 (m, 1H), 8.63 (dd, 1H), 8.36-8.34 (m, 1H), 8.17 (d, 1H), 7.61 (dd, 1H ), 7.22 (d, 1H), 3.97-3.79 (m, 5H), 2.01-1.90 (m, 3H), 1.86-1.81 (m, 2H), 1.77-1.72 (m, 5H), 1.34-0.97 (m , 3H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.61 LC-MS m/z (ESI) = 456.2 [M+1], 478.2 [M+23].

[實施例10] 氮-(8-氮雜雙環[3.2.1]辛烷-內-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 10N-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image498
Figure 02_image500
[Example 10] Nitrogen-(8-azabicyclo[3.2.1]octane-end-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 10 N-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1- yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image498
Figure 02_image500

第一步： N-叔丁氧羰基-(8-氮雜雙環[3.2.1]辛烷-內-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 10b N-Boc-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入 N-Boc-exo-3-氨基托烷 10a(65.6 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，加水淬滅反應，旋乾溶劑，直接投下一步反應。 The first step : N -tert-butoxycarbonyl-(8-azabicyclo[3.2.1]octane-in-3-yl)-3-(4-cyanonaphthalene-1-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 10b N -Boc-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4 -cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (50 mg, 0.14 mmol) in N,N -dimethylformamide 2 mL, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding N -Boc-exo-3-aminotropane 10a (65.6 mg, 0.29 mmol), Stir at room temperature for 3 h. The reaction of the raw materials is complete, the reaction is quenched by adding water, the solvent is spin-dried, and the reaction is directly used for the next step.

第二步： N-(8-氮雜雙環[3.2.1]辛烷-內-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 10 N-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將上述粗產物 10a溶於氯化氫二氧六環溶液中，室溫攪拌3 h，原料反應完全，MPLC分離 (乙腈:水= 43:57)，得到目標產物 N-(8-氮雜雙環[3.2.1]辛烷-內-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 10(黃色固體，58 mg，91%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.63 (d, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.01-3.61 (m, 5H), 2.23-2.18 (m, 2H), 1.99 (d, 1H), 1.71-1.23 (m, 7H), 0.43-0.22 (m, 3H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.64 LC-MSm/z (ESI)= 456.2 [M+1]。 The second step: N -(8-azabicyclo[3.2.1]octane-in-3-yl)-3-(4-cyanonaphthalene-1-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 10 N -(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide The above crude product 10a was dissolved in hydrogen chloride dioxane solution, stirred at room temperature for 3 h, the raw materials were completely reacted, separated by MPLC (acetonitrile : water=43:57), obtain target product N- (8-azabicyclo[3.2.1]octane-in-3-yl)-3-(4-cyanonaphthalene-1-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 10 (yellow solid, 58 mg, 91%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.63 (d, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.60 (dd, 1H), 7.23 ( d, 1H), 4.01-3.61 (m, 5H), 2.23-2.18 (m, 2H), 1.99 (d, 1H), 1.71-1.23 (m, 7H), 0.43-0.22 (m, 3H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.64 LC-MS m/z (ESI) = 456.2 [M+1].

[實施例11] 3-(8-氰基喹啉-5-基)- N-(1-環丙基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 113-(8-cyanoquinolin-5-yl)- N-(1-cyclopropylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image502
Figure 02_image504
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入4-氨基-1-環丙基哌啶 11a(40.7 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，依次用 N,N-二甲基甲醯胺、水、甲醇、丙酮打漿，過濾，得到目標產物3-(8-氰基喹啉-5-基)-氮-(1-環丙基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 11(黃色固體，19 mg，29%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.64 (d, 1H), 8.17 (d, 1H), 8.06-7.98 (m, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.01-3.82 (m, 4H), 2.93-2.84 (m, 1H), 2.23-2.12 (m, 3H), 1.99 (d, 2H), 1.74-1.53 (m, 5H), 1.47-1.23 (m, 2H), 0.40-0.20 (m, 3H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.61 LC-MSm/z (ESI)= 470.2 [M+1], 492.2 [M+23]。 [Example 11] 3-(8- cyanoquinolin -5-yl)-N-(1-cyclopropylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-carboxamide Compound 11 3-(8- cyanoquinolin -5-yl)-N-(1-cyclopropylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] hexane-1-carboxamide
Figure 02_image502
Figure 02_image504
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and stirred at room temperature for 10 min, add 4-amino-1-cyclopropylpiperidine 11a (40.7 mg, 0.29 mmol), and stir at room temperature for 3 h. The reaction of the raw materials is complete, followed by beating with N,N -dimethylformamide, water, methanol, and acetone, and filtering to obtain the target product 3-(8-cyanoquinolin-5-yl)-nitrogen-(1-cyclo Propylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 11 (yellow solid, 19 mg, 29%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.64 (d, 1H), 8.17 (d, 1H), 8.06-7.98 (m, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.01-3.82 (m, 4H), 2.93-2.84 (m, 1H), 2.23-2.12 (m, 3H), 1.99 (d, 2H), 1.74-1.53 (m, 5H), 1.47-1.23 (m, 2H), 0.40-0.20 (m, 3H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.61 LC-MS m/z (ESI) = 470.2 [M+1], 492.2 [M+23].

[實施例12] 3-(4-氰基萘-1-基)- N-(2-(二乙氨基)乙基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 123-(4-cyanonaphthalen-1-yl)- N-(2-(diethylamino)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image506
Figure 02_image508
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg，0.22 mmol)，室溫攪拌10 min，加入 N,N-二乙基乙二胺 12a(34 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水= 25%:75%)，得到目標產物3-(4-氰基萘-1-基)- N-(2-(二乙氨基)乙基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 12(黃色油狀液體，42 mg，67%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02 (dd, 1H), 8.64-8.62 (m, 1H), 8.58-8.47 (m, 1H), 8.19 (d, 1H), 7.62 (dd, 1H), 7.24 (d, 1H), 3.98-3.79 (m, 4H), 3.21-3.04 (m, 4H), 2.73-2.67 (m, 2H), 2.33-2.32 (m, 2H), 1.99-1.98 (m, 1H), 1.75-1.70 (m, 1H), 1.28-1.13 (m, 6H)。 19 F NMR(376 MHz, DMSO- d 6) δ -73.51 LC-MSm/z (ESI)= 446.2 [M+1], 468.1 [M+23]。 [Example 12] 3-(4-cyanonaphthalene-1-yl) -N-( 2-(diethylamino)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]Hexane-1-carboxamide Compound 12 3-(4- cyanonaphthalen -1-yl)-N-(2-(diethylamino)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxamide
Figure 02_image506
Figure 02_image508
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and stirred at room temperature for 10 min, add N,N -diethylethylenediamine 12a (34 mg, 0.29 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, and MPLC separates (acetonitrile: water=25%: 75%), obtains target product 3-(4- cyanonaphthalene -1-yl)-N-(2-(diethylamino)ethyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 12 (yellow oily liquid, 42 mg, 67%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (dd, 1H), 8.64-8.62 (m, 1H), 8.58-8.47 (m, 1H), 8.19 (d, 1H), 7.62 (dd, 1H ), 7.24 (d, 1H), 3.98-3.79 (m, 4H), 3.21-3.04 (m, 4H), 2.73-2.67 (m, 2H), 2.33-2.32 (m, 2H), 1.99-1.98 (m , 1H), 1.75-1.70 (m, 1H), 1.28-1.13 (m, 6H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -73.51 LC-MS m/z (ESI) = 446.2 [M+1], 468.1 [M+23].

[實施例13] 3-(8-氰基喹啉-5-基)- N-[( 1R,5S)-1,5-二氫-3-氮雜雙環[3.1.0]己-6-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 133-(8-cyanoquinolin-5-yl)- N-[(1R,5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image510
Figure 02_image512
[Example 13] 3-(8-cyanoquinolin-5-yl) -N -[( 1R,5S )-1,5-dihydro-3-azabicyclo[3.1.0]hexa-6- Base]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 13 3-(8-cyanoquinolin-5-yl) -N -[(1R, 5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image510
Figure 02_image512

第一步：叔丁基-6-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-醯胺]-1,5-二氫-3-氮雜雙環[3.1.0]-3-羧酸己酯 13atert-butyl-6-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexane-3-carboxylate 將化合物1 (50 mg, 0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入(1R,5S,6S)-6-氨基-3-氮雜雙環[3.1.0]己烷-3-羧酸叔丁酯 (57.5 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，加水淬滅反應，MPLC純化 (乙腈:水= 75%:25%)，得到黃色固體，直接投下一步反應。 The first step: tert-butyl-6-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Amide]-1,5-dihydro-3-azabicyclo[3.1.0]-3-hexylcarboxylate 13a tert-butyl-6-[3-(8-cyanoquinolin-5-yl)-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexane-3-carboxylate Compound 1 (50 mg, 0.14 mmol) was dissolved in N,N -dimethylformamide 2 mL, then add HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stir at room temperature for 10 min, add (1R,5S,6S)-6 -Amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (57.5 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw material was complete, and water was added to quench the reaction, and purified by MPLC (acetonitrile: water=75%: 25%) to obtain a yellow solid, which was directly put into the next reaction.

第二步：3-(8-氰基喹啉-5-基)- N-[( 1R,5S)-1,5-二氫-3-氮雜雙環[3.1.0]己-6-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 133-(8-cyanoquinolin-5-yl)- N-[(1R,5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 13a溶解於氯化氫二氧六環溶液中，室溫攪拌3h。待原料反應完，旋乾溶劑，MPLC純化 (乙腈:水= 45%:55%)，3-(8-氰基喹啉-5-基)- N-[( 1R,5S)-1,5-二氫-3-氮雜雙環[3.1.0]己-6-基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 13(淡黃色固體，33 mg，55%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.62 (dd, 1H), 8.19-8.16 (m, 2H), 7.60 (dd, 1H), 7.21 (d, 1H), 3.98-3.78 (m, 4H), 2.99 (d, 2H), 2.77 (d, 2H), 2.67-2.66 (m, 1H), 2.34-2.32 (m, 1H), 1.95 (d, 1H), 1.62 (d, 1H), 1.51 (d, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58 LC-MSm/z (ESI)= 428.2 [M+1], 450.2 [M+23]。 The second step: 3-(8-cyanoquinolin-5-yl) -N -[( 1R,5S )-1,5-dihydro-3-azabicyclo[3.1.0]hex-6-yl ]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 13 3-(8-cyanoquinolin-5-yl) -N -[(1R,5S )-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve 13a in dioxane hydrogen chloride Ring solution, stirred at room temperature for 3h. After the reaction of the raw materials is complete, the solvent is spin-dried, purified by MPLC (acetonitrile:water=45%:55%), 3-(8-cyanoquinolin-5-yl) -N -[( 1R,5S )-1,5 -Dihydro-3-azabicyclo[3.1.0]hex-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 13 (pale yellow solid, 33 mg, 55%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.62 (dd, 1H), 8.19-8.16 (m, 2H), 7.60 (dd, 1H), 7.21 (d, 1H), 3.98-3.78 (m, 4H), 2.99 (d, 2H), 2.77 (d, 2H), 2.67-2.66 (m, 1H), 2.34-2.32 (m, 1H), 1.95 (d, 1H), 1.62 ( d, 1H), 1.51 (d, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58 LC-MS m/z (ESI) = 428.2 [M+1], 450.2 [M+23].

[實施例14] N-[(3a R,6a R)-3a,6a-二氫-八氫環戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 14 N-[(3aR,6aR)-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image514
Figure 02_image516
[Example 14] N -[(3a R, 6a R )-3a,6a-dihydro-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 14 N -[(3aR,6aR)-3a,6a-dihydrogenio-octahydrocyclopenta[c] pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image514
Figure 02_image516

第一步：叔丁基 (3a R, 6a R)-5-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-醯胺]-3a, 6a-二氫-八氫環戊[c]吡咯-2-羧酸酯 14atert-butyl (3a R,6a R)-5-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrole-2-carboxylate 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入反式-5-氨基-2-BOC-六氫-環戊二烯並[C]吡咯鹽酸鹽 (76.2 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，加水淬滅反應，MPLC純化 (乙腈:水= 65%:35%)，得到黃色固體 14a，直接投下一步反應。 The first step: tert-butyl (3a R , 6a R )-5-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]Hexane-1-amide]-3a, 6a-dihydro-octahydrocyclopenta[c]pyrrole-2-carboxylate 14a tert-butyl (3a R ,6a R )-5-[3-( Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, stirred at room temperature for 10 min, and trans -5-Amino-2-BOC-hexahydro-cyclopenta[C]pyrrole hydrochloride (76.2 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw material was complete, and the reaction was quenched by adding water, and purified by MPLC (acetonitrile: water = 65%: 35%) to obtain a yellow solid 14a , which was directly used for the next reaction.

第二步： N-[(3a R,6a R)-3a,6a-二氫-八氫環戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 14 N-[(3a R,6a R)-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 14a溶解於氯化氫二氧六環溶液中，室溫攪拌3 h。待原料反應完，旋乾溶劑，MPLC純化 (乙腈:水=45%:55%)， N-[(3a R,6a R)-3a,6a-二氫-八氫環戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 14(淡黃色固體，22 mg，35%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 8.03-8.01 (m, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.21-3.80 (m, 6H), 3.06-3.0 (m, 2H), 2.68-2.66 (m, 1H), 2.34-2.32 (m, 2H), 2.00-1.95 (m, 1H), 1.75-1.56 (m, 6H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.70 LC-MSm/z (ESI)= 456.2 [M+1], 478.2 [M+23]。 The second step: N -[(3a R, 6a R )-3a,6a-dihydro-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 14 N -[(3a R ,6a R )-3a,6a-dihydrogenio-octahydrocyclopenta[c ]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve 14a in hydrogen chloride dioxane solution , stirred at room temperature for 3 h. After the reaction of the raw materials is complete, the solvent is spin-dried, purified by MPLC (acetonitrile:water=45%:55%), N -[(3a R, 6a R )-3a,6a-dihydro-octahydrocyclopenta[c]pyrrole- 5-yl]-3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 14 ( Pale yellow solid, 22 mg, 35%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 8.03-8.01 (m, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.21-3.80 (m, 6H), 3.06-3.0 (m, 2H), 2.68-2.66 (m, 1H), 2.34-2.32 (m, 2H), 2.00-1.95 (m, 1H ), 1.75-1.56 (m, 6H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.70 LC-MS m/z (ESI) = 456.2 [M+1], 478.2 [M+23].

[實施例15] N-[(3a R,6a R)-3a,6a-二氫-2-甲基-八氫環戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 15 N-[(3a R,6a R)-3a,6a-dihydrogenio-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image518
Figure 02_image520
將 化合物 14(100 mg，0.22 mmol) 溶解於甲醇5 mL中，隨後加入多聚甲醛 (139 mg，1.54 mmol) 和氰基硼氫化鈉 (25 mg，0.66 mmol)，加熱回流3 h。原料反應完全，水淬滅反應。MPLC分離 (乙腈:水= 45%:55%)，得到目標產物 N-[(3a R,6a R)-3a,6a-二氫-2-甲基-八氫環戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 15(黃色固體，25 mg，24%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, J= 4.1, 1.4 Hz, 1H), 8.63 (dd, J= 8.7, 1.4 Hz, 1H), 8.16 (d, J= 8.2 Hz, 1H), 7.98 (d, J= 7.5 Hz, 1H), 7.60 (dd, J= 8.7, 4.2 Hz, 1H), 7.21 (d, J= 8.3 Hz, 1H), 4.31-4.21 (m, 1H), 4.01-3.80 (m, 4H), 2.64-2.60 (m, 2H), 2.32-2.25 (m, 6 H), 1.97 (d, J= 4.0 Hz, 1H), 1.62-1.59 (m, 5H), 1.23 (s, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.70。 LC-MSm/z (ESI)= 470.2 [M+1], 492.2 [M+23]。 [Example 15] N -[(3a R ,6a R )-3a,6a-dihydro-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinone Lin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 15 N -[(3a R ,6a R )-3a,6a -dihydrogenio-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image518
Figure 02_image520
Compound 14 (100 mg, 0.22 mmol) was dissolved in methanol 5 mL, then paraformaldehyde (139 mg, 1.54 mmol) and sodium cyanoborohydride (25 mg, 0.66 mmol) were added, and heated to reflux for 3 h. The starting material reacted to completion and the reaction was quenched by water. MPLC separation (acetonitrile:water=45%:55%), the target product N -[(3aR, 6aR ) -3a ,6a-dihydro-2-methyl-octahydrocyclopenta[c]pyrrole-5 -yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 15 (yellow solids, 25 mg, 24%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, J = 4.1, 1.4 Hz, 1H), 8.63 (dd, J = 8.7, 1.4 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.60 (dd, J = 8.7, 4.2 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.31-4.21 (m, 1H), 4.01-3.80 (m, 4H), 2.64-2.60 (m, 2H), 2.32-2.25 (m, 6H), 1.97 (d, J = 4.0 Hz, 1H), 1.62-1.59 (m, 5H), 1.23 (s, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.70. LC-MS m/z (ESI) = 470.2 [M+1], 492.2 [M+23].

[實施例 16] 3-(8-三氟甲基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 163-(8-trifluoromethylquinolin-5-yl)- N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image522
Figure 02_image524
[Example 16] 3-(8-trifluoromethylquinolin-5-yl) -N-( 1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 16 3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin - 4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] hexane-1-carboxamide
Figure 02_image522
Figure 02_image524

第一步：3-(8-三氟甲基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 16b3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2氛圍下，將 1e(193 mg，0.84 mmol) 溶於1,4-二氧六環10 mL中，隨後加入 16a(250 mg，0.9 mmol)，N 2置換氣三次，依次加入碳酸銫 (1.23 g，3.8 mmol) 和Ruphos Pdg3 (70 mg，0.084 mmol)， N 2置換氣三次，升溫至90 ℃反應2.5 h。矽藻土過濾，旋乾溶劑，粗產物 16b直接投下一步。 LC-MSm/z (ESI)= 419.1 [M+1], 441.1 [M+23]。 The first step: 3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 16b 3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2 atmosphere, 1e (193 mg, 0.84 mmol) was dissolved in 1,4 - Dioxane 10 mL, followed by adding 16a (250 mg, 0.9 mmol), N 2 replacement gas three times, followed by adding cesium carbonate (1.23 g, 3.8 mmol) and Ruphos Pdg3 (70 mg, 0.084 mmol), N 2 The gas was replaced three times, and the temperature was raised to 90 °C for 2.5 h. Filter through celite, spin dry the solvent, and the crude product 16b is directly sent to the next step. LC-MS m/z (ESI) = 419.1 [M+1], 441.1 [M+23].

第二步：3-(8-三氟甲基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 16c3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 將 16b的粗產品 (351 mg，0.84 mmol) 溶於四氫呋喃溶液10 mL中，將無水氫氧化鋰 (201 mg，8.4 mmol) 的水溶液10 mL滴入反應液中，室溫攪拌過夜。待反應結束，旋乾四氫呋喃，乙酸乙酯萃取，保留水相，用2 M鹽酸水溶液將水相PH調至3-4，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水= 47:53)，得到目標產物3-(8-三氟甲基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 16c(黃色固體，271 mg，83%)。 1 H NMR(400 MHz, DMSO- d 6) δ 13.26 (s, 1H), 9.00 (dd, J= 4.1, 1.6 Hz, 1H), 8.60 (dd, J= 8.7, 1.7 Hz, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.62 (dd, J= 8.6, 4.1 Hz, 1H), 7.30 (d, J= 8.2 Hz, 1H), 3.89-3.53 (m, 4H), 2.04-2.00 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -58.04, -61.99。 LC-MSm/z (ESI)= 391.1 [M+1], 413.0 [M+23]。 The second step: 3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 16c 3- (8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid The crude product of 16b (351 mg, 0.84 mmol) was dissolved in 10 mL of tetrahydrofuran solution, 10 mL of an aqueous solution of anhydrous lithium hydroxide (201 mg, 8.4 mmol) was dropped into the reaction solution, and stirred overnight at room temperature. After the reaction is complete, spin dry THF, extract with ethyl acetate, retain the water phase, adjust the pH of the water phase to 3-4 with 2 M hydrochloric acid aqueous solution, extract with ethyl acetate, wash the organic phase with saturated saline, dry over anhydrous sodium sulfate, and vacuum Solvent was removed. MPLC separates (acetonitrile: water=47:53), obtains target product 3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxylic acid 16c (yellow solid, 271 mg, 83%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.26 (s, 1H), 9.00 (dd, J = 4.1, 1.6 Hz, 1H), 8.60 (dd, J = 8.7, 1.7 Hz, 1H), 8.02 ( d, J = 8.1 Hz, 1H), 7.62 (dd, J = 8.6, 4.1 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 3.89-3.53 (m, 4H), 2.04-2.00 (m , 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -58.04, -61.99. LC-MS m/z (ESI) = 391.1 [M+1], 413.0 [M+23].

第三步：3-(8-三氟甲基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 163-(8-trifluoromethylquinolin-5-yl)- N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 16c(50 mg，0.13 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (76.5 mg，0.2 mmol) 和DIPEA (26 mg，0.2 mmol)，室溫攪拌10 min，加入4-氨基-1-甲基哌啶 (30 mg，0.26 mmol)，室溫攪拌3 h。原料反應完全，加水淬滅，MPLC純化，得到目標產物3-(8-三氟甲基喹啉-5-基)- N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 16(白色固體，17 mg，27%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00-8.99 (m, 1H), 8.58 (dd, J= 8.5, 1.6 Hz, 1H), 8.04-8.02 (m, 2H), 7.61 (dd, J= 8.6, 4.0 Hz, 1H), 7.29 (d, J= 8.7 Hz, 1H), 3.93-3.69 (m, 4H), 2.78-2.66 (m, 3H), 2.33-2.32 (m, 2H), 2.16-2.13 (m, 3H), 1.98 (d, J= 6.1 Hz, 1H), 1.78-1.75 (m, 1H), 1.70-1.39 (m, 4H)。 19 F NMR(376 MHz, DMSO- d 6) δ -57.99, -63.49 LC-MSm/z (ESI)= 487.2 [M+1], 509.2 [M+23]。 The third step: 3-(8-trifluoromethylquinolin-5-yl) -N-( 1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-carboxamide Compound 16 3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin - 4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]hexane-1-carboxamide Dissolve 16c (50 mg, 0.13 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (76.5 mg, 0.2 mmol) and DIPEA (26 mg, 0.2 mmol), stirred at room temperature for 10 min, added 4-amino-1-methylpiperidine (30 mg, 0.26 mmol), stirred at room temperature for 3 h. The reaction of the raw material was complete, quenched with water, and purified by MPLC to obtain the target product 3-(8-trifluoromethylquinolin-5-yl) -N- (1-methylpiperidin-4-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 16 (white solid, 17 mg, 27%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00-8.99 (m, 1H), 8.58 (dd, J = 8.5, 1.6 Hz, 1H), 8.04-8.02 (m, 2H), 7.61 (dd, J = 8.6, 4.0 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 3.93-3.69 (m, 4H), 2.78-2.66 (m, 3H), 2.33-2.32 (m, 2H), 2.16- 2.13 (m, 3H), 1.98 (d, J = 6.1 Hz, 1H), 1.78-1.75 (m, 1H), 1.70-1.39 (m, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -57.99, -63.49 LC-MS m/z (ESI) = 487.2 [M+1], 509.2 [M+23].

[實施例17] 5-(1-[(4-(嗎啉-4-基)哌啶-1-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-甲腈 化合物 175-(1-[(4-(morpholin-4-yl)piperidin-1-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure 02_image526
Figure 02_image528
將 化合物 17a(100 mg，0.21 mmol，製備方法見實施例56、57) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入4-(4-哌啶基)嗎啉 (53 mg，0.31 mmol)，碳酸鉀 (58 mg，0.42 mmol) 和碘化鈉 (32 mg，0.21 mmol)，100 ℃避光攪拌3 h。原料反應完全，MPLC分離 (乙腈:水= 45%:55%)，得到目標產物5-(1-[(4-(嗎啉-4-基)哌啶-1-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-甲腈 化合物 17(黃色固體，50 mg，49%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, J= 4.1, 1.4 Hz, 1H), 8.72-8.56 (m, 1H), 8.13 (d, J= 8.2 Hz, 1H), 7.61 (dd, J= 8.7, 4.2 Hz, 1H), 7.18 (d, J= 8.3 Hz, 1H), 3.97 (dd， J= 8.0 Hz, 1H), 3.81-3.73 (m, 2H), 3.59-3.54 (m, 5H), 2.21-2.11 (m, 1H), 2.97-2.83 (m, 2H), 2.44-2.40 (m, 4H), 2.33-2.20 (m, 1H), 2.17-1.94 (m, 2H), 1.88-1.65 (m, 3H), 1.61-1.57 (m, 1H), 1.44-1.32 (m, 3H)。 19 F NMR(376 MHz, DMSO- d 6) δ -61.86 LC-MSm/z (ESI)= 486.2 [M+1], 508.2 [M+23]。 [Example 17] 5-(1-[(4-(morpholin-4-yl)piperidin-1-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hex-3-yl)quinoline-8-carbonitrile Compound 17 5-(1-[(4-(morpholin-4-yl)piperidin-1-yl)methyl]-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile
Figure 02_image526
Figure 02_image528
Compound 17a (100 mg, 0.21 mmol, see Example 56 and 57 for the preparation method) was dissolved in 2 mL of N,N -dimethylformamide, and then 4-(4-piperidinyl)morpholine (53 mg, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol) and sodium iodide (32 mg, 0.21 mmol), stirred at 100 ℃ for 3 h in the dark. Raw material reaction is complete, and MPLC separates (acetonitrile: water=45%: 55%), obtains target product 5-(1-[(4-(morpholin-4-yl) piperidin-1-yl) methyl]-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 17 (yellow solid, 50 mg, 49%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, J = 4.1, 1.4 Hz, 1H), 8.72-8.56 (m, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.61 ( dd, J = 8.7, 4.2 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 3.97 (dd, J = 8.0 Hz, 1H), 3.81-3.73 (m, 2H), 3.59-3.54 (m , 5H), 2.21-2.11 (m, 1H), 2.97-2.83 (m, 2H), 2.44-2.40 (m, 4H), 2.33-2.20 (m, 1H), 2.17-1.94 (m, 2H), 1.88 -1.65 (m, 3H), 1.61-1.57 (m, 1H), 1.44-1.32 (m, 3H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -61.86 LC-MS m/z (ESI) = 486.2 [M+1], 508.2 [M+23].

[實施例18] 3-(8-氰基喹啉-5-基)- N-(1-(丙-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 18-A 和化合物 18-B3-(8-cyanoquinolin-5-yl)- N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image530
Figure 02_image532
[Example 18] 3-(8-cyanoquinolin-5-yl) -N-( 1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-formamide Compound 18-A and Compound 18-B 3-(8- cyanoquinolin -5-yl)-N-(1-(propan-2-yl) piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image530
Figure 02_image532

第一步：3-(8-氰基喹啉-5-基)- N-(1-(丙-2-基) 哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 183-(8-cyanoquinolin-5-yl)- N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg，0.22 mmol)，室溫攪拌10 min，加入1-異丙基-4-哌啶胺 18a(41 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水= 45%:55%)，得到目標產物3-(8-氰基喹啉-5-基)- N-(1-(丙-2-基) 哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 18(黃色固體，60 mg，91%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.16 (d, 1H), 8.09 (d, 8.0 Hz, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03-3.81 (m, 4H), 2.90-2.73 (m, 4H), 2.29 (s, 2H), 1.99 (d, 1H), 1.75-1.46 (m, 5H), 0.99 (d, 6H)。 19 F NMR(565 MHz, DMSO- d 6) δ -63.61 LC-MSm/z (ESI) = 472.2 [M+1], 494.2 [M+23]。 The first step: 3-(8-cyanoquinolin-5-yl) -N-( 1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 18 3-(8- cyanoquinolin -5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5 -(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (83 mg , 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirred at room temperature for 10 min, added 1-isopropyl-4-piperidinamine 18a (41 mg, 0.29 mmol), stirred at room temperature for 3 h. Raw material reaction is complete, and MPLC separates (acetonitrile: water=45%: 55%), obtains target product 3-(8- cyanoquinoline -5-yl)-N-(1-(propan-2-yl) piperidine -4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 18 (yellow solid, 60 mg, 91%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.16 (d, 1H), 8.09 (d, 8.0 Hz, 1H), 7.60 (dd, 1H) , 7.22 (d, 1H), 4.03-3.81 (m, 4H), 2.90-2.73 (m, 4H), 2.29 (s, 2H), 1.99 (d, 1H), 1.75-1.46 (m, 5H), 0.99 (d, 6H). 19 F NMR (565 MHz, DMSO- d 6 ) δ -63.61 LC-MS m/z (ESI) = 472.2 [M+1], 494.2 [M+23].

第二步：3-(8-氰基喹啉-5-基)- N-(1-(丙-2-基) 哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 18-A 和化合物 18-B3-(8-cyanoquinolin-5-yl)- N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 通過手性製備高效液相色譜拆分化合物18製備得到化合物 18-A和化合物 18-B。分析方法：手性柱AD-3，流動相為乙醇+0.2%二乙胺，流速1 mL/min,化合物 18-A保留時間為3.101 min，化合物 18-B保留時間為5.757 min。 The second step: 3-(8-cyanoquinolin-5-yl) -N-( 1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 18-A and Compound 18-B 3-(8- cyanoquinolin -5-yl)-N-(1-(propan-2-yl)piperidin -4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 18 was resolved by chiral preparative high-performance liquid chromatography to obtain compound 18-A and compound 18-B . Analysis method: chiral column AD-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 18-A is 3.101 min, and the retention time of compound 18-B is 5.757 min.

[實施例19] 3-(8-氰基喹啉-5-基)-氮-(反式-4-甲氧基環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 193-(8-cyanoquinolin-5-yl)- N-(trans-4-methoxycyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image534
Figure 02_image536
將化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入反式-4-甲氧基環己胺 19a(31.0 mg，0.24 mmol)，室溫攪拌1 h。TLC監測反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)-氮-(反式-4-甲氧基環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 19(黃色固體，65 mg，88.7%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.00 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.00 (d, 1H), 3.94 (dd, 2H), 3.82 (d, 1H), 3.63-3.55 (m, 1H), 3.22 (s, 3H), 3.11-3.04 (m, 1H), 1.98 (d, 3H), 1.79-1.68 (m, 2H), 1.62 (d, 1H), 1.30-1.21 (m, 2H), 1.20-1.11 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58。 LC-MSm/z (ESI)= 459.2 [M+1]。 [Example 19] 3-(8-cyanoquinolin-5-yl)-nitrogen-(trans-4-methoxycyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 19 3-(8- cyanoquinolin -5-yl)-N-(trans-4-methoxycyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxamide
Figure 02_image534
Figure 02_image536
Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added, and stirred at room temperature for 10 min, add trans-4-methoxycyclohexylamine 19a (31.0 mg, 0.24 mmol), and stir at room temperature for 1 h. The completion of the reaction was monitored by TLC, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, Purified by column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinoline-5-yl)-nitrogen-(trans-4-methoxycyclohexyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 19 (yellow solid, 65 mg, 88.7%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.00 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.00 (d, 1H), 3.94 (dd, 2H), 3.82 (d, 1H), 3.63-3.55 (m, 1H), 3.22 (s, 3H), 3.11-3.04 (m, 1H) , 1.98 (d, 3H), 1.79-1.68 (m, 2H), 1.62 (d, 1H), 1.30-1.21 (m, 2H), 1.20-1.11 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 459.2 [M+1].

[實施例20] 3-(8-氰基喹啉-5-基)- N-(反式-4-甲基環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 203-(8-cyanoquinolin-5-yl)- N-(trans-4-methylcyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image538
Figure 02_image540
將 化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入反式4-甲基環己胺鹽酸鹽 20a(35.9 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(反式-4-甲基環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 20(黃色固體，64 mg，91.9%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 7.98 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.01 (d, 1H), 3.93 (dd, 2H), 3.81 (d, 1H), 3.60-3.50 (m, 1H), 1.99 (d, 1H), 1.81-1.64 (m, 4H), 1.61 (d, 1H), 1.39-1.26 (m, 1H), 1.25-1.15 (m, 2H), 0.99-0.90 (m, 2H), 0.86 (d, 3H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.53。 LC-MSm/z (ESI)= 443.2 [M+1]。 [Example 20] 3-(8- cyanoquinolin -5-yl)-N-(trans-4-methylcyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexane-1-carboxamide Compound 20 3-(8- cyanoquinolin -5-yl)-N-(trans-4-methylcyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxamide
Figure 02_image538
Figure 02_image540
Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added and stirred at room temperature for 10 min, add trans-4-methylcyclohexylamine hydrochloride 20a (35.9 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:methanol=10:1), obtain target product 3-(8- cyanoquinolin -5-yl)-N-(trans-4-methylcyclohexyl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 20 (yellow solid, 64 mg, 91.9%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 7.98 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.01 (d, 1H), 3.93 (dd, 2H), 3.81 (d, 1H), 3.60-3.50 (m, 1H), 1.99 (d, 1H), 1.81-1.64 (m, 4H) , 1.61 (d, 1H), 1.39-1.26 (m, 1H), 1.25-1.15 (m, 2H), 0.99-0.90 (m, 2H), 0.86 (d, 3H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.53. LC-MS m/z (ESI) = 443.2 [M+1].

[實施例21] (8-氰基喹啉-5-基)- N-(反式-4-(二甲基氨基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 21(8-cyanoquinolin-5-yl)- N-(trans-4-(dimethylamino)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image542
Figure 02_image544
將 化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 反式 N,N-二甲基環己烷-1,4-二胺鹽酸鹽 21a(42.9 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物 (8-氰基喹啉-5-基)- N-(反式-4-(二甲基氨基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 21(淡黃色固體，65 mg，86.7%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.16 (d, 1H), 8.01 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.01 (d, 1H), 3.93 (d, 2H), 3.81 (d, 1H), 3.55 (d, 1H), 2.52 (s, 1H), 2.23 (s, 6H), 1.99 (d, 1H), 1.80 (s, 4H), 1.61 (d, 1H), 1.29-1.14 (m, 4H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.52 LC-MSm/z (ESI)= 472.2 [M+1]。 [Example 21] (8- cyanoquinolin -5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-carboxamide Compound 21 (8- cyanoquinolin -5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] hexane-1-carboxamide
Figure 02_image542
Figure 02_image544
Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added, and stirred at room temperature for 10 min, trans- N,N -dimethylcyclohexane-1,4-diamine hydrochloride 21a (42.9 mg, 0.24 mmol) was added, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:methanol=10:1) to obtain the target product (8- cyanoquinolin -5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 21 (pale yellow solid, 65 mg, 86.7%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.16 (d, 1H), 8.01 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.01 (d, 1H), 3.93 (d, 2H), 3.81 (d, 1H), 3.55 (d, 1H), 2.52 (s, 1H), 2.23 (s, 6H), 1.99 (d , 1H), 1.80 (s, 4H), 1.61 (d, 1H), 1.29-1.14 (m, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.52 LC-MS m/z (ESI) = 472.2 [M+1].

[實施例22] 3-(8-氰基喹啉-5-基)- N-(1-甲基氮雜環丁烷-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 223-(8-cyanoquinolin-5-yl)- N-(1-methylazetidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image258
Figure 02_image547
將 化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入1-甲基氮雜啶-3-胺 22a(20.7 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(1-甲基氮雜環丁烷-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 22(黃色固體，65 mg，98.5%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.77-8.55 (m, 2H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 4.28 (q, 1H), 4.01 (d, 1H), 3.95 (d, 2H), 3.81 (d, 1H), 3.53 (q, 2H), 3.07-2.90 (m, 2H), 2.26 (s, 3H), 2.00 (d, 1H), 1.66 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.56。 LC-MSm/z (ESI)= 416.1 [M+1]。 [Example 22] 3-(8-cyanoquinolin-5-yl) -N-( 1-methylazetidin-3-yl)-5-(trifluoromethyl)-3-azepam Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 22 3-(8-cyanoquinolin-5-yl) -N -(1-methylazetidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-carboxamide
Figure 02_image258
Figure 02_image547
Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added and stirred at room temperature for 10 min, add 1-methylazidine-3-amine 22a (20.7 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:methanol=10:1) to obtain the target product 3-(8- cyanoquinoline -5-yl)-N-(1-methylazetidin-3-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 22 (yellow solid, 65 mg, 98.5%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.77-8.55 (m, 2H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 4.28 (q, 1H), 4.01 (d, 1H), 3.95 (d, 2H), 3.81 (d, 1H), 3.53 (q, 2H), 3.07-2.90 (m, 2H), 2.26 (s, 3H) , 2.00 (d, 1H), 1.66 (d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.56. LC-MS m/z (ESI) = 416.1 [M+1].

[實施例23] 3-(8-氰基喹啉-5-基)- N-((1 R,5S)-9-甲基-9-氮雜雙環[3.3.1]壬基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 233-(8-cyanoquinolin-5-yl)- N-((1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image549
Figure 02_image551
將 化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入外向-3-氨基-9-甲基-9-氮雜雙環[3,3,1]壬烷 23a(40.1 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲=10:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(1 R,5S)-9-甲基-9-氮雜雙環[3.3.1]壬基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 23(黃色固體，70 mg，90.9%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.67-8.60 (m, 1H), 8.31-8.04 (m, 2H), 7.73-7.54 (m, 1H), 7.23 (dd, 1H), 4.54 (s, 1H), 4.11-3.94 (m, 3H), 3.83 (dd, 1H), 3.56 (d, 2H), 2.88 (dd, 3H), 2.10 (s, 1H), 2.07 (d, 1H), 2.04 (d, 1H), 1.99 (d, 2H),  1.92 (d, 1H), 1.84 (s, 1H), 1.80 (d, 1H), 1.72 (d, 1H), 1.69-1.64 (m, 2H), 1.35-1.21 (m, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.49, -73.77。 LC-MSm/z (ESI)= 484.2 [M+1]。 [Example 23] 3-(8-cyanoquinolin-5-yl) -N -(( 1R,5S )-9-methyl-9-azabicyclo[3.3.1]nonyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 23 3-(8-cyanoquinolin-5-yl) -N -((1R,5S)-9 -methyl-9-azabicyclo[3.3.1]nonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image549
Figure 02_image551
Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added, and stirred at room temperature for 10 min, add exo-3-amino-9-methyl-9-azabicyclo[3,3,1]nonane 23a (40.1 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:formaldehyde=10:1) to obtain the target product 3-(8- cyanoquinolin -5-yl)-N-( 1R,5S )-9-methyl-9-nitrogen Heterobicyclo[3.3.1]nonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 23 (yellow solid, 70 mg, 90.9%) . 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.67-8.60 (m, 1H), 8.31-8.04 (m, 2H), 7.73-7.54 (m, 1H), 7.23 (dd , 1H), 4.54 (s, 1H), 4.11-3.94 (m, 3H), 3.83 (dd, 1H), 3.56 (d, 2H), 2.88 (dd, 3H), 2.10 (s, 1H), 2.07 ( d, 1H), 2.04 (d, 1H), 1.99 (d, 2H), 1.92 (d, 1H), 1.84 (s, 1H), 1.80 (d, 1H), 1.72 (d, 1H), 1.69-1.64 (m, 2H), 1.35-1.21 (m, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.49, -73.77. LC-MS m/z (ESI) = 484.2 [M+1].

[實施例24] 3-(8-氰基喹啉-5-基)- N-(((1 R,3 R,5S)-9-甲基-9-氮雜雙環[3.3.1]壬南-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 243-(8-cyanoquinolin-5-yl)- N-((1 R,3 r,5 S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image553
Figure 02_image555
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺4 mL中，隨後加入HATU (65.7 mg，0.17 mmol) 和DIPEA (37.15 mg，0.29 mmol)，冰浴下攪拌活化10 min，加入 (1R,3S,4R)-4-甲基奎寧環丁-3-胺化合物 24a(26 mg，0.17 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅，用二氯甲烷萃取兩遍，反相C18柱層析純化 (鹼法)，得到目標產物3-(8-氰基喹啉-5-基)- N-(((1 R,3 r,5 S)-9-甲基-9-氮雜雙環[3.3.1]壬南-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 24(黃色固體，51 mg，75.4%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 7.90 (d, 1H), 7.68-7.52 (m, 1H), 7.23 (d, 1H), 4.14 (d, 1H), 3.98 (dd, 3H), 3.81 (dd, 1H), 3.17 (d, 1H), 2.99 (s, 2H), 2.41 (s, 2H), 2.15-1.96 (m, 3H), 1.96-1.80 (m, 3H), 1.63 (d, 2H), 1.43 (d, 1H), 1.32 (s, 2H), 0.93 (s, 1H)。 LC-MSm/z (ESI)= 484.2 [M+1] [Example 24] 3-(8-cyanoquinolin-5-yl) -N -(((1 R, 3 R, 5S )-9-methyl-9-azabicyclo[3.3.1]nonane Nan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 24 3-(8-cyanoquinolin-5-yl)- N - ((1 R ,3 r ,5 S )-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image553
Figure 02_image555
Compound 1 (50 mg, 0.14 mmol) was dissolved in 4 mL of N,N -dimethylformamide, then HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol) were added, and stirred in an ice bath After activation for 10 min, (1R,3S,4R)-4-methylquinuclidin-3-amine compound 24a (26 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, extracted twice with dichloromethane, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product 3-(8-cyanoquinolin-5-yl) -N -(( (1 R ,3 r ,5 S )-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide compound 24 (yellow solid, 51 mg, 75.4%). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 7.90 (d, 1H), 7.68-7.52 (m, 1H), 7.23 (d, 1H), 4.14 (d, 1H), 3.98 (dd, 3H), 3.81 (dd, 1H) , 3.17 (d, 1H), 2.99 (s, 2H), 2.41 (s, 2H), 2.15-1.96 (m, 3H), 1.96-1.80 (m, 3H), 1.63 (d, 2H), 1.43 (d , 1H), 1.32 (s, 2H), 0.93 (s, 1H). LC-MS m/z (ESI)= 484.2 [M+1]

[實施例25] 5-(1-(3-氨基氮雜環丁烷-1-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-腈 化合物 255-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure 02_image557
Figure 02_image559
[Example 25] 5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl) Quinoline-8-carbonitrile Compound 25 5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonyl
Figure 02_image557
Figure 02_image559

第一步：叔丁基 (1-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)氮雜丁-3-基)氨基甲酸酯 25btert-butyl (1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carbonyl)azetidin-3-yl)carbamate 將 化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入3-氮-叔丁氧羰基胺基環丁胺 25a(41.3 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲=10:1)，得到中間體叔丁基 (1-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)氮雜丁-3-基)氨基甲酸酯 25b粗品 (黃色固體，66 mg)。 The first step: tert-butyl (1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carbonyl) azetidin-3-yl) carbamate 25b tert-butyl (1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane- 1-carbonyl)azetidin-3-yl)carbamate Dissolve compound 1 (55 mg, 0.16 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (68.8 mg, 0.18 mmol) and DIPEA ( 23.3 mg, 0.18 mmol), stirred at room temperature for 10 min, added 3-N-tert-butoxycarbonylaminocyclobutylamine 25a (41.3 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:formazine=10:1) gave intermediate tert-butyl (1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carbonyl)azetidin-3-yl)carbamate 25b crude (yellow solid, 66 mg).

第二步：5-(1-(3-氨基氮雜環丁烷-1-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-腈 化合物 255-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 將中間體叔丁基 (1-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)氮雜丁-3-基)氨基甲酸酯 25b溶於2 mL二氧六環中，隨後冰浴加入鹽酸二氧六環溶液2 mL，室溫攪拌1 h。TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物5-(1-(3-氨基氮雜環丁烷-1-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-腈 化合物 25(淡黃色固體，47 mg，73.4%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.77-8.55 (m, 1H), 8.15 (dd, 1H), 7.63-7.58 (m, 1H), 7.24 (dd, 1H), 4.50 (q, 1H), 4.26-4.02 (m, 2H), 3.97 (s, 2H), 3.87-3.77 (m, 2H), 3.75-3.69 (m, 1H), 3.60-3.49 (m, 1H), 1.70 (dd, 1H), 1.63 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.51。 LC-MSm/z (ESI)= 402.2 [M+1]。 The second step: 5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinone Phenyl-8-carbonitrile Compound 25 5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonyl The intermediate tert-Butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)azepine But-3-yl) carbamate 25b was dissolved in 2 mL of dioxane, then 2 mL of dioxane hydrochloride solution was added in ice bath, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkali method) to obtain the target product 5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoroform yl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 25 (pale yellow solid, 47 mg, 73.4%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.77-8.55 (m, 1H), 8.15 (dd, 1H), 7.63-7.58 (m, 1H), 7.24 (dd, 1H ), 4.50 (q, 1H), 4.26-4.02 (m, 2H), 3.97 (s, 2H), 3.87-3.77 (m, 2H), 3.75-3.69 (m, 1H), 3.60-3.49 (m, 1H ), 1.70 (dd, 1H), 1.63 (d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.51. LC-MS m/z (ESI) = 402.2 [M+1].

[實施例26] N-(氮雜環丁烷-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 26 N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image561
Figure 02_image563
[Example 26] N- (azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] hexane-1-carboxamide compound 26 N -(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxamide
Figure 02_image561
Figure 02_image563

第一步：3-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)氮雜環丁烷-1-羧酸叔丁酯 26btert-butyl 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)azetidine-1-carboxylate 將 化合物 1(55 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入1-叔丁氧羰基-3-胺基環丁胺 26a(41.3 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到中間體3-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)氮雜環丁烷-1-羧酸叔丁酯 26b粗品 (黃色固體，70 mg)。 The first step: 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide) Azetidine-1-carboxylate tert-butyl 26b tert-butyl 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamido)azetidine-1-carboxylate Dissolve compound 1 (55 mg, 0.16 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirred at room temperature for 10 min, added 1-tert-butoxycarbonyl-3-aminocyclobutylamine 26a (41.3 mg, 0.24 mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:methanol=10:1) gave intermediate 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-carboxamide) tert-butyl azetidine-1-carboxylate 26b crude product (yellow solid, 70 mg).

第二步： N-(氮雜環丁烷-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 26 N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將中間體3-((3-(8-氰基喹啉-5-基)-3-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)氮雜環丁-1-甲酸叔丁酯 26b溶於2 mL二氧六環中，隨後冰浴加入鹽酸二氧六環溶液2 mL，室溫攪拌1 h。TLC反應完畢，反應液直接濃縮，MPLC純化 (鹼法)，得到目標產物 N-(氮雜環丁烷-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 26(淡黃色固體，40 mg，62.5%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.77 (d, 1H), 8.63 (dd, , 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 4.54 (d, 1H), 3.98 (dd, 4H), 3.80 (d, 1H), 3.65 (d, 2H), 3.52 (s, 1H), 2.02 (d, 1H), 1.67 (s, 1H), 1.23 (s, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.55。 LC-MSm/z (ESI)= 402.2 [M+1]。 The second step: N- (azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]Hexane-1-carboxamide Compound 26 N -(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide The intermediate 3-((3-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-methyl Amide) azetidine-1-carboxylic acid tert-butyl ester 26b was dissolved in 2 mL of dioxane, then 2 mL of dioxane hydrochloride solution was added in ice bath, and stirred at room temperature for 1 h. The TLC reaction was completed, and the reaction solution Direct concentration, MPLC purification (alkali method), to obtain the target product N- (azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 26 (light yellow solid, 40 mg, 62.5%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.77 (d, 1H), 8.63 (dd, , 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 4.54 (d, 1H), 3.98 (dd, 4H), 3.80 (d, 1H), 3.65 (d, 2H), 3.52 (s, 1H), 2.02 (d, 1H), 1.67 (s, 1H), 1.23 (s, 1H). 19 F NMR (376 MHz, DMSO - d6 ) δ -63.55. LC-MS m/z (ESI) = 402.2 [M+1].

[實施例27] 1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-羧酸酯 化合物 27-A 、 27-B1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

Figure 02_image565
Figure 02_image567
[Example 27] 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexa-1-carboxylate compound 27-A , 27-B 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxylate
Figure 02_image565
Figure 02_image567

第一步：3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 27a3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 將 化合物 1(100 mg，0.29 mmol) 溶解於DCM 5 mL中，隨後加入二氯亞碸 (1 mL) 和DMF (1滴)，回流攪拌2 h。TLC反應完畢，直接濃縮反應液，得到中間體3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 27a粗品 (黃色油狀物，110 mg)。 The first step: 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 27a 3-(8 -cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride Compound 1 (100 mg, 0.29 mmol) was dissolved in DCM 5 mL, followed by addition of dichlorohydrin Sodium (1 mL) and DMF (1 drop), stirred at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate 3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Crude carbonyl chloride 27a (yellow oil, 110 mg).

第二步：1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-羧酸酯 化合物 271-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 將中間體3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 26a溶於2 mL DCM中，隨後冰浴滴加1-甲基-4-哌啶醇 (40.0 mg，0.35 mmol)、三乙胺 (58.7 mg，0.58 mmol)的DCM溶液，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中，加入乙酸乙酯萃取兩次，合併有機相用飽和食鹽水洗兩遍 (15 mL × 2)，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-羧酸酯 化合物 27(淡黃色固體，74 mg，57.8%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02 (dd, 1H), 8.63 (dd, 1H), 8.18 (d, 1H), 7.62 (dd, 1H), 7.28 (d, 1H), 4.85-4.73 (m, 1H), 4.03 (d, 1H), 3.95 (d, 1H), 3.89 (d, 1H), 3.82 (d, 1H), 2.51 (s, 1H), 2.20 (s, 1H), 2.17 (s, 3H), 2.09 (d, 1H), 2.01-1.93 (m, 1H), 1.82 (d, 2H), 1.65-1.57 (m, 2H), 1.22 (d, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.08。 LC-MSm/z (ESI)= 445.2 [M+1]。 The second step: 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxylate Compound 27 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 26a was dissolved in 2 mL of DCM, followed by A DCM solution of 1-methyl-4-piperidinol (40.0 mg, 0.35 mmol) and triethylamine (58.7 mg, 0.58 mmol) was added dropwise in an ice bath, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice by adding ethyl acetate, the combined organic phase was washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and placed on a silica gel column. Chromatographic purification (dichloromethane:methanol=10:1), to obtain the target product 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoroform yl)-3-azabicyclo[3.1.0]hexan-1-carboxylate compound 27 (pale yellow solid, 74 mg, 57.8%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (dd, 1H), 8.63 (dd, 1H), 8.18 (d, 1H), 7.62 (dd, 1H), 7.28 (d, 1H), 4.85- 4.73 (m, 1H), 4.03 (d, 1H), 3.95 (d, 1H), 3.89 (d, 1H), 3.82 (d, 1H), 2.51 (s, 1H), 2.20 (s, 1H), 2.17 (s, 3H), 2.09 (d, 1H), 2.01-1.93 (m, 1H), 1.82 (d, 2H), 1.65-1.57 (m, 2H), 1.22 (d, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.08. LC-MS m/z (ESI) = 445.2 [M+1].

第三步：1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-羧酸酯 化合物 27-A 、 27-B1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 通過手性製備高效液相色譜拆分化合物27製備得到 化合物 27-A 和 27-B。分析方法：手性柱AD-3，流動相為乙醇+0.2%二乙胺，流速1 mL/min， 化合物 27-A保留時間為3.002 min， 化合物 27-B保留時間為5.152 min。 The third step: 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxylate compound 27-A , 27-B 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxylate Compound 27 was resolved by chiral preparative high-performance liquid chromatography to obtain compounds 27-A and 27-B . Analysis method: chiral column AD-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 27-A is 3.002 min, and the retention time of compound 27-B is 5.152 min.

[實施例28] 3-(8-氰基喹啉-5-基)- N-(哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 283-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image569
Figure 02_image571
[Example 28] 3-(8-cyanoquinolin-5-yl) -N-( piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 28 3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide
Figure 02_image569
Figure 02_image571

第一步：4-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺基)哌啶-1-羧酸叔丁酯 28btert-butyl 4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)piperidine-1-carboxylate 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65.7 mg，0.17 mmol) 和DIPEA (37.15 mg，0.29 mmol)，冰浴下攪拌活化10 min，加入4-氨基哌啶-1-羧酸叔丁酯 28a(34.6 mg，0.17 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後，用二氯甲烷萃取兩遍，合併有機相並旋乾得到 28b粗品，直接投下一步。 The first step: 4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamido ) tert-butyl piperidine-1-carboxylate 28b tert-butyl 4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido) piperidine-1-carboxylate Dissolve compound 1 (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol) , stirred and activated under ice bath for 10 min, added tert-butyl 4-aminopiperidine-1-carboxylate 28a (34.6 mg, 0.17 mmol), and stirred at room temperature for 1 h. The raw materials reacted completely, quenched by adding water, extracted twice with dichloromethane, combined the organic phases and spin-dried to obtain the crude product 28b , which was directly used for the next step.

第二步：3-(8-氰基喹啉-5-基)- N-(哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 283-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 中間體 28b溶於3 mL鹽酸二氧六環溶液室溫攪拌20 min，得到目標產物3-(8-氰基喹啉-5-基)- N-(哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 28(黃色固體，16 mg，26.6%)。 1H NMR (600 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.39 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.04 (s, 1H), 4.00-3.93 (m, 2H), 3.84 (s, 1H), 3.25 (d, 2H), 2.94 (td, 2H), 2.48 (s, 1H), 1.87-1.79 (m, 2H), 1.70 (t, 2H), 0.99 (t, 2H)。 LC-MSm/z (ESI)= 430.2 [M+1], 452.2 [M+23]。 The second step: 3-(8-cyanoquinolin-5-yl) -N-( piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide Compound 28 3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Intermediate 28b was dissolved in 3 mL dioxane hydrochloride solution and stirred at room temperature for 20 min to obtain the target product 3-(8- cyanoquinolin -5-yl)-N-(piperidin-4-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 28 (yellow solid, 16 mg, 26.6%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.39 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.04 (s, 1H), 4.00-3.93 (m, 2H), 3.84 (s, 1H), 3.25 (d, 2H), 2.94 (td, 2H), 2.48 (s, 1H), 1.87 -1.79 (m, 2H), 1.70 (t, 2H), 0.99 (t, 2H). LC-MS m/z (ESI) = 430.2 [M+1], 452.2 [M+23].

[實施例29] 3-(8-氰基喹啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 29-A、 29-B、 29-C和 29-D3-(8-cyanoquinolin-5-yl)- N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image573
Figure 02_image575
[Example 29] 3-(8-cyanoquinolin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compounds 29-A , 29-B , 29-C and 29-D 3-(8-cyanoquinolin-5-yl) -N -((4- methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image573
Figure 02_image575

第一步：3-(8-氰基喹啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 293-(8-cyanoquinolin-5-yl)- N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65.7 mg，0.17 mmol) 和DIPEA (37.15 mg，0.29 mmol)，冰浴下攪拌活化10 min，加入 (4-甲基嗎啉-2-基)甲胺 29a(23 mg，0.17 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅，用二氯甲烷萃取兩遍，MPLC純化 (鹼法)，得到目標產物3-(8-氰基喹啉-5-基)-氮-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 29(黃色固體，24 mg，37.3%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 (dd, 1H), 4.03-3.90 (m, 3H), 3.94 (d, 1H), 3.82 (d, 1H), 3.75 (dd, 1H), 3.45-3.39 (m, 2H), 3.21-3.06 (m, 2H), 2.63 (d, 1H), 2.14 (s, 3H), 1.99-1.95 (m, 1H), 1.70-1.55 (m, 2H), 1.05 (t, 1H)。 LC-MSm/z (ESI)= 460.2 [M+1], 482.2 [M+23]。 The first step: 3-(8-cyanoquinolin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 29 3-(8-cyanoquinolin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol) was activated by stirring in an ice bath for 10 min, and (4-methylmorpholin-2-yl)methanamine 29a (23 mg, 0.17 mmol) was added, and stirred at room temperature for 1 h. The raw material reacted completely, quenched with water, extracted twice with dichloromethane, and purified by MPLC (alkali method) to obtain the target product 3-(8-cyanoquinoline-5-yl)-nitrogen-((4-methylmethanol) olin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 29 (yellow solid, 24 mg, 37.3%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 ( dd, 1H), 4.03-3.90 (m, 3H), 3.94 (d, 1H), 3.82 (d, 1H), 3.75 (dd, 1H), 3.45-3.39 (m, 2H), 3.21-3.06 (m, 2H), 2.63 (d, 1H), 2.14 (s, 3H), 1.99-1.95 (m, 1H), 1.70-1.55 (m, 2H), 1.05 (t, 1H). LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

第二步：3-(8-氰基喹啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 29-A、 29-B、 29-C和 29-D3-(8-cyanoquinolin-5-yl)- N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide A,通過手性製備高效液相色譜拆分化合物29製備得到 化合物 29-A 、 29-B、 29-C和 29-D。分析方法：手性柱OD-3，流動相為 乙醇+0.2%二乙胺，流速1 mL/min, 化合物 29-A保留時間為3.297 min， 化合物 29-B保留時間為3.620 min， 化合物 29-C保留時間為4.456 min， 化合物 29-D保留時間為4.561 min。 The second step: 3-(8-cyanoquinolin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compounds 29-A , 29-B , 29-C and 29-D 3-(8-cyanoquinolin-5-yl) -N -((4-methylmorpholin -2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide A, prepared by chiral preparative high performance liquid chromatography to resolve compound 29 Compound 29-A , 29- B , 29-C and 29-D . Analysis method: chiral column OD-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 29-A is 3.297 min, the retention time of compound 29-B is 3.620 min, and the retention time of compound 29- The retention time of C was 4.456 min, and that of compound 29-D was 4.561 min.

[實施例30] 3-(8-氰基喹啉-5-基)- N-(((1 R,3 S,4 R)-奎寧環丁-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 303-(8-cyanoquinolin-5-yl)-N-((1 R,3 S,4 R)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image577
Figure 02_image579
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65.7 mg，0.17 mmol) 和DIPEA (37.15 mg，0.29 mmol)，冰浴下攪拌活化10 min，加入 (1S,4s)-奎尼丁-3-胺 30a(34.5 mg，0.17 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅，用二氯甲烷萃取兩遍，MPLC純化 (鹼法)，得到目標產物3-(8-氰基喹啉-5-基)- N-(((1R,3S,4R)-奎寧環丁-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 30(黃色固體，16 mg，25.1%)。 1 H NMR(600 MHz, DMSO- d 6) δ 9.02 (d, 1H), 8.64 (dd, 1H), 8.55 (dd, 1H), 8.22-8.14 (m, 1H), 8.07 (s, 0H), 7.62 (dd, 1H), 7.30-7.21 (m, 1H), 5.28-5.22 (m, 1H), 4.33-4.25 (m, 1H), 4.03-3.95 (m, 2H), 3.55-3.43 (m, 2H), 3.29-3.22 (m, 1H), 2.61 (t, 1H), 2.38 (t, 1H), 2.15-2.07 (m, 2H), 2.05-1.97 (m, 2H), 1.92-1.84 (m, 1H), 1.75-1.72 (m, 1H), 1.28-1.19 (m, 2H), 0.85 (t, 1H)。 LC-MSm/z (ESI)= 456.2 [M+1], 478.2 [M+23]。 [Example 30] 3-(8-cyanoquinolin-5-yl) -N -(((1 R, 3 S, 4 R )-quinuclidin-3-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 30 3-(8-cyanoquinolin-5-yl)-N-((1 R ,3 S ,4 R )- quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image577
Figure 02_image579
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol) were added, and stirred in an ice bath After activation for 10 min, (1S,4s)-quinidine-3-amine 30a (34.5 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The raw material reacted completely, quenched with water, extracted twice with dichloromethane, and purified by MPLC (alkaline method) to obtain the target product 3-(8-cyanoquinoline-5-yl) -N -(((1R,3S, 4R)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 30 (yellow solid, 16 mg, 25.1 %). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.02 (d, 1H), 8.64 (dd, 1H), 8.55 (dd, 1H), 8.22-8.14 (m, 1H), 8.07 (s, 0H), 7.62 (dd, 1H), 7.30-7.21 (m, 1H), 5.28-5.22 (m, 1H), 4.33-4.25 (m, 1H), 4.03-3.95 (m, 2H), 3.55-3.43 ( m, 2H), 3.29-3.22 (m, 1H), 2.61 (t, 1H), 2.38 (t, 1H), 2.15-2.07 (m, 2H), 2.05-1.97 (m, 2H), 1.92-1.84 ( m, 1H), 1.75-1.72 (m, 1H), 1.28-1.19 (m, 2H), 0.85 (t, 1H). LC-MS m/z (ESI)= 456.2 [M+1], 478.2 [M +23].

[實施例31] 3-(8-氰基喹啉-5-基)- N-(((1 S,3 R,4 S)-奎寧環丁-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 313-(8-cyanoquinolin-5-yl)- N-((1 S,3 R,4 S)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image581
Figure 02_image583
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65.7 mg，0.17 mmol) 和DIPEA (37.15 mg，0.29 mmol)，冰浴下攪拌活化10 min，加入 (1R,3S,4R)-4-甲基奎寧環丁-3-胺 31a(34.5 mg，0.17 mmol)室溫攪拌1 h。原料反應完全，加水淬滅，用二氯甲烷萃取兩遍，MPLC純化 (鹼法)，得到目標產物3-(8-氰基喹啉-5-基)- N-(((1 S,3 R,4 S)-奎寧環丁-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 31(黃色固體，32 mg，50.2%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.65 (ddd, 1H), 8.19 (ddd, 2H), 7.61 (dd, 4.2Hz, 1H), 7.23 (dd, 1H), 4.10-4.03 (m, 1H), 4.03-3.93 (m, 2H), 3.86 (q, 2H), 3.19 (d, 1H), 2.97-2.70 (m, 4H), 2.70-2.58 (m, 1H), 1.98 (dd, 1H), 1.85-1.70 (m, 2H), 1.70-1.52 (m, 3H), 1.39 (t, 1H)。 LC-MSm/z (ESI)= 456.2 [M+1], 478.2 [M+23]。 [Example 31] 3-(8-cyanoquinolin-5-yl) -N -(((1 S, 3 R, 4 S )-quinuclidin-3-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 31 3-(8-cyanoquinolin-5-yl) -N -((1 S ,3 R ,4 S )- quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image581
Figure 02_image583
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol) were added, and stirred in an ice bath After activation for 10 min, (1R,3S,4R)-4-methylquinuclidin-3-amine 31a (34.5 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The raw material reacted completely, quenched with water, extracted twice with dichloromethane, and purified by MPLC (alkali method) to obtain the target product 3-(8-cyanoquinoline-5-yl) -N -(((1 S, 3 R, 4 S )-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 31 (yellow solid, 32 mg, 50.2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.65 (ddd, 1H), 8.19 (ddd, 2H), 7.61 (dd, 4.2Hz, 1H), 7.23 (dd, 1H), 4.10-4.03 (m, 1H), 4.03-3.93 (m, 2H), 3.86 (q, 2H), 3.19 (d, 1H), 2.97-2.70 (m, 4H), 2.70- 2.58 (m, 1H), 1.98 (dd, 1H), 1.85-1.70 (m, 2H), 1.70-1.52 (m, 3H), 1.39 (t, 1H).LC -MS m/z (ESI)= 456.2 [M+1], 478.2 [M+23].

[實施例32] N-(9-氮雜雙環[3.3.1]壬南-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙[3.1.0]己烷-1-甲醯胺 化合物 32 N-(9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image585
Figure 02_image587
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65.7 mg，0.17 mmol) 和DIPEA (37.15 mg，0.29 mmol)，冰浴下攪拌活化10 min，加入3-氨基-9-氮雜雙環[3.3.1]壬烷-9-羧酸叔丁酯 32a(41 mg，0.17 mmol)，室溫攪拌1 h。加水淬滅後，用二氯甲烷萃取兩遍，合併有機相並旋乾得到 32b，加入3 mL鹽酸二氧六環溶液室溫攪拌20 min原料反應完全，體系旋乾用三乙胺鹼化，MPLC純化 (鹼法)，得到目標產物 N-(9-氮雜雙環[3.3.1]壬南-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙[3.1.0]己烷-1-甲醯胺 化合物 32(黃色固體，51 mg，77.7%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.77-8.55 (m, 1H), 8.17 (dd, 1H), 8.02 (dd, 1H), 7.60 (dd, 1H), 7.22 (dd, 1H), 4.56 (s, 1H), 4.01 (d, 1H), 3.94 (dd, 2H), 3.82 (dd, 1H), 3.16 (s, 1H), 2.05-1.93 (m, 2H), 1.92-1.80 (m, 3H), 1.70 (s, 2H), 1.65-1.55 (m, 3H), 1.49-1.40 (m, 1H), 1.39-1.19 (m, 2H)。 LC-MSm/z (ESI)= 470.2 [M+1]。 [Example 32] N -(9-Azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 32 N -(9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image585
Figure 02_image587
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol) were added, and stirred in an ice bath After activation for 10 min, tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate 32a (41 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. After quenching by adding water, extract twice with dichloromethane, combine the organic phases and spin dry to obtain 32b , add 3 mL of dioxane hydrochloride solution and stir at room temperature for 20 min. MPLC purification (alkali method) to obtain the target product N- (9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinoline-5-yl)-5-(tri Fluoromethyl)-3-azabis[3.1.0]hexane-1-carboxamide Compound 32 (yellow solid, 51 mg, 77.7%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.77-8.55 (m, 1H), 8.17 (dd, 1H), 8.02 (dd, 1H), 7.60 (dd, 1H), 7.22 (dd, 1H), 4.56 (s, 1H), 4.01 (d, 1H), 3.94 (dd, 2H), 3.82 (dd, 1H), 3.16 (s, 1H), 2.05-1.93 (m, 2H) , 1.92-1.80 (m, 3H), 1.70 (s, 2H), 1.65-1.55 (m, 3H), 1.49-1.40 (m, 1H), 1.39-1.19 (m, 2H). LC-MS m/z (ESI) = 470.2 [M+1].

[實施例33] N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲醯胺 化合物 33-A和 化合物 33-B N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide

Figure 02_image589
Figure 02_image591
[Example 33] N- [3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]- 1-Methylpiperidine-4-carboxamide Compound 33-A and Compound 33-B N -[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexan-1-yl]-1-methylpiperidine-4-carboxamide
Figure 02_image589
Figure 02_image591

第一步： N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲醯胺 化合物 33 N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide 將1-甲基哌啶-4-甲酸 33a(118 mg，1.03 mmol) 溶解於 N,N-二甲基甲醯胺5 mL中，隨後加入HATU (573 mg，1.5 mmol) 和DIPEA (193 mg, 1.5 mmol)，室溫攪拌10 min，加入 化合物 4(330 mg，1.03 mmol)，室溫攪拌2 h。原料反應完全，MPLC分離 (乙腈:水=35%：65%)，得到目標產物 N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲醯胺 化合物 33(黃色固體，47 mg，11%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, J= 4.1, 1.2 Hz, 1H), 8.66-8.63 (m, 2H), 8.13 (d, J= 8.3 Hz, 1H), 7.59 (dd, J= 8.7, 4.2 Hz, 1H), 7.15 (d, J= 8.4 Hz, 1H), 3.95-3.89 (m, 3H), 3.81-3.79 (m, 1H), 3.19-3.10 (m, 3H), 2.5 (s, 3H), 2.33-2.24(m, 2H), 1.78-1.59 (m, 6H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.53, -69.19, -71.08 LC-MSm/z (ESI)= 444.2 [M+1]。 The first step: N -[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]-1 -Methylpiperidine-4-formamide Compound 33 N -[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1 -methylpiperidine-4-carboxamide Dissolve 1-methylpiperidine-4-carboxylic acid 33a (118 mg, 1.03 mmol) in 5 mL of N,N -dimethylformamide, then add HATU (573 mg, 1.5 mmol ) and DIPEA (193 mg, 1.5 mmol), stirred at room temperature for 10 min, added compound 4 (330 mg, 1.03 mmol), stirred at room temperature for 2 h. Raw material reaction is complete, and MPLC separates (acetonitrile: water=35%: 65%), obtains target product N- [3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide Compound 33 (yellow solid, 47 mg, 11%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, J = 4.1, 1.2 Hz, 1H), 8.66-8.63 (m, 2H), 8.13 (d, J = 8.3 Hz, 1H), 7.59 ( dd, J = 8.7, 4.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.95-3.89 (m, 3H), 3.81-3.79 (m, 1H), 3.19-3.10 (m, 3H) , 2.5 (s, 3H), 2.33-2.24 (m, 2H), 1.78-1.59 (m, 6H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.53, -69.19, -71.08 LC-MS m/z (ESI) = 444.2 [M+1].

第二步： N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲醯胺 化合物 33-A和 化合物 33-B N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide 通過手性製備高效液相色譜拆分化合物33製備得到化合物 33-A和化合物 33-B。分析方法：手性柱Ig-3，流動相為乙醇+0.2%二乙胺，流速1 mL/min, 化合物 33-A保留時間為2.746  min， 化合物 33-B保留時間為3.514 min。 The second step: N -[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]-1 -Methylpiperidine-4-carboxamide Compound 33-A and Compound 33-B N -[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan -1-yl]-1-methylpiperidine-4-carboxamide Compound 33-A and Compound 33-B were prepared by resolving compound 33 by chiral preparative high performance liquid chromatography. Analysis method: Chiral column Ig-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 33-A is 2.746 min, and the retention time of compound 33-B is 3.514 min.

[實施例34] 3-(8-氰基喹啉-5-基)- N-{[(3 R)-4-甲基嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 343-(8-cyanoquinolin-5-yl)- N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image593
Figure 02_image595
[Example 34] 3-(8-cyanoquinolin-5-yl) -N -{[(3 R )-4-methylmorpholin-3-yl]methyl}-5-(trifluoroform Base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 34 3-(8-cyanoquinolin-5-yl) -N -{[(3R)-4-methylmorpholin-3-yl ]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image593
Figure 02_image595

第一步：叔丁基 (3 R)-3-{ (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)甲醯胺]甲基}嗎啉-4-羧酸鹽 34atert-butyl (3 R)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine-4-carboxylate 將 化合物 1(200 mg，0.56 mmol) 溶解於 N,N-二甲基甲醯胺5 mL中，隨後加入HATU (330 mg，0.88 mmol) 和DIPEA (117 mg， 0.88 mmol)，室溫攪拌10 min，加入( R)-3-(氨基甲基)嗎啉-4-羧酸叔丁酯 (250 mg，1.16 mmol)，室溫攪拌3 h。原料反應完全。MPLC純化 (乙腈:水=65%:35%)，得到 34a黃色固體，直接投下一步反應。 The first step: tert-butyl (3 R )-3-{(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hex-1-yl)formamide]methyl}morpholine-4-carboxylate 34a tert-butyl (3 R )-3-{[(3-(8-cyanoquinolin-5-yl)-5-( trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine-4-carboxylate Dissolve compound 1 (200 mg, 0.56 mmol) in N,N -dimethylformamide 5 mL , then added HATU (330 mg, 0.88 mmol) and DIPEA (117 mg, 0.88 mmol), stirred at room temperature for 10 min, added ( R )-3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (250 mg, 1.16 mmol), stirred at room temperature for 3 h. The raw material reacted completely. Purified by MPLC (acetonitrile:water=65%:35%), 34a was obtained as a yellow solid, which was directly put into the next reaction.

第二步：3-(8-氰基喹啉-5-基)- N-{[(3 R)-嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 34b3-(8-cyanoquinolin-5-yl)- N-{[(3R)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 34a溶解於氯化氫二氧六環溶液中，室溫攪拌過夜。待原料反應完，旋乾溶劑，MPLC純化 (乙腈:水=35%:65%)，3-(8-氰基喹啉-5-基)- N-{[(3 R)-嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 34b(淡黃色固體，195 mg，78%)。 LC-MSm/z (ESI)= 446.2 [M+1], 468.2 [M+23]。 The second step: 3-(8-cyanoquinolin-5-yl) -N -{[(3 R )-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-formamide 34b 3-(8-cyanoquinolin-5-yl) -N -{[(3R)-morpholin-3-yl]methyl}-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve 34a in dioxane hydrogen chloride solution and stir overnight at room temperature. After the reaction of the raw materials is complete, the solvent is spin-dried, purified by MPLC (acetonitrile: water = 35%: 65%), 3-(8-cyanoquinoline-5-yl) -N -{[(3 R )-morpholine- 3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 34b (pale yellow solid, 195 mg, 78%). LC-MS m/z (ESI) = 446.2 [M+1], 468.2 [M+23].

第三步：3-(8-氰基喹啉-5-基)- N-{[(3 R)-4-甲基嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 343-(8-cyanoquinolin-5-yl)- N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將化合物 34b(100 mg，0.23 mmol) 溶解於甲醇5 mL中，隨後加入多聚甲醛 (141 mg，1.57 mmol) 和氰基硼氫化鈉 (26 mg, 0.69 mmol)，加熱回流3 h。原料反應完全，水淬滅反應。MPLC分離 (乙腈:水=45%:55%)，得到目標產物3-(8-氰基喹啉-5-基)- N-{[(3 R)-4-甲基嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 34(黃色固體，60 mg，57%)。 1 H NMR(400 MHz, DMSO- d 6) 1H NMR (400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (d, 1H), 8.23-8.16 (m, 2H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.01-3.92 (m, 3H), 3.83-3.80 (m, 1H), 3.65-3.62 (m, 2H), 3.47-3.40 (m, 2H), 3.13-3.11 (m, 1H), 2.96-2.90 (m, 1H), 2.62-2.59 (m, 1H), 2.23 (s, 3H), 2.17-2.05 (m, 2H), 1.93 (d, 1H), 1.63(d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.55。 LC-MSm/z (ESI)= 460.2 [M+1], 482.2 [M+23]。 The third step: 3-(8-cyanoquinolin-5-yl) -N -{[(3 R )-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 34 3-(8-cyanoquinolin-5-yl) -N -{[(3R)-4-methylmorpholin-3-yl] methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 34b (100 mg, 0.23 mmol) in methanol 5 mL, then add paraformaldehyde (141 mg, 1.57 mmol ) and sodium cyanoborohydride (26 mg, 0.69 mmol), heated to reflux for 3 h. The starting material reacted to completion and the reaction was quenched by water. MPLC separation (acetonitrile: water=45%:55%), obtain target product 3-(8-cyanoquinoline-5-yl) -N -{[(3 R )-4-methylmorpholine-3- Methyl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 34 (yellow solid, 60 mg, 57%). 1 H NMR (400 MHz, DMSO- d 6 ) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (d, 1H), 8.23-8.16 (m, 2H), 7.60 ( dd, 1H), 7.23 (d, 1H), 4.01-3.92 (m, 3H), 3.83-3.80 (m, 1H), 3.65-3.62 (m, 2H), 3.47-3.40 (m, 2H), 3.13- 3.11 (m, 1H), 2.96-2.90 (m, 1H), 2.62-2.59 (m, 1H), 2.23 (s, 3H), 2.17-2.05 (m, 2H), 1.93 (d, 1H), 1.63( d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.55. LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

[實施例35] 3-(8-氰基喹啉-5-基)- N-{[(3 S)-4-甲基嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 353-(8-cyanoquinolin-5-yl)- N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image597
Figure 02_image599
[Example 35] 3-(8- cyanoquinoline -5-yl) -N -{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoroform Base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 35 3-(8-cyanoquinolin-5-yl) -N -{[(3S)-4-methylmorpholin-3-yl ]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image597
Figure 02_image599

第一步：叔丁基 (3 S)-3-{ (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)甲醯胺]甲基}嗎啉-4-羧酸鹽 35atert-butyl (3S)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexan-1-yl)formamido]methyl}morpholine-4-carboxylate 將 化合物 1(200 mg，0.56 mmol) 溶解於 N,N-二甲基甲醯胺5 mL中，隨後加入HATU (330 mg，0.88 mmol) 和DIPEA (117 mg， 0.88 mmol)，室溫攪拌10 min，加入( S)-3-(氨基甲基)嗎啉-4-羧酸叔丁酯 (250 mg，1.16 mmol)，室溫攪拌3 h。原料反應完全。MPLC純化 (乙腈:水= 65%:35%)，得到黃色固體，直接投下一步反應。 The first step: tert-butyl (3 S )-3-{(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hex-1-yl)formamide]methyl}morpholine-4-carboxylate 35a tert-butyl (3S)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine-4-carboxylate Compound 1 (200 mg, 0.56 mmol) was dissolved in N,N -dimethylformamide 5 mL , followed by adding HATU (330 mg, 0.88 mmol) and DIPEA (117 mg, 0.88 mmol), stirring at room temperature for 10 min, adding ( S )-3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester ( 250 mg, 1.16 mmol), stirred at room temperature for 3 h. The raw material reacted completely. Purified by MPLC (acetonitrile:water=65%:35%) to obtain a yellow solid, which was directly used for the next reaction.

第二步：3-(8-氰基喹啉-5-基)- N-{[(3 S)-嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 35b3-(8-cyanoquinolin-5-yl)- N-{[(3 S)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 35a溶解於氯化氫二氧六環溶液中，室溫攪拌過夜。待原料反應完，旋乾溶劑，MPLC純化 (乙腈:水= 35%:65%)，3-(8-氰基喹啉-5-基)- N-{[(3 S)-嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 35b(淡黃色固體，206 mg，83 %)。 LC-MSm/z (ESI)= 446.2[M+1], 468.22 [M+23]。 The second step: 3-(8-cyanoquinolin-5-yl) -N -{[(3 S )-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 35b 3-(8-cyanoquinolin-5-yl) -N -{[(3 S )-morpholin-3-yl]methyl}-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve 35a in dioxane hydrogen chloride solution and stir overnight at room temperature. After the reaction of the raw materials is complete, the solvent is spin-dried, purified by MPLC (acetonitrile: water = 35%: 65%), 3-(8-cyanoquinoline-5-yl) -N -{[(3 S )-morpholine- 3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 35b (pale yellow solid, 206 mg, 83%). LC-MS m/z (ESI) = 446.2 [M+1], 468.22 [M+23].

第三步：3-(8-氰基喹啉-5-基)- N-{[(3 S)-4-甲基嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 353-(8-cyanoquinolin-5-yl)- N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將化合物 35b(100 mg，0.23 mmol) 溶解於甲醇5 mL中，隨後加入多聚甲醛 (141 mg, 1.57 mmol) 和氰基硼氫化鈉 (26 mg, 0.69 mmol)，加熱回流3 h。原料反應完全，水淬滅反應。MPLC分離 (乙腈:水= 45%:55%)，得到目標產物3-(8-氰基喹啉-5-基)- N-{[(3 S)-4-甲基嗎啉-3-基]甲基}-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 35(黃色固體，66 mg，63%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (d, 1H), 8.23-8.15(m, 2H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.01-3.92 (m, 3H), 3.83-3.80 (m, 1H), 3.65-3.62 (m, 2H), 3.47-3.40 (m, 2H), 3.16-3.11 (m, 1H), 2.96-2.90 (m, 1H), 2.61-2.59 (m, 1H), 2.23 (s, 3H), 2.17-2.07 (m, 2H), 1.94 (d, J= 4.0 Hz, 1H), 1.65(d, J= 4.0 Hz, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.53 LC-MSm/z (ESI)= 460.2 [M+1], 482.2 [M+23]。 The third step: 3-(8-cyanoquinolin-5-yl) -N -{[(3 S )-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 35 3-(8-cyanoquinolin-5-yl) -N -{[(3S)-4-methylmorpholin-3-yl] methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 35b (100 mg, 0.23 mmol) in methanol 5 mL, then add paraformaldehyde (141 mg, 1.57 mmol ) and sodium cyanoborohydride (26 mg, 0.69 mmol), heated to reflux for 3 h. The starting material reacted to completion and the reaction was quenched by water. MPLC separates (acetonitrile: water=45%: 55%), obtains target product 3-(8- cyanoquinoline -5-yl) -N -{[(3S)-4-methylmorpholine-3- Methyl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 35 (yellow solid, 66 mg, 63%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (d, 1H), 8.23-8.15(m, 2H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.01-3.92 (m, 3H), 3.83-3.80 (m, 1H), 3.65-3.62 (m, 2H), 3.47-3.40 (m, 2H), 3.16-3.11 (m, 1H), 2.96-2.90 (m , 1H), 2.61-2.59 (m, 1H), 2.23 (s, 3H), 2.17-2.07 (m, 2H), 1.94 (d, J = 4.0 Hz, 1H), 1.65(d, J = 4.0 Hz, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.53 LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

[實施例36] 3-(8-氰基喹啉-5-基)-N-(1-(2-羥乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 363-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image346
Figure 02_image602
將 化合物 1(55 mg，0.16 mmol) 溶解於DMF 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入2-(4-氨基-1-哌啶)乙醇 36a(41.8 mg，0.29 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(1-(2-羥乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 36(黃色固體，55 mg，83.3%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02-8.98 (m, 1H), 8.65-8.61 (m, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.63-7.59 (m, 1H), 7.22 (d, 1H), 4.35 (s, 1H), 4.01 (d, 1H), 3.96 -3.89 (m, 2H), 3.82 (d, 1H), 3.67-3.55 (m, 1H), 3.46 (d, 2H), 2.88-2.72 (m, 2H), 2.35 (t, 2H), 2.11-1.91 (m, 2H), 1.63 (t, 2H), 1.46-1.41 (m, 2H), 0.97 (d, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.60 LC-MSm/z (ESI)= 474.2 [M+1]。 [Example 36] 3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compound 36 3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image346
Figure 02_image602
Compound 1 (55 mg, 0.16 mmol) was dissolved in DMF 2 mL, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added, stirred at room temperature for 10 min, and 2-(4-amino -1-piperidine)ethanol 36a (41.8 mg, 0.29 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8- cyanoquinoline -5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 36 (yellow solid, 55 mg, 83.3%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02-8.98 (m, 1H), 8.65-8.61 (m, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.63-7.59 (m , 1H), 7.22 (d, 1H), 4.35 (s, 1H), 4.01 (d, 1H), 3.96 -3.89 (m, 2H), 3.82 (d, 1H), 3.67-3.55 (m, 1H), 3.46 (d, 2H), 2.88-2.72 (m, 2H), 2.35 (t, 2H), 2.11-1.91 (m, 2H), 1.63 (t, 2H), 1.46-1.41 (m, 2H), 0.97 ( d, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.60 LC-MS m/z (ESI) = 474.2 [M+1].

[實施例37] (1 R,5 S)或(1 S,5R)-3-(8-氰基喹啉-5-基)- N-(1-(2-羥乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 37(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)- N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image604
Figure 02_image606
將 化合物 1-A(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg，0.22 mmol)，室溫攪拌10 min，加入2-(4-氨基-1-哌啶)乙醇 (42 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水= 35%:65%)，得到目標產物(1R,5S)-3-(8-氰基喹啉-5-基)- N-(1-(2-羥乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 37(黃色固體，16 mg，26%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.35 (t, 1H), 4.02-3.81 (m, 4H), 3.65-3.52 (m, 1H), 3.48-3.44 (m, 2H), 2.84-2.80 (m, 2H), 2.35-2.33 (m, 2H), 2.00-1.95 (m, 3H), 1.68-1.61 (m, 3H), 1.47-1.35 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.59 LC-MSm/z (ESI)= 474.20 [M+1], 496.20 [M+23]。 [Example 37] ( 1R ,5S) or ( 1S ,5R )-3-(8- cyanoquinolin -5-yl)-N-(1-(2-hydroxyethyl)piperidine- 4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 37 (1 R ,5 S ) / (1 S ,5 R )- 3-(8- cyanoquinolin -5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image604
Figure 02_image606
Dissolve compound 1-A (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), room temperature Stir for 10 min, add 2-(4-amino-1-piperidine)ethanol (42 mg, 0.29 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, and MPLC separates (acetonitrile: water=35%: 65%), obtains target product (1R, 5S)-3-(8- cyanoquinoline -5-yl)-N-(1-(2- Hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 37 (yellow solid, 16 mg, 26% ). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.35 (t, 1H), 4.02-3.81 (m, 4H), 3.65-3.52 (m, 1H), 3.48-3.44 (m, 2H), 2.84-2.80 (m, 2H), 2.35- 2.33 (m, 2H), 2.00-1.95 (m, 3H), 1.68-1.61 (m, 3H), 1.47-1.35 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.59 LC-MS m/z (ESI) = 474.20 [M+1], 496.20 [M+23].

[實施例38] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(1-(2-羥乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷 -1-甲醯胺 化合物 38(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)- N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image608
Figure 02_image610
將 化合物 1-B(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入2-(4-氨基-1-哌啶)乙醇 (42 mg, 0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水= 35%:65%)，得到目標產物(1 S,5 R)-3-(8-氰基喹啉-5-基)- N-(1-(2-羥乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 38(黃色固體，44 mg，71.6%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.06-8.91 (m, 1H), 8.73-8.55 (m, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.35 (t, 1H), 4.02-3.81 (m, 4H), 3.61-3.54 (m, 1H), 3.48-3.44 (m, 2H), 2.83-2.80 (m, 2H), 2.37-2.33 (m, 2H), 2.00-1.95 (m, 3H), 1.67-1.61 (m, 3H), 1.46-1.38 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.59 LC-MSm/z (ESI)= 474.20 [M+1], 496.20 [M+23]。 [Example 38] ( 1S , 5R ) or ( 1R ,5S)-3-(8- cyanoquinolin - 5-yl)-N-(1-(2-hydroxyethyl)piperidine -4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 38 (1 S ,5 R ) / (1 R ,5 S ) -3-(8-cyanoquinolin-5-yl) -N -(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image608
Figure 02_image610
Dissolve compound 1-B (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), room temperature Stir for 10 min, add 2-(4-amino-1-piperidine)ethanol (42 mg, 0.29 mmol), and stir at room temperature for 3 h. Raw material reaction is complete, and MPLC separates (acetonitrile: water=35%: 65%), obtains target product (1 S , 5 R )-3-(8- cyanoquinoline -5-yl)-N-(1-( 2-Hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 38 (yellow solid, 44 mg, 71.6%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.06-8.91 (m, 1H), 8.73-8.55 (m, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H ), 7.22 (d, 1H), 4.35 (t, 1H), 4.02-3.81 (m, 4H), 3.61-3.54 (m, 1H), 3.48-3.44 (m, 2H), 2.83-2.80 (m, 2H ), 2.37-2.33 (m, 2H), 2.00-1.95 (m, 3H), 1.67-1.61 (m, 3H), 1.46-1.38 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.59 LC-MS m/z (ESI) = 474.20 [M+1], 496.20 [M+23].

[實施例39] 3-(8-氰基喹啉-5-基)- N-反式-(4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 393-(8-cyanoquinolin-5-yl)- N-trans-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image612
Figure 02_image614
將 化合物 1(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (60 mg，0.16 mmol) 和DIPEA (130 ul，0.74 mmol)，冰浴下攪拌活化10 min，加入4-(4-(環丙基甲基)哌嗪-1-基)環己胺 39a(56 mg，0.16 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1R,5S)-3-(8-氰基喹啉-5-基)- N-反式-(4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 39(黃色固體，21 mg，25.2%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.04 – 8.96 (m, 1H), 8.66 – 8.60(m, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.66 – 7.57 (m, 1H), 7.24 (dd, 1H), 4.09 – 3.89 (m, 3H), 3.85 – 3.70 (m, 2H), 2.24 – 2.05(m, 3H), 2.03-1.90 (dd, 3H), 1.86-1.70 (s, 3H), 1.61 (d, 1H), 1.45 (s, 1H), 1.35-1.2 (m, 9H), 0.91 – 0.72 (m, 2H), 0.43 (dd, 2H), 0.07-0.02 (m, 2H)。 LC-MSm/z (ESI)= 567.3 [M+1],589.3 [M+23]。 [Example 39] 3-(8-cyanoquinolin-5-yl) -N -trans-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5 -(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide compound 39 3-(8-cyanoquinolin-5-yl) -N -trans-(4-(4- (cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image612
Figure 02_image614
Compound 1 (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (60 mg, 0.16 mmol) and DIPEA (130 ul, 0.74 mmol) were added, and stirred in an ice bath After activation for 10 min, add 4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexylamine 39a (56 mg, 0.16 mmol), and stir at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, spin-dried, and passed MPLC to obtain the target product (1R, 5S)-3-(8-cyanoquinoline-5-yl) -N -trans-(4-(4-( Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 39 (yellow solid, 21 mg, 25.2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.04 – 8.96 (m, 1H), 8.66 – 8.60 (m, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.66 – 7.57 (m , 1H), 7.24 (dd, 1H), 4.09 – 3.89 (m, 3H), 3.85 – 3.70 (m, 2H), 2.24 – 2.05(m, 3H), 2.03-1.90 (dd, 3H), 1.86-1.70 (s, 3H), 1.61 (d, 1H), 1.45 (s, 1H), 1.35-1.2 (m, 9H), 0.91 – 0.72 (m, 2H), 0.43 (dd, 2H), 0.07-0.02 (m , 2H). LC-MS m/z (ESI) = 567.3 [M+1], 589.3 [M+23].

[實施例40] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)- N-(4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 40(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)- N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image616
Figure 02_image618
將 化合物 1-A(50 mg, 0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (112 mg，0.88 mmol)，室溫攪拌10 min，加入4-[4-(環丙基甲基)-1-哌嗪基]-環己胺三鹽酸鹽 40a(101 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水= 40%:60%)，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)- N-(4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 40(黃色固體，40 mg，54%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (m, 1H), 8.63 (dd, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.61 (m, 1H), 7.24 (dd, 1H), 4.03-3.72 (m, 6H), 3.66-3.34 (m, 9H), 2.23-2.05 (m, 2H), 2.02-1.90 (m, 2H), 1.86-1.72 (m, 2H), 1.50-1.02 (m, 7H), 0.86-0.74 (m, 1H), 0.46-0.39 (m, 1H), 0.07-0.05 (m, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.61。 LC-MSm/z (ESI)= 567.30 [M+1], 589.30 [M+23]。 [Example 40] (1 R ,5 S ) or (1 S ,5 R )-3-(8- cyanoquinolin -5-yl)-N-(4-(4-(cyclopropylmethyl )piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 40 (1 R ,5 S )/( 1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N -(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] hexane-1-carboxamide
Figure 02_image616
Figure 02_image618
Dissolve compound 1-A (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (83 mg, 0.22 mmol) and DIPEA (112 mg, 0.88 mmol), room temperature Stir for 10 min, add 4-[4-(cyclopropylmethyl)-1-piperazinyl]-cyclohexylamine trihydrochloride 40a (101 mg, 0.29 mmol), and stir at room temperature for 3 h. The raw material reacted completely, separated by MPLC (acetonitrile:water=40%:60%), and the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinoline-5-yl )- N -(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Formamide Compound 40 (yellow solid, 40 mg, 54%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (m, 1H), 8.63 (dd, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.61 (m, 1H), 7.24 ( dd, 1H), 4.03-3.72 (m, 6H), 3.66-3.34 (m, 9H), 2.23-2.05 (m, 2H), 2.02-1.90 (m, 2H), 1.86-1.72 (m, 2H), 1.50-1.02 (m, 7H), 0.86-0.74 (m, 1H), 0.46-0.39 (m, 1H), 0.07-0.05 (m, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.61. LC-MS m/z (ESI) = 567.30 [M+1], 589.30 [M+23].

[實施例41] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 41(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)- N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image620
Figure 02_image622
將 化合物 1-b(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (112 mg，0.88 mmol)，室溫攪拌10 min，加入4-[4-(環丙基甲基)-1-哌嗪基]-環己胺三鹽酸鹽 41a(101 mg，0.29 mmol)，室溫攪拌3h。原料反應完全，MPLC分離 (乙腈:水= 40%:60%)，得到目標產物(1 S,5 R)或(1 R,5S)-3-(8-氰基喹啉-5-基)- N-(4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 41(黃色固體，40 mg，54%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (td, 1H), 8.63 (dd, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.61 (m, 1H), 7.24 (dd, 1H), 4.03-3.72 (m, 6H), 3.65-3.35(m, 9H), 2.17-2.07 (m, 2H), 2.02-1.95 (m, 2H), 1.82-1.75 (m, 2H), 1.25-1.20 (m, 7H), 0.87-0.73 (m, 1H), 0.45-0.39 (m, 1H), 0.06-0.02 (m, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.61 LC-MSm/z (ESI)= 567.30 [M+1]。 [Example 41] (1 S ,5 R ) or (1 R ,5 S )-3-(8- cyanoquinolin -5-yl)-N-(4-(4-(cyclopropylmethyl )piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 41 (1 S ,5 R ) / ( 1 R ,5 S )-3-(8-cyanoquinolin-5-yl) -N -(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] hexane-1-carboxamide
Figure 02_image620
Figure 02_image622
Compound 1-b (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (112 mg, 0.88 mmol) were added at room temperature Stir for 10 min, add 4-[4-(cyclopropylmethyl)-1-piperazinyl]-cyclohexylamine trihydrochloride 41a (101 mg, 0.29 mmol), and stir at room temperature for 3 h. The raw material reacted completely, separated by MPLC (acetonitrile: water = 40%: 60%) to obtain the target product (1 S , 5 R ) or (1 R , 5S)-3-(8-cyanoquinolin-5-yl) - N -(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Formamide Compound 41 (yellow solid, 40 mg, 54%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (td, 1H), 8.63 (dd, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.61 (m, 1H), 7.24 ( dd, 1H), 4.03-3.72 (m, 6H), 3.65-3.35(m, 9H), 2.17-2.07 (m, 2H), 2.02-1.95 (m, 2H), 1.82-1.75 (m, 2H), 1.25-1.20 (m, 7H), 0.87-0.73 (m, 1H), 0.45-0.39 (m, 1H), 0.06-0.02 (m, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.61 LC-MS m/z (ESI) = 567.30 [M+1].

[實施例42] 3-(8-氰基喹啉-5-基)- N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 423-(8-cyanoquinolin-5-yl)- N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image286
Figure 02_image625
[Example 42] 3-(8- cyanoquinolin -5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compound 42 3-(8-cyanoquinolin-5-yl) -N -(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image286
Figure 02_image625

第一步： (1-(環丙基甲基)哌啶-4-基)氨基甲酸叔丁酯 42ctert-butyl (1-(cyclopropylmethyl)piperidin-4-yl)carbamate 50 mL圓底燒瓶中，將 42a(1 g，5 mmol) 溶於30 mL乙腈中，冰浴下加入 42b(877 mg，6.5 mmol) 和DIPEA (1.65 mL，10 mmol)，80 ℃攪拌5 h。將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物(1-(環丙基甲基)哌啶-4-基)氨基甲酸叔丁酯 42c(黃色油狀液體，1.5 g，粗品)，直接用於下一步。 LC-MSm/z (ESI)= 255.2 [M+1]。 The first step : (1-(cyclopropylmethyl)piperidin-4-yl)carbamate tert-butyl ester 42c tert-butyl (1-(cyclopropylmethyl)piperidin-4-yl)carbamate In a 50 mL round bottom flask, 42a (1 g, 5 mmol) was dissolved in 30 mL of acetonitrile, 42b (877 mg, 6.5 mmol) and DIPEA (1.65 mL, 10 mmol) were added under ice cooling, and stirred at 80 °C for 5 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product (1-(cyclopropylmethyl)piperidin-4-yl) tert-Butyl carbamate 42c (yellow oily liquid, 1.5 g, crude) was used directly in the next step. LC-MS m/z (ESI) = 255.2 [M+1].

第二步：1-(環丙基甲基)哌啶-4-胺 42d1-(cyclopropylmethyl)piperidin-4-amine 50 mL圓底燒瓶中，將 42c(100 mg，5 mmol) 溶於10 mL二氯甲烷中，隨後加入三氟乙酸 (1 mL)，室溫反應2 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物1-(環丙基甲基)哌啶-4-胺 42d(無色油狀液體，100 mg，粗品)，直接用於下一步。 LC-MSm/z (ESI)= 155.2 [M+1]。 Second step: 1-(cyclopropylmethyl)piperidin-4-amine 42d 1-(cyclopropylmethyl)piperidin-4-amine In a 50 mL round bottom flask, dissolve 42c (100 mg, 5 mmol) in 10 mL In dichloromethane, trifluoroacetic acid (1 mL) was added subsequently, and reacted at room temperature for 2 h. Saturated ammonium chloride quenched the reaction, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, dried the organic phase with anhydrous sodium sulfate, and spin-dried to obtain the target product 1-(cyclopropylmethyl)piperidin-4-amine 42d (colorless oily liquid, 100 mg, crude product), used directly in the next step. LC-MS m/z (ESI) = 155.2 [M+1].

第三步：3-(8-氰基喹啉-5-基)- N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 423-(8-cyanoquinolin-5-yl)- N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 42d(37.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇= 10:1)，得到目標產物3-(8-氰基喹啉-5-基)-N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 42(黃色固體，26 mg，38.5%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.03-8.97 (m, 1H), 8.66-8.61 (m, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.62-7.58 (m, 1H), 7.22 (d, 1H), 4.01 (d, 1H), 3.97-3.91 (m, 2H), 3.82 (d, 1H), 3.59 (d, 1H), 2.94 (d, 2H), 2.18 (d, 2H), 1.99 (d, 3H), 1.73-1.58 (m, 3H), 1.48-1.42 (m, 2H), 0.87-0.75 (m, 1H), 0.52-0.38 (m, 2H), 0.06 (d, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.48。 LC-MSm/z (ESI)= 484.2 [M+1]。 The third step: 3-(8- cyanoquinolin -5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 42 3-(8- cyanoquinolin -5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl) -3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirred at room temperature for 10 min, added 42d (37.0 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 42 (yellow solid, 26 mg, 38.5%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03-8.97 (m, 1H), 8.66-8.61 (m, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.62-7.58 (m , 1H), 7.22 (d, 1H), 4.01 (d, 1H), 3.97-3.91 (m, 2H), 3.82 (d, 1H), 3.59 (d, 1H), 2.94 (d, 2H), 2.18 ( d, 2H), 1.99 (d, 3H), 1.73-1.58 (m, 3H), 1.48-1.42 (m, 2H), 0.87-0.75 (m, 1H), 0.52-0.38 (m, 2H), 0.06 ( d, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.48. LC-MS m/z (ESI) = 484.2 [M+1].

[實施例43] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)- N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 43(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)- N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image627
Figure 02_image629
將 化合物 1-A(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 43d(37.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇= 10:1)，得到目標產物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)- N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 43(黃色固體，30 mg，47.8%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03-3.81 (m, 4H), 3.67-3.50 (m, 1H), 2.98-2.85(m, 2H), 2.14 (d, J= 8.2, 2H), 2.00-1.90 (m, 3H), 1.71-1.62 (m, 3H), 1.50-1.36 (m, 2H), 0.81-0.76 (m, 1H), 0.45-0.41 (m, 2H), 0.05-0.03 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58 LC-MSm/z (ESI)= 484.20 [M+1]，506.20 [M+Na]。 [Example 43] ( 1R ,5S) or ( 1S , 5R )-3-(8- cyanoquinolin -5-yl) -N- (1-(cyclopropylmethyl)piperidine -4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 43 (1 R ,5 S ) / (1 S ,5 R ) -3-(8-cyanoquinolin-5-yl) -N -(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image627
Figure 02_image629
Dissolve compound 1-A (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), room temperature Stir for 10 min, add 43d (37.0 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1R,5S) or (1S,5R)-3-(8- cyanoquinolin -5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 43 (yellow solid, 30 mg, 47.8%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.03-3.81 (m, 4H), 3.67-3.50 (m, 1H), 2.98-2.85(m, 2H), 2.14 (d, J = 8.2, 2H), 2.00-1.90 (m, 3H ), 1.71-1.62 (m, 3H), 1.50-1.36 (m, 2H), 0.81-0.76 (m, 1H), 0.45-0.41 (m, 2H), 0.05-0.03 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58 LC-MS m/z (ESI) = 484.20 [M+1], 506.20 [M+Na].

[實施例44] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 44(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)- N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image631
Figure 02_image633
將 化合物 1-B(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 44d(37.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇= 10:1)，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(1-(環丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 44(黃色固體，30 mg，47.8%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03-3.81 (m, 4H), 3.61-3.54 (m, 1H), 2.94-2.90 (m, 2H), 2.14 (d, J= 8.2, 2H), 2.00-1.90 (m, 3H), 1.69-1.62 (m, 3H), 1.49-1.39 (m, 2H), 0.83-0.76 (m, 1H), 0.45-0.42 (m, 2H), 0.06-0.02 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58。 LC-MSm/z (ESI)= 484.20 [M+1]，506.20 [M+Na]。 [Example 44] ( 1S , 5R ) or ( 1R ,5S)-3-(8- cyanoquinolin -5-yl) -N- (1-(cyclopropylmethyl)piperidine -4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 44 (1 S ,5 R ) / (1 R ,5 S ) -3-(8-cyanoquinolin-5-yl) -N -(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image631
Figure 02_image633
Compound 1-B (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added at room temperature Stir for 10 min, add 44d (37.0 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1 S ,5 R ) or (1 R ,5 S )-3-(8- cyanoquinolin -5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 44 (yellow solid, 30 mg, 47.8%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.03-3.81 (m, 4H), 3.61-3.54 (m, 1H), 2.94-2.90 (m, 2H), 2.14 (d, J = 8.2, 2H), 2.00-1.90 (m, 3H ), 1.69-1.62 (m, 3H), 1.49-1.39 (m, 2H), 0.83-0.76 (m, 1H), 0.45-0.42 (m, 2H), 0.06-0.02 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 484.20 [M+1], 506.20 [M+Na].

[實施例45] 3-(8-氰基喹啉-5-基)- N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 453-(8-cyanoquinolin-5-yl)- N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image294
Figure 02_image636
[Example 45] 3-(8- cyanoquinolin -5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethane Base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 45 3-(8- cyanoquinolin -5-yl)-N-(1-(oxetan-3-yl)piperidin-4 -yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image294
Figure 02_image636

第一步： (1-(氧雜環丁烷-3-基)哌啶-4-基)氨基甲酸叔丁酯 45ctert-butyl (1-(oxetan-3-yl)piperidin-4-yl)carbamate 50 mL圓底燒瓶中，將 45a(1 g，5 mmol) 溶於30 mL二氯甲烷中，冰浴下加入 45b(720 mg，10 mmol) 和三乙醯氧基氰基硼氫化鈉 (4.24 g，20 mmol)，加入冰醋酸調節pH至4-5，室溫攪拌2 h。將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物(1-(氧雜環丁烷-3-基)哌啶-4-基)氨基甲酸叔丁酯 45c(黃色油狀液體，1.5 g，粗品)，直接用於下一步。 LC-MSm/z (ESI)= 257.2 [M+1]。 The first step : (1-(oxetan-3-yl)piperidin-4-yl)carbamate tert-butyl ester 45c tert-butyl (1-(oxetan-3-yl)piperidin-4-yl) In a carbamate 50 mL round bottom flask, 45a (1 g, 5 mmol) was dissolved in 30 mL of dichloromethane, and 45b (720 mg, 10 mmol) and sodium triacetyloxycyanoborohydride ( 4.24 g, 20 mmol), adding glacial acetic acid to adjust the pH to 4-5, stirring at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product (1-(oxetan-3-yl)piperidine- 4-yl) tert-butyl carbamate 45c (yellow oily liquid, 1.5 g, crude), used directly in the next step. LC-MS m/z (ESI) = 257.2 [M+1].

第二步：1-(氧雜環丁烷-3-基)哌啶-4-胺 45d1-(oxetan-3-yl)piperidin-4-amine 50 mL圓底燒瓶中，將 45c(100 mg，5 mmol) 溶於10 mL二氯甲烷中，隨後加入三氟乙酸 (1 mL)，室溫反應2 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物1-(氧雜環丁烷-3-基)哌啶-4-胺 45d(無色油狀液體，100 mg，粗品)，直接用於下一步。 LC-MSm/z (ESI)= 157.1 [M+1]。 The second step: 1-(oxetan-3-yl)piperidin-4-amine 45d 1-(oxetan-3-yl)piperidin-4-amine 50 mL round bottom flask, 45c (100 mg , 5 mmol) was dissolved in 10 mL of dichloromethane, then trifluoroacetic acid (1 mL) was added, and reacted at room temperature for 2 h. Saturated ammonium chloride quenched the reaction, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, dried the organic phase with anhydrous sodium sulfate, and spin-dried to obtain the target product 1-(oxetane-3-yl)piperidine- 4-Amine 45d (colorless oily liquid, 100 mg, crude product) was used directly in the next step. LC-MS m/z (ESI) = 157.1 [M+1].

第三步：3-(8-氰基喹啉-5-基)- N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 453-(8-cyanoquinolin-5-yl)- N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(50 mg，0.17 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 45d(37.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)- N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 45(黃色固體，32 mg，47.1%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02-8.99 (m, 1H), 8.65-8.60 (m, 1H), 8.16 (d, 1H), 8.07 (d, 1H), 7.63-7.59 (m, 1H), 7.22 (d, 1H), 4.51 (t, 2H), 4.39 (t, 2H), 4.01 (d, 1H), 3.97-3.92 (m, 2H), 3.82 (d, 1H), 3.68-3.56 (m, 1H), 3.37 (s, 1H), 2.72-2.60 (m, 2H), 1.99 (d, 1H), 1.79 (t, 2H), 1.73-1.61 (m, 2H), 1.53-1.39 (m, 2H), 1.06 (s, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58。 LC-MSm/z (ESI)= 486.2 [M+1]。 The third step: 3-(8- cyanoquinolin -5-yl)-N-(1-(oxetane-3-yl)piperidin-4-yl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 45 3-(8- cyanoquinolin -5-yl)-N-(1-(oxetan-3-yl)piperidin-4- yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (50 mg, 0.17 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirred at room temperature for 10 min, added 45d (37.0 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8- cyanoquinolin -5-yl)-N-(1-(oxetane-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 45 (yellow solid, 32 mg, 47.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02-8.99 (m, 1H), 8.65-8.60 (m, 1H), 8.16 (d, 1H), 8.07 (d, 1H), 7.63-7.59 (m , 1H), 7.22 (d, 1H), 4.51 (t, 2H), 4.39 (t, 2H), 4.01 (d, 1H), 3.97-3.92 (m, 2H), 3.82 (d, 1H), 3.68- 3.56 (m, 1H), 3.37 (s, 1H), 2.72-2.60 (m, 2H), 1.99 (d, 1H), 1.79 (t, 2H), 1.73-1.61 (m, 2H), 1.53-1.39 ( m, 2H), 1.06 (s, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 486.2 [M+1].

[實施例46] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)- N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 46(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)- N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image638
Figure 02_image640
將 化合物 1-A(50 mg，0.17 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 46d(37.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 46(黃色固體，30 mg，47.6%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.12-7.95 (m, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.52-4.38 (m, 4H), 4.02-3.75 (m, 4H), 3.64-3.51 (m, 1H), 2.68-2.62 (m, 2H), 2.35-2.30 (m, 1H), 2.01-1.98(m, 1H), 1.84-1.62 (m, 5H), 1.50-1.40 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.60。 LC-MSm/z (ESI)= 486.20 [M+1]，508.20 [M+Na]。 [Example 46] (1 R ,5 S ) or (1 S ,5 R )-3-(8- cyanoquinolin -5-yl)-N-(1-(oxetane-3- Base) piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 46 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N -(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxamide
Figure 02_image638
Figure 02_image640
Compound 1-A (50 mg, 0.17 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added at room temperature Stir for 10 min, add 46d (37.0 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetane-3-yl)piperidine- 4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 46 (yellow solid, 30 mg, 47.6%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.12-7.95 (m, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.52-4.38 (m, 4H), 4.02-3.75 (m, 4H), 3.64-3.51 (m, 1H), 2.68-2.62 (m, 2H), 2.35-2.30 (m, 1H ), 2.01-1.98(m, 1H), 1.84-1.62 (m, 5H), 1.50-1.40 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.60. LC-MS m/z (ESI) = 486.20 [M+1], 508.20 [M+Na].

[實施例47] (1 S,5 R)或·(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 47(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)- N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image642
Figure 02_image644
將化合物 1-b(50 mg，0.17 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入 47d(37.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(1-(氧雜環丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 47(黃色固體，30 mg，47.6%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, J= 4.1, 1.4 Hz, 1H), 8.64 (dd, J= 8.9, 1.6 Hz, 1H), 8.17 (d, J= 8.2 Hz, 1H), 8.06 (d, J= 8.4 Hz, 1H), 7.60 (dd, J= 8.3, 4.3 Hz, 1H), 7.23 (d, J= 8.5 Hz, 1H), 4.52-4.38 (m, 4H), 4.03-3.81 (m, 4H), 3.68-3.54 (m, 1H), 2.72-2.61(m, 2H), 2.33-2.32 (m, 1H), 2.01-1.97 (m, 1H), 1.83-1.60 (m, 5H), 1.49-1.37 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.60。 LC-MSm/z (ESI)= 486.20 [M+1]，508.20 [M+Na]。 [Example 47] (1 S ,5 R ) or (1 R ,5 S )-3-(8- cyanoquinolin -5-yl)-N-(1-(oxetane-3 -yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 47 (1 S ,5 R ) / (1 R ,5 S )-3-(8-cyanoquinolin-5-yl) -N -(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]Hexane-1-carboxamide
Figure 02_image642
Figure 02_image644
Compound 1-b (50 mg, 0.17 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added at room temperature Stir for 10 min, add 47d (37.0 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1 R ,5 S )-3-(8- cyanoquinolin -5-yl)-N-(1-(oxetane-3-yl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 47 (yellow solid, 30 mg, 47.6%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, J = 4.1, 1.4 Hz, 1H), 8.64 (dd, J = 8.9, 1.6 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.3, 4.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 4.52-4.38 (m, 4H), 4.03-3.81 (m, 4H), 3.68-3.54 (m, 1H), 2.72-2.61(m, 2H), 2.33-2.32 (m, 1H), 2.01-1.97 (m, 1H), 1.83-1.60 (m , 5H), 1.49-1.37 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.60. LC-MS m/z (ESI) = 486.20 [M+1], 508.20 [M+Na].

[實施例48] 3-(8-氰基喹啉-5-基)- N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 48-A、 48-B、 48-C和 48-D3-(8-cyanoquinolin-5-yl)- N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image646
Figure 02_image648
[Example 48] 3-(8-cyanoquinolin-5-yl) -N -[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compounds 48-A , 48-B , 48-C and 48-D 3-(8-cyanoquinolin-5-yl) -N -[(1- methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image646
Figure 02_image648

第一步：3-(8-氰基喹啉-5-基)- N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 483-(8-cyanoquinolin-5-yl)- N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1(200 mg，0.56 mmol) 溶解於 N,N-二甲基甲醯胺4 mL中，隨後加入HATU (330 mg，0.88 mmol) 和DIPEA (114 mg，0.88 mmol)，冰浴下攪拌活化10 min，加入(1-甲基吡咯烷-2-基)甲胺化合物 48a(140ul，1.12 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物3-(8-氰基喹啉-5-基)- N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 48(黃色固體，252 mg，57%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (m, 1H), 8.18 (dd, 2H), 7.60 (dd, 1H), 7.22 (d, 1H)，4.03-3.81 (m, 4H), 2.95-2.89 (m, 2H), 2.28-2.20 (m, 4H), 2.13-2.06 (m, 1H), 1.94-1.91 (m, 1H), 1.82-1.41 (m, 6H)。 LC-MSm/z (ESI)= 444.2 [M+1], 466.2 [M+23]。 The first step: 3-(8-cyanoquinolin-5-yl) -N -[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 48 3-(8-cyanoquinolin-5-yl)- N -[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 1 (200 mg, 0.56 mmol) in 4 mL of N,N -dimethylformamide, then add HATU (330 mg, 0.88 mmol) and DIPEA (114 mg, 0.88 mmol) was activated by stirring in an ice bath for 10 min, and (1-methylpyrrolidin-2-yl)methanamine compound 48a (140ul, 1.12 mmol) was added, and stirred at room temperature for 1 h. The reaction of the raw material is complete, quenched by adding water, spin-dried, and passed MPLC to obtain the target product 3-(8-cyanoquinolin-5-yl) -N -[(1-methylpyrrolidin-2-yl)methyl] -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 48 (yellow solid, 252 mg, 57%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (m, 1H), 8.18 (dd, 2H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03- 3.81 (m, 4H), 2.95-2.89 (m, 2H), 2.28-2.20 (m, 4H), 2.13-2.06 (m, 1H), 1.94-1.91 (m, 1H), 1.82-1.41 (m, 6H ). LC-MS m/z (ESI) = 444.2 [M+1], 466.2 [M+23].

第二步：3-(8-氰基喹啉-5-基)- N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 48-A、 48-B、 48-C和 48-D3-(8-cyanoquinolin-5-yl)- N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide A,通過手性製備高效液相色譜拆分化合物48製備得到 化合物 48-A 、 48-B、 48-C和 48-D。分析方法：手性柱Ig-3，流動相為 乙醇+0.2%二乙胺，流速1 mL/min, 化合物 48-A保留時間為5.156 min， 化合物 48-B保留時間為5.784 min， 化合物 48-C保留時間為6.234 min， 化合物 48-D保留時間為7.314 min。 The second step: 3-(8-cyanoquinolin-5-yl) -N -[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compounds 48-A , 48-B , 48-C and 48-D 3-(8-cyanoquinolin-5-yl) -N -[(1-methylpyrrolidin -2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide A, compound 48 was prepared by chiral preparative high performance liquid chromatography to obtain compound 48-A , 48- B , 48-C and 48-D . Analysis method: chiral column Ig-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 48-A is 5.156 min, the retention time of compound 48-B is 5.784 min, and the retention time of compound 48- The retention time of C was 6.234 min, and the retention time of compound 48-D was 7.314 min.

[實施例49] 3-(8-氰基喹啉-5-基)- N-(2-嗎啉乙基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 493-(8-cyanoquinolin-5-yl)- N-(2-morpholinoethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image300
Figure 02_image651
將 化合物 1(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65 mg，0.17 mmol) 和DIPEA (52 ul，0.29 mmol)，冰浴下攪拌活化10 min，加入2-嗎啉代乙胺 化合物 49a(23 mg，0.17 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1R,5S)-3-(8-氰基喹啉-5-基)- N-(2-嗎啉乙基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 49(黃色固體，62 mg，91.8%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.20 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.05-3.89 (m, 3H), 3.81 (d, 1H), 3.55 (t, 4H), 3.23 (q, 2H), 2.45-2.26 (m, 6H), 1.95 (d, 1H), 1.64 (d, 1H)。 LC-MSm/z (ESI)= 460.2 [M+1],482.2 [M+23]。 [Example 49] 3-(8- cyanoquinolin -5-yl)-N-(2-morpholinoethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 49 3-(8-cyanoquinolin-5-yl) -N -(2-morpholinoethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image300
Figure 02_image651
Compound 1 (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added, and stirred in an ice bath After activation for 10 min, 2-morpholinoethylamine compound 49a (23 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1R,5S)-3-(8- cyanoquinolin -5-yl)-N-(2-morpholineethyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 49 (yellow solid, 62 mg, 91.8%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.20 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.05-3.89 (m, 3H), 3.81 (d, 1H), 3.55 (t, 4H), 3.23 (q, 2H), 2.45-2.26 (m, 6H), 1.95 (d, 1H) , 1.64 (d, 1H). LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

[實施例50] (1R,5S)-3-(8-氰基喹啉-5-基)- N-(2-(吡咯烷-1-基)乙基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1 -甲醯胺 化合物 50(1R,5S)-3-(8-cyanoquinolin-5-yl)- N-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image302
Figure 02_image654
將 化合物 1(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65 mg，0.17 mmol) 和DIPEA (52 ul，0.29 mmol)，冰浴下攪拌活化10 min，加入2-嗎啉代乙胺 50a(20 mg，0.17 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1R,5S)-3-(8-氰基喹啉-5-基)- N-(2-(吡咯烷-1-基)乙基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1 -甲醯胺 化合物 50(黃色固體，32 mg，50.1%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.23 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.00 (d, 1H), 3.94 (d, 2H), 3.80 (d, 1H), 3.21 (q, 2H), 2.44 (m, 6H), 1.95 (d, 1H), 1.65 (m, 5H)。 LC-MSm/z (ESI)= 444.2 [M+1],466.2 [M+23]。 [Example 50] (1R,5S)-3-(8- cyanoquinolin -5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 50 (1R,5S)-3-(8- cyanoquinolin -5-yl)-N-(2-(pyrrolidin-1- yl)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image302
Figure 02_image654
Compound 1 (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added, and stirred in an ice bath After activation for 10 min, 2-morpholinoethylamine 50a (20 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched by adding water, spin-dried, and passed MPLC to obtain the target product (1R,5S)-3-(8- cyanoquinoline -5-yl)-N-(2-(pyrrolidin-1-yl )ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 50 (yellow solid, 32 mg, 50.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.23 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.00 (d, 1H), 3.94 (d, 2H), 3.80 (d, 1H), 3.21 (q, 2H), 2.44 (m, 6H), 1.95 (d, 1H), 1.65 (m , 5H). LC-MS m/z (ESI) = 444.2 [M+1], 466.2 [M+23].

[實施例51] 3-(8-氰基喹啉-5-基)-5-甲基- N-(1-甲基哌啶-4-基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 513-(8-cyanoquinolin-5-yl)-5-methyl- N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image304
Figure 02_image657
[Example 51] 3-(8-cyanoquinolin-5-yl)-5-methyl- N- (1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0] Hexane-1-formamide Compound 51 3-(8-cyanoquinolin-5-yl)-5-methyl- N -(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1- carboxamide
Figure 02_image304
Figure 02_image657

第一步： 1-苄基-4-甲基-2,5-二氫-1H-吡咯-3-羧酸乙酯 51cethyl 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylate N 2氛圍下，將 51a(10 g，60 mmol) 溶於30 mL二氯甲烷中，冰浴下滴加 51b(14.4 g，60 mmol)的二氯甲烷溶液 (10 mL)，隨後滴加三氟乙酸 (684 mg，6 mmol)的二氯甲烷溶液 (10 mL)，室溫攪拌2 h。將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚=1:10)，得到目標產物1-苄基-4-甲基-2,5-二氫-1H-吡咯-3-羧酸乙酯 51c(黃色油狀液體，7.1 g，產率50.4%)，直接用於下一步。 The first step : 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 51c ethyl 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole -3-carboxylate N Under the atmosphere, 51a (10 g , 60 mmol) was dissolved in 30 mL of dichloromethane, and a solution of 51b (14.4 g, 60 mmol) in dichloromethane (10 mL) was added dropwise under ice-cooling, Then a dichloromethane solution (10 mL) of trifluoroacetic acid (684 mg, 6 mmol) was added dropwise, and stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain the target The product ethyl 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylate 51c (yellow oily liquid, 7.1 g, yield 50.4%) was directly used in the next step.

第二步：3-苄基-5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 51dethyl -3-benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2氛圍下，將三甲基碘化亞碸 (3.5 g，15.8 mmol) 溶於10 mL二甲亞碸中，冰浴下分批次加入氫化鈉 (633.6 mg，15.8 mmol)的二甲亞碸溶液 (5 mL)，室溫攪拌30 min。隨後滴加 51c(4.3 g，14.4 mmol)的二甲亞碸溶液 (5 mL)，60 ℃反應5 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚=1:10)，得到目標產物3-苄基-5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 51d(無色油狀液體，3.2 g， 產率78.9%)，直接用於下一步。 LC-MSm/z (ESI)= 260.1 [M+1]。 The second step: 3-benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 51d ethyl-3-benzyl-5-methyl-3-azabicyclo[3.1. 0]Hexane-1-carboxylate N 2 atmosphere, trimethyl sulfide iodide (3.5 g, 15.8 mmol) was dissolved in 10 mL dimethyl sulfide, sodium hydride (633.6 mg, 15.8 mmol) in dimethyl oxide solution (5 mL), stirred at room temperature for 30 min. Then a solution of 51c (4.3 g, 14.4 mmol) in dimethyloxide (5 mL) was added dropwise and reacted at 60 °C for 5 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain The target product 3-benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 51d (colorless oily liquid, 3.2 g, yield 78.9%) was directly used in Next step. LC-MS m/z (ESI) = 260.1 [M+1].

第三步：5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 51eethyl -5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate H 2氛圍下，將 51d(1 g，3.2 mmol) 溶於乙醇50 mL中，隨後加入Pd/C (681 mg，0.64 mmol)，升溫至60 ℃反應3 h。矽藻土過濾，旋乾溶劑，得到目標產物5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 51e(無色油狀液體，487 mg，產率90.1%)，直接用於下一步。 LC-MSm/z (ESI)= 170.1 [M+1]。 The third step: 5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 51e ethyl -5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate H 2 Under atmosphere, 51d (1 g, 3.2 mmol) was dissolved in 50 mL of ethanol, then Pd/C (681 mg, 0.64 mmol) was added, and the temperature was raised to 60 °C for 3 h. Celite was filtered, and the solvent was spin-dried to obtain the target product 5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 51e (colorless oily liquid, 487 mg, yield 90.1% ), used directly in the next step. LC-MS m/z (ESI) = 170.1 [M+1].

第四步：(3-(8-氰基喹啉-5-基)-5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 51 g3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate N 2氛圍下，將 51f(654 mg，2.9 mmol) 溶於1,4-二氧六環30 mL中，隨後加入 51e(487 mg，2.9 mmol)，N 2置換氣三次，依次加入碳酸鉀 (1.8 g，13.05 mmol) 和Ruphos Pdg3 (486 mg，0.58 mmol)， N 2置換氣三次，升溫至90 ℃反應24 h。旋乾溶劑，乙酸乙酯萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，粗產物 51 g直接投下一步。 LC-MSm/z (ESI)= 322.1 [M+1]。 The fourth step: (3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 51 g 3-(8 -cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate 51f (654 mg, 2.9 mmol) was dissolved in 1,4-dioxane 30 under N 2 atmosphere mL, followed by adding 51e (487 mg, 2.9 mmol), N replacement gas three times, followed by adding potassium carbonate (1.8 g, 13.05 mmol) and Ruphos Pdg3 (486 mg, 0.58 mmol), N replacement gas three times, warming up to React at 90°C for 24 h. Spin to dry the solvent, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin to dry the solvent, and 51 g of the crude product is directly used in the next step. LC-MS m/z (ESI)= 322.1 [ M+1].

第五步：3-(8-氰基喹啉-5-基)-5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸 51h3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 將 51 g的粗產品 (1.0 g，2.9 mmol) 溶於四氫呋喃溶液10 mL中，將無水氫氧化鋰 (243 mg，5.8 mmol)的水溶液10 mL滴入反應液中，室溫攪拌過夜。待反應結束，旋乾四氫呋喃，乙酸乙酯萃取，保留水相，用2 M鹽酸水溶液將水相PH調至3-4，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水=47:53)，得到目標產物3-(8-氰基喹啉-5-基)-5-甲基-3-氮雜雙環[3.1.0]己烷-1-羧酸 51h(黃色固體，333 mg，39.2%)。 1 H NMR(400 MHz, DMSO- d 6) δ 12.61 (s, 1H), 9.01-8.95 (m, 1H), 8.66-8.60 (m, 1H), 8.09 (d, 1H), 7.58-7.53 (m, 1H), 7.06 (d, 1H), 3.87 (s, 3H), 3.43 (d, 1H), 1.38 (s, 3H), 1.36-1.31 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.55。 LC-MSm/z (ESI)= 294.1 [M+1]。 The fifth step: 3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 51h 3-(8-cyanoquinolin-5 -yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 51 g of the crude product (1.0 g, 2.9 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and anhydrous lithium hydroxide (243 mg, 5.8 mmol) of aqueous solution 10 mL was dropped into the reaction liquid, and stirred overnight at room temperature. After the reaction is complete, spin dry THF, extract with ethyl acetate, retain the water phase, adjust the pH of the water phase to 3-4 with 2 M hydrochloric acid aqueous solution, extract with ethyl acetate, wash the organic phase with saturated saline, dry over anhydrous sodium sulfate, and vacuum Solvent was removed. MPLC separation (acetonitrile: water=47:53), to obtain the target product 3-(8-cyanoquinoline-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1- Carboxylic acid 51h (yellow solid, 333 mg, 39.2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.01-8.95 (m, 1H), 8.66-8.60 (m, 1H), 8.09 (d, 1H), 7.58-7.53 (m , 1H), 7.06 (d, 1H), 3.87 (s, 3H), 3.43 (d, 1H), 1.38 (s, 3H), 1.36-1.31 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.55. LC-MS m/z (ESI) = 294.1 [M+1].

第六步：3-(8-氰基喹啉-5-基)-5-甲基- N-(1-甲基哌啶-4-基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 513-(8-cyanoquinolin-5-yl)-5-methyl- N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將化合物 51h(50 mg，0.16 mmol) 溶解於 N,N-二甲基甲醯胺 2 mL中，隨後加入HATU (68.8 mg，0.18 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入4-氨基-1-甲基哌啶 51i(31.0 mg，0.24 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)-5-甲基- N-(1-甲基哌啶-4-基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 51(黃色固體，67 mg，84.1%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01-8.95 (m, 1H), 8.67-8.61 (m, 1H), 8.11 (d, 1H), 7.57-7.53 (m, 2H), 7.05 (d, 1H), 3.98 (d, 1H), 3.87-3.81 (m, 2H), 3.69-3.61 (m, 1H), 3.40 (d, 1H), 2.83 (d, 2H), 2.22 (s, 3H), 2.06 (s, 2H), 1.69 (d, 2H), 1.59-1.47 (m, 2H), 1.39 (d, 1H), 1.25 (s, 3H), 1.12 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.60 LC-MSm/z (ESI)= 390.2 [M+1]。 The sixth step: 3-(8-cyanoquinolin-5-yl)-5-methyl- N- (1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide Compound 51 3-(8-cyanoquinolin-5-yl)-5-methyl- N -(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 51h (50 mg, 0.16 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol) were added, and stirred at room temperature for 10 min, add 4-amino-1-methylpiperidine 51i (31.0 mg, 0.24 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-5-methyl- N- (1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1- Formamide Compound 51 (yellow solid, 67 mg, 84.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01-8.95 (m, 1H), 8.67-8.61 (m, 1H), 8.11 (d, 1H), 7.57-7.53 (m, 2H), 7.05 (d , 1H), 3.98 (d, 1H), 3.87-3.81 (m, 2H), 3.69-3.61 (m, 1H), 3.40 (d, 1H), 2.83 (d, 2H), 2.22 (s, 3H), 2.06 (s, 2H), 1.69 (d, 2H), 1.59-1.47 (m, 2H), 1.39 (d, 1H), 1.25 (s, 3H), 1.12 (d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.60 LC-MS m/z (ESI) = 390.2 [M+1].

[實施例52] 2-(二乙氨基)乙基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 化合物 522-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

Figure 02_image310
Figure 02_image660
[Example 52] 2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxylate compound 52 2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate
Figure 02_image310
Figure 02_image660

第一步：3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 化合物 52a3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 將 化合物 1(100 mg，0.29 mmol) 溶解於DCM 5 mL中，隨後加入二氯亞碸 (1 mL) 和DMF (1滴)，回流攪拌2 h。TLC反應完畢，直接濃縮反應液，得到中間體3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 52a 粗品(黃色油狀物，110 mg)。 The first step: 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 52a 3-( 8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride Dissolve compound 1 (100 mg, 0.29 mmol) in 5 mL of DCM, then add dichloro Add acetone (1 mL) and DMF (1 drop), and stir at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate 3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Crude carbonyl chloride 52a (yellow oil, 110 mg).

第二步：2-(二乙氨基)乙基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 化合物 522-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxylate 將中間體3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 52a溶於2 mL DCM中，隨後冰浴滴加二乙氨基乙醇 52b(42.0 mg，0.36 mmol)、三乙胺 (58.7 mg，0.58 mmol)的DCM溶液，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物2-(二乙氨基)乙基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 化合物 52(淡黃色固體，79 mg，61.2%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.05-9.00 (m, 1H), 8.66-8.61 (m, 1H), 8.18 (d, 1H), 7.65-7.59 (m, 1H), 7.26 (d, 1H), 4.25 – 4.11 (m, 2H), 4.02-3.97 (m, 2H), 3.90 (d, 1H), 3.79 (d, 1H), 2.65 (t, 2H), 2.51 (s, 4H), 2.07 (d, 1H), 1.99 – 1.93 (m, 1H), 0.94 (t, 6H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.28 LC-MSm/z (ESI)= 447.2 [M+1]。 The second step: 2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxylate Compound 52 2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxylate Intermediate 3-( 8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 52a was dissolved in 2 mL of DCM, then dropped in an ice bath Add diethylaminoethanol 52b (42.0 mg, 0.36 mmol) and triethylamine (58.7 mg, 0.58 mmol) in DCM, and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 2-(Diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Ester Compound 52 (pale yellow solid, 79 mg, 61.2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.05-9.00 (m, 1H), 8.66-8.61 (m, 1H), 8.18 (d, 1H), 7.65-7.59 (m, 1H), 7.26 (d , 1H), 4.25 – 4.11 (m, 2H), 4.02-3.97 (m, 2H), 3.90 (d, 1H), 3.79 (d, 1H), 2.65 (t, 2H), 2.51 (s, 4H), 2.07 (d, 1H), 1.99 – 1.93 (m, 1H), 0.94 (t, 6H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.28 LC-MS m/z (ESI) = 447.2 [M+1].

[實施例53] 3-(8-氰基喹喔啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 53-A、 53-B、 53-C和 53-D3-(8-cyanoquinoxalin-5-yl)- N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image662
Figure 02_image664
[Example 53] 3-(8-cyanoquinoxalin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-formamide Compound 53-A , 53-B , 53-C and 53-D 3-(8-cyanoquinoxalin-5-yl) -N -((4 -methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image662
Figure 02_image664

第一步： 3-(8-氰基喹喔啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 53bethyl 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxylate N 2氛圍下，將 1e(700 mg，3.2 mmol) 溶於1,4-二氧六環30 mL中，隨後加入 53a(499 mg，2.1 mmol)，N 2置換氣三次，依次加入碳酸鉀 (1.8 g，13.05 mmol) 和Ruphos Pdg3  (486 mg，0.58 mmol)， N 2置換氣三次，升溫至90 ℃反應2 h。旋乾溶劑，乙酸乙酯萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，粗產物 53b直接投下一步。 LC-MSm/z (ESI)= 377.1 [M+1]。 The first step : 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 53b ethyl 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxylate N 2 atmosphere, 1e (700 mg, 3.2 mmol) was dissolved in 1,4 - Dioxane 30 mL, followed by adding 53a (499 mg, 2.1 mmol), N 2 replacement gas three times, followed by adding potassium carbonate (1.8 g, 13.05 mmol) and Ruphos Pdg3 (486 mg, 0.58 mmol), N 2 The gas was replaced three times, and the temperature was raised to 90 °C for 2 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried. The crude product 53b was directly used in the next step. LC-MS m/z (ESI) = 377.1 [M+1].

第二步：3-(8-氰基喹喔啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 53c3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 將 53b的粗產品 (1.0 g，3.2 mmol) 溶於四氫呋喃溶液10 mL中，將無水氫氧化鋰 (243 mg，5.8 mmol)的水溶液10 mL滴入反應液中，室溫攪拌過夜。待反應結束，旋乾四氫呋喃，乙酸乙酯萃取，保留水相，用2 M鹽酸水溶液將水相PH調至3-4，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水=47:53)，得到目標產物3-(8-氰基喹喔啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 53c(黃色固體，448 mg，40.3%)。 1 H NMR(400 MHz, DMSO- d 6) δ 13.36 (s, 1H), 9.01 (s, 1H), 8.93 (d, H), 8.13 (d, 1H), 6.97 (d, 1H), 4.80 (d, 1H), 4.62 (d, 1H), 4.24 (d, 1H), 4.10 (d, 1H), 2.11 (d, 1H), 1.58-1.51 (m, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.48 LC-MSm/z (ESI)= 349.1 [M+1]。 The second step: 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 53c 3-( 8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid The crude product of 53b (1.0 g, 3.2 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 10 mL of an aqueous solution of anhydrous lithium hydroxide (243 mg, 5.8 mmol) was dropped into the reaction solution, and stirred overnight at room temperature. After the reaction is complete, spin dry THF, extract with ethyl acetate, retain the water phase, adjust the pH of the water phase to 3-4 with 2 M hydrochloric acid aqueous solution, extract with ethyl acetate, wash the organic phase with saturated saline, dry over anhydrous sodium sulfate, and vacuum Solvent was removed. MPLC separation (acetonitrile: water=47:53), to obtain the target product 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxylic acid 53c (yellow solid, 448 mg, 40.3%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.36 (s, 1H), 9.01 (s, 1H), 8.93 (d, H), 8.13 (d, 1H), 6.97 (d, 1H), 4.80 ( d, 1H), 4.62 (d, 1H), 4.24 (d, 1H), 4.10 (d, 1H), 2.11 (d, 1H), 1.58-1.51 (m, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.48 LC-MS m/z (ESI) = 349.1 [M+1].

第三步：3-(8-氰基喹喔啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 533-(8-cyanoquinoxalin-5-yl)- N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將化合物 53c(200 mg，0.57 mmol) 溶解於 N,N-二甲基甲醯胺5 mL中，隨後加入HATU (218.5 mg，0.57 mmol) 和DIPEA (0.2 mL，1.15 mmol)，室溫攪拌10 min，加入4-甲基嗎啉-2-甲胺 53d(89.8 mg，0.69 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹喔啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 53(黃色固體，184 mg，70.2%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.92 (d, 1H), 8.48 (q, 1H), 8.13 (d, 1H), 6.95 (d, 1H), 4.69 (d, 1H), 4.54 (d, 1H), 4.25 (d, 1H), 4.14 (d, 1H), 3.76 (d, 1H), 3.47-3.42 (m, 2H), 3.23-3.07 (m, 2H), 2.64 (d, 1H), 2.56 (d, 1H), 2.15 (s, 3H), 2.03 (d, 1H), 1.96-1.87 (m, 1H), 1.65 (t, 1H), 1.33 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -64.30 LC-MSm/z (ESI)= 461.2 [M+1]。 The third step: 3-(8-cyanoquinoxalin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 53 3-(8-cyanoquinoxalin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl) -3-azabicyclo[3.1.0]hexane-1-carboxamide Dissolve compound 53c (200 mg, 0.57 mmol) in 5 mL of N,N -dimethylformamide, then add HATU (218.5 mg, 0.57 mmol) and DIPEA (0.2 mL, 1.15 mmol), stirred at room temperature for 10 min, added 4-methylmorpholine-2-methylamine 53d (89.8 mg, 0.69 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinoxalin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-formamide Compound 53 (yellow solid, 184 mg, 70.2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.92 (d, 1H), 8.48 (q, 1H), 8.13 (d, 1H), 6.95 (d, 1H), 4.69 ( d, 1H), 4.54 (d, 1H), 4.25 (d, 1H), 4.14 (d, 1H), 3.76 (d, 1H), 3.47-3.42 (m, 2H), 3.23-3.07 (m, 2H) , 2.64 (d, 1H), 2.56 (d, 1H), 2.15 (s, 3H), 2.03 (d, 1H), 1.96-1.87 (m, 1H), 1.65 (t, 1H), 1.33 (d, 1H ). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.30 LC-MS m/z (ESI) = 461.2 [M+1].

第四步：3-(8-氰基喹喔啉-5-基)- N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 53-A、 53-B、 53-C和 53-D3-(8-cyanoquinoxalin-5-yl)- N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 經手性製備高效液相色譜拆分化合物53，得到手性 化合物 53-A、 53-B 、 53-C 、 53-D。分析方法：手性柱OD-3，流動相為 乙醇+0.2%二乙胺，流速1 mL/min, 化合物 53-A保留時間為3.554 min， 化合物 53-B保留時間為3.963 min， 化合物 53-C保留時間為4.200 min， 化合物 53-D保留時間為4.822 min。 The fourth step: 3-(8-cyanoquinoxalin-5-yl) -N -((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compounds 53-A , 53-B , 53-C and 53-D 3-(8-cyanoquinoxalin-5-yl) -N -((4- methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide was resolved by chiral preparative high-performance liquid chromatography to obtain chiral compounds 53-A , 53- B , 53-C , 53-D . Analysis method: chiral column OD-3, the mobile phase is ethanol + 0.2% diethylamine, the flow rate is 1 mL/min, the retention time of compound 53-A is 3.554 min, the retention time of compound 53-B is 3.963 min, and the retention time of compound 53- The retention time of C is 4.200 min, and the retention time of compound 53-D is 4.822 min.

[實施例54] 5-(1-(氨基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 545-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure 02_image274
Figure 02_image667
[Example 54] 5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 54 5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile
Figure 02_image274
Figure 02_image667

第一步： (1R,5S)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 54a(1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 在500 mL單口瓶中將化合物 1d(粗品 5.5 g) 溶於甲醇 (150 mL)，另外將無水氫氧化鋰 (2.2 g，52.7 mmol) 溶解到100 mL水中，溶解完後室溫下緩慢加入之前的甲醇溶液中，40 ℃反應1.5 h。原料水解完全，旋乾甲醇後用乙酸乙酯和水酸鹼洗倒置除雜，得到目標產物 (1R,5S)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 54a(3.1 g)，直接用於下一步。 LC-MSm/z (ESI)= 286.1 [M+1], 308.1 [M+23]。 The first step : (1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 54a (1R,5S)-3- benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Dissolve compound 1d (crude product 5.5 g) in methanol (150 mL) in a 500 mL one-port bottle, and add anhydrous lithium hydroxide (2.2 g, 52.7 mmol) was dissolved in 100 mL of water, and slowly added to the previous methanol solution at room temperature after dissolution, and reacted at 40 °C for 1.5 h. The raw material was completely hydrolyzed, spin-dried methanol, and washed with ethyl acetate and water to remove impurities by inversion to obtain the target product (1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxylic acid 54a (3.1 g), used directly in the next step. LC-MS m/z (ESI) = 286.1 [M+1], 308.1 [M+23].

第二步：3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 54b3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將化合物 54a(100 mg，0.35 mmol) 溶解於 N,N-二甲基甲醯胺10 mL中，隨後加入HATU (160 mg，0.42 mmol) 和DIPEA (124 uL，0.7 mmol)，冰浴下攪拌活化10 min，加入碳酸氫銨 (55.3 mg，0.7 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，萃取3次，得到目標粗產物(1R,5S)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 54b(粗產品 1.1 g)，直接用於下一步。 LC-MSm/z (ESI)= 285.1 [M+1], 307.1 [M+23]。 The second step: 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 54b 3-benzyl-5-(trifluoromethyl)-3-azabicyclo [3.1.0]Hexane-1-carboxamide Dissolve compound 54a (100 mg, 0.35 mmol) in 10 mL of N,N -dimethylformamide, then add HATU (160 mg, 0.42 mmol) and DIPEA (124 μL, 0.7 mmol), stirred and activated in ice bath for 10 min, added ammonium bicarbonate (55.3 mg, 0.7 mmol), stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched by adding water, spin-dried, and extracted 3 times to obtain the target crude product (1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexyl Alkane-1-carboxamide 54b (crude product 1.1 g) was used directly in the next step. LC-MS m/z (ESI) = 285.1 [M+1], 307.1 [M+23].

第三步：3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1)-甲胺 54c3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanam-ine 將 54b(粗產品 1.1 g) 溶解於四氫呋喃20 mL中，加入硼烷四氫呋喃絡合物50 mL，60 ℃下攪拌3h，原料反應完全。冰浴下緩慢滴加甲醇淬滅反應，直到無氣泡產生後緩慢滴加水，直至淬滅完全。旋乾有機溶劑後用乙酸乙酯/水和二氯甲烷/水萃取多次後旋乾有機相。拿到目標粗產物((1S,5S)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1)-甲胺 54c(粗產品 780 mg)。 LC-MSm/z (ESI)= 271.1 [M+1], 293.1 [M+23]。 The third step: 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1)-methylamine 54c 3-benzyl-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexan-1-yl)methanam-ine Dissolve 54b (crude product 1.1 g) in 20 mL of tetrahydrofuran, add 50 mL of borane tetrahydrofuran complex, stir at 60 °C for 3 h, and the reaction of raw materials is complete. Slowly add methanol dropwise under ice bath to quench the reaction until no bubbles are generated, then slowly add water dropwise until the quenching is complete. After the organic solvent was spin-dried, the organic phase was extracted several times with ethyl acetate/water and dichloromethane/water. Get the target crude product ((1S,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1)-methylamine 54c (crude product 780 mg ). LC-MS m/z (ESI) = 271.1 [M+1], 293.1 [M+23].

第四步：((3-苄基-5-(三氟甲基)-3氮雜雙環[3.1.0] 己-1-基)甲基) 氨基甲酸叔丁酯 54dtert-butyl ((3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate 將 54c(粗產品 780 mg) 溶於四氫呋喃50 mL中，加入Boc酸酐 (792.8 uL，3.4 mmol)，三乙胺 (805.6 uL，5.8 mmol) 和4-二甲氨基吡啶 (38.4 mg，0.3 mmol)。室溫反應2 h，原料反應完全，旋乾後用甲醇溶解反相純化，得到目標產物(((1S,5S)-3-苄基-5-(三氟甲基)-3氮雜雙環[3.1.0] 己-1-基)甲基) 氨基甲酸叔丁酯 54d(530 mg，粗產品)，直接用於下一步。 LC-MSm/z (ESI)= 371.1 [M+1], 393.1 [M+23]。 The fourth step: ((3-benzyl-5-(trifluoromethyl)-3 azabicyclo[3.1.0]hex-1-yl)methyl)tert-butyl carbamate 54d tert-butyl ((3 -benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate Dissolve 54c (crude product 780 mg) in THF 50 mL, add Boc anhydride (792.8 uL, 3.4 mmol ), triethylamine (805.6 uL, 5.8 mmol) and 4-dimethylaminopyridine (38.4 mg, 0.3 mmol). After reacting at room temperature for 2 h, the reaction of the raw materials was complete. After spin-dried, they were dissolved in methanol and purified by reverse phase to obtain the target product (((1S,5S)-3-benzyl-5-(trifluoromethyl)-3azabicyclo[ 3.1.0] Hex-1-yl)methyl)carbamate tert-butyl ester 54d (530 mg, crude product) was used directly in the next step. LC-MS m/z (ESI) = 371.1 [M+1], 393.1 [M+23].

第五步：叔丁基((5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基)氨基甲酸酯 54etert-butyl ((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl) methyl) carbamate H 2氛圍下，將 54d(530 mg，1.4 mmol) 溶於乙醇50 mL中，隨後加入Pd/C (681 mg，0.64 mmol)，升溫至60 ℃反應3 h。矽藻土過濾，旋乾溶劑，得到目標產物叔丁基((5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基)氨基甲酸酯 54e(無色油狀液體，352 mg，產率90.1%)，直接用於下一步。 LC-MSm/z (ESI)= 281.1 [M+1]。 The fifth step: tert-butyl ((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl)carbamate 54e tert-butyl ((5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate H 2 atmosphere, 54d (530 mg, 1.4 mmol) was dissolved in ethanol 50 mL, then Pd/C (681 mg , 0.64 mmol), heated to 60 °C for 3 h. Diatomaceous earth is filtered, and the solvent is spin-dried to obtain the target product tert-butyl ((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl)carbamate 54e (colorless oily liquid, 352 mg, yield 90.1%) was used directly in the next step. LC-MS m/z (ESI) = 281.1 [M+1].

第六步：叔丁基((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基)氨基甲酸酯 54ftert-butyl ((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate N 2氛圍下，將 54e(352 mg，1.4 mmol) 溶於1,4-二氧六環30 mL中，隨後加入5-溴喹啉-8-甲腈 (396.4 mg，1.72 mmol)，依次加入碳酸銫 (2.1 g，6.4 mmol) 和Ruphos Pdg3  (119.7 mg，0.14 mmol)， N 2置換氣三次，升溫至90 ℃反應24 h。旋乾溶劑，乙酸乙酯萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，粗產物 54f直接投下一步。 LC-MSm/z (ESI)= 433.2 [M+1]。 The sixth step: tert-butyl ((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl) Methyl)carbamate 54f tert-butyl ((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate N 2 Under atmosphere, 54e (352 mg, 1.4 mmol) was dissolved in 1,4-dioxane 30 mL, then 5-bromoquinoline-8-carbonitrile (396.4 mg, 1.72 mmol) was added, followed by cesium carbonate (2.1 g, 6.4 mmol) and Ruphos Pdg3 (119.7 mg, 0.14 mmol), replaced by N 2 three times, and heated to 90 °C for 24 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried. The crude product 54f was directly used in the next step. LC-MS m/z (ESI) = 433.2 [M+1].

第七步：5-(1-(氨基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 545-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 50 mL圓底燒瓶中，將 54f(粗產品，1.43 mmol) 溶於10 mL二氯甲烷中，隨後加入三氟乙酸 (1 mL)，室溫反應2 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，反相純化得到目標產物5-(1-(氨基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 54(40 mg，淡黃色固體)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02-8.97 (m, 1H), 8.68-8.62 (m, 1H), 8.13 (d, 1H), 7.63-7.57 (m, 1H), 7.13 (d, 1H), 3.97-3.92 (m, 2H), 3.78 (d, 1H), 3.70 (d, 1H), 2.87 (q, 2H), 1.71 (s, 2H), 1.39 (d, 1H), 1.32 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.27 LC-MSm/z (ESI)= 333.1 [M+1]。 The seventh step: 5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 54 5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile In a 50 mL round bottom flask, 54f (crude product, 1.43 mmol) Dissolve in 10 mL of dichloromethane, then add trifluoroacetic acid (1 mL), and react at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, dried with anhydrous sodium sulfate, spin-dried, and purified by reverse phase to obtain the target product 5-(1-(aminomethyl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 54 (40 mg, pale yellow solid). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02-8.97 (m, 1H), 8.68-8.62 (m, 1H), 8.13 (d, 1H), 7.63-7.57 (m, 1H), 7.13 (d , 1H), 3.97-3.92 (m, 2H), 3.78 (d, 1H), 3.70 (d, 1H), 2.87 (q, 2H), 1.71 (s, 2H), 1.39 (d, 1H), 1.32 ( d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.27 LC-MS m/z (ESI) = 333.1 [M+1].

[實施例55] 5-(1-((1-甲基哌啶-4-基)氨基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 555-(1-(((1-methylpiperidin-4-yl)amino)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure 02_image306
Figure 02_image670
50 mL圓底燒瓶中，將 化合物 54(30 mg，0.09 mmol) 溶於30 mL二氯甲烷中，冰浴下加入 55a(20.4 mg，0.18 mmol) 和三乙醯氧基氰基硼氫化鈉 (76.3 mg，0.36 mmol)，加入冰醋酸調節pH至4-5，室溫攪拌2 h。將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物(1-(氧雜環丁烷-3-基)哌啶-4-基)氨基甲酸叔丁酯 化合物 55(黃色固體，23 mg，59.6%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.08-9.03 (m, 1H), 8.72-8.67 (m, 1H), 8.19 (d, 1H), 7.68-7.64 (m, 1H), 7.35 (d, 1H), 7.20 (d, 1H), 4.03-3.98 (m, 2H), 3.84 (s, 1H), 3.68 (d, 1H), 3.07 (s, 1H), 3.04 (s, 2H), 2.84 (d, 1H), 2.64 (s, 1H), 2.45 (s, 3H), 1.92 (s, 2H), 1.50-1.46 (m, 4H), 1.28 (s, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.45 LC-MSm/z (ESI)= 430.2 [M+1]。 [Example 55] 5-(1-((1-methylpiperidin-4-yl)amino)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -3-yl)quinoline-8-carbonitrile Compound 55 5-(1-(((1-methylpiperidin-4-yl)amino)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan -3-yl)quinoline-8-carbonitrile
Figure 02_image306
Figure 02_image670
In a 50 mL round bottom flask, compound 54 (30 mg, 0.09 mmol) was dissolved in 30 mL of dichloromethane, and 55a (20.4 mg, 0.18 mmol) and sodium triacetyloxycyanoborohydride ( 76.3 mg, 0.36 mmol), adding glacial acetic acid to adjust the pH to 4-5, stirring at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain the target product (1-(oxetane-3-yl)piperidine- 4-yl) tert-butyl carbamate Compound 55 (yellow solid, 23 mg, 59.6%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.08-9.03 (m, 1H), 8.72-8.67 (m, 1H), 8.19 (d, 1H), 7.68-7.64 (m, 1H), 7.35 (d , 1H), 7.20 (d, 1H), 4.03-3.98 (m, 2H), 3.84 (s, 1H), 3.68 (d, 1H), 3.07 (s, 1H), 3.04 (s, 2H), 2.84 ( d, 1H), 2.64 (s, 1H), 2.45 (s, 3H), 1.92 (s, 2H), 1.50-1.46 (m, 4H), 1.28 (s, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.45 LC-MS m/z (ESI) = 430.2 [M+1].

[實施例56] 5-(1-(羥甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 565-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure 02_image282
Figure 02_image673
[Example 56] 5-(1-(Hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 56 5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile
Figure 02_image282
Figure 02_image673

第一步：(3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)甲醇 56a(3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol 50 mL圓底燒瓶中，將 化合物 1d(500 mg，1.6 mmol) 溶於20 mL四氫呋喃中，冰浴下加入四氫鋰鋁 (61.0 mg，1.6 mmol)，緩慢升至室溫攪拌2 h。將反應淬滅，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物 (3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)甲醇 56a(無色油狀，446 mg，粗產品)。 LC-MSm/z (ESI)= 272.2 [M+1]。 The first step: (3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl)methanol 56a (3-benzyl-5-(trifluoromethyl)-3- In azabicyclo[3.1.0]hexan-1-yl)methanol 50 mL round bottom flask, compound 1d (500 mg, 1.6 mmol) was dissolved in 20 mL tetrahydrofuran, and lithium aluminum tetrahydrogen (61.0 mg, 1.6 mmol), slowly raised to room temperature and stirred for 2 h. The reaction was quenched, extracted three times with DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, and spin-dried to obtain the target product (3-benzyl-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hex-1-yl)methanol 56a (colorless oil, 446 mg, crude product). LC-MS m/z (ESI) = 272.2 [M+1].

第二步：(5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲醇 56b(5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol H 2氛圍下，將 56a(446 mg，1.6 mmol) 溶於乙醇50 mL中，隨後加入Pd/C (681 mg，0.64 mmol)，升溫至60 ℃反應3 h。矽藻土過濾，旋乾溶劑，得到目標產物 (5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲醇 56b(無色油狀液體，300 mg，粗產物)，直接用於下一步。 LC-MSm/z (ESI)= 182.1 [M+1]。 The second step: (5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methanol 56b (5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan- Under the atmosphere of 1-yl)methanol H 2 , 56a (446 mg, 1.6 mmol) was dissolved in 50 mL of ethanol, then Pd/C (681 mg, 0.64 mmol) was added, and the temperature was raised to 60 °C for 3 h. Celite was filtered, and the solvent was spin-dried to obtain the target product (5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methanol 56b (colorless oily liquid, 300 mg, crude product) was used directly in the next step. LC-MS m/z (ESI) = 182.1 [M+1].

第三步：5-(1-(羥甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 565-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile N 2氛圍下，將 56b(300 mg，1.6 mmol) 溶於1,4-二氧六環30 mL中，隨後加入5-溴喹啉-8-甲腈 (443.5 mg，1.92 mmol)，依次加入碳酸銫 (2.3 g，7.2 mmol) 和Ruphos Pdg3  (134 mg，0.16 mmol)， N 2置換氣三次，升溫至90 ℃反應4 h。旋乾溶劑，乙酸乙酯萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，反相純化得產物 化合物 56(60 mg，黃色固體)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01-8.98 (m, 1H), 8.68-8.60 (m, 1H), 8.13 (d, 1H), 7.62-7.56 (m, 1H), 7.14 (d, 1H), 5.04 (t, 1H), 3.93 (t, 2H), 3.78 (d, 2H), 3.71-3.61 (m, 2H), 1.46 (d, 1H), 1.35 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.56 LC-MSm/z (ESI)= 334.1 [M+1]。 The third step: 5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 56 5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile N 2 atmosphere, 56b (300 mg, 1.6 mmol) was dissolved in 1,4-dioxane 30 mL, then added 5-bromoquinoline-8-carbonitrile (443.5 mg, 1.92 mmol), followed by adding cesium carbonate (2.3 g, 7.2 mmol) and Ruphos Pdg3 (134 mg, 0.16 mmol), N 2 was replaced three times, and the temperature was raised to 90 °C for 4 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was spin-dried, and purified by reverse phase to obtain the product compound 56 (60 mg, yellow solid). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01-8.98 (m, 1H), 8.68-8.60 (m, 1H), 8.13 (d, 1H), 7.62-7.56 (m, 1H), 7.14 (d , 1H), 5.04 (t, 1H), 3.93 (t, 2H), 3.78 (d, 2H), 3.71-3.61 (m, 2H), 1.46 (d, 1H), 1.35 (d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.56 LC-MS m/z (ESI) = 334.1 [M+1].

[實施例57] 5-(1-((1-甲基哌啶-4-基)氧基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-碳腈 化合物 575-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure 02_image292
Figure 02_image676
[Example 57] 5-(1-((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexyl -3-yl)quinoline-8-carbonitrile Compound 57 5-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan -3-yl)quinoline-8-carbonitrile
Figure 02_image292
Figure 02_image676

第一步：(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基4-甲基苯磺酸鹽 57a(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 4-methylbenzenesulfonate 將 化合物 56(60 mg，0.18 mmol) 溶於20 mL DCM中，隨後加入DMAP (44.0 mg，0.36 mmol)、三乙胺 (36.1 mg，0.36 mmol)，45 ℃回流攪拌2 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:丙酮=20:1)，得到目標產物 (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基4-甲基苯磺酸鹽 57a(淡黃色固體，74 mg，84.4%)，直接用於下一步。 LC-MSm/z (ESI)= 488.1 [M+1]。 The first step: (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 4- Tosylate 57a (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 4-methylbenzenesulfonate Compound 56 (60 mg , 0.18 mmol) was dissolved in 20 mL of DCM, followed by adding DMAP (44.0 mg, 0.36 mmol), triethylamine (36.1 mg, 0.36 mmol), and stirring at 45 °C for 2 h at reflux. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with 15 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:acetone=20:1) to obtain the target product (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 4-methylbenzenesulfonate Salt 57a (pale yellow solid, 74 mg, 84.4%) was used directly in the next step. LC-MS m/z (ESI) = 488.1 [M+1].

第二步：5-(1-((1-甲基哌啶-4-基)氧基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-碳腈 化合物 575-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 將 57a(37 mg，0.07 mmol) 溶於2 mL乙腈中，加入1-甲基-4-哌啶醇 57b(10.5 mg，0.09 mmol)、碘化鈉 (11.4 mg，0.07 mmol) 和碳酸鉀 (21.0 mg，0.15 mmol)，80 ℃攪拌反應2 h。待反應結束，濃縮，乙酸乙酯萃取，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水=47:53)，得到目標產物5-(1-((1-甲基哌啶-4-基)氧基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-碳腈 化合物 57(黃色固體，16 mg，53.3%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.03 (d, 1H), 8.75-8.69 (m, 1H), 8.21 (d, 1H), 7.69-7.60 (m, 1H), 7.35 (d, 1H), 4.31-4.19 (m, 2H), 4.02-3.95 (m, 1H), 3.77-3.71 (m, 4H), 3.63-3.42 (m, 4H), 3.20 (s, 3H), 2.10 (d, 1H), 1.97 (d, 1H), 1.89 (d, 2H), 1.87-1.65 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.63 LC-MSm/z (ESI)= 431.2 [M+1]。 The second step: 5-(1-((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexyl- 3-yl)quinoline-8-carbonitrile Compound 57 5-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan- 3-yl)quinoline-8-carbonitrile Dissolve 57a (37 mg, 0.07 mmol) in 2 mL of acetonitrile, add 1-methyl-4-piperidinol 57b (10.5 mg, 0.09 mmol), sodium iodide (11.4 mg, 0.07 mmol) and potassium carbonate (21.0 mg, 0.15 mmol), stirred at 80°C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. MPLC separation (acetonitrile: water=47:53), obtain target product 5-(1-((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 57 (yellow solid, 16 mg, 53.3%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03 (d, 1H), 8.75-8.69 (m, 1H), 8.21 (d, 1H), 7.69-7.60 (m, 1H), 7.35 (d, 1H ), 4.31-4.19 (m, 2H), 4.02-3.95 (m, 1H), 3.77-3.71 (m, 4H), 3.63-3.42 (m, 4H), 3.20 (s, 3H), 2.10 (d, 1H ), 1.97 (d, 1H), 1.89 (d, 2H), 1.87-1.65 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.63 LC-MS m/z (ESI) = 431.2 [M+1].

[實施例58] 5-(1-(哌嗪-1-基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 585-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl) quinoline-8-carbonitrile

Figure 02_image290
Figure 02_image679
[Example 58] 5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline- 8-carbonitrile Compound 58 5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl) quinoline-8-carbonitrile
Figure 02_image290
Figure 02_image679

第一步：4-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基)哌嗪-1-羧酸叔丁酯 58btert-butyl 4-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)piperazine-1-carboxylate 將 57a(50 mg，0.1 mmol) 溶於2 mL乙腈中，加入1-叔丁氧羰基哌嗪(28.7 mg，0.15 mmol)、碘化鈉 (15.4 mg，0.1 mmol) 和碳酸鉀 (28.4 mg，0.21 mmol)，80 ℃攪拌反應2 h。待反應結束，濃縮，乙酸乙酯萃取，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水=47:53)，得到目標產物4-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基)哌嗪-1-羧酸叔丁酯 58b(黃色固體，20 mg，粗產品)，直接用於下一步。 LC-MSm/z (ESI)= 502.3 [M+1]。 The first step: 4-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methanol Base) piperazine-1-carboxylate tert-butyl 58b tert-butyl 4-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1- yl)methyl)piperazine-1-carboxylate Dissolve 57a (50 mg, 0.1 mmol) in 2 mL of acetonitrile, add 1-tert-butoxycarbonylpiperazine (28.7 mg, 0.15 mmol), sodium iodide (15.4 mg, 0.1 mmol) and potassium carbonate (28.4 mg, 0.21 mmol), stirred at 80°C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. MPLC separation (acetonitrile: water=47:53), obtain target product 4-((3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexan-1-yl)methyl)piperazine-1-carboxylate tert-butyl ester 58b (yellow solid, 20 mg, crude product), used directly in the next step. LC-MS m/z (ESI) = 502.3 [M+1].

第二步：5-(1-(哌嗪-1-基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 585-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 50 mL圓底燒瓶中，將 58b(20 mg，0.1 mmol) 溶於10 mL二氯甲烷中，隨後加入三氟乙酸 (1 mL)，室溫反應2 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，反相純化得到目標產物5-(1-(哌嗪-1-基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物 58(16 mg)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.03-8.98 (m, 1H), 8.66-8.62 (m, 1H), 8.17-8.10 (m, 1H), 7.65-7.58 (m, 1H), 7.21-7.17 (m, 1H), 4.00 (d, 1H), 3.84 (d, 1H), 3.76 (d, 1H), 3.58 (d, 1H), 3.09-2.93 (m, 4H), 2.66 (s, 2H), 2.47-2.42 (m, 2H), 2.31 (d, 1H), 2.19-1.93 (m, 1H), 1.75 (s, 1H), 1.59 (d, 1H), 1.45-1.30 (m, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.58 LC-MSm/z (ESI)= 402.2 [M+1]。 The second step: 5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8 -Carbonitrile Compound 58 5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 50 mL round bottom flask, Dissolve 58b (20 mg, 0.1 mmol) in 10 mL of dichloromethane, then add trifluoroacetic acid (1 mL), and react at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, dried with anhydrous sodium sulfate, spin-dried, and purified by reverse phase to obtain the target product 5-(1-(piperazin-1-ylmethyl yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 58 (16 mg). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03-8.98 (m, 1H), 8.66-8.62 (m, 1H), 8.17-8.10 (m, 1H), 7.65-7.58 (m, 1H), 7.21 -7.17 (m, 1H), 4.00 (d, 1H), 3.84 (d, 1H), 3.76 (d, 1H), 3.58 (d, 1H), 3.09-2.93 (m, 4H), 2.66 (s, 2H ), 2.47-2.42 (m, 2H), 2.31 (d, 1H), 2.19-1.93 (m, 1H), 1.75 (s, 1H), 1.59 (d, 1H), 1.45-1.30 (m, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.58 LC-MS m/z (ESI) = 402.2 [M+1].

[實施例59] (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基1-甲基哌啶-4-羧酸酯 化合物 59(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine-4-carboxylate

Figure 02_image312
Figure 02_image682
[Example 59] (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 1 -Methylpiperidine-4-carboxylate compound 59 (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine -4-carboxylate
Figure 02_image312
Figure 02_image682

第一步：1-甲基哌啶-4-羰基氯 59b1-methylpiperidine-4-carbonyl chloride 將化合物 59a(25.8 mg，0.18 mmol) 溶解於DCM 5 mL中，隨後加入二氯亞碸 (1 mL) 和DMF (1滴)，回流攪拌2 h。TLC反應完畢，直接濃縮反應液，得到1-甲基哌啶-4-羰基氯 59b(無色油狀物，30 mg)。 The first step: 1-methylpiperidine-4-carbonyl chloride 59b 1-methylpiperidine-4-carbonyl chloride Dissolve compound 59a (25.8 mg, 0.18 mmol) in 5 mL of DCM, and then add dichloride (1 mL ) and DMF (1 drop), stirred at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain 1-methylpiperidine-4-carbonyl chloride 59b (colorless oil, 30 mg).

第二步：(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基1-甲基哌啶-4-羧酸酯 化合物 59(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine-4-carboxylate 將 59b溶於2 mL DCM中，隨後冰浴滴加 化合物 56(50.0 mg，0.15 mmol)、三乙胺 (58.7 mg，0.58 mmol)的DCM溶液，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物 (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)甲基1-甲基哌啶-4-羧酸酯 化合物 59(13 mg)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.08–8.95 (m, 1H), 8.64 (d, 1H), 8.14 (t, 1H), 7.60 (d, 1H), 7.19 (d, 1H), 4.55 (d, 1H), 4.18 (d, 1H), 3.97-3.91 (m, 2H), 3.77-3.73 (m, 2H), 3.70-3.59 (m, 2H), 2.77-2.73 (m, 2H), 2.36-2.30 (m, 1H), 2.19 (d, 3H), 1.79 (d, 2H), 1.65-1.52 (m, 4H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.67 LC-MSm/z (ESI)= 459.2 [M+1]。 The second step: (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 1- Methylpiperidine-4-carboxylate Compound 59 (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine- 4-carboxylate 59b was dissolved in 2 mL of DCM, then the DCM solution of compound 56 (50.0 mg, 0.15 mmol) and triethylamine (58.7 mg, 0.58 mmol) was added dropwise in ice bath, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 1-methylpiperidine -4-Carboxylate Compound 59 (13 mg). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.08–8.95 (m, 1H), 8.64 (d, 1H), 8.14 (t, 1H), 7.60 (d, 1H), 7.19 (d, 1H), 4.55 (d, 1H), 4.18 (d, 1H), 3.97-3.91 (m, 2H), 3.77-3.73 (m, 2H), 3.70-3.59 (m, 2H), 2.77-2.73 (m, 2H), 2.36-2.30 (m, 1H), 2.19 (d, 3H), 1.79 (d, 2H), 1.65-1.52 (m, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.67 LC-MS m/z (ESI) = 459.2 [M+1].

[實施例60] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(順式-4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 60(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image684
Figure 02_image686
將 化合物 1-A(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65 mg，0.17 mmol) 和DIPEA (52 ul，0.29 mmol)，冰浴下攪拌活化10 min，加入順式-4-[4-(環丙基甲基)-1-哌嗪]-環己烷 60a(50 mg，0.21 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(順式-4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 60(黃色固體，55 mg，75%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.03 – 8.99 (m, 1H), 8.65 – 8.60(m, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.64 – 7.57 (m, 1H), 7.24 (dd, 1H), 4.08 – 3.89 (m, 3H), 3.84 – 3.70 (m, 2H), 2.24 – 2.05(m, 3H), 2.03-1.90 (dd, 3H), 1.85-1.70 (s, 3H), 1.61 (d, 1H), 1.45 (s, 1H), 1.23 (s, 9H), 0.90 – 0.73 (m, 2H), 0.44 (dd, 2H), 0.07-0.02 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.68 LC-MSm/z (ESI)= 567.30 [M+1], 589.30 [M+23]。 [Example 60] (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(cis-4-(4-(cyclopropyl Methyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 60 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl)- 3-azabicyclo [3.1.0] hexane-1-carboxamide
Figure 02_image684
Figure 02_image686
Compound 1-A (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added in an ice bath After stirring for 10 min to activate, cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 60a (50 mg, 0.21 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N- (cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Formamide Compound 60 (yellow solid, 55 mg, 75%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03 – 8.99 (m, 1H), 8.65 – 8.60 (m, 1H), 8.17 (dd, 1H), 8.00 (d, 1H), 7.64 – 7.57 (m , 1H), 7.24 (dd, 1H), 4.08 – 3.89 (m, 3H), 3.84 – 3.70 (m, 2H), 2.24 – 2.05(m, 3H), 2.03-1.90 (dd, 3H), 1.85-1.70 (s, 3H), 1.61 (d, 1H), 1.45 (s, 1H), 1.23 (s, 9H), 0.90 – 0.73 (m, 2H), 0.44 (dd, 2H), 0.07-0.02 (m, 2H ). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.68 LC-MS m/z (ESI) = 567.30 [M+1], 589.30 [M+23].

[實施例61] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(順式-4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 61(1 S,5 R)或(1 R,5S)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image688
Figure 02_image690
將 化合物 1-B(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65 mg，0.17 mmol) 和DIPEA (52 ul，0.29 mmol)，冰浴下攪拌活化10 min，加入順式-4-[4-(環丙基甲基)-1-哌嗪]-環己烷 61a(50 mg，0.21 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(順式-4-(4-(環丙基甲基)哌嗪-1-基)環己基)-5-(三氟甲基)-3-氮雜雙環[3.1. 0]己烷-1-甲醯胺 化合物 61(黃色固體，45 mg，61%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.04 – 8.96 (m, 1H), 8.66 – 8.58 (m, 1H), 8.17 (dd, 1H), 7.99 (d, 1H), 7.66 – 7.56 (m, 1H), 7.24 (dd, 1H), 4.09 – 3.88 (m, 3H), 3.85 – 3.69 (m, 2H), 2.24 – 2.04 (m, 3H), 2.00 (dd, 3H), 1.78 (s, 3H), 1.61 (d, 1H), 1.45 (s, 1H), 1.23 (s, 9H), 0.91 – 0.72 (m, 2H), 0.43 (dd, 2H), 0.07-0.02 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.68。 LC-MSm/z (ESI)= 567.30 [M+1], 589.30 [M+23]。 [Example 61] (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(cis-4-(4-(cyclopropyl Methyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 61 (1 S ,5 R ) or (1 R ,5S)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl)-3 -azabicyclo [3.1.0] hexane-1-carboxamide
Figure 02_image688
Figure 02_image690
Compound 1-B (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added in an ice bath After stirring for 10 min to activate, cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 61a (50 mg, 0.21 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N- (cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Formamide Compound 61 (yellow solid, 45 mg, 61%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.04 – 8.96 (m, 1H), 8.66 – 8.58 (m, 1H), 8.17 (dd, 1H), 7.99 (d, 1H), 7.66 – 7.56 (m , 1H), 7.24 (dd, 1H), 4.09 – 3.88 (m, 3H), 3.85 – 3.69 (m, 2H), 2.24 – 2.04 (m, 3H), 2.00 (dd, 3H), 1.78 (s, 3H ), 1.61 (d, 1H), 1.45 (s, 1H), 1.23 (s, 9H), 0.91 – 0.72 (m, 2H), 0.43 (dd, 2H), 0.07-0.02 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.68. LC-MS m/z (ESI) = 567.30 [M+1], 589.30 [M+23].

[實施例62] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-[反式-4-(二甲氨基)環己基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 62(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image692
Figure 02_image694
將 化合物 1-A(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65 mg，0.17 mmol) 和DIPEA (52 μl，0.29 mmol)，冰浴下攪拌活化10 min，加入順式-4-[4-(環丙基甲基)-1-哌嗪]-環己烷 62a(23 mg，0.15 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-[反式-4-(二甲氨基)環己基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷 -1-甲醯胺 化合物 62(黃色固體，17 mg，28%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (d, 1H), 8.63 (d, J= 9.3 Hz, 1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H)，4.01-3.80 (m, 4H), 2.37-2.26 (m, 6H), 2.00-1.97 (m, 2H), 1.87-1.74 (m, 3H), 1.63-1.61 (m, 1H), 1.23 (s, 6H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58。 LC-MSm/z (ESI)= 472.20 [M+1], 494.20 [M+23]。 [Example 62] (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino) ring Hexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 62 (1 R ,5 S ) / (1 S ,5 R )-3- (8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image692
Figure 02_image694
Compound 1-A (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 μl, 0.29 mmol) were added, and ice-bathed After stirring for 10 min to activate, cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 62a (23 mg, 0.15 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N- [trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 62 (yellow solid, 17 mg , 28%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (d, 1H), 8.63 (d, J = 9.3 Hz, 1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.01-3.80 (m, 4H), 2.37-2.26 (m, 6H), 2.00-1.97 (m, 2H), 1.87-1.74 (m, 3H), 1.63-1.61 ( m, 1H), 1.23 (s, 6H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 472.20 [M+1], 494.20 [M+23].

[實施例63] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-[反式-4-(二甲氨基)環己基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 63(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image696
Figure 02_image698
將 化合物 1-B(50 mg，0.15 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (65 mg，0.17 mmol) 和DIPEA (52 ul，0.29 mmol)，冰浴下攪拌活化10 min，加入順式-4-[4-(環丙基甲基)-1-哌嗪]-環己烷 63a(23 mg，0.15 mmol)，室溫攪拌1 h。原料反應完全，加水淬滅後旋乾，過MPLC，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-[(1s,4s)-4-(二甲氨基)環己基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷 -1-甲醯胺 化合物 63(黃色固體，16 mg，28%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (d, J= 3.9 Hz, 1H), 8.63 (d, J= 9.3 Hz, 1H), 8.17 (d, J= 8.2 Hz, 1H), 8.02 (d, J= 7.2 Hz, 1H), 7.60 (dd, J= 8.5, 4.1 Hz, 1H), 7.22 (d, J= 8.2 Hz, 1H)，4.02-3.80 (m, 4H), 2.36-2.26 (m, 6H), 2.02-1.98 (m, 2H), 1.87-1.72 (m, 3H), 1.63-1.61 (m, 1H), 1.23 (s, 6H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58. LC-MSm/z (ESI)= 472.20 [M+1], 494.20 [M+23]。 [Example 63] (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino) ring Hexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 63 (1 S ,5 R ) / (1 R ,5 S )-3- (8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image696
Figure 02_image698
Compound 1-B (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added in an ice bath After stirring for 10 min to activate, cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 63a (23 mg, 0.15 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw material was complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N- [(1s,4s)-4-(Dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 63 (yellow solid , 16 mg, 28%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (d, J = 3.9 Hz, 1H), 8.63 (d, J = 9.3 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.60 (dd, J = 8.5, 4.1 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.02-3.80 (m, 4H), 2.36-2.26 ( m, 6H), 2.02-1.98 (m, 2H), 1.87-1.72 (m, 3H), 1.63-1.61 (m, 1H), 1.23 (s, 6H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 472.20 [M+1], 494.20 [M+23].

[實施例64] (4-甲基嗎啉-2-基)甲基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 化合物 64(4-methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

Figure 02_image700
Figure 02_image702
[Example 64] (4-methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] hexane-1-carboxylate Compound 64 (4-methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxylate
Figure 02_image700
Figure 02_image702

第一步：3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 64b3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 將 化合物 1(100 mg，0.29 mmol) 溶解於DCM 5 mL中，隨後加入二氯亞碸 (1 mL) 和DMF (1滴)，回流攪拌2 h。TLC反應完畢，直接濃縮反應液，得到中間體3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 64b粗品 (黃色油狀物，110 mg)。 The first step: 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 64b 3-(8 -cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride Compound 1 (100 mg, 0.29 mmol) was dissolved in DCM 5 mL, followed by the addition of dichlorohydrin Sodium (1 mL) and DMF (1 drop), stirred at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Crude carbonyl chloride 64b (yellow oil, 110 mg).

第二步：(4-甲基嗎啉-2-基)甲基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 化合物 64(4-methylmorpholin-2-yl)methyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 將中間體3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基氯 64b溶於2 mL DMF中，隨後冰浴滴加4-甲基-2-嗎啉甲醇 (45.6 mg，0.35 mmol)、三乙胺 (58.7 mg，0.58 mmol)的DCM溶液，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物(4-甲基嗎啉-2-基)甲基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 化合物 64(淡黃色固體，35 mg，26.3%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.05-9.00 (m, 1H), 8.72-8.45 (m, 1H), 8.18 (d, 1H), 7.64-7.69 (m, 1H), 7.28 (d, 1H), 4.22-4.08 (m, 2H), 4.02-3.97 (m, 2H), 3.88-3.84 (m, 2H), 3.79-3.70 (m, 2H), 3.64 (s, 1H), 3.53-3.42 (m, 2H), 2.63-2.58 (m, 2H), 2.16 (s, 3H), 2.00-1.90 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -62.35。 LC-MSm/z (ESI)= 461.2 [M+1]。 The second step: (4-methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]Hexane-1-carboxylate Compound 64 (4-methylmorpholin-2-yl)methyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxylate Dissolve the intermediate 3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 64b In 2 mL of DMF, a DCM solution of 4-methyl-2-morpholine methanol (45.6 mg, 0.35 mmol) and triethylamine (58.7 mg, 0.58 mmol) was added dropwise in an ice bath, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (4-Methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxylate Compound 64 (pale yellow solid, 35 mg, 26.3%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.05-9.00 (m, 1H), 8.72-8.45 (m, 1H), 8.18 (d, 1H), 7.64-7.69 (m, 1H), 7.28 (d , 1H), 4.22-4.08 (m, 2H), 4.02-3.97 (m, 2H), 3.88-3.84 (m, 2H), 3.79-3.70 (m, 2H), 3.64 (s, 1H), 3.53-3.42 (m, 2H), 2.63-2.58 (m, 2H), 2.16 (s, 3H), 2.00-1.90 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -62.35. LC-MS m/z (ESI) = 461.2 [M+1].

[實施例65] N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-2-(4-甲基嗎啉-2-基)乙醯胺 化合物 65N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(4-methylmorpholin-2-yl)acetamide

Figure 02_image704
Figure 02_image706
[Example 65] N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)- 2-(4-Methylmorpholin-2-yl)acetamide Compound 65 N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan- 1-yl)-2-(4-methylmorpholin-2-yl)acetamide
Figure 02_image704
Figure 02_image706

第一步： 叔丁基2-(2-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)氨基)-2-氧乙基)嗎啉-4-羧酸酯 65ctert-butyl 2-(2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexan-1-yl)amino)-2-oxoethyl)morpholine-4-carboxylate 將化合物 65a(46.3 mg，0.19 mmol) 溶解於DMF 5 mL中，隨後加入HATU (71.7 mg，0.19 mmol) 和DIPEA (41.3 mg，0.32 mmol)，室溫攪拌10 min，加入 化合物 4(50 mg，0.16 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物叔丁基2-(2-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)氨基)-2-氧乙基)嗎啉-4-羧酸酯 65c(黃色固體，55 mg)。直接用於下一步。 LC-MSm/z (ESI)= 546.2 [M+1]。 The first step : tert-butyl 2-(2-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-yl)amino)-2-oxyethyl)morpholine-4-carboxylate 65c tert-butyl 2-(2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- 3-azabicyclo [3.1.0]hexan-1-yl)amino)-2-oxoethyl)morpholine-4-carboxylate Compound 65a (46.3 mg, 0.19 mmol) was dissolved in DMF 5 mL, then HATU (71.7 mg, 0.19 mmol) and DIPEA (41.3 mg, 0.32 mmol), stirred at room temperature for 10 min, added compound 4 (50 mg, 0.16 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product tert-butyl 2-(2-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl) Amino)-2-oxyethyl)morpholine-4-carboxylate 65c (yellow solid, 55 mg). used directly in the next step. LC-MS m/z (ESI) = 546.2 [M+1].

第二步：N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-2-(嗎啉-2-基)乙醯胺 65dN-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(morpholin-2-yl)acetamide 將 65c的粗產品 (55 mg，0.16 mmol) 溶於二氯甲烷10 mL中，加入三氟乙酸 (6.2 mg，0.06 mmol)，室溫攪拌過夜。待反應結束，旋乾。MPLC分離 (乙腈:水=47:53)，得到目標產物N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-2-(嗎啉-2-基)乙醯胺 65d(黃色油狀，45 mg)。直接用於下一步。 The second step: N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2 -(morpholin-2-yl)acetamide 65d N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2 -(morpholin-2-yl)acetamide Dissolve the crude product of 65c (55 mg, 0.16 mmol) in 10 mL of dichloromethane, add trifluoroacetic acid (6.2 mg, 0.06 mmol), and stir overnight at room temperature. After the reaction is complete, spin dry. MPLC separates (acetonitrile: water=47:53), obtains target product N-(3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexan-1-yl)-2-(morpholin-2-yl)acetamide 65d (yellow oil, 45 mg). used directly in the next step.

第三步：N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-2-(4-甲基嗎啉-2-基)乙醯胺 化合物 65N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(4-methylmorpholin-2-yl)acetamide 50 mL圓底燒瓶中，將化合物 65d(45 mg，0.16 mmol) 溶於20 mL二氯甲烷中，冰浴下加入多聚甲醛 (14.4 mg，0.16 mmol) 和三乙醯氧基氰基硼氫化鈉 (76.3 mg，0.36 mmol)，加入冰醋酸調節pH至4-5，室溫攪拌2 h。將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，得到目標產物N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-2-(4-甲基嗎啉-2-基)乙醯胺 化合物 65(黃色固體，52 mg，71.2%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01-8.97 (m, 1H), 8.67-8.63 (m, 2H), 8.13 (d, 1H), 7.62-7.58 (m, 1H), 7.19-7.13 (m, 1H), 3.93 (d, 1H), 3.91 (s, 1H), 3.87-3.83 (m, 1H), 3.81 (d, 1H), 3.74-3.69 (m, 2H), 3.48-3.41 (m, 1H), 2.70 -2.67 (m, 1H), 2.57 (d, 1H), 2.34-2.29 (m, 2H), 2.15 (s, 3H), 1.99-1.95 (m, 1H), 1.74-1.68 (m, 2H), 1.62-1.57 (m, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -64.28. LC-MSm/z (ESI)= 460.2 [M+1]。 The third step: N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2 -(4-Methylmorpholin-2-yl)acetamide Compound 65 N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1 -yl)-2-(4-methylmorpholin-2-yl)acetamide In a 50 mL round bottom flask, compound 65d (45 mg, 0.16 mmol) was dissolved in 20 mL of dichloromethane, and paraformaldehyde ( 14.4 mg, 0.16 mmol) and sodium triacetyloxycyanoborohydride (76.3 mg, 0.36 mmol), added glacial acetic acid to adjust the pH to 4-5, and stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, and spin-dried to obtain the target product N-(3-(8-cyanoquinolin-5-yl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-(4-methylmorpholin-2-yl)acetamide Compound 65 (yellow solid , 52 mg, 71.2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01-8.97 (m, 1H), 8.67-8.63 (m, 2H), 8.13 (d, 1H), 7.62-7.58 (m, 1H), 7.19-7.13 (m, 1H), 3.93 (d, 1H), 3.91 (s, 1H), 3.87-3.83 (m, 1H), 3.81 (d, 1H), 3.74-3.69 (m, 2H), 3.48-3.41 (m , 1H), 2.70 -2.67 (m, 1H), 2.57 (d, 1H), 2.34-2.29 (m, 2H), 2.15 (s, 3H), 1.99-1.95 (m, 1H), 1.74-1.68 (m , 2H), 1.62-1.57 (m, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.28. LC-MS m/z (ESI) = 460.2 [M+1].

[實施例66] N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 66N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl) quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image708
Figure 02_image710
[Example 66] N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 66 N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl )quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image708
Figure 02_image710

第一步：將化合物 16c(100 mg，0.26 mmol) 溶解於DMF 2 mL中，隨後加入HATU (97.5 mg，0.26 mmol) 和DIPEA (23.3 mg，0.18 mmol)，室溫攪拌10 min，加入化合物 66a(40.1 mg，0.31 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物N-((4-甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 66(白色固體，91 mg，69.7%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.03-8.98 (m, 1H), 8.61-8.57 (m, 1H), 8.36-8.31 (m, 1H), 8.03 (d, 1H), 7.63-7.58 (m, 1H), 7.29 (d, 1H), 3.91 (d, 1H), 3.84-3.80 (m, 2H), 3.75-3.69 (m, 2H), 3.49-3.37 (m, 2H), 3.16-3.12 (m, 2H), 2.63 (d, 1H), 2.55 (d, 1H), 2.14 (s, 3H), 2.01-1.88 (m, 2H), 1.78 (d, 1H), 1.68-1.60 (m, 1H)。 LC-MSm/z (ESI)= 503.2 [M+1]。 Step 1: Dissolve compound 16c (100 mg, 0.26 mmol) in DMF 2 mL, then add HATU (97.5 mg, 0.26 mmol) and DIPEA (23.3 mg, 0.18 mmol), stir at room temperature for 10 min, add compound 66a (40.1 mg, 0.31 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 66 (white solid, 91 mg, 69.7%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03-8.98 (m, 1H), 8.61-8.57 (m, 1H), 8.36-8.31 (m, 1H), 8.03 (d, 1H), 7.63-7.58 (m, 1H), 7.29 (d, 1H), 3.91 (d, 1H), 3.84-3.80 (m, 2H), 3.75-3.69 (m, 2H), 3.49-3.37 (m, 2H), 3.16-3.12 (m, 2H), 2.63 (d, 1H), 2.55 (d, 1H), 2.14 (s, 3H), 2.01-1.88 (m, 2H), 1.78 (d, 1H), 1.68-1.60 (m, 1H ). LC-MS m/z (ESI) = 503.2 [M+1].

[實施例67] 3-(8-氰基喹啉-5-基)-5-甲基-N-((4-甲基嗎啉-2-基)甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 673-(8-cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image712
Figure 02_image714
將化合物 51h(200 mg，0.68 mmol) 溶解於DMF 5 mL中，隨後加入HATU (259.4 mg，0.68 mmol) 和DIPEA (175.4 mg，1.36 mmol)，室溫攪拌10 min，加入化合物 67a(106.6 mg，0.82 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物3-(8-氰基喹啉-5-基)-5-甲基-N-((4-甲基嗎啉-2-基)甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 67(黃色固體，245 mg，89.1%)。 1 H NMR(400 MHz, DMSO- d 6) δ 8.99-8.94 (m, 1H), 8.65 (d, 1H), 8.11 (d, 1H), 7.84 (t, 1H), 7.58-7.52 (m, 1H), 7.04 (d, 1H), 4.01 (s, 1H), 3.87-3.84 (m, 2H), 3.76 (d, 1H), 3.53-3.44 (m, 2H), 3.41 (d, 1H), 3.18-3.12 (m, 2H), 2.67 (d, 1H), 2.57 (d, 1H), 2.16 (s, 3H), 1.97-1.93 (m, 1H), 1.73-1.63 (m, 1H), 1.39 (d, 1H), 1.27 (s, 3H), 1.14 (d, 1H)。 LC-MSm/z (ESI)= 406.2 [M+1]。 [Example 67] 3-(8-cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[ 3.1.0] Hexane-1-formamide Compound 67 3-(8-cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1 .0] hexane-1-carboxamide
Figure 02_image712
Figure 02_image714
Compound 51h (200 mg, 0.68 mmol) was dissolved in DMF 5 mL, then HATU (259.4 mg, 0.68 mmol) and DIPEA (175.4 mg, 1.36 mmol) were added, stirred at room temperature for 10 min, compound 67a (106.6 mg, 0.82 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexyl Alkane-1-carboxamide Compound 67 (yellow solid, 245 mg, 89.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.99-8.94 (m, 1H), 8.65 (d, 1H), 8.11 (d, 1H), 7.84 (t, 1H), 7.58-7.52 (m, 1H ), 7.04 (d, 1H), 4.01 (s, 1H), 3.87-3.84 (m, 2H), 3.76 (d, 1H), 3.53-3.44 (m, 2H), 3.41 (d, 1H), 3.18- 3.12 (m, 2H), 2.67 (d, 1H), 2.57 (d, 1H), 2.16 (s, 3H), 1.97-1.93 (m, 1H), 1.73-1.63 (m, 1H), 1.39 (d, 1H), 1.27 (s, 3H), 1.14 (d, 1H). LC-MS m/z (ESI) = 406.2 [M+1].

[實施例68] 3-(8-氰基喹啉-5-基)-N-((4-(甲基-d3)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 68-A3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image716
2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4,4-雙 (甲基-d3)嗎啉-4-碘 化合物 68-B2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin-4-ium
Figure 02_image718
Figure 02_image720
[Example 68] 3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 68-A 3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2 -yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image716
2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)methyl) -4,4-bis(methyl-d3)morpholine-4-iodo Compound 68-B 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin-4-ium
Figure 02_image718
Figure 02_image720

第一步：叔丁基2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)嗎啉-4-羧酸酯 68ctert-butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxamido)methyl)morpholine-4-carboxylate 將 化合物 1(100 mg，0.29 mmol) 溶解於DMF 5 mL中，隨後加入HATU (110.3 mg，0.29 mmol) 和DIPEA (74 mg，0.58 mmol)，室溫攪拌10 min，加入化合物 68b(74.8 mg，0.58 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物叔丁基2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)嗎啉-4-羧酸酯 化合物 68c(黃色固體，105 mg)。直接用於下一步。 LC-MSm/z (ESI)= 546.2 [M+1]。 The first step: tert-butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Formamide) methyl) morpholine-4-carboxylate 68c tert-butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane -1-carboxamido)methyl)morpholine-4-carboxylate Dissolve compound 1 (100 mg, 0.29 mmol) in 5 mL of DMF, then add HATU (110.3 mg, 0.29 mmol) and DIPEA (74 mg, 0.58 mmol), room Stir at room temperature for 10 min, add compound 68b (74.8 mg, 0.58 mmol), and stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product tert-Butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide) Methyl)morpholine-4-carboxylate Compound 68c (yellow solid, 105 mg). used directly in the next step. LC-MS m/z (ESI) = 546.2 [M+1].

第二步：3-(8-氰基喹啉-5-基)-N-(嗎啉-2-基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 68d3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 68c的粗產品 (105 mg，0.29 mmol) 溶於二氯甲烷10 mL中，加入三氟乙酸 (30.0 mg，0.29 mmol)，室溫攪拌過夜。待反應結束，旋乾。MPLC分离 (乙腈:水=47:53)，得到目標產物3-(8-氰基喹啉-5-基)-N-(嗎啉-2-基甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 68d(黃色油狀，85 mg)。直接用於下一步。 LC-MSm/z (ESI)= 446.2 [M+1]。 The second step: 3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]Hexane-1-formamide 68d 3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide The crude product of 68c (105 mg, 0.29 mmol) was dissolved in 10 mL of dichloromethane, added trifluoroacetic acid (30.0 mg, 0.29 mmol), and stirred overnight at room temperature. After the reaction is complete, spin dry. MPLC separation (acetonitrile: water = 47:53), to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carboxamide 68d (yellow oil, 85 mg). used directly in the next step. LC-MS m/z (ESI) = 446.2 [M+1].

第三步：3-(8-氰基喹啉-5-基)-N-((4-(甲基-d3)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 68-A3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4,4-雙 (甲基-d3)嗎啉-4-碘 化合物 68-B2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin-4-ium 50 mL圓底燒瓶中，將 化合物 68d(50 mg，0.11 mmol) 溶於5 mL DMF中，冰浴下加入碳酸鈉 (23.3 mg，0.21 mmol) 和氘代碘甲烷 (18 mg，0.12 mmol)，室溫攪拌0.5 h。将反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，MPLC純化，得到目標產物3-(8-氰基喹啉-5-基)-N-((4-(甲基-d3)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 68-A(黃色固體，12 mg)；2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4,4-雙 (甲基-d3)嗎啉-4-碘 化合物 68-B(黃色固體，23 mg)。 The third step: 3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-formamide Compound 68-A 3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2- yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-formamide)methyl)-4,4-bis(methyl-d3)morpholine-4-iodine Compound 68-B 2-(( 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin-4-ium In a 50 mL round bottom flask, compound 68d (50 mg, 0.11 mmol) was dissolved in 5 mL of DMF, sodium carbonate (23.3 mg, 0.21 mmol) and deuteroiodomethane (18 mg, 0.12 mmol) were added under ice-cooling, Stir at room temperature for 0.5 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by MPLC to obtain the target product 3-(8-cyanoquinolin-5-yl) -N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formyl Amine Compound 68-A (yellow solid, 12 mg); 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholine-4-iodo Compound 68-B (yellow solid, 23 mg).

化合物 68-A ： 1 H NMR(400 MHz, DMSO- d 6) δ 9.03-8.98 (m, 1H), 8.68-8.62 (m, 1H), 8.35 (t, 1H), 8.17 (d, 1H), 7.63-7.58 (m, 1H), 7.23 (d, 1H), 4.01 (d, 1H), 3.97-3.90 (m, 2H), 3.82 (d, 1H), 3.77-3.72 (m, 1H), 3.47-3.40 (m, 2H), 3.16-3.12 (m, 2H), 2.62-2.58 (m, 2H), 2.15-1.83 (m, 3H), 1.64 (d, 2H), 1.54-1.37 (m, 1H), 1.28 (s, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -64.32. LC-MSm/z (ESI)= 463.2 [M+1]。 Compound 68-A : 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03-8.98 (m, 1H), 8.68-8.62 (m, 1H), 8.35 (t, 1H), 8.17 (d, 1H), 7.63-7.58 (m, 1H), 7.23 (d, 1H), 4.01 (d, 1H), 3.97-3.90 (m, 2H), 3.82 (d, 1H), 3.77-3.72 (m, 1H), 3.47- 3.40 (m, 2H), 3.16-3.12 (m, 2H), 2.62-2.58 (m, 2H), 2.15-1.83 (m, 3H), 1.64 (d, 2H), 1.54-1.37 (m, 1H), 1.28 (s, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.32. LC-MS m/z (ESI) = 463.2 [M+1].

化合物 68-B ： 1 H NMR(400 MHz, DMSO- d 6) δ 9.02 (d, 1H), 8.72-8.54 (m, 2H), 8.21-8.15 (m, 1H), 7.65-7.60 (m, 1H), 7.25 (d, 1H), 3.97 (s, 5H), 3.82 (d, 1H), 3.43 (d, 2H), 3.14 (s, 2H), 3.07 (t, 1H), 2.08-1.93 (m, 2H), 1.70 (s, 1H), 1.43 (d, 1H)。 19 F NMR(376 MHz, DMSO- d 6) δ -64.36. LC-MSm/z (ESI)= 480.2 [M]。 Compound 68-B : 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (d, 1H), 8.72-8.54 (m, 2H), 8.21-8.15 (m, 1H), 7.65-7.60 (m, 1H ), 7.25 (d, 1H), 3.97 (s, 5H), 3.82 (d, 1H), 3.43 (d, 2H), 3.14 (s, 2H), 3.07 (t, 1H), 2.08-1.93 (m, 2H), 1.70 (s, 1H), 1.43 (d, 1H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.36. LC-MS m/z (ESI) = 480.2 [M].

[實施例69] (1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(反式-4-嗎啉環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 69(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image722
Figure 02_image724
將 化合物 1-A(50 mg，0.14 mmol) 溶解於DMF 5 mL中，隨後加入HATU (53 mg，0.14 mmol) 和DIPEA (36.1 mg，0.28 mmol)，室溫攪拌10 min，加入化合物 69b(29.2 mg，0.16 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物 (1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(反式-4-嗎啉環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 69(黃色固體，47 mg，65.5%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02-8.97 (m, 1H), 8.65-8.62 (m, 1H), 8.16 (d, 1H), 7.99 (d, 1H), 7.63-7.59 (m, 1H), 7.22 (d, 1H), 4.00 (d, 1H), 3.94 (s, 2H), 3.81 (d, 1H), 3.53 (d, 5H), 2.44 (t, 4H), 2.13 (s, 1H), 1.98 (d, 1H), 1.80 (s, 4H), 1.61 (d, 1H), 1.23 (s, 4H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58. LC-MSm/z (ESI)= 514.2 [M+1]。 [Example 69] ( 1R,5S ) or ( 1S ,5R)-3-(8- cyanoquinolin -5-yl)-N-(trans-4-morpholinocyclohexyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 69 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin -5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image722
Figure 02_image724
Compound 1-A (50 mg, 0.14 mmol) was dissolved in DMF 5 mL, then HATU (53 mg, 0.14 mmol) and DIPEA (36.1 mg, 0.28 mmol) were added, stirred at room temperature for 10 min, compound 69b (29.2 mg, 0.16 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 69 (yellow solid, 47 mg, 65.5%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02-8.97 (m, 1H), 8.65-8.62 (m, 1H), 8.16 (d, 1H), 7.99 (d, 1H), 7.63-7.59 (m , 1H), 7.22 (d, 1H), 4.00 (d, 1H), 3.94 (s, 2H), 3.81 (d, 1H), 3.53 (d, 5H), 2.44 (t, 4H), 2.13 (s, 1H), 1.98 (d, 1H), 1.80 (s, 4H), 1.61 (d, 1H), 1.23 (s, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 514.2 [M+1].

[實施例70] (1 S,5R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(反式-4-嗎啉環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 70(1S,5R) / (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image726
Figure 02_image728
將 化合物 1-B(50 mg，0.14 mmol) 溶解於DMF 5 mL中，隨後加入HATU (53 mg，0.14 mmol) 和DIPEA (36.1 mg，0.28 mmol)，室溫攪拌10 min，加入化合物 70b(29.2 mg，0.16 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (二氯甲烷:甲醇=10:1)，得到目標產物 (1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(反式-4-嗎啉環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 70(黃色固體，46 mg，64.1%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.05-8.96 (m, 1H), 8.67-8.60 (m, 1H), 8.16 (d, 1H), 7.99 (d, 1H), 7.63-7.57 (m, 1H), 7.22 (d, 1H), 4.00 (d, 1H), 3.93 (d, 2H), 3.81 (d, 1H), 3.53 (d, 5H), 2.44 (t, 4H), 2.12 (s, 1H), 1.98 (d, 1H), 1.79 (s, 4H), 1.61 (d, 1H), 1.23 (s, 4H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.58. LC-MSm/z (ESI)= 514.2 [M+1]。 [Example 70] ( 1S,5R ) or ( 1R ,5S)-3-(8- cyanoquinolin -5-yl)-N-(trans-4-morpholinocyclohexyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 70 (1S,5R) / (1S,5R)-3-(8-cyanoquinolin-5-yl )-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image726
Figure 02_image728
Compound 1-B (50 mg, 0.14 mmol) was dissolved in DMF 5 mL, then HATU (53 mg, 0.14 mmol) and DIPEA (36.1 mg, 0.28 mmol) were added, stirred at room temperature for 10 min, compound 70b (29.2 mg, 0.16 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 70 (yellow solid, 46 mg, 64.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.05-8.96 (m, 1H), 8.67-8.60 (m, 1H), 8.16 (d, 1H), 7.99 (d, 1H), 7.63-7.57 (m , 1H), 7.22 (d, 1H), 4.00 (d, 1H), 3.93 (d, 2H), 3.81 (d, 1H), 3.53 (d, 5H), 2.44 (t, 4H), 2.12 (s, 1H), 1.98 (d, 1H), 1.79 (s, 4H), 1.61 (d, 1H), 1.23 (s, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.58. LC-MS m/z (ESI) = 514.2 [M+1].

[實施例71] 3-(8-氰基喹啉-5-基)-N-(3,3-二氟-1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 713-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image730
Figure 02_image732
[Example 71] 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 71 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image730
Figure 02_image732

第一步： (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-醯胺基)-3,3-二氟哌啶-1-羧酸叔丁酯 71ctert-butyl-4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido)-3,3-difluoropiperidine-1-carboxylate 將 化合物 1(300 mg，0.87 mmol) 溶解於DMF 5 mL中，隨後加入HATU (115 mg，1.3 mmol) 和DIPEA (168 mg，1.3 mmol)，室溫攪拌10 min，加入化合物 71b(411 mg，1.74 mmol)，室溫攪拌2 h。原料反應完畢，加入15 mL水中淬滅，體系用乙酸乙酯萃取三遍，合併有機相並用飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC (乙腈:水= 60:40)分離純化，得到目標產物4-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-醯胺基)-3,3-二氟哌啶-1-羧酸叔丁酯 71c(黃色固體，490 mg)。直接用於下一步。 LC-MSm/z (ESI)= 566.2 [M+1]。 The first step : (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido)-3 , tert-butyl 3-difluoropiperidine-1-carboxylate 71c tert-butyl-4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-amido)-3,3-difluoropiperidine-1-carboxylate Dissolve compound 1 (300 mg, 0.87 mmol) in 5 mL of DMF, then add HATU (115 mg, 1.3 mmol) and DIPEA (168 mg, 1.3 mmol ), stirred at room temperature for 10 min, added compound 71b (411 mg, 1.74 mmol), and stirred at room temperature for 2 h. The reaction of the raw materials was completed, quenched by adding 15 mL of water, the system was extracted three times with ethyl acetate, the organic phases were combined and washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, MPLC (acetonitrile:water=60:40 ) separation and purification to obtain the target product 4-(3-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-acyl Amino)-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester 71c (yellow solid, 490 mg). used directly in the next step. LC-MS m/z (ESI) = 566.2 [M+1].

第二步：3-(8-氰基喹啉-5-基)-N-(3,3-二氟哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 71d3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide 將 71c(490 mg，0.87 mmol) 溶於氯化氫二氧六環溶液 (10 mL)中，室溫攪拌過夜。待反應結束，旋乾。MPLC分離 (乙腈:水=40:60)，得到目標產物3-(8-氰基喹啉-5-基)-N-(3,3-二氟哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 71d(黃色固體，404 mg)。直接用於下一步。 LC-MSm/z (ESI)= 466.1 [M+1]。 The second step: 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-formamide 71d 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [ 3.1.0] hexane-1-carboxamide 71c (490 mg, 0.87 mmol) was dissolved in dioxane hydrogen chloride solution (10 mL), and stirred overnight at room temperature. After the reaction is complete, spin dry. MPLC separation (acetonitrile: water=40:60), obtain target product 3-(8-cyanoquinoline-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 71d (yellow solid, 404 mg). used directly in the next step. LC-MS m/z (ESI) = 466.1 [M+1].

第三步：3-(8-氰基喹啉-5-基)-N-(3,3-二氟-1-甲基哌啶4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 713-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 50 mL圓底燒瓶中，將 化合物 71d(404 mg，0.87 mmol) 溶於15 mL 無水甲醇中，隨後加入多聚甲醛 (549 mg，6.09 mmol) 和氰基硼氫化鈉 (987 mg, 2.61 mmol)，加熱回流3 h。將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，MPLC純化 (乙腈:水=45:55)，得到目標產物3-(8-氰基喹啉-5-基)-N-(3,3-二氟-1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 71(黃色固體，145 mg，35%)。 1 H NMR(400 MHz, DMSO-d 6) δ 9.01 (dd, J= 4.1, 1.3 Hz, 1H), 8.64 (dd, J= 8.6, 1.5 Hz, 1H), 8.40 (d, J= 8.9 Hz, 1H), 8.18 (d, J= 8.2 Hz, 1H), 7.61 (dd, J= 8.7, 4.2 Hz, 1H), 7.24 (d, J= 8.3 Hz, 1H)。 4.25-3.85 (m, 5H), 3.05-2.98 (m, 1H), 2.79-2.67(m, 1H), 2.36-2.26 (m, 1H), 2.22 (s, 3H), 2.14-2.04 (m, 1H), 1.98 (d, J= 8.0 Hz, 1H), 1.75-1.59 (m, 3H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.71, -63.93。 LC-MSm/z (ESI)= 480.2 [M+1]。 The third step: 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin 4-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compound 71 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5 -(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide In a 50 mL round bottom flask, compound 71d (404 mg, 0.87 mmol) was dissolved in 15 mL of anhydrous methanol, and then paraformaldehyde (549 mg, 6.09 mmol) and sodium cyanoborohydride (987 mg, 2.61 mmol), heated to reflux for 3 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by MPLC (acetonitrile:water=45:55) to obtain the target product 3-(8- Cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxamide Compound 71 (yellow solid, 145 mg, 35%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (dd, J = 4.1, 1.3 Hz, 1H), 8.64 (dd, J = 8.6, 1.5 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 8.7, 4.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H). 4.25-3.85 (m, 5H), 3.05-2.98 (m, 1H), 2.79-2.67(m, 1H), 2.36-2.26 (m, 1H), 2.22 (s, 3H), 2.14-2.04 (m, 1H ), 1.98 (d, J = 8.0 Hz, 1H), 1.75-1.59 (m, 3H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.71, -63.93. LC-MS m/z (ESI) = 480.2 [M+1].

[實施例72] 3-(8-氰基喹啉-5-基)- N-(9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬南-7-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 723-(8-cyanoquinolin-5-yl)- N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image734
Figure 02_image736
將 化合物 1(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg， 0.22 mmol)，室溫攪拌10 min，加入內-7-氨基-9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬烷二鹽酸鹽 72b(66 mg，0.29 mmol)，室溫攪拌3h。原料反應完全，MPLC分離 (乙腈:水=45%:55%)，得到目標產物3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬南-7-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 72(淡黃色固體，27 mg，40%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.50 (d, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.29-4.23 (m, 1H), 4.03-3.81 (m, 6H), 3.59 (dd, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.48。 LC-MSm/z (ESI)= 486.2 [M+1], 508.2 [M+23]。 [Example 72] 3-(8- cyanoquinolin -5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 72 3-(8- cyanoquinolin -5-yl)-N-(9-methyl-3 -oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image734
Figure 02_image736
Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and stirred at room temperature for 10 min, add endo-7-amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane dihydrochloride 72b (66 mg, 0.29 mmol), and stir at room temperature for 3h. Raw material reaction is complete, and MPLC separates (acetonitrile: water=45%: 55%), obtains target product 3-(8-cyanoquinoline-5-yl)-N-(9-methyl-3-oxa-9 -Azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 72 (pale yellow solid , 27 mg, 40%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.50 (d, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.29-4.23 (m, 1H), 4.03-3.81 (m, 6H), 3.59 (dd, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.48. LC-MS m/z (ESI) = 486.2 [M+1], 508.2 [M+23].

[實施例73] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)- N-(9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬南-7-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 73(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)- N-(9-methyl-3-oxa-9-azabicyclo[3.3.1] nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image738
Figure 02_image740
將 化合物 1-A(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg, 0.22 mmol)，室溫攪拌10 min，加入內-7-氨基-9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬烷二鹽酸鹽 (66 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水=45%:55%)，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬南-7-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 73(淡黃色固體，40 mg，63%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.50 (d, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.29-4.23 (m, 1H), 4.03-3.81 (m, 6H), 3.59 (dd, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.48。 LC-MSm/z (ESI)= 486.2 [M+1]。 [Example 73] (1 R ,5 S ) or (1 S ,5 R )-3-(8- cyanoquinolin -5-yl)-N-(9-methyl-3-oxa-9 -Azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 73 (1 R , 5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)- N -(9-methyl-3-oxa-9-azabicyclo[3.3.1] nonan-7-yl)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image738
Figure 02_image740
Dissolve compound 1-A (50 mg, 0.14 mmol) in 2 mL of N,N -dimethylformamide, then add HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), room temperature Stir for 10 min, add endo-7-amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29 mmol), and stir at room temperature for 3 h . The reaction of the raw material is complete, separated by MPLC (acetonitrile:water=45%:55%), and the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl )-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide Compound 73 (pale yellow solid, 40 mg, 63%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.50 (d, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.29-4.23 (m, 1H), 4.03-3.81 (m, 6H), 3.59 (dd, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.48. LC-MS m/z (ESI) = 486.2 [M+1].

[實施例74] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)- N-(9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬南-7-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 74(1 S,5 R)或(1 R,5 S)-3-(8-cyanoquinolin-5-yl)- N-(9-methyl-3-oxa-9-azabicyclo[3.3.1] nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image742
Figure 02_image744
將 化合物 1-B(50 mg，0.14 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入HATU (83 mg，0.22 mmol) 和DIPEA (27.9 mg, 0.22 mmol)，室溫攪拌10 min，加入內-7-氨基-9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬烷二鹽酸鹽 (66 mg，0.29 mmol)，室溫攪拌3 h。原料反應完全，MPLC分離 (乙腈:水=45%:55%)，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧雜-9-氮雜雙環[3.3.1]壬南-7-基)-5-(三氟甲基)- 3-氮雜雙環[3.1.0]己烷-1-羧醯胺 化合物 74(淡黃色固體，40 mg，66%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.50 (d, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.29-4.23 (m, 1H), 4.03-3.81 (m, 6H), 3.59 (dd, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.48 LC-MSm/z (ESI)= 486.2 [M+1] [Example 74] (1 S ,5 R ) or (1 R ,5 S )-3-(8- cyanoquinolin -5-yl)-N-(9-methyl-3-oxa-9 -Azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 74 (1 S , 5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl) -N -(9-methyl-3-oxa-9-azabicyclo[3.3.1] nonan-7-yl)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image742
Figure 02_image744
Compound 1-B (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N -dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added at room temperature Stir for 10 min, add endo-7-amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29 mmol), and stir at room temperature for 3 h . The reaction of the raw material is complete, separated by MPLC (acetonitrile:water=45%:55%), and the target product (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinoline-5-yl )-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide Compound 74 (pale yellow solid, 40 mg, 66%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.50 (d, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.29-4.23 (m, 1H), 4.03-3.81 (m, 6H), 3.59 (dd, 2H), 2.58 (s, 2H), 2.40 (s, 3H), 2.31-2.25 (m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.48 LC-MS m/z (ESI)= 486.2 [M+1]

[實施例75] 5-(1-[(嗎啉-4-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-甲腈 化合物 755-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl) quinoline-8-carbonitrile

Figure 02_image746
Figure 02_image748
將 化合物 75a(100 mg，0.21 mmol) 溶解於 N,N-二甲基甲醯胺2 mL中，隨後加入嗎啉 (27 mg，0.31 mmol)，碳酸鉀 (58 mg，0.42 mmol)，碘化鈉 (32 mg， 0.21 mmol)，100 ℃避光攪拌3 h。原料反應完全，MPLC分離 (乙腈:水=40%:60%)，得到目標產物5-(1-[(嗎啉-4-基)甲基]-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-甲腈 化合物 76(淡黃色固體，40 mg，99%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.02 (dd, J= 4.1, 1.3 Hz, 1H), 8.77-8.57 (m, 1H), 8.19 (d, J= 8.2 Hz, 1H), 7.63 (dd, J= 8.7, 4.2 Hz, 1H), 7.21 (d, J= 8.2 Hz, 1H), 4.14-3.58 (m, 12H), 3.23-3.04 (m, 2H), 1.83-1.62 (m, 2H)。 19 F NMR(376 MHz, DMSO- d 6) δ -61.72 LC-MSm/z (ESI)= 403.2 [M+1] [Example 75] 5-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline -8-carbonitrile Compound 75 5-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl) quinoline-8-carbonitrile
Figure 02_image746
Figure 02_image748
Compound 75a (100 mg, 0.21 mmol) was dissolved in 2 mL of N,N -dimethylformamide, followed by addition of morpholine (27 mg, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol), iodide Sodium (32 mg, 0.21 mmol), stirred at 100 ℃ for 3 h in the dark. Raw material reaction is complete, and MPLC separates (acetonitrile:water=40%:60%), obtains target product 5-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 76 (pale yellow solid, 40 mg, 99%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (dd, J = 4.1, 1.3 Hz, 1H), 8.77-8.57 (m, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.63 ( dd, J = 8.7, 4.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.14-3.58 (m, 12H), 3.23-3.04 (m, 2H), 1.83-1.62 (m, 2H) . 19 F NMR (376 MHz, DMSO- d 6 ) δ -61.72 LC-MS m/z (ESI)= 403.2 [M+1]

[實施例76] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(反式-3-嗎啉代環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 76(1 R,5 S)或(1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-( trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image750
Figure 02_image752
[Example 76] (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide compound 76 (1 R ,5 S ) or (1 R ,5 S )-3-( 8-cyanoquinolin-5-yl)-N-( trans -3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image750
Figure 02_image752

第一步：順式-3-((叔丁氧基羰基)氨基)環丁基4-甲基苯磺酸鹽 76b cis-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 將化合物 76a(3.0 g，16 mmol) 溶於20 mL DCM中，隨後加入DMAP (3.9 g，32 mmol)、三乙胺 (4.4 mL，32 mmol)、對甲苯磺醯氯(3.0 g，16 mmol)，45 ℃回流攪拌2 h。TLC反應完畢，將反應液加入50 mL水中水洗，飽和食鹽水50 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚=10:1)，得到目標產物反式-3-((叔丁氧基羰基)氨基)環丁基4-甲基苯磺酸鹽 76b(白色固體，5.3 g，98.1%)。 LC-MSm/z (ESI)= 342.2 [M+1]。 The first step: cis-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 76b cis -3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate compound 76a (3.0 g, 16 mmol) was dissolved in 20 mL DCM, followed by addition of DMAP (3.9 g, 32 mmol), triethylamine (4.4 mL, 32 mmol), p-toluenesulfonyl chloride (3.0 g, 16 mmol), 45 °C and reflux for 2 h. After the TLC reaction was completed, the reaction solution was washed with 50 mL of water, washed with 50 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:1) to obtain the target Product trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 76b (white solid, 5.3 g, 98.1%). LC-MS m/z (ESI) = 342.2 [M+1].

第二步：(反式-3-嗎啉代環丁基)氨基甲酸叔丁酯 76ctert-butyl ( trans-3-morpholinocyclobutyl)carbamate 將 76b(1.0 g，2.93 mmol) 溶於10 mL DMF中，加入嗎啉 (306.6 mg，3.52 mmol)、碘化鈉 (88.0 mg，0.58 mmol) 和碳酸鉀 (808.0 mg，5.86 mmol)，90 ℃攪拌反應2 h。待反應結束，濃縮，乙酸乙酯萃取，無水硫酸鈉乾燥，真空除去溶劑。矽膠柱層析純化 (乙酸乙酯:石油醚=1:1)，得到目標產物(反式-3-嗎啉代環丁基)氨基甲酸叔丁酯 76c(無色油狀，350 mg，46.7%)。直接用於下一步。 LC-MSm/z (ESI)= 257.2 [M+1]。 The second step: (trans-3-morpholinocyclobutyl)carbamate tert-butyl ester 76c tert-butyl ( trans -3-morpholinocyclobutyl)carbamate Dissolve 76b (1.0 g, 2.93 mmol) in 10 mL DMF, Add morpholine (306.6 mg, 3.52 mmol), sodium iodide (88.0 mg, 0.58 mmol) and potassium carbonate (808.0 mg, 5.86 mmol), and stir the reaction at 90°C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1), the target product (trans-3-morpholinocyclobutyl) tert-butyl carbamate 76c (colorless oil, 350 mg, 46.7% ). used directly in the next step. LC-MS m/z (ESI) = 257.2 [M+1].

第三步：(反式-3-嗎啉代環丁基)氨基 76d trans-3-morpholinocyclobutan-1-amine 將 76c(256 mg，1.0 mmol) 溶於二氯甲烷10 mL中，加入三氟乙酸 (114.0 mg，1.0 mmol)，室溫攪拌過夜。待反應結束，旋乾。得((1R,3R)-3-嗎啉代環丁基)氨基 76d粗產品 (無色油狀，200 mg)。直接用於下一步。 LC-MSm/z (ESI)= 157.2 [M+1]。 The third step: (trans-3-morpholinocyclobutyl) amino 76d trans -3-morpholinocyclobutan-1-amine Dissolve 76c (256 mg, 1.0 mmol) in dichloromethane 10 mL, add trifluoroacetic acid (114.0 mg, 1.0 mmol), stirred overnight at room temperature. After the reaction is complete, spin dry. The crude product of ((1R,3R)-3-morpholinocyclobutyl)amino 76d (colorless oil, 200 mg) was obtained. used directly in the next step. LC-MS m/z (ESI) = 157.2 [M+1].

第四步：(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-((1R,3R)-3-嗎啉代環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 76(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((1R,3R)-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1-A(173.5 mg，0.5 mmol) 溶解於DMF 2 mL中，隨後加入HATU (190.1 mg，0.5 mmol) 和DIPEA (129.1 mg，1.0 mmol)，室溫攪拌10 min，加入化合物 76d(78.0 mg，0.5 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC純化，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(反式-3-嗎啉代環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 76(白色固體，100 mg，41.3%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.01 (d, 1H), 8.67-8.61 (m, 1H), 8.41-8.38 (m, 1H), 8.19-8.14 (m, 1H), 7.63-7.60 (m, 1H), 7.26-7.21 (m, 1H), 4.17-4.08 (m, 1H), 4.04-3.98 (m, 2H), 3.98-3.92 (m, 1H), 3.80 (t, 1H), 3.59-3.54 (m, 4H), 2.86-2.65 (m, 1H), 2.46-2.28 (m, 2H), 2.18 (d, 4H), 1.99-1.95 (m, 2H), 1.75 (d, 1H), 1.63 (t, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.61。 LC-MSm/z (ESI)= 486.2 [M+1]。 The fourth step: (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((1R,3R)-3-morpholino ring Butyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 76 (1 R ,5 S ) / (1 S ,5 R )-3 Compound 1-A ( 173.5 mg, 0.5 mmol) was dissolved in 2 mL of DMF, then HATU (190.1 mg, 0.5 mmol) and DIPEA (129.1 mg, 1.0 mmol) were added, stirred at room temperature for 10 min, compound 76d (78.0 mg, 0.5 mmol) was added, Stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide Compound 76 (white solid, 100 mg, 41.3%). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, 1H), 8.67-8.61 (m, 1H), 8.41-8.38 (m, 1H), 8.19-8.14 (m, 1H), 7.63-7.60 ( m, 1H), 7.26-7.21 (m, 1H), 4.17-4.08 (m, 1H), 4.04-3.98 (m, 2H), 3.98-3.92 (m, 1H), 3.80 (t, 1H), 3.59- 3.54 (m, 4H), 2.86-2.65 (m, 1H), 2.46-2.28 (m, 2H), 2.18 (d, 4H), 1.99-1.95 (m, 2H), 1.75 (d, 1H), 1.63 ( t, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.61. LC-MS m/z (ESI) = 486.2 [M+1].

[實施例77] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(反式-3-嗎啉環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 77(1 S,5 R) / (1 R,5 S) -3-(8-cyanoquinolin-5-yl)-N-( trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image754
Figure 02_image756
將 化合物 1-B(173.5 mg，0.5 mmol) 溶解於DMF 2 mL中，隨後加入HATU (190.1 mg，0.5 mmol) 和DIPEA (129.1 mg，1.0 mmol)，室溫攪拌10 min，加入化合物 76d(78.0 mg，0.5 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC純化，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(反式-3-嗎啉環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 77(白色固體，102 mg，42.1%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.01 (d, 1H), 8.70-8.59 (m, 1H), 8.41-8.37 (m, 1H), 8.19-8.16 (m, 1H), 7.64-7.58 (m, 1H), 7.26-7.22 (m, 1H), 4.15 (d, 1H), 4.08-3.98 (m, 1H), 3.97-3.92 (m, 2H), 3.80 (t, 1H), 3.56 (d, 4H), 2.77 (q, 1H), 2.44-2.30 (m, 2H), 2.18 (d, 4H), 1.99-1.96 (m, 2H), 1.75 (q, 1H), 1.63 (t, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.67。 LC-MSm/z (ESI)= 486.2 [M+1]。 [Example 77] (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinecyclobutyl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 77 (1 S ,5 R ) / (1 R ,5 S ) -3-(8 -cyanoquinolin-5-yl)-N-( trans -3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image754
Figure 02_image756
Compound 1-B (173.5 mg, 0.5 mmol) was dissolved in DMF 2 mL, then HATU (190.1 mg, 0.5 mmol) and DIPEA (129.1 mg, 1.0 mmol) were added, stirred at room temperature for 10 min, and compound 76d (78.0 mg, 0.5 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1 S , 5 R ) or (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinecyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxamide Compound 77 (white solid, 102 mg, 42.1%). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, 1H), 8.70-8.59 (m, 1H), 8.41-8.37 (m, 1H), 8.19-8.16 (m, 1H), 7.64-7.58 ( m, 1H), 7.26-7.22 (m, 1H), 4.15 (d, 1H), 4.08-3.98 (m, 1H), 3.97-3.92 (m, 2H), 3.80 (t, 1H), 3.56 (d, 4H), 2.77 (q, 1H), 2.44-2.30 (m, 2H), 2.18 (d, 4H), 1.99-1.96 (m, 2H), 1.75 (q, 1H), 1.63 (t, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.67. LC-MS m/z (ESI) = 486.2 [M+1].

[實施例78] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(順式-3-嗎啉代環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 78(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-( cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image758
Figure 02_image760
[Example 78] (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 78 (1 R ,5 S ) / (1 S ,5 R )-3-( 8-cyanoquinolin-5-yl)-N-( cis -3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image758
Figure 02_image760

第一步：反式-3-((叔丁氧基羰基)氨基)環丁基4-甲基苯磺酸鹽 78btrans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 將化合物 78a(3.7 g，20 mmol) 溶於20 mL DCM中，隨後加入DMAP (4.9 g，40 mmol)、三乙胺 (4.0 g，40 mmol)、對甲苯磺醯氯(3.7g，20 mmol)，45 ℃回流攪拌2 h。TLC反應完畢，將反應液加入50 mL水中水洗，飽和食鹽水50 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚=10:1)，得到目標產物 反式-3-((叔丁氧基羰基)氨基)環丁基4-甲基苯磺酸鹽 78b(白色固體，4.9 g，72.1%)。 LC-MSm/z (ESI)= 342.1[M+1]。 The first step: trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 78b trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate compound 78a (3.7 g, 20 mmol) was dissolved in 20 mL of DCM, followed by addition of DMAP (4.9 g, 40 mmol), triethylamine (4.0 g, 40 mmol), p-toluenesulfonyl chloride (3.7 g, 20 mmol), 45 °C and reflux for 2 h. After the TLC reaction was completed, the reaction solution was washed with 50 mL of water, washed with 50 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:1) to obtain the target Product trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 78b (white solid, 4.9 g, 72.1%). LC-MS m/z (ESI) = 342.1 [M+1].

第二步：順式-3-嗎啉代環丁基)氨基甲酸叔丁酯 78ctert-butyl ( cis-3-morpholinocyclobutyl)carbamate 將 78b(1.0 g，3.0 mmol) 溶於10 mL DMF中，加入嗎啉 (522.7 mg，6.0 mmol)、碘化鈉 (150.0 mg，3.0 mmol) 和碳酸鉀 (828.0 mg，6.0 mmol)，90 ℃攪拌反應2 h。待反應結束，濃縮，乙酸乙酯萃取，無水硫酸鈉乾燥，真空除去溶劑。矽膠柱層析純化 (乙酸乙酯:石油醚=1:1)，得到目標產物(順式-3-嗎啉代環丁基)氨基甲酸叔丁酯 78c(無色油狀，550 mg，72.3%)。直接用於下一步。 LC-MSm/z (ESI)= 257.2 [M+1]。 The second step: cis-3-morpholinocyclobutyl) tert-butyl carbamate 78c tert-butyl ( cis -3-morpholinocyclobutyl) carbamate Dissolve 78b (1.0 g, 3.0 mmol) in 10 mL DMF, add Morpholine (522.7 mg, 6.0 mmol), sodium iodide (150.0 mg, 3.0 mmol) and potassium carbonate (828.0 mg, 6.0 mmol) were stirred at 90°C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1), the target product (cis-3-morpholinocyclobutyl) tert-butyl carbamate 78c (colorless oil, 550 mg, 72.3% ). used directly in the next step. LC-MS m/z (ESI) = 257.2 [M+1].

第三步：(順式-3-嗎啉代環丁基)氨基 78d cis-3-morpholinocyclobutan-1-amine 將 78c(256.0 mg，1.0 mmol) 溶於二氯甲烷10 mL中，加入三氟乙酸 (114.0 mg，1.0 mmol)，室溫攪拌過夜。待反應結束，旋乾。得到(順式-3-嗎啉代環丁基)氨基 78d粗產品 (無色油狀，200 mg)。直接用於下一步。 LC-MSm/z (ESI)= 157.2 [M+1]。 The third step: (cis-3-morpholinocyclobutyl) amino 78d cis -3-morpholinocyclobutan-1-amine Dissolve 78c (256.0 mg, 1.0 mmol) in dichloromethane 10 mL, add trifluoroacetic acid (114.0 mg, 1.0 mmol), stirred overnight at room temperature. After the reaction is complete, spin dry. The crude product of (cis-3-morpholinocyclobutyl)amino 78d was obtained (colorless oil, 200 mg). used directly in the next step. LC-MS m/z (ESI) = 157.2 [M+1].

第四步：(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(反式-3-嗎啉代環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 78(1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-( trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1-A(100.0 mg，0.3 mmol) 溶解於DMF 2 mL中，隨後加入HATU (109.5 mg，0.3 mmol) 和DIPEA (77.4 mg，0.6 mmol)，室溫攪拌10 min，加入化合物 78d(67.0 mg，0.4 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC純化，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(順式-3-嗎啉代環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 78(白色固體，102 mg，70.3%)。 1 H NMR(400 MHz, DMSO-d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.34 (d, 1H), 8.16 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.02 (d, 2H), 3.95-3.89 (m, 2H), 3.79 (d, 1H), 3.54 (t, 4H), 2.46-2.36 (m, 1H), 2.35-2.28 (m, 2H), 2.22 (s, 4H), 2.00 (d, 1H), 1.74 (dd, 2H), 1.62 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.57 LC-MSm/z (ESI)= 486.2 [M+1]。 The fourth step: (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 78 (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)- N-( trans -3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 1-A (100.0 mg, 0.3 mmol) was dissolved in DMF 2 mL, then added HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol) were stirred at room temperature for 10 min, compound 78d (67.0 mg, 0.4 mmol) was added, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide Compound 78 (white solid, 102 mg, 70.3%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.34 (d, 1H), 8.16 (d, 1H), 7.60 (dd, 1H), 7.22 ( d, 1H), 4.02 (d, 2H), 3.95-3.89 (m, 2H), 3.79 (d, 1H), 3.54 (t, 4H), 2.46-2.36 (m, 1H), 2.35-2.28 (m, 2H), 2.22 (s, 4H), 2.00 (d, 1H), 1.74 (dd, 2H), 1.62 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.57 LC-MS m/z (ESI) = 486.2 [M+1].

[實施例79] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(順式-3-嗎啉環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 79(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-( cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image762
Figure 02_image764
將 化合物 1-B(100.0 mg，0.3 mmol) 溶解於DMF 2 mL中，隨後加入HATU (109.5 mg，0.3 mmol) 和DIPEA (77.4 mg，0.6 mmol)，室溫攪拌10 min，加入化合物 78d(67.0 mg，0.4 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC純化，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(順式-3-嗎啉環丁基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 79(白色固體，108 mg，74.0%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.00 (d, 2H), 3.96-3.89 (m, 2H), 3.79 (d, 1H), 3.54 (t, 4H), 2.44-2.36 (m, 1H), 2.35-2.28 (m, 2H), 2.22 (s, 4H), 2.00 (d, 1H), 1.79-1.73 (m, 2H), 1.62 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.63 LC-MSm/z (ESI)= 486.2 [M+1]。 [Example 79] (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinecyclobutyl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 79 (1 S ,5 R ) / (1 R ,5 S )-3-(8 -cyanoquinolin-5-yl)-N-( cis -3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image762
Figure 02_image764
Compound 1-B (100.0 mg, 0.3 mmol) was dissolved in DMF 2 mL, then HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol) were added, stirred at room temperature for 10 min, and compound 78d (67.0 mg, 0.4 mmol), stirred at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was added to 15 mL of water and washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1 S , 5 R ) or (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinecyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxamide Compound 79 (white solid, 108 mg, 74.0%). 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.22 (d , 1H), 4.00 (d, 2H), 3.96-3.89 (m, 2H), 3.79 (d, 1H), 3.54 (t, 4H), 2.44-2.36 (m, 1H), 2.35-2.28 (m, 2H ), 2.22 (s, 4H), 2.00 (d, 1H), 1.79-1.73 (m, 2H), 1.62 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.63 LC-MS m/z (ESI) = 486.2 [M+1].

[實施例80] (1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(順式-4-嗎啉代環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 80(1 R, 5 S) / (1 S,5 R) -3-(8-cyanoquinolin-5-yl)-N-( cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image766
Figure 02_image768
[Example 80] ( 1R ,5S) or ( 1S , 5R )-3-(8- cyanoquinolin -5-yl)-N-(cis-4-morpholinocyclohexyl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 80 (1 R , 5 S ) / (1 S ,5 R ) -3-(8 -cyanoquinolin-5-yl)-N-( cis -4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image766
Figure 02_image768

第一步：反式-4-((叔丁氧羰基)氨基)環己基4-甲基苯磺酸鹽 80b trans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate 將化合物 80a(4.3 g，20 mmol) 溶於20 mL DCM中，隨後加入DMAP (4.9 g，40 mmol)、三乙胺 (4.0 g，40 mmol)、對甲苯磺醯氯(3.8 g，20 mmol)，45 ℃回流攪拌2 h。TLC反應完畢，將反應液加入50 mL水中水洗，飽和食鹽水50 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化 (乙酸乙酯:石油醚=10:1)，得到目標產物反式-4-((叔丁氧羰基)氨基)環己基4-甲基苯磺酸鹽 80b(白色固體，5.4 g，73.0%)。 LC-MSm/z (ESI)= 370.1[M+1]。 The first step: trans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate 80b trans -4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate compound 80a (4.3 g, 20 mmol) was dissolved in 20 mL DCM, followed by adding DMAP (4.9 g, 40 mmol), triethylamine (4.0 g, 40 mmol), p-toluenesulfonyl chloride (3.8 g, 20 mmol), and refluxed at 45 °C Stir for 2 h. After the TLC reaction was completed, the reaction solution was washed with 50 mL of water, washed with 50 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:1) to obtain the target The product trans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate 80b (white solid, 5.4 g, 73.0%). LC-MS m/z (ESI) = 370.1 [M+1].

第二步：順式-4-嗎啉代環己基)氨基甲酸叔丁酯 80ctert-butyl ( cis-4-morpholinocyclohexyl)carbamate 將 80b(1.1 g，3.0 mmol) 溶於10 mL DMF中，加入嗎啉 (522.7 mg，6.0 mmol)、碘化鈉 (150.0 mg，3.0 mmol) 和碳酸鉀 (828.0 mg，6.0 mmol)，90 ℃攪拌反應2 h。待反應結束，濃縮，乙酸乙酯萃取，無水硫酸鈉乾燥，真空除去溶劑。矽膠柱層析純化 (乙酸乙酯:石油醚=1:1)，得到目標產物(( cis-4-嗎啉代環丁基)氨基甲酸叔丁酯 80c(無色油狀，283 mg，33.2%)。直接用於下一步。 LC-MSm/z (ESI)= 285.3 [M+1]。 Step 2: Dissolve 80b ( 1.1 g, 3.0 mmol) in 10 mL of DMF, add Phenyl (522.7 mg, 6.0 mmol), sodium iodide (150.0 mg, 3.0 mmol) and potassium carbonate (828.0 mg, 6.0 mmol), stirred at 90 ℃ for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1), the target product (( cis -4-morpholinocyclobutyl)tert-butyl carbamate 80c (colorless oil, 283 mg, 33.2% ). Used directly in the next step. LC-MS m/z (ESI) = 285.3 [M+1].

第三步：(順式-4-嗎啉代環丁基)氨基 80d cis-4-morpholinocyclohexan-1-amine 將 80c(283.0 mg，1.0 mmol) 溶於二氯甲烷10 mL中，加入三氟乙酸 (114.0 mg，1.0 mmol)，室溫攪拌過夜。待反應結束，旋乾。得(順式-4-嗎啉代環丁基)氨基 80d粗產品 (無色油狀，220 mg)。直接用於下一步。 LC-MSm/z (ESI)= 185.2 [M+1]。 The third step: (cis-4-morpholinocyclobutyl)amino 80d cis -4-morpholinocyclohexan-1-amine Dissolve 80c (283.0 mg, 1.0 mmol) in dichloromethane 10 mL, add trifluoroacetic acid (114.0 mg, 1.0 mmol), stirred overnight at room temperature. After the reaction is complete, spin dry. The crude product (cis-4-morpholinocyclobutyl)amino 80d (colorless oil, 220 mg) was obtained. used directly in the next step. LC-MS m/z (ESI) = 185.2 [M+1].

第四步：(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(順式-4-嗎啉代環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 80(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-( cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1-A(100.0 mg，0.3 mmol) 溶解於DMF 2 mL中，隨後加入HATU (109.5 mg，0.3 mmol) 和DIPEA (77.4 mg，0.6 mmol)，室溫攪拌10 min，加入化合物 80d(67.0 mg，0.4 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC純化，得到目標產物(1 R,5 S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-( cis-4-嗎啉代環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 80(白色固體，98 mg，63.7%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.16 (d, 1H), 8.00 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03 (dd, 1H), 3.98-3.90 (m, 2H), 3.89-3.72 (m, 2H), 3.59-3.52 (m, 4H), 2.45-2.35 (m, 4H), 2.09-1.92 (m, 2H), 1.77 (d, 3H), 1.60 (t, 2H), 1.43 (dd, 3H), 1.23 (s, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.61。 LC-MSm/z (ESI)= 514.3 [M+1]。 The fourth step: (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 80 (1 R ,5 S ) / (1 S ,5 R )-3-(8- cyanoquinolin-5-yl)-N-( cis -4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 1-A (100.0 mg, 0.3 mmol) was dissolved in DMF 2 mL, then added HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol), stirred at room temperature for 10 min, added compound 80d (67.0 mg, 0.4 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-( cis -4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 80 (white solid, 98 mg, 63.7%). 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.16 (d, 1H), 8.00 (d, 1H), 7.60 (dd, 1H), 7.22 (d , 1H), 4.03 (dd, 1H), 3.98-3.90 (m, 2H), 3.89-3.72 (m, 2H), 3.59-3.52 (m, 4H), 2.45-2.35 (m, 4H), 2.09-1.92 (m, 2H), 1.77 (d, 3H), 1.60 (t, 2H), 1.43 (dd, 3H), 1.23 (s, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.61. LC-MS m/z (ESI) = 514.3 [M+1].

[實施例81] (1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(順式-4-嗎啉代環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 81(1 S,5 R)或(1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-( cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image770
Figure 02_image772
將 化合物 1-B(100.0 mg，0.3 mmol) 溶解於DMF 2 mL中，隨後加入HATU (109.5 mg，0.3 mmol) 和DIPEA (77.4 mg，0.6 mmol)，室溫攪拌10 min，加入化合物 80d(67.0 mg，0.4 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，MPLC純化，得到目標產物(1 S,5 R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(反式-4-嗎啉代環己基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 81(白色固體，100 mg，65.4%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.16 (d, 1H), 8.00 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03 (dd, 1H), 3.96-3.91 (m, 2H), 3.88-3.73 (m, 2H), 3.55 (d, 4H), 2.41 (d, 4H), 2.04 (s, 1H), 1.97 (d, 1H), 1.77 (d, 3H), 1.60 (t, 2H), 1.43 (dd, 3H), 1.23 (s, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.67。 LC-MSm/z (ESI)= 514.3 [M+1]。 [Example 81] (1 S ,5 R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 81 (1 S ,5 R ) or (1 R ,5 S )-3-(8 -cyanoquinolin-5-yl)-N-( cis -4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image770
Figure 02_image772
Compound 1-B (100.0 mg, 0.3 mmol) was dissolved in DMF 2 mL, then HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol) were added, stirred at room temperature for 10 min, compound 80d (67.0 mg, 0.4 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1 S , 5 R ) or (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxamide Compound 81 (white solid, 100 mg, 65.4%). 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.16 (d, 1H), 8.00 (d, 1H), 7.60 (dd, 1H), 7.22 (d , 1H), 4.03 (dd, 1H), 3.96-3.91 (m, 2H), 3.88-3.73 (m, 2H), 3.55 (d, 4H), 2.41 (d, 4H), 2.04 (s, 1H), 1.97 (d, 1H), 1.77 (d, 3H), 1.60 (t, 2H), 1.43 (dd, 3H), 1.23 (s, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.67. LC-MS m/z (ESI) = 514.3 [M+1].

[實施例82] (1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(( R)-嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 82(1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-((( R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image774
Figure 02_image776
[Example 82] ( 1R,5S ) or ( 1S ,5R)-3-(8-cyanoquinolin-5-yl)-N-( (R ) -morpholin-2-yl)methanol Base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 82 (1 R ,5 S )-3-(8-cyanoquinolin-5-yl )-N-((( R )-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image774
Figure 02_image776

第一步：( R)-2-((甲苯氧基)甲基)嗎啉-4-羧酸叔丁酯 82btert-butyl (R)-2-((tosyloxy)methyl)morpholine-4-carboxylate 將化合物 82a(500 mg，2.3 mmol)溶於20 mL DCM中，隨後加入對甲苯磺醯氯(526.5.0 mg，2.76 mmol)、DMAP(562.0 mg，4.6 mmol)、三乙胺(465.5 mg，4.6 mmol)，45 °C回流攪拌2 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化(二氯甲烷：丙酮=20：1)，得到目標產物( R)-2-((甲苯氧基)甲基)嗎啉-4-羧酸叔丁酯 82b(白色固體，743 mg，87.1%)，直接用於下一步。 LC-MSm/z (ESI)= 394.1 [M+23]。 The first step: ( R )-2-((tosyloxy)methyl)morpholine-4-carboxylate 82b tert-butyl (R)-2-((tosyloxy)methyl)morpholine-4-carboxylate Compound 82a (500 mg, 2.3 mmol) was dissolved in 20 mL of DCM, then p-toluenesulfonyl chloride (526.5.0 mg, 2.76 mmol), DMAP (562.0 mg, 4.6 mmol), triethylamine (465.5 mg, 4.6 mmol), stirred at reflux for 2 h at 45 °C. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with water, then washed with 15 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane: acetone = 20: 1) to obtain the target product ( R )-tert-butyl 2-((methylphenoxy)methyl)morpholine-4-carboxylate 82b (white solid, 743 mg, 87.1%) was used directly in the next step. LC-MS m/z (ESI) = 394.1 [M+23].

第二步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 82c(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxamide 將 化合物 1-A(500 mg，1.44 mmol)溶解於DMF 5 mL中，隨後加入HATU(547.9 mg，1.44 mmol)和DIPEA(0.5 mL，2.88 mmol)，室溫攪拌10 min，加入氯化銨(92.4mg，1.73 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，矽膠柱層析純化(二氯甲烷：甲醇=10：1)，得到目標產物(1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 82c(淡黃色固體，423 mg)。直接用於下一步。 LC-MSm/z (ESI)= 347.1 [M+1]。 The second step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-formamide 82c (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] hexane-1-carboxamide Dissolve compound 1-A (500 mg, 1.44 mmol) in 5 mL of DMF, then add HATU (547.9 mg, 1.44 mmol) and DIPEA (0.5 mL, 2.88 mmol), stir at room temperature After 10 min, ammonium chloride (92.4 mg, 1.73 mmol) was added and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated saline, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide 82c (pale yellow solid, 423 mg). used directly in the next step. LC-MS m/z (ESI) = 347.1 [M+1].

第三步：叔丁基( S)-2-((1 R,5S)或(1 R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)嗎啉-4-羧酸酯 82dtert-butyl ( S)-2-(((1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)morpholine-4-carboxylate 將化合物 82b(430.0 mg，1.16 mmol)溶於5 mL乙腈中，加入化合物 82c(200.0 mg，0.58 mmol)和氫氧化鉀(65.0 mg，1.16 mmol)，100 °C攪拌反應2 h。待反應結束，濃縮，乙酸乙酯萃取，無水硫酸鈉乾燥，真空除去溶劑。得到粗產物叔丁基( S)-2-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)嗎啉-4-羧酸酯 82d。直接用於下一步。 LC-MSm/z (ESI)= 546.3 [M+1]。 The third step: tert-butyl ( S )-2-((1 R,5S ) or (1 R,5S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-formamide)methyl)morpholine-4-carboxylate 82d tert-butyl ( S )-2-(((1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)morpholine-4-carboxylate will Compound 82b (430.0 mg, 1.16 mmol) was dissolved in 5 mL of acetonitrile, compound 82c (200.0 mg, 0.58 mmol) and potassium hydroxide (65.0 mg, 1.16 mmol) were added, and the reaction was stirred at 100 °C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude product tert-butyl ( S )-2-(( 1R,5S ) or ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl) -3-azabicyclo[3.1.0]hexane-1-carboxamide)methyl)morpholine-4-carboxylate 82d . used directly in the next step. LC-MS m/z (ESI) = 546.3 [M+1].

第四步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( R)-嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 82(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 82d的粗產品(316.0 mg，0.58 mmol)溶於二氯甲烷10 mL中，加入三氟乙酸(126.0 mg，1.16 mmol)，室溫攪拌2 h。待反應結束，旋乾。MPLC分離(乙腈：水=47：53)，得到目標產物(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( R)-嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 82(黃色固體，141 mg，54.6%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.06-8.98 (m, 1H), 8.92 (s, 1H), 8.64 (d, 1H), 8.51 (t, 1H), 8.18 (d, 1H), 7.61-7.59 (m, 1H), 7.23 (d, 1H), 4.03 – 3.91 (m, 4H), 3.82 (d, 1H), 3.72-3.59 (m, 1H), 3.66-3.59 (m, 1H), 3.26-3.19 (m, 4H), 2.96 (d, 1H), 2.73 (d, 1H), 1.98 (d, 1H), 1.68 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ 64.54。 LC-MSm/z (ESI)= 446.1 [M+1]。 The fourth step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( R )-morpholin-2-yl)methyl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide compound 82 (1 R ,5 S ) / (1 S ,5 R )-3-(8 The crude product of 82d ( 316.0 mg, 0.58 mmol) was dissolved in 10 mL of dichloromethane, added trifluoroacetic acid (126.0 mg, 1.16 mmol), and stirred at room temperature for 2 h. After the reaction is complete, spin dry. MPLC separation (acetonitrile: water = 47:53) to obtain the target product (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( R ) -Morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 82 (yellow solid, 141 mg, 54.6% ). 1 H NMR (400 MHz, DMSO-d6) δ 9.06-8.98 (m, 1H), 8.92 (s, 1H), 8.64 (d, 1H), 8.51 (t, 1H), 8.18 (d, 1H), 7.61 -7.59 (m, 1H), 7.23 (d, 1H), 4.03 – 3.91 (m, 4H), 3.82 (d, 1H), 3.72-3.59 (m, 1H), 3.66-3.59 (m, 1H), 3.26 -3.19 (m, 4H), 2.96 (d, 1H), 2.73 (d, 1H), 1.98 (d, 1H), 1.68 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ 64.54. LC-MS m/z (ESI) = 446.1 [M+1].

[實施例83] (1 S,5R)或(1 R,5S)-3-(8-氰基喹啉-5-基)-N-(( R)-嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 83(1 S,5 R) / (1 R, 5 S)-3-(8-cyanoquinolin-5-yl)-N-((( R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image778
操作同 化合物 82，得到黃色固體 化合物 83。 1 H NMR(400 MHz, DMSO-d6) δ 9.06-8.98 (m, 1H), 8.95 (s, 1H), 8.65-8.59 (m, 1H), 8.50 (t, 1H), 8.18 (d, 1H), 7.63-7.55 (m, 1H), 7.23 (d, 1H), 4.01 – 3.90 (m, 4H), 3.81 (d, 1H), 3.73-3.69 (m, 1H), 3.63-3.58 (m, 1H), 3.27 – 3.08 (m, 4H), 2.95 (d, 1H), 2.74 (t, 1H), 1.98 (d, 1H), 1.68 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ 64.59。 LC-MSm/z (ESI)= 446.1 [M+1]。 [Example 83] ( 1S,5R ) or ( 1R,5S )-3-(8-cyanoquinolin-5-yl)-N-(( R )-morpholin-2-yl)methyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 83 (1 S ,5 R ) / (1 R , 5 S )-3-( 8-cyanoquinolin-5-yl)-N-((( R )-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image778
The operation was the same as that of compound 82 to obtain compound 83 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.06-8.98 (m, 1H), 8.95 (s, 1H), 8.65-8.59 (m, 1H), 8.50 (t, 1H), 8.18 (d, 1H) , 7.63-7.55 (m, 1H), 7.23 (d, 1H), 4.01 – 3.90 (m, 4H), 3.81 (d, 1H), 3.73-3.69 (m, 1H), 3.63-3.58 (m, 1H) , 3.27 – 3.08 (m, 4H), 2.95 (d, 1H), 2.74 (t, 1H), 1.98 (d, 1H), 1.68 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ 64.59. LC-MS m/z (ESI) = 446.1 [M+1].

[實施例84] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 84(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((( S)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image780
操作同 化合物 82，得到黃色固體 化合物 84。 1 H NMR(400 MHz, DMSO-d6) δ 9.09-8.99 (m, 1H), 8.96 (s, 1H), 8.66-8.59 (m, 1H), 8.50 (t, 1H), 8.18 (d, 1H), 7.66-7.56 (m, 1H), 7.23 (d, 1H), 4.01 – 3.93 (m, 4H), 3.81 (d, 1H), 3.77-3.66 (m, 1H), 3.66 – 3.55 (m, 1H), 3.31-3.09 (m, 4H), 2.96 (s, 1H), 2.84-2.67 (m, 1H), 1.98 (d, 1H), 1.68 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ 64.57。 LC-MSm/z (ESI)= 446.1 [M+1]。 [Example 84] ( 1R,5S ) or ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-morpholin-2-yl)methyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 84 (1 R ,5 S ) / (1 S ,5 R )-3-( 8-cyanoquinolin-5-yl)-N-((( S )-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image780
The operation was the same as that of compound 82 to obtain compound 84 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.09-8.99 (m, 1H), 8.96 (s, 1H), 8.66-8.59 (m, 1H), 8.50 (t, 1H), 8.18 (d, 1H) , 7.66-7.56 (m, 1H), 7.23 (d, 1H), 4.01 – 3.93 (m, 4H), 3.81 (d, 1H), 3.77-3.66 (m, 1H), 3.66 – 3.55 (m, 1H) , 3.31-3.09 (m, 4H), 2.96 (s, 1H), 2.84-2.67 (m, 1H), 1.98 (d, 1H), 1.68 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ 64.57. LC-MS m/z (ESI) = 446.1 [M+1].

[實施例85] (1 S,5R)或(1 R,5S)-3-(8-氰基喹啉-5-基)-N-(( S)-嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 85(1 S,5 R) / (1 R, 5 S)-3-(8-cyanoquinolin-5-yl)-N-((( S)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image782
操作同 化合物 82，得到黃色固體 化合物 85。 1 H NMR(400 MHz, DMSO-d6) δ 9.04-8.98 (m, 1H), 8.94 (s, 1H), 8.66-8.59 (m, 1H), 8.51 (t, 1H), 8.18 (d, 1H), 7.64-7.57 (m, 1H), 7.23 (d, 1H), 4.07 – 3.92 (m, 4H), 3.82 (d, 1H), 3.74 – 3.67 (m, 1H), 3.64 – 3.57 (m, 1H), 3.31 – 3.13 (m, 4H), 2.96 (d, 1H), 2.80-2.64 (m, 1H), 1.98 (d, 1H), 1.68 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ 64.55。 LC-MSm/z (ESI)= 446.1 [M+1]。 [Example 85] ( 1S,5R ) or ( 1R,5S )-3-(8-cyanoquinolin-5-yl)-N-(( S )-morpholin-2-yl)methyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 85 (1 S ,5 R ) / (1 R , 5 S )-3-( 8-cyanoquinolin-5-yl)-N-((( S )-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image782
The operation was the same as that of compound 82 to obtain compound 85 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.04-8.98 (m, 1H), 8.94 (s, 1H), 8.66-8.59 (m, 1H), 8.51 (t, 1H), 8.18 (d, 1H) , 7.64-7.57 (m, 1H), 7.23 (d, 1H), 4.07 – 3.92 (m, 4H), 3.82 (d, 1H), 3.74 – 3.67 (m, 1H), 3.64 – 3.57 (m, 1H) , 3.31 – 3.13 (m, 4H), 2.96 (d, 1H), 2.80-2.64 (m, 1H), 1.98 (d, 1H), 1.68 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ 64.55. LC-MS m/z (ESI) = 446.1 [M+1].

[實施例86] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-N-(( S)-4,6,6-三甲基嗎啉-2-基)甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 86(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image784
Figure 02_image786
[Example 86] ( 1R,5S ) or ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(( S )- 4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 86 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo [3.1.0] hexane-1-carboxamide
Figure 02_image784
Figure 02_image786

第一步：叔丁基( S)-6-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-2,2-二甲基嗎啉-4-羧酸酯 86btert-butyl ( S)-6-(((1 R,5 S) / (1 S, 5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-2,2-dimethylmorpholine-4-carboxylate 將 化合物 1-A(347.0 mg，1.0 mmol)溶解於DMF 5 mL中，隨後加入HATU(380.0 mg，1.0 mmol)和DIPEA(258.0 mg，2.0 mmol)，室溫攪拌10 min，加入化合物 86a(334.4 mg，1.0 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾，得到粗產品叔丁基(S)-6-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-2,2-二甲基嗎啉-4-羧酸酯 86b(黃色油狀)。直接用於下一步。 LC-MSm/z (ESI)= 574.3 [M+1]。 The first step: tert-butyl ( S )-6-((1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-formamide)methyl)-2,2-dimethylmorpholine-4-carboxylate 86b tert-butyl ( S )-6- (((1 R ,5 S ) / (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido) methyl)-2,2-dimethylmorpholine-4-carboxylate Dissolve compound 1-A (347.0 mg, 1.0 mmol) in 5 mL of DMF, then add HATU (380.0 mg, 1.0 mmol) and DIPEA (258.0 mg, 2.0 mmol) , stirred at room temperature for 10 min, added compound 86a (334.4 mg, 1.0 mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with 15 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain the crude product tert-butyl (S)-6-(( 1R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide) Methyl)-2,2-dimethylmorpholine-4-carboxylate 86b (yellow oil). used directly in the next step. LC-MS m/z (ESI) = 574.3 [M+1].

第二步：(1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(( R)-6,6-二甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 86c(1 R,5 S)或(1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(((R)-6,6-dimethylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 86b的粗產品溶於二氯甲烷10 mL中，加入三氟乙酸(180.0 mg，2.0 mmol)，室溫攪拌2 h。待反應結束，旋乾。MPLC分離(乙腈：水=47：53)，得到目標產物(1 R,5S)-3-(8-氰基喹啉-5-基)-N-(( R)-6,6-二甲基嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯 86c(黃色油狀，420 mg，88.8%)。直接用於下一步。 LC-MSm/z (ESI)= 474.3 [M+1]。 The second step: (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(( R )-6,6-dimethylmorpholine -2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide 86c (1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(((R)-6,6-dimethylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Dissolve the crude product of 86b in 10 mL of dichloromethane, add trifluoroacetic acid (180.0 mg, 2.0 mmol), and stir at room temperature for 2 h. After the reaction is complete, spin dry. MPLC separation (acetonitrile: water = 47:53) to obtain the target product ( 1R,5S )-3-(8-cyanoquinolin-5-yl)-N-(( R )-6,6-dimethyl Morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formyl 86c (yellow oil, 420 mg, 88.8%) . used directly in the next step. LC-MS m/z (ESI) = 474.3 [M+1].

第三步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-N-((S)-4,6,6-三甲基嗎啉-2-基)甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 86(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 50 mL圓底燒瓶中，將化合物 86c(420.0 mg，0.89 mmol)溶於5 mL甲醇中，室溫下加入多聚甲醛(159.9 mg，1.77 mmol)和氰基硼氫化鈉(223.7 mg，3.56 mmol)，室溫攪拌0.5 h。TLC檢測反應完畢後，將反應液加入30 mL水中，DCM萃取三次，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，MPLC純化，得到目標產物(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-N-(( S)-4,6,6-三甲基嗎啉-2-基)甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 86(黃色固體，272 mg，55.9%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.02-8.99 (m, 1H), 8.66-8.60 (m, 1H), 8.35 (t, 1H), 8.17 (d, 1H), 7.64-7.56 (m, 1H), 7.23 (d, 1H), 4.02 (d, 1H), 3.96-3.90 (m, 2H), 3.82 (d, 1H), 3.72-3.65 (m, 1H), 3.21-3.09 (m, 1H), 3.03-2.98 (m, 1H), 2.65 (d, 1H), 2.49-2.42 (m, 1H), 2.10 (s, 3H), 1.94 (d, 1H), 1.69-1.58 (m, 2H), 1.43 (t, 1H), 1.20 (s, 3H), 1.08 (s, 3H)。 19 F NMR(376 MHz, DMSO-d6) δ 64.42 LC-MSm/z (ESI)= 488.3 [M+1]。 The third step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-((S)-4 ,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 86 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[ 3.1.0] In a 50 mL round bottom flask of hexane-1-carboxamide, compound 86c (420.0 mg, 0.89 mmol) was dissolved in 5 mL of methanol, and paraformaldehyde (159.9 mg, 1.77 mmol) and cyano Sodium borohydride (223.7 mg, 3.56 mmol), stirred at room temperature for 0.5 h. After the reaction was detected by TLC, the reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by MPLC to obtain the target product (1R ,5S ) or ( 1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(( S )-4,6,6-trimethylmorpholine-2 -yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 86 (yellow solid, 272 mg, 55.9%). 1 H NMR (400 MHz, DMSO-d6) δ 9.02-8.99 (m, 1H), 8.66-8.60 (m, 1H), 8.35 (t, 1H), 8.17 (d, 1H), 7.64-7.56 (m, 1H), 7.23 (d, 1H), 4.02 (d, 1H), 3.96-3.90 (m, 2H), 3.82 (d, 1H), 3.72-3.65 (m, 1H), 3.21-3.09 (m, 1H) , 3.03-2.98 (m, 1H), 2.65 (d, 1H), 2.49-2.42 (m, 1H), 2.10 (s, 3H), 1.94 (d, 1H), 1.69-1.58 (m, 2H), 1.43 (t, 1H), 1.20 (s, 3H), 1.08 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ 64.42 LC-MS m/z (ESI) = 488.3 [M+1].

[實施例87] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2-氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 87(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image788
Figure 02_image790
將 化合物 1-A(50.0 mg，0.14 mmol)溶解於DMF 2 mL中，隨後加入HATU(54.8 mg，0.14 mmol)和DIPEA(74.5 mg，0.57 mmol)，室溫攪拌10 min，加入化合物 87a(31.6 mg，0.14 mmol)，室溫攪拌1 h。TLC反應完畢，將反應液加入15 mL水中水洗，飽和食鹽水15 mL洗，有機相用無水硫酸鈉乾燥旋乾MPLC純化，得到目標產物(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2-氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 87(白色固體，22 mg，33.1%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.04-8.96 (m, 1H), 8.68-8.60 (m, 1H), 8.17 (d, 1H), 8.05 (d, 1H), 7.64-7.55 (m, 1H), 7.22 (d, 1H), 4.56 (t, 1H), 4.44 (t, 1H), 4.01 (d, 1H), 3.97-3.91 (m, 2H), 3.82 (d, 1H), 3.65-3.53 (m, 1H), 2.94-2.81 (m, 2H), 2.62-2.56 (m, 2H), 2.10-1.91 (m, 3H), 1.73-1.56 (m, 3H), 1.51-1.34 (m, 2H), 1.00 (s, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ 64.49。 LC-MSm/z (ESI)= 476.3 [M+1]。 [Example 87] (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidine-4 -yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 87 (1 R ,5 S ) / (1 S ,5 R )-3 -(8-cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
Figure 02_image788
Figure 02_image790
Compound 1-A (50.0 mg, 0.14 mmol) was dissolved in DMF 2 mL, then HATU (54.8 mg, 0.14 mmol) and DIPEA (74.5 mg, 0.57 mmol) were added, stirred at room temperature for 10 min, compound 87a (31.6 mg, 0.14 mmol), stirred at room temperature for 1 h. After the TLC reaction was complete, the reaction solution was added to 15 mL of water to wash, followed by 15 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried for MPLC purification to obtain the target product (1R ,5S ) or ( 1S,5R )-3 -(8-cyanoquinoline-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 87 (white solid, 22 mg, 33.1%). 1 H NMR (400 MHz, DMSO-d6) δ 9.04-8.96 (m, 1H), 8.68-8.60 (m, 1H), 8.17 (d, 1H), 8.05 (d, 1H), 7.64-7.55 (m, 1H), 7.22 (d, 1H), 4.56 (t, 1H), 4.44 (t, 1H), 4.01 (d, 1H), 3.97-3.91 (m, 2H), 3.82 (d, 1H), 3.65-3.53 (m, 1H), 2.94-2.81 (m, 2H), 2.62-2.56 (m, 2H), 2.10-1.91 (m, 3H), 1.73-1.56 (m, 3H), 1.51-1.34 (m, 2H) , 1.00 (s, 1H). 19 F NMR (376 MHz, DMSO-d6) δ 64.49. LC-MS m/z (ESI) = 476.3 [M+1].

[實施例88] (1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(( S)-4-(甲基-d3)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 88(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((( S)-4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image792
Figure 02_image794
[Example 88] (1R ,5S ) or ( 1S ,5R)-3-(8- cyanoquinolin -5-yl)-N-(( S )-4-(methyl-d3) Morpholine-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 88 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((( S )-4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3- azabicyclo[3.1.0] hexane-1-carboxamide
Figure 02_image792
Figure 02_image794

第一步：( R)-(4-(甲基-d3)嗎啉-2-基)甲基4-甲基苯磺酸 88b( R)-(4-(methyl-d3)morpholin-2-yl)methyl 4-methylbenzenesulfonate 將化合物 88a(1 g，3.7 mmol)溶解於乙腈20 mL中，隨後加入碳酸鈉 (1.5 g，14.8 mmol)，冰浴降溫，低溫攪拌5 min，緩慢滴加氘帶碘甲烷 (642 mg，4.4 mmol)，低溫攪拌1 h。TLC檢測反應完畢，將矽膠加入反應液中，減壓濃縮，矽膠柱層析純化 (石油醚：乙酸乙酯 = 100：1)，得到中間體( R)-(4-(甲基-d3)嗎啉-2-基)甲基4-甲基苯磺酸 88b(白色固體，200 mg)。 1 H NMR(400 MHz, DMSO- d 6) δ 7.78 (d, 2H), 7.48 (d, 2H), 4.08 – 3.91 (m, 2H), 3.73-3.68 (m, 1H), 3.62-3.56 (m, 1H), 3.44-3.33 (m, 1H), 2.56 (d, 2H), 2.42 (s, 3H), 1.96-1.89 (m, 1H), 1.73 (t, 1H)。 LC-MSm/z (ESI)= 289.2 [M+1]。 The first step: ( R )-(4-(methyl-d3)morpholin-2-yl)methyl 4-methylbenzenesulfonic acid 88b ( R )-(4-(methyl-d3)morpholin-2- yl)methyl 4-methylbenzenesulfonate Dissolve compound 88a (1 g, 3.7 mmol) in 20 mL of acetonitrile, then add sodium carbonate (1.5 g, 14.8 mmol), cool in an ice bath, stir at low temperature for 5 min, slowly add deuterium and iodine Methane (642 mg, 4.4 mmol), stirred at low temperature for 1 h. After the reaction was detected by TLC, silica gel was added to the reaction solution, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain the intermediate ( R )-(4-(methyl-d3) Morpholin-2-yl)methyl 4-methylbenzenesulfonic acid 88b (white solid, 200 mg). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.78 (d, 2H), 7.48 (d, 2H), 4.08 – 3.91 (m, 2H), 3.73-3.68 (m, 1H), 3.62-3.56 (m , 1H), 3.44-3.33 (m, 1H), 2.56 (d, 2H), 2.42 (s, 3H), 1.96-1.89 (m, 1H), 1.73 (t, 1H). LC-MS m/z (ESI) = 289.2 [M+1].

第二步：雙叔丁基( S)-(4-(甲基-D 3)嗎啉-2-基)甲基)氨基甲酸酯 88cDi tert-butyl (S)-(4-(methyl-D 3) morpholine-2-yl) methyl) carbamate 將中間體( R) -(4-(甲基-d3)嗎啉-2-基)甲基4-甲基苯磺酸 88b(200 mg, 0.69mmol)溶於N,N-二甲基甲醯胺 (20 ml)中，隨後加入碳酸銫 (674 mg，2.07mmol)，碘化鈉 (20 mg，0.13mmol)，雙(叔丁氧羰基)胺 (181mg，0.83mmol)，緩慢升溫至90 °C，攪拌2 h。TLC反應完畢，反應液直接濃縮，矽膠柱層析純化 (乙酸乙酯)，得到中間體雙叔丁基( S)-(4-(甲基-d3)嗎啉-2-基)甲基)氨基甲酸酯 88c(白色固體，157 mg)。 LC-MSm/z (ESI)= 334.2[M+1]。 The second step: Di-tert-butyl ( S )-(4-(methyl-D 3 )morpholin-2-yl)methyl)carbamate 88c Di tert-butyl (S)-(4-(methyl -D 3 ) morpholine-2-yl) methyl) carbamate Intermediate ( R ) -(4-(methyl-d3) morpholin-2-yl) methyl 4-methylbenzenesulfonic acid 88b (200 mg, 0.69mmol) was dissolved in N,N-dimethylformamide (20 ml), then cesium carbonate (674 mg, 2.07mmol), sodium iodide (20 mg, 0.13mmol), bis(tert-butoxycarbonyl ) amine (181mg, 0.83mmol), slowly warming up to 90 ° C, stirring for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated, and purified by silica gel column chromatography (ethyl acetate) to obtain the intermediate bis-tert-butyl ( S )-(4-(methyl-d3)morpholin-2-yl)methyl) Carbamate 88c (white solid, 157 mg). LC-MS m/z (ESI) = 334.2 [M+1].

第三步：( S)-(4-(甲基-D 3)嗎啉-2-基)甲醯胺鹽酸鹽 88d( S)-(4-(methyl-d3) morpholine-2-yl) formamide hydrochloride 將雙叔丁基(S)-(4-(甲基-D 3)嗎啉-2-基)甲基)氨基甲酸酯 88c(218 mg, 0.65 mmol)加入5 ml二氧六環氯化氫溶液中，緩慢升溫至55 °C，攪拌2 h。TLC反應完畢，反應液直接濃縮，得到中間體 ( S) -(4-(甲基-d3)嗎啉-2-基)甲醯胺鹽酸鹽 88d(白色固體，157 mg)。 LC-MSm/z (ESI)= 134.2[M+1]。 The third step: ( S )-(4-(methyl-D 3 ) morpholin-2-yl) formamide hydrochloride 88d ( S )-(4-(methyl-d3) morpholine-2-yl) formamide hydrochloride Bis-tert-butyl (S)-(4-(methyl-D 3 )morpholin-2-yl)methyl)carbamate 88c (218 mg, 0.65 mmol) was added to 5 ml of dioxane In hydrogen chloride solution, the temperature was slowly raised to 55 °C, and stirred for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate ( S )-(4-(methyl-d3)morpholin-2-yl)formamide hydrochloride 88d (white solid, 157 mg). LC-MS m/z (ESI) = 134.2 [M+1].

第四步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 88(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1-A(200 mg, 0.59mmol)溶於6 mL二氧六環中，隨後冰浴加入HATU (87 mg, 0.65 mmol)，DIPEA (304 mg, 0.78 mmol)低溫攪拌5 min，然後加入(S) -(4-(甲基-d3)嗎啉-2-基甲醯胺鹽酸鹽 88d，攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4-(甲基-d3)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 88(淡黃色固體，173 mg，72.6%)。 1 H NMR(400 MHz, DMSO-d 6) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.48 (s, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.05 – 3.87 (m, 4H), 3.82 (d, 1H), 3.57 (d, 2H), 3.24-3.15 (m, 2H), 3.15 – 3.04 (m, 3H), 1.98 (d, 1H), 1.72 – 1.64 (m, 1H), 1.23 (s, 1H)。 LC-MSm/z (ESI)= 463.2 [M+1]。 The fourth step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3)morpholine -2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 88 (1 R ,5 S ) / (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0]Hexane-1-carboxamide Compound 1-A (200 mg, 0.59mmol) was dissolved in 6 mL of dioxane, then HATU (87 mg, 0.65 mmol), DIPEA (304 mg, 0.78 mmol) and stirred at low temperature for 5 min, then added (S)-(4-(methyl-d3)morpholin-2-ylformamide hydrochloride 88d , stirred for 0.5 h, the TLC reaction was completed, the reaction solution was directly concentrated, and the reaction Phase C18 column chromatography purification (alkali method) to obtain the target product (1R ,5S ) or ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( S )- 4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide Compound 88 (light yellow solid, 173 mg, 72.6%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (dd, 1H), 8.63 (dd, 1H), 8.48 (s, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.05 – 3.87 (m, 4H), 3.82 (d, 1H), 3.57 (d, 2H), 3.24-3.15 (m, 2H), 3.15 – 3.04 (m, 3H), 1.98 (d, 1H), 1.72 – 1.64 (m, 1H), 1.23 (s, 1H). LC-MS m/z (ESI) = 463.2 [M+1].

[實施例89] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)嗎啉-2-基)甲基-d2)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 89(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((( S)-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image796
Figure 02_image798
[Example 89] (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3) Lin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 89 (1 R ,5 S ) / ( 1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((( S )-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl) -3-azabicyclo [3.1.0] hexane-1-carboxamide
Figure 02_image796
Figure 02_image798

第一步：4-(叔丁基)2-甲基( R)-嗎啉-2,4-二甲酸酯 89b4-(tert-butyl) 2-methyl (R)-morpholine-2,4-dicarboxylate 將化合物 89a(1 g，5.5 mmol)溶解於二氯甲烷20mL中，隨後加入三乙胺(2.2 g，22 mmol)，冰浴降溫，然後加入二碳酸二叔丁酯 (1.4 g，6.6 mmol)，常溫攪拌3 h。TLC檢測反應完畢，將矽膠加入反應液中，減壓濃縮，矽膠柱層析純化 (二氯甲烷：甲醇=140：1)，得到中間體4-(叔丁基)2-甲基( R)-嗎啉-2,4-二甲酸酯 89b(白色固體，1.2 g)。 LC-MSm/z (ESI)= 246.20 [M+1]。 The first step: 4-(tert-butyl) 2-methyl ( R )-morpholine-2,4-dicarboxylate 89b 4-(tert-butyl) 2-methyl (R)-morpholine-2,4 -dicarboxylate Dissolve compound 89a (1 g, 5.5 mmol) in 20 mL of dichloromethane, then add triethylamine (2.2 g, 22 mmol), cool in an ice bath, then add di-tert-butyl dicarbonate (1.4 g, 6.6 mmol), stirred at room temperature for 3 h. The completion of the reaction was detected by TLC, silica gel was added to the reaction solution, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol=140:1) to obtain the intermediate 4-(tert-butyl)2-methyl ( R ) -Morpholine-2,4-dicarboxylate 89b (white solid, 1.2 g). LC-MS m/z (ESI) = 246.20 [M+1].

第二步：( R)-(4-(甲基-D 3)嗎啉-2-基)甲烷-D 2-醇化合物 89c( R)-(4-(methyl-D 3)morpholin-2-yl)methan-D 2-ol 將中間體4-(叔丁基)2-甲基( R)-嗎啉-2,4-二甲酸酯 89b(1.2 g, 4.9 mmol)溶於10 ml四氫呋喃中，隨後加入氘帶鋁鋰氫 (823 mg, 19.6 mmol)，緩慢升溫至60 °C，攪拌1 h。TLC反應完畢，隨後加入500 ml水，1 ml 10%氫氧化鈉水溶液，1.5 ml水攪拌，有固體析出，用矽藻土過濾，濾液濃縮至幹得到中間體( R) -(4-(甲基-d3)嗎啉-2-基)甲烷-D 2-醇 89c(黃色固體，642 mg)。 1 H NMR(400 MHz, DMSO-D 6) δ 4.61 (s, 1H), 3.73 (ddd, 1H), 3.45 (td, 1H), 3.38 (dd, 1H), 2.68 (m, 1H), 2.55 (m, 1H), 1.91 (m, 1H), 1.66 (dd, 1H)。 LC-MSm/z (ESI)= 137[M+1]。 The second step: ( R )-(4-(methyl-D 3 )morpholin-2-yl)methane-D 2 -alcohol compound 89c ( R )-(4-(methyl-D 3 )morpholin-2- yl)methan-D 2 -ol The intermediate 4-(tert-butyl)2-methyl( R )-morpholine-2,4-dicarboxylate 89b (1.2 g, 4.9 mmol) was dissolved in 10 ml THF , then added deuterium-banded aluminum lithium hydrogen (823 mg, 19.6 mmol), slowly warming up to 60 ° C, and stirring for 1 h. After the TLC reaction was completed, 500 ml of water, 1 ml of 10% aqueous sodium hydroxide solution, and 1.5 ml of water were added and stirred. Solids were precipitated, filtered with diatomaceous earth, and the filtrate was concentrated to dryness to obtain intermediate ( R )-(4-(formyl yl-d3)morpholin- 2 -yl)methane-D2-ol 89c (yellow solid, 642 mg). 1 H NMR (400 MHz, DMSO-D 6 ) δ 4.61 (s, 1H), 3.73 (ddd, 1H), 3.45 (td, 1H), 3.38 (dd, 1H), 2.68 (m, 1H), 2.55 ( m, 1H), 1.91 (m, 1H), 1.66 (dd, 1H). LC-MS m/z (ESI) = 137 [M+1].

第三步：( R)-(4-(甲基-D 3)嗎啉-2-基)甲基-D 24-甲基苯磺酸鹽 89d( R)-(4-(methyl-d3)morpholin-2-yl)methyl-d2 4-methylbenzenesulfonate 將 89c加入6 ml二氯甲烷中，然後加入三乙胺 (949 mg, 9.4 mmol)，對甲苯磺醯氯 (1 g, 5.6 mmol)，N,N-二甲基吡啶 (57 mg, 0.47 mmol)常溫攪拌2 h。TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物得到中間體( R)-(4-(甲基-D 3)嗎啉-2-基)甲基-D 24-甲基苯磺酸鹽 89d(白色固體，900 mg)。 1 H NMR(400 MHz, DMSO-d 6) δ 7.81 – 7.75 (m, 2H), 7.48 (d, 2H), 3.69 (ddd, 1H), 3.58 (dd, 1H), 3.41 (td, 1H), 2.58 – 2.51 (m, 1H), 2.50 (s, 1H), 2.42 (s, 3H), 1.90 (td, 1H), 1.69 (dd, 1H)。 LC-MSm/z (ESI)= 291.2[M+1]。 The third step: ( R )-(4-(methyl-D 3 )morpholin-2-yl)methyl-D 2 4-methylbenzenesulfonate 89d ( R )-(4-(methyl-d3 )morpholin-2-yl)methyl-d2 4-methylbenzenesulfonate Add 89c to 6 ml of dichloromethane, then add triethylamine (949 mg, 9.4 mmol), p-toluenesulfonyl chloride (1 g, 5.6 mmol), N , N-lutidine (57 mg, 0.47 mmol) and stirred at room temperature for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated, purified by reverse phase C18 column chromatography (alkali method), and the target product was obtained to obtain the intermediate ( R )-(4-(methyl-D 3 )morpholin-2-yl)methyl -D 2 4- Methylbenzenesulfonate 89d (white solid, 900 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.81 – 7.75 (m, 2H), 7.48 (d, 2H), 3.69 (ddd, 1H), 3.58 (dd, 1H), 3.41 (td, 1H), 2.58 – 2.51 (m, 1H), 2.50 (s, 1H), 2.42 (s, 3H), 1.90 (td, 1H), 1.69 (dd, 1H). LC-MS m/z (ESI) = 291.2 [M+1].

第四步：叔丁基( S)-(4-(甲基-D 3)嗎啉-2-基)甲基-D 2)氨基甲酸酯 89etert-butyl ( S)-(4-(methyl-d3) morpholine-2-yl) methyl-d2) carbamate 將 89d(900 mg, 3.1 mmol)溶於6 ml N,N-二甲基甲醯胺中，隨後加入碳酸銫 (3 g，9.3 mmol)，碘化鈉 (93 mg,0.62 mmol)，雙(叔丁氧羰基)胺 (808 mg,3.7 mmol)，緩慢升溫至90 °C，攪拌4 h。TLC反應完畢，反應液直接濃縮，矽膠柱層析純化 (二氯甲烷：甲醇=100:1~20:1)，得到中間體雙叔丁基( S)-(4-(甲基-D 3)嗎啉-2-基)甲基-D 2)氨基甲酸酯 89e(白色固體，370 mg)。 1 H NMR(400 MHz, DMSO-d 6) δ 6.83 (s, 1H), 3.73 (ddd, 1H), 3.48 – 3.34 (m, 2H), 2.58 (m, 2H), 1.91 (td, 1H), 1.61 (t, 1H), 1.37 (s, 9H)。 LC-MSm/z (ESI)= 236.2[M+1]。 The fourth step: tert-butyl ( S )-(4-(methyl-D 3 ) morpholin-2-yl) methyl-D 2 ) carbamate 89e tert-butyl ( S )-(4-( methyl-d3) morpholine-2-yl) methyl-d2) carbamate 89d (900 mg, 3.1 mmol) was dissolved in 6 ml N,N-dimethylformamide, followed by the addition of cesium carbonate (3 g, 9.3 mmol ), sodium iodide (93 mg, 0.62 mmol), bis(tert-butoxycarbonyl)amine (808 mg, 3.7 mmol), slowly warming up to 90 °C, and stirring for 4 h. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by silica gel column chromatography (dichloromethane:methanol=100:1~20:1) to obtain the intermediate bis-tert-butyl ( S )-(4-(methyl-D 3 )morpholin- 2 -yl)methyl-D2)carbamate 89e (white solid, 370 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.83 (s, 1H), 3.73 (ddd, 1H), 3.48 – 3.34 (m, 2H), 2.58 (m, 2H), 1.91 (td, 1H), 1.61 (t, 1H), 1.37 (s, 9H). LC-MS m/z (ESI) = 236.2 [M+1].

第五步：( S)-(4-(甲基-D 3)嗎啉-2-基)甲烷-D 2-胺 89f( S)-(4-(methyl-D 3)morpholin-2-yl)methan-d2-amine 將雙叔丁基(S)-(4-(甲基-D 3)嗎啉-2-基)甲基-D 2)氨基甲酸酯 89e(370 mg, 1.1 mmol)加入6 ml二氧六環氯化氫溶液中，緩慢升溫至55 °C，攪拌2 h。TLC反應完畢，反應液直接濃縮，得到中間體( S) -(4-(甲基-D 3)嗎啉-2-基)甲烷-D 2-胺 89f(白色固體，粗品)。 1 H NMR(400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.24 (s, 3H), 4.16 (dd, 1H), 4.06 (dd, 1H), 3.88 (td, 1H), 3.43 – 3.34 (m, 2H), 3.04 (d, 1H), 2.92 – 2.80 (m, 1H)。 LC-MSm/z (ESI)= 136.2[M+1]。 The fifth step: ( S )-(4-(methyl-D 3 )morpholin-2-yl)methane-D 2 -amine 89f ( S )-(4-(methyl-D 3 )morpholin-2-yl )methan-d2-amine Bis-tert-butyl (S)-(4-(methyl-D 3 )morpholin-2-yl)methyl-D 2 )carbamate 89e (370 mg, 1.1 mmol) Add 6 ml of dioxane hydrogen chloride solution, slowly warm up to 55 °C, and stir for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate ( S )-(4-(methyl-D 3 )morpholin-2-yl)methane-D 2 -amine 89f (white solid, crude product). 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.24 (s, 3H), 4.16 (dd, 1H), 4.06 (dd, 1H), 3.88 (td, 1H), 3.43 – 3.34 (m, 2H), 3.04 (d, 1H), 2.92 – 2.80 (m, 1H). LC-MS m/z (ESI) = 136.2 [M+1].

第六步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4-(甲基-d3)嗎啉-2-基)甲基-d2)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 89(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((( S)-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1-A(200 mg, 0.5 mmol)溶於6 mL二氧六環中，隨後冰浴加入HATU (269 mg, 0.63 mmol)，DIPEA (304 mg, 0.78 mmol)低溫攪拌5 min，然後加入(S) -(4-(甲基-D 3)嗎啉-2-基)甲烷-D 2-胺 89f(85 mg, 0.63 mmol) ，攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4-(甲基-d3)嗎啉-2-基)甲基-d2)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 89(淡黃色固體，60 mg，43.2%)。 1 H NMR(400 MHz, DMSO-d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.35 (s, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.04 – 3.88 (m, 3H), 3.81 (d, 1H), 3.75 (ddd, 1H), 3.44 (ddd, 2.4 Hz, 2H), 2.63 (dt, 1H), 2.60 – 2.52 (m, 1H), 2.01 – 1.87 (m, 2H), 1.70 – 1.59 (m, 2H)。 19 F NMR(376 MHz, DMSO-d 6) δ -63.50 LC-MSm/z (ESI)= 465.3 [M+1]。 The sixth step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-4-(methyl-d3)morpholine -2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 89 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((( S )-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 1-A (200 mg, 0.5 mmol) was dissolved in 6 mL of dioxane, then HATU (269 mg, 0.63 mmol) was added in ice bath, DIPEA ( 304 mg, 0.78 mmol) stirred at low temperature for 5 min, then added (S) -(4-(methyl-D 3 )morpholin-2-yl)methane-D 2 -amine 89f (85 mg, 0.63 mmol), stirred After 0.5 h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product ( 1R,5S ) or ( 1S,5R )-3-(8-cyanoquinoline -5-yl)-N-(( S )-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 89 (pale yellow solid, 60 mg, 43.2%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.35 (s, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 ( d, 1H), 4.04 – 3.88 (m, 3H), 3.81 (d, 1H), 3.75 (ddd, 1H), 3.44 (ddd, 2.4 Hz, 2H), 2.63 (dt, 1H), 2.60 – 2.52 (m , 1H), 2.01 – 1.87 (m, 2H), 1.70 – 1.59 (m, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -63.50 LC-MS m/z (ESI) = 465.3 [M+1].

[實施例90] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 90(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image800
Figure 02_image802
將(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 1-A(100 mg, 0.28 mmol)溶於6 mL二氧六環中，隨後冰浴加入HATU (127 mg, 0.31 mmol)，DIPEA (144 mg, 1.12 mmol)低溫攪拌5 min，然後加入1-(2,2,2-三氟乙基)哌啶-4-胺 90a(57.6 mg, 0.3 mmol) ，攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 90(淡黃色固體，50 mg，47.8%)。 1 H NMR(400 MHz, DMSO) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 8.04 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.04 – 3.89 (m, 3H), 3.82 (d, 1H), 3.68 – 3.55 (m, 1H), 3.14 (q, 2H), 2.93 – 2.83 (m, 2H), 2.44 – 2.32 (m, 2H), 1.99 (d, 1H), 1.65 (dd, 3H), 1.50-1.39 (m, 2H)。 19 F NMR(376 MHz, DMSO-d 6) δ -63.60, -68.14。 LC-MSm/z (ESI)= 512.3 [M+1]。 [Example 90] (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl )piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 90 (1 R ,5 S ) / (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]Hexane-1-carboxamide
Figure 02_image800
Figure 02_image802
(1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxylic acid Compound 1-A (100 mg, 0.28 mmol) was dissolved in 6 mL of dioxane, then HATU (127 mg, 0.31 mmol) was added in ice bath, DIPEA (144 mg, 1.12 mmol) was stirred at low temperature 5 min, then added 1-(2,2,2-trifluoroethyl)piperidin-4-amine 90a (57.6 mg, 0.3 mmol), stirred for 0.5 h, TLC reaction was completed, the reaction solution was directly concentrated, reversed phase C18 Purified by column chromatography (alkaline method) to obtain the target product (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2 , 2-trifluoroethyl) piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 90 (pale yellow solid, 50 mg, 47.8%). 1 H NMR (400 MHz, DMSO) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 8.04 (d, 1H), 7.60 (dd, 1H), 7.22 (d, 1H ), 4.04 – 3.89 (m, 3H), 3.82 (d, 1H), 3.68 – 3.55 (m, 1H), 3.14 (q, 2H), 2.93 – 2.83 (m, 2H), 2.44 – 2.32 (m, 2H ), 1.99 (d, 1H), 1.65 (dd, 3H), 1.50-1.39 (m, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -63.60, -68.14. LC-MS m/z (ESI) = 512.3 [M+1].

[實施例91] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟-1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 91(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image804
Figure 02_image806
[Example 91] (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(4-fluoro-1-methylpiperidine-4- Base) methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 91 (1 R ,5 S ) / (1 S ,5 R ) -3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide
Figure 02_image804
Figure 02_image806

第一步：叔丁基4-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4-氟哌啶-1-羧酸酯 91b(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl) methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將 化合物 1-A(150 mg, 0.43 mmol)溶於6 mL二氧六環中，隨後冰浴加入HATU (196 mg, 0.51 mmol)，DIPEA (166 mg, 1.29 mmol)低溫攪拌5 min，然後加入4-(氨基甲基)-4-氟哌啶-1-羧酸叔丁酯 91a(110 mg, 0.647 mmol) ，攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物叔丁基4-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4-氟哌啶-1-羧酸酯 91b(淡黃色固體，250 mg，87%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.47 (t, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.05 – 3.90 (m, 3H), 3.84 (d, 1H), 3.73 (d, 2H), 3.41 – 3.35 (m, 1H), 2.93 (d, 2H), 1.97 (d, 2H), 1.71 – 1.48 (m, 5H), 1.38 (s, 9H)。 LC-MSm/z (ESI)= 562.2 [M+1]。 The first step: tert-butyl 4-((1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate 91b (1 R ,5 S ) / (1 S ,5 R )-3 -(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide will Compound 1-A (150 mg, 0.43 mmol) was dissolved in 6 mL of dioxane, then HATU (196 mg, 0.51 mmol) was added in ice bath, DIPEA (166 mg, 1.29 mmol) was stirred at low temperature for 5 min, and then 4 -(Aminomethyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester 91a (110 mg, 0.647 mmol), stirred for 0.5 h, TLC reaction was completed, the reaction solution was concentrated directly, and purified by reverse phase C18 column chromatography ( Alkali method) to obtain the target product tert-butyl 4-((1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate 91b (pale yellow solid, 250 mg, 87%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.47 (t, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.05 – 3.90 (m, 3H), 3.84 (d, 1H), 3.73 (d, 2H), 3.41 – 3.35 (m, 1H), 2.93 (d, 2H), 1.97 (d, 2H) , 1.71 – 1.48 (m, 5H), 1.38 (s, 9H). LC-MS m/z (ESI) = 562.2 [M+1].

第二步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺鹽酸鹽 91c(1 R, 5 S) / (1 S, 5 R) -3-(8-cyanoquinoline-5-yl) -N-(4-fluoropiperidine-4-yl) methyl) -5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-formamide hydrochloride 將叔丁基4-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4-氟哌啶-1-羧酸酯 91b(250 mg, 0.44 mmol)加入10 ml二氧六環氯化氫溶液中，緩慢升溫至55 °C，攪拌1 h。TLC反應完畢，反應液直接濃縮，得到中間體(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺鹽酸鹽 91c(白色固體，110 mg)。 LC-MSm/z (ESI)= 462.20[M+1]。 The second step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(4-fluoropiperidin-4-yl)methyl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide hydrochloride 91c (1 R , 5 S ) / (1 S , 5 R ) -3-( 8-cyanoquinoline-5-yl) -N-(4-fluoropiperidine-4-yl) methyl) -5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-formamide hydrochloride tert-butyl 4-( (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-formamido)methyl)-4-fluoropiperidine-1-carboxylate 91b (250 mg, 0.44 mmol) was added into 10 ml of dioxane hydrogen chloride solution, slowly warmed up to 55 °C, stirred for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(4-fluoropiperidine- 4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 91c (white solid, 110 mg). LC-MS m/z (ESI) = 462.20 [M+1].

第三步：叔丁基4-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4-氟哌啶-1-羧酸酯 化合物 91(1 R,5 S) / (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl) methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將(1 R,5S) 或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺鹽酸鹽 91c(25 mg, 0.26 mmol)，溶於6 mL甲醇中，隨後加入三乙胺100 μL，多聚甲醛 (64 mg, 0.78 mmol), 氰基硼氫化鈉 (20 mg, 0.52 mmol)逐步升溫至65 °C攪拌4 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物叔丁基4-((1 R,5S) 或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)甲基)-4-氟哌啶-1-羧酸酯 化合物 91(淡黃色固體，47 mg，76%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.43 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.24 (d, 1H), 4.00 (q, 2H), 3.92 (d, 1H), 3.84 (d, 1H), 3.42 – 3.36 (m, 1H), 3.31 (d, 1H), 2.56 – 2.50 (m, 2H), 2.15 (s, 3H), 2.09 (t, 2H), 1.97 (d, 1H), 1.72 – 1.61 (m, 4H), 1.60 – 1.50 (m, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.51。 LC-MSm/z (ESI)= 476.20[M+1]。 The third step: tert-butyl 4-((1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate compound 91 (1 R ,5 S ) / (1S,5R)-3- (8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide will ( 1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(4-fluoropiperidin-4-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 91c (25 mg, 0.26 mmol), dissolved in 6 mL of methanol, then added 100 μL of triethylamine, more Polyoxymethylene (64 mg, 0.78 mmol), sodium cyanoborohydride (20 mg, 0.52 mmol) was gradually heated to 65 °C and stirred for 4 h. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkali method), to obtain the target product tert-butyl 4-((1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate Compound 91 (pale yellow solid, 47 mg, 76%). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.43 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.24 (d , 1H), 4.00 (q, 2H), 3.92 (d, 1H), 3.84 (d, 1H), 3.42 – 3.36 (m, 1H), 3.31 (d, 1H), 2.56 – 2.50 (m, 2H), 2.15 (s, 3H), 2.09 (t, 2H), 1.97 (d, 1H), 1.72 – 1.61 (m, 4H), 1.60 – 1.50 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.51. LC-MS m/z (ESI) = 476.20 [M+1].

[實施例92] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4,4-二氟-1-甲基哌啶-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 92(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-(( S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image808
Figure 02_image810
[Example 92] ( 1R,5S ) or ( 1S ,5R)-3-(8-cyanoquinolin-5-yl)-N-(( S )-4,4-difluoro-1 -Methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 92 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] hexane-1-carboxamide
Figure 02_image808
Figure 02_image810

第一步：叔丁基( S)-3-((1R,5 S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)-4,4-二氟哌啶-1-羧酸鹽 92btert-butyl( S)-3-((1 R,5 S)或(1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamido)-4,4-difluoropiperidine-1-carboxylate 將(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 1-A(150 mg, 0.43 mmol)溶於6 mL二氧六環中，隨後冰浴加入HATU (196 mg, 0.51 mmol)，DIPEA (166 mg, 1.29 mmol)低溫攪拌5 min，然後加入(S)-3-氨基-4,4-二氟哌啶-1-羧酸叔丁酯 92a(110 mg, 0.647 mmol)，攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物叔丁基(S)-3-((1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)-4,4-二氟哌啶-1-羧酸鹽 92b(淡黃色固體，250 mg，87%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.65 (dd, 1H), 8.40 (d, 1H), 8.17 (d, 1H), 7.62-7.58 (m, 1H), 7.24 (d, 1H), 4.24 (s, 1H), 4.112-4.10(m, 1H), 4.03-3.98 (m, 2H), 3.96 – 3.85 (m, 2H), 3.70 (s, 1H), 3.16 (d, 2H), 2.18 (d, 1H), 2.07 – 1.90 (m, 2H), 1.69 (d, 1H), 1.36 (s, 9H)。 LC-MSm/z (ESI)= 566.2 [M+1]。 The first step: tert-butyl ( S )-3-((1R, 5S ) or (1S ,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-formamide)-4,4-difluoropiperidine-1-carboxylate 92b tert-butyl( S )-3-((1 R ,5 S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamido)-4,4- Difluoropiperidine-1-carboxylate will (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxylic acid Compound 1-A (150 mg, 0.43 mmol) was dissolved in 6 mL of dioxane, then HATU (196 mg, 0.51 mmol), DIPEA (166 mg, 1.29 mmol) and stirred at low temperature for 5 min, then added (S)-3-amino-4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester 92a (110 mg, 0.647 mmol), stirred for 0.5 h, and the TLC reaction was complete , the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product tert-butyl (S)-3-((1 R,5S ) or (1 S,5R )-3-(8- Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)-4,4-difluoropiperidine-1- Carboxylate 92b (pale yellow solid, 250 mg, 87%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.65 (dd, 1H), 8.40 (d, 1H), 8.17 (d, 1H), 7.62-7.58 (m, 1H), 7.24 (d, 1H), 4.24 (s, 1H), 4.112-4.10(m, 1H), 4.03-3.98 (m, 2H), 3.96 – 3.85 (m, 2H), 3.70 (s, 1H), 3.16 ( d, 2H), 2.18 (d, 1H), 2.07 – 1.90 (m, 2H), 1.69 (d, 1H), 1.36 (s, 9H). LC-MS m/z (ESI) = 566.2 [M+1].

第二步：(1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4,4-二氟哌啶-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺鹽酸鹽 92c(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinoline-5-yl)-N-((s)-4,4-difluoropyridine-3-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-formamide hydrochloride 將叔丁基( S)-3-((1 R,5S) 或(1 S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺)-4,4-二氟哌啶-1-羧酸鹽 92b(194 mg, 0.43 mmol)加入10 ml 二氧六環氯化氫溶液中，緩慢升溫至55 °C，攪拌1 h。TLC反應完畢，反應液直接濃縮，得到中間體 (1 R,5S) 或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4,4-二氟哌啶-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺鹽酸鹽 92c(白色固體，110 mg)。 LC-MSm/z (ESI)= 466.20[M+1]。 The second step: (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-4,4-difluoropiperidine-3 -yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide hydrochloride 92c (1 R ,5 S ) / (1 S ,5 R ) -3-(8-cyanoquinoline-5-yl)-N-((s)-4,4-difluoropyridine-3-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-formamide Hydrochloride tert-butyl ( S )-3-((1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide)-4,4-difluoropiperidine-1-carboxylate 92b (194 mg, 0.43 mmol) was added to 10 ml dioxane hydrogen chloride solution, slowly warming up to 55 °C and stirring for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate ( 1R,5S ) or ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-4, 4-Difluoropiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 92c (white solid, 110 mg) . LC-MS m/z (ESI) = 466.20 [M+1].

第三步：(1 R,5 S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟-1-甲基哌啶-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 92(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將(1 R,5S) 或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟哌啶-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺鹽酸鹽 92c(150 mg, 0.32 mmol)，溶於6 mL甲醇中，隨後加入三乙胺100 µL，多聚甲醛 (60 mg, 0.64 mmol), 氰基硼氫化鈉 (50 mg, 1.28 mmol)逐步升溫至65 °C攪拌4 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物(1 R,5S) 或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(( S)-4,4-二氟-1-甲基哌啶-3-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 92(淡黃色固體，44 mg，34%)。 1 H NMR(400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.31 (m, 1H), 4.05 (d, 1H), 4.01 – 3.84 (m, 3H), 2.71 – 2.55 (m, 2H), 2.21 (s, 3H), 2.20 – 1.92 (m, 5H), 1.65 (d, 1H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.95, -102.84, -103.46。 LC-MSm/z (ESI)= 480.30[M+1]。 The third step: (1 R ,5 S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1- Methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 92 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]hexane-1-carboxamide will (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-di Haloperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 92c (150 mg, 0.32 mmol), dissolved in In 6 mL of methanol, 100 µL of triethylamine, paraformaldehyde (60 mg, 0.64 mmol), and sodium cyanoborohydride (50 mg, 1.28 mmol) were added gradually to 65 °C and stirred for 4 h, and the TLC reaction was completed. The reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N -(( S )-4,4-Difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-methanol Amide Compound 92 (pale yellow solid, 44 mg, 34%). 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, 1H), 8.64 (dd, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 (d , 1H), 4.31 (m, 1H), 4.05 (d, 1H), 4.01 – 3.84 (m, 3H), 2.71 – 2.55 (m, 2H), 2.21 (s, 3H), 2.20 – 1.92 (m, 5H ), 1.65 (d, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -63.95, -102.84, -103.46. LC-MS m/z (ESI) = 480.30 [M+1].

[實施例93] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-N-(4-羥基-1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 93(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl) methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image812
Figure 02_image814
[Example 93] (1 R,5S ) or (1 S,5R )-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxy-1-methylpiperidine-4- Base)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 93 (1 R ,5 S ) / (1 S ,5 R ) -3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide
Figure 02_image812
Figure 02_image814

第一步：(1-(叔丁氧羰基)-4-羥基哌啶-4-基)甲基(1 S,5R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 93b(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl (1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 將(1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 化合物 1-A(150 mg, 0.43 mmol)溶於6 mL二氧六環中，隨後冰浴加入HATU (196 mg, 0.51 mmol)，DIPEA (166 mg, 1.29 mmol)低溫攪拌5分鐘，然後加入4-(氨基甲基)-4-羥基哌啶-1-羧酸叔丁酯 93a(109 mg, 0.47 mmol) ，攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物(1-(叔丁氧羰基)-4-羥基哌啶4-基)甲基(1 S,5R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸酯 93b(淡黃色固體，130 mg，76%)。 LC-MSm/z (ESI)= 560.2 [M+1]。 The first step: (1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl (1 S,5R ) or (1 R ,5 S )-3-(8-cyanoquinoline -5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 93b (1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl )methyl (1 S ,5 R ) / (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate will (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxylic acid Compound 1-A (150 mg, 0.43 mmol) was dissolved in 6 mL of dioxane, then HATU (196 mg, 0.51 mmol) was added in ice bath, DIPEA (166 mg, 1.29 mmol) was stirred at low temperature 5 minutes, then added tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate 93a (109 mg, 0.47 mmol), stirred for 0.5 h, TLC reaction was completed, the reaction solution was directly concentrated, reversed phase Purification by C18 column chromatography (alkali method) to obtain the target product (1-(tert-butoxycarbonyl)-4-hydroxypiperidin 4-yl)methyl (1 S,5R ) or (1 R ,5 S )-3 -(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 93b (pale yellow solid, 130 mg, 76%). LC-MS m/z (ESI) = 560.2 [M+1].

第二步：(1 S,5R)或(1 R,5S)-3-(8-氰基喹啉-5-基)-N-(4-羥基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 鹽酸鹽 93c(1 S, 5 R) / (1 R, 5 S)-3-(8-cyanoquinoline-5-yl)-N-(4-hydroxypiperidine-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-formamide hydrochloride 將 93b(130 mg, 0.23 mmol)加入10 ml 二氧六環氯化氫溶液中，緩慢升溫至55 °C，攪拌1 h。TLC反應完畢，反應液直接濃縮，得到中間體 (1 S,5R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(4-羥基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 鹽酸鹽 93c(白色固體，197 mg)。 LC-MSm/z (ESI)= 460.20[M+1]。 The second step: (1 S,5R ) or (1 R ,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxypiperidin-4-yl)methyl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide hydrochloride 93c (1 S , 5 R ) / (1 R , 5 S )-3-( 8-cyanoquinoline-5-yl)-N-(4-hydroxypiperidine-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] hexane-1-formamide hydrochloride 93b (130 mg, 0.23 mmol) was added to 10 ml of dioxane hydrogen chloride solution, the temperature was slowly raised to 55 °C, and stirred for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate (1 S,5R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxypiperidine -4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 93c (white solid, 197 mg). LC-MS m/z (ESI) = 460.20 [M+1].

第三步：(1 S,5R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(4-羥基-1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 93(1 S,5 R) / (1 R,5 S)-3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將(1 S,5R)或(1 R,5 S)-3-(8-氰基喹啉-5-基)-N-(4-羥基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 鹽酸鹽 93c(197 mg, 0.43 mmol)，溶於6 mL甲醇中，隨後加入三乙胺100 μL，多聚甲醛 (58 mg, 0.64 mmol), 氰基硼氫化鈉 (49 mg, 1.29 mmol)逐步升溫至65 °C攪拌4 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目标产物 化合物 93(淡黄色固体，80 mg，73%)。 1 H NMR(400 MHz, DMSO- d 6) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.07 (t, 1H), 7.61 (dd, 1H), 7.24 (d, 1H), 4.30 (s, 1H), 3.99 (s, 2H), 3.92 (d, 1H), 3.84 (d, 1H), 3.12 (t, 2H), 2.42 – 2.29 (m, 2H), 2.20 (m, 2H), 1.94 (d, 1H), 1.64 (d, 1H), 1.54 – 1.32 (m, 4H)。 19 F NMR(376 MHz, DMSO- d 6) δ -63.45。 LC-MSm/z (ESI)= 474.20[M+1]。 The third step: (1 S,5R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxy-1-methylpiperidine-4- Base) methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 93 (1 S ,5 R ) / (1 R ,5 S ) -3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carboxamide will (1 S,5R ) or (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxypiperidin-4-yl)methyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 93c (197 mg, 0.43 mmol), dissolved in 6 mL of methanol, followed by addition of triethylamine 100 μL, paraformaldehyde (58 mg, 0.64 mmol), sodium cyanoborohydride (49 mg, 1.29 mmol) was gradually heated to 65 °C and stirred for 4 h, the reaction was completed by TLC, the reaction solution was directly concentrated, reversed-phase C18 column Purification by analysis (alkali method) gave the target product Compound 93 (pale yellow solid, 80 mg, 73%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.01 (dd, 1H), 8.64 (dd, 1H), 8.17 (d, 1H), 8.07 (t, 1H), 7.61 (dd, 1H), 7.24 ( d, 1H), 4.30 (s, 1H), 3.99 (s, 2H), 3.92 (d, 1H), 3.84 (d, 1H), 3.12 (t, 2H), 2.42 – 2.29 (m, 2H), 2.20 (m, 2H), 1.94 (d, 1H), 1.64 (d, 1H), 1.54 – 1.32 (m, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.45. LC-MS m/z (ESI) = 474.20 [M+1].

[實施例94] (1 R,5S)或(1 S,5R)-3-(8-氰基喹啉-5-基)-氮-(( S)-4-(環丙基甲基)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 94(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((( S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure 02_image816
Figure 02_image818
[Example 94] ( 1R,5S ) or ( 1S,5R )-3-(8-cyanoquinolin-5-yl)-nitrogen-(( S )-4-(cyclopropylmethyl) Morpholine-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 94 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((( S )-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] hexane-1-carboxamide
Figure 02_image816
Figure 02_image818

第一步：( R)-嗎啉-2-基甲醇 鹽酸鹽 94b( R)-morpholine-2-yl methanol hydrochloride 將( R)-2-(羥甲基)嗎啉-4-羧酸叔丁酯 94a(2 g, 9.2 mmol)溶於20 mL鹽酸二氧六環中，緩慢升溫至55 °C，攪拌1 h。TLC反應完畢，反應液直接濃縮，得到中間體 ( R) -嗎啉-2-基甲醇 鹽酸鹽 94b(白色固體，110 mg)。 LC-MS m/z (ESI)= 118.20[M+1]。 The first step: ( R )-morpholine-2-ylmethanol hydrochloride 94b ( R )-morpholine-2-yl methanol hydrochloride ( R )-2-(hydroxymethyl) morpholine-4-carboxylic acid Butyl ester 94a (2 g, 9.2 mmol) was dissolved in 20 mL of dioxane hydrochloride, slowly heated to 55 °C, and stirred for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate ( R )-morpholin-2-ylmethanol hydrochloride 94b (white solid, 110 mg). LC-MS m/z (ESI) = 118.20 [M+1].

第二步：叔丁基( R)-2-(羥甲基)嗎啉-4-羧酸酯(R)-(4-(環丙基甲基)嗎啉-2-基)甲醇 94c( R)-(4-(cyclopropylmethyl)morpholin-2-yl)methanol 將化合物 94b(500 mg，4.2 mmol)溶解於N,N-二甲基甲醯胺20mL中，隨後加入三乙胺 (1.27 g，12.6 mmol)，然後加入環丙甲基溴 (692 mg, 5.1 mmol)，緩慢升溫至55°C攪拌3 h。TLC檢測反應完畢，減壓濃縮，得到中間體叔丁基( R)-2-(羥甲基)嗎啉-4-羧酸酯( R)-(4-(環丙基甲基)嗎啉-2-基)甲醇 94c(無色油狀物，510 mg)。 LC-MSm/z (ESI)= 172.2 [M+1]。 Second step: tert-butyl ( R )-2-(hydroxymethyl)morpholine-4-carboxylate (R)-(4-(cyclopropylmethyl)morpholine-2-yl)methanol 94c ( R )-(4-(cyclopropylmethyl)morpholin-2-yl)methanol Dissolve compound 94b (500 mg, 4.2 mmol) in 20 mL of N,N-dimethylformamide, then add triethylamine (1.27 g, 12.6 mmol), then cyclopropylmethyl bromide (692 mg, 5.1 mmol) was added, and the temperature was slowly raised to 55°C and stirred for 3 h. TLC detects that the reaction is complete, and is concentrated under reduced pressure to obtain intermediate tert-butyl ( R )-2-(hydroxymethyl)morpholine-4-carboxylate ( R )-(4-(cyclopropylmethyl)morpholine -2-yl)methanol 94c (colorless oil, 510 mg). LC-MS m/z (ESI) = 172.2 [M+1].

第三步：( R)-(4-(環丙基甲基)嗎啉-2-基)甲基4-甲基苯磺酸鹽 94d( R)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 將化合物 94c(510g，2.9 mmol)溶解於N,N-二甲基甲醯胺20 mL中，隨後加入三乙胺 (602 mg，5.8 mmol)，4-二甲氨基吡啶 (35 mg, 0.29 mmol)，緩慢加入對甲苯磺醯氯 (608 mg，3.19 mmol)，室溫攪拌1 h。TLC監測反應完畢，減壓濃縮，得到中間體(R) -(4-(環丙基甲基)嗎啉-2-基)甲基4-甲基苯磺酸鹽 94d(白色固體，640 mg)。 LC-MSm/z (ESI)= 326.2 [M+1]。 The third step: ( R )-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 94d ( R )-(4-(cyclopropylmethyl)morpholin-2- yl)methyl 4-methylbenzenesulfonate Dissolve compound 94c (510 g, 2.9 mmol) in 20 mL of N,N-dimethylformamide, then add triethylamine (602 mg, 5.8 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol), slowly added p-toluenesulfonyl chloride (608 mg, 3.19 mmol), and stirred at room temperature for 1 h. The completion of the reaction was monitored by TLC, and concentrated under reduced pressure to obtain intermediate (R)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 94d (white solid, 640 mg ). LC-MS m/z (ESI) = 326.2 [M+1].

第四步：雙叔丁基(S)-(4-(環丙基甲基)嗎啉-2-基)甲基)氨基甲酸酯 94eDi tert-butyl ( S)-(4-(cyclopropylmethyl) morpholine-2-yl) methyl) carbamate 將中間體( R) -(4-(環丙基甲基)嗎啉-2-基)甲基4-甲基苯磺酸鹽 94d(640 mg, 1.9mmol)溶於60 ml N,N-二甲基甲醯胺中，隨後加入碳酸銫 (1.9 g，5.9mmol)，碘化鈉(60 mg,0.39 mmol)，雙BOC胺 (413 mg, 2.3 mmol)，緩慢升溫至90°C，攪拌2 h。TLC監測反應完畢，反應液直接濃縮，矽膠柱層析純化 (乙酸乙酯：石油醚=1:3)，得到中間體雙叔丁基(S)-(4-(環丙基甲基)嗎啉-2-基)甲基)氨基甲酸酯 94e(白色固體，400 mg)。 LC-MSm/z (ESI)= 371.2[M+1]。 The fourth step: bis-tert-butyl (S)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl)carbamate 94e Di tert-butyl ( S )-(4-(cyclopropylmethyl ) morpholine-2-yl) methyl) carbamate Intermediate ( R ) -(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 94d (640 mg, 1.9 mmol) was dissolved in 60 ml N,N-dimethylformamide, followed by cesium carbonate (1.9 g, 5.9 mmol), sodium iodide (60 mg, 0.39 mmol), bis-BOC amine (413 mg, 2.3 mmol ), slowly warming up to 90 ° C, stirring for 2 h. The completion of the reaction was monitored by TLC, the reaction solution was directly concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:3) to obtain the intermediate bis-tert-butyl (S)-(4-(cyclopropylmethyl)? (olin-2-yl)methyl)carbamate 94e (white solid, 400 mg). LC-MS m/z (ESI) = 371.2 [M+1].

第五步：( S)-(4-(環丙基甲基)嗎啉-2-基)甲醯胺 鹽酸鹽 94f( S)-(4-(cyclopropylmethyl) morpholine-2-yl) formamide hydrochloride 將雙叔丁基( S)-(4-(環丙基甲基)嗎啉-2-基)甲基)氨基甲酸酯 94e(400 mg, 1.08 mmol)加入5 ml 二氧六環氯化氫溶液中，緩慢升溫至55 °C，攪拌1 h。TLC監測反應完畢，反應液直接濃縮，得到中間體( S) -(4-(環丙基甲基)嗎啉-2-基)甲醯胺 鹽酸鹽 94f(白色固體，460 mg)。 LC-MSm/z (ESI)= 171.2[M+1]。 The fifth step: ( S )-(4-(cyclopropylmethyl)morpholine-2-yl) formamide hydrochloride 94f ( S )-(4-(cyclopropylmethyl)morpholine-2-yl) formamide hydrochloride Bis-tert-butyl ( S )-(4-(cyclopropylmethyl)morpholin-2-yl)methyl)carbamate 94e (400 mg, 1.08 mmol) was added to 5 ml dioxane hydrogen chloride solution , slowly warming up to 55 °C, and stirring for 1 h. The completion of the reaction was monitored by TLC, and the reaction solution was directly concentrated to obtain the intermediate ( S )-(4-(cyclopropylmethyl)morpholin-2-yl)formamide hydrochloride 94f (white solid, 460 mg). LC-MS m/z (ESI) = 171.2 [M+1].

第六步：(1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(( S)-4-(環丙基甲基)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 94(1 R,5 S) / (1 S,5 R)-3-(8-cyanoquinolin-5-yl)-N-((( S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 將化合物 1-A(100 mg, 0.28mmol)溶於N,N二甲基甲醯胺6 ml中，隨後冰浴加入HATU(127 mg, 0.33 mmol)，DIPEA(108 mg, 0.84 mmol)低溫攪拌5分鐘，然後加入 94f(75 mg, 0.3 mmol)攪拌0.5 h，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化 (鹼法)，得到目標產物(1 R,5S)或(1 S,5 R)-3-(8-氰基喹啉-5-基)-N-(( S)-4-(環丙基甲基)嗎啉-2-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 化合物 94(淡黃色固體,80 mg,78%)。 1 H NMR(400 MHz, DMSO-d 6) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.40 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 4.01 (d, 1H), 3.98 – 3.90 (m, 2H), 3.80 (dd, 2H), 3.54 – 3.40 (m, 2H), 3.14 (m, 2H), 2.92 – 2.65 (m, 2H), 2.15 (s, 2H), 1.98 (t, 2H), 1.66 (t, 2H), 0.82 (d, 1H), 0.44 (d, 2H), 0.11 – 0.01 (m, 2H)。 19 F NMR(376 MHz, DMSO-d6) δ -63.52。 LC-MSm/z (ESI)= 500.20 [M+1]。 The sixth step: (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-4-(cyclopropylmethyl) Morpholine-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 94 (1 R ,5 S ) / (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-((( S )-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0]Hexane-1-carboxamide Dissolve compound 1-A (100 mg, 0.28mmol) in 6 ml of N,N dimethylformamide, then add HATU (127 mg, 0.33 mmol) in ice bath, DIPEA (108 mg, 0.84 mmol) was stirred at low temperature for 5 minutes, then added 94f (75 mg, 0.3 mmol) and stirred for 0.5 h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product (1 R,5S ) or (1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-N-(( S )-4-(cyclopropylmethyl)morpholine-2 -yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 94 (pale yellow solid, 80 mg, 78%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (dd, 1H), 8.63 (dd, 1H), 8.40 (t, 1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.23 ( d, 1H), 4.01 (d, 1H), 3.98 – 3.90 (m, 2H), 3.80 (dd, 2H), 3.54 – 3.40 (m, 2H), 3.14 (m, 2H), 2.92 – 2.65 (m, 2H), 2.15 (s, 2H), 1.98 (t, 2H), 1.66 (t, 2H), 0.82 (d, 1H), 0.44 (d, 2H), 0.11 – 0.01 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -63.52. LC-MS m/z (ESI) = 500.20 [M+1].

[生物測試][biological test]

HEK-Blue-hTLR7/8/9細胞抑制實驗 1、將HEK-Blue-hTLR7/8細胞 (1×10 4個/孔)、HEK-Blue-hTLR9細胞(1.5×10 4個/孔)接種于384孔細胞培養板中，每孔體積為30 µL。置於37 °C，5% CO 2培養箱培養4 h。 2、將化合物用DMSO配製，用DMEM培養基稀釋10個濃度 (1:3稀釋)，終濃度分別為10000，3333.3，1111.1，370.4，123.5，41.2，13.7，4.6，1.5，0.5 nM；R848使用DMSO配製，用DMEM培養基稀釋，終濃度為0.8 μM(HEK-Blue-hTLR7)、3 μM(HEK-Blue-hTLR8)；ODN2006使用無內毒素水配製，用DMEM培養基稀釋，終濃度為1 μM。 3、以DMSO處理的細胞為空白對照組，同時設立單獨用Resiquimod (R848)處理的細胞為HEK-Blue-hTLR7/8的陽性對照組，單獨用ODN2006處理的細胞為HEK-Blue-hTLR9的陽性對照組。以受試化合物與R848或ODN2006處理的細胞為測試組。每組設2個平行孔，放入置於37 °C，5% CO 2培養箱培養。 4、培養4 h後，從培養箱中取出HEK-Blue-hTLR7/8的384孔板，每孔單獨加入R848或者同時加入R848和稀釋後的化合物。置於37 °C，5% CO 2培養箱培養16 h；從培養箱中取出HEK-Blue-hTLR9的384孔板，每孔單獨加入ODN2006或者同時加入ODN2006和稀釋後的化合物。置於37 °C，5% CO 2培養箱培養16 h。 5、培養16 h後，從培養箱中取出384孔板，1000 rpm離心1分鐘，使用多功能酶標儀讀取每個孔在620nm處的光密度值。 6、計算細胞抑制率=(1-(OD620測試組-OD620空白組)/(OD620陽性組-OD620空白組))×100%，通過曲線擬合計算半數抑制濃度(half maximal inhibitory concentration, IC 50)。 HEK-Blue-hTLR7/8/9 cell inhibition experiment 1. Inoculate HEK-Blue-hTLR7/8 cells (1×10 4 cells/well) and HEK-Blue-hTLR9 cells (1.5×10 4 cells/well) in In a 384-well cell culture plate, the volume of each well is 30 µL. Place in a 37 °C, 5% CO 2 incubator for 4 h. 2. Prepare the compound with DMSO, dilute 10 concentrations with DMEM medium (1:3 dilution), the final concentrations are 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, 0.5 nM; R848 uses DMSO Prepared and diluted with DMEM medium, the final concentration is 0.8 μM (HEK-Blue-hTLR7), 3 μM (HEK-Blue-hTLR8); ODN2006 was prepared with endotoxin-free water, diluted with DMEM medium, the final concentration was 1 μM. 3. The cells treated with DMSO were used as the blank control group, and the cells treated with Resiquimod (R848) alone were set up as the positive control group of HEK-Blue-hTLR7/8, and the cells treated with ODN2006 alone were positive for HEK-Blue-hTLR9 control group. The cells treated with the test compound and R848 or ODN2006 were used as the test group. Two parallel wells were set up in each group, and placed in a 37°C, 5% CO 2 incubator for culture. 4. After culturing for 4 hours, take out the 384-well plate of HEK-Blue-hTLR7/8 from the incubator, and add R848 to each well or add R848 and the diluted compound at the same time. Place in a 37 °C, 5% CO 2 incubator for 16 h; remove the 384-well plate of HEK-Blue-hTLR9 from the incubator, and add ODN2006 alone or ODN2006 and the diluted compound to each well. Placed in a 37 °C, 5% CO 2 incubator for 16 h. 5. After culturing for 16 hours, take out the 384-well plate from the incubator, centrifuge at 1000 rpm for 1 minute, and read the optical density value of each well at 620 nm using a multi-functional microplate reader. 6. Calculate the cell inhibition rate = (1-(OD620 test group-OD620 blank group)/(OD620 positive group-OD620 blank group))×100%, calculate the half maximal inhibitory concentration (IC 50 ) by curve fitting ).

表1：本發明化合物在HEK-Blue-hTLR7/8/9細胞測定中的活性 化合物 TLR7 IC 50(nM) TLR8 IC 50(nM) TLR9 IC 50(nM) 化合物2 5.1 14.3 4454 化合物2-A 3.4 15 5566 化合物2-B 16.3 9.3 6337 化合物5 4 28 2292 化合物5-A 13.8 52.7 2959 化合物5-B 6.1 - 5379 化合物5-C 1.7 31.8 1319 化合物5-D 3.4 34.1 1099 化合物6 6.2 60.5 ＞10000 化合物7 7.1 - ＞10000 化合物10 - - ＞10000 化合物11 4.3 8.9 ＞10000 化合物12 27 - ＞10000 化合物15 2.1 21 4242 化合物16 25.5 22 ＞10000 化合物18 8.5 13 6480 化合物18-A 8.8 5.7 3779 化合物18-B 3.6 19.4 4532 化合物20 46.1 - ＞10000 化合物21 10.6 36.6 5601 化合物22 13.7 - 6945 化合物23 4.6 47 1193 化合物24 4.9 48 2733 化合物27 5.6 2.9 3615 化合物27-A 4.9 1.3 1121 化合物27-B 1.8 2.9 1339 化合物29 10.8 41.2 ＞10000 化合物29-A 17.2 68 ＞10000 化合物29-B 21 - ＞10000 化合物29-C 59.7 - ＞10000 化合物29-D 65 47.6 ＞10000 化合物30 11.9 80.5 677.2 化合物32 28.2 - 1136 化合物33 14.4 24.2 ＞10000 化合物33-A 4.9 7.3 5966 化合物33-B 40.7 33.7 ＞10000 化合物34 57 - ＞10000 化合物35 51.9 - ＞10000 化合物36 15.2 37.6 3035 化合物37 12.2 41.6 2768 化合物38 65.4 23.3 3654 化合物39 3.1 6.2 1071 化合物40 3.4 5.8 2223 化合物41 11.2 7.4 1506 化合物42 4.2 6.3 3378 化合物43 3.1 8 2836 化合物44 9.7 3.3 2901 化合物45 59.4 - ＞10000 化合物46 71.5 ＞10000 ＞10000 化合物48 3.2 84.2 5377 化合物48-A 6.1 47.5 4532 化合物48-B 8.1 29.6 4917 化合物48-C 2.9 58 5301 化合物48-D 2 48.4 5550 化合物49 71.4 - ＞10000 化合物50 5.1 - 5347 化合物51 2.5 7.1 2347 化合物53-A 3.6 9.6 ＞10000 化合物53-B 5.4 21.2 ＞10000 化合物53-C 7.1 35.7 ＞10000 化合物53-D 3.2 12.5 ＞10000 化合物54 46.9 - 3859 化合物55 70.9 39.3 424.8 化合物58 15.8 6.5 4627 化合物59 19.6 18.2 5645 化合物60 1.3 8.5 1166 化合物61 4.9 11.9 1068 化合物62 4.2 30.6 ＞10000 化合物63 18.4 63 ＞10000 化合物64 32.5 13.6 ＞10000 化合物65 34.6 55.6 ＞10000 化合物66 23.3 54.8 ＞10000 化合物67 33.4 35.5 ＞10000 化合物68-A 23.6 92.2 ＞10000 化合物69 29.6 53.9 ＞10000 化合物70 1.9 7.2 4423 化合物74 7.6 - ＞10000 化合物76 ＜100 - ＞10000 化合物77 - ＜100 ＞10000 化合物82 16 91 7626 化合物83 42 - 5445 化合物84 9 - 8057 化合物85 12 26 2879 化合物86 18 - ＞10000 化合物87 9 70 ＞10000 化合物88 11 60 ＞10000 化合物89 14 97 ＞10000 化合物90 22 - ＞10000 化合物91 2 24 4839 化合物92 43 - ＞10000 化合物93 77 - 2763 化合物94 10 29 7440 Table 1: Activity of compounds of the invention in HEK-Blue-hTLR7/8/9 cell assays compound TLR7 IC 50 (nM) TLR8 IC 50 (nM) TLR9 IC 50 (nM) Compound 2 5.1 14.3 4454 Compound 2-A 3.4 15 5566 Compound 2-B 16.3 9.3 6337 Compound 5 4 28 2292 Compound 5-A 13.8 52.7 2959 Compound 5-B 6.1 - 5379 Compound 5-C 1.7 31.8 1319 Compound 5-D 3.4 34.1 1099 Compound 6 6.2 60.5 >10000 Compound 7 7.1 - >10000 Compound 10 - - >10000 Compound 11 4.3 8.9 >10000 Compound 12 27 - >10000 Compound 15 2.1 twenty one 4242 Compound 16 25.5 twenty two >10000 Compound 18 8.5 13 6480 Compound 18-A 8.8 5.7 3779 Compound 18-B 3.6 19.4 4532 Compound 20 46.1 - >10000 Compound 21 10.6 36.6 5601 Compound 22 13.7 - 6945 Compound 23 4.6 47 1193 Compound 24 4.9 48 2733 Compound 27 5.6 2.9 3615 Compound 27-A 4.9 1.3 1121 Compound 27-B 1.8 2.9 1339 Compound 29 10.8 41.2 >10000 Compound 29-A 17.2 68 >10000 Compound 29-B twenty one - >10000 Compound 29-C 59.7 - >10000 Compound 29-D 65 47.6 >10000 Compound 30 11.9 80.5 677.2 Compound 32 28.2 - 1136 Compound 33 14.4 24.2 >10000 Compound 33-A 4.9 7.3 5966 Compound 33-B 40.7 33.7 >10000 Compound 34 57 - >10000 Compound 35 51.9 - >10000 Compound 36 15.2 37.6 3035 Compound 37 12.2 41.6 2768 Compound 38 65.4 23.3 3654 Compound 39 3.1 6.2 1071 Compound 40 3.4 5.8 2223 Compound 41 11.2 7.4 1506 Compound 42 4.2 6.3 3378 Compound 43 3.1 8 2836 Compound 44 9.7 3.3 2901 Compound 45 59.4 - >10000 Compound 46 71.5 >10000 >10000 Compound 48 3.2 84.2 5377 Compound 48-A 6.1 47.5 4532 Compound 48-B 8.1 29.6 4917 Compound 48-C 2.9 58 5301 Compound 48-D 2 48.4 5550 Compound 49 71.4 - >10000 Compound 50 5.1 - 5347 Compound 51 2.5 7.1 2347 Compound 53-A 3.6 9.6 >10000 Compound 53-B 5.4 21.2 >10000 Compound 53-C 7.1 35.7 >10000 Compound 53-D 3.2 12.5 >10000 Compound 54 46.9 - 3859 Compound 55 70.9 39.3 424.8 Compound 58 15.8 6.5 4627 Compound 59 19.6 18.2 5645 Compound 60 1.3 8.5 1166 Compound 61 4.9 11.9 1068 Compound 62 4.2 30.6 >10000 Compound 63 18.4 63 >10000 Compound 64 32.5 13.6 >10000 Compound 65 34.6 55.6 >10000 Compound 66 23.3 54.8 >10000 Compound 67 33.4 35.5 >10000 Compound 68-A 23.6 92.2 >10000 Compound 69 29.6 53.9 >10000 Compound 70 1.9 7.2 4423 Compound 74 7.6 - >10000 Compound 76 <100 - >10000 Compound 77 - <100 >10000 Compound 82 16 91 7626 Compound 83 42 - 5445 Compound 84 9 - 8057 Compound 85 12 26 2879 Compound 86 18 - >10000 Compound 87 9 70 >10000 Compound 88 11 60 >10000 Compound 89 14 97 >10000 Compound 90 twenty two - >10000 Compound 91 2 twenty four 4839 Compound 92 43 - >10000 Compound 93 77 - 2763 Compound 94 10 29 7440

結論：本發明化合物對HEK-Blue-hTLR7/8細胞有明顯拮抗作用，同時對HEK-Blue-hTLR9細胞無明顯拮抗作用。Conclusion: the compound of the present invention has obvious antagonistic effect on HEK-Blue-hTLR7/8 cells, but has no obvious antagonistic effect on HEK-Blue-hTLR9 cells.

IL-6的體內抑制實驗 實驗材料：化合物溶液的配製：R848用純水配製 (滅菌)，最終濃度25µg/100µL；受試化合物用pH=3的檸檬酸鈉緩衝液配製，最終濃度0.1 mg/mL。 實驗動物：C57BL/6雌鼠，購自集萃藥康，6-8周齡。 實驗方法：C57BL/6雌鼠隨機分為空白組、對照組和實驗組，每組8只。 空白組：小鼠禁食12 h後取血。 對照組：小鼠禁食12 h後灌胃PH=3的檸檬酸鈉緩衝液，其餘操作與實驗組一致； 實驗組：小鼠禁食12 h後灌胃給予受試化合物 (1 mg/kg)，1 h後腹腔注射25 µg R848 (購自MCE)，2 h後摘眼球取血，血清室溫靜置30 min，接著離心10 min (3000 rpm)，取上清液，用IL-6 ELISA試劑盒測量血清IL-6濃度，通過對照組和實驗組IL-6血清濃度，計算IL-6抑制率。計算公式：抑制率=(C2-C3)/(C2-C1)×100%。 C1：空白組血清IL-6濃度； C2: 對照組血清IL-6濃度； C3: 實驗組血清IL-6濃度。 In vivo inhibition experiment of IL-6 Experimental materials: Preparation of compound solution: R848 was prepared with pure water (sterilized), with a final concentration of 25 µg/100 µL; the test compound was prepared with pH=3 sodium citrate buffer, with a final concentration of 0.1 mg/mL. Experimental animals: C57BL/6 female mice, purchased from Jicui Yaokang, aged 6-8 weeks. Experimental method: C57BL/6 female mice were randomly divided into blank group, control group and experimental group, with 8 rats in each group. Blank group: mice were fasted for 12 h and blood was collected. Control group: After fasting for 12 hours, the mice were intragastrically administered sodium citrate buffer solution with pH=3, and the rest of the operations were the same as those of the experimental group; Experimental group: After fasting for 12 hours, the mice were given the test compound (1 mg/kg) by intragastric administration, 1 hour later, 25 µg R848 (purchased from MCE) was injected intraperitoneally, and 2 hours later, the eyeballs were removed to collect blood, and the serum was allowed to stand at room temperature 30 min, then centrifuged for 10 min (3000 rpm), the supernatant was taken, and the serum IL-6 concentration was measured with an IL-6 ELISA kit, and the IL-6 inhibition rate was calculated by the IL-6 serum concentration of the control group and the experimental group. Calculation formula: inhibition rate=(C2-C3)/(C2-C1)×100%. C1: Serum IL-6 concentration of blank group; C2: serum IL-6 concentration of the control group; C3: Serum IL-6 concentration of the experimental group.

表2：IL-6的體內抑制實驗 化合物 IL-6抑制率 化合物27-A 97.1% 化合物27-B 99.8% 化合物29-A 98% 化合物29-B 99.7% 化合物29-C 90.5% 化合物29-D 90% 化合物43 93.8% 化合物44 90% 化合物53-A 97.2% 化合物53-B 99.3% 化合物53-C 100% 化合物53-D 97.8% 化合物69 68.9% 化合物73 94.4% 化合物74 92.2% Table 2: In vivo inhibition experiments of IL-6 compound IL-6 inhibition rate Compound 27-A 97.1% Compound 27-B 99.8% Compound 29-A 98% Compound 29-B 99.7% Compound 29-C 90.5% Compound 29-D 90% Compound 43 93.8% Compound 44 90% Compound 53-A 97.2% Compound 53-B 99.3% Compound 53-C 100% Compound 53-D 97.8% Compound 69 68.9% Compound 73 94.4% Compound 74 92.2%

結論：本發明化合物對IL-6有明顯的抑制作用。Conclusion: the compound of the present invention has obvious inhibitory effect on IL-6.

本發明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，不能理解為對本發明的限制，對於本領域技術人員來說，在不脫離本發明原理的前提下，通過對本發明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發明的申請專利範圍的保護範圍內。The description of the present invention has described specific implementations in detail, and those skilled in the art should recognize that the above-mentioned implementations are exemplary and cannot be construed as limitations on the present invention. Under the premise of the present invention, several improvements and modifications are made to the present invention, and the technical solutions obtained by these improvements and modifications also fall within the protection scope of the patent application scope of the present invention.

Figure 111109958-A0101-11-0001-1
Figure 111109958-A0101-11-0001-1

Claims (15)

一種如通式(I)所示的化合物，或者其立體異構物、氘代物或藥物可接受的鹽：
Figure 03_image001
(I) 其中： X為C或N； R 1為C 1-6烷基，所述C 1-6烷基任選地進一步被1個或多個鹵素取代； R 2為-CN或C 1-6烷基，所述C 1-6烷基任選地進一步被1個或多個鹵素取代； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-(R a1) m-(R a2) n，所述R a任選地進一步被1個或多個選自D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羥基取代的C 1-6烷基、鹵素取代的C 1-6烷基、C 3-10環烷基、C 3-10雜環烷基和C 1-6烷基-C 3-10環烷基的取代基取代； R a1為-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10環烷基或C 3-10雜環烷基，所述C 1-6烷基任選地進一步被1個或多個D取代； R a2為H、D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、C 3-10環烷基或C 3-10雜環烷基，所述C 1-6烷基任選地進一步被1個或多個D取代； R b、R c各自獨立地為H或C 1-6烷基； m為1、2或3； n為0、1、2、3或4。 A compound as shown in general formula (I), or its stereoisomer, deuterated or pharmaceutically acceptable salt:
Figure 03_image001
(I) wherein: X is C or N; R 1 is C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by 1 or more halogens; R 2 is -CN or C 1 -6 alkyl, the C 1-6 alkyl is optionally further substituted by one or more halogens; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -(R a1 ) m -(R a2 ) n , and said R a is optionally further selected from one or more of D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C Substituents of 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl; R a1 is -O-, - NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkyl is optionally Further substituted by 1 or more D; R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl Or C 3-10 heterocycloalkyl, said C 1-6 alkyl is optionally further substituted by 1 or more D; R b , R c are each independently H or C 1-6 alkyl; m is 1, 2 or 3; n is 0, 1, 2, 3 or 4. 如請求項1所述的化合物，或者其立體異構物、氘代物或藥物可接受的鹽： 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-(R a1) m-(R a2) n，所述R a任選地進一步被1個或多個選自D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羥基取代的C 1-6烷基、鹵素取代的C 1-6烷基、C 3-10環烷基、C 3-10雜環烷基和C 1-6烷基-C 3-10環烷基的取代基取代； R a1為-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10環烷基或C 3-10雜環烷基，所述C 1-6烷基任選地進一步被1個或多個D取代； R a2為H、D、-OH、鹵素、-NR bR c、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 1-6烷基任選地進一步被1個或多個D取代； R b、R c各自獨立地為H或C 1-6烷基； m為1、2或3； n為0、1、2、3或4。 The compound as described in Claim 1, or its stereoisomer, deuterium or pharmaceutically acceptable salt: wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further selected from D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkyl substituted by D, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by halogen, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl And C 1-6 alkyl-C 3-10 cycloalkyl substituent substitution; R a1 is -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkyl is optionally further substituted by 1 or more D; R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, the C 1-6 alkyl is optionally further Substituted by 1 or more D; R b and R c are each independently H or C 1-6 alkyl; m is 1, 2 or 3; n is 0, 1, 2, 3 or 4. 如請求項1或2所述的化合物，或者其立體異構物、氘代物或藥物可接受的鹽： 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、C 1-6烷基、
Figure 03_image004
、
Figure 03_image006
、
Figure 03_image008
、
Figure 03_image010
、
Figure 03_image012
、
Figure 03_image014
、
Figure 03_image016
、
Figure 03_image018
、
Figure 03_image020
、
Figure 03_image022
、
Figure 03_image024
、
Figure 03_image026
、
Figure 03_image028
、
Figure 03_image030
、
Figure 03_image032
、
Figure 03_image034
、
Figure 03_image036
、
Figure 03_image038
、
Figure 03_image040
、
Figure 03_image042
、
Figure 03_image044
、
Figure 03_image046
、
Figure 03_image048
、
Figure 03_image050
、
Figure 03_image052
、
Figure 03_image054
、
Figure 03_image056
或
Figure 03_image058
，且R a任選地進一步被1至多個選自D、-OH、鹵素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羥基取代的C 1-6烷基、鹵素取代的C 1-6烷基、C 3-10環烷基、C 3-10雜環烷基和C 1-6烷基-C 3-10環烷基的取代基取代； R b、R c各自獨立地為H或C 1-6烷基。 The compound as described in Claim 1 or 2, or its stereoisomer, deuterium or pharmaceutically acceptable salt: wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is - CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is - NH 2 , -OH, piperidinyl, C 1-6 alkyl,
Figure 03_image004
,
Figure 03_image006
,
Figure 03_image008
,
Figure 03_image010
,
Figure 03_image012
,
Figure 03_image014
,
Figure 03_image016
,
Figure 03_image018
,
Figure 03_image020
,
Figure 03_image022
,
Figure 03_image024
,
Figure 03_image026
,
Figure 03_image028
,
Figure 03_image030
,
Figure 03_image032
,
Figure 03_image034
,
Figure 03_image036
,
Figure 03_image038
,
Figure 03_image040
,
Figure 03_image042
,
Figure 03_image044
,
Figure 03_image046
,
Figure 03_image048
,
Figure 03_image050
,
Figure 03_image052
,
Figure 03_image054
,
Figure 03_image056
or
Figure 03_image058
, and R a is optionally further substituted by 1 to more selected from D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted C 1-6 alkane C 1-6 alkyl group, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 Cycloalkyl substituents are substituted; R b and R c are each independently H or C 1-6 alkyl. 如請求項1至3中任一項所述的化合物，或者其立體異構物、氘代物或藥物可接受的鹽： 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為-NH 2、-OH、哌啶基、
Figure 03_image060
、
Figure 03_image062
、
Figure 03_image006
、
Figure 03_image008
、
Figure 03_image064
、
Figure 03_image010
、
Figure 03_image012
、
Figure 03_image066
、
Figure 03_image068
、
Figure 03_image070
、
Figure 03_image072
、
Figure 03_image074
、
Figure 03_image076
、
Figure 03_image078
、
Figure 03_image080
、
Figure 03_image082
、
Figure 03_image020
、
Figure 03_image084
、
Figure 03_image086
、
Figure 03_image024
、
Figure 03_image088
、
Figure 03_image090
、
Figure 03_image092
、
Figure 03_image094
、
Figure 03_image096
、
Figure 03_image098
、
Figure 03_image030
、
Figure 03_image032
、
Figure 03_image100
、
Figure 03_image102
、
Figure 03_image104
、
Figure 03_image106
、
Figure 03_image108
、
Figure 03_image110
、
Figure 03_image040
、
Figure 03_image042
、
Figure 03_image112
、
Figure 03_image114
、
Figure 03_image048
、
Figure 03_image116
、
Figure 03_image118
、
Figure 03_image120
、
Figure 03_image122
、
Figure 03_image124
、
Figure 03_image052
、
Figure 03_image054
、
Figure 03_image056
、
Figure 03_image058
、
Figure 03_image126
、
Figure 03_image128
或
Figure 03_image130
，且R a任選地進一步被1個或2個C 1-6烷基取代。 The compound as described in any one of claims 1 to 3, or its stereoisomer, deuterated substance or pharmaceutically acceptable salt: wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is -NH 2 , -OH, piperidinyl,
Figure 03_image060
,
Figure 03_image062
,
Figure 03_image006
,
Figure 03_image008
,
Figure 03_image064
,
Figure 03_image010
,
Figure 03_image012
,
Figure 03_image066
,
Figure 03_image068
,
Figure 03_image070
,
Figure 03_image072
,
Figure 03_image074
,
Figure 03_image076
,
Figure 03_image078
,
Figure 03_image080
,
Figure 03_image082
,
Figure 03_image020
,
Figure 03_image084
,
Figure 03_image086
,
Figure 03_image024
,
Figure 03_image088
,
Figure 03_image090
,
Figure 03_image092
,
Figure 03_image094
,
Figure 03_image096
,
Figure 03_image098
,
Figure 03_image030
,
Figure 03_image032
,
Figure 03_image100
,
Figure 03_image102
,
Figure 03_image104
,
Figure 03_image106
,
Figure 03_image108
,
Figure 03_image110
,
Figure 03_image040
,
Figure 03_image042
,
Figure 03_image112
,
Figure 03_image114
,
Figure 03_image048
,
Figure 03_image116
,
Figure 03_image118
,
Figure 03_image120
,
Figure 03_image122
,
Figure 03_image124
,
Figure 03_image052
,
Figure 03_image054
,
Figure 03_image056
,
Figure 03_image058
,
Figure 03_image126
,
Figure 03_image128
or
Figure 03_image130
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups. 如請求項1至4中任一項所述的化合物，或者其立體異構物、氘代物或藥物可接受的鹽： 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為
Figure 03_image060
、
Figure 03_image062
、
Figure 03_image064
、
Figure 03_image066
、
Figure 03_image068
、
Figure 03_image072
、
Figure 03_image080
、
Figure 03_image024
、
Figure 03_image094
、
Figure 03_image098
、
Figure 03_image030
、
Figure 03_image102
、
Figure 03_image104
、
Figure 03_image106
、
Figure 03_image110
、
Figure 03_image114
、
Figure 03_image048
、
Figure 03_image116
、
Figure 03_image118
、
Figure 03_image120
、
Figure 03_image122
、
Figure 03_image054
或
Figure 03_image844
，且R a進一步被1個或2個C 1-6烷基取代。 The compound as described in any one of claims 1 to 4, or its stereoisomer, deuterated substance or pharmaceutically acceptable salt: wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is
Figure 03_image060
,
Figure 03_image062
,
Figure 03_image064
,
Figure 03_image066
,
Figure 03_image068
,
Figure 03_image072
,
Figure 03_image080
,
Figure 03_image024
,
Figure 03_image094
,
Figure 03_image098
,
Figure 03_image030
,
Figure 03_image102
,
Figure 03_image104
,
Figure 03_image106
,
Figure 03_image110
,
Figure 03_image114
,
Figure 03_image048
,
Figure 03_image116
,
Figure 03_image118
,
Figure 03_image120
,
Figure 03_image122
,
Figure 03_image054
or
Figure 03_image844
, and R a is further substituted by 1 or 2 C 1-6 alkyl groups. 如請求項1至5任一項所述的化合物，或者其立體異構物、氘代物或藥物可接受的鹽： 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN或-CF 3； R為-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R a為
Figure 03_image060
、
Figure 03_image064
、
Figure 03_image066
、
Figure 03_image068
、
Figure 03_image072
、
Figure 03_image080
、
Figure 03_image024
、
Figure 03_image098
、
Figure 03_image102
、
Figure 03_image104
、
Figure 03_image106
、
Figure 03_image110
、
Figure 03_image048
、
Figure 03_image116
、
Figure 03_image118
、
Figure 03_image054
或
Figure 03_image844
，且R a任選地進一步被1個或2個C 1-6烷基取代。 The compound as described in any one of claim items 1 to 5, or its stereoisomer, deuterium or pharmaceutically acceptable salt: wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN or -CF 3 ; R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a is
Figure 03_image060
,
Figure 03_image064
,
Figure 03_image066
,
Figure 03_image068
,
Figure 03_image072
,
Figure 03_image080
,
Figure 03_image024
,
Figure 03_image098
,
Figure 03_image102
,
Figure 03_image104
,
Figure 03_image106
,
Figure 03_image110
,
Figure 03_image048
,
Figure 03_image116
,
Figure 03_image118
,
Figure 03_image054
or
Figure 03_image844
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups. 如請求項1至6任一項所述的化合物，或者其立體異構物、氘代物或藥物可接受的鹽： 其中： X為C或N； R 1為-CF 3或-CH 3； R 2為-CN； R為-CONHR a、-COOR a或-NHCOR a； R a為
Figure 03_image064
、
Figure 03_image068
、
Figure 03_image072
、
Figure 03_image098
、
Figure 03_image104
、
Figure 03_image106
或
Figure 03_image054
，且R a任選地進一步被1個或2個C 1-6烷基取代。 The compound as described in any one of claim items 1 to 6, or its stereoisomer, deuterium or pharmaceutically acceptable salt: wherein: X is C or N; R 1 is -CF 3 or -CH 3 ; R 2 is -CN; R is -CONHR a , -COOR a or -NHCOR a ; R a is
Figure 03_image064
,
Figure 03_image068
,
Figure 03_image072
,
Figure 03_image098
,
Figure 03_image104
,
Figure 03_image106
or
Figure 03_image054
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups. 如請求項1-7中任一項所述的化合物或者其立體異構物、氘代物或藥物可接受的鹽，其中所述鹵素為F。The compound as described in any one of claims 1-7, or its stereoisomer, deuterated product or pharmaceutically acceptable salt, wherein the halogen is F. 一種如通式(II)所示的化合物，或者其立體異構物、氘代物或藥物可接受的鹽：
Figure 03_image214
(II) 其中： R為-COOH、-NH 2、-CONH 2、-COR a或-COOR a； R a為-NH 2、哌啶基、
Figure 03_image060
、
Figure 03_image062
、
Figure 03_image006
、
Figure 03_image008
、
Figure 03_image064
、
Figure 03_image132
、
Figure 03_image010
、
Figure 03_image012
、
Figure 03_image068
、
Figure 03_image070
、
Figure 03_image072
、
Figure 03_image074
、
Figure 03_image076
、
Figure 03_image078
、
Figure 03_image080
、
Figure 03_image082
、
Figure 03_image020
、
Figure 03_image216
、
Figure 03_image086
、
Figure 03_image098
、
Figure 03_image030
或
Figure 03_image032
，且R a任選地進一步被1個或2個C 1-6烷基取代。 A compound as shown in general formula (II), or its stereoisomer, deuterated or pharmaceutically acceptable salt:
Figure 03_image214
(II) Wherein: R is -COOH, -NH 2 , -CONH 2 , -COR a or -COOR a ; R a is -NH 2 , piperidinyl,
Figure 03_image060
,
Figure 03_image062
,
Figure 03_image006
,
Figure 03_image008
,
Figure 03_image064
,
Figure 03_image132
,
Figure 03_image010
,
Figure 03_image012
,
Figure 03_image068
,
Figure 03_image070
,
Figure 03_image072
,
Figure 03_image074
,
Figure 03_image076
,
Figure 03_image078
,
Figure 03_image080
,
Figure 03_image082
,
Figure 03_image020
,
Figure 03_image216
,
Figure 03_image086
,
Figure 03_image098
,
Figure 03_image030
or
Figure 03_image032
, and R a is optionally further substituted by 1 or 2 C 1-6 alkyl groups. 如請求項1至9中任一項所述的化合物或者其立體異構物、氘代物或藥物可接受的鹽，所述化合物為：
Figure 03_image218
、
Figure 03_image220
、
Figure 03_image222
、
Figure 03_image224
、
Figure 03_image226
、
Figure 03_image228
、
Figure 03_image230
、
Figure 03_image232
、
Figure 03_image234
、
Figure 03_image236
、
Figure 03_image238
、
Figure 03_image240
、
Figure 03_image242
、
Figure 03_image244
、
Figure 03_image246
、
Figure 03_image248
、
Figure 03_image250
、
Figure 03_image252
、
Figure 03_image254
、
Figure 03_image256
、
Figure 03_image258
、
Figure 03_image260
、
Figure 03_image262
、
Figure 03_image264
、
Figure 03_image266
、
Figure 03_image268
、
Figure 03_image270
、
Figure 03_image272
、
Figure 03_image274
、
Figure 03_image276
、
Figure 03_image278
、
Figure 03_image280
、
Figure 03_image282
、
Figure 03_image284
、
Figure 03_image286
、
Figure 03_image288
、
Figure 03_image290
、
Figure 03_image292
、
Figure 03_image294
、
Figure 03_image296
、
Figure 03_image298
、
Figure 03_image300
、
Figure 03_image302
、
Figure 03_image304
、
Figure 03_image306
、
Figure 03_image308
、
Figure 03_image310
、
Figure 03_image312
、
Figure 03_image314
、
Figure 03_image316
、
Figure 03_image318
、
Figure 03_image320
、
Figure 03_image322
、
Figure 03_image324
、
Figure 03_image326
、
Figure 03_image328
、
Figure 03_image330
、
Figure 03_image332
、
Figure 03_image334
、
Figure 03_image336
、
Figure 03_image338
、
Figure 03_image340
、
Figure 03_image342
、
Figure 03_image344
、
Figure 03_image346
、
Figure 03_image872
或
Figure 03_image874
。 The compound or its stereoisomer, deuterium or pharmaceutically acceptable salt as described in any one of claims 1 to 9, said compound is:
Figure 03_image218
,
Figure 03_image220
,
Figure 03_image222
,
Figure 03_image224
,
Figure 03_image226
,
Figure 03_image228
,
Figure 03_image230
,
Figure 03_image232
,
Figure 03_image234
,
Figure 03_image236
,
Figure 03_image238
,
Figure 03_image240
,
Figure 03_image242
,
Figure 03_image244
,
Figure 03_image246
,
Figure 03_image248
,
Figure 03_image250
,
Figure 03_image252
,
Figure 03_image254
,
Figure 03_image256
,
Figure 03_image258
,
Figure 03_image260
,
Figure 03_image262
,
Figure 03_image264
,
Figure 03_image266
,
Figure 03_image268
,
Figure 03_image270
,
Figure 03_image272
,
Figure 03_image274
,
Figure 03_image276
,
Figure 03_image278
,
Figure 03_image280
,
Figure 03_image282
,
Figure 03_image284
,
Figure 03_image286
,
Figure 03_image288
,
Figure 03_image290
,
Figure 03_image292
,
Figure 03_image294
,
Figure 03_image296
,
Figure 03_image298
,
Figure 03_image300
,
Figure 03_image302
,
Figure 03_image304
,
Figure 03_image306
,
Figure 03_image308
,
Figure 03_image310
,
Figure 03_image312
,
Figure 03_image314
,
Figure 03_image316
,
Figure 03_image318
,
Figure 03_image320
,
Figure 03_image322
,
Figure 03_image324
,
Figure 03_image326
,
Figure 03_image328
,
Figure 03_image330
,
Figure 03_image332
,
Figure 03_image334
,
Figure 03_image336
,
Figure 03_image338
,
Figure 03_image340
,
Figure 03_image342
,
Figure 03_image344
,
Figure 03_image346
,
Figure 03_image872
or
Figure 03_image874
. 一種製備如請求項1至10中任一項所述的化合物的中間體，或者其立體異構物、氘代物或藥物可接受的鹽，所述中間體為：
Figure 03_image352
、
Figure 03_image354
、
Figure 03_image356
、
Figure 03_image358
、
Figure 03_image360
、
Figure 03_image362
、
Figure 03_image364
、
Figure 03_image366
、
Figure 03_image368
、
Figure 03_image370
、
Figure 03_image372
、
Figure 03_image374
、
Figure 03_image376
、
Figure 03_image378
、
Figure 03_image380
、
Figure 03_image382
、
Figure 03_image384
、
Figure 03_image386
、
Figure 03_image388
、
Figure 03_image390
、
Figure 03_image392
、
Figure 03_image394
、
Figure 03_image396
、
Figure 03_image398
、
Figure 03_image400
、
Figure 03_image402
、
Figure 03_image404
、
Figure 03_image406
、
Figure 03_image408
、
Figure 03_image410
、
Figure 03_image412
、
Figure 03_image414
、
Figure 03_image416
、
Figure 03_image418
、
Figure 03_image420
、
Figure 03_image422
、
Figure 03_image424
、
Figure 03_image426
、
Figure 03_image428
、
Figure 03_image430
、
Figure 03_image432
、
Figure 03_image434
、
Figure 03_image436
、
Figure 03_image438
、
Figure 03_image440
、
Figure 03_image442
、
Figure 03_image444
、
Figure 03_image446
、
Figure 03_image448
、
Figure 03_image450
或
Figure 03_image452
。 An intermediate for preparing the compound as described in any one of claims 1 to 10, or its stereoisomer, deuterated product or pharmaceutically acceptable salt, the intermediate is:
Figure 03_image352
,
Figure 03_image354
,
Figure 03_image356
,
Figure 03_image358
,
Figure 03_image360
,
Figure 03_image362
,
Figure 03_image364
,
Figure 03_image366
,
Figure 03_image368
,
Figure 03_image370
,
Figure 03_image372
,
Figure 03_image374
,
Figure 03_image376
,
Figure 03_image378
,
Figure 03_image380
,
Figure 03_image382
,
Figure 03_image384
,
Figure 03_image386
,
Figure 03_image388
,
Figure 03_image390
,
Figure 03_image392
,
Figure 03_image394
,
Figure 03_image396
,
Figure 03_image398
,
Figure 03_image400
,
Figure 03_image402
,
Figure 03_image404
,
Figure 03_image406
,
Figure 03_image408
,
Figure 03_image410
,
Figure 03_image412
,
Figure 03_image414
,
Figure 03_image416
,
Figure 03_image418
,
Figure 03_image420
,
Figure 03_image422
,
Figure 03_image424
,
Figure 03_image426
,
Figure 03_image428
,
Figure 03_image430
,
Figure 03_image432
,
Figure 03_image434
,
Figure 03_image436
,
Figure 03_image438
,
Figure 03_image440
,
Figure 03_image442
,
Figure 03_image444
,
Figure 03_image446
,
Figure 03_image448
,
Figure 03_image450
or
Figure 03_image452
. 一種藥物組合物，所述藥物組合物包含： (1)如請求項1至10中任一項所述的化合物或者其立體異構物、氘代物或藥物可接受的鹽； (2)任選的一種或者多種其他活性成分；以及 (3)藥學上可接受的載體和/或賦形劑。 A pharmaceutical composition comprising: (1) The compound as described in any one of claims 1 to 10 or its stereoisomer, deuterated substance or pharmaceutically acceptable salt; (2) Optional one or more other active ingredients; and (3) Pharmaceutically acceptable carriers and/or excipients. 如請求項1至10中任一項所述的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者權利要求12所述的藥物組合物在製備用於治療自身免疫疾病的藥物中的用途。The compound as described in any one of claims 1 to 10 or its stereoisomer, deuterium or pharmaceutically acceptable salt, or the pharmaceutical composition described in claim 12 is used in the preparation of medicines for the treatment of autoimmune diseases use in . 一種如請求項1至10中任一項所述的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者如請求項12所述的藥物組合物在製備用於治療與TLR7、TLR8或TLR9相關的疾病中的用途。A compound as described in any one of claim items 1 to 10 or its stereoisomer, deuterated substance or pharmaceutically acceptable salt, or a pharmaceutical composition as described in claim item 12 in the preparation for the treatment of TLR7, Use in a TLR8 or TLR9 related disease. 一種如請求項1至10中任一項所述的化合物或者其立體異構物、氘代物或藥物可接受的鹽，或者如請求項12所述的藥物組合物在製備IL-6抑制劑中的用途。A compound as described in any one of claims 1 to 10 or its stereoisomer, deuterated or pharmaceutically acceptable salt, or a pharmaceutical composition as described in claim 12 in the preparation of an IL-6 inhibitor the use of.
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