TW202227452A - Fused azaheterocyclic compounds, preparation methods, methods of inhibiting tyrosine kinase, pharmaceutical composition and uses thereof - Google Patents

Fused azaheterocyclic compounds, preparation methods, methods of inhibiting tyrosine kinase, pharmaceutical composition and uses thereof Download PDF

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TW202227452A
TW202227452A TW110145234A TW110145234A TW202227452A TW 202227452 A TW202227452 A TW 202227452A TW 110145234 A TW110145234 A TW 110145234A TW 110145234 A TW110145234 A TW 110145234A TW 202227452 A TW202227452 A TW 202227452A
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邱關鵬
鄧代國
雷曾榮
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大陸商廣州費米子科技有限責任公司
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Abstract

The invention relates to fused azaheterocyclic compounds, preparation methods, methods of inhibiting tyrosine kinase, pharmaceutical composition and uses thereof. The fused azaheterocyclic compounds have structures of general formula (I). The fused azaheterocyclic compounds have excellent tyrosine kinase JAK inhibitory activity, and may be used as tyrosine kinase JAK inhibitors for the treatment of inflammatory diseases or tumor diseases involved various JAK-STAT signal pathways. Specific details of general formula (I) are as defined in the specification.

Description

氮雜並環化合物、其製備方法、抑制酪氨酸激 酶的方法、藥物組成物及其用途 Azanocyclic compound, preparation method thereof, inhibition of tyrosine stimulation Enzyme methods, pharmaceutical compositions and uses thereof

本發明涉及醫藥技術領域，特別是一種氮雜並環化合物、其製備方法、抑制酪氨酸激酶的方法、藥物組成物及其用途。 The invention relates to the technical field of medicine, in particular to an aza-heterocyclic compound, a preparation method thereof, a method for inhibiting tyrosine kinase, a pharmaceutical composition and use thereof.

酪氨酸激酶JAK(Janus kinase)為細胞內非受體酪氨酸激酶家族，介導細胞因數產生的信號，並通過JAK-STAT信號通路傳遞下去。酪氨酸激酶JAK既能磷酸化與其相結合的細胞因數受體，又能磷酸化多個含特定SH2結構域的信號分子。JAK蛋白家族共包括4個成員：JAK1、JAK2、JAK3以及Tyk2，它們在結構上有7個JAK同源結構域(JAK homology domain，JH)，其中JH1結構域為激酶區、JH2結構域是“假”激酶區、JH6和JH7是受體結合區域。已知JAK3和γc亞單位與連鎖嚴重聯合免疫(SCID)有關。JAK2對紅細胞和血小板的生成至關重要，JAK2突變還可導致骨 髓增生性疾病。而JAK1與真性紅細胞增多症有關。 The tyrosine kinase JAK (Janus kinase) is a family of intracellular non-receptor tyrosine kinases, which mediate the signals generated by cytokines and transmit them through the JAK-STAT signaling pathway. The tyrosine kinase JAK can not only phosphorylate the cytokine receptors bound to it, but also phosphorylate multiple signaling molecules containing specific SH2 domains. The JAK protein family includes 4 members: JAK1, JAK2, JAK3 and Tyk2. They have 7 JAK homology domains (JH) in structure, of which the JH1 domain is the kinase domain, and the JH2 domain is the "JAK homology domain". The pseudo" kinase domains, JH6 and JH7, are receptor binding domains. The JAK3 and γc subunits are known to be involved in linked severe combined immunity (SCID). JAK2 is essential for the production of red blood cells and platelets, and JAK2 mutations can also cause bone Myeloproliferative disease. JAK1 is associated with polycythemia vera.

JAK-STAT信號通路是一條由細胞因數刺激的信號轉導通路，參與細胞的增殖、分化、凋亡以及免疫調節等許多重要的生物學過程。JAK-STAT信號通路是細胞外信號(細胞因數)膜受體和細胞核之間的快速細胞內通訊途徑。與其它信號通路相比，JAK-STAT信號通路的傳遞過程相對簡單，它主要由三個成分組成，即酪氨酸激酶相關受體、酪氨酸激酶JAK和轉錄因數STAT。JAK-STAT信號通路被已知的50多種不同的細胞因數受體啟動，這些信號來自於促炎細胞因數，抗炎細胞因數，造血細胞生長因數和代謝因數。目前與疾病及藥物創新相關的研究都集中於炎症性疾病及腫瘤性疾病。其中，炎症性疾病主要包括類風濕性關節炎、犬皮炎、銀屑病、潰瘍性結腸炎及克羅恩病；而腫瘤性疾病則主要涉及骨髓纖維化、真性紅細胞增多症及原發性血小板增多症。 The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. The JAK-STAT signaling pathway is a rapid intracellular communication pathway between extracellular signal (cytokine) membrane receptors and the nucleus. Compared with other signaling pathways, the transmission process of JAK-STAT signaling pathway is relatively simple, and it is mainly composed of three components, namely tyrosine kinase-related receptors, tyrosine kinase JAK and transcription factor STAT. The JAK-STAT signaling pathway is activated by more than 50 different cytokine receptors known to be derived from pro-inflammatory cytokines, anti-inflammatory cytokines, hematopoietic growth factors and metabolic factors. The current research related to disease and drug innovation focuses on inflammatory diseases and tumor diseases. Among them, inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn's disease; while tumor diseases mainly involve myelofibrosis, polycythemia vera and essential platelets hyperplasia.

因此，新型酪氨酸激酶JAK抑制劑的研發具有廣闊應用前景並且也是迫切需要的。現有技術披露了一些JAK抑制劑，然而，本領域對於具有高選擇性的JAK抑制劑仍存在需求。 Therefore, the development of novel tyrosine kinase JAK inhibitors has broad application prospects and is also urgently needed. The prior art discloses some JAK inhibitors, however, there is still a need in the art for JAK inhibitors with high selectivity.

基於此，本發明提供了一種氮雜並環化合物，該氮雜並環化合物具有優異的酪氨酸激酶JAK抑制活性，可以作為酪氨酸激酶JAK抑制劑，解決多種JAK-STAT信號通路相關的炎症性疾 病或腫瘤性疾病。 Based on this, the present invention provides an azanocyclic compound, which has excellent tyrosine kinase JAK inhibitory activity, and can be used as a tyrosine kinase JAK inhibitor to solve various JAK-STAT signaling pathways related problems. inflammatory disease disease or neoplastic disease.

具體技術方案如下： The specific technical solutions are as follows:

具有通式(I)所示結構的氮雜並環化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： The azacyclic compound having the structure represented by the general formula (I) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, and prodrugs:

Figure 110145234-A0101-12-0003-344
Figure 110145234-A0101-12-0003-344

其中，L0選自單鍵和NR1； Wherein, L 0 is selected from single bond and NR 1 ;

X1選自CH和N； X 1 is selected from CH and N;

X2選自CR4和N； X 2 is selected from CR 4 and N;

R4為氰基， R 4 is cyano,

R1選自-H和C1-C3烷基，或R1可以與R4一起形成5~6元飽和或不飽和環；所述5~6元飽和或不飽和環任選被R6取代； R 1 is selected from -H and C 1 -C 3 alkyl, or R 1 can form a 5- to 6-membered saturated or unsaturated ring together with R 4 ; the 5- to 6-membered saturated or unsaturated ring is optionally surrounded by R 6 replace;

R6選自-H、=O、-OH、C1-C4烷基和C1-C4烷基羥基； R 6 is selected from -H, =O, -OH, C 1 -C 4 alkyl and C 1 -C 4 alkyl hydroxyl;

X3選自CH和N； X 3 is selected from CH and N;

n選自1和2； n is selected from 1 and 2;

m=2；兩個R0取代於同一碳原子之上或取代於相鄰碳原子之上，且兩個R0互相連接形成4~6元飽和氮雜環或4~6元飽和碳環；所述4~6元飽和氮雜環和4~6元飽和碳環分別獨立地任選被R2取代； m=2; two R 0 are substituted on the same carbon atom or on adjacent carbon atoms, and the two R 0 are connected to each other to form a 4-6 membered saturated nitrogen heterocycle or a 4-6 membered saturated carbocycle; The 4-6 membered saturated nitrogen heterocycle and the 4-6 membered saturated carbocycle are independently optionally substituted by R ;

R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、 -C(O)CH2CN、-NH-S(O)2(C1-C6烷基)、-NH-S(O)2(CH2)q-(3-6元環 烷基)、-NH-C(O)CH2CN、

Figure 110145234-A0101-12-0004-345
和
Figure 110145234-A0101-12-0004-346
； R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN,
Figure 110145234-A0101-12-0004-345
and
Figure 110145234-A0101-12-0004-346
;

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)； R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl);

q、p分別獨立選自0、1、2和3； q, p are independently selected from 0, 1, 2 and 3;

條件是，當X2為N時，R2不為-C(O)CH2CN；當X2為N，且兩個R0取代於相鄰碳原子之上時，兩個R0互相連接形成4~6元飽和碳環。 The condition is that when X 2 is N, R 2 is not -C(O)CH 2 CN; when X 2 is N, and two R 0 are substituted on adjacent carbon atoms, the two R 0 are connected to each other A 4- to 6-membered saturated carbocyclic ring is formed.

在其中一個示例中，式(I)中，L0選自單鍵和NR1；R1選自-H和C1-C3烷基。在另外一個示例中，L0還可以選自烷基、環烷基和雜環基。在另外一個示例中，R1還可以選自其它烷基、環烷基和雜環基。 In one example, in formula (I), L 0 is selected from single bond and NR 1 ; R 1 is selected from -H and C 1 -C 3 alkyl. In another example, L 0 may also be selected from alkyl, cycloalkyl and heterocyclyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups.

在其中一個示例中，式(I)中，X1選自CH和N。 In one example, in formula (I), X 1 is selected from CH and N.

在其中一個示例中，式(I)中，X2選自CR4和N。其中，R4選自氰基。在另外一個示例中，R4還可以選自烷基、環烷基、雜環基、芳基和雜芳基。 In one example, in formula (I), X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

在其中一個示例中，R1與R4一起形成5~6元不飽和環；所述5~6元不飽和環被R6取代；R6選自-H、=O、-OH、C1-C4烷基和C1-C4烷基羥基。更進一步地，R1與R4一起形成的5~6元不飽和環包括但不限於如下基團之一： In one example, R 1 and R 4 together form a 5- to 6-membered unsaturated ring; the 5- to 6-membered unsaturated ring is substituted by R 6 ; R 6 is selected from -H, =O, -OH, C 1 -C 4 alkyl and C 1 -C 4 alkyl hydroxy. Further, the 5-6 membered unsaturated ring formed by R 1 and R 4 together includes but is not limited to one of the following groups:

Figure 110145234-A0101-12-0005-347
Figure 110145234-A0101-12-0005-347

其中，X5、X7、X9、X10分別獨立地選自NR6、CHR6和C(R6)2； wherein, X 5 , X 7 , X 9 , and X 10 are independently selected from NR 6 , CHR 6 and C(R 6 ) 2 ;

X6、X8、X11分別獨立地選自N和CR6。 X 6 , X 8 , and X 11 are each independently selected from N and CR 6 .

在其中一個示例中，式(I)中，X3選自CH和N。 In one example, in formula (I), X 3 is selected from CH and N.

在其中一個示例中，式(I)中，m=2；兩個R0取代於同一碳原子之上或取代於相鄰碳原子之上，且兩個R0互相連接形成4~6元飽和氮雜環或4~6元飽和碳環。 In one example, in formula (I), m=2; two R 0 are substituted on the same carbon atom or on adjacent carbon atoms, and the two R 0 are connected to each other to form a 4- to 6-membered saturation Nitrogen heterocycle or 4~6 membered saturated carbocycle.

在其中一個實施方案中，所述4~6元飽和氮雜環和4~6元飽和碳環選自如下基團中的一種，環原子中有1或2個碳原子 為與基團

Figure 110145234-A0101-12-0005-348
n所共有的碳原子： In one embodiment, the 4- to 6-membered saturated nitrogen heterocycle and the 4- to 6-membered saturated carbocycle are selected from one of the following groups, and 1 or 2 carbon atoms in the ring atoms are with the group
Figure 110145234-A0101-12-0005-348
Carbon atoms shared by n :

Figure 110145234-A0101-12-0005-349
、
Figure 110145234-A0101-12-0005-350
、
Figure 110145234-A0101-12-0005-351
。
Figure 110145234-A0101-12-0005-349
,
Figure 110145234-A0101-12-0005-350
,
Figure 110145234-A0101-12-0005-351
.

在另外一個示例中，兩個R0還可以互相連接形成雜環基或環烷基。 In another example, two R 0 can also be connected to each other to form a heterocyclic group or a cycloalkyl group.

進一步地，4~6元飽和氮雜環和4~6元飽和碳環分別獨立地被R2取代； Further, the 4-6 membered saturated nitrogen heterocycle and the 4-6 membered saturated carbocycle are independently substituted by R 2 ;

R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN、-NH-S(O)2(C1-C6烷基)、-NH-S(O)2(CH2)q-(3-6元環烷基)、-NH-C(O)CH2CN和如下基團： R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN and the following groups:

Figure 110145234-A0101-12-0006-352
Figure 110145234-A0101-12-0006-352

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)；q、p分別獨立選自0、1、2和3。 R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，所述的化合物具有如下式(I-1)所示的結構特徵： In one of the embodiments, the compound has the structural features shown in the following formula (I-1):

Figure 110145234-A0101-12-0006-354
Figure 110145234-A0101-12-0006-354

在其中一個實施方案中，R2選自

Figure 110145234-A0101-12-0006-353
； In one of these embodiments, R 2 is selected from
Figure 110145234-A0101-12-0006-353
;

其中，R5選自-S-(3-5元環烷基)、C1-C3烷氧基或-S-C1-C3烷基。 Wherein, R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy or -SC 1 -C 3 alkyl.

在其中一個示例中，式(I-1)中，X1選自CH和N。進一步地，X1選自CH。 In one example, in formula (I-1), X 1 is selected from CH and N. Further, X 1 is selected from CH.

在其中一個示例中，式(I-1)中，R4選自氰基。 In one example, in formula (I-1), R 4 is selected from cyano.

在其中一個示例中，式(I-1)中，R1選自-H和C1-C3烷基。進一步地R1選自C1-C2烷基。更進一步地，R1選自甲基。在另外一個示例中，R1還可以選自其它烷基、環烷基和雜環基。 In one example, in formula (I-1), R 1 is selected from -H and C 1 -C 3 alkyl. Further R 1 is selected from C 1 -C 2 alkyl. Still further, R 1 is selected from methyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups.

在其中一個示例中，式(I-1)中，R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN和如下基團： In one example, in formula (I-1), R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN and the following groups:

Figure 110145234-A0101-12-0007-355
Figure 110145234-A0101-12-0007-355

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、C1-C5烷基巰基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)；q、p分別獨立選自0、1、2和3。 R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl mercapto, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.

在其中一個實施方案中，R1選自C1-C2烷基。 In one of these embodiments, R 1 is selected from C 1 -C 2 alkyl.

在其中一個實施方案中，X1選自CH。 In one of these embodiments, X1 is selected from CH.

更進一步地，R2選自如下基團： Further, R 2 is selected from the following groups:

Figure 110145234-A0101-12-0007-356
Figure 110145234-A0101-12-0007-356

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，所述的化合物具有如下式(I-2)或所述結構特徵： In one embodiment, the compound has the following formula (I-2) or the structural features:

Figure 110145234-A0101-12-0007-357
Figure 110145234-A0101-12-0007-357

在其中一個示例中，式(I-2)中，X1選自CH和N。進一 步地，X1選自CH。 In one example, in formula (I-2), X 1 is selected from CH and N. Further, X 1 is selected from CH.

在其中一個示例中，式(I-2)中，X2選自CR4和N。其中，R4選自氰基。在另外一個示例中，R4還可以選自烷基、環烷基、雜環基、芳基和雜芳基。進一步地，X2選自C-CN。進一步地，X2選自N。 In one example, in formula (I-2), X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Further, X 2 is selected from C-CN. Further, X 2 is selected from N.

在其中一個示例中，式(I-2)中，R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN和如下基團： In one example, in formula (I-2), R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN and the following groups:

Figure 110145234-A0101-12-0008-358
Figure 110145234-A0101-12-0008-358

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、C1-C5烷基巰基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)；q、p分別獨立選自0、1、2和3。 R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl mercapto, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.

在其中一個實施方案中，X2為N；R2選自-S(O)2(C1-C3 烷基)、-S(O)2CH2-(3-4元環烷基)和

Figure 110145234-A0101-12-0008-359
；其中，R5選自 -S-(3-5元環烷基)、C1-C3烷氧基和-S-C1-C3烷基。 In one embodiment, X 2 is N; R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl) and
Figure 110145234-A0101-12-0008-359
; wherein, R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

更進一步地，R2選自如下基團中的一種： Further, R 2 is selected from one of the following groups:

-S(O)2-丙基、-S(O)2-O-環丙基、

Figure 110145234-A0101-12-0008-360
、
Figure 110145234-A0101-12-0008-361
、
Figure 110145234-A0101-12-0008-362
 -S(O) 2 -propyl, -S(O) 2 -O-cyclopropyl,
Figure 110145234-A0101-12-0008-360
,
Figure 110145234-A0101-12-0008-361
,
Figure 110145234-A0101-12-0008-362

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包 含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，X2為CR4； In one of these embodiments, X 2 is CR 4 ;

R2選自-S(O)2(C1-C3烷基)、-S(O)2CH2-(3-4元環烷基)、 -C(O)CH2CN和

Figure 110145234-A0101-12-0009-363
；R5選自C1-C3烷氧基。 R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl), -C(O)CH 2 CN and
Figure 110145234-A0101-12-0009-363
; R 5 is selected from C 1 -C 3 alkoxy.

更進一步地，R2選自如下基團中的一種： Further, R 2 is selected from one of the following groups:

-S(O)2-丙基、-S(O)2-O-環丙基和-C(O)CH2CN。 -S(O) 2 -propyl, -S(O) 2 -O-cyclopropyl and -C(O) CH2CN .

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，X1選自CH。 In one of these embodiments, X1 is selected from CH.

在其中一個實施方案中，所述的化合物具有如下式(I-3)所述結構特徵： In one of the embodiments, the compound has the structural features described in the following formula (I-3):

Figure 110145234-A0101-12-0009-364
Figure 110145234-A0101-12-0009-364

在其中一個示例中，式(I-3)中，X1選自CH和N。進一步地，X1選自CH。 In one example, in formula (I-3), X 1 is selected from CH and N. Further, X 1 is selected from CH.

在其中一個示例中，式(I-3)中，X2選自CR4和N。其中，R4選自氰基。在另外一個示例中，R4還可以選自烷基、環烷基、雜環基、芳基和雜芳基。進一步地，X2為N。 In one example, in formula (I-3), X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Further, X 2 is N.

在其中一個示例中，式(I-3)中，R1選自-H和C1-C3烷基。 在另外一個示例中，R1還可以選自其它烷基、環烷基和雜環基。進一步地，R1選自CH3。 In one example, in formula (I-3), R 1 is selected from -H and C 1 -C 3 alkyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups. Further, R 1 is selected from CH 3 .

在其中一個示例中，式(I-3)中，R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN、-NH-S(O)2(C1-C6烷基)、-NH-S(O)2(CH2)q-(3-6元環烷基)、-NH-C(O)CH2CN和如下基團： In one example, in formula (I-3), R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN, -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3- 6-membered cycloalkyl), -NH-C(O)CH 2 CN and the following groups:

Figure 110145234-A0101-12-0010-365
Figure 110145234-A0101-12-0010-365

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)；q、p分別獨立選自0、1、2和3。 R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，X2為N； In one of these embodiments, X 2 is N;

R2選自

Figure 110145234-A0101-12-0010-366
；其中，R5選自C1-C3烷氧基和-S-C1-C3 烷基。 R 2 is selected from
Figure 110145234-A0101-12-0010-366
; wherein, R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

更進一步地，R2選自如下基團： Further, R 2 is selected from the following groups:

Figure 110145234-A0101-12-0010-367
Figure 110145234-A0101-12-0010-367

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包 含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，R1選自CH3。 In one of these embodiments, R 1 is selected from CH 3 .

在其中一個實施方案中，X1選自CH。 In one of these embodiments, X1 is selected from CH.

在其中一個實施方案中，所述的化合物具有如下式(I-4)所述結構特徵： In one of the embodiments, the compound has the structural features described in the following formula (I-4):

Figure 110145234-A0101-12-0011-369
Figure 110145234-A0101-12-0011-369

在其中一個示例中，式(I-4)中，X1選自CH和N。進一步地，X1選自CH。 In one example, in formula (I-4), X 1 is selected from CH and N. Further, X 1 is selected from CH.

在其中一個示例中，式(I-4)中，X2選自CR4和N。其中，R4選自氰基。在另外一個示例中，R4還可以選自烷基、環烷基、雜環基、芳基和雜芳基。進一步地，X2為N。 In one example, in formula (I-4), X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Further, X 2 is N.

在其中一個示例中，式(I-4)中，R1選自-H和C1-C3烷基。在另外一個示例中，R1還可以選自其它烷基、環烷基和雜環基。進一步地，R1選自CH3。 In one example, in formula (I-4), R 1 is selected from -H and C 1 -C 3 alkyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups. Further, R 1 is selected from CH 3 .

在其中一個示例中，式(I-4)中，R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN和如下基團： In one example, in formula (I-4), R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN and the following groups:

Figure 110145234-A0101-12-0011-368
Figure 110145234-A0101-12-0011-368

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6 元環烷基)；q、p分別獨立選自0、1、2和3。 R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，X2為N；R2選自-S(O)2(C1-C3烷基)或如下基團： In one of these embodiments, X 2 is N; R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl) or the following groups:

Figure 110145234-A0101-12-0012-370
；其中，R5選自C1-C3烷氧基或-S-C1-C3烷 基。更進一步地，R2選自S(O)2-丙基和如下基團：
Figure 110145234-A0101-12-0012-370
; wherein, R 5 is selected from C 1 -C 3 alkoxy or -SC 1 -C 3 alkyl. Further, R 2 is selected from S(O) 2 -propyl and the following groups:

Figure 110145234-A0101-12-0012-371
Figure 110145234-A0101-12-0012-371

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，R1選自CH3。 In one of these embodiments, R 1 is selected from CH 3 .

在其中一個實施方案中，X1選自CH。 In one of these embodiments, X1 is selected from CH.

在其中一個實施方案中，所述的化合物具有如下式(I-5)所述結構特徵： In one of the embodiments, the compound has the structural features described in the following formula (I-5):

Figure 110145234-A0101-12-0012-372
Figure 110145234-A0101-12-0012-372

X4選自CH或N； X 4 is selected from CH or N;

環A表示所述5~6元飽和或不飽和環。 Ring A represents the 5- to 6-membered saturated or unsaturated ring.

在其中一個實施方案中，環A選自如下基團之一： In one of these embodiments, Ring A is selected from one of the following groups:

Figure 110145234-A0101-12-0013-373
Figure 110145234-A0101-12-0013-373

其中，X5、X7、X9、X10分別獨立地選自NR6、CHR6或C(R6)2； wherein, X 5 , X 7 , X 9 and X 10 are independently selected from NR 6 , CHR 6 or C(R 6 ) 2 ;

X6、X8、X11分別獨立地選自N或CR6。 X 6 , X 8 , and X 11 are each independently selected from N or CR 6 .

進一步地，環A選自

Figure 110145234-A0101-12-0013-374
。 Further, ring A is selected from
Figure 110145234-A0101-12-0013-374
.

在其中一個示例中，式(I-5)中，X1選自CH和N。進一步地，X1選自CH。 In one example, in formula (I-5), X 1 is selected from CH and N. Further, X 1 is selected from CH.

在其中一個示例中，式(I-5)中，X4選自CH。在另外一個實施方案中，X4選自N。 In one example, in formula (I-5), X 4 is selected from CH. In another embodiment, X4 is selected from N.

在其中一個示例中，式(I-5)中，R6選自-H、-OH、C1-C4烷基和C1-C4烷基羥基。 In one example, in formula (I-5), R 6 is selected from -H, -OH, C 1 -C 4 alkyl and C 1 -C 4 alkylhydroxy.

進一步地，式(I-5)中，R6選自-H、-OH、C1-C3烷基和C1-C3烷基羥基。更進一步地，R6選自-H、-OH、甲基和-CH(CH3)OH。 Further, in formula (I-5), R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkyl hydroxyl. Still further, R6 is selected from -H, -OH, methyl and -CH( CH3 ) OH.

在其中一個示例中，式(I-5)中，R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN、-NH-S(O)2(C1-C6烷基)、-NH-S(O)2(CH2)q-(3-6元環烷基)、-NH-C(O)CH2CN和如下 基團：

Figure 110145234-A0101-12-0013-375
、
Figure 110145234-A0101-12-0013-376
； In one example, in formula (I-5), R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN, -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3- 6-membered cycloalkyl), -NH-C(O)CH 2 CN and the following groups:
Figure 110145234-A0101-12-0013-375
,
Figure 110145234-A0101-12-0013-376
;

R5選自C1-C5烷基、氰基、3-5元的飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)；q、p分別獨立選自0、1、2和3。 R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.

進一步地，R2選自如下基團： Further, R 2 is selected from the following groups:

Figure 110145234-A0101-12-0014-377
Figure 110145234-A0101-12-0014-377

R5選自C1-C3烷氧基。 R 5 is selected from C 1 -C 3 alkoxy.

更進一步地，R2選自如下基團中的一種： Further, R 2 is selected from one of the following groups:

Figure 110145234-A0101-12-0014-378
Figure 110145234-A0101-12-0014-378

在另外一個示例中，R2還可以選自烷基、環烷基、烷氧基、環烷基、雜環基、芳基和雜芳基。作為優選地，前述R2中包含-S-或-S(O)2-，或者被至少一個氰基或巰基取代。 In another example, R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferably, the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.

在其中一個實施方案中，R6選自-H、-OH、C1-C3烷基、C1-C3烷基羥基。 In one of these embodiments, R 6 is selected from -H, -OH, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy.

在其中一個實施方案中，R2選自如下基團： In one of these embodiments, R 2 is selected from the following groups:

Figure 110145234-A0101-12-0014-379
Figure 110145234-A0101-12-0014-379

R5選自C1-C3烷氧基或-S-C1-C3烷基。 R 5 is selected from C 1 -C 3 alkoxy or -SC 1 -C 3 alkyl.

在其中一個實施方案中，X1選自CH。 In one of these embodiments, X1 is selected from CH.

在其中一個實施方案中，所述氮雜並環化合物選自如下化合物中的一種： In one of these embodiments, the azacyclic compound is selected from one of the following compounds:

Figure 110145234-A0101-12-0015-380
Figure 110145234-A0101-12-0015-380

本發明還提供一種氮雜並環化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥的製備方法，所述的化合物的製備方法包括如下步驟： The present invention also provides a method for preparing aza-heterocyclic compounds or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, and prodrugs. The preparation method of the compound comprises the steps:

Figure 110145234-A0101-12-0016-381
中間體1
Figure 110145234-A0101-12-0016-381
Intermediate 1

Figure 110145234-A0101-12-0016-382
中間體2
Figure 110145234-A0101-12-0016-382
Intermediate 2

Figure 110145234-A0101-12-0016-385
Figure 110145234-A0101-12-0016-385

中間體1與中間體2進行取代反應，製備式(I)化合物； Intermediate 1 and Intermediate 2 are subjected to substitution reaction to prepare the compound of formula (I);

式(I)化合物與包含R2的化合物進行取代或縮合反應； A compound of formula (I) is subjected to a substitution or condensation reaction with a compound comprising R 2 ;

作為選擇，L0中的R1可以與X2中的R4一起形成5~6元不飽和環；所述5~6元不飽和環被R6取代； Alternatively, R 1 in L 0 can form a 5- to 6-membered unsaturated ring together with R 4 in X 2 ; the 5- to 6-membered unsaturated ring is substituted by R 6 ;

其中包含R2的化合物選自如下化合物中的一種： The compound wherein R is selected from one of the following compounds:

R2-X、R2-H、

Figure 110145234-A0101-12-0016-383
和
Figure 110145234-A0101-12-0016-384
； R 2 -X, R 2 -H,
Figure 110145234-A0101-12-0016-383
and
Figure 110145234-A0101-12-0016-384
;

X表示鹵素，L0、R1、R0、R2、R6、X1、X2、R4、X3、n和m的定義同上所述。 X represents halogen, and L 0 , R 1 , R 0 , R 2 , R 6 , X 1 , X 2 , R 4 , X 3 , n and m are as defined above.

本發明還提供一種藥物組成物，所述藥物組成物包含如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥。 The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs type, prodrug.

本發明還提供如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、 多晶型、前藥在製備具有酪氨酸激酶JAK抑制活性的藥物中的應用。 The present invention also provides compounds as described above or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, Application of polymorphic forms and prodrugs in the preparation of drugs with tyrosine kinase JAK inhibitory activity.

本發明還提供如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥在製備具有預防或治療自身免疫性疾病、皮膚病、變應性疾病、器官排斥、癌症、乾眼病、骨髓纖維化、紅細胞增多症的功效的藥物中的應用。 The present invention also provides compounds as described above or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs in the preparation of prophylactic or therapeutic properties Use in medicaments for the efficacy of immune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, polycythemia.

在其中一個實施方案中，所述自身免疫性疾病為狼瘡、多發性硬化、類風濕性關節炎、青少年關節炎、銀屑病、潰瘍性結腸炎、克羅恩氏病或自體免疫性甲狀腺疾病；所述皮膚病為牛皮癬、皮疹或特應性皮炎；所述變應性病症為哮喘或鼻炎病；所述器官移植排斥為異體抑制排斥或移植物抗宿主疾病；所述癌症為腎癌、肝癌、胰腺癌、胃癌、乳腺癌、***癌、頭頸部癌、甲狀腺癌、肺癌、膠質母細胞瘤、黑素瘤、淋巴瘤或白血病。 In one embodiment, the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease; the skin disease is psoriasis, rash or atopic dermatitis; the allergic condition is asthma or rhinitis; the organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease; the cancer is kidney cancer , liver cancer, pancreatic cancer, stomach cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma or leukemia.

與現有技術相比較，本發明具有如下有益效果中的一種或多種： Compared with the prior art, the present invention has one or more of the following beneficial effects:

本發明提供了一種氮雜並環化合物，其可以作為新型的酪氨酸激酶JAK抑制劑，發揮較佳的酪氨酸激酶JAK抑制活性，能夠解決多種JAK-STAT信號通路相關的炎症性疾病或腫瘤性疾病。同時，在研究過程中發現，該氮雜並環化合物對JAK1具有良好的選擇性抑制活性。在大鼠關節炎模型(CIA)研究中，與對照相比，本發明化合物顯著降低CIA大鼠後肢足容積和關節炎指數 (AI)。另外，本發明化合物具有明顯的藥代動力學優勢。 The present invention provides an azacyclic compound, which can be used as a novel tyrosine kinase JAK inhibitor, exert better tyrosine kinase JAK inhibitory activity, and can solve various inflammatory diseases related to JAK-STAT signaling pathway or neoplastic disease. At the same time, during the research, it was found that the azanocyclic compound has a good selective inhibitory activity on JAK1. In a rat arthritis model (CIA) study, the compounds of the present invention significantly reduced hind paw volume and arthritic index in CIA rats compared to controls (AI). In addition, the compounds of the present invention possess significant pharmacokinetic advantages.

圖1、每天1次連續2周經口灌胃給予化合物對CIA大鼠體重的影響。 Figure 1. The effect of oral gavage of compounds once a day for 2 weeks on the body weight of CIA rats.

圖2、每天1次連續2周經口灌胃給予化合物對CIA大鼠後足足容積的影響(n=10)。 Figure 2. Effects of oral gavage of compounds administered once a day for 2 consecutive weeks on hind paw volume in CIA rats (n=10).

圖3、每天1次連續2周經口灌胃給予化合物對CIA大鼠關節炎指數的影響(n=10)。 Figure 3. The effect of oral gavage administration of compounds once a day for 2 weeks on arthritis index in CIA rats (n=10).

圖4、每天1次連續2周經口灌胃給予化合物對CIA大鼠後足足容積的影響。 Figure 4. Effects of oral gavage of compounds once a day for 2 weeks on hind paw volume in CIA rats.

圖5、每天1次連續2周經口灌胃給予化合物對CIA大鼠關節炎指數的影響。 Figure 5. The effect of oral gavage of compounds once a day for 2 weeks on arthritis index in CIA rats.

以下結合具體實施例對本發明的氮雜並環化合物、其製備方法及其用途作進一步詳細的說明。本發明可以以許多不同的形式來實現，並不限於本文所描述的實施方式。相反地，提供這些實施方式的目的是使對本發明公開內容理解更加透徹全面。 The azacyclic compounds of the present invention, their preparation methods and their uses will be described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.

除非另有定義，本文所使用的所有的技術和科學術語與屬於本發明的技術領域的技術人員通常理解的含義相同。本文在說明書中所使用的術語只是為了描述具體的實施例的目的，不是 旨在於限制本發明。文所使用的術語“和/或”意指一個或多個相關的所列專案中的任意一種和所有專案的組合。 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms used herein in the specification are for the purpose of describing particular embodiments only, not It is intended to limit the invention. As used herein, the term "and/or" means any and all combinations of one or more of the associated listed items.

術語“光學異構體”如果沒有特殊說明，應包括所有異構體中的一種或它們的混合物，例如，雙鍵、環中的幾何異構體(E型、Z型、順式的(cis)、反式的(trans))，直鏈烷基和支鏈烷基中由存在不對稱碳原子等而產生的光學異構體(R型、S型)及它們任意比例的混合物。外消旋混合物以及所有的由互變異構體產生的異構體均包括在本發明中。另外，每種化合物結構均可以為具有相同分子式的不同立體異構體，其中的立體異構體還包括對映異構體和非對映異構體，對映異構體即為光學異構體，非對映異構體為不成手性對映的立體異構體，與本發明化合物具有相同分子式的不同異構體也在本發明的保護範圍內。 The term "optical isomer", unless otherwise specified, shall include one of all isomers or their mixtures, for example, double bonds, geometric isomers in rings (E, Z, cis (cis) ), trans (trans)), optical isomers (R-type, S-type) arising from the presence of asymmetric carbon atoms in straight-chain alkyl and branched-chain alkyl groups, and mixtures thereof in any ratio. Racemic mixtures and all isomers resulting from tautomers are included in the present invention. In addition, each compound structure can be different stereoisomers with the same molecular formula, among which stereoisomers also include enantiomers and diastereomers, and enantiomers are optical isomers Diastereomers are stereoisomers of achiral enantiomers, and different isomers with the same molecular formula as the compounds of the present invention are also within the protection scope of the present invention.

術語“藥學上可接受的鹽”是指化合物可以通過傳統的方法轉化為相應的鹽，其在化學上或物理上與構成某藥物劑型的其它成分相相容，並在生理上與受體相相容。該鹽可以為化合物與無機和/或有機酸和/或與無機和/或有機堿形成的酸式和/或鹼式鹽，也包括兩性離子鹽(內鹽)，還包括季銨鹽，例如烷基銨鹽。這些鹽可以是在化合物的最後分離和純化中直接得到。也可以是通過將本發明的化合物或其立體異構體或溶劑合物，與一定數量的酸或堿適當混合而得到的。這些鹽可能在溶液中形成沉澱而以過濾方法收集，或在溶劑蒸發後回收而得到，或在水介質中反應後冷卻乾燥制得。具體地，鹽優選為水溶性的藥學上可接受的無毒 酸加成鹽，實例為氨基與無機酸(如鹽酸、氫溴酸、磷酸、硫酸以及高氯酸)或與有機酸(如乙酸、草酸、順丁烯二酸、酒石酸、檸檬酸、琥珀酸或丙二酸)形成的鹽，或通過使用本領域中傳統的其他方法(例如離子交換法)形成的鹽。其他藥學上可接受的鹽包括己二酸鹽、藻酸鹽、抗壞血酸鹽、天冬氨酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、甲酸鹽、富馬酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘化物、2-羥基-乙烷磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲烷磺酸鹽、2-萘磺酸鹽、煙酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對-甲苯磺酸鹽、十一烷酸鹽、戊酸鹽等。適當時，另外的藥學上可接受的鹽還可以包括衍生自適當堿的鹽，包括鹼金屬鹽、鹼土金屬鹽以及銨鹽。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽等。適當時，另外的藥學上可接受的鹽包括使用如鹵離子、氫氧根、羧酸根、硫酸根、磷酸根、硝酸根、低級烷基磺酸根以及芳基磺酸根等平衡離子與無毒銨、季銨以及胺陽離子形成的鹽。 The term "pharmaceutically acceptable salts" refers to compounds that can be converted by conventional methods into the corresponding salts which are chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and which are physiologically compatible with the receptor. compatible. The salts may be acid and/or base salts of compounds with inorganic and/or organic acids and/or with inorganic and/or organic halides, also including zwitterionic salts (inner salts), as well as quaternary ammonium salts, such as Alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or phosphonium. These salts may form precipitates in solution and be collected by filtration, or recovered after evaporation of the solvent, or obtained by cooling and drying after reaction in an aqueous medium. In particular, the salts are preferably water-soluble, pharmaceutically acceptable non-toxic Acid addition salts, examples are amino acids with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acid), or by using other methods conventional in the art (eg, ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate , camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate salt, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate acid salt, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate , thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Additional pharmaceutically acceptable salts may also include salts derived from suitable phosphoniums, including alkali metal, alkaline earth metal, and ammonium salts, as appropriate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include the use of counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates with nontoxic ammonium, Salts of quaternary ammonium and amine cations.

術語“溶劑化物”也可以稱為“溶劑化合物”、“溶劑合物”，指的是含有溶劑分子的化合物，其中溶劑分子可以以包括配位 鍵、共價鍵、範德華力、離子鍵、氫鍵等方式與化合物分子相結合。常規溶劑包括包括水、甲醇、乙醇、乙酸、DMSO、THF、***等。本文所述的化合物可製備成，例如，結晶形式，且可被溶劑化。合適的溶劑化物包括藥學上可接受的溶劑化物且進一步包括化學計量的溶劑化物和非化學計量的溶劑化物。在一些情況下，所述溶劑化物將能夠分離，例如，當一或多個溶劑分子摻入結晶固體的晶格中時。“溶劑化物”包括溶液狀態的溶劑化物和可分離的溶劑化物。代表性的溶劑化物包括水合物、乙醇合物和甲醇合物。 The term "solvate" may also be referred to as "solvate", "solvate" and refers to a compound containing solvent molecules, wherein the solvent molecules can be coordinated to include Bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds, etc., are combined with compound molecules. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

術語“前藥”是指當被施用至生物體時由於自發化學反應、酶催化的化學反應、光解和/或代謝化學反應而產生藥物，即活性成分的任何化合物。前藥因此是治療活性化合物的共價改性的類似物或潛在形式。合適的實例包括但不限於：化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、碸酯、亞碸酯、氨基化合物、氨基甲酸鹽、偶氮化合物、磷醯胺、葡萄糖苷、醚、乙縮醛等形式。 The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, ie, an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. Suitable examples include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulphate, sulfite, sulfite, amino compounds, carbamates, azo compounds, phosphamide, glucose glycosides, ethers, acetals and other forms.

"任選的"或"任選地"意味著隨後所描述的事件或環境可以但不必發生，包括該事件或環境發生或不發生的場合。例如，“芳基任選被烷基取代”意味著烷基可以但不必須存在，該術語包括芳基被烷基取代的情形和芳基不被烷基取代的情形。 "Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, including where it does or does not occur. For example, "an aryl group is optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the term includes instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an alkyl group.

“藥學上可接受的載體”指藥學上可接受的材料、組成物或媒劑，例如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封 材料。如本文所用，術語“藥學上可接受的載體”包括與藥物施用相容的緩衝劑、注射用無菌水、溶劑、分散介質、包衣、抗細菌劑及抗真菌劑、等滲劑及吸收延遲劑及諸如此類。在與配製物中其他成分相容且對患者無害的意義上，每種載體必須為“藥學上可接受的”。合適的實例包括但不限於：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)澱粉，例如玉米澱粉、馬鈴薯澱粉及經取代或未經取代的β-環糊精；(3)纖維素及其衍生物，例如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素；(4)粉狀黃蓍膠；(5)麥芽；(6)明膠；(7)滑石；(8)賦形劑，例如可哥脂及栓劑蠟；(9)油類，例如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯類，例如油酸乙酯及月桂酸乙酯；(13)瓊脂；(14)緩衝劑，例如氫氧化鎂及氫氧化鋁；(15)海藻酸；(16)無熱原水；(17)等滲鹽水；(18)林格氏溶液；(19)乙醇；(20)磷酸鹽緩衝液；及(21)藥物配製物中所採用的其他無毒相容物質。 "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating agent Material. As used herein, the term "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents compatible with pharmaceutical administration agents and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) Excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) drug Other non-toxic compatible substances employed in the formulation.

術語“代謝產物”是指物質包括本發明化合物在體內新陳代謝中產生的產物，包括中間代謝產物和最終代謝產物。 The term "metabolite" refers to a substance including the products of the compounds of the present invention produced during metabolism in vivo, including intermediate metabolites and final metabolites.

術語“多晶型”是指特定晶體堆積排列的化合物的結晶形式(或其鹽、水合物或溶劑化物)。所有的多晶型物具有相同的元素組成。不同的結晶形式通常具有不同的X射線衍射圖、紅外光譜、熔點、密度、硬度、晶體形狀、光電性質、穩定性和溶解度。重結晶溶劑、結晶速率、貯存溫度和其他因素可導致一種結晶形式 占優。化合物的各種多晶型物可在不同的條件下通過結晶製備。 The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can lead to a crystalline form dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

術語“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其組合的飽和烴。烷基優選為例如C1-C6烷基、C1-C5烷基、C1-C4烷基和C1-C3烷基。以“C1-C3烷基”為例，其是指包含1~3個碳原子的烷基，每次出現時，可以互相獨立地為C1烷基、C2烷基、C3烷基。合適的實例包括但不限於：甲基(Me、-CH3)、乙基(Et、-CH2CH3)、1-丙基(n-Pr、n-丙基、-CH2CH2CH3)、2-丙基(i-Pr、i-丙基、-CH(CH3)2)。 The term "alkyl" refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Alkyl groups are preferably, for example, C 1 -C 6 -alkyl, C 1 -C 5 -alkyl, C 1 -C 4 -alkyl and C 1 -C 3 -alkyl groups. Taking "C 1 -C 3 alkyl" as an example, it refers to an alkyl group containing 1 to 3 carbon atoms, and each time it appears, it can be independently C 1 alkyl, C 2 alkyl, C 3 alkane base. Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH( CH3 ) 2 ).

“烯基”是本發明定義的烷基中包含至少一個碳-碳雙鍵。在其中一個實例中，所述烯基含有2至20個碳原子，優選2至12個碳原子，進一步優選2至8個碳原子，更進一步優選為2至6個碳原子。烯基的非限定實例包括取代或未取代的乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、4-戊烯基、3-戊烯基、2-己烯基、3-己烯基、2-庚烯基、3-庚烯基、4-庚烯基、3-辛烯基、3-壬烯基或4-癸烯基等。當被取代時，取代基優選為1至5個，並且取代基獨立地選自F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、羥基、硝基、氰基和氨基。 "Alkenyl" is an alkyl group as defined herein containing at least one carbon-carbon double bond. In one example, the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl or 4-decenyl and the like. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.

“炔基”是本發明定義的烷基中包含至少一個碳-碳三鍵。在其中一個實例中，所述炔基含有2至20個碳原子，優選2至12個碳原子，進一步優選2至8個碳原子，更進一步優選2-6個碳原子。炔基的非限定實例包括取代或未取代的乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、4-戊炔基、3-戊炔基、 2-己炔基、3-己炔基、3-丁炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基或4-癸炔基等，當被取代時，取代基優選為1至5個，並且取代基獨立地選自F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、羥基、硝基、氰基和氨基。 "Alkynyl" is an alkyl group as defined herein containing at least one carbon-carbon triple bond. In one example, the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2-6 carbon atoms. Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl , 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl or 4- Decynyl, etc., when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, Hydroxy, nitro, cyano and amino.

術語“飽和或不飽和環”包括如下定義的碳環基、雜環基、芳基和雜芳基。 The term "saturated or unsaturated ring" includes carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined below.

“碳環基”或“環烷基”是指飽和或者部分不飽和的環狀含碳基團，例如4-6元(例如5-6元)的飽和碳環和5-6元的部分不飽和碳環。在其中一個實施方案中，碳環基是3至4元的單環、3至5元的單環、3至6元的單環、3至8元的單環、3至10元的單環、5至8元的單環、5至6元的單環、4至12元雙環或者10至15元三環系統。碳環包括橋環或者螺環。碳環基的非限制性實例包括環丙基、環丁基、環戊基、環己基、環己烯基、環庚基、環戊烯基、環己二烯基、環庚三烯基、苯並環戊基、二環[3.2.1]辛烷基、二環[5.2.0]壬烷基、三環[5.3.1.1]十二烷基、金剛烷基或螺[3.3]庚烷基等。碳環基可以任選被取代。當被取代時，取代基優選為1至5個，並且所述取代基獨立地選自F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、羥基、硝基、氰基和氨基。 "Carbocyclyl" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 4-6 membered (eg, 5-6 membered) saturated carbocycle and a 5-6 membered partially Saturated carbocycle. In one embodiment, the carbocyclyl group is a 3- to 4-membered monocycle, a 3- to 5-membered monocycle, a 3- to 6-membered monocycle, a 3- to 8-membered monocycle, a 3- to 10-membered monocycle , 5 to 8 membered monocyclic, 5 to 6 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring systems. Carbocycles include bridged or spiro rings. Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl or spiro[3.3]heptane Base et al. Carbocyclyl groups can be optionally substituted. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro group, cyano group and amino group.

進一步，術語“飽和環烷基”包含環碳原子的非芳香族烴，可以為單環烷基或橋環烷基。包含該術語的短語，例如，“3-6元的飽和環烷基”是指包含3~6個碳原子的環烷基，每次出現時，可以互相獨立地為C3環烷基、C4環烷基、C5環烷基或C6環烷基。 合適的實例包括但不限於：環丙基、環丁基、環戊基和環己基。優選地，飽和環烷基為4-6元飽和碳環，進一步優選為5-6元飽和碳環。 Further, the term "saturated cycloalkyl" comprises a non-aromatic hydrocarbon containing ring carbon atoms and may be a monocycloalkyl or a bridged cycloalkyl. Phrases containing this term, for example, "3-6 membered saturated cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which may independently be C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl or C 6 cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably, the saturated cycloalkyl is a 4-6 membered saturated carbocycle, more preferably a 5-6 membered saturated carbocycle.

相應地，術語“飽和氮雜環基”是指飽和環烷基中至少一個環碳原子被N取代。 Correspondingly, the term "saturated nitrogen heterocyclyl" refers to a saturated cycloalkyl group in which at least one ring carbon atom is substituted with N.

術語“鹵素”是指-F、-Cl、-Br或-I。進一步，術語“鹵代烷基”是指經鹵素基團取代的烷基，其中烷基如上文所定義，優選為鹵代C1-6烷基、鹵代C1-5烷基、鹵代C1-4烷基、鹵代C1-3烷基和鹵代C1-2烷基。 The term "halogen" refers to -F, -Cl, -Br or -I. Further, the term "haloalkyl" refers to an alkyl group substituted with a halogen group, wherein the alkyl group is as defined above, preferably haloC1-6 alkyl, haloC1-5 alkyl, haloC1 -4 alkyl, halogenated C 1-3 alkyl and halogenated C 1-2 alkyl.

術語“氰基”是指-CN。 The term "cyano" refers to -CN.

術語“巰基”是指-SH。 The term "mercapto" refers to -SH.

術語“羥基”是指-OH。進一步，術語“烷基羥基”是指經羥基取代的烷基，其中烷基如上文所定義，優選為C1-6烷基羥基、C1-5烷基羥基、C1-4烷基羥基、C1-3烷基羥基和C1-2烷基羥基。 The term "hydroxy" refers to -OH. Further, the term "alkylhydroxy" refers to an alkyl group substituted with a hydroxyl group, wherein the alkyl group is as defined above, preferably C1-6 alkylhydroxyl, C1-5 alkylhydroxyl, C1-4 alkylhydroxyl , C 1-3 alkyl hydroxyl and C 1-2 alkyl hydroxyl.

術語“烷氧基”是指具有-O-烷基的基團，即如上所定義的烷基經由氧原子連接至母核結構。包含該術語的短語，例如，“C1-C5烷氧基”是指烷基部分包含1~5個碳原子，“C1-C3烷氧基”是指烷基部分包含1~3個碳原子。 The term "alkoxy" refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, "C 1 -C 5 alkoxy" means that the alkyl moiety contains 1 to 5 carbon atoms, and "C 1 -C 3 alkoxy" means that the alkyl moiety contains 1 to 5 carbon atoms. 3 carbon atoms.

術語“芳基”是指在芳香環化合物的基礎上除去一個氫原子衍生的芳族烴基，可以為單環芳基、或稠環芳基、或多環芳基，優選為6-10元芳基。對於多環的環種，至少一個是芳族環系。包含該術語的短語，例如，“5-6元芳基”是指芳香環系包含5-6個環 原子。優選地，芳基為苯基。 The term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which can be a monocyclic aryl group, a fused-ring aryl group, or a polycyclic aryl group, preferably a 6-10 membered aryl group base. For polycyclic ring species, at least one is an aromatic ring system. Phrases containing this term, for example, "5-6 membered aryl" means that the aromatic ring system contains 5-6 rings atom. Preferably, the aryl group is phenyl.

術語“雜芳基”是指含有雜原子的芳基，其可為單環或稠合環，所述雜原子獨立地選自N、O和S，優選為5-12元雜芳基，優選為5-8元雜芳基，更優選為5-6元雜芳基，更優選為5元雜芳基。雜芳基包括但不限於吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、異噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、噠嗪基、喹啉基、異喹啉基、***基、四氫吡咯基和噻二唑基。在某一方案中，典型地含1個或多個，優選1-3個獨立選自N、O和S的雜原子的5-6元單環雜芳基。除非另外說明，“5-元雜芳基”為包含一個雜原子的示例性5-元雜芳基基團包括但不限於，吡咯基、呋喃基以及噻吩基；包含兩個雜原子的示例性5-元雜芳基基團包括但不限於，咪唑基、吡唑基、噁唑啉基、異噁唑啉基、噻唑基以及異噻唑基；包含三個雜原子的示例性5-元雜芳基基團包括但不限於，噻唑基、噁二唑基以及噻二唑基；包含四個雜原子的示例性5-元雜芳基基團包括但不限於，四唑基。 The term "heteroaryl" refers to aryl groups containing heteroatoms, which may be monocyclic or fused, independently selected from N, O and S, preferably 5-12 membered heteroaryl groups, preferably is a 5-8-membered heteroaryl group, more preferably a 5-6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group. Heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, Isoquinolinyl, triazolyl, tetrahydropyrrolyl and thiadiazolyl. In one embodiment, a 5-6 membered monocyclic heteroaryl group typically contains 1 or more, preferably 1-3 heteroatoms independently selected from N, O and S. Unless otherwise specified, "5-membered heteroaryl" is an exemplary 5-membered heteroaryl group containing one heteroatom including, but not limited to, pyrrolyl, furyl, and thienyl; exemplary groups containing two heteroatoms 5-membered heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroatoms containing three heteroatoms Aryl groups include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.

“雜環基”或“雜環”是指取代的或未取代的飽和或者部分不飽和的含雜原子的環狀基團，所述雜原子選自N、O和S。進一步，術語“雜環基”指的是非芳香環的一個或多個構成環的原子是雜原子、其餘為碳的穩定的3-10元飽和雜環系統的基團。所述的雜原子包括而不限於氮原子、氧原子和硫原子等。所述雜環基可以是3至8元的單環、5至8元的單環、5至6元的單環、4至12元雙環或者10至15元三環系統，優選3至10元雜環基，且包含 至少1個，優選1至4個選自N、O或S的雜原子。除非本說明書中另外特別指明，否則雜環烷基基團可以是單環的(“單環的雜環烷基”)，或者是雙環、三環或更多環的環體系，其可包括並環的(稠合的)、橋聯的(橋環的)或螺的環系統(例如二環系統(“二環的雜環烷基”)。二環雜環烷基的環系統可以在一個或兩個環中包括一個或多個雜原子；並且是飽和的。示例性3-元雜環基基團包括但不限於，氮雜環丙基、環氧乙烷基以及硫雜環丙烷基，或者其立體異構體；示例性4-元雜環基基團包括但不限於，氮雜環丁烷基，環氧丙烷基，硫雜環丁烷基，或者其同分異構體和立體異構體；示例性5-元雜環基基團包括但不限於，四氫呋喃基，四氫噻吩基，吡咯烷基，噻唑烷基，異噻唑烷基，噁唑烷基，異噁唑烷基，咪唑烷基，吡唑烷基，二氧戊環基，氧雜硫雜環戊基，二硫雜環戊基，或者其同分異構體和立體異構體。示例性6-元雜環基基團包括但不限於，呱啶基，四氫吡喃基，硫雜環己烷基，嗎啉基，硫嗎啉基，二噻烷基，二噁烷基，呱嗪基，三嗪烷基，或者其同分異構體和立體異構體；示例性7-元雜環基基團包括但不限於，氮雜環庚烷基，氧雜環庚烷基，硫雜環庚烷基，以及二氮雜環庚烷基，或者其同分異構體和立體異構體。在某一方案中，典型的雜環基為含1個或多個，優選1-4個，更優選1-3個獨立選自N、O和S的雜原子的5-6元單環雜環基。在一個實施方案中，“雜環烷基”為4-6元雜環烷基，其中雜原子選自N、O和S中的一種或多種，雜原子數為1、2或3個。 "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing a heteroatom selected from N, O and S. Further, the term "heterocyclyl" refers to a non-aromatic group of a stable 3-10 membered saturated heterocyclic ring system wherein one or more of the ring-constituting atoms are heteroatoms and the remainder is carbon. The heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms, sulfur atoms, and the like. The heterocyclyl group may be a 3- to 8-membered monocyclic ring, a 5- to 8-membered monocyclic ring, a 5- to 6-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, preferably a 3- to 10-membered ring system Heterocyclyl, including At least 1, preferably 1 to 4 heteroatoms selected from N, O or S. Unless specifically stated otherwise in this specification, a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or more cyclic ring system, which may include and Cyclic (fused), bridged (bridged), or spiro ring systems (eg, bicyclic ring systems ("bicyclic heterocycloalkyl"). The ring systems of bicyclic heterocycloalkyl groups may be in a and is saturated. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane , or a stereoisomer thereof; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietane, or isomers thereof and Stereoisomers; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidine radical, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, or isomers and stereoisomers thereof. Exemplary 6-membered Heterocyclyl groups include, but are not limited to, oxidyl, tetrahydropyranyl, thiane, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, oxazinyl, Triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiacycle Heptyl group, and diazepanyl group, or its isomers and stereoisomers. In a certain scheme, a typical heterocyclic group contains 1 or more, preferably 1-4 , more preferably a 5-6 membered monocyclic heterocyclyl with 1-3 heteroatoms independently selected from N, O and S. In one embodiment, "heterocycloalkyl" is a 4-6 membered heterocycloalkyl , wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

在本發明的各部分，描述了連接取代基。當該結構清楚地需要連接基團時，針對該基團所列舉的馬庫什變數應理解為連接基團。例如，如果該結構需要連接基團並且針對該變數的馬庫什基團定義列舉了“烷基”或“芳基”，則應該理解，該“烷基”或“芳基”分別代表連接的亞烷基基團或亞芳基基團。在一些具體的結構中，當烷基基團清楚地表示為連接基團時，則該烷基基團代表連接的亞烷基基團，例如，基團“-C1-C3鹵代烷基”中的烷基應當理解為亞烷基。 In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and "alkyl" or "aryl" is listed for the definition of a Markush group for that variable, it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group. In some specific structures, when an alkyl group is clearly represented as a linking group, then the alkyl group represents the alkylene group to which it is attached, eg, the group " -C1 - C3 haloalkyl" Alkyl in should be understood to mean alkylene.

除非另有規定，本文使用的所有技術術語和科學術語具有要求保護主題所屬領域的標準含義。倘若對於某術語存在多個定義，則以本文定義為准。應該理解，在本發明中使用的單數形式，如“一種”，包括複數指代，除非另有規定。 Unless otherwise defined, all technical and scientific terms used herein have the standard meaning in the art to which the claimed subject matter belongs. If more than one definition exists for a term, the definitions herein prevail. It should be understood that singular forms such as "a" used in the present invention include plural referents unless stated otherwise.

此外，術語“包括”、“包含”是開放性限定並非封閉式，即包括本發明所指明的內容，但並不排除其他方面的內容。 In addition, the terms "comprising" and "comprising" are open definition rather than closed, that is, the content specified in the present invention is included, but other aspects are not excluded.

除非另有說明，本發明採用質譜、核磁等傳統方法鑒定化合物，各步驟和條件可參照本領域常規的操作步驟和條件。 Unless otherwise specified, the present invention adopts traditional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to the routine operation steps and conditions in the art.

除非另有指明，本發明採用分析化學、有機合成化學和光學的標準命名及標準實驗室步驟和技術。在某些情況下，標準技術被用於化學合成、化學分析、發光器件性能檢測。 Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

另外，需要說明的是，除非以其他方式明確指出，在本發明中所採用的描述方式“...分別獨立地”應做廣義理解，是指所描述的各個個體之間是相互獨立的，可以獨立地為相同或不同的具 體基團。更詳細地，描述方式“...分別獨立地”既可以是指在不同基團中，相同符號之間所表達的具體選項之間互相不影響；也可以表示在相同的基團中，相同符號之間所表達的具體選項之間互相不影響。 In addition, it should be noted that, unless clearly stated otherwise, the description method "...respectively independently" used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other, can be independently the same or different body group. In more detail, the description mode "...respectively independently" can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same The specific options expressed by the symbols do not affect each other.

本領域技術人員可以理解，根據本領域中使用的慣例， 本申請描述基團的結構式中所使用的“

Figure 110145234-A0101-12-0029-386
”是指，相應的基團通過 該位點與化合物中的其它片段、基團進行連接。在不違背本領域常識的基礎上，上述各優選條件，可任意組合，即得本發明各較佳實例。 It can be understood by those skilled in the art that, according to the convention used in the art, the ""
Figure 110145234-A0101-12-0029-386
"means that the corresponding group is connected to other fragments and groups in the compound through this site. On the basis of not violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily, that is, the preferred conditions of the present invention can be obtained. instance.

本發明所用試劑和原料均市售可得。 The reagents and raw materials used in the present invention are all commercially available.

本發明涉及如下技術方案： The present invention relates to the following technical solutions:

在一個實施方案中，本發明提供具有通式(I)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： In one embodiment, the present invention provides a compound having the structure represented by general formula (I) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug:

Figure 110145234-A0101-12-0029-387
Figure 110145234-A0101-12-0029-387

其中，L0選自單鍵和NR1； Wherein, L 0 is selected from single bond and NR 1 ;

X1選自CH和N； X 1 is selected from CH and N;

X2選自CR4和N； X 2 is selected from CR 4 and N;

R4為氰基，R1選自-H和C1-C3烷基，或R1與R4一起形成5~6元飽和或不飽和環；所述5~6元飽和或不飽和環被R6取代； R 4 is a cyano group, R 1 is selected from -H and C 1 -C 3 alkyl, or R 1 and R 4 together form a 5- to 6-membered saturated or unsaturated ring; the 5- to 6-membered saturated or unsaturated ring replaced by R 6 ;

R6選自-H、=O、-OH、C1-C4烷基和C1-C4烷基羥基； R 6 is selected from -H, =O, -OH, C 1 -C 4 alkyl and C 1 -C 4 alkyl hydroxyl;

X3選自CH和N； X 3 is selected from CH and N;

n選自1和2； n is selected from 1 and 2;

m=2；兩個R0取代於同一碳原子之上或取代於相鄰碳原子之上，且兩個R0互相連接形成4~6元飽和氮雜環或4~6元飽和碳環；所述4~6元飽和氮雜環或4~6元飽和碳環分別獨立地被R2取代； m=2; two R 0 are substituted on the same carbon atom or on adjacent carbon atoms, and the two R 0 are connected to each other to form a 4-6-membered saturated nitrogen heterocycle or a 4-6 membered saturated carbocycle; The 4-6-membered saturated nitrogen heterocycle or the 4-6 membered saturated carbocycle is independently substituted by R ;

R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN、-NH-S(O)2(C1-C6烷基)、-NH-S(O)2(CH2)q-(3-6元環 烷基)、-NH-C(O)CH2CN、

Figure 110145234-A0101-12-0030-388
和
Figure 110145234-A0101-12-0030-389
； R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN,
Figure 110145234-A0101-12-0030-388
and
Figure 110145234-A0101-12-0030-389
;

R5選自C1-C5烷基、氰基、3-5元飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)； R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p -(3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl);

q、p分別獨立選自0、1、2和3； q, p are independently selected from 0, 1, 2 and 3;

條件是，當X2為N時，R2不為-C(O)CH2CN；當X2為N，且兩個R0取代於相鄰碳原子之上時，兩個R0互相連接形成4~6元飽和碳環。 The condition is that when X 2 is N, R 2 is not -C(O)CH 2 CN; when X 2 is N, and two R 0 are substituted on adjacent carbon atoms, the two R 0 are connected to each other A 4- to 6-membered saturated carbocyclic ring is formed.

在一個實施方案中，本發明提供如上式(I)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述4~6元飽和氮雜環、4~6元飽和碳環選自如下基團中的一種，環原子中有 1或2個碳原子為與基團

Figure 110145234-A0101-12-0031-390
所共有的碳原子： In one embodiment, the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, The prodrug is characterized in that the 4-6 membered saturated nitrogen heterocycle and the 4-6 membered saturated carbocyclic ring are selected from one of the following groups, and 1 or 2 carbon atoms in the ring atoms are associated with the group
Figure 110145234-A0101-12-0031-390
Shared carbon atoms:

Figure 110145234-A0101-12-0031-391
Figure 110145234-A0101-12-0031-391

在一個實施方案中，本發明提供如上式(I)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述的化合物具有如下式(I-1)或所述結構特徵： In one embodiment, the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the following formula (I-1) or the structural feature:

Figure 110145234-A0101-12-0031-393
Figure 110145234-A0101-12-0031-393

在一個實施方案中，本發明提供如上式(I-1)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，R2選自

Figure 110145234-A0101-12-0031-392
In one embodiment, the present invention provides the compound represented by the above formula (I-1) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, characterized in that R 2 is selected from
Figure 110145234-A0101-12-0031-392

其中，R5選自-S-(3-5元環烷基)、C1-C3烷氧基和-S-C1-C3烷基。 wherein R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

在一個實施方案中，本發明提供如上式(I-1)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，R1選自C1-C2烷基。 In one embodiment, the present invention provides the compound represented by the above formula (I-1) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that R 1 is selected from C 1 -C 2 alkyl.

在一個實施方案中，本發明提供如上式(I-1)所示的化合 物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X1選自CH。 In one embodiment, the present invention provides the compound represented by the above formula (I-1) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.

在一個實施方案中，本發明提供如上式(I)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述的化合物具有如下式(I-2)所述結構特徵： In one embodiment, the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-2):

Figure 110145234-A0101-12-0032-396
Figure 110145234-A0101-12-0032-396

在一個實施方案中，本發明提供如上式(I-2)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X2為N； In one embodiment, the present invention provides the compound represented by the above formula (I-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterized in that, X is N ;

R2選自-S(O)2(C1-C3烷基)、-S(O)2CH2-(3-4元環烷基)和

Figure 110145234-A0101-12-0032-394
；其中，R5選自-S-(3-5元環烷基)、C1-C3烷氧基和 -S-C1-C3烷基。 R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl) and
Figure 110145234-A0101-12-0032-394
; wherein, R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

在一個實施方案中，本發明提供如上式(I-2)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X2為CR4； In one embodiment, the present invention provides the compound represented by the above formula (I-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 2 is CR 4 ;

R2選自-S(O)2(C1-C3烷基)、-S(O)2CH2-(3-4元環烷基)、 -C(O)CH2CN和

Figure 110145234-A0101-12-0032-395
；R5選自C1-C3烷氧基。 R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl), -C(O)CH 2 CN and
Figure 110145234-A0101-12-0032-395
; R 5 is selected from C 1 -C 3 alkoxy.

在一個實施方案中，本發明提供如上式(I-2)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X1選自CH。 In one embodiment, the present invention provides the compound represented by the above formula (I-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.

在一個實施方案中，本發明提供如上式(I)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述的化合物具有如下式(I-3)所述結構特徵： In one embodiment, the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-3):

Figure 110145234-A0101-12-0033-398
Figure 110145234-A0101-12-0033-398

在一個實施方案中，本發明提供如上式(I-3)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X2為N； In one embodiment, the present invention provides the compound represented by the above formula (I-3) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterized in that, X is N ;

R2選自

Figure 110145234-A0101-12-0033-397
； R 2 is selected from
Figure 110145234-A0101-12-0033-397
;

其中，R5選自C1-C3烷氧基和-S-C1-C3烷基。 wherein R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

在一個實施方案中，本發明提供如上式(I-3)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，R1選自CH3。 In one embodiment, the present invention provides the compound represented by the above formula (I-3) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that R 1 is selected from CH 3 .

在一個實施方案中，本發明提供如上式(I-3)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X1選自CH。 In one embodiment, the present invention provides the compound represented by the above formula (I-3) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.

在一個實施方案中，本發明提供如上式(I)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述的化合物具有如下式(I-4)所述結構特徵： In one embodiment, the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-4):

Figure 110145234-A0101-12-0034-400
Figure 110145234-A0101-12-0034-400

在一個實施方案中，本發明提供如上式(I-4)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X2為N； In one embodiment, the present invention provides the compound represented by the above formula (I-4) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterized in that, X is N ;

R2選自-S(O)2(C1-C3烷基)和如下基團： R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl) and the following groups:

Figure 110145234-A0101-12-0034-399
；其中，R5選自C1-C3烷氧基和-S-C1-C3烷基。
Figure 110145234-A0101-12-0034-399
; wherein, R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

在一個實施方案中，本發明提供如上式(I-4)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，R1選自CH3。 In one embodiment, the present invention provides the compound represented by the above formula (I-4) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that R 1 is selected from CH 3 .

在一個實施方案中，本發明提供如上式(I-4)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X1選自CH。 In one embodiment, the present invention provides the compound represented by the above formula (I-4) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.

在一個實施方案中，本發明提供如上式(I)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述的化合 物具有如下式(I-5)所述結構特徵： In one embodiment, the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound The compound has the structural characteristics described in the following formula (I-5):

Figure 110145234-A0101-12-0035-402
Figure 110145234-A0101-12-0035-402

X4選自CH或N； X 4 is selected from CH or N;

環A表示所述5~6元飽和或不飽和環。 Ring A represents the 5- to 6-membered saturated or unsaturated ring.

在一個實施方案中，本發明提供如上式(I-5)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，環A選自如下基團之一： In one embodiment, the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterised in that ring A is selected from one of the following groups:

Figure 110145234-A0101-12-0035-401
Figure 110145234-A0101-12-0035-401

其中，X5、X7、X9、X10分別獨立地選自NR6、CHR6和C(R6)2； wherein, X 5 , X 7 , X 9 , and X 10 are independently selected from NR 6 , CHR 6 and C(R 6 ) 2 ;

X6、X8、X11分別獨立地選自N和CR6。 X 6 , X 8 , and X 11 are each independently selected from N and CR 6 .

在一個實施方案中，本發明提供如上式(I-5)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，R6選自-H、-OH、C1-C3烷基和C1-C3烷基羥基。 In one embodiment, the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, characterized in that R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkyl hydroxyl.

在一個實施方案中，本發明提供如上式(I-5)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、 藥學上可以接受的鹽、多晶型、前藥，其特徵在於，R2選自如下基團： In one embodiment, the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterised in that R 2 is selected from the following groups:

Figure 110145234-A0101-12-0036-403
Figure 110145234-A0101-12-0036-403

R5選自C1-C3烷氧基和-S-C1-C3烷基。 R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.

在一個實施方案中，本發明提供如上式(I-5)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，X1選自CH。 In one embodiment, the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.

在一個實施方案中，本發明提供如上式(I-5)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於： In one embodiment, the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug, is characterized in that:

X4為N； X 4 is N;

環A為

Figure 110145234-A0101-12-0036-404
或
Figure 110145234-A0101-12-0036-405
； Ring A is
Figure 110145234-A0101-12-0036-404
or
Figure 110145234-A0101-12-0036-405
;

R2為

Figure 110145234-A0101-12-0036-406
； R2 is
Figure 110145234-A0101-12-0036-406
;

R5選自C1-C3烷氧基和-S-C1-C3烷基； R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl;

X5各自獨立地為NR6或CHR6； X5 is each independently NR6 or CHR6 ;

X6各自獨立地為N或CR6； X 6 is each independently N or CR 6 ;

R6選自-H、-OH、C1-C3烷基和C1-C3烷基羥基。 R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkylhydroxy.

在一個實施方案中，本發明提供如上式(I-5)所示的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於： In one embodiment, the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug, is characterized in that:

X4為N； X 4 is N;

環A

Figure 110145234-A0101-12-0037-407
； Ring A
Figure 110145234-A0101-12-0037-407
;

R2為

Figure 110145234-A0101-12-0037-408
； R2 is
Figure 110145234-A0101-12-0037-408
;

R5為C1-C3烷氧基； R 5 is C 1 -C 3 alkoxy;

X6之一為N，另一個為CR6； One of X 6 is N and the other is CR 6 ;

R6為C1-C3烷基。 R 6 is C 1 -C 3 alkyl.

在一個實施方案中，本發明提供具有通式(a)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： In one embodiment, the present invention provides a compound having the structure represented by general formula (a) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs Type, prodrug:

Figure 110145234-A0101-12-0037-409
Figure 110145234-A0101-12-0037-409

其中： in:

L為NRc或鍵； L is NR c or bond;

Y1選自CH或N； Y 1 is selected from CH or N;

Y2選自CH或N； Y 2 is selected from CH or N;

Y3選自CH或N； Y 3 is selected from CH or N;

Ra選自-C(O)R7、-C(O)NR8R9、-S(O)2R10和-S(O)2NR10R11； R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;

Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;

Rc為H或C1-6烷基； R c is H or C 1-6 alkyl;

R7為含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基，其任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R9選自-H、C1-6烷基和鹵代C1-6烷基； R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

R10選自C1-6烷基、6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ;

R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

R’和R”各自獨立地選自-H、C1-6烷基和鹵代C1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供具有通式(b)、(b-1)或(b-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： In one embodiment, the present invention provides a compound having a structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs:

Figure 110145234-A0101-12-0039-410
Figure 110145234-A0101-12-0039-410

Figure 110145234-A0101-12-0039-411
Figure 110145234-A0101-12-0039-411

其中： in:

Y1選自CH和N，其中當Y1為CH時，其取代有Rb； Y 1 is selected from CH and N, wherein when Y 1 is CH, it is substituted with R b ;

Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;

Ra選自-C(O)R7、-C(O)NR8R9、-S(O)2R10和-S(O)2NR10R11； R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;

R7為含有1-3個獨立選自N、O和S的雜原子的5-8元雜 芳基，其任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R9選自-H、C1-6烷基和鹵代C1-6烷基； R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

R10選自C1-6烷基、6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ;

R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(b)、(b-1)或(b-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、 溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, Solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

Y1為N； Y 1 is N;

Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ;

R9為-H； R 9 is -H;

R8選自6-10元芳基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 heteroatoms independently selected from N, O and S 5-8 membered heterocyclyl of heteroatoms; each of said aryl, heteroaryl and heterocyclyl is optionally substituted with 1-3 substituents independently selected from: -H, -ORx , -SRx , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(b)、(b-1)或(b-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

Y1為N； Y 1 is N;

Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ;

R9為-H； R 9 is -H;

R8選自苯基和含有1-3個獨立選自N、O和S的雜原子的5-6元雜芳基；所述苯基和雜芳基各自任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx和-CN； R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x and -CN;

Rx選自C1-6烷基和鹵代C1-6烷基； R x is selected from C 1-6 alkyl and halogenated C 1-6 alkyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(b)、(b-1)或(b-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

Y1為N； Y 1 is N;

Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ;

R9為-H； R 9 is -H;

R8為含有1-3個獨立選自N和S的雜原子的5-6元雜芳基；所述雜芳基任選經1-2個獨立選自以下的取代基取代：-ORx和-SRx； R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-2 substituents independently selected from: -OR x and -SR x ;

Rx為C1-4烷基； R x is C 1-4 alkyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(b)、(b-1)或(b-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

Y1為N； Y 1 is N;

Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ;

R9為-H； R 9 is -H;

R8為含有3個獨立選自N和S的雜原子的5元雜芳基；所述雜芳基經獨立選自以下的取代基取代：-ORx和-SRx； R 8 is a 5-membered heteroaryl containing 3 heteroatoms independently selected from N and S; the heteroaryl is substituted with substituents independently selected from: -ORx and -SRx ;

Rx為C1-4烷基，優選為甲基或乙基； R x is C 1-4 alkyl, preferably methyl or ethyl;

m1為0； m1 is 0;

m2為3； m2 is 3;

n1為2； n1 is 2;

n2為1。 n2 is 1.

在一個實施方案中，本發明提供具有通式(c)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： In one embodiment, the present invention provides a compound having the structure represented by general formula (c) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug:

Figure 110145234-A0101-12-0044-412
Figure 110145234-A0101-12-0044-412

其中： in:

Ra選自-C(O)R7、-C(O)NR8R9、-S(O)2R10和-S(O)2NR10R11； R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;

Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;

R7為含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基，其任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R9選自-H、C1-6烷基和鹵代C1-6烷基； R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

R10選自C1-6烷基、6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、 -ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ;

R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

R’和R”各自獨立地選自-H、C1-6烷基和鹵代C1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(c)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (c) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, poly Crystalline forms, prodrugs, wherein:

Ra選自-S(O)2R10和-S(O)2NR10R11； Ra is selected from -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;

Rb選自-CN、鹵素、-ORx和-SRx； R b is selected from -CN, halogen, -OR x and -SR x ;

R10選自C1-6烷基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基；所述雜芳基任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl and 5-8-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; the heteroaryl is optionally selected from 1-3 independently Substituted from the following substituents: -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基和鹵代C1-6烷基； R x is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(c)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (c) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, multiple Crystalline forms, prodrugs, wherein:

Ra選自-S(O)2R10； Ra is selected from -S(O) 2 R 10 ;

Rb為-CN； R b is -CN;

R10為C1-6烷基； R 10 is C 1-6 alkyl;

m1為0、1、2或3； m1 is 0, 1, 2 or 3;

m2為0、1、2或3； m2 is 0, 1, 2 or 3;

n1為1、2或3； n1 is 1, 2 or 3;

n2為1、2或3。 n2 is 1, 2 or 3.

在一個實施方案中，本發明提供上述具有通式(c)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中：Ra為-S(O)2R10； In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (c) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, poly Crystal form, prodrug, wherein: R a is -S(O) 2 R 10 ;

Rb為-CN； R b is -CN;

R10為C1-4烷基，優選為丙基； R 10 is C 1-4 alkyl, preferably propyl;

m1為0； m1 is 0;

m2為2； m2 is 2;

n1為2； n1 is 2;

n2為1。 n2 is 1.

在一個實施方案中，本發明提供具有通式(d)、(d-1)或(d-2) 所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥， In one embodiment, the present invention provides compounds of formula (d), (d-1) or (d-2) Compounds of the indicated structures or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs,

Figure 110145234-A0101-12-0047-413
Figure 110145234-A0101-12-0047-413

Figure 110145234-A0101-12-0047-414
Figure 110145234-A0101-12-0047-414

其中： in:

Y1選自CH和N； Y 1 is selected from CH and N;

R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;

Rc選自-H、C1-6烷基和鹵代C1-6烷基； R c is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rd選自-H、C1-6烷基和鹵代C1-6烷基； R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Re選自-H、C1-6烷基和鹵代C1-6烷基； R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

R’和R”各自獨立地選自-H、C1-6烷基和鹵代C1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

p1為0、1或2； p1 is 0, 1 or 2;

p2為0、1或2； p2 is 0, 1 or 2;

q1為0、1或2； q1 is 0, 1 or 2;

q2為0、1或2。 q2 is 0, 1 or 2.

在一個實施方案中，本發明提供具有通式(e)、(e-1)或(e-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥， In one embodiment, the present invention provides a compound having a structure represented by general formula (e), (e-1) or (e-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs,

Figure 110145234-A0101-12-0048-415
Figure 110145234-A0101-12-0048-415

Figure 110145234-A0101-12-0048-416
Figure 110145234-A0101-12-0048-416

其中： in:

R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選 自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rc選自-H、C1-6烷基和鹵代C1-6烷基； R c is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rd選自-H、C1-6烷基和鹵代C1-6烷基； R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Re選自-H、C1-6烷基和鹵代C1-6烷基； R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

p1為0、1或2； p1 is 0, 1 or 2;

p2為0、1或2； p2 is 0, 1 or 2;

q1為0、1或2； q1 is 0, 1 or 2;

q2為0、1或2。 q2 is 0, 1 or 2.

在一個實施方案中，本發明提供上述具有通式(e)、(e-1)或(e-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (e), (e-1) or (e-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

R8選自苯基和含有1-3個獨立選自N、O和S的雜原子的5-6元雜芳基；所述苯基和雜芳基各自任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx、-CN和鹵素； R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x , -CN and halogen;

Rc選自-H和C1-6烷基； R c is selected from -H and C 1-6 alkyl;

Rd選自-H和C1-6烷基； R d is selected from -H and C 1-6 alkyl;

Re選自-H和C1-6烷基； R e is selected from -H and C 1-6 alkyl;

Rx選自-H、C1-6烷基和鹵代C1-6烷基； R x is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

p1為0、1或2； p1 is 0, 1 or 2;

p2為0、1或2； p2 is 0, 1 or 2;

q1為0、1或2； q1 is 0, 1 or 2;

q2為0、1或2。 q2 is 0, 1 or 2.

在一個實施方案中，本發明提供上述具有通式(e)、(e-1)或(e-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (e), (e-1) or (e-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

R8為含有1-3個獨立選自N和S的雜原子的5-6元雜芳基；所述雜芳基任選經1-3個獨立選自以下的取代基取代：-ORx和-SRx； R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-3 substituents independently selected from: -OR x and -SR x ;

Rc選自-H和C1-4烷基； R c is selected from -H and C 1-4 alkyl;

Rd選自-H和C1-4烷基； R d is selected from -H and C 1-4 alkyl;

Re選自-H和C1-4烷基； R e is selected from -H and C 1-4 alkyl;

Rx為C1-4烷基； R x is C 1-4 alkyl;

p1為1或2； p1 is 1 or 2;

p2為1或2； p2 is 1 or 2;

q1為1或2； q1 is 1 or 2;

q2為1或2。 q2 is 1 or 2.

在一個實施方案中，本發明提供上述具有通式(e)、(e-1) 或(e-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above having general formula (e), (e-1) Or the compound of the structure shown in (e-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, prodrug, wherein:

R8為含有3個獨立選自N和S的雜原子的5元雜芳基；所述雜芳基經-ORx取代； R 8 is a 5-membered heteroaryl group containing 3 heteroatoms independently selected from N and S; the heteroaryl group is substituted with -OR x ;

Rc為C1-4烷基，優選為甲基； R c is C 1-4 alkyl, preferably methyl;

Rd為-H； R d is -H;

Re為-H； Re is -H;

Rx為C1-4烷基，優選為甲基； R x is C 1-4 alkyl, preferably methyl;

p1為1； p1 is 1;

p2為1； p2 is 1;

q1為1； q1 is 1;

q2為1。 q2 is 1.

在一個實施方案中，本發明提供具有通式(f)、(f-1)或(f-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥， In one embodiment, the present invention provides a compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs,

Figure 110145234-A0101-12-0051-417
Figure 110145234-A0101-12-0051-417

Figure 110145234-A0101-12-0052-418
Figure 110145234-A0101-12-0052-418

R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rc和Rf與它們所連接的原子一起形成含有1-2個獨立選自N、O和S的雜原子的5-8元雜芳基或含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述雜芳基或雜環基經獨立選自以下的取代基取代：-H、氧代、-ORx、-SRx、-CN、鹵素、C1-6烷基、鹵代C1-6烷基和羥基取代的C1-6烷基； Rc and Rf together with the atoms to which they are attached form a 5-8 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S or 1-3 heteroatoms independently selected from N, O and A 5-8 membered heterocyclyl of a heteroatom of S; the heteroaryl or heterocyclyl is substituted with a substituent independently selected from the group consisting of: -H, oxo, -ORx , -SRx , -CN, halogen , C 1-6 alkyl, halogenated C 1-6 alkyl and hydroxy substituted C 1-6 alkyl;

Rd選自-H、C1-6烷基和鹵代C1-6烷基； R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Re選自-H、C1-6烷基和鹵代C1-6烷基； R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;

Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;

p1為0、1或2； p1 is 0, 1 or 2;

p2為0、1或2； p2 is 0, 1 or 2;

q1為0、1或2； q1 is 0, 1 or 2;

q2為0、1或2。 q2 is 0, 1 or 2.

在一個實施方案中，本發明提供上述具有通式(f)、(f-1)或(f-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

R8選自苯基和含有1-3個獨立選自N、O和S的雜原子的5-6元雜芳基；所述苯基和雜芳基各自任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx、-CN和鹵素； R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x , -CN and halogen;

Rc和Rf與它們所連接的原子一起形成含有1-2個獨立選自N、O和S的雜原子的5-6元雜芳基；所述雜芳基經1-2個獨立選自以下的取代基取代：-ORx、-SRx、C1-4烷基和羥基取代的C1-4烷基； Rc and Rf , taken together with the atoms to which they are attached, form a 5-6 membered heteroaryl group containing 1-2 heteroatoms independently selected from N, O, and S; the heteroaryl group is independently selected from 1-2 Substituted from the following substituents: -OR x , -SR x , C 1-4 alkyl and hydroxy substituted C 1-4 alkyl;

Rd選自-H和C1-4烷基； R d is selected from -H and C 1-4 alkyl;

Re選自-H和C1-4烷基； R e is selected from -H and C 1-4 alkyl;

Rx選自-H、C1-4烷基和鹵代C1-4烷基； R x is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;

p1為0、1或2； p1 is 0, 1 or 2;

p2為0、1或2； p2 is 0, 1 or 2;

q1為0、1或2； q1 is 0, 1 or 2;

q2為0、1或2。 q2 is 0, 1 or 2.

在一個實施方案中，本發明提供上述具有通式(f)、(f-1)或(f-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其 中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, which middle:

R8為含有1-3個獨立選自N和S的雜原子的5-6元雜芳基；所述雜芳基任選經1-3個-ORx取代； R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-3 -OR x ;

Rc和Rf與它們所連接的原子一起形成含有2個N原子的5-6元雜芳基；所述雜芳基經1-2個選自-H、C1-4烷基和羥基取代的C1-4烷基的取代基取代； R c and R f taken together with the atoms to which they are attached form a 5-6 membered heteroaryl group containing 2 N atoms; the heteroaryl group is selected from -H, C 1-4 alkyl and hydroxy through 1-2 Substituent substitution of substituted C 1-4 alkyl;

Rd為-H； R d is -H;

Re為-H； Re is -H;

Rx為C1-4烷基； R x is C 1-4 alkyl;

p1為1； p1 is 1;

p2為1； p2 is 1;

q1為1； q1 is 1;

q2為1。 q2 is 1.

在一個實施方案中，本發明提供上述具有通式(f)、(f-1)或(f-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其中： In one embodiment, the present invention provides the above-mentioned compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:

R8為含有3個獨立選自N和S的雜原子的5元雜芳基；所述雜芳基經-ORx取代； R 8 is a 5-membered heteroaryl group containing 3 heteroatoms independently selected from N and S; the heteroaryl group is substituted with -OR x ;

Rc和Rf與它們所連接的原子一起形成含有2個N原子的5元雜芳基；所述雜芳基經C1-4烷基優選甲基取代； R c and R f together with the atoms to which they are attached form a 5-membered heteroaryl group containing 2 N atoms; the heteroaryl group is substituted with C 1-4 alkyl, preferably methyl;

Rd為-H； R d is -H;

Re為-H； Re is -H;

Rx為C1-4烷基，優選為甲基； R x is C 1-4 alkyl, preferably methyl;

p1為1； p1 is 1;

p2為1； p2 is 1;

q1為1； q1 is 1;

q2為1。 q2 is 1.

在其中一個具體的實施方案中，所述的化合物選自如下結構： In one specific embodiment, the compound is selected from the following structures:

Figure 110145234-A0101-12-0056-502
Figure 110145234-A0101-12-0056-502

本發明的實施方案還提供所述化合物的製備方法，包括如下步驟： Embodiments of the present invention also provide a method for preparing the compound, comprising the steps of:

Figure 110145234-A0101-12-0057-420
中間體1
Figure 110145234-A0101-12-0057-420
Intermediate 1

Figure 110145234-A0101-12-0057-421
中間體2
Figure 110145234-A0101-12-0057-421
Intermediate 2

Figure 110145234-A0101-12-0057-424
Figure 110145234-A0101-12-0057-424

中間體1與中間體2進行取代反應，製備式(I)化合物； Intermediate 1 and Intermediate 2 are subjected to substitution reaction to prepare the compound of formula (I);

式(I)化合物與包含R2的化合物進行取代或縮合反應； A compound of formula (I) is subjected to a substitution or condensation reaction with a compound comprising R 2 ;

作為選擇，L0中的R1可以與X2中的R4一起形成5~6元不飽和環；所述5~6元不飽和環被R6取代； Alternatively, R 1 in L 0 can form a 5-6 membered unsaturated ring together with R 4 in X 2 ; the 5-6 membered unsaturated ring is substituted by R 6 ;

其中包含R2的化合物選自如下化合物中的一種： The compound wherein R is selected from one of the following compounds:

R2-X、R2-H、

Figure 110145234-A0101-12-0057-422
和
Figure 110145234-A0101-12-0057-423
； R 2 -X, R 2 -H,
Figure 110145234-A0101-12-0057-422
and
Figure 110145234-A0101-12-0057-423
;

X表示鹵素，L0、R1、R0、R2、R6、X1、X2、R4、X3、n和m如上面所定義。 X represents halogen, and L 0 , R 1 , R 0 , R 2 , R 6 , X 1 , X 2 , R 4 , X 3 , n and m are as defined above.

可以理解地，當R2-X時，式(I)化合物與包含R2的化合物進行取代反應； It can be understood that when R 2 -X, the compound of formula (I) undergoes a substitution reaction with a compound comprising R 2 ;

當包含R2的化合物為R2-H時，式(I)化合物與包含R2的化合物進行縮合反應。具體地，採用的試劑可以為N,N’-羰基二咪唑(CDI)。 When the compound containing R 2 is R 2 -H, the compound of formula (I) is subjected to a condensation reaction with the compound containing R 2 . Specifically, the reagent used may be N,N'-carbonyldiimidazole (CDI).

當包含R2的化合物為

Figure 110145234-A0101-12-0058-426
或
Figure 110145234-A0101-12-0058-425
時，式(I)化合物 與包含R2的化合物進行酯交換反應。 When the compound containing R2 is
Figure 110145234-A0101-12-0058-426
or
Figure 110145234-A0101-12-0058-425
, the compound of formula (I) undergoes a transesterification reaction with a compound comprising R 2 .

在其中一個示例中，R4為-NH2，R1為-H；L0中的R1可以與X2中的R4一起形成5~6元不飽和環是指進行環化反應。 In one example, R 4 is -NH 2 , and R 1 is -H; R 1 in L 0 can form a 5- to 6-membered unsaturated ring together with R 4 in X 2 , which refers to a cyclization reaction.

本發明的實施方案還提供一種藥物組成物，其特徵在於，所述藥物組成物包含如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥。 An embodiment of the present invention also provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the above-mentioned compound or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically Acceptable salts, polymorphs, prodrugs.

本發明的實施方案還提供如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥在製備具有酪氨酸激酶JAK抑制活性的藥物中的應用。 Embodiments of the present invention also provide compounds as described above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs thereof prepared with phenol Use of a drug for the inhibitory activity of the amino-kinase JAK.

本發明的實施方案還提供如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥在製備具有預防或治療自身免疫性疾病、皮膚病、變應性疾病、器官排斥、癌症、乾眼病、骨髓纖維化、紅細胞增多症的功效的藥物中的應用。 Embodiments of the present invention also provide compounds as described above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs thereof, prepared with prophylactic Or the application in the medicine of the efficacy of treating autoimmune disease, skin disease, allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis, polycythemia.

本發明的實施方案還提供如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥或如上所述的藥物組成物，其用於抑制酪氨酸激酶JAK。 Embodiments of the present invention also provide compounds as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, prodrug or as described above thereof A pharmaceutical composition for inhibiting the tyrosine kinase JAK.

本發明的實施方案還提供如上所述的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥或如上所述的藥物組成物，其用於預防或治療選自以下的疾病：自身免疫性疾病、皮膚病、變應性疾病、器官排斥、癌症、乾眼病、骨髓纖維化和紅細胞增多症。 Embodiments of the present invention also provide compounds as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, prodrug or as described above thereof The pharmaceutical composition for preventing or treating diseases selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis and polycythemia.

本發明的實施方案還提供一種抑制酪氨酸激酶JAK的方法，其包括給予如上所述的化合物或其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型或前藥或如上所述的藥物組成物。 Embodiments of the present invention also provide a method of inhibiting the tyrosine kinase JAK comprising administering a compound as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable The salts, polymorphs or prodrugs or pharmaceutical compositions as described above.

本發明的實施方案還提供一種預防或治療選自以下的疾病的方法：自身免疫性疾病、皮膚病、變應性疾病、器官排斥、癌症、乾眼病、骨髓纖維化和紅細胞增多症，其包括給予如上所述的化合物或其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型或前藥或如上所述的藥物組成物。 Embodiments of the present invention also provide a method of preventing or treating a disease selected from the group consisting of autoimmune disease, skin disease, allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis and polycythemia, including A compound as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a pharmaceutical composition as described above, is administered.

在一個具體的實施方案中，所述自身免疫性疾病為狼瘡、多發性硬化、類風濕性關節炎、青少年關節炎、銀屑病、潰瘍性結腸炎、克羅恩氏病或自體免疫性甲狀腺疾病；所述皮膚病為牛皮癬、皮疹或特應性皮炎；所述變應性病症為哮喘或鼻炎病；所述器官移植排斥為異體抑制排斥或移植物抗宿主疾病；所述癌症為腎癌、肝癌、胰腺癌、胃癌、乳腺癌、***癌、頭頸部癌、甲狀腺癌、肺癌、膠質母細胞瘤、黑素瘤、淋巴瘤或白血病。 In a specific embodiment, the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmunity Thyroid disease; the skin disease is psoriasis, rash or atopic dermatitis; the allergic condition is asthma or rhinitis; the organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease; the cancer is kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma or leukemia.

以下通過具體實施例詳細說明本發明的實施過程和產生的有益效果，旨在幫助閱讀者更好地理解本發明的實質和特點，不作為對本案可實施範圍的限定。 The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present case.

化合物的結構是通過核磁共振(NMR)或(和)質譜(MS)來確定的。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定是用(Bruker Avance III 400和Bruker Avance 300)核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，內標為四甲基矽烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) , the internal standard is tetramethylsilane (TMS).

MS的測定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。 For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC的測定使用安捷倫1260DAD高壓液相色譜儀(Zorbax SB-C18 100×4.6mm)。 For the HPLC measurement, an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm) was used.

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.20mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm, and the specification used for TLC separation and purification products is 0.4mm ~0.5mm.

柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

本發明的己知的起始原料可以採用或按照本領域已知的方法來合成，或可購買於泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、百靈威科技等公司。 The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.

氮氣氛是指反應瓶連接一個約1L容積的氮氣氣球。 Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

氫化反應通常抽真空，充入氫氣，反復操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

實施例中無特殊說明，反應在氮氣氛下進行。 There is no special description in the examples, and the reaction is carried out under nitrogen atmosphere.

實施例中無特殊說明，溶液是指水溶液。 There is no special description in the examples, and the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫。 There is no special description in the examples, and the reaction temperature is room temperature.

室溫為最適宜的反應溫度，為20℃~30℃。 Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C.

化學合成相關縮寫： Abbreviations related to chemical synthesis:

Et：乙基； Et: ethyl;

Me：甲基； Me: methyl;

Bn：苄基； Bn: benzyl;

Bz：苯甲醯基； Bz: benzyl;

TBSOTf：叔丁基二甲基甲矽烷基三氟甲磺酸酯； TBSOTf: tert-butyldimethylsilyl triflate;

DIEA：N,N-二異丙基乙胺； DIEA: N,N-diisopropylethylamine;

i-PrOH：異丙醇； i-PrOH: isopropanol;

EA：乙酸乙酯； EA: ethyl acetate;

HPLC：高效液相色譜； HPLC: high performance liquid chromatography;

SEMCl：(2-(氯甲氧基)乙基)三甲基矽烷 SEMCl: (2-(chloromethoxy)ethyl)trimethylsilane

TFA：三氟乙酸； TFA: trifluoroacetic acid;

CDI：N,N'-羰基二咪唑； CDI: N,N'-carbonyldiimidazole;

DCM：二氯甲烷； DCM: dichloromethane;

rt：室溫； rt: room temperature;

h：小時 h: hours

overnight：過夜； overnight: overnight;

THF：四氫呋喃； THF: tetrahydrofuran;

DMF：二甲基甲醯胺； DMF: dimethylformamide;

TsOH：對甲苯磺酸； TsOH: p-toluenesulfonic acid;

TsCl：4-甲基苯磺醯氯； TsCl: 4-methylbenzenesulfonyl chloride;

Pd/C：鈀/炭； Pd/C: palladium/carbon;

EtOAc：乙酸乙酯。 EtOAc: ethyl acetate.

實施例1Example 1

4-(1-(2-氰基乙醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(化合物1) 4-(1-(2-Cyanoacetyl)-1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-methyl Nitrile (Compound 1)

Figure 110145234-A0101-12-0062-427
Figure 110145234-A0101-12-0062-427

第一步：6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯(1B) The first step: 6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl Esters (1B)

Figure 110145234-A0101-12-0062-428
Figure 110145234-A0101-12-0062-428

將4-氯-1H-吡咯並[2,3-b]吡啶-5-甲腈1A(300mg,1.69mmol)，1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯(323mg,1.52mmol)和N,N-二異丙基乙胺(439mg,3.38mmol)溶於異丙醇(8mL)中，並 將混合物在氮氣保護下在100℃攪拌反應16小時。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-5%)，得到白色固體化合物6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯1B(400mg，產率：67%)。 4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 1A (300 mg, 1.69 mmol), 1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl The ester (323 mg, 1.52 mmol) and N,N-diisopropylethylamine (439 mg, 3.38 mmol) were dissolved in isopropanol (8 mL) and the The mixture was stirred for 16 hours at 100°C under nitrogen protection. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-5%) to obtain a white solid compound 6-(5-cyano-1H-pyrrolo[ 2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate tert-butyl ester 1B (400 mg, yield: 67%).

MS m/z(ESI)：354.0[M+1]. MS m/z(ESI): 354.0[M+1].

第二步：4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(1C) Step 2: 4-(1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1C)

Figure 110145234-A0101-12-0063-429
Figure 110145234-A0101-12-0063-429

將6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯1B(400mg,1.13mmol)溶於氯化氫的乙酸乙酯溶液中(10mL,1.5mol/L)，並將溶液在室溫下攪拌反應過夜。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-10%)，得到黃色固體化合物4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈1C(280mg，產率：98%)。 6-(5-Cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate tert-butyl ester 1B ( 400 mg, 1.13 mmol) was dissolved in an ethyl acetate solution of hydrogen chloride (10 mL, 1.5 mol/L), and the solution was stirred at room temperature to react overnight. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-10%) to obtain a yellow solid compound 4-(1,6-diazaspiro[3.4] ]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 1C (280 mg, yield: 98%).

MS m/z(ESI)：254.0[M+1]. MS m/z(ESI): 254.0[M+1].

第三步：4-(1-(2-氰基乙醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(化合物1) Step 3: 4-(1-(2-Cyanoacetyl)-1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine -5-carbonitrile (compound 1)

Figure 110145234-A0101-12-0064-430
Figure 110145234-A0101-12-0064-430

將4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈1C(100mg，0.39mmol)、2-氰基乙酸2,5-二氧代吡咯烷-1-基酯(85mg,0.47mmol)和三乙胺(80mg,0.79mmol)溶於乙醇(5mL)中，並將混合物在室溫下攪拌反應過夜。反應結束後旋乾溶劑。粗產品通過製備型HPLC純化，凍乾得到白色固體化合物4-(1-(2-氰基乙醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(化合物1)(14mg，收率：11.2%)。 4-(1,6-Diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 1C (100 mg, 0.39 mmol), 2- 2,5-dioxopyrrolidin-1-yl cyanoacetate (85 mg, 0.47 mmol) and triethylamine (80 mg, 0.79 mmol) were dissolved in ethanol (5 mL), and the mixture was stirred at room temperature to react overnight. After the reaction was completed, the solvent was spin-dried. The crude product was purified by preparative HPLC and lyophilized to give a white solid compound 4-(1-(2-cyanoacetyl)-1,6-diazaspiro[3.4]octan-6-yl)-1H- Pyrolo[2,3-b]pyridine-5-carbonitrile (Compound 1) (14 mg, yield: 11.2%).

取12mg化合物1用手性SFC分離(SFC150；手性柱AD，250×25mm，10um；超臨界CO2/甲醇+甲醇氨0.1%=55：45；80mL/min)得到化合物1-P1(Rt=1.27min,2.2mg)和化合物1-P2(Rt=1.81min,3.2mg)均為白色固體。 12mg of compound 1 was separated by chiral SFC (SFC150; chiral column AD, 250×25mm, 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=55:45; 80mL/min) to obtain compound 1-P 1 ( Rt=1.27 min, 2.2 mg) and compound 1 -P2 (Rt=1.81 min, 3.2 mg) were both white solids.

MS m/z(ESI)：321.0[M+1]. MS m/z(ESI): 321.0[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.80(d,1 H),8.04(s,1 H),7.26-7.18(d,1 H),6.75(d,1 H),4.22(dd,1 H),4.06-3.98(m,3 H),3.71(s,2 H),2.70(dd,1 H),2.66-2.60(m,1 H),2.54(t,1 H),2.40(t,1 H),2.31(m,1 H),2.24-2.14(m,1 H). 1 H NMR (400MHz, DMSO-d6)δ 11.80(d,1H), 8.04(s,1H), 7.26-7.18(d,1H), 6.75(d,1H), 4.22(dd,1 H), 4.06-3.98(m, 3 H), 3.71(s, 2 H), 2.70(dd, 1 H), 2.66-2.60(m, 1 H), 2.54(t, 1 H), 2.40(t , 1 H), 2.31(m, 1 H), 2.24-2.14(m, 1 H).

實施例2Example 2

4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-7H-吡咯並[2,3-d]嘧啶(化合物2) 4-(1-(Propylsulfonyl)-1,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (Compound 2)

Figure 110145234-A0101-12-0065-431
Figure 110145234-A0101-12-0065-431

第一步：4-氯-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶(2B) Step 1: 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2B)

Figure 110145234-A0101-12-0065-432
Figure 110145234-A0101-12-0065-432

在250mL的三口圓底燒瓶中加入氫化鈉(60%)(7.81g,97mmol)，溶於THF(30mL)中，氮氣保護下降溫至0℃。將4-氯-7H-吡咯並[2,3-d]嘧啶2A(10g,65.12mmol)溶於THF中，然後緩慢加入到上述混合物中，並在0℃反應30分鐘。然後緩慢加入(2-(氯甲氧基)乙基)三甲基矽烷(13.03g，78.14mmol)，在室溫反應2小時。加入飽和NH4Cl(100mL)溶液，用乙酸乙酯(100mL×3)萃取。有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：20-1：10)得到無色油狀的化合物4-氯-7-((2-(三 甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶2B(11g，收率59.52%)。 Sodium hydride (60%) (7.81 g, 97 mmol) was added to a 250 mL three-necked round bottom flask, dissolved in THF (30 mL), and the temperature was lowered to 0°C under nitrogen protection. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 2A (10 g, 65.12 mmol) was dissolved in THF, then slowly added to the above mixture and reacted at 0°C for 30 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (13.03 g, 78.14 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. Saturated NH 4 Cl (100 mL) solution was added and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:20-1:10) to give compound 4-chloro-7-((2-(trimethylsilyl)ethoxy) as colorless oil Methyl)-7H-pyrrolo[2,3-d]pyrimidine 2B (11 g, 59.52% yield).

MS m/z(ESI)：284.0[M+1]. MS m/z(ESI): 284.0[M+1].

第二步：6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-甲酸叔丁基酯2C Step 2: 6-(7-((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6 - tert-butyl diazaspiro[3.4]octane-1-carboxylate 2C

Figure 110145234-A0101-12-0066-433
Figure 110145234-A0101-12-0066-433

將4-氯-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶2B(650mg，2.29mmol)和1,6-二氮雜螺[3.4]辛烷-1-甲酸叔丁酯(437mg,2.06mmol)溶於i-PrOH(10mL)，然後加入三乙胺(347mg，3.44mmol)，氮氣保護下反應16h。反應完畢後，濃縮反應液，加水(20mL)，用乙酸乙酯(20mL×3)萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：5-1：3)得到無色油狀的化合物6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-甲酸叔丁基酯2C(900mg，收率85.5%)。 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 2B (650 mg, 2.29 mmol) and 1,6 -Diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (437mg, 2.06mmol) was dissolved in i-PrOH (10mL), then triethylamine (347mg, 3.44mmol) was added, and the reaction was carried out under nitrogen protection for 16h. After completion of the reaction, the reaction solution was concentrated, water (20 mL) was added, extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:5-1:3) to give compound 6-(7-((2-(trimethylsilyl)ethoxy)methan as colorless oily) yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester 2C (900 mg, 85.5% yield ).

MS m/z(ESI)：460.0[M+1]. MS m/z(ESI): 460.0[M+1].

第三步：4-(1,6-二氮雜螺[3.4]辛烷-6-基)-7H-吡咯並[2,3-d]嘧啶(2D) Step 3: 4-(1,6-Diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (2D)

Figure 110145234-A0101-12-0067-434
Figure 110145234-A0101-12-0067-434

將6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-甲酸叔丁基酯2C(300mg,0.65mmol)溶於MeOH(3mL)，然後加入TFA(1mL)，攪拌4h。真空旋乾反應混合物得到粗品。將粗品溶於MeOH(2mL)，加入氨水(2mL)，攪拌15min。反應結束後真空旋乾反應混合物，得到粗品4-(1,6-二氮雜螺[3.4]辛烷-6-基)-7H-吡咯並[2,3-d]嘧啶2D(260mg)。 6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazo Heteraspiro[3.4]octane-1-carboxylic acid tert-butyl ester 2C (300 mg, 0.65 mmol) was dissolved in MeOH (3 mL), then TFA (1 mL) was added and stirred for 4 h. The reaction mixture was spun dry in vacuo to give the crude product. The crude product was dissolved in MeOH (2 mL), ammonia water (2 mL) was added, and the mixture was stirred for 15 min. After the reaction was completed, the reaction mixture was spin-dried in vacuo to obtain crude 4-(1,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine 2D (260 mg).

MS m/z(ESI)：230.0[M+1]。 MS m/z (ESI): 230.0 [M+1].

第四步：4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-7H-吡咯並[2,3-d]嘧啶(化合物2) The fourth step: 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (compound 2)

Figure 110145234-A0101-12-0067-435
Figure 110145234-A0101-12-0067-435

將4-(1,6-二氮雜螺[3.4]辛烷-6-基)-7H-吡咯並[2,3-d]嘧啶(2D)(260mg，1.13mmol)溶於DCM(2mL)，在氮氣保護下加入三乙胺(172mg,1.70mmol)和丙烷-1-磺醯氯(194mg，1.36mmol)，室溫反應6小時。濃縮反應液，然後通過製備型HPLC純化，凍 乾得白色固體狀的化合物4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-7H-吡咯並[2,3-d]嘧啶(化合物2)(15mg，產率3.94%)。 4-(1,6-Diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (2D) (260 mg, 1.13 mmol) was dissolved in DCM (2 mL) , and added triethylamine (172 mg, 1.70 mmol) and propane-1-sulfonyl chloride (194 mg, 1.36 mmol) under nitrogen protection, and reacted at room temperature for 6 hours. The reaction solution was concentrated, then purified by preparative HPLC, frozen Compound 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.4]octan-6-yl)-7H-pyrrolo[2,3-d] was dried as a white solid Pyrimidine (Compound 2) (15 mg, 3.94% yield).

取13.6mg化合物2用手性SFC分離(SFC150；手性柱IC，250×25mm，10um；超臨界CO2/甲醇+甲醇氨0.1%=55：45；80mL/min)得到化合物2-P1(Rt=5.15min,2.6mg)和化合物2-P2(Rt=5.47min,2.8mg)均為白色固體。 13.6mg of compound 2 was separated by chiral SFC (SFC150; chiral column IC, 250×25mm, 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=55:45; 80mL/min) to obtain compound 2-P 1 (Rt=5.15 min, 2.6 mg) and compound 2-P 2 (Rt=5.47 min, 2.8 mg) were both white solids.

MS m/z(ESI)：336.0[M+1]. MS m/z(ESI): 336.0[M+1].

1H NMR(400MHz,CD3OD)δ 8.16(s,1 H),7.27(d,1 H),6.87(d,1 H),4.43(s,1 H),4.28-3.80(m,5 H),3.00(m,2 H),2.86-2.75(m,1 H),2.58-2.38(m,3 H),1.79(q,2 H),1.02(t,3 H). 1 H NMR (400MHz, CD 3 OD) δ 8.16(s,1H), 7.27(d,1H), 6.87(d,1H), 4.43(s,1H), 4.28-3.80(m,5 H), 3.00 (m, 2 H), 2.86-2.75 (m, 1 H), 2.58-2.38 (m, 3 H), 1.79 (q, 2 H), 1.02 (t, 3 H).

實施例3Example 3

N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物3) N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-di Azaspiro[3.5]nonane-1-carboxamide (compound 3)

Figure 110145234-A0101-12-0068-436
Figure 110145234-A0101-12-0068-436

第一步：6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁基酯(3A) The first step: 6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6 -Diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester (3A)

Figure 110145234-A0101-12-0069-437
Figure 110145234-A0101-12-0069-437

將4-氯-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶2B(413mg,1.46mmol)，1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁酯(300mg,1.33mmol)和N,N-二異丙基乙胺(0.66mL,3.98mmol)溶於異丙醇(5mL)，然後將混合物在氮氣保護下在80℃攪拌16小時。反應結束後濃縮反應液，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-15%)得到無色油狀的化合物6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁基酯3A(590mg，產率93.9%)。 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 2B (413 mg, 1.46 mmol), 1,6 - tert-butyl diazaspiro[3.5]nonane-1-carboxylate (300 mg, 1.33 mmol) and N,N-diisopropylethylamine (0.66 mL, 3.98 mmol) in isopropanol (5 mL) , and then the mixture was stirred at 80 °C for 16 h under nitrogen protection. After the reaction, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-15%) to obtain a colorless oily compound 6-(7-((2-(tri Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid tert-Butyl ester 3A (590 mg, 93.9% yield).

MS m/z(ESI)：474.0[M+1]. MS m/z(ESI): 474.0[M+1].

第二步：4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7H-吡咯並[2,3-d]嘧啶(3B) Step 2: 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (3B)

Figure 110145234-A0101-12-0069-438
Figure 110145234-A0101-12-0069-438

將6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁基酯3A(150 mg，0.31mmol)溶於二氯甲烷(3mL)，並在攪拌下加入三氟乙酸(1mL)。將混合物在室溫下攪拌2小時。然後旋乾。將旋乾後的混合物溶於四氫呋喃(3mL)並加入氨水(1mL)，在室溫下攪拌30分鐘。旋乾得到4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7H-吡咯並[2,3-d]嘧啶3B(100mg，粗產品)。 6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazo Heterospiro[3.5]nonane-1-carboxylate tert-butyl ester 3A (150 mg, 0.31 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added with stirring. The mixture was stirred at room temperature for 2 hours. Then spin dry. The spin-dried mixture was dissolved in tetrahydrofuran (3 mL), ammonia water (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Spin dry to give 4-(1,6-diazaspiro[3.5]nonan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine 3B (100 mg, crude).

MS m/z(ESI)：244.0[M+1]. MS m/z(ESI): 244.0[M+1].

第三步：N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物3) The third step: N-(3-methoxy-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,6-Diazaspiro[3.5]nonane-1-carboxamide (Compound 3)

Figure 110145234-A0101-12-0070-439
Figure 110145234-A0101-12-0070-439

將5-氨基-3-甲氧基-1,2,4-噻唑(35mg，0.27mmol)溶於二氯甲烷(3mL)，並於攪拌下加入N,N'-羰基二咪唑(47mg，0.29mmol)和三乙胺(0.23mL，1.61mmol)。將混合物在室溫攪拌下反應2小時。然後加入4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7H-吡咯並[2,3-d]嘧啶3B(100mg，粗產品)，並將混合物在室溫攪拌下繼續反應16小時。反應結束後，濃縮反應混合物，殘餘物通過製備型HPLC純化。凍乾得到白色固體化合物N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物3)(12mg，收率9.4%)。 5-Amino-3-methoxy-1,2,4-thiazole (35 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL) and N,N'-carbonyldiimidazole (47 mg, 0.29 mmol) was added with stirring mmol) and triethylamine (0.23 mL, 1.61 mmol). The mixture was reacted with stirring at room temperature for 2 hours. Then 4-(1,6-diazaspiro[3.5]nonan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine 3B (100 mg, crude product) was added, and the mixture was brought to room temperature The reaction was continued for 16 hours with stirring. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by preparative HPLC. Lyophilized to give white solid compound N-(3-methoxy-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1,6-diazaspiro[3.5]nonane-1-carboxamide (compound 3) (12 mg, yield 9.4%).

MS m/z(ESI)：401.2[M+1]. MS m/z(ESI): 401.2[M+1].

1H NMR(400MHz,CD3OD)δ 8.13(s,1 H),7.14(d,1 H),6.66(d,1 H),5.06(d,1 H),4.69(d,1 H),4.19-4.03(m,2 H),3.96(s,3 H),3.69(d,1 H),3.11(t,1 H),2.62-2.44(m,1 H),2.27-2.15(m,1 H),2.09(m,2 H),1.96-1.83(m,1 H),1.71(d,1 H). 1 H NMR (400MHz, CD 3 OD) δ 8.13(s,1H), 7.14(d,1H), 6.66(d,1H), 5.06(d,1H), 4.69(d,1H) , 4.19-4.03(m, 2 H), 3.96(s, 3 H), 3.69(d, 1 H), 3.11(t, 1 H), 2.62-2.44(m, 1 H), 2.27-2.15(m , 1 H), 2.09(m, 2 H), 1.96-1.83(m, 1 H), 1.71(d, 1 H).

取10.8mg化合物3用手性SFC分離(SFC150；手性柱IC，250×25mm，10um；超臨界CO2/甲醇+甲醇氨0.1%=45：55；80mL/min)得到3-P1(Rt=2.44min,3.1mg)和3-P2(Rt=3.24min,3.5mg)均為白色固體。 10.8mg of compound 3 was separated by chiral SFC (SFC150; chiral column IC, 250×25mm, 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=45:55; 80mL/min) to obtain 3-P 1 ( Rt=2.44 min, 3.1 mg) and 3 -P2 (Rt=3.24 min, 3.5 mg) were both white solids.

實施例4Example 4

4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(化合物4) 4-(1-(Propylsulfonyl)-1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile ( Compound 4)

Figure 110145234-A0101-12-0071-440
Figure 110145234-A0101-12-0071-440

第一步：6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯(4B) The first step: 6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl Esters (4B)

Figure 110145234-A0101-12-0071-441
Figure 110145234-A0101-12-0071-441

將4-氯-1H-吡咯並[2,3-b]吡啶-5-甲腈1A(300mg,1.69mmol)，1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯(323mg,1.52mmol)和N,N-二異丙基乙胺(439mg,3.38mmol)溶於異丙醇(8mL)中，並將混合物在氮氣保護下在100℃攪拌反應16小時。反應結束後旋乾溶劑，粗產品通過矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-20%)，得到白色固體化合物6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯4B(400mg，產率：67%)。 4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 1A (300 mg, 1.69 mmol), 1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl The ester (323 mg, 1.52 mmol) and N,N-diisopropylethylamine (439 mg, 3.38 mmol) were dissolved in isopropanol (8 mL), and the mixture was stirred for 16 hours at 100 °C under nitrogen protection. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-20%) to obtain a white solid compound 6-(5-cyano-1H-pyrrolo[ 2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate tert-butyl ester 4B (400 mg, yield: 67%).

MS m/z(ESI)：354.0[M+1]. MS m/z(ESI): 354.0[M+1].

第二步：4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(4C) Step 2: 4-(1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (4C)

Figure 110145234-A0101-12-0072-442
Figure 110145234-A0101-12-0072-442

將6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧酸叔丁酯1B(400mg,1.13mmol)溶於氯化氫的乙酸乙酯溶液中(10mL,1.5mol/L)，並將溶液在室溫下攪拌反應過夜。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-50%)，得到黃色固體化合物4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈4C(280mg，產率：98%)。 6-(5-Cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate tert-butyl ester 1B ( 400 mg, 1.13 mmol) was dissolved in an ethyl acetate solution of hydrogen chloride (10 mL, 1.5 mol/L), and the solution was stirred at room temperature to react overnight. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-50%) to obtain a yellow solid compound 4-(1,6-diazaspiro[3.4] ]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 4C (280 mg, yield: 98%).

MS m/z(ESI)：254.0[M+1]. MS m/z(ESI): 254.0[M+1].

第三步：4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(化合物4) The third step: 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5 -carbonitrile (compound 4)

Figure 110145234-A0101-12-0073-443
Figure 110145234-A0101-12-0073-443

將4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈4C(100mg，0.39mmol)和三乙胺(80mg,0.79mmol)溶於二氯甲烷(5mL)中，並在攪拌條件下將丙烷-1-磺醯氯(62mg,0.43mmol)滴加到反應液中。將混合物在室溫下攪拌反應過夜。反應結束後旋乾溶劑，粗產品通過製備型HPLC純化，凍乾得到白色固體化合物4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.4]辛烷-6-基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(化合物4)(12mg，收率：8.6%)。 4-(1,6-Diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 4C (100 mg, 0.39 mmol) and triethyl The amine (80 mg, 0.79 mmol) was dissolved in dichloromethane (5 mL), and propane-1-sulfonyl chloride (62 mg, 0.43 mmol) was added dropwise to the reaction with stirring. The mixture was stirred overnight at room temperature. After the reaction, the solvent was spin-dried, the crude product was purified by preparative HPLC, and lyophilized to obtain a white solid compound 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.4]octane-6- yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (Compound 4) (12 mg, yield: 8.6%).

取10mg化合物4用手性SFC分離(SFC150；手性柱IG，250×25mm，10um；超臨界CO2/甲醇+甲醇氨0.1%=45：55；70mL/min)得到化合物4-P1(Rt=2.58min,1.1mg)和化合物4-P2(Rt=3.08min,1.9mg)均為白色固體。 10mg of compound 4 was separated by chiral SFC (SFC150; chiral column IG, 250×25mm, 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=45:55; 70mL/min) to obtain compound 4-P 1 ( Rt=2.58 min, 1.1 mg) and compound 4-P 2 (Rt=3.08 min, 1.9 mg) were both white solids.

MS m/z(ESI)：360.0[M+1]. MS m/z(ESI): 360.0[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.87(s,1 H),8.05(s,1 H),7.24(d,1 H),6.74(d,1 H),4.34(d,1 H),4.22-4.10(m,2 H),4.01-3.79(m,3 H),3.17-2.97(m,2 H),2.59-2.52(m,1 H),2.48- 2.42(m,1 H),2.38-2.26(m,2 H),1.77-1.64(q,2 H),0.97(t,3 H). 1 H NMR (400MHz, DMSO-d6)δ 11.87(s,1H), 8.05(s,1H), 7.24(d,1H), 6.74(d,1H), 4.34(d,1H) , 4.22-4.10(m, 2 H), 4.01-3.79(m, 3 H), 3.17-2.97(m, 2 H), 2.59-2.52(m, 1 H), 2.48- 2.42(m, 1 H) ,2.38-2.26(m,2H),1.77-1.64(q,2H),0.97(t,3H).

實施例5Example 5

4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.5]壬烷-6-基)-7H-吡咯並[2,3-d]嘧啶(化合物5) 4-(1-(Propylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (Compound 5)

Figure 110145234-A0101-12-0074-444
Figure 110145234-A0101-12-0074-444

第一步：6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁酯(5B) The first step: 6-(7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid Tert-Butyl Ester (5B)

Figure 110145234-A0101-12-0074-445
Figure 110145234-A0101-12-0074-445

將4-氯-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5A(200mg,0.65mmol)，1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁酯(147mg,0.65mmol)和N,N-二異丙基乙胺(180mg,1.3mmol)溶於異丙醇(8mL)中，並將混合物在氮氣保護下在100℃攪拌反應16小時。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-5%)，得到白色固體化合物6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁酯5B(130mg，產率：40%)。 4-Chloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine 5A (200 mg, 0.65 mmol), 1,6-diazaspiro[3.5]nonane-1-carboxylic acid tert-Butyl ester (147 mg, 0.65 mmol) and N,N-diisopropylethylamine (180 mg, 1.3 mmol) were dissolved in isopropanol (8 mL), and the mixture was stirred for 16 hours at 100 °C under nitrogen protection . After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-5%) to obtain a white solid compound 6-(7-toluenesulfonyl-7H-pyrrole). [2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester 5B (130 mg, yield: 40%).

MS m/z(ESI)：498.0[M+1]. MS m/z(ESI): 498.0[M+1].

第二步：4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶(5C) Step 2: 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (5C)

Figure 110145234-A0101-12-0075-446
Figure 110145234-A0101-12-0075-446

將6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁酯5B(130mg,0.26mmol)溶於二氯甲烷溶液(10mL)中，加入TBSOTf(103mg,0.39mmol)，將溶液在室溫下攪拌，反應過夜。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-10%)，得到黃色固體化合物4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5C(90mg，產率：90.5%)。 6-(7-Tosylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester 5B (130 mg, 0.26 mmol) was dissolved in a dichloromethane solution (10 mL), TBSOTf (103 mg, 0.39 mmol) was added, and the solution was stirred at room temperature and reacted overnight. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-10%) to obtain a yellow solid compound 4-(1,6-diazaspiro[3.5] ]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine 5C (90 mg, yield: 90.5%).

MS m/z(ESI)：398.0[M+1]. MS m/z(ESI): 398.0[M+1].

第三步：4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5D The third step: 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2, 3-d]pyrimidine 5D

Figure 110145234-A0101-12-0075-447
Figure 110145234-A0101-12-0075-447

將4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5C(90mg，0.234mmol)和三乙胺(50mg,0.5mmol)溶於二氯甲烷(5mL)中，並在攪拌條件下將丙烷-1-磺醯氯(62mg, 0.43mmol)滴加到反應液中。混合物在室溫下攪拌反應過夜。反應結束後旋乾溶劑，粗產品通過製備型TLC純化，得到白色固體化合物4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5D(91mg，收率：86.4%)。 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine 5C (90 mg, 0.234 mmol) and Triethylamine (50 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and propane-1-sulfonyl chloride (62 mg, 0.43 mmol) was added dropwise to the reaction solution. The mixture was stirred at room temperature overnight. After the reaction, the solvent was rotated to dryness, and the crude product was purified by preparative TLC to obtain a white solid compound 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl) -7-Tosylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine 5D (91 mg, yield: 86.4%).

MS m/z(ESI)：504.0[M+1]. MS m/z(ESI): 504.0[M+1].

第四步：4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.5]壬烷-6-基)-7H-吡咯並[2,3-d]嘧啶(化合物5) The fourth step: 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (compound 5)

Figure 110145234-A0101-12-0076-448
Figure 110145234-A0101-12-0076-448

將4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5D(91mg，0.201mmol)和1N NaOH溶液(1mL)溶於THF/水(4mL/1mL)中，並將混合物在室溫下攪拌反應過夜。反應結束後旋乾溶劑，粗產品通過製備型HPLC純化，凍乾得到白色固體化合物4-(1-(丙基磺醯基)-1,6-二氮雜螺[3.5]壬烷-6-基)-7H-吡咯並[2,3-d]嘧啶(化合物5)(22mg，收率：16.6%)。 4-(1-(Propylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d ] Pyrimidine 5D (91 mg, 0.201 mmol) and IN NaOH solution (1 mL) were dissolved in THF/water (4 mL/1 mL), and the mixture was stirred at room temperature overnight. After the reaction, the solvent was spin-dried, the crude product was purified by preparative HPLC, and lyophilized to obtain a white solid compound 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.5]nonane-6- yl)-7H-pyrrolo[2,3-d]pyrimidine (Compound 5) (22 mg, yield: 16.6%).

取20mg產品用手性SFC分離(SFC150；手性柱IG，250×25mm，10um；超臨界CO2/乙醇+甲醇氨0.1%=45：55；70mL/min)得到化合物5-P1(Rt=2.28min,5.1mg)和化合物5-P2(Rt=2.952min,4.9mg)均為白色固體。 20mg of the product was separated by chiral SFC (SFC150; chiral column IG, 250×25mm, 10um; supercritical CO 2 /ethanol+methanol ammonia 0.1%=45:55; 70mL/min) to obtain compound 5-P 1 (Rt = 2.28 min, 5.1 mg) and compound 5-P 2 (Rt = 2.952 min, 4.9 mg) were both white solids.

MS m/z(ESI)：350.1[M+1]. MS m/z(ESI): 350.1[M+1].

1H NMR(400MHz,CD3OD)δ 8.16(s,1 H),7.17(d,1 H),6.66(d,1 H),5.12(d,1 H),4.64(d,1 H),3.89-3.85(m,2 H),3.55(d,1 H),3.15-3.06(m,1 H),3.06-2.95(m,2 H),2.33-2.00(m,4 H),1.94-1.87(m,1 H),1.82-1.78(m,2 H),1.77-1.63(m,1 H),1.07(t,3 H). 1 H NMR (400MHz, CD 3 OD) δ 8.16(s,1H), 7.17(d,1H), 6.66(d,1H), 5.12(d,1H), 4.64(d,1H) ,3.89-3.85(m,2H),3.55(d,1H),3.15-3.06(m,1H),3.06-2.95(m,2H),2.33-2.00(m,4H),1.94 -1.87(m,1H),1.82-1.78(m,2H),1.77-1.63(m,1H),1.07(t,3H).

實施例6Example 6

N-(3-甲氧基-1,2,4-噻二唑-5-基)-7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物6) N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)- 2-Azaspiro[3.5]nonane-2-carboxyamide (Compound 6)

Figure 110145234-A0101-12-0077-449
Figure 110145234-A0101-12-0077-449

第一步：7-(甲基氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁酯(6B) The first step: tert-butyl 7-(methylamino)-2-azaspiro[3.5]nonane-2-carboxylate (6B)

Figure 110145234-A0101-12-0077-450
Figure 110145234-A0101-12-0077-450

在一個50mL的三口圓底燒瓶中加入7-氧代-2-氮雜螺[3.5]壬烷-2-羧酸叔丁酯(500mg,2.4mmol)，甲胺水溶液(5mL)和NaBH3CN(630mg,10mmol)於DCE(10mL)中，並在室溫反應16小時。用乙酸乙酯(10mL×3)萃取反應混合物，有機相用無水硫酸鈉乾燥，過濾，濃縮，得到無色油狀的7-(甲基氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁酯6B(500mg，粗產品)。 In a 50 mL three-necked round bottom flask were added tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (500 mg, 2.4 mmol), methylamine aqueous solution (5 mL) and NaBH 3 CN (630 mg, 10 mmol) in DCE (10 mL) and reacted at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7-(methylamino)-2-azaspiro[3.5]nonane-2 as a colorless oil. - tert-butyl carboxylate 6B (500 mg, crude).

MS m/z(ESI)：255.0[M+1]. MS m/z(ESI): 255.0[M+1].

第二步：7-(甲基(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁基酯(6C) Step 2: 7-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino )-2-Azaspiro[3.5]nonane-2-carboxylate tert-butyl ester (6C)

Figure 110145234-A0101-12-0078-451
Figure 110145234-A0101-12-0078-451

將7-(甲基氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁酯6B(500mg，粗產品)，4-氯-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶(561mg,2mmol)和DIEA(278mg,2mmol)溶於DMF(10mL)中，並在氮氣保護下於130℃反應6h。加入30mL水，用乙酸乙酯(20mL×3)萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：5-1：3)得到化合物7-(甲基(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧酸 叔丁基酯6C(180mg，收率25.1%)。 7-(Methylamino)-2-azaspiro[3.5]nonane-2-carboxylate tert-butyl ester 6B (500 mg, crude product), 4-chloro-7-(((2-(trimethylmethane) Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (561 mg, 2 mmol) and DIEA (278 mg, 2 mmol) were dissolved in DMF (10 mL) and dissolved under nitrogen at 130 ℃ reaction 6h. 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:5-1:3) to obtain compound 7-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl) )-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-Butyl ester 6C (180 mg, 25.1% yield).

MS m/z(ESI)：502.0[M+1]. MS m/z(ESI): 502.0[M+1].

第三步：N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-胺(6D) Step 3: N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-Pyrrolo[2,3-d]pyrimidin-4-amine (6D)

Figure 110145234-A0101-12-0079-452
Figure 110145234-A0101-12-0079-452

將7-(甲基(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁基酯6C(180mg,0.32mmol)溶於HCL/MeOH(3mL)，並在室溫攪拌16h。然後真空旋乾反應混合物，得到粗品N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-胺6D(200mg，粗產品)。 7-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2 - Azaspiro[3.5]nonane-2-carboxylate tert-butyl ester 6C (180 mg, 0.32 mmol) was dissolved in HCL/MeOH (3 mL) and stirred at room temperature for 16 h. The reaction mixture was then spun dry in vacuo to give crude N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-((2-(trimethylsilyl)ethoxy) )methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 6D (200 mg, crude).

MS m/z(ESI)：402.0[M+1]. MS m/z(ESI): 402.0[M+1].

第四步：N-(3-甲氧基-1,2,4-噻二唑-5-基)-7-(甲基(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(6E) The fourth step: N-(3-methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7-((2-(trimethylsilyl)ethoxy) (6E)

Figure 110145234-A0101-12-0079-453
Figure 110145234-A0101-12-0079-453

將N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-胺6D粗品(200mg，粗產品)溶於THF(2mL)，並在氮氣保護下加入三乙胺(41mg, 0.4mmol)和(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(175mg，0.3mmol)，於60℃反應6小時。濃縮反應液，加入水10mL，用乙酸乙酯(10mL×3)萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物用矽膠柱純化(石油醚：乙酸乙酯=1：5-1：3)得到N-(3-甲氧基-1,2,4-噻二唑-5-基)-7-(甲基(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺6E為白色固體(180mg，產率50.4%)。 N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole The crude [2,3-d]pyrimidin-4-amine 6D (200 mg, crude product) was dissolved in THF (2 mL) and triethylamine (41 mg, 0.4 mmol) and (3-methoxy-1,2,4-thiadiazol-5-yl)carbamic acid phenyl ester (175 mg, 0.3 mmol), reacted at 60°C for 6 hours. The reaction solution was concentrated, 10 mL of water was added, extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column (petroleum ether:ethyl acetate=1:5-1:3) to obtain N-(3-methoxy-1,2,4-thiadiazol-5-yl)-7-( Methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro [3.5]Nonane-2-carboxyamide 6E was a white solid (180 mg, 50.4% yield).

MS m/z(ESI)：559.0[M+1]. MS m/z(ESI): 559.0[M+1].

第五步：N-(3-甲氧基-1,2,4-噻二唑-5-基)-7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物6) The fifth step: N-(3-methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl) )amino)-2-azaspiro[3.5]nonane-2-carboxyamide (Compound 6)

Figure 110145234-A0101-12-0080-454
Figure 110145234-A0101-12-0080-454

將N-(3-甲氧基-1,2,4-噻二唑-5-基)-7-(甲基(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺6E(180mg，0.32mmol)溶於DCM(4mL)，加入TFA(2mL)，室溫反應2小時。濃縮反應液，經製備型HPLC純化後凍乾得到N-(3-甲氧基-1,2,4-噻二唑-5-基)-7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物6)為白色固體(5mg，收率3.6%)。 N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl) yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide 6E (180 mg, 0.32 mmol) was dissolved in DCM ( 4 mL), added TFA (2 mL), and reacted at room temperature for 2 hours. The reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain N-(3-methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide (compound 6) was a white solid (5 mg, 3.6% yield).

MS m/z(ESI)：429.1[M+1]. MS m/z(ESI): 429.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.77(s,1 H),11.59(s,1 H),8.09(s,1 H),7.14-7.10(m,1 H),6.54(d,1 H),4.66(s,1 H),3.89(s,3 H),3.78(d,4 H),3.14(s,3 H),2.00(d,2 H),1.66-1.62(m,6 H). 1 H NMR (400MHz, DMSO-d6) δ 11.77(s, 1 H), 11.59(s, 1 H), 8.09(s, 1 H), 7.14-7.10(m, 1 H), 6.54(d, 1 H), 4.66(s, 1 H), 3.89(s, 3 H), 3.78(d, 4 H), 3.14(s, 3 H), 2.00(d, 2 H), 1.66-1.62(m, 6 H).

實施例7Example 7

N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物7) N-(3-(Methylthio)-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6 - Diazaspiro[3.5]nonane-1-carboxamide (compound 7)

Figure 110145234-A0101-12-0081-455
Figure 110145234-A0101-12-0081-455

第一步：3-(甲硫基)-1,2,4-噻二唑-5-胺(7B) The first step: 3-(methylthio)-1,2,4-thiadiazol-5-amine (7B)

Figure 110145234-A0101-12-0081-456
Figure 110145234-A0101-12-0081-456

將硫氰酸鈉(15.5g,192mmol)溶於甲醇(100mL)，並於0℃攪拌下加入甲脒基甲基硫醚7A(13.9g,73mmol)和三乙胺(15.4mL，87.6mmol)。將混合物在0℃在攪拌下同時滴加三乙胺(14mL，73mmol)和液溴(16.3g，146mmol)。室溫反應2小時後，濃縮反應液，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-30%)得到黃色固體3-(甲硫基)-1,2,4-噻二唑-5-胺7B(8.5g，37.4%)。 Sodium thiocyanate (15.5 g, 192 mmol) was dissolved in methanol (100 mL) and formamidinyl methyl sulfide 7A (13.9 g, 73 mmol) and triethylamine (15.4 mL, 87.6 mmol) were added with stirring at 0°C . The mixture was added dropwise triethylamine (14 mL, 73 mmol) and liquid bromine (16.3 g, 146 mmol) simultaneously with stirring at 0°C. After 2 hours of reaction at room temperature, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-30%) to obtain a yellow solid 3-(methylthio)-1, 2,4-Thiadiazol-5-amine 7B (8.5 g, 37.4%).

MS m/z(ESI)：148.0[M+1]. MS m/z(ESI): 148.0[M+1].

第二步：(3-(甲硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯 (7C) The second step: (3-(methylthio)-1,2,4-thiadiazol-5-yl) phenylcarbamate (7C)

Figure 110145234-A0101-12-0082-457
Figure 110145234-A0101-12-0082-457

將3-(甲硫基)-1,2,4-噻二唑-5-胺7B(500mg，3.4mmol)溶於二氯甲烷(10mL)，並於攪拌下加入三乙胺(0.71mL,5.09mmol)。將混合物在0℃在攪拌下加入氯甲酸苯酯(584mg，3.74mmol)。混合物在氮氣保護下在室溫攪拌2小時。反應結束後加入水(15mL)，經二氯甲烷萃取(15mL×3)。有機相經無水硫酸鈉乾燥，粗產品用矽膠柱色譜分離提純(乙酸乙酯：石油醚(v/v)=0-10%)得到黃色固體化合物(3-(甲硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯7C(250mg，產率27.5%)。 3-(Methylthio)-1,2,4-thiadiazol-5-amine 7B (500 mg, 3.4 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.71 mL, 5.09 mmol). To the mixture was added phenyl chloroformate (584 mg, 3.74 mmol) with stirring at 0°C. The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL×3). The organic phase was dried over anhydrous sodium sulfate, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v)=0-10%) to obtain a yellow solid compound (3-(methylthio)-1,2). , 4-thiadiazol-5-yl)carbamate phenyl ester 7C (250 mg, 27.5% yield).

第三步：N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(7D) The third step: N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)-6-(7-toluenesulfonyl-7H-pyrrolo[2,3-d] ]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (7D)

Figure 110145234-A0101-12-0082-458
Figure 110145234-A0101-12-0082-458

將4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5C(200mg，0.5mmol)，(3-(甲硫基)-1,2,4-噻二唑 -5-基)氨基甲酸苯基酯7C(201mg，0.75mmol)，三乙胺(101mg，1.0mmol)溶於DMF(5mL)。將混合物在60℃攪拌下繼續反應2小時。反應結束後濃縮，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-40%)得到白色固體化合物N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺7D(160mg，產率55.7%)。 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine 5C (200 mg, 0.5 mmol), (3-(Methylthio)-1,2,4-thiadiazole Phenyl-5-yl)carbamate 7C (201 mg, 0.75 mmol), triethylamine (101 mg, 1.0 mmol) was dissolved in DMF (5 mL). The mixture was stirred for 2 hours at 60°C. After the reaction, it was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-40%) to obtain a white solid compound N-(3-(methylthio)-1,2, 4-Thiadiazol-5-yl)-6-(7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5] Nonane-1-carboxyamide 7D (160 mg, 55.7% yield).

MS m/z(ESI)：571.0[M+1]。 MS m/z (ESI): 571.0 [M+1].

第四步：N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物7) The fourth step: N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1,6-Diazaspiro[3.5]nonane-1-carboxamide (Compound 7)

Figure 110145234-A0101-12-0083-459
Figure 110145234-A0101-12-0083-459

將化合物N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺7D(160mg，0.28mmol)溶於四氫呋喃(3mL)，加入1M的氫氧化鈉溶液(1.4mL，1.4mmol)，並將混合物在60℃攪拌2小時。反應結束後濃縮反應液，通過製備型HPLC純化，凍乾得到白色固體化合物N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物7)(35mg，收率29.9%)。 The compound N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)-6-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide 7D (160 mg, 0.28 mmol) was dissolved in tetrahydrofuran (3 mL), 1 M sodium hydroxide solution (1.4 mL, 1.4 mmol), and the mixture was stirred at 60°C for 2 hours. After the reaction, the reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)-6-(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (compound 7) (35 mg, yield 29.9%).

取32mg化合物7用手性SFC分離(SFC150；手性柱IC，250×25mm，10um；超臨界CO2/甲醇+甲醇氨0.1%=45：55；100mL/min)得到化合物7-P1(Rt=1.18min,14mg)和化合物7-P2(Rt=1.54min,16mg)均為白色固體。 32mg of compound 7 was separated by chiral SFC (SFC150; chiral column IC, 250×25mm, 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=45:55; 100mL/min) to obtain compound 7-P 1 ( Rt=1.18 min, 14 mg) and compound 7-P 2 (Rt=1.54 min, 16 mg) were both white solids.

MS m/z(ESI)：417.1[M+1]. MS m/z(ESI): 417.1[M+1].

1H NMR(400MHz,CD3OD)δ 8.18(s,1 H),7.19(d,1 H),6.74(d,1 H),4.98(d,1 H),4.63(d,1 H),4.26-4.02(m,2 H),3.82(d,1 H),3.27-3.17(m,1 H),2.58(s,3 H),2.57-2.47(m,1 H),2.29-2.18(m,1 H),2.17-2.06(m,2 H),2.00-1.92(m,1 H),1.81-1.66(m,1 H). 1 H NMR (400MHz, CD 3 OD) δ 8.18(s,1H), 7.19(d,1H), 6.74(d,1H), 4.98(d,1H), 4.63(d,1H) , 4.26-4.02(m, 2 H), 3.82(d, 1 H), 3.27-3.17(m, 1 H), 2.58(s, 3 H), 2.57-2.47(m, 1 H), 2.29-2.18 (m, 1 H), 2.17-2.06 (m, 2 H), 2.00-1.92 (m, 1 H), 1.81-1.66 (m, 1 H).

實施例8Example 8

N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物8) N-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6 - Diazaspiro[3.5]nonane-1-carboxamide (compound 8)

Figure 110145234-A0101-12-0084-460
Figure 110145234-A0101-12-0084-460

第一步：3-(乙硫基)-1,2,4-噻二唑-5-胺(8B) The first step: 3-(Ethylthio)-1,2,4-thiadiazol-5-amine (8B)

Figure 110145234-A0101-12-0084-461
Figure 110145234-A0101-12-0084-461

將硫氰酸鈉(3.86g,47.57mmol)溶於甲醇(40mL)，然後在0℃攪拌下加入甲脒基乙基硫醚8A(3.7g,18.29mmol)和三乙胺(3.06mL，21.95mmol)。將混合物在0℃在攪拌下同時滴加三乙胺 (2.55mL，18.29mmol)和液溴(5.85g，36.59mmol)。室溫反應2小時後，濃縮反應液，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-30%)得到黃色固體化合物3-(乙硫基)-1,2,4-噻二唑-5-胺8B(2.3g，77.9%)。 Sodium thiocyanate (3.86 g, 47.57 mmol) was dissolved in methanol (40 mL), then carboxamidinoethyl sulfide 8A (3.7 g, 18.29 mmol) and triethylamine (3.06 mL, 21.95 were added with stirring at 0° C. mmol). The mixture was added dropwise with triethylamine at 0°C with stirring (2.55 mL, 18.29 mmol) and liquid bromine (5.85 g, 36.59 mmol). After 2 hours of reaction at room temperature, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-30%) to obtain a yellow solid compound 3-(ethylthio)-1 , 2,4-thiadiazol-5-amine 8B (2.3 g, 77.9%).

第二步：(3-(乙硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(8C) The second step: (3-(ethylthio)-1,2,4-thiadiazol-5-yl) phenylcarbamate (8C)

Figure 110145234-A0101-12-0085-462
Figure 110145234-A0101-12-0085-462

將3-(乙硫基)-1,2,4-噻二唑-5-胺8B(2.3g，14.26mmol)溶於二氯甲烷(20mL)，然後在攪拌下加入三乙胺(2.98mL,21.4mmol)。在0℃攪拌下向混合物中加入氯甲酸苯酯(2.46g，15.69mmol)。將混合物在氮氣保護下室溫攪拌2小時。反應結束後加入水(15mL)，用二氯甲烷萃取(15mL×3)。無水硫酸鈉乾燥有機相，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-10%)得到黃色固體化合物(3-(乙硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯8C(1.2g，產率29.9%)。 3-(Ethylthio)-1,2,4-thiadiazol-5-amine 8B (2.3 g, 14.26 mmol) was dissolved in dichloromethane (20 mL), then triethylamine (2.98 mL) was added with stirring , 21.4 mmol). To the mixture was added phenyl chloroformate (2.46 g, 15.69 mmol) with stirring at 0°C. The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL×3). The organic phase was dried over anhydrous sodium sulfate, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-10%) to obtain a yellow solid compound (3-(ethylthio)-1,2, Phenyl 4-thiadiazol-5-yl)carbamate 8C (1.2 g, 29.9% yield).

MS m/z(ESI)：282.1[M+1]. MS m/z(ESI): 282.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 13.19(s,1 H),7.49-7.45(m,2 H),7.35-7.30(m,3 H),3.20-3.14(q,2 H),1.37-1.33(t,3 H). 1 H NMR (400MHz, DMSO-d6) δ 13.19(s,1H), 7.49-7.45(m,2H), 7.35-7.30(m,3H), 3.20-3.14(q,2H), 1.37 -1.33(t,3H).

第三步：N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(8D) The third step: N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-6-(7-toluenesulfonyl-7H-pyrrolo[2,3-d] ]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (8D)

Figure 110145234-A0101-12-0086-463
Figure 110145234-A0101-12-0086-463

將4-(1,6-二氮雜螺[3.5]壬烷-6-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶5C(200mg，0.5mmol)，(3-(乙硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯8C(201mg，0.75mmol)和三乙胺(101mg，1.0mmol)溶於N,N-二甲基甲醯胺(5mL)。將混合物在60℃攪拌下繼續反應2小時。反應結束後濃縮反應混合物，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-40%)得到白色固體化合物N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺8D(230mg，產率73.7%)。 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine 5C (200 mg, 0.5 mmol), Phenyl (3-(ethylthio)-1,2,4-thiadiazol-5-yl)carbamate 8C (201 mg, 0.75 mmol) and triethylamine (101 mg, 1.0 mmol) were dissolved in N,N - Dimethylformamide (5 mL). The mixture was stirred for 2 hours at 60°C. After the reaction, the reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-40%) to obtain a white solid compound N-(3-(ethylthio)-1, 2,4-Thiadiazol-5-yl)-6-(7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[ 3.5] Nonane-1-carboxyamide 8D (230 mg, 73.7% yield).

MS m/z(ESI)：584.0[M+1]. MS m/z(ESI): 584.0[M+1].

第四步：N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物8) Step 4: N-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1,6-Diazaspiro[3.5]nonane-1-carboxamide (Compound 8)

Figure 110145234-A0101-12-0086-464
Figure 110145234-A0101-12-0086-464

將化合物N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-6-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯 胺8D(230mg，0.39mmol)溶於四氫呋喃(3mL)，然後加入1M的氫氧化鈉溶液(1.95mL，1.95mmol)。將混合物在60℃攪拌2小時。反應結束後濃縮反應液，通過製備型HPLC純化，凍乾得到白色固體化合物N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧醯胺(化合物8)(60mg，收率35.4%)。 The compound N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-6-(7-tosylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine -4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate Amine 8D (230 mg, 0.39 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 1 M sodium hydroxide solution (1.95 mL, 1.95 mmol). The mixture was stirred at 60°C for 2 hours. After the reaction, the reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)-6-(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (compound 8) (60 mg, 35.4% yield).

取55mg化合物8用手性SFC分離(SFC150；手性柱OJ，250×25mm，10um；超臨界CO2/甲醇+甲醇氨0.1%=45：55；80mL/min)得到化合物8-P1(Rt=1.18min,24mg)和化合物8-P2(Rt=2.09min,23mg)均為白色固體。 55mg of compound 8 was separated by chiral SFC (SFC150; chiral column OJ, 250×25mm, 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=45:55; 80mL/min) to obtain compound 8-P 1 ( Rt=1.18 min, 24 mg) and compound 8-P 2 (Rt=2.09 min, 23 mg) were both white solids.

MS m/z(ESI)：431.2[M+1]. MS m/z(ESI): 431.2[M+1].

1H NMR(400MHz,CD3OD)δ 8.15(s,1H),7.16(d,1H),6.69(d,1H),5.03(d,1H),4.67(d,1H),4.22-4.01(m,2H),3.75(d,1H),3.21-3.12(m,3H),2.58-2.49(m,1H),2.26-2.17(m,1H),2.16-2.04(m,2H),1.99-1.85(m,1H),1.81-1.66(m,1H),1.38(t,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.15(s, 1H), 7.16(d, 1H), 6.69(d, 1H), 5.03(d, 1H), 4.67(d, 1H), 4.22-4.01( m, 2H), 3.75(d, 1H), 3.21-3.12(m, 3H), 2.58-2.49(m, 1H), 2.26-2.17(m, 1H), 2.16-2.04(m, 2H), 1.99- 1.85(m,1H),1.81-1.66(m,1H),1.38(t,3H).

實施例9Example 9

N-((2s,3aR,5r,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(化合物9) N-((2s,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl) Propane-1-sulfonamide (Compound 9)

Figure 110145234-A0101-12-0088-465
Figure 110145234-A0101-12-0088-465

第一步：(3aR,6aS)-5’,5’-二甲基四氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5(3H)-酮(9B) The first step: (3aR,6aS)-5',5'-dimethyltetrahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5(3H )-keto (9B)

Figure 110145234-A0101-12-0088-466
Figure 110145234-A0101-12-0088-466

將(3as,6as)-四氫並環戊二烯-2,5(1H，3H)-二酮9A(2g,14.48mmol)溶於甲苯(toluene)(15mL)，然後在攪拌下加入2,2-二甲基丙烷-1,3-二醇(1.51g,14.48mmol)和一水合對甲苯磺酸(25mg，0.14mmol)。將混合物在110℃下攪拌6小時。反應結束後濃縮反應液，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-10%)得到白色固體化合物(3aR,6aS)-5’,5’-二甲基四氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5(3H)-酮9B(1.5g，產率46.2%)。 (3as,6as)-tetrahydrocyclopentadiene-2,5(1H,3H)-dione 9A (2 g, 14.48 mmol) was dissolved in toluene (15 mL), then 2, 2-Dimethylpropane-1,3-diol (1.51 g, 14.48 mmol) and p-toluenesulfonic acid monohydrate (25 mg, 0.14 mmol). The mixture was stirred at 110°C for 6 hours. After the reaction, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-10%) to obtain a white solid compound (3aR,6aS)-5',5'-di Methyltetrahydro-1H-spiro[pcyclopentadien-2,2'-[1,3]dioxane]-5(3H)-one 9B (1.5 g, 46.2% yield).

1H NMR(400MHz,CDCl3)δ 3.48(s,2 H),3.45(s,2 H),2.90-2.76(m,2 H),2.53-2.37(m,2 H),2.35-2.25(m,2 H),2.23- 2.11(m,2 H),1.87-1.77(m,2 H),0.96(s,6 H). 1 H NMR (400MHz, CDCl 3 )δ 3.48(s,2H), 3.45(s,2H), 2.90-2.76(m,2H), 2.53-2.37(m,2H), 2.35-2.25( m, 2 H), 2.23-2.11 (m, 2 H), 1.87-1.77 (m, 2 H), 0.96 (s, 6 H).

第二步：(3aR,5s,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-醇(9C) The second step: (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5 - Alcohol (9C)

Figure 110145234-A0101-12-0089-467
Figure 110145234-A0101-12-0089-467

將化合物(3aR,6aS)-5’,5’-二甲基四氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5(3H)-酮9B(1.5g，6.69mmol)溶於乙酸乙酯(15mL)，然後在0℃攪拌下加入1M的三叔丁氧基氫化鋁鋰(13.4mL,13.37mmol)。將混合物在0℃攪拌下2小時。反應結束後加入水(20mL)，乙酸乙酯萃取(30mL×3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-10%)得到白色固體化合物(3aR,5s,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-醇9C(1.5g，產率99%)。 The compound (3aR,6aS)-5',5'-dimethyltetrahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5(3H)- Ketone 9B (1.5 g, 6.69 mmol) was dissolved in ethyl acetate (15 mL), then 1 M lithium tri-tert-butoxyaluminum hydride (13.4 mL, 13.37 mmol) was added at 0°C with stirring. The mixture was stirred at 0°C for 2 hours. After the reaction, water (20 mL) was added, extracted with ethyl acetate (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-10%) to obtain a white solid compound (3aR,5s,6aS)-5',5'-dimethylhexahydro- 1H-Spiro[opcyclopentadien-2,2'-[1,3]dioxan]-5-ol 9C (1.5 g, 99% yield).

1H NMR(400MHz,CDCl3)δ 4.25-4.18(m,1 H),3.50(s,2 H),3.47(s,2 H),2.62-2.46(m,2 H),2.27-2.17(m,2 H),2.13-2.06(m,2 H),1.96-1.86(m,2 H),1.58-1.47(m,2 H),0.96(s,6 H). 1 H NMR (400 MHz, CDCl 3 ) δ 4.25-4.18 (m, 1 H), 3.50 (s, 2 H), 3.47 (s, 2 H), 2.62-2.46 (m, 2 H), 2.27-2.17 ( m, 2 H), 2.13-2.06 (m, 2 H), 1.96-1.86 (m, 2 H), 1.58-1.47 (m, 2 H), 0.96 (s, 6 H).

第三步：甲磺酸(3aR,5s,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基酯(9D) The third step: methanesulfonic acid (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane ]-5-yl ester (9D)

Figure 110145234-A0101-12-0090-468
Figure 110145234-A0101-12-0090-468

將化合物(3aR,5s,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-醇(0.5g，2.2mmol)9C溶於二氯甲烷(5mL)，然後在攪拌下加入三乙胺(0.5mL,2.4mmol)。混合物在0℃攪拌下加入甲基磺醯氯(0.3g，2.6mmol)。混合物在氮氣保護下於室溫攪拌3小時，反應結束後濃縮反應液得到白色固體化合物甲磺酸(3aR,5s,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基酯9D(700mg，粗產品)。 The compound (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[p-cyclopentadien-2,2'-[1,3]dioxan]-5-ol (0.5 g, 2.2 mmol) 9C was dissolved in dichloromethane (5 mL), then triethylamine (0.5 mL, 2.4 mmol) was added with stirring. To the mixture was added methylsulfonyl chloride (0.3 g, 2.6 mmol) with stirring at 0°C. The mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to obtain a white solid compound methanesulfonic acid (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[and Cyclopentadien-2,2'-[1,3]dioxan]-5-yl ester 9D (700 mg, crude).

第四步：(3aR,5r,6aS)-N,5’,5’-三甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-胺(9E) The fourth step: (3aR,5r,6aS)-N,5',5'-trimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane] -5-Amine (9E)

Figure 110145234-A0101-12-0090-469
Figure 110145234-A0101-12-0090-469

將白色固體化合物甲磺酸(3aR,5s,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基酯9D(700mg，2.3mmol)溶於甲醇(3mL)，然後在0℃在攪拌下加30%的甲胺乙醇溶液(5mL，11.5mmol)，混合物在室溫攪拌下繼續反應16小時。反應結束後濃縮，粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-10%)得到黃色油狀的化合物(3aR,5r,6aS)-N,5’,5’-三甲基六氫 -1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-胺9E(90mg，產率16.3%)。 The white solid compound methanesulfonic acid (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane ]-5-yl ester 9D (700 mg, 2.3 mmol) was dissolved in methanol (3 mL), then 30% methylamine ethanol solution (5 mL, 11.5 mmol) was added at 0 °C with stirring, and the mixture was stirred at room temperature to continue the reaction 16 hours. After the reaction, it was concentrated, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-10%) to obtain a yellow oily compound (3aR,5r,6aS)-N,5',5 '-trimethylhexahydro -1H-Spiro[opcyclopentadiene-2,2'-[1,3]dioxane]-5-amine 9E (90 mg, 16.3% yield).

第五步：N-((3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基)-N-甲基-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺(9F) The fifth step: N-((3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane ]-5-yl)-N-methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9F)

Figure 110145234-A0101-12-0091-470
Figure 110145234-A0101-12-0091-470

將化合物(3aR,5r,6aS)-N,5’,5’-三甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-胺9E(90mg，0.37mmol)，4-氯-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶(115mg，0.37mmol)和N,N-二異丙基乙胺(0.2mL,1.13mmol)溶於異丙醇(5mL)。將混合物在氮氣保護下於100℃攪拌16小時。反應結束後濃縮反應液，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-20%)得到白色固體化合物N-((3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基)-N-甲基-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺9F(140mg，產率72.9%)。 Compound (3aR,5r,6aS)-N,5',5'-trimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5 - Amine 9E (90 mg, 0.37 mmol), 4-chloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (115 mg, 0.37 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.13 mmol) dissolved in isopropanol (5 mL). The mixture was stirred at 100°C for 16 hours under nitrogen protection. After the reaction, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-20%) to obtain a white solid compound N-((3aR,5r,6aS)-5' ,5'-Dimethylhexahydro-1H-spiro[pcyclopentadiene-2,2'-[1,3]dioxan]-5-yl)-N-methyl-7-toluenesulfonic acid yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 9F (140 mg, 72.9% yield).

MS m/z(ESI)：511.0[M+1]. MS m/z(ESI): 511.0[M+1].

1H NMR(400MHz,DMSO-d6)δ 7.23(s,1 H),7.01(d,2 H),6.57(d,1 H),6.40(d,2 H),5.91(d,1 H),4.40(s,1 H),2.55(d,4 H),2.19(s,3 H),1.68(s,2 H),1.48-1.33(m,5 H),1.02-0.90(m, 2 H),0.72-0.55(m,4 H). 1 H NMR (400MHz, DMSO-d6)δ 7.23(s,1H), 7.01(d,2H), 6.57(d,1H), 6.40(d,2H), 5.91(d,1H) , 4.40(s, 1 H), 2.55(d, 4 H), 2.19(s, 3 H), 1.68(s, 2 H), 1.48-1.33(m, 5 H), 1.02-0.90(m, 2 H),0.72-0.55(m,4H).

第六步：(3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮(9G) The sixth step: (3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentanedi En-2(1H)-one (9G)

Figure 110145234-A0101-12-0092-471
Figure 110145234-A0101-12-0092-471

將化合物N-((3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基)-N-甲基-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺9F(140mg，0.27mmol)溶於丙酮(acetone)：水=40：1(3mL)，然後於攪拌下加入一水合對甲苯磺酸(5.2mg,0.027mmol)。將混合物在室溫下攪拌16小時。旋乾，殘餘物中加入水(5mL)，用乙酸乙酯萃取(10mL×3)。無水硫酸鈉乾燥有機相得到(3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮9G(110mg，粗產品)。 The compound N-((3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]- 5-yl)-N-methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 9F (140 mg, 0.27 mmol) in acetone: water = 40 : 1 (3 mL), then p-toluenesulfonic acid monohydrate (5.2 mg, 0.027 mmol) was added with stirring. The mixture was stirred at room temperature for 16 hours. Spin to dryness, add water (5 mL) to the residue, and extract with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate to give (3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydro Cyclopentadien-2(1H)-one 9G (110 mg, crude).

第七步：(2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-醇(9H) Step 7: (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclo Pentadien-2-ol (9H)

Figure 110145234-A0101-12-0092-472
Figure 110145234-A0101-12-0092-472

將(3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫並環戊二烯-2(17H)-酮9G(110mg，0.25mmol) 溶於乙酸乙酯(3mL)，然後在0℃於攪拌下加入三叔丁氧基氫化鋁鋰(1M,0.51mL,0.5mmol)。將混合物在0℃攪拌下2小時。反應結束後加入水(10mL)，用乙酸乙酯萃取(15mL x 3)，用無水硫酸鈉乾燥得到(2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-醇9H(120mg，粗產品)。 (3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentadiene-2 (17H)-keto 9G (110 mg, 0.25 mmol) Dissolve in ethyl acetate (3 mL), then add lithium tri-tert-butoxyaluminum hydride (1 M, 0.51 mL, 0.5 mmol) at 0 °C with stirring. The mixture was stirred at 0°C for 2 hours. After the reaction, water (10 mL) was added, extracted with ethyl acetate (15 mL x 3), and dried with anhydrous sodium sulfate to obtain (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H) -pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-ol 9H (120 mg, crude).

第八步：甲磺酸(2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基酯(9I) Step 8: Methanesulfonic acid (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octa Hydrocyclopentadien-2-yl ester (9I)

Figure 110145234-A0101-12-0093-473
Figure 110145234-A0101-12-0093-473

將(2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-醇9H(120mg，0.28mmol)溶於二氯甲烷(3mL)，然後於攪拌下加入三乙胺(56mg,0.56mmol)。將混合物在0℃攪拌下加入甲基磺醯氯(38mg，0.33mmol)。將混合物在氮氣保護下於室溫攪拌3小時。反應結束後濃縮反應液得到黃色油狀甲磺酸(2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基酯9I(150mg，粗產品)。 (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadiene -2-ol 9H (120 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL), then triethylamine (56 mg, 0.56 mmol) was added with stirring. To the mixture was added methylsulfonyl chloride (38 mg, 0.33 mmol) with stirring at 0°C. The mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction, the reaction solution was concentrated to obtain (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-4)-methanesulfonic acid as yellow oil. -yl)amino)octahydrocyclopentadien-2-yl ester 9I (150 mg, crude).

第九步：N-((2r,3aR,5s,6aS)-5-疊氮基八氫並環戊二烯-2-基)-N-甲基-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺(9J) Step 9: N-((2r,3aR,5s,6aS)-5-azidooctahydrocyclopentadien-2-yl)-N-methyl-7-toluenesulfonyl-7H-pyrrole Do[2,3-d]pyrimidin-4-amine (9J)

Figure 110145234-A0101-12-0094-474
Figure 110145234-A0101-12-0094-474

將甲磺酸(2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基酯9I(80mg，0.198mmol)溶於乙腈(3mL)，然後於攪拌下加入四丁基疊氮化胺(112mg,0.396mmol)。將混合物在氮氣保護下於90℃攪拌3小時。反應結束後濃縮反應混合物，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-10%)得到無色油狀化合物N-((2r,3aR,5s,6aS)-5-疊氮基八氫並環戊二烯-2-基)-N-甲基-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺9J(60mg，產率83.8%)。 Methanesulfonic acid (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclo Pentadien-2-yl ester 9I (80 mg, 0.198 mmol) was dissolved in acetonitrile (3 mL) and tetrabutylamine azide (112 mg, 0.396 mmol) was added with stirring. The mixture was stirred at 90°C for 3 hours under nitrogen protection. After the reaction, the reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-10%) to obtain a colorless oily compound N-((2r,3aR,5s,6aS) -5-Azidooctahydrocyclopentadien-2-yl)-N-methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 9J (60 mg , the yield is 83.8%).

第十步：(2s,3aR,5r,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺(9K) Step 10: (2s,3aR,5r,6aS)-N 2 -methyl-N 2 -(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro cyclopentadiene-2,5-diamine (9K)

Figure 110145234-A0101-12-0094-475
Figure 110145234-A0101-12-0094-475

將化合物N-((2r,3aR,5s,6aS)-5-疊氮基八氫並環戊二烯-2-基)-N-甲基-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺9J(60mg，0.13mmol)溶於乙酸乙酯(3mL)，然後於攪拌下加入10%的濕鈀/炭(10mg)。混合物在氫氣下於室溫攪拌16小時。反應結束後過濾濃縮反應混合物，粗產品用矽膠板色譜分離提純(甲醇/二氯甲烷 (v/v)=5%+0.5%氨水)得到白色固體化合物(2s,3aR,5r,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺9K(37mg，產率65.4%)。 The compound N-((2r,3aR,5s,6aS)-5-azidooctahydrocyclopentadien-2-yl)-N-methyl-7-toluenesulfonyl-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine 9J (60 mg, 0.13 mmol) was dissolved in ethyl acetate (3 mL) and 10% wet palladium on carbon (10 mg) was added with stirring. The mixture was stirred at room temperature under hydrogen for 16 hours. After the reaction, the reaction mixture was filtered and concentrated, and the crude product was separated and purified by silica gel plate chromatography (methanol/dichloromethane (v/v)=5%+0.5% ammonia water) to obtain a white solid compound (2s, 3aR, 5r, 6aS)-N 2 -Methyl-N2-(7-Tosylsulfonyl - 7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopentadiene-2,5-diamine 9K (37 mg , the yield is 65.4%).

第十一步：N-((2s,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(9L) Step 11: N-((2s,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) Octahydrocyclopentadien-2-yl)propane-1-sulfonamide (9L)

Figure 110145234-A0101-12-0095-476
Figure 110145234-A0101-12-0095-476

將(2s,3aR,5r,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺9K(150mg，0.35mmol)溶於二氯甲烷(3mL)，然後於攪拌下加入三乙胺(71mg，0.7mmol)和丙基磺醯氯(75mg，0.52mmol)。將混合物在室溫攪拌下反應4小時。反應結束後濃縮反應混合物，粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-5%)得到N-((2s,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺9L(200mg，收率88.9%)。 (2s,3aR,5r,6aS)-N2 - methyl - N2-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopenta Diene-2,5-diamine 9K (150 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), then triethylamine (71 mg, 0.7 mmol) and propylsulfonyl chloride (75 mg, 0.52 mmol) were added with stirring ). The mixture was reacted with stirring at room temperature for 4 hours. After the reaction, the reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-5%) to obtain N-((2s, 3aR, 5r, 6aS)-5-(methyl) (7-Tosylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)propane-1-sulfonamide 9L (200mg , the yield is 88.9%).

MS m/z(ESI)：532.0[M+1]. MS m/z(ESI): 532.0[M+1].

第十二步：N-((2s,3aR,5r,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(化合物9) Step 12: N-((2s,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadiene -2-yl)propane-1-sulfonamide (compound 9)

Figure 110145234-A0101-12-0096-477
Figure 110145234-A0101-12-0096-477

將N-((2s,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺9L(200mg，0.37mmol)溶於四氫呋喃(2mL)，攪拌下加入氫氧化鈉溶液(1M,2mL)，將混合物在60℃下攪拌2小時。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物N-((2s,3aR,5r,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(化合物9)(48.5mg，收率33.8%)。 N-((2s,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclo Pentadien-2-yl)propane-1-sulfonamide 9L (200 mg, 0.37 mmol) was dissolved in tetrahydrofuran (2 mL), sodium hydroxide solution (1 M, 2 mL) was added with stirring, and the mixture was stirred at 60 °C for 2 Hour. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound N-((2s,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4) -yl)amino)octahydrocyclopentadien-2-yl)propane-1-sulfonamide (compound 9) (48.5 mg, 33.8% yield).

MS m/z(ESI)：378.3[M+1]. MS m/z(ESI): 378.3[M+1].

1H NMR(400MHz,CD3OD)δ 8.13(s,1 H),7.12(d,1 H),6.67(d,1 H),5.32-5.15(m,1 H),3.99-3.83(m,1 H),3.23(s,3 H),3.11-2.95(m,2 H),2.80(s,2 H),2.15-1.90(m,4 H),1.88-1.60(m,6 H),1.07(t,3 H). 1 H NMR (400MHz, CD 3 OD) δ 8.13(s,1H), 7.12(d,1H), 6.67(d,1H), 5.32-5.15(m,1H), 3.99-3.83(m , 1 H), 3.23(s, 3 H), 3.11-2.95(m, 2 H), 2.80(s, 2 H), 2.15-1.90(m, 4 H), 1.88-1.60(m, 6 H) ,1.07(t,3H).

實施例10Example 10

6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.5]壬烷-1-甲醯胺(化合物10) 6-(5-Cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)- 1,6-Diazaspiro[3.5]nonane-1-carboxamide (Compound 10)

Figure 110145234-A0101-12-0097-478
Figure 110145234-A0101-12-0097-478

第一步：4-氯-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(10A) The first step: 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (10A)

Figure 110145234-A0101-12-0097-479
Figure 110145234-A0101-12-0097-479

在一個1000mL的三口圓底燒瓶中加入氫化鈉(60%)(337mg,8.45mmol)，溶於THF(10mL)中，氮氣保護下降溫至0℃。將4-氯-1H-吡咯並[2,3-b]吡啶-5-甲腈1A(1g,5.63mmol)溶於THF中，緩慢加入其中，於0℃反應30分鐘。然後緩慢加入(2-(氯甲氧基)乙基)三甲基矽烷(1.13g，6.76mmol)，於室溫反應2小時。加入飽和NH4Cl(100mL)溶液，用乙酸乙酯(100mL×3)萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：20-1：10)得到黃色油狀的化合物4-氯-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-5-甲腈10A(1.2g，收率69.22%)。 Sodium hydride (60%) (337 mg, 8.45 mmol) was added to a 1000 mL three-necked round-bottomed flask, dissolved in THF (10 mL), and heated to 0°C under nitrogen protection. 4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 1A (1 g, 5.63 mmol) was dissolved in THF, slowly added thereto, and reacted at 0° C. for 30 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (1.13 g, 6.76 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. Saturated NH 4 Cl (100 mL) solution was added, extracted with ethyl acetate (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:20-1:10) to give compound 4-chloro-1-((2-(trimethylsilyl)ethoxy) as yellow oil Methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 10A (1.2 g, 69.22% yield).

MS m/z(ESI)：308.0[M+1]. MS m/z(ESI): 308.0[M+1].

第二步：6-(5-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁基酯(10B) Step 2: 6-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )-1,6-diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester (10B)

Figure 110145234-A0101-12-0098-480
Figure 110145234-A0101-12-0098-480

將4-氯-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-5-甲腈10A(700mg，2.27mmol)和1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁酯(463mg,2.05mmol)溶於DMF(10ml)，然後加入DIEA(0.82mL，4.55mmol)，氮氣保護下於100℃反應16h。反應完畢後，濃縮反應液，殘餘物中加入乙酸乙酯(30mL)，用水(20mL×3)洗滌，有機相用無水硫酸鈉乾燥。過濾，濃縮，殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：5-1：3)得到黃色油狀的化合物6-(5-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁基酯10B(830mg，收率73.34%)。 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 10A (700 mg, 2.27 mmol ) and tert-butyl 1,6-diazaspiro[3.5]nonane-1-carboxylate (463 mg, 2.05 mmol) were dissolved in DMF (10 ml), then DIEA (0.82 mL, 4.55 mmol) was added, under nitrogen protection React at 100°C for 16h. After the reaction was completed, the reaction solution was concentrated, ethyl acetate (30 mL) was added to the residue, washed with water (20 mL×3), and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration, the residue was purified by silica gel column (petroleum ether:ethyl acetate=1:5-1:3) to obtain compound 6-(5-cyano-1-((2-(trimethyl) as yellow oil Silyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate tert-butyl base ester 10B (830 mg, 73.34% yield).

MS m/z(ESI)：498.0[M+1]. MS m/z(ESI): 498.0[M+1].

第三步：4-(1,6-二氮雜螺[3.5]壬烷-6-基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-5-甲腈(10C) The third step: 4-(1,6-diazaspiro[3.5]nonan-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrrolo[2,3-b]pyridine-5-carbonitrile (10C)

Figure 110145234-A0101-12-0098-481
Figure 110145234-A0101-12-0098-481

將6-(5-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)-1,6-二氮雜螺[3.5]壬烷-1-羧酸叔丁基酯10B(830mg,1.67mmol)溶於HCl/EA(3mL)，反應16h。反應結束後真空旋乾反應混合物，得到4-(1,6-二氮雜螺[3.5]壬烷-6-基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-5-甲腈10C(600mg，粗品)。 6-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1 , 6-Diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester 10B (830 mg, 1.67 mmol) was dissolved in HCl/EA (3 mL) and reacted for 16 h. After the completion of the reaction, the reaction mixture was spin-dried in vacuo to obtain 4-(1,6-diazaspiro[3.5]nonan-6-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 10C (600 mg, crude).

MS m/z(ESI)：398.0[M+1]. MS m/z(ESI): 398.0[M+1].

第四步：6-(5-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.5]壬烷-1-甲醯胺(10D) Step 4: 6-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )-N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (10D)

Figure 110145234-A0101-12-0099-482
Figure 110145234-A0101-12-0099-482

將4-(1,6-二氮雜螺[3.5]壬烷-6-基)-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-5-甲腈10C(300mg，0.75mmol)溶於DMF(10mL)，然後加入(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(284mg，1.13mmol)和三乙胺(0.21mL，1.51mmol)。將混合物在60℃攪拌下反應2小時。濃縮反應混合物，粗產品用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=30-50%)得到無色油狀的化合物6-(5-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5- 基)-1,6-二氮雜螺[3.5]壬烷-1-甲醯胺10D(180mg，收率43%)。 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[ 2,3-b]pyridine-5-carbonitrile 10C (300 mg, 0.75 mmol) was dissolved in DMF (10 mL), then (3-methoxy-1,2,4-thiadiazol-5-yl)amino was added Phenyl formate (284 mg, 1.13 mmol) and triethylamine (0.21 mL, 1.51 mmol). The mixture was reacted with stirring at 60°C for 2 hours. The reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=30-50%) to obtain compound 6-(5-cyano-1-((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(3-methoxy-1,2,4-thione oxadiazole-5- yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide 10D (180 mg, 43% yield).

MS m/z(ESI)：555.0[M+1]. MS m/z(ESI): 555.0[M+1].

第五步：6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.5]壬烷-1-甲醯胺(化合物10) Step 5: 6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(3-methoxy-1,2,4-thiadiazole-5 -yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (Compound 10)

Figure 110145234-A0101-12-0100-483
Figure 110145234-A0101-12-0100-483

將6-(5-氰基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.5]壬烷-1-甲醯胺10D(180mg，0.33mmol)溶於二氯甲烷(2mL)，然後在攪拌下加入三氟乙酸(1mL)。將混合物在室溫下攪拌2小時，然後旋乾。將旋乾後的混合物溶於四氫呋喃(3mL)並加入氨水(1mL)，在室溫下攪拌30分鐘。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.5]壬烷-1-甲醯胺(化合物10)(8.6mg，6.24%)。 6-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N -(3-Methoxy-1,2,4-thiadiazol-5-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide 10D (180 mg, 0.33 mmol) in solution Dissolve in dichloromethane (2 mL), then add trifluoroacetic acid (1 mL) with stirring. The mixture was stirred at room temperature for 2 hours and then spun dry. The spin-dried mixture was dissolved in tetrahydrofuran (3 mL), ammonia water (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(3-methoxy yl-1,2,4-thiadiazol-5-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (Compound 10) (8.6 mg, 6.24%).

MS m/z(ESI)：425.2[M+1]. MS m/z(ESI): 425.2[M+1].

1H NMR(400MHz,DMSO-d6)δ 12.06(s,1H),11.63(s,1H),8.26(s,1H),7.46-7.37(m,1H),6.63-6.57(m,1H),4.12(d,J =11.6Hz,1H),4.03(t,J=7.2Hz,2H),3.88(d,J=11.6Hz,5H),3.18(t,J=11.2Hz,1H),2.38-2.29(m,1H),2.13-2.03(m,3H),1.83(s,2H). 1 H NMR (400MHz, DMSO-d6)δ 12.06(s,1H), 11.63(s,1H), 8.26(s,1H), 7.46-7.37(m,1H), 6.63-6.57(m,1H), 4.12(d, J =11.6Hz, 1H), 4.03(t, J =7.2Hz, 2H), 3.88(d, J =11.6Hz, 5H), 3.18(t, J =11.2Hz, 1H), 2.38- 2.29(m,1H),2.13-2.03(m,3H),1.83(s,2H).

實施例11Example 11

(3aR,5s,6aS)-5-((5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物11) (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3-(methylthio) )-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 11)

Figure 110145234-A0101-12-0101-484
Figure 110145234-A0101-12-0101-484

第一步：4-氯-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈(11A) The first step: 4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (11A)

Figure 110145234-A0101-12-0101-485
Figure 110145234-A0101-12-0101-485

在一個250mL的三口圓底燒瓶中加入氫化鈉(60%)(495mg,12.4mmol)，溶於THF(10mL)中，於氮氣保護下降溫至0℃，將4-氯-1H-吡咯並[2,3-b]吡啶-5-甲腈1A(1.1g,6.2mmol)溶於THF 中，然後緩慢加入，於0℃反應30分鐘。緩慢加入4-甲基苯磺醯氯(1.54g，8.01mmol)，室溫反應2小時。加入飽和NH4Cl(20mL)溶液，用乙酸乙酯(20mL×3)萃取。有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：20-1：10)得到白色固體的化合物4-氯-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈11A(1.8g，收率87%)。 In a 250 mL three-necked round-bottomed flask was added sodium hydride (60%) (495 mg, 12.4 mmol), dissolved in THF (10 mL), warmed to 0 °C under nitrogen protection, and 4-chloro-1H-pyrrolo[ 2,3-b]pyridine-5-carbonitrile 1A (1.1 g, 6.2 mmol) was dissolved in THF, then slowly added and reacted at 0°C for 30 minutes. 4-Methylbenzenesulfonyl chloride (1.54 g, 8.01 mmol) was slowly added, and the mixture was reacted at room temperature for 2 hours. Saturated NH 4 Cl (20 mL) solution was added and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:20-1:10) to give the compound 4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine as a white solid -5-Carbononitrile 11A (1.8 g, 87% yield).

MS m/z(ESI)：332.0[M+1]. MS m/z(ESI): 332.0[M+1].

第二步：(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯(11B) Step 2: (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino ) Hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (11B)

Figure 110145234-A0101-12-0102-486
Figure 110145234-A0101-12-0102-486

將4-氯-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈11A(450mg，1.36mmol)和(3aR,5s,6aS)-5-(甲基氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯(359mg，1.49mmol)溶於DMF(5mL)，然後加入DIEA(0.36mL，2.03mmol)，氮氣保護下於100℃反應16h。反應完畢後，濃縮反應液，加水(20mL)，用乙酸乙酯(20mL×3)萃取。有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：4-1：3)得到白色固體的化合物(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶 -4-基)(甲基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯11B(420mg，收率57.8%)。 4-Chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 11A (450 mg, 1.36 mmol) and (3aR,5s,6aS)-5-(methyl Amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (359 mg, 1.49 mmol) was dissolved in DMF (5 mL), then DIEA (0.36 mL, 2.03 mmol) was added, under nitrogen The reaction was carried out at 100°C for 16h. After the completion of the reaction, the reaction solution was concentrated, added with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:4-1:3) to obtain compound (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl) as a white solid -1H-pyrrolo[2,3-b]pyridine -4-yl)(methyl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 11B (420 mg, 57.8% yield).

MS m/z(ESI)：536.0[M+1]. MS m/z(ESI): 536.0[M+1].

第三步：4-(甲基((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)氨基)-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈(11C) The third step: 4-(methyl((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)amino)-1-toluenesulfonyl-1H-pyrrolo[2 ,3-b]pyridine-5-carbonitrile (11C)

Figure 110145234-A0101-12-0103-487
Figure 110145234-A0101-12-0103-487

將(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯11B(420mg,0.78mmol)溶於DCM(3mL)，加入叔丁基二甲基甲矽烷基三氟甲磺酸酯(0.25mg,0.94mmol)，室溫攪拌3h。真空旋乾反應混合物，殘留物通過矽膠柱純化(二氯甲烷：甲醇=1：15-1：10)得到白色固體的化合物4-(甲基((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)氨基)-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈11C(280mg，收率82%)。 (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)hexahydro Cyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 11B (420 mg, 0.78 mmol) was dissolved in DCM (3 mL) and tert-butyldimethylsilyl trifluoromethanesulfonic acid was added The ester (0.25 mg, 0.94 mmol) was stirred at room temperature for 3 h. The reaction mixture was spin-dried in vacuo, and the residue was purified by silica gel column (dichloromethane:methanol=1:15-1:10) to obtain compound 4-(methyl((3aR,5s,6aS)-octahydrocyclopentane) as a white solid Dieno[c]pyrrol-5-yl)amino)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile 11C (280 mg, 82% yield).

MS m/z(ESI)：436.0[M+1]. MS m/z(ESI): 436.0[M+1].

第四步：(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(11D) The fourth step: (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino )-N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (11D)

Figure 110145234-A0101-12-0104-488
Figure 110145234-A0101-12-0104-488

將4-(甲基((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)氨基)-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈11C(140mg，0.32mmol)和(3-(甲硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(95mg，0.35mmol)溶於DMF(3mL)，然後加入三乙胺(0.1mL，0.64mmol)，氮氣保護下於60℃反應3h。濃縮反應混合物，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：50-1：20)得到白色固體的化合物(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺11D(118mg，收率60%)。 4-(methyl((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)amino)-1-toluenesulfonyl-1H-pyrrolo[2,3- b] Pyridine-5-carbonitrile 11C (140 mg, 0.32 mmol) and phenyl (3-(methylthio)-1,2,4-thiadiazol-5-yl)carbamate (95 mg, 0.35 mmol) Dissolve in DMF (3 mL), then add triethylamine (0.1 mL, 0.64 mmol), and react at 60 °C for 3 h under nitrogen protection. The reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:50-1:20) to obtain a white solid compound (3aR,5s,6aS)-5-((5 -Cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3-(methylthio)-1,2, 4-Thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 11D (118 mg, 60% yield).

MS m/z(ESI)：609.0[M+1]. MS m/z(ESI): 609.0[M+1].

第五步：(3aR,5s,6aS)-5-((5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物11) Step 5: (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3- (Methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 11)

Figure 110145234-A0101-12-0104-489
Figure 110145234-A0101-12-0104-489

將(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六 氫環戊二烯並[c]吡咯-2(1H)-羧醯胺11D(118mg，0.19mmol)溶於四氫呋喃(3mL)，攪拌下加入氫氧化鈉(1M)溶液(1mL)，然後加入甲醇(0.1mL)，在60℃下攪拌1小時。反應結束後濃縮反應混合物，殘餘物通過製備型HPLC純化，凍乾得到白色固體化合物：(3aR,5s,6aS)-5-((5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物11)(3.5mg，3.9%)。 (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N -(3-(Methylthio)-1,2,4-thiadiazol-5-yl)hexa Hydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 11D (118 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL), sodium hydroxide (1 M) solution (1 mL) was added with stirring, followed by methanol (0.1 mL) and stirred at 60°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated, the residue was purified by preparative HPLC, and lyophilized to obtain a white solid compound: (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b] Pyridin-4-yl)(methyl)amino)-N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole- 2(1H)-Carboxamide (Compound 11) (3.5 mg, 3.9%).

MS m/z(ESI)：455.1[M+1]. MS m/z(ESI): 455.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.93(s,1 H),11.64(s,1 H),8.15(s,1 H),7.28-7.27(m,1 H),6.66-6.64(m,1H),4.78-4.70(q,1 H),3.68-3.66(d,2 H),3.20(s,2 H),2.88(m,2 H),2.56(s,2 H),2.19-2.08(m,2H),1.91-1.85(m,2 H). 1H NMR (400MHz, DMSO-d6)δ 11.93(s,1H), 11.64(s,1H), 8.15(s,1H), 7.28-7.27(m,1H), 6.66-6.64(m, 1H), 4.78-4.70(q, 1 H), 3.68-3.66(d, 2 H), 3.20(s, 2 H), 2.88(m, 2 H), 2.56(s, 2 H), 2.19-2.08 (m,2H),1.91-1.85(m,2H).

實施例12Example 12

(3aR,5s,6aS)-5-((5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物12) (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3-(ethylthio) )-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 12)

Figure 110145234-A0101-12-0105-490
Figure 110145234-A0101-12-0105-490

第一步：(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基) 六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(12A) The first step: (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino )-N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl) Hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (12A)

Figure 110145234-A0101-12-0106-234
Figure 110145234-A0101-12-0106-234

將4-(甲基((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)氨基)-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈11C(140mg，0.32mmol)和(3-(乙硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(99mg，0.35mmol)溶於DMF(3mL)，然後加入三乙胺(0.1mL，0.64mmol)，氮氣保護下於60℃反應3h。濃縮，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：50-1：20)得到白色固體的化合物(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺12A(120mg，收率60%)。 4-(methyl((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)amino)-1-toluenesulfonyl-1H-pyrrolo[2,3- b] Pyridine-5-carbonitrile 11C (140 mg, 0.32 mmol) and phenyl (3-(ethylthio)-1,2,4-thiadiazol-5-yl)carbamate (99 mg, 0.35 mmol) Dissolve in DMF (3 mL), then add triethylamine (0.1 mL, 0.64 mmol), and react at 60 °C for 3 h under nitrogen protection. Concentrated, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:50-1:20) to obtain the compound (3aR,5s,6aS)-5-((5-cyano) as a white solid yl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3-(ethylthio)-1,2,4- Thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 12A (120 mg, 60% yield).

MS m/z(ESI)：623.0[M+1]. MS m/z(ESI): 623.0[M+1].

第二步：(3aR,5s,6aS)-5-((5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物12) Step 2: (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3- (Ethylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 12)

Figure 110145234-A0101-12-0106-491
Figure 110145234-A0101-12-0106-491

將(3aR,5s,6aS)-5-((5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺12A(120mg，0.19mmol)溶於四氫呋喃(3mL)，於攪拌下加入氫氧化鈉溶液(1M,1mL)，然後加入甲醇(0.1mL)，在60℃攪拌1小時。反應結束後濃縮反應混合物，殘餘物通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-5-((5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)(甲基)氨基)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物12)(8.5mg，9.4%)。 (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N -(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 12A (120 mg, 0.19 mmol ) was dissolved in tetrahydrofuran (3 mL), sodium hydroxide solution (1 M, 1 mL) was added with stirring, then methanol (0.1 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the completion of the reaction, the reaction mixture was concentrated, the residue was purified by preparative HPLC, and lyophilized to obtain a white solid compound (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridine) -4-yl)(methyl)amino)-N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2 (1H)-Carboxamide (Compound 12) (8.5 mg, 9.4%).

MS m/z(ESI)：469.1[M+1]. MS m/z(ESI): 469.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.93(s,1 H),8.15(s,1 H),7.27(s,1 H),6.65(d,1 H),4.80-4.69(m,1 H),3.67(s,2 H),3.35(s,2 H),3.20(s,3 H),3.14-3.08(m,2 H),2.87(s,2 H),2.21-2.11(m,2 H),1.91-1.83(m,2 H),1.32(t,3 H). 1 H NMR (400MHz, DMSO-d6)δ 11.93(s, 1 H), 8.15(s, 1 H), 7.27(s, 1 H), 6.65(d, 1 H), 4.80-4.69(m, 1 H), 3.67(s, 2 H), 3.35(s, 2 H), 3.20(s, 3 H), 3.14-3.08(m, 2 H), 2.87(s, 2 H), 2.21-2.11(m ,2H),1.91-1.83(m,2H),1.32(t,3H).

實施例13Example 13

(3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物13) (3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(3-methoxy-1, 2,4-Thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxyamide (Compound 13)

Figure 110145234-A0101-12-0108-284
Figure 110145234-A0101-12-0108-284

第一步：(3aR,5r,6aS)-5-羥基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯(13B) The first step: (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (13B)

Figure 110145234-A0101-12-0108-236
Figure 110145234-A0101-12-0108-236

將5-氧代六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13A(2g，8.88mmol)溶於THF(15mL)，降溫至0℃，慢慢加入三叔丁氧基氫化鋰鋁(8.8mL，17.76mmol)，室溫反應3h。向反應混合物中加入水(30mL)，用乙酸乙酯(30mL×3)萃取。有機相用無水硫酸鈉乾燥，過濾，濃縮，得到粗品無色油狀化合物(3aR,5r,6aS)-5-羥基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13B(2.4g，粗品)。 Dissolve 5-oxohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13A (2 g, 8.88 mmol) in THF (15 mL), cool down to 0 °C, and slowly add three Lithium aluminum tert-butoxide (8.8 mL, 17.76 mmol) was reacted at room temperature for 3 h. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give crude colorless oily compound (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid tert-butyl Ester 13B (2.4 g, crude).

第二步：(3aR,5r,6aS)-5-((甲磺醯基)氧基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯(13C) The second step: (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (13C)

Figure 110145234-A0101-12-0109-237
Figure 110145234-A0101-12-0109-237

將(3aR,5r,6aS)-5-羥基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13B(2.4g，10.56mmol)溶於DCM(25mL)，降溫至0℃，加入三乙胺(2.23mL，15.84mmol)，然後慢慢加入甲烷磺醯氯(1.45g，12.67mmol)，室溫反應2h。濃縮反應混合物，得到粗品無色油狀化合物(3aR,5r,6aS)-5-((甲磺醯基)氧基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13C(3g，粗品)。 (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13B (2.4 g, 10.56 mmol) was dissolved in DCM (25 mL), cooled down At 0°C, triethylamine (2.23 mL, 15.84 mmol) was added, then methanesulfonyl chloride (1.45 g, 12.67 mmol) was added slowly, and the reaction was carried out at room temperature for 2 h. The reaction mixture was concentrated to give crude colorless oily compound (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid tert. Butyl ester 13C (3 g, crude).

第三步：(3aR,5s,6aS)-5-疊氮基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯(13D) The third step: (3aR,5s,6aS)-5-azidohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (13D)

Figure 110145234-A0101-12-0109-238
Figure 110145234-A0101-12-0109-238

將(3aR,5r,6aS)-5-((甲磺醯基)氧基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13C(7.2g，粗品)和四丁基疊氮化銨(4.02g，14.15mmol)溶於乙腈(30mL)，氮氣保護下於90℃反應4h。反應完畢後，濃縮反應液，殘留物通過矽膠柱純化(石油醚：乙酸乙酯=1：15-1：10)得到黃色油狀化合物(3aR,5s,6aS)-5-疊氮基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯13D(3.5g)。 (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13C (7.2 g, crude) and tetrabutylammonium azide (4.02 g, 14.15 mmol) was dissolved in acetonitrile (30 mL), and reacted at 90° C. for 4 h under nitrogen protection. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column (petroleum ether:ethyl acetate=1:15-1:10) to obtain a yellow oily compound (3aR,5s,6aS)-5-azidohexahydro Cyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13D (3.5 g).

第四步：(3aR,5s,6aS)-5-氨基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯(13E) The fourth step: (3aR,5s,6aS)-5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (13E)

Figure 110145234-A0101-12-0110-239
Figure 110145234-A0101-12-0110-239

將(3aR,5s,6aS)-5-疊氮基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯13D(3.5g，13.87mmol)溶於甲醇(30mL)，加入Pd/C(350mg，10%)，氫氣保護下反應16h。反應完畢後用矽藻土過濾掉Pd/C，濃縮濾液。殘留物通過矽膠柱純化(二氯甲烷：甲醇=1：10~1：8)得到黃色油狀化合物(3aR,5s,6aS)-5-氨基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13E(2.9g，92.38%)。 (3aR,5s,6aS)-5-azidohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13D (3.5 g, 13.87 mmol) was dissolved in methanol (30 mL) ), added Pd/C (350 mg, 10%), and reacted under the protection of hydrogen for 16 h. After completion of the reaction, Pd/C was filtered off with celite, and the filtrate was concentrated. The residue was purified by silica gel column (dichloromethane:methanol=1:10~1:8) to obtain yellow oily compound (3aR,5s,6aS)-5-aminohexahydrocyclopentadieno[c]pyrrole-2 (1H)-tert-Butylcarboxylate 13E (2.9 g, 92.38%).

第五步：(3aR,5s,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯(13G) The fifth step: (3aR,5s,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexa Hydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (13G)

Figure 110145234-A0101-12-0110-240
Figure 110145234-A0101-12-0110-240

將(3aR,5s,6aS)-5-氨基六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁酯13E(1.1g，4.86mmol)和4-氯-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶13F(1.81g，5.35mmol)溶於異丙醇(30mL)，然後加入DIEA(1.31mL，7.29mmol)，氮氣保護下100℃反應16h。反應完畢後，濃縮反應液，加水(50mL)，用乙酸乙酯(50mL× 3)萃取。有機相用無水硫酸鈉乾燥，過濾，濃縮。殘留物通過矽膠柱純化(石油醚/乙酸乙酯=1：4~1：3)得到黃色固體的化合物(3aR,5s,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯13G(990mg，收率38.6%)。 (3aR,5s,6aS)-5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13E (1.1 g, 4.86 mmol) and 4-chloro-5-nitro yl-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine 13F (1.81 g, 5.35 mmol) was dissolved in isopropanol (30 mL), then DIEA (1.31 mL, 7.29 mmol) was added , and reacted at 100°C for 16h under nitrogen protection. After the completion of the reaction, the reaction solution was concentrated, water (50 mL) was added, and ethyl acetate (50 mL× 3) Extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1:4~1:3) to obtain compound (3aR,5s,6aS)-5-((5-nitro-1-(benzenesulfonyl) as a yellow solid yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13G (990 mg, received rate 38.6%).

MS m/z(ESI)：528.0[M+1]. MS m/z(ESI): 528.0[M+1].

第六步：5-硝基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺(13H) Step 6: 5-Nitro-N-((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)-1-(phenylsulfonyl)-1H-pyrrole Do[2,3-b]pyridin-4-amine (13H)

Figure 110145234-A0101-12-0111-241
Figure 110145234-A0101-12-0111-241

將(3aR,5s,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯13G(300mg,0.57mmol)溶於DCM(3mL)，然後加入叔丁基二甲基甲矽烷基三氟甲磺酸酯(180mg,0.68mmol)，室溫攪拌3h。然後真空旋乾，殘留物通過矽膠柱純化(二氯甲烷：甲醇=1：15-1：10)得到白色固體的化合物5-硝基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺13H(240mg，收率98%)。 (3aR,5s,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclopentane Dieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester 13G (300 mg, 0.57 mmol) was dissolved in DCM (3 mL) followed by the addition of tert-butyldimethylsilyl triflate (180 mg, 0.68 mmol), stirred at room temperature for 3 h. Then spin to dry in vacuo, and the residue was purified by silica gel column (dichloromethane:methanol=1:15-1:10) to obtain compound 5-nitro-N-((3aR,5s,6aS)-octahydrocycle as a white solid Pentadieno[c]pyrrol-5-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 13H (240 mg, 98% yield).

MS m/z(ESI)：427.0[M+1]. MS m/z(ESI): 427.0[M+1].

第七步：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5- 基)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(13I) The seventh step: (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazole-5- yl)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclopentadieno[c] Pyrrole-2(1H)-carboxyamide (13I)

Figure 110145234-A0101-12-0112-242
Figure 110145234-A0101-12-0112-242

將5-硝基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺13H(240mg，0.562mmol)和(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(155mg，0.62mmol)溶於DMF(3mL)，然後加入三乙胺(0.12mL，0.84mmol)，氮氣保護下於60℃反應3h。濃縮反應混合物，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：50-1：25)得到黃色固體的化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13I(275mg，收率83.8%)。 5-nitro-N-((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2 ,3-b]pyridin-4-amine 13H (240 mg, 0.562 mmol) and phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate (155 mg, 0.62 mmol) Dissolve in DMF (3 mL), then add triethylamine (0.12 mL, 0.84 mmol), and react at 60° C. for 3 h under nitrogen protection. The reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:50-1:25) to obtain a yellow solid compound (3aR,5s,6aS)-N-(3- Methoxy-1,2,4-thiadiazol-5-yl)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine- 4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13I (275 mg, 83.8% yield).

MS m/z(ESI)：585.0[M+1]. MS m/z(ESI): 585.0[M+1].

第八步：(3aR,5s,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(13J) Step 8: (3aR,5s,6aS)-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)- N-(3-Methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (13J)

Figure 110145234-A0101-12-0113-243
Figure 110145234-A0101-12-0113-243

將(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13I(275mg，0.47mmol)，鐵粉(131mg，2.35mmol)溶於乙醇(5mL)，然後加入飽和氯化銨水溶液(2mL)，在60℃下攪拌3小時。用矽藻土過濾反應液，濃縮，殘餘物用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：12-1：10)得到淡黃色固體的化合物(3aR,5s,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13J(160mg，收率61.3%)。 (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-((5-nitro-1-(benzenesulfonyl) -1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13I (275mg, 0.47mmol), iron powder (131 mg, 2.35 mmol) was dissolved in ethanol (5 mL), then a saturated aqueous ammonium chloride solution (2 mL) was added, and the mixture was stirred at 60° C. for 3 hours. The reaction solution was filtered with celite, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:12-1:10) to obtain compound (3aR, 5s, 6aS) as a pale yellow solid )-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-N-(3-methoxy-1 ,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13J (160 mg, 61.3% yield).

MS m/z(ESI)：555.0[M+1]. MS m/z(ESI): 555.0[M+1].

第九步：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(13K) The ninth step: (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(6-(benzenesulfonyl)imidazo[ 4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (13K)

Figure 110145234-A0101-12-0113-244
Figure 110145234-A0101-12-0113-244

將(3aR,5s,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13J(120mg，0.22mmol)，原甲酸三乙酯(Triethoxymethane)(160mg，1.08mmol)和對甲苯磺酸(7.45mg，0.043mmol)溶於甲苯(3mL)，在105℃下攪拌4小時。反應結束後濃縮反應混合物，殘餘物用矽膠柱色譜分離提純(二氯甲烷：甲醇(v/v)=1：20-1：15)得到淡黃色固體的化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13K(65mg，收率53.2%)。 (3aR,5s,6aS)-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-N-( 3-Methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13J (120 mg, 0.22 mmol), orthoformic acid Triethoxymethane (160 mg, 1.08 mmol) and p-toluenesulfonic acid (7.45 mg, 0.043 mmol) were dissolved in toluene (3 mL) and stirred at 105° C. for 4 hours. After the reaction, the reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v)=1:20-1:15) to obtain compound (3aR,5s,6aS)-N as a pale yellow solid -(3-Methoxy-1,2,4-thiadiazol-5-yl)-5-(6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3- b] Pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13K (65 mg, 53.2% yield).

MS m/z(ESI)：565.0[M+1]. MS m/z(ESI): 565.0[M+1].

第十步：(3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物13) Step 10: (3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(3-methoxy yl-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 13)

Figure 110145234-A0101-12-0114-104
Figure 110145234-A0101-12-0114-104

將(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13K(65mg，0.12mmol)溶於四氫呋喃(2mL)，攪拌下加入氫氧化鈉溶液(1M,1mL)，並加入甲醇 (0.1mL)，在60℃下攪拌1小時。反應結束後濃縮反應混合物，殘餘物通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物13)(9.2mg，18.8%)。 (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(6-(benzenesulfonyl)imidazo[4,5 -d]pyrrolo[2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13K (65 mg, 0.12 mmol) was dissolved in Tetrahydrofuran (2 mL), sodium hydroxide solution (1 M, 1 mL) was added with stirring, and methanol was added (0.1 mL), stirred at 60°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated, the residue was purified by preparative HPLC, and lyophilized to obtain a white solid compound (3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b] Pyridin-1(6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)- Carboxamide (compound 13) (9.2 mg, 18.8%).

MS m/z(ESI)：425.1[M+1]. MS m/z(ESI): 425.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.85(s,1 H),8.57(s,1 H),8.31(s,1 H),7.43(s,1 H),6.71(s,1H),5.28(m,1 H),3.88(s,3H),3.70(s,2H),3.52(s,3H),3.04(s,2H),2.40(s,2H),2.20(s,2H). 1H NMR (400MHz, DMSO-d6)δ 11.85(s,1H), 8.57(s,1H), 8.31(s,1H), 7.43(s,1H), 6.71(s,1H), 5.28 (m, 1 H), 3.88(s, 3H), 3.70(s, 2H), 3.52(s, 3H), 3.04(s, 2H), 2.40(s, 2H), 2.20(s, 2H).

實施例14Example 14

(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-甲基咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物14) (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(2-methylimidazo[4,5-d]pyrrolo [2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 14)

Figure 110145234-A0101-12-0115-285
Figure 110145234-A0101-12-0115-285

第一步：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-甲基-6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(14A) The first step: (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(2-methyl-6-(benzenesulfonyl) ( 14A)

Figure 110145234-A0101-12-0116-245
Figure 110145234-A0101-12-0116-245

將((3aR,5s,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13J(220mg，0.39mmol)，原乙酸三乙酯(triethyl orthoacetate)(322mg，1.98mmol)和對甲苯磺酸(13.7mg，0.079mmol)溶於甲苯(3mL)，在105℃下攪拌4小時。反應結束後濃縮反應混合物，殘餘物用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：20-1：15)得到淡黃色固體的化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-甲基-6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺14A(60mg，收率26.1%)。 ((3aR,5s,6aS)-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-N- (3-Methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13J (220 mg, 0.39 mmol), formerly Triethyl orthoacetate (322 mg, 1.98 mmol) and p-toluenesulfonic acid (13.7 mg, 0.079 mmol) were dissolved in toluene (3 mL) and stirred at 105° C. for 4 hours. After the reaction was completed, the reaction mixture was concentrated and the residue Separation and purification by silica gel column chromatography (dichloromethane/methanol (v/v)=1:20-1:15) gave the compound (3aR,5s,6aS)-N-(3-methoxy-1) as a pale yellow solid ,2,4-thiadiazol-5-yl)-5-(2-methyl-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine- 1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 14A (60 mg, 26.1% yield).

MS m/z(ESI)：579.0[M+1]. MS m/z(ESI): 579.0[M+1].

第二步：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-甲基咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物14) The second step: (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(2-methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 14)

Figure 110145234-A0101-12-0117-105
Figure 110145234-A0101-12-0117-105

將(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-甲基-6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺14A(60mg，0.10mmol)溶於四氫呋喃(2mL)，然後在攪拌下加入氫氧化鈉溶液(1M,1mL)，並加入甲醇(0.1mL)，在60℃下攪拌1小時。反應結束後濃縮反應混合物，通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-甲基咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物14)(4.3mg，9.46%)。 (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(2-methyl-6-(benzenesulfonyl)imidazole Do[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 14A (60 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), then sodium hydroxide solution (1 M, 1 mL) was added with stirring, and methanol (0.1 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, the reaction mixture was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl) -5-(2-Methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H )-carboxyamide (compound 14) (4.3 mg, 9.46%).

MS m/z(ESI)：439.1[M+1]. MS m/z(ESI): 439.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.82(s,1 H),8.46(s,1 H),7.44(s,1 H),6.50(s,1 H),5.32-5.18(m,1 H),3.90(s,3 H),3.83(s,2 H),3.47(d,2 H),3.23(s,3 H),2.63(s,3 H),2.56(d,2 H),2.16-2.06(m,2 H). 1 H NMR (400MHz, DMSO-d6)δ 11.82(s, 1 H), 8.46(s, 1 H), 7.44(s, 1 H), 6.50(s, 1 H), 5.32-5.18(m, 1 H), 3.90(s, 3 H), 3.83(s, 2 H), 3.47(d, 2 H), 3.23(s, 3 H), 2.63(s, 3 H), 2.56(d, 2 H) ,2.16-2.06(m,2H).

實施例15Example 15

(3aR,5s,6aS)-5-(2-((R)-1-羥乙基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二 烯並[c]吡咯-2(1H)-羧醯胺(化合物15) (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentanedi Eno[c]pyrrole-2(1H)-carboxyamide (Compound 15)

Figure 110145234-A0101-12-0118-286
Figure 110145234-A0101-12-0118-286

第一步：(3aR,5s,6aS)-5-(2-((R)-1-羥乙基)-6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(15A) The first step: (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole- 2(1H)-Carboxamide (15A)

Figure 110145234-A0101-12-0118-246
Figure 110145234-A0101-12-0118-246

將3aR,5s,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺13J(150mg，0.27mmol)溶於(R)-乳酸((R)-lactate)(0.5mL)，然後在125℃下攪拌3小時。反應結束後加水(10mL)，用乙酸乙酯(10mL×3)萃取，有機相用無水硫酸鈉乾燥。過濾，濃縮，殘餘物用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：12-1：10)得到白色固體的化合物(3aR,5s,6aS)-5-(2-((R)-1-羥乙基)-6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊 二烯並[c]吡咯-2(1H)-羧醯胺15A(40mg，收率24.3%)。 3aR,5s,6aS)-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-N-(3 -Methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide 13J (150 mg, 0.27 mmol) was dissolved in (R )-lactic acid ((R)-lactate) (0.5 mL), then stirred at 125°C for 3 hours. After the reaction, water (10 mL) was added, extracted with ethyl acetate (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:12-1:10) to obtain compound (3aR,5s,6aS)-5-(2- as a white solid) ((R)-1-Hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N- (3-Methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentane Dieno[c]pyrrole-2(1H)-carboxamide 15A (40 mg, 24.3% yield).

MS m/z(ESI)：609.0[M+1]. MS m/z(ESI): 609.0[M+1].

第二步：(3aR,5s,6aS)-5-(2-((R)-1-羥乙基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物15) Step 2: (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1( 6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide ( Compound 15)

Figure 110145234-A0101-12-0119-106
Figure 110145234-A0101-12-0119-106

攪拌下，將(3aR,5s,6aS)-5-(2-((R)-1-羥乙基)-6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺15A(40mg，0.067mmol)溶於四氫呋喃(1mL)，然後加入氫氧化鈉溶液(1M,1mL)並加入甲醇(0.1mL)，在60℃下攪拌1小時。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-5-(2-((R)-1-羥乙基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺(化合物15)(2.2mg，7.15%)。 Under stirring, (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole- 2(1H)-Carboxamide 15A (40 mg, 0.067 mmol) was dissolved in tetrahydrofuran (1 mL), then sodium hydroxide solution (1 M, 1 mL) was added, methanol (0.1 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)imidazo[4,5-d] Pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[ c] Pyrrole-2(1H)-carboxyamide (compound 15) (2.2 mg, 7.15%).

MS m/z(ESI)：469.1[M+1]. MS m/z(ESI): 469.1[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.88(s,1 H),8.56(s,1 H),7.47(s,1 H),6.50(s,1 H),5.65(d,2 H),5.17(s,1 H),3.87(s,6 H),3.17(s,2 H),2.66(s,2 H),2.62(s,4H),2.07(s,2 H),1.61(d,3 H). 1 H NMR (400MHz, DMSO-d6)δ 11.88(s,1H), 8.56(s,1H), 7.47(s,1H), 6.50(s,1H), 5.65(d,2H) ,5.17(s,1H),3.87(s,6H),3.17(s,2H),2.66(s,2H),2.62(s,4H),2.07(s,2H),1.61( d,3H).

實施例16Example 16

1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物16) 1-(3-Methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea (Compound 16)

Figure 110145234-A0101-12-0120-287
Figure 110145234-A0101-12-0120-287

第一步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(16A) The first step: 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7-toluene) Sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea (16A)

Figure 110145234-A0101-12-0120-248
Figure 110145234-A0101-12-0120-248

攪拌下將(2s,3aR,5r,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺9K(150mg，0.35mmol)溶於N,N-二甲基甲醯胺(3mL)，然後加入三乙胺(71mg，0.7mmol)和(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(88mg，0.35mmol)。將混合物在60℃攪拌下反應數小時。反應結束後濃縮，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)= 0-40%)得到1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲16A(150mg，收率73%)。 (2s,3aR,5r,6aS)-N2 - methyl - N2-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro Cyclopentadiene-2,5-diamine 9K (150 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (3 mL), then triethylamine (71 mg, 0.7 mmol) and (3-methylformamide) were added Phenyloxy-1,2,4-thiadiazol-5-yl)carbamate (88 mg, 0.35 mmol). The mixture was reacted with stirring at 60°C for several hours. After the reaction was completed, it was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-40%) to obtain 1-(3-methoxy-1,2,4-thiadiazole) -5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino ) octahydrocyclopentadien-2-yl)urea 16A (150 mg, 73% yield).

MS m/z(ESI)：583.0[M+1]. MS m/z(ESI): 583.0[M+1].

第二步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物16) The second step: 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7H-pyrrole) [2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea (Compound 16)

Figure 110145234-A0101-12-0121-107
Figure 110145234-A0101-12-0121-107

攪拌下，將1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲16A(150mg，0.25mmol)溶於四氫呋喃(2mL)，然後加入氫氧化鈉溶液(1M,1mL)。然後將混合物在60℃下攪拌2小時。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物16)(34mg，收率30.8%)。 Under stirring, 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7-toluene) Sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 16A (150 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL), Sodium hydroxide solution (1 M, 1 mL) was then added. The mixture was then stirred at 60°C for 2 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s ,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea (Compound 16) (34 mg, received rate 30.8%).

MS m/z(ESI)：429.2[M+1]. MS m/z(ESI): 429.2[M+1].

1H NMR(400MHz,DMSO-d6)δ 11.66(s,1 H),10.87(s,1 H),8.13(s,1 H),7.20-7.12(m,1 H),6.79(s,1 H),6.58(s,1 H), 5.29(s,1 H),4.14(d,1 H),3.88(s,3 H),3.16(s,3 H),2.68(s,2 H),2.06-1.92(m,2 H),1.90-1.77(m,2 H),1.67-1.50(m,4 H). 1 H NMR (400MHz, DMSO-d6) δ 11.66(s, 1 H), 10.87(s, 1 H), 8.13(s, 1 H), 7.20-7.12(m, 1 H), 6.79(s, 1 H), 6.58(s, 1 H), 5.29(s, 1 H), 4.14(d, 1 H), 3.88(s, 3 H), 3.16(s, 3 H), 2.68(s, 2 H) ,2.06-1.92(m,2H),1.90-1.77(m,2H),1.67-1.50(m,4H).

實施例17Example 17

(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-氧代-3,6-二氫咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(2H)-基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物17) (3aR,5s,6aS)-N-(3-methoxy - 1,2,4-thiadiazol-5-yl)-5-(2-oxo-3,6-dihydroimidazo[4 ,5- d ]pyrrolo[2,3-b]pyridin-1( 2H )-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide ( Compound 17 )

Figure 110145234-A0101-12-0122-288
Figure 110145234-A0101-12-0122-288

第一步：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-氧代-6-(苯基磺醯基)-3,6-二氫咪唑[4,5-d]吡咯並[2,3-b]吡啶-1(2H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺17A The first step: (3aR,5s,6aS)-N-(3-methoxy - 1,2,4-thiadiazol-5-yl)-5-(2-oxo-6-(phenylsulfonic acid) Acyl)-3,6-dihydroimidazo[4,5- d ]pyrrolo[2,3- b ]pyridin-1( 2H )-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-Carboxyamide 17A

Figure 110145234-A0101-12-0122-249
Figure 110145234-A0101-12-0122-249

將(3aR,5s,6aS)-5-((5-氨基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺13J(250mg,0.45mmol)和三光氣(triphosgene)(268mg,0.90mmol)溶於DCM(6mL)中，並將反應 溶液在氮氣保護下在冰浴0℃攪拌反應3小時。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-10%)，得到白色固體化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-氧代-6-(苯基磺醯基)-3,6-二氫咪唑[4,5-d]吡咯並[2,3-b]吡啶-1(2H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺17A(160mg，產率：61%) (3aR,5s,6aS)-5-((5-amino-1-(benzenesulfonyl) -1H -pyrrolo[2,3- b ]pyridin-4-yl)amino) -N- ( 3-Methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H ) -carboxamide 13J (250 mg, 0.45 mmol) and triphosgene (triposgene) (268 mg, 0.90 mmol) was dissolved in DCM (6 mL), and the reaction solution was stirred at 0°C in an ice bath under nitrogen protection for 3 hours. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-10%) to obtain a white solid compound (3aR,5s,6aS) -N- (3- Methoxy-1,2,4-thiadiazol-5-yl)-5-(2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d ]pyrrolo[2,3- b ]pyridin-1( 2H )-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide 17A (160 mg, yield: 61%)

MS m/z(ESI)：581.1[M+1] MS m/z(ESI): 581.1[M+1]

第二步：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-氧代-3,6-二氫咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(2H)-基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物17) The second step: (3aR,5s,6aS)-N-(3-methoxy - 1,2,4-thiadiazol-5-yl)-5-(2-oxo-3,6-dihydro Imidazo[4,5- d ]pyrrolo[2,3-b]pyridin-1( 2H )-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide ( Compound 17 )

Figure 110145234-A0101-12-0123-108
Figure 110145234-A0101-12-0123-108

將(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-氧代-6-(苯基磺醯基)-3,6-二氫咪唑[4,5-d]吡咯並[2,3-b]吡啶-1(2H)-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺17A(160mg，0.28mmol)和氫氧化鈉(22mg,0.55mmol)溶於四氫呋喃/水(1v/1v,10mL)中。將混合物在油浴60℃下攪拌反應1h。反應結束後旋乾溶劑，粗產品通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(2-氧代-3,6-二氫 咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(2H)-基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物17)(63mg，收率：51%)。 (3aR,5s,6aS)-N-(3-methoxy - 1,2,4-thiadiazol-5-yl)-5-(2-oxo-6-(phenylsulfonyl) -3,6-Dihydroimidazo[4,5- d ]pyrrolo[2,3- b ]pyridin-1( 2H )-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )- Carboxamide 17A (160 mg, 0.28 mmol) and sodium hydroxide (22 mg, 0.55 mmol) were dissolved in tetrahydrofuran/water (1 v/1 v, 10 mL). The mixture was stirred in an oil bath at 60 °C for 1 h. After the reaction, the solvent was spin-dried, the crude product was purified by preparative HPLC, and lyophilized to obtain a white solid compound (3aR,5s,6aS)-N-(3-methoxy - 1,2,4-thiadiazole-5- yl)-5-(2-oxo-3,6-dihydroimidazo[4,5- d ]pyrrolo[2,3-b]pyridin-1( 2H )-yl)hexahydrocyclopentadiene And[c]pyrrole-2( 1H )-carbamide ( compound 17 ) (63 mg, yield: 51%).

MS m/z(ESI)：441.3[M+1] MS m/z(ESI): 441.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.59(s,1 H),10.92(s,1 H),7.92(s,1 H),7.43-7.37(m,1 H),6.53(dd,1 H),5.18-5.09(m,1 H),3.90(s,3 H),3.72-3.68(m,2 H),3.46-3.43(m,2 H),3.10(s,2 H),2.63-2.54(m,3 H),1.99-1.90(m,2 H). 1 H NMR (400MHz, DMSO-d6) δ 11.59(s, 1 H), 10.92(s, 1 H), 7.92(s, 1 H), 7.43-7.37(m, 1 H), 6.53(dd, 1 H), 5.18-5.09(m, 1 H), 3.90(s, 3 H), 3.72-3.68(m, 2 H), 3.46-3.43(m, 2 H), 3.10(s, 2 H), 2.63 -2.54(m,3H),1.99-1.90(m,2H).

實施例18Example 18

N-((2r,3aR,5r,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(化合物18) N-((2r,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl) Propane-1-sulfonamide ( compound 18 )

Figure 110145234-A0101-12-0124-289
Figure 110145234-A0101-12-0124-289

第一步：(2s,3aR,5s,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺18A The first step: (2s,3aR,5s,6aS)-N 2 -methyl-N 2 -(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro cyclopentadiene-2,5-diamine 18A

Figure 110145234-A0101-12-0124-250
Figure 110145234-A0101-12-0124-250

將(3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮9G(680mg，1.60mmol) 溶於甲醇(5mL)，於室溫攪拌下加入甲酸銨(200mg,3.20mmol)，將混合物在室溫攪拌下2小時。然後加入氰基硼氫化鈉(503mg，8.0mmol)，並將混合物在室溫下攪拌16小時。反應結束後旋乾。加入水(10mL)，乙酸乙酯萃取(15mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-5%)得到無色油狀化合物(2s,3aR,5s,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺18A(500mg，產率73.3%)。 (3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentadiene-2 (1H) -ketone 9G (680 mg, 1.60 mmol) was dissolved in methanol (5 mL), ammonium formate (200 mg, 3.20 mmol) was added with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. Then sodium cyanoborohydride (503 mg, 8.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. Spin dry after the reaction. Water (10 mL) was added, extracted with ethyl acetate (15 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-5%) to obtain a colorless oily compound (2s, 3aR, 5s, 6aS)-N 2 -methyl-N 2 -( 7-Tosylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopentadiene-2,5-diamine 18A (500 mg, 73.3% yield).

MS m/z(ESI)：426.1[M+1] MS m/z(ESI): 426.1[M+1]

第二步：N-((2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺18B Step 2: N-((2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octa Hydrocyclopentadien-2-yl)propane-1-sulfonamide 18B

Figure 110145234-A0101-12-0125-251
Figure 110145234-A0101-12-0125-251

將(2s,3aR,5s,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺18A(500mg，1.17mmol)溶於二氯甲烷(5mL)，於攪拌下加入三乙胺(0.33mL，2.35mmol)和丙基磺醯氯(251mg，1.76mmol)，將混合物在室溫攪拌下反應16小時。反應結束後濃縮，加入水(10mL)，乙酸乙酯萃取(15mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離 提純(乙酸乙酯/石油醚(v/v)=0-50%)得到N-((2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺18B(200mg，收率32%)。 (2s,3aR,5s,6aS)-N2 - methyl - N2-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopenta Diene-2,5-diamine 18A (500 mg, 1.17 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.33 mL, 2.35 mmol) and propylsulfonyl chloride (251 mg, 1.76 mmol) were added with stirring ), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated, water (10 mL) was added, extracted with ethyl acetate (15 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-50%) to obtain N-((2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonic acid) Acyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)propane-1-sulfonamide 18B (200 mg, 32% yield) .

MS m/z(ESI)：532.2[M+1] MS m/z(ESI): 532.2[M+1]

第三步：N-((2r,3aR,5r,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(化合物18) The third step: N-((2r,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadiene- 2-yl)propane-1-sulfonamide ( compound 18 )

Figure 110145234-A0101-12-0126-110
Figure 110145234-A0101-12-0126-110

將N-((2r,3aR,5r,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺18B(200mg，0.37mmol)溶於四氫呋喃(2mL)，於攪拌下加入1M的氫氧化鈉溶液(2mL)，並將混合物在60℃下攪拌2小時。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物N-((2r,3aR,5r,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)丙烷-1-磺醯胺(化合物18)(23mg，收率16%)。 N-((2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclo Pentadien-2-yl)propane-1-sulfonamide 18B (200 mg, 0.37 mmol) was dissolved in tetrahydrofuran (2 mL), 1 M sodium hydroxide solution (2 mL) was added with stirring, and the mixture was heated at 60 °C Stir for 2 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound N-((2r,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4) -yl)amino)octahydrocyclopentadien-2-yl)propane-1-sulfonamide ( Compound 18 ) (23 mg, 16% yield).

MS m/z(ESI)：378.3[M+1] MS m/z(ESI): 378.3[M+1]

1H NMR(400MHz,CD3OD)δ 11.62(s,1 H),8.11(s,1 H),7.25(d,1 H),7.13(d,1 H),6.58(d,1 H),5.35(s,1 H),3.14(s,3 H),3.02-2.90(m,2 H),2.48-2.40(m,2 H),2.23-2.12(m,2 H),1.92- 1.80(m,2 H),1.74-1.62(m,2 H),1.56-1.48(m,2 H),1.26-1.15(m,2 H),0.98(t,3 H). 1 H NMR (400MHz, CD 3 OD) δ 11.62(s,1H), 8.11(s,1H), 7.25(d,1H), 7.13(d,1H), 6.58(d,1H) , 5.35(s, 1 H), 3.14(s, 3 H), 3.02-2.90(m, 2 H), 2.48-2.40(m, 2 H), 2.23-2.12(m, 2 H), 1.92- 1.80 (m, 2 H), 1.74-1.62 (m, 2 H), 1.56-1.48 (m, 2 H), 1.26-1.15 (m, 2 H), 0.98 (t, 3 H).

實施例19Example 19

1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物19) 1-(3-Methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( Compound 19 )

Figure 110145234-A0101-12-0127-290
Figure 110145234-A0101-12-0127-290

第一步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲19A The first step: 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7-toluene) Sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 19A

Figure 110145234-A0101-12-0127-252
Figure 110145234-A0101-12-0127-252

將化合物((2s,3aR,5s,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺18A(280 mg，0.65mmol)，(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(250mg，0.98mmol)，三乙胺(0.18mL,1.32mmol)溶於DMF(5mL)，並將混合物在氮氣保護下在60℃攪拌2小時。反應結束後濃縮反應液，加入水10mL水，乙酸乙酯萃取(10mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-50%)得到白色固體化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲19A(80mg，產率20.8%)。 Compound ((2s,3aR,5s,6aS)-N 2 -methyl-N 2 -(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro Cyclopentadiene-2,5-diamine 18A (280 mg, 0.65 mmol), phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate (250 mg, 0.98 mmol), triethylamine (0.18 mL, 1.32 mmol) was dissolved in DMF (5 mL), and the mixture was stirred at 60° C. for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, 10 mL of water was added, and ethyl acetate was extracted. (10mL x 3), the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-50%) to obtain a white solid compound 1-(3-methoxyl yl-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 19A (80 mg, 20.8% yield).

MS m/z(ESI)：583.1[M+1] MS m/z(ESI): 583.1[M+1]

第二步：(1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物19) The second step: (1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( Compound 19 )

Figure 110145234-A0101-12-0128-111
Figure 110145234-A0101-12-0128-111

將1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲19A(80mg,0.13mmol)溶於四氫呋喃(1mL)，於攪拌下加入1M的氫氧化鈉溶液(1mL)，並將混合物在60℃下攪拌2小時。反應結束後濃縮，通過製備型 HPLC純化，凍乾得到白色固體化合物(1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物19)(8mg，收率13.6%)。 1-(3-Methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl) -7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 19A (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL) and stirred with stirring 1M sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 60°C for 2 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound (1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR, 5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( compound 19 ) (8 mg, yield 13.6%).

MS m/z(ESI)：429.2[M+1] MS m/z(ESI): 429.2[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.66(s,1 H),11.02(s,1 H),8.13(s,1 H),7.15-7.12(m,1 H),7.12-7.05(m,1 H),6.59(d,1 H),5.39(s,1 H),3.88(s,3 H),3.84-3.72(m,1 H),3.16(s,3 H),2.57-2.51(m,2 H),2.26-2.10(m,2 H),1.94-1.80(m,2 H),1.62-1.46(m,2 H),1.20-1.16(m,2 H). 1 H NMR (400MHz, DMSO-d6) δ 11.66(s, 1 H), 11.02(s, 1 H), 8.13(s, 1 H), 7.15-7.12(m, 1 H), 7.12-7.05(m , 1 H), 6.59(d, 1 H), 5.39(s, 1 H), 3.88(s, 3 H), 3.84-3.72(m, 1 H), 3.16(s, 3 H), 2.57-2.51 (m, 2 H), 2.26-2.10 (m, 2 H), 1.94-1.80 (m, 2 H), 1.62-1.46 (m, 2 H), 1.20-1.16 (m, 2 H).

實施例20Example 20

1-((2r,3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲(化合物20) 1-((2r,3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydrocyclopentadiene -2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea (compound 20 )

Figure 110145234-A0101-12-0129-291
Figure 110145234-A0101-12-0129-291

第一步：(3aR,5r,6aS)-5-疊氮基-5',5'-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]20A The first step: (3aR,5r,6aS)-5-azido-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3] Dioxane] 20A

Figure 110145234-A0101-12-0130-253
Figure 110145234-A0101-12-0130-253

將甲磺酸(3aR,5s,6aS)-5',5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基酯9D(16g，粗品)和四丁基疊氮化銨(22.4g，78.84mmol)溶於乙腈(30mL)，於氮氣保護下在90℃反應4h。反應完畢後，濃縮反應液，殘留物通過矽膠柱純化(石油醚/乙酸乙酯=1：15~1：10)得到黃色油狀化合物(3aR,5r,6aS)-5-疊氮基-5',5'-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]20A(7.08g，收率：53.8%)。 Methanesulfonic acid (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5 -Base ester 9D (16 g, crude product) and tetrabutylammonium azide (22.4 g, 78.84 mmol) were dissolved in acetonitrile (30 mL) and reacted at 90 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column (petroleum ether/ethyl acetate=1:15~1:10) to obtain a yellow oily compound (3aR,5r,6aS)-5-azido-5 ',5'-Dimethylhexahydro-1H-spiro[pcyclopentadiene-2,2'-[1,3]dioxane] 20A (7.08 g, yield: 53.8%).

第二步：(3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-胺20B The second step: (3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5 -Amine 20B

Figure 110145234-A0101-12-0130-255
Figure 110145234-A0101-12-0130-255

將(3aR,5r,6aS)-5-疊氮基-5',5'-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]20A(7.08g，28.2mmol)溶於甲醇(50)，加入Pd/C 700mg，10%)，並在氫氣保護下反應16h。反應完畢後， 用矽藻土過濾掉Pd/C，濃縮濾液，得到黃色油狀化合物(3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-胺20B(6.3g，粗產品)。 (3aR,5r,6aS)-5-azido-5',5'-dimethylhexahydro-1H-spiro[p-cyclopentadiene-2,2'-[1,3]dioxane ] 20A (7.08g, 28.2mmol) was dissolved in methanol (50), added Pd/C 700mg, 10%), and reacted under the protection of hydrogen for 16h. After the reaction was completed, Pd/C was filtered off with celite, and the filtrate was concentrated to obtain a yellow oily compound (3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[p-cyclopentadi] En-2,2'-[1,3]dioxane]-5-amine 20B (6.3 g, crude).

第三步：N-((3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基)-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺20C The third step: N-((3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane ]-5-yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 20C

Figure 110145234-A0101-12-0131-256
Figure 110145234-A0101-12-0131-256

將(3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-胺20B(6.3g，28mmol)和4-氯-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶(10.4g，30.85mmol)溶於異丙醇(50mL)，然後加入DIEA(7.51mL，41.9mmol)，於氮氣保護下在100℃反應16h。反應完畢後，濃縮反應液，加水(50mL)，用乙酸乙酯(50mL x 3)萃取，有機相用無水硫酸鈉乾燥，過濾並濃縮。殘留物通過矽膠柱純化(石油醚/乙酸乙酯=1：4~1：3)得到黃色固體的化合物N-((3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基)-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺20C(6.2g，收率42.1%)。 (3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[p-cyclopentadiene-2,2'-[1,3]dioxane]-5-amine 20B (6.3 g, 28 mmol) and 4-chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.4 g, 30.85 mmol) in isopropanol ( 50 mL), then DIEA (7.51 mL, 41.9 mmol) was added, and the reaction was carried out at 100 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction solution was concentrated, water (50 mL) was added, extracted with ethyl acetate (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=1:4~1:3) to obtain compound N-((3aR,5r,6aS)-5',5'-dimethylhexahydro- 1H-spiro[p-cyclopentadiene-2,2'-[1,3]dioxan]-5-yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2 ,3-b]pyridin-4-amine 20C (6.2 g, 42.1% yield).

MS m/z(ESI)：527.1[M+1] MS m/z(ESI): 527.1[M+1]

第四步：(3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮20D The fourth step: (3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexa Hydrocyclopentadien-2(1H)-one 20D

Figure 110145234-A0101-12-0132-257
Figure 110145234-A0101-12-0132-257

將N-((3aR,5r,6aS)-5’,5’-二甲基六氫-1H-螺[並環戊二烯-2,2'-[1,3]二噁烷]-5-基)-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺20C(6.2g,11.7mmol)溶於丙酮(30mL)，加入水(10mL)和TsOH(203mg,1.18mmol)，並於室溫攪拌15h。然後真空旋乾，殘留物通過矽膠柱純化(二氯甲烷/甲醇=1：30~1：20)得到白色固體的化合物得到(3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮20D(4.8g，收率93%)。 N-((3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[p-cyclopentadiene-2,2'-[1,3]dioxane]-5 -yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 20C (6.2 g, 11.7 mmol) was dissolved in acetone (30 mL), added Water (10 mL) and TsOH (203 mg, 1.18 mmol) and stirred at room temperature for 15 h. Then spin to dry in vacuo, and the residue was purified by silica gel column (dichloromethane/methanol=1:30~1:20) to obtain a white solid compound to obtain (3aR,5r,6aS)-5-((5-nitro-1) -(Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclopentadien-2(1H)-one 20D (4.8 g, 93% yield) ).

MS m/z(ESI)：441.1[M+1] MS m/z(ESI): 441.1[M+1]

第五步：(2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-醇20E The fifth step: (2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) octahydrocyclopentadien-2-ol 20E

Figure 110145234-A0101-12-0133-258
Figure 110145234-A0101-12-0133-258

將(3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮20D(2.2g，4.99mmol)溶於乙酸乙酯(3mL)，於0℃在攪拌下加入1M的三叔丁氧基氫化鋁鋰(9.99mL,9.99mmol)，將混合物在0℃攪拌下2小時。反應結束後加入水(20mL)，乙酸乙酯萃取(20mL x 3)，真空旋乾，殘留物通過矽膠柱純化(二氯甲烷/甲醇=1：10~1：15)得到白色固體的化合物得到(2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-醇20E(2.1g，收率95%)。 (3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclo Pentadien-2(1H)-one 20D (2.2 g, 4.99 mmol) was dissolved in ethyl acetate (3 mL), 1 M lithium tri-tert-butoxyaluminum hydride (9.99 mL, 9.99 mmol) was added at 0°C with stirring ) and the mixture was stirred at 0°C for 2 hours. After the reaction was completed, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), spin-dried in vacuo, and the residue was purified by silica gel column (dichloromethane/methanol=1:10~1:15) to obtain a white solid compound. (2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydro Cyclopentadien-2-ol 20E (2.1 g, 95% yield).

MS m/z(ESI)：442.1[M+1] MS m/z(ESI): 442.1[M+1]

第六步：甲磺酸(2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基酯20F The sixth step: methanesulfonic acid (2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-4- base) amino) octahydrocyclopentadien-2-yl ester 20F

Figure 110145234-A0101-12-0133-259
Figure 110145234-A0101-12-0133-259

將(2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並 [2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-醇20E(2.1g，4.75mmol)溶於二氯甲烷(15mL)，於攪拌下加入三乙胺(1mL,7.12mmol)。將混合物在0℃在攪拌下加入甲基磺醯氯(7.07mg，6.17mmol)，並將混合物在氮氣保護下在室溫攪拌3小時。反應結束後濃縮反應液得到黃色油狀甲磺酸(2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基酯20F(3.5g，粗產品)。 (2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydro Cyclopentadien-2-ol 20E (2.1 g, 4.75 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (1 mL, 7.12 mmol) was added with stirring. To the mixture was added methylsulfonyl chloride (7.07 mg, 6.17 mmol) with stirring at 0°C, and the mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction, the reaction solution was concentrated to obtain yellow oily methanesulfonic acid (2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3- b] Pyridin-4-yl)amino)octahydrocyclopentadien-2-yl ester 20F (3.5 g, crude).

MS m/z(ESI)：521.1[M+1] MS m/z(ESI): 521.1[M+1]

第七步：N-((2r,3aR,5s,6aS)-5-疊氮基八氫並環戊二烯-2-基)-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺20G The seventh step: N-((2r,3aR,5s,6aS)-5-azidooctahydrocyclopentadien-2-yl)-5-nitro-1-(benzenesulfonyl)-1H -pyrrolo[2,3-b]pyridin-4-amine 20G

Figure 110145234-A0101-12-0134-260
Figure 110145234-A0101-12-0134-260

將甲磺酸(2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基酯20F(3.5g，6.72mmol)溶於DMF(20mL)，於攪拌下加入疊氮化鈉(874mg,13.45mmol)。將混合物在氮氣保護下90℃攪拌3小時。反應結束後濃縮，粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=1：1~1：3)得到無色油狀化合物N-((2r,3aR,5s,6aS)-5-疊氮基八氫並環戊二烯-2-基)-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺20G(380mg，產率12%)。 Methanesulfonic acid (2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) octahydrocyclopentadien-2-yl ester 20F (3.5 g, 6.72 mmol) was dissolved in DMF (20 mL) and sodium azide (874 mg, 13.45 mmol) was added with stirring. The mixture was stirred at 90°C for 3 hours under nitrogen protection. After the reaction, it was concentrated, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1:1~1:3) to obtain a colorless oily compound N-((2r,3aR,5s,6aS) )-5-azidooctahydrocyclopentadien-2-yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 20G (380 mg, 12% yield).

MS m/z(ESI)：468.1[M+1] MS m/z(ESI): 468.1[M+1]

第八步：(2s,3aR,5r,6aS)-N2-(5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)八氫並環戊二烯-2,5-二胺20H The eighth step: (2s,3aR,5r,6aS)-N 2 -(5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)octa Hydrogenocyclopentadiene-2,5-diamine 20H

Figure 110145234-A0101-12-0135-261
Figure 110145234-A0101-12-0135-261

將化合物N-((2r,3aR,5s,6aS)-5-疊氮基八氫並環戊二烯-2-基)-5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-胺20G(380mg，0.813mmol)溶於THF/H2O(5：1)(10mL)，於攪拌下加入三甲基磷(309mg，4.06mmol)，在室溫攪拌16小時。反應結束後過濾濃縮，粗產品用矽膠板色譜分離提純(甲醇/二氯甲烷(v/v)=5%+0.5%氨水)得到白色固體化合物(2s,3aR,5r,6aS)-N2-(5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)八氫並環戊二烯-2,5-二胺20H(230mg，產率64.1%)。 Compound N-((2r,3aR,5s,6aS)-5-azidooctahydrocyclopentadien-2-yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrole [2,3-b]pyridin-4-amine 20G (380 mg, 0.813 mmol) was dissolved in THF/H 2 O (5:1) (10 mL), and trimethylphosphorus (309 mg, 4.06 mmol) was added with stirring , and stirred at room temperature for 16 hours. After the reaction, it was filtered and concentrated, and the crude product was separated and purified by silica gel plate chromatography (methanol/dichloromethane (v/v)=5%+0.5% ammonia water) to obtain a white solid compound (2s, 3aR, 5r, 6aS)-N 2 - (5-Nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)octahydrocyclopentadiene-2,5-diamine 20H (230 mg, yield 64.1%).

MS m/z(ESI)：442.1[M+1] MS m/z(ESI): 442.1[M+1]

第九步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)脲20I Step 9: 1-(3-Methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5r,6aS)-5-((5-nitro- 1-(Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 20I

Figure 110145234-A0101-12-0136-262
Figure 110145234-A0101-12-0136-262

將(2s,3aR,5r,6aS)-N2-(5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)八氫並環戊二烯-2,5-二胺20H(230mg，0.521mmol)和(3-(甲氧基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(170mg，0.77mmol)溶於DMF(3mL)，然後加入三乙胺(0.15mL，1.044mmol)，於氮氣保護下在60℃反應3h。然後濃縮，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：50-1：25)得到黃色固體的化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)脲20I(220mg，收率71%)。 (2s,3aR,5r,6aS)-N2-(5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)octahydrocyclopenta Diene-2,5-diamine 20H (230 mg, 0.521 mmol) and phenyl (3-(methoxy)-1,2,4-thiadiazol-5-yl)carbamate (170 mg, 0.77 mmol) ) was dissolved in DMF (3 mL), then triethylamine (0.15 mL, 1.044 mmol) was added, and the reaction was carried out at 60° C. for 3 h under nitrogen protection. Then concentrated, the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:50-1:25) to obtain compound 1-(3-methoxy-1,2,4 as a yellow solid) -Thiadiazol-5-yl)-3-((2s,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3- b] Pyridin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 20I (220 mg, 71% yield).

MS m/z(ESI)：599.1[M+1] MS m/z(ESI): 599.1[M+1]

第十步：1-((2s,3aR,5r,6aS)-5-((5-氨基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲20J Step 10: 1-((2s,3aR,5r,6aS)-5-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ) amino) octahydrocyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea 20J

Figure 110145234-A0101-12-0137-263
Figure 110145234-A0101-12-0137-263

攪拌下，向1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)脲20I(220mg，0.37mmol)中加入10%的濕鈀/炭(30mg)。將混合物在氫氣下在室溫攪拌16小時。然後用矽藻土過濾反應液，濃縮，用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：12-1：10)得到淡黃色固體的化合物1-((2s,3aR,5r,6aS)-5-((5-氨基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲20J(140mg，收率67%)。 Under stirring, add 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5r,6aS)-5-((5-nitro- 1-(Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 20I (220 mg, 0.37 mmol) was added 10% wet palladium on carbon (30 mg). The mixture was stirred under hydrogen at room temperature for 16 hours. Then, the reaction solution was filtered through celite, concentrated, and separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:12-1:10) to obtain compound 1-((2s,3aR) as a pale yellow solid ,5r,6aS)-5-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydrocyclopentadiene- 2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea 20J (140 mg, 67% yield).

MS m/z(ESI)：569.1[M+1] MS m/z(ESI): 569.1[M+1]

第十一步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)脲20K The eleventh step: 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(6-(benzenesulfonic acid) Acyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)urea 20K

Figure 110145234-A0101-12-0138-264
Figure 110145234-A0101-12-0138-264

將1-((2s,3aR,5r,6aS)-5-((5-氨基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲20J(140mg，0.25mmol)，原甲酸三乙酯(182mg，1.23mmol)和對甲苯磺酸(8.48mg，0.049mmol)溶於甲苯(3mL)，在105℃下攪拌4小時。反應結束後，濃縮，用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：20-1：15)得到淡黃色固體的化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)脲20K(95mg，收率66.72%)。 1-((2s,3aR,5r,6aS)-5-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Octahydrocyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea 20J (140 mg, 0.25 mmol), triethyl orthoformate (182 mg, 1.23 mmol) and p-toluenesulfonic acid (8.48 mg, 0.049 mmol) were dissolved in toluene (3 mL) and stirred at 105°C for 4 hours. After the reaction, concentrated, separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:20-1:15) to obtain compound 1-(3-methoxy-1,2) as a pale yellow solid ,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)urea 20K (95 mg, 66.72% yield).

MS m/z(ESI)：579.1[M+1] MS m/z(ESI): 579.1[M+1]

第十二步：1-((2r,3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲(化合物20) Step 12: 1-((2r,3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydro cyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea (Compound 20 )

Figure 110145234-A0101-12-0139-112
Figure 110145234-A0101-12-0139-112

將1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)脲20K(95mg，0.16mmol)溶於四氫呋喃(2mL)，於攪拌下加入氫氧化鈉(1M)溶液(1mL)，並加入甲醇(0.1mL)，在60℃下攪拌1小時。反應結束後，濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物1-((2r,3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲(化合物20)(2mg，2.78%)。 1-(3-Methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(6-(benzenesulfonyl)imidazole Lo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)urea 20K (95 mg, 0.16 mmol) was dissolved in tetrahydrofuran ( 2 mL), sodium hydroxide (1 M) solution (1 mL) was added with stirring, methanol (0.1 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-((2r,3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3- b] Pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea (compound 20 ) (2 mg, 2.78%).

MS m/z(ESI)：439.2[M+1] MS m/z(ESI): 439.2[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.92(s,1H),10.96(s,1 H),8.60(s,1 H),7.50(d,1 H),7.31(d,1 H),6.86(m,1 H),6.72(m,1 H),5.23-5.13(m,1 H),4.21(d,1 H),3.88(s,3 H),2.81(s,2 H),2.46-2.37(m,2 H),2.03-2.00(m,2 H),1.80-1.78(m,4 H) 1H NMR (400MHz, DMSO-d6)δ 11.92(s,1H), 10.96(s,1H), 8.60(s,1H), 7.50(d,1H), 7.31(d,1H), 6.86 (m, 1 H), 6.72 (m, 1 H), 5.23-5.13 (m, 1 H), 4.21 (d, 1 H), 3.88 (s, 3 H), 2.81 (s, 2 H), 2.46 -2.37(m, 2 H), 2.03-2.00(m, 2 H), 1.80-1.78(m, 4 H)

實施例21Example 21

1-((2s,3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶 -1(6H)-基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲(化合物21) 1-((2s,3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydrocyclopentadiene -2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea ( compound 21 )

Figure 110145234-A0101-12-0140-293
Figure 110145234-A0101-12-0140-293

第一步：(2s,3aR,5s,6aS)-N2-(5-硝基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)八氫並環戊二烯-2,5-二胺21A The first step: (2s,3aR,5s,6aS)-N 2 -(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) Octahydrocyclopentadiene-2,5-diamine 21A

Figure 110145234-A0101-12-0140-265
Figure 110145234-A0101-12-0140-265

將化合物(3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)六氫並環戊二烯-2(1H)-酮20D(2.3g，5.22mmol)溶於甲醇(20mL)，攪拌下加入甲酸銨(1.65g,26.11mmol)。將混合物在室溫在氮氣保護下攪拌16小時，然後加入氰基硼氫化鈉繼續攪拌16小時。旋乾反應混合物，加入水(20mL)，用乙酸乙酯萃取(20mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(甲醇/二氯甲烷(v/v)=0-10%)得到黃色油狀化合物(2s,3aR,5s,6aS)-N2-(5-硝基-1-(苯基磺醯基)-1H-吡咯並 [2,3-b]吡啶-4-基)八氫並環戊二烯-2,5-二胺21A(920mg，產率39.9%)。 Compound (3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydro Cyclopentadien-2(1H)-one 20D (2.3 g, 5.22 mmol) was dissolved in methanol (20 mL) and ammonium formate (1.65 g, 26.11 mmol) was added with stirring. The mixture was stirred at room temperature under nitrogen for 16 hours, then sodium cyanoborohydride was added and stirring was continued for 16 hours. The reaction mixture was spin-dried, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0-10%) to obtain a yellow oily compound (2s, 3aR, 5s, 6aS)-N 2 -(5-nitro-1) -(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)octahydrocyclopentadiene-2,5-diamine 21A (920 mg, 39.9% yield).

MS m/z(ESI)：442.1[M+1] MS m/z(ESI): 442.1[M+1]

第二步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)脲21B Step 2: 1-(3-Methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5r,6aS)-5-((5-nitro- 1-(Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 21B

Figure 110145234-A0101-12-0141-266
Figure 110145234-A0101-12-0141-266

將化合物(2s,3aR,5s,6aS)-N2-(5-硝基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)八氫並環戊二烯-2,5-二胺21A(920mg，2.08mmol)溶於N,N-二甲基甲醯胺(10mL)，室溫攪拌下加入(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(785mg,3.13mmol)和三乙胺(0.58mL,4.17mmol)，將混合物在60℃攪拌下2小時。反應結束後，向反應混合物中加入水(10mL)，乙酸乙酯萃取(15mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-40%)得到黃色油狀化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)脲21B(1.1g，產率88.1%)。 Compound (2s,3aR,5s,6aS)-N 2 -(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)octahydro Cyclopentadiene-2,5-diamine 21A (920 mg, 2.08 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (3-methoxy-1,2) was added with stirring at room temperature. , phenyl 4-thiadiazol-5-yl)carbamate (785 mg, 3.13 mmol) and triethylamine (0.58 mL, 4.17 mmol), and the mixture was stirred at 60° C. for 2 hours. After the reaction, water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (15 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-40%) to obtain a yellow oily compound 1-(3-methoxy-1,2,4-thiadiazole- 5-yl)-3-((2r,3aR,5r,6aS)-5-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)octahydrocyclopentadien-2-yl)urea 21B (1.1 g, 88.1% yield).

MS m/z(ESI)：599.0[M+1] MS m/z(ESI): 599.0[M+1]

第三步：1-((2r,3aR,5r,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲21C The third step: 1-((2r,3aR,5r,6aS)-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4- yl)amino)octahydrocyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea 21C

Figure 110145234-A0101-12-0142-267
Figure 110145234-A0101-12-0142-267

將化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2r,3aR,5r,6aS)-5-((5-硝基-1-(苯磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)脲21B(1.1g，1.84mmol)溶於乙醇/水=4/1(10mL)，攪拌下加入還原鐵粉(513mg,9.19mmol)和氯化銨(491mg,9.19mmol)。將混合物在60℃攪拌16小時。反應結束後過濾旋乾，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-10%)得到1-((2r,3aR,5r,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲21C(420mg，產率40.19%)。 Compound 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5r,6aS)-5-((5-nitro-1- (Benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 21B (1.1 g, 1.84 mmol) in ethanol /water=4/1 (10 mL), reduced iron powder (513 mg, 9.19 mmol) and ammonium chloride (491 mg, 9.19 mmol) were added with stirring. The mixture was stirred at 60°C for 16 hours. After the reaction, it was filtered and spin-dried, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-10%) to obtain 1-((2r,3aR,5r,6aS)-5-(( 5-Amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)octahydrocyclopentadien-2-yl)-3-(3 -Methoxy-1,2,4-thiadiazol-5-yl)urea 21C (420 mg, 40.19% yield).

MS m/z(ESI)：569.0[M+1] MS m/z(ESI): 569.0[M+1]

第四步：1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)脲21D The fourth step: 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(6-(benzenesulfonyl) yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)urea 21D

Figure 110145234-A0101-12-0143-268
Figure 110145234-A0101-12-0143-268

將1-((2r,3aR,5r,6aS)-5-((5-氨基-1-(苯基磺醯基)-1H-吡咯並[2,3-b]吡啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲21C(120mg，0.217mmol)溶於N,N-二甲基甲醯胺(3mL)，攪拌下加入原甲酸三乙酯(80mg,0.52mmol)和一水合對甲苯磺酸(5mg,0.02mmol)。將混合物在氮氣保護下在110℃攪拌2小時。反應結束後濃縮，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-10%)得到無色油狀化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)脲21D(120mg，產率98%)。 1-((2r,3aR,5r,6aS)-5-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) octahydrocyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea 21C (120 mg, 0.217 mmol) in N,N - Dimethylformamide (3 mL), triethyl orthoformate (80 mg, 0.52 mmol) and p-toluenesulfonic acid monohydrate (5 mg, 0.02 mmol) were added with stirring. The mixture was stirred at 110°C for 2 hours under nitrogen protection. After the reaction, it was concentrated, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-10%) to obtain a colorless oily compound 1-(3-methoxy-1,2,4- Thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)urea 21D (120 mg, 98% yield).

MS m/z(ESI)：579.1[M+1] MS m/z(ESI): 579.1[M+1]

第五步：1-((2s,3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲(化合物21) Step 5: 1-((2s,3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydro Cyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea (Compound 21)

Figure 110145234-A0101-12-0144-113
Figure 110145234-A0101-12-0144-113

將化合物1-(3-甲氧基-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(6-(苯磺醯基)咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)脲21D(120mg，0.2mmol)溶於四氫呋喃(2mL)，攪拌下加入1M的氫氧化鈉溶液(1mL)。將混合物在60℃下攪拌2小時。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物1-((2s,3aR,5s,6aS)-5-(咪唑並[4,5-d]吡咯並[2,3-b]吡啶-1(6H)-基)八氫並環戊二烯-2-基)-3-(3-甲氧基-1,2,4-噻二唑-5-基)脲(化合物21)(5.6mg，收率6.1%)。 Compound 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(6-(benzenesulfonyl) Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)urea 21D (120 mg, 0.2 mmol) in tetrahydrofuran (2 mL), 1 M sodium hydroxide solution (1 mL) was added with stirring. The mixture was stirred at 60°C for 2 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-((2s,3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b] ]pyridin-1(6H)-yl)octahydrocyclopentadien-2-yl)-3-(3-methoxy-1,2,4-thiadiazol-5-yl)urea (Compound 21 ) (5.6 mg, 6.1% yield).

MS m/z(ESI)：439.3[M+1] MS m/z(ESI): 439.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.88(s,1 H),11.35(s,1 H),8.59(s,1 H),8.31(s,1 H),7.49(t,1 H),7.08(s,1 H),6.72(s,1 H),5.18(s,1 H),3.87(s,4 H),2.68(s,2 H),2.34-2.16(m,4 H),2.15-2.01(m,2 H),1.50-1.35(m,2 H). 1 H NMR (400MHz, DMSO-d6)δ 11.88(s,1H), 11.35(s,1H), 8.59(s,1H), 8.31(s,1H), 7.49(t,1H) , 7.08(s, 1 H), 6.72(s, 1 H), 5.18(s, 1 H), 3.87(s, 4 H), 2.68(s, 2 H), 2.34-2.16(m, 4 H) ,2.15-2.01(m,2H),1.50-1.35(m,2H).

實施例22Example 22

1-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲 (化合物22) 1-((2r,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl) -3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea ( Compound 22 )

Figure 110145234-A0101-12-0145-294
Figure 110145234-A0101-12-0145-294

第一步：1-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲22A The first step: 1-((2r,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octa Hydrocyclopentadien-2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea 22A

Figure 110145234-A0101-12-0145-269
Figure 110145234-A0101-12-0145-269

將化合物(2s,3aR,5r,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺9K(200mg，0.47mmol)，(3-(甲硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(150mg，0.56mmol)，三乙胺(0.13mL,0.96mmol)溶於DMF(5mL)，混合物在氮氣保護下在60℃攪拌2小時。反應結束後濃縮反應液，加入水10mL，乙酸乙酯萃取(10mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-40%)得到黃色油狀化合物1-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲22A(220mg，產率78%)。 The compound (2s,3aR,5r,6aS)-N2 - methyl - N2-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclo Pentadiene-2,5-diamine 9K (200 mg, 0.47 mmol), phenyl (3-(methylthio)-1,2,4-thiadiazol-5-yl)carbamate (150 mg, 0.56 mmol), triethylamine (0.13 mL, 0.96 mmol) was dissolved in DMF (5 mL), and the mixture was stirred at 60 °C for 2 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-40%) to obtain a yellow oily compound 1-((2r,3aR,5s,6aS)-5-(methyl( 7-Tosylsulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)-3-(3-(methylthio)- 1,2,4-Thiadiazol-5-yl)urea 22A (220 mg, 78% yield).

MS m/z(ESI)：599.1[M+1] MS m/z(ESI): 599.1[M+1]

第二步：1-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲(化合物22) Step 2: 1-((2r,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadiene- 2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea ( Compound 22 )

Figure 110145234-A0101-12-0146-114
Figure 110145234-A0101-12-0146-114

將1-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲22A(220mg，0.36mmol)溶於四氫呋喃(2mL)，攪拌下加入1M的氫氧化鈉溶液(2mL)，將混合物在60℃下攪拌2小時。反應結束後濃縮反應混合物，通過製備型HPLC純化，凍乾得到白色固體化合物1-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲(化合物22)(83mg，收率50.8%)。 1-((2r,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclo Pentadien-2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea 22A (220 mg, 0.36 mmol) was dissolved in tetrahydrofuran (2 mL) and stirred 1 M sodium hydroxide solution (2 mL) was added at the bottom, and the mixture was stirred at 60°C for 2 hours. After the reaction, the reaction mixture was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-((2r,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine) -4-yl)amino)octahydrocyclopentadien-2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea ( Compound 22 ) (83 mg, 50.8% yield).

MS m/z(ESI)：445.3[M+1] MS m/z(ESI): 445.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.64(s,1 H),10.92(s,1 H),8.12(s,1 H),7.14-7.10(m,1 H),6.86(s,1 H),6.57(d,1 H),5.30(m,1 H),4.18-4.13(m,1 H),3.15(s,3 H),2.69(m,2 H),2.55(s,3 H),2.03-1.93(m,2 H),1.89-1.84(m,2 H),1.65-1.53(m,4 H). 1 H NMR (400MHz, DMSO-d6) δ 11.64(s, 1 H), 10.92(s, 1 H), 8.12(s, 1 H), 7.14-7.10(m, 1 H), 6.86(s, 1 H), 6.57(d, 1 H), 5.30(m, 1 H), 4.18-4.13(m, 1 H), 3.15(s, 3 H), 2.69(m, 2 H), 2.55(s, 3 H), 2.03-1.93 (m, 2 H), 1.89-1.84 (m, 2 H), 1.65-1.53 (m, 4 H).

實施例23Example 23

1-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲(化合物23) 1-((2s,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl) -3-(3-(Methylthio)-1,2,4-thiadiazol-5-yl)urea ( Compound 23 )

Figure 110145234-A0101-12-0147-295
Figure 110145234-A0101-12-0147-295

第一步：1-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲23A The first step: 1-((2s,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octa Hydrocyclopentadien-2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea 23A

Figure 110145234-A0101-12-0147-270
Figure 110145234-A0101-12-0147-270

將化合物(2s,3aR,5s,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺18A(200mg，0.46mmol)，(3-甲硫基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(188mg，0.70mmol)，三乙胺(0.13mL,0.93mmol)溶於DMF(3mL)，並將混合物在氮氣保護下在60℃攪拌2小時。反應結束後濃縮反應液，加入水10mL，乙酸乙酯萃取(10mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-50%)得到白色固體化合物1-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2- 基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲23A(180mg，產率63.9%)。 Compound (2s,3aR,5s,6aS)-N 2 -methyl-N 2 -(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclo Pentadiene-2,5-diamine 18A (200 mg, 0.46 mmol), phenyl (3-methylthio-1,2,4-thiadiazol-5-yl)carbamate (188 mg, 0.70 mmol) , triethylamine (0.13 mL, 0.93 mmol) was dissolved in DMF (3 mL), and the mixture was stirred at 60 °C for 2 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-50%) to obtain a white solid compound 1-((2s,3aR,5s,6aS)-5-(methyl (7 -Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)-3-(3-(methylthio)-1 ,2,4-thiadiazol-5-yl)urea 23A (180 mg, 63.9% yield).

MS m/z(ESI)：599.1[M+1] MS m/z(ESI): 599.1[M+1]

第二步：1-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲(化合物23) Step 2: 1-((2s,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadiene- 2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea ( Compound 23 )

Figure 110145234-A0101-12-0148-115
Figure 110145234-A0101-12-0148-115

將1-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲23A(180mg，0.30mmol)溶於四氫呋喃(2mL)，於攪拌下加入1M的氫氧化鈉溶液(2mL)。將混合物在60℃下攪拌2小時。反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物1-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)-3-(3-(甲硫基)-1,2,4-噻二唑-5-基)脲(化合物23)(26mg，收率19.4%)。 1-((2s,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclo Pentadien-2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea 23A (180 mg, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL) in 1M sodium hydroxide solution (2 mL) was added with stirring. The mixture was stirred at 60°C for 2 hours. After the reaction, it was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-((2s,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)amino)octahydrocyclopentadien-2-yl)-3-(3-(methylthio)-1,2,4-thiadiazol-5-yl)urea ( compound 23 ) (26 mg , the yield is 19.4%).

MS m/z(ESI)：445.3[M+1] MS m/z(ESI): 445.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.61(s,1 H),11.08(s,1 H),8.12(s,1 H),7.13(m,2 H),6.58(d,1 H),5.40(m,1 H),3.87-3.80(m,1 H),3.16(s,3 H),2.54(s,3 H),2.51(m,2 H),2.23-2.20 (m,2H),1.91-1.86(m,2 H),1.57-1.53(m,2 H),1.26-1.18(m,2 H). 1 H NMR (400MHz, DMSO-d6)δ 11.61(s,1H), 11.08(s,1H), 8.12(s,1H), 7.13(m,2H), 6.58(d,1H) ,5.40(m,1H),3.87-3.80(m,1H),3.16(s,3H),2.54(s,3H),2.51(m,2H),2.23-2.20(m,2H) ),1.91-1.86(m,2H),1.57-1.53(m,2H),1.26-1.18(m,2H).

實施例24Example 24

1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物24) 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea (Compound 24)

Figure 110145234-A0101-12-0149-296
Figure 110145234-A0101-12-0149-296

第一步：1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲24A The first step: 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7 -Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 24A

Figure 110145234-A0101-12-0149-271
Figure 110145234-A0101-12-0149-271

將(2s,3aR,5r,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺9K(200mg，0.47mmol)和(3-(乙硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(145mg，0.52mmol)溶於DMF(3mL)，然後加入三乙胺(0.1mL，0.70mmol)，氮氣保護下60℃反應3h。濃縮反應混合物，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=1：50-1：20)得到白色固體的化合物 1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲24A(230mg，收率79.8%)。 (2s,3aR,5r,6aS)-N2 - methyl - N2-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopenta Diene-2,5-diamine 9K (200 mg, 0.47 mmol) and phenyl (3-(ethylthio)-1,2,4-thiadiazol-5-yl)carbamate (145 mg, 0.52 mmol) ) was dissolved in DMF (3 mL), then triethylamine (0.1 mL, 0.70 mmol) was added, and the reaction was carried out at 60° C. for 3 h under nitrogen protection. The reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:50-1:20) to obtain compound 1-(3-(ethylthio)-1 as a white solid, 2,4-Thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 24A (230 mg, 79.8% yield).

MS m/z(ESI)：613.2[M+1] MS m/z(ESI): 613.2[M+1]

第二步：1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物24) The second step: 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7H) -pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( compound 24 )

Figure 110145234-A0101-12-0150-116
Figure 110145234-A0101-12-0150-116

將1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲24A(230mg，0.19mmol)溶於四氫呋喃(3mL)，攪拌下加入氫氧化鈉(1M)溶液(1mL)，並加入甲醇(0.1mL)，並在60℃下攪拌1小時。反應結束後濃縮反應混合物，通過製備型HPLC純化，凍乾得到白色固體化合物1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2r,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物24)(55mg，23.9%)。 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl) Acyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 24A (230 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL) and stirred Sodium hydroxide (1M) solution (1 mL) was added under the hood, and methanol (0.1 mL) was added, followed by stirring at 60°C for 1 hour. After the reaction, the reaction mixture was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2r ,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( Compound 24 ) (55mg, 23.9%).

MS m/z(ESI)：459.1[M+1] MS m/z(ESI): 459.1[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.69(s,1 H),10.94(s,1 H),8.14(s,1 H),7.18-7.13(m,1 H),6.85(m,1 H),6.58(d,1 H),5.28(m,1 H),4.16(m,1 H),3.16(s,3 H),3.12(q,2 H),2.69(m,2 H),2.01-1.94(m，2 H),1.91-1.84(m,2 H),1.64-1.54(m,4 H),1.33(t,3 H). 1 H NMR (400MHz, DMSO-d6) δ 11.69(s, 1 H), 10.94(s, 1 H), 8.14(s, 1 H), 7.18-7.13(m, 1 H), 6.85(m, 1 H), 6.58 (d, 1 H), 5.28 (m, 1 H), 4.16 (m, 1 H), 3.16 (s, 3 H), 3.12 (q, 2 H), 2.69 (m, 2 H) , 2.01-1.94(m, 2 H), 1.91-1.84(m, 2 H), 1.64-1.54(m, 4 H), 1.33(t, 3 H).

實施例25Example 25

1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物25) 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( Compound 25 )

Figure 110145234-A0101-12-0151-297
Figure 110145234-A0101-12-0151-297

第一步：1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲25A The first step: 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7 -Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 25A

Figure 110145234-A0101-12-0151-272
Figure 110145234-A0101-12-0151-272

將化合物((2s,3aR,5s,6aS)-N2-甲基-N2-(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)八氫並環戊二烯-2,5-二胺18A(230mg，0.54mmol),(3-乙硫基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(228mg，0.81mmol)，三乙胺(0.15mL,1.08mmol)溶於DMF(3mL)， 並將混合物在氮氣保護下在60℃攪拌2小時。反應結束後濃縮反應液，加入水10mL，乙酸乙酯萃取(10mL x 3)，無水硫酸鈉乾燥有機相。粗產品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-50%)得到白色固體化合物1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲25A(180mg，產率36.2%)。 Compound ((2s,3aR,5s,6aS)-N 2 -methyl-N 2 -(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro Cyclopentadiene-2,5-diamine 18A (230 mg, 0.54 mmol), phenyl (3-ethylsulfanyl-1,2,4-thiadiazol-5-yl)carbamate (228 mg, 0.81 mmol) ), triethylamine (0.15 mL, 1.08 mmol) was dissolved in DMF (3 mL), and the mixture was stirred under nitrogen protection at 60° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated, 10 mL of water was added, and ethyl acetate was extracted (10 mL x 3), dry organic phase with anhydrous sodium sulfate.The crude product is separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-50%) to obtain white solid compound 1-(3-(ethylthio) )-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 25A (180 mg, 36.2% yield).

MS m/z(ESI)：613.2[M+1] MS m/z(ESI): 613.2[M+1]

第二步：1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物25) Step 2: 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7H -pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( compound 25 )

Figure 110145234-A0101-12-0152-117
Figure 110145234-A0101-12-0152-117

將1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲25A(120mg，0.19mmol)溶於四氫呋喃(2mL)，攪拌下加入1M的氫氧化鈉溶液(2mL)，並將混合物在60℃下攪拌2小時。反應結束後濃縮反應液，通過製備型HPLC純化，凍乾得到白色固體化合物1-(3-(乙硫基)-1,2,4-噻二唑-5-基)-3-((2s,3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)八氫並環戊二烯-2-基)脲(化合物25)(32mg，收率35.6%)。 1-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl) Acyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 25A (120 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL) and stirred 1M sodium hydroxide solution (2 mL) was added under the hood, and the mixture was stirred at 60°C for 2 hours. After the reaction, the reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 1-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-3-((2s ,3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea ( Compound 25 ) (32 mg, 35.6% yield).

MS m/z(ESI)：459.3[M+1] MS m/z(ESI): 459.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.64(s,1 H),11.14(s,1 H),8.13(s,1 H),7.13(m,2 H),6.58(d,1 H),5.41(m,1 H),3.81(s,1 H),3.16(s,3 H),3.10(q,2 H),2.51(m,2 H),2.21-2.11(m,2 H),1.91-1.83(m,2 H),1.57-1.53(m,2 H),1.31(t,3 H),1.26-1.18(m,2 H). 1 H NMR (400MHz, DMSO-d6)δ 11.64(s,1H), 11.14(s,1H), 8.13(s,1H), 7.13(m,2H), 6.58(d,1H) , 5.41(m, 1 H), 3.81(s, 1 H), 3.16(s, 3 H), 3.10(q, 2 H), 2.51(m, 2 H), 2.21-2.11(m, 2 H) ,1.91-1.83(m,2H),1.57-1.53(m,2H),1.31(t,3H),1.26-1.18(m,2H).

實施例26Example 26

(3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物26) (3aR,5s,6aS)-5-(methyl( 7H -pyrrolo[2,3- d ]pyrimidin-4 - yl)amino)-N-(3-(methylthio)-1,2, 4-Thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide ( Compound 26 )

Figure 110145234-A0101-12-0153-298
Figure 110145234-A0101-12-0153-298

第一步：(3aR,5s,6aS)-5-(甲基(7-對甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯26B The first step: (3aR,5s,6aS)-5-(methyl(7-p-toluenesulfonyl- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopentane Dieno[c]pyrrole-2( 1H )-carboxylate tert-butyl ester 26B

Figure 110145234-A0101-12-0153-273
Figure 110145234-A0101-12-0153-273

將(3aR,5s,6aS)-5-(甲胺基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯26A(1.0g,4.16mmol),4-氯-7-甲苯磺醯基 -7H-吡咯並[2,3-d]嘧啶(1.9g,6.24mmol)和N,N-二異丙基乙胺(1.6g,12.48mmol)溶於異丙醇(20mL)中，將混合物在氮氣保護下在100℃攪拌反應16小時。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=0-60%)，得到白色固體化合物(3aR,5s,6aS)-5-(甲基(7-對甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯26B(1.35g，產率：63%) (3aR,5s,6aS)-5-(methylamino)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxylate tert-butyl ester 26A (1.0 g, 4.16 mmol), 4 -Chloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (1.9 g, 6.24 mmol) and N ,N-diisopropylethylamine (1.6 g, 12.48 mmol) were dissolved in In isopropanol (20 mL), the mixture was stirred for 16 hours at 100 °C under nitrogen protection. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=0-60%) to obtain a white solid compound (3aR, 5s, 6aS)-5-(methyl) (7-p-toluenesulfonyl-7H-pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxylic acid tert-Butyl ester 26B (1.35 g, yield: 63%)

MS m/z(ESI)：512.2[M+1] MS m/z(ESI): 512.2[M+1]

第二步：N-甲基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺26C Second step: N -methyl- N -((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)-7-toluenesulfonyl- 7H -pyrrolo[ 2,3- d ]pyrimidin-4-amine 26C

Figure 110145234-A0101-12-0154-274
Figure 110145234-A0101-12-0154-274

將(3aR,5s,6aS)-5-(甲基(7-對甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-羧酸叔丁基酯26B(1.35g,2.64mmol)溶於氯二氯甲烷中(10mL,1.5mol/L)，冰浴條件下，將叔丁基二甲矽基三氟甲磺酸酯(1.31.4g,5.28mmol)滴加到反應液中。滴加完畢後撤去冰浴，溶液在室溫下攪拌反應過夜。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-20%)，得到白色固體化合物N-甲基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-7-甲苯磺醯基-7H- 吡咯並[2,3-d]嘧啶-4-胺26C(900mg，產率：83%) (3aR,5s,6aS)-5-(methyl(7-p-toluenesulfonyl- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopentadieno [c]pyrrole-2( 1H )-carboxylate tert-butyl ester 26B (1.35g, 2.64mmol) was dissolved in chlorodichloromethane (10mL, 1.5mol/L), under ice bath conditions, the tert-butyl Dimethylsilyl triflate (1.31.4 g, 5.28 mmol) was added dropwise to the reaction solution. After the dropwise addition, the ice bath was removed, and the solution was stirred overnight at room temperature. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-20%) to obtain a white solid compound N -methyl- N -((3aR,5s, 6aS) -Octahydrocyclopentadieno [c]pyrrol-5-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3- d ]pyrimidin-4-amine 26C (900 mg, yield : 83%)

MS m/z(ESI)：412.2[M+1] MS m/z(ESI): 412.2[M+1]

第三步：(3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲基硫)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺26D The third step: (3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino) -N- (3 -(Methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide 26D

Figure 110145234-A0101-12-0155-275
Figure 110145234-A0101-12-0155-275

將N-甲基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺26C(300mg，0.73mmol)，(3-(甲硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(234mg,0.87mmol和三乙胺(148mg,1.46mmol)溶於N,N-二甲基甲醯胺(10mL)中。混合物在油浴60℃下攪拌反應過夜。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=0-60%)，得到白色固體化合物(3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲基硫)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺26D(360mg，產率：84%) N -methyl- N -((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)-7-toluenesulfonyl- 7H -pyrrolo[2,3 - d ] Pyrimidine-4-amine 26C (300 mg, 0.73 mmol), phenyl (3-(methylthio)-1,2,4-thiadiazol-5-yl)carbamate (234 mg, 0.87 mmol and Triethylamine (148mg, 1.46mmol) was dissolved in N,N-dimethylformamide (10mL). The mixture was stirred and reacted at 60°C in an oil bath overnight. After the reaction was completed, the solvent was spin-dried, and the crude product was chromatographed on a silica gel column. Separation and purification (petroleum ether/ethyl acetate (v/v)=0-60%) to obtain a white solid compound (3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl- 7H -pyrrole) [2,3- d ]pyrimidin-4-yl)amino) -N- (3-(methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[ c]pyrrole-2( 1H )-carboxyamide 26D (360 mg, yield: 84%)

MS m/z(ESI)：585.1[M+1] MS m/z(ESI): 585.1[M+1]

第四步：(3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡 咯-2(1H)-甲醯胺(化合物26) Fourth step: (3aR,5s,6aS)-5-(methyl( 7H -pyrrolo[2,3- d ]pyrimidin-4 - yl)amino)-N-(3-(methylthio)- 1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide ( compound 26 )

Figure 110145234-A0101-12-0156-118
Figure 110145234-A0101-12-0156-118

將(3aR,5s,6aS)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲基硫)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-羧醯胺26D(360mg，0.62mmol)和氫氧化鈉(49mg,1.23mmol)溶於四氫呋喃/水(1v/1v,16mL)中。混合物在油浴60℃下攪拌反應1h。反應結束後旋乾溶劑，粗產品通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物26)(157mg，收率：59%)。 (3aR,5s,6aS)-5-(methyl(7-toluenesulfonyl- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino) -N- (3-(methyl) thio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide 26D (360 mg, 0.62 mmol) and sodium hydroxide (49 mg, 1.23 mmol) was dissolved in tetrahydrofuran/water (1 v/1 v, 16 mL). The mixture was stirred in an oil bath at 60 °C for 1 h. After the reaction, the solvent was spin-dried, the crude product was purified by preparative HPLC, and lyophilized to obtain a white solid compound (3aR,5s,6aS)-5-(methyl( 7H -pyrrolo[2,3- d ]pyrimidine-4) -yl)amino)-N-(3-(methylthio)-1,2,4 - thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-methyl Amide ( compound 26 ) (157 mg, yield: 59%).

MS m/z(ESI)：431.3[M+1] MS m/z(ESI): 431.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.67(s,1 H),11.60(s,1 H),8.08(s,1 H),7.12-7.04(m,1 H),6.53(d,1 H),5.46(m,1 H),3.71-3.66(m,2 H),3.39(m,2 H),3.15(s,3 H),2.89(s,2 H),2.57(s,3 H),2.03-2.00(m,2 H),1.80-1.75(m,2 H). 1 H NMR (400MHz, DMSO-d6) δ 11.67(s, 1 H), 11.60(s, 1 H), 8.08(s, 1 H), 7.12-7.04(m, 1 H), 6.53(d, 1 H), 5.46(m, 1 H), 3.71-3.66(m, 2 H), 3.39(m, 2 H), 3.15(s, 3 H), 2.89(s, 2 H), 2.57(s, 3 H), 2.03-2.00 (m, 2 H), 1.80-1.75 (m, 2 H).

實施例27Example 27

(3aR,5s,6aS)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-5-(甲基 (7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物27) (3aR,5s,6aS)-N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d] ]pyrimidin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide ( Compound 27 )

Figure 110145234-A0101-12-0157-299
Figure 110145234-A0101-12-0157-299

第一步：(3aR,5s,6aS)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺27A The first step: (3aR,5s,6aS)-N-(3-(ethylthio)-1,2,4-thiadiazol - 5-yl)-5-(methyl(7-toluenesulfonyl) -7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide 27A

Figure 110145234-A0101-12-0157-276
Figure 110145234-A0101-12-0157-276

將N-甲基-N-((3aR,5s,6aS)-八氫環戊二烯並[c]吡咯-5-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺26C(300mg，0.73mmol)，(3-(乙基硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(246mg,0.88mmol和三乙胺(148mg,1.46mmol)溶於N,N-二甲基甲醯胺(10mL)中。混合物在油浴60℃下攪拌反應過夜。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=0-60%)，得到白色固體化合物(3aR,5s,6aS)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺27A(370mg，產率：85%) N -methyl- N -((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)-7-toluenesulfonyl- 7H -pyrrolo[2,3 - d ] Pyrimidine-4-amine 26C (300 mg, 0.73 mmol), (3-(ethylsulfanyl)-1,2,4-thiadiazol-5-yl)carbamic acid phenyl ester (246 mg, 0.88 mmol) and triethylamine (148 mg, 1.46 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was stirred and reacted at 60 ° C in an oil bath overnight. After the reaction was completed, the solvent was spin-dried, and the crude product was treated with a silica gel column. Purification by chromatography (petroleum ether/ethyl acetate (v/v) = 0-60%) to obtain a white solid compound (3aR,5s,6aS)-N-(3-(ethylthio)-1,2,4 -Thiadiazol -5-yl)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopentadieno [c]pyrrole-2( 1H )-carboxamide 27A (370 mg, yield: 85%)

MS m/z(ESI)：599.1[M+1] MS m/z(ESI): 599.1[M+1]

第二步：(3aR,5s,6aS)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物27) The second step: (3aR,5s,6aS)-N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2] ,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide ( Compound 27 )

Figure 110145234-A0101-12-0158-119
Figure 110145234-A0101-12-0158-119

將((3aR,5s,6aS)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-5-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺27A(370mg，0.62mmol)和氫氧化鈉(49mg,1.23mmol)溶於四氫呋喃/水(1v/1v,16mL)中。混合物在油浴60℃下攪拌反應2h。反應結束後旋乾溶劑，粗產品通過製備型HPLC純化，凍乾得到白色固體化合物(3aR,5s,6aS)-N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)六氫環戊二烯並[c]吡咯-2(1H)-甲醯胺(化合物27)(267mg，收率：97%)。 ((3aR,5s,6aS)-N-(3-(ethylthio)-1,2,4-thiadiazol - 5-yl)-5-(methyl(7-toluenesulfonyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2( 1H )-carboxamide 27A (370 mg, 0.62 mmol) and hydroxide Sodium (49mg, 1.23mmol) was dissolved in tetrahydrofuran/water (1v/1v, 16mL). The mixture was stirred and reacted at 60°C in an oil bath for 2h. After the reaction was completed, the solvent was spin-dried, and the crude product was purified by preparative HPLC and lyophilized to obtain White solid compound (3aR,5s,6aS)-N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide ( compound 27 ) (267 mg, yield: 97%).

MS m/z(ESI)：445.3[M+1] MS m/z(ESI): 445.3[M+1]

1H NMR(400MHz,DMSO-d6 δ 11.59(s,1 H),8.08(s,1 H),7.04(m,1 H),6.52(d,1 H),5.46(m,1 H),3.67(m,2 H),3.36-3.34(m,2 H),3.17(s,3 H),3.13(q,2 H),2.89(m,2 H),2.05-1.97 (m,2 H),1.80-1.75(m,2 H),1.34(t,3 H). 1 H NMR (400MHz, DMSO-d6δ 11.59(s,1H), 8.08(s,1H), 7.04(m,1H), 6.52(d,1H), 5.46(m,1H), 3.67 (m, 2 H), 3.36-3.34 (m, 2 H), 3.17 (s, 3 H), 3.13 (q, 2 H), 2.89 (m, 2 H), 2.05-1.97 (m, 2 H) ),1.80-1.75(m,2H),1.34(t,3H).

實施例28Example 28

7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物28) 7-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(3-(methylthio)-1,2,4-thiadiazol-5-yl )-2-azaspiro[3.5]nonane-2-carboxyamide ( compound 28 )

Figure 110145234-A0101-12-0159-300
Figure 110145234-A0101-12-0159-300

第一步：7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁基酯28A The first step: 7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2- Carboxylic acid tert-butyl ester 28A

Figure 110145234-A0101-12-0159-277
Figure 110145234-A0101-12-0159-277

將粗產品化合物7-(甲基氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁酯6B(2.2g)溶於DMF(30mL)，加入N,N-二異丙基乙胺(1.62g,12.55mmol)攪拌5分鐘，加入4-氯-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶(1.93g,6.28mmol)，混合物攪拌下5小時。反應結束後加入水(20mL)，乙酸乙酯萃取(30mL x 3)，無水硫酸鈉乾燥有機相。有機相真空濃縮得到粗品化合物7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁基酯28A(2.3g，粗產品)。 The crude product compound 7-(methylamino)-2-azaspiro[3.5]nonane-2-carboxylate tert-butyl ester 6B (2.2 g) was dissolved in DMF (30 mL), and N,N-diisopropyl was added Ethylamine (1.62 g, 12.55 mmol) was stirred for 5 minutes, 4-chloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (1.93 g, 6.28 mmol) was added, and the mixture was stirred for 5 minutes. Hour. After the reaction, water (20 mL) was added, extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to give the crude compound 7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane - 2-Carboxylic acid tert-butyl ester 28A (2.3 g, crude).

第二步：N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-甲苯磺醯 基-7H-吡咯並[2,3-d]嘧啶-4-胺28B Step 2: N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-4- Amine 28B

Figure 110145234-A0101-12-0160-278
Figure 110145234-A0101-12-0160-278

將粗品化合物7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧酸叔丁基酯28A(800mg)溶於二氯甲烷(20mL)，攪拌下加入叔丁基二甲矽基三氟甲磺酸酯(2g,7.61mmol)。混合物在室溫攪拌2小時，反應結束後濃縮反應液得到粗產品用矽膠柱色譜分離提純(二氯甲烷/甲醇(v/v)=0-10%)得到得到白色固體化合物N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺28B(490mg，產率：75%)。 The crude compound 7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxy Acid tert-butyl ester 28A (800 mg) was dissolved in dichloromethane (20 mL) and tert-butyldimethylsilyl triflate (2 g, 7.61 mmol) was added with stirring. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=0-10%) to obtain a white solid compound N-methyl- N-(2-Azaspiro[3.5]nonan-7-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 28B (490 mg, yield: 75 %).

第三步：7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-2-氮雜螺[3.5]壬烷-2-羧醯胺28C The third step: 7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(3-(methylthio)-1, 2,4-thiadiazol-5-yl)-2-azaspiro[3.5]nonane-2-carboxamide 28C

Figure 110145234-A0101-12-0160-279
Figure 110145234-A0101-12-0160-279

將白色固體化合物N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺28B(250mg，0.59mmol)溶於DMF(5mL)，加入三乙胺(178mg，1.76mmol)，攪拌 下加入(3-(甲硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(235mg，0.88mmol)，混合物在60℃攪拌下繼續反應2小時。反應結束後加入水(20mL)，乙酸乙酯萃取(30mL x 3)，無水硫酸鈉乾燥有機相。有機相真空濃縮，得到的粗品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-20%)得到白色固體化的化合物7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-2-氮雜螺[3.5]壬烷-2-羧醯胺28C(310mg，產率88.13%)。 The white solid compound N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-4- Amine 28B (250 mg, 0.59 mmol) was dissolved in DMF (5 mL), triethylamine (178 mg, 1.76 mmol) was added, and (3-(methylthio)-1,2,4-thiadiazole-5-) was added with stirring phenyl)carbamate (235 mg, 0.88 mmol), and the mixture was stirred at 60°C for 2 hours. After the reaction, water (20 mL) was added, extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo, and the obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-20%) to obtain a white solid compound 7-(methyl(7-toluenesulfonyl) -7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(3-(methylthio)-1,2,4-thiadiazol-5-yl)-2-nitrogen Heterospiro[3.5]nonane-2-carboxamide 28C (310 mg, 88.13% yield).

第四步：7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物28) Step 4: 7-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(3-(methylthio)-1,2,4-thiadiazole -5-yl)-2-azaspiro[3.5]nonane-2-carboxamide ( compound 28 )

Figure 110145234-A0101-12-0161-120
Figure 110145234-A0101-12-0161-120

將化合物7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-2-氮雜螺[3.5]壬烷-2-羧醯胺28C(310mg，0.52mmol)溶於四氫呋喃(5mL)中，攪拌下加入1M/L鹽酸溶液(3mL)，混合物60℃攪拌1小時。反應結束後濃縮反應液，通過製備型HPLC純化，凍乾得到白色固體化合物7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-N-(3-(甲硫基)-1,2,4-噻二唑-5-基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物 28)(20mg，收率8.69%)。 Compound 7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(3-(methylthio)-1,2, 4-Thiadiazol-5-yl)-2-azaspiro[3.5]nonane-2-carboxamide 28C (310 mg, 0.52 mmol) was dissolved in tetrahydrofuran (5 mL), and 1M/L hydrochloric acid solution was added with stirring (3 mL), and the mixture was stirred at 60°C for 1 hour. After the reaction, the reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound 7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(3- (Methylthio)-1,2,4-thiadiazol-5-yl)-2-azaspiro[3.5]nonane-2-carboxamide ( compound 28 ) (20 mg, yield 8.69%).

MS m/z(ESI)：445.1[M+1] MS m/z(ESI): 445.1[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.83(s,1 H),11.59(s,1 H),8.09(s,1 H),7.14-7.10(m,1 H),6.54(s,1 H),4.66(m,1 H),3.86-3.69(m,4 H),3.14(s,3 H),2.55(s,3 H),2.00(m,2 H),1.63(m,6 H). 1 H NMR (400MHz, DMSO-d6) δ 11.83(s, 1 H), 11.59(s, 1 H), 8.09(s, 1 H), 7.14-7.10(m, 1 H), 6.54(s, 1 H), 4.66(m, 1 H), 3.86-3.69(m, 4 H), 3.14(s, 3 H), 2.55(s, 3 H), 2.00(m, 2 H), 1.63(m, 6 H).

實施例29Example 29

N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物29) N-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino )-2-azaspiro[3.5]nonane-2-carboxyamide ( compound 29 )

Figure 110145234-A0101-12-0162-301
Figure 110145234-A0101-12-0162-301

第一步：N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺29A The first step: N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide 29A

Figure 110145234-A0101-12-0162-280
Figure 110145234-A0101-12-0162-280

將白色固體化合物N-甲基-N-(2-氮雜螺[3.5]壬烷-7-基)-7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-胺28B(250mg，0.59mmol)溶於DMF(5mL)，加入三乙胺(178mg，1.76mmol)，攪拌 下加入(3-(乙硫基)-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(150mg，0.53mmol)，混合物在60℃攪拌下繼續反應2小時。反應結束後加入水(20mL)，乙酸乙酯萃取(30mL x 3)，無水硫酸鈉乾燥有機相。有機相真空濃縮得到粗品用矽膠柱色譜分離提純(乙酸乙酯/石油醚(v/v)=0-20%)得到白色固體化的化合物N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺29A(120mg，產率33.33%)。 The white solid compound N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-4- Amine 28B (250 mg, 0.59 mmol) was dissolved in DMF (5 mL), triethylamine (178 mg, 1.76 mmol) was added, and (3-(ethylthio)-1,2,4-thiadiazole-5-) was added with stirring phenyl)carbamate (150 mg, 0.53 mmol), and the mixture was stirred for 2 hours at 60°C. After the reaction, water (20 mL) was added, extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to obtain the crude product, which was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0-20%) to obtain a white solid compound N-(3-(ethylthio)-1,2). ,4-thiadiazol-5-yl)-7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro [3.5] Nonane-2-carboxyamide 29A (120 mg, 33.33% yield).

第二步：N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物29) Step 2: N-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-7-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4 -yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide ( compound 29 )

Figure 110145234-A0101-12-0163-121
Figure 110145234-A0101-12-0163-121

將化合物N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-7-(甲基(7-甲苯磺醯基-7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺29A(120mg，0.20mmol)溶於四氫呋喃(5mL)中，攪拌下加入1M/L鹽酸溶液(3mL)，混合物60℃攪拌1小時。反應結束後濃縮反應液，通過製備型HPLC純化，凍乾得到白色固體化合物N-(3-(乙硫基)-1,2,4-噻二唑-5-基)-7-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)氨基)-2-氮雜螺[3.5]壬烷-2-羧醯胺(化合物29)(20mg，收 率22.27%)。 The compound N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-7-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide 29A (120mg, 0.20mmol) was dissolved in tetrahydrofuran (5mL), and 1M/L hydrochloric acid solution was added under stirring (3 mL), and the mixture was stirred at 60°C for 1 hour. After the reaction, the reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid compound N-(3-(ethylthio)-1,2,4-thiadiazol-5-yl)-7-(methyl) (7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide ( compound 29 ) (20 mg, yield 22.27%).

MS m/z(ESI)：459.0[M+1] MS m/z(ESI): 459.0[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.85(s,1 H),11.59(s,1 H),8.09(s,1 H),7.11(t,1 H),6.54(s,1 H),4.66(m,1 H),3.88-3.75(m,4 H),3.16-3.10(m,5 H),2.00(m,2 H),1.63(m,6 H),1.33(t,3 H). 1 H NMR (400MHz, DMSO-d6)δ 11.85(s,1H), 11.59(s,1H), 8.09(s,1H), 7.11(t,1H), 6.54(s,1H) ,4.66(m,1 H),3.88-3.75(m,4 H),3.16-3.10(m,5 H),2.00(m,2 H),1.63(m,6 H),1.33(t,3 H).

實施例30Example 30

N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧醯胺(化合物30) N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-di Azaspiro[3.4]octane-1-carboxamide ( compound 30 )

Figure 110145234-A0101-12-0164-302
Figure 110145234-A0101-12-0164-302

第一步：N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-甲醯胺30B The first step: N-(3-methoxy-1,2,4-thiadiazol-5-yl)-6-(7-((2-(trimethylsilyl)ethoxy)methyl yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxamide 30B

Figure 110145234-A0101-12-0164-281
Figure 110145234-A0101-12-0164-281

將5-氨基-3-甲氧基-1,2,4-噻唑(73mg，0.56mmol)溶於 二氯甲烷(3mL)攪拌下加入N,N'-羰基二咪唑(99mg，0.61mmol)和DIEA(0.39mL，2.78mmol)，混合物在室溫攪拌下反應2小時後加入4-(1,6-二氮雜螺[3.4]辛烷-6-基)-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶30A(200mg，粗產品)，混合物在室溫攪拌下繼續反應16小時。反應結束後濃縮，粗產品用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=30-50%)得到無色油狀的化合物N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-甲醯胺30B(110mg，收率38%)。 5-Amino-3-methoxy-1,2,4-thiazole (73 mg, 0.56 mmol) was dissolved in dichloromethane (3 mL) and N,N'-carbonyldiimidazole (99 mg, 0.61 mmol) and N,N'-carbonyldiimidazole (99 mg, 0.61 mmol) were added with stirring. DIEA (0.39 mL, 2.78 mmol), the mixture was stirred at room temperature for 2 hours and then added 4-(1,6-diazaspiro[3.4]octan-6-yl)-7-((2-(tris Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 30A (200 mg, crude) and the mixture was stirred at room temperature for 16 hours. After the reaction, it was concentrated, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=30-50%) to obtain a colorless oily compound N-(3-methoxy-1,2, 4-Thiadiazol-5-yl)-6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl)-1,6-diazaspiro[3.4]octane-1-carboxamide 30B (110 mg, 38% yield).

MS m/z(ESI)：517.2[M+1] MS m/z(ESI): 517.2[M+1]

第二步：N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧醯胺(化合物30) The second step: N-(3-methoxy-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,6-diazaspiro[3.4]octane-1-carboxamide ( compound 30 )

Figure 110145234-A0101-12-0165-122
Figure 110145234-A0101-12-0165-122

將N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-甲醯胺30B(110mg，0.21mmol)溶於二氯甲烷(2mL)，攪拌下加入三氟乙酸(1mL)，混合物在室溫下攪拌2小時後旋乾。旋乾後的混合物溶於四氫呋喃(3mL)並加入氨水(1mL)，在室溫下 攪拌30分鐘，反應結束後濃縮，通過製備型HPLC純化，凍乾得到白色固體化合物N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(7H-吡咯並[2,3-d]嘧啶-4-基)-1,6-二氮雜螺[3.4]辛烷-1-羧醯胺(化合物30)(19mg，收率23.3%)。取17.8mg產品用手性SFC分離(SFC150；手性柱IC 250*25mm 10um；超臨界CO2/甲醇+甲醇氨0.1%=50：50；80mL/min)得到化合物30-P 1 (Rt=3.43min,3.6mg)和化合物30-P 2 (Rt=3.94min,4.1mg)均為白色固體。 N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-6-(7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxamide 30B (110 mg, 0.21 mmol) was dissolved in dichloromethane ( 2 mL), trifluoroacetic acid (1 mL) was added with stirring, and the mixture was stirred at room temperature for 2 hours and then spun dry. The spin-dried mixture was dissolved in tetrahydrofuran (3 mL) and ammonia water (1 mL) was added, stirred at room temperature for 30 minutes, concentrated after the reaction, purified by preparative HPLC, and lyophilized to obtain a white solid compound N-(3-methoxyl yl-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane Alkane-1-carboxyamide ( compound 30 ) (19 mg, yield 23.3%). Take 17.8mg of the product and separate it by chiral SFC (SFC150; chiral column IC 250*25mm 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=50:50; 80mL/min) to obtain compound 30-P 1 (Rt= 3.43 min, 3.6 mg) and compound 30-P 2 (Rt=3.94 min, 4.1 mg) were both white solids.

MS m/z(ESI)：387.1[M+1] MS m/z(ESI): 387.1[M+1]

1H NMR(400MHz,DMSO-d6)δ11.67(s,1 H),11.60(s,1 H)8.08(s,1H),7.12-7.08(m,1H),6.61-6.60(m,1 H),4.28-4.18(m,1 H),4.08(d,J=7.2Hz,2H),3.96(s,2H),3.88(s,3H),2.74-2.63(m,1 H),2.45-2.29(m,3 H),2.26-2.16(m,1H) 1 H NMR (400MHz, DMSO-d6) δ 11.67(s, 1 H), 11.60(s, 1 H) 8.08(s, 1H), 7.12-7.08(m, 1H), 6.61-6.60(m, 1 H), 4.28-4.18(m, 1 H), 4.08(d, J =7.2Hz, 2H), 3.96(s, 2H), 3.88(s, 3H), 2.74-2.63(m, 1 H), 2.45 -2.29(m,3H),2.26-2.16(m,1H)

實施例31Example 31

6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.4]辛烷-1-甲醯胺(化合物31) 6-(5-Cyano- 1H -pyrrolo[2,3- b ]pyridin-4-yl) -N- (3-methoxy-1,2,4-thiadiazol-5-yl) -1,6-Diazaspiro[3.4]octane-1-carboxamide ( Compound 31 )

Figure 110145234-A0101-12-0166-303
Figure 110145234-A0101-12-0166-303

第一步：6-(5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.4]辛烷-1- 羧醯胺31B The first step: 6-(5-cyano-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)-N-(3 - methoxy-1,2 ,4-thiadiazol-5-yl)-1,6-diazaspiro[3.4]octane-1-carboxamide 31B

Figure 110145234-A0101-12-0167-282
Figure 110145234-A0101-12-0167-282

將4-(1,6-二氮雜螺[3.4]辛烷-6-基)-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-5-甲腈31A(300mg,0.73mmol),(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯基酯(222mg,0.88mmol)和三乙胺(372mg,3.68mmol)溶於DMF(6mL)中，反應溶液在氮氣保護下60℃攪拌反應16小時。反應結束後旋乾溶劑，粗產品用矽膠柱色譜分離提純(石油醚/乙酸乙酯(v/v)=0-60%)，得到白色固體化合物6-(5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.4]辛烷-1-羧醯胺31B(250mg，產率：61%) 4-(1,6-Diazaspiro[3.4]octan-6-yl)-1-toluenesulfonyl- 1H -pyrrolo[2,3-b]pyridine-5-carbonitrile 31A ( 300mg, 0.73mmol), (3-methoxy-1,2,4-thiadiazol-5-yl) phenylcarbamate (222mg, 0.88mmol) and triethylamine (372mg, 3.68mmol) were dissolved in In DMF (6 mL), the reaction solution was stirred under nitrogen protection at 60°C for 16 hours. After the reaction, the solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=0-60%) to obtain a white solid compound 6-(5-cyano-1-toluenesulfonic acid) Acyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl)-N-(3-methoxy - 1,2,4-thiadiazol-5-yl)-1,6- Diazaspiro[3.4]octane-1-carboxamide 31B (250 mg, yield: 61%)

MS m/z(ESI)：565.1[M+1] MS m/z(ESI): 565.1[M+1]

第二步：6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.4]辛烷-1-甲醯胺(化合物31) Second step: 6-(5-cyano- 1H -pyrrolo[2,3- b ]pyridin-4-yl) -N- (3-methoxy-1,2,4-thiadiazole- 5-yl)-1,6-diazaspiro[3.4]octane-1-carboxamide ( Compound 31 )

Figure 110145234-A0101-12-0168-123
Figure 110145234-A0101-12-0168-123

將6-(5-氰基-1-甲苯磺醯基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.4]辛烷-1-羧醯胺31B(250mg，0.44mmol)和氫氧化鈉(35mg,0.88mmol)溶於四氫呋喃/水(1v/1v,8mL)中。混合物在油浴60℃下攪拌反應1h。反應結束後旋乾溶劑，粗產品通過製備型HPLC純化，凍乾得到白色固體化合物6-(5-氰基-1H-吡咯並[2,3-b]吡啶-4-基)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-1,6-二氮雜螺[3.4]辛烷-1-甲醯胺(化合物31)(90mg，收率：50%)。取88mg產品用手性SFC分離(SFC150；手性柱OD 250*25mm 10um；超臨界CO2/甲醇+甲醇氨0.1%=75：25；70mL/min)得到化合物31-P 1 (Rt=0.92min,8mg)和化合物31-P 2 (Rt=1.28min,11mg)均為白色固體。 6-(5-Cyano-1-toluenesulfonyl- 1H -pyrrolo[2,3- b ]pyridin-4-yl) -N- (3-methoxy-1,2,4- Thiadiazol-5-yl)-1,6-diazaspiro[3.4]octane-1-carboxamide 31B (250 mg, 0.44 mmol) and sodium hydroxide (35 mg, 0.88 mmol) in tetrahydrofuran/water (1v/1v, 8mL). The mixture was stirred in an oil bath at 60 °C for 1 h. After the reaction, the solvent was spin-dried, the crude product was purified by preparative HPLC, and lyophilized to obtain a white solid compound 6-(5-cyano- 1H -pyrrolo[2,3- b ]pyridin-4-yl) -N- (3-Methoxy-1,2,4-thiadiazol-5-yl)-1,6-diazaspiro[3.4]octane-1-carboxamide ( Compound 31 ) (90 mg, yield : 50%). 88mg of the product was separated by chiral SFC (SFC150; chiral column OD 250*25mm 10um; supercritical CO 2 /methanol+methanol ammonia 0.1%=75:25; 70mL/min) to obtain compound 31-P 1 (Rt=0.92 min, 8 mg) and compound 31-P 2 (Rt=1.28 min, 11 mg) were both white solids.

化合物31-PCompound 31-P 11 ：:

MS m/z(ESI)：411.3[M+1] MS m/z(ESI): 411.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.85(s,1 H),11.72(s,1 H),8.05(s,1 H),7.23(m,1 H),6.79(m,1 H),4.50(d,1 H),4.11(m,2 H),4.05(m,2 H),3.89(s,3 H),2.72-2.67(m,1 H),2.45-2.22(m,4 H). 1 H NMR (400MHz, DMSO-d6)δ 11.85(s,1H), 11.72(s,1H), 8.05(s,1H), 7.23(m,1H), 6.79(m,1H) , 4.50(d, 1 H), 4.11(m, 2 H), 4.05(m, 2 H), 3.89(s, 3 H), 2.72-2.67(m, 1 H), 2.45-2.22(m, 4 H).

化合物31-P 2 ： Compound 31-P 2 :

MS m/z(ESI)：411.3[M+1] MS m/z(ESI): 411.3[M+1]

1H NMR(400MHz,DMSO-d6)δ 11.85(s,1 H),11.72(s,1 H),8.05(s,1 H),7.23(m,1 H),6.79(m,1 H),4.49(d,1 H),4.10(m,2 H),4.05-4.02(m,2 H),3.88(s,3 H),2.72-2.67(m,1 H),2.33-2.21(m,4 H). 1 H NMR (400MHz, DMSO-d6)δ 11.85(s,1H), 11.72(s,1H), 8.05(s,1H), 7.23(m,1H), 6.79(m,1H) ,4.49(d,1H),4.10(m,2H),4.05-4.02(m,2H),3.88(s,3H),2.72-2.67(m,1H),2.33-2.21(m ,4H).

測試例1、JAK激酶抑制活性的測定Test Example 1. Measurement of JAK Kinase Inhibitory Activity

體外JAK1激酶活性的抑制通過以下的方法進行測試。 Inhibition of JAK1 kinase activity in vitro was tested by the following method.

1.1 試劑配製 1.1 Reagent preparation

1.1.1 1X激酶反應緩衝液 1.1.1 1X Kinase Reaction Buffer

Figure 110145234-A0101-12-0169-304
Figure 110145234-A0101-12-0169-304

1.1.2 JAK1酶溶液 1.1.2 JAK1 enzyme solution

Figure 110145234-A0101-12-0169-305
Figure 110145234-A0101-12-0169-305

1.1.3 底物混合物配方 1.1.3 Substrate mix formulation

Figure 110145234-A0101-12-0169-306
Figure 110145234-A0101-12-0169-306

Figure 110145234-A0101-12-0170-307
Figure 110145234-A0101-12-0170-307

1.2 實驗步驟： 1.2 Experimental steps:

a)用DMSO將待測化合物(10mM儲液)稀釋10倍，在384稀釋板中以1：3進行等比稀釋，10+0劑量； a) Dilute the test compound (10 mM stock solution) 10-fold with DMSO, 1:3 equal dilution in 384 dilution plate, 10+0 dose;

b)用Echo轉移0.1μL的待測化合物(a步驟中準備)到384反應板中，每個濃度兩個複孔。1000rpm/min，離心1min； b) Use Echo to transfer 0.1 μL of the test compound (prepared in step a) into a 384 reaction plate, with two duplicate wells for each concentration. 1000rpm/min, centrifugation for 1min;

c)轉移5μL的激酶到384反應板中，1000rpm/min，離心1min，25℃孵育15min； c) Transfer 5 μL of kinase to 384 reaction plate, 1000rpm/min, centrifuge for 1min, and incubate at 25°C for 15min;

d)轉移5μL底物混合物到384反應板中，1000rpm/min，離心1min，25℃孵育60min；PF-06700841終濃度10,3.33,1.11,0.37,0.12,0.04,0.014,0.0046,0.0015,0.0005,0μM。待測化合物終濃度：10,3.33,1.11,0.37,0.12,0.04,0.014,0.0046,0.0015,0.0005,0μM。DMSO終濃度均為1%； d) Transfer 5μL of substrate mixture to 384 reaction plate, centrifuge at 1000rpm/min for 1min, and incubate at 25°C for 60min; 0 μM. Final concentrations of the compounds to be tested: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, 0 μM. The final concentration of DMSO is 1%;

e)轉移10μL ADP-Glo試劑到384反應板中，1000rpm/min，離心1min，25℃孵育60min； e) Transfer 10 μL of ADP-Glo reagent to 384 reaction plate, 1000rpm/min, centrifuge for 1min, and incubate at 25°C for 60min;

f)轉移20μL檢測試劑到384反應板中，1000rpm/min，離心1min，25℃孵育60min； f) Transfer 20 μL of detection reagent to 384 reaction plate, centrifuge at 1000rpm/min for 1min, and incubate at 25°C for 60min;

g)使用Envision多功能讀板機讀取螢光信號。 g) Use the Envision multi-function plate reader to read the fluorescent signal.

1.3 資料分析 1.3 Data Analysis

a)化合物抑制率(%抑制)=(陰性對照平均值-化合物)/(陰性對照平均值-陽性對照平均值)*100% a) Compound inhibition rate (% inhibition) = (mean value of negative control-compound)/(mean value of negative control-mean value of positive control)*100%

陰性對照：DMSO Negative control: DMSO

陽性對照：10μM PF-06700841 Positive control: 10 μM PF-06700841

PF-06700841(CAS號：1883299-62-4)結構如下： The structure of PF-06700841 (CAS No.: 1883299-62-4) is as follows:

Figure 110145234-A0101-12-0171-308
Figure 110145234-A0101-12-0171-308

b)利用以下非線性擬合公式來得到化合物的IC50(半數抑制濃度)： b) Use the following nonlinear fitting formula to obtain the IC50 (50% inhibitory concentration) of the compound:

Y=底部+(頂部-底部)/(1+10^((LogIC50-X)*HillSlope)) Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

X：化合物濃度log值 X: compound concentration log value

Y：化合物抑制率(%抑制) Y: compound inhibition rate (% inhibition)

以相同的方法來進行JAK2、JAK3、TYK2激酶的活性測定。 Activity assays of JAK2, JAK3, TYK2 kinases were performed in the same manner.

表1.本發明的化合物對JAK1、JAK2、JAK3、TYK2激酶的抑制活性

Figure 110145234-A0101-12-0171-310
Table 1. Inhibitory activity of compounds of the present invention on JAK1, JAK2, JAK3, TYK2 kinases
Figure 110145234-A0101-12-0171-310

Figure 110145234-A0101-12-0172-311
Figure 110145234-A0101-12-0172-311

Figure 110145234-A0101-12-0173-312
Figure 110145234-A0101-12-0173-312

以上的結果表明本發明的化合物對JAK1具有良好的抑制活性和選擇性。 The above results show that the compounds of the present invention have good inhibitory activity and selectivity to JAK1.

測試例2、藥代動力學評價Test Example 2. Pharmacokinetic Evaluation

以大鼠為受試動物，應用LC/MS/MS法測定了大鼠口服和靜脈注射給予化合物3-P1、4-P2、7-P1、8-P1和16後不同時刻血漿中的藥物濃度。研究本發明化合物在大鼠體內的藥代動力學行為，評價其藥動學特徵。 Taking rats as the test animals, the plasma of rats after oral and intravenous administration of compounds 3-P 1 , 4-P 2 , 7-P 1 , 8-P 1 and 16 was determined by LC/MS/MS method at different times. drug concentration in . The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

試驗藥品： Test drug:

化合物3-P1、4-P2、7-P1、8-P1和16。 Compounds 3-P 1 , 4-P 2 , 7-P 1 , 8-P 1 and 16.

試驗動物： Test animals:

健康成年SD大鼠，雄性，共10組，每組3只，購自上海西普爾-必凱實驗動物有限公司，實驗動物生產許可證號：SCXK(滬)2018-0006。 Healthy adult SD rats, male, with a total of 10 groups, 3 rats in each group, were purchased from Shanghai Sipple-Bikai Laboratory Animal Co., Ltd., and the experimental animal production license number: SCXK (Shanghai) 2018-0006.

藥物配製： Drug preparation:

稱取一定量藥物溶於5%二甲基乙醯胺(DMA)+5%聚乙二醇-15羥基硬脂酸酯(solutol)+90%鹽溶液配置成0.2mg/mL溶液用於靜脈注射。 Weigh a certain amount of the drug and dissolve it in 5% dimethylacetamide (DMA) + 5% polyethylene glycol-15 hydroxystearate (solutol) + 90% saline solution to prepare a 0.2 mg/mL solution for intravenous use injection.

稱取一定量藥物溶於5%二甲基乙醯胺(DMA)+5%聚乙二醇-15羥基硬脂酸酯(solutol)+90%鹽溶液配置成0.5mg/mL或0.3mg/mL溶液用於口服給藥。 Weigh a certain amount of drug and dissolve it in 5% dimethylacetamide (DMA) + 5% polyethylene glycol-15 hydroxystearate (solutol) + 90% salt solution to prepare 0.5mg/mL or 0.3mg/mL. mL solution for oral administration.

給藥： Dosing:

SD大鼠禁食過夜後口服和靜脈注射給藥，口服給藥劑量為5.0mg/kg或3.0mg/kg，靜脈注射給藥劑量均為1.0mg/kg。 SD rats were fasted overnight and were administered orally and intravenously. The oral dose was 5.0 mg/kg or 3.0 mg/kg, and the intravenous dose was 1.0 mg/kg.

試驗操作： Test operation:

大鼠口服和靜脈注射給藥化合物3-P1、4-P2、7-P1、8-P1和16，於給藥後0.083,0.25,0.5,1,2,4,8和24小時由頜下靜脈或其他合適血管采血0.2mL，置於K2-EDTA試管中後儲存於冰上，在一小時內2-8℃、6800g離心6分鐘分離血漿，於-80℃保存，進行LC/MS/MS分析，大鼠在給藥後4小時進食。 Compounds 3-P 1 , 4-P 2 , 7-P 1 , 8-P 1 and 16 were administered orally and intravenously to rats at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 post-dose 0.2 mL of blood was collected from the submandibular vein or other suitable blood vessels after 1 hour, placed in a K2-EDTA test tube and stored on ice, centrifuged at 2-8°C for 6 minutes at 6800g within one hour to separate plasma, and stored at -80°C for LC. /MS/MS analysis, rats were fed 4 hours after dosing.

表2、大鼠IV藥代動力學參數Table 2. Rat IV pharmacokinetic parameters

Figure 110145234-A0101-12-0174-313
Figure 110145234-A0101-12-0174-313

Figure 110145234-A0101-12-0175-314
Figure 110145234-A0101-12-0175-314

表3、大鼠PO藥代動力學參數Table 3. Rat PO pharmacokinetic parameters

Figure 110145234-A0101-12-0175-315
Figure 110145234-A0101-12-0175-315

結論：本發明化合物的藥代吸收良好，具有明顯的藥代動力學優勢。 Conclusion: The compounds of the present invention have good pharmacokinetic absorption and obvious pharmacokinetic advantages.

測試例3.化合物在II型膠原誘導的大鼠關節炎模型(CIA)的單劑量藥效學研究Test Example 3. Single-dose pharmacodynamics study of compound in type II collagen-induced rat arthritis model (CIA)

1.摘要1. Summary

檢測多個化合物在大鼠CIA模型的抗關節炎藥效。 The anti-arthritis efficacy of multiple compounds in the rat CIA model was examined.

2.試驗方案2. Experimental protocol

2.1 試驗藥物2.1 Test drug

Abrocitinib(陽性化合物)、化合物3-P1、化合物4-P2、化合物7-P1、化合物8-P1。 Abrocitinib (positive compound), compound 3-P 1 , compound 4-P 2 , compound 7-P 1 , compound 8-P 1 .

Abrocitinib(CAS號：1622902-68-4)結構如下： The structure of Abrocitinib (CAS No: 1622902-68-4) is as follows:

Figure 110145234-A0101-12-0176-333
Figure 110145234-A0101-12-0176-333

2.2 實驗動物2.2 Experimental animals

Wistar大鼠，雄性，SPF級別，購自上海斯萊克實驗動物有限責任公司 Wistar rats, male, SPF grade, purchased from Shanghai Slack Laboratory Animal Co., Ltd.

2.3 試驗方法2.3 Test method

2.3.1 造模2.3.1 Modeling

實驗動物適應環境5天后，除正常組(n=10)外，其餘大鼠在第0天於尾根部皮內注射0.2mL等體積混合CII(II型膠原，2mg/mL)和CFA(完全氟氏佐劑，4mg/mL)製備的乳劑進行第一次免疫，在第7天進行第二次增強免疫，以誘發大鼠CIA模型。 After the experimental animals were acclimated to the environment for 5 days, except for the normal group (n=10), the other rats were injected intradermally with 0.2 mL equal volume of CII (type II collagen, 2 mg/mL) and CFA (complete fluoride) at the base of the tail on day 0. The first immunization was carried out with an emulsion prepared with Radix's adjuvant, 4 mg/mL), and the second booster immunization was carried out on the 7th day to induce the rat CIA model.

2.3.2 動物分組與給藥2.3.2 Animal grouping and administration

二免後6天(即第13天)，動物發病足達2分左右時，根據體重、足容積和AI評分情況選取大鼠，共6組，每組10只，隨後開始給予相應藥物治療，連續給藥2周。分組及給藥資訊如下表4： Six days after the second immunization (i.e., the 13th day), when the onset of the animal reached about 2 points, rats were selected according to body weight, foot volume and AI score, and there were 6 groups of 10 rats in each group. Dosing for 2 weeks. The grouping and dosing information is shown in Table 4 below:

表4.試驗分組資訊與給藥資訊Table 4. Trial grouping information and dosing information

Figure 110145234-A0101-12-0176-316
Figure 110145234-A0101-12-0176-316

Figure 110145234-A0101-12-0177-317
Figure 110145234-A0101-12-0177-317

p.o：口服給藥；q.d：每天一次 p.o: oral administration; q.d: once a day

2.3.3 檢測指標2.3.3 Detection indicators

1)體重監測：2次/周 1) Weight monitoring: 2 times/week

2)足趾腫脹測定：第二次免疫後3天開始，每週2次測量雙側後足足趾容積並記錄。測量前，用記號筆在大鼠踝關節處畫線標記位置，儀器內加入乾淨清水後儀器數值清零準備測量。將大鼠後肢放入水中使踝關節處的標記線位於液體表面，此時踩下腳踏讀數，為大鼠足容積。測量結束後再次踩下腳踏清零準備測量下一隻。 2) Measurement of toe swelling: 3 days after the second immunization, the toe volume of bilateral hind feet was measured and recorded twice a week. Before measurement, use a marker pen to draw a line at the ankle joint of the rat to mark the position. After adding clean water to the instrument, the value of the instrument is cleared to prepare for measurement. Put the hind limbs of the rat into the water so that the marking line at the ankle joint is on the surface of the liquid, and at this time, step on the foot to read, which is the volume of the rat's foot. After the measurement is over, step on the foot pedal again to clear and prepare to measure the next one.

3)關節炎指數(AI)：第二次免疫後，每週2次測量足容積，同時對四個足趾腫脹按表5進行評分，每只足評0~4分，每只大鼠最高評分為16分。 3) Arthritis Index (AI): After the second immunization, the foot volume was measured twice a week, and the swelling of the four toes was scored according to Table 5. Each foot was scored 0 to 4 points, and each rat was the highest. The rating is 16 points.

表5.關節炎指數(Arthritis Index)評分標準Table 5. Arthritis Index scoring criteria

Figure 110145234-A0101-12-0177-318
Figure 110145234-A0101-12-0177-318

Figure 110145234-A0101-12-0178-319
Figure 110145234-A0101-12-0178-319

3.試驗結果 3. Test results

3.1 每天1次連續2周經口灌胃給予化合物對CIA模型大鼠體重的影響3.1 The effect of oral administration of compounds once a day for 2 consecutive weeks on the body weight of CIA model rats

模型組動物在第11天開始出現四肢腫脹，第13天發病足達到2分左右，體重顯著低於正常組，第22~29天逐漸升高。與模型組相比，15mg/kg的化合物3-P1和化合物7-P1在第18~29天動物體重顯著升高，Abrocitinib、化合物4-P2和化合物8-P1在15mg/kg的劑量下亦可一定程度的增加CIA動物體重，但未出現統計學差異。 The animals in the model group began to have swelling of limbs on the 11th day, and the onset of the disease reached about 2 points on the 13th day. The body weight was significantly lower than that of the normal group, and gradually increased from the 22nd to the 29th day. Compared with the model group, compound 3-P1 and compound 7-P1 at 15 mg/kg significantly increased the body weight of animals on days 18 to 29, and Abrocitinib, compound 4-P2 and compound 8-P1 at the dose of 15 mg/kg also The body weight of CIA animals can be increased to a certain extent, but there is no statistical difference.

同等劑量下(15mg/kg)，化合物3-P1和化合物7-P1組動物體重在第18~29天均顯著高於陽性對照組Abrocitinib組(圖1，表6)。 At the same dose (15 mg/kg), the body weight of the animals in the compound 3-P 1 and compound 7-P 1 groups was significantly higher than that in the positive control group Abrocitinib on days 18 to 29 (Figure 1, Table 6).

表6.每天1次連續2周經口灌胃給予化合物對CIA大鼠體重的影響(n=10，

Figure 110145234-A0101-12-0178-339
±s)
Figure 110145234-A0101-12-0178-320
 Table 6. Effects of oral gavage of compounds administered once a day for 2 weeks on body weight in CIA rats (n=10,
Figure 110145234-A0101-12-0178-339
±s)
Figure 110145234-A0101-12-0178-320

Figure 110145234-A0101-12-0179-321
Figure 110145234-A0101-12-0179-321

3.2 每天1次連續2周經口灌胃給予化合物對CIA模型大鼠後足足容積的影響3.2 The effect of oral gavage of compounds once a day for 2 weeks on the hind paw volume of CIA model rats

與正常組相比，模型組大鼠後足足趾容積顯著升高；各給藥組在第15~29天后足足趾容積均明顯低於模型組，說明Abrocitinib、化合物3-P1、化合物4-P2、化合物7-P1和化合物8-P1在15mg/kg的劑量下均可有效抑制CIA大鼠雙後足足腫脹，且抑制作用相當(表7，圖2)。 Compared with the normal group, the rear toe volume of the rats in the model group was significantly increased; the toe volume of each administration group was significantly lower than that of the model group on the 15th to 29th day, indicating that Abrocitinib, Compound 3-P1, Compound 4 -P2, compound 7-P1 and compound 8-P1 can effectively inhibit the swelling of both hind paws in CIA rats at a dose of 15 mg/kg, and the inhibition effects are comparable (Table 7, Figure 2).

表7.每天1次連續2周經口灌胃給予受試物對CIA大鼠後足足容積的影響

Figure 110145234-A0101-12-0179-322
Table 7. Effects of oral gavage once a day for 2 weeks on the hind paw volume of CIA rats
Figure 110145234-A0101-12-0179-322

Figure 110145234-A0101-12-0180-323
Figure 110145234-A0101-12-0180-323

3.3 每天1次、連續2周經口灌胃給予化合物對CIA大鼠四肢關節炎指數(AI)的影響3.3 The effect of oral gavage of compounds once a day for 2 consecutive weeks on the arthritis index (AI) of the limbs of CIA rats

實驗動物在第11天開始出現四肢腫脹，在第13天發病足達到2分左右時，開始分組給予藥物治療。結果顯示：15mg/kg的Abrocitinib、化合物3-P1、化合物4-P2和化合物7-P1組動物AI評分在第15~29天均顯著低於模型組；化合物8-P1組在第18~29天CIA大鼠AI評分亦顯著降低，所有給藥組中化合物3-P1組大鼠AI評分始終最低(表8，圖3)。 On the 11th day, the limbs of the experimental animals began to swell, and on the 13th day, when the onset of the disease reached about 2 points, they began to be given drug treatment in groups. The results showed that the AI scores of the 15 mg/kg Abrocitinib, Compound 3-P 1 , Compound 4-P 2 and Compound 7-P 1 groups were significantly lower than those of the model group on days 15-29 ; The AI scores of CIA rats were also significantly decreased on days 18 to 29, and the AI scores of the rats in the compound 3-P 1 group were always the lowest among all administration groups (Table 8, Figure 3).

表8.每天1次連續2周經口灌胃給予化合物對CIA大鼠關節炎指數的影響

Figure 110145234-A0101-12-0180-324
****P<0.0001 vs.模型組，使用two-way ANOVA統計 Table 8. Effects of oral gavage of compounds administered once a day for 2 weeks on arthritis index in CIA rats
Figure 110145234-A0101-12-0180-324
 ****P<0.0001 vs. model group, using two-way ANOVA statistics

4.試驗結論 4. Test conclusion

在CIA大鼠模型中，Abrocitinib、化合物3-P1、化合物4-P2、化合物7-P1和化合物8-P1在15mg/kg的劑量下，每天一次經口灌胃連續給藥14天均可有效降低大鼠後足足趾容積及關節炎指數(AI)評分，對CIA大鼠均具有良好的治療作用。化合物3-P1在改善模型大鼠體重和AI評分的藥效上優於陽性化合物Abrocitinib，化合物7-P1在改善模型大鼠體重分的藥效上優於陽性化合物。 In the CIA rat model, Abrocitinib, Compound 3-P1, Compound 4-P2, Compound 7-P1, and Compound 8-P1 were effective at a dose of 15 mg/kg once a day for 14 consecutive days by oral gavage Reducing the volume of the hind toes and the arthritis index (AI) score of the rats has a good therapeutic effect on the CIA rats. Compound 3-P1 was better than the positive compound Abrocitinib in improving the body weight and AI score of the model rats, and compound 7-P1 was better than the positive compound in improving the body weight score of the model rats.

測試例4.化合物在II型膠原誘導的大鼠關節炎模型(CIA)的劑量探索藥效學研究Test Example 4. Dose-finding pharmacodynamics study of compound in type II collagen-induced rat arthritis model (CIA)

1、摘要1. Abstract

檢測兩個化合物在大鼠CIA模型的抗關節炎藥效。 The anti-arthritis efficacy of the two compounds in the rat CIA model was examined.

2、試驗方案2. Test plan

2.1 試驗藥物2.1 Test drug

Abrocitinib(陽性化合物)、化合物3-P1、化合物16 Abrocitinib (positive compound), compound 3-P 1 , compound 16

2.2 實驗動物2.2 Experimental animals

Wistar大鼠，雄性，SPF級別，購自浙江維通利華實驗動物技術有限公司 Wistar rats, male, SPF grade, purchased from Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd.

2.3 試驗方法2.3 Test method

2.3.1 造模2.3.1 Modeling

實驗動物適應環境6天后，除正常組(n=6)外，其餘大鼠在第0天於尾根部皮內注射0.2mL等體積混合CII(2mg/mL)和CFA(4mg/mL)製備的乳劑進行第一次免疫，在第7天進行第二次增強免疫，以誘發大鼠CIA模型。 After 6 days of acclimation to the environment, except for the normal group (n=6), the other rats were injected intradermally at the base of the tail with 0.2 mL equal volume of mixed CII (2 mg/mL) and CFA (4 mg/mL) on the 0th day. The first immunization was performed with the emulsion and the second booster immunization was performed on day 7 to induce the rat CIA model.

2.3.2 動物分組與給藥2.3.2 Animal grouping and administration

在第14天，即二免後7天，發病足AI評分在1~2分時，造模動物選取根據體重、足容積和AI評分分成7組，每組8只，加上正常一共8組，隨後開始給予相應藥物治療，連續給藥2周。分組及給藥資訊如下表9： On the 14th day, that is, 7 days after the second vaccination, when the AI score of the onset foot was 1-2 points, the model animals were selected and divided into 7 groups according to body weight, foot volume and AI score, with 8 animals in each group, plus a total of 8 normal groups. , and then began to give the corresponding drug treatment, continuous administration for 2 weeks. The grouping and dosing information is shown in Table 9 below:

表9.試驗分組資訊與給藥資訊Table 9. Trial grouping information and dosing information

Figure 110145234-A0101-12-0182-325
Figure 110145234-A0101-12-0182-325

p.o：口服給藥；q.d：每天一次 p.o: oral administration; q.d: once a day

2.3.3 檢測指標2.3.3 Detection indicators

1)體重監測：2次/周 1) Weight monitoring: 2 times/week

2)足趾腫脹測定：第二次免疫後3天開始，每週2次測量 雙側後足足趾容積並記錄。測量前，用記號筆在大鼠踝關節處畫線標記位置，儀器內加入乾淨清水後儀器數值清零準備測量。將大鼠後肢放入水中使踝關節處的標記線位於液體表面，此時踩下腳踏讀數，為大鼠足容積。測量結束後再次踩下腳踏清零準備測量下一隻。 2) Determination of toe swelling: 3 days after the second immunization, measured twice a week The toe volumes of the hind feet were recorded on both sides. Before measurement, use a marker pen to draw a line at the ankle joint of the rat to mark the position. After adding clean water to the instrument, the value of the instrument is cleared to prepare for measurement. Put the hind limbs of the rat into the water so that the marking line at the ankle joint is on the surface of the liquid, and at this time, step on the foot to read, which is the volume of the rat's foot. After the measurement is over, step on the foot pedal again to clear and prepare to measure the next one.

3)關節炎指數(AI)：第二次免疫後，每週2次測量足容積，同時對四個足趾腫脹按表5進行評分，每只足評0~4分，每只大鼠最高評分為16分。 3) Arthritis Index (AI): After the second immunization, the foot volume was measured twice a week, and the swelling of the four toes was scored according to Table 5. Each foot was scored 0 to 4 points, and each rat was the highest. The rating is 16 points.

3、試驗結果3. Test results

3.1 化合物對模型大鼠體重的影響3.1 Effects of compounds on body weight of model rats

第一次免疫後14天實驗動物分組開始給藥。正常組動物體重在實驗期間穩定增長。模型組動物體重也逐漸增高，但增長幅度小，體重在第14~28天均顯著低於正常組。其餘各給藥組大鼠體重在實驗期間輕微波動，與模型組動物體重相比均無統計學上的顯著性差異(表10)。 14 days after the first immunization, the experimental animals were divided into groups and started to be administered. The body weight of the animals in the normal group increased steadily during the experiment. The body weight of the animals in the model group also increased gradually, but the increase rate was small, and the body weight was significantly lower than that of the normal group on the 14th to 28th day. The body weight of the rats in the other administration groups fluctuated slightly during the experiment, and there was no statistically significant difference compared with the body weight of the animals in the model group (Table 10).

表10 每天1次連續2周經口灌胃給予化合物對CIA大鼠體重的影響(Mean±SEM)Table 10 Effects of oral gavage administration of compounds once a day for 2 weeks on body weight of CIA rats (Mean±SEM)

Figure 110145234-A0101-12-0183-326
Figure 110145234-A0101-12-0183-326

Figure 110145234-A0101-12-0184-327
Figure 110145234-A0101-12-0184-327

3.2 化合物對模型大鼠後足足容積的影響3.2 Effects of compounds on the hind paw volume of model rats

與正常組相比，模型組動物足容積在一免後第18~28天均顯著升高。大鼠後肢腫脹程度逐漸加重，第25天足容積達到最高值，第28天足容積略有降低。 Compared with the normal group, the foot volume of the animals in the model group was significantly increased on the 18th to 28th days after the first immunization. The swelling degree of the hindlimbs of rats gradually increased, and the foot volume reached the highest value on the 25th day, and the foot volume decreased slightly on the 28th day.

Abrocitinib 3mg/kg組動物足容積在第18~28天與模型組相比均顯著降低。 The foot volume of the animals in the Abrocitinib 3mg/kg group was significantly lower than that in the model group on days 18-28.

化合物3-P1 3mg/kg、1mg/kg和0.3mg/kg劑量組動物足容積在第18~28天與模型組相比均顯著降低。其中化合物3-P1 3mg/kg和化合物3-P1 1mg/kg對CIA大鼠後肢腫脹的治療作用均優於Abrocitinib 3mg/kg。化合物3-P1 0.3mg/kg對CIA大鼠後足腫脹的治療作用與Abrocitinib 3mg/kg相近。化合物3-P1對降低CIA大鼠後肢足容積的作用與其劑量呈正相關。 Compound 3-P 1 3 mg/kg, 1 mg/kg and 0.3 mg/kg dose groups showed significantly lower foot volume compared with the model group on days 18-28. Among them, compound 3-P 1 3 mg/kg and compound 3-P 1 1 mg/kg had better therapeutic effects on hindlimb swelling in CIA rats than Abrocitinib 3 mg/kg. The therapeutic effect of compound 3-P 1 0.3 mg/kg on hind paw swelling in CIA rats was similar to that of Abrocitinib 3 mg/kg. The effect of compound 3-P 1 on reducing the volume of hindlimbs of CIA rats was positively correlated with its dose.

化合物16 10mg/kg和3mg/kg組動物足容積在第21~28天與模型組相比均顯著降低，且與劑量呈正相關(表11，圖4)。 Compared with the model group, the foot volume of the compound 16 10 mg/kg and 3 mg/kg groups was significantly decreased on the 21st to 28th day, and was positively correlated with the dose (Table 11, Figure 4).

表11 每天1次連續2周經口灌胃給予化合物對CIA大鼠後足足容積的影響(平均值(mean)±SEM)Table 11 Effects of oral gavage of compounds once a day for 2 weeks on hind paw volume in CIA rats (mean ± SEM)

Figure 110145234-A0101-12-0184-328
Figure 110145234-A0101-12-0184-328

Figure 110145234-A0101-12-0185-330
Figure 110145234-A0101-12-0185-330

3.3 化合物對實驗大鼠四肢關節炎指數(AI)的影響3.3 Effects of compounds on the arthritis index (AI) of experimental rats

實驗動物在一免後第14天發病足評分達到1~2分，開始分組給予藥物治療。結果顯示，模型組動物AI評分在第14~25天持續升高，第28天略有下降，在第14~28天均顯著高於正常組。 On the 14th day after the first immunization, the onset foot score of the experimental animals reached 1-2 points, and drug treatment was started in groups. The results showed that the AI scores of the animals in the model group continued to increase on the 14th to 25th days, slightly decreased on the 28th day, and were significantly higher than those of the normal group on the 14th to 28th days.

Abrocitinib 3mg/kg動物AI評分在第18~28天與模型組相比均顯著降低。 The AI scores of Abrocitinib 3mg/kg animals were significantly lower than those of the model group on days 18-28.

化合物3-P1 3mg/kg、1mg/kg和0.3mg/kg劑量組動物AI評分在第18~28天與模型組相比均顯著降低，且化合物3-P1三個劑量對CIA大鼠四肢腫脹的治療作用均優於Abrocitinib 3mg/kg。化合物3-P1對降低CIA大鼠AI評分的作用與其劑量呈正相關。 Compound 3-P 1 3 mg/kg, 1 mg/kg and 0.3 mg/kg dose groups had significantly lower AI scores compared with the model group on days 18 to 28, and three doses of compound 3-P 1 had a significant effect on CIA rats. The therapeutic effect of extremity swelling was better than that of Abrocitinib 3mg/kg. The effect of compound 3-P 1 on reducing AI score in CIA rats was positively correlated with its dose.

化合物16 10mg/kg和3mg/kg劑量組動物AI評分在第21~28天與模型組相比均顯著降低，藥效與劑量呈正相關(表12，圖5)。 Compared with the model group, the AI scores of the 10 mg/kg and 3 mg/kg dose groups of compound 16 were significantly reduced on days 21 to 28, and the drug efficacy was positively correlated with the dose (Table 12, Figure 5).

表12. 每天1次連續2周經口灌胃給予化合物對CIA大Table 12. Compounds administered by oral gavage once daily for 2 weeks on CIA increase 鼠關節炎指數的影響Effects of Rat Arthritis Index

Figure 110145234-A0101-12-0186-332
Figure 110145234-A0101-12-0186-332

4、試驗結論4. Test conclusion

化合物每天1次經口灌胃給藥，連續2周，化合物3-P1和化合物16均可不同程度的改善CIA大鼠關節炎症狀，且其治療作用呈現較強的劑量相關性。 Compound 3-P 1 and compound 16 can improve the arthritis symptoms of CIA rats to varying degrees by oral gavage once a day for 2 consecutive weeks, and their therapeutic effects show a strong dose correlation.

其中所有化合物對CIA大鼠後肢足容積腫脹的治療作用從強到弱依次為：化合物3-P1 3mg/kg>化合物3-P1 1mg/kg>Abrocitinib 3mg/kg

Figure 110145234-A0101-12-0186-340
化合物3-P1 0.3mg/kg>化合物16 10mg/kg>化合物16 3mg/kg。所有化合物對降低CIA大鼠關節炎指數的治療作用從強到弱依次為：化合物3-P1 3mg/kg>化合物3-P1 1mg/kg>化合物3-P1 0.3mg/kg>Abrocitinib 3mg/kg>化合物16 10mg/kg>化合物16 3mg/kg。 The therapeutic effects of all compounds on the swelling of hindlimb foot volume in CIA rats are in descending order: Compound 3-P 1 3mg/kg>Compound 3-P 1 1mg/kg>Abrocitinib 3mg/kg
Figure 110145234-A0101-12-0186-340
Compound 3-P 1 0.3 mg/kg>Compound 16 10 mg/kg>Compound 16 3 mg/kg. The therapeutic effects of all compounds on reducing the arthritis index in CIA rats are in descending order: Compound 3-P 1 3mg/kg>Compound 3-P 1 1mg/kg>Compound 3-P 1 0.3mg/kg>Abrocitinib 3mg /kg>Compound 16 10mg/kg>Compound 16 3mg/kg.

綜上所述，同等給藥劑量下，化合物3-P1在CIA大鼠關節炎模型上藥效強於陽性對照化合物Abrocitinib。 In conclusion, under the same dosage, compound 3-P 1 is more effective than the positive control compound Abrocitinib in CIA rat arthritis model.

以上所述實施例的各技術特徵可以進行任意的組合，為使描述簡潔，未對上述實施例中的各個技術特徵所有可能的組合都進行描述，然而，只要這些技術特徵的組合不存在矛盾，都應當認為是本說明書記載的範圍。 The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.

以上所述實施例僅表達了本發明的幾種實施方式，其描述較為具體和詳細，但並不能因此而理解為對發明專利範圍的限制。應當指出的是，對於本領域的普通技術人員來說，在不脫離本發明構思的前提下，還可以做出若干變形和改進，這些都屬於本發明的保護範圍。因此，本發明專利的保護範圍應以所附申請專利範圍為准。 The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the scope of the appended patent application.

Figure 110145234-A0101-11-0002-343
Figure 110145234-A0101-11-0002-343

Claims (16)

一種氮雜並環化合物，具有通式(I)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： An azacyclic compound, a compound having the structure represented by the general formula (I) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, Prodrugs:
Figure 110145234-A0101-13-0001-124
Figure 110145234-A0101-13-0001-124
 其中，L0選自單鍵和NR1； Wherein, L 0 is selected from single bond and NR 1 ; X1選自CH和N； X 1 is selected from CH and N; X2選自CR4和N； X 2 is selected from CR 4 and N; R4為氰基，R1選自-H和C1-C3烷基，或R1與R4一起形成5~6元飽和或不飽和環；所述5~6元飽和或不飽和環被R6取代； R 4 is a cyano group, R 1 is selected from -H and C 1 -C 3 alkyl, or R 1 and R 4 together form a 5- to 6-membered saturated or unsaturated ring; the 5- to 6-membered saturated or unsaturated ring replaced by R 6 ; R6選自-H、=O、-OH、C1-C4烷基和C1-C4烷基羥基； R 6 is selected from -H, =O, -OH, C 1 -C 4 alkyl and C 1 -C 4 alkyl hydroxyl; X3選自CH和N； X 3 is selected from CH and N; n選自1和2； n is selected from 1 and 2; m=2；兩個R0取代於同一碳原子之上或取代於相鄰碳原子之上，且兩個R0互相連接形成4~6元飽和氮雜環或4~6元飽和碳環；所述4~6元飽和氮雜環或4~6元飽和碳環分別獨立地被R2取代； m=2; two R 0 are substituted on the same carbon atom or on adjacent carbon atoms, and the two R 0 are connected to each other to form a 4-6-membered saturated nitrogen heterocycle or a 4-6 membered saturated carbocycle; The 4-6-membered saturated nitrogen heterocycle or the 4-6 membered saturated carbocycle is independently substituted by R ; R2選自-S(O)2(C1-C6烷基)、-S(O)2(CH2)q-(3-6元環烷基)、-C(O)CH2CN、-NH-S(O)2(C1-C6烷基)、-NH-S(O)2(CH2)q-(3-6元環 烷基)、-NH-C(O)CH2CN、
Figure 110145234-A0101-13-0001-125
和
Figure 110145234-A0101-13-0001-126
； R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN,
Figure 110145234-A0101-13-0001-125
and
Figure 110145234-A0101-13-0001-126
; R5選自C1-C5烷基、氰基、3-5元飽和環烷基、C1-C5烷氧基、-S-C1-C5烷基、-O-(CH2)p-(3-6元環烷基)和-S-(CH2)p-(3-6元環烷基)； R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p -(3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q、p分別獨立選自0、1、2和3； q, p are independently selected from 0, 1, 2 and 3; 條件是，當X2為N時，R2不為-C(O)CH2CN；當X2為N，且兩個R0取代於相鄰碳原子之上時，兩個R0互相連接形成4~6元飽和碳環； The condition is that when X 2 is N, R 2 is not -C(O)CH 2 CN; when X 2 is N, and two R 0 are substituted on adjacent carbon atoms, the two R 0 are connected to each other A 4-6 membered saturated carbocyclic ring is formed; 優選地，所述4~6元飽和氮雜環、4~6元飽和碳環選自如下基 團中的一種，環原子中有1或2個碳原子為與基團
Figure 110145234-A0101-13-0002-131
所共有的 碳原子： Preferably, the 4-6 membered saturated nitrogen heterocyclic ring and the 4-6 membered saturated carbocyclic ring are selected from one of the following groups, and 1 or 2 carbon atoms in the ring atoms are associated with the group
Figure 110145234-A0101-13-0002-131
Shared carbon atoms:
Figure 110145234-A0101-13-0002-492
Figure 110145234-A0101-13-0002-492
 進一步優選地，所述化合物具有如下式(I-1)或所述結構特徵： Further preferably, the compound has the following formula (I-1) or the structural features:
Figure 110145234-A0101-13-0002-493
Figure 110145234-A0101-13-0002-493
 優選地，R2選自
Figure 110145234-A0101-13-0002-129
； Preferably, R 2 is selected from
Figure 110145234-A0101-13-0002-129
; 其中，R5選自-S-(3-5元環烷基)、C1-C3烷氧基和-S-C1-C3烷基； wherein, R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl; 優選地，R1選自C1-C2烷基； Preferably, R 1 is selected from C1-C2 alkyl; 優選地，X1選自CH； Preferably, X 1 is selected from CH; 進一步優選地，所述化合物具有如下式(I-2)所述結構特徵： Further preferably, the compound has the structural features described in the following formula (I-2):
Figure 110145234-A0101-13-0003-494
Figure 110145234-A0101-13-0003-494
 優選地，X2為N； Preferably, X 2 is N; R2選自-S(O)2(C1-C3烷基)、-S(O)2CH2-(3-4元環烷基)和
Figure 110145234-A0101-13-0003-133
；其中，R5選自-S-(3-5元環烷基)、C1-C3烷氧基和 -S-C1-C3烷基； R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl) and
Figure 110145234-A0101-13-0003-133
; wherein, R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl; 優選地，X2為CR4； Preferably, X 2 is CR 4 ; R2選自-S(O)2(C1-C3烷基)、-S(O)2CH2-(3-4元環烷基)、 -C(O)CH2CN和
Figure 110145234-A0101-13-0003-134
；R5選自C1-C3烷氧基； R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl), -C(O)CH 2 CN and
Figure 110145234-A0101-13-0003-134
; R 5 is selected from C 1 -C 3 alkoxy; 優選地，X1選自CH； Preferably, X 1 is selected from CH; 進一步優選地，所述化合物具有如下式(I-3)所述結構特徵： Further preferably, the compound has the structural features described in the following formula (I-3):
Figure 110145234-A0101-13-0003-495
Figure 110145234-A0101-13-0003-495
 優選地，X2為N； Preferably, X 2 is N; R2選自
Figure 110145234-A0101-13-0003-136
； R 2 is selected from
Figure 110145234-A0101-13-0003-136
; 其中，R5選自C1-C3烷氧基和-S-C1-C3烷基； wherein, R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl; 優選地，R1選自CH3； Preferably, R 1 is selected from CH 3 ; 優選地，X1選自CH； Preferably, X 1 is selected from CH; 進一步優選地，所述化合物具有如下式(I-4)所述結構特徵： Further preferably, the compound has the structural features described in the following formula (I-4):
Figure 110145234-A0101-13-0004-498
Figure 110145234-A0101-13-0004-498
 優選地，X2為N； Preferably, X 2 is N; R2選自-S(O)2(C1-C3烷基)和如下基團： R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl) and the following groups:
Figure 110145234-A0101-13-0004-137
；其中，R5選自C1-C3烷氧基和-S-C1-C3烷基；
Figure 110145234-A0101-13-0004-137
; wherein, R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl; 優選地，R1選自CH3； Preferably, R 1 is selected from CH 3 ; 優選地，X1選自CH； Preferably, X 1 is selected from CH; 進一步優選地，所述化合物具有如下式(I-5)所述結構特徵： Further preferably, the compound has the structural features described in the following formula (I-5):
Figure 110145234-A0101-13-0004-497
Figure 110145234-A0101-13-0004-497
 X4選自CH或N； X 4 is selected from CH or N; 環A表示所述5~6元飽和或不飽和環； Ring A represents the 5-6 membered saturated or unsaturated ring; 優選地，環A選自如下基團之一： Preferably, ring A is selected from one of the following groups:
Figure 110145234-A0101-13-0004-496
Figure 110145234-A0101-13-0004-496
 其中，X5、X7、X9、X10分別獨立地選自NR6、CHR6和C(R6)2； wherein, X 5 , X 7 , X 9 , and X 10 are independently selected from NR 6 , CHR 6 and C(R 6 ) 2 ; X6、X8、X11分別獨立地選自N和CR6； X 6 , X 8 , X 11 are each independently selected from N and CR 6 ; 優選地，R6選自-H、-OH、C1-C3烷基和C1-C3烷基羥基； Preferably, R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkyl hydroxyl; 優選地，R2選自如下基團： Preferably, R 2 is selected from the following groups:
Figure 110145234-A0101-13-0005-499
Figure 110145234-A0101-13-0005-499
 R5選自C1-C3烷氧基和-S-C1-C3烷基； R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl; 優選地，X1選自CH； Preferably, X 1 is selected from CH; 優選地： Preferably: X4為N； X 4 is N; 環A為
Figure 110145234-A0101-13-0005-142
或
Figure 110145234-A0101-13-0005-143
； Ring A is
Figure 110145234-A0101-13-0005-142
or
Figure 110145234-A0101-13-0005-143
; R2為
Figure 110145234-A0101-13-0005-144
； R2 is
Figure 110145234-A0101-13-0005-144
; R5選自C1-C3烷氧基和-S-C1-C3烷基； R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl; X5各自獨立地為NR6或CHR6； X5 is each independently NR6 or CHR6 ; X6各自獨立地為N或CR6； X 6 is each independently N or CR 6 ; R6選自-H、-OH、C1-C3烷基和C1-C3烷基羥基； R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkyl hydroxyl; 優選地： Preferably: X4為N； X 4 is N; 環A
Figure 110145234-A0101-13-0005-145
； Ring A
Figure 110145234-A0101-13-0005-145
; R2為
Figure 110145234-A0101-13-0005-146
； R2 is
Figure 110145234-A0101-13-0005-146
; R5為C1-C3烷氧基； R 5 is C 1 -C 3 alkoxy; X6之一為N，另一個為CR6； One of X 6 is N and the other is CR 6 ; R6為C1-C3烷基。 R 6 is C 1 -C 3 alkyl. 一種氮雜並環化合物，具有通式(a)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： An azacyclic compound, a compound having the structure represented by general formula (a) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, Prodrugs:
Figure 110145234-A0101-13-0006-147
Figure 110145234-A0101-13-0006-147
 其中： in: L為NRc或鍵； L is NR c or bond; Y1選自CH或N； Y 1 is selected from CH or N; Y2選自CH或N； Y 2 is selected from CH or N; Y3選自CH或N； Y 3 is selected from CH or N; Ra選自-C(O)R7、-C(O)NR8R9、-S(O)2R10和-S(O)2NR10R11； R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ; Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ; Rc為H或C1-6烷基； R c is H or C 1-6 alkyl; R7為含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基， 其任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R9選自-H、C1-6烷基和鹵代C1-6烷基； R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; R10選自C1-6烷基、6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ; R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; R’和R”各自獨立地選自-H、C1-6烷基和鹵代C1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3。 n2 is 1, 2 or 3. 一種氮雜並環化合物，具有通式(b)、(b-1)或(b-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： An azacyclic compound, a compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite , pharmaceutically acceptable salts, polymorphs, prodrugs:
Figure 110145234-A0101-13-0008-148
Figure 110145234-A0101-13-0008-148
 其中： in: Y1選自CH和N，其中當Y1為CH時，其取代有Rb； Y 1 is selected from CH and N, wherein when Y 1 is CH, it is substituted with R b ; Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ; Ra選自-C(O)R7、-C(O)NR8R9、-S(O)2R10和-S(O)2NR10R11； R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ; R7為含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基，其任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S 的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently 5-8 membered heterocyclic group of heteroatoms selected from N, O and S; each of said aryl, cycloalkyl, heteroaryl and heterocyclic groups is optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R9選自-H、C1-6烷基和鹵代C1-6烷基； R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; R10選自C1-6烷基、6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ; R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中： Preferably, wherein: Y1為N； Y 1 is N; Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ; R9為-H； R 9 is -H; R8選自6-10元芳基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、雜芳基和雜環基各自任選經1-3個獨立 選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 heteroatoms independently selected from N, O and S 5-8 membered heterocyclyl of heteroatoms; each of said aryl, heteroaryl and heterocyclyl is optionally substituted with 1-3 substituents independently selected from: -H, -ORx , -SRx , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中： Preferably, wherein: Y1為N； Y 1 is N; Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ; R9為-H； R 9 is -H; R8選自苯基和含有1-3個獨立選自N、O和S的雜原子的5-6元雜芳基；所述苯基和雜芳基各自任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx和-CN； R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x and -CN; Rx選自C1-6烷基和鹵代C1-6烷基； R x is selected from C 1-6 alkyl and halogenated C 1-6 alkyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中： Preferably, wherein: Y1為N； Y 1 is N; Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ; R9為-H； R 9 is -H; R8為含有1-3個獨立選自N和S的雜原子的5-6元雜芳基；所述雜芳基任選經1-2個獨立選自以下的取代基取代：-ORx和-SRx； R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-2 substituents independently selected from: -OR x and -SR x ; Rx為C1-4烷基； R x is C 1-4 alkyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中： Preferably, wherein: Y1為N； Y 1 is N; Ra選自-C(O)NR8R9； R a is selected from -C(O)NR 8 R 9 ; R9為-H； R 9 is -H; R8為含有3個獨立選自N和S的雜原子的5元雜芳基；所述雜芳基經獨立選自以下的取代基取代：-ORx和-SRx； R 8 is a 5-membered heteroaryl containing 3 heteroatoms independently selected from N and S; the heteroaryl is substituted with substituents independently selected from: -ORx and -SRx ; Rx為C1-4烷基，優選為甲基或乙基； R x is C 1-4 alkyl, preferably methyl or ethyl; m1為0； m1 is 0; m2為3； m2 is 3; n1為2； n1 is 2; n2為1。 n2 is 1. 一種氮雜並環化合物，具有通式(c)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥： An azacyclic compound, a compound having the structure represented by the general formula (c) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, Prodrugs:
Figure 110145234-A0101-13-0012-149
Figure 110145234-A0101-13-0012-149
 其中： in: Ra選自-C(O)R7、-C(O)NR8R9、-S(O)2R10和-S(O)2NR10R11； R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ; Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ; R7為含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基，其任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R9選自-H、C1-6烷基和鹵代C1-6烷基； R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; R10選自C1-6烷基、6-10元芳基、5-8元環烷基、含有1-3個 獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ; R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; R’和R”各自獨立地選自-H、C1-6烷基和鹵代C1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中： Preferably, wherein: Ra選自-S(O)2R10和-S(O)2NR10R11； Ra is selected from -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ; Rb選自-CN、鹵素、-ORx和-SRx； R b is selected from -CN, halogen, -OR x and -SR x ; R10選自C1-6烷基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基；所述雜芳基任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 10 is selected from C 1-6 alkyl and 5-8-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; the heteroaryl is optionally selected from 1-3 independently Substituted from the following substituents: -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; R11選自-H、C1-6烷基和鹵代C1-6烷基； R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基和鹵代C1-6烷基； R x is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中： Preferably, wherein: Ra選自-S(O)2R10； Ra is selected from -S(O) 2 R 10 ; Rb為-CN； R b is -CN; R10為C1-6烷基； R 10 is C 1-6 alkyl; m1為0、1、2或3； m1 is 0, 1, 2 or 3; m2為0、1、2或3； m2 is 0, 1, 2 or 3; n1為1、2或3； n1 is 1, 2 or 3; n2為1、2或3； n2 is 1, 2 or 3; 優選地，其中：Ra為-S(O)2R10； Preferably, wherein: R a is -S(O) 2 R 10 ; Rb為-CN； R b is -CN; R10為C1-4烷基，優選為丙基； R 10 is C 1-4 alkyl, preferably propyl; m1為0； m1 is 0; m2為2； m2 is 2; n1為2； n1 is 2; n2為1。 n2 is 1. 一種氮雜並環化合物，具有通式(d)、(d-1)或(d-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥， An azacyclic compound, a compound having the structure represented by general formula (d), (d-1) or (d-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite , pharmaceutically acceptable salts, polymorphs, prodrugs,
Figure 110145234-A0101-13-0015-150
Figure 110145234-A0101-13-0015-150
 其中： in: Y1選自CH和N； Y 1 is selected from CH and N; R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; Rb選自-H、-CN、鹵素、C1-6烷基、鹵代C1-6烷基、-NR’R”、-ORx和-SRx； R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ; Rc選自-H、C1-6烷基和鹵代C1-6烷基； R c is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rd選自-H、C1-6烷基和鹵代C1-6烷基； R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Re選自-H、C1-6烷基和鹵代C1-6烷基； R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; R’和R”各自獨立地選自-H、C1-6烷基和鹵代C1-6烷基； R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; p1為0、1或2； p1 is 0, 1 or 2; p2為0、1或2； p2 is 0, 1 or 2; q1為0、1或2； q1 is 0, 1 or 2; q2為0、1或2。 q2 is 0, 1 or 2. 一種氮雜並環化合物，具有通式(e)、(e-1)或(e-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥， An azacyclic compound, a compound having the structure represented by general formula (e), (e-1) or (e-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite , pharmaceutically acceptable salts, polymorphs, prodrugs,
Figure 110145234-A0101-13-0016-151
Figure 110145234-A0101-13-0016-151
 其中： in: R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取 代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; Rc選自-H、C1-6烷基和鹵代C1-6烷基； R c is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rd選自-H、C1-6烷基和鹵代C1-6烷基； R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Re選自-H、C1-6烷基和鹵代C1-6烷基； R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; p1為0、1或2； p1 is 0, 1 or 2; p2為0、1或2； p2 is 0, 1 or 2; q1為0、1或2； q1 is 0, 1 or 2; q2為0、1或2； q2 is 0, 1 or 2; 優選地，其中： Preferably, wherein: R8選自苯基和含有1-3個獨立選自N、O和S的雜原子的5-6元雜芳基；所述苯基和雜芳基各自任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx、-CN和鹵素； R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x , -CN and halogen; Rc選自-H和C1-6烷基； R c is selected from -H and C 1-6 alkyl; Rd選自-H和C1-6烷基； R d is selected from -H and C 1-6 alkyl; Re選自-H和C1-6烷基； R e is selected from -H and C 1-6 alkyl; Rx選自-H、C1-6烷基和鹵代C1-6烷基； R x is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; p1為0、1或2； p1 is 0, 1 or 2; p2為0、1或2； p2 is 0, 1 or 2; q1為0、1或2； q1 is 0, 1 or 2; q2為0、1或2； q2 is 0, 1 or 2; 優選地，其中： Preferably, wherein: R8為含有1-3個獨立選自N和S的雜原子的5-6元雜芳基；所述雜芳基任選經1-3個獨立選自以下的取代基取代：-ORx和-SRx； R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-3 substituents independently selected from: -OR x and -SR x ; Rc選自-H和C1-4烷基； R c is selected from -H and C 1-4 alkyl; Rd選自-H和C1-4烷基； R d is selected from -H and C 1-4 alkyl; Re選自-H和C1-4烷基； R e is selected from -H and C 1-4 alkyl; Rx為C1-4烷基； R x is C 1-4 alkyl; p1為1或2； p1 is 1 or 2; p2為1或2； p2 is 1 or 2; q1為1或2； q1 is 1 or 2; q2為1或2； q2 is 1 or 2; 優選地，其中： Preferably, wherein: R8為含有3個獨立選自N和S的雜原子的5元雜芳基；所述雜芳基經-ORx取代； R 8 is a 5-membered heteroaryl group containing 3 heteroatoms independently selected from N and S; the heteroaryl group is substituted with -OR x ; Rc為C1-4烷基，優選為甲基； R c is C 1-4 alkyl, preferably methyl; Rd為-H； R d is -H; Re為-H； Re is -H; Rx為C1-4烷基，優選為甲基； R x is C 1-4 alkyl, preferably methyl; p1為1； p1 is 1; p2為1； p2 is 1; q1為1； q1 is 1; q2為1。 q2 is 1. 一種氮雜並環化合物，具有通式(f)、(f-1)或(f-2)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥， An azacyclic compound, a compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite , pharmaceutically acceptable salts, polymorphs, prodrugs,
Figure 110145234-A0101-13-0019-152
Figure 110145234-A0101-13-0019-152
 R8選自6-10元芳基、5-8元環烷基、含有1-3個獨立選自N、O和S的雜原子的5-8元雜芳基和含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述芳基、環烷基、雜芳基和雜環基各自任選經1-3個獨立選自以下的取代基取代：-H、-ORx、-SRx、-CN、鹵素、C1-6烷基和鹵代C1-6烷基； R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; Rc和Rf與它們所連接的原子一起形成含有1-2個獨立選自N、O和S的雜原子的5-8元雜芳基或含有1-3個獨立選自N、O和S的雜原子的5-8元雜環基；所述雜芳基或雜環基經獨立選自 以下的取代基取代：-H、氧代、-ORx、-SRx、-CN、鹵素、C1-6烷基、鹵代C1-6烷基和羥基取代的C1-6烷基； Rc and Rf together with the atoms to which they are attached form a 5-8 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S or 1-3 heteroatoms independently selected from N, O and A 5-8 membered heterocyclyl of a heteroatom of S; the heteroaryl or heterocyclyl is substituted with a substituent independently selected from the group consisting of: -H, oxo, -ORx , -SRx , -CN, halogen , C 1-6 alkyl, halogenated C 1-6 alkyl and hydroxy substituted C 1-6 alkyl; Rd選自-H、C1-6烷基和鹵代C1-6烷基； R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Re選自-H、C1-6烷基和鹵代C1-6烷基； R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl; Rx選自-H、C1-6烷基、鹵代C1-6烷基、C2-6烯基和-C2-6炔基； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl; p1為0、1或2； p1 is 0, 1 or 2; p2為0、1或2； p2 is 0, 1 or 2; q1為0、1或2； q1 is 0, 1 or 2; q2為0、1或2； q2 is 0, 1 or 2; 優選地，其中： Preferably, wherein: R8選自苯基和含有1-3個獨立選自N、O和S的雜原子的5-6元雜芳基；所述苯基和雜芳基各自任選經1-3個獨立選自以下的取代基取代：-ORx、-SRx、-CN和鹵素； R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x , -CN and halogen; Rc和Rf與它們所連接的原子一起形成含有1-2個獨立選自N、O和S的雜原子的5-6元雜芳基；所述雜芳基經1-2個獨立選自以下的取代基取代：-ORx、-SRx、C1-4烷基和羥基取代的C1-4烷基； Rc and Rf , taken together with the atoms to which they are attached, form a 5-6 membered heteroaryl group containing 1-2 heteroatoms independently selected from N, O, and S; the heteroaryl group is independently selected from 1-2 Substituted from the following substituents: -OR x , -SR x , C 1-4 alkyl and hydroxy substituted C 1-4 alkyl; Rd選自-H和C1-4烷基； R d is selected from -H and C 1-4 alkyl; Re選自-H和C1-4烷基； R e is selected from -H and C 1-4 alkyl; Rx選自-H、C1-4烷基和鹵代C1-4烷基； R x is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl; p1為0、1或2； p1 is 0, 1 or 2; p2為0、1或2； p2 is 0, 1 or 2; q1為0、1或2； q1 is 0, 1 or 2; q2為0、1或2； q2 is 0, 1 or 2; 優選地，其中： Preferably, wherein: R8為含有1-3個獨立選自N和S的雜原子的5-6元雜芳基；所述雜芳基任選經1-3個-ORx取代； R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-3 -OR x ; Rc和Rf與它們所連接的原子一起形成含有2個N原子的5-6元雜芳基；所述雜芳基經1-2個選自-H、C1-4烷基和羥基取代的C1-4烷基的取代基取代； R c and R f taken together with the atoms to which they are attached form a 5-6 membered heteroaryl group containing 2 N atoms; the heteroaryl group is selected from -H, C 1-4 alkyl and hydroxy through 1-2 Substituent substitution of substituted C 1-4 alkyl; Rd為-H； R d is -H; Re為-H； Re is -H; Rx為C1-4烷基； R x is C 1-4 alkyl; p1為1； p1 is 1; p2為1； p2 is 1; q1為1； q1 is 1; q2為1； q2 is 1; 優選地，其中： Preferably, wherein: R8為含有3個獨立選自N和S的雜原子的5元雜芳基；所述雜芳基經-ORx取代； R 8 is a 5-membered heteroaryl group containing 3 heteroatoms independently selected from N and S; the heteroaryl group is substituted with -OR x ; Rc和Rf與它們所連接的原子一起形成含有2個N原子的5元雜芳基；所述雜芳基經C1-4烷基優選甲基取代； R c and R f together with the atoms to which they are attached form a 5-membered heteroaryl group containing 2 N atoms; the heteroaryl group is substituted with C 1-4 alkyl, preferably methyl; Rd為-H； R d is -H; Re為-H； Re is -H; Rx為C1-4烷基，優選為甲基； R x is C 1-4 alkyl, preferably methyl; p1為1； p1 is 1; p2為1； p2 is 1; q1為1； q1 is 1; q2為1。 q2 is 1. 如請求項1所述的氮雜並環化合物，其特徵在於，所述氮雜並環化合物選自如下化合物中的一種： The aza-heterocyclic compound according to claim 1, wherein the aza-heterocyclic compound is selected from one of the following compounds:
Figure 110145234-A0101-13-0022-154
Figure 110145234-A0101-13-0022-154
Figure 110145234-A0101-13-0023-501
Figure 110145234-A0101-13-0023-501
 一種氮雜並環化合物的製備方法，所述氮雜並環化合物具有通式(I)所示結構的化合物或者其立體異構體、N-氧化物、水合物、溶劑化物、代謝產物、藥學上可以接受的鹽、多晶型、前藥，其特徵在於，所述製備方法包括如下步驟： A kind of preparation method of aza-heterocyclic compound, described aza-heterocyclic compound has the compound of the structure represented by general formula (I) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmacy The acceptable salt, polymorphic form and prodrug above, characterized in that the preparation method comprises the steps:
Figure 110145234-A0101-13-0023-156
中間體1
Figure 110145234-A0101-13-0023-156
Intermediate 1
Figure 110145234-A0101-13-0023-157
中間體2
Figure 110145234-A0101-13-0023-157
Intermediate 2
Figure 110145234-A0101-13-0023-158
Figure 110145234-A0101-13-0023-158
 中間體1與中間體2進行取代反應，製備式(I)化合物； Intermediate 1 and Intermediate 2 are subjected to substitution reaction to prepare the compound of formula (I); 式(I)化合物與包含R2的化合物進行取代或縮合反應； A compound of formula (I) is subjected to a substitution or condensation reaction with a compound comprising R 2 ; 作為選擇，L0中的R1可以與X2中的R4一起形成5~6元不飽和環；所述5~6元不飽和環被R6取代； Alternatively, R 1 in L 0 can form a 5-6 membered unsaturated ring together with R 4 in X 2 ; the 5-6 membered unsaturated ring is substituted by R 6 ; 其中包含R2的化合物選自如下化合物中的一種： The compound wherein R is selected from one of the following compounds: R2-X、R2-H、
Figure 110145234-A0101-13-0024-159
和
Figure 110145234-A0101-13-0024-160
； R 2 -X, R 2 -H,
Figure 110145234-A0101-13-0024-159
and
Figure 110145234-A0101-13-0024-160
; X表示鹵素，L0、R1、R0、R2、R6、X1、X2、R4、X3、n和m的定義同請求項1~8中任一項所述。 X represents halogen, and the definitions of L 0 , R 1 , R 0 , R 2 , R 6 , X 1 , X 2 , R 4 , X 3 , n and m are as described in any one of claims 1 to 8. 一種藥物組成物，其特徵在於，所述藥物組成物包含請求項1~8任一項所述的氮雜並環化合物。 A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the azacyclic compound according to any one of claims 1 to 8. 一種如請求項1~8任一項所述的氮雜並環化合物在製備具有酪氨酸激酶JAK抑制活性之藥物的用途。 A use of the aza-heterocyclic compound according to any one of claims 1 to 8 in the preparation of a medicament with tyrosine kinase JAK inhibitory activity. 一種如請求項1~8任一項所述的氮雜並環化合物在製備具有預防或治療自身免疫性疾病、皮膚病、變應性疾病、器官排斥、癌症、乾眼病、骨髓纖維化、紅細胞增多症的功效之藥物的用途； An aza-heterocyclic compound as described in any one of claims 1 to 8 is prepared to prevent or treat autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, red blood cells Use of drugs that increase the efficacy of the disorder; 優選地，所述自身免疫性疾病為狼瘡、多發性硬化、類風濕性關節炎、青少年關節炎、銀屑病、潰瘍性結腸炎、克羅恩氏病或自體免疫性甲狀腺疾病；所述皮膚病為牛皮癬、皮疹或特應性皮炎；所述變應性病症為哮喘或鼻炎病；所述器官移植排斥為異體抑制排斥或移植物抗宿主疾病；所述癌症為腎癌、肝癌、胰腺癌、胃癌、乳腺癌、***癌、頭頸部癌、甲狀腺癌、肺癌、膠質母細胞瘤、黑素瘤、淋巴瘤、白血病。 Preferably, the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease or autoimmune thyroid disease; the The skin disease is psoriasis, rash or atopic dermatitis; the allergic condition is asthma or rhinitis; the organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease; the cancer is kidney cancer, liver cancer, pancreas Cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, leukemia. 如請求項1-8中任一項所述的氮雜並環化合物或如請求項10所述的藥物組成物，其用於抑制酪氨酸激酶JAK。 The azacyclic compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10, for inhibiting the tyrosine kinase JAK. 如請求項1-8中任一項所述的氮雜並環化合物或如請求項10所述的藥物組成物，其用於預防或治療選自以下的疾病：自身免疫性疾病、皮膚病、變應性疾病、器官排斥、癌症、乾眼病、骨髓纖維化和紅細胞增多症。 The azacyclic compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10, which is used for the prevention or treatment of diseases selected from the group consisting of autoimmune diseases, skin diseases, Allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis and polycythemia. 如請求項14所述的氮雜並環化合物或如請求項14所述的組成物，其中所述自身免疫性疾病為狼瘡、多發性硬化、類風濕性關節炎、青少年關節炎、銀屑病、潰瘍性結腸炎、克羅恩氏病或自體免疫性甲狀腺疾病；所述皮膚病為牛皮癬、皮疹或特應性皮炎；所述變應性病症為哮喘或鼻炎病；所述器官移植排斥為異體抑制排斥或移植物抗宿主疾病；所述癌症為腎癌、肝癌、胰腺癌、胃癌、乳腺癌、***癌、頭頸部癌、甲狀腺癌、肺癌、膠質母細胞瘤、黑素瘤、淋巴瘤或白血病。 The azacyclic compound of claim 14 or the composition of claim 14, wherein the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis , ulcerative colitis, Crohn's disease or autoimmune thyroid disease; the skin disease is psoriasis, rash or atopic dermatitis; the allergic disease is asthma or rhinitis; the organ transplant rejection For allogeneic suppression rejection or graft versus host disease; the cancer is kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma tumor or leukemia. 一種抑制酪氨酸激酶JAK的方法，其包括給予如請求項1~8中任一項所述的氮雜並環化合物或如請求項10所述的藥物組成物。 A method for inhibiting tyrosine kinase JAK, comprising administering the azacyclic compound as claimed in any one of claims 1 to 8 or the pharmaceutical composition as claimed in claim 10.
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