TW202239758A - Tyk2 inhibitors and use thereof - Google Patents

Abstract

The invention belongs to the field of medicine, in particular to a macrocyclic TYK2 inhibitor compound, pharmaceutically acceptable salt, ester, isomer, isotopic label, and use in treatment of TYK2-mediated disease thereof.

Description

TYK2 inhibitors and uses thereof

The invention belongs to the field of medicine, and specifically relates to a macrocyclic TYK2 inhibitor compound, its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, its composition, use and treatment method.

Janus kinase (JAK kinase for short) is a non-receptor tyrosine protein kinase that plays a pivotal role in signal transduction mediated by many cytokine receptors and participates in the proliferation, differentiation and apoptosis of various types of cells in organisms , angiogenesis and immune regulation and other important physiological processes.

The JAKs family has four different subtypes in mammals, namely JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase2). JAK1, JAK2 and TYK2 are expressed in various tissue cells of the human body, and JAK-3 is mainly expressed in various in hematopoietic cells. The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway is the most important pathway mediated by JAKs in vivo, which consists of ligands (such as cytokines), transmembrane receptors, JAK kinases and transcription factors STAT consists of four parts. JAK is a non-receptor tyrosine kinase that activates receptor-coupled JAKs when extracellular ligands, including specific growth factors, growth hormones, chemokines, and cytokines, bind to cytokine receptors on the surface, It has tyrosine kinase activity and binds in pairs, the dimeric JAK can undergo spontaneous phosphorylation, bind to STAT protein, and the activated STAT protein detaches from the receptor and forms a phosphorylated dimer, which is transferred to the nucleus , combined with specific DNA sequences to exert physiological functions and regulate the transcription of target genes. Type I and II cytokines bind their receptors to subsequent intracellular signaling through the JAK kinase and signal transducer and activator of transcription (JAK–STAT) pathway.

As a subtype of the JAK family, TYK2 mainly mediates the functions of cytokines such as IFN-α, IL-6, IL-10, IL-12 and IL-23. TYK2-deficient mice are resistant to collagen-induced arthritis, colitis, psoriasis, and experimental allergic encephalomyelitis, suggesting that TYK2-mediated signaling plays a role in autoimmune and inflammatory-related diseases. important role. Genome-wide association studies show that TYK2 variants are associated with autoimmune disorders such as Crohn's disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis, further demonstrating the importance of TYK2 in autoimmune and inflammation-related diseases . Studies have shown that TYK2 selective inhibitors can inhibit the signal transduction cascade of IL-12, IL-23 and type I interferon receptors, including systemic lupus erythematosus, inflammatory bowel disease, psoriasis, A variety of autoimmunity and inflammation-related animal models including rheumatoid arthritis play a therapeutic role, and TYK2 selective inhibitors are currently undergoing Phase II or III clinical trials for systemic lupus erythematosus, Crohn's disease and psoriasis indications However, there is no TYK2 selective inhibitor on the market.

Therefore, it is still an urgent problem to be solved in this field to develop new selective TYK2 inhibitor compounds, enrich the types of clinical drugs, and improve the availability of drugs.

The problem to be solved by the present invention is to provide a macrocyclic compound with a good inhibitory effect on the TYK2 signaling pathway and a novel structure. The inhibitory effect on JAK1, JAK2 and/or JAK3 signaling pathways has stronger selectivity; further, the present invention provides a TYK2 inhibitor compound with high selectivity, better bioavailability, better drug efficacy and low toxicity .

或其藥學可接受的鹽、其酯、其異構體、其同位素標記物，其中， X選自CH、N； R ¹選自氫、C _1-6烷基、氘代C _1-6烷基、環烷基； R ⁸選自氫、C _1-6烷基、C _1-6烷氧基； 或R ¹與R ⁸相連，和與其連接的氮原子一起形成雜環； X ¹、X ²分別獨立地選自CH ₂、NH、O； 環C選自芳基、雜芳基、環烷基、雜環基； R獨立地選自R ²或R ³； n選自0、1、2、3； R ²選自氫、-OH、C _1-6烷基、氘代C _1-6烷基、C _1-6烷氧基、氘代C _1-6烷氧基、C _1-6烷基-C(O)-、C _1-6烷基-S-、C _1-6烷基-S(O)-、C _1-6烷基-S(O) ₂-； R ³選自氫、C _1-6烷氧基-C(O)-、(R ⁵)(R ⁶)N-C(O)-，或者任選被一個或多個R ^a取代的如下基團：苯基、雜芳基、雜環基、環烷基； R ^a選自氫、鹵素、-CN、羧基、(R ⁵)(R ⁶)N-C(O)-、C _1-6烷基、C _1-6烷基-C(O)-、C _1-6烷基-C(O)-NH-、鹵代C _1-6烷基、鹵代C _1-6烷氧基、羥基C _1-6烷基、C _1-6烷氧基、環烷基、環烷基-(CH ₂)p-O-、NC-環烷基，或者任意相鄰兩個R ^a相連並與其所連接的原子共同形成雜環；p選自0、1、2、3； L ¹選自任選被一個或多個R ^b取代的C _1-8亞烷基，所述C _1-8亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S、-S(O)-、-S(O) _2-和/或-O-取代； R ^b選自C _1-6烷基、或兩個位於同一碳原子上的R ^b和與其連接的碳原子一起形成環烷基、雜環基； 或者，L ¹選自

，其中環A端與式（II’）的X ²相連，L ²端與環C相連； 環A選自芳基、雜芳基； L ²選自任選被一個或多個R ^c取代的C _1-6亞烷基，所述C _1-6亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S-、-S(O)-、-S(O) ₂-和/或-O-取代；R ^c選自C _1-6烷基、或兩個位於同一碳原子上的R ^c和與其相連的碳原子一起形成環烷基、雜環基； R ⁴選自氫、鹵素、C _1-6烷基、鹵代C _1-6烷基、苯基、環烷基，所述的苯基任選被一個或多個選自鹵素、C _1-6烷基、C _1-6烷氧基或鹵代C _1-6烷基的基團所取代； m選自0、1、2、3； R ⁵、R ⁶分別獨立的選自氫、-OH、C _1-6烷基、環烷基，或R ⁵、R ⁶相連，和與其相連的氮原子一起形成雜環； R ⁷選自氫、C _1-6烷基、C _1-6烷氧基、C _1-6烷基-C(O)-、-C(O)OCH ₂Ph。 The technical scheme of the present invention is as follows: In the first aspect, the present invention provides the compound represented by the following general formula (II'),

Or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-6 alkyl, deuterated C _1-6 alkane Base, cycloalkyl; R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy; or R ¹ is connected to R ⁸ , and forms a heterocyclic ring with the nitrogen atom connected to it; X ¹ , X ² are independently selected from CH ₂ , NH, O; Ring C is selected from aryl, heteroaryl, cycloalkyl, heterocyclic; R is independently selected from R ² or R ³ ; n is selected from 0, 1, 2,3; R ² is selected from hydrogen, -OH, C _1-6 alkyl, deuterated C _1-6 alkyl, C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _{1-6 6} Alkyl-C(O)-, C _1-6 Alkyl-S-, C _1-6 Alkyl-S(O)-, C _1-6 Alkyl-S(O) ₂ -; R ³ optional from hydrogen, C _1-6 alkoxy-C(O)-, (R ⁵ )(R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, Heteroaryl, heterocyclyl, cycloalkyl; R ^a is selected from hydrogen, halogen, -CN, carboxyl, (R ⁵ )(R ⁶ )NC(O)-, C _1-6 alkyl, C _1-6 Alkyl-C(O)-, C _1-6 alkyl-C(O)-NH-, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl , C _1-6 alkoxy, cycloalkyl, cycloalkyl-(CH ₂ )pO-, NC-cycloalkyl, or any two adjacent R ^a are linked together to form a heterocyclic ring with the atoms to which they are attached; p is selected from 0, ¹ , 2, 3; L is selected from C _1-8 alkylene optionally substituted by one or more R ^b , one or more CH in the C _1-8 alkylene ₂ is optionally substituted by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/or -O-; R ^b is selected from C _1-6 alkane group, or two R ^b located on the same carbon atom and the carbon atom connected to it together form a cycloalkyl group, ^a heterocyclic group; or, L is selected from

, wherein the end of ring A is connected to X ² of formula (II'), and the end of L ² is connected to ring C; Ring A is selected from aryl and heteroaryl; L ² is selected from the group optionally substituted by one or more R ^c C _1-6 alkylene, one or more CH ₂ in the C _1-6 alkylene is optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O)- , -S(O) ₂ - and/or -O-substituted; R ^c is selected from C _1-6 alkyl, or two R ^c located on the same carbon atom and the carbon atom connected to it together form a cycloalkyl group, Heterocyclyl; R ⁴ is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, phenyl, cycloalkyl, and the phenyl is optionally selected from one or more halogen , C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl; m is selected from 0, 1, 2, 3; R ⁵ and R ⁶ are independently selected From hydrogen, -OH, C _1-6 alkyl, cycloalkyl, or R ⁵ , R ⁶ are connected, and form a heterocyclic ring together with the nitrogen atom connected to it; R ⁷ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-C(O)-, -C(O)OCH ₂ Ph.

或其藥學可接受的鹽、其酯、其異構體、其同位素標記物，其中， X選自CH、N； R ¹選自氫、C _1-6烷基、氘代C _1-6烷基、環烷基； R ⁸選自氫、C _1-6烷基、C _1-6烷氧基； 或R ¹與R ⁸相連，和與其連接的氮原子一起形成3-8元雜環； R ²選自氫、-OH、C _1-6烷基、氘代C _1-6烷基、C _1-6烷氧基、氘代C _1-6烷氧基、C _1-6烷基-C(O)-、C _1-6烷基-S-、C _1-6烷基-S(O)-、C _1-6烷基-S(O) ₂-； R ³選自氫、C _1-6烷氧基-C(O)-、(R ⁵)(R ⁶)N-C(O)-，或者任選被一個或多個R ^a取代的如下基團：苯基、雜芳基、雜環基、環烷基； R ^a選自氫、鹵素、-CN、羧基、(R ⁵)(R ⁶)N-C(O)-、C _1-6烷基、C _1-6烷基-C(O)-、C _1-6烷基-C(O)-NH-、鹵代C _1-6烷基、鹵代C _1-6烷氧基、羥基C _1-6烷基、C _1-6烷氧基、3-8元環烷基、3-8元環烷基-O-、3-8元環烷基-C _1-6烷氧基、NC-3-8元環烷基，或者任意相鄰兩個R ^a相連並與其所連接的原子共同形成3-8元雜環； p選自0、1、2、3； L ¹選自任選被一個或多個R ^b取代的C _1-8亞烷基，所述C _1-8亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S、-S(O)-、-S(O) _2-和/或-O-取代；R ^b選自C _1-4烷基、或兩個位於同一碳原子上的R ^b和與其連接的碳原子一起形成3-5元環烷基； 或者，L ¹選自

，其中環A端與式（I’）的NH相連，L ²端與苯環相連； 環A選自苯基、雜芳基； L ²選自任選被一個或多個R ^c取代的C _1-6亞烷基，所述C _1-6亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S-、-S(O)-、-S(O) ₂-和/或-O-取代；R ^c選自C _1-6烷基、或兩個位於同一碳原子上的R ^c和與其連接的碳原子一起形成3-8元環烷基； R ⁴選自氫、鹵素、C _1-6烷基、鹵代C _1-6烷基、苯基、3-8元環烷基，所述的苯基任選被一個或多個選自鹵素、C _1-6烷基、C _1-6烷氧基或鹵代C _1-6烷基的基團取代； m選自0、1、2、3； R ⁵、R ⁶分別獨立的選自氫、-OH、C _1-6烷基、3-8元環烷基，或R ⁵、R ⁶相連，和與其連接的氮原子一起形成3-8元雜環； R ⁷選自氫、C _1-6烷基、C _1-6烷氧基、C _1-6烷基-C(O)-、-C(O)OCH ₂Ph。 In a preferred version of the formula (II'), it has the structure shown in the following formula (I'),

Or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-6 alkyl, deuterated C _1-6 alkane Base, cycloalkyl; R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy; or R ¹ is connected to R ⁸ , and forms a 3-8 membered heterocyclic ring together with the nitrogen atom connected to it; R ² is selected from hydrogen, -OH, C _1-6 alkyl, deuterated C _1-6 alkyl, C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 alkyl- C(O)-, C _1-6 alkyl-S-, C _1-6 alkyl-S(O)-, C _1-6 alkyl-S(O) _2- ; R ³ is selected from hydrogen, C _1-6 alkoxy-C(O)-, (R ⁵ )(R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, heteroaryl, Heterocyclyl, cycloalkyl; R ^a is selected from hydrogen, halogen, -CN, carboxyl, (R ⁵ )(R ⁶ )NC(O)-, C _1-6 alkyl, C _1-6 alkyl-C (O)-, C _1-6 alkyl-C(O)-NH-, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _{1- 6} -alkoxy, 3-8-membered cycloalkyl, 3-8-membered cycloalkyl-O-, 3-8-membered cycloalkyl-C _1-6 alkoxy, NC-3-8-membered cycloalkyl, Or any adjacent two R ^a are connected and jointly form a 3-8 membered heterocyclic ring with the atoms connected thereto; p is selected from 0, ¹ , 2, 3; L is selected from the group optionally substituted by one or more R ^b C _1-8 alkylene, one or more CH ₂ in the C _1-8 alkylene is optionally replaced by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/or -O-substituted; R ^b is selected from C _1-4 alkyl, or two R ^b on the same carbon atom and the carbon atom connected to it together form a 3-5 membered ring Alkyl ^; Alternatively, L is selected from

, wherein the ring A end is connected to the NH of formula (I'), and the L ² end is connected to the benzene ring; Ring A is selected from phenyl, heteroaryl; L ² is selected from C optionally substituted by one or more R ^c _1-6 alkylene, one or more CH ₂ in the C _1-6 alkylene is optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O)-, -S(O) ₂ - and/or -O-substituted; R ^c is selected from C _1-6 alkyl, or two R ^c on the same carbon atom and the carbon atom connected to it together form a 3-8 membered ring Alkyl; R ⁴ is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, phenyl, 3-8 membered cycloalkyl, and the phenyl is optionally replaced by one or more Substituted by a group selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl; m is selected from 0, 1, 2, 3; R ⁵ , R ⁶ are independent is selected from hydrogen, -OH, C _1-6 alkyl, 3-8 membered cycloalkyl, or R ⁵ , R ⁶ are connected, and form a 3-8 membered heterocyclic ring together with the nitrogen atom connected to it; R ⁷ is selected from Hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-C(O)-, -C(O)OCH ₂ Ph.

，其中環A端與式（I’）的NH相連，L ²端與苯環相連； 環A選自苯基、雜芳基； L ²選自任選被一個或多個R ^c取代的C _1-6亞烷基，所述C _1-6亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S-、-S(O)-、-S(O) ₂-和/或-O-取代； R ^c選自C _1-6烷基、或兩個位於同一碳原子上的R ^c和與其連接的碳原子一起形成3-8元環烷基； R ⁴選自氫、鹵素、C _1-6烷基、鹵代C _1-6烷基、苯基、3-8元環烷基，所述的苯基任選被一個或多個選自鹵素、C _1-6烷基、C _1-6烷氧基或鹵代C _1-6烷基的基團所取代； m選自0、1、2、3； R ⁵、R ⁶分別獨立的選自氫、C _1-6烷基； R ⁷選自氫、C _1-6烷基、C _1-6烷氧基、C _1-6烷基-C(O)-、-C(O)OCH ₂Ph； R ⁸選自氫、C _1-6烷基、C _1-6烷氧基。 In a preferred version of formula (II') or (I'), wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-6 alkyl, deuterated C _1-6 alkyl, cycloalkane R ² is selected from hydrogen, -OH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-C (O)-, C _1-6 alkyl-S-, C _1-6 alkyl-S(O)-, C _1-6 alkyl-S(O) ₂ -; R ³ is selected from hydrogen, C _1-6 alkoxy-C(O)-, (R ⁵ ) (R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, heteroaryl; R ^a is selected from hydrogen, halogen, (R ⁵ )(R ⁶ )NC (O)-, C _1-6 alkyl, halogenated C _{1-6 alkyl} , C _1-6 alkoxy; L is selected from C ^1-8 alkylene ^optionally substituted by one or more R group, one or more CH ₂ in the C _1-8 alkylene group is optionally replaced by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _{2 -} and/or -O-substituted; R ^b is selected from C _1-4 alkyl, or two R ^b on the same carbon atom and the carbon atom connected to it together form a 3-5 membered cycloalkyl group; or, L ¹ from

, wherein the ring A end is connected to the NH of formula (I'), and the L ² end is connected to the benzene ring; Ring A is selected from phenyl, heteroaryl; L ² is selected from C optionally substituted by one or more R ^c _1-6 alkylene, one or more CH ₂ in the C _1-6 alkylene is optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O)-, -S(O) ₂ - and/or -O-substituted; R ^c is selected from C _1-6 alkyl, or two R ^c on the same carbon atom and the carbon atom connected to it together form a 3-8 membered ring Alkyl; R ⁴ is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, phenyl, 3-8 membered cycloalkyl, and the phenyl is optionally replaced by one or more Replaced by a group selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl; m is selected from 0, 1, 2, 3; R ⁵ and R ⁶ are respectively Independently selected from hydrogen, C _1-6 alkyl; R selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl ^- C (O)-, -C ( O) OCH ₂ Ph; R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy.

X選自CH、N； R ¹選自氫、C _1-4烷基、氘代C _1-4烷基、3-6元環烷基； R ²選自氫、-OH、C _1-4烷基、氘代C _1-4烷基、C _1-4烷氧基、C _1-4烷基-C(O)-、C _1-4烷基-S-、C _1-4烷基-S(O)-、C _1-4烷基-S(O) ₂-； R ³選自氫、C _1-4烷氧基-C(O)-、(R ⁵)(R ⁶)N-C(O)-，或者任選被一個或多個R ^a取代的如下基團：苯基、5-6元雜芳基、5-6元雜環基； R ^a選自氫、鹵素、-CN、羧基、(R ⁵)(R ⁶)N-C(O)-、C _1-4烷基、C _1-4烷基-C(O)-、C _1-4烷基-C(O)-NH-、C _1-4烷氧基、鹵代C _1-4烷基、鹵代C _1-4烷氧基、羥基C _1-4烷基、3-6元環烷基、3-6元環烷基-O-、3-6元環烷基-C _1-4烷氧基、NC-3-6元環烷基，或者任意相鄰兩個R ^a相連並與其所連接的原子共同形成3-6元雜環； L ¹選自任選被一個或多個R ^b取代的C _1-8亞烷基，所述C _1-8亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S、-S(O)-、-S(O) _2-和/或-O-取代； R ^b選自C _1-4烷基、或兩個位於同一碳原子上的R ^b和與其連接的碳原子一起形成3-5元環烷基； 或者，L ¹選自

，其中環A端與式（I）的NH端相連，L ²端與苯環相連； 環A選自苯基、5-6雜芳基、或8-10元稠環雜芳基； L ²選自C _1-6亞烷基，所述C _1-6亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ⁷-、-S-、-S(O)-、-S(O) ₂-和/或-O-取代； R ⁴選自氫、鹵素、C _1-4烷基、鹵代C _1-4烷基、苯基、3-6元環烷基，所述的苯基任選被一個或多個選自鹵素、C _1-4烷基、或鹵代C _1-4烷基的基團取代； m選自0、1、2、3； R ⁵、R ⁶分別獨立的選自氫、C _1-4烷基、3-6元環烷基，或R ⁵、R ⁶相連，和與其相連的氮原子一起形成3-6元雜環； R ⁷選自氫、C _1-4烷基、C _1-4烷基-C(O)-、-C(O)OCH ₂Ph。 In a preferred embodiment of formula (II') or (I'), it has the structure shown in the following formula (I),

X is selected from CH, N; R ¹ is selected from hydrogen, C _1-4 alkyl, deuterated C _1-4 alkyl, 3-6 membered cycloalkyl; R ² is selected from hydrogen, -OH, C _1-4 Alkyl, deuterated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S-, C _1-4 alkyl- S(O)-, C _1-4 alkyl-S(O) ₂ -; R ³ is selected from hydrogen, C _1-4 alkoxy-C(O)-, (R ⁵ )(R ⁶ )NC( O)-, or the following group optionally substituted by one or more R ^a : phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group; R ^a is selected from hydrogen, halogen, -CN, Carboxyl, (R ⁵ )(R ⁶ )NC(O)-, C _1-4 Alkyl, C _1-4 Alkyl-C(O)-, C _1-4 Alkyl-C(O)-NH- , C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, hydroxy C _1-4 alkyl, 3-6-membered cycloalkyl, 3-6-membered cycloalkane Group-O-, 3-6 membered cycloalkyl-C _1-4 alkoxyl group, NC-3-6 membered cycloalkyl group, or any adjacent two R ^a are connected and form a 3- 6-membered heterocyclic ring; L ¹ is selected from C _1-8 alkylene optionally substituted by one or more R ^b , and one or more CH ₂ in the C _1-8 alkylene are optionally replaced by -C (O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/or -O-substituted; R ^b is selected from C _1-4 alkyl, or two R ^b on the same carbon atom and the carbon atom attached to it together form ^a 3-5 membered cycloalkyl group; or, L is selected from

, wherein the ring A end is connected to the NH end of formula (I), and the L ² end is connected to the benzene ring; Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl; L ² selected from C _1-6 alkylene groups, one or more CH ₂ in the C _1-6 alkylene groups are optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O )-, -S(O) ₂ - and/or -O-substituted; R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, phenyl, 3-6 membered ring Alkyl, the phenyl is optionally substituted by one or more groups selected from halogen, C _1-4 alkyl, or halogenated C _1-4 alkyl; m is selected from 0, 1, 2, 3 ; R ⁵ , R ⁶ are independently selected from hydrogen, C _1-4 alkyl, 3-6 membered cycloalkyl, or R ⁵ , R ⁶ are connected, and form a 3-6 membered heterocyclic ring together with the nitrogen atom connected to it ; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O)-, -C(O)OCH ₂ Ph.

，其中環A端與式（I）的NH端相連，L ²端與苯環相連； 環A選自苯基、5-6雜芳基、或8-10元稠環雜芳基； L ²選自C _1-6亞烷基，所述C _1-6亞烷基中的一個或多個CH ₂任選被-C(O)-、-NR ^7-、-S-、-S(O)-、-S(O) ₂-和/或-O-取代； R ⁴選自氫、鹵素、C _1-4烷基、鹵代C _1-4烷基、苯基、3-6元環烷基，所述的苯基任選被一個或多個選自鹵素、C _1-4烷基、或鹵代C _1-4烷基的基團所取代； m選自0、1、2、3； R ⁵、R ⁶分別獨立的選自氫、C _1-4烷基； R ⁷選自氫、C _1-4烷基、C _1-4烷基-C(O)-、-C(O)OCH ₂Ph。 In a preferred embodiment of (II'), formula (I') or formula (I), wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-4 alkyl, deuterated C _{1- 4} alkyl, 3-6 membered cycloalkyl; R ² is selected from hydrogen, -OH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) _2- ; R ³ is selected from hydrogen, C _1-4 alkoxy- C(O)-, (R ⁵ )(R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, 5-6 membered heteroaryl; R ^a is selected From hydrogen, halogen, (R ⁵ )(R ⁶ )NC(O)-, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl; L ¹ is selected from One or more C _1-8 alkylene groups substituted by R ^b , one or more CH ₂ in the C _1-8 alkylene groups are optionally replaced by -C(O)-, -NR ^7- , -S , -S(O)-, -S(O) ₂ - and/or -O-substituted; R ^b is selected from C _1-4 alkyl, or two R ^b on the same carbon atom and the carbon attached to it Atoms together form ^a 3-5 membered cycloalkyl group; alternatively, L is selected from

, wherein the ring A end is connected to the NH end of formula (I), and the L ² end is connected to the benzene ring; Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl; L ² selected from C _1-6 alkylene groups, one or more CH ₂ in the C _1-6 alkylene groups are optionally replaced by -C(O)-, -NR ^7- , -S-, -S(O )-, -S(O) ₂ - and/or -O-substituted; R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, phenyl, 3-6 membered ring Alkyl, the phenyl is optionally substituted by one or more groups selected from halogen, C _1-4 alkyl, or halogenated C _1-4 alkyl; m is selected from 0, 1, 2, 3; R ⁵ and R ⁶ are independently selected from hydrogen, C _1-4 alkyl; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O)-, -C( O) OCH ₂ Ph.

In a preferred embodiment of (II'), formula (I') or formula (I), X is selected from N.

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), R ¹ is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CD ₃ ,

.

； R ⁸選自H； 或者R ¹與R ⁸相連，和與其連接的氮原子一起形成

、

、

。 在式（II’）、式（I’）或式（I）的一優選實施方案中，其中，R ¹選自H、-CH ₃、-CD ₃、

。 In a preferred embodiment of (II'), formula (I') or formula (I), R ¹ is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CD ₃ ,

; R ⁸ is selected from H; or R ¹ is connected to R ⁸ , and the nitrogen atom connected to it forms together

,

,

. In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ¹ is selected from H, -CH ₃ , -CD ₃ ,

.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ¹ is selected from -CH ₃ or -CD ₃ .

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ¹ is selected from -CH ₃ or -CD ₃ ; R ⁸ is selected from H.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ² is selected from -OH, -OCH ₃ , -C(O)CH ₃ , -SCH ₃ , - S(O) _CH3 , -S(O _{) 2CH3} .

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ² is selected from -OH, -OCH ₃ .

、

； R ^a選自H、F、-CN、-COOH、-CH ₃、-CH ₂CH ₃、-CH ₂F、-CHF ₂、-CF ₃、-OCH ₃、-OCH ₂CH ₃、-O-CH(CH ₃) ₂、-CF ₂CH ₃、-C(O)CH ₃、-OCHF ₂、-C(O)-N(CH ₃) ₂、-C(O)-NHCH ₃、-NHC(O)CH ₃、-C(O)-NH ₂、

、

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、

，或者相鄰兩個R ^a相連並與其所連接的原子共同形成四氫呋喃、四氫吡咯。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from hydrogen, -C(O)-OCH ₃ , -C(O)-NH ₂ , -C(O)-N(CH ₃ ) ₂ , or the following groups optionally substituted by 1-2 R ^a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2, 4-Triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidinyl, pyridyl, pyridyl,

,

_; ^_ _{_ _ _ _ _ _ _ _} -CH(CH ₃ ) ₂ , -CF ₂ CH ₃ , -C(O)CH ₃ , -OCHF ₂ , -C(O)-N(CH ₃ ) ₂ , -C(O)-NHCH ₃ , -NHC (O)CH ₃ , -C(O)-NH ₂ ,

,

,

,

,

,

,

,

,

,

,

, or two adjacent R ^a are connected to form tetrahydrofuran or tetrahydropyrrole together with the atoms connected to them.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from hydrogen, -C(O)-OCH ₃ , -C(O)-NH ₂ , -C(O)-N(CH ₃ ) ₂ , or selected from the following groups optionally substituted by 1-2 R ^a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1, 2,4-triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidinyl, pyridyl, pyridyl; R ^a is selected from hydrogen, F, -CH ₃ , -CH ₂ CH ₃ , - _CH2F , -CHF2, _-CF3 , _-OCH3 , -C(O)-N( _{CH3 )2 .}

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from hydrogen, -C(O)-OCH ₃ , -C(O)-NH ₂ , Or be selected from the following groups optionally substituted by 1-2 R ^a : pyrazolyl, imidazolyl, 1,2,4-triazolyl, phenyl, pyridyl, pyrimidinyl; R ^a is selected from hydrogen, F, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ .

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from the following groups optionally substituted by 1-2 R ^a : pyrazolyl, pyrimidine Base, pyridyl; R ^a is selected from hydrogen, F, -CH ₃ , -OCH ₃ , -O-CH(CH ₃ ) ₂ .

、

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、

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from the following groups: hydrogen, -C(O)-OCH ₃ , -C(O) -NH ₂ , -C(O)-N(CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

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、

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、

、

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、

、

、

、

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from the following groups: hydrogen, -C(O)-OCH ₃ , -C(O) -NH ₂ , -C(O)-N(CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

、

、

、

、

、

、

、

、

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ³ is selected from the following groups: hydrogen, -C(O)-OCH ₃ , -C(O) -NH ₂ ,

,

,

,

,

,

,

,

,

,

,

.

、

、

、

、

、

、

、

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), R ³ is selected from the following groups:

,

,

,

,

,

,

,

,

,

.

、

、

、

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), R ³ is selected from the following groups:

,

,

,

,

,

.

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), ^R is selected from

,

,

.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ¹ is selected from C _6-7 linear alkylene optionally substituted by 1-2 R ^b , 1-3 CH ₂ in the C _6-7 linear alkylene group are optionally substituted by -C(O)-, -NH- and/or -O-; R ^b is selected from -CH ₃ , or Two R ^b located on the same carbon atom together with the carbon atom to which it is attached form a cyclopropyl group.

、

、

，“a”表示通過此端與X ²或NH相連。 In a preferred embodiment of formula (II'), formula (I') or formula ( ^I ), L is selected from

,

,

, "a" indicates that it is connected to ^X2 or NH through this end.

時，環A選自苯基、吡啶基、嘧啶基、吡𠯤基、嗒𠯤基、吡咯基、吡唑基、咪唑基、㗁唑基、噻唑基、

； R ⁴選自氫、氟、-CH ₃、-CF ₃、

、

、

； m選自0、1或2。 In a preferred version of formula (II'), formula (I') or formula (I), wherein, when L ¹ is selected from

When, ring A is selected from phenyl, pyridyl, pyrimidyl, pyridyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,

; R ⁴ is selected from hydrogen, fluorine, -CH ₃ , -CF ₃ ,

,

,

m is selected from 0, 1 or 2.

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, ring A is selected from phenyl, pyridyl, pyrazolyl, imidazolyl, thiazolyl,

.

、

；m選自0、1或2。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, R ⁴ is selected from hydrogen, fluorine, -CH ₃ ,

,

; m is selected from 0, 1 or 2.

時，其中，環A選自吡啶基；R ⁴選自-CH ₃；m選自0或1。 In a preferred embodiment of formula (II'), formula (I') or formula ( ^I ), when L is selected from

, wherein, ring A is selected from pyridyl; R ⁴ is selected from -CH ₃ ; m is selected from 0 or 1.

、

、

、

、

、

、

、

、

、

，“a”表示通過此端與X ²或NH相連。 In a preferred embodiment of formula (II'), formula (I') or formula (I), ring A is selected from

,

,

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end.

、

、

、

、

、

、

，“a”表示通過此端與X ²或NH相連。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, ring A is selected from

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end.

，“a”表示通過此端與X ²或NH相連。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein ring A is selected from

, "a" indicates that it is connected to ^X2 or NH through this end.

選自

、

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，“a”表示通過此端與X ²或NH相連。 In a preferred version of formula (II'), formula (I') or formula (I), wherein, the structural unit

selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end.

選自

、

、

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、

、

、

、

、

、

，“a”表示通過此端與X ²或NH相連。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, the structural unit

selected from

,

,

,

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end.

選自

、

、

、

、

、

、

、

，“a”表示通過此端與X ²或NH相連。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, the structural unit

selected from

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end.

選自

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, the structural unit

selected from

,

.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ² is selected from C _3-6 linear alkylene groups optionally substituted by 1-2 R ^c , 1-2 CH ₂ in the C _3-6 linear alkylene group are optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O) ₂ - and/or -O - Substitution; R ^c is selected from -CH ₃ , -CH ₂ CH ₃ , or two R ^c located on the same carbon atom are connected to each other, and the carbon atoms connected to it form a cyclopropyl group; R ⁷ is selected from hydrogen, - _CH3 , -CH2CH3, -C(O) _CH3 , _-C (O _{) OCH2Ph} .

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ² is selected from C _3-6 straight chain alkylene, said C _3-6 straight chain alkylene 1-2 CH ₂ in the group are optionally substituted by -C(O)-, -NR ⁷ -, -S-, -S(O) ₂ - and/or -O-; R ⁷ is selected from hydrogen, - _CH3 , _-C (O)OCH2Ph.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ² is selected from C _3-4 straight chain alkylene, said C _3-4 straight chain alkylene 1-2 CH ₂ in the group are optionally substituted by -NR ⁷ -, -S-, -S(O) ₂ - and/or -O-; R ⁷ is selected from hydrogen, -CH ₃ .

，q ₁、q ₂分別獨立的為0、1、2、3、4；Y為-O-、-S-、-NR ⁷-、-NR ⁷-C(O)-、-C(R ⁷) ₂-、-O-C(O)-、-S(O)-、-S(O) ₂-；R ⁷選自氫、C _1-4烷基、C _1-4烷基-C(O)-、-C(O)OCH ₂Ph，優選地，R ⁷選自氫、C _1-4烷基。 In a preferred embodiment of formula (II'), formula (I') or formula (I), L ² is

, q ₁ , q ₂ are independently 0, 1, 2, 3, 4; Y is -O-, -S-, -NR ⁷ -, -NR ⁷ -C(O)-, -C(R ⁷ ) ₂ -, -OC(O)-, -S(O)-, -S(O) ₂ -; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O) -, -C(O)OCH ₂ Ph, preferably, R ⁷ is selected from hydrogen, C _1-4 alkyl.

，q ₁、q ₂分別獨立的為0、1、2、3、4；Y為-O-、-S-、-NR ⁷-、-NR ⁷-C(O)-、-C(R ⁷) ₂-、-O-C(O)-、-S(O)-、-S(O) ₂-；R ⁷選自氫、-CH ₃、-CH ₂CH ₃、-C(O)CH ₃、-C(O)OCH ₂Ph。 In a preferred embodiment of formula (II'), formula (I') or formula (I), L ² is

, q ₁ , q ₂ are independently 0, 1, 2, 3, 4; Y is -O-, -S-, -NR ⁷ -, -NR ⁷ -C(O)-, -C(R ⁷ ) ₂ -, -OC(O)-, -S(O)-, -S(O) ₂ -; R ⁷ is selected from hydrogen, -CH ₃ , -CH ₂ CH ₃ , -C(O)CH ₃ , _-C (O)OCH2Ph.

，q ₁、q ₂分別獨立的為0、1、2、3、4；Y為-O-、-S-、-NR ⁷-、-NR ⁷-C(O)-、-C(R ⁷) ₂-、-O-C(O)-、-S(O)-、-S(O) ₂-；R ⁷選自氫、-CH ₃、-C(O)OCH ₂Ph。 In a preferred embodiment of formula (II'), formula (I') or formula (I), L ² is

, q ₁ , q ₂ are independently 0, 1, 2, 3, 4; Y is -O-, -S-, -NR ⁷ -, -NR ⁷ -C(O)-, -C(R ⁷ ) ₂ -, -OC(O)-, -S(O)-, -S(O) ₂ -; R ⁷ is selected from hydrogen, -CH ₃ , -C(O)OCH ₂ Ph.

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein Y is -O-, -S-, -NH-.

In a preferred embodiment of formula (II'), formula (I') or formula (I), the sum of q ₁ and q ₂ is 2-5; preferably 3 or 4.

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、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ² is selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

、

、

、

、

、

、

、

、

、

、

、

。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ² is selected from

,

,

,

,

,

,

,

,

,

,

,

.

、

，“b”表示通過此端與環A相連。 In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, L ² is selected from

,

, "b" indicates that it is connected to ring A through this end.

其中，R ¹、R ²、R ³、R ^a、R ⁴、L ²、環A、m可選自本發明任一方案的定義。 In a preferred embodiment of formula (II'), formula (I') or formula (I), the present invention further provides compounds represented by the following general formula, their pharmaceutically acceptable salts, their esters, and their isomers , its isotopic label:

Wherein, R ¹ , R ² , R ³ , R ^a , R ⁴ , L ² , ring A, and m can be selected from the definitions of any scheme of the present invention.

Any substituent in the technical solution described in the present invention and any optional group thereof can be combined with each other to form a new complete technical solution, and the new technical solution formed has the same or similar technology as the solution recorded in the present invention. Effects are all included within the scope of the present invention.

In a preferred embodiment of formula (II'), formula (I') or formula (I), the compound of the present invention, or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, Compounds selected from the following:

According to the second aspect of the present invention, there is also provided a pharmaceutical preparation composition, which contains the compound described in any scheme of the first aspect of the present invention, its pharmaceutically acceptable salt, its ester, its isomer, its isotope label substance, and one or more pharmaceutically acceptable excipients. The pharmaceutical preparation can be in any pharmaceutically acceptable dosage form.

According to the present invention, a pharmaceutically acceptable excipient is a substance which is non-toxic, compatible with the active ingredient and otherwise biologically suitable for the organism. The choice of a particular excipient will depend on the mode of administration or the type and state of the disease being used to treat the particular patient. Examples of pharmaceutically acceptable excipients include, but are not limited to: conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricating agents in the pharmaceutical field Agents, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants, etc. Flavoring agents, preservatives and sweeteners, etc. can also be added to the pharmaceutical composition when necessary.

In certain embodiments, the pharmaceutical formulation composition described above may be administered orally, parenterally, rectally, or pulmonary to a patient or subject in need of such treatment. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. For parenteral administration, the above pharmaceutical preparations can also be made into injections, including injections, sterile powders for injections and concentrated solutions for injections. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, no additives can be added, or appropriate additives can be added according to the properties of the medicine. For rectal administration, the pharmaceutical composition can be made into suppositories and the like. For pulmonary administration, the pharmaceutical composition can be made into inhalation preparations, aerosols, powder mists or sprays and the like.

According to the third aspect of the present invention, there is also provided a pharmaceutical composition, which contains the compound described in any scheme of the first aspect of the present invention, its pharmaceutically acceptable salt, its ester, its isomer, its isotope label , and one or more second therapeutically active agents, the second therapeutically active agents may be selected from immunosuppressants, such as hormone drugs, such as corticosteroids; selected from cytokine inhibitors; selected from kinase inhibitors; selected from Nuclear translocation inhibitors; selected from non-steroidal anti-inflammatory drugs, such as ibuprofen; selected from antiviral agents, such as abacavir; selected from antiproliferative agents; selected from antimalarial drugs; selected from TNF-alpha inhibitors agent etc.

According to the fourth aspect of the present invention, there is also provided the use of the compound described in any scheme in the first aspect of the present invention, its pharmaceutically acceptable salt, its ester, its isomer, and its isotope label in the preparation of medicine , the drug is used to prevent and/or treat TYK2-mediated diseases in patients or subjects; preferably, the TYK2-mediated diseases include autoimmune diseases, transplant-related diseases, inflammation Sexual or inflammatory disease.

In another embodiment, the TYK2-mediated related disease is mediated by IL-12, IL-23 and/or IFNα signaling pathway.

In another embodiment, the autoimmune disease is selected from the group consisting of type 1 diabetes, Gray's disease, rheumatoid arthritis, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, discoid lupus erythematosus, lupus Nephritis, multiple sclerosis, systemic sclerosis, Sjogren's syndrome, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

In another embodiment, the inflammatory or inflammatory disease is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease, Cryopyrin-related Periodic Syndrome (CAPS), Tumor Necrosis Factor Receptor-Associated Periodic Fever Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Adult Still's Syndrome, Systemic Juvenile Idiopathic Arthritis, Gout, Gouty Joints inflammation, osteoarthritis.

According to the fifth aspect of the present invention, the present invention also provides a method for treating related diseases mediated by TYK2, comprising administering to patients or subjects an effective amount of the compound described in any scheme of the first aspect of the present invention, its Pharmaceutically acceptable salts, their esters, their isomers, and their isotope labels.

In another embodiment, the present invention also provides a method for treating related diseases mediated by IL-12, IL-23 and/or IFNα, comprising administering to patients or subjects an effective amount of the first aspect of the present invention The compound described in any scheme, its pharmaceutically acceptable salt, its ester, its isomer, its isotope label.

In another embodiment, the present invention also provides a method for treating autoimmune diseases, comprising administering to patients or subjects an effective amount of the compound described in any scheme of the first aspect of the present invention, or its pharmaceutically acceptable Salts, esters, isomers, and isotope labels.

According to the sixth aspect of the present invention, the present invention provides the compound described in any scheme in the first aspect, its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, which can be used for the treatment of TYK2-mediated related diseases.

Description and Definition

In the present invention, unless otherwise specified, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art to which the present invention belongs, but for a better understanding of the present invention, some terms are provided below Definition. When the definitions of the terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art to which the present invention belongs, the definitions and explanations of the terms provided in the present invention shall prevail.

The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and with a reasonable benefit/risk ratio Comparable to those compounds, materials, compositions and/or dosage forms.

The "pharmaceutically acceptable salt" in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO ₃ H, etc.) present in the compound and an appropriate inorganic or organic cation (base), including Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as _-NH2 , etc.) present in compounds with suitable inorganic or organic anions (acids) , including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).

The "ester" in the present invention refers to the product formed by dehydration of acid and alcohol; when there is a -COOH group in the structure of the compound of the present invention, it can be dehydrated with a pharmaceutically acceptable alcohol compound to form an ester; when the present invention There is -OH in the compound structure, which can be dehydrated with a pharmaceutically acceptable organic acid or inorganic acid compound to form an ester. The ester compound can produce the active compound of the present invention through metabolism or hydrolysis in an organism, and the ester can have similar biological activity to the free body or have no or weak biological activity in vitro.

The "isomers" mentioned in the present invention include geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, tautomers, and racemates thereof spin mixtures and other mixtures, all such mixtures are within the scope of the present invention. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to one of the functional isomers having different points of attachment of hydrogens by shifting one or more double bonds, for example, a ketone and its enol form are keto-enol tautomerisms Construct. The term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and which are in a non-mirror-image relationship. The term "cis-trans isomers" refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms in the molecule cannot freely rotate.

The terms "therapeutically effective amount" and "effective amount" refer to an amount sufficient to produce a beneficial or desired effect when administered to a subject compound or composition or dosage form of the present invention; said effect may be the prevention of autoimmune symptoms Produce, and/or inhibit, reduce the development and spread of autoimmune symptoms, and/or improve clinical symptoms or indicators associated with autoimmune diseases. It should be recognized, however, that the total daily dosage of the compounds of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; the patient. age, weight, general health, sex, and diet; the timing of administration, route of administration, and rate of excretion of the specific compound employed; duration of treatment; drugs used in combination or concomitantly with the specific compound employed; Similar factors are known in the art. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.

The term "optionally substituted" in the present invention refers to two situations in which one or more hydrogen atoms of the substituent group can be "substituted" or "unsubstituted" by one or more substituents.

In the present invention, when any variable (substituent R) appears more than once in the composition or structure of the compound, its definition in each case is independent, and the substituents may be the same or different; generally, the variable Can be selected from the same or different substituent groups of the same technical scheme; for example, when m in general formula (I) is ² , ring ^A is substituted by two R4 groups, wherein the definition of each R4 is independent of each other ; For example, said R ³ is substituted by one or more R ^a , wherein each R ^a is also independent of each other. Also, preferably, combinations of substituents and/or variables are present only if such combinations result in stable compounds.

表示取代基R ⁴可以在苯環上的任意一個位置發生取代。 When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring. For example, the structural unit

Indicates that the substituent R ⁴ can be substituted at any position on the benzene ring.

When a substituent is listed without indicating through which atom the substituent is attached to a given group or to a given formula, then the substituent may be attached through any of its bondable atoms.

；當兩個R ^a是雜環基或環烷基的取代基時，結構類型如

、

、

。 In the present invention, for the expression "any adjacent two R ^a are connected and together form a heterocyclic ring with the atoms they are connected to", wherein "any adjacent" means that two R ^a are respectively connected at the ortho position of the substituent on the atom. For example, when two R ^a are substituents of aromatic groups (such as phenyl, heteroaryl), the structure type is as

; When two R ^a are substituents of heterocyclyl or cycloalkyl, the structure type is as

,

,

.

Where nitrogen atoms are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent to obtain other compounds of the invention. Therefore, unless otherwise indicated, all shown and claimed groups containing nitrogen atoms are to be understood as covering both non-nitroxyl groups and their nitrogen oxide groups (N→O).

表示該原子為鍵合原子，例如，

表示嘧啶環上的C原子為鍵合原子。 When the substituent structure appears

Indicates that the atom is a bonded atom, for example,

Indicates that the C atom on the pyrimidine ring is a bonding atom.

The appearance of a dash "-" in a substituent structure indicates the point of attachment for the substituent, eg _-SCH3 is attached through a sulfur atom.

The "halogen" in the present invention refers to fluorine atom, chlorine atom, bromine atom or iodine atom.

"Alkyl" in the present invention refers to a branched or straight-chain saturated aliphatic alkane with specified number of carbon atoms minus one hydrogen-derived group. For example, "C _1-10 alkyl" refers to C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ alkyl, including "C _1-6 Alkyl", "C _1-4 alkyl", "C _1-3 alkyl"; specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, second butyl, 2- Methylbutyl, 1,1-dimethylbutyl, etc.

The "alkylene" in the present invention refers to a branched or straight-chain saturated aliphatic alkane with the specified number of carbon atoms minus two hydrogen-derived groups. For example, "C _1-10 alkylene" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , and C ₁₀ alkylene, including "C _1-8 Alkylene", "C _1-6 alkylene", "C _1-4 alkylene", "C _3-4 alkylene", "C _6-8 alkylene", "C _6-7 Alkylene", "C _1-6 alkylene"; preferably, the "alkylene" in the present invention is "straight-chain alkylene"; specific examples include but are not limited to: -CH ₂ -, - CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ -, -CH (CH ₂ CH ₃ )CH ₂ -, -C(CH ₃ )(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -, etc.

The "haloalkyl" in the present invention refers to the group obtained by replacing the hydrogen in the alkyl group with one or more halogens, such as "fluoromethyl" including monofluoromethyl, difluoromethyl, trifluoromethyl ; Preferably, the "halogenated alkyl" in the present invention is "halogenated C _1-6 alkyl", "halogenated C _1-4 alkyl". Alkyl is as defined above.

The "deuterated alkyl" in the present invention refers to the group obtained by replacing the hydrogen in the alkyl group with one or more deuterium (D), such as DCH ₂ -, D ₂ CH-, D ₃ C-; preferably Specifically, the "deuterated alkyl" in the present invention refers to "deuterated C _1-6 alkyl", "deuterated C _1-4 alkyl". Alkyl is as defined above.

The "hydroxyl C _1-6 alkyl" in the present invention refers to the group obtained by replacing the hydrogen in the alkyl group with one or more hydroxyl groups, such as HOCH ₂ -, HOCH ₂ -CH(OH)-, etc.; preferably Specifically, the "hydroxyl C _1-6 alkyl group" in the present invention is a hydroxyl C _1-4 alkyl group. Alkyl is as defined above.

、

、

等。環烷基如本說明書中所定義。 The "NC-cycloalkyl" in the present invention refers to the group obtained by replacing any hydrogen atom on the cycloalkyl with a cyano group, such as

,

,

Wait. Cycloalkyl is as defined in this specification.

In the "cycloalkyl-(CH ₂ )pO-" mentioned in the present invention, when p is 0, the cycloalkyl is connected with O through a chemical bond, that is, cycloalkyl-O- is formed.

The "alkoxy" in the present invention refers to the alkyl defined herein connected to other groups through an oxygen atom, ie "alkyl-O-". Including "C _1-6 alkoxy" (structure is C _1-6 alkyl-O-), "C _1-4 alkoxy", specific examples include but not limited to methoxy, ethoxy, propoxy base, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy etc.; preferably, the "alkoxy" in the present invention is C _1-4 alkoxy, more preferably C _1-3 alkoxy.

，所述化合物包括以下兩種：

和

；當L ²為

時，所述化合物包括以下兩種：

和

。 In the present invention, when L ¹ and L ² are specific "C _1-8 alkylene" or "C _1-6 alkylene", unless otherwise specified, the writing method of the specific group does not limit it to the The direction of attachment of the substituent. For example ^L1 is

, the compounds include the following two:

with

; when L ² is

, the compounds include the following two:

with

.

The "cycloalkyl" in the present invention refers to a saturated cyclic alkyl group derived from a cycloalkane by removing one hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon groups refer to two or more A polycyclic group formed by linking cyclic alkyl structures through spiro, bridge, fused, etc. The carbon atoms in the cycloalkyl group can be further oxoated, ie to form C(O). Unless otherwise specified, the "certain membered cycloalkyl group" described herein can be understood as a monocyclic cycloalkyl group, and when it is polycyclic, it will be specifically indicated as a spiro, condensed or bridged ring group. The cycloalkyl includes "3-8 membered cycloalkyl", "3-6 membered cycloalkyl", "3-5 membered cycloalkyl". Preferably, the cycloalkyl is a monocyclic, saturated structure; specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The "heterocyclic group" in the present invention refers to a saturated cyclic group derived from the substitution of ring carbon atoms in a cycloalkyl group by one or more heteroatoms, including monocyclic or polycyclic heterocyclic groups; Ring heterocyclic group refers to a polycyclic group formed by connecting a monocyclic heterocyclic group with other heterocyclic groups or cycloalkyl groups through spiro, bridge, fused, etc.; the heteroatoms are generally selected from N, O, S; the carbon atom or heteroatom in the heterocyclic group can be further oxo, that is, to form C(O), N(O), SO, SO ₂ ; preferably, the heteroatom is independently selected from 1 - 3 N's and/or O's. Unless otherwise specified, the "certain-membered heterocyclic group" described herein can be understood as a monocyclic heterocyclic group, and if it is a polyheterocyclic group, it will be specifically indicated as a spiro, condensed or bridged ring group; the heterocyclic group includes "3-8 membered heterocyclic group", "3-6 membered heterocyclic group", "3-5 membered heterocyclic group", "5-6 membered heterocyclic group". Preferably, the heterocyclic group is a monocyclic, saturated structure; specific examples include but are not limited to azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl and the like. Said "heterocycle" refers to this definition.

The "aryl" in the present invention refers to a cyclic unsaturated aromatic group formed by carbon atoms as ring atoms, which may be a single ring or multiple rings fused together. Examples of C _6-10 membered aryl groups include, but are not limited to, phenyl, naphthyl.

The "heteroaryl" mentioned in the present invention refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms in the ring, and the heteroatoms are generally selected from N, O, and S; preferably, the The heteroatoms in are independently selected from 1-3 N and/or O, in addition, the N atom and the S atom may be optionally oxidized and the N atom may be optionally quaternized. The "heteroaryl" includes "monocyclic heteroaryl" and "condensed ring heteroaryl". The fused ring heteroaryl refers to two or more ring structures sharing two adjacent ring structures. An aromatic group formed by atoms containing one or more heteroatoms. Unless otherwise specified, the "heteroaryl" described herein can generally be understood as a "monocyclic heteroaryl", such as the "5-6 membered heteroaryl" described herein, which also does not have the ability to form a fused ring heteroaryl Possibility; when it is a "fused ring heteroaryl", it will be specified as a "condensed" heteroaryl structure, such as "8-10 membered fused ring heteroaryl". The heteroaryl group described in the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5-6 membered nitrogen-containing aryl group", and the heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, For example, containing only 1, 2 or 3 nitrogen atoms, or, containing 1 nitrogen atom and other 1 or 2 heteroatoms (such as S and/or O atoms), or, containing 2 nitrogen atoms and other 1 or 2 heteroatoms. Specific examples of such heteroaryl groups include, but are not limited to: furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl , pyrazolyl, etc.

The present invention includes all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. As non-limiting general examples, isotopes of hydrogen include protium (often denoted H), deuterium (often denoted D), and tritium (often denoted T); isotopes of carbon ^include12C , ^13C , ^and14C . Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those having ordinary skill in the art to which this invention pertains, or by methods analogous to those described herein using a suitable isotopically labeled reagent in place of an otherwise employed unlabeled reagent. to prepare.

Combinations of substituents and/or variables described herein are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is one that is sufficiently stable to undergo chemical reactions, be isolated to a useful degree of purity, and be formulated as an effective therapeutic drug.

其中，X、R ¹、R ²、R ³、L ²、R ⁴、m、環A如本發明第一方面的技術方案所定義； Hal獨立為鹵素，優選為Cl、Br； P為胺基保護基團，其可以來自於酸酐化合物、醯氯化合物、鹵代物等，常見保護基團包括但不限於：第三丁氧羰基（Boc）、苄氧羰基（Cbz）、2-聯苯基-2-丙氧羰基（BPoc）、鄰苯二甲醯亞胺基（pht）、對甲苯磺醯基（Tosyl）、三苯甲基（Trityl）、甲醯基（formyl）Fmoc、Alloc、Teoc等；優選為Boc、Cbz。 According to the seventh aspect of the present invention, a method for preparing some compounds of the present invention is further provided, which includes the following steps:

Wherein, X, R ¹ , R ² , R ³ , L ² , R ⁴ , m, and ring A are as defined in the technical solution of the first aspect of the present invention; Hal is independently halogen, preferably Cl, Br; P is an amino group Protecting groups, which can come from acid anhydride compounds, acyl chloride compounds, halides, etc. Common protecting groups include but are not limited to: tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-biphenyl- 2-propoxycarbonyl (BPoc), phthalimide (pht), tosyl (Tosyl), trityl (Trityl), formyl (formyl) Fmoc, Alloc, Teoc, etc. ; preferably Boc, Cbz.

step 1:

Intermediate 3 is obtained by reacting intermediate 1 and intermediate 2 in a polar organic solvent under basic conditions.

The polar organic solvent includes, but is not limited to, one or more of the following: tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethyl ether, N-methylpyrrolidone, dimethylsulfoxide, and acetonitrile.

The basic condition can be adding a basic catalyst, and the basic catalyst includes but is not limited to one or more of the following: bis(trimethylsilyl)amide sodium, NaH, bis(trimethylsilyl) Lithium amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, second butyl lithium, third butyl lithium, third butoxide potassium, third butyl Sodium alkoxide, sodium methoxide, sodium ethoxide, methyl bromide (chloride) magnesium, ethyl bromide (chloride) magnesium, second butyl bromide (chloride) magnesium and other inorganic bases, as well as triethylamine, N,N- Diisopropylethylamine, 4-dimethylaminopyridine, DBU (1,8-diazabicycloundec-7-ene) and other organic bases.

Step 2:

Intermediate 3 was deprotected under acidic conditions to obtain intermediate 4.

The acidic condition refers to the presence of organic acid and/or inorganic acid. Among them, inorganic acid can be used, preferably hydrochloric acid; organic acid can also be used, preferably trifluoroacetic acid.

Step 3:

Intermediate 4 is reacted to obtain a product by adding a coupling catalyst and a metal chelate ligand under alkaline conditions.

Described alkaline condition can be to add alkaline catalyst, and described alkaline catalyst includes but not limited to following one or more: cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium tertiary butoxide, Sodium tert-butoxide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, triethylamine, N,N-diisopropylethylamine, DBU.

The coupling catalyst is selected from palladium catalyst, and the palladium catalyst is selected from tridibenzylidene acetone dipalladium, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2', 4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3), palladium acetate , Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl phen-2-yl)palladium(II) (XPhos Pd G3), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)( 2-Amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, bis(dibenzylidene phenylacetonate) palladium, tetrakis (triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, dichloro [1,1'-bis (ear third butylphosphine) ferrocene palladium (II), di (Tri-tert-butylphosphine)palladium, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (Pd-PEPPSI) one or more.

The metal chelating ligand is selected from 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (xantphos), 2-(dicyclohexylphosphine)-3,6-dimethyl Oxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (BrettPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 2 -(Di-tert-butylphosphine)biphenyl (JohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 2-bicyclohexylphosphine-2' ,6'-dimethoxybiphenyl (SPhos), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1 ,1'-bisphenyl (tBuBrettPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos), 2-dicyclohexylphosphine-2',4' , one or more of 6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos).

In another preferred embodiment, in the preparation method of formula (II), wherein, X is selected from CH; R ¹ is selected from C _1-4 alkyl; R ² is selected from C _1-4 alkoxy; R ³ is selected from 5-6 membered heteroaryl optionally substituted by 1-2 R ^a ; R ^a is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; ring A is selected from benzene Base, pyridyl, pyrimidinyl; R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl; m is selected from 0,1.

In another preferred embodiment, in the preparation method of formula (II), R ² is selected from -OCH ₃ ; R ³ is selected from pyrazolyl, pyrimidinyl optionally substituted by 1-2 R ^a , pyridyl; R ^a is selected from hydrogen, F, -CH ₃ , -OCH ₃ , -O-CH(CH ₃ ) ₂ . Y is -O-, -S-, -NH-; Ring A is selected from phenyl, pyridyl, pyrimidinyl; R ⁴ is selected from hydrogen, fluorine, -CH ₃ ; m is selected from 0,1.

時，中間體1結構為：

，其中Y為-O-、-S-、-NR ⁷-、-C(R ⁷) ₂-、-NR ⁷-C(O)-、-O-C(O)-、-S(O)-、-S(O) ₂-；R ⁷選自氫、C _1-4烷基、C _1-4烷基-C(O)-、-C(O)OCH ₂Ph，優選地，R ⁷選自氫、C _1-4烷基；q ₁、q ₂分別獨立的為0、1、2、3、4，優選地，q ₁、q ₂之和為2-5，優選為3或4。 ^In another preferred scheme, when the L2 structure type is:

, the structure of intermediate 1 is:

, wherein Y is -O-, -S-, -NR ⁷ -, -C(R ⁷ ) ₂ -, -NR ⁷ -C(O)-, -OC(O)-, -S(O)-, -S(O) ₂ -; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O)-, -C(O)OCH ₂ Ph, preferably, R ⁷ is selected from Hydrogen, C _1-4 alkyl; q ₁ , q ₂ are independently 0, 1, 2, 3, 4, preferably, the sum of q ₁ , q ₂ is 2-5, preferably 3 or 4.

In another preferred scheme, in intermediate 1a: R ² is selected from C _1-4 alkoxy; R ³ is selected from 5-6 membered heteroaryl optionally substituted by 1-2 R ^a ; R ^a selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; Y is -O-, -S-, -NH-; Ring A is selected from phenyl, pyridyl, pyrimidinyl; R ⁴ selected from hydrogen, halogen, C _1-4 alkyl; m selected from 0,1.

In another preferred scheme, in intermediate 1a: R ² is selected from -OCH ₃ ; R ³ is selected from pyrazolyl, pyrimidinyl, pyridyl optionally substituted by 1-2 R ^a ; R ^a is selected from Hydrogen, F, -CH ₃ , -OCH ₃ , -O-CH(CH ₃ ) ₂ . Y is -O-, -S-, -NH-; Ring A is selected from phenyl, pyridyl, pyrimidinyl; R ⁴ is selected from hydrogen, fluorine, -CH ₃ ; m is selected from 0,1.

R ²、R ³、R ⁴、m、R ^a、q ₁、q ₂、Y、P如任一前述方案所定義； In another preferred embodiment, intermediate 1a is selected from the structures shown below:

R ² , R ³ , R ⁴ , m, R ^a , q ₁ , q ₂ , Y, P are as defined in any of the preceding schemes;

Preferably, R ^a is selected from H, F, -CH ₃ , -OCH ₃ .

G ₁、G ₂分別獨立的代表鹵素、-C(O)R’、NH ₂、OH、SH；R’代表OH或鹵素； 優選地，R ²、R ³、R ⁴、m、環A、q ₁、q ₂、Y、P如任一前述方案所定義。 Intermediate 1a can be prepared by the following process:

G ₁ and G ₂ independently represent halogen, -C(O)R', NH ₂ , OH, SH; R' represents OH or halogen; preferably, R ² , R ³ , R ⁴ , m, ring A, q ₁ , q ₂ , Y, P are as defined in any of the preceding schemes.

step: Intermediate A and intermediate B undergo condensation reaction under suitable conditions to obtain intermediate C, and intermediate C is then reduced to obtain intermediate 1a.

The suitable conditions include but are not limited to: ① Adding a basic catalyst, such as NaH, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bis(trimethylsilyl)amide, bis(trimethylsilyl) ) lithium amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, second butyl lithium, third butyl lithium, third potassium butoxide, third Inorganic bases such as sodium butoxide, sodium methoxide, sodium ethoxide, methyl magnesium bromide (chloride), ethyl bromide (chloride) magnesium, second butyl bromide (chloride) magnesium and/or triethylamine, N, Organic bases such as N-diisopropylethylamine, 4-dimethylaminopyridine, DBU; ② add dehydrating agent or condensation agent or coupling agent, specifically can be selected from: T3P (propyl phosphoric anhydride), DCC ( Dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate), HBTU (O-benzotriazole-tetramethylurea hexafluorophosphate), HCTU (6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate), EDCI ((1-ethyl-3(3-dimethylpropylamine)carbodiimide )), HOBT (1-hydroxybenzotriazole), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid), TSTU (2-succinimide Amino-1,1,3,3-tetramethyluronium tetrafluoroborate), TNTU (2-(5-norbornene-2,3-dimethylimido)-1,1,3 , 3-tetramethylurea tetrafluoroborate quaternary ammonium salt) and so on.

The reduction includes: Pd/C reduction, ferric acid reduction, catalytic hydrogenation, sodium sulfide and thiosulfuric acid reduction, hydrazine hydrate Raney nickel reduction, etc.

In another preferred embodiment, in the preparation method of intermediate 1a, R ² is selected from C _1-4 alkoxy; R ³ is selected from 5-6 optionally substituted by 1-2 R ^a Yuan heteroaryl; R ^a is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; Y is -O-, -S-, -NH-; Ring A is selected from phenyl, pyridine Base, pyrimidinyl; R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl; m is selected from 0,1.

In another preferred embodiment, in the preparation method of intermediate ^1a , R ² is selected from -OCH ₃ ; R ³ is selected from pyrazolyl, pyrimidinyl, Pyridyl; R ^a is selected from hydrogen, F, -CH ₃ , -OCH ₃ , -O-CH(CH ₃ ) ₂ . Y is -O-, -S-, -NH-; Ring A is selected from phenyl, pyridyl, pyrimidinyl; R ⁴ is selected from hydrogen, fluorine, -CH ₃ ; m is selected from 0,1.

Further, intermediate 1a and intermediate 2 are further reacted to form a compound with the following structure (refer to the preparation process steps 1-3 of formula (II)):

R ¹、R ⁴、m、R ^a、q ₁、q ₂、P、Y、Hal、G1、G2、環A如前一方案所定義； 具備製備方法及條件參考中間體1a以及式（II）化合物的製備方法。 Further, the present invention provides a preparation method of formula (II-b), which includes the following reaction process:

R ¹ , R ⁴ , m, R ^a , q ₁ , q ₂ , P, Y, Hal, G1, G2, ring A are as defined in the previous scheme; with preparation methods and conditions refer to intermediate 1a and formula (II) Compound preparation methods.

In the examples of the present invention, the name of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the name of the compound and the structure of the compound, it can be determined by comprehensively related information and reaction routes; if it cannot be confirmed by other methods, the structural formula of the given compound shall prevail.

The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited therein, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be adjusted appropriately according to different reactants.

The compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art of the present invention, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the technology of the present invention There are equivalents known to those of ordinary skill in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

1. Summary of experimental equipment:

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is carried out with Varian 400M or Bruker Ascend 400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or heavy water ( D ₂ O), the internal standard was tetramethylsilane (TMS).

Agilent 1260-6120B/6125B single quadrupole mass spectrometer (the ion source is electrospray ionization) was used for the determination of liquid chromatography mass spectrometry LC-MS, and the column was Waters CORTECS column (C18, 2.7 um, 4.6*30 mm) .

The determination of HPLC uses Waters H-class UPLC and Agilent 1260 infinity II high performance liquid chromatography.

Preparative HPLC uses Waters MS-triggered prep-HPLC and Waters UV-triggered prep-HPLC (column is Welch Ultimate AQ-C18 21.2*250mm, 10 µm or Welch Xtimate C18 21.2*250mm, 10 µm) or Gilson GX-281 (column For Welch Ultimate AQ-C18 30*250mm, 10 µm or Welch Xtimate C18 30*250mm, 10 µm )

Waters UPCC was used for chiral HPLC determination; chromatographic columns were Daicel chiralpak AD-3 (3 um, 3*150 mm), Daicel chiralpak AS-3 (3 um, 4.6*150 mm), Daicel chiralcel OD-3 (3 um, 4.6*150 mm), Daicel chiralcel OJ-3 (3 um, 4.6*150 mm), Daicel chiralcel OZ-3 (3 um, 3*150 mm), Daicel chiralpak IA-3 (3 um, 3*150 mm) , Daicel chiralpak IB-3 (3 um, 3*150 mm), Daicel chiralpak IC-3 (3 um, 3*150 mm), Daicel chiralpak ID-3 (3 um, 3*150 mm), Daicel chiralpak IE- 3 (3 um, 3*150 mm), Daicel chiralpak IF-3 (3 um, 3*150 mm), Daicel chiralpak IG-3 (3 um, 3*150 mm), Daicel chiralpak IH-3 (3 um, 3*150 mm), Daicel chiralpak AY-3 (3 um, 3*150 mm), Daicel chiralpak AZ-3 (3 um, 3*150 mm), Daicel chiralpak OX-3 (3 um, 3*150 mm) , REGIS CHIRAL (R,R)-Whelk O1 (3.5 um, 4.6*150 mm) and REGIS CHIRAL (S,S)-Whelk O1 (3.5 um, 4.6*150 mm).

Supercritical fluid chromatography (SFC) uses Waters SFC 80Q and Waters SFC 150Q, and the chromatographic column is Daicel Chiralcel OJ (30 x 250 mm, 10 um), Daicel Chiralcel OD-H/OJ-H/OZ-H (20 x 250 mm, 5 um), Daicel Chiralpak IA/IB-N/ID/IE/IF/IH/AY/AZ/OX/AD/AS/OD (30 x 250 mm, 10 um), Daicel Chiralpak IC/IG/ AD-H/AS-H (20 x 250 mm, 5 um), REGIS (R,R)-Whelk O1 (20 x 250 mm, 5 um) or REGIS (S,S)-Whelk O1 (30 x 250 mm , 10um).

Thin-layer chromatography silica gel plates use GF254 silica gel plates from Yantai Jiangyou Silicone Rubber Development Co., Ltd. or Rushan Shangbang New Materials Co., Ltd. GF254 silica gel plates. The specifications used by TLC are 0.15 mm to 0.20 mm. Analysis is generally used in 200~300 mesh silica gel as a carrier in Chenghua Chemical Industry.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.

Unless otherwise specified, the ratio of the mixed solvent used in the examples of the present invention is its volume ratio, and the expressions include but are not limited to: EA:PE=10:1, dichloromethane/methanol=17/3, etc.

Unless otherwise specified, all reactions in the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of the reaction temperature is °C.

Unless otherwise specified, the component ratios of the mixed solvents or column chromatography eluents used in the examples of the present invention are volume ratios.

In the embodiments of the present invention, the unit "M" means "mol/L", which is the reagent concentration. The abbreviations used in the embodiments of the present invention and their corresponding chemical names are as follows: abbreviation describe EA ethyl acetate PE petroleum ether PhIO Iodine benzene ACN Acetonitrile DMF N,N-Dimethylformamide dioxane 1,4-dioxane NaHMDS Sodium bis(trimethylsilyl)amide Pd ₂ (dba) ₃ Trisdibenzylideneacetone dipalladium Xantphos bis-diphenylphosphine-9,9-dimethylxanthene DMAP 4-Dimethylaminopyridine THF Tetrahydrofuran Pd(PPh ₃ ) ₂ Cl ₂ Dichlorobistriphenylphosphine palladium DIBAL-H Diisobutylaluminum hydride Trimethylboroxine Trimethylboroxane DCM Dichloromethane T3P 2-propanephosphonic anhydride TEA Triethylamine Pd(dppf)Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride DIAD Diisopropyl azodicarboxylate

第一步：4-(2-羥乙基)-2-硝基苯酚的製備 將亞碘醯苯(796 mg，3.62 mmol)，九水合硝酸鋁(2172 mg，5.79 mmol)混溶於乙腈(40 mL)並攪拌10 分鐘，隨後將其冷卻至0 ℃。將4-(2-羥乙基)苯酚(2000 mg，14.47 mmol)緩慢加入反應中。反應升溫至室溫並攪拌12小時。加入飽和食鹽水(40 mL)淬滅反應，然後用乙酸乙酯(3×50 mL)萃取，無水硫酸鈉乾燥，過濾，濃縮。通過快速柱層析(EA：PE= 10：1)純化得到標題化合物(1500 mg，收率35%)。 ¹H NMR (400 MHz, CDCl ₃) δ:10.49 (s, 1H), 7.98 (d, J= 1.9 Hz, 1H), 7.49 (dd, J= 8.6, 2.0 Hz, 1H), 7.12 (d, J= 8.6 Hz, 1H), 3.88 (dd, J= 7.0, 5.8 Hz, 2H), 2.86 (t, J= 6.4 Hz, 2H). 第二步：2-(4-甲氧基-3-硝基苯基)乙醇的製備 4-(2-羥乙基)-2-硝基苯酚(1000 mg，5.46 mmol)溶於DMF(10 mL)中，加入碳酸鉀(1509 mg，10.92 mmol)。冰浴下滴加碘甲烷(930 mg，6.55 mmol)。然後室溫下攪拌4小時。LC-MS顯示反應已完成。加水(50ml)，並用乙酸乙酯(40ml×3)萃取，鹽水洗滌，無水硫酸鈉乾燥，然後濃縮。通過快速矽膠柱層析(EA：PE= 10：3)純化，得到標題化合物 (1100 mg，收率92%)。 MS m/z (ESI): 198.1 [M + H] ⁺. 第三步：第三丁基(6-((4-甲氧基-3-硝基苯乙氧基)甲基)吡啶-2-基胺基甲酸酯的製備 2-(4-甲氧基-3-硝基苯基)乙醇(400 mg，2.02 mmol)溶於N,N-二甲基甲醯胺(10 mL)。冰浴下加入氫化鈉(121 mg，3.04 mmol)，並攪拌此懸濁液20 分鐘，然後將 [6-(氯甲基)吡啶-2-基]胺基甲酸第三丁酯(494 mg，2.02 mmol)溶於N,N-二甲基甲醯胺(2 mL)的溶液滴加到反應混合物中。繼續在冰浴下反應2 小時。反應完成後加入飽和的氯化銨水溶液淬滅反應。加水(50 mL)，並用乙酸乙酯(30 mL×3)萃取、鹽水洗滌、無水硫酸鈉乾燥，然後濃縮，快速矽膠柱層析(EA/PE=0-30%)純化得到標題化合物 (500 mg，收率58%)。 MS m/z (ESI): 404.2 [M + H] ⁺. 第四步：第三丁基 -(6-((3-胺基-4-甲氧基苯乙氧基)甲基)-吡啶-2-基胺基甲酸酯的製備 第三丁基-(6-((4-甲氧基-3-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(500 mg，1.24 mmol)溶於乙醇和水的混合溶劑中(40 mL，乙醇:水=5:1)中，並加入鐵粉(346 mg，346 mmol)和氯化銨粉末(331 mg，6.20 mmol)。加熱到60 ℃攪拌反應2 小時。LC-MS顯示反應完成，反應冷卻至室溫。過濾後並用乙酸乙酯(30 mL)洗滌濾餅，濾液濃縮然後加水(50 mL)，並用乙酸乙酯(30 mL×3)萃取，鹽水洗滌，合併的有機層用無水硫酸鈉乾燥，然後濃縮。通過快速矽膠柱層析(EA / PE=0-40%)純化得到標題化合物(410 mg，收率88%)。 MS m/z (ESI): 374.2 [M + H] ⁺. 第五步：第三丁基-(6-((3-氯-3-(甲胺甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基 -(6-((3-胺基-4-甲氧基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (400 mg，1.06 mmol)、4,6-二氯-N-甲基嗒𠯤-3-甲醯胺7(220 mg，1.06 mmol)混溶於四氫呋喃(15 mL)中，滴加雙(三甲基矽基)胺基鈉(2.1 mL，0.42 mmol)。25 ℃攪拌2小時。LC-MS顯示反應已完成。加入飽和的氯化銨溶液(10mL)淬滅反應。加水(30 mL)，用乙酸乙酯(30 mL×3)萃取，鹽水洗滌，合併有機層，用無水硫酸鈉乾燥。通過快速矽膠柱層析純化，得到標題化合物(400 mg, 收率65%)。 MS m/z (ESI): 543.1 [M + H] ⁺. 第六步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基苯基)胺基)-6-氯-N-甲基嗒𠯤-3-甲醯胺的製備 (6-((3-((6-氯-3-(甲基氨甲醯)嗒𠯤-4-基)胺基)-4-甲氧基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(400 mg，0.74 mmol)溶於鹽酸二氧六環(10 mL，4 M)的溶液中。將此反應懸濁液在25 °C攪拌2小時。LC-MS顯示反應已完成。在減壓下濃縮得到標題化合物 (300 mg，收率87%)。 MS m/z (ESI): 443.1 [M + H] ⁺. 第七步：5 ⁶-甲氧基-N-甲基-8-氧代-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備 4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基苯基)胺基)-6-氯-N-甲基嗒𠯤-3-甲醯胺(60 mg，0.13 mmol)、碳酸銫(115 mg，0.54 mmol)、Pd ₂(dba) ₃(25 mg，0.04 mmol)、4,5-雙二苯基膦-9,9-二甲基氧雜蒽(24 mg，0.04 mmol)混溶於1,4-二氧六環(10 mL)中。氮氣氛圍下置換三次，然後將反應混合物在130 °C下在密封管中攪拌2 小時。過濾，濾液濃縮得到粗產品，然後將粗品經製備液相色譜法提純得到標題化合物 (16 mg, 收率28%)。 MS m/z (ESI): 407.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ) δ:11.07 (s, 1H), 10.29 (s, 1H), 9.00 (s, 1H), 8.98 (s, 1H), 7.63 (dd, J= 8.2, 7.4 Hz, 1H), 7.56 (d, J= 1.8 Hz, 1H), 7.09 (d, J= 8.2 Hz,1H), 7.03 (d, J= 8.3 Hz, 1H), 6.95 (dd, J= 8.3, 1.8 Hz, 1H), 6.85 (d, J= 7.2 Hz, 1H), 4.40 (s, 2H), 3.84 (s, 3H), 3.70 - 3.69 (m, 2H), 2.84 (d, J= 4.8 Hz, 3H), 2.80 - 2.78 (m, 2H). Example 1: 5 ⁶ -methoxy-N-methyl-8-oxo-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5( 1,3)-Benzcyclononane-3 ⁶ -formamide

The first step: the preparation of 4-(2-hydroxyethyl)-2-nitrophenol benzene iodide (796 mg, 3.62 mmol), aluminum nitrate nonahydrate (2172 mg, 5.79 mmol) were dissolved in acetonitrile ( 40 mL) and stirred for 10 minutes, then cooled to 0 °C. 4-(2-Hydroxyethyl)phenol (2000 mg, 14.47 mmol) was slowly added to the reaction. The reaction was warmed to room temperature and stirred for 12 hours. Add saturated brine (40 mL) to quench the reaction, then extract with ethyl acetate (3×50 mL), dry over anhydrous sodium sulfate, filter and concentrate. Purification by flash column chromatography (EA:PE=10:1) gave the title compound (1500 mg, yield 35%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 10.49 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.6, 2.0 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 3.88 (dd, J = 7.0, 5.8 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H). The second step: 2-(4-methoxy-3-nitro Preparation of phenyl)ethanol 4-(2-hydroxyethyl)-2-nitrophenol (1000 mg, 5.46 mmol) was dissolved in DMF (10 mL), and potassium carbonate (1509 mg, 10.92 mmol) was added. Iodomethane (930 mg, 6.55 mmol) was added dropwise under ice cooling. Then it was stirred at room temperature for 4 hours. LC-MS showed the reaction was complete. Water (50ml) was added and extracted with ethyl acetate (40ml×3), washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash silica gel column chromatography (EA:PE=10:3) gave the title compound (1100 mg, yield 92%). MS m/z (ESI): 198.1 [M + H] ⁺ . The third step: tert-butyl(6-((4-methoxy-3-nitrophenethoxy)methyl)pyridine-2 Preparation of -yl carbamate 2-(4-methoxy-3-nitrophenyl)ethanol (400 mg, 2.02 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (121 mg, 3.04 mmol) was added under ice-cooling, and the suspension was stirred for 20 minutes, and then [6-(chloromethyl)pyridin-2-yl]carbamic acid tert-butyl ester (494 mg, 2.02 mmol) dissolved in N,N-dimethylformamide (2 mL) was added dropwise to the reaction mixture. Continue to react under ice bath for 2 hours. After the reaction was completed, add saturated aqueous ammonium chloride solution to quench the reaction Added water (50 mL), extracted with ethyl acetate (30 mL×3), washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel column chromatography (EA/PE=0-30%) to obtain the title compound ( 500 mg, yield 58%). MS m/z (ESI): 404.2 [M + H] ⁺ . The fourth step: tertiary butyl-(6-((3-amino-4-methoxybenzene Preparation of ethoxy)methyl)-pyridin-2-yl carbamate 2-yl)carbamate (500 mg, 1.24 mmol) was dissolved in a mixed solvent of ethanol and water (40 mL, ethanol:water=5:1), and iron powder (346 mg, 346 mmol) was added and ammonium chloride powder (331 mg, 6.20 mmol). Heated to 60 °C and stirred for 2 hours. LC-MS showed that the reaction was complete, and the reaction was cooled to room temperature. After filtering and washing the filter cake with ethyl acetate (30 mL), the filtrate Concentrate and then add water (50 mL), and extract with ethyl acetate (30 mL×3), wash with brine, and the combined organic layer is dried over anhydrous sodium sulfate, and then concentrated. By flash silica gel column chromatography (EA/PE=0-40 %) was purified to obtain the title compound (410 mg, yield 88%). MS m/z (ESI): 374.2 [M + H] ⁺ . The fifth step: tertiary butyl-(6-((3-chloro- The preparation of 3-(methylaminoformyl) pyridyl (4-yl) amino) -4-methoxyphenethoxy) methyl) pyridin-2-yl) carbamate yl-(6-((3-amino-4-methoxyphenethoxy)methyl)pyridin-2-yl)carbamate (400 mg, 1.06 mmol), 4,6-dichloro -N-Methylpyrrole-3-formamide 7 (220 mg, 1.06 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium bis(trimethylsilyl)amide (2.1 mL, 0.42 mmol ). Stir at 25°C for 2 hours. LC-MS showed the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution (10 mL). Add water (30 mL), extract with ethyl acetate (30 mL×3), wash with brine, combine the organic layers, and dry over anhydrous sodium sulfate. Purification by flash silica gel column chromatography gave the title compound (400 mg, yield 65%). MS m/z (ESI): 543.1 [M + H] ⁺ . The sixth step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 -methoxyphenyl) amino)-6-chloro-N-methylcarbamate-3-formamide preparation (6-((3-((6-chloro-3-(methylcarbamoyl )(((4-methoxyphenethoxy)methyl)pyridin-2-yl)carbamate (400 mg, 0.74 mmol) dissolved in dioxane hydrochloride (10 mL, 4 M) solution. The reaction suspension was stirred at 25 °C for 2 hours. LC-MS showed the reaction was complete. Concentration under reduced pressure gave the title compound (300 mg, yield 87%). MS m/z (ESI): 443.1 [M + H] ⁺ . The seventh step: 5 ⁶ -methoxy-N-methyl-8-oxo-2,4-diaza-3(3,5 )-Pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide 4-((5-(2-((6-amino Pyridin-2-yl)methoxy)ethyl)-2-methoxyphenyl)amino)-6-chloro-N-methylpyridine-3-carboxamide (60 mg, 0.13 mmol), Cesium carbonate (115 mg, 0.54 mmol), Pd ₂ (dba) ₃ (25 mg, 0.04 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (24 mg, 0.04 mmol ) was miscible in 1,4-dioxane (10 mL). After three replacements under nitrogen atmosphere, the reaction mixture was stirred at 130 °C in a sealed tube for 2 h. After filtration, the filtrate was concentrated to obtain a crude product, which was then purified by preparative liquid chromatography to obtain the title compound (16 mg, yield 28%). MS m/z (ESI): 407.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.07 (s, 1H), 10.29 (s, 1H), 9.00 (s, 1H) , 8.98 (s, 1H), 7.63 (dd, J = 8.2, 7.4 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.95 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 4.40 (s, 2H), 3.84 (s, 3H), 3.70 - 3.69 (m, 2H), 2.84 (d, J = 4.8 Hz, 3H), 2.80 - 2.78 (m, 2H).

第一步：2-(4-氟-3-硝基-苯基)乙醇的製備 將(4-氟-3-硝基-苯基)-乙酸(3 g，15 mmol)在二甲氧基乙烷(15 ml)中的溶液冷卻至-15°C，然後攪拌下加入4-甲基嗎福林(1.53 g，15 mmol)，逐滴加入氯甲酸異丁酯(2.15g，15.7mmol)。幾分鐘後，濾出N-甲基嗎福林鹽酸鹽的沉澱，並用二甲氧基乙烷(3×5ml)洗滌3次。將該溶液轉移至250 毫升小瓶中，並用冰鹽浴冷卻，加入硼氫化鈉(0.855g，23mmol)的水(7mL)溶液。觀察到有氫氣排出，然後溶液變成橙色，用水(375mL)稀釋。將該溶液用乙酸乙酯萃取三次。用水洗滌有機相，用硫酸鎂乾燥，然後濃縮至乾。殘餘物經色譜分離洗脫（庚烷:乙酸乙酯=1:1），得到標題化合物 (1g，收率36%)。 MS m/z (ESI): 186 [M + H] ⁺. 第二步：2-(4-(甲硫基)-3 -硝基硝基)乙-1-醇的製備 向2-(4-氟-3-硝基苯基)乙醇(1 g，1 eq)的DMF(20 mL)溶液中添加硫代甲醇鈉(0.42g，1.1 eq)，碳酸鉀(1.64g，2.2eq)。將所得混合物在70℃下攪拌1h。將反應混合物用水(70mL)稀釋，將所得混合物用乙酸乙酯(2×100mL)萃取。合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物，將殘餘物通過矽膠快速色譜純化(石油醚:乙酸乙酯＝60:40)，得到標題化合物(0.7 g，收率61%)。 ¹H NMR (400 MHz, CDCl ₃- d1) δ:8.15 (d, J= 1.6 Hz, 1H), 7.49 (dd, J= 8.4, 1.6 Hz, 1H), 7.32 (d, J= 8.4 Hz, 1H), 3.92 (t, J= 6.4 Hz, 2H), 2.93 (t, J= 6.4 Hz, 2H), 2.49 (s, 3H), 1.54 (s, 1H). 第三步：第三丁基(6-((4-(甲硫基)-3-硝基苯乙氧基)甲基)吡啶-2-基胺基甲酸酯的製備 將2-(4-(甲硫基)-3-硝基苯基)乙-1-醇(600 mg)在DMF (10 mL)中的溶液冷卻到0°C，加入氫化鈉(170 mg)。將所得反應混合物在0℃下攪拌0.5h。然後在0℃下向混合物中加入胺基甲酸第三丁酯(6-(溴甲基)-2-基吡啶-2-基) (810mg，1 eq)，將得到的反應混合物在25℃下攪拌4h。將混合物用氯化銨溶液(30mL)稀釋，並用乙酸乙酯(2×50mL)萃取。合併的有機層用鹽水(50mL)洗滌，經無水硫酸鈉乾燥，過濾，然後通過矽膠柱純化，得到標題化合物(0.7 g，收率59%)。 MS m/z (ESI): 420 [M + H] ⁺. 第四步：第三丁基(6-((3-胺基-4-(甲硫基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將(6-((4-(甲硫基)-3-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯(500 mg)溶解在乙醇(5mL)和水(1mL)中，在室溫下，向反應混合物中加入Fe (318mg)，氯化銨(333mg)。將所得反應混合物在50℃下攪拌1h。將反應混合物過濾。濃縮有機層，得到粗產物。粗品通過快速柱色譜純化，得到標題化合物(400mg，收率77%)。 MS m/z (ESI): 390 [M + H] ⁺. 第五步：第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-(甲硫基)苯乙氧基)甲基)吡啶-2-2-基)胺基甲酸酯的製備 室溫下向胺基甲酸第三丁酯(6-(((3-胺基-4-(甲硫基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯(400 mg，1.1 eq)的四氫呋喃(5 mL)溶液中加入4,6-二氯-N-甲基嗒𠯤-3-羧醯胺(232 mg，1.1 eq)、雙(三甲基甲矽烷基)醯胺鈉(1mL，1.1 eq)。將反應混合物在25℃下攪拌0.5h。向反應混合物中加入水(5mL)。所得混合物用乙酸乙酯(10 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物。粗產物通過矽膠柱快速色譜純化，得到標題化合物(400 mg，收率69%)。 MS m/z (ESI): 559 [M + H] ⁺. 第六步：4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-(甲硫基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺的製備 室溫下向第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤4-基)胺基)-4-(甲硫基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(400mg)在二氯甲烷(3mL)中加入，並向反應混合物中加入鹽酸的1,4-二氧六環(1.8mL，4M)溶液。將反應混合物在50℃下攪拌2h。濃縮反應混合物，得到標題化合物(300 mg，收率92%)。 MS m/z (ESI): 459[M + H] ⁺. 第七步：N-甲基-5 ⁶-(甲硫基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備 將4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-(甲硫基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺(300 mg，1 eq)溶解在1,4-二氧六環(6 mL)中，氮氣保護下向反應混合物中加入三(二亞苄基丙酮)二鈀(89 mg，0.15 eq)，4,5-雙(二苯基膦基)-9,9-二甲基氧雜蒽(76 mg，0.2 eq)，碳酸銫(639 mg，3 eq)。將得到的反應混合物在135℃下攪拌16小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗產物通過製備色譜柱純化，得到標題化合物(200 mg，收率73%)。 MS m/z (ESI): 423[M + H] ⁺. ¹H NMR (400 MHz, DMSO- d6) δ:11.02 (s, 1H), 10.30 (s, 1H), 9.05 (d, J= 4.8 Hz, 1H), 8.75 (s, 1H), 7.65-7.59 (m, 1H), 7.48 (s, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.11- 7.05 (m, 2H), 6.84 (d, J= 7.2 Hz, 1H), 4.38 (s, 2H), 3.75 - 3.69 (m, 2H), 2.86-2.82 (m, 5H), 2.41 (s, 3H). Example 2: N-methyl-5 ⁶ -(methylthio)-8-oxa-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine- Preparation of 5(1,3)-benzocyclononane-3 ⁶ -formamide

Step 1: Preparation of 2-(4-fluoro-3-nitro-phenyl)ethanol (4-fluoro-3-nitro-phenyl)-acetic acid (3 g, 15 mmol) in dimethoxy The solution in ethane (15 ml) was cooled to -15°C, then 4-methylmorphine (1.53 g, 15 mmol) was added with stirring, and isobutyl chloroformate (2.15 g, 15.7 mmol) was added dropwise . After a few minutes, the precipitate of N-methylmorphine hydrochloride was filtered off and washed 3 times with dimethoxyethane (3 x 5 ml). The solution was transferred to a 250 mL vial and cooled with an ice-salt bath, and a solution of sodium borohydride (0.855 g, 23 mmol) in water (7 mL) was added. Evolution of hydrogen gas was observed, then the solution turned orange and was diluted with water (375 mL). The solution was extracted three times with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was separated and eluted by chromatography (heptane: ethyl acetate = 1:1) to obtain the title compound (1 g, yield 36%). MS m/z (ESI): 186 [M + H] ⁺ . The second step: the preparation of 2-(4-(methylthio)-3-nitronitro)ethan-1-ol to 2-(4 -To a solution of -fluoro-3-nitrophenyl)ethanol (1 g, 1 eq) in DMF (20 mL) were added sodium thiomethoxide (0.42 g, 1.1 eq), potassium carbonate (1.64 g, 2.2 eq). The resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was diluted with water (70 mL), and the resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, and then concentrated to obtain a crude product, and the residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate=60:40) to obtain the title compound (0.7 g, yield 61%) . ¹ H NMR (400 MHz, CDCl ₃ - d1 ) δ: 8.15 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H ), 3.92 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.49 (s, 3H), 1.54 (s, 1H). The third step: tertiary butyl (6 -((4-(methylthio)-3-nitrophenethoxy)methyl)pyridin-2-ylcarbamate by 2-(4-(methylthio)-3-nitro A solution of phenyl)ethan-1-ol (600 mg) in DMF (10 mL) was cooled to 0°C, and sodium hydride (170 mg) was added. The resulting reaction mixture was stirred at 0°C for 0.5h. Then in To the mixture was added tert-butyl carbamate (6-(bromomethyl)-2-ylpyridin-2-yl) (810 mg, 1 eq) at 0 °C, and the resulting reaction mixture was stirred at 25 °C for 4 h The mixture was diluted with ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column to give The title compound (0.7 g, yield 59%). MS m/z (ESI): 420 [M + H] ⁺ . The fourth step: tertiary butyl (6-((3-amino-4-(methyl Thio) phenethoxy) methyl) pyridin-2-yl) carbamate preparation (6-((4-(methylthio)-3-nitrophenethoxy) methyl) Pyridin-2-yl) tert-butyl carbamate (500 mg) was dissolved in ethanol (5 mL) and water (1 mL), and Fe (318 mg), ammonium chloride (333 mg ). The resulting reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was filtered. The organic layer was concentrated to obtain a crude product. The crude product was purified by flash column chromatography to obtain the title compound (400 mg, yield 77%). MS m/z ( ESI): 390 [M + H] ⁺ . The fifth step: tertiary butyl (6-((3-((6-chloro-3-(methylaminoformyl) palladium-4-yl) Amino)-4-(methylthio)phenethoxy)methyl)pyridin-2-2-yl)carbamate to tertiary butyl carbamate (6-(( To a solution of tert-butyl (3-amino-4-(methylthio)phenethoxy)methyl)pyridin-2-yl)carbamate (400 mg, 1.1 eq) in tetrahydrofuran (5 mL) was added 4,6-dichloro-N-methylpyrrole-3-carboxamide (232 mg, 1.1 eq), sodium bis(trimethylsilyl)amide (1m L, 1.1 eq). The reaction mixture was stirred at 25 °C for 0.5 h. Water (5 mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by silica gel column flash chromatography to obtain the title compound (400 mg, yield 69%). MS m/z (ESI): 559 [M + H] ⁺ . The sixth step: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)- Preparation of 2-(methylthio)phenyl)amino)-6-chloro-N-methylpyridium-3-carboxamide to tertiary butyl (6-((3-((6 -Chloro-3-(methylaminoformyl)pyridine-4-yl)amino)-4-(methylthio)phenethoxy)methyl)pyridin-2-yl)carbamate (400 mg) was added in dichloromethane (3 mL), and a solution of hydrochloric acid in 1,4-dioxane (1.8 mL, 4M) was added to the reaction mixture. The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated , to obtain the title compound (300 mg, yield 92%). MS m/z (ESI): 459[M + H] ⁺ . The seventh step: N-methyl-5 ⁶ -(methylthio)-8- Oxa-2,4-diazepine-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide Preparation of 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-(methylthio)phenyl)amino)-6-chloro- N-Methylpyrrole-3-carboxamide (300 mg, 1 eq) was dissolved in 1,4-dioxane (6 mL), and tris(dibenzylideneacetone was added to the reaction mixture under nitrogen protection) ) Dipalladium (89 mg, 0.15 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76 mg, 0.2 eq), cesium carbonate (639 mg, 3 eq ). The resulting reaction mixture was stirred at 135 ° C for 16 hours. The reaction mixture was filtered and the organic layer was concentrated to obtain a crude product. The crude product was purified by preparative chromatography to obtain the title compound (200 mg, yield 73%). MS m/z (ESI): 423[M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ: 11.02 (s, 1H), 10.30 (s, 1H), 9.05 (d, J = 4.8 Hz , 1H), 8.75 (s, 1H), 7.65-7.59 (m, 1H), 7.48 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.11- 7.05 (m, 2H), 6.84 ( d, J = 7.2 Hz, 1H), 4.38 (s, 2H), 3.75 - 3.69 (m, 2H), 2.86-2.82 (m, 5H), 2.41 (s, 3H).

將N-甲基-5 ⁶-(甲硫基)-8-氧雜-2,4-二氮雜3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺 (40 mg，1 eq)溶解在醋酸(2 mL)中。在室溫下向反應混合物中加入硫酸過氧鉀(145 mg，2.5 eq)。將所得反應混合物在70℃下攪拌0.5小時，濃縮反應混合物，得到粗產物。粗產品通過製備色譜純化，得到標題化合物(5.2 mg，收率12%)。 MS m/z (ESI): 455 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d6) δ:11.34 (s, 1H), 10.40 (s, 1H), 9.05 (d, J= 4.8 Hz, 1H), 8.58 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.72 (s, 1H), 7.67- 7.61 (m, 1H),7.33 (d, J = 8.2 Hz, 1H), 7.06 (t, J= 7.7 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 4.41 (s, 2H), 3.81 -3.75 (m, 2H), 3.14 (s, 3H), 2.99- 2.93 (m, 2H), 2.85 (d, J = 4.8 Hz,3H). Example 3: N-methyl-5 ⁶ -(methylsulfonyl)-8-oxa-2,4-diaza-3(3,5)-diazepine-1(2,6)- Preparation of pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide

N-methyl-5 ⁶ -(methylthio)-8-oxa-2,4-diazepine 3(3,5)-pyridine-1(2,6)-pyridine-5(1, 3)-Benzcyclononane-3 ⁶ -formamide (40 mg, 1 eq) was dissolved in acetic acid (2 mL). Potassium peroxosulfate (145 mg, 2.5 eq) was added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at 70° C. for 0.5 hours, and the reaction mixture was concentrated to obtain a crude product. The crude product was purified by preparative chromatography to afford the title compound (5.2 mg, yield 12%). MS m/z (ESI): 455 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ: 11.34 (s, 1H), 10.40 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.58 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.67- 7.61 (m, 1H), 7.33 (d, J = 8.2 Hz, 1H ), 7.06 (t, J = 7.7 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 4.41 (s, 2H), 3.81 -3.75 (m, 2H), 3.14 (s, 3H), 2.99 - 2.93 (m, 2H), 2.85 (d, J = 4.8 Hz,3H).

將N-甲基-5 ⁶-(甲硫基)-8-氧雜-2,4-二氮雜3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺 (20mg，1 eq)溶解在甲醇和四氫呋喃的混合溶劑（4mL，甲醇：四氫呋喃=1:1）中。在室溫下向反應混合物中加入過硫酸氫鉀(58mg，2 eq)。將得到的反應混合物在25℃攪拌2h。濃縮反應混合物，得到粗產物。通過製備色譜純化粗產品，得到標題化合物(3.6 mg，收率18%)。 MS m/z (ESI): 439 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d6) δ:11.15 (s, 1H), 10.41 (s, 1H), 9.14 (d, J= 4.8 Hz, 1H), 8.70 (s, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.64-7.62 (m, 2H), 7.36 (d, J= 8.0 Hz, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.87 (d, J= 7.3 Hz, 1H), 4.41 (q, J= 11.2 Hz, 2H), 3.83 – 3.72 (m, 2H), 3.03 – 2.90 (m, 2H), 2.86 (d, J= 4.8 Hz, 3H), 2.69 (s, 3H). Example 4: N-methyl-5 ⁶ -(methylsulfinyl)-8-oxa-2,4-diaza-3(3,5)-diazepine-1(2,6) - Preparation of pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide

N-methyl-5 ⁶ -(methylthio)-8-oxa-2,4-diazepine 3(3,5)-pyridine-1(2,6)-pyridine-5(1, 3)-Benzcyclononane-3 ⁶ -formamide (20 mg, 1 eq) was dissolved in a mixed solvent of methanol and tetrahydrofuran (4 mL, methanol: tetrahydrofuran = 1:1). Potassium persulfate (58 mg, 2 eq) was added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give crude product. The crude product was purified by preparative chromatography to afford the title compound (3.6 mg, yield 18%). MS m/z (ESI): 439 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ: 11.15 (s, 1H), 10.41 (s, 1H), 9.14 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.41 (q, J = 11.2 Hz, 2H), 3.83 – 3.72 (m, 2H), 3.03 – 2.90 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H), 2.69 (s, 3H).

將N-甲基-5 ⁶-(甲硫基)-8-氧雜-2,4-二氮雜3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的溶液(40mg，1 eq)溶解在二氯甲烷(4mL)中。在室溫下向反應混合物中加入3-氯過氧苯甲酸(98mg，6 eq)。將所得反應混合物在50 ℃下攪拌3小時。濃縮反應混合物，得到粗產物。粗產物通過製備色譜純化，得到標題化合物(4.9 mg，收率11%)。 MS m/z (ESI): 471 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d6) δ :11.26 (s, 1H), 10.35 (s, 1H), 9.00 (s, 1H), 8.79 (d, J= 4.8 Hz, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.30 (d, J= 8.0 Hz, 1H), 6.97 (d, J= 7.2 Hz, 1H), 4.44 (s, 2H), 3.85- 3.73 (m, 2H), 3.15 (s, 3H), 2.98- 2.90 (m, 2H), 2.80 (d, J = 4.8 Hz, 3H). Example 5: 3 ⁶ -(methylaminoformyl)-5 ⁶ -(methylsulfonyl)-8-oxa-2,4-diazepine-3(3,5)-diazepine Preparation of -1(2,6)-pyridine-5(1,3)-benzocyclononane-1 ¹ -oxide

N-methyl-5 ⁶ -(methylthio)-8-oxa-2,4-diazepine 3(3,5)-pyridine-1(2,6)-pyridine-5(1, 3) A solution of -benzocyclononane ^- 36-carboxamide (40 mg, 1 eq) was dissolved in dichloromethane (4 mL). 3-Chloroperoxybenzoic acid (98 mg, 6 eq) was added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was concentrated to give crude product. The crude product was purified by preparative chromatography to afford the title compound (4.9 mg, yield 11%). MS m/z (ESI): 471 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ : 11.26 (s, 1H), 10.35 (s, 1H), 9.00 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.85- 3.73 (m, 2H), 3.15 (s, 3H), 2.98- 2.90 (m, 2H) , 2.80 (d, J = 4.8 Hz, 3H).

第一步：2-溴-4-(2-羥乙基)苯酚的製備 將4-(2-羥乙基)苯酚(30 g, 217.4 mmol)和溴化鈉(22.17g, 217.4mmol) 溶於丙酮 (600 mL)，在-10°C下滴加單過硫酸氫鉀(200g，1190.5 mmol)的水(1L)溶液，反應液在20°C反應1小時，監測反應結束後，乙酸乙酯萃取(3×500mL)，有機相用飽和食鹽水洗(800 mL)，無水硫酸鈉乾燥，濃縮後得到標題化合物(44.4 g，收率85%)。 MS m/z (ESI)：199.1，201.1[M+H] ⁺. 第二步：2-羥基-5-(2-羥乙基)苯甲酸甲酯的製備 向2-溴-4-(2-羥乙基)苯酚(2000 mg，9.21 mmol)的甲醇(150 mL)溶液中加入1,1-雙(二苯膦基)二茂鐵二氯化鈀(II)二氯甲烷複合物(751.86 mg，0.92 mmol)、 N, N-二異丙基乙胺(5954.09 mg，46 mmol)。反應液在80°C，一氧化碳氛圍(1.2MPa)下反應16小時。LC-MS 監測反應完全(m/z 196.1)，將反應液減壓濃縮，濃縮後將得到的殘留物用矽膠柱(乙酸乙酯:石油醚=1:1)純化，得標題化合物(1.8 g, 收率95%)。 MS m/z (ESI)：196.1 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ: 10.61 (s, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.33 (dd, J= 8.4, 2.4 Hz, 1H), 6.94 (d, J= 8.4 Hz, 1H), 3.95 (s, 3H), 3.85 (t, J= 6.4 Hz, 2H), 2.81 (t, J= 6.4 Hz, 2H). 第三步：5-(2-乙醯氧基乙基)-2-羥基苯甲酸甲酯的製備 將2-羥基-5-(2-羥乙基)苯甲酸甲酯(1.8 g, 9.17 mmol) 溶於乙酸乙酯 (50 mL)，加入濃硫酸(100 mg, 0.3536mmol)，反應液在60°C下反應16小時，監測反應結束後，減壓濃縮，濃縮後將得到的殘留物用快速矽膠柱(乙酸乙酯/石油醚=0:1- 4:1)純化，得標題化合物(1.8 g, 收率60%)。 MS m/z (ESI)：179.1 [M-59] ⁺. 第四步：5-(2-乙醯氧基乙基)-2-羥基-3-硝基苯甲酸甲酯的製備 向5-(2-乙醯氧基乙基)-2-羥基苯甲酸甲酯(1.8 g, 7.555mmol)的醋酸 (20 mL) 溶液中加入硝酸(2.3 g, 15.11mmol)， 反應液在室溫反應16小時。反應結束後，加入水(80mL)淬滅，乙酸乙酯萃取(3×60mL)，合併有機相，用飽和食鹽水( 80mL)洗滌，有機相用無水硫酸鈉乾燥，濃縮後，將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得到標題化合物(1.7 g, 收率63%)。 MS m/z (ESI)：225.3[M-58] ⁺. 第五步：5-(2-乙醯氧基乙基)-2-甲氧基-3-硝基苯甲酸甲酯的製備 將5-(2-乙醯氧基乙基)-2-羥基-3-硝基苯甲酸甲酯(1.7 g, 6.0021mmol) 溶於 N,N-二甲基甲醯胺 (20 mL)，依次加入碳酸鉀(1.66 g, 12mmol) 和碘甲烷(1022.33mg, 7.20mmol)，反應液在70°C下反應8小時。反應結束後冷至室溫，加入水(160 mL)，乙酸乙酯萃取(3×30mL)，有機相用無水硫酸鈉乾燥、濃縮後，將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0~50%)純化，得到標題化合物(1.8 g，收率98%)。 MS m/z (ESI)：298.1[M+H] ⁺. 第六步：5-(2-羥乙基)-2-甲氧基-3-硝基苯甲酸甲酯的製備 將5-(2-乙醯氧基乙基)-2-甲氧基-3-硝基苯甲酸甲酯(1.8 g, 6.05mmol) 溶於甲醇 (20 mL)，加入碳酸鉀(5.4g, 39.06 mmol)，反應液在室溫下反應30分鐘。反應結束後過濾，濾餅用甲醇(10 mL)洗滌2次，收集濾液，加入水(20 mL)，二氯甲烷萃取(4×30mL)，有機相用無水硫酸鈉乾燥、濃縮後，將得到的殘留物用矽膠柱(甲醇/二氯甲烷=0-8%)純化，得到標題化合物(920 mg，收率59%)。 MS m/z (ESI)：256.1[M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ:7.92-7.89 (m, 1H), 7.82-7.79 (m, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.93-3.89 (m,2H), 2.92-2.79 (m, 2H). 第七步：5-(2-羥乙基)-2-甲氧基-3-硝基苯甲醯胺的製備 將5-(2-羥乙基)-2-甲氧基-3-硝基苯甲酸甲酯(680mg, 2.66mmol) 的氨-甲醇 (10 mL, 7M)的混合液在室溫反應16小時。反應結束後直接濃縮, 得到標題化合物 (550 mg, 收率80%)。 MS m/z (ESI)：263.0[M+Na] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ: 7.73-7.69 (m, 2H), 3.82 (s, 3H), 3.68 (t, J= 6.4 Hz, 2H), 2.77 (t, J= 6.4 Hz, 2H). 第八步：2-(4-甲氧基-3-硝基-5-(1H-1,2,4-三唑-3-基)苯基)乙烷-1-醇的製備 將5-(2-羥乙基)-2-甲氧基-3-硝基苯甲醯胺(550 mg, 2.29mmol) 的 N,N-二甲基甲醯胺、二甲縮醛(5 mL) 的混合液在95°C下反應一小時，然後減壓濃縮，用乙醇(3 mL)稀釋備用。另取一個圓底燒瓶，加入乙醇(4.5 mL)，冷至0°C，加入醋酸(2.5 mL)，保持0°C攪拌0.1小時，再加入水合肼(1.0 g, 16.027mmol)，反應液在0°C反應0.25小時。隨後加入之前備用的乙醇溶液，整個反應液在室溫下反應4小時。反應結束後減壓濃縮，用乙酸乙酯(20 mL)稀釋，用飽和碳酸氫鈉水溶液(5 mL)洗滌2次，有機相用無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(甲醇/二氯甲烷=0-10%)純化，得到標題化合物(460 mg, 收率76%)。 MS m/z (ESI)：265.1[M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ:8.40 (s, 1H), 8.09 (d, J= 2.0 Hz, 1H), 7.86 (d, J= 2.0 Hz, 1H), 3.85 (t, J= 6.4 Hz, 2H), 3.80 (s, 3H), 2.93 (t, J= 6.4 Hz, 2H). 第九步：2-(4-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)-5-硝基苯基)乙烷-1-醇的製備 將2-(4-甲氧基-3-硝基-5-(1H-1,2,4-三唑-3-基)苯基)乙烷-1-醇(400 mg, 1.51mmol) 溶於 N,N-二甲基甲醯胺 (4 mL)，依次加入碳酸鉀(292.91mg, 2.12mmol) 和碘甲烷(279.33mg, 1.97mmol)，反應液在20°C下反應1小時。反應結束後，加入水(30 mL)，乙酸乙酯萃取(3×20mL)，有機相用無水硫酸鈉乾燥、濃縮後，將得到的殘留物用矽膠柱(甲醇/二氯甲烷=0-10%)純化，得到標題化合物(280 mg，收率66%)。 MS m/z (ESI)：279.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ:8.40 (s, 1H), 7.90 (d, J= 2.4 Hz, 1H), 7.65 (d, J= 2.4 Hz, 1H), 3.92 (s, 3H), 3.74 – 3.68 (m, 5H), 2.81 (t, J= 6.4 Hz, 2H)。 第十步：2-溴-6-((4-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)-5-硝基苯乙氧基)甲基)吡啶的製備 將2-(4-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)-5-硝基苯基)乙烷-1-醇(220mg,0.79 mmol) 溶於 N,N-二甲基甲醯胺(4mL)，0°C下依次加入氫化鈉 (94.86mg, 2.37mmol)，15-冠-5(2滴), 2-溴-6-(氯甲基)吡啶(326.47 mg, 1.58mmol)，反應液在室溫反應1小時。反應結束後，加入冰水(30 mL)淬滅，乙酸乙酯萃取(3×20mL)，有機相用無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-75%)純化，得到標題化合物(180 mg，收率51%)。 MS m/z (ESI)：448.1, 450.0[M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ: 8.41 (s, 1H), 7.93 (d, J= 2.4 Hz, 1H), 7.68 (d, J= 2.4 Hz, 1H), 7.53 (t, J= 7.6 Hz, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.27 (d, J= 7.6 Hz, 1H), 4.47 (s, 2H), 3.93 (s, 3H), 3.74 (t, J= 6.4 Hz, 2H), 3.71 (s, 3H), 2.93 (t, J= 6.4 Hz, 2H). 第十一步：第三丁基(6-((4-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 向2-溴-6-((4-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)-5-硝基苯乙氧基)甲基)吡啶(150mg, 0.33mmol) 的1,4-二氧六環(5mL)溶液中依次加入胺基甲酸第三丁酯(78.39mg, 0.67mmol)，三(二亞苄基丙酮)二鈀(0) (30.64 mg,0.03mmol)，碳酸銫(327.06mg, 1.mmol)，反應液在氮氣氛圍，90°C下反應1小時。反應結束後直接減壓濃縮，殘留物用矽膠柱(乙酸乙酯/石油醚=0-95%)純化，得到標題化合物(160 mg，收率94%)。 MS m/z (ESI)：485.2[M+H] ⁺. 第十二步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((4-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (160 mg, 0.33 mmol)溶於乙醇和水的混合液中（10 mL，乙醇/水 = 4：1），依次加入還原鐵粉(257 mg, 4.6 m mol)和氯化銨(352 mg, 6.59 mmol)，反應液在80°C反應1小時。反應結束後，加入水(30mL)淬滅，二氯甲烷萃取(3×40mL)，有機相用無水硫酸鈉乾燥、濃縮後，將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得標題化合物(100 mg，收率63%)。 MS m/z (ESI)：455.2 [M+H] ⁺. 第十三步：第三丁基(6-((3-((6-氯-3-(甲基氨甲醯)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(100 mg, 0.22mmol)溶於四氫呋喃(3 mL)，依次加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺(68 mg, 0.33mmol) 和雙(三甲基矽基)醯胺鈉(0.3 mL)，反應液室溫反應10分鐘。反應結束後，加入水(5mL)淬滅，二氯甲烷萃取(3×30mL)，有機相用無水硫酸鈉乾燥、濃縮後，將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得到標題化合物 (80 mg，收率55%)。 MS m/z (ESI)：625.2 [M+H] ⁺. 第十四步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-甲醯胺的製備 將第三丁基(6-((3-((6-氯-3-(甲基氨甲醯)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(80 mg, 0.128mmol) 溶於鹽酸二氧六環溶液(4M，3 mL)中，混合液於30 ^oC下攪拌1小時。反應結束後直接濃縮，得到標題化合物(60 mg，收率80%)。 MS m/z (ESI)：524.2 [M+H] ⁺. 第十五步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-1,2,4-三唑-3-基)-8-氧代-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備（化合物6-1） 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-甲醯胺 (60 mg, 0.11mmol) 溶於1,4-二氧六環 (3 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(2 mg, 0.0038mmol)，三(二亞苄基丙酮)二鈀 (3.5 mg, 0.0038mmol) 和碳酸銫 (37 mg, 0.1146mmol)。混合液於130 ^oC下攪拌4小時。反應結束後直接濃縮，殘留物用矽膠柱(二氯甲烷/甲醇=10/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備、純化後，得到標題化合物 (22 mg，收率38%)。 MS m/z (ESI)：487.2 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ:11.81 (s, 1H), 10.01 (s, 1H), 9.29 (s, 1H), 8.12-8.21 (m, 1H), 7.87 -7.59 (m, 4H), 6.91-6.82 (m, 2H), 4.52 (s, 2H), 4.02-4.00 (m, 3H), 3.87 -3.80(m, 5H), 3.16 -2.93 (m, 5H). 第十六步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-1,2,4-三唑-3-基)-8-氧代-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺三鹽酸鹽的製備（化合物6-2） 將5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-1,2,4-三唑-3-基)-8-氧代-2,4-重氮-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺(10 mg, 0.02mmol) 溶於鹽酸二氧六環溶液4M (3 mL) 中，混合液於30 ^oC下攪拌1小時。反應結束後直接濃縮，得到標題化合物(12 mg，收率95%). MS m/z (ESI)：487.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ:9.60 (s, 1H), 9.23 (s, 1H), 7.88 (d, J= 1.8 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.65 (d, J= 1.8 Hz, 1H), 7.03-6.99 (m, 2H), 4.46 (s, 2H), 4.09 (s, 3H), 3.82 - 3.74 (m, 2H), 3.71 (s, 3H), 2.97 - 2.90 (m, 2H), 2.89 (s, 3H). Example 6-1 and Example 6-2: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1 H -1,2,4-triazol-3-yl)- 8-Oxo-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formyl Preparation of amine and its hydrochloric acid

The first step: the preparation of 2-bromo-4-(2-hydroxyethyl)phenol 4-(2-hydroxyethyl)phenol (30 g, 217.4 mmol) and sodium bromide (22.17g, 217.4mmol) were dissolved In acetone (600 mL), a solution of potassium monopersulfate (200 g, 1190.5 mmol) in water (1 L) was added dropwise at -10° C., and the reaction solution was reacted at 20° C. for 1 hour. After monitoring the reaction, ethyl acetate Ester was extracted (3×500 mL), the organic phase was washed with saturated brine (800 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (44.4 g, yield 85%). MS m/z (ESI): 199.1, 201.1[M+H] ⁺ . The second step: the preparation of 2-hydroxy-5-(2-hydroxyethyl) methyl benzoate to 2-bromo-4-(2 -Hydroxyethyl)phenol (2000 mg, 9.21 mmol) in methanol (150 mL) was added with 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (751.86 mg, 0.92 mmol), N , N -diisopropylethylamine (5954.09 mg, 46 mmol). The reaction solution was reacted for 16 hours at 80° C. under a carbon monoxide atmosphere (1.2 MPa). LC-MS monitored that the reaction was complete (m/z 196.1), and the reaction solution was concentrated under reduced pressure. After concentration, the obtained residue was purified with a silica gel column (ethyl acetate:petroleum ether=1:1) to obtain the title compound (1.8 g , yield 95%). MS m/z (ESI): 196.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ: 10.61 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.33 (dd , J = 8.4, 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.85 (t, J = 6.4 Hz, 2H), 2.81 (t, J = 6.4 Hz , 2H). The third step: the preparation of 5-(2-acetyloxyethyl)-2-hydroxybenzoic acid methyl ester 2-hydroxy-5-(2-hydroxyethyl) benzoic acid methyl ester (1.8 g, 9.17 mmol) was dissolved in ethyl acetate (50 mL), and concentrated sulfuric acid (100 mg, 0.3536 mmol) was added, and the reaction solution was reacted at 60°C for 16 hours. After monitoring the completion of the reaction, it was concentrated under reduced pressure. After concentration, The residue was purified by flash silica gel column (ethyl acetate/petroleum ether=0:1-4:1) to obtain the title compound (1.8 g, yield 60%). MS m/z (ESI): 179.1 [M-59] ⁺ . The fourth step: the preparation of 5-(2-acetyloxyethyl)-2-hydroxy-3-nitrobenzoic acid methyl ester to 5- Nitric acid (2.3 g, 15.11 mmol) was added to a solution of methyl (2-acetyloxyethyl)-2-hydroxybenzoate (1.8 g, 7.555 mmol) in acetic acid (20 mL), and the reaction solution was reacted at room temperature for 16 Hour. After the reaction was completed, quenched by adding water (80mL), extracted with ethyl acetate (3×60mL), combined the organic phases, washed with saturated brine (80mL), dried the organic phases with anhydrous sodium sulfate, concentrated, and obtained the residual The compound was purified by silica gel column (ethyl acetate/petroleum ether=0-80%) to obtain the title compound (1.7 g, yield 63%). MS m/z (ESI): 225.3[M-58] ⁺ . The fifth step: the preparation of 5-(2-acetyloxyethyl)-2-methoxy-3-nitrobenzoic acid methyl ester will 5-(2-Acetyloxyethyl)-2-hydroxy-3-nitrobenzoic acid methyl ester (1.7 g, 6.0021mmol) was dissolved in N,N -dimethylformamide (20 mL), followed by Potassium carbonate (1.66 g, 12 mmol) and iodomethane (1022.33 mg, 7.20 mmol) were added, and the reaction solution was reacted at 70° C. for 8 hours. After the reaction was completed, cool to room temperature, add water (160 mL), extract with ethyl acetate (3 × 30 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and use a silica gel column (ethyl acetate/petroleum ether = 0~50%) to obtain the title compound (1.8 g, yield 98%). MS m/z (ESI): 298.1[M+H] ⁺ . The sixth step: the preparation of 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzoic acid methyl ester 5-( 2-Acetyloxyethyl)-2-methoxy-3-nitrobenzoic acid methyl ester (1.8 g, 6.05 mmol) was dissolved in methanol (20 mL), potassium carbonate (5.4 g, 39.06 mmol) was added, The reaction solution was reacted at room temperature for 30 minutes. After the reaction was completed, filter, the filter cake was washed twice with methanol (10 mL), the filtrate was collected, water (20 mL) was added, extracted with dichloromethane (4 × 30 mL), the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain The residue was purified by silica gel column (methanol/dichloromethane=0-8%) to obtain the title compound (920 mg, yield 59%). MS m/z (ESI): 256.1[M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.92-7.89 (m, 1H), 7.82-7.79 (m, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.93-3.89 (m,2H), 2.92-2.79 (m, 2H). The seventh step: 5-(2-hydroxyethyl)-2-methoxy-3- Preparation of nitrobenzamide Methyl 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzoate (680 mg, 2.66 mmol) in ammonia-methanol (10 mL, 7M) The mixture was reacted at room temperature for 16 hours. Concentrate directly after the reaction to obtain the title compound (550 mg, yield 80%). MS m/z (ESI): 263.0[M+Na] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.73-7.69 (m, 2H), 3.82 (s, 3H), 3.68 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H). Step 8: 2-(4-methoxy-3-nitro-5-(1H-1,2,4-triazole Preparation of -3-yl)phenyl)ethan-1-ol 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzamide (550 mg, 2.29mmol) in N , The mixture of N -dimethylformamide and dimethyl acetal (5 mL) was reacted at 95°C for one hour, then concentrated under reduced pressure, and diluted with ethanol (3 mL) for later use. Take another round bottom flask, add ethanol (4.5 mL), cool to 0 ° C, add acetic acid (2.5 mL), keep stirring at 0 ° C for 0.1 hour, then add hydrazine hydrate (1.0 g, 16.027 mmol), and the reaction solution is in 0°C for 0.25 hours. Subsequently, the previously reserved ethanol solution was added, and the whole reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), washed twice with saturated aqueous sodium bicarbonate (5 mL), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the obtained residue was applied to a silica gel column ( methanol/dichloromethane=0-10%) to obtain the title compound (460 mg, yield 76%). MS m/z (ESI): 265.1[M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.40 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.86 ( d, J = 2.0 Hz, 1H), 3.85 (t, J = 6.4 Hz, 2H), 3.80 (s, 3H), 2.93 (t, J = 6.4 Hz, 2H). Step 9: 2-(4- Preparation of methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenyl)ethan-1-ol 2-(4-methyl Oxy-3-nitro-5-(1H-1,2,4-triazol-3-yl)phenyl)ethan-1-ol (400 mg, 1.51mmol) dissolved in N,N -dimethyl Formamide (4 mL), potassium carbonate (292.91mg, 2.12mmol) and methyl iodide (279.33mg, 1.97mmol) were added sequentially, and the reaction solution was reacted at 20°C for 1 hour. After the reaction, add water (30 mL), extract with ethyl acetate (3 × 20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and use a silica gel column (methanol/dichloromethane=0-10 %) was purified to obtain the title compound (280 mg, yield 66%). MS m/z (ESI): 279.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.40 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.65 ( d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 3.74 – 3.68 (m, 5H), 2.81 (t, J = 6.4 Hz, 2H). Step 10: 2-bromo-6-((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenylethoxy ) Preparation of methyl) pyridine 2-(4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenyl)ethane -1-alcohol (220mg, 0.79 mmol) was dissolved in N,N -dimethylformamide (4mL), sodium hydride (94.86mg, 2.37mmol) was added successively at 0°C, 15-crown-5 (2 drops ), 2-bromo-6-(chloromethyl)pyridine (326.47 mg, 1.58mmol), and the reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, it was quenched by adding ice water (30 mL), extracted with ethyl acetate (3 × 20 mL), the organic phase was dried over anhydrous sodium sulfate, and the obtained residue was concentrated on a silica gel column (ethyl acetate/petroleum ether = 0-75%) to obtain the title compound (180 mg, yield 51%). MS m/z (ESI): 448.1, 450.0[M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.41 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.47 ( s, 2H), 3.93 (s, 3H), 3.74 (t, J = 6.4 Hz, 2H), 3.71 (s, 3H), 2.93 (t, J = 6.4 Hz, 2H). The eleventh step: the third Butyl(6-((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenethoxy)methyl)pyridine -2-yl)carbamate preparation to 2-bromo-6-((4-methoxyl-3-(1-methyl-1H-1,2,4-triazol-3-yl) -5-Nitrophenethoxy)methyl)pyridine (150mg, 0.33mmol) in 1,4-dioxane (5mL) solution was added successively tertiary butyl carbamate (78.39mg, 0.67mmol) , tris(dibenzylideneacetone)dipalladium(0) (30.64 mg, 0.03mmol), cesium carbonate (327.06mg, 1.mmol), and the reaction solution was reacted under nitrogen atmosphere at 90°C for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate/petroleum ether=0-95%) to obtain the title compound (160 mg, yield 94%). MS m/z (ESI): 485.2[M+H] ⁺ . The twelfth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H -1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate The tertiary butyl (6-((4-methoxy -3-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (160 mg, 0.33 mmol) was dissolved in a mixture of ethanol and water (10 mL, ethanol/water = 4:1), and reduced iron powder (257 mg, 4.6 mmol) and ammonium chloride (352 mg, 6.59 mmol) were added in turn ), the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, quenched by adding water (30mL), extracted with dichloromethane (3×40mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained residue was applied to a silica gel column (ethyl acetate/petroleum ether=0 -80%) was purified to obtain the title compound (100 mg, yield 63%). MS m/z (ESI): 455.2 [M+H] ⁺ . Thirteenth step: tertiary butyl (6-((3-((6-chloro-3-(methylcarbamoyl)) 4-yl)amino)-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl ) Preparation of carbamate: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazole-3- yl)phenethoxy)methyl)pyridin-2-yl)carbamate (100 mg, 0.22mmol) was dissolved in tetrahydrofuran (3 mL), and 4,6-dichloro-N-methylpyridine was added successively 𠯤-3-Formamide (68 mg, 0.33mmol) and sodium bis(trimethylsilyl)amide (0.3 mL) were reacted at room temperature for 10 minutes. After the reaction was completed, quenched by adding water (5mL), extracted with dichloromethane (3×30mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained residue was applied to a silica gel column (ethyl acetate/petroleum ether=0 -80%) was purified to obtain the title compound (80 mg, yield 55%). MS m/z (ESI): 625.2 [M+H] ⁺ . The fourteenth step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)- 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-methyl The preparation of amide will be tertiary butyl (6-((3-((6-chloro-3-(methylcarbamoyl) pyridyl-4-yl) amino)-4-methoxy-5- (1-Methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (80 mg, 0.128mmol) dissolved in hydrochloric acid In dioxane solution (4M, 3 mL), the mixture was stirred at 30 ^° C for 1 hour. After the reaction, it was directly concentrated to obtain the title compound (60 mg, yield 80%). MS m/z (ESI): 524.2 [M+H] ⁺ . Step 15: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-1,2,4- Triazol-3-yl)-8-oxo-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclo Preparation of nonane-3 ⁶ -formamide (compound 6-1) 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methyl Oxygen-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-formamide ( 60 mg, 0.11mmol) was dissolved in 1,4-dioxane (3 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene ( 2 mg, 0.0038mmol), tris(dibenzylideneacetone)dipalladium (3.5 mg, 0.0038mmol) and cesium carbonate (37 mg, 0.1146mmol). The mixture was stirred at 130 ^o C for 4 hours. Concentrate directly after the reaction, and the residue is separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain the crude product, which is then prepared and purified by reverse column (acetonitrile:water=1:1) to obtain the title Compound (22 mg, yield 38%). MS m/z (ESI): 487.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ: 11.81 (s, 1H), 10.01 (s, 1H), 9.29 (s, 1H), 8.12 -8.21 (m, 1H), 7.87 -7.59 (m, 4H), 6.91-6.82 (m, 2H), 4.52 (s, 2H), 4.02-4.00 (m, 3H), 3.87 -3.80(m, 5H) , 3.16 -2.93 (m, 5H). The sixteenth step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-1,2,4-triazol-3-yl )-8-oxo-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ - Preparation of formamide trihydrochloride (compound 6-2) 5 ⁶ -methoxy-N-methyl-5 ^5- (1-methyl-1H-1,2,4-triazole-3- Base)-8-oxo-2,4-diazo-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ - Formamide (10 mg, 0.02mmol) was dissolved in 4M dioxane hydrochloride solution (3 mL), and the mixture was stirred at 30 ^o C for 1 hour. Concentration directly after the reaction was completed to obtain the title compound (12 mg, yield 95%). MS m/z (ESI): 487.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ: 9.60 ( s, 1H), 9.23 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.03-6.99 (m , 2H), 4.46 (s, 2H), 4.09 (s, 3H), 3.82 - 3.74 (m, 2H), 3.71 (s, 3H), 2.97 - 2.90 (m, 2H), 2.89 (s, 3H).

第一步：第三丁基(6-((3-((6-氯-3-((甲基-d3)氨甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (180 mg, 0.395mmol) 溶於四氫呋喃 (3 mL) ，依次加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺 (162 mg, 0.79mmol) 和雙(三甲基矽基)醯胺鈉(0.3 mL)，反應液室溫反應10分鐘。反應結束後，加入水(5mL)淬滅，二氯甲烷萃取(3×30mL)，有機相用無水硫酸鈉乾燥、濃縮後，將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得到標題化合物 (200 mg，收率72%). MS m/z (ESI)：627.2 [M+H] ⁺. 第二步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-(甲基-d3)嗒𠯤-3-甲醯胺的製備 將第三丁基(6-((3-((6-氯-3-((甲基-d3)氨甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (200 mg, 0.32mmol) 溶於鹽酸二氧六環溶液(3 mL，4mol/L) 中，混合液於40 ^oC下攪拌1小時。反應結束後直接濃縮，得到標題化合物(120 mg，收率60% )。 MS m/z (ESI)：527.2 [M+H] ⁺. 第三步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-1,2,4-三唑-3-基)-8-氧代-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-(甲基-d3)嗒𠯤-3-甲醯胺(80 mg, 0.15mmol) 溶於1,4-二氧六環 (3 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(8.8 mg, 0.015mmol)，三(二亞苄基丙酮)二鈀 (13.9 mg, 0.015mmol) 和碳酸銫 (148 mg, 0.45mmol)。混合液於130 ^oC下攪拌4小時。反應結束後直接濃縮，殘留物用矽膠柱(二氯甲烷/甲醇=10/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備，純化後得到標題化合物 (5 mg，收率6%)。 MS m/z (ESI)：491.3 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ:12.05 (s, 1H), 9.37 (s, 1H), 8.79 - 8.50 (m, 1H), 8.13 (s, 1H), 7.75-7.71 (m, 2H), 7.68 -7.57 (m, 2H), 7.08-7.01 (m, 1H), 6.90 (d, J= 7.8 Hz, 1H), 4.52 (s, 2H), 4.03 (s, 3H), 3.89-3.85 (m, 5H), 3.15 -2.87 (m, 2H). Example 7: 5 ⁶ -methoxy-N-(methyl-d3)-5 ⁵ -(1-methyl-1H-1,2,4-triazol-3-yl)-8-oxo- Preparation of 2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide

The first step: tertiary butyl (6-((3-((6-chloro-3-((methyl-d3)carbamoyl)acid-4-yl)amino)-4-methoxy Preparation of base-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate Base (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridine- 2-yl)carbamate (180 mg, 0.395mmol) was dissolved in tetrahydrofuran (3 mL), and 4,6-dichloro-N-methylpyridium-3-formamide (162 mg, 0.79 mmol) and sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes. After the reaction was completed, quenched by adding water (5mL), extracted with dichloromethane (3×30mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained residue was applied to a silica gel column (ethyl acetate/petroleum ether=0 -80%) to obtain the title compound (200 mg, yield 72%). MS m/z (ESI): 627.2 [M+H] ⁺ . The second step: 4-((5-(2-(( 6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-6-chloro-N-(methyl-d3) the preparation of thiamine-3-formamide will tertiary butyl (6-((3-((6-chloro-3-((methyl -d3) carbamoyl) ((4-yl) amino) -4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl) phenyl ethyl Oxy)methyl)pyridin-2-yl)carbamate (200 mg, 0.32mmol) was dissolved in dioxane hydrochloride solution (3 mL, 4mol/L), and the mixture was stirred at 40 ^o C 1 hour. After the reaction was completed, it was directly concentrated to obtain the title compound (120 mg, yield 60%). MS m/z (ESI): 527.2 [M+H] ⁺ . The third step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-1,2,4-tri Azol-3-yl)-8-oxo-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane Preparation of alkane-3 ⁶ -formamide 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1 -Methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)pyrrole-3-formamide (80 mg, 0.15mmol) was dissolved in 1,4-dioxane (3 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (8.8 mg, 0.015mmol), tris(dibenzylideneacetone)dipalladium (13.9 mg, 0.015mmol) and cesium carbonate (148 mg, 0.45mmol). The mixture was stirred at 130 ^o C for 4 hours. Concentrate directly after the reaction, and the residue is separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain the crude product, which is then prepared by reverse column (acetonitrile:water=1:1), and the title compound is obtained after purification (5 mg, yield 6%). MS m/z (ESI): 491.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ: 12.05 (s, 1H), 9.37 (s, 1H), 8.79 - 8.50 (m, 1H) , 8.13 (s, 1H), 7.75-7.71 (m, 2H), 7.68 -7.57 (m, 2H), 7.08-7.01 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.52 (s , 2H), 4.03 (s, 3H), 3.89-3.85 (m, 5H), 3.15 -2.87 (m, 2H).

第一步：4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙酸乙酯的製備 將3-溴-4-甲氧基-5-硝基苯乙酸乙酯 (500 mg, 1.57 mmol) 溶於混合溶液（8 mL ，1,4-二氧六環：水=3：1）中，在氮氣氛圍下加入 [1,1’-雙(二苯基膦)二茂鐵] 二氯化鈀 (115 mg, 0.15 mmol)，碳酸鉀 (652 mg, 4.72 mmol) 和 1-甲基-3-(4,4,5,5-四甲基-1,3,2-二㗁硼烷-2-基)-1H-吡唑(360 mg, 1.73 mmol)，混合液於90 ℃下攪拌1小時。反應結束後，用乙酸乙酯 (3×5 mL) 萃取，有機相合併後，用無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱（石油醚/乙酸乙酯=1/1）純化後得到標題化合物(480 mg，收率77%)。 MS m/z (ESI)：320.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ: 8.01 (d, J= 2.4 Hz, 1H), 7.83 (d, J= 2.4 Hz, 1H), 7.74 (d, J= 2.4 Hz, 1H), 6.73 (d, J= 2.4 Hz, 1H), 4.25 (t, J= 6.0 Hz, 2H), 3.93(s, 3H), 3.69 (s, 3H), 2.97 (t, J= 6.0 Hz, 2H), 1.99 (s, 3H). 第二步：2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙基-1-醇的製備 將4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙酸乙酯 (480 mg, 1.50 mmol)溶於甲醇 (4 mL) 中，再加入甲醇鈉 (41 mg, 0.75 mmol)，混合液於25 ℃下攪拌 2小時。反應結束後，用水 (10 mL) 淬滅，並用乙酸乙酯 (3×10 mL) 萃取，有機相合併後用無水硫酸鈉乾燥，濃縮後，將得到的殘留物用矽膠柱（二氯甲烷/甲醇=1/0）純化後得到標題化合物 (240 mg，收率46%)。 MS m/z (ESI)：278.1 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ: 7.98 (d, J= 4.0 Hz, 1H), 7.83 (d, J= 4.0 Hz, 1H), 7.68 (d, J= 4.0 Hz, 1H), 6.72 (d, J= 4.0 Hz, 1H), 4.70 (t, J= 6.0 Hz, 1H), 3.93 (d, J= 2.0 Hz, 3H), 3.71 (s, 3H), 3.62 (t, J= 4.0 Hz, 2H), 2.79 (t, J= 8.0 Hz, 2H). 第三步：第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)吡啶-2-基)胺基甲酸酯的製備 將 2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙基-1-醇 (240 mg, 0.86 mmol) 溶於N,N-二甲基甲醯胺 (5 mL) 中，再加入氫化鈉 (62 mg, 2.60 mmol)，混合液於0 ^oC下攪拌10分鐘。反應結束後，用飽和氯化銨水溶液 (10 mL) 淬滅，並用乙酸乙酯 (3×10 mL) 萃取，有機相合併後用無水硫酸鈉乾燥，濃縮後得到標題化合物 (400 mg)，直接用於下一步反應。 MS m/z (ESI)：484.1 [M+H] ⁺. 第四步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)吡啶-2-基)胺基甲酸酯(400 mg, 0.82 mmol)溶於乙醇和水 (EtOH: H ₂O=4:1，5 mL)的混合溶液中，加入鐵粉（645 mg, 11.56 mmol) 和氯化銨 (883 mg, 16.5 mmol)，混合液於80 ^oC下回流1小時。反應結束後，過濾，得濾液，濃縮後，將得到的殘留物用矽膠柱（石油醚/乙酸乙酯=1/1）純化，得到標題化合物(130 mg，收率24%)。 MS m/z (ESI)：454.2 [M+H] ⁺. 第五步：第三丁基(6-((3-((6-氯-3-(甲醯胺基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基) 胺基甲酸酯 (130 mg, 0.29 mmol) 和4,6-二氯-N-甲基嗒𠯤-3-甲醯胺 (59 mg, 0.29 mmol) 溶於四氫呋喃 (3 mL)中，緩慢滴加雙(三甲基矽基)氨化鈉 (2M, 0.29 mL, 0.58 mmol)，混合液於25 ^oC下攪拌10分鐘。反應結束後，用甲醇 (10 mL) 淬滅，濃縮後，將得到的殘留物用矽膠柱（二氯甲烷/甲醇=17/3）純化，得標題化合物 (90 mg，收率35%)。 MS m/z (ESI)：624.2 [M+H] ⁺. 第六步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-胺基甲酸酯的製備 將(6-((3-((6-氯-3-(甲醯胺基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (90 mg, 0.14 mmol) 溶於鹽酸二氧六環的混合液中（HCl/dioxane=4mol/L ，4 mL）中，混合液於25 ^oC下攪拌1小時。反應結束後直接濃縮，殘留物用柱層析（石油醚:乙酸乙酯=1:4）分離純化後得到標題化合物 (60 mg，收率48%)。 MS m/z (ESI)：523.2 [M+H] ⁺. 第七步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-3-基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-胺基甲酸酯 (60 mg, 0.11 mmol) 溶於1,4-二氧六環(3 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(13 mg, 0.02 mmol)，三(二亞苄基丙酮)二鈀 (10 mg, 0.01 mmol) 和碳酸銫 (112 mg, 0.34 mmol)。混合液於130 ^oC下攪拌4小時。反應結束後直接濃縮，殘留物用矽膠柱（二氯甲烷/甲醇=17/3）分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備，純化後得到標題化合物(2.3 mg，收率4%)。 MS m/z (ESI)：487.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ: 11.84 (s, 1H), 9.94 (s, 1H), 9.34 (s, 1H), 7.86 (s, 1H), 7.68 (d, J= 2.0 Hz, 1H), 7.62-7.59 (m, 2H), 7.42 (d, J= 2.4 Hz,1H), 6.94 (d, J= 8.4 Hz, 1H), 6.90-6.83 (m, 2H), 4.51 (s, 2H), 3.99 (s, 3H), 3.90-3.84 (m, 2H), 3.72 (s, 3H), 3.06 (d, J= 4.8 Hz, 3H), 2.98-2.92 (m, 2H). Example 8: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide

The first step: the preparation of ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenylacetate 3-bromo-4-methoxy-5 -Ethyl nitrophenylacetate (500 mg, 1.57 mmol) was dissolved in the mixed solution (8 mL, 1,4-dioxane:water=3:1), and [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg, 0.15 mmol), potassium carbonate (652 mg, 4.72 mmol) and 1-methyl-3-(4,4,5,5-tetra Methyl-1,3,2-diborolan-2-yl)-1H-pyrazole (360 mg, 1.73 mmol), and the mixture was stirred at 90°C for 1 hour. After the reaction, extract with ethyl acetate (3×5 mL), combine the organic phases, dry with anhydrous sodium sulfate, concentrate and purify the obtained residue with silica gel column (petroleum ether/ethyl acetate=1/1) The title compound (480 mg, yield 77%) was obtained. MS m/z (ESI): 320.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 8.01 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.4 Hz , 1H), 7.74 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.93(s, 3H), 3.69 (s , 3H), 2.97 (t, J = 6.0 Hz, 2H), 1.99 (s, 3H). The second step: 2-(4-methoxy-3-(1-methyl-1H-pyrazole-3 4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenylacetic acid Ethyl ester (480 mg, 1.50 mmol) was dissolved in methanol (4 mL), and sodium methoxide (41 mg, 0.75 mmol) was added, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, it was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the obtained residue was applied to a silica gel column (dichloromethane/ Methanol=1/0) to obtain the title compound (240 mg, yield 46%) after purification. MS m/z (ESI): 278.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 7.98 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 4.0 Hz , 1H), 7.68 (d, J = 4.0 Hz, 1H), 6.72 (d, J = 4.0 Hz, 1H), 4.70 (t, J = 6.0 Hz, 1H), 3.93 (d, J = 2.0 Hz, 3H ), 3.71 (s, 3H), 3.62 (t, J = 4.0 Hz, 2H), 2.79 (t, J = 8.0 Hz, 2H). The third step: tertiary butyl (6-((4-methoxy Preparation of base-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)pyridin-2-yl)carbamate with 2-(4-methoxy Dimethyl-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethyl-1-ol (240 mg, 0.86 mmol) dissolved in N,N-dimethylformaldehyde Amide (5 mL), then added sodium hydride (62 mg, 2.60 mmol), and the mixture was stirred at 0 ^o C for 10 minutes. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride (10 mL) and washed with acetic acid Ethyl ester (3×10 mL) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (400 mg), which was directly used in the next reaction. MS m/z (ESI): 484.1 [M+H ] ⁺ . The fourth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenethoxy) methyl Base) the preparation of pyridin-2-yl) carbamate the tertiary butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5 -Nitrophenethoxy)pyridin-2-yl)carbamate (400 mg, 0.82 mmol) was dissolved in a mixed solution of ethanol and water (EtOH:H ₂ O=4:1, 5 mL), Iron powder (645 mg, 11.56 mmol) and ammonium chloride (883 mg, 16.5 mmol) were added, and the mixture was refluxed at 80 ^o C for 1 hour. After the reaction was completed, it was filtered to obtain the filtrate, which was concentrated and the obtained residue Purify with silica gel column (petroleum ether/ethyl acetate=1/1) to obtain the title compound (130 mg, yield 24%). MS m/z (ESI): 454.2 [M+H] ⁺ . The fifth step: tertiary butyl(6-((3-((6-chloro-3-(formylamino)pyrthal-4-yl)amino)-4-methoxy-5-(1-methyl- 1H-pyrazol-3-yl)phenethoxy)methyl) The preparation of pyridin-2-yl) carbamate will tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl )phenethoxy)methyl)pyridin-2-yl)carbamate (130 mg, 0.29 mmol) and 4,6-dichloro-N-methylpyridine-3-formamide (59 mg , 0.29 mmol) was dissolved in tetrahydrofuran (3 mL), and bis(trimethylsilyl) sodium amide (2M, 0.29 mL, 0.58 mmol) was slowly added dropwise, and the mixture was stirred at 25 ^o C for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), concentrated, and the obtained residue was purified with a silica gel column (dichloromethane/methanol=17/3) to obtain the title compound (90 mg, yield 35%). MS m/z (ESI): 624.2 [M+H] ⁺ . The sixth step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 The preparation of -methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-carbamate (6-((3-((6-chloro-3-(formylamino)pyridyl-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazole -3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (90 mg, 0.14 mmol) dissolved in a mixture of dioxane hydrochloride (HCl/dioxane=4mol/L , 4 mL), the mixture was stirred at 25 ^o C for 1 hour. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain the title compound (60 mg, yield 48%). MS m/z (ESI): 523.2 [M+H] ⁺ . The seventh step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl) -8-oxa-2,4-diaza-3(3,5)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formyl Preparation of amines Azol-3-yl)phenyl)amino)-6-chloro-N-methylpyridium-3-carbamate (60 mg, 0.11 mmol) dissolved in 1,4-dioxane (3 mL), added 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (13 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium ( 10 mg, 0.01 mmol) and cesium carbonate (112 mg, 0.34 mmol). The mixture was stirred at 130 ^o C for 4 hours. Concentrate directly after the reaction, and the residue is separated and purified by silica gel column (dichloromethane/methanol=17/3) to obtain the crude product, which is then prepared by reverse column (acetonitrile:water=1:1), and the title compound is obtained after purification (2.3 mg, yield 4%). MS m/z (ESI): 487.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.84 (s, 1H), 9.94 (s, 1H), 9.34 (s, 1H) , 7.86 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.62-7.59 (m, 2H), 7.42 (d, J = 2.4 Hz,1H), 6.94 (d, J = 8.4 Hz, 1H), 6.90-6.83 (m, 2H), 4.51 (s, 2H), 3.99 (s, 3H), 3.90-3.84 (m, 2H), 3.72 (s, 3H), 3.06 (d, J = 4.8 Hz , 3H), 2.98-2.92 (m, 2H).

第一步：第三丁基(6-((3-((6-氯-3-((甲基-d ₃)甲醯胺基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基) 胺基甲酸酯 (製備方法參見實施例8，270 mg, 0.59 mmol) 和4,6-二氯-N-(甲基-d ₃)嗒𠯤-3-甲醯胺 (124 mg, 0.59 mmol) 溶於四氫呋喃 (5 mL)中，緩慢滴加雙(三甲基矽基)氨化鈉 (2M, 0.59 mL, 1.19 mmol)，混合液於25 ^oC 下攪拌10 分鐘。反應結束後，用甲醇 (10 mL) 淬滅，濃縮後，將得到的殘留物用矽膠柱（二氯甲烷/甲醇=9/1）純化得標題化合物 (200 mg，收率37%)。 MS m/z (ESI)：626.3[M+H] ⁺. 第二步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯- N-(甲基-d ₃)嗒𠯤-3-胺基甲酸酯的製備 將純化的第三丁基(6-((3-((6-氯-3-((甲基-d ₃)甲醯胺基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (200 mg, 0.32 mmol) 溶於鹽酸二氧六環的混合液 (HCl/dioxane=4mol/L, 5 mL) 中，混合液於25 ^oC下攪拌4小時。反應結束後直接濃縮，得到標題化合物 (100 mg，收率35%)。 MS m/z (ESI)：526.3 [M+H] ⁺. 第三步：5 ⁶-甲氧基- N-(甲基-d ₃)-5 ⁵-(1-甲基-1H-吡唑-3-基)-8-氧雜-2,4-二氮-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯- N-(甲基-d ₃)嗒𠯤-3-胺基甲酸酯 (100 mg, 0.19 mmol) 溶於1,4-二氧六環 (5 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(66 mg, 0.11 mmol)，三(二亞苄基丙酮)二鈀 (52 mg, 0.05 mmol) 和碳酸銫 (557 mg, 1.71 mmol)。 混合液於130 ^oC下攪拌6小時。反應結束後直接濃縮，殘留物用矽膠柱（二氯甲烷/甲醇=4/1）分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備，純化後，得到標題化合物(4.5 mg，收率4%)。 MS m/z (ESI)：490.1 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ: 11.37 (s, 1H), 10.36 (s, 1H), 9.05 (s, 2H), 7.77 (d, J= 2.0 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.57 (d, J= 1.6 Hz, 1H), 7.48 (d, J= 1.6 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 6.74 (d, J= 2.0 Hz, 1H), 4.44 (s, 2H), 3.91 (s, 3H), 3.75 (t, J= 4.8 Hz, 2H), 3.60 (s, 3H), 2.86 (t, J= 4.8 Hz, 2H). Example 9: 5 ⁶ -methoxy-N-(methyl-d ₃ )-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-oxa-2,4-di Preparation of nitrogen-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide

The first step: tertiary butyl (6-((3-((6-chloro-3-((methyl-d ₃ )formamido)acid-4-yl)amino)-4-methanol Preparation of oxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate by tertiary butyl (6-( (3-Amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (Preparation See Example 8 for the method, 270 mg, 0.59 mmol) and 4,6-dichloro-N-(methyl-d ₃ ) pyridoxine-3-formamide (124 mg, 0.59 mmol) were dissolved in tetrahydrofuran (5 mL ), slowly dropwise added sodium bis(trimethylsilyl)amide (2M, 0.59 mL, 1.19 mmol), and the mixture was stirred at 25 ^o C for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), concentrated, and the resulting residue was purified with a silica gel column (dichloromethane/methanol=9/1) to obtain the title compound (200 mg, yield 37%). MS m/z (ESI): 626.3[M+H] ⁺ . Second step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 -Methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d ₃ )pyrazole-3-aminomethyl The preparation of ester will purify the tertiary butyl (6-((3-((6-chloro-3-((methyl-d ₃ )formylamino)pyrrole-4-yl)amino)- 4-Methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (200 mg, 0.32 mmol) In a mixture of dioxane hydrochloride (HCl/dioxane=4mol/L, 5 mL), the mixture was stirred at 25 ^o C for 4 hours. After the reaction was completed, it was directly concentrated to obtain the title compound (100 mg, yield 35%). MS m/z (ESI): 526.3 [M+H] ⁺ . The third step: 5 ⁶ -methoxy-N-(methyl-d ₃ )-5 ⁵ -(1-methyl-1H-pyrazole -3-yl)-8-oxa-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane- 3. Preparation of ⁶ -formamide 4-((5-(2-((6-aminopyridin-2-yl) methoxy) ethyl) Base-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d ₃ )pyrazole-3-carbamate (100 mg, 0.19 mmol) dissolved in 1,4-Dioxane (5 mL), add 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (66 mg, 0.11 mmol) under nitrogen atmosphere, three (dibenzylideneacetone)dipalladium (52 mg, 0.05 mmol) and cesium carbonate (557 mg, 1.71 mmol). The mixture was stirred at 130 ^o C for 6 hours. Concentrate directly after the reaction, and the residue is separated and purified by silica gel column (dichloromethane/methanol=4/1) to obtain the crude product, which is then prepared by reverse column (acetonitrile:water=1:1), and after purification, the title Compound (4.5 mg, yield 4%). MS m/z (ESI): 490.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.37 (s, 1H), 10.36 (s, 1H), 9.05 (s, 2H) , 7.77 (d, J = 2.0 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 4.44 (s, 2H), 3.91 (s, 3H), 3.75 (t, J = 4.8 Hz, 2H), 3.60 (s, 3H), 2.86 (t, J = 4.8 Hz, 2H).

第一步：第三丁基 (第三丁氧羰基)(5-氟-6-甲基吡啶-2-基)胺基甲酸酯的製備 將5-氟-6-甲基吡啶-2-胺基（5.0 g, 39.68 mmol）溶於乙腈（50 mL）中，向溶液中加入二碳酸二第三丁酯（21.63 g, 99.20 mmol, 2.5 eq），三乙胺（10.02 g, 99.20 mmol, 2.5 eq），4-二甲胺基吡啶（0.91 g, 7.94 mmol, 0.2 eq）。反應液在室溫下攪拌16 h。反應結束後，將反應液濃縮，粗產品經柱層析純化（石油醚/乙酸乙酯＝5/1）得到標題化合物（9.05 g,，收率70%）。 MS m/z (ESI)：349.0[M+Na] ⁺. 第二步：第三丁基(6-(溴甲基)-5-氟吡啶-2-基)(第三丁氧羰基)胺基甲酸酯的製備 將上一步得到的產物第三丁基 (第三丁氧羰基)(5-氟-6-甲基吡啶-2-基)胺基甲酸酯（8.8 g, 26.99 mmol）溶於四氯化碳（30 mL）中，依次加入N-溴代丁二醯亞胺（5.76 g, 32.39 mmol, 1.2 eq），偶氮二異丁腈（0.44 g, 2.70 mmol, 0.1 eq），反應液在80 ^oC下攪拌16 h。反應結束後，將反應液濃縮，粗產品經柱層析純化（石油醚/乙酸乙酯＝5/1）得到標題化合物（4.36 g, 收率40%）。 MS m/z (ESI)：427.0[M+Na] ⁺. 第三步：第三丁基(5-氟-6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙-1-醇（1.14 g, 4.14 mmol，1.5 eq）溶於DMF（10 mL）中，在0 ℃下加入氫化鈉（0.4 g, 16.56 mmol, 4 eq），攪拌10 min，再向反應液中加入第三丁基(6-(溴甲基)-5-氟吡啶-2-基)(第三丁氧羰基)胺基甲酸酯（1.12 g, 2.76 mmol, 1 eq），混合液在0 ℃下反應4 h。反應結束後，緩慢滴加水，二氯甲烷萃取，有機相用無水硫酸鈉乾燥，濃縮後的粗產品經柱層析（石油醚/乙酸乙酯＝2/1）分離純化得到標題化合物（0.42 g, 收率31%）。 MS m/z (ESI)：502.1[M+H] ⁺. 第四步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)-5-氟吡啶-2-基)胺基甲酸酯的製備 將第三丁基 (5-氟-6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯（0.4 g, 0.82 mmol）溶於乙醇和氯化銨（乙醇/氯化銨=4/1，15 mL）的飽和水溶液中，再加入鐵粉（0.92 g, 16.4 mmol, 20 eq），反應液在80 ℃下攪拌1 h。反應結束後，反應液經濃縮後的粗產品經柱層析（石油醚/乙酸乙酯＝2/1）分離純化，得到標題化合物（0.27 g, 收率70%）。 MS m/z (ESI)：472.1[M+H] ⁺. 第五步：第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯基乙氧基)甲基)-5-氟吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)-5-氟吡啶-2-基)胺基甲酸酯（0.27 g, 0.58 mmol）以及4,6-二氯-N-甲基嗒𠯤-3-羧醯胺（0.36 g, 1.74 mmol, 3 eq）溶於四氫呋喃（10 mL）中，向反應液中加入NaHMDS（0.64 g, 3.48 mmol, 6 eq），反應液在室溫下攪拌10 min，反應結束後將反應液濃縮，粗產品經柱層析（石油醚/乙酸乙酯＝1/1）分離純化，得到標題化合物（128 mg, 收率35%）。 MS m/z (ESI)：641.1[M+H] ⁺. 第六步：4-((5-(2-((6-胺基-3-氟吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-胺基甲酸酯的製備 將第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯基乙氧基)甲基)-5-氟吡啶-2-基)胺基甲酸酯（128 mg, 0.20 mmol）溶於二氯甲烷（5 mL）中，並向反應混合物中加入鹽酸的二氧六環（10 mL，4M）溶液。將反應混合物在40 ℃下攪拌2 h。濃縮反應混合物，得到標題化合物（91.8 mg， 收率85%）。 MS m/z (ESI)：541.1[M+H] ⁺. 第七步：1 ⁵-氟-5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-3-基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-羧醯胺的製備 將4-((5-(2-((6-胺基-3-氟吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-胺基甲酸酯（90 mg, 0.16 mmol）溶解在1,4-二氧六環（5 mL）中，氮氣保護下向反應混合物中加入三（二亞苄基丙酮）二鈀（44 mg，0.048 mmol, 0.3 eq），4,5-雙（二苯基膦基）-9,9-二甲基黃嘌呤（55.5 mg，0.096 mmol, 0.6 eq），碳酸銫（156.4 mg, 0.48 mmol, 3 eq）。 將得到的反應混合物在130 ℃下攪拌4小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗產物通過製備色譜純化，得到標題化合物（6.5 mg，收率8%）。 MS m/z (ESI)：505.1[M+H] ⁺. 1H NMR (400 MHz, DMSO- d6) δ: 11.32 (s, 1H), 10.43 (s, 1H), 9.07 (d, J= 4.8 Hz, 1H), 8.89 (s, 1H), 7.78 (d, J= 2.2 Hz, 1H), 7.65 (t, J= 9.2 Hz, 1H), 7.54 (d, J= 1.8 Hz, 1H), 7.50 (d, J= 1.8 Hz, 1H), 7.16 (dd, J= 9.0, 3.2 Hz, 1H), 6.74 (d, J= 2.2 Hz, 1H), 4.57 (d, J= 2.4 Hz, 2H), 3.91 (s, 3H), 3.81 -3.76 (m, 2H), 3.59 (s, 3H), 2.89 - 2.85 (m, 5H). Example 10: 1 ⁵ -fluoro-5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-oxa-2,4-di Preparation of aza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

The first step: the preparation of tertiary butyl (tertiary butoxycarbonyl) (5-fluoro-6-methylpyridin-2-yl) carbamate 5-fluoro-6-methylpyridine-2- Amino group (5.0 g, 39.68 mmol) was dissolved in acetonitrile (50 mL), di-tert-butyl dicarbonate (21.63 g, 99.20 mmol, 2.5 eq), triethylamine (10.02 g, 99.20 mmol, 2.5 eq), 4-dimethylaminopyridine (0.91 g, 7.94 mmol, 0.2 eq). The reaction solution was stirred at room temperature for 16 h. After the reaction, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound (9.05 g, yield 70%). MS m/z (ESI): 349.0[M+Na] ⁺ . The second step: tert-butyl(6-(bromomethyl)-5-fluoropyridin-2-yl)(tert-butoxycarbonyl)amine Preparation of carbamate The product obtained in the previous step tert-butyl (tertiary butoxycarbonyl) (5-fluoro-6-methylpyridin-2-yl) carbamate (8.8 g, 26.99 mmol) Dissolve in carbon tetrachloride (30 mL), add N-bromosuccinimide (5.76 g, 32.39 mmol, 1.2 eq) and azobisisobutyronitrile (0.44 g, 2.70 mmol, 0.1 eq) in sequence , and the reaction solution was stirred at 80 ^o C for 16 h. After the reaction, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound (4.36 g, yield 40%). MS m/z (ESI): 427.0[M+Na] ⁺ . The third step: tertiary butyl (5-fluoro-6-((4-methoxy-3-(1-methyl-1H-pyridine Preparation of oxazol-3-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate 2-(4-methoxy-3-(1-methyl- 1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-ol (1.14 g, 4.14 mmol, 1.5 eq) was dissolved in DMF (10 mL), and sodium hydride (0.4 g, 16.56 mmol, 4 eq), stirred for 10 min, then added tertiary butyl (6-(bromomethyl)-5-fluoropyridin-2-yl) (tertiary butoxycarbonyl) amino group to the reaction solution Formate (1.12 g, 2.76 mmol, 1 eq), the mixture was reacted at 0 °C for 4 h. After the reaction was completed, water was slowly added dropwise, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The concentrated crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the title compound (0.42 g , yield 31%). MS m/z (ESI): 502.1[M+H] ⁺ . The fourth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H- Preparation of pyrazol-3-yl)phenethoxy)methyl)-5-fluoropyridin-2-yl)carbamate The tertiary butyl (5-fluoro-6-((4-methoxy yl-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (0.4 g, 0.82 mmol) Dissolve in a saturated aqueous solution of ethanol and ammonium chloride (ethanol/ammonium chloride=4/1, 15 mL), then add iron powder (0.92 g, 16.4 mmol, 20 eq), and stir the reaction solution at 80 °C for 1 h . After the reaction, the reaction solution was concentrated and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the title compound (0.27 g, yield 70%). MS m/z (ESI): 472.1[M+H] ⁺ . The fifth step: tertiary butyl (6-((3-((6-chloro-3-(methylaminoformyl)da -4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenylethoxy)methyl)-5-fluoropyridin-2-yl ) Preparation of carbamate: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenylethoxy )methyl)-5-fluoropyridin-2-yl)carbamate (0.27 g, 0.58 mmol) and 4,6-dichloro-N-methylpyridine-3-carboxamide (0.36 g, 1.74 mmol, 3 eq) was dissolved in tetrahydrofuran (10 mL), NaHMDS (0.64 g, 3.48 mmol, 6 eq) was added to the reaction solution, and the reaction solution was stirred at room temperature for 10 min. After the reaction was completed, the reaction solution was concentrated. The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the title compound (128 mg, yield 35%). MS m/z (ESI): 641.1[M+H] ⁺ . The sixth step: 4-((5-(2-((6-amino-3-fluoropyridin-2-yl)methoxy)ethyl Base)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-carbamic acid The preparation of the ester is the tert-butyl (6-((3-((6-chloro-3-(methylaminoformyl) pyridyl-4-yl) amino)-4-methoxy-5 -(1-Methyl-1H-pyrazol-3-yl)phenylethoxy)methyl)-5-fluoropyridin-2-yl)carbamate (128 mg, 0.20 mmol) was dissolved in di Chloromethane (5 mL), and a solution of hydrochloric acid in dioxane (10 mL, 4M) was added to the reaction mixture. The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated to obtain the title compound (91.8 mg, yield 85%). MS m/z (ESI): 541.1[M+H] ⁺ . The seventh step: 1 ⁵ -fluoro-5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazole -3-yl)-8-oxa-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane -3 Preparation of ⁶ -carboxamide 4-((5-(2-((6-amino-3-fluoropyridin-2-yl)methoxy)ethyl)-2-methoxy-3 -(1-Methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrazol-3-carbamate (90 mg, 0.16 mmol) was dissolved in In 1,4-dioxane (5 mL), tris(dibenzylideneacetone)dipalladium (44 mg, 0.048 mmol, 0.3 eq), 4,5-bis(di Phenylphosphino)-9,9-dimethylxanthine (55.5 mg, 0.096 mmol, 0.6 eq), cesium carbonate (156.4 mg, 0.48 mmol, 3 eq). The resulting reaction mixture was stirred at 130 °C for 4 hours. The reaction mixture was filtered and the organic layer was concentrated to give crude product. The crude product was purified by preparative chromatography to afford the title compound (6.5 mg, yield 8%). MS m/z (ESI): 505.1[M+H] ⁺ .1H NMR (400 MHz, DMSO- d6 ) δ: 11.32 (s, 1H), 10.43 (s, 1H), 9.07 (d, J = 4.8 Hz , 1H), 8.89 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.65 (t, J = 9.2 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.50 (d , J = 1.8 Hz, 1H), 7.16 (dd, J = 9.0, 3.2 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 4.57 (d, J = 2.4 Hz, 2H), 3.91 (s , 3H), 3.81 -3.76 (m, 2H), 3.59 (s, 3H), 2.89 - 2.85 (m, 5H).

第一步：(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)胺基甲酸第三丁酯的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙-1-胺(300 mg, 1.08 mmol)，三乙胺(545 mg, 5.40 mmol)混溶於二氯甲烷(20 mL)中。在冰浴下將二碳酸二第三丁酯(796 mg, 3.24 mmol)滴加到反應液中。然後室溫攪拌過夜。反應完成後減壓濃縮，通過快速柱層析法(二氯甲烷 / 甲醇＝ 3%)，得到標題化合物(400 mg，收率98%)。 MS m/z (ESI): 377.3 [M + H] ⁺. 第二步：(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)(甲基)胺基甲酸第三丁酯的製備 將(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)胺基甲酸酯(400 mg，1.06 mmol)溶於DMF(10 mL)中的溶液中，並在0°C下添加鈉氫(76mg，3.18mmol)，反應攪拌15分鐘後，在室溫下加入CH ₃I(150mg，5.30mmol)並攪拌反應3小時。加入飽和的氯化銨溶液淬滅反應，加入水(50 mL)，乙酸乙酯(30 mL×3)萃取。 合併有機層，用鹽水洗滌，無水硫酸鈉乾燥，濃縮。通過快速柱層析法純化(EA / PE ＝ 30%)，得到標題化合物 (350 mg，收率85%)。 MS m/z (ESI): 391.3 [M + H] ⁺. 第三步：2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)-N-甲基乙烷-1-胺的製備 將(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)(甲基)胺基甲酸第三丁酯(350 mg, 0.90 mmol)溶於鹽酸二氧六環(10 mL，4 M)的溶液中。將此反應懸濁液在25°C攪拌2小時。LC-MS顯示反應已完成。在減壓下濃縮，得到標題化合物(250 mg，收率96%)。 MS m/z (ESI): 291.2 [M + H] ⁺. 第四步：第三丁基(第三丁氧羰基)(6-(((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)(甲基)胺基)甲基)吡啶-2-基 胺基甲酸酯的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)-N-甲基乙烷-1-胺(250 mg, 0.86 mmol)溶於DMF(10 mL)中的溶液中，並在0°C下添加氫化鈉 (41 mg, 1.72 mmol)，反應攪拌15分鐘後，在室溫下加入(6-(溴甲基)吡啶-2-基)(第三丁氧羰基)胺基甲酸第三丁酯 (398 mg, 1.03 mmol)，並攪拌反應3小時。加入飽和的氯化銨溶液淬滅反應，加入水(50 mL)，乙酸乙酯(30 mL×3)萃取。 合併有機層，用鹽水洗滌，無水硫酸鈉乾燥，濃縮。通過快速柱層析法純化(EA / PE ＝ 30%)，得到標題化合物 (400 mg，收率78%)。 MS m/z (ESI): 597.3 [M + H] ⁺. 第五步：第三丁基(6-((((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)(甲基)胺基)甲基)吡啶-2-基)(叔-丁氧羰基)胺基甲酸酯的製備 將第三丁基(第三丁氧羰基)(6-(((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)(甲基)胺基)甲基)吡啶-2-基 胺基甲酸酯(400 mg, 0.67 mmol)，鐵粉(300 mg, 5.36 mmol)和氯化銨(289 mg, 5.36 mmol)混溶於乙醇和水的混合液(乙醇:水=4:1, 20 mL)中。將反應在50°C下攪拌2小時。反應完成後過濾、減壓濃縮，通過快速柱層析法(二氯甲烷 / 甲醇＝ 3%)，得到標題化合物 (350 mg，收率92%)。 MS m/z (ESI): 567.3 [M + H] ⁺. 第六步：第三丁基(6-((((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基) 苯乙基)(甲基)胺基)甲基)吡啶-2-基胺基甲酸酯的製備 將第三丁基(6-((((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)(甲基)胺基)甲基)吡啶-2-基)(第三丁氧羰基)胺基甲酸酯(350 mg, 0.62 mmol)，4,6-二氯-N-甲基嗒𠯤-3-甲醯胺(190 mg, 0.93 mmol)混溶於四氫呋喃(10 mL)中，室溫下滴加雙(三甲基矽基)胺基鈉(1.6 mL, 3.1 mmol，2M的四氫呋喃溶液)。 將混合物在25°C下攪拌1小時。 反應完成後加入飽和的氯化銨水溶液淬滅反應。加入水(30 mL)，乙酸乙酯(30mL×3)萃取。合併的有機層用鹽水洗滌，無水硫酸鈉乾燥，然後濃縮。通過快速柱層析法純化(PE / EA ＝ 0~100%)，得到標題化合物 (300 mg，收率76%)。 MS m/z (ESI): 636.3 [M + H] ⁺. 第七步：4-((5-(2-(((((6-胺基吡啶-2-基)甲基)(甲基)胺基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基 )胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺的製備 在100 mL 的燒瓶中加入上一步得到的標題化合物第三丁基(6-((((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)(甲基)胺基)甲基)吡啶-2-基胺基甲酸酯(300 mg, 0.47 mmol)。然後，緩慢滴加4 M 的鹽酸二氧六環溶液(8 mL)。在25°C下攪拌4小時。反應完成後，減壓濃縮，得到標題化合物 (200 mg，收率 80%)。 MS m/z (ESI): 536.2 [M + H] ⁺. 第八步：5 ⁶-甲氧基-N,8-二甲基-5 ⁵-(1-甲基-1H-吡唑-3-基)-2,4,8-三氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-羧醯胺的製備 將4-((5-(2-(((((6-胺基吡啶-2-基)甲基)(甲基)胺基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基 )胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺(200 mg, 0.37 mmol)，碳酸銫(360 mg, 1.11 mmol)，Pd ₂(dba) ₃(68 mg, 0.08 mmol)，4,5-雙二苯基膦-9,9-二甲基氧雜蒽(43 mg, 0.07 mmol)混溶於1,4-二氧六環(10 mL)中。氮氣氛圍下置換三次，然後將反應混合物在密閉管中加熱到130 °C攪拌2 小時。反應完成後過濾，濃縮，得到粗產物。將粗產物通過製備液相色譜法純化，得到標題化合物(1.5 mg，收率7%)。 MS m/z (ESI)：500.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 11.35 (s, 1H), 10.34 (s, 1H), 9.12 (s, 1H), 9.07 (d, J= 4.8 Hz, 1H), 7.77 (d, J= 2.2 Hz, 1H), 7.67 (d, J= 2.0 Hz, 1H), 7.65 – 7.59 (m, 1H), 7.46 (d, J= 2.0 Hz,1H), 7.07 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 8.0 Hz, 1H), 6.73 (d, J= 2.0 Hz, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 3.48 (s, 2H), 2.86 (d, J=4.8 Hz, 2H), 2.82 – 2.80 (m, 2H), 2.69 – 2.67 (m, 3H), 1.96 (s, 3H). Example 11: 5 ⁶ -methoxy-N,8-dimethyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-2,4,8-triaza-3( Preparation of 3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

The first step: the preparation of (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl) tertiary butyl carbamate with 2-( 4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-amine (300 mg, 1.08 mmol), triethylamine (545 mg , 5.40 mmol) was dissolved in dichloromethane (20 mL). Di-tert-butyl dicarbonate (796 mg, 3.24 mmol) was added dropwise to the reaction solution under ice-cooling. It was then stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the title compound (400 mg, yield 98%) was obtained by flash column chromatography (dichloromethane/methanol = 3%). MS m/z (ESI): 377.3 [M + H] ⁺ . Second step: (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrobenzene Preparation of ethyl) (methyl) tertiary butyl carbamate (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl) Carbamate (400 mg, 1.06 mmol) was dissolved in a solution in DMF (10 mL), and sodium hydrogen (76 mg, 3.18 mmol) was added at 0°C, and after the reaction was stirred for 15 minutes, at room temperature _CH3I (150 mg, 5.30 mmol) was added and the reaction was stirred for 3 hours. Add saturated ammonium chloride solution to quench the reaction, add water (50 mL), and extract with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE = 30%) afforded the title compound (350 mg, yield 85%). MS m/z (ESI): 391.3 [M + H] ⁺ . The third step: 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrate (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl ) Tert-butyl (methyl)carbamate (350 mg, 0.90 mmol) was dissolved in a solution of dioxane hydrochloride (10 mL, 4 M). The reaction suspension was stirred at 25°C for 2 hours. LC-MS showed the reaction was complete. Concentration under reduced pressure gave the title compound (250 mg, yield 96%). MS m/z (ESI): 291.2 [M + H] ⁺ . The fourth step: tertiary butyl (tertiary butoxycarbonyl) (6-(((4-methoxy-3-(1-methyl -1H-pyrazol-3-yl)-5-nitrophenethyl) (methyl) amino) methyl) pyridin-2-yl carbamate with 2-(4-methoxy -3-(1-Methyl-1H-pyrazol-3-yl)-5-nitrophenyl)-N-methylethan-1-amine (250 mg, 0.86 mmol) was dissolved in DMF (10 mL ), and sodium hydride (41 mg, 1.72 mmol) was added at 0°C, and after the reaction was stirred for 15 minutes, (6-(bromomethyl)pyridin-2-yl)(6-(bromomethyl)pyridin-2-yl) was added at room temperature Tributoxycarbonyl) tert-butyl carbamate (398 mg, 1.03 mmol), and stirred for 3 hours. Add saturated ammonium chloride solution to quench the reaction, add water (50 mL), ethyl acetate (30 mL × 3) extraction.The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated.Purified by flash column chromatography (EA/PE=30%) to obtain the title compound (400 mg, yield 78%).MS m/z (ESI): 597.3 [M + H] ⁺ . The fifth step: tertiary butyl (6-((((3-amino-4-methoxy-5-(1-methyl-1H -pyrazol-3-yl)phenethyl)(methyl)amino)methyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate Butoxycarbonyl)(6-(((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)(methyl)amino)methyl Base) pyridin-2-ylcarbamate (400 mg, 0.67 mmol), iron powder (300 mg, 5.36 mmol) and ammonium chloride (289 mg, 5.36 mmol) were dissolved in a mixture of ethanol and water ( Ethanol: water=4:1, 20 mL). The reaction was stirred at 50°C for 2 hours. After the reaction was completed, it was filtered, concentrated under reduced pressure, and passed through flash column chromatography (dichloromethane/methanol=3%), The title compound (350 mg, yield 92%) was obtained. MS m/z (ESI): 567.3 [M + H] ⁺ . The sixth step: tertiary butyl (6-((((3-((6- Chloro-3-(methylaminoformyl)pyridium-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl ) (methyl) amino) methyl) pyridin-2-yl carbamate is prepared by tertiary butyl (6-((((3-amino-4-methoxy-5-(1 -Methyl-1H-pyrazol-3-yl)phenethyl)(methyl)amino)methyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate (350 mg, 0.62 mmol), 4,6-di Chloro-N-methylpyridine-3-formamide (190 mg, 0.93 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium bis(trimethylsilyl)amide (1.6 mL) was added dropwise at room temperature , 3.1 mmol, 2M solution in tetrahydrofuran). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, saturated aqueous ammonium chloride solution was added to quench the reaction. Water (30 mL) was added and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (PE/EA = 0~100%) afforded the title compound (300 mg, yield 76%). MS m/z (ESI): 636.3 [M + H] ⁺ . The seventh step: 4-((5-(2-(((((6-aminopyridin-2-yl)methyl)(methyl )amino)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3 -Preparation of carboxamide In a 100 mL flask, add the title compound tertiary butyl (6-((((3-((6-chloro-3-(methylaminoformyl)pyridine) obtained in the previous step 𠯤-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)(methyl)amino)methyl)pyridine-2 N-yl carbamate (300 mg, 0.47 mmol). Then, slowly add 4 M dioxane hydrochloride solution (8 mL) dropwise. Stirred at 25 ° C for 4 hours. After the reaction was completed, concentrated under reduced pressure , to obtain the title compound (200 mg, yield 80%). MS m/z (ESI): 536.2 [M + H] ⁺ . The eighth step: 5 ⁶ -methoxy-N,8-dimethyl-5 ^5- (1-methyl-1H-pyrazol-3-yl)-2,4,8-triaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1 ,3) Preparation of benzocyclononane-3 ⁶ -carboxamide 4-((5-(2-(((((6-aminopyridin-2-yl)methyl)(methyl) Amino)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrazole-3- Carboxamide (200 mg, 0.37 mmol), cesium carbonate (360 mg, 1.11 mmol), Pd ₂ (dba) ₃ (68 mg, 0.08 mmol), 4,5-bisdiphenylphosphine-9,9-bis Methylxanthene (43 mg, 0.07 mmol) was miscible in 1,4-dioxane (10 mL). Under nitrogen atmosphere, it was replaced three times, and then the reaction mixture was heated to 130 ° C in a closed tube and stirred for 2 Hour.Filter after completion of the reaction and concentrate to obtain crude product.The crude product is purified by preparative liquid chromatography to obtain the title compound (1.5 mg, yield 7%).MS m/z (ESI):500.2 [M+H ] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ : 11.35 (s, 1H), 10.34 (s, 1H), 9.12 (s, 1H), 9.07 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.65 – 7.59 (m, 1H), 7.46 (d, J = 2.0H z,1H), 7.07 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 3.60 ( s, 3H), 3.48 (s, 2H), 2.86 (d, J =4.8 Hz, 2H), 2.82 – 2.80 (m, 2H), 2.69 – 2.67 (m, 3H), 1.96 (s, 3H).

第一步：2-[4-甲氧基-3-(1-甲基吡唑-3-基)-5-硝基苯]乙基4-甲苯磺酸鹽的製備 將2-[4-甲氧基-3-(1-甲基吡唑-3-基)-5-硝基苯]乙醇(500 mg, 1.80 mmol) 溶於二氯甲烷 (10 mL) ，依次加入三乙胺(546 mg, 5.41 mmol) ，4-甲苯磺醯氯(413 mg, 2.16 mmol) 和4-二甲胺基吡啶(22 mg, 0.18 mmol).  反應液在25°C反應16小時，監測反應結束後，加入水(30mL)淬滅，二氯甲烷萃取(3×30mL)，有機相用飽和食鹽水洗(10 mL×2)，無水硫酸鈉乾燥，然後濃縮，將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-20%)純化，得標題化合物(930 mg，收率96%)。 MS m/z (ESI)：432.2 [M+H] ⁺. 第二步：2-[4-甲氧基-3-(1-甲基吡唑-3-基)-5-硝基苯基]乙硫醇的製備 將2-[4-甲氧基-3-(1-甲基吡唑-3-基)-5-硝基苯]乙基4-甲苯磺酸鹽(930 mg, 2.15 mmol) 溶於乙醇 (20 mL) ，加入硫脲(328 mg, 4.31 mmol) 並在80°C反應16小時，LC-MS 監測反應完全(m/z 336.1)，將20% 氫氧化鈉溶液（7mL）加入反應液並在80°C繼續攪拌1小時，然後用10% HCl中和至pH = 3-4 ，二氯甲烷萃取(3×30mL)，有機相用飽和食鹽水洗(10 mL×2)，無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-20%)純化，得標題化合物(392 mg，收率56%)。 MS m/z (ESI)：294.1 [M+H] ⁺. 第三步：第三丁基{6-[({2-[4-甲氧基-3-(1-甲基吡唑基-3-基)-5-硝基苯基]乙基}磺醯基)甲基]吡啶-2-基}胺基甲酸酯的製備 將2-[4-甲氧基-3-(1-甲基吡唑-3-基)-5-硝基苯基]乙硫醇(392 mg, 1.34 mmol) 溶於N,N-二甲基甲醯胺 (3 mL) 並氮氣保護，加入氫化鈉 (96 mg, 4.01 mmol)，反應液在0°C反應0.5小時後，加入溶在N,N-二甲基甲醯胺 (1mL) 的[6-(溴甲基)吡啶-2-基]胺基甲酸第三丁酯(770 mg, 2.67 mmol)，反應在氮氣下0°C進行10分鐘，監測反應結束後，加入水(30mL)淬滅，乙酸乙酯萃取(3×30mL)，有機相用飽和食鹽水洗(10 mL×2)，無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-20%)純化，得標題化合物(288 mg，收率30%)。 MS m/z (ESI)：500.2 [M+H] ⁺. 第四步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑基-3-基)苯乙基)硫代)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基{6-[({2-[4-甲氧基-3-(1-甲基吡唑基-3-基)-5-硝基苯基]乙基}磺醯基)甲基]吡啶-2-基}胺基甲酸酯 (400 mg, 0.82 mmol) 溶於乙醇和水的混合液中(乙醇/水 = 4：1 ，20 mL) ，依次加入還原鐵粉(645 mg, 11.56m mol) 和氯化銨(883 mg, 16.5 mmol)，反應液在80°C反應1小時。反應結束後，加入水(30mL)淬滅，二氯甲烷萃取(3×40mL)，有機相用無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得標題化合物(150 mg，收率24%). MS m/z (ESI)：470.2 [M+H] ⁺. 第五步：第三丁基(6-((3-((6-氯-3-(甲基氨甲醯)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)硫代)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑基-3-基)苯乙基)硫代)甲基)吡啶-2-基)胺基甲酸酯 (150 mg, 0.33mmol) 溶於四氫呋喃 (3 mL) ，依次加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺 (68 mg, 0.33mmol) 和雙(三甲基矽基)醯胺鈉(0.3 mL)，室溫反應10分鐘。反應結束後，加入水(5 mL)淬滅，二氯甲烷萃取(3×30mL)，有機相用無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得到標題化合物(100 mg，收率39%)。 MS m/z (ESI)：639.2 [M+H] ⁺. 第五步：4-((5-(2-((6-胺基吡啶-2-基)甲基)硫代)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-甲醯胺的製備 將第三丁基(6-((3-((6-氯-3-(甲基氨甲醯)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)硫代)甲基)吡啶-2-基)胺基甲酸酯 (100 mg, 0.157mmol) 溶於鹽酸二氧六環溶液4M (3 mL)中，混合液於30 ^oC下攪拌1小時。反應結束後直接濃縮得到標題化合物 (20 mg，收率34%). MS m/z (ESI)：539.2 [M+H] ⁺. 第六步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-3-基)-8-噻-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲基)硫代)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-甲醯胺(20 mg, 0.037mmol) 溶於1,4-二氧六環 (3 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(2 mg, 0.0038mmol)，三(二亞苄基丙酮)二鈀 (3.5 mg, 0.0038mmol) 和碳酸銫 (37 mg, 0.1146mmol)。混合液於130 ^oC下攪拌4小時。反應結束後直接濃縮，殘留物用矽膠柱(二氯甲烷/甲醇=10/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1)純化後，得到標題化合物 (5 mg，收率25%)。 MS m/z (ESI)：503.1 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ: 11.40 (s, 1H), 9.06 (s, 1H), 8.93 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.59 - 7.51 (m, 2H), 7.41 (s, 1H), 6.93 (d, J= 7.2 Hz, 1H), 6.87 (s, 1H), 6.76 (d, J= 8.1 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 2H), 3.71 (s, 3H), 3.07-2.94 (m, 4H). Example 12: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-thia-2,4-diaza-3(3 ,5)-Pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide

The first step: the preparation of 2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethyl 4-toluenesulfonate 2-[4- Methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethanol (500 mg, 1.80 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (546 mg, 5.41 mmol), 4-toluenesulfonyl chloride (413 mg, 2.16 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol). The reaction solution was reacted at 25°C for 16 hours, and after the end of the monitoring reaction, Add water (30mL) to quench, dichloromethane extraction (3 × 30mL), the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and then concentrated, the obtained residue was applied to a silica gel column (ethyl acetate ester/petroleum ether=0-20%) to obtain the title compound (930 mg, yield 96%). MS m/z (ESI): 432.2 [M+H] ⁺ . Second step: 2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl ] Preparation of ethanethiol 2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethyl 4-toluenesulfonate (930 mg, 2.15 mmol) was dissolved in ethanol (20 mL), thiourea (328 mg, 4.31 mmol) was added and reacted at 80°C for 16 hours, LC-MS monitored that the reaction was complete (m/z 336.1), and 20% sodium hydroxide solution ( 7mL) was added to the reaction solution and stirred at 80°C for 1 hour, then neutralized with 10% HCl to pH = 3-4, extracted with dichloromethane (3×30mL), and the organic phase was washed with saturated brine (10 mL×2 ), dried over anhydrous sodium sulfate, concentrated and purified the resulting residue with a silica gel column (ethyl acetate/petroleum ether=0-20%) to obtain the title compound (392 mg, yield 56%). MS m/z (ESI): 294.1 [M+H] ⁺ . The third step: tertiary butyl{6-[({2-[4-methoxy-3-(1-methylpyrazolyl- 3-base)-5-nitrophenyl]ethyl}sulfonyl)methyl]pyridin-2-yl}carbamate 2-[4-methoxy-3-(1- Methylpyrazol-3-yl)-5-nitrophenyl]ethanethiol (392 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (3 mL) under nitrogen protection, and sodium hydride was added (96 mg, 4.01 mmol), after the reaction solution was reacted at 0°C for 0.5 hours, [6-(bromomethyl)pyridin-2-yl] dissolved in N,N-dimethylformamide (1mL) was added Tertiary butyl carbamate (770 mg, 2.67 mmol), the reaction was carried out at 0 ° C under nitrogen for 10 minutes, after monitoring the end of the reaction, quenched by adding water (30 mL), extracted with ethyl acetate (3 × 30 mL), organic The phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, concentrated and the resulting residue was purified by silica gel column (ethyl acetate/petroleum ether=0-20%) to obtain the title compound (288 mg, yield rate 30%). MS m/z (ESI): 500.2 [M+H] ⁺ . The fourth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H- Preparation of pyrazolyl-3-yl) phenethyl) thio) methyl) pyridin-2-yl) carbamate The tertiary butyl {6-[({2-[4-methoxy -3-(1-Methylpyrazolyl-3-yl)-5-nitrophenyl]ethyl}sulfonyl)methyl]pyridin-2-yl}carbamate (400 mg, 0.82 mmol) was dissolved in a mixture of ethanol and water (ethanol/water = 4:1, 20 mL), and reduced iron powder (645 mg, 11.56 mmol) and ammonium chloride (883 mg, 16.5 mmol) were added in turn, and the reaction The solution was reacted at 80°C for 1 hour. After the reaction was completed, quenched by adding water (30mL), extracted with dichloromethane (3×40mL), dried the organic phase with anhydrous sodium sulfate, and concentrated the obtained residue with a silica gel column (ethyl acetate/petroleum ether=0- 80%) to obtain the title compound (150 mg, yield 24%). MS m/z (ESI): 470.2 [M+H] ⁺ . The fifth step: tertiary butyl (6-((3-( (6-Chloro-3-(methylcarbamoyl)pyrazole-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl Base) thio) methyl) pyridin-2-yl) carbamate preparation The tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl- 1H-pyrazolyl-3-yl)phenethyl)thio)methyl)pyridin-2-yl)carbamate (150 mg, 0.33mmol) was dissolved in tetrahydrofuran (3 mL), and 4, 6-Dichloro-N-methylpyrrole-3-formamide (68 mg, 0.33mmol) and sodium bis(trimethylsilyl)amide (0.3 mL) were reacted at room temperature for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL), extracted with dichloromethane (3 × 30 mL), the organic phase was dried over anhydrous sodium sulfate, and the obtained residue was concentrated on a silica gel column (ethyl acetate/petroleum ether=0 -80%) was purified to obtain the title compound (100 mg, yield 39%). MS m/z (ESI): 639.2 [M+H] ⁺ . The fifth step: 4-((5-(2-((6-aminopyridin-2-yl)methyl)thio)ethyl) The preparation of -2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridium-3-formamide will tertiary butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridium-4-yl)amino)-4-methoxy-5-(1-methyl -1H-pyrazol-3-yl)phenethyl)thio)methyl)pyridin-2-yl)carbamate (100 mg, 0.157mmol) dissolved in dioxane hydrochloride solution 4M (3 mL ), the mixture was stirred at 30 ^o C for 1 hour. Concentrate directly after the reaction to obtain the title compound (20 mg, yield 34%). MS m/z (ESI): 539.2 [M+H] ⁺ . The sixth step: 5 ⁶ -methoxy-N-methyl- 5 ⁵ -(1-Methyl-1H-pyrazol-3-yl)-8-thia-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine- Preparation of 5(1,3)-benzocyclononane-3 ⁶ -formamide Base)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-formamide ( 20 mg, 0.037mmol) was dissolved in 1,4-dioxane (3 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene ( 2 mg, 0.0038mmol), tris(dibenzylideneacetone)dipalladium (3.5 mg, 0.0038mmol) and cesium carbonate (37 mg, 0.1146mmol). The mixture was stirred at 130 ^o C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by a silica gel column (dichloromethane/methanol=10/1) to obtain a crude product, and then purified by a reverse column (acetonitrile:water=1:1) to obtain the title compound ( 5 mg, yield 25%). MS m/z (ESI): 503.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ : 11.40 (s, 1H), 9.06 (s, 1H), 8.93 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.59 - 7.51 (m, 2H), 7.41 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.87 (s, 1H), 6.76 ( d, J = 8.1 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 2H), 3.71 (s, 3H), 3.07-2.94 (m, 4H).

第一步：6-(雙(第三丁氧基羰基）胺基）吡啶甲酸甲酯的製備 將6-胺基吡啶-2-羧酸甲酯(1.0 g, 6.58 mmol），4-二甲胺基吡啶(80 mg, 0.66 mmol）混溶於四氫呋喃 (20 mL) 中。在冰浴下將二碳酸二第三丁酯(4.30 g, 19.74 mmol）滴加到反應液中。然後室溫攪拌過夜。反應完成後減壓濃縮，通過快速柱層析法(二氯甲烷 / 甲醇＝ 3%），得到標題化合物 (2.0 g，收率87%）。 MS m/z (ESI): 353.2 [M + H] ⁺. 第二步：6-((第三丁氧羰基）胺基）吡啶甲酸的製備 將6-(雙(第三丁氧基羰基）胺基)吡啶甲酸甲酯(2.0 g, 5.68 mmol）和氫氧化鋰(1.36 g, 56.8 mmol）溶於四氫呋喃/乙醇/水 (3:1:1, 30 mL) 中。 將反應在70°C下攪拌2小時。反應完成後調節pH至6，加入水(50 mL），乙酸乙酯(30 mL×3）萃取。 合併有機層用鹽水洗滌，無水硫酸鈉乾燥，濃縮。通過快速柱層析法純化(EA / PE＝0-30%），得到標題化合物 (1.20 g，收率 89%）。 MS m/z (ESI): 239.1 [M + H] +. 第三步：2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)異吲哚啉-1,3-二酮的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基）-5-硝基苯基）乙-1-醇1(500 mg，1.80 mmol）溶於THF(20 mL）中並冷卻至0°C，分別加入三苯基膦(943 mg，3.60 mmol），異吲哚啉-1，3-二酮(318 mg，3.60 mmol）和DIAD(727 mg，3.6 mmol），反應室溫攪拌2 h。加入水(50 mL），乙酸乙酯(30 mL×3）萃取。合併有機層，用鹽水洗滌，無水硫酸鈉乾燥，濃縮。通過快速柱層析法純化(EA / PE＝0-30%），得到標題化合物 (586 mg，收率80%）。 MS m/z (ESI): 407.1 [M + H] ⁺. 第四步：2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙-1-胺的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)異吲哚啉-1,3-二酮(586 mg，1.44 mmol)溶於EtOH(100 mL)，並加入水合肼(4 mL)。 將混合物在80°C下攪拌3小時。將混合液減壓濃縮過濾，加入水(50 mL)，乙酸乙酯(30 mL×3)萃取。合併有機層，用鹽水洗滌，無水硫酸鈉乾燥，濃縮。通過快速柱層析法純化(EA / PE ＝0-30%)，得到標題化合物 (358 mg，收率90%)。 MS m/z (ESI): 277.1 [M + H] ⁺. 第五步：第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)胺基甲醯基)吡啶-2-基)胺基甲酸酯的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙-1-胺(350 mg，1.27 mmol)和6-((第三丁氧羰基)胺基)吡啶甲酸(302mg，1.27 mmol)溶於二氯甲烷(30 mL)中，分別加入三乙胺(647 mg，6.35 mmol)和2-丙烷膦酸酐(1.61 g，2.54 mmol，50% wt於EtOAc中)。 將溶液在室溫攪拌1小時。加入水(50 mL)，二氯甲烷(30 mL×3)萃取。 合併有機層用鹽水洗滌，無水硫酸鈉乾燥，濃縮。通過快速柱層析法純化(EA / PE ＝0-30%)，得到標題化合物 (400 mg，收率 63% )。 MS m/z (ESI): 497.2 [M + H] ⁺. 第六步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)胺基甲醯基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙基)胺基甲醯基)吡啶-2-基)胺基甲酸酯(400 mg, 0.81 mmol)，鐵粉(362 mg, 6.48 mmol)和氯化銨(350 mg, 6.48 mmol)混溶於乙醇和水的混合液 (乙醇:水 =4:1, 20 mL) 中。將反應在50°C下攪拌2小時。反應完成後過濾、減壓濃縮，通過快速柱層析法(二氯甲烷/甲醇＝ 0-3%)，得到標題化合物 (350 mg，收率93%)。 MS m/z (ESI): 467.2 [M + H] ⁺. 第七步：第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基 胺基甲醯基)吡啶-2-基胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)胺基甲醯基)吡啶-2-基)胺基甲酸酯7(350 mg, 0.75 mmol)，4，6-二氯-N-甲基嗒𠯤-3-甲醯胺(230 mg, 1.12 mmol)混溶於四氫呋喃(10 mL)中，室溫下滴加 雙(三甲基矽基)胺基鈉(1.9 mL, 3.75 mmol，2M的四氫呋喃溶液)。將混合物在25°C下攪拌1小時。 反應完成後加入飽和的氯化銨水溶液淬滅反應。加入水(30 mL)，乙酸乙酯(30 mL×3)萃取。合併的有機層用鹽水洗滌，無水硫酸鈉乾燥，然後濃縮。通過快速柱層析法純化(PE / EA＝0-100%)，得到標題化合物 (300 mg，收率76%)。 MS m/z (ESI): 636.2 [M + H] ⁺. 第八步：4-((5-(2-(6-胺基吡啶甲醯胺基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3 -羧醯胺的製備 在100 mL 的燒瓶中加入第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基胺基甲醯基)吡啶-2-基胺基甲酸酯(300 mg, 0.47 mmol)。然後，緩慢滴加4 M 的鹽酸二氧六環溶液(8 mL)。在25°C下攪拌4小時。反應完成後，減壓濃縮，得到標題化合物 (200 mg，收率80%)。 MS m/z (ESI): 536.2 [M + H] ⁺. 第九步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-3-基)-9-氧代-2,4,8-三氮雜-3(3,5)-嗒𠯤-1(2,6 )-吡啶-5(1,3)-苯并環壬基-3 ⁶-羧醯胺的製備 4-((5-(2-(6-胺基吡啶甲醯胺基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3 -羧醯胺(200 mg, 0.37 mmol)，碳酸銫(360 mg, 1.11 mmol)，Pd ₂(dba) ₃(68 mg, 0.08 mmol)，4,5-雙二苯基膦-9,9-二甲基氧雜蒽(43 mg, 0.07 mmol)混溶於1,4-二氧六環(10 mL)中。氮氣氛圍下置換三次，然後將反應混合物在密閉管中加熱到130°C攪拌2 小時。反應完成後過濾，濃縮，得到粗產物。將粗產物通過製備液相色譜法純化，得到標題化合物 (26 mg，收率 14%)。 MS m/z (ESI)：500.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ) δ:11.11 (s, 1H), 10.56 (s, 1H), 9.11 (d, J= 4.0 Hz, 1H), 8.64 (s, 1H), 8.29 (t, J= 4.0 Hz, 1H), 7.83 (t, J= 8.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.73 (d, J= 2.0 Hz, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 6.73 (d, J= 2.0 Hz, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.50 (d, J= 4.0 Hz, 2H), 2.88 (s, 2H), 2.88 (d, J= 4.0 Hz, 3H). Example 13: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-9-oxo-2,4,8-triaza- 3(3,5)-Pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

The first step: the preparation of 6-(bis(tert-butoxycarbonyl)amino)picolinate methyl 6-aminopyridine-2-carboxylate (1.0 g, 6.58 mmol), 4-dimethyl Aminopyridine (80 mg, 0.66 mmol) was dissolved in tetrahydrofuran (20 mL). Di-tert-butyl dicarbonate (4.30 g, 19.74 mmol) was added dropwise to the reaction solution under ice cooling. It was then stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the title compound (2.0 g, yield 87%) was obtained by flash column chromatography (dichloromethane/methanol = 3%). MS m/z (ESI): 353.2 [M + H] ⁺ . The second step: the preparation of 6-((tertiary butoxycarbonyl)amino)picolinic acid 6-(bis(tertiary butoxycarbonyl) Amino)methyl picolinate (2.0 g, 5.68 mmol) and lithium hydroxide (1.36 g, 56.8 mmol) were dissolved in tetrahydrofuran/ethanol/water (3:1:1, 30 mL). The reaction was stirred at 70°C for 2 hours. After the reaction was completed, the pH was adjusted to 6, water (50 mL) was added, and ethyl acetate (30 mL×3) was extracted. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE=0-30%) afforded the title compound (1.20 g, yield 89%). MS m/z (ESI): 239.1 [M + H] +. The third step: 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrate 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitro Phenyl)ethan-1-ol 1 (500 mg, 1.80 mmol) was dissolved in THF (20 mL) and cooled to 0°C, triphenylphosphine (943 mg, 3.60 mmol), isoindoline- 1,3-Diketone (318 mg, 3.60 mmol) and DIAD (727 mg, 3.6 mmol), and the reaction was stirred at room temperature for 2 h. Add water (50 mL), and extract with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE=0-30%) afforded the title compound (586 mg, yield 80%). MS m/z (ESI): 407.1 [M + H] ⁺ . The fourth step: 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrate 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenylethyl)isoindole Phenyl-1,3-dione (586 mg, 1.44 mmol) was dissolved in EtOH (100 mL), and hydrazine hydrate (4 mL) was added. The mixture was stirred at 80°C for 3 hours. The mixture was concentrated and filtered under reduced pressure, water (50 mL) was added, and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE = 0-30%) afforded the title compound (358 mg, yield 90%). MS m/z (ESI): 277.1 [M + H] ⁺ . The fifth step: tertiary butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazole-3- Base)-5-nitrophenethyl)aminoformyl)pyridin-2-yl)carbamate 2-(4-methoxy-3-(1-methyl-1H- Pyrazol-3-yl)-5-nitrophenyl)ethan-1-amine (350 mg, 1.27 mmol) and 6-((tertiary butoxycarbonyl) amino) picolinic acid (302 mg, 1.27 mmol) In dichloromethane (30 mL), triethylamine (647 mg, 6.35 mmol) and 2-propanephosphonic anhydride (1.61 g, 2.54 mmol, 50% wt in EtOAc) were added separately. The solution was stirred at room temperature for 1 hour. Water (50 mL) was added and extracted with dichloromethane (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE = 0-30%) afforded the title compound (400 mg, yield 63%). MS m/z (ESI): 497.2 [M + H] ⁺ . The sixth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H- The preparation of pyrazol-3-yl) phenethyl) aminoformyl) pyridin-2-yl) carbamate will tertiary butyl (6-((4-methoxy-3-(1 -Methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)aminoformyl)pyridin-2-yl)carbamate (400 mg, 0.81 mmol), iron powder ( 362 mg, 6.48 mmol) and ammonium chloride (350 mg, 6.48 mmol) are miscible in a mixture of ethanol and water (ethanol:water=4:1, 20 mL). The reaction was stirred at 50°C for 2 hours. After the reaction was completed, it was filtered, concentrated under reduced pressure, and flash column chromatography (dichloromethane/methanol = 0-3%) to obtain the title compound (350 mg, yield 93%). MS m/z (ESI): 467.2 [M + H] ⁺ . The seventh step: tertiary butyl (6-((3-((6-chloro-3-(methylaminoformyl)da -4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethylaminoformyl)pyridin-2-ylcarbamate Preparation of ester )pyridin-2-yl)carbamate 7 (350 mg, 0.75 mmol), 4,6-dichloro-N-methylpyridium-3-carboxamide (230 mg, 1.12 mmol) was dissolved in In tetrahydrofuran (10 mL), sodium bis(trimethylsilyl)amide (1.9 mL, 3.75 mmol, 2M solution in tetrahydrofuran) was added dropwise at room temperature. The mixture was stirred at 25°C for 1 hour. After the reaction was completed The reaction was quenched by adding saturated aqueous ammonium chloride. Added water (30 mL), extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated. By flash column chromatography (PE/EA=0-100%) to obtain the title compound (300 mg, yield 76%). MS m/z (ESI): 636.2 [M + H] ⁺ . The eighth step: 4-(( 5-(2-(6-aminopyridinecarboxamido)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)- Preparation of 6-chloro-N-methylpyrrole-3-carboxamide Add tert-butyl (6-((3-((6-chloro-3-(methylaminomethyl Acyl)acid (4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethylaminoformyl)pyridine-2- Carbamate (300 mg, 0.47 mmol). Then, 4 M dioxane hydrochloride solution (8 mL) was slowly added dropwise. Stirred at 25° C. for 4 hours. After the reaction was completed, concentrated under reduced pressure, The title compound (200 mg, yield 80%) was obtained. MS m/z (ESI): 536.2 [M + H] ⁺ . The ninth step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1 -Methyl-1H-pyrazol-3-yl)-9-oxo-2,4,8-triaza-3(3,5)-pyridine-1(2,6 )-pyridine-5( Preparation of 1,3)-benzocyclononyl-3 ⁶ -carboxamide 4-((5-(2-(6-aminopyridinecarboxamido)ethyl)-2-methoxy-3 -(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrazole-3-carboxamide (200 mg, 0.37 mmol), cesium carbonate ( 360 mg, 1.11 mmol), Pd ₂ ( dba) ₃ (68 mg, 0.08 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (43 mg, 0.07 mmol) was dissolved in 1,4-dioxane ( 10 mL). After replacing three times under a nitrogen atmosphere, the reaction mixture was heated to 130°C in a closed tube and stirred for 2 hours. After the reaction was completed, it was filtered and concentrated to obtain a crude product. The crude product was purified by preparative liquid chromatography to afford the title compound (26 mg, yield 14%). MS m/z (ESI): 500.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.11 (s, 1H), 10.56 (s, 1H), 9.11 (d, J = 4.0 Hz, 1H), 8.64 (s, 1H), 8.29 (t, J = 4.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.73 (d , J = 2.0 Hz, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.50 (d, J = 4.0 Hz, 2H), 2.88 (s, 2H), 2.88 (d, J = 4.0 Hz , 3H).

第一步：第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(製備方法參考實施例23，50 mg，0.11 mmol)和4,6-二氯-N-甲基嗒𠯤-3-羧醯胺(45 mg，0.22 mmol)溶於THF(2 mL)，加入NaHMDS (0.3 mL, 0.55 mmol)。反應溶液在25 ^oC下攪拌1小時。反應完成後加入飽和的氯化銨水溶液(3mL)淬滅反應，用乙酸乙酯(10 mL×2)萃取， 合併的有機層用鹽水(10 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化，得到標題化合物 (50 mg，收率61.5%)。 MS m/z (ESI): 624.3[M + H] ⁺. 第二步：4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺的製備 第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (50 mg，0.08 mmol)溶於二氯甲烷(2 mL)，加入4M的鹽酸二氧六環溶液(0.2 mL，0.32 mmol)。反應在40 ^oC下攪拌1小時。減壓除去溶劑，得到標題化合物(30 mg，收率63%)。 MS m/z (ESI): 523.1[M + H] ⁺. 第三步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-4-基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬基-3 ⁶-羧醯胺的製備 將4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺 (50 mg, 0.09 mmol) 溶解在1,4-二氧六環(10 mL)中，氮氣保護下向反應混合物中加入三(二亞苄基丙酮)二鈀(26 mg，0.028 mmol)，4,5-雙(二苯基膦基)-9,9-二甲基黃嘌呤(22 mg，0.038 mmo)，碳酸銫(94 mg, 0.28 mmol)。 將得到的反應混合物在130 ℃下攪拌12小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗產物通過製備型HPLC純化，得到標題化合物 (0.3 mg，收率0.6%)。 MS m/z (ESI): 487.3 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 11.31 (s, 1H), 10.32 (s, 1H), 9.09 - 8.91 (m, 2H), 8.14 (s, 1H), 7.88 (s, 1H), 7.62 (t, J= 7.8 Hz, 1H), 7.46 (s, 1H), 7.21 (s, 1H), 7.08 (d, J= 8.3 Hz, 1H), 6.85 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.87 (s, 3H), 3.77 – 3.70 (m, 2H), 3.56 (s, 3H), 2.83 (t, J= 5.6 Hz, 5H). Example 14: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-4-yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

The first step: tertiary butyl(6-((3-((6-chloro-3-(methylaminoformyl)buta-4-yl)amino)-4-methoxy-5 -(1-methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate preparation tertiary butyl (6-((3-amino -4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (preparation method reference example 23 , 50 mg, 0.11 mmol) and 4,6-dichloro-N-methylpyridium-3-carboxamide (45 mg, 0.22 mmol) were dissolved in THF (2 mL), and NaHMDS (0.3 mL, 0.55 mmol ). The reaction solution was stirred at 25 ^° C for 1 hour. After the reaction was complete, a saturated aqueous ammonium chloride solution (3 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×2), and the combined organic layers were washed with brine (10 mL×1), dried over anhydrous sodium sulfate and Concentrate under reduced pressure. Purification by flash column chromatography afforded the title compound (50 mg, yield 61.5%). MS m/z (ESI): 624.3[M + H] ⁺ . Second step: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)- Preparation of 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-carboxamide Butyl(6-((3-((6-chloro-3-(methylaminoformyl)pyridium-4-yl)amino)-4-methoxy-5-(1-methyl -1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (50 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL), and 4M hydrochloric acid was added Dioxane solution (0.2 mL, 0.32 mmol). The reaction was stirred at 40 ^° C. for 1 hour. The solvent was removed under reduced pressure to give the title compound (30 mg, yield 63%). MS m/z (ESI): 523.1 [M + H] ⁺ . The third step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-4-yl)-8-oxa-2,4 -Diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononyl-3 ⁶ -carboxamide preparation 4-(( 5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)benzene Base)amino)-6-chloro-N-methylpyrrole-3-carboxamide (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (10 mL), and reacted under nitrogen protection Tris(dibenzylideneacetone)dipalladium (26 mg, 0.028 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (22 mg, 0.038 mmol) were added to the mixture , cesium carbonate (94 mg, 0.28 mmol). The resulting reaction mixture was stirred at 130° C. for 12 hours. The reaction mixture was filtered and the organic layer was concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain the title compound (0.3 mg, yield 0.6%). MS m/z (ESI): 487.3 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.31 (s, 1H), 10.32 (s, 1H ), 9.09 - 8.91 (m, 2H), 8.14 (s, 1H), 7.88 (s, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.21 (s, 1H) , 7.08 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 4.42 (s , 2H), 3.87 (s, 3H), 3.77 – 3.70 (m, 2H), 3.56 (s, 3H), 2.83 (t, J = 5.6 Hz, 5H).

第一步：(第三丁氧羰基)(8-羥基喹啉-2-羥基)胺基甲酸第三丁酯的製備 將2-胺基喹啉-8-羥基(2g，1 eq)溶解在四氫呋喃(60 mL)中，加入4-DMAP (0.46g，0.3 eq)， Boc ₂O(3.27 g，2.2 eq)。室溫攪拌過夜。將反應混合物在真空中濃縮，並進行色譜分離，得到標題化合物( 3 g，收率66.7%)。 MS m/z (ESI)：361[M+H] ⁺. 第二步：第三丁基(第三丁氧基羰基)(8-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)喹啉-2-基)胺基甲酸酯的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙-1-醇(800 mg，1 eq)溶解在四氫呋喃(20 mL)中，向反應混合物加入(第三丁氧羰基)(8-羥基喹啉-2-羥基)胺基甲酸第三丁酯(1045mg，1 eq)，三苯基膦(908mg，1.2 eq)，將得到的反應混合物在25℃下攪拌0.2小時。向反應混合物中加入偶氮二羧酸二第三丁酯(797mg，1.2 eq)，將得到的反應混合物在25℃下攪拌16h。將混合物濃縮，得到粗產物。粗產物通過快速柱色譜法純化，得到標題化合物(560mg，收率30%)。 MS m/z (ESI)：620 [M+H] ⁺. 第三步：第三丁基(8-(3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)喹啉-2-基)(第三丁氧羰基)胺基甲酸酯的製備 將第三丁基(第三丁氧基羰基)(8-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)喹啉-2-基)胺基甲酸酯(560 mg，1 eq)溶解在乙醇(15 mL)和水(5 mL)中，向反應混合物中加入鐵粉(252 mg，5 eq)，氯化銨 (241mg，5 eq)。將得到的反應混合物在70℃下攪拌1h。將反應混合物過濾。濃縮有機層，得到粗產物。通過矽膠柱純化粗產物，得到標題化合物(160 mg，收率30%)。 MS m/z (ESI)：590[M+H] ⁺. 第四步：第三丁基(第三丁氧羰基)(8-(3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)喹啉-2-基)胺基甲酸酯的製備 將第三丁基(8-(3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)喹啉-2-基)(第三丁氧羰基)胺基甲酸酯(400mg，1eq)溶解在四氫呋喃(20mL)中，加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺的溶液(139mg，1 eq)，雙(三甲基甲矽烷基)醯胺鈉 (0.7 mL)，將所得混合物在25℃下攪拌0.5h。向反應混合物中加入水(5mL)。所得混合物用乙酸乙酯(10×2mL)萃取。合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物。粗產物通過快速矽膠柱色譜純化，得到產物(330 mg，收率64%)。 MS m/z (ESI)：759 [M+H] ⁺. 第五步：4-((5-(2-(((2-胺基喹啉-8-基)氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺的製備 將第三丁基(第三丁氧羰基)(8-(3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3 -基)苯乙氧基)喹啉-2-基)胺基甲酸酯(330 mg，1 eq)溶解在二氯甲烷(3 mL)中，向反應混合物中加入鹽酸的二氧六環溶液( 2.2 mL)。將反應混合物在65℃下攪拌2h。濃縮反應混合物，得到產物標題化合物(200 mg，收率82.3%)。 MS m/z (ESI)：559 [M+H] ⁺. 第六步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1 H-吡唑-3-基)-8-氧雜-2,4-二氮雜-1(2,8)-喹啉-3(3,5)-嗒𠯤5(1,3)-苯并環辛烷-3 ⁶-羧醯胺的製備 將4-((5-(2-(((2-胺基喹啉-8-基)氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺(100 mg，1 eq)溶解在二氧六環(3 mL)中，向反應混合物中加入三(二苄叉基丙酮)二鈀 (25 mg，0.15 eq)，4,5-雙二苯基膦-9,9-二甲基氧雜蒽 (21 mg，0.2 eq)，碳酸銫(175mg，3 eq)。將得到的反應混合物在135℃下攪拌16h。將反應混合物過濾。濃縮有機層，得到粗產物，經純化得到標題化合物(1.4 mg，收率1.5%)。 MS m/z (ESI)：523[M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ:10.35 (s, 1H), 9.30 – 9.34(m, 1H), 7.80 (s, 1H), 7.74-7.76 (m, 1H), 7.51 (s, 1H), 7.44 - 7.46(m, 2H), 7.35 – 7.30 (m, 1H), 7.22 (s, 1H), 7.08 -7.10 (m, 2H), 6.97 (s, 1H), 6.64 -6.66 (m, 1H), 4.95 – 4.73 (m, 2H), 3.90 (s, 3H), 3.51 (s, 3H), 2.87 - 2.95 (m, 5H). Example 15: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1 H -pyrazol-3-yl)-8-oxa-2,4-diaza-1 Preparation of (2,8)-quinoline-3(3,5)-pyridine 5(1,3)-benzocyclooctane-3 ⁶ -carboxamide

The first step: preparation of (tertiary butoxycarbonyl) (8-hydroxyquinoline-2-hydroxyl) tertiary butyl carbamate 2-aminoquinoline-8-hydroxyl (2 g, 1 eq) was dissolved in To tetrahydrofuran (60 mL), were added 4-DMAP (0.46 g, 0.3 eq), Boc ₂ O (3.27 g, 2.2 eq). Stir overnight at room temperature. The reaction mixture was concentrated in vacuo and chromatographed to afford the title compound (3 g, yield 66.7%). MS m/z (ESI): 361[M+H] ⁺ . The second step: tertiary butyl (tertiary butoxycarbonyl) (8-(4-methoxy-3-(1-methyl- Preparation of 1H-pyrazol-3-yl)-5-nitrophenethoxy)quinolin-2-yl)carbamate 2-(4-methoxy-3-(1-methyl -1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-ol (800 mg, 1 eq) was dissolved in tetrahydrofuran (20 mL), and (tert-butoxycarbonyl) was added to the reaction mixture Tert-butyl (8-hydroxyquinoline-2-hydroxy)carbamate (1045 mg, 1 eq), triphenylphosphine (908 mg, 1.2 eq), and the resulting reaction mixture was stirred at 25°C for 0.2 hours. Di-tert-butyl azodicarboxylate (797 mg, 1.2 eq) was added to the reaction mixture, and the resulting reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to give crude product. The crude product was purified by flash column chromatography to obtain the title compound (560 mg, yield 30%). MS m/z (ESI): 620 [M+H] ⁺ . The third step: tert-butyl (8-(3-amino-4-methoxy-5-(1-methyl-1H-pyridine Preparation of oxazol-3-yl) phenethoxy) quinoline-2-yl) (tertiary butoxycarbonyl) carbamate The tertiary butyl (tertiary butoxycarbonyl) (8-(4 -Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)quinolin-2-yl)carbamate (560 mg, 1 eq ) was dissolved in ethanol (15 mL) and water (5 mL), and iron powder (252 mg, 5 eq) and ammonium chloride (241 mg, 5 eq) were added to the reaction mixture. The resulting reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered. The organic layer was concentrated to obtain crude product. The crude product was purified by silica gel column to obtain the title compound (160 mg, yield 30%). MS m/z (ESI): 590[M+H] ⁺ . The fourth step: tertiary butyl (tertiary butoxycarbonyl) (8-(3-((6-chloro-3-(methylamino Formyl) pyridyl-4-yl) amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)quinolin-2-yl) The preparation of carbamate is tert-butyl (8-(3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)quinone Phenyl-2-yl)(tert-butoxycarbonyl)carbamate (400mg, 1eq) was dissolved in tetrahydrofuran (20mL) and 4,6-dichloro-N-methylpyrrole-3-formyl A solution of amine (139 mg, 1 eq), sodium bis(trimethylsilyl)amide (0.7 mL), and the resulting mixture was stirred at 25°C for 0.5 h. Water (5 mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (10 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by flash silica gel column chromatography to obtain the product (330 mg, yield 64%). MS m/z (ESI): 759 [M+H] ⁺ . The fifth step: 4-((5-(2-(((2-aminoquinolin-8-yl)oxy)ethyl)- The preparation of 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl) phenyl) amino)-6-chloro-N-methylpyridium-3-carboxamide Tributyl(tertiary butoxycarbonyl)(8-(3-((6-chloro-3-(methylaminoformyl)pyrrole-4-yl)amino)-4-methoxy- 5-(1-Methyl-1H-pyrazol-3-yl)phenethoxy)quinolin-2-yl)carbamate (330 mg, 1 eq) was dissolved in dichloromethane (3 mL) In the reaction mixture, dioxane solution of hydrochloric acid (2.2 mL) was added. The reaction mixture was stirred at 65 ° C for 2 h. The reaction mixture was concentrated to obtain the product title compound (200 mg, yield 82.3%). MS m/ z (ESI): 559 [M+H] ⁺ . The sixth step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1 H -pyrazol-3-yl)-8 -Oxa-2,4-diaza-1(2,8)-quinoline-3(3,5)-pyramidal 5(1,3)-benzocyclooctane-3 ⁶ -carboxamide The preparation of 4-((5-(2-(((2-aminoquinolin-8-yl)oxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Azol-3-yl)phenyl)amino)-6-chloro-N-methylpyridium-3-carboxamide (100 mg, 1 eq) was dissolved in dioxane (3 mL) and charged to the reaction Tris(dibenzylideneacetone)dipalladium (25 mg, 0.15 eq), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (21 mg, 0.2 eq), carbonic acid Cesium (175 mg, 3 eq). The resulting reaction mixture was stirred at 135 °C for 16 h. The reaction mixture was filtered. The organic layer was concentrated to give a crude product, which was purified to give the title compound (1.4 mg, yield 1.5%). MS m /z (ESI): 523[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 10.35 (s, 1H), 9.30 – 9.34(m, 1H), 7.80 (s, 1H) , 7.74-7.76 (m, 1H), 7.51 (s, 1H), 7.44 - 7.46(m, 2H), 7.35 – 7.30 (m, 1H), 7.22 (s, 1H), 7.08 -7.10 (m, 2H) , 6.97 (s, 1H), 6.64 -6.66 (m, 1H), 4.95 – 4.73 (m, 2H), 3.90 (s, 3H), 3.51 (s, 3H), 2.87 - 2.95 (m, 5H).

第一步：6-胺基-3-甲基吡啶甲酸甲酯的製備 將6-胺基-3-溴吡啶甲酸甲酯(4 g, 17.31 mmol)溶於二氧六環(50 mL)中，向反應液中加入三甲基環三硼氧烷的四氫呋喃溶液(4.34 g, 34.62 mmol, 2 eq)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(1.26 g, 1.73 mmol, 0.1 eq)，碳酸鉀(7.18 g, 51.93 mmol, 3 eq)，反應混合物在110℃下攪拌4h。反應結束後，將反應液濃縮，經柱層析純化(石油醚/乙酸乙酯＝3/1)，得到標題化合物(2.6 g，收率90%)。 MS m/z (ESI)：167.1[M+H] ⁺. 第二步：6-(雙(第三丁氧基羰基)胺基)-3-甲基吡啶甲酸甲酯的製備 將6-胺基-3-甲基吡啶甲酸甲酯(2.6 g, 15.64 mmol)溶於乙腈(30 mL)中，向溶液中加入二碳酸二第三丁酯(8.53 g, 39.1 mmol, 2.5 eq)，4-二甲胺基吡啶(0.38 g, 3.13 mmol, 0.2 eq) 。反應液在室溫下攪拌16h。反應結束後，將反應液濃縮，粗產品經柱層析純化(石油醚/乙酸乙酯＝5/1)得到標題化合物(2.5 g，收率44%)。 MS m/z (ESI)：367.1[M+H] ⁺. 第三步：(6-(羥甲基)-5-甲基吡啶-2-基)胺基甲酸第三丁酯的製備 將6-(雙(第三丁氧基羰基)胺基)-3-甲基吡啶甲酸甲酯(2.5 g, 6.82 mmol)溶於四氫呋喃(30 mL)中，在0℃下緩慢滴加LiAlH ₄(0.52 g, 13.64 mmol, 2.0 eq)，反應液在0℃下攪拌1h。反應結束後，向反應液中加入水，再經乙酸乙酯萃取(3x30 mL)，有機相用無水硫酸鈉乾燥，濃縮後；經柱層析純化(石油醚/乙酸乙酯＝5/1)，得到標題化合物(0.8 g，收率49%)。 MS m/z (ESI)：239.2[M+H] ⁺. 第四步：(6-(溴甲基)-5-甲基吡啶-2-基)胺基甲酸第三丁酯的製備 將6-(羥甲基)-5-甲基吡啶-2-基)胺基甲酸第三丁酯(0.8 g, 3.36 mmol)溶於二氯甲烷(20 mL)中，在0℃下加入三苯基膦(1.06 g, 4.03 mmol, 1.2 eq)，再加入四溴化碳(1.34 g, 4.03 mmol, 1.2 eq)，再在室溫下攪拌30min，反應結束後，將反應液濃縮，粗產品經柱層析純化(石油醚/乙酸乙酯＝10/1)，得到標題化合物(0.7 g，收率69%)。 MS m/z (ESI)：301.1[M+H] ⁺. 第五步：第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)甲基)-5-甲基吡啶-2-基)胺基甲酸酯的製備 將2-(4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯基)乙-1-醇(0.96 g, 3.48 mmol，1.5 eq)溶於DMF(5 mL)中，在0℃下加入氫化鈉(0.22 g, 9.28 mmol, 4 eq)，攪拌10min，再向反應液中加入(6-(溴甲基)-5-甲基吡啶-2-基)胺基甲酸第三丁酯(0.7 g, 2.32 mmol)，混合液在0℃下反應10min，反應結束後，緩慢滴加水，二氯甲烷萃取，有機相用無水硫酸鈉乾燥，濃縮後的粗產品經柱層析(石油醚/乙酸乙酯＝2/1)分離純化，得到標題化合物(0.2 g，收率17%)。 MS m/z (ESI)：498.2[M+H] ⁺. 第六步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)-5-甲基吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-3-基)-5-硝基苯乙氧基)甲基)-5-甲基吡啶-2-基)胺基甲酸酯(0.2 g, 0.4 mmol)溶於乙醇/氯化銨飽和水溶液=4/1(10mL)中，再加入鐵粉(0.45 g, 8 mmol, 20 eq)，反應液在80℃下攪拌1h，反應結束後，反應液濃縮的粗產品經濃縮後的粗產品經柱層析(石油醚/乙酸乙酯＝1/1)分離純化，得到標題化合物(80 mg，收率43%)。 MS m/z (ESI)：468.3[M+H] ⁺. 第七步：第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)-5-甲基吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)-5-甲基吡啶-2-基)胺基甲酸酯(80 mg, 0.17 mmol)以及4,6-二氯-N-甲基嗒𠯤-3-羧醯胺(105 mg, 0.51 mmol, 3 eq)溶於四氫呋喃(5 mL)中，向反應液中加入NaHMDS(187 mg, 1.02 mmol, 6 eq)，反應液在室溫下攪拌10min，反應結束後將反應液濃縮，粗產品經柱層析(石油醚/乙酸乙酯＝1/1)分離純化得到標題化合物(50 mg，收率46%)。 MS m/z (ESI)：637.3[M+H] ⁺. 第八步：4-((5-(2-(((6-胺基-3-甲基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺的製備 將第三丁基(6-((3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙氧基)甲基)-5-甲基吡啶-2-基)胺基甲酸酯(50 mg, 0.078 mmol)溶於二氯甲烷(5 mL)中，並向反應混合物中加入鹽酸的二氧六環(5 mL，4M)溶液。將反應混合物在40℃下攪拌2h。濃縮反應混合物，得到標題化合物(40 mg，收率95%)。 MS m/z (ESI)：537.2[M+H] ⁺. 第九步：5 ⁶-甲氧基-N，1 ⁵-二甲基-5 ⁵-(1-甲基-1 H-吡唑-3-基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-羧醯胺的製備 將4-((5-(2-(((6-胺基-3-甲基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-3-基)苯基)胺基)-6-氯-N-甲基嗒𠯤-3-羧醯胺(40 mg, 0.074 mmol,)溶解在1,4-二氧六環(5 mL)中，氮氣保護下向反應混合物中加入三(二亞苄基丙酮)二鈀(20 mg，0.022 mmol, 0.3 eq)，4,5-雙(二苯基膦基)-9,9-二甲基黃嘌呤(25 mg，0.044 mmol, 0.6 eq)，碳酸銫(72 mg, 0.22 mmol, 3 eq)。將得到的反應混合物在130℃下攪拌16小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗產物通過製備色譜柱純化，得到標題化合物(1 mg，收率3%)。 MS m/z (ESI)：501.2[M+H] ⁺. ¹H NMR (400 MHz, DMSO- d6) δ 11.25 (s, 1H), 10.17 (s, 1H), 9.01 (q, J= 4.8 Hz, 1H), 8.90 (s, 1H), 7.75 (d, J= 2.0 Hz, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.45 (m, 2H), 6.99 (d, J= 8.0 Hz, 1H), 6.71 (d, J= 2.0 Hz, 1H), 4.48 (s, 2H), 3.89 (s, 3H), 3.79 - 3.72 (m, 2H), 3.56 (s, 3H), 2.85 (m, 5H), 2.14 (s, 3H). Example 16: 5 ⁶ -methoxy-N,1 ⁵ -dimethyl-5 ⁵ -(1-methyl-1 H -pyrazol-3-yl)-8-oxa-2,4-di Preparation method of aza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

Step 1: Preparation of 6-amino-3-methylpicolinate Methyl 6-amino-3-bromopicolinate (4 g, 17.31 mmol) was dissolved in dioxane (50 mL) , add trimethylboroxane tetrahydrofuran solution (4.34 g, 34.62 mmol, 2 eq) to the reaction solution, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.26 g, 1.73 mmol, 0.1 eq), potassium carbonate (7.18 g, 51.93 mmol, 3 eq), and the reaction mixture was stirred at 110°C for 4h. After the reaction, the reaction liquid was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the title compound (2.6 g, yield 90%). MS m/z (ESI): 167.1[M+H] ⁺ . The second step: the preparation of 6-(bis(tertiary butoxycarbonyl)amino)-3-methylpicolinate Methyl-3-methylpicolinate (2.6 g, 15.64 mmol) was dissolved in acetonitrile (30 mL), and di-tert-butyl dicarbonate (8.53 g, 39.1 mmol, 2.5 eq) was added to the solution, 4- Dimethylaminopyridine (0.38 g, 3.13 mmol, 0.2 eq). The reaction solution was stirred at room temperature for 16 h. After the reaction, the reaction solution was concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound (2.5 g, yield 44%). MS m/z (ESI): 367.1[M+H] ⁺ . The third step: the preparation of (6-(hydroxymethyl)-5-methylpyridin-2-yl) tertiary butyl carbamate with 6 -(bis(tert-butoxycarbonyl)amino)-3-methylpicolinate (2.5 g, 6.82 mmol) was dissolved in tetrahydrofuran (30 mL), and LiAlH ₄ (0.52 g, 13.64 mmol, 2.0 eq), the reaction solution was stirred at 0°C for 1h. After the reaction was completed, water was added to the reaction solution, followed by extraction with ethyl acetate (3x30 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated; purified by column chromatography (petroleum ether/ethyl acetate=5/1) , to obtain the title compound (0.8 g, yield 49%). MS m/z (ESI): 239.2[M+H] ⁺ . The fourth step: the preparation of (6-(bromomethyl)-5-methylpyridin-2-yl) tertiary butyl carbamate with 6 -(Hydroxymethyl)-5-methylpyridin-2-yl)carbamate (0.8 g, 3.36 mmol) was dissolved in dichloromethane (20 mL), and triphenyl Phosphine (1.06 g, 4.03 mmol, 1.2 eq), then added carbon tetrabromide (1.34 g, 4.03 mmol, 1.2 eq), then stirred at room temperature for 30 min, after the reaction was completed, the reaction solution was concentrated, and the crude product was passed through the column Purification by chromatography (petroleum ether/ethyl acetate=10/1) gave the title compound (0.7 g, yield 69%). MS m/z (ESI): 301.1[M+H] ⁺ . The fifth step: tertiary butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazole-3- Base)-5-nitrophenethoxy)methyl)-5-methylpyridin-2-yl)carbamate 2-(4-methoxy-3-(1-methyl -1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-ol (0.96 g, 3.48 mmol, 1.5 eq) was dissolved in DMF (5 mL), and sodium hydride ( 0.22 g, 9.28 mmol, 4 eq), stirred for 10min, then added (6-(bromomethyl)-5-methylpyridin-2-yl) tertiary butyl carbamate (0.7 g, 2.32 mmol), the mixed solution was reacted at 0° C. for 10 min, after the reaction was finished, slowly added water dropwise, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and the concentrated crude product was subjected to column chromatography (petroleum ether/ethyl acetate= 2/1) separation and purification to obtain the title compound (0.2 g, yield 17%). MS m/z (ESI): 498.2[M+H] ⁺ . The sixth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H- The preparation of pyrazol-3-yl) phenethoxy) methyl)-5-methylpyridin-2-yl) carbamate the tertiary butyl (6-((4-methoxy-3 -(1-Methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)methyl)-5-methylpyridin-2-yl)carbamate (0.2 g, 0.4 mmol) was dissolved in ethanol/ammonium chloride saturated aqueous solution=4/1 (10mL), then iron powder (0.45 g, 8 mmol, 20 eq) was added, and the reaction solution was stirred at 80°C for 1h. After the reaction, the reaction solution The concentrated crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the title compound (80 mg, yield 43%). MS m/z (ESI): 468.3[M+H] ⁺ . The seventh step: tertiary butyl (6-((3-((6-chloro-3-(methylaminoformyl)butane -4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5-methylpyridin-2-yl ) Preparation of carbamate: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenylethoxy )methyl)-5-methylpyridin-2-yl)carbamate (80 mg, 0.17 mmol) and 4,6-dichloro-N-methylpyridine-3-carboxamide (105 mg , 0.51 mmol, 3 eq) was dissolved in tetrahydrofuran (5 mL), and NaHMDS (187 mg, 1.02 mmol, 6 eq) was added to the reaction solution, and the reaction solution was stirred at room temperature for 10 min. After the reaction was completed, the reaction solution was concentrated, The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the title compound (50 mg, yield 46%). MS m/z (ESI): 637.3[M+H] ⁺ . The eighth step: 4-((5-(2-(((6-amino-3-methylpyridin-2-yl)methoxy )ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-carboxylate Preparation of amines -(1-Methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5-methylpyridin-2-yl)carbamate (50 mg, 0.078 mmol) was dissolved in di Chloromethane (5 mL), and a solution of hydrochloric acid in dioxane (5 mL, 4M) was added to the reaction mixture. The reaction mixture was stirred at 40° C. for 2 h. The reaction mixture was concentrated to obtain the title compound (40 mg, rate 95%). MS m/z (ESI): 537.2[M+H] ⁺ . Ninth step: 5 ⁶ -methoxy-N, 1 ⁵ -dimethyl-5 ⁵ -(1-methyl- 1 H -pyrazol-3-yl)-8-oxa-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1,3)- The preparation of benzocyclononane-3 ⁶ -carboxamide 4-((5-(2-(((6-amino-3-methylpyridin-2-yl)methoxy)ethyl)- 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyrazole-3-carboxamide (40 mg, 0.074 mmol,) was dissolved in 1,4-dioxane (5 mL), and tris(dibenzylideneacetone) dipalladium (20 mg, 0.022 mmol, 0.3 eq) was added to the reaction mixture under nitrogen protection, 4 ,5-bis(diphenylphosphino)-9,9-dimethylxanthine (25 mg, 0.044 mmol, 0.6 eq), cesium carbonate (72 mg, 0.22 mmol, 3 eq). The resulting reaction mixture Stirred at 130°C for 16 hours. The reaction mixture was filtered and the organic layer was concentrated to give the crude product. The crude product was purified by preparative chromatography to give the title compound (1 mg, yield 3%). MS m/z (ESI): 501.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 11.25 (s, 1H), 10.17 (s, 1H), 9.01 (q, J = 4.8 Hz, 1H), 8.90 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.45 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6. 71 (d, J = 2.0 Hz, 1H), 4.48 (s, 2H), 3.89 (s, 3H), 3.79 - 3.72 (m, 2H), 3.56 (s, 3H), 2.85 (m, 5H), 2.14 (s, 3H).

第一步：4，6-二氯-N-甲基吡啶-3-甲醯胺的製備 將4,6-二氯吡啶-3-羧酸(5 g，1 eq)溶於二氯甲烷(100 mL)中，向溶液中加入甲胺鹽酸鹽(1.93 g，1.1 eq)，三甲胺(7.89g，3 eq)，T ₃P(18.2 g，1.1 eq)，反應混合物在25℃下攪拌1小時。向反應混合物中加入水溶液(100mL)，用二氯甲烷萃取兩次，將合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物。將粗品通過矽膠柱純化，得到標題化合物(4g，收率75%)。 MS m/z (ESI)：205[M+H] ⁺. 第二步：第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1 H-吡唑-3-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 向第三丁基 (6((3-胺基-4-甲氧基-5-(1-甲基-1 H-吡唑-3-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(200 mg，1 eq)的四氫呋喃(20mL)溶液中加入4,6-二氯-N-甲基吡啶-3-甲醯胺(90mg，1 eq)，雙(三甲基甲矽烷基)醯胺鈉(1.3mL)。反應混合物在25℃下攪拌0.5小時。向反應混合物中加入水(5mL)。所得混合物用乙酸乙酯(30×2 mL)萃取。合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物。通過矽膠柱純化粗產物，得到標題化合物(220 mg，收率72.9%)。 MS m/z (ESI)：622 [M+H] ⁺. 第三步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1 H-吡唑-3-基)苯基)胺基)-6-氯- N-甲基煙醯胺的製備 將第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1 H-吡唑-3-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(220 mg，1 eq)溶於二氯甲烷(3 mL)中，向該反應中加入鹽酸的二氧六環溶液(2 mL)。將反應混合物在50℃攪拌1小時。濃縮反應混合物得到標題化合物(150 mg，收率81.2%)。 MS m/z (ESI)： 522 [M+H] ⁺. 第四步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1 H-吡唑-3-乙基)-8-氧雜-2,4-二氮雜-1(2,6),3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-羧醯胺的製備 將4-((5- (2-((6-胺基吡啶-2-基)甲氧基)乙基) -2-甲氧基-3-(1-甲基-1 H-吡唑-3-基)苯基)胺基)-6-氯- N-甲基煙醯胺(150 mg，1 eq)溶於二氧六環(3 mL)，向反應混合物中加入三(二亞苄基丙酮)二鈀(40 mg，0.15 eq)，Xantphos(33 mg，0.20 eq)，Cs ₂CO ₃(281mg，3 eq)。將得到的反應混合物在135℃下攪拌16h。將反應混合物過濾。濃縮有機層，得到粗產物，經純化得到標題化合物(2 mg，收率1.4%)。 MS m/z (ESI)：486[M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ:11.02 (s, 1H), 9.78 (s, 1H), 8.71 (s, 1H), 8.53-8.44 (m, 2H), 8.14 (s, 1H), 7.76-7.78 (m, 1H), 7.60-7.53 (m, 2H), 7.41 (s, 1H),6.98-7.00 (m 1H), 6.81- 6.83 (m, 1H), 6.73-6.75 (m, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.78-3.72 (m, 2H), 3.59 (s, 3H), 2.87-2.76 (m, 5H). Example 17: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1 H -pyrazole-3-ethyl)-8-oxa-2,4-diaza- Preparation of 1(2,6),3(2,4)-dipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: preparation of 4,6-dichloro-N-methylpyridine-3-carboxamide 4,6-dichloropyridine-3-carboxylic acid (5 g, 1 eq) was dissolved in dichloromethane ( 100 mL), methylamine hydrochloride (1.93 g, 1.1 eq), trimethylamine (7.89 g, 3 eq), T ₃ P (18.2 g, 1.1 eq) were added to the solution, and the reaction mixture was stirred at 25°C 1 hour. Aqueous solution (100 mL) was added to the reaction mixture, extracted twice with dichloromethane, the combined organic layers were dried over anhydrous sodium sulfate, and then concentrated to give crude product. The crude product was purified by silica gel column to obtain the title compound (4 g, yield 75%). MS m/z (ESI): 205[M+H] ⁺ . The second step: tertiary butyl (6-((3-((2-chloro-5-(methylaminoformyl)pyridine- 4-yl)amino)-4-methoxy-5-(1-methyl- 1H -pyrazol-3-yl)phenylethoxy)methyl)pyridin-2-yl)aminomethyl Preparation of ester ) pyridin-2-yl) carbamate (200 mg, 1 eq) in tetrahydrofuran (20 mL) was added 4,6-dichloro-N-methylpyridine-3-carboxamide (90 mg, 1 eq ), sodium bis(trimethylsilyl)amide (1.3 mL). The reaction mixture was stirred at 25°C for 0.5 hours. Water (5 mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (30 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by silica gel column to obtain the title compound (220 mg, yield 72.9%). MS m/z (ESI): 622 [M+H] ⁺ . The third step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 -Methoxyl-3-(1-methyl- 1H -pyrazol-3-yl)phenyl)amino)-6-chloro- N -methylnicotinamide Preparation of tertiary butyl (6 -((3-((2-chloro-5-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1 H -pyridine Azol-3-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate (220 mg, 1 eq) was dissolved in dichloromethane (3 mL) and hydrochloric acid was added to the reaction dioxane solution (2 mL). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated to give the title compound (150 mg, yield 81.2%). MS m/z (ESI): 522 [M+H] ⁺ . The fourth step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1 H -pyrazole-3-ethane Base)-8-oxa-2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxy Preparation of Amide -pyrazol-3-yl)phenyl)amino)-6-chloro- N -methylnicotinamide (150 mg, 1 eq) was dissolved in dioxane (3 mL), tris (dibenzylideneacetone)dipalladium (40 mg, 0.15 eq), Xantphos (33 mg, 0.20 eq), _Cs2CO3 (281 mg, ₃ eq). The resulting reaction mixture was stirred at 135 °C for 16 h. The reaction mixture was filtered. The organic layer was concentrated to give a crude product, which was purified to give the title compound (2 mg, yield 1.4%). MS m/z (ESI): 486[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ : 11.02 (s, 1H), 9.78 (s, 1H), 8.71 (s, 1H) , 8.53-8.44 (m, 2H), 8.14 (s, 1H), 7.76-7.78 (m, 1H), 7.60-7.53 (m, 2H), 7.41 (s, 1H),6.98-7.00 (m 1H), 6.81- 6.83 (m, 1H), 6.73-6.75 (m, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.78-3.72 (m, 2H), 3.59 (s, 3H), 2.87- 2.76 (m, 5H).

第一步：2- (4-甲氧基-3-硝基-5-(嘧啶-2-基)苯基)乙酸乙酯的製備 將2-(3-溴-4-甲氧基-5-硝基苯基)乙酸乙酯(3 g，1 eq)溶解在二氧六環(20 mL)中，向反應混合物中添加2-(三丁基錫烷基)嘧啶(4.51 g，1.3 eq)，雙(三第三丁基膦)鈀(0)(0.48 g，0.1 eq)。將得到的反應混合物在120℃下攪拌16小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗品通過矽膠柱純化，得到標題化合物 (1.2 g，收率40%)。 MS m/z (ESI)：318[M+H] ⁺. 第二步：2- (4-甲氧基-3-硝基-5-(嘧啶-2-基)苯基)乙醇的製備 將2- (4-甲氧基-3-硝基-5-(嘧啶-2-基)苯基)乙酸乙酯(1.2 g，1 eq)溶解在甲醇(30 mL)中，向反應混合物中加入碳酸鉀(1.58g，3 eq)，將得到的反應混合物在25℃下攪拌1h。將反應混合物過濾。濃縮有機層，得到粗產物。粗品通過矽膠柱純化，得到標題化合(700 mg，收率67.2%)。 MS m/z (ESI)：276 [M+H] ⁺. 第三步：第三丁基(6-((2- (4-甲氧基-3-硝基-5-(嘧啶-2-基)苯基)乙氧基)甲基)吡啶基- 2-甲酸胺基甲酸甲酯的製備 將2- ((4-甲氧基-3-硝基-5-(嘧啶-2-基)苯基)乙醇(700 mg，1 eq)溶解在四氫呋喃(20 mL)中，在0℃下向混合物中添加氫化鈉 (3 eq)，將得到的反應混合物在0℃攪拌0.5h。然後在0℃向混合物中添加((6-(溴甲基)吡啶-2-基)胺基甲酸第三丁酯(879mg，1.2 eq)，將得到的反應混合物在25℃下攪拌16h。向反應混合物中加入水(20mL)。所得混合物用乙酸乙酯(30×2mL)萃取。合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物。通過矽膠柱純化粗產物，得到標題化合物(400 mg，收率32.7%)。 MS m/z (ESI)：482[M+H] ⁺. 第四步：(6-((2- (3-胺基-4-甲氧基-5-(嘧啶-2-基)苯基)乙氧基)甲基)吡啶-2-基)胺基叔-甲酸丁酯的製備 將(6-((2- (4-甲氧基-3-硝基-5-(嘧啶-2-基)苯基)乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁基酯(400 mg，1 eq)溶解在乙醇(5 mL)和水(1 mL)中。向反應混合物中加入鐵粉(231mg，5 eq)，氯化銨(221mg，5 eq)。將得到的反應混合物在50℃下攪拌1h。將反應混合物過濾。濃縮有機層，得到粗產物。粗產物通過矽膠柱純化，得到標題化合物(200mg，收率53.3%)。 MS m/z (ESI)：452[M+H] ⁺. 第五步：第三丁基(6-((2-(3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤4-基)胺基) -4-甲氧基-5-(嘧啶-2-基)苯基)乙氧基]甲基)吡啶-2-基)胺基甲酸酯的製備 將(6-((2- (3-胺基-4-甲氧基-5-(嘧啶-2-基)苯基)乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯的溶液(200 mg，1 eq)溶解在四氫呋喃(20mL)中，加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺(273mg，1 eq)，雙(三甲基甲矽烷基)醯胺鈉(1.3mL)。將所得混合物在25℃下攪拌0.5h。向反應混合物中加入水(5mL)。所得混合物用乙酸乙酯(10×2mL)萃取。合併的有機層經無水硫酸鈉乾燥，然後濃縮，得到粗產物。通過矽膠柱色譜法純化粗產物，得到標題化合物(200mg，收率58%)。 MS m/z (ESI)：621 [M+H] ⁺. 第六步：4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(嘧啶-2-基)苯基)胺基)-6-氯-N-甲基嗒𠯤- 3-羧醯胺的製備 將第三丁基(6-((2-(3-((6-氯-3-(甲基胺基甲醯基)嗒𠯤4-基]胺基) -4-甲氧基-5-(嘧啶-2-基)苯基)乙氧基)甲基)吡啶-2-基)胺基甲酸酯(200mg，1 eq)溶解在二氯甲烷(3 mL)中，加入鹽酸的二氧六環溶液(3 mL)。將反應混合物在65℃下攪拌0.2h。濃縮反應混合物，得到標題化合物(130mg，收率77.5%)。 MS m/z (ESI)：521[M+H] ⁺. 第七步：5 ⁶-甲氧基-N-甲基-5 ⁵-(嘧啶-2-基)-8-氧雜-2,4-二氮雜3(3,5)-嗒𠯤-1(2,6)-吡啶-5 ⁵(1, 3)-苯并環壬烷-3 ⁶-羧醯胺的製備 將4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(嘧啶-2-基)苯基)胺基)-6-氯-N-甲基嗒𠯤- 3-羧醯胺(50 mg，1 eq)溶解在二氧六環(3 mL)中，向反應混合物中加入三(二苄叉基丙酮)二鈀(13 mg，0.15 eq)，Xantphos(11 mg，0.2 eq)，Cs ₂CO ₃(94 mg，3 eq)。將得到的反應混合物在135℃下攪拌16h。將反應混合物過濾，濃縮有機層，得到粗產物。將粗品通過製備純化，得到標題化合物(3.6 mg，收率7.7%)。 MS m/z (ESI)：485[M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆) δ:11.33 (s, 1H), 10.39 (s, 1H), 9.05 - 9.06 (m, 2H), 8.94 - 8.95 (m, 2H), 7.74-7.75(m, 2H), 7.51-7.52(m, 1H), 7.32 (s, 1H), 7.12- 7.15(m, 1H), 6.88 – 6.92 (m, 1H), 4.46 (s, 2H), 3.72 (m, 2H),3.71 (s, 3H), 2.98- 2.79 (m, 5H). Example 18: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(pyrimidin-2-yl)-8-oxa-2,4-diaza-3(3,5)-diazepine- Preparation of 1(2,6)-pyridine-5 ⁵ (1,3)-benzocyclononane-3 ⁶ -carboxamide

The first step: the preparation of 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethyl acetate 2-(3-bromo-4-methoxy-5 -Nitrophenyl)ethyl acetate (3 g, 1 eq) was dissolved in dioxane (20 mL), 2-(tributylstannyl)pyrimidine (4.51 g, 1.3 eq) was added to the reaction mixture, Bis(tri-tert-butylphosphine)palladium(0) (0.48 g, 0.1 eq). The resulting reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered and the organic layer was concentrated to give crude product. The crude product was purified by silica gel column to obtain the title compound (1.2 g, yield 40%). MS m/z (ESI): 318[M+H] ⁺ . The second step: the preparation of 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethanol will Ethyl 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)acetate (1.2 g, 1 eq) was dissolved in methanol (30 mL), and to the reaction mixture was added Potassium carbonate (1.58 g, 3 eq) and the resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered. The organic layer was concentrated to obtain crude product. The crude product was purified by silica gel column to obtain the title compound (700 mg, yield 67.2%). MS m/z (ESI): 276 [M+H] ⁺ . The third step: tertiary butyl (6-((2- (4-methoxy-3-nitro-5-(pyrimidine-2- Base) phenyl) ethoxy) methyl) pyridyl-2-formic acid carbamate methyl ester 2-((4-methoxy-3-nitro-5-(pyrimidin-2-yl) Phenyl)ethanol (700 mg, 1 eq) was dissolved in tetrahydrofuran (20 mL), sodium hydride (3 eq) was added to the mixture at 0 ° C, and the resulting reaction mixture was stirred at 0 ° C for 0.5 h. Then °C To the mixture was added ((6-(bromomethyl)pyridin-2-yl)tert-butyl carbamate (879 mg, 1.2 eq), and the resulting reaction mixture was stirred at 25 °C for 16 h. To the reaction mixture Water (20 mL) was added. The resulting mixture was extracted with ethyl acetate (30×2 mL). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to give the crude product. The crude product was purified by silica gel column to give the title compound (400 mg, Yield 32.7%). MS m/z (ESI): 482[M+H] ⁺ . The fourth step: (6-((2-(3-amino-4-methoxy-5-(pyrimidine- 2-yl) phenyl) ethoxy) methyl) pyridin-2-yl) amino tert-butyl formate (6-((2-(4-methoxy-3-nitro-5 -(pyrimidin-2-yl)phenyl)ethoxy)methyl)pyridin-2-yl)carbamate (400 mg, 1 eq) was dissolved in ethanol (5 mL) and water (1 mL). Iron powder (231 mg, 5 eq), ammonium chloride (221 mg, 5 eq) were added to the reaction mixture. The resulting reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was filtered. The organic layer was concentrated to obtain Crude product. The crude product was purified by silica gel column to obtain the title compound (200 mg, yield 53.3%). MS m/z (ESI): 452[M+H] ⁺ . The fifth step: tertiary butyl (6-( (2-(3-((6-Chloro-3-(methylaminoformyl)pyridyl4-yl)amino)-4-methoxy-5-(pyrimidin-2-yl)phenyl (6-((2-(3-amino-4-methoxy-5-(pyrimidin-2-yl) A solution of tert-butyl carbamate (200 mg, 1 eq) was dissolved in tetrahydrofuran (20 mL) and 4,6-dichloro-N- Methylpyrrole-3-carboxamide (273 mg, 1 eq), sodium bis(trimethylsilyl) amide (1.3 mL). The resulting mixture was stirred at 25° C. for 0.5 h. To the reaction mixture was added water (5 mL). The resulting mixture was extracted with ethyl acetate (10×2 mL). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to give the crude product. Passed through a silica gel column The crude product was purified by chromatography to obtain the title compound (200 mg, yield 58%). MS m/z (ESI): 621 [M+H] ⁺ . The sixth step: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)- The preparation of 2-methoxy-3-(pyrimidin-2-yl) phenyl) amino)-6-chloro-N-methylpyrrole-3-carboxamide will be tertiary butyl (6-(( 2-(3-((6-Chloro-3-(methylaminoformyl)pyridyl4-yl]amino)-4-methoxy-5-(pyrimidin-2-yl)phenyl) Ethoxy)methyl)pyridin-2-yl)carbamate (200 mg, 1 eq) was dissolved in dichloromethane (3 mL), and hydrochloric acid in dioxane (3 mL) was added. The reaction The mixture was stirred at 65°C for 0.2h. The reaction mixture was concentrated to obtain the title compound (130 mg, yield 77.5%). MS m/z (ESI): 521[M+H] ⁺ . The seventh step: 5 ⁶ -methoxy Base-N-methyl-5 ⁵ -(pyrimidin-2-yl)-8-oxa-2,4-diaza 3(3,5)-pyridine-1(2,6)-pyridine-5 Preparation of ⁵ (1, 3)-benzocyclononane-3 ⁶ -carboxamide )-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)-6-chloro-N-methylpyrrole-3-carboxamide (50 mg, 1 eq) was dissolved in di Oxycycline (3 mL), tris(dibenzylideneacetone)dipalladium (13 mg, 0.15 eq), Xantphos (11 mg, 0.2 eq), Cs ₂ CO ₃ (94 mg, 3 eq).The resulting reaction mixture was stirred at 135°C for 16h.The reaction mixture was filtered, and the organic layer was concentrated to obtain a crude product.The crude product was purified by preparation to obtain the title compound (3.6 mg, yield 7.7%). MS m/ z (ESI): 485[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.33 (s, 1H), 10.39 (s, 1H), 9.05 - 9.06 (m, 2H), 8.94 - 8.95 (m, 2H), 7.74-7.75(m, 2H), 7.51-7.52(m, 1H), 7.32 (s, 1H), 7.12- 7.15(m, 1H), 6.88 - 6.92 (m, 1H ), 4.46 (s, 2H), 3.72 (m, 2H),3.71 (s, 3H), 2.98- 2.79 (m, 5H).

將5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-3-基)-8-噻-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶-5(1,3)-苯并環壬烷-3 ⁶-甲醯胺溶於丙酮和水的混合液（丙酮/水 1：1, 10 mL)中，緩慢加入過氧單磺酸鉀(366 mg, 0.597mmol)，混合液於25 ^oC 下攪拌16小時。反應結束後，用水(10 mL) 淬滅，二氯甲烷萃取(3×20mL), 濃縮後將得到的殘留物用矽膠柱(二氯甲烷/甲醇=10/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備純化後得到標題化合物(5 mg，收率15%)。 MS m/z (ESI)：535.1 [M+H] ⁺. ¹H NMR (400 MHz, CDCl ₃) δ 10.68 (s, 1H), 9.20 (d, J= 15.3 Hz, 2H), 7.97 (d, J= 4.6 Hz, 1H), 7.82 (s, 1H), 7.64 (t, J= 7.8 Hz, 1H), 7.51 -7.35 (m, 2H), 7.11(d, J= 7.4 Hz, 1H), 6.92 (d, J= 8.3 Hz, 1H), 6.81 (d, J= 2.0 Hz, 1H), 3.99 (s, 3H), 3.98 (s, 2H), 3.72 (s, 3H), 3.53 - 3.37 (m, 2H), 3.34 -3.21 (m, 2H), 3.06 (d, J= 4.8 Hz, 3H). Example 19: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-thia-2,4-diaza-3(3 ,5)-Pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide 8,8-dioxide

5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-thia-2,4-diazepine-3(3,5) -Acetone-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -formamide dissolved in a mixture of acetone and water (acetone/water 1:1, 10 mL ), slowly added potassium peroxymonosulfonate (366 mg, 0.597 mmol), and the mixture was stirred at 25 ^o C for 16 hours. After the reaction was completed, it was quenched with water (10 mL), extracted with dichloromethane (3 × 20 mL), concentrated, and the residue obtained was separated and purified with a silica gel column (dichloromethane/methanol=10/1) to obtain a crude product. Then the title compound (5 mg, yield 15%) was obtained after preparation and purification by reverse column (acetonitrile: water = 1: 1). MS m/z (ESI): 535.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.68 (s, 1H), 9.20 (d, J = 15.3 Hz, 2H), 7.97 (d, J = 4.6 Hz, 1H), 7.82 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.51 -7.35 (m, 2H), 7.11(d, J = 7.4 Hz, 1H), 6.92 ( d, J = 8.3 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 3.99 (s, 3H), 3.98 (s, 2H), 3.72 (s, 3H), 3.53 - 3.37 (m, 2H ), 3.34 -3.21 (m, 2H), 3.06 (d, J = 4.8 Hz, 3H).

第一步：N-(3-((2-氯-5-(甲基氨甲醯)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)環丙烷-1,1-二甲醯胺的製備 N-(3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)環丙烷-1,1-二甲醯胺(110 mg，0.30 mmol), 4,6-二氯-N-甲基嗒𠯤-3-甲醯胺(126 mg，0.61 mmol)混溶於四氫呋喃(10 mL)中，室溫下滴加雙(三甲基矽基)胺基鈉(0.62 mL，1.24 mmol，2M的四氫呋喃溶液)。 將混合物在25 ℃下攪拌1小時。 反應完成後加入飽和的氯化銨水溶液淬滅反應。加入水(30 mL)，乙酸乙酯(30 mL×3)萃取。合併的有機層用鹽水洗滌，無水硫酸鈉乾燥，然後濃縮。通過快速柱層析法純化(二氯甲烷/甲醇＝0-10%)，得到標題化合物(30 mg，收率17%)。 MS m/z (ESI): 526.1 [M + H] ⁺. 第二步：6'-甲氧基-N-甲基-5'-(1-甲基-1H-吡唑-3-基)-7'，9'-二氧螺[環丙烷-1,8'-2,6,10-三氮雜-1(4,2)-吡啶-3(1,3)-苯并環癸烷]-5'-甲醯胺的製備 N-(3-((2-氯-5-(甲基氨甲醯)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-3-基)苯乙基)環丙烷-1,1-二甲醯胺(30 mg，0.05 mmol)，碳酸銫(111 mg，0.34 mmol)，三(二亞苄基丙酮)二鈀(5 mg，0.001 mmol)，4,5-雙二苯基膦-9,9-二甲基氧雜蒽(6 mg，0.01 mmol)混溶於1,4-二氧六環(10 mL)中。氮氣氛圍下置換三次，然後將反應混合物在密閉管中加熱到130℃攪拌12 小時。反應完成後過濾，濃縮，得到粗產物。將粗產物通過製備液相色譜法純化，得到標題化合物 (1.0 mg，收率2%)。 MS m/z (ESI): 490.1 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ) δ:10.43 (s, 1H), 9.86 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 7.77 (s, 1H), 7.50 (d, J= 13.2 Hz, 2H), 7.01 (d, J= 22.4 Hz, 2H), 6.71 (s,1H), 3.91 (s, 3H), 3.55 (s, 3H), 2.81 (d, J= 3.6 Hz, 3H), 2.73 - 2.65 (m, 4H), 2.00 (d, J= 6.8 Hz, 2H), 1.35 (s, 2H). Example 20: 6'-methoxy-N-methyl-5'-(1-methyl-1H-pyrazol-3-yl)-7', 9'-dioxaspiro[cyclopropane-1, Preparation of 8'-2,6,10-Triaza-1(4,2)-pyridine-3(1,3)-benzocyclodecane]-5'-formamide

The first step: N-(3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H- Preparation of pyrazol-3-yl)phenethyl)cyclopropane-1,1-dimethylamide N-(3-amino-4-methoxy-5-(1-methyl-1H-pyrazole) -3-yl)phenethyl)cyclopropane-1,1-dimethylamide (110 mg, 0.30 mmol), 4,6-dichloro-N-methylpyridium-3-formamide (126 mg , 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium bis(trimethylsilyl)amide (0.62 mL, 1.24 mmol, 2M solution in tetrahydrofuran) was added dropwise at room temperature. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, saturated aqueous ammonium chloride solution was added to quench the reaction. Water (30 mL) was added and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (dichloromethane/methanol = 0-10%) gave the title compound (30 mg, yield 17%). MS m/z (ESI): 526.1 [M + H] ⁺ . The second step: 6'-methoxy-N-methyl-5'-(1-methyl-1H-pyrazol-3-yl) -7',9'-dioxaspiro[cyclopropane-1,8'-2,6,10-triaza-1(4,2)-pyridine-3(1,3)-benzocyclodecane ]-5'-Formamide N-(3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1 -methyl-1H-pyrazol-3-yl)phenethyl)cyclopropane-1,1-dimethylamide (30 mg, 0.05 mmol), cesium carbonate (111 mg, 0.34 mmol), tris(diethylene Benzylacetone) dipalladium (5 mg, 0.001 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (6 mg, 0.01 mmol) in 1,4-diox Hexacyclic (10 mL). After replacing three times under nitrogen atmosphere, the reaction mixture was heated to 130°C in a closed tube and stirred for 12 hours. After the reaction was completed, it was filtered and concentrated to obtain a crude product. The crude product was purified by preparative liquid chromatography to afford the title compound (1.0 mg, yield 2%). MS m/z (ESI): 490.1 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 10.43 (s, 1H), 9.86 (s, 1H), 8.68 (s, 1H) , 8.48 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 13.2 Hz, 2H), 7.01 (d, J = 22.4 Hz, 2H), 6.71 (s,1H), 3.91 (s, 3H), 3.55 (s, 3H), 2.81 (d, J = 3.6 Hz, 3H), 2.73 - 2.65 (m, 4H), 2.00 (d, J = 6.8 Hz, 2H), 1.35 (s, 2H).

第一步：第三丁基(6-((3-((6-氯-3-(甲胺基甲醯)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (100 mg, 0.22mmol) 溶於四氫呋喃 (3 mL) ，依次加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺 (90 mg, 0.44mmol) 和雙(三甲基矽基)醯胺鈉(0.3 mL)，反應液室溫反應10分鐘。反應結束後，加入水(5 mL)淬滅，二氯甲烷萃取(3×30mL)，有機相用無水硫酸鈉乾燥，濃縮後將得到的殘留物用矽膠柱(80% 乙酸乙酯/石油醚)純化，得到標題化合物(80 mg, 收率52%)。 MS m/z (ESI)：623.1 [M+H] ⁺. 第二步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-甲基煙醯胺的製備 將第三丁基(6-((3-((6-氯-3-(甲胺基甲醯)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (80 mg, 0.13mmol) 溶於鹽酸二氧六環溶液4M (3 mL) 中，混合液於40 ^oC下攪拌1小時。反應結束後直接濃縮得到標題化合物(50 mg, 收率80% )。 MS m/z (ESI)：523.2 [M+H] ⁺. 第三步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-1,2,4-三唑-3-基)-8-氧代-2,4-二氮雜-1(2,6)，3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-甲基煙醯胺(20 mg, 0.0384mmol) 溶於1,4-二氧六環 (3 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(2.21 mg, 0.0038mmol)，三(二亞苄基丙酮)二鈀 (3.59 mg, 0.0038mmol) 和碳酸銫 (37 mg, 0.12mmol)。 混合液於130 ^oC下攪拌4小時。反應結束後直接濃縮，殘留物用矽膠柱(二氯甲烷/甲醇=10/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備，純化後，得到標題化合物 (5 mg，收率27%)。 MS m/z (ESI)：487.2 [M+H]+. ¹H NMR (400 MHz, CDCl ₃) δ10.90 (s, 1H), 9.32 (s, 1H), 8.89 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.76 (d, J= 1.6 Hz, 1H), 7.64 - 7.47 (m, 2H), 6.79 (d, J= 7.7Hz, 2H), 6.65 (s, 1H), 4.48 (s, 2H), 4.01 (s, 3H), 3.86-3.80 (m, 5H), 3.14 – 2.81 (m, 5H). Example 21: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-1,2,4-triazol-3-yl)-8-oxo-2,4- Preparation of diaza-1(2,6), 3(2,4)-dipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: tertiary butyl (6-((3-((6-chloro-3-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(1 -Methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate The tertiary butyl (6-(( 3-Amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)amino Formate (100 mg, 0.22mmol) was dissolved in tetrahydrofuran (3 mL), and 4,6-dichloro-N-methylpyridium-3-formamide (90 mg, 0.44mmol) and bis(tris Sodium methylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL), extracted with dichloromethane (3 × 30 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated and the obtained residue was applied to a silica gel column (80% ethyl acetate/petroleum ether ) to obtain the title compound (80 mg, yield 52%). MS m/z (ESI): 623.1 [M+H] ⁺ . Second step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 -methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide Tributyl(6-((3-((6-chloro-3-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H -1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (80 mg, 0.13mmol) dissolved in dioxane hydrochloride solution 4M ( 3 mL), the mixture was stirred at 40 ^o C for 1 hour. Concentrate directly after the reaction to obtain the title compound (50 mg, yield 80%). MS m/z (ESI): 523.2 [M+H] ⁺ . The third step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-1,2,4-tri Azol-3-yl)-8-oxo-2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane- 3. Preparation of ⁵ -formamide Base-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide (20 mg, 0.0384mmol) dissolved in 1,4-diox Hexacyclic (3 mL), added 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2.21 mg, 0.0038 mmol), tris(dibenzylideneacetone) under nitrogen atmosphere ) Dipalladium (3.59 mg, 0.0038mmol) and cesium carbonate (37 mg, 0.12mmol). The mixture was stirred at 130 ^o C for 4 hours. Concentrate directly after the reaction, and the residue is separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain the crude product, which is then prepared by reverse column (acetonitrile:water=1:1), and after purification, the title Compound (5 mg, yield 27%). MS m/z (ESI): 487.2 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.90 (s, 1H), 9.32 (s, 1H), 8.89 (s, 1H), 8.28 ( s, 1H), 8.11 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.64 - 7.47 (m, 2H), 6.79 (d, J = 7.7Hz, 2H), 6.65 (s, 1H ), 4.48 (s, 2H), 4.01 (s, 3H), 3.86-3.80 (m, 5H), 3.14 – 2.81 (m, 5H).

第一步：第三丁基(6-((3-((2-氯-5-((甲基-d3)氨甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (100 mg, 0.22mmol) 溶於四氫呋喃 (3 mL) ，依次加入4,6-二氯-N-甲基嗒𠯤-3-甲醯胺 (91 mg, 0.43mmol) 和雙(三甲基矽基)醯胺鈉(0.3 mL)，反應液室溫反應10分鐘。反應結束後，加入水(5 mL)淬滅，二氯甲烷萃取(3×30mL)，有機相用無水硫酸鈉乾燥，濃縮後，將得的殘留物用矽膠柱(乙酸乙酯/石油醚=0-80%)純化，得到標題化合物(80 mg，收率53%)。 MS m/z (ESI)：626.2 [M+H] ⁺. 第二步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-(甲基-d3)煙醯胺的製備 將第三丁基(6-((3-((2-氯-5-((甲基-d3)氨甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-1,2,4-三唑-3-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (80 mg, 0.13mmol) 溶於鹽酸二氧六環溶液4M (3 mL) 中，混合液於40 ^oC下攪拌1小時。反應結束後直接濃縮得到標題化合物(50 mg，收率67% )。 MS m/z (ESI)：526.2 [M+H] ⁺. 第三步：5 ⁶-甲氧基-N-(甲基-d3)-5 ⁵-(1-甲基-1H-1,2,4-三唑-3-基)-8-氧代-2,4-二氮雜-1(2,6)，3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)-6-氯-N-(甲基-d3)煙醯胺(50 mg, 0.095mmol) 溶於1,4-二氧六環 (3 mL) 中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(5.5 mg, 0.0095mmol)，三(二亞苄基丙酮)二鈀 (8.7 mg, 0.0095mmol) 和碳酸銫 (93 mg, 0.285mmol)。 混合液於130 ^oC下攪拌4小時。反應結束後直接濃縮，殘留物用矽膠柱(二氯甲烷/甲醇=10/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1) 製備，純化後，得到標題化合物 (5 mg，收率10%)。 MS m/z (ESI)：490.2 [M+H]+. ¹H NMR (400 MHz, CDCl ₃) δ 11.04 (s, 1H), 10.35 (s, 1H), 8.90 (d, J= 9.3 Hz, 1H), 8.57 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.67 – 7.45 (m, 2H),6.88 (d, J= 8.4 Hz, 1H), 6.80 (d, J= 7.2 Hz, 1H), 4.47 (s, 2H), 4.02 (s, 3H), 3.90 – 3.76 (m, 5H), 2.99 – 2.87 (m, 2H). Example 22: 5 ⁶ -methoxy-N-(methyl-d3)-5 ⁵ -(1-methyl-1H-1,2,4-triazol-3-yl)-8-oxo- Preparation of 2,4-diaza-1(2,6),3(2,4)-dipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: tertiary butyl (6-((3-((2-chloro-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxy -5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridine-2 -yl) carbamate (100 mg, 0.22mmol) was dissolved in tetrahydrofuran (3 mL), and 4,6-dichloro-N-methylpyridium-3-formamide (91 mg, 0.43mmol) was added successively ) and sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes. After the reaction was completed, quenched by adding water (5 mL), extracted with dichloromethane (3 × 30 mL), dried the organic phase with anhydrous sodium sulfate, concentrated, and used a silica gel column (ethyl acetate/petroleum ether = 0-80%) to obtain the title compound (80 mg, yield 53%). MS m/z (ESI): 626.2 [M+H] ⁺ . Second step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 -Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)nicotinamide The preparation of tert-butyl(6-((3-((2-chloro-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxy- 5-(1-Methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (80 mg, 0.13mmol) In dioxane hydrochloride solution 4M (3 mL), the mixture was stirred at 40 ^o C for 1 hour. After the reaction was completed, it was directly concentrated to obtain the title compound (50 mg, yield 67%). MS m/z (ESI): 526.2 [M+H] ⁺ . The third step: 5 ⁶ -methoxy-N-(methyl-d3)-5 ⁵ -(1-methyl-1H-1,2 ,4-triazol-3-yl)-8-oxo-2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzo The preparation of cyclononane-3 ⁵ -formamide 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy (1-Methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)nicotinamide (50 mg, 0.095mmol) Dissolve in 1,4-dioxane (3 mL), add 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (5.5 mg, 0.0095 mmol) under nitrogen atmosphere , tris(dibenzylideneacetone)dipalladium (8.7 mg, 0.0095 mmol) and cesium carbonate (93 mg, 0.285 mmol). The mixture was stirred at 130 ^o C for 4 hours. Concentrate directly after the reaction, and the residue is separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain the crude product, which is then prepared by reverse column (acetonitrile:water=1:1), and after purification, the title Compound (5 mg, yield 10%). MS m/z (ESI): 490.2 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.04 (s, 1H), 10.35 (s, 1H), 8.90 (d, J = 9.3 Hz, 1H), 8.57 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.67 – 7.45 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H ), 6.80 (d, J = 7.2 Hz, 1H), 4.47 (s, 2H), 4.02 (s, 3H), 3.90 – 3.76 (m, 5H), 2.99 – 2.87 (m, 2H).

第一步：4-甲氧基-3-(1-甲基-1H-吡唑-4-基)-5-硝基苯乙酸乙酯的製備 向3-溴-4-甲氧基-5-硝基苯乙酸乙酯(2.51 g，0.8 mmol)的1,4-二氧六環/水=3：1(20 mL)溶液中，加入(1-甲基-1H-吡唑-4-基)硼酸(1 g，0.8 mmol)，Pd(dppf)Cl ₂(0.58 g，0.07 mmol)和碳酸鉀(2.18 g，1.6 mmol)，在氮氣氛圍中置換三次。將混合液在氮氣氛圍90 ^oC下攪拌反應1小時。反應完成後，用乙酸乙酯(50 mL×2)萃取，合併的有機層用鹽水(20 mL×2)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(PE / EA＝1/1)，得到標題化合物(1.2 g，收率43%)。 MS m/z (ESI): 320.1[M + H] ⁺. 第二步：2-(4-甲氧基-3-(1-甲基-1H-吡唑-4-基)-5-硝基苯基)-1-乙醇的製備 4-甲氧基-3-(1-甲基-1H-吡唑-4-基)-5-硝基苯乙酸乙酯(405 mg，1.6 mmol)溶於甲醇(5 mL)中，加入甲醇鈉(0.3 mL，1.6 mmol)。反應在25 ^oC下攪拌2小時。反應完成後加水(2 mL)淬滅，混合液減壓濃縮後用乙酸乙酯(10mL×3)萃取，合併的有機層用鹽水(10 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析純化(DCM / MeOH＝20/1)，得到標題化合物 (400 mg，收率87.5%)。 MS m/z (ESI): 278.1 [M + H] ⁺. 第三步：第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-4-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 2-(4-甲氧基-3-(1-甲基-1H-吡唑-4-基)-5-硝基苯基)-1-乙醇(500 mg，1.8 mmol)溶於DMF(10 mL )中，在0 ^oC下加入NaH (220 mg，5.4mmol)，15-冠-5(10mg，0.0036mmol)和(6-(溴甲基)吡啶-2-基)胺基甲酸第三丁酯(620 mg，2.1mmol)。反應在25 ^oC攪拌1小時。反應完成後加入飽和的氯化銨水溶液(5mL)淬滅反應，用乙酸乙酯(10 mL×3)萃取，合併的有機層用鹽水(10 mL×3)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(PE / EA ＝ 1/2)，得到標題化合物 (130 mg，收率17%)。 MS m/z (ESI): 484.2 [M + H] ⁺. 第四步：第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 第三丁基(6-((4-甲氧基-3-(1-甲基-1H-吡唑-4-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(120 mg，0.25 mmol)溶於EtOH:H ₂O=4:1(10 mL )加入鐵粉 (69 mg，1.2 mmol)和氯化銨(66 mg，1.2 mmol)。反應在80 ^oC攪拌1小時。反應完成後將反應液減壓濃縮，用乙酸乙酯(10 mL×2)萃取，合併的有機層用鹽水(10 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(DCM / MeOH ＝ 20/1)，得到標題化合物 (120 mg，收率93%)。 MS m/z (ESI): 454.3 [M + H] ⁺. 第五步：第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 第三丁基(6-((3-胺基-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (120 mg，0.26 mmol)和4,6-二氯-N-甲基煙醯胺(108.5 mg，0.52mmol)溶於THF(5 mL)，加入NaHMDS (0.7 mL, 1.3mmol)。反應溶液在25 ^oC下攪拌1小時。反應完成後加入飽和的氯化銨水溶液(3mL)淬滅反應，用乙酸乙酯(10 mL×2)萃取， 合併的有機層用鹽水(10 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(PE / EA ＝ 0/1)，得到標題化合物(100 mg，收率55%)。 MS m/z (ESI): 623.2[M + H] ⁺. 第六步：4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)胺基)-6-氯-N-甲基煙醯胺的製備 將第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (100 mg，0.16mmol)溶於二氯甲烷(2 mL)，加入4M的鹽酸二氧六環溶液(0.2 mL，0.64 mmol)。反應在40 ^oC下攪拌1小時。減壓除去溶劑，得到標題化合物(60 mg，收率62%)。 MS m/z (ESI): 523.2[M + H] ⁺. 第七步：5 ⁶-甲氧基-N-甲基-5 ⁵-(1-甲基-1H-吡唑-4-基)-8-氧雜-2,4-二氮雜-1(2,6)，3(2,4)-二吡啶-5(1,3)-苯環環壬基-3 ⁵-羧醯胺的製備 將4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(1-甲基-1H-吡唑-4-基)苯基)胺基)-6-氯-N-甲基煙醯胺(50 mg, 0.09mmol) 溶解在1,4-二氧六環(12 mL)中，氮氣保護下向反應混合物中加入三(二亞苄基丙酮)二鈀(26 mg，0.028 mmol)，4,5-雙(二苯基膦基)-9,9-二甲基黃嘌呤(22 mg，0.038 mmo)，碳酸銫(94 mg, 0.28 mmol)。將得到的反應混合物在130 ℃下攪拌12小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗產物通過製備色譜純化，得到標題化合物 (5.5 mg，收率11%)。 MS m/z (ESI): 486.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 11.00 (s, 1H), 9.77 (s, 1H), 8.69 (s, 1H), 8.58 – 8.42 (m, 2H), 8.15 (s, 1H), 7.90 (s, 1H), 7.57 (t, J= 7.7 Hz, 1H), 7.47 (s,1H), 7.15 (s, 1H), 6.98 (d, J= 8.3 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.41 (s, 2H), 3.89 (s, 3H), 3.78-3.74 (m, 2H), 3.57 (s, 3H), 2.90 – 2.74 (m, 5H). Example 23: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-4-yl)-8-oxa-2,4-diaza-1( Preparation of 2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: the preparation of 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenylacetic acid ethyl ester to 3-bromo-4-methoxy-5 -In a solution of ethyl nitrophenylacetate (2.51 g, 0.8 mmol) in 1,4-dioxane/water=3:1 (20 mL), add (1-methyl-1H-pyrazole-4- base) boronic acid (1 g, 0.8 mmol), Pd(dppf)Cl ₂ (0.58 g, 0.07 mmol) and potassium carbonate (2.18 g, 1.6 mmol), were replaced three times under nitrogen atmosphere. The mixture was stirred and reacted at 90 ^o C under a nitrogen atmosphere for 1 hour. After the reaction was complete, it was extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (PE/EA=1/1) gave the title compound (1.2 g, yield 43%). MS m/z (ESI): 320.1[M + H] ⁺ . The second step: 2-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrate Preparation of 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenylacetic acid ethyl ester (405 mg, 1.6 mmol) In methanol (5 mL), sodium methoxide (0.3 mL, 1.6 mmol) was added. The reaction was stirred at 25 ^° C for 2 hours. After the reaction was completed, water (2 mL) was added to quench, the mixture was concentrated under reduced pressure and extracted with ethyl acetate (10 mL×3), the combined organic layer was washed with brine (10 mL×1), dried over anhydrous sodium sulfate and evaporated under reduced pressure. Concentrate under pressure. Purification by flash column chromatography (DCM/MeOH=20/1) afforded the title compound (400 mg, yield 87.5%). MS m/z (ESI): 278.1 [M + H] ⁺ . The third step: tertiary butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazole-4- Base)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate preparation 2-(4-methoxy-3-(1-methyl-1H-pyrazole- 4-yl)-5-nitrophenyl)-1-ethanol (500 mg, 1.8 mmol) was dissolved in DMF (10 mL), NaH (220 mg, 5.4 mmol) was added at 0 ^o C, 15-crown -5 (10 mg, 0.0036 mmol) and tert-butyl (6-(bromomethyl)pyridin-2-yl)carbamate (620 mg, 2.1 mmol). The reaction was stirred at 25 ^° C for 1 hour. After the reaction was complete, a saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the combined organic layers were washed with brine (10 mL×3), dried over anhydrous sodium sulfate and Concentrate under reduced pressure. Purification by flash column chromatography (PE/EA=1/2) afforded the title compound (130 mg, yield 17%). MS m/z (ESI): 484.2 [M + H] ⁺ . The fourth step: tertiary butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H- Preparation of pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate tertiary butyl (6-((4-methoxy-3-(1-methyl -1H-pyrazol-4-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (120 mg, 0.25 mmol) dissolved in EtOH:H ₂ O=4 :1 (10 mL) iron powder (69 mg, 1.2 mmol) and ammonium chloride (66 mg, 1.2 mmol) were added. The reaction was stirred at 80 ^° C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (10 mL×2), and the combined organic layers were washed with brine (10 mL×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (DCM/MeOH=20/1) afforded the title compound (120 mg, yield 93%). MS m/z (ESI): 454.3 [M + H] ⁺ . The fifth step: tertiary butyl (6-((3-((2-chloro-5-(methylaminoformyl)pyridine- 4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate Preparation of tert-butyl(6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridine-2 -yl) carbamate (120 mg, 0.26 mmol) and 4,6-dichloro-N-methylnicotinamide (108.5 mg, 0.52 mmol) were dissolved in THF (5 mL), and NaHMDS (0.7 mL , 1.3mmol). The reaction solution was stirred at 25 ^° C for 1 hour. After the reaction was complete, a saturated aqueous ammonium chloride solution (3 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×2), and the combined organic layers were washed with brine (10 mL×1), dried over anhydrous sodium sulfate and Concentrate under reduced pressure. Purification by flash column chromatography (PE/EA=0/1) afforded the title compound (100 mg, yield 55%). MS m/z (ESI): 623.2[M + H] ⁺ . The sixth step: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)- The preparation of 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl) phenyl) amino)-6-chloro-N-methylnicotinamide will be tertiary butyl (6 -((3-((2-chloro-5-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazole -4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (100 mg, 0.16mmol) was dissolved in dichloromethane (2 mL), and a 4M solution of dioxane hydrochloride was added (0.2 mL, 0.64 mmol). The reaction was stirred at 40 ^o C for 1 hour. The solvent was removed under reduced pressure to give the title compound (60 mg, yield 62%). MS m/z (ESI): 523.2[M+H] ⁺ . The seventh step: 5 ⁶ -methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-4-yl)-8-oxa-2,4-diaza- 1(2,6), the preparation of 3(2,4)-bipyridine-5(1,3)-phenylcyclononyl-3 ⁵ -carboxamide 4-((5-(2-(( (6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6 -Chloro-N-methylnicotinamide (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (12 mL), and tris(dibenzylideneacetone) di Palladium (26 mg, 0.028 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (22 mg, 0.038 mmol), cesium carbonate (94 mg, 0.28 mmol). The resulting reaction mixture was stirred at 130° C. for 12 hours. The reaction mixture was filtered and the organic layer was concentrated to obtain a crude product. The crude product was purified by preparative chromatography to obtain the title compound (5.5 mg, yield 11%). MS m/z ( ESI): 486.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.00 (s, 1H), 9.77 (s, 1H), 8.69 (s, 1H), 8.58 – 8.42 ( m, 2H), 8.15 (s, 1H), 7.90 (s, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.47 (s,1H), 7.15 (s, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.41 (s, 2H) , 3.89 (s, 3H), 3.78-3.74 (m, 2H), 3.57 (s, 3H), 2.90 – 2.74 (m, 5H).

第一步：第三丁基(6-((3-((6-氯-3-((甲基-d ₃)胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(嘧啶-2-基)苯乙氧基)甲基吡啶-2-基胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(200 mg，0.44 mmol)和4,6-二氯-N-(甲基-d ₃)嗒𠯤-3-羧醯胺(273 mg，1.32 mmol)溶於四氫呋喃(10 mL)中，緩慢滴加雙(三甲基矽基)氨化鈉(2M，1.3 mL，2.65 mmol)，混合液於25℃下攪拌10分鐘。反應結束後，用甲醇(10 mL) 淬滅，濃縮後將得到的殘留物用矽膠柱(洗脫劑：二氯甲烷/甲醇 = 4/1)純化，得到第三丁基(6-((3-((6-氯-3-((甲基-d ₃)胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(嘧啶-2-基)苯乙氧基)甲基吡啶-2-基胺基甲酸酯(200 mg，收率65%)。 MS m/z(ESI)：624 [M+H] ⁺。 第二步：4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(嘧啶-2-基)苯基)胺基)-6-氯-N-(甲基-d ₃)嗒𠯤-3-羧醯胺的製備 將第三丁基(6-((3-((6-氯-3-((甲基-d ₃)胺基甲醯基)嗒𠯤-4-基)胺基)-4-甲氧基-5-(嘧啶-2-基)苯乙氧基)甲基吡啶-2-基胺基甲酸酯(200 mg，0.38 mmol)溶於二氯甲烷(3 mL)中，加入鹽酸和1，4-二氧六環的混合液中(鹽酸/1，4-二氧六環 = 4 mol/L，10 mL)。混合液於50℃下攪拌1小時。反應結束後直接濃縮，得到4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(嘧啶-2-基)苯基)胺基)-6-氯-N-(甲基-d ₃)嗒𠯤-3-羧醯胺(150 mg，收率60%)。 MS m/z(ESI)：524 [M+H] ⁺。 第三步：5 ⁶-甲氧基-N-(甲基-d ₃)-5 ⁵-(嘧啶-2-基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶- 5(1,3)-苯并環壬烷-3 ⁶-羧醯胺的製備 將4-((5-(2-(((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(嘧啶-2-基)苯基)胺基)-6-氯-N-(甲基-d ₃)嗒𠯤-3-羧醯胺(150mg，0.29 mmol)溶於1,4-二氧六環(10 mL)中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(34 mg，0.06 mmol)，三(二亞苄基丙酮)二鈀(40 mg，0.04 mmol)和碳酸銫(284 mg，0.86 mmol)。混合液於130℃下攪拌16小時。反應結束後直接濃縮，殘留物用矽膠柱(洗脫劑：二氯甲烷/甲醇 = 4/1)分離純化後得到粗產物，然後通過反向柱(乙腈：水 = 1：1)製備，純化後，得到5 ⁶-甲氧基-N-(甲基-d ₃)-5 ⁵-(嘧啶-2-基)-8-氧雜-2,4-二氮雜-3(3,5)-嗒𠯤-1(2,6)-吡啶- 5(1,3)-苯并環壬烷-3 ⁶-羧醯胺(37 mg，收率25%)。 MS m/z(ESI)：488.3 [M+H] ⁺. ¹H NMR(400 MHz, DMSO- d ₆) δ:11.34 (s, 1H), 10.39 (s, 1H), 9.10-9.06 (m, 2H), 8.95 -8.93 (m, 2H), 7.82-7.74 (m, 1H), 7.72-7.68 (m, 1H), 7.51 (s, 1H), 7.35-7.32 (m, 1H), 7.15-7.11 (m, 1H), 6.92-6.88 (m, 1H), 4.46 (s, 2H), 3.79-3.72 (m, 2H), 3.69 (s, 3H), 2.93-2.86 (m, 2H). Example 36: 5 ⁶ -Methoxy-N-(methyl-d ₃ )-5 ⁵ -(pyrimidin-2-yl)-8-oxa-2,4-diaza-3(3,5 Preparation of )-pyridine-1(2,6)-pyridine-5(1,3)-phenylcyclononane-3 ⁶ -carboxamide

The first step: tertiary butyl (6-((3-((6-chloro-3-((methyl-d ₃ ) aminoformyl) pyridyl-4-yl) amino)-4- Preparation of methoxy-5-(pyrimidin-2-yl)phenethoxy)methylpyridin-2-ylcarbamate The tertiary butyl (6-((3-amino-4-methyl Oxy-5-(pyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (200 mg, 0.44 mmol) and 4,6-dichloro-N-(form Group-d ₃ ) carboxamide (273 mg, 1.32 mmol) was dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilyl) sodium amide (2M, 1.3 mL, 2.65 mmol), the mixture was stirred at 25°C for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), concentrated and the residue obtained was applied to a silica gel column (eluent: dichloromethane/methanol=4/1 ) purification to obtain tertiary butyl (6-((3-((6-chloro-3-((methyl-d ₃ ) aminoformyl) pyridyl-4-yl) amino)-4- Methoxy-5-(pyrimidin-2-yl)phenethoxy)methylpyridin-2-ylcarbamate (200 mg, yield 65%). MS m/z (ESI): 624 [ M+H] ⁺ . The second step: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidine -2-base) phenyl) amino) -6-chloro-N-(methyl-d ₃ ) thiamine-3-carboxamide preparation The tertiary butyl (6-((3-((6 -Chloro-3-((methyl-d ₃ )aminoformyl)pyridium-4-yl)amino)-4-methoxy-5-(pyrimidin-2-yl)phenethoxy) Pyridin-2-ylcarbamate (200 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL), and added to a mixture of hydrochloric acid and 1,4-dioxane (hydrochloric acid/1, 4-dioxane=4 mol/L, 10 mL). The mixture was stirred at 50°C for 1 hour. After the reaction, it was directly concentrated to obtain 4-((5-(2-(((6-aminopyridine -2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)-6-chloro-N-(methyl-d ₃ )butadiene -3-Carboxamide (150 mg, yield 60%). MS m/z (ESI): 524 [M+H] ⁺ . The third step: 5 ⁶ -methoxy-N-(methyl-d ₃ )-5 ⁵ -(pyrimidin-2-yl)-8-oxa-2,4-diaza-3(3,5)-pyridine-1(2,6)-pyridine-5(1, 3) Preparation of -benzocyclononane-3 ⁶ -carboxamide 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2- Methoxy-3-(pyrimidin-2-yl)phenyl)amino)-6-chloro-N-(methyl-d ₃ ) Carboxamide (150 mg, 0.29 mmol) was dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine)-9 was added under nitrogen atmosphere , 9-dimethylxanthene (34 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (40 mg, 0.04 mmol) and cesium carbonate (284 mg, 0.86 mmol). The mixture was stirred at 130°C for 16 hours. Concentrate directly after the reaction, and the residue is separated and purified with a silica gel column (eluent: dichloromethane/methanol=4/1) to obtain a crude product, which is then prepared and purified by a reverse column (acetonitrile:water=1:1) After that, 5 ⁶ -methoxy-N-(methyl-d ₃ )-5 ⁵ -(pyrimidin-2-yl)-8-oxa-2,4-diazepine-3(3,5) -Pyridine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide (37 mg, yield 25%). MS m/z (ESI): 488.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.34 (s, 1H), 10.39 (s, 1H), 9.10-9.06 (m, 2H), 8.95 -8.93 (m, 2H), 7.82-7.74 (m, 1H), 7.72-7.68 (m, 1H), 7.51 (s, 1H), 7.35-7.32 (m, 1H), 7.15-7.11 ( m, 1H), 6.92-6.88 (m, 1H), 4.46 (s, 2H), 3.79-3.72 (m, 2H), 3.69 (s, 3H), 2.93-2.86 (m, 2H).

第一步：2-(3-溴-4-甲氧基-5-硝基苯基)乙-1-醇的製備 將3-溴-4-甲氧基-5-硝基苯乙酸乙酯(5 g，0.016 mol)溶於甲醇(50 mL )中，在室溫條件下加入碳酸鉀(4.34 g ，0.032 mol)，反應在室溫下攪拌2小時。反應完成後反應液用水(10 mL)淬滅，反應液減壓濃縮後用乙酸乙酯(50 mL×3)萃取，合併的有機層用鹽水(50 mL×2)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(石油醚 / 乙酸乙酯＝ 1/1)，得到標題化合物2-(3-溴-4-甲氧基-5-硝基苯基)乙-1-醇 (4.5 g，收率98.7%)。 MS m/z (ESI): 275.0 [M + H] ⁺. 第二步：(6-((3-溴-4-甲氧基-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯的製備 將2-(3-溴-4-甲氧基-5-硝基苯基)乙-1-醇(5.3 g，0.019 mol)和(6-(溴甲基)吡啶-2-基)胺基甲酸第三丁酯(5.24 g，0.018 mol)溶於四氫呋喃(60 mL)中，在0℃下加入氫化鈉 (1.54 g，0.038 mol)，反應在0℃下攪拌30分鐘，反應完成後加入冰水(15 mL)淬滅反應，用乙酸乙酯(50 mL×3)萃取，合併的有機層用鹽水(50 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(石油醚 / 乙酸乙酯＝ 85%/15%)，得到標題化合物6-((3-溴-4-甲氧基-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯 (5.0 g，收率53.6%)。 MS m/z (ESI): 482.0[M + H] +. 第三步：第三丁基(6-((4-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 向6-((3-溴-4-甲氧基-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯(5 g，10.3 mmol)的1，4-二氧六環(60 mL)溶液中, 加入雙頻哪醇硼酸酯(7.85 g，30.9 mmol)，1,1-雙(二苯基磷)二茂鐵氯化鈀(1.5 g，2.06 mmol)和乙酸鉀(3.0 g，30.9 mmol)，在氮氣氛圍中置換三次。 將混合液在氮氣氛圍90℃下攪拌反應2小時。反應完成後，反應液過濾，濾液減壓濃縮後加水，用乙酸乙酯(50 mL×3)萃取，合併的有機層用鹽水(50 mL×2)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(石油醚/乙酸乙酯＝4/1)，得到標題化合物第三丁基(6-((4-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (4.3 g，收率77.7%)。 MS m/z (ESI): 530.3[M + H] +. 第四步：(6-((4-甲氧基-3-(5-甲基嘧啶-2-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯的製備 將第三丁基(6-((4-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(1.5 g，2.8 mmol)溶於1，4-二氧六環和水的混合液 (1，4-二氧六環：水=5：1，12 mL)中，然後加入2-溴-5-甲基嘧啶(0.4 g，3.1 mmol)，1,1-雙(二苯基磷)二茂鐵氯化鈀(0.41 g，0.56 mmol)和碳酸鉀(0.97 g，7.0 mmol)，在氮氣氛圍中置換三次。反應在90 ℃下攪拌2小時。反應完成後，反應液過濾，濾液減壓濃縮後加水用乙酸乙酯(20 mL×3)萃取，合併的有機層用鹽水(20 mL×2)洗滌，用無水硫酸鈉乾燥並減壓濃縮。粗品通過快速柱層析法純化(石油醚/乙酸乙酯＝ 2/3)，得到標題化合物 (6-((4-甲氧基-3-(5-甲基嘧啶-2-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯 (1.1 g，收率78.6%)。 MS m/z (ESI): 496.2 [M + H] +. 第五步：第三丁基(6-((3-胺基-4-甲氧基-5-(5-甲基嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將(6-((4-甲氧基-3-(5-甲基嘧啶-2-基)-5-硝基苯乙氧基)甲基)吡啶-2-基)胺基甲酸第三丁酯(800 mg，1.6 mmol)溶於乙醇和水的混合液中(乙醇：水=4：1，10 mL)，加入鐵粉 (450 mg，8.1 mmol)和氯化銨(430 mg，8.1 mmol)。反應在80℃攪拌1小時。反應完成後將反應液減壓濃縮，用乙酸乙酯(30 mL×2)萃取，合併的有機層用鹽水(30 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(二氯甲烷/甲醇＝ 95%/5%)，得到標題化合物第三丁基(6-((3-胺基-4-甲氧基-5-(5-甲基嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(700 mg，收率93.1%)。 MS m/z (ESI): 466.3 [M + H] +. 第六步：第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(5-甲基嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(5-甲基嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯(700 mg，1.5 mmol)和4,6-二氯-N-甲基煙醯胺(620 mg，3.0 mmol)溶於THF(10 mL)，加入二(三甲基矽基)胺基鈉(3.8 mL，7.5 mmol)。反應溶液在室溫下攪拌0.5小時。反應完成後加入甲醇(3 mL)淬滅反應，在減壓下濃縮，通過快速柱層析法純化(二氯甲烷/甲醇＝ 95%/5%)，得到目標化合物第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(5-甲基嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (650 mg，收率53.3%)。 MS m/z (ESI): 634.2[M + H] +. 第七步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(5-甲基嘧啶-2-基)苯基)胺基)-6-氯-N-甲基煙醯胺的製備 將化合物第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(5-甲基嘧啶-2-基)苯乙氧基)甲基)吡啶-2-基)胺基甲酸酯 (650 mg，1.0 mmol)溶於二氯甲烷(2 mL)，加入4M的鹽酸二氧六環溶液(2 mL，10.2 mmol)。反應在40 ℃下攪拌1小時。減壓除去溶劑，粗品溶於二氯甲烷(20 mL )，加入飽和的碳酸氫鈉水溶液調節pH至8-9，混合液用二氯甲烷(30 mL×3)萃取， 合併有機層，用鹽水(30 mL×1)洗滌，用無水硫酸鈉乾燥並在減壓下濃縮。通過快速柱層析法純化(二氯甲烷/甲醇＝ 95%/5%)，得到標題化合物4-((5-(2-((6-胺基吡啶-2-基) 甲氧基) 乙基)-2-甲氧基-3-(5-甲基嘧啶-2-基)苯基)胺基)-6-氯-N-甲基煙醯胺(450 mg，收率77%) 。 MS m/z (ESI): 534.2[M + H] +. 第八步：5 ⁶-甲氧基-N-甲基-5 ⁵-(5-甲基嘧啶-2-基)-8-氧雜-2,4-二氮雜-1(2,6),3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-羧醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(5-甲基嘧啶-2-基) 苯基) 胺基)-6-氯-N-甲基煙醯胺(450 mg, 0.84 mmol) 溶解在1,4-二氧六環(15 mL)中，氮氣保護下向反應混合物中加入三(二亞苄基丙酮)二鈀(217 mg，0.25 mmol)，4,5-雙(二苯基膦基)-9,9-二甲基黃嘌呤(183 mg，0.34 mmol)，碳酸銫(771 mg, 2.5 mmol)。 將得到的反應混合物在130 ℃下攪拌8小時。將反應混合物過濾，濃縮有機層，得到粗產物。粗產物通過製備型HPLC(氨水體系)純化，得到標題化合物5 ⁶-甲氧基-N-甲基-5 ⁵-(5-甲基嘧啶-2-基)-8-氧雜-2,4-二氮雜-1(2,6),3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-羧醯胺(230.3 mg，收率54.9%)。 MS m/z (ESI): 498.2 [M + H] ⁺. ¹H NMR (400 MHz, DMSO-d6) δ: 10.99 (s, 1H), 9.79 (s, 1H), 8.78 (s, 2H)，8.71 (s, 1H), 8.50 -8.47 (m, 2H), 7.70 (d, J=1.6 Hz, 1H), 7.60-7.56 (m, 1H), 7.21 (d, J=1.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.74 (t, J = 4.4 Hz, 2H), 3.67 (s, 3H), 2.87 (t, J = 4.8 Hz, 2H), 2.78 (d, J = 4.4 Hz, 3H), 2.34 (s, 3H). Example 52: 5 ⁶ -Methoxy-N-methyl-5 ⁵ -(5-methylpyrimidin-2-yl)-8-oxa-2,4-diaza-1(2,6) , Preparation of 3(2,4)-dipyridine-5(1,3)-benzocyclononyl-3 ⁵ -carboxamide

The first step: the preparation of 2-(3-bromo-4-methoxy-5-nitrophenyl)ethan-1-alcohol 3-bromo-4-methoxy-5-nitrophenylacetic acid ethyl ester (5 g, 0.016 mol) was dissolved in methanol (50 mL), and potassium carbonate (4.34 g, 0.032 mol) was added at room temperature, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with water (10 mL), the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (50 mL×3), the combined organic layer was washed with brine (50 mL×2), and dried over anhydrous sodium sulfate. and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether/ethyl acetate=1/1) gave the title compound 2-(3-bromo-4-methoxy-5-nitrophenyl)ethan-1-ol (4.5 g, yield 98.7%). MS m/z (ESI): 275.0 [M + H] ⁺ . Second step: (6-((3-bromo-4-methoxy-5-nitrophenethoxy)methyl)pyridine-2 2-(3-bromo-4-methoxy-5-nitrophenyl)ethan-1-ol (5.3 g, 0.019 mol) and (6-( Bromomethyl)pyridin-2-yl)tert-butyl carbamate (5.24 g, 0.018 mol) was dissolved in tetrahydrofuran (60 mL), and sodium hydride (1.54 g, 0.038 mol) was added at 0°C, and the reaction was Stir at 0°C for 30 minutes, add ice water (15 mL) to quench the reaction after the reaction is complete, extract with ethyl acetate (50 mL×3), wash the combined organic layers with brine (50 mL×1), and wash with anhydrous sulfuric acid Sodium dried and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether/ethyl acetate = 85%/15%) afforded the title compound 6-((3-bromo-4-methoxy-5-nitrophenethoxy)methyl ) pyridin-2-yl) tert-butyl carbamate (5.0 g, yield 53.6%). MS m/z (ESI): 482.0[M + H] +. The third step: tertiary butyl (6-((4-methoxy-3-nitro-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate to 6-((3-bromo- 4-methoxy-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (5 g, 10.3 mmol) in 1,4-dioxane (60 mL ) solution, bispinacol borate (7.85 g, 30.9 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.5 g, 2.06 mmol) and potassium acetate (3.0 g , 30.9 mmol), replaced three times in nitrogen atmosphere. The mixture was stirred and reacted at 90° C. under nitrogen atmosphere for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and water was added, extracted with ethyl acetate (50 mL×3), the combined organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and evaporated under reduced pressure. Concentrate. Purification by flash column chromatography (petroleum ether/ethyl acetate=4/1) gave the title compound tert-butyl(6-((4-methoxy-3-nitro-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (4.3 g, yield 77.7% ). MS m/z (ESI): 530.3[M + H] +. The fourth step: (6-((4-methoxy-3-(5-methylpyrimidin-2-yl)-5-nitrobenzene Ethoxy) methyl) pyridin-2-yl) tertiary butyl carbamate preparation tertiary butyl (6-((4-methoxy-3-nitro-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (1.5 g, 2.8 mmol) In a mixture of 1,4-dioxane and water (1,4-dioxane:water=5:1, 12 mL), then add 2-bromo-5-methylpyrimidine (0.4 g, 3.1 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.41 g, 0.56 mmol) and potassium carbonate (0.97 g, 7.0 mmol), were replaced three times under nitrogen atmosphere. The reaction was stirred at 90°C for 2 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then extracted with ethyl acetate (20 mL×3) by adding water. The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=2/3) to obtain the title compound (6-((4-methoxy-3-(5-methylpyrimidin-2-yl)-5 -Nitrophenethoxy)methyl)pyridin-2-yl)tert-butylcarbamate (1.1 g, yield 78.6%). MS m/z (ESI): 496.2 [M + H] +. The fifth step: tertiary butyl (6-((3-amino-4-methoxy-5-(5-methylpyrimidine-2 -yl) phenethoxy) methyl) pyridin-2-yl) carbamate preparation (6-((4-methoxyl-3-(5-methylpyrimidin-2-yl)- 5-nitrophenylethoxy)methyl)pyridin-2-yl)tert-butyl carbamate (800 mg, 1.6 mmol) was dissolved in a mixture of ethanol and water (ethanol:water=4:1, 10 mL), iron powder (450 mg, 8.1 mmol) and ammonium chloride (430 mg, 8.1 mmol) were added. The reaction was stirred at 80°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (30 mL×2), and the combined organic layers were washed with brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (dichloromethane/methanol = 95%/5%) gave the title compound tert-butyl (6-((3-amino-4-methoxy-5-(5-methyl ylpyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (700 mg, yield 93.1%). MS m/z (ESI): 466.3 [M + H] +. The sixth step: tertiary butyl (6-((3-((2-chloro-5-(methylaminoformyl)pyridine- 4-yl)amino)-4-methoxy-5-(5-methylpyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate Tributyl(6-((3-amino-4-methoxy-5-(5-methylpyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate Ester (700 mg, 1.5 mmol) and 4,6-dichloro-N-methylnicotinamide (620 mg, 3.0 mmol) were dissolved in THF (10 mL), and sodium bis(trimethylsilyl)amide was added (3.8 mL, 7.5 mmol). The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, methanol (3 mL) was added to quench the reaction, concentrated under reduced pressure, and purified by flash column chromatography (dichloromethane/methanol=95%/5%) to obtain the target compound tert-butyl (6- ((3-((2-chloro-5-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methylpyrimidin-2-yl) phenethoxy)methyl)pyridin-2-yl)carbamate (650 mg, yield 53.3%). MS m/z (ESI): 634.2[M + H] +. The seventh step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2 -methoxy group-3-(5-methylpyrimidin-2-yl) phenyl) amino)-6-chloro-N-methyl nicotinamide preparation Compound tertiary butyl (6-((3 -((2-Chloro-5-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methylpyrimidin-2-yl)phenethoxy (1)methyl)pyridin-2-yl)carbamate (650 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL), and 4M dioxane hydrochloride solution (2 mL, 10.2 mmol) was added. The reaction was stirred at 40°C for 1 hour. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane (20 mL), and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9, the mixture was extracted with dichloromethane (30 mL×3), the organic layers were combined, and washed with brine (30 mL×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (dichloromethane/methanol = 95%/5%) afforded the title compound 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl Base)-2-methoxy-3-(5-methylpyrimidin-2-yl)phenyl)amino)-6-chloro-N-methylnicotinamide (450 mg, yield 77%). MS m/z (ESI): 534.2[M + H] +. Step 8: 5 ⁶ -Methoxy-N-methyl-5 ⁵ -(5-methylpyrimidin-2-yl)-8-oxo Preparation of hetero-2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide by combining 4 -((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methylpyrimidin-2-yl)phenyl) Amino)-6-chloro-N-methylnicotinamide (450 mg, 0.84 mmol) was dissolved in 1,4-dioxane (15 mL), and tris(diethylene oxide) was added to the reaction mixture under nitrogen protection benzylacetone) dipalladium (217 mg, 0.25 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (183 mg, 0.34 mmol), cesium carbonate (771 mg, 2.5 mmol). The resulting reaction mixture was stirred at 130 °C for 8 hours. The reaction mixture was filtered and the organic layer was concentrated to give crude product. The crude product was purified by preparative HPLC (ammonia) to give the title compound 5 ⁶ -methoxy-N-methyl-5 ⁵ -(5-methylpyrimidin-2-yl)-8-oxa-2,4 -Diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide (230.3 mg, yield 54.9%) . MS m/z (ESI): 498.2 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ: 10.99 (s, 1H), 9.79 (s, 1H), 8.78 (s, 2H), 8.71 (s, 1H), 8.50 -8.47 (m, 2H), 7.70 (d, J=1.6 Hz, 1H), 7.60-7.56 (m, 1H), 7.21 (d, J=1.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.74 (t, J = 4.4 Hz, 2H), 3.67 (s, 3H), 2.87 (t, J = 4.8 Hz, 2H), 2.78 (d, J = 4.4 Hz, 3H), 2.34 (s, 3H).

第一步：4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯乙酸乙酯的製備 將4-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)苯乙酸乙酯(9 g，24.6 mol)溶於1，4-二氧六環和水的混合液（1,4-二氧六環：水 = 3：1，100 mL)中，在氮氣氛圍下加入碳酸鉀(10.18 g，73.8 mol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(1.8 g，2.4 mol)和2-溴-5-甲氧基嘧啶(5.11 g，27 mol)，混合液於90 ℃下攪拌2小時。反應結束後，用乙酸乙酯萃取(3×100 mL)，有機層用飽和食鹽水(3 x 10 mL)洗滌，接著用無水硫酸鈉乾燥，過濾，然後濃縮，將得到的殘留物用矽膠柱(洗脫劑：石油醚/乙酸乙酯 = 7/3)純化，得到4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯乙酸乙酯(7.2 g，收率77%)。 MS m/z(ESI)：348.1 [M+H] ⁺第二步：2-(4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯基)乙醇的製備 將4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯乙酸乙酯(7 g，20.2 mol)溶於甲醇(100 mL)中，加入碳酸鉀(4.18 g，30.3 mol)，混合液於室溫下攪拌2小時。反應結束後，過濾並濃縮，將得到的殘留物用矽膠柱(洗脫劑：石油醚/乙酸乙酯 = 3/2)純化，得到2-(4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯基)乙醇(5.2 g，收率81%)。 MS m/z(ESI)：306.1 [M+H] ⁺第三步：2-(5-(2-((6-溴吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-硝基苯基)-5-甲氧基嘧啶的製備 將2-(4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯基)乙醇(1000 mg，3.3 mmol)和2-溴-6-(氯甲基)吡啶鹽酸鹽(1360 mg，6.6 mmol)溶於N，N-二甲基甲醯胺(10 mL)中，在冰浴下加入氫化鈉(400 mg，16.5 mmol)，混合液於25 ℃下攪拌2小時。反應結束後，加水(100 mL)淬滅，乙酸乙酯萃取(3×50 mL)，有機層用飽和食鹽水(3×10 mL)洗滌，接著用無水硫酸鈉乾燥，過濾並濃縮後將得到的殘留物用矽膠柱(洗脫劑：石油醚/乙酸乙酯 = 1/1)純化，得到2-(5-(2-((6-溴吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-硝基苯基)-5-甲氧基嘧啶(1200 mg，收率54%)。 MS m/z(ESI)：475.1 [M+H] ⁺第四步：第三丁基(6-((4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將2-(5-(2-((6-溴吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-硝基苯基)-5-甲氧基嘧啶(1200 mg，2.5 mmol)溶於1,4-二氧六環(20 mL)中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(290 mg，0.5 mmol)，三(二亞苄基丙酮)二鈀(231 mg，0.25mmol)和碳酸銫(165 mg，0.5 mmol)。混合液於90℃下攪拌1小時。反應結束後直接濃縮，將得到的殘留物用矽膠柱(洗脫劑：石油醚/乙酸乙酯 = 2/3)純化，得到第三丁基(6-((4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(850 mg，收率52%)。 MS m/z(ESI)：512.3 [M+H] ⁺第五步：第三丁基(6-((3-胺基-4-甲氧基-5-(5-甲氧基嘧啶-2-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((4-甲氧基-3-(5-甲氧基嘧啶-2-基)-5-硝基苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(850 mg，1.7 mmol)溶於乙醇和水（乙醇：水 = 4：1，20 mL)的混合溶液中，加入鐵粉(470 mg，8.4 mmol)和氯化銨(450 mg，8.4 mmol)，混合液於80 ℃下回流 1 小時。反應結束後，過濾得濾液，濃縮後，將得到的殘留物用矽膠柱(洗脫劑：二氯甲烷/甲醇 = 19/1)純化，得到第三丁基(6-((3-胺基-4-甲氧基-5-(5-甲氧基嘧啶-2-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(600 mg，收率58%)。 MS m/z(ESI)：482.1[M+H] ⁺第六步：第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(5-甲氧基嘧啶-2-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯的製備 將第三丁基(6-((3-胺基-4-甲氧基-5-(5-甲氧基嘧啶-2-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(300 mg，0.6 mmol)和4,6-二氯-N-甲基煙醯胺(140 mg, 0.6 mmol)溶於四氫呋喃(10 mL)中，緩慢滴加雙(三甲基矽基)氨化鈉(2M，0.16 mL, 1.8 mmol)，混合液於室溫下攪拌10分鐘。反應結束後，用甲醇(10 mL) 淬滅，濃縮後將得到的殘留物用矽膠柱(洗脫劑：二氯甲烷/甲醇 = 93/7)純化，得到第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(5-甲氧基嘧啶-2-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(210 mg，收率50%)。 MS m/z(ESI)：651.3 [M+H] ⁺第七步：4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(5-甲氧基嘧啶-2-基)苯基)胺基)-6-氯-N-甲基煙醯胺的製備 將第三丁基(6-((3-((2-氯-5-(甲基胺基甲醯基)吡啶-4-基)胺基)-4-甲氧基-5-(5-甲氧基嘧啶-2-基)苯基乙氧基)甲基)吡啶-2-基)胺基甲酸酯(210 mg，0.3 mmol)溶於二氯甲烷(2 mL)中，加入鹽酸和1,4-二氧六環的混合液中（鹽酸/1，4-二氧六環 = 4 mol/L，5 mL)，混合液於40℃下攪拌1小時。反應結束後直接濃縮得到4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(5-甲氧基嘧啶-2-基)苯基)胺基)-6-氯-N-甲基煙醯胺(120 mg，粗品)。 MS m/z(ESI)：552.2 [M+H] ⁺。 第八步：5 ⁶-甲氧基-5 ⁵-(5-甲氧基嘧啶-2-基)-N-甲基-8-氧雜-2,4-二氮雜-1(2,6),3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-甲醯胺的製備 將4-((5-(2-((6-胺基吡啶-2-基)甲氧基)乙基)-2-甲氧基-3-(5-甲氧基嘧啶-2-基)苯基)胺基)-6-氯-N-甲基煙醯胺(120 mg，0.21 mmol)溶於1,4-二氧六環(10 mL)中，在氮氣氛圍下加入4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(25 mg，0.04 mmol)，三(二亞苄基丙酮)二鈀(20 mg，0.02 mmol)和碳酸銫(213 mg，0.65 mmol)。混合液於130 ℃下攪拌10小時。反應結束後直接濃縮，然後通過反向柱(乙腈：水 = 1：1)製備，純化後，得到5 ⁶-甲氧基-5 ⁵-(5-甲氧基嘧啶-2-基)-N-甲基-8-氧雜-2,4-二氮雜-1(2,6),3(2,4)-二吡啶-5(1,3)-苯并環壬烷-3 ⁵-甲醯胺(38.2 mg，收率34%)。 MS m/z(ESI)：514.2 [M+H] ^{+ 1}H NMR(400 MHz, DMSO-d ₆)δ: 10.98(s, 1H), 9.79(s, 1H), 8.71(s, 1H), 8.67(s, 2H), 8.50 - 8.46(m, 2H), 7.68(d, J=1.6 Hz, 1H), 7.60-7.56(m, 1H), 7.20(d, J = 2.0 Hz, 1H), 6.98(d, J =8.0 Hz, 1H), 6.81(d, J=7.2 Hz, 1H), 4.42 (s, 2H), 3.97(s, 3H), 3.76-3.72(m, 2H), 3.67(s, 3H), 2.89-2.85(m, 2H), 2.78(d, J = 4.4 Hz, 3H). 採用以上相同或相似的製備方法，進一步製備獲得以下結構化合物 實施例編號 化合物結構 ¹H NMR MS m/z (ESI) 24

(400 MHz, DMSO- d ₆ ) δ:10.45 (s, 1H), 10.42 (s, 1H), 9.71 (s, 1H), 9.03-9.05 (m, 1H), 8.07 (s, 1H), 7.66-7.63 (m, 1H), 7.10-6.94 (m, 2H), 7.01 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 7.4 Hz, 1H), 4.59 (s, 2H), 4.34 (s, 2H), 3.88 (s, 3H), 2.85 (d, J= 4.8 Hz, 3H). 393.16 [M + H] ⁺.   25

(400 MHz, DMSO- d ₆) δ: 10.57 (s, 1H), 9.87 (s, 1H), 9.03 - 9.05 (m, 1H), 8.17 - 8.19 (m, 1H), 7.72 - 7.74 (m, 1H), 7.53 - 7.43(m, 3H), 7.09 (s, 1H), 6.79 -6.81 (m, 1H), 6.67 - 6.69 (m, 1H), 4.49 (s, 2H), 3.87 (s, 3H), 3.74 - 3.76 (m, 2H), 3.52 (s, 3H), 2.83 - 2.86 (m, 5H). 487.2 [M+H] ⁺.   26

(400 MHz, DMSO-d6) δ: 10.30 (s, 1H), 10.15 (s, 1H), 9.05 (d, J= 4.8 Hz, 1H), 8.34 (s, 1H), 7.80 - 7.72 (m, 2H), 7.61 - 7.51 (m, 2H), 6.73 - 6.63 (m, 2H), 6.35 (d, J= 8.0 Hz, 1H), 4.83 -4.81 (m, 2H), 3.90 (s, 3H), 3.55 (s, 3H), 3.04-3.02 (m, 2H), 2.86 (d, J= 4.8 Hz, 3H). 473.3 [M+H] ⁺  27

(400 MHz, DMSO) δ: 10.31 (s, 1H), 10.15 (s, 1H), 9.02 (s, 1H), 8.55 (s, 2H), 7.76 - 7.74 (m, 2H), 7.58 (s, 1H), 7.54 (d, J= 2.0 Hz, 1H), 6.69 (dd, J= 5.2, 2.8 Hz, 2H), 6.35 (d, J= 7.6 Hz, 1H), 4.83-4.81 (m, 2H), 3.90 (s, 3H), 3.55 (s, 3H), 3.05-3.02 (m, 2H). 476.1 [M+H] ⁺ 28

(400 MHz, DMSO- d ₆ ) δ10.72 (s, 1H), 9.70 (s, 1H), 9.02 (d, J= 4.8 Hz, 1H), 8.50 (d, J= 7.2 Hz, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 6.70 (d, J= 2.0 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.57 (s, 3H), 2.88-2.80 (m, 7H). 503.1 [M+H] ⁺ 29

(400 MHz, DMSO- d ₆) δ:10.35 (s, 1H), 9.30 - 9.34(m, 1H), 7.80 (s, 1H), 7.74-7.76 (m, 1H), 7.51 (s, 1H), 7.44 - 7.46(m, 2H), 7.35 - 7.30 (m, 1H), 7.22 (s, 1H), 7.08 -7.10 (m, 2H), 6.97 (s, 1H), 6.64 -6.66 (m, 1H), 4.95 - 4.73 (m, 2H), 3.90 (s, 3H), 3.51 (s, 3H), 2.87 - 2.95 (m, 5H). 523 [M+H] ⁺ 30

(400 MHz, DMSO) δ 11.18 (s, 1H), 10.33 (s, 1H), 9.10 (d, J= 4.4 Hz, 1H), 8.39 (s, 1H), 7.81 (s, 1H), 7.58 (t, J= 8.0 Hz, 1H), 7.35 (s, 1H), 6.78 (d, J= 7.6 Hz, 1H), 6.29 (d, J= 8.0 Hz, 1H), 4.22-4.20 (m, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.87 (d, J= 4.4 Hz, 3H), 2.81-2.79 (m, 2H), 2.08-2.05 (m, 2H). 465.2 [M+H] ⁺.   31

(400 MHz, DMSO- d ₆ ) δ:10.25 (s, 2H), 9.21 (d, J= 4.8 Hz, 1H), 7.77 (s, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.34 (s, 1H), 7.17 (s, 1H), 3.77 (s, 3H), 2.87 (d, J= 4.8 Hz, 3H), 2.56 (s, 2H), 2.00 (dd, J= 14.4, 6.9 Hz, 2H), 1.85 (s, 2H), 1.45 (s, 2H), 1.16 (s, 6H) 457.3 [M + H] ⁺ 32

(400 MHz, DMSO- d ₆ ) δ:11.39 (s, 1H), 10.51 (s, 1H), 9.10 (d, J= 4.8 Hz, 1H), 9.03 (s, 1H), 7.78 (d, J= 2.2 Hz, 1H), 7.65 (d, J= 8.5 Hz, 1H), 7.58 (d, J= 1.8 Hz, 1H),7.49 (d, J= 1.8 Hz, 1H), 7.42 (dd, J= 8.7, 5.5 Hz, 2H), 7.31 (t, J= 8.9 Hz, 2H), 7.21 (d, J= 8.5 Hz, 1H), 6.74 (d, J= 2.2 Hz, 1H), 4.40 (s, 2H), 3.91(s, 3H), 3.74-3.69 (m, 2H), 3.61 (s, 3H), 2.89-2.85 (m, 5H). 581.2 [M+H ⁺]     33

 (400 MHz, DMSO- d6) δ: 11.36 (s, 1H), 10.54 (s, 1H), 9.10 (d, J= 4.8 Hz, 1H), 9.03 (s, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 2.0 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.62 (d, J= 8.0 Hz, 2H), 7.58 (d, J= 1.6 Hz, 1H), 7.49 (d, J= 1.6 Hz, 1H), 7.24 (d, J= 8.8 Hz, 1H), 6.75 (d, J= 2.0 Hz, 1H), 4.41 (s, 2H), 3.91 (s, 3H), 3.76 - 3.68 (m, 2H), 3.61 (s, 3H), 2.92 - 2.81 (m, 5H).   631.3 [M + H] ⁺. 34

(400 MHz, DMSO) δ11.12 (s, 1H), 9.65 (s, 1H), 9.08 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.32 (t, J= 7.7 Hz, 1H), 7.13 (d, J= 7.5 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J= 7.5 Hz, 1H), 6.70 (d, J= 2.1 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 2H), 3.57 (s, 3H), 2.95 - 2.87 (m, 2H), 2.85 (d, J= 4.6 Hz, 3H), 2.43 (d, J= 5.6 Hz, 2H).   502.2 [M+H] ⁺.   35

(400 MHz, DMSO- d ₆ ) δ11.02 (s, 1H), 9.77 (s, 1H), 8.71 (s, 1H), 8.48-8.44 (m, 2H), 7.76 (d, J= 2.0 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.41 (s, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 6.73 (d, J= 2.0 Hz, 1H), 4.41 (s, 2H), 3.91 (s, 3H), 3.74 (t, J= 4.8 Hz, 2H), 3.58 (s, 3H), 2.84 (t, J= 4.4 Hz,2H). 489.1 [M+H] ⁺ 37

(400 MHz, DMSO- d ₆ ) δ: 10.69 (s, 1H), 10.42 (s, 1H), 9.24 (d, J= 4.8 Hz, 1H), 7.77 (d, J= 2.4 Hz, 1H), 7.55 (d, J= 2.0 Hz, 2H), 7.20 (s, 1H), 7.01 (s,1H), 6.71 (d, J= 2.4 Hz, 1H), 3.91 (s, 3H), 3.55 (s, 3H), 3.33-3.30 (m, 2H), 2.87 (d, J= 4.8 Hz, 3H), 2.69-2.65 (m, 2H), 1.40-1.36 (m, 2H), 0.94-0.92 (m, 2H) 491.2 [M+H] ⁺ 38

(400 MHz, DMSO- d ₆ ) δ 11.67 (s, 1H), 10.96 (s, 1H), 9.17 (s, 1H), 8.84 (s, 1H), 7.74-7.65 (m, 5H), 6.75 (s, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.49-3.45 (m, 2H), 2.89-2.85 (m, 5H). 506.2 [M+H] ⁺ 39

(400 MHz, CDCl ₃) δ: 11.18 (s, 1H), 9.33 (s, 1H), 8.48 (d, J= 18.2 Hz, 1H), 7.47 (d, J= 1.6 Hz, 1H), 7.39 (d, J= 2.1 Hz, 1H), 7.35-7.30 (m, 4H), 7.22 (s, 1H), 7.05 - 6.87 (m, 2H), 6.82 (d, J= 2.2 Hz, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.67 (s, 3H), 2.99 (s, 3H), 2.93 - 2.82 (m, 2H), 2.59 - 2.45 (m, 2H). 501.3 [M+H] ⁺.   40

(400 MHz, DMSO- d ₆ ) δ: 10.76 (s, 1H), 9.90 (s, 1H), 9.06 (d, J= 4.0 Hz, 1H), 8.13 (t, J= 6.0 Hz, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.50 (s, 1H), 7.33 (t, J= 8.0 Hz, 1H), 7.25 (s, 1H), 7.18 (t, J= 8.0 Hz, 1H), 7.11 (s, 1H), 6.70 (d, J= 2.0 Hz, 1H), 6.68 (d, J= 8.0 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 2.84 (d, J= 4.0 Hz, 3H), 2.69-2.65 (m, 2H), 2.35-2.31 (m, 1H), 1.25-1.21 (m, 1H). 517.2 [M+H] ⁺ 41

(400 MHz, DMSO- d ₆ ) δ11.34 (s, 1H), 9.73 (s, 1H), 9.12 (d, J= 4.2 Hz, 1H), 8.81 (s, 1H), 7.78 (s, 1H), 7.72-7.61 (m, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.01 (d, J= 8.0 Hz, 1H), 6.74 (s, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 3.78-3.74 (m, 2H), 3.60 (s, 3H), 2.90-2.85 (m, 5H). 505.1 [M+H] ⁺ 42

(400 MHz, DMSO- d ₆ ) δ11.00 (s, 1H), 9.80 (s, 1H), 8.98-8.94 (m, 2H), 8.72 (s, 1H), 8.49-8.45 (m, 2H), 7.75-7.72 (m, 1H), 7.65-7.58 (m, 1H), 7.55-7.50 (m, 1H), 7.24 (s, 1H), 7.05-7.00 (m, 1H), 6.82 (s, 1H), 4.45(s, 2H), 3.77-3.73 (m, 2H), 3.69 (s, 3H), 2.80-2.76 (m, 2H), 2.50 (s, 3H). 484.2 [M+H] ⁺ 43

(400 MHz, DMSO- d ₆ ) δ10.60 (s, 1H), 10.16 (s, 1H), 9.03 (d, J= 4.8 Hz, 1H), 8.44 (s, 1H), 7.75 (d, J= 2.0 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.29 (d, J= 2.0 Hz, 1H), 6.96 (d, J= 8.0 Hz, 1H), 6.73 (d, J= 7.2 Hz, 1H), 6.69 (d, J= 2.2 Hz, 1H), 3.91 (s, 3H), 3.61-3.57 (m, 5H), 3.32-3.30 (m, 2H), 2.85 (d, J= 4.8 Hz, 3H), 2.75 (t, J= 5.2 Hz, 2H), 2.33 (t, J= 7.2 Hz, 2H), 1.70-1.61 (m, 2H). 515.2 [M+H] ⁺ 44

(400 MHz, DMSO- d ₆ ) δ11.02 (s, 1H), 9.81 (s, 1H), 9.04 (s, 2H), 8.72 (s, 1H), 8.57 - 8.41 (m, 2H), 7.74 (d, J=1.6 Hz, 1H), 7.59 (t, J= 7.6 Hz, 1H), 7.24 (d, J= 1.6 Hz, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.82 (d,  J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.76 (t, J= 4.4 Hz, 2H), 3.69 (s, 3H), 2.89 (t, J= 4.8 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H). 502.1 [M+H] ⁺ 45

(400 MHz, DMSO- d ₆ ) δ11.02 (s, 1H), 9.80 (s, 1H), 9.03 (s, 2H), 8.72 (s, 1H), 8.56-8.42 (m, 2H), 7.74 (s, 1H), 7.59 (t, J= 7.8 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.76 (t, J= 4.4 Hz, 2H), 3.68 (s, 3H), 2.89 (t, J= 4.8 Hz, 2H). 505.2 [M+H] ⁺ 46

(400 MHz, DMSO- d ₆ ) δ11.01 (s, 1H), 9.80 (s, 1H), 8.94 (d, J= 4.8 Hz, 2H), 8.72 (s, 1H), 8.54-8.40 (m, 2H), 8.13 (s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.58 (dd, J= 8.2, 7.4 Hz, 1H), 7.50 (s, 1H), 7.24 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.2 Hz, 1H), 6.82 (s, 1H), 4.42 (s, 2H), 3.75 (t, J= 4.8 Hz, 2H), 3.68 (s, 3H), 2.88 (t, J= 4.8 Hz, 2H). 487.3 [M+H] ⁺ 47

(400 MHz, DMSO- d ₆ ) δ13.82 (s, 1H), 10.98 (s, 1H), 9.77 (s, 1H), 9.02-9.00 (m, 1H), 8.77-8.72 (m, 1H), 8.49-8.44 (m, 2H), 8.16 - 8.15 (m, 1H), 7.99-7.95 (m, 1H), 7.78-7.72 (m, 1H), 7.58-7.53 (m, 2H), 6.99-6.96 (m 1H), 6.84-6.80 (m, 1H), 4.41 (s, 2H), 3.79 (t, J= 4.8 Hz, 2H), 2.85 (t, J= 4.8 Hz, 2H). 473.2 [M+H] ⁺ 48

(400 MHz, DMSO- d ₆ ) δ11.34 (s, 1H), 10.39 (s, 1H), 9.13-9.01 (m, 4H), 7.75 (d, J= 1.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.32 (d, J= 1.8 Hz, 1H), 7.11 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 4.46 (s, 2H), 3.79-3.72 (m, 2H), 3.69 (s, 3H), 2.95-2.88 (m, 2H), 2.86 (d, J= 4.8 Hz, 3H). 503.1 [M+H] ⁺ 49

(400 MHz, DMSO- d ₆ ) δ11.30 (s, 1H), 10.34 (s, 1H), 9.07 (d, J= 4.8 Hz, 1H), 9.02 (s, 1H), 7.68-7.65 (m, 2H), 7.65-7.61 (m, 2H), 7.47 (d, J= 1.6 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 4.44 (s, 2H), 3.78-3.74 (m, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 2.87-2.54 (m, 5H). 487.3 [M+H] ⁺ 50

(400 MHz, DMSO- d ₆ ) δ11.19 (s, 1H), 10.17 (s, 1H), 8.83 (d, J= 4.0 Hz, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.45 (s, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.79-6.76 (m, 2H), 3.95 (s, 3H), 3.84 (s, 2H), 3.64 (s, 3H), 2.99-2.96 (m, 2H), 2.95 (d, J= 4.0 Hz, 3H), 2.90-2.86 (m, 2H). 486.2 [M+H] ⁺ 51

(400 MHz, DMSO- d ₆ ) δ10.58 (s, 1H), 10.41 (s, 1H), 9.29 (s, 1H), 9.07 (d, J= 4.0 Hz, 1H), 7.78 (d, J= 2.0 Hz, 1H), 7.67 (t, J= 8.0 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.49-7.38 (m, 4H), 7.36 (d, J= 6.0 Hz, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.84 (s, 1H), 6.74 (d, J= 2.0 Hz, 1H), 5.22 (s, 2H), 4.20 (s, 2H), 3.92 (s, 3H), 3.61 (s, 3H), 3.54-3.43 (m, 2H), 2.89 -2.80 (m, 5H). 620.3 [M+H] ⁺ 54

(400 MHz, DMSO- d ₆ ) δ:10.45 (s, 1H), 10.42 (s, 1H), 9.71 (s, 1H), 9.03-9.05 (m, 1H), 8.07 (s, 1H), 7.66-7.63 (m, 1H), 7.10-6.94 (m, 2H), 7.01 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 7.4 Hz, 1H), 4.59 (s, 2H), 4.34 (s, 2H), 3.88 (s, 3H), 2.85 (d, J= 4.8 Hz, 3H). 393.16 [M+ H] ⁺.   55

(400 MHz, DMSO-d6) δ: 11.35 (s, 1H), 10.39 (s, 1H), 9.10-9.05 (m, 2H), 7.66-7.63 (m,  2H),  7.12 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 4.45 (s, 2H), 3.70-3.66 (m, 5H), 3.02 (s, 3H), 2.87-2.83 (m, 5H), 2.82 (s, 3H). 478.2 [M+H] ⁺ 56

(400 MHz, DMSO- d ₆ ) δ: 11.01 (s, 1H), 9.81 (s, 1H), 8.70 (s, 1H), 8.51-8.47 (m,  2H),  7.64 (d, J= 1.8 Hz, 1H), 7.58 (dd, J= 8.2 Hz,  7.4 Hz, 1H), 6.89 (d, J= 8.2 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 6.74 (d, J= 1.8 Hz, 1H), 4.42 (s, 2H), 3.68-3.64 (m, 5H), 3.01 (s, 3H), 2.84-2.76 (m, 8H). 477.2 [M+H] ⁺ 57

(400 MHz, DMSO- d ₆ ) δ : 11.33 (s, 1H), 10.34 (s, 1H),  9.04-9.00 (m, 2H), 8.15 (s, 1H), 7.90 (s, 1H), 7.63 (t, J= 8.0 Hz, 1H), 7.47 (s, 1H), 7.22 (d, J= 1.2 Hz, 1H), 7.10 (d,  J= 8.3 Hz,  1H), 6.87 (d, J= 7.3 Hz, 1H), 4.43 (s, 2H),  3.89 (s,  3H), 3.76 (t, J= 4.8 Hz, 2H), 3.57 (s,  3H), 2.83 (t, J= 4.8 Hz, 2H). 490.3 [M+H] ⁺ 58

（400 MHz, DMSO- d ₆）δ: 11.33（s, 1H）, 10.30（s, 1H）, 9.14（dd, J= 4.8, 1.6 Hz, 1H）, 9.00-8.96（m, 2H）, 7.97（dd, J= 8.8, 1.6 Hz, 1H）, 7.71-7.67（m, 2H）, 7.58-7.53（m, 1H）, 7.27（d, J= 1.6 Hz, 1H）, 7.01（d, J= 8.4 Hz, 1H）, 6.79（d, J= 7.2 Hz, 1H）, 4.37（s, 2H）, 3.70-3.66（m, 2H）, 3.37（s, 3H）, 2.85-2.81（m, 2H）, 2.75（d, J= 4.8 Hz, 3H）. 485.1 [M+H] ⁺  59

 (400 MHz, DMSO- d ₆ ) δ : 10.73 (s, 1H), 10.36 (s, 1H), 9.10-9.06 (m, 2H), 7.78 (d, J= 2.0 Hz, 1H), 7.65-7.59 (m, 2H), 7.14 – 6.93 (m, 2H), 6.85 (d, J= 8.0 Hz, 1H), 6.75 (d, J= 2.0 Hz, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 3.44 (s, 2H), 2.93 (br. s, 2H), 2.87 (d, J= 4.0 Hz, 3H), 2.77 (br. s, 1H), 2.28 (br. s, 1H), 2.15 (s, 3H). 528.2 [M+H] ⁺ 60

（400 MHz, DMSO- d ₆）δ : 9.81（s, 1H）, 9.43（s, 1H）, 8.73（s, 1H）8.34（s, 1H）, 7.76（d, J= 2.0 Hz, 1H）, 7.61-7.57（m, 1H）,7.56（d, J= 2.0 Hz, 1H）, 7.40（d, J= 2.0 Hz, 1H）, 6.99（d, J= 8.4 Hz, 1H）, 6.83（d, J= 7.2 Hz, 1H）, 6.72（d, J= 2.4 Hz, 1H）, 4.42（s, 2H）, 3.90（s, 3H）, 3.77-3.74（m, 2H）, 3.62（s, 3H）, 3.58（s, 3H）, 3.33（s, 3H）, 2.86-2.83（m, 2H）. 504.1 [M+H] ⁺  61

(400 MHz, DMSO- d ₆ ) δ : 11.01 (s, 1H), 9.77 (s, 1H), 8.69 (s, 1H), 8.46 (s,  2H),  8.15 (s, 1H), 7.90 (s, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.47 (d, J= 1.6 Hz , 1H), 7.15 (d, J= 1.7 Hz ,1H), 6.98 (d, J= 8.3 Hz, 1H), 6.81 (d,  J= 7.2 Hz, 1H), 4.41 (s, 2H), 3.89 (s,  3H), 3.76 (t, J= 4.8 Hz ,2H), 3.58 (s, 3H), 2.82 (t, J= 4.8 Hz ,2H). 489.3 [M+H] ⁺. 62

（400 MHz, DMSO- d ₆）δ:  11.10（s, 1H）, 9.83（s, 1H）, 8.71（s, 1H）, 8.56 （d, J= 4.8 Hz, 1H）, 8.50（s, 1H）, 7.76（d, J= 2.0 Hz, 1H）, 7.68（d, J= 1.6 Hz, 1H）, 7.60 – 7.56（m, 1H）, 7.39（d, J= 0.8 Hz, 1H）, 6.98（d, J= 8.4 Hz, 1H）, 6.82（d, J= 8.4 Hz, 1H）, 4.42（s, 2H）, 3.78 – 3.75（m, 2H）, 3.74（s, 3H）, 2.92 – 2.89（m, 2H）, 2.81（d, J= 4.4 Hz, 3H）, 2.45（s, 3H）. 503.1 [M+H] ⁺ 63

 (400 MHz, DMSO- d ₆ ) δ:10.96 (s, 1H), 9.76 (s, 1H), 8.68 (s, 1H), 8.49 (dd, J= 8.4, 4.1 Hz, 1H), 8.46 (s, 1H), 7.65 (s, 1H), 7.62 (d, J= 1.2 Hz, 1H), 7.60-7.56 (m, 2H), 7.46 (d, J= 2.0 Hz, 1H), 6.97 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.41 (s, 2H), 3.78 – 3.74 (m, 2H), 3.72 (s, 3H), 3.64 (s, 3H), 2.86 – 2.82 (m, 2H), 2.80 (d, J= 4.8 Hz, 3H). 486.1 [M+H] ⁺ 64

（400 MHz, DMSO- d ₆）δ : 11.42（s, 1H）, 10.42（s, 1H）, 9.13（d, J= 4.8 Hz, 1H）, 9.05（s, 1H）, 7.83（d, J= 2.0 Hz, 1H）, 7.70（d, J= 1.6 Hz, 1H）, 7.68-7.64（m, 1H）,7.41（d, J= 0.8 Hz, 1H）, 7.11（d, J= 8.4 Hz, 1H）, 6.89（d, J= 7.2 Hz, 1H）, 4.45（s, 2H）, 3.77-3.75（m, 2H）, 3.75（s, 3H）, 2.95-2.91（m, 2H）, 2.87（d, J= 4.8 Hz, 3H）, 2.45（s, 3H）. 504.1 [M+H] ⁺ 65

(400 MHz, DMSO-d6) δ:  11.37 (s, 1H), 10.41 (s, 1H), 9.13 (d, J= 4.8 Hz, 1H), 9.03 (s, 1H), 7.80 (s, 1H), 7.67-7.64 (m, 3H), 7.11 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 4.45 (s, 2H), 3.77-3.74 (m, 5H), 2.91 (s, 2H), 2.88 (d, J= 4.8 Hz, 3H), 2.44 (s, 3H). 504.2 [M+H] ⁺  66

(400 MHz, DMSO- d ₆ ) δ:  11.45 (s, 1H), 10.43 (s, 1H), 9.15 (d, J= 4.3 Hz, 1H), 9.06 (s, 1H), 8.63 (s, 1H), 7.83-7.79 (m, 2H), 7.69 - 7.62 (m,, 1H),7.12 (d, J= 8.3 Hz, 1H), 6.89 (d, J= 7.2 Hz, 1H), 4.46 (s, 2H), 3.81 (s, 3H), 3.79 - 3.74 (m, 2H), 2.99 - 2.94 (m, 2H), 2.88 (d, J= 4.5 Hz, 3H). 558.1 [M+H] ⁺  67

(400 MHz, DMSO-d6) δ:  11.45 (s, 1H), 10.42 (s, 1H), 9.09 (d, J= 4.8 Hz, 1H), 9.05 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.66 (t, J= 8.0 Hz, 1H), 7.51 (s, 1H), 7.11 (d, J= 8.4 Hz, 1H), 6.89 (d, J= 7.2 Hz, 1H), 4.45 (s, 2H), 3.77-3.74 (m, 5H), 2.92-2.89 (m, 2H), 2.87 (d, J= 4.4 Hz, 3H), 2.19 (s, 3H). 488.1 [M+H] ⁺  68

(400 MHz, DMSO-d6) δ : 11.41 (s, 1H), 10.39 (s, 1H), 9.09 (d, J= 4.8 Hz, 1H), 9.07 (s, 1H), 8.35 (d, J= 2.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.48 (d, J= 1.6 Hz, 1H), 7.39-7.37 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.99 (d, J= 2.8 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 4.45 (s, 2H), 3.79 – 3.74 (m, 2H), 3.62 (s, 3H), 2.92 – 2.88 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ :74.17 (s), -94.08 (s). 523.1 [M+H] ⁺  69

 (400 MHz, DMSO- d ₆ ) δ: 11.36 (s, 1H), 10.39 (s, 1H), 9.07-9.03 (m, 4H), 7.77 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.12 (d, J= 8.0 Hz, 1H), 6.88 (d, J= 6.8 Hz, 1H), 4.46 (s, 2H), 3.78-3.72 (m, 5H), 3.05 (s, 6H), 2.94-2.90 (m, 2H), 2.86 (s, 3H). 556.3 [M+H] ⁺. 70

(400 MHz, DMSO- d ₆ ) δ:  11.36 (s, 1H), 10.32 (s, 1H), 9.17 (s, 1H), 9.06 (s, 1H), 7.77-7.73 (m 2H), 7.66 – 7.56 (m, 1H), 7.46 (s, 1H), 7.06 (d, J= 8.0 Hz, 1H), 6.87 (d, J= 6.0 Hz, 1H), 6.74 (s, 1H), 3.91 (s, 3H), 3.63 (s, 2H), 3.60 (s, 3H), 2.87 (s, 3H), 2.76-2.72 (m, 4H), 2.22 (d, J= 4.0 Hz, 2H), 0.65-0.61 (m, 3H). 514.3 [M+H] ⁺.   71

 (400 MHz, DMSO- d ₆ ) δ:  10.94 (s, 1H), 9.61 (s, 1H), 8.58 (s, 1H), 8.51 – 8.39 (m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.55 (s, 1H), 7.42-7.38 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 4.48 (s, 2H), 3.91 (s, 3H), 3.82 – 3.73 (m, 2H), 3.57 (s, 3H), 2.92 – 2.82 (m, 2H), 2.79 (d, J = 4.3 Hz, 3H), 2.15 (s, 3H). 500.1 [M+H ⁺]   72

（400 MHz, DMSO- d ₆）δ:  11.91（s, 1H）, 10.03（s, 1H）, 8.69-8.65（m, 2H）, 8.53（d, J= 4.0 Hz, 1H）, 7.75 – 7.69（m, 2H）, 7.27（s, 1H）, 7.10（d, J= 7.2 Hz, 1H）, 6.99（d, J= 8.0 Hz, 1H）, 6.71（d, J= 1.6 Hz, 1H）, 4.51（s, 2H）, 3.89（s, 3H）, 3.65 – 3.61（m, 2H）, 3.60（s, 3H）, 2.81（d, J= 4.0 Hz, 3H）, 2.78 – 2.74（m, 2H）. 487.2 [M+H] ⁺  73

 (400 MHz, DMSO- d6)δ : 11.43 (s, 1H), 10.41 (s, 1H), 9.12-9.08 (m, 1H), 9.07 (s, 1H), 8.80 - 8.78 (m,, 1H), 8.65 (d, J= 2.5 Hz, 1H), 7.76 (d , J=1.8 Hz, 1H), 7.70 – 7.61 (m, 1H), 7.37 (d, J= 1.8 Hz, 1H), 7.12 (d, J= 8.4 Hz, 1H), 6.89 (d, J= 7.2 Hz, 1H), 4.47 (s, 2H), 3.82 – 3.74 (m, 2H), 3.53 (s, 3H), 2.94- 2.90 (m, 2H), 2.86 (d, J= 4.8 Hz, 3H). 485.2 [M+H] ⁺  74

(400 MHz, DMSO- d6) δ:  11.10 (s, 1H), 9.81 (s, 1H), 9.09 (d, J= 1.3 Hz, 1H), 8.81 – 8.76 (m, 1H), 8.73 (s, 1H), 8.64 (d, J= 2.5 Hz, 1H), 8.52 (d, J= 4.5Hz, 1H), 8.49 (s, 1H), 7.74 (d, J= 1.5 Hz, 1H), 7.63 – 7.53 (m, 1H), 7.29 (d, J= 1.6 Hz, 1H), 6.99 (d, J= 8.3 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.44 (s, 2H), 3.86 – 3.72 (m, 2H), 3.52 (s, 3H), 2.96 – 2.84 (m, 2H), 2.80 (d, J= 4.4 Hz, 3H). 484.2 [M+H] ⁺ 75

（400 MHz, DMSO- d ₆）δ :  10.95（s, 1H）, 9.62（s, 1H）, 8.59（s, 1H）, 8.47 （d, J= 4.4 Hz, 1H）, 8.44（s, 1H）, 7.76（d, J= 2.4 Hz, 1H）, 7.56（d, J= 2.0 Hz, 1H）, 7.42（d, J= 1.6 Hz, 1H）, 7.27（d, J= 8.8 Hz, 1H）, 6.89（d, J= 8.4 Hz, 1H）, 6.73（d, J= 2.0 Hz, 1H）, 4.68（s, 2H）, 3.91（s, 3H）, 3.81 – 3.77（m, 2H）, 3.58 （s, 3H）, 2.89 – 2.85（m, 2H）, 2.79（d, J= 4.4 Hz, 3H）, 1.87 – 1.82（m, 1H）, 0.90 – 0.85（m, 2H）, 0.58 – 0.53（m, 2H）. 526.3 [M+H] ⁺ 76

(400 MHz, DMSO- d ₆ ) δ:  10.97 (s, 1H), 9.79 (s, 1H), 8.71 (s, 1H), 8.50 (d,  J= 4.0 Hz,  1H),  8.42 (s, 1H), 7.77 (d,  J= 2.0 Hz, 1H), 7.61-7.53 (m, 2H) , 7.41(d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.4 Hz ,1H),  6.81 (d,  J= 7.2 Hz, 1H), 6.74 (d,  J= 2.0 Hz, 1H), 4.42 (s, 2H), 3.91 (s,  3H), 3.75 (t, J= 4.8 Hz, 2H), 3.60 (s, 3H), 2.86 (t, J= 4.8 Hz,  2H), 2.08 (s, 1H), 0.76-0.57 (m, 4H). 512.2 [M+H] ⁺.   77

 (400 MHz, DMSO- d ₆ ) δ : 11.00 (s, 1H), 9.79 (s, 1H), 8.71 (s, 1H), 8.52 (t, J= 5.6 Hz, 1H), 8.47 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.41 (d, J= 2.0 Hz, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 6.73 (d, J= 2.4 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.75 (t, J= 4.8 Hz, 2H), 3.58 (s, 3H), 3.32 - 3.22 (m, 2H), 2.84 (t, J= 4.8 Hz, 2H), 1.15 (t, J= 7.2 Hz, 3H).   500.3 [M+H] ⁺. 78

(400 MHz, DMSO- d ₆ ) δ : 9.73 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.65 - 7.49 (m, 2H), 7.40 (d, J= 1.6 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.79 (d, J= 7.2 Hz, 1H), 6.71 (d, J= 2.4 Hz, 1H), 4.43-4.37 (m, 4H), 3.91 (s, 3H), 3.74 (t, J= 4.8 Hz, 2H), 3.65 - 3.57 (m, 5H), 2.84 (t, J= 4.8 Hz, 2H), 1.96 (t, J= 5.2 Hz, 2H). 512.3 [M+H] ⁺ 79

(400 MHz, DMSO- d ₆) δ: 10.99 (s, 1H), 9.80 (s, 1H), 8.71 (s, 1H), 8.67 (s, 2H), 8.47 (br. s, 2H), 7.68 (s, 1H), 7.60 - 7.56 (m, 1H), 7.20 (d, J= 2.0 Hz, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.97 (s, 3H), 3.76 - 3.73 (m, 2H), 3.67 (s, 3H), 2.89 - 2.85 (m, 2H). 517.2 [M+H] ⁺  80

(400 MHz, DMSO- d ₆) δ: 11.30 (s, 1H), 10.21 (s, 1H), 9.03 (s, 1H), 8.90 (s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.31 (d, J= 8.4 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.70 (d, J= 1.6 Hz, 1H), 4.68 (s, 2H), 3.88 (s, 3H), 3.77 - 3.74 (m, 2H), 3.56 (s, 3H), 2.88-2.84 (m, 2H), 2.82 (d, J= 4.8 Hz, 3H), 1.85 - 1.80 (m, 1H), 0.89 - 0.83 (m, 2H), 0.58 - 0.52 (m, 2H). 527.2 [M+H] ⁺  81

(400 MHz, DMSO- d ₆) δ :11.31 (s, 1H), 10.38 (s, 1H), 9.07 (d, J= 4.4 Hz, 1H), 9.05 (s, 1H), 8.68 (s, 2H), 7.70 (s, 1H), 7.65 (t, J= 8.0 Hz, 1H), 7.28 (s, 1H),7.11 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 6.8 Hz, 1H), 4.45 (s, 2H), 3.98 (s, 3H), 3.77 - 3.72 (m, 2H), 3.67 (s, 3H), 2.92 - 2.87 (m, 2H), 2.85 (d, J= 4.4 Hz, 3H).   515.2 [M+H] ⁺  82

(400 MHz, DMSO- d ₆) δ: 11.32 (s, 1H), 10.38 (s, 1H), 9.05 (br. s, 2H), 8.68 (s, 2H), 7.69 (d, J= 1.6 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.28 (d, J= 2.0 Hz, 1H), 7.11 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 4.45 (s, 2H), 3.98 (s, 3H), 3.76 - 3.73 (m, 2H), 3.68 (s, 3H), 2.91 - 2.87 (m, 2H).   518.2 [M+H] ⁺  83

(400 MHz, DMSO) δ :11.05 (s, 1H), 9.80 (s, 1H), 8.70 (s, 1H), 8.63 (d, J = 1.2 Hz, 1H), 8.51 (d, J= 4.4 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J= 1.2 Hz, 1H), 7.66 (d, J= 1.6 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.26 (d, J= 1.6 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 5.25-5.20 (m, 1H), 4.42 (s, 2H), 3.78 - 3.72 (m, 2H), 3.52 (s, 3H), 2.91-2.85 (m, 2H), 2.79 (d, J= 4.4 Hz, 3H), 2.45 (dd, J= 10.2, 7.2 Hz, 2H), 2.19 - 2.10 (m, 2H), 1.84 - 1.81 (m, 1H), 1.73 - 1.65 (m, 1H). 554.2 [M+H] ⁺ 84

(400 MHz, DMSO- d ₆ ) δ:11.04 (s, 1H), 9.81 (s, 1H), 9.17 (s,2H), 8.72 (s, 1H), 8.51 – 8.48 (m, 2H), 7.77 (d, J= 1.6 Hz ,1H), 7.61 - 7.57 (m,1H), 7.42 - 7.15 (t, J=55.2 Hz, 1H), 7.31 (d, J= 2.0 Hz, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.6 Hz, 1H), 4.43 (s, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.71 (s, 3H), 2.89 (t, J= 5.2 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H).   534.1 [M+H] ⁺. 85

(400 MHz, DMSO- d ₆ ) δ :11.00 (s, 1H), 9.80 (s, 1H), 8.91 (s, 2H), 8.71 (s, 1H), 8.51 - 8.47 (m, 2H), 7.73 (d, J= 2.0 Hz, 1H), 7.65 - 7.47 (m, 1H), 7.61 - 7.57 (m, 1H), 7.26 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.83 (d, J= 7.6 Hz, 1H), 4.43 (s, 2H), 3.75 (t, J= 5.2 Hz, 2H), 3.69 (s, 3H), 2.89 (t, J= 5.2 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H).   550.2 [M+H] ⁺ 86

(400 MHz, DMSO- d ₆ ) δ : 11.32 (s, 1H), 10.38 (s, 1H), 9.08 - 9.05 (m, 2H), 8.79 (s, 2H), 7.72 (s, 1H), 7.68 - 7.64 (m, 1H), 7.29 (d, J= 1.2 Hz, 1H), 7.12 (d, J= 8.4 Hz, 1H), 6.88 (d, J= 7.2 Hz, 1H), 4.46 (s, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.68 (s, 3H), 2.90 (t, J= 4.8 Hz, 2H), 2.86 (d, J= 4.8 Hz, 3H), 2.35 (s, 3H).   499.1 [M+H] ⁺ 87

(400 MHz, DMSO- d ₆) δ: 11.31 (s, 1H), 10.21 (s, 1H), 9.11 (s, 2H), 8.74 (s, 1H), 8.68 (s, 1H), 8.49 (d, J= 9.2 Hz, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.01 (d, J= 8.0 Hz, 1H), 6.91 (s, 1H), 4.45 (s, 2H), 3.78 - 3.74 (m, 2H), 3.68 (s, 3H), 3.05 (s, 3H), 2.94 - 2.90 (m, 2H), 2.80 (d, J= 4.0 Hz, 3H), 1.29 - 1.20 (m, 1H), 0.65 - 0.59 (m, 2H), 0.54 - 0.48 (m, 2H).   581.3 [M+H] ⁺  88

(400 MHz, DMSO) δ: 11.08 (s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.55 - 8.53 (m, 2H), 8.26 (s, 1H), 8.14 (s, 1H), 7.62 - 7.56 (m, 2H), 7.30 (s, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.82 (d, J= 6.8 Hz, 1H), 4.42 (s, 2H), 3.77-3.73 (m, 2H), 3.59 (s, 3H), 3.56 (s, 3H), 2.88-2.84 (m, 2H), 2.79 (d, J= 3.6 Hz, 3H). 514.2 [M+H] ⁺  89

(400 MHz, DMSO- d ₆) δ: 11.03 (s, 1H), 9.81 (s, 1H), 9.02 (s, 2H), 8.72 (s, 1H), 8.50 (d, J= 4.8 Hz, 1H), 8.48 (s, 1H), 7.75 (d, J= 2.0 Hz, 1H), 7.60 – 7.56 (m, 1H), 7.32 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.76 – 3.73 (m, 2H), 3.71 (s, 3H), 3.05 (s, 6H), 2.91 – 2.87 (m, 2H), 2.79 (d, J= 4.4 Hz, 3H). 555.2 [M+H] ⁺ 90

(400 MHz, DMSO- d ₆ ) δ : 11.04 (s, 1H), 9.81 (s, 1H), 9.38 (s,2H), 8.72 (s, 1H), 8.52 -  8.48 (m, 2H), 7.78 (d, J= 1.6 Hz ,1H), 7.61 - 7.57 (m, 1H), 7.35 (d, J= 2.0 Hz, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.76 (t, J= 4.8 Hz, 2H), 3.73 (s, 3H),2.90 (t, J= 4.8 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H), 2.70 (s, 3H).   526.1 [M+H] ⁺ 91

(400 MHz, DMSO- d ₆ ) δ : 11.05 (s, 1H), 9.81 (s, 1H), 9.42 (s, 2H), 8.71 (s, 1H), 8.52 (d, J= 4.8 Hz, 1H), 8.48 (s, 1H), 7.80 (d, J= 2.0 Hz, 1H), 7.61 - 7.57 (m, 1H),7.38 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.75 (t, J= 4.8 Hz, 2H), 3.72 (s, 3H), 2.90 (t, J= 4.8 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H).   509.1 [M+H] ⁺ 92

(400 MHz, DMSO- d ₆) δ: 10.97 (s, 1H), 9.78 (s, 1H), 8.70 (s, 1H), 8.65 (s, 2H), 8.48 (d, J= 4.4 Hz, 1H), 8.46 (s, 1H), 7.67 (s, 1H), 7.58 (t, J= 8.0 Hz, 1H), 7.20 (s, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 4.29 - 4.23(m, 2H), 3.76 - 3.72 (m, 2H), 3.66 (s, 3H), 2.88 - 2.82 (m, 2H), 2.78 (d, J= 4.0 Hz, 3H), 1.39 (t, J= 6.8 Hz, 3H).   528.3 [M+H] ⁺ 93

(400 MHz, DMSO- d ₆) δ: 10.98 (s, 1H), 9.79 (s, 1H), 8.75 (s, 2H), 8.70 (s, 1H), 8.49 (d, J= 4.4 Hz, 1H), 8.47 (s, 1H), 7.68 (d, J= 2.0 Hz, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.21 (d, J= 1.6 Hz, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.6 Hz, 1H), 4.42 (s, 2H), 4.18 - 4.14 (m, 1H), 3.76 - 3.72 (m, 2H), 3.68 (s, 3H), 2.89 - 2.84 (m, 2H), 2.78 (d, J= 4.4 Hz, 3H), 0.91 - 0.86 (m, 2H), 0.81 - 0.77 (m, 2H). 540.2 [M+H] ⁺ 94

(400 MHz, DMSO- d ₆) δ :11.02 (s, 1H), 9.80 (s, 1H), 9.09 (s, 2H), 8.72 (s, 1H), 8.50 (d, J= 4.4 Hz, 1H), 8.47 (s, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.58 (dd, J= 8.0, 7.2 Hz, 1H), 7.31 (d, J= 1.6 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.77 - 3.73 (m, 2H), 3.71 (s, 3H), 3.58 - 3.50 (m, 4H), 2.91 - 2.86 (m, 2H), 2.78 (d, J= 4.4 Hz, 3H), 1.92 - 1.86 (m, 4H). 581.2 [M+H] ⁺  95

(400 MHz, DMSO- d ₆ ) δ :11.02 (s, 1H), 9.81 (s, 1H), 9.18 (s, 2H), 8.71 (s, 1H), 8.50 (t, J= 4.4 Hz, 2H), 7.76 (d, J= 1.6 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.30 (d, J= 2.0 Hz, 1H),  6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.75 (t, J= 4.8 Hz, 2H), 3.72 (s, 3H), 2.89 (t, J= 4.8 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H), 2.14 (t, J= 19.2 Hz, 3H). 548.2 [M+H] ⁺ 96

(400 MHz, DMSO- d ₆ ) δ: 11.19 (s, 1H), 10.08 (s, 1H), 8.71-8.65 (m, 3H), 8.65 - 8.61 (m, 1H), 8.46 (s, 1H), 7.67 (d, J= 2.0 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.27 (s, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.89 (d, J= 7.6 Hz, 1H), 4.42 (s, 2H), 3.75 – 3.71 (m, 2H), 3.65 (s, 3H), 2.89-2.85 (m, 2H), 2.78 (d, J= 4.6 Hz, 3H), 2.01-1.97 (m, 1H), 1.09 – 1.05 (m, 2H), 0.92 – 0.88 (m, 2H). 524.2 [M+H] ⁺  97

(400 MHz, DMSO- d ₆) δ :11.04 (s, 1H), 9.81 (s, 1H), 9.26 (s, 2H), 8.86 (d, J= 4.4 Hz, 1H), 8.72 (s, 1H), 8.51 (d, J= 4.4 Hz, 1H), 8.48 (s, 1H), 7.76 (d, J= 1.6 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.32 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.6 Hz, 1H), 4.42 (s, 2H), 3.77 - 3.73 (m, 2H), 3.70 (s, 3H), 2.92 - 2.87 (m, 2H), 2.85 (d, J= 4.8 Hz, 3H), 2.78 (d, J= 4.4 Hz, 3H). 541.2 [M+H] ⁺  98

(400 MHz, DMSO) δ: 11.08 (s, 1H), 9.79 (s, 1H), 8.72 (s, 1H) ,8.51 - 8.47 (m, 2H), 8.26 (s, 1H), 8.14 (s, 1H), 7.60 - 7.56 (m, 2H), 7.29 (d, J= 1.6 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.2 Hz,1H), 4.42 (s, 2H), 3.75 (t, J= 4.8 Hz, 2H), 3.59 (s, 3H), 3.55 (s, 3H), 2.85 (t, J= 4.4 Hz, 2H), 2.79 (d, J= 4.4 Hz, 3H).   514.2 [M+H] ⁺  99

(400 MHz, DMSO- d ₆ ) δ :11.38 (s, 1H), 10.41 (s, 1H), 9.00 (s, 2H), 8.78 - 8.71 (m, 2H), 8.51 (s, 1H), 7.73 - 7.69 (m, 2H), 7.37 (d, J= 1.6 Hz, 1H), 7.00 - 6.96 (m, 2H), 4.46 (s, 2H), 3.74 (t, J= 4.8 Hz, 2H), 3.70 (s, 3H), 2.91 (t, J= 4.8 Hz, 2H), 2.81 (d, J= 4.4 Hz, 3H), 1.54 (s, 6H). 542.2 [M+H] ⁺  100

(400 MHz, DMSO- d ₆)δ :10.98 (s, 1H), 9.80 (s, 1H), 8.71 (s, 1H), 8.64 (s, 2H), 8.49 (d, J= 4.4 Hz, 1H), 8.46 (s, 1H), 7.67 (s, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.91 - 4.85 (m, 1H), 4.42 (s, 2H), 3.76 - 3.71 (m, 2H), 3.67 (s, 3H), 2.89 - 2.84 (m, 2H), 2.78 (d, J= 4.4 Hz, 3H), 1.35 (d, J= 6.0 Hz, 6H). 542.2 [M+H] ⁺ 101

(400 MHz, DMSO- d ₆) δ :10.98 (s, 1H), 9.79 (s, 1H), 8.70 (s, 1H), 8.65 (s, 2H), 8.49 (d, J= 4.4 Hz, 1H), 8.46 (s, 1H), 7.68 (d, J= 2.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.19 (d, J= 2.0 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 4.06 (d, J= 7.2 Hz, 2H), 3.76 - 3.72 (m, 2H), 3.66 (s, 3H), 2.88 - 2.84 (m, 2H), 2.78 (d, J= 4.4 Hz, 3H), 1.31 - 1.26 (m, 1H), 0.64 - 0.60 (m, 2H), 0.38 (d, J= 6.0 Hz, 2H). 554.2 [M+H] ⁺  102

(400 MHz, DMSO- d ₆) δ: 11.09 (s, 1H), 9.81 (s, 1H), 8.74 – 8.73 (m, 2H), 8.51 (d, J= 4.4 Hz, 1H), 8.47 (s, 1H), 7.96 – 7.93 (m, 2H), 7.70 (d, J= 2.0 Hz, 1H), 7.58 (dd, J= 8.0, 7.2 Hz, 1H), 7.31 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.78 - 3.75 (m, 2H), 3.50 (s, 3H), 3.03 (s, 3H), 3.00 (s, 3H), 2.90 - 2.86 (m, 2H), 2.79 (d, J= 4.4 Hz, 3H). 554.2 [M+H] ⁺  103

(400 MHz, DMSO- d ₆) δ :11.10 (s, 1H), 9.81 (s, 1H), 9.24 (dd, J= 4.8, 1.6 Hz, 1H), 8.74 (s, 1H), 8.52 (d, J= 4.4 Hz, 1H), 8.48 (s, 1H), 8.06 (dd, J= 8.4, 1.6 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.61 - 7.56 (m, 1H), 7.30 (d, J= 1.6 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.2 Hz, 1H), 4.44 (s, 2H), 3.80-3.75 (m, 2H), 3.47 (s, 3H), 2.93 - 2.88 (m, 2H), 2.79 (d, J= 4.4 Hz, 3H).   484.2 [M+H] ⁺ 104

(400 MHz, DMSO- d ₆) δ: 11.03 (s, 1H), 9.82 (s, 1H), 9.23 (s, 2H), 8.85 (d, J= 4.0 Hz, 1H), 8.72 (s, 1H), 8.51 (d, J= 4.4 Hz, 1H), 8.47 (s, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.31 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.77 - 3.73 (m, 2H), 3.69 (s, 3H), 2.92 - 2.87 (m, 3H), 2.78 (d, J= 4.4 Hz, 3H), 0.77 - 0.73 (m, 2H), 0.64 - 0.60 (m, 2H).   567.2 [M+H] ⁺  105

(400 MHz, DMSO- d ₆) δ: 11.03 (s, 1H), 9.81 (s, 1H), 9.13 (s, 2H), 8.72 (s, 1H), 8.50 (d, J= 4.8 Hz, 1H), 8.48 (s, 1H), 7.76 (d, J= 1.6 Hz, 1H), 7.58 (dd, J= 8.4, 7.6 Hz, 1H), 7.33 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.47 (t, J= 7.6 Hz, 2H), 4.42 (s, 2H), 4.11 (t, J= 7.6 Hz, 2H), 3.76 - 3.73 (m, 2H), 3.71 (s, 3H), 2.91 - 2.87 (m, 2H), 2.78 (d, J= 4.4 Hz, 3H), 2.34 - 2.29 (m, 2H).   567.2 [M+H] ⁺  106

(400 MHz, DMSO- d ₆) δ: 11.04 (s, 1H), 9.81 (s, 1H), 9.30 (s, 2H), 8.72 (s, 1H), 8.50 (d, J= 4.4 Hz, 1H), 8.48 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.57 (t, J= 7.6 Hz, 1H), 7.34 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.77 - 3.73 (m, 2H), 3.70 (s, 3H), 2.91 - 2.88 (m, 2H), 2.79 (d, J= 4.4 Hz, 3H). 528.10 [M+H] ⁺  107

(400 MHz, DMSO- d ₆ ) δ : 10.98 (s, 1H), 9.78 (s, 1H), 8.89 (d, J= 5.2 Hz, 1H), 8.67 (s, 1H), 8.49 - 8.45 (m, 2H), 7.70 (d,  J= 1.6 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.24 (d, J= 2.0 Hz,  1H), 6.97 (d, J= 8.2 Hz, 1H), 6.79 (d, J= 7.2 Hz, 1H), 4.40 (s, 2H), 3.72 (t, J= 4.4 Hz, 2H),  3.64 (s, 3H), 2.85 (t, J= 4.8 Hz, 2H), 2.76 (d, J= 4.4 Hz, 3H), 1.98 - 1.94 (m, 2H), 1.89 - 1.85 (m, 2H).   549.3 [M + H] ⁺. 108

(400 MHz, DMSO- d ₆) δ: 11.03 (s, 1H), 9.81 (s, 1H), 9.29 (s, 2H), 8.72 (s, 1H), 8.50 (d, J= 4.4 Hz, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 7.83 (s, 1H), 7.76 (d, J= 2.0 Hz, 1H), 7.60 – 7.56 (m, 1H), 7.32 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.77 - 3.73 (m, 2H), 3.70 (s, 3H), 2.91 - 2.87 (m, 2H), 2.78 (d, J= 4.4 Hz, 3H).   527.2 [M+H] ⁺ 109

(400 MHz, DMSO- d ₆ ) δ : 11.00 (s, 1H), 10.47 (s, 1H), 9.80 (s, 1H), 9.09 (s, 2H), 8.71 (s, 1H), 8.49 - 8.47 (m, 2H), 7.70 (d, J= 2.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.24 (d, J= 1.6 Hz,  1H), 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.74 (t, J= 5.2 Hz, 2H), 3.67 (s, 3H), 2.87 (t, J= 4.8 Hz, 2H), 2.78 (d, J= 4.4 Hz, 3H), 2.14 (s, 3H).   541.3 [M+H] ⁺  110

(400 MHz, DMSO- d ₆) δ :11.01 (s, 1H), 9.80 (s, 1H), 8.89 (s, 1H), 8.72 (s, 1H), 8.49 (d, J= 4.8 Hz, 1H), 8.47 (s, 1H), 7.72 (d, J= 1.6 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.23 (d, J= 1.6 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 7.6 Hz, 1H), 5.19 (s, 2H), 5.02 (s, 2H), 4.42 (s, 2H), 3.76 - 3.72 (m, 2H), 3.68 (s, 3H), 2.90 - 2.86 (m, 2H), 2.78 (d, J= 4.0 Hz, 3H). 526.1 [M+H] ⁺  111

(400 MHz, DMSO- d ₆) δ :11.55 (s, 1H), 10.60 (s, 1H), 8.83 (s, 1H), 8.73 (d, J= 5.6 Hz, 1H), 8.51 (d, J= 7.6 Hz, 1H), 8.43 (d, J= 2.4 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.63 (d, J= 1.6 Hz, 1H), 7.55 (dd, J= 8.4, 2.8 Hz, 1H), 7.39 (s, 1H), 7.05-7.49 (m, 2H), 4.47 (s, 2H), 3.90 (s, 3H), 3.79 - 3.75 (m, 2H), 3.48 (s, 3H), 2.93 - 2.87 (m, 2H), 2.82 (d, J= 4.4 Hz, 3H).   513.2 [M+H] ⁺  112

(400 MHz, DMSO- d ₆) δ: 11.06 (s, 1H), 9.79 (s, 1H), 8.71 (s, 1H), 8.50 (d, J= 4.4 Hz, 1H), 8.47 (s, 1H), 8.36 (d, J= 2.0 Hz, 1H), 7.92 (dd, J= 8.4, 2.4 Hz, 1H), 7.63 (d, J= 1.6 Hz, 1H), 7.58 (t, J= 8.0 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.94 – 6.90 (m, 2H), 6.82 (d, J= 7.2 Hz, 1H), 4.43 (s, 2H), 3.91 (s, 3H), 3.79 - 3.75 (m, 2H), 3.38 (s, 3H), 2.88 - 2.84 (m, 2H), 2.79 (d, J= 4.0 Hz, 3H). 513.2 [M+H] ⁺ 113

(400 MHz, DMSO- d ₆) δ :10.99 (s, 1H), 9.76 (s, 1H), 8.69 (s, 1H), 8.48 (d, J= 4.4 Hz, 1H), 8.45 (s, 1H), 7.57 (t, J= 8.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.12 (s, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.86 (d, J= 1.2 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.42 (s, 2H), 3.79 - 3.74 (m, 2H), 3.73 (s, 3H), 3.57 (s, 3H), 3.10 (s, 6H), 2.85 - 2.80 (m, 2H), 2.79 (d, J= 4.4 Hz, 3H). 556.2 [M+H] ⁺ 114

(400 MHz, DMSO- d ₆ ) δ: 11.11 (s, 1H), 9.82 (s, 1H), 9.09 (d, J= 1.6 Hz, 1H), 8.78 (dd, J= 2.4, 1.6 Hz, 1H), 8.73 (s, 1H), 8.64 (d, J= 2.4 Hz, 1H), 8.51-8.47 (m, 2H), 7.74 (d, J= 2.0 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.29 (d, J= 1.6 Hz, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.83 (d, J= 7.2 Hz, 1H), 4.44 (s, 2H), 3.77 (t, J= 4.8 Hz, 2H), 3.52 (s, 3H), 2.9 (t, J= 4.8 Hz, 2H). 487.2 [M+H] ⁺  Example 53: 5 ⁶ -Methoxy-5 ⁵ -(5-methoxypyrimidin-2-yl)-N-methyl-8-oxa-2,4-diaza-1(2,6 ), 3(2,4)-dipyridine-5(1,3)-benzocyclononane-3 ⁵ -formamide

The first step: the preparation of 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetic acid ethyl ester 4-methoxy-3-nitro-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl phenylacetate (9 g, 24.6 mol) dissolved in 1,4-dioxane and water (1,4-dioxane: water = 3:1, 100 mL), add potassium carbonate (10.18 g, 73.8 mol) under nitrogen atmosphere, [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (1.8 g, 2.4 mol) and 2-bromo-5-methoxypyrimidine (5.11 g, 27 mol), and the mixture was stirred at 90°C for 2 hours. After the reaction was completed, it was extracted with ethyl acetate (3×100 mL), the organic layer was washed with saturated brine (3×10 mL), then dried over anhydrous sodium sulfate, filtered, and then concentrated, and the obtained residue was applied to a silica gel column (Eluent: petroleum ether/ethyl acetate=7/3) purify, obtain 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetic acid ethyl ester (7.2 g, yield 77%). MS m/z (ESI): 348.1 [M+H] ⁺ second step: 2-(4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenyl) Preparation of ethanol Dissolve ethyl 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetate (7 g, 20.2 mol) in methanol (100 mL), add Potassium carbonate (4.18 g, 30.3 mol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was filtered and concentrated, and the resulting residue was purified with silica gel column (eluent: petroleum ether/ethyl acetate=3/2) to obtain 2-(4-methoxy-3-(5-methyl Oxypyrimidin-2-yl)-5-nitrophenyl)ethanol (5.2 g, yield 81%). MS m/z (ESI): 306.1 [M+H] ⁺ third step: 2-(5-(2-((6-bromopyridin-2-yl)methoxy)ethyl)-2-methoxy Preparation of base-3-nitrophenyl)-5-methoxypyrimidine 2-(4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenyl) Ethanol (1000 mg, 3.3 mmol) and 2-bromo-6-(chloromethyl)pyridine hydrochloride (1360 mg, 6.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), in Sodium hydride (400 mg, 16.5 mmol) was added under ice cooling, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, it was quenched with water (100 mL), extracted with ethyl acetate (3×50 mL), the organic layer was washed with saturated brine (3×10 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give The residue was purified with silica gel column (eluent: petroleum ether/ethyl acetate=1/1) to obtain 2-(5-(2-((6-bromopyridin-2-yl)methoxy)ethyl )-2-methoxy-3-nitrophenyl)-5-methoxypyrimidine (1200 mg, yield 54%). MS m/z (ESI): 475.1 [M+H] ⁺ the fourth step: tertiary butyl (6-((4-methoxy-3-(5-methoxypyrimidin-2-yl)-5 - Preparation of nitrophenylethoxy) methyl) pyridin-2-yl) carbamate 2-(5-(2-((6-bromopyridin-2-yl) methoxy) ethyl Base)-2-methoxy-3-nitrophenyl)-5-methoxypyrimidine (1200 mg, 2.5 mmol) was dissolved in 1,4-dioxane (20 mL), under nitrogen atmosphere Add 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (290 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (231 mg, 0.25 mmol) and carbonic acid Cesium (165 mg, 0.5 mmol). The mixture was stirred at 90°C for 1 hour. Concentrate directly after the end of the reaction, and the residue obtained is purified with a silica gel column (eluent: petroleum ether/ethyl acetate=2/3) to obtain tertiary butyl (6-((4-methoxy-3- (5-methoxypyrimidin-2-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)carbamate (850 mg, yield 52%). MS m/z (ESI): 512.3 [M+H] ⁺ the fifth step: tertiary butyl (6-((3-amino-4-methoxy-5-(5-methoxypyrimidine-2 -yl) phenylethoxy) methyl) pyridin-2-yl) carbamate preparation tertiary butyl (6-((4-methoxy-3-(5-methoxypyrimidine -2-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)carbamate (850 mg, 1.7 mmol) was dissolved in ethanol and water (ethanol:water=4:1 , 20 mL), iron powder (470 mg, 8.4 mmol) and ammonium chloride (450 mg, 8.4 mmol) were added, and the mixture was refluxed at 80 °C for 1 hour. After the reaction was completed, the filtrate was filtered, and after concentration, the obtained residue was purified with a silica gel column (eluent: dichloromethane/methanol=19/1) to obtain tert-butyl (6-((3-amino -4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate (600 mg, yield 58%) . MS m/z (ESI): 482.1[M+H] ⁺ the sixth step: tert-butyl (6-((3-((2-chloro-5-(methylaminoformyl)pyridine-4 -yl) amino)-4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate will tert-butyl(6-((3-amino-4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl)amine Carbamate (300 mg, 0.6 mmol) and 4,6-dichloro-N-methylnicotinamide (140 mg, 0.6 mmol) were dissolved in tetrahydrofuran (10 mL), and bis(trimethyl Silicyl) sodium amide (2M, 0.16 mL, 1.8 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), and after concentration, the obtained residue was purified with silica gel column (eluent: dichloromethane/methanol=93/7) to obtain tert-butyl (6-(( 3-((2-Chloro-5-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methoxypyrimidin-2-yl)benzene (ethoxy)methyl)pyridin-2-yl)carbamate (210 mg, yield 50%). MS m/z (ESI): 651.3 [M+H] ⁺ the seventh step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2- The preparation of methoxy-3-(5-methoxypyrimidin-2-yl) phenyl) amino)-6-chloro-N-methyl nicotinamide will be tertiary butyl (6-((3- ((2-Chloro-5-(methylaminoformyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethyl Oxy)methyl)pyridin-2-yl)carbamate (210 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), and added to a mixture of hydrochloric acid and 1,4-dioxane (hydrochloric acid/1,4-dioxane=4 mol/L, 5 mL), and the mixture was stirred at 40°C for 1 hour. Concentrate directly after the reaction to obtain 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methoxypyrimidine -2-yl)phenyl)amino)-6-chloro-N-methylnicotinamide (120 mg, crude). MS m/z (ESI): 552.2 [M+H] ⁺ . The eighth step: 5 ⁶ -methoxy-5 ⁵ -(5-methoxypyrimidin-2-yl)-N-methyl-8-oxa-2,4-diaza-1(2,6 ), the preparation of 3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -formamide 4-((5-(2-((6-aminopyridine -2-yl)methoxy)ethyl)-2-methoxy-3-(5-methoxypyrimidin-2-yl)phenyl)amino)-6-chloro-N-methylnicotinyl Amine (120 mg, 0.21 mmol) was dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxane was added under nitrogen atmosphere Anthracene (25 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol) and cesium carbonate (213 mg, 0.65 mmol). The mixture was stirred at 130°C for 10 hours. Concentrate directly after the reaction, and then prepare by reverse column (acetonitrile: water = 1:1). After purification, 5 ⁶ -methoxy-5 ⁵ -(5-methoxypyrimidin-2-yl)-N -Methyl-8-oxa-2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ - Formamide (38.2 mg, yield 34%). MS m/z(ESI): 514.2 [M+H] ^{+ 1} H NMR(400 MHz, DMSO-d ₆ )δ: 10.98(s, 1H), 9.79(s, 1H), 8.71(s, 1H), 8.67(s, 2H), 8.50 - 8.46(m, 2H), 7.68(d, J=1.6 Hz, 1H), 7.60-7.56(m, 1H), 7.20(d, J=2.0 Hz, 1H), 6.98 (d, J =8.0 Hz, 1H), 6.81(d, J=7.2 Hz, 1H), 4.42 (s, 2H), 3.97(s, 3H), 3.76-3.72(m, 2H), 3.67(s, 3H), 2.89-2.85(m, 2H), 2.78(d, J = 4.4 Hz, 3H). Using the same or similar preparation method above, the compound with the following structure was further prepared Example number Compound structure ^1H NMR MS m/z (ESI) twenty four

(400 MHz, DMSO- d ₆ ) δ: 10.45 (s, 1H), 10.42 (s, 1H), 9.71 (s, 1H), 9.03-9.05 (m, 1H), 8.07 (s, 1H), 7.66- 7.63 (m, 1H), 7.10-6.94 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 4.59 (s, 2H), 4.34 (s , 2H), 3.88 (s, 3H), 2.85 (d, J = 4.8 Hz, 3H). 393.16 [M + H] ⁺ . 25

(400 MHz, DMSO- d ₆ ) δ : 10.57 (s, 1H), 9.87 (s, 1H), 9.03 - 9.05 (m, 1H), 8.17 - 8.19 (m, 1H), 7.72 - 7.74 (m, 1H ), 7.53 - 7.43(m, 3H), 7.09 (s, 1H), 6.79 -6.81 (m, 1H), 6.67 - 6.69 (m, 1H), 4.49 (s, 2H), 3.87 (s, 3H), 3.74 - 3.76 (m, 2H), 3.52 (s, 3H), 2.83 - 2.86 (m, 5H). 487.2 [M+H] ⁺ . 26

(400 MHz, DMSO-d6) δ: 10.30 (s, 1H), 10.15 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 7.80 - 7.72 (m, 2H ), 7.61 - 7.51 (m, 2H), 6.73 - 6.63 (m, 2H), 6.35 (d, J = 8.0 Hz, 1H), 4.83 -4.81 (m, 2H), 3.90 (s, 3H), 3.55 ( s, 3H), 3.04-3.02 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H). 473.3 [M+H] ⁺ 27

(400 MHz, DMSO) δ: 10.31 (s, 1H), 10.15 (s, 1H), 9.02 (s, 1H), 8.55 (s, 2H), 7.76 - 7.74 (m, 2H), 7.58 (s, 1H ), 7.54 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 5.2, 2.8 Hz, 2H), 6.35 (d, J = 7.6 Hz, 1H), 4.83-4.81 (m, 2H), 3.90 (s, 3H), 3.55 (s, 3H), 3.05-3.02 (m, 2H). 476.1 [M+H] ⁺ 28

(400 MHz, DMSO- d ₆ ) δ 10.72 (s, 1H), 9.70 (s, 1H), 9.02 (d, J = 4.8 Hz, 1H), 8.50 (d, J = 7.2 Hz, 1H), 7.76 ( d, J = 2.0 Hz, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 6.70 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.57 (s, 3H), 2.88-2.80 (m, 7H). 503.1 [M+H] ⁺ 29

(400 MHz, DMSO- d ₆ ) δ: 10.35 (s, 1H), 9.30 - 9.34(m, 1H), 7.80 (s, 1H), 7.74-7.76 (m, 1H), 7.51 (s, 1H), 7.44 - 7.46(m, 2H), 7.35 - 7.30 (m, 1H), 7.22 (s, 1H), 7.08 -7.10 (m, 2H), 6.97 (s, 1H), 6.64 -6.66 (m, 1H), 4.95 - 4.73 (m, 2H), 3.90 (s, 3H), 3.51 (s, 3H), 2.87 - 2.95 (m, 5H). 523 [M+H] ⁺ 30

(400 MHz, DMSO) δ 11.18 (s, 1H), 10.33 (s, 1H), 9.10 (d, J = 4.4 Hz, 1H), 8.39 (s, 1H), 7.81 (s, 1H), 7.58 (t , J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.22-4.20 (m, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.87 (d, J = 4.4 Hz, 3H), 2.81-2.79 (m, 2H), 2.08-2.05 (m, 2H). 465.2 [M+H] ⁺ . 31

(400 MHz, DMSO- d ₆ ) δ: 10.25 (s, 2H), 9.21 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.34 (s, 1H), 7.17 (s, 1H), 3.77 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H), 2.56 (s, 2H), 2.00 (dd, J = 14.4, 6.9 Hz, 2H), 1.85 (s, 2H), 1.45 (s, 2H), 1.16 (s, 6H) 457.3 [M + H] ⁺ 32

(400 MHz, DMSO- d ₆ ) δ: 11.39 (s, 1H), 10.51 (s, 1H), 9.10 (d, J = 4.8 Hz, 1H), 9.03 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H),7.49 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.7, 5.5 Hz, 2H), 7.31 (t, J = 8.9 Hz, 2H), 7.21 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 4.40 (s, 2H), 3.91 (s, 3H), 3.74-3.69 (m, 2H), 3.61 (s, 3H), 2.89-2.85 (m, 5H). 581.2 [M+H ⁺ ] 33

(400 MHz, DMSO- d6 ) δ: 11.36 (s, 1H), 10.54 (s, 1H), 9.10 (d, J = 4.8 Hz, 1H), 9.03 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.41 (s, 2H), 3.91 (s, 3H), 3.76 - 3.68 (m, 2H), 3.61 (s, 3H), 2.92 - 2.81 (m, 5H). 631.3 [M + H] ⁺ . 34

(400 MHz, DMSO) δ 11.12 (s, 1H), 9.65 (s, 1H), 9.08 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.53 (s , 1H), 7.42 (s, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J = 7.5 Hz , 1H), 6.70 (d, J = 2.1 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 2H), 3.57 (s, 3H), 2.95 - 2.87 (m, 2H), 2.85 (d, J = 4.6 Hz, 3H), 2.43 (d, J = 5.6 Hz, 2H). 502.2 [M+H] ⁺ . 35

(400 MHz, DMSO- d ₆ ) δ 11.02 (s, 1H), 9.77 (s, 1H), 8.71 (s, 1H), 8.48-8.44 (m, 2H), 7.76 (d, J = 2.0 Hz, 1H ), 7.60 - 7.54 (m, 2H), 7.41 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 2.0 Hz , 1H), 4.41 (s, 2H), 3.91 (s, 3H), 3.74 (t, J = 4.8 Hz, 2H), 3.58 (s, 3H), 2.84 (t, J = 4.4 Hz, 2H). 489.1 [M+H] ⁺ 37

(400 MHz, DMSO- d ₆ ) δ: 10.69 (s, 1H), 10.42 (s, 1H), 9.24 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 2H), 7.20 (s, 1H), 7.01 (s, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.55 (s, 3H) , 3.33-3.30 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H), 2.69-2.65 (m, 2H), 1.40-1.36 (m, 2H), 0.94-0.92 (m, 2H) 491.2 [M+H] ⁺ 38

(400 MHz, DMSO- d ₆ ) δ 11.67 (s, 1H), 10.96 (s, 1H), 9.17 (s, 1H), 8.84 (s, 1H), 7.74-7.65 (m, 5H), 6.75 (s , 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.49-3.45 (m, 2H), 2.89-2.85 (m, 5H). 506.2 [M+H] ⁺ 39

(400 MHz, CDCl ₃ ) δ : 11.18 (s, 1H), 9.33 (s, 1H), 8.48 (d, J = 18.2 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.39 (d , J = 2.1 Hz, 1H), 7.35-7.30 (m, 4H), 7.22 (s, 1H), 7.05 - 6.87 (m, 2H), 6.82 (d, J = 2.2 Hz, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.67 (s, 3H), 2.99 (s, 3H), 2.93 - 2.82 (m, 2H), 2.59 - 2.45 (m, 2H). 501.3 [M+H] ⁺ . 40

(400 MHz, DMSO- d ₆ ) δ: 10.76 (s, 1H), 9.90 (s, 1H), 9.06 (d, J = 4.0 Hz, 1H), 8.13 (t, J = 6.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 2.84 (d, J = 4.0 Hz, 3H), 2.69-2.65 (m, 2H), 2.35-2.31 (m, 1H), 1.25-1.21 (m, 1H). 517.2 [M+H] ⁺ 41

(400 MHz, DMSO- d ₆ ) δ 11.34 (s, 1H), 9.73 (s, 1H), 9.12 (d, J = 4.2 Hz, 1H), 8.81 (s, 1H), 7.78 (s, 1H), 7.72-7.61 (m, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 4.45 (s, 2H), 3.91 (s, 3H), 3.78-3.74 (m, 2H), 3.60 (s, 3H), 2.90-2.85 (m, 5H). 505.1 [M+H] ⁺ 42

(400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H), 9.80 (s, 1H), 8.98-8.94 (m, 2H), 8.72 (s, 1H), 8.49-8.45 (m, 2H), 7.75 -7.72 (m, 1H), 7.65-7.58 (m, 1H), 7.55-7.50 (m, 1H), 7.24 (s, 1H), 7.05-7.00 (m, 1H), 6.82 (s, 1H), 4.45 (s, 2H), 3.77-3.73 (m, 2H), 3.69 (s, 3H), 2.80-2.76 (m, 2H), 2.50 (s, 3H). 484.2 [M+H] ⁺ 43

(400 MHz, DMSO- d ₆ ) δ 10.60 (s, 1H), 10.16 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H), 3.91 (s, 3H), 3.61-3.57 (m, 5H), 3.32-3.30 (m, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.75 (t, J = 5.2 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 1.70-1.61 (m, 2H). 515.2 [M+H] ⁺ 44

(400 MHz, DMSO- d ₆ ) δ 11.02 (s, 1H), 9.81 (s, 1H), 9.04 (s, 2H), 8.72 (s, 1H), 8.57 - 8.41 (m, 2H), 7.74 (d , J =1.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.76 (t, J = 4.4 Hz, 2H), 3.69 (s, 3H), 2.89 (t, J = 4.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H). 502.1 [M+H] ⁺ 45

(400 MHz, DMSO- d ₆ ) δ 11.02 (s, 1H), 9.80 (s, 1H), 9.03 (s, 2H), 8.72 (s, 1H), 8.56-8.42 (m, 2H), 7.74 (s , 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.43 (s , 2H), 3.76 (t, J = 4.4 Hz, 2H), 3.68 (s, 3H), 2.89 (t, J = 4.8 Hz, 2H). 505.2 [M+H] ⁺ 46

(400 MHz, DMSO- d ₆ ) δ 11.01 (s, 1H), 9.80 (s, 1H), 8.94 (d, J = 4.8 Hz, 2H), 8.72 (s, 1H), 8.54-8.40 (m, 2H ), 8.13 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.2, 7.4 Hz, 1H), 7.50 (s, 1H), 7.24 (d, J = 2.0 Hz , 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 4.42 (s, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.68 (s, 3H), 2.88 (t, J = 4.8 Hz, 2H). 487.3 [M+H] ⁺ 47

(400 MHz, DMSO- d ₆ ) δ 13.82 (s, 1H), 10.98 (s, 1H), 9.77 (s, 1H), 9.02-9.00 (m, 1H), 8.77-8.72 (m, 1H), 8.49 -8.44 (m, 2H), 8.16 - 8.15 (m, 1H), 7.99-7.95 (m, 1H), 7.78-7.72 (m, 1H), 7.58-7.53 (m, 2H), 6.99-6.96 (m 1H ), 6.84-6.80 (m, 1H), 4.41 (s, 2H), 3.79 (t, J = 4.8 Hz, 2H), 2.85 (t, J = 4.8 Hz, 2H). 473.2 [M+H] ⁺ 48

(400 MHz, DMSO- d ₆ ) δ 11.34 (s, 1H), 10.39 (s, 1H), 9.13-9.01 (m, 4H), 7.75 (d, J = 1.8 Hz, 1H), 7.70-7.60 (m , 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.46 (s, 2H), 3.79-3.72 (m, 2H), 3.69 (s, 3H), 2.95-2.88 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H). 503.1 [M+H] ⁺ 49

(400 MHz, DMSO- d ₆ ) δ 11.30 (s, 1H), 10.34 (s, 1H), 9.07 (d, J = 4.8 Hz, 1H), 9.02 (s, 1H), 7.68-7.65 (m, 2H ), 7.65-7.61 (m, 2H), 7.47 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.44 (s , 2H), 3.78-3.74 (m, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 2.87-2.54 (m, 5H). 487.3 [M+H] ⁺ 50

(400 MHz, DMSO- d ₆ ) δ 11.19 (s, 1H), 10.17 (s, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.79-6.76 (m , 2H), 3.95 (s, 3H), 3.84 (s, 2H), 3.64 (s, 3H), 2.99-2.96 (m, 2H), 2.95 (d, J = 4.0 Hz, 3H), 2.90-2.86 ( m, 2H). 486.2 [M+H] ⁺ 51

(400 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 10.41 (s, 1H), 9.29 (s, 1H), 9.07 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.49-7.38 (m, 4H), 7.36 (d, J = 6.0 Hz, 1H ), 7.07 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.74 (d, J = 2.0 Hz, 1H), 5.22 (s, 2H), 4.20 (s, 2H), 3.92 (s , 3H), 3.61 (s, 3H), 3.54-3.43 (m, 2H), 2.89 -2.80 (m, 5H). 620.3 [M+H] ⁺ 54

(400 MHz, DMSO- d ₆ ) δ: 10.45 (s, 1H), 10.42 (s, 1H), 9.71 (s, 1H), 9.03-9.05 (m, 1H), 8.07 (s, 1H), 7.66- 7.63 (m, 1H), 7.10-6.94 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 4.59 (s, 2H), 4.34 (s , 2H), 3.88 (s, 3H), 2.85 (d, J = 4.8 Hz, 3H). 393.16 [M+ H] ⁺ . 55

(400 MHz, DMSO-d6) δ: 11.35 (s, 1H), 10.39 (s, 1H), 9.10-9.05 (m, 2H), 7.66-7.63 (m, 2H), 7.12 (d, J = 8.2 Hz , 1H), 6.88 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 4.45 (s, 2H), 3.70-3.66 (m, 5H), 3.02 (s, 3H) , 2.87-2.83 (m, 5H), 2.82 (s, 3H). 478.2 [M+H] ⁺ 56

(400 MHz, DMSO- d ₆ ) δ: 11.01 (s, 1H), 9.81 (s, 1H), 8.70 (s, 1H), 8.51-8.47 (m, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.2 Hz, 7.4 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 1.8 Hz , 1H), 4.42 (s, 2H), 3.68-3.64 (m, 5H), 3.01 (s, 3H), 2.84-2.76 (m, 8H). 477.2 [M+H] ⁺ 57

(400 MHz, DMSO- d ₆ ) δ : 11.33 (s, 1H), 10.34 (s, 1H), 9.04-9.00 (m, 2H), 8.15 (s, 1H), 7.90 (s, 1H), 7.63 ( t, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.22 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.43 (s, 2H), 3.89 (s, 3H), 3.76 (t, J = 4.8 Hz, 2H), 3.57 (s, 3H), 2.83 (t, J = 4.8 Hz, 2H). 490.3 [M+H] ⁺ 58

(400 MHz, DMSO- d ₆ ) δ: 11.33 (s, 1H), 10.30 (s, 1H), 9.14 (dd, J = 4.8, 1.6 Hz, 1H), 9.00-8.96 (m, 2H), 7.97 ( dd, J = 8.8, 1.6 Hz, 1H), 7.71-7.67 (m, 2H), 7.58-7.53 (m, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 8.4 Hz , 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.37 (s, 2H), 3.70-3.66 (m, 2H), 3.37 (s, 3H), 2.85-2.81 (m, 2H), 2.75 ( d, J = 4.8 Hz, 3H). 485.1 [M+H] ⁺ 59

(400 MHz, DMSO- d ₆ ) δ : 10.73 (s, 1H), 10.36 (s, 1H), 9.10-9.06 (m, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.65-7.59 ( m, 2H), 7.14 – 6.93 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 3.60 (s, 3H ), 3.44 (s, 2H), 2.93 (br. s, 2H), 2.87 (d, J = 4.0 Hz, 3H), 2.77 (br. s, 1H), 2.28 (br. s, 1H), 2.15 ( s, 3H). 528.2 [M+H] ⁺ 60

(400 MHz, DMSO- d ₆ ) δ : 9.81 (s, 1H), 9.43 (s, 1H), 8.73 (s, 1H) 8.34 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 4.42 (s, 2H), 3.90 (s, 3H), 3.77-3.74 (m, 2H), 3.62 (s, 3H), 3.58 (s, 3H), 3.33 (s, 3H), 2.86-2.83 (m, 2H). 504.1 [M+H] ⁺ 61

(400 MHz, DMSO- d ₆ ) δ : 11.01 (s, 1H), 9.77 (s, 1H), 8.69 (s, 1H), 8.46 (s, 2H), 8.15 (s, 1H), 7.90 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 1.7 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H) , 6.81 (d, J = 7.2 Hz, 1H), 4.41 (s, 2H), 3.89 (s, 3H), 3.76 (t, J = 4.8 Hz ,2H), 3.58 (s, 3H), 2.82 (t, J = 4.8 Hz ,2H). 489.3 [M+H] ⁺ . 62

(400 MHz, DMSO- d ₆ ) δ: 11.10 (s, 1H), 9.83 (s, 1H), 8.71 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H) , 7.76 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.60 – 7.56 (m, 1H), 7.39 (d, J = 0.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.42 (s, 2H), 3.78 – 3.75 (m, 2H), 3.74 (s, 3H), 2.92 – 2.89 (m, 2H ), 2.81(d, J = 4.4 Hz, 3H), 2.45(s, 3H). 503.1 [M+H] ⁺ 63

(400 MHz, DMSO- d ₆ ) δ: 10.96 (s, 1H), 9.76 (s, 1H), 8.68 (s, 1H), 8.49 (dd, J = 8.4, 4.1 Hz, 1H), 8.46 (s, 1H), 7.65 (s, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.60-7.56 (m, 2H), 7.46 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.41 (s, 2H), 3.78 – 3.74 (m, 2H), 3.72 (s, 3H), 3.64 (s, 3H), 2.86 – 2.82 (m, 2H), 2.80 (d, J = 4.8 Hz, 3H). 486.1 [M+H] ⁺ 64

(400 MHz, DMSO- d ₆ ) δ : 11.42 (s, 1H), 10.42 (s, 1H), 9.13 (d, J = 4.8 Hz, 1H), 9.05 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.41 (d, J = 0.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H) , 6.89 (d, J = 7.2 Hz, 1H), 4.45 (s, 2H), 3.77-3.75 (m, 2H), 3.75 (s, 3H), 2.95-2.91 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H), 2.45 (s, 3H). 504.1 [M+H] ⁺ 65

(400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 10.41 (s, 1H), 9.13 (d, J = 4.8 Hz, 1H), 9.03 (s, 1H), 7.80 (s, 1H), 7.67-7.64 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.45 (s, 2H), 3.77-3.74 (m, 5H), 2.91 (s, 2H), 2.88 (d, J = 4.8 Hz, 3H), 2.44 (s, 3H). 504.2 [M+H] ⁺ 66

(400 MHz, DMSO- d ₆ ) δ: 11.45 (s, 1H), 10.43 (s, 1H), 9.15 (d, J = 4.3 Hz, 1H), 9.06 (s, 1H), 8.63 (s, 1H) , 7.83-7.79 (m, 2H), 7.69 - 7.62 (m,, 1H),7.12 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 4.46 (s, 2H) , 3.81 (s, 3H), 3.79 - 3.74 (m, 2H), 2.99 - 2.94 (m, 2H), 2.88 (d, J = 4.5 Hz, 3H). 558.1 [M+H] ⁺ 67

(400 MHz, DMSO-d6) δ: 11.45 (s, 1H), 10.42 (s, 1H), 9.09 (d, J = 4.8 Hz, 1H), 9.05 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 4.45 (s, 2H), 3.77-3.74 (m, 5H), 2.92-2.89 (m, 2H), 2.87 (d, J = 4.4 Hz, 3H), 2.19 (s, 3H). 488.1 [M+H] ⁺ 68

(400 MHz, DMSO-d6) δ : 11.41 (s, 1H), 10.39 (s, 1H), 9.09 (d, J = 4.8 Hz, 1H), 9.07 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.48 (d, J = 1.6 Hz, 1H), 7.39-7.37 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.99 (d , J = 2.8 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.45 (s, 2H), 3.79 – 3.74 (m, 2H), 3.62 (s, 3H), 2.92 – 2.88 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ :74.17 (s), -94.08 (s). 523.1 [M+H] ⁺ 69

(400 MHz, DMSO- d ₆ ) δ: 11.36 (s, 1H), 10.39 (s, 1H), 9.07-9.03 (m, 4H), 7.77 (s, 1H), 7.66 (s, 1H), 7.40 ( s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 6.8 Hz, 1H), 4.46 (s, 2H), 3.78-3.72 (m, 5H), 3.05 (s, 6H ), 2.94-2.90 (m, 2H), 2.86 (s, 3H). 556.3 [M+H] ⁺ . 70

(400 MHz, DMSO- d ₆ ) δ: 11.36 (s, 1H), 10.32 (s, 1H), 9.17 (s, 1H), 9.06 (s, 1H), 7.77-7.73 (m 2H), 7.66 – 7.56 (m, 1H), 7.46 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 6.0 Hz, 1H), 6.74 (s, 1H), 3.91 (s, 3H) , 3.63 (s, 2H), 3.60 (s, 3H), 2.87 (s, 3H), 2.76-2.72 (m, 4H), 2.22 (d, J = 4.0 Hz, 2H), 0.65-0.61 (m, 3H ). 514.3 [M+H] ⁺ . 71

(400 MHz, DMSO- d ₆ ) δ: 10.94 (s, 1H), 9.61 (s, 1H), 8.58 (s, 1H), 8.51 – 8.39 (m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.55 (s, 1H), 7.42-7.38 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 4.48 (s, 2H), 3.91 (s, 3H), 3.82 – 3.73 (m, 2H), 3.57 (s, 3H), 2.92 – 2.82 (m, 2H), 2.79 (d, J = 4.3 Hz, 3H), 2.15 (s, 3H) . 500.1 [M+H ⁺ ] 72

(400 MHz, DMSO- d ₆ ) δ: 11.91 (s, 1H), 10.03 (s, 1H), 8.69-8.65 (m, 2H), 8.53 (d, J = 4.0 Hz, 1H), 7.75 – 7.69 ( m, 2H), 7.27 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.51 ( s, 2H), 3.89 (s, 3H), 3.65 – 3.61 (m, 2H), 3.60 (s, 3H), 2.81 (d, J = 4.0 Hz, 3H), 2.78 – 2.74 (m, 2H). 487.2 [M+H] ⁺ 73

(400 MHz, DMSO- d6) δ : 11.43 (s, 1H), 10.41 (s, 1H), 9.12-9.08 (m, 1H), 9.07 (s, 1H), 8.80 - 8.78 (m,, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.76 (d , J = 1.8 Hz, 1H), 7.70 – 7.61 (m, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 4.47 (s, 2H), 3.82 – 3.74 (m, 2H), 3.53 (s, 3H), 2.94- 2.90 (m, 2H) , 2.86 (d, J = 4.8 Hz, 3H). 485.2 [M+H] ⁺ 74

(400 MHz, DMSO- d6 ) δ: 11.10 (s, 1H), 9.81 (s, 1H), 9.09 (d, J = 1.3 Hz, 1H), 8.81 – 8.76 (m, 1H), 8.73 (s, 1H ), 8.64 (d, J = 2.5 Hz, 1H), 8.52 (d, J = 4.5Hz, 1H), 8.49 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.63 – 7.53 (m , 1H), 7.29 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.86 – 3.72 (m, 2H), 3.52 (s, 3H), 2.96 – 2.84 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H). 484.2 [M+H] ⁺ 75

(400 MHz, DMSO- d ₆ ) δ : 10.95 (s, 1H), 9.62 (s, 1H), 8.59 (s, 1H), 8.47 (d, J = 4.4 Hz, 1H), 8.44 (s, 1H) , 7.76 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 4.68 (s, 2H), 3.91 (s, 3H), 3.81 – 3.77 (m, 2H), 3.58 (s, 3H), 2.89 – 2.85 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H), 1.87 – 1.82 (m, 1H), 0.90 – 0.85 (m, 2H), 0.58 – 0.53 (m, 2H) . 526.3 [M+H] ⁺ 76

(400 MHz, DMSO- d ₆ ) δ: 10.97 (s, 1H), 9.79 (s, 1H), 8.71 (s, 1H), 8.50 (d, J = 4.0 Hz, 1H), 8.42 (s, 1H) , 7.77 (d, J = 2.0 Hz, 1H), 7.61-7.53 (m, 2H) , 7.41(d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.75 (t, J = 4.8 Hz, 2H), 3.60 (s, 3H), 2.86 (t, J = 4.8 Hz, 2H), 2.08 (s, 1H), 0.76-0.57 (m, 4H). 512.2 [M+H] ⁺ . 77

(400 MHz, DMSO- d ₆ ) δ : 11.00 (s, 1H), 9.79 (s, 1H), 8.71 (s, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.47 (s, 1H) , 7.76 (d, J = 2.0 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.41 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.75 (t, J = 4.8 Hz, 2H), 3.58 (s, 3H), 3.32 - 3.22 (m, 2H), 2.84 (t, J = 4.8 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). 500.3 [M+H] ⁺ . 78

(400 MHz, DMSO- d ₆ ) δ : 9.73 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.65 - 7.49 (m, 2H), 7.40 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H) , 4.43-4.37 (m, 4H), 3.91 (s, 3H), 3.74 (t, J = 4.8 Hz, 2H), 3.65 - 3.57 (m, 5H), 2.84 (t, J = 4.8 Hz, 2H), 1.96 (t, J = 5.2 Hz, 2H). 512.3 [M+H] ⁺ 79

(400 MHz, DMSO- d ₆ ) δ: 10.99 (s, 1H), 9.80 (s, 1H), 8.71 (s, 1H), 8.67 (s, 2H), 8.47 (br. s, 2H), 7.68 ( s, 1H), 7.60 - 7.56 (m, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.97 (s, 3H), 3.76 - 3.73 (m, 2H), 3.67 (s, 3H), 2.89 - 2.85 (m, 2H). 517.2 [M+H] ⁺ 80

(400 MHz, DMSO- d ₆ ) δ: 11.30 (s, 1H), 10.21 (s, 1H), 9.03 (s, 1H), 8.90 (s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 1.6 Hz, 1H), 4.68 (s, 2H), 3.88 (s, 3H), 3.77 - 3.74 (m, 2H), 3.56 (s, 3H), 2.88-2.84 (m, 2H), 2.82 (d, J = 4.8 Hz, 3H), 1.85 - 1.80 (m, 1H), 0.89 - 0.83 (m, 2H), 0.58 - 0.52 (m, 2H). 527.2 [M+H] ⁺ 81

(400 MHz, DMSO- d ₆ ) δ :11.31 (s, 1H), 10.38 (s, 1H), 9.07 (d, J = 4.4 Hz, 1H), 9.05 (s, 1H), 8.68 (s, 2H) , 7.70 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 6.8 Hz, 1H) , 4.45 (s, 2H), 3.98 (s, 3H), 3.77 - 3.72 (m, 2H), 3.67 (s, 3H), 2.92 - 2.87 (m, 2H), 2.85 (d, J = 4.4 Hz, 3H ). 515.2 [M+H] ⁺ 82

(400 MHz, DMSO- d ₆ ) δ: 11.32 (s, 1H), 10.38 (s, 1H), 9.05 (br. s, 2H), 8.68 (s, 2H), 7.69 (d, J = 1.6 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.45 ( s, 2H), 3.98 (s, 3H), 3.76 - 3.73 (m, 2H), 3.68 (s, 3H), 2.91 - 2.87 (m, 2H). 518.2 [M+H] ⁺ 83

(400 MHz, DMSO) δ :11.05 (s, 1H), 9.80 (s, 1H), 8.70 (s, 1H), 8.63 (d, J = 1.2 Hz, 1H), 8.51 (d, J = 4.4 Hz, 1H), 8.47 (s, 1H), 8.39 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.26 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 5.25-5.20 (m, 1H), 4.42 (s, 2H), 3.78 - 3.72 (m , 2H), 3.52 (s, 3H), 2.91-2.85 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.45 (dd, J = 10.2, 7.2 Hz, 2H), 2.19 - 2.10 ( m, 2H), 1.84 - 1.81 (m, 1H), 1.73 - 1.65 (m, 1H). 554.2 [M+H] ⁺ 84

(400 MHz, DMSO- d ₆ ) δ:11.04 (s, 1H), 9.81 (s, 1H), 9.17 (s,2H), 8.72 (s, 1H), 8.51 – 8.48 (m, 2H), 7.77 ( d, J = 1.6 Hz ,1H), 7.61 - 7.57 (m,1H), 7.42 - 7.15 (t, J =55.2 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 4.43 (s, 2H), 3.75 (t, J = 4.4 Hz, 2H), 3.71 (s, 3H), 2.89 (t, J = 5.2 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H). 534.1 [M+H] ⁺ . 85

(400 MHz, DMSO- d ₆ ) δ :11.00 (s, 1H), 9.80 (s, 1H), 8.91 (s, 2H), 8.71 (s, 1H), 8.51 - 8.47 (m, 2H), 7.73 ( d, J = 2.0 Hz, 1H), 7.65 - 7.47 (m, 1H), 7.61 - 7.57 (m, 1H), 7.26 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H ), 6.83 (d, J = 7.6 Hz, 1H), 4.43 (s, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.69 (s, 3H), 2.89 (t, J = 5.2 Hz, 2H ), 2.79 (d, J = 4.4 Hz, 3H). 550.2 [M+H] ⁺ 86

(400 MHz, DMSO- d ₆ ) δ : 11.32 (s, 1H), 10.38 (s, 1H), 9.08 - 9.05 (m, 2H), 8.79 (s, 2H), 7.72 (s, 1H), 7.68 - 7.64 (m, 1H), 7.29 (d, J = 1.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.46 (s, 2H), 3.75 (t, J = 4.4 Hz, 2H), 3.68 (s, 3H), 2.90 (t, J = 4.8 Hz, 2H), 2.86 (d, J = 4.8 Hz, 3H), 2.35 (s, 3H). 499.1 [M+H] ⁺ 87

(400 MHz, DMSO- d ₆ ) δ: 11.31 (s, 1H), 10.21 (s, 1H), 9.11 (s, 2H), 8.74 (s, 1H), 8.68 (s, 1H), 8.49 (d, J = 9.2 Hz, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 4.45 ( s, 2H), 3.78 - 3.74 (m, 2H), 3.68 (s, 3H), 3.05 (s, 3H), 2.94 - 2.90 (m, 2H), 2.80 (d, J = 4.0 Hz, 3H), 1.29 - 1.20 (m, 1H), 0.65 - 0.59 (m, 2H), 0.54 - 0.48 (m, 2H). 581.3 [M+H] ⁺ 88

(400 MHz, DMSO) δ: 11.08 (s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.55 - 8.53 (m, 2H), 8.26 (s, 1H), 8.14 (s, 1H ), 7.62 - 7.56 (m, 2H), 7.30 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H), 4.42 (s, 2H), 3.77 -3.73 (m, 2H), 3.59 (s, 3H), 3.56 (s, 3H), 2.88-2.84 (m, 2H), 2.79 (d, J = 3.6 Hz, 3H). 514.2 [M+H] ⁺ 89

(400 MHz, DMSO- d ₆ ) δ: 11.03 (s, 1H), 9.81 (s, 1H), 9.02 (s, 2H), 8.72 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H) , 8.48 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.60 – 7.56 (m, 1H), 7.32 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.76 – 3.73 (m, 2H), 3.71 (s, 3H), 3.05 (s, 6H), 2.91 – 2.87 (m , 2H), 2.79 (d, J = 4.4 Hz, 3H). 555.2 [M+H] ⁺ 90

(400 MHz, DMSO- d ₆ ) δ : 11.04 (s, 1H), 9.81 (s, 1H), 9.38 (s,2H), 8.72 (s, 1H), 8.52 - 8.48 (m, 2H), 7.78 ( d, J = 1.6 Hz ,1H), 7.61 - 7.57 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.76 (t, J = 4.8 Hz, 2H), 3.73 (s, 3H), 2.90 (t, J = 4.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.70 (s, 3H). 526.1 [M+H] ⁺ 91

(400 MHz, DMSO- d ₆ ) δ : 11.05 (s, 1H), 9.81 (s, 1H), 9.42 (s, 2H), 8.71 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H) , 8.48 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.61 - 7.57 (m, 1H),7.38 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.72 (s, 3H), 2.90 (t, J = 4.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H). 509.1 [M+H] ⁺ 92

(400 MHz, DMSO- d ₆ ) δ: 10.97 (s, 1H), 9.78 (s, 1H), 8.70 (s, 1H), 8.65 (s, 2H), 8.48 (d, J = 4.4 Hz, 1H) , 8.46 (s, 1H), 7.67 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 4.29 - 4.23(m, 2H), 3.76 - 3.72 (m, 2H), 3.66 (s, 3H), 2.88 - 2.82 (m, 2H), 2.78 (d, J = 4.0 Hz, 3H), 1.39 (t, J = 6.8 Hz, 3H). 528.3 [M+H] ⁺ 93

(400 MHz, DMSO- d ₆ ) δ: 10.98 (s, 1H), 9.79 (s, 1H), 8.75 (s, 2H), 8.70 (s, 1H), 8.49 (d, J = 4.4 Hz, 1H) , 8.47 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 4.18 - 4.14 (m, 1H), 3.76 - 3.72 (m, 2H), 3.68 (s, 3H), 2.89 - 2.84 (m, 2H), 2.78 (d, J = 4.4 Hz, 3H), 0.91 - 0.86 (m, 2H), 0.81 - 0.77 (m, 2H). 540.2 [M+H] ⁺ 94

(400 MHz, DMSO- d ₆ ) δ :11.02 (s, 1H), 9.80 (s, 1H), 9.09 (s, 2H), 8.72 (s, 1H), 8.50 (d, J = 4.4 Hz, 1H) , 8.47 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.0, 7.2 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.77 - 3.73 (m, 2H), 3.71 (s, 3H), 3.58 - 3.50 (m, 4H ), 2.91 - 2.86 (m, 2H), 2.78 (d, J = 4.4 Hz, 3H), 1.92 - 1.86 (m, 4H). 581.2 [M+H] ⁺ 95

(400 MHz, DMSO- d ₆ ) δ :11.02 (s, 1H), 9.81 (s, 1H), 9.18 (s, 2H), 8.71 (s, 1H), 8.50 (t, J = 4.4 Hz, 2H) , 7.76 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.72 (s, 3H), 2.89 (t, J = 4.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.14 (t, J = 19.2 Hz, 3H). 548.2 [M+H] ⁺ 96

(400 MHz, DMSO- d ₆ ) δ: 11.19 (s, 1H), 10.08 (s, 1H), 8.71-8.65 (m, 3H), 8.65 - 8.61 (m, 1H), 8.46 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 3.75 – 3.71 (m, 2H), 3.65 (s, 3H), 2.89-2.85 (m, 2H), 2.78 (d, J = 4.6 Hz, 3H), 2.01 -1.97 (m, 1H), 1.09 – 1.05 (m, 2H), 0.92 – 0.88 (m, 2H). 524.2 [M+H] ⁺ 97

(400 MHz, DMSO- d ₆ ) δ :11.04 (s, 1H), 9.81 (s, 1H), 9.26 (s, 2H), 8.86 (d, J = 4.4 Hz, 1H), 8.72 (s, 1H) , 8.51 (d, J = 4.4 Hz, 1H), 8.48 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 3.77 - 3.73 (m, 2H), 3.70 (s, 3H), 2.92 - 2.87 (m, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.78 (d, J = 4.4 Hz, 3H). 541.2 [M+H] ⁺ 98

(400 MHz, DMSO) δ: 11.08 (s, 1H), 9.79 (s, 1H), 8.72 (s, 1H) ,8.51 - 8.47 (m, 2H), 8.26 (s, 1H), 8.14 (s, 1H) ), 7.60 - 7.56 (m, 2H), 7.29 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz,1H), 4.42 (s , 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.59 (s, 3H), 3.55 (s, 3H), 2.85 (t, J = 4.4 Hz, 2H), 2.79 (d, J = 4.4 Hz , 3H). 514.2 [M+H] ⁺ 99

(400 MHz, DMSO- d ₆ ) δ :11.38 (s, 1H), 10.41 (s, 1H), 9.00 (s, 2H), 8.78 - 8.71 (m, 2H), 8.51 (s, 1H), 7.73 - 7.69 (m, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.00 - 6.96 (m, 2H), 4.46 (s, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.70 (s , 3H), 2.91 (t, J = 4.8 Hz, 2H), 2.81 (d, J = 4.4 Hz, 3H), 1.54 (s, 6H). 542.2 [M+H] ⁺ 100

(400 MHz, DMSO- d ₆ )δ :10.98 (s, 1H), 9.80 (s, 1H), 8.71 (s, 1H), 8.64 (s, 2H), 8.49 (d, J = 4.4 Hz, 1H) , 8.46 (s, 1H), 7.67 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H) , 6.81 (d, J = 7.2 Hz, 1H), 4.91 - 4.85 (m, 1H), 4.42 (s, 2H), 3.76 - 3.71 (m, 2H), 3.67 (s, 3H), 2.89 - 2.84 (m , 2H), 2.78 (d, J = 4.4 Hz, 3H), 1.35 (d, J = 6.0 Hz, 6H). 542.2 [M+H] ⁺ 101

(400 MHz, DMSO- d ₆ ) δ :10.98 (s, 1H), 9.79 (s, 1H), 8.70 (s, 1H), 8.65 (s, 2H), 8.49 (d, J = 4.4 Hz, 1H) , 8.46 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.19 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 4.06 (d, J = 7.2 Hz, 2H), 3.76 - 3.72 (m, 2H), 3.66 (s, 3H), 2.88 - 2.84 (m, 2H), 2.78 (d, J = 4.4 Hz, 3H), 1.31 - 1.26 (m, 1H), 0.64 - 0.60 (m, 2H), 0.38 (d, J = 6.0 Hz, 2H) . 554.2 [M+H] ⁺ 102

(400 MHz, DMSO- d ₆ ) δ: 11.09 (s, 1H), 9.81 (s, 1H), 8.74 – 8.73 (m, 2H), 8.51 (d, J = 4.4 Hz, 1H), 8.47 (s, 1H), 7.96 – 7.93 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.0, 7.2 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.78 - 3.75 (m, 2H), 3.50 (s, 3H), 3.03 (s , 3H), 3.00 (s, 3H), 2.90 - 2.86 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H). 554.2 [M+H] ⁺ 103

(400 MHz, DMSO- d ₆ ) δ :11.10 (s, 1H), 9.81 (s, 1H), 9.24 (dd, J = 4.8, 1.6 Hz, 1H), 8.74 (s, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.48 (s, 1H), 8.06 (dd, J = 8.4, 1.6 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.61 - 7.56 (m, 1H), 7.30 (d , J = 1.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.80-3.75 (m, 2H), 3.47 (s, 3H), 2.93 - 2.88 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H). 484.2 [M+H] ⁺ 104

(400 MHz, DMSO- d ₆ ) δ: 11.03 (s, 1H), 9.82 (s, 1H), 9.23 (s, 2H), 8.85 (d, J = 4.0 Hz, 1H), 8.72 (s, 1H) , 8.51 (d, J = 4.4 Hz, 1H), 8.47 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.77 - 3.73 (m, 2H), 3.69 (s, 3H), 2.92 - 2.87 (m, 3H), 2.78 (d, J = 4.4 Hz, 3H), 0.77 - 0.73 (m, 2H), 0.64 - 0.60 (m, 2H). 567.2 [M+H] ⁺ 105

(400 MHz, DMSO- d ₆ ) δ: 11.03 (s, 1H), 9.81 (s, 1H), 9.13 (s, 2H), 8.72 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H) , 8.48 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.4, 7.6 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.47 (t, J = 7.6 Hz, 2H), 4.42 (s, 2H), 4.11 (t, J = 7.6 Hz, 2H) , 3.76 - 3.73 (m, 2H), 3.71 (s, 3H), 2.91 - 2.87 (m, 2H), 2.78 (d, J = 4.4 Hz, 3H), 2.34 - 2.29 (m, 2H). 567.2 [M+H] ⁺ 106

(400 MHz, DMSO- d ₆ ) δ: 11.04 (s, 1H), 9.81 (s, 1H), 9.30 (s, 2H), 8.72 (s, 1H), 8.50 (d, J = 4.4 Hz, 1H) , 8.48 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.77 - 3.73 (m, 2H), 3.70 (s, 3H), 2.91 - 2.88 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H). 528.10 [M+H] ⁺ 107

(400 MHz, DMSO- d ₆ ) δ : 10.98 (s, 1H), 9.78 (s, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.67 (s, 1H), 8.49 - 8.45 (m, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.24 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.79 ( d, J = 7.2 Hz, 1H), 4.40 (s, 2H), 3.72 (t, J = 4.4 Hz, 2H), 3.64 (s, 3H), 2.85 (t, J = 4.8 Hz, 2H), 2.76 ( d, J = 4.4 Hz, 3H), 1.98 - 1.94 (m, 2H), 1.89 - 1.85 (m, 2H). 549.3 [M + H] ⁺ . 108

(400 MHz, DMSO- d ₆ ) δ: 11.03 (s, 1H), 9.81 (s, 1H), 9.29 (s, 2H), 8.72 (s, 1H), 8.50 (d, J = 4.4 Hz, 1H) , 8.48 (s, 1H), 8.36 (s, 1H), 7.83 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.60 – 7.56 (m, 1H), 7.32 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.77 - 3.73 (m, 2H), 3.70 (s, 3H ), 2.91 - 2.87 (m, 2H), 2.78 (d, J = 4.4 Hz, 3H). 527.2 [M+H] ⁺ 109

(400 MHz, DMSO- d ₆ ) δ : 11.00 (s, 1H), 10.47 (s, 1H), 9.80 (s, 1H), 9.09 (s, 2H), 8.71 (s, 1H), 8.49 - 8.47 ( m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.24 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.67 (s, 3H), 2.87 (t, J = 4.8 Hz, 2H), 2.78 (d, J = 4.4 Hz, 3H), 2.14 (s, 3H). 541.3 [M+H] ⁺ 110

(400 MHz, DMSO- d ₆ ) δ :11.01 (s, 1H), 9.80 (s, 1H), 8.89 (s, 1H), 8.72 (s, 1H), 8.49 (d, J = 4.8 Hz, 1H) , 8.47 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 5.02 (s, 2H), 4.42 (s, 2H), 3.76 - 3.72 (m, 2H), 3.68 ( s, 3H), 2.90 - 2.86 (m, 2H), 2.78 (d, J = 4.0 Hz, 3H). 526.1 [M+H] ⁺ 111

(400 MHz, DMSO- d ₆ ) δ :11.55 (s, 1H), 10.60 (s, 1H), 8.83 (s, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 1.6 Hz , 1H), 7.55 (dd, J = 8.4, 2.8 Hz, 1H), 7.39 (s, 1H), 7.05-7.49 (m, 2H), 4.47 (s, 2H), 3.90 (s, 3H), 3.79 - 3.75 (m, 2H), 3.48 (s, 3H), 2.93 - 2.87 (m, 2H), 2.82 (d, J = 4.4 Hz, 3H). 513.2 [M+H] ⁺ 112

(400 MHz, DMSO- d ₆ ) δ: 11.06 (s, 1H), 9.79 (s, 1H), 8.71 (s, 1H), 8.50 (d, J = 4.4 Hz, 1H), 8.47 (s, 1H) , 8.36 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H) , 6.98 (d, J = 8.4 Hz, 1H), 6.94 – 6.90 (m, 2H), 6.82 (d, J = 7.2 Hz, 1H), 4.43 (s, 2H), 3.91 (s, 3H), 3.79 - 3.75 (m, 2H), 3.38 (s, 3H), 2.88 - 2.84 (m, 2H), 2.79 (d, J = 4.0 Hz, 3H). 513.2 [M+H] ⁺ 113

(400 MHz, DMSO- d ₆ ) δ :10.99 (s, 1H), 9.76 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H) , 7.57 (t, J = 8.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.12 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.79 - 3.74 (m, 2H), 3.73 (s, 3H), 3.57 (s, 3H), 3.10 (s, 6H ), 2.85 - 2.80 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H). 556.2 [M+H] ⁺ 114

(400 MHz, DMSO- d ₆ ) δ: 11.11 (s, 1H), 9.82 (s, 1H), 9.09 (d, J = 1.6 Hz, 1H), 8.78 (dd, J = 2.4, 1.6 Hz, 1H) , 8.73 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.51-8.47 (m, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.52 (s, 3H), 2.9 (t, J = 4.8 Hz, 2H). 487.2 [M+H] ⁺

Biological activity test The inhibitory effect of the compound of the present invention on TYK2 kinase or TYK2 signaling pathway and other in vivo and in vitro effects are further described below through specific embodiments, so as to show that the compound of the present invention can be effectively used in the treatment of TYK2 target-related diseases. The beneficial effects of the compound of the present invention include but are not limited to the following specific implementation content.

Experimental example 1, compound of the present invention binds to TYK2 JH2 pseudokinase and inhibits activity to JAK1/2/3 TYK2 kinase. Inhibition of JAK1/2/3 TYK2 kinase activity, TYK2 JH2 pseudokinase binding and half-inhibitory concentration IC ₅₀ of JAK1/2/3 TYK2 kinase activity. 1. Experimental reagents Reagent name supplier ddH ₂ O Milli-Q Reference system TYK2/JH2 Bioduro Tracer (Homemade) (10mM in DMSO) Bioduro MAb Anti-6HIS Tb cryptate Gold-20000 tests Cisbio Hepes Invitrogen MgCl2 1M Sigma Brij L23 solution (Brij-35) Sigma DTT Sigma BSA Sigma Tofacitinib Selleck JAK1, 2, 3(JH1 Domain) Thermo TYK2(JH1 Domian) Carna HTRF® KinEASE™-TK 20000 tests kit Cisbio ATP solution (100mM) Sigma EGTA Sigma Brij-35 Sigma DTT Sigma MgCl2 Sigma MnCl2 Sigma 2. Experimental consumables name supplier 384 Well Low Volume White F-Bottom Polystyrene Hibase Med Binding Microplate Greiner 96-well plate-V bottom for CMPD dilution Greiner bio-one 384-LDV plate LABCYTE BioHit Multichannel Pipette tips BioHit 3. Experimental method 3.1 Prepare 1X experimental working solution TYK2 JH2 pseudokinase experimental buffer formula ingredients Storage concentration (mM) Final concentration (mM) Hepes pH7.5 1000 20 MgCl2 1000 10 Brij-35 5% 0.015% DTT 1000 2 BSA 100mg/mL (10%) 50ug/mL JAK1 JH1 Kinase Assay Buffer ingredients Storage concentration (mM) Final concentration (mM) 5X Enzymatic buffer 5X Enzymatic buffer 1X Enzymatic buffer MgCl2 1000 5 EGTA 455 0.625 SEB (µM) 2.5 0.06 Brij-35 0.05 0.0001 DTT 1000 1 JAK2,3 JH1 Kinase Assay Buffer ingredients Storage concentration (mM) Final concentration (mM) 5X Enzymatic buffer 5X Enzymatic buffer 1X Enzymatic buffer MgCl2 1000 5 DTT 1000 1 TYK2 JH1 Kinase Assay Buffer ingredients Storage concentration (mM) Final concentration (mM) 5X Enzymatic buffer 5X Enzymatic buffer 1X Enzymatic buffer MgCl2 1000 5 MnCl2 1000 1 SEB (µM) 2.5µM 0.0125µM DTT 1000 1 3.2 Pseudokinase experiments were performed as follows: Compounds were dissolved in DMSO to a stock concentration of 10 mM. A compound concentration of 200 times the final concentration was prepared in the compound dilution plate, and diluted from the highest concentration point according to the 27-fold dilution method, a total of 4 concentration points were transferred to the Echo plate. The compound was pulsed from the Echo plate to the 384 assay plate with the Echo instrument, so that the compound became a 3-fold dilution matrix with 11 concentration points. Add 5µL of 3X TYK2 JH2 kinase to the 384 assay plate. Add 5µL 3X Tb to the 384 assay plate. Add 5µL 3X Tracer to a 384-well assay plate. Centrifuge for 30 seconds and incubate at room temperature for 60 minutes. Envision microplate reader (PerkinElmer) 495/520 fluorescence signal value. 3.3 Kinase experiments were performed as follows: Compounds were dissolved in DMSO to a stock concentration of 10 mM. A compound concentration of 100 times the final concentration was prepared in the compound dilution plate, and diluted from the highest concentration point according to the 27-fold dilution method, a total of 4 concentration points were transferred to the Echo plate. The compound was pulsed from the Echo plate to the 384 assay plate with the Echo instrument, so that the compound became a 3-fold dilution matrix with 11 concentration points. Prepare 1X working solution containing kinase with the buffer corresponding to the kinase, and add 5 µL per well to a 384-well assay plate, and incubate the compound and kinase at room temperature for 15 minutes. Add 5ul matrix (containing ATP) per well to the 384-well plate. Incubate at room temperature for 45 minutes. Add the detection reagent mixture to the 384-well plate, centrifuge for 30 seconds, and incubate at room temperature for 60 minutes. Envision microplate reader (PerkinElmer) 665/615 fluorescence signal value. 3.4 Data analysis XL-Fit software was used for data analysis, and the IC50 of the compound was obtained. 4. Experimental results 4.1 The compounds of the examples of the present invention have good binding activity to TYK2 JH2 pseudokinase, and the binding activity does not exceed 30nM; when the binding activity< When 1nM, it is represented by letter A; when 1nM<binding activity≤5nM, it is represented by letter B; when binding activity>5nM, it is represented by letter C; see Table 1 for specific results. 4.2 The compounds of the examples of the present invention have no inhibitory activity on TYK2 JH1 kinase domain (IC50 is preferably greater than 10 μM); no inhibitory activity or weak inhibitory activity on JAK1/2/3 (IC50 is greater than 3 μM, preferably greater than 10 μM). Table 1 Binding activity of some compounds of the present invention to TYK2 JH2 pseudokinase domain Example number TYK2 binding activity (nM) Example number TYK2 binding activity (nM) Example number TYK2 binding activity (nM) Example 6-1 A Example 55 B Example 85 A Example 6-2 A Example 56 B Example 86 A Example 7 A Example 57 A Example 87 C Example 9 A Example 58 A Example 88 A Example 12 A Example 59 B Example 89 A Example 10 A Example 60 A Example 90 A Example 11 B Example 61 A Example 91 A Example 13 A Example 62 A Example 92 A Example 17 A Example 63 A Example 93 A Example 18 A Example 64 A Example 94 A Example 19 B Example 65 A Example 95 A Example 20 B Example 66 C Example 96 A Example 21 A Example 67 A Example 97 A Example 23 A Example 68 A Example 98 A Example 25 C Example 69 A Example 99 A Example 26 C Example 70 B Example 100 A Example 27 C Example 71 A Example 101 A Example 30 C Example 72 C Example 102 A Example 32 A Example 73 A Example 103 A Example 33 B Example 74 A Example 104 A Example 34 B Example 75 A Example 105 A Example 35 A Example 76 B Example 106 A Example 36 A Example 77 A Example 107 B Example 38 B Example 78 C Example 108 A Example 39 A Example 79 A Example 109 A Example 41 A Example 80 A Example 110 A Example 42 A Example 81 A Example 111 A Example 43 A Example 82 A Example 112 B Example 52 A Example 83 A Example 113 A Example 53 A Example 84 A Example 114 A Example 54 B

Experimental Example 2. Inhibitory activity of compounds of the present invention on TYK2 signaling pathway in PBMC cells 1. Experimental purpose: This experiment uses flow cytometry, adopts human PBMC, stimulates and activates TYK2 signaling pathway through IFNα, and detects the effect of compounds on CD3 T cells and its downstream The inhibitory activity of STAT5 phosphorylation, and the half inhibitory concentration IC ₅₀ of the compound on the activity of TYK2 signaling pathway was obtained. 2. Experimental materials: Human PBMCs were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd. 1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, and DPBS buffer were purchased from GIBCO. Fix buffer I, Perm buffer III were purchased from BD Biosciences. FITC CD3 antibody was purchased from Biolegend. Alexa647 pSTAT5 (pY694) antibody was purchased from BD Biosciences. Universal type I IFNα protein was purchased from R&D Systems. 96-well U-shaped cell culture plates were purchased from Coring Company. 3. Experimental instruments: The centrifuge (5810R) was purchased from Eppendorf Company, the pipette was purchased from RAMIN Company, and the Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD Company. 4. Experimental method: 1) The PBMC cells for analysis were thawed and suspended in 1640 medium containing 10% serum, and incubated in a carbon dioxide incubator for 1 hour. 2) Dilute the cells to 2.22E6 cells/ml so that there are 2E5 cells in 90µL per well. Add 10 µL of serially diluted compound (maximum concentration 10 µM, 1:3, 11 dilutions) or DMSO solution to each well, and incubate for 1 hour in a carbon dioxide incubator. 3) Stimulation: add 11µL IFNα (final concentration: 2000U/mL) to each well, and incubate in a carbon dioxide incubator for 30 minutes. 4) Fix: add 110µL preheated Fix buffer I, and incubate for 10 minutes in a carbon dioxide incubator. 5) Centrifuge at 400 g for 5 min at 4°C. Discard the supernatant and wash once with 250 µL FACS buffer (DPBS+1% FBS) per well. 6) Membrane rupture: Add 150 mL Perm buffer III and incubate on ice for 30 minutes. 7) Centrifuge at 400 g for 5 min at 4°C. Wash twice with 250µl FACS buffer (DPBS+1% FBS) per well. 8) Antibody incubation: Add diluted FITC-CD3 and Alexa647 pSTAT5 (pY694) antibodies (100 µL/well) to each well and incubate at room temperature for 1 hour. 9) Centrifuge at 400 g for 5 min at 4°C. Resuspend the cells in 100µL FACS buffer, and test on the machine. 5. Experimental data processing: The phosphorylation of STAT5 was quantified by the mean fluorescence intensity (MFI) of Alexa647 in CD3+ T cells, and the IC50 value was calculated by fitting different concentrations and corresponding MFI data to a 4-parameter nonlinear logic formula using GraphPad prism 8.0 . 6. Experimental results: Through the above scheme, it can be concluded that the IC ₅₀ of the compounds shown in the examples of the present invention in the activity experiment of inhibiting the TYK2 signaling pathway in cells does not exceed 10 μM; when the IC ₅₀ ≤ 50nM, it is represented by the letter A; when 50nM< When IC ₅₀ ≤100nM, it is represented by letter B; when IC ₅₀ >100nM, it is represented by letter C; see Table 2 for specific results. Table 2 Inhibitory activity of some compounds of the present invention on TYK2 signaling pathway in PBMC cells Example number PBMC pSTAT5 (IC ₅₀ , nM) Example number PBMC pSTAT5 (IC ₅₀ , nM) Example number PBMC pSTAT5 (IC ₅₀ , nM) Example 6-1 A Example 55 C Example 85 A Example 6-2 A Example 56 C Example 86 A Example 7 A Example 57 A Example 87 A Example 8 A Example 58 B Example 88 C Example 9 A Example 59 C Example 89 A Example 10 B Example 60 B Example 90 A Example 11 B Example 61 A Example 91 B Example 12 A Example 62 C Example 92 A Example 13 C Example 63 C Example 93 A Example 14 A Example 64 C Example 94 A Example 16 A Example 65 C Example 95 C Example 17 A Example 66 C Example 96 A Example 18 A Example 67 C Example 97 B Example 19 C Example 68 C Example 98 C Example 21 A Example 69 A Example 99 A Example 23 A Example 70 C Example 100 A Example 25 C Example 71 A Example 101 A Example 27 C Example 72 C Example 102 A Example 30 C Example 73 B Example 103 A Example 32 C Example 74 A Example 104 B Example 33 C Example 75 A Example 105 A Example 34 C Example 76 C Example 106 B Example 35 C Example 77 C Example 107 C Example 36 A Example 78 C Example 108 B Example 38 C Example 79 B Example 109 B Example 39 C Example 80 A Example 110 B Example 41 B Example 81 A Example 111 A Example 42 A Example 82 A Example 112 C Example 43 A Example 83 C Example 113 A Example 52 A Example 84 B Example 114 A Example 53 A

Experimental example 3, the inhibitory activity of the compound of the present invention on the JAK1/3 signaling pathway in PBMC cells 1. Experimental purpose: This experiment uses flow cytometry, adopts human PBMC, activates the JAK1/3 signaling pathway through IL-2 stimulation, and detects The inhibitory activity of the compound on the phosphorylation of downstream STAT5 of CD3 T cells, and the half inhibitory concentration IC ₅₀ of the compound on the activity of JAK1/3 signaling pathway. 2. Experimental materials: Human PBMCs were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd. 1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, and DPBS buffer were purchased from GIBCO. Fix buffer I, Perm buffer III were purchased from BD Biosciences. FITC CD3 antibody was purchased from Biolegend. Alexa647 pSTAT5 (pY694) antibody was purchased from BD Biosciences. IL-2 protein was purchased from Nearshore Protein Technology Co., Ltd. 96-well U-shaped cell culture plates were purchased from Coring Company. 3. Experimental equipment: The centrifuge (5810R) was purchased from Eppendorf Company. Pipettes were purchased from RAMIN Company. Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD Company. 4. Experimental method: 1) Thaw PBMC cells for analysis and suspend them in 1640 medium containing 10% serum, and incubate in a carbon dioxide incubator for 1 hour. 2) Dilute the cells to 2.22E6 cells/ml so that there are 2E5 cells in 90µL per well. Add 10 µL of serially diluted compound (maximum concentration 10 µM, 1:3, 11 dilutions) or DMSO solution to each well, and incubate in a carbon dioxide incubator for 1 hour. 3) Stimulation: Add 11µL IL-2 (final concentration: 20ng/ml) to each well and incubate in a carbon dioxide incubator for 20 minutes. 4) Fix: add 110µL preheated Fix buffer I, and incubate for 10 minutes in a carbon dioxide incubator. 5) Centrifuge at 400 g for 5 min at 4°C. Discard the supernatant and wash once with 250 µL FACS buffer (DPBS+1% FBS) per well. 6) Membrane rupture: Add 150µL Perm buffer III and incubate on ice for 30 minutes. 7) Centrifuge at 400 g for 5 min at 4°C. Wash twice with 250µL FACS buffer (DPBS+1% FBS) per well. 8) Antibody incubation: Add diluted FITC-CD3 and Alexa647 pSTAT5 (pY694) antibodies (100 µL/well) to each well and incubate at room temperature for 1 hour. 9) Centrifuge at 400 g for 5 min at 4°C. Resuspend the cells in 100µL FACS buffer, and test on the machine. 5. Experimental data processing: The phosphorylation of STAT5 was quantified by the mean fluorescence intensity (MFI) of Alexa647 in CD3+ T cells, and the IC ₅₀ was calculated by fitting different concentrations and corresponding MFI data to a 4-parameter nonlinear logic formula using GraphPad prism 8.0 value. 6. Experimental results: The experimental results show that the compounds of the examples of the present invention have no inhibitory activity or very weak inhibitory activity on the JAK1/3 signaling pathway in cells.

Experimental example 4, the inhibitory activity of the compound of the present invention on the JAK2 signaling pathway in U937 cells 1. Experimental purpose This experiment utilizes flow cytometry, adopts the U937 cell line, stimulates and activates the JAK2 signaling pathway through GM-CSF, and detects the effect of the compound on the JAK2 signaling pathway. The inhibitory activity of downstream STAT5 phosphorylation, and the half inhibitory concentration IC ₅₀ of the compound on JAK2 signaling pathway activity was obtained. 2. Experimental materials: U937 cell line was purchased from ATCC. 1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, and DPBS buffer were purchased from GIBCO. Fix buffer I and Perm buffer III were purchased from BD Biosciences. Alexa647 pSTAT5 (pY694) antibody was purchased from BD Biosciences. GM-CSF protein was purchased from Kaijia Biological Company. 96-well U-shaped cell culture plates were purchased from Coring Company. 3. Experimental equipment: A centrifuge (5810R) was purchased from Eppendorf. Pipettes were purchased from RAMIN Company. Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD Company. 4. Experimental method: 1) Resuspend the cells in good growth state to 1.11E6 cells/ml, so that there are 1E5 cells in 90 µL per well. Add 10 µL of serially diluted compound (maximum concentration 10 µM, 1:3, 10 dilutions) or DMSO solution to each well, and incubate for 1 hour in a carbon dioxide incubator. 2) Stimulation: Add 11 µL of GM-CSF (final concentration: 20 ng/mL) to each well and incubate for 15 minutes in a carbon dioxide incubator. 3) Fix: add 110µL preheated Fix buffer I, and incubate for 10 minutes in a carbon dioxide incubator. 4) Centrifuge at 400 g for 5 min at 4°C. Discard the supernatant and wash once with 250 µL FACS buffer (DPBS+1% FBS) per well. 5) Membrane rupture: Add 150µL Perm buffer III and incubate on ice for 30 minutes. 6) Centrifuge at 400 g for 5 min at 4°C. Wash twice with 250µL FACS buffer (DPBS+1% FBS) per well. 7) Antibody incubation: Add diluted Alexa647 pSTAT5 (pY694) antibody (100µL/well) to each well and incubate at room temperature for 1 hour. 8) Centrifuge at 400 g for 5 min at 4°C. Resuspend the cells in 100µL FACS buffer, and test on the machine. 5. Experimental data processing: The phosphorylation of STAT5 was quantified by the mean fluorescence intensity (MFI) of Alexa647, and the IC50 value was calculated by fitting different concentrations and corresponding MFI data to a 4-parameter nonlinear logic formula using GraphPad prism 8.0. 6. Experimental results: The experimental results show that the compounds of the examples of the present invention have no inhibitory activity or very weak inhibitory activity on the JAK2 signaling pathway in cells.

The experimental results of comprehensive experimental examples 2-4 show that the compound of the present invention has better selectivity to TYK2 kinase than JAK1/2/3, indicating that the compound of the present invention has important clinical applications that can effectively reduce side effects and improve safety value.

Experimental example 5. Inhibitory activity of compounds of the present invention on TYK2 in primary human Th17 cells In this experiment, phosphorylated STAT3 intracellular staining and flow cytometry were used to analyze the inhibitory effect of compounds on TYK2 activity in primary human Th17 cells , and the half inhibitory concentration IC50 of the compound inhibiting TYK2 activity was obtained. 1. Experimental materials Primary peripheral blood mononuclear cells (PBMC) from healthy people were purchased from Miaoshun Biotechnology. Human CD4+ T cell negative sorting kit was purchased from STEM CELL Company. 1640 medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from Gibco. Recombinant human IL6, IL1b, IL23 and TGFb were purchased from Novoprotein Company. Anti-human CD3 antibody and anti-human CD28 antibody were purchased from Biolegend Company. Anti-phosphorylated STAT3 flow cytometry antibody, cell fixation solution and membrane permeation solution were purchased from BD Bioscience. 2. Experimental method 2.1 In vitro induction and differentiation of primary human TH17 cells 1) Induction and differentiation of primary human TH17 cells in vitro: CD4+ T cells were sorted from PBMC cells of healthy people using a negative sorting kit for human CD4+ T cells Cells, according to the density of 40,000 cells per well, inoculate the sorted CD4+ T cells in the 96-well flat-bottomed plate pre-coated with anti-human CD3 antibody, 200 µL per well, and add anti-human CD28 antibody and four kinds of cells at the same time Factors: IL6, IL23, IL1b and TGFb, cultured in a cell culture incubator (37°C, 5% CO2) for 7 to 10 days, half of the fresh medium containing differentiation-inducing stimuli was renewed every other day. 2) Deactivation of primary human TH17 cells: Collect the induced TH17 in a 50mL centrifuge tube, collect the cells by centrifugation, and resuspend them in the basic fresh medium, and seed the cells in a new 96-well flat-bottomed plate, each well 200 µL, cultured overnight in a cell culture incubator (37°C, 5% CO ₂ ). 2.2 Inhibition test of test compound on STAT3 phosphorylation in primary human TH17 cells 1) Inoculate primary human TH17 cells in the deactivated state in a 96-well flat-bottomed plate at a density of 150,000 cells per well. 120 µL. 2) Add 40 µL of the compound to be tested in a gradient dilution to the cell culture medium on the culture plate, mix gently, and culture in a cell culture incubator (37°C, 5% CO ₂ ) for 1 hour. 3) Add 40 ul of diluted recombinant human IL23 to the cell culture medium on the culture plate, mix gently, and culture in a cell culture incubator (37°C, 5% CO ₂ ) for 0.5 hours. 4) Phosphorylated STAT3 staining: collect the cells by centrifugation, wash once with pre-cooled PBS, add the prepared Live/Dead dye, incubate at room temperature for 10 minutes, wash once with pre-cooled flow staining solution, add 37°C preheated Fixative, fixed at 37°C for 15 minutes, washed twice with pre-cooled flow staining solution, added pre-cooled permeabilization solution, fixed at 4°C for 0.5 hours, washed twice with pre-cooled flow staining solution, added the prepared anti-membrane solution Phosphorylated STAT3 antibody staining solution, incubated at 4°C for 0.5 hours, washed twice with pre-cooled flow staining solution, resuspended cells in each well in 200 µL flow staining solution, and collected data information on the flow cytometry machine. 3. Experimental data processing The Flowjo software was used to analyze the flow data, and the GraphPad Prism 6 software was used for statistical analysis of the data, and the IC ₅₀ of the compound on phosphorylated STAT3 was obtained. 4. Experimental results The experimental results show that some of the compounds of the present invention have good inhibitory activity on the TYK2 signaling pathway activated by IL-23 in primary human Th17 cells, with IC ₅₀ not exceeding 10 nM.

Experimental example 6. Inhibitory activity of the compounds of the present invention on the TYK2 signaling pathway in NK-92 cells 1. Experimental purpose: This experiment uses enzyme-linked immunosorbent assay (ELISA), using NK-92 cells, through IL-12 and IL-18 stimulates and activates the TYK2 signaling pathway, detects the inhibitory effect of the compound on the expression level of IFNγ secreted by NK-92 cells, and obtains the half inhibitory concentration IC ₅₀ of the compound on the activity of the TYK2 signaling pathway. 2. Experimental materials: NK-92 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. MEMα medium, fetal bovine serum (FBS), Penicillin-Streptomycin, and 2-ME were purchased from GIBCO. Horse serum (Horse serum) was purchased from Hyclone Company. IL-12 and IL-18 proteins were purchased from Nearshore Protein Technology Co., Ltd. IL-12 protein was purchased from Sino Biologicals. Company. Folic acid was purchased from Sigma Company. ELISA coated plates were purchased from Thermo Fisher Scientific. Human IFNγ ELISA kit, Stop Solution was purchased from Biolegend Company. 3. Experimental equipment: A centrifuge (5810R) was purchased from Eppendorf. Pipettes were purchased from RAMIN Company. Envision multifunctional microplate reader was purchased from PerkinElmer. 4. Experimental method: 1) Collect NK-92 cells in good growth state and resuspend in complete medium without IL-12 (MEMα+12.5% FBS+12.5 % Horse serum+0.1 mM 2-ME+0.02mM folic acid ), count, and dilute the cells to 1.11E6 cells/ml, so that there are 1E5 cells in 90 µL per well. 2) Add 10µL of serially diluted compound (maximum concentration 10µM, 1:3, 11 dilutions) or DMSO solution to each well, and add IL-12 (2ng/mL) and IL-18 (5ng/mL ), and incubated in a carbon dioxide incubator for 24 hours. 3) Collect the cell supernatant, and detect the level of IFNγ according to the instructions of the human IFNγ ELISA kit. 4) Read the absorbance at 450nm and 570nm. 5) Calculate the IFNγ value of each sample according to the standard. 5. Experimental data processing: Use GraphPad prism 8.0 to fit different concentrations and corresponding IFNγ values to a 4-parameter nonlinear logic formula, and calculate the IC50 value. 6. Experimental results: Experimental results show that some of the compounds of the present invention have good inhibitory activity on the TYK2 signaling pathway activated by IL-12 in NK-92 cells, and their IC ₅₀ does not exceed 100nM.

Experimental Example 7. Determination of the pharmacokinetics of the compound of the present invention in C57BL/6 mice Taking C57BL/6 mice as the test animals, the compound of the present invention was studied under the intravenous injection of 1 mg/kg and the dose of 5 mg/kg. Pharmacokinetic behavior of plasma in mice after oral administration. 1. Experimental scheme 1.1 Experimental drugs: some compounds of the present invention. 1.2 Experimental animal C57BL/6 6 (3 animals/group), male, Shanghai Lingchang Biotechnology Co., Ltd., animal production license number (SCXK (Shanghai) 2018-0003). 1.3 Administration: 6 C57BL/6 mice, male; iv and po respectively after free feeding, the dose of IV administration was 1 mg/kg, and the administration volume was 5 mL/kg; the dose of PO administration was 10 mg/kg kg, the administration volume is 10 mL/kg. 1.4 Experimental Equipment Centrifuge (5810 R) was purchased from Eppendorf Company, the pipette was purchased from Eppendorf Company, and the vortex instrument was purchased from Scientific Industries Company. At 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, 0.1 mL of blood was collected from the saphenous vein, placed in an EDTA-K2 test tube, centrifuged at 4600 rpm at 4 °C for 5 min, and the plasma was separated, and placed in - Store at 80°C. 1.6 Sample processing 1) Add 50 µL of plasma sample to 200 µL methanol/acetonitrile (1/1) for precipitation, mix and centrifuge at 2773 X g for 15 minutes. 2) Take 50 µL of the treated supernatant solution and dissolve it in the diluent (methanol/water=1/1 containing 0.1% formic acid), and analyze the concentration of the test compound by LC/MS/MS. 1.7 Liquid phase analysis Liquid phase conditions: Shimadzu LC-30AD pump Mass spectrometry conditions: AB Sciex API 5500 mass spectrometer chromatographic column: Phenomenex Kinetex 2.6 µm C18 50 3.0 mm Mobile phase: Liquid A is 0.1% formic acid 50 millimolar ammonium acetate solution, Solution B is 0.1% formic acid in acetonitrile Flow rate: 0.7 mL/min Elution time: Gradient elution 0-3.0 minutes. 2. Experimental results and analysis The main parameters of pharmacokinetics are calculated by WinNonlin 8.0. The pharmacokinetic parameters of intravenous injection and oral administration of drugs in mice are shown in Table 3 and Table 4 below: Table 3 Pharmacokinetic parameters Example Dose (mg/kg) CL (mL/min/kg) Vss (L/kg) T _1/2 (hr) MRT _Inf (hr) AUC (hr*ng/mL) Example 8 0.973 14.3 2.32 3.17 2.71 1133 Example 9 1 22.6 2.68 2.09 1.97 740 Example 16 1 30.9 1.9 1.27 1.04 541 Example 17 1 11.6 0.842 1.45 1.22 1482 Example 18 1 20.8 3.05 2.8 2.51 816 Example 44 1 6.72 1.11 2.43 2.76 2511 Example 52 1 7.29 0.92 3.39 2.08 2306 Example 71 1 14.9 0.943 1.19 1.05 1122 Example 81 1 18.2 1.92 1.68 1.75 899 Example 82 1 23.1 2.71 2.12 1.96 722 Example 100 1 10.8 0.487 1.08 0.748 1549 Example 111 1 6.88 0.755 1.47 1.84 2432 Table 4 mice oral pharmacokinetic parameters of some compounds of the present invention Example number Dose (mg/kg) C _max (ng/mL) AUC (hr*ng/mL) T _1/2 (hr) MRT _Inf (hr) F (%) Example 8 10 1593 18134 2.9 5.87 156 Example 9 10 2063 10874 3.01 4.34 147 Example 16 10 1627 9475 3.03 4.8 175 Example 17 10 3543 20320 2.73 4.34 137 Example 18 10 1237 7487 2.71 4.53 91.7 Example 44 10 3107 23053 2.2 4.99 91.8 Example 52 10 5777 24845 2.12 3.78 108 Example 71 10 2743 16613 2.26 4.35 148 Example 81 10 1380 9107 3.6 6.42 101 Example 82 10 1703 8477 2.93 4.53 117 Example 100 10 3837 11459 3.99 5.5 74.2 Example 111 10 3223 27251 3.38 5.47 112 The main parameters of pharmacokinetics are calculated with WinNonlin 8.0, and the experimental results show that the compounds of the embodiments of the present invention exhibit good pharmacokinetic properties in animals, with good exposure, suitable clearance rate and half-life, preferably The bioavailability indicates that the compound of the present invention has good clinical application potential.

Experimental Example 8 Study on the efficacy of the compound of the present invention in the psoriasis-like model of mice induced by imiquimod (IMQ) Drug efficacy in psoriasis-like model 2. Experimental method: 2.1 Experimental equipment Equipment name model factory Electronic balance QUINTIX124-1CN Mettler-Toledo Instruments (Shanghai) Co., Ltd. electronic scale YP10001 Shanghai Yueping Scientific Instrument Co., Ltd. ultrasonic cleaner KQ3200E Kunshan Ultrasonic Instrument Co., Ltd. Vortex shaker Vortex-Genie2 (SI-0256) Scientific Industries Anesthesia Machine 50318 MIPs 2.2 Experimental reagents Reagent name manufacturers Item No. imiquimod cream (IMQ) 3M Health Care Limited Specification: 250mg: 12.5mg, batch number: GVJ013A PEG400 Sigma 81172 DMSO Anaiji Chemical E081359 Isoflurane Hebei Yipin H19980141 EtOH Adamas-beta 64-17-5 PEG300 MCE HY-Y0873 Vitamin E TPGS Sigma 57668-25G Some compounds of the present invention Qilu Pharma / 3. Experimental methods 3.1 Purchase of animals: Male BALB/c mice, weighing about 18-20 g, started the experiment after 7 days of adaptation. 3.2 Grouping: Randomly divided into 8 groups according to body weight, 10 rats in each group of 1-4 groups, and 8 rats in each group of 5-8 groups. 3.3 Psoriasis model establishment: 1) One day before applying IMQ, mice shaved their back hair (approximately 2×3 cm), and applied 82.5 mg of IMQ cream to each animal every day, 62.5 mg on the shaved part of the back, and left ear 20 mg for 7 consecutive days (from day 0 to day 6). The date of first application of IMQ is 0 days. 2) For the normal control group, 82.5 mg of Vaseline was applied to each animal per day, 62.5 mg on the shaved part of the back, and 20 mg on the left ear, for 7 consecutive days (from day 0 to day 6). 3) Drug treatment group: intragastric administration, twice a day, from the 0th day to the 6th day, a total of 7 days. 3.4 Drug treatment: From the 0th day to the 6th day, the vehicle and the compound were administered for 7 consecutive days, and the dosage and route of administration are shown in the table below. Grouping and dosing regimen group animal handling number of animals Dosing volume (mL/kg) Dosage (mg/kg) Route of administration Dosing frequency 1 model group 8 10 -- PO BID 7 days (day0-day6) and QD once (day 7); day 0-day7 2 drug group 8 10 30 PO 3 drug group 8 10 10 PO 3.5 Recording parameters: 1) Body weight: From the 0th day to the 7th day, the body weight of the mice was recorded every day. 2) Clinical disease scores for erythema, psoriasis, and thickness were performed daily according to the scoring system, and the total score was calculated. 3) Take photos on days 0, 3, 5, and 7 to observe changes in the skin. One picture was taken for each mouse, and three pictures were taken for each group, that is, three mice. 4) Measure the thickness of the left ear at 0, 3, 5, and 7 days. PASI scoring system: erythema, crusting, skin thickness Fraction Clinical symptoms 0 none 1 slight 2 Moderate 3 significant 4 very significant 3.6 Endpoint: On the seventh day of the experiment, after scoring, measuring, photographing and administration were completed, the mice in each group were euthanized by CO ₂ inhalation. 4. Experimental results The compound of the present invention can effectively improve the symptoms of psoriasis in the imiquimod-induced mouse psoriasis-like model.

none

none

Claims (37)

A compound represented by formula (II'),

Or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-6 alkyl, deuterated C _1-6 alkane Base, cycloalkyl; R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy; or R ¹ is connected to R ⁸ , and forms a heterocyclic ring with the nitrogen atom connected to it; X ¹ , X ² are independently selected from CH ₂ , NH, O; Ring C is selected from aryl, heteroaryl, cycloalkyl, heterocyclic; R is independently selected from R ² or R ³ ; n is selected from 0, 1, 2,3; R ² is selected from hydrogen, -OH, C _1-6 alkyl, deuterated C _1-6 alkyl, C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _{1-6 6} Alkyl-C(O)-, C _1-6 Alkyl-S-, C _1-6 Alkyl-S(O)-, C _1-6 Alkyl-S(O) ₂ -; R ³ optional from hydrogen, C _1-6 alkoxy-C(O)-, (R ⁵ )(R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, Heteroaryl, heterocyclyl, cycloalkyl; R ^a is selected from hydrogen, halogen, -CN, carboxyl, (R ⁵ )(R ⁶ )NC(O)-, C _1-6 alkyl, C _1-6 Alkyl-C(O)-, C _1-6 alkyl-C(O)-NH-, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl , C _1-6 alkoxy, cycloalkyl, cycloalkyl-(CH ₂ )pO-, NC-cycloalkyl, or any two adjacent R ^a are connected and together form a heterocyclic ring with the atoms to which they are connected; p is selected from 0, ¹ , 2, 3; L is selected from C _1-8 alkylene optionally substituted by one or more R ^b , one or more CH in the C _1-8 alkylene ₂ is optionally substituted by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/or -O-; R ^b is selected from C _1-6 alkane group, or two R ^b located on the same carbon atom and the carbon atom connected to it together form a cycloalkyl group, ^a heterocyclic group; or, L is selected from

, wherein the ring A end is connected to X ² , and the L ² end is connected to ring C; Ring A is selected from aryl, heteroaryl; L ² is selected from C _1-6 alkylene optionally substituted by one or more R ^c group, one or more CH ₂ in the C _1-6 alkylene group is optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O)-, -S(O) ₂ - and/or -O-substituted; R ^c is selected from C _1-6 alkyl, or two R ^c on the same carbon atom and the carbon atom connected to it together form a cycloalkyl, heterocyclic group; R ⁴ selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, phenyl, cycloalkyl, the phenyl is optionally replaced by one or more selected from halogen, C _1-6 alkane Substituted by group, C _1-6 alkoxy group or halogenated C _1-6 alkyl group; m is selected from 0, 1, 2, 3; R ⁵ , R ⁶ are independently selected from hydrogen, -OH, C _1-6 alkyl, cycloalkyl, or R ⁵ , R ⁶ are connected, and the nitrogen atom connected to it together forms a heterocyclic ring; R ⁷ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 alkyl-C(O)-, -C(O)OCH ₂ Ph. The compound as described in Claim 1, which has the structure shown in the following formula (I'),

Or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-6 alkyl, deuterated C _1-6 alkane Base, cycloalkyl; R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy; or R ¹ is connected to R ⁸ , and forms a 3-8 membered heterocyclic ring together with the nitrogen atom connected to it; R ² is selected from hydrogen, -OH, C _1-6 alkyl, deuterated C _1-6 alkyl, C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 alkyl- C(O)-, C _1-6 alkyl-S-, C _1-6 alkyl-S(O)-, C _1-6 alkyl-S(O) _2- ; R ³ is selected from hydrogen, C _1-6 alkoxy-C(O)-, (R ⁵ )(R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, heteroaryl, Heterocyclyl, cycloalkyl; R ^a is selected from hydrogen, halogen, -CN, carboxyl, (R ⁵ )(R ⁶ )NC(O)-, C _1-6 alkyl, C _1-6 alkyl-C (O)-, C _1-6 alkyl-C(O)-NH-, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _{1- 6} -alkoxy, 3-8-membered cycloalkyl, 3-8-membered cycloalkyl-(CH ₂ )pO-, NC-3-8-membered cycloalkyl, or any two adjacent R ^a are connected to each other The connected atoms together form a 3-8 membered heterocyclic ring; p is selected from 0, ¹ , 2, 3; L is selected from C _1-8 alkylene optionally substituted by one or more R ^b , said C ₁ One or more CH ₂ atoms in the _-8 alkylene group are optionally replaced by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/or- O-substituted; R ^b is selected from C _1-4 alkyl, or two R ^b on the same carbon atom and the carbon atom connected to it together form a 3-5 membered cycloalkyl group; or, L ¹ is selected from

, wherein the ring A end is connected to the NH of formula (I'), and the L ² end is connected to the benzene ring; Ring A is selected from phenyl, heteroaryl; L ² is selected from C optionally substituted by one or more R ^c _1-6 alkylene, one or more CH ₂ in the C _1-6 alkylene is optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O)-, -S(O) ₂ - and/or -O-substituted; R ^c is selected from C _1-6 alkyl, or two R ^c on the same carbon atom and the carbon atom connected to it together form a 3-8 membered ring Alkyl; R ⁴ is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, phenyl, 3-8 membered cycloalkyl, and the phenyl is optionally replaced by one or more Replaced by a group selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl; m is selected from 0, 1, 2, 3; R ⁵ and R ⁶ are respectively Independently selected from hydrogen, -OH, C _1-6 alkyl, 3-8 membered cycloalkyl, or R ⁵ , R ⁶ are connected together, and form a 3-8 membered heterocyclic ring together with the nitrogen atom connected to it; R ⁷ is selected from From hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-C(O)-, -C(O)OCH ₂ Ph. The compound as described in Claim 1 or 2 has the structure shown in the following formula (I),

Or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, wherein, X is selected from CH, N; R ¹ is selected from hydrogen, C _1-4 alkyl, deuterated C _1-4 alkane Base, 3-6 membered cycloalkyl; R ² is selected from hydrogen, -OH, C _1-4 alkyl, deuterated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl- C(O)-, C _1-4 alkyl-S-, C _1-4 alkyl-S(O)-, C _1-4 alkyl-S(O) _2- ; R ³ is selected from hydrogen, C _1-4 alkoxy-C(O)-, (R ⁵ )(R ⁶ )NC(O)-, or the following groups optionally substituted by one or more R ^a : phenyl, 5-6 members Heteroaryl, 5-6 membered heterocyclic group; R ^a is selected from hydrogen, halogen, -CN, carboxyl, (R ⁵ )(R ⁶ )NC(O)-, C _1-4 alkyl, C _1-4 Alkyl-C(O)-, C _1-4 alkyl-C(O)-NH-, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy , Hydroxy C _1-4 alkyl, 3-6-membered cycloalkyl, 3-6-membered cycloalkyl-O-, 3-6-membered cycloalkyl-CH ₂ -O-, NC-3-6-membered cycloalkane group, or any adjacent two R ^a are linked together _{to form a 3-6 membered heterocyclic ring; L is selected from C 1-8} ^alkylene groups optionally substituted by one or more R ^b , so One or more CH ₂ in the C _1-8 alkylene group is optionally replaced by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/ Or -O-substituted; R ^b is selected from C _1-4 alkyl, or two R ^b on the same carbon atom and the carbon atom connected to it together form a 3-5 membered cycloalkyl group; or, L ¹ is selected from

, wherein the ring A end is connected to the NH end of formula (I), and the L ² end is connected to the benzene ring; Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl; L ² selected from C _1-6 alkylene groups, one or more CH ₂ in the C _1-6 alkylene groups are optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S(O )-, -S(O) ₂ - and/or -O-substituted; R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, phenyl, 3-6 membered ring Alkyl, the phenyl is optionally substituted by one or more groups selected from halogen, C _1-4 alkyl, or halogenated C _1-4 alkyl; m is selected from 0, 1, 2, 3; R ⁵ and R ⁶ are independently selected from hydrogen, C _1-4 alkyl, 3-6 membered cycloalkyl, or R ⁵ , R ⁶ and the nitrogen atom connected to it are connected together to form a 3-6 membered heterocyclic ring ; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O)-, -C(O)OCH ₂ Ph. The compound as claimed in item 1 or 2, wherein R ¹ is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CD ₃ ,

, R ⁸ is selected from H; or R ¹ is connected to R ⁸ , and the nitrogen atom connected to it forms together

,

,

. The compound according to any one of claims 1-4, wherein R ¹ is selected from -CH ₃ or -CD ₃ ; R ⁸ is selected from H. The compound according to any one of claims 1-5, wherein R ² is selected from -OH, -OCH ₃ , -C(O)CH ₃ , -SCH ₃ , -S(O)CH ₃ , -S( O) ₂ CH ₃ . The compound according to any one of claims 1-6, wherein R ² is selected from -OH, -OCH ₃ . The compound as claimed in any one of claims 1-7, wherein R ³ is selected from hydrogen, -C(O)-OCH ₃ , -C(O)-NH ₂ , -C(O)-N(CH ₃ ) ₂ , or the following groups optionally substituted by 1-2 R ^a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,4-triazolyl, tetrazole Base, phenyl, pyridyl, pyrimidinyl, pyridyl, pyridyl,

,

_; ^_ _{_ _ _ _ _ _ _ _} -CH(CH ₃ ) ₂ , -CF ₂ CH ₃ , -C(O)CH ₃ , -OCHF ₂ , -C(O)-N(CH ₃ ) ₂ , -C(O)-NHCH ₃ , -NHC (O)CH ₃ , -C(O)-NH ₂ ,

,

,

,

,

,

,

,

,

,

,

, or adjacent two R ^a form tetrahydrofuran, tetrahydropyrrole. The compound as claimed in any one of claims 1-8, wherein ^R is selected from the following groups optionally substituted by 1-2 R ^a : pyrazolyl, pyrimidinyl, pyridyl; R ^a is selected from hydrogen , F, -CH ₃ , -OCH ₃ , -O-CH(CH ₃ ) ₂ . The compound as claimed in any one of claims 1-9, wherein R ³ is selected from the following groups: hydrogen, -C(O)-OCH ₃ , -C(O)-NH ₂ , -C(O)- N(CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

. The compound as described in any one of claims 1-10, wherein ^R is selected from the following groups:

,

,

,

,

,

,

,

,

,

. The compound as described in any one of claims 1-11, wherein ^R is selected from the following groups:

,

,

,

,

,

. The compound as claimed in any one of claims ^1-12 , wherein L is selected from C _6-7 straight chain alkylene optionally substituted by 1-2 R ^b , said C _6-7 straight chain alkylene 1-3 CH ₂ in the alkyl group are optionally substituted by -C(O)-, -NH- and/or -O-, R ^b is selected from -CH ₃ , or two R ^b on the same carbon atom and the carbon atom attached thereto form ^a cyclopropyl group; preferably, L is selected from

,

,

, "a" end means connecting with ^X2 or NH. The compound as described in any one of claim items ^1-12 , wherein, when L is selected from

When, ring A is selected from phenyl, pyridyl, pyrimidyl, pyridyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,

; R ⁴ is selected from hydrogen, fluorine, -CH ₃ , -CF ₃ ,

,

,

m is selected from 0, 1 or 2. The compound as described in any one of claim items ^1-12 , wherein, when L is selected from

When , Ring A is selected from pyridyl; R ⁴ is selected from -CH ₃ ; m is selected from 0 or 1. The compound as claimed in item 14, wherein Ring A is selected from

,

,

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end. The compound as claimed in item 16, wherein Ring A is selected from

. The compound as described in any one of claims 1-12, 14-17, wherein the structural unit

selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end. The compound as described in any one of claims 1-12, 14-18, wherein the structural unit

selected from

,

,

,

,

,

,

,

, "a" indicates that it is connected to ^X2 or NH through this end. The compound as described in any one of claims 1-12, 14-19, wherein the structural unit

selected from

,

. The compound as claimed in any one of claims 1-12, 14-20, wherein L ² is selected from C _3-6 linear alkylene groups optionally substituted by 1-2 R ^c , said C _3- 1-2 CH ₂ in ₆ linear alkylene groups are optionally substituted by -C(O)-, -NR ⁷ -, -S-, -S(O) ₂ - and/or -O-; R ^c Selected from -CH ₃ , -CH ₂ CH ₃ , or two R ^c located on the same carbon atom are connected to each other, and the carbon atom connected to it forms a cyclopropyl group together; R ⁷ is selected from hydrogen, -CH ₃ , -CH ₂ CH ₃ , -C(O)CH ₃ , -C(O)OCH ₂ Ph. The compound as described in any one of claim items 1-12, 14-21, wherein, L ² is selected from C _3-6 straight-chain alkylene, and 1-2 in the C _3-6 straight-chain alkylene Each CH ₂ is optionally substituted by -C(O)-, -NR ⁷ -, -S-, -S(O) ₂ - and/or -O-; R ⁷ is selected from hydrogen, -CH ₃ , -C( O) OCH ₂ Ph. The compound as claimed in claim 22, wherein L ² is selected from C _3-4 straight chain alkylene, and 1-2 CH ₂ in the C _3-4 straight chain alkylene are optionally replaced by -NR ⁷ -, -S-, -S(O) ₂ - and/or -O-substituted; R ⁷ is selected from hydrogen, -CH ₃ . ^The compound as described in any one of claims 1-12, 14-23, wherein, L is selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

. The compound as described in claim item 24, wherein, L ² is selected from

,

, the "b" end indicates that it is connected to ring A through this end. The compound as described in any one of claims 1-25 has the structure shown in the following general formula:

or its pharmaceutically acceptable salt, its ester, its isomer, its isotope label, M is selected from CH or N; m is selected from 0, 1 or 2; R ¹ , R ² , R ³ , R ^a , R ⁴ , L ² , ring A are as defined in any one of claim items 1-25. A compound as described below, or a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, or an isotope label thereof:

. A pharmaceutical composition, containing the compound described in any one of claims 1-27, its pharmaceutically acceptable salt, its isomer, its isotope label and one or more pharmaceutically acceptable carriers. A pharmaceutical composition, containing the compound described in any one of claims 1-27, its pharmaceutically acceptable salt, its isomer, its isotope label or a pharmaceutical composition comprising it and one or more second treatments active agent. Use of the compound as described in any one of claims 1-27, its pharmaceutically acceptable salts, its isomers, and its isotope labels in the preparation of medicines for prevention and/or treatment of subjects related diseases mediated by TYK2. The use as described in claim 30, the TYK2-mediated related diseases are selected from autoimmune diseases, transplant-related diseases, inflammation or inflammatory diseases; Preferably, the related disease mediated by TYK2 is an autoimmune disease; More preferably, the autoimmune disease is selected from type I diabetes, Graham's disease, rheumatoid arthritis, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis, multiple Sexual sclerosis, systemic sclerosis, Sjogren's syndrome, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease; More preferably, the inflammatory or inflammatory disease is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease, cryopyrin-related periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), familial Mediterranean fever (FMF), adult Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis, osteoarthritis arthritis. A method for preparing a compound of formula (II), comprising the following steps:

Among them, X, R ¹ , R ² , R ³ , L ² , R ⁴ , m, ring A are as defined in any one of claims 1-26; Hal is halogen, preferably Cl, Br; P is amino protection Groups, which come from acid anhydride compounds, acyl chloride compounds, halides; preferably, P is selected from the group consisting of tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-biphenyl-2-propoxycarbonyl ( BPoc), phthalimide (pht), p-toluenesulfonyl (Tosyl), trityl (Trityl), formyl (formyl), Fmoc, Alloc, Teoc; more preferably Boc, Cbz; Step 1: React Intermediate 1 and Intermediate 2 in a polar organic solvent under basic conditions to obtain Intermediate 3; Preferably, the polar organic solvent includes one or more of the following: tetrahydrofuran, ether, N, In N-dimethylformamide, dimethyl ether, N-methylpyrrolidone, dimethylsulfoxide, and acetonitrile; the basic condition is to add a basic catalyst; preferably, the basic catalyst is selected from From an organic base or an inorganic base; Step 2: Intermediate 3 is deprotected under acidic conditions to obtain Intermediate 4; The acidic condition refers to the presence of an organic acid or an inorganic acid; Step 3: Intermediate 4 in Under basic conditions, add coupling catalyst, metal chelate ligand, react to obtain product; Described basic condition is to add basic catalyst; Preferably, described basic catalyst is selected from cesium carbonate, potassium carbonate, carbonic acid Sodium, sodium bicarbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, triethylamine, N , one or more in N-diisopropylethylamine, DBU; Preferably, described coupling catalyst is selected from palladium catalyst; Described palladium catalyst is preferably tridibenzylidene acetone dipalladium, methanesulfonic acid (2 -dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'- Biphenyl-2-yl)palladium(II) (BrettPhos Pd G3), palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1 '-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Pd G3), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Pd G3), 1,1' - Bisdiphenylphosphinoferrocenepalladium dichloride, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bistriphenylphosphinopalladium dichloride, dichloro[1,1' -bis(tri-butylphosphine)ferrocenepalladium(II), bis(tri-butylphosphine)palladium, [1,3-bis(2,6-diisopropylphenyl)imidazole-2- Fork] (3-chloropyridine) palladium dichloride (Pd-PEPPSI) in one or more; Preferably , the metal chelating ligand, preferably 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (xantphos), 2-(dicyclohexylphosphine)-3,6-dimethyl Oxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (BrettPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 2 -(Di-tert-butylphosphine)biphenyl (JohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1 ,1'-bisphenyl (tBuBrettPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos), 2-dicyclohexylphosphine-2',4' , one or more of 6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos). An intermediate of the structure shown below,

or a pharmaceutically acceptable salt thereof, wherein Y is -O-, -S-, -NR ⁷ -, -C(R ⁷ ) ₂ -, -NR ⁷ -C(O)-, -OC(O) -, -S(O)-, -S(O) ₂ -; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O)-, -C(O)OCH ₂ Ph, preferably, R ⁷ is selected from hydrogen, C _1-4 alkyl; q ₁ , q ₂ are independently 0, 1, 2, 3, 4, preferably, the sum of q ₁ , q ₂ is 2- 5. More preferably, the sum of q ₁ and q ₂ is 3 or 4; R ² , R ³ , R ⁴ , ring A are as defined in any one of claims 1-26; P is as defined in claim 32. The intermediate as claimed in claim 33, wherein R ² is selected from C _1-4 alkoxy; R ³ is selected from 5-6 membered heteroaryl optionally substituted by 1-2 R ^a ; R ^a is selected from From hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; Y is -O-, -S-, -NH-; Ring A is selected from phenyl, pyridyl, pyrimidinyl; R ⁴ is selected From hydrogen, halogen, C _1-4 alkyl; m is selected from 0,1. The intermediate as described in Claim 33 or 34 has the following structure:

R ² , R ³ , R ⁴ , m, R ^a , q ₁ , q ₂ , P are as defined in claim 33 or 34; preferably, R ^a is selected from H, F, -CH ₃ , -OCH ₃ . A method for preparing the intermediate 1a described in any one of claim items 33-35, characterized in that it comprises the following steps:

G ₁ and G ₂ independently represent halogen, -C(O)R', NH ₂ , OH, SH, R' represents -OH or halogen; R ² , R ³ , R ⁴ , m, ring A, q ₁ , q ₂ , Y, and P are as defined in any one of claim items 33-35; Steps: Intermediate A and intermediate B undergo condensation reaction under suitable conditions to obtain intermediate C, and intermediate C is then reduced to obtain intermediate 1a; Preferably, the suitable conditions include: ① adding a basic catalyst, preferably NaH, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bis(trimethylsilyl)amide, bis(trimethylsilyl) ) lithium amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyl lithium, second butyl lithium, third butyl lithium, third potassium butoxide, third Inorganic bases of sodium butoxide, sodium methoxide, sodium ethoxide, methylmagnesium bromide (chloride), ethylmagnesium bromide (chloride), second butylmagnesium bromide (chloride), or triethylamine, N,N -Organic bases of diisopropylethylamine, 4-dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); ② adding dehydrating agent or condensing agent Or coupling agent, specifically can be selected from: T3P (propyl phosphoric anhydride), DCC (dicyclohexylcarbodiimide), CDI (N, N'-carbonyldiimidazole), HATU (2-(7-nitrogen Hexabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (O-benzotriazole-tetramethyluronium hexafluorophosphate), HCTU ( 6-Chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate), EDCI ((1-ethyl-3(3-dimethylpropylamine) carbodiimide)), HOBT (1-hydroxybenzotriazole), TBTU (O-benzotriazole-N,N,N ',N'-Tetramethyluronium tetrafluoroboric acid), TSTU (2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate), TNTU (2-(5- norbornene-2,3-dimethylimido)-1,1,3,3-tetramethyluronium tetrafluoroborate quaternary ammonium salt); the reduction includes: Pd/C reduction, ferric acid reduction method, catalytic hydrogenation reduction, sodium sulfide and thiosulfuric acid reduction, hydrazine hydrate Raney nickel reduction, etc. A preparation method for preparing product formula (II-a), characterized in that it comprises the following steps:

Wherein, Y is -O-, -S-, -NR ⁷ -, -C(R ⁷ ) ₂ -, -NR ⁷ -C(O)-, -OC(O)-, -S(O)-, -S(O) ₂ -; R ⁷ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkyl-C(O)-, -C(O)OCH ₂ Ph, preferably, R ⁷ is selected from hydrogen, C _1-4 alkyl; q ₁ , q ₂ are independently 0, 1, 2, 3, 4, preferably, the sum of q ₁ , q ₂ is 2-5, more preferably, q ₁ , The sum of q ₂ is 3 or 4; R ¹ , R ² , R ³ , R ⁴ , m, ring A, Hal, P are as defined in any one of claim items 1-35; the specific preparation steps are as described in claim item 32 .