WO2022213980A1

WO2022213980A1 - Tyk2 inhibitor and use thereof

Info

Publication number: WO2022213980A1
Application number: PCT/CN2022/085308
Authority: WO
Inventors: 陈晓菁; 陈波; 廉兵; 萨卡苏博斯•曼; 余辰
Original assignee: 上海齐鲁制药研究中心有限公司
Priority date: 2021-04-07
Filing date: 2022-04-06
Publication date: 2022-10-13
Also published as: TW202239758A; CN116888125A; CN116888125B; TWI804266B

Abstract

Disclosed are a compound of formula (II') as a macrocyclic TYK2 inhibitor, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotope marker thereof, and the use thereof in the treatment of TYK2-mediated related diseases.

Description

TYK2 inhibitors and their uses

technical field

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

Background technique

Janus kinase (JAK kinase for short) is a non-receptor tyrosine protein kinase that plays a pivotal role in many cytokine receptor-mediated signal transduction, and is involved in the proliferation, differentiation, Important physiological processes such as apoptosis, angiogenesis and immune regulation.

The JAKs family has 4 different subtypes in mammals, namely JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase2). JAK1, JAK2 and TYK2 are expressed in various tissues and cells of the human body. JAK-3 is mainly expressed in various tissues and cells. in hematopoietic cells. The JAK-STAT (Janus kinase-signal transducer and activator of tanscription) signaling pathway is the most important pathway mediated by JAKs in vivo. This pathway 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 , make it have tyrosine kinase activity and bind in pairs, the dimeric JAK can undergo spontaneous phosphorylation, bind to STAT protein, the activated STAT protein is detached from the receptor and forms a phosphorylated dimer, which is transferred to the nucleus It binds to 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 inflammation-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 autoimmune and inflammation-related animal models, including rheumatoid arthritis, play a therapeutic role, and a TYK2 selective inhibitor is currently undergoing II or III for systemic lupus erythematosus, Crohn's disease and psoriasis indications Phase clinical research, no TYK2 selective inhibitor has been listed.

Therefore, developing novel selective TYK2 inhibitor compounds, enriching the types of clinical drugs, and improving the availability of drugs are still urgent problems to be solved in this field.

SUMMARY OF THE INVENTION

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 compound specifically targets the TYK2 regulatory protein domain (pseudokinase) and has an inhibitory effect on the TYK2 pathway. Compared with the inhibitory effect of JAK1, JAK2 and/or JAK3 signaling pathway, it has stronger selectivity; further, the present invention provides a TYK2 inhibitor with high selectivity, good bioavailability, good efficacy and low toxicity class compounds.

The technical scheme of the present invention is as follows:

In a first aspect, the present invention provides a compound represented by the following general formula (II'),

or its pharmaceutically acceptable salt, its ester, its isomer, its isotopic label, wherein,

X is selected from CH, N;

R ¹ is selected from hydrogen, C _1-6 alkyl, deuterated C _1-6 alkyl, 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 heterocycle together with the nitrogen atom to which it is connected;

X ¹ and X ² are independently selected from CH ₂ , NH, and O;

Ring C is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl;

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 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 with one or more ^Ra : 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 to form a heterocycle together with the atoms to which they are connected; p is selected from 0, 1, 2, 3;

L ¹ is selected from C _1-8 alkylene optionally substituted by one or more R ^b , and one or more CH ₂ in said C _1-8 alkylene is optionally substituted by -C(O)-, -NR ⁷ -, -S, -S(O)-, -S(O) _2- and/or -O-substituted;

R ^b is selected from C _1-6 alkyl, or two R ^b located on the same carbon atom and the carbon atom to which it is attached together form cycloalkyl, heterocyclyl;

Alternatively, L ¹ is selected from

Wherein the ring A end is connected with the X of ^formula ( ^II '), and the L end is connected with the 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 , and one or more CH ₂ in said C _1-6 alkylene is optionally substituted 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 both are located on the same carbon atom R ^c and its attached carbon atoms together form cycloalkyl, heterocyclyl;

R ⁴ is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, phenyl, cycloalkyl, and the phenyl is optionally composed of one or more selected from halogen, C _{1-6 6} alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl group substituted;

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 and R ⁶ are connected together, and together with the nitrogen atom to which they are connected, form a heterocycle;

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.

In a preferred embodiment of formula (II'), it has the structure shown in the following formula (I'),

X is selected from CH, N;

R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy;

Or R ¹ is connected with R ⁸ to form a 3-8 membered heterocycle together with the nitrogen atom to which it is connected;

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 two adjacent R ^a Connected to and together form a 3-8 membered heterocycle with the atoms to which it is connected;

p is selected from 0, 1, 2, 3;

L ¹ is selected from C _1-8 alkylene optionally substituted by one or more R ^b , and one or more CH ₂ in said C _1-8 alkylene is optionally substituted 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 carbon atoms located on the same carbon atom. R ^b together with the carbon atom to which it is attached forms a 3-5 membered cycloalkyl;

Alternatively, L ¹ is selected from

Wherein the ring A end is connected with the NH of formula (I'), and the L ² end is connected with the benzene ring;

Ring A is selected from phenyl, heteroaryl;

L ² is selected from C _1-6 alkylene optionally substituted by one or more R ^c , and one or more CH ₂ in said C _1-6 alkylene is optionally substituted 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 both are located on the same carbon atom The R ^c and the carbon atom to which it is attached together form a 3-8 membered cycloalkyl;

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 selected from one or more halogens , C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl group substitution;

m is selected from 0, 1, 2, 3;

R ⁵ , R ⁶ are independently selected from hydrogen, -OH, C _1-6 alkyl, 3-8 membered cycloalkyl, or R ⁵ and R ⁶ are connected together, and together with the nitrogen atom to which they are connected, form a 3-8 membered Heterocycle;

In a preferred embodiment of formula (II') or (I'), wherein,

X is selected from CH, N;

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 with one or more ^Ra : 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;

R ^b is selected from C _1-4 alkyl, or two R ^b located on the same carbon atom together with the carbon atom to which it is attached form a 3-5 membered cycloalkyl;

Alternatively, L ¹ is selected from

Ring A is selected from phenyl, heteroaryl;

L ² is selected from C _1-6 alkylene optionally substituted by one or more R ^c , and one or more CH ₂ in said C _1-6 alkylene is optionally substituted 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 together with the carbon atom to which it is attached form a 3-8 membered cycloalkyl;

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 selected from one or more halogens , C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl group;

m is selected from 0, 1, 2, 3;

R ⁵ and R ⁶ are independently selected from hydrogen and C _1-6 alkyl;

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;

R ⁸ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy.

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 groups optionally substituted with one or more ^Ra : Phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl;

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-C _1-4 alkoxy, NC-3-6 membered cycloalkyl, or any two adjacent R ^a Connected to and together form a 3-6 membered heterocycle with the atoms to which it is connected;

Alternatively, L ¹ is selected from

Wherein the ring A end is connected with the NH end of formula (I), and the L ² end is connected with the benzene ring;

Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl;

L ² is selected from C _1-6 alkylene, and one or more CH ₂ in said C _1-6 alkylene is optionally replaced by -C(O)-, -NR ⁷ -, -S-, -S (O)-, -S(O) ₂ - and/or -O- substitution;

R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, phenyl, 3-6 membered cycloalkyl, the phenyl is optionally by one or more selected from halogen , C _1-4 alkyl, or halogenated C _1-4 alkyl group substitution;

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 and R ⁶ are connected together, and together with the nitrogen atom to which they are connected, form a 3-6-membered heterocycle;

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), wherein,

X is selected from CH, N;

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 with one or more ^Ra : 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 C _1-8 alkylene optionally substituted by one or more R ^b , and one or more CH ₂ in said C _1-8 alkylene is optionally substituted by -C(O)-, -NR ^7- , -S, -S(O)-, -S(O) ₂ - and/or -O- substituted;

Alternatively, L ¹ is selected from

L ² is selected from C _1-6 alkylene, one or more CH ₂ in said C _1-6 alkylene is optionally replaced by -C(O)-, -NR ^7- , -S-, -S (O)-, -S(O) ₂ - and/or -O- substitution;

R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, phenyl, 3-6 membered cycloalkyl, the phenyl is optionally by one or more selected from halogen , C _1-4 alkyl, or halogenated C _1-4 alkyl group;

m is selected from 0, 1, 2, 3;

R ⁵ and R ⁶ are independently selected from hydrogen and C _1-4 alkyl;

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 ,

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 ^is selected from H;

Or R ¹ is attached to R ⁸ to form together with the nitrogen atom to which it is attached

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)CH ₃ , -S(O) ₂ CH ₃ .

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

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 with 1-2 R ^a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2, 4-triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,

^{Ra is} selected from H, F, -CN, _-COOH , _-CH3 , _-CH2CH3 , _-CH2F , _-CHF2 , _-CF3 , _-OCH3 , _-OCH2CH3 , _-O- 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 and the atoms to which they are connected together form tetrahydrofuran and tetrahydropyrrole.

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( _CH3 ) ₂ , or selected from the following groups optionally substituted with 1-2 R ^a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1, 2,4-triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl; R ^a is selected from hydrogen, F, -CH ₃ , -CH ₂ CH ₃ , - CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₃ , -C(O)-N(CH ₃ ) 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 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 is selected from the following groups optionally substituted with 1-2 R ^a : pyrazolyl, pyrimidine base, pyridyl;

^Ra is selected from hydrogen, F, _-CH3 , _-OCH3 , -O-CH( _CH3 ) ₂ .

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein R ³ is selected from the group consisting of 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 group consisting of 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 is selected from

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein L ¹ is selected from C _6-7 straight chain alkylene optionally substituted with 1-2 R ^b , 1-3 CH ₂ in the C _6-7 straight-chain alkylene 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 they are attached form a cyclopropyl group.

In a preferred embodiment of formula (II'), formula (I') or formula (I), L ¹ is selected from

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

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein, when L ¹ is selected from

When ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 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,

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.

In a preferred embodiment of formula (II'), formula (I') or formula (I), when L ¹ is selected from

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

In a preferred embodiment of formula (II'), formula (I') or formula (I), ring A is selected from

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

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein Ring A is selected from

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

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

selected from

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

selected from

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

selected from

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

selected from

In a preferred embodiment of formula (II'), formula (I') or formula (I), wherein L ² is selected from C _3-6 straight-chain alkylene optionally substituted by 1-2 R ^c , 1-2 CH ₂ in the C _3-6 straight-chain alkylene are optionally -C(O)-, -NR ⁷ -, -S-, -S(O) ₂ - and/or -O -Substituted; 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 together with the carbon atom to which they are connected, form a cyclopropyl;

^R7 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, the C _3-6 straight chain alkylene 1-2 CH ₂ in the base 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, the 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 .

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

q ₁ and q ₂ are independently 0, 1, 2, 3, and 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 and q ₂ are independently 0, 1, 2, 3, and 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 and q ₂ are independently 0, 1, 2, 3, and 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.

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

"b" indicates connection to ring A through this end.

In a preferred embodiment of formula (II'), formula (I') or formula (I), the present invention further provides the compound represented by the following general formula, its pharmaceutically acceptable salt, its ester, its isomer , its isotopic label:

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

Any substituent in the technical solution of the present invention and any optional group thereof can be combined with each other to form a new and complete technical solution, and the formed new technical solution has the same or similar technology as the solution described in the present invention The effects are all included in 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 isotopic label, selected from the following compounds:

According to the second aspect of the present invention, there is also provided a pharmaceutical preparation composition comprising the compound described in any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotope thereof marker, and one or more pharmaceutically acceptable excipients. The pharmaceutical formulation can be any pharmaceutically acceptable dosage form.

According to the present invention, a pharmaceutically acceptable excipient is a substance that 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 disease type and state used to treat the particular patient. Examples of pharmaceutically acceptable excipients include, but are not limited to, solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, Lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, mold release agents, coating agents, flavoring agents, antioxidants, etc. When necessary, flavoring agents, preservatives, sweetening agents, etc. can also be added to the pharmaceutical preparation composition.

In certain embodiments, the above-described pharmaceutical formulation compositions may be administered orally, parenterally, rectally, or via pulmonary administration 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, can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc. When preparing an oral preparation, suitable fillers, binders, disintegrants, lubricants and the like can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be prepared into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When preparing the injection, it can be produced by the conventional methods in the existing pharmaceutical field. When preparing the injection, no additives can be added, or suitable additives can be added according to the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories and the like. For pulmonary administration, the pharmaceutical composition can be formulated into inhalation formulations, aerosol formulations, powder aerosol formulations or spray formulations, and the like.

According to the third aspect of the present invention, there is also provided a pharmaceutical composition comprising the compound described in any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotopic label thereof and one or more second therapeutically active agents, the second therapeutically active agents can be selected from immunosuppressants, such as hormonal drugs, such as corticosteroids; from cytokine inhibitors; 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 anti-proliferative agents; selected from antimalarial drugs; selected from TNF - alpha inhibitors, etc.

According to the fourth aspect of the present invention, there is also provided the use of the compound described in any one of the first aspect of the present invention, its pharmaceutically acceptable salts, its esters, its isomers, and its isotopic labels in the preparation of medicines , the medicine is used to prevent and/or treat the related diseases mediated by TYK2 in patients or subjects; preferably, the related diseases mediated by TYK2 include autoimmune diseases, transplant-related diseases, inflammation Sexual or inflammatory disease.

In another embodiment, the TYK2-mediated related disease is mediated by the 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, Sjögren's syndrome, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

In another embodiment, the inflammatory or inflammatory disease is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease, Cold porphyrin-associated 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.

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 a patient or subject an effective amount of the compound described in any one of the first aspects of the present invention, Its pharmaceutically acceptable salts, its esters, its isomers, its isotopic labels.

In another embodiment, the present invention also provides a method of treating a related disease mediated by IL-12, IL-23 and/or IFNα, comprising administering to a patient or subject an effective amount of the first of the present invention A compound of any one of the aspects, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotopic label thereof.

In another embodiment, the present invention also provides a method of treating an autoimmune disease, comprising administering to a patient or subject an effective amount of the compound described in any one of the first aspects of the present invention, or a pharmaceutically acceptable compound thereof. Accepted salts, esters thereof, isomers thereof, isotopic labels thereof.

According to a sixth aspect of the present invention, the present invention provides a compound according to any one of the first aspects, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, an isotopic label thereof, which can be used for the treatment of TYK2-mediated related diseases.

Description and Definitions

In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for better understanding of the present invention, definitions of some terms are provided below. When the definitions of terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of 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, with a reasonable benefit/risk ratio equivalent to those compounds, materials, compositions and/or dosage forms.

The "pharmaceutically acceptable salt" in the present invention refers to a salt formed by an acidic functional group (such as -COOH, -OH, -SO ₃ H, etc.) existing in a compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and salts with appropriate inorganic or organic anions (acids) of basic functional groups (such as -NH ₂ , etc.) present in the compounds , including salts formed with inorganic or organic acids (eg, carboxylic acids, etc.).

The "ester" in the present invention refers to the product formed by the 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 pharmaceutically acceptable organic or inorganic acid compounds to form esters. The ester compound can produce the active compound of the present invention by means of metabolism or hydrolysis in vivo, and the ester can have biological activity similar to the free body or no or weak biological activity in vitro.

The "isomers" in the present invention include geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, tautomers, and external isomers thereof. Racemic and other mixtures, all of which are within the scope of this invention. The term "enantiomers" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to a type of functional group isomer that has a different point of attachment of the hydrogen by displacement of one or more double bonds, for example, ketone and its enol form are keto-enol Tautomers. The term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules 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 cannot rotate freely in the molecule.

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

In the present invention, "optionally substituted" refers to two situations in which one or more hydrogen atoms of the substituted group may 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 substituent may be the same or different; in general, the Variables can be selected from the same or different substituent groups in the same technical scheme; for example, when m is ² in general formula (I), ring ^A is substituted with two R groups, wherein each R is defined independently of each other ; for example, the R ³ is substituted with one or more R ^a , wherein each R ^a is also independent of each other. Furthermore, combinations of substituents and/or variables are preferably only present if such combinations result in stable compounds.

When a substituent's bond can be cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. For example, structural unit

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

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

In the present invention, for the expression "any adjacent two R ^a are connected and the atoms to which they are connected together form a heterocycle", "any adjacent" means that the two R ^a are connected at the vicinal positions of the substituted group, respectively on the atom. For example, when two R ^a are substituents of an aromatic group (eg, phenyl, heteroaryl), the structure types such 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 present invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent to obtain other compounds of the present invention. Accordingly, unless otherwise specified, all shown and claimed nitrogen atom-containing groups are understood to encompass both non-nitroxide groups and their nitroxide groups (N→O).

when the substituents appear in the structure

Indicates that the atom is a bonding 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 a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"Alkyl" as used in the present invention refers to a branched or straight-chain saturated aliphatic alkane having a specified number of carbon atoms with one hydrogen-derived group removed. For example, "C _1-10 alkyl" is meant to include 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, sec-butyl, 2-methyl butyl, 1,1-dimethylbutyl, etc.

In the present invention, "alkylene" refers to a branched or straight-chain saturated aliphatic alkane having a specified number of carbon atoms, a group derived by removing two hydrogens. 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 , 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""Alkylene","C _1-6 alkylene"; preferably, the "alkylene" in the present invention is a "straight-chain alkylene"; specific examples include but are not limited to: -CH ₂ -, - CH2CH2-,- _CH2CH2CH2 -,- _CH ( _CH3 ) _CH2 _- , _- _CH2CH2CH2CH2 _- ,- _CH ( _CH3 ₎ CH2CH2 _- , _- _CH ( _CH2CH3 ₎ CH2-, _-C ₍ _CH3 ₎ ₍ _CH3 ₎ _CH2- , _{-CH2CH2CH2CH2CH2-} , etc.

The "haloalkyl" in the present invention refers to a 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 group" in the present invention is "halogenated C _1-6 alkyl group" and "halogenated C _1-4 alkyl group". Alkyl is as defined above.

The "deuterated alkyl group" in the present invention refers to a 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 Typically, the "deuterated alkyl group" in the present invention is "deuterated C _1-6 alkyl group" and "deuterated C _1-4 alkyl group". Alkyl is as defined above.

The "hydroxy C _1-6 alkyl group" in the present invention refers to a 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 Typically, the "hydroxy C _1-6 alkyl group" in the present invention is a hydroxy C _1-4 alkyl group. Alkyl is as defined above.

The "NC-cycloalkyl" in the present invention refers to a group obtained by substituting any hydrogen atom on a cycloalkyl with a cyano group, such as

Wait. Cycloalkyl is as defined in this specification.

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

The "alkoxy" in the present invention refers to an alkyl group as 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 are not limited to methoxy, ethoxy, propoxy , 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy Preferably, the "alkoxy" in the present invention is a C _1-4 alkoxy group, more preferably a C _1-3 alkoxy group.

In the present invention, when L ¹ and L ² are specific "C _1-8 alkylene" and "C _1-6 alkylene", unless otherwise specified, the writing mode of the specific group does not limit its relationship with the two sides. The direction of attachment of the substituents. For example, ^L1 is

The compounds include the following two:

When ^L2 is

, the compounds include the following two:

The "cycloalkyl group" in the present invention refers to a saturated cyclic alkyl group derived from a cycloalkane by removing one hydrogen atom, including a monocyclic or polycyclic saturated hydrocarbon group; the polycyclic saturated hydrocarbon group refers to a group consisting of two or more Cyclic alkyl structures are polycyclic groups formed by spiro, bridge, condensed, etc. connections. The carbon atoms in the cycloalkyl group may be further oxo, ie to form C(O). Unless otherwise specified, "a certain membered cycloalkyl group" described herein can be understood as a monocyclic cycloalkyl group, and when it is a polycyclic ring, it will be specifically indicated as a spiro, fused or bridged ring group. The cycloalkyl group includes "3-8 membered cycloalkyl", "3-6 membered cycloalkyl" and "3-5 membered cycloalkyl". Preferably, the cycloalkyl group 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 a ring carbon atom in a cycloalkyl by one or more heteroatoms, including a monocyclic or polycyclic heterocyclic group; Cyclic heterocyclic group refers to a polycyclic group formed by connecting a monocyclic heterocyclic group with other heterocyclic groups or cycloalkyl groups through spiro, bridge, condensed, etc.; the heteroatom is 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 Ns and/or Os. Unless otherwise specified, "a certain membered heterocyclic group" described herein can be understood as a monocyclic heterocyclic group, and if it is a multi-heterocyclic group, it will be specifically indicated as a spiro, fused or bridged ring group; the heterocyclic group includes "3-8 membered heterocyclyl", "3-6 membered heterocyclyl", "3-5 membered heterocyclyl", "5-6 membered heterocyclyl". 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. The "heterocycle" reference applies this definition.

The "aryl group" in the present invention refers to a cyclic unsaturated and aromatic group formed by carbon atoms as ring atoms, which can be a single ring or a plurality of rings fused together. Examples of _C6-10 membered aryl groups include, but are not limited to, phenyl, naphthyl.

The "heteroaryl" 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 of are independently selected from 1-3 N and/or O, in addition, the N and S atoms may be optionally oxidized and the N atom may be optionally quaternized. The "heteroaryl group" includes "monocyclic heteroaryl group" and "fused ring heteroaryl group", and the said fused ring heteroaryl group means that two or more cyclic structures share two adjacent adjacent to each other. A group formed by atoms containing one or more heteroatoms and having overall aromaticity. 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 "fused ring heteroaryl", it will be specifically indicated as "fused" heteroaryl structure, such as "8-10-membered fused ring heteroaryl". The heteroaryl group of the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5- to 6-membered nitrogen-containing aryl group", and the heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, For example, only 1, 2, or 3 nitrogen atoms, or, 1 nitrogen atom and 1 or 2 other heteroatoms (eg, S and/or O atoms), or 2 nitrogen atoms and other 1 or 2 heteroatoms. Specific examples of the heteroaryl group 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 represented by H), deuterium (often represented by D), and tritium (often represented by T); isotopes of carbon ^include12C , ^13C , ^and14C . Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the otherwise employed unlabeled reagent.

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

According to the seventh aspect of the present invention, a preparation method of some compounds of the present invention is further provided, which comprises 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 protecting group, which can be derived from acid anhydride compounds, acid chloride compounds, halides, etc. Common protecting groups include but are not limited to: tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-biphenyl -2-Propoxycarbonyl (BPoc), Phthalimido (pht), p-toluenesulfonyl (Tosyl), Trityl (Trityl), formyl (formyl) Fmoc, Alloc, Teoc, etc.; Preferred are Boc and Cbz.

step 1:

Intermediate 1 and intermediate 2 are reacted in a polar organic solvent under basic conditions to obtain intermediate 3.

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

Described basic condition can be to add basic catalyst, described basic catalyst includes but not limited to following one or more: bis (trimethylsilyl) sodium amide, NaH, bis (trimethylsilyl) ) lithium amide, bis(trimethylsilyl) potassium amide, lithium diisopropylamide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, Inorganic bases such as sodium ethoxide, magnesium methyl bromide (chloride), magnesium ethyl bromide (chloride), magnesium sec-butyl bromide (chloride), and triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, DBU (1,8-diazabicycloundec-7-ene) and other organic bases.

Step 2:

Deprotection of intermediate 3 under acidic conditions affords intermediate 4.

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

Step 3:

The intermediate 4 is added with a coupling catalyst and a metal chelate ligand under alkaline conditions, and the product is obtained by the reaction.

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

Described coupling catalyst is selected from palladium catalyst, and described palladium catalyst is selected from tridibenzylideneacetone 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'-bisdiphenylphosphinoferrocene palladium dichloride, bis(dibenzylideneacetone) Palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, dichloro[1,1'-bis(er-tert-butylphosphine)ferrocene palladium(II), bis(tri-tert-butyl) One or more of [1,3-bis(2,6-diisopropylbenzene)imidazole-2-idene](3-chloropyridine)palladium dichloride (Pd-PEPPSI) .

The metal chelating ligand is selected from 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (xantphos), 2-(dicyclohexylphosphine)-3,6-dimethyl Oxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (BrettPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 2 -(Di-tert-butylphosphino)biphenyl (JohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 2-dicyclohexylphosphino-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-dicyclohexylphosphino-2',4',6' - One or more of triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos).

In another preferred scheme, in the preparation method of the 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 phenyl, pyridyl, pyrimidinyl;

R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl;

m is selected from 0 and 1.

R ² is selected from -OCH ₃ ;

R ³ is selected from pyrazolyl, pyrimidinyl, pyridyl optionally substituted by 1-2 R ^a ;

^Ra is selected from hydrogen, F, _-CH3 , _-OCH3 , -O-CH( _CH3 ) 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 and 1.

In another preferred solution, when the L ² 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 each independently 0, 1, 2, 3, 4, preferably, the sum of q ₁ and 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 ^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, pyridyl, pyrimidinyl;

R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl;

m is selected from 0 and 1.

In another preferred scheme, in intermediate 1a:

R ² is selected from -OCH ₃ ;

^Ra is selected from hydrogen, F, _-CH3 , _-OCH3 , -O-CH( _CH3 ) 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 and 1.

In another preferred embodiment, the intermediate 1a is selected from the structures shown below:

R ² , R ³ , R ⁴ , m, ^Ra , q ₁ , q ₂ , Y, P are as defined in any of the preceding schemes; preferably, ^Ra is selected from H, F, -CH ₃ , -OCH ₃ .

Intermediate 1a can be prepared by the following procedure:

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 are subjected to condensation reaction under suitable conditions to obtain intermediate C, which is then reduced to obtain intermediate 1a.

Described suitable conditions include but are not limited to: ① Add basic catalyst, such as NaH, sodium hydroxide, potassium hydroxide, lithium hydroxide, bis (trimethylsilyl) sodium amide, bis (trimethylsilyl) Lithium amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, ethanol Inorganic bases such as sodium, methyl bromide (chloride) magnesium, ethyl bromide (chloride) magnesium, sec-butyl bromide (chloride) magnesium and/or triethylamine, N,N-diisopropylethylamine, Organic bases such as 4-dimethylaminopyridine, DBU; ② add 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-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), HBTU(O - Benzotriazole-tetramethylurea hexafluorophosphate), HCTU (6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate), PyBOP (hexafluorophosphate) Benzotriazol-1-yl-oxytripyrrolidinophosphate), EDCI ((1-ethyl-3(3-dimethylpropylamine)carbodiimide)), HOBT (1-hydroxybenzoic acid) triazole), TBTU (O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid), TSTU (2-succinimidyl-1,1,3,3 -Tetramethylurea tetrafluoroborate), TNTU (2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethylurea tetrafluoroboric acid quaternary ammonium salts) etc.

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

In another preferred embodiment, in the preparation method of the intermediate 1a, wherein,

R ² is selected from C _1-4 alkoxy;

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, pyridyl, pyrimidinyl;

R ⁴ is selected from hydrogen, halogen, C _1-4 alkyl;

m is selected from 0 and 1.

R ² is selected from -OCH ₃ ;

^Ra is selected from hydrogen, F, _-CH3 , _-OCH3 , -O-CH( _CH3 ) 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 and 1.

Further, intermediate 1a and intermediate 2 are further reacted to form the following structural compounds (for the preparation process, refer to formula (II) preparation method steps 1-3):

Further, the present invention provides a preparation method of formula (II-b), which comprises the following reaction process:

R ¹ , R ⁴ , m, ^Ra , q ₁ , q ₂ , P, Y, Hal, G1, G2, ring A are as defined in the previous scheme;

For the preparation method and conditions, please refer to the preparation method of the intermediate 1a and the compound of formula (II).

Detailed ways

In the examples of the present invention, the nomenclature of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by synthesizing relevant information and reaction routes; if it cannot be confirmed by other methods, the given compound structural formula 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 charging ratio of the reactants, the reaction solvent, and the reaction temperature can be appropriately adjusted according to the different reactants.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.

1. Summary of experimental instruments:

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 ([delta]) are given in parts per million (ppm). NMR was measured by Varian 400M or Bruker Ascend 400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or heavy water ( D ₂ O), the internal standard is tetramethylsilane (TMS).

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

The HPLC assay used Waters H-class UPLC and Agilent 1260 infinity II high performance liquid chromatography.

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

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

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

The thin-layer chromatography silica gel plate is made of GF254 silica gel plate of Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate of Rushan Shangbang New Materials Co., Ltd. Generally used in the chemical industry 200 ~ 300 mesh silica gel as the carrier.

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

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

Unless otherwise specified, all the reactions of 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 reaction temperature is °C.

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

In the embodiment of the present invention, the unit "M" represents "mol/L", which is the concentration of the reagent.

Abbreviations used in the embodiments of the present invention and their corresponding chemical names are as follows:

缩写abbreviation	描述describe
EAEA	乙酸乙酯Ethyl acetate
PEPE	石油醚Petroleum ether
PhIOPhIO	亚碘酰苯iodophenone
ACNACN	乙腈Acetonitrile

DMFDMF	N,N-二甲基甲酰胺N,N-Dimethylformamide
dioxanedioxane	1,4-二氧六环1,4-Dioxane
NaHMDSNaHMDS	双(三甲基硅基)氨基钠Sodium Bis(trimethylsilyl)amide
Pd ₂(dba) ₃ Pd ₂ (dba) ₃	三二亚苄基丙酮二钯Tridibenzylideneacetone dipalladium
XantphosXantphos	双二苯基膦-9,9-二甲基氧杂蒽Bisdiphenylphosphine-9,9-dimethylxanthene
DMAPDMAP	4-二甲氨基吡啶4-Dimethylaminopyridine
THFTHF	四氢呋喃tetrahydrofuran
Pd(PPh ₃) ₂Cl ₂ Pd(PPh ₃ ) ₂ Cl ₂	二氯二三苯基膦钯Dichloroditriphenylphosphine palladium
DIBAL-HDIBAL-H	二异丁基氢化铝Diisobutylaluminum hydride
TrimethylboroxineTrimethylboroxine	三甲基环三硼氧烷Trimethylcyclotriboroxane
DCMDCM	二氯甲烷Dichloromethane
T3PT3P	2-丙烷膦酸酐2-Propanephosphonic anhydride
TEATEA	三乙胺triethylamine
Pd(dppf)Cl ₂ Pd(dppf)Cl ₂	[1,1'-双(二苯基膦基)二茂铁]二氯化钯[1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride
DIADDIAD	偶氮二甲酸二异丙酯Diisopropyl azodicarboxylate

Example 1:

5 ⁶ -Methoxy-N-methyl-8-oxo-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3) -benzocyclononane ^- 36-carboxamide

The first step: the preparation of 4-(2-hydroxyethyl)-2-nitrophenol

Iodoxylbenzene (796 mg, 3.62 mmol), aluminum nitrate nonahydrate (2172 mg, 5.79 mmol) were mixed 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. Saturated brine (40 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash column chromatography (EA:PE=10:1) gave the title compound (1500 mg, 35% yield).

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= 8.6Hz, 1H), 3.88 (dd, J=7.0, 5.8Hz, 2H), 2.86 (t, J=6.4Hz, 2H).

The second step: the preparation of 2-(4-methoxy-3-nitrophenyl) 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 an ice bath. It was then stirred at room temperature for 4 hours. LC-MS showed that the reaction was complete. Water (50 ml) was added, extracted with ethyl acetate (40 ml×3), washed with brine, dried over anhydrous sodium sulfate, and then 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: the preparation of tert-butyl (6-((4-methoxy-3-nitrophenethoxy) methyl) pyridin-2-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 an ice bath, and the suspension was stirred for 20 minutes, then tert-butyl [6-(chloromethyl)pyridin-2-yl]carbamate (494 mg, 2.02 mmol) was dissolved in A solution 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, saturated aqueous ammonium chloride solution was added to quench the reaction. Water (50 mL) was added, extracted with ethyl acetate (30 mL×3), washed with brine, dried over anhydrous sodium sulfate, then 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: the preparation of tert-butyl-(6-((3-amino-4-methoxyphenethoxy)methyl)-pyridin-2-yl carbamate

tert-Butyl-(6-((4-methoxy-3-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (500 mg, 1.24 mmol) was dissolved in a mixture of ethanol and water In a solvent (40 mL, ethanol:water=5:1), iron powder (346 mg, 346 mmol) and ammonium chloride powder (331 mg, 6.20 mmol) were added. Heat to 60°C and stir the reaction for 2 hours. LC-MS showed 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 was concentrated and then water (50 mL) was added, and extracted with ethyl acetate (30 mL×3), washed with brine, the combined organic layers were dried over anhydrous sodium sulfate, and then concentrated. Purification by flash silica gel column chromatography (EA/PE=0-40%) gave the title compound (410 mg, yield 88%).

MS m/z(ESI): 374.2[M+H] ⁺ .

The fifth step: tert-butyl-(6-((3-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxyphenethoxy)methyl)pyridine- Preparation of 2-yl)carbamate

tert-Butyl-(6-((3-amino-4-methoxyphenethoxy)methyl)pyridin-2-yl)carbamate (400 mg, 1.06 mmol), 4,6-dichloro -N-Methylpyridazine-3-carboxamide 7 (220 mg, 1.06 mmol) was dissolved in tetrahydrofuran (15 mL) and sodium bis(trimethylsilyl)amide (2.1 mL, 0.42 mmol) was added dropwise. Stir at 25°C for 2 hours. LC-MS showed that the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution (10 mL). Water (30 mL) was added, extracted with ethyl acetate (30 mL×3), washed with brine, and the organic layers were combined and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography gave the title compound (400 mg, 65% yield).

MS m/z(ESI): 543.1[M+H] ⁺ .

Step 6: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxyphenyl)amino)-6-chloro-N-methyl Preparation of pyridazine-3-carboxamide

(6-((3-((6-Chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxyphenethoxy)methyl)pyridin-2-yl ) carbamate (400 mg, 0.74 mmol) was dissolved in a solution of hydrochloric acid dioxane (10 mL, 4 M). The reaction suspension was stirred at 25°C for 2 hours. LC-MS showed that the reaction was complete. Concentration under reduced pressure gave the title compound (300 mg, 87% yield).

MS m/z(ESI): 443.1[M+H] ⁺ .

The seventh step: 5 ⁶ -methoxy-N-methyl-8-oxo-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5( Preparation of 1,3)-benzocyclononane-3 ⁶ -carboxamide

4-((5-(2-((6-Aminopyridin-2-yl)methoxy)ethyl)-2-methoxyphenyl)amino)-6-chloro-N-methylpyridazine- 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-dimethyl The xanthene (24 mg, 0.04 mmol) was mixed in 1,4-dioxane (10 mL). After three displacements under nitrogen atmosphere, the reaction mixture was stirred at 130°C in a sealed tube for 2 hours. Filtration and concentration of the filtrate gave the crude product, which was then purified by preparative liquid chromatography to give the title compound (16 mg, 28% yield).

MS m/z(ESI): 407.2[M+H] ⁺ .

¹ H NMR (400MHz, 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＝1.8Hz, 1H), 7.09(d, J＝8.2Hz, 1H), 7.03(d, J＝8.3Hz, 1H), 6.95(dd, J＝8.3, 1.8 Hz,1H),6.85(d,J＝7.2Hz,1H),4.40(s,2H),3.84(s,3H),3.70-3.69(m,2H),2.84(d,J＝4.8Hz,3H ),2.80-2.78(m,2H).

Example 2:

N-methyl-5 ⁶ -(methylthio)-8-oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1, 3) Preparation of-benzocyclononane-3 ⁶ -carboxamide

The first step: the preparation of 2-(4-fluoro-3-nitro-phenyl)ethanol

A solution of (4-fluoro-3-nitro-phenyl)-acetic acid (3g, 15mmol) in dimethoxyethane (15ml) was cooled to -15°C, then 4-methylmorpholine was added with stirring (1.53 g, 15 mmol) and isobutyl chloroformate (2.15 g, 15.7 mmol) was added dropwise. After a few minutes, the precipitate of N-methylmorpholine hydrochloride was filtered off and washed 3 times with dimethoxyethane (3 x 5 ml). The solution was transferred to a 250 mL vial, 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 eluted by chromatography (heptane:ethyl acetate=1:1) to give the title compound (1 g, yield 36%).

MS m/z(ESI): 186[M+H] ⁺ .

The second step: preparation of 2-(4-(methylthio)-3-nitronitro)ethan-1-ol

To a solution of 2-(4-fluoro-3-nitrophenyl)ethanol (1 g, 1 eq) in DMF (20 mL) was 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 give crude product, the residue was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=60:40) to give 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＝6.4Hz,2H),2.93(t,J＝6.4Hz,2H),2.49(s,3H),1.54(s,1H).

The third step: preparation of tert-butyl (6-((4-(methylthio)-3-nitrophenethoxy)methyl)pyridin-2-yl carbamate

A solution of 2-(4-(methylthio)-3-nitrophenyl)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 0.5 h. To the mixture was then 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 then 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: the preparation of tert-butyl (6-((3-amino-4-(methylthio) phenethoxy) methyl) pyridin-2-yl) carbamate

Dissolve tert-butyl (6-((4-(methylthio)-3-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (500 mg) in ethanol (5 mL) and water (1 mL) ), Fe (318 mg), ammonium chloride (333 mg) were added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered. The organic layer was concentrated to give crude product. The crude product was purified by flash column chromatography to give the title compound (400 mg, 77% yield).

MS m/z(ESI): 390[M+H] ⁺ .

The fifth step: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-(methylthio)phenethoxy ) methyl) pyridin-2-2-yl) carbamate preparation

To tert-butyl carbamate (6-(((3-amino-4-(methylthio)phenethoxy)methyl)pyridin-2-yl)carbamate (400 mg, 1.1 eq) at room temperature To a solution of tetrahydrofuran (5 mL) was added 4,6-dichloro-N-methylpyridazine-3-carboxamide (232 mg, 1.1 eq), sodium bis(trimethylsilyl)amide (1 mL, 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 then concentrated to obtain Crude product. The crude product was purified by silica gel column flash chromatography to give the title compound (400 mg, 69% yield).

MS m/z(ESI): 559[M+H] ⁺ .

Step 6: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-(methylthio)phenyl)amino)-6-chloro- Preparation of N-methylpyridazine-3-carboxamide

To tert-butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin 4-yl)amino)-4-(methylthio)phenethoxy)methyl at room temperature yl)pyridin-2-yl)carbamate (400 mg) in dichloromethane (3 mL), and to the reaction mixture was added hydrochloric acid in 1,4-dioxane (1.8 mL, 4M). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated to give the title compound (300 mg, 92% yield).

MS m/z(ESI): 459[M+H] ⁺ .

The seventh step: N-methyl-56-(methylthio)-8 ^- oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine- Preparation of 5(1,3)-benzocyclononane-3 ⁶ -carboxamide

4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-(methylthio)phenyl)amino)-6-chloro-N-methyl pyridazine-3-carboxamide (300 mg, 1 eq) was dissolved in 1,4-dioxane (6 mL), and tris(dibenzylideneacetone)dipalladium (89 mg, 0.15 g) was added to the reaction mixture under nitrogen protection. eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (76mg, 0.2eq), cesium carbonate (639mg, 3eq). The resulting reaction mixture was heated at 135°C Stirred 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 (200 mg, 73% yield).

MS m/z(ESI): 423[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6)δ: 11.02(s, 1H), 10.30(s, 1H), 9.05(d, J=4.8Hz, 1H), 8.75(s, 1H), 7.65-7.59(m ,1H),7.48(s,1H),7.35(d,J=8.0Hz,1H),7.11-7.05(m,2H),6.84(d,J=7.2Hz,1H),4.38(s,2H) ,3.75-3.69(m,2H),2.86-2.82(m,5H),2.41(s,3H).

Example 3:

N-methyl-56-(methylsulfonyl)-8 ^- oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1 Preparation of ,3)-benzocyclononane-3 ⁶ -carboxamide

N-methyl-56-(methylthio)-8 ^- oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1, 3)-Benzocyclononane ^- 36-carboxamide (40 mg, 1 eq) was dissolved in acetic acid (2 mL). Potassium peroxysulfate (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 give the crude product. The crude product was purified by preparative chromatography to give the title compound (5.2 mg, 12% yield).

MS m/z(ESI): 455[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6)δ: 11.34(s, 1H), 10.40(s, 1H), 9.05(d, J=4.8Hz, 1H), 8.58(s, 1H), 7.90(d, J =8.0Hz,1H),7.72(s,1H),7.67-7.61(m,1H),7.33(d,J=8.2Hz,1H),7.06(t,J=7.7Hz,1H),6.86(t , J=7.5Hz, 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=4.8Hz, 3H).

Example 4:

N-methyl-56-(methylsulfinyl)-8 ^- oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5( Preparation of 1,3)-benzocyclononane-3 ⁶ -carboxamide

N-methyl-56-(methylthio)-8 ^- oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1, 3)-benzocyclononane ^- 36-carboxamide (20 mg, 1 eq) was dissolved in a mixed solvent of methanol and tetrahydrofuran (4 mL, methanol:tetrahydrofuran=1:1). Potassium hydrogen 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 give the title compound (3.6 mg, 18% yield).

MS m/z(ESI): 439[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6)δ: 11.15(s, 1H), 10.41(s, 1H), 9.14(d, J=4.8Hz, 1H), 8.70(s, 1H), 7.78(d, J ＝8.0Hz,1H),7.64-7.62(m,2H),7.36(d,J＝8.0Hz,1H),7.07(d,J＝8.0Hz,1H),6.87(d,J＝7.3Hz,1H) ), 4.41(q, J＝11.2Hz, 2H), 3.83-3.72(m, 2H), 3.03-2.90(m, 2H), 2.86(d, J＝4.8Hz, 3H), 2.69(s, 3H) .

Example 5:

3 ^6- (Methylcarbamoyl)-5 ^6- (methylsulfonyl)-8-oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6) - Preparation of pyridine-5(1,3)-benzocyclononane-1 ¹ -oxide

N-methyl-56-(methylthio)-8 ^- oxa-2,4-diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1, A solution of 3)-benzocyclononane ^- 36-carboxamide (40 mg, 1 eq) was dissolved in dichloromethane (4 mL). To the reaction mixture was added 3-chloroperoxybenzoic acid (98 mg, 6 eq) 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 give the title compound (4.9 mg, 11% yield).

MS m/z(ESI): 471[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6)δ: 11.26(s, 1H), 10.35(s, 1H), 9.00(s, 1H), 8.79(d, J=4.8Hz, 1H), 7.88(d, J ＝8.0Hz,1H),7.72-7.70(m,2H),7.45(d,J＝8.4Hz,1H),7.30(d,J＝8.0Hz,1H),6.97(d,J＝7.2Hz,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=4.8Hz, 3H).

Example 6-1 and Example 6-2:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4-diaza- Preparation of 3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide 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 (22.17 g, 217.4 mmol) were dissolved in acetone (600 mL), and potassium monopersulfate (200 g, 1190.5mmol) solution in water (1L), the reaction solution was reacted at 20°C for 1 hour, after monitoring the reaction, extracted with ethyl acetate (3×500mL), the organic phase was washed with saturated brine (800mL), dried over anhydrous sodium sulfate, The title compound (44.4 g, 85% yield) was obtained after concentration.

MS m/z(ESI): 199.1, 201.1 [M+H] ⁺ .

The second step: preparation of methyl 2-hydroxy-5-(2-hydroxyethyl) benzoate

To a solution of 2-bromo-4-(2-hydroxyethyl)phenol (2000 mg, 9.21 mmol) in methanol (150 mL) was added 1,1-bis(diphenylphosphino)ferrocene palladium(II) chloride Dichloromethane complex (751.86 mg, 0.92 mmol), N,N-diisopropylethylamine (5954.09 mg, 46 mmol). The reaction solution was reacted at 80° C. under a carbon monoxide atmosphere (1.2 MPa) for 16 hours. LC-MS monitored the completion of the reaction (m/z 196.1), the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column (ethyl acetate:petroleum ether=1:1) to obtain the title compound (1.8g) , the yield is 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= 8.4Hz, 1H), 3.95(s, 3H), 3.85(t, J=6.4Hz, 2H), 2.81(t, J=6.4Hz, 2H).

The third step: the preparation of methyl 5-(2-acetoxyethyl)-2-hydroxybenzoate

Methyl 2-hydroxy-5-(2-hydroxyethyl)benzoate (1.8 g, 9.17 mmol) was dissolved in ethyl acetate (50 mL), concentrated sulfuric acid (100 mg, 0.3536 mmol) was added, and the reaction solution was heated at 60 °C After the reaction was monitored for 16 hours, the reaction was monitored and concentrated under reduced pressure. After concentration, the obtained residue was purified with a flash silica gel column (ethyl acetate/petroleum ether=0:1-4:1) to obtain the title compound (1.8 g, yield). rate 60%).

MS m/z(ESI): 179.1[M-59] ⁺ .

The fourth step: the preparation of methyl 5-(2-acetoxyethyl)-2-hydroxy-3-nitrobenzoate

To a solution of methyl 5-(2-acetoxyethyl)-2-hydroxybenzoate (1.8 g, 7.555 mmol) in acetic acid (20 mL) was added nitric acid (2.3 g, 15.11 mmol), and the reaction solution was reacted at room temperature for 16 Hour. After the reaction, water (80 mL) was added to quench, extracted with ethyl acetate (3×60 mL), the organic phases were combined, washed with saturated brine (80 mL), and the organic phase was dried with anhydrous sodium sulfate. The residue 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 methyl 5-(2-acetoxyethyl)-2-methoxy-3-nitrobenzoate

Methyl 5-(2-acetoxyethyl)-2-hydroxy-3-nitrobenzoate (1.7 g, 6.0021 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by adding carbonic acid Potassium (1.66 g, 12 mmol) and methyl iodide (1022.33 mg, 7.20 mmol), the reaction solution was reacted at 70° C. for 8 hours. After the reaction was completed, it was cooled to room temperature, water (160 mL) was added, extracted with ethyl acetate (3×30 mL), the organic phase was dried with anhydrous sodium sulfate and concentrated, and the obtained residue was filtered on a silica gel column (ethyl acetate/petroleum ether). =0-50%) to obtain the title compound (1.8 g, 98% yield).

MS m/z(ESI): 298.1[M+H] ⁺ .

The sixth step: the preparation of methyl 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzoate

Methyl 5-(2-acetoxyethyl)-2-methoxy-3-nitrobenzoate (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, the filter was filtered, 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), and the organic phase was dried with anhydrous sodium sulfate and concentrated. 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 (400MHz, 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: the preparation of 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzamide

A mixture of methyl 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzoate (680 mg, 2.66 mmol) in ammonia-methanol (10 mL, 7 M) was reacted at room temperature for 16 hours. After the reaction was completed, it was directly concentrated to obtain the title compound (550 mg, yield 80%).

MS m/z(ESI): 263.0[M+Na] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ: 7.73-7.69 (m, 2H), 3.82 (s, 3H), 3.68 (t, J=6.4Hz, 2H), 2.77 (t, J=6.4Hz, 2H) ).

Step 8: Preparation of 2-(4-methoxy-3-nitro-5-(1H-1,2,4-triazol-3-yl)phenyl)ethane-1-ol

A mixture of 5-(2-hydroxyethyl)-2-methoxy-3-nitrobenzamide (550 mg, 2.29 mmol) in N,N-dimethylformamide and dimethylacetal (5 mL) The solution was reacted at 95°C for one hour, then concentrated under reduced pressure, diluted with ethanol (3 mL) for use. Take another round-bottomed flask, add ethanol (4.5mL), cool to 0°C, add acetic acid (2.5mL), keep stirring at 0°C for 0.1 hour, then add hydrazine hydrate (1.0g, 16.027mmol), the reaction solution is at 0°C The reaction was carried out for 0.25 hours. Subsequently, the previously prepared ethanol solution was added, and the entire 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 solution (5 mL), and the organic phase was dried over anhydrous sodium sulfate. /dichloromethane=0-10%) to obtain the title compound (460 mg, 76% yield).

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=6.4Hz, 2H).

Step 9: 2-(4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenyl)ethane-1-ol preparation

2-(4-Methoxy-3-nitro-5-(1H-1,2,4-triazol-3-yl)phenyl)ethan-1-ol (400 mg, 1.51 mmol) was dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (292.91 mg, 2.12 mmol) and methyl iodide (279.33 mg, 1.97 mmol) were sequentially added, and the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, water (30 mL) was added, extracted with ethyl acetate (3×20 mL), the organic phase was dried with anhydrous sodium sulfate and concentrated, and the obtained residue was filtered on a silica gel column (methanol/dichloromethane=0-10 %) to obtain the title compound (280 mg, 66% yield).

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=6.4Hz, 2H).

Step 10: 2-Bromo-6-((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenethoxy ) methyl) pyridine preparation

2-(4-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenyl)ethane-1-ol (220 mg, 0.79 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (94.86 mg, 2.37 mmol), 15-crown-5 (2 drops), 2-bromo-6-( Chloromethyl)pyridine (326.47 mg, 1.58 mmol), the reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, ice water (30 mL) was added to quench, and ethyl acetate was extracted (3×20 mL). The organic phase was dried with anhydrous sodium sulfate. 0-75%) to give the title compound (180 mg, 51% yield).

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=7.6Hz, 1H), 7.27(d, J=7.6Hz, 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=6.4Hz, 2H).

The eleventh step: tert-butyl (6-((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenethoxy Preparation of yl)methyl)pyridin-2-yl)carbamate

to 2-bromo-6-((4-methoxy-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 with tert-butyl carbamate (78.39mg, 0.67mmol), tris(dibenzylideneacetone)dipalladium(0) (30.64 mg, 0.03 mmol), cesium carbonate (327.06 mg, 1. mmol), the reaction solution was reacted at 90° C. for 1 hour under nitrogen atmosphere. 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: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy ) methyl) pyridin-2-yl) preparation of carbamate

tert-Butyl(6-((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenethoxy)methyl ) pyridin-2-yl)carbamate (160mg, 0.33mmol) was dissolved in a mixture of ethanol and water (10mL, ethanol/water=4:1), and reduced iron powder (257mg, 4.6mmol) was added in turn and ammonium chloride (352 mg, 6.59 mmol), the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, water (30 mL) was added to quench, and the mixture was extracted with dichloromethane (3×40 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated. 0-80%) to give the title compound (100 mg, 63% yield).

MS m/z(ESI): 455.2[M+H] ⁺ .

The thirteenth step: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1 - Preparation of methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (68 mg, 0.33 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, water (5 mL) was added to quench, and dichloromethane was extracted (3×30 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated. The obtained residue was filtered through a silica gel column (ethyl acetate/petroleum ether= 0-80%) to give the title compound (80 mg, 55% yield).

MS m/z(ESI): 625.2[M+H] ⁺ .

Step Fourteen: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1 Preparation of ,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

tert-Butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl- 1H-1,2,4-Triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (80 mg, 0.128 mmol) was dissolved in hydrochloric acid in dioxane (4M, 3 mL), the mixture was stirred at 30 °C for 1 hour. After the reaction was completed, it was directly concentrated to obtain the title compound (60 mg, yield 80%).

MS m/z(ESI): 524.2[M+H] ⁺ .

The fifteenth step: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4 - Preparation of Diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide (Compound 6-1)

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-methylpyridazine-3-carboxamide (60 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL), 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene (2 mg, 0.0038 mmol), tris(dibenzylideneacetone)dipalladium (3.5 mg, 0.0038 mmol) were added under nitrogen atmosphere ) and cesium carbonate (37 mg, 0.1146 mmol). The mixture was stirred at 130°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain crude product, which was then prepared and purified by reverse column (acetonitrile:water=1:1) to obtain the title Compound (22 mg, 38% yield).

MS m/z(ESI): 487.2[M+H] ⁺ .

¹ H NMR (400MHz, 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).

Sixteenth step: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4 - Preparation of diazepine-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide trihydrochloride (compound 6-2)

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4-diazo- 3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide (10 mg, 0.02 mmol) was dissolved in dioxane hydrochloride In solution 4M (3 mL), the mixture was stirred at 30°C for 1 hour. After the reaction was completed, it was directly concentrated to obtain the title compound (12 mg, yield 95%).

MS m/z(ESI): 487.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ: 9.60(s, 1H), 9.23(s, 1H), 7.88(d, J=1.8Hz, 1H), 7.76-7.69(m, 1H), 7.65(d , J=1.8Hz, 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 7:

5 ⁶ -Methoxy-N-(methyl-d3)-5 ^5- (1-methyl-1H-1,2,4-triazol-3-yl)-8-oxo-2,4- Preparation of Diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: tert-butyl (6-((3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5 Preparation of -(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (180 mg, 0.395 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (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, water (5 mL) was added to quench, and dichloromethane was extracted (3×30 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated. The obtained residue was filtered through a silica gel column (ethyl acetate/petroleum ether= 0-80%) to give the title compound (200 mg, 72% yield).

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, Preparation of 2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)pyridazine-3-carboxamide

tert-Butyl(6-((3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1 -Methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (200 mg, 0.32 mmol) dissolved in dioxane hydrochloride In the solution (3 mL, 4 mol/L), the mixture was stirred at 40° C. for 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: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4- Preparation of Diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

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)pyridazine-3-carboxamide (80 mg, 0.15 mmol) dissolved in 1,4-dioxane ( 3 mL), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (8.8 mg, 0.015 mmol), tris(dibenzylideneacetone)dipalladium ( 13.9 mg, 0.015 mmol) and cesium carbonate (148 mg, 0.45 mmol). The mixture was stirred at 130°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain crude product, which was then prepared by reverse column (acetonitrile:water=1:1), and the title compound was obtained after purification (5 mg, 6% yield).

MS m/z(ESI): 491.3[M+H] ⁺ .

¹ H NMR (400MHz, 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=7.8Hz, 1H), 4.52(s, 2H), 4.03(s, 3H), 3.89-3.85(m, 5H),3.15-2.87(m,2H).

Example 8:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-oxa-2,4-diaza-3(3,5) - Preparation of pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: preparation of ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenylacetate

Ethyl 3-bromo-4-methoxy-5-nitrophenylacetate (500 mg, 1.57 mmol) was dissolved in a mixed solution (8 mL, 1,4-dioxane:water=3:1), in Under nitrogen atmosphere were added [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-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (360 mg, 1.73 mmol), and the mixture was stirred at 90° C. for 1 hour. After the reaction, extracted with ethyl acetate (3×5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the obtained residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1) after concentration The title compound (480 mg, 77% yield) 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＝2.4Hz, 1H), 4.25(t, J＝6.0Hz, 2H), 3.93(s, 3H), 3.69(s, 3H), 2.97(t, J＝6.0Hz, 2H), 1.99 (s,3H).

The second step: preparation of 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethyl-1-ol

Ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenylacetate (480 mg, 1.50 mmol) was dissolved in methanol (4 mL) and methanol was added Sodium (41 mg, 0.75 mmol), and the mixture was stirred at 25°C for 2 hours. After the reaction, 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 filtered on a silica gel column (dichloromethane/methanol). = 1/0) to obtain the title compound (240 mg, 46% yield) 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=4.0Hz, 1H), 4.70 (t, J=6.0Hz, 1H), 3.93 (d, J=2.0Hz, 3H), 3.71 (s, 3H), 3.62 (t, J=4.0Hz) ,2H),2.79(t,J＝8.0Hz,2H).

The third step: tert-butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)pyridin-2-yl ) Preparation of carbamate

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethyl-1-ol (240 mg, 0.86 mmol) was dissolved in N , N-dimethylformamide (5 mL), sodium hydride (62 mg, 2.60 mmol) was added, and the mixture was stirred at 0° C. for 10 minutes. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (3×10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the title compound (400 mg) was obtained, which was used directly for next reaction.

MS m/z(ESI): 484.1[M+H] ⁺ .

The fourth step: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenethoxy) methyl) pyridine-2 - group) preparation of carbamates

tert-Butyl(6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)pyridin-2-yl)aminomethane The acid ester (400mg, 0.82mmol) was dissolved in a mixed solution of ethanol and water (EtOH:H ₂ O=4:1, 5mL), iron powder (645mg, 11.56mmol) and ammonium chloride (883mg, 16.5mmol) were added , the mixture was refluxed for 1 hour at 80° C. After the reaction was completed, the filtrate was obtained by filtration, and after concentration, the obtained residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1) to obtain the title compound (130 mg , the yield is 24%).

MS m/z(ESI): 454.2[M+H] ⁺ .

The fifth step: tert-butyl (6-((3-((6-chloro-3-(formamido)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of -1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-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-methylpyridazine-3-carboxamide (59 mg, 0.29 mmol) were dissolved in tetrahydrofuran (3 mL) and bis(trimethyl) was slowly added dropwise (2M, 0.29 mL, 0.58 mmol), and the mixture was stirred at 25°C for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), and after concentration, the obtained residue was purified by silica gel column (dichloromethane/methanol=17/3) to obtain the title compound (90 mg, yield 35%).

MS m/z(ESI): 624.2[M+H] ⁺ .

Step 6: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole Preparation of -3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carbamate

(6-((3-((6-Chloro-3-(carboxamido)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazole- 3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (90mg, 0.14mmol) was dissolved in a mixture of hydrochloric acid dioxane (HCl/dioxane=4mol/L, 4mL) , the mixture was stirred at 25°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: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridazine 1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole-3- (yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carbamate (60 mg, 0.11 mmol) was dissolved in 1,4-dioxane (3 mL) under nitrogen atmosphere Add 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°C for 4 hours. After the reaction, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=17/3) to obtain crude product, which was then prepared by reverse column (acetonitrile:water=1:1), and the title compound was obtained after purification (2.3 mg, 4% yield).

MS m/z(ESI): 487.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ: 11.84(s, 1H), 9.94(s, 1H), 9.34(s, 1H), 7.86(s, 1H), 7.68(d, J=2.0Hz, 1H), 7.62-7.59(m, 2H), 7.42(d, J=2.4Hz, 1H), 6.94(d, J=8.4Hz, 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=4.8Hz,3H),2.98-2.92(m,2H).

Example 9:

⁵⁶ -Methoxy-N-(methyl- _d3 )-55-( ¹ -methyl-1H-pyrazol-3-yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: tert-butyl (6-((3-((6-chloro-3-((methyl-d ₃ )carboxamido)pyridazin-4-yl)amino)-4-methoxy- Preparation of 5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl) Carbamate (see Example 8 for preparation, 270 mg, 0.59 mmol) and 4,6-dichloro-N-(methyl-d ₃ )pyridazine-3-carboxamide (124 mg, 0.59 mmol) in tetrahydrofuran (5 mL), sodium bis(trimethylsilyl)amide (2M, 0.59 mL, 1.19 mmol) was slowly added dropwise, and the mixture was stirred at 25° C. for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), and after concentration, the obtained residue was purified by silica gel column (dichloromethane/methanol=9/1) to obtain the title compound (200 mg, yield 37%).

MS m/z(ESI): 626.3[M+H] ⁺ .

Step 2: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole Preparation of -3-yl)phenyl)amino)-6-chloro-N-(methyl- _d3 )pyridazine-3-carbamate

The purified tert-butyl(6-((3-((6-chloro-3-((methyl- _d3 )carboxamido)pyridazin-4-yl)amino)-4-methoxy-5 -(1-Methyl-1H-pyrazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (200mg, 0.32mmol) in dioxane hydrochloride (HCl/dioxane=4mol/L, 5mL), the mixture was stirred at 25°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: ⁵⁶ -methoxy-N-(methyl- _d3 )-55-( ¹ -methyl-1H-pyrazol-3-yl)-8-oxa-2,4-di Preparation of nitrogen-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole-3- (yl)phenyl)amino)-6-chloro-N-(methyl- _d3 )pyridazine-3-carbamate (100 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 mL) , 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (66mg, 0.11mmol), tris(dibenzylideneacetone)dipalladium (52mg, 0.05mmol) were added under nitrogen atmosphere ) and cesium carbonate (557 mg, 1.71 mmol). The mixture was stirred at 130°C for 6 hours. After the reaction, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=4/1) to obtain crude product, which was then prepared by reverse column (acetonitrile:water=1:1), and after purification, the title was obtained Compound (4.5 mg, 4% yield).

MS m/z(ESI): 490.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ: 11.37(s, 1H), 10.36(s, 1H), 9.05(s, 2H), 7.77(d, J=2.0Hz, 1H), 7.65(t, J=7.6Hz,1H),7.57(d,J=1.6Hz,1H),7.48(d,J=1.6Hz,1H),7.10(d,J=8.4Hz,1H),6.88(d,J= 7.2Hz, 1H), 6.74(d, J=2.0Hz, 1H), 4.44(s, 2H), 3.91(s, 3H), 3.75(t, J=4.8Hz, 2H), 3.60(s, 3H) ,2.86(t,J=4.8Hz,2H).

Example 10:

¹⁵ -Fluoro-56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8 ^- oxa-2,4-diaza-3 Preparation of (3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: the preparation of tert-butyl (tert-butoxycarbonyl) (5-fluoro-6-methylpyridin-2-yl) carbamate

5-Fluoro-6-methylpyridine-2-amino (5.0 g, 39.68 mmol) was dissolved in acetonitrile (50 mL), to the solution was added di-tert-butyl dicarbonate (21.63 g, 99.20 mmol, 2.5 eq), Triethylamine (10.02g, 99.20mmol, 2.5eq), 4-dimethylaminopyridine (0.91g, 7.94mmol, 0.2eq). 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: the preparation of tert-butyl (6-(bromomethyl)-5-fluoropyridin-2-yl) (tert-butoxycarbonyl) carbamate

The product tert-butyl(tert-butoxycarbonyl)(5-fluoro-6-methylpyridin-2-yl)carbamate (8.8 g, 26.99 mmol) obtained in the previous step was dissolved in carbon tetrachloride (30 mL) In this, N-bromosuccinimide (5.76g, 32.39mmol, 1.2eq) and azobisisobutyronitrile (0.44g, 2.70mmol, 0.1eq) were added successively, and the reaction solution was stirred at 80° C. for 16h. 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: tert-butyl (5-fluoro-6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy) methyl Preparation of yl)pyridin-2-yl)carbamate

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-ol (1.14g, 4.14mmol, 1.5eq) Dissolve in DMF (10 mL), add sodium hydride (0.4 g, 16.56 mmol, 4 eq) at 0 °C, stir for 10 min, and then add tert-butyl (6-(bromomethyl)-5-fluoropyridine) to the reaction solution -2-yl) (tert-butoxycarbonyl) carbamate (1.12 g, 2.76 mmol, 1 eq), the mixture was reacted at 0 °C for 4 h. After the reaction, water was slowly added dropwise, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and 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: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5- Preparation of fluoropyridin-2-yl)carbamate

tert-Butyl(5-fluoro-6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)methyl)pyridine -2-yl)carbamate (0.4 g, 0.82 mmol) was dissolved in a saturated aqueous solution of ethanol and ammonium chloride (ethanol/ammonium chloride = 4/1, 15 mL), and iron powder (0.92 g, 16.4 mL) was added. mmol, 20eq), the reaction solution was stirred at 80 °C for 1 h. After the reaction, the concentrated crude product of the reaction solution 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: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenylethoxy)methyl)-5-fluoropyridin-2-yl)carbamate

The tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5-fluoropyridine- 2-yl)carbamate (0.27g, 0.58mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (0.36g, 1.74mmol, 3eq) were dissolved in tetrahydrofuran (10mL) , NaHMDS (0.64g, 3.48mmol, 6eq) was added to the reaction solution, the reaction solution was stirred at room temperature for 10min, the reaction solution was concentrated after the reaction, and the crude product was subjected to column chromatography (petroleum ether/ethyl acetate=1/1 ) was isolated and purified to obtain the title compound (128 mg, yield 35%).

MS m/z(ESI): 641.1[M+H] ⁺ .

Step 6: 4-((5-(2-((6-amino-3-fluoropyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl- Preparation of 1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carbamate

tert-Butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-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 dichloromethane (5 mL) and added to To the reaction mixture was added hydrochloric acid in dioxane (10 mL, 4M). The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated to give the title compound (91.8 mg, 85% yield).

MS m/z(ESI): 541.1[M+H] ⁺ .

Step 7: ¹⁵ -Fluoro-56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8 ^- oxa-2,4-di Preparation of aza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

4-((5-(2-((6-amino-3-fluoropyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine oxazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carbamate (90 mg, 0.16 mmol) was dissolved in 1,4-dioxane (5 mL), Tris(dibenzylideneacetone)dipalladium (44mg, 0.048mmol, 0.3eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine was added to the reaction mixture under nitrogen protection (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 give the title compound (6.5 mg, 8% yield).

MS m/z(ESI): 505.1[M+H] ⁺ .

1H NMR (400MHz, DMSO-d6) δ: 11.32(s, 1H), 10.43(s, 1H), 9.07(d, J=4.8Hz, 1H), 8.89(s, 1H), 7.78(d, J= 2.2Hz, 1H), 7.65 (t, J=9.2Hz, 1H), 7.54 (d, J=1.8Hz, 1H), 7.50 (d, J=1.8Hz, 1H), 7.16 (dd, J=9.0, 3.2Hz, 1H), 6.74(d, J=2.2Hz, 1H), 4.57(d, J=2.4Hz, 2H), 3.91(s, 3H), 3.81-3.76(m, 2H), 3.59(s, 3H),2.89-2.85(m,5H).

Example 11:

5 ⁶ -Methoxy-N,8-dimethyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-2,4,8-triaza-3(3,5) - Preparation of pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: preparation of (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl) tert-butyl carbamate

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 an ice bath. It was then stirred at room temperature overnight. After completion of the reaction, 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] ⁺ .

The second step: the preparation of (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl) (methyl) carbamate tert-butyl ester

(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)carbamate (400 mg, 1.06 mmol) was dissolved in DMF (10 mL) to the solution in , and sodium hydrogen (76 mg, 3.18 mmol) was added at 0°C. After the reaction was stirred for 15 minutes, _CH3I (150 mg, 5.30 mmol) was added at room temperature and the reaction was stirred for 3 hours. Saturated ammonium chloride solution was added to quench the reaction, water (50 mL) was added, and ethyl acetate (30 mL×3) was used for extraction. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE=30%) gave 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-nitrophenyl)-N-methylethane-1-amine preparation

Dissolve tert-butyl (4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)(methyl)carbamate (350 mg, 0.90 mmol) in dioxane hydrochloride (10 mL, 4M). The reaction suspension was stirred at 25°C for 2 hours. LC-MS showed that the reaction was complete. Concentration under reduced pressure gave the title compound (250 mg, 96% yield).

MS m/z(ESI): 291.2[M+H] ⁺ .

The fourth step: tert-butyl (tert-butoxycarbonyl) (6-(((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl ) (methyl) amino) methyl) pyridin-2-yl carbamate preparation

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)-N-methylethane-1-amine (250 mg, 0.86 mmol) in DMF (10 mL), and sodium hydride (41 mg, 1.72 mmol) was added at 0° C. After stirring the reaction for 15 min, (6-(bromomethyl)pyridine-2- (tert-butoxycarbonyl)carbamate (398 mg, 1.03 mmol), and the reaction was stirred for 3 hours. Saturated ammonium chloride solution was added to quench the reaction, water (50 mL) was added, and ethyl acetate (30 mL×3) was used for extraction. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (EA/PE=30%) gave the title compound (400 mg, yield 78%).

MS m/z(ESI): 597.3[M+H] ⁺ .

The fifth step: tert-butyl (6-((((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl) phenethyl) (methyl) amino ) methyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate preparation

tert-Butyl(tert-butoxycarbonyl)(6-(((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)(methyl base)amino)methyl)pyridin-2-ylcarbamate (400mg, 0.67mmol), iron powder (300mg, 5.36mmol) and ammonium chloride (289mg, 5.36mmol) were mixed in a mixture of ethanol and water (ethanol:water=4:1, 20mL). 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%) to obtain The title compound (350 mg, 92% yield).

MS m/z(ESI): 567.3[M+H] ⁺ .

The sixth step: tert-butyl (6-((((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-( Preparation of 1-Methyl-1H-pyrazol-3-yl)phenethyl)(methyl)amino)methyl)pyridin-2-ylcarbamate

tert-Butyl(6-((((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)(methyl)amino)methyl ) pyridin-2-yl)(tert-butoxycarbonyl)carbamate (350mg, 0.62mmol), 4,6-dichloro-N-methylpyridazine-3-carboxamide (190mg, 0.93mmol) mixed Dissolved in tetrahydrofuran (10 mL), sodium bis(trimethylsilyl)amide (1.6 mL, 3.1 mmol, 2M in tetrahydrofuran) was added dropwise at room temperature. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, a saturated solution was added. The reaction was quenched with an aqueous solution of ammonium chloride. 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 then concentrated. Purified by flash column chromatography ( PE/EA=0-100%) to obtain the title compound (300 mg, yield 76%).

MS m/z(ESI): 636.3[M+H] ⁺ .

Step 7: 4-((5-(2-(((((6-aminopyridin-2-yl)methyl)(methyl)amino)ethyl)-2-methoxy-3-(1 Preparation of -methyl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

To a 100 mL flask was added the title compound tert-butyl(6-((((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4 obtained in the previous step -Methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)(methyl)amino)methyl)pyridin-2-ylcarbamate (300 mg, 0.47 mmol) Then, 4M hydrochloric acid dioxane solution (8 mL) was slowly added 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: 56 ^- methoxy-N,8-dimethyl-55-( ¹ -methyl-1H-pyrazol-3-yl)-2,4,8-triaza-3( Preparation of 3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-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-methylpyridazine-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-bisdiphenylphosphino-9,9-dimethylxanthene (43 mg, 0.07 mmol) was mixed in 1,4-dioxane (10 mL) Replaced three times under nitrogen atmosphere, then the reaction mixture was heated to 130°C in a closed tube and stirred for 2 hours. After the reaction was completed, filtered and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain the title compound ( 1.5 mg, 7% yield).

MS m/z(ESI): 500.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ: 11.35(s, 1H), 10.34(s, 1H), 9.12(s, 1H), 9.07(d, J=4.8Hz, 1H), 7.77(d, J=2.2Hz, 1H), 7.67 (d, J=2.0Hz, 1H), 7.65–7.59 (m, 1H), 7.46 (d, J=2.0Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 6.84(d, J＝8.0Hz, 1H), 6.73(d, J＝2.0Hz, 1H), 3.91(s, 3H), 3.60(s, 3H), 3.48(s, 2H), 2.86( d, J=4.8Hz, 2H), 2.82–2.80 (m, 2H), 2.69–2.67 (m, 3H), 1.96 (s, 3H).

Example 12:

5 ⁶ -Methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-thi-2,4-diaza-3(3,5)- Preparation of Pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

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-nitrobenzene]ethanol (500 mg, 1.80 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of three Ethylamine (546mg, 5.41mmol), 4-toluenesulfonyl chloride (413mg, 2.16mmol) and 4-dimethylaminopyridine (22mg, 0.18mmol). The reaction solution was reacted at 25°C for 16 hours. After monitoring the reaction, water was added (30 mL) was quenched, extracted with dichloromethane (3×30 mL), the organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, and then concentrated. Petroleum ether = 0-20%) to obtain the title compound (930 mg, 96% yield).

MS m/z(ESI): 432.2[M+H] ⁺ .

The second step: the preparation of 2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]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) ), added thiourea (328 mg, 4.31 mmol) and reacted at 80°C for 16 hours, LC-MS monitored the completion of the reaction (m/z 336.1), 20% sodium hydroxide solution (7 mL) was added to the reaction solution and continued at 80°C Stir for 1 hour, then neutralize with 10% HCl to pH=3-4, extract with dichloromethane (3×30 mL), wash the organic phase with saturated brine (10 mL×2), dry over anhydrous sodium sulfate, and concentrate to obtain The residue was purified by 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: tert-butyl{6-[({2-[4-methoxy-3-(1-methylpyrazolyl-3-yl)-5-nitrophenyl]ethyl}sulfonyl ) methyl]pyridin-2-yl}carbamate preparation

2-[4-Methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethanethiol (392 mg, 1.34 mmol) was dissolved in N,N-dimethyl Formamide (3 mL) was under nitrogen protection, sodium hydride (96 mg, 4.01 mmol) was added, the reaction solution was reacted at 0 °C for 0.5 h, [6-(bromo) dissolved in N,N-dimethylformamide (1 mL) was added Methyl)pyridin-2-yl]carbamate tert-butyl ester (770mg, 2.67mmol), the reaction was carried out at 0°C for 10 minutes under nitrogen, after monitoring the reaction was completed, water (30mL) was added to quench, and ethyl acetate was extracted (3 × 30 mL), the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column (ethyl acetate/petroleum ether=0-20%) to obtain the title compound (288 mg, 30% yield).

MS m/z(ESI): 500.2[M+H] ⁺ .

The fourth step: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazolyl-3-yl)phenethyl)thio)methyl) Preparation of pyridin-2-yl)carbamate

tert-Butyl {6-[({2-[4-methoxy-3-(1-methylpyrazol-3-yl)-5-nitrophenyl]ethyl}sulfonyl)methyl ]pyridin-2-yl}carbamate (400mg, 0.82mmol) was dissolved in a mixture of ethanol and water (ethanol/water=4:1, 20mL), and reduced iron powder (645mg, 11.56mmol) was added in turn and ammonium chloride (883 mg, 16.5 mmol), the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, water (30 mL) was added to quench, extracted with dichloromethane (3×40 mL), the organic phase was dried with anhydrous sodium sulfate, and the obtained residue was concentrated with silica gel column (ethyl acetate/petroleum ether=0 -80%) to obtain the title compound (150 mg, 24% yield).

MS m/z(ESI): 470.2[M+H] ⁺ .

The fifth step: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenethyl)thio)methyl)pyridin-2-yl)carbamate

tert-Butyl(6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)thio)methyl)pyridine-2 -yl)carbamate (150 mg, 0.33 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (68 mg, 0.33 mmol) and bis(tris Sodium methylsilyl)amide (0.3 mL) was reacted at room temperature for 10 minutes. After the reaction, water (5 mL) was added to quench, extracted with dichloromethane (3×30 mL), the organic phase was dried with anhydrous sodium sulfate, and the residue obtained after concentration was filtered on a silica gel column (ethyl acetate/petroleum ether=0 -80%) was purified to give the title compound (100 mg, 39% yield).

MS m/z(ESI): 639.2[M+H] ⁺ .

The fifth step: 4-((5-(2-((6-aminopyridin-2-yl)methyl)thio)ethyl)-2-methoxy-3-(1-methyl-1H- Preparation of pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

tert-Butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl- 1H-pyrazol-3-yl)phenethyl)thio)methyl)pyridin-2-yl)carbamate (100mg, 0.157mmol) was dissolved in hydrochloric acid dioxane solution 4M (3mL), mixed The solution was stirred at 30°C for 1 hour. After the reaction was completed, it was directly concentrated to obtain the title compound (20 mg, yield 34%).

MS m/z(ESI): 539.2[M+H] ⁺ .

The ^sixth step: 56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-thi-2,4-diaza-3(3 Preparation of ,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

4-((5-(2-((6-aminopyridin-2-yl)methyl)thio)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole- 3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (20 mg, 0.037 mmol) was dissolved in 1,4-dioxane (3 mL) under nitrogen atmosphere Add 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2 mg, 0.0038 mmol), tris(dibenzylideneacetone)dipalladium (3.5 mg, 0.0038 mmol) and cesium carbonate (37 mg, 0.1146 mmol). The mixture was stirred at 130°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain the crude product, and then purified by 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 (400MHz, 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=7.2Hz, 1H), 6.87(s, 1H), 6.76(d, J=8.1Hz, 1H), 3.98(s, 3H), 3.81(s, 2H), 3.71(s, 3H), 3.07-2.94(m, 4H).

Example 13:

56 ^- Methoxy-N-methyl-55-( ¹ -methyl-1H-pyrazol-3-yl)-9-oxo-2,4,8-triaza-3(3, 5)-Pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide

The first step: preparation of methyl 6-(bis(tert-butoxycarbonyl)amino)picolinate

Methyl 6-aminopyridine-2-carboxylate (1.0 g, 6.58 mmol), 4-dimethylaminopyridine (80 mg, 0.66 mmol) were mixed in tetrahydrofuran (20 mL). Di-tert-butyl dicarbonate (4.30 g, 19.74 mmol) was added dropwise to the reaction solution under an ice bath. It was then stirred at room temperature overnight. After completion of the reaction, 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-((tert-butoxycarbonyl)amino)picolinic acid

Methyl 6-(bis(tert-butoxycarbonyl)amino)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, 30mL). The reaction was stirred at 70°C for 2 hours. After the completion of the reaction, adjust the pH to 6, add water (50 mL), and extract 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 (EA/PE=0-30%) gave 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-nitrophenethyl)isoindoline-1,3-dione preparation

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-ol 1 (500 mg, 1.80 mmol) was dissolved in THF (20 mL) and cooled to 0°C, added triphenylphosphine (943 mg, 3.60 mmol), isoindoline-1,3-dione (318 mg, 3.60 mmol) and DIAD (727 mg, 3.6 mmol), respectively, and reacted Stir at room temperature for 2h. 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%) gave the title compound (586 mg, yield 80%).

MS m/z(ESI): 407.1[M+H] ⁺ .

The fourth step: the preparation of 2-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-amine

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)isoindoline-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 the mixture was 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%) gave the title compound (358 mg, yield 90%).

MS m/z(ESI): 277.1[M+H] ⁺ .

The fifth step: tert-butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)carbamoyl)pyridine- Preparation of 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-( (tert-Butoxycarbonyl)amino)picolinic acid (302 mg, 1.27 mmol) was dissolved in dichloromethane (30 mL), triethylamine (647 mg, 6.35 mmol) and 2-propanephosphonic anhydride (1.61 g, 2.54 mmol) were added, respectively. 50% wt in EtOAc). The solution was stirred at room temperature for 1 hour. Water (50 mL) was added, and dichloromethane (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%) gave the title compound (400 mg, yield 63%).

MS m/z(ESI): 497.2[M+H] ⁺ .

The sixth step: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)carbamoyl)pyridine-2 - group) preparation of carbamates

tert-Butyl(6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethyl)carbamoyl)pyridin-2-yl ) carbamate (400mg, 0.81mmol), iron powder (362mg, 6.48mmol) and ammonium chloride (350mg, 6.48mmol) were dissolved in a mixture of ethanol and water (ethanol:water=4:1,20mL) middle. The reaction was stirred at 50°C for 2 hours. After completion of the reaction, the reaction was filtered, concentrated under reduced pressure, and subjected to 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: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenethylcarbamoyl)pyridin-2-ylcarbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)carbamoyl)pyridin-2-yl) Carbamate 7 (350 mg, 0.75 mmol), 4,6-dichloro-N-methylpyridazine-3-carboxamide (230 mg, 1.12 mmol) were dissolved in tetrahydrofuran (10 mL), and bisulfite was added dropwise at room temperature Sodium (trimethylsilyl)amide (1.9 mL, 3.75 mmol, 2M in tetrahydrofuran). The mixture was stirred at 25°C for 1 hour. After the reaction was completed, 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%) gave 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)benzene Preparation of yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

In a 100 mL flask was added tert-butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-( 1-Methyl-1H-pyrazol-3-yl)phenethylcarbamoyl)pyridin-2-ylcarbamate (300 mg, 0.47 mmol). Then, a 4M solution of hydrochloric acid in dioxane was slowly added dropwise (8 mL). Stir at 25° C. for 4 hours. After completion of the reaction, concentrate under reduced pressure to obtain the title compound (200 mg, yield 80%).

MS m/z(ESI): 536.2[M+H] ⁺ .

Step 9: 56 ^- methoxy-N-methyl-55-( ¹ -methyl-1H-pyrazol-3-yl)-9-oxo-2,4,8-triaza- Preparation of 3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononyl-3 ⁶ -carboxamide

4-((5-(2-(6-Aminopicolinamido)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino) -6-Chloro-N-methylpyridazine-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-bis Diphenylphosphine-9,9-dimethylxanthene (43 mg, 0.07 mmol) was mixed in 1,4-dioxane (10 mL). After three displacements under 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 the crude product. The crude product was purified by preparative liquid chromatography to give the title compound (26 mg, 14% yield).

MS m/z(ESI): 500.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ: 11.11(s, 1H), 10.56(s, 1H), 9.11(d, J=4.0Hz, 1H), 8.64(s, 1H), 8.29(t, J=4.0Hz, 1H), 7.83(t, J=8.0Hz, 1H), 7.78(d, J=2.0Hz, 1H), 7.73(d, J=2.0Hz, 1H), 7.58(d, J= 2.0Hz, 1H), 7.46(d, J＝8.0Hz, 1H), 7.38(d, J＝8.0Hz, 1H), 6.73(d, J＝2.0Hz, 1H), 3.92(s, 3H), 3.59 (s, 3H), 3.50(d, J=4.0Hz, 2H), 2.88(s, 2H), 2.88(d, J=4.0Hz, 3H).

Example 14:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ⁴ -yl)-8-oxa-2,4-diaza-3(3,5) - Preparation of pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl(6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)amino Formate (refer to Example 23 for preparation method, 50 mg, 0.11 mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (45 mg, 0.22 mmol) were dissolved in THF (2 mL), and NaHMDS was added (0.3 mL, 0.55 mmol). The reaction solution was stirred at 25°C for 1 hour. After the completion of the reaction, saturated aqueous ammonium chloride solution (3 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×2), the combined organic layers were washed with brine (10 mL×1), dried over anhydrous sodium sulfate and reduced under reduced pressure. Press down to concentrate. Purification by flash column chromatography gave the title compound (50 mg, 61.5% yield).

MS m/z(ESI): 624.3[M+H] ⁺ .

Step 2: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Preparation of oxazol-4-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

tert-Butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-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 a 4M solution of hydrochloric acid in dioxane was added (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, 63% yield).

MS m/z(ESI): 523.1[M+H] ⁺ .

The third step: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ⁴ -yl)-8-oxa-2,4-diaza-3( Preparation of 3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononyl ^- 36-carboxamide

4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole-4 -yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (10 mL), and the reaction was carried out under nitrogen protection. To the mixture was added tris(dibenzylideneacetone)dipalladium (26mg, 0.028mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (22mg, 0.038mmol), carbonic acid Cesium (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 give the crude product. The crude product was purified by preparative HPLC to give the title compound (0.3 mg, collected rate 0.6%).

MS m/z(ESI): 487.3[M+H] ⁺ .

¹ H NMR (400MHz, 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＝7.8Hz,1H),7.46(s,1H),7.21(s,1H),7.08(d,J＝8.3Hz,1H),6.85(d,J＝7.2Hz,1H), 4.42(s, 2H), 3.87(s, 3H), 3.77–3.70(m, 2H), 3.56(s, 3H), 2.83(t, J=5.6Hz, 5H).

Example 15:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-oxa-2,4-diaza-1(2,8) -Preparation of quinoline-3(3,5)-pyridazine 5(1,3)-benzocyclooctane ^- 36-carboxamide

The first step: the preparation of (tert-butoxycarbonyl) (8-hydroxyquinoline-2-hydroxy) tert-butyl carbamate

2-Aminoquinoline-8-hydroxy (2 g, 1 eq) was dissolved in tetrahydrofuran (60 mL), 4-DMAP (0.46 g, 0.3 eq), Boc ₂ O (3.27 g, 2.2 eq) were added. Stir overnight at room temperature. The reaction mixture was concentrated in vacuo and chromatographed to give the title compound (3 g, 66.7% yield).

MS m/z(ESI): 361[M+H] ⁺ .

The second step: tert-butyl (tert-butoxycarbonyl) (8-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy) ) Preparation of 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) ), to the reaction mixture was added tert-butyl (tert-butoxycarbonyl)(8-hydroxyquinoline-2-hydroxy)carbamate (1045 mg, 1 eq), triphenylphosphine (908 mg, 1.2 eq), and the resulting reaction The mixture was stirred at 25°C for 0.2 hours. To the reaction mixture was added di-tert-butyl azodicarboxylate (797 mg, 1.2 eq) 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 give the title compound (560 mg, 30% yield).

MS m/z(ESI): 620[M+H] ⁺ .

The third step: tert-butyl (8-(3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)quinolin-2-yl) Preparation of (tert-butoxycarbonyl)carbamate

tert-Butyl(tert-butoxycarbonyl)(8-(4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)quinoline -2-yl)carbamate (560 mg, 1 eq) was dissolved in ethanol (15 mL) and water (5 mL), and iron powder (252 mg, 5 eq), 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 give crude product. The crude product was purified by silica gel column to give the title compound (160 mg, 30% yield).

MS m/z(ESI): 590[M+H] ⁺ .

The fourth step: tert-butyl (tert-butoxycarbonyl) (8-(3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy- Preparation of 5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)quinolin-2-yl)carbamate

The tert-butyl (8-(3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)quinolin-2-yl)(tert-butyl oxycarbonyl)carbamate (400mg, 1eq) was dissolved in tetrahydrofuran (20mL), a solution of 4,6-dichloro-N-methylpyridazine-3-carboxamide (139mg, 1eq) was added, bis(tris Sodium methylsilyl)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 then concentrated to give crude product. The crude product was purified by flash silica gel column chromatography to give the product (330 mg, 64% yield).

MS m/z(ESI): 759[M+H] ⁺ .

The fifth step: 4-((5-(2-(((2-aminoquinolin-8-yl)oxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Preparation of oxazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

tert-Butyl(tert-butoxycarbonyl)(8-(3-((6-chloro-3-(methylcarbamoyl)pyridazin-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) and added to the reaction mixture Hydrochloric acid in dioxane (2.2 mL). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated to give the product title compound (200 mg, 82.3% yield).

MS m/z(ESI): 559[M+H] ⁺ .

The ^sixth step: 56-methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-oxa-2,4-diaza-1( Preparation of 2,8)-quinoline-3(3,5)-pyridazine 5(1,3)-benzocyclooctane-3 ⁶ -carboxamide

4-((5-(2-(((2-Aminoquinolin-8-yl)oxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole-3 -yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (100 mg, 1 eq) was dissolved in dioxane (3 mL) and tris(dibenzylidene) was added to the reaction mixture acetone) dipalladium (25mg, 0.15eq), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (21mg, 0.2eq), cesium carbonate (175mg, 3eq). The obtained The reaction mixture was stirred at 135° C. for 16 h. The reaction mixture was filtered. The organic layer was concentrated to give the crude product, which was purified to give the title compound (1.4 mg, 1.5% yield).

MS m/z(ESI): 523[M+H] ⁺ .

¹ H NMR (400MHz, 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 16:

⁵⁶ -Methoxy-N, ¹⁵ -dimethyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-oxa-2,4-diaza-3( Preparation method of 3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide

The first step: the preparation of methyl 6-amino-3-methylpicolinate

Methyl 6-amino-3-bromopicolinate (4 g, 17.31 mmol) was dissolved in dioxane (50 mL), and a solution of trimethylcyclotriboroxane in tetrahydrofuran (4.34 g, 34.62 mmol) was added to the reaction solution. mmol, 2eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.26g, 1.73mmol, 0.1eq), potassium carbonate (7.18g, 51.93mmol, 3eq), The reaction mixture was stirred at 110 °C for 4 h. After completion of the reaction, the reaction solution 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(tert-butoxycarbonyl)amino)-3-methylpicolinate methyl ester

Methyl 6-amino-3-methylpicolinate (2.6g, 15.64mmol) was dissolved in acetonitrile (30mL), to the solution was added di-tert-butyl dicarbonate (8.53g, 39.1mmol, 2.5eq), 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) tert-butyl carbamate

Methyl 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) was slowly added dropwise at 0 °C , 13.64mmol, 2.0eq), 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 (3×30 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and 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) tert-butyl carbamate

Dissolve tert-butyl 6-(hydroxymethyl)-5-methylpyridin-2-yl)carbamate (0.8 g, 3.36 mmol) in dichloromethane (20 mL) and add triphenylphosphine at 0 °C (1.06g, 4.03mmol, 1.2eq), then carbon tetrabromide (1.34g, 4.03mmol, 1.2eq) was added, and stirred at room temperature for 30min. After the reaction, the reaction solution was concentrated, and the crude product was subjected to column chromatography Purification (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: tert-butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)methyl)-5 - Preparation of methylpyridin-2-yl)carbamate

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenyl)ethan-1-ol (0.96g, 3.48mmol, 1.5eq) It was dissolved in DMF (5mL), sodium hydride (0.22g, 9.28mmol, 4eq) was added at 0°C, stirred for 10min, and (6-(bromomethyl)-5-methylpyridine-2) was added to the reaction solution - base) tert-butyl carbamate (0.7g, 2.32mmol), the mixed solution was reacted at 0 ° C for 10min, after the reaction was completed, water was slowly added dropwise, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, and the concentrated The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the title compound (0.2 g, yield 17%).

MS m/z(ESI): 498.2[M+H] ⁺ .

The sixth step: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5- Preparation of methylpyridin-2-yl)carbamate

tert-Butyl(6-((4-methoxy-3-(1-methyl-1H-pyrazol-3-yl)-5-nitrophenethoxy)methyl)-5-methyl Pyridin-2-yl)carbamate (0.2g, 0.4mmol) was dissolved in ethanol/saturated aqueous ammonium chloride solution=4/1 (10mL), then iron powder (0.45g, 8mmol, 20eq) was added, and the reaction solution Stir at 80°C for 1 h, after the reaction, the concentrated crude product of the reaction solution 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: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1- Preparation of methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5-methylpyridin-2-yl)carbamate

tert-Butyl(6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethoxy)methyl)-5-methylpyridine -2-yl)carbamate (80mg, 0.17mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (105mg, 0.51mmol, 3eq) were dissolved in tetrahydrofuran (5mL), NaHMDS (187mg, 1.02mmol, 6eq) was added to the reaction solution, the reaction solution was stirred at room temperature for 10min, the reaction solution was concentrated after the reaction, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate=1/1) Purification gave the title compound (50 mg, 46% yield).

MS m/z(ESI): 637.3[M+H] ⁺ .

Step 8: 4-((5-(2-(((6-amino-3-methylpyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl) Preparation of yl-1H-pyrazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

tert-Butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl- 1H-Pyrazol-3-yl)phenethoxy)methyl)-5-methylpyridin-2-yl)carbamate (50 mg, 0.078 mmol) was dissolved in dichloromethane (5 mL) and added to To the reaction mixture was added hydrochloric acid in dioxane (5 mL, 4M). The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated to give the title compound (40 mg, 95% yield).

MS m/z(ESI): 537.2[M+H] ⁺ .

The ninth step: ⁵⁶ -methoxy-N, ¹⁵ -dimethyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-oxa-2,4-diaza Preparation of Hetero-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-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-methylpyridazine-3-carboxamide (40 mg, 0.074 mmol,) was dissolved in 1,4-dioxane (5 mL) , Tris(dibenzylideneacetone)dipalladium (20mg, 0.022mmol, 0.3eq), 4,5-bis(diphenylphosphino)-9,9-dimethyl yellow was added to the reaction mixture under nitrogen protection Purine (25 mg, 0.044 mmol, 0.6 eq), cesium carbonate (72 mg, 0.22 mmol, 3 eq). The resulting reaction mixture was stirred at 130 °C for 16 hours. The reaction mixture was filtered and the organic layer was concentrated to give crude product. Crude product Purification by preparative chromatography gave the title compound (1 mg, 3% yield).

MS m/z(ESI): 501.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δ 11.25(s, 1H), 10.17(s, 1H), 9.01(q, J=4.8Hz, 1H), 8.90(s, 1H), 7.75(d, J =2.0Hz,1H),7.54(d,J=2.0Hz,1H),7.45(m,2H),6.99(d,J=8.0Hz,1H),6.71(d,J=2.0Hz,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 17:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -ethyl)-8-oxa-2,4-diaza-1(2,6 Preparation of ),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: the preparation of 4,6-dichloro-N-methylpyridine-3-carboxamide

4,6-Dichloropyridine-3-carboxylic acid (5g, 1eq) was dissolved in dichloromethane (100mL), to the solution was added methylamine hydrochloride (1.93g, 1.1eq), trimethylamine (7.89g) , 3eq), _T3P (18.2g, 1.1eq), the reaction mixture was stirred at 25°C for 1 hour. An aqueous solution (100 mL) was added to the reaction mixture, extracted twice with dichloromethane, and 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 (4 g, 75% yield).

MS m/z(ESI): 205[M+H] ⁺ .

The second step: tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of yl-1H-pyrazol-3-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate

To tert-butyl (6((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenylethoxy)methyl)pyridin-2-yl) To a solution of carbamate (200mg, 1eq) in tetrahydrofuran (20mL) was added 4,6-dichloro-N-methylpyridine-3-carboxamide (90mg, 1eq), bis(trimethylsilyl)amide Sodium (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 then concentrated to give crude product. The crude product was purified by silica gel column to give 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-methoxy-3-(1-methyl-1H-pyrazole Preparation of -3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide

tert-Butyl(6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H -Pyrazol-3-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate (220 mg, 1 eq) was dissolved in dichloromethane (3 mL), to the reaction was added dihydrochloric acid Oxane 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, 81.2% yield).

MS m/z(ESI): 522[M+H] ⁺ .

The fourth step: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -ethyl)-8-oxa-2,4-diaza-1 Preparation of (2,6),3(2,4)-bipyridine- ⁵ (1,3)-benzocyclononane-35-carboxamide

4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyrazole-3- (yl)phenyl)amino)-6-chloro-N-methylnicotinamide (150 mg, 1 eq) was dissolved in dioxane (3 mL) and to the reaction mixture was added tris(dibenzylideneacetone)dipalladium (40 mg , 0.15eq), Xantphos (33mg, 0.20eq), _Cs2CO3 ( _281mg , 3eq). The resulting reaction mixture was stirred at 135 °C for 16 h. The reaction mixture was filtered. The organic layer was concentrated to give the crude product, which was purified to give the title compound (2 mg, 1.4% yield).

MS m/z(ESI): 486[M+H] ⁺ .

¹ H NMR (400MHz, 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 18:

⁵⁶ -Methoxy-N-methyl-55-(pyrimidin- ² -yl)-8-oxa-2,4-diaza-3(3,5)-pyridazine-1(2, Preparation of ⁶ )-pyridine- ⁵⁵ (1,3)-benzocyclononane-36-carboxamide

The first step: preparation of ethyl 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)acetate

Ethyl 2-(3-bromo-4-methoxy-5-nitrophenyl)acetate (3 g, 1 eq) was dissolved in dioxane (20 mL) and 2-(tributyltin) was added to the reaction mixture Alkyl)pyrimidine (4.51 g, 1.3 eq), 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 give the title compound (1.2 g, 40% yield).

MS m/z(ESI): 318[M+H] ⁺ .

The second step: preparation of 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethanol

Ethyl 2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)acetate (1.2 g, 1 eq) was dissolved in methanol (30 mL) and carbonic acid was added to the reaction mixture Potassium (1.58 g, 3 eq), the resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered. The organic layer was concentrated to give crude product. The crude product was purified by silica gel column to give the title compound (700 mg, 67.2% yield).

MS m/z(ESI): 276[M+H] ⁺ .

The third step: tert-butyl (6-((2-(4-methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethoxy)methyl)pyridyl-2- Preparation of methyl carbamate formate

2-((4-Methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethanol (700 mg, 1 eq) was dissolved in tetrahydrofuran (20 mL) and added to the mixture at 0 °C sodium hydride (3eq) and the resulting reaction mixture was stirred at 0°C for 0.5h. To the mixture was then added tert-butyl ((6-(bromomethyl)pyridin-2-yl)carbamate (879mg, 1.2°C) at 0°C eq), the resulting reaction mixture was stirred at 25° C. for 16 h. Water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (30×2 mL). The combined organic layers were dried over anhydrous sodium sulfate, then Concentration gave the crude product. The crude product was purified by silica gel column to give the title compound (400 mg, 32.7% yield).

MS m/z(ESI): 482[M+H] ⁺ .

The fourth step: (6-((2-(3-amino-4-methoxy-5-(pyrimidin-2-yl)phenyl)ethoxy)methyl)pyridin-2-yl)amino tertiary- Preparation of butyl formate

(6-((2-(4-Methoxy-3-nitro-5-(pyrimidin-2-yl)phenyl)ethoxy)methyl)pyridin-2-yl)carbamic acid tert-butyl The ester (400 mg, 1 eq) was dissolved in ethanol (5 mL) and water (1 mL). To the reaction mixture was added iron powder (231 mg, 5 eq), ammonium chloride (221 mg, 5 eq). The resulting reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered. The organic layer was concentrated to give crude product. The crude product was purified by silica gel column to give the title compound (200 mg, yield 53.3%).

MS m/z(ESI): 452[M+H] ⁺ .

The fifth step: tert-butyl (6-((2-(3-((6-chloro-3-(methylcarbamoyl)pyridazin 4-yl)amino)-4-methoxy-5-( Preparation of pyrimidin-2-yl)phenyl)ethoxy]methyl)pyridin-2-yl)carbamate

tert-butyl (6-((2-(3-amino-4-methoxy-5-(pyrimidin-2-yl)phenyl)ethoxy)methyl)pyridin-2-yl)carbamate The solution (200mg, 1eq) was dissolved in tetrahydrofuran (20mL), 4,6-dichloro-N-methylpyridazine-3-carboxamide (273mg, 1eq), sodium bis(trimethylsilyl)amide was added (1.3 mL). 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 then concentrated to give crude product. The crude product was purified by silica gel column chromatography to obtain the title compound (200 mg, yield 58%).

MS m/z(ESI): 621[M+H] ⁺ .

Step 6: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl ) Amino)-6-chloro-N-methylpyridazine-3-carboxamide preparation

tert-Butyl(6-((2-(3-((6-chloro-3-(methylcarbamoyl)pyridazin4-yl]amino)-4-methoxy-5-(pyrimidine-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 mixture was stirred for 0.2 h at 65° C. The reaction mixture was concentrated to give the title compound (130 mg, 77.5% yield).

MS m/z(ESI): 521[M+H] ⁺ .

Step 7: ⁵⁶ -methoxy-N-methyl-55-(pyrimidin- ² -yl)-8-oxa-2,4-diaza-3(3,5)-pyridazine-1 Preparation of (2,6)-pyridine- ⁵⁵ (1,3)-benzocyclononane ^- 36-carboxamide

4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino) -6-Chloro-N-methylpyridazine-3-carboxamide (50 mg, 1 eq) was dissolved in dioxane (3 mL), to the reaction mixture was added tris(dibenzylideneacetone)dipalladium (13 mg, 0.15eq), Xantphos (11mg, 0.2eq), _Cs2CO3 ( _94mg , 3eq). The resulting reaction mixture was stirred at 135°C for 16h. The reaction mixture was filtered and the organic layer was concentrated to give the crude product. Pass the crude product through Preparative purification gave the title compound (3.6 mg, 7.7% yield).

MS m/z(ESI): 485[M+H] ⁺ .

¹ H NMR (400MHz, 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 19:

5 ⁶ -Methoxy-N-methyl-5 ⁵ -(1-methyl-1H-pyrazol-3-yl)-8-thi-2,4-diaza-3(3,5)- Preparation of Pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane-3 ⁶ -carboxamide 8,8-dioxide

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ³ -yl)-8-thi-2,4-diaza-3(3,5) -pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide was dissolved in a mixture of acetone and water (acetone/water 1:1, 10 mL) , potassium peroxomonosulfonate (366 mg, 0.597 mmol) was slowly added, and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, it was quenched with water (10 mL), extracted with dichloromethane (3×20 mL), and the obtained residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) after concentration to obtain the crude product, and then The title compound (5 mg, 15% yield) was obtained after preparative 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=7.8Hz,1H),7.51-7.35(m,2H),7.11(d,J=7.4Hz,1H),6.92(d,J=8.3Hz,1H),6.81(d,J= 2.0Hz, 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 =4.8Hz,3H).

Example 20:

6'-Methoxy-N-methyl-5'-(1-methyl-1H-pyrazol-3-yl)-7',9'-dioxospiro[cyclopropane-1,8'-2 Preparation of ,6,10-triaza-1(4,2)-pyridine-3(1,3)-benzocyclodecane]-5'-carboxamide

The first step: N-(3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyridine Preparation of oxazol-3-yl)phenethyl)cyclopropane-1,1-dicarboxamide

N-(3-Amino-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenethyl)cyclopropane-1,1-dicarboxamide (110 mg, 0.30 mmol) ,4,6-Dichloro-N-methylpyridazine-3-carboxamide (126 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium bis(trimethylsilyl)amide (0.62 mmol) was added dropwise at room temperature. mL, 1.24 mmol, 2M in tetrahydrofuran). The mixture was stirred at 25°C for 1 hour. After the reaction was completed, 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'-dioxospiro[cyclopropane-1, Preparation of 8'-2,6,10-triaza-1(4,2)-pyridine-3(1,3)-benzocyclodecane]-5'-carboxamide

N-(3-((2-Chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-pyrazole-3- yl)phenethyl)cyclopropane-1,1-dicarboxamide (30 mg, 0.05 mmol), cesium carbonate (111 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.001 mmol), 4 ,5-Bisdiphenylphosphine-9,9-dimethylxanthene (6 mg, 0.01 mmol) was mixed in 1,4-dioxane (10 mL). After three displacements 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 the crude product. The crude product was purified by preparative liquid chromatography to give the title compound (1.0 mg, 2% yield).

MS m/z(ESI): 490.1[M+H] ⁺ .

¹ H NMR (400MHz, 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=13.2Hz, 2H), 7.01(d, J=22.4Hz, 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=6.8Hz, 2H), 1.35(s, 2H).

Example 21:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4-diaza- Preparation of 1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: tert-butyl (6-((3-((6-chloro-3-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of -1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (90 mg, 0.44 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, water (5 mL) was added to quench, extracted with dichloromethane (3×30 mL), the organic phase was dried with anhydrous sodium sulfate, and the residue obtained after concentration was filtered on a silica gel column (80% ethyl acetate/petroleum ether). ) was purified to give the title compound (80 mg, 52% yield).

MS m/z(ESI): 623.1[M+H] ⁺ .

The second step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide

tert-Butyl(6-((3-((6-chloro-3-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H- 1,2,4-Triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (80 mg, 0.13 mmol) was dissolved in hydrochloric acid in dioxane 4M (3 mL) , and the mixture was stirred at 40 °C for 1 hour. After the reaction was completed, it was directly concentrated to obtain the title compound (50 mg, yield 80%).

MS m/z(ESI): 523.2[M+H] ⁺ .

The third step: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-1,2,4-triazol- ³ -yl)-8-oxo-2,4- Preparation of Diaza-1(2,6),3(2,4)-bipyridine- ⁵ (1,3)-benzocyclononane-35-carboxamide

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 (20 mg, 0.0384 mmol) was dissolved in 1,4-dioxane (3 mL) and added under nitrogen atmosphere 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2.21 mg, 0.0038 mmol), tris(dibenzylideneacetone)dipalladium (3.59 mg, 0.0038 mmol) and cesium carbonate (37 mg, 0.12 mmol). The mixture was stirred at 130°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain crude product, which was then prepared by reverse column (acetonitrile:water=1:1), and after purification, the title was obtained Compound (5 mg, 27% yield).

MS m/z(ESI): 487.2[M+H]+.

¹ H NMR (400MHz, 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=1.6Hz, 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 22:

5 ⁶ -Methoxy-N-(methyl-d3)-5 ^5- (1-methyl-1H-1,2,4-triazol-3-yl)-8-oxo-2,4- Preparation of Diaza-1(2,6),3(2,4)-bipyridine- ⁵ (1,3)-benzocyclononane-35-carboxamide

The first step: tert-butyl (6-((3-((2-chloro-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxy-5- Preparation of (1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenethoxy)methyl) Pyridin-2-yl)carbamate (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of 4,6-dichloro-N-methylpyridazine-3-carboxamide (91 mg, 0.43 mmol) and Sodium bis(trimethylsilyl)amide (0.3 mL), the reaction solution was reacted at room temperature for 10 minutes. After the reaction, water (5 mL) was added to quench, extracted with dichloromethane (3×30 mL), the organic phase was dried with anhydrous sodium sulfate, and after concentration, the obtained residue was filtered on a silica gel column (ethyl acetate/petroleum ether= 0-80%) to give the title compound (80 mg, 53% yield).

MS m/z(ESI): 626.2[M+H] ⁺ .

The second step: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-(methyl-d3)nicotinamide

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, 0.13 mmol) in hydrochloric acid in dioxane In 4M (3 mL), the mixture was stirred at 40°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- Preparation of 2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

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 (50 mg, 0.095 mmol) was dissolved in 1,4-dioxane (3 mL) in Under nitrogen atmosphere, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (5.5 mg, 0.0095 mmol), tris(dibenzylideneacetone)dipalladium (8.7 mg, 0.0095 mmol) were added ) and cesium carbonate (93 mg, 0.285 mmol). The mixture was stirred at 130°C for 4 hours. After the reaction was completed, it was directly concentrated, and the residue was separated and purified by silica gel column (dichloromethane/methanol=10/1) to obtain crude product, which was then prepared by reverse column (acetonitrile:water=1:1), and after purification, the title was obtained Compound (5 mg, 10% yield).

MS m/z(ESI): 490.2[M+H]+.

¹ H NMR (400MHz, CDCl ₃ ) δ 11.04(s, 1H), 10.35(s, 1H), 8.90(d, J=9.3Hz, 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=8.4Hz,1H),6.80(d,J=7.2Hz,1H),4.47( s, 2H), 4.02 (s, 3H), 3.90–3.76 (m, 5H), 2.99–2.87 (m, 2H).

Example 23:

⁵⁶ -Methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ⁴ -yl)-8-oxa-2,4-diaza-1(2,6) Preparation of ,3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: preparation of ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenylacetate

To a solution of ethyl 3-bromo-4-methoxy-5-nitrophenylacetate (2.51 g, 0.8 mmol) in 1,4-dioxane/water=3:1 (20 mL) was added (1 -Methyl-1H-pyrazol-4-yl)boronic acid (1 g, 0.8 mmol), Pd(dppf)Cl2 (0.58 _g , 0.07 mmol) and potassium carbonate (2.18 g, 1.6 mmol), replaced under nitrogen three times. The mixture was stirred and reacted under nitrogen atmosphere at 90°C for 1 hour. After the reaction was completed, it was extracted with ethyl acetate (50 mL×2), 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: preparation of 2-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenyl)-1-ethanol

Ethyl 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenylacetate (405 mg, 1.6 mmol) was dissolved in methanol (5 mL), and sodium methoxide ( 0.3 mL, 1.6 mmol). 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 layers were washed with brine (10 mL×1), dried over anhydrous sodium sulfate and dried under reduced pressure. Concentrated below. Purification by flash column chromatography (DCM/MeOH=20/1) gave the title compound (400 mg, yield 87.5%).

MS m/z(ESI): 278.1[M+H] ⁺ .

The third step: tert-butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenethoxy)methyl)pyridine- Preparation of 2-yl)carbamate

2-(4-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenyl)-1-ethanol (500 mg, 1.8 mmol) was dissolved in DMF (10 mL) , NaH (220 mg, 5.4 mmol), 15-crown-5 (10 mg, 0.0036 mmol) and tert-butyl (6-(bromomethyl)pyridin-2-yl)carbamate (620 mg, 2.1 mmol) were added at 0°C mmol). The reaction was stirred at 25°C for 1 hour. After the completion of the reaction, 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 added under reduced pressure. Press down to concentrate. Purification by flash column chromatography (PE/EA=1/2) gave the title compound (130 mg, yield 17%).

MS m/z(ESI): 484.2[M+H] ⁺ .

The fourth step: tert-butyl (6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl) phenethoxy) methyl) pyridine-2 - group) preparation of carbamates

tert-Butyl (6-((4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl) The carbamate (120 mg, 0.25 mmol) was dissolved in EtOH: _H2O = 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 completion of the reaction, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (10 mL×2), 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) gave the title compound (120 mg, yield 93%).

MS m/z(ESI): 454.3[M+H] ⁺ .

The fifth step: tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl) Preparation of yl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl(6-((3-amino-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)amino Formate (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, 1.3 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. After the completion of the reaction, saturated aqueous ammonium chloride solution (3 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×2), the combined organic layers were washed with brine (10 mL×1), dried over anhydrous sodium sulfate and reduced under reduced pressure. Press down to concentrate. Purification by flash column chromatography (PE/EA=0/1) gave the title compound (100 mg, yield 55%).

MS m/z(ESI): 623.2[M+H] ⁺ .

Step 6: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(1-methyl-1H-pyridine Preparation of azol-4-yl)phenyl)amino)-6-chloro-N-methylnicotinamide

tert-Butyl(6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(1-methyl-1H -Pyrazol-4-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (100 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) and a 4M solution of hydrochloric acid in dioxane was added (0.2 mL, 0.64 mmol). The reaction was stirred at 40°C for 1 hour. The solvent was removed under reduced pressure to give the title compound (60 mg, 62% yield).

MS m/z(ESI): 523.2[M+H] ⁺ .

The seventh step: ⁵⁶ -methoxy-N-methyl-55-(1-methyl-1H-pyrazol- ⁴ -yl)-8-oxa-2,4-diaza-1( Preparation of 2,6),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-pyrazole-4 -yl)phenyl)amino)-6-chloro-N-methylnicotinamide (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (12 mL), to the reaction mixture was added tris( dibenzylideneacetone) dipalladium (26 mg, 0.028 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (22 mg, 0.038 mmol), cesium carbonate (94 mg, 0.28 The resulting reaction mixture was stirred at 130° C. for 12 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 (5.5 mg, 11% yield).

MS m/z(ESI): 486.2[M+H] ⁺ .

¹ H NMR (400MHz, 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=7.7Hz, 1H), 7.47(s, 1H), 7.15(s, 1H), 6.98(d, J=8.3Hz, 1H), 6.81(d, J =7.2Hz,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 36:

5 ⁶ -Methoxy-N-(methyl-d ₃ )-5 ⁵ -(pyrimidin-2-yl)-8-oxa-2,4-diaza-3(3,5)-pyridazine Preparation of -1(2,6)-pyridine-5(1,3)-phenylcyclononane ^- 36-carboxamide

The first step: tert-butyl (6-((3-((6-chloro-3-((methyl-d ₃ )carbamoyl)pyridazin-4-yl)amino)-4-methoxy- Preparation of 5-(pyrimidin-2-yl)phenethoxy)methylpyridin-2-ylcarbamate

tert-Butyl (6-((3-amino-4-methoxy-5-(pyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (200 mg, 0.44 mmol) and 4,6-dichloro-N-(methyl-d ₃ )pyridazine-3-carboxamide (273 mg, 1.32 mmol) were dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilyl) was slowly added dropwise ) sodium amide (2M, 1.3 mL, 2.65 mmol), and the mixture was stirred at 25°C for 10 minutes. After the reaction was completed, it was quenched with methanol (10 mL), and the obtained residue was purified by silica gel column (eluent: dichloromethane/methanol=4/1) after concentration to obtain tert-butyl (6-((3- ((6-chloro-3-((methyl- _d3 )carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(pyrimidin-2-yl)phenethoxy) Methylpyridin-2-ylcarbamate (200 mg, 65% yield).

MS m/z (ESI): 624 [M+H] ⁺ .

Step 2: 4-((5-(2-(((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl ) amino)-6-chloro-N-(methyl-d ₃ ) pyridazine-3-carboxamide preparation

tert-Butyl(6-((3-((6-chloro-3-((methyl- _d3 )carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-( Pyrimidin-2-yl)phenethoxy)methylpyridin-2-ylcarbamate (200 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL), hydrochloric acid and 1,4-dioxane were added In the mixed solution (hydrochloric acid/1,4-dioxane=4mol/L, 10 mL). The mixed solution was stirred at 50° C. for 1 hour. After the reaction was finished, it was directly concentrated to obtain 4-((5-(2-(( (6-Aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(pyrimidin-2-yl)phenyl)amino)-6-chloro-N-(methyl-d ₃ ) Pyridazine-3-carboxamide (150 mg, 60% yield).

MS m/z (ESI): 524 [M+H] ⁺ .

The third step: ⁵⁶ -methoxy-N-(methyl- _d3 )-55-(pyrimidin- ² -yl)-8-oxa-2,4-diaza-3(3,5 Preparation of )-pyridazine-1(2,6)-pyridine-5(1,3)-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- _d3 )pyridazine-3-carboxamide (150 mg, 0.29 mmol) was dissolved in 1,4-dioxane (10 mL) and 4,5 was added under nitrogen atmosphere - bis(diphenylphosphine)-9,9-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. After the reaction was completed, it was directly concentrated, and the residue was separated and purified with a silica gel column (eluent: dichloromethane/methanol=4/1) to obtain a crude product, which was then passed through a reverse column. (acetonitrile:water=1:1), after purification, ⁵⁶ -methoxy-N-(methyl- _d3 )-55-(pyrimidin- ² -yl)-8-oxa-2, 4-Diaza-3(3,5)-pyridazine-1(2,6)-pyridine-5(1,3)-benzocyclononane ^- 36-carboxamide (37 mg, 25% yield ).

MS m/z(ESI): 488.3[M+H] ⁺ .

¹ H NMR (400MHz, 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 52:

⁵⁶ -Methoxy-N-methyl-55-( ⁵ -methylpyrimidin-2-yl)-8-oxa-2,4-diaza-1(2,6), 3(2 Preparation of ,4)-bipyridine-5(1,3)-benzocyclononyl-3 ⁵ -carboxamide

The first step: the preparation of 2-(3-bromo-4-methoxy-5-nitrophenyl) ethan-1-ol

Ethyl 3-bromo-4-methoxy-5-nitrophenylacetate (5 g, 0.016 mol) was dissolved in methanol (50 mL), potassium carbonate (4.34 g, 0.032 mol) was added at room temperature, and the reaction was carried out in Stir at room temperature for 2 hours. After the completion of the reaction, 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 layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate and placed in Concentrate 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] ⁺ .

The second step: the preparation of (6-((3-bromo-4-methoxy-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamic acid tert-butyl ester

2-(3-Bromo-4-methoxy-5-nitrophenyl)ethan-1-ol (5.3 g, 0.019 mol) and (6-(bromomethyl)pyridin-2-yl)carbamic acid Tert-butyl ester (5.24 g, 0.018 mol) was dissolved in tetrahydrofuran (60 mL), sodium hydride (1.54 g, 0.038 mol) was added at 0 °C, the reaction was stirred at 0 °C for 30 minutes, and ice water (15 mL) was added after the completion of the reaction. ) quenched the reaction, extracted with ethyl acetate (50 mL×3), the combined organic layers were washed with brine (50 mL×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether/ethyl acetate = 85%/15%) gave the title compound 6-((3-bromo-4-methoxy-5-nitrophenethoxy)methyl ) tert-butyl pyridin-2-yl)carbamate (5.0 g, 53.6% yield).

MS m/z(ESI): 482.0[M+H]+.

The third step: tert-butyl (6-((4-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 Preparation of -yl)phenethoxy)methyl)pyridin-2-yl)carbamate

To 1,4-dibutyl 6-((3-bromo-4-methoxy-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate (5 g, 10.3 mmol) To the oxane (60 mL) solution, add bispinacol borate (7.85 g, 30.9 mmol), 1,1-bis(diphenylphosphonium)ferrocene palladium chloride (1.5 g, 2.06 mmol) and Potassium acetate (3.0 g, 30.9 mmol), replaced three times under nitrogen atmosphere. The mixture was stirred under nitrogen atmosphere at 90°C for 2 hours. After the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, water was added, extracted with ethyl acetate (50 mL×3), the combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate and dried 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-dioxaboran-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (4.3 g, 77.7% yield).

MS m/z(ESI): 530.3[M+H]+.

The fourth step: (6-((4-methoxy-3-(5-methylpyrimidin-2-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamic acid tertiary Preparation of butyl ester

tert-Butyl (6-((4-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-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 2-bromo-5-methylpyrimidine (0.4 g, 3.1 mmol), 1,1-bis(diphenylphosphonium)ferrocene palladium chloride (0.41 g, 0.56 mmol) and potassium carbonate (0.97 g, 7.0 mmol), replaced three times under nitrogen. 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, water was added and extracted with ethyl acetate (20 mL×3), 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 give the title compound (6-((4-methoxy-3-(5-methylpyrimidin-2-yl)-5) -Nitrophenethoxy)methyl)pyridin-2-yl)carbamate tert-butyl ester (1.1 g, 78.6% yield).

MS m/z(ESI): 496.2[M+H]+.

The fifth step: tert-butyl (6-((3-amino-4-methoxy-5-(5-methylpyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)amino Preparation of formate

tert-butyl (6-((4-methoxy-3-(5-methylpyrimidin-2-yl)-5-nitrophenethoxy)methyl)pyridin-2-yl)carbamate ( 800 mg, 1.6 mmol) was dissolved in a mixture of ethanol and water (ethanol: water = 4:1, 10 mL), and 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 completion of the reaction, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (30 mL×2), 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-methylpyrimidine) -2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (700 mg, 93.1% yield).

MS m/z(ESI): 466.3[M+H]+.

The sixth step: tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methyl) Preparation of pyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl(6-((3-amino-4-methoxy-5-(5-methylpyrimidin-2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (700 mg, 1.5 mmol) and 4,6-dichloro-N-methylnicotinamide (620 mg, 3.0 mmol) were dissolved in THF (10 mL), sodium bis(trimethylsilyl)amide (3.8 mL, 7.5 mmol) was added ). The reaction solution was stirred at room temperature for 0.5 hour. After the reaction was completed, 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-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methylpyrimidin-2-yl)phenethoxy) Methyl)pyridin-2-yl)carbamate (650 mg, 53.3% yield).

MS m/z(ESI): 634.2[M+H]+.

Step 7: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methylpyrimidin-2-yl )Phenyl)amino)-6-chloro-N-methylnicotinamide preparation

Compound tert-butyl(6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methylpyrimidine -2-yl)phenethoxy)methyl)pyridin-2-yl)carbamate (650 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and a 4M solution of hydrochloric acid in dioxane (2 mL) was added, 10.2 mmol). 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), a 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 brine (30 mL) was used. ×1) Washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (dichloromethane/methanol=95%/5%) gave the title compound 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl )-2-methoxy-3-(5-methylpyrimidin-2-yl)phenyl)amino)-6-chloro-N-methylnicotinamide (450 mg, 77% yield).

MS m/z(ESI): 534.2[M+H]+.

Step 8: ⁵⁶ -methoxy-N-methyl-55-( ⁵ -methylpyrimidin-2-yl)-8-oxa-2,4-diaza-1(2,6) Preparation of ,3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

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(dibenzylideneacetone) was added to the reaction mixture under nitrogen protection ) 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 (aqueous ammonia system) to give the title compound ⁵⁶ -methoxy-N-methyl-55-( ⁵ -methylpyrimidin-2-yl)-8-oxa-2,4 - Diaza-1(2,6),3(2,4)-dipyridine- ⁵ (1,3)-benzocyclononane-35-carboxamide (230.3 mg, 54.9% yield).

MS m/z(ESI): 498.2[M+H] ⁺ .

¹ H NMR (400MHz, 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＝1.6Hz,1H),7.60-7.56(m,1H),7.21(d,J＝1.6Hz,1H),6.99(d,J＝8.4Hz,1H),6.82(d,J＝ 7.2Hz, 1H), 4.42(s, 2H), 3.74(t, J=4.4Hz, 2H), 3.67(s, 3H), 2.87(t, J=4.8Hz, 2H), 2.78(d, J= 4.4Hz, 3H), 2.34(s, 3H).

Example 53:

56-Methoxy- ^55- ( ⁵ -methoxypyrimidin-2-yl)-N-methyl-8-oxa-2,4-diaza-1(2,6),3( Preparation of 2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

The first step: preparation of ethyl 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetate

Ethyl 4-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenylacetate (9 g , 24.6mol) was dissolved in a mixture of 1,4-dioxane and water (1,4-dioxane:water=3:1,100mL), potassium carbonate (10.18g, 73.8mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.8g, 2.4mol) and 2-bromo-5-methoxypyrimidine (5.11g, 27mol) , 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 washed with a silica gel column (washed). Removal agent: petroleum ether/ethyl acetate = 7/3) and purified to obtain ethyl 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetate (7.2 g, yield 77%).

MS m/z(ESI): 348.1[M+H] ⁺

The second step: preparation of 2-(4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenyl)ethanol

Ethyl 4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylacetate (7 g, 20.2 mol) was dissolved in methanol (100 mL), potassium carbonate (4.18 g) was added , 30.3 mol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, filtration and concentration were carried out, and the obtained residue was purified by 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, 81% yield).

MS m/z(ESI): 306.1[M+H] ⁺

The third step: 2-(5-(2-((6-bromopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-nitrophenyl)-5-methoxy Preparation of pyrimidines

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) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (400 mg, 16.5 mmol) was added under an ice bath, and the mixture was stirred at 25°C for 2 hours . After the reaction was completed, add water (100 mL) to quench, extract with ethyl acetate (3×50 mL), wash the organic layer with saturated brine (3×10 mL), then dry with anhydrous sodium sulfate, filter and concentrate the obtained residue The compound was purified by silica gel column (eluent: petroleum ether/ethyl acetate=1/1) to give 2-(5-(2-((6-bromopyridin-2-yl)methoxy)ethyl)- 2-Methoxy-3-nitrophenyl)-5-methoxypyrimidine (1200 mg, 54% yield).

MS m/z(ESI): 475.1[M+H] ⁺

The fourth step: tert-butyl (6-((4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylethoxy)methyl)pyridine-2- base) preparation of carbamates

2-(5-(2-((6-bromopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-nitrophenyl)-5-methoxypyrimidine (1200 mg , 2.5 mmol) was dissolved in 1,4-dioxane (20 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (290 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (231 mg, 0.25 mmol) and cesium carbonate (165 mg, 0.5 mmol). The mixture was stirred at 90°C for 1 hour. After the reaction was completed, it was directly concentrated, and the obtained residue was purified by silica gel column (eluent: petroleum ether/ethyl acetate=2/3) to obtain tert-butyl (6-((4-methoxy-3-( 5-Methoxypyrimidin-2-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)carbamate (850 mg, 52% yield).

MS m/z(ESI): 512.3[M+H] ⁺

The fifth step: tert-butyl (6-((3-amino-4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl ) Preparation of carbamate

tert-Butyl(6-((4-methoxy-3-(5-methoxypyrimidin-2-yl)-5-nitrophenylethoxy)methyl)pyridin-2-yl)amino Formate (850mg, 1.7mmol) was dissolved in a mixed solution of ethanol and water (ethanol:water=4:1, 20mL), iron powder (470mg, 8.4mmol) and ammonium chloride (450mg, 8.4mmol) were added, The mixture was refluxed at 80°C for 1 hour. After the reaction, the filtrate was filtered to obtain the filtrate. After concentration, the obtained residue was purified by 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, 58% yield).

MS m/z(ESI): 482.1[M+H] ⁺

The sixth step: tert-butyl (6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methyl) Preparation of oxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate

tert-Butyl(6-((3-amino-4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethoxy)methyl)pyridin-2-yl)aminomethyl Acetate (300 mg, 0.6 mmol) and 4,6-dichloro-N-methylnicotinamide (140 mg, 0.6 mmol) were dissolved in tetrahydrofuran (10 mL), and sodium bis(trimethylsilyl)amide was slowly added dropwise. (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 the obtained residue was purified by silica gel column (eluent: dichloromethane/methanol=93/7) after concentration to obtain tert-butyl (6-((3- ((2-Chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methoxypyrimidin-2-yl)phenylethoxy) Methyl)pyridin-2-yl)carbamate (210 mg, 50% yield).

MS m/z(ESI): 651.3[M+H] ⁺

Step 7: 4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methoxypyrimidine-2- Preparation of yl)phenyl)amino)-6-chloro-N-methylnicotinamide

tert-Butyl(6-((3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-4-methoxy-5-(5-methoxypyrimidine -2-yl)phenylethoxy)methyl)pyridin-2-yl)carbamate (210 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), hydrochloric acid and 1,4-dioxane were added In the mixed solution of rings (hydrochloric acid/1,4-dioxane=4 mol/L, 5 mL), the mixed solution was stirred at 40° C. for 1 hour. After the reaction was completed, it was directly concentrated 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: 56-methoxy- ^55- ( ⁵ -methoxypyrimidin-2-yl)-N-methyl-8-oxa-2,4-diaza-1(2,6 Preparation of ),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ -carboxamide

4-((5-(2-((6-aminopyridin-2-yl)methoxy)ethyl)-2-methoxy-3-(5-methoxypyrimidin-2-yl)benzene yl)amino)-6-chloro-N-methylnicotinamide (120 mg, 0.21 mmol) was dissolved in 1,4-dioxane (10 mL) and 4,5-bis(diphenyl) was added under nitrogen phosphine)-9,9-dimethylxanthene (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. After the reaction, it was directly concentrated, and then prepared by reverse column (acetonitrile:water=1:1), after purification, 56-methoxy- ^55- ( ⁵ -methoxypyrimidin-2-yl)-N was obtained -Methyl-8-oxa-2,4-diaza-1(2,6),3(2,4)-bipyridine-5(1,3)-benzocyclononane-3 ⁵ - Formamide (38.2 mg, 34% yield).

MS m/z(ESI): 514.2[M+H] ⁺

¹ H NMR (400MHz, 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＝1.6Hz,1H),7.60-7.56(m,1H),7.20(d,J＝2.0Hz,1H),6.98(d,J＝8.0Hz,1H),6.81(d,J ＝7.2Hz, 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=4.4Hz, 3H).

Using the same or similar preparation methods above, the following structural compounds were further prepared

Biological Activity Test

The following specific embodiments will further describe the inhibitory effect of the compounds of the present invention on TYK2 kinase or TYK2 signaling pathway and other in vitro and in vivo effects, so as to show that the compounds of the present invention can be effectively used for the treatment of TYK2 target-related diseases. The beneficial effects of the compounds of the present invention include but are not limited to the following specific implementation contents.

Experimental Example 1. The compound of the present invention binds to TYK2 JH2 pseudokinase and inhibits JAK1/2/3 TYK2 kinase activity

In this experiment, the method of fluorescence resonance energy transfer (TR-FRET) was used to test the inhibitory effect of the compounds of the present invention on the binding of TYK2 JH2 pseudokinase and the activity of JAK1/2/3 TYK2 kinase, and the binding of TYK2 JH2 pseudokinase and JAK1/2/3 TYK2 kinase. The median inhibitory concentration _IC50 of activity.

1. Experimental reagents

2. Experimental consumables

3. Experimental method

3.1 Prepare 1X experimental working solution

TYK2 JH2 Pseudokinase Assay Buffer Recipe

JAK1 JH1 Kinase Assay Buffer

JAK2,3 JH1 Kinase Assay Buffer

TYK2 JH1 Kinase Assay Buffer

3.2 The pseudokinase experiment is performed as follows:

Compounds were dissolved in DMSO to a stock concentration of 10 mM.

The compound dilution plate was equipped with a compound concentration of 200 times the final concentration. According to the 27-fold ratio dilution method, diluted from the highest concentration point, a total of 4 concentration points, and transferred to the Echo plate.

Compounds were pulsed from an Echo plate to a 384 assay plate using an Echo instrument, resulting in a 3-fold dilution matrix, 11 concentration points.

Add 5 μL of 3X TYK2 JH2 kinase to the 384 assay plate.

Add 5 μL of 3X Tb to the 384 assay plate.

Add 5 μL of 3X Tracer to a 384-well assay plate.

Centrifuge for 30 seconds and incubate for 60 minutes at room temperature.

Envision microplate reader (PerkinElmer) 495/520 fluorescence signal value.

3.3 Kinase experiment operation is as follows:

Compounds were dissolved in DMSO to a stock concentration of 10 mM.

The compound dilution plate is equipped with a compound concentration of 100 times the final concentration. According to the 27-fold ratio dilution method, the compound is diluted from the highest concentration point, a total of 4 concentration points, and transferred to the Echo plate.

Prepare 1X kinase-containing working solution with the corresponding buffer for kinase, and add 5 μL per well to a 384-well experimental plate, and incubate compound and kinase for 15 minutes at room temperature.

Add 5ul of substrate (containing ATP) per well to a 384-well plate.

Incubate for 45 minutes at room temperature.

Add the detection reagent mixture to a 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

Data analysis was performed using XL-Fit software to obtain compound IC50.

4. Experimental results

4.1 The compounds of the examples of the present invention have good binding activity to TYK2 JH2 pseudokinase, and their binding activity does not exceed 30nM; when the binding activity is less than 1nM, it is represented by letter A; when 1nM<binding activity≤5nM, it is represented by letter B ; When the binding activity is >5nM, it is represented by the letter C; the specific results are shown in Table 1.

4.2 The compounds of the examples of the present invention have no inhibitory activity on TYK2 JH1 kinase domain (IC ₅₀ is preferably greater than 10 μM); no inhibitory activity or weak inhibitory activity on JAK1/2/3 (IC ₅₀ is greater than 3 μM, preferably greater than 10 μM).

Table 1 Part of the binding activity of compounds of the present invention to the TYK2 JH2 pseudokinase domain

Experimental Example 2. Inhibitory activity of the compounds of the present invention on TYK2 signaling pathway in PBMC cells

1. The purpose of the experiment:

In this experiment, flow cytometry was used to activate the TYK2 signaling pathway through IFNα stimulation with human PBMC, and the inhibitory activity of the compounds on the phosphorylation of downstream STAT5 in CD3 T cells was detected, and the half-inhibitory concentration _IC50 of the compounds on the activity of the 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 Company.

Fix buffer I, Perm buffer III were purchased from BD Biosciences.

FITC CD3 antibody was purchased from Biolegend Company.

Alexa647pSTAT5 (pY694) antibody was purchased from BD Biosciences.

Generic type I IFNα protein was purchased from R&D Systems.

The 96-well U-shaped cell culture plate was purchased from Coring Company.

3. Experimental equipment:

Centrifuge (5810R) was purchased from Eppendorf Company,

The pipette was purchased from RAMIN Company,

Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD.

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 per 90 μL well. Add 10 μL of compound diluted in gradient (10 μM at the highest concentration, 1:3, 11 dilutions) or DMSO solution to each well, and incubate in a carbon dioxide incubator for 1 hour.

3) Stimulation: Add 11 μL IFNα to each well (final concentration is 2000 U/mL), and incubate in a carbon dioxide incubator for 30 minutes.

4) Fixation: Add 110 μL of preheated Fix buffer I, and incubate in a carbon dioxide incubator for 10 minutes.

5) Centrifuge at 400g for 5min at 4°C. The supernatant was discarded, and each well was washed once with 250 μL of FACS buffer (DPBS+1% FBS).

6) Membrane rupture: add 150mL Perm buffer III and incubate on ice for 30 minutes.

7) Centrifuge at 400g for 5min at 4°C. Wash twice with 250 μl FACS buffer (DPBS+1% FBS) per well.

8) Antibody incubation: add diluted FITC-CD3 and Alexa647pSTAT5 (pY694) antibodies (100 μL/well) to each well, and incubate at room temperature for 1 hour.

9) Centrifuge at 400g for 5min at 4°C. Resuspend the cells in 100 μL FACS buffer and test on the machine.

5. Experimental data processing:

Phosphorylation of STAT5 was quantified by the mean fluorescence intensity (MFI) of Alexa647 in CD3+ T cells, and IC50 values were calculated by fitting different concentrations and corresponding MFI data to a 4-parameter nonlinear logistic formula using GraphPad prism 8.0.

6. Experimental results:

According to the above scheme, the IC ₅₀ of the compounds shown in the examples of the present invention in the inhibition of cellular TYK2 signaling pathway is no more than 10 μM; when IC ₅₀ ≤ 50 nM, it is represented by letter A; when 50 nM<IC ₅₀ ≤ 100 nM , represented by letter B; when IC ₅₀ >100nM, represented by letter C; see Table 2 for specific results.

Table 2 Part of the inhibitory activity of the compounds of the present invention on TYK2 signaling pathway in PBMC cells

Experimental Example 3. Inhibitory activity of the compounds of the present invention on JAK1/3 signaling pathway in PBMC cells

1. Experimental purpose:

In this experiment, flow cytometry and human PBMC were used to activate the JAK1/3 signaling pathway through IL-2 stimulation, and the inhibitory activity of the compound on the phosphorylation of downstream STAT5 in CD3 T cells was detected, and the activity of the compound on the JAK1/3 signaling pathway was obtained. The half inhibitory concentration _IC50 .

2. Experimental materials:

Human PBMCs were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd.

Fix buffer I, Perm buffer III were purchased from BD Biosciences.

FITC CD3 antibody was purchased from Biolegend Company.

Alexa647 pSTAT5 (pY694) antibody was purchased from BD Biosciences.

IL-2 protein was purchased from Nearshore Protein Technology Co., Ltd.

The 96-well U-shaped cell culture plate was purchased from Coring Company.

3. Experimental equipment:

A centrifuge (5810R) was purchased from Eppendorf.

Pipettes were purchased from RAMIN Corporation.

Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD.

4. Experimental method:

3) Stimulation: Add 11 μL of IL-2 to each well (final concentration is 20ng/ml), and incubate in a carbon dioxide incubator for 20 minutes.

6) Membrane rupture: add 150 μL Perm buffer III and incubate on ice for 30 minutes.

7) Centrifuge at 400g for 5min at 4°C. 250 μL FACS buffer (DPBS+1% FBS) per well was washed twice.

5. Experimental data processing:

Phosphorylation of STAT5 was quantified as the mean fluorescence intensity (MFI) of Alexa647 in CD3+ T cells, and _IC50 values were calculated using GraphPad prism 8.0 to fit the different concentrations and corresponding MFI data to a 4-parameter nonlinear logistic formula.

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. Inhibitory activity of the compounds of the present invention on JAK2 signaling pathway in U937 cells

1. The purpose of the experiment

In this experiment, flow cytometry was used to use U937 cell line to activate the JAK2 signaling pathway through GM-CSF stimulation, and the inhibitory activity of the compound on its downstream STAT5 phosphorylation was detected, and the median inhibitory concentration _IC50 of the compound on the activity of the JAK2 signaling pathway was obtained. .

2. Experimental materials:

U937 cell line was purchased from ATCC.

Fix buffer I and Perm buffer III were purchased from BD Biosciences.

Alexa647pSTAT5 (pY694) antibody was purchased from BD Biosciences.

GM-CSF protein was purchased from Kaiqi Biological Company.

The 96-well U-shaped cell culture plate was purchased from Coring Company.

3. Experimental equipment:

A centrifuge (5810R) was purchased from Eppendorf.

Pipettes were purchased from RAMIN Corporation.

Fortessa (LSRFortessa) analytical flow cytometer was purchased from BD.

4. Experimental method:

1) Resuspend well-grown cells to 1.11E6 cells/ml so that 90 μL per well has 1E5 cells. To each well, add 10 μL of compound that has been serially diluted (the highest concentration of 10 μM, 1:3, 10 dilutions) or DMSO solution, and incubate in a carbon dioxide incubator for 1 hour.

2) Stimulation: Add 11 μL of GM-CSF to each well (final concentration is 20 ng/mL), and incubate in a carbon dioxide incubator for 15 minutes.

3) Fixation: Add 110 μL of preheated Fix buffer I, and incubate in a carbon dioxide incubator for 10 minutes.

4) Centrifuge at 400g for 5min at 4°C. The supernatant was discarded, and each well was washed once with 250 μL of FACS buffer (DPBS+1% FBS).

5) Membrane rupture: add 150 μL Perm buffer III and incubate on ice for 30 minutes.

6) Centrifuge at 400g for 5min at 4°C. 250 μL FACS buffer (DPBS+1% FBS) per well was washed twice.

7) Antibody incubation: Add diluted Alexa647pSTAT5 (pY694) antibody (100 μL/well) to each well, and incubate at room temperature for 1 hour.

8) Centrifuge at 400g for 5min at 4°C. Resuspend the cells in 100 μL FACS buffer and test on the machine.

5. Experimental data processing:

Phosphorylation of STAT5 was quantified by the mean fluorescence intensity (MFI) of Alexa647, and IC50 values were calculated by fitting different concentrations and corresponding MFI data to a 4-parameter nonlinear logistic 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 compounds of the examples of the present invention have better selectivity for TYK2 kinase relative to JAK1/2/3, indicating that the compounds of the present invention have important clinical applications of effectively reducing side effects and improving safety. value.

Experimental Example 5. Inhibitory activity of the compounds of the present invention on TYK2 in human primary Th17 cells

In this experiment, the strategies of phosphorylated STAT3 intracellular staining and flow cytometry were used to analyze the inhibitory effect of compounds on TYK2 activity in human primary Th17 cells, and the median inhibitory concentration IC50 of compounds to inhibit TYK2 activity was obtained.

1. Experimental materials

Primary peripheral blood mononuclear cells (PBMCs) 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 Company.

Recombinant human IL6, IL1b, IL23 and TGFb were purchased from Novoprotein.

Anti-human CD3 antibody and anti-human CD28 antibody were purchased from Biolegend Company.

Anti-phospho-STAT3 flow antibody, cell fixative and permeabilization fluid were purchased from BD Bioscience.

2. Experimental method

2.1 In vitro differentiation of human primary TH17 cells

1) In vitro differentiation of human primary TH17 cells: CD4+ T cells were sorted from healthy human PBMC cells using a negative sorting kit for human CD4+ T cells, and the cells were divided according to the density of 40,000 cells per well. The selected CD4+ T cells were seeded in a 96-well flat bottom plate pre-coated with anti-human CD3 antibody, 200 μL per well, and anti-human CD28 antibody and four cytokines: IL6, IL23, IL1b and TGFb were added at the same time. The cells were cultured in an incubator (37°C, 5% CO2) for 7 to 10 days, and the fresh medium containing the differentiation-inducing stimuli was replaced in half every other day.

2) Deactivation of human primary TH17 cells: collect the induced TH17 in a 50 mL centrifuge tube, collect the cells by centrifugation, and resuspend them in basal fresh medium. 200 μL of the well was placed in a cell incubator (37° C., 5% CO 2 ) for overnight incubation.

2.2 Inhibition test of compounds to be tested on STAT3 phosphorylation in human primary TH17 cells

1) At a density of 150,000 cells per well, primary human TH17 cells in a deactivated state were seeded in a 96-well flat bottom plate, 120 μL per well.

2) Add 40 μL of the compound to be tested in a gradient dilution to the cell culture medium of the culture plate respectively, and after gentle mixing, place it in a cell incubator (37° C., 5% CO 2 ) for 1 hour.

3) Add 40 ul of diluted recombinant human IL23 to the cell culture medium of the culture plate, and after gentle mixing, place it in a cell culture incubator (37° C., 5% CO 2 ) for 0.5 hours.

4) Phosphorylated STAT3 staining: collect cells by centrifugation, wash once with pre-cooled PBS, add the prepared Live/Dead dye, incubate for 10 minutes at room temperature, wash once with pre-cooled flow staining solution, add pre-warmed 37°C fixative solution, fixed at 37°C for 15 minutes, washed twice with pre-cooled flow-through staining solution, added pre-cooled permeabilization solution, fixed at 4°C for 0.5 hours, washed twice with pre-cooled flow-through staining solution, added the prepared anti-phosphoric acid Add STAT3 antibody staining solution, incubate at 4°C for 0.5 hours, wash twice with pre-cooled flow staining solution, resuspend cells in each well in 200 μL flow staining solution, and collect data information by flow cytometry.

3. Experimental data processing

Flow data were analyzed using Flowjo software, and GraphPad Prism 6 software was used for statistical analysis of data to obtain the IC ₅₀ of the compounds for phosphorylated STAT3.

4. Experimental results

The experimental results show that some of the compounds of the examples of the present invention have good inhibitory activity on the TYK2 signaling pathway activated by IL-23 in human primary Th17 cells, and the IC ₅₀ does not exceed 10 nM.

Experimental Example 6. Inhibitory activity of the compounds of the present invention on TYK2 signaling pathway in NK-92 cells

1. The purpose of the experiment:

In this experiment, enzyme-linked immunosorbent assay (ELISA) was used to use NK-92 cells to stimulate and activate TYK2 signaling pathway through IL-12 and IL-18. The median inhibitory concentration IC ₅₀ of the compound on TYK2 signaling pathway activity was obtained. 2. Experimental materials:

NK-92 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

MEMα medium, fetal bovine serum (FBS), Penicillin-Streptomycin, 2-ME were purchased from GIBCO Company.

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 Corporation.

The Envision multifunctional microplate reader was purchased from PerkinElmer.

4. Experimental method:

1) Collect well-grown NK-92 cells, resuspend in complete medium without IL-12 (MEMα+12.5%FBS+12.5%Horse serum+0.1mM 2-ME+0.02mM folicacid), count, Cells were diluted to 1.11E6 cells/ml so that there were 1E5 cells per 90 μL well.

2) To each well, add 10 μL of compound that has been serially diluted (the highest concentration of 10 μM, 1:3, 11 dilutions) or DMSO solution, and at the same time 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 values at 450nm and 570nm.

5) Calculate the value of IFNγ expressed by each sample according to the standard.

5. Experimental data processing:

IC50 values were calculated by fitting different concentrations and corresponding IFNγ values to a 4-parameter nonlinear logistic formula using GraphPad prism 8.0.

6. Experimental results:

The experimental results show that some of the compounds of the examples 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 100 nM.

Experimental Example 7. In vivo pharmacokinetic determination of the compounds of the present invention in C57BL/6 mice

C57BL/6 mice were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in the plasma of mice administered at a dose of 1 mg/kg intravenously and orally at a dose of 5 mg/kg.

1. Experimental protocol

1.1 Test drug:

Some compounds of the present invention.

1.2 Experimental animals

C57BL/6 6 (3/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 p.o. 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, and the administration volume was 10 mL/kg kg.

1.4 Experimental equipment

Centrifuge (5810R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, vortexer was purchased from Scientific Industries company

1.5 Sample Collection

After the mice were administered, 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 4 °C 4600 rpm for 5 min, and separated. Plasma, stored at -80°C.

1.6 Sample processing

1) Add 200 μL of methanol/acetonitrile (1/1) to 50 μL of plasma sample to precipitate, and centrifuge at 2773×g for 15 minutes after mixing.

2) Dissolve 50 μL of the supernatant solution after treatment in a diluent (methanol/water=1/1 containing 0.1% formic acid), and perform LC/MS/MS to analyze the concentration of the compound to be tested.

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 2.6μm C18 50 3.0mm

Mobile phase: A solution is 0.1% formic acid 50 mM ammonium acetate solution, B solution is 0.1% formic acid acetonitrile

Flow rate: 0.7mL/min

Elution time: gradient elution 0-3.0 minutes.

2. Experimental results and analysis

The main parameters of pharmacokinetics are calculated with WinNonlin 8.0, and the pharmacokinetic parameters of intravenous injection and oral drugs in mice are shown in Table 3 and Table 4 below:

Table 3 Pharmacokinetic parameters of intravenous injection of some compounds of the present invention in mice

Table 4. Pharmacokinetic parameters of oral administration of some compounds of the present invention in mice

The main parameters of pharmacokinetics were calculated with WinNonlin 8.0, and the experimental results showed that the compounds of the examples of the present invention exhibited good pharmacokinetic properties in animals, with good exposure, suitable clearance and half-life, and better The bioavailability indicates that the compound of the present invention has good potential for clinical application.

Experimental Example 8 Pharmacodynamic study of the compounds of the present invention in imiquimod (IMQ)-induced mouse psoriasis-like model

1. The purpose of the experiment:

Testing the efficacy of the compounds of the present invention in an imiquimod (IMQ)-induced mouse psoriasis-like model

2. Experimental method:

2.1 Experimental instrument

仪器设备名称Equipment name	型号model	厂家factory
电子天平Electronic balance	QUINTIX124-1CNQUINTIX124-1CN	梅特勒-托利多仪器(上海)有限公司METTLER TOLEDO Instruments (Shanghai) Co., Ltd.
电子称Electronic scale	YP10001YP10001	上海越平科学仪器有限公司Shanghai Yueping Scientific Instrument Co., Ltd.
超声波清洗器Ultrasonic cleaner	KQ3200EKQ3200E	昆山市超声仪器有限公司Kunshan Ultrasound Instrument Co., Ltd.
涡旋振荡器Vortex Shaker	Vortex-Genie2(SI-0256)Vortex-Genie2(SI-0256)	Scientific IndustriesScientific Industries
麻醉机Anesthesia Machine	5031850318	MIPMIP

2.2 Experimental reagents

3. Experimental method

3.1 Animal purchase: Male BALB/c mice, weighing about 18-20g, start the experiment after 7 days of adaptation.

3.2 Grouping: randomly divided into 8 groups according to body weight, 10 animals in each group of 1-4 groups, and 8 animals in each group of 5-8 groups.

3.3 Psoriasis model establishment:

1) One day before applying IMQ, the mice shave their back hair (about 2×3 cm), apply 82.5 mg of IMQ cream per animal every day, 62.5 mg on the shaved part of the back, and 20 mg on the left ear, for 7 consecutive days (from the first Day 0 to Day 6). The date of the first application of IMQ is 0 days.

2) In the normal control group, 82.5 mg of Vaseline was applied to each animal every day, 62.5 mg of the back shaved part and 20 mg of the left ear, for 7 consecutive days (from the 0th day to the 6th day).

3) Drug treatment group: intragastric administration, twice a day, from the 0th day to the 6th day, for a total of 7 days.

3.4 Drug therapy:

Vehicle and compound were administered for 7 consecutive days from day 0 to day 6, and the doses and routes of administration are shown in the table below.

Grouping and dosing schedule

3.5 Record parameters:

1) Body weight: From day 0 to day 7, the body weight of 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) Photographs were taken on days 0, 3, 5, and 7 to observe skin changes. One photo was taken for each rat, and three photos were taken for each group, that is, three rats.

4) Left ear thickness was measured at 0, 3, 5, and 7 days.

PASI scoring system: erythema, crusting, skin thickness

3.6 End point:

On the seventh day of the experiment, after scoring, measuring, photographing and administering, the mice in each group were euthanized by CO ₂ inhalation.

4. Experimental results

The compounds of the present invention can effectively improve the symptoms of psoriasis in the imiquimod-induced mouse psoriasis-like model.

Claims

The compound represented by formula (II'),

or its pharmaceutically acceptable salt, its ester, its isomer, its isotopic label, wherein,

X is selected from CH, N;

R 1 is selected from hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, 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 heterocycle together with the nitrogen atom to which it is connected;

X 1 and X 2 are independently selected from CH 2 , NH, and O;

Ring C is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl;

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 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 with one or more Ra : 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 form a heterocycle together with the atoms to which they are connected;

p is selected from 0, 1, 2, 3;

L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted by -C(O)-, -NR 7 -, -S, -S(O)-, -S(O) 2- and/or -O-substituted;

R b is selected from C 1-6 alkyl, or two R b located on the same carbon atom and the carbon atom to which it is attached together form cycloalkyl, heterocyclyl;

Alternatively, L 1 is selected from
Wherein ring A end is connected with X 2 , L 2 end is connected with 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 , and one or more CH 2 in said C 1-6 alkylene is optionally substituted 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 to which it is attached together form cycloalkyl, heterocyclyl;

R 4 is selected from hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, phenyl, cycloalkyl, and the phenyl is optionally composed of one or more selected from halogen, C 1-6 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl group substituted;

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 and R 6 are connected together, and together with the nitrogen atom to which they are connected, form a heterocycle;

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 according to claim 1, which has the structure shown in the following formula (I'),

or its pharmaceutically acceptable salt, its ester, its isomer, its isotopic label, wherein,

X is selected from CH, N;

R 1 is selected from hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, cycloalkyl;

R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

Or R 1 is connected with R 8 to form a 3-8 membered heterocycle together with the nitrogen atom to which it is connected;

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 with one or more Ra : 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 and the atoms to which they are connected together form 3-8 membered heterocycle;

p is selected from 0, 1, 2, 3;

L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 subs in said C 1-8 alkylene are optionally substituted 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 located on the same carbon atom together with the carbon atom to which it is attached form a 3-5 membered cycloalkyl;

Alternatively, L 1 is selected from
Wherein the ring A end is connected with the NH of formula (I'), and the L 2 end is connected with the benzene ring;

Ring A is selected from phenyl, heteroaryl;

L 2 is selected from C 1-6 alkylene optionally substituted by one or more R c , and one or more CH 2 in said C 1-6 alkylene is optionally substituted 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 together with the carbon atom to which it is attached form a 3-8 membered cycloalkyl;

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 selected from one or more halogens , C 1-6 alkyl, C 1-6 alkoxy 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, 3-8 membered cycloalkyl, or R 5 and R 6 are connected together, and together with the nitrogen atom to which they are connected, form a 3-8 membered Heterocycle;

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 according to claim 1 or 2 has the structure shown in the following formula (I),

or its pharmaceutically acceptable salt, its ester, its isomer, its isotopic label, 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, 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 with one or more Ra : Phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl;

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 Cycloalkyl, 3-6-membered cycloalkyl-O-, 3-6-membered cycloalkyl-CH 2 -O-, NC-3-6-membered cycloalkyl, or any two adjacent R a are connected together It forms a 3-6 membered heterocycle together with the atoms to which it is attached;

L 1 is selected from C 1-8 alkylene optionally substituted by one or more R b , and one or more CH 2 in said C 1-8 alkylene is optionally substituted 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 located on the same carbon atom together with the carbon atom to which it is attached form a 3-5 membered cycloalkyl;

Alternatively, L 1 is selected from
Wherein the ring A end is connected with the NH end of formula (I), and the L 2 end is connected with the benzene ring;

Ring A is selected from phenyl, 5-6 heteroaryl, or 8-10 membered fused ring heteroaryl;

L 2 is selected from C 1-6 alkylene, and one or more CH 2 in said C 1-6 alkylene is optionally replaced by -C(O)-, -NR 7 -, -S-, -S (O)-, -S(O) 2 - and/or -O- substitution;

R 4 is selected from hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, phenyl, 3-6 membered cycloalkyl, the phenyl is optionally by one or more selected from halogen , C 1-4 alkyl, or halogenated C 1-4 alkyl group;

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 and the nitrogen atom to which they are attached are connected together to form a 3-6-membered heterocycle;

R 7 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl-C(O)-, -C(O)OCH 2 Ph.
The compound according to claim 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 attached to R 8 to form together with the nitrogen atom to which it is attached
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 of 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 of any one of claims 1-6, wherein R 2 is selected from -OH, -OCH 3 .
The compound of any one of claims 1-7, wherein R3 is selected from hydrogen, -C(O) -OCH3 , -C(O) -NH2 , -C(O)-N( CH3 ) 2 , or the following groups optionally substituted by 1-2 R a : pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, 1,2,4-triazolyl, tetrazolium base, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,

Ra is selected from hydrogen , F, -CN, -COOH, -CH3 , -CH2CH3 , -CH2F , -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -O- 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 Ras form tetrahydrofuran or tetrahydropyrrole.
The compound of any one of claims 1-8, wherein R is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridyl, optionally substituted with 1-2 R a ;

Ra is selected from hydrogen, F, -CH3 , -OCH3 , -O-CH( CH3 ) 2 .
The compound of any one of claims 1-9, wherein R 3 is selected from the group consisting of hydrogen, -C(O)-OCH 3 , -C(O)-NH 2 , -C(O)- N(CH 3 ) 2 ,
The compound of any one of claims 1-10, wherein R is selected from the group consisting of:
The compound of any one of claims 1-11, wherein R is selected from the group consisting of:
The compound of any one of claims 1-12, wherein L 1 is selected from C 6-7 straight-chain alkylene optionally substituted with 1-2 R b , the 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 located on the same carbon atom together with the carbon atom to which it is attached to form a cyclopropyl;

Preferably, L 1 is selected from
The "a" terminal indicates that it is attached to X2 or NH.
The compound according to any one of claims 1-12, wherein when L 1 is selected from
When ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 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 according to any one of claims 1-12, wherein when L 1 is selected from
, ring A is selected from pyridyl; R 4 is selected from -CH 3 ; m is selected from 0 or 1.
The compound of claim 14, wherein Ring A is selected from

"a" indicates that it is attached to X2 or NH through this end.
The compound of claim 16, wherein Ring A is selected from
The compound according to any one of claims 1-12, 14-17, wherein the structural unit
selected from

"a" indicates that it is attached to X2 or NH through this end.
The compound according to any one of claims 1-12, 14-18, wherein the structural unit
selected from

"a" indicates that it is attached to X2 or NH through this end.
The compound according to any one of claims 1-12, 14-19, wherein the structural unit
selected from
The compound according to any one of claims 1-12, 14-20, wherein L 2 is selected from C 3-6 straight-chain alkylene optionally substituted with 1-2 R c , the C 3- 1-2 CH in 6 straight-chain alkylene 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 to form a cyclopropyl together with the carbon atom to which they are connected;

R7 is selected from hydrogen, -CH3 , -CH2CH3, -C(O) CH3 , -C (O ) OCH2Ph .
The compound according to any one of claims 1-12 and 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 CH 2 is optionally substituted with -C(O)-, -NR 7 -, -S-, -S(O) 2 - and/or -O-;

R7 is selected from hydrogen, -CH3 , -C (O)OCH2Ph.
The compound of 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 -NR 7 -, -S-, -S(O) 2 - and/or -O- substitution;

R7 is selected from hydrogen, -CH3 .
The compound of any one of claims 1-12, 14-23, wherein L 2 is selected from
The compound of claim 24 , wherein L is selected from
The "b" end indicates connection to ring A through this end.
The compound according to any one of claims 1-25, has the structure shown in the following general formula:

or pharmaceutically acceptable salts thereof, esters thereof, isomers thereof, isotopic labels thereof,

M is selected from CH or N;

m is selected from 0, 1 or 2;

R 1 , R 2 , R 3 , Ra , R 4 , L 2 , Ring A are as defined in any one of claims 1-25.
Compounds as described below, or pharmaceutically acceptable salts thereof, esters thereof, isomers thereof, isotopic labels thereof:
A pharmaceutical composition comprising the compound of any one of claims 1-27, a pharmaceutically acceptable salt thereof, an isomer thereof, an isotopic label thereof, and one or more pharmaceutically acceptable carriers.
A pharmaceutical composition comprising the compound of any one of claims 1-27, a pharmaceutically acceptable salt thereof, an isomer thereof, an isotopic label thereof or a pharmaceutical composition comprising the same and one or more A second therapeutically active agent.
Use of the compound of any one of claims 1-27, its pharmaceutically acceptable salt, its isomer, and its isotopic label in the preparation of a medicament for preventing and/or treating a subject related diseases mediated by TYK2.
The use according to claim 30, wherein the TYK2-mediated related diseases are selected from autoimmune diseases, transplantation-related disorders, inflammatory or inflammatory diseases;

Preferably, the TYK2-mediated related disease is an autoimmune disease;

More preferably, the autoimmune disease is selected from the group consisting of type I diabetes, Gray's disease, rheumatoid arthritis, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis, multiple Sexual sclerosis, systemic sclerosis, Sjögren'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, cold porphyrin Associated 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.
A kind of preparation method of formula (II) compound, is characterized in that, comprises the following steps:

wherein X, R 1 , R 2 , R 3 , L 2 , R 4 , m, and Ring A are as defined in any one of claims 1-26;

Hal is halogen, preferably Cl, Br;

P is an amino protecting group, which is derived from acid anhydride compounds, acid chloride compounds, and halides;

Preferably, P is selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-biphenyl-2-propoxycarbonyl (BPoc), phthalimido (pht), p-toluene Sulfonyl (Tosyl), Trityl (Trityl), formyl (formyl), Fmoc, Alloc, Teoc; more preferably Boc, Cbz;

step 1:

The intermediate 1 and the intermediate 2 are reacted in a polar organic solvent under alkaline conditions to obtain the intermediate 3;

Preferably, the polar organic solvent includes one or more of the following: tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethyl ether, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile ;

Described basic condition is to add basic catalyst;

Preferably, the basic catalyst is selected from organic bases or inorganic bases;

Step 2:

Intermediate 3 is deprotected under acidic conditions to obtain intermediate 4;

Described acidic condition refers to in the presence of organic acid or inorganic acid;

Step 3:

Under alkaline conditions, intermediate 4 is added with a coupling catalyst and a metal chelate ligand, and the reaction is carried out to obtain a product;

Described basic condition is to add basic catalyst;

Preferably, the basic catalyst is selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, bis(trimethylsilyl) lithium amide, bis( One or more of trimethylsilyl) potassium amide, triethylamine, N,N-diisopropylethylamine, DBU;

Preferably, the coupling catalyst is selected from palladium catalysts; the palladium catalysts are preferably tridibenzylideneacetone 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), acetic acid Palladium, 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'-bisdiphenylphosphinoferrocene palladium dichloride, bis(dibenzylidene) Acetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, dichloro[1,1'-bis(tert-butylphosphine)ferrocene palladium(II), bis(triphenylphosphine)palladium(II) One of tert-butylphosphine) palladium, [1,3-bis(2,6-diisopropylbenzene)imidazole-2-idene](3-chloropyridine)palladium dichloride (Pd-PEPPSI) or variety;

Preferably, the metal chelating ligands are preferably 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (xantphos), 2-(dicyclohexylphosphine)-3,6- Dimethoxy-2'-4'-6'-tri-1-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-dicyclohexylphosphino-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-dicyclohexylphosphino-2',4', One or more of 6'-triisopropylbiphenyl (XPhos) and 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos).
Intermediates of the structures 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, and 4, preferably, the sum of q 1 and q 2 is 2-5, and more preferably, the sum of q 1 and q 2 is 3 or 4;

R 2 , R 3 , R 4 , m ring A are as defined in any one of claims 1-26;

P is as defined in claim 32.
The intermediate of 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 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 and 1.
The intermediate according to claim 33 or 34, having the structure shown below:

R 2 , R 3 , R 4 , m, Ra , q 1 , q 2 , P are as defined in claim 33 or 34;

Preferably, Ra is selected from H, F, -CH3 , -OCH3 .
A method for preparing the intermediate 1a described in any one of claims 33-35, characterized in that, comprising the following steps:

G 1 and G 2 independently represent halogen, -C(O)R', NH 2 , OH, SH, and R' represents -OH or halogen;

R 2 , R 3 , R 4 , m, ring A, q 1 , q 2 , Y, P are as defined in any one of claims 33-35;

step:

Intermediate A and intermediate B are subjected to 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 an alkaline catalyst, preferably NaH, sodium hydroxide, potassium hydroxide, lithium hydroxide, bis(trimethylsilyl) sodium amide, bis(trimethylsilyl) Lithium amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, ethanol Inorganic bases of sodium, magnesium methyl bromide (chloride), magnesium ethyl bromide (chloride), magnesium sec-butyl bromide (chloride), or triethylamine, N,N-diisopropylethylamine, 4 -Organic base of dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); ②Add 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-azabenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate), HBTU (O-benzotriazole-tetramethylurea hexafluorophosphate), HCTU (6-chlorobenzotriazole-1 , 1,3,3-tetramethylurea hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate), EDCI ((1-ethyl-3( 3-dimethylpropylamine) carbodiimide)), HOBT (1-hydroxybenzotriazole), TBTU (O-benzotriazole-N,N,N',N'-tetramethylurea tetra Fluoroboric acid), TSTU (2-succinimidyl-1,1,3,3-tetramethylurea tetrafluoroborate), TNTU (2-(5-norbornene-2,3-dimethyl) imido)-1,1,3,3-tetramethylurea tetrafluoroborate quaternary ammonium salt);

The reduction includes: Pd/C reduction, ferric acid reduction, catalytic hydrogenation reduction, sodium sulfide and thiosulfuric acid reduction, hydrazine Raney nickel reduction, and the like.
A preparation method for preparing product formula (II-a), is characterized in that, 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 and q 2 are independently 0, 1, 2, 3, and 4, preferably, the sum of q 1 and q 2 is 2-5, and more preferably, the sum of q 1 and 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 claims 1-35;

The specific preparation steps are described in claim 32.